Transition state base catalysed

In an attempt to develop effective UGT inhibitors, transition-state based inhibitors were synthesized taking advantage of the high affinity of UGT for the UDP moiety and the structural requirement for the acceptor substrate, w.w.o)-Triphenylalkyl-UDP derivatives (Fig. 31.40) have been shown to be powerful inhibitors of UGT bilirubin isoform. In the same manner, DMSU was an efficient inhibitor of phenol glucuronidation catalysed by UGT1A6. ... 

A large primary isotope effect kH/kD = 3.6 had also been found earlier by Ibne-Rasa122 in the nitrosation of 2,6-dibromophenol in the 4 position which was also shown to be base-catalysed. These values are not unexpected in view of the isotope effect found with diazonium coupling which involves a similarly unreactive electrophile, so that the rate-determining transition state will be displaced well towards products. Furthermore, the intermediate will have a quinonoid structure and will, therefore, be of low energy consequently, the energy barrier for the second step of the reaction will be high. 

It is possible to take advantage of the differing characteristics of the periphery and the interior to promote chemical reactions. For example, a dendrimer having a non-polar aliphatic periphery with highly polar inner branches can be used to catalyse unimolecular elimination reactions in tertiary alkyl halides in a non-polar aliphatic solvent. This works because the alkyl halide has some polarity, so become relatively concentrated within the polar branches of the dendrimer. This polar medium favours the formation of polar transition states and intermediates, and allows some free alkene to be formed. This, being nonpolar, is expelled from the polar region, and moves out of the dendrimer and into the non-polar solvent. This is a highly efficient process, and the elimination reaction can be driven to completion with only 0.01 % by mass of a dendrimer in the reaction mixture in the presence of an auxiliary base such as potassium carbonate. 

The oxidation by Mn(lII) chloride involves three complexes and the kinetic data of Taube " are summarised in Table 15. The greater thermal stability of the /m-complex is considered to result from the lowering of the free energy relative to the transition state as compared with bis- and mono-complexes. The study of MnC204 was based on the Mn(III)-catalysed chlorine oxidation of oxalic acid. ... 

If we now extend our consideration of base-catalysed (BAC2), and acid-catalysed (Aac2), hydrolysis to esters in general, including aliphatic ones (RC02Et), we see that there is a close similarity between the transition states (42b or 42a) for the rate-limiting step in each of the two pathways they are both tetrahedral and differ... 

Schultz and coworkers (Jackson et a ., 1988) have generated an antibody which exhibits behaviour similar to the enzyme chorismate mutase. The enzyme catalyses the conversion of chorismate [49] to prephenate [50] as part of the shikimate pathway for the biosynthesis of aromatic amino acids in plants and micro-organisms (Haslam, 1974 Dixon and Webb, 1979). It is unusual for an enzyme in that it does not seem to employ acid-base chemistry, nucleophilic or electrophilic catalysis, metal ions, or redox chemistry. Rather, it binds the substrate and forces it into the appropriate conformation for reaction and stabilizes the transition state, without using distinct catalytic groups. 

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... 

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. 

By way of example, compare the transition state [16] for a typical general base catalysed reaction (E.1.6) with that for the corresponding reaction involving a nucleophilic mechanism [17] (A.2.35). We have already seen that the EM s for these mechanisms are 13 M and 2.6 x 107 M, respectively. In the... 

Kluger and Brandi (1986b) also studied the decarboxylation and base-catalysed elimination reactions of lactylthiamin, the adduct of pyruvate and thiamin (Scheme 2). These reactions are nonenzymic models for reactions of the intermediates formed during the reaction catalysed by the enzyme pyruvate decarboxylase. The secondary j3-deuterium KIE for the decarboxylation was found to be 1.09 at pH 3.8 in 0.5 mol dm-3 sodium acetate at 25°C. In the less polar medium, 38% ethanolic aqueous sodium acetate, chosen to mimic the nonpolar reactive site in the enzyme, the reaction is significantly faster but the KIE was, within experimental error, identical to the KIE found in water. This clearly demonstrates that the stabilization of the transition state by hyperconjugation is unaffected by the change in solvent. 

TWo of the monoclonal antibodies produced, 7D4 and 22C8, proved to be completely stereoselective, separately catalysing the endo and the exo Diels-Alder reactions, with a fccat of 3.44 X 10-3 and 3.17 X 10 3 min-1 respectively at 25°C. That the turnover numbers are low was attributed in part to limitations in transition state representation modelling studies had shown that the transition states for both the exo and endo processes were asynchronous whereas both TSAs [61] and [62] were based on synchronous transition states (Gouverneur et al., 1993). 

Antibody 15C5 was able to catalyse the hydrolysis of the triester [105] with cat 2.65 x 10 3 min 1 whilst a second antibody from the same immunization programme was later found to hydrolyse the acetylcholinesterase inhibitor Paraoxon [106] with kcat = 1.95 x 10 3min-1 at 25°C (Appendix entry 6.2) (Lavey and Janda, 1996b). Antibody 3H5 showed Michaelis-Menten kinetics and was strongly inhibited by the hapten [104]. It exhibited a linear dependence of the rate of hydrolysis on hydroxide ion concentration, suggesting that 3H5 effects catalysis by transition state stabilization rather than by general acid/base catalysis. 

Furthermore, although the intercepts k kiK/k- ) and the slope (kikjK/k-i) are equally influenced by the dimerization constant K in equation 28, this does not imply that they should show the same effect on changing the solvent. According to the dimer mechanism , it could be expected that the base catalysed decomposition of the transition state SB2, measured by Ag, should be more depressed by small additions of protic solvents than the spontaneous decomposition measured by Ag. Indeed, the overwhelming evidence on the classical base catalysis by amines shows that usually Ag is more important in aprotic than in protic solvents1. 

Catalysis by DABCO in the reactions of FDNB with piperidine, r-butylamine, aniline, p-anisidine and m-anisidine (usually interpreted as base catalysis as in Section B) was also assumed to occur by the formation of a complex between DABCO and the substrate14913. The high (negative) p-value of —4.88 was deemed inappropriate for the usually accepted mechanism of the base-catalysed step (reaction 1). For the reactions with p-chloroaniline, m- and p-anisidines and toluidines in benzene in the presence of DABCO a p-value of —2.86 was found for the observed catalysis by DABCO (fc3DABC0). The results were taken to imply that the transition state of the step catalysed by DABCO and that of the step catalysed by the nucleophile have similar requirements, and in both the nucleophilic (or basicity) power of the nucleophile is involved. This conclusion is in disagreement with the usual interpretation of the base-catalysed step. 

In contrast, for a proton transfer from a hydrogen-bonded acid occurring by the mechanism in (24), the predicted dependence of kf and on the strength of the catalysing base is quite different. In this case, when the pA bh of the base and the p -value of the hydrogen-bonded acid are closely matched, that is at Ap 0, it would be predicted that the proton in the transition state will be roughly half-transferred and Bronsted exponents a and p of around 0.5 should be observed. 

A theoretical investigation of iV-methylmethanephosphonamidate (300), N-methylmethanephosphamide (302), and A-methylmethanesulfonamide (301) as protease transition-state isosteres has revealed that the anionic phosphonamidate (300) is the best mimic of the tetrahedral intermediate for base-catalysed A-methylacetamide (299) hydrolysis. " ... 

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