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Biology LibreTexts

Transition State Stabilization

Linus Pauling postulated long ago that the only thing that a catalyst must do is bind the transition state more tightly than the substrate. That this must be the case can be seen from the diagram below, which shows how \(S\) and \(S*\) (the transition state) can react with E to form a complex which then proceeds to product, or can go to product in the absence of \(E\). From this diagram, it should be evident that \(c - a = d -b\), where \(a\) is the \(\Delta G^o\) for the binding of \(S\) to \(E\), and \(b\) is the \(\Delta G^o\) for the binding of S* to E. For an enzyme to be a catalyst the activation energy for the reaction in the presence of \(E\), \(d\), must be less than in the absence of enzyme, \(c\). Therefore \(c-d = a-b > 0\). Since \(\Delta G^o = -RT\,\ln\, K_{eq}\), \(K_{eq}\) for binding of \(S*\) to \(E\) is greater than for \(S\) binding to \(E\).





The stability of the transition state also affects the reaction kinetics (which makes sense given that the activation energy clearly affects the speed of a reaction). As you probably remember from organic chemistry, SN2 reactions are slow when the central atom where the substitution will occur is surrounded by bulky substitutents (sterics once again). We discussed this in context to nucleophiliic substitution on a sp2 hybridized carbonyl carbon in carboxylic acid derivatives versus on a sp3 hybridized phosphorous in phosphoesters and diesters.; The explanation for this phenomena has usually been attributed to hindered access of the central atom caused by bulky substituents (intrinsic effects). Is this true?; Recent studies on SN2 reactions of methylchloroacetonitrile and t-butylchloroacetonitrile (with the reagent labeled with 35Cl) using 37Cl- as the incoming nucleophile in the gas phase shown that the more hindered t-butyl derivative's activation energy was only 1.6 kcal/mol higher than the methyl derivative, but in aqueous solution, the difference is much greater for comparable reactions. They attributed the differences to solvation effects of the transition state. The bulkier the substituents on the central atom, the more difficult it is to solvate the transition state since water can't reorient around it as well. In effect there is steric hindrance for both reactant and solvent.