Sulfoxidation inside a C3-vanadium(V) bowl-shaped catalyst

Article abstract of DOI:10.1021/acscatal.7b01886

The confined enantiopure oxido-vanadium complex SSS-RRR-1 was synthesized and tested as a catalyst for the oxidation of sulfides into sulfoxides. This catalyst is very efficient with a reaction rate more than 300 times higher than that of the model compound SSS-RRR-3, and a turnover number (TON) close to 10⁵ was reached in combination with a good selectivity (more than 90%) in the sulfoxide product. Moreover, enantiomerically enriched sulfoxide can be obtained, breaking through the major limitation of the previous chiral vanatrane catalysts that show no detectable enantiomeric excess (ee). Further investigations revealed that the complex SSS-RRR-1 adopts a bowl-shaped structure with an open hydrophobic pocket. The microenvironment of the chiral pocket above the metal center accounts for the strong improvement in catalytic activity and enantioselectivity.

Full text of DOI:10.1021/acscatal.7b01886

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Article
Sulfoxidation inside A C3-Vanadium(V) Bowl-Shaped Catalyst
Dawei Zhang, Jean-Pierre Dutasta, Veronique Dufaud, Laure Guy, and Alexandre Martinez
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b01886 • Publication Date (Web): 05 Sep 2017
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Sulfoxidation inside A C3-Vanadium(V) Bowl-Shaped
Catalyst
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Dawei Zhang,b Jean-Pierre Dutasta,b Veronique Dufaud,c Laure Guy,b Alexandre
Martinez*a
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a
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Aix Marseille Univ, CNRS, Centrale Marseille, iSm2, Marseille, France
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Laboratoire de Chimie, École Normale Supérieure de Lyon, CNRS, UCBL, 46 allée d’Italie, F-69364 Lyon,
France.
c
Laboratoire de Chimie, Catalyse, Polymères, Procédés CNRS, UMR 5265, Université Claude Bernard Lyon1,
CPE Lyon, 43 Bd du 11 novembre 1918, 69616, Villeurbanne cedex, France.
10 ABSTRACT
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A confined enantiopure oxido-vanadium complex SSS-RRR-1 was synthesized and tested as
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catalyst for the oxidation of sulfides into sulfoxides. This catalyst is very efficient with a
reaction rate more than 300 times higher than the model compound SSS-RRR-3, and a
turnover number (TON) close to 105 was reached combined with a good selectivity (more
than 90%) in the sulfoxide product. Moreover, enantiomerically enriched sulfoxide can be
obtained, breaking through the major limitation of the previous chiral vanatrane catalysts
that show no detectable enantiomeric excess (ee). Further investigations revealed that the
complex SSS-RRR-1 adopts a bowl-shaped structure with an open hydrophobic pocket. The
microenvironment of the chiral pocket above the metal center accounts for the strong
improvement in catalytic activity and enantioselectivity.
21 KEY WORDS
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Sulfoxidation; enantioselectivity; supramolecular catalysis; oxido-vanadium complex; high
TON; chiral pocket
24 INTRODUCTION
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Confined catalysts in supramolecular architectures are very attractive since they offer precise
spatial control of chemical transformations by surrounding the surfaces of reactants,1
bringing substrates into close proximity, and imposing a specific orientation of the substrate
in the vicinity of catalytic sites;2 hence high activities and selectivities can be reached with
such bio-inspired catalysts. Nevertheless, supramolecular catalysts frequently display low
reactivity because of the high rigidity of their skeleton, which blocks the access of substrates
to the catalytic sites, or because of product inhibition, which prevents any catalytic cycles.3
Thus, a right balance between flexibility and rigidity of the structure should be considered
when designing a confined catalyst, which should favor the binding of the substrates and the
release of the products.4
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Among the reactions that have been catalyzed by confined catalysts, the selective oxidation
of sulfides into sulfoxides appears as particularly appealing.5 Indeed, sulfoxidation is a
challenging and important process since sulfoxides are key intermediates in the synthesis of
bioactive compounds, including several marketed pharmaceuticals and agrochemicals,6 or
can serve as chiral auxiliaries in organic synthesis or as chiral ligands in enantioselective
catalysis.7 In nature, vanadium haloperoxidases catalyze this reaction with high efficiency
and selectivity, for instance, vanadium bromoperoxidase from the brown seaweed
ascophyllum nodosum, converts thioanisol to the R-enantiomer of the sulfoxide with 55%
yield and 85% enantiomeric excess (ee).8 The confined active site of such enzymes displays a
vanadium atom in trigonal bipyramidal geometry with an axial V=O bond, three equatorial
O and an axial N donor.9 In order to mimic the high activity of these enzymes, bio-inspired
oxido-vandium complexes have been reported.5g Nevertheless, moderate reactivities
associated with a limited substrate scope are often observed and an excess amount of oxidant
is necessary to achieve high yields in sulfoxides.5a,10
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Figure 1. Structures of previous supramolecular and model catalysts, and the new catalyst SSS-RRR-1.
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To date, most of the synthetic model complexes focus only on the first coordination sphere
around the metal and the influence of the second coordination sphere on catalysis has often
been neglected. However, vanadium catalysts confined in a hydrophobic environment have
been revealed very efficient for this reaction, leading to high yields and selectivities in
sulfoxide: the higher hydrophilicity of sulfoxides, when compared to sulfides, increases the
concentration of the latter in the vicinity of the vanadium site and help to expel the former
once the reaction has occurred.11 In this context, our group have recently reported a series of
oxido-vanadium(V) cage complexes for oxidation of sulfides into sulfoxides (complexes
SSS-SSS-1 and the four diastereomers of 2, Figure 1).12 These systems combine both an active
site similar to that of vanadate-dependent haloperoxidases, and a well-defined hydrophobic
pocket just above the vanadium center. The hemicryptophane catalysts 2, which associate a
cyclotriveratrylene (CTV), binaphthols and an oxido-vanadium(V) moiety were found to be
the most efficient supramolecular catalysts, isolating the sulfide and the transition state from
the bulk of the solvent and expelling the hydrophilic sulfoxide from the hydrophobic
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molecular cavity. They exhibit a catalytic rate 3- and 33-fold higher than that of the SSS-SSS-1
and SSS-RRR-3 catalysts, respectively. Moreover, at low loading, a remarkable turnover
number (TON) close to 104 was reached with complexes 2. Despite this high reactivity, no
enantioselectivity was observed and the sulfoxide was obtained as a racemic mixture.
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Here, we report on the catalytic activity of the vanadium complex SSS-RRR-1. The smaller
cavity in 1, when compared to previously reported hemicryptophane vanadium complexes,
was initially designed to improve the confinement effect. Unexpectedly, remarkable
differences in catalytic behavior are observed between diastereomers SSS-SSS-1 and
SSS-RRR-1. Reaction rates 24-, 9-, and 301-fold faster with the catalyst SSS-RRR-1 than with
SSS-SSS-1, 2, and 3, were respectively obtained in the oxidation of thioanisol. Furthermore, a
TON of 8.6×104 was reached. A modest enantioselectivity, but unprecedented for chiral
vanatrane catalysts, was also achieved with this complex.
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13 RESULTS AND DISCUSSION
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Catalytic properties
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The vanadium complex SSS-RRR-1 was obtained using the procedure described for
SSS-SSS-1 (Figures S1-S4).12 This new catalyst was first tested in the oxidation of thioanisol
into sulfoxide, using cumene hydroperoxide (CHP) or tert-butyl hydroperoxide (TBHP) as
o
the terminal oxidant, with 1.5 mol% catalyst loading in CH
2
Cl2
at 0 C for 20 min.
Unexpectedly, SSS-RRR-1 was found to be much more efficient than our previous systems. A
higher conversion (90%) with a good selectivity for the sulfoxide product (92%) over the
sulfone (8%) was observed using either CHP or TBHP as oxidant (entries 3 and 4, Table 1),
whereas only 20-30% yields were reached with diastereomer SSS-SSS-1 (entries 1 and 2,
Table 1). The previous most effective supramolecular catalyst, hemicryptophane
M-SSS-RRR-2, also showed much lower yields (36% and 61% respectively with CHP and
TBHP) and conversions (40% and 62% respectively with CHP and TBHP) (entries 5 and 6,
Table 1). Moreover, opposite to the previous catalysts that were unable to induce
enantioselectivity for this reaction, ee values of 10% and 17% were achieved using SSS-RRR-1
with CHP and TBHP as oxidant, respectively. Although good enantioselectivities were
reported with Schiff bases vanadium complexes,5i,10a,13 other vanadium-included systems
generally gave low or no ee.5a,5k,14 In particular, several attempts have been undertaken to
obtain enantiomerically enriched sulfoxides with chiral vanatrane catalysts, but
enantioselectivity has never been observed,4,12 probably because of the C
-symmetry of the
3
ligand.15 These remarkable changes in the catalytic behavior, including both activity and
enantioselectivity improvements, indicate that the structure and conformation of the
SSS-RRR-1 complex should strongly differ from those of our previous systems.
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Table 1 Oxidation of thioanisol with CHP or TBHP catalyzed by oxido-vanadium derived complexes.a
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Entry
Catalyst
Oxidant Yield (%)b Conversion (%)b Selectivity (%)b ee (%)b
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9
1
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6
CHP
TBHP
CHP
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34
85
85
36
61
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35
92
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40
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92
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90
98
< 3
< 3
10
SSS-SSS-1c
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SSS-RRR-1
TBHP
CHP
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< 3
< 3
M-SSS-RRR-2c
TBHP
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b
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4
Conditions: 1.5 mol% catalyst, 1.0 equiv of oxidant, CH
2
Cl
2
, 0 oC, 20 min. Yield, conversion,
selectivity and ee were determined by HPLC with benzophenone as the internal standard. Selectivity
is defined as the yield/conversion ratio. c Previous results.12
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To compare more accurately the catalytic activities of these systems, the catalyst loading was
decreased to 0.4 mol% and CHP was used as the oxygen source while keeping the other
conditions identical. As shown in Figure 2, the reaction rate with SSS-RRR-1 is much faster
than with SSS-SSS-1 achieving 90% conversion of thioanisol in 120 min. Based on the initial
rate, the kinetic constant with SSS-RRR-1 was estimated to be 24-fold higher than with
SSS-SSS-1. Combined with the previous results,12 catalyst SSS-RRR-1 displays reaction rates
24-, 9- and 301-fold faster than those obtained with complexes SSS-SSS-1, 2 and 3,
respectively.
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SSS-RRR-1
SSS-SSS-1
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Time (min)
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Figure 2. Oxidation of thioanisol with catalysts SSS-SSS-1 and SSS-RRR-1 (0.4 mol% catalyst, 1.0 equiv
of CHP, 0 oC, CH
Cl ).
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The absence of product inhibition and the strong improvement of the reaction rate prompted
us to investigate the TON efficiency of catalyst SSS-RRR-1. Figure 3 shows that, with a
catalyst loading of 0.001 mol%, a TON of 8.6×104 can be reached after 7 days. Albeit the
catalyst loading was extremely low, the high selectivity of the reaction was retained (90%),
which suggests that SSS-RRR-1 remains stable over the whole period. SSS-RRR-1 even
outperforms our previous most efficient confined complex, hemicryptophane M-SSS-RRR-2,
with a TON 10 times higher.12
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Figure 3. Oxidation of thioanisol catalyzed by catalyst SSS-RRR-1 (0.001 mol% catalyst, 1.0 equiv of
CHP, r.t., CH Cl ).
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To investigate the substrate scope with this supramolecular catalyst, the oxidation of other
sulfides with various substituents was performed (Table 2). These substrates were chosen to
discern the effect of electronic and steric properties of the catalyst on reactivity and
selectivity: from substrate A to D, the steric hindrance increases, while the electron density of
the phenyl ring gradually increases from E to F. As shown in Table 2, all the substrates A-F
exhibit conversions between 70-90% after 90 min with whichever CHP or TBHP as oxidant,
underlining that the efficiency of the catalyst is not substrate-dependent. However, changes
in ee value can be observed for different sulfides and oxidants: (i) for the oxidation of almost
all substrates (except D, with no detectable ee), the use of TBHP always gives rise to higher ee
values than the use of CHP; (ii) from substrates B to D (entries 4-8), with the increase of the
number of aromatic rings and steric hindrance, the ee values decrease; this result indicates
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that π-π interactions between the phenyl ring neighboring the S atom of the substrate and the
binaphthol walls might take place for asymmetric induction, as reported by Licini et al.;16
indeed, the presence of other large aromatic moieties within the substrate may disrupt this
favoured π-π interaction and conformation, lowering the ee values; this is also consistent with
the observation that when using different oxidants, the cumyl ring of CHP results in lower ee
values compared to TBHP; (iii) from substrate E (entries 9 and 10) to A (entries 1 and 2) and
F (entries 11 and 12), the ee values increase with the increase of the electron density of the
phenyl ring, i.e. with the decrease of the reactivity.
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Table 2 Oxidation of various sulfides in the presence of the catalyst SSS-RRR-1.a
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Entry
Substrate
Oxidant Yield (%)b Conversion (%)b Selectivity (%)b ee (%)b
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2
CHP
TBHP
CHP
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83
76
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D
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TBHP
CHP
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CHP
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< 3
< 3
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TBHP
CHP
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TBHP
CHP
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TBHP
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Conditions: 0.4 mol% catalyst SSS-RRR-1, 1.0 equiv of oxidant, CH
2
Cl
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, 0 oC, 90 min. Yield,
conversion, selectivity and ee were determined by HPLC with benzophenone as the internal standard.
Selectivity is defined as the yield/conversion ratio.
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Enantioselective oxidation
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A kinetic study was carried out to investigate if the measured ee resulted from the direct
enantioselective oxidation of sulfide or from the kinetic resolution of the resulting sulfoxide
through its subsequent oxidation into sulfone (Figure 4a).16 The kinetic profile for the
oxidation of thioanisol in the presence of 0.4 mol% of catalyst SSS-RRR-1 and 1.0 equiv. of
TBHP showed that the ee value of sulfoxide almost kept constant (18% in favor of R
enantiomer) with the R-enantiomer generated 1.5-times faster than the S-one (Figure S5).
After 120 min, the yield of sulfoxide reached 84% and 7% of sulfone was also obtained. The
constant ee value indicates that the direct asymmetric oxidation of sulfide to sulfoxide is the
primary source accounting for the ee value.5b,17
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Figure 4. (a) Oxidation of thioanisol catalyzed by catalyst SSS-RRR-1 (for the first 120 min, 0.4 mol%
catalyst, 1.0 equiv of TBHP, 0 oC, CH
Cl ; after 120 min, the catalyst loading was increased to 1.5 mol%
and another 1.0 equiv of TBHP was added). (b) Oxidation of racemic methyl phenyl sulfoxide (1.5 mol%
catalyst, 1.0 equiv of TBHP, 0 oC, CH
Cl ).
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To study whether the subsequent kinetic resolution could further improve the ee, the catalyst
loading was increased to 1.5 mol% after 120 min, and one additional equiv of TBHP was
added.13,18 As shown in Figure 4a, the initial 18% ee value obtained after 120 min increased to
42% after 480 min accompanied with 87% of sulfone and 13% of unreacted sulfoxide. This
phenomenon indicated that the kinetic resolution could be used to further improve the ee. To
confirm this, catalytic oxidation of racemic methyl phenyl sulfoxide to sulfone was
performed. As shown in Figure 4b, over time the ee value slowly increased with the
formation of sulfone, and 20% ee (R-enantiomer being the major species) was achieved
associated with a yield of 85% in sulfone and 15% of remaining sulfoxide. Thus, the
S-sulfoxide enantiomer is oxidized faster than R-sulfoxide whereas the direct asymmetric
oxidation of sulfide favoured the R-enantiomer, this account for the improvement of the ee
observed.
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Mechanism investigation
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Since the catalytic properties of SSS-RRR-1 are significantly different from those of SSS-SSS-1,
we decided to investigate the origin of this specific behavior. As structure and properties of a
catalyst are strongly correlated, the structure and conformation of SSS-RRR-1 should
strongly differ from those of SSS-SSS-1. In order to get further insight into the structure of
SSS-RRR-1, we compared its NMR and mass spectrometry data with those of diastereomer
SSS-SSS-1 that was fully characterized previously.12 Firstly, the HRMS spectrum of the
complex SSS-RRR-1 exhibits the same m/z species as that of the SSS-SSS-1 one. Secondly,
1
1
whereas the complex SSS-SSS-1 displays sharp H NMR signals, the H NMR spectrum of
SSS-RRR-1 exhibits slightly broad signals but still corresponding to an overall C molecular
3
symmetry (Figure S6). Equilibrium between different conformers, induced by a
conformational rigidification of the whole structure, could account for such an NMR
behavior.19 Thirdly, 51V NMR spectra of the two complexes display similar chemical shifts
indicating, in both cases, a trigonal bipyramidal geometry for the vanadium with N-tertiary
amine trans to the oxo group (Figure S7),20 and ruling out the formation of polymeric species.
1H DOSY NMR experiments (Figure S8-S9) further confirmed this point: the diffusion
coefficient of SSS-RRR-1 (1.4 ×10-10 m2s-1) was slightly larger than that of SSS-SSS-1 (0.9 ×10-10
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m2s-1), suggesting similar sizes of the two complexes. These results prompt us to propose a
bowl-shaped conformation for the complex SSS-RRR-1, as illustrated in Figure 1. This
3
conformation is in agreement with the rigidification of the C structure and the similarities
3
4
observed in the NMR and mass spectra of the two diastereomers. It results from the
vanadium coordination to the inverted trialkanolamine core of the imploded tris-binaphthyl
ligand,21 as previously observed with other cage compounds containing the trialkanolamine
unit.22 To confirm this hypothesis, ROESY experiments were performed: a clear NOE
correlation between the protons of the phenyl group and the methylene protons linked to the
nitrogen of the trialkanolamine unit are observed (Figure 5), while this cross peak is not
detected in the ROESY spectrum of SSS-SSS-1 (Figure S10), strongly supporting the
proposed structure. The collapsed structure of complex SSS-RRR-1 has been also optimized
by an MM3 model using SCIGRESS software package (Figure S11)23, which shows that the
vanatrane unit locates centrally in an aromatic pocket.
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Figure 5. Overlap between the partial COSY (orange) and ROESY (blue) spectra of SSS-RRR-1 in
CDCl
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(500.1 MHz, 25 °C). The phenyl protons, the methylene protons of the trialkanolamine core, and
their NOE correlations are indicated.
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After obtaining the structural information on SSS-RRR-1, the high activity of SSS-RRR-1 in
sulfoxidation could be rationalized. As shown in Figure 6, compared to the cage structure of
SSS-SSS-1 or the expended conformation of SSS-RRR-3, the bowl-shaped conformation of
SSS-RRR-1 is neither too rigid nor too flexible. The right balance between rigidity and
flexibility and the existence of an open hydrophobic pocket promote the accommodation of
the hydrophobic sulfides near the active site and facilitates to a large extent the release of the
hydrophilic sulfoxides,4,12 while the preserved chiral microenvironment of the cavity gives
rise to the observed asymmetric induction.24
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Figure 6. Proposed conformations for SSS-SSS-1, SSS-RRR-1 and SSS-RRR-3, and the rationalized
catalytic mechanism of SSS-RRR-1.
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CONCLUSION
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In summary, we have described herein a new enantiopure oxido-vanadium supramolecular
catalyst SSS-RRR-1 for the selective oxidation of sulfides into sulfoxides. This new catalyst is
very efficient compared to its diastereomer SSS-SSS-1, and to the previous most efficient
hemicryptophane catalysts 2. The oxidation of thioanisol using SSS-RRR-1 exhibited reaction
rates 24-, 9- and 301-fold faster than with SSS-SSS-1, 2 and 3, respectively. A TON close to 105
was reached with an extremely low catalyst loading (0.001 mol%). Moreover, the new
catalyst also showed an asymmetric catalytic effect, in which the enantioselectivity of the
reaction was found to mainly originate from the direct asymmetric oxidation (ee of 19%
associated with a yield of 83% in the oxidation of thionaisol), although the strategy of kinetic
resolution could also be used in this work to improve the ee (up to 42%, with a yield of 13%
in anisol-sulfoxide). Despite higher ee values have been reported with other vanadium
catalysts, like Schiff bases complexes,5d,5i,10a,,25 the catalyst presented here showed an
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unprecedented asymmetric catalytic effect for C symmetrical vanadium complexes, breaking
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through the major limitation of the previous vanatrane catalysts. HRMS, H and V NMR,
DOSY and ROESY experiments, revealed that, different from the cage conformation of
SSS-SSS-1 and 2, SSS-RRR-1 adopts a bowl-shaped structure with an open hydrophobic
chiral pocket. The microenvironment above the metal centre leads to a strong improvement
in catalytic activity and to some extent in enantioselectivity. Oxidation of other substituted
sulfides indicated the role of aromatic interactions. Future work will seek to apply this highly
efficient vanadium catalyst to other oxidation reactions, for instance for asymmetric
epoxidation of alkenes.
26 SUPPORTING INFORMATION
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1H, 13C, and 2D NMR spectra, catalysis details.
29 ACKNOWLEDGMENT
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A.M. would like to thank ANR OH-risque for funding, grant number:
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ANR-14-OHRI-0015-01.
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AUTHOR INFORMATION
*E-mail for A.M.: alexandre.martinez@centrale-marseille.fr;
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