Synthesis of Janus All- Tetrafluorocyclohexanes Carrying 1,4-Diether Motifs.

Nucleophilic aromatic substitutions (SAr) of alkoxides on pentafluoroaryl ethers are explored as a first step in a synthesis sequence to generate all- 2,3,5,6-tetrafluorocyclohexyl-1,4-dialkyl ethers . The SAr reaction was explored both experimentally and theoretically to rationalize // selectivities. -Butyl deprotection of products followed by phenol alkylations introduces versatility to the synthesis.

Synthesis and Analysis of (γ,γ',γ''-Trifluoro)neopentyl (TFNP) Aryl Ethers as a Polar Fluoroaliphatic Motif.

A route is developed to (γ,γ',γ'''-trifluoro)neopentyl (TFNP) aryl ethers to extend the methods for the introduction of the tert-butyl group, carrying a fluorine on each of the methyl substituents. The route combines neopentyltosylate 3 with phenols and thiophenols to give efficient substitution reactions to the corresponding TFNP aryl ethers. The three C-F bonds adopt a helical propeller conformation as revealed by computation and single crystal X-ray structure analysis.

Conformational Analysis Explores the Role of Electrostatic Nonclassical CF···HC Hydrogen Bonding Interactions in Selectively Halogenated Cyclohexanes.

The conformational equilibria of selectively halogenated cyclohexanes are explored both experimentally (VT-NMR) for 1,1,4,-trifluorocyclohexane and by computational analysis (M06-2X/aug-cc-pVTZ level), with the latter approach extending to a wider range of more highly fluorinated cyclohexanes. Perhaps unexpectedly, is preferred over the conformation by Δ = 1.06 kcal mol, contradicting the accepted norm for substituents on cyclohexanes.

The pitfalls of using spin-spin coupling constants to infer hydrogen bond formation in organofluorine compounds.

Theoretical decomposition of "through space" spin-spin coupling constants (SSCCs) in organofluorine compounds signal that intramolecular hydrogen bonds (H-bonds) are not the primary mechanism of transmission for SSCCs. Increasing solvent polarity may disrupt H-bonds, but not necessarily the SSCC. Substituent effects may drastically alter the SSCC transmission pathway.

Aryl (β,β',β″-Trifluoro)--butyl: A Candidate Motif for the Discovery of Bioactives.

The (β,β',β″-trifluoro)--butyl (TFTB) group has received very little attention in the literature. This work presents a direct synthesis of this group and explores its properties. The TFTB group arises when the methyl groups of a -butyl moiety are exchanged for fluoromethyl groups.

Contribution of Hyperconjugation and Inductive Effects to the -anomeric Effect in 4-Substituted Methoxycyclohexanes.

The importance of electrostatic nonconventional hydrogen bonds (NCHBs) to the -anomeric effect of 4-substituted methoxycyclohexanes is evaluated using theory [natural bond orbital (NBO)] to deconvolute electrostatic from other contributing effects. There is an interesting interplay between σ → σ hyperconjugation and the electropositive charge on 3,5-axial hydrogens (H). In essence, better σ (or π) acceptors increase the charge on 3,5-CH, which in turn strengthens CH···OMe NCHB interactions.

Unexpected triaxial preferences in some all- 1,3,5-trifluorocyclohexanes.

Theory and solution NMR indicate that all- 1,3,5-trifluorocyclohexane 5 adopts the expected tri-equatorial conformation, however in the solid state the more polar triaxial conformation is observed. This and the favoured conformations of substituted (Me, OMe, NH(CO)Me, NHBoc) derivatives of 5 are investigated to explore triaxial C-F preferences.

Janus faced fluorocyclohexanes for supramolecular assembly: synthesis and solid state structures of equatorial mono-, di- and tri alkylated cyclohexanes and with tri-axial C-F bonds to impart polarity.

Concise and general synthesis protocols are reported to generate all- mono-, di- and tri-alkylated cyclohexanes where a single fluorine is located on the remaining carbons of the ring. The alkyl groups are positioned to lie equatorially and to have triaxial C-F bonds imparting polarity to these ring systems. Intermolecular electrostatic interactions in the solid-state structure of the trialkylated systems are explored and the resultant supramolecular order opens up prospects for design in soft materials.

Supramolecular packing of alkyl substituted Janus face all- 2,3,4,5,6-pentafluorocyclohexyl motifs.

This study uses X-ray crystallography, theory and Langmuir isotherm analysis to explore the conformations and molecular packing of alkyl all- 2,3,4,5,6-pentafluorocyclohexyl motifs, which are prepared by direct aryl hydrogenations from alkyl- or vinyl-pentafluoroaryl benzenes. Favoured conformations retain the more polar triaxial C-F bond arrangement of the all- 2,3,4,5,6-pentafluorocyclohexyl ring systems with the alkyl substituent adopting an equatorial orientation, and accommodating strong supramolecular interactions between rings. Langmuir isotherm analysis on a water subphase of a long chain fatty acid and alcohol carrying terminal all- 2,3,4,5,6-pentafluorocyclohexyl rings do not show any indication of monolayer assembly relative to their cyclohexane analogues, instead the molecules appear to aggregate and form higher molecular assemblies prior to compression.

The contribution of non-classical CHOC hydrogen bonds to the anomeric effect in fluoro and oxa-methoxycyclohexanes.

In this theory study we demonstrate the dominance of non-classical 1,3-diaxial CHOC hydrogen bonds (NCHBs) dictating a 'pseudo' anomeric effect in selectively fluorinated methoxycyclohexanes and also influencing the axial preference in the classical anomeric exhibitor 2-methoxytetrahydropyran, a phenomenon which is most often described as a consequence of hyperconjugation. Analogues of methoxycyclohexane where ring CH's are replaced by CF can switch to an axial preference and theory methods (NBO, QTAIM, NCI) indicate the dominance of 1,3-CHOMe interactions over hyperconjugation. For 2-methoxytetrahydropyran, it is revealed that the global contribution to the anomeric effect is from electrostatic interactions including NCHBs, not hyperconjugation, although hyperconjugation (n→σ* or n→σ*) remains the main contributor to the exo-anomeric phenomenon.

Fluorine-Induced Pseudo-Anomeric Effects in Methoxycyclohexanes through Electrostatic 1,3-Diaxial Interactions.

We report counter-intuitive axial preferences in non-stereochemically biased, selectively fluorinated methoxycyclohexanes. These pseudo-anomeric effects are apparent when electronegative CF groups are placed at the C-2, C-4 and C-6 positions of the cyclohexane ring to render the C-3/5 axial hydrogen atoms electropositive. The electrostatic interaction between these axial hydrogen atoms and the -OMe oxygen is stabilising.