Substrates, structure-reactivity correlations

In the case of enzymes reacting at measurable rates with a wide variety of substrates, structure-reactivity correlations are useful to establish mechanistic similarities with model reactions involving proton transfers [11]. As with most other methods applied to enzyme mechanisms, use of this criterion alone can be misleading. For a-chymotrypsin, for example, a limited series of substrates can be found which shows reactivities not inconsistent with the active-site imidazole acting as a nucleophile [12], whereas overwhelming evidence from all other methods shows that the imidazole acts as a general base [13,14]. 

Resonance Raman spectroscopy (RR), Sec. 6.1, is a powerful technique in the field of enzymology. An extremely accurate structure-reactivity correlation was obtained by observing the wavenumber of the carbonyl group during catalytic attack by acyl serin proteases (Tonge and Carey, 1990). Evidence of bonds formed with substrates at more... 

In the case of enzymes working via a ternary complex mechanism, we have two extreme cases. The easiest to comprehend is the rapid equilibrium random mechanism (Scheme 5.4) this is the mechanism where the chemistry is most likely to be rate determining and kinetic isotope effects or structure-reactivity correlations are likely to be mechanistically informative. Enzymes acting on their physiological substrates at optimal pH are likely to show a degree of preference for one or the other substrate binding first, but they can often be induced to revert to a rapid equilibrium random mechanism by the use of non-optimal substrates or pH. 

Structure correlation to map reaction pathways might become important in the field of the monoclonal catalytic antibodies [145, 146]. These proteins are produced by the immune system to bind molecules which resemble the transition state of a chemical reaction. They show catalytic properties with high substrate specificity. Reactions can be imagined for which a biochemical catalyst is not yet known (e.g. the Diels-Alder reaction). The rational design of catalysts for these reactions requires detailed information about possible transition-state structures, geometrical and energetic aspects of the ligand/receptor interface and results from structure/reactivity relationships which are available from structure correlation. 

A quantitative description of relations between structural parameters of solid catalysts or substrates on one side and reaction rates or adsorption equilibria on the other side, even if valid only in limited areas, may form an important step in the development of a general theory of catalysis. Some years ago, Boudart 1) noticed that such correlations in heterogeneous catalysis can be divided into two broad classes. In the first type a series of catalysts is tested by means of a standard reaction and some kinetic parameter is related to a property of the solid catalyst. In correlations of the second type, the reactivity of a series of compounds is studied on a single catalyst and some kinetic parameter is related to a property of the reacting molecules. Boudart pointed out that correlations of the first type are more frequent in the literature than those of the second type. He also presented some examples of both types. Correlations between the substrate structure and its reactivity were qualitative or semiquantitative. 

The first-order kinetics, lack of dependence of rate upon pressure in the gas phase above 1 torr, absence of catalysis, and stereospecificity all show that vinyl allyl ether isomerizations are unimolecular reactions. The effects of substrate structure and solvents on reactivity indicate that the rate-limiting transition state does not resemble an ion pair. Methyl substituents on the a and y carbons of the allylic group increase reactivity by only about 10- and 2.5-fold respectively, which is very much less than substituent effects on ionic allylic reactions. While the isomerization of vinyl a-methylallyl ether is about ten times faster in organic solvents than in the vapor phase, the solvent effect is small and does not correlate with solvent polarity. 

Once the protein interaction pattern is translated from Cartesian coordinates into distances from the reactive center of the enzyme and the structure of the ligand has been described with similar fingerprints, both sets of descriptors can be compared [25]. The hydrophobic complementarity, the complementarity of charges and H-bonds for the protein and the substrates are all computed using Carbo similarity indices [26]. The prediction of the site of metabolism (either in CYP or in UGT) is based on the hypothesis that the distance between the reactive center on the protein (iron atom in the heme group or the phosphorous atom in UDP) and the interaction points in the protein cavity (GRID-MIF) should correlate to the distance between the reactive center of the molecule (i.e. positions of hydrogen atoms and heteroatoms) and the position of the different atom types in the molecule [27]. 

This approach has been applied (Tee, 1989) to kinetic data for the bromination of phenols and phenoxide ions catalysed by a-CD. For 15 different substrates (nine phenols and six phenoxides) Krs values vary only between 0.07 and 0.8 mM, with most being between 0.1 and 0.5 mM, indicating very similar transition state stabilization for substrates with a range of reactivity of 40 million (Table A4.2). Moreover, the values of Krs show no clear correlation with Ks- This lack of dependence of KTS on the structure of the substrate is strong evidence that the transition state for the catalysed process is one in which the phenol moiety is basically outside the CD cavity while the bromine is inside ([9]— [10]). The same conclusion was... 

Nucleophilic substitution reactions are among the most widely studied reactions in chemistry (1). This is due, in part, to their synthetic utility, to the wide range of substrates and reactants, and to their relatively clean kinetic behavior. In contrast to thermodynamically based studies of structure and reactivity (e.g., Hammett correlations of acidity), a satisfactory understanding of kinetic reactivity in S 2 reactions has yet to be achieved, albeit not for lack of talent or effort expended. 

Correlation of structure and reactivity in the oxidation of substituted aromatic anils by pyridinium fluorochromate (PFC) has been attempted using Grunwald-Winstein and Hammett equations. The stoichiometry between the substrate and oxidant is 1 2 in the oxidation of cyclic ketones by PFC to 1,2-diketones. PFC oxidation of secondary alcohols has been investigated. ... 

A major method of modeling the effect of structural variation on chemical reactivity, physical properties or biological activity of a set of substrates is the use of correlation analysis. In this method it is assumed that the effect of structural variation of a substituent X upon some chemical, physical or biological property of interest is a linear function of parameters which constitute a measure of electrical, steric, and transport effects. 

Because systematic variations in selectivity with reactivity are commonly quite mild for reactions of carbocations with n-nucleophiles, and practically absent for 71-nucleophiles or hydride donors, many nucleophiles can be characterized by constant N and s values. These are valuable in correlating and predicting reactivities toward benzhydryl cations, a wide structural variety of other electrophiles and, to a good approximation, substrates reacting by an Sn2 mechanism. There are certainly failures in extending these relationships to too wide a variation of carbocation and nucleophile structures, but there is a sufficient framework of regular behavior for the influence of additional factors such as steric effects to be rationally examined as deviations from the norm. Thus comparisons between benzhydryl and trityl cations reveal quite different steric effects for reactions with hydroxylic solvents and alkenes, or even with different halide ions... 

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