Organic Chemistry Text Book (CHEM 3401 and 3402)

This is probably the single most important reaction of carboxylic acid derivatives. The overall transformation is defined by the following equation, and may be classified either as nucleophilic substitution at an acyl group or as acylation of a nucleophile. For certain nucleophilic reagents the reaction may assume other names as well. If Nuc-H is water the reaction is often called hydrolysis, if Nuc–H is an alcohol the reaction is called alcoholysis, and for ammonia and amines it is called aminolysis.

Different carboxylic acid derivatives have very different reactivities, acyl chlorides and bromides being the most reactive and amides the least reactive, as noted in the following qualitatively ordered list. The change in reactivity is dramatic. In homogeneous solvent systems, reaction of acyl chlorides with water occurs rapidly, and does not require heating or catalysts. Amides, on the other hand, react with water only in the presence of strong acid or base catalysts and external heating.

Because of these differences, the conversion of one type of acid derivative into another is generally restricted to those outlined in the following diagram. Methods for converting carboxylic acids into these derivatives were shown in a previous section, but the amide and anhydride preparations were not general and required strong heating. A better and more general anhydride synthesis can be achieved from acyl chlorides, and amides are easily made from any of the more reactive derivatives. Specific examples of these conversions will be displayed by clicking on the product formula. The carboxylic acids themselves are not an essential part of this diagram, although all the derivatives shown can be hydrolyzed to the carboxylic acid state (light blue formulas and reaction arrows). Base catalyzed hydrolysis produces carboxylate salts.

This is probably the single most important reaction of carboxylic acid derivatives. The overall transformation is defined by the following equation, and may be classified either as nucleophilic substitution at an acyl group or as acylation of a nucleophile. For certain nucleophilic reagents the reaction may assume other names as well. If Nuc-H is water the reaction is often called hydrolysis, if Nuc–H is an alcohol the reaction is called alcoholysis, and for ammonia and amines it is called aminolysis.

Different carboxylic acid derivatives have very different reactivities, acyl chlorides and bromides being the most reactive and amides the least reactive, as noted in the following qualitatively ordered list. The change in reactivity is dramatic. In homogeneous solvent systems, reaction of acyl chlorides with water occurs rapidly, and does not require heating or catalysts. Amides, on the other hand, react with water only in the presence of strong acid or base catalysts and external heating.

Because of these differences, the conversion of one type of acid derivative into another is generally restricted to those outlined in the following diagram. Methods for converting carboxylic acids into these derivatives were shown in a previous section, but the amide and anhydride preparations were not general and required strong heating. A better and more general anhydride synthesis can be achieved from acyl chlorides, and amides are easily made from any of the more reactive derivatives. Specific examples of these conversions will be displayed by clicking on the product formula. The carboxylic acids themselves are not an essential part of this diagram, although all the derivatives shown can be hydrolyzed to the carboxylic acid state (light blue formulas and reaction arrows). Base catalyzed hydrolysis produces carboxylate salts.

Before proceeding further, it is important to review the general mechanism by means of which all these acyl transfer or acylation reactions take place. Indeed, an alert reader may well be puzzled by the facility of these nucleophilic substitution reactions. After all, it was previously noted that halogens bonded to sp² or sp hybridized carbon atoms do not usually undergo substitution reactions with nucleophilic reagents. Furthermore, such substitution reactions of alcohols and ethers are rare, except in the presence of strong mineral acids. Clearly, the mechanism by which acylation reactions occur must be different from the S_N1 and S_N2 procedures described earlier.
In any substitution reaction two things must happen. The bond from the substrate to the leaving group must be broken, and a bond to the replacement group must be formed. The timing of these events may vary with the reacting system. In nucleophilic substitution reactions of alkyl compounds examples of bond-breaking preceding bond-making (the S_N1 mechanism), and of bond-breaking and bond-making occurring simultaneously (the S_N2 mechanism) were observed. On the other hand, for most cases of electrophilic aromatic substitution bond-making preceded bond-breaking. 

As illustrated in the following diagram, acylation reactions generally take place by an addition-elimination process in which a nucleophilic reactant bonds to the electrophilic carbonyl carbon atom to create a tetrahedral intermediate. This tetrahedral intermediate then undergoes an elimination to yield the products. In this two-stage mechanism bond formation occurs before bond cleavage, and the carbonyl carbon atom undergoes a hybridization change from sp² to sp³ and back again. The facility with which nucleophilic reagents add to a carbonyl group was noted earlier for aldehydes and ketones.

Before proceeding further, it is important to review the general mechanism by means of which all these acyl transfer or acylation reactions take place. Indeed, an alert reader may well be puzzled by the facility of these nucleophilic substitution reactions. After all, it was previously noted that halogens bonded to sp² or sp hybridized carbon atoms do not usually undergo substitution reactions with nucleophilic reagents. Furthermore, such substitution reactions of alcohols and ethers are rare, except in the presence of strong mineral acids. Clearly, the mechanism by which acylation reactions occur must be different from the S_N1 and S_N2 procedures described earlier.
In any substitution reaction two things must happen. The bond from the substrate to the leaving group must be broken, and a bond to the replacement group must be formed. The timing of these events may vary with the reacting system. In nucleophilic substitution reactions of alkyl compounds examples of bond-breaking preceding bond-making (the S_N1 mechanism), and of bond-breaking and bond-making occurring simultaneously (the S_N2 mechanism) were observed. On the other hand, for most cases of electrophilic aromatic substitution bond-making preceded bond-breaking. 

As illustrated in the following diagram, acylation reactions generally take place by an addition-elimination process in which a nucleophilic reactant bonds to the electrophilic carbonyl carbon atom to create a tetrahedral intermediate. This tetrahedral intermediate then undergoes an elimination to yield the products. In this two-stage mechanism bond formation occurs before bond cleavage, and the carbonyl carbon atom undergoes a hybridization change from sp² to sp³ and back again. The facility with which nucleophilic reagents add to a carbonyl group was noted earlier for aldehydes and ketones.

Although amines are among the most reactive nucleophiles, only 1º and 2º-amines give stable amide products. Reaction of 3º-amines with strong acylating reagents may generate acylammonium species reversibly (see below), but these are as reactive as acyl chlorides and will have only a very short existence. This explains why reactions #2 & 3 do not give amide products.

 

RCOCl

+

R'3N

RCONR'3(+) Cl(–)   (an acylammonium salt)

 

Reactions #4 & 5 display the acylating capability of anhydrides. Bear in mind that anhydrides may also be used as reagents in Friedel-Crafts acylation reactions. Esters are less reactive acylating reagents than anhydrides, and the ester exchange reaction (#6) requires a strong acid or base catalyst. The last example demonstrates that nitrogen is generally more nucleophilic than oxygen. Indeed, it is often possible to carry out reactions of amines with acyl chlorides and anhydrides in aqueous sodium hydroxide solution! Not only is the amine more nucleophilic than water, but the acylating reagent is generally not soluble in or miscible with water, reducing the rate of its hydrolysis.
No acylation reactions of amides were shown in these problems. The most important such reaction is hydrolysis, and this normally requires heat and strong acid or base catalysts. One example, illustrating both types of catalysis, is shown here. Mechanisms for catalyzed reactions of this kind were presented earlier.

 

R–CO2(–)  +   CH3NH2

OH(–) & heat

R–CO–NH(CH3)  +  H2O

H(+) & heat

R–CO2H  +  CH3NH3(+)