Conformational equilibria, isotope effects

It was also shown that the syn 1,3- and 1,5-diaxial interaction of one methyl group at C-1 with two hydrogens at C-3 and C-5 is sufficient to observe a conformational equilibrium isotope effect in N-trideuterio-methyl-N-methylpiperidinium ion [54] and in the deuteriated trans-1,3-dimethylcyclohexane [55] and trans-2,6- and /ranj-3,5-dimethylcyclo-hexanones [56] and [57] (Robinson and Baldry, 1977b). 

Recent calculations of the conformational equilibrium isotope effect for [65] using a scaled quantum mechanical 3-21 G force field are in qualitative accord with the experiment and confirm the zero point energy origin of the effect (Williams, 1986). 

The isotope shifts observed in the H nmr spectrum of c/s-3,5-dideutcrio-cyclopentene [67] (Anet and Leyendecker, 1973) have their origin most probably in conformational equilibrium isotope effects and could be explained in a similar way to the effects in cycloheptatriene, although the size of the effects is different because of different conformational arrangements. 

Primary isotope effects are defined as the difference in magnetic shielding of the isotopes of nuclei of the same element. Secondary isotope effect on nuclear shielding are considered as intrinsic isotope effects and equilibrium isotope effects. The former effects are caused by isotopic substitution, the later by conformational changes or shifts in equilibria as a consequence of isotopic substitution. 

Steric isotope effects are less clear cut, possibly because many small effects considered to be steric are in fact a mix of steric and stereoelectronic. Early work on the racemisation of optically active biphenyls gave a value of kne/ De of 0.85 for a 2,2 -dimethylbiphenyl also containing a 6,6 ethylene bridge (4,5-dimethyl 9,10 dihydrophenanthrene), and 1-deuteriocyclohexane prefers the deuterium-axial conformation by 25 J mol V but the preference decreases next to a heteroatom. Effects of deuterium substitution of carbon-bound protons in glucose on the anomeric equilibrium in water cannot be simply rationalised by a single effect the equilibrium isotope effect (defined as [P]H[a]D/[p]D[a]H) being 1.043 for HI, 1.027 for H2, 1.027 for H3, 1.001 for H4, 1.036 for H5 and 0.998 for H6,6. ... 

Trideuterio-2-methylcyclohexanone shows isotope effects on the chemical shifts which could not be explained assuming intrinsic effects only (Wehrli and Wirthlin, 1976). Saunders et u/(1980a) have suggested that the origin of these effects is an equilibrium isotope effect. Conformational isotope effects have been observed in deuteriated 1,4-dioxanes (Jensen and Neese, 1971) and in substituted 1,3-dioxanes (Robinson, 1971). 

A long range intrinsic deuterium isotope shift in 2,2-bis(trideuterio-methyl-5,5-dimethyl-l,3-dioxane [61] was observed by Anet and Dekmezian (1979). This molecule does not show an equilibrium isotope effect because the two rapidly interconverting chair isomers have exactly the same energy. 2-D-5.5-Dimethyl-l,3-dioxane, however, exhibits an isotope effect on the conformational equilibrium (Anet and Kopelevich, 1986a). Deuterium is preferred in the equatorial position (AG° = —49cal mol at 25°C). 

The magnitude of -deuterium equilibrium isotope effects The magnitude of the p-secondary deuterium kinetic isotope effects in solvolyses which proceed via a cationic transition state have been shown to be conformationally dependent (Sunko and Hehre, 1983). Shiner furnished two important representative examples relating the dihedral angle between an adjacent C—H or C—D bond and the vacant p-orbital of the cationic transition state with the magnitude of the kinetic isotope effect. In the... 

Dimethyl- and 2,4,4,6-tetramethyl-heptyl cations The total isotope effect of a CD3-group is independent of conformation (Sunko et al., 1977), and the CDj-substituted cations [155] and [156] can therefore serve as a model for a dihedral angle of 0° whereas the cations [157] and [158] deuteriated in the methylene group provide information on the conformational dependence of the equilibrium isotope effect. 

The similarity between the equilibrium isotope effects in [157] and the 1,2-dimethylcyclopentyl cation [104] points to a similar conformation in the vicinity of the C -carbon. The magnitude of the equilibrium isotope effect can thus be used as a new means of aiding in the assignment of conformation and structure in solution. 

Because of isotope effects on the chemical equilibrium constant, a phenomenon which is well understood, there are additional effects on the NMR spectrum by isotopic substitution. Since the equilibrium constant for a conformational equilibrium is different for different isotopically related molecules, the relative concentrations of conformers vary. These are equilibrium isotope effects and quite apart from the intrinsic isotope effects we have discussed above. The two types are no longer distinct when the barrier separating the two species is very low. ... 

These studies had therefore found the tunneling phenomenon, with coupled motion, as the explanation for failures of these systems to conform to the expectations that the kinetic secondary isotope effects would be bounded by unity and the equilibrium effect and that the primary and secondary effects would obey the Rule of the Geometric Mean (Chart 3), as well as being consistent with the unusual temperature dependences for isotope effects that were predicted by Bell for cases involving tunneling. 

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