Evidence of two key intermediates contributing to the selectivity of P450-biomimetic oxidation of sulfides to sulfoxides and sulfones

Article abstract of DOI:10.1002/asia.201200422

A mild process for the selective oxidation of sulfides is in great demand. Therefore, probing the mechanism underlying the biological oxidation of sulfides under ambient conditions may provide valuable insights for the development of such a reaction. Based on porphyrin models of P450 enzymes, evidence of two key intermediates, Int0 and Int1, in this reaction is provided. Spectroscopic studies indicated the formation of a hydroperoxide-iron(III) species (Int0) upon addition of H₂O₂. This intermediate proved to be highly selective for sulfoxide production. By contrast, a defined porphyrin oxoiron(IV) cation radical (Int1) directly reacted with sulfoxides, leading selectively to the corresponding sulfones. Interestingly, the available sulfoxides reversibly act as a new axial ligand for Int0 forming a more active species Int0 _SO. The amount of Int0 increased in the presence of alkyl, aryl, or aromatic sulfides, while Int1 formed in the absence of these sulfides. Thus, sulfoxides and sulfones would selectively form under conditions that favor the corresponding intermediates, which elucidate the biological oxidation pathway. A mild process for the selective oxidation of sulfides is in great demand. Therefore, probing the mechanism underlying the biological oxidation of sulfides under ambient conditions may provide valuable insights for the development of such a reaction. Based on porphyrin models of P450 enzymes, evidence of two key intermediates, Int0 and Int1, in this reaction is provided. Copyright

Full text of DOI:10.1002/asia.201200422

DOI: 10.1002/asia.201200422
Evidence of Two Key Intermediates Contributing to the Selectivity of P450-
Biomimetic Oxidation of Sulfides to Sulfoxides and Sulfones
Xinrui Zhou,*[a] Xian Chen,[a] Yaqin Jin,[a] and Istvan E. Markꢀ*[a, b]
Abstract: A mild process for the selec-
tive oxidation of sulfides is in great
demand. Therefore, probing the mech-
anism underlying the biological oxida-
tion of sulfides under ambient condi-
tions may provide valuable insights for
the development of such a reaction.
Based on porphyrin models of P450 en-
zymes, evidence of two key intermedi-
ates, Int0 and Int1, in this reaction is
provided. Spectroscopic studies indicat-
ed the formation of a hydroperoxide-
iron
(III) species (Int0) upon addition
fones. Interestingly, the available sulf-
oxides reversibly act as a new axial
ligand for Int0 forming a more active
species Int0SO. The amount of Int0 in-
creased in the presence of alkyl, aryl,
or aromatic sulfides, while Int1 formed
in the absence of these sulfides. Thus,
sulfoxides and sulfones would selec-
tively form under conditions that favor
the corresponding intermediates, which
elucidate the biological oxidation path-
way.
of H2O2. This intermediate proved to
be highly selective for sulfoxide pro-
duction. By contrast, a defined porphy-
rin oxoiron(IV) cation radical (Int1) di-
rectly reacted with sulfoxides, leading
selectively to the corresponding sul-
Keywords: biomimetic oxidation ·
porphyrin · reactive intermediates ·
sulfone · sulfoxide
Introduction
Since cytochrome P450 was discovered in a wide range of
organisms, immense attention has been paid to such kind of
enzymes that mediate broad and diverse oxidation under
physiological conditions. Synthetic chemistry has shown that
multiple intermediates are involved in oxidation, with por-
phyrins as P450 models. An extremely active species, oxoiro-
n(IV) porphyrin cation radical ([PorFeIV =O]+·, Cpd1), is
widely considered as the key intermediate when hydrocar-
bons are initially used as substrates.[1–3] Another key inter-
Scheme 1. Biological pathway for the P450-type oxidation of dibenzothio-
phene (DBT).
Cpd1 was inherently considered as the active intermediate
in the P450 enzymatic sulfoxidation,[6–8] but it is surprising
that this extremely active radical could oxidize sulfides so
mildly to sulfoxides rather than to sulfones.[9,10] Some work
supported the notion that Cpd0 is a competent oxidant for
the transformation of sulfides by using carefully designed
oxidation systems. Among others, these involve 1) a synthet-
ic stable ligand, such as corrole and corrolazine, instead of
a sensitive porphyrin ligand,[11,12] 2) a Mn complex instead of
a Fe complex,[13,14] and 3) the use of m-chloroperoxybenzoic
acid (mCPBA) instead of H2O2.[15,16] In addition, little effort
has been devoted to demonstrate that these stabilized com-
plexes are identical to the putative intermediates participat-
ing in the biochemical processes. Few of these contributions
provided direct evidence for the exquisite selectivity dis-
played by the biologic process in favoring sulfoxide or sul-
fone.[4,5,17,18]
Herein, the mechanism underlying the biological sulfide
oxidation was investigated by using a mimetic method, with
special attention paid to the activity and selectivity dis-
played by the various intermediates. Iron porphyrin was di-
rectly employed as the P450 model with the purpose that
the various intermediates would mostly resemble the ones
involved in the active biochemical processes. With the same
aim, the reaction conditions were chosen to be as close as
possible to the natural environment, that is, room tempera-
mediate, the low-valent hydroperoxy ironACTHNUTRGNE(NUG III) species Cpd0,
is much less reactive than Cpd1. However, it is a key precur-
sor to Cpd1 by heterolytic cleavage of the peroxide bond.
Interestingly, whether these intermediates behave the same
way on sulfide substrates has been barely investigated, espe-
cially when the substrates are heteroaromatic compounds
such as dibenzothiophene (DBT) derivatives. The biological
pathway for the P450-type oxidation of DBT was reported
previously and includes a two-step reaction comprising sul-
foxidation and sulfone formation (Scheme 1).[4,5]
[a] Dr. X. Zhou, X. Chen, Y. Jin, Prof. I. E. Markꢀ
State Key Laboratory of Fine Chemicals
Dalian University of Technology
Dalian 116024 (P. R. China)
E-mail: xinrui@dlut.edu.cn
[b] Prof. I. E. Markꢀ
Laboratory of Organic and Medicinal Chemistry
Universitꢁ catholique de Louvain
Place Louis Pasteur 1, B-1348 Louvain-la-Neuve (Belgium)
E-mail: istvan.marko@uclouvain.be
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200422.
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ture and using a neutral protonic solvent and a physiological
oxidant (H2O2). The oxidation reactions of various sulfides,
which were added at very low concentrations to slow down
the reaction rate, were monitored by UV/Vis spectroscopy
and gas chromatography (GC). A Cpd0-like intermediate,
a hydroperoxide-ironACTHNUTRGNE(NUG III) (Int0), is proposed and its struc-
ture established. Int0 results in a high selectivity in favor of
the sulfoxide product. On the other hand, a definite porphy-
rin oxoiron(IV) cation radical (Int1) was shown to react di-
rectly with sulfoxides, affording selectively sulfones as the
final products. The increase in the two intermediates and
their interchange over time could be controlled by the pres-
ence or absence of sulfides. Our spectroscopic results, cou-
pled with additional experimental data from designed ex-
periments, provide a firm basis for the discussion of the
mechanism of sulfide oxidation mediated by P450 enzymes,
including the nature of the intermediates, their activity
toward the substrates, and their selectivity in favor of the
final products (Figure 1).[7,8]
Figure 2. Absorbance spectra of the reaction of complex 1 with H2O2 in
the absence of sulfide. The spectra were recorded at time intervals of
10 s. Inset: APEI mass spectrum of complex 1 in ethanol after addition
of H2O2. The peak at m/z of 684.2 corresponds to Int1.
Cpd0-like intermediate. The isotopic exchange experiment,
which followed the typical procedure in the presence of 18O-
labeled water (10 wt.%) in ethanol, showed that 18O was
not incorporated into the sulfoxide product, as demonstrat-
ed by GC–MS. This experiment does not support the pro-
posal that Int0 is the oxoiron (IV) porphyrin cation radical
(Cpd1-like intermediate).[20]
Figure 1. Proposed mechanism involving the two putative intermediates
Int0 and Int1 (see Scheme 2 for structures). 1, meso-tetraphenylporphine
iron (III) chloride.
Results and Discussion
UV/Vis spectra obtained after DBS oxidation carried out
under the typical conditions displayed a series of interesting
changes (Figure 3) that suggest that Int0 exists as two dis-
crete species. Upon addition of 0.1–0.2 equiv H2O2
(0.1 equiv were added every 5 min), the typical Soret band
(at 415 nm) was not altered but its intensity increased slight-
ly. This observation indicated that the coordination of H2O2
to the porphyrin most likely occurred along the sixth axial
direction (Scheme 2), as this approach minimizes the
The stability of meso-tetraphenylporphine iron (III) chloride
(1) in ethanol was examined in the presence of H2O2 as
a control in absence of sulfides (see the Experimental Sec-
tion). As observed in numerous previous studies, the intense
color of complex 1 in ethanol decreased rapidly with the ad-
dition of the first aliquot of aqueous H2O2 (30 wt.%) at
room temperature. The Soret band (415 nm) of complex 1,
detected by UV/Vis spectrocopy, disappeared completely
within one minute (Figure 2), thus indicating that the por-
phyrin p conjugation of complex 1 had been broken. It fur-
À
ther suggests that both HOC radicals from the O O homolyt-
ic cleavage and the Cpd1-like intermediate, formed from
H2O2, could contribute to this decomposition.[19] The oxoiro-
n(IV) tetraphenylporphyrin cationic species [TPPFeIV =O]+C
(Int1) was detected by atmospheric pressure electrospray
ionization mass spectrometry (APEI-MS, positive mode) at
m/z of 684.2 during this decomposition (Figure 2, inset). In-
terestingly, in the presence of di-n-butylsulfide (DBS), the
decomposition of p conjugation was retarded and, coinci-
dentally, the peak at 684.2 m/z disappeared, suggesting that
DBS inhibits the formation of Int1 and, therefore, retards
the decomposition of the porphyrin. Since our results indi-
cated that neither H2O2 nor complex 1 interacted directly
with DBS, this oxidation must begin with a different species
incorporating complex 1 and H2O2 (Int0). This alternative to
the Cpd1-like intermediate is suggested to resemble the
Figure 3. UV/Vis spectra of the reaction of DBS with H2O2 catalyzed by
complex 1 at various molar ratios of H2O2 to DBS.
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Intermediates in the P450-Biomimetic Oxidation of Sulfides
Scheme 2. Suggested intermediates involved in the P450 biomimetic oxi-
dation.
Figure 4. APEI mass spectra of complex 2 bearing respectively DBSO,
DMSO, and DPSO as a ligand.
changes in the UV spectra.[19] The sixth coordination nor-
mally results in a change of the spin state of the ironACTHUNTGRNEUNG(III)
center, thereby activating the peroxide bond.[21] After
adding 0.3 equiv H2O2, the typical signal at 415 nm dropped
sharply and then gradually shifted to 397 nm, while a new
peak appeared at 530 nm. A similar shift also occurred
when diphenylsulfide (DPS) and dibenzothiophene (DBT)
were used instead of DBS. However, the time required for
the shift to occur was dependent on the steric hindrance of
the substrate in the order: DBS <DPS <DBT (Figures S1
and S2 in the Supporting Information). These spectral
changes indicated that Int0 was transformed into a new spe-
cies that we assign the structure Int0SO (Scheme 2).
To obtain some information about the activity of Int0 on
the substrates and its selectivity on the products, reactions
performed using the typical procedure were analyzed by
GC. Using the corresponding sulfoxide and sulfone as stand-
ards, which were preparatively isolated and characterized,
GC analysis indicated that the products from DBS and DBT
were exclusively sulfoxides (Figure 5). With time, a small
Two subsequent experiments supported the notion that
Int0SO was formed through addition of a sulfoxide molecule
to the Int0 species with exchange of the axial ClÀ ligand.
Firstly, when 1 was continuously treated in ethanol with ali-
quots of a DBSO solution, the characteristic peak of the
iron porphyrin in the UV/Vis spectra also shifted from
415 nm to 397 nm (Figure 3, inset; Figure S3 in the Support-
ing Information). This displacement is consistent with the
changes in the UV/Vis spectra detected in the previous 1/
H2O2/DBS reaction. Secondly, exchanging the axial ClÀ
group first by a strong ligand, nucleophilic N, N-(dimethyla-
mino)pyridine (DMAP), results in the disappearance of the
397 nm peak (Figure S4 in the Supporting Information), sug-
gesting that the DBSO coordination takes place on the axial
position under exchange of the axial ClÀ ligand.[22]
When a neutral sulfoxide replaces the ClÀ group, the in-
termediate Int0SO would bear a positive charge. After trans-
ferring H2O2 to the substrate, it changes to a cationic species
2. With DBSO, a peak at m/z of 830.1 corresponding to
complex 2 was detected by APEI-MS in the positive mode
Figure 5. Plots of the yield of product as a function of the molar ratio of
H2O2 to substrate (DBS or DBT) for the Int0-dependent oxidation.
amount of over-oxidized sulfones (1.6 wt.% selectivity to
DBSO2, and 2.5 wt.% selectivity to DBTO2) could be de-
tected, which could possibly be due to the generation of
some Int1 from Int0 when the DBS or DBT concentration
became too low (see below). The turning points of the dy-
namic curves for DBS and DBT were at 0.2 and 0.4 equiv
H2O2 with regard to the substrate, at which point the UV/
Vis spectra indicated the beginning of Int0SO formation.
After these points, the reaction rates increased distinctly, in-
dicating that the sulfoxide ligand can enhance the oxidizing
ability of Int0. In addition, since DBT is more sterically hin-
dered and its S atom has a low electron density, the turning
(Figure 4, [TPPFeACHTUNGTRENNUNG
(DBSO)]+, M=C52H46FeN4OS, calcd
830.3). As some molecular fragments formed from the por-
phyrin by APEI may have the same molecular weight as
DBSO, these experiments were repeated with the substrates
dimethylsulfide (DMS) and diphenylsulfide (DPS). The re-
spective peaks, detected at 746.1 and 870.3, correspond to
Int0 with DMSO and DPSO ligands respectively ([TPPFe-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Thus, these spectra further confirmed the suggestion that
a sulfoxide molecule coordinated to the Int0 species.
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Xinrui Zhou, Istvan E. Markꢀ et al.
FULL PAPER
point of the DBT curve appeared later than the one of
DBS. With the DBS concentration decreasing, the peak at
397 nm (Figure 3) decreased and finally disappeared. Some
isosbestic points (at 360, 440, 510, and 550 nm) were detect-
ed during this decomposition, which agrees well with the
UV spectral characteristics of biliverdin decomposition.
Thus, the data suggest that Int0 is gradually transformed
into a high-valent iron porphyrin, Int1, which undergoes
self-decomposition in the presence of H2O2 rather than
oxygen atom transfer.[19] When DBSO and DBTO were em-
ployed as the substrates, no sulfones could be detected. The
Soret band at 395 nm disappeared within 5 min (Figure S5
in the Supporting Information).
One way to increase the stability of porphyrin intermedi-
ates for mechanistic studies is to introduce electron-with-
drawing groups on the p ring. Therefore, meso-tetrakis(2-
chlorophenyl)porphine iron (III) chloride (TCPPFeCl) was
tested under the conditions described above. In the ob-
served UV/Vis spectra the peaks at 411 nm and 581 nm de-
creased and new peaks at 394 nm and at 685 nm (broad) ap-
peared at increasing molar ratio of H2O2 to DBS (Figure 6).
This new set of spectra fitted very well with the characteris-
tics of Cpd1-like intermediates reported previously.[24] The
peak in the mass spectrum corresponding to [TCPPFeIVO]+C
at m/z of 820.0 (calculated m/z 820.0) further confirmed the
presence of this cation radical (Figure 6, inset).
To examine the reactivity of Int1, we synthesized an ox-
oiron (IV) porphyrin cation radical by the reaction of com-
plex 1 with iodosobenzene (PhIO) at room temperature, ac-
cording to the reported procedure.[23] In the presence or ab-
sence of DBS, APEI-MS spectra displayed a peak at m/z of
684.2 corresponding to Int1. In contrast to Int0, Int1 rapidly
oxidized DBSO to DBSO2 and DBTO to DBTO2, respec-
tively, in essentially quantitative yields (Table 1, entries 3
and 4). DBS and DBT were oxidized to a mixture of sulfox-
Table 1. Yields of products and selectivities in the oxidation by Int1.[a]
Entry Substrate
Product (yield, selectivity) [%]
1
(14.0, 14.0)
(30.6, 32.7)
(86.0, 86.0)
(63.0, 67.3)
Figure 6. UV/Vis spectra and APEI mass spectra for Int1 [TCPPFeIVO]+C
at various molar ratios of H2O2 to DBS.
2
AHCTUNGTRENN(GUN 100, 100)
3
4
Conclusions
AHCTUNGTRENN(GUN 100, 100)
In summary, this study provides evidence of two active inter-
mediates from tetraphenylporphine iron (III), which play
a key role in the product selectivity. Sulfoxides and sulfones
were selectively produced by Int0 and Int1 species. Int0 was
generated in the presence of alkyl or aryl sulfides, while Int1
formed in the absence of these sulfides. Thus, Int0 is the
first oxidant in the oxidation of sulfides to sulfoxide. Fur-
thermore, the coordination of sulfoxides with Int0 and en-
hanced its reactivity. Our results indicate that sulfoxides are
the primary products of this transformation. The observa-
tion is consistent with the proposed biological oxidation
mechanism.
[a] Conditions: Substrate (0.9 mmol) and complex 1 (11 mmol) were dis-
solved in 8 mL MeOH at rt. Next, every 5 min a 0.2 mL aliquot of a solu-
tion of PhIO (2.5 equiv, 0.5 g) in 5 mL MeOH was added.
ides and sulfones, with the latter ones predominating (see
entries 1 and 2 in Table 1 and also Figures S6, S7 in the Sup-
porting Information). Whilst we monitored this process, we
did not observe the usual changes in the UV/Vis spectra,
probably because Int1 is too labile and short-lived. Al-
though Int1 generated with PhIO oxidized sulfides to sulfox-
ides, its enhanced reactivity enables it to further convert
sulfoxides into sulfones.However, using the H2O2 protocol,
only traces of sulfones could be detected. Together with the
spectroscopic evidence that, under addition of H2O2, Int1 is
gradually formed from Int0 and rapidly decomposes
(Figure 3), it appears that Int0 is the most likely oxidant for
the first step of the catalytic transformation of sulfides into
sulfoxides and sulfones.
Experimental Section
Materials and General Measurements
All reagents including solvents were used as received unless otherwise
noted. Di-n-butylsulfide (DBS, 98%), dimethylsulfide (DMS, 99%), and
diphenylsulfide (DPS, 98%) were purchased from Alfa Aesar. Dibenzo-
thiophene (DBT, analytical reagent (AR) grade) was obtained from
Acros Organics. H2O2 (30% aqueous solution) and cyclohexene (99%)
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Intermediates in the P450-Biomimetic Oxidation of Sulfides
were purchased from Sinopharm Chemical Reagent Co. Ltd, and titrated
with 0.02m potassium permanganate before use. H218O (97 atom%,
99%) was obtained from Aladdin Reagent Inc. Meso-tetraphenylpor-
[2] W. Nam, Y. O. Ryu, W. J. Song, J. Biol. Inorg. Chem. 2004, 9, 654–
660.
[3] M. Newcomb, R. E. P. Chandrasena, Biochem. Biophys. Res.
Commun. 2005, 338, 394–403.
phine iron
ACHTUNGTRENNUNG
kis(2-chlorophenyl)porphine iron
G
[4] N. L. Klyachko, A. M. Klibanov, Appl. Biochem. Biotechnol. 1992,
37, 53–68.
[5] J. Calzada, S. Heras, A. Alcon, V. E. Santos, F. Garcia-Ochoa,
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[6] J. T. Groves, Y. Watanabe, J. Am. Chem. Soc. 1986, 108, 7834–7836.
[7] E. Baciocchi, M. F. Gerini, A. Lapi, J. Org. Chem. 2004, 69, 3586–
3589.
according to the published method.[25] Iodosobenzene was prepared ac-
cording to published procedures.[26] Sulfoxides and sulfones serving as
standard reference were purified from the reaction solution and their
structure further confirmed by gas chromatography–mass spectrometry
(GC-MS, HP6890GC/5793MS), infrared spectroscopy (IR, Nicolet-
20DXB), and NMR spectroscopy (Varian 400-MR).
[8] E. Baciocchi, M. F. Gerini, O. Lanzalunga, A. Lapi, M. G. L. Piparo,
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[9] A. Alcon, V. E. Santos, A. B. Martin, P. Yustos, F. Garcia-Ochoa,
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123, 9447–9448.
UV/Vis absorption spectroscopy (HP-8453) and gas chromatography
with a flame ionization detector (GC-FID, HP6890) were used to moni-
tor all oxidative reactions. The gas chromatograph was equipped with
a HP-5 capillary column (30 mꢃ0.32 mmꢃ0.25 mm) and highly purified
nitrogen (ꢀ99.9995 wt%) was used as the carrying gas. The temperature
of the column was set at 508C, then gradually increased to 1308C at
a rate of 158CminÀ1, and finally held at 1308C for 10 min. Mass spectra
for the intermediates were recorded by atmospheric pressure electro-
spray ionization mass spectrometry (APEI-MS, HP 1100 LC/MSD).
Typical Procedure for the Oxidative Reactions
[13] N. Jin, D. E. Lahaye, J. T. Groves, Inorg. Chem. 2010, 49, 11516–
11524.
Reactions were performed at room temperature under a nitrogen blan-
[14] A. Mahammed, Z. Gross, J. Am. Chem. Soc. 2005, 127, 2883–2887.
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[18] A. R. Han, Y. J. Jeong, Y. Kang, J. Y. Lee, M. S. Mi Sook Seo, W.
Nam, Chem. Commun. 2008, 1076–1078.
ket. Complex
1 or TCPPFeCl (2.5 mg, 3 mmol), DBS (0.16 mL,
0.9 mmol), and dodecane (internal standard, 0.2 mL, 0.9 mmol) were dis-
solved in 10 mL EtOH. To this solution, aqueous H2O2 (0.1 equiv to the
substrate) was added every 5 min (up to 2 equiv). Samples (150 mL) were
taken 1 min after each addition of H2O2 for UV/Vis, GC-FID, and
APEI-MS analyses. For APEI-MS analysis, the sample was immediately
diluted (in the syringe) to 2.5 mL with EtOH to prolong the lifetime of
the intermediate.
[19] G. Lente, I. Fabian, Dalton Trans. 2007, 4268–4275.
[20] W. D. Kerber, B. Ramdhanie, D. P. Goldberg, Angew. Chem. 2007,
119, 3792–3795.
[21] J. T. Groves, Y. Watanabe, J. Am. Chem. Soc. 1988, 110, 8443–8452.
[22] M. Selke, J. S. Valentine, J. Am. Chem. Soc. 1998, 120, 2652–2653.
[23] M. E. Crestoni, S. Fornarini, F. Lanucara, Chem. Eur. J. 2009, 15,
7863–7866.
Isotopic Exchange Experiments
This reaction followed the typical procedure described above except that
it was performed in dried EtOH (9 mL) containing H218O (1 mL). Sam-
ples from the reaction solution were analyzed by GC-FID and then by
GC-MS.
[24] J. T. Groves, R. C. Haushalter, M. Nakamura, T. E. Nemo, B. J. Ev-
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Acknowledgements
The authors are grateful to the National Science Foundations of China
(No. 21076036) for financial support.
[26] H. Saltzman, J. G. Sharefkin, Org. Synth. 1973, 5, 660–661.
Received: May 10, 2012
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Bioinorganic Chemistry
A mild process for the selective oxida-
tion of sulfides is in great demand.
Therefore, probing the mechanism
underlying the biological oxidation of
sulfides under ambient conditions may
provide valuable insights for the devel-
opment of such a reaction. Based on
porphyrin models of P450 enzymes,
evidence of two key intermediates,
Int0 and Int1, in this reaction is pro-
vided.
Xinrui Zhou,* Xian Chen, Yaqin Jin,
Istvan E. Markꢀ*
&&&& — &&&&
Evidence of Two Key Intermediates
Contributing to the Selectivity of
P450-Biomimetic Oxidation of Sulfides
to Sulfoxides and Sulfones
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