Reactivity of biomimetic iron(II)-2-aminophenolate complexes toward dioxygen: Mechanistic investigations on the oxidative C-C bond cleavage of substituted 2-aminophenols

Article abstract of DOI:10.1021/ic403043e

The isolation and characterization of a series of iron(II)-2-aminophenolate complexes [(6-Me₃-TPA)Fe^II(X)]⁺ (X = 2-amino-4-nitrophenolate (4-NO₂-HAP), 1; X = 2-aminophenolate (2-HAP), 2; X = 2-amino-3-methylphenolate (3-Me-HAP), 3; X = 2-amino-4-methylphenolate (4-Me-HAP), 4; X = 2-amino-5-methylphenolate (5-Me-HAP), 5; X = 2-amino-4-tert-butylphenolate (4-^tBu-HAP), 6 and X = 2-amino-4,6-di-tert-butylphenolate (4,6-di-^tBu-HAP), 7) and an iron(III)-2-amidophenolate complex [(6-Me₃-TPA)Fe^III(4,6- di-^tBu-AP)]⁺ (7^Ox) supported by a tripodal nitrogen ligand (6-Me₃-TPA = tris(6-methyl-2-pyridylmethyl)amine) are reported. Substituted 2-aminophenols were used to prepare the biomimetic iron(II) complexes to understand the effect of electronic and structural properties of aminophenolate rings on the dioxygen reactivity and on the selectivity of C-C bond cleavage reactions. Crystal structures of the cationic parts of 5·ClO₄ and 7·BPh₄ show six-coordinate iron(II) centers ligated by a neutral tetradentate ligand and a monoanionic 2-aminophenolate in a bidentate fashion. While 1·BPh ₄ does not react with oxygen, other complexes undergo oxidative transformation in the presence of dioxygen. The reaction of 2·ClO ₄ with dioxygen affords 2-amino-3H-phenoxazin-3-one, an auto-oxidation product of 2-aminophenol, whereas complexes 3·BPh ₄, 4·BPh₄, 5·ClO₄ and 6·ClO₄ react with O₂ to exhibit C-C bond cleavage of the bound aminophenolates. Complexes 7·ClO₄ and 7 ^Ox·BPh₄ produce a mixture of 4,6-di-tert-butyl-2H- pyran-2-imine and 4,6-di-tert-butyl-2-picolinic acid. Labeling experiments with ¹⁸O₂ show the incorporation of one oxygen atom from dioxygen into the cleavage products. The reactivity (and stability) of the intermediate, which directs the course of aromatic ring cleavage reaction, is found to be dependent on the nature of ring substituent. The presence of two tert-butyl groups on the aminophenolate ring in 7·ClO₄ makes the complex slow to cleave the C-C bond of 4,6-di-^tBu-HAP, whereas 4·BPh₄ containing 4-Me-HAP displays fastest reactivity. Density functional theory calculations were conducted on [(6-Me ₃-TPA)Fe^III(4-^tBu-AP)]⁺ (6 ^Ox) to gain a mechanistic insight into the regioselective C-C bond cleavage reaction. On the basis of the experimental and computational studies, an iron(II)-2-iminobenzosemiquinonate intermediate is proposed to react with dioxygen resulting in the oxidative C-C bond cleavage of the coordinated 2-aminophenolates.

Full text of DOI:10.1021/ic403043e

Article
pubs.acs.org/IC
Reactivity of Biomimetic Iron(II)-2-aminophenolate Complexes
toward Dioxygen: Mechanistic Investigations on the Oxidative C−C
Bond Cleavage of Substituted 2‑Aminophenols§
Biswarup Chakraborty,† Sourav Bhunya,‡ Ankan Paul,‡ and Tapan Kanti Paine*,†
‡
†Department of Inorganic Chemistry, Raman Center for Atomic, Molecular and Optical Sciences, Indian Association for the
Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, India
S
* Supporting Information
ABSTRACT: The isolation and characterization of a series of iron(II)-2-
aminophenolate complexes [(6-Me3-TPA)FeII(X)]+ (X = 2-amino-4-nitro-
phenolate (4-NO2-HAP), 1; X = 2-aminophenolate (2-HAP), 2; X = 2-amino-
3-methylphenolate (3-Me-HAP), 3; X = 2-amino-4-methylphenolate (4-Me-
HAP), 4; X = 2-amino-5-methylphenolate (5-Me-HAP), 5; X = 2-amino-4-tert-
butylphenolate (4-tBu-HAP), 6 and X = 2-amino-4,6-di-tert-butylphenolate
(4,6-di-tBu-HAP), 7) and an iron(III)-2-amidophenolate complex [(6-Me3-
TPA)FeIII(4,6-di-tBu-AP)]+ (7Ox) supported by a tripodal nitrogen ligand (6-
Me3-TPA = tris(6-methyl-2-pyridylmethyl)amine) are reported. Substituted 2-aminophenols were used to prepare the
biomimetic iron(II) complexes to understand the effect of electronic and structural properties of aminophenolate rings on the
dioxygen reactivity and on the selectivity of C−C bond cleavage reactions. Crystal structures of the cationic parts of 5·ClO4 and
7·BPh4 show six-coordinate iron(II) centers ligated by a neutral tetradentate ligand and a monoanionic 2-aminophenolate in a
bidentate fashion. While 1·BPh4 does not react with oxygen, other complexes undergo oxidative transformation in the presence
of dioxygen. The reaction of 2·ClO4 with dioxygen affords 2-amino-3H-phenoxazin-3-one, an auto-oxidation product of 2-
aminophenol, whereas complexes 3·BPh4, 4·BPh4, 5·ClO4 and 6·ClO4 react with O2 to exhibit C−C bond cleavage of the bound
aminophenolates. Complexes 7·ClO4 and 7Ox·BPh4 produce a mixture of 4,6-di-tert-butyl-2H-pyran-2-imine and 4,6-di-tert-butyl-
2-picolinic acid. Labeling experiments with 18O2 show the incorporation of one oxygen atom from dioxygen into the cleavage
products. The reactivity (and stability) of the intermediate, which directs the course of aromatic ring cleavage reaction, is found
to be dependent on the nature of ring substituent. The presence of two tert-butyl groups on the aminophenolate ring in 7·ClO4
makes the complex slow to cleave the C−C bond of 4,6-di-tBu-HAP, whereas 4·BPh4 containing 4-Me-HAP displays fastest
reactivity. Density functional theory calculations were conducted on [(6-Me3-TPA)FeIII(4-tBu-AP)]+ (6Ox) to gain a mechanistic
insight into the regioselective C−C bond cleavage reaction. On the basis of the experimental and computational studies, an
iron(II)-2-iminobenzosemiquinonate intermediate is proposed to react with dioxygen resulting in the oxidative C−C bond
cleavage of the coordinated 2-aminophenolates.
1). Very recently, the crystal structures of APD from
Comamonas sp. strain CNB-1 as the apoenzyme, the
holoenzyme and as complexes with the lactone intermediate
(4Z,6Z)-3-iminooxepin-2(3H)-one, and the product 2-amino-
muconic acid-6-semialdehyde with the suicide inhibitor 4-
nitrocatechol have been reported.26 The active site structure in
the resting state shows the binding of aminophenolate to the
INTRODUCTION
■
Aromatic C−C bond cleavage is a crucial step in the
biodegradation of organic compounds such as catechols,
aminophenols, hydroquinones, salicylic acid, gentisic acid, etc.
by aerobic microorganism.1−7 A variety of nonheme iron
oxygenases are involved in catalyzing the C−C bond cleavage
of aromatic compounds in the biodegradation pathway.8−17
Catechol dioxygenases are most familiar in this class of enzymes
which is categorized as extradiol and intradiol dioxygenases
depending upon the position of ring cleavage of catechol.9,18−20
2-Aminophenol dioxygenases catalyze the ring cleavage at meta
position of 2-aminophenols in the biodegradation of nitro-
aromatics.21−23 2-Aminophenol-1,6-dioxygenase (APD), the
nonheme iron enzyme isolated and purified from Pseudomonas
pseudoalcaligenes, catalyzes the oxygenolytic ring cleavage of 2-
aminophenols under aerobic conditions.11,24,25 The reaction
occurs via oxidative C1−C6 bond cleavage to form 2-
aminomuconic acid semialdehyde which spontaneously cyclizes
with loss of a water molecule to form 2-picolinic acid (Scheme
Scheme 1. Reaction Catalyzed by 2-Aminophenol
Dioxygenases
Received: December 11, 2013
© XXXX American Chemical Society
A
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ferrous ion and the other structures provide insight into the
reaction mechanism. Another related enzyme, 3-hydroxyan-
thranilate-3,4-dioxygenase (HAD), isolated from Saccharomyces
cerevisiae, catalyzes the C3−C4 bond cleavage of 3-hydroxyan-
thranilate to quinolinic acid in the tryptophan catabolism
pathway.27−30 A similar pathway is followed in the degradation
of other nitroaromatic compounds.25,31−34 Both HAD and
APD exhibit a common “2-His-1-carboxylate” structural motif
and show functional similarity with extradiol dioxygenases.
On the basis of structural and biochemical studies on HAD
and APD, a mechanistic proposal similar to that of extradiol
catechol dioxygenases has been reported (Scheme 2).29,30 The
the enzymes. Wieghardt and Chaudhuri reported a number of
metal complexes where the coordinated aminophenolates
exhibited different oxidation states.36−42 Fiedler and co-workers
have recently reported an iron(II)-2-aminophenolate complex
with a facial N3 donor ligand. Reaction of the iron(II) complex
with an oxidant led to the isolation of an iron(II)-2-
iminobenzosemiquinonate and iron(III)-2-iminobenzosemiqui-
none complexes.43,44 In biomimetic chemistry, reactivity of
model iron(II)-aminophenolate is less explored. Recently, we
have reported a six-coordinate iron(II)-aminophenolate com-
plex of a tetradentate ligand, [(6-Me3-TPA)FeII(4-tBu-HAP)]+
(6-Me3-TPA = tris(6-methyl-2-pyridylmethyl)amine), as the
first functional model of 2-aminophenol dioxygenases.45 The
complex reacts with dioxygen under ambient conditions to
undergo oxidative C−C bond cleavage of 2-amino-4-tert-
butylphenol resulting in the formation of 4-tert-butyl-2-picolinic
acid as the only product.45 In the model system, the iron(II)-
aminophenolate complex initially reacts with O2 to form the
corresponding iron(III)-amidophenolate complex. For further
understanding of the mechanism of C−C bond cleavage of 2-
aminophenol on the iron(II) complex of N4 ligand, we have
studied the dioxygen reactivity of a series of iron(II)-2-
aminophenolate complexes with different substituents on the
aminophenolate ring. In this Article, we report the synthesis
and characterization of six iron(II)-2-aminophenolate com-
plexes with the general formula [(6-Me3-TPA)FeII(X)]+ (X =
2-amino-4-nitrophenolate (4-NO2−HAP), 2-aminophenolate
(HAP), 2-amino-3-methylphenolate (3-Me-HAP), 2-amino-4-
methylphenolate (4-Me-HAP), 2-amino-5-methylphenolate (5-
Me-HAP), and 2-amino-4,6-di-tert-butylphenolate (4,6-di-tBu-
HAP)) (Scheme 4). The influence of structural and electronic
properties of substituent on the dioxygen reactivity and on the
oxidative C−C bond cleavage of aminophenols is discussed. On
the basis of experimental and computational studies, a
mechanism of the aromatic C−C bond cleavage reaction of
substituted 2-aminophenols on an iron complex is presented.
Scheme 2. Proposed Catalytic Cycle of 2-Aminophenol
Dioxygenases
substrate binds to the ferrous ion and the enzyme−substrate
complex (II) activates dioxygen. An iron(II)-peroxide inter-
mediate (IV) is subsequently generated via an iron(II)-2-
iminobenzosemiquiononate species (III) upon electron transfer
from the aminophenolate ring to the metal center. A lactone
intermediate (V) is formed via Criegee rearrangement of the
iron(II)-peroxide intermediate (IV) with the incorporation of
one oxygen atom into the lactone ring. Hydrolysis of the
lactone affords the cleavage product. The conversion of 2-
amino muconic acid semialdehyde to 2-picolinic acid then takes
place through a nonenzymatic pathway.33 Most of the
intermediates have been successfully characterized crystallo-
graphically in APD similar to the structures isolated with
different enzyme stains of homoprotocatechuate 2,3-dioxyge-
nase (HPCD).26,35
The ring cleavage reactivity of 2-aminophenol dioxygenases
(HAD and APD) has fuelled the interest in studying the
reactivity of iron-coordinated 2-aminophenols. The “redox non-
innocent” nature of aminophenols (Scheme 3) is the key
electronic feature responsible for dioxygen activation and
subsequent aromatic C−C bond cleavage reaction catalyzed by
EXPERIMENTAL SECTION
■
Materials and Physical Measurements. All reagents and
solvents were purchased from commercial sources and were used
without further purification. Solvents were distilled and dried before
use. Preparation and handling of air-sensitive materials were carried
out under an inert atmosphere in a glovebox. Ligand 6-Me3-TPA was
prepared according to a literature procedure.46 Fourier transform
infrared spectroscopy (FT-IR) on KBr pellets was performed on a
Shimadzu FT-IR 8400S instrument. Elemental analyses were
performed on a PerkinElmer 2400 series II CHN analyzer. Electro-
spray ionization (ESI) mass spectra were recorded with a Waters
QTOF Micro YA263 instrument. Solution electronic spectra (single
and time-dependent) were measured on an Agilent 8453 diode array
spectrophotometer. All room temperature NMR (Nuclear Magnetic
Resonance) spectra were collected on a Bruker Avance 500 MHz
spectrometer. Room temperature magnetic data were collected on
Gouy balance (Sherwood Scientific, Cambridge, UK). Diamagnetic
contributions were calculated for each compound using Pascal’s
constants. GC-MS (Gas Chromatography−Mass Spectrometry)
measurements were carried out on a PerkinElmer Clarus 680 GC
and SQ8T MS, using Elite 5 MS (30 m x 0.25 mm x 0.25 μm) column
with maximum temperature of 300 °C. X-band EPR (Electron
Paramagnetic Resonance) measurements were performed on a JEOL
JES-FA 200 instrument. Labeling experiments were carried out with
18O2 gas (99 atom %) or H2O18 (98 atom %) purchased from Icon
Scheme 3. Redox Non-innocence of 2-Aminophenolates
Services Inc., USA.
General Procedure for the Syntheses of Iron(II)-2-amino-
phenol Complexes. Iron(II) perchlorate hydrate (0.36 g, 1.00
B
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Scheme 4. Synthesis of Iron(II)-2-aminophenolate Complexes
mmol) was added to a solution of the ligand (1.00 mmol) in methanol
(5 mL). To the resulting mixture was added a solution of aminophenol
(1.00 mmol) and 1 equiv of Et3N in methanol (5 mL). The solution
was then allowed to stir at room temperature for 4 h. The solution was
concentrated and diethyl ether was added. The resulting mixture was
stirred further for 4−5 h to precipitate a solid. The solid was isolated
by filtration, washed two to three times with diethyl ether and dried.
Tetraphenylborate salts of the complexes were isolated from the
reaction of the perchlorate salt with 1 equiv of sodium
tetraphenylborate in methanol.
1464(m), 1311(m), 1094(vs), 781(m), 625(s). UV−vis in CH3CN:
403 nm (ε = 2110 M−1cm−1). Magnetic moment μeff (298 K): 4.9 μB.
[(6-Me3-TPA)FeII(4-Me-HAP)](BPh4) (4·BPh4). Yellow solid. Yield:
0.62 g (75%). Anal. Calcd for C52H52BFeN5O (829.66 g/mol): C,
75.28; H, 6.32; N, 8.44. Found: C, 74.78; H, 6.51; N, 8.35%. IR (KBr,
cm−1): 3431(br), 3053(m), 2922(m), 1605(s), 1578(m), 1491(vs),
1458(s), 1298(vs), 1010(w), 787(m), 739(s), 706(vs), 615. UV−vis in
CH3CN: 404 nm (ε = 2100 M−1cm−1). Magnetic moment μeff (298
K): 4.8 μB. 1H NMR (500 MHz, CDCl3, 298 K): δ (ppm) 52.9 (6H),
44.1 (3H), 38.2 (3H), 28.4 (3H), 19.0 (3H), 7.4 (3H), 7.3 (8H), 7.0
(8H), 6.7 (4H), −26.3 (9H).
[(6-Me3-TPA)FeII(4-NO2-HAP)](BPh4) (1·BPh4). Red solid. Yield:
0.61 g (71%). Anal. Calcd for C51H49BFeN6O3 (860.63 g/mol): C,
71.17; H, 5.74; N, 9.76. Found: C, 70.69; H, 5.61; N, 9.91%. IR (KBr,
cm−1): 3443(br), 3292(m), 3055(m), 1601(s), 1578(m), 1499(s),
1456(m), 1286(vs), 1086(m), 787(s), 735(s), 708(s). UV−vis in
CH3CN: 378 nm (ε = 16 000 M−1cm−1). Magnetic moment μeff (298
K): 4.8 μB. 1H NMR (500 MHz, CD3CN, 298 K): δ (ppm) 57.5 (6H)
46.7 (3H), 41.5 (3H), 31.3 (3H), 17.5 (1H), 16.3 (1H), 7.3 (8H), 6.9
(8H), 6.8 (4H), −33.2 (9H).
[(6-Me3-TPA)FeII(5-Me-HAP)](ClO4) (5·ClO4). Yellow solid. Yield:
0.29 g (48%). Anal. Calcd for C28H32ClFeN5O5 (609.88 g/mol): C,
55.14; H, 5.29; N, 11.48. Found: C, 55.17; H, 5.18; N, 11.44%. IR
(KBr, cm−1): 3433(br), 3028(m), 2922(m), 1603(s), 1580(m),
1497(s), 1456(vs), 1302(s), 1157(m), 1120(vs), 1090(vs), 1009(m),
783(m), 627(m). UV−vis in CH3CN: 401 nm (ε = 2200 M−1cm−1).
1
Magnetic moment μeff (298 K): 5.1 μB. H NMR (500 MHz, CDCl3,
298 K): δ (ppm) 51.7 (3H), 43.9 (3H), 10.4 (3H), 7.4 (3H), −26.3
(9H).
[(6-Me3-TPA)FeII(HAP)](ClO4) (2·ClO4). Yellow solid. Yield: 0.31 g
(52%). Anal. Calcd for C27H30ClFeN5O5 (595.86 g/mol): C, 54.42; H,
5.07; N, 11.75. Found: C, 53.99; H, 4.84; N, 11.57%. IR (KBr, cm−1):
3452(br), 3331(m), 1605(s), 1578(m), 1487(s), 1456(s), 1294(s),
1117(vs), 1094(vs), 781(m). UV−vis in CH3CN: 401 nm (ε = 950
[(6-Me3-TPA)FeII(4-tBu-HAP)](ClO4) (6·ClO4). The complex was
synthesized according to the reported procedure.45
[(6-Me3-TPA)FeII(4,6-di-tBu-HAP)](ClO4) (7·ClO4). Yellow solid.
Yield: 0.31 g (44%). Anal. Calcd for C35H46ClFeN5O5 (708.07 g/
mol): C, 59.37; H, 6.55; N, 9.89. Found: C, 59.41; H, 6.58; N, 9.93%.
IR (KBr, cm−1): 3425(m), 2950(s), 2864(m), 1605(s), 1578(m),
1460(s), 1443(m), 1302(m), 1277(m), 1115(vs), 1094(vs), 789(m),
635(m). UV−vis in CH3CN: 405 nm (ε = 2250 M−1cm−1) . Magnetic
moment μeff (298 K): 5.2 μB.
1
M−1cm−1). Magnetic moment μeff (298 K): 5.1 μB. H NMR (500
MHz, CDCl3, 298 K): δ (ppm) 51.9 (6H), 44.0 (3H), 37.3 (3H), 19.6
(3H), 7.4 (4H), −26.4 (9H).
[(6-Me3-TPA)FeII(3-Me-HAP)](BPh4) (3·BPh4). Yellow solid. Yield:
0.63 g (76%). Anal. Calcd for C52H52BFeN5O (829.66 g/mol): C,
75.28; H, 6.32; N, 8.44. Found: C, 75.31; H, 6.40; N, 8.27%. IR (KBr,
cm−1): 3431(br), 3055(m), 2926(m), 1605(s), 1578(s), 1466(vs),
1429(m), 1310(m), 785(m), 735(s), 706(vs). UV−vis in CH3CN: 401
[(6-Me3-TPA)FeII(4,6-di-tBu-HAP)](BPh4) (7·BPh4). Yellow solid.
Yield: 0.62 g (67%). Anal. Calcd for C59H66BFeN5O (927.84 g/
mol): C, 76.37; H, 7.17; N, 7.55. Found: C, 75.97; H, 7.21; N, 7.64%.
IR (KBr, cm−1): 3522(m), 3321(m), 3055(m), 2949(m), 1605(s),
1578(s), 1456(vs), 1302(s), 1277(m), 733(vs), 706(vs), 611(s). UV−
vis in CH3CN: 403 nm (ε = 2300 M−1cm−1). Magnetic moment μeff
1
nm (ε = 1900 M−1cm−1). Magnetic moment μeff (298 K): 4.9 μB. H
NMR (500 MHz, CDCl3, 298 K): δ (ppm) 43.9 (3H), 36.1 (3H), 19.6
(3H), 7.4 (3H), 7.3 (8H), 7.0 (8H), 6.7 (4H), −27.6 (9H).
1
(298 K): 5.2 μB. H NMR (500 MHz, CDCl3, 298 K): δ (ppm) 53.6
[(6-Me3-TPA)FeII(4-Me-HAP)](ClO4) (4·ClO4). Yellow solid. Yield:
0.25 g (41%). Anal. Calcd for C28H32ClFeN5O5 (609.88 g/mol): C,
55.14; H, 5.29; N, 11.48. Found: C, 54.93; H, 5.22; N, 11.70%. IR
(KBr, cm−1): 3431(br), 3311(m), 2924(m), 1603(s), 1574(m),
(6H), 43.7 (3H), 37.3 (3H), 18.4 (3H), 7.4 (2H), 7.3 (8H), 7.0 (8H),
6.7 (4H), −25.9 (9H).
[(6-Me3-TPA)FeIII(4,6-di-tBu-AP)](BPh4) (7Ox·BPh4). Complex 7·
BPh4 (37 mg, 0.04 mmol) was dissolved in dichloromethane (10
C
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mL). To the solution was added KMnO4 (6.3 mg, 0.04 mmol) or
2,4,6-tri-tert-butylphenoxy radical (10.4 mg, 0.04 mmol). The reaction
mixture was stirred for 3 h and filtered to remove the solid particles.
The filtrate was then concentrated to dryness and the residue was
washed thoroughly with diethyl ether for two to three times. The dark
green solid was then isolated by filtration and dried under vacuum.
Yield: 23 mg (62%). Anal. Calcd for C59H65BFeN5O (926.84 g/mol):
C, 76.46; H, 7.07; N, 7.56. Found: C, 76.61; H, 7.13; N, 7.66%. IR
(KBr, cm−1): 3435(br), 3053(m), 2957(s), 1605(s), 1578(s),
1460(vs), 1300(m), 1271(m), 787(m), 735(s), 706(vs), 611(s).
UV−vis in CH3CN: 366 nm (ε = 3000 cm−1 M−1), 618 nm (ε =
1900 cm−1 M−1), and 925 nm (ε = 2700 cm−1 M−1).
Table 1. Crystallographic Data for 5·ClO4 and 7·BPh4·
CH3OH
a
b
5·ClO4
7·BPh4·CH3OH
empirical formula
C28H32ClFeN5O5
609.89
monoclinic
P2(1)/n
17.034(7)
9.392(4)
19.457(11)
90
C60H70BFeN5O2
959.87
formula weight
crystal system
space group
a, Å
monoclinic
P2(1)/c
22.532(3)
10.964(1)
22.470(3)
90.00
b, Å
c, Å
α, deg
Reaction of the Complexes with Dioxygen and Analysis of
Organic Products. In a typical reaction, dry oxygen gas was bubbled
through a solution of iron(II)-aminophenol complex (0.02 mmol) in
dry acetonitrile (10 mL) for 2 min. The solution was kept for stirring
at room temperature under oxygen environment. The yellow solution
immediately turned deep green and then slowly to orange. The solvent
was evaporated to dryness and the residue was treated with 2 M HCl
solution (10 mL) to maintain the pH between 2 and 3. The organic
products were then extracted with diethyl ether (3 × 15 mL), the
combined organic layer was washed with a saturated brine solution,
and dried over anhydrous Na2SO4. After removal of the solvent the
β, deg
114.958(10)
90
108.980(4)
90.00
γ, deg
volume, Å3
2822(2)
4
5249.0(12)
4
Z
D
calcd., Mg/m3
1.435
1.215
μ Mo Kα, mm−1
0.676
0.335
F(000)
1272
2048
θ range, deg
reflections collected
reflns unique
R(int)
1.34−22.03
18 825
3435
0.96−26.00
63 203
1
solid mass was analyzed by H NMR and GC-MS without further
10 244
purification.
0.1519
2260
0.0486
1
To identify the organic products, H NMR spectra were compared
data (I > 2σ(I))
parameters refined
goodness-of-fit on F2
R1 [I > 2σ(I)]
wR2
8781
with that of the commercially available standards (2-picolinic acid) or
previously reported similar compounds (4-tert-butyl-2-picolinic acid
and 4,6-di-tert-butyl-2-pyrone).45,47 Quantification of organic product
365
633
1.079
1.129
0.0736
0.1922
0.0526
1
was performed by H NMR spectroscopy with respect to the sharp
0.1368
singlet resonance at 6.8 ppm for four aromatic protons of p-
benzoquinone standard.
a
b
Also known as [(6-Me3-TPA)FeII(5-Me-HAP)]ClO4. Also known
as [(6-Me3-TPA)FeII(4,6-di-tBu-HAP)](BPh4)·CH3OH.
1H NMR (500 MHz, CDCl3, 298 K): 3-Methyl-2-picolinic acid: δ
(ppm) 8.49 (d, 1H, J = 4 Hz), 7.95 (d, 1H, J = 4 Hz), 7.46 (t, 1H, J = 5
Hz), 2.12 (s, 3H). 4-Methyl-2-picolinic acid: δ (ppm) 8.60 (d, 1H, J =
4 Hz), 7.98 (s, 1H), 7.53 (d, 1H, J = 5 Hz), 1.66 (s, 3H). 5-Methyl-2-
picolinic acid: δ (ppm) 8.57 (s, 1H), 8.04 (d, 1H, J = 6 Hz), 7.64 (d,
1H, J = 5 Hz), 1.67 (s, 3H). 4,6-Di-tert-butyl-2-picolinic acid: δ(ppm)
8.07 (s, 1H), 7.59 (s, 1H), 1.27 (s, 9H), 1.40 (s, 9H). 4,6-Di-tert-
butylpyran-2-imine: δ (ppm) 6.05 (s, 1H), 1.21 (s, 9H), 1.36 (s, 9H).
A control experiment with iron(II) perchlorate hydrate and sodium
2-amino-4,6-di-tert-butylphenolate (0.02 mmol) in acetonitrile sol-
ution under oxygen environment was performed to understand the
role of the ligand and to ensure that no residual aminophenolate was
present in the aqueous part after acidic work-up. After stirring the
reaction mixture for 24 h under oxygen atmosphere, the solution was
evaporated to dryness. The residue was treated with 2 M HCl solution
(10 mL) to maintain the pH in the range of 2−3. The solution was
then extracted with diethyl ether (3 × 15 mL) and the organic layer
density functional B3LYP50−54 along with 6-31G(d) basis functions for
N, C, H, O and effective core potential LANL2 along with LANL2DZ
basis set on Fe atom.55,56 All computations were conducted using the
Gaussian 09 quantum chemistry suite.57 Gas-phase enthalpy and free-
energy values were computed for 1 atmospheric pressure and 298 K
temperature. Using the CPCM solvent model58−60 for acetonitrile,
relative free energy activation barriers were computed with 6-31+G(d,
p) basis sets on N, C, H, O atoms; effective core potential LANL2
along with LANL2DZ on Fe atom are reported in the ensuing
discussion.56,61 For solvent phase free energy changes the solvent
phase entropies of entities were used. The solvent phase entropies
were derived by empirically scaling the corresponding gas phase
entropies with a factor of 0.5.62,63 This is a standard approximation
that has been used in other quantum chemical studies.64−66
1
was dried over anhydrous Na2SO4. Analyses of organic species by H
RESULTS AND DISCUSSION
NMR spectroscopy revealed quantitative isolation of 2-amino-4,6-di-
tert-butylphenol without any C−C bond cleavage.
■
Syntheses and Characterization. Reactions of equimolar
amounts of ligand and iron(II) perchlorate hydrate with
respective 2-aminophenols in the presence of triethylamine
under N2 atmosphere afford the corresponding iron(II)-
aminophenolate complexes (Scheme 4). The complexes are
isolated either as perchlorate or tetraphenylborate salts.
Although the complexes are isolated in good to moderate
yields (75−41%), there is no correlation between the yield of
the complex and the nature of the substituent on the
aminophenolate ring. The isolated yields of the perchlorate
salts are found to be low due to their high solubility in
methanol. The complexes are air-stable in solid state but are
extremely sensitive in solution. IR spectra of the complexes in
solid state exhibit strong band at around 1600 cm−1
characteristic of metal-coordinated monoanionic aminopheno-
lates.45,67 The presence of bands due to counterions
(perchlorate or tetraphenylborate) in the IR spectra suggests
Methyl-4,6-di-tert-butyl-2-picolinate. The organic product, iso-
lated from the reaction solution according to the procedure mentioned
above, was reacted with excess diazomethane in dry diethyl ether (5
mL) at 0 °C. The reaction solution was stirred for 5 min. After
separating the insoluble part, the clear ether layer was analyzed by GC-
MS. 1H NMR (500 MHz, CDCl3, 298 K): δ (ppm) 7.92 (s, 1H), 7.49
(s, 1H), 3.97 (s, 3H), 1.40 (s, 9H), 1.26 (s, 9H).
Crystal Structure Analysis. Diffraction data for 5·ClO4 and 7·
BPh4 were collected on a Bruker Smart APEX II (Mo Kα radiation, λ =
0.710 73 Å). Crystallographic data of the complexes are presented in
Table 1. Cell refinement, indexing and scaling of the data set were
carried out using the APEX2 v2.1−0 software.48 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.49 In all the complexes the hydrogen atoms were fixed. The
non-hydrogen atoms were treated anisotropically.
Density Functional Theory Calculations. All intermediates and
transition-state geometries were optimized in vacuum using the hybrid
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monocationic nature of the complexes. Complex 1·BPh4 in
acetonitrile exhibits an intense absorbance band at 378 nm in
the optical spectrum, whereas other complexes show absorption
band at around 400 nm (Supporting Information, Figures S1
and S2). The complexes exhibit room temperature magnetic
moment values between 4.8 and 5.2 μB. 1H NMR spectra of the
complexes display paramagnetically shifted resonances of the
protons in the region between −40 and 60 ppm (Supporting
Information, Figures S3−S8). A comparison of 1H NMR
spectra of the iron(II) complexes suggests that the broad signal
appeared in the upfield region between −25 ppm and −35 ppm
is attributable to the resonance of α-CH3 protons of 6-Me3-
TPA ligand.68,69 Sharp peaks from the pyridyl protons of 6-
Me3-TPA ligand are observed in the downfield region between
35 and 50 ppm. The methylene protons are too broad to be
observed in the spectra. The aromatic protons of 2-amino-
phenols appear in between 7 and 9 ppm. The 1H NMR spectra
along with the magnetic moment values strongly suggest the
complexes to be mononuclear high-spin iron(II) species.
Complexes 5·ClO4 and 7·BPh4 were further characterized by
single-crystal X-ray diffraction. Single crystals of 5·ClO4 and 7·
BPh4·CH3OH were grown from a solvent mixture of
dichloromethane, methanol and diethyl ether at room temper-
ature.
Table 2. Selected Bond Lengths (Å) and Angles (deg) of 5·
ClO4 and 7·BPh4·CH3OH
bond distance/angles
5·ClO4 (Å/deg)
7·BPh4·CH3OH (Å/deg)
Fe(1)−N(1)
Fe(1)−N(2)
Fe(1)−N(3)
Fe(1)−N(4)
Fe(1)−N(5)
Fe(1)−O(1)
C(22)−O(1)
C(27)−N(5)
C(22)−C(23)
C(23)−C(24)
C(24)−C(25)
C(25)−C(26)
C(26)−C(27)
C(27)−C(22)
O(1)−Fe(1)−N(1)
O(1)−Fe(1)−N(2)
O(1)−Fe(1)−N(3)
O(1)−Fe(1)−N(4)
O(1)−Fe(1)−N(5)
N(1)−Fe(1)−N(2)
N(1)−Fe(1)−N(3)
N(1)−Fe(1)−N(4)
N(1)−Fe(1)−N(5)
N(2)−Fe(1)−N(3)
N(2)−Fe(1)−N(4)
N(2)−Fe(1)−N(5)
N(3)−Fe(1)−N(4)
N(3)−Fe(1)−N(5)
N(4)−Fe(1)−N(5)
2.317(7)
2.210(7)
2.264(7)
2.208(7)
2.299(7)
1.954(5)
1.353(9)
1.442(10)
1.401(11)
1.401(12)
1.352(13)
1.385(13)
1.379(12)
1.397(12)
104.5(2)
170.5(2)
104.1(3)
109.0(2)
78.7(2)
2.281(2)
2.232(2)
2.342(2)
2.225(2)
2.238(2)
1.970(2)
1.335(3)
1.458(3)
1.425(3)
1.398(3)
1.398(4)
1.390(3)
1.385(3)
1.407(3)
105.60(7)
171.56(7)
105.28(7)
108.01(7)
79.99(7)
73.73(7)
148.75(7)
93.84(7)
91.90(7)
75.02(7)
80.41(7)
91.60(7)
81.08(7)
88.81(7)
168.43(7)
75.9(2)
150.7(3)
84.2(2)
The structure of the mononuclear complex cation of 5·ClO4
shows a six-coordinate iron center coordinated by four nitrogen
donors from the N4 ligand and a bidentate monoanionic
aminophenolate (Figure 1). The aminophenolate ring coor-
90.3(2)
74.8(3)
80.4(2)
91.9(2)
92.5(2)
89.1(2)
171.4(2)
butylcatechol) with comparable metal−ligand bond parame-
ters.70 A bidentate binding motif of 2-amino-4,6-di-tert-
butylphenolate (4,6-di-tBu-HAP) (Figure 2), similar to that in
5·ClO4 and 6·BPh4, is observed. The steric interaction between
the tert-butyl group on the aminophenolate ring and the methyl
groups on the pyridine rings of the ligand forces the metal ion
to adopt a distorted octahedral coordination geometry with the
axial N2−Fe1−O1 angle of 171.56(7)° (Table 2). Average C−
C bond distances of 1.386 and 1.400 Å for aminophenol rings
Figure 1. ORTEP plot of the complex cation of 5·ClO4 with 40%
thermal ellipsoid parameters. The counterions and H atoms except
those on N5 were omitted for clarity.
dinates through one phenolate oxygen (O1) and one amine
nitrogen (N5) with the Fe1−O1 and Fe1−N5 distances of
1.954(5) and 2.299(7) Å, respectively (Table 2). The average
Fe1−N distance of the ligand is found to be 2.250(7) Å, similar
to that reported for a related complex [(6-Me3-TPA)FeII(4-tBu-
HAP)](BPh4) (6·BPh4).45 The coordination geometry of the
iron center is distorted octahedron where the axial positions are
occupied by one of the pyridine nitrogens (N4) of the
tetradentate ligand and the amine nitrogen (N5) of amino-
phenolate with the N4−Fe1−N5 angle of 171.4(2)° (Table 2).
The equatorial plane is composed of O1, N1, N2, and N3
donors.
The cationic part of complex 7·BPh4·CH3OH is iso-
structural and iso-electronic with the iron(II)-catecholate
complex, [(6-Me3-TPA)FeII(DBCH)]+ (DBCH2 = 3,5-di-tert-
Figure 2. ORTEP plot of the complex cation of 7·BPh4·CH3OH with
40% thermal ellipsoid parameters. The counterions and H atoms
except those on N5 were omitted for clarity.
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in 5·ClO4 and 7·BPh4, respectively, are consistent with fully
delocalized π bonding in the aromatic rings. In 5·ClO4, the
C22−O1 and C27−N5 distances are found to be 1.353(9) and
1.442(10) Å, respectively, and for 7·BPh4 the distances are
1.335(3) and 1.458(3) Å, respectively (Table 2). In the
complexes, the C−N bonds are typical C−N single bonds and
the C−O distances are typical for organic phenolates.36 The
bond parameters are very similar to those observed in
[(TpPh2)FeII(4,6-di-tBu-HAP)] and [(6-Me3-TPA)FeII(4-tBu-
HAP)](BPh4) (6·BPh4) supporting the coordination of
aminophenolate to the iron center with an anionic phenolate
oxygen and a neutral amine nitrogen.43,45
The crystal structure of the substrate bound APD reveals the
binding of a suicide inhibitor, monoanionic 4-nitrocatechol,
consistent with the crystal structure of homoprotocatechuate
2,3-dioxygenase.26,35 The bidentate binding of monoanionic 2-
aminophenolate to the iron(II) in biomimetic complexes43,45
structurally mimics the enzyme−substrate adduct of 2-amino-
phenol dioxygenases. Although the X-ray diffraction quality
single crystals could not be isolated for 1·BPh4, 2·ClO4, 3·BPh4,
and 4·BPh4 after several attempts, the spectroscopic and
analytical data suggest the cationic part of theses complexes to
be mononuclear with six-coordinate geometry at the iron(II)
center similar to that in 5, 7, and [(6-Me3-TPA)FeII(4-tBu-
HAP)]+ (6).
formation of a relatively sharp band at 360 nm. The EPR signal
changes as the reaction progresses and the final oxidized
solution exhibits a rhombic EPR signals at g = 4.2 along with a
signal at g = 1.99 (Supporting Information, Figure S9).
The 1H NMR spectrum of the organic product derived from
2-aminophenol after acidic work-up of the final oxidized
solution of 2·ClO4 shows proton resonances in between 6 and
8 ppm attributable to aromatic protons (Supporting
Information, Figure S10). The positions of the proton
resonances match well with those of 2-amino-3H-phenoxazin-
3-one.71 In the reaction, about 85% 2-amino-3H-phenoxazin-3-
one was quantified by 1H NMR spectroscopy. The weak signals
1
in the H NMR spectrum may arise from other auto-oxidation
products from 2-aminophenol. EPR and optical spectral data of
the final reaction solution suggest the presence of a mixture of
iron(III) species and 2-aminophenolate derived products. The
C−C bond cleavage product (2-picolinic acid) is not observed
in the reaction (Supporting Information, Figure S10b). The
reaction of an equimolar mixture of iron(II) perchlorate
hydrate and 2-aminophenol affords the same auto-oxidation
product (Supporting Information, Figure S10c). It can
therefore be concluded that the reaction of 2·ClO4 with
dioxygen forms 2-amino-3H-phenoxazin-3-one via an auto-
oxidation pathway (Scheme 5). The formation of 2-amino-3H-
phenoxazin-3-one from 2-aminophenol on iron(II) complex is
reminiscent of the reactions catalyzed by 2-aminophenol
oxidase and tyrosinase.72
Dioxygen Reactivity. All the iron(II)-2-aminophenolate
complexes, except 1·BPh4, are extremely sensitive toward
dioxygen in solution. Exposure of an acetonitrile solution of 2·
ClO4 to dioxygen results in a color change from yellow to deep
green. Over a period of 15 min, the charge transfer (CT) band
at 402 nm disappears, and three new bands at around 365 nm,
560 and 920 nm appear (Figure 3). The new bands, in analogy
Scheme 5. Reaction of [(6-Me3-TPA)FeII(HAP)]+ (2) with
Dioxygen
The reactions of complexes 3·BPh4, 4·BPh4, and 5·ClO4 with
dioxygen, on the contrary, involve three consecutive steps. In
the first step, the yellow solutions of the complexes turn dark
green immediately upon exposure to dioxygen. For [(6-Me3-
TPA)FeII(3-Me-HAP)](BPh4) (3·BPh4), the charge transfer
band at around 401 nm disappears with the formation of two
intense bands at around 620 and 935 nm within 5 min (Figure
4a). X-band EPR spectrum of the green solution exhibits a
signal at g = 4.2 supports the formation of a rhombic iron(III)
species in the first step (Supporting Information, Figure S11).
A molecular ion peak at m/z = 509.21 with the isotope
distribution pattern calculated for [(6-Me3-TPA)Fe(3-Me-AP]+
is observed in the ESI-mass spectrum of the green solution
(Figure 5a). The first step thus involves the generation of an
iron(III)-2-amidophenolate species.
Further exposure of the dark green solution to dioxygen
leads to a faint green solution. During the time period of 12
min, the sharp band at 935 nm disappears with concomitant
formation of a distinct absorption band at 645 nm (Figure 4b).
During the reaction a signal is appeared at g = 8.4 in the EPR
spectrum (Supporting Information, Figure S11). The band at
645 nm then slowly decays to form a light orange solution over
a period of 16 h (Figure 4c). The final reaction solution
Figure 3. Time-dependent optical spectral changes during the reaction
of 2·ClO4 with dioxygen at 298 K (concentration: 0.5 mM in
acetonitrile).
to the that observed in the reaction of [(6-Me3-TPA)FeII(4-tBu-
HAP)](ClO4) (6·ClO4) with dioxygen, are assigned to the 2-
amidophenolate-to-iron(III) charge-transfer.45,67 The solution
exhibits a molecular ion peak at m/z = 494.03 with the isotope
distribution pattern calculated for [(6-Me3-TPA)Fe(AP)]+. The
spectral data of the reaction solution after 15 min thus support
the formation of an iron(III)-2-amidophenolate species, [(6-
Me3-TPA)FeIII(AP)](ClO4). Further exposure of the green
solution to dioxygen slowly yields an orange solution during
which time the 920 nm band diminishes with concomitant
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Figure 4. Optical spectral changes with time during the reaction of 3·BPh4 (0.5 mM in acetonitrile) with dioxygen at 298 K for (a) initial 5 min, (b)
for the next 12 min, and (c) for the next 16 h.
appear almost at the same positions, the multiplicity and the
peak area of the proton resonances strongly support the
formation of 5-methyl-2-picolinic acid from 5·ClO4 (Figure 6),
3-methyl-2-picolinic acid from 3·BPh4 and 4-methyl-2-picolinic
acid from 4·BPh4 (Supporting Information, Figure S15 and
Scheme 6). In all the cases, no unreacted aminophenol is
observed at the end of the reaction. The methyl substituted
Figure 5. ESI-mass spectra of the species formed (a) after 5 min and
(b) at the end of the reaction of 3·BPh4 with dioxygen at 298 K. The
bar plots represent the simulated isotopic distribution pattern for (a)
[(6-Me3-TPA)Fe(3-Me-AP]+ and (b) [(6-Me3-TPA)Fe(3-Me-2-pico-
linate)]+.
displays a rhombic signal at g = 4.2 along with a weak signal at g
= 1.99 in the EPR spectrum (Supporting Information, Figure
S11). Similar changes in the optical and EPR spectra are
observed for complexes 4·BPh4 and 5·ClO4 (Supporting
Information, Figures S12, S13a, S14a, S13b, and S14b) The
ESI−mass spectrum of the final oxidized solution of 3·BPh4
show ion peak at m/z = 524.28 with the isotope distribution
calculated for [(6-Me3-TPA)Fe(3-Me-2-picolinate)]+ (Figure
5b). Final oxidized solutions of 4·BPh4 and 5·ClO4 also display
similar ESI-mass spectra.
1H NMR spectra of organic products obtained from the final
oxidized solutions of the iron(II) complexes of methyl
substituted aminophenolates display three proton resonances
in the aromatic region between 7.5 and 8.6 ppm along with one
sharp singlet at around 2.25 ppm (see Experimental Section).
Although the peaks from organic products in all three cases
Figure 6. 1H NMR spectra (500 MHz, 295 K, CDCl3) of (a) 2-amino-
5-methylphenol and (b) the organic product obtained from the
oxidized solution of 5·ClO4. The peaks marked as * represent the
fragments from the 6-Me3-TPA ligand, and the peak marked as # is the
residual CHCl3 in CDCl3.
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Scheme 6. Reaction of the Iron(II)-2-aminophenolate
Complexes with Dioxygen and the C−C Cleavage Products
Figure 8. X-band EPR spectral changes with time during the reaction
of 7·BPh4 with dioxygen in acetonitrile. (Experimental conditions:
temperature = 77 K, microwave frequency = 9.10 GHz, microwave
power = 0.998 mW, modulation amplitude = 100 kHz, modulation
width = 1 mT, time constant = 0.03 s).
aminophenolates are quantitatively converted to the corre-
sponding 2-picolinic acids.
On the contrary, the spectral change during the reaction of 7·
BPh4 with oxygen is completely different than that observed
with other complexes discussed above. In the reaction, the CT
band at 402 nm decays and two new bands at 520 and 665 nm
are formed over a period of 10 min in acetonitrile at 298 K
(Figure 7a). The ESI-mass spectrum of the solution exhibits a
molecular ion peak at m/z = 565.23 with the isotopic
distribution calculated for [(6-Me3-TPA)Fe(4,6-di-tBu-AP)]+.
The green solution displays a rhombic EPR signal at g = 4.2
typical of a high-spin iron(III) species. Additionally a sharp
signal at g = 1.99 is observed possibly due to the presence of a
ligand-based radical species in solution (Figure 8). The
intensity of the EPR signal at g = 1.99 slowly diminishes as
the reaction proceeds. After 10 min, the CT bands at 520 and
665 nm slowly decay over a period of 22 h (Figure 7b).
Although the final oxidized complex could not be analyzed by
ESI-MS, the X-band EPR spectrum suggests the formation of a
high-spin iron(III) species (Figure 8).
Figure 9. 1H NMR spectrum (500 MHz, 295 K, CDCl3) of the
organic products obtained from the final oxidized solution of 7·ClO4
after removal of the metal ion. The peak marked as # is the residual
CHCl3 in CDCl3.
The organic products from the oxidized solution of 7·ClO4
were isolated by acidic work-up and subsequent extraction with
1
1
diethyl ether for analysis by H NMR and GC-MS. The H
NMR spectrum of organic products shows three sharp singlets
at 8.07, 7.59, and 6.05 ppm (Figure 9). The sharp signals
observed in the range of 1.44−1.16 ppm represent the aliphatic
protons of the tert-butyl groups. The absence of aromatic
protons at 6.81 and 6.91 ppm strongly suggests that no
unreacted 4,6-di-tBu-HAP is present in the oxidized solution.
The protons of 4,6-di-tert-butyl-2H-pyran-2-one, an extradiol
cleavage product from 3,5-di-tert-butylcatechol, exhibit a singlet
resonance at 6.05 ppm in the 1H NMR spectrum. These results
unambiguously support the formation of 4,6-di-tert-butyl-2H-
pyran-2-imine via oxidative C−C cleavage of 4,6-di-tBu-HAP.
Figure 7. Optical spectral changes during the reaction of 7·BPh4 (0.5 mM solution in acetonitrile) with dioxygen at 298 K (a) over a time period of
10 min and (b) over the next 22 h.
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1
Comparing the H NMR spectrum of 4-tert-butylpicolinic acid
place. The ESI-mass spectrum also supports the incorporation
of one oxygen atom into each organic product derived from
4,6-di-tBu-HAP (Supporting Information, Figure S18). Mixed
labeling experiment with 16O2 and H218O shows the
incorporation of one oxygen atom from water into picolinic
acid (Supporting Information, Figure S19).
To understand the pathway for the reaction of 7·BPh4 with
oxygen, controlled one-electron chemical oxidation of 7·BPh4
using a stoichiometric amount of KMnO4 was carried out under
nitrogen environment to isolate 7Ox·BPh4. Unfortunately, all
attempts to isolate single crystals of 7Ox·BPh4 failed. The
acetonitrile solution of 7Ox·BPh4 is dark green in color and
exhibits sharp bands at 366 nm (ε = 3000 cm−1 M−1), 618 nm
(ε = 1900 cm−1 M−1) and 925 nm (ε = 2700 cm−1 M−1) under
nitrogen environment (Figure 11). Three prominent signals at
derived from 4-tBu-HAP,45 the sharp singlets at 8.07 and 7.59
ppm are assigned to the aromatic protons of 4,6-di-tert-
butylpicolinic acid (Scheme 6). The organic products, 4,6-di-
tert-butyl-2H-pyran-2-imine (35%) and 4,6-di-tert-butyl-2-pico-
linic acid (65%), are quantified by calculating the relative ratio
of the aromatic protons. For further confirmation, the organic
products obtained from the oxidized solution of 7·ClO4 were
treated with a freshly prepared diazomethane solution. In
addition to sharp peaks between 1.12 and 1.51 ppm, four
singlet resonances at 7.92, 7.49, 6.05, and 4.00 ppm are
observed in the 1H NMR spectrum confirming the formation of
methyl-4,6-di-tert-butyl-2-picolinate and 4,6-di-tert-butyl-2H-
pyran-2-imine in the reaction (Supporting Information, Figure
S16). GC-MS analysis of the organic products after
esterification shows two distinct ion peaks at m/z = 208 and
249 with the expected fragmentation patterns of 4,6-di-tert-
butyl-2H-pyran-2-one and methyl-4,6-di-tert-butyl-2-picolinate
(Figure 10a,b). The imine product gets hydrolyzed during
Figure 11. Optical spectra of 7Ox·BPh4 (0.5 mM in acetonitrile) under
nitrogen atmosphere (bold line) and after exposure to dioxygen (dash
dot line).
around g = 8.6, 5.07, and 3.71 are observed in the EPR
spectrum at 77K describing an S = 5/2 spin system in solution
(Supporting Information, Figure S20). Therefore, the con-
trolled chemical oxidation of 7·BPh4 leads to the formation of
an iron(III) species [(6-Me3-TPA)FeIII(4,6-di-tBu-AP)](BPh4)
(7Ox·BPh4). An instantaneous decay of the band at 925 nm
followed by a concomitant shift of the band at 618 to 665 nm is
observed upon exposure of an acetonitrile solution of 7Ox·BPh4
to dioxygen (Figure 11).
Complex 6·ClO4 has been reported to react with dioxygen
over a period of 6 h yielding 4-tert-butyl-2-picolinic acid as the
only product (Scheme 6). Labeling experiment with 18O2
supports the incorporation of one 18O atom into 4-tert-butyl-
2-picolinic acid. Additionally, a mixed labeling experiment with
16O2 and H218O exhibits about 30% incorporation of one
oxygen atom from water into picolinic acid.45 At room
temperature, 6·ClO4 reacts with dioxygen to form a species
which exhibits three bands at 366 nm, 600 and 934 nm. The
corresponding iron(III) species (6Ox) prepared by oxidation
with KMnO4 shows similar spectral features.45 On the contrary,
when the reaction of an acetonitrile solution of 6·ClO4 with
dioxygen is carried out at 248 K (Figure 12), the optical
spectral changes closely match with those observed in the
reaction of 7·BPh4 with O2 at room temperature. The X-band
EPR spectrum of the species obtained from 6·ClO4 at 248 K
Figure 10. GC-mass spectra of organic products obtained after
removal of metal ion and subsequent treatment of a freshly prepared
diazomethane after reaction of 7·ClO4 with 16O2 (a, b) and with 18O2
(c, d).
acidic work-up to form 4,6-di-tert-butyl-2H-pyran-2-one. The
ESI-mass spectrum also supports the formation of these two
products (Supporting Information, Figure S17). It is important
to mention here that the iron(II)-catecholate complex, [(6-
Me3-TPA)FeII(DBCH)]+, of the same ligand yields only
intradiol cleavage products, 3,5-di-tert-butyl-1-oxacyclohepta-
3,5-diene-2,7-dione (53%) and 3,5-di-tert-butyl-5-(carboxy-
methyl)-2-furanone (36%).70
The reaction of 7·ClO4 with 18O2 was carried out to establish
the source of oxygen atoms into the cleavage products. The
organic phase was treated with diazomethane and was analyzed
by GC-MS. The ion peaks are shifted two mass unit higher for
4,6-di-tert-butyl-2H-pyran-2-one and methyl-4,6-di-tert-butyl-2-
picolinate. The isotope distribution patterns for 4,6-di-tert-
butyl-2H-pyran-2-one and methyl-4,6-di-tert-butyl-2-picolinate
observed in the spectra (Figure 10c,d) support the incorpo-
ration of one 18O atom into each product. While 80%
incorporation of labeled oxygen into pyrone is observed, only
40% incorporation of one oxygen atom into picolinate takes
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Scheme 7. Proposed Mechanism for the Formation of
Iron(II)-2-iminobenzosemiquinonate Species
Figure 12. Change in optical spectra during the reaction of 6·ClO4
(0.5 mM in acetonitrile) with dioxygen at 248 K. (inset) X-band EPR
spectrum of the green species at 77 K.
Density Functinal Theory Calculations. DFT calculations
were conducted on [(6-Me3-TPA)FeIII(4-tBu-HAP)]+ (6Ox) to
unravel the probable reaction pathways of regioselective C−C
bond cleavage of 2-aminophenols. As observed experimentally,
an iron(II)-2-aminophenolate complex (A) reacts rapidly with
dioxygen to form an iron(III)-2-amidophenolate (B) via an
outer sphere one-electron oxidation process. The plausible
pathway for the formation of iron(III)-peroxo species from a
six-coordinate iron(III)-2-amidophenolate (B) was investigated
(Figure 13). The free-energy difference between the sextet and
shows a weak rhombic signal at g = 4.2 and an isotropic signal
at g = 1.99 (Figure 12).
In the oxidative C−C bond cleavage pathway, the iron
complexes of alkyl substituted aminophenolates form inter-
mediate species that display broad absorption features between
450 and 700 nm. Similar spectral features have been reported
for M-iminobenzosemiquinonate (M-ISQ) complexes (M =
Co(III), Ni(II), Cu(II), Fe(II), and Fe(III))37,41,43,44,67,73 and
for a structurally characterized 4,6-di-tert-butyl-2-tert-butylimi-
nosemiquinone species.74 In analogy to the spectra reported for
M-ISQ complexes, the absorption features may be attributed to
the intraligand transitions of ISQ radical. Therefore, formation
of iron(II)-2-iminobenzosemiquinonate intermediate ([(L)-
FeII(ISQ)]+) is proposed in the reaction of iron-amino-
phenolate complexes with dioxygen. The EPR spectra
exhibiting isotropic signal at g = 1.99 support the formation
of ISQ radical species. For 7·BPh4, the [(L)FeII(ISQ)]+ species
is formed directly from the iron(II)-aminophenolate complex
via ligand-centered oxidation. Two tert-butyl groups on the
aminophenolate ring in 7·BPh4 stabilize the resulting ISQ
radical to be observed at room temperature. Whereas, in
complex 6·ClO4, one tert-butyl group present on the amino-
phenolate ring cannot stabilize the corresponding ISQ radical
to be observed at 298 K, but the formation of the iron(II)-ISQ
species is observed at low temperature. In both the cases,
however, a small amount of iron(III)-amidophenolate species is
also formed initially which subsequently converts to the radical
intermediate.
Figure 13. Free-energy profile of the reaction of 6Ox with dioxygen on
quartet surface. Corresponding relative ΔH values are provided in the
parentheses.
quartet spin state of B is predicted to be 11.1 kcal/mol, where
the former is more stable with Fe−Namide and Fe−Ophenolate
distances of 2.156 and 1.991 Å, respectively. In fact the ground
electronic state of B is the sextet electronic state. However, B
being a six-coordinate iron center, dioxygen activation at the
metal center is not favored. In analogy to the mechanism
proposed for the oxidative decarboxylation of a six-coordinate
iron(II)-α-hydroxy acid complex [(6-Me3-TPA)-
FeII(mandelate)](BPh4) reported by Paine et al., it can be
suggested that the dissociation of one of the pyridyl arms from
the metal center results in a five-coordinate iron(III)-2-
phenolate (C) species providing a vacant site on the metal
for dioxygen activation to form an iron(III)-peroxo species
(D).69 Dissociation of the iron imide bond could also be
another possibility for the formation of the iron(III)-peroxo
species. Optimization of the iron(III)-peroxo species was
For all other cases, [(L)FeII(ISQ)]+ species is formed in the
reaction of [(L)FeII(HAP)]+ with dioxygen via [(L)FeIII(AP)]+
species. Generation of a species with absorption bands at 520
and 665 nm upon exposure of the iron(III)-imidophenolate
complex 7Ox·BPh4 to dioxygen supports this proposal.
Dioxygen is probably involved in controlling the formation of
radical intermediate from [(L)FeIII(AP)]+ species. It is
conjectured that [(L)FeIII(AP)]+ reacts with dioxygen to
form iron(III)-iminobenzosemiquinonate species ([(L)-
FeIII(ISQ)]2+) and superoxide radical anion (Scheme 7). The
resulting superoxide radical anion again participates in the
reduction of [(L)FeIII(ISQ)]2+ to generate [(L)FeII(ISQ)]+
species via outer-sphere mechanism.75 The radical intermediate
further activates dioxygen to exhibit the C−C bond cleavage
reactivity.
J
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performed considering both the possibilities. However,
calculations suggest that there exists a stable intermediate
after dissociation of one pyridyl arm in sextet spin state of the
metal complex, but no minima could be located for iron-imide
bond dissociation. This result strongly indicates that the initial
oxygen activation by B involves opening of a pyridyl arm from
the metal center. The ground electronic state of C, a five-
coordinate complex formed by the dissociation of the pyridyl
ligand arm is predicted to be the sextet spin state. C is 4.8 kcal/
mol higher in free energy compared to B for the sextet spin
state of the metal complex. Of note, the dissociation of a pyridyl
arm for the iron(II) complex is predicted to be more
endothermic and the separation between the six-coordinate
iron(II) complex and the five-coordinate iron(II) complex is
estimated to be 7.98 kcal/mol (Supporting Information, Figure
S21). The reaction of C with dioxygen proceeds on a quartet
surface that results from electron pairing of the triplet dioxygen
which has two unpaired electrons interacting with two opposite
spin electrons out of the five unpaired electrons of the sextet
spin metal complex (Supporting Information, Figure S22). As
reported earlier by Georgiev and co-workers the peroxo species
is formed on a quartet surface.76 The highest occupied singly
occupied molecular orbital (SOMO), which has significant
contributions from orbitals of the aminophenolate ligand in the
metal complex, indicates that dioxygen is activated by
([(L)FeII(ISQ)]+ (C′). So in this case, dioxygen is activated
by both the substrate and the metal center. The substantial
mixing of the metal-substrate orbitals in the SOMO precludes
the formation of a metal ligated superoxo species in these
calculations. The resulting quartet iron(III)-peroxo species (D)
lies 26.2 kcal/mol above with respect to the reactants. In the
optimized geometry of the peroxo species (D) the Fe−O, O−
O, and C−O distances are found to be 1.796, 1.448, and 1.448
Å, respectively (Supporting Information, Figure S23). The
homolytic cleavage of O−O bond of the peroxo species (D) on
the quartet surface was studied. The free-energy activation
barrier involved in this process is a staggering 41.9 kcal/mol. A
large O−O dissociation energy on the quartet state indicates
that the C−C bond cleavage does not take place via homolytic
O−O bond dissociation route.
It was suggested earlier that the loss of a proton occurs
during the formation of iron(III)-2-amidophenolate (B) from
the corresponding iron(II)-2-aminophenolate complex. This
proton plays a crucial role in the O−O bond cleavage step. A
protonated peroxo species may form in the reaction pathway as
a reactive intermediate. The role of proton in the regioselective
C−C bond cleavage of catechol has recently been implicated.77
The solvent acetonitrile is not a good proton acceptor.
However, like any other solvents it is likely to contain trace
amounts of water. The highly polar water molecules are
expected to cluster around the charged ionic species in
acetonitrile medium. Water molecules can accept protons and
release those protons to facilitate reactions. To mimic such a
condition a H3O+ was included in the computational model,
which takes into account the lost proton in the first oxidation
step of conversion of A to B. It was found that a hyrdronium
can act as a proton source and can protonate one of the peroxo
oxygens favorably in E. Optimized structure of E on the quartet
surface shows that the hydroperoxide group ligated to the
iron(III) center is positioned axially with respect to the
amidophenolate ring (Figure 14). In such geometry, the O−O
bond is aligned antiperiplanar with the C1−C6 bond, which is
an essential requirement for obtaining selective cleavage
Figure 14. Transition-state geometry of the protonated peroxo species
in quartet state.
product.20 The heterolytic O−O bond dissociation free-energy
barrier of the protonated peroxo species (E) to form C−C
cleaved product (F) was calculated. The required free-energy
activation barrier for O−O bond cleavage is 21.7 kcal/mol on
the quartet surface, which indicates that the reaction pathway is
feasible under the aforementioned experimental conditions.
Formation of the C−C cleavage product, a seven member
lactone ring, is highly exoergic (calculated 53.7 kcal/mol) in
nature. Computational studies reveal that one of the pyridine
rings cis to the aminophenolate ring gets dissociated from the
coordination site for dioxygen activation and a proton is
essential to trigger the heterolytic O−O bond cleavage. The
antiperiplanar arrangement of C1−C6 bond with the O−O
bond of protonated-peroxide results in selective C−C bond
cleavage product.
The presence of an electron withdrawing nitro group at the
4-position on the aminophenolate ring in 1 makes it unreactive
toward dioxygen. Two-electron oxidation of 2-aminophenol to
iminoquinone followed by coupling with another molecule of
2-aminophenol is observed in the reaction of 2 resulting in
phenoxazinone product. However, incorporation of electron
donating groups such as methyl (3-Me-HAP; 3/4-Me-HAP; 4/
5-Me-HAP; 5), tert-butyl (4-tBu-HAP; 6 and 4,6-di-tBu-HAP;
7) results in oxygenolytic aromatic ring cleavage reaction
(Scheme 6). It is expected that other electron-withdrawing
group such as CN would make the iron(II) complex inert
toward dioxygen. A more strongly electron donating sub-
stituent such as OMe is expected to show faster C−C bond
cleavage reactivity. The substitutions on the aminophenolate
ring control the stability of the O2-activating iron(II)-2-
iminobenzosemiquinonate species. The intermediate gets
stabilized by two tert-butyl groups on the aminophenolate
ring and as a result complex 7 exhibits slow reactivity compared
to complex 6 (22 h for 7 vs 6 h for 6). Total time required for
the reaction of iron(II) complexes of methyl substituted
aminophenolates depends on the position of methyl group on
the aromatic ring. While complex 4 requires about 1 h 50 min,
complexes 3 and 5 take about 16.5 and 8.5 h, respectively.
Although the iron(II)-2-iminobenzosemiquinonate species
could not be isolated, a mechanism is proposed on the basis of
experimental results and theoretical calculations (Scheme 8).
The iron(II)-2-aminophenolate complex (A) initially reacts
with oxygen to form an iron(III)-2-amidophenolate (B) species
as depicted for the reported iron(II)-catecholate and iron(II)-
aminophenol complexes.47,67,70 Dissociation of one of the
pyridyl arms from the metal center of B results in a five-
coordinate iron(III)-2-amidophenolate (C). The redox isomer
of C, an iron(II)-2-iminobenzosemiquinonate species (C′) then
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Scheme 8. Proposed Mechanism for the Aromatic C−C Bond Cleavage of 2-Aminophenols on Biomimetic Iron Complex
reacts further with oxygen to form iron(III)-peroxide (D).
Theoretical studies with the extradiol catechol dioxygenases
suggest that initially oxygen activation occurs at the metal
center followed by an attack of iron(III)-superoxide to the
substrate to form a peroxo intermediate.78 The protonation of
iron(III)-peroxide (D) species preferably at the oxygen
attached to the metal center results in a protonated peroxo
species E. Heterolytic O−O bond cleavage of the protonated
peroxo species (E) through alkenyl migration leads to the
formation of a lactone intermediate (F). Muconic acid
semialdehyde is formed via hydrolysis of the lactone species
by the metal-coordinated hydroxide. A subsequent rearrange-
ment followed by loss of a water molecule forms picolinic acid.
Loss of a CO molecule from the lactone yields pyranimine
product observed for 7.
of the coordinated 2-aminophenolates. 18O2 labeling experi-
ments clearly demonstrate the incorporation of one oxygen
atom from molecular oxygen into the cleavage products. The
oxidative transformation of substituted 2-aminophenols to the
corresponding picolinic acids on an iron(II) complex in a single
step using molecular oxygen functionally mimic the activity of
2-aminophenol dioxygenases. Experimental results and DFT
calculations indicate the involvement of an iron(II)-2-
iminobenzosemiquinonate species in the reaction pathway.
The results described herein show the influence of substituent
on the C−C bond cleavage of aminophenols. This mechanistic
information would provide useful insight into the development
of catalytic functional models of 2-aminophenol dioxygenases.
ASSOCIATED CONTENT
■
S
* Supporting Information
CONCLUSION
Crystallographic data in CIF format, electronic spectra, ESI-
mass spectra, GC-mass spectra, EPR spectra, NMR spectra, and
DFT-optimized geometries. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
We isolated and characterized a series of iron(II)-2-amino-
phenolate complexes supported by a tripodal N4 ligand. The
diverse substitution on aminophenolate ring offers different
electronic environment of the corresponding iron(II) com-
plexes. X-ray crystal structures reveal six-coordinate iron(II)
center in the cationic complexes with bidentate binding of the
monoanionic aminophenolates. The iron(II)-4-nitroaminophe-
nolate complex is unreactive toward dioxygen which bears
resemblance to 4-nitrocatechol, the suicide inhibitor of 2-
aminophenol dioxygenases and catechol dioxygenases. The
iron(II)-2-aminophenolate complex reacts with dioxygen to
form 2-amino-3H-phenoxazin-3-one and the reactivity pattern
is similar to that of aminophenol oxidase or tyrosinase. The C−
C cleavage product, 2-picolinic acid is observed in the reaction
of alkyl substituted aminophenolate complexes with molecular
oxygen. On the other hand, the reaction of iron(II)-2-amino-
4,6-di-tert-butylphenolate complex with oxygen results in a
mixture of 4,6-di-tert-butyl-2H-pyran-2-imine and 4,6-di-tert-
butyl-2-picolinic acid. The products are found to be
regioselective and are resulted from the C1−C6 bond cleavage
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ictkp@iacs.res.in. Fax: +91-33-2473-2805. Phone:
+91-33-2473-4971.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Department of Science and
Technology (DST), Government of India (Project SR/S1/IC-
51/2010), and the Indian National Science Academy (Project
for INSA Young Scientist Awardee) for financial support. 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 Cultivation of
L
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(37) Chun, H.; Bill, E.; Bothe, E.; Weyhermuller, T.; Wieghardt, K.
Inorg. Chem. 2002, 41, 5091.
(38) Chun, H.; Verani, C. N.; Chaudhuri, P.; Bothe, E.; Bill, E.;
̈
Science. B.C. and S.B. acknowledge the Council of Scientific
and Industrial Research (CSIR), India, for research fellowships.
Weyhermuller, T.; Wieghardt, K. Inorg. Chem. 2001, 40, 4157.
̈
DEDICATION
■
(39) Chun, H.; Weyhermuller, T.; Bill, E.; Wieghardt, K. Angew.
̈
§Dedicated to Professor Phalguni Chaudhuri on the occasion of
his 70th birthday.
Chem., Int. Ed. 2001, 40, 2489.
(40) Chun, H.; Bill, E.; Weyhermuller, T.; Wieghardt, K. Inorg. Chem.
̈
2003, 42, 5612.
(41) Min, K. S.; Weyhermuller, T.; Wieghardt, K. Dalton Trans. 2003,
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