Types of acylation reactions

In general, acylation reactions for chromatography are carried out with three main types of acylating reagent acid anhydrides, acid halides and reactive acyl derivatives such as acylated imidazoles, acylated amides or acylated phenols, and the different types are chosen for different reasons. Acyl halides are highly reactive, which may be important with compounds that are difficult to acylate, because of steric factors for instance. A drawback to acyl halides is that a basic acceptor for the halogen acid produced in the reaction is usually required (equation (8)), 

Getting rid of the excess of reagent and of the halide salt formed with the acceptor may be awkward. Anhydrides may therefore be preferred because excess of reagent is easier to remove, leaving a cleaner product (equation (9)). 

However, excess of the reagent may need to be removed before analysis, usually by some kind of washing or extraction procedure. Provided that this is acceptable, small scale acylations for chromatography, in common with other derivatization reactions, work well because they usually involve a large molar excess of acylating agent to drive the reaction to completion. 

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After separating steric effect by the STERIMOL term, the slope of the ct° terms in Eq. 40 and 41 is close to those observed for the same type of acylation reactions in a number of physical organic systems37>. Thus, STERIMOL values can well be used as free-energy-related parameters in combination with ct and parameters and provide informations about three-dimensional aspects of the interactions between drugs and biomolecules. 

This is the second type of acylation reaction. However, in this type the xenobiotic itself is activated, and it is therefore a type 2 reaction. Organic acids, either aromatic such as salicylic... 

Amino Acid Conjugation. In the second type of acylation reaction, exogenous carboxylic acids are activated to form S-CoA derivative in a reaction involving ATP and CoA. These CoA derivatives then acylate the amino group of a variety of amino acids. Glycine and glutamate appear to be the most common acceptor of amino acids in mammals in other organisms, other amino acids are involved. These include ornithine in reptiles and birds and taurine in fish. 

Acetylation is an important route of metabolism for aromatic amines, sulphonamides, hydrazines and hydrazides and there is a wide variety of substrates. This metabolic reaction is one of two types of acylation reaction and involves an activated conjugating agent, acetyl CoA. It is hence a type 1 reaction. Acetylation is notable in that the product may be less water soluble than the parent compound. This fact gave rise to problems with sulphonamides when these were administered in high doses. The acetylated metabolites, being less soluble in urine, crystallized out in the kidney tubules, causing tubular necrosis (table 4,1). The enzymes which catalyse the acetylation reaction, acetyltransferases, are cytosolic and are found in the liver, in both hepatocytes and Kupffer cells, in the gastrointestinal mucosa and in white blood cells. The enzyme has been purified and its mechanism of action extensively studied and is now well understood. This involves first acetylation of the enzyme by acetyl CoA... 

TYPES OF ACYLATION REACTIONS 34 glucuronides with simultaneous ... 

Besides Zr02 —S04 , a superacidic perfluororesin sulfonic acid (Nafion-H ) is reported to be catalytically active for several types of acylation reactions. ... 

The main type of hydrolysis reaction is that of halogenoaryl compounds to hydroxyaryl compounds, eg, the aqueous caustic hydrolysis of 0- and /)-chloronitrobenzene derivatives to nitrophenols. Another important reaction is the hydrolysis of A/-acyl derivatives back to the parent arylamine, where the acyl group is frequently used to protect the amine. 

Biochemical reactions include several types of decarboxylation reactions as shown in Eqs. (1)-(5), because the final product of aerobic metabolism is carbon dioxide. Amino acids result in amines, pyruvic acid and other a-keto acids form the corresponding aldehydes and carboxylic acids, depending on the cooperating coenzymes. Malonyl-CoA and its derivatives are decarboxylated to acyl-CoA. -Keto carboxylic acids, and their precursors (for example, the corresponding hydroxy acids) also liberate carbon dioxide under mild reaction conditions. 

Thus, the cis configuration of the acyl moiety favors intramolecular cyclization, competing effectively with migration to the ortho position [66]. The same type of side reaction has been observed with phthalates due to the proximity of... 

Some acyl halides are reactive enough to effect Friedel-Crafts acylation on the neutral heterocycles without a catalyst. For pyrrole such reactions are known, for example, with trifluoroacetyl chloride and trichloroacetyl chloride. Indole reacts smoothly in cold ether with oxalyl chloride and on heating with acetic anhydride. Some examples of these types of acylation are collected in Table 10. 

Because of the special structural requirements of the resin-bound substrate, this type of cleavage reaction lacks general applicability. Some of the few examples that have been reported are listed in Table 3.19. Lactones have also been obtained by acid-catalyzed lactonization of resin-bound 4-hydroxy or 3-oxiranyl carboxylic acids [399]. Treatment of polystyrene-bound cyclic acetals with Jones reagent also leads to the release of lactones into solution (Entry 5, Table 3.19). Resin-bound benzylic aryl or alkyl carbonates have been converted into esters by treatment with acyl halides and Lewis acids (Entry 6, Table 3.19). Similarly, alcohols bound to insoluble supports as benzyl ethers can be cleaved from the support and simultaneously converted into esters by treatment with acyl halides [400]. Esters have also been prepared by treatment of carboxylic acids with an excess of polystyrene-bound triazenes here, diazo-nium salts are released into solution, which serve to O-alkylate the acid (Entry 7, Table 3.19). This strategy can also be used to prepare sulfonates [401]. 

A number of types of cyclization reaction have been reported in which the reactivity of the acyl silane grouping is a factor in the transformation. These are discussed below. 

Related classes of gitonic superelectrophiles are the previously mentioned protoacetyl dications and activated acyl cationic electrophiles. The acyl cations themselves have been extensively studied by theoretical and experimental methods,22 as they are intermediates in many Friedel-Crafts reactions. Several types of acyl cations have been directly observed by spectroscopic methods and even were characterized by X-ray crystal structure analysis. Acyl cations are relative weak electrophiles as they are effectively stabilized by resonance. They are capable of reacting with aromatics such as benzene and activated arenes, but do not generally react with weaker nucleophiles such as deactivated arenes or saturated alkanes. 

A treatment of the many types of replacement reaction which have received study by carbohydrate chemists would of necessity be superficial and thus defeat the present purpose. Instead, an attempt will be made to gather all information which sheds light on the mechanisms of a few types of reaction. The reactions of 0-acyl derivatives of sugars, glycosides, and glycosyl halides were chosen because of the central role these substances play in carbohydrate chemistry. 

Acyl azides are conveniently prepared by treating an acetone, ether, or dioxane solution of the corresponding acyl halides with an aqueous solution of sodium azide. The reaction is rapid at 0-25°, and, in general, the azides are isolated in excellent yields. Many types of acyl halides have been used. ... 

Pyrophosphate is then hydrolyzed to orthophosphate, and so the equivalents of two compounds having high phosphoryl transfer potential are consumed in the activation of acetate. We will return to this type of activation reaction in fatty acid degradation (Section 22.2.2). where it is used to form fatty acyl CoA, and in protein synthesis, where it is used to link amino acids to transfer RNAs (Section 29.2.1). 

Under the conditions used in peptide synthesis, unprotected aliphatic hydroxy groups can undergo two types of side reactions they can be acylated or dehydrated, the latter leading to dehydroamino acids. The hydroxy group of serine is a primary alcoholic function and therefore exhibits the highest reactivity. The secondary alcoholic functions of threonine, hydroxyproline, (3-phenylserine, hydroxynorvaline, and hydroxynorleucine, as well as of other noncoded amino acids, are less reactive and thus more suited for use in the unprotected form. The aromatic hydroxy group of tyrosine is more acidic than the ahphatic hydroxy groups nevertheless, it can be acylated to form esters. These are active esters which in turn can react with primary amines to form amide bonds. 

Carboxylic acids contain a carbonyl group, but it does not undergo the type of addition reactions that occur with the aldehydes and ketones. The carbonyl group in carboxylic acids, esters, amides or acyl chlorides has the electronegative atoms O, N or Cl next to the C=0, and these stop it from acting as a proper C=0 group should (Figure 7.2.15). 

Some drugs contain an acyl group, RCO in the compound RCOX, where X is called the leaving group. The most important types of acyl or carboxylic compounds, also called carboxylic acid derivatives are given in Table 1. The characteristic reaction of acyl compounds involves cleavage of the C-X bond. The net result of the attack of a nucleophile on an acyl compound is cleavage of the C-X bond and formation of the C-Y bond these reactions, shown in Eq. (1), are, therefore, called acyl transfers. 

The major advances in this field have been brought about by the authors group at Osaka University. As a strategy for attaining highly selective reactions via acyllithium, we employed intramolecular conversion. A number of tactics as shown in Scheme 5-2 and following sections were devised. It should be mentioned that these reactions are no longer acylation via acyllithium but, rather, various type of enolate reactions derived from them. 

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