MSCCH-502

M. Sc. I Semester
ORGANIC CHEMISTRY-I

SCHOOL OF SCIENCES
DEPARTMENT OF CHEMISTRY
UTTARAKHAND OPEN UNIVERSITY
 MSCCH-502

ORGANIC CHEMISTRY-I

SCHOOL OF SCIENCES
DEPARTMENT OF CHEMISTRY
UTTARAKHAND OPEN UNIVERSITY

Phone No. 05946-261122, 261123

Toll free No. 18001804025
Fax No. 05946-264232, E. mail info@[Link]
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 Expert Committee
Prof. [Link] Prof. A.K. Pant
Department of Chemistry Department of Chemistry
Indira Gandhi National Open University [Link] Agriculture, University
Maidan Garhi, New Delhi Pantnagar

Prof. A. B. Melkani Prof. Diwan S Rawat

Department of Chemistry Department of Chemistry
DSB Campus, Delhi University
Kumaun University, Nainital Delhi

Dr. Hemant Kandpal Dr. Charu C. Pant

Assistant Professor Academic Consultant
School of Health Science Department of Chemistry
Uttarakhand Open University, Haldwani Uttarakhand Open University,

Board of Studies
Prof. A.B. Melkani Prof. G.C. Shah
Department of Chemistry Department of Chemistry
DSB Campus, Kumaun University SSJ Campus, Kumaun University
Nainital Nainital

Prof. [Link] Prof. [Link]

Department of Chemistry Director I/C, School of Sciences
Gurukul Kangri Vishwavidyalaya Uttarakhand Open University
Haridwar Haldwani

Dr. Shalini Singh Dr. Charu C. Pant

Assistant Professor Academic Consultant
Department of Chemistry Department of Chemistry
School of Sciences School of Science
Uttarakhand Open University, Haldwani Uttarakhand Open University,

Programme Coordinator

Dr. Shalini Singh

Assistant Professor
Department of Chemistry
Uttarakhand Open University
Haldwani
Unit Written By Unit No.
1. Dr. Tanuja Bisht 01
Assistant Professor
Department of Chemistry
Govt. Degree College, Champawat
2. Prof. Om Prakash 02
Department of Chemistry
College of basic Sciences and Humanities
G.B. Pant University of Agriculture & Technology
Pantnager
3. Dr. Charu C. Pant 03
Department of Chemistry
Uttarakhand Open University, Haldwani
4. Dr. Girdhar Joshi 04 & 05
Assistant Professor
Department of Chemistry
Govt. P.G. College, Gopeshwar
5. Dr. Manisha Bisht 07
Assistant Professor
Department of Chemistry
LSM Govt. PG. College, Pithoragarh

6. Nandan Singh Karki 06

Assistant Professor
Department of Chemistry
LSM Govt. PG. College, Pithoragarh

Course Editor
Dr. M. C. Purohit
Department of Chemistry
[Link] University Campus,
Pauri (Garhwal) -246001

Title : : Organic Chemistry-I

ISBN No.: :
Copyright : Uttarakhand Open University
Edition : 2021
Published by : Uttarakhand Open University, Haldwani, Nainital- 263139
 CONTENTS

BLOCK- 1 STRUCTURE AND BONDING IN ORGANIC

MOLECULES

Unit 1: Nature of Bonding in Organic Molecules 1-49

Unit 2: Structure and Reactivity 50-95
Unit 3: Reactive Intermediates 96-124

BLOCK-2 STEREOCHEMISTRY

Unit 4: Stereochemistry-I 125-166

Unit 5: Stereochemistry –II 167-211

BLOCK-3 NUCLEOPHILIC SUBSTITUTION

Unit 6 Aliphatic Nucleophilic Substitution 212-236

Unit 7 Aromatic Nucleophilic Substitution 237-267

ORGANIC CHEMISTRY-I MSCCH-502

UNIT 1: NATURE OF BONDING IN ORGANIC

MOLECULES

CONTENTS
1.1 Objectives
1.2 Introduction
1.3 Delocalized chemical bonding
1.4 Conjugation and Cross-conjugation
1.5 Resonance
1.6 Hyperconjugation
1.7 Tautomerism
1.8 Hückel’s rules and Aromaticity
1.9 Anti-aromaticity
1.10 Homoaromaticity
1.11 Benzenoid and non-benzenoid aromatic compounds
1.12 Alteranant and non-alteranant hydrocarbon
1.13 Annulenes
1.14 Addition compounds
1.14.1 Crown ether complexes
[Link] Synthesis of crown ethers: A historic background
[Link] Applications of Crown ethers
1.14.2 Cryptands
[Link] Synthesis of cryptands
[Link] Properties and uses
1.14.3 Inclusion compounds
[Link] Cyclodextrins
[Link] Calixarenes
[Link] Uses of inclusion compounds
1.14.4 Catenanes and rotaxanes
[Link] Synthesis of catenanes and rotaxanes

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[Link]. Applications of catenanes and rotaxanes

1.14.5 Ionic liquids
[Link] Synthesis of Ionic liquids
[Link] Properties of Ionic liquids
[Link] Applications of Ionic liquids
1.15 Summary
1.16 References/ Bibliography
1.17 Suggested reading
1.18 Terminal questions

1.1 OBJECTIVE
• To describe localized and delocalized bonding
• To explain conjugation and related concepts
• To illustrate Hückel’s rule and aromaticity
• To compare aromatic, non-aromatic and anti-aromatic compounds
• Introduction, synthesis and applications of crown ethers, cryptands, and inclusion compounds
• Synthesis and applications of catenanes, rotaxanes and ionic liquids

1.2 INTRODUCTION
Organic compounds have great importance in human’s life. The carbon comes from a
variety of sources like plants, animals and vegetables etc. What are these products? How they are
formed? By the term “organic,” we actually mean about the molecules that are created from the
carbon element (C). Carbon shows striking flexibility in its ability to form various different
bonding arrangements with other carbon atoms as well as with elements such as nitrogen (N),
oxygen (O), sulfur (S), and phosphorus (P). As such, the presence of covalent bonds is the
characteristic of organic (carbon) compounds. The linkages in carbon chemistry are called
bonding which is chiefly responsible for the synthesis of various organic products.

1.3 DELOCALIZED CHEMICAL BONDING

In organic chemistry, it has been realized that the concept of having delocalized electrons is
invoked repeatedly to explain the behavior as well as different properties of organic compounds.
Indeed, the electronic delocalization is a very important concept. The electrons that are limited to

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a particular region are generally called localized electrons. The localized electrons are confirmed
between two atoms or belong to a single atom while some electrons are not confirmed to a single
atom or bond. The electrons which neither belong to a single atom nor are limited to a bond
between the two atoms, but are shared by three or more atoms are known as delocalized
electrons. Thus, delocalization is a characteristic feature of π-electrons, where the π-electrons
changes their locations (in between different sub-orbitals).

Figure 1 Structures of (left) the acetate ion and (right) benzene (resonance hybrid)

In Figure 1, have you noticed that the two electrons stand for a π-bond of the COO−group are
common between one carbon and two oxygen atoms? The dashed lines indicate that the two
electrons are delocalized (shared) over three atoms. However, a drawback of using dashed lines
to represent delocalized electron is that they do not tell us about how many π-electrons are there
in the molecules. For example, the dashed lines inside the hexagon in the representation of
benzene indicate that the π-electrons are shared uniformly by all the six carbon atoms and that all
the carbon-carbon bonds have the same bond lengths, but they do not entail about the exact
number of π-electrons in the benzene ring (Figure 1, right side). For this reason, chemists prefer
to use structures with localized electrons to approximate the actual structure having delocalized
electrons. The main factor which influences delocalization is the extra availability of sub-orbitals
of about same energy than those of the number of electrons. The delocalization usually involves
sp2, sp3, and other complex hybridizations. It chiefly occurs due to the presence of double and
triple bonds which are the characteristics of hybridization.

1.3.1 Types of delocalization: The delocalization in chemical bonds can be carried out in
different ways, and in different systems. Some of these systems are briefly discussed as follows.

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1. Isolated systems: The delocalization of electrons occurs in those compounds in which

double bonds are separated by more than one single bond.
2. Conjugated systems: The systems in which alternate single and double bond exist. For
example, benzene.
3. Cumulated systems: If double bonds are adjacent to each other as in 1,2-dipropene
(H2C=C=CH2).The delocalization is carried out by forming a delocalized bond to uphold
the stability of the molecule. Hyperconjugation is also the result of delocalization.
1.3.2 Consequences of electron delocalization:

a) Intermediate bond length: In simple molecules, C-C (alkanes) and C=C (alkenes)
bond lengths are 1.54 and 1.34 Å, respectively but in case of benzene, all C-C bond
lengths (single, double, and delocalized) are 1.39 Å (see below).

1.54 1.34 1.39 1.39

b) Stability of diene: Compounds having delocalized bonds are more stable than those of
normal compounds. For instance, 1,3-pentadiene is more stable than 1,4-pentadiene by
28KJ/mol as shown below.

c) Acidity: Delocalization increases the acidity of compounds e.g. carboxylic acids

(RCOOH) are much more acidic than those of alcohols (ROH).
d) Stability of carbonium ion: It contributes toward the stability of a carbocation
intermediate. e.g. allylic and benzylic carbocations have delocalized electrons, and thus
they are more stable than other primary carbocations.

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e) Dipole moment: Dipole moment also increases due to the delocalization of electrons,
which are involved in resonance.
1.3.3 Orbital picture of delocalization:
The orbital picture of delocalization can get somewhat complicated. We start by noting
different varieties of sp2-hybridized carbon atoms. The most important and common sp2-
hybridized carbons are neutral and positively-charged sp2 carbons. Substances having neutral
sp2 carbons are regular alkenes. Species containing positively-charged sp2 carbons are
called carbonium ions. The central carbon in a carbocation has trigonal planar geometry with an
unhybridized empty p orbital. These concepts can be best conveyed as shown in Figure 2.

p orbital
(a) Me (b) Me (c)

C
C Me sp2 orbitals C
Me Me Me
Empty

Figure 2 (a) top and (b) side view of a carbonium ion in Lewis and 3D representation while (c)
is an orbital overview of a carbonium ion or carbocation

A combination of Lewis and orbital or 3D formula is a popular means of representing certain

features that we may want to highlight. For example, if we omit sp2 orbitals and just focus on the
role of p orbitals, we can use the following notation.

Let’s now focus on two simple systems where the delocalization of π-electrons exists. In
particular, one of these systems contain two π-bonds in conjugation while the other has a π-bond
next to a positively-charged carbon atom. The line drawing along with the orbital picture of these
systems can be presented as follows.

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The two π-molecular orbitals shown in blue color on the left below are close enough to overlap.
Indeed, the overlapping of orbitals is a good sign as it helps in the delocalization of the electrons
and spreads them over a larger area, and thus imparts stability to the system. It is however time-
consuming to draw orbitals all the time, and a delocalized system can be presented as shown on
the right below. An analogous process applicable to the carbocation can lead to a similar picture.

It would be worthwhile to mention here that the resonance representation conveys the idea of
delocalization of charge and electrons rather well (see below).

Me Me

On a final note, the following representations are sometimes also used, but again, the simpler
they are, the less accurately they represent the delocalization picture.

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1.4 CONJUGATION AND CROSS-CONJUGATION

A system or molecule which has alternate single and double bonds simply serves as a
conjugated system. Conjugation relies on the partial overlap of p-orbitals on adjacent double or
triple bonds. A very familiar conjugated system is 1,3-dienes such as 1,3-butadiene. In a
conjugated system, overlap of p-orbitals allows electrons to be delocalized over a larger portion
of the molecule, thus lowering the energy of the molecule and making it more stable. The
conjugation effect is at a maximum when the axes of the orbitals are aligned in a parallel style
because this allows a maximum orbital overlap. The word "conjugation" is derived from a Latin
word that means "to link together". Conjugation provides an electron highway for electrons to
delocalize from one side of a molecule to another. Due to delocalization of electrons, a
delocalized bond is formed by fluctuation of π-bonds resulting in different structures, which are
known as resonance or contributing structures.
Notably, any atom that is capable of donating a p orbital can be the part of a conjugated
system, and thus the atoms with lone pairs, radicals or carbonium ion may be the part of a
conjugated system as shown in Figure 3.

Figure 3 Representative conjugated systems: (a) radical; (b) carbocation; (c) an atom with a lone
pair, and (d) carbanion

Aside from that, conjugated compounds may be linear, cyclic, and also of mixed types
(Figure 4). Conjugation is broken completely by the introduction of saturated (sp3-hybridized)

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carbon atom. Systems containing conjugated double bonds are more stable than those containing
non-conjugated double bonds, i.e. 3-Cyclohexenone is less stable than 2-Cyclohexenone.

Figure 4 Examples of different conjugated systems; (a) cyclic, (b) linear, (c) mixed, and (d)
cross-conjugated systems

Alongside of conjugation phenomenon, it would be worthwhile to know about cross-conjugation.

Specifically, cross conjugation is a special type of conjugation in which three double bonds are
present; out of which two double bonds are not conjugated with each other although each one is
conjugated with the third double bond (Figure 4d). i.e interruption of the strict alteration of
single and double bonds.

1.5 RESONANCE

Most of the organic covalent compounds have a single Lewis structure (dot structure).The
Lewis structure explains the bonding in that molecule, but for many molecules, two or more dot
structures are also possible. To explain the structure and physico-chemical properties of such
covalent compounds that could not be represented by a single structure, Heisenberg introduced
the phenomenon of resonance. Specifically, resonance is a situation in which more than one
plausible structures can be written for a species but not the true structure at all. For example, the
acetate ion can be represented by two equivalent structures, (a) and (b) as shown below:

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Resonating structures (a) and (b) of an acetate anion

Of the above two structures, one structure cannot exactly describe all the properties of acetate
ion, and thus each of these two structures can contribute to the true structure of the acetate ion.
These types of different structures are called ‘resonance or canonical structures’. The structure
with localized electrons is called a resonance contributor, a resonance structure, or a contributing
resonance structure while the actual structure with delocalized electrons is called a resonance
hybrid as shown for benzene (Figure 5). The resonance structures are just alternate Lewis
structures for a given ion or molecule. The stability of a real molecule is usually measured in
terms of resonance energy or resonance stabilization energy. The resonance energy is defined as
the energy difference between the most stable resonating structures and the resonance
hybrid form. In benzene, the experimentally measured carbon-carbon bond length is 140 pm,
which is intermediate of C-C (154 pm) and C=C (134 pm) bond lengths, suggesting that a
resonance hybrid is a true representation.

Figure 5 Resonating structures (A and B) and resonance hybrid form (C) of benzene

Resonance is very important and significant feature of many organic molecules. Resonance
influences the structure, chemical reactions and physical properties of such molecules. In order
to fully understand this phenomenon, one must be able to draw the contributing resonance
structures as well as the resonance hybrid form.

Characteristics of resonance/resonance structures

• All the atoms in the molecules taking part in resonance must be coplanar. This is
essential for successful overlap of the p-orbitals.

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• The sp3-hybridized atoms do not participate in resonance. They exist only in those parts
of molecules that are composed of sp or sp2 atoms; p-orbitals are an absolute requirement
for resonance.
• While making a resonance structure, electrons (lone pairs/π-electrons/a negative charge
or the unpaired electrons present on radicals) move only between the adjacent atoms. In
particular, these electrons move to the ‘resonance acceptor atom’ from a ‘resonance
donor atom’, which must be adjacent to the acceptor atom. An atom with a formal
positive charge, can also be a resonance acceptor atom as long as the atom does not
accept more electrons than it can normally accommodate.
• The resonance structures (or contributing structures) are only the imaginary structures.
Thus, the resonance structures do not have a real existence as the individual species.
These imaginary structures only proposed to explain the properties of a molecule, and
none of these ‘resonance structures’ can be prepared in the laboratory.
• The resonance hybrid is the real structure. Due to the resonance conjugation fact, the
bond lengths in resonating structures exhibit equal values.
• In different resonating structures, the position of the nuclei must be the same in all the
structures and the total charge should also be constant.
• The resonance hybrid has lower energy and thus greater stability than any of the
contributing structures.
• Greater the resonance energy, greater is the stability of the molecule.
• The structures with similar charges on adjacent atoms are irrelevant due to electrostatic
repulsion, and consequently, show instability.
• Those structures have small contribution where negative charge (when separating charge
giving rise to ions) is on the less electronegative elements.
For clarity, the resonating or canonical structures of some selected species are given below.

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1.6 HYPERCONJUGATION
In an elegant work, Baker and Nathan suggested that alkyl groups with at least one α-
hydrogen atom, when attached to an unsaturated carbon atom, are capable to release electrons by
a mechanism similar to that of the electromeric effect. This effect is known as hyperconjugation
or Baker-Nathan effect. Hyperconjugation is an unusual type of resonance in which
delocalization of electrons takes place through the overlapping between the sigma (σ) bond
orbital(usually C-H or C-C) with an adjacent empty or partially filled p-orbital or a π-orbital
giving an extended molecular orbital that increases the stability of the system. The stabilization
arises because the orbital interaction leads to the electrons being in a lower energy orbital (Figure
6a). Hyperconjugation occurs due to the partial overlap of sp3-s σ bond orbital and the empty p-
orbital or π-bond orbital of an adjacent carbon atom.

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Figure 6 The orbital pictures of hyperconjugation

From figure 6b, we observe that one of the three C-H bonds of the methyl group can align in the
plane of the empty p-orbital and the electrons constituting the C-H bond in a plane with this p-
orbital can then be delocalized into the empty p-orbital. This results in the delocalization of π-
electrons and increase the stability of molecule.

Figure 7 Resonating structures of propene exemplifying hyperconjugation effect

As can be seen in the resonating structures of propene (Figure 7), there is no bond between
carbon and hydrogen ion, therefore, hyper conjugation is also called as no bond resonance.
Based on the valence bond model of bonding, hyperconjugation can be described as “double
bond-no bond resonance”. This type of delocalization involves σ and π-orbitals, and thus it is
also called as σ-π conjugation. Notably, Hyperconjugation effect is a permanent effect. What is
the key difference between hyperconjugation and resonance? Hyperconjugation is a factor in
explaining why increasing the number of alkyl substituents on a carbocation or radical centre
leads to an increase in stability.

Examples of Hyperconjugation
There are many molecules and reaction intermediates which can show hyperconjugation effect.
Some of the common examples are as following.

1. Carbonium ion: In carbocation or carbonium ion such as ethyl carbocation, the σ electrons
of Csp3-hydrogen bond are delocalized with an empty p-orbital of positively-charged carbon

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atom and can show four contributing structures, similar to that of propene as discussed
above.

2. Free radicals: Like carbonium ion, free radicals get stabilized through hyperconjugation.
The σ electrons of C-H bonds of methyl group next to the carbon atom contain an odd
electron and interact with p-orbital having an odd electron. As the number of α-carbon-
hydrogen bond increases, the number of contributing structures also increases resulting in
greater stability.
3. Alkene: In 2-butene, the interaction of π-bond with α-carbon-hydrogen bond can form six
resonating structures of 2-butene (not shown here).
4. Nitromethane: The nitrogen-oxygen π-bond can interact with α-carbon-hydrogen bond as
shown below.

5. Toluene: The carbon-hydrogen σ bond interacts with π-bond of aromatic ring to form four
contributing structures of toluene (Figure 8).

Figure 8 The orientation influence of methyl group in toluene due to hyperconjugation effect

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Applications of hyperconjugation effect

1. Stability of alkenes and other unsaturated hydrocarbons:

The stability of unsaturated hydrocarbons like nitriles and alkenes depends upon hyper
conjugation. The more possible contributing structures in hyperconjugation usually increase the
stability of the molecule. Since hyperconjugation mainly involves α-carbon-hydrogen σ bond
and π-electrons, therefore, as the number ofα-, σ bonds increases, hyperconjugation also
increases. For instance, 2-butene consists of six α-carbon-hydrogen σ bonds while there are only
two carbon-hydrogen bonds next to the double-bonded carbon atom in 1-butene. Hence 2-butene
can shows six contributing structures while 1-butene shows only two structures, making 2-butene
more stable over 1-butene (Exercise: can you draw these structures? give a try by yourself).
In other words, most- substituted alkenes are more stable than those of less-substituted alkenes.

2. Stability of reaction intermediates

Hyperconjugation is also observed in reaction intermediates like carbocations and free
radicals which stabilize the intermediates as it helps in the dispersal of positive charge. Thus, we
can say that greater the number of alkyl groups attached to a positively-charged carbon atom, the
greater is the hyperconjugation interaction, and thus the stabilization of the carbonation. For
example; in primary carbocation like ethyl carbocation, there are three α-carbon-hydrogen bonds
which can delocalize into an empty p-orbital. However, in secondary (isopropyl) and tertiary
(tert-butyl) carbocations, there are six and nine α-carbon-hydrogen bonds, respectively.
Consequently, the increasing order of stability of carbocations can be written as:

CH3

H3C C (CH3)2CH2 CH3CH2

CH3

Hyperconjugation stability

Similarly, the increasing order of stability of free radicals would be primary < secondary <
tertiary free radical.

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3. Dipole moment & bond length

Hyperconjugation induces polarity in the molecule which influences both the dipole moment
and bond length of the molecule. As the polarity increases, dipole moment also increases while
bond length decreases.

4. Anomeric effect
Anomeric Effect may explain as the tendency of anomeric substituents to favor an axial
configuration over an equatorial position. The high stability of αα-methyl glucoside than that of
ββ-anomer can be explained based on the hyperconjugation effect. Whereas an αα-anomer can
show hyperconjugation of lone pair of oxygen atom with axial methyl group, hyperconjugation is
not possible in ββ-anomer due to equatorial position.

1.7 TAUTOMERISM
Tautomerism is defined as the phenomenon in which a single compound exists in two readily
interconvertible structures that differ noticeably in the relative position of at least one atomic
nucleus, generally hydrogen. The term ‘tautomer’ is made by two words; one is tauto (same) and
meros (parts). The term tautomerism is also known as desmotropism (Greek desmos-bond;
tropos-turn) based on the interconversion of the two forms involving a change of bonds or
dynamic isomerism (as the two forms are in dynamic equilibrium with each other). The most
common tautomers exist in pairs, which mean that the proton is located at one of the two
positions. In other words or more specifically, the most common form involves a hydrogen
changing place with a double bond.
The tautomerism is frequently observed in carbonyl or keto compounds and unsaturated
hydroxyl compounds or enols. For this reason, the tautomerism is also known as keto-enol
tautomerism. In this context, the structural change is the shift of a hydrogen atom between atoms
of carbon and oxygen with the rearrangement of bonds. Needless to say that the enol form differs
from the keto form in its polarity, acidity, and nucleophilicity. However, the keto form is
typically much more stable than the enol form with K's of ca. 10-5. Indeed, this is essential
because the C=O bond is much more stable than the C=C double bond. The keto form is also
more thermodynamically stable than enol form by 12 kcal/mol (48 kJ/mol). Although

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the keto form is mainly stable for aldehydes and ketones in most situations yet some factors can
shift the equilibrium towards the enol form as mentioned below.

1. Aromaticity: In case of phenol, theoretically keto form should be more stable, but the
enol form is greatly favored due to an aromatic stabilization (see left below).
2. Hydrogen Bonding: In the presence of a Lewis basic group, the intermolecular hydrogen
bonding stabilizes an enol form (see right below). However, the ratio of the two forms
will also depend upon the solvent(s) used.

Besides these two factors, three more subtle effects are also observed in keto-enol tautomerism.

Solvent: Solvent play an important role in the relative stability of the enol form. For example,
the enol form of 2,4-pentanedione predominates over the keto form in benzene. However, the
stability reverses completely in the water i.e. the keto form becomes more stable in water as
shown below. In a protic solvent, the lone pairs will be occupied in hydrogen bonding with the
solvent, making them less accessible to hydrogen bond with the enol form.

Conjugation and substitution: The presence of conjugation and substituents in a molecule

always shift the equilibrium towards enol form. (Exercise 1: Which enol form will be favored
for a given below ketone?)

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Exercise 2: Which one of these given below ketones will more favor the enol form? Hint: what
is the stability pattern of alkenes?

Types of Tautomerism:
The tautomerism can occur in both diad and triad systems. In diad system, hydrogen or any other
group migrates from atom no. 1 to an electronegative atom no. 2 as shown below. The same can
be applied for a triad system. Some selected examples of triad systems are given in Figure 9.

Figure 9 Keto-enol tautomerism in triad systems. In systems (a-c), all keto forms exist as major
(>99.97%)

Mechanisms of Tautomerism:

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1. Acid-catalysed mechanism: In acid-catalysed enolization, a proton (from an acid) reacts

with water molecule and forms hydronium ion (H3O+). A lone pair of electrons is removed
from the carbonyl oxygen by the H3O+. Finally, water abstracts a proton from α-carbon atom,
resulting in the formation of the enol form (Scheme 1a). However, if the starting compound
is an enol, Markovnikov’s addition of hydrogen ion occurs (Scheme 1b).

Scheme 1 An acid-catalyzed mechanism for keto-enol tautomerism

2. Base-catalyzed mechanism: The formation of an enol under base catalysis involves the
formation of an intermediate enolate, the conjugate base of the carbonyl compound. In the
first step, hydroxyl group abstract an α-proton and an enolate ion is formed. The enolate ion
is stabilized by resonance and accepts a proton from water to form enol compound in the
final step (Scheme 2).

Scheme 2 A base-catalyzed mechanism for keto-enol tautomerism

Differences between tautomerism and resonance:

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The tautomeric forms are chemically distinct entities and can be separated and characterized. On
the other hand, resonating forms differ only in the distribution of electrons and can never be
separated from one form to another since neither of them have any real existence. The important
differences between resonance and tautomerism are given below.

1. Tautomerism engages a change in the position of atom (generally hydrogen), while resonance
involves a change in the position of the bonds and electrons.

2. Tautomers may be separated and isolated. Resonating structures are only imaginary and
cannot be isolated.

3. The two tautomeric forms have different functional groups but the various resonating
structures have the same functional group.

4. In case of tautomerism, bond length does not change while resonance significantly affects the
bond length (single bond is shortened while the double bond becomes longer).

5. Resonance decreases the energy and hence increases the stability of compounds, while
tautomerism does not lower the energy of the molecule, and hence does not play any role in
stabilizing the molecule.

6. Tautomerism is represented by ( ) but the resonance is represented by ( ) symbol.

7. Tautomerism can occur in planar as well as non-planar molecules while only planar molecules
can show the phenomenon of resonance.

1.8 HUUCKEL’S RULE AND AROMATICITY

Compounds such as benzene having relatively fewer hydrogen atoms than those of
carbons are typically found in oils, which, in turn are produced from trees and other plants.
Because of their pleasant fragrance (aroma), early chemists called such compounds as aromatic
compounds. However, the chemical definition of aromatic now signifies certain kinds of
chemical structures. Aromatic compounds are a special class of organic compounds and have
attracted considerable attention due to their potential applications in various fields of
chemistry. Among them, the formation, reactions and stability of such cyclic (aromatic)
compounds are always of particular interest owing to their vast array of potential applications.

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Aromaticity:
Benzene is a planar compound with a cyclic cloud of delocalized electrons both above and
below the plane of the ring as shown above. Because its π-electrons are delocalized, all the C-
C bonds in benzene have the equal length- partway between the length of a typical single and
double bonds. We have noticed that the benzene is a particularly stable compound because it
has extraordinarily large resonance energy (36 Kcal/mol). The compounds such as benzene
with unusually large resonance energies are typically called aromatic compounds, and the
cause which explains the extra stability of such cyclic molecules is termed as ‘aromaticity’. In
aromatic compounds, resonance phenomenon (for details, see resonance section) typically
increases the stability of the molecule, and therefore, the energy is called resonance energy.
The concept of aromaticity can be best explained based on the Hückel’s rule as discussed
below:

Hückel’s rule: For a compound to be aromatic, the following conditions must be followed
(i) A compound must have an uninterrupted cyclic cloud of π-electrons. For the πcloud to
be cyclic, a compound must be cyclic and planar or nearly planar.
(ii) The πcloud must contain an odd number of pairs of π-electron.
(iii) The German chemist Erich Hückel was the first to recognize that an aromatic
compound must obeys [4n + 2] π-electron rule. The rule states that a cyclic and planar
compound would be aromatic, if its uninterrupted πcloud contains [4n + 2] π-electrons,
where n = 0,1,2,3… n is generally called Hückel’s number or aromaticity index (For
clarity about the concept, also see Table 1).
Table 1: Concept of aromaticity
[4n + 2] π-electrons 4n π-electrons
Resonance Resonance Resonance Resonance
Planar Never Anti- Non-Planar Planar Never Non-Planar
Aromatic Aromatic Non- Anti- Aromatic Non-

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Aromatic Aromatic Aromatic

For applying Hückel’s rule in any system, one will need to count the number of π-electrons.
The number of π-electrons can be calculated as follows:
• Double bond or triple bond contributes 2 π-electrons to the system.

Cyclobutadiene, benzene, naphthalene and cyclooctatetraene has two, three, five and four
pairs of π-electrons, respectively. Benzene and naphthalene fulfill the conditions for
aromaticity but cyclobutadiene and cyclooctatetraene are not aromatic because they have
an even number of pairs of π-electrons. There is an additional reason why cyclooctatetraene
is not aromatic – it is not planar but, instead tub-shaped.
• Negative charge or lone pair of electron also contributes 2p electrons, if they are in
conjugation with π-electrons. However, if they are not involved in resonance, then not
counted.
Aromaticity in heterocyclic compounds: So far, we have only considered compounds having a
carbon skeleton. However, many compounds found in nature are cyclic compounds with an
element other than carbon in the ring. These are called Heterocyclic compounds. Further, some
of them may be aromatic compounds and are termed as heteroaromatic compounds as given
below.

1.9 ANTI-AROMATICITY
Cyclic conjugated flat or planar molecules having 4n π-electrons are termed as anti-aromatic
compounds. Unlike highly stable aromatic compounds, which typically follow Hückel’s
rule ([4n + 2] π electrons), anti-aromatic compounds are highly unstable as well as quite reactive.

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The unexpected instability of 4n π-electron cyclic conjugated system has been termed as "anti-
aromaticity". For instance, the cyclopentadienyl cation is extremely unstable and difficult to
make. Similarly, the oxirene itself has never been observed despite having an exciting traces of
its fleeting existence, and by the way, neither has the 1H-azirene and/or thiirene, the nitrogen
analogues (Figure 10).

Figure 10 Structures of cyclopentadienyl cation and some elusive three-membered anti-aromatic

ring compounds

The simple pentalene hydrocarbon is quite unstable above -100°C and does not exist while its
hexaphenyl derivative is air sensitive. Similarly, though the 12π-electron-containing planar
heptalene has been prepared yet is found to be extremely reactive (even more than that of
cyclooctatetraene). Apart from that, all attempts to isolate 1,3-cyclobutadiene (4π-electron
system) have always resulted a dimer. The structures of as-mentioned anti-aromatic compounds
are shown in Figure 11 (Upper column).

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Figure 11 Upper column: Structures of some typical anti-aromatic compounds; Lower column:
structure of cyclooctatetraene and its tub conformer

It would be worthwhile to mention here that some molecules may change shape and become
non-planar in order to avoid the instability due to anti-aromaticity. As such, the molecules can
break some of the typical π interactions. For instance, 1,3,5,7-cyclooctatetraene is a non-planar
compound and adopts a tub-shaped conformation to avoid the destabilization that results from
anti-aromaticity (Figure 11, lower column). If it were planar, it would have a single 8π-electron
system around the ring, but it instead adopts a boat-like shape having four individual π bonds.
The compound can be readily prepared and undergoes addition reactions, typical of alkenes. The
catalytic hydrogenation of this cyclooctatetraene produces cyclooctane.

1.10 HOMOAROMATICITY

In the previous section, we discussed about aromaticity. In 1959, Saul Winstein introduced
a new class of aromatic compounds based on the structural properties of “tris-
homocyclopropenyl” cation. In this cation, aromaticity was found to be discontinued due to the
presence of single sp3-hybridized atom. These types of molecules were termed as homoaromatic
molecules. Thus, we can say that homoaromaticity refers to a special case of aromaticity in
which conjugation is interrupted by a single sp3-hybridized carbon atom. Due to the poor
overlapping of p-orbitals, these compounds are definitely less stable than the aromatic
compounds (having complete delocalization of electron). To date, homoaromatic compounds are
known to exist as both cationic and anionic species while some studies also support the existence
of neutral homoaromatic molecules, though these are less common. Among these, the cationic
homoaromatic compounds are the most studied species for homoaromaticity. For example, the
homotropylium cation (Figure 12). Similar to those of cationic counterparts, the anionic
homoaromatics have also been accepted to exhibit the "true" homoaromaticity. The anionic
homoaromatics are generally prepared from their neutral parent compounds through reduction
with lithium metal. Notably, in bis, tris, (etc.) homoaromatic species, two, three, (etc.) single sp3-
hybridized centres separately interrupt the pi-electron system.

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Figure 12 Structures of different tropylium cations

Synthesis of homotropylium cation:

When cyclooctatetraene is dissolved in concentrated sulfuric acid, a proton adds to one of the
double bonds to form the homotropylium ion. In this species, an aromatic sextet extends over
seven carbon atoms similar to that of tropylium ion (Figure 13). As the eighth carbon atom is
sp3-hybridized, it cannot take part in the aromaticity.

Figure 13 Synthesis of homotropylium cation from cyclooctatetraene

1.11 BENZENOID AND NON-BENZONOID AROMATIC COMPOUNDS

Benzene is simplest aromatic compound. There are three alternative π-bonds in the cyclic
ring of benzene. However, it is not essential that all aromatic compounds contain a benzene ring.
On these ground, aromatic compounds can be classified as benzenoid and non-benzenoid
compounds.
Benzenoid compounds: Those compounds which are derived from benzene are known as
benzenoid compounds. These compounds show a complete delocalization in the ring.
benzenoid compounds can be further divided into isolated and fused benzenoid compounds.
Isolated benzenoid compounds: These types of compounds usually contain a benzene ring or
benzene ring is connected by only one bond. Some selected examples of isolated benzenoid
compounds including benzene are given below.

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Fused benzenoid compounds: Benzene rings may be fused together to give larger polycyclic
aromatic compounds. Such type of molecules containing these kinds of fused rings are generally
referred as linear or angular polyacenes. Thus, acenes are a class of organic compounds and/or
polycyclic aromatic hydrocarbons made up of linearly-fused benzene rings such as naphthalene,
anthracene, phenanthrene, and chrysene. The structures of these compounds are given below.

Non-benzenoid compounds: Non benzenoid aromatic compound are the compounds containing
five to seven carbon atom rings with conjugated π-electron system. Thus, these compounds
exhibit aromaticity due to an arrangement of alternate π-bonds in the molecule. As these
compounds do not contain any benzene ring, they are termed as non-benzenoid compounds.
Nevertheless, the chemical reactions of these compounds are like benzenoid compounds only.
The chemical structures of some non-benzenoid compounds are given in Figure 14 followed by a
brief discussion of some selected compounds from Figure 14.

Figure 14: Examples of non-benzenoid compounds

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Tropone and Tropolone: Tropone and tropolone are non-benzenoid seven-membered aromatic
compounds having three conjugated double bonds. While former contains a keto group, the latter
contains an α-hydroxy group w.r.t. a keto group, and can show keto-enol tautomerism. The
tropone moiety has been found in several natural products. However, tropolone and tropolone
ether (with an α-alkoxyl group) are much more common in nature.
Tropyliumion: The carbonium ion with a molecular formula of [C7H7]+ is known as tropylium
ion. Salts of tropylium ions are stable due to aromaticity and have greater stability than most
other typical carbonium ion (For detail: see homo- and anti-aromaticity section).
Azulene: Azulene is a 10π-electron system made up of the ‘fusion’ of two aromatic ions;
cycloheptatrienyl (tropylium) cation and cyclopentadienyl anion. Azulene is an isomer of
naphthalene and has a similar smell, but instead of white, its crystals are dark blue. The word
‘Azul’ is derived from the Spanish word, which means blue. Azulene can be synthesized from an
octahydronaphthalene. Azulene can undergo many reactions such as Friedel-Crafts substitutions.
Like cyclopentadienyl anion and tropylium cation, it can also form π-complexes with certain
metals.
Pentafulvene: Fulvenes are cyclic cross-conjugated olefins. Pentafulvenes have same formula as
that of benzene but the ring contains five carbon atoms only. Pentafulvene contains alternative π-
bonds making it an aromatic compound. They have been widely used as valuable building blocks
in the synthesis of several natural products such as hirsutene,1 capnellene,2 and β-vetivone3.

1.12 ALTERANANT AND NON-ALTERANANT HYDROCARBON

An alternant and non-alternant classification is one of the suitable ways to predict the
properties of a conjugated hydrocarbon. As such, the alternant and non-alternant classification is
a starring process in which the carbon atoms are divided into two sets; all the carbons in one set
are marked with a star in such a way that no two starred or unstarred atoms are bonded to each
other. A conjugated hydrocarbon will be alternant if no two stars are adjacent to each other.
However, it will be non-alternant if two or more adjacent centers receive the stars (Figure 15).

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Figure 15 Selected examples of alternant and non-alternant hydrocabons

As can be seen in Figure 15, structures (a), (b) and (e) are alteranant hydrocarbons because no
two stars are adjacent to each other in these structures. However, in remaining structures, a
random way of placing the stars on alternate carbon atoms eventually leads to two adjacent
stars. An alternant hydrocarbon is any conjugated hydrocarbon which does not possess an odd-
membered ring. For this reason, the tropylium ion (d) is also considered as a non-alternant
hydrocarbon. The alterant hydrocarbons can be divided into two categories as mentioned below.

1. Even-alternant hydrocarbon: If system has an equal numbers of starred and unstarred

carbons, it is known as even-alternant hydrocarbon. An even-alternant molecule has an equal
numbers of bonding and antibonding orbitals, which are symmetrically, distributed with no
non-bonding [Link] these hydrocarbons, all the bonding orbitals are filled and the
electrons are uniformly spread over the unsaturated atoms (Figure 16).
2. Odd-alternant hydrocarbon: If the numbers in the two sets are not equal, it is called
an odd-alternant hydrocarbon. An odd-alternant system will have more starred than unstarred
atoms. The odd-alternant structures have an equal numbers of bonding and antibonding
orbitals along with a non-bonding [Link] in allylic systems, odd-alternant hydrocarbons
(which must be carbocations, carbanions, or radicals) also have a non-bonding orbital of zero

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energy in addition to an equal and opposite bonding and antibonding orbitals. When an odd
number of orbital overlaps, an odd number is created.

Figure 16 The energy levels in odd- and even-alternant hydrocarbons. The arrows represent
electrons. The orbitals are shown as having different energies, but some may be degenerate.

1.13 ANNULENES
Monocyclic and completely conjugated polyenes or hydrocarbons having alternate single
and double bonds are usually called annulenes. A prefix in brackets denotes the number of
carbons in the rings. They are either aromatic or non-aromatic, but can never be anti-aromatic.
For instance,
[4]Annulene: ex. Cyclobutadiene− either anti-aromatic on non-aromatic, but never be aromatic
[6]Annulene: ex. Benzene− They are either aromatic or non-aromatic, but never be anti-
aromatic.
[8] Annulene: ex. Cyclooctatetraene
[10] Annulene: Beyond benzene, [10] annulene is the first hydrocarbon to satisfy the Hückel’s
rule. A structure in which all the double bonds are cis, however, would be a regular 10-sided
polygon requiring bond angles of 144° (instead of the 120° as required for sp2-hybridized
carbon), and would suffer a significant angle strain (see left below). The destabilization (owing
to the angle strain) apparently exceeds the stabilization associated with aromaticity, and makes
all-cis-cyclodecapentaene a highly reactive substance. Aside from this, an isomer in which two

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of the double bonds are trans should, in principle, be free of angle strain. It is destabilized,
however, by a repulsive force between two hydrogen atoms (that are forced together in the
interior of the ring), and for this reason, it is relatively reactive. As can be seen at right below,
the planarity of ring is disturbed in II isomer by the repulsion of internal H atom. However, if
this H-atom is replaced by rings then aromaticity can be achieved with slight disturbance in
planarity.

[12]Annulene: Anti-aromatic or non-aromatic, but never be aromatic.

Non-Huckel's lone pair

H
H H N

12 -electron systems

[14] Annulene: Some selected examples are given below. Whereas system (a) is not exactly
planar (slightly aromatic), the central π-bond does not involve in resonance in system (b), and
it simply behaves like an ethylenic bond as exemplified by its bromination reaction. Dehydro
[14] annulene (c) is another example of [14] annulene system and is counted as aromatic
compound.

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[18] Annulene: [18] Annulene is predicted to be aromatic by the Hückel’s rule (4n + 2 = 18
when n = 4). The structures shown below have a shape that make them free of angle strain and
large enough so that the repulsive forces between hydrogen atoms in the interior are minimal.
The thermochemical measurements indicate that the molecules have a resonance energy of
ca.100 kcal/mole while the structural studies have revealed that the molecule are planar with all
its bond distances falling in the range of ca. 1.37-1.43 Å. In terms of chemical reactivity,
however, the [18]-annulene system resembles more an alkene than that of benzene.

1.14 ADDITION COMPOUNDS

When two compounds reacted to form a product that contains all the mass of the two
compounds, the product is called an addition compound. There are several kinds. Here we will
discuss addition compounds in which the molecules of the starting materials remain more or less
intact and weak bonds hold two or more molecules together. Examples: crown ethers complexes
and similar compounds, inclusion compounds, and catenanes.

1.14.1 CROWN ETHER COMPLEXES

Cyclic heterocyclic compounds that consist of a ring with several ether groups are known
as crown ethers. The most common crown ethers constitute the cyclic oligomers of ethylene
oxide having ethyleneoxy (–CH2CH2O–) as the repeating unit. The most common and important
members of crown ethers are tetramer (n = 4), pentamer (n = 5), and hexamer (n = 6) as shown
in Figure 17. Due to the resemblance of their cavity shape with a crown, the term “crown” is
generally used in their nomenclature, and they are named as x-crown-y. The first number (x)
consigns to the total number of atoms in the cycle while the second number (y) refers to the
number of oxygen atoms. However, in place of oxygen, S and N atoms may also be present, and
such crown ethers are known as thia and aza crown ethers, respectively.

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Crown ethers has high binding affinity for a variety of metal ions, and neutral and ionic
organic species. Thus crown ethers play a key role in the area of host-guest chemistry and in the
construction of a variety of non-covalent supramolecular assemblies. Specifically, a crown ether
has an electron rich (oxygen lone pairs) cavity which facilitates binding with certain cations.
This hydrophilic cavity (with ether oxygen atoms) is surrounded by hydrophobic ethylenic
groups. The wrapping around of crown ether on the metal ions makes it feasible to solubilize
metals into organic solvents. In particular, the oxygens-rich cavity of crown ether possess great
affinity towards certain alkali and alkaline earth metal cations leading to the formation of
complex compounds. This property of crown ethers makes them an appealing candidates in the
field of coordination chemistry while also opens the window for numerous other applications.
However, a stable complex is not formed if the size of the cation is very large or it does not fit in
the cavity of the crown ether. It has been well documented that the ionic diameters of certain
crown ethers such as 12-crown-4, 15-crown-5 and 18-crown-6 are well matched with Li+, Na+,
and K+ alkali metal cations, respectively.

Figure 17 Representative examples of crown ethers

[Link] Synthesis of Crown Ethers: A historic background

The initial credit for the discovery of crown ethers goes to Charles J. Pedersen (Retired
from the DuPont company), one of the three recipients of Nobel Prize for chemistry in 1987 for

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the development of crown ethers and other molecules. While working in the lab, Pedersen
obtained a very small amount of a white, fibrous, and crystalline 2,3,11,12-dibenzo-
1,4,7,10,13,16-hexaoxacyclooctadeca-2,ll-diene 4 crown ether as a by-product from the reaction
of bis(2-chloroethyl) ether 2with the sodium salt of 2-(o-hydroxyphenoxy)tetrahydropyran1
forming bis[2-(o-hydroxyphenoxy)ethyl] ether3 (Scheme 3).

Scheme 3 Pedersen’s synthesis of Dibenzo-18-crown-6

Having gone through the analysis, Pedersen found an unusual solubility of the compound 4 in the
presence of sodium salts, and later he recognized that the cyclic polyether ring 4 can form a
complex with the sodium cation (Figure 18).

Figure 18 A complex of Dibenzo-18-crown-6 with sodium salt

Template synthesis of crown ethers:

The crown ether macrocycles can be synthsized following atemplate synthesis using certain
metal ions as organizing agents. The basic principleof template effect synthesis is that the cyclic

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compound may be formed using a particular compound which can work both as the nucleophile
and elcetrophile with ease.

[Link] Applications of Crown ethers

Crown ethers are of enormous interest and importance in different areas of science
covering, but not limited to, chemical science, catalysis, materials science, separation, transport
and encapsulated processes. In line with this, they are useful in the design and synthesis of
various synthetic systems with definite properties, diverse capabilities, and programmable
functions. The chemistry of crown ethers involves the complexation of oxygen atoms (host) with
a variety of ionic species (guest), and this phenomenon is termed as ‘host-guest chemistry’ as
mentioned above. The ‘phase-transfer catalysis’ is probably one of the most attractive
applications of crown ethers and increasingly used to boost the solubility of inorganic salts in
organic solutions for a variety of reactions such as esterifications, oxidations, saponifications,
elimination reactions, alkylations, aromatic substitution reactions, displacement reactions, and
carbene generation, to name but a few. Some of these reactions are appropriately discussed
below.
1. “Purple benzene” or potassium permanganate oxidation
Potassium permanganate (KMnO4) is a well-known oxidizing agent and routinely used for
the oxidation of organic compounds in aqueous solutions. However, many organic compounds
are either insoluble or poorly soluble in water, and thus restrict the wide use of KMnO4 in some
commonly employed organic solvents except acetone, butanol, acetic acid etc. This problem can
be addressed effectively using crown ether such as dicyclohexano-18-crown-6 in conjunction
with benzene and KMnO4. Specifically, crown ether forms a permanganate complex (Scheme
4a) and permanganate becomes soluble in benzene forming an ion-pair. The as-resulted “purple
benzene” works as an excellent oxidizing agent for a variety of substrates in organic solvents.
For example, the oxidation of α-pinene furnishes pinonic acid in 90% yield under above-
described conditions (Scheme 4b).4 As such the solubilizing effect of crown ethers on insoluble
inorganic salts are spectacular. For instance, the solubility of potassium thiocyanate complex can
increase by 100-times using crown ethers. Aside from that ofKMnO4, potassium tertiary-
butoxide and a mixture of PdC12+ 2KCl can be dissolved in liquid aromatic hydrocarbons
simply by adding dicyclohexano-18-crown-6.

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Scheme 4 (a) Complexation of potassium ion with crown ether and (b) Conversion of α-pinene
into pinonic acid

2. Superoxide anion reaction

Superoxides such as K2O or NaO2 also suffer with their limited solubility in organic solvents,
similar to those of inorganic salts. However, the use of crown ethers with a superoxide has been
proven as an excellent way for the oxidative dimerization reaction (Scheme 5).5

3. Saponification
The hydrolysis of sterically hindered esters can be easily done using a hydrophobic and
hydrocarbon soluble crown ether that can form a potassium hydroxide complex in toluene
(Scheme 6).6

Scheme 5 Crown ether-assisted dimerization of indole derivative

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Scheme 6 Crown ether-assisted saponification reaction

4. Generation of carbene
Trans-stilbene and cyclohexene can be converted into gem-dihalocyclopropanes in
moderate to good yields at 40°C using a mixture of dicyclohexyl-18-crown-6 and sodium
hydroxide toluene. Similarly, dibenzo-18-crown-6 has been found suitable as liquid-liquid
phase-transfer catalyst in carbene generation.7 Aside from those of typical applications of
crown ethers in Organic Chemistry; the derivatives of the same have recently been touted as
powerful anti-tumor agents.

1.14.2 CRYPTANDS
Cryptands are three dimensional (3D) flexible molecules with two nitrogen atoms
connected by three bridges composed of ethyleneoxy units. The term cryptand implies that this
ligand can bind a substrate in a crypt, interring the visitor as in a burial. The 3D interior cavity of
a cryptand provides a binding site for specific "guest" ions. The complex formed of a guest and a
cryptand is called a cryptate, and are generally lipophilic. The cryptates (meaning hidden) are so
called because they can wrap around and hide the metal ions. This arrangement allows the
molecule to completely encapsulate a metal ion. Because of their highly selective (than those of
crown ethers) and unique complexing properties, cryptands are of great interest to chemists
worldwide. These interesting compounds were first prepared over twenty years ago in the
laboratory of Jean-Marie Lehn (the father of supramolecular chemistry), who shared the Nobel
Prize in Chemistry (1987) with Donald J. Cram and Charles J. Pedersen for their efforts in
discovering and determining the applications of cryptands and crown ethers. As mentioned
above, the more rigid 3D structures of cryptands confer higher selectivity and complex the guest
ions more strongly than similar-sized crown ethers. Presumably, this is due to a combination of
cryptands having a more defined ‘hole’ size than the more flexible crown ethers, which means
that cryptands cannot expand to accommodate the ions of the wrong size. In addition, the 3D
cryptands are relatively more preorganized into a binding conformation than crown ethers,
providing the limited or less rearrangement for the cryptand as it goes from an uncomplexed to a
complexed state. Due to the presence of N and O atoms (sometimes S or P atoms), cryptands
show relatively a higher density than the crown ethers. 1,10-diaza-4,7,13,16,21,24-

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hexaoxabicyclo[8.8.8]hexacosane is one of the most widely used cryptands (Figure 19), and also
termed as [2,2,2] cryptand based on the number of ether oxygens in the chains.

Figure 19 Chemical structure and numbering of a [2,2,2] cryptand

[Link] SYNTHESIS OF CRYPTANDS

The synthesis of cryptands remained a challenging task for chemists over the years. As
the synthesis involves many steps and requires high dilution techniques, the yields of cryptands
are generally low. In pioneering work, Lehn (1985) described the major strategies adopted in the
synthesis of cryptands starting from acyclic components. Later on, a number of cryptands were
synthesized following a one-pot Kulstad-Malmsten synthesis approach. Specifically, the base-
catalyzed treatment of ditosylate derivative of triethylene glycol with its diamine analog
furnished a [2,2,2]cryptand in ca. 38% yield (Scheme 7).8 Almost similar results were obtained
when dimesylate was used in place of ditosylate derivative. However, the use of ditosylate is
preferred due to its easy availability. Aside from that of [2,2,2]cryptand, the use of ditosylate
also allows the preparation of [2,2,1], [3,2,2] (50%), [3,3,2] (40%), and other similar cryptands.

Scheme 7 Synthesis of [2,2,2]Cryptand

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[Link] PROPERTIES AND USES

Cryptands find applications in many attractive areas of chemistry, material sciences and
biochemistry due to their architectural and functional plasticity. Though cryptands are more
expensive and difficult to prepare, they offer much better selectivity and strength of binding
(binding constants) than other complexants for alkali metals such as crown ethers. For instance,
the binding constant of [2,2,2] cryptand for K+ is ca. 104 times higher than for 18-crown-6. Aside
from those of alkali metals, cryptands can also form complexes with hard acids such as
ammonium ion, alkali earth metals, and few transition and lanthanide ions. Their 3D
encapsulation mode offer ssome size-selectivity, enabling discrimination among alkali metal
cations (e.g. Li+, Na+ and K+). For example, [2,1,1] cryptand exhibits a binding constant for Li+
over 100-times higher than that for Na+ in water. Similarly, [2,2,1] cryptand has been found to
have a high preference for Na+ over K+. The cryptands are able to extract otherwise insoluble
salts into organic solvents. Cryptands increase the reactivity of anions in salts since they can
successfully break up ion-pairs. Besides their importance in supramolecular chemistry, cryptands
can also be used as potential carriers in ion-transportation, as stationary phases in column
chromatographic separations, as redox active materials, and in photophysical studies and non-
linear optics.

1.14.3 INCLUSION COMPOUNDS

Inclusion compounds are unique type of chemical compounds or complexes which are
formed as a result of the inclusion of one type of molecule (guest) in the cavities of molecules of
another type (host). The incoming molecules are also referred as foreign substances. This type of
spatial complex formation does not occur by means of any ionic, covalent, or coordinate
covalent bonds but rather depends upon dispersion forces like electrostatic, van der waals,
hydrogen bonding and hydrophobic interactions, and possibly upon highly oriented dipoles for
stability, contrasting markedly with the usual concept of chemical complexation. The capacity of
a substance to form inclusion compounds depends on the presence of molecular-sized cavities.
Inclusion compounds are generally formed by mixing two components and, less often, triturating
the components. They are usually unstable, and often decompose to the original substances in
solutions. Despite having a wide variety of inclusion compounds, we will briefly focus on two
most important types for the same.

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[Link] CYCLODEXTRINS
Cyclodextrins (CDs) or cycloamyloses belong to a family of compounds composed of
sugar molecules bound together in a ring. In particular, the naturally occurring CDs (α, β, and γ)
are cyclic oligosaccharides consisting of 6, 7 and 8 glucopyranose units, respectively. These
compounds have relatively stiff doughnut-shaped structures, and have proven to be very practical
monomolecular hosts in supramolecular chemistry. The CDs and their inclusion compounds can
be crystallized from water and have studied by X-ray crystallography as either empty molecules
or host-guest complexes. The chemical structures of α- and β-CDs are given below.

[Link] CALIXARENES
Calixarenes are conformationally flexible macrocycles or cyclic oligomers that are
produced by the hydroxyl alkylation of phenols and aldehydes. The word calixarene is derived
from calix or chalice (as they resemble a pot) while the word arene refers to an aromatic
component. The nomenclature of calixarenes relies on counting the number of repeating units in
the ring. For instance, a calix[n]arene; where n = 4, 5, 6 and 8 refers to calix[4]arene,
calix[5]arene calix[6]arene and calix[8]arene, respectively (Figure 20). Calixarenes have
hydrophobic cavities that can hold smaller molecules or ions and thus have significant
importance in supramolecular host-guest chemistry. Over the last decade, calixarenes have been
used as optical sensors, ion sensitive electrodes, chiral recognition devices for solid phase
extraction, as a stationary phase and modifiers, to name but a few.

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Figure 20 The chemical structures of a variety of calixarenes

[Link] USES OF INCLUSION COMPOUNDS

Separation: The inclusion compounds can be used for the separation of different
compounds in a mixture. Urea and thiourea, for example, respectively allow the separation of
unbranched and branched hydrocarbons, which they bind in inclusion compounds. Zeolites
prepared with various cavity dimensions are used industrially for the drying of gases as well as in
the separation of substances through ion-exchange processes.

Drug delivery: Drug delivery is a dynamic process whereby a drug molecule continuously
associates with or dissociates from a host molecules such as CD. Specifically, the complexation
of a drug molecule (D) to CD occurs through a non-covalent interaction between D and the
cavity of CD. Different mechanisms can play important roles in drug release from a D-CD
complex. However, assuming a 1:1 complexation, the interaction will be as follows:

The complexation constant (K) and the lifetime of the complex, are two very important
parameters for the drug release mechanism. Besides, dilution also plays an important role in drug
delivery as evidenced recently for miconazole, which can bound more strongly than that of
prednisolone drug, and thus supports the probable role of dilution. Notably, the dilution is
minimal when a D-CD complex is directed ophthalmically.

1.14.4 CATENANES AND ROTAXANES

A mechanically interlocked molecular structure consisting of two or more interlocked
macrocycles i.e. molecules containing two or more intertwined rings are known as catenanes.
Catenane is derived from the Latin word ‘catena’ meaning ‘chain’. On the other hand,
Rotaxanes are mechanically interlocked molecules consisting of “dumbbell-shaped molecules”
which are threaded through a macrocycle. The name rotaxane is derived from the Latin word rota

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and axle which means wheel and axis, respectively. The nomenclature of catenanes is
determined by the number of rings, i.e. how many rings are interlocked to each other. For
instance, a [2]catenane consists of two interlocked rings. A catenand is the free ligand that can
form a catenate complex in the presence of a metal centre. Rotaxanes can be named in an
analogous manner too. The two rings cannot be separated without breaking the covalent bonds of
the macrocycles. Rotaxanes can be separated via deformations of one of the components. In
other words, rotaxanes are threaded species stabilized by steric interactions.

[Link] SYNTHESIS OF CATENANES AND ROTAXANES

The Catenanes are synthesized in two different ways; statistical and template-directed
synthesis. Over the last few years, the template-directed clipping reaction based on imine chemistry
has become one of the most efficient methods for the construction of functionalized rotaxanes and
catenanes. The synthesis of both can only be efficiently accomplished, if a suitable template is
used, providing a means either to thread a string-like molecule through a macrocycle or to
wrap an open macrocycle around a string.

Figure 21 Cartoon representations for the synthesis of catenane (clipping reaction)

As shown in Figure 21, one- or two cyclization reactions can be involved in the clipping
synthesis of catenanes. Specifically, in a double-clipping reaction, two macrocycles which are
not fully closed are interlocked, and two subsequent ring-closing reactions are performed in
order to form the catenanes. Aside from that of catenane, there can be five primary routes
enabling the formation of a rotaxane (Figure 22). The first method is capping in which a
pseudorotaxane is formed by threading the thread through the macrocycle. The ends of the thread
are often closed-off with large stopper groups to make sure that the thread stays inside the
macrocycle. Snapping involves two different parts of the thread, both containing a bulky group.

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Whereas the one part of the thread is threaded through the macrocycle to form a semi-rotaxane,
the end is usually closed-off by another part of the thread, forming a rotaxane. The third route,
i.e. the clipping involves the formation of a rotaxane by a ring-closing reaction of the
macrocycle. The thread already contains the two bulky groups at the ends of the thread, but the
macrocycle is not yet fully closed. The macrocycle clips over the thread and a rotaxane is formed
after ring-closing reaction. Slipping, the fourth method, is achievable only when the bulky end
groups are of appropriate size to fit through the macrocycle at quite higher temperatures. The last
primary route relies on the use of active metal template for the synthesis of rotaxane.

Figure 22 Cartoon representation for the synthesis of rotaxane: (a) capping, (b) snapping, (c)
clipping, (d) slipping, and (e) active metal template methods

[Link]. Applications of Catenanes and Rotaxanes

a. Catalysis
The [1]rotaxane contains a weakly basic tertiary amine, which has been used as a catalyst in the
Knoevenagel reaction of malononitrile with acetone in CHCl3. It has been proposed that
malononitrile reacts with the rotaxane via its active hydrogens forming a zwitterionic species.

b. Polymer

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The group of Takata et al. synthesized a polymer consisting of rotaxane cross-links. Rotaxane
with a thread consisting of a polytetrahydrofuran-based bulky group and a vinyl end group was
threaded through a γ-cyclodextrin. The as-formed rotaxane cross-linked polymer showed the
superior properties in terms of higher elongation, more stress at breakage and fracture energy
than covalently cross-linked polymers. Aside from these, both catenanes and rotaxanes have
been significantly used in the supramolecular chemistry for binding and recognition of different
ions, and as molecular shuttles.

1.14.5 IONIC LIQUIDS

The demand for eco-friendly chemical processes, products and energy requires the
development of new fresh and cost-effective approaches to prevent or minimize environmental
pollution. In this context, ‘green chemistry’, mainly introduced by Paul T. Anastas, is one of the
most attractive theories in chemical sciences. Scientifically, green chemistry can be defined as
the operation of a set of principles that not only reduces or eliminates the use or generation of
harmful substances in the design, manufacture and applications of chemical products but also
provides an appropriate measurement criteria to measure the environmental acceptability of the
processes being used.
Ionic liquids (ILs), one of the most important tenets of green chemistry, are generally
defined as liquid electrolytes composed entirely of organic ions that may undergo almost
unlimited structural variations. Nevertheless, a melting point criteria is normally used to
distinguish between molten salts and ILs (< 100 °C). In general, the term IL implies a material
that is fluid at room temperature (or close to), colorless, has a low viscosity and can be simply
handled. Since the respective discoveries of ethylammonium nitrate [EtNH3][NO3] (1914) and 1-
alkyl-3-methylimidazolium salts (1982) by Walden and Wilkes, ILs have received worldwide
attention and become a major scientific area. Whereas the former serves as a first IL, the latter
are defined as room temperature ILs (RTILs). In general, RTILs are sterically hindered organic
salts of a variety of cations, including, but not limited to tetraalkylammonium,
tetraalkylphosphonium, N-alkylpyridinium, 1,3-dialkylimidazolium and trialkylsulfonium
cations (Figure 23).

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Figure 23 Structures of some common organic cations

Owing to their low or negligible vapor pressure, heat-resistance or tolerance for large
temperature variations, non-volatility, absence of flammability and reusability, RTILs have
particularly emerged as an alternative revolutionary candidates in the replacement of
conventional organic solvents over the last few decades, and increasingly used for large
technological applications.

[Link] Synthesis of Ionic liquids

In a broader context, ILs can be classified into two major categories; first one is simple
salts (made up of a single anion and cation) and second one is binary ILs (salts where an
equilibrium is involved). For example, [Et4N][NO3] is a simple salt whereas a mixture of
aluminum(III) chloride and 1,3-dialkylimidazolium chloride constitutes a binary IL system
having a number of different ionic species. It is noteworthy that the melting point and properties
of a binary IL depend upon the mole fractions of components present, giving them an acidic,
basic and neutral characteristics. The synthesis of an IL is usually carried out in two easy steps.

(1) Synthesis of a Desired Cation: A desired cation can be easily synthesized either by a
protonation reaction by an acid or through quaternization reactions with a haloalkane.
(2) Anion Exchange Reaction: An anion exchange reaction is usually performed treatment of
halide salt with a Lewis acid following an anion metathesis.
As a representative case, the overall synthesis of 1-butyl-3-methylimidazolium
tetrafluoroborate [bmim][BF4] is depicted in Scheme 8.

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Scheme 8 Synthesis of 1-butyl-3-methylimidazolium tetrafluoroborate, [bmim][BF4]

[Link] Properties of Ionic liquids:

The innovative fluids, ILs, exhibit a significant number of intriguing properties as briefly
mentioned below.
• Stability/Thermal decomposition: Most ILs are quite stable at high temperature. For
instance, the imidazolium cation is stable even above 300°C.
• Density:The density of ILs are least effected by temperature variation or impurity. The
density of all imidazolium-based ionic liquids are greater than 1.
• Viscosity: Though least viscous RTILs are quite viscous when compared to conventional
solvents yet the viscosity of ILs can be fairly manipulated with ease. For example, ILs
with short alkyl chain and/or functionalized alkyl chain has lower viscosity than those
having longer alkyl chain. This can be attributed to the increased van der Waals.
Similarly, the use of BF4 anion contributes toward lower viscosity of ILs than that of PF6
anion.
• Non-flammable
• Negligible vapor pressure
• High thermal/chemical/electrochemical stability
• Solvating ability
• Large liquids range (span of temperatures between melting and boiling point of a liquid)
• Facile recovery and recyclability
• Non-coordinating with metals and enzymes
• Tunable polarity and miscibility with water/organic solvents

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• Highly stable; can be stored for longer duration without decomposition

• Chiral ionic liquids may control stereoselectivity

[Link] Applications of Ionic liquids

Indubitably, over the last decade, the above-stated properties of ILs have triggered an
enormous interest among scientific community to be used them with a diversified range of
applications such as sensors, plasticizers, fuel cells, batteries, capacitors, thermal fluids,
extractants, ionogels, lubricants, and most importantly as catalysts and solvents in the synthesis,
analysis and separation, to name but a few. In line with this, the newer applications of ILs in
pharmaceutical industry or as energetic compounds are still emerging. Some of these
applications of ILs are briefly outlined below.
1. As an extractant: The water insoluble ILs such as [bmim][PF6] are used in the extraction of
water soluble by-products following simple extraction techniques. Some transition metal
catalysts that are soluble in ILs may be recycled together with the ILs, after extraction with
water and the non-polar organic solvents used in the product separation.
2. As a separation and storage media for toxic gases: It has been found that many gases,
including CO2, are highly soluble in ILs, and thus ILs can also be used as a gas separator.
Further, if an IL preferentially dissolves a definite gaseous species, it can be conveniently
used for conventional gas absorption applications. Specifically, the non-volatile nature of ILs
plays two important roles. Firstly, the regeneration of the solvent becomes easy. However, an
easy flash or mild distillation step is required to remove the gas from the solvent. Secondly,
during operation, there will be no cross-contamination of the gas stream by the solvent,
meaning no solvent loss and air pollution.
3. As a lubricant: Due to their tribological performance, ILs was first introduced as lubricants
in 2001. The primary advantages of ILs over conventional lubricants lie in their better
capability to form tribo films in conjunction with eco-friendliness, high thermal stability, and
adaptability to a variety of such applications. A notable reduction in friction and wear has
been observed after the addition of ILs in oil- or water-based media and even in grease,
suggesting that ILs are quite capable materials to be used either as neat lubricants or lubricant
additives.

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4. As a catalyst for organic transformations:Although ILs were originally introduced as

alternative green reaction media because of their unique physicochemical properties yet a
wide range of ILs have been designed and synthesized over a period of time for catalytic
applications. In this regime, an easy recovery and recyclability of IL catalysts certainly
leading to the reduction in the costs of different chemical processes. Despite having a huge
library of catalytically active ILs at present, herein, we will limit our discussion to only
acidic and basic types of IL catalysts. Generally speaking, the incorporation of acidic or basic
functional groups into either cations or anions of the ILs results in the formation of a variety
of acidic and basic ILs. Such functionalized ILs are particularly important and referred as
task-specific ILs (TSILs).
5. Brønsted acidic ionic liquids as catalysts: ILs made up of polynuclear metallic anions such
as chloroaluminate (III) have been known for a long time as powerful Lewis acids and can
promote certain reactions based on the use of AlCl3. For instance, a typical Friedel-Crafts
reaction can work well with such ILs. However, supporting a Brönsted acid (HF or HCl) in
the ILs through the formation of X(HX)n type anion (X = F or Cl) is one of the most
intriguing ways to reduce the volatility of an acid catalyst, and thus imparting the Brönsted
acidity to the resulting IL. Aside from that, carboxylate or a variety of alkane sulfonic groups
can be covalently tethered to imidazolium, pyridinium, ammonium, and other different
cations. The as-formed Brönsted acidic ILs (AILs) have emerged as revolutionary candidates
in the replacement of conventional homogeneous and heterogeneous acid catalysts, and have
been exploited for many organic reactions or transformations, including, but not limited to,
Aldol condensation, Beckmann rearrangement, Pechmann reaction, Koch carbonylation,
Mannich reaction, Aza-Michael reaction, Hantzsch reaction, synthesis of chalcones, furfural,
and biodiesel.
6. Interestingly, the use of AILs (containing sulfobutylimidizolium and pyridinium, N-methyl-
2-pyrrolidonium, and prolinium cations) as catalysts has been proved as a highly productive
methodology in the one-flask condensation reaction of pyrrole with cyclohexanone in
aqueous solution. In particular, under experimental conditions, the reaction can produce
primarily N-confused calix[4]pyrrole, a valuable tetrapyrrolic macrocycle in supramolecular
chemistry, in significantly higher yields (Scheme 9).

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Scheme 9 Brønsted AILs-catalyzed synthesis of N-confused calix[4]pyrrole

7. Basic ionic liquids as catalysts: Since the pioneering discovery of functional basic ILs for
CO2 capture application, basic ILs have aroused significant interest in green catalysis. In
these types of ILs, an amine organic base is generally tethered to IL cations. Despite their
lesser development than AILs, basic ILs have been successfully used to catalyze a number of
reactions including Michael addition, aza-Michael addition, condensation of aldehydes and
ketones with hydroxylamine, and in the synthesis of quinolines. Scheme 10 highlights a β-
hydroxyl-functionalized imidazolium cation-based basic IL that exhibit superior catalytic
activity in the synthesis of cyclic carbonates from CO2 and epoxides. The catalyst could be
re-used up to five consecutive times without much loss in the catalytic activity.

Scheme 10 A schematic for the synthesis of cyclic carbonates using a basic IL catalyst

1.15 SUMMARY
This chapter provides concise details about the fundamentals of the concepts in organic
chemistry. Chapter covers several important topics including delocalized chemical bond,
resonance, conjugation, hyperconjugation, and aromaticity etc.. Other topics such as benzenoid
and non-benzenoid compounds along with annulenes are given with logical diagrams. A variety

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of addition compounds such as inclusion compounds, catenanes, and rotaxenes are reasonably
discussed in conjunction with their synthesis and applications. Furthermore, we envisage that the
topic on ionic liquids, one of the tenets of green chemistry, may stimulate the interest of readers
to the advanced studies in organic chemistry.

1.16 References/ Bibliography

1. Wang, J.-C.; Krische, M. J. Angew. Chem., Int. Ed. 2003, 42, 5855.
2. Tanaka, K.; Ogasawara, K. Chem. Commun. 1996, 15, 1839.
3. Revial, G.; Jahin, I.; Pfau, M. Tetrahedron: Asymmetry 2000, 11, 4975.
4. D. Sam and H. E. Simmons, J. Am. Chem. Soc., 1972, 94, 4024.
5. G. W. Gokel, S. A. Dibiase and B. A. Lipiska, Tetrahedron Lett., 1976, 3495.
6. C. J. Pedersen and H. K. Friensdorff, Angew. Chem. Int. Ed., 1972, 11, 16.
7. M. Makosza and M. Ludwikow, Angew. Chem. Int. Ed., 1974, 2983.
8. K. E. Krakowiak, P. A. Krakowiak, and J. S. Bradshaw, Tetrahedron Lett., 1993, 36, 777.

1.17 Suggested Reading

1. Clayden, Organic Chemistry (English) 2nd Edition (Paperback).

2. March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th
Edition.
3. Gottfried Schill, Catenanes, Rotaxanes, and Knots, 1st edition, Academic Press.
4. Lei, Zhigang, Introduction: Ionic Liquids, Chem. Rev., 2017, 117 (10), pp 6633–6635
5. Sylvan G. Frank, Inclusion Compounds, Journal of Pharmaceutical Sciences, 1975, 64,
1585-1604.

1.18 Terminal Questions

Q.1 What is the Huckel’s rule of aromaticity of organic compounds?

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Q.2 Giving suitable examples, discuss the following

a. Cross-conjugation
b. Delocalization involving π, p-conjugation
c. Anti-aromaticity
Q.3 Write short notes on the following topics :
a. Inclusion compounds
b. Annulenes
c. Homo aromaticity
Q.4 What are cryptands?
Q.5 How to synthesize a supramolecular catenane and rotaxane?
Q.6 How will you differentiate resonance and tautomerism with suitable examples?
Q.7 What are alteranant and non-alteranant Hydrocarbons?
Q.8 What is an ionic liquid? Give synthesis and applications of Ionic Liquids?
Q.9 With suitable examples, disuss benzenoid and non-benzenoid compounds?
Q.10 Discuss Inclusion compounds with suitable examples?

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UNIT 2: STRUCTURE AND REACTIVITY

CONTENTS:
2.1 Objectives
2.2 Introduction
2.3 Types of reactions
2.4 Kinetics of reactions
2.5 Thermodynamics of the reactions
2.6 Hammon’d postulates
2.7 Curtin –Hammond principle
2.8 Reaction co-ordinate
2.9 Potential energy diagram
2.10 Transition states and intermediates
2.11 Methods of determining mechanisms
2.12 Isotope effect
2.13 Summary
2.14 Terminal questions
2.15 Answers (MCQs)
2.16 Refgerences

2.1 OBJECTIVES

The objective of this unit is to educate the students about the relation of structures with their
reactive nature. How the molecular structure influence the kinetis and therodynamics of the
[Link] know how the reaction co-ordinates represent the reaction and their thermodynamic
and kinetic progress? Generally this unit describes about the terminologies necessary for
describibg the mechanisms of organic reactions like Hammon’d postulates, Curtin –Hammond
principle, Potential energy diagram, Transition states and intermediates along with the methods
of determining mechanisms and Isotope effect.

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2.2 INTRODUCTION

Reactivity is an impetus in chemistry for which a chemikcal species undergo reaction, either by
itself or with other materials, with an overall release of output of energy. Reactivity refers to the
chemical reactions of a single substance, the chemical reactions of two or more substances that
interact with each other, the systematic study of sets of reactions of these two kinds,
methodology that applies to the study of reactivity of chemicals of all kinds, experimental
methods that are used to observe these processes theories to predict and to account for these
processes. The chemical reactivity of a single substance (reactant) covers its behavior in which it
decomposes, forms new substances by addition of atoms from another reactant or reactants and
interacts with two or more other reactants to form two or more [Link] chemical reactivity
of a substance can refer to the variety of circumstances (conditions that include temperature,
pressure, presence of catalysts) in which it reacts, in combination with the Variety of substances
with which it reacts, equilibrium point of the reaction (i.e., the extent to which all of it reacts),
rate of the reaction.

2.3 TYPES OF REACTIONS

On the basis of their reactivity there are elementary and complex reactions. Simple or elementary
reactions are those reactions in which reactants give products in a single step, like conversion of
ethyl iodide to ethyle chloride

CH3CH3I + Cl- CH3CH2Cl + I-

Simple/ elementary reaction

Likewise the complex reactions occur in multiple steps and each individual step of a complex
reaction that is proper chemical reaction in its own right is an elementary reaction viz,
conversion of tert. butyl chloride into terty. butyl alcohol with H2O is a two step reac\tion and
each step is elementary in nature

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Cl OH
-
CH3 C CH3 + OH CH3 C CH3
-
- Cl
CH3 CH3

Cl
+ -
CH3 C CH3 CH3 C CH3 Br step I
CH3 CH3
elementary reaction
OH
+
CH3 C CH3 -
+ OH CH3 C CH3 step II
CH3 CH3
elementary reaction

Similarly the concerted reactions are those reactions in which bond formation between attacking
group and bond breaking between leaving group takes place simultaneously. The concerted
reactions are facilitated by transition states.
H H
H C I Cl C H + I-
attacking group Cl- H H
Substrate leaving group

2.4 KINETICS OF REACTIONS

Kinetic study of the reactions deal with the rate of reactions and their dependence on the
concentration of the various reacting species. In contrast to thermodynamics time is very
important variable parameter in kinetics. Chemical kinetis is an important technique to
investigate the mechanism of chemical reactions. Thermodynamically it is mentioned that
change in free energy ∆G tells only relative difference between the stability of the reactants and
the stability of the products. It does not tell anything about the energy barrier of the reaction. The
energy barrier is the energy barrier that must be crossed for the reactants to be converted into the
products. The higher the energy barrier, the slower is the reaction. The energy barrier is indicated
by ∆Gǂ or Ea and is called enery of activation. It is represented as follow

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Ea or ∆Gǂ = (free energy of the T.S.) – (free energy of the reactants)

The greater the Ea, the slower is the reaction. ∆G and ∆Gǂ both are enthalpy components and
entropy components. Notice that any component that relates to thev T.S. is represented by the
symble (ǂ = double dagger)
∆Gǂ = ∆Hǂ - T∆Sǂ

∆Hǂ = (enthalpy of the T.S) – (enthalpy of the reactants)

∆Sǂ = (entropy of the T.S) – (entropy of the reactants)
The relative stability of reactant and product does not define the feasibility of any reaction all by
itself. For any reaction to proceed the starting material must have enough energy to cross over an
energy barrier (∆G≠) and the rate of reaction is dependent on the height of this barrier. A low
energy barrier corresponds to a fast reaction and high energy barrier corresponds to a slow
reaction. A reaction is in equilibrium when the rate of forward reaction is equal to the rate of
reverse reaction. Such a reaction is said to be reversible. In principle, all the reactions are
reversible but in some cases the equilibrium lies so much towards the product side that it is
impossible to see the starting material Fig. 1 describes the relation between ∆G0 the free energy
change and ∆Gǂ (energy barrier) –ve value of ∆G0 indicates exergonic reaction while the +ve
∆G0 show endergonic reaction
Fig
1

Reaction Coordinate Diagrams showing favorable or unfavorable and slow or fast reactions
Exergonic reaction: The reactions which releases more energy into the system than it consumed

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from the system is called exergonic reaction. Is such reactions ∆G of the product is less than the
∆G of the product, for exergonic reaction ∆G0 = -ve
Endergonic reactions: If products have a higher energy than the reactants, ∆G0 will be
positive and the reaction will consume more energy from system than is released into the system.
For exergonic reaction ∆G0 = +ve
It must be noticed that ∆G relates the equilibrium constant of the reaction , where ∆Gǂ relates the
rate of the [Link] thermodynamic stability of a compound is indicated by ∆G0 Viz; if ∆G
is negative, the product is thermodynamically stable compared to reactant and if ∆G is positive
than the product will be thermodynamically unstable compared to reactant. The kinetic stability
of a compound is indicated by ∆Gǂ. If it is large, the compound is kinetically stable. In other
words, it is not very reactive, while if ∆Gǂ is small, the compound is kinetically unstable (it is
reactive)
The rate of reaction depends on the following factors;
1. The number of collisions that takes place between the reacting molecules in a given period of
[Link] greater is the number of collisions, the faster of the rate of reaction
2. The fraction of collisions that occur with sufficient energy to get the reacting molecule over
the energy barrier. Smaller the energy of activation/energy barrier (Ea or ∆Gǂ) more of the
collisions will lead to reaction and large the energy of activation/energy barrier(Ea or ∆Gǂ) less
collisions will lead to the reaction.
3. The fraction of the collision that occur with proper orientation, viz; tn the reaction of
CH3CH=CHCH3 with HBr, reaction will occur only if the molecule collide with H of HBr
approaching the π –bond of CH3CH=CHCH3. If collision occurs with H approaching the methyl
group of CH3CH=CHCH3, no reaction will take place regardless of the energy of collision
Rate of reaction = Number of collision/unit of time × Fraction with sufficient energy × Fraction
with proper orientation

Increasing the temperature enhance the motion of the molecule. This increase the rate of reaction
because it increase the number of collisions that occur in a given period of time and it increases
the number of collisions that have sufficient energy to get the reacting molecules over energy
barrier.
Ist order reaction: Reactions in which single reactant (R) molecule is converted into a product

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(P), in such reaction rate of reaction is proportional to the concentration of reactant. if the con. of
R is increased the rate of reaction will be double and if it is increased to triple, the rate of
reaction will also be triple
R P
R = f (P)
Rat = f (R)
Rate = k [R]
k = proportionality constant known as rate constant.
IInd order reaction: Reaction whose rate of reaction dependends upon the concentrations of
two reactants say R and S. If the concentration of R or S is doubled, the rate of the reaction will
double. If the concentration of both R and S are doubled, the rate of the reaction will increase by
afactor of 4. The rate constant is second order rate constant.
R+ S P+Q
Rate = k[R] [S]
It is essential to understand the difference between rate of reaction and rate constant.
A. The reaction rate is ameasure of the amount of product that is formed/unit time. That is what
we actually measure in the laboratory.
B. The rate constant (k) tells us how easy it reach to the T.S. (how easy it crocss the energy
barrier).
The smaller the free energy of activation ∆Gǂ , the greaterthe rate constant i.e. low energy
barriers are associated with large rate constant, whereas high energybarriers have smaller rate
constant. From the following reaction co-ordinate (fig.2) the concept of rate of reaction and rate
constant can easily be predicted.

k
A B
k
C D
E
a G b
G

P ro g ress o f reac tio n P ro g re ss o f re actio n

a = A re actio n w ith larg e rate c on stan t k b = A rea ctio n w ith a sm a ll rate co n stan t k
Fig.2 Reaction coordinates for rate constant

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The second defference is that the reaction rates are dependent on concentration while rate
constant are concentration independent of concentration. The rate constant is temperature
dependent. i.e. increasing the temperature increase the rate constant. The Arrhenius equation
relates the rate constant of areaction of a reaction to the energy of activation and to the
temperature at which the reaction is carried out.
The Arrehenius equation is:
k = Ae-Ea/RT
or log10 k = log10 A –Ea/2.303RT
Where k = rate constant, Ea = experimental energy of activation, R = gas constant, T = absolute
temperature, a = frequency factor

2.5 THERMODYNAMICS OF THE REACTIONS

All chemical reactions are reversible and reactant and products interconvert to different degree.
A state is said to be in equilibrium if the concentration of both reactant and product do not
change. In most of the cases the equilibrium lies on the side of the [Link] this happens, the
reaction is said to have gone to [Link] such case the arrow indicating reversible reaction
is generally omitted chemical reaction proceeds when products are more stable than
[Link] equliberium constant depends upon the enthalpy change (∆H) and on entropy (∆S).
When entropy change is taken with absolute temperature (T) it gives the free energy change
(∆G) as follow;
∆G = ∆H - T∆S
It should be noted that a reaction proceeds in the forward direction only when ∆G of the reaction
is negative. A positive ∆G, on the other hand indicates that the reaction has a tendency to go
backward.
The relationship between the equilibrium constant (k) and ∆G0 is given as follow:
∆G0 = - RT ln K
Where k = equilibrium vonstant, R = gas constant, T = Absolute temperature
Consicely it can be predicted as:
Equilibria In Organic Reactions (Thermodynamics)

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The equilibrium of a reaction describes how much of a particular reactant

Will be converted to product during the course of the reaction.
A. Equilibrium constant and the Gibbs Free-energy equation
1. The equilibrium constant (Keq) is the molar ratio of products over reactants.
2. The Gibbs free energy equation relates the equilibrium constant to the energy required for the
reaction to occur.
∆G° = ∆H° - T∆S° or ∆G° = -RT lnKeq
a. (∆H°): The bond dissociation energy is the total energy required to homolytically break a bond
into two radicals at 25°C in the gas phase.
b. (∆S°): The entropy factor is the total disorder caused by a given reaction.
B. Equilibria and reaction energy diagrams:
1. A reaction energy diagram describes the relative energies of all species involved in a reaction
and how that reaction proceeds.
2. The free-energy (∆G°) is the energy difference between reactants and products.
a. A negative ∆G° indicates the products are more stable than the reactants (exothermic
reaction).
b. A positive ∆G° indicates the reactants are more stable than the products (endothermic
reaction).
Thermodynamics vs Kinetics
Thermodynamicsis all about “if”
• If a process or a reaction can occur or not
• If a systems is in stable or metastable equilibrium
• If sufficient driving force is present to enforce a favourable transformation
Kinetics is all about “how”
• How fast or slow a process can occur, i.e., determining the rate
• How transition from nonequilibrium to equilibrium systems or between two equilibrium states
occurs
• How to overcome the energy barrier to finish the transformation from the starting (reactant)
state to the final (product) state.
For a reactionirreversible under mild conditions and reversible under vigorous conditions at a
certain temperature one product changes to another. At this particular temperature there is

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change between a kinetic and a thermodynamic product (fig 3)

Thermodynamics Kinetics
Talks about how stable a material (or system) Considers how quickly or slowly a change
is in one state can occur
Tells that a reaction should go if the products Tells how fast the reaction will go, it doesn't
are more stable (have a lower free energy) tell anything about the final state.
than the reactants i.e,the reaction has a
negative free energy change.
The most stable state of a thermodynamic The most stable states of a kinetic reaction
reaction is that of being in the state of are those of the reactants, in which an input
products, because the reaction will happen of energy will be required to move the
Spontaneously, without the need for energy reaction from a state of stability, to that of
to be added to make the reaction go forward. reacting and converting itself to products.
Thermodynamics is related to stability. Kinetics is related to reactivity.
At high temperature, the reaction is under At low temperature, the reaction is under
Thermodynamic control (equilibrium, kinetic control (rate, irreversible conditions)
reversible conditions) and the major product and the major product is that from fastest
is the more stable system. reaction.
The thermodynamic product is the most The kinetic product is the product that is
stable product.
formed most rapidly
The thermodynamic product predominates The kinetic product predominates when the
when the reaction is reversible
reaction is irreversible (kinetic control)
thermodynamic control)

B is b o th th e k in e tic a n d A is k in e tic p ro d u c t w h ile

th e rm o d y n a m ic p ro d u c t B is th e rm o d y n a m ic p ro d u c t

S m a ll p re fe re n c e fo r A
u n d e r k in e tic c o n tro l P refe ren c e o f A u n d e r
k in e tic c o n tro l
E
E

L arg e p refere n c e fo r B u n d e r P re fere n ce o f B u n d er

th e rm o d y n a m ic c o n tro l th e rm o d y n a m ic c o n tro l

P ro g re s s o f re a c tio n P ro g re s s o f re a c tio n

Fig .[Link] profile for a thermodynamic and kinetic product

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Selected Examples of thermodymanicallyand kinetically controlled reactions

Addition of HCl to conjugated dienes
The addition of HCl to 1,3- butadiene can give two products one is 1,2-and another is 1,4-
addition product. The amount of each will depend upon the reaction conditions.
The 1,2- product is called kinetic product and 1,4-is thermodynamic product.

H H
+ HCl +

Cl
Cl
1, 3
_ butadiene
1, 2 - addition product 1, 4 - addition product
kinetic product thermodynamic product
At low temperature -80 or 0 oC the kinetic product is obtained as major due to low Ea. While at
high temperature 40-45oC the thermodynamic product is major, due to greater [Link] 1,4-
addition product is more stable as greater the number of alkyl groups attached to a sp2 carbon
more stable it is (more substitute alkene). But, 1,2-addition product is formed faster, as the
transition state for formation of 1,2-product is more stable(fig. 4 ). The transition state for 1,4-
addition has positive charge is on lesssubstituted carbon,therefore its activation energy is large
and formed slowly. Whereas, thetransition state for 1,2-addition has positive charge on more
substituted carbon, and has lesser activation energy thus formed faster.

H H
- 80 0C
+ HCl +

Cl
Cl
1, 3
_ butadiene
1, 2 - addition product 1, 4 - addition product
80 % 20%

H H
45 0C
+ HCl +

Cl
Cl
1, 3
_ butadiene
1, 2 - addition product 1, 4 - addition product
15% 85%

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1, 4
1,2

Ea 1, 4
Ea 1, 2

CH3 CH CH CH2
E 0
H 1,2 +
Intermediate Major product
0 at 40 0 C
H 1,4
CH3 CH CH CH2
Cl
major product
,
1 2 product
- 80 0 C or at 0 0 C
(formed faster) CH3 CH CH CH2Cl
Fig.4:

Reaction co ordinate
Reaction coordinate diagram for addition of HCl to 1,3-butadiene{‡(1,2) represents
Transition state for 1,2-addition; ‡(1,4) represents transition state for 1,4-addition}

2.6 HAMMON’D POSTULATES

“If two states, for example, a transition state and an unstable intermediate, occur consecutively
during a reaction process and have nearly the same energy content, their interconversion will
involve only a small reorganization of the molecular structures”
The structure of the transition state for an exothermic reaction is reached early in the reaction, so
it resembles reactants more than products. Conversely, the structure of the transition state for an
endothermic reaction step is reached relatively late, so it resembles products more then
reactants.”
• In reactions where the starting material is higher in energy(A), the transition state more
closely resembles the starting material
• In reactions where the product is higher in energy(B), the transition state more closely
resembles the product (fig.5)
• Explanation: Effectively, the postulate states that the structure of a transition state
resembles that of the species nearest to it in free energy. This can be explained with

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reference to potential energy diagrams (fig.6):

T .S .

In th is c a s e (e x o th e rm ic re a c tio n ) th e e n e rg y o f th e T .S . m o re re se m b le w ith th e
e n e rg y o f re a c ta n t (R ) ra th e r th a n th e e n e rg y o f in te rm e d ia te (I) o r p ro d u c t (P )
H e n c e a c c o rd in g to th e p o s tu la te th e g e o m e try o f th e T .S . m o re c lo se ly re se m b le
E to th a t o f th e re a c ta n t Fig. 5
R = R e a c ta n t reaction coordinate for Hammond,s postulate
I = In te rm e d ia te

P = p ro d u c t

P ro g re ss o f th e re a c tio n

T .S .

E In th is c a se e n e rg y o f T .S . c lo se to n e ith e r th e re a c ta n t n o r th e p ro d u c t, m a k in g n o n e o f th e m
a g o o d s tru c tu ra l m o d e l fo r th e T .S . F u rth e r in fo rm a tio n is n e e d e in o rd e r to p re d ic t th e th e
g e o m e try o r c h a ra c te ris tic o f th e T .S .

R = R e a c ta n t

I = In te rm e d ia te

P = p ro d u c t

P ro g re s s o f th e re a c tio n
T .S .
R = re a c ta n t

I = in te rm e d ia te

P = P ro d u c t
E
T h is e n e rg y d ia g ra m d e p ic t th e e n d o th e rm ic re a c tio n a n d th e e n e rg y o f T .S . m o re c lo s e ly
re s e m b le to th e e n e rg y o f in te rm e d ia te (I) o r p ro d u c t (P ). a c c o rd in g to th e H a m m o n d 's p o stu la te
th e g e o m e try o f th e T .S . w o u ld m o re c lo se ly re se m b le w ith th e g e o m e try o f in te rm e d ia te /p ro d u c t

P ro g re s s o f re a c tio n
Fig.6. Interpretation of Hammond’s postulates

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The significance of Hammond’s postulate is that it explain the T.S. in terms of the reactants (R),
intermediates (I) , or products( P). If the T.S. more closely resembles the reactants, the transition
state is called “early” T.S. and if it resembles more with the intermediate or the product, it is
called “late” T.S.
Chlorination is the good example of early T.S. as it favors the products because exothermic
nature, i.e. products is lower in energy than the reactants. When we look at the adjacent diagram
(representation of an "early" transition state), one must focus on the transition state, which is not
able to be observed during an experiment. To understand what is meant by an “early” transition
state, the Hammond postulate represents a curve that shows the kinetics of this reaction. Since
the reactants are higher in energy, the transition state appears to be right after the reaction starts.
Similarly bromination is an example of late T.S. Bromination favors the reactants because it is
an endothermic reaction, which means that the reactants are lower in energy than the products.
Structure of transition states:
SN1 reactions: Hammond's postulate can be used to examine the structure of the transition states
of a SN1 reaction. In particular, the dissociation of the leaving group is the first transition state in
a SN1 reaction. The stabilities of the carbocations formed by this dissociation are known to
follow the trend:

CH3 CH3
CH3 C CH CH3 CH2 CH3
CH3 CH3

Stability order

Since the tertiary carbocation is relatively stable and therefore close in energy to the R-X
reactant, then the tertiary transition state will have a structure that is fairly similar to the R-X
reactant. In terms of the graph of reaction coordinate versus energy, this is shown by the fact that
the tertiary transition state is further to the left than the other transition states. In contrast, the
energy of a methyl carbocation is very high, and therefore the structure of the transition state is
more similar to the intermediate carbocation than to the R-X reactant. Accordingly, the methyl
transition state is very far to the right fig.7.

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CH3

CH3 CH2

CH3
CH Stability order
CH3

CH3
CH3 C
CH3

Fig. 7 Reaction coordinates for SN1 and SN2 reactions

SN2 reactions: SN2 reactions are concerted reactions, the reaction occurs in one step, where the
bonds are broken, while new bonds are formed. Therefore, to interpret this reaction, it is
important to look at the transition state, which resembles the concerted rate limiting step. In the
"Depiction of SN2 Reaction" figure, the nucleophile forms a new bond to the carbon, while the
halide (L) bond is broken.
E1 reactions: An E1 reaction consists of unimolecular elimination, where the rate determining
step of the mechanism depends on the removal of a single molecular species. This is a two-step
mechanism. The more stable the carbocation intermediate is, the faster the reaction will proceed,
favoring the products. Stabilization of the carbocation intermediate lowers the activation energy.

The reactivity order is (CH3)3C- > (CH3)2CH- > CH3CH2- > CH3

Furthermore, studies describe a typical kinetic resolution process that starts out with two
enantiomers that are energetically equivalent and, in the end, form two energy-inequivalent

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intermediates, referred to as diastereomers. According to Hammond's postulate, the more stable

diastereomer is formed faster (fig.8)

Progress of recation

Fig. 8: Unimolecular Elimination Reaction Coordinate

E2 reactions: E2 reactions are one step, concerted reaction where both base and substrate
participate in the rate limiting step. In an E2 mechanism, a base takes a proton near the leaving
group, forcing the electrons down to make a double bond, and forcing off the leaving group-all in
one concerted step. The rate law depends on the first order concentration of two reactants;
Factors that affect the rate determining step are stereochemistry, leaving groups, and base
strength.
A theory, for an E2 reaction, by Joseph Bunnett suggests the lowest pass through the energy
barrier between reactants and products is gained by an adjustment between the degrees of Cβ-H
and Cα-X rupture at the transition state. The adjustment involves much breaking of the bond
more easily broken, and a small amount of breaking of the bond which requires more energy.

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This conclusion by Bunnett is a contradiction from the Hammond postulate. The Hammond
postulate is the opposite of what Bunnett theorized. In the transition state of a bond breaking step
it involves little breaking when the bond is easily broken and much breaking when it is difficult
to break. Despite these differences, the two postulates are not in conflict since they are concerned
with different sorts of processes. Hammond focuses on reaction steps where one bond is made or
broken, or the breaking of two or more bonds occur simultaneously. The E2 theory transition
state concerns a process when bond formation or breaking is not simultaneous
Applications of Hammonds postulates:
1. It can be inferred from Hammond's postulate is that it is useful for understanding the
relationship between the rate of a reaction and the stability of the products. The rate of a reaction
depends just on the activation energy (∆G‡), while the final ratios of products in chemical
equilibrium depends only on the ∆G. The ratio of the final products at equilibrium corresponds
directly with the stability of those products.
2. Hammond's postulate is helpful for structural comparison between the starting materials,
products, and the possible "stable intermediates" that led to the understanding that the most
stable product is not always the one that is favored in a reaction process.

3. Hammond's postulate is especially important we look at the rate-determining step of a

reaction. However, one must be cautious when examining a multistep reaction or one with the
possibility of rearrangements during an intermediate stage. In some cases, the final kinetic
productare more stable product than the thermodynamic product. In this case one must examine
the rate-limiting step and the intermediates. Often, the rate-limiting step is the initial formation of
an unstable species such as a carbocation. Then, once the carbocation is formed, subsequent
rearrangements can occur. In these kinds of reactions, especially when run at lower temperatures,
the reactants simply react before the rearrangements necessary to form a more stable
intermediate have time to occur. At higher temperatures when microscopic reversal is easier, the
more stable thermodynamic product is favored because these intermediates have time to
rearrange. Whether run at high or low temperatures, the mixture of the kinetic and
thermodynamic products eventually reach the same ratio, one in favor of the more stable
thermodynamic product, when given time to equilibrate due to microreversal.

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2.7 CURTIN –HAMMOND PRINCIPLE

The Curtin–Hammett principle deals with the systems in which different products are formed
from two substrates in equilibrium with one another. The rapidly interconverting reactants can
have any relationship between themselves like stereoisomers, constitutional isomers,
conformational isomers, etc. Product formation must be irreversible, and the different products
must be unable to interconvert.
For example, given species A and B that equilibrate rapidly while A turns irreversibly into C,
and B turns irreversibly into D:
K
k1 k2
C A B D
Product from A Product from B
Two substrate
at equlibrium

K = equlibrium constant between A and B

k1 = Rate constant for the fromation C from D

k2 = Rate constant for the formation of D from B

If the rate of interconversion between A and B is much faster than either k1 or k2, then the
Curtin–Hammett principle tells us that the C:D product ratio is not equal to the A:B reactant
ratio, but is instead determined by the relative energy of the transition states. If reactants A and B
were at identical energies, the product ratio would depend only on the activation energy of the
reactions leading to each respective product. However, in a real scenario, the two reactants are
likely at somewhat different energy levels, although the barrier to their interconversion must be
low for the Curtin–Hammett scenario to apply. In this case, the product distribution depends both
on the relative quantity of A and B and on the relative activation barriers to the corresponding
products C and D.

The ratio of products only depends on the value labeled ∆∆G‡ in the figure: C will be the major
product, because the energy of TS1 is lower than the energy of TS2. The commonly made
assertion that the product distribution does not in any way reflect the relative free energies of
substrates A and B is incorrect; it reflects the relative free energies of the substrates and the
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relative activation energies. As shown in the derivation below, the product ratio can be expressed
either as a function of K, k1, and k2, or as a function of ∆∆G‡.(fig.9)

K
k1 k2
C A B D

Product from A Two substrate Product from B

at equlibrium

E/G

Reaction coordinate
Fig.9. Reaction coordinate for Curtin –Hammond,s princilpal
Classes of reactions under Curtin–Hammett control
There are three main classes of reactions that can be explained by the Curtin–Hammett principle.
A. One category of reactions under Curtin–Hammett control includes transformations in which
the more stable conformer reacts more quickly. This occurs when the transition state from the
major intermediate to its respective product is lower in energy than the transition state from the
minor intermediate to the other possible product. The major product is then derived from the
major conformer, and the product distribution does not mirror the equilibrium conformer
distribution. Viz; oxidation of piperidines. In the case of N-methyl piperidine, inversion at
nitrogen between diastereomeric conformers is much faster than the rate of amine oxidation. The
conformation which places the methyl group in the equatorial position is 3.16 kcal/mol more
stable than the axial conformation The product ratio of 95:5 indicates that the more stable
conformer leads to the major product

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N N

Less stable More stable

H2O2
H2O2

O
N O
N

Minor product
Major product

B. A second category of reactions under Curtin–Hammett control includes those in which the
less stable conformer reacts more quickly. In this case, despite an energetic preference for the
less reactive species, the major product is derived from the higher-energy species. An important
implication is that the product of a reaction can be derived from a conformer that is at
sufficiently low concentration as to be unobservable in the ground state.

The alkylation of tropanes with methyl iodide is a classic example of a Curtin–Hammett scenario
in which a major product can arise from a less stable conformation.[ Here, the less stable
conformer reacts via a more stable transition state to form the major product. Therefore, the
ground state conformational distribution does not reflect the product distribution.

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CH3
CH3 N
N
rapid

interconvesrion
Less stable More stable

13
13 slow CH3 I
CH3 I fast
13
13 CH3 CH3
CH3 CH3 N
N

Minor product
Major product

C. It is hypothetically possible that two different conformers in equilibrium could react through
transition states that are equal in energy. In this case, product selectivity would depend only on
the distribution of ground-state conformers. In this case, both conformers would react at the same
rate.
Ernest L. Eliel has proposed that the hypothetical reaction of cyclohexyl iodide with radiolabeled
iodide would result in a completely symmetric transition state. Because both the equatorial and
axial-substituted conformers would react through the same transition state, ∆∆G‡ would equal
zero. By the Curtin–Hammett principle, the distribution of products should then be 50% axial
substituted and 50% equatorial substituted. However, equilibration of the products precludes
observation of this phenomenon.
I

L e s s s ta b le
M o re s ta b le

S N2 I H
I* H S N
2
I* v ia I*
v ia I*
I

H y p o th itic a l p ro d u c t r a tio 1 :1

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The Curtin–Hammett principle is used to explain the selectivity ratios for some stereoselective
reactions.
Application to dynamic kinetic resolution
The Curtin–Hammett principle can explain the observed dynamics in transformations employing
dynamic kinetic resolution, such as the Noyori asymmetric hydrogenation and enantioselective
lithiation.
Noyori asymmetric hydrogenation
Rapid equilibration between enantiomeric conformers and irreversible hydrogenation place the
reaction under Curtin–Hammett control. The use of a chiral catalyst results in a higher-energy
and a lower-energy transition state for hydrogenation of the two enantiomers. The transformation
occurs via the lower-energy transition state to form the product as a single enantiomer.[14]
Consistent with the Curtin–Hammett principle, the ratio of products depends on the absolute
energetic barrier of the irreversible step of the reaction, and does not reflect the equilibrium
distribution of substrate conformers. The relative free energy profile of one example of the
Noyori asymmetric hydrogenation is shown below:

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(R) - BINAP- Ru
(S) - ketoester

(R) - BINAP - Ru
(R) - ketoester

3
4
2

1 5

Progress of reaction
O O- O O O
O
(R) - BINAP - Ru
(R) - BINAP - Ru OCH3 OCH3
OCH3
H2 H2
2 4
3
fast slow

OH O
OH O
OCH3
OCH3

1 5
Anti observed product
Syn not observed

2.8 REACTION CO-ORDINATE

During the course of reactions energy change takes place, as the erwactant are converted to
products. This reactant to product conversion can be visualized by using coordinate diagrams
known as enery coordinate or energy profile diagram. In energy profile diagrams the energy of
the reaction involved is plotted against the progress of the reactions or reaction coordinate
Generally a chemical reaction progresses from left to right starting with the reactant and ending

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with the products. In energy profile diagram the energy of the reactant is plotted on left side on
the x-axis and that of product is plotted on the right side on the x-axis. Thermodynamically the
stability of the species on diagram is indicated by lower energy. A typical reaction coordinate
diagram of the following reaction can be depicted in fig.10

CH3 I + Cl- CH3 Cl + I-

T .S .

S in g le fre e e n e rg y b a rrie r

Cl + CH3 I
CH3 Cl + I

P r o g r e s s o f th e r e a c tio n

Fig.10 reaction coordinate diagram for the reaction between CH3-I and Cl-
There are many reactions in organic chemistry which takes place in steps with the involment of
short lived reactive species known as reaction intermediate and follow more than one T.S. to
convert the final product. Such reactions can be represented as in fig. 11 (a-b) energy profile
diagram. The thermodynamic stability of products and intermediates can be indicated by low
energy

T .S . T .S .

P
R

S ta rt R e a c tio n End
p ro g re s s

Fig.11a reaction coordinate diagram for multistep reactions

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T.S.
Multistep reaction involving intermediate
T.S. A C E

E R = reactant
P1 C = product P1 obtained from A
via T.S. B
R
P2 E = product P2 obtained from C (P1)
via T.S. D
Reaction coordinate
Fig.11 b reaction coordinate diagram for multistep reactions

2.9 POTENTIAL ENERGY DIAGRAM

In a chemical reaction, some bonds are broken and some bonds are formed. During the course of
the reaction, there exists an intermediate stage, where chemical bonds are partially broken and
partially formed. This intermediate exists at a higher energy level than the starting reactants; it is
very unstable and is referred to as the transition state. The energy required to reach this transition
state is called activation energy. We can define activation energy as the minimum amount of
energy required to initiate a reaction,
An potential energy diagram can be defined as a diagram showing the relative potential energies
of reactants, transition states, and products as a reaction progresses with time. Viz; in energy
potential diagrams for endothermic reaction, the reactants are at a lower energy level compared
to the products—as shown in the energy diagram below. In other words, the products are less
stable than the reactants. Since we are forcing the reaction in the forward direction towards more
unstable entities, overall ∆H for the reaction is positive, i.e., energy is absorbed from the
surroundings. In the case of an exothermic reaction, the reactants are at a higher energy level as
compared to the products, as shown below in the energy diagram. In other words, the products
are more stable than the reactants. Overall ∆H for the reaction is negative, i.e., energy is released
in the form of heat (fig.12)

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Exothermic recation R= reactant R= reactant

Endothermic recation
P= product P= product
T.S. T.S.
T.S. = Transition state T.S. = Transition state

Potential Potential
energy energy
R Energy P
E act. _ released
H Eact. + H Energy
P R absorbed

Progress of reaction Progress of reaction

Fig.12 Energy coordinate diagram for eno and Exothermic reactions

2.10 TRANSITION STATES AND INTERMEDIATES:

The concerted reactions takes place in a single step in which bond breaking and bond formation
takes place with the involvement of thermodynamically unstable state having a particular
configuration along the reaction coordinate known as transition state. The transition state of a
chemical corresponding to the highest potential energy along the reaction coordinates. Similarly
a reaction intermediate is a molecular entity which is formed from the reactants or preceding
reaction intermediates (multisteped reactions) and reacts further to give the directly observed
products of a chemical reaction.
The reaction intermediates are generated in either unimolecular reactions like SN1 or in
bimolecular reactions like E1cb. The important characteristics of reaction intermediates is that
they are real chemical species with finite life [Link] are highly reactive and undergo
chemical reaction and may occasionally be trapped by suitable reagent or observed
spectroscopically. The intervention of reaction intermediates in a mechanism of chemical
reaction is represented by a local minimum in potential energy diagram. Activated complex and
T.S. are represented by maxima in the reaction coordinate and are intrinsically different from
reaction intermediates fig.13.a -b

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T.S.1
T.S.2

CH3
CH3 C Br
Potential
energy CH3
Reaction
Reactant
intermediate

Product
CH3
CH3
CH3 C Br +
HOH
CH3 C OH + Br
CH3
CH3

Reaction progress

Fig.13. a. reaction coordinate diagram for atwo step reaction (SN1)

T .S .1
T .S .2

P o te n tia l -
Br F e B r4
en erg y
R e a c tio n
R e a c ta n t in te rm e d ia te

P ro d u c t

F e B r3 Br
+ B r2
+ HBr + F e B r3

R e a c tio n p ro g re s s

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Fig.13. b. reaction coordinate diagram for atwo step reaction (electrophilic substitution)

2.11 METHODS OF DETERMINING MECHANISMS:

There are a number of commonly used methods for determining mechanisms. In most cases, one
method is not sufficient and the problem is generally approached from several directions.
1. Identification of products
Any mechanism proposed for a reaction must account for all the products obtained and their
relative propor tions. A proposed mechanism cannot be correct if it fails to predict the products
in approximately the observed [Link]; (i) Identification of hydroperoxide
hydroperoxide ROOR as a major product of autooxidation of simple hydrocarbons lead to the
concept of free radical mechanism.

RH + O O R + OOR

R+ O O OOR

RH + OOR R O O R + R
(ii) Hydrolysis of isomeric allyl chloride (I) and (II) as follow gives 85% of 30 alcohol and 15%
of 10 alcohols. From this reaction it can be inferred that the a common mechanism is being
followed as the composition of the products remains the same in either cases

OH
Cl
15 %

HO
Cl
85 %
(iii) A little ethane accompanies CH3Cl when CH4 is chlorinated in the presence of hv.
Hexafluroethane is similarly a by product when flurone reacts with CH4 Free radical mechanism
accounts for these facts readily but ionic mechanism cannot.
hv
Cl2 Cl + Cl hv
F2 F + F
CH3 H + Cl CH3 + HCl CH3 H + F CH3 + HF
CH3 + Cl2 CH3 Cl + Cl CH3 + F2 CH3 F + F
CH3 + CH3 CH3 CH3
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CF3 + CF3 CF3 CF3
hexafluroethane
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(iv) Toluene and chlorine give benzyl chloride in presence of light, but ortho and para-
chlorotoluene in presence of iron or iodine at boiling temperature. The different product from the
same reactant under different conditions indicates different mechanisms. In fact, the former
follows free radical pathway and the latter, an iononic mechanism.

CH3 hv
CH2Cl

+ Cl2 + HCl
Fe or I
CH3 + Cl CH3

Cl
(v) Acetaphenone reacts with hydroxylamine to form two oxime isomers as
N-methybezamide I and N-phenylacetamide II in Beckmann rearrangemen (takes place in
presence of H2SO4/ SOCl2/ PCl5). This rearrangement reaction indicates that there is atrans
migration of the groups with respect to hydroxyl group of the oxime.

O
H+ C CH3 C CH3
C CH3 + NH2OH +
heat HO N N OH

SOCl2
SOCl2

O O
CH3 N C CH3 C N
H H
I II

2. Determination of Prescence of an Intermediate: One or more reaction intermediates are

formed in complex reactions; they may be detected by physical methods if isolated. Some times
the intermediates may be trapped by chemical reaction with an added compound and the
compound is known as trapping agent. Reaction kinetics in some cases indicates the formation of
an intermediate.

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(i) Isolation of an Intermediate: An intermediate can be isolated from a reaction mixture by

stopping the reaction after a short time or by the use of very mild conditions. If the isolated
compound gives the same product when subjected to the reaction conditions and at a rate no
slower than the starting compound, this gives strong evidence that the reaction involves that
intermediate. Viz; (i) isolation of intermediates N-bromoamide (A) its anion (B) and isocyanate
(C) during the formation of primary amine RNH2 from amide by Hoffmann rearrangement is one
of few cases. These can be readily converted into RNH2. Thus any proposed mechanism for this
rearrangement must account for the formation of all these intermediates.

O O
NaOBr R NH2
R C NH2 R NH2 R C N Br
or Br2/NaOH
B
O
NaOBr HOH R NH2
R C NHBr R NH2 R N C O
A C
(ii) Biomolecular aromatic nucleophilic substitution reaction takes place by the formation of
cyclohexadienylide anion (also known as Meisenheimer complex or σ complex)
X Nu
X Nu

+ Nu + X

In most of the cases the intermediates have been isolated from the reaction. Viz; the slat (A)

formed either by the action of C2H5OK on 2, 4, 6-trinitroanisole or CH3OK on trinitrophenetol

OCH3 H3CO OC2H5 OC2H5

NO2 NO2 NO2 NO2 NO2 NO2
C2H5OK CH3OK
- 78 0 C - 78
0
C
NO2 NO2 NO2
(iii) Biomolecular aromatic E+ (A) substitution reactions takes
place through benzenium ion (σ- complex) formation. Some stable σ- complexes as (B) and (C)

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have been isolated from the reaction mixture and also prepared in the form of salts.

H
E
+ + E
E + H+
CH3 CH3

HF/BF3
- 78
0
C
+ BF4
H3C CH3 H3C CH3
H H
(B)
CF3 CF3
HF/BF3
0
- 78 C + BF4
H3C NO2 H3C NO2
H
(C)

3. Detection of an intermediate: Intermediates can be detected by IR, NMR, or some other

spectra. For example, the detection of NO2+ by Raman spectra was regarded as strong evidence
that this is an intermediate in the nitration of benzene. Free radicals and triplet intermediates can
be detected by ESR and CIDNP (chemically induced dynamic nuclear polarization)
NMR- spectroscopy is a powerfull and versatile tool for detecting organic reaction intermediates.
1
H-NMR is most useful because it provides the greatest sensitivity of the nuclei of intrest in
13
organic chemistry. C is less sensitive but development high field instruments and the use of
FT-methods have greately enhanced the sensitivity so that NMR can be used to detect
characteristic signals of reaction intermediates.

4. Trapping of an intermediate: In some cases, the intermediates may react with a certain
compound in a given way. The intermediate can be trapped by running the reaction in the
precsence of that compound. For exampe, (i) benzyne react with dienes in the Diels-Alder
reaction. The detection of the Diels - Alder adduct indicate that the benzyne was probably
present.

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+ O O

triptycene a highely
stable compound
Aromatic Nu- substitution reaction of chlorobwenzene in the presence of NaNH2 takes place
through the formation of benzyne as areaction intermediate. In this reaction formation of
benzyne has been confirmed by trapping it with anthracene
Cl

NaNH2/NH3(l)
triptycene a highely
stable compound
heat
Isotopic Labeling

Independent existence of benzyne has been confirmed as follow.

O
COOH COOH
NaNO2/Con. HCl
OH O
0
0 C
NH2 N N
N N

Dimerisation

Benzyne cannot be isolated as (A) it react itself to

(B)
form dimer having a four membered ring between two benzene rings. If the Zwitterion is injected
into a mass spectrometer, there is a peak at M/z 152 corresponding for dimer (B) but also astrong

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peak at M/z 76 is of benzyne itself (A) fig .14. The lifetime of a particle in MS is about 20 nano-
seconds so the benzyne can exist for at least that long time in the gas phase.
100

Natural
abundance 152
50
(%) 56

m/z

Fig.14. Representation of mass spec trum of benzyne reaction intermediate

(ii) Trapping of alkene with carbine inidate the formation of carbine intermediate as when
alkenes are treated with carbine, acyclopropane ring is formed. Carbene exists in singlet and
triplet form the stereoselective reactions of carbine with alkene is indicative of type of carbine
reaction intermediate as follow.
R H
R H

H trans R
H R
trapping trans product from trans alkene
trans alkene CH2
R R singlet carbene R R

H H H cis H
cis alkene cis product from cis alkene

R H

H R
R H R R
trapping
trans alkene CH2 +

R R triplet carbene H R H H
trans cis
H H
cis alkene Both the products from either of alkene

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(iii) Trapping reagent of nitrenes is benzene. It react with nitrenes to give ring expended product
and/or N-

.. H
+ RN.. H+
N R NHR

NHR

N H

azepine

substituted anilines. Both type of products are formed by intial nitrene attack on the π- system of
benzene.
5. Isotopic labeling: Informations about the reaction mechanism can be obtained by using
molecules that have been isotopically labeled and tracing the path of the reaction in this way.
Radioactive isotopes as well as stable isotopes can be used as tracers.O-18 can be detected by
mass spectrometry. D can be determined by IR and NMR spectra when used as a substitute for
H. Also, C-13 which is non-radioactive can be detected by C-13 NMR. Viz hydrolysis of
carboxylic ester may involve either (A) an acyl-oxygen bond fission or (B) an alkyl-oxygen bond
fission

Acyl oxygen bond fission

O O

R O R' R OH + R' OH

(A)
alkyl oxygen bond fission
O O

R O R' R OH + R' OH

(B)
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O O H O H
18 H 18 18
R C O R C O + R' O
R O R'
+
..O
H OR H H

O
18
R C OH + R' OH

The above mechanism has been solved by hydrolyzing ester in H2O18 . If the acyl –oxygen bond
breaks, the labeled oxygen will appear in the acid otherwise it will be in alcohol. The reaction
thus confirms that during the course of hydrolysis acyl-oxygen bond breaks.
Similarly in the rearrangement of Claisen-reaction the phenyl allyl ether on heating at about
2000C, undergo inversion. This mechanism has been proofed by labeling the terminal CH2 (γ)-
position with C14 isotop. The location of this radioactive isotop bonded as alpha- carbon of the
side chain to the o- position is done by oxidation method. The Oxidation of o- allylphenol yields
HCHO not H14CHO. This result shows that there is inversion of the allyl group.

beta 14
O CH2 CH CH2
alpha gama OH
14
2000
C CH2 CH CH2
i. KMnO4 /OH/HOH
ii HIO4

OH

CH2 CHO + HCHO

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Another evidence is the hydride ion transfer in Cannizzaro reaction in which two molecules of
aldehydes devoiding α- hydrogen are condensed in presence of NaOH, a alcohol and sodium slat
of corresponding carboxylic acid is formed as follow

CHO CH2OH COONa

NaOH
2 +

CHO CH2OH

NaOH
+ HCHO + HCOONa

NaOH
2 HCHO CH3OH + HCOONa

In this reaction second hydrogen in –CH2- group in alcohol ( say benzyl alcohol) may come from
either a second molecule of aldehyde (say benzaldehyde) or from the solvent H2O. By carrying
out the reaction in D2O it has been shown that it comes from another molecule of benzaldehyde
by hydride (H-) ion transfer. Deuterium appeared in the hydroxyl group (as OD) of the alcohol
but not as methylene deuterium (-CHD-). This mechanism should be giben as I not as II in
following representation.

O O D O
C H C
H + OD-
O H

hydride (H-) ion

transfer
O O
O OD C C H
OD +
C C H D
O +
D
I
(Found)

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O O
O D
C H C
H + OD-
O H

O O
O OH C C H
OH +
C C H D
O +
D
(not found)
II
6. Stereochemistry: Stereochemical evidences If the products of a reaction are capable of

C2H5 H3C C OH

HOH C2H5
SN1
Racemic mixture
H3C C Cl
CH3
C2H5
planar carbocation

HO C CH3
C2H5
existing in more than one stereoisomeric form, the form that is obtained may give information
about the mechanism. For example, in SN1 reaction mechanism formation of racemic mixture
indicate that the product formation takes by the formation of planar carbocation as follow.
7. Kinetic evidence: Several types of mechanistic informations can be obtained from kinetic
studies such as the order of the reaction, the rate determining step etc. The rate constant obtained
from kinetic data is most important since it tells the effect of changes in the structure of the
reactants, the solvent, ionic strength, addition of catalyst etc. on the reaction rate.

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2.12 ISOTOPE EFFECT

It is basically kinetic isotopic effect (KIE) abd is defined as the change in the reaction rate of a
chemical reaction when one of the atoms in the reactants is replaced by one of its isotopes.
Formally, it is the ratio of rate constants for the reactions involving the light (KL) and the heavy
(KH) isotopically substituted reactants:

KH
KIE
KD

KH = rate with substrate containing hydrogen (1H) and KD = rate with the substrate containing
deuterium (2H)
The kinetic isotopic effect is of two types:
B. Primary Kinetic Isotope Effect: In this effect bond to isotope is broken in the reaction.
The H/D has a large effect and easy to measure.
Changing the H for D can effect the rate of reaction only if that H ( or D) is involved in the rate
determining step. In this case the KH/KD is known as primary kinetic isotope effect. The
theoretical maximum is 7 for the reactions taking place at room temperature in which abond H or
D is being broken. Viz; compairing the rates of following reactions the KH/KD has been found
7.1 at 250C

CH3CH2O-
Rate = K H CH2
Cl

CH3CH2O-
Cl CH2
Rate = KD
D D CD

The kinetic isotop effect educates us that the C-H or C-D bond is broken during the rate
determining step.
Vibrational frequency of a bond (C-H) is given by following equation.

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1 k (m1 + m2)
v=
2 c m1m2

Where k = the force constant for the bond C-H (or C-D), m1 =mass of carbon atom, m2 = mass
of hydrogen (or deuterium atom) ,v = vibrational frequency of the bond and c= velocity of
light
The bond energy depends upon the vibrational frequency, which in turn depends upon the
reduced mass of the two atoms that formed the chemical [Link] energy of H and D in the
similar vibrational state are different .Because of large mass of D the vibrational frequency of C-
H is greater than that of a C-D [Link] less energy will be required to break a C-H bond than a
C-D bond. Since differencies in vibrational energy between C-H and C-D bonds decreases with
increasing in temperature, KH/KD ratio falls as the temperature of reaction increases. It is 7 at
250C, 4.7 at 1000C and 3.4 at 2000C. The ratio is much smaller for weakening or partial cleavage
of a C-D bond. Very smaller value indicates no primary kinetic isotopic [Link] potential
energy diagram for primary kinetic isotop effect if presented in fig. 15.

Potential energy curve for bond vibration

Energy required to break
C H and C D bonds

GD GH
E

Zero point C H
energy for C D
C H bond Zero point energy
for C D bond

Displacement
Fig.15. Energy profile diagram for primary kinetic isotop effect
Some of the examples of primary isotop effects are as follow:
B. The base catalysed bromination of acetone is second order reaction, firse order with respect
to acetone and first order with respect to –OH but independent to the concentration of

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bromine. A primary kinetic isotop effect of about 7 has been observed in bromibation. This
indicates that the rate determining step involves removal of hydrogen by catalyst base
leading to the formation of the conjugate base of acetone as follow.
C.
O O O
OH CH 3 C CH 2
CH 3 C CH 3 CH 3 C CH 2
Slow k
H
Fast
Br 2

O
CH 3 C CH 2 Br
O O O
OH
CH 3 C CD 3 CH 3 C CD 2 CH 3 C CD 2
Slow k
D
Fast
Br2
kH
(ii) =7 O Solvolysis of isopropyl bromide: In
kD CH 3 C CD 2Br
this reaction as discussed follow this
molecule undergoes both SN2 and SN1 reaction because of its borderline behavior. It also
undergoes E2 reaction. If the deuterated compound CD3-(CHBr) –CD3 is taken for reactions,
primary kinetic effect is observedwith the KH/KD ratio of about 6.7. The effect is observed only
in elimination reaction because in elimination reaction C-H or C-D bonds are broken.
Carbon-13 isotope effects: Most organic reactions involve the breaking and making of bonds to a
carbon; thus, it is reasonable to expect detectable carbon isotope effects. When 13C is used as the
label, the change in mass of the isotope is only ~8%, though, which limits the observable kinetic
isotope effects to much smaller values than the ones observable with hydrogen isotope effects.
B. Secondary Kinetic Isotope Effect: Secondary kinetic effects arise from rate differences
caused by isotopically labeled bonds that are not made or broken in the rate determining
[Link] deuterium kinetic isotopic effect can be normal or inverse. Generally for
deuterium these effects come from change in hybridization and hyperconjugation. The secondary
kinetic effects are smaller than primary and are usually in the range of KH/KD =0.7 – 1.5.
Secondary isotope effects may be normal (KH/KD > 1) or inverse ((KH/KD < 1). They are also

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classified as α or β [Link] ob the location of the isotopic substitution with respect to the
reacting carbon. Secondary isotopic effect results from a tightening or loosening of a C-H bond
at the T.S. The strength of bond may change because of a hybridization change or change in the
extent of hyperconjugation.
Secondary isotope effect at β- position has been especially thoroughly studied in nucleophilic
substitution reactions. When carbonium ions are involved as reaction intermediate. Substituted
β- isotope effects are observed. This happens because the bo-bond resonance stabilization by β-
hydrogens weakens the C-H bond. Viz; KH/KD = 1.5 for solvolysis of 1 – chloro – 1- phenyl

Cl
CH CH
CH3 CH3

Cl
CH CH
CD3 CD3

ethane in 50% aqueous ethanol at 250C. Here the C-Cl bond breaks to form the carbocation
which is stablised by hyperconjugation by H or D. Heavier D stabilize the carbonium ion less
effectively than H. hence there is a fall in reaction rate.

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In Cope rearrangement secondary deuterium isotope effect is observed due to conversion of sp2
hybrid carbon into sp3 hybrid carbon in the T.S.

160 0C O
O 3
KH CH2 sp
CH2

sp 2 KH
= 0.976
KD
O 160 0C O
3
CD2 KD CD2 sp

sp 2

Secondary deuterium isotope effect is also observed in Nu- addition reaction of carbonyl
compounds. In these case effect is due to the conversion of sp2 hybrid into sp3 hybrid carbon

O O
25 0
C H + CN C C H
KH CN
KH
= 0.883
KD
O O
25 0
C D + CN C C D
KD CN

In above example when sp2-hybrid carbon converts into sp3 hybrid carbon than the value of
KH/KD is less than 1.0 On the other hand when sp3 hybrid carbon converts into sp2 hybrid carbon
in the T.S. then the value of KH/KD is greater than 1.0

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2.13 SUMMARY
This unit describes about the basic concepts which are essential to know prior to study the
reaction mechanism. The concepts like type of reactions, their kinetic feasibility and
thermodynamic stability and has been described in dtetails with suitable examples. Regarding the
thermodynamic study it has been outlined that the thermodynamics is concern only with the finat
state of the system, while kinetics of the reaction describes how fast the equilibrium is reached.
The thermodynamics stability determines the equilibrium constant, while kinetic stability
determines the rate constant. It has also been described in this unit that if ∆Gǂ >, the reaction is
kinetically stable and if ∆G0 is negative, the reaction is thermodynamically stable and exothermic
in nature while positive value of∆G0 indicates the endothermic reaction. For graphical
representation of the reaction mechanism the energy coordinate diagrams has been depicted. The
Hammonds postulates have been described in detail alongwith their reaction coordinate
representations. Reactions intermediates are very important species to understand the reaction
mechanism in organic reaction. Evidences of formation of reaction intermediates to speculate the
mechanism of the reaction has been exaplained in detail along with their potential energy
diagram [Link] know the mechanism of the reaction various methods for determining
the mechanism viz, Kinetic evidence, stereochemistry, isotopic labeling, irapping of an
intermediate, detection of an intermediate, determination of prescence of an intermediate,
identification of products etc have been described with examples. The kinetic isotopic effect is
very important tool to understand the mechanism of organic reactions. In this study the isotopes
14
like deuterium, C etc are used and the ratio of KH/KD is studied which tells us the possible
mechanism of the [Link] concept has bben described with example in present unit

2.14 TERMINAL QUESTIONS

Q.1. MCQs
Tick out the correct options
i. Geometry of methy free radical is:
A. Planar B. Pyramidal
C. Tetradehral D. Linear

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ii. Which of the following reaction take place via the formation of carbonium ion as areaction
intermediate?
1. SN1 2.E1 3. E2 4.SN2
A. Only 1 B. Only 2
C. 1 and 2 D. 1, 2 and 4
iii. The reaction is said to be kinetically stable if:
A. ∆Gǂ value is large B. ∆Gǂ value is small
C. ∆Gǂ is zero D. ∆G0 is (-) ve

iv. For secondary kinetic isotopic effct the responsible factor(s) is/are:
A. Channge in hybridization and stability ob bond between carbon and deuterium
B. Change in hybridization and no-bond resonance
C. Hyperconjugation
D. D. hybridization
v. Singlet/ triplet carbine reaction intermediate can be studied and distinguished by:
A. Trapping reactions with olifines B. Reactions with benzene
C. Beckmann reaction D. Diels- Alder reaction
vi. Benzyne can be trapped by which of the following

O
1 2 3 4

A. Only1 B. Only 3 and 4

C. 2,3 qnd 4 D. 1,2,3 and 4
vii. Exothermic” processes:
A. Absorb energy B. Give off energy
C. Have no energy change D. It is impossible to predict the energy change
of an exothermic process.
viii. Which of the following phase changes would this type of energy diagram refer to?

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A. Melting B. Condensation
C. Evaporation D. Sublimation
ix. What letter represents the activation energy?

A
E D C
F

B
Reaction coordinate (time)

A. D B. B
C. A D.C
x. Which of the following reactions will show a significant kinetic isotope effect?
O O
CH3ONa
A. CD2 C OCH3 Heat D. CH3 CD2 C CH3 CH3ONa
Heat
CD3
CH3ONa C. All of these ractions show kinetic isotopic effect
B. CD3 C CH2Br
Heat
H

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Q.2. Write brief notes on:

1. Hammond’s postulates
2. Curtin – Hammett principle
3. Kinetically and thermodynamically controlled reactions
Q.3. What is reaction coordinate? How various types of reactions are depicted graphically by
using reaction coordinate diagrams? Explain your answer with examples.
Q.4. What different methods for determining the the mechanism of organic reactions. Discuss
with suitable reactions.
Q.5. Explain primary and secondary kinetic isotopic effects (KIE) with suitable examples.
Q.6. Discuss that one of the hydrogen in –CH2- of -CH2OH (alcohole) in Cannizzaro reaction
comes from hydride shift.
Q.7. Discuss with example;
1. Isotopic effect
2. Trapping reactions of benzynes
3. Potential energy diagram
Q.8. Discuss the mechanism of SN1 and E1 reactions using deuterium isotopic displacement.

Q.9. How kinetics and thermodynamics help us to understand the feasibility of reaction ?
Q.10. Discuss the Hammond’s postulates in details.

2.15 ANSWERS (MCQs)

i A ii C iii A iv B v A
vi D vii B viii B ix A x A

2.16 REFGERENCES

Jagdamba S. and Yadav L.D.S. Advanced organic chemistry, Pragati Prakashan, Meerut, 2004

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ISBN No. 81-7556 -673 - 6

George S. Hammond, J. Am. Chem. Soc. 1955, 77, 334-338.
Meany, J.E. "Application of Hammond's postulate". Journal of Chemical Education. 01. 2 (78):
204. 2001
Fox, Marye Anne, F.M.; Whitesell, James K. Organic Chemistry Third Edition. Sudbury, MA:
Jones and Barlett Publishers. p. 356., 2004
Sorrell, Thomas N. Organic Chemistry Third Edition. Sausalito, CA: University Science Books.
pp. 370–371, 2005.
Jeffrey I. Seeman (1983). "Effect of Conformational Change on Reactivity in Organic Chemistry.
Evaluations, Application, and Extensions of Cutin–Hammett/Winstein–Holness Kinetics".
Chemical Reviews. 83 (2): 83–134. 1983.

Jeffrey I. Seeman (1986). "The Curtin–Hammett Principle and the Winstein–Holness Equation".
Journal of Chemical Education. 63 (1): 42–48. Bibcode:

Beak, P; Basu, A; Donald J. Gallagher; Park;Y. S, Thayumanavan, S (1996). "Regioselective,

Diastereoselective, and Enantioselective Lithiation−Substitution Sequences:  Reaction Pathways
and Synthetic Applications". Accounts of Chemical Research. 29 (11): 552–560.

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UNIT 3: REACTIVE INTERMEDIATES

CONTENTS:

3.1 Objectives
3.2 Introduction
3.3 Generation, structure, stability and reactivity of Reaction Intermediates:
3.3.1 carbocations
3.3.2 carbanions
3.3.3 Carbon free radicals
3.3.4 carbenes
3.3.5 nitrenes

3.3.6 Benzyne

3.4 Quantitative relationship between molecular structure and Chemical reactivity:

3.4.1 Hammett equation

3.4.2 Taft equation

3.5 Summary

3.6 Terminal Questions

3.1 OBJECTIVES

In the beginning of this chapter, we introduced about reactive intermediates of the organic
reaction. We also learn about Generation, structure, stability and reactivity of Reaction
Intermediates. Describe the properties of carbocations, carbanions, carbon radicals, carbenes,
nitrenes and benzynes including their structure, hybridization, geometry, and reason for
reactivity.

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3.2 INTRODUCTION
A reactive intermediate is a short-lived, high-energy, highly reactive molecule. When generated
in a chemical reaction, it will quickly convert into a more stable molecule. Only in exceptional
cases can these compounds be isolated and stored, e.g. low temperatures, matrix isolation. When
their existence is indicated, reactive intermediates can help explain how a chemical reaction
takes place

Most chemical reactions take more than one elementary step to complete, and a reactive
intermediate is a high-energy, yet stable, product that exists only in one of the intermediate steps.
The series of steps together make a reaction mechanism. A reactive intermediate differs from a
reactant or product or a simple reaction intermediate only in that it cannot usually be isolated but
is sometimes observable only through fast spectroscopic methods. Some important examples of
reactive intermediates are: carbocation, carbanions, free radicqals, carbenes, nitrenes and
benzyne.

3.3 GENERATION, STRUCTURE, STABILITY AND REACTIVITY

OF REACTION INTERMEDIATES
1.3.1 Carbocations:

An Organic species which has a carbon atom containing only six electrons in its
outermost shell and has appositive charge is called a carbocation reaction intermediate. The
carbon atom of the carbocation is Sp2 hybridized, it use the three hybrid orbitals for single
bonding to three substituents and remaining p- orbital is empty. The carbocations thus has a
planner structure having all the three covalent bonds are in plane with the bond angle of 1200
between them.

Formation of carbocations: These are formed by the heterolytic cleavage of the covalent bonds
in which the leaving in which the leaving group takes away with it the shared pair of electrons.
For example,

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CH3 CH3
∆
CH3 C Cl CH3 C+ + Cl-

CH3 CH3
tert-Butyl chloride tert-Butyl carbocation

Classification of carbonium ion: Carbocations are classified as primary (10), secondary (20) and
tertiary (30) according to the positive charge is present on a primary, secondary and tertiary
carbon atom respectively. For examples:

1. Alkyl Carbonium ion:

Like free radical carbinium ion also classified in to three classes-

a. Primary carbonium ion: In this type of carbonium ion one carbon atom is attached with
the positive carbon atom.
+
R C H

H
Where R is the alkyl group

b. Secondary carbonium ion-

In this type of carbonium ion two H atoms are replaced by two alkyl groups from the +
charge bearing carbon.

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+
R C H

R
Where R is the alkyl group

Isopropyl carbonium ion

+
R C H

CH2-CH3
Where R is the alkyl group

c. Tertary carbonium ion:

In this type of carbonium ion 3 hydrogen atoms are replaced by 3 alkyl groups from the
positive charge bearing carbon.
+
R C R

R
Where R is the alkyl group

tert. Butyl carbonium ion

+
R C R

CH2-CH3
Where R is the alkyl group
2. Benzylic carbocations:

+ + +
C H C H C

10 20 30

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3. Allylic carbocations:
+ +
CH2 = CH-CH2+ CH2 = CH-CH CH3 CH2 = CH-C CH3

10 20 30 CH3
4. Vinylic carbocation:
+
CH2 CH
5. clopropylmethyl carbocation
Stability of carbonium ion:
The relative stability of carbonium ion is explained with the help of Inductive effect. In the case
of 10 carbonium ion the CH3 group contains +I affect, so it release the electron towards the
carbon that bearing positive charge. So some charge neutralize and also somewhat positive
charge created on the methyl group carbon, so the + charge become dispersed and gives the
stability. Hence we can say that greater is the dispersed is the positive charge greater will be the
stability. Hence 30 carbocation is most stable in compare to 20, 10 and methyl cabocation.

+ + + +
R C R R C H R C H H C H

R R H H
30 20 10 Methylcarbocation

Orbital structure: The carbocations are planner species. The carbon atom carrying the positive
charge is sp2 hybrized. The three sp2 hybrised orbitals of this carbon form three σ bonds with
monovalent atoms or groups which lie in a plane and are inclined to each other at an angle of
1200. The unhybridized 2p orbital which is perpendicular to the plane of the three σ- bonds is,
however, empty which are given as follow:
Empty p- orbital

R
σ σ
1200 C R
σ
R

sp2 hybridized carbon

3.3.2. Carbanaions:

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These are chemical species which possess a negatively charged on carbon and possessing eight
electrons in its valence shell are called carbanions. Like the Carbocations the Carbanions are also
formed by hetertolytic fission of covalent C-Y molecules

R CH2 Y R CH2- + Y+

Here Y is an atom which is more electropositive than Carbon. This is why during the heterolytic
fission the shared pair of electrons is drawn towards the Carbon atom to develop a negative
charge over it.

Generation of carbanions: Carbanions are generated as intermediate in various organic

reactions. Some of the methods for the generation of carbanion are given as:
a) Proton abstraction
b) Decarboxylation
c) Addition of nucleophile to alkene
d) Formation of organometallic compounds

(a) Proton abstraction: When proton is abstracted from a carbon centre then the resulting anion
is called a carbanion.

R H R- + H+

The acidic hydrogen of an organic substrate can be abstracted by an appropriate base. For
example carbanion generated from carbonyl compounds.
Here, are some examples showing generation of carbanion by abstraction of the acidic proton
using a base (OH─, NH2─ and RO─).
O O

+ NH2- R CH C R' + NH3

R CH2 C R'

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O O

+ NR2 R CH C R' + NHR2

R CH2 C R'

R CH2 NO2 + OH R CH NO2

(b) Decarboxylation: Decarboxylation of carboxylates ion to form carbanion intermediate.

O
R C O R + CO2

(c) Addition of nucleophile to alkene: Carbanions are generated by the attack of nucleophiles
on one of the carbon of an alkene. It results into the development of negative charge on the other
carbon atom.

H H H
H X
C C C C
H H H
H X

(d) Formation of organometallic compounds: Metals which are less electronegative than
carbon (such as magnesium, lithium, potassium, sodium, zinc, mercury, lead, thallium) react
with alkyl halides under appropriate conditions to form a carbon-metal bond where the carbon
carries negative charge and metal positive charge.
For example, alkyl bromides react with magnesium in the presence of dry diethyl ether to form
alkyl magnesium halides also known as Grignard reagent.
R Br + Mg R-MgBr

Stability of Carbanion: Factors which can stabilize the negative charge on carbon will stabilize
a carbanion. The stability of carbanion depends on the following factors:
a) Inductive effect
b) Extent of conjugation of the anion
c) Hybridization of the charge-bearing atom
d) Aromaticity

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(a) Inductive effect: If the electron donating groups are attached to carbanion they will increase
the negative charge on carbon and thus destabilize it. However, electron withdrawing groups
adjacent to the negatively charged carbon will stabilize the carbanion.
All alkyl groups are electron donating in nature due to inductive effect (+I effect). More the
number of alkyl groups attached lesser will be the stability. Therefore the order of stability order
of alkyl carbanion is methyl > 1o > 2o > 3o carbanion.

R R R
H
C R C R C
H C H

H H R
H
methyal carbanion 10 22 30
(b) Extent of conjugation of the anion: If negatively charged carbon is in conjugation with a
double bond the resonance effects will stabilize the anion by spreading out the charge by
rearranging the electron pairs.

CH3 CH CH CH2 CH3 CH CH CH2

Enolate of ester:
O -
O

R CH C R' R CH C R'

(c) Hybridization of the charge bearing atom: Stability of anion will depend upon the s
character of carbanion i.e. more the s character, higher will be the stability of anion. The
percentage s character in the hybrid orbitals is as follows: sp (50%) > sp2 (33.33%) > sp3 (25%).
R C C R2 C CH Ar R3C CH2
Sp Sp2 Sp3

Explanation of the order of stability:

Propargyl anion > propenyl anion > propyl anion
The order of stability can be understood as follows. In propargyl anion, the triply bonded carbon
is sp hybridized, in propenyl anion the doubly bonded carbon is sp2 hybridized while in propyl
anion the carbon is sp3 hybridized. Orbital with greater s character is more close to the nucleus

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and having more nuclear charge. The sp hybridized atoms are more electronegative than sp2 and
sp3. The distance of lone pair and nucleus is less if the lone pair is sp hybridized than in a sp2
hybrid orbital. Since, it is more favorable for the negative charge of an anion to be in an orbital
close to the positively charged nucleus. Therefore sp hybrid anion is more stable than sp2.

(d) Aromaticity: In some carbanions, the lone pair of electrons of the negative charge is
involved in delocalization to add on to the aromatic character of the molecule which gives them
extra stability.
For example, in cyclopentadienyl anion there are 6π electron and thus it obeys Huckel
aromaticity rule, (4n+2)π electron. This anion is stabilized by aromatization.

Reactivity of Carbanion: Carbocations are strong Lewis acids while carbanions are strong
bases (Lewis and Bronsted bases). Carbanions are part of most of the common reaction types
such as displacement, elimination, condensation, addition, rearrangement, polymerisation etc.
1. Displacement Reaction: Such reactions are nucleophilic substitu (SN2) reactions observed in
alkyl halide.
H H
H H

C X R C + X
R +

H H

2. Elimination reaction: In a Conjugate Base Elimination reaction (E1cb) the C-H bond breaks
with formation of carbanion as intermediate. The developed negative charge on carbon assist in
the loss of leaving group, leading to the formation of alkene.

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OH
H H H H

H C C Cl C C Cl CH2 CH2

H H H H

3. Rearrangement reactions: In some cases, carbanions may rearrange to form more stable
species. Consider the rearrangement in triphennylmethyl carbanion.

(C6H5)3C CH2 (C6H5)2C CH2 C6H5

4. Condensation reactions:
Claisen condensation: Formation of β-keto esters from carboxylic esters is known as Clasien
ester condensation.
O
O
C2H5O CH2 C OC2H5
CH3 C OC2H5
It is generated by heterolytic fission and bearing - ve Charge and the number of valence electrons
are 8 in it called carbanion reaction intermediate.

Example:

H H
CH3

_ , CH3 C
_ , CH3 C_
H C
CH3

H H

Hybridization in carbanion ion:

The carbanion ion shows SP3 hybridization with one loan pair of electron. Hence its geometry
will be tetrahedral.

E.g.

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Structure of Carbanion: The structure of simple carbanion is usually pyramidal just like those
of ammonia and amines. The carbon atom carrying the negative charge is sp3 hybridized. Three
of the four sp3 hybridized orbitals from three σ- bonds with monovalent atoms while the four sp3
orbital contains the loan pair of electrons.

Loan pair sp3 orbitals

..
C σ
σ
σ
3
sp hybrized carbon

3.3.3. Carbon Free Radicals:

A free radical (often simply called a radical) may be defined as a species that contains
one or more unpaired electrons. Note that this definition includes certain stable inorganic
molecules (e.g., NO and NO2), as well as many individual atoms (e.g., Na and Cl). As with
carbocations and carbanions, simple alkyl radicals are very reactive. Their lifetimes are
extremely short in solution, but they can be kept for relatively long periods frozen within the
crystal lattices of other molecules. Since the lifetime of a radical depends not only on its inherent
stability, but also on the conditions under which it is generated, the terms persistent and stable
are usually used for the different senses. A stable radical is inherently stable; a persistent radical
has a relatively long lifetime under the conditions at which it is generated, although it may not be
very stable.
Generation of Free Radicals: Formation of free radicals is favoured by the presence of UV
light, heat and organic peroxide. An important characteristic of free radical reactions is that, once
initiated, they proceed very fast. The free radicals can be detected by magnetic susceptibility
measurement.

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hν .
Cl Cl 2Cl
free radical

Thermal .
CH3CO O OCOCH3 2CH3COO
free radical

Example: CH3º, CH3CH2 º, Hº etc.

The free radicals are strongly reactive because they have stronger tendency to become paired and
their nature is paramagnetic.

Stability of free radicals: The bond dissociation energies give us an idea of the ease with which
radicals can form; they can also give us an idea of the stability of those radicals once they have
formed. The lower the bond dissociation energy, the higher will be the stability. Alkyl radicals
are stabilized by adjacent lone-pair-bearing heteroatom and by the π bonds. The various factors
responsible for the stability of free radicals are:

1. Inductive effect
2. Hyperconjugative effect
3. Resonance effect

1. Inductive effect: Greater the number of alkyl groups attached to the free radical carbon centre
more will be the stability of the radical. This is due to the electron donating inductive effect (+ I
effect) of the alkyl groups which decrease the electron deficiency of the radical.
The bond dissociation energies, of the C-H bonds for the formation of a free radical of
methane, ethane, and other alkanes, clearly shows that radical centres are stabilized by the
replacement of one, two, or three of the hydrogens of the methyl radical by alkyl groups.
Thus, the order of stability is 3o > 2o >1o.

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2. Hyperconjugative effect: Hyperconjugative effect also gives stability to free radicals as in the
case of carbocations. Thus, Greater the number of hyperconjugative structures more will be the
Stability of the radical. The
Stability order of alkyl free radicals is tertiary > secondary > primary > CH3.

3. Resonance Effect: In the free radicals where the carbon centre is in conjugation to a double
bond, the resonance effect leads to stabilisation of these molecules. The stabilising effects of
vinyl groups (in allyl radicals) and phenyl groups (in benzyl radicals) are very significant and
can be satisfactorily explained by resonance. Allyl and benzyl free radicals are more stable than
alkyl free radicals but still have only a transient existence under ordinary conditions.
Resonance in benzyl free radical:

Reactivity of free radical: Some important reactions of free radicals are described below:
1. Halogenation of aliphatic hydrocarbons: In the presence of sunlight, halogenation of
saturated hydrocarbons like alkane gives haloalkane.
CH4 + Cl2 CH3 Cl + HCl

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Mechanism of Halogenation: It involves three main steps (i) Initiation (ii) Propagation and (ii)
Termination.
(i) Initiation: In this step, free radicals required for the reaction are generated in situ by
irradiation or heating of the reagent or by carrying out the reaction in the presence of an initiator
like peroxides. The process is always endothermic.

hν .
Cl Cl 2Cl

(ii) Chain propagation: Second step is chain propagation. In this step the highly reactive
chlorine radicals with unpaired electron reacts further. They are electrophilic, thus each seeks an
electron to complete its unfilled shell of electrons. In a reaction with methane, a chlorine atom
readily removes hydrogen from the methane. Free radical chain reactions work best when all
propagation steps are exothermic.
.
Cl .
CH3 H CH3 + HCl

. .
CH3 + Cl - Cl CH3 Cl + Cl

(iii) Chain termination: The final step is chain termination in which two reactive radicals
combine together.

2. Addition reaction: The anti-Markovnikov addition of HBr to alkenes was probably the first
free radical addition reaction to be discovered.

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3. Rearrangement reaction: Free radicals may also undergo rearrangement to form a more
stable radical and then the final product.

Structure:
Alkyl free radicals like carbocationa are planner species. The only difference being that in
carbocations, the unhybridized p- orbital is empty while in free radicals, it contains the odd
electron.
p-orbital

Unpaired electron
H σ

1200 C σ H
σ
H
sp2-hybridized orbital

3.3.4. Carbene Reaction intermediate:

Carbenes are netural, divalent, highly reactive intermediate carbon species. It is defined as a
netural reactive divalent species which consist six electrons in its outermost shell is known as
Carbene.

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H Cl
C:
C:
H Cl

Carbenes are highly reactive because they have stronger tendency to complete their octate.

Methods of preparation

1. From diazomethane: Diazomethane on decomposition under the action of light

gives carbene.

Light(hv) H
CH2N2 C: + N2
H

2. From chlororm: hloroform on react with sodium ethoxide gives dichloro carbine by
releasing C2H5OH.

Step 1

H H
Cl C Cl + Cl C+ + NaCl + C2H5O-
Cl
Cl

Step 2
H H
+ H+
Cl C+ Cl C:

Cl Carbene

Step 3

C2H5O- + H+ C2H5OH

Properties of carbine:
Carbene is ahighly reactivereaction intermediate and it gives easily reaction.
1. Reaction with Alkene: carbine on react alkene gives cycloalkanes.

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CH2 CH2
+ C: CH2
CH2 CH2

Cyclo propane

e.g.
CH3 CH3
CH3 CH3 CH2
+ C:
CH2
CH2
Methyl cyclo propane
2. Reaction with alcohol: Carbene on react with alcohol gives addition compound
ether.

+ R O CH3
R OH :CH2
CH3 O CH3
+ :CH2
CH3 O H
3. Insertation Reaction: In this reaction carbine react with those functional groups
which are bi-valent and from both sides they are link with another groups
undergoes insertation reaction reaction with carbine.
Note: ketone on react with carbene gives higher member of ketone.

O O
CH3 C CH3 + CH2 CH3 C CH2 CH3
O O
CH3 C CH2 CH3 + :CH2 CH3CH2 C CH2 CH3

4. Reaction with alcohol: Alkanes on react with carbene gives higher number of
alkane series.

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H H H

H C H + CH2 H C C H

H H H

Classification of caebene: Carbenes are classified in to two classes by name these are-
1. Singlate carbene
2. Triplet carbene
1. Singlet carbene: In this type of carbene SP2 hybridization is observed and the unshared
pair of electron is present in one p- orbital.
Vacent p- orbitals

H
C :
H

SP2

Multiplicity = S = 1/2n
(Where n is the number of unpaired electron)
In this case n = 0
Since multiplicity = 2s + 1
=2x0+1
= 1 (singlet)
2. Triplet carbene: In this type of carbene the unshared pair of electron is exist in to two
unhybridised p- orbital. So they show Sp- hybridization with linear geometry.

H C H

SP

S=½n
S=½x2
S=1
Since multiplicity = 2s + 1
= 2 x1 + 1

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= 3 (Triplet)
Stability of singlet and triplet carbene: Out of singlet and triplet carbene is more stable
because in singlet carbene there is the repulsion between unshared electrons.

3.3.5. Nitrenes:
Nitrenes are defined as “A neutral reactive monovalent species which consist six electron in its
outermost shell is known as nitrene”. The nomenclature follows that of carbene. Substituted
nitrenes are simply named as substituted derivative of carbene. For example:
..
C6H5 N
.. Phenylnitrene

..
CH3SO2N
.. Methanesulphonyl nitrene

..
R N
.. Alkylnitrene
In nitrenes the nitrogen atom N has 1 l.p. of electron and 1 unshared pair of electron.
Method of preparation:
1. From hydrozoic acid- Hydrozoic acid (HN3) on decomposition gives nitrene.
+ - ..
H N N N Decomposition N: +
H N2

..
+ - Decomposition CH3 N + N2
CH3 N N N ..
2. From Ammonia: Ammonia (NH3) on decomposition gives nitrene by removing H2 gas.

Decomposition ..
NH3 N
.. H + H2

3. From hydrazen: Hydrazene on decomposition gives nitrene.

H N H Heat ..
N N H + NH3
..
H H
Properties: Nitrenes are highly reactive because they have stronger tendency to complete their
octate.

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1. Insertion reaction: In this type of reaction nitrene react with alkane to give amino
derivative compound.
H
..
H C H + N.. H CH3-NH2

H
Aminomethane
2. Reaction with alkene: Nitrene on react with alkenes gives cyclic amino compounds.

CH2 .. CH2
+ N H N H
.. CH2
CH2
Cyclo amine ethylene

3. Di- marization reaction: In this type of reaction two nitrenes are combined together
to form the product.
..
N H + N H H N N H
azo hydrogen
Classification of nitrenes: Nitrenes are classified into two classes one is singlet and other is
triplet nitene.
1. Singlet nitrene: In this type of nitrene the unshared pair of electron is present in
one p-orbital and it consist Sp2 hybridization, its geometry is as follow.
.. unshaired pair of e-

H N
.. l.P

SP2
For multiplicity:
Unshaired pair of e- n = 0
S=½n=½x0=0
Since multiplicity = 2s + 1
=2x0+1

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= 1 (singlet)
2. Triplet nitrene: In this type of nitrene N atom shows Sp hybridization and the
unshared electron are present in to two different p- orbitals.
..
unshaired e-

H N .. l.p.

Sp
For multiplicity: No. of unpaired e- (n= 2)
s = ½ n= ½ x 2 = 1
So multiplicity = 2s + 1
= 2 x1 + 1
= 3 (Triplet)

3.3.6. Benzyne:
Benzynes or arynes are highly reactive species derived from an aromatic ring by removal of two
ortho substituents. Arynes are usually best described as having a strained triple bond; however,
they possess some biradical character as well.
The aryne nomenclature derives from the fact that the C6H4 can be represented as an alkyne,
although systematically the species should be named as didehydro aromatic compounds, i.e. 1,2-
didehydrobenzene.

Benzyne can be represented as a singlet molecule with a carbob-carbon triple bond. Although it
has triple bond but it is not normal alkyne bond. In benzyne out of two π-bond of triple bond, one
π-bondis normal and the other π-bond is abnormal and is formed by overlap of two Sp2 orbitals
outside the ring. This is called external π-bond. It can be represented as follow.

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Abnormalpi-bond

Two Sp2 orbitals outside the ring

Preparation of benzyne:
1. From halobenzene: When halogbenzene are react with sodamide in liquid
ammonia then it gives benzyne.
X

+ NaNH2 + NaX + NH3

Mechanism: Br
Br

+ - + Na+ -NaBr
NH2 -NH
3 -

2. From 0- dihalobenzene: When o-dihalobenzene is treated with lithium amalgam

or Mg, then it gives benzyne.
Cl

Li/Mg + MgCl2

Cl

3. From benzenediazonium-2- carboxylic acid: benzenediazonium-2- carboxylic

acid when heated in the presence of heat and sun light then it gives benzynes.

N N
hv/heat
+ CO2 + N2

C O-

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3.4 QUANTITATIVE RELATIONSHIP BETWEEN MOLECULAR

STRUCTURE AND CHEMICAL REACTIVITY

1.4.1 Hammett equation:

The Hammett equation in organic chemistry describes a linear free-energy relationship relating
reaction rates and equilibrium constants for many reactions involving benzoic acid derivatives
with meta- and para-substituents to each other with just two parameters: a substituent constant
and a reaction constant. This equation was developed and published by Louis Plack Hammett in
1937as a follow-up to qualitative observations in a 1935 publication.
The basic idea is that for any two reactions with two aromatic reactants only differing
in the type of substituent, the change in free energy of activation is proportional to the change in
Gibbs free energy. This notion does not follow from elemental thermochemistry or chemical
kinetics and was introduced by Hammett intuitively.
The basic equation is:

Relating the equilibrium constant, K, for a given equilibrium reaction with substituent R and the
reference K0 constant when R is a hydrogen atom to the substituent constant σ which depends
only on the specific substituent R and the reaction constant ρ which depends only on the type of
reaction but not on the substituent used.

The equation also holds for reaction rates k of a series of reactions with substituted benzene
derivatives:

n this equation k0 is the reference reaction rate of the unsubstituted reactant, and k that of a
substituted reactant.
A plot of log (K/K0) for a given equilibrium versus log(k/k0) for a given reaction rate with many
differently substituted reactants will give a straight line.
Substituent constants:

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The starting point for the collection of the substituent constants is a chemical equilibrium for
which both the substituent constant and the reaction constant are arbitrarily set to 1: the
ionization of benzoic acid (R and R' both H) in water at 25 °C.

Having obtained a value for K0, a series of equilibrium constants (K) are now determined based
on the same process, but now with variation of the para substituent—for instance, p-
hydroxybenzoic acid (R=OH, R'=H) or p-aminobenzoic acid (R=NH2, R'=H). These values,
combined in the Hammett equation with K0 and remembering that ρ = 1, give the para
substituent constants compiled in table 1 for amine, methoxy, ethoxy, dimethylamino, methyl,
fluorine, bromine, chlorine, iodine, nitro and cyano substituents. Repeating the process with
meta-substituents afford the meta substituent constants. This treatment does not include ortho-
substituents, which would introduce steric effects.

The σ values displayed in the Table above reveal certain substituent effects. With ρ = 1, the
group of substituents with increasing positive values—notably cyano and nitro—cause the
equilibrium constant to increase compared to the hydrogen reference, meaning that the acidity of
the carboxylic acid (depicted on the left of the equation) has increased. These substituents
stabilize the negative charge on the carboxylate oxygen atom by an electron-withdrawing
inductive effect (-I) and also by a negative mesomeric effect (-M).

The next set of substituents is the halogens, for which the substituent effect is still positive but
much more modest. The reason for this is that while the inductive effect is still negative, the
mesomeric effect is positive, causing partial cancellation. The data also show that for these
substituents, the meta effect is much larger than the para effect, due to the fact that the
mesomeric effect is greatly reduced in a meta substituent. With meta substituents a carbon atom
bearing the negative charge is further away from the carboxylic acid group (structure 2b).

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This effect is depicted in scheme 3, where, in a para substituted arene 1a, one
resonance structure 1b is a quinoid with positive charge on the X substituent, releasing electrons
and thus destabilizing the Y substituent. This destabilizing effect is not possible when X has a
meta orientation.

-
Y Y Y
Y

+
X
X
X X+
Other substituents, like methoxy and ethoxy, can even have opposite signs for the substituent
constant as a result of opposing inductive and mesomeric effect. Only alkyl and aryl substituents
like methyl are electron-releasing in both respects.
When the sign for the reaction constant is negative, only substituents with a likewise negative
substituent constant will increase equilibrium constants.
Determination of ρ- value:
With knowledge of substituent constants it is now possible to obtain reaction constants for a
wide range of organic reactions. The archetypal reaction is the alkaline hydrolysis of ethyl
benzoate (R=R'=H) in a water/ethanol mixture at 30°C. Measurement of the reaction rate k0
combined with that of many substituted ethyl benzoates ultimately result in a reaction constant of
+2.498.

The reaction constant, or sensitivity constant, ρ, describes the susceptibility of the reaction to
substituents, compared to the ionization of benzoic acid. It is equivalent to the slope of the

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Hammett plot. Information on the reaction and the associated mechanism can be obtained based
on the value obtained for ρ. If the value of:
1. ρ>1, the reaction is more sensitive to substituents than benzoic acid and negative
charge is built during the reaction (or positive charge is lost).
2. 0<ρ<1, the reaction is less sensitive to substituents than benzoic acid and negative
charge is built (or positive charge is lost).
3. ρ=0, no sensitivity to substituents, and no charge is built or lost.
4. ρ<0, the reaction builds positive charge (or loses negative charge).
These relations can be exploited to elucidate the mechanism of a reaction. As the value of ρ is
related to the charge during the rate determining step, mechanisms can be devised based on this
information. If the mechanism for the reaction of an aromatic compound is thought to occur
through one of two mechanisms, the compound can be modified with substituents with different
σ values and kinetic measurements taken. Once these measurements have been made, a Hammett
plot can be constructed to determine the value of ρ. If one of these mechanisms involves the
formation of charge, this can be verified based on the ρ value. Conversely, if the Hammett plot
shows that no charge is developed, i.e. a zero slope, the mechanism involving the building of
charge can be discarded.
3.4.2 Taft equation:
The Taft equation is a linear free energy relationship (LFER) used in physical organic chemistry
in the study of reaction mechanisms and in the development of quantitative structure activity
relationships for organic compounds. It was developed by Robert W. Taft in 1952 as a
modification to the Hammett equation. While the Hammett equation accounts for how field,
inductive, and resonance effects influence reaction rates, the Taft equation also describes the
steric effects of a substituent. The Taft equation is written as:

Where is the ratio of the rate of the substituted reaction compared to the reference

reaction, σ* is the polar substituent constant that describes the field and inductive effects of the
substituent, Es is the steric substituent constant, ρ* is the sensitivity factor for the reaction to
polar effects, and δ is the sensitivity factor for the reaction to steric effects.

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Polar substituent constants, σ*:

Polar substituent constants describe the way a substituent will influence a reaction through polar
(inductive, field, and resonance) effects. To determine σ* Taft studied the hydrolysis of methyl
esters (RCOOMe). The use of ester hydrolysis rates to study polar effects was first suggested by
Ingold in 1930. The hydrolysis of esters can occur through either acid and base catalyzed
mechanisms, both of which proceed through a tetrahedral intermediate. In the base catalyzed
mechanism the reactant goes from a neutral species to negatively charged intermediate in the rate
determining (slow) step, while in the acid catalyzed mechanism a positively charged reactant
goes to a positively charged intermediate.

Due to the similar tetrahedral intermediates, Taft proposed that under identical conditions any
steric factors should be nearly the same for the two mechanisms and therefore would not
influence the ratio of the rates. However, because of the difference in charge buildup in the rate
determining steps it was proposed that polar effects would only influence the reaction rate of the
base catalyzed reaction since a new charge was formed. He defined the polar substituent constant
σ* as:

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where log (ks/kCH3)B is the ratio of the rate of the base catalyzed reaction compared to the
reference reaction, log(ks/kCH3)A is ratio of a rate of the acid catalyzed reaction compared to the
reference reaction, and ρ* is a reaction constant that describes the sensitivity of the reaction
series. For the definition reaction series, ρ* was set to 1 and R = methyl was defined as the
reference reaction (σ* = zero). The factor of 1/2.48 is included to make σ* similar in magnitude
to the Hammett σ values.
Steric substituent constants, Es:
Although the acid catalyzed and base catalyzed hydrolysis of esters gives transition states for the
rate determining steps that have differing charge densities, their structures differ only by two
hydrogen atoms. Taft thus assumed that steric effects would influence both reaction mechanisms
equally. Due to this, the steric substituent constant Es was determined from solely the acid
catalyzed reaction, as this would not include polar effects. Es was defined as:

Where ks is the rate of the studied reaction and kCH3 is the rate of the reference reaction (R =
methyl). δ is a reaction constant that describes the susceptibility of a reaction series to steric
effects. For the definition reaction series δ was set to 1 and Es for the reference reaction was set
to zero. This equation is combined with the equation for σ* to give the full Taft equation.

3.5 SUMMARY

In this unit we have discussed the about Reactive intermediates. These species are carbocation,
carbanion, carbine, nitrene benzyne and free radical. These species are highly reactive and
mostly exist as intermediates in the reactions. Besides these species there is one more species
called nitrene which is the nitrogen analog of carbene. In this unit we have also discussed the
structure, stability, generation and reactions of these reaction intermediates.

3.6. TERMINAL QUESTIONS

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1. What are carbanian? How they are generated? Discuss their stability order.
2. What are Cabenes? How they are generated? Give the structure of Singlet and Triplet
carbenes.
3. Discuss some reactions of benzynes.
4. What are benzynes? Give there structure.
5. What are Singlet and Triplet nitrenes.
6. Give the Relative stability of free radicals with the help of hyperconjugation effect.
7. Give the relative stability of the alkyl carbo cations.
8. What are the important factors affecting the stability of carbanions? Discuss the
structure of carbanions.
9. How will you distinguish between singlet and triplet carbenes based on their stability
and stereochemical bahaviour in addition reactions?
10. Explain the structure and stability of carbon free radicals.
11. Discuss the structure, stability and reactions of carbanions.
12. Write a note on the stability of carbocation and carbanion.
13. What are free radicals? Write the methods of generation of free radicals.

References:
1. Eric Anslyn, E.; Dougherty, D. A. Modern Physical Organic Chemistry; University
Science Books, 2006, p 455.
2. Taft, R. W. J. Am. Chem. Soc. 1952, 74, 2729.
3. Hammett, L. P. J. Am. Chem. Soc. 1937, 59, 96.
4. Charton, M. J. Am. Chem. Soc. 1975, 97, 1552; Charton, M. J. Org. Chem. 1976, 41,
2217.
5. Advanced Organic Chemistry by, Jagdamba Singh and L.D.S. Yadav, Pragati
Prakashana.
6. Organic Reactions and Their Mechanisms, by P. S. Kalsi, New edge Science.
7. R. L. Madan, S. Chand and company Pvt. Ltd.

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UNIT 4: STEREOCHEMISTRY 1

CONTENTS

4.1 Objectives
4.2 Introduction
4.3 Isomerism
4.4 Structural (Constitutional) Isomerism
4.5 Stereo (Configurational) isomerism
4.5.1 Geometrical Isomerism
4.5.2 Optical Isomerism
4.6 Element of Symmetry
4.7 Stereogenic centre (Stereogenicity)
4.7.1 Optical activity and Enantiomerism
4.7.2 Properties of enantiomerism
4.7.3 Chiral and achiral molecules with two stereogenic centers
4.7.4 Diastereomers
4.7.5 Properties of Diastereomers
4.7.6 Erythro (syn) Threo (anti) diastereomers
4.7.7 Meso compounds
4.8 Relative and absolute configurations
4.8.1 D/L nomenclature
4.8.2 R/S nomenclature
4.8.3 Sequence Rule
4.9 Newman and sawhorse projection formulae
4.10 Fisher flying and wedge formulae
4.11 Racemic mixture (racemates)
4.12 Quasi enantiomers
4.13 Quasi racemates
4.14 Stereochemistry of allenes, spiranes, biphenyls, ansa compounds, cyclophanes and related
compounds

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4.15 Summary
4.16 Terminal Questions
4.17 Answers

4.1 OBJECTIVES

In this unit learner will be able to:

Depict various types of isomerism exhibited by organic compounds and their

representation
Analyze the three dimensional depictions of organic compounds and their two
dimensional representations.
Learn Stereogenicity, chirality, enantiomerism, diastereomerism, their relative and
absolute configurations
Learn about the various stereo chemical descriptors such as (cis-trans, E/Z, D/L, d/l,
erythro/threo, R/S and syn/anti) given to organic molecules differ
Describe the stereochemistry of various rigid and complex molecules like spiranes,
adamentanes, catenanes, cyclophanes etc.

4.2 INTRODUCTION
In undergraduate level chemistry course we have learn about the fundamental concepts of
isomerism and stereochemistry. Isomerism and stereochemistry provides the information about
the different kind of depictions for organic compounds with similar structural formulas.
Chemical compounds are represented by specific structural formulas. These chemical formulas
were first organized by three scientists Kekule, Couper and Butlerov in 1874. The three
dimensional representation of depiction of organic molecules were independently suggested by J
H van’t Hoff and J A LeBel. J H van’t Hoff was honored by Nobel Prize for his work in 1901; he
was the first recipient of Nobel Prize in Chemistry.

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4.3 ISOMERISM
The word isomerism originated from Greek word isomer (iso= equal; mers = part). When two or
more organic compounds having similar molecular formula but exhibit differences in their
chemical and/or physical properties are called isomers, and the phenomenon is known as
isomerism. However, the stereochemistry of an organic compound can be defined as the
chemistry of that compound in space and as a function of molecular geometry.
Generally isomerism can be divided in to two categories;
a. Structural (constitutional) Isomerism
b. Stereo (configurational) Isomerism

4.4 STRUCTURAL (CONSTITUTIONAL) ISOMERISM

Structural isomerism is also known as ‘constitutional isomerism’. Structural isomerism arises
when a molecule can be represented in to two or more than two different structures. The
difference in structure is due to the difference in the arrangement of atoms within the molecules,
irrespective of their position in space. In other words, structural isomers are compounds those
have identical molecular formulae but different structural formulae; and the phenomenon is
called structural isomerism.
Examples 1: Structural isomer of Butane (C4H10) and Bromobutane (C4H9Br)
CH3CH2CH2CH3 CH3CH2CH2CH2Br
n-Butane 1-Bromobutane
C4H10 C4H9Br
Butane CH3CHCH3 Bromobutane CH3CHCH2CH3

CH3 Br
Isobutane 2-Bromobutane

Structural isomerism can also be subdivided in to five types.

1) Chain Isomerism
2) Functional Isomerism
3) Position Isomerism
4) Metamerism
5) Tautomerism
1) Chain Isomerism:

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Chain isomers are those isomers having difference in the order in which the carbon atoms are
bonded to each other. In other words chain isomers have variable amounts of branching along the
hydrocarbon chain.
If you observe two or more than two molecules having similar molecular formulae, but
difference in their hydrocarbon chain length, you should recognize them as chain isomers
of each other.

Example 2: Chain isomers of Butane (A) and Pentane (B)

A) C4H10 B) C5H12
Butane Pantane CH3
CH3CH2CH2CH3 CH3CHCH3 CH3CH2CH2CH2CH3 CH3CHCH2CH3 CH3CCH3

CH3 CH3 CH3

n-Butane Isobutane n-Pantane Isopetane Neopetane

2) Functional Isomerism:
Two or more than two molecules those having the same molecular formulae but have different
functional groups are called functional isomers and the phenomenon is termed as functional
isomerism.
If you observe two or more than two molecules having same molecular formulae, but
difference in their functional groups, you should understand that these are functional
isomers of each other.
Example 3: Ethyl alcohol and Dimethyl ether
CH3CH2OH CH3OCH3
Ethyl alcohol Dimethyl ether
Example 4: n-Butyl alcohol and Diethyl ether
CH3CH2CH2CH2OH CH3CH2OCH2CH3
n-Butayl alcohol Diethyl ether
3) Position Isomerism:
Two or more than two molecules those having same molecular formulae but having difference in
the position of functional group on the carbon chain are called position isomers and the
phenomenon is called as position isomerism.

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If you observe two or more than two molecules having same molecular formulae, but
difference in their functional groups, you should understand that these are functional
isomers of each other.
Example 5: 1-Butene and 2-Butene
CH 3CH2CH CH 2 CH 3CH CHCH3
1-Butene 2-Butene
Example 6:1-Butyl alcohol, 2-Butyl alcohol and t-Butyl alcohol
CH3
CH3CH2CH2CH2OH CH3CHCH2CH3 CH3C OH

OH CH3
1-Butyl alcohol 2-Butyl alcohol t-Butyl alcohol

4) Metamerism:
Two or more than two molecules those having same molecular formulae and functional group
but having difference in the distribution of carbon atoms on either side of functional group are
called metamers and the phenomenon is called the metamerism.
When you see two or more than two molecule with identical molecular formulae but
while structural representation you observe there is a difference in the alkyl group
attached to same functional group you should understand these molecules are
metamers of each other.
Example 7: Diethyl ether, Methylpropyl ether and isopropyl methyl ether
CH3
CH3CH2OCH2CH3 CH3CH2CH2OCH3 CH3CHOCH3
Diethyl ether Methyl propyl ether Isopropyl methylether

Example 8: Diethyl amine, Methylpropyl amine and isopropyl methyl amine

CH3
CH3CH2NHCH2CH3 CH3CH2CH2NHCH3 CH3CHNHCH3
Diethyl amine Methyl propyl amine Isopropyl methylamine

5) Tautomerism:
This is a special kind of isomerism where both the isomers are interconvertible and always exist
in a dynamic equilibrium to each other. Due to their interconversion change in functional group

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takes place that gives two different isomers of an organic compound. This phenomenon is called
Tautomerism.
When you observe two different isomeric forms of an organic compound are rapidly
interconvertible to each other you should recognize them as tautomer of each other.
Remember: Tautomers are not the resonance structure of same compound
Example 9: Acetone exists in taotomeric equilibrium with Prop-1-en-2-ol
O OH
CH3CCH 3 CH3C CH2
Acetone Prop-1-ene-2-ol
(keto form) (enol form)
<99% >1%
Example 10: Tautomeric forms of Ethyl acetoacetate under taotomeric equilibrium

O O OH O
CH3CCH2COC2H5 CH3C CHCOC2H5
(keto form) (enol form)
93% 7%

4.5 STEREO (or CONFIGURATIONAL) ISOMERISM

Stereoisomerism is arises due to the difference in arrangement (configuration) of atoms or
groups in space. When two or more than two isomers have the same structural formulae but
having difference in the arrangement (configuration) of atoms in space are called stereo isomer
and the phenomenon is called stereo isomerism.
Stereo isomerism can be further classified as
i. Geometrical or cis-trans isomerism
ii. Optical isomerism
4.5.1 GEOMETRICAL ISOMERISM:
Geometrical isomerism is generally observed in alkenes and cyclic compounds due to their
restricted rotation around carbon- carbon bond. The rotation about a double bond in alkene or
about a single bond in a cyclic/ring like compound is restricted. Double bonded system consists
of a σ (sigma) and a π (pi) bond perpendicular to each other. It is not possible to rotate the
molecule about carbon-carbon bond. The rotation will break the π bond as a result the molecule
will lose its identity. In some cased the rotation about single bond is also restricted due to steric

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hindrance. Geometrical isomerism is shown by various groups of compounds the major class of
compounds that exhibit geometrical isomerism are classified as:

i. Compounds having double bond;

C=C, C=N, N=N

For example cis- and trans-2-butene have same connection of bond and molecular formulae.

If you observe two similar groups are on the same side of C=C bond this is
called cis- isomer; whereas, if two similar groups are on opposite side of C=C
bond this is known as trans- isomer.

Example 1: cis- and trans- isomerism in 2-butene

H3C CH3 H3C H

H H H CH3

cis-2-butene trans-2-butene

You can understand that due to the presence of one σ (sigma) and one π (pi) bond in
carbon–carbon double bond, rotation around C=C bond is not possible. The restricted
rotation around C=C bond is responsible for geometrical isomerism in alkenes.
ii. Cyclic compounds like homocyclic, heterocyclic and fused-ring systems

You can easily observe that rotation around C-C bond is also not possible in cyclic compounds
as the rotation would break the bonds and break the ring. Thus Geometrical isomerism is also
possible in cyclic compounds.

Example 2: cis- and trans- isomers of 1,2-dimethylcyclopropane

CH3 CH3

H H
CH3 H

H
cis trans CH3

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Conditions for geometrical isomerism:

Following two conditions are necessary for any compounds to show geometrical isomerism

a) There should be restricted (not allowed) rotation about a bond in a molecule.

b) Both substituent/atoms on each carbon about which rotation is not allowed should
(restricted) be different.

Remember: Geometrical isomers are non-mirror image of each other hence they are
called diastereomers. Therefore their physical and chemical properties are different.
Triple bonded molecules do not exhibit any kind of stereoisomerism because such
molecule shows cylindrical symmetry.
E & Z system of nomenclature for geometrical isomers:

We have already discussed about the cis- and trans- nomenclature of geometrical isomerism. The
cis- and trans- nomenclature is the oldest and most fundamental nomenclature system for
geometrical isomerism. The cis- and trans- nomenclature system is applicable only for those
geometrical isomers in which at least one identical atoms/groups is bonded with each double
bonded carbon. If both the identical groups/atoms are on same side of double bond the isomer is
called as cis- isomer; whereas, if both identical groups/atoms are on opposite side of the double
bond the isomer is called as trans- isomer (see example 1 of this unit).

The cis- and trans- nomenclature method is limited to the molecule in which identical
groups/atoms are attached to double bonded carbon. If all the atoms/groups on double bonded
carbon are different then the configuration of such molecule could not be assigned as cis- and
trans- nomenclature. A more general nomenclature (i.e. E/Z nomenclature) was introduced
which was based on Cahn-Ingold-Prelog system. In E/Z system the configuration is specified by
the relative positions of two highest priority groups/atoms on the two carbons of the double
bond.

Let us understand the E/Z nomenclature system by considering an example which we have
already discussed in the beginning of this Unit (example 1).

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H3C CH3 H3C H

C C C C

H H H CH3
cis-2-butene trans-2-butene
You can easily identify which one is cis- isomer and which one is trans- just by looking the
position of similar atoms/groups. It is a simple and visual way of telling the two isomers apart.
So why do we need an alternative system?

Now consider one another example in which we will change all the atoms/groups in above
example by replacing one CH3- by Br, other CH3- by Cl, and one H- by F. Now try to predict the
nomenclature of these two isomers of 2-bromo-1-chloro-1-fluoroethene (I and II). Could you
name these isomers using cis- and trans- nomenclature? The simplest answer is ‘NO’.

Br Cl Br F

C C C C

H F H Cl
I II

Because all four atoms attached to the carbon-carbon double bond are different, therefore it is not
so simple that you can predict them as cis- and trans- to each other. The E/Z system of
nomenclature provides the most appropriate solution to above problem. This system is based on
the priority of the attached atoms/groups on each double bonded carbon. The priority of the
atoms/groups can be assigned as per the ‘Sequence Rule’ or ‘CIP Rule’ given by Cahn-Ingold-
Prelog. We have discussed the detail about ‘Sequence Rule’ in later part of this Unit. Now assign
priority to atoms/groups attached to each double bonded carbon in above example.

1 1 1 2
Br Cl Br F

C C C C
2 2 2 1
H F H Cl
Molecular Plane
I II

We can easily observe that the both higher priority atoms/groups on each double bonded carbon
of isomer I are on same side; whereas, the higher priority atoms/groups on each double bonded

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carbon of isomer II are on opposite side. If the two groups with the higher priorities are on the
same side of the double bond, such isomer is designated as the (Z)- isomer. So you would write it
as (Z)-name of compound. The symbol Z comes from a German word ZUSAMMEN, which
means together. If the two groups with the higher priorities are on opposite sides of the double
bond, then such isomer is designated as (E)- isomer. E comes from the German ENTGEGEN,
which means opposite. Thus in given example the isomer I is having both higher priority
groups/atoms are on same side of double bond, hence it is Z- isomer; whereas, the isomer II is
having both higher priority groups/atoms are on opposite side of the double bond, hence it is E-
isomer.

1 1 1 2
Br Cl Br F

C C C C
2 2 2 1
H F H Cl
Molecular Plane
I II
(Z)-2-bromo-1-chloro-1-fluoroethene (E)-2-bromo-1-chloro-1-fluoroethene

Example 10: Some other examples of geometrical isomers with E and Z configuration

1 2 1 2
H 3C F D F 1 1
H 3C C2 H 5
C C C C
2 1 2 1 C C
H Cl H Cl 2 2
H CH 3
(E)-1-chloro-1- (E)-Deuterated1-chloro-1-
(Z)-3-methylpent-2-ene
fluoroprop-1-ene fluoroprop-1-ene

1 1 1 2 2 2
H 3C OCH3 H 3C CH2OH H 3C CH 2CH3

C C C C C C
2 2 2 1 1 1
H OH H CHO C2H 5 CH CH2
(Z)-3-ethyl-4-
(Z)-1-methoxyprop-1-en-1-ol (E)-2-(hydroxymethyl)but-2-enal
methylhexa-1,3-diene

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Geometrical isomerism in oximes and cyclic compounds:

Nitrogen containing compounds like >C=N- as well as –N=N- bond also exhibit geometrical
isomerism. The important classes of compounds that exhibit geometrical isomerism due to
>C=N- bond are:
(a) Oximes
(b) Nitrones
(c) Semicarbazones
(d) Hydrazones

H Ph H3C Ph Ph CH3 Ph CH3

C C C C

N N N N
OH O H NH2 NHCONH2
(E)-1-(1- (E)-1-(1-
(Z)-benzaldehyde (E)-nitrone phenylethylidene) phenylethylidene)
oxime hydrazine semicarbazide

Oximes are the most common compounds among all above classes. Both carbon and nitrogen
atom in oxime are sp2 hybridized the C=N bond of oxime consists a sigma (σ) and a pi (π) bond.
Therefore, there is no free rotation possible around C=N bond; hence, oximes of aldehyde and
ketones (unsymmetrical) exhibit geometrical isomerism. The configuration of such compounds is
also based on priority of the groups/atoms attached to the double bonded carbon and nitrogen.
Lone pair of the nitrogen always considered to be the lowest priority group. The priority of the
groups/atoms is assigned as per the sequence rule which we have already discussed in Unit 4. If
the higher priority groups/atom on double bonded carbon and nitrogen are on same side of the
double bond the isomer is considered as Z- isomer, whereas if the higher priority groups/atoms
are on opposite side the isomer is considered as E- isomer.

Example 11:E/Z isomerism is shown by i) benzaldoxime, ii) ethylmethylketoxime and iii)

methylphenylketoxime

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H Ph Ph H H3C C2H 5 C2 H 5 CH3

C C C C
i) ii)
N N N N
OH OH OH OH
(Z)- (E)-
(Z)-benzaldehyde (E)-benzaldehyde ethylmethyl ethylmethyl
oxime oxime ketoxime ketoxime

Ph CH3 H 3C Ph
C C
iii)
N N
OH OH
(E)-acetophenone oxime (Z)-acetophenone oxime

We have already discussed that the geometrical isomerism is usually arises due to restricted
rotation about a bond. Since, there is no rotation possible about the carbon-carbon bond in a
cyclic compound or cycloalkanes like cyclopropane, cyclobutane, cyclopantane, cyclohexane,
etc. Hence, such molecule also exhibit geometrical isomerism, and can be designated as cis- and
trans- isomer. In a disubstituted cycloalkanes, where the two atoms/groups are bonded on
different carbons, can be represented in to two geometrical isomers. The isomer in which the two
atoms/groups are located on the same side of the ring is called cis-isomer; whereas, the isomer in
which the two atoms/groups are located on the opposite side of the ring is called trans-isomer.

Example 12: Geometrical isomers of disubstituted cyclopropane, cyclobutane, cyclopantane and

cyclohexane.
COOH H

CH3 CH3 CH3 H

HOOC H COOH COOH

H H H CH3
cis-1,2- trans-1,2- H cis-cyclobutane-1,3- H trans-cyclobutane-
dimethylcycl dimethylcycl
dicarboxylic acid 1,3-dicarboxylic
opropane opropane
acid

H H H CH3 CHO H H H

Cl CH3 Cl H H CHO CHO CHO

cis-1-chloro-3- trans-1-chloro-3- trans-cyclohexane- cis-cyclohexane-1,4-
methylcyclopentane methylcyclopentan 1,4-dicarbaldehyde dicarbaldehyde
e

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4.5.2 OPTICAL (CONFIGURATIONAL) ISOMERISM:

Optical isomerism is another class of stereoisomerism. The organic compounds that exhibit
optical isomerism must have a unique ability to rotate the plane polarized light either towards left
or towards right hand directions. This unique ability is generally known as optical activity.
Optical activity of any compound is measured by analyzing the sample in an instrument called
Polarimeter. A solution of known concentration of optically active compound is when exposed
to the beam of plane polarized light, the beam of plane polarized light is rotated through a certain
number of degrees, either to the clockwise (right) direction or anti-clockwise (left) direction. The
compound which rotates the plane polarized light towards clockwise direction is called to be
dextrorotatory (represented by +); whereas, the compound which rotates the plane polarized
light towards anti-clockwise direction is called to be levorotatory (represented by -). Figure 1
shows the schematic representation of polarimeter.

Figure 1. Schematic representation of simple polarimeter

The degree of rotation depends upon the number of the molecules of the compounds
falls in the path of beam. To compare the rotating power of different optically active
compounds, the specific rotation of each compound is calculated and then comparison
should be made.
Specific rotation is defined as the degree of rotation offered for the given wavelength
of plane polarized light at given temperature by a solution of 1g/mL concentration is
filled in a 10 cm length sample cell. Specific rotation is represented by and can
be calculated as

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Where α is observed angle of rotation; t is the temperature of during experiment; λ is the

wavelength of light used; l is the length of the tube in decimeter; and c is the concentration of the
compounds per 100 mL of solution.
i. Remember:
Optically active compounds always exist in two isomeric forms which rotates the plane polarized
light by equal degrees in opposite directions. The optical isomer which rotates the plane
polarized light towards right (clockwise direction) is known as Dextrorotatory Isomer or (+)-
isomer, whereas, the optical isomer which rotates the plane polarized light towards left
(anticlockwise direction) is known as Levorotatory Isomer or (-)-isomer.

4.6 ELEMENTS OF SYMMETRY

All optically active molecules/object are chiral and they exhibit enantiomerism (Figure 2). A
chiral molecule is that which cannot be superimposed on its mirror image; however, both the
non-super imposable isomers are called enantiomers. We will learn more about chirality and
enantiomerism in separate section of this unit.

Figure 2. (a) Non super imposable mirror image relationship of right and left hands. (b) Ball and
stick model of tetravalent chiral carbon atom.

Elements of symmetry are a simple tool to identify whether a molecule is chiral or not. The
necessary condition for optically active molecule to be chiral is that, the molecule should not
possess any kind of symmetry elements. The elements of symmetry are generally categorized as
follows:
(i) Simple axis of symmetry (Cn)
(ii) Plane of symmetry (σ)
(iii) Centre of symmetry (Ci)

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(iv) Alternating axis of symmetry (Sn)

(i) Simple axis of symmetry (Cn):

When a rotation of 360°/n (where n is any integer like 1,2,3…etc.) around the axis of a molecule
or object is applied, and the rotated form thus obtained is non-differentiable from the original,
then the molecule/object is known to have a simple axis of symmetry. It is represented by Cn.
Example 13: Water molecule has C2 (two fold axis of symmetry) whereas chloroform has C3
axis of symmetry.

H
O
C
Cl
H H Cl
Cl
C2 C3
water Chloroform

From above example you can easily understand that if you rotate the water molecule
by 180° (i.e. 360°/2=180°) along its molecular axis you will get the identical (non-
differentiable) form of water molecule, hence water molecule has two fold of
symmetry. Similarly, if you rotate the chloroform molecule by 120° (i.e. 360°/3=120°)
along its molecular axis you will get the identical (non-differentiable) form of
chloroform molecule, hence chloroform molecule has three fold of symmetry.

(ii) Plane of symmetry (σ):

It is defined as ‘when a plane that devised a molecule or object in to two equal halves which are
related to object and mirror image is known as plane of symmetry. It is represented by σ.
Example 14: Plane of symmetry in Tartaric acid
Palne that devides
d molecule in two equal halves COOH
a C b H C OH
a C b H C OH

d COOH
Sybmbolic representation 2,3-dihydroxysuccinic acid
(Tartaric acid)

From above example you can easily understand that if we put a mirror plane/reflection
plane exactly at the centre axis of the molecule/object; you will found that the mirror

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image thus obtained is the complementary of the original and both will give us the
appearance of complete molecule/object.

COOH
Real object
H C OH
H C OH
Mirror palne that devides Mirror image of
molecule in two equal halves COOH real object

2,3-dihydroxysuccinic acid
(Tartaric acid)

(iii) Centre of symmetry (Ci):

A molecule has a centre of symmetry when, for any atom in the molecule, an identical atom
exists diametrically (diagonally) opposite to this centre and at equal distance from it.
Example 15: An isomer of 1,3-dichloro-2,4-dibromocyclobutane has a centre of symmetry

H Cl

Br H
H Br

Cl H
Center of Symmetry
(Ci)

From above example you may understand that all the identical atoms are situated
diagonally and at equal distance from the centre. This is called centre of symmetry.

(iv) Alternating axis of symmetry (Sn):

An alternate axis of symmetry is defined as, when a molecule is rotated by 360°/n degrees about
its axis and then a reflection plane is placed exactly at perpendicular to the axis, and the
reflection of the molecule thus obtained is identical to the original. It is represented by Sn.

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Example [Link] isomer of 1,3-dichloro-2,4-dibromocyclobutane has a 2 fold alternate axis of

symmetry

H Cl Br H

Br H H Cl
180o roation
H Br Cl H
about axis

Cl H H Br Mirror Plane perpendicular to

axis of rotation

H Cl
Same

Br H
H Br

Cl H

MOLECULAR CHIRALITY, ENANTIOMERISM:

The necessary condition for a molecule to have optical isomerism is that molecule should not
have any kind of symmetry elements present in it, in other words the molecule should be
dissymmetric. Such molecules are called ‘Chiral’ and the property is called ‘molecular
chirality’. Optically active chiral molecules which are non-super imposable on their mirror
images are called ‘enantiomers’ and the phenomenon is known as ‘enantiomerism’. To exhibit
optical isomerism an organic compound must have at least one asymmetric carbon atom. An
asymmetric carbon atom is that which is bonded to four different atoms or groups.
We can easily understand the chirality by comparing our hands (left hand and right
hand). Our left hand and right hand are the best example of non-super imposable
mirror image of each other. Each hand is therefore considered as chiral.
ii. Remember: Our left hand and right hand are non-super imposable mirror image of
each other each one of them is chiral.

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iii. Remember: Chirality is the necessary and sufficient condition for the existence of
enantiomers.
Example [Link] acid has two asymmetric carbon and it exists in four forms, out of them two
form are optically active and two are optically inactive.
Two asymmetric
COOH carbon atoms of
chiral Tartaric acid
H C* OH
*
H C OH

COOH
Mirror plane divides molecule in two equal
halves

COOH COOH COOH COOH

HO C H H C OH H C OH HO C H

H C OH HO C H H C OH HO C H

COOH COOH COOH COOH

Non-superimposable mirror images Non-superimposable mirror images

(Enantiomers) with each one having plane of symmetry
optically inactive

4.7 STEREOGENIC CENTRE (STEREOGENICITY)

As we discussed in previous section that if a molecule contains one carbon atom which is
directly bonded with four different groups or atoms, and the molecule do not have any kind of
symmetry element present in it, such molecule is called asymmetric or chiral.
When the interchange of the position of two directly bonded groups or atoms of a centre carbon
atom results a new stereoisomer, such chiral centre is called stereo centre or stereogenic centre
and the property is called stereogenicity.

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If the new stereoisomer is a non-super imposable mirror image of the original molecule such
carbon centre is called chiral carbon centre.
iv. Remember: All the chiral centers are stereogenic centers but all stereogenic centers
are not chiral centre.
Example 18: Bromochlorofluoroidomethane exhibits chiral carbon centre
interchange
F F and Cl Cl

I C Cl I C F

Br Br

Interchange of F and Cl results

non-superimposable stereoisomers
4.7.1 OPTICAL ACTIVITY (ENANTIOMERISM):
It is already known to you (from section 4.5) that the optical activity is an ability of a chiral
molecule to rotate the plane of plane-polarized light either towards left or right direction. The
rotation is measured by an instrument called Polarimeter. When a beam of plane polarized light
passes through a sample that can rotate the plane polarized light, the light appears to dim because
it no longer passes straight through the polarizing filters. The amount of rotation is quantified as
the number of degrees that the analyzing lens must be rotated to observe the no dimming of light
appears. Optical rotation can be measured by using the following formulae

Where α is observed angle of rotation; t is the temperature of during experiment; λ is the

wavelength of light used; l is the length of the tube in decimeter; and c is the concentration of the
compounds per 100 mL of solution.
Optically active chiral compounds that are non-super imposable mirror image of each other are
called enantiomers.
4.7.2 Properties of enantiomers:
The main properties of enantiomers are given as follow
Enantiomers always exist in pair
Enantiomers are non-super imposable mirror image to each other

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Enantiomers have same physical properties (like boiling point, melting point, solubility,
density, viscosity, refractive index etc.)and chemical properties in achiral environment
Each enantiomers have opposite behavior with respect to plane polarized light, if one of
them will rotate the plane polarized light towards right hand direction then definitely the
other will rotate the plane polarized light towards left hand direction.
Each enantiomers shows the same chemical reactivity with achiral reagent; however
they have different reactivity with chiral reagent.
Example 19: Glyceraldehyde molecule is a chiral molecule. It has a pair of enantiomers with
same physical properties except their behavior towards plane polarized light
Mirror CHO
CHO

HO C H H C OH

CH2OH CH2OH Enantiomeric pair of

Glycerldehyde
Molecular formula : C3H6O3 Molecular formula : C3H 6O3
Mol. Wt.: 90.08 Mol. Wt.: 90.08
Boiling point : 228oC Boiling point : 228oC
Melting point : 145 °C Melting point : 145 °C
Density : 1.455 g/cm3 Density : 1.455 g/cm3

You can see that the glyceraldehyde molecule can exists in two enantiomeric forms
which differ only in the arrangement of bonded atoms around the centre chiral
carbon. The physical properties (like molecular formula, molecular weight, melting
point, boiling point and density etc.) of both the isomers are same. But if one isomer
will rotate the plane polarized light towards right hand direction (dextrorotatory) then
the other one will rotate the plane polarized light towards left hand direction
(levorotatory).
4.7.3 CHIRAL AND ACHIRAL MOLECULES WITH TWO
STEREOGENIC CENTRES:
As we have discussed earlier in this unit (sec. 4.6) that chiral molecules are those in which the
centre carbon atom is bonded directly through four different atoms/groups and do not have any
kind of symmetry element present in it and the molecule has non-super imposable mirror image.
However, those molecule in which centre carbon atom is directly bonded through four different

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atoms of groups and it satisfied any kind of symmetry elements are called achiral molecule.
Achiral molecules have super imposable mirror images.
Let us consider the stereoisomers of Tartaric acid which has two stereo centers with identical
atoms/groups attached to both the stereo centers. The tartaric acid have two stereo centers and
can have four stereoisomers out of which two stereoisomers are non-super imposable mirror
image of each other called enantiomers and chiral; and rest two are identical to each other and
also have plane of symmetry hence it can be divided in to two equal halves, therefore are achiral.
Example 20: Tartaric acid has two stereo centers with three stereoisomers (two are chiral and
one achiral stereoisomer)

Mirror
COOH COOH COOH
Mirror H C OH
HO C H H C OH
H C OH HO C H H C OH

COOH COOH COOH

Chiral Tartaric acid Achiral Tartaric acid

4.7.4 DIASTEREOMERS:
Diastereomers are those stereoisomers that are not mirror image of each other, in other words
you can understand the diastereomers are stereoisomers that are not enantiomers. Diastereomers
are non-enantiomeric stereoisomers with two or more stereo centers. The pair of stereoisomer
that differs in the arrangement of atoms/groups bonded with at least one stereo centre is called
diastereomers.
Example 21: D-Galactose, D-Glucose and D-Mannose are the non-mirror image stereoisomer of
each other. Therefore are called diastereomers.
CHO CHO CHO

H C OH H C OH HO C H

HO C H HO C H HO C H
HO C H H C OH H C OH
H C OH H C OH H C OH
CH2OH CH2OH CH2OH
D-Galactose D-Glucose D-Mannose

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Example 22: cis- and trans-2-butenes are non-mirror image stereoisomers of each other hence
are called diastereomers.
H3 C CH3 H 3C H

H H H CH3

cis-2-butene trans-2-butene

4.7.5 PROPERTIES OF DIASTEREOMERS:

The main properties of diastereomers are given as follows:
All the stereoisomers except enantiomers are diastereomers.
Diastereomers have different physical properties like boiling point, melting point,
density, solubility, density, viscosity, refractive index etc.
Diastereomers have different chemical properties like rates of reactions, reactivity
even in achiral reaction medium.
This difference in physical and chemical properties of diastereomers is very
useful in the separation of enantiomers from their mixture.

4.7.6 ERYTHRO (SYN) AND THREO (ANTI) DIASTEREOMERS:

Threo and erythro nomenclature method is designated by organic chemists to assign appropriate
name to diastereomers. The threo and erythro naming is given only to those diastereomers
having two adjacent stereocentres. The nomenclature is applicable to these diastereomers if there
are two common atoms/groups bonded to each adjacent stereo centre. In other words the terms
erythro and threo are generally applied only to those molecules which do not have symmetric
ends. However, when the ends are symmetric then instead of erythro and threo the meso and dl
nomenclature is preferred. We will discuss separately about meso and dl in this unit.
If the similar groups/atoms on adjacent stereocentres of diastereomer are on same (syn) side it is
designated as erythro, whereas if the similar groups/atoms on adjacent stereocentres of
diastereomer are on opposite (anti) side the diastereomer is designated as threo.
Example 23: You can easily understand the erythro and threo nomenclature by taking examples
of 3-bromo-2-butanol and 2,3-dibromo pentane.

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CH3 CH3 CH2CH3 CH2CH3

H C Cl Cl C H H C Br Br C H

H C OH H C OH H C Br H C Br

CH3 CH3 CH3 CH3

Erythro Threo Erythro Threo

3-Chloro-2-butanol 2,3-Dibromopentane

You can see if both the hydrogen atom on two adjacent stereocentres of 3-chloro-
2butanol lies on same (syn) side the isomer is called erythro, whereas, when both the
hydrogen atoms on two adjacent stereocentres of 3-chloro-2butanol lies on opposite
(anti) side the isomer is called threo. Similarly you can find the same observation with
2,3-dibromopentane and designate the isomers as erythro and threo.
You must also remember that the each erythro and threo stereo isomer can have their
non-super imposable mirror image (enantiomers). Thus there will be always one
enantiomeric pair of erythro and one enantiomeric pair of threo stereoisomer exists
for a stereoisomer with two similar atoms on adjacent stereocentres.

4.7.7 MESO COMPOUNDS:

A compound with two or more carbon stereo centre but also having a plane of symmetry is
called meso compounds. All the carbon centers have four different atoms/groups but the
compound can be divided in to two equal halves which are super imposable mirror image.
Example 24: 2,3-dibromobutane have two stereocentres, but the molecule have two symmetric
ends therefore it can be divided in to two equal halves. In other words the molecule have plane of
symmetry.

CH3 Mirror CH3

H C Br Br C H

H C Br Br C H

CH3 CH3
2,3-Dibromobutane

We can see that even the 2,3-dibromobutane have non super imposable mirror image
but this molecule have an internal plane of symmetry hence this molecule is optically

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inactive or achiral. This molecule will not be able to rotate the plane polarized light in
any direction. If one half of the molecule will rotate the plane polarized light towards
right hand direction with some degrees; the other half will rotate the plane polarized
light towards left hand direction with same degrees of rotation. Thus the net rotation
of the plane polarized light is zero. Such molecules are called meso compounds.

CH3

H C Br Direction of rotation of
plane polarized light
H C Br

CH3

Example 25: Another example of meso compound is one of the stereo isomeric forms of
Tartaric acid (2, 3-dihydroxysuccinic acid). The molecule is optically inactive because it has
internal plane of symmetry.
COOH

H C OH

H C OH

COOH
meso-Tartaric acid

4.8 RELATIVE AND ABSOLUTE CONFIGURATION

Relative and absolute configuration of a compound discusses about the spatial arrangement of
atoms/groups around the centre chiral atom. Relative configuration is a comparison of the spatial
arrangement of attached atoms/groups of two different chiral centers. Relative configuration is a
geometrical property which do not changes on reflection; whereas, the absolute configuration is
the precise arrangement of atoms in three dimensional space. The D/L system is usually known
as relative configuration whereas, the R/S stereo descriptor or nomenclature system for chiral
molecules is known as absolute configuration. The absolute configuration is a topographic
property which changes on reflection.

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4.8.1 D/L NOMENCLATURE:

The D/L nomenclature is the oldest nomenclature system for enantiomers. In this nomenclature
system the configuration of all the compounds were given with respect to glyceraldehyde
molecule, where the configuration of glyceraldehyde molecule is taken as an arbitrary standard.
According to this nomenclature if in glyceraldehyde molecule the –OH group on right and –H on
left, the –CHO and –CH2OH groups being on top and bottom, respectively the molecule is
designated as (+) Glyceraldehyde and it was arbitrary given the configuration symbol D. The
mirror image of this compound (-) glyceraldehyde was given the configuration L.
CHO CHO

H C OH HO C H

CH2OH CH2OH
D-(+)-glyceraldehyde L-(+)-glyceraldehyde
Any compound that can be prepared, or converted in to D-(+)-glyceraldehyde will belong to D
series (relative configuration), whereas, any compound that can be prepared, or converted in to
L-(+)-glyceraldehyde will belong to L series.
Example 26: Lactic acid obtained from D-(+)-glyceraldehyde and hence assigned D
configuration
CHO COOH COOH
i. Oxiation Reduction
H C OH H C OH H C OH
ii. PBr3
CH2OH CH2Br CH3
D-(+)-glyceraldehyde D-(+)-Lactic acid

Remember:
There is no correlation between the D and L designation and the sign of rotation. D
form of isomer may be levorotatory, and L form of isomer may be dextrorotatory and vice
versa.
The D/L nomenclature is limited to the compound that can pe prepared or converted
from the glyceraldehyde.
It is limited to only one chiral atom.

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4.8.2 R/S NOMENCLATURE:

Since you have been noted from the above discussion on D/L configuration, there are several
drawbacks associated with the D/L nomenclature system. Hence a definite and universally
applicable nomenclature system was needed to specifying the absolute configuration of each
chiral centre in a molecule. Cahn and coworkers (1956, 1966) have proposed a new and
universally applicable nomenclature pattern for the determination of absolute configuration of
any chiral molecule. This is known as the R/S system or Cahn-Ingold-Prelog (CIP)
nomenclature. It involves following two steps.
In first step we need to assign the priority to the four different atoms/groups attached
to a chiral centre.
Priorities to the groups/atoms can be assigned as per the sequence rule.
After assigning the priority to the atoms/groups attached to the chiral centre, the
molecule is oriented in such a way that the lowest priority group is directed away to
the observer.
Now the arrangement of the remaining atoms/groups is viewed by following
deceasing order of priorities from highest priority to lowest priority.
While viewing the atoms/groups in their decreasing order if your eyes follow the
clockwise direction then the chiral centre will have R configuration; whereas if your
eyes follow anticlockwise direction the chiral centre will have S configuration.
When a molecule has two or more than two chiral centers then the same process
should be followed to assign their configuration.
4.8.3 SEQUENCE RULE:
To assign the priorities to all four different groups/atoms attached with the chiral centre
following sequence rule should be followed. The sequence rule is given by the three scientists
Cahn-Ingold-Prelog therefore it is also called the CIP rule. The sequence rules are arbitrary but
consistent. The main observations of sequence rules are listed below.
1. If all the atoms directly attached to the chiral centre are different, the sequence of
priorities is determined by their atomic number. The atom with higher atomic number is
given higher priority. If two atoms are isotopes of same element, the isotope with higher
mass number has the higher priority.

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(4) (4)
H H Deuterium (D) is an isotope
(3) (2) (3) (2) of Hydrogen with mass
OH C Cl D C Cl number 2 hence get higher
priority than H
Br Br
(1) (1)
Bromochloromethanol Deuterio bromochloromethane
1-2-3 order is anticlockwise 1-2-3 order is anticlockwise
the configuration is S the configuration is S

2. If two or more atoms attached to the chiral centre having same atomic number, the
priorities are assigned by comparing the atomic numbers of the next atoms attached to
each group/atom.
(4)
H
(2) (3)
CH3CH2 C CH3

Br
(1)
2-bromobutane
1-2-3 order is clockwise
configuration is R

3. If the atoms or groups attached to the centre atom are further linked with some other
atoms via double and triple bonds. Then the double or triple bonded atoms are considered
to be duplicate or triplicate. As per sequence rule the triple bond gets priority over double
bond, similarly double bond gets priority over single bond.
O (2) H (4)
C H
(4) (1) (3) O
H C OH HOH2C C C (2)
H
CH2OH OH
(3) (1)
2,3-dihydroxypropanal
1-2-3 order is anticlockwise
configuration is S

4.9 NEWMAN AND SAWHORSE PROJECTION FORMULA

The different spatial arrangements of atoms in a molecule which is readily interconvertible by

rotation about single bonds are called conformations. The study of various preferred
conformations of a molecule and the correlation of physical and chemical properties to the most

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preferred conformer is called conformational analysis. Due to rapid interchange of the spatial
positions of groups/atoms these conformers are non-separable under normal conditions. Since,
different conformations arises because of the rotation about single bonds, hence, they are also
called the rotamers. The conformational and configurational isomerisms are related to energy
barrier for interconversions of different spatial arrangements of atoms in a molecule. If the
energy barrier for interconversion of different spatial arrangements is between 0.6 kcal/mol-16.0
kcal/mol; it result the conformational isomers or conformers; whereas, if this energy barrier is
more than or equal to 16 kcal/mol than the configurational isomers are obtained.

The Newman representation formula: Newman Projections are used mainly for determining
conformational relationships. Recall that, conformers are molecules that can be converted into
one another by a rotation around a single bond. Newman Projections are also useful when
studying a reaction involving prochiral molecules that have a double bond, in which the addition
of a new group creates a new [Link] this notation, you are actually viewing a molecule
by looking down a particular carbon-carbon bond. The Newman representation formula is a
planar representation of the sawhorse formula. The molecule is viewed along the axis of a
carbon-carbon bond. The carbon atom in front of the viewer is represented by a dot (●), whereas
the carbon atom away to the viewer is represented by circle. The rest of the atoms/groups are
located on each carbon atoms at +120° or -120° angles to each other as shown below:

H H
H H H
H H
Circle carbon
120o

H H
H HH
Ponit Carbon

Newman representation formula of ethane

Addition of more carbons makes Newman Projections more complicated. For example, Newman
Projections can be made for butane, such that it’s eclipsed, gauche, and anti-conformations can
be seen. (Recall that these three forms of butane are conformational isomers of one another.) In
this case, the front dot represents the second carbon in the butane chain, and the back circle

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represents the third carbon in the butane chain. The Newman Projection condenses the bond
between these two carbons.

CH3 H
H H H
H H
Circle carbon
120o

H H
CH3 CH3
CH3
Ponit Carbon

Newman representation formula of butane

The Sawhorse representation formula: Sawhorse Projections are very similar to Newman
Projections, but are used more often because the carbon-carbon bond that is compressed in a
Newman Projection is fully drawn out in a Sawhorse Projection. When properly laid-out,
Sawhorse Projections are useful for determining enantiomeric or diastereomeric relationships
between two molecules, because the mirror image or superimposibility relationships are clearer.
Like with Newman Projections, a Sawhorse Projection is a view of a molecule down a particular
carbon-carbon bond, and groups connected to both the front and back carbons are drawn using
sticks at 120 degree angles. Sawhorse Projections can also be drawn so that the groups on the
front carbon are staggered (60 degrees apart) or eclipsed (directly overlapping) with the groups
on the back carbon. Below are two Sawhorse Projections of ethane. The structure on the left is
staggered, and the structure on the right is eclipsed. These are the simplest Sawhorse Projections
because they have only two carbons, and all of the groups on the front and back carbons are
identical. The sawhorse representation formula is the spatial arrangement of all the atoms/groups
on two adjacent carbon atoms. The bond between adjacent carbon atoms is represented by a
diagonal line and rest of the atoms are located on each carbon at +120° or -120° angles to each
other. The sawhorse representation is shown as:

diagonal line H
H H

H H
OR
120o H H 120o H
H
viewpoint H
H viewpoint H

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Sawhorse representation formula of ethane

Addition of more carbons makes Sawhorse Projections slightly more complicated. Similar to
Newman Projections, Sawhorse Projections can also be made for butane, such that it’s eclipsed,
gauche, and anti-conformations can be seen. (Recall that these three forms of butane are
conformational isomers of one another).

CH3
H H H CH3
CH3 CH3 CH3

120o H H 120o CH3 120o H

H H H H H H

Eclipsed Anti Gauche

Sawhorse representation formula of butane

4.10 FISCHER AND FLYING WEDGE FORMULA

The sp3 hybridized tetrahedral carbon is three dimensional in nature. Generally it is very difficult
to represent a three dimensional structure in a two dimensional plane paper. There are many
methods have been developed for two dimensional representation of a three dimensional
structure. Out of them the flying-wedge and Fischer representation methods are most commonly
used for two dimensional representation of a three dimensional structure.

The flying-wedge: This is the most commonly used model for the two dimensional
representation of a three dimensional molecule. In this model the bonds are presented in
continuous, solid thick and dashed lines. A solid this line represents a bond projecting above the
plane of the paper; it is considered that the bond with solid thick line is pointing towards
observer. A dashed line represents a bond below the plane of the paper; it is considered that the
bond with dashed line is pointing away to the observer. The bonds with continuous lines
represent the bonds in the plane of paper. Let us consider an example of R-Lactic acid and S-
Lactic acid.

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On the
O OH plane O OH

Below the
plane
H3C OH H3C OH
H
H
R-lactic acid S-lactic acid
above the
plane

Flying-wedge representation of R- and S-Lactic acid

Fischer projection formula: It is a simplification of flying-wedge representation, in Fischer

projection formula all bonds are drawn as solid lines in a plane paper. Fischer Projections are
used often in drawing sugars and hydrocarbons, because the carbon backbone is drawn as a
straight vertical line, making them very easy to draw. When properly laid-out, Fischer
Projections are useful for determining enantiomeric or diastereomeric relationships between two
molecules, because the mirror image relationship is very clear. In a Fischer Projection, each
place where the horizontal and vertical lines cross represents a carbon. The vertical lines are
actually oriented away from you (similar to dashes in the Wedge-Dash Notation) and the
horizontal lines are oriented toward you (similar to wedges in the Wedge-Dash Notation).

Fischer projection is not as demonstrative as flying –wedge representation. It does not represent
the actual shape of the molecule. Usually the Fischer projection formula is drawn so that the
longest carbon chain in the molecule is vertical with the highly oxidized group on the top.

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Let us consider an example for conversion of flying-wedge formula to Fischer projection

formula for R- and S- Lactic acid.
COOH COOH COOH

OH H C OH H C OH
H 3C
H view point CH3 CH3
(R)-Lactic acid
(R)-Lactic acid
Fischer Projection

COOH COOH COOH

OH HO C H HO C H
H 3C
H view point
CH3 CH3
(S)-Lactic acid (S)-Lactic acid
Fischer Projection

Conversion of flying wedge to Fischer projection formula for Lactic acid

4.11 RACEMIC MIXTURE (RACEMATES)

A Racemic mixture is an equimolar mixture of a pair of enantiomers. The racemic mixture or

racemates are optically inactive due to mutual or external compensation of two enantiomeric
constituents. Racemic mixture in liquid and vapor phase shows physical properties (like boiling
points, density, refractive index etc.) identical to those of pure enantiomers. However, the solid
phase enantiomeric mixtures have some properties different from the pure enantiomers.

i. Remember: Racemic mixture is not a meso compound; since both are optically inactive.
The racemic mixture is an equimolar mixture of two enantiomers whereas meso is a
single compound. Meso compounds are optically inactive because of the internal
compensation; however, the racemic mixtures (racemates) are optically inactive
because of the external compensation.

You might have aware with that the enantiomerically pure compounds are of great importance in
chemical and pharmaceutical areas. But during the synthesis of optically active compounds using
achiral reaction condition and achiral reagents, it always gives racemic mixture (racemates).
Therefore to obtain the pure enantiomers we must have to separate the racemic mixture in to
corresponding pure enantiomers. Thus, the separation process of a racemic mixture in to its pure

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individual enantiomeric constituents is called resolution of racemic mixtures (resolution of

enantiomers).Since enantiomers have identical physical properties(like solubility, boiling point,
melting point, density, refractive index etc.),therefore, they cannot be separated by common
physical techniques such as direct crystallization, distillation or basic chromatography. There are
four general methods that are extensively being used for the resolution of racemic mixtures.
i. Mechanical separation (crystallization method) method
ii. Diastereomer formation method
iii. Chromatographic method
iv. Biochemical/enzymatic methods
Example 27: The addition of HBr on beta-Methyl styrene gives an equimolar mixture of
enantiomers.

H3C H H 3C H H3C H
+ HBr Br + H
H
H Br

50% S 50% R
beta-Methyl styrene enantiomer enantiomer

4.12 QUASI-ENANTIOMERS
Quasi enantiomers are defined as, two different chemical compounds those are closely related to
the sense of chirality. Although chemically different, they are sterically similar (isosteric) and are
still able to form a racemic crystalline phase. One of the compound have a property to rotate the
plane polarized light towards left hand direction; whereas, the other have a tendency to rotate the
plane polarized light towards right hand direction. The first quasi-enantiomeric pair was studied
by Pasteur in 1853.
Example 28: (R)-2-bromobutane is a quasi-enantiomer of (S)-2-chlorobutane.

H H
CH3CH2 C CH3 H3C C CH2CH3
Br Cl
(R)-2-Bromobutane (S)-2-Chlorobutane

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4.13 QUASI-RACEMATE
Quasi-racemate is defined as a 1:1 mixture of quasi-enantiomers that may form a compound, a
eutectic mixture, or a solid solution and shows typical compound behaviour in the phase
diagram.
Example 29: Equimolar mixture of (+)-Chlorosuccinic acid and (+)-Bromosuccinic acid form a
quasi-racemate and shows eutectic behaviour similar to that of a conglomerate.
H Cl H Br

COOH COOH
HOOC HOOC
(R)-2-chlorosuccinic acid (R)-2-bromosuccinic acid

4.14 STEREOCHEMISTRY OF ALLENES, SPIRANES;

BIPHENYLS, ANSA COMPOUNDS CYCLOPHANES AND
RELATED COMPOUNDS
In above sections of this unit we have discussed about the compounds containing one or more
stereocentres and their chirality is specified at these centres. However, there are a class of
compounds with nonsuperimposable mirror images it is not possible to identify a stereocentre,
then to predict the stereochemistry of such compounds it becomes necessary to focus our
attention on other aspects of the molecule. Thus, the presence of stereocentre is not a necessary
and sufficient condition for molecular dissymmetry. The overall chirality of a molecule can be
categorised in to three elements; i) stereocentres; ii) stereoaxes; and iii) stereoplanes, one other
element of chirality is still there and called helicity.

Chirality due to axes (Axial chirality): Such type of chirality is produced in a molecule when
there is no chiral centre present in the molecule. As discussed, in order to produce chirality it is
not necessary for all of the substituents to be different. However, it is sufficient to have each
substituent different from its nearest neighbour.

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When four atoms/groups attached to a central atom are located on the corners of tetrahedron the
central atom is termed as chiral centre. If the chiral centre is replaced by a linear grouping like C-
C or C=C=C, the tetrahedron geometry get extended along the axis of the grouping and thus
generates a chiral axis. Depending on the nature of groups attached with the carbon atoms, some
examples of molecules with chiral axis are allenes, biphenyls, alkylidenecycloalkanes, spiranes,
adamentanes etc.; are shown below (Figure 3).
a d
a a a d
a a d a
C C C b c
b c b b
b c
b b
Allene Biphenyl alkylidenecycloalkane Spirane Adamantane

Figure: 3 examples of molecules with chiral axis are allenes, biphenyls, alkylidenecycloalkanes,
spiranes and adamentane

Allenes: Allenes are compounds with two or more double bonds side-by-side. Such bonds are
called cumulated double bonds. The central carbon of allene forms two sigma bonds and two pi
bonds. The central carbon is sp-hybridized and the two terminal carbons are sp2-hybridized. The
two π-bonds attached to the central carbon are perpendicular to each other. The geometry of the
π-bonds causes the groups attached to the end carbon atoms to lie in perpendicular planes (Figure
4). The bond angle formed by the three carbons is 180°, indicating linear geometry for the
carbons of allene.

Figure 4: Planar depiction of allene molecule

Stereochemistry of Allenes: When three or more adjacent carbon atoms in a molecule are
bonded by double bonds, the compounds is called cumulene or said to have cumulative double

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bonds. Allene is the simplest example of this class. Allenes are chiral and they have
nonsuperimposable mirror images and exist as enantiomers although they have no chiral centre.
HOOC COOH
COOH HOOC
C C C C C C
H H
H H
Nonsuperimposable Mirror images
(Enantiomeric Pair)

Stereochemistry of Alkylidenecycloalkanes: The replacement of double bonds in allene by a

cycloalkane ring gives the alkylidenecycloalkane; such replacement does not change the basic
geometry of the molecule. The suitably substituted alkylidenecycloalkanes also exhibit
enantiomerism. The enantiomerism in such compounds is also due to the presence of chiral axis.
For example, 4-methylcyclohexyldene acetic acid has been resolved into two enantiomers.

H 3C H H
CH3
H COOH HOOC H

4-methylcyclohexyldene acetic acid

Stereochemistry of Spiranes: When both the double bonds in allenes are replaced with the ring
system the resulting compounds are known as spiranes or spiro compounds. The conditions for
chirality in spiranes are similar to those of allenes. The two rings of spiranes are perpendicular to
each other; therefore, proper substitution on the terminal carbon will make the molecule chiral
and thus exhibit enantiomerism. The chirality in the spiranes is also due to the presence of chiral
axis. For example, Diaminospiroheptane can be resolved in to its enantiomers.
H H H
H
NH2
H2N NH2 H2N
Diaminospiroheptane

Stereochemistry of Biphenyls: Stereoisomers obtained due to the restricted rotation about

carbon-carbon single bond are called atropisomers and the phenomenon is called
atropisomerism. Such compounds also have the chirality due to the axis. Suitably substituted
biphenyls exhibit enantiomerism due to the presence of chiral axis. This enantiomerism arises

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due to atropisomerism i.e. restricted rotation around C-C bond between two phenyl rings. This
steric hindrance of substituents at ortho- position of the each ring is responsible for such
restricted rotation. To maintain the maximum stability, molecule orients itself in such a manner
so that both the ortho- substituted phenyl rings lie in different plane.
Biphenyl shows the enantiomerism when the molecule has the following properties.
a) Each ring must be unsymmetrically substituted. Each of the rings should not contain any
kind of symmetry element.
a a a b a b
b b b

a b a b b b
I II III

nonresolvable Biphenyl resolvable Biphenyls

(optically inactive due to plane of (optically active due to absence
symmetry) of symmetry elements)

b) Suitable substitution (at least one substitution) at ortho- position must be there at each
rings.
c) othro- substituents must be larger in size (-Cl, -Br, -I, -COOH, -NO2, -NHCOCH3, -
SO3H, -R groups etc.).
The smaller groups at othro- position make the compounds planar in nature and thus do not
exhibit atropisomerism.
COOH
COOH HOOC

I II HOOC

nonresolvable Biphenyl nonresolvable Biphenyl

(optically inactive due to (optically inactive due to
plane of symmetry) centre of symmetry)

Chirality due to Plane (Planar Chirality): Chirality shown by a molecule due to the
asymmetry in molecular plane is called chirality due to plane. The chirality is particularly due to
the out of the plane arrangement of atoms or groups in the molecule with respect to reference
plane, hence called chiral plane. The most important example of the molecule with chiral plane is
cyclophanes. Other examples are trans-cyclooctene, bridged annulenes and metallocenes etc.

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CH2
n
CH2 CH2

O O

COOH HOOC
Br
Polymethylene ether of hydroquinone paracyclophane paracyclophane
(S)- (R)-

trans-cyclooctene

The polymethylene bridge is perpendicular to the plane of the benzene ring; the substituent Br
restricts the rotation of the benzene nucleus inside the methyl bridge, that makes the molecule
chiral. Similarly the simple paracyclophane can be resolved because the benzene ring cannot
rotate in such a way that the carboxylic passes through the acyclic ring. The plane of both the
aromatic rings is approximately parallel to each other. Similarly the trans-cyclooctene also
exhibits the chirality due to the presence of chiral plane.

4.15 SUMMARY
The stereochemistry, determines many chemical, physical and biochemical properties of
the compounds.
The types of stereo-chemical situations are divided into classes called geometrical
isomers, conformational isomers and configurational isomers.
All of the isomers are studied as a way to understand the shapes and properties of organic
compounds.
Alkenes and cyclic compounds display geometrical isomers.
In alkenes, geometrical isomers are labeled as cis- or trans- for the longest chain in the
alkene, or as E and Z for substituents of higher priority attached to the alkene.
Cyclic alkanes are designated only as cis- or trans-.
Stereochemistry is all about the 3Dimensional spatial aspects of chemistry.
Molecules that differ only in the arrangement of bonds in 3Dimensional space are
called "stereoisomers"

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Many objects (including molecules) are non-differentiable from their mirror images,
but other objects, such as your left and right hands, are differentiable. An object that has a
non-superimposable mirror image is said to be "chiral" (Greek = "handedness") and one
that has a superimposable mirror image is called "achiral".
Pairs of molecules that are non-superimposable mirror images of each other are called
"enantiomers"
The most common type of "chirality" is observed when a carbon atom has four
different groups attached to it. This carbon atom is then described as a chiral or
asymmetric or stereogenic center. This later term can also be contracted to a stereocenter.
Enantiomers have the same chemical and physical properties (melting points, boiling
points, heat of combustion etc.), except for their interaction with plane polarized light or
with other chiral molecules (reagents, solvents, catalysts, etc). (Think about how your
feet feel if you put them in the wrong shoes).
Diastereomers are stereoisomers that are not enantiomers.
The differing interaction with plane polarized light gives rise to optical activity.
Enantiomers cause the plane of polarized light to rotate in opposite directions, but to the
same extent (clockwise = +ve, counterclockwise = -ve). This can be measured using a
polarimeter. An achiral molecule is optically inactive.
A 50:50 mixture of a pair of enantiomers is called a racemic mixture. This is optically
inactive since the rotations produced by each of the enantiomers must cancel each other
out.
If there is more of one enantiomer than the other, then the optical purity of a sample can
be determined by measuring the rotation and comparing it to that of a pure enantiomer.
This can be used to establish the enantiomeric excess (ee) of the mixture.
Despite what one may observe, most molecules are not 2D objects, they are 3D as a
result of the spatial arrangement of the atoms, groups and bonds. The interaction of
molecules (reactions) which occur as the result of collisions between these 3D objects in
3D spacecan therefore also have 3D requirements and characteristics. Stereochemistry is
all about the 3D properties of molecules and reactions.

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4.16 TERMINAL QUESTION

1. What do you understand by Isomerism? Give its types.
2. What is chirality? Explain the necessary condition for a molecule to be chiral.
[Link] do you understand by optical activity? How is it measured?
4. What are enantiomers and diastereomers?
5. What are symmetry elements? How they affect optical isomerism?
6. Explain relative and absolute configuration.
7. What is racemization?

4.17 ANSWERS
Ans.1. When two or more compounds having the same molecular formula but difference in their
chemical and/or physical properties are called isomers and the phenomenon is known as
isomerism. Isomerism has following types:
a. Structural (constitutional) Isomerism
b. Stereo (configurational) Isomerism

Ans. [Link] organic compound with four different atoms/groups attached to center carbon and
have non-superimposable mirror image is called chiral compound and the phenomenon is called
chirality. The presence of four different atoms/groups attached to center carbon and absence of
any kind of element of symmetry are the necessary condition for a molecule to be chiral.

Ans. [Link] tendency of an organic compound to rotate the plane polarized light towards left or
right hand direction is called optical activity. Optical activity of any compound is measured by
analyzing the sample in an instrument called Polarimeter. A solution of known concentration of
optically active compound is when exposed to the beam of plane polarized light, the beam of
plane polarized light is rotated through a certain number of degrees, either to the clockwise
(right) direction or anti-clockwise (left) direction. The compound which rotates the plane
polarized light towards clockwise direction is called to be dextrorotatory (represented by
+);whereas, the compound which rotates the plane polarized light towards anti-clockwise
direction is called to be levorotatory (represented by -).

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Ans. [Link] active chiral compounds that are non-superimposable mirror image of each
other are called enantiomers. Whereas, optically active compounds which are non-mirror image
of each other are called diastereomers.

Ans. [Link] of symmetry are a simple tool to identify whether a molecule is chiral or not.
The necessary condition for optically active molecule to be chiral is that, the molecule should not
possess any kind of symmetry elements. The elements of symmetry are generally categorized as
follows:

(i) Simple axis of symmetry (Cn)

(ii) Plane of symmetry (σ)
(iii) Centre of symmetry (Ci)
(iv) Alternating axis of symmetry (Sn)
Optically active compound should not have any kind of symmetry elements.

Ans.6. Relative and absolute configuration of a compound discusses about the spatial
arrangement of atoms/groups around the centre chiral atom. Relative configuration is a
comparison of the spatial arrangement of attached atoms/groupsof two different chiral centres.
Relative configuration is a geometrical property which do not changes on reflection. The
absolute configuration is the precise arrangement of atoms in space. The D/L system is usually
known as relative configuration whereas, the R/S stereo descriptor or nomenclature system for
chiral molecules is known as absolute configuration. The absolute configuration is a topographic
property which changes on reflection.

[Link] process of conversion of an optically active compound in to the racemic

mixture/racemate is called racemization. The racemization process may take place under the
influence of temperature, light or chemical reagents.

Bibliography:

Following books are referred for compiling the material of present unit.

1. Organic Chemistry Vol. 1 by I L Finar, Published by Pearson Education; ISBN 10:

8177585428.

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2. Organic Chemistry by T. W. Graham Solomons, Published by John Wiley; ISBN-10:

1118133579.
3. Stereochemistry of Organic Compounds by Ernest L. Eliel; Published by John Wiley;
ISBN- 0-471-01670-5
4. Organic Chemistry by Leroy G. Wade. Published by Pearson Education; ISBN-
9780321768414
5. Stereochemistry: Conformation and Mechanism by P. S. Kalsi. Published by New Age
International Publication. ISBN-10: 8122435645;ISBN-13: 978-8122435641
6. Stereochemistry of Organic Compounds: Principles and Applications by D Nasipuri,
Published by New Academic Science ISBN-10: 190657491X; ISBN-13: 978-
1906574918

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UNIT 5: STEREOCHEMISTRY-II

CONTENTS

5.1 Objectives
5.2 Introduction
5.3 Topicity
5.3.1 Prochiral center and prochiral molecule
5.3.2 Homotopic ligands
5.3.3 Stereoheterotopic ligands
5.3.4 Prochirality
5.3.5 Homotopic ligands and faces
5.3.6 Enantiotopic ligands and faces
5.3.7 Nomenclature of enantiotopic ligands and faces
5.3.8 Diastereotopic ligands and faces
5.4 Asymmetric Induction or Synthesis
5.4.1 Principles of asymmetric synthesis
5.4.2 Stereospecific and stereoselective synthesis
5.5 Enantiomeric excess
5.6 Diastereomeric excess
5.7 Cram’s rule
5.8 Prelog’s rule
5.9 Conformational analysis of alkanes
5.9.1 Conformational analysis of ethane
5.9.2 Conformational analysis of n-butane
5.9.3 Conformational analysis of cyclohexanes
5.9.4 Conformational analysis of mono- substituted cyclohexane
5.9.5 Conformational analysis of di- substituted cyclohexane
5.9.6 Conformations of decalins
5.10 Stereochemistry of compounds containing N, P and S
5.10.1 Stereochemistry of Nitrogen compounds

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5.10.2 Stereochemistry of Phosphorous compounds

5.10.3 Stereochemistry of Sulphur compounds
5.11 Summary
5.12 Terminal Question
5.13 Answers

5.1 OBJECTIVES
In this unit learner will be able to

Define prochiral property of an achiral molecule

Differentiate between two similar atoms or groups attached with a prochiral center
Learn about the homotopic, heterotopic, enantiotopic and diastereotopic ligands and
faces
Define stereospecific and stereoselective synthesis
Learn about the principle of asymmetric synthesis
Learn about the various conformations of cyclohexanes and decalins
Know about the stereochemistry of compounds containing N, P and S

5.2 INTRODUCTION
Stereochemistry is a sub-discipline of chemistry that involves the study of the relative spatial
arrangement of atoms. The study of stereochemistry focuses on stereoisomers, which by
definition have the same molecular formula and sequence of bonded atoms (constitution), but
differ in the three-dimensional orientations of their atoms in space. For this reason, it is also
known as 3D chemistry-the prefix "stereo-" means "three-dimensionality". Stereochemistry
includes methods for determining and describing these relationships; the effect on
the physical or biological properties these relationships impart upon the molecules in question,
and the manner in which these relationships influence the reactivity of the molecules in question
(dynamic stereochemistry). Thus stereochemistry is all about the 3D properties of molecules and
reactions and has its own language and terms that need to be appreciated.

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5.3 TOPOCITY

Stereo-chemical relationships between individual atoms or groups within a single molecule can
be defined in terms of topicity. Thus, two atoms equated by a mirror reflection of the molecule
are enantiotopic and two atoms in equivalent environments (i.e., the methylene protons in n-
propane) are homotopic. Two protons placed in diastereomeric positions by a mirror reflection
are in diastereotopic environments.

Examples 1: Propane has homotopic ligands; however, propionic acid has enantiotopic ligands

O O O
simultaneous replacement
H3C of Ha and Hb by OH H3 C H3 C
OH OH OH
Ha Hb Ha OH HO Hb

Propionic acid Both the compounds are enantiomer

(prochiral molecule Ha and Hb are
enantiotopic)
simultaneous replacement HO Hb
Ha Hb of Ha and Hb by OH Ha OH
H3 C CH3
H3 C CH3 H3C CH3
Propane Ha and Hb Both the compounds are identical
are homotopic

5.3.1 PROCHIRAL CENTER AND PROCHIRAL MOLECULE:

As we discussed in Unit 4 (Stereochemistry I) of this module; a tetrahedrally bonded atom with

four different atoms or groups (Cabcd) is called a chiral molecule. However, a tetrahedrally
bonded atom with two identical atoms or groups (Cabbc) is called an achiral molecule.

If replacement of one of the identical groups in an achiral molecule of type Cabbc with a
different group when gives an asymmetric molecule then the achiral center is called prochiral
center and the molecule is called prochiral molecule. This property is called prochirality.

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Example 2: Propionic acid is a prochiral molecule with centre carbon atom as prochiral centre.
Replacement of one of the hydrogen atom by a different group gives the optically active
compound.

O O O
simultaneousreplacement
C2H5 of Ha and Hb by Cl C2H5 C2H5
OH OH OH
Ha Hb Ha Cl Cl Hb
Butanoic acid Both the compounds are enantiomer
(prochiral molecule Ha and Hb
are enantiotopic)

5.3.2 HOMOMORPHIC LIGANDS:

Two apparently identical atoms/groups of a prochiral centre are called homomorphic

atoms/groups. These are also known as homomorphic ligands. Homomorphic is a Greek name
where homos meaning similar and morphe meaning form. Thus two homomorphic ligands are
indistinguishable during their isolation. Two hydrogen atoms of Propionic acid are apparently
identical groups i.e. H atoms of methylene group are called homomorphic atoms or ligands.

5.3.2 STEREOHETEROTOPIC LIGANDS:

Consider two molecules, Butanoic acid in which two identical hydrogen atoms attached with
methylene carbon, and 2-butanol in which two identical hydrogen atoms of methylene carbon.
Replacement of any one of the homomorphic ligands in butanoic acid will give a pair of
enantiomer; however, replacement of any one of the homomorphic ligands in 2-butanol will give
the formation of two diastereomers. Since enantiomers and diastereomers are stereoisomers
therefore the homomorphic groups or ligands are also called stereoheterotopic groups or ligands.

Example 3: Stereoheterotopic ligands (Ha and Hb) of butanoic acid and 2-butanol.
Simultaneous replacement of Ha and Hb in both the compounds leads the formation
stere

O O O oiso
sim ultaneous replacem ent
C 2H 5
OH of H a and H b by C l C 2H 5 C 2H 5 mers.
OH OH
Ha Hb Ha Cl Cl Hb
B utanoic acid
B oth the com pounds are enantiom er
(prochiral m olecule H a and H b
are enantiotopic)
OH OH
OH
sim ultaneous replacem ent H 3C
H C 3 of H a and H b by C l H C CH3
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H
CH3 OPEN UNIVERSITY
Cl Hb
CH3 Ha Page
Cl 170
Ha b

2-butanol B oth the com pounds are diastereom ers

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5.3.4 PROCHIRALITY:

It is the property of some molecules due to which these molecules can be converted in to
stereoisomers (enantiomers or diastereomers) by replacing one of the identical atoms or groups
by a different atom or group. It is also known as ‘prostereoisomerism’ more specifically. If the
replacement of such atoms or groups leads the formation of enantiomer the atoms or groups are
called enantiotopic; whereas, if such replacement lead the formation of diastereomers the atoms
or groups are termed as diastereotopic.

5.3.5 HOMOTOPIC LIGANDS AND FACES:

When replacement of two H atom in a methylene carbon of a molecule generates two identical
compounds instead of stereoisomers, these two hydrogen atoms are called homotopic ligands.

Example 4: Let us consider the case of formaldehyde, the two hydrogen atoms of formaldehyde
when replaced with a different atom or group generates two identical compounds hence both the
hydrogen atom of formaldehyde molecules are homotopic atoms or homotopic groups.

O O O
simultaneous replacement
of Ha and Hb by Cl Cl Hb
Ha Hb Ha Cl

Identical

Example 5: Similarly there is no way to differentiate between the two faces of formaldehyde
molecule. The addition of Grignard reagent RMgX to either faces gives the identical compound
ethanol. Hence, two faces of formaldehyde are also homotopic faces.

O HO OH
Ha Ha
RMgX R Hb Hb R
Ha Hb
dry ether
Identical

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Substitution/addition and symmetry are the two key criteria to determine the topicity of
homomorphic ligands and faces. Two homomorphic ligands are called homotopic if replacement
of each one of them by another atom or group leads to the identical structure. Thus we can
consider three hydrogen atom of acetic acid as homotopic hydrogen, similarly three hydrogen of
toluene are also called homotopic hydrogen, because replacement of each one of them will lead
the same structure.

Example 6: In (2R,3R)-2,3-dihydroxytartaric acid two homotopic hydrogen atoms are present;

replacement of each one of them by a different atom gives identical compounds.
Identical

COOH COOH COOH

1 simultaneous replacement 1 1
H C OH of Ha and Hb by Cl Cl C OH H C OH
HO C H HO C H HO C Cl
2
2 2
COOH COOH COOH
(2R,3R) 2,3-Dihydroxytartaric acid (2S)-2-chloro-2,3-dihydroxysuccinic acid

Example 7: In a double bonded compound like cis-2-butene, two faces of double bond are
homotopic since addition on either faces gives the same product. The epoxidation of double
bond on either face gives meso product [(2R,3S)-2,3-dimethyloxirane].

H H O
Epoxidation
C C H C C H
H3 C CH3 H3C CH3
Cl O OH
cis-2-butene O (2R,3S)-2,3-dimethyloxirane
(meso-epoxide)

Homotopic ligands and faces can also be determined by employing symmetry operations on the
molecule. Let us consider an example of acetic acid, in which all three hydrogen atom of methyl
group are homotopic. Two successive rotation of methyl group around its C3 axis (with the
rotation angle of 120°) allow each hydrogen atom to occupy the position of either of the other
two hydrogen atoms without effecting any structural changes. As we know that hydrogen atom
of methyl group interchanges their position rapidly in 3 dimensional planes, due to this rapid
interchange of hydrogen atoms of methyl group leads the formation of indistinguishable
structure, that’s why these hydrogen atoms are called homotopic hydrogen (homotopic ligands).

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120o 120o 120o

COOH COOH COOH

C C C
Ha Hc Hc Hb Hb Ha
Hb Ha Hc

All the hydrogen atoms of methyl group are homotopic (homotopic ligands)

Similarly, both the faces of cis-2-butene, formaldehyde and symmetrical ketones are homotopic,
hence called homotopic faces.

120o 120o
120o
O O H H
C C
Ha Hb H3 C CH3 H3 C CH3

Formaldehyde Acetone cis-2-butene

Homotopic Faces

Remember: A molecule contains two equivalent atoms/groups they would not be

homotopic if the other two groups are different. Such molecules are known as prochiral
molecule.

5.3.6 ENANTIOTOPIC LIGANDS AND FACES:

When the replacement of each equivalent atom or groups by a different atom given enantiomeric
products, such equivalent atoms or groups are called enantiotopic atoms or enantiotopic ligands.
Example 8: For example, two hydrogen atoms of meso-tartaric acid are enantiotopic since the
replacement of each one of them by a different atom or group gives the enantiomeric pair of
(2S)-2-chloro-2,3-dihydroxysuccinic acid and (2R)-2-chloro-2,3-dihydroxysuccinic acid.

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Enantiomer

COOH COOH COOH

1 simultaneous replacement
H C OH hydrogen by Cl Cl C OH H C OH
H C OH HO C H Cl C OH
2
COOH COOH COOH
(2S)-2-chloro-2,3- (2R)-2-chloro-2,3-
2,3-dihydroxysuccinic acid
dihydroxysuccinic acid dihydroxysuccinic acid
(meso)

Similarly, when two faces of a double bond gives enantiomers on addition of suitable reagents,
such faces are called enantiotopic faces. For example, trans-2-butene and unsymmetrical ketones
have enantiotopic faces since they also give enantiomers on addition of suitable reagents.

Example 9: Epoxidation of trans-2-butene on either face of double bonds gives the enantiomeric
pair of (2R,3R)-2,3-dimethyloxirane and (2S,3S)-2,3-dimethyloxirane.

H CH3 O H CH3
Epoxidation H3C H
C C H C C CH3 + C C
H3C H H3C H O
Cl O OH
trans-2-butene O (2R,3R)-2,3-dimethyloxirane (2S,3S)-2,3-dimethyloxirane

Example 10: Similarly, addition of the Grignard reagent (RMgX; R=C2H5) or other
organometallic reagents on either faces of unsymmetrical carbonyl compounds gives
enantiomers. Hence, faces ‘a’ and ‘b’ of acetaldehyde (1) and Pentan-2-one (2) are called
enantiotopic faces.

H C2H5

a OH
H3C
H
dry ether (S)-butan-2-ol
(1) O + C2H5MgX
H3C
H OH
b
Acetaldehyde
H3C C2H5
(R)-butan-2-ol

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C3H7 C2H5

a OH
H3C
C3H7
dry ether (S)-3-methylhexan-3-ol
(2) O + C2H5MgX
H3C
C3H7 OH
b
Pentan-2-one
H3C C2H5
(R)-3-methylhexan-3-ol

Unlike homotopic ligands and faces, enantiotopic ligands and faces cannot be interchanged by a
simple axis of symmetry (Cn). However, they can be interchanged by plane of symmetry, center
of symmetry (i) and alternative axis of symmetry (Sn).

5.3.7 NOMENCLATURE OF ENANTIOTOPIC LIGANDS AND FACES:

Naming of enantiotopic ligands and faces is based on the CIP sequence rule by arbitrarily
assigning priority to the homomorphic groups/ligands/faces.

Example 11: Let us consider ethanol with two homomorphic ligands (Ha and Hb). If Ha is
arbitrarily preferred over Hb in the sequence rule, the priority order of the attached groups at
central carbon will be OH>CH3> Ha> Hb and the hypothetical configuration of the stereocenter
will be R, thus Ha is designated as pro-R and Hb is designated as pro-S. Similarly, if Hb was
arbitrarily given higher priority over Ha in that case according to sequence rule priority order
would have been OH>CH3> Hb> Ha and the hypothetical configuration of ethanol would be S,
thus Hb is designated as pro-S and Ha is designated as pro-R. Replacement of Ha by deuterium
‘D’ gives (R)-ethanol-1-D, hence, Ha is pro-R; similarly, replacement of Hb by D gives (S)-
ethanol-1-D, hence, Hb is pro-S.

OH OH OH
simultaneous replacement
of Ha and Hb by D
Ha Hb D H H D
Ethanol (R)-Ethanol-1-D (R)-Ethanol-1-D
pro-R pro-S

Similalry, two faces of carbonyl carbon are termed as enantiotopic faces. These faces can be
designated as Re-Si nomenclature. The groups around the carbonyl group are given priorities as

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per CIP sequence rule for R and S nomenclature. While going from the highest priority group to
the lowest priority group around the faces of carbonyl group, if the path followed is clockwise
the faces is Re and if it is anticlockwise, the face is Si.

1 1
O O
2 2
3 3

Si-face Re-face

5.3.8 DIASTEREOTOPIC LIGANDS AND FACES:

When the replacement of either of two homomorphic ligands or atoms of a molecule by a

different atom generates diastereomers, such homomorphic ligands or atoms are called
diastereotopic ligands or atoms.

Example 12: Let us consider an example of propene in which two homomorphic hydrogen are
present. Replacement of one of the homomorphic hydrogen with a hetero atom Cl gives Z-alkene
((Z)-1-chloroprop-1-ene) while replacement of other homomorphic hydrogen atom by Cl
generates E-alkene ((E)-1-chloroprop-1-ene). Both, (Z)-1-chloroprop-1-ene and (E)-1-
chloroprop-1-ene are stereoisomer but non mirror image of each other, hence are called
diastereomer. Thus, two hydrogen atoms (i.e. Ha and Hb) of 1-propene are diastereotopic.

H Cl
C C
H3C H
H Ha simultaneous replacement
of Ha and Hb by Cl (E)-1-chloroprop-1-ene
C C
H3C Hb
H H
1-propene C C
H3C Cl
(Z)-1-chloroprop-1-ene

Example 13: Consider another interesting example of R-2-butanol with a stereocenter at C1 and
two homomorphic hydrogen atoms (Ha and Hb) at C2. Replacement of Ha leads to the formation

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of (2R,3R)-3-chlorobutan-2-ol, and replacement of Hb leads the formation of (2R,3S)-3-

chlorobutan-2-ol. Therefore, these two products are diastereomers, and the two protons (Ha and
Hb) of R-2-butanol are diastereotopic.
HO H
H3C
CH3
Cl H
HO H simultaneous replacement
H3C of Ha and Hb by Cl (2R,3R)-3-chlorobutan-2-ol
CH3
Ha Hb H
HO
H3 C
R-2-butanol CH3
H Cl
(2R,3S)-3-chlorobutan-2-ol

The two faces of carbonyl group next to a stereocenter are diastereotopic. Since, addition of
reagents (like HCN, RMgX, HCl etc.) from either faces gives diastereomers. Thus, two faces of
such carbonyl group are termed as diastereotopic faces.

Example 14: For example, let us consider addition of HCN to the either faces of carbonyl group
of (S)-3-phenylbutan-2-one leads to the formation of, (2S,3S)-2-hydroxy-2-methyl-3-
phenylbutanenitrile and (2R,3S)-2-hydroxy-2-methyl-3-phenylbutanenitrile, a pair of
diastereomers.

C6H5 CH3 a
C6H5 C6H5 CH3
addition of HCN from CH3 CN
CN
H O + HCN face 'a' and face 'b' +
H H
OH
H3 C OH H3C
H3C
b
(S)-3-phenylbutan-2-one (2S,3S)-2-hydroxy-2-methyl- (2R,3S)-2-hydroxy-2-methyl-
3-phenylbutanenitrile 3-phenylbutanenitrile

Example 15: Similarly, consider another example of 4-t-butylcyclohexanone in which addition

of hydride on either faces of carbonyl group leads the formation of trans- and cis- 4-t-
butylcyclohexanol (diastereomers). Thus two faces of 4-t-butylcyclohexanone are diastereotopic
faces.

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H
a a H3C
H- H3 C OH
O
H3C
b trans- 4-tert-butylcyclohexanol
(diequatorial)
H3C
addition of hydride on OH
H3C either faces
CH3 H3C
b H
4-tert-butylcyclohexanone H3C
H3C
cis-4-tert-butylcyclohexanol

The addition of hydride on either faces of 4-t-butylcyclohexanone gives two diastereomers

(achiral) products. Hence, the carbonyl carbon is considered as prostereo center rather than
prochiral center.

5.4 ASYMMETRIC INDUCTION

Before 1940, the optically active compounds could be obtained in stereoisomerically pure form
only by isolation of racemic mixture of optically active compounds from natural products and
their subsequent enzymatic resolution. Since, equimolar amount of enantiomers (racemic
mixture) is obtained when a prochiral molecule undergoes reaction in the absence of chiral
environment. As we know the physical and chemical properties of enantiomers are always same
in the absence of a chiral environment. However, enantiomers have entirely different reactivities
in biological system.

Asymmetric induction is a stereo chemical transformation (reaction) that results the preferential
formation of one enantiomer or diastereomer over other in the presence of a chiral substrate,
reagent, catalyst or environment. This is also known as asymmetric synthesis. The chiral agent
must play an active part in the asymmetric induction. Such chiral agent has an important role in
the formation of transition state.

The direct synthesis of an optically active substance from optically inactive compound with or
without the use of any optically active compound is called asymmetric synthesis. In general
asymmetric synthesis can also be defined as the synthesis which converts a prochiral unit in to a
chiral unit and formation of unequal amount of stereoisomers.

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5.4.1 PRINCIPLE OF ASYMMETRIC SYNTHESIS:

There are three principle of asymmetric synthesis

a) The substrate molecule must be prochiral i.e. the substrate must have either
enantiotopic or diastereotopic ligands or faces.

b) There must be presence of chirality in the reaction/asymmetric transformation for the

preferential formation of one stereoisomer over the other. Either the substrate, or the
reagent, or the solvent, or the catalyst must be enantiomerically pure.

c) The chiral agent must play an important role in the reaction and must involve in the
formation of two diastereomeric transition states.

Example 16: Let us consider hydrogenation of Acetphenone by sodiumborohydride (NaBH4).

Since, both the reagent and substrate are achiral (optically inactive) and also the reaction takes
place in the medium of methanol (achiral), hence, equal amount of (R)-1-phenylethanol and (S)-
1-phenylethanol (racemic mixture) is formed.

O HO H HO H
NaBH4 CH3
CH3 CH3 +
Achiral reagent
Acetophenone (S)-1-phenylethanol (R)-1-phenylethanol
(Achiral) 50% 50%

Example 17: However, when the above reaction is allowed to proceed in the presence of a chiral
reagent the (S)-1-phenylethanol is formed preferentially over (R)-1-phenylethanol.

O HO H HO H
H2 gas
CH3 CH3 + CH3
chiral Ruthenium
Acetophenone complex (S)-1-phenylethanol (R)-1-phenylethanol
(Achiral) 97.5 ee 2.5 ee

Some more example of asymmetric synthesis in presence of chiral reagents is shown in figure 1.

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H CH3 H CH3
H2 gas
COOH COOH + COOH
MeO chiral Ruthenium MeO MeO
complex
2-(6-methoxynaphthalen- (R)-2-(6-methoxynaphthalen- (S)-2-(6-methoxynaphthalen-
2-yl) acrylic acid 2-yl)propanoic acid 2-yl) propanoic acid
97.0 ee 3.0 ee

O O H2 gas HO H O HO H O
+
OMe chiral Ruthenium OMe OMe
complex (R)-methyl 3-hydroxybutanoate (S)-methyl 3-hydroxybutanoate
98.5 ee 1.5 ee

Figure 1: Examples of asymmetric synthesis

5.4.2 STEREOSPECIFIC AND STEREOSELECTIVE REACTIONS:

Stereospecific reactions: Stereospecific reactions or synthesis are those reactions in which

a particular stereoisomer reacts with given reagent to give one specific stereoisomer of the
product. This property is called stereospecificity. Thus each individual stereoisomeric substrate
under stereospecific synthesis gives a different isomer of the product.

Example 17: For example, anti addition of bromine to cis-2-butene gives racemic mixture of
2,3-dibromobutane, while the anti addition of bromine to trans-2-butene gives meso-2,3-
dibromobutane. These kinds of reactions are called stereospecific because different
stereoisomeric substrate leads different stereoisomeric products.

Br2 (anti addition) Br Br

H H + H H (Racemic compound)
H H Br
Br
cis-2-butene (2R,3R)-2,3-dibromobutane (2S,3S)-2,3-dibromobutane

Br Br
H Br2 (anti addition) H H
+ (meso compound)
H H
H Br Br
trans-2-butene (2R,3S)-2,3-dibromobutane (2S,3R)-2,3-dibromobutane

Similarly, syn addition of peroxyacid to cis- and trans- alkenes gives stereospecific reaction.
Example 18: For example, syn addition of meta-chloroperbenzoic acid (m-CPBA) to cis-2-
butene gives cis-2-dimethyloxirane [(2R,3S)-2,3-dimethyloxirane], while syn addition of meta-

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chloroperbenzoic acid (m-CPBA) to trans-2-butene gives trans-2,3-dimethyloxirane [(2R,3R)-

2,3-dimethyloxirane]. Thus the reaction is stereospecific.

m-chloroperbenzoic O O
acid H H H H
O +
H H CH3 CH3
cis-2-butene OOH H3C H3C
Cl (2R,3S)-2,3-dimethyloxirane (2S,3R)-2,3-dimethyloxirane
(cis) (cis)

H m-chloroperbenzoic H O H H O H
acid +
H O H3C CH3 H3C CH3
trans-2-butene OOH
Cl (2R,3R)-2,3-dimethyloxirane (2S,3S)-2,3-dimethyloxirane
(trans) (trans)

Example 19: Another example of stereospecific reaction is also considered as the ring opening
freactions of oxirans (epoxides). Hydrolysis of epoxides (oxiranes) obtained by the syn addition
of peroxyacid to cis- and trans- alkenes leads to the formation trans- diols (diols = dihydroxy
compounds) in which both the vicinal hydroxy groups are trans to each other.

H O H H+/H2O
CH3 HO OH + HO OH
H 3C H H H H
(2R,3S)-2,3-dimethyloxirane (2S,3S)-butane-2,3-diol (2R,3R)-butane-2,3-diol
(cis) (trans diol) (trans diol)

H H
H O H H+/H2O HO HO
OH + OH
H3 C CH3 H H
(2R,3R)-2,3-dimethyloxirane (2R,3S)-butane-2,3-diol (2S,3R)-butane-2,3-diol
(trans) (trans diol) (trans diol)

Stereoselective reactions: Stereoselective reactions or synthesis are those reactions in

which one stereoisomer (or one pair of enantiomers) is formed predominantly or exclusively out
of several possible stereoisomers. This property is called stereoselectivity. In such reactions one
stereoisomer is formed more rapidly than other, thus one stereoisomer forms in excess in the
resulting mixture of the products. For every stereoselective reaction there is more than one
mechanistic path by which reaction may proceed; however, it is observed that the reaction

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proceeds either via the most favorable path (for which rate of reaction is fast i.e. kinetic control)
or via the path that gives the most stable stereoisomer as the major product ( i.e. thermodynamic
control). The stereoselective reactions/synthesis or the stereoselectivity can be further subdivided
in to two categories, a) enantioselective reactions/synthesis or enantioselectivity, b)
diastereoselective reactions/synthesis or diastereoselectivity.

a) Enantioselective reactions or enantioselectivity: Enantioselective reactions are defined as

the reactions or processes in which one of the enantiomer forms predominantly over the other.
This property is known as enantioselectivity. Enantioselectivity is achieved when a
stereoselective reaction is performed in the presence of using a chiral environment (i.e. either a
chiral substrate, or a chiral reagent, or a chiral catalyst, or a chiral solvent).

Example 20: For example, Fumaric acid when hydrolyzed in presence of Fumarase (a chiral
enzyme) gives (S)-2-hydroxysuccinic acid exclusively.

O O
OH H2O OH
HO HO
O Fumarase enzyme OH O
fumaric acid (S)-2-hydroxysuccinic acid

Example 21: Similalry, reduction of carbonyl group by Baker’s yeast exclusively leads to the
formation of S- enantiomer. Examples of reduction of carbonyl groups by baker’s yeast are
shown below.

O O OH O
[H]
H3 C O CH3 Baker's yeast H3C O CH3
ethyl 3-oxobutanoate (S)-ethyl 3-hydroxybutanoate

O OH
[H] CH3
CH3
Baker's yeast Cl
Cl
(S)-1-(4-chlorophenyl)ethanol
1-(4-chlorophenyl)
ethanone

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The Sharpless epoxidation of allylic alcohol in presence of titanium tetraisopropoxide, t-

butylhydroperoxide and enantiomerically pure diethyltartrate (DET) gives enantiomerically pure
epoxide. The stereochemistry of product depends on the stereochemistry of diethyltartrate. The
diethyltartrate is readily available in its enantiomerically pure forms (i.e. R,R and S,S). (R,R)-
diethyltartrate (DET) gives (S,S)- epoxide, whereas, (S,S)-diethyltartrate (DET) gives (R,R)-
epoxide.

Ti(OPri)4 O
H
HO HO
(R,R)-DET, t-BuOOH
CH3 H CH3
(E)-but-2-en-1-ol ((2S,3S)-3-methyloxiran-2-yl)methanol

Ti(OPri)4 O
H
HO HO
(S,S)-DET, t-BuOOH
CH3 H CH3
(E)-but-2-en-1-ol ((2R,3R)-3-methyloxiran-2-yl)methanol

b) Diastereoselective reactions or diastereoselectivity: Diastereoselective reactions are defined

as the reactions or processes in which one of the diastereomer forms predominantly or
exclusively over the other. This property is known as diastereoselectivity. Diastereoselectivity is
usually achieved through in the presence of steric hindrance.

Example 22: Let us consider the conjugate addition of lithium dimethylcuprate [(CH3)2CuLi] to
4-methylcyclohexenone. In this reaction cuprate reagent has equal possibilities to react from the
either faces of the 4-methylcyclohexenone; however, the bulky cuprate reagent prefers to
approach from the less hindered face (i.e. opposite to the methyl group) of the 4-
methylcyclohexenone. As a result one diastereoisomer (i.e. trans- product: methyl groups are
trans- to each other) out of two possible diastereoisomers forms in excess. Thus, this reaction is
called diastereoselective reaction.

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O O O
(i) (CH3)2CuLi
+
(ii) H /H2O CH3 CH3
CH3 CH3 CH3
(S)-4-methylcyclohex- (3S,4S)-3,4-dimethyl (3R,4S)-3,4-dimethyl
2-enone cyclohexanone (98%) cyclohexanone (2%)

Example 23: Another example of diastereoselective reaction/synthesis is the epoxidation of

cyclic alkenes with peroxyacids. In such reactions the epoxidation also takes place from the less
hindered face. Epoxidation of 4-methylcyclohexene by peroxyacetic acid gives 80% addition
product from the less hindered face (i.e. opposite to the methyl group) and 20% addition product
from the more hindered face (i.e. from the face of methyl group).

H CH3COOOH
H O + H O
H3C H3C H3C
(S)-4-methyl cis-epoxide 20% trans- epoxide 80%
cyclohex-1-ene

Example 24: Similarly, synthesis of alcohols from alkenes by the hydroboration-oxidation is

another class of example of diastereoselective reactions. Hydroboration-oxidation of 1-
methylcyclohexene gives the trans- product as the major product.

BH3 H2O/OH-
syn- addition H3C H H3C H
H3C H H BH2 H OH
1-methylcyclohex-1-ene (1R,2R)-2-methylcyclohexanol
(trans product)

5.4 ENANTIOMERIC EXCESS (ee):

It is a measurement of optical purity of a chiral substances formed in an asymmetric synthesis. It
reflects the degree to which a mixture of enantiomer contains one enantiomer in greater amounts
than the other. A racemic mixture has an ee of 0%, while a single and pure enantiomer has an ee
of 100%. A sample with 70% of one enantiomer and 30% of the other has an ee of 40% (70% −
30%). Enantiomeric excess can be determined by the following mathematical expression.

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[R] - [S]
Enantiomeric excess (% ee) = x 100
[R] + [S]

5.5 DIASTEREOMERIC EXCESS (de)

It is the measurement of % excess formation of one of the diastereomers over the other in an
asymmetric synthesis. It reflects the degree to which a mixture of diastereomer contains one
diastereomers in greater amounts than the other. Diastereomeric excess can be determined by the
following mathematical expression.

[D1] - [D2]
Diastereomeric excess (% de) = x 100
[D1] + [D2]

5.6 CRAM’S RULE

Diastereoselectivity of nucleophilic addition on carbon-oxygen double bond of aldehyde and

ketones containing an asymmetric α carbon is explained by D. J. Cram and co-workers.
According to this the formation of the major product was correctly predicted by a model in
which the largest group was eclipsed with the other carbonyl substituent. This empirical
relationship became known as Cram’s rule. Since, during nucleophilic addition on symmetrical
sp2 carbonyl carbon, the nucleophile has equal possibilities to give addition on carbonyl carbon
from either faces. However, when α-carbon of sp2 carbonyl carbon is asymmetric, the nucleophile
would experience more steric hindrance from one side, leading to unequal synthesis of the two
diastereomers. The Cram’s rule predicts the formation of major product based on most stable
conformation of carbonyl compound. Following points may be considered during the prediction
of the most stable conformation of carbonyl compound:

• The existing asymmetric center would have a Small, Medium and Large group,
denoted S, M and L respectively (Fig 2).

• In the reactive conformation, the carbonyl group would orient itself in such a way that it
will rest between the Small group and the Medium group.

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• The attacking nucleophile would prefer to attack from the side of the small group,
resulting in the predominant formation of one diastereomer in the product.

As shown in figure 2 path A is preferred over path B.

Nu
O Nu Nu
M S S S
OM M
A)

R
O
LR LR L
eclipsed staggered
Nu
O O Nu
M S S S
Nu M M
B)

O
R
LR LR L
eclipsed staggered

Figure 2: Schematic representation of Cram’s rule

For example, the reduction of α-phenylpropionaldehyde (PhCH(CH3)CHO) with Grignard

reagent yields the erythro diastereomer as the major product according to Cram’s rule, where
(S=H, M=Me, L=Ph) [Fig 3(1)]. Similarly, reaction of HCN with 2-methylbutanal to form
cyanohydrins with diastereoselectively and the major product will be erythro diastereomer [Fig
3(2)].

CH3MgBr
O CH3 CH3
CH3 H H H
CH3 CH3

1) +

OH H
H H HO
Ph Ph Ph
α−phenylpropionaldehyde minor product major product
CN threo erhythro
O CN CN
CH3 H H H
CH3 CH3
2) +

OH H
H H HO
C 2H 5 C2H5 C2H5
2−methylbutanal minor product major product
threo erhythro

Figure 3: Examples of Cram’s rule

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5.7 PRELOG’S RULE

Prelog’s rule is an extension of Cram’s hypothesis of reactive conformation to nucleophilic

addition on chiral esters of -ketoesters (pyruvates) and was reported in 1953. It is generally the
addition of Grignard reagent to chiral pyruvates to form chiral alcohols. The rule has been
applied for asymmetric synthesis of α-hydroxyacids and for assigning the configuration of
secondary and tertiary alcohols. The anti configurational arrangement of the two α-carbonyl
moieties could be rationalized. The negative end of these dipoles would prefer to be as far as
possible. The attack from the side of the small (S) group is an extension of Cram's Rules. The
asymmetric induction in such reaction is not very effective due to the large distance between the
reaction center and the asymmetric center inducing asymmetry at the developing chiral center.

Example 25: Reaction of pyruvates with Grignard reagent (extension of Cram’s rule)

O
Ph OH Ph OH
O L PhMgX O L Hydrolysis
R OH
OS M R
OS M R
O

5.8 CONFORMATIONAL ANALYSIS OF ALKANES

The different spatial arrangements of atoms in a molecule which is readily interconvertible

by rotation about single bonds are called conformations. The study of various preferred
conformations of a molecule and the correlation of physical and chemical properties to the most
preferred conformer is called conformational analysis. Due to rapid interchange of the spatial
positions of groups/atoms these conformers are non-separable under normal conditions. Since,
different conformations arises because of the rotation about single bonds, hence, they are also
called the rotamers. The conformational and configurational isomerisms are related to energy
barrier for interconversions of different spatial arrangements of atoms in a molecule. If the
energy barrier for interconversion of different spatial arrangements is between 0.6 kcal/mol-16.0
kcal/mol; it result the conformational isomers or conformers; whereas, if this energy barrier is
more than or equal to 16 kcal/mol than the configurational isomers are obtained.

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5.8.1 CONFORMATIONAL ANALYSIS OF ETHANE:

When ethane molecule rotates around carbon-carbon single bond, two extreme conformations
(one is highly stable and other is highly unstable) are obtained. The highly stable conformation
of ethane is called ‘staggered conformation’ and the highly unstable conformation of ethane is
called ‘eclipsed conformation’. In between these two extreme conformations (i.e. staggered and
eclipsed), an infinite number of conformations are also possible.
Staggered conformation: A conformation with a 60° dihedral angle is known as staggered
conformation. The angle between the atoms attached to the front and rear carbon atom is called
dihedral angle.

H 60o
H H

H H
H

Staggered conformation
Eclipsed conformation: A conformation with a 0° dihedral angle is known as eclipsed
conformation.
H
H H 0o
H

HH

Eclipsed conformation

In staggered conformation the atoms are located at maximum possible distance from each other
hence they are in their most relaxed spatial arrangement thus the staggered conformation is
considered as the most stable conformation; whereas, in eclipsed conformation the atoms are
located at minimum distance, hence due to repulsion between the atoms the eclipsed
conformation is considered as the least stable (high energy) conformation. There are two
methods for the representation of staggered and eclipsed conformations, a) the Sawhorse
representation formula and, b) the Newman representation formula.

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a) The Sawhorse representation formula: In sawhorse representation formula the spatial

arrangement of all the atoms/groups on two adjacent carbon atoms. The bond between
adjacent carbon atoms is represented by a diagonal line and rest of the atoms are located
on each carbon at +120° or -120° angles to each other. The sawhorse representation is
shown as:
diagonal line H
H H

H H
OR
120o H H 120o H

viewpoint H
H H viewpoint H

Sawhorse representation formula

b) The Newman representation formula is a planar representation of the sawhorse formula.

The molecule is viewed along the axis of a carbon-carbon bond. The carbon atom in front
of the viewer is represented by a dot (●), whereas the carbon atom away to the viewer is
represented by circle. The rest of the atoms/groups are located on each carbon atoms at
+120° or -120° angles to each other as shown below:

H H
H H H
H H
Circle carbon
120o

H H
H HH
Ponit Carbon

Newman representation formula

The different conformations of ethane are not equally stable. The staggered form in which the
hydrogen atoms are ‘perfectly staggered’ (dihedral angle is 60°) is the most stable conformation.
This is because, in this conformation the all carbon hydrogen (C-H) bonds are located at
maximum possible distance to each other, and hence they feel minimum repulsive energy from
each other. In eclipsed conformation of ethane, the hydrogen atoms attached to each carbon are
directly opposing to each other. This result the minimum separation of the atoms or groups, and

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hence they feel maximum repulsive energy from each other. The eclipsed conformation
therefore, of highest energy and has the lowest stability. A graph plot for the energy profile for
various conformations of ethane is shown on figure 4. The relative stability of various
conformations of ethane is
Staggered >> Eclipsed

Figure 4: Energy profile diagram of conformational isomer of ethane

5.8.2 CONFORMATIONAL ANALYSIS OF N-BUTANE:

n-Butane (C4H10) has three carbon-carbon single bonds (Figure 5); therefore the molecule can
rotate about each of them. The rotation about C2 and C3 bond will provide the symmetrical
conformations. To study the conformational analysis of n-butane, we must consider it as a
derivative of ethane molecule, where one hydrogen at each carbon of ethane is replaced by
methyl group (-CH3).
H H
1 4
H3C C C CH3
2 3
H H

Figure 5: Butane molecule

Various conformation of n-butane can be obtained by rotation about C2 and C3 bond are shown
in figure 6:

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Figure 6: Energy profile diagram of conformational isomer of n-butane

From figure 3, we can see that n-butane has three staggered conformations (I, III and V).
Conformer I, in which two methyl groups are as far as possible, and hence is more stable than
other two staggered conformers (i.e. III and V), because conformer I, has minimum repulsive
energy. As you can see from figure 3; in conformer I, both the methyl groups are located
opposite to each other. The most stable conformer of n-butane, in which both the methyl groups
are located opposite to each other is called the anti-conformer, whereas other two staggered
conformers (i.e. III and V) are called gauche conformer. Due to difference in steric strain
(repulsion between dihedral atoms/groups) the repulsive energy of anti and gauche conformers
are also different. Three eclipsed conforms (II, IV and VI in figure 6) are also exits for n-butane,
in which the dihedral atoms/groups are in front of each other (i.e. dihedral angle is 0°). The fully
eclipsed conformer IV, in which the two methyl groups are closest to each other, has maximum
steric strain; hence it is of higher energy than the other eclipsed conformers (II and VI).Thus the
relative stabilities of the six conformers of n-butane in their decreasing order is given as follows:

Anti > Gauche > Eclipsed > Fully eclipsed

I III and V IV II and VI

5.8.3 CONFORMATION OF CYCLOHEXANE:

It is known to you that in cycloalkane, all the ring carbons are sp3 hybridized, hence must have
tetrahedral geometry with all bond angles of 109.5°. But to sustain its cyclic structure the

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cycloalkane could not be able to maintain the bond angle of 109.5°. As a result there is a
deviation from the normal tetrahedral bond angle. This deviation leads the development of strain
in the molecule. Thus the cycloalkanes exhibit angle strain, due to which cycloalkanes are not as
stable as their non-cyclic homolog. To minimize the angle strain the structure of cycloalkane is
keep on changing from one cyclic form to another which are readily interconvertible by rotation
about single bond. This is the reason why cyclohexane and larger rings are non-planar.

Cyclohexane exists in two readily interconvertible forms which are called the chair and boat
conformations of cyclohexane (Figure 7).
1
4
2 4

3 3
1 6 2 5
5 6
Chair Boat
Conformation of Conformation of
cyclohexane cyclohexane
Figure 7:
Two readily interconvertible conformations of cyclohexane

Both chair and boat forms are free from angle strain. In chair form carbon C1, C3 and C5
are in one plane and carbon C2, C4 and C6 are in different plane. Similarly, in boat form carbon
C1 and C4 are in one plane and carbon C2, C3, C5 and C6 are in other plane. The
interconversions of chair to boat and boat to chair via various other intermediate conformations
are shown in Figure [Link] chair conformation (I and V scheme 1) is considered as a rigid
conformation of cyclohexane in comparison to boat conformation; because during
interconversion from chair to boat conformation, some angular deformations are required. These
angular deformations usually increase the energy barrier for interconversion from chair to boat
conformation. Therefore the chair conformation of cyclohexane is the most stable conformation.

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I II III IV
Chair Half chair Boat Half chair

V
II A III A Chair
twisted boat Twisted boat

Figure 8: Conformational analysis of cyclohexane

Chair form on distortion gives half chair (II and IV figure 8) conformations which are of
highest energy conformations. In comparison to chair conformation, the boat conformation (III
figure 8) is flexible and can readily distort into many steps to reduce the C-H bond eclipsing.
The boat conformation can be interconvertible in to twisted boat (IIA and IIIA figure 8)
conformations, which has comparatively less angular and steric strains. The twisted boat
conformations have lower energy than the boat conformation, hence is more stable than boat
conformation. At room temperature 99.9% cyclohexane molecules exist in the most stable chair
conformation.
The energy profile diagram along with various possible conformations of cyclohexane is
shown in figure 9.

Figure 9: Energy profile diagram of conformation of cyclohexane

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5.8.3.1AXIAL AND EQUATORIAL BOND:

In chair conformation of cyclohexane, there are two different positions occupied by the 12
hydrogen atoms of cyclohexane. Out of total 12 Hydrogen atoms of cyclohexane, six hydrogen
atoms are located towards perpendicular to average plane of the ring; these perpendicular
hydrogen atoms are called axial hydrogens (a), and respective bonds are called axial bonds. The
other six hydrogen atoms are located along with the average plane of the ring; these hydrogens
are called equatorial hydrogens (e), and the respective bonds are called equatorial bond.
a a
a a
e e
e e
a e e a
a a
e e e e
e e
a a a
a

a = axial; e = equatorial

Cyclohexane is rapidly interconvertible (flips) in to its mirror image chair conformations at

room temperature. During flipping all the axial hydrogens becomes equatorial and all the
equatorial hydrogens becomes [Link] flipping of the cyclohexane is so rapid that it is not
possible to differentiate between equatorial and axial hydrogens. These hydrogens can be
differentiated at very low temperature (i.e. -80°) and analyzed by 1H NMR spectroscopy.

5.8.4 CONFORMATION OF MONO SUBSTITUTED CYCLOHEXANE:

If one hydrogen atom of cyclohexane is replaced by a larger atom or group, the molecule
becomes highly hindered. As a result the repulsion between atoms increases. Axial atoms/groups
usually face more repulsive interaction in comparison to equatorial atoms/groups. Since three
axial atoms/groups are located in one side of the average plane of ring, whereas rest three
atoms/groups are located in other side of the average plane of ring. The repulsive interaction
experienced by three axial atoms is called 1,3-diaxial [Link] minimize the 1,3-diaxial
interaction and resulting repulsive energy, the monosubstituted cyclohexane acquires a chair
conformation in which the substituents occupies an equatorial position. There are two possible
chair conformations for methyl cyclohexane. In one conformation the methyl group located at
axial position (I), whereas in other conformation the methyl group is located at equatorial

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position (II). When methyl group is at axial position, it has 1,3-diaxial interaction with hydrogen
atoms at C3 and C5 carbons due to which the energy of such conformation is very high in
comparison to the conformer in which the methyl group is at equatorial position. The conformer
with methyl group at equatorial position does not have any kind of 1,3-diaxial interaction hence
is more stable.
CH3 H
H H
H H3C
H H

Axial conformer with Equatorial conformer

1,3-diaxial interaction with no 1,3-diaxial
(I) interaction (II)

5.8.5 CONFORMATION OF DISUBSTITUTED CYCLOHEXANES:

Disubstituted cyclohexanes are of three types viz. 1,2-; 1,3- and 1,4- with respect to each other.
Therefore, the conformational analysis of all three types of disubstituted cyclohexanes is
discussed separately in this section. It is also important to note that whether the substituents are
either cis- or trans- to each other. In general, it is observed that in disubstituted cyclohexanes
either the chair conformation with both the substituents in equatorial positions will be the
preferred conformation, or the conformation with bulkier substituent at equatorial position will
be the preferred conformation. Let us consider the disubstituted cyclohexanes containing methyl
group as both the substituents.

1,2-Dimethylcyclohexane: For 1,2-dimethylcyclohexane, two isomeric forms (i.e. cis- and

trans-) are possible. The 1,2-dimethylcyclohexane with substituents at one axial and one
equatorial positions is known to have a cis- configuration, whereas, the 1,2-dimethylcyclohexane
with both the substituents at either axial or equatorial positions is known to have a trans-
configuration. Out of three conformations shown in figure 10, the conformation with diaxial
substituent is the least stable conformation of cyclohexane since two axial methyl group causes
four 1,3-diaxial interaction (repulsive interaction) between axial methyl group and hydrogen
atom.

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CH3
CH3
CH3
CH3
CH3
CH3
cis-1,2-dimethylcyclohexane trans-1,2-dimethylcyclohexane trans-1,2-dimethylcyclohexane
a,e or e,a a,a (diaxial) e,e (diequatorial)
(more stable) (least stable) (most stable)

Figure 10: Conformational isomers of 1,2-dimethylcyclohaxane

Whereas, the conformation with diequatorial substituent id the most stable conformation of
cyclohexane since there are no 1,3-diaxial interaction between methyl group and hydrogen atom.
However, the conformation of 1,2-dimethylcyclohaxane, with one methyl at axial and one
methyl at equatorial, causes two 1.3-diaxial interactions hence it is more stable than diaxial
conformation and less stable than diequatorial conformation of 1,2-dimethylcyclohaxane. Thus
the decreasing order of stability of different conformations of 1,2-dimethylcyclohexane is:
ee>ae~ea>aa.

1,2-dimethylcyclohexane shows enantiomerism. It has 2 chiral centers, hence can have four
stereoisomers possible, since cis-1,2-dimethylcyclohexane is not superimposable on its mirror
image but they are readily interconvertible by flipping one chair conformer in to other, hence,
only three stereoisomers are exist for 1,2-dimethylcyclohexane (Figure 11). These two readily
interconvertible conformers are called conformational enantiomers. It must be noted that the cis-
1,2-dimethylcyclohexane constitutes a non resolvable racemic mixture, hence it is not a meso
compound.

CH3 CH3

CH3 H3 C

cis-1,2-dimethylcyclohexane
a,e or e,a
(readily interconvertible non resolvable racemic mixture)

Figure 11: Interconvertible (racemic mixture) of cis-1,2-dimethylcyclohaxane

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However, trans-1,2-dimethylcyclohexane (ee) and its mirror image are non superimposable,
hence they constitute an enantiomeric pair. They cannot be interconvertible readily by flipping.
On flipping ee chair conformer leads the formation of aa chair conformer. These two
stereoisomers are called configurational enantiomers (Figure 12).

CH3 H3C
CH3 H3C

trans-1,2-dimethylcyclohexane
ee
(non interconvertible)

Figure 12: Non-interconvertible (enantiomeric mixture) of trans-1,2-dimethylcyclohaxane

1,3-Dimethylcyclohexane: In case of 1,3-Dimethylcyclohexane (molecule with two identical

substituents) two cis- and one trans- chair conformations are possible as shown in figure 13.

CH3 CH3 CH3

H3C CH3
H3 C

cis-1,3-dimethylcyclohexane cis-1,3-dimethylcyclohexane
trans-1,2-dimethylcyclohexane
a,a (diaxial) e,e (diequatorial)
a,e or e,a
(least stable) (most stable)

Figure 13: Conformational isomers of 1,3-dimethylcyclohaxane

In the case of 1,3-dimethylcyclohexane the cis- stereoisomer (ee) is more stable than the trans-
stereoisomer (ae). Since, cis- stereoisomer (ee) has no 1,3-diaxial interactions, while, trans-
stereoisomer (ae) has two 1,3-diaxial interactions between hydrogen of cyclohexane and methyl
group. However, another cis- stereoisomer (aa) of 1,3-dimethylcyclohexane is the least stable
stereoisomer due to maximum 1,3-diaxial interactions. The decreasing order of stability of these
stereoisomers is: ee>ae~ea>aa.

Likewise 1,2-dimethylcyclohexane, 1,3-dimethylcyclohexane has also two chiral centers, hence,

it must have four stereoisomers. However, both the conformational isomers of cis-1,3-
dimethylcyclohexane has plane of symmetry, hence, it is achiral and called meso compound

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Figure 14. The trans-1,3-dimethylcyclohexane does not have plane of symmetry hence it exist in
two configurational enantiomeric forms. These two configurational enantiomers are not
interconvertible by flipping of the chair forms Figure 14.

CH3 CH3 CH3 CH3

H3 C CH3 H3 C CH3

cis-1,3-dimethylcyclohexane trans-1,2-dimethylcyclohexane
Plane of symmetry a,e or e,a
meso compound Conformational enantiomer

Figure 14: Stereochemistry of 1,3-dimethylcyclohaxane conformations

1,4-Dimethylcyclohexane: Similar to 1,2-Dimethylcyclohexane, 1,4-dimethylcyclohexane have

also one cis- and two trans- conformational isomers are possible, as shown in figure 15.
CH3
CH3
H3 C CH3
H 3C
CH3
trans-1,2-dimethylcyclohexane trans-1,2-dimethylcyclohexane cis-1,2-dimethylcyclohexane
a,a (diaxial) e,e (diequatorial) a,e or e,a
(least stable) (most stable) (more stable)

Figure 15: Conformational isomers of 1,4-dimethylcyclohaxane

Due to plane of symmetry in all the isomeric forms of 1,4-dimethylcyclohexane does not have
any chiral center. It exists only in cis- and trans- diastereomers. Neither its cis- nor trans-
diastereomeric forms is chiral.

As we have observed that, if cyclohexane is substituted with alkyl groups diequatorial

conformation is the most stable conformation in all types of disubstituted cyclohexanes.
However, if the substituents are different than methyl group then the above observation may not
be applicable. For example, when methyl groups are replaced with halogens (i.e. Cl or Br), the
trans- conformations (i.e. ee and aa) of 1,4-dihalocyclohexane are equally populated, and most
of the trans-1,4-dihalocyclohexane exists predominantly in aa conformation due to dipole and
gauche interactions Figure 16. Similarly, for 1,2-dihalocyclohexane the aa conformation is more

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stable than ee conformation Figure 16. In the case of 1,3-cyclohexnediol, it is observed that the
aa conformation is found to be more stable than the ee conformation due to the stabilization of
diaxial conformation by formation of hydrogen bonding between the oxygen atom of one
hydroxyl group and hydrogen atom of other hydroxyl group (intramolecular H bonding).

X
X

X
trans-1,2-dihalocyclohexane trans-1,2-halocyclohexane
a,a (diaxial) e,e (diequatorial)
(more stable) (less stable)

Figure 16: Stability of trans-1,4-dimethylcyclohexane

In the case of 1,3-cyclohexnediol the preferred conformation is the chair form; while, when the
hydroxyl substituent are at 1, 4- position (1,4-cyclohexnediol) then the boat conformation is
preferred to stabilize the 1,4-cyclohexnediol via formation of intramolecular hydrogen bonding
(Figure 17).

H Bonding
H
OH OH O
OH

cis-1,3-cyclohexanediol
(chair conformation) 1,4-Cyclohexanediol
(more stable) boat conformation
(more stable)

Figure 17: Hydrogen bonding in trans-1,4-dihydroxycyclohexane

5.8.6 CONFORMATION OF DECALINS:

Decalin is a bicyclic compound. Generally, bicyclo [4,4,0] decane is known as decalin. Two
cyclohexane rings are fused together in chair conformation to generate decalin. It exists in two
diastereomeric forms (i.e. cis- and trans-decalins). Decalin is structural analogous to 1,2-

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disubstituted cyclohexane. When both the cyclohexane rings are fused together in ea form the
decalin thus formed is called cis-decalin. However, when two cyclohexane rings are fused
together in ee form the decalin thus formed is called trans-decalin. The cis- and trans-decalins
are shown in figure 19.

cis-decalin trans-decalin
(ea) (ee)

Figure 19: Conformations of decalin

The trans-decalin is more stable than cis-decalin by 2.7 kcal/mol of energy. Thus cis-decalin can
be easily converted in to trans-decalin but the reverse process is not possible. Due to flexibility
in structure of cis-decalin, its ring flipping is possible. Thus cis-decalin exists in two
interconvertible conformational isomers Figure 20. In comparison to cis-decalin, the trans-
decalin is a rigid molecule. Due to the presence of two equatorial bonds the ring flipping of
trans-decalin is not possible.

cis-decalin cis-decalin
(ea) (ea)

Figure 20: Flipping of cis-decalin

The cis-decalin is chiral in both the conformation, since, these conformations are non-
superimposable mirror image of each other. Hence, cis-decalin exists in a conformational
enantiomeric pair. On the other hand, the trans-decalin due to center of symmetry is achiral. In
case of substituted decalins, the substituent located at the fusion point of both the rings. In the
case of cis-decalin the substituent at fusion point is axial with respect to one ring and equatorial
with respect to other ring. On the other hand, in trans-decalin the substituent is located at axial

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position with respect to both the rings (Figure 21). It must be noted that the substituent to the cis-
decalin is free to adopt the equatorial position.

CH3 H H CH3 H
H H H

Methyl substituted cis-decalin Methyl substituted trans-decalin

There are twor sets of 1,3-diaxial interaction There are four sets of 1,3-diaxial interaction
with axial methyl substituent with axial methyl substituent
(more stable) (less stable) Fi
gure 21: Position of substituents on cis- and trans-decalin

5.9 STEREOCHEMISTRY OF COMPOUNDS CONTAINING N, P

AND S.

Like tetravalent carbon compounds, the nitrogen, phosphorous and sulphur containing
compounds also exhibit stereochemical behaviour. Compounds of N, P and S show both
enantiomerism and/or geometrical isomerism. This section deals with the brief discussion on the
stereochemistry of compounds of N, P and S.

5.9.1 STEREOCHEMISTRY OF NITROGEN COMPOUNDS:

Geometrical isomerism of nitrogen compounds: Nitrogen containing compounds like
>C=N- as well as –N=N- bond also exhibit geometrical isomerism. The important classes of
compounds that exhibit geometrical isomerism due to >C=N- bond are (Figure 22):
(e) Oximes
(f) Nitrones
(g) Semicarbazones
(h) Hydrazones

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H Ph H3C Ph Ph CH3 Ph CH3

C C C C

N N N N
OH O H NH2 NHCONH2
(E)-1-(1- (E)-1-(1-
(Z)-benzaldehyde (E)-nitrone phenylethylidene) phenylethylidene)
oxime hydrazine semicarbazide

Figure 22: Geometrical isomers of compounds having >C=N

Oximes are the most common compounds among all above classes. Both carbon and nitrogen
atom in oxime are sp2 hybridized the C=N bond of oxime consists a sigma (σ) and a pi (π) bond.
Therefore, there is no free rotation possible around C=N bond; hence, oximes of aldehyde and
ketones (unsymmetrical) exhibit geometrical isomerism.

Some examples of compounds exhibiting geometrical isomerism containing –N=N- are shown in
figure 23.

Ph Ph O
Ar
N N
N
N N
N
ONa Ph Ph
(E)-
(Z)-Diazoate (E)-Azobenzene Azoxybenzene

Figure 23: Geometrical isomers of compounds having -N=N

The configuration of such compounds is also based on priority of the groups/atoms attached to
the double bonded carbon and nitrogen. Lone pair of the nitrogen always considered to be the
lowest priority group. The priority of the groups/atoms is assigned as per the sequence rule
which we have already discussed in Unit 4. If the higher priority groups/atom on double bonded
carbon and nitrogen are on same side of the double bond the isomer is considered as Z- isomer,
whereas if the higher priority groups/atoms are on opposite side the isomer is considered as E-
isomer.

Example 26: E/Z isomerism is shown by i) benzaldoxime, ii) ethylmethylketoxime and iii)
methylphenylketoxime

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H Ph Ph H H 3C C2 H 5 C2 H 5 CH3
C C C C
i) ii)
N N N N
OH OH OH OH
(Z)- (E)-
(Z)-benzaldehyde (E)-benzaldehyde ethylmethyl ethylmethyl
oxime oxime ketoxime ketoxime

Ph CH3 H 3C Ph
C C
iii)
N N
OH OH
(E)-acetophenone oxime (Z)-acetophenone oxime

Enantiomerism of nitrogen compounds: The tetrahedral concept of carbon has also

been successfully extended to nitrogen containing compounds. The only difference in nitrogen
compounds is that one of the sp3 hybridized orbital of nitrogen usually contains a lone pair of
electrons which is not involved in bonding. Thus nitrogen containing compound have three
ligands and one lone pair in sp3 orbital. Thus in terms of a chiral center, nitrogen is analogous to
carbon. The tertiary amines of with all three different atoms or groups attached with center
nitrogen atom have chiral nitrogen, but do not have optical activity. Thus is due to the rapid
interconversion of lone pair from one face of the other resulting in rapid racemization Figure 24.
The amine interconversion is described as an inversion, such enantiomers are called invertomers.

CH3
CH3 H C 2H5
N H N N
CH3
H C2H5
C 2H5
R-ethylmethylamine transition state is planar S-ethylmethylamine

Figure 24: Inversion of lone pair in nitrogen containing compounds

5.9.2 STEREOCHEMISTRY OF COMPOUNDS CONTAINING P:

Phosphorous can also exhibit covalencies of 3, 4 and 5, hence they give rise to more possible
configuration than nitrogen. In tetravalent phosphorous compounds the valence deposition is
tetrahedral (sp3 hybridized) in which one sp3 orbital being occupied by lone pair, whereas, in

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quinquevalent (pentavalent) phosphorous compounds the valence deposition is trigonal

bipyramidal (sp3d). The following are examples of the various resolvable compounds of
phosphorous in its different hybrid states (Figure 26).

O O O
P P P C 2 H5 P SH
CH3 CH3 CH3 P CH2Ph C2H5 CH3
C 3 H7 H
C 6 H5 C6 H 5 C6 H 5 C 6 H5 OC2H5
(S)-methyl(phenyl) (R)-methyl(phenyl)
(propyl)phosphine phosphine
Fi
gure 27: Examples of the various resolvable compounds of phosphorous

5.9.3 STEREOCHEMISTRY OF COMPOUNDS CONTAINING S:

Similar to nitrogen and phosphorous containing compounds, various sulphur containing

compounds have also been identified to exhibit enantiomerism. Some common examples are
Sulphonium salts, Sulphuris esters, Sulphoxides and Sulphines, Figure 28.

NH2
COOH
Br Br
S S
S CH3 O C6H5 S O
C 2 H5 S O
CH3 C2H5 OC2H5 H3 C S
CH2COOH CH2COOH O
3-(methylsulfinyl)
Sulphine
3-(p-tolylsulfinyl) benzoic acid
benzenamine

Figure 28: Examples are Sulphonium salts, Sulphuris esters, Sulphoxides and Sulphines

5.10 SUMMARY

The present unit may be summarized as:

Topicity is the stereo-chemical relationships between individual atoms or groups within a

single molecule.
The property by which the replacement of two similar atoms or groups of a carbon center
generates the chirality is called prochirality.

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Two apparently identical atoms/groups of a prochiral centre are called homomorphic

atoms/groups.
If the replacement of two homomorphic ligands generates enantiomers the ligands are
called enantiotopic ligands.
If the replacement of two homomorphic ligands generates diastereomers the ligands are
called diastereotopic ligands.
Stereo chemical transformation (reaction) that results the preferential formation of one
enantiomer or diastereomer over other in the presence of a chiral substrate, reagent,
catalyst or environment is called asymmetric induction.
Those reactions in which one stereoisomer (or one pair of enantiomers) is formed
predominantly or exclusively out of several possible stereoisomers are called
stereoselective reactions.
The reactions or processes in which one of the enantiomer forms predominantly over the
other is called enantioselective reaction.
The reactions or processes in which one of the diastereomer forms predominantly or
exclusively over the other are called diastereoselective reaction.
Rotation around bonds in alkane structures, exemplified in ethane and butane, gives rise to
conformational isomers.
In the staggered form, the torsional angle between attached groups is at 60o. In the eclipsed
form, it is at 0o.
A staggered conformation of ethane or butane has a lower rotational energy than the
eclipsed conformation.
Anti-conformations are usually the more stable with gauche and eclipsed structures of
higher energy.
Analysis of cyclohexane derivatives pays attention to substituents in axial and equatorial
positions, with equatorial substituents being more stable.
The most stable form of cyclohexane is the chair conformation. In this form, the molecule
has both axial and equatorial substituents.
Cyclohexane undergoes a chair-boat-chair ring flip in which the axial substituents become
equatorial, and vice versa.

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Interconversions between chair forms involve higher energy structures known as boat,
twist and half-chair structures that are unstable.
Cyclohexanes with axial substituents are less stable than those with the same
substituents equatorial, because of unfavorable interactions among axial substituents.

5.11 TERMINAL QUESTION

Q.1 Define Topicity.
Q.2 What is prochirality?
Q.3 What are enantiotopic ligands and faces?
Q. 4 What do you understand with asymmetric synthesis?
Q. 5 Define configurational and conformational isomers.
Q. 6 Why the geometrical isomers are called diastereomers?
Q. 7 What is cyclization method for determination of configuration of geometrical isomers?
Q. 8 How do you determine the configuration of geometrical isomerism using physical
method?
Q. 9 What are staggered and eclipsed conformations of alkanes?
Q. 10 Which conformation of cyclohexane is the most stable and why?
Q. 11 What will be the preferred position for methyl group in the conformation of methyl
cyclohexane?

5.12 ANSWERS
1. Stereo-chemical relationships between individual atoms or groups within a single
molecule can be defined in terms of topicity. Thus, two atoms equated by a mirror
reflection of the molecule are enantiotopic and two atoms in equivalent environments
(i.e., the methylene protons in n-propane) are homotopic. Two protons placed in
diastereomeric positions by a mirror reflection are in diastereotopic environments.

Examples: Propane has homotopic ligands; however, propionic acid has enantiotopic
ligands

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O O O
simultaneous replacement
H3C of Ha and Hb by OH H3 C H3 C
OH OH OH
Ha Hb Ha OH HO Hb

Propionic acid Both the compounds are enantiomer

(prochiral molecule Ha and Hb are
enantiotopic)
simultaneous replacement HO Hb
Ha Hb of Ha and Hb by OH Ha OH
H3 C CH3
H3 C CH3 H3C CH3
Propane Ha and Hb Both the compounds are identical
are homotopic

2. It is the property of some molecules due to which these molecules can be converted in to
stereoisomers (enantiomers or diastereomers) by replacing one of the identical atoms or
groups by a different atom or group. It is also known as ‘prostereoisomerism’ more
specifically. If the replacement of such atoms or groups leads the formation of enantiomer
the atoms or groups are called enantiotopic; whereas, if such replacement lead the
formation of diastereomers the atoms or groups are termed as diastereotopic.
3. When the replacement of each equivalent atom or groups by a different atom given
enantiomeric products, such equivalent atoms or groups are called enantiotopic atoms or
enantiotopic ligands.
Example: For example, two hydrogen atoms of meso-tartaric acid are enantiotopic since
the replacement of each one of them by a different atom or group gives the enantiomeric
pair of (2S)-2-chloro-2,3-dihydroxysuccinic acid and (2R)-2-chloro-2,3-
dihydroxysuccinic acid.
Enantiomer

COOH COOH COOH

1 simultaneous replacement
H C OH hydrogen by Cl Cl C OH H C OH
H C OH HO C H Cl C OH
2
COOH COOH COOH
(2S)-2-chloro-2,3- (2R)-2-chloro-2,3-
2,3-dihydroxysuccinic acid
dihydroxysuccinic acid dihydroxysuccinic acid
(meso)

Similarly, when two faces of a double bond gives enantiomers on addition of suitable
reagents, such faces are called enantiotopic faces. For example, trans-2-butene and

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unsymmetrical ketones have enantiotopic faces since they also give enantiomers on
addition of suitable reagents.

Example: Epoxidation of trans-2-butene on either face of double bonds gives the

enantiomeric pair of (2R,3R)-2,3-dimethyloxirane and (2S,3S)-2,3-dimethyloxirane.
H CH3 O H CH3
Epoxidation H3C H
C C H C C CH3 + C C
H3C H H3C H O
Cl O OH
trans-2-butene O (2R,3R)-2,3-dimethyloxirane (2S,3S)-2,3-dimethyloxirane

4. Asymmetric induction is a stereo chemical transformation (reaction) that results the

preferential formation of one enantiomer or diastereomer over other in the presence of a
chiral substrate, reagent, catalyst or environment. This is also known as asymmetric
synthesis.
Example: Let us consider hydrogenation of Acetphenone by sodiumborohydride
(NaBH4). Since, both the reagent and substrate are achiral (optically inactive) and also the
reaction takes place in the medium of methanol (achiral), hence, equal amount of (R)-1-
phenylethanol and (S)-1-phenylethanol (racemic mixture) is formed.
O HO H HO H
H2 gas
CH3 CH3 + CH3
chiral Ruthenium
Acetophenone complex (S)-1-phenylethanol (R)-1-phenylethanol
(Achiral) 97.5 ee 2.5 ee

5. The stereoisomerism which is due to the rotation about a single bond is referred to as
conformation. Conformers are easily interconvertible and it is difficult to isolate the
isomer. On the other hand, when two compounds are different in their configuration, e.g.,
a pair of enantiomers of bromofluoromethane, or a pair of geometrical isomers, maleic
acid and fumaric acid, these are distinguishable compounds, and their isolation is possible

6. Geometrical isomers are non-mirror image of each other hence they are called
diastereomers. Therefore their physical and chemical properties are different.

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7. Cyclization method: Cyclization within a molecule (intramolecular) is usually depends

upon the distance of two associating groups of a molecule. In other words if the reacting
groups are closer to each other than the intramolecular cyclization takes place more
effectively. This principal is also helps to identify the configuration of geometrical
isomers.
Let us take an example of two geometrical isomer of Butenedioic acid (i.e. Maleic acid
and Fumaric acid) can be differentiated by possibility of formation of anhydride. Maleic
acid which is cis- form of Butenedioic acid can only give the respective anhydride on
heating; whereas, the trans- form of Butenedioic acid (i.e. Fumaric acid) does not give its
anhydride on heating. If the Fumaric acid is strongly heated it get converted into Maleic
acid.
Example : Cyclization of Maleic acid to Maleic anhydride. Fumaric acid does not give
the anhydride on heating.

O
H COOH H C H COOH
C Heat C C Heat
-H2O O No anhydried
C C C formation
H COOH H C HOOC H
O
Maleic acid Maleic anhydried Fumaric acid
cis- isomer trans- isomer

8. The geometrical isomers are non-mirror image of each other hence are called
diastereomers. We have discussed in Unit 4 that diastereomers have different physical
and chemical properties. Based on this fact, we can determine the configuration of
geometrical isomers by comparing their physical properties. For example the melting
point and absorption intensity of the cis-isomer are lower than the trans-isomer. Similarly
the boiling point, solubility, heat of hydrogenation, density, refractive index, dipole
moment and dissociation constant of cis-isomer is greater than the trans-isomer.
Thus if you have a set of geometrical isomers, then by comparing their above mentioned
physical properties you can assign their configuration (means you can identify the cis-
and trans-isomers).

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Example : Diethyl maleate and diethyl fumarate are the cis- and trans- form to each
other. The configuration of these can be determined by comparing their dipole moment.
The dipole moment of diethyl maleate is 2.54D whereas the dipole moment of diethyl
fumarate is 2.38D. Based on the fact that the dipole moment of trans- form of an isomer
is lower than that of cis- form, you can easily predict the cis- and trans- form for diethyl
maleate and diethyl fumarate.

H COOC2H5 H COOC2 H5
C C

C C
H COOC2H5 C2H5OOC H
diethyl maleate diethyl fumarate
dipole moment = 2.54D dipole moment = 2.38D

9. Conformation with a 60° dihedral angle is known as staggered conformation. The angle
between the atoms attached to the front and rear carbon atom is called dihedral angle.A
conformation with a 0° dihedral angle is known as eclipsed conformation.

H 60o H
H H H 0o
H H

H H
H HH

Staggered conformation Eclipsed conformation

10. The chair conformation is considered as a rigid conformation of cyclohexane in

comparison to boat conformation; because during interconversion from chair to boat
conformation, some angular deformations are required. These angular deformations
usually increase the energy barrier for interconversion from chair to boat conformation.
Therefore the chair conformation of cyclohexane is the most stable conformation.
11. There are two possible chair conformations for methyl cyclohexane. In one
conformation the methyl group located at axial position, whereas in other conformation
the methyl group is located at equatorial position. When methyl group is at axial position,
it has 1,3-diaxial interaction with hydrogen atoms at C3 and C5 carbons due to which the

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energy of such conformation is very high in comparison to the conformer in which the
methyl group is at equatorial position. The conformer with methyl group at equatorial
position does not have any kind of 1,3-diaxial interaction hence is more stable.
CH3 H
H H
H H 3C
H H

Axial conformer with Equatorial conformer

1,3-diaxial interaction with no 1,3-diaxial
interaction

Bibliography:
Following books are referred for compiling the material of present unit.
7. Organic Chemistry Vol. 1 by I L Finar, Published by Pearson Education; ISBN 10:
8177585428.
8. Organic Chemistry by T. W. Graham Solomons, Published by John Wiley; ISBN-10:
1118133579.
9. Stereochemistry of Organic Compounds by Ernest L. Eliel; Published by John Wiley;
ISBN- 0-471-01670-5
10. Organic Chemistry by Leroy G. Wade. Published by Pearson Education; ISBN-
9780321768414
11. Stereochemistry: Conformation and Mechanism by P. S. Kalsi. Published by New Age
International Publication. ISBN-10: 8122435645; ISBN-13: 978-8122435641
12. Stereochemistry of Organic Compounds: Principles and Applications by D Nasipuri,
Published by New Academic Science ISBN-10: 190657491X; ISBN-13: 978-
1906574918

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UNIT 6: ALIPHATIC NUCLEOPHILIC SUBSTITUTION

CONTENTS:

6.1 Objectives
6.2 Introduction
6.3 Nucleophilic Reaction
6.3.1 The SN2, SN1
6.3.2 Mixed SN1 and SN2, SNi and SET mechanisms.
6.4 The neighbouring group mechanism
6.5 Anchimeric assistance
6.6 Classical and nonclassical carbocations
6.7 Norbornyl cation
6.8 Common carbocation rearrangements-
6.8.1 Pinacol-Pinacolone rearrangement
6.8.2 Dakin Reaction
6.8.3Wagner-Meerwein rearrangement
6.8.4 Benzilic acid rearrangement
6.8.5 Allylic rearrangement
6.8.6 Hofman reaction, Schmidt reaction
6.8.7 Curtius rearrangements
6.8.7 Lossen rearrangement and Dakin reaction
6.9 Summary
6.10 Terminal Questions

6.1 OBJECTIVES

After studying this chapter, you shall be able to:

Know what is Nucleophilic Reaction

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Learn mechanism of Nucleophilic Reactions like SN2, SN1, Mixed SN1 and SN2, SNi
and SET mechanisms.
Learn neighbouring group mechanism
Learn mechanism of anchimeric assistance
Identify functional groups taking part in anchimeric assistance
Evaluate outcomes of anchimeric assistance for various reactions
To know about Classical and nonclassical carbocations
To know about various Common carbocation rearrangements reaction

6.2 INTRODUCTION

In organic chemistry, nucleophilic substitution is a fundamental class of reactions in

which an electron rich nucleophile selectively bonds with or attacks the positive or partially
positive charge of an atom or a group of atoms to replace a leaving group; the positive or
partially positive atom is referred to as an electrophile. The whole molecular entity of which the
electrophile and the leaving group are part is usually called the substrate.

The most common aliphatic nucleophilic reaction may be given as the following:

Nuc: + R-LG → R-Nuc + LG:

The electron pair (:) from the nucleophile (Nuc) attacks the substrate (R-LG) forming a new
bond, while the leaving group (LG) departs with an electron pair. The principal product in this
case is R-Nuc. The nucleophile may be electrically neutral or negatively charged, whereas the
substrate is typically neutral or positively charged.

6.3 NUCLEOPHILIC REACTION

6.3.1 The SN2, SN1 Reaction:
SN1 reaction:

The SN1 reaction is a substitution reaction in organic chemistry. "SN" stands for nucleophilic
substitution and the "1" represents the fact that the rate-determining step is unimolecular. Thus,

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the rate equation is often shown as having first-order dependence on electrophile and zero-order
dependence on nucleophile. This relationship holds for situations where the amount of
nucleophile is much greater than that of the carbocation intermediate.

This type of mechanism involves two steps. The first step is the reversible ionization of Alkyl
halide in the presence of aqueous acetone or an aqueous ethyl alcohol. This step provides a
carbocation as an intermediate. In the second step this carbocation is attacked by the nucleophile
to form the product.

Mechanism:

An example of a reaction taking place with an SN1 reaction mechanism is the hydrolysis of tert-
butyl bromide with water forming tert-butanol.:

This SN1 reaction takes place in three steps:

Step 1: Formation of carbocation: Formation of a tert-butyl carbocation by separation of a

leaving group (a bromide anion) from the carbon atom: this step is slow and reversible.

Step 2: Nucleophilic attack: the carbocation reacts with the nucleophile. If the nucleophile is a
neutral molecule (i.e. a solvent) a third step is required to complete the reaction. When the
solvent is water, the intermediate is an oxonium ion. This reaction step is fast.

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Step 3: Deprotonation: Removal of a proton on the protonated nucleophile by water acting as a

base forming the alcohol and a hydronium ion. This reaction step is fast.

Factor Affecting the SN1 reaction:

Some of the factor which can affect the SN1 reaction are given below:

(a) Nature of substrate:

For SN1 reaction reactant should be of the such type that can generate stable carbocation
intermediate.

According to the concept reactivity order of the alkyl halide for SN1reaction can be given
as:

-Increase stability of corresponding carbocation.

-Increase reactivity of alkyl halide toward the SN1 reaction.
(b) Nature of Nucleophile:

Nature of Nu does not affect the SN1 reaction because Nu does not involve in the slow
step of SN1 reaction.

(b) Nature of leaving group:

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For the SN1 reaction always leaving group less basic in nature.
Stereochemistry of SN1 reaction:

Reaction is the two step reaction during which there can occur the inversion as well as retention
of configuration i.e. there can occur racemization during the SN1 reaction

Effect of the solvent on the rate of SN1 reaction: During the slow step or rate determining step
of the SN1 reaction there occurs the formation of polar nature of transition state before
generating the carbocation. The polar solvent with high dielectric constant value stabilize the
transition state by which energy of activation for the slow step or rate determining step is
decrease in the dielectric constant value of polar solvent. While on the other hand nonpolar
solvent does not interact with T.S. of substrate due to which they does not decrease the activation
energy of rate determining step i.e. they does not affect the rate of SN1 reaction.

SN1

Figure: 1

Polar solvent stabilizes the T.S. of SN1 reaction and increase the rate of reaction.

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Relative rate of SN1 in t-butyl chloride according to the dielectric constant of same polar solvent
can be given as:

Solvent Dielectric constant Relative rate

Acetic acid 6 1
Methanol 33 4
Formic acid 58 5,000
Water 78 1,50,000

Potential energy diagram for SN1 reaction:

SN1 reaction is the two step reaction for with P.E diagram can be represented as:

Figure.2

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SN2 Reaction:

The SN2 reaction is a type of reaction mechanism that is common in organic chemistry. In this
mechanism, one bond is broken and one bond is formed synchronously, i.e., in one step. SN2 is a
kind of nucleophilic substitution reaction mechanism. Since two reacting species are involved in
the slow (rate-determining) step, this leads to the term substitution nucleophilic (bi-molecular) or
SN2, the other major kind is SN1. Many other more specialized mechanisms describe
substitution reactions.

Mechanism of SN2 reaction:

The reaction most often occurs at an aliphatic sp3 carbon center with an electronegative, stable
leaving group attached to it (often denoted X), which is frequently a halide atom. The breaking
of the C–X bond and the formation of the new bond (often denoted C–Y or C–Nu) occur
simultaneously through a transition state in which a carbon under nucleophilic attack is
pentacoordinate, and approximately sp2 hybridised.

The nucleophile attacks the carbon at 180° to the leaving group, since this provides the best
overlap between the nucleophile's lone pair and the C–X σ* antibonding orbital. The leaving
group is then pushed off the opposite side and the product is formed with inversion of the
tetrahedral geometry at the central atom.

In an example of the SN2 reaction, the attack of Br− (nucleophile) on an ethyl chloride
(electrophile) results in ethyl bromide, with chloride ejected as the leaving group.:

Factor affecting SN2 Reaction:

Some of the factors which can affect the SN2 reaction are given below:

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(a) Nature of Substrate:

For the SN2 reaction substrate should contain less bulky atoms or group otherwise backside
attack of nucleophile will not be possible. On the basis of the above given concept the order of
reactivity for 1o, 2o and 3o alkyl halide toward the SN2 reaction will becomes as:

-Increase number of bulky substituent.

-Decrease possibility of back attack of Nu.
-Decease reactivity of alkyl halide toward the SN2 reaction.
(b) Nature of nucleophile:
(i) For the SN2 reaction nucleophile should be less bulky otherwise back side
attack of Nu will not possible due to steric reason.
(ii) For the SN2 reaction Nu should more basic in nature. Sometime bulkiness
factor of Nu can be dominated over the basicity factor.
Example: CH3Cl exhibit 1000 times faster reaction with CH3O- in compare to the reaction with
more basic (CH3)3CO-.

H H3C H3C

C Cl + C ONa C O CH3 + NaCl

H H3C
H H2C CH3 H3C

(more basic Nucleophile) (slow)

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(c) Nature of leaving group: For the SN2 reaction leaving group should be less basic in
nature.
(d) Always basicity of Nu should be more in compare to the basicity of leaving group
otherwise reaction will not be possible.
EXAMPLE:

This reaction is possible due to more basic strength of OH- ion (nucleophile) than the Cl- ion (leaving
group)

Example:

This reaction is not possible due to less basic strength of Cl- ion (Nucleophile) than the OH- ion
(leaving group)

Stereochemistry of SN2 reaction:

During the SN2 reaction attack from the back side in the substrate due to which always there will
occur the inversion in configuration.

Walden Inversion:

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If the inversion in configuration occur at chiral center by the SN2 reaction than such type of
inversion in configuration is called as Walden inversion.

6.3.2 Mixed SN1 and SN2 Nucleophilic Substitution:

Mixed SN1 and SN2 reaction consists of a nucleophile and a substrate. When a nucleophile
reacts with a substrate, substitution takes place. This substitution is known as nucleophilic
substitution reaction. A substitution reaction occurs and the leaving group from the substrate
departs. The nucleophile is an electron pair donor. The substrate acts an electrophile (electron
pair acceptor). The electrophile has sp3 hybridization. There must be a leaving group in the
electrophile.

Substitution Nucleophilic Unimolecular (SN1) Reaction:

In SN1 reaction, there is one molecule reacting in the reaction intermediate state or the transition
state. A carbocation which is planar in nature is first formed. Then a nucleophile attacks on the
carbocation to form the intermediate or the transition state. Here the nucleophile is free to attack
from either side of the substrate. Therefore, there occurs racemization.

CH3 CH3

-Cl-
C Cl C+

CH3 CH3 CH3 CH3

Carbocation
CH3 CH3 CH3

-Nu-
C+ C C

Nu Nu
CH3 CH3 CH3 CH3
CH3 CH3
Carbocation Racemization

Substitution Nucleophilic Bimolecular (SN2) Reaction:

In SN2 reaction, there are two molecules react in the reaction intermediate state or the transition
state. The leaving group departs simultaneously as soon as the nucleophile attacks the molecule
or the substrate from the backside. Hence in the product side, there occurs inversion of the
configuration.

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CH3 CH3

-Cl-
C Cl C
-
-Nu
Nu
CH3 CH3 CH3 CH3

Inversion of configuration

In the above, both nucleophilic substitution reactions (mixed SN1 and SN2), there is a
competition between the leaving group and the nucleophile.

SNi Mechanism: SNi or Substitution Nucleophilic internal stands for a specific but not often
encountered nucleophilic aliphatic substitution reaction mechanism. This reaction type is linked
to many forms of neighbouring group participation, for instance the reaction of the sulfur or
nitrogen lone pair in sulfur mustard or nitrogen mustard to form the cationic intermediate.

This reaction mechanism is supported by the observation that addition of pyridine to the reaction
leads to inversion. The reasoning behind this finding is that pyridine reacts with the intermediate
sulfite replacing chlorine. The dislodged chlorine has to resort to nucleophilic attack from the
rear as in a regular nucleophilic substitution.

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6.4 THE NEIGHBOURING GROUP MECHANISM

During the SN2 reaction if hydrocarbons of heteroatom like N, S etc. being present at β position
or π bond being present at the γ- position with respect to the leaving group than there occur the
enhancement (increase) in the rate of the SN2 reaction. The mechanism operating in such
neighboring group participation.

During the neighbouring group mechanism there occurs the formation of highly reactive three
membered cyclic intermediate by the intramolecular reaction but the final substitution product
formation occur with the retention of configuration because there occur the two consecutive SN2
reactions.

Due to the formation of highly reactive three membered cuclic intermediate these reaction being
thousand times faster than the normal SN2 reaction.

NGP by an alkene:

The π orbitals of an alkene can stabilize a transition state by helping to delocalize the positive
charge of the carbocation. For instance the unsaturated tosylate will react more quickly (1011
times faster for aqueous solvolysis) with a nucleophile than the saturated tosylate.

The carbocationic intermediate will be stabilized by resonance where the positive charge is
spread over several atoms; in the diagram below this is shown.

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NGP by a cyclopropane, cyclobutane or a homoallyl group:

If Cyclopropylmethyl chloride is reacted with ethanol and water then a mixture of 48%
cyclopropylmethyl alcohol, 47% cyclobutanol and 5% homoallyl alcohol (but-3-enol) is
obtained. This is because the carbocationic intermediate is delocalised onto many different
carbons through a reversible ring opening.

6.5 ANCHIMERIC ASSISTANCE

When a catalytic functional group or atom is part of the reacting molecule, the catalysis is called
intra-molecular catalysis. Anchimeric assistance (anchimeric in Greek means “adjacent parts”) is
a case of intra-molecular catalysis where a suitably placed intra-molecular nucleophile assists in
a substitution reaction by enhancing rate of reaction.

Mechanism of anchimeric assistance:

The bimolecular mechanisms for nucleophilic substitution are termed SN2 reactions. SN2
reactions follow second order rate kinetics. The geometric alignment of transition state for SN2
mechanism is such that the nucleophile attacks from the rear of the leaving group, leading to
inversion of configuration.

However, there are some examples of retention of configuration in SN2 reactions, where an atom
or group (Z) close to the carbon undergoing subsitution assist in the reaction with its available
pair of electrons. Such a group is called a neighbouring group (NG) and the assistance provided
is termed neighbouring group participation (NGP). If such participation leads to an enhanced
reaction rate, the group is said to provide anchimeric assistance.

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Step-I

Z +
Z
CH3
CH3 C Slow CH3 C
CH3 C CH3 CH3 + X-
CH3 C

X
CH3

Step-2

+
Z Z

Slow CH3
CH3 C CH3 C
CH3 C CH3 Y- CH3 C CH3

CH3 Y

The mechanism for anchimeric assistance is a two step mechanism where two consecutive SN2
reaction leads to retention of configuration. In the first step, the neighbouring group (Z) acts as a
nucleophile, attacking the substitution centre and expelling out the leaving group. In the next
step, the external nucleophile (Y) attack from backside displacing the neighbouring group and
retaining the overall configuration. Since the first step is slow and is rate determining, the
reaction follows first order kinetics and there is no effect of concentration of Y- on rate of
reaction.

6.6 CLASSICAL AND NON-CLASSICAL CARBOCATIONS

Carbocations discussed so far are called classical carbocations. Classical carbocations are those
which get stabilised by the movement of either the loan pair of electrons or C-H sigma –electrons
or pi- electrons, in conjugation to the positive charged carbon atom to form a new pi- bond.
+ + +
CH3 CH2 H CH2 CH2 H.CH2= CH2

σ C-H New π bond

electrons are in conjugation
to positive charge

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On the other hand, if in a carbocation the positive charge does not get conjugated with the pi-
bond, and then the resonance structure cannot be written in a normal way. However, in some
cases the resonance structures can ce written by the participation of the neighbouring groups.
The resultant in the formation of bridged cation which are called non-classical carbocation.

+ + +
CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2
* * *
* I
Nonconjugation

In structure (I) two carbons, carbon -1 and carbon- 2 are bonded together by sigma bon. The
third carbon is bonded with other two carbons by two electrons three centered bon. The thired
atom however, can also be a hydron atom. The leades the formation of bridiged structure. These
bridiged structures which involve delocalised of sigma electrons and formation of three centered,
two electron bonds are called non- classical ion. In classical carbocation positive charge is either
located on one carbon or is delocalised due to conjugation of pi- electrons or loan pair of
electrons in allylic position. In non- classical carbocation positive charge is delocalised either by
sigma electrons of C-C or C-H bond of carbob carbon double bond which is not in allylic
position.

6.7 NORBORNYL CATION

Vaious naturally occurring terpenes are derivatives of Norbornane. Molecular rearrangements
are common among these bicyclic terpenes. Winstein and roberts (1950) actively pursued the
mechanism of the rearrangemts and the associated stereochemical problems using the basic
norbornyl system.
Acetolysis of 2-norbornyl brosylates:
Each of the isomeric brosylates (1 and 2) is prepared and subjected to acetolysis. (solvolysis
using acetic acid as solvent and nucleophile)

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In the above reactions following observations takes place:

(i) Rate of solvolysis of 1 to 2 is about 400
(ii) Both 1 and 2 give 3, the exo-acetate
(iii) Optically active exo-brosylate (1) gives 3 which is racemic (±)
(iv) The recovered brosylate (1) is also racemic
(v) The rate of racemisation (measured from specific Rotation) is greater than solvolysis in the
case of the exo-isomer
(vi) The rate of racemization is equal to the rate of solvolysis in the case of endoisomer.

6.8 COMMON CARBOCATION REARRANGEMENTS

6.8.1 Pinacol-Pinacolone rearrangement:

Acid catalysed rearrangement of vicinal diol (Pinacol) into ketone or aldehyde (Pinacolone)
is known as Pinacol-Pinacolone Rearrangement.

CH 3 CH3 O CH 3
H 2SO 4
H3C C C CH3 H 3C C C CH3
OH OH CH 3

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Mechanism:

CH 3 CH 3 H CH 3 CH 3 -H 2O CH 3 CH 3
H 3C C C CH3 H 3C C C CH3 H 3C C C CH3
OH OH OH OH 2 OH

1,2 Me shift

O CH 3 -H CH 3 CH 3 CH 3 CH 3
H 3C C C CH3 C C CH3 C C CH3
CH 3 OH CH 3 OH CH 3

This reaction can be catalysed by the protic acids like H2SO4, H3PO4, HClO4 etc.
During the Pinacol-Pinacolone Rearrangement the migrating aptitude of various atoms or groups
having following order:
H>Aryl>Alkyl
Some of the examples related to these reactions can be given as:
This order of the migrating aptitude being applicable during reactions.

Ph CH 3

Ph CH 3 Ph C C CH 3

Ph C C CH 3 OH

LESS STABLE
OH OH

Ph CH 3

Ph C C CH 3

CH 3
Ph O
MORE STABLE
Ph C C CH3

CH3

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In the case of aryl subsistent if there will be. EDG in the aryl–substitutent than migrating
aptitude will further be higher while there will be EWG in the aryl substituent then migrating
aptitude will be lower than un substituted aryl group.

Ph Ph
HO Ph O
OH
Ph
H

OH OH
H
O

6.8.2 Dakin Reaction:

Replacement of an aldehyde or keto group by the hydroxyl group when it is present ortho or para
with respect to the hydroxyl or amino group, on treating with alkaline H2O2 is called as Dakin
Reactions.

CHO OH
alkaline
H 2O2
OH OH

Mechanism:

OH
HOOH HOO
-H 2 O

O O O
CH - C O-OH O CH OH
O OH OH
H i OH
+ HCOOH
OH OH ii H3O
OH OH

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Some other examples of these reactions can be given as:

O
HO
CH 2CN Alkaline CN

HO H 2 O2 HO

H 2 O2 / -OH

HO CHO HO OH

CHO H 2 O2 / -OH OH

NH2 NH2

CHO CHO
H 2 O2 / -OH

OH OH

6.8.3Wagner-Meerwein rearrangement:
All those chemical reactions (Generally substitution or elimination reactions) which give the
product through the carbocation intermediate with the rearranged carbon skeleton are called as
Wagner- Meerwein Rearrangement reactions.
During these reaction carbocation intermediate having the tendency to increase their
stability.

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CH3 CH3 CH3

HBr
CH3 C CH2 OH CH3 C CH2 CH3 + CH3 C CH2 CH3

CH3 Br

Mechanism:

CH3 CH3 CH3

+
H + +
CH3 C CH2 OH CH3 C CH2 OH2 CH3 C CH2
-H2O
CH3 CH3 CH3
10 carbocation
CH3 less stable
Br-
CH3 C CH2 CH3
CH3
1,2 methyl shift
Br
CH3 C CH3
+
CH3
-H+ 30 carbocation
CH3 C CH2 CH3 more stable

6.8.4 Benzilic acid rearrangement:

Rearrangement of α-diketone into α-hydroxyl acid in the presence of any strong base is known as
benzilic Acid rearrangement.

Mechanism:

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6.8.5 Allylic rearrangement:

An allylic rearrangement or allylic shift is an organic reaction in which the double bond in an
allyl chemical compound shifts to the next carbon atom. It is encountered in nucleophilic
substitution.

Mechanism:

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6.8.6 Hofman reaction, Schmidt reaction:

Hofman reaction:

In this reaction amide is converted in to primary amine.

Mechanism:

Schmidt reaction:

When the carboxylic acid react with the hydrazoic acid in the presence of conc. H2SO4 than
their occur the formation of isocyanate which on reaction with H2O gives amine. This reactions
is known as Schmidt reaction.

HN 3 H2O
R COOH R N C O R NH 2

Mechanism:

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O O O H
H
R C OH R C OH2 R C N N N
H2O

O H H O H2O H2O
R N C O R NH2
R C N N N R C N N N

Some other example of these reactions can be given as:

COOH NH 2
NH 3 /H2SO4

H 2O O2 N NO2
O2 N NO2

COOH NH 3 /H2 SO4 NH 2

H 2O

NH 3 /H2 SO4
C 6 H5 CH CH COOH C 6 H5 CH CH NH 2

NH 3 /H2 SO4
CH 3 COOH CH 3 NH 2
H2O

6.8.7 Curtius Rearrangement:

Thermal decomposition of the acyl azide into corresponding isocyanates is known as curtius
rearrangement.

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6.8.7 Lossen rearrangement and Dakin reaction:

Lossen rearrangement:
Consversio of o-acyl derivative of hydroxamic acid into isocyanate on reaction with base is
known as Lossen rearrangement reaction.

Dakin reaction:
The Dakin reaction is an organic redox reaction in which an ortho- or para-hydroxylated phenyl
aldehyde (2-hydroxybenzaldehyde or 4-hydroxybenzaldehyde) or ketone reacts with hydrogen
peroxide in base to form a benzenediol and a carboxylate.

6.9 SUMMARY

Replacement or displacement of an atom or group by any other atom or group is known as

substitution reaction. If displacement takes place by nucleophile then it is known as nucleophilic
substitution while on the other hand if substitution tahes place by electrophile then it is known as
electrophilic substitution reaction. All nucleophiles are Lewis base and contain atleast one loan

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pair of electrons. In nucleolhilic substitutions a nucleophile attacks the substrate carbon with its
unshared electrons to form a covalent bond, and the leaving groupn ( nucleophile) departs with
electron pair of the breaking bond.

6.10 TERMINAL QUESTIONS

1. Write a mechanism of SN2 reaction.

2. Write a mechanism of SN1 reaction.
3. What is the difference between SN1 and SN2 reaction?
4. Write a short note on Anchimeric assistance.
5. What is neighbouring group participation.
6. Explain brief on Classical and nonclassical carbocations.
7. Write the mechanism of the followings:
a) Pinacol-Pinacolone rearrangement
b) Dakin Reaction
c) Wagner-Meerwein rearrangement
d) Hofman reaction and Schmidt reaction
e) Curtius rearrangements

REFERENCES
1. L. G. Wade, Jr., Organic Chemistry, 6th ed., Pearson/Prentice Hall, Upper Saddle River,
New Jersey, USA, 2005
2. March, J. (1992). Advanced Organic Chemistry (4th ed.). New York: Wiley. ISBN 0-
471-60180-2.
3. Advanced Organic Chemistry By Jagdamba Singh and L.D.S. Yada, Volume- I, Pragati
Prakashan.

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UNIT-7 AROMATIC NUCLEOPHILIC SUBSTITUTION

CONTENTS:

7.1-Objectives

7.2-Introduction

7.3-Types of Aromatic nucleophilic substitution reactions

7.3.1-Addition-elimination SNAr2

7.3.2-Elimination-addition SNAr2

7.3.3-Radical-nucleophilic aromatic substitution or SRN1

7.3.4-Ionic mechanism of nucleophilic aromatic substitution (SN1)

7.4- Reactivity-effect of substrate structure, leaving group and attacking nucleophile in

nucleophilic aromatic substitution reactions

7.4.1-Effect of substrate structure

7.4.2-Effect of leaving group

7.4.3-Effect of attacking nucleophile

7.5- Summary

7.6- Glossary

7.7-Self Assessment Question

7.8- References

7.9-Suggested Readings

7.10-Terminal Questions

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7.1 OBJECTIVES

• After studying this unit you will be able to know what are aromatic nucleophilic substitution
(ANS) reactions.
• Learn about the different possible mechanism of ANS reactions.
• Identify the benzyne mechanism.
• Evaluate the product formation of ANS reactions.
• Identify the mechanistic differentness between addition-elimination and elimination-addition
mechanisms.
• Learn about the factors which affect the rates of aromatic nucleophilic substitution reaction.
• Identify suitable substrates, leaving groups and incoming nucleophiles for SRN1 reactions,
benzyne reactions and SN1 and SN2 type reactions.

7.2 INTRODUCTION

Why do aromatic compounds give nuclophilic substitution reactions when aromatic ring itself
act as nucleophile! If it is giving aromatic nucleophilic substitution reactions what will be the
condisions? are their mechanism like an aliphatic reaction?

Nucleophilic substitutions on aromatic ring are relatively less common reactions that involved
bond formation between aromatic carbon atom and nucleophile along with bond breaking to the
leaving group. Because of the following reasons:

1. The presence of π-electrons of aromatic ring. These π-electrons make the aromatic
system an electron rich system that is more liked by electrophile rather than nucleophile.
2. Secondly aromatic ring loses its stabilization if a nucleophile attack because it looses
aromaticity which subsequently gained by the removal of leaving group (six π-electrons
in conjugation).
3. The back side attack (as in SN2) and inversion are prohibited by the geometry of the
aromatic ring.

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4. The formation of phenyl cation in nucleophilic substitution of aromatic ring render less
stable than a primary carbocation (as in SN1).

Therefore overall under special reaction conditions such as high pressure, high temperature and
the presence of different electron withdrawing groups (NO2, CN, -CO etc.), aromatic substitution
reactions are facilitated that we shall learned in this unit.

Example; The early industrial synthesis of phenols and anilines in fact were based on the
nucleophilic aromatic substitution reaction (operated under high temperature and pressure).

Fig 7.1: Early industrial synthesis of phenol at high temperature and pressure

Note: Both true SN1 and SN2 reactions are not energetically feasible in aromatic systems.

7.3 TYPES OF MECHANISMS

There are four principal mechanisms for aromatic nucleophilic substitution which are similar to
that of aliphatic nucleophilic substitution but required special conditions to proceed.
SN Ar

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SN Ar1 SN Ar2 (SN2)

Free radical Ionic Addition- Elimination-

mechanism mechanism Elimination Addition
(SRN1)
(SN1) mechanism mechanism

Fig 7.2: Different mechanisms of aromatic nucleophilic substitution reactions

7.3.1 Nucleophilic Aromatic Substitution (SNAr2) by Addition–Elimination

Mechanism of SNAr2 by Addition–Elimination is depicted in figure 7.3 with leaving group (X ),

nucleophile (Nu:‒ ) and a general electron-withdrawing group W.
The mechanism of SNAr2 proceeds in two steps, in first step [1] nucleophile attacks to the
aromatic substrate and forms a resonance-stabilized intermediate carbanion structure called
Meisenheimer complex with a new C-Nu bond as shown in Figure 7.3. This step is a slow step
and rate determining. In second step [2], loss of leaving group re-forms the aromatic ring. This
step is fast compared to the first step.

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Fig 7.3: Mechanism of SNAr2 addition-elimination

The presence of electron withdrawing group (W) on the aromatic ring facilitatates the attack of
nucleophile while the presence of electron donating group (D) on aromatic ring slow-down the
rate of reaction. However this effect is more pronounced when W present at ortho or para
position compared to meta position on aromatic ring with respect to the leaving group (X) as
shown in figure 7.4 (A) and (B).

Therefore, electron withdrawing group (W) is activating at ortho, para-positions compared to

meta position in nucleophilic attack. These principles are opposite of those that apply to
electrophilic substitution.

Note:
i. Generally leaving groups(X) in aromatic nucleophilic substitution are
Halogens, Alkoxy, NO2, Sulfonyl.
ii. and Nucleophiles are Alkoxides, Phenoxides, Sulfides, fluoride ion or
amines.

Fig 7.4: Attack of nucleophile on aromatic ring with respect to electron withdrawing group (W)
present at para-position(A) and at meta position(B).

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7.3.2 Nucleophilic Aromatic Substitution (SNAr2) by Elimination-Addition

(benzyne mechanism)
Nucleophilic aromatic substitution reactions proceeding through elimination-addition mechanism
lead the formation of intermediate benzyne, therefore elimination-addition reaction mechanism
also called benzyne mechanism of aromatic nucleophilic substitution.

In such reactions products with substitution on the carbon directly bonded to the leaving group or
to the carbon adjacent to it are formed in equal proportion. As an example, treatment of p-
chlorotoluene with NaNH2 forms para- and meta-substitution products,

shown in fig.7.5

Fig 7.5: Ellimination-addition reaction results in two products in almost equal proportions.

The mechanism of elimination-addition reaction proceeds in two steps fig 7.6, in first step,
attacking of strong base or nucleophile (-OH) removes the proton from adjacent carbon relative
to the leaving group attached carbon followed by the removal of leaving group and the
formation of benzyne takes place. In second step, further addition of nucleophile to generate
carboanion and protonation of carboanion takes place.

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Fig 7.6: Mechanism of elimination-addition reaction (benzyne mechanism)

The benzyne intermediate has a triple bond in benzene ring which makes it a highly reactive
species (very unstable). When ortho and para-substituent are present on the substrate, only one
benzyne intermediate can formed as shown below:

Fig. 7.7: Benzyne mechanism of aromatic nucleophilic substitution at ortho and para positions

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However, if meta substituent are present then two benzynes may be formed (as shown in fig 7.8)
based on which protons are more acidic. More acidic protons will be removed for benzyne
formation.

Fig. 7.8: Benzyne mechanism of aromatic nucleophilic substitution at meta-position

The nature of substituent Z is decisive towards benzyne intermediate formation. An electron

withdrawing Z group favors removal of the ortho-hydrogen, whereas, an electron-releasing Z
group favors removal of the para-hydrogen. Also, once the aryne intermediate is formed, there
are two possible sites where the nucleophile may attack, again the field effect of substituent Z
plays an important role and an intermediate carbanion which gets better stabilization by Z will be
favoured. For substituent with -I effect, the more stable carbanion is the one in which the
negative charge is closer to the substituent. Unlike addition-elimination, the order of halogen
reactivity in these reactions is I > Br > Cl > F.

7.3.4 Radical-nucleophilic aromatic substitution or SRN1

The SRN1 (Unimolecular Radical Nucleophilic Substitution) is a process through which
nucleophilic substitution is achieved on aromatic and aliphatic compounds that do not react or
react slowly through polar nucleophilic mechanisms. This reaction type was discovered in 1970
by Bunnett and Kim. A number of useful reactions proceed via this mechanism including photo
stimulation reactions, electrochemical reactions.

Due to involvement of radical anions, the SRN1 reactions may occur via a chain or non-chain
mechanism. Fig 7.9 shows the generalized reaction with an aryl halide. This transformation takes
place through electron transfer steps with radicals and radical anions as intermediates.

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Fig 7.9: Generalized nucleophilic substitution reaction

The key steps of the SRN1 reaction mechanism proceeding through chain process are presented in
Scheme I.

As depicted below in fig 8, in the SRN1 mechanism, the initial attack takes place via an electron
donor, rather than a nucleophile. The radical anion thus formed leads to removal of leaving
group and left behind a radical available for attack by the incoming nucleophile.

As shown in fig 10, the aryl halide substrate first accept an electron from a donor and becomes
an anion radical (Eq 1) , which losses the halide anion giving rise to an aryl radical (Eq 2), which
can be easily attacked by the nucleophile to form a new radical anion (Eq 3), electron transfer
from this radical anion to the substrate reforms the substrate radical anion (Eq 4), and the
propagation cycle continues. Summation of Eqs. 1–4 leads to the net nucleophilic substitution.

Because the SRN1 reaction is a chain process, its overall rate depends on the efficiency of the
initiation, propagation and termination steps. Any of the intermediates (radicals and radical
anions) can initiate the chain, but by far the most commonly used is the radical anion of the
substrate. Destruction of any of the intermediates can terminate the process. One important
practical consequence of the chain mechanism is that SRN1 reactions should be carried out under
an inert atmosphere to avoid inhibition by oxygen. Some terminations depend on the method of
initiation, while others depend on the intermediates involved and the solvent used.
For instance, electron transfer from any radical anion to an aryl radical (Eq. 5) is one of the
proposed termination steps in solvents such as liquid ammonia that are poor hydrogen donors.
Hydrogen atom abstraction by the aryl radical (Eq. 6) is a possible termination step in organic
solvents. The net effect of these termination reactions is formation of the reduced dehalogenated
product.
.

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Fig 7.10: SRN1 reaction mechanism proceeding through chain process

For example the reaction of 5-iodo-1,2,4-trimethylbenzene with a strong base such as KNH2 in
presence of NH3 (fig 7.11), two products were formed in the ratio of 0.63:1 different from
benzyne mechanism where products formed in equal ratio.

Fig. 7.11: SRN1 reaction in 5-iodo-1,2,4-trimethylbenzene

Additionally, it was discovered that the SRN1 reaction can occur via a non-chain mechanism as
well. Non-chain SRN1 reactions are less known. Non-chain SRN1 reactions occur in solvent cages,
which are defined as a region of space which includes the reacting species surrounded by solvent
molecules. The solvent cage restricts the movement of reactive intermediates thereby not

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allowing a propagation, while, stepwise substitution occur giving rise to product formation only.
Following is an example of non chain SRN1 reaction (fig 7.12).

Fig. 7.12: An example of non-chain SRN1 reaction

7.3.5 Nucleophilic Aromatic Substitution by ionic mechanism (SN1)

The SN1 mechanism operates in the reaction of diazonium salts with nucleophiles (fig 7.13).
This is because in diazonium salts the leaving group is di-nitrogen, which is an excellent leaving
group, and on leaving it affords a positive charge on benzene ring, making it available for attack
by incoming nucleophiles. The rate of reaction depends only upon the nature of substrate and
there is no effect of concentration of incoming nucleophile.

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Fig 7.13: General mechanism of SN1 proceeds in two steps, Step (I) removal of N2 and
formation of aryl cation, Step (II) attack of nucleophile and formation of
corresponding product.
For example synthesis of phenol from aromatic diazonium salt explained below in fig 7.14

Fig 7.14: Synthesis of Phenol by heating a benzenediazonium salt.

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7.4 REACTIVITY-EFFECT OF SUBSTRATE STRUCTURE,

LEAVING GROUP AND ATTACKING NUCLEOPHILE IN
NUCLEOPHILIC AROMATIC SUBSTITUTION REACTIONS

The common factors influencing rate of all these three mechanisms are substrate structure,
leaving group and solvent. We shall discuss each of them separately.

7.4.1 Effect of Substrate Structure

As explained above in normal conditions, it is difficult for a nucleophile to attack an electron

rich ring that is more liked by electrophile rather than nucleophile. When the aromatic ring
contains electron withdrawing groups (W), the reactions go faster. However, contrary, the
reactions proceed slowly if the ring contains electron donating group (D).

W at ortho or para position considerably facilitates to aromatic ring to delocalize negative

charge and to form additionally more resonating anionic structures compared to W at meta
position (Fig 7.15). This additional contribution makes the system more susceptible to
nucleophilic attack (Nu:‒) and elimination of leaving group (X) in ortho, para positions
compared to meta position. Meta position is inductively stabilized not by mesomeric effect.

Fig 7.15: Presence of electron withdrawing group (W) at ortho and para-position compared to
leaving group (X)

Following is the order of electron donating groups in increasing ability to activate aromatic rings
for SNAr substitutions

N2+>NO>NO2>SO2Me>NMe3+>CF3>CN>CHO>COR>COOH>SO-3>Br>Cl>I>COO->H

Table 1: Descending order of activating ability of different groups in SNAr mechanism.

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Diazonium salt group (-N2+) Activate halogen exchange at room

Cationic carbon (-CR2+) temperature or below

Activate replacement by strong

nucleophilic reagents at room
Alkylated hetero nitrogen
temperature

Nitroso group(NO) Activate reaction with strong

Nitro group (NO2) nucleophilic reagents at 80-100 oC
temperature
Hetero nitrogen atom

Methylsulfonyl (CH2SO2) With nitro also present, activate

Trimethylammonia ((CH2)2N+) reaction with strong nucleophilic
Trifluoromethyl (CF3) reagents at room temperature
Acyl group (RCO)
Cyano groups (CN)
Carboxyl (COOH) With nitro also present, activate
Ionized sulfo (SO3‒) reaction with strong nucleophilic
Halogens (Cl, Br, I) reagents at 40-60 oC temperature
Carboxylate (COO‒)
Phenyl

7.4.2 Effect of Leaving Group

However most of the leaving groups such as sulfate, halide, NR3+, sulfonate etc. are common in
both aliphatic nucleophilic substitution and aromatic nucleophilic substitution reactions. But the
groups, NO2, OR, OAr, SO2R, and SR, which are not generally lost in aliphatic systems, are also
act as leaving groups when attached to aromatic rings.

As greater the electronegativity of leaving-group or polarity of bond between aromatic carbon

and leaving group (X) faster will be the release of leaving group by lowering the activation
energy while increasing the rate of reaction.

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An approximate order of leaving-group ability is

F > NO2 > OTs > SOPh > Cl, Br, I > N3 > NR3+> OAr, OR, SR, NH2

Amongst the halogens, fluoro is generally a much better leaving group than the other halogens,
because of its highest electronegativity,

The order is usually F>Cl>Br>I, but not always.

The leaving-group order is quite different from that for the SNAr1. The most likely explanation is
that the first step of the SNAr mechanism is usually rate determining, and this step is promoted
by groups with strong -I effects. This would explain why fluoro and nitro are such good leaving
groups when this mechanism is operating. Fluoro is the poorest leaving group of the halogens
when the second step of the SNAr mechanism is rate determining or when the benzyne
mechanism is operating. The only important leaving group in the SNAr1 mechanism is N2+.

7.4.3 Effect of Attacking Nucleophile

Generally the strength of nucleophile or substituting capability of nculeophile depends on the

basicity. Greater the basicity of attacking atom more will be the nucleophilicity. However as in
aromatic nucleophilic substitution reactions, the strength of nucleophile or substituting capability
of nculeophile depends not only on the basicity but also on the types of substrates and reaction
conditions. Therefore, it is not possible to construct a constant nucleophilicity order, however, an
overall approximate order is as given below:

-
NH2 > Ph3C-> PhNH- (aryne mechanism)>ArS->RO->R2NH>ArO->-OH>ArNH2>NH3>I- Br-
>Cl->H2O>ROH

Nucleophilicity increases as the attacking atom moves down a column in the periodic table
except some exceptions e.g., -OH a stronger base than ArO-, is a poorer nucleophile.

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7.5 VON-RICHTER REACTION

The Von-Richter reaction, also named Von-Richter rearrangement, is a name reaction in

the organic chemistry. It is named after Victor von Richter, who discovered this reaction in year
1871. It is the chemical reaction of aromatic nitro compounds with potassium
cyanide giving carboxylation ortho to the position of the former nitro group.
When cyanide ion treated to aromatic nitro compounds it displaces nitro group and a carboxyl
group enters with cine substitution, always ortho to the displaced group, never meta or para as
shown in fig. 7.16. The von Richter reaction can be inhibited in the presence of potassium
ferricyanide (K3Fe(CN)6) and sodium sulfite.

Fig 7.16 Von-Richter reaction

As with other nucleophilic aromatic substitutions, the reaction gives best results when electron-
withdrawing groups are in ortho and para positions, but yields are low, usually 50%. This
reaction has a limited application in organic synthesis.

Mechanism of Victor Von Richter Reaction

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The reaction proceeds through a nucleophilic attack of cyanide ion ortho to nitro group followed
by intramolecular rearrangement, as shown in fig 7.17

First, the cyanide attacks the carbon-atom in ortho-position to the nitro-group. After this the
compound regains its aromaticity once again. In the latter step, the negative charged oxygen-
atom attack the neighbouring carbon-atom and a five-membered ring is build. It opens under
building a carboxylic acid group. Next, another five-membered ring is formed. After a
condensation reaction, (resembling Michael reaction) a double bond is built between the two
nitrogen-atoms. Elemental nitrogen then leaves the system for opening the ring. In the last step,
the compound is protonated and the 3-halogenbenzoic acid is built.

7.6 SOMMELET-HAUSER REARRANGEMENT

The rearrangement involves the reaction of benzyl quaternary ammonium salts in presence of
sodium amide or another alkali metal amide to form N-dialkyl benzyl amine having a new alkyl
group in the aromatic ortho position is known as Sommelet–Hauser rearrangement as shown in
fig 7.18.

As the α-hydrogen is too weak acidic to induce hydroxide ion based rearrangement, a strong base
such as amide ion in liquid ammonia is to be used. The Sommelet-Hauser reaction is highly
favored in polar solvents like, NH3, DMSO, HMPA. Low temperature conditions also favour the
reaction.

The reaction proceeds with deprotonation of the benzylic methylene proton which is acidic to
yield benzylic ylide. The ylide formed is in equilibrium with the second ylide which is formed by
deprotonation of one of the ammonium methyl groups. The second ylide which is present in
much smaller amounts undergoes a [2,3] sigmatropic rearrangement and subsequent
aromatization in order to form the final product as shown in fig 7.19.

Sommelet-Hauser rearrangement is in competition with Stevens rearrangement as shown in fig

7.20.

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Fig 7.17: Mechanism of Victor Von Richter Reaction

Fig 7.18: Sommelet-Hauser Rearrangement

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Fig 7.19 Mechanism of Sommelet-Hauser Rearrangement

Fig 7.20: Stevens vs. Sommelet-Hauser Rearrangement

7.7 SMILE REARRANGEMENT

The Smiles rearrangement is an example of intramolecular nucleophilic substitution (fig 7.21). It
involves attacking on an aromatic system possessing an activating electron-withdrawing group at
ortho- or para-position to the reaction centre connected to a heteroatom. Smiles rearrangement is
further involves the migration of an aromatic ring from the heteroatom binding to the reaction
centre to a more nucleophilic heteroatom.

Fig 7.21: Smiles intramolecular rearrangement

Where, X can be a sulfone, a sulfide, ether or any other substituent which can dislodge from the
arene with a negative charge.

The terminal functional group in the chain end i.e, Y acts as a strong nucleophile for example an
alcohol, amine or thiol. In the Smiles rearrangement, the nucleophile Y is generally the conjugate

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base of SH, SO2NHR, SO2NH2, NH2, NHR, OH, [Link] mechanism of smiles
interamolecular rearrangement shown in fig 7.22.

It has been observed that a moderate electron-withdrawing group, preferably in the aromatic
ortho position, such as chloro and alkoxide can accelerate this rearrangement. On the contrary,
the steric hindrance that arises from a substituent at a particular position in the aromatic ring may
help in making the rearrangement more facile. The solvent, such as THF has been found to give
positive effect and increase the rate of the Smiles rearrangement. This reaction has been
thoroughly modified by the use of different ethers as well as various reaction conditions

Fig 7.22: Molecular mechanism of Smiles Rearrangement

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7.8 SUMMARY

• Aromatic nucleophilic substitution reactions are rare where nucleophile attack on substituted
aromatic rings
• These are classified as unimolecular or bimolecular reactions.
• Bimolecular SNAr reactions operate via two mechanisms; addition/elimination or
elimination/addition.
• Meisenheimer complexes are 1:1 reaction adducts intermediates in bimolecular nucleophilic
aromatic substitution that are stable and isolated as early as in 1902.
• Aromatic nucleophilic substitutions are favored by electron withdrawing substituents on
benzene ring and good leaving groups.
• Bimolecular SNAr reactions proceeding through the formation of "benzyne" intermediate
called elimination-addition.
• In elimination-addition reactions products with substitution on the carbon directly bonded to
the leaving group or to the carbon adjacent to it are formed in equal proportion.
• For substituents with -I effect, the more stable carbanion is the one in which the negative
charge is closer to the substituent in case of benzyne mechanism.
• If the electron withdrawing groups are present on the ortho or para positions to the leaving
group, great accelerations in rate of reactions in case of SNAr reactions has been observed,
however, the reverse is observed for electron donating groups.

• The common leaving groups in aliphatic nucleophilic substitution (halide, sulfate, sulfonate,
NR3+etc.) are also common leaving groups in aromatic nucleophilic substitutions, but the
groups NO2, OR, OAr, SO2R, and SR, which are not generally lost in aliphatic systems, are
leaving groups when attached to aromatic rings.

• Fluoro and nitro are good leaving groups in SNAr reactions, but poor leaving groups in case
of the benzyne mechanism depending upon the intermediates formed in the rate determining
step.

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• Aromatic nucleophilic substitution reactions of diazonium salts with nucleophiles operate

unimolecularly and called SN1 reactions.

• In SN1 reactions, diazonium is a good substrate as di-nitrogen is a good leaving group

affording a positive charge on benzene ring making it available for attack by incoming
nucleophiles.

• Nucleophilic aromatic substitution reactions on an aromatic compound mediated through

intermediary free radical species called Unimolecular Radical-Nucleophilic aromatic
Substitution or SRN1 reactions.

• SRN1 reactions are usually performed in either liquid ammonia or dipolar aprotic solvents
such as dimethyl sulphoxide or hexa methyl phosphoric acid.

• Unlike SNAr mechanism that require suitably substituted substrates and benzyne mechanism
which require strong basic conditions, the SRN1 mechanisms proceed under relatively milder
conditions and give convenient yields.
• Initiation of SRN1 reactions can be achieved by a number of methods, the most commonly
used being photo stimulation, introduction of solvated electrons or thermal reactions.
• The reaction of aromatic nitro compounds with potassium cyanide to generate a carboxylic
acid ortho to the nitro group is known as Victor von Richter reaction.
• The rearrangement reaction of certain benzyl quaternary ammonium salts in presence of
sodium amide or another alkali metal amide to form N-dialkyl benzyl amine with a new alkyl
group in the aromatic ortho position is known as Sommelet–Hauser rearrangement. The
Sommelet-Hauser reaction is highly favored in polar solvents.
• The Smiles rearrangement is an example of intramolecular nucleophilic substitution. It
involves attacking on an aromatic system bearing an activating electron-withdrawing group
at ortho- or para-position to the reaction center connected to a heteroatom.

7.9 GLOSSARY

Aromatic compounds: A cyclic (ring-shaped), planar (flat) molecule having each atom in
conjugation (resonance) and must having [4n+2] pi electrons.

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Acidic protons: Protons attached to some function group directly or electronegative atom (O, S,
N).
Aromatic carbon: A carbon of aromatic ring.
Aprotic solvents: An aprotic solvent is a solvent that has no O-H or N-H bonds or do not have
any free -H (protons) to participate in reaction or interaction.
Benzyne: Described as having a strained triple bond formed by removal of two ortho
substituents from an aromatic ring .
Benzylic ylide: The structure formed after the removal of acidic proton from benzylic methylene
called benzylic ylide.
Benzyl quaternary ammonium salts :A quaternary ammonium salt attached to benzyl group
Bimolecular reaction: A reaction whose order depends upon two reacting molecules.
Carbanion: A carbanion is an anion in which carbon has an unshared pair of electrons and bears
a negative charge.

Electrophile: An electrophile is a species that accepts a pair of electrons to form a new covalent
bond.

Electron-withdrawing group: An atom or group that draws electron density from neighboring
atoms towards itself, usually by resonance or inductive effects.

Electron donating group: An atom or group that releases electron density from neighboring
atoms towards itself, usually by resonance or inductive effects.

Electronegativity: Electronegativity is a measure of the tendency of an atom to attract a bonding

pair of electrons.

α-Hydrogen: A hydrogen atom directly bonded to an α-carbon.

Leaving group: A leaving group is a molecular fragment that departs with a pair of electrons in
heterolytic bond cleavage.

Meta -position: Two benzene ring substituents on two benzene ring carbons separated by
one benzene ring carbon.

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Meisenheimer complex: Meisenheimer complex in organic chemistry is a 1:1 reaction adduct

between an arene carrying electron withdrawing groups and nucleophile. These complexes are
found as reactive intermediates in nucleophilic aromatic substitution.

Nucleophile: A nucleophile is a reactant that provides a pair of electrons to form a new covalent
bond.

Ortho-position: The relationship between two benzene ring substituents on adjacent benzene
ring carbons.

Para-position: Para describes a molecule with substituents at the 1 and 4 positions on

an aromatic compound. In other words, the substituent is directly opposite the primary carbon of
the ring.

Polarity: It's a power of electronegativity difference between atoms in a bond. Partial negative
charges are found on the most electronegative atoms, the others are partially positively charged.

Polar solvents: A solvent with high dielectric constant.

Radical species: A radical that carries an electric charge. A positively charged radical is called a
'radical cation' (e.g. the benzene radical cation C6H6 ·+); a negatively charged radical is called a
'radical anion' (e.g. the benzene radical anion C6H6·- ).

Strong base: A strong base is a base that is completely dissociated in an aqueous solution.
These compounds ionize in water to yield one or more hydroxide ion (OH )̶ per molecule of base.

Solvent cages: Defined as a region of space which includes the reacting species surrounded by
solvent molecules.

Sigmatropic rearrangement: Molecular rearrangements in which a σ-bonded atom or group,

flanked by one or more π-electron systems, shifts to a new location with a corresponding
reorganization of the π-bonds are called sigmatropic reactions.

Steric hindrance: Steric hindrance at a given atom in a molecule is the congestion caused by the
physical presence of the surrounding ligands, which may slow down or prevent reactions at the
atom.

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Unimolecular reaction: A reaction whose order depends upon one reacting molecule.

7.10 SELF ASSESSMENT QUESTIONS

7.10.1 Multiple choice questions:

1. Which one of them is strongest nucleophile in aromatic nucleophilic substitution reactions?

(a) ̶ NH2 (b) ̶ OH

(c) ̶ Cl (d) ArO ̶

2. Which one of the substituted benzenes undergoes easily in addition-elimination of

nucleophilic substitution reaction?

(a) (i) (b) (ii)

(c) (iv) (d) (iii)

3. Which one of the options is true regarding the product formation in the following reaction?

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(a) (i) (b) (ii)

(c) (iii) (d) (i), (ii) & (iii)

4. Which one the reactions proceed at room temperature?

(a) (i) (b) (ii)

(c) (iii) (d) (iv)

5. Which one of the type of aromatic nucleophilic substitution reactions proceeds with the
formation of benzyne intermediate?

(a) SNAr2 (Addition-elimination) (b) SNAr2 (Elimination-Addition)

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(c) SN1 (d) SRN1

6. Which one of the halogen atom easily substituted by nucleophile in elimination-addition

reaction (SNAr2)?

(a) F (b) Cl

(c) Br (d) I

7. Which one of the halogen atom easily substituted by nucleophile in addition-elimination

reaction (SNAr2)?

(a) F (b) Cl

(c) Br (d) I

8. Why aryl halide gives nucleophilic substitution reaction under drastic conditions?

(a) Halide is ring activating (b) Aryl ring act as an electrophile

(c) Aryl ring act as a nucleophile (d) All are correct

9. In aromatic nucleophilic substitution reaction, substrate should have

(a) Ring activating substituent (b) Ring deactivating substituent

(c) Both activating or deactivating substituents (d) None of them

10. The order of elimination-addition (SNAr2) reaction ?

(a) 1 (b) 0

(c) 2 (d) 1.5

7.10.2 Fill in the blanks and True/False:

(1) Aromatic nucleophilic substitution reactions of diazonium salts with nucleophiles operate
via _______order.

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(2) Unimolecular Radical-Nucleophilic aromatic Substitution or SRN1 reactions proceeds

with the formation of intermediary ______________

(3) Substituents at ortho and para positions lead to one type of benzyne intermediate
compared to meta in elimination-addition aromatic nucleophilic substitution reactions
(SNAr2).
(4) 2,4-dinitro-fluorobenzene undergoes faster compared 2,4-dinitro-chlorobenzene in
addition-elimination reaction (SNAr2).

(5) In SN1 Nucleophilic Aromatic Substitution reaction, benzenediazonium chloride lead to

the formation of intermediate benzonium cation.

(6) p-chlorotoluene with strong base (NaNH2) lead to the formation of para- and meta-
substitution products.

(7) "Meisenheimer" complex is an intermediate in the__________________ reactions.

(8) The Sommelet-Hauser reaction is highly favoured in _______solvents.

(9) Aromatic nitro compounds with potassium cyanide giving carboxylation at_______ to the
position of the former nitro group.

(10) SRN1 reactions can be proceed by photo stimulation .

7.10.3 Very short answer questions:

(1) Define nucleophile?

(2) Draw the structure of benzyne?
(3) Write the order of F, Cl, Br and I substitution in addition-elimination aromatic nucleophilic
substitution reactions (SNAr2)?
(4) Write the order of F, Cl, Br and I substitution in elimination-addition aromatic nucleophilic
substitution reactions (SNAr2)?
(5) Write down the order of reactivity of chlorobenzene, ortho-nitrochlorobenzene, Para-
nitrochlorobenzene, ortho-para-dinitrobenzene in addition-elimination aromatic nucleophilic
substitution reactions (SNAr2)?

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(6) Draw the structure of product formed in the reaction of meta-chlorotoluene with strong base
(NaNH2) in liquid ammonia?
(7) Why there is no product formed when 2,6-dimethylchlorobenzene reacts with strong base
(NaNH2) in liquid ammonia?
(8) Draw the structure of benzenediazonium chloride?
(9) When 4-nitrochlorobenzene reacts with potassium cyanide will give carboxylation at ortho
or para to the position of the former nitro group?
(10) Why electron withdrawing group promotes aromatic nucleophilic substitution reactions?

Answer key: 1-a, 2-c, 3-d, 4-c, 5-b, 6-d, 7-a, 8-c, 9-a, 10-c
Answer key: (1)Fast, (2)Benzene radical, (3)True, (4)True, (5)True, (6)True, (7)Addition-
elimination SNAR2, (8)Polar, (9)meta, (10) True

7.11 REFERENCES

(1) Jacques Mortier, Arene Chemistry: Reaction Mechanisms and Methods for Aromatic
Compounds, John Wiley & Sons Inc, Germany, 2015.
(2) Chupakhin, O.N., Charushin, V.N., and van der Plas, H.C. (1994) Nucleophilic Aromatic
Substitution of Hydrogen, Academic Press, San Diego, CA.
(3) Norris, R.K. (1983) in The Chemistry of Functional Groups (eds S. Patai and Z.
Rappoport) Supplement D, Chapter 16, John Wiley & Sons, Inc., New York, pp. 681 701.
(4) Bunnett, J. F., & Zahler, R. E. (1951) Chemical Reviews, 49(2), 273-412.
(5) Artamkina, G., Egorov, M.P., and Beletskaya, I.P. (1982) Chem. Rev., 82, 427.
(6) Strauss, M.J. (1970) Chem. Rev., 70, 667.
(7) Buncel, E., Dust, J.M., and Terrier, F. (1995) Chem. Rev., 95, 2261.
(8) Vlasov, V.M. (2006) Russ. Chem. Rev., 75, 765.
(9) Vlasov, V.M. (1993) J. Fluorine Chem., 61, 193. (b) Vlasov, V.M. (2003) Russ. Chem.
Rev., 72, 681.
(10) a) Buncel, E. and Terrier, F. (2010) Org. Biomol. Chem., 8, 2985. (b) Terrier, F., Dust,
J.M., and Buncel, E. (2012) Tetrahedron, 68, 1829.

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7.12 SUGGESTED READINGS

(1) R.O.C. Norman and C. M. Coxon, Principles of Organic Synthesis, CRC Press, New York,
2009.
(2) F. Terrier, Modern Nucleophilic Aromatic Substitution, Wiley‐VCH , Germany, 2013.
(3) B. P. Mundy, M. G. Ellerd, F. G. Favaloro Jr, Name Reactions and Reagents in Organic
Synthesis, Wiley Interscience, New Jersey, 2005.
(4) J. Clayden, N. Geeves, S. Warren, organic chemistry, Oxford University Press, 2012, 18th
ed.
(5) P.Y. Bruice, Organic Chemistry. Upper Saddle River, NJ: Pearson/Prentice Hall, 2004.

7.13 TERMINAL QUESTIONS

7.13.1 Short answer questions:

(1) Describe, why 2,4,6-Trinitrochlorobenzene reacts with NaOH just in warm water while
chlorobenzene do not ?
(2) Write down the product formed in reaction of benzyne with furan?
(3) Write down the reaction between 2,4,6-trinitrophenetole and sodium amide (NaNH2)?
(4) Explain why para-nitrofluorobenzene reacts with sodium methoxide quickly in methanol
compared para-nitrochlorobenzene?
(5) What product will be formed if anthracene reacts with benzyne? Write down the reaction.
(6) Write down the reaction of bezenediazonium chloride with water.
(7) Rank the aryl halides in each group in order of increasing reactivity in nucleophilic aromatic
substitution by an addition–elimination mechanism.
a. chlorobenzene, p-fluoronitrobenzene, m-fluoronitrobenzene
b. 1-fluoro-2,4-dinitrobenzene, 1-fluoro-3,5-dinitrobenzene, 1-fluoro-3,4-dinitrobenzene
c. 1-fluoro-2,4-dinitrobenzene, 4-chloro-3-nitrotoluene, 4-fluoro-3-nitrotoluene

8. Explained why p-nitrochlorobenzene reacts with aqueous sodium bicarbonate at 100 oC but
m- nitrochlorobenzene do not?
9. What product will be formed if benzyne reacts and methanol?

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10. What product will be formed if 1, 2-dinitrobenzene reacts with aqueous sodium bicarbonate
at 100 oC ?
7.13.2 Long answer question:

(1) Describe the reaction mechanism of addition-elimination aromatic nucleophilic substitution

reactions (SNAr2).
(2) Describe the mechanism of m-chlorotoluene reaction with sodamide in liquid ammonia.
(3) Describe the reaction mechanism of 4-iodo-1, 2, 4-trimethylbenzene with a strong base such
as KNH2 in presence of NH3.
(4) Describe the reaction mechanism of SN1.
(5) Describe the smile rearrangement.

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