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Nitrogen Based Carbonyl Reactions

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)

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Nitrogen Based Carbonyl Reactions

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  1. Nitrogen Based Carbonyl Reactions

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

  3. Enamine from 2o amines

  4. Question • The compound below is best classified as a(n) (CH3)3CCH2CH=NCH3 • A) carbinolamine. • B) enamine. • C) hydrazone. • D) imine.

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

  6. The Wittig Reaction

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

  8. A A + – (C6H5)3P (C6H5)3P C C •• B B The Wittig Reaction Synthetic method for preparing alkenes. One of the reactants is an aldehyde or ketone. The other reactant is a phosphorus ylide. A key property of ylides is that they have a negatively polarized carbon and are nucleophilic.

  9. Charge distribution in a ylide

  10. R A + – •• C O (C6H5)3P C •• •• B R' R A + – •• + C C (C6H5)3P O •• •• B R' The Wittig Reaction +

  11. + – •• O (C6H5)3P CH2 •• •• + – •• CH2 (C6H5)3P O •• •• Example + dimethyl sulfoxide (DMSO) or tetrahydrofuran (THF) is the customary solvent DMSO + (86%)

  12. R R •• •• C O R' •• •• C O R' A A C P(C6H5)3 + •• P(C6H5)3 C B – B Mechanism Step 1

  13. R •• R – •• R' R' O •• C O •• •• C + P(C6H5)3 C A C P(C6H5)3 + B A B Mechanism Step 2

  14. Alkene Synthesis viathe Wittig Reaction

  15. R A C C B R' Retrosynthetic Analysis There will be two possible Wittig routes toan alkene. Analyze the structure retrosynthetically. Disconnect the doubly bonded carbons. One will come from the aldehyde or ketone, theother from the ylide.

  16. C6H5CH CH2 O O + – + – + HCH (C6H5)3P C6H5CH CHC6H5 (C6H5)3P CH2 •• •• + Retrosynthetic Analysis of Styrene Both routesare acceptable.

  17. A A + + (C6H5)3P X (C6H5)3P CH CH •• B B + X– Preparation of Ylides Ylides are prepared from alkyl halides by atwo-stage process. The first step is a nucleophilic substitution.Triphenylphosphine is the nucleophile.

  18. A A + + – (C6H5)3P (C6H5)3P C C H •• B B – base H base •• Preparation of Ylides In the second step, the phosphonium salt istreated with a strong base in order to removea proton from the carbon bonded to phosphorus.

  19. A + (C6H5)3P C H B base H Preparation of Ylides Typical strong bases include organolithium reagents (RLi), and the conjugate base of dimethyl sulfoxide as its sodium salt[NaCH2S(O)CH3]. A + – (C6H5)3P C •• B – base ••

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

  21. Question

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

  23. H3C CH3 O H3C CH3 H3C CH3 OH H OH H 80% Example NaBH4 20%

  24. – H3B—H Preferred direction of approach is to less hindered (bottom) face of carbonyl group. Steric Hindrance to Approach of Reagent This methyl group hindersapproach of nucleophilefrom top.

  25. CO2H O HO H CH3CCO2H CH3 Biological Reductions are Highly Stereoselective pyruvic acid S-(+)-lactic acid NADH H+ Enzyme is lactate dehydrogenase

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

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

  28. Oxidation of Aldehydes

  29. O O CH COH O O Example K2Cr2O7 H2SO4 H2O (75%)

  30. Baeyer-Villiger Oxidationof Ketones Oxidation of ketones with peroxy acidsgives esters by a novel rearrangement.

  31. O O O O R"COOH R"COH ROCR' RCR' General + + Ketone Ester

  32. O O O C6H5COOH CCH3 OCCH3 Example Oxygen insertion occurs between carbonyl carbon and more substituted group. Methyl ketones give acetate esters. CHCl3 (67%)

  33. O O O C6H5COOH OCCH3 H3C CCH3 H3C H H H H Stereochemistry Reaction is stereospecific. Oxygen insertion occurs with retention ofconfiguration. CHCl3 (66%)

  34. O O O O ROCR' R"COOH RCR' H O R R' C OCR" O O Mechanism + + R"COH First step is nucleophilicaddition of peroxy acidto the carbonyl group of the ketone.

  35. O O O O ROCR' R"COOH RCR' H O R R' C OCR" O O Mechanism + + R"COH Second step is migrationof group R from carbonto oxygen. The weak O—O bond breaks in thisstep.

  36. O2.cyclohexanonemonooxygenase, coenzymes O O O Biological Baeyer-Villiger Oxidation Certain bacteria use hydrocarbons as a source of carbon. Oxidation proceeds via ketones, which then undergo oxidation of the Baeyer-Villiger type. bacterialoxidation

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

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