3-Fluoropiperidines and N-methyl-3-fluoropiperidinium salts: the persistence of axial fluorine.
It has previously been shown that the fluorine atom in N-protonated 3-fluoropiperidine salts in water strongly prefers the axial orientation in the six-membered ring chairs. In the present work we examine the proposition that the N-methyl salts are equally disposed to present axial fluorine. Initially, we explored this point by comparing the structures of the corresponding NH2+, NHMe+, and NMe2+ salts by means of density functional theory (DFT), ab initio, and MMFF force field calculations with and without aqueous solvation models. The predictions unambiguously pointed to axial fluorine for all salts investigated, including those with simultaneous axial F and (N)Me. The calculations were followed by synthesis of the corresponding series of 4,4-diphenylpiperidinium salts. These were evaluated by one- and two-dimensional NMR spectroscopy in [D6]DMSO to fully corroborate the axial disposition of the fluorine in each of the compounds. X-ray crystal structure determinations were likewise performed for the diphenyl-3-fluoro NH2+ and NMe2+ systems to substantiate axial-F. Comparison of the X-ray structures of the fluorinated and unfluorinated NMe2+ salts reveals that the fluorine resides axial in spite of substantial steric compression. While the charge-dipole phenomenon responsible for the axial-F conformation in the parent protonated fluoropiperidinium compounds carries over to doubly alkylated salts, we show that it extends to molecular orientation in the packing of the unit cells in the solid state as well. Finally, using the computational methods that successfully motivated our synthesis and structural work, we have made predictions for a number of new structures and re-examined some parallel results reported by the Eliel group in the early 1970s. Although C-F...H-N hydrogen bonds are reported to be weak and few in number, the CF...HN charge-dipole orienting effect is a powerful directing force that matches the hydrogen-bond in both its energetic contribution and conformational consequences.
Sun
Aiming
A
Department of Chemistry, Emory University, Atlanta, GA 30322, USA.
Lankin
David C
DC
Hardcastle
Kenneth
K
Snyder
James P
JP
D018360:Crystallography, X-Ray; D005461:Fluorine / Q000737:chemistry*; D006845:Hydrocarbons, Fluorinated / Q000097:blood / Q000138:chemical synthesis; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry*; D013816:Thermodynamics
D006845:Hydrocarbons, Fluorinated; D010880:Piperidines; D005461:Fluorine