Acylation, mechanism with esters

Similar additions have been successfully carried out with carboxylic acids, anhydrides, acyl halides, carboxylic esters, nitriles, and other types of compounds. These reactions are not successful when the alkene contains electron-withdrawing groups such as halo or carbonyl groups. A free-radical initiator is required, usually peroxides or UV light. The mechanism is illustrated for aldehydes but is similar for the other compounds ... 

Fig. 7.1. a) Specific acid catalysis (proton catalysis) with acyl cleavage in ester hydrolysis. Pathway a is the common mechanism involving a tetrahedral intermediate. Pathway b is SN1 mechanism observed in the presence of concentrated inorganic acids. Not shown here is a mechanism of alkyl cleavage, which can also be observed in the presence of concentrated inorganic acids, b) Schematic mechanism of general acid catalysis in ester hydrolysis. 

Fig. 7.2. a) The most common mechanism of base-catalyzed ester hydrolysis, namely specific base catalysis (HCT catalysis) with tetrahedral intermediate and acyl cleavage. Not shown here are an W mechanism with alkyl cleavage observed with some tertiary alkyl esters, and an 5n2 mechanism with alkyl cleavage sometimes observed with primary alkyl esters, particularly methyl esters, b) Schematic mechanism of general base catalysis in ester hydrolysis. Intermolecular catalysis (bl) and intramolecular catalysis (b2). c) The base-catalyzed hydrolysis of esters is but a particular case of nucleophilic attack. Intermolecular (cl) and intramolecular (c2). d) Spontaneous (uncatalyzed) hydrolysis. This becomes possible when the R moiety is... 

The consecutive formation of o-hydroxybenzophenone (Figure 3) occurred by Fries transposition over phenylbenzoate. In the Fries reaction catalyzed by Lewis-type systems, aimed at the synthesis of hydroxyarylketones starting from aryl esters, the mechanism can be either (i) intermolecular, in which the benzoyl cation acylates phenylbenzoate with formation of benzoylphenylbenzoate, while the Ph-O-AfCL complex generates phenol (in this case, hydroxybenzophenone is a consecutive product of phenylbenzoate transformation), or (ii) intramolecular, in which phenylbenzoate directly transforms into hydroxybenzophenone, or (iii) again intermolecular, in which however the benzoyl cation acylates the Ph-O-AfCL complex, with formation of another complex which then decomposes to yield hydroxybenzophenone (mechanism of monomolecular deacylation-acylation). Mechanisms (i) and (iii) lead preferentially to the formation of p-hydroxybenzophenone (especially at low temperature), while mechanism (ii) to the ortho isomer. In the case of the Bronsted-type catalysis with zeolites, shape-selectivity effects may favor the formation of the para isomer with respect to the ortho one (11,12). 

The mechanism of action of anticholinesterases is to form a stable covalent complex with the Achase enzyme. Achase is one of several enzymes known as serine esterases. Other examples include the intestinal enzymes trypsin and chymotrypsin as well as the blood clotting agent thrombin. During the course of the catalysis the alcohol -OH of a serine side chain in the active site of the enzyme forms an ester complex, called the acyl-enzyme, with the substrate. So, acetylcholine will go through similar chemical reactions with Achase. 

Most nucleophiles are both more basic and more reactive towards sp -hybridized carbon than is water. Thus catalysis is readily observed wilh those esters which undergo hydrolysis at a significant rate in neutral solution, that is, with esters activated by electron withdrawing substituents in either the acyl or the leaving group. Hydroxide ion, however, is basic enough to attack any ester, and since the mechanism of alkaline hydrolysis appears to be relatively simple this reaction will be discussed first. 

A Claisen condensation is the acylation of an ester enolate by the corresponding ester. By deprotonating an ester with MOR, only a small concentration of the ester enolate is generated and this enolate is in equilibrium with the ester (cf. Table 13.1). The mechanism of the Claisen condensation is illustrated in detail in Figure 13.57 for the example of the condensation of ethyl butyrate. Both the deprotonation of the ester to give enolate A and the subsequent acylation of the latter are reversible. This acylation occurs via a tetrahedral intermediate (B in Figure 13.57) just like the acylations of other nucleophiles (Chapter 6). The equilibrium between two molecules of ethyl butyrate and one molecule each of the condensation product C and ethanol does not lie completely on the side of the products. In fact, Claisen condensations go to completion only... 

The phosphorus-based nerve gases and insecticides act by deactivating acetylcholinesterase. Note that all of these compounds have a good leaving group on the phosphorus. They react readily with the nucleophilic hydroxy group of the enzyme to form a phosphate triester in a reaction that is very similar, both in its mechanism and its product, to the reaction of an acyl chloride with an alcohol to form an ester ... 

With this reaction as a model, you should be able to work out the mechanism of ester formation from acetic anhydride and cyclohexanol. Try to write it down without looking at the acyl chloride mechanism above, and certainly not at the answer below. Here it is, with pyridine as the base. Again, addition of the nucleophile gives an unstable intermediate, which undergoes an elimination reaction, this time losing a carboxylate anion, to give an ester. 

The reaction of 0-acyl thiohydroxamates with tris(phenylthio)phosphorus, initiated by adventitious oxygen at room temperature, leads in the first instance to alkylbis(phenylthio)phosphines (Scheme 2) by a chain mechanism. Combination of the latter with the disulfide by product affords a phosphotus(V) species which on woik-up gives a]kylbis(phenylduo)phosphonates (Scheme 2 and equation 38) widh moderate to good yields. lliis reaction sequence provides a convenient meduxl for die overall transformation of a carboxylic acid into a readily hydrolyzable ester of the analogous phosphonic acid. 

The second step of the mechanism is deacylation, which involves an attack by water on the carbonyl of the newly formed ester. This step is rate-determining with ester substrates but is faster than acylation with peptides. 

Similarly the carbanion (XI) need not have been derived from an ester. Methyl ketones in the presence of sodamide23 can be acylated with, esters to give /3-diketones of the type RCOCHoCOR. The mechanism appears to be ... 

Further persuasive evidence in support of the expectation that the mechanism of the ECH-catalyzed reaction involves an Elcb mechanism with a stabilized thioester enolate anion intermediate is obtained from the membership of ECH in the mechanistically diverse enoyl-CoA hydratase superfamily [70]. Such superfamilies are derived from a common ancestor by divergent evolution the members of these share a partial reaction, usually formation of a common intermediate, e.g., an enolate anion. The reactions catalyzed by members of the enoyl-CoA hydratase superfamily (almost) always utilize acyl esters of CoA as substrates the reactions invariably can be rationalized with mechanisms that involve the formation of a thioester enolate anion intermediate, e.g., 1,3-proton transfer, 1,5-proton transfer, Dieckman and reverse Dieckman condensations, and yS-decarboxylation. Although mechanisms with thioester enolate anion intermediates are plausible for each of these reactions, as in the ECH-catalyzed reaction, evidence for their existence on the reaction coordinate is circumstantial because the intermediates do not accumulate, thereby avoiding spectroscopic detection. 

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