Primary solvent kinetic isotope effect

Denu, J. M., and Fitzpatrick, P. F., 1994, Intrinsic primary, secondary, and solvent kinetic isotope effects on the reductive half-reaction of D-amino acid oxidase evidence against a concerted mechanism. Biochemistry 33 400194007. 

Solvent isotope effects. Much mechanistic information can be obtained about reactions involving proton transfer from solvent kinetic isotope effects, particularly in solvents of mixed isotopic composition. For practical reasons work is essentially confined to H/D effects, especially those in water. Unlike ordinary primary hydrogen isotope effects, solvent isotope effects have to take into account a host of exchangeable sites, subject to equilibrium as well as kinetic isotope effects. A key concept is that of the fractionation factor, (p, which is the deuterium occupancy of a site in a 1 1 H2O/D2O mixture more formally it is defined by equation l.l ... 

The well-known oxidations of primary and secondary alcohols with Cr species proceed through chromate esters. The definitive mechanistic expeii-ments " demonstrating that previously observed chromate esters were indeed on the reaction pathway showed that either formation or decomposition of the ester could be rate-determining. The rates of oxidation of cyclohexanol and the secondary hydroxyl group of a very steiically hindered steroid in aqueous acetic acid were measured as a function of the solvent composition. The former increased radically as the acetic add concentration increased whereas the latter remained invariant. The former exhibited a primary deuterium kinetic isotope effect of 5, whereas there was no KIE on the oxidation of the crowded steroid. Therefore, the rate-determining step in the oxidation of the cyclohexanol was decomposition of the chromate ester and in the oxidation of the steroid it was its formation, with the ester an obligate intermediate in both reactions. 

The details of proton-transfer processes can also be probed by examination of solvent isotope effects, for example, by comparing the rates of a reaction in H2O versus D2O. The solvent isotope effect can be either normal or inverse, depending on the nature of the proton-transfer process in the reaction mechanism. D3O+ is a stronger acid than H3O+. As a result, reactants in D2O solution are somewhat more extensively protonated than in H2O at identical acid concentration. A reaction that involves a rapid equilibrium protonation will proceed faster in D2O than in H2O because of the higher concentration of the protonated reactant. On the other hand, if proton transfer is part of the rate-determining step, the reaction will be faster in H2O than in D2O because of the normal primary kinetic isotope effect of the type considered in Section 4.5. 

Bromination has been shown not to exhibit a primary kinetic isotope effect in the case of benzene, bromobenzene, toluene, or methoxybenzene. There are several examples of substrates which do show significant isotope effects, including substituted anisoles, JV,iV-dimethylanilines, and 1,3,5-trialkylbenzenes. The observation of isotope effects in highly substituted systems seems to be the result of steric factors that can operate in two ways. There may be resistance to the bromine taking up a position coplanar with adjacent substituents in the aromatization step. This would favor return of the ff-complex to reactants. In addition, the steric bulk of several substituents may hinder solvent or other base from assisting in the proton removal. Either factor would allow deprotonation to become rate-controlling. 

A second reason for the larger isotope effect observed by Jones and Maness (140) might be that in the less polar acetic acid solvent, there might be a small degree of E2 elimination (with solvent acting as base) superimposed on the dominant Sn 1 mechanism. Such an elimination would involve a primary kinetic deuterium isotope effect with a kn/ko s 2 to 6, and hence even a 1 to 5% contribution from such a pathway would have a significant effect on the experimentally observed kinetic isotope effect. 

Interest has been shown by several groups on the effect of solvent and of added anions upon the oxidation of alcohols. The oxidation of isopropanol proceeds 2500 times faster in 86.5 % acetic acid than in water at the same hydrogen ion concentration . The kinetics and primary kinetic isotope effect are essentially the same as in water. Addition of chloride ion strongly inhibits the oxidation and the spectrum of chromic acid is modified. The effect of chloride ion was rationalised in terms of the equilibrium,... 

Mechanistic studies have been designed to determine if the concerted cyclic TS provides a good representation of the reaction. A systematic study of all the E- and Z-decene isomers with maleic anhydride showed that the stereochemistry of the reaction could be accounted for by a concerted cyclic mechanism.19 The reaction is only moderately sensitive to electronic effects or solvent polarity. The p value for reaction of diethyl oxomalonate with a series of 1-arylcyclopentenes is —1.2, which would indicate that there is little charge development in the TS.20 The reaction shows a primary kinetic isotope effect indicative of C—H bond breaking in the rate-determining step.21 There is good agreement between measured isotope effects and those calculated on the basis of TS structure.22 These observations are consistent with a concerted process. 

The kinetic solvent-isotope effects on these reactions are made up of primary and secondary kinetic isotope effects as well as a medium effect, and for either scheme it is difficult to estimate the size of these individual contributions. This means that the value of the isotope effect does not provide evidence for a choice between the two schemes (Kresge, 1973). The effect of gradual changes in solvent from an aqueous medium to 80% (v/v) Me2SO—H20 on the rate coefficient for hydroxide ion catalysed proton removal from the monoanions of several dicarboxylic acids was interpreted in terms of Scheme 6 (Jensen et al., 1966) but an equally reasonable explanation is provided by Scheme 5. 

Lectka and co-workers (252) subsequently extended this system to the catalysis of the imino ene reaction. This reaction proceeds in low conversion albeit good selectivity in dichloromethane. The optimal solvent proved to be benzotrifluoride (BTF), possessing solubility properties similar to dichloromethane while accelerating the rate of the ene reaction presumably due to its aromaticity. A variety of 1,1-disubstituted alkenes participated in the ene reaction, providing amino acid derivatives in high yields and selectivities (85-99% ee). Evidence for the concerted nature of this reaction was provided by a high primary kinetic isotope effect (ku/kr) = 4.4). 

The solvent isotope effect has widely been used in distinguishing between whether proton transfer occurs prior to or in the rate-determining step. When proton transfer is the rate determining step, the rate in D20 will be less than in H20. This is a normal primary kinetic isotope effect. However, if there is a fast reversible proton transfer prior to the rate determining step, the reactions occur more rapidly in D20 than in H20. 

The nucleophile in the S.v2 reactions between benzyldimethylphenylammonium nitrate and sodium para-substituted thiophenoxides in methanol at 20 °C (equation 42) can exist as a free thiophenoxide ion or as a solvent-separated ion-pair complex (equation 43)62,63. The secondary alpha deuterium and primary leaving group nitrogen kinetic isotope effects for these Sjv2 reactions were determined to learn how a substituent on the nucleophile affects the structure of the S.v2 transition state for the free ion and ion-pair reactions64. 

The pyridinium chlorochromate (PCC) oxidations of pentaamine cobalt(III)-bound and unbound mandelic and lactic acids have been studied and found to proceed at similar rates.Free-energy relationships in the oxidation of aromatic anils by PCC have been studied. Solvent effects in the oxidation of methionine by PCC and pyridinium bromochromate (PBC) have been investigated the reaction leads to the formation of the corresponding sulfoxide and mechanisms have been proposed. The major product of the acid-catalysed oxidation of a range of diols by PBC is the hydroxyaldehyde. The reaction is first order with respect to the diol and exhibits a substantial primary kinetic isotope effect. Proposed acid-dependent and acid-independent mechanisms involve the rapid formation of a chromate ester in a pre-equilibrium step, followed by rate-determining hydride ion transfer via a cyclic intermediate. PBC oxidation of thio acids has been studied. ... 

Laser flash photolysis of phenylchlorodiazirine was used to measure the absolute rate constants for intermolecular insertion of phenylchlorocarbene into CH bonds of a variety of co-reactants. Selective stabilization of the carbene ground state by r-complexation to benzene was proposed to explain the slower insertions observed in this solvent in comparison with those in pentane. Insertion into the secondary CH bond of cyclohexane showed a primary kinetic isotope effect k ikY) of 3.8. l-Hydroxymethyl-9-fluorenylidene (79), generated by photolysis of the corresponding diazo compound, gave aldehyde (80) in benzene or acetonitrile via intramolecular H-transfer. In methanol, the major product was the ether, formed by insertion of the carbene into the MeO-H bond, and the aldehyde (80) was formed in minor amounts through H-transfer from the triplet carbene to give a triplet diradical which can relax to the enol. 

The lifetime of 56 can be extended by deuteration CD3CCD3 lives 3.2 times longer in pentane than does CH3CCH3. This longevity is the result of a substantial primary kinetic isotope effect where k 2-n > 1,2-0- Tunneling is important here the H shift occurs in part by tunneling, a pathway not as available to the D shift. On the other hand, polar solvents increase / i, 2-h and decrease the lifetime of 56, in accord with the increase in charge stabilization in the 1,2-H shift transition state. 34 ... 

The remarkable solvent isotope effect on the kinetics of oxidation of guanine by 2AP radicals has been detected in H2O and D2O solutions [14]. In H2O, the rate constants of G(-H) formation are larger than those in D2O by a factor of 1.5-2.0 (Table 1). This kinetic isotope effect indicates that the electron transfer reaction from guanine to 2AP radicals is coupled to deprotonation/ protonation reactions of the primary electron-transfer products (Scheme 1). 

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