This work was supported by the Engineering and Physical Sciences Research Council (EPSRC) and the European Research Council (ERC). The authors acknowledge the EPSRC National Mass Spectrometry Facility (Swansea). D.O’H. thanks the Royal Society for a Wolfson Research Merit Award.2,2-Dimethyl-5-phenyl-1,1,3,3-tetrafluororocyclohexane has been prepared and characterised as an example of a facially polarised cyclohexane containing 1,3 related CF2 groups. The dipolar nature of the ring arises from the axial orientation of two of the C-F bonds pointing in the same direction, and set by the chair conformation of the cyclohexane. This electrostatic profile is revealed experimentally both in the solid-state (X-ray) packing of the rings and by solution (NMR) in different solvents. A computationally derived electrostatic profile of this compound is consistent with a more electronegative and a more electropositive face of the cyclohexane ring. This placing of CF2 groups 1,3 to each other in a cyclohexane ring is introduced as a new design strategy which could be applicable to the preparation of polar hydrophobic cyclohexane motifs.Publisher PDFPeer reviewe

Bühl, Michael

Callejo, Ricardo

Jones, Mathew J.

O'Hagan, David

Slawin, Alexandra M. Z.

Beilstein Journal of Organic Chemistry

PubMed

2,2-Dimethyl-5-phenyl-1,1,3,3-tetrafluororocyclohexane has been prepared and characterised as an example of a facially polarised cyclohexane containing 1,3 related CF2 groups. The dipolar nature of the ring arises from the axial orientation of two of the C-F bonds pointing in the same direction, and set by the chair conformation of the cyclohexane. This electrostatic profile is revealed experimentally both in the solid-state (X-ray) packing of the rings and by solution (NMR) in different solvents. A computationally derived electrostatic profile of this compound is consistent with a more electronegative and a more electropositive face of the cyclohexane ring. This placing of CF2 groups 1,3 to each other in a cyclohexane ring is introduced as a new design strategy which could be applicable to the preparation of polar hydrophobic cyclohexane motifs.</p

University of St. Andrews - Pure

Organofluorine chemistry:difluoromethylene motifs spaced 1,3 to each other imparts facial polarity to a cyclohexane ring

St Andrews Research Repository

2823Organofluorine chemistry: Difluoromethylene motifs spaced1,3 to each other imparts facial polarity to a cyclohexane ringMathew J. Jones, Ricardo Callejo, Alexandra M. Z. Slawin, Michael Bühland David O'Hagan*Full Research Paper Open AccessAddress:EaStCHEM School of Chemistry, University of St. Andrews, St.Andrews, Fife KY16 9ST, UKEmail:David O'Hagan* - do1@st-andrews.ac.uk* Corresponding authorKeywords:aliphatic rings; C–F bond; cyclohexane conformation;difluoromethylene group; organofluorine chemistryBeilstein J. Org. Chem. 2016, 12, 2823–2827.doi:10.3762/bjoc.12.281Received: 07 September 2016Accepted: 30 November 2016Published: 22 December 2016Associate Editor: V. Gouverneur© 2016 Jones et al.; licensee Beilstein-Institut.License and terms: see end of document.Abstract2,2-Dimethyl-5-phenyl-1,1,3,3-tetrafluororocyclohexane has been prepared and characterised as an example of a facially polarisedcyclohexane containing 1,3 related CF2 groups. The dipolar nature of the ring arises from the axial orientation of two of the C–Fbonds pointing in the same direction, and set by the chair conformation of the cyclohexane. This electrostatic profile is revealed ex-perimentally both in the solid-state (X-ray) packing of the rings and by solution (NMR) in different solvents. A computationallyderived electrostatic profile of this compound is consistent with a more electronegative and a more electropositive face of the cyclo-hexane ring. This placing of CF2 groups 1,3 to each other in a cyclohexane ring is introduced as a new design strategy which couldbe applicable to the preparation of polar hydrophobic cyclohexane motifs.IntroductionSelective incorporation of fluorine atoms is a powerful strategyfor modulating the properties of organic compounds [1-3]. Forinstance, the replacement of hydrogen by fluorine is commonlypractised in medicinal [4,5] and agrochemical [6,7] researchprogrammes. The dipole moment associated with the C–F bondhas also rendered fluorine containing compounds important inthe development of organic materials such as liquid crystals[8,9]. Strategic fluorination can add polarity to a molecule,however, such compounds do not generally increase in theirhydrophilic capacity, thus selective fluorination leads to polar-hydrophobic properties [10]. Although selective mono-fluori-nation and CF3 incorporation have had wide currency, thedifluoromethylene (CF2) motif has received relatively lessattention despite possessing unique properties [11-14]. For ex-ample CH2F2 shows the highest molecular dipole (1.97 D) ofthe fluoromethane series, relative to CH3F (1.87 D) or CHF3(1.65 D) [15,16]. Also (poly)vinylidine fluoride (~CF2CH2~) isthe prototypical piezoelectric polymer, when the CF2 group areorientated (poled) in the melt [17].The search for new and more diverse polar hydrophobic scaf-folds is attractive for drug discovery research and new materi-Beilstein J. Org. Chem. 2016, 12, 2823–2827.2824Scheme 2: Preparation of starting materials 5c and 6a–c.als [18]. In our own lab we have been exploring the synthesisand properties of differently fluorinated aliphatic structuresbased on the cyclopentane (1) and cyclohexane (2 and 3) rings,compounds which can show quite large dipole momentsdepending on the stereochemistry [19,20] (Figure 1). All-syn1,2,3,4,5,6-hexafluorocyclohexane, which was preparedrecently, emerges as among the most polar aliphatic com-pounds reported in the literature [21]. The specific arrangementwith all of the fluorines “up” induces a facial polarisation to thecyclohexane, a unique phenomenon which may have unex-plored utility in organic chemistry. For example derivatives ofthese compounds could be potentially useful as polar hydro-phobic substituents in drug discovery that will simultaneouslycontact both electropositive and electronegative domains withina target protein.Figure 1: Selected fluorinated polar alicyclic scaffolds.In this paper, we now report the design, synthesis and character-isation of a novel tetrafluorocyclohexane structure 4, renderedpolar by placing two CF2 groups located 1,3 from each other(Scheme 1). This forces two C–F bonds to lie 1,3-diaxial toeach other while the cyclohexane adopts the classic chair con-formation. To the best of our knowledge, 2,2,6,6-tetrafluoro-cyclohexanol is the only derivative containing this feature re-ported so far. It was prepared in an eight step synthesis [22]. Atthe outset we explored a more direct synthesis of this arrange-ment based on deoxofluorination of 1,3-diketones 5 with DASTor Deoxo-Fluor® [23] (Scheme 1). An alternative route envis-aged a fluorodesulfurisation using 1,3-bis-dithianes 6 as sub-strates [24] (Scheme 1). Both synthetic approaches have beenwidely used for the introduction of the CF2 group in open-chainand (macro)cyclic systems [23,24], but not in a 1,3 relationship.Scheme 1: Retrosynthetic plan to the preparation of 1,1,3,3-tetra-fluorocyclohexane structures.Results and DiscussionThe preparation of diketones 5a–c and bis-dithianes 6a–c wascarried out by previously described methods. The dimethyl-diketone 5c was prepared by double methylation of 5b [25](Scheme 2). Two different O-alkylated products 7 and 8 werealso obtained as significant byproducts.The reaction of ketones 5a–c with 1,2-ethanedithiol in the pres-ence of catalytic BF3·OEt2 afforded the corresponding bis-dithi-anes 6a–c in moderate to good yields [26] (Scheme 2). Thereaction of diketone 5c also afforded the monoderivatised ke-tone 9 as a minor product.Beilstein J. Org. Chem. 2016, 12, 2823–2827.2825Figure 2: X-ray structure of compound 4c. The image shows two molecules stacked with the non-fluorine face pointing to an adjacent phenyl ringconsistent with an electrostatic ordering. The structure has been deposited in the Cambridge Crystallographic Data Centre (CCDC) 1502954.Direct fluorination of diketones 5a–c was explored with DASTor Deoxo-Fluor® (Scheme 3). When diketones 5a and 5b weretreated with DAST or Deoxo-Fluor®, either neat or in DCM asa solvent, only complex and intractable products were obtained.These highly enolisable diketones [27,28] were incompatiblewith deoxyfluorination. In order to block enolisation, diketone5c containing two methyl groups α to the ketones was subject tofluorination with DAST and Deoxo-Fluor®. In this case thereaction was successful and the desired tetrafluorocyclohexane4c could be obtained, most preferably with DAST although in alow overall yield (Scheme 3). The presence of the gem-dimethylmotif renders the carbonyl groups independent of each otherand this facilitates the difluorination process relative to 5a and5b. Nevertheless, other unidentified byproducts were also ob-tained, which made purification of 4c by column chromatogra-phy difficult and compromised the yield.Scheme 3: Deoxofluorination of diketones 5. Reagents and conditions:a) DAST, DCM, rt, overnight, 4a (traces), 4b (traces), 4c (14%);b) Deoxo-Fluor®, DCM, rt, overnight, 4a (traces), 4b (traces), 4c(10%).Treatment of bis-dithianes 6 with NIS and HF·Py as previouslydescribed for linear systems [28] proved unsuccessful(Scheme 4) and did not offer a way forward.Scheme 4: Fluorodesulfurisation of bis-dithianes 6. Reagents andconditions: a) NIS, HF·Py, DCM, −78 °C to rt, overnight.Tetrafluorocyclohexane 4c was a crystalline solid (mp 70 ºC).The structure of this compound was established by NMR,showing a characteristic AB system in 19F NMR for axial/equa-torial fluorines, and a triplet (1JCF = 250 Hz) in 13C NMR forthe CF2 group. In addition, single crystal X-ray diffraction datawere obtained for 4c which confirmed the structure (Figure 2).The C–CF2–C angles in the cyclohexane ring are considerablywider (≈116°) than that of the C–CH2–C angles (≈112°), whichis now recognised as a general phenomenon of the CF2 group inan aliphatic chain/ring [10-13]. The two axial fluorines flexaway from each other with widened right angles of 96.3°, dis-torting a co-parallel orientation. This distortion is also observedfor the 1,3-diaxial C–F bonds in the solid state structures of 2[20] and 3 [21] consistent with electrostatic dipolar repulsionbetween these C–F bonds and indicative of the origin of thepolarity of these molecules. In terms of intermolecular packingin the solid state there are interactions between the non-fluorineface of the cyclohexyl ring and the phenyl group of a neigh-bouring molecule (Figure 2). These C-H···π interactions are afeature of the solid state packing found in phenyl derivatives of2 [29].Beilstein J. Org. Chem. 2016, 12, 2823–2827.2826Figure 3: 1H NMR spectra of 4c. A) shows the spectrum in [2H8]-toluene, and B) shows the spectrum in chloroform (CDCl3). There are significantupfield-shifted proton signals in toluene, consistent with an electrostatic interaction between toluene and the electropositive hydrogen face of 1,1,3,3-tetrafluorocyclohexyl 4c.This electrostatic ordering was reinforced by an NMR shift ex-periment in different solvents. Selected 1H NMR signals of 4cshowed a very clear upfield shift in [2H8]-toluene when com-pared with the spectrum obtained in chloroform (CDCl3)(Figure 3). In particular, the two axial protons H-3 and the axialmethyl group at C-4 display higher upfield shifts in toluene(Δδ ≈ 0.5 ppm and Δδ ≈ 0.3 ppm, respectively), whereas that ofthe equatorial protons H-2, the equatorial methyl group at C-5and the axial proton H-1 do not experience shifts of the samemagnitude (Δδ ≈ 0.2 ppm, Δδ ≈ −0.1 ppm and Δδ ≈ 0.1 ppm, re-spectively). These observations are consistent with theanisotropic influence of the electronegative aromatic solvent(toluene) interacting with the more electropositive (non-fluo-rine) face of the cyclohexane ring (Figure 3).To extend these experimental observations, a DFT computa-tional study, at the B3LYP-D3/6-311+G(d,p) level, was carriedout in order to obtain an electrostatic potential map of cyclo-hexane 4c. The profile confirms the presence of an electronega-tive face (in red) determined by the two 1,3-diaxial C–F bondsand an electropositive face (dark blue), which is most intense atthe hydrogens of the diaxial C–H bonds pointing antiperiplanarto the diaxial C–F bonds (Figure 4). A molecular dipolemoment for compound 4c was calculated at 3.1 D and can becompared for example to 1,2,4,5-tetrafluorocyclohexane (2,5.2 D) [18].Figure 4: Electrostatic potential map for 4c calculated at the B3LYP/6-311G(d,p) level for an optimised structure calculated at the B3LYP-D3/6-311+G(d,p) level. The image is plotted on a colour scale from−0.003 a.u. (red) to +0.003 a.u. (blue) and mapped onto an isodensitysurface (ρ = 4 × 10−4 a.u.); hydrogen atoms are omitted for clarity.ConclusionIn this study we have prepared a novel polar aliphatic structure4c based on the 1,1,3,3-tetrafluorocyclohexyl motif. The com-pound was prepared by direct difluorination of the correspond-ing α,α-dimethylated 1,3-diketone with DAST. The presence ofthe two 1,3-diaxial fluorine atoms in structure 4c is responsiblefor the facial polarisation on the cyclohexane ring. We havedemonstrated the intermolecular electrostatic interaction of thepositive non-fluorous face with the π-system of an aromatic ringBeilstein J. Org. Chem. 2016, 12, 2823–2827.2827by single crystal X-ray diffraction and NMR experiments. Ad-ditionally, the polarity of 4c has been calculated by computa-tional optimisations. It follows that functionalised cyclo-hexanes containing the 1,3-di-CF2 motif would offer new possi-bilities for the design of performance molecules extending fromorganic materials research to medicinal chemistry.Supporting InformationSupporting Information File 1Experimental part and NMR spectra of new synthesisedcompounds.[http://www.beilstein-journals.org/bjoc/content/supplementary/1860-5397-12-281-S1.pdf]AcknowledgementsThis work was supported by the Engineering and PhysicalSciences Research Council (EPSRC) and the EuropeanResearch Council (ERC). The authors acknowledge the EPSRCNational Mass Spectrometry Facility (Swansea) and Mrs Caro-line Horsburgh (University of St Andrews) for analytical assis-tance. D.O’H. thanks the Royal Society for a Wolfson ResearchMerit Award.References1. Liu, W.; Huang, X.; Cheng, M.-J.; Neilson, R. J.; Goddard, W. A., III;Groves, J. T. Science 2012, 337, 1322–1325.doi:10.1126/science.12223272. O’Hagan, D. Chem. Soc. 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Organofluorine chemistry : difluoromethylene motifs spaced 1,3 to each other imparts facial polarity to a cyclohexane ring

2,2-Dimethyl-5-phenyl-1,1,3,3-tetrafluororocyclohexane has been prepared and characterised as an example of a facially polarised cyclohexane containing 1,3 related CF2 groups. The dipolar nature of the ring arises from the axial orientation of two of the C–F bonds pointing in the same direction, and set by the chair conformation of the cyclohexane. This electrostatic profile is revealed experimentally both in the solid-state (X-ray) packing of the rings and by solution (NMR) in different solvents. A computationally derived electrostatic profile of this compound is consistent with a more electronegative and a more electropositive face of the cyclohexane ring. This placing of CF2 groups 1,3 to each other in a cyclohexane ring is introduced as a new design strategy which could be applicable to the preparation of polar hydrophobic cyclohexane motifs

Mathew J. Jones

Ricardo Callejo

Alexandra M. Z. Slawin

Michael Bühl

David O'Hagan

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Organofluorine chemistry: Difluoromethylene motifs spaced 1,3 to each other imparts facial polarity to a cyclohexane ring

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Organofluorine chemistry : difluoromethylene motifs spaced 1,3 to each other imparts facial polarity to a cyclohexane ring

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