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.

Acyl Group.svg

CA Derivatives.svg

 

The stability of a negative charge on a Y group can be gauged by the pKa of its corresponding conjugate acid (HY). A low conjugate acid pKa 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 pKa 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 AC.svg Cl H-Cl -7
Acid Anhydride AA.svg Carboxylate LG.svg CA LG.svg 3-5
Ester Ester.svg OR’ H-OR’ 15-16
Carboxylic Acid CA.svg OH H-OH 15.7
Amide Amide.svg NH2 H-NH2 36
Ketone Ketone.svg R’ H-R’ 50
Aldehyde Ald.svg 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.

 

Aldehyde poor leaving group.svg

Nucleophilic acyl substitution.svg

 

  • 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.

Nu Addition Mechanism Overview.svg

 

 

1) Nucleophilic Addition

Nu Addition Mechanism Step 1.svg

 

 

2) Leaving Group Removal

Nu Addition Mechanism Step 2.svg

 

 

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.

 

 

Carbonyl Stability

The rate of the first mechanistic step is mainly affected by the stability of the carbonyl moiety. The ability of substituents attached to the carbonyl carbon to donate or withdraw electron density is the primary factor determining carbonyl stabilization.

CA Derivatives Resonance.svg

 

Leaving Group Ability

The leaving group ability of the Y group is the most important factor in determining the rate of the second mechanistic step of nucleophilic acyl substitution. The Y group structural features which allow for the stabilization of a negative charge also allow for the stabilization of the transition state of the second step of the mechanism. Overall, the better the leaving group ability of the Y group, the higher the rate of second step of the mechanism.

21.3 acid derivative reactivity.svg

 

How the two effects actually combine to produce the overall reactivity for each carboxylic acid derivative is slightly different. As comparison of one of the more reactive carboxylic acid derivatives, acid chlorides, and one of the least reactive, amides, will be used as a discussion.

 

Stabilizing Effects.svg

Acid Derivative Interconversion

Highly reactive acid chlorides, when combined with the appropriate nucleophile, can be directly converting into acid anhydrides, thioester, esters, and amides. However, the less reactive amides cannot be directly converted into ester, thioester, anhydrides, or acid chlorides. It is possible to make these conversions with an amide, but multiple reaction steps are required.

21.3 acid derivative conversion.svg

 

Nucleophilic reactions.

  • Hydrolysis: A reaction with water as a nucleophile to create a carboxylic acid.
  • Alcoholysis: A reaction with an alcohol nucleophile to create an ester.
  • Aminolysis: A reaction with ammonia or an amine nucleophile to create an amide.
  • Reduction: A reaction with a hydride nucleophile to create an aldehyde or 1o alcohol.
  • Organometallic: A reaction with a carbanion nucleophile from an organometallic reagent to create a ketone or a 3o alcohol.

 

 

Predicting the Product of a Nucleophilic Acyl Substitution Reaction

There are two major pieces of a nucleophilic acyl substitution reaction which need to be identified in order to predict the product:

  • the leaving group of the carboxylic acid derivative (Y)
  • the nucleophile. It is important to identify if the nucleophile is neutral (i.e. water, alcohols, ammonia, amines) or negatively charged (i.e. hydroxide, alkoxides, hydrides, carbanions).

 

Negatively Charged Nucleophiles

Predicting the Products Negative.svg

 

Neutral Nucleophiles

Prdicting the Products Neutral.svg

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