Dr. Wolf's CHM 201 & The Wittig Reaction

Dr. Wolf's CHM 201 & Some reactions of aldehydes and ketones progress beyond the nucleophilic addition stage Acetal formation Imine formation Compounds related to imines Enamines The Wittig reaction

Dr. Wolf's CHM 201 & Some reactions of aldehydes and ketones progress beyond the nucleophilic addition stage Acetal formation Imine formation Compounds related to imines Enamines The Wittig reaction

Dr. Wolf's CHM 201 & The Wittig Reaction Synthetic method for preparing alkenes. One of the reactants is an aldehyde or ketone. The other reactant is a phosphorus ylide. (C 6 H 5 ) 3 P C +AB – (C 6 H 5 ) 3 P CAB A key property of ylides is that they have a negatively polarized carbon and are nucleophilic.

Dr. Wolf's CHM 201 & Figure Charge distribution in a ylide

Dr. Wolf's CHM 201 & The Wittig Reaction (C 6 H 5 ) 3 P C +AB – + + CC R R' A B (C 6 H 5 ) 3 P O + – CORR'

Dr. Wolf's CHM 201 & ExampleExample + + (C 6 H 5 ) 3 P O+ – (C 6 H 5 ) 3 P CH 2 +– O DMSO (86%) dimethyl sulfoxide (DMSO) or tetrahydrofuran (THF) is the customary solvent

Dr. Wolf's CHM 201 & MechanismMechanism CORR' P(C 6 H 5 ) 3 + CAB – OC C RR' B A Step 1

Dr. Wolf's CHM 201 & MechanismMechanism OC C P(C 6 H 5 ) 3 RR' B A Step 2 P(C 6 H 5 ) 3 + – O R'RA B C C +

Dr. Wolf's CHM 201 & Planning an Alkene Synthesis via the Wittig Reaction

Dr. Wolf's CHM 201 & Retrosynthetic Analysis There will be two possible Wittig routes to an alkene. Analyze the structure retrosynthetically. Disconnect the doubly bonded carbons. One will come from the aldehyde or ketone, the other from the ylide. CCRR' A B

Dr. Wolf's CHM 201 & Retrosynthetic Analysis of Styrene C 6 H 5 CH CH 2 HCH O + (C 6 H 5 ) 3 P CHC 6 H 5 + – C 6 H 5 CH O+ (C 6 H 5 ) 3 P CH 2 + – Both routes are acceptable.

Dr. Wolf's CHM 201 & Preparation of Ylides Ylides are prepared from alkyl halides by a two-stage process. The first step is a nucleophilic substitution. Triphenylphosphine is the nucleophile. (C 6 H 5 ) 3 P + CHAB X + (C 6 H 5 ) 3 P CHAB + X–X–X–X–

Dr. Wolf's CHM 201 & Preparation of Ylides In the second step, the phosphonium salt is treated with a strong base in order to remove a proton from the carbon bonded to phosphorus. (C 6 H 5 ) 3 P CAB + H base – (C 6 H 5 ) 3 P CAB + – H base

Dr. Wolf's CHM 201 & Preparation of Ylides Typical strong bases include organolithium reagents (RLi), and the conjugate base of dimethyl sulfoxide as its sodium salt [NaCH 2 S(O)CH 3 ]. (C 6 H 5 ) 3 P CAB + H base (C 6 H 5 ) 3 P C A B + – – Hbase

Dr. Wolf's CHM 201 & Stereoselective Addition to Carbonyl Groups Nucleophilic addition to carbonyl groups sometimes leads to a mixture of stereoisomeric products.

Dr. Wolf's CHM 201 & % ExampleExample CH 3 H3CH3CH3CH3CO 80% OHOHOHOH H H3CH3CH3CH3C OHOHOHOH H H3CH3CH3CH3C NaBH 4

Dr. Wolf's CHM 201 & this methyl group hinders approach of nucleophile from top H 3 B—H – preferred direction of approach is to less hindered (bottom) face of carbonyl group preferred direction of approach is to less hindered (bottom) face of carbonyl group Steric Hindrance to Approach of Reagent

Dr. Wolf's CHM 201 & Biological reductions are highly stereoselective pyruvic acid  S-(+)-lactic acid O CH 3 CCO 2 H NADH H+H+H+H+ enzyme is lactate dehydrogenase CO 2 H HOHOHOHO H CH 3

Dr. Wolf's CHM 201 & Figure One face of the substrate can bind to the enzyme better than the other.

Dr. Wolf's CHM 201 & Figure Change in geometry from trigonal to tetrahedral is stereoselective. Bond formation occurs preferentially from one side rather than the other.

Dr. Wolf's CHM 201 & in aqueous solution RCH RCH RCOHOOH OH H2OH2OH2OH2OO Oxidation of Aldehydes

Dr. Wolf's CHM 201 & K 2 Cr 2 O 7 H 2 SO 4 H2OH2OH2OH2O O O CH O O COH (75%) via O OH CH OH ExampleExample

Dr. Wolf's CHM 201 & Baeyer-Villiger Oxidation of Ketones Oxidation of ketones with peroxy acids gives esters by a novel rearrangement.

Dr. Wolf's CHM 201 & R"COOH O RCR' O + R"COH O + KetoneEster ROCR' O GeneralGeneral

Dr. Wolf's CHM 201 & C 6 H 5 COOH O (67%) Oxygen insertion occurs between carbonyl carbon and larger group. Methyl ketones give acetate esters. CHCl 3 ExampleExample CCH 3 O OCCH 3 O

Dr. Wolf's CHM 201 & C 6 H 5 COOH O (66%) Reaction is stereospecific. Oxygen insertion occurs with retention of configuration. CHCl 3 StereochemistryStereochemistry O CCH 3 H3CH3CH3CH3C HH OCCH 3 O H3CH3CH3CH3C HH

Dr. Wolf's CHM 201 & R"COOH O RCR' O + ROCR' O R"COH O + First step is nucleophilic addition of peroxy acid to the carbonyl group of the ketone. O O C O H R R' OCR" MechanismMechanism

Dr. Wolf's CHM 201 & R"COOH O RCR' O + ROCR' O R"COH O + O O C OHR R' OCR" Second step is migration of group R from carbon to oxygen. The weak O—O bond breaks in this step. MechanismMechanism

Dr. Wolf's CHM 201 & Certain bacteria use hydrocarbons as a source of carbon. Oxidation proceeds via ketones, which then undergo oxidation of the Baeyer-Villiger type. Biological Baeyer-Villliger Oxidation O bacterial oxidation O O O 2. cyclohexanone monooxygenase, coenzymes

Dr. Wolf's CHM 201 & Section Spectroscopic Analysis of Aldehydes and Ketones

Dr. Wolf's CHM 201 & Presence of a C=O group is readily apparent in infrared spectrum C=O stretching gives an intense absorption at cm-1 In addition to peak for C=O, aldehydes give two weak peaks near 2720 and 2820 nm for H—C=O Infrared Spectroscopy

Dr. Wolf's CHM 201 & Francis A. Carey, Organic Chemistry, Fifth Edition. Copyright © 2003 The McGraw-Hill Companies, Inc. All rights reserved Wave number, cm -1 Figure Infrared Spectrum of Butanal C=O CH 3 CH 2 CH 2 CH=O H—C=O 2720 cm cm cm -1

Dr. Wolf's CHM 201 & Aldehydes: H—C=O proton is at very low field (  9-10 ppm). Methyl ketones: CH 3 singlet near  2 ppm. 1 H NMR

Dr. Wolf's CHM 201 & Chemical shift ( , ppm) HCO CH(CH 3 ) 2

Dr. Wolf's CHM 201 & Chemical shift ( , ppm) CH 3 CO CH 3 CH 2

Dr. Wolf's CHM 201 & C NMR Carbonyl carbon is at extremely low field-near  200 ppm Intensity of carbonyl carbon is usually weak

Dr. Wolf's CHM 201 & Chemical shift ( , ppm) CH 3 CH 2 CCH 2 CH 2 CH 2 CH 3 O

Dr. Wolf's CHM 201 & UV-VISUV-VIS Aldehydes and ketones have two bands in the UV region:  * and n  *  *: excitation of a bonding  electron to an antibonding  * orbital  *: excitation of a nonbonding electron on oxygen to an antibonding  * orbital

Dr. Wolf's CHM 201 & UV-VISUV-VIS H3CH3CH3CH3C H3CH3CH3CH3C C O  * max 187 nm n  * max 270 nm

Dr. Wolf's CHM 201 & Molecular ion fragments to give an acyl cation m/z 86 + m/z 57 Mass Spectrometry CH 2 CH 3 CH 3 CH 2 CCH 2 CH 3 +O CH 3 CH 2 C O +