Nitrogen Based Carbonyl Reactions

Some reactions of aldehydes and ketones progress beyond the nucleophilic addition stage Acetal formation Imines Compounds related to imines Enamines The Wittig reaction

Enamine from 2 o amines

Question The compound below is best classified as a(n) (CH 3 ) 3 CCH 2 CH=NCH 3 A)carbinolamine. B)enamine. C)hydrazone. D)imine.

Question Identify the product isolated when cyclopentanone reacts with dimethyl amine. A)B) C)D)

The Wittig Reaction

Some reactions of aldehydes and ketones progress beyond the nucleophilic addition stage Acetal formation Imine formation Compounds related to imines Enamines The Wittig reaction

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.

Charge distribution in a ylide

The Wittig Reaction (C 6 H 5 ) 3 P C +AB – + + CC R R' A B (C 6 H 5 ) 3 P O + – CORR'

Example + + (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

Mechanism CORR' P(C 6 H 5 ) 3 + CAB – OC C RR' B A Step 1

Mechanism 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 +

Alkene Synthesis via the Wittig Reaction

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

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.

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–

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

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

Question Select the product isolated when butanal reacts with the slide shown below. A)B) C)D)

Question

Stereoselective Addition to Carbonyl Groups Nucleophilic addition to carbonyl groups sometimes leads to a mixture of stereoisomeric products.

20% Example CH 3 H3CH3CH3CH3CO 80% OHOHOHOH H H3CH3CH3CH3C OHOHOHOH H H3CH3CH3CH3C NaBH 4

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

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

Figure 1 One face of the substrate can bind to the enzyme better than the other.

Figure 2 Change in geometry from trigonal to tetrahedral is stereoselective. Bond formation occurs preferentially from one side rather than the other.

Oxidation of Aldehydes

K 2 Cr 2 O 7 H 2 SO 4 H2OH2OH2OH2O O O CH O O COH (75%) Example

Baeyer-Villiger Oxidation of Ketones Oxidation of ketones with peroxy acids gives esters by a novel rearrangement.

R"COOH O RCR' O + R"COH O + KetoneEster ROCR' O General

C 6 H 5 COOH O (67%) Oxygen insertion occurs between carbonyl carbon and more substituted group. Methyl ketones give acetate esters. CHCl 3 Example CCH 3 O OCCH 3 O

C 6 H 5 COOH O (66%) Reaction is stereospecific. Oxygen insertion occurs with retention of configuration. CHCl 3 Stereochemistry O CCH 3 H3CH3CH3CH3C HH OCCH 3 O H3CH3CH3CH3C HH

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" Mechanism

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. Mechanism

Certain bacteria use hydrocarbons as a source of carbon. Oxidation proceeds via ketones, which then undergo oxidation of the Baeyer-Villiger type. Biological Baeyer-Villiger Oxidation O bacterial oxidation O O O 2. cyclohexanone monooxygenase, coenzymes

Question What is the product of the following Baeyer-Villiger oxidation reaction?