Kinetic isotope effects primary hydrogen-deuterium

Calculated primary kinetic isotope effects for hydrogen/deuterium at 298 K... 

A special type of substituent effect which has proved veiy valuable in the study of reaction mechanisms is the replacement of an atom by one of its isotopes. Isotopic substitution most often involves replacing protium by deuterium (or tritium) but is applicable to nuclei other than hydrogen. The quantitative differences are largest, however, for hydrogen, because its isotopes have the largest relative mass differences. Isotopic substitution usually has no effect on the qualitative chemical reactivity of the substrate, but often has an easily measured effect on the rate at which reaction occurs. Let us consider how this modification of the rate arises. Initially, the discussion will concern primary kinetic isotope effects, those in which a bond to the isotopically substituted atom is broken in the rate-determining step. We will use C—H bonds as the specific topic of discussion, but the same concepts apply for other elements. 

Table 6-5. Calculated Hydrogen/Deuterium Primary Kinetic Isotope Effects" ...

The first term was found to correspond to the rate of enolisation (measured by an NMR study of hydrogen-deuterium exchange at the methylene group). The second term predominates at [Cu(II)] > 10 M and is characterised by a primary kinetic isotope effect of 7.4 (25 °C) and a p value of 1.24. Addition of 2,2 -bipridyl (bipy) caused an increase in 2 up to a bipy Cu(II) ratio of 1 1 but at ratios greater than this 2 fell gradually until the enolisation term dominated. The oxidation of a-methoxyacetophenone is much slower but gives a similar rate... 

Primary kinetic isotope effects are also observable with pairs of isotopes other than hydrogen/deuterium, but as the relative mass difference must needs be smaller their maximum values will be correspondingly smaller. Thus the following have been observed ... 

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 results from these experiments also allowed Hannon and Traylor to determine the primary and secondary hydrogen deuterium kinetic isotope effects for the hydride abstraction reaction. If one assumes that there is no kinetic isotope effect associated with the formation of 3-deutero-l-butene, i.e. that CH2=CHCHDCH3 is formed at the same rate (k ) from both the deuterated and undeuterated substrate (Scheme 25), then one can obtain both the primary (where a deuteride ion is abstracted) and the secondary deuterium... 

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 primary hydrogen-deuterium kinetic isotope effect for the reaction was 3.7 and the secondary alpha-deuterium kinetic isotope effect was found to be 1.1. It is worth noting that the primary hydrogen-deuterium kinetic isotope effect of 3.7 is in excellent agreement... 

Song and Beak found intramolecular and intermolecular hydrogen-deuterium kinetic isotope effects of 1.1 0.2 and 1.2 0.1, respectively, for the tin tetrachloride catalysed ene reaction. Since significant intramolecular and intermolecular primary deuterium kinetic isotope effects of between two and three have been found for other concerted ene addition reactions161, the tin-catalysed reaction must proceed by the stepwise pathway with the k rate determining step (equation 107). 

Abeywickrema and Beckwith162 have measured the primary hydrogen-deuterium kinetic isotope effect for the reaction between an aryl radical and tributyltin hydride. The actual isotope effect was determined by reacting tributyltin hydride and deuteride with the ort/ro-alkcnylphcnyl radical generated from 2-(3-butenyl)bromobenzene (equation 111). 

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. 

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. 

Several workers have measured the primary hydrogen-deuterium kinetic isotope effects for the reaction between organic radicals and tributyltin hydrides (equation 114). 

In one study, Ingold and coworkers166 measured the rate constants for the reactions of several alkyl radicals with tributyltin hydride using a laser flash photolytic technique and direct observation of the tributyltin radical. They also used this technique with tributyltin deuteride to determine the primary hydrogen-deuterium kinetic isotope effects for three of these reactions. The isotope effects were 1.9 for reaction of the ethyl radical, and 2.3 for reaction of the methyl and n -butyl radicals with tributyltin hydride at 300 K. 

Other primary hydrogen-deuterium kinetic isotope effects have been measured for radical reactions with tributyltin hydride. For example, Carlsson and Ingold167 found primary hydrogen-deuterium kinetic isotope effects of 2.7 and 2.8, respectively, for the... 

Finally, Franz and coworkers171 measured the rate constants and primary hydrogen-deuterium kinetic isotope effects for the radical reactions between tributyltin hydride and the neophyl and the 2-allylbenzyl radical in diphenyl ether. The isotope effect in the first reaction was 1.64 at 192.5 °C and that in the second reaction was 1.91 at 236 °C. These values compare well with those predicted from Kozuka and Lewis s primary... 

B. Primary Hydrogen-Deuterium Kinetic Isotope Effects. 895... 

Several monographs2-5 have detailed discussions dealing with heavy-atom and primary and secondary hydrogen-deuterium kinetic isotope effects. The monograph by Melander and Saunders5 covers the entire area particularly well. For this reason, only a brief summary of the theory of kinetic isotope effects as well as their important uses in the determination of reaction mechanism and transition-state geometry will be presented. 

It may be concluded that for reactions where the proton is less or more than one-half transferred in the transition state, i.e. the A—H and H—B force constants are unequal, the primary hydrogen-deuterium kinetic isotope effect will be less than the maximum of seven. The maximum isotope effect will be observed only when the proton is exactly half-way between A and B in the transition state. This relationship is also found for carbon kinetic isotope effects where the isotopically labelled carbon is transferred between two atoms in the reaction10,11. This makes interpreting carbon isotope effects difficult. 

TABLE 13. The secondary alpha hydrogen-deuterium and primary nitrogen kinetic isotope effects for the SN2 reaction between sodium thiophenoxide and benzyldimethylphenylammonium nitrate at different ionic strengths in DMF at 0 C... 

This non-competitive method has several practical limitations. Since the ordinary precision of determination of rate constants, (8kL/kL) or (Ske/kn), is on the order of a few percent, the method is limited as a practical matter to large, primary kinetic isotope effects, generally of hydrogen. This, because deuterium, the common heavy isotopomer for hydrogen, is available at 100% abundance at reasonable cost, and for hydrogen KIE s are usually large enough to constrain the relative error, 8(kL/kH)/(kL/kH), to acceptable values. 

These reactions proceed through symmetrical transition states [H H H] and with rate constants kn,HH and kH,DH, respectively. The ratio of rate constants, kH,HH/kH,DH> defines a primary hydrogen kinetic isotope effect. More precisely it should be regarded as a primary deuterium kinetic isotope effect because for hydrogen there is also the possibility of a tritium isotope effect. The term primary indicates that bonds at the site of isotopic substitution the isotopic atom are being made or broken in the course of reaction. Within the limits of TST such isotope effects are typically in the range of 4 to 8 (i.e. 4 < kH,HH/kH,DH < 8). 

---