Theoretical studies are presented, aimed a t the elucidation of through-space effects exerted by bridgehead oxygen and nitrogen atoms on cisoidal proton spin-spin coupling constants in 7-hetero-substituted norbornanes. The finite perturbation theory intermediate neglect of differential overlap ( INDO) self-consistent field (SCF) molecular orbital (MO) method, modified according to the description given by Barfield [J. Am. Chem. SOC., 102,1(1980)], was employed. It is predicted that the known nonequivalence between JendHndo and J,,,,, in norbornanes, which is in part mediated by the bridgehead methylene group (Barfield transmission effect), also occurs in 7-heteronorbornanes. A trend is recognized in which the nonequivalence induced by oxygen is rather smaller than that induced by the rear lobe of the N-H bond or by the nitrogen lone pair. It is shown that the Barfield effect also explains the observed nonequivalence between cisoidal H-Cfl-CT-H and H-CT-Cb-H couplings in prolines. The calculations also predict similar, though smaller, effects on cisoidal couplings in the tetrahydrofurany1 ring system. Special attention was paid to the practical consequences of the existence of this effect with regard to the pseudorotation analysis of the five-membered sugar ring in nucleic acids. It is found that, in addition to the recently introduced correction for electronegativity and orientation of substituents Altona, Tetrahedron 36,2783 (1980)], a cos2 dependency of 3Jcis upon the phase angle of pseudorotation must be taken into account, especially in the case of deoxyribofuranoses.

NMR and model-building studies were carried out on the duplex d(CTGGTGCGG).d(CCGCCCAG), referred to as (9+8)-mer, which contains an unpaired thymidine residue. Resonances of the base and of several sugar protons of the (9+8)-mer were assigned by means of a NOESY experiment. Interresidue NOEs between dG(4) and dT(5) as well as between dT(5) and dG(6) provided evidence that the extra dT is stacked into the duplex. Thermodynamic analysis of the chemical shift vs temperature profiles yielded an average TmD value of 334 K and delta HD of -289 kJmol-1 for the duplex in equilibrium random-coil transition. The shapes of the shift profiles as well as the thermodynamic parameters obtained for the extra dT residue and its neighbours again indicate that the unpaired dT base is incorporated inside an otherwise intact duplex. This conclusion is further supported by (a) the observation of an imino-proton resonance of the unpaired dT; (b) the relatively small dispersion in 31P chemical shifts (approximately 0.5 ppm) for the (9+8)-mer, which indicates the absence of t/g or g/t combinations for the phosphate diester torsion angles alpha/zeta. An energy-minimized model of the (9+8)-mer, which fits the present collection of experimental data, is presented.

The magnitude of the NMR spin-spin coupling constant, 3J(CH), between a vicinal I3C-'H pair depends, inter afia, on the value of the torsion angle CD, #CX-C-H) and is influenced by the presence of an electronegative substituent located on the coupling "C nucleus. The form and magnitude of the effect of the orientation Yxc of such an a-substituent were examined. The coupling constant between C-1 and a hydrogen atom located on C-3 in a series of a-substituted propanes were studied by means of the semi-empirical INDO method. In the calculations both CD and Y(X-13C-C-C)were systematically varied in steps of 30". These calculations reveal that the variation of Y at a constant CD has a pronounced effect on the calculated coupling constant JCalc. The magnitude of this effect is shown to be strongly dependent on the electronegativity x of the a-substituent. Thus, it is shown that Jealc depends on CD and Y , in addition to 2. The resulting set of two-dimensional Karplus-type surfaces can be described by an equation that contains only nine adjustable parameters. Measurement of 3J(CH) in cis-and trans-2,2,6,6-tetradeuterio-4-tert-butylcyclohexanol confirmed some of the theoretical predictions. In the cis compound (mCH = MOO, Y, = 60") 3J(C-1,H-3eq) is 7.1 Hz, whereas in the trans compound (CDCH = 180", I,, = 180O) 3J(CH) equals 10.4 Hz, in qualitative agreement with the INDO calculations.

Model-building studies were carried out on the trimer AUA. Bulge-out structures which allow incorporation into a continuous RNA helix were generated and energy-minimized. All geometrical features obtained by previous NMR studies on purine-pyrimidine-purine sequences are accounted for in these models. One of the models was used to fit into a double helical fragment. Only minor changes were necessary to construct a central bulge-out in an otherwise intact duplex. NMR and model-building studies were performed on the duplex (CUGGUGCGG).(CCGCCCAG) which contains an unpaired uridine residue. NOE data, chemical-shift profiles and imino-proton resonances provided evidence that the extra U is bulged out of the duplex. The relatively small dispersion in 31P chemical shifts (approximately equal to 0.7 ppm) indicate the absence of t/g or g/t combinations for the phosphodiester angles zeta/alpha. An energy-minimized model of the duplex, which fits the present collection of data, is presented.

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