Organic Chemistry

CB1103

Asst Prof Phillip S. Grant

School of Chemical and Biomedical Engineering
Nanyang Technological University

1
 Organic Chemistry: Part 1
4. Alkyl Halides and Reactions
Naming and structures of alkyl halides;
Free radical halogenation;
SN2 and SN1 reactions;
E1 and E2 reactions

CB1103 Chapter 4 2
 Introduction of Alkyl Halides
• Industrial and household cleaners (good solvents)
• Anesthetics:
• CHCl3 used originally as general anesthetic but it is toxic and carcinogenic.

• CF3CHClBr is a mixed halide sold as Halothane.

• Freons are used as refrigerants and foaming agents.
• Freons can harm the ozone layer, so they have been replaced by low-
boiling hydrocarbons or carbon dioxide.
• Pesticides such as DDT are extremely toxic to insects but not as toxic to
mammals.
• Haloalkanes can not be destroyed by bacteria, so they accumulate in the soil
to a level that can be toxic to mammals, especially humans.

CB1103 Chapter 4 3
 4.1 Classes of Halides
• Alkyl halides: Halogen is directly bonded to sp3 carbon.
• Vinyl halides: Halogen is bonded to sp2 carbon of alkene.
• Aryl halides: Halogen is bonded to sp2 carbon on benzene ring.

H H I
H H
H C C Br C C
H H H Cl
Alkyl halide Vinyl halide Aryl halide

CB1103 Chapter 4 4
 4.2 Nomenclature
IUPAC
• Name as haloalkane: Chloroalkane; Bromoalkane; Iodoalkane
• Choose the longest carbon chain, even if the halogen is not bonded to
any of those carbons in the main-chain carbon.
• Use lowest possible numbers for position.

Halo in
substituent
2-chlorobutane 4-(2-fluoroethyl)heptane

cis-3-bromo-1-fluorocyclohexane
1 2 3 4 5 6 7 8 9
cis-1-bromo-3-fluorocyclohexane (Yes)
6-bromo-2-methylnonane

The substituent with the higher alphabetical order has the smaller number.

CB1103 Chapter 4 5
 4.2 Nomenclature
Systematic Common Names
• The alkyl group is a substituent on halide.
• Useful only for small alkyl groups

isobutyl bromide sec-butyl bromide

tert-butyl bromide
• CH2X2 is called methylene halide.
• CHX3 is a haloform.
• CX4 is carbon tetrahalide.

Common halogenated solvents:

CH2Cl2 is methylene chloride. CHCl3 is chloroform. CCl4 is carbon tetrachloride.
Geminal dihalide: Two halogen atoms are bonded to the same
carbon.
Vicinal dihalide: Two halogen atoms are bonded to adjacent
carbons.

CB1103 Chapter 4 6
 4.3 Properties
Polarity and Reactivity
• Halogens are more electronegative than C.
• Carbon—halogen bond is polar, so carbon has partial positive
charge.
• Carbon (electrophilic carbon) can be attacked by a nucleophile.
Halogen can leave with the electron pair.

Electronegativities of the halides: F > Cl > Br > I

CB1103 Chapter 4 7
 4.3 Properties
Boiling points
• Greater intermolecular forces, higher b.p.
• Dipole-dipole attractions not significantly different for different
halides. (not a major factor)
• Van der forces greater for larger atoms. [Major factor]
• Greater mass, higher b.p.
• Spherical shape decreases b.p. [Surface area effect]

Size

Shape

CB1103 Chapter 4 8
 • Synthesis
• Reactions

CB1103 Chapter 4 9
 4.4 Syntheses of Halides
• Free radical halogenation (Chapter 2)

• Free radical allylic halogenation

• Halogen is placed on a saturated carbon directly attached to
the double bond （ allylic position).

sp3 C next to C=C

CB1103 Chapter 4 10
 4.4 Syntheses of Halides
Allylic/Benzylic halogenation
Bromination occurs with good yield at the allylic position (sp3 C next to C=C).

• Allylic radicals are resonance stabilized.

• The mechanism involves an allylic radical stabilized by resonance.
• Both allylic radicals can react with bromine.

CB1103 Chapter 4 11
 4.4 Syntheses of Halides
N-Bromosuccinimide (NBS) is an allylic brominating agent.
Use NBS to keep the concentration of Br2 low so to better control the reaction.

CB1103 Chapter 4 12
 4.5 Reactions of Alkyl Halide

SN2; SN1

i. Mechanism; ii. Stereochemistry; iii. factors affecting the reaction

E2; E1

CB1103 Chapter 4 13
 4.5 Nucleophilic Substitutions: SN2
SN2 Mechanism
• One-Step nucleophilic substitution
• SN2 stands for substitution, nucleophilic, bimolecular
• Bimolecular means that transition state of the rate-limiting step involves
the collision of two molecules

• Concerted reaction: New bond forming and old bond breaking at same time.
• Reaction is second order overall.
• Rate = kr[alkyl halide][nucleophile].

CB1103 Chapter 4 14
 4.5 Nucleophilic Substitutions: SN2
SN2 Mechanism
The SN2 reaction is a one-step reaction.
Transition state is highest in energy.

SN2 Energy Diagram

CB1103 Chapter 4 15
 4.5 Nucleophilic Substitutions: SN2
SN2 Mechanism

CB1103 Chapter 4 16
 4.5 Nucleophilic Substitutions: SN2
Stereochemistry
SN2 reactions will result in an inversion of configuration also called a
Walden inversion.

CB1103 Chapter 4 17
 Factors affecting SN2
1. Substrate Reactivity
2. Nucleophilic Strength
3. Leaving group ability
4. Solvent effect

Solvent

CB1103 Chapter 4 18
 4.5 Nucleophilic Substitutions: SN2
a. SN2: Substrate Reactivity (Steric hindrance)
• Relative rates for SN2:
CH3X > 1° > 2° >> 3°
• Tertiary halides DO NOT react via the SN2 mechanism, due to steric
hindrance.

CB1103 Chapter 4 19
 4.5 Nucleophilic Substitutions: SN2
a. SN2: Substrate Reactivity (Steric hindrance)
• The degree of carbon linked to the electrophilic carbon matters

CB1103 Chapter 4 20
 4.5 Nucleophilic Substitutions: SN2
b. SN2: Nucleophilic Strength
• Stronger nucleophiles react faster.
• Strong bases are strong nucleophiles, but not all strong nucleophiles are strong bases.

Strong nucleophiles

Strong bases (H+)

Strong nucleophiles

CB1103 Chapter 4 21
 4.5 Nucleophilic Substitutions: SN2
b. SN2: Nucleophilic Strength (reactivity)

1. A negatively charged nucleophile is stronger than its neutral counterpart:

2. Nucleophilicity increases from top to bottom in the periodic table:

The more electronegative the atom, the more strongly held the electrons and
therefore less reactive toward forming new bonds (weaker nucleophilicity).

3. Increase as size and polarizability increase:

CB1103 Chapter 4 22
 4.5 Nucleophilic Substitutions: SN2
SN2: Nucleophilic Strength
Polarizability Effect In polar solvent

Larger elements → larger, more diffuse, and more polarizable electron clouds →
more effective orbital overlap in T.S. → lower T.S. energy → faster reaction.

CB1103 Chapter 4 23
 4.5 Nucleophilic Substitutions: SN2
c. Leaving group ability

The best leaving groups are:

• Electron-withdrawing, to polarize the carbon atom. (Electrophilic carbon)
• Polarizable, to stabilize the transition state.
• Stable (not a strong base) once they have left.

CB1103 Chapter 4 24
 4.5 Nucleophilic Substitutions: SN2
d. Solvent effect

• Polar protic solvents have acidic hydrogens (O—H or N—H) that can solvate
the nucleophile, reducing their nucleophilicity.

CB1103 Chapter 4 25
 Polar Solvent
Polar solvents have large dipole moments, which contain bonds between
atoms with very different electronegativities, such as oxygen and hydrogen.

Polar aprotic solvents

CH3-C(=O)-CH3 H-C(=O)N(CH3)2 CH3-C≡N
Tetrahydrofuran (THF); Acetone; Dimethylformamide (DMF); Acetonitrile;

Polar protic solvents

CH3-CH2-OH CH3-CH2-OH CH3-C(=O)OH H-O-H
Ethanol Methanol Acetic acid Water

Non-polar solvents contain bonds between atoms with similar electronegativities,

such as carbon and hydrogen

CH3-CH2-CH2-CH2-CH2-CH3
Hexane Benzene Toluene

CB1103 Chapter 4 26
 4.5 Nucleophilic Substitutions: SN2
d. Solvent effect

• Polar protic solvents have acidic hydrogens (O—H or N—H) that can solvate
the nucleophile, reducing their nucleophilicity.

CB1103 Chapter 4 27
 4.5 Nucleophilic Substitutions: SN2
c. Solvent effect
• Polar aprotic solvents do not have acidic protons and therefore cannot
form hydrogen bond.
• Some aprotic solvents are acetonitrile, DMF, acetone, and DMSO.
• SN2 reactions proceed faster in polar aprotic solvents.

CB1103 Chapter 4 28
 Nucleophilic vs Basicity (Halogen Anions)

Basicity > > >

In polar aprotic solvent

Nucleophilicity: F-> Cl- >Br- > I- [charge density consideration]

In polar protic solvent

Nucleophilicity: F-< Cl- < Br- < I- [hydrogen bonding consideration]

CB1103 Chapter 4 29
 4.5 Nucleophilic Substitutions: SN1
SN1 Mechanism
• The SN1 reaction is a unimolecular nucleophilic substitution.
• Two steps
• It has a carbocation intermediate.
• Rate = kr[alkyl halide].
• Racemization occurs. [Stereochemistry]

Step 1: Formation of the carbocation.

Rate-determining step:

Step 2: Attack of the nucleophile.

CB1103 Chapter 4 30
 4.5 Nucleophilic Substitutions: SN1
SN1 Mechanism
If the nucleophile was neutral, a third step (deprotonation) will be needed.

Step 1: Carbocation formation

Step 2: Nucleophile Attack

Neutral Nucleophile
Weak
Step 3: Deprotonation

CB1103 Chapter 4 31
 4.5 Nucleophilic Substitutions: SN1
SN1 Energy Diagram

Forming the carbocation is an endothermic

step.
Step 2 is fast with a low activation energy.

CB1103 Chapter 4 32
 4.5 Nucleophilic Substitutions: SN1
Stereochemistry
• Carbocation is sp2 hybridized and trigonal planar. The lobes of the empty p orbital
are on both sides of the trigonal plane.
• Nucleophilic attack can occur from either side, producing mixtures of retention and
inversion of configuration if the carbon is chiral.

CB1103 Chapter 4 33
 4.5 Nucleophilic Substitutions: SN1
a. Substrate (Stability of C+)
Order of reactivity follows stability of carbocations (opposite to SN2).
3° > 2° > 1° >> CH3X
More stable carbocation requires less energy to form.
Rate-determining step

CB1103 Chapter 4 34
 4.5 Nucleophilic Substitutions: SN1
a. Substrate (Rearrangements)

CB1103 Chapter 4 35
 4.5 Nucleophilic Substitutions: SN1
a. Substrate (Rearrangements)

• Carbocations can rearrange to form a more stable carbocation.

• Move the smallest group on the adjacent carbon of halogen-substituted C:
• Hydride shift: H- on adjacent carbon moves.
• Methyl shift: CH3- on adjacent carbon moves.

CB1103 Chapter 4 36
 4.5 Nucleophilic Substitutions: SN1
a. Substrate (Rearrangements)

Since a primary carbocation cannot form, the methyl group on the adjacent carbon
will move (along with both bonding electrons) to the primary carbon, displacing the
bromide and forming a tertiary carbocation.

The smallest groups on the adjacent carbon will move: If there is a hydrogen, it will
give a hydride shift.

CB1103 Chapter 4 37
 4.5 Nucleophilic Substitutions: SN1
b. Attacking Nucleophile (Nuc:−)
The nucleophile not involved in rate-limiting step, no kinetic role – does not affect
rate.
Step 1: Formation of the carbocation.

Rate-determining step:

Step 2: Attack of the nucleophile.

Does not affect rate.

CB1103 Chapter 4 38
 4.5 Nucleophilic Substitutions: SN1
c. Leaving group (X)

Step 1: Formation of the carbocation.

Rate-determining step:
Leaving group

Step 2: Attack of the nucleophile.

• Best leaving groups are those most stable conjugate bases (X−) – able to
accommodate the negative charge
• Same order as for SN2

CB1103 Chapter 4 39
 4.5 Nucleophilic Substitutions: SN1
c. Solvent effect
Step 1: Formation of the carbocation.

Rate-determining step

Polar protic solvent is best because it can solvate both ions strongly through
hydrogen bonding.

CB1103 Chapter 4 40
 4.5 Nucleophilic Substitutions
SN2 SN1
CH3X > 1º > 2º (Steric Hindrance) 3º > 2º (Stability of carbocation)

Strong nucleophile (Step 1: Rate- Weak nucleophile (may also be

determining step) used as solvent) (Step 2)

Polar aprotic solvent Polar protic solvent

Rate = k[alkyl halide][Nuc] Rate = k[alkyl halide]

Inversion at chiral carbon Racemization

CB1103 Chapter 4 41
 4.6 Elimination Reactions
• Elimination reactions produce double bonds.
• Also called dehydrohalogenation (-HX).

E1

E2

CB1103 Chapter 4 42
 4.6 Elimination Reactions: E1
Mechanism
• Unimolecular elimination.
• Two groups lost: a hydrogen and the halide.
• Nucleophile acts as base (accept proton).
• The E1 and SN1 reactions have the same conditions so a mixture of products
will be obtained.

Step 1: Ionization to form a carbocation

Rate-determining step

Step 2: Base abstracts a proton to form an alkene.

E1 S N1
Product Product

CB1103 Chapter 4 43
 4.6 Elimination Reactions: E1
Double-Bond formation in Step 2 E1 Energy Diagram

sp3 to sp2

The E1 and the SN1 reactions have the

same first step: carbocation formation
is the rate-determining step for both
mechanisms.

CB1103 Chapter 4 44
 4.6 Elimination Reactions: E1
Double Bond Substitution Patterns

tetrasubstituted trisubstituted disubstituted monosubstituted

• The more substituted double bond is more stable

(Hyperconjugation effect).
• In elimination reactions, the major product of the reaction is the
more substituted double bond: Zaitsev’s rule.

CB1103 Chapter 4 45
 4.6 Elimination Reactions: E1
Zaitsev’s Rule

• If more than one elimination product is possible, the most-substituted

alkene is the major product (most stable).

CB1103 46
 4.6 Elimination Reactions: E2
• Elimination, bimolecular.
• Requires a strong base.
• This is a concerted reaction (one-step): The proton is abstracted, the
double bond forms, and the leaving group leaves, all in one step.

•Order of reactivity for alkyl halides:

3° > 2 ° > 1°
•Mixture may form, but Zaitsev
product predominates.

CB1103 Chapter 4 47
 4.6 Elimination Reactions: E2
Base Strength (B:−)

• Base (B:), the stronger the base the faster the E2 reaction
• A strong base is also a strong nucleophile; SN2 may then compete
favorably
• Use a bulky, strong base to encourage E2 and discourage SN2
(sensitive to steric effect)
SN2 ??

SN2

CB1103 Chapter 4 48
 4.6 Elimination Reactions: E2
Leaving Group and Solvent Effects
• Leaving group similar to SN2 : I– > Br– > Cl–

• Strong bases are usually used in E2; although there may be

solvent effect, it is not as important as it is in SN2.

Leaving group

CB1103 Chapter 4 49
 4.6 Elimination Reactions

E1 E2
• Tertiary > secondary • Tertiary > secondary
• Base strength unimportant (usually • Strong base required (abstract H)
weak)
• Good ionizing solvent (stabilize the • Solvent polarity not important.
carbocation)

• Rate = k[alkylhalide][base]
• Rate = k[alkyl halide]
• Zaitsev product
• Zaitsev product
• Coplanar leaving groups (usually anti)
• No required geometry

CB1103 Chapter 4 50