Kemp decarboxylation

The mechanism of both the Kemp elimination and Kemp decarboxylation are outlined here. 

To estimate the impact of these molecular solvent effects the division of solvents into protic (H-bond donor and acceptor) and aprotic (at most H-bond acceptor) ones is very helpful since the formation of specific hydrogen bonds often increases or decreases the reaction rate drastically. The rate for Kemp decarboxylations of benzisoxazole-3-carboxylic acid derivatives accelerate by a factor of about 10 when the solvent character changes from polar protic to polar aprotic. Hydrogen bonds between the reacting anion and the protic solvent were determined to be the most important factor for this acceleration [655, 656]. 

Acevedo O, Jorgensen WL (2005) Influence of inter- and intramolecular hydrogen bonding on Kemp decarboxylations from QM/MM simulations. J Am Chem Soc 127 8829-8834... 

The unimolecular decarboxylation of 3-carboxybenzisoxazoles (Figure 10, often called Kemp decarboxylation) is enormously accelerated by aprotic, polar solvents. For example, reactions of 6-nitrobenzisoxazole-3-... 

In addition to multiparametric equations, mixed quantum and molecular mechanics simulations reproduced the observed solvent effects quite well. These simulations also support the conclusion from previous work about the anticatalytic role of hydrogen bonds in the Kemp decarboxylation. 

A catalytic antibody raised to bind the hydrophobic dye 2-bromoaceta-mido-l,5-naphthalenedisulfonate was also found to catalyze the Kemp decarboxylation, with a rate acceleration, defined as fecat/feuncat, of 10, which was roughly 1000-fold more than the acceleration brought about by the simple CTAB micelles (fecat was found to be equal to 17 min at pH 8. 0, 20 °C). It was proposed that partitioning of the substrate into the significantly hydrophobic antibody active site resulted in s pificant rate acceleration. However, subsequent structural analyses su ested a more complex active site of the antibody, with an alternation of polar and nonpolar residues. This result is in agreement with the findings in simpler systems, such as the rate acceleration brought about by the simple cationic... 

Similar to what was found for the Kemp decarboxylation, catalytic antibodies were found to provide substantial rate acceleration to the Kemp elimination too. In particular, antibody 34E4 catalyzed the Kemp elimination of 5NBI with a fecat/ M pH 7.4 of 5.5 x 10 s, which corresponded... 

Although Ce(IV) oxidation of carboxylic acids is slow and incomplete under similar reaction conditions , the rate is greatly enhanced on addition of perchloric acid. No kinetics were obtained but product analysis of the oxidations of -butyric, isobutyric, pivalic and acetic acids indicates an identical oxidative decarboxylation to take place. Photochemical decomposition of Ce(IV) carbo-xylates is highly efficient unity) and Cu(ll) diverts the course of reaction in the same way as in the thermal oxidation by Co(IIl). Direct spectroscopic evidence for the intermediate formation of alkyl radicals was obtained by Greatorex and Kemp ° who photoirradiated several Ce(IV) carboxylates in a degassed perchloric acid glass at 77 °K in the cavity of an electron spin resonance spectro-... 

Spontaneous decarboxylations of carboxylate ions and hydrolyses of aryl phosphate dianions and aryl sulfate monoanions are much faster in organic solvents than in water (Thomson, 1970 Kemp and Paul, 1970 Bunton et al., 1967 Kirby and Varvoglis, 1967). This solvent effect is consistent with the Hughes-Ingold qualitative solvent theory because these reactions involve dispersion of charge in forming the transition state. 

Decarboxylation of 6-nitrobenzisoxazole-3-carboxylate [52] has been most widely investigated in aqueous systems, since this reaction is remarkably solvent dependent (Kemp and Paul, 1970 Kemp and Paul, 1975 Kemp et al.,... 

Kemp et al., 1978). The rate is slowest in an aqueous solution and is enhanced in aprotic and/or dipolar solvents. The rate augmentation of 106—108 is attainable in dipolar aprotic solvents such as dimethyl sulfoxide and hexamethylphosphoramide (HMPA). Interestingly, the decarboxylation rate of 4-hydroxybenzisoxazole-3-carboxylate [53], a substance which contains its own protic environment, is very slow and hardly subject to a solvent effect (1.3 x 10-6 s-1 in water and 8.9 x 10-6 s-1 in dimethylformamide Kemp et al., 1975). The result is consistent with the fact that hydrogen-bonding with solvent molecules suppresses the decarboxylation. 

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. 

The model of the polymer derived from magnetic resonance and fluorescence spectroscopy studies has proved very useful in suggesting other types or reactions besides hydrolytic ones in which catalytic effects might be achieved. For example, it has been shown by Kemp and Paul46-47 that the decarboxylation of certain benzisoxazole carboxylic acids is very markedly accelerated in apolar, aprotic solvents, in contrast to water. Such an apolar solvent apparently lowers the energy of the charge-delocalized transition state in this decarboxylation reaction. Since... 

The predictive capabilities of results of theoretical calculations of isotope effects have again been questioned,94 following an experimental and theoretical study of the decarboxylation of 3-carboxybenzisoxazole at room temperature (Kemp s reaction). The experimentally determined 15N isotope effect in acetone is 1.0312 0.0006 and the 13C isotope effect (1.0448, 1.0445, 1.0472, and 1.0418 in 1,4-dioxane, acetonitrile, DMF, and water, respectively) is independent of solvent polarity even though the reaction rate is markedly solvent dependent. Theoretical models at die semiempirical (AMI, PM3, SAMI) and ab initio (up to B3LYP/6-31+ + G ) levels were all unable to predict die experimental results quantitatively. 

D. S. Kemp, D. D. Cox, K. G. Paul, Physical organic-chemistry of benzisoxazoles. 4. Origins and catalytic nature of solvent rate acceleration for decarboxylation of 3-carboxybenzisoxa-zoles, J. Am. Chem. Soc, 1975, 97, 7312-7318. 

Equation [10.3.29] reproduces acceptably well the sensitivity of the decarboxylation rate of 3 -carboxybenzisoxazole in pure solvents observed by Kemp and Paul. In addition, it clearly shows that such a rate increases dramatically with increasing polarity and, also, to a lesser degree, with solvent basicity. By contrast, it decreases markedly with increasing solvent acidity. This behavior is consistent with the accepted scheme for this decarboxylation reaction. 

Kemp, D.S. and Paul, K.G. (1975) The physical organic chemistry of benzisoxazoles. ni. The mechanism and the effects of solents on rates of decarboxylation of benzisoxazole-3-carboxylic acids, J, Am. Chem. Soc. 97, 7305. 

The next reaction to be studied was the decarboxylation reaction of 3-car-boxybenzisoxazole (Eq. [43]). The interest in this reaaion stems from the elegant and thorough investigation of the molecule and derivatives in various solvents by Kemp and co-workers.244445 Jhey discovered that the reaction rate can increase 10 -fold on going from aqueous solution to hexamethylphos-phoramide (HMPA). 

D. S. Kemp and K. G. Paul, ]. Am. Chem. Soc., 97, 7305 (1975). The Physical Organic Chemistry of Benzisoxaroles. 111. The Mechanism and the Effects of Solvents on Rates of Decarboxylation of Benzisoxazole-3-Carboxylic Acids. 

H. Zipse and K. N. Houk,/. Am. Chem. Soc., 117, in press (1995). A Quantum Mechanical and Statistical Mechanical Exploration of the Thermal Decarboxylation of Kemp s Other Acid (Benzisoxazole-3-Carboxylic Acid). The Influence of Solvation on the Transition State Geometries and Kinetic Isotope Effects of a Reaction with a Gigantic Solvent Effect. 

The interpretation of the large solvent effect started from the observation of Kemp and coworkers that decarboxylation of 5-hydroxy-3-carboxyben-zisoxazole was accelerated by approximately four orders of magnitude by dimethylacetamide, but this acceleration was only ninefold in case of 4-hydroxy-3-carboxybenzisoxazole (Figure 11). This result suggested that a... 

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