The Close Interaction of a C-F Bond with an Amide Carbonyl: Crystallographic and Spectroscopic Characterization

Abstract

The putative interaction of a C-F bond with an amide carbonyl has been an intriguing topic of interest in this century for reasons spanning basic physical organic chemistry to biochemistry. However, to date, there exist no examples of a close, well-defined interaction in which its unique aspects can be identified and exploited. Herein, we finally present an engineered system possessing an exceptionally tight C-F-amide interaction, allowing us to obtain spectroscopic, crystallographic, and kinetic details of a distinctive, biochemically relevant chemical system for the first time. In turn, we also explore Lewis acid coordination, C-F bond promotion of amide isomerization, enantiomerization, and ion protonation processes.

Keywords: Amides; Fluorine; Non-Covalent Interactions.

Figure 1

Fluorine‐amide carbonyl interaction.

Figure 2

C−F bond—amide carbonyl interactions from crystal structures in the CCBD within van der Waals radii of C and F (F=green, C=gray, O=red, N=blue); Isostar program, CCDB. a) aliphaticCON(aromatic). b) aromaticCON(aliphatic). c) aromaticCON(aromatic). d) aliphaticCON‐(aliphatic).

Figure 3

Synthetic routes to 3, 4 and 7.

Figure 4

a) X‐ray crystal structure of diamide 3 (50 % thermal ellipsoids). b) Cut‐away of probe region revealing amide pyramidalization and the angle of distortion (improper torsion C18−N2−C19−C20 159.73°).

Figure 5

Contour slices of the static deformation density map in the vicinity of the F‐amide region of 3 (positive (blue) and negative (red) contours are drawn at intervals 0.05 e Å⁻³, black=0.00 e Å⁻³). a) Primarily electrostatic interaction along the F−carbonyl axis, (C18 denotes the probe carbonyl carbon). b) Alternate view including the C−O axis. c) Anomalous electron density surrounding the pyramidalized probe amide nitrogen. d) NBO‐derived electron density contour slice calculated at M062X/6‐311++G** (0.04 isovalue) of 3 bisecting the axis of the C−F—C=O interaction (Spartan Program). The purple polygon marks an effective saddle point.

Figure 6

Electrostatic potential surface maps of the probe regions calculated at M062X/6‐311++G** (0.02 e au⁻³; property range −215 to 515 kJ); red negative; blue positive. a) Diamide 3. b) Diester 4.

Figure 7

Lewis acid complexation of diamide 3.

Figure 8

Calculated intramolecular nucleophilic promotion of amide isomerization (AI) in diamide 3; variable‐temperature ¹H NMR in DMSO.

Figure 9

Postulated mechanism of racemization of 3 (calcs. performed at M062X/6‐311++G**).

Figure 10

a) Calculated energy diagram for racemization of 3 (M062X/6‐311++G**). b) VT ¹⁹F NMR of 3’s enantiomerization process.

Figure 11

Gas phase ions.