Secondary kinetic isotope

Solvolytic experiments specifically designed to test Bartell s theory were carried out by Karabatsos et al. (1967), who were primarily interested in an assessment of the relative contributions of hyperconjugation and non-bonded interactions to secondary kinetic isotope effects. Model calculations of the (steric) isotope effect in the reaction 2- 3 were performed, as well as that in the solvolyses of acetyl chloride... 

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. 

Kaplan and Thornton (1967) determined secondary kinetic isotope effects in two 8 2 displacement reactions, one of which involved quatemi-zation of N,N-dimethylaniline and N,N-dimethyl-eig-aniline with methyl p-toluenesulphonate (CHgOTs). The reactions were carried out in... 

Support for such an interaction of the H—C bonds with the carbon atom carrying the positive charge is provided by substituting H by D in the original halide, the rate of formation of the ion pair is then found to be slowed down by 10% per deuterium atom incorporated a result compatible only with the H—C bonds being involved in the ionisation. This is known as a secondary kinetic isotope effect, secondary... 

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. 

Experimental studies of the oxidative cleavage of cinnamic acid by acidic permanganate [35] resulted in secondary kinetic isotope effects, kn/kp, of 0.77 (a) and 0.75 (P), while another paper from the same group on the same reaction with quaternary ammonium permanganates [36] reported very different isotope effects of 1.0 (a) and 0.91 - 0.94 (P) depending on the counterion. Different mechanisms were discussed in the literature [37, 38] to explain the variety of experimental results available, but the mechanistic issues were unresolved. The reported activation energy for the oxidation of... 

In the preceding sections, the bond to the isotopic atom is broken or formed in the rate-determining step of the reaction. In these cases, the change in rate is referred to as a primary kinetic isotope effect. Isotopic substitution at other sites in the molecule has much smaller effects on the rate. These small isotope effects are collectively referred to as secondary kinetic isotope effects. 

T-secondary isotope effect can be determined. As recounted in the last item of Chart 3, such effects are expected to be measures of transition-state structure. If the transition state closely resembled reactants, then no change in the force field at the isotopic center would occur as the reactant state is converted to the transition state and the -secondary kinetic isotope effect should be 1.00. If the transition state closely resembled products, then the transition-state force field at the isotopic center would be very similar to that in the product state, and the a-secondary kinetic isotope effect should be equal to the equilibrium isotope effect, shown by Cook, Blanchard, and Cleland to be 1.13. Between these limits, the kinetic isotope effect should change monotonically from 1.00 to 1.13. 

Kurz and Frieden in 1977 and 1980 determined -secondary kinetic isotope effects for the unusual desulfonation reaction shown in Table 1, both in free solution and with enzyme catalysis by glutamate dehydrogenase. The isotope effects (H/D) were in the range of 1.14-1.20. At the time, the correct equilibrium isotope effect had not been reported and their measurements yielded an erroneous value... 

Secondary kinetic isotope effects are observed if an isotopic label is located adjacent to or remote from the bond that is being broken or formed during the reaction. Again, these depend on the internal energy of the decomposing ions. Secondary kinetic isotope effects, 4ec, are generally much smaller than their primary analogues. 

Example The ratio [M-CH3]V[M-CD3] from isopropylbenzene molecular ions decomposing by benzylic cleavage (Chap. 6.4) varied from 1.02 for ion source fragmentations (70eVEI) over 1.28 for metastable ions in the FFR to 1.56 in the 2 FFR, thus clearly demonstrating the dependence of the secondary kinetic isotope effect on internal energy. [77]... 

Example Secondary kinetic isotope effects on the a-cleavage of tertiary amine molecular ions occurred after deuterium labeling both adjacent to and remote from the bond cleaved (Chap. 6.2.5). They reduced the fragmentation rate relative to the nonlabeled chain by factors of 1.08-1.30 per D in case of metastable ion decompositions (Fig. 2.18), but the isotope effect vanished for ion source processes. [78] With the aid of field ionization kinetic measurements the reversal of these kinetic isotope effects for short-lived ions (lO -lO" s) could be demonstrated, i.e., then the deuterated species decomposed slightly faster than their nonlabeled isoto-pomers (Fig. 2.17). [66,76]... 

Hydrogen abstraction from propan-2-ol and propan-2-ol- /7 by hydrogen and deuterium atoms has been studied by pulsed radiolysis FT-ESR. A secondary kinetic isotope effect was observed for H (D ) abstraction from the C—H (C—D) bonds. The results were compared with ab initio data. In similar work, the kinetic isotope effects in H and D abstraction from a variety of other alcohols in aqueous solvents have been measured. It was found that, compared with the gas phase, the reactions exhibit higher activation energies in agreement with the ability of solvation to decrease the dipole moment from the reactant alcohol to the transition state. 

Reactions of (ii)-l-decenyl(phenyl)iodonium salt (6a) with halide ions have been examined under various conditions. The products are those of substitution and elimination, usually (Z)-l-halodec-l-ene (6b) and dec-l-yne (6c), as well as iodobenzene (6d), but F gives exclusively elimination. In kinetic studies of secondary kinetic isotope effects, leaving-group substituent effects, and pressure effects on the rate, the results are compatible with the in-plane vinylic mechanism for substitution with inversion. The reactions of four ( )-jS-alkylvinyl(phenyl)iodonium salts with CP in MeCN and other solvents at 25 °C have been examined. Substitution with inversion is usually in competition with elimination to form the alk-l-yne. 

Anchimeric assistance may also explain slight changes in mechanism resulting from the presence of a neighboring group. One likely case is the acid-catalyzed hydrolysis of phenylglycosides. Raftery s group" found that the secondary kinetic isotope effect (/tr/ d) was 1.13 for acid hydrolysis of phenyl-4-0-(2-acetamido-2-deoxy-j8-D-glu-... 

Let us consider the classical secondary kinetic isotope experiments on lysozyme-catalyzed hydrolysis of glycosides. Earlier X-ray work indicated that the enzyme... 

Hammett relations, secondary kinetic isotope effects ", pressure studies and viscosity-independent rates ° have all pointed to a two-bond homolysis taking place via TS 3. The rates are, however, insensitive to change of the solvents = —1.18 in CDCI3, p+ = —1.17 in CCLt and p+ = —1.0 in C6H5CI at 80 °C). This may indicate that there is little solvent interaction taking place via 3. The variation of the activation parameters with the substituent can be solely dependent on the formation and cleavage of the bonds a and b in 3. 

Similar conclusions attend the insertions of CCI2 (from the thermolysis of ClsCCOONa at 120 °C) into a-deuteriocumene and cumene in which the primary fen/feo = 2.6, similar to Seyferth s finding with 32, and the p-secondary kinetic isotope effect is 1.20-1.25 for six deuteriums. Here, hyperconjugation at the p-CH (CD) bonds is thought to stabilize the partial cationic charge at the reaction center in transition state 33. 

Substitution of H by 2H in the CH3 group has a larger effect. This secondary kinetic isotope effect (or a-deuterium... 

Kinetic isotope effect for lysozyme. A secondary kinetic isotope effect is expected because a molecule with H in the number 1 position can be converted to the corresponding oxocarbenium ion somewhat more easily than the molecule with 2H in the same position (Eq. 12-13). For example, in the nonenzymatic acid-catalyzed hydrolysis of a methyl- glucoside, a reaction also believed to proceed through a carbocation intermediate,41 75 the ratio h / h, is 1.14 for the a anorner and 1.09 for the (3 anorner.53 In the base-catalyzed hydrolysis of the same compound, which is believed to occur by a double-displacement reaction involving participation of the neighboring OH group on C-2, the ratio /c1h / /c2h is 1.03. The corresponding ratio measured... 

Second order reactions 458 Secondary kinetic isotope effect 592, 600 on fumarate hydratase 684 Secondary plots for kinetics of multisubstrate enzymes 465 Secondary structure 63... 

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