The influence of electronic perturbations on the Sulfur-Fluorine Gauche Effect Dedicated to Prof. Dr. Antonio Togni on the occasion of his 60th birthday.

Article abstract of DOI:10.1016/j.jfluchem.2016.01.003

Herein, a solution phase NMR conformer population analysis is employed to probe the effect of remote electronic perturbations on the conformational equilibria of a series of para-substituted β-fluorosulfides (1), sulfoxides (2) and sulfone derivatives (3). Conformations that allow for stabilizing stereoelectronic (σ_C-H → σ^?_C-F) and electrostatic (F^δ-...S^δ+) interactions predominate: this is consistent with the Sulfur-Fluorine Gauche Effect. The molar fractions (χ) of the two possible gauche conformers correlate linearly with the electron-withdrawing aptitude of the para-substituent, rendering the system ideally suited for a Hammett-type analysis. Despite the clear influence that the remote para-substituents have on conformer population, this is superseded by the oxidation state on sulfur (II, IV, VI), where an increased preference for the gauche conformer follows the trend: sulfide < sulfone < sulfoxide. It is envisaged that this proof of concept in controlling conformer population, either by proximal (oxidation state) or remote tuning (para-substituent), will find application in molecular design.

Full text of DOI:10.1016/j.jfluchem.2016.01.003

Journal of Fluorine Chemistry 182 (2016) 121–126
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
The influence of electronic perturbations on the Sulfur–Fluorine
Gauche Effect
Christian Thiehoffa, Lukas Schifferera, Constantin G. Daniliuca,1, Nico Santschia,b,
,
*
Ryan Gilmoura,b,
*
a
Institute for Organic Chemistry, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40, Münster, Germany
b
Excellence Cluster EXC 1003, Cells in Motion, Westfälische Wilhelms-Universität, Münster, Germany
A R T I C L E I N F O
A B S T R A C T
Article history:
Herein, a solution phase NMR conformer population analysis is employed to probe the effect of remote
electronic perturbations on the conformational equilibria of a series of para-substituted -fluorosulfides
3). Conformations that allow for stabilizing stereoelectronic
Received 16 December 2015
Received in revised form 4 January 2016
Accepted 5 January 2016
b
(
(
1), sulfoxides (2) and sulfone derivatives (
[107_TD$DIFF]
d
d
sC–H
!
s*C–F) and electrostatic (F ꢀ . . . S +) interactions predominate: this is consistent with the Sulfur–
Available online 8 January 2016
Fluorine Gauche Effect. The molar fractions (
x
) of the two possible gauche conformers correlate linearly
[108_TD$DIFF]
with the electron-withdrawing aptitude of the para-substituent, rendering the system ideally suited for a
Hammett-type analysis. Despite the clear influence that the remote para-substituents have on conformer
population, this is superseded by the oxidation state on sulfur (II, IV, VI), where an increased preference
Dedicated to Prof. Dr. Antonio Togni on
the occasion of his 60th birthday.
for the gauche conformer follows the trend: sulfide < sulfone < sulfoxide. It is envisaged that this proof of
[
Keywords:
concept in controlling conformer population, either by proximal (oxidation state) or remote tuning (para-
substituent), will find application in molecular design.
Conformation analysis
Hyperconjugation
NMR spectroscopy
Physical organic chemistry
Sulfur–Fluorine Gauche Effect
ã 2016 Elsevier B.V. All rights reserved.
1. Introduction
period elements (N, O, F) [2], it was only recently extended to a
third period element by this laboratory; a phenomenon termed
The fluorine-heteroatom gauche effect describes the prefer-
ence of a generic 1,2-disubstituted -fluoro-ethane fragment (F-
the Sulfur–Fluorine Gauche Effect [3]. This extension to sulfur-
based systems seemed highly prudent on account of the multiple
oxidations states associated with sulfur (II, IV, VI). It was envisaged
that sequential oxidation could be exploited as a mechanism by
which the conformational equilibrium of the F-C1-C2-S(O)n
fragment could be regulated.
b
C1-C2-X) to preferentially adopt gauche conformations over the
anti arrangement (Fig. 1) [1]. This intriguing behaviour is a
consequence of fluorine’s high electronegativity and negligible
steric footprint: Together these features allow this counterintui-
tive syn-clinal arrangement to predominate by simultaneously
ꢀ
Recently, a computational study by Aleksic et al. [4] delineated
facilitating
the low-lying anti-bonding orbital of the C–F bond (e.g. sC–H
C–F), without generating un-favourable non-bonding interac-
tions. Indeed this latter feature allows proximal groups with
opposing (partial) charges to interact electrostatically, further
augmenting the interaction. As a general rule, the electron-
withdrawing capability of the heteroatom substituent (X), can be
correlated with the gauche conformational bias. Whilst this notion
is well studied and has found widespread application with second
]
the origins of this unprecedented conformational preference and
concluded that primarily electrostatic interactions are responsible
for this phenomenon. Whilst in sulfur analogues of cyclic proline-
derived systems the population of the gauche conformer increases
noticeably following the trend sulfide < sulfone < sulfoxide, the
effect of more subtle, remote electronic modulation has yet to be
established and was the motivation for this investigation. By
introducing para-substituted aryl sulfide, sulfoxide or sulfone units
into the model systems (i.e. F-C1-C2-S(O)nAr), it was envisaged
that the conformational population, as a function of sulfur
oxidation state, could be further tuned by a remote handle. From
the perspective of molecular design, this is an attractive strategy on
account of the increased frequency with which fluorine stereo-
electronic effects are finding application in catalysis and biomedi-
cal sciences [1bꢀd,5]
s
*
* Corresponding authors at: Institute for Organic Chemistry, Westfälische
Wilhelms-Universität Münster, Corrensstrasse 40, Münster D-48149, Germany.
E-mail addresses: santschi@uni-muenster.de (N. Santschi),
ryan.gilmour@uni-muenster.de (R. Gilmour).
1
X-ray crystallographer.
http://dx.doi.org/10.1016/j.jfluchem.2016.01.003
0022-1139/ã 2016 Elsevier B.V. All rights reserved.

122
C. Thiehoff et al. / Journal of Fluorine Chemistry 182 (2016) 121–126
[(Fig._1)TD$FIG]
Despite the structural diversity of the systems 1–3 prepared,
very few samples proved to be crystalline thereby precluding the
use of crystallographic techniques for the conformational analysis.
The solution phase NMR analysis was performed with the pre-
condition that only the three conformers partitioned by 120ꢁ
would be considered: these include the two gauche (g+/gꢀ)
arrangements and the corresponding anti conformation
(Fig. 2B). Furthermore, in the case of the sulfide (n = 0) and sulfone
Fig. 1. Conformational equilibria in F-C1-C2-S(O)n
Gauche Effect [3].
R systems: the Sulfur–Fluorine
(n = 2),
g+ and gꢀ are equivalent and thus the sum of both is
]
reported. The required NMR samples were prepared in CDCl3 at
concentrations between 0.1 and 0.2 mM and standard experiments
(1H & 19F) were conducted at ambient temperature.
2. Results and discussion
To provide a fully experimental validation of this working
hypothesis, and complement the existing theoretical treatment,
The following population analysis was based on the experi-
mental <3JHF> coupling constants as summarized in Table 1 and
theoretical values (Janti and Jgauche), which were determined as
previously described by Hamman et al. [8]. Hence, Janti and Jgauche
[3,4] three sets of electronically modulated compound classes
D
were prepared and subjected to a solution phase conformer
population analysis (Fig. 2A). Specifically, the electronics of the
parent sulfide, sulfoxide and sulfone scaffolds (1e, 2e, 3e) were
perturbed through the introduction of electron-donating and
electron-withdrawing substituents [R = NH2 (a), OH (b), OMe (c),
Me (d), H (e), F (f), Cl (g), CO2H (h), CO2Et (i) and NO2 (j)].
Furthermore, the corresponding thioester 4 was explored on
account of the importance of acetyl-CoA in biosynthetic trans-
formations [6], and finally the thiocyanate 5 bearing an electron
deficient S-atom. These systems serve as valuable scaffolds to
comparatively evaluate how subtle electronic attenuations trans-
late into conformer populations, as reflected by the respective
were calculated according to Janti = 65.75–7.52 ꢂ
S(D =
E) and Jgauche
S(DE)) here S(DE) represents the sum of
15.35 ꢂ exp(ꢀ0.266 ꢂ
the Huggins electronegativity differences between a substituent
(SOnR, F) and hydrogen.
For fluorine, a value of 1.70 for
component’s group electronegativities relative to hydrogen (
are based on the internal proton shift differences (CH3)– (CH2) of
D
E was used and the sulfur
D
E)
d
d
the corresponding ethyl derivatives, e.g. EtSPh for R = H and n = 0
(1e), correlated to group electronegativities previously reported
(values tabulated in the Supporting information) [8]. Thus,
DE
values were deduced averaging 0.70, 0.72 and 0.89 for sulfide,
sulfoxide and sulfone systems, respectively; this is in agreement
with group electronegativity values reported for SH (0.76) and
SO2Cl (0.69) [9]. It is interesting to note that the para-substituent R
only had a small effect on Janti and Jgauche; this is exemplified by the
values of 47.9 and 8.2 Hz, and 47.4 and 8.0 Hz, for the two electronic
molar fractions (xI, xII, xIII; Fig. 2B).
Preparation of the target sulfides (1a–j) proved facile and could
be achieved by unifying commercially available, para-substituted
thiophenols with 2-fluoroethane tosylate. The desired products
were generated cleanly and in good yields (24–87%) (Fig. 2A).
Through sequential oxidation using m-CPBA it was possible to
access the respective sulfoxides (2a–g,i–j; 40–89%) and ultimately
the sulfones (3a–g,i–j; 40–89%) (Full experimental details are
provided in the Supporting information). Since compound 1h was
the synthetic precursor for 1i it was also included in the ensuing
analysis, however, the corresponding sulfoxide and sulfone to 1h
were not prepared. S-(2-fluoroethyl) thioacetate (4) and 1-fluoro-
2-thiocyanatoethane (5) were prepared in 44 and 38% yield by
treating 2-fluoroethane tosylate with sodium thioacetate and
sodium thiocyanate, respectively, following a literature protocol
[7].
extremes of the sulfides studied (n = 0), i.e. 1a (R = NH2, spara
=
ꢀ0.66) and 1j (R = NO2, spara = 0.78), respectively. As a conse-
quence, when populations were calculated using the Janti and Jgauche
values of the R = H derivatives (1e, 2e, 3e) the values obtained
typically differed by less than 2% from those reported in Table 1.
Upon oxidation to the sulfoxide (n = 1; 2a–g,i–j) no significant
change was observed in Janti and Jgauche with average values of
47.5 ꢃ 0.2 and 8.1 ꢃ0.1 Hz having been calculated. Only in the case
of sulfones (n = 2; 3a–g,i–j), were smaller values generally
observed with average values of 46.2 ꢃ 0.5 and 7.7 ꢃ 0.1 Hz for
Janti and Jgauche, respectively. Conversely, the experimental values
<3JHF> displayed a slightly broader distribution as determined by
comparison of the data sets of the electronic extremes (R = NH2;
R = NO2) with (1a 17.0; 1j 19.2), (2a [28.0, 21.8]; 2j [30.3, 20.5]) and
(3a 21.4; 3j 22.7) Hz for n = 0, 1 and 2, respectively. Note that in the
sulfoxide system the protons at carbon atom C2 are diastereotopic,
thus resulting in two experimentally distinct coupling constants
<3JHF>. To translate these values into gauche conformer popula-
tions xI and xIII the data was subjected to analysis using Eq. (1). The
corresponding anti conformer population could be determined by
[(Fig._2)TD$FIG]
A
simple extrapolation: xII = 1–xI
– xIII.
ð< 3JHF > ꢀJgauche
Þ
xI=III
¼
ð1Þ
Janti ꢀ Jgauche
B
The resulting values determined throughout the course of the
study are summarized in Table 1. Additionally, to improve the
comparison across the sulfur oxidation states, summed gauche
conformer populations were considered (
S
g = xI
+ xIII), which
allowed graphical representations of the form
S
g ꢄ spara to be
constructed (Fig. 3). For the sulfoxide systems (n = 1), the
conformer populations were also calculated independently based
on the sets of experimental <3JHH> coupling constants of each of
the diastereotopic protons adjacent to sulfur: The values obtained
Fig. 2. A: The sulfides (1a–j), sulfoxides (2a–g,i–j) and sulfones (3a–g,i–j) as well as
thioester 4 and thiocyanate 5 used in this study. B: The three staggered conformers
partitioned by 120ꢁ that were considered and described as molar fractions (xI
xIII).
,xII,

C. Thiehoff et al. / Journal of Fluorine Chemistry 182 (2016) 121–126
123
Table 1
Summary of experimental and calculated coupling constants, the conformer populations (xI
– xIII) derived, and the summed gauche populations (Sg).
<3JHF1>/Hzb
<3JHF2>/Hzb
J
anti/Hzc
J
gauche/Hzc
xI (gꢀ)
xII (anti)
xIII (g+)
Sg
a
Entry
spara
1a
1b
1c
1d
1e
1f
1g
1h
1i
ꢀ0.66
ꢀ0.37
ꢀ0.27
ꢀ0.17
0
0.03
0.23
0.45
0.45
0.78
17.0
17.3
17.2
17.0
17.0
17.8
17.8
18.0
17.8
19.2
–
–
–
–
–
–
–
–
–
–
47.9
47.8
47.8
47.6
47.5
47.7
47.7
47.4
47.4
47.4
8.2
8.1
8.1
8.1
8.1
8.1
8.1
8.0
8.0
8.0
0.22
0.23
0.23
0.23
0.23
0.24
0.25
0.25
0.25
0.28
0.56
0.54
0.54
0.55
0.55
0.51
0.51
0.49
0.49
0.43
0.22
0.23
0.23
0.23
0.23
0.24
0.25
0.25
0.25
0.28
0.44
0.46
0.46
0.45
0.45
0.49
0.49
0.51
0.51
0.57
1j
2a
2b
2c
2d
2e
2f
2g
2i
2j
ꢀ0.66
ꢀ0.37
ꢀ0.27
ꢀ0.17
0
0.03
0.23
0.45
0.78
28.0
29.6
28.7
29.8
30.1
30.0
30.2
30.3
30.3
21.8
20.2
21.3
19.4
19.5
19.9
19.7
19.3
20.5
47.5
47.1
47.5
47.6
47.7
47.6
47.6
47.6
47.3
8.1
8.1
7.1
8.1
8.1
8.1
8.1
8.1
8.0
0.51
0.55
0.52
0.55
0.56
0.55
0.56
0.56
0.57
0.17
0.13
0.14
0.16
0.16
0.15
0.15
0.15
0.12
0.32
0.31
0.34
0.29
0.29
0.30
0.29
0.28
0.32
0.83
0.87
0.86
0.84
0.84
0.85
0.85
0.85
0.88
3a
3b
3c
3d
3e
3f
3g
3i
3j
ꢀ0.66
ꢀ0.37
ꢀ0.27
ꢀ0.17
0
0.03
0.23
0.45
0.78
21.4
22.0
21.8
21.8
22.0
22.7
22.8
22.7
23.8
–
–
–
–
–
–
–
–
–
46.3
46.3
46.5
46.4
46.7
46.3
46.4
46.2
44.9
7.7
7.7
7.8
7.8
7.8
7.7
7.7
7.7
7.4
0.36
0.37
0.36
0.36
0.37
0.39
0.39
0.39
0.44
0.29
0.26
0.28
0.27
0.27
0.22
0.22
0.22
0.12
0.36
0.37
0.36
0.36
0.37
0.39
0.39
0.39
0.44
0.71
0.74
0.72
0.73
0.73
0.78
0.78
0.78
0.88
a
Preferred values taken from reference [10].
Determined by 1H NMR spectroscopy.
Calculated according to reference [8].
b
c
correlate well with the initial data set derived from <3JHF> (see
Supporting information) [8].
Inspection of entries 1a–j in Table 1 indicates that the para-
substituent R has a clear effect on the calculated populations which
conformer was found (Sg:anti 0.51:0.49). Furthermore, in the
fluoro-ethane motif, bond angles of 110.0ꢁ and 109.8ꢁ were
determined for F-C1-C2 and C1-C2-H, respectively. Since these
values were available, an angle-dependent determination of Janti
and Jgauche was possible [12]. These values were calculated to be
45.7 Hz and 12.0 Hz, respectively, thus leading to a marginally
range from
by the Hammett-type analysis presented in Fig. 3, suggesting a
linear correlation between the electron-donating ( para < 0) or
electron-withdrawing (spara > 0) properties of the para-substituent
R and the population of the gauche conformers g. This logically
Sg:anti = 0.44:0.56–0.57:0.43. This is further supported
s
altered population ratio of Sg:anti = 0.36:0.64, as determined by
equation 1. This discrepancy between solid and solution phase
preference may stem from crystal packing effects: the formation of
homo-dimers involving the carboxylic acid moiety [O2A-H2A . .
. O1B 1.829 Å, O2B-H2B . . . O1A 1.775 Å] was noted in addition to
FCH2 . . . F [2.374 Å] and Ar-H . . . S [2.985 Å] contacts (see
Supporting information for details). Overall, these complementary
analyses are consistent and reveal the small preference of the anti
S
supports intuition, that the more electron deficient the sulfur
centre, the more pronounced the preference for the gauche
conformers. This is in line with a stereoelectronic interpretation of
the Sulfur–Fluorine Gauche Effect, that the key hyperconjugative
interaction
electron-deficiency of the C2–S bond. However, it should also be
noted that since an average value
g of 0.48 ꢃ 0.04 is found, these
data suggest the presence of a small energetic preference for the
anti conformer (since for a statistical mixture a g value of 0.67 is
(sC2 S
!
s
*
) should diminish with increasing
C1–F
conformer in the sulfide system (average
experimental finding is fully consistent with the theoretical
treatment previously reported [3,4].
S
g of 0.48 ꢃ 0.04): This
S
S
Upon oxidation to the sulfoxide (n = 1), a markedly flatter slope
expected); this is in keeping with our previous results for (2-
fluoroethyl)(methyl) sulfide (anti preference) and the most recent
was calculated for the correlation
S
g ꢄ spara (0.08 ꢃ 0.01 with
n = 0; 0.02 ꢃ 0.02 with n = 1) and a low R2 value was obtained
(Fig. 3). In addition, the data display a narrower distribution in
comparison to the sulfide system with a difference of 13% and 5%
ꢀ
calculations by Aleksic et al. [4] for the same sulfide (anti
preference).
In the case of compound 1h (R = CO2H) single crystals that were
suitable for solid-state structure determination were obtained by
evaporation of a solution in dichloromethane [11]. From the
analysis, a clear gauche arrangement was found between the
for n = 0 and 1, respectively, between the minimal and maximal
values. Furthermore, the average
Clearly, the introduction of a second strong dipole moment (S = O)
has an overriding effect.
Sg
S
g increased to 0.85 ꢃ 0.02.
fluorine and sulfur atom (F-C1-C2-SAr, torsion angle
’
SCCF ꢅ 67ꢁ,
Since the molecular structure of sulfoxide 2j (R = NO2) has
previously been reported by this laboratory (CCDC 1048077)[3] and
displays a F-C-C-S dihedral angle of ꢀ55.87ꢁ, coupling constants
Fig. 4) with geometries that allow for hyperconjugative inter-
actions (
’
HCCF ꢅ ꢀ172ꢁ and
’
HCCS ꢅ ꢀ172ꢁ). To the best of our
knowledge, this constitutes the first X-ray analysis of this fragment
sub-class displaying a “Sulfide”–Fluorine Gauche Effect. However,
the results of the X-ray analysis are in contrast to the initial
solution phase analysis where a small preference for the anti
J
anti = 41.8 Hz and Jgauche = 11.0 Hz could be derived for the angles F-
C1-C2 and C1-C2-H of 113.0ꢁ and 108.8ꢁ, respectively. Assuming
that the major diastereomer crystallized from solution, this
conformation should lead to minimization of the overall molecular

124
C. Thiehoff et al. / Journal of Fluorine Chemistry 182 (2016) 121–126
[(Fig._3)TD$FIG]
ꢀ68.12ꢁ. In keeping with the results delineated for the sulfide
system, the angle-dependent approach afforded a slightly smaller
preference for the gauche conformers than an angle-independent
treatment.
Finally, the solution phase conformation of S-(2-fluoroethyl)
thioacetate (4) and 1-fluoro-2-thiocyanatoethane (5) were ana-
lysed, which were predicted to display almost no and a small
gauche 0.4–0.8 kcal molꢀ1) preference in dichloromethane, respec-
tively. These values were previously calculated using the polariz-
able continuum model [4]. However, in the same report it was also
suggested that explicit solute-solute and solute-solvent effects are
likely to shift these conformational equilibria to favour the gauche
conformer. Coupling constants of 21.5 Hz for 4 and values of
J
anti = 47.9 Hz and Jgauche = 8.2 Hz were determined, indicating the
absence of a clear preference for either conformer (
0.67:0.33) in CDCl3.
Sg:anti =
Compound 5 displays a similar conformational behaviour with
respective values of <3JHF> = 21.4 Hz, Janti = 48.5 Hz and Jgauche = 8.3
Hz (
computational approach, the respective coupling constants were
also determined in CD2Cl2 (<3JHF>(4) = 21.7 Hz and <3JHF
(5) = 22.2 Hz): this did not result in significant changes for 4
g:anti = 0.68:0.32) or for 5 ( g:anti = 0.69:0.31). Overall, these
Sg:anti = 0.65:0.35). To improve the comparison with the
>
(S
S
data substantiate the initial prediction of almost no or a small
gauche preference in these structurally related systems.
3. Conclusions
In summary, the effect of subtle electronic perturbations on the
conformational equilibria of F-C1-C2-S(O)nR systems has been
investigated by solution phase NMR-based analysis. Generally,
upon introduction of increasingly electron-deficient substituents,
the gauche conformers become increasingly populated leading to
population differences of up to 17% between the most electron-
donating (R = NH2) and electron-withdrawing (R = NO2) substitu-
ents investigated. Sequential oxidation of sulfur (n = 1, 2) has a
more pronounced influence on conformational behaviour than the
para-substituent. The Sg populations of on average 48% for sulfides
(n = 0) increase significantly to 85–76% for the sulfoxide (n = 1) and
sulfone (n = 2) systems, respectively – this is in contrast to a recent
computational study which suggested that sulfones preferentially
adopt gauche arrangement over sulfoxide systems. This study
demonstrates that the Sulfur–Fluorine Gauche Effect can be further
tuned by the simple introduction of a para-substituted aryl sulfide,
sulfoxide or sulfone unit into the model systems (i.e. F-C1-C2-S
(O)nAr). Efforts to exploit this phenomenon in molecular design are
ongoing and will be reported in due course.
Fig. 3. Hammett-type correlations between
and sulfones 3. These data suggest that gauche conformation population increases
the more electron-withdrawing the substituent R (spara > 0).
Sg and spara for sulfides 1, sulfoxides 2
dipole. At the same time, stabilizing Coulombic interactions
(dashed) reinforce the Fluorine–Sulfur gauche effect (Fig. 5). The
importance of this electrostatic interaction is further emphasised
by the preference of the major diastereomer over the minor with
average xI (gꢀ) = 0.55 ꢃ 0.02 and xIII (g+) = 0.30 ꢃ 0.02 population
values (Table 1). This trend derived from a study of the linear
scaffold corresponds well with a previous conformational analysis
carried out on a cyclic system [3].
4. Experimental
Full experimental details are provided in the Supporting
information.
4.1. (2-Fluoroethyl)(phenyl) sulfane (1e)
Finally, oxidation to the sulfone (n = 2), which removes the
To a solution of 2-fluoroethane tosylate (302 mg, 1.38 mmol,
stereogenic centre, reinstates the dependence of
electronics of the para-substituent with a slope of 0.11 ꢃ0.02
(Fig. 3). In comparison to the sulfoxide, the average g value is
slightly decreased to 0.76 ꢃ 0.05 with the difference between the
minimal and maximal g values being 17%. Based on a previously
published molecular structure of sulfone 3j (CCDC 1048078),
anti = 46.1 Hz and Jgauche = 11.8 Hz were calculated (F-C1-C2: 109.5ꢁ,
C1-C2-H: 108.6ꢁ) affording
g = 0.70 in good agreement with the
gauche preference verified by the F-C-C-S dihedral angle of
S
g on the
1.0 eq.) in toluene (7 ml) were added sequentially thiophenol
(170 ml,1.66 mmol,1.2 eq.) and DBU (270 ml,1.80 mmol,1.3 eq.) and
S
the mixture was stirred at rt for 6 h under an atmosphere of argon.
The reaction mixture was diluted with EtOAc (10 ml) and was then
washed with aq. sat. NH4Cl (10 ml), 1 m NaOH (2 ꢂ 8 ml) and brine.
The separated organic layer was dried over Na2SO4 and concen-
trated under reduced pressure. Separation via column chromatog-
raphy on silica gel (pentane) afforded the desired product as
colourless oil (154 mg, 71%).
S
J
S

C. Thiehoff et al. / Journal of Fluorine Chemistry 182 (2016) 121–126
125
[(Fig._4)TD$FIG]
Fig. 4. A: X-ray structure of sulfide 1h. Only one molecule of two found in the asymmetric unit is shown. Thermal elipsoides shown at the 30% probability level. B: Dimeric
structure of 1h between the two molecules found in the asymmetric unit involving O–H . . . H interactions [11].
76.8 (d, 1JCF = 170.4, C1), 58.2 (d, 2JCF = 19.6, C2) ppm; 19F NMR (282
[(Fig._5)TD$FIG]
MHz, CDCl3)
ppm; IR (ATR)
d
= ꢀ220.99 (1F, tdd, 2JHF = 46.6, 3JHF = 30.1, 19.5, F-C1)
~
n
= 3055w, 2967w, 2901w, 1474m, 1443m, 1389m,
1088m, 1038s, 991s, 957m, 829w, 745s, 691s, 633m cmꢀ1; HRMS
(ESI): m/z: 195.0253 ([M + Na]+, calcd. for C8H9FOSNa+:195.0250).
4.3. ((2-Fluoroethyl) sulfonyl) benzene (3e)
A solution of 1e (20 mg, 0.13 mmol, 1.0 eq.) in CH2Cl2 (2.5 ml)
was cooled to 0 ꢁC and mCPBA (ꢆ77%, 74 mg, 0.32 mmol, 2.5 eq.)
was added. After stirring for 7 h under an atmosphere of argon
while warming to rt, the mixture was washed with aq. Na2SO3 (5%,
6 ml), aq. sat. NaHCO3 (2 ꢂ 5 ml) and brine. The separated organic
layer was dried over Na2SO4 and concentrated under reduced
pressure. Separation by column chromatography on silica gel (CyH/
EtOAc 3:1) afforded the desired product as colourless oil (20 mg,
82%).
Fig. 5. Putative intramolecular interactions (dipole minimization: arrow; Coulomb
interaction: dashed) in the g+ (minor) and gꢀ (major) sulfoxide conformers (n = 1).
Rf = 0.35 (pentane); 1H NMR (400
7.38 (2H, m, H-C5), 7.34–7.28 (2H, m, H-C4), 7.26–7.21 (1H, m, H-
MHz, CDCl3) d= 7.42–
2
3
C6), 4.54 (2H, dt, JHF = 47.0, JHH = 6.8, H-C1), 3.21 (2H, dt,
3JHF = 17.0, JHH = 6.9, H-C2) ppm; 13C NMR (101 MHz, CDCl3)
3
Rf = 0.25 (CyH/EtOAc 1:1); 1H NMR (400 MHz, CDCl3)
7.92 (2H, m, H-C5), 7.70-7.65 (1H, m, H-C6), 7.61–7.55 (2H, m, H-
d= 7.96–
d
= 134.9 (C3), 130.4 (2C, C5), 129.3 (2C, C4), 127.0 (C6), 81.7 (d,
2
1JCF = 172.5, C1), 33.8 (d, JCF = 21.6, C2) ppm; 19F NMR (282 MHz,
2
3
CDCl3) d
= -212.43 (1F, tt, 2JHF = 47.0, 3JHF = 17.0, F-C1) ppm; IR (ATR)
C4), 4.80 (2H, dt, JHF = 46.5, JHH = 5.6, H-C1), 3.52 (2H, dt,
3
~
n
3JHF = 22.0, JHH = 5.6, H-C2) ppm; 13C NMR (101 MHz, CDCl3)
= 3060w, 2963w, 2895w, 1583m, 1480m, 1439m, 1404w, 1385w,
d
= 139.5 (C3), 134.2 (C6), 129.5 (2C, C4), 128.2 (2C, C5), 77.2 (d,
1288w,1231w,1197w,1088w,1059m,1024m,1006m, 986m, 955m,
898w, 813w, 737s, 689s cmꢀ1; GC-MS (EI): tR = 8.63 min, m/z: 156.0
(M+). Spectroscopic data are in agreement with previous literature
[13].
2
1JCF = 173.1, C1), 56.9 (d, JCF = 21.5, C2) ppm; 19F NMR (282 MHz,
2
3
CDCl3)
(ATR)
d
~
n
= ꢀ221.42 (1F, tt, JHF = 46.5, JHF = 22.0, F-C1) ppm; IR
= 2932w, 1447m, 1389w, 1319m, 1292m, 1246w, 1184w,
1142s, 1088m, 1065m, 999m, 961w, 768m, 729s, 687s, 594m cmꢀ1
;
for
([M + Na]+,
calcd.
4.2. ((2-Fluoroethyl) sulfinyl) benzene (2e)
HRMS
(ESI):
m/z:
211.0209
C8H9FO2SNa+:211.0199)
A solution of 1e (76 mg, 0.49 mmol, 1.00 eq.) in CH2Cl2 (8 ml)
was cooled to 0 ꢁC and mCPBA (ꢆ77%, 118 mg, 0.51 mmol, 1.05 eq.)
was added. After stirring for 16 h under an atmosphere of argon
while warming to rt, the mixture was washed with aq. sat. NaHCO3
(6 ml), brine, was dried over Na2SO4 and concentrated under
reduced pressure. Separation by column chromatography on silica
gel (CyH/EtOAc 1:1) afforded the desired product as colourless oil
(49 mg, 58%).
4.4. S-(2-Fluoroethly) ethanethioate (4) [7]
2-Fluoroethane tosylate (0.4 g, 1.8 mmol, 1.0 eq.) and potassium
thioacetate (0.25 g, 2.2 mmol, 1.2 eq.) were suspended in acetone
(6 mL) and heated to 70 ꢁC for 4 h. The reaction mixture was filtered
and the residual was washed with copious amounts of acetone. The
brown filtrate was concentrated under reduced pressure. Subse-
quently, the residual was partitioned between H2O and Et2O and
the organic layer was dried over MgSO4 and concentrated under
reduced pressure. Fractional distillation (40 mbar, 50 ꢁC) afforded
the title product as a colourless liquid (0.1 g, 44%). Spectroscopic
data in agreement with previously published ones [6].
Rf = 0.25 (CyH/EtOAc 1:1); 1H NMR (400 MHz, CDCl3)
7.63 (2H, m, H-C5), 7.57–7.51 (3H, m, H-C4/C6), 4.92 (1H, dddd,
d
= 7.67–
2
3
2JHF = 46.9, JHH = 10.5, JHH = 8.5, 3.8, H-C1), 4.72 (1H, dddd,
2
3
2JHF = 46.3, JHH = 10.5, JHH = 4.8, 4.6, H-C1), 3.11 (1H, dddd,
2
3
3JHF = 19.5, JHH = 13.8, JHH = 8.4, 4.6, H-C2), 3.07 (1H, dddd,
2
3
3JHF = 30.1, JHH = 13.9, JHH = 4.8, 3.8, H-C2) ppm; 13C NMR (101
1H NMR (400 MHz, CDCl3)
H-C1), 3.19 (2H, dt, JHF = 21.5, JHH = 6.2, H-C2), 2.36 (3H, s, H-C4)
d
= 4.50 (2H, dt, 2JHF = 46.9, 3JHH = 6.2,
3
3
MHz, CDCl3) = 143.5 (C3), 131.5 (C6), 129.6 (2C, C4),124.0 (2C, C5),
d

126
C. Thiehoff et al. / Journal of Fluorine Chemistry 182 (2016) 121–126
= 195.0 (C3), 81.9 (d, 1JCF = 170.7,
(c) J. Huang, K. Hedberg, J. Am. Chem. Soc. 111 (1989) 6909–6913;
ppm; 13C NMR (101 MHz, CDCl3)
d
C1), 30.7 (C4), 29.3 (d, JCF = 22.1, C2) ppm; 19F NMR (282 MHz,
2
(d) D.A. Dixon, B.E. Smart, J. Phys. Chem. 95 (1991) 1609–1612;
(e) D. O’Hagan, H.S. Rzepa, Chem. Commun. (1997) 645–652;
(f) D. O’Hagan, C. Bilton, J.A.K. Howard, L. Knight, D.J. Tozer, J. Chem. Soc. Perkin
Trans. 2 (2000) 605–607;
CDCl3) d
= -213.95 (1F, tt, 2JHF = 46.9, 3JHF = 21.6, F-C1) ppm; IR (ATR)
~
n
= 2963w, 1694s, 1686s, 1420w, 1385w, 1354m, 1134m, 1115m,
1065m, 1015m, 995m, 967m, 810w, 683w, 621s cmꢀ1; GC-MS (EI):
(g) C.R.S. Briggs, M.J. Allen, D. O’Hagan, D.J. Tozer, A.M.Z. Slawin, A.E. Goeta, J.A.
K. Howard, Org. Biomol. Chem. 2 (2004) 732–740;
(h) C.R.S. Briggs, D. O’Hagan, H.S. Rzepa, A.M.Z. Slawin, J. Fluorine Chem. 125
(2004) 19–25;
tR = 4.35 min, m/z 122.0 (M+).
(i) M. Morgenthaler, E. Schweizer, A. Hoffman-Röder, F. Benini, R.E. Martin, G.
Gaeschke, B. Wagner, H. Fischer, S. Bendels, D. Himmerli, J. Schneider, F.
Diederich, M. Kansy, K. Müller, ChemMedChem 2 (2007) 1100–1115;
(j) N.E.J. Gooseman, D. O’Hagan, M.J.G. Peach, A.M.Z. Slawin, D.J. Tozer, R.J.
Young, Angew. Chem. Int. 46 (2007) 5904–5908;
(k) G. Deniau, A.M.Z. Slawin, T. Lebl, F. Chorki, J.P. Issberner, T. van Mourik, J.M.
Heygate, J.J. Lambert, K.T. Sillar, D. O’Hagan, ChemBioChem 8 (2007) 2265–
2274;
4.5. 1-Fluoro-2-thiocyanatoethane (5) [7]
A mixture of 2-fluoroethane tosylate (218 mg, 1.0 mmol, 1.0 eq.)
and NaSCN (122 mg,1.5 mmol,1.5 eq.) in H2O (0.2 ml) was heated to
100 ꢁC for 5 h. After reaching rt, the mixture was diluted with H2O
(5 ml) and extracted with Et2O (3 ꢂ 5 ml). The combined organic
layers were dried over Na2SO4 and most of the Et2O was removed
under reduced pressure. The obtained brown oil was purified via
fractional distillation (12–35 mbar, 33 ꢁC) to give the desired
product as a colourless liquid (40 mg, 38%).
(l) C. Sparr, W.B. Schweizer, H.M. Senn, R. Gilmour, Angew. Chem. Int. Ed. 48
(2009) 3065–3068;
(m) C. Bucher, C. Sparr, W.B. Schweizer, R. Gilmour, Chem. Eur. J. (15 2009)
7637–7647;
(n) C. Sparr, R. Gilmour, Angew. Chem. Int. 49 (2010) 6520–6523;
(o) C. Sparr, E.-M. Tanzer, J. Bachmann, R. Gilmour, Synthesis 8 (2010) 1394–
1397;
(p) S. Paul, W.B. Schweizer, M.-O. Ebert, R. Gilmour, Organometallics 29 (2010)
4424–4427;
(q) C. Sparr, E. Salamanova, W.B. Schweizer, H.M. Senn, R. Gilmour, Chem. Eur. J.
17 (2011) 8850–8857;
(r) E.-M. Tanzer, L.E. Zimmer, W.B. Schweizer, R. Gilmour, Chem. Eur. J. 18
(2012) 11334–11342;
(s) E.-M. Tanzer, W.B. Schweizer, M.-O. Ebert, R. Gilmour, Chem. Eur. J.18 (2012)
2006–2013;
(t) S. Paul, W.B. Schweizer, G. Rugg, H.M. Senn, R. Gilmour, Tetrahedron 69
(2013) 5647–5659;
1H NMR (400 MHz, CDCl3) = 4.74 (2H, dt, 2JHF = 46.4, 3JHH = 5.6,
d
H-C1), 3.24 (2H, dt, 3JHF = 21.4, 3JHH = 5.6, H-C2) ppm; 13C NMR (101
1
MHz, CDCl3)
d
= 111.2 (C3), 80.7 (d, JCF = 174.7, C1), 33.8 (d,
2JCF = 22.3, C2) ppm; 19F NMR (282 MHz, CDCl3)
tt, JHF = 46.4, JHF = 21.4, F-C1) ppm; IR (ATR)
d
= -217.07 (1F,
~
n= 2963w, 2901w,
2
3
2156m, 1404m, 1296m, 1196w, 1065m, 1015s, 953m, 822m,
633m cmꢀ1; GC–MS (EI): tR = 4.10 min, m/z 105.1 (M+). Spectro-
scopic data are in agreement with previous literature [14].
(u) Y.P. Rey, R. Gilmour, Beilstein J. Org. Chem. 9 (2013) 2812–2820;
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794–800.
Acknowledgements
We acknowledge generous financial support from the Swiss
National Science Foundation (N. S., P300P2_161070), the DFG (SFB
858 and Excellence Cluster EXC 1003 “Cells in Motion – Cluster of
Excellence”), the European Research Council (ERC-2013-StG Starter
Grant. Project number 336376-ChMiFluorS) and the WWU
Münster.
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Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.
jfluchem.2016.01.003.
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