Organic Chemistry

M. R. Naimi-Jamal

Faculty of Chemistry

Iran University of Science & Technology

Chapter 7-2. Reactions of Alkyl Halides: Nucleophilic Substitutions

Based on McMurry’s Organic Chemistry, 6th edition

3

Alkyl Halides React with Nucleophiles and Bases

Alkyl halides are polarized at the carbon-halide bond, making the carbon electrophilic

Nucleophiles will replace the halide in C-X bonds of many alkyl halides (reaction as Lewis base)

4

Alkyl Halides React with Nucleophiles and Bases

Nucleophiles that are Brønsted bases produce

elimination

5

Substitution vs. Elimination

6

The Nature of Substitution

Substitution requires that a "leaving group", which is also a Lewis base, departs from the reacting molecule.

A nucleophile is a reactant that can be expected to participate as a Lewis base in a substitution

reaction.

7

The Discovery of the Walden Inversion

In 1896, Paul Walden showed that (-)-malic acid

could be converted to (+)-malic acid by a series of

chemical steps with achiral reagents

This established that optical rotation was directly

related to chirality and that it changes with

chemical alteration

Reaction of (-)-malic acid with PCl5 gives (+)-

chlorosuccinic acid

Further reaction with wet silver oxide gives (+)-malic acid

The reaction series starting with (+) malic acid gives (-)

acid

8

The Walden Inversion (1896)

9

Significance of the Walden Inversion

The reactions involve substitution at the

chiral center

Therefore, nucleophilic substitution can

invert the configuration at a chirality center

10

Stereochemistry of Nucleophilic Substitution

A more rigorous Walden

cycle using 1-phenyl-2-

propanol (Kenyon and

Phillips, 1929)

Only the second and fifth

steps are reactions at

carbon

Inversion must occur in

the substitution step

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12

Two Stereochemical Modes of Substitution

Substitution with inversion:

Substitution with retention:

X

H3C

RH

HO

CH3

RH

OH-

+ X-

X

H3C

RH

OH-

+ X-OH

H3C

RH

13

Substitution Mechanisms

SN1

Two steps with carbocation intermediate

Occurs in 3°, allyl, benzyl

SN2

Two steps combine - without intermediate

Occurs in primary, secondary

14

Kinetics of Nucleophilic Substitution

Rate is the change in concentration with time

Depends on concentration(s), temperature,

inherent nature of reaction (energy of

activation)

A rate law describes the relationship

between the concentration of reactants and

the overall rate of the reaction

A rate constant (k) is the proportionality

factor between concentration and rate

15

Kinetics of Nucleophilic Substitution

Rate = d[CH3Br]/dt = k[CH3Br][OH-1]

This reaction is second order: two

concentrations appear in the rate law

SN2: Substitution Nucleophilic 2nd order

16

The SN2 Reaction

Reaction occurs with inversion at reacting center

Follows second order reaction kinetics

Ingold nomenclature to describe rate-

determining step:

S=substitution

N (subscript) = nucleophilic

2 = both nucleophile and substrate in rate-

determining step (bimolecular)

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SN2 Process

The transition state for the rate-determining

(and only) step contains both reactants

(substrate alkyl halide and nucleophile).

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SN2 Transition State

The transition state of an SN2 reaction has a

planar arrangement of the carbon atom and

the remaining three groups

Hybridization is sp2

19

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Characteristics of the SN2 Reaction

Sensitive to steric effects

Methyl halides are most reactive

Primary are next most reactive

Unhindered secondary halides react under some conditions

Tertiary are unreactive by this path

No reaction at C=C (vinyl or aryl halides)

22

Steric Effects on SN2 Reactions

X

23

Order of Reactivity in SN2

The more alkyl groups connected to the reacting carbon, the slower the reaction

24

Vinyl and Aryl Halides:

25

The Nucleophile

Neutral or negatively charged Lewis base

Reaction increases coordination (adds a new bond) at the nucleophile

Neutral nucleophile acquires positive charge

Anionic nucleophile becomes neutral

26

For example:

Br+ CN-

C N+ Br-

CH2 Cl + H2O CH2 OH2 + Cl-

27

28

Relative Reactivity of Nucleophiles

Depends on reaction and conditions

More basic nucleophiles react faster

Better nucleophiles are lower in a column of the

periodic table

Anions are usually more reactive than neutrals

29

30

The Leaving Group

A good leaving group reduces the energy of

activation of a reaction

Stable anions that are weak bases (conjugate

bases of strong acids) are usually excellent

leaving groups

Stronger bases (conjugate bases of weaker

acids) are usually poorer leaving groups

31

32

Poor Leaving Groups

If a group is very basic or very small, it does

not undergo nucleophilic substitution.

33

Summary of SN2 Characteristics:

Substrate: CH3->1o>2o>>3o (Steric effect)

Nucleophile: Strong, basic nucleophiles favor the reaction

Leaving Groups: Good leaving groups (weak bases) favor the reaction

Solvent: Aprotic solvents favor the reaction; protic reactions slow it down by solvating the nucleophile

Stereochemistry: 100% inversion

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Prob.: Arrange in order of SN2 reactivity

35

The SN1 Reaction

Tertiary alkyl halides react rapidly in protic

solvents by a mechanism that involves

departure of the leaving group prior to the

addition of the nucleophile.

Reaction occurs in two distinct steps, while SN2

occurs in one step (concerted).

Rate-determining step is formation of

carbocation:

36

SN1 Reactivity:

37

SN1 Energy Diagram

38

Rate-Limiting Step

The overall rate of a reaction is controlled by

the rate of the slowest step

The rate depends on the concentration of the

species and the rate constant of the step

The step with the largest energy of activation

is the rate-limiting or rate-determining step.

39

SN1 Energy Diagram

40

41

Stereochemistry of SN1 Reaction

The planar carbocation intermediate leads to

loss of chirality

Product is racemic or has some inversion

42

43

Characteristics of the SN1 Reaction

Tertiary alkyl halide is most reactive by this

mechanism

Controlled by stability of carbocation

44

Relative Reactivity of Halides:

45

Allylic and Benzylic Halides

Allylic and benzylic intermediates stabilized by

delocalization of charge

Primary allylic and benzylic are also more

reactive in the SN1 mechanism

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47

Effect of Leaving Group on SN1

Critically dependent on leaving group

Reactivity: the larger halides ions are better leaving

groups

In acid, OH of an alcohol is protonated and leaving

group is H2O, which is still less reactive than halide

p-Toluensulfonate (TosO-) is an excellent leaving group

48

Summary of SN1 Characteristics:

Substrate: Benzylic~allylic > 3o > 2o

Nucleophile: Does not affect reaction (although

strong bases promote elimination)

Leaving Groups: Good leaving groups (weak

bases) favor the reaction

Solvent: Polar solvents favor the reaction by

stabilizing the carbocation.

Stereochemistry: racemization (with some

inversion)

49

Prob.: Arrange in order of SN1 reactivity

50

Practice Problem: SN1 or SN2?

51

Problem: SN1 or SN2?

52

Chapter 7-2, Questions

27, 29, 31, 32,

46, 47