Chemistry 5.12 Spring 2003 Substitution Reactions (SN2 versus SN1) SN2 SN1 Mechanism: Concerted Two Steps (Look for carbocation rearrangements.) Rate Equation: Rate = kr[R–X][Nuc] Rate = kr[R–X] Stereochemistry: Stereospecific (inversion) Loss of Stereochemistry Substrate: Sterics (methyl > 1° > 2°) No SN2 with 3°! Orbital Overlap (methyl ≅ benzylic > allylic > 1°) Cation Stability (benzylic > allylic > 3° > 2°) No 1° or methyl R+ without extra stabilization! Nucleophile: Strong/Moderate Required strong: RS–, I–, R2N–, R2NH, RO–, CN– moderate: RSH, Br–, RCO2– Not Important Leaving Group: Moderately Important (same trend as SN1) Very Important (–OTf >> –OTs ≅ –OMs >> –I > –Br > –Cl) Solvent: Polar Aprotic Polar Protic Elimination Reactions: E2 versus E1 E2 E1 Mechanism: Concerted Two Steps (Look for carbocation rearrangements.) Rate Equation: Rate = kr[R–X][Base] Rate = kr[R–X] Stereochemistry: Stereospecific (antiperiplanar TS) Not Stereospecific Substrate: Alkene Stability (3° > 2° > 1°) Cation Stability (benzylic > allylic > 3° > 2°) Base: Strong Base Required (RO–, R2N–) Not Important: Usually Weak (ROH, R2NH) Leaving Group: Moderately Important (same trend as SN1) Very Important (same trend as SN1) Wide Range of Solvents Polar Protic Solvent: Product Ratio: Saytzeff Rule: The most highly substituted alkene usually predominates. Hofmann Product: Use of a sterically hindered base will result in formation of the least substituted alkene (Hofmann product). 1 Generic Reaction-Energy Diagrams Substitution ‡ Elimination ‡ R δ− δ+ Nuc δ− X RR ‡ X δ− B energy energy ‡ RR H R R δ− R R X Nuc– X B– R R R R R Nuc X– R R B H R reaction coordinate (SN2) reaction coordinate (E2) Bimolecular δ− X R δ+ ‡ RR R δ− ‡ RDS ‡ Unimolecular Nuc CHR2 δ− δ+ X δ+ RR ‡ RDS ‡ RR RR ‡ ‡ B R X– R energy energy ‡ R R H δ− R R+ X– Nuc– δ+ R B– R R X Nuc– X B– R R R R R R R Nuc X– reaction coordinate (SN1) B H R reaction coordinate (E1) Predicting the Products: Substitution versus Elimination Start Bimolecular Reaction yes Is Nuc/Base strong? no What kind of substrate? 1° Is Nuc/Base bulky? 2°, 3°, or stabilized 1° Unfavorable Reaction yes Unimolecular Reaction E2 no 3° mostly E1* What kind of substrate? yes Is Nuc/Base bulky? 2° methyl or 1° SN2 SN2 + E2 no mostly SN1* * Under conditions that favor a unimolecular reaction (weak nuc/base and polar protic solvent), mixtures of SN1 and E1 are usually obtained. 2