Conformational analysis of fluorinated pyrrolidines using 19F-1H scalar couplings and heteronuclear NOEs.

Combettes LE, Clausen-Thue P, King MA, Odell B, Thompson AL, Gouverneur V, Claridge TDW

A series of 3-fluoropyrrolidines have been studied to investigate the influence of the stereoelectronic fluorine gauche effect on ring conformations in the solid state by single-crystal X-ray analysis and in solution phase by NMR spectroscopy. As part of these studies 1D (19)F-(1)H heteronuclear NOE (HOESY) experiments have been optimised for applications to small molecules and are described in detail. These have been employed to estimate (19)F-(1)H internuclear distances and were combined with vicinal (3)J(F,H) and (3)J(H,H) scalar coupling constants to analyse the ring conformations. Where possible the derived solution-phase structural data have been compared with those of the crystalline state. The results demonstrate the influence of the gauche effect in stabilising C(γ)-exo conformations of the fluorinated pyrrolidines. It was further shown that when steric interactions were also present, this conformational bias was diminished and the contribution of the alternative C(γ)-endo conformation was seen to increase in solution at lower sample temperatures.

Keywords:

Crystallography, X-Ray

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Fluorine Radioisotopes

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Halogenation

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Magnetic Resonance Spectroscopy

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Models, Molecular

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Molecular Conformation

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Pyrrolidines

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Solutions