Can acyclic conformational control be achieved via a sulfur–fluorine gauche effect?

Herein detailed conformational analyses of β-fluorosulfides, -sulfoxides and -sulfones are disclosed, thus extending the scope of the fluorine gauche effect to the 3rd Period (X = SR, SOR, SO2R; φFCCS ≈ 60°).

Controlling rotation about C(sp 3 )-C(sp 3 ) bonds is strategically important in molecular design, not least to determine the spatial positioning of substituents on the component atoms. 1 Of the various acyclic conformational control strategies in common practice, the uorine gauche effect 2 has gained momentum in recent years on account of the minimal steric footprint imposed by this substituent; this oen leads to conformer populations that are inaccessible by traditional steric locking approaches. The counterintuitive preference of the parent 1,2-diuoroethane scaffold to populate the gauche conformer preferentially can be rationalised by invoking hyperconjugative s C-H / s * C-F interactions. This conformational preference is conserved in a number of F-C-C-X systems where X is electron decient (Fig. 1). 3 A simplied donor-acceptor model is didactically valuable in rationalising and predicting conformation, while more detailed analysis reveals that both orbital and electrostatic effects are involved. 4 This is particularly true when X carries a (partial) positive charge, and electrostatic interactions contribute signicantly. The strategic installation of the F-C-C-X motif can lead to predictable molecular topologies on account of the gauche effect (f FCCX z 60 ): the caveat that stereoelectronic effects can be overridden by prevailing steric factors must always be considered.
This approach to molecular design has found widespread application in catalysis, 5 bioactive molecule design, 6 material science 7 and agrochemistry. 8 In the majority of cases, the substituent (X) is a Period 2 atom, typically oxygen or nitrogen. In contrast, the manifestation of this phenomenon in combination with 3rd row elements has been largely ignored despite the importance of sulfur and phosphorus containing compounds in industry and academia. Recent interest in the Fig. 1 The fluorine gauche effect. Selected literature precedence for a potential sulfur-fluorine gauche effect. Lower left: fluorinated deoxy-4 0 -thio pyrimidine nucleosides A and B. 11 Lower right: proneurogenic compound P7C3 and its b-fluorinated sulfone derivative (C). 12 preparation 9 and properties of compounds containing the F-C-C-S(O) n (n ¼ 0, 1 and 2) unit prompted this study.
There is limited structural evidence consistent with the postulated sulfur-uorine gauche effect. In the mid-1980s, Carretero and co-workers reported a NMR study of b-uorinated thioethane derivatives, including various suldes, sulfoxides, sulfones and sulfonium salts. 10 Vicinal coupling constant analysis is consistent with a gauche orientation of the sulfur and uorine atoms. Further evidence of this phenomenon derives from the X-ray structure analyses of uorinated deoxy-4 0 -thiopyrimidine nucleosides such as A and B (Fig. 1), where torsional angles of f FCCS z 80 approach the expected stereoelectronic requirements despite the constraints imposed by the ring. 11 Finally, a recent study by Ready and co-workers identied carbazole P7C3 as displaying potent neuroprotective activity. 12 A lead structure in this investigation is derivative C, containing the b-uorosulfone unit. Herein we report a combined experimental and computational study of the uorine-sulfur gauche effect with specic emphasis on suldes, sulfoxides and sulfones.
Our recent interest in the uorine gauche effect in pyrrolidine organocatalysts (X ¼ N) 5a,b,f led us to explore tetrahydrothiophene derivatives 2, 3 and 4 (Scheme 1) as scaffolds for this study. It was envisaged that the diffuse nature of sulfur orbitals, and the polarised nature of the oxidised forms (e.g., S + -O À , SO 2 ) would generate hyperconjugative and/or chargedipole interactions that might manifest themselves in diagnostic conformations. The heterocycles can exist as synclinalendo and synclinal-exo conformers that can easily be distinguished by vicinal ( 3 J) coupling constant analysis. Structures 2, 3 and 4 were prepared from the intermediate 1 (Scheme 1). 13 Direct deoxyuorination of 1 was facile and furnished 2 in 54% yield. This is noteworthy given the dearth of information of uorination of this substrate class. Subsequent oxidation to the corresponding sulfoxide 3 proceeded smoothly in 68% yield and with excellent levels of diastereoselectivity (97 : 3), giving a rst insight into the possible role of uorine in inuencing the conformation of such systems. Finally, upon exposure to excess mCPBA, the sulfone 4 was generated in 85% yield.

X-ray crystal structure analysis
Single crystals suitable for X-ray analysis were obtained in all cases (Fig. 2). 14 Each structure exhibited a gauche preference, favouring the synclincal-endo conformation (2, 3, 4, f FCCS ¼ À62.07 , À60.89 , À62.37 , respectively; Table 1). Common to all structures is an unusually long S1-C4 bond length as compared to the S1-C1 bond length (Table 1, Dd z 0.027Å, 0.039Å, 0.053Å, for 2, 3 and 4, respectively). To place this observation in context with comparable sulfur containing structures, a selection of C-S bond lengths are provided in Table  1 (right column). 15 This may be noteworthy in view of the importance of fractional bonds in translating small changes in ground state structures to reactivity. 16 Importantly, the vicinal C-H and C-F bonds are antiperiplanar (179 , À177 , 178.15 ) thus allowing for stabilising hyperconjugative interactions (s C-H / s * C-F ), with C-F bond lengths of 1.41Å, 1.42Å and 1.42Å, for 2, 3 and 4 respectively. The solid state structure of sulfoxide 3, prepared by diastereoselective oxidation, reveals a conformation in which the C-F and S-O dipoles are minimised.
To ensure that the gauche orientation observed in the tetrahydrothiophene derivatives 2, 3 and 4 is not a consequence of unfavourable non-bonding interactions with the ring, a sterically less demanding, linear system was synthesised for comparison. Reaction of 4-nitrothiophenol with tosylated 2-uoroethanol 17 afforded the linear sulde 5; this was subsequently converted to sulfoxide 6 and sulfone 7 (Scheme 2). It was possible to grow crystals of compounds 6 and 7 that were suitable for X-ray analysis. 14 In both cases, the C-S and C-F bonds were oriented in the expected gauche arrangement (6 and 7, f FCCS ¼ À55.87 , À68.12 , respectively; Table 1). These conformations allow for s C-H / s * C-F interactions, again indicating that this effect likely is due in part to hyperconjugative stabilisation. Consistent with structure 3 (Fig. 2, centre), the X-ray analysis of sulfoxide 6 reveals a conformation where the C-F and S-O dipoles oppose each other. In sulfone 7, the C-F bond adopts a gauche arrangement that circumvents interaction with the SO 2 unit.

NMR solution phase conformational analysis
To complement the solid state investigation, a solution phase NMR conformer population analysis of the cyclic compounds was performed. 18 Assuming that only staggered conformers with torsion angles of À60 (Àgauche), 60 (+gauche) and 180 (anti) contribute signicantly to the population in solution phase, the measured coupling constant hJi can be described by the equation hJi ¼ x Àg J Àg + x +g J +g + x a J a . Furthermore, the approximation that the dependency of J is symmetrical about 0 (ref. 19) renders the following simplication valid: J Àg ¼ J +g ¼ J g . Hence, the molar fraction of the anti conformer can be determined according to the following expression: x a ¼ (hJi À J g )/(J a À J g ). 20 Whilst literature values for 3 J CF are available (J g ¼ 1.2 Hz, J a ¼ 11.2 Hz) 21 the related 3 J HF can be calculated based on a modied Karplus equation. 22 Inserting the measured 3 J coupling constants (Table 2) allows for the determination of combined populations of the Àgauche and +gauche conformers of >80% in all cases. Comparison of the 3 J HF Scheme 2 Syntheses and X-ray crystal structure analyses 14 of linear sulfoxide 6 and sulfone 7. (a) mCPBA (1.0 eq.), CH 2 Cl 2 , 0 C to rt, 26 h; (b) mCPBA (3.0 eq.), CH 2 Cl 2 , 0 C to rt, 17 h. Thermal ellipsoids shown at 50% probability level.  4 and 7, respectively). These analyses reveal that the major solution phase conformers closely resemble the solid state structures determined by crystallography, and are fully consistent with the notion of a sulfur-uorine gauche effect.

DFT conformational analysis
In order to quantify the observed conformational preferences using DFT, a series of structures containing the key F-C-C-S(O) n unit (n ¼ 0, 1 and 2) were optimised at the B3LYP 24 /6-311+G(d,p) 25 level of theory. Solvation by dichloromethane was taken into account using the integral equation formalism polarizable continuum model (IEFPCM). 26 Dichloromethane was chosen to ensure consistency with the NMR solution phase conformational analysis. The choice of basis set was based on a previous computational study of the gauche effect in a-X-b-uoro-ethane derivatives (X ¼ F, NR, OR, CR) by O'Hagan and co-workers. 4c All computations were performed using Gaussian09. 27 Free energy corrections were calculated using Truhlar's quasi-harmonic approximation. 28 The lowest energy conformers of 1,2-diuoroethane (8) and the corresponding (2-uoroethyl)-(methyl)-derivatives (sulde ¼ 9, sulfoxide ¼ 10, sulfone ¼ 11) were investigated (Table 3). Additionally, the C a -C b bond rotational proles (step size ¼ 5 , 72 steps, B3LYP/6-  311+G(d,p) in vacuum) of 9-11, with both the CSCC anti and gauche conformations, were calculated and compared to the rotational prole of 1,2-diuoroethane (8) (Fig. 3, top). This analysis conrmed that the well known gauche preference of 1,2-diuoroethane (8) is also inherent to the linear sulfoxide and sulfone derivatives (DG anti/gauche ¼ 1.9, 1.0, and 1.6 kcal mol À1 , for 8, 10 and 11 respectively). However, the sulde derivative 9 displays a slight preference for the anti conformation (DG gauche/anti ¼ 0.5 kcal mol À1 ); this is at variance with the X-ray structures of 2 (Fig. 2). As expected, the gauche conformation appears to be more pronounced in structures bearing a more electropositive vicinal sulfur atom (S + -O À , SO 2 ).
As a quantitative measurement for this effect, the Mulliken atomic charges (Q S ) of the sulfur atom in each of the conformers studied were calculated. These are listed in Table 3 (right). Interestingly, comparison of the energy minima in compounds 9-11 displayed some variation with respect to the CSCC chain. Whereas the sulde 9 and the sulfone 11 position the two alkylgroups gauche to each other in the lowest lying minima, the sulfoxide 10 preferentially orients the groups anti (Fig. 3).
A computational analysis of the linear 4-nitrothiophenol derived systems 5-7 (Table 4) revealed similar trends to those observed with the ethane derivatives (Table 3, also see Scheme 2). The sulde derivative 5 displayed no signicant preference for the gauche or anti conformation (5, DG gauche/anti ¼ 0.1 kcal mol À1 ), whilst the sulfoxide and sulfone derivatives both exhibited a gauche preference (6 and 7, DG anti/anti ¼ 1.3 and 1.3 kcal mol À1 , respectively).
The three possible rotamers of cyclic compounds 2, 3 and 4 were also investigated (Table 5). For the sulfoxide derivative 3 both diastereoisomers (oxygen anti 3a, and syn 3b) were Table 4 Calculated relative conformational energies and torsion angle of (2-fluoroethyl) (4-nitrophenyl)-sulfide (5), -sulfoxide (6), and -sulfone (7). Results obtained with B3LYP/6-311+G(d,p)/IEFPCM. Only the gauche conformer is shown for simplicity  considered, although only the anti diastereoisomer was isolated following oxidation. In this case, the syn conformer is signicantly higher in energy than the anti (DG syn/anti ¼ 3.7 kcal mol À1 ). The sulde (2) again shows the smallest energetic difference between the lowest lying anti and syn conformations, consistent with the results for the acyclic derivatives. Contrary to the other structures investigated, this cyclic derivative exhibits a signicant preference for the gauche conformation (DG anti/gauche ¼ 1.7 kcal mol À1 ). For the derivatives bearing a more electron decient sulfur atom, the gauche preference is more pronounced (3 and 4, DG anti/gauche ¼ 2.4 and 2.9 kcal mol À1 , respectively). The synclinal-endo conformation is signicantly lower in energy than the synclinal-exo conformation, and the latter is higher in energy than the anti. The optimised structures displayed the same lengthening of the S1-C4 bond as was observed by crystallography. The global energy minima for compounds 2, 3 and 4 are shown in Fig. 4 and closely match the corresponding X-ray structures (Fig. 2).

Conclusions
Computation and experiment conrm that the F-C-C-S motif has an intrinsic gauche conformational preference. Conformational analysis in both solid and solution phase conrmed that the C-F bond aligns anti to a vicinal C-H bond, reasonably to allow for stabilising hyperconjugative interactions of the type s C-H / s * C-F . The DG gauche/anti value is larger when the sulfur centre is more electron decient; this is especially pronounced in sulfoxides. Computational analyses indicate that the conformational preference is not solely due to overall molecular dipole minimisation (Table 3, 4 and 5, right column). This study extends the well-known gauche effect to 3 rd Period substituents, and validates the notion that the F-C-C-S(O) n unit may be strategically embedded into functional scaffolds to achieve acyclic conformational control.