Nucleophilic Substitution in Acyl Chlorides

Acyl chlorides are readily prepared from carboxylic acids by reaction with thionyl chloride (Section 12.7). 

On treatment with the appropriate nucleophile, an acyl chloride may be converted to an acid anhydride, an ester, an amide, or a carboxylic acid. Examples are presented in Table 20.2. 

PROBLEM 20.3 Apply the knowledge gained by studying Table 20.2 to help you predict the major organic product obtained by reaction of benzoyl chloride with each of the following  

SAMPLE SOLUTION (a) As noted in Table 20.2, the reaction of an acyl chloride with a carboxylic acid yields an acid anhydride. 

CsHbCCI + CH3COH Benzoyl chloride Acetic acid 

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Nucleophilic substitution in acyl chlorides is much faster than in alkyl chlorides... 

There are alternatives to the addition-elimination mechanism for nucleophilic substitution of acyl chlorides. Certain acyl chlorides are known to react with alcohols by a dissociative mechanism in which acylium ions are intermediates. This mechanism is observed with aroyl halides having electron-releasing substituents. Other acyl halides show reactivity indicative of mixed or borderline mechanisms. The existence of the SnI-like dissociative mechanism reflects the relative stability of acylium ions. 

On examining the specific examples in the table, we see that nucleophilic substitutions of acyl chlorides are often carried out in the presence of pyridine. Pyridine is both a catalyst and a weak base. As a catalyst it increases the rate of acylation. As a base it prevents the build-up of HCl, which is a strong acid. 

The addition of nucleophiles to 1-acylpyridinium salts has surfaced as a powerful method for the synthesis of substituted pyridines. The 1-acylpyridinium salts are formed in situ by adding an acyl chloride to a pyridine in an aprotic solvent such as tetrahydrofuran. The formation of the 1-acylpyridinium salt is very rapid and will occur in the presence of various organometallics without significant competition from the reaction of the nucleophile and the acyl chloride. The addition of ethyl chloroformate to a mixture of pyridine and ethylmagnesium bromide gives 1,2- and 1-4-dihydropyridines 29 and 30 in a ratio of 64/36. Although these dihydropyridine intermediates can be aromatized with hot sulfur to 2- and 4-alkylpyridines, the poor regioselectivity makes this procedure unattractive. 

Cariwxylic Acid Derivatives.— The anion generated by treatment of (pentafluoro-phenyl)acetonitrile with sodium hydride in 1,2-dimethoxyethane (DME) effects nucleophilic substitution in polyfiuoroarenes to give diarylacetonitriles (123 X = F, CFs, H, Br, Cl, Me, or COaEt) - hydrolysis of the first five of these yields the related acids (124), the first two of which undergo conventional acid-catalysed est ification or conversion into acyl chlorides. Some Friedel-Crafts reactions of bispentafiuorophenylacetyl chloride are also shown in Scheme 30 (the ketone CeFs-CHPh-COPh has been made by a similar sequence starting from PhCHa-... 

The mechanism is similar to that for the formation of chlorides from alcohols and thionyl chloride. The hydroxyl group is converted to a good leaving group by thionyl chloride, followed by a nucleophilic acyl substitution in which chloride is the nucleophile (compare with Sec. 7.10). Phosphorus pentachloride and other reagents can also be used to prepare acyl chlorides from carboxylic acids. 

The 5/) -hybridized carbon of an acyl chloride is less sterically hindered than the sp -hybridized carbon of an alkyl chloride, making an acyl chloride more open toward nucleophilic attack. Also, unlike the Sn2 transition state or a carbocation intennediate in an SnI reaction, the tetrahedral intennediate in nucleophilic acyl substitution has a stable anangement of bonds and can be fonned via a lower energy transition state. 

Conversions of acid anhydrides to other carboxylic acid derivatives are illustrated in Table 20.2. Because a more highly stabilized carbonyl group must result in order for nucleophilic acyl substitution to be effective, acid anhydrides are readily converted to carboxylic acids, esters, and fflnides but not to acyl chlorides. 

The first example in Table 20.2 introduces a new aspect of nucleophilic acyl substitution that applies not only to acid anhydrides but also to acyl chlorides, thioesters, esters, and amides. Nucleophilic acyl substitutions can be catalyzed by acids. 

From acyl chlorides (Sections 15.8 and 20.4) Alcohols react with acyl chlorides by nucleophilic acyl substitution to yield esters. These reactions are typically performed in the presence of a weak base such as pyridine. 

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