The Emergence and Properties of Selectively Fluorinated ‘Janus’ Cyclohexanes

Abstract

This account describes the evolution of a research programme that started by linking fluoromethylene (−CHF−) groups along aliphatic chains and then progressing to alicyclic rings with contiguous fluorine atoms. Different stereoisomers of aliphatic chains tend to adopt low polarity conformations. In order to force polar conformations, the programme began to address ring systems and in particular cyclohexanes, to restrain conformational freedom and co‐aligned C−F bonds. The flagship molecule, all‐cis‐1,2,3,4,5,6‐hexafluorocyclohexane 7, emerged to be the most polar aliphatic compound recorded. The polarity arises because there are three co‐aligned triaxial C−F bonds and the six fluorines occupy one face of the ring. Conversely the electropositive hydrogens occupy the other face. These have been termed Janus face cyclohexanes after the Roman god with two faces. The review outlines progress by our group and others in preparing derivatives of the parent cyclohexane 7, in order to explore properties and potential applications of these Janus cyclohexanes.

gem‐Difluoro‐3‐azabicyclo[3.n.1]alkanes and Their Derivatives – Bicyclic Fluorinated Piperidine Isosteres for Drug Discovery

“…A considerable difference in the lipophilicity for 30 and 28 d (1.59 versus 2.18 LogP units) is worth noting. [35] On the contrary, gem-difluorination of hetera-substituted analogs 31 and 32 increased the LogP values by 0.35 and 0.54 units, respectively (compare with ΔLogP = 0.12 for the piperidine and its 4,4-difluoro derivatives). [13] These effects can be partially explained by compensation of dipole moment vectors for the case of hetera-substituted analogs (Figure 4, B); this hypothesis does not work for tetrafluorinated derivative 28 e.…”

Synthesis and supramolecular properties of all-cis-2,4,6-trifluorocyclohexane-1,3,5-triol

“…Since the calculated gas-phase energy difference between the conformers of 2 was only 0.8 kcal mol −1 , we attempted to observe the ring flip isomers by low temperature NMR spectroscopy. However, even at a temperature of −80 °C in acetone, when coalescence should have occurred, 9,10 we could only observe one signal in the 19 F NMR spectrum (Fig. S9, ESI†).…”

“…With this in mind, we thought of developing a tripodal architecture based on all- cis -1,2,3,4,5,6-hexafluorocyclohexane (all- cis C 6 H 6 F 6 ). 9,10 All- cis C 6 H 6 F 6 with its positive and negatively polarized regions and world-record (aliphatic) dipole moment (6.2 debye) holds potential for applications in supramolecular chemistry, 11 material chemistry 12–15 and medicinal chemistry 16,17 (Fig. 1).…”