1

A little organic chemistry

SH S

Nucleophilic Substitution

R X Y R Y X

H O CH3 Br CH3 OH Br

+ +

substrate nucleophile product leavinggroup

+

e.g.,

substitutionreaction

Nucleophilic SubstitutionQuestion. Identify the substrate, nucleophile, leaving group and product for each.

CH3Br + NaOH

Br + CH3S-

Br + CN-

Nucleophilic SubstitutionTwo mechanisms

general: Rate = k1[RX] + k2[RX][Y–]

RX = CH3X 1º 2º 3º

k1 increases

k2 increases

k1 ~ 0

Rate = k2[RX][Y–](bimolecular)

SN2

k2 ~ 0

Rate = k1[RX](unimolecular)

SN1

SN2 MechanismKinetics

e.g., CH3I + OH– CH3OH + I–

find: Rate = k[CH3I][OH–], i.e., bimolecular

both CH3I and OH– involved in RLS

and recall, reactivity: R-I > R-Br > R-Cl >> R-F

C-X bond breaking involved in RLS

concerted, single-step mechanism:

CH3I + OH–

CH3OH + I–

[HO---CH3---I]–

SN2 Mechanism

SN2 MechanismSteric effects

e.g., R–Br + I– R–I + Br–

1. branching at the carbon ( X–C–C–C.... )

Compound Rel. Rate

methyl CH3Br 150

1º RX CH3CH2Br 1

2º RX (CH3)2CHBr 0.008

3º RX (CH3)3CBr ~0

increasingsteric hindrance

SN2 MechanismSteric effects

1. branching at the carbon

C Br

H

HH

I

H C

H

C Br

CHH

H

H

H

H

CHI

minimal steric hindrance

maximum steric hindrance

SN2 MechanismSteric effects

branching at the carbon

Reactivity toward SN2:

CH3X > 1º RX > 2º RX >> 3º RX

reactreadilyby SN2

(k2 large)

moredifficult

does notreact by

SN2(k2 ~ 0)

SN2 MechanismSteric effects

branching at the carbon

CH3 CH2 CH2 Br

CH3 CH CH2 Br

CH3

CH3 C CH2 Br

CH3

CH3

Rel. Rate

1

0.003

0.00001

increasingsteric

hindrance

~ no SN2 with very hindered substrates

SN2 MechanismNucleophiles and nucleophilicity

Summary:very good Nu: I–, HS–, RS–, H2N–

good Nu: Br–, HO–, RO–, CN–, N3–

fair Nu: NH3, Cl–, F–, RCO2–

poor Nu: H2O, ROHvery poor Nu: RCO2H

Nucleophilic SubstitutionLeaving groups

++ XR YYR Xstronger

baseweaker

base

K > 1

Br F+ NaF + NaBr

SB WB

Br I+ NaI + NaBr (s)

WB SB

acetone

reactivity: R-I > R-Br > R-Cl >> R-Fbest L.G.

most reactiveworst L.G.

least reactive

precipitatedrives rxn(Le Châtelier)

SN2 Mechanism

Question. Which reaction will proceed faster in each of the following pairs?What will be the product?

ClNaN3

NaN3I

Br

Br

NaCN

I

I

NaOH

NaOH

NaCN

Br

Br

NaSH

NaOH

SN1 MechanismKinetics

C

CH3

H3C

CH3

Br CH3OH CH3C

CH3

CH3

O CH3 HBr+ +e.g.,

3º, no SN2

Find: Rate = k[(CH3)3CBr] unimolecular

RLS depends only on (CH3)3CBr

SN1 MechanismKinetics

C

CH3

H3C

CH3

Br

CH3C

CH3

CH3

O CH3 HBr+

RLS: C

CH3

H3C

CH3

+ Br

C

CH3

H3C

CH3

HOCH3 C

CH3

H3C

CH3

O

H

CH3

C

CH3

H3C

CH3

O

H

CH3

-H+

SN1 MechanismKinetics

Two-step mechanism:

RBr + CH3OH

R+

ROCH3 + HBr

SN1 MechanismCarbocation stability

R+ stability: 3º > 2º >> 1º > CH3+

R-X reactivity toward SN1: 3º > 2º >> 1º > CH3X

CH3+

1º R+

2º R+

3º R+

SN1 Mechanism

Question. Which of the following compounds will react fastest by SN1? Which by SN2?

BrBr

Br

BrBr

Br

A.

B.

SN1 vs SN2Solvent effects

nonpolar: hexane, benzenemoderately polar: ether, acetone, ethyl acetate

polar protic: H2O, ROH, RCO2Hpolar aprotic: DMSO DMF acetonitrile

CH

O

N(CH3)2

CH3 C NCH3

S

O

CH3

SN1 mechanism promoted by polar protic solvents

stabilize R+, X– relative to RX

RX

R+X–

in less polar solventsin more polar solvents

SN1 vs SN2Solvent effects

SN2 mechanism promoted by moderately polar & polar aprotic solvents

destabilize Nu–, makethem more nucleophilic

e.g., OH– in H2O: strong H-bonding to water makes OH– less reactive

OH– in DMSO: weaker solvation makes OH– more reactive (nucleophilic)

RX + OH–

ROH + X–

in DMSO

in H2O

SN1 vs SN2Summary

RX = CH3X 1º 2º 3º

rate of SN1 increases (carbocation stability)

rate of SN2 increases (steric hindrance)

reactprimarilyby SN2

(k1 ~ 0, k2 large)

reactsprimarilyby SN1

(k2 ~ 0, k1 large)

may goby either

mechanism

SN2 promoted good nucleophile (Rate = k2[RX][Nu])-usually in polar aprotic solvent

SN1 occurs in absence of good nucleophile (Rate = k1[RX])-usually in polar protic solvent (solvolysis)

Rate = k1[RX] + k2[RX][Nu]

SN1 vs SN2

Question. What would be the predominant mechanism in each of the following reactions? What would be the product?

Br H2O

Br CH3OH

BrNaSCH3

DMF

Br

KCNDMSO