Aldehydes and Ketones Reactions Dr. Sapna Gupta
Reactions of Aldehydes and Ketones Nucleophilic Addition A strong nucleophile attacks the carbonyl carbon, forming an alkoxide ion that is then protonated. A weak nucleophile will attack a carbonyl if it has been protonated, thus increasing its reactivity. Aldehydes are more reactive than ketones. (WY?) Aldehydes and Ketones Reactions 2
Reactions of Aldehydes and Ketones 1) Nucleophilic addition a) Carbon nucleophile i. Grignard reaction ii. Addition of CN iii. Wittig reaction b) xygen nucleophile i. Addition of water ii. Addition of alcohol c) Nitrogen nucleophile 2) xidation 3) Reduction 1) RMgX or RLi 2) 3 1) CN 2) 3 Ph 3 P - C 2-2, 3 R, 3 1) RN 2 2) 3 R CN C 2 R R NR 2 Cr 4 acids - but aldehydes only 1) NaB 4 or LA 2) 3 Aldehydes and Ketones Reactions 3
(C-Nu) Grignard Reactions C 3 C 2 -MgBr GR Formaldehyde gives a 1 alcohol. - [ MgBr] ether Cl C 3 C 2 -MgBr - C- C 3 C 2 -C 2 C 2 3 C 2 -C 2 Mg 2 Formaldehyde Mg Br ether A magnesium 1-Propanol alkoxide (a 1 alcohol) - [ MgBr] Acetaldehyde C 2 3 C 2 -C 2 Mg 2 A magnesium 1-Propanol alkoxide (a - [ 1 MgBr] alcohol) Cl GR any other CRC 3 2 (an -Caldehyde) gives 2 a 2 alcohol. Mg Br ether Acetaldehyde (an aldehyde) Ph- MgBr Ph- MgBr Phenyl- - [ Acetone MgBr] Cl bromide Mg 2 ether 2 - [ MgBr] Cl A magnesium Ph 1-Cyclohexylethanol 2 Ph Acetone alkoxide A magnesium(a 2 alcohol; 2-Phenyl-2-propanol (a ketone) alkoxide (racemic) (a 3 alcohol) GR ketone gives magnesium a 3 (a alcohol. ketone) Phenylmagnesium bromide - C- Formaldehyde ether A magnesium alkoxide ether Cl 2 Mg 2 Aldehydes and Ketones Reactions 4 Mg 2 1-Cyclohexylethanol (a 2 alcohol; (racemic) - [ MgBr] Cl Mg 2
(C-Nu) ther rganometallics rganolithium compounds are generally more reactive in C= addition reactions than RMgX, and typically give higher yields. Li Phenyllithium 3,3-Dimethyl-2- butanone - Li A lithium alkoxide (racemic) Cl 2 Addition of an alkyne anion followed by treatment with 3 gives an - acetylenic alcohol. 3,3-Dimethyl-2-phenyl- 2-butanol (racemic) C C: - Na Sodium acetylide Cyclohexanone C C - Na A sodium alkoxide Cl 2 C C 1-Ethynylcyclohexanol Aldehydes and Ketones Reactions 5
(C-Nu) Addition of CN CN is highly toxic. Use NaCN or KCN in base to add cyanide, then protonate to add. Reactivity formaldehyde > aldehydes > ketones >> bulky ketones. The cyano group can be hydrolyzed or reduced ydrolysis of a cyanohydrin produces an -hydroxycarboxylic acid (Sec. 18.8) Reduction of a cyanohydrin produces a b-aminoalcohol Aldehydes and Ketones Reactions 6
(C-Nu) Wittig Reaction Nucleophilic addition of phosphorus ylides. Product is alkene. C= becomes C=C. Formation of the Ylide Aldehydes and Ketones Reactions 7
(C-Nu) Mechanism of Wittig Reaction The negative C on ylide attacks the positive C of carbonyl to form a betaine. xygen combines with phosphine to form the phosphine oxide. _ Ph 3 P CC 3 ylide 3 C Ph C carbonyl Ph 3 P C C C 3 C 3 Ph _ Ph 3 P C C C 3 C 3 Ph Ph 3 P C C C 3 C 3 Ph betaine Ph 3 P 3 C C C C 3 Ph alkene Aldehydes and Ketones Reactions 8
(C-Nu) Wittig Reaction contd Can be used for monosubstituted, disubstituted, and trisubstituted alkenes but not tetrasubstituted alkenes The reaction yields a pure alkene of known structure For comparison, addition of C 3 MgBr to cyclohexanone and dehydration with, yields a mixture of two alkenes Aldehydes and Ketones Reactions 9
(-Nu) Addition of Water Formation of ydrate (gem diol) In acid, water is the nucleophile. In base, hydroxide is the nucleophile. Mechanism C 2 C K = 2000 C 3 C C 3 2 C C 3 C 3 K = 0.002 Aldehydes and Ketones Reactions 10
(-Nu) Addition of Alcohol - Acetals Reaction of alcohol with aldehyde gives acetals Reaction of alcohol with ketone gives ketals Aldehydes and Ketones Reactions 11
(-Nu) Mechanism of Acetal Formation Is acid-catalyzed. Adding to carbonyl makes it more reactive with weak nucleophile, R. emiacetal forms first, then acid-catalyzed loss of water, then addition of second molecule of R forms acetal. All steps are reversible. Mechanism next slide Aldehydes and Ketones Reactions 12
(-Nu) Mechanism of Acetal Formation Aldehydes and Ketones Reactions 13
(-Nu) ydrolysis of the Acetal Since all acetal formations are reversible; they can be converted back to aldehyde or ketone using water. Aldehydes and Ketones Reactions 14
(-Nu) Cyclic Acetals Addition of a diol produces a cyclic acetal. Sugars commonly exist as acetals or hemiacetals. Aldehydes and Ketones Reactions 15
(-Nu) Acetals as Protecting Groups Acetal protecting groups are stable to most reagents except aqueous acid Aldehydes more reactive than ketones so if there is an aldehyde and ketone to protect then aldehyde will be protected first. Example: An ester can be reduced in the presence of a ketone protected as an acetal Aldehydes and Ketones Reactions 16
(N-Nu) Addition of Ammonia and Amines Ammonia, 1 aliphatic amines, and 1 aromatic amines react with the C= group of aldehydes and ketones to give imines (Schiff bases). Cyclohexanone C 3 C N 3 N 2 Ammonia An imine (a S chiff base) 2 N C 3 C=N 2 Formation of an imine occurs in two steps: Step 1: Carbonyl addition followed by proton transfer. Step 2: Loss of 2 and proton transfer to solvent. Acetaldehyde Aniline An imine (a Schiff base) C 2 N-R : - C N-R C N-R C N-R C N-R C N-R 2 An imine Aldehydes and Ketones Reactions 17
(N-Nu) ther Ammonia Derivatives Aldehydes and Ketones Reactions 18
(N-Nu) Specific Reactions of Amines The reaction of carbonyl with 2,4-dinitrophenyl hydrazine is used as a qualitative test. The product is usually a solid and a stable compound (and orange!) Wolf Kishner Reduction: Reaction with hydrazine followed by reaction with K reduces the ketone to methylene. C 2 C 2 N N 2 C 2 C NN 2 K heat C 2 C3 Aldehydes and Ketones Reactions 19
(N-Nu) Reactions with Secondary Amines Secondary amines react with the C= group of aldehydes and ketones to form enamines. -N N 2 Cyclohexanone Piperidine (a secondary amine) An enamine The mechanism of enamine formation involves formation of a tetrahedral carbonyl addition compound followed by its acid-catalyzed dehydration. We discuss the chemistry of enamines in more detail in amines. Aldehydes and Ketones Reactions 20
xidation: f Aldehydes Easily oxidized to carboxylic acids. Tollens Test: Add ammonia solution to AgN 3 until precipitate dissolves. Aldehyde reaction forms a silver mirror. R RC C 2 Ag(N 3 ) 2 3 _ 2 Ag(N 3 ) 2 3 _ 2 2 Ag R C _ 4 4N N 3 3 2 2 2 2 Aldehydes and Ketones Reactions 21
xidation: f Ketones Iodoform Test Methyl ketones oxidize to carboxylic acids with Na and KI. Na, KI CI 3 carboxylic acid iodoform (yellow ppt) Aldehydes and Ketones Reactions 22
Reduction: f Aldehydes and Ketones Sodium borohydride, NaB 4, reduces C=, but not C=C. Lithium aluminum hydride, LiAl 4, much stronger, difficult to handle. Catalytic ydrogenation ydrogen gas with catalyst also reduces the C=C bond. Raney nickel, fine Ni (or Pt or Rh) powder saturated with hydrogen gas. Raney Ni Aldehydes and Ketones Reactions 23
Reduction: f Carbonyl to Methylene Clemmensen reduction if molecule is stable in hot acid. C C 2 C 3 Zn(g) C 2 C 2 C 3 Cl, 2 Wolff-Kishner reduction if molecule is stable in very strong base. C 2 C 2 N N 2 C 2 C NN 2 K heat C 2 C3 Using thioacetal (like acetals but using thiols instead of alcohols) Aldehydes and Ketones Reactions 24
Key Concepts 1) Nucleophilic addition a) Carbon nucleophile i. Grignard reaction ii. Addition of CN iii. Wittig reaction b) xygen nucleophile i. Addition of water ii. Addition of alcohol c) Nitrogen nucleophile 2) xidation 3) Reduction Aldehydes and Ketones Reactions 25