Kemp elimination

Treatment of benzisoxazole with base results in the ring-opening product, salicy-lonitrile. 

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Work linking the two classes has been reported by the Kirby and Hilvert groups. The report of Thorn and Hilvert1171 of antibodies that catalysed the Kemp elimination (3 —> 4) remarkable efficiently led Hollfelder et al.1181 to screen a small but carefully selected set of common proteins for evidence of similar catalysis. 

The Kemp elimination is of special interest because it is known to be extraordinarily sensitive to the medium, and particularly well suited as a test reaction for potential enzyme mimics because it is a simple, one-step process. The joint conclusions from this work were that catalysis involves a combination of a number of different factors, even for this simple reaction by these simple catalysts. 

Most of the characteristics invoked to explain rate accelerations and rate retardations by micelles are valid for vesicles as well. For example, the alkaline hydrolysis of A-methyl-A-nitroso-p-toluenesulfonamide is accelerated by cationic vesicles (dioctade-cyldimethylammonium chloride). This rate acceleration is the result of a higher local OH concentration which more than compensates for the decreased polarity of the vesicular pseudophase (compared to both water and micelles) resulting in a lower local second-order rate constant. Similar to effects found for micelles, the partial dehydration of OH and the lower local polarity are considered to contribute significantly to the catalysis of the Kemp elimination " by DODAB vesicles. Even the different... 

Similarly, vesicular reactivity is dependent on bilayer fluidity and Arrhenius (or Eyring) plots for the decarboxylation of 6-NBIC show a break around Tm. " For the Kemp elimination in different bilayers, it was found that the bilayer for which kinetic data had been gathered below its was least effective as a catalyst. Ester hydrolysis has also been found to be faster above r. For the decarboxylation of 6-NBIC, the increase in catalytic efficiency was attributed to different aggregate surface dynamics based on the observation that vesicles above showed intermediate activation parameters between vesicles below and micelles. One could, of course, discuss causality here considering the fact that many of the bilayer... 

The effect of additives betrays the intricacy of the balance of rate effects even more. The addition of cholesterol to catalytic bilayers has been found to be beneficial for the Kemp eleminiation but to inhibit the decarboxylation of 6-NBIC. In general, the effects of additives on the decarboxylation of 6-NBIC appear to subtly depend on the structure of the hydrophobic tail and hydrophilic headgroup of additives. Similarly subtle effects were found for the Kemp elimination and nucleophilic attack by Br and water on aromatic alkylsulfonates depending on the choice of additive, hydrogen bonding effects, reactivity of partially dehydrated OH , and local water concentrations all played a role and vesicular catalysis could be increased or decreased. 

Kemp elimination was used as a probe of catalytic efficiency in antibodies, in non-specific catalysis by other proteins, and in catalysis by enzymes. Several simple reactions were found to be catalyzed by the serum albumins with Michaelis-Menten kinetics and could be shown to involve substrate binding and catalysis by local functional groups (Kirby, 2000). Known binding sites on the protein surface were found to be involved. In fact, formal general base catalysis seems to contribute only modestly to the efficiency of both the antibody and the non-specific albumin system, whereas antibody catalysis seems to be boosted by a non-specific medium effect. 

Rothlisberger D et al (2008) Kemp elimination catalysts by computational enzyme design. Nature 453 190-195... 

The last design we present here is for a catalyst of the Kemp elimination, shown in Reaction 9.8. A hapten for this reaction, utilizing acetate as the base and acetic... 

The mechanisms by which solvents and catalysts, such as catalytic antibodies and serum albumins, influence the rates of the Kemp elimination, that is, the base-promoted E2 elimination of substituted benzisoxazoles such as 5 (Equation 2), have also been explored theoretically moreover, the predictions concerning the efficiency of antibody 34E4 as catalyst... 

Figure 2 Free-energy profile for the Kemp elimination of 5-nitro-benzisoxazole by antibody 4B2. The reaction coordinate for the proton transfer is r(0-H)-r(H-C) with r(0-H)+r(H-C)=2.85 A. Maximum free-energy values are truncated to 30 kcal/mol for clarity.

Comparable speed gains were also obtained for another Kemp elimination featuring the piperidine-catalyzed ring opening of benzisoxazole in the condensed-phase environment provided by the ionic liquid l-butyl-3-methylimida-zolium hexafluorophosphate, [BMIM][PF6], (Scheme 2) [23]. While these... 

Scheme 2 Kemp elimination reaction of benzisoxazole with piperidine.

Acevedo, O. Role of water in the multifaceted catalytic antibody 4B2 for allylic isomerization and Kemp elimination reactions. J. Phys. Chem. B 2009,113,15372-81. 

Rothlisberger, D., Khersonsky, O., Wollacott, A.M., Jiang, L., DeChancie, J., Betker, J., et al. Kemp elimination catalysts by computational enzyme design. Nature 2008, 453,190-5. 

Alexandrova, A.N., Rothlisberger, D., Baker, D., Jorgensen, W.L. Catalytic mechanism and performance of computationally designed enzymes for Kemp elimination. J. Am. Chem. Soc. 2008,130, 15907-15. 

Genre-Grandpierre, A., Tellier, C., Loirat, M., Blanchard, D., Hodgson, D.R.W., Hollfelder, H., et al. Catalysis of the Kemp elimination by antibodies elicited against a cationic hapten. Bioorg. Med. Chem. Lett. 1997, 7, 2497-502. 

D Anna, E, La Marca, S., Noto, R. Kemp elimination A probe reaction to study ionic liquids... 

One model reaction that has proved a popular and appropriate probe for general base catalysis by potential binders of hydrophobic substrates is the Kemp elimination, the simple, single transition state ring-opening elimination of benzisoxazoles 4.19 (Scheme 2.39). 

Kemp elimination (unnatural reaction, for Catalytic promiscuity 95... 

Examples for a high degree of promiscuity obviously include nonenzymatic proteins such as serum albumins that exhibit promiscuous catalytic activities (Table 1, entry 14). Other cases may include catalysis of unnatural reactions, meaning reactions for which, to our knowledge, no natural enzyme has evolved (e.g., the Kemp elimination performed by serum albumin (Table 1, entry 14, or siloxane hydrolysis by lipase (Table 1, entry 7)). 

The Kemp Elimination Rate-limiting Proton Transfer... 

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