h a p t e r T w e n t y o n e : Enols, Enolates, and Aldollike ondensations Li LDA 1. R TF R 2. 3 R A directed aldol reaction, used in the synthesis of periplanone B, a cockroach attractant
M 323: Summary of Important oncepts Yoncepts for hapter 21: Enols, Enolates, and Aldollike ondensations I. Properties A. The " s of aldehydes and ketones are relatively acidic with pk a of about 2025. This is due to the inductively acidifying effect of the = group: δ δ R() α R() 1. onsequences of " acidity: a. Just as the of the = group is electrophilic and readily undergoes bondforming reactions with nucleophiles, the " s of aldehydes and ketones are nucleophilic and readily undergo bondforming reactions with electrophiles. b. Nucleophilicity of " is activated by acid or base catalysis: i. Acid: Enol formation I. Enol forms according to Zaitsev's rule:.... α R() α keto tautomer R() α R().... α R() α R() enol tautomer " is nucleophilic 193
ii. Base: Enolate formation I. Enolate forms according to Zaitsev's rule: α R() R() 2 α α R() " is nucleophilic an enolate (conjugate base of enol) II. Reactions of enols and enolates A. Acidcatalyzed monohalogenation of aldehydes and ketones 1. Markovnikovtype addition of X to the = bond of an enol:.... B. Basecatalyzed polyhalogenation of aldehydes and ketones 1. Markovnikovtype addition of X to the = bond of an enolate 2. As a consequence of the increased acidity of any remaining " s in the product, all " s are replaced by an X: 194
R() R() 2 pk a = 25 R() R() 2 R() pk a = 18 3. In the case of a methyl ketone, all three " s are replaced by X to give a 1,1,1trihalo2alkanone product. This product is unstable and undergoes a subsequent additionelimination reaction to result in a carboxylic acid and haloform. The net reaction is called the haloform reaction: R() R() R() (mechanism is as above) R() R(). Basecatalyzed Aldol and rossed Aldol ondensations 1. A nucleophilic enolate reacts adds to the electrophilic of the = bond of an aldehyde or a ketone to provide an aldol, which is a hydroxyaldehyde or hydroxyketone. If the reaction is performed with heating, the aldol product undergoes subsequent elimination of 2 to provide an aldoldehydration product, a conjugated alkenone: 195
t 4 9 t 4 9 t 4 9 t 4 9 (this alcohol, called an aldol, forms when reaction is run cold) t 4 9 a. ombinations of aldehydes & ketones that provide a single aldol reaction product: i. 2 identical aldehydes ii. 2 identical ketones iii. 1 aldehyde with " s and 1 aldehyde with no " s iv. 1 aldehyde with " s and 1 ketone with no " s v. 1 ketone with " s and 1 aldehyde with no " s vi. 1 ketone with " s and 1 ketone with no " s D. onjugate or 1,4 Additions 1. onjugated alkenones formed from aldoldehydration reactions have electrophilic $ s. An illustration showing acidcatalyzed electrophilic activation of the $ :.. α β α β α β α β 196
2. A nucleophile can react with a conjugated alkenone at its electrophilic $. The resultant product is a 1,4diketone 3. Typical nucleophiles: a. enolates (this reaction is called the Michael addition; the mechanism of the addition is virtually identical to that of the aldol reaction) b. N c. SR d. uli reagents 4. ther, stronger, more basic nucleophiles usually add to the of the = group by a 1,2addition process (yielding kinetic products) 5. The mechanism of conjugate addition is a 1,4addition (yielding thermodynamic products) 6. Typical example: ( 2 =) 2 uli 1. ether 2. 3 E. Enolate alkylations 1. In the aldol reaction, an enolate is being alkylated with an electrophilic = containing compound 2. In general, enolates will undergo nucleophilic, " Z bond forming reactions with any reasonably reactive electrophile, Z 3. Typical electrophiles: a. 3 X b. 1E RX c. allylic or benzylic RX 4. In practice, polyalkylation competes when product has " s; see part B above. 5. A typical example: 3 I K 2 minor major ( other multiply methylated products, too) 197
F. Stork enamine synthesis 1. Enamines (see review of chapter 15) have chemical behavior analogous to enols and enolates: N.. N R R " is nucleophilic 2. They can be alkylated with electrophiles at their nucleophilic ". Unlike ketones and aldehydes, the products do not undergo polyalkylation. ydrolysis of the products in dilute acid returns the now alkylated ketone or aldehyde: N N 3 I N I 3 N 2 I (you should be able to write a mechanism for this sequence without much trouble) 198
1. onsidering the structure of the ketone below, provide a clear, reasonable mechanism for the observation that optically active (R)piperitone is converted to racemic piperitone when dissolved in a solution of 3 2 Na in 3 2. (R)Piperitone 2. The compounds below yield a single major product when subjected to the reaction conditions given. Provide the structure of the product for the reaction, including stereochemical information if appropriate: 2, 40 E 199
3. Prepare the following compounds using the starting materials given and according to the restrictions provided. a. from propanal, acetylene, and any other reagents you require. b. from acetophenone and acetaldehyde l 200
c. 4methylpentanol from isopropyl alcohol 4. Provide short answers for each of the following questions: a. Define tautomerism. b. Neglecting (E),(Z) stereoisomers, there are three tautomeric forms possible for phenylacetone (1phenyl2propanone). Draw them. 201
c. Label which group of " hydrogens in phenylacetone is more acidic by drawing the molecule and circling the more acidic group of hydrogens. d. Rank these compounds in order from strongest to weakest base: 3 2 ( 3 2 ) 2 N 3 2 3 3 2 MgI A B D 3 2 6 5 2 3 E F 5. Using what you know concerning NMR and resonance theory, explain the following observations: At 30 E, N,Ndimethylformamide (shown below) exhibits an 1 NMR spectrum consisting of three singlets with area ratio 1:3:3. When heated to 150 E, two of these singlets merge to form a new singlet, while the remaining singlet is unchanged. The resultant spectrum is that of two singlets with area ratio 1:6. When recooled to room temperature, the original NMR spectrum reappears. 3 N 3 202
6. Provide a reasonable, clear, complete reaction mechanism for the following transformation: Na N aq. Na 203
204