Enamines are similar to enols and enolates in that they also undergo alpha substitution reactions.
The process of performing a carbonyl alpha substitution reaction via an enamine intermediate is called the Stork enamine synthesis. Let's work through this reaction.
Draw in the structures for the enamine and show it attacking the alkyl halide to form the "3º imine." Also draw the structure of the final and carbonyl product.
Enamines attack alkyl halides just as enolates do.
The trick to the Stock enamine synthesis is to remember how enamines (and imines) are related to carbonyls:
Enamines are formed from carbonyls and 2º amines.
Enamines (and imines) are converted back to carbonyls with H3O+ (acidic hydrolysis).
MendelSet practice problem # 742 submitted by Matt on July 27, 2011.
Enolates are nucleophiles and react with a variety of electrophiles.
Carbonyls are electrophiles. But aldehydes/ketones and esters/acid chlorides often form different products.
Use curved arrows to draw a mechanism for each reaction below. How do the two products differ?
When enolates attack, the arrow is drawn from the double bond to the electrophile, and NOT from the negatively charged oxygen! The enolate's carbonyl reforms, and a new bond is created at the alpha position.
But Aldehydes and ketones react differently than ester and acid chlorides.
a) Aldehydes and ketones are oxidation state II carbonyls (the carbonyl has carbon-heteroatom bonds- the double bonded oxygen counts twice).
They do not have a built-in leaving group, and so undergo nucleophilic acyl addition reactions. The carbonyl on the electrophile becomes an alcohol.
So the product from this reaction is a beta hydroxyl carbonyl. If this β-hydroxyl carbonyl is heated up, the hydroxyl will eliminate to from an alpha, beta unsaturated carbonyl.
The mechanism for a) is very similiar to that of an aldol condensation reaction.
b) Esters (and acid chlorides) are oxidation state III carbonyls (the carbonyl carbon has three carbon-heteroatom bonds). They have a built-in leaving group (-OR in the case of an ester, and Cl- for an acid chloride), and so undergo nucleophilic acyl substitution reactions. ("up, down, kick"). The carbonyl on the electrophile is reformed.
So the product from this reaction is a beta keto carbonyl.
The mechanism for b) is very similiar to that of a Claisen condensation reaction.
MendelSet practice problem # 743 submitted by Matt on July 27, 2011.
After a sample of optically pure (S)-2-ethyl-cyclohexanone is dissolved in an aqueous solution for several hours, a significant loss of optical activity is observed. Explain.
Carbonyls are in equilibrium with their enol forms. This process is called keto-enol tautomerization. (See problems 738 and 739). So when this compound is placed in water a small amount of it will constantly be converted to its enol form, and then back again to the carbonyl form.
But the enol form is achiral! (the alpha carbon is sp2 instead of sp3 as in the carbonyl form).
So when the achiral enol goes back to its carbonyl form, half will become (S) and the other half will become (R). The stereocenter becomes "scrambled." The process of an optically pure compound becoming a racemic mixture is called racemization.
MendelSet practice problem # 744 submitted by Matt on July 27, 2011.
The molecule below has five different types of hydrogens (A through E). Rank each in order of decreasing acidity.
(1 = most acidic). Explain your reasoning.
Hydrogens D and E are alpha to two carbonyls and so will be the more acidic than C, which is only alpha to one carbonyl. This is because the enolates that arise from deprotonate at D and E have more resonance forms than the enolate that arrises at C.
Because ketones are more electron withdrawing than esters, D will be more acidic than E. So far we have:
D > E > C > (other)
The carbanions that would arrise from deprotonation of carbons A and B both do not have any resonance forms, so we don't expect either to be acidic. But because A is next to a fluorine atom, which is an electron withdrawing group, A will be more acidic than B. So the overall order is:
(most acidic) D > E > C > A > B (least acidic)
MendelSet practice problem # 745 submitted by Matt on July 27, 2011.
Show what combination of aldehyde, ketone, and/or ester can prepare each compound below. Every compound is a Claisen or aldol product.
When doing synthesis problems involving enolates (carbonyl alpha substitutions, aldol and Claisen condensations), there are some things to keep in mind:
The alpha carbon must have been the enolate (nucleophile). So it's importnant to identify the alpha carbon!
The bond is always made between the alpha and beta carbon.
Beta hydroxyl products come from aldol condensations (aldehydes/ketones), beta carbonyl products come from Claisen condensations (esters/acid chlorides). (See problem 743 for these mechanisms.)
Also, α,β-unsaturated products come from β-hydroxy products, which come from aldol condensations.
After finding the alpha carbon, it's a good idea to mark the "cut" or "disconnection" where the new bond was formed. This will always be between the alph and beta carbons. I mark this with a dotted line.
a) This product is an α,β-unsaturated carbonyl, which must have come from a β-hydroxyl carbonyl. So this is an aldol condensation.
The α carbon must have come form the enolate. Because the β carbon is an alcohol, the electrophile must have been an aldehyde or ketone. So the two carbons on the right were the enolate, and the two carbons (and phenyl) on the left were an aldehyde.
b) The product is β-keto so this must have been a Claisen condensation.
The β carbon is an ketone, so the electrophile must have been an ester.
There are actually two different combinations of esters that would result in this product. I arbitrarily chose the alpha carbon to belong to the left carbonyl.
c) β-keto product so this must have been a Claisen style condensation. It's easiest if you have the alpha carbon belong to the left carbonyl, so an intramolecule reaction isn't necessary.
The β carbon is already an ester, so the electrophile had to have been more than an ester, as regular esters become ketones after a Claisen condensation.
d) This is a Robinson annulation product, which comes from an intramolecular condensation.
The α,β-unsaturated carbonyl must have come from a β-hydroxyl carbonyl. (aldol condensation)
Because the β carbon became an alcohol, the electrophile must have been an aldehyde or ketone.
MendelSet practice problem # 746 submitted by Matt on July 27, 2011.
Show a combination of enolate (nucleophile) and electrophile that can produce each compound below.
Remember that all enolates come from carbonyls.
This problem is similar to problem 746, except each synthesis is a little harder.
The general strategy for carbonyl alpha substitution synthesis problems is the same: locatte the alpha carbon, and remember that the bond is always formed between the alpha and beta carbons.
a) The carbonyl on the left contains the alpha carbon, so that must have been the enolate.
So the beta carbon on the right must have been the electrophile (and been attacked by the enolate).
So how can the beta carbon keep its carbonyl AND keep an -OEt group? Doesn't the -OEt group act as a leaving group in a Claisen condensation? The starting ester must have had two -OEt groups!
b) This one is intimidating because it's intramolecular, but the same logic applies. The left carbonyl has the alpha carbon and so must have been the enolate.
The beta carbon is now an alcohol, so before it was attacked it must have been a ketone (aldol condensation).
c) This is one of the hardest synthesis problems you will see relating to enolates and carbonyl alpha substitution reactions. Why is it hard? Because you have to use a special electrophile.
Usually you add a carbon chain to the alpha position of a carbonyl by reacting an enolate with an alkyl halide, suhc as propyl bromide.
So how do you add a carbon chain that wraps and meets again at the alpha carbon? By using 1,3-dibromo propane and doing two consecutive alkyl additions.
MendelSet practice problem # 747 submitted by Matt on July 27, 2011.
Alpha bromination is usually carried out under acidic conditions via the enol intermediate.
Alpha bromination is uncontrollable under basic conditions, which goes through the enolate intermediate. Let's explore why.
a) Rank each carbonyl below in order of decreasing alpha-proton acidity (1= most acidic). Explain.
b) based on a), why does the reaction below lead to polyhalogenation?
a) Bromine is an electron withdrawing group (EWG), which makes nearby protons more acidic. So the carbonyl with two bromines is the most acidic.
b) To perform alpha bromination, the enolate (or enol) must first be formed, which then attacks Br2.
The problem with doing this under basic conditions is that each successive bromination leads to a carbonyl that is more acidic, and so forms an enolate even more easily. So once this reaction starts, it's difficult to control.
Enols are less nucleophilic than enolates, so this react can be controlled under acidic conditions. (Br2/H3O+ instead of Br2/NaOH).
MendelSet practice problem # 748 submitted by Matt on July 27, 2011.