DOI: 10.1002/chem.201201577 Conformational Analysis of Fluorinated Pyrrolidines Using 19 F– 1 H Scalar Couplings and Heteronuclear NOEs Lorraine E. Combettes, [a] Philip Clausen-Thue, [a] Michael A. King, [b] Barbara Odell, [a] Amber L. Thompson, [a] VØronique Gouverneur,* [a] and Tim D. W. Claridge* [a] Introduction The conformations of small flexible cyclic molecules are governed by a balance of factors such as stereoelectronic ef- fects, steric hindrance and long-range non-bonding interac- tions. The introduction of strongly electronegative atoms, in- cluding fluorine, into flexible molecules, such as pyrroli- dines, may impart a conformational bias whereby the gauche effect confers rigidity to the structure. [1, 2] This stereoelec- tronic interaction, although comparatively weak, shifts the conformational equilibrium of the ring pucker by establish- ing a gauche N-C-C-F arrangement as a result of hypercon- jugative delocalization. [3] In this, an antiperiplanar relation- ship of C  F and C  H bonds allows donation of electron density from the electron-releasing s CH molecular orbital into the adjacent low-lying electron-accepting s* CF molecu- lar orbital, which serves to maximize the stabilisation of this geometry. [4] For example, it has been reported that when proline is substituted with fluorine at the 4 position the pyr- rolidine ring adopts, almost exclusively, either the C g -exo or C g -endo conformation for the 4(R) and 4(S) configurations, respectively, whereas in the absence of the fluorine substitu- ent both conformations are significantly populated (  2:1 endo/exo). [5] The influence of the fluorine on the conforma- tional preference of fluoroproline has also been shown to in- crease the structural and thermal stability of collagen mimics, [6] and has been used to probe stereoelectronic ef- fects in proline hydroxylation pertinent to the human oxygen sensing machinery. [7] Pyrrolidine ring fluorination has also been demonstrated to influence the binding mode of a pyrrolidine-containing G-quadruplex DNA binding ligand. [8] In this work we wished to investigate the influence of the fluorine atom as a conformation-directing element on the ring puckering of a variety of 3-fluoro pyrrolidines and a tet- rahydrofuran (Figure 1), the syntheses of which were descri- bed in the preceding paper. [9] In particular we wished to seek experimental data that supported the anticipated domi- nance of the C g -exo conformation (Figure 2) in both the solid state and solution phase. Most studies reporting the in- fluence of the fluorine gauche effect have used solid-state single-crystal X-ray diffraction studies. However, in the solid state, crystal packing can influence conformation, so in addi- tion to this, we wished to utilise NMR spectroscopy support- ed by molecular modelling to investigate conformational ef- fects in the solution state, in which there have been rather fewer detailed investigations. [5] It is well known that the conformational analysis of satu- rated five-membered rings in solution is complicated by their inherent flexibility, and the interpretation of proton– proton scalar coupling constants (JACHTUNGTRENNUNG(H,H)) and nuclear Over- Abstract: A series of 3-fluoropyrroli- dines have been studied to investigate the influence of the stereoelectronic fluorine gauche effect on ring confor- mations 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 heteronu- clear 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 JACHTUNGTRENNUNG(F,H) and 3 JACHTUNGTRENNUNG(H,H) scalar coupling constants to analyse the ring conformations. Where possible the derived solution- phase structural data have been com- pared with those of the crystalline state. The results demonstrate the in- fluence of the gauche effect in stabilis- ing C g -exo conformations of the fluori- nated pyrrolidines. It was further shown that when steric interactions were also present, this conformational bias was diminished and the contribu- tion of the alternative C g -endo confor- mation was seen to increase in solution at lower sample temperatures. Keywords: fluorine · HOESY · NMR spectroscopy · nitrogen het- erocycles · stereoelectronic effects [a] L. E. Combettes, P. Clausen-Thue, Dr. B. Odell, Dr. A. L. Thompson, Prof. V. Gouverneur, Dr. T.D. W. Claridge Chemistry Research Laboratory University of Oxford 12 Mansfield Road, Oxford, OX1 3TA (UK) Fax: (+ 44) 1865-285002 E-mail : veronique.gouverneur@chem.ox.ac.uk tim.claridge@chem.ox.ac.uk [b] Dr. M. A. King CADD Group, UCB Celltech 208 Bath Road, Slough, SL1 3WE (UK) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201201577. Chem. Eur. J. 2012, 00,0–0  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim These are not the final page numbers! ÞÞ &1& FULL PAPER