Acylation of Nucleophilic Oxygen and Nitrogen Groups

The conversion of alcohols to esters by O-acylation and of amines to amides by N-acylation are fundamental organic reactions that are the reverse of the hydrolyses discussed in the preceding sections. In Section 3.4 of Part B we discuss these reactions from the point of view of synthetic applications and methods. 

Although the previous two sections of this chapter emphasized hydrolytic processes, two mechanism that led to O or N-acylation were considered. In the discussion of acid-catalyzed ester hydrolysis, it was pointed out that this reaction is reversible (p. 654). Thus it is possible to acylate alcohols by acid-catalyzed reaction with a carboxylic acid. This is called the Fischer esterification method. To drive the reaction forward, the alcohol is usually used in large excess, and it may also be necessary to remove water as it is formed. This can be done by azeotropic distillation in some cases. 

The most common O- and N-acylation procedures use acylating agents that are more reactive than carboxylic acids or their esters. Acyl chlorides and anhydrides react rapidly with most unhindered alcohols and amines to give esters and amides, respectively. 

Acylation of alcohols is often performed in the presence of an organic base such as pyridine. The base serves two purposes it neutralizes the protons generated in the reaction and prevents the development of high acid concentrations. Pyridine also becomes directly involved in the reaction as a nucleophilic catalyst (see p. 657). 

Pyridine is more nucleophilic than an alcohol toward the carbonyl center of an acyl chloride. The product that results, an acylpyridinium ion, is, in turn, more reactive toward an alcohol than the original acyl chloride. The conditions required for nucleophilic catalysis therefore exist, and acylation of the alcohol by acid chloride is faster in the presence of pyridine than in its absence. Among the evidence that supports this 

The second reaction that should be recalled is the aminolysis of esters (p. 479). This reaction leads to the formation of amides by N-acylation  

The equihbiium constant for this reaction is ordinarily favorable, but the reactions are rather slow. 

SECTION 8.6. ACYLATION OF NUCLEOPHILIC OXYGEN AND NITROGEN GROUPS 

This finding suggests that some of the ester is being formed via a ketene inter- 

Kinetic studies of the reaction of alcohols with acid chlorides in polar solvents in the absence of basic catalysts generally reveal terms both first-order and second- 

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Carbonyl Activation. The title reagent (1) reacts with acyl chlorides to produce 2-acylthio-l-methylpyridinium salts (2) as stable hygroscopic solids (eq 1). These may then be treated with a variety of oxygen and nitrogen nucleophiles in the presence of base to effect transfer of the acyl group to the nucleophilic species to produce (3) and regenerate (1). ... 

However, most nucleophiles attack 5-oxazolones at the carbonyl group and the products are derivatives of a-amino acids formed by acyl-oxygen fission. Thus the action of alcohols, thiols, ammonia and amines leads, respectively, to esters, thioesters and amides orthophosphate anion gives acyl phosphates (Scheme 18). The use of a-amino acids in this reaction results in the establishment of a peptide link. Cysteine is acylated at the nitrogen atom in preference to the sulfur atom. Enzymes, e.g. a-chymotrypsin and papain, also readily combine with both saturated and unsaturated azlactones. A useful reagent for the introduction of an a-methylalanine residue is compound (202). Both the trifluoroacetamido and ester groups in the product are hydrolyzed by alkali to give a dipeptide. The alkaline hydrolyzate may be converted into the benzyloxycarbonyl derivative, which forms a new oxazolone on dehydration. Reaction with an ester of an amino acid then yields a protected tripeptide (equation 45). 

Fig. 3.S Putative catalytic mechanism of the novel active site in fl7. The reaction begins when the nucleophilic oxygen of Thr-1 donates its proton to its own a-amino group and attacks the carbonyl carbon of the substrate. The negatively charged tetrahedral intermediate is stabilized by hydrogen bonding. The acylation step is complete when the a-amino group of Thr donates a proton to the nitrogen of the scissile peptide bond. A covalent bond is formed between the substrate...

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