General add base catalysis

Figure 10 Possible transition state for the reaction of an epoxide hydroiase-oxide-HjO complex, illustrating a general add-base catalysis mechanism for the hydrolysis of benzo[a]pyrene-4,5-oxide. (Taken from Armstrong, 1987.)...

General add-base catalysis is typically inefficient, compared with nucleophilic catalysis, and this is particularly well documented for intramolecular reactions, as discussed above (Section 2.3.1). The reasons for this disparity have been discussed in terms of broad generalizations, citing most often the looseness, and thus relatively low entropy, of the transition state for a general acid-base catalyzed reaction compared with a cyclization process in which ring formation is complete apart from one partial covalent bond. (Compare, for example, the observed general base catalyzed hydrolysis 5.1 and the abortive but lO times faster nucleophilic reaction... 

Simultaneous General Add-Base Catalysis Involving an Enzyme and an External Catalysis, Biochemistry 23, 3626-3635. 

A similar treatment for base-catalyzed reactions can be used to develop corresponding equations for general base catalysis. For a detailed discussion of general add-base catalysis of aqueous reactions, see Jencks, W. P. Chem. Rev. 1972, 72,705. See also Ault, A. /. Chem. Uuc. 2007, 54, 38 Kwan, E. E. /. Chem. Educ. 2007,84,39. 

Jencks, W.P. (1972) General add-base catalysis of complex reactions in water. Chemical Reviews, Vol. 72, No.6, p>p. 705-718... 

Washabaugh, M. W. Jencks, W. P. Thiazolium C(2)-proton exchange general base catalysis, direct proton transfer, and add inhibition. 

These experiments employing acidic media were at best only semi-quantitative, and none comprised a systematic investigation of the catalysis. Nevertheless, they placed the transformation in a new light and broadened the opportunities for investigating its mechanism. From the dependence of the reactions on the concentrations of formate, acetate, or succinate ions, Ashmarin argued for a general add and base catalysis. The results of Petuely s experiments implied the same kind of catalytic effect, and Petuely wrote the reaction as an enolization catalyzed by acids and bases. 

There are several types of pH-dependent kinetic behavior that can be interpreted in terms of one or more of the various forms of the specific acid-base catalysis relation [equation (7.3.2)]. Skrabal (33) classified the various possibilities that may arise in reactions of this type, and Figure 7.3 is based on this classification. The various forms of the plots of log k versus pH reflect the relative importance of each of the various terms in equation (73.2) as the pH shifts. Curve a represents the most general type of behavior. This curve consists of a region where add catalysis is superimposed on the noncatalytic reaction, a region where neither acid nor base catalysis is significant. 

As noted above, there is not an activation barrier for the formation of a tetrahedral intermediate (Tl) from hydroxide ion and formamide in the gas phase. The barrier in solution has been attributed to the increase in free energy that must accompany the partial desolvation of hydroxide ion that is required for formation of Tl by attack of hydroxide on the carbonyl group. Two slightly different mechanisms for this process have been proposed, as shown in Figure 7.30. In path a, two water molecules are lost from the solvated hydroxide ion, (H20)4HO , before hydroxide adds to the carbonyl. In path b, one of the waters of hydration provides the nucleophilic oxygen, and the hydroxide ion then provides general-base catalysis for the reaction. 

The elimination can be subject to general base catalysis. Loudon and Noyce found general base catalysis in the dehydration of substituted l-aryl-2-phenylethanols in aqueous dioxane solution with 1 1 dichloroacetic add-soditun dichloroacetate buffers. Loudon, G. M. Noyce, D. S. /. Am. Chem. Soc. 1%9, 91,1433. 

Although early investigators considered that general add-general base catalysis was operative in the mutarotation of tetramethyl-D-glucose in benzene and in... 

In base catalysis, the role of the base generally appears to be to convert a protonbearing nucleophile (i.e., Nu-H) into an anionic species (Nu ) by rapid, reversible proton abstraction. The negatively charged nucleophile can then add, in a slow (rate determining) step, to the carbon of the carbonyl (C=0) group, and, in a final fast step, the adduct thus formed can abstract a proton from the protonated base, regenerating the base and the fully formed adduct. These steps are illustrated in Scheme 9.35. 

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