Efficient Intramolecular General Acid-Base Catalysis

Efficient Intramolecular General Acid-Base Catalysis 

16) in detail [39]. General acid catalysis is easily observed because it is highly eflR-cient in salicylic acid derivatives [40] and Buffet and Lamaty estimated an EM lO M for the reaction of 3.3 [41]. (Possible because there is measurable intermolecular general acid catalysis of the hydrolysis of aryl alkyl acetals of benzaldehyde.) 

New systems designed to test this conclusion confirm the central importance of the intramolecular hydrogen bond. Note that the proton transfer in mechanism 3.2 follows Jencks libido rule, evolving from strongly unfavorable in the reactant to strongly favorable in the product so the hydrogen bond could be dose to its strongest in the transition state. 

Since systems 3.4 are hydrolyzed faster, by up to an order of magnitude, than similar derivatives of salicylic acid, EMs of up to 10 may be estimated. However, it is not generally possible to measure EMs systematically because the necessary control - the corresponding intermolecular reaction - is often too slow to be observed above background. The most relevant measure of catalytic efficiency, for comparison with similar reactions in enzyme active sites (where pH is not simply meaningful) is the ratio of the rates of the pH-independent reactions (Eig. 2.1) in the presence and absence of the catalytic group. We use this parameter in the discussion which follows. 

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Efficient Intramolecular 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. 

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. ... 

The most efficient system of this sort - and the only one to show intramolecular general acid catalysis of the hydrolysis of a methoxymethyl acetal derived from an aliphatic alcohol - is compound 3.13, based on the most reactive aromatic system... 

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. 

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. 

The intermediate is considered to be (303) which either reverts to starting material or yields the o -hydroxy compound (304) by either acid or base catalysis. Rates of reaction are very dependent on positions of the substituents and while the conversion of (305) to (306) is efficient, the corresponding process of (307) proceeds slowly. Introduction of dimethylamino substituents markedly reduces the photoreactivity of the azoxybenzene and products derived from intramolecular hydrogen abstraction and cleavage of N=N or C=N bonds become evident. The conversion of (305) to (307) is reported to be a general one-way process for these systems and the azoxy isomer formed is always that with the N-oxide function far from the arene moiety which has the stronger electron donating substituent. 

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