Nucleophilic catalysis alcohols, acylation

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 acyl chloride is faster in the presence of pyridine than in its absence. Among the evidence that supports this mechanism is spectroscopic observation of the acetylpyridinium ion. An even more effective catalyst is 4-dimeftiyIaminopyridine (DMAP), which functions in the same wsy but is more reactive because of the electron-donating dimethylamino substituent. ... 

The reaction between acyl halides and alcohols or phenols is the best general method for the preparation of carboxylic esters. It is believed to proceed by a 8 2 mechanism. As with 10-8, the mechanism can be S l or tetrahedral. Pyridine catalyzes the reaction by the nucleophilic catalysis route (see 10-9). The reaction is of wide scope, and many functional groups do not interfere. A base is frequently added to combine with the HX formed. When aqueous alkali is used, this is called the Schotten-Baumann procedure, but pyridine is also frequently used. Both R and R may be primary, secondary, or tertiary alkyl or aryl. Enolic esters can also be prepared by this method, though C-acylation competes in these cases. In difficult cases, especially with hindered acids or tertiary R, the alkoxide can be used instead of the alcohol. Activated alumina has also been used as a catalyst, for tertiary R. Thallium salts of phenols give very high yields of phenolic esters. Phase-transfer catalysis has been used for hindered phenols. Zinc has been used to couple... 

There are many reactions in which pyridines are used as bases. However in a large number of reactions only pyridine itself is reactive. a-Substituted pyridines behave differently, e.g. in the catalysis of acylation reactions with acyl chlorides or anhydrides [45]. The sterical hinderance of the a-substituents decelerates reactions in which a pyridine reacts as a nucleophile. A reaction which can be base-catalyzed by a-substituted pyridines is the addition of alcohols to hetero-cumulenes such as ketenes and isocyanates. Therefore this reaction was investigated as a model reaction for base catalysis by concave pyridines. 

The reaction between acyl halides and alcohols or phenols is the best general method for the preparation of carboxylic esters. It is believed to proceed by a Sn2 mechanism.As with 16-57, the mechanism can be S l or tetrahedral. ° Pyridine catalyzes the reaction by the nucleophilic catalysis route (see 16-58). Lewis acids such as lithium perchlorate can be used. 

Let us return to the reaction we mentioned at the very start of the chapter - the reaction of a chiral alcohol to form an ester. DMAP is used to catalyse the acylation of alcohols reactions by nucleophilic catalysis. 

The acylation of alcohols by anhydrides, catalyzed by 4-(dimethylamino)pyridine (DMAP), is one of the most frequently described in the literature examples of nucleophilic catalysis (Figure 5.6). 

In the preceding examples, the asymmetric catalyst is a Lewis acid and hence the catalytic processes reported so far involve electrophilic activation by a metal-centred chiral Lewis acid. There is another strategy, although less explored, which consists of designing chiral Lewis bases for nucleophilic catalysis. It is well known that Lewis bases such as nitrogen heterocycles and tertiary phosphines and amines catalyse a variety of important chemical processes. For instance 4-(dimethylamino)pyridine (DMAP) catalyses the acylation of alcohols by anhydrides the mechanism by which DMAP accelerates this process provides an instmctive illustration of how nucleophiles can... 

One of the most common methods to catalyze acyl transfers is the addition of a nucleophile, particularly when using acid halide reactants. For example, consider the reaction of an alcohol or water with an acid halide, but with the addition of triethyl amine. We add the tri-ethylamine to neutralize the HX produced in this reaction, but it also significantly enhances the rate of the reaction (Eq. 10.109 also see Section 9.2.5 for a discussion of nucleophilic catalysis). Initial attack of the amine is faster than attack by the less nucleophilic alcohol or water, creating an intermediate with a positive charge. This is a highly reactive carbonyl that now adds nucleophiles faster than the starting acid halide. 

The mechanism for the lipase-catalyzed reaction of an acid derivative with a nucleophile (alcohol, amine, or thiol) is known as a serine hydrolase mechanism (Scheme 7.2). The active site of the enzyme is constituted by a catalytic triad (serine, aspartic, and histidine residues). The serine residue accepts the acyl group of the ester, leading to an acyl-enzyme activated intermediate. This acyl-enzyme intermediate reacts with the nucleophile, an amine or ammonia in this case, to yield the final amide product and leading to the free biocatalyst, which can enter again into the catalytic cycle. A histidine residue, activated by an aspartate side chain, is responsible for the proton transference necessary for the catalysis. Another important factor is that the oxyanion hole, formed by different residues, is able to stabilize the negatively charged oxygen present in both the transition state and the tetrahedral intermediate. 

The scope of this reaction is similar to that of 10-21. Though anhydrides are somewhat less reactive than acyl halides, they are often used to prepare carboxylic esters. Acids, Lewis acids, and bases are often used as catalysts—most often, pyridine. Catalysis by pyridine is of the nucleophilic type (see 10-9). 4-(A,A-Dimethylamino)pyridine is a better catalyst than pyridine and can be used in cases where pyridine fails. " Nonbasic catalysts are cobalt(II) chloride " and TaCls—Si02. " Formic anhydride is not a stable compound but esters of formic acid can be prepared by treating alcohols " or phenols " with acetic-formic anhydride. Cyclic anhydrides give monoesterified dicarboxylic acids, for example,... 

Acyl chlorides are highly reactive acylating agents and react very rapidly with alcohols and other nucleophiles. Preparative procedures often call for use of pyridine as a catalyst. Pyridine catalysis involves initial formation of an acyl pyridinium ion, which then reacts with the alcohol. Pyridine is a better nucleophile than the neutral alcohol, but the acyl pyridinium ion reacts more rapidly with the alcohol than the acyl chloride.103... 

The intermediate N-acylpyridinium salt is highly stabilized by the electron donating ability of the dimethylamino group. The increased stability of the N-acylpyridinium ion has been postulated to lead to increased separation of the ion pair resulting in an easier attack by the nucleophile with general base catalysis provided by the loosely bound carboxylate anion. Dialkylamino-pyridines have been shown to be excellent catalysts for acylation (of amines, alcohols, phenols, enolates), tritylation, silylation, lactonization, phosphonylation, and carbomylation and as transfer agents of cyano, arylsulfonyl, and arylsulfinyl groups (lj-3 ). 

Hubbard and Kirsch (1972) have recently proposed that histidine may act as a nucleophile in a-chymotrypsin acylation reactions of esters having a good leaving group (jO-nitrophenol). This suggestion was based on a similarity in p-value for acylation by p-substituted nitrophenyl and dinitrophenyl benzoates and nucleophilic attack on these compounds by imidazole, in contrast with less positive p-values for hydroxide ion catalysis. Hammett p-values for hydrolysis of substituted phenyl esters are given in Table 6 and show little apparent trend. The values for hydroxide ion and alcoholate ions are... 

Miller also explored the ASD of glycerol derivatives through an enantioselective acylation process which relies on the use of a pentapeptide-catalyst which incorporates an A-terminal nucleophilic 3-(l-imidazolyl)-(5)-alanine residue [171], Most recently, Miller has probed in detail the role of dihedral angle restriction within a peptide-based catalyst for ferf-alcohol KR [172], site selective acylation of erythromycin A [173], and site selective catalysis of phenyl thionoformate transfer in polyols to allow regioselective Barton-McCombie deoxygenation [174],... 

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