The Emergence and Properties of Selectively Fluorinated ‘Janus’ Cyclohexanes

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.     

An NMR study of the conformational equilibrium of 5-fluoro-1,3-dioxan in solution. Dependence on solvent

The ¹H and ¹⁹F NMR parameters of 5-fluoro-1,3-dioxan ( 1 ) dissolved in a number of solvent systems are interpreted on the basis of fast inversion between two chair conformations. In cyclohexane solution the two chair conformations are almost equally populated, whereas in more polar solvents, such as chloroform, the conformation having the fluorine substituent in an axial position is strongly preferred. Addition of acetic acid to a solution of 1 in cyclohexane increases the preference of the fluorine substituent for the axial orientation. Possible reasons for these observations are discussed.     

Janus Face All-cis 1,2,4,5-tetrakis(trifluoromethyl)- and All-cis 1,2,3,4,5,6-hexakis(trifluoromethyl)- Cyclohexanes

We report the synthesis of all-cis 1,2,4,5-tetrakis (trifluoromethyl)- and all-cis 1,2,3,4,5,6-hexakis (trifluoromethyl)- cyclohexanes by direct hydrogenation of precursor tetrakis- or hexakis- (trifluoromethyl)benzenes. The resultant cyclohexanes have a stereochemistry such that all the CF₃ groups are on the same face of the cyclohexyl ring. All-cis 1,2,3,4,5,6-hexakis(trifluoromethyl)cyclohexane is the most sterically demanding of the all-cis hexakis substituted cyclohexanes prepared to date, with a barrier (ΔG) to ring inversion calculated at 27 kcal mol⁻¹. The X-ray structure of all-cis 1,2,3,4,5,6-hexakis(trifluoromethyl)cyclohexane displays a flattened chair conformation and the electrostatic profile of this compound reveals a large diffuse negative density on the fluorine face and a focused positive density on the hydrogen face. The electropositive hydrogen face can co-ordinate chloride (K≈10³) and to a lesser extent fluoride and iodide ions. Dehydrofluorination promoted decomposition occurs with fluoride ion acting as a base.     

Supramolecular packing of alkyl substituted Janus face all-cis 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-cis 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-cis 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-cis 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 study indicates the power and potential of this ring system as a motif for ordering supramolecular assembly.

Theory and Langmuir isotherm analysis was used to explore the conformations and molecular packing of alkyl all-cis 2,3,4,5,6-pentafluorocyclohexyl motifs, which are prepared by direct aryl hydrogenations from alkyl- or vinyl-pentafluoroaryl benzenes.     

Comprehensive structural studies of 2',3'-difluorinated nucleosides: comparison of theory, solution, and solid state

The conformations of three 2',3'-difluoro uridine nucleosides were studied by X-ray crystallography, NMR spectroscopy, and ab initio calculations in an attempt to define the roles that the two vicinal fluorine atoms play in the puckering preferences of the furanose ring. Two of the compounds examined contained fluorine atoms in either the arabino or xylo dispositions at C2' and C3' of a 2',3'-dideoxyuridine system. The third compound also incorporated fluorine atoms in the xylo configuration on the furanose ring but was substituted with a 6-azauracil base in place of uracil. A battery of NMR experiments in D 2O solution was used to identify conformational preferences primarily from coupling constant and NOE data. Both (1)H and (19)F NMR data were used to ascertain the preferred sugar pucker of the furanose ring through the use of the program PSEUROT. Compound-dependent parameters used in the PSEUROT calculations were newly derived from complete sets of conformations calculated from high-level ab initio methods. The solution and theoretical data were compared to the conformations of each molecule in the solid state. It was shown that both gauche and antiperiplanar effects may be operative to maintain a pseudodiaxial arrangement of the C2' and C3' vicinal fluorine atoms. These data, along with previously reported data by us and others concerning monofluorinated nucleoside conformations, were used to propose a model of how fluorine influences different aspects of nucleoside conformations.     

Carboboration-Driven Generation of a Silylium Ion for Vinylic C−F Bond Functionalization by B(C6F5)3 Catalysis

Strong main-group Lewis acids such as silylium ions are known to effectively promote heterolytic C(sp³)−F bond cleavage. However, carrying out the C(sp²)−F bond transformation of vinylic C−F bonds has remained an unmet challenge. Herein, we describe our development of a new and simple strategy for vinylic C−F bond transformation of α-fluorostyrenes with silyl ketene acetals catalyzed by B(C₆F₅)₃ under mild conditions. Our theoretical calculations revealed that a stabilized silylium ion, which is generated from silyl ketene acetals by carboboration, cleaves the C−F bond of α-fluorostyrenes. A comparative study of α-chloro or bromostyrenes demonstrated that our reaction can be applied only to α-fluorostyrenes because the strong silicon-fluorine affinity facilitates an intramolecular interaction of silylium ions with fluorine atom to cleave the C−F bond. A broad range of α-fluorostyrenes as well as a range of silyl ketene acetals underwent this C−F bond transformation.     

On the Stereoselectivity of Fluorine and Acetylhypofluorite Additions to Glycals: The Synthesis of 2-Deoxy-2-Fldorohexoses

Electrophilic syn additions of fluorine and acetylhypofluorite across double bonds in 3,4,6-tri-0-acetyl-D-glucal (1a) and D-glucal (1b) followed by acid hydrolysis gave mixtures of 2-deoxy-2-fluoro-D-glucose (8) and 2-deoxy-2-fluoro-D-mannose (9). These addition reactions were conducted in various solvents with a view to investigating the reaction mechanism based on the product distribution analysis by ¹⁹F NMR. Tight ion pair intermediates (4 and 5) have been invoked to explain the stereospecific characteristics of the addition of fluorine or acetylhypofluorite to glycals. The relative stabilities of these intermediates control the product distributions and are governed by a) the anomeric effect (axial vs equatorial preference of C(1) electronegative substituents in pyranose rings), b) dipole-dipole interactions of the lone pairs of electrons on the ring oxygen and the electronegative substituents on C(2), and c) the gauche relationship that exists between the C(2) fluorine and polar groups in the molecule. The overall contribution of these three factors largely depends upon the polarity of the solvent. A rationale for the ¹⁹F NMR chemical shifts as well as the anomeric distributions of the α and β anomers of 2-FDG (8) and 2-FDM (9) has been proposed.     

Synthesis and Conformation of Fluorinated β‐Peptidic Compounds

Experimental and theoretical data indicate that, for α‐fluoroamides, the F? C? C(O)? N(H) moiety adopts an antiperiplanar conformation. In addition, a gauche conformation is favoured between the vicinal C? F and C? N(CO) bonds in N‐β‐fluoroethylamides. This study details the synthesis of a series of fluorinated β‐peptides ( 1 – 8 ) designed to use these stereoelectronic effects to control the conformation of β‐peptide bonds. X‐ray crystal structures of these compounds revealed the expected conformations: with fluorine β to a nitrogen adopting a gauche conformation, and fluorine α to a C?O group adopting an antiperiplanar conformation. Thus, the strategic placement of fluorine can control the conformation of a β‐peptide bond, with the possibility of directing the secondary structures of β‐peptides.     

Synthetic Advantages of Defluorinative C−F Bond Functionalization

Much progress has been made in the development of methods to both create compounds that contain C−F bonds and to functionalize C−F bonds. As such, C−F bonds are becoming common and versatile synthetic functional handles. This review summarizes the advantages of defluorinative functionalization reactions for small molecule synthesis. The coverage is organized by the type of carbon framework the fluorine is attached to for mono- and polyfluorinated motifs. The main challenges, opportunities and advances of defluorinative functionalization are discussed for each class of organofluorine. Most of the text focuses on case studies that illustrate how defluorofunctionalization can improve routes to synthetic targets or how the properties of C−F bonds enable unique mechanisms and reactions. The broader goal is to showcase the opportunities for incorporating and exploiting C−F bonds in the design of synthetic routes, improvement of specific reactions and advent of new methods.     

Recent Advances in Ring‐Opening Functionalization of Cycloalkanols by C–C σ‐Bond Cleavage

Cycloalkanols prove to be privileged precursors for the synthesis of distally substituted alkyl ketones and polycyclic aromatic hydrocarbons (PAHs) by virtue of cleavage of their cyclic C−C bonds. Direct functionalization of cyclobutanols to build up other chemical bonds (e. g., C−F, C−Cl, C−Br, C−N, C−S, C−Se, C−C, etc.) has been achieved by using the ring‐opening strategy. Mechanistically, the C−C cleavage of cyclobutanols can be involved in two pathways: (a) transition‐metal catalyzed β‐carbon elimination; (b) radical‐mediated ‘radical clock’‐type ring opening. The recent advances of our group for the ring‐opening functionalization of tertiary cycloalkanols are described in this account.     

Stereoelectronic Aspects of the Anomeric Effect in Fluoromethylamine

High-level ab initio calculations have been made for fluoromethylamine to study structural and energetic effects of the relative orientation of the N lone pair to the C? F bond. The anti-conformer (N lone pair anti-planar to the C? F bond) corresponds to the global energy minimum. It has the longest C? F distance, the shortest C? N distance, and is 7.5 kcal·mol^?1 more stable than the related perpendicular conformation (lone pair perpendicular to the C? F bond). The syn-conformation also shows hallmarks of the anomeric effect: long C? F bond, short C? N bond, and energetic stability when allowance is made for the two pairs of eclipsed hydrogens. The transition state for N inversion is close to the syn-structure; rotation about the C? N bond is strongly coupled with this inversion process. Small bond distance changes of ca. 0.02 Å between parallel and perpendicular conformations are associated with dissociation energy differences of ca. 30 kcal·mol^?1. Various criteria for assessing the strength of the anomeric effect are discussed.     

Fluorinated Rings: Conformation and Application

The introduction of fluorine atoms into molecules and materials across many fields of academic and industrial research is now commonplace, owing to their unique properties. A particularly interesting feature is the impact of fluorine substitution on the relative orientation of a C−F bond when incorporated into organic molecules. In this Review, we will be discussing the conformational behavior of fluorinated aliphatic carbo- and heterocyclic systems. The conformational preference of each system is associated with various interactions introduced by fluorine substitution such as charge-dipole, dipole-dipole, and hyperconjugative interactions. The contribution of each interaction on the stabilization of the fluorinated alicyclic system, which manifests itself in low conformations, will be discussed in detail. The novelty of this feature will be demonstrated by presenting the most recent applications.     

Propellanes. Part LXXI. Confirmation of predicted regiospecificity in Diels-Alder reactions of certain propellanes with 4-phenyl-1,2,4-triazoline-3,5-dione

Two isomeric propellane epoxides 1a and 1b containing a cyclohexadiene ring are attacked by the title dienophile as predicted, syn to the five-membered ether ring whose α-hydrogens exert less repulsion than the α-epoxy hydrogens or the epoxide oxygen, respectively, of the cyclobutane ring.     

Geminal interaction and “anomeric effect”

Quantum-chemical calculations by the methods of RHF/6-31G(d) and MP2/6-31+G(d) show equal ratio of the lengths of axial and equatorial bonds and electron density on the atoms forming them in cyclohexane and its mono derivatives and in six-membered heterocyclic molecules as well. This feature is due to the interaction of atoms in the chair form of these molecules regardless of the presence in them of a heteroatom. Introducing heteroatom to a cyclohexane ring leads only to increase in the difference between axial and equatorial bonds. This equation excludes the possibility to ascribe the elongation of axial bonds and increase in the electron density on atoms forming them in the heterocyclic molecules to the p,σ*-conjugation of the lone electron pair of the ring heteroatom with the antibonding orbital of the axial bond. Features of molecular geometry defined by the mutual influence of atoms in them, including inductive and non-inductive interaction of geminal atoms in triatomic groups Y-Z-M, result in energetic preference of gauche conformations of these molecules and “anomeric effect” in them.     

Understanding organofluorine chemistry. An introduction to the C-F bond

Fluorine is the most electronegative element in the periodic table. When bound to carbon it forms the strongest bonds in organic chemistry and this makes fluorine substitution attractive for the development of pharmaceuticals and a wide range of speciality materials. Although highly polarised, the C-F bond gains stability from the resultant electrostatic attraction between the polarised C delta+ and F delta- atoms. This polarity suppresses lone pair donation from fluorine and in general fluorine is a weak coordinator. However, the C-F bond has interesting properties which can be understood either in terms of electrostatic/dipole interactions or by considering stereoelectronic interactions with neighbouring bonds or lone pairs. In this tutorial review these fundamental aspects of the C-F bond are explored to rationalise the geometry, conformation and reactivity of individual organofluorine compounds.     

α- and β-Eliminations in Transition Metal Complexes: Strategies to Cleave Unstrained C−C and C−F Bonds

Oxidative addition is the standard process for single-bond activation in transition metal catalysis and it is known to operate for many types of bonds, but challenging σ-bonds e. g. C(sp³)−F and C(sp³)−C(sp³) bonds are the exceptions in this respect. This short review aims at demonstrating how both α- and β-eliminations may be better options for activation of unstrained C−F and C−C single bonds. Selected examples of such eliminations are presented with a mechanistic focus indicating how unstrained and unactivated C−C and C−F bonds can be broken by employing α- and β-eliminations in transition metal hydrocarbyl ligands. Our examples show that the reaction barrier in β-eliminations is controlled by the s-character of the participating bonds where a higher s-character gives a better overlap in the multi-center transition state thereby increasing the reactivity; still β-aryl eliminations can compete with the classical β-hydrogen eliminations in certain cases.     

Formal Insertion of Alkenes Into C(sp3)−F Bonds Mediated by Fluorine-Hydrogen Bonding

C−F Insertion reactions represent an attractive approach to prepare valuable fluorinated compounds. The high strength of C−F bonds and the low reactivity of the fluoride released upon C−F bond cleavage, however, mean that examples of such processes are extremely scarce in the literature. Here we report a reaction system that overcomes these challenges using hydrogen bond donors that both activate C−F bonds and allow for downstream reactions with fluoride. In the presence of hexafluoroisopropanol, benzyl and propargyl fluorides undergo efficient formal C−F bond insertion across α-fluorinated styrenes. This process, which does not require any additional fluorinating reagent, occurs under mild conditions and delivers products featuring the gem-difluoro motif, which is attracting increasing interest in medicinal chemistry. Moreover, readily available organic bromides can be engaged directly in a one-pot process that avoids the isolation of organic fluorides.     

Palladium‐Catalyzed Carbon–Fluorine and Carbon–Hydrogen Bond Alumination of Fluoroarenes and Heteroarenes

Through serendipitous discovery, a palladium bis(phosphine) complex was identified as a catalyst for the selective transformation of sp²C−F and sp²C−H bonds of fluoroarenes and heteroarenes to sp²C−Al bonds (19 examples, 1 mol % Pd loading). The carbon–fluorine bond functionalization reaction is highly selective for the formation of organoaluminium products in preference to hydrodefluorination products (selectivity=4.4:1 to 27:1). Evidence is presented for a tandem catalytic process in which hydrodefluorination is followed by sp²C−H alumination.     

Designing Fluorinated Cinchona Alkaloids for Enantioselective Catalysis: Controlling Internal Rotation by a Fluorine‐Ammonium Ion gauche Effect (φNCCF)

The C9 position of cinchona alkaloids functions as a molecular hinge, with internal rotations around the C8? C9 (τ₁) and C9? C4′ (τ₂) bonds giving rise to four low energy conformers ( 1 ; anti‐closed, anti‐open, syn‐closed, and syn‐open). By substituting the C9 carbinol centre by a configurationally defined fluorine substituent, a fluorine‐ammonium ion gauche effect (σ_C?H→σ_C?F*; F^δ????N⁺) encodes for two out of the four possible conformers ( 2 ). This constitutes a partial solution to the long‐standing problem of governing internal rotations in cinchonium‐based catalysts relying solely on a fluorine conformational effect.     

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 CF₂ 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. The effect is explored using high-level ab initio and DFT calculations in the framework of NBO, QTAIM and NCI analysis across a range of derivatives, and experimentally (¹⁹F{¹H}-NMR at −80 °C) for some illustrative examples. The effect is significant in energy terms for a weak interaction, and illustrates a new stereoelectronic aspect attributed to selective fluorine substitution in organic chemistry.