Carboxylic acid isotope effects

A number of studies of the acid-catalyzed mechanism of enolization have been done. The case of cyclohexanone is illustrative. The reaction is catalyzed by various carboxylic acids and substituted ammonium ions. The effectiveness of these proton donors as catalysts correlates with their pK values. When plotted according to the Bronsted catalysis law (Section 4.8), the value of the slope a is 0.74. When deuterium or tritium is introduced in the a position, there is a marked decrease in the rate of acid-catalyzed enolization h/ d 5. This kinetic isotope effect indicates that the C—H bond cleavage is part of the rate-determining step. The generally accepted mechanism for acid-catalyzed enolization pictures the rate-determining step as deprotonation of the protonated ketone ... 

Terabe, S., Yashima, T., Tanaka, N., and Araki, M., Separation of oxygen isotopic benzoic acids by capillary zone electrophoresis based on isotope effects on the dissociation of the carboxyl group, Anal. Chem., 60,1673, 1988. 

Tetrahedral intermediates, derived from carboxylic acids, spectroscopic detection and the investigation of their properties, 21, 37 Topochemical phenomena in solid-state chemistry, 15, 63 Transition state structure, crystallographic approaches to, 29, 87 Transition state structure, in solution, effective charge and, 27, 1 Transition state structure, secondary deuterium isotope effects and, 31, 143 Transition states, structure in solution, cross-interaction constants and, 27, 57 Transition states, the stabilization of by cyclodextrins and other catalysts, 29, 1 Transition states, theory revisited, 28, 139... 

The authors have also synthesized134 fatty acids labelled with deuterium and carbon-11 in order to investigate if kinetic isotope effects related to fatty acid metabolism can be observed in vivo by pet133,135-137. In vitro, the large kinetic deuterium isotope effects are observed in the oxidation of deuteriated aliphatic carboxylic acids with alkaline permanganate and manganate135-139. 

The absence of an isotope effect when the reaction was carried out in benzene suggested to the authors that no significant change in bonding occurred to the -H, the hydroxyl H or the carboxyl H in the rate-determining step of the reaction. Hence they proposed that Pb(OAc)4 undergoes rapid anion exchange with mandelic acid in the non-polar medium... 

It can be concluded that the [3+2] pathway seems to be the only feasible reaction pathway for the dihydroxylation by permanganate. The study on the free activation energies for the oxidation of a. P unsaturated carboxylic acids by permanganate shows that the [3+2] mechanism is in better agreement with experimental data than the [2+2] pathway. Experimentally determined kinetic isotope effects for cinnamic acid are in good agreement with calculated isotope effects for the [3+2] pathway, therefore it can be concluded that a pathway via an oxetane intermediate is not feasible. 

Interpretation of KIEs on enzymatic processes (see Chapter 11) has been frequently based on the assumption that the intrinsic value of the kinetic isotope effect is known. Chemical reactions have long been used as models for catalytic events occurring in enzyme active sites and in some cases this analogy has worked quite well. One example is the decarboxylation of 4-pyridylacetic acid presented in Fig. 10.9. Depending on the solvent, either the zwitterionic or the neutral form dominates in the solution. Since the reaction rates in D20/H20 solvent mixtures are the same (see Section 11.4 for a discussion of aqueous D/H solvent isotope effects), as are the carbon KIEs for the carboxylic carbon, it is safe to assume that this is a single step reaction. The isotope effects on pKa are expected to be close to the value of 1.0014 determined for benzoic acid. This in mind, changes in the isotope effects have been attributed to changes in solvation. 

Lipscomb has commented that glutamic acid-245 might act either as a general base or a nucleophile. The available mechanistic information has been reviewed by Kaiser and Kaiser (1972), who postulated that the carboxylate anion of glutamic acid-245 acts as a nucleophile forming an anhydride intermediate [equation (29)]. The divergent D2O solvent isotope effects, =... 

Good selectivity for the oxidation of primary alcohols in the presence of secondary ones can be achieved. By appropriate choice of the reaction conditions, overoxidation of the aldehyde from a primary alcohol to carboxylic acid can be minimized. Kinetic isotope effects in the range of 2 to 3 testify about the relevance of the H+-elimination step upon the overall reactivity . In general, the efficiency of oxidation of alkanols is slightly lower... 

Intermolecular hydrogen bonding, peroxy carboxylic acids, 160 Intermolecular isotope effect, intrazeolite photooxygenation, 872-3... 

SOLVENT ISOTOPE EFFECTS FOR NEUTRAL WATER REACTIONS OF CARBOXYLIC ACID DERIVATIVES... 

R and S isomers of HDT]acetic acid were synthesized by chemical and enzymatic methods that yield products of known stereochemistry.1819 The two isomers were then distinguished by using the following ingenious enzymatic assays. The acetic acid was first converted to acetyl-coenzyme A (by a reaction of the carboxyl group—and not the methyl—of acetic acid). The acetyl-coenzyme A was then condensed with glyoxylate to form malate in an essentially irreversible reaction catalyzed by malate synthase (equation 8.27). The crucial feature of this reaction is that it is subject to a normal kinetic isotope effect, so that more H than D... 

Deng and co-workers have also applied the cinchona derivatives to the kinetic resolution of protected a-amino acid N-carboxyanhydrides 51 [48]. A variety of alkyl and aryl-substituted amino acids may be prepared with high se-lectivities (krei=23-170, see Scheme 10). Hydrolysis of the starting material, in the presence of the product and catalyst, followed by extractive workup allows for recovery of ester, carboxylic acid, and catalyst. The catalyst may be recycled with little effect on selectivity (run 1, krei=114 run 2, krei=104). The reaction exhibits first-order dependence on methanol and catalyst and a kinetic isotope effect (A MeOH/ MeOD=l-3). The authors postulate that this is most consistent with a mechanism wherein rate-determining attack of alcohol is facilitated by (DHQD)2AQN acting as a general base. 5-Alkyl 1,3-dioxolanes 52 may also... 

The unexpected formation of the blue crystalline radical cation (97) from the reaction of triazinium salt (98) with tetracyanoethylene has been reported and the product identified by its EPR spectrum and by X-ray crystallography (Scheme 42).199 Carboxylic acids react with the photochemically produced excited state of N-t-a-phenynitrone (PBN) to furnish acyloxy spin adducts RCOOPBN. The reaction was assumed to proceed via ET oxidation of PBN to give the PBN radical cation followed by reaction with RCO2H.200 The mechanism of the protodiazoniation of 4-nitrobenzenediazonium fluoroborate to nitrobenzene in DMF has been studied.201 Trapping experiments were consistent with kinetic isotope effects calculated for the DMF radical cation. The effect of the coupling of radicals with different sulfur radical cations in diazadithiafulvalenes has been investigated.202... 

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