Intramolecular general acid base catalysis

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. 

Examples of possible intramolecular general acid-base catalysis were reported by Kupchan et al. (1962). The methanolysis of coprostanol acetate and coprostane 3/3, 5/3-diol 3-monoacetate [12] in aqueous methanol was conducted in triethylamine-triethyl-ammonium acetate buffer. The rates of methanolysis at constant... 

The intermolecular general-base catalysis of the hydrolysis may also be measured. Comparing the rate constants for this with those of the intramolecular reaction shows that a 13-M solution of an external base is required to give the same first-order rate as the intramolecular reaction has.12 The effective concentration of the carboxylate ion in aspirin is therefore 13 M. This is a typical value for intramolecular general-acid-base catalysis. 

The most common type of biocatalytic reactions is proton transfer (115). Nearly, every enzymatic reaction involves one or more proton-coupled steps. Transition-state proton bridging and intramolecular proton transfer (general acid-base catalysis) are important strategies to accelerate substrate conversion processes. Moreover, proton transfer also plays a fundamental role in bioenergetics (116). 

Efficient Intramolecular General Acid-Base Catalysis... 

There is an interesting contrast between the large contribution (a factor of ca. 10 ) to the rate enhancement of intramolecular and enzyme-catalysed reactions by nucleophilic catalysis and the much smaller contribution (ca. 1-10) of general acid-base catalysis. 

So far in this chapter, the chemical biology reader has been introduced to examples of biocatalysts, kinetics assays, steady state kinetic analysis as a means to probe basic mechanisms and pre-steady-state kinetic analysis as a means to measure rates of on-catalyst events. In order to complete this survey of biocatalysis, we now need to consider those factors that make biocatalysis possible. In other words, how do biocatalysts achieve the catalytic rate enhancements that they do This is a simple question but in reality needs to be answered in many different ways according to the biocatalyst concerned. For certain, there are general principles that underpin the operation of all biocatalysts, but there again other principles are employed more selectively. Several classical theories of catalysis have been developed over time, which include the concepts of intramolecular catalysis, orbital steering , general acid-base catalysis, electrophilic catalysis and nucleophilic catalysis. Such classical theories are useful starting points in our quest to understand how biocatalysts are able to effect biocatalysis with such efficiency. 

The impact of nucleophilic and electrophilic groups of the active center on the substrate at the contact area in the enzyme-substrate complex (the effect of synchronous intramolecular catalysis). The polyfunctional catalysis involves a great many processes push-pull mechanisms, processes involving a relay charge transfer, as well as a general acid-base catalysis. Presumably, the enzyme in the initial state of the enzymatic reaction already contains structural elements of the transition state and in this case the reaction must be thermodynamically more advantageous. 

Analysis of the structure-reactivity cross-correlations shows the existence of isoparametric relationships in the reactions of Y-substituted benzyl bromides with X-substituted anilines in dioxane and in its mixtures with DMSO at 40 The kinetics of hydrolysis of 1-arylethyl ethers of salicyclic acid, catalysed intramolecularly by 0-CO2H, have been studied. Analysis of substituent effects in both arylethyl and leaving groups provides the most detailed available mechanistic insight into a reaction involving efficient intramolecular proton-transfer catalysis. The mechanism is very different from classical general acid-base catalysis. ... 

Intramolecular general-acid-base catalysis by phenolic groups in reactions of derivatives of carboxylic acids... 

Khan, M.N., Ohayagha, J.E. Kinetics and mechanism of the cleavage of phthal-imide in buffers of tertiary and secondary amines evidence of intramolecular general acid-base catalysis in the reactions of phthalimide with secondary amines. J. Phys. Org. Chem. 1991, 4, 547-561. 

Khan, M.N. Intramolecular general acid-base catalysis and the rate-determining step in the nucleophilic cleavage of maleimide with primary amines. J. Chem. Soc. Perkin Trans. 2. 1985, 1977-1984. 

Intramolecular general acid catalysis in reactions of salicylic acid derivatives 196 Why are EM s for general acid-base catalysed reactions so low 198 EM and the nature of the transition state 200 The formation of small rings 205... 

General add-base catalysis is typically inefficient, compared with nucleophilic catalysis, and this is particularly well documented for intramolecular reactions, as discussed above (Section 2.3.1). The reasons for this disparity have been discussed in terms of broad generalizations, citing most often the looseness, and thus relatively low entropy, of the transition state for a general acid-base catalyzed reaction compared with a cyclization process in which ring formation is complete apart from one partial covalent bond. (Compare, for example, the observed general base catalyzed hydrolysis 5.1 and the abortive but lO times faster nucleophilic reaction... 

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