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Nucleophilic Neighboring Group Participation Case I: Consider the following data: R OBs + HCOOH SN2 conditions R O C H + BsOH O OBs krelative ( 75o C ) 1 CH3 (CH2 )2 CH2 OBs l.00 (reference) 2 CH3 OCH2 CH2 OBs 0.10 3 CH3 OCH2 CH2 CH2 OBs 0.33 4 CH3 OCH2 CH2 CH2 CH2 OBs 461.0 5 CH3 O(CH2 )4 CH2 OBs 32.6 6 CH3 O(CH2 )5 CH2 OBs 1.13 Compound # R Nucleophilic Neighboring Group Participation Case I: Rationale Rationale to explain enhanced rates of substitution for compounds 4 & 5: OBs O internal displacement + O CH3 CH3 HCOOH product HCOOH product - OBs cyclic oxonium ion O CH3 internal OBs displacement + O CH3 OBs- cyclic oxonium ion In addition to the available S N 2 pathway, a more favorable alternate pathway for displacement of brosylate is possible for compounds 4 & 5. The internal displacement pathway leads to the formation of relatively stable 5- and 6membered cyclic oxonium salts. As the chain length increases, the likelihood of cyclic oxonium ion formation diminishes, and rates approach that of the reference case where only S N 2 attack by HCOOH is possible. Nucleophilic NGP Case II Consider the following: CH3 CH2 S CH CH2 OH HCl CH3 CH2 S CH CH2 Cl + CH3 CH CH2 S CH3 CH3 CH2 CH3 Cl "normal" product "rearranged" product Rationale: - Cl H OH2 H3 C C CH2 + S CH2 CH3 H H3 C NGP Cl C - C H H products + S CH2 CH3 episulfonium ion An S N 1 pathway leading to a primary carbocationic intermediate is not as favorable as a neighboring group participation (internal displacement) pathway leading to an episulfonium ion intermediate. Nucleophilic NGP Case III Consider the following: (erythro)-3-iodo-2-butanol (threo)-3-iodo-2-butanol Rationale: CH3 H I H HCl (erythro)-2-chloro-3-iodobutane (only product) HCl (threo)-2-chloro-3-iodobutane (only product) I HCl H OH + H2 O OH2 H3 C H3 C I CH3 H (erythro reactant) Cl - H CH3 H3 C a + I I CH3 CH3 Cl b H b a H H3 C Cl - H H H H3 C only one erythro product Cl Likewise, for threo reactant, only one threo product is obtained. In both erythro and threo reactions, neighboring group participation by an iodonium ion intermediate is more favorable than formation of an open carbocationic intermediate. “Non-nucleophilic” NGP Acetolysis of Phenyl tosylates Consider the following: H CH H C H 3 3 H CH3 CH COOH 3 H H OTs OAc AcO L-threo-3-phenyl2-butyl acetate (32%) L-threo-3-phenyl2-butyl tosylate CH3 H OTs H3 C L-erythro-3-phenyl2-butyl tosylate D-threo-3-phenyl2-butyl acetate (32%) CH3 H CH3 COOH + H H + CH3 H3 C H3 C H + OAc H3 C L-erythro-3-phenyl2-butyl acetate 23% alkenes 36% alkenes Possible explanations for the results of the acetolysis reactions Direct bimolecular nucleophilic attack at C-2 Inconsistent with the experimental data. Why? Formation of a secondary carbocation at C-2 Inconsistent with the experimental data. Why? Rapidly equilibrating secondary carbocations to account for the acetolysis results? The “Windshield-Wiper” Effect CH3 H H H3 C CH3 COOH OTs + H H3 C L-erythro (a) CH3 H H H3 C O C CH3 O L-erythro CH3 H H H3 C + CH3 H CH3 COOH (a) (b) (b) H H3 C H3 C CH3 C O H O L-erythro A rapidly equilibrating pair of secondary carbocations in which 1,2-phenyl shifts effectively prevent topside attack by acetic acid. Additional data concerning acetolysis of phenyl tosylates Fact One - Scrambling of a label * CH3 H H H3 C OTs L-erythro * CH3 H CH3 COOH H H3 C O C CH3 O L-erythro 50% H H3 C + H3 C * CH3 H C O O L-erythro 50% Additional data concerning acetolysis of phenyl tosylates Fact Two - Substituent effects Z CH3 H OTs H H3 C As the electron-donating ability of substituent Z increases, the rate of acetolysis increases. 7 k acetolys is (x10 ) Cl H CH 3 OCH3 0.39 2.39 19.0 228.0 Additional data concerning acetolysis of phenyl tosylates Fact Three - Formation of Spirane products H H H2 O Alcohols + OTs H H H H HO H H O CH 3 H - OH /H 2 O Alcohols + OTs H H3 C H H3 C CH 3 H Additional data concerning acetolysis of phenyl tosylates Fact Four - Unusual Kinetics OTs O C H O k1 HCOOH OTs O C O HCOOH k 1 = 1000 k 2 H k2 Explanation to account for the acetolysis results Phenonium ion participation Z + A phenonium ion: -electron donation from an electron rich benzene system leading to internal displacement of the leaving group and formation of a cyclopropyl spirane intermediate. Alkyl Participation - bridged complexes Consider the following reactions: CH3 (CH3 )3 C CH2 OH HBr CH3 C CH2 CH3 Br CH3 + Ag H2 O (CH3 )3 C CH2 I (only org. prod.) CH3 C CH2 CH3 + AgI OH (only org. prod.) Rationale CH3 CH3 -1 CH3 C CH2 -I I slow CH3 + + H3 C H3 C C CH2 I (CH3 )2 C CH2 CH3 H2 O - Supporting evidence H H H B B H H H B2 H6 H3 C H3 C CH3 Al Al CH3 Al2 (CH3 )6 CH3 CH3 alc. prod. Corroborating evidence for alkyl participation Observation: H H3 C CHBr 3 (CH3 )3 C C* OH KOH D optically active H C C H3 C + H3 C CH2 D + CH3 C C C CH3 H3 C * CHDCH 3 CH3 optically active Preliminary explanation: The above reaction generates carbocationic intermediates under strongly basic conditions. In general: - - CBr3 + H2 O CHBr 3 + OH - - ROH + OH - CBr3 -Br H2 O + RO - CBr2 (an electrophilic carbene) - CBr2 + RORO C Br + R O C ROCBr2 -Br- -Br- RO C Br + RO C + + R + O C R O C Open carbocation possibility H3 C H3 C H3 C D +O H C -CO H3 C + H3 C D H H3 C H3 C rotation + D H3 C H3 C 1,2-Me shift 1,2-Me shift CH3 CH3 H3 C + D H H3 C -H H3 C C CH2 + H3 C H D H3 C + -H 2-butenes + H + 2-butenes CH3 D H + H3 C C CH2 CH3 H D (S-enantiomer) (R-enantiomer) Racemic mixture- no optical activity Methyl bridged intermediate D H3 C +O H3 C H3 C CH3 D H H3 C H3 C C + + H O C + -CO CH3 CH3 H3 C H3 C + D H -H + 2-butenes + H3 C C CH2 D H (S-enantiomer) Optically active Even if the bridged pathway only competes with the open carbocation pathway, one alkene enantiomer will still be produced in excess, and there will be residual optical activity in the product. Data for the solvolysis of cyclohexyl tosylates Cons isder the following s olvolysis data: H * CH 3 H * CH 3 OTs H (CH 3 )3 C * + CH 3 -OTs k ax (CH 3 )3 C optically active (CH 3 )3 C H only alkene product (racemic mixture) H * CH 3 H * (CH 3 )3 C CH 3 optically active + -OTs k eq (CH 3 )3 C CH 3 TsO (CH 3 )3 C H optically active optically active k ax ~ = 70-80k eq H * Rationale for cyclohexyl tosylate solvolysis Ordinarily, an axial leaving group, because it experiences more steric interactions, is solvolyzed 2 to 3 times faster than an equatorial leaving group. The greater rate of solvolysis (70-80 times as fast) for axial tosylate relative to equatorial tosylate is suggestive of neighboring group participation. H H * CH3 (CH3 )3 C + (CH3 )3 C TsO H CH3 E-1 -OTs H optically active -H H H * * CH3 CH3 + (CH3 )3 C (CH3 )3 C optically active optically active + Rationale for cyclohexyl tosylate solvolysis cont’d. -Hydrogen participation H H OTs * CH3 OTs (CH3 )3 C (CH3 )3 C optically active H * CH3 + - -OTs H + H CH3 (CH3 )3 C + + H H * CH3 (CH3 )3 C 3o R * CH3 + (CH3 )3 C racemic alkene products -H + Solvolysis of unsaturated tosylates Consider the following observations: a) (CH3 )2 C CH CH2 CH2 OTs CH3 COOH (CH3 )2 C CH CD2 CH2 OTs CH3 COOH b) or (CH3 )2 C CH CH2 CD2 OTs (CH3 )2 C CH CH2 CH2 O C CH3 O (CH3 )2 C CH CD2 CH2 O + (CH3 )2 C CH CH2 CD2 O C CH3 O C CH3 O both labelled products are obtained from either labelled reactant (CH3 )2 CHCH2 CH2 CH2 OTs CH3 COOH (CH3 )2 CHCH2 CH2 CH2 O C CH3 O c) (CH3 )2 C CH CH2 CH2 OTs k CH3 COOH unsat'd. >> k (CH3 )2 C CH CH2 CH2 O C CH3 O s at'd. Possible explanations for solvolysis of unsaturated tosylates Possible explanation I: + Formation of (CH3 )2 C CH CH2 CH2 ; Unlikely, this is a primary R Possible explanation II: (CH3 )2 C . O CH3 CH CH2 CH2 + + C OTs CH2 CH CH3 HO C CH3 CH2 The above explanation invokes the intermediacy of a tertiary carbocation formed with -electron NGP; no primary carbocation is involved.Further, the above tertiary carbocation can account for the scrambling observed with labelled reactants and for the enhanced rate of solvolysis in the case of the unsaturated vs. saturated tosylate reactants. O However: CH2 a different set of solvolysis products CH3 C OH (CH3 )2 C CH relative to those obtained from the unsaturated tosylate reactants CH2 Cl Best explanation: CH2 [ (CH ) C 3 2 CH + [ (CH ) C ] 3 2 CH2 3 2 CH CH2 CH2 [ (CH ) C CH2 CH CH2 A homoallyl carbocation + ] + ]