The carbon atom directly adjacent to a carbonyl group is known as the a-carbon, while hydrogen atoms attached to the a-carbon are known as a-hydrogens.

• Carbonyl-containing molecules, such as aldehydes, ketones, and esters, have a moderately acidic a position, with pKa values in the 21–25 range.

• The relative acidity of a carbon-bound H atom is mostly attributable to the stability of the resonance stabilized anion, known as an enolate anion, formed after deprotonation.

• The best way to depict enolate anions is as a hybrid of two contributing structures.

One contributing structure has a carbonyl p bond and imparts the negative charge on the a-carbon atom^^. The other contributing structure has a C"C p bond and deposits the negative charge on the oxygen atom.^^

• Because O is more electronegative than C and hence better able to accept the negative charge, the contributing structure with the negative charge on the O atom is the predominant contributor to the hybrid.

• Despite their charge distribution, enolate anions respond as carbon nucleophiles, forming new carbon-carbon bonds, making them significant in organic synthesis.

• In SN2 reactions, enolate anions react with haloalkanes.

In carbonyl addition reactions, enolate anions react with aldehydes, ketones, and esters.

• Enolate anions react predominantly at C rather than O in electrophilic processes for at least two reasons.

• The reaction at C produces more stable compounds with a reasonably strong C "The op bond.

Reaction at O would result in products with a lower C "– C p bond The enolate O atom, which carries the majority of the resonance hybrid's negative charge, is more closely connected with a counterion such as Na1 or Li1.

• The counterion provides a shielding effect that inhibits electrophilic processes, which is increased by the aggregate structure of enolate anions in solution.

• Enolate anions formed from aldehydes or ketones combine with a second molecule of aldehyde or ketones to produce a carbonyl addition reaction and form a new carbon-carbon bond in the aldol reaction.

The mechanism of base-catalyzed aldol reactions involves first deprotonating the a-hydrogen in the base to produce an enolate anion, which is a strong nucleophile that attacks another aldehyde or ketone molecule to produce a carbonyl addition intermediate, which then reacts with water to produce a b-hydroxy aldehyde or ketone product and regenerates the original base.

• The aldol reaction is termed base-catalyzed since the base is replenished at the conclusion of the reaction.

• Acid may also catalyze the aldol process.

• The acid-catalyzed aldol reaction mechanism

One or two additional chiral centers are frequently formed in both acid- and base-catalyzed aldol reactions, resulting in racemic mixtures unless the original aldehyde, ketone, or catalyst is chiral and present as a single enantiomer.

• Aldol reactions are easily reversible, especially in bases.

• Equilibrium in aldol reactions favors products in the case of aldehydes, whereas little product is frequently produced in the case of ketones.

• The b-hydroxy aldehyde or ketone products of aldol reactions dehydrate rapidly and lose H2O to provide an a,b-unsaturated aldehyde or ketone.

Dehydration can occur under aldol reaction conditions, or it can be accomplished by heating in acid, in which case the carbonyl tautomerizes to the enol form, the other (non-enol) OH group is protonated, and H2O departs with a proton to provide the a,b-unsaturated aldehyde or ketone.

• In the presence of two distinct aldehydes or ketones, crossed aldol reactions with high yields of a desired product are often not attainable.

• Crossed aldol reactions with catalytic hydroxide and two distinct aldehydes or ketones do not often provide high yields of a desired product because a mixture of products occurs.

Intramolecular aldol reactions can be utilized to build five- or six-membered rings from dicarbonyl compounds (either aldehydes or ketones), which form preferentially to smaller or bigger rings that could form.

To become proficient in retrosynthetic analysis, it is necessary to understand that the a,b-unsaturated carbonyl and b-hydroxy carbonyl functional groups are the typical result of an aldol reaction.

• The aldol reaction involves the nucleophilic addition of an aldehyde or ketone's enolate anion to the carbonyl group of another aldehyde or ketone.

An aldol reaction produces b-hydroxyaldehyde or b-hydroxyketone. An aldol reaction can be either basic or acid catalyzed. It is base catalyzed if the base is regenerated at the conclusion of the reaction, and acid catalyzed if the acid is regenerated.

• Claisen condensation: refers to involving two ester molecules reacting in base to give a b-ketoester product

• The Claisen condensation mechanism involves the reaction of one ester molecule with a base to form an enolate, which then reacts as a nucleophile with another ester molecule to form a tetrahedral carbonyl addition intermediate, in which the!OR group is lost to form a b-ketoester, which is deprotonated at the a position by the RO2.

• In a Claisen condensation, the base is RO2, with R selected to match the alkoxy groups on the ester starting material.

When RO2 is employed as the base, the position of equilibrium for the initial enolate-forming step is much to the side of the beginning ester depending on relative acid-base strengths; hence, the modest quantity of enolate anion generated will have plenty of ester to react with.

• Enamines are C-containing compounds "C—N bonds are produced via the interaction of an aldehyde or ketone with a secondary amine, most often pyrrolidine or morpholine.

• Enamines are essential in synthesis because the b-carbon is a nucleophile due to C conjugation "The electron pair on nitrogen forms a C p bond with C.

In their reactions, enamines are similar to enols and enolate anions, although severe conditions (i.e., strong acid or base) are not necessary.

• In an SN2 reaction with methyl and primary haloalkanes, enamines can be alkylated on the b-carbon.

• Acid chlorides and acid anhydrides can be used to acylate enamines on the b-carbon.

• After the alkylation or acylation procedure, aqueous acid is utilized to turn the enamine back into a carboxylic acid.