A New Generalized Karplus-Type Equation Relating Vicinal Proton-Fluorine Coupling Constants to H−C−C−F Torsion Angles

A new seven-parameter Karplus-type relation between vicinal proton−fluorine coupling constants and the corresponding H−C−C−F torsion angles has been developed. The optimum values of the seven parameters were determined using a data set consisting of 57 3 J HF values and the corresponding Φ HF torsion angles (ranging from cis, gauche, and trans regions) based upon ab initio structures as well as on the conformational analysis of temperature-dependent 3 J HH of monofluorinated nucleosides 1 − 11, which were also complemented with the data from conformationally fixed compounds 12 − 22 . The best fit generalized Karplus-type equation shows the difference between input and back-calculated 3 J HF below 2.9 Hz with the overall rms deviation of 1.38 Hz, amounting to a total of 4% error for transoid coupling of ≈40−46 Hz, which compares very well with about 5% error encountered earlier in the experimental and the back-calculated 3 J HH of 8−9 Hz in the latest Karplus−Altona equation (ref 14). This is the first use of a new Karplus-type equation correlating 3 J HF with the H−C−C−F torsion angle in a quantitative manner (by making use of correction terms for substituent electronegativity as well as for H−C−C and F−C−C bond angles) to explore the pseudorotational equilibria of monofluorinated nucleosides 24 and 25 as well as difluorinated nucleosides 26 − 29 with the use of both 3 J HH and 3 J HF coupling constants in an iterative manner. The use of temperature-dependent 3 J HF in combination with 3 J HH greatly facilitates the conformational analysis of fluorinated sugar moieties of nucleosides because of the overwhelming increase of the number of experimental data points over the unknowns defining the pseudorotational equilibrium. This enables the pseudorotational parameters P and Ψ m of the two interconverting conformers to be more accurately defined. The best use of our new generalized Karplus-type relation is that it enables solution structure determination of fluorinated nucleosides or any other fluorinated compounds in which the number of measurable vicinal proton−proton couplings are not adequate enough to fully define the geometry of the system as in difluorinated nucleosides 26 − 29 .