Aliphatic C-C Bond Cleavage of α-Hydroxy Ketones by Non-Heme Iron(II) Complexes: Mechanistic Insight into the Reaction Catalyzed by 2,4′-Dihydroxyacetophenone Dioxygenase

Article abstract of DOI:10.1021/acs.inorgchem.5b01235

2,4′-Dihydroxyacetophenone dioxygenase (DAD) is a bacterial non-heme enzyme that carries out oxygenative aliphatic C-C bond cleavage of 2,4′-dihydroxyacetophenone (an α-hydroxy ketone) with the incorporation of both the oxygen atoms of dioxygen into the cleavage products. The crystal structure of the iron enzyme DAD has recently been determined, but very little is known about the mechanism of the C-C bond cleavage reaction. With the objective of gaining insights into the mechanism of the reaction catalyzed by DAD, six new biomimetic iron(II)-α-hydroxy ketone complexes, [(Tp^Ph2)Fe^II(PHAP)] (1), [(Tp^Ph2)Fe^II(HCH)] (2), [(Tp^Ph2)Fe^II(HBME)] (3), [(Tp^Ph2)Fe^II(CHPE)] (4), [(6-Me₃-TPA)Fe^II(PHAP)]⁺ (5), and [(6-Me₃-TPA)Fe^II(HCH)]⁺ (6) (Tp^Ph2 = hydrotris(3,5-diphenylpyrazol-1-yl)borate, 6-Me₃-TPA = tris(6-methyl-2-pyridylmethyl)amine, PHAP-H = 2-phenyl-2-hydroxyacetophenone, HCH-H = 2-hydroxycyclohexanone, HBME-H = 2-hydroxy-1,2-bis(4-methoxyphenyl)ethanone, and CHPE-H = 1-(4-chlorophenyl)-2-hydroxy-2-phenylethanone), have been isolated and characterized. The single-crystal X-ray structure of 2 shows a five-coordinate iron(II) complex with one tridentate facial ligand and a monoanionic bidentate α-hydroxy ketone, resulting in a distorted-square-pyramidal coordination geometry at the iron center. The iron(II) complexes react with dioxygen to oxidatively cleave the aliphatic C-C bonds of the coordinated α-hydroxy ketones to afford 2 equiv of carboxylic acids. Mechanistic studies reveal that the C-C bond cleavage reaction proceeds through an intradiol pathway. Additionally, the coordinated α-hydroxy ketones in all of the complexes, except in complex 4, undergo two-electron oxidation to form the corresponding 1,2-diketones. However, the yields of 1,2-diketones are higher with the iron complexes of the tripodal N₄ ligand (6-Me₃-TPA) in comparison to the facial N₃ ligand (Tp^Ph2). These results strongly support the natural selection of a facial N₃ environment at the active site of the iron enzyme DAD.

Full text of DOI:10.1021/acs.inorgchem.5b01235

Article
pubs.acs.org/IC
Aliphatic C−C Bond Cleavage of α‑Hydroxy Ketones by Non-Heme
Iron(II) Complexes: Mechanistic Insight into the Reaction Catalyzed
by 2,4′-Dihydroxyacetophenone Dioxygenase
Rubina Rahaman, Sayantan Paria, and Tapan Kanti Paine*
Department of Inorganic Chemistry, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur,
Kolkata 700032, India
S
* Supporting Information
ABSTRACT: 2,4′-Dihydroxyacetophenone dioxygenase
(DAD) is a bacterial non-heme enzyme that carries out
oxygenative aliphatic C−C bond cleavage of 2,4′-dihydrox-
yacetophenone (an α-hydroxy ketone) with the incorporation
of both the oxygen atoms of dioxygen into the cleavage
products. The crystal structure of the iron enzyme DAD has
recently been determined, but very little is known about the
mechanism of the C−C bond cleavage reaction. With the
objective of gaining insights into the mechanism of the reaction
catalyzed by DAD, six new biomimetic iron(II)-α-hydroxy
ketone complexes, [(TpPh2)FeII(PHAP)] (1), [(TpPh2)-
FeII(HCH)] (2), [(TpPh2)FeII(HBME)] (3), [(TpPh2)-
FeII(CHPE)] (4), [(6-Me3-TPA)FeII(PHAP)]+ (5), and [(6-Me3-TPA)FeII(HCH)]+ (6) (TpPh2 = hydrotris(3,5-diphenylpyr-
azol-1-yl)borate, 6-Me3-TPA = tris(6-methyl-2-pyridylmethyl)amine, PHAP-H = 2-phenyl-2-hydroxyacetophenone, HCH-H = 2-
hydroxycyclohexanone, HBME-H = 2-hydroxy-1,2-bis(4-methoxyphenyl)ethanone, and CHPE-H = 1-(4-chlorophenyl)-2-
hydroxy-2-phenylethanone), have been isolated and characterized. The single-crystal X-ray structure of 2 shows a five-coordinate
iron(II) complex with one tridentate facial ligand and a monoanionic bidentate α-hydroxy ketone, resulting in a distorted-square-
pyramidal coordination geometry at the iron center. The iron(II) complexes react with dioxygen to oxidatively cleave the
aliphatic C−C bonds of the coordinated α-hydroxy ketones to afford 2 equiv of carboxylic acids. Mechanistic studies reveal that
the C−C bond cleavage reaction proceeds through an intradiol pathway. Additionally, the coordinated α-hydroxy ketones in all
of the complexes, except in complex 4, undergo two-electron oxidation to form the corresponding 1,2-diketones. However, the
yields of 1,2-diketones are higher with the iron complexes of the tripodal N4 ligand (6-Me3-TPA) in comparison to the facial N3
ligand (TpPh2). These results strongly support the natural selection of a facial N3 environment at the active site of the iron
enzyme DAD.
Scheme 1. Reaction Catalyzed by DAD
INTRODUCTION
■
Different microorganisms in soil and groundwater biodegrade
various toxic chemicals and xenobiotics.1,2 In the bacterial
biodegradation pathway of 2,2-bis(4-hydroxyphenyl)propane
(bisphenol A),3−6 a small amount of 2,4′-dihydroxyacetophe-
none is formed as an end product which is not metabolized by
bisphenol A-degrading bacterium.7 2,4′-Dihydroxyacetophe-
none dioxygenase (DAD), an enzyme isolated from the aerobic
soil bacterium Alcaligenes sp. grown on 4-hydroxyacetophe-
none, catalyzes the cleavage of 2,4′-dihydroxyacetophenone
into 4-hydroxy benzoate and formate under aerobic conditions
with the incorporation of both oxygen atoms of O2 into
products (Scheme 1).8−10 The enzyme does not show
significant sequence homology to other known dioxyge-
nases.10,11 DAD has been reported to be a member of the
cupin superfamily of enzymes and is a homotetramer
containing iron in the active site.11
This enzyme has been reported to be a homotetramer
containing 1.63−1.69 equiv of iron per mole of the enzyme.
On the basis of optical spectral data of the enzyme and of the
enzyme in the presence of substrate, binding of the substrate to
the iron(III) center has been proposed. It has further been
reported that the α-hydroxy ketone unit of the substrate was
essential to exhibit enzymatic activity. A mechanism similar to
that of intradiol catechol dioxygenases has been proposed for
this enzyme.12 However, in the absence of any strong
spectroscopic evidence, the oxidation state of iron in the
The isolation, purification, and catalytic reactivity of a DAD
Received: June 1, 2015
from Burkholderia Sp. AZ11 have recently been reported.12
© XXXX American Chemical Society
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enzyme remains a speculation. Therefore, a detailed inves-
tigation is needed to establish the oxidation state of iron as well
as its role in the C−C bond cleavage mechanism.
RESULTS AND DISCUSSION
Synthesis and Characterization. The iron(II) complexes
1−6 were isolated from the reactions of equimolar amounts of
ligand and iron(II) perchlorate hexahydrate with the respective
monoanionic α-hydroxy ketone in methanol at room temper-
ature (Scheme 2). The iron(II) complexes of 2-hydroxy-1,2-
■
Biomimetic functional model complexes have been reported
to provide valuable information in understanding the
mechanism of the reactions catalyzed by aliphatic C−C bond
cleaving oxygenases.2,13−23 However, the model chemistry of
DAD has not been developed well because of the absence of
structural and detailed spectroscopic characterization of this
enzyme. A number of crystallographic studies on this enzyme
have been performed,24 but until very recently the 3D structure
of the enzyme was not known. In 2012, we reported a five-
coordinate iron(II) complex of a facial tridentate ligand,
[(TpPh2)FeII(HAP)] (TpPh2 = hydrotris(3,5-diphenylpyrazol-
1-yl)borate, HAP-H = 2-hydroxyacetophenone), as the first
model complex of DAD.25 The basis of using a facial N3 ligand
was to mimic the facial three-histidines motif observed in a
crystallographically characterized cupin nonheme iron enzyme,
gentisate 1,2-dioxygenase.26 The complex has been shown to
react with oxygen to cleave the aliphatic C−C bond of 2-
hydroxyacetophenone to afford benzoic acid and formic acid
quantitatively. A labeling experiment with 18O2 suggests the
incorporation of one 18O atom (40% incorporation) into each
of the products exhibiting typical dioxygenase type reactivity.25
Very recently, Cooper and co-workers reported the X-ray
diffraction data collected at a resolution of 2.2 Å at a
synchrotron that allowed the first 3D structure determination
of DAD from Alcaligenes sp.27,28 The structure reveals that the
catalytic iron is ligated by three histidines along with an
additional ligand tentatively assigned as a dianionic carbonate.
The additional ligand is proposed to be replaced by the α-
hydroxy ketone substrate during catalysis.28 The enzyme has
been reported to contain ferrous iron in the active site. The
model complex [(TpPh2)FeII(HAP)] has several key features in
common with the active site of the enzyme, including the
coordination of an N3 facial triad and bidentate binding of the
α-hydroxy ketone to the iron(II) center.25 Cooper and his
group investigated the mechanism of the enzymatic reaction28
on the basis of our proposal on the aliphatic C−C bond
cleavage of 2-hydroxyacetophenone with dioxygen by the
TpPh2FeII complex.
To gain further insight into the mechanism of the aliphatic
C−C bond cleavage reaction by DAD, we have explored the
reactivity of several iron(II)-α-hydroxy ketone complexes using
nitrogen donor polydentate ligands. In this study, we used one
facial N3 and one tripodal N4 ligand to evaluate the effect of
ligand denticity in directing the C−C bond cleavage pathway.
We report herein the synthesis and characterization of six new
biomimetic iron(II)-α-hydroxy ketone complexes: [(TpPh2)-
FeII(PHAP)] (1), [(TpPh2)FeII(HCH)] (2), [(TpPh2)-
FeII(HBME)] (3), [(TpPh2)FeII(CHPE)] (4), [(6-Me3-TPA)-
FeII(PHAP)]+ (5), and [(6-Me3-TPA)FeII(HCH)]+ (6) (6-
Me3-TPA = tris(6-methyl-2-pyridylmethyl)amine, PHAP-H =
2-phenyl-2-hydroxyacetophenone, HCH-H = 2-hydroxycyclo-
hexanone, HBME-H = 2-hydroxy-1,2-bis(4-methoxyphenyl)-
ethanone, and CHPE-H = 1-(4-chlorophenyl)-2-hydroxy-2-
phenylethanone) (Scheme 2). The reactivity of the complexes
toward dioxygen and the mechanism of the oxidative C−C
bond cleavage of coordinated α-hydroxy ketones on the
iron(II) complexes are presented in this work.
Scheme 2. Synthesis of Iron(II)-α-Hydroxy Ketone
Complexes
bis(4-methoxyphenyl)ethanone and 1-(4-chlorophenyl)-2-hy-
droxy-2-phenylethanone using the 6-Me3-TPA ligand, however,
could not be isolated in pure form. The isolated complexes are
soluble in common organic solvents and are stable under a
nitrogen atmosphere.
The optical spectrum of 1 is dominated by two absorption
bands at 515 and 570 nm. These absorption bands arise from
the charge-transfer (CT) transitions from the filled d orbital of
the iron(II) to the empty π* orbital of the keto group of PHAP
(Figure 1).25 The CT bands shift slightly higher in energy to
500 and 555 nm upon introduction of electron-donating
methoxy groups on the phenyl rings of α-hydroxy ketone in 3.
Figure 1. Optical spectra of iron(II)-α-hydroxy ketone complexes (0.5
mM in C6H6 for 1−4 and in CH3CN for 5−6) at 298 K.
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For complex 4, in which the α-hydroxy ketone contains one
electron-withdrawing chloro group, the CT bands shift to lower
energy at 530 and 580 nm. Although complex 2 displays similar
absorption features, the CT bands are blue-shifted in
comparison to those of 1. The energy of the π* orbital of
keto group of the coordinated HCH is increased due to lack of
conjugation (Figure 1). The UV−vis spectrum of 5 shows CT
bands at around 560 nm similar to those of iron(II) α-keto acid
complexes of N4 donor ligands.29 Another band at 390 nm in 5
may be attributed to CT transition from the filled d orbital of
iron(II) to the π* orbital of pyridine rings of the ligand.29
These CT bands, however, get shifted to higher energy in
complex 6 (Figure 1). The optical spectral data support the
bidentate binding of α-hydroxy ketones to the metal center in
In the complex, HCH coordinates to the iron center in a
bidentate mode through one carbonyl oxygen (O1) and one
alcoholate oxygen (O2) with Fe1−O1 and Fe1−O2 distances
of 2.281(2) and 1.916(2) Å, respectively (Table 1). The C46−
O1 (1.227(4) Å), C47−O2 (1.394(4) Å), and C46−C47
(1.507(4) Å) distances indicate that HCH coordinates to the
iron center in a keto form. The C−C and C−O bond distances
of the coordinated α-hydroxy ketone in 2 are found to be very
similar to those of the reported metal complexes with α-
hydroxy ketone ligands, further confirming the monoanionic
binding of HCH without enolization.30−34 While the iron
center in [(TpPh2)FeII(HAP)]25 adopts a distorted-trigonal-
bipyramidal coordination geometry (τ = 0.62),35 the iron
center in 2 adopts a distorted-square-pyramidal coordination
geometry (τ = 0.45). In the complex, the cyclohexane ring of
HCH adopts a chair conformation where the keto and the
alcoholate groups are positioned equatorially, enabling the α-
hydroxy ketone to bind to the iron center in a bidentate
fashion.
1
keto forms. The H NMR spectra exhibit paramagnetically
shifted proton resonances of the ligands in the region between
80 and −40 ppm, indicating the high-spin nature of the iron(II)
complexes (see the Experimental Section and Figures S1−S6 in
the Supporting Information). Room-temperature magnetic
moment values for the complexes are found to be in the
range of 4.9−5.3 μB, typical of high-spin iron complexes with an
S = 2 ground state. The analytical and spectroscopic data
confirm the composition of the complexes (for ESI-MS, see
Table S1 in the Supporting Information). Additionally, the
presence of solvent molecules in the analytical samples of 1 and
2 was further confirmed by thermogravimetric analysis (TGA)
(Figures S7 and S8 in the Supporting Information).
X-ray Crystal Structure. To assess the binding mode of α-
hydroxy ketones to the iron center, attempts were made to
grow single crystals of the complexes. While X-ray-quality single
crystals of 2 were grown by layer diffusion of methanol into a
dichloromethane solution of the complex at ambient temper-
ature, other iron(II)-α-hydroxy ketone complexes could not be
crystallized. Complex 2 crystallizes in the monoclinic system
with P21/c space group. The crystal structure of the neutral
complex reveals a mononuclear five-coordinate iron center
coordinated by three nitrogen donors from the monoanionic
N3 ligand and two oxygen donors of a bidentate 2-
hydroxycyclohexanoate (HCH) ring (Figure 2). The iron−
nitrogen bond distances are found in the range of 2.107(2)−
2.193(2) Å, which are in good agreement with the only
reported high-spin iron(II)-α-hydroxy ketone complex of the
TpPh2 ligand (Table 1).25
Reactions of Iron(II)-α-Hydroxy Ketone Complexes
with Dioxygen. All of the iron(II) α-hydroxy ketone
complexes are sensitive toward dioxygen. Exposure of a
benzene solution of 1 to dioxygen at 10 °C results in a very
rapid decay of the CT bands at 515 and 570 nm following
pseudo-first-order kinetics (kobs = [1.8( 0.6)] × 10−2 s−1 at 10
°C) (Figure 3a). The complex reacts with dioxygen ∼20 times
faster than does the iron(II)-α-keto acid complex [(TpPh2)-
FeII(benzoylformate)].36 The faster reactivity of 1 could be
attributed to an increased electron donating ability of the
hydroxyl group.37 Complex 2 reacts with O2 in dry benzene at
10 °C for over 1 h (kobs = [1.0( 0.8)] × 10−3 s−1 at 10 °C),
during which time the CT bands at 330 and 380 nm disappear
to produce a light yellow solution (Figure 3b). Complexes 3
and 4 exhibit similar optical spectral changes during the
reaction with dioxygen, where the CT bands disappear
following a pseudo-first-order rate equation with the respective
k
obs values of [3.3( 0.3)] × 10−3 and [3.8( 0.3)] × 10−2 s−1 at
10 °C (Figure S9 in the Supporting Information).
The ESI-mass spectra of the oxidized solutions of all four
complexes exhibit an ion peak at m/z 725.11 with an isotope
distribution pattern attributable to [(TpPh2)Fe]+ (Figure 3b,
inset). In addition, the oxidized solution of 1 exhibits resonance
36
1
signals similar to those of [(TpPh2)FeII(benzoate)] in the H
NMR spectrum (Figure S10 in the Supporting Information).
During the reaction, intramolecular ligand hydroxylation is not
observed, but the resulting iron(II)-benzoate complex, as
reported earlier,36 slowly reacts with dioxygen to afford
intramolecular oxygenated complex. Other complexes, after
the reaction with dioxygen, also exhibit paramagnetically shifted
proton resonances typical of a high-spin iron(II) complex of
TpPh2 (Figure S11 in the Supporting Information). Moreover,
the final oxidized solutions of 1, 2, and 4 are X-band EPR silent
at 77 K. Therefore, the iron(II)-α-hydroxy ketone complexes
undergo oxidative transformation to form the corresponding
iron(II)-carboxylate products. In the reaction, no decom-
position of the supporting ligand is observed.
The organic products from each of the oxidized solutions of
1−4, after separation of the metal ion by acidic workup, were
analyzed by GC-MS and 1H NMR spectroscopy. In the case of
1, PHAP is oxidized to a mixture of benzoic acid (85( 3)%)
and benzil (12( 3)%) (Table 2, Figure 4, and Scheme 3), and
for 2, 85( 3)% adipic acid and 13( 2)% cyclohexane-1,2-
dione are formed from HCH (Table 2 and Figure 5). Complex
Figure 2. ORTEP plot of [(TpPh2)FeII(HCH)] (2) with 40% thermal
ellipsoid parameters. All hydrogen atoms, except those on B1 and C47,
have been omitted for clarity.
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Table 1. Selected Bond Lengths (Å) and Angles (deg) for [(TpPh2)FeII(HCH)] (2)
Fe(1)−N(2)
Fe(1)−N(4)
Fe(1)−N(6)
Fe(1)−O(1)
N(4)−Fe(1)−O(1)
N(4)−Fe(1)−O(2)
N(4)−Fe(1)−N(2)
N(4)−Fe(1)−N(6)
N(2)−Fe(1)−O(1)
2.193(2)
2.107(2)
2.119(2)
2.281(2)
C(46)−O(1)
C(47)−O(2)
C(46)−C(47)
Fe(1)−O(2)
O(2)−Fe(1)−O(1)
O(2)−Fe(1)−N(2)
N(6)−Fe(1)−N(2)
N(6)−Fe(1)−O(1)
N(6)−Fe(1)−O(2)
1.227(4)
1.394(4)
1.507(4)
1.916(2)
78.18(8)
104.03(9)
83.27(9)
91.03(8)
145.60(9)
94.10(8)
121.32(9)
90.65(9)
91.69(9)
172.69(8)
Figure 3. UV−vis spectral changes of (a) complex 1 and (b) complex 2 (1 mM in benzene) during the reaction with dioxygen at 283 K. Insets: (a)
absorbance as a function of time; (b) ESI-mass spectrum of the oxidized solution of 2.
Table 2. Percentages of Different Oxidation Products Derived from α-Hydroxy Ketones
complex
C−C cleavage product (%) 1,2-diketone product (%) unreacted product (%) conversion of α-hydroxy ketone (%)
[(TpPh2)FeII(PHAP)] (1)
85( 3)
12( 3)
13( 2)
18( 2)
0
0
97
[(TpPh2)FeII(HCH)] (2)
85( 3)
98
[(TpPh2)FeII(HBME)] (3)
[(TpPh2)FeII(CHPE)] (4)
76( 2)
2( 2)
0
94
quantitative
38( 3)
quantitative
[(6-Me3-TPA)FeII(PHAP)]BPh4 (5)
[(6-Me3-TPA)FeII(HCH)]BPh4 (6)
53( 3)
37( 1)
9( 3)
8( 3)
0
91
55( 3)
92
a
[(TpPh2)FeII(HAP)]
quantitative
quantitative
a
Reference 25.
Scheme 3. C−C Bond Cleavage Products of α-Hydroxy
Ketones on the Iron(II) Complexes
1
Figure 4. H NMR (500 MHz, CDCl3, 295 K) spectrum of organic
products isolated from the oxidized solution of [(TpPh2)FeII(PHAP)]
(1).
3 affords p-methoxybenzoic acid (76( 2)%) and 1,2-bis(4-
methoxyphenyl)ethane-1,2-dione (18( 2)%) (Table 2 and
Figure S12 in the Supporting Information). In contrast,
complex 4 yields p-chlorobenzoic acid (52( 2)%) and benzoic
acid (48( 2)%) without any diketone (Table 2, Scheme 4, and
Figure S13 in the Supporting Information). The formation of
adipic acid from 2 was also confirmed by 13C NMR
spectroscopy (Figure S14 in the Supporting Information). It
is important to mention here that neither the C−C bond
cleavage product (benzoic acid or adipic acid) nor the diketone
is observed in control experiments with equimolar amounts of
iron(II) salt and α-hydroxy ketones. In the control experiments,
however, addition of triethylamine to the reaction mixture
results in the formation of about 25−30% of dione products
without any C−C bond cleavage product.
Adipic acid obtained from the oxidized solution of 2 was
1
esterified for further analysis. In the H NMR spectrum, the
phenacyl ester of adipic acid exhibits three sets of methylenic
protons (Figure S15 in the Supporting Information). The ESI-
mass spectrum of the ester displays molecular ion peaks at m/z
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560 nm decay slowly (Figure 6a). The reaction of 6 with
dioxygen takes about 6 h with a kobs value of [1.5( 0.3)] ×
10−6 s−1 at 25 °C (Figure 6b). The ESI-mass spectrum of the
oxidized solution of 5 displays an ion peak at m/z 509.02 with
the isotope distribution pattern calculated for [(6-Me3-TPA)-
1
FeII(benzoate)]+ (Figure 6a, inset). The H NMR spectrum of
the solution also matches with that of the reported [(6-Me3-
TPA)FeII(benzoate)]+ complex (Figure S17 in the Supporting
Information).38 Additionally, the X-band EPR spectrum (at 77
K) of the oxidized solution of 5 shows a weak signal at g = 4.2
typical of a high-spin iron(III) complex. Thus, in addition to
the paramagnetic benzoate complex, the oxidized solution of 5
contains other iron species that could not be characterized
(Figure S17 (inset)).
Analyses of organic products from 5 and 6 reveal that the
percentage of oxidative C−C bond cleavage is low; the
corresponding 1,2-diketones are formed in higher amounts.
While complex 5 affords 38( 3)% benzoic acid and 53( 3)%
benzil (Figure S18 in the Supporting Information), complex 6
yields 55( 3)% adipic acid and 37( 1)% cyclohexane-1,2-
dione (Scheme 3 and Table 2). In both cases, about 8−9% of
the α-hydroxy ketone remains unreacted.
1
Figure 5. H NMR (300 MHz, DMSO-d6, 295 K) spectrum of 2-
hydroxycyclohexanone-derived product after the reaction of [(TpPh2)-
FeII(HCH)] (2) with dioxygen. Peaks marked with “a” are from
residual solvents.
Scheme 4. Reactivity of the α-Hydroxy Ketones That Do Not
Contain Any α-C−H Bond
The α-hydroxy ketones discussed above contain one α-C−H
bond. To establish the role of the α-C−H bond in the C−C
bond cleavage, attempts were made to isolate iron(II)
complexes of the α-hydroxy ketones that do not contain an
α-C−H bond. Unfortunately, the iron complex of 2-hydroxy-2-
methyl-1-phenylpropane-1-one (HMPO) or 1-hydroxycyclo-
hexyl-1-phenylmethanone (HCPM) could not be isolated. The
reaction of equimolar amounts of the ligand KTpPh2, iron(II)
perchlorate, HMPO (or HCPM), and triethylamine with
dioxygen in a benzene/methanol (9/1) solvent mixture does
not produce any C−C bond cleavage product (Scheme 4 and
Figures S19 and S20 in the Supporting Information). On the
other hand, reactions involving mixtures of nitrogen donor
ligand, iron(II) salt, base, dioxygen, and α-hydroxy ketones
containing one α-H atom lead to a mixture of the C−C
cleavage products and diketones, although the yields of oxidized
products (30−40% overall) are found to be less than those
involving isolated complexes and dioxygen. These results
therefore support that the presence of a C−H bond in α-
hydroxy ketone is essential for the oxygen-dependent C−C
bond cleavage reaction.
421.16 and 405.16 for [C22H22O6 + K]+ and [C22H22O6 + Na]+,
respectively, along with the expected fragmentation patterns,
confirming the formation of adipic acid in the oxidative C−C
bond cleavage of HCH (Figure S16 in the Supporting
Information).
The dioxygen reactivity of the iron(II) complexes (5 and 6)
of the tetradentate ligand is slow compared to that of the
complexes (1−4) of the tridentate ligand. An acetonitrile
solution of 5 reacts with dioxygen over a period of 3 h (kobs
=
Mechanistic Studies. To gain an understanding of the
mechanism of the C−C bond cleavage reactions of α-hydroxy
ketones, isotope labeling experiments were performed. The
[3.9( 0.8)] × 10−4 s−1 at 25 °C), during which the brown
solution turns yellow. In the reaction, the CT bands at 390 and
Figure 6. Optical spectral changes of (a) 5 and (b) 6 (0.5 mM in acetonitrile) during the reaction with dioxygen at 298 K. Insets: (a) isotope
distribution pattern in the ESI-mass spectrum of the oxidized solution of 5; (b) absorption intensity as a function of time for 6.
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Table 3. Incorporation of Labeled Oxygen Atoms from 18O2 and H218O into the Oxidized Products of α-Hydroxy Ketones
18O atom incorporated into C−C cleavage product
(%)
18O atom incorporated into diketone product (%)
complex
from 18O2
from H218O
from 18O2
from H218O
a
b
[(TpPh2)FeII(HAP)]
40
5
not applicable
not applicable
b
b
[(TpPh2)FeII(PHAP)] (1)
[(TpPh2)FeII(HCH)] (2)
55
15
0
0
0
not determined
b
b
c
47
10
25
d
d
c
[(6-Me3-TPA)FeII(PHAP)]+ (5)
70
20
10
a
b
c
d
Reference 25. Quantified by GC-MS of the ester of carboxylic acids. Quantified by GC-MS. Quantified by ESI-MS (positive ion mode in
acetonitrile) of the carboxylate-coordinated metal complex.
GC-mass spectrum of methyl ester of the benzoic acid obtained
from the reaction between 1 with 18O2 shows around 55%
incorporation of one 18O atom into benzoate, where the ion
peak at m/z 136 shifts to 138 (Table 3 and Figure S21a,b in the
Supporting Information). Additionally, a small peak observed at
m/z 140 indicates the incorporation of two labeled oxygen
atoms into benzoate (Figure S21b). In a mixed labeling
experiment with O2 and H218O, complex 1 yields benzoic acid,
the ester of which shows about 15% 18O incorporation (Table 3
and Figure S21c). Of note, methyl ester of benzoic acid derived
from [(TpPh2)FeII(HAP)]25 shows only 5% incorporation of
one labeled oxygen atom from H218O (Figure S22 in the
Supporting Information).
exchanges its oxygen atom with water during the reaction. The
best way to verify this hypothesis is carry out labeling
experiments with a system where the C−C bond cleavage
product (carboxylate) remains coordinated to the iron center.
Unfortunately, no ion peak corresponding to the iron species
with coordinated carboxylate could be observed in the ESI-MS
of the oxidized solutions of 1−4. Therefore, complex 5 was
used to obtain further information if solvent water is exchanged
during the C−C cleavage pathway. The ion peak of the
oxidized solution of the complex at m/z 509.02 is shifted to m/
z 511.02 when the reaction is carried out with 18O2 (Figure 8a).
For complex 2, the labeling experiment with 18O2 supports
the incorporation of both singly and doubly labeled oxygen
atoms into the C−C cleavage product, adipic acid. In the ESI-
mass spectrum, the ion peak at m/z 405.16 of the sodium
adduct of the phenacyl ester of adipic acid shifts to 407.16 (47%
18O incorporation) and 409.16 (18% 18O incorporation) (Table
3 and Figure 7a,b). When the labeling experiment is carried out
Figure 8. ESI-mass spectra (positive ion mode in acetonitrile) of the
solution after oxidation of 5 with (a) 18O2 and with (b) H218O and
16O2.
This indicates that one labeled oxygen atom from 18O2 is
incorporated (70% incorporation) into benzoate. The labeling
experiment with 16O2 and H218O exhibits about 20%
incorporation of one labeled oxygen atom from water into
benzoate (Figure 8b). For complex 1 (and 2), some loss of
labeled oxygen may take place during acidic workup of the
carboxylic acid product, resulting in the low level of 18O
incorporation from 18O2 in the C−C bond cleavage reaction. It
is important to mention here that free benzoic acid or metal-
coordinated benzoate in [(TpPh2)FeII(benzoate)] does not
exchange its oxygen atoms with H218O under the experimental
conditions.
In the labeling experiments with 18O2, the two-electron-
oxidized products (1,2-diketones) of α-hydroxy ketones show
no incorporation of labeled oxygen atom. However, in the
reaction with 16O2 and H218O, the diketones contain partially
labeled oxygen atoms (Scheme 5). Cyclohexane-1,2-dione
derived from 2, which exhibits m/z 112 in the GC-MS, is
found to contain one labeled oxygen (25% 18O incorporation)
from H218O (Figure S23 in the Supporting Information). The
two-electron oxidation product of benzoin from 5, i.e. benzil,
also contains a small percentage (10%) of labeled oxygen atom
from H218O (Figure S24 in the Supporting Information).
Partial incorporation of labeled oxygen atom into the two-
electron-oxidized species indicates that solvent water is
Figure 7. ESI-mass spectra of phenacyl ester of the adipic acid formed
in the reaction of 2 with (a) 16O2, (b) 18O2, and (c) H218O and 16O2.
with 16O2 and H218O, both singly and doubly oxygen labeled
peaks are observed but with only 10% incorporation of labeled
oxygen (Figure 7c).
As observed in [(TpPh2)FeII(HAP)],25 the incorporation of a
labeled oxygen atom from 18O2 into the C−C bond cleavage
product is found to be low for 1 and 2 (Table 3). This low
incorporation of labeled oxygen atom into carboxylic acid
products indicates that a metal−oxygen intermediate species
F
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thioanisole oxide formation corroborates the higher percentage
of diketone formation with 5. The reaction of 5 (and 6) with 1-
octene (100 equiv) yields a small amount (about 5%) of
octane-1,2-diol, whereas no diol product is observed in the case
of 1 and 2 (Scheme 6 and Figure S28 in the Supporting
Information). Other alkene substrates such as cyclohexene and
trans-2-heptene are not oxidized under similar experimental
conditions. Importantly, external substrates have no effect on
the yields of the oxidation products of α-hydroxy ketones.
These results support the two-electron reduction of dioxygen
on the iron(II) center with concomitant oxidation of α-hydroxy
ketone to 1,2-diketone. When diketone is used as a substrate
instead of α-hydroxy ketone, no C−C bond cleavage product is
observed. Moreover, time-resolved experiments with complex 3
show that the yields of the diketone and carboxylic acid slowly
increase over a period of 15 min (Figure S29 in the Supporting
Information). Thus, diketone is not an intermediate product in
the C−C bond cleavage pathway.
Scheme 5. Incorporation of Isotope-Labeled Oxygen in the
Reaction of Iron(II)-α-Hydroxy Ketone Complexes with
Dioxygen
exchanged into the keto oxygen before the C−C bond cleavage
step. Solvent water is known to exchange into the keto oxygen
of α-hydroxy ketone.39 Interestingly, treatment of complex 2
with H218O under a nitrogen atmosphere displays an ion peak
two mass units higher at m/z 841.15 due to the exchange of
metal-bound keto oxygen of the α-hydroxy ketone with labeled
water (30% exchange with H218O) (Figure S25 in the
Supporting Information). For complex 5, about 55% 18O
incorporation from H218O is observed under a nitrogen
atmosphere (Figure S26 in the Supporting Information).
Therefore, solvent water is exchanged into the keto oxygen of
the coordinated α-hydroxy ketone prior to the reaction with
dioxygen (Scheme 5). It should be noted that the addition of
water to the iron(II) complexes has no impact on the rate of
the reactions with O2 or the product distributions.
The iron(II)-α-hydroxy acid complexes of the TpPh2 ligand
have been reported to activate dioxygen, where the metal-
coordinated α-hydroxy acid anions acted as two-electron
reductants (Scheme 7).40 A nucleophilic oxidant, intercepted
Scheme 7. Reactivity of a Putative Iron(II)-Hydroperoxide
Oxidant Generated in the Oxidative Decarboxylation of
[(TpPh2)FeII(benzilate)] Complex40,41
To get an idea about the nature of metal−oxygen
intermediates involved in the reaction, oxidation products
from different intercepting reagents were analyzed (Scheme 6).
Scheme 6. (Top) Oxidation of External Substrates in the
Reaction between Iron(II)-α-Hydroxy Ketone Complexes
and Dioxygen and (Bottom) Yields of Oxidized Products
from External Substrates in the Reaction with Iron(II)
Complex
by external substrates, has been reported to exhibit versatile
oxidative transformation reactions such as oxygen atom transfer
to sulfides, aliphatic C−H bond activation, and olefin cis-
dihydroxylation. On the basis of interception and mechanistic
studies, the active oxidant was proposed to be a side-on
iron(II)-hydroperoxide species. In the absence of any substrate,
the oxidant intramolecularly hydroxylates (90%) the ortho
40
position of one of the phenyl rings of TpPh2
.
The iron(II)-α-hydroxy ketone complexes (1-4) of TpPh2
ligand react with dioxygen to exhibit C−C bond cleavage
reactivity of the respective α-hydroxy ketone. In all of the cases,
the C−C bond cleavage products are formed as major products.
However, complex 3 exhibits a relatively higher percentage
(about 20%) of 1,2-diketone formation in comparison to the
other complexes (1, 2, and 4). The oxidation of α-hydroxy
ketone to 1,2-diketone is a two-electron process; therefore, the
amount of the iron−oxygen species corresponds to the amount
of 1,2-diketone formed in the reactions. Thus, the iron−oxygen
oxidant generated in the diketone formation pathway oxidizes
thioanisole and 1-octene. For complex 3, the amount of iron−
oxygen oxidant may reach a value close to 20%, and as a result,
formation of intramolecular oxygenated product is expected.
The ESI-mass spectrum and the optical spectrum of the
oxidized solution of 3 confirm the intraligand hydroxylation to
an extent of about 8% (Figure S30 in the Supporting
Information). Furthermore, the solution shows a rhombic
EPR (X-band at 77 K) signal at g = 4.2 typical of high-spin
Similar to what was observed with [(TpPh2)FeII(HAP)],25
complex 1 oxidizes 2,4-di-tert-butylphenol (10 equiv) to
3,3′,5.5′-tetra-tert-butyl-2,2′-biphenol (DTBP). Reactions of
iron(II)-α-hydroxy ketone complexes with dioxygen in the
presence of thioanisole (10 equiv) afford thioanisole oxide. The
yield of thioanisole oxide is found to be 2−3% with 1 and 2,
about 8% with 3, and 9−10% with 5 and 6 (Scheme 6 and
Figure S27 in the Supporting Information). A higher amount of
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Scheme 8. Proposed Mechanism for the Oxidative C−C Bond Cleavage of α-Hydroxy Ketones on Iron Complexes
iron(III) species (Figure S30). The intraligand hydroxylation,
however, gets inhibited in the presence of thioanisole (10
equiv). Thus, in analogy to that observed with the iron(II)-α-
hydroxy acid complexes of the TpPh2 ligand,40 an iron(II)-
hydroperoxide species is proposed to form in the diketone
formation pathway. However, in the absence of any direct
experimental evidence, formation of such a species remains a
proposal.
The iron(II) complexes of the tetradentate ligand afford
higher percentages of 1,2-diketones. In the two-electron
oxidation pathway, complex 5 is expected to form a maximum
of 53% active iron−oxygen species. Although the resulting iron
oxygen oxidant oxidizes thioanisole in a yield relatively higher
than that observed with the tridentate ligand system, the yield
of thioanisole oxide (9%) in the reaction between 5 and O2 is
low. The rest of the oxidant most likely decays to some
unidentified iron species.
hydroxy-2-phenylethanone (CHPE), containing an electron-
withdrawing chloro substituent on the phenyl ring connected to
the keto group, undergoes the oxidative C−C bond cleavage
pathway only. This result supports the formation of the
peroxide intermediate III through nucleophilic attack of the
peroxide group to the keto oxygen in II. For the tetradentate
ligand, a high percentage of II participates in the diketone
formation pathway, which limits the yields of C−C cleavage
products. In this case, one of the pyridyl arms may dissociate
during the reaction that leads to the C−C bond cleavage
pathway. The weakly coordinated keto oxygen of α-hydroxy
ketone may also dissociate, leading to the formation of two-
electron-oxidized products. Formation of the alkylperoxo
intermediate III is proposed in the C−C bond cleavage
pathway by the catechol cleaving dioxygenases and gentisate
1,2-dioxygenase.1,45 A Baeyer−Villiger type reaction of the
alkylperoxo intermediate results in O−O bond scission to
generate an anhydride intermediate (IV). The iron(II)-
hydroxide moiety of anhydride intermediate IV can exchange
with water, which is responsible for the low incorporation of
labeled oxygen into the cleavage products.
On the basis of the results described above, a mechanistic
proposal for the C−C bond cleavage pathway of α-hydroxy
ketones is put forward (Scheme 8). The reaction is initiated by
activation of dioxygen at the iron(II) center to form an
iron(III)-superoxide radical species (I). The superoxide species
may either attack the carbonyl group or abstract the hydrogen
atom of an α-C−H bond of the coordinated α-hydroxy ketone.
In the case of nucleophilic attack of an iron(III)-superoxide, as
CONCLUSION
■
In conclusion, we have isolated a series of biomimetic iron(II)-
α-hydroxy ketone complexes supported by a facial N3 ligand
and a tripodal N4 ligand. These iron(II) complexes react with
dioxygen to oxidatively cleave the aliphatic C−C bond of α-
hydroxy ketones, yielding 2 equiv of carboxylic acid. In the C−
C bond cleavage reaction, an oxygen atom from dioxygen is
incorporated into each carboxylate unit. An iron(III)-superoxo
intermediate is proposed to initiate the oxidative transformation
reaction, and the C−C bond cleavage reaction follows the
mechanism of an intradiol cleavage pathway. The iron
complexes of the tridentate ligand afford a higher amount of
C−C cleavage products in comparison to those of the
tetradentate ligand, supporting the natural selection of a “3-
His facial motif” in the active site of DAD. The C−C bond
cleavage of α-hydroxy ketones reported in this work provides
useful insight into the mechanism of oxygen-dependent
transformation reaction carried out by DAD.
in the mechanism of α-keto acid dependent enzymes,42
a
carbonyl compound (aldehyde or ketone) would form along
with carboxylic acid product. Moreover, an iron(IV)-oxo
species generated in that pathway would hydroxylate the
aromatic ring to a large extent. The experimental results,
however, rule out the possibility of an α-keto acid-dependent
enzymelike mechanism in the C−C bond cleavage pathway of
α-hydroxy ketone. Iron(III)-superoxide species are known to
abstract hydrogen atom from an O−H or C−H group.43,44 We
have recently shown that the oxidative C−C bond cleavage of
α-hydroxy acid was initiated via hydrogen atom abstraction
from O−H bonds by an iron(III) superoxide species.37 The
hydroperoxo intermediate (II) releases a proton and attacks the
keto carbon to generate an alkylperoxo intermediate (III) in
the C−C bond cleavage pathway. In another pathway,
intermediate II forms 1,2-diketone and iron(II)-oxygen oxidant
(Scheme 8). Transformation of II to III is dependent on the
denticity of the supporting ligand and also on the electronic
properties of the coordinated α-hydroxy ketones. With the
tridentate ligand, the C−C bond cleavage of the α-hydroxy
ketone is the major pathway and the formation of diketone is
the minor pathway. The substrate 1-(4-chlorophenyl)-2-
EXPERIMENTAL SECTION
■
Materials and Methods. Commercial grade chemicals were used
for the synthesis and reactivity studies. Caution! Although no problem
was encountered during the synthesis of the complexes, perchlorate
salts are potentially explosive and should be handled with care.46 The
ligands KTpPh2 and 6-Me3-TPA were synthesized according to the
H
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reported procedure.47,48 Air-sensitive complexes were prepared and
stored in an inert-atmosphere glovebox.
methanol (1/2) solvent mixture. Yield: 0.36 g (72%). Anal. Calcd for
C61H49BFeN6O4 (996.74 g/mol): C, 73.51; H, 4.96; N, 8.43. Found:
C, 73.24; H, 4.78; N, 8.67. IR (KBr, cm−1): 3433 (br), 3063 (m), 2926
(m), 2623 (m), 1636 (s), 1601 (m), 1547 (s), 1475 (vs), 1410 (s),
1391 (s), 1360 (m), 1236 (m), 1171 (vs), 1070 (vs), 1011 (s), 918
(m), 814 (m), 764 (vs), 696 (vs), 671 (m), 571 (m). ESI-MS (positive
ion mode, benzene-acetonitrile): m/z 725.23 (C35H34BFeN6 expected
at m/z 725.23) ([(TpPh2)Fe]+), 766.29 (C47H37BFeN expected at m/z
766.26) ([(TpPh2)Fe(CH3CN]+), 945.24 (C60H46BFeN8 expected at
m/z 945.33) ([(TpPh2)Fe(3,5-diphenylpyrazole)]+). UV−vis in
benzene (λ, nm; ε, M−1cm−1): 500 (585), 555 (395). 1H NMR
(500 MHz, C6D6, 295 K): δ 58.5, 51.8, 49.1, 35.3, 25.9, 18.9, 14.3,
13.6, 11.1, 10.6, 10.4, 8.7, 8.0, 7.6, 6.7, 4.3, −10.9, −20.9 ppm (Eight
proton resonances for TpPh2 ligand and seven proton resonances for
HBME are expected). Magnetic moment (298 K) = 5.1 μB.
Fourier transform infrared spectroscopy on KBr pellets was
performed on a Shimadzu FT-IR 8400S instrument. Elemental
analyses were performed on a PerkinElmer 2400 series II CHN
analyzer. Electrospray ionization mass spectra were recorded with a
Waters QTOF Micro YA263 instrument. All room-temperature NMR
spectra were collected on a Bruker 500 or 300 MHz spectrometer.
Solution electronic spectra were recorded on an Agilent 8453 diode
array spectrophotometer. GC-MS measurements were carried out with
a PerkinElmer Clarus 680 GC and SQ8T MS using an Elite 5 MS (30
m × 0.25 mm × 0.25 μm) column with a maximum temperature of
300 °C. Room-temperature magnetic moment data were collected on
a Gouy balance (Sherwood Scientific, Cambridge, U.K.). Diamagnetic
contributions were estimated for each compound by using Pascal’s
constants. X-band EPR measurements were performed on a JEOL JES-
FA 200 instrument. Labeling experiments were carried out with 18O2
gas (99 atom %) or H218O (98 atom %) purchased from Icon Services
Inc., USA.
[(TpPh2)FeII(CHPE)] (4). Complex 4 was synthesized according to the
procedure described for complex 1, except that 1-(4-chlorophenyl)-2-
hydroxy-2-phenylethanone (CHPE-H; 0.12 g, 0.50 mmol) was used
instead of 2-phenyl-2-hydroxyacetophenone. The pink crystalline solid
of 4 was isolated by recrystallization from a dichloromethane/
methanol (1/2) solvent mixture. Yield: 0.31 g (64%). Anal. Calcd for
C59H44BClFeN6O2 (971.13 g/mol): C, 72.97; H, 4.57; N, 8.65.
Found: C, 72.46; H, 4.34; N, 8.72. IR (KBr, cm−1): 3450 (br), 3063
(m), 2926 (m), 2615 (m), 1641 (m), 1593 (s), 1547 (s), 1479 (vs),
1410 (vs), 1360 (m), 1234 (m), 1171 (vs), 1072 (vs), 1011 (m), 916
(m), 812 (m), 764 (vs), 696 (vs), 629 (m), 567 (m). ESI-MS (positive
ion mode, benzene-acetonitrile): m/z 725.13 (C35H34BFeN6 expected
at m/z 725.23) ([(TpPh2)Fe]+), 945.14 (C60H46BFeN8 expected at m/
Synthesis of Complexes. [(TpPh2)FeII(PHAP)] (1). To a methanolic
(2 mL) suspension of the ligand KTpPh2 (0.35 g, 0.50 mmol) was
added iron(II) perchlorate hexahydrate (0.18 g, 0.50 mmol). To the
suspension was added a mixture of 2-phenyl-2-hydroxyacetophenone
(PHAP-H; 0.11 g, 0.50 mmol) and triethylamine (70 μL) in 1 mL of
methanol with constant stirring. The mixture was stirred at room
temperature for 2 h to precipitate a pink solid. The solid was filtered
and washed several times with methanol. A microcrystalline solid was
isolated after recrystallization of the complex from a solvent mixture of
dichloromethane and methanol (1/2). Yield: 0.34 g (67%). Anal.
Calcd for 1·CH2Cl2 (C60H47BCl2FeN6O2, 1021.62 g/mol): C, 70.54;
H, 4.64; N, 8.23. Found: C, 70.48; H, 4.27; N, 8.57. IR (KBr, cm−1):
3458 (br), 3061 (m), 2928 (m), 2615 (m), 1593 (s), 1545 (s), 1518
(vs), 1477 (vs), 1389 (vs), 1362 (s), 1306 (m), 1232 (m), 1171 (s),
1068 (s), 1009 (m), 918 (m), 808 (m), 760 (vs), 696 (vs), 669 (s),
526 (m). ESI-MS (positive ion mode, benzene-acetonitrile): m/z
725.12 (C45H34BFeN6 expected at m/z 725.23) ([(TpPh2)Fe]+),
743.15 (C45H36BFeN6O expected at m/z 743.24) ([(TpPh2)Fe-
(H2O)]+), 766.22 (C47H37BFeN7 expected at m/z 766.26) ([(TpPh2)-
Fe(CH3CN)]+). UV−vis in benzene (λ, nm; ε, M−1 cm−1): 515 (450),
570 (350). 1H NMR (500 MHz, C6D6, 295 K): δ 52.2, 48.3, 35.5, 18.7,
18.1, 13.4, 12.9, 10.9, 8.6, 7.8, 6.0, −20.3 ppm (8 proton resonances for
TpPh2 ligand and 7 proton resonances for PHAP are expected).
Magnetic moment (298 K): 5.1 μB.
z
945.33) ([(TpPh2)Fe(3,5-diphenylpyrazole)]+), 971.21
(C59H45BClFeN6O2 expected at m/z 971.27) ([(TpPh2)Fe(CHPE) +
H]+). UV−vis in benzene (λ, nm; ε, M−1 cm−1): 530 (440), 580
1
(360). H NMR (500 MHz, C6D6, 295 K): δ 59.2, 52.6, 48.7, 35.6,
18.8, 18.3, 13.6, 11.0, 9.8, 9.3, 8.7, 6.8, −20.9 ppm (8 proton
resonances for TpPh2 ligand and 6 proton resonances for CHPE are
expected). Magnetic moment (298 K): 5.1 μB.
[(6-Me3-TPA)FeII(PHAP)]BPh4 (5). Equimolar amounts of 6-Me3-
TPA (0.16 g, 0.50 mmol), iron(II) perchlorate hexahydrate (0.18 g,
0.50 mmol), 2-phenyl-2-hydroxyacetophenone (PHAP-H; 0.11 g, 0.50
mmol), and triethylamine (70 μL) in 5 mL of methanol were stirred
under a nitrogen atmosphere for 4 h. The solution was concentrated to
1 mL, and diethyl ether (10 mL) was added. The mixture was then
stirred for another 2 h to give a brown solid of the perchlorate salt of
the complex ([(6-Me3-TPA)FeII(PHAP)]ClO4). A methanolic
solution of sodium tetraphenylborate (0.17 g, 0.50 mmol) was
added to the methanolic reaction solution to precipitate a brown solid.
The solid was isolated by filtration, washed with methanol, and dried.
Yield: 0.28 g (61%). Anal. Calcd for C59H55BFeN4O2 (918.75 g/mol):
C, 77.13; H, 6.03; N, 6.10. Found: C, 75.86; H, 6.01; N, 6.06. IR (KBr,
cm−1): 3443 (br), 3055 (s), 2924 (m), 1639 (s), 1603 (s), 1578 (s),
1452 (vs), 1254 (m), 1163 (m), 1126 (s), 1007 (m), 787 (m), 737
(vs), 704 (vs), 613 (m). ESI-MS (positive ion mode, acetonitrile): m/z
333.09 (C21H25N4 expected at m/z 333.20) ([(6-Me3-TPA) + H]+),
599.09 (C35H35FeN4O2 expected at m/z 599.21) ([(6-Me3-TPA)Fe-
(PHAP)]+). UV−vis in acetonitrile (λ, nm; ε, M−1 cm−1): 390 (1600),
[(TpPh2)FeII(HCH)] (2). Complex 2 was synthesized according to the
procedure described for complex 1, except that 2-hydroxycyclohex-
anone (HCH-H) (0.06 g, 0.50 mmol) was used instead of 2-phenyl-2-
hydroxyacetophenone. X-ray-quality single crystals of 2 were isolated
by recrystallization of the light green solid from a dichloromethane/
methanol (1/2) solvent mixture. Yield: 0.30 g (66%). Anal. Calcd for
2·CH3OH (C53H51BFeN6O4, 902.67 g/mol): C, 70.52; H, 5.69; N,
9.31. Found: C, 70.41; H, 5.86; N, 9.49. IR (KBr, cm−1): 3418 (br),
3057 (m), 2932 (m), 2627 (m), 1674 (s), 1544 (s), 1479 (vs), 1462
(vs), 1414 (s), 1360 (m), 1306 (m), 1236 (m), 1169 (vs), 1070 (vs),
1008 (s), 916 (m), 810 (m), 764 (vs), 698 (vs), 669 (m), 569 (m).
ESI-MS (positive ion mode, benzene-acetonitrile): m/z 725.12
(C45H34BFeN6 expected at m/z 725.23) ([(TpPh2)Fe]+), 766.22
(C47H37BFeN7 expected at m/z 766.26) ([(TpPh2)Fe(CH3CN)]+),
839.10 (C51H44BFeN6O2 expected at m/z 839.29) ([(TpPh2)Fe-
(HCH) + H]+), 945.10 (C60H46BFeN8 expected at m/z 945.33)
([(TpPh2)Fe(3,5-diphenylpyrazole)]+). UV−vis in benzene (λ, nm; ε,
1
560 (315). H NMR of [(6-Me3-TPA)FeII(PHAP)]ClO4 (300 MHz,
CD3CN, 295 K): δ 50.7, 43.4, 23.5, 17.2, 15.9, 14.8, 14.0, 10.9, 9.7, 7.9,
6.1, −50.1 ppm (4 proton resonances for 6-Me3-TPA ligand and 7
proton resonances for PHAP are expected; the methylene protons of
6-Me3-TPA ligand are too broad to be observed). Magnetic moment
(298 K): 4.9 μB.
1
M−1 cm−1): 330 (335), 380 (170). H NMR (500 MHz, C6D6, 295
[(6-Me3-TPA)FeII(HCH)](BPh4) (6). Complex 6 was synthesized
according to the protocol described for 5, except that 2-
hydroxycyclohexanone (HCH-H; 0.06 g, 0.50 mmol) was used instead
of 2-phenyl-2-hydroxyacetophenone. The tetraphenylborate salt of the
complex was isolated upon addition of 1 equiv of sodium
tetraphenylborate to the reaction solution. A deep yellow crystalline
solid was obtained by recrystallization of the complex from a solvent
mixture of dichloromethane and methanol (1/2). Yield: 0.27 g (66%).
Anal. Calcd for C51H53BFeN4O2 (820.65 g/mol): C, 74.64; H, 6.51; N,
6.83. Found: C, 74.83; H, 6.23; N, 6.69. IR (KBr, cm−1): 3439 (br),
K): δ 65.0, 58.6, 52.2, 46.3, 31.6, 27.2, 24.1, 20.3, 14.1, 12.2, 11.6, 11.3,,
8.7, 6.3, −12.8, −17.3, −25.3 ppm (8 proton resonances for TpPh2
ligand and 9 proton resonances for HCH are expected). Magnetic
moment (298 K): 5.3 μB.
[(TpPh2)FeII(HBME)] (3). Complex 3 was synthesized according to
the procedure described for complex 1, except that 2-hydroxy-1,2-
bis(4-methoxyphenyl)ethanone (HBME-H; 0.14 g, 0.50 mmol) was
used instead of 2-phenyl-2-hydroxyacetophenone. The pink crystalline
solid of 3 was isolated by recrystallization from a dichloromethane/
I
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Table 4. Crystallographic Data for [(TpPh2)FeII(HCH)] (2)
3053 (s), 2930 (m), 2858 (m), 1672 (s), 1603 (s), 1578 (s), 1452
(vs), 1267 (m), 1155 (m), 1126 (m), 841 (m), 789 (m), 737 (vs), 706
(vs), 615 (m). UV−vis in acetonitrile (λ, nm; ε, M−1 cm−1): 325
empirical formula
formula wt
cryst syst
C51H43BFeN6O2
838.57
monoclinic
P21/c
1
(1610), 390 (1575). H NMR (500 MHz, CD3CN, 295 K): δ 59.3,
49.9, 39.8, 35.4, 33.9, 32.3, 30.3, 20.9, 19.9, 13.3, 10.8, 7.2, 6.9, 6.8,
−18.7, −23.1, −49.1 ppm (4 proton resonances for 6-Me3-TPA ligand,
3 resonances for BPh4 counterion, and 9 proton resonances for HCH
are expected; the methylene protons of 6-Me3-TPA ligand are too
broad to be observed). Magnetic moment (298 K): 5.3 μB.
space group
a, Å
14.485(7)
19.058(9)
16.974(8)
90
b, Å
c, Å
Reaction of Iron(II)-α-Hydroxy Ketone Complexes with
Oxygen and Analysis of Organic Products. The iron(II) complex
(0.02 mmol) was dissolved in 10 mL of dry organic solvent. Pure
oxygen gas was bubbled through the solution for 2 min and the
solution was stirred at room temperature under an oxygen
environment. After the reaction (5 min for 1, 1 h for 2, 13 min for
3, 10 min for 4, 3 h for 5, and 6 h for 6), the solvent was removed
under vacuum and the residue was treated with 10 mL of 2 M
hydrochloric acid solution. The organic products were extracted with
diethyl ether (3 × 15 mL) (with ethyl acetate in the case of 2 and 6),
and the organic layer was dried over anhydrous sodium sulfate. After
removal of the solvent, the colorless residue was analyzed without
further purification. All experiments were repeated three times to
calculate the yields of oxidized products. The α-hydroxy ketone
starting materials and organic products are found to be stable under
acidic and aerobic conditions. Quantification of benzoic acid, benzil,
α, deg
β, deg
111.307(2)
90
γ, deg
V, Å3
4365.6(4)
4
Z
ρcalcd., Mg/m3
1.276
T, K
100(2)
0.393
μ(Mo Kα), mm−1
F(000)
1752.0
2.50−23.36
51337
θ range, deg
no of rflns collected
no. of unique rflns
R(int)
7673
0.0669
5877
no. of data (I > 2σ(I))
no. of params refined
goodness of fit on F2
R1 (I > 2σ(I))
wR2
1
and adipic acid was carried out by H NMR integration using 1,4-
550
benzoquinone (or 1,3,5-trimethoxybenzene) as an internal standard.
In the quantification experiments, the products were analyzed
immediately after workup using 1,4-benzoquinone standard. Quanti-
fication experiments were carried out in triplicate, which gave
consistent results for the 1,4-benzoquinone standard. Cyclohexane-
1,2-dione was quantified by GC-MS using naphthalene as an internal
standard.
Ester Derivative of Benzoic Acid. The methyl ester of benzoic
acid was prepared by mixing benzoic acid (isolated from the oxidized
solution according to the procedure as described above) with excess
diazomethane in dry diethyl ether (2 mL) at 0 °C. After the reaction
solution was stirred for 5 min, the insoluble parts were separated and
the clear ether layer was injected for GC-MS analysis.
Ester Derivative of Adipic Acid. Complex 2 (0.02 mmol) was
dissolved in dry benzene (10 mL), and dry dioxygen gas was bubbled
through the solution for 2 min. The solution was then stirred at room
temperature for 1 h 15 min under an oxygen atmosphere. Acidic
workup of the oxidized solution with ethyl acetate resulted in a white
crude mass, which was treated with α-bromoacetophenone (0.02
mmol) and potassium fluoride (0.04 mmol) in DMF (2 mL).49 The
reaction mixture was stirred at room temperature for 24 h. The
product was then extracted from the reaction mixture with diethyl
ether, and the organic extract was washed several times with equal
volumes of water. The organic layer was then dried over anhydrous
sodium sulfate and was analyzed by 1H NMR and ESI-mass
spectrometry.
1.015
0.0489
0.1420
hydrogen atoms were treated anisotropically. The hydrogen atoms
were geometrically fixed. The unit cell contains eight disordered
methanol molecules, which were treated as a diffuse contribution to
the overall scattering without specific atom positions by SQUEEZE/
PLATON.52
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.5b01235.
■
S
All spectral data (PDF)
X-ray crystallographic data (CIF)
AUTHOR INFORMATION
Corresponding Author
*T.K.P.: e-mail, ictkp@iacs.res.in; fax, +91-33-2473-2805; tel,
+91-33-2473-4971.
■
Notes
Interception Studies. A mixture of the iron complex (0.02 mmol)
and 10 equiv of thioanisole or 100 equiv of 1-octene as intercepting
agent in oxygen-saturated dry organic solvent was stirred at ambient
temperature. The reaction was quenched by removing the solvent and
adding 10 mL of 2 M HCl. The organic products were extracted with
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
T.K.P. gratefully acknowledges the Indian National Science
Academy for financial support (Project for INSA Young
Scientist Awardee). R.R. thanks the Council of Scientific and
Industrial Research (CSIR), India, for a research fellowship. X-
ray diffraction data of the complex were collected at the DST-
funded National Single Crystal Diffractometer Facility at the
Department of Inorganic Chemistry, Indian Association for the
Cultivation of Science.
1
diethyl ether (3 × 15 mL) and characterized by H NMR and GC-
mass spectrometry. In each case, a control experiment was carried out
under an oxygen atmosphere in the absence of iron complex. No
product derived from the external substrate was formed in the control
experiment.
X-ray Crystallographic Data Collection and Refinement of
the Structure. Diffraction data of 2 were collected at 100 K on a
Bruker Smart APEX II (Mo Kα radiation, λ = 0.71073 Å) instrument.
Crystallographic data are provided in Table 4. Cell refinement,
indexing, and scaling of the data set were carried out using the APEX2
v2.1-0 software.50 The structures were solved by direct methods and
subsequent Fourier analyses and refined by the full-matrix least-
squares method based on F2 with all observed reflections.51 The non-
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