Hydride transfers, isotope effects

This method gave a primary hydrogen-deuterium kinetic isotope effect of 1.3 for the reaction between the aryl radical and tributyltin hydride. This isotope effect is smaller than the isotope effect of 1.9 which San Filippo and coworkers reported for the reaction between the less reactive alkyl radicals and tributyltin hydride163 (vide infra). The smaller isotope effect of 1.3 in the aryl radical reaction is reasonable, because an earlier transition state with less hydrogen transfer, and therefore a smaller isotope effect164, should be observed for the reaction with the more reactive aryl radicals. 

Additionally, it has been noted that Tetralin operates via hydride transfer, at least in its reduction of quinones. Thus it has been shown that Tetralin readily donates hydrogen to electron-poor systems, such as quinones at 50°-160°C. The reaction is accelerated by electron-withdrawing substituents on the H-acceptor and polar solvents, and is unaffected by free radical initiators (6). These observations are consistent with hydride transfer, as is the more recent finding of a tritium isotope effect for the reaction (7). 

Three mechanisms have been proposed for this reaction (Scheme 21). The reaction is first order in each of the reactants. In another study, Reutov and coworkers159 found a large primary hydrogen-deuterium kinetic isotope effect of 3.8 for the reaction of tri-(para-methylphenyl)methyl carbocation with tetrabutyltin. This isotope effect clearly demonstrates that the hydride ion is transferred in the slow step of the reaction. This means that the first step must be rate-determining if the reaction proceeds by either of the stepwise mechanisms in Scheme 21. The primary hydrogen-deuterium kinetic isotope effect is, of course, consistent with the concerted mechanism shown in Scheme 21. 

The primary hydrogen-deuterium kinetic isotope effect is obtained from the percent cw-2-butene obtained from the deuterated and undeuterated stannanes. This is possible because a hydride and a deuteride are transferred to the carbocation when the undeuterated and deuterated stannane, respectively, forms c -2-butene. The secondary deuterium kinetic isotope effect for the hydride transfer reaction is obtained from the relative amounts of fraws-2-butene in each reaction. This is because a hydride is transferred from a deuterated and undeuterated stannane when trans-2-butene is formed. 

The exo and the endo ring closures (the kc reactions) are in competition with the aryl radical-tributyltin hydride transfer (the ks or ku reaction). These workers162 used this competition to determine the primary hydrogen-deuterium kinetic isotope effect in the hydride transfer reaction between the aryl radical and tributyltin hydride and deuteride. 

San Filippo and coworkers163 have determined the temperature dependence of the primary hydrogen-deuterium kinetic isotope effects for the hydrogen transfer reactions between several organic radicals and tributyltin hydride (deuteride) see equation 116. 

The pyridine-catalysed lead tetraacetate oxidation of benzyl alcohols shows a first-order dependence in Pb(OAc)4, pyridine and benzyl alcohol concentration. An even larger primary hydrogen kinetic isotope effect of 5.26 and a Hammett p value of —1.7 led Baneijee and Shanker187 to propose that benzaldehyde is formed by the two concurrent pathways shown in Schemes 40 and 41. Scheme 40 describes the hydride transfer mechanism consistent with the negative p value. In the slow step of the reaction, labilization of the Pb—O bond resulting from the coordination of pyridine occurs as the Ca—H bond is broken. The loss of Pb(OAc)2 completes the reaction with transfer of +OAc to an anion. 

Experiments have implied that quantum mechanical effects can be involved in the proton and hydride transfer of several biological processes. Specifically, large kinetic isotope effects (KIE) observed for... 

An interesting catalytic ruthenium system, Ru(7/5-C5Ar4OH)(CO)2H based on substituted cyclopentadienyl ligands was discovered by Shvo and coworkers [95— 98]. This operates in a similar fashion to the Noyori system of Scheme 3.12, but transfers hydride from the ruthenium and proton from the hydroxyl group on the ring in an outer-sphere hydrogenation mechanism. The source of hydrogen can be H2 or formic acid. Casey and coworkers have recently shown, on the basis of kinetic isotope effects, that the transfer of H+ and TT equivalents to the ketone for the Shvo system and the Noyori system (Scheme 3.12) is a concerted process [99, 100]. 

Andres, J., Moliner, V. and Safont, V. S. Theoretical kinetic isotope effects for the hydride-transfer step in Lactate Dehydrogenase, J. Chem. Soc. Faraday Trans., 90 (1994),... 

Isotope effects have been used to determine whether the hydride transfer from the enzyme cofactor nicotinamide-adenine dinucleotide (NADH) (reaction (43)) takes place as a hydride ion transfer in a single kinetic step or in a multistep reaction via an uncoupled electron and hydrogen transfer. 

The consequences on the magnitude of the secondary a-deuterium KIE of coupling the motion of the nontransferring a-hydrogen into the reaction coordinate motion, as suggested by Kurz and Frieden, was investigated in some model calculations by Huskey and Schowen (1983). They used two different models to calculate the secondary isotope effects for the hydride transfer reaction (45). 

The practical usefulness of Equations 11.46 through 11.53 has been demonstrated for the malic enzyme catalyzed conversion of L-malate to pyruvate (Equation 11.72). Table 11.1 lists experimentally determined isotope effects for this reaction. Comparison of carbon kinetic isotope effects for protio and deutero-malate substituted at position 2 (the carbon that undergoes sp3 to sp2 transition) rules out the possibility that the hydride transfer and the decarboxylation events are concerted. This conclusion follows from Equation 11.48 which, for a concerted reaction, predicts that 13(V/K) should be smaller than 13(V/K)D, which is opposite to the order observed experimentally. 

There are two mechanistic possibilities left, either hydride transfer precedes decarboxylation, or vice versa. These two possibilities can be distinguished using Equations 11.51 and 11.53. Within experimental error only Equation 11.51 is consistent with the isotope effect data collected in Table 11.1, thus confirming that the reaction proceeds via a stepwise mechanism with hydride transfer to triphosphate nucleotide (NADP+) and intermediate formation of oxalacetate preceding decarboxylation ... 

For this reaction the transition state drawn in Equation 11.82 involving simultaneous proton and hydride transfers has been proposed to explain the observed isotope effects. 

If secondary isotope effects arise strictly from changes in force constants at the position of substitution, with none of the vibrations of the isotopic atom being coupled into the reaction coordinate, then a secondary isotope effect will vary from 1.00 when the transition state exactly resembles the reactant state (thus no change in force constants when reactant state is converted to transition state) to the value of the equilibrium isotope effect when the transition state exactly resembles the product state (so that conversion of reactant state to transition state produces the same change in force constants as conversion of reactant state to product state). For example in the hydride-transfer reaction shown under point 1 above, the equilibrium secondary isotope effect on conversion of NADH to NAD is 1.13. The kinetic secondary isotope effect is expected to vary from 1.00 (reactant-like transition state), through (1.13)° when the stmctural changes from reactant state to transition state are 50% advanced toward the product state, to 1.13 (product-like transition state). That this naive expectation... 

In the following year, Cleland and his coworkers reported further and more emphatic examples of the phenomenon of exaltation of the a-secondary isotope effects in enzymic hydride-transfer reactions. The cases shown in Table 1 for their studies of yeast alcohol dehydrogenase and horse-liver alcohol dehydrogenase would have been expected on traditional grounds to show kinetic isotope effects between 1.00 and 1.13 but in fact values of 1.38 and 1.50 were found. Even more impressively, the oxidation of formate by NAD was expected to exhibit an isotope effect between 1.00 and 1/1.13 = 0.89 - an inverse isotope effect because NAD" was being converted to NADH. The observed value was 1.22, normal rather than inverse. Again the model of coupled motion, with a citation to Kurz and Frieden, was invoked to interpret the findings. 

The report of Basran et al. (entry 5 of Table 2) contains two studies involving hydride transfer with nicotinamide cofactors. In morphinone-reductase catalyzed reduction by NADH of the flavin cofactor FMN (schematic mechanism in Fig. 5), the primary isotope effects are modest (around 4 for H/D), but exhibit a small value of Ajj/Aq (0.13) and an exalted isotopic difference in energies of activation (8.2kJ/mol) that alone would have generated an isotope effect around 30. The enthalpies of activation are in the range of 35-45 kJ/mol. This is behavior typical of Bell tunneling as discussed above. It can also be reproduced by more complex models, as will be discussed in later parts of this review. 

The solvent isotope effect produces an A-ratio (HOH/DOD) of three with isotope-independent A// of 17-18 kJ/mol. This result is more difficult to interpret, because it is unknown how many isotopic sites in the enzyme or water structure contribute to the isotope effect of 2-3. If a single site should be the origin of the effect, then the site could reasonably be a solvent-derived protonic site of the enzyme involved in general-acid catalysis of the hydride transfer, most simply by protonic interaction with the carbonyl oxygen of cyclohexenone or possibly by proton transfer to an olefinic carbon of cyclohexenone. 

Kurz, L.C. and Erieden, C. (1980). Anomalous equilibrium and kinetic alpha-deuterium secondary isotope effects accompanying hydride transfer from reduced nicotinamide adenine dinucleotide. J. Am. Chem. Soc. 102, 4198-4203... 

Karsten, W.E., Gavva, S.R., Park, S.H. and Cook, P.E. (1995). Metal ion activator effects on intrinsic isotope effects for hydride transfer from decarboxylation in the reaction catalyzed by the NAD-malic enzyme from Ascaris suum. Biochemistry 34, 3253-3260... 

Powell, M.F. and Bruice, T.C. (1983). Effect of isotope scrambling and tunneling on the kinetic and product isotope effects for reduced nicotinamide adenine dinucleotide model hydride transfer reactions. J. Am. Chem. Soc. 105, 7139-7149... 

It is difficult to correlate the kyi/k values with the operation of a hydride, proton or H atom transfer. The temperature dependence of the kinetic isotope effect, which is now easier to measure accurately, is more diagnostic of mechanism but has been applied mainly to organic systems. ... 

In the aldol-Tishchenko reaction, a lithium enolate reacts with 2 mol of aldehyde, ultimately giving, via an intramolecular hydride transfer, a hydroxy ester (51) with up to three chiral centres (R, derived from rYhIO). The kinetics of the reaction of the lithium enolate of p-(phenylsulfonyl)isobutyrophenone with benzaldehyde have been measured in THF. ° A kinetic isotope effect of fee/ o = 2.0 was found, using benzaldehyde-fil. The results and proposed mechanism, with hydride transfer rate limiting, are supported by ab initio MO calculations. 

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