Secondary 3-deuterium KIEs

Secondary /3-deuterium KIEs are observed when the hydrogen(s) on the /3-carbon are replaced by deuterium(s). These isotope effects (kH/kD)p are 

Ionic strength (kHlko)a ku/k14 Relative transition state structure 

Corresponding to this valence bond view is a molecular orbital picture. The three cr-orbitals of a CH3 group are regarded as a basis from which three group orbitals may be constructed. One of the possible combinations of the tr-orbitals has the same local symmetry as the vacant p-orbital on the cationic centre, and hence may overlap with it. Therefore, a withdrawal of electrons from the methyl group can take place. The orbital from which electron density 

Other studies by Shiner and co-workers (Shiner and Humphrey, 1963 Shiner and Jewett, 1965) have demonstrated that the magnitude of secondary /3-deuterium KIEs is related to the dihedral angle between the Cp—H(D) orbital and the developing p-orbital on the a-carbon. The study in which Shiner and Humphrey (1963) measured the secondary /3-deuterium KIEs for the hydrolysis of ll-methyl-ll-chloro-9,10-dihydro-9,10-ethanoanthracene [4] and its 12,12-d2 [5] and 9,10-d2 [6] analogues in 60% aqueous ethanol at 45°C is particularly elegant. 

A value of ku/kD = 1.07 per /3-D was observed when the deuteriums were on the bridge at C-12 [5] and the dihedral angle between the p-orbital of the carbocation and the Cp—H bonds was approximately 30° and hyperconjuga-tion could occur. When [6] was used, the dihedral angle was 90° and there was no overlap between the empty p-orbital of the carbocation and the Cp—H bonds i.e. no hyperconjugation could occur and only a small inverse, inductive KIE, kH/fcD = 0.99, was observed. This study and other studies by Shiner and co-workers (Shiner, 1970b) have established that the maximum secondary /3-deuterium KIE in any system is observed when the dihedral angle is either 0° or 180°, i.e. where the overlap between the Cp—H and the p-orbital on the 

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The secondary deuterium KIEs for the retro-Diels-Alder reaction of ethanoanthracene has been investigated also207 (equation 87)206. 

These experimental secondary deuterium KIEs observed in Diels-Alder reactions have been compared with the respective theoretical KIEs for the stepwise mechanism involving a diradical intermediate (equation 88a) and for concerted synchronous and asynchronous mechanisms (equation 88b) for the Diels-Alder reaction of butadiene with ethylene207. 

All the 14C primary KIE data above and the C(4) and C(6) secondary deuterium KIEs have been fitted to BEBOVIB modeling calculations and it has been deduced that, in the transition state of the reaction of 234a, 70-80% bond breaking and 20% bond making occurs, while for 234b both bond breaking and bond formation amount to 30-40%. 

Large secondary deuterium KIEs in hydride transfer reactions 213... 

Since the bond to the isotopic atom is not formed or broken in the transition state of the rate-determining step of the reaction, the difference between the rate constant for the reaction of the undeuterated and deuterated substrates is usually small. As a result, secondary deuterium KIEs are usually close to unity, i.e. the maximum secondary deuterium KIE is 1.25 per deuterium (Shiner, 1970a) and most of these KIEs are less than 1.10 (Westaway, 1987a). Therefore, careful kinetic measurements with an error of approximately 1 % in each rate constant or specially designed competitive methods are required to determine them with an acceptable degree of accuracy. 

Table 17 Secondary deuterium KIEs for the Menshutkin reactions of deuterated pyridines and alkyl iodides in nitrobenzene at 25°C.a...

The steric rather than the inductive origin of the secondary deuterium KIE is also suggested because kH/kD = 0.994 per deuterium found in the per-deuteropyridine-methyl iodide reaction is smaller (less inverse) than the kH/kn = 0.988 per deuterium found for the 4-deuteropyridine reaction. A secondary inductive KIE should be more inverse when a deuterium is substituted for a hydrogen nearer the reaction centre, i.e. at the meta- or ortho-rather than at the para-position of the pyridine ring. Thus, if the KIE were inductive in origin, the KIE in the perdeuteropyridine reaction should be more inverse than that observed for the 4-deuteropyridine reaction. If the observed KIE were the result of a steric KIE, on the other hand, a less inverse KIE per deuterium could be found in the perdeuteropyridine reaction, i.e. a less inverse KIE per deuterium would be expected if there were little or no increase in steric hindrance around the C—H(D) bonds as the substrate was converted into the SN2 transition state. Since the KIE per D for the perdeuteropyridine reaction is less than 1%, the transition state must not be sterically crowded and the KIE must be steric in origin. Finally, the secondary deuterium KIEs observed in the reactions between 2-methyl-d3-pyridine and methyl-, ethyl- and isopropyl iodides (entries 3, 7 and 9, Table 17) are not consistent with an inductive KIE. If an inductive KIE were important in these reactions, one would expect the same KIE for all three reactions because the deuteriums would increase the nucleophilicity of the pyridine by the same amount in each reaction. The different KIEs for these three reactions are consistent with a steric KIE because the most inverse KIE is observed in the isopropyl iodide reaction, which would be expected to have the most crowded transition state, and the least inverse KIE is found in the methyl iodide reaction, where the transition state is the least crowded. 

Kaplan and Thornton (1967) also concluded that the secondary deuterium KIEs found in these SN2 reactions were not inductive in origin. Although the large inverse secondary deuterium KIE (kH/kD = 0.883 0.008) found in the... 

This KIE was also attributed to hyperconjugation. The authors suggested that smaller secondary deuterium KIEs were found in radical reactions because hyperconjugation was less important in radicals than in carbocations. 

Because unexpectedly large primary deuterium KIEs are observed in reactions where tunnelling is important, and unexpectedly large secondary deuterium KIEs have been observed in some hydron transfers in elimination and enzyme-catalysed hydride transfer reactions, Saunders (vide infra) wondered whether very large secondary deuterium KIEs were also indicative of tunnelling. 

LARGE SECONDARY DEUTERIUM KIEs IN HYDRIDE TRANSFER REACTIONS... 

In one of these studies, Kurz and Frieden (1980) observed the first unexpectedly large secondary a-deuterium KIE. They found that the secondary a-deuterium KIE for the nonenzymatic hydride ion reduction of 4-cyano-2,6-dinitrobenzenesulfonate by NADH (reaction (44)) was 1.156 0.018 and 1.1454 0.0093 using direct and competitive kinetic methods, respectively. The corresponding equilibrium isotope effects (EIEs) were found to be 1.013 0.020 and 1.0347 0.0087, respectively. Thus, the secondary deuterium KIE was much larger than the EIE. The magnitude of a secondary a-deuterium KIE is normally attributed to the rehybridization of the a-carbon that takes place when the reactant is transformed into the... 

Fig. 17 Plot of the calculated secondary deuterium KIE versus the extent of O—H bond formation for the model elimination reaction at 45°C Models 1 and 2 have different imaginary frequencies and no coupling of the Ca—D bending vibrational motion with the C0—H stretching motion in the transition state. Models 3,4 and 5 have increasing extents of coupling between the Ca—D bending and C —H stretching motion in the transition state. Reproduced, with permission, from Saunders (1997).

The secondary deuterium KIEs obtained by converting the secondary tritium KIEs found for the E2 reactions of several different 2-arylethyl substrates into secondary deuterium KIEs with the Swain-Schaad equation (Swain et al., 1958) are in Table 36. As discussed above, one would expect the secondary deuterium isotope effect to reflect the extent to which rehybridization of the /3-carbon from sp3 of the reactant to sp2 in the product has taken place in the transition state. According to this reasoning, the secondary tritium EIE should be a good estimate of the maximum secondary tritium KIE. Because these reactions were not reversible, the EIE could not be measured. However, one can estimate the EIE (the maximum expected secondary KIE) using Hartshorn and Shiner s (1972) fractionation factors. The predicted EIE (Kh/Kd) values were 1.117 at 40°C and 1.113 at 50°C. Seven of the reactions... 

Saunders (1985) extended his investigation of the effect of tunnelling on the magnitude of secondary deuterium KIEs in a theoretical study of the E2 reaction between hydroxide ion and a model substrate (reaction (54)). 

The results of these calculations have implications on the applicability of the rule of the geometric mean, which indicates that the KIE for a doubly labelled species should be the product of the KIEs for the corresponding singly labelled substrates. For instance, the KIE for the doubly labelled [17] should be the product of the secondary deuterium KIE, ]/ ]> associated with the nontransferring hydrogen and the primary deuterium KIE, / , produced by the transferring hydrogen (equation 58)). 

Recently, Brown and co-workers (Nagorski et al., 1994 Slebocka-Tilk et al., 1995) have found large remote secondary deuterium KIEs in their extensive investigation of the electrophilic addition of bromine to 7-norbornylidene-7 -norbornane under a variety of conditions. 

A large inverse secondary deuterium KIE of 0.64 was observed in acetic acid at 25°C when the perdeutero (d2o) compound was the deuterated substrate. This large inverse deuterium KIE was attributed to the KIE for the rate-determining formation of the bromonium ion (62). Although a portion of this KIE is undoubtedly due to the inductive effect (deuterium is more electron-donating than hydrogen and the deuterated bromonium ion would... 

Scheme 3) a large inverse secondary deuterium KIE is observed both in the presence, and in the absence, of added bromide ion. However, in acetic acid, the KIE becomes even more inverse as the concentration of bromide ion increases, i.e. it decreases from kH/kD = 0.64 to a minimum of 0.55 as the bromide ion concentration increases from zero to 0.04 mol dm-3 (Table 44). In methanol, on the other hand, the inverse secondary deuterium KIE of 0.56 0.04 is effectively independent of bromide ion concentration. 

In the mechanism preferred by the authors, the observed KIE is the product of the EIE for the reversible formation of the bromonium ion and the KIE for the rate-determining formation of the /3-bromocarbocation (Scheme 3). Because the steric crowding of the C-2, C-2, C-3 and C-3 endo-hydrogens in the bromonium ion would be relieved in going to the /3-bromocarbocation intermediate, one would expect the secondary deuterium KIE for the k2 step of the reaction to be normal, i.e. >1.00. If this is the case, the EIE for the formation of the bromonium ion must be significantly more inverse than the KIE for the k step of the reaction, i.e. the KIE for the formation of the... 

New methods for the accurate determination of secondary deuterium KIEs... 

Secondary isotope effects are small. In fact, most of the secondary deuterium KIEs that have been reported are less than 20% and many of them are only a few per cent. In spite of the small size, the same techniques that are used for other kinetic measurements are usually satisfactory for measuring these KIEs. Both competitive methods where both isotopic compounds are present in the same reaction mixture (Westaway and Ali, 1979) and absolute rate measurements, i.e. the separate determination of the rate constant for the single isotopic species (Fang and Westaway, 1991), are employed (Parkin, 1991). Most competitive methods (Melander and Saunders, 1980e) utilize isotope ratio measurements based on mass spectrometry (Shine et al., 1984) or radioactivity measurements by liquid scintillation (Ando et al., 1984 Axelsson et al., 1991). However, some special methods, which are particularly useful for the accurate determination of secondary KIEs, have been developed. These newer methods, which are based on polarimetry, nmr spectroscopy, chromatographic isotopic separation and liquid scintillation, respectively, are described in this section. The accurate measurement of small heavy-atom KIEs is discussed in a recent review by Paneth (1992). 

Deuterium nmr spectroscopy has been utilized for the last decade to determine large (primary deuterium) KIEs in reactions with isotopes present at the natural abundance level (Pascal et al., 1984,1986 Zhang, 1988). A great advantage of this approach is that labelled materials do not have to be synthesized. Neither is there any need for selective degradation procedures, which are often necessary to produce the molecules of low mass, e.g. C02, acceptable for isotope ratio mass spectrometry. Moreover, the KIEs for several positions can be determined from one sample. However, until quite recently the relatively low precision of the nmr integrations that are used for the quantitative assessment of the amount of deuterium at specific molecular sites has limited the applicability of this technique for determining small (secondary deuterium) KIEs. 

Remote double labelling techniques have been used successfully in the determination of enzyme KIEs (Kiick, 1991). A variant of this technique was applied to a nonenzymatic reaction by Matsson and co-workers (Axelsson et al., 1990). They determined the primary carbon and secondary deuterium KIEs for the SN2 reaction between methyl iodide and hydroxide ion in 50% dioxane-water at 25°C. The a-carbon KIE was determined by the UC method (Axelsson et al. 1987,1991). In this method, a mixture of substrate molecules labelled with UC (tm = 20.4 min) and 14C is used. The reactants and products... 

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