Aryl Fluoroalkyl Sulfoxides: Optical Stability and pKa Measurement

Article abstract of DOI:10.1002/ejoc.202100816

The enantiomeric separation of aryl trifluoromethyl and difluoromethyl sulfoxides was realized via chiral chromatography. The configurational stability of each set of enantiomers was then studied by thermal enantiomerization. The ΔG^≠ values obt

Full text of DOI:10.1002/ejoc.202100816

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Aryl Fluoroalkyl Sulfoxides: Optical Stability and pKa
Measurement
Amélia Messara,[a] Nicolas Vanthuyne,[b] Patrick Diter,[c] Mourad Elhabiri,[a] Armen Panossian,[a]
Gilles Hanquet,*[a] Emmanuel Magnier,*[c] and Frédéric R. Leroux*[a]
The enantiomeric separation of aryl trifluoromethyl and
difluoromethyl sulfoxides was realized via chiral chromatogra-
phy. The configurational stability of each set of enantiomers
was then studied by thermal enantiomerization. The ΔG� values
difluoromethyl sulfoxides. Furthermore, the acidities of six aryl
difluoromethyl sulfoxides were determined in DMSO by an
overlapping indicator method using UV-visible spectrophoto-
metric titrations. The pKa values fall in range of 20.3–22.5 and
differ by about 10 log units compared to non-fluorinated
analogues.
obtained cover a range of 38.2–41.0 kcalmolÀ 1 at 214 C, thus
°
demonstrating their optical stability at room temperature.
However, a shorter half-life time has been observed for
Introduction
trifluoromethyl sulfoxides as common precursors of both
sulfoniums[5] and sulfoximines,[6] two of the most widely used
classes of electrophilic and radical di- or trifluoromethylation
reagents.[7] Considering difluoromethyl sulfoxides, one of our
groups (Leroux and coworkers) employed the enantiopure
difluoromethanesulfinyl moiety as a chiral auxiliary to access
highly enantioenriched α-difluoromethyl alcohols by deproto-
nation and trapping with electrophiles such as aldehydes or
prochiral ketones.[8] Indeed, the valuable properties of the
À CHF2 group, a motif known to be a good hydrogen bond
donor and a bioisostere of hydroxy, thiol and amine groups,[9]
have motivated the development of numerous methods for its
non-stereoselective introduction;[10] however, the enantioselec-
tive synthesis of CHF2-containing scaffolds is less described.[11]
Regarding the access to such α-polyfluorinated alkyl aryl
sulfoxides, Magnier and coworkers developed methods for
either the direct introduction of the trifluoromethanesulfinyl
group onto aryl derivatives,[5b,6a] or its construction via simple
oxidation of the corresponding sulfides using TFPAA.[12] Un-
fortunately, all the attempts of asymmetric synthesis of aryl
trifluoromethyl sulfoxides led to racemates.[13] To the best of our
knowledge, there is only one example of preparation of an
enantioenriched trifluoromethyl sulfoxide[14] and no example
with an aryl group. On the other hand, Leroux and coworkers
recently succeeded in developing an efficient synthesis of
enantiopure aryl α,α-difluoromethyl sulfoxides, starting with a
Fluorinated moieties such as À CF3, À CHF2, À OCF3, À SCF3 or À SF5
can deeply modify the lipophilicity, the metabolic stability, the
acidity or the conformational preference of compounds.[1] Such
perfluoroalkyl groups have shown
a growing interest in
pharmaceutical and agrochemical fields due to their ability to
impact the properties of bioactive molecules. Among the
various strategies used to introduce the prized À CF3 and À CHF2
groups, the use of α-fluorinated sulfur derivatives proved highly
resourceful in various types of nucleophilic, electrophilic, and
radical reactions.[2] In particular, when the trifluoromethyl
moiety is bonded to a sulfinyl moiety, a very original and
versatile group is then created. The most illustrative examples
À
of its importance include its use as a precursor of CF3 as
demonstrated by Prakash et al.,[3] or as a source of in situ
generation of trifluoromethylcopper as shown by the group of
Hu.[4] Another major application is the use of difluoro- and
[a] A. Messara, Dr. M. Elhabiri, Dr. A. Panossian, Dr. G. Hanquet,
Dr. F. R. Leroux
Université de Strasbourg
Université de Haute-Alsace
CNRS, UMR 7042-LIMA, ECPM,
25 rue Becquerel, Strasbourg 67087, France
E-mail: ghanquet@unistra.fr
frederic.leroux@unistra.fr
http://lima.unistra.fr
https://coha.unistra.fr
Reformatsky-type reaction on
a sulfinyloxazolidinone and
followed by a Krapcho dealkoxycarbonylation.[8] As mentioned
above, the subsequent use of the obtained difluoromethyl
sulfoxides required a deprotonation, which brought to our
attention that the pKa of aryl difluoromethyl sulfoxides was
unknown and deserved to be explored (Scheme 1).
http://ecpm2.unistra.fr/umr7509/labo_davioudcharvet
[b] Dr. N. Vanthuyne
Aix Marseille Université, CNRS, Centrale Marseille, UMR 7313-iSm2
52 Avenue Escadrille Normandie Niemen, Marseille 13013, France
https://ism2.univ-amu.fr
[c] Dr. P. Diter, Dr. E. Magnier
Université Paris-Saclay, UVSQ, CNRS, UMR 8180
In view of our precedent works on the synthesis of
fluoroalkyl sulfoxides, it appeared essential to tackle several
issues, in particular the isolation of enantiomerically pure
trifluoromethyl sulfoxides, the study of the configurational
stability of difluoro- and trifluoromethyl sulfoxides as well as
the acidity of the difluoromethyl species (Scheme 1). Conse-
Institut Lavoisier de Versailles
45 avenue des Etats-Unis, Versailles 78035, France
E-mail: emmanuel.magnier@uvsq.fr
https://www.ilv.uvsq.fr
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100816
Part of the joint “ECPM Strasbourg Institute Feature” Collection with EurJIC.
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quently, the first objective of the present study was to isolate
for the first time the enantiomers of trifluoromethyl sulfoxides.
The second was the determination of the inversion energy
barriers for the enantiomerization of aryl fluoroalkyl sulfoxides
Amélia Messara was born in Mulhouse (France)
in 1996. She obtained a master’s degree in
molecular and supramolecular chemistry from
the University of Strasbourg (France). She is
currently a PhD student under the supervision of
Dr. Frédéric Leroux and Dr. Gilles Hanquet,
working on new methodologies for the asym-
metric introduction of the difluoromethyl group
on polyfunctionalized molecules.
Gilles Hanquet studied biochemistry and chemistry
at the University of Paris Sud (Orsay) and obtained
his PhD in 1993 from the ICSN (Institut de Chimie
des Substances Naturelles) in Gif-sur-Yvette
(France). He spent two years at UCL (University of
Louvain la Neuve, Belgium) as a postdoctoral
collaborator of Prof. Leon Ghosez, and obtained a
second postdoctoral position under the super-
vision of Prof. Albert Eschenmoser at ETH Zurich,
Switzerland (1995–1996). He moved in 1996, as a
CNRS researcher, to the University of Strasbourg in
the group of Prof. Guy Solladié and he has been a
Senior Scientist (Directeur de Recherche) since
2007. His main interests are (a) total synthesis of
natural products, (b) enantioselective construction
of stereogenic centers bearing an emergeant
fluorine substituent and (c) medicinal chemistry.
Nicolas Vanthuyne graduated from the Ecole
Nationale Supérieure de Synthèse, de Procédés
et d’Ingénierie Chimiques d’Aix-Marseille (ENSS-
PICAM) in 2000 and obtained his PhD in 2004
under the supervision of Professor Christian
Roussel. Afterwards, he developed enantioselec-
tive chromatography and chiroptical detection
at Aix- Marseille University to study chiral
recognition mechanisms, atropisomerism and
dynamic stereochemistry.
Emmanuel Magnier obtained his PhD in 1997,
under the guidance of Prof. Yves Langlois in the
Université Paris-Sud (Orsay). He spent one year as
postdoctoral fellow with Prof. William Motherwell
at the University College London. He then came
back to Orsay for one year as a lecturer in the
laboratory of Profs. Henri Kagan and Jean-Claude
Fiaud. In 1999, he was appointed as a CNRS
permanent researcher in the group of Claude
Wakselman in Versailles. He is now in charge of
the fluorine group at Institut Lavoisier of Versailles.
The group’s research interests are the synthesis
and developments of electrophilic perfluoroalkylat-
ing reagents (sulfonium salts, sulfilimines, sulfox-
imines), the perfluoroalkytion by photoredox catal-
ysis, the fluorinated analogs of natural compounds
or of therapeutic interest, the emergent fluorinated
substituents (mainly OCF3), the use of new media
for green chemistry purposes (fluorous solvents,
ionic liquids) and the preparation of fluorinated
ligands for porous solids.
Patrick Diter studied chemistry at the University of
Paris Sud (Orsay) and obtained his PhD in 1994
under the supervision of Prof. Henri Kagan (ICMO,
Orsay France). He spent two years at Imperial
College (London, UK) for a postdoctoral position in
the group of Dr. Susan Gibson. After one year as
temporary assistant professor at the Université
Paris Sud (Orsay, France), he became in 1997
Maître de Conférences (assistant professor) at
UVSQ (University of Versailles St-Quentin en yvs,
France). His research interests focus on the control
of chirality and fluorine chemistry.
Mourad Elhabiri obtained his PhD at Strasbourg
University in 1997, in Prof. R. Brouillard’s group.
During this period, he was interested in the
chemistry of anthocyanins and their interactions
with metal ions. In 1997, he joined the group of
Prof. Jean-Claude Bünzli at EPFL in Lausanne
(Switzerland) and worked on the synthesis and
photophysical characterization of bimetallic lantha-
nides triple-stranded helicates. In 1999, he was
recruited by the CNRS and focused his interests on
the physicochemical characterization of natural,
biomimetic and bioinspired chelators as well as
functional supramolecular edifices. During the last
10 years, he has been developing redox-active
drugs against viral/parasitic pathogens and eluci-
dating their mechanism of action. He is currently
developing innovative functional Vis-NIR fluores-
cent dyes for bioimaging.
Frederic Leroux obtained a Ph.D. from the Univer-
sity of Konstanz (Germany) in 1997. After
a
postdoctoral stay with Prof. M. Schlosser at the
University of Lausanne (Switzerland) he became
Assistant Professor in 1998. In 2001, he moved
then to the Swiss Federal Institute of Technology
in Lausanne (EPFL). In 2003, he joined the CNRS as
Research Associate and was promoted CNRS
Research Director in 2009. The philosophy of his
research is based on a fruitful interplay of several
objectives: (a) the synthesis of biologically relevant
molecules, (b) asymmetric methodologies using
organic and organometallic chemistry, (c) organo-
ofluorine chemistry and (d) application of the
objectives to industrial problems, which led to
strong industrial collaborations.
Armen Panossian carried out his PhD studies
under the supervision of Dr. Angela Marinetti at
the ICSN (Gif-sur-Yvette, France). In 2009, he
moved to the ICIQ (Tarragona, Spain) for
a
postdoctoral position in the group of Dr. Anton
Vidal-Ferran. After one year as temporary assistant
professor at the Université Pierre et Marie Curie
(Paris, France), he became in 2011 CNRS Research
Associate (Chargé de Recherche). He obtained his
Habilitation in 2019. His research interests focus on
the control of chirality, heavy metal-free methods,
the organic chemistry of heteroelements of the
main group.
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Scheme 2. Pyramidal inversion mechanism and inversion energy barriers
[20]
°
calculated at 25 C of alkyl aryl, dialkyl and diaryl sulfoxides.
a [2,3]-sigmatropic rearrangement with inversion energy bar-
riers approaching 22 kcalmolÀ 1.
Scheme 1. Investigated properties of aryl fluoroalkyl sulfoxides.
Understanding the stereomutation of aryl fluoroalkyl sulf-
oxides that cannot undergo such a rearrangement is therefore
essential to control the optical stability of enantiomers for
synthetic applications and its investigation is unfortunately still
lacking. Previously, we were able to separate perfluorinated
sulfilimines by SFC while demonstrating their enantiomeric
stability.[13] Herein, the enantiomeric separation of
trifluoromethyl (2a–2b) and difluoromethyl (3a–3g) sulfoxides
(Scheme 3) was first performed by chiral HPLC before inves-
tigating their enantiomerization kinetics.
by a kinetic study. Thirdly, the acidity of several aryl α,α-
difluoromethyl sulfoxides was evaluated by UV-visible absorp-
tion spectrophotometric means in DMSO to determine the
impact of the two α-fluorine atoms on the pKa value of
sulfoxides as well as the electronic effects of the aryl substituent
on the α,α-difluoromethanesulfinyl moiety. These results are
fully detailed in the following text.
The racemic sulfoxides 1, 2a–b and 3a–g were synthesized
by our previously reported methods.[8,12] Enantiomers were then
separated by preparative HPLC on a chiral stationary phase and
obtained up to the gram scale (see ESI). Their absolute
configuration was determined by comparing experimental and
TD-DFT calculated electronic circular dichroism spectra (see ESI).
Results and discussion
Determination of inversion energy barriers
In the non-fluorinated series, the physico-chemical properties of
sulfoxides have been thoroughly investigated. Non-fluorinated
sulfoxides are known to be highly configurationally stable. Only
the enantiomerization of allyl,[15] benzyl,[16] vinyl[17] sulfoxides
and arenethiolsulfinates[18] requires milder conditions. For
dialkyl, diaryl and alkyl aryl sulfoxides, the thermal enantiomeri-
zation is suggested to occur through a pyramidal inversion
°
Solutions of enantiopure sulfoxides were then heated to 214 C
(487 K) in 1,2,4-trichlorobenzene and samples were injected on
a chiral chromatography column at different times to obtain
the corresponding kinetic traces (see ESI). The enantiomeriza-
tion process is considered as a reversible first order reaction,
mechanism with
a
planar non-chiral transition state
(Scheme 2).[19] However, this process only happens at temper-
[20]
°
atures above 200 C. Agranat et al.
reported a theoretical
study on the inversion energy barriers of some chiral and
achiral sulfoxides. The energies were calculated by DFT
methods and were found to be in a range of 40–46 kcalmolÀ 1
(Scheme 2). They demonstrated that with the presence of a
phenyl ring, the transition state is stabilized by a resonance
effect, decreasing the energy barrier compared to an alkyl
sulfoxide. By introducing an electron-withdrawing moiety such
as a cyano group at the para position of the aromatic ring, the
energy is further reduced. To the best of our knowledge, in the
fluorinated series, the only example of enantiomerization was
reported by Cahard et al.[14] They demonstrated the sponta-
neous enantiomerization of allylic trifluoromethyl sulfoxides via
Scheme 3. Enantiomerization process and sulfoxides investigated in this
approach.
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where k1 and k2 are the rate constants of the forward and
the sulfur atoms in the planar transition state. This repulsion
would be minimized in the tetrahedral geometry. In summary,
given the relative size of the À CF3 group (A value=
2.37 kcalmolÀ 1) compared to the À CH3 group (A value=
1.74 kcalmolÀ 1),[23] the steric effect most likely compensates for
the electronic effect, leading to similar inversion energy barriers
for the corresponding sulfoxides. In contrast, the size of the
À CHF2 unit (A value=1.85 kcalmolÀ 1)[24] is much smaller than
the À CF3 moiety and only slightly larger than a À CH3
substituent. Therefore, for aryl difluoromethyl sulfoxides, the
electron-withdrawing effect overwhelms the steric one, result-
ing in lower inversion energy barriers.
backward reactions, respectively (Scheme 2 and Scheme 3, i.e.,
for an enantiomerization process, kenantiomerization =k1 =k2).[21] The
rate constants kenantiomerization were then determined experimen-
tally (see ESI) by monitoring via HPLC the percentage of the SS
enantiomer. The rate constant kenantiomerization, the inversion
energy barrier ΔG� and the half-life time t1/2 (see ESI) were
determined for each compound and are summarized in Table 1.
In the non-fluorinated series, the configurationally stable
diaryl, alkyl aryl or dialkyl sulfoxides enantiomerize with
activation parameters ΔH� and ΔS� ranging from 35 to
42 kcalmolÀ 1 and from À 8 to 4 e.u. (i.e., entropy unit, 1 e.u.=
4.184 J.KÀ 1 molÀ 1), respectively.[19b] For methyl phenyl sulfoxide 1
(Scheme 3), we measured an inversion energy barrier of
We then evaluated the influence of the aromatic ring on the
inversion energy barriers of the corresponding sulfoxides. The
comparison of compounds 2a and 2b clearly shows that the
inversion properties are not significantly altered, with however
41.1 kcalmolÀ 1 at 214 C. Inversion energies determined for aryl
°
trifluoromethyl sulfoxides 2a–b were found to be comparable
to those measured for non-fluorinated analogues. By contrast,
aryl difluoromethyl sulfoxides 3a–g were found to be less
optically stable (i.e., faster inversion process, Table 1) with a
difference of up to ~3 kcalmolÀ 1 units when compared to non-
fluorinated analogues (e.g., 2a versus 3a and 2b versus 3g).
For fluorinated aryl sulfoxides, much lower inversion energy
barriers were initially expected taking into account the strong
electron-withdrawing effect of fluorine. For non-fluorinated
analogues,[19] it has been suggested that the four atoms (C, C, O,
S) of the sulfinyl group are positioned in a planar array in the
transition state of the pyramidal inversion mechanism
(Scheme 2). This induces a resonance effect between the π-
electrons of the aromatic ring, the unshared electron pair of the
sulfur atom and the electrons of the sulfur-Oxygen “double”[22]
bond, which stabilizes the planar transition state. Hyperconju-
gation of the methyl group to the partially positively charged
sulfur centre also contributes to stabilize this transition
state.[19b,20] Substitution on the alkyl moiety of the sulfoxide by a
fluorine atom would therefore destabilize the planar transition
state by: 1) disfavouring the delocalization of the electron
density at sulfur into the phenyl ring by resonance, 2) weaken-
ning or fully suppressing the (α-CH)-sulfur hyperconjugation,
and 3) depleting the electron density at sulfur via the known
hyperconjugation between non-bonding electrons at sulfur and
the antibonding σ*C-F orbital. On the other hand, steric effects
could also play a significant role and increase the inversion
energy barriers due to repulsion interactions between the
unshared electron pairs of the fluorine atoms, the oxygen and
a
slightly faster enantiomerization for 2b (i.e., stronger
resonance effect with a naphthalene ring). The comparison of
compounds 2b (CF3) and 3g (CHF2) supports our hypotheses
on the electronic/steric effects of these substituents.
We next turned our attention to the effects of the
substituents at the para position of the phenyl ring. In the non-
fluorinated series, Mislow and co-authors[19b] showed that the
more electron-rich the benzene ring, the slower the enantiome-
rization; however, these electronic effects were assumed to play
a minor role (for diaryl sulfoxides R-C6H4S(O)p-Tol with R=H, Cl,
CF3 or OCH3, the energy difference does not exceed
0.7 kcalmolÀ 1). Electrostatic repulsion between the π electrons
of the aryl ring and the lone electron pair on the sulfur atom
was proposed to explain this property. With electron-donating
groups (EDG), this effect is reinforced in the planar transition
state leading to higher inversion barrier. For electron-with-
drawing groups (EWG), the planar transition state will be
stabilized due to a conjugation from the lone electron pair on
the sulfur atom to the EWG causing a decrease of the energy
barrier. Similarly to non-fluorinated sulfoxides, we observed
negligible energy variations for difluoromethyl sulfoxides 3a–f,
which do not exceed 0.8 kcalmolÀ 1 (3d – R=CF3 versus 3a –
R=H). Our results follow the same reasoning and are therefore
consistent with the reported data.
Determination of the pKa values
Another interesting property of aryl alkyl sulfoxides that has
been investigated in depth is the acidity of the α-protons of
sulfoxides. A survey of literature shows that their pKa values
are ranging from 24.6 to 35.1 in DMSO (e.g., pKa =33.0 for 1)
depending on the nature of the group linked to the sulfur
atom (Scheme 4).[25,26] Besides, aryl sulfoxides are more acidic
than their alkyl congeners with two pKa units less due to the
resonance effect of the aryl ring that stabilizes the anionic
form. It is also worth mentioning that sulfoxides are also
weakly basic and can be protonated at their oxygen centres
(e.g., pKa =À 0.488 for 1 in acetic anhydride).[27] Substitution at
the para-position of methyl phenyl sulfoxide markedly affects
Table 1. Rate constants, inversion energy barriers and half-life times for
°
sulfoxides 1, 2a–b, 3a–g at 214 C (487 K) in 1,2,4-trichlorobenzene.
Sulfoxide
k
enantiomerization [sÀ 1
]
ΔG� [kcalmolÀ 1
]
t1/2 [min or h]
1
3.84.10À 6
4.00.10À 6
4.68.10À 6
3.16.10À 5
3.48.10À 5
3.21.10À 5
5.89.10À 5
3.49.10À 5
3.57.10À 5
3.00.10À 5
41.1
41.0
40.9
39.0
38.7
38.9
38.2
39.0
38.9
39.1
25.1 h
24.1 h
20.6 h
183 min
166 min
180 min
98 min
166 min
162 min
192 min
2a
2b
3a
3b
3c
3d
3e
3f
3g
this corresponding pKa value as
a
consequence of the
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Scheme 4. pKa values of selected non-fluorinated sulfoxides in DMSO.[25,26]
resonance effect of the substituent. A difference of 4 pKa units
is indeed observed between an EDG (pKa =0.555 for OCH3
substitution) and an EWG (pKa =À 3.51 for NO2 substitution).
Introducing two fluorine atoms in α-position (i.e., affording a
difluoromethyl group) is anticipated to significantly lower the
pKa value of the α-protons of sulfoxides due to the strong
electron-withdrawing character of the fluorine atoms. None-
theless, no pKa value of difluoromethyl aryl sulfoxides has
been reported in the literature. So far, only one pKa value for
difluoromethylated compounds has been reported by Bord-
well et al. who determined a pKa value of 20.2[25c] for 2,2-
difluoroacetophenone in DMSO. Introduction of one (2-
fluoroacetophenone, pKa =21.7) or two fluorine (2,2-difluoroa-
cetophenone, pKa =20.2) atoms thus induces a significant
stepwise increase of the acidity of the compound when
compared to acetophenone (pKa of 24.7).[25c] On the other
hand, Xue et al. recently reported the pKa values of a series of
(α-monofluoro)(phenylsulfonyl)methane derivatives.[28] Surpris-
ingly, introduction of a α-fluorine substituent weakens the α-
Scheme 5. Indicators with their pKa values in DMSO[25b] and aryl
difluoromethyl sulfoxides investigated in this approach.
The proton exchange (Kex) between HA and InÀ was monitored
and quantified by measuring the absorption alterations. The pKa
values of the investigated aryl difluoromethyl sulfoxides were
then evaluated from the exchange constant Kex and the pKa
value of the indicator used.
For the method to be reliable, the pKa values of the acid
and the indicator must not differ by more than two units. In
addition, the indicator must be sufficiently stable over the
duration of the titration. Six indicators were first tested for their
ability to act as efficient colorimetric reporters in their basic
form in DMSO: carbazole (pKa =19.9), 2-naphthyl-acetonitrile
(pKa =20.7),[34] 4-nitro-aniline (pKa =20.9),[35] indole (pKa =
21.0),[36] 9-benzyl-fluorene (pKa =21.8)[37] and 9-methyl-fluorene
(pKa =22.3).[25b] Only the anions derived from carbazole, 9-
methyl-fluorene and 4-nitro-aniline were found to be suffi-
ciently stable in solution to allow absorption titrations with aryl
difluoromethyl sulfoxides 3b–g (see ESI). The pKa values of
sulfoxides 3b–g were determined in duplicate or triplicate and
in some cases several indicators were used to confirm their
value (see ESI). As an example, Figure 1 depicts the absorption
spectrophotometric titration of the anion (InÀ ) derived from 4-
nitroaniline with the aryl difluoromethyl sulfoxide 3d acting as
the acid (HA). Upon addition of 3d, proton exchange is clearly
evidenced by the gradual decrease of the In– anion absorption
and the concomitant formation of a new absorption related to
the protonated neutral indicator (see ESI). The presence of an
isosbestic point at 412 nm confirms that proton exchange is the
only equilibrium that takes place
C
sp3-H acidity of most the investigated derivatives. Destabiliza-
tion of α-fluorocarbanions by lone-pair repulsions, attenuation
of the stabilizing inductive effect of fluorine by the polar
saturation effect, as well as stabilization of the parent acid
form by the double bond-no bond resonance were proposed
to explain this peculiar behaviour.[28]
These reported data highlight that physico-chemical charac-
terizations of sulfoxide derivatives remain scarce and their
reactivity difficult to predict.
Several bases were shown to be effective to deprotonate
aryl α,α-difluoromethyl sulfoxides. Strong bases such as
KHMDS or LiHMDS (pKa =25.8 in THF),[29] t-BuOK (pKa =32.2 in
DMSO),[25c]
Schwesinger’s
superbase
(pKa =42.6
in
acetonitrile)[8,30] were found to be suitable,[8,31] in contrast to
DBU (pKa =24.2 in THF).[32]
Aryl difluoromethyl sulfoxides are weakly absorbing in the
UV region either under neutral (protonated, see ESI) or
negatively (deprotonated) charged states and, therefore, not
valuable chromophores to directly assess their deprotonation
properties. An indirect colorimetric method previously applied
to non-fluorinated sulfoxides by Bordwell[25b] (i.e., Bordwell’s
indicator overlapping method) was consequently used for
compounds 3b--3g (Scheme 5). Using absorption spectropho-
tometry (i.e., an original setup composed of optical fibres and a
quartz suprasil immersion probe was used to measure the
absorption in a two-necked round-bottom tube under strict
argon atmosphere), a deprotonated coloured indicator (noted
InÀ ; freshly prepared from dimsyl potassium) was titrated by
aryl difluoromethyl sulfoxides (noted HA; 3b--3g) in DMSO.[33]
Table 2 gathers the pKa values which fall between 20.3 and
22.5. Compared to methyl phenyl sulfoxide (Scheme 4, pKa =
33.0 in DMSO),[25d] the acidity of p-tolyl difluoromethyl sulfoxide
3b decreased by more than 10 pKa units. This increase in acidity
is for example much higher than that observed for compounds
of the acetophenone series (ΔpKa=4.5). This clearly demon-
strates
a
marked stabilizing effect of the two fluorine
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Scheme 6. Comparison of the pKa values for selected compounds in DMSO.
their acidity, with variations not exceeding 2 pKa units. Com-
pound 3c is the least acidic derivative due to the mesomeric
electron- donating effect of the methoxy group, while with the
strong electron-withdrawing inductive effect of the
trifluoromethyl group, compound 3d displays the lowest pKa
value. Furthermore, comparison of compound 3g (pKa =21.7)
with 3b (pKa =22.3) demonstrates the weak impact of an
extended resonance effect on the α-Csp3-H acidity.
Figure 1. UV-visible absorption spectra of the anion InÀ derived from 4-
nitroaniline after each addition of the sulfoxide 3d in DMSO. [InÀ ]=0.1 mM;
°
T=25 C; argon atmosphere. The absorption spectra are not corrected from
dilution effects.
Table 2. pKa values of aryl α,α-difluoromethyl sulfoxides 3b--g measured
°
in DMSO at 25 C under argon.
Sulfoxide
pKa
Indicator used
3b
3c
3d
22.3�0.2
22.5�0.4
20.3�0.6
9-Methylfluorene
9-Methylfluorene
4-Nitroaniline
Carbazole
Conclusion
The present study allowed us to unravel the optical stability of
aryl fluoroalkyl sulfoxides by thermal enantiomerization via
enantioselective chromatography. The results indicate that the
enantiomers of these compounds are strongly configurationally
stable at room temperature and have a reasonable stability up
3e
21.7�0.6
9-Methylfluorene
4-Nitroaniline
Carbazole
9-Methylfluorene
9-Methylfluorene
3f
3g
21.8�0.2
21.7�0.1
°
to 214 C. However, the shorter half-life time obtained for
difluoromethyl sulfoxides shows that their enantiomerization is
°
substituents on the carbanion, in addition to the previously
mentioned stabilization provided by the sulfinyl group in α-
position.
Furthermore our observations are in contrast to the proper-
ties of the (α-fluoro)(phenylsulfonyl)methane derivatives re-
cently reported.[28] Weak to no effect (ΔpKa =0.5) was observed
between α-fluoro(phenylsulfonyl)methane and its non-fluori-
nated analogue (Scheme 6).
For aryl difluoromethyl sulfoxides, stabilization of the anion
could be rationalized by combined factors, starting with the
attractive inductive effect of the two fluorine atoms, decreasing
electron density at the negatively charged carbon. Moreover, a
shortening of the sulfur-carbon bond can be proposed on the
basis of, on the one hand, the same inductive effect of the two
fluorine atoms and, on the other hand, the negative hyper-
conjugation between the sulfur lone pair and the antibonding
faster when reaching 214 C. Besides, the pKa values in DMSO of
six aryl α,α-difluoromethyl sulfoxides were determined by
means of the overlapping indicator method using UV-visible
absorption spectrophotometric titrations. Introduction of two
fluorine atoms significantly increases the α-Csp3-H acidity by
more than 10 pKa units whereas substitution in the para-
position of the phenyl group only weakly modulated the acidity
of the sulfoxide. The data obtained are important to deepen
our understanding of the reactivity of aryl fluoroalkyl sulfoxides,
in particular the effect of fluorine substitution on key properties
such as inversion energy barriers or acidities compared to non-
fluorinated analogues. This will help fully exploiting the
potential of fluoroalkyl sulfoxides in the synthesis of (chiral)
fluorinated building blocks.
σ*C-F orbital, both contributing in bringing closer the negative Experimental Section
charge to the electron-deficient sulfinyl group. Altogether, the
Synthetic procedures, calculations and experimental details for the
formed carbanion would be more stabilized than the non-
fluorinated analogue and the acidity of the corresponding
sulfoxide would increase.
enantiomeric separation and the determination of inversion energy
barriers as well as for pKa measurements are provided in the
supporting information.
As observed for the enantiomerization process (i.e., weak
influence of the phenyl substitution on the inversion energy
barrier), the nature of the substituent in the para position of
aryl difluoromethyl sulfoxides has a very slight influence on
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Acknowledgements
2018, 54, 10423–10426; b) C. Batisse, M. F. Céspedes Dávila, M. Castello,
A. Messara, B. Vivet, G. Marciniak, A. Panossian, G. Hanquet, F. R. Leroux,
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We gratefully acknowledge the French Agence Nationale pour la
Recherche (ANR) (grant number ANR-17-CE07-0008-01, DEFIS), the
CNRS and the Université de Strasbourg for financial support. A. M.
is much grateful to the French Ministry of Education and Research
for funding. The French Fluorine Network (GIS Fluor) is also
acknowledged. This work was supported by the computing
facilities of the CRCMM, “Centre Régional de Compétences en
Modélisation Moléculaire de Marseille”.
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Conflict of Interest
The authors declare no conflict of interest.
Keywords: Absorption · Acidity · Enantiomerization · Fluorine ·
Sulfoxide
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FULL PAPERS
Key properties of chiral aryl fluoroalk-
yl sulfoxides with strong synthetic
potential were studied. After resolu-
tion by enantioselective chromatog-
raphy, their optical stability was in-
vestigated by thermal
A. Messara, Dr. N. Vanthuyne, Dr. P.
Diter, Dr. M. Elhabiri, Dr. A. Panossian,
Dr. G. Hanquet*, Dr. E. Magnier*,
Dr. F. R. Leroux*
1 – 9
Aryl Fluoroalkyl Sulfoxides: Optical
Stability and pKa Measurement
enantiomerization via enantioselec-
tive chromatography. Their ΔG�
values range from 38.2 to
41.0 kcalmolÀ 1 at 214 C. In addition,
°
the pKa values of six aryl
difluoromethyl sulfoxides were deter-
mined via indirect UV-visible spectro-
photometric titrations in DMSO and
are in the range of 20.3–22.5.