Intramolecular base catalysis

These findings are compatible with a mechanism of intramolecular catalysis for both acyl migration and hydrolysis, as proposed in Fig. 8.5. Also, the possibility that both reactions share a common intermediate is emphasized. Reactions a and b in Fig. 8.5 involve a first step of deprotonation, in agreement with the observed specific base catalysis. Intramolecular nucleophilic attack (Reactions c and d) generates a tetrahedral intermediate that can result in acyl migration or hydrolysis (Reaction e). 

Note that for 4.42, in which no intramolecular base catalysis is possible, the elimination side reaction is not observed. This result supports the mechanism suggested in Scheme 4.13. Moreover, at pH 2, where both amine groups of 4.44 are protonated, UV-vis measurements indicate that the elimination reaction is significantly retarded as compared to neutral conditions, where protonation is less extensive. Interestingy, addition of copper(II)nitrate also suppresses the elimination reaction to a significant extent. Unfortunately, elimination is still faster than the Diels-Alder reaction on the internal double bond of 4.44. 

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. 

A true intramolecular proton transfer in the second step of an azo coupling reaction was found by Snyckers and Zollinger (1970a, 1970b) in the reaction of the 8-(2 -pyridyl)-2-naphthoxide ion (with the transition state 12.151). This compound shows neither a kinetic deuterium isotope effect nor general base catalysis, in contrast to the sterically similar 8-phenyl-2-naphthoxide ion. Obviously the heterocyclic nitrogen atom is the proton acceptor. 

Of the many reagents, both heterogeneous and homogeneous, that can facilitate chemical reactions, the cycloamyloses stand out. Reactions can be catalyzed with many species such as hydronium ions, hydroxide ions, general acids, general bases, nucleophiles, and electrophiles. More effective catalysis can sometimes be achieved by combinations of catalytic species as in multiple catalysis, intramolecular catalysis, and catalysis by com-plexation. Only the latter catalysis can show the real attributes of an efficient catalytic system, namely speed and selectivity. In analogy to molecular sieves, selectivity can be attained by stereospecific complexation and speed can be likewise attained if the stereochemistry within the complex is correct. The cycloamyloses, of any simple chemical compound, come the closest to these goals. 

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... 

The solution to this problem is to compare the rate constant for the intramolecular reaction with that for the corresponding intermolecular process. In the case of aspirin hydrolysis [3] this would be general base catalysis of the hydrolysis [5] of aspirin by an external carboxylate group, RCOO-, of the same basicity as the carboxylate group of aspirin. The necessary data are... 

Relatively few data are available (Table H) for reactions involving intramolecular general acid catalysis, but in most cases the EM s fall in the same range as those for general base catalysis (Tables E-G). This is expected if EM is a characteristic transition-state property, because a general acid catalysed reaction is always the microscopic reverse of a general base catalysed process as shown in equation (5), although in no case has the EM been measured in both directions. 

As we have seen (Section 4, p. 191) the range of effective molarities associated with ring-closure reactions is very much greater than that characteristic of intramolecular general acid-base catalysis the main classification is therefore in terms of mechanism. By far the largest section (I, Tables A-D) gives EM s for intramolecular nucleophilic reactions. These can be concerted displacements (mostly at tetrahedral carbon), stepwise displacements (mostly addition-elimination reactions at trigonal carbon), or additions, and they have been classified in terms of the nucleophilic and electrophilic centres. 

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... 

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