Secondary isotope effects evidence from

Thus the primary and secondary isotope effects are all within the semiclassical limits and their relationship is in full accord with the semiclassical Swain-Schaad relationship. There is no indication from the magnitudes of the secondary isotope effects in particular of any coupling between motion at the secondary center and the reaction-coordinate for hydride transfer. Thus the sole evidence taken to indicate tunneling is the rigorous temperature-independence of the primary isotope effects. 

A key line of evidence for a multistep mechanism, as opposed to the one-step hydride-transfer mechanism, had been derived from isotope effects measured in reduction of various substrates with monodeuterated analogs of NADH. One can compare the observed rate constants kHH and kno, which in the case of negligible secondary isotope effects should obey the relationship koH/kHM = (1 + kro/kyi])/2, allowing the calculation of the primary isotope effect kn/ku (if undeuterated, monodeuterated and dideuterated hydride donors are all used, both primary and secondary isotope effects can be obtained). In addition, for an oxidizing agent Acceptor one can determine the isotope ratio in the product Acceptor-H/Acceptor-D, called in these studies the product isotope effect Th/Td-... 

The interpretation of solvent isotope effects can be complicated by the large number of secondary isotope effects that can conceivably operate when it is the solvent molecule that is the site of isotopic substitution. The quantitative evaluation of solvent isotope effects is a very difficult problem. The relationship between the magnitude of the solvent isotope effect and the occurrence of equilibrium protonation as opposed to rate-limiting proton transfer is sufficiently general to be of significant value in mechanistic studies. As with nearly all mechanistic criteria, however, there are circumstances that permit exceptions, so corroborating evidence obtained from other types of studies is always desirable. 

Evidence in favor of the [2+2] mechanism is circumstantial, but it does include several types of studies. This evidence includes nonlinear free energy relationships between the substituent parameters on vinylarenes and the rates of the dihydroxylation, and it includes temperature effects on selectivity. It also includes the results of studies on the cleavage of Cp Re(0)(diolate) complexes to Cp ReOj and free olefin. The electronic effects, enthalpy of activation versus the strain of the olefin, and secondary deuterium isotope effects obtained from these studies on the rhenium complex support a stepwise cleavage process that could occur by initial formation of an oxametallacyclobutane intermediate. In the end, however, the combination of computational data and isotope-effect measurements seem to have led the community to accept that osmium tetroxide reacts by the direct [3+2] pathway. The mechanism of the reaction of OjOsNR with olefins during aminohydroxylation presumably follows the same type of [3+2] pathway. 

Kinetic data, which comprise the bulk of the available experimental results, can only be evaluated in terms of a model for the transition state. In their presentation here most reliance will be placed on reactions the mechanisms of which are based on strong independent evidence, and least on those for which the best mechanistic support is a secondary isotope effect itself. Experimental precision is of the utmost importance when quantitative conclusions must be drawn from... 

Important additional evidence for aryl cations as intermediates comes from primary nitrogen and secondary deuterium isotope effects, investigated by Loudon et al. (1973) and by Swain et al. (1975 b, 1975 c). The kinetic isotope effect kH/ki5 measured in the dediazoniation of C6H515N = N in 1% aqueous H2S04 at 25 °C is 1.038, close to the calculated value (1.040-1.045) expected for complete C-N bond cleavage in the transition state. It should be mentioned, however, that a partial or almost complete cleavage of the C — N bond, and therefore a nitrogen isotope effect, is also to be expected for an ANDN-like mechanism, but not for an AN + DN mechanism. 

Brown and McDonald (1966) provided another type of kinetic evidence for these size relationships by determining secondary kinetic isotope effects in reactions of pyridine-4-pyridines with alkyl iodides. For example, the isotopic rate ratio in the reaction between 4-(methyl-d3)-pyridine and methyl iodide at 25-0 C in nitrobenzene solution was determined to be kjyfk = l-OOl, while that in the corresponding reaction with 2,6-(dimethyl-d6)-pyridine was 1-095. (Brown and McDonald (1966) estimate an uncertainty of 1% in the k jk values.) Furthermore, the isotopic rate ratio in the case of the 2-(methyl-d3)-compound increased from 1 030 to 1-073 as the alkyl group in the alkyl iodide was changed from methyl to isopropyl, i.e. the isotope effect increased with increasing steric requirements of the alkyl iodide. 

Discussion of ketone oxidation has centred around the identity of the molecule undergoing oxidation. This has been clearly resolved in some, but not all, cases, the evidence resting on (i), the relative rates of enolisation and oxidation, (ii) kinetic orders and (ih) isotope effects. A general feature of the oxidations of ketones by one-equivalent reagents is that the rate for a given oxidant exceeds that for oxidation of a secondary alcohol by the same oxidant. The most attractive explanation is that the radical formed from a ketone is stabilised by delocalisation, viz. 

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. 

Much attention has been focused on defining the transition state of FTase and the structural determinants of the chemical step. For FTase, there is evidence for both an electrophilic contribution to the transition state, obtained from studies with fluoromethyl FPP analogues, and a nucleophilic contribution, obtained from the metal-substitution and pH studies [31,40,41]. These results are supported by the inability to trap a carbocation intermediate, inversion of configuration at Cl of the farnesyl group during the reaction, and an a-secondary kinetic isotope effect near unity [31,42,43]. Taken together, the available data suggest that the transition state of FTase... 

---