Oxidative decarboxylation of benzilic acid by a biomimetic iron(II) Complex: Evidence for an iron(IV)-oxo-hydroxo oxidant from O2

Article abstract of DOI:10.1002/anie.201103971

O₂-dependent transformation: An iron(II)-benzilate complex of a tridentate N3 donor ligand reacts with O₂ to undergo oxidative decarboxylation. Cyclohexene is selectively converted into cis-cyclohexane-1,2- diol in the reaction. Copyright

Full text of DOI:10.1002/anie.201103971

DOI: 10.1002/anie.201103971
Dioxygen Activation
Oxidative Decarboxylation of Benzilic Acid by a Biomimetic Iron(II)
Complex: Evidence for an Iron(IV)–Oxo–Hydroxo Oxidant from O2**
Sayantan Paria, Lawrence Que, Jr.,* and Tapan Kanti Paine*
The existence of dioxygen-activating nonheme iron enzymes
that carry out four-electron substrate oxidations requires a
mechanism where the initially formed iron(III)–superoxide
species must be involved as an oxidant to initiate the
reaction.[1–4] Such a step has been proposed for many aromatic
tate ligand, iron(II) perchlorate, benzilic acid, and triethyl-
amine in methanol. The 1H NMR spectrum of 1 shows broad
and paramagnetically shifted peaks indicative of the high-spin
nature of the iron(II) complex (Figure S1 in the Supporting
Information). The X-ray crystal structure of 1 shows a
distorted square-pyramidal iron(II) center (t = 0.46[9]) that
[1,5]
ꢀ
and aliphatic C C bond cleaving dioxygenases.
Recently
is coordinated by the facial tridentate TpPh ligand and the
2
discovered examples include 2-hydroxyethylphosphonate
(HEP) dioxygenase (HEPD) which catalyzes the cleavage
carboxylate of the benzilate monoanion (Figure 1). The
ꢀ
of the HEP C1 C2 bond to form hydroxymethylphosphonate
and formate,[3] and CloR, which is involved in the conversion
of a mandelate moiety to benzoate in the biosynthesis of
chlorobiocin, an aminocoumarin antibiotic.[6] For the above
examples, the substrate provides all four electrons needed for
the reduction of O2 to water. In contrast, the Rieske
dioxygenases require two electrons from NADH to carry
[1,7]
=
out the cis-dihydroxylation of aromatic C C bonds.
A
high-valent iron–oxo–hydroxo intermediate has been pro-
posed to carry out this transformation.
Recently, a synthetic iron(II)–mandelate complex sup-
ported by a tripodal N4 donor ligand was reported by us[8] to
undergo nearly quantitative oxidative decarboxylation in the
II
Figure 1. Molecular structure of [ðTpPh ÞFe (benzilate)] (1). All hydro-
2
ꢀ
gen atoms except that attached to O3 and B1 have been omitted for
clarity. Selected bond lengths [ꢀ] and angles [deg] for 1: Fe1–O1
2.346(3), Fe1–O2 2.008(3), Fe1–N2 2.075(3), Fe1–N4 2.120(3),
Fe1–N6 2.082(3), C46–O1 1.248(4), C46–O2 1.273(5); O1-Fe1-N4
162.16(11), O1-Fe1-N6 107.88(10), O1-Fe1-N2 98.23(10), O2-Fe1-N2
134.82(11), O2-Fe1-N6 131.04(11), O2-Fe1-N4 103.85(12), O1-Fe1-O2
59.83(10), N2-Fe1-N4 88.75(11).
presence of dioxygen, thereby mimicking the C C bond
cleavage reaction of CloR. An iron(III)–superoxo species has
been implicated in the reaction pathway. In exploring the O2
reactivity of related iron(II)–a-hydroxy acid complexes,
specifically those of benzilic acid (2,2-diphenyl-2-hydroxy-
acetic acid), we discovered a new mode of O2 activation that
leads to the formation of an iron(IV)–oxo–hydroxo oxidant.
These intriguing results are reported here.
II
The iron(II) model complex [ðTpPh ÞFe (benzilate)] (1),
average Fe N bond length of 2.092 ꢀ is comparable to
2
ꢀ
where TpPh = hydrotris(3,5-diphenylpyrazolyl)borate, was
those of other FeIIðTpPh Þ complexes,
while the iron–
[10]
2
2
synthesized by reacting equimolar amounts of the polyden-
carboxylate distances indicate an unsymmetric bidentate
ꢀ
ꢀ
binding mode (r(Fe1 O1), 2.346(3) and r(Fe1 O2),
2.008(3) ꢀ) (Table S1). The hydroxy group of the benzilate
does not coordinate with the iron center, possibly due to the
[*] S. Paria, Dr. T. K. Paine
Department of Inorganic Chemistry
steric crowding from the phenyl rings on the TpPh ligand.
2
Indian Association for the Cultivation of Science
2A&2B Raja S.C. Mullick Road, Jadavpur, Kolkata-700032 (India)
E-mail: ictkp@iacs.res.in
Structural parameters are quite similar to those obtained
previously for [FeIIðTpPh Þ(benzoate)] and [FeIIðTpPh Þ-
2
2
(benzoylformate)] (2).[10]
Prof. Dr. L. Que Jr.
The colorless solution of 1 in benzene reacts with pure O2
at ambient temperature over a period of 10–15 min to
generate a green solution with a broad charge transfer band
at 600 nm (Figure S2). The green solution corresponds to the
Department of Chemistry and Center for Metals in Biocatalysis,
University of Minnesota
207 Pleasant Street SE, Minneapolis, MN 55455 (USA)
E-mail: larryque@umn.edu
formation of an iron(III)–phenolate complex of the TpPh *
[**] T.K.P. acknowledges the DST, Govt. of India (Project SR/S1/IC-51/
2010) for financial support. S.P. thanks CSIR, India, for a fellowship.
L.Q. acknowledges the US National Science Foundation (Grant
CHE-1058248) for support. The crystal-structure determination was
performed at the DST-funded National Single Crystal Diffractometer
Facility at the Department of Inorganic Chemistry, IACS.
2
ligand in which an ortho carbon of one 3-phenyl ring on the
ligand becomes hydroxylated. The ESI-MS spectrum of the
green solution shows ion peak at m/z 740.2 with the expected
isotope distribution pattern calculated for [(TpPh *)Fe]+ ion
2
(Figure 2a and Figure S3). Upon acidic work-up of the
oxidized solution, H NMR analysis clearly establishes the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103971.
1
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Communications
Figure 2. ESI-MS of the reaction solution after oxidation of 1 with
a) 16O2 and b) 18O2.
quantitative decarboxylation of benzilate to benzophenone
(Figure S4), a result supported by GC analysis of the reaction
mixture after the removal of metal components. The reaction
also affords about 90% of the ring-hydroxylated product
Figure 3. Percentage of ligand hydroxylation during the reaction of 1
with dioxygen in the presence of different substrates: A: no substrate;
B: 100 equiv fluorene; C: 100 equiv cyclohexene; D: 10 equiv thio-
anisole.
[(TpPh *)FeIII]+ (3), as estimated from its extinction coeffi-
2
cient.[10]
The fate of the atomic constituents of dioxygen was
determined by 18O labeling experiments. ESI-MS analysis of
the reaction solution after reaction of 1 with 18O2 in benzene
shows a peak at m/z 742.2 (Figure 2b) with expected isotope
+
+
corresponding to [PhS(O)CH3)]C and [PhSO(O)CH3)]C ,
respectively (Figure S6). 1H NMR analysis of the organic
products supports the formation of about 85% methyl phenyl
sulfoxide (relative to Fe) and only a very small amount (6–
8%) of methyl phenyl sulfone (Figure S7). In addition,
benzilate is converted quantitatively to benzophenone. The
oxidant that is generated by this reaction is thus capable of
intermolecular oxo transfer.
The reaction of 1 with dioxygen in the presence of 100
equiv of fluorene inhibits the intramolecular ring hydroxyl-
ation by 70% (Figure S5). GC analysis shows that benzilate is
converted to benzophenone in 80% yield, while fluorene is
oxidized to fluorenone in 50% yield (relative to Fe). This
result shows that the oxidant formed is also capable of
intermolecular hydrogen-atom abstraction. Therefore it is
reasonable to postulate the formation of a high-valent iron–
oxo species upon oxidative decarboxylation of the bound
benzilate, similar to that proposed in the reaction of the
corresponding benzoylformate complex 2 with O2.
The results of cyclohexene interception reveal, however,
that the oxidant formed in this reaction is not identical to that
formed in the reaction of the benzoylformate complex.
Cyclohexene is also quite an effective interception agent,
with 100 equiv inhibiting the ring hydroxylation to the extent
of 85–90% (Figure S5), while the decarboxylation of benzi-
late to benzophenone is quantitative. Most interestingly, the
1H NMR spectrum of the reaction solution shows the
formation of approximately 60% of cis-cyclohexane-1,2-diol
(C6H12O2) as the only product derived from cyclohexene
(Figure S8). GC-MS analysis of the oxidized product exhibits
distribution pattern attributable to [(TpPh *)Fe]+. This indi-
2
cates that one oxygen atom from 18O2 is incorporated into the
ligand backbone. However, the decarboxylated product from
benzilate (i.e. benzophenone) does not contain any labeled
oxygen. It can thus be assumed that the second atom from O2
is converted to water.
The ring hydroxylation of TpPh ligand along with the
2
formation of benzoic acid has previously been reported in the
[10,11]
reaction of [FeIIðTpPh Þ(benzoylformate)] with O2.
This
2
hydroxylation reaction can be inhibited by the presence of
different reagents that can intercept the putative high-spin
FeIV O oxidant formed in the oxidative decarboxylation of
=
the iron(II)–benzoylformate complex 2.[11] As aromatic ring
hydroxylation also takes place in the reaction of 1 with
dioxygen, we have studied the reaction in the presence of
different intercepting reagents to gain insight into the nature
of the active oxidant (Scheme 1). Figure 3 shows the effects of
+
a predominant peak at m/z 116.02 attributable to [C6H12O2]C .
This m/z value increases by four units when 18O2 is used in
place of 16O2, clearly demonstrating O2 to be the source of
both oxygen atoms of the diol (Figure S9). Furthermore a
mixed 16O2/18O2 labeling experiment showed that both oxygen
atoms on the diol product derived from one O2. The results
implicate that 1 can activate O2 to form an oxidant capable of
transferring both oxygen atoms to cyclohexene. It is impor-
tant to note here that addition of H216O in the labeling
Scheme 1. Oxidation of different substrates during the reaction of 1
with dioxygen.
adding fluorene, cyclohexene, or thioanisole to the amount of
[Fe(TpPh *)]+ formed. Thioanisole is most effective with
2
10 equiv resulting in a 92% interception of the oxidant
(Figure S5). GC-MS analysis of the reaction mixture after
separation of the metal shows ions at m/z 140.03 and 156.03
experiment with 18O2 does not show incorporation of any 16
into the diol formed.
O
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On the basis of the above experimental results, we
propose the mechanism shown in Scheme 2. O2 binding to 1
forms an adduct that is best described as an iron(III)–
superoxide complex. As we have previously shown that
iron(III)–superoxide species derived from related biomimetic
monium hydroxide returns the CT band back to 600 nm
(Figure S10). These observations are consistent with a hy-
droxide ion coordinated to the FeIII(TpPh *) center after the
2
oxidation of 1. The basic hydroxide ligand would decrease the
Lewis acidity of the iron(III) center, resulting in the observed
higher-energy CT band relative to those of corresponding
nonheme iron complexes are capable of hydrogen-atom
[8,12]
abstraction from C H or O H groups,
we propose that
FeIII(TpPh *) complexes with bound water (from protonation
2
ꢀ
ꢀ
of the hydroxide) or benzoate (from oxidative decarboxyla-
tion of 2). It is important to mention here that the peak at
600 nm slowly shifts to 650 nm upon standing the reaction
solution for 2 days.
As previously documented for the corresponding ben-
zoylformate complex 2, intermolecular oxidation of added
substrates competes with intramolecular ligand hydroxyl-
ation. Thioanisole and cyclohexene are both good substrates
for 1, inhibiting ligand hydroxylation by 92% and 85%,
respectively. Oxo transfer occurs for thioanisole, affording the
corresponding sulfoxide as expected. Interestingly however,
cyclohexene is converted to cis-cyclohexane-1,2-diol, an
outcome completely different from that observed for 2,
where 1,3-cyclohexadiene was identified as the product. This
difference presumably arises from the nature of the anionic
ligand bound to the nascent oxoiron(IV) center, hydroxide in
the case of 1 and benzoate in the case of 2. The data presented
herein strongly suggest the formation of an iron(IV)–oxo–
hydroxo oxidant in the oxygenation of 1 that is capable of the
cis-dihydroxylation of an alkene.
There is ample supporting evidence from the biochemical
and biomimetic literature. A similar high-valent iron–oxo–
hydroxo oxidant has been postulated for the cis-dihydrox-
ylation of arenes that occurs at the mononuclear nonheme
iron active site of Rieske dioxygenases.[14–17] For the enzymes,
the accumulated mechanistic evidence favors an iron(V)–
oxo–hydroxo oxidant,[14–16] although the corresponding
iron(IV)–oxo–hydroxo species has also been suggested.[17]
Indirect evidence for a high-valent iron–oxo–hydroxo oxidant
has also been obtained from studies of biomimetic nonheme
iron complexes that catalyze alkene cis-dihydroxylation using
hydrogen peroxide as oxidant;[18–21] an iron(V)–oxo–hydroxo
oxidant is proposed for iron catalysts with tetradentate N4
ligands,[19–21] while a dihydroxoiron(IV) oxidant is postulated
for iron catalysts with facial N,N,O ligands.[18]
In summary, we have reported a biomimetic iron(II)
complex (1) which reacts with O2 to oxidatively cleave
benzilic acid to benzophenone. The oxidant formed is capable
of converting cyclohexene to cis-cyclohexane-1,2-diol with
both oxygen atoms derived from O2. An iron(IV)–oxo–
hydroxo intermediate has been proposed as the active oxidant
in the reaction pathway. Thus 1 serves as a functional model of
Rieske dioxygenases where the monoanionic benzilate ligand
serves as the sacrificial co-substrate to provide two electrons
and one proton to carry the cis-dihydroxylation of cyclo-
hexene. The results discussed here show the importance of
model complexes in developing bioinspired oxidation cata-
lysts. With small-molecule models, the presence of a reductant
is necessary to carry out catalytic oxygen-dependent trans-
formation reactions. Detailed studies in this direction are in
progress in our laboratories.
Scheme 2. Proposed mechanism for the oxidation of 1 in the presence
of dioxygen.
the bound superoxide radical of the 1·O2 adduct abstracts the
hydrogen atom from the OH group of benzilate to form an
iron(III)–hydroperoxide species and a bound benzilate oxyl
radical. The latter spontaneously decomposes, resulting in
ꢀ
C C bond cleavage to form benzophenone and CO2 with
concomitant reduction of iron(III) to iron(II). The thus
formed iron(II)–hydroperoxide intermediate then undergoes
ꢀ
O O bond cleavage to generate an iron(IV)–oxo–hydroxo
oxidant that carries out the various observed oxidations.
In the absence of any external substrate, the oxoiron(IV)
species hydroxylates one of the 3-phenyl rings of the TpPh
2
supporting ligand, as previously observed for the correspond-
ing benzoylformate complex. The resulting iron(II)–pheno-
late complex readily reacts with the residual O2 present and is
oxidized to an iron(III)–phenolate species with a charge-
transfer (CT) band at 600 nm. This result is somewhat distinct
from that reported for the reaction of O2 with the corre-
sponding benzoylformate complex, which forms a green
chromophore with lmax at 650 nm.[10,11,13] When the oxidized
solution of 1 is treated with 10 equiv of pyridinium- or
lutidinium perchlorate, the CT band immediately shifts from
600 to 650 nm and subsequent treatment with tetrabutylam-
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Communications
Experimental Section
[1] M. Costas, M. P. Mehn, M. P. Jensen, L. Que, Jr., Chem. Rev.
2004, 104, 939.
[2] R. M. Cicchillo, H. Zhang, J. A. V. Blodgett, J. T. Whitteck, G.
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[5] W. A. van der Donk, C. Krebs, J. M. Bollinger, Jr., Curr. Opin.
Struct. Biol. 2010, 20, 673.
½FeIIðTpPh ÞðbenzilateÞꢁ (1). To
a
suspension of KTpPh (0.35 g,
2
2
0.5 mmol) and Fe(ClO4)2·6H2O (0.12 g, 0.5 mmol) in methanol
(5 mL) was added a methanolic solution (5 mL) of benzilic acid
(0.114 g, 0.5 mmol) and triethylamine (70 mL). The resulting white
suspension was stirred at room temperature for 2 h to isolate a white
solid. Single crystals suitable for X-ray diffraction were grown by
diffusing diethylether into a solution of 1 in dichloromethane. Yield:
0.41 g (86%). Elemental analysis calcd (%) for C59H45BFeN6O3
(952.68 gmolꢀ1): C 74.38, H 4.76, N 8.82; found: C 73.8, H 4.7, N
~
8.5. IR (KBr): n = 3466(br), 2924(vs), 2856(s), 1741(m), 1639(br),
[6] F. Pojer, R. Kahlich, B. Kammerer, S.-M. Li, L. Heide, J. Biol.
Chem. 2003, 278, 30661.
1553(m), 1468(m), 1354(m), 1169(s), 1068(s), 764(vs), 694(vs),
403(vs) cmꢀ1
.
[7] A. Karlsson, J. V. Parales, R. E. Parales, D. T. Gibson, H.
Eklund, S. Ramaswamy, Science 2003, 299, 1039.
[8] T. K. Paine, S. Paria, L. Que, Jr., Chem. Commun. 2010, 46, 1830.
[9] A. W. Addison, T. N. Rao, J. Reedijk, J. van Rijn, G. C.
Verschoor, J. Chem. Soc. Dalton Trans. 1984, 1349.
[10] M. P. Mehn, K. Fujisawa, E. L. Hegg, L. Que, Jr., J. Am. Chem.
Soc. 2003, 125, 7828.
[11] A. Mukherjee, M. Martinho, E. L. Bominaar, E. Mꢂnck, L.
Que, Jr., Angew. Chem. 2009, 121, 1812; Angew. Chem. Int. Ed.
2009, 48, 1780.
[12] A. Mukherjee, M. A. Cranswick, M. Chakrabarti, T. K. Paine, K.
Fujisawa, E. Mꢂnck, L. Que, Jr., Inorg. Chem. 2010, 49, 3618.
[13] T. K. Paine, H. Zheng, L. Que, Jr., Inorg. Chem. 2005, 44, 474.
[14] M. D. Wolfe, D. J. Altier, A. Stubna, C. V. Popescu, E. Mꢂnck,
J. D. Lipscomb, Biochemistry 2002, 41, 9611.
[15] L. P. Wackett, L. D. Kwart, D. T. Gibson, Biochemistry 1988, 27,
1360.
[16] M. B. Neibergall, A. Stubna, Y. Mekmouche, E. Mꢂnck, J. D.
Lipscomb, Biochemistry 2007, 46, 8004.
[17] M. Tarasev, D. P. Ballou, Biochemistry 2005, 44, 6197.
[18] P. D. Oldenburg, Y. Feng, I. Pryjomska-Ray, D. Ness, L. Que, Jr.,
J. Am. Chem. Soc. 2010, 132, 17713.
[19] P. D. Oldenburg, L. Que, Jr., Catal. Today 2006, 117, 15.
[20] K. Chen, M. Costas, J. Kim, A. K. Tipton, L. Que, Jr., J. Am.
Chem. Soc. 2002, 124, 3026.
Crystal data of 1: MF = C63H55BFeN6O4, Mr = 1026.79, triclinic,
space group P1, a = 11.861(4), b = 14.817(5), c = 15.909(6) ꢀ, a =
ꢀ
100.616(8)8, b = 100.626(8)8, g = 101.458(7)8, V= 2621.4(15) ꢀ3, Z =
2, 1 = 1.301 mgmꢀ3, m(MoKa) = 0.344 mmꢀ1, F(000) = 1076, GOF =
1.061. A total of 25593 reflections were collected in the range
1.34 ꢂ q ꢂ 26.00, 10250 of which were unique (Rint = 0.0717). R1-
(wR2) = 0.0532(0.1327) for 672 parameters and 10250 reflections (I >
2s(I)). CCDC 826082 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
Analysis of organic products after reaction with oxygen: The
iron(II) complex (0.020 mmol) was dissolved in 10 mL of dioxygen-
saturated benzene. The solution was stirred at room temperature, and
after the reaction the solvent was removed under vacuum and the
residue treated with 10 mL of 2m hydrochloric acid solution. The
organic products were extracted with diethyl ether (3 ꢁ 15 mL), and
the organic layer was dried over anhydrous sodium sulfate. After
removal of solvent, the colorless residue was analyzed by GC-MS and
1H NMR spectroscopy. Quantification of benzophenone was done by
comparing the peak area of four aromatic ortho protons (d =
7.81 ppm) with one CH proton (d = 6.23 ppm) of 3,5-di-tert-butyl-
benzoquinone (internal standard).
Received: June 10, 2011
Revised: August 18, 2011
Published online: September 28, 2011
[21] A. Company, Y. Feng, M. Gꢂell, X. Ribas, J. M. Luis, L. Que, Jr.,
M. Costas, Chem. Eur. J. 2009, 15, 3359.
Keywords: benzilic acid · bioinorganic chemistry ·
.
cis-dihydroxylation · iron · oxidative decarboxylation
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