Chapter 11: Nucleophilic Substitution and Elimination Walden Inversion

O HO O OH PCl5 OH HO O Cl O OH

(S)-(-) Malic acid [a]D= -2.3 Ag2O, H2O

(+)-2-Chlorosuccinic acid Ag2O, H2O

O O HO O Cl OH PCl5 HO O OH OH

(-)-2-Chlorosuccinic acid

(R)-(+) Malic acid [a]D= +2.3

The displacement of a leaving group in a nucleophilic substitution reaction has a defined stereochemistry

Stereochemistry of nucleophilic substitution p-toluenesulfonate ester (tosylate): converts an alcohol into a leaving group; tosylate are excellent leaving groups. abbreviates as Tos
Nu: C X X= Cl, Br, I O Cl S O O C OH + C O S O CH3 tosylate O
-

Nu C

+ X-

CH3

O Nu: C O S O CH3 Nu C +

S O

CH3

O Tos-Cl H O H pyridine H O Tos H3C OO O H CH3 + TosO -

[a]D= +33.0
HOO TosO - + H O O H3C CH3 O-

[a]D= +31.1

[a]D= -7.06
HO-

Tos-Cl O Tos H pyridine O H H

[a]D= -7.0

[a]D= -31.0

[a]D= -33.2

The nucleophilic substitution reaction inverts the Stereochemistry of the carbon (electrophile)- Walden inversion

Kinetics of nucleophilic substitution Reaction rate: how fast (or slow) reactants are converted into product (kinetics) Reaction rates are dependent upon the concentration of the reactants. (reactions rely on molecular collisions) Consider:
H HO
_

H C Br HO C H H Br _

At a given temperature: If [OH-] is doubled, then the reaction rate may be doubled If [CH3-Br] is doubled, then the reaction rate may be doubled A linear dependence of rate on the concentration of two reactants is called a second-order reaction (molecularity)

H HO
_

H C Br HO C H H Br _

Reaction rates (kinetic) can be expressed mathematically: reaction rate = disappearance of reactants (or appearance of products) For the disappearance of reactants: rate = k [CH3Br] [OH-] [CH3Br] = CH3Br concentration [OH-] = OH- concentration k= constant (rate constant)

L molsec

For the reaction above, product formation involves a collision between both reactants, thus the rate of the reaction is dependent upon the concentration of both.

Nucleophilic Substitution comes in two reaction types: SN2 S= substitution N= nucleophilic 2= biomolecular rate = k [R-X] [Nu:] S N1 S= substitution N= nucleophilic 1= unimolecular rate = k [R-X]

The SN2 Reaction: Mechanism

Steric effects in the SN2 reaction: For an SN2 reaction, the nucleophile approaches the electrophilic carbon at an angle of 180 from the leaving group (backside attack) the rate of the SN2 reaction decrease as the steric hindrance (substitution) of the electrophile increases.

Increasing reactivity in the SN2 reaction

CH3 H3C C Br CH3 CH3 CH3 CH3 H

<

H3C C CH2 Br CH3

<

H3C C Br H

<

H C Br H

<

H C Br H

tertiary realtive reactivity << 1

neopentyl 1

secondary 500

primary 40,000

methyl 2,000,000

Vinyl and aryl halides do not react in nucleophilc substitution reactions

X R3 R2 X + R1 Nu: Nu + R2 Nu Nu:

R3

R1

R3 R2

X + R1 (CH3)2CuLi

R3 R2

CH3 R1

From Chapter 10: NOT a nucleophilc substitution reaction

The nature of the nucleophile in the SN2 Reaction: The measure of nucleophilicity is imprecise. Anionic Neutral
Nu: _ + R-X Nu-R + X: _

Nu:

R-X

+ Nu-R

X:

Nu + H3C-Br Nu = H2O CH3CO2NH3 ClHOCH3OINCHS-

Nu-CH3 + Br relative reactivity= 1 500 700 1,000 16,000 25,000 100,000 125,000 125,000

Nucleophiles are Lewis bases Nucleophilicity roughly parallels basicity when comparing nucleophiles that have the same attacking atom Nu: CH3Orelative reactivity: 25,000 pKa of the conj. acid: 15.5 HO16,000 15.7 CH3CO2500 4.7 H2O 1 -1.7

Nucleophilicity usually increases going down a column of the periodic chart. Thus, sulfur nucleophiles are more reactive than oxygen nucleophiles. I- > Br- > Cl-. Negatively charges nucleophiles are usually more reactive than neutral nucleophiles.

The role of the leaving group in SN2 reactions:

H Nu _ H C X H C X+ H Nu C H H H

X_

H Nu
_

H HO C H H

The leaving group is usually displaced with a negative charge The best leaving groups are those with atoms or groups that can best stabilize a negative charge. Good leaving groups are the conjugate bases of strong acids H-X H+ + X-

the lower the pKa of H-X, the stronger the acid.

H Nu _ H C X H

dNu

H C H H

dX

H Nu C H H

X_

Increasing reactivity in the SN2 reaction LG: HO-, H2N-, RO<<1 >15 F1 3.45 Cl200 -7.0 BrITosO60,000

Relative Reactivity: pKa:

10,000 30,000 -8.0

Charged Leaving Groups: conversion of a poor leaving group to a good one

H H C OH H H+ Nu _ + C OH H H H H H Nu C H H

OH2

pKa of H3O+= -1.7

The role of the solvent in SN2 reactions: Descriptor 1: polar: high dipole moment
d H
+

d_ O

Hd

d_ O

O Hd
+

S +

water

alcohols

DMSO

non-polar: low dipole moment (hexanes) Descriptor 2: protic: acidic hydrogens that can form hydrogen bonds (water, alcohols) aprotic: no acidic hydrogens
O + _ [(CH3)2N]3P O O S + _ CH3C N H N CH3 CH3

hexamethylphosphoramide (HMPA)

DMSO

acetonitrile

dimethylformamide (DMF)

Solvation: solvent molecules form shells around reactants and dramatically influence their reactivity.
H H O d+ H _ Od
+

H H H O d+ _ H Od H d+ d+ d+ H d+ H O d_
_ H d O

d H d_ O H H H O

Y+
H Od_ H

d H d+ O H d+

d+ H O H O H d_

H d+

Polar protic solvents stabilize the nucleophile, thereby lowering its energy. This will raise the activation energy of the reactions. SN2 reactions are not favored by polar protic solvents. Polar aprotic solvents selectively solvate cations. This raises the energy of the anion (nucleophile), thus making it more reactive. SN2 reactions are favored by polar aprotic solvents.

CH3CH2CH2CH2CH2Br + N3Solvent: CH3OH relative reativity: 1 H2O 7 DMSO 1,300

CH3CH2CH2CH2CH2Br + BrDMF 2,800 CH3CN 5,000 HMPA 200,000

DE

DE

The SN1 Reaction: kinetics: first order reaction (unimolecular) rate = k [R-X] [R-X]= alkyl halide conc. The nucleophile does not appear in the rate expressionchanging the nucleophile concentration does not affect the rate of the reaction! Must be a two-step reaction The overall rate of a reaction is dependent upon the slowest step: rate-limiting step

The Mechanism of the SN1 Reaction

DGstep 2

step 1

DGstep 1 >> DGstep 2 DGstep 1 is rate-limiting

Reactivity of the Alkyl Halide in the SN1 Reaction: Formation of the carbocation intermediate is rate-limiting. Thus, carbocation stability greatly influence the reactivity.
H H C+ H Methyl H R C+ H C C C+ + H R C+ R R R C+ R

<

Primary (1)

<

Allylic

~ _

Benzylic

~ _

Secondary (2)

<

Tertiary (3)

Increasing carbocation stability The order of reactivity of the alkyl halide in the SN1 reaction exactly parallels the carbocation stability

10

Allylic and benzylic carbocations are stablized by resonance

Stereochemistry of the SN1 Reaction: it is actually a complicated issue. For the purpose of Chem 220a, sect. 2 the stereochemistry of the SN1 reaction gives racemization. A chiral alkyl halide will undergo SN1 substitution to give a racemic product
OH2 Cl H3C CH2CH2CH2CH3 H3CH2C H2O

H3C H3CH2C

CH2CH2CH2CH3

OH2 OH H3C CH2CH2CH2CH3 H3CH2C H3CH2C CH2CH2CH2CH3 H3C OH Carbocation is achiral

enantiomers: produced in equal amount

11

The role of the leaving group in SN1 reactions: same as for the SN2 reaction TosO- > I- > Br- > Cl- ~ _ H2O Charged Leaving Groups: conversion of a poor leaving group to a good one
R R C OH R H+ + C OH R R H R -H2O R R + C Nu: R R R C Nu R

The role of the nucleophile in SN1 reactions: None Involvement of the nucleophile in the SN1 reaction is after the rate-limiting step. Thus, the nucleophile does not appear in the rate expression. The nature of the nucleophile plays no role in the rate of the SN1 reaction.

The role of the solvent in SN1 reactions: polar solvents are fovored over non-polar for the SN1 reaction protic solvents are favored over aprotic for the SN1 reaction Solvent polarity is measured by dielectric constant (e) Hexane (CH3CH2)2O HMPA DMF DMSO CH3CH2OH CH3OH H2O e = 1.9 4.3 30 38 48 24 34 80 nonpolar aprotic polar protic

12

CH3 H3C C Cl CH3

CH3 + ROH H3C C OR CH3 + HCl

Solvent: Rel. reactivity:

Ethanol 1

40% H2O 60% Ethanol 100

80% H2O 20% Ethanol 14,000

H2O 100,000

Increasing reactivity in the SN1 reaction

H
H H R R C Cl R
3

H H O H O

H H O H

O H R + d_ d C Cl R R H O H

H _ H Od
_ H d O

d _O H d C +
_

H H H H d
+

O H

d+

sp tetrahedral

d_ H O H

d_ H O H

O H

Cl

_ d+
H O H

d+ H O H

sp2 trigonal planar

Solvent stablization of the transition state

Solvent stablization of the intermediates

Stabilization of the intermediate carbocation and the transition state by polar protic solvents in the SN1 reaction

13

Elimination Reactions: Nucleophiles are Lewis bases. In the reaction with alkyl halides, they can also promote elimination reactions rather than substitution.
_ R X 1 alkyl halide _ H elimination H R R H SN2

R C C:

R C C CH2R

R C C:

H R

R X

2 alkyl halide

Elimination is a competitive reaction with nucleophilic substitution.

Zaitsevs Rule: When more than one alkene product is possible from the base induced elimination of an alkyl halide, the most highly substituted (most stable) alkene is usually the major product.
Br H3CH2C C CH3 CH3 CH3CH2O - Na+ CH3CH2OH H C C H3CH2C CH3 81% Br H3CH2C C CH3 H CH3CH2O - Na+ CH3CH2OH H C C H3CH2C H CH3 H C C CH3 H CH3 H3C H C C H3CH2CH2C 19% H C C H3CH2CH2C H H H

H3CH2C

70%

30%

14

The E2 Elimination: rate = k [R-X] [Base]

The E2 elimination takes place in a single step with no intermediate

Stereochemistry of the E2 Elimination: The H being abstracted and the leaving group must be in the same plane
H X H X XH H

Syn periplanar: the H and X are eclipsed dihedral angle = 0

Anti periplanar: the H and X are anti staggered dihedral angle = 180

Generally, the anti periplanar geometry is energetically preferred (staggered conformation vs eclipsed)

15

In the periplanar conformation, the orbitals are already aligned for p-bond formation

The E2 elimination has a defined geometric (stereochemical) outcome:

H Br Ph

H Br Ph

B:

H Br Ph

Ph

Br

will be cis on the alkene

H Br

Ph Ph

Br

will be cis on the alkene

Br Ph

H Ph

meso

anti periplanar
Br H Ph will be cis on the alkene Ph Ph H

E
favored

H Br Ph

Br Ph H will be cis on the alkene Br Ph

BrH

syn periplanar

Anti periplanar geometry is usually preferred for E2 elimination

16

E2 elimination with halocyclohexane reactants

17

The E1 Elimination: rate = k [R-X]

No geometric requirements for E1 elimination. Usually follows Zaitsevs Rule

18

SN2 vs E2 For primary alkyl halides SN2 is favored with most nucleophiles E2 is favored with bulky bases (t-butoxide)
CH3 H3C C O CH3 _

t-butoxide is too bulky to undergo SN2

H C _ H C X H3C C O H H CH3 CH3

SN2

CH3 H3C C O C CH3 H

X
H H

C H H H

CH3 H3C C O CH3

H C H H

E2 C X H

C C H

CH3 + H3C C OH CH3

Secondary halides: E2 is competitive with SN2 and often gives a mixture of substitution and elimination products Tertiary Halides: E2 elimination occurs with strong bases such as HO-, RO-, H2N- (strongly basic conditions) E1 elimination occurs with heat and weak bases such as H2O or ROH. (neutral conditions) The E1 elimination product is often a minor product with the major product arising from SN1 reaction. SN2 reaction does not occur with 3 halides

19