The C–F bond as a conformational tool in organic and biological chemistry

Abstract

SummaryOrganofluorine compounds are widely used in many different applications, ranging from pharmaceuticals and agrochemicals to advanced materials and polymers. It has been recognised for many years that fluorine substitution can confer useful molecular properties such as enhanced stability and hydrophobicity. Another impact of fluorine substitution is to influence the conformations of organic molecules. The stereoselective introduction of fluorine atoms can therefore be exploited as a conformational tool for the synthesis of shape-controlled functional molecules. This review will begin by describing some general aspects of the C–F bond and the various conformational effects associated with C–F bonds (i.e. dipole–dipole interactions, charge–dipole interactions and hyperconjugation). Examples of functional molecules that exploit these conformational effects will then be presented, drawing from a diverse range of molecules including pharmaceuticals, organocatalysts, liquid crystals and peptides.

Stabilising Peptoid Helices Using Non‐Chiral Fluoroalkyl Monomers

“…This ability of fluorine to enforce the preorganization of its local environment is most keenly observed when fluorine atoms are located β to electron‐withdrawing groups. In such an arrangement, the fluorine gauche effect is seen (Figure 1 d) 12, 13. Notably, the fluorine gauche effect is more pronounced in β‐fluoroamides than in other related systems 12, 13.…”

“…In such an arrangement, the fluorine gauche effect is seen (Figure 1 d) 12, 13. Notably, the fluorine gauche effect is more pronounced in β‐fluoroamides than in other related systems 12, 13. However, in α‐fluoroamides, CF/C=O dipolar interactions dominate, and the fluorine atom adopts a trans ‐periplanar arrangement (Figure 1 e) 14.…”

“…Fluorine is a relatively small atom, close in size to hydrogen, but a H to F swap can give rise to significant changes in the electronic and structural properties of a molecule 11, 12. For example, fluorine may engage in stereoelectronic hyperconjugative interactions with neighbouring C−H bonds (σ(CH)→σ*(CF)).…”

Synthesis, Characterization and Crystal Structure of 1,4,5,8-Tetrakis(Perfluoropyridin4-yloxy) Naphthalene

“…Organofluorine compounds find many different applications, ranging from pharmaceuticals and agrochemicals to advanced materials and polymers [1]. The unique properties of the fluorine atom, such as high electronegativity, low polarizability, and small covalent radius together with the great strength of the C-F bond and its tendency to increase lipophilicity of organic molecules are behind its wide impact.…”

Nucleophilic trifluoromethylation of carbonyl compounds and derivatives

“…The special nature of fluorine inside a therapeutic or diagnostic small molecule candidate for a pharmaceutical compound imparts a variety of properties, which can enhance a number of pharmacokinetic and/or pharmacodynamic properties including increased membrane permeability, favourable proteinligand interactions, improved metabolic stability, changes in physical properties, and selective reactivities with a profound effect on its bioactivity, stability and lipophilicity. [5][6][7] Moreover, the effect of fluorine on the biological activity of agrochemicals such as herbicides, insecticides, fungicides, and plant growth regulators has earned fluorine a unique place in the toolbox of the agrochemical chemist, given that it represents about the 35 to 40% of the active ingredients in crop protection products. 8 Likewise, fluorine has been recognized as a key element in materials science.…”