(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
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
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
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