Functional models of α-keto acid dependent nonheme iron oxygenases: Synthesis and reactivity of biomimetic iron(II) benzoylformate complexes supported by a 2,9-dimethyl-1,10-phenanthroline ligand

Article abstract of DOI:10.1007/s00775-013-0984-6

Two biomimetic iron(II) benzoylformate complexes, [LFe^II(BF) ₂] (2) and [LFe^II(NO₃)(BF)] (3) (L is 2,9-dimethyl-1,10-phenanthroline and BF is monoanionic benzoylformate), have been synthesized from an iron(II)-dichloro complex [LFe^IICl ₂] (1). All the iron(II) complexes have been structurally and spectroscopically characterized. The iron(II) center in 2 is coordinated by a bidentate NN ligand (2,9-dimethyl-1,10-phenanthroline) and two monoanionic benzoylformates to form a distorted octahedral coordination geometry. One of the benzoylformates binds to the iron in 2 via both carboxylate oxygens but the other one binds in a chelating bidentate fashion via one carboxylate oxygen and the keto oxygen. On the other hand, the iron(II) center in 3 is ligated by one NN ligand, one bidentate nitrate, and one monoanionic chelating benzoylformate. Both iron(II) benzoylformate complexes exhibit the facial NNO donor environment in their solid-state structures. Complexes 2 and 3 are stable in noncoordinating solvents under an inert atmosphere, but react with dioxygen under ambient conditions to undergo oxidative decarboxylation of benzoylformate to benzoate in high yields. Evidence for the formation of an iron(IV)-oxo intermediate upon oxidative decarboxylation of benzoylformate was obtained by interception and labeling experiments. The iron(II) benzoylformate complexes represent the functional models of α-keto acid dependent oxygenases.

Full text of DOI:10.1007/s00775-013-0984-6

J Biol Inorg Chem (2013) 18:401–410
DOI 10.1007/s00775-013-0984-6
ORIGINAL PAPER
Functional models of a-keto acid dependent nonheme iron
oxygenases: synthesis and reactivity of biomimetic iron(II)
benzoylformate complexes supported by a 2,9-dimethyl-1,10-
phenanthroline ligand
Oindrila Das
•
Sayanti Chatterjee Tapan Kanti Paine
•
Received: 15 October 2012 / Accepted: 31 January 2013 / Published online: 16 February 2013
Ó SBIC 2013
Abstract Two biomimetic iron(II) benzoylformate com-
experiments. The iron(II) benzoylformate complexes rep-
II
plexes, [LFe (BF) ] (2) and [LFe (NO )(BF)] (3) (L is 2,9-
II
resent the functional models of a-keto acid dependent
oxygenases.
2
3
dimethyl-1,10-phenanthroline and BF is monoanionic
benzoylformate), have been synthesized from an iron(II)–
II
dichloro complex [LFe Cl ] (1). All the iron(II) complexes
Keywords Iron ꢀ Benzoylformate ꢀ O–O activation ꢀ
Decarboxylation ꢀ Functional models
2
have been structurally and spectroscopically characterized.
The iron(II) center in 2 is coordinated by a bidentate NN
ligand (2,9-dimethyl-1,10-phenanthroline) and two mono-
anionic benzoylformates to form a distorted octahedral
coordination geometry. One of the benzoylformates binds
to the iron in 2 via both carboxylate oxygens but the other
one binds in a chelating bidentate fashion via one car-
boxylate oxygen and the keto oxygen. On the other hand,
the iron(II) center in 3 is ligated by one NN ligand, one
bidentate nitrate, and one monoanionic chelating benzoyl-
formate. Both iron(II) benzoylformate complexes exhibit
the facial NNO donor environment in their solid-state
structures. Complexes 2 and 3 are stable in noncoordinat-
ing solvents under an inert atmosphere, but react with
dioxygen under ambient conditions to undergo oxidative
decarboxylation of benzoylformate to benzoate in high
yields. Evidence for the formation of an iron(IV)–oxo
intermediate upon oxidative decarboxylation of benzoyl-
formate was obtained by interception and labeling
Introduction
a-Ketoglutarate (a-KG)-dependent oxygenases are an
important class of dioxygen-activating nonheme iron
enzymes that exhibit a diverse range of biological activities
[1–3]. The members of this superfamily of enzymes, in
spite of their diverse reactivity, contain a common ‘‘2-His-
1-carboxylate’’ facial triad in their active site and require
an a-keto acid, iron(II), and O [4–8]. X-ray crystallo-
2
graphic studies have provided useful information about the
structures of this superfamily of enzymes. The a-keto acid
dependent enzyme taurine dioxygenase (TauD), which
catalyzes the hydroxylation of taurine, has been crystallo-
graphically characterized in three different forms [9]. The
structure of the as-isolated form reveals the iron center with
the ‘‘2-His-1-carboxylate’’ facial triad and three water
molecules. The TauD–aKG form shows a bidentate bind-
ing of a-KG by replacement of two water molecules. The
structure of the enzyme–a-KG–taurine complex reveals the
binding of taurine to form a five-coordinate iron(II) center.
The enzyme–a-KG–substrate complex allows the binding
of dioxygen at the sixth coordination site to initiate the
reaction. In a common mechanism for this class of non-
heme enzymes, an iron(III)–superoxo intermediate has
Electronic supplementary material The online version of this
article (doi:10.1007/s00775-013-0984-6) contains supplementary
material, which is available to authorized users.
O. Das ꢀ S. Chatterjee ꢀ T. K. Paine (&)
Department of Inorganic Chemistry,
Indian Association for the Cultivation of Science,
been proposed to form via activation of O at the iron(II)
2
2
A & 2B Raja S. C. Mullick Road,
a-keto acid center [1]. Subsequent O–O bond cleavage and
decarboxylation of the iron–oxygen intermediate result in
Jadavpur 700032, Kolkata, India
e-mail: ictkp@iacs.res.in
123

4
02
J Biol Inorg Chem (2013) 18:401–410
formation of an iron(IV)–oxo intermediate, which has been
shown experimentally to be the active oxidant in many
oxygen-dependent transformation reactions [10–21]. The
activation of dioxygen and the involvement of iron(IV)–
oxo oxidant in the catalytic pathway of a-KG-dependent
enzymes have been studied by theoretical calculations
under a nitrogen environment in an inert atmosphere glove
box. Fourier transform infrared (FT-IR) spectra were
recorded using a Shimadzu FT-IR 8400S instrument. Ele-
mental analyses were performed with a PerkinElmer 2400
series II CHN analyzer. Solution electronic spectra were
measured at room temperature with an Agilent 8453 diode-
array spectrophotometer. Electrospray ionization mass
spectra were recorded with a Waters QTOF Micro YA263
[
16, 22–24].
Model complexes play an important role in under-
1
standing the nature of the intermediate species involved in
the catalytic reaction pathway. Synthetic mononuclear
Fe(IV)=O complexes supported by nonheme ligands have
been isolated and characterized [25–30]. These Fe(IV)=O
complexes exhibit versatile reactivity such as hydrogen-
atom abstraction, hydroxylation, and oxo-atom transfer
reactions [29, 31, 32]. A number of biomimetic iron a-keto
acid complexes have been reported as models of a-keto
acid dependent oxygenases in the literature. Most of the
biomimetic complexes employed NNNN, NNNO, or NNN
chelating ligands and different a-keto acids as model
substrates [33–42]. Several nonheme iron complexes with
NNO donor ligands have also been reported [43–50].
Additionally, the use of NN donors in combination with
bulky carboxylates as ‘‘2-His-1-carboxylate’’ mimics has
been documented in the literature [51]. However, examples
of biomimetic complexes with the NNO facial triad as
models for a-keto acid dependent oxygenases are rare [52].
We have initiated a project on the development of bio-
mimetic iron complexes using substituted 1,10-phenanthr-
olines. 1,10-Phenanthrolines are oxidatively robust and find
applications in bioinspired catalysis. The oxo-bridged
diiron(III) complexes of 1,10-phenanthroline have been
used as catalysts for alkene epoxidation, sulfide oxidation,
and alkane hydroxylation using peroxides as oxidants
system. H NMR spectra were measured using a Bruker
Avance III 500-MHz spectrometer. Room temperature
magnetic data were collected with a Gouy balance (Sher-
wood Scientific, Cambridge, UK). Diamagnetic contribu-
tions were estimated for each compound by using Pascal’s
constants. Gas chromatography (GC)–mass spectrometry
(MS) measurements were conducted with a PerkinElmer
Clarus 680 GC and SQ8T MS system, using an Elite 5 MS
column (30 m 9 0.25 mm 9 0.25 lm) with 300 °C max-
imum temperature. Labeling experiments were conducted
1
8
18
with O gas (99 atom %) or H O (98 atom %) from
2
2
Icon Services (USA).
II
For synthesis of [LFe Cl ] (1), 2,9-dimethyl-1,10-phe-
2
nanthroline (0.104 g, 0.5 mmol) was reacted with FeCl2
(0.0633 g, 0.5 mmol) in dry dichloromethane (10 mL) at
room temperature. The resulting solution was stirred for
30 min to precipitate a yellow solid. The solid was isolated
by filtration. X-ray-quality single crystals of the complex
were isolated from a solvent mixture of dichloromethane
and diethyl ether. Yield: 0.15 g (90 %). Anal Calcd for
-
1
C H Cl FeN (335.01 g mol ): C, 50.19; H, 3.61; N,
2
1
4
12
2
8.36 %. Found: C, 50.16; H, 3.55; N, 8.38 %. FT-IR (KBr)
-
1
(cm ): 3,422 (br), 3,067 (w), 2,924 (w), 2,855 (vw),
1,622 (m), 1,591 (s), 1,566 (m), 1,504 (vs), 1,425 (m),
1,379 (w), 1,296 (w), 1,222 (m), 1,153 (m), 1,036 (s),
864 (vs), 781 (s), 729 (s). UV–vis (dichloromethane)
[
53–56]. However, there is no report of an iron(II) phe-
-
1
-1
nanthroline complex acting as a functional model of oxy-
gen-activating nonheme iron enzymes. As an outcome of
our work in this direction, we report herein the synthesis
and structural characterization of two mononuclear iron(II)
[kmax, nm (e, M cm )]: 335 (sh). l (20 °C): 5.09 lB.
eff
II
For synthesis of [LFe (BF) ] (2), a dichloromethane
2
solution (15 mL) of 1 (0.1675 g, 0.5 mmol) was treated
with sodium benzoylformate (0.172 g, 1 mmol). The
solution was stirred at room temperature for 12 h, during
which time the solution turned violet. The solution was
then filtered and the filtrate was kept for layer diffusion
with diethyl ether to isolate X-ray-quality single crystals of
2. Yield: 0.16 g (60 %). Anal Calcd for C H FeN O
2 6
II
II
benzoylformate complexes, [LFe (BF) ] (2) and [LFe
2
(
NO )(BF)] (3), where L is 2,9-dimethyl-1,10-phenanthro-
3
line and BF is monoanionic benzoylformate. Both model
iron(II) benzoylformate complexes exhibit the facial NNO
donor environment as observed from their X-ray single-
crystal structures. The dioxygen activation by the iron(II)
benzoylformate complexes and the mechanistic studies of
oxidative decarboxylation of benzoylformate are reported.
3
0
22
-
1
(562.35 g mol ): C, 64.06; H, 3.94; N, 4.98. Found: C,
-
1
64.18; H, 3.86; N, 5.03 %. FT-IR (KBr) (cm ):
3,450 (br), 3,070 (w), 2,924 (w), 1,672 (vs), 1,627 (vs),
1
1
,593 (vs), 1,504 (m), 1,444 (m), 1,431 (m), 1,385 (w),
,234 (vs), 1,176 (m), 1,153 (w), 1,001 (m), 860 (m),
Materials and methods
815 (m), 715 (m), 681 (s). UV–vis (dichloromethane)
-1
-
1
[
kmax, nm (e, M cm )]: 580 (550), 528 (620), 480 (sh).
All chemicals were purchased from commercial sources.
Solvents were distilled and dried before use. The synthesis
and manipulation of air-sensitive complexes were done
leff (20 °C): 4.76 lB.
For synthesis of [LFe (NO )(BF)] (3), a dichlorometh-
ane solution (15 mL) of 1 (0.1675 g, 0.5 mmol) was
II
3
1
23

J Biol Inorg Chem (2013) 18:401–410
403
treated with a mixture of sodium benzoylformate (0.086 g,
Organic product derived from 2,4-di-tert-butylphenol
0
.5 mmol) and AgNO (0.127 g, 0.75 mmol). The solution
3
1
0
0
0
was stirred for 12 h, during which time the solution turned
violet. The violet solution was then filtered and the filtrate
was kept for layer diffusion with hexane to isolate a purple
crystalline solid. Yield: 0.099 g (42 %). Anal Calcd for
H NMR data of 4,4 ,6,6 -tetra-tert-butyl-2,2 -biphenol
(500 MHz, CDCl ; d, ppm): 1.32 (s, 18H), 1.45 (s, 18H),
3
5.28 (s, 2H), 7.11 (d, J = 2.5 Hz, 2H), 7.40 (d, J = 2.5 Hz,
2H). The yield of biphenol was calculated on the basis of
starting Fe(II) complexes: 60 and 45 % with 2 and 3,
respectively. Control experiments were also performed in
the absence of iron complexes. No biphenol was formed in
the control experiments.
-
1
C H FeN O (475.23 g mol ): C, 55.60; H, 3.61; N,
2
2
17
3 6
8
.84. Found: C, 55.53; H, 3.47; N, 9.01 %. FT-IR (KBr)
-
cm ): 3,435 (br), 3,065 (w), 1,684 (vs), 1,630 (vs),
1
(
1
,591 (vs), 1,506–1,477 (s), 1,383 (vs), 1,288 (s),
,230 (vs), 1,175 (m), 1,155 (m), 1,026 (m), 1,001 (m),
87 (m), 862 (s), 818 (m), 775 (w), 752 (m), 729 (m),
1
9
Organic product derived from 2,4,6-tri-tert-butylphenol
6
85 (s). UV–vis (dichloromethane) [kmax
cm )]: 580 (335), 525 (400), 490 (435). leff (20 °C):
.83 lB.
,
nm (e,
-
1
-1
1
M
H
NMR data of 2,6-di-tert-butyl-1,4-benzoquinone
; d, ppm): 1.27–1.28 (br, 18H), 6.51 (s,
H). Yield: 90 % for 2 and 75 % for 3.
4
(500 MHz, CDCl
3
2
Reactivity with dioxygen
Interception studies with dimethyl sulfide/dimethyl
sulfoxide
The iron(II) benzoylformate complex (0.02 mmol) was
dissolved in 10 mL dry solvent (dichloromethane or
acetonitrile). Pure oxygen gas was bubbled through the
solution for 3 min, and the solution was then stirred at
room temperature under an oxygen atmosphere. The light-
orange solution thus formed was dried by use of a rotary
evaporator to remove the solvent, and the residue was
treated with 3.0 M HCl solution (10 mL). The organic
products were then extracted with diethyl ether
The iron(II) benzoylformate complex (0.02 mmol) was
dissolved in dry acetonitrile (10 mL). To the solution was
added 10 equiv of external substrates (0.2 mmol). Pure
oxygen gas was bubbled through the solution for 3 min,
and the solution was stirred at room temperature under an
oxygen atmosphere for 20 h. The solvent was then
removed from the reaction mixture and distilled benzene
was added. A slight excess of sodium dithionite
(0.04 mmol) was then added to the benzene solution, fol-
(
3 9 15 mL), dried over anhydrous Na SO , and analyzed
2 4
1
by H NMR spectroscopy in CDCl . A control experiment
3
lowed by addition of D O, and the resulting solution was
2
was performed in the absence of the iron complex by
analyzing a solution of sodium benzoylformate under
oxygen with stirring for 20 h. No appreciable decompo-
sition of benzoylformate was observed in the control
experiment.
stirred for 30 min. To the solution was added 1,10-phe-
nanthroline monohydrate (0.06 mmol), and the solution
was then stirred for an additional 15 min. The D O layer
2
1
was then collected and analyzed by H NMR spectroscopy.
1
H NMR data of dimethyl sulfoxide derived from dimethyl
sulfide (500 MHz, D O; d, ppm) 2.74 (s, 6H). Yield: 33 %
2
1
for 2 and 23 % for 3. H NMR data of dimethyl sulfone
Interception studies with phenols
from dimethyl sufoxide (500 MHz, D O; d, ppm) 3.17 (s,
2
The iron(II) benzoylformate complex (0.02 mmol) was
dissolved in 10 mL dry acetonitrile. To the solution was
added 10 equiv of phenols (0.2 mmol). Pure oxygen gas
was bubbled through the solution for 3 min, and the
solution was then stirred at room temperature under an
oxygen atmosphere for 20 h. The reaction solution was
then dried by use of a rotary evaporator, and the residue
was treated with 3.0 M HCl solution (10 mL). The
organic products were extracted with diethyl ether
6H). Yield: 18 % for 2. Control experiments were also
performed in the absence of iron complexes. No oxidation
of external substrates occurred in the control experiments.
X-ray crystallographic data collection and refinement
of the structures
Diffraction data for 1, 2, and 3 were collected at 20 °C with
˚
Mo Ka radiation (k = 0.71073 A). Each crystal was fixed
(
3 9 15 mL) and dried over Na SO . The ether solution
2
on the tip of a glass capillary and mounted on a on a Bruker
Smart APEX II CCD diffractometer. Crystallographic data
for the complexes are summarized in Table 1. Cell
refinement, indexing, and scaling of the data sets were done
using APEX2, version 2.1-0 [57]. The structures were
solved by the Patterson method and subsequent Fourier
4
was then filtered through a silica gel column and washed
several times with diethyl ether. The solvent was
removed from the filtrate, dried under a vacuum, and the
1
organic products were characterized by
spectroscopy.
H NMR
123

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J Biol Inorg Chem (2013) 18:401–410
II
II
Table 1 Crystallographic data of [LFe Cl
2
] (1), [LFe (BF)
)(BF)] (3), where L is 2,9-dimethyl-1,10-phenan-
throline and BF is monoanionic benzoylformate
2
] (2),
positive-definite displacement in an anisotropic refinement
and was refined isotropically.
II
and [LFe (NO
3
Crystal
parameters
1
2
3
Results and discussion
Empirical
formula
14
C H
12Cl
2
FeN
2
C
30
H22FeN
O
2 6
22 3 6
C H17FeN O
Synthesis and characterization
Formula weight 335.01
562.35
475.24
The iron(II) benzoylformate complexes were synthesized
from a precursor iron(II)–chloro complex. The precursor
Crystal system
Space group
Orthorhombic
Pnma
Triclinic
P-1
Monoclinic
1
P2 /c
complex 1 was prepared by mixing FeCl with 2,9-dime-
2
˚
a (A)
11.2381 (7)
7.5280 (5)
17.8070 (11)
90
8.494 (2)
10.793 (2)
15.107 (4)
15.581 (14)
7.163 (6)
17.791 (15)
90
thyl-1,10-phenanthroline in dichloromethane [59, 60]. The
1
H NMR spectrum (Fig. S1) of 1 in CDCl displays para-
3
˚
b (A)
˚
c (A)
magnetically shifted proton resonances typical of high-spin
iron(II) complexes as observed in the analogous complex
a (°)
b (°)
c (°)
93.887 (10)
104.292 (8)
109.261 (6)
1,250.1 (5)
2
90
94.432 (12)
90
0
0
[
(dmby)FeCl2] (dmby is 6,6 -dimethyl-2,2 -bipyridine)
61]. The room temperature effective magnetic moment of
90
[
3
˚
Volume (A )
1,506.48 (17)
4
1,980 (3)
4
5
.09 l for 1 is in good agreement with the spin-only value
B
Z
calculated for high-spin iron(II) complexes [62].
-
3
)
Dcalc (g cm
1.477
1.494
1.594
The complex was further characterized by single-crystal
X-ray diffraction studies. X-ray-quality single crystals of 1
were grown from a solvent mixture of dichloromethane and
diethyl ether. The single-crystal structure of the neutral com-
plex confirmed an iron(II) center coordinated by a bidentate
NN donor ligand (2,9-dimethyl-1,10-phenanthroline) and two
chlorides, resulting in a tetrahedral coordination geometry
F(000)
680
580.0
976.0
l Mo Ka
1.342
0.653
0.810
-
1
(
mm
Temperature
K)
)
293 (2)
293 (2)
293 (2)
(
R
int
0.0363
0.0359
0.0781
h range data
2.14–27.74
1.41–25.00
1.31–19.65
(
Fig. 1). The iron–nitrogen and iron–chloro distances
Table 2) are typical of high-spin iron(II) complexes and are in
collection (°)
(
Reflections
collected
15,315
1,893
1,434
14,219
4,394
3,641
6,929
1,691
1,066
the range of those reported for [(dmby)FeCl ] [61].
2
Unique
reflections
Observed
reflections
[
I [ 2r(I)]
Parameters
114
354
286
Goodness of fit 0.862
2
on F
1.098
1.059
Final R indices
I [ 2r(I)]
R
1
= 0.0335
= 0.1101 wR
= 0.0491
= 0.1243 wR
R
1
= 0.0355
= 0.0952 wR
= 0.0459
= 0.1019 wR
R
1
= 0.0552
= 0.1401
= 0.0946
= 0.1676
[
wR
2
2
2
R indices (all
data)
R
1
R
1
R
1
wR
2
2
2
analyses and refined by the full-matrix least-squares
2
method based on F with all observed reflections. All non-
Fig. 1 ORTEP plot (40 % probability of thermal ellipsoids) of
II
2
hydrogen atoms were refined anisotropically and hydrogen
atoms were placed in ideal positions. All the calculations
were performed using the WinGX system, version 1.80.05
[LFe Cl ] (1), where L is 2,9-dimethyl-1,10-phenanthroline. All
hydrogen atoms have been omitted for clarity
[
58]. Complex 3 diffracts at low angle with poor resolution
of the data set as a distinctive feature of the crystals. The
Table 2 Selected bond distances ( A˚ ) and angles (°) for 1
Fe1–N1
2.111 (3)
2.2209 (6)
79.06 (9)
Fe1–N2
2.120 (2)
2
final full-matrix least-squares refinement on F converged
Fe1–Cl1
to R = 0.0335 and wR = 0.1243 for 1, R = 0.0355 and
1
2
1
N1–Fe1–N2
N2–Fe1– Cl1
N1–Fe1–Cl1
Cl1–Fe1–Cl1
112.22 (3)
122.83 (4)
wR = 0.1019 for 2, and R = 0.0552 and wR = 0.1676
2
1
2
111.07 (3)
for 3. The N3 nitrogen atom of nitrate ion in 3 exhibits non-
1
23

J Biol Inorg Chem (2013) 18:401–410
405
Scheme 1 Syntheses of iron(II) benzoylformate complexes
II
Fig. 2 Optical spectra at 23 °C of 1 mM [LFe (BF)
2
] (2) and 1 mM
II
[LFe (NO
and BF is monoanionic benzoylformate
Complex 2 was isolated from the reaction of 1 with 2
equiv of sodium benzoylformate. When 1 equiv of sodium
benzoylformate was used in the reaction, the yield of 2 was
found to be low as a result of the isolation of unreacted 1
from the reaction solution. Complex 3 was prepared from 1
using equimolar amounts of reagents in the presence of
3
)(BF)] (3), where L is 2,9-dimethyl-1,10-phenanthroline
1
.5 equiv of AgNO (Scheme 1).
3
The complexes were characterized by different spec-
troscopic and analytical techniques. Both iron(II) ben-
zoylformate complexes show strong infrared peaks in the
-
1
1
,680–1,590-cm region, indicating the binding of a-keto
acid anion. The bidentate binding of benzoylformate was
supported by the characteristic purple-to-violet color of the
complexes in dichloromethane with kmax values falling in
the region of 500–600 nm (Fig. 2) [33, 38, 63]. These
features in the optical spectra, by analogy to reported data,
are assigned to the iron(II) to a-keto acid charge transfer
transition. In a-KG-dependent TauD, the charge transfer
transition has been observed at 530 nm in the presence of
iron(II) and a-KG under anaerobic conditions [1]. Room
Fig. 3 Changes in optical spectra on addition of sodium benzoylfor-
mate (NaBF) in methanol to a dichloromethane solution of 1 (1 mM)
at 23 °C. Inset: Absorbance at 528 nm versus number of equivalents
of sodium benzoylformate added
temperature magnetic moments of 4.76 and 4.83 l for 2
B
and 3, respectively, suggest the high-spin nature of the
iron(II) complexes. The mononuclear iron(II) benzoylfor-
mate complexes are stable under a nitrogen atmosphere.
To determine the binding affinity of benzoylformate for
LFe(II) in solution, optical spectral titrations were per-
formed by gradual addition of sodium benzoylformate to a
dichloromethane solution of 1 under an inert atmosphere.
The intensity of the characteristic metal to a-keto acid
charge transfer transitions at 580 and 528 nm increases
linearly with the concentration of sodium benzoylformate.
The intensity of the metal-to ligand charge transfer
2
of solvent, which possibly causes a change of the j -ben-
1
zoylformate coordination to a j -benzoylformate coordi-
nation (Fig. 2) [33]. The resonances for benzoylformate
1
protons appear between 20.00 and 7.50 ppm in the H
NMR spectra of the iron(II) benzoylformate complexes.
The peak positions of benzoylformate protons in CD CN
3
and CDCl3 support a change in coordination mode of
benzoylformate in acetonitrile (Figs. S2–S5).
To obtain a structural understanding of the complexes,
single crystals were grown from a solvent mixture of
dichloromethane and diethyl ether (for 2) or dichloro-
methane and hexane (for 3). The X-ray single crystal
structure of the neutral complex 2 reveals a six-coordinate
(
MLCT) band attains a maximum value after addition of
.4 equiv of sodium benzoylformate and remains unaltered
1
upon further addition of the a-keto acid (Fig. 3). The loss
of MLCT intensity in acetonitrile is due to the coordination
123

4
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J Biol Inorg Chem (2013) 18:401–410
mononuclear iron complex representing the crystallo-
graphic asymmetric unit (Fig. 4). The iron center is coor-
dinated by a bidentate ligand and two monoanionic
benzoylformates. One of the benzoylformates binds to the
metal center via both the carboxylate oxygens, whereas the
other benzoylformate coordinates in a chelating bidentate
fashion through one carboxylate oxygen and the carbonyl
oxygen. The two nitrogen donors (N1 and N2) of the
bidentate ligand and the oxygen donor (O5) of the car-
boxylate group of one of the coordinated benzoylformates
constitute the facial triad as described in the ‘‘2-His-1-
carboxylate’’ structural motif in the active site of a-KG-
dependent metalloenzymes. The other face of the coordi-
nation sphere is occupied by the carboxylate oxygen (O4),
the keto oxygen (O3), and carboxylate oxygen (O2) of the
chelating benzoylformate. The pyridine nitrogen (N1) and
the keto oxygen (O3) of benzoylformate occupy the axial
positions, with an N1–Fe1–O3 angle of 161.37 (6)°
147.58 (7)° and 155.93 (7)°, respectively. The Fe–N bond
˚
distances [2.188 (2) and 2.154 (2) A] are typical of a high-
spin iron (II) complex [52]. The five-membered chelate ring
at the iron(II) center formed by the chelating benzoylformate
contains two different Fe–O bonds, i.e., Fe–O(keto) of
˚
˚
2.2630 (16) A and Fe–O(carboxylate) of 1.9986 (17) A,
similar to those observed in other iron(II) benzoylformate
complexes [33, 35, 38]. A four-membered chelate ring is
formed by the asymmetrically coordinated carboxylate
group of a benzoylformate with Fe1–O4 and Fe1–O5 dis-
˚
tances of 2.335 (2) and 2.1350 (17) A, respectively. The
benzoylformate chelate is almost coplanar with the phenyl
ring, exhibiting a dihedral angle of 16.48°. In contrast, both
benzoylformates bind in a bidentate chelating fashion in a
related complex, [(dmby)Fe(BF) ], where the chelate rings
2
at the metal center deviate from planarity as a result of the
intramolecular face-to-face ‘‘pꢀꢀꢀp’’ interaction between the
phenyl rings of the two benzoylformates [52].
(
Table 3). The other pyridine nitrogen (N2), carboxylate
Although the diffraction data for 3 were obtained at low
h angle with poor resolution of the data set, the structural
determination allowed us to clarify some relevant geomet-
rical features (Fig. S6). The iron center in 3 is coordinated
by a bidentate ligand (2,9-dimethyl-1,10-phenanthroline),
one monoanionic bidentate nitrate, and one monoanionic
chelated benzoylformate. In this case, two nitrogen donors
oxygen (O2) of benzoylformate, and two carboxylate oxy-
gens (O4 and O5) of the other benzoylformate occupy
equatorial sites, with N2–Fe1–O4 and O2–Fe1–O5 angles of
(N1 and N2) of 2,9-dimethyl-1,10-phenanthroline and an
oxygen donor (O5) of the bidentate nitrate form the NNO
facial triad. Pyridine nitrogen N1 and keto oxygen O3
occupy the axial positions of the distorted octahedral
coordination geometry around the iron(II) center. The
chelating benzoylformate shows a slightly stronger Fe–
˚
O(keto) bond, with a length of 2.210 (7) A (Table S1),
possibly due to better conjugation of the keto group with the
phenyl ring. This is also reflected in a small dihedral angle
value of 10.49° between the bidentate benzoylformate
chelate and the phenyl ring.
Fig. 4 ORTEP diagram of 2 with thermal ellipsoids drawn at the
40 % probability level. All hydrogen atoms have been omitted for
clarity
Reactivity with dioxygen
Both iron(II) benzoylformate complexes (2 and 3) are
reactive towards dioxygen. The reactivities of 2 and 3 were
studied in acetonitrile and in dichloromethane. Complex 2
reacts slowly with dioxygen in acetonitrile over a period of
˚
Table 3 Selected bond distances (A) and angles (°) for 2
Fe(1)–N(1)
2.1875 (17)
2.1537 (18)
1.9986 (17)
77.66 (7)
Fe(1)–O(3)
2.2630 (16)
2.335 (2)
Fe(1)–N(2)
Fe(1)–O(4)
2
0 h. The reaction was monitored by analyzing the organic
Fe(1)–O(2)
Fe(1)–O(5)
2.1350 (17)
73.48 (6)
1
products with time (Fig. 5). The H NMR and GC–MS
spectra of the organic products from 2 after removal of the
metal ion by acidic workup of the reaction solution show
almost quantitative conversion of benzoylformic acid to
benzoic acid after 20 h (Fig. 5, Fig. S7).
N(1)–Fe(1)–N(2)
O(5)–Fe(1)–O(4)
N(2)–Fe(1)–O(4)
O(2)–Fe(1)–N(2)
O(2)–Fe(1)–N(1)
O(5)–Fe(1)–O(3)
O(2)–Fe(1)–O(4)
O(3)–Fe(1)–O(4)
O(2)–Fe(1)–O(3)
N(1)–Fe(1)–O(3)
O(2)–Fe(1)–O(5)
O(5)–Fe(1)–N(2)
O(5)–Fe(1)–N(1)
N(2)–Fe(1)–O(3)
N(1)–Fe(1)–O(4)
57.91 (7)
161.37 (6)
155.93 (7)
92.27 (7)
147.58 (7)
100.43 (7)
88.53 (7)
114.30 (7)
109.77 (7)
101.83 (7)
In dichloromethane, complex 2 reacts with dioxygen for
0 h, during which the characteristic purple color, origi-
83.03 (6)
2
111.99 (7)
81.14 (7)
nating from MLCT bands at 580 and 528 nm, slowly
decays to light orange following pseudo-first-order kinetics
1
23

J Biol Inorg Chem (2013) 18:401–410
407
complexes are therefore functional mimics of a-keto acid
dependent enzymes.
To understand the involvement of the iron–oxygen
intermediate in the decarboxylation pathway of iron(II)
benzoylformate complexes, the reaction of 2 (or 3) with
dioxygen was conducted at -40 °C in acetonitrile. No
feature for any iron–oxygen intermediate species was
observed spectrophotometrically under the experimental
conditions; therefore the reactions were studied in the
presence of external probes such as thioanisole, dimethyl
sulfide, dimethyl sulfoxide, dihydroanthracene, 2,4-di-tert-
butylphenol, and 2,4,6-tri-tert-butylphenol to intercept
metal–oxygen species. Iron(III) superoxide and copper(II)
superoxide intermediates are known to cleave the O–H
1
Fig. 5 H HMR spectra of organic products after a 2 h, b 5 h, and
c 20 h reaction of 2 with dioxygen in acetonitrile at 23 °C. Peaks
marked as A are from benzoylformic acid and peaks marked as B are
from benzoic acid
1
bond of phenols homolytically [33, 40, 64, 65]. The H
NMR spectra of the organic products derived from 2,4-di-
tert-butylphenol after the reaction suggest the formation of
0 0 0
3,3 ,5,5 -tetra-tert-butyl-2,2 -biphenol in 60 and 45 % yield
with 2 and 3, respectively (Scheme 2). This result supports
the formation of a phenoxyl radical by abstraction of a
hydrogen atom of phenol by an iron–oxygen intermediate.
Similarly, 2,4,6-tri-tert-butylphenol affords 2,6-di-tert-bu-
tylbenzoquinone (90 % and 75 % yield with 2 and 3,
respectively) as a result of the decomposition of 2,4,6-tri-
tert-butylphenoxyl radical formed in situ on hydrogen-
atom abstraction. The formation of 2,4,6-tri-tert-butyl-
phenoxyl radical in the interception reaction was proved by
X-band EPR spectroscopy. Of note, the presence of
external substrates does not affect the decarboxylation of
benzoylformate.
1
Fig. 6 H NMR spectra of organic products after a 3 h, b 5 h, c 8 h,
Although no interception is observed in the presence of
thioanisole or dihydroanthracene, reaction of iron(II) ben-
zoylformate complex 2 with dioxygen in the presence of
dimethyl sulfide affords dimethyl sulfoxide in 33 % yield.
When dimethyl sulfoxide is used as intercepting reagent,
18 % dimethyl sulfone is formed as the only product
and d 16 h reaction of 3 with dioxygen in acetonitrile at 23 °C. Peaks
marked as A are from benzoylformic acid and peaks marked as B are
from benzoic acid
1
Fig. S8). The H NMR spectrum of the reaction solution
(
reveals the oxidative decarboxylation of benzoylformic
acid to benzoic acid in quantitative yield. Similarly, com-
plex 3 reacts with dioxygen in acetonitrile to give almost
quantitative yield of benzoic acid after 20 h (Fig. 6).
During the reaction, the MLCT bands at 525 and 580 nm
slowly decay following pseudo-first-order kinetics (Fig.
S9). A dichloromethane solution of 3 slowly reacts with
dioxygen under ambient conditions, during which the light-
1
8
(Fig. S11). Additionally, decarboxylation of 2 with O in
2
the presence of dimethyl sulfoxide affords sulfone, where
one labeled oxygen atom is incorporated into sulfone and
the other one is incorporated into benzoic acid (Figs. S10,
1
8
S12). Moreover, addition of H O in the reaction of 2 with
2
1
6
O in the presence of sulfoxide results in about 10 %
2
1
8
incorporation of O into sulfone (Fig. S13). These results
support the formation of an iron(IV)–oxo intermediate
during the decarboxylation of benzoylformate. The iro-
n(IV)–oxo, exchangeable with water, is involved in oxo-
atom transfer to dimethyl sufide/sulfoxide, resulting in the
formation of dimethyl sulfoxide/sulfone and O–H atom
abstraction from phenols (Scheme 2).
1
purple solution changes to a light-yellow solution. The H
NMR spectrum of the organic products after removal of the
metal ion reveals almost complete conversion of benzoyl-
formic acid to benzoic acid.
1
8
The reaction of 2 with O was performed to under-
2
stand the fate of oxygen atoms from molecular oxygen.
The analysis of organic product by GC–MS clearly sug-
gests the incorporation of one labeled oxygen atom from
Oxidative decarboxylation of the a-keto acid substrate
has been observed upon oxygenation of several biomimetic
iron(II) benzoylformate complexes with N and N donor
1
8
O into benzoic acid during the decarboxylation of ben-
2
3
4
Me2
zoylformate (Fig. S10). The iron(II) benzoylformate
ligands. An in situ generated complex—[(Tp )Fe(BF)],
123

4
08
J Biol Inorg Chem (2013) 18:401–410
Scheme 2 Proposed pathway for oxidative decarboxylation of iron(II) benzoylformate complex 2
Me2
where Tp
is hydrotris(3,5-dimethylpyrazol-1-yl)bo-
geometry. The second benzoylformate, if bound in a che-
lating mode, would face steric interactions with the two
methyl groups of the planar ligand, 2,9-dimethyl-1,10-
phenanthroline. To avoid the steric interaction, the second
benzoylformate coordinates to the iron center through the
carboxylate oxygens. The optical spectral data (Fig. 2)
indicate the existence of a dynamic equilibrium in solution
between the species containing benzoylformate ligated to
the iron(II) center with different binding motifs. In solu-
tion, a five-coordinate iron(II) species (with a monodentate
benzoylformate in 2 and a monodentate nitrate in 3) is
therefore proposed to activate dioxygen to form an iron(III)
superoxide intermediate (Scheme 2). The chelated ben-
zoylformate is expected to undergo oxidative decarboxyl-
ation; the yield of benzoic acid would be at maximum
50 % with respect to two benzoylformates. A quantitative
yield of benzoic acid in acetonitrile suggests the partici-
pation of both benzoylformates in dioxygen activation. The
iron(III) superoxide anion attacks the keto carbon to effect
the decarboxylation of benzoylformate with concomitant
formation of an iron(IV)–oxo species. The active oxidant
then oxidizes external substrates such as substituted phe-
nols, sulfides, and sulfoxides. The isolation of 2,9-dime-
thyl-1,10-phenanthroline quantitatively after the reaction
indicates that the ligand remains unaffected during the
oxidative transformation. The benzoate formed in the
decarboxylation reaction may coordinate to the iron center
rate—of a monoanionic facial N donor ligand has been
3
shown to carry out epoxidation of cis-stilbene in the
presence of dioxygen [34]. Another iron(II) benzoylfor-
Ph2
mate complex—[(Tp )Fe(BF)], where Tp
Ph2
is hydro-
tris(3,5-diphenylpyrazol-1-yl)borate—reacts with dioxygen
to undergo oxidative decarboxylation of benzoylformate
with concomitant hydroxylation of one of the phenyl rings
on the ligand backbone [38]. Model iron(II) benzoylfor-
?
mate complexes [(6Me TPA)Fe(BF)]
3
and [(TPA)-
?
Fe(BF)(MeOH)] with tripodal N donor ligands, where
4
6
Me TPA is tris[(6-methyl-2-pyridyl)methyl]amine and
3
TPA is tris(2-pyridylmethyl)amine, show quantitative
decarboxylation of benzoylformate to benzoate upon
exposure to dioxygen [33]. A model iron(II) benzoylfor-
mate complex, [(dmby)Fe(BF) ], with a facial NNO
2
coordination environment has recently been shown to
undergo oxidative decarboxylation of benzoylformate but
with a low yield of benzoic acid [52]. In spite of the slow
reaction, the high yield of benzoic acid with the present
system is an improvement over the yield with the previ-
ously reported iron(II) benzoylformate complex with the
facial NNO donor environment. Moreover, the biomimetic
iron(II) complexes reported here differ from most common
model complexes that rely on nitrogen-rich ligands.
The five-membered chelate ring formed upon bidentate
binding of benzoylformate prefers to adopt a planar
1
23

J Biol Inorg Chem (2013) 18:401–410
409
and the second benzoylformate may then realign itself to
bind as a chelating ligand for further oxygen activation and
decarboxylation. The resulting iron(II) benzoate complexes
most likely are oxidized further to iron(III) compounds.
Unfortunately, all attempts to isolate the final oxidized iron
compounds failed in both cases.
10. Price JC, Barr EW, Glass TE, Krebs C, Bollinger JM Jr (2003) J
Am Chem Soc 125:13008–13009
1
1. Krebs C, Fujimori DG, Walsh CT, Bollinger JM Jr (2007) Acc
Chem Res 40:484–492
12. Hoffart LM, Barr EW, Guyer RB, Bollinger JM Jr, Krebs C
(2006) Proc Natl Acad Sci USA 103:14738–14743
1
3. Galonic DP, Barr EW, Walsh CT, Bollinger JM Jr, Krebs C
2007) Nat Chem Biol 3:113–116
(
1
4. Price JC, Barr EW, Tirupati B, Bollinger JM Jr, Krebs C (2003)
Biochemistry 42:7497–7508
Conclusion
15. Proshlyakov DA, Henshaw TF, Monterosso GR, Ryle MJ, Hau-
singer RP (2004) J Am Chem Soc 126:1022–1023
1
6. Sinnecker S, Svensen N, Barr EW, Ye S, Bollinger JM Jr, Neese
F, Krebs C (2007) J Am Chem Soc 129:6168–6179
We have isolated and structurally characterized two bio-
mimetic iron(II) benzoylformate complexes supported by a
17. Price JC, Barr EW, Hoffart LM, Krebs C, Bollinger JM Jr (2005)
Biochemistry 44:8138–8147
1
1
,10-phenanthroline-based ligand. The facial NNO ligand
8. Hoffart LM, Barr EW, Guyer RB, Bollinger JM Jr, Krebs C
2006) Proc Natl Acad Sci USA 103:14738–14743
environment, provided by a bidentate NN donor ligand and
an O donor from either benzoylformate or nitrate, with a
coordinated benzoylformate in ternary iron(II) complexes
structurally mimics the ‘‘2-His-1-carboxylate’’ facial triad
motif observed in the superfamily of nonheme iron
enzymes. Both iron(II) benzoylformate complexes react
with dioxygen to show oxidative decarboxylation of ben-
zoylformic acid in high yield and functionally mimic the
nonheme a-keto acid dependent enzymes. An iron(III)
superoxide radical intermediate has been proposed to ini-
tiate the reaction leading to the formation of an Fe(IV)=O
species. Indirect evidence for the formation of an Fe(IV)=O
intermediate in the decarboxylation reaction was obtained
by interception studies using different external reagents.
The results demonstrate the role played by the phenan-
throline-derived ligand in providing the necessary struc-
tural and electronic environment to carry out the oxidative
decarboxylation reaction.
(
1
9. Matthews ML, Krest CM, Barr EW, Vaillancourt FH, Walsh CT,
Green MT, Krebs C, Bollinger JM Jr (2009) Biochemistry
48:4331–4333
0. Galoni c´ Fujimori D, Barr EW, Matthews ML, Koch GM, Yonce
JR, Walsh CT, Bollinger JM Jr, Krebs C, Riggs-Gelasco PJ
2
(
2007) J Am Chem Soc 129:13408–13409
21. Riggs-Gelasco PJ, Price JC, Guyer RB, Brehm JH, Barr EW,
Bollinger JM Jr, Krebs C (2004) J Am Chem Soc 126:8108–8109
2
2. Bassan A, Borowski T, Siegbahn PEM (2004) Dalton Trans
153-3162
3
2
3. Borowski T, Bassan A, Siegbahn PEM (2004) Chem Eur J
10:1031–1041
24. de Visser SP (2007) Chem Commun 171–173
2
5. Rohde J-U, In JH, Lim MH, Brennessel WW, Bukowski MR,
Stubna A, M u¨ nck E, Nam W, Que L Jr (2003) Science
2
99:1037–1039
26. Lim MH, Rohde J-U, Stubna A, Bukowski MR, Costas M, Ho
RYN, M u¨ nck E, Nam W, Que L Jr (2003) Proc Natl Acad Sci
USA 100:3665–3670
2
7. England J, Martinho M, Farquhar ER, Frisch JR, Bominaar EL,
M u¨ nck E, Que L Jr (2009) Angew Chem Int Ed 46:3622–3626
8. England J, Guo Y, Farquhar ER, Young VG Jr, M u¨ nck E, Que L
Jr (2010) J Am Chem Soc 132:8635–8644
2
Acknowledgments We are grateful to the Department of Science
and Technology (DST), Government of India, for financial support
29. Que L Jr (2007) Acc Chem Res 40:493–500
30. Klinker EJ, Kaizer J, Brennessel WW, Woodrum NL, Cramer CJ,
Que L Jr (2005) Angew Chem Int Ed 44:3690–3694
31. Kaizer J, Klinker EJ, Oh NY, Rohde J-U, Song WJ, Stubna A,
Kim J, Nam W, M u¨ nck E, Que L Jr (2004) J Am Chem Soc
126:472–473
(
project SR/SI/IC-51/2010). X-ray diffraction data were collected at
the DST-funded National Single Crystal Diffractometer Facility at the
Department of Inorganic Chemistry, Indian Association for the Cul-
tivation of Science. S.C. is thankful to the Council of Scientific and
Industrial Research (CSIR), India, for a fellowship.
3
2. England J, Guo Y, Van Heuvelen KM, Cranswick MA, Rohde
GT, Bominaar EL, M u¨ nck E, Que L Jr (2011) J Am Chem Soc
1
33:11880–11883
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