Chapter 8: Nucleophilic Substitution Chem 331, Chapter 8 Chapter 8: Nucleophilic Substitution The SN2 Reaction

Nucleophilic Substitution Functional group transformation Leaving groups Two mechanisms SN2 Mechanism Kinetics Stereochemistry Mechanism Steric effects Nucleophiles and nucleophilicity SN1 Mechanism Carbocation stability Solvent effects Substitution vs Elimination Substitutions of Alcohols Sulfonate esters Reaction with HX Chem 331, Chapter 8

I. Nucleophilic Substitution Chem 331, Chapter 8 I. Nucleophilic Substitution substitution reaction

I. Nucleophilic Substitution Chem 331, Chapter 8 I. Nucleophilic Substitution A. Functional group transformation

I. Nucleophilic Substitution Chem 331, Chapter 8 I. Nucleophilic Substitution B. Leaving groups weaker base = better leaving group reactivity: R-I > R-Br > R-Cl >> R-F best L.G. most reactive worst L.G. least reactive precipitate drives rxn (Le Châtelier)

I. Nucleophilic Substitution Chem 331, Chapter 8 I. Nucleophilic Substitution C. Two mechanisms general: Rate = k1[RX] + k2[RX][Y–] k1 increases RX = CH3X 1º 2º 3º k2 increases k1 ~ 0 Rate = k2[RX][Y–] (bimolecular) SN2 k2 ~ 0 Rate = k1[RX] (unimolecular) SN1

II. SN2 Mechanism A. Kinetics e.g., CH3I + OH–  CH3OH + I– Chem 331, Chapter 8 II. SN2 Mechanism A. Kinetics 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: [HO---CH3---I]– CH3I + OH– CH3OH + I–

II. SN2 Mechanism B. Stereochemistry: inversion of configuration Chem 331, Chapter 8 II. SN2 Mechanism B. Stereochemistry: inversion of configuration Stereospecific reaction: (R)-(–)-2-bromooctane (S)-(+)-2-octanol Reaction proceeds with inversion of configuration.

II. SN2 Mechanism C. Mechanism Back-side attack: Chem 331, Chapter 8 II. SN2 Mechanism C. Mechanism Back-side attack: inversion of configuration sp3 sp2 high energy TS sp3

II. SN2 Mechanism D. Steric effects e.g., R–Br + I–  R–I + Br– Chem 331, Chapter 8 II. SN2 Mechanism D. Steric effects e.g., R–Br + I–  R–I + Br– 1. branching at the a carbon ( X–C–C–C.... ) a b g Compound Rel. Rate methyl CH3Br 150 1º RX CH3CH2Br 1 2º RX (CH3)2CHBr 0.008 3º RX (CH3)3CBr ~0 increasing steric hindrance

II. SN2 Mechanism D. Steric effects 1. branching at the a carbon Chem 331, Chapter 8 II. SN2 Mechanism D. Steric effects 1. branching at the a carbon minimal steric hindrance - methyl bromide maximum steric hindrance – tert-butyl bromide

II. SN2 Mechanism D. Steric effects 1. branching at the a carbon Chem 331, Chapter 8 II. SN2 Mechanism D. Steric effects 1. branching at the a carbon Reactivity toward SN2: CH3X > 1º RX > 2º RX >> 3º RX react readily by SN2 (k2 large) more difficult does not react by SN2 (k2 ~ 0)

II. SN2 Mechanism D. Steric effects 2. branching at the b carbon Chem 331, Chapter 8 II. SN2 Mechanism D. Steric effects 2. branching at the b carbon Rel. Rate 1 0.003 0.00001 increasing steric hindrance ~ no SN2 with neopentyl substrates

II. SN2 Mechanism E. Nucleophiles and nucleophilicity anions Chem 331, Chapter 8 II. SN2 Mechanism E. Nucleophiles and nucleophilicity anions neutral species solvolysis reactions hydrolysis alcoholysis

II. SN2 Mechanism E. Nucleophiles and nucleophilicity nucleophilicity Chem 331, Chapter 8 II. SN2 Mechanism E. Nucleophiles and nucleophilicity nucleophilicity charged species are more nucleophilic than neutral species when nucleophilic atoms are in the same row, nucleophilicity follows basicity when nucleophilic atoms are in the same column, nucleophilicity follows ionic radius (polarizability) HO– > H2O RO– > ROH HS– > H2S H2N– > HO– > F– H3N > H2O RO– > RCO2– I– > Br– > Cl– > F– HS– > HO– PH3 > NH3

II. SN2 Mechanism E. Nucleophiles and nucleophilicity Summary: Chem 331, Chapter 8 II. SN2 Mechanism E. Nucleophiles 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, ROH very poor Nu: RCO2H

Chem 331, Chapter 8 II. SN2 Mechanism Which reaction will proceed faster in each of the following pairs? What will be the product?

III. SN1 Mechanism A. Kinetics e.g., 3º, no SN2 Chem 331, Chapter 8 III. SN1 Mechanism A. Kinetics e.g., 3º, no SN2 Find: Rate = k[(CH3)3CBr] unimolecular  RLS depends only on (CH3)3CBr

Chem 331, Chapter 8 III. SN1 Mechanism A. Kinetics

III. SN1 Mechanism A. Kinetics Two-step mechanism: R+ RBr + CH3OH Chem 331, Chapter 8 III. SN1 Mechanism A. Kinetics Two-step mechanism: R+ RBr + CH3OH ROCH3 + HBr

III. SN1 Mechanism B. Stereochemistry: stereorandom Chem 331, Chapter 8 III. SN1 Mechanism B. Stereochemistry: stereorandom

III. SN1 Mechanism C. Carbocation stability Chem 331, Chapter 8 III. SN1 Mechanism C. Carbocation stability R+ stability: 3º > 2º >> 1º > CH3+ R-X reactivity toward SN1: 3º > 2º >> 1º > CH3X CH3+ 1º R+ 2º R+ 3º R+

III. SN1 Mechanism C. Carbocation stability Rearrangements possible: Chem 331, Chapter 8 III. SN1 Mechanism C. Carbocation stability Rearrangements possible:

Chem 331, Chapter 8 III. SN1 Mechanism Which of the following compounds will react fastest by SN1? Which by SN2?

IV. SN1 vs SN2 A. Solvent effects nonpolar: hexane, benzene Chem 331, Chapter 8 IV. SN1 vs SN2 A. Solvent effects nonpolar: hexane, benzene moderately polar: ether, acetone, ethyl acetate polar protic: H2O, ROH, RCO2H polar aprotic: DMSO DMF acetonitrile SN1 mechanism promoted by polar protic solvents stabilize R+, X– relative to RX in less polar solvents in more polar solvents R+X– RX

them more nucleophilic Chem 331, Chapter 8 IV. SN1 vs SN2 A. Solvent effects SN2 mechanism promoted by moderately polar & polar aprotic solvents destabilize Nu–, make them 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) in DMSO in H2O RX + OH– ROH + X–

IV. SN1 vs SN2 RX = CH3X 1º 2º 3º B. Summary Chem 331, Chapter 8 IV. SN1 vs SN2 Rate = k1[RX] + k2[RX][Nu] B. Summary rate of SN1 increases (carbocation stability) RX = CH3X 1º 2º 3º rate of SN2 increases (steric hindrance) react primarily by SN2 (k1 ~ 0, k2 large) may go by either mechanism reacts primarily by SN1 (k2 ~ 0, k1 large) 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)

Chem 331, Chapter 8 IV. SN1 vs SN2 What would be the predominant mechanism in each of the following reactions? What would be the product?

V. Substitution vs Elimination Chem 331, Chapter 8 V. Substitution vs Elimination A. Unimolecular or bimolecular reaction? (SN1, E1) (SN2, E2) Rate = k1[RX] + k2[RX][Nu or B] this term gets larger as [Nu or B] increases  bimolecular reaction (SN2, E2) favored by high concentration of good Nu or strong B this term is zero when [Nu or B] is zero  unimolecular reaction (SN1, E1) occurs in absence of good Nu or strong B

V. Substitution vs Elimination Chem 331, Chapter 8 V. Substitution vs Elimination B. Bimolecular: SN2 or E2? Rate = kSN2[RX][Nu] + kE2[RX][B] 1. substrate structure: steric hindrance decreases rate of SN2, has no effect on rate of E2  E2 predominates steric hindrance increases sterically hindered nucleophile

V. Substitution vs Elimination Chem 331, Chapter 8 V. Substitution vs Elimination B. Bimolecular: SN2 or E2? 2. base vs nucleophile stronger base favors E2 better nucleophile favors SN2 good Nu weak B good Nu strong B poor Nu strong B

V. Substitution vs Elimination Chem 331, Chapter 8 V. Substitution vs Elimination C. Unimolecular: SN1 or E1? for both, Rate = k[R+][H2O]  no control over ratio of SN1 and E1

V. Substitution vs Elimination Chem 331, Chapter 8 V. Substitution vs Elimination D. Summary 1. bimolecular: SN2 & E2 Favored by high concentration of good Nu or strong B good Nu, weak B: I–, Br–, HS–, RS–, NH3, PH3 favor SN2 good Nu, strong B: HO–, RO–, H2N– SN2 & E2 poor Nu, strong B: tBuO– (sterically hindered) favors E2 Substrate: 1º RX mostly SN2 (except with tBuO–) 2º RX both SN2 and E2 3º RX E2 only b-branching hinders SN2

V. Substitution vs Elimination Chem 331, Chapter 8 V. Substitution vs Elimination D. Summary 2. unimolecular: SN1 & E1 Occurs in absence of good Nu or strong B poor Nu, weak B: H2O, ROH, RCO2H Substrate: 1º RX SN1 and E1 (only with rearrangement) 2º RX 3º RX can’t control ratio of SN1 to E1 SN1 and E1 (may rearrange)

V. Substitution vs Elimination Chem 331, Chapter 8 V. Substitution vs Elimination

VI. Substitution of Alcohols Chem 331, Chapter 8 VI. Substitution of Alcohols Can’t substitute directly: R–OH + Y–  R–Y + OH– strong base, very poor leaving group when Y– is a stronger base than OH– R–O– + HY

VI. Substitution of Alcohols Chem 331, Chapter 8 VI. Substitution of Alcohols A. Review: reactions of ROH with HX R–OH + HX  R–X + H2O 1º ROH: SN2 3º ROH: SN1

VI. Substitution of Alcohols Chem 331, Chapter 8 VI. Substitution of Alcohols A. Review: reactions of ROH with HX 2º ROH: mixture of SN1 and SN2 26% racemization (SN1) 74% inversion (SN2) Rearrangements possible:

VI. Substitution of Alcohols Chem 331, Chapter 8 VI. Substitution of Alcohols B. Substitution via sulfonate esters Scheme:

VI. Substitution of Alcohols Chem 331, Chapter 8 VI. Substitution of Alcohols B. Substitution via sulfonate esters

VI. Substitution of Alcohols Chem 331, Chapter 8 VI. Substitution of Alcohols B. Substitution via sulfonate esters e.g., Formation of sulfonate esters occurs with retention of configuration:

VI. Substitution of Alcohols Chem 331, Chapter 8 VI. Substitution of Alcohols C. Other inorganic esters

VI. Substitution of Alcohols Chem 331, Chapter 8 VI. Substitution of Alcohols C. Other inorganic esters