An Electrostatic Gauche Effect in β‐Fluoro‐ and β‐Hydroxy‐N‐ethylpyridinium Cations

Abstract

There has been a recent interest in electrostatic interactions in organic chemistry and in their influence on the conformation and reactivity of organic molecules. [1,2] It emerges that organic cations containing oxygen and fluorine find stabilization through such interactions: polarized C À OH and C À F bonds orient towards charged centers when the molecular conformation allows. This effect has been particularly noted by Snyder, Lankin, and co-workers, who reported the conformational preferences of 3-fluoropiperidinium (1) and related ring systems, such as 3-fluoro-N,N-dimethylpiperidinium (2). [3][4][5][6] They established that there is a strong preference (calculated energy difference of 4.0-5.4 kcal mol À1 between the gas-phase anti and gauche conformations) for the structures with the fluorine atom in the axial position (1 a/ 2 a) over those with the fluorine atom in the equatorial position (1 b/2 b; Scheme 1). [5] In our computational studies, we have explored the conformational preferences of bfluoroethylamine (3) and its protonated counterpart bfluoroethylammonium (4).[7] Our density functional theory (DFT) calculations indicated that there is no intrinsic gauche effect for the neutral amine 3; the neutral molecule only prefers a gauche conformation because there is a weakly stabilizing intramolecular NÀH···FÀC hydrogen bond. When the nitrogen atom is formally charged in 4, however, the bfluoroethylammonium cation displays a very strong preference (5.8 kcal mol À1 ) for the gauche conformation (4 a). This phenomenon extends to 2-fluoroethanol (5) and to protonated 2-fluoroethanol (6).[7] The slight gauche preference in the neutral molecule 5 is almost entirely attributable to a weak bridging hydrogen bond. In contrast, there is a significant intrinsic gauche preference in 6 of about 4.4 kcal mol À1 , which increases to 7.2 kcal mol À1 when one hydrogen atom of the H 2 O + group is in a bridging endo position. These charged systems exhibit a much larger gauche preference than do neutral molecules such as 1,2-difluoroethane (7), for which the energy difference was calculated to be in the range 0.5-1.0 kcal mol À1 .[7]More recently, we studied the conformation of 3-fluoroazetidinium (8).[8] Owing to the ring constraint, it was not possible to establish gauche and anti conformations, and the energy stabilization of the electrostatic interaction could not be calculated directly. We, therefore, instead investigated the influence of the interaction on the conformation, by comparing structures both with and without a positive charge. For the cation 8, our DFT calculations were consistent with the singlecrystal X-ray structure, indicating a puckered conformation that brings the C À F and N + À H bonds into proximity. Note that the positive Mulliken charge density on the hydrogen atoms is significant. When an additional electron was added to 8 to give the neutral (but sterically identical) azetidine 9, however, the ring puckered in the opposite direction, consistent with the removal of a favorable C À F···H À N + i...

The fluorine-NHC gauche effect: a structural and computational study

“…This value is typical of the stabilisation imparted by antiperiplanar hyperconjugative σ C-H → σ* C-F and σ C-H → σ* C-N interactions, in preference to σ C-N → σ* C-F and σ C-F → σ* C-N . Similar stereoelectronic gauche effects in NCCF systems have previously been described for imines, [44] amines, [6,[45][46][47] and amides. [6,48] Free NHCs and their precursor cations therefore follow the pattern found in other NCCF systems as far as the gauche preference is concerned.…”

“…The magnitude of this stabilisation is characteristic of an electrostatic gauche effect, which orients the partially negatively charged fluorine preferentially towards the cationic moiety, similarly to the situation seen in N-(2-fluoroethyl)iminium, [7a] -pyridinium, [45] or -ammonium [6,46,47] systems. The Hirshfeld partial charges for 23 (which are practically independent of the torsion angle) are -0.13e (F), 0.00 (both N), and +0.24e (C carb H).…”

NMR‐Solution Structures of Fluoro‐Substituted β‐Peptides: A 314‐Helix and a Hairpin Turn. The First Case of a 90° OCCF Dihedral Angle in an α‐Fluoro‐Amide Group

“…-heptapeptide was shown by this method to be able to destroy the helix. Obviously, the well-known preference, according to theoretical calculations 6 -8 kcal/mol [4d] [7], of a CÀF bond in an a-fluoro amide for being antiperiplanar (ap) to the C¼O bond is a strong enough effect to enforce a conformation of the (2S,3S)-3-amino-2-fluorobutanoic acid moiety (Table 1: Y ¼ F in A, X ¼ H, n ¼ 3, m ¼ 1), which causes a bend in the backbone; in the (2R,3S)-epimer, the CÀF bond is in the favorable ap-disposition with the C¼O bond occupying an axial position in the 3 14 helix. The degree to which the ap conformation is stabilized is evident from the result of a search in the Cambridge Structural Database, shown in Fig.…”

“…1. The (M)-3 14 -helix with allowed (blue) and forbidden (black) positions for substituents R 2 and R 3 in the 2-and 3-position of each bhXaa residue. The b 2 -, b 3 -, and b 2,3 -amino acids, which can be incorporated in a peptide folding to the (M)-3 14 -helix, are shown.…”

“…The (M)-3 14 -helix with allowed (blue) and forbidden (black) positions for substituents R 2 and R 3 in the 2-and 3-position of each bhXaa residue. The b 2 -, b 3 -, and b 2,3 -amino acids, which can be incorporated in a peptide folding to the (M)-3 14 -helix, are shown. A pitch of the helix may comprise more than exactly three residues, as seen in the NMR-solution structure of a b 3 -icosamer [3].…”