Nucleophilic acyl substitution

Class of substitution reactions involving nucleophiles and acyl compounds

Nucleophilic acyl substitution (SNAcyl) describes a class of substitution reactions involving nucleophiles and acyl compounds. In this type of reaction, a nucleophile – such as an alcohol, amine, or enolate – displaces the leaving group of an acyl derivative – such as an acid halide, anhydride, or ester. The resulting product is a carbonyl containing compound in which the nucleophile has taken the place of the leaving group present in the original acyl derivative. Because acyl derivatives react with a wide variety of nucleophiles, and because the product can depend on the particular type of acyl derivative and nucleophile involved, nucleophilic acyl substitution reactions can be used to synthesize a variety of different products.

Carbonyl compounds react with nucleophiles via an addition mechanism: the nucleophile attacks the carbonyl carbon, forming a tetrahedral intermediate. This reaction can be accelerated by acidic conditions, which make the carbonyl more electrophilic, or basic conditions, which provide a more anionic and therefore more reactive nucleophile. The tetrahedral intermediate itself can be an alcohol or alkoxide, depending on the pH of the reaction. The tetrahedral intermediate of an acyl compound contains a substituent attached to the central carbon that can act as a leaving group. After the tetrahedral intermediate forms, it collapses, recreating the carbonyl C=O bond and ejecting the leaving group in an elimination reaction. As a result of this two step addition/elimination process, the nucleophile takes the place of the leaving group on the carbonyl compound by way of an intermediate state that does not contain a carbonyl. Both steps are reversible and as a result, nucleophilic acyl substitution reactions are equilibrium processes. Because the equilibrium will favor the product containing the best nucleophile, the leaving group must be a comparatively poor nucleophile in order for a reaction to be practical.

Under acidic conditions, the carbonyl group of the acyl compound 1 is protonated, which activates it towards nucleophilic attack. In the second step, the protonated carbonyl 2 is attacked by a nucleophile (H−Z) to give tetrahedral intermediate 3. Proton transfer from the nucleophile (Z) to the leaving group (X) gives 4, which then collapses to eject the protonated leaving group (H−X), giving protonated carbonyl compound 5. The loss of a proton gives the substitution product, 6. Because the last step involves the loss of a proton, nucleophilic acyl substitution reactions are considered catalytic in acid. Also note that under acidic conditions, a nucleophile will typically exist in its protonated form (i. e. H−Z instead of Z−).

Under basic conditions, a nucleophile (Nuc) attacks the carbonyl group of the acyl compound 1 to give tetrahedral alkoxide intermediate 2. The intermediate collapses and expels the leaving group (X) to give the substitution product 3. While nucleophilic acyl substitution reactions can be base catalyzed, the reaction will not occur if the leaving group is a stronger base than the nucleophile (i. e. the leaving group must have a higher pKa than the nucleophile). Unlike acid catalyzed processes, both the nucleophile and the leaving group exist as anions under basic conditions. This mechanism is supported by isotope labeling experiments. When ethyl propionate with an oxygen 18 labeled ethoxy group is treated with sodium hydroxide (NaOH), the oxygen 18 label is completely absent from propionic acid and is found exclusively in the ethanol.

There are five main types of acyl derivatives. Acid halides are the most reactive towards nucleophiles, followed by anhydrides, esters, and amides. Carboxylate ions are essentially unreactive towards nucleophilic substitution, since they possess no leaving group. The reactivity of these five classes of compounds covers a broad range; the relative reaction rates of acid chlorides and amides differ by a factor of 1013. A major factor in determining the reactivity of acyl derivatives is leaving group ability, which is related to acidity. Weak bases are better leaving groups than strong bases; a species with a strong conjugate acid (e. g. hydrochloric acid) will be a better leaving group than a species with a weak conjugate acid (e. g. acetic acid). Thus, chloride ion is a better leaving group than acetate ion. The reactivity of acyl compounds towards nucleophiles decreases as the basicity of the leaving group increases, as the table shows. Compound Name Structure Leaving Group pKa of Conjugate Acid Acetyl chloride −7 Acetic anhydride 4.76 Ethyl acetate 15.9 Acetamide 38 Acetate anion N/a N/a

Another factor that plays a role in determining the reactivity of acyl compounds is resonance. Amides exhibit two main resonance forms. Both are major contributors to the overall structure, so much so that the amide bond between the carbonyl carbon and the amide nitrogen has significant double bond character. The energy barrier for rotation about an amide bond is 75–85 kJ/mol (18–20 kcal/mol), much larger than values observed for normal single bonds. For example, the C–C bond in ethane has an energy barrier of only 12 kJ/mol (3 kcal/mol). Acid halides hydrolyze in the presence of water to produce carboxylic acids, but this type of reaction is rarely useful, since carboxylic acids are typically used to synthesize acid halides. Most reactions with acid halides are carried out in the presence of a non nucleophilic base, such as pyridine, to neutralize the hydrohalic acid that is formed as a byproduct. Acid halides will react with carbon nucleophiles, such as Grignards and enolates, though mixtures of products can result. While a carbon nucleophile will react with the acid halide first to produce a ketone, the ketone is also susceptible to nucleophilic attack, and can be converted to a tertiary alcohol. For example, when benzoyl chloride (1) is treated with two equivalents of a Grignard reagent, such as methyl magnesium bromide (MeMgBr), 2 phenyl 2 propanol (3) is obtained in excellent yield. Although acetophenone (2) is an intermediate in this reaction, it is impossible to isolate because it reacts with a second equivalent of MeMgBr rapidly after being formed. Unlike most other carbon nucleophiles, lithium dialkylcuprates – often called Gilman reagents – can add to acid halides just once to give ketones. The reaction between an acid halide and a Gilman reagent is not a nucleophilic acyl substitution reaction, however, and is thought to proceed via a radical pathway. In the Friedel–Crafts acylation, acid halides act as electrophiles for electrophilic aromatic substitution. A Lewis acid – such as zinc chloride (ZnCl2), iron(III) chloride (FeCl3), or aluminum chloride (AlCl3) – coordinates to the halogen on the acid halide, activating the compound towards nucleophilic attack by an activated aromatic ring. For especially electron rich aromatic rings, the reaction will proceed without a Lewis acid.

The chemistry of thioesters and acid halides is similar, the reactivity being reminiscent of, but milder, than acid chlorides.

The chemistry of acid halides and anhydrides is similar. While anhydrides cannot be converted to acid halides, they can be converted to the remaining acyl derivatives. Anhydrides also participate in Schotten–Baumann type reactions to furnish esters and amides from alcohols and amines, and water can hydrolyze anhydrides to their corresponding acids. As with acid halides, anhydrides can also react with carbon nucleophiles to furnish ketones and/or tertiary alcohols, and can participate in both the Friedel–Crafts acylation and the Weinreb ketone synthesis. Acid catalyzed hydrolysis of esters is also an equilibrium process – essentially the reverse of the Fischer esterification reaction. Because an alcohol (which acts as the leaving group) and water (which acts as the nucleophile) have similar pKa values, the forward and reverse reactions compete with each other. As in transesterification, using a large excess of reactant (water) or removing one of the products (the alcohol) can promote the forward reaction. Basic hydrolysis of esters, known as saponification, is not an equilibrium process; a full equivalent of base is consumed in the reaction, which produces one equivalent of alcohol and one equivalent of a carboxylate salt. The saponification of esters of fatty acids is an industrially important process, used in the production of soap. A specific example of this is the Baker–Venkataraman rearrangement, in which an aromatic ortho acyloxy ketone undergoes an intramolecular nucleophilic acyl substitution and subsequent rearrangement to form an aromatic β diketone. The Chan rearrangement is another example of a rearrangement resulting from an intramolecular nucleophilic acyl substitution reaction.

Because of their low reactivity, amides do not participate in nearly as many nucleophilic substitution reactions as other acyl derivatives do. Amides are stable to water, and are roughly 100 times more stable towards hydrolysis than esters. Here, phenyllithium 1 attacks the carbonyl group of DMF 2, giving tetrahedral intermediate 3. Because the dimethylamide anion is a poor leaving group, the intermediate does not collapse and another nucleophilic addition does not occur. Upon acidic workup, the alkoxide is protonated to give 4, then the amine is protonated to give 5. Elimination of a neutral molecule of dimethylamine and loss of a proton give benzaldehyde, 6.

Carboxylic acids are not especially reactive towards nucleophilic substitution, though they can be converted to other acyl derivatives. Converting a carboxylic acid to an amide is possible, but not straightforward. Instead of acting as a nucleophile, an amine will react as a base in the presence of a carboxylic acid to give the ammonium carboxylate salt. Heating the salt to above 100 °C will drive off water and lead to the formation of the amide. This method of synthesizing amides is industrially important, and has laboratory applications as well. In the presence of a strong acid catalyst, carboxylic acids can condense to form acid anhydrides. The condensation produces water, however, which can hydrolyze the anhydride back to the starting carboxylic acids. Thus, the formation of the anhydride via condensation is an equilibrium process. Under acid catalyzed conditions, carboxylic acids will react with alcohols to form esters via the Fischer esterification reaction, which is also an equilibrium process. Alternatively, diazomethane can be used to convert an acid to an ester. While esterification reactions with diazomethane often give quantitative yields, diazomethane is only useful for forming methyl esters.