Carboxylic acid derivatives and acyl groups

• Carboxylic acid derivatives can be distinguished from aldehydes and ketones by the presence of a group containing an electronegative heteroatom – usually oxygen or nitrogen– bonded directly to the carbonyl carbon and represented by the symbol Y.
• The rest of the carboxylic acid derivative is called the acyl group which is made up of the carbonyl group and the attached alkyl group (R).
• Being electronegative, the Y group has the potential of receiving electrons from the alkoxide intermediate created during a nucleophilic acyl substitution and acting as a leaving group.
• Elimination of a leaving group allows for carbonyl bond reformation and C-Y bond cleavage to complete a substitution reaction.

The stability of a negative charge on a Y group can be gauged by the pK_a of its corresponding conjugate acid (HY). A low conjugate acid pK_a implies that the Y leaving group is a weak base with a stable negative charge and thus would make an efficient leaving group. Likewise, a high conjugate acid pK_a means the Y group would likely make a poor leaving group.

Carbonyl Compounds and their Leaving Groups

Name	Carbonyl Compound	Leaving Group	Conjugate Acid of the Leaving Group	pKa
Acid Chloride		Cl–	H-Cl	-7
Acid Anhydride				3-5
Ester		–OR’	H-OR’	15-16
Carboxylic Acid		–OH	H-OH	15.7
Amide		–NH2	H-NH2	36
Ketone		–R’	H-R’	50
Aldehyde		–H	H-H	Very Large

The Mechanism of Nucleophilic Acyl Substitution

• Aldehydes, ketones and carboxylic acid derivatives have the C=O carbonyl bond in common. Thus, the electrophilic character of the carbonyl carbon plays an important part in the reactivity of all of these compounds.
• the carbonyl carbon of aldehydes and ketones do not contain hydroxyl group, suitable leaving groups, their primary reaction is fundamentally different than carboxylic acid derivatives.

• Carboxylic acid derivatives nucleophilic acyl substitution.
• mechanism starts with a nucleophilic attack on an electrophilic carbonyl carbon, forming a tetrahedral alkoxide intermediate.
• The alkoxide negative charge can gain stability by being transferred to the Y leaving group.
• Elimination of the Y leaving group in the second mechanistic step, allows the C=O carbonyl bond to reform thus creating a new acyl compound.
• The reaction is considered a substitution due to the Y group of the carboxylic acid derivative being exchanged with an incoming nucleophile.

The Relative Reactivity of Carboxylic Acid Derivatives

The relative reactivity of carboxylic acid derivatives is an important concept for entering into a detailed examination of nucleophilic acyl substitutions. Factors that determine the differences in reactivity:

• the stability of the carbonyl
• the effectiveness of the Y leaving group.