Substrates, structure-reactivity

Shin J., Kim B., Exploring the Active Site of Amine Pyruvate Aminotransferase on the Basis of the Substrate Structure-Reactivity Relationship How the Enzyme Controls Substrate Specificity and Stereoselectivity,/. Org. Chem. 2002, 67, 2848-2853. 

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]. 

Technologists are not always aware of the surfactant-substrate structure-reactivity relationships and in many cases will select a surfactant on the basis of producer recommendations or a trial-and-error approach. 

J.-S. Shin, B.-G. Kim, Exploring the active site of amineipyruvate aminotransferase on the basis of the substrate structure-reactivity relationship how the enzyme controls substrate specificity and stereoselectivity, J. Oq . Chem. 67 (2002) 2848-2853. 

Absolute rate data for Friedel-Crafts reactions are difficult to obtain. The reaction is complicated by sensitivity to moisture and heterogeneity. For this reason, most of the structure-reactivity trends have been developed using competitive methods, rather than by direct measurements. Relative rates are established by allowing the electrophile to compete for an excess of the two reagents. The product ratio establishes the relative reactivity. These studies reveal low substrate and position selectivity. 

There are several examples of successful dienol epoxidations (Table 9.2). Catalytic SAE conditions are generally better than stoichiometric for reactive substrates (Entry 1), whilst stoichiometric conditions, on the other hand, are useful for less reactive substrates. Small variations in substrate structure can cause large differences in reactivity and product stability pentadienol could be epoxidized in acceptable yield, whereas hexadienol gave a complex mixture of products (Entries 1, 2). 

The effect on the reactivity of a change in substrate structure depends on the mechanism. 

In the discussion of electrophilic aromatic substitution (Chapter 11) equal attention was paid to the effect of substrate structure on reactivity (activation or deactivation) and on orientation. The question of orientation was important because in a typical substitution there are four or five hydrogens that could serve as leaving groups. This type of question is much less important for aromatic nucleophilic substitution, since in most cases there is only one potential leaving group in a molecule. Therefore attention is largely focused on the reactivity of one molecule compared with another and not on the comparison of the reactivity of different positions within the same molecule. 

These treatments have been also applied to S/yAr. For example, for a neutral nucleophile, all the classical pathways identified at present are represented by the general reaction mechanism shown by Scheme 2. A concerted mechanism, indicated by the diagonal path in Scheme 2, had not been discussed until lately, but was observed, among other systems, in the hydrolysis of l-chloro-2,4,6-trinitrobenzene and 1-picrylimidazole. The study was then extended to other related substrates and structure-reactivity relationships could be obtained78. 

In Chapters 12 and 13, it will.be seen how the transition state theory may be used quantitatively in enzymatic reactions to analyze structure reactivity and specificity relationships involving discrete changes in the structure of the substrate. In Chapters 18 and 19, transition state theory is similarly applied to protein folding. 

In Scheme 3 we modify the simple SW1 mechanism to include the ion-pair idea. Change of substrate structure so as to make the carbocation less reactive,... 

As mentioned earlier, Ding et al.15 captured a number of dichlorohetero-cyclic scaffolds where one chloro atom is prone to nucleophilic aromatic substitution onto resin-bound amine nucleophiles (Fig. 1). Even though it was demonstrated that in many cases the second chlorine may be substituted with SNAr reactions, it was pointed out that palladium-catalyzed reactions offer the most versatility in terms of substrate structure. When introducing amino, aryloxy, and aryl groups, Ding et al.15 reported Pd-catalyzed reactions as a way to overcome the lack of reactivity of chlorine at the purine C2 position and poorly reactive halides on other heterocycles (Fig. 10). 

A wide variety of enzyme controlled stereospecific transformations are known. These transformations include oxidations, reductions, reductive animations, addition of ammonia, transaminations and hydrations. In each case the configuration of the new asymmetric centre will depend on the structure of the substrate. However, substrates whose reactive centres have similar structures will often produce asymmetric centres with the same configuration. Enzyme based methods are economical in their use of chiral material but suffer from the disadvantage that they can require large quantities of the enzyme to produce significant quantities of the drug. 

In addition to these requirements related to substrate structure, an ary] donor capable of undergoing transmetalation with Pd(II) intermediates under conditions suitable for C-H bond activation is necessary. Among the Ph-BX2/Ph-SiX3/ Ph-SnX3 trio, silanols have the desired reactivity. Although monophenyl silanol, silanediol, and silonate can be used as the aryl group donor, diphenylsilanol proved superior. 

One of the reactions catalyzed by esterases and lipases is the reversible hydrolysis of esters (Figure 19.1, Reaction 2). These enzymes also catalyze transesterilications and the desymmetrization of mew-substrates (vide infra). Many esterases and lipases are commercially available, making them easy to use for screening desired biotransformations without the need for culture collections and/or fermentation capabilities.160 In addition, they have enhanced stability in organic solvents, require no co-factors, and have a broad substrate specificity, which make them some of the most ideal industrial biocatalysts. Alteration of reaction conditions with additives has enabled enhancement and control of enantioselectivity and reactivity with a wide variety of substrate structures.159161164... 

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