The Effect of the Fluorine Substitution on the Enantioselective Oxidation of Sulfides with Chiral Titanium Catalysts: A Combined Computational and Experimental Investigation

Article abstract of DOI:10.1002/cctc.201200456

The results of a combined computational-experimental study of the oxidation of various fluorinated aryl benzyl sulfides using tert-butyl hydroperoxide (TBHP) in the presence of a complex of titanium and (S,S)-hydrobenzoin are presented. As observed in previous studies for other aryl benzyl sulfides, the reaction leads to enantiopure sulfoxides (ee>98%) in good isolated yields (81-96%) except the case of pentafluorobenzyl pentafluorophenyl sulfide for which a lower ee (61%) is observed. DFT computations on a model-system formed by the substrate, the oxidant TBHP and the [(S,S)-hydrobenzoin]₂-Ti complex satisfactorily explain this unexpected item. The enantioselectivity is governed by the relative energy of the two diastereomeric octahedral complexes that form if TBHP approaches the initial complex between substrate and [(S,S)-hydrobenzoin]₂-Ti before the oxygen transfer. For pentafluorobenzyl pentafluorophenyl sulfide, the two octahedral complexes are almost degenerate and, thus, they form in similar amounts. As the two corresponding diastereomeric transition states are similar in energy, the probability to follow one or the other diastereomeric reaction channel becomes comparable, which leads to the lower enantiomeric excess experimentally observed. Our computations indicate that the particular folded conformation , adopted by the substrate only if both phenyl rings are fluorinated, is the key factor that determines the near degeneracy of the two diastereomeric octahedral complexes.

Full text of DOI:10.1002/cctc.201200456

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DOI: 10.1002/cctc.201200456
The Effect of the Fluorine Substitution on the
Enantioselective Oxidation of Sulfides with Chiral Titanium
Catalysts: A Combined Computational and Experimental
Investigation
Maria Annunziata M. Capozzi,[b] Francesco Capitelli,[c] Andrea Bottoni,*[d] Matteo Calvaresi,[d]
and Cosimo Cardellicchio*[a]
Dedicated to Prof. Francesco Naso on the occasion of his 75th birthday
The results of a combined computational-experimental study
of the oxidation of various fluorinated aryl benzyl sulfides
using tert-butyl hydroperoxide (TBHP) in the presence of a com-
plex of titanium and (S,S)-hydrobenzoin are presented. As ob-
served in previous studies for other aryl benzyl sulfides, the re-
action leads to enantiopure sulfoxides (ee>98%) in good iso-
lated yields (81–96%) except the case of pentafluorobenzyl
pentafluorophenyl sulfide for which a lower ee (61%) is ob-
served. DFT computations on a model-system formed by the
substrate, the oxidant TBHP and the [(S,S)-hydrobenzoin]2-Ti
complex satisfactorily explain this unexpected item. The enan-
tioselectivity is governed by the relative energy of the two dia-
stereomeric octahedral complexes that form if TBHP ap-
proaches the initial complex between substrate and [(S,S)-hy-
drobenzoin]2-Ti before the oxygen transfer. For pentafluoro-
benzyl pentafluorophenyl sulfide, the two octahedral com-
plexes are almost degenerate and, thus, they form in similar
amounts. As the two corresponding diastereomeric transition
states are similar in energy, the probability to follow one or
the other diastereomeric reaction channel becomes compara-
ble, which leads to the lower enantiomeric excess experimen-
tally observed. Our computations indicate that the particular
“folded conformation”, adopted by the substrate only if both
phenyl rings are fluorinated, is the key factor that determines
the near degeneracy of the two diastereomeric octahedral
complexes.
Introduction
Enantiopure sulfoxides are widely employed in stereoselective
synthesis as useful chiral auxiliaries and intermediates; they
can exert high asymmetric induction and are characterised by
the significant configurational stability of the sulfinyl
moiety.[1–4] In addition to their synthetic value, some chiral sulf-
oxides are of uttermost importance in medicinal chemistry and
pharmacology thanks to their biological activity.[5–7] A notable
example is the well-known anti-ulcer agent (S)-omeprazole,[6–7]
which was sold for many years as a racemic mixture, but is
now available on the market in enantiopure form.
Various methodologies have been proposed during the last
half century for the synthesis of these valuable intermediates
and a large number of examples are now available in litera-
ture[1–4] For instance, organometallic reagents can be used to
displace leaving groups from suitable sulfinyl compounds with
a complete inversion at the sulfur stereogenic centre.[1–3] The
Andersen reaction, in which menthyl (S)- or (R)-p-toluenesulfi-
nates react with Grignard reagents, can be considered the pro-
totypical example of this procedure.[8,9]
[a] Dr. C. Cardellicchio
CNR ICCOM—Dipartimento di Chimica
Universitꢀ di Bari
via Orabona 4. 70125 Bari (Italy)
Fax: (+39)0805539596
E-mail: cardellicchio@ba.iccom.cnr.it
An alternative methodology is the enantioselective oxidation
of sulfides.[1–4] The most common catalysts of this type are
based on titanium complexes, as proposed almost simultane-
ously and independently by Modena et al.[10] and Kagan
et al.,[11] who used titanium iso-propoxide Ti(O-iPr)4 as a metal
source, enantiopure diethyl tartrate as the chiral modifier and
an alkyl hydroperoxide as the real oxidant. Since then, many
different oxidation catalysts have been proposed,[1–4] and some
of them have been successfully employed in the industrial pro-
ductions of bioactive sulfoxides.[12]
[b] Dr. M. A. M. Capozzi
Dipartimento di Chimica
Universitꢀ di Bari
via Orabona 4. 70125 Bari (Italy)
[c] Dr. F. Capitelli
CNR IC
via Salaria, Km 29.300, 00195 Monterotondo (Rome)
[d] Prof. A. Bottoni, Dr. M. Calvaresi
Dipartimento di Chimica “G. Ciamician”
Universitꢀ di Bologna
via Selmi 2, 40126 Bologna (Italy)
In our previous work,[13–21] we have described the results ob-
tained in the asymmetric synthesis of chiral non-racemic sulf-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201200456.
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oxides using either enantioselective oxidation[15–21] or Grignard
reagents reacting with suitable sulfinyl compounds.[13–17] In the
latter case, unconventional displacement of carbanionic leav-
ing groups was observed. However, during the last
decade,[17–21] we have focused our research on the enantiose-
lective oxidation of sulfides with hydroperoxides in the pres-
ence of catalytic amounts of a complex of titanium and (S,S)-
or (R,R)-hydrobenzoin, which is a cheap and easily available
chiral auxiliary.[22] This oxidation procedure is straightforward,
because it proceeds at room temperature, non-chlorinated sol-
vents are used and no particular experimental work-up is re-
quired. The use of a catalyst based on a metal complex of the
hydrobenzoin, or hydrobenzoin-like diols, was first proposed
by Yamamoto et al. in 1989[23] and subsequently employed by
Rosini et al.[24] Later this procedure was also employed in the
synthesis of bioactive sulfoxides[25] and of Omeprazole, or
Omeprazole-like molecules.[26]
some cases as edge-to-face arene interactions or T-shaped
CH···p interactions).[27–28] A schematic representation of the
model-system used in ref. [20] is given in Figure 1. These weak
interactions gained a recent interest mainly in crystal engineer-
ing research,[27] but they were also invoked to explain reaction
mechanisms in asymmetric synthesis.[28]
We used this protocol for the oxidation of aryl b-ketosul-
fides[18] and aryl benzyl sulfides[17,20–21] and we consistently ob-
served a high enantioselectivity (ee in the range 91–>98%). In
only a few cases were slightly lower values (ee in the range
81–88%) obtained.[20] Notably, as far as aryl benzyl sulfides
were concerned,[20–21] this high enantioselectivity was obtained
regardless of the nature, steric hindrance and position of vari-
ous substituents on both aryl groups (Ar1 and Ar2 in
Scheme 1).
Figure 1. A schematic representation of the preliminary titanium complex
involving two hydrobenzoin molecules, TBHP and the substrate sulfide.
In the present paper, we describe the unexpected behaviour
observed in the case of fluoro-substituted benzyl phenyl sul-
fides. Although for partially fluorinated substrates we mea-
sured the usual excellent ee values (>98%), upon use of the
same oxidation protocol on the substrate in which the aryl
groups were completely fluorinated (pentafluorobenzyl penta-
fluorophenyl sulfide), we found for the first time a lower enan-
tioselectivity (ee 61%). In light of our previous experimental re-
sults, this finding was rather surprising and not easy to explain
on the basis of the previous computational model (i.e. exis-
tence and relative stability of preliminary titanium complexes).
To check the reliability of our mechanistic hypothesis, we have
examined two test-cases with the same DFT computational ap-
proach: 1) the oxidation of the sulfide in which the aryl groups
were completely fluorinated (pentafluorobenzyl pentafluoro-
phenyl sulfide) characterized by the unexpectedly lower ee and
2) the oxidation of a partially fluorinated substrate exhibiting
the usual excellent ee (pentafluorobenzyl phenyl sulfide). Our
aim was to answer the following questions: 1) does the topolo-
gy of the reaction surface significantly change in the presence
of a complete substrate fluorination? 2) Does the formation of
the preliminary complexes remain the key-step in determining
the preference for one of the two diastereomeric pathways?
3) Do the weak aromatic CH···p interactions still play a funda-
mental role in determining the relative energy of the two reac-
tion channels? In both cases 1) and 2) the model-system is
similar to that used in our previous study[20] and consists of the
substrate molecule (pentafluorobenzyl pentafluorophenyl sul-
fide or pentafluorobenzyl phenyl sulfide), the tert-butyl hydro-
peroxide (TBHP) and the [(S,S)-hydrobenzoin]2-Ti complex.
Scheme 1. Enantioselective oxidation of aryl benzyl sulfides with TBHP in
the presence of a titanium/(S,S)-hydrobenzoin catalyst.
Interestingly, the oxidation of substrates differing in the
structure from that of aryl benzyl sulfides, such as alkyl aryl sul-
fides, afforded a significantly lower enantioselectivity (52–62%
ee values).[21] Similarly, Sulindac sulfides alkyl esters, that are
precursors of bioactive molecules and are structurally similar to
alkyl aryl sulfides, showed a lower enantioselectivity if oxidised
by the same catalytic system.[19] From a synthetic point of
view, the ee values obtained in the oxidation of these aryl alkyl
sulfides could be increased if a kinetic resolution process in
the over-oxidation of sulfoxide to sulfone was allowed.[19,21]
Recently, we also performed a combined computational-ex-
perimental study on the cited asymmetric oxidation of aryl
benzyl sulfides bearing different substituents.[20] We used, as
a model-system, unsubstituted benzyl phenyl sulfide reacting
with tert-butyl hydroperoxide in the presence of complexes of
titanium with (S,S)-hydrobenzoin and we found that the exper-
imentally observed enantioselectivity depends on the relative
energy of two preliminary octahedral titanium complexes that
form in the first reaction phase. These complexes provide two
diastereomeric pathways leading to (R)- and (S)-sulfoxide. The
relative stability of these crucial intermediates was determined
by the presence of weak interactions involving the aryl groups,
in particular, aromatic CH···p interactions (also denoted in
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oxide 3b (ee value > 98%) in high isolated yield (96%). Finally,
we performed the oxidation of benzyl pentafluorophenyl sul-
fide 4a[32] (completely fluorinated non-benzyl phenyl group)
and we found again a high isolated yield (86%; Table 1,
entry 4) of the corresponding sulfoxides 4b, obtained in enan-
tiopure form (ee value >98%). These results indicate that only
the simultaneous complete fluorination of both phenyl rings
represents the structural feature responsible for the lower ee
observed for sulfide 1a.
Results and Discussion
Experimental enantioselective oxidation: Reactivity of
fluorinated aryl benzyl sulfides
In a previous paper, we performed the oxidation of o- and p-
bromophenyl pentafluorobenzyl sulfide using TBHP in the
presence of a complex of titanium and (S,S)- or (R,R)-hydroben-
zoin. Our purpose was to investigate the effect of the com-
plete fluorination of the phenyl moiety of the benzyl group on
the reaction enantioselectivity.[21] As reported in the case of
other differently substituted aryl benzyl sulfides,[17,20–21] we ob-
tained the usual enantiopure sulfoxides (ee value >98%) in
good isolated yields (81–97%).
Configurations and crystal structures of the enantiopure
sulfoxides
On the basis of our previous work,[17–21] and in accordance with
our earlier model,[20–21] (R)-sulfoxides 1b–4b are the expected
product if (S,S)-hydrobenzoin is used as a ligand of titanium.
As we were not able to obtain suitable crystals of sulfoxide 2b
for X-ray diffraction experiments, we inferred its (R)-configura-
tion on the basis of circular dichroism spectra. This approach
provides highly reliable information for this class of molecules,
as demonstrated in our recent theoretical and experimental
papers on this topic[21,33]. Sulfoxide 2b displayed the expected
Mislow pattern[9] for the (R)-configuration, as shown in Fig-
ure S1 of the Supporting Information. Moreover, the same pat-
tern was also shown by the enantioenriched sulfoxide 1b, in
which the predominant enantiomer should have the (R)-config-
uration too (Figure S1).
However, upon use of the same protocol to oxidise penta-
fluorobenzyl pentafluorophenyl sulfide 1a,[29] (i.e. the sulfide in
which both phenyl rings are completely fluorinated), we ob-
tained a low yield (19%) of the corresponding sulfoxide 1b
and a significantly lower enantioselectivity (61% ee value).
Thus, after a series of examples of aryl benzyl sulfides that we
have systematically oxidised with the same protocol to the cor-
responding sulfoxides with very high ee values,[17,20–21] we ob-
served the first case of an unsatisfactory reactivity and a lower
ee (Table 1, entry 1).
Table 1. Enantioselective oxidation of fluorinated aryl benzyl sulfides
with TBHP in the presence of a titanium/(S,S)-hydrobenzoin complex.
For sulfoxides 3b and 4b it was possible to assign the abso-
lute configurations by X-ray diffraction experiments. We also
observed the (R)-configuration in these cases. The crystal struc-
tures of 3b and 4b are depicted in Figure S2 and S3 (Support-
ing Information). The aryl groups of 2-fluorophenyl pentafluor-
obenzyl sulfoxide 3b are arranged in a gauche conformation
(dihedral angle=65.08), whereas the same moieties of the
benzyl pentafluorophenyl sulfoxide 4b are characterised by an
anti periplanar conformation (dihedral angle=179.68). Further-
more, aryl groups are ordered into parallel displaced stacking
structures,[34–35] a supramolecular arrangement which features
molecules containing perfluorinated aryl groups.
Entry
Ar1
Ar2
Yield[a] [%]
ee[b] [%]
61[c] (R)[d]
>98 (R)[d]
>98 (R)[e]
>98 (R)[e]
1
2
3
4
C6F5
C6H5
2-F-C6H4
C6H5
C6F5
C6F5
C6F5
C6F5
19
91
96
86
[a] Yields refer to pure isolated products. [b] The ee values were measured
by HPLC. [c] The ee value increased to 65% after crystallisation. [d] Con-
figuration established by circular dichroism spectroscopy. [e] Configura-
tion established by X-ray diffraction analysis.
In view of this unexpected result, we decided to examine
other fluorinated aryl benzyl sulfides to provide a more reliable
analysis of the reaction performance. Thus, we oxidised the
pentafluorobenzyl phenyl sulfide 2a,[30] that is, the sulfide in
which only the phenyl moiety of the benzyl group is fluorinat-
ed and the other one bears no substituents. In this case, we
obtained the usual enantiopure sulfoxide 2b[31] (ee value
>98%) in high isolated yield (91%; Table 1, entry 2). In a further
experiment, we oxidised the 2-fluorophenyl pentafluorobenzyl
sulfide 3a, a substrate structurally similar to the already investi-
gated[21] 2-bromophenyl pentafluorobenzyl sulfide, in which
the bromine atom is replaced by the potentially more prob-
lematic fluorine one. In principle, this substitution close to the
reaction centre could affect the reaction pathway, as reported
in the case of the lower enantioselectivity observed if the me-
thoxy group is present on the ortho- or meta-position of the
phenyl group (84–88% ee).[20] However, even in case of sulfide
3a (Table 1, entry 3), we obtained the usual enantiopure sulf-
Computational mechanistic study
The energy profile for the oxidation of the pentafluorobenzyl
pentafluorophenyl sulfide by TBHP in the presence of the
[(S,S)-hydrobenzoin]2-Ti complex is shown in Figure 2. Schemat-
ic representations of the structure of the critical points located
on the surface are reported in Figure 3–6. The asymptotic limit
(AL) used as a reference in Figure 2 corresponds to the three
non-interacting reactant molecules, that is the titanium(hydro-
benzoin)2 tetrahedral complex, the substrate pentafluorobenzyl
pentafluorophenyl sulfide and TBHP, at infinite distance. At the
beginning of the process, the approaching of substrate to the
titanium complex affords two different intermediates M1 and
M1’, depending on the relative orientation of the two mole-
cules. As found in our previous work,[20] the subsequent inter-
action with TBHP does not require any activation barrier and
gives two new intermediate species M2 and M2’ in which the
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Figure 2. Computed energy profile for the enantioselective oxidation of
pentafluorobenzyl pentafluorophenyl sulfide 1a in the presence of the
[(S,S)-hydrobenzoin]2-Ti catalyst.
Figure 4. A schematic representation of the structure of the two diastereo-
meric octahedral titanium complexes a) M2’ and b) M2 for pentafluoroben-
zyl pentafluorophenyl sulfide 1a. Bond lengths (R) are in [ꢁ], energies in
[kcalmolꢀ1] relative to AL.
Figure 5. A schematic representation of the structure of the octahedral tita-
nium complexes complex M2(a) for pentafluorobenzyl pentafluorophenyl sul-
fide 1a. Bond lengths (R) are in [ꢁ], energies in [kcalmolꢀ1] relative to AL.
Figure 3. A schematic representation of the structures of the two diastereo-
meric titanium pentacoordinate adducts a) M1’ and b) M1 for pentafluoro-
benzyl pentafluorophenyl sulfide 1a and c) the substrate. Bond lengths (R)
are in [ꢁ], energies in [kcalmolꢀ1] relative to AL.
Even if this energy profile is qualitatively similar to that com-
puted in our previous investigation, in which a non-fluorinated
substrate (i.e. benzyl phenyl sulfide) was used as a model-
system,[20] important differences in the comparison between
the two reaction surfaces can be detected. The new profile
shows an increase of the energy gap between the two prelimi-
nary complexes M1 and M1’. This quantity, which was 1.7 kcal
molꢀ1 for benzyl phenyl sulfide, is now 3.3 kcalmolꢀ1. However,
the major and most important change caused by complete
substrate fluorination is found in the M2–M2’ energy gap: al-
though in the non-fluorinated case M2’ was 5.1 kcalmolꢀ1
lower in energy than M2, these two adducts are almost degen-
peroxide group is oriented toward the sulfur atom. Along the
reaction path which stems from M1, we have located an addi-
tional critical point M2(a), which differs from M2 in the confor-
mation of the substrate molecule. TS and TS’ are transition
states in which an oxygen atom moves from the peroxide
group to sulfur to form the final sulfoxide species. As the two
reaction pathways M1!M2!TS and M1’!M2’!TS’ afford
a final sulfoxide product with configuration S and R at the
sulfur atom, respectively, they are denoted in Figure 2 as pro-S
and pro-R channel.
erate in this experiment (the difference is only 0.4 kcalmolꢀ1
,
with M2’ more stable than M2). The secondary minimum M2(a)
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planar for both phenyl pairs (B1-B4 and B1’-B3), but they are
displaced in such a way that an electron-rich fluorine atom of
the substrate can interact with the carbon atoms of the hydro-
benzoin phenyl group. This parallel-displaced arrangement is
the most favourable one,[34–35] as demonstrated in accurate
computational studies by Tsuzuki et al.[36] Typical FꢀC distances
that feature these interactions are in the range 3.2–3.5 ꢁ, as
shown in Figure 3a; these values are in agreement with those
reported in literature.[34–35] In addition to the previously cited
interactions, a hydrogen bond involving a B3 fluorine atom
and a B1 CꢀH bond contributes to the stabilisation M1’ (the
computed (B1)CꢀH···F(B3) distance is 2.36 ꢁ). This value is in
rather good agreement with the H···F distance found in the
crystal structure of some fluorobenzenes characterized by the
presence of this type of hydrogen bonds.[37–38]
In M1 (see Figure 3b), the substrate abandons the linear
conformation that characterises M1’ and adopts a bent confor-
mation, which is almost identical to that of the isolated sub-
strate (depicted in Figure 3c). As a consequence, the interac-
tion pattern between the substrate and the two hydrobenzoin
ligands completely changes with respect to M1’ and the analo-
gous M1 complex found in the case of benzyl phenyl sulfide.[20]
In the present case, the fluorinated rings form a sort of dis-
placed “sandwich” structure in which one electron-rich fluorine
atom of ring B3 can effectively interact with two electron-poor
carbon atoms of ring B4 (an extra partial perspective of M1 is
provided in Figure 3b to illustrate these interactions). The
nature of these F···C interactions is only apparently similar to
that previously discussed for M1’. In M1 they are expected to
be more effective because the carbon atoms are now electron-
poorer than in the previous case, each carbon atom being
bonded to a fluorine atom. Thus, they can be considered to be
real strong p-donor/p-acceptor interactions. Their augmented
strength, as a result of the complete fluorination of the phenyl
groups, is confirmed by the shorter FꢀC distances computed
for the B3-B4 pair (3.14 and 3.15, as shown in Figure 3b) with
respect to the values obtained for the B4-B1 pair in M1’ (3.19
and 3.40 ꢁ are the shortest (B4)F···C(B1) distances computed in
that case). Notably, these values are in good agreement with
the shortest distances between stacked fluorinated phenyl
rings found in the crystal structures of sulfoxides 3b and 4b.
Two additional important interactions have been revealed
by our computations on M1. One interaction is given by an
edge-to-face (or T-shaped) configuration[27–28,34] involving the
ring pair B1’-B4. In this edge-to-face structure, which is made
possible by the particular “folded” substrate arrangement, the
plane of the hydrobenzoin phenyl ring B1’ is roughly orthogo-
nal to the plane of the substrate ring B4 (3.03 and 3.04 ꢁ are
the shortest distances between one (B1’)CꢀH bond and the B4
carbon atoms). This structure was demonstrated to be more
stabilising than “parallel-displaced” and “sandwich” structures
because of the additional contribution of H-bonding.[34–36] In
the present case the CꢀH bond points to the middle of
a (B4)CꢀC bond (CꢀH···p interaction) and interacts at the same
time with an electron-rich fluorine atom (CꢀH···F distance=
3.39 ꢁ). This value is longer with respect to crystallographic
data[37–38] and that previously found in M1’. This difference is
Figure 6. A schematic representation of the structure of the two diastereo-
meric transition states a) TS’ and b) TS for pentafluorobenzyl pentafluoro-
phenyl sulfide 1a. Bond lengths (R) are in [ꢁ], energies in [kcalmolꢀ1
]
relative to AL.
is 8.1 kcalmolꢀ1 higher than M2. No significant variation was
found in the relative energy of the two transition states TS
and TS’, which are almost degenerate (as found in our previ-
ous study), their energy difference being only 0.2 kcalmolꢀ1.
However, in the present case they lie slightly above the asymp-
totic limit, TS being 1.6 kcalmolꢀ1 higher than AL.
The near degeneracy of M2 and M2’, which are the lowest
energy minima along the two reaction channels, has important
effects on the enantioselectivity of the reaction. As pointed
out in our previous work,[20] the ee is determined by the ener-
getics and kinetic features of the first phase of the reaction af-
fording M2 and M2’. Owing to their near degeneracy, these
two adducts should form in similar amounts. Also, because the
two transition states are very close in energy, the two corre-
sponding reaction channels are both significantly populated
and the relative yield of the two final products (differing in
sulfur configuration) must be similar, in agreement with the
lower ee experimentally observed.
Our aim is now to understand the structural and electronic
factors that, upon complete fluorination of the two substrate
benzene rings, affect the relative energy of the intermediate
adducts (M1 compared to M1’, M2 compared to M2’, and
M2(a) compared to M2) and transition states (TS and TS’). In-
spection of Figure 3 shows that the two penta-coordinated ti-
tanium complexes M1 and M1’ significantly differ in the way
the benzene rings of the hydrobenzoin ligands (B1, B2, B1’ and
B2’) interact with the substrate. More precisely, the structural
features of M1’ are rather similar to those already outlined for
the corresponding complex in the non-fluorinated case.[20] The
substrate has roughly a linear structure that allows the activa-
tion of p-stacking interactions (as shown in Figure 3a) be-
tween the perfluorophenyl rings of the substrate (B3 and B4)
and the phenyl rings B1 and B1’ of both hydrobenzoin ligands.
However, because of the presence of fluorine atoms on both
substrate rings, the nature and strength of these interactions
differ from those discussed in our earlier study. In the present
case, the planes of the interacting rings are approximately
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probably a result of the particular edge-to-face arrangement of
the two rings B1’ and B4 and the simultaneous presence of
other interactions. The other interaction involves the substrate
methylene group, the B1 benzene ring and one hydrobenzoin
oxygen O1. Inspection of Figure 3b shows that one of the CꢀH
methylene bonds points toward B1: the computed distances
between this (methylene)CꢀH bond and three B1 carbon
atoms (2.85, 3.03 and 3.13 ꢁ) indicate a non-negligible interac-
tion of the CꢀH bond with the p-electron cloud of B1 (CꢀH···p
interaction). The second (methylene)CꢀH bond is involved into
a hydrogen interaction with the hydrobenzoin O1 oxygen, the
(methylene)CꢀH···O1 distance being 2.50 ꢁ. This computational
finding suggests that the particular displaced “sandwich” struc-
ture that features the substrate in the M1 complex (which
allows a significant interaction between the two rings B3 and
B4) and the interaction of the substrate methylene group with
B1 and O1, are the factors responsible for the energy lowering
of M1 and the augmented M1–M1’ energy gap (from 1.7 in
the non-fluorinated molecule to 3.3 kcalmolꢀ1 in the present
case).
ported in the bottom part of Figure 4b). Furthermore, since
the hydrobenzoin molecule is pushed apart by the entering
TBHP, the substrate methylene is now too far away to maintain
the hydrogen bond with O1. However, to compensate the loss
of this stabilising interaction, both CꢀH bonds of the substrate
methylene now effectively interact with the B1 p electron
cloud (CꢀH···p interaction), as demonstrated by the (methyle-
ne)CꢀH···C(B1) distances reported in the Figure (2.89 and
2.84 ꢁ are characteristic values). A further important interaction
revealed by our computations (and which differentiates this
M2 structure from that computed in the non-fluorinated case
of ref. 20) is the interaction between a B4 fluorine atom and
a hydrogen atom on B1’, the B(4)F···HꢀC(B1’) distance being
2.90 ꢁ. On the basis of our analysis, it is reasonable to believe
that the ”displaced sandwich-conformation” of the substrate is
the key factor that determines the energy lowering of M2 and
the consequent near degeneracy of the two intermediates M2’
and M2. It is important to outline that the other stabilising in-
teractions detected in M2 (i.e. the interaction of the substrate
methylene CꢀH bonds with B1 and the hydrogen interaction
B(4)F···HꢀC(B1’)) are a consequence of the particular bent con-
formation of the substrate molecule.
Particularly important now is to elucidate the factors that
determine the near degeneracy of M2 and M2’. Inspection of
Figure 4 shows that in M2’ the substrate maintains the approx-
imately linear conformation of M1’ and the resulting structure
is apparently similar to that obtained in the non-fluorinated
case.[20] However, a more detailed analysis shows that the pres-
ence of fluorine atoms is responsible for some important struc-
tural changes. Upon addition of TBHP, one hydrobenzoin mole-
cule is pushed closer to the substrate and the B1 ring rotates
around the CꢀC bond to make room in the metal coordination
sphere. As a consequence of this rotation, the most effective
interactions between B1 and B4 are now determined by a rela-
tive arrangement of the two rings similar to an edge-to-face
configuration (or T-shaped-like), even if the B1 and B4 planes
form a dihedral angle much lower than 908. As a result of the
complete fluorination, the (B1)CꢀH bonds approximately point
towards two electron-rich fluorine atoms on B4: 3.34 and
3.16 ꢁ are the shortest (B1)CꢀH···F(B4) computed distances.
Furthermore, an important hydrogen bond has been detected
between one B4 fluorine atom and one hydrogen of the hy-
drobenzoin methylene unit adjacent to B2, the (B4)F···H-
C(methylene) distance being 2.48 ꢁ. An additional significant
interaction involves another B4 fluorine atom and the hydro-
Our analysis concerning the factors that are responsible for
the stabilisation of M2 is confirmed by the existence of an ad-
ditional structure (showing the same substrate orientation that
features M2) in which the substrate molecule maintains the
linear conformation found in M2’. Since in the subsequent
transition state TS the substrate has a linear conformation, this
secondary minimum (denoted as M2(a)) must represent an in-
termediate belonging to the pro-S channel (M1!M2!M2(a)!
TS). The formation of M2(a) after “substrate unfolding” allows
the reacting system to enter the transition region. M2(a), which
lies 8.1 kcalmolꢀ1 higher in energy with respect to M2, is sche-
matically represented in Figure 5 in two different perspectives.
Interestingly, the M2(a)–M2 energy gap is not very different
from that between M2’ and M2 computed in the non-fluori-
nated case (5.1 kcalmolꢀ1) in which M2 was characterised by
a linear conformation.[20] This result unambiguously points to
the “sandwich” structure (or “folded” conformation) of the sub-
strate molecule as the key factor that stabilises M2.
In the transition state TS, as previously outlined, the distinc-
tive “sandwich” structure that stabilises M1 and M2, disap-
pears. In both TS and TS’ (see Figure 6), that are almost degen-
gen atom of a methyl group of TBHP (the computed (B4)F···Hꢀ erate, the substrate molecule is approximately linear and the
C(methyl) distance is 2.73 ꢁ). The relative arrangement of the
two rings B1’ and B3 is analogous to that found in M1’. These
two rings form a parallel-displaced structure in which an elec-
tron rich fluorine atom of B3 interacts with two electron-poor
carbon atoms of B1’: the shortest (B3)F···C(B1’) distances are
3.16 and 3.37 ꢁ, which are close to the values found in M1’.
If we neglect the approaching TBHP molecule (responsible
for the new octahedral configuration of titanium), the structure
of M2 (see Figure 4b) closely resembles that of M1: the sub-
strate is again characterised by the bent conformation (“dis-
placed sandwich-structure”) in which electron-rich fluorine
atoms of B3 interact with electron-poor carbon atoms of B4
(the shortest (B3)F···C(B4) distances are 3.02 and 3.34 ꢁ, as re-
arrangement of the various ligands around the metal is rather
similar to that found in the non-fluorinated case.[20] We believe
it is important to point out again that the TS structure unam-
biguously indicates that the secondary minimum M2(a) (in
which the substrate has attained a linear conformation) repre-
sents a “necessary” conformational arrangement that must be
adopted by the reacting system before reaching the transition
state region. In Figure 6, we have highlighted the migrating
O4 oxygen atom, the breaking O3-O4 bond (1.84 and 1.82 ꢁ in
TS’ and TS, respectively) and the new forming O4ꢀS bond
(2.12 and 2.14 ꢁ). During the migration, the O4 bonded hydro-
gen atom moves closer to O3 and, in both TS and TS’, forms
a strong hydrogen bond that anticipates the O3ꢀH bond in
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the final product (the O4-H···O3 distance is 2.14 and 2.11 ꢁ in
TS’ and TS, respectively). Notably, if O4 moves from O3 to S
and the hydrogen atom comes nearer to O3, the hydrogen-
bond between this hydrogen atom and O1’ is maintained in
the transition structures, which helps to stabilises the migra-
tion pathway.
A schematic representation of M2’, M2 and M2(a) is given in
Figure S4 of the Supporting Information. The structure of M2’
is very similar to the corresponding structure found for penta-
fluorobenzyl pentafluorophenyl sulfide: the substrate is charac-
terised by a linear conformation and similar interactions involv-
ing the two ring pairs B3 and B1’ and B1 and B4 can be recog-
nised. The most interesting result concerns M2 and M2(a), that
is, the two structures differing in the substrate conformation.
Unlike the results obtained for the completely fluorinated sul-
fide, in this case the more stable structure is M2(a), which is fea-
tured by a linear conformation of the substrate while the
“sandwich” folded conformation is found in M2.
This computational finding, which is reversed with respect
to that found for pentafluorobenzyl pentafluorophenyl sulfide
1a, indicates that, in the presence of a partial fluorination of
the substrate, the folded “sandwich” structure does not stabi-
lise M2 strongly enough to make it degenerate to M2’. The
factors that make the sandwich conformation less effective in
stabilising M2 are evident from the analysis of Figure S4c (Sup-
porting Information). The lacking of fluorine atoms on the
phenyl ring (B4) partly cancels the strong stabilising interac-
tions between one B4 fluorine atom and the ring B1’: in partic-
ular the hydrogen bond between fluorine and a B1’ ring hy-
drogen definitely disappears. Finally, no significant differences
are evident in the comparison of TS and TS’ to the corre-
sponding transition structures found for the completely fluori-
nated substrate (see Figure S5 of the Supporting Information).
The small energy gap between the two transition states con-
firms that the interaction pattern does not change significantly.
In addition to the oxidation of the completely fluorinated
sulfide 1a, we investigated also the case of the pentafluoro-
benzyl phenyl sulfide 2a, that was oxidised with the same pro-
cedure yielding the enantiopure sulfoxide 2b. Since the key
features of the surface determining the enantioselectivity of
the reaction are the relative energies of the M2- and M2’-type
intermediates and TS and TS’ transition states, we focused our
investigation on these two regions of the potential surface,
which is depicted in Figure 7. As previously found, in the inter-
Figure 7. Computed energy profile for the enantioselective oxidation of pen-
tafluorobenzyl phenyl sulfide 2a in the presence of the [(S,S)-hydroben-
zoin]2-Ti catalyst.
Conclusions
We performed a combined computational and experimental
study of the oxidation of fluorinated aryl benzyl sulfides using
tert-butyl hydroperoxide (TBHP) in the presence of a complex
between titanium and (S,S)-hydrobenzoin. In a framework char-
acterised by an invariantly high enantioselective oxidation (ee
values >98%), the particular case of pentafluorobenzyl penta-
fluorophenyl sulfide 1a emerged as the only exception, for
which the oxidation was characterised by a lower enantioselec-
tivity (61% ee value). To explain this unexpected stereochemi-
cal result, we examined the reaction potential energy surface
at the DFT level for two test-cases: 1) the pentafluorobenzyl
phenyl sulfide, which shows the usual excellent ee value and
2) the pentafluorobenzyl pentafluorophenyl sulfide character-
ised by a less satisfactory enantioselectivity. To this purpose we
used a model-system formed by the substrate molecule, the
oxidant TBHP and the [(S,S)-hydrobenzoin]2-Ti complex. The
model-system is identical to that employed in a previous work
to rationalise the results for other substituted aryl benzyl
sulfides.
mediate region we have located two critical points M2 and
M2(a), again differing in the conformation of the substrate mol-
ecule (M2 and M2(a) denote, as in the previous discussion, the
two structures with “folded” and “unfolded” linear conforma-
tion of the substrate, respectively). The most significant
change caused by the partial substrate fluorination (only the
phenyl ring of the benzyl group is fluorinated) is given by the
variation of the energy difference between the M2- and M2’-
type intermediates. In this case, the two adducts are no longer
degenerate and M2’ is 6.2 kcalmolꢀ1 lower in energy than
M2(a). Interestingly, this value is close to that previously
found,[20] for benzyl phenyl sulfide (5.1 kcalmolꢀ1). The other
minimum M2 (folded substrate structure) is 0.8 kcalmolꢀ1
higher than M2(a). Furthermore, the two transition states are
again close in energy, TS’ being only 1.2 kcalmolꢀ1 lower than
TS. The resulting energy diagram (almost identical to that re-
ported in ref. [20]) for the non-fluorinated substrate, suggests
that the M2’ adducts forms almost exclusively during the first
reaction phase and the dominant reaction channel is the one
affording configuration R (pro-R channel) at the sulfur atom in
the sulfoxide product, in agreement with the experimental
evidence.
As discovered in our previous study, we found that the
enantioselectivity is governed by the relative energy of the
two octahedral complexes that form if the oxidant approaches
the initial complex between [(S,S)-hydrobenzoin]2-Ti and the
substrate. These octahedral complexes form in the first reac-
tion phase before the oxygen transfer. They are diastereomers
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dichroism spectra were recorded in acetonitrile solution by using
a Jasco J-810 spectropolarimeter.
differing in the orientation of the substrate with respect to the
metal and the oxidant. Two distinct diastereomeric pathways
stem from these complexes and lead to the two sulfoxides
that differ in the configuration of the newly formed sulfur
chiral centre.
Sulfides 2a–4a were synthesised by standard reaction of the corre-
sponding benzyl bromides in acetone with the sodium salt of com-
mercially available thiols at 508C. Sulfide 1a was obtained by re-
acting for 18 h pentafluorothiophenol with triethylamine and pen-
tafluorobenzyl bromide in acetone at ꢀ208C to avoid the forma-
tion of large amounts of side products.
In the case of pentafluorobenzyl pentafluorophenyl sulfide
the two octahedral complex intermediates are almost degener-
ate (their energy difference is only 0.4 kcalmolꢀ1) and they
should form in similar amounts. Since the two transition states
that originate from these intermediate species are very close in
energy, the probabilities to follow one or the other diastereo-
meric reaction channel (pro-R or pro-S) become comparable,
which leads to the lower experimentally observed enantiomer-
ic excess.
Syntheses and Characterisation data
Pentafluorobenzyl pentafluorophenyl sulfide (1a):[29] M.p. 73–748C
(n-hexane).
Pentafluorobenzyl phenyl sulfide (2a):[30] Kugelrohr oven temp 90–
928C, p=0.1 mbar.
Our computations indicate that the “displaced sandwich-
conformation” of the substrate is the key factor that deter-
mines the energy lowering of M2 and the consequent near de-
generacy of M2 and M2’. Furthermore, other stabilising inter-
actions detected in M2 (i.e. the interaction of the substrate
methylene CꢀH bonds with the p cloud of ring B1 and the hy-
drogen interaction B(4)F···H-C(B1’) are a consequence of the
unusual and unexpected bent conformation of the substrate
moiety.
2-Fluorophenyl pentafluorobenzyl sulfide (3a): Kugelrohr oven
temp 85–888C, p=0.1 mbar. 1H NMR (500 MHz, CDCl3): d=7.36–
7.30 (m, 2H, HAr), 7.12–7–08 (m, 1H, HAr), 7.07–7.03 (m, 1H, HAr),
4
4.08 ppm (t, JH,F =1.2 Hz, 2H, CH2); 13C NMR (125 MHz, CDCl3): d=
1
1
162.9 (d, JC,F =248 Hz, CAr), 144.9 (d-like, JC,F =256 Hz, CAr), 140.4
(d-like, 1JC,F =254 Hz, CAr), 137.2 (d-like, 1JC,F =255 Hz, CAr), 135.8
3
3
(CAr), 131.1 (d, JC,F =8.3 Hz, CAr), 124.5 (d, JC,F =3.5 Hz, CAr), 120.0
(d, 2JC,F =18.7 Hz, CAr), 116.0 (d, 2JC,F =22.9 Hz, CAr), 112.3 (m, CAr),
26.0 ppm (CH2); elemental analysis calcd (%) for C13H6F6S: C 50.65,
H 1.96; found: C 50.70, H 2.22.
For pentafluorobenzyl phenyl sulfide we found that the
complex leading to configuration R (M2’) is significantly more
stable than that affording configuration S (M2), the energy gap
being 6.2 kcalmolꢀ1. As pointed out in the above discussion,
the ee is determined by the energetics and kinetic features of
the first reaction phase affording M2 and M2’. Thus, because
M2’ is much more populated than M2, the reacting system
preferentially follows the pathway that originates from the
more stable intermediate, leading to the (R) configuration at
the sulfur stereogenic centre.
Benzyl pentafluorophenyl sulfide (4a):[32] Kugelrohr oven temp 83–
858C, p=0.1 mbar.
Racemic sulfoxides 1b–4b (used in the setting up of the chiral
HPLC separation) were synthesised by standard mCPBA oxidation.
Enantioenriched sulfoxides 1b–4b were produced by the TBHP-ox-
idation according to our protocol[17–21] in n-hexane, in the presence
of 5 mol% of titanium/hydrobenzoin catalyst (see also Supporting
Information).
Pentafluorobenzyl pentafluorophenyl sulfoxide (1b): M.p. 133–
1358C (n-hexane/ethanol 1:1). ½aꢁ2D5 = +23.3 (c=0.8, CHCl3) for
Our computations clearly indicate that if the substrate is
only partially fluorinated the folded “sandwich” structure does
not stabilise M2 strongly enough to make it degenerate to
M2’ and the arrangement of M2 becomes similar to that ob-
served for other phenyl benzyl sulfides.[20] In particular, the
lacking of fluorine atoms on the sulfide phenyl ring cancels the
strong stabilising interactions observed in the pentafluoroben-
zyl pentafluorophenyl sulfide between one phenyl fluorine
atom and one hydrobenzoin phenyl ring. These results are fur-
ther evidence of the value and reliability of the computational
model that we proposed in a previous paper[20] to explain the
persistent high enantioselectivity found in the catalysed oxida-
tion of a large series of differently substituted aryl benzyl
sulfides.
1
a sulfoxide with an ee of 65%; H NMR (500 MHz, CDCl3): d=4.69–
4.68 ppm (m, 2H, CH2); 13C NMR (125 MHz, CDCl3): d=145.7 (d-like,
1JC,F =251 Hz, CAr), 145.4 (d-like, 1JC,F =256 Hz, CAr), 144.1 (d-like,
1JC,F =260 Hz, CAr), 143.7 (d-like, 1JC,F =257 Hz, CAr), 137.7 (d-like,
1JC,F =254 Hz, CAr), 116.4 (m, CAr), 103.4 (m, CAr), 47.2 ppm (CH2); ele-
mental analysis calcd (%) for C13H2F10OS: C 39.41, H 0.51; found: C
39.54, H 0.61; the ee value was measured by HPLC (Column: Chiral-
cel OD-H. Eluent: hexane/i-propanol 70:30).
Pentafluorobenzyl phenyl sulfoxide (2b):[31] M.p. 169–1718C (n-
hexane/ethanol 8:2). ½aꢁD25 = +190.7 (c=1.1, CHCl3). The ee value
was measured by HPLC (Column: Whelk-O1. Eluent: hexane/i-prop-
anol 90:10).
2-Fluorophenyl pentafluorobenzyl sulfoxide (3b): M.p. 103–1058C
(n-hexane/acetone 8:2). ½aꢁ2D5 = +278.6 (c=1.1, CHCl3); 1H NMR
(500 MHz, CDCl3): d=7.57–7.51 (m, 2H, HAr), 7.35–7.31 (m, 1H, HAr),
2
7.18–7.12 (m, 1H, HAr), 4.42 (d, JH,H =13.3 Hz, 1H, CH2), 4.27 ppm
Experimental Section
2
(d, JH,H =13.3 Hz, 1H, CH2); 13C NMR (125 MHz, CDCl3): d=158.0 (d,
Chemicals were purchased from Sigma–Aldrich and were used as
received. n-Hexane employed in the enantioselective oxidation
protocol was distilled from 4 ꢁ molecular sieves prior to use. NMR
spectra were recorded by using a Bruker AM500 spectrometer.
HPLC analyses were performed on a Agilent 1100 chromatograph,
equipped with a DAD detector. Elemental analyses were performed
by using a Carlo Erba CHNS-O EA1108 elemental analyser. Circular
1JC,F =247 Hz, CAr), 145.8 (d-like, 1JC,F =247 Hz, CAr), 141.2 (d-like,
1
3
1JC,F =256 Hz, CAr), 137.3 (d-like, JC,F =254 Hz, CAr), 133.7 (d, JC,F
=
2
4
7.6 Hz, CAr), 129.5 (d, JC,F =16.6 Hz, CAr), 125.9 (d, JC,F =2.1 Hz, CAr),
125.3 (d, 3JC,F =3.5 Hz, CAr), 115.7 (d, 2JC,F =20.1 Hz, CAr), 103.7 (m,
CAr), 47.8 ppm (CH2); the ee value was measured by HPLC (Column:
Whelk-O1. Eluent: hexane/i-propanol 90:10); elemental analysis
calcd (%) for C13H6F6OS: C 48.16, H 1.87; found: C 47.96, H 1.61.
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Benzyl pentafluorophenyl sulfoxide (4b): M.p. 115–1178C (n-
spectra and Mr. Giuseppe Chita (CNR, Istituto di Cristallografia,
Bari, Italy) for X-ray data collection.
hexane); ½aꢁ2D5 =ꢀ64.0 (c=0.6, CHCl3); 1H NMR (500 MHz, CDCl3):
2
d=7.37–7.28 (m, 3H, HAr), 7.20–7.14 (m, 2H, HAr), 4.68 (d, JH,H
=
12.4 Hz, 1H, CH2), 4.53 ppm (d, 2JH,H =12.4 Hz, 1H, CH2); 13C NMR
(125 MHz, CD3COCD3): d=147.2 (d-like, JC,F =250 Hz, CAr), 143.2 (d-
1
Keywords: density functional calculations · enantioselectivity ·
oxidation · reaction mechanisms · titanium
1
1
like, JC,F =250 Hz, CAr), 139.5 (d-like, JC,F =255 Hz, CAr), 132.2 (CAr),
131.4 (CAr), 130.7 (CAr), 130.5 (CAr), 119.7 (CAr), 62.0 ppm (CH2); the
ee value was measured by HPLC (Column: Chiralcel OD-H. Eluent:
hexane/i-propanol 70:30); elemental analysis calcd (%) for
C13H7F5OS: C 50.98, H 2.30; found: C 50.80, H 2.53.
´
´
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As the investigated model-system involves aryl groups in the sub-
strate and ligands, it is reasonable to believe that a reliable esti-
mate of interactions involving p systems (p–p stacking interac-
tions, T-shaped interactions) is essential in the computation of the
potential surface. It is well known that this class of interactions
cannot be correctly treated at the DFT level because the most pop-
ular functionals (for instance, B3LYP) are inaccurate for interactions
in which medium-range correlation effects are dominant such as
aromatic-aromatic stacking.[43] The MP2 method can satisfactorily
describe these interactions but, given the size of the model-system
used here, these computations would require too much computa-
tional time for a practical and extensive usage. However, a new
hybrid functional (denoted as MPWB1K), which is capable of treat-
ing medium-range correlation effects, has been proposed.[44] This
functional has been demonstrated to provide a good estimate of
the p–p interactions and reaction energetic[45–46] using reasonable
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Received: July 10, 2012
Published online on November 23, 2012
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ChemCatChem 2013, 5, 210 – 219 219