8.3 The S N 2 Mechanism of Nucleophilic Substitution

Many nucleophilic substitutions follow a second-order rate law. CH 3 Br + HO –  CH 3 OH + Br – rate = k[CH 3 Br][HO – ] inference: rate-determining step is bimolecular Kinetics

HO – CH 3 Br + HOCH 3 Br – + one step concerted Bimolecular mechanism

HO – CH 3 Br + HOCH 3 Br – + one step concerted Bimolecular mechanism

HO – CH 3 Br + HOCH 3 Br – + one step concerted HO CH 3 Br  transition state Bimolecular mechanism

8.4 Stereochemistry of S N 2 Reactions

Nucleophilic substitutions that exhibit second-order kinetic behavior are stereospecific and proceed with inversion of configuration. Generalization

nucleophile attacks carbon from side opposite bond to the leaving group Inversion of Configuration

nucleophile attacks carbon from side opposite bond to the leaving group three-dimensional arrangement of bonds in product is opposite to that of reactant Inversion of Configuration

A stereospecific reaction is one in which stereoisomeric starting materials give stereoisomeric products. The reaction of 2-bromooctane with NaOH (in ethanol-water) is stereospecific. (+)-2-Bromooctane  (–)-2-Octanol (–)-2-Bromooctane  (+)-2-Octanol Stereospecific Reaction

CH CH 3 Br CH 3 (CH 2 ) 5 CH CH 3 HO (CH 2 ) 5 CH 3 NaOH (S)-(+)-2-Bromooctane (R)-(–)-2-Octanol Stereospecific Reaction

The Fischer projection formula for (+)-2-bromooctane is shown. Write the Fischer projection of the (–)-2-octanol formed from it by nucleophilic substitution with inversion of configuration. Problem 8.4

H Br CH 3 CH 2 (CH 2 ) 4 CH 3 The Fischer projection formula for (+)-2-bromooctane is shown. Write the Fischer projection of the (–)-2-octanol formed from it by nucleophilic substitution with inversion of configuration. HOH CH 3 CH 2 (CH 2 ) 4 CH 3 Problem 8.4

8.5 How S N 2 Reactions Occur

: Br C H.... –.... HO CH 3 (CH 2 ) 5 H3CH3CH3CH3C

: Br C H.... –.... HO C H Br  –.... HO :.... CH 3 (CH 2 ) 5 H3CH3CH3CH3C CH 3

: Br C H.... –.... HO C H Br  –.... HO :.... C H HO.... –.... : Br CH 3 (CH 2 ) 5 H3CH3CH3CH3C (CH 2 ) 5 CH 3 CH 3 (CH 2 ) 5 CH 3

8.6 Steric Effects in S N 2 Reactions

The rate of nucleophilic substitution by the S N 2 mechanism is governed by steric effects. Crowding at the carbon that bears the leaving group slows the rate of bimolecular nucleophilic substitution. Crowding at the Reaction Site

RBr + LiI  RI + LiBr AlkylClassRelative bromiderate CH 3 BrMethyl221,000 CH 3 CH 2 BrPrimary1,350 (CH 3 ) 2 CHBrSecondary1 (CH 3 ) 3 CBrTertiarytoo small to measure Table 8.2 Reactivity toward substitution by the S N 2 mechanism

CH 3 Br CH 3 CH 2 Br (CH 3 ) 2 CHBr (CH 3 ) 3 CBr Decreasing S N 2 Reactivity

CH 3 Br CH 3 CH 2 Br (CH 3 ) 2 CHBr (CH 3 ) 3 CBr Decreasing S N 2 Reactivity

The rate of nucleophilic substitution by the S N 2 mechanism is governed by steric effects. Crowding at the carbon adjacent to the one that bears the leaving group also slows the rate of bimolecular nucleophilic substitution, but the effect is smaller. Crowding Adjacent to the Reaction Site

RBr + LiI  RI + LiBr AlkylStructureRelative bromiderate EthylCH 3 CH 2 Br1.0 PropylCH 3 CH 2 CH 2 Br0.8 Isobutyl(CH 3 ) 2 CHCH 2 Br0.036 Neopentyl(CH 3 ) 3 CCH 2 Br Table 8.3 Effect of chain branching on rate of S N 2 substitution