Chapter 11: Nucleophilic Substitution and Elimination Walden Inversion

O PCl5 HO HO OH OH O OH O Cl ()-(-) Malic (+)-2-Chlorosuccinic acid [a]= -2.3 °

Ag2O, H2O Ag2O, H2O O O HO PCl5 OH HO OH O OH O Cl ()-(+) Malic acid (-)-2-Chlorosuccinic acid [a]D= +2.3 °

The displacement of a in a nucleophilic has a defined

Stereochemistry of nucleophilic substitution

p-toluenesulfonate (tosylate): converts an into a leaving group; tosylate are excellent leaving groups. abbreviates as Tos

C Nu + X- Nu: X= Cl, Br,

O Cl S O O + C OH C O S CH3 O

CH3 tosylate O -O S O O Nu C + Nu: C O S CH3 O

CH3

1 O

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

[a]D= +33.0 [a]D= +31.1 [a]D= -7.06

HO- HO-

O

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

[a]D= -7.0 [a]D= -31.0 [a]D= -33.2

The nucleophilic substitution reaction “inverts” the Stereochemistry of the ()- 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)

H H Consider: HO C _ _ C Br Br HO H H H H At a given temperature: If [OH-] is doubled, then the 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 ()

2 H H HO C _ _ C Br Br HO H H H H

Reaction rates (kinetic) can be expressed mathematically: reaction rate = disappearance of reactants (or appearance of products)

For the disappearance of reactants: - rate = [CH3Br] [OH ] [CH3Br] = CH3Br concentration [OH-] = OH- concentration k= constant (rate constant) mol•sec 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 SN1

S= substitution S= substitution = nucleophilic N= nucleophilic 2= biomolecular 1= unimolecular

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

3 The SN2 Reaction: Mechanism

Steric effects in the SN2 reaction: • For an SN2 reaction, the 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.

4 Increasing reactivity in the SN2 reaction

CH3 CH3 CH3 CH3 H

H3C C Br < H3C C CH2 Br < H3C C Br < H C Br < H C Br CH3 CH3 H H H

neopentyl primary methyl realtive reactivity << 1 1 500 40,000 2,000,000

Vinyl and aryl halides do not react in nucleophilc substitution reactions

X Nu

R3 X R3 R1 + Nu: + Nu: R R X R2 Nu 2 1 X

R3 X R3 CH3 From Chapter 10: + (CH3)2CuLi NOT a nucleophilc

R2 R1 R2 R1 substitution reaction

The nature of the nucleophile in the SN2 Reaction: The measure of nucleophilicity is imprecise.

_ _ Anionic Nu: + R-X Nu-R + X:

+ _ Neutral Nu: + R-X Nu-R + X:

- Nu + H3C-Br Nu-CH3 + Br

Nu = H2O relative reactivity= 1 - CH3CO2 500 NH3 700 Cl- 1,000 HO- 16,000 - CH3O 25,000 I- 100,000 N≡C- 125,000 HS- 125,000

5 are Lewis bases

Nucleophilicity roughly parallels basicity when comparing nucleophiles that have the same attacking

- - - Nu: CH3O HO CH3CO2 H2O relative reactivity: 25,000 16,000 500 1 pKa of the conj. acid: 15.5 15.7 4.7 -1.7

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

Negatively charges nucleophiles are usually more reactive than neutral nucleophiles.

The role of the leaving group in SN2 reactions:

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

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

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

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

6 ‡ H d- H d- H Nu C _ _ C X Nu C X + X Nu H H H H H H

Increasing reactivity in the SN2 reaction

------LG: HO , H2N , RO Cl Br I TosO

Relative <<1 1 200 10,000 30,000 60,000 Reactivity: pKa: >15 3.45 -7.0 -8.0

Charged Leaving Groups: conversion of a poor leaving group to a good one Nu _ H + H H H + pKa of C O H C O H Nu C + OH2 + H H H H H O = -1.7 H H H 3

The role of the in SN2 reactions: 1: polar: “high” dipole moment _ d _ d _ O + O + O + S d H H d R H d + DMSO non-polar: low dipole moment (hexanes)

Descriptor 2: protic: acidic that can form bonds (water, alcohols) aprotic: no acidic hydrogens O + _ _ O CH3 [(CH3)2N]3P O C N H N S 3 + CH3 hexamethylphosphoramide DMSO acetonitrile dimethylformamide (HMPA) (DMF)

7 : solvent form “shells” around reactants and dramatically influence their reactivity.

H H + d + O d O H H _ H O d d + H H H O _ H H O d + _ H d + _ d + _ d _ d H d _ d + H + d O H X H O d O O H + H + H + H d H d d + H H O d _ O O d H H O d _ H H

Polar protic stabilize the nucleophile, thereby lowering its energy. This will raise the 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 HMPA relative reativity: 1 7 1,300 2,800 5,000 200,000

DE‡ DE‡

8 The SN1 Reaction: kinetics: first order reaction (unimolecular) rate = k [R-X] [R-X]= halide conc.

The nucleophile does not appear in the rate expression- changing 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

9 ‡ DG step 2

step 1

‡ˇ ‡ DG step 1 >> DG step 2 ‡ˇ DG step 1 is rate-limiting

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

H H + H R + C H C R C + R C + R C + C C + H H R R

Methyl < 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 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 . A chiral alkyl halide will undergo SN1 substitution to give a racemic product

OH2

Cl H2O H3C H3C CH2CH2CH2CH3 CH2CH2CH2CH3 H3CH2C H3CH2C

OH2 Carbocation is achiral OH

H3C CH2CH2CH2CH3 H3CH2C enantiomers: produced in equal amount H3CH2C CH2CH2CH2CH3 H3C OH

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 R H + -H2O R + Nu: C O H C O H C R C Nu R R H R R R R 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 ()

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

12 CH3 CH3 + HCl + ROH H3C C OR H3C C Cl CH3 CH3

Solvent: 40% H2O 80% H2O H2O 60% Ethanol 20% Ethanol Rel. reactivity: 1 100 14,000 100,000

Increasing reactivity in the SN1 reaction

H ‡ H H d _ O H H d _ O + H O H O H d H H R R _ H d _ + O d + d _ O H d _ d + C Cl H C Cl H O H d C H O H Cl H O R O + _ R H R R d O H _ H H H d O d + H H O H O sp3 O H O H H H H tetrahedral H sp2 trigonal planar Solvent stablization of Solvent stablization of the 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 SN2 _ R C C CH R R C C: 2 X

1° alkyl halide

_ H H R R C C: H R elimination

R H R X H 2° alkyl halide

Elimination is a competitive reaction with nucleophilic substitution.

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

H CH H3C H Br CH CH O - Na+ 3 3 2 C C + C C H CH C C CH 3 2 3 H CH CH C H CH3CH2OH H3CH2C CH3 3 2 2 CH3 81% 19%

Br - + H CH H H H H CH3CH2O Na 3 + H3CH2C C CH3 C C + C C C C CH3CH2OH H H3CH2C H H3CH2C CH3 H3CH2CH2C H

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

H XH

X

Syn periplanar: Anti periplanar: the H and X the H and X are are eclipsed anti staggered dihedral angle = 0 ° 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:

B: H H H H H Ph will be H Ph will be Br H cis on the cis on the Br Br Br Ph Ph Br alkene Br alkene Ph Ph Br Ph Ph meso anti periplanar E favored

Br Br Ph H Br H

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

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 Zaitsev’s Rule

18 SN2 vs E2

For primary alkyl halides SN2 is favored with most nucleophiles

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

CH 3 _ H C C O 3 t-butoxide is too bulky to undergo SN2 CH3

H S 2 CH H CH C N 3 C 3 H _ C X H C C O C H H C C O 3 3 H X H H CH3 H CH3

H E2 H CH3 CH3 C C _ H + H3C C OH H C C O C X C 3 H H H CH H 3 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

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