HARAMBEE UNIVERSITY
Department of Pharmacy
Chapter -4: Substitution Reactions
May, 2025
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Out line
• Introduction
• SN1 and SN2 mechanisims
Application of substitution reactions
Alcohols, ethers and carboxylic acid
Alkanes,alkenes,and alkynes
Amines, epoxide ring opening
Reactions of malonic ester and acetoacetic esters
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Introduction
Virtually all organic reactions fall on to one of four categories :
Substitutions, addition, eliminations and rearrangements.
SUBSTITUTION REACTIONS
- Are the characteristic reactions of saturated compounds such as alkyl halides
and of aromatic compounds /even though they are unsaturated/.
Substitution is a reaction in which an atom or a group of atoms is replaced by
another atom or group of atoms.
Eg . H3C-Cl + Na+OH- H2O H3C-OH + Na+Cl-
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Cont’d
Eg . H3C-Cl + Na+OH- H2O H3C-OH + Na+Cl-
Substitution reactions involve bonds δ: one δ bond breaks and another forms
at the same carbon atom. The most common examples of substitution occur
when Z is hydrogen or a heteroatom that is more electronegative than carbon.
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Cont’d
A reaction can occur either in one step or in a series of steps.
A one-step reaction is called a concerted reaction. No matter how many
bonds are broken or formed, a starting material is converted directly to a
product. Eg. A B
A stepwise reaction involves more than one step. A starting material is
first converted to an unstable intermediate, called a reactive
intermediate, which then goes on to form the product.
A reactive intermediate B
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Cont’d
Nucleophilic substitution reaction
General reactions:
Nucleophile: is a reagent that seeks a positive center.
Leaving group: is a substitute that can leave as basic molecule or anion.
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Cont’d
e.g.
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SN2 Reaction
SN2Reaction –(Substitution, Nucleophilic, Bimolecular)
This reaction is said to be second order overall.
Two species are involved in the step whose rate is being measured.
Rate= k [Rx] [Nu-]
Reaction mechanism is a detailed description of how bonds are broken and
formed as a starting material is converted to a product. In SN2 reaction:
This involves only one step.
There are no intermediates.
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Cont’d
The reaction under go through a series of unstable arrangements of atoms
called transition state.
The nucleophile approaches the carbon bearing the leaving group from the
back side (the side directly opposite to the leaving group).
Eg. Nu : + R-L R-Nu+ + :L-
Reaction- HO- + CH3Cl CH3OH + Cl
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Cont’d
Mechanisim:
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Cont’d
There is an evidence that SN2 reactions proceed exclusively by the back
side attack and not by the front side attack.
Reaction Intermediates-Most organic reactions are not simple one-
step (one transition state processes).
The reaction usually involve some type of intermediate.
An intermediate is a species, often of high energy, which is
formed during the course of a reaction.
An intermediate is different from transition state which
contains at least one partial bonds.
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Cont’d
If a reaction takes place in series of steps, and if one step is intrinsically
slower than all others, then the rate of the overall reaction will be
essentially the same as the rate of this slow step called rate limiting step.
Consider, for example, the displacement of a chloride ion by a hydroxide
ion in cis-1-chloro-3-methylcyclopentane.
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Cont’d
The sole product is the trans alcohol, which is the out come of backside
attack.
If there had been any front side attack, cis alcohol would have been
formed.
Front side attack would lead to incorporation of radioactivity with no
change in optical activity.
It is found, however, that the radioactive alkyl iodide product is of
inverted configuration, as expected for a backside attack.
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Cont’d
The configuration of the starting alkyl halide is inverted and also the optical
activity is changed from (+) to (-). This is the result of backside attack.
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Cont’d
Why is the backside attack preferred?
It is speculated that during the reaction, the transition state resembles an
SP2 hybridized carbon with the P-orbital perpendicular to a plane defined
by the central carbon and its three substituents.
The nucleophile and the leaving group can be partially bonded to the lobes
of the p-orbital. The central carbon undergoes a type of flipping, called
Walden inversion.
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Cont’d
Consider the following multi step reaction
The rate constant of slow-step (step 1) is very much slower than rate
constant of fast steps (steps 2 and 3) That is, K1<< K2 or K3.
the concentrations of intermediates always very small because of the
slowness of step 1.
The energy of unstable intermediate is close to that of the two transition
states.
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Factors Affecting SN2 Reactions
1. The substrate
The rate of an SN2 reaction depends on the number and type of
substituent on the central carbon.
Relative rate of SN2 reaction verses the substrate type.
R Relative rate of SN2
CH3- 30
CH3CH2- 1
(CH3)2CH- 0.03
(CH3)3CCH2- 10-5 17
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(CH3)3C- Too slow to measure
Cont’d
Vinylic halides (R2C=CRX) and aryl halides are completely not reactive
toward attempted SN2 displacements.
This lack of reactivity probably is due to steric factors, since the incoming
nucleophile would have to approach in the plane of the carbon-carbon
double bond in order to be able to carry out backside displacements.
Moreover, pi electron cloud of the substrate repels the incoming
nucleophile (electron rich by itself)
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Cont’d
2. The nucleophile
The relative rate of SN2 reaction also depends on the relative reactivity of
various nucleophiles on a single substrate in a single solvent system.
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Cont’d
Nucleophilicity roughly parallels basicity when comparing nucleophiles
that have same attacking atom. Hydroxide ion, for example, is both more
basic and more nucleophilic than water.
Since “nucleophilicity” measures the affinity of a Lewis base for a carbon
atom in the SN2 reaction, and “basicity” measures the affinity of a base for
a proton.
Nucleophilicity usually increases on going down a column of the periodic
table. thus, HS- is more nucleophilic than HO-, and the halide reactivity
order is I->Br->Cl- 20
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Cont’d
Activity-compare the nucleophilicity of each pair.
a)(CH3)2N- and (CH3)2NH b) (CH3)2B and (CH3)2N
c) H2O and H2S.
[Link] Leaving group
Since, the leaving group is expelled with a negative charge in SN2 reactions,
the best leaving groups are those that best stabilize the negative charge.
Furthermore, since the stability of an ion is related to basicity, the best
leaving groups should be the weakest bases.
The weakest bases (anions derived from the strongest acids) are indeed the
best leaving groups.
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Cont’d
Example
ToSO=sulphonated ester called tosylate
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Cont’d
[Link] Solvent
Protic solvents that contain – OH groups, are generally the worst solvents
for SN2 reactions;
Protic solvents such as methanol and ethanol slow down SN2 reactions by
affecting the energy level of the nucleophilic reactant rather than the
energy level of the transition state .
Protic solvent molecules are able to form hydrogen bonds to negatively
charged nucleophiles, orienting themselves into a “cage” around the
nucleophile.
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Cont’d
This solvation strongly stabilizes the nucleophile, decreasing its reactivity
toward electrophiles in the SN2 reaction.
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Cont’d
polar aprotic solvents, which have strong dipoles but don’t have
-OH or –NH groups, are the best.
Particularly valuable are acetonitrile, CH3CN; dimethylformide,
(CH3)2NCHO (DMF); dimethyl sulfoxide, (CH3)2SO (DMSO);
and hexamethyl phosphoramide, [(CH3)2N]3PO (HMPA).
These solvents are able to dissolve many salts because of their
high polarity, but they tend to surround the metal cations rather
than the nucleophilic anions.
As a result, the unsolvated anions have a greater effective
nucleophilicity in these solvents, and SN2 reactions take place at
a correspondingly faster rate. 25
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Cont’d
.
CH3CH2CH2CH2 Br + N3- CH3CH2CH2CH2 N3 + Br-
Solvent = HMPA CH3CN DMF DMSO H2O CH3OH
Relative reactivity 200 5.0 2.8 1.3 0.007 0.001
Reactivity as solvent
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SN1 MECHANISM
SN1-Substitution Nucleophilic Unimolecular
When tert-butyl chloride reacts with sodium hydroxide in a mixture of water
and acetone
(CH3)3CCl + NaOH 2H2O (CH3)3COH + H3O+ + CI-
The rate of formation of tert-butyl alcohol is dependent on the concentration
of tert-butyl chloride, but it is independent of the concentration of OH- ion.
Doubling the tert-butyl chloride concentration doubles the rate of the
reaction, but changing the OH- ion concentration has no effect.
Rate= k[RCl]
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CONT’D
Kinetics and Factors Affecting SN1 Reactions
When treated in protic solvents with non-basic nucleophiles under neutral
or acidic condition, the order of reactivity of alkyl halides is reversed as
compared to SN2.
Tertiary alkyl halides often react several thousand times faster than
primary or secondary ones.
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Order of reactivity:
RBr + H2O ROH + HBr
(CH3)3CBr (CH3)2CH Br CH3CH2Br CH3Br
Relative
Reactivity 1,200 0.012 0.001 0.001
Reactivity
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CONT’D
A mechanism for the SN1 Reaction
The mechanism involves three steps.
Step 1. Tert- butyl chloride ionizes and becomes tert-butyl cation and
chloride ion.( slow step)
Step 2 The intermediate tert-butyl (cat ion) reacts rapidly with water to
produce a tert-butyl oxonium ion (another intermediate).
Step 3 oxonium rapidly transfers a proton to a water molecule producing
tert-butyl alcohol.
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Cont’d
.
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STEREOCHEMISTRY OF THE SN1 REACTION
If SN1 reactions occur through carbocation intermediates, the
stereochemical consequences should differ from those for SN2 reactions.
Thus, if we carry out an SN1 reaction on one enantiomer of a chiral
starting material and go through an achiral carbocation intermediate, then
the product must be optically inactive (The SN1 displacements occur with
complete racemization)
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The following reaction coordinate diagram shows an example of a an SN1
reaction with a negatively charged nucleophile
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Cont’d
The carbocation intermediate, with a plane of symmetry, is equally likely to
be attacked with the nucleophiles from both sides.
Thus, mixtures of mirror image stereoisomers are formed.
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Factors Affecting SN1 Reaction
1. The Substrate
The SN1 reaction is favoured whenever stabilized carbocation
intermediates are formed.
The stability order of carbocations is exactly the order of SN1 reactivity.
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Cont’d
2. The Leaving group
The leaving group is involved in the rate-limiting step, thus the
SN1reactivity increases if the leaving group is stable.
ToSO-> I->Br->Cl-~H2O
3. The nucleophile
The nucleophile doesn’t enter into the reaction until after rate-limiting
dissociation has occurred and thus cannot affect the rate of the reaction.
The reaction of 2-methyl-2- propanol with HX for example, occurs at the
same rate regardless of whether x is Cl, Br, or I.
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Cont’d
Eg.
4. The Solvent
Polar solvents such as water, methanol, dimethylsulfoxide and so forth are
good at solvating ions, but most ether and hydrocarbon solvents are very
poor at solvating ions.
The SN1 reactions take place much more rapidly in highly polar solvents than
in non-polar solvents.
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Cont’d
Eg.
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Applications of Substitution Reactions
The reaction of primary haloalkanes with cyanide ions
For example, using 1-bromopropane as a typical primary haloalkane:
CH3CH2CH2Br + CN- CH3CH2CH2CN + Br-
You could write the full equation rather than the ionic one, but it slightly
obscures what's going on:
CH3CH2CH2Br + KCN CH3CH2CH2CN + KBr
The bromine (or other halogen) in the haloalkane is simply replaced by a -
CN group - hence a substitution reaction. In this example, butanenitrile is
formed.
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