4.5: Nucleophilic acyl substitution reactions (2023)

Base-promoted mechanism

The nucleophile in its more reactive basic form \(\ce{Nu^{-}}\) and neutral substrate \(\ce{R-\!\!{\overset{\overset{\huge\enspace\!{\overset{\Large{\delta{-}}}{O}}}|\!\!|\enspace}{\overset{\delta{+}}{C}}}\!\!-}\) can coexist in a basic medium. The nucleophile \(\ce{Nu^{-}}\) attacks the electrophilic carbonyl \(\ce{\overset{\delta{+}}{C}}\) and, simultaneously, the \(\ce{\overset{\delta{+}}{C}}\) breaks the weakest bond, which is the polar \(\pi\)-bond prone to heterolytic bond breakage as shown in step#1 of the mechanism below. The electrophilic \(\ce{C}\) changes its hybridization from sp² in the reactant to sp³ in the product. Therefore, the intermediate, i.e., the product of step#1 and reactant of step#2, is also called a tetrahedral intermediate.

The nucleophilic \(\ce{O^{-}}\) created in the first step is attached with the electrophilic \(\ce{\overset{\delta{+}}{C}}\) and the two re-establish the \(\pi\)-bond in the second step when the \(\ce{\overset{\delta{+}}{C}}\) breaks one of the two polar bonds, i.e., either \(\ce{\overset{\delta{+}}{C}{-}\overset{\delta{-}}{Nu}}\) or \(\ce{\overset{\delta{+}}{C}{-}\overset{\delta{-}}{Lv}}\)-bond. This step is also called the collapse of the tetrahedral intermediate. Breakage of \(\ce{\overset{\delta{+}}{C}{-}\overset{\delta{-}}{Nu}}\)-bond reverses the first step and breakage of \(\ce{\overset{\delta{+}}{C}{-}\overset{\delta{-}}{Lv}}\)-bond leads to the products of step#2. Later is more likely to happen because \(\ce{-Lv}\) is a better leaving group. The second step is usually not reversible because \(\ce{Lv^{-}}\) is a poor nucleophile. The leaving group ultimately picks up a proton from any acid molecule in the medium as shown in step#3.

The rate of reaction is increased by converting the neutral or acid form of the nucleophile (\(\ce{HNu}\)) to its more reactive conjugate base form (\(\ce{Nu^{-}}\). Therefore, it is also called base promoted nucleophilic acyl substitution mechanism.

Acid-catalyzed mechanism

In this mechanism, the nucleophile is in less reactive neutral \(\ce{HNu}\) form but the substrate is in a more reactive protonated \(\ce{R-\!\!\!\!\!\!{\overset{\overset{\huge\enspace\enspace{\overset{\Large{+}}{O}H}}|\!\!\!\!\!\!\!|\enspace\enspace}{\overset{\delta{+}}{C}}}\!\!\!\!\!\!-\overset{\delta{-}}{Lv}}\) form in an acidic medium. The medium is a mixture of several molecules, including the reactants, solvent, and any acid or base added. Medium is amphoteric with some acidic groups generalized as \(\ce{H-B^{+}}\) and some basic groups generalized as \(\ce{:\!\!B}\). Step#1 is the protonation of the carbonyl \(\ce{O}\) in a fast acid-base reaction that activates the carbonyl \(\ce{C}\) as shown in the mechanics below.

Nucleophile \(\ce{HNu}\) attacks the activated electrophilic carbonyl \(\ce{\overset{\delta{+}}{C}}\) and, simultaneously, the \(\pi\)-bond breaks in step#2, leading to tetrahedral intermediate-I. The neutral nucleophile becomes +ve charged after donating its lone pair of electrons to the bond. A proton on a +ve charge specie in the intermediates is strongly acidic. It is removed by a fast acid-base reaction using any basic molecule (\(\ce{:B}\) in step#3 leading to tetrahedral intermediate-II. Medium is acidic and it can protonate any of the basic portions of the intermediate, including \(\ce{-Nu}\) or \(\ce{-Lv}\)-groups. Protonation of \(\ce{-Nu}\) reverses the reaction but protonation of \(\ce{-Lv}\) increasing its leaving propensity leads to tetrahedral intermediate-III in step#4. The lone pair on \(\ce{O}\) re-establish the \(\pi\)-bond with the electrophilic \(\ce{C}\), and at the same time, the leaving group leaves, leading to a protonated acyl group in the step#5 of the mechanism. The acidic proton on the protonated acyl product is removed in the final fast acid-base reaction by any base \(\ce{:B}\) molecule in the medium in step#6, leading to the product.

Acid is added in trace amounts as it is consumed in step#1 but re-generated in step#6, i.e., acid is a catalyst in this reaction. The acid catalyst increases the reaction in two ways: i) by converting neutral substrates \(\ce{R-\!\!{\overset{\overset{\huge\enspace\!{\overset{\Large{\delta{-}}}{O}}}|\!\!|\enspace}{\overset{\delta{+}}{C}}}\!\!-}\) to its more reactive protonated \(\ce{R-\!\!\!\!\!\!{\overset{\overset{\huge\enspace\enspace{\overset{\Large{+}}{O}H}}|\!\!\!\!\!\!\!|\enspace\enspace}{\overset{\delta{+}}{C}}}\!\!\!\!\!\!-\overset{\delta{-}}{Lv}}\) form and ii) by converting neutral leaving group \(\ce{-Lv}\) in tetrahedra intermediate-II to its better leaving protonated \(\ce{-Lv^{+}H}\) form in tetrahedral intermediate-III

1. All the steps in this mechanism are reversible. It means there is an equilibrium between reactants and products. Three situations can arise. If the incoming nucleophile (\(\ce{HNu}\) is a poor nucleophile compared to the leaving group (\(\ce{HLv}\), the reactants dominate,
2. If the incoming nucleophile (\(\ce{HNu}\) is a better nucleophile compared to the leaving group (\(\ce{HLv}\), the products dominate, and
3. If the nucleophilicity of the incoming nucleophile (\(\ce{HNu}\) is comparable to that of the leaving group (\(\ce{HLv}\), about an equal-equal mixture of reactants and products exists.

In situation#3, the reaction can be manipulated to favor product or reactants by making use of Le Chatelier’s principle. That is, using one of the reactants in excess or removing one of the products drives the reaction forwards. Similarly, adding one of the products in excess or removing one of the reactants drives the reaction in the reverse direction.

Neutral nucleophile and neutral substrate reaction mechanism

In this mechanism, both the nucleophile \(\ce{HNu}\) and the substrate \(\ce{R-\!\!{\overset{\overset{\huge\enspace\!{\overset{\Large{\delta{-}}}{O}}}|\!\!|\enspace}{\overset{\delta{+}}{C}}}\!\!-}\) are in their less reactive neutral forms in a neutral medium. Nucleophile \(\ce{HNu}\) attacks the electrophilic carbonyl \(\ce{\overset{\delta{+}}{C}}\) and, simultaneously, the \(\pi\)-bond breaks in step#1, leading to tetrahedral intermediate-I. The acidic proton on the incoming nucleophile in intermediate-I is removed by a fast acid-base reaction using any basic molecule (\(\ce{:B}\) in step#2 leading to tetrahedral intermediate-II.

The nucleophilic \(\ce{O^{-}}\) re-establish the \(\pi\)-bond in step#3 when the \(\ce{\overset{\delta{+}}{C}}\) breaks \(\ce{\overset{\delta{+}}{C}{-}\overset{\delta{-}}{Lv}}\)-bond leading to the products. The leaving group picks up a proton from any acid molecule in the medium as shown in step#4. Since both the nucleophile and the substrate are in their less reactive neutral forms, it works only in situations where a better leaving group (\(\ce{-Lv}\) is attached to the acyl substrate. Therefore, \(\ce{\overset{\delta{+}}{C}{-}\overset{\delta{-}}{Lv}}\)-bond is broken preferentially in step#3. It is usually not a reversible step because \(\ce{Lv^{-}}\) is a poor nucleophile.

Reactions of acid halides

The acid halides, such as acid chlorides are the most reactive class of acyl substrates that can react with neutral nucleophiles and neutral substrates in a neutral media as well as by base-promoted mechanism. For example, acid chlorides can react with carboxylic acid, water, alcohol, or amines to form acid anhydrides, carboxylic acids, esters, and amines, respectively, as shown below.

Reactions of acid anhydrides

The acid anhydrides are reactive acyl substrates, second only to acid halides. There an acid anhydride can react with water to produce two equivalents of carboxylic acid, with alcohols to produce one equivalent of ester and one equivalent of carboxylic acid, and with two amine to produce one equivalent of amide and one equivalent of an amine salt of carboxylic acid, as shown below.

Two moles of amine are needed in the last reaction because initially formed carboxylic acid reacts by a fast acid-base reaction with an amine reactant which is a good base and produces an amine salt.

Reactions of carboxylic acids

Carboxylic acids cannot be converted to acid halides and acid anhydrides as they are less reactive than these products and the reactions in the reverse direction are favored. Base-promoted reactions also cannot take place because the acids will neutralize the bases in a fast acid-base reaction before the nucleophilic acyl substitution reactions, as shown below.

The carboxylate anion (\(\ce{R-COO^{-}}\) produced by the neutralization of carboxylic acid is the least reactive acyl substrate that is below amides in the reactivity order.

Carboxylic acids react with alcohols to produce ester but slowly and the reactions are reversible because the reactivity of the incoming nucleophiles is about the same as that of leaving nuclophiles. Acid-catalysis is applied to accelerate these reactions as shown in the example below.

Either excess alcohol is used or water is removed from the product to drive the reaction forward. Alcohol reactant is usually also the solvent in these reactions, so these are also called alcoholysis reactions. Revers of it is a reaction of an ester with water, called hydrolysis, that splits the ester into a carboxylic acid and an alcohol.

The carboxylic acids do not perform nucleophilic acyl substitution with amines as the fast acid-base reaction consumes the reactants forming ammonium salt.

Protonated amines in the ammonium salts do not have a lone-pair of electrons and they are not nuclophiles.

Reactions of esters

Esters are comparable in reactivity with carboxylic acids, but they do not have acidic protons. Therefore, both acid-catalysis and base-promoted reactions can be carried out with esters. For example, esters are hydrolyzed by water under acidic conditions in a reaction that is the reverse of the alcoholysis of acid, as shown below.

It is a reversible reaction that can be driven forward by employing excess water or by removing the alcohol product. The alkoxy group of esters can be substituted by an alkoxy group of another alcohol, in a reaction called acid-catalyzed transesterification as shown in an example below.

It is a reversible reaction that can be driven forward by employing excess reactant alcohol or by removing the product alcohol.

Base-promoted reactions of esters

Transesterification of esters can be performed by employing conjugated base of the alcohol which is more reactive than the neutral alcohol, as shown in the following example.

Similarly, esters can be hydrolyzed by using alkali, i.e., hydroxide ions in the place of neutral water, as shown in the example below.

The base-promoted hydrolysis of esters is also called saponification. The saponification process is commercially employed to hydrolyze fats which are tri-esters of long-chain fatty acids and glycerol, as shown in Figure \(\PageIndex{1}\). below. Soaps are salts of fatty acids.

Reactions of amides

Amides are the least reactive among the acyl substrates. Therefore, they do not react with halides, water, or alcohols under neutral conditions. However, amides are hydrolyzed by water and converted to esters by reacting with alcohols under acid-catalysis conditions as shown below.

The amine product of hydrolysis or alcoholysis converts into ammonium ions by a fast acid-base reaction with the acid present in the medium. Ammoniun ions are not nucleophiles which makes these reactions not reversible. Since the reactions of amides are slow, the mixture is heated to accelerate the reaction.

Activating carboxylic acids in the laboratory and in biochemical systems

Carboxylic acids, esters, and amides are common in nature. They need to be converted into acid halides or acid anhydrides that can be easily converted into any of these products. Chemists in the laboratory convert carboxylic acids into acid chlorides by reacting them with thionyl chloride (\(\ce{SOCl2}\)), phosphorous trichloride (\(\ce{PCl3}\)), or phosphorous pentachloride (\(\ce{PCl5}\)).

Biochemical systems convert carboxylic acids to acyl phosphate or acyl adenylate for this purpose by reacting carboxylate anions with adenosine triphosphate (ATP), as illustrated below.

Both phosphate and adenylate are good leaving groups. Which one of the two is formed, it depends on the enzyme carrying out the conversion.

Thioesters also have a good leaving group containing sulfur. For example, coenzyme-A (CoASH) that contains a thiol (\(\ce{-SH}\)) group. It reacts with acyl adenylate and converts it into a thioester acetyl-SCoA. The thioester, in turn, reacts with choline and converts it into a neurotransmitter called acetylcholine, as illustrated below.