Polar Organofluorine Substituents: Multivicinal Fluorines on Alkyl Chains and Alicyclic Rings

Abstract

This Review outlines the progression, primarily of our own work, but with important contributions from other labs, on the synthesis and properties of multiple vicinally fluorinated alkyl chains and rings. Chain conformations of individual diastereoisomers with -CHF- at adjacent carbons are influenced by stereoelectronic factors associated with the polar C-F bond and the polarised geminal hydrogens. Generally, the chain will prefer a conformation which acts to minimise overall molecular polarity, and where the C-F bonds orient away from each other. However, when vicinal fluorine atoms are positioned on a ring then conformations are more constrained. The ring will adopt optimal conformations such as a chair in cyclohexane and then C-F bonds can be introduced with a stereochemistry that forces parallel (axial) orientations. In the case of cyclohexane, 1,3-diaxial arrangements of C-F bonds impart considerable polarity to the ring, resulting in an electronegative 'fluorine face' and an electropositive 'hydrogen face'. For all-syn 1,2,3,4,5,6-hexafluorocyclohexane, this arrangement generates an unusually polar aliphatic ring system. Most recently the concept has been extended to the preparation of all-syn 1,2,3-trifluorocyclopropanes, a rigid ring system with fluorine atoms on one face and hydrogens on the other. Lipophilicity Log P values of such compounds indicate that they are significantly more polar than their parent alicyclic hydrocarbons and give some positive indication for a future role of such substituents in medicinal chemistry. Expanding to such a role will require access to improved synthesis methods to these motifs and consequently access to a broader a range of building blocks, however some exciting new methods have emerged recently and these are briefly reviewed.

Keywords: X-ray crystallography; fluorination; fluorine; hydrogen; stereochemistry.