Questions regarding the nature and strength of noncovalent interactions formed by organic fluorine atoms are increasingly being addressed and debated in the literature.[1] We have been exploring noncovalent interactions of fluorine by carrying out a systematic fluorine scan [2] at the active site of thrombin.[3] While exploring the hydrophobic D pocket of this serine protease, we noticed that the potency of a closely related family of fluorinated inhibitors was strongly influenced by the position of the fluorine atom (Figure 1).[3a] The 4-fluorobenzyl derivative (AE )-4 exhibits fivefold better inhibition than any other member of the family. The X-ray structure of the (+)-4-enzyme complex showed two close contacts between the fluorine atom and the C a ÀH atom as well as the carbonyl C atom of Asn98 (Figure 1 b). Subsequent searches in the Cambridge Structural Database and RCSB Protein Data Bank provided numerous examples of similar sub van der Waals contacts between organic fluorine atoms and carbonyl carbon atoms in chemical and biological samples. These interactions have a characteristic geometry: the fluorine atom tends to reside orthogonally above the pseudotrigonal axis of the carbonyl group, and the C À F bond approaches the plane of the carbonyl group from an angle between 1008 and, at very short F···C distances, 1408.[3a]Herein we report the first model system to evaluate the energetics of the proposed C À F···amide interactions.The distinct geometry of the orthogonal CÀF···amide interaction presented an unusual challenge. We found an answer in the "molecular torsion balance" derived by Wilcox et al. from the Tröger base-a system designed for the accurate measurement of edge-to-face aromatic-aromatic interactions by the observation of a simple conformational equilibrium.[4] We found through examination of existing crystal structures [5] that appropriate substitution of the Tröger base skeleton would provide the perpendicular arrangement of functional groups required for our study (Scheme 1). The use of a trifluoromethyl group was required to approximate the optimal C À F···amide geometry. Based on the similarity of the results obtained from database searches for fluorine atoms attached to sp 2 -and sp 3 -hybridized carbon atoms, we anticipated that this substitution would have a negligible effect on the energetics of the proposed interaction.The second challenge in characterizing fluorine-amide interactions is their expected weakness. The relative K i values for compounds (AE )-1-(AE )-7 suggest that the fluorine substitution provides approximately 4 kJ mol À1 of stabilizing energy. Hunter and co-workers have popularized chemical double-mutant cycles for the measurement of very small interaction energies in supramolecular systems, and have used this method to accurately measure various noncovalent interactions as weak as 1 kJ mol À1 .[6] The application of this strategy to the Wilcox torsion balance is straightforward. The edge-to-face aromatic-aromatic interaction is the primary force behind the folding ...

Questions regarding the nature and strength of noncovalent interactions formed by organic fluorine atoms are increasingly being addressed and debated in the literature.[1] We have been exploring noncovalent interactions of fluorine by carrying out a systematic fluorine scan [2] at the active site of thrombin.[3] While exploring the hydrophobic D pocket of this serine protease, we noticed that the potency of a closely related family of fluorinated inhibitors was strongly influenced by the position of the fluorine atom (Figure 1).[3a] The 4-fluorobenzyl derivative (AE )-4 exhibits fivefold better inhibition than any other member of the family. The X-ray structure of the (+)-4-enzyme complex showed two close contacts between the fluorine atom and the C a ÀH atom as well as the carbonyl C atom of Asn98 (Figure 1 b). Subsequent searches in the Cambridge Structural Database and RCSB Protein Data Bank provided numerous examples of similar sub van der Waals contacts between organic fluorine atoms and carbonyl carbon atoms in chemical and biological samples. These interactions have a characteristic geometry: the fluorine atom tends to reside orthogonally above the pseudotrigonal axis of the carbonyl group, and the C À F bond approaches the plane of the carbonyl group from an angle between 1008 and, at very short F···C distances, 1408.[3a]Herein we report the first model system to evaluate the energetics of the proposed C À F···amide interactions.The distinct geometry of the orthogonal CÀF···amide interaction presented an unusual challenge. We found an answer in the "molecular torsion balance" derived by Wilcox et al. from the Tröger base-a system designed for the accurate measurement of edge-to-face aromatic-aromatic interactions by the observation of a simple conformational equilibrium.[4] We found through examination of existing crystal structures [5] that appropriate substitution of the Tröger base skeleton would provide the perpendicular arrangement of functional groups required for our study (Scheme 1). The use of a trifluoromethyl group was required to approximate the optimal C À F···amide geometry. Based on the similarity of the results obtained from database searches for fluorine atoms attached to sp 2 -and sp 3 -hybridized carbon atoms, we anticipated that this substitution would have a negligible effect on the energetics of the proposed interaction.The second challenge in characterizing fluorine-amide interactions is their expected weakness. The relative K i values for compounds (AE )-1-(AE )-7 suggest that the fluorine substitution provides approximately 4 kJ mol À1 of stabilizing energy. Hunter and co-workers have popularized chemical double-mutant cycles for the measurement of very small interaction energies in supramolecular systems, and have used this method to accurately measure various noncovalent interactions as weak as 1 kJ mol À1 .[6] The application of this strategy to the Wilcox torsion balance is straightforward. The edge-to-face aromatic-aromatic interaction is the primary force behind the folding ...

Derivatives of the Trˆger base are finding increasing application in supramolecular chemistry: they are introduced as rigid scaffolds into synthetic receptors and −molecular torsional balances× to quantify weak intermolecular interactions, and serve as efficient −covalent templates× in the tether-directed remote functionalization of fullerenes. This paper describes the facile synthesis of symmetrically (Schemes 1 and 2) and unsymmetrically (Schemes 4 and 5) substituted Trˆger base derivatives starting from the corresponding, readily available dihalo compounds. A variety of metal-catalyzed cross-coupling reactions, including Suzuki couplings, palladium-catalyzed cyanation and boronation, and copper-catalyzed amidations are used to achieve these transformations. . Recently, derivatives of the Trˆger base were introduced as chiral tethers for the regio-and stereoselective tether-directed remote functionalization of fullerenes [10] [11]. Many of these increasingly sophisticated scaffolds require intensive synthetic efforts, and, to this end, halogenated derivatives of the Trˆger base have recently been transformed by metal-catalyzed cross-coupling methodologies to provide a variety of acetylenic and biaryl derivatives [12] [13]. We report herein the application of metal-catalyzed cross-coupling methodologies to create two different classes of Trˆger base derivatives, one bearing identical substituents at the two aryl rings (see A) and the other featuring two different substituents at atoms C(2) and C(8) (see B) ( Fig.).