ALDEHYDES AND KETONES: NUCLEOPHILIC ADDITION TO THE CARBONYL GROUP 431 Step 4: CH,CH CHACH CdHC—9cH2CH3+:O I CH COCH, CH3+ H Hemiacetal Step 5: CH,CH3 CHCH CHCH C6HSCH--OCH, CH3 H CHCH-O C6HSCH CHCH + O: H CH, CH3 CHCH+ C6HSCH H- 17.10 The conversion requires reduction; however, the conditions necessary (LiAlH,) would also reduc the ketone carbonyl. The ketone functionality is therefore protected as the cyclic acetal HOCH, CH, OH CHC COH o-C COH Reduction of the carboxylic acid may now be carried out O 1. LiAlH, COH CHOH C Hydrolysis to remove the protecting group completes the synthesis CH, H2O,HCI CHOH Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
Step 4: Step 5: Step 6: Step 7: 17.10 The conversion requires reduction; however, the conditions necessary (LiAlH4) would also reduce the ketone carbonyl. The ketone functionality is therefore protected as the cyclic acetal. Reduction of the carboxylic acid may now be carried out. Hydrolysis to remove the protecting group completes the synthesis. CH2OH CH3C CH2OH O H2O, HCl 4-Acetylbenzyl alcohol O O C H3C COH O CH2OH 1. LiAlH4 2. H2O O O C H3C O O C H3C 4-Acetylbenzoic acid COH O CH3C O HOCH2CH2OH p-toluenesulfonic acid, benzene COH O O O C H3C O H CH2CH3 O H CH2CH3 C6H5CH O C6H5CH O H H O H CH2CH3 O H CH2CH3 C6H5CH O C6H5CH OH H O H CH2CH3 H O H CH2CH3 O H CH2CH3 OCH2CH3 C6H5CH HO C6H5CH OH O H CH2CH3 H O H CH2CH3 C6H5C OCH2CH3 O H H H C6H5C OCH2CH3 H HO Hemiacetal ALDEHYDES AND KETONES: NUCLEOPHILIC ADDITION TO THE CARBONYL GROUP 431 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
432 ALDEHY DES AND KETONES: NUCLEOPHI ON TO THE CARBONYL GROUP 17.11(b) Nucleophilic addition of butylamine to benzaldehyde gives the carbinolamine OH -CH CH..CHNH CH-NCHCH.CH Carbinolamine intermediate Dehydration of the carbinolamine produces the imine CH— NCH CHCH CH =NCH, CH, CH, CH3 (c) Cyclohexanone and tert-butylamine react according to the equation HO NC(CH, NC(CH 3)3 +( Ch3)cNH Cyclohexanone tert-Butylamine Carbinolamine N-Cyclohexylidene- intermediate NH C6H CCH3+ C6HSCCH3 -H,O C6HSCCH3 Carb 17.12 (b) Pyrrolidine, a secondary amine, adds to 3-pentanone to give a carbinolamine CHa CH,CCH, CH3 CHCH, CCH, CH3 3-Pentanone Pyrrolidine Dehydration ices the enamine CHCH,CCH,CH CH CHECCHCH hO Carbinolamine Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
17.11 (b) Nucleophilic addition of butylamine to benzaldehyde gives the carbinolamine. Dehydration of the carbinolamine produces the imine. (c) Cyclohexanone and tert-butylamine react according to the equation (d) 17.12 (b) Pyrrolidine, a secondary amine, adds to 3-pentanone to give a carbinolamine. Dehydration produces the enamine. Carbinolamine 3-Pyrrolidino-2-pentene intermediate CH3CH2CCH2CH3 OH H2O N CH3CH CCH2CH3 N 3-Pentanone CH3CH2CCH2CH3 O Carbinolamine intermediate CH3CH2CCH2CH3 OH Pyrrolidine H N N Acetophenone Carbinolamine Cyclohexylamine intermediate C6H5CCH3 OH NH NH2 C6H5CCH3 O N-(1-Phenylethylidene)- cyclohexylamine C6H5CCH3 N H2O H2O O Cyclohexanone HO NC(CH3)3 H Carbinolamine intermediate (CH3)3CNH2 tert-Butylamine NC(CH3)3 N-Cyclohexylidenetert-butylamine N-Benzylidenebutylamine CH NCH2CH2CH2CH3 OH H H2O CH NCH2CH2CH2CH3 Carbinolamine intermediate CH CH3CH2CH2CH2NH2 O Benzaldehyde Butylamine CH NCH2CH2CH2CH3 OH H 432 ALDEHYDES AND KETONES: NUCLEOPHILIC ADDITION TO THE CARBONYL GROUP Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
ALDEHYDES AND KETONES: NUCLEOPHILIC ADDITION TO THE CARBONYL GROUP 433 C6HSCCH3+ CH-CCH H2o CHC=CH2 Piperidine Carbinolamine Here we see an example of the Wittig reaction applied to diene synthesis by use of an ylide containing a carbon-carbon double bond CHaCHCH,CH +(C6H5)3P--CHCH=CH CH, CH, CH, CH=CHCH=CH, +(CKHsaP-0 Butanal Allylidenetriphenylphosphorane 1, 3-Heptadiene(52%) Triphenylphosphine (c) Methylene transfer from methylenetriphenylphosphorane is one of the most commonly used Wittig reactions CH3+(CH)一(H2 CCH3+(C6H5)3P一 Cyclohexyl methyl Methylenetriphenyl- 2-Cyclohexylpropene Triphenylphosphine phosphorane 17.14 A second resonance structure can be written for a phosphorus ylide with a double bond between phosphorus and carbon. As a third-row element, phosphorus can have more than 8 electrons in its (CHS)3P- →(C6H5)3P=CH2 Methylenetriphenylphosphorane 17.15 (b) Two Wittig reaction routes lead to 1-pentene. One is represented retrosynthetically by the disc CH, CH, CH, CH=CH, CH,CH, CH,CH +(C H5)3P--CH 1-Pentene Methylenetriphenyl The other route is CH_ CH, CH, CH=CH? CH, CH,CH2CH--P(C6H5)3+ Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
(c) 17.13 (b) Here we see an example of the Wittig reaction applied to diene synthesis by use of an ylide containing a carbon–carbon double bond. (c) Methylene transfer from methylenetriphenylphosphorane is one of the most commonly used Wittig reactions. 17.14 A second resonance structure can be written for a phosphorus ylide with a double bond between phosphorus and carbon. As a third-row element, phosphorus can have more than 8 electrons in its valence shell. 17.15 (b) Two Wittig reaction routes lead to 1-pentene. One is represented retrosynthetically by the disconnection The other route is 1-Pentene CH3CH2CH2CH CH2 Formaldehyde O HCH Butylidenetriphenylphosphorane CH3CH2CH2CH P(C6H5)3 1-Pentene CH3CH2CH2CH CH2 CH3CH2CH2CH O Butanal Methylenetriphenylphosphorane CH2 (C6H5)3P Methylenetriphenylphosphorane (C6H5) CH2 3P CH2 (C6H5)3P CCH3 O Cyclohexyl methyl ketone CCH3 CH2 2-Cyclohexylpropene (66%) Triphenylphosphine oxide O (C6H5)3P Methylenetriphenylphosphorane (C6H5)3P CH2 Allylidenetriphenylphosphorane 1,3-Heptadiene (52%) Triphenylphosphine oxide Butanal CH3CH2CH2CH CH3CH2CH2CH O (C6H5)3P CH CHCH 2 CHCH CH2 (C6H5)3P O Carbinolamine intermediate 1-Piperidino-1- phenylethene Acetophenone Piperidine C6H5CCH3 O H C6H5CCH3 OH H2O C6H5C CH2 N N N ALDEHYDES AND KETONES: NUCLEOPHILIC ADDITION TO THE CARBONYL GROUP 433 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
434 ALDEHYDES AND KETONES: NUCLEOPHILIC ADDITION TO THE CARBONYL GROUP 17.16 Ylides are prepared by the reaction of an alkyl halide with triphenylphosphine, followed by treat ment with strong base. 2-Bromobutane is the alkyl halide needed in this case (C6H5)3P CH3 CHCH, CH3-(CH5)3P-CHCH2CH3 Br CH3 2-Bromobutane (1-Methylpropyl)triphenyl (C HS)P-CHCH,CH, Br NaCH,SCH (C6H5)2P—CCH2CH2 Sodiomethyl 17.17 The overall reaction is CCH3+ C COOH OCCH3+ C6HS COH Cyclohexyl methyl Peroxybenzoic Cyclohexyl Benzoic In the first step, the peroxy acid adds to the carbonyl group of the ketone to form a peroxy monoester CCH CHCOOH CCH OOCCSH Peroxy monoester The intermediate then undergoes rearrangement. Alkyl group migration occurs at the same time as cleavage of the o-o bond of the peroxy ester In general, the more substituted group migrates HC H-C O+ HOCC6Hs SOCC.H 17.18 The formation of a carboxylic acid from Baeyer-Villiger oxidation of an aldehyde requires o COCC.H Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
17.16 Ylides are prepared by the reaction of an alkyl halide with triphenylphosphine, followed by treatment with strong base. 2-Bromobutane is the alkyl halide needed in this case. 17.17 The overall reaction is In the first step, the peroxy acid adds to the carbonyl group of the ketone to form a peroxy monoester of a gem-diol. The intermediate then undergoes rearrangement. Alkyl group migration occurs at the same time as cleavage of the O@O bond of the peroxy ester. In general, the more substituted group migrates. 17.18 The formation of a carboxylic acid from Baeyer–Villiger oxidation of an aldehyde requires hydrogen migration. C6H5COOH O O CH O2N m-Nitrobenzaldehyde O COH O2N m-Nitrobenzoic acid OH C H O OCC6H5 O O2N H3C O C O O HOCC6H5 C OCC6H5 O OH O H3C O C6H5COOH O CCH3 Peroxy monoester OH OOCC6H5 O CCH3 Peroxybenzoic acid O C6H5COOH Cyclohexyl methyl ketone O CCH3 Benzoic acid O C6H5COH Cyclohexyl acetate O OCCH3 Br CH3 CHCH2CH3 (C6H5)3P (1-Methylpropyl)triphenylphosphonium bromide Sodiomethyl methyl sulfoxide O NaCH2SCH3 Ylide CH3 CCH2CH3 (C6H5)3P Br CH3 CHCH2CH3 (C6H5)3P (1-Methylpropyl)triphenylphosphonium bromide CH3CHCH2CH3 Br 2-Bromobutane (C6H5)3P Triphenylphosphine 434 ALDEHYDES AND KETONES: NUCLEOPHILIC ADDITION TO THE CARBONYL GROUP Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
ALDEHYDES AND KETONES: NUCLEOPHILIC ADDITION TO THE CARBONYL GROUP 435 17.19 (a) First consider all the isomeric aldehydes of molecular formula CsHioo. Pentanal 3-Methylbutanal H (S)-2-Methylbutanal (R)-2-Methylbutanal 2, 2-Dimethylpropanal There are three isomeric ketones. 2-Pentanone 3-Pentanone 3.Methyl-2-butanone (b) Reduction of an aldehyde to a primary alcohol does not introduce a stereogenic center into the molecule. The only aldehydes that yield chiral alcohols on reduction are therefore those that already contain a stereogenic center. H OH CH,OH (S)-2-Methylbutanal (S)-2-Methyl-1-butanol (R)-2-Methylbutanal (R)-2-Methyl-l-butanol Among the ketones, 2-pentanone and 3-methyl-butanone are reduced to chiral alcohols 2-Pentanone 2-Pentanol (chiral but racemic OH 3-Pentanone 3-Pentanol 3-Methyl-2-butanone Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
17.19 (a) First consider all the isomeric aldehydes of molecular formula C5H10O. There are three isomeric ketones: (b) Reduction of an aldehyde to a primary alcohol does not introduce a stereogenic center into the molecule. The only aldehydes that yield chiral alcohols on reduction are therefore those that already contain a stereogenic center. Among the ketones, 2-pentanone and 3-methyl-butanone are reduced to chiral alcohols. NaBH4 CH3OH O 3-Methyl-2-butanone OH 3-Methyl-2-butanol (chiral but racemic) NaBH4 CH3OH O 3-Pentanone OH 3-Pentanol (achiral) NaBH4 CH3OH O 2-Pentanone OH 2-Pentanol (chiral but racemic) (R)-2-Methylbutanal (R)-2-Methyl-1-butanol NaBH4 CH3OH H O H OH H H (S)-2-Methylbutanal (S)-2-Methyl-1-butanol NaBH4 CH3OH O OH H H 2-Pentanone 3-Pentanone 3-Methyl-2-butanone O O O H H (S)-2-Methylbutanal O (R)-2-Methylbutanal O 2,2-Dimethylpropanal H H H O O H Pentanal O H 3-Methylbutanal ALDEHYDES AND KETONES: NUCLEOPHILIC ADDITION TO THE CARBONYL GROUP 435 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website