1

Chapter 11: Nucleophilic Substitution and EliminationWalden Inversion

O OHOH

HOO

(S)-(-) Malic acid[a]D= -2.3 °

PCl5

O ClOH

HOO

Ag2O, H2O

O OHOH

HOO

(R)-(+) Malic acid[a]D= +2.3 °

PCl5

Ag2O, H2O

O ClOH

HOO

(+)-2-Chlorosuccinic acid

(-)-2-Chlorosuccinic acid

The displacement of a leaving group in a nucleophilic substitutionreaction has a defined stereochemistry

Stereochemistry of nucleophilic substitution

p-toluenesulfonate ester (tosylate): converts an alcohol intoa leaving group; tosylate are excellent leaving groups.abbreviates as Tos

C XNu:CNu + X-

X= Cl, Br, I

C OH

S OO

Cl

CH3

+ C O SO

OCH3

tosylate

C O SO

OCH3Nu: CNu

S OO

-O

CH3

+

2

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

OH

Tos-Cl

pyridine OHH Tos

[a]D= +33.0

H3C O-

O

HO

O CH3

[a]D= +31.1 [a]D= -7.06

+ TosO -

HO-

HOH

[a]D= -33.2

Tos-Cl

pyridineHO

Tos

[a]D= -31.0

H3C O-

O

OH

O CH3

HO-

TosO - +

[a]D= -7.0

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:

At a given temperature:If [OH-] is doubled, then the reaction rate may be doubledIf [CH3-Br] is doubled, then the reaction rate may be doubled

A linear dependence of rate on the concentration of two reactants iscalled a second-order reaction (molecularity)

C BrH

HHHO _

CHOH

HH Br _

3

C BrH

HHHO _

CHOH

HH 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- concentrationk= constant (rate constant)

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.

Lmol•sec

Nucleophilic Substitution comes in two reaction types:

SN2 SN1

S= substitution S= substitution N= nucleophilic N= nucleophilic

2= biomolecular 1= unimolecular

rate = k [R-X] [Nu:] rate = k [R-X]

4

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.

5

CH3CCH3

CH3

Br CH3CCH3

CH3

CH2 Br CH3CCH3

HBr CH

CH3

HBr CH

H

HBr

tertiary neopentyl secondary primary methyl

< < < <

realtivereactivity << 1 1 500 40,000 2,000,000

Increasing reactivity in the SN2 reaction

Vinyl and aryl halides do not react in nucleophilc substitution reactions

X

R1R2

R3+ Nu:

R1

NuR2

R3XX

+ Nu: XNu

X

R1R2

R3+ (CH3)2CuLi

CH3

R1R2

R3 From Chapter 10: NOT a nucleophilcsubstitution 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-CH3 + Br -

Nu = H2O relative reactivity= 1CH3CO2

- 500NH3 700Cl- 1,000HO- 16,000CH3O- 25,000I- 100,000N≡C- 125,000HS- 125,000

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Nucleophiles are Lewis bases

Nucleophilicity roughly parallels basicity when comparing nucleophilesthat have the same attacking atom

Nu: CH3O- HO- CH3CO2- H2O

relative reactivity: 25,000 16,000 500 1pKa of the conj. acid: 15.5 15.7 4.7 -1.7

Nucleophilicity usually increases going down a column of the periodicchart. Thus, sulfur nucleophiles are more reactive than oxygennucleophiles. I- > Br- > Cl-.

Negatively charges nucleophiles are usually more reactive than neutralnucleophiles.

The role of the leaving group in SN2 reactions:

C XH

HHNu _

CNuH

HH X _

C XH

HHNu _ CHO

H

HH

+ X

+

+

The leaving group is usually displaced with a negative chargeThe 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.

7

HO-, H2N-, RO- F- Cl- Br- I- TosO-

<<1 1 200 10,000 30,000 60,000

>15 3.45 -7.0 -8.0

LG:

Relative Reactivity:

Increasing reactivity in the SN2 reaction

pKa:

C XH

HHNu _

CNuH

HH X _+C X

H

HHNud- d- ‡

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

pKa ofH3O+= -1.7C O

H

HH

Nu _

CNuH

HH

+H

H+ OH2C OH

HH

HH+

The role of the solvent in SN2 reactions:Descriptor 1:

polar: “high” dipole moment

non-polar: low dipole moment (hexanes)

Descriptor 2:protic: acidic hydrogens that can form hydrogen bonds

(water, alcohols)aprotic: no acidic hydrogens

H HO S

O

+

_

d +

d _

d + R HOd _

d +

water alcohols DMSO

SO

+

_

DMSO

[(CH3)2N]3P O_+

hexamethylphosphoramide(HMPA)

CH3C N

acetonitrile

H N

OCH3

CH3

dimethylformamide(DMF)

8

Solvation: solvent molecules form “shells” around reactants anddramatically influence their reactivity.

X_

HH

O

d _H

HO

HH

O

H

HO

H

HO

HH O

HH

O

d _

d _

d _

d +

d +

d +

d +

d +Y+

H

HOH

HO

HH O

H

HO

H

HOH

H O d +d +

d +

d +

d +

d +

d _

d _d _

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 + N3- CH3CH2CH2CH2CH2Br + Br-

Solvent: CH3OH H2O DMSO DMF CH3CN HMPArelativereativity: 1 7 1,300 2,800 5,000 200,000

DE‡ DE‡

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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 expression-changing the nucleophile concentration does not affectthe rate of the reaction!

Must be a two-step reaction

The overall rate of a reaction is dependent upon the sloweststep: rate-limiting step

The Mechanism of the SN1 Reaction

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step 1

DG‡step 2

DG‡ˇstep 1 >> DG‡

step 2DG‡ˇ

step 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.

CH

HR

Primary (1°)

CR

HR

Secondary (2°)

CR

RR

Tertiary (3°)< <

+ + +

<C

CC +

Allylic

+CH

HH +

Methyl Benzylic _~_~

Increasing carbocation stability

The order of reactivity of the alkyl halide in the SN1 reactionexactly parallels the carbocation stability

11

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 willundergo SN1 substitution to give a racemic product

CH2CH2CH2CH3

Cl

H3CH2CH3C

H2O

CH2CH2CH2CH3H3C

H3CH2C

Carbocation is achiral

OH2

OH2

CH2CH2CH2CH3

OH

H3CH2CH3C

CH2CH2CH2CH3

OH

H3CH2CH3C

enantiomers: produced in equal amount

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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

C OR

RR H

H+C OR

RR

HH+ -H2O

RCRR

+C Nu

R

RR

Nu:

The role of the nucleophile in SN1 reactions: NoneInvolvement 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 reactionprotic solvents are favored over aprotic for the SN1 reaction

Solvent polarity is measured by dielectric constant (e)

Hexane e = 1.9(CH3CH2)2O 4.3HMPA 30DMF 38DMSO 48CH3CH2OH 24CH3OH 34H2O 80

protic

aprotic

nonpolar

polar

13

C ClCH3

CH3

H3C + ROH C ORCH3

CH3

H3C + HCl

Solvent: Ethanol 40% H2O 80% H2O H2O60% Ethanol 20% Ethanol

Rel. reactivity: 1 100 14,000 100,000

Increasing reactivity in the SN1 reaction

CR

RR

Cl CR

RRCld _d +

H

H O

H HO

H

HO

HH O

H

HO

H

HO

‡

sp3

tetrahedral

Solvent stablization of the intermediates

Solvent stablization of the transition state

Cl_

HH

O

H

HO

HH

O

H

HO

d +

d +

d +

d +C+ H

HO

H

HO

H

HOH

H O

H

HO

HH

O

d _d _

d _

d _

d _

d _

sp2

trigonal planar

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

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Elimination Reactions: Nucleophiles are Lewis bases. In the reactionwith alkyl halides, they can also promote elimination reactionsrather than substitution.

C C:R_

R

X

1° alkylhalide

SN2C CR CH2R

C C:R

XR

H RH_ elimination

HHR

H R

2° alkylhalide

Elimination is a competitive reaction with nucleophilic substitution.

Zaitsev’s Rule: When more than one alkene product is possiblefrom the base induced elimination of an alkyl halide, the most highly substituted (most stable) alkene is usually themajor product.

CH3CH2CBr

CH3H

CH3CH2O - Na+

CH3CH2OHC C

H3CH2C

H CH3

HC C

H3CH2C

H H

CH3

C CH3CH2CH2C

H H

H+ +

CH3CH2CBr

CH3CH3

CH3CH2O - Na+

CH3CH2OHC C

H3CH2C

H CH3

CH3

+ C CH3CH2CH2C

H3C H

H

81% 19%

70% 30%

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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

Syn periplanar:the H and X are eclipsed

dihedral angle = 0 °

Anti periplanar:the H and X areanti staggered

dihedral angle = 180 °

XH

X

HXH

X

H

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

16

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

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

Ph

HH

BrPh

Br BrBr

H PhH

Ph

meso anti periplanar

B:

H

BrH

BrPh

Ph

Br

H PhH

PhBr

Ph

Br

H

H

PhBr

will becis on the

alkene

will becis on the

alkene

H

Ph

Br

Ph

syn periplanar

will becis on the

alkenewill be

cis on thealkene

Ph

H

Br

Ph

E

Z

Anti periplanar geometry is usually preferred for E2 elimination

favored

17

E2 elimination with halocyclohexane reactants

18

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

No geometric requirements for E1 elimination. Usually follows Zaitsev’s Rule

19

SN2 vs E2

For primary alkyl halides SN2 is favored with most nucleophiles

E2 is favored with “bulky” bases (t-butoxide)

CCH3

CH3

H3C O_

CCH3

CH3

H3C O_ C X

H

C

HC

H

C

HCCH3

CH3

H3C OXHH

HH

C XH

C

H

HH

CCH3

CH3

H3C O_

SN2

E2 CC

HH

H+ C

CH3

CH3

H3C OH

t-butoxide is too bulky to undergo SN2

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 asH2O 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