Intramolecular general base catalysis

The relative importance of the potential catalytic mechanisms depends on pH, which also determines the concentration of the other participating species such as water, hydronium ion, and hydroxide ion. At low pH, the general acid catalysis mechanism dominates, and comparison with analogous systems in which the intramolecular proton transfer is not available suggests that the intramolecular catalysis results in a 25- to 100-fold rate enhancement At neutral pH, the intramolecular general base catalysis mechanism begins to operate. It is estimated that the catalytic effect for this mechanism is a factor of about 10. Although the nucleophilic catalysis mechanism was not observed in the parent compound, it occurred in certain substituted derivatives. 

Obviously, in such cases the CD is acting as a true catalyst in esterolysis. The basic cleavage of trifluoroethyl p-nitrobenzoate by a-CD occurs by both pathways approximately 20% by nucleophilic attack and approximately 80% by general base catalysis (GBC) (Komiyama and Inoue, 1980c). The two processes are discernible because only the former leads to the observable p-nitrobenzoyl-CD. For the ester, Ks = 3.4 mM and kjka = 4.4 for the GBC route (1.25 for the nucleophilic route), and so KTS = 0.77 mM. For reaction within the ester CD complex [28], it was estimated that the effective molarity of the CD hydroxyl anion was 21-210 m (for Br0nsted /3 = 0.4 to 0.6 for GBC). Such values are quite reasonable for intramolecular general base catalysis (Kirby, 1980). 

II INTRAMOLECULAR GENERAL BASE CATALYSIS 259 E Catalysis by the ionized carboxyl group 259... 

E. l Intramolecular general base catalysis of ester hydrolysis 259, E.2 Intramolecular... 

F Intramolecular general base catalysis by phenolate oxygen 264... 

F. l Catalysis of ester hydrolysis 264, F.2 Catalysis of enolization 265 G Intramolecular general base catalysis by nitrogen 266... 

G. 1 Catalysis of ester hydrolysis 266, G.2 Intramolecular general base catalysis of... 

One class of reaction, conventionally designated as intramolecular general base catalysis, which is actually unimolecular is enolization catalysed by a neighbouring basic centre [22]. It might be thought that this reaction has as... 

F INTRAMOLECULAR GENERAL BASE CATALYSIS BY PHENOLATE OXYGEN F. 1 Catalysis of ester hydrolysis... 

G.3 Intramolecular general base catalysis of aminolysis by the amino-group... 

The salicylimides (4.169) were found to be markedly more resistant to chemical hydrolysis than 4.166. These compounds were hydrolyzed exclusively at the distal amide bond, meaning that hydrolysis produced only sali-cylamide (4.170) and not salicylic acid. This behavior has been ascribed to steric hindrance by the 2-OH group. An intramolecular general base catalysis does not seem to be involved since, as stated, the salicylamides were less reactive than the corresponding benzamides. The rate of plasma-catalyzed hydrolysis of the A-acylsalicylamides was also dependent on the nature of... 

A scheme depicting general base catalysis is shown in Fig. 7.2,b. Because the HO anion is more nucleophilic than any base-activated H20 molecule, intermolecular general base catalysis (Fig. 7.2,bl) is all but impossible in water, except for highly reactive esters (see below). In contrast, entropy may greatly facilitate intramolecular general base catalysis (Fig. 7.2,b2) under conditions of very low HO anion concentrations. Alkaline ester hydrolysis is a particular case of intermolecular nucleophilic attack (Fig. 7.2,cl). Intramolecular nucleophilic attacks (Fig. 7.2,c2) are reactions of cyclization-elimination to be discussed in Chapt. 8. 

All external conditions being identical, the level and width of the minimum in log /cobs plots is highly substrate-dependent. Thus, a mechanism of spontaneous hydrolysis will increase the level and enlarge the width of this minimum. A comparable effect can be expected with intramolecular general base catalysis in the pH region of low acidity. 

Diamines of varying structure show rate enhancements of 20-200 fold, compared to monofunctional aliphatic amines, in nucleophilic reactions with N-acetylimidazole (Page and Jencks, 1972). These were attributed to intramolecular general base catalysis of proton removal from the attacking nitrogen, viz.. 

Intramolecular general base catalysis of hycholysis (21a) was unexpected since the ester has a phenolic leaving group. Felton and Bruice (1968, 1969) reasoned that, if nucleophilic attack occurred, the leaving phenolate ion group would be properly positioned to attack the intermediate acylimidazole and thereby reverse the reaction. The normally less efficient general base reaction then becomes the favoured pathway, as in hydrolysis of acetyl salicylate (see Section 4). Likewise, Fife and McMahon (1970) explained bimolecular general base catalysis by imidazole (21b) in hydrolysis of o-(4-nitrophenylene) carbonate 3 49) by reversibility... 

The relative sizes of the Hammett p and Bronsted a constants will determine the relative rate of 5-nitrosalicylamide. If intramolecular base catalysis applies, then 5-nitrosalicylamide should hydrolyse more rapidly, since the nitro group will increase the susceptibility of the amide bond to attack by hydroxide ion and increase the efficiency of the phenolic hydroxyl as a general acid catalyst. The value of Jtobs at the plateau region was found to be 18 times smaller for the 5-nitrosalicylamide than for salicylamide a mechanism of intramolecular general base catalysis is, therefore, the preferred mechanism. 

A typical example of an intramolecularly catalyzed reaction is the hydrolysis of aspirin (equation 2.15).12 The hydrolysis of the ester bond is achieved by intramolecular general-base catalysis. Comparison with the uncatalyzed hydrolysis rate of similar compounds gives a rate enhancement of some 100-fold from the catalysis.13 This may be extrapolated to a figure of 5000-fold if the pKa of the base is 7 rather than the value of 3.7 in aspirin. 

In a kinetic study of the reactions of a series of hydroxamates, RCONHO-, with 4-nitrophenyl tosylate, their well-known a-nucleophile reactivities were confirmed, but anomalously high nucleophilicity was observed for anions possessing amino substituents capable of providing intramolecular general base catalysis.59... 

First, intramolecular general base catalysis has been demonstrated for aliphatic and aromatic keto-carboxylates ([3]—151) (Bell and Fluendy, 1963 Harper and Bender, 1965 Bell et al., 1972 Bell and Covington, 1975), keto-dialkylamino compounds ([6] and [7]) (Coward and Bruice, 1969 Bell and Timimi, 1973) and for the anion of o-hydroxyacetophenone [8 (Bell et al.,... 

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