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C h a p t e r T w e n t y: Aldehydes and Ketones O OH O (S)-Warfarin (named for the Wisconsin Alumni Research Foundation), a useful clinical anticoagulant which as a racemate is also a rat poison Note: Problems with italicized numbers are more challenging. You may want to try them last. Copyright© 2012 by Martin Hulce. All rights reserved. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a data base or retrieval system, without the prior permission of the copyright holder CHM 323: Summary of Important Concepts YConcepts for Chapter 20: Aldehydes and Ketones I. Nomenclature and Properties A. IUPAC 1. Aldehydes a. RCHO, alkanal i. Sometimes also named as alkylcarboxaldehydes, where R = alkyl b. when the –CHO group is named as a substituent, it is the formyl substituent c. example: i. CH3CH2CH2CH(CH3)CH2CH2CHO 4-methylheptanal d. common aldehydes: i. H2C=O formaldehyde acetaldehyde ii. CH3CHO benzaldehyde iii. C6H5CHO 2. Ketones a. RR’C=O, alkanone i. Sometimes also named as alkyl alkyl ketones b. example: i. CH3CH2C=OCH2CH(CH3)CH2CH(CH3)2 5,7-dimethyl-3-octanone c. common ketones: i. CH3C=OCH3 acetone ii. C6H5C=OCH3 acetophenone benzophenone iii. C6H5C=OC6H5 B. Properties 1. Both C and O in C=O are sp2-hybridized 2. Are pretty polar (RCHO have μ . 2.5 D) 3. Thermodynamic stability: ketones > aldehydes II. Preparations of aldehydes and ketones A. Methods from previous chapters 1. Ozonolysis of alkenes R R R 1 H 2. 2 R 1. O3 2. Zn, H3O+ R O R + O 1 H Hydrolysis of alkynes R R O H2SO4, H2O HgSO4 155 R R 2 3. Oxidations of alcohols O RCH2OH PCC CH2Cl2 H R (Collins reagent also efffects this oxidation) RR1CHOH III. Jones reagent O R 1 R Reactions of aldehydes and ketones A. Key element of chemical reactivity The C of the C=O bond is electrophilic. It will react directly with a good (charged) nucleophile to provide a new C–Nu bond. Nu- + H2C=O 6 Nu–CH2–O- B. It will react with a poor (neutral) nucleophile after activation by acid catalysis Reactions 1. Reduction of C=O to CH2: Clemmenson or Wolff-Kishner reductions a. Wolff-Kishner Reduction: uses H2NNH2, KOH, Δ b. Clemmenson Reduction: uses Zn(Hg), HCl, Δ 2. Reduction of C=O to alcohols a. Using H2 / Pt b. Using LiAlH4 or, less generally, NaBH4 c. Using RM like organolithium or Grignard reagents 3. Addition of H2O to C=O: Hydration a. Product is a geminal diol; also called a hydrate b. Mechanism is nucleophilic addition to C=O c. Is reversible; usually Keq < 1 d. Is catalyzed by either H+ or -OH e. Aldehydes are more reactive than ketones f. Example: acid catalysis of the aldehyde chloral + H2O 6 chloral hydrate: 156 .. .. O H + H CCl3 + H O H O H + H H CCl3 H O H CCl3 H O O H O + + H .. .O . H H CCl3 + H+ H 4. Addition of two ROH to C=O: Acetal formation a. Product is a geminal diether, called an acetal b. Mechanism is nucleophilic addition to C=O followed by an SN1 ether synthesis c. Is reversible; usually H2O is removed to drive the reaction is completion d. Is catalyzed by H+ e. Aldehydes are more reactive than ketones f. Acetals serve as "masked" C=O groups; can be hydrolyzed back to C=O using H2O + H+, just like any ether g. Example: acetone + 2 CH3CH2OH 6 diethyl acetal of acetone: 157 .. .. O H3C + + CH3 O h3C H+ H3C H H CH3 + H .. .O . .. H .. O H3C CH3 O O O + + H+ CH3 H H H3C O + O H H H3C CH3 O H H3C O 5. .. O .. + CH3 + + + H3O+ O O H3C CH3 O CH3 + H+ Addition of H–CN to C=O: Cyanohydrin formation a. Mechanism is essentially the same as H+-catalyzed hydration b. Example: methyl ethyl ketone + HCN 6 cyanohydrin of methyl ethyl ketone: CH3C(=O)CH2CH3 + H+ -CN 6 CH3C(OH)(CN)CH2CH3 6. Addition of 1E amines to C=O: Formation of imines a. Product is a C=N containing compound, called an imine b. Mechanism is a nucleophilic addition of RNH2 to C=O followed by C=N formation by E1 elimination of H2O c. Usually is H+-catalyzed 158 d. Different classes of RNH2 provide different classes of imines, illustrated using acetone here: i. H2N–OH + (CH3)2C=O 6 (CH3)2C=NOH an oxime ii. H2N–NH2 + (CH3)2C=O 6 (CH3)2C=NNH2 a hydrazone iii. H2N–NRR1 + (CH3)2C=O 6 (CH3)2C=NNRR1 a dialkylhydrazone H2N–NHC(=O)NH2 +(CH3)2C=O 6 (CH3)2C=NNHC(=O)NH2 a semicarbazone Example: benzaldehyde + CH3CH2NH2 6 ethyl imine of benzaldehyde using acid catalysis: iv. e. . . .. O + O H + H H .. . H O. N H .. . . O + + H N H .. H H H H N H O + + H N.. H + N N H + H H + H H H H H 159 O H + H 7. Addition of 2E amines to C=O: Formation of enamines a. Mechanism is a nucleophilic addition of RR'NH2 to C=O followed by C=C formation by E1 elimination of H2O b. Usually is H+-catalyzed c. Example using cyclohexanone and diethyl amine: . . .. O + H + H .. . H O. N O H + N H .. + H H H O + N + N H N H2O + H+ + 8. The Wittig Reaction: conversion of C=O into C=C a. Forms alkenes from an aldehyde or ketone and an ylide b. Ylide formation: Prepare according to a two step process: i. Make a phosphonium salt: RR'CHBr + :P(C6H5)3 6 RR'CH–P+(C6H5)3 Brii. Make the ylide: RR'CH–P+(C6H5)3 Br- + C4H9Li 6 RR'C-–P+(C6H5)3 + LiBr + C4H10 c. d. Mechanism is somewhat unusual; an intermediate betaine is formed Example: synthesis of a trisubstituted alkene: 160 + P(C6H5)3 O O + P(C6H5)3 + - P(C6H5)3 O + 9. O P(C6H5)3 Oxidations of aldehydes to give carboxylic acids a. Standard reagents can be used: i. Jones reagent ii. KMnO4, -OH, Δ b. A special reagent that is selective for oxidation of aldehydes to carboxylic acids and does not oxidize alcohols is Tollens reagent i. AgO in aqueous base; dilute acid is added after to isolate the carboxylic acid product ii. Example: (CH3)2CHCH2CHO + AgO 6 (CH3)2CHCH2CO2H + Ag IV. Spectroscopic properties A. IR 1. C=O stretch 1705 - 1750 cm-1, usually the strongest absorption in the spectrum 2. Aldehydes have a Fermi overtone bands at 2720 and 2820 cm-1; ketones do not 1 B. H NMR 1. RCHO appears at δ 9.0 - 10.0 2. H on a C α to the C=O group will appear at δ 2.1 - 2.4 13 C. C NMR 1. Characteristic, usually not very intense resonance at δ 190 -210. 161 162 1. Provide the major product that is produced with the compounds below are subjected to the stated reaction conditions, including stereochemistry when appropriate. If there is no reaction, indicate so by writing NR. a. Br HO O H+ + HO b. O O + H2NNHCNH2 c. OH 1. H2CrO4, H2O, acetone Br 2. 2 CH3CH2OH, H+, ∆ d. O O H 5% aq. HCl 25 EC O e. O Li 1. CH3O , ether 2. H3O+ 163 2. Prepare the following compounds from the starting materials given and any other reagents that you require: a. b. from cyclohexane and (C6H5)3P Br from allyl alcohol and any other reagents you require. OH 164 c. O d. from HC/CH and any other reagents you require. From cyclopentane and any other organic compounds of 3 carbons or less. O 165 3. Compounds known as nitrones are formed when N-substituted derivatives of hydroxylamine react with aldehydes and ketones: H O N + OH N + O a. Write a clear, reasonable mechanism for this reaction. b. Will the (E)- or the (Z)-nitrone be formed as the major product? ________________ 166 4. Citral, C10H16O, is a natural product present in lemongrass, which gives it its distinctive citrus odor and tea made from lemongrass their distinctive flavor. It has two possible E,Z isomers, has the selected IR and NMR properties reported below and undergoes the following chemical reactions: C10H16O2 C O Jones reagent + O OH HO 1. KMnO4 2. Citral C10H16O H3O+ H2NOH O C10H17ON B IR: 1710, 820, 810 cm-1 + NMR: d 10, s, 1H 5.1, s, 1H O OH O a. Provide chemical structures for citral, compound A, and compound B. 167 5. A naïve graduate student (who for our purposes will remain nameless) set out to prepare the compound (C6H5)2CHOH by adding C6H5MgBr to benzaldehyde. To insure that the chemical yield would be high, our dedicated student prepared one mole of the Grignard reagent, added two moles of benzaldehyde, and, after working up the reaction, was delighted to obtain a good yield of a crystalline product. Unfortunately, the product that had been formed was benzophenone! On closer examination of the reaction, an equimolar amount of C6H5CH2OH also was found to have formed. Provide our bewildered friend with reasonable mechanistic interpretation of why these products form. 168 6. An alternative to Clemmenson and Wolff-Kishner reductions of ketones is a process called dithioacetalization–desulfurization. It is illustrated below using the ketone cyclohexanone: O S + HSCH2CH2SH S H+ + H2O H2 Raney Ni A The first step of the reaction sequence is analogous to acetal formation. The ketone is reacted with dithioethanol (HSCH2CH2SH) using a catalytic amount of acid to provide a dithioacetal, A. Provide a clear, reasonable, detailed mechanism that accounts for the synthesis of A from cyclohexanone. 169 7. Formaldehyde, H2C=O, actually is a highly unstable gas that cannot be stored. It readily undergoes a spontaneous, exothermic reaction upon standing to provide a compound called 1,3,5-trioxane. 1,3,5-Trioxane is a stable, crystalline solid, mp 61-62EC, of molecular formula C3H6O3. It has an NMR spectrum that consists of a single resonance at δ 5.4 ppm; its IR spectrum shows no significant absorptions outside of the fingerprint region other than C–H stretching immediately below 3000 cm-1. a. Draw the structure of 1,3,5-trioxane. b. Provide a reasonable, clear, detailed mechanism indicating how formaldehyde is transformed into 1,3,5-trioxane. 170 8. Provide a clear, detailed, reasonable mechanism for the following reaction: O OCH3 H Cl CH3ONa CH3OH 171 OCH3 OH 9. Allylic alcohols are found to be oxidized to ketones when treated with Br2, light, and a base such as sodium carbonate: OH O + Br2 NaCO 3 light Provide a clear, detailed, reasonable mechanism for the reaction. 172 10. Will the following reaction proceed if a stoichiometric amount instead of a catalytic amount of acid is used? Provide a mechanistic reason for your answer. NCH3 O + CH3NH2 H2SO4 toluene 173 + H2O 11. Bombykol is the sex pheromone of the silkworm moth. Provide structures for compounds A through G and for Bombykol when it is prepared by the following route: 1-pentyne + n-C4H9MgBr ))))Q™ A C5H7MgBr ))))Q™ B C6H10O A + formaldehyde B + PBr3 ))))Q™ C C + (C6H5)3P ))))Q™ D C24H24BrP D + n-C4H9Li ))))Q™ E C6H9Br C24H23P E + HC(=O)(CH2)8CO2C2H5 ))))Q™ F + H2 G + LiAlH4 Lindlar ))))Q™ catalyst 1. ether ))))Q™ 2. H2O G F C18H30O2 C18H32O2 Bombykol C16H30O 174 (Note: Wittig reagents don’t react with esters) 12. When dimethoxyacetophenone is reacted with lithium aluminum hydride, compound A is produced. Compound A in turn is found to undergo unusual reactions with acids and bases. When reacted with dilute, aqueous HCl, A provides product C, which exhibits no C=O stretch in its IR spectrum. When A is reacted with the strong base lithium diisopropyl amide, product B is isolated; it has neither C=O or O–H stretches in its IR spectrum. Provide structures for A, B, and C: N O OCH3 OCH3 1. LiAlH4 2. H2O B C9H10O2 NMR: δ 7.1 (s, 5H); 5.6 (d, 1H); 4.4 (d, 1H); 3.9 (s, 3H) Li A C10H14O3 IR: 3550 cm-1 aq. HCl 175 C C16H16O4 IR: 3550 cm-1 NMR: δ 7.1 (s, 10H); 5.6 (d, 2H); 4.4 (d, 2H); 3.3 (s, 2H) 13. Identify two different ways to prepare alcohol Z using a Grignard reagent and an aldehyde or a ketone by drawing a clear chemical reaction for each way below. HO Z 176 177