Chapter 9

Elimination reactions of alkyl halides. Competition between substitution and elimination.

Elimination Reactions of Alkyl Halides (9.1)

In elimination reactions both the halogen and a proton from an adjacent carbon atom are removed alkenes are formed.

Elimination Reactions
Two types: E2 E1

E2
Elimination 2-(bi)molecular
Rate [RX][Base]

Base

CH3CH2X

H2C=CH2 +

Base-H +

Elimination Reactions of Alkyl Halides (9.1)

The E2 (bimolecular elimination) reaction (9.1)

HO

H H C H

H C H Br

H C C H

H H

H2O

+ Br

E2 reactions (like S N2) take plac e in a single step, without intermediates. The rate of an E2 reaction depends on the concentrat ion of both the alkyl halide and the base, therefore is a bimolecular reaction.
5

Elimination Reactions of Alkyl Halides (9.1)

Br MeO MeOH

Product distribution from 2-bromobutane:

Br

MeO MeOH

CH3CH=CHCH3 (mixture E and Z) 80 %

+ 20 %

The more substituted alkene is the major product because it comes from a more st able transition state, (next sl ide).
6

An E2 reaction is regioselective (9.2)

p 392

The T.S. has an alkene-like sructure

7

Example:

Br

HO H2O
minor product

-carbon -carbon -carbon

Br

p 393
10

Elimination Reactions of Alkyl Halides (9.2)

11

12

p. 395

Steric hindrance also affects the product distribution

a a

p 394
13

Conjugated alkene products are preferred over the more substituted alkene product

p 394

Do not use Zaitsevs rule to predict the major product in these cases 14

Another exception to Zaitsevs rule - alkyl fluorides

15 p 396

Consider the elimination of 2-fluoropentane

p. 16 407

p 396

A carbanion-like transition state - 1 is best

17

Relative stabilities of carbanions

p 397

R R C: - < R
tertiary carbanion

R R C: - < H
secondary carbanion

R H C: H
primary carbanion

<

H H C: H
methyl anion

least stable

most stable
18

Eliminations only
HO Cl HO F

HO Cl HO F

HO Br
19

Problem: which alkyl halide is the more reactive in an E2 reaction?

Br or Br

or Br

Br

Br or Br

or Br Br
20

E1
Elimination 1-(mono)molecular
Rate [RX] only
CH3 + H3C C X CH3 H3C C CH2 + Base-H + H3C

Base

X
21

Elimination Reactions of Alkyl Halides (9.3)

The E1 (eliminat ion uni molecular) reaction (9.3)

H2O Br

H3O

Br

E1 reactions (like S N1) take plac e in two steps, and involve a carbocation intermediate . The rate of an E1 reaction depends on ly on the concentratio n of the alkyl halide, therefore it is a unimolec ular reaction.
22

Elimination Reactions of Alkyl Halides (9.3)

p 398

The first step (formation of carbocation) is the rate-determining step

23

Elimination Reactions of Alkyl Halides (9.3)

Generally, the major product of a E1 reaction is the more substituted alkene because it comes from the more stable transition state (follows Zaitsev's rule). Order of reactivities of alkyl halides in E1 reactions (same as the stability order of carbocations):

p 400
24

Elimination Reactions of Alkyl Halides (9.3)

Example:

CH3OH Cl
major minor

25

Elimination Reactions of Alkyl Halides (9.3)

Carbocation rearrangements : Because E1 reactions involve the formation of carbocation intermediates, rearrangements can occur (1,2-hydride or 1,2-methyl shifts ).

26

Examples:

p 400
27

Examples:

p 400

28

Elimination Reactions of Alkyl Halides (9.4)

Comparison: Alkyl Halide 1o 2o 3o Reaction E2 only E2 and E1 E2 and E1

Competit ion between E2 and E1 reactions (9.4) An E2 reaction is favored by a high concentrat ion of a strong base and a polar aprotic solvent (e.g. DMSO, DMF ). An E1 reaction is favored by a weak base and a polar protic solvent (H2O, alcohol).
29

Eliminations only...

CH3OH Br H2O Br

CH3O

HO

CH3CH2OH

CH3CH2O Br

E1

E2
30

Problem:Draw detailed arrow-pushing mechanisms for

each of the following transformations:

H+

Cl

CH3OH

31

H+

Cl

CH3OH

H+ H B-

32

Cl

CH3OH

CH3OH H Cl

33

Elimination Reactions of Alkyl Halides (9.5)

34

Elimination Reactions of Alkyl Halides (9.5)

The anti-periplanar conformation is required due to: 1. 2. Backside displacement Minimal electron repulsion between the electron rich strong base and the leaving group X-

When there is a choice of -hydrogens to abstract, the alkene with the bulkiest groups on opposite sides of the C=C (more stable) is the major product. The isomer formed can depend on the configuration of the reactant.
HX

35

Stereochemistry of E2 Elimination
NaOEt Br DMF Heat + +

major
H H3C H H X CH3 H3C H CH3 H FAVORED
PRODUCT

minor

or
B H H H CH3 X CH3 CH3 H CH3 H

Both are POSSIBLE anti-periplanar E2 eliminations from the same alkyl halide. 36 When there is a choice the favored pathway gives a more stable alkene

In the example below there is no choice: H H3C H CH2CH3 X CH3 H3C H CH3 CH2CH3 FAVORED
PRODUCT

37

To reiteratethe particular alkene isomer that is formed depends on the configuration of the reactant

p 406
38

Problems: what is the major product? Indicate the

stereochemistry where appropriate
H H3C Ph CH3 H Br

OH

H3C Ph

CH3

H Ph H3C

CH3 H Br

OH

Ph H3C

CH3

Ph

Ph H3C H

Br H CH3

OH
H3 C CH3

Ph H H3C

Br H CH3

OH

H 3C Ph CH 3
39

More problems: : what is the major product? Indicate the stereochemistry where appropriate
HO Br

HO

Cl

HO Cl

40

Problem (brings parts of course together):

CH3 C6H5 H H Br C6H5 CH3O in CH3OH (E2 Condns.)
C 6H 5 H Br C 6H 5

?
Alkene
H CH3

H3C Br H H C6H5

C6H5

CH3 C6H5 H H Br C6H5

CH3 C6H5 C H H C Br C6H5

C6H5 C6H5 Br H

H CH3

E2
CH3 C6H5 H H Br C6H5 H3C CH3O in CH3OH (E2 Condns.) H C6H5 C6H5

H3C H C6H5 C6H5

41

Elimination Reactions of Alkyl Halides (9.5)

Stereochemistry of the E1 reaction (9.5) In the E1 reaction a planar carbocation intermediate is formed. Therefore, both syn and anti elimina tion are possible and the major product has the bulkiest groups on opposite sides of the alkene (more stable).
H Me Ph
Me H Ph H Me Ph

Me Ph

H Me Ph

Br Ph Me

H Me Ph

Br

H H Br Ph

H Me Ph

Me

Ph EtOH heat

Me Ph

Ph
+

Me Ph

Me
+

Br

Me

Ph

Me Ph

H Ph

major elimination product

42

Stereochemistry of the E1 Reaction

p 407

43

Examples:

Cl

CH3OH
MAJOR ELIMINATION PRODUCT

CH3OH Br

MAJOR ELIMINATION PRODUCT

44

Elimination Reactions of Alkyl Halides (9.6)

Eliminati on from cyclic compounds (9.6) For the E2 pathway, both substituents must be axial to achieve the requisite anti-periplanar conformatio n.
(a)
Cl CH3CH2O-

p 409

45

(b)
Cl

CH3CH2O-

p 409

46

Examples
Br
Br Br

CH3

OMAJOR ELIMINATION PRODUCT

H H

Br CH3OMAJOR ELIMINATION PRODUCT

H Br H H Br H

47

Elimination Reactions of Alkyl Halides (9.6)

In E1 reactions, both groups do not have to be axial (because the reaction is not concerted):

p 410

48

Beware of 1,2-shifts CARBOCATIONS in E1!!

p 411

1,2-hydride shift

49

Problem:
Cl CH3 Cl H H CH3

CH3O
Cl Cl

MAJOR E2 PRODUCT

CH3OH

MAJOR E1 PRODUCT
CH3 Cl CH3
50

Which undergoes E2 most rapidly?

Br

VERY UNFAVORABLE
H3C CH CH3 3

Br

CH3 CH3 CH3

Br

Br or H3C CH3 CH3

H3C CH CH3 3

Br H H

CH3 CH3 CH3

H3C Br

CH3 CH3

51

Competition Between Substitution and Elimination

Alkyl halides can undergo SN2, SN1, E2 and E1
1) decide whether the reaction conditions favor SN2/E2 or SN1/E1
SN2/E2 reactions are favored by a high concentration of nucleophile/strong base SN1/E1 reactions are favored by a poor nucleophile/weak base

2) decide how much of the product will be the substitution product and how much of the product will be the elimination product
52

Elimination Reactions of Alkyl Halides (9.8)

Competit ion between Substi tution and Elimination (9.8) First question: reaction conditions favor SN2/E2 or SN1/E1? Alkyl Ha lide 1o 2o SN2 vs. E2 Mainl y SN2 unless h indered Both SN2 and E2. E2 favored by: 1. high temperature 2. strong, bulky base only E2 SN1 vs. E1 Neither Both SN1 and E1. E1 favored by: high temperature Both SN1 and E1. E1 favored by: high temperature
53

3o

Consider the SN2/E2 conditions

CH3 H3C CO CH3 Br CH3O OCH3

1o RX favor SN2
Br CH3O

A bulky base or bulky alkyl halide encourages elimination over substitution

E2: 3o >2o >1o SN2: 1o >2o >3o

54

 A weak base encourages substitution over elimination A strong base encourages elimination over substitution High temperature encourages elimination SN2/E2 conditions
weak base
CH3COO OCCH3 O CH3COOH Br

strong base
CH3CH2O CH3CH2OH

2o RX

CH3OH high T Br

CH3OH low T OCH3

55

Tertiary alkyl halide (3o RX) preferentially undergoes elimination reaction

SN2/E2 conditions

Br

CH3CH2O-

3o RX

E2: 3o >2o >1o SN2: 1o >2o >3o

56

Therefore, if you want to synthesize an alkene the most hindered alkyl halide should be used
Br Br

p. 419

57

Elimination Reactions of Alkyl Halides (9.9)

Substitution and Elimination reactions in synthesis (9.9) The Williamson Ether Synthesis an SN2 reaction
NaH or Na Br

OH

O H2

Na+

O
dipropyl ether 1-propoxypropane

The less hindered alkyl group comes from the alkyl halide and the more h indered alkyl group comes from the alkoxide ion.

58

In synthesizing an ether, the less hindered group should be provided by the alkyl halide
1. NaH
OH

O
2. Br

because....

Br

Br + O or 1. NaH O + Br

59

Problems
1. NaH OH 2. I

1. NaH

HO

2.

OH

Br
1. NaH 2. Br
60

OH

Elimination Reactions of Alkyl Halides (9.9)

REMINDER!
Alkyne Synthesis an SN2 reaction
Br CH3 C C CH3 C C CH2CH2CH3

CH3 C CH

NH2

Use only primary halides and methyl halides (to favor substitution)

61

Elimination Reactions of Alkyl Halides (9.10)

Consecut ive E2 reactions (9.10) Alkyl dihalides can undergo two consecutive elimination s to give products that contai n two C=C or one tr iple bond (from geminal or vicinal alkyl dihalides). Examples:
2 mol OH
Br Br

Br

Br2, CH2Cl2
Br

2 mol NH2

Br Br

NaNH2 (2 equiv)

62

Elimination Reactions of Alkyl Halides (9.11)

Designing a Synthesis II (9.11) Design the following syntheses:

Br

?
O

?
Br O

63

Br

?
O

Br vicinal Br Br geminal Br

1. a ketone comes from addition of H2O to an a lkyne 2. an alkyne comes from two successive E2 reactions of a vicinal (or geminal) dihalide 3. a vicinal dihalide comes from an alkene 4. the alkene comes from an elimination reaction

Retrosynthetic analysis:
Br
O

Br

Br

Synthesis:
Br O Br2 Br OH
64

Br

NH2

H2O, H+ Hg2+
O

Br

1 2

1. 2.

O intramolecular reaction using OH as nucleophile an alcohol comes from addition of water to an alkene

Retrosynthetic analysis

Br

Br

HO

Br

Synthesis: H2O/H+ Br Br OH Na0 O

65

Using any necessary organic and/or inorganic reagents show how the following syntheses can be carried out:

CH3

(1)
(2)

NH2 O HO

(4)

CH3 OH

Br

(5)
CN

Br O

(3)

Cl

Cl Cl

(6)

66

(1) NH2

NH2

Br

HBr Br

NH3 NH2

67

O (2) HO

O HO

Br

HO

HO

HBr

HO

Br

Na

Br O

68

(3)

CN

CN

Br

HBr

Br

CN

CN

69

(4)

CH3 Br

CH3 OH

CH3 OH CH3 Br

CH3

CH3 Br

KO Bu

CH3

1. BH3, THF 2. H2O2, OH-, H2O

CH3 OH

70

Br (5) O

Br O O H3C C OOH peracid

Br

KOtBu

71

Cl (6)

Cl Cl

Cl Cl Cl KO Bu
t

Cl

Cl2

Cl Cl

72