C h a p t e r T w e n t y: Aldehydes and Ketones (S)-Warfarin (named for the Wisconsin Alumni Research Foundation), a useful clinical anticoagulant which as a racemate is also a rat poison
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CM 323: Summary of Important Concepts YConcepts for Chapter 20: Aldehydes and Ketones I. Nomenclature and Properties A. IUPAC 1. Aldehydes a. RC, alkanal i. Sometimes also named as alkylcarboxaldehydes, where R = alkyl b. when the C group is named as a substituent, it is the formyl substituent c. example: i. C 3 C 2 C 2 C(C 3 )C 2 C 2 C 4-methylheptanal d. common aldehydes: i. 2 C= formaldehyde ii. C 3 C acetaldehyde iii. C 6 5 C benzaldehyde 2. Ketones a. RR C=, alkanone i. Sometimes also named as alkyl alkyl ketones b. example: i. C 3 C 2 C=C 2 C(C 3 )C 2 C(C 3 ) 2 5,7-dimethyl-3-octanone c. common ketones: i. C 3 C=C 3 acetone ii. C 6 5 C=C 3 acetophenone II. iii. C 6 5 C=C 6 5 benzophenone B. Properties 1. Both C and in C= are sp 2 -hybridized 2. Are pretty polar (RC have µ. 2.5 D) 3. Thermodynamic stability: ketones > aldehydes Preparations of aldehydes and ketones A. Methods from previous chapters 1. zonolysis of alkenes R R 1 R 2 R 1. 3 2. Zn, 3 R 1 R 2 2. ydrolysis of alkynes R R 2 S 4, 2 gs 4 R R 155
3. xidations of alcohols RC 2 PCC C 2 Cl 2 R (Collins reagent also efffects this oxidation) RR 1 C Jones reagent R R 1 III. Reactions of aldehydes and ketones A. Key element of chemical reactivity The C of the C= bond is electrophilic. It will react directly with a good (charged) nucleophile to provide a new C Nu bond. Nu - 2 C= 6 Nu C 2 - It will react with a poor (neutral) nucleophile after activation by acid catalysis B. Reactions 1. Reduction of C= to C 2 : Clemmenson or Wolff-Kishner reductions a. Wolff-Kishner Reduction: uses 2 NN 2, K, b. Clemmenson Reduction: uses Zn(g), Cl, 2. Reduction of C= to alcohols a. Using 2 / Pt b. Using LiAl 4 or, less generally, NaB 4 c. Using RM like organolithium or Grignard reagents 3. Addition of 2 to C=: ydration a. Product is a geminal diol; also called a hydrate b. Mechanism is nucleophilic addition to C= c. Is reversible; usually K eq < 1 d. Is catalyzed by either or - e. Aldehydes are more reactive than ketones f. Example: acid catalysis of the aldehyde chloral 2 6 chloral hydrate: 156
... CCl 3 CCl 3... CCl 3 CCl 3 4. Addition of two R to C=: Acetal formation a. Product is a geminal diether, called an acetal b. Mechanism is nucleophilic addition to C= followed by an S N 1 ether synthesis c. Is reversible; usually 2 is removed to drive the reaction is completion d. Is catalyzed by e. Aldehydes are more reactive than ketones f. Acetals serve as "masked" C= groups; can be hydrolyzed back to C= using 2, just like any ether g. Example: acetone 2 C 3 C 2 6 diethyl acetal of acetone: 157
3 C... C 3 3 C C 3... h 3 C C 3 3 C... C 3 3 C C 3 3 C C 3... 3 3 C C 3 3 C C 3 5. Addition of CN to C=: Cyanohydrin formation a. Mechanism is essentially the same as -catalyzed hydration b. Example: methyl ethyl ketone CN 6 cyanohydrin of methyl ethyl ketone: C 3 C(=)C 2 C 3 - CN 6 C 3 C()(CN)C 2 C 3 6. Addition of 1E amines to C=: Formation of imines a. Product is a C=N containing compound, called an imine b. Mechanism is a nucleophilic addition of RN 2 to C= followed by C=N formation by E 1 elimination of 2 c. Usually is -catalyzed 158
d. Different classes of RN 2 provide different classes of imines, illustrated using acetone here: i. 2 N (C 3 ) 2 C= 6 (C 3 ) 2 C=N an oxime ii. 2 N N 2 (C 3 ) 2 C= 6 (C 3 ) 2 C=NN 2 a hydrazone iii. 2 N NRR 1 (C 3 ) 2 C= 6 (C 3 ) 2 C=NNRR 1 a dialkylhydrazone iv. 2 N NC(=)N 2 (C 3 ) 2 C= 6 (C 3 ) 2 C=NNC(=)N 2 a semicarbazone e. Example: benzaldehyde C 3 C 2 N 2 6 ethyl imine of benzaldehyde using acid catalysis:.... N N...... N N...... N N 159
7. Addition of 2E amines to C=: Formation of enamines a. Mechanism is a nucleophilic addition of RR'N 2 to C= followed by C=C formation by E 1 elimination of 2 b. Usually is -catalyzed c. Example using cyclohexanone and diethyl amine:.... N N...... N N N 2 8. The Wittig Reaction: conversion of C= 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'CBr :P(C 6 5 ) 3 6 RR'C P (C 6 5 ) 3 Br - ii. Make the ylide: RR'C P (C 6 5 ) 3 Br - C 4 9 Li 6 RR'C - P (C 6 5 ) 3 LiBr C 4 10 c. Mechanism is somewhat unusual; an intermediate betaine is formed d. Example: synthesis of a trisubstituted alkene: 160
- P(C 6 5 ) 3 P(C 6 5 ) 3 P(C 6 5 ) 3 P(C 6 5 ) 3 9. xidations of aldehydes to give carboxylic acids a. Standard reagents can be used: i. Jones reagent ii. KMn 4, -, b. A special reagent that is selective for oxidation of aldehydes to carboxylic acids and does not oxidize alcohols is Tollens reagent i. Ag in aqueous base; dilute acid is added after to isolate the carboxylic acid product ii. Example: (C 3 ) 2 CC 2 C Ag 6 (C 3 ) 2 CC 2 C 2 Ag IV. Spectroscopic properties A. IR 1. C= 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 B. 1 NMR 1. RC appears at δ 9.0-10.0 2. on a C α to the C= group will appear at δ 2.1-2.4 C. 13 C NMR 1. Characteristic, usually not very intense resonance at δ 190-210. 161
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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 b. 2 NNCN 2 c. Br 1. 2 Cr 4, 2, acetone 2. 2 C 3 C 2,, d. 5% aq. Cl 25 EC e. 1. Li, ether C 3 2. 3 163
2. Prepare the following compounds from the starting materials given and any other reagents that you require: a. from cyclohexane and (C 6 5 ) 3 P b. Br from allyl alcohol and any other reagents you require. 164
c. from C/C and any other reagents you require. d. From cyclopentane and any other organic compounds of 3 carbons or less. 165
3. Compounds known as nitrones are formed when N-substituted derivatives of hydroxylamine react with aldehydes and ketones: N N 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, C 10 16, 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: C 10 16 2 C 1. KMn 4 2. 3 Citral C 10 16 Jones reagent 2 N C 10 17 N B IR: 1710, 820, 810 cm -1 NMR: d 10, s, 1 5.1, s, 1 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 (C 6 5 ) 2 C by adding C 6 5 MgBr 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! n closer examination of the reaction, an equimolar amount of C 6 5 C 2 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: S S SC 2 C 2 S 2 2 Raney Ni A The first step of the reaction sequence is analogous to acetal formation. The ketone is reacted with dithioethanol (SC 2 C 2 S) 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, 2 C=, 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 C 3 6 3. 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 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: Cl C 3 Na C 3 C 3 C 3 171
9. Allylic alcohols are found to be oxidized to ketones when treated with Br 2, light, and a base such as sodium carbonate: Br 2 NaC 3 light a clear, detailed, reasonable mechanism for the reaction. Provide 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. NC 3 2 S 4 C 3 N 2 2 toluene 173
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-c 4 9 MgBr ))))Q A C 5 7 MgBr A formaldehyde ))))Q B C 6 10 B PBr 3 ))))Q C C 6 9 Br C (C 6 5 ) 3 P ))))Q D C 24 24 BrP D n-c 4 9 Li ))))Q E C 24 23 P E C(=)(C 2 ) 8 C 2 C 2 5 ))))Q F C 18 30 2 (Note: Wittig reagents don t react with esters) Lindlar F 2 ))))Q G C 18 32 2 catalyst 1. ether G LiAl 4 ))))Q Bombykol C 16 30 2. 2 174
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 Cl, A provides product C, which exhibits no C= stretch in its IR spectrum. When A is reacted with the strong base lithium diisopropyl amide, product B is isolated; it has neither C= or stretches in its IR spectrum. Provide structures for A, B, and C: B C 3 C 3 1. LiAl 4 2. 2 A C 10 14 3 IR: 3550 cm -1 N Li C 9 10 2 NMR: δ 7.1 (s, 5); 5.6 (d, 1); 4.4 (d, 1); 3.9 (s, 3) aq. Cl C C 16 16 4 IR: 3550 cm -1 NMR: δ 7.1 (s, 10); 5.6 (d, 2); 4.4 (d, 2); 3.3 (s, 2) 175
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. Z 176