1-Acylpyridinium ions

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 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 ). 

Pyridine has another useful attribnte, in that it behaves as a nncleophilic catalyst, forming an intermediate acylpyridinium ion, which then reacts with the nucleophile. Pyridine is more nucleophilic than the carboxylate anion, and the acylpyridinium ion has an excellent leaving group (pATa pyridinium 5.2). The reaction thus becomes a double nucleophilic substitution. 

Acyl chlorides are highly reactive acylating agents and react very rapidly with amines. For alcohols, preparative procedures often call for use of pyridine as a catalyst. Pyridine catalysis involves initial formation of an acylpyridinium ion, which then reacts with the alcohol. Pyridine is a better nucleophile than the neutral alcohol, but the acylpyridinium ion reacts more rapidly with the alcohol than the acyl chloride.94 95... 

Since formamide is a weak nucleophile, the use of imidazole or 4-dimethylaminopyridine (DMAP) is necessary for acyl transfer to formamide via an activated amide (imidazolide) or acylpyridinium ion. As Scheme 22 illustrates, the reaction starts with the oxidative addition of aryl bromide 152 to Pd(0) species, followed by CO insertion to form acyl-Pd complex 154. Imidazole receives the aroyl group to form imidazolide 155 and liberates HPdBr species. Then, imidazolide 155 reacts with formamide to form imide 156. Finally, decarbonylation of imide 156 gives amide 157. In fact, the formations of imidazolide intermediate 155 and imide 156 as well as the subsequent slow transformation of imide 156 to amide 157 by releasing CO were observed. This mechanism can accommodate the CO pressure variations observed during the first few hours of aminocarbonylation. When the reaction temperature (120 °C) was reached, a fast drop of pressure occurred. This corresponds to the formation of the intermediary imide 156. Then, the increase of pressure after 3 h of reaction was observed. This phenomenon corresponds to the release of CO from imide 156 to form amide 157. ... 

The electron-poor aromatic ring of 1-acylpyridinium ions is known to easily undergo nucleophilic addition by carbon nucleophiles an example was proposed by Comins and coworkers, who exploited the addition of zinc enolate 68 to enantiopure 67 (R = trans-2-(a-cumyl)cyclohexyl) in a total synthesis of (-F)-cannabisativine (equation 42)125. 

A/-Acyl and related groups. 1-Acylpyridinium ions are very susceptible to attack by nucleophilic reagents at the carbonyl carbon and thus are good acylating agents. They are generally encountered only as... 

Figure 4.19. Complications of pyridinium additions due to ring symmetry, (a) Homotopic faces of C-2 and C-6 (b) Equivalence of 100% selective addition to only the front face with no regio-selectivity and 100% regioselectivity with no face selectivity (c) A bulky group at C-3 simplifies the situation by blocking attack at C-2 (and coincidentally C-4) (d) Comins s conformational model favoring Re-face (back side) attack at C-6 of an acylpyridinium ion [112].

Write a two-step mechanism for the formation of the acylpyridinium ion, using curved arrows to show the flow of electrons. 

Acylpyridinium ions are probably involved as intermediates in those reactions of acyl chlorides that are carried out in the presence of pyridine. 

The proposed catalytic cycle for DMAP-catalysed acylation with an acid anhydride to yield ester 6 is depicted in Figure 22.1. Acylation proceeds through acylpyridinium ion 3 generated by nucleophilic attack of DMAP to... 

OH and the indole NH of catalyst 8 may participate in further increasing the site-selectivity. Based on these results, transition-state model C was proposed (Fig. 3), in which the acylpyridinium ion is expected to recognize the substrate structure precisely via dual hydrogen bonding interaction. The C2-symmetric structure of catalyst 8 seems to be important because the substrate approach to the reactive acylpyridinium ion from its p-face should reach the transition state exactly the same as from the a-face. The decrease in site-selectivity observed in the acylation catalyzed by Cy-symmetric catalyst 14 is compatible with this rationale... 

Pyridine is more nucleophilic than an alcohol toward the carbonyl center of an acid chloride. The product that results, an acylpyridinium ion, is, in turn, more reactive toward an alcohol than the original acid chloride. The conditions required for... 

The high efficiency of 4-dimethylaminopyridine (DMAP) as a catalyst in acylation reactions has long been recognized. The reactive intermediates of these acylation reactions are N-acylpyridinium ions [225],... 

The reaction of an acyl chloride with an alcohol to form an ester occurs rapidly and does not require an acid catalyst. Pyridine is often added to the reaction mixture to react with the HCI that forms. (Pyridine may also react with the acyl chloride to form an acylpyridinium ion, an intermediate that is even more reactive toward the nucleophile than the acyl chloride is.)... 

As a mechanistic rationale, the pyridine is Ukely to be activated by formation of an N-acylpyridinium ion 61, which undergoes (presumably coordination-directed) C-2-addition of intermediately formed Cu-acetylide 62 providing 1,2-dihydropyridine 60. 

The mechanism of catalysis by dimethylaminopyridine is considered to involve an A -acylpyridinium ion. However, the identity of the anion also affects the reactivity so that a complete formulation requires attention to the ion pair characteristics of the acylpyridinium ion. Interestingly, in the presence of 4-dimethylaminopyridine, acetic anhydride is a more reactive acylating agent than acetyl chloride. This is a reversal of their normal reactivity. This reversal can be explained if the counterion acetate, a stronger base than chloride, is involved in deprotonating the alcohol. " ... 

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