1 A little organic chemistry

Nucleophilic Substitution substitution reaction

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

Nucleophilic Substitution Two mechanisms general: Rate = k 1 [RX] + k 2 [RX][Y – ] RX =CH 3 X1º2º3º k 1 increases k 2 increases k 1 ~ 0 Rate = k 2 [RX][Y – ] (bimolecular) S N 2 k 2 ~ 0 Rate = k 1 [RX] (unimolecular) S N 1

S N 2 Mechanism Kinetics e.g., CH 3 I + OH –  CH 3 OH + I – find: Rate = k[CH 3 I][OH – ], i.e., bimolecular  both CH 3 I 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: CH 3 I + OH – CH 3 OH + I – [HO---CH 3 ---I] –

S N 2 Mechanism

Steric effects e.g., R–Br + I –  R–I + Br – 1. branching at the  carbon( X–C–C–C.... )  CompoundRel. Rate methylCH 3 Br150 1º RXCH 3 CH 2 Br1 2º RX(CH 3 ) 2 CHBr º RX(CH 3 ) 3 CBr~0 increasing steric hindrance

S N 2 Mechanism Steric effects 1. branching at the  carbon minimal steric hindrance maximum steric hindrance

S N 2 Mechanism Steric effects branching at the  carbon  Reactivity toward S N 2: CH 3 X > 1º RX > 2º RX >> 3º RX react readily by S N 2 (k 2 large) more difficult does not react by S N 2 (k 2 ~ 0)

S N 2 Mechanism Steric effects branching at the  carbon Rel. Rate increasing steric hindrance ~ no S N 2 with very hindered substrates

S N 2 Mechanism Nucleophiles and nucleophilicity Summary: very good Nu:I –, HS –, RS –, H 2 N – good Nu:Br –, HO –, RO –, CN –, N 3 – fair Nu:NH 3, Cl –, F –, RCO 2 – poor Nu:H 2 O, ROH very poor Nu:RCO 2 H

Nucleophilic Substitution Leaving groups reactivity: R-I > R-Br > R-Cl >> R-F best L.G. most reactive worst L.G. least reactive precipitate drives rxn (Le Châtelier)

S N 2 Mechanism Question. Which reaction will proceed faster in each of the following pairs? What will be the product?

S N 1 Mechanism Kinetics e.g., 3º, no S N 2 Find: Rate = k[(CH 3 ) 3 CBr]unimolecular  RLS depends only on (CH 3 ) 3 CBr

S N 1 Mechanism Kinetics

S N 1 Mechanism Kinetics Two-step mechanism: RBr + CH 3 OH R+R+ ROCH 3 + HBr

S N 1 Mechanism Carbocation stability R + stability: 3º > 2º >> 1º > CH 3 + R-X reactivity toward S N 1: 3º > 2º >> 1º > CH 3 X CH 3 + 1º R + 2º R + 3º R +

S N 1 Mechanism Question. Which of the following compounds will react fastest by S N 1? Which by S N 2? A. B.

S N 1 vs S N 2 Solvent effects nonpolar:hexane, benzene moderately polar:ether, acetone, ethyl acetate polar protic:H 2 O, ROH, RCO 2 H polar aprotic:DMSODMFacetonitrile S N 1 mechanism promoted by polar protic solvents stabilize R +, X – relative to RX RX R+X–R+X– in less polar solvents in more polar solvents

S N 1 vs S N 2 Solvent effects S N 2 mechanism promoted by moderately polar & polar aprotic solvents destabilize Nu –, make them more nucleophilic e.g., OH – in H 2 O: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 H 2 O

S N 1 vs S N 2 Summary RX =CH 3 X1º2º3º rate of S N 1 increases(carbocation stability) rate of S N 2 increases(steric hindrance) react primarily by S N 2 (k 1 ~ 0, k 2 large) reacts primarily by S N 1 (k 2 ~ 0, k 1 large) may go by either mechanism S N 2 promoted good nucleophile (Rate = k 2 [RX][Nu]) -usually in polar aprotic solvent S N 1 occurs in absence of good nucleophile (Rate = k 1 [RX]) -usually in polar protic solvent (solvolysis) Rate = k 1 [RX] + k 2 [RX][Nu]

S N 1 vs S N 2 Question. What would be the predominant mechanism in each of the following reactions? What would be the product?