Acylation, nucleophilic catalysis

Small amounts of salt-like addition products (85) formed by reaction on the ring nitrogen may be present in the medium. (Scheme 60) but. as the equilibrium is shifted by further reaction on the exocyclic nitrogen, the only observed products are exocyclic acylation products (87) (130. 243. 244). Challis (245) reviewed the general features of acylation reactions these are intervention of tetrahedral intermediates, general base catalysis, nucleophilic catalysis. Each of these features should operate in aminothiazoles reactivity. 

Ester hydrolysis can also be promoted by nucleophilic catalysis. If a component of the reaction system is a more effective nucleophile toward the carbonyl group than hydroxide ion or water under a given set of conditions, an acyl-transfer reaction can take place to form an intermediate ... 

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... 

As with the tetrahedral mechanism at an acyl carbon, nucleophilic catalysis (p. 427) has been demonstrated with an aryl substrate, in certain cases. 

This reagent combination also converts carboxylic acids to acyl chlorides (see Section 3.4.1). The mechanistic basis for the special effectiveness of benzotriazole has not yet been determined, but it seems likely that nucleophilic catalysis is involved. Sulfinyl ester intermediates may be involved, because Z-2-butene-l,4-diol gives a cyclic sulfite ester with one equivalent of reagent but the dichloride with two equivalents. 

In 1967, (3) it was discovered that DMAP catalyzes the benzoylation of m-chloroaniline 10 times faster than pyridine. This enormous increase in reaction rate is unmatched by any other nucleophilic acylation catalyst (3. It was shown that the catalytic action of DMAP and PPY is not primarily due to their larger pKa s with respect to pyridine, but is a result of enhanced nucleophilic catalysis. 

In the 1990s, short peptides,and other nucleophiles °° ° were used as organocatalysts for a number of enantioselective acyl transfer processes transformations that set the stage for the more recent research in the area of nucleophilic catalysis.One of the most appealing approaches to enantioselective acyl transfer was outlined by Fu using an azaferrocene catalyst (6) [Eq. (11.6)]. While these pyridyl systems are not organic catalysts in the strictest sense, these azaferrocene compounds function as chiral dimethylaminopyridine equivalents for a broad range of acyl transfer processes ... 

Keywords Acylation Asymmetric desymmebisation resolution Nucleophilic catalysis... 

Anhydrides are somewhat more difficult to hydrolyze than acyl halides, but here too water is usually a strong enough nucleophile. The mechanism is usually tetrahedral. Only under acid catalysis does the SnI mechanism occur and seldom even then.s06 Anhydride hydrolysis can also be catalyzed by bases. Of course, OH- attacks more readily than water, but other bases can also catalyze the reaction. This phenomenon, called nucleophilic catalysis (p. 334). is actually the result of two successive tetrahedral mechanisms. For example, pyridine catalyzes the hydrolysis of acetic anhydride in this manner.507... 

In addition to participating in acid-base catalysis, some amino acid side chains may enter into covalent bond formation with substrate molecules, a phenomenon that is often referred to as covalent catalysis.174 When basic groups participate this may be called nucleophilic catalysis. Covalent catalysis occurs frequently with enzymes catalyzing nucleophilic displacement reactions and examples will be considered in Chapter 12. They include the formation of an acyl-enzyme intermediate by chymotrypsin (Fig. 12-11). Several of the coenzymes discussed in Chapters 14 and 15 also participate in covalent catalysis. These coenzymes combine with substrates to form reactive intermediate compounds whose structures allow them to be converted rapidly to the final products. 

The above types of catalysis function by stabilizing the transition state of the reaction without changing the mechanism. Catalysts may also involve a different reaction, pathway. A typical example is nucleophilic catalysis in an acyl transfer or hydrolytic reaction. The hydrolysis of acetic anhydride is greatly enhanced by pyridine because of the rapid formation of the highly reactive acetylpyridinium ion (equation 2.12). For nucleophilic catalysis to be efficient, the nucleophile... 

Fig. 8.1 Nucleophilic catalysis cycle for a Type I acyl transfer process [35],...

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. 

In order to bypass the problem of designing a pocket from scratch, Bolon and Mayo [27] introduced a catalytically active His residue in thioredoxin, a well-defined 108-residue protein for which much structural and functional information was available. The design was based on the well-known reaction mechanism of p-nitrophenyl acetate hydrolysis and thioredoxin was redesigned by computation to accommodate a histidine with an acylated side chain to mimic transition state stabilization. The thioredoxin mutant was catalytically active and the reaction followed saturation kinetics with a k at of 4.6 x 10 s and a Km of 170 xM. The catalytic efficiency, after correction for differential protonation and nucleophilicity, can be estimated to be a factor of 50 greater than that of 4-methylimidazole, due to nucleophilic catalysis and proximity effects, see Section 5.2.3. 

In nucleophilic catalysis, an anion of a secondary hydroxyl group of the cyclodextrin (CD-OH) attacks at the electrophilic center of the ester substrate included in the cavity of the cyclodextrin, resulting in the formation of acyl-cyclodextrin (2) together with the release of the leaving group (see Scheme 1 for ester hydrolysis). The catalysis is completed by the regeneration of the cyclodextrin through the hydrolysis of 2. 

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). 

At present, major progress in efficiency is found in the case of the nucleophilic catalysis. Table 8—1 lists apparent rate constants of acylation, deacylation, and turnover available at near pH 8 in some nucleophilic catalyses of the PNPA hydrolysis, and these data compared with those for a-chymotrypsin. PNPA was selected as standard substrate because of its wide use. It is noteworthy that substrate binding was not observed for any of the synthetic systems. 

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