Secondary deuterium isotope effects isomerization

For an elegant study of the secondary deuterium isotope effects on a non-Schenck sensitized cis-trans isomerization, see Refs. 85-87. 

To supplement the data on prolyl isomerization, I will draw on the literature describing rotation about the C-N bond in secondary amides. Early studies in this field were described by Stewart and Siddall in an excellent 1970 review. As we will see, these reactions are related to prolyl isomerization and support the mechanism to be proposed for prolyl isomerization. The mechanism is based on results from a variety of experimental approaches. In all cases, experiments employing kinetic-based probes will be used to obtain an accurate picture of the activated complex in the rate-limiting transition state. The experiments that will be described include thermodynamics, in which activation parameters (i.e., AG, AHt, and ASt) will be described solvent effects, in which the influence of organic solvents and deuterium oxide will be reviewed acid-base catalysis substituent effects and secondary deuterium isotope effects. 

The single most revealing mechanistic parameter for prolyl isomerization and amide rotation is the secondary deuterium isotope effect. In general for such studies, the hydrogens on the carbon that is bonded to the carbonyl carbon of the amide or imide (the /3-hydrogens ) are substituted with deuterium and reaction rate constants are measured for... 

Secondary deuterium isotope effects have been measured for the cis-to-trans prolyl isomerization of Suc-Ala-Gly-cis-Pro-Phe-pNA (where pNA is p-nitroanilide) and C-N rotation in DMA. In the former case, the isotope effect for the two hydrogens of glycine is 1.05 0.02 (Fischer et al., 1989a Harrison et ai, 1990 Harrison and Stein, 1990a), and for C—N rotation in DMA, the isotope effect for the three hydrogens of the acetyl moiety is 1.10 0.05. Significantly, the effect for two deuteriums in DMA can be calculated to be 1.05 (Fujihara and Schowen, 1985). 

The entropy of activation for isomerization of allyl thionbenzoate, — 10 eu, is similar to entropies of activation for other cyclic, concerted allylic iso-merizations. Additional support for a concerted mechanism is provided by secondary deuterium isotope effects on the rate of isomerization of allyl thionbenzoate. Each a-deuterium atom lowers the isomerization rate by about 6%, while each y-deuterium atom increases the rate by about 3%. Since allylic reactions which proceed by carbonium ion, carbanion, and radical pathways are known to be retarded by about twice as much for each a-deuteron, while an allylic chloride solvolysis exhibited a y deuterium isotope effect of zero, the observed secondary isotope effects provide support for a concerted process whose transition state has little carbonium ion, carbanion, or radical character. 

Subsequent work with deuterated exomethylene materials established that the products were formed with a substantial normal secondary deuterium isotope effect 1.30), but the geometric isomerization of the starting material had... 

Thus the secondary and primary deuterium isotope effects determined in this study also indicate that entropy and zero-point energy factors associated with breaking of the C—D bond and migration in the activated complexes are important for the structural isomerization to yield butene-1 and butene-2, and reaction path B (equation 197) must be included in the mechanistic considerations concerning the cyclopropane isomerization. But the higher activation energy for isobutane formation (g = 64.3 kcal mol" ) than that for butene-2 or butene-1 (Q = 62.0 0.6 kcal mol" ) indicates also that the rupture of... 

A different experimental approach to the relative importance of one-center and two-center epimerizations in cyclopropane itself was based on the isomeric l-13C-l,2,3-d3-cyclopropanes165"169. Here each carbon has the same substituents, one hydrogen and one deuterium, and should be equally involved in stereomutation events secondary carbon-13 kinetic isotope effects or diastereotopically distinct secondary deuterium kinetic isotope effects may be safely presumed to be inconsequential. Unlike the isomeric 1,2,3-d3-cyclo-propanes (two isomers, only one phenomenological rate constant, for approach to syn, anti equilibrium), the l-13C-l,2,3-d3-cyclopropanes provide four isomers and two distinct observables since there are two chiral forms as well as two meso structures (Scheme 4). Both chiral isomers were synthesized, and the phenomenological rate constants at 407 °C were found to be k, = (4 l2 + 8, ) = (4.63 0.19)x 10 5s l and ka = (4kl2 + 4, ) = (3.10 0.07) x 10 5 s 1. The ratio of rate constants k, kl2 is thus 1.0 0.2 both one-center and two-center... 

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