Substitution and Elimination

Substitution and Elimination

Substitution and Elimination Reactions of Alkyl Halides Substitution, Nucleophilic, Bimolecular SN2 Nuc : C X Nuc C

X Nuc C transition state Rate = k[Nuc: ][R-X] Second Order Rate Kinetics + X Reaction Profile for SN2 Reaction (Wade) Stereochemistry of SN2 Reaction

Inversion of Configuration CN Br + (S) KCN + KBr (R) Proof of Inversion of Configuration at a Chiral Center CH2 benzyl (Bz) O

OCCH3 -OAc, acetate OH H Bz OTs TsCl CH3 (S)(-) []D = -33o CH3 CH3

(S) KOAc SO2Cl p-toluenesulfonyl chloride RO-H (Ts-Cl) O CH3 H Bz S O R O a tosylate (ROTs) H

Bz CH3 OH (R)(+) []D = +33o H 2O H Bz CH3 OAc (R) Acetate Approaches from 180

Behind Leaving Group Bz AcO H CH3 OTs (S) AcO Bz CH3 H

OTs o Bz AcO (R) H CH3 OTs Inversion on a Ring is often more Obvious: Cis Trans

Substrate Reactivity Since the energy of the transition state is significant in determining the rate of the reaction, a primary substrate will react more rapidly than secondary (which is much more rapid than tertiary). R Rate: ~0 Br + Cl R Cl + Br 6 1 500

40,000 (CH3)3CBr (CH3)3CCH2Br (CH3)2CHBr CH3CH2Br CH3Br tertiary neopentyl secondary

primary methyl 2 x 10 1 > 2 >> 3 Bulkiness of Substrate o o o Polar, Aprotic Solvents Solvents should be able to "cage" the metal cation O CH3SCH3

DMSO O O CH3CN HCN(CH3)2 CH3CCH3 acetonitrile DMF acetone Polar, protic solvents lower energy of nucleophile by solvation HOCH3 CH3OH Br

CH3OH HOCH3 Nucleophilicity Nucleophile strength roughly parallels basicity - - - - CH3 > NH2 > OH > F Nucleophile strength increases going down a group OH < SH

- - - - F < Cl < Br < I NH3 < PH3 A base is always a stronger nucleophile than its conjugate acid - NH2 > NH3 - OCH3 > CH3OH

Iodide vs. Fluoride as Nucleophiles Nucleophiles (preferably non-basic) basic - - non-basic - - -

- - - HS > :P(CH3)3 > CN > I > OCH3 > OH > Br > Cl > NH3 > OAc Good Leaving Groups are Weak Bases C LG bond is broken during RDS Quality of leaving groups is crucial Sulfonates are excellent leaving groups O CH3 SO

O O CH3SO tosylate O mesylate TsO- MsO- Common Leaving Groups TsO- = MsO- > NH 3- > I- > H2O- = Br- > Cl- >> F- Sulfonates are easily prepared from alcohols

O CH3OH + ClSR in pyridine O CH3OSR + HCl O O tosylate R = mesylate R = CH3 CH3 SN2 and E2 SN2

H R1 C R2 Nuc: C Br H Nuc R1 C R2 C

+ Br E2 H R1 C R2 C B: Br rate = k[R-Br][B -] R1 R2 C

C + B-H + Br Bimolecular Elimination - E2 Nucleophile acts as Bronsted Base Base: H C C C Br

+ base-H + Br -Elimination Base C H C C

Br SN2 Competes with E2 Depends on the Nature of the Nucleophile CH3CO2 Br CH3CHCH 3 wk. base CH3CH2O str. base Substitution OAc CH3CHCH 3 100%

CH2=CHCH 3 0% OEt CH3CHCH 3 CH2=CHCH 3 20% Elimination 80% SN2 Competes with E2 Depends on the Size of the Base CH3CH2O str. base

CH3CH2CH2CH2Br (CH3)3CO CH3CH2CH2CH2OEt 90% CH3CH2CH=CH2 10% CH3CH2CH2CH2OtBu CH3CH2CH=CH2 str. bulky base 85% 15% SN2 Competes with E2 Depends on the Nature of the Substrate CN CH3CH2CH2CH2Br

CH3CH2CH2CH2CN str. nuc.; wk. base o 100% SN2 1 (CH3)3CBr 3o CN CH2=C(CH3)2 100% E2 Stereochemistry of E2 rate = k[R-X][base] second order rate kinetics CH3O

H C C C Br H on carbon is anti to leaving group C + CH3OH + Br Anti-Coplanar Conformation

3(R),4(R) 3-Bromo-3,4dimethylhexane CH2CH3 Br CH3 NaOCH3 H CH3 in CH3OH heat CH2CH3

H and Br Anti-coplanar orientation CH3O H Me Et C C C Et Me (R) (R) Br Me Et

H Br Me Et Me C Et OCH3 Et Me Me Et

Et Me In a Cyclohexane, Leaving Group must be Axial KOC(CH 3)3 OTs in t-BuOH / + KOTs OTs OTs has no anti-coplanar H

H OtBu H Zaitsevs Rule NaOCH3 in CH3OH Br + 85% 15% Zaitsev's Rule: In an elimination reaction, the more highly substituted alkene (usually) predominate

More Stable Alkene Predominates Hyperconjugation bond associates with adjacent C-H bond 1-butene trans 2-butene C C C C mono-substituted disubstituted

With Bulky Base, Hofmann Product Forms Which will react more rapidly? CH3 Cl NaOEt in EtOH heat CH(CH3)2 Menthyl chloride CH3 Cl CH(CH3)2

Neomenthyl chloride NaOEt in EtOH heat Reactive Conformations Menthyl chloride (CH3)2CH Neomenthyl chloride Cl CH3 CH3 (CH3)2CH

Cl stable H H stable and reactive flip CH(CH3)2 NaOEt CH3 CH3 CH(CH3)2

CH(CH3)2 H NaOEt Cl reactive CH3 E2 Reaction of (R,R) 2-iodo-3-methylpentane I CH3CHCHCH2CH3 CH3 (R,R) CH3

H NaOCH2CH3 C in ethanol C CH3 CH2CH3 OR CH2=CHCHCH 2CH3 CH3

CH2CH3 H OR C CH3 C CH3 Stereochemistry is Important reactive conformation I H CH3

C C CH2CH3 CH3 OEt (R,R) H I H CH3

CH3 CH3CH2 C=C CH3 H CH3CH2 H CH3 E2 Reaction of a Vicinal Dibromide using Zn dust or Iodide Br

H CH3 H CH3 C C (R) (R) Br anti conformation Br H CH3 H

CH3 Br Zn HOAc CH3 CH3 C C H H only cis forms

Unimolecular Substitution and Elimination SN1 and E1 CH3 CH3 C Br in warm CH3OH CH3 Rate = k[R-Br] 1st order rate kinetics CH3 CH3

C CH3 SN1 CH3 OCH3 + C=CH2 CH3 + HBr E1 SN1 mechanism (Wade) st 1 step is rate determining Reaction Profiles (Wade)

SN 1 S N2 Hammonds Postulate Related species that are close in energy are close in structure. In an endothermic reaction, the transition state is similar to the product in structure and stability. In an exothermic reaction, the transition state is similar to the reactant in structure and stability. i.e. the structure of the transition state resembles the structure of the most stable species. Endo- transition state looks like product Exo- transition state looks like reactant SN1 Transition State

SN1 Solvent Effects CH3 CH3 C ROH Cl react.: 1 CH3 C

OR + HCl CH3 CH3 EtOH CH3 40% H2O / 60% EtOH 100 80% H2O / 20% EtOH 14,000 H2O

100,000 Transition state energy is lowered by polar protic solvents Partial Racemization in SN1 Carbocation Stability more highly substituted, lower energy Carbocation Stability CH3 CH3 H C

> CH3 CH3 CH3 > secondary = primary allylic = tertiary C = CH2=CH CH2 = CH2 > CH3CH2 primary benzylic > primar resonance stabilized

Carbocations can Rearrange 1,2-Hydride Shift Br CH3 C H H C CH3 CH3 H2O H CH3 C

H OH C CH3 + HBr CH3 Carbocations can Rearrange 1,2-Methide Shift Hydride shift H 2 o

Hydride shift H 3 o Ring Expansion a a b c c

b 2 o 2 o Rings Contract, too hydride shift a b

H ring contraction a b E1 Mechanism E1 and SN1 Compete b) a) OTs CH3OH /

CH3 + Zaitsev a) CH3OH H H CH3 CH3 b) CH3OH CH3 OCH3 CH3

Synthetic Chemists Nightmare Br CH3OH CH3O CH3O CH3O CH3O Ring Expansion to a More Stable 6-membered Ring H Br

via hydride shift c CH3OH b H a b c

a via ring expansion hydride shift Dehydration of Alcohols E1 OH H H2SO4 (aq) cat. + H2O H regenerated H

O HSO4 or H2O H -H2O H Methide Shift is Faster than + Loss of H OH CH3 CH3

CH3 CH3 CH3 H2SO4 (aq) CH3 + distill major minor

+ H2 O Provide a Mechanism H Br OCH3 CH3O H OCH3 CH3OH, warm +

+ + HBr (or CH3OH2) H Br OCH3 CH3O H OCH3 CH3OH, warm +

+ b) H a) CH3OH a) b) Br + HBr OCH3 (or CH3OH2) ring expansion (squiggly bond = both isomers)

H hydride shift CH3OH H CH3OH H OCH3 c) Can R-X form a good LG? No

Yes no reaction classification of carbon 1 o 3 o o 2 nuc. hindered, strong base? Yes E2

nuc. a strong base? No Yes No Yes No polar solvent? good nuc., nonbasic? (some SN2) Yes No

SN2 (slow SN2) E2 No good nuc., non-basic? Yes strong base? E2 SN2 solvent polar? Yes Yes

SN1* E1 SN1* E1 * SN1 is favored over E1 unless high temp. and trace amounts of base are used. Give the Major Product & Predict the Mechanism OH CH3 6M H2SO4 120oC, distill OH

CH3 6M H2SO4 120oC, distill E1 CH3 NaNH2 in liq. NH3 OTs NaNH2 in liq. NH3 OTs E2 H CH3

CH2CH3 OTs KBr in acetone, 20oC H CH3 CH2CH3 OTs KBr in acetone, 20oC SN2 Br

CH3 H CH2CH3 Br 1% AgNO3 in CH3CH2OH Br 1% AgNO3 in CH3CH2OH SN1 CH3CH2O

+ AgBr Br CH3CH2CH2OH warm Br CH3CH2CH2OH warm SN1/E1 OCH2CH2CH3 + CH3


H 2O (phase transfer cat.) I OH H 2O (phase transfer cat.) SN1 (E1) + I CH3 CH3

NaOCH2CH3 in refluxing ethanol I CH3 CH3 NaOCH2CH3 in refluxing ethanol E2 CH3 CH3 NaOCH3 CH3CH2CH2CH2CH2Cl in methanol, room temp.

NaOCH3 CH3CH2CH2CH2CH2Cl in methanol, room temp. SN2 O Which Reacts More Rapidly in E2 Reaction? (CH3)2CH I A (CH3)2CH I B

Cis Reacts more Rapidly trans I reactive (CH3)2CH CH(CH3)2 I stable I cis

(CH3)2CH reactive & stable H reacts more rapidly

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