Iron-promoted ortho-And/or ipso-hydroxylation of benzoic acids with H 2O2

Article abstract of DOI:10.1002/chem.200901296

Regioselective hydroxylation of aromatic acids with hydrogen peroxide proceeds readily in the presence of iron(II) complexes with tetradentate aminopyridine ligands [Fe^II(BPMEN)-(CH₃CN) ₂](ClO₄)₂ (1) and [Fe^II(TPA)- (CH₃CN)₂](OTf)₂ (2), where BPMEN=N, N'-dimethyl-N, N'-bis(2-pyridylmethyl)-1,2-ethylenediamine, TPA=tris-(2- pyridylmethyl)amine. Two cis-sites, which are occupied by labile acetonitrile molecules in 1 and 2, are available for coordination of H₂O ₂ and substituted benzoic acids. The hydroxylation of the aromatic ring occurs exclusively in the vicinity of the anchoring carboxylate functional group: ortho-hydroxylation affords salicylates, whereas ipso-hydroxylation with concomitant decarboxylation yields phenolates. The outcome of the substituent directed hydroxylation depends on the electronic properties and the position of substituents in the molecules of substrates:3-substituted benzoic acids are preferentially ortho-hydroxylated, whereas 2-and, to a lesser extent, 4-substituted substrates tend to undergo ipso-hydroxylation/decarboxylation. These two pathways are not mutually exclusive and likely proceed via a common intermediate. Electron-withdrawing substituents on the aromatic ring of the carboxylic acids disfavor hydroxylation, indicating an electrophilic nature for the active oxidant. Complexes 1 and 2 exhibit similar reactivity patterns, but 1 generates a more powerful oxidant than 2. Spectroscopic and labeling studies exclude acylperoxoiron(III) and Fe^IV=O species as potential reaction intermediates, but strongly indicate the involvement of an Fe^III-OOH intermediate that undergoes intramolecular acid-promoted heterolytic O-O bond cleavage, producing a transient iron(V) oxidant.

Full text of DOI:10.1002/chem.200901296

FULL PAPER
DOI: 10.1002/chem.200901296
Iron-Promoted ortho- and/or ipso-Hydroxylation of Benzoic Acids with H2O2
Olga V. Makhlynets,[a] Parthapratim Das,[b] Sonia Taktak,[a] Margaret Flook,[a]
Rubꢀn Mas-Ballestꢀ,[b] Elena V. Rybak-Akimova,*[a] and Lawrence Que, Jr.*[b]
Abstract: Regioselective hydroxylation
of aromatic acids with hydrogen perox-
ide proceeds readily in the presence of
iron(II) complexes with tetradentate
whereas ipso-hydroxylation with con-
comitant decarboxylation yields pheno-
lates. The outcome of the substituent-
directed hydroxylation depends on the
electronic properties and the position
of substituents in the molecules of sub-
strates: 3-substituted benzoic acids are
common intermediate. Electron-with-
drawing substituents on the aromatic
ring of the carboxylic acids disfavor hy-
droxylation, indicating an electrophilic
nature for the active oxidant. Com-
plexes 1 and 2 exhibit similar reactivity
patterns, but 1 generates a more power-
ful oxidant than 2. Spectroscopic
aminopyridine ligands [FeII
(CH3CN)2]
(ClO4)2 (1) and [FeII
(CH3CN)2](OTf)2 (2),
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
BPMEN=N,N’-dimethyl-N,N’-bis(2-
pyridylmethyl)-1,2-ethylenediamine,
TPA=tris-(2-pyridylmethyl)amine.
preferentially
ortho-hydroxylated,
whereas 2- and, to a lesser extent, 4-
substituted substrates tend to undergo
ipso-hydroxylation/decarboxylation.
These two pathways are not mutually
and
labeling
studies
exclude
acylperoxoiron
AHCTUNGTRENNUNG
Two cis-sites, which are occupied by
labile acetonitrile molecules in 1 and 2,
are available for coordination of H2O2
and substituted benzoic acids. The hy-
droxylation of the aromatic ring occurs
exclusively in the vicinity of the an-
choring carboxylate functional group:
ortho-hydroxylation affords salicylates,
as potential reaction intermediates, but
strongly indicate the involvement of an
FeIII OOH intermediate that under-
À
exclusive and likely proceed via
a
goes intramolecular acid-promoted het-
À
erolytic O O bond cleavage, producing
Keywords: aromatic hydroxylation ·
hydrogen peroxide · iron · oxida-
tion · regioselective hydroxylation
a transient iron(V) oxidant.
Introduction
families, highly regioselective hydroxylations are accom-
plished by properly orienting the aromatic rings with respect
to the metal active sites in the enzyme pockets. Strong evi-
dence has been obtained for the involvement of high-valent
iron–oxo species[10–12] that carry out electrophilic attack of
the target aromatic rings.[13–15] Despite significant recent
progress in understanding the mechanisms of enzymatic aro-
matic hydroxylations, a detailed mechanistic picture has yet
to be developed for these reactions.
In nature, aromatic hydroxylations are catalyzed by mono-
nuclear non-heme iron centers in pterin-dependent aromatic
amino acid hydroxylases,[1–5] and non-heme diiron centers in
bacterial multicomponent monooxygenases (BMMs) such as
methane and toluene monooxygenases.[6–9] In both enzyme
[a] O. V. Makhlynets, Dr. S. Taktak, M. Flook,
Prof. Dr. E. V. Rybak-Akimova
Synthetically, aromatic hydroxylations involving cheap,
environment-friendly catalysts and oxidants (such as iron
compounds and hydrogen peroxide) are very attractive for
the late-stage oxidative derivatization and for metabolite
preparation. Iron-catalyzed arene hydroxylations have been
reported with Fentonꢀs reagent (Fe salt/H2O2) and related
systems.[16–18] Most of these reactions generate hydroxyl radi-
cals,[19–21] but metal-based oxidants were also proposed in
some cases.[22–27] While these reactions are undoubtedly
useful, they are often non-selective, yielding isomers of aro-
matic hydroxylation compounds as well as products of side
chain oxidation.
Department of Chemistry, Tufts University
62 Talbot Ave., Medford, MA 02155 (USA)
Fax : (+1)617-627-3443
E-mail: erybakak@tufts.edu
[b] P. Das, Dr. R. Mas-Ballestꢁ, Prof. Dr. L. Que, Jr.
Department of Chemistry and Center for Metals in Biocatalysis
University of Minnesota
207 Pleasant St. SE, Minneapolis, MN 55455 (USA)
Fax : (+1)612-624-7029
E-mail: larryque@umn.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901296.
Chem. Eur. J. 2009, 15, 13171 – 13180
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
13171

Recently, efficient and selective intramolecular aromatic
hydroxylations were reported with mononuclear[28,29] or di-
nuclear[30–34] iron complexes in which the aromatic ring is
forced into close proximity of the iron center by a covalent
linkage to the supporting polydentate ligand. The need to
independently prepare the compounds containing both reac-
tive iron center and the aromatic substrate, however, limits
the applicability of these systems. Finding new selective in-
termolecular aromatic hydroxylation reactions remains an
important challenge.
of substituted benzoic acids with H2O2 to generate salicylate
products. Furthermore, a new reaction pathway has been
found wherein the benzoic acid is hydroxylated at the ipso
position with concomitant decarboxylation. A mechanistic
scheme is proposed that invokes a common oxidant despite
the divergent outcomes.
Results and Discussion
Orienting aromatic rings in close proximity to the metal
center can be accomplished by coordinating aromatic sub-
strates, via an anchoring group, to a vacant or labile site at
the redox-active iron complex with a polydentate ligand. In
one example of this strategy, phenols pre-bound to the iron
center were hydroxylated selectively into the corresponding
catecholato complexes.[35] We and others recently communi-
cated additional examples of selective inner-sphere aromatic
hydroxylation at non-heme iron centers: ortho-hydroxyl-
ation of benzoic acid with hydrogen peroxide promoted by
ortho-Hydroxylation: We recently reported that addition of
hydrogen peroxide to [FeII
A
ACHTUGTNRENG(NU CH3CN)2]ACTHNUGTRENNNUG
formation of [FeIII
ACHTUNGTRENNUNG
ture.[36,55] The reaction was accompanied by the appearance
of a deep blue color (lmax =590 nm). The final UV/Vis spec-
trum was identical to that of the independently prepared
salicylate complex [FeIII
ACHTUNTGRNENUG(BPMEN)(salicylate)]ACHTUGNTREN(NUGN ClO4), which
was crystallographically characterized.[36] A similar ortho-hy-
droxylation reaction was reported with a related iron(II)
[FeII
ic acids promoted by [FeII
G
aminopyridine complex, [FeII
ACHTUNGTRENGNU(N TPA)ACHTUNRTEGGN(NNU CH3CN)2]ACHTNGUERTN(NUGN OTf)2 (2),
A
but with m-chloroperbenzoic acid as oxidant.[37] To probe
substituent effects on the ortho-hydroxylation reactions per-
formed by these complexes, further studies have been car-
ried out on both 1 and 2 and a variety of substituted benzoic
acids with H2O2 as oxidant.
Both 1 and 2 were found to effect the ortho-hydroxylation
of various benzoic acids with H2O2 as oxidant, but the
amounts of salicylate formed depended upon the nature of
ring substituents and the iron complex (Table 1). The out-
Table 1. The amounts of ortho- and ipso-hydroxylation products relative
to iron complex observed from the reactions of 1 and 2 with a FeL/ben-
zoic acid/H2O2 ratio of 1/2/3 at room temperature based on UV/Vis[a]
(ortho) and GC (ipso) data.[b]
Scheme 1. Complexes studied herein: [FeII
(1); [FeII
(TPA)(CH3CN)2](OTf)2 (2).
ACHTUNGTRNEGNU(N BPMEN)ACHNUTRGTEG(NNUN CH3CN)2]ACHTNGUTREN(NUGN ClO4)2
G
N
ACHTUNGTRENNUNG
Substituent
Position
Yield of the hydroxylated products [%]
1
2
ligand structures). Both complexes have aminopyridine li-
gands and are known to catalyze a number of oxidation re-
actions by activating H2O2,[38–41] including olefin epoxidation
ortho
ipso[c]
ortho
ipso[c]
2-
3-
4-
–
52
–
70
–
22
–
48
–
14
–
–
OMe
or cis-dihydroxylation[42–44] and alkane hydroxylation.[45,46]
A
recent detailed comparative study of 1 and 2 in olefin epoxi-
dation with H2O2 in the presence of acetic acid[44] provided
important mechanistic information on the role of various
iron-oxygen intermediates, supporting carboxylic acid-assist-
[d]
2-
3-
4-
45
–
21
–
58
–
26
–
30
Me
H
>95
[d]
À
ed heterolytic O O bond cleavage as the key step in gener-
94
–
51
21
ating a proposed FeV=O oxidant. Although 1 and 2 share
common reaction pathways in olefin epoxidation, 1 is the
more active catalyst. However, only limited characterization
is available for the rather short-lived intermediates derived
from 1,[47,48] while the intermediates associated with 2 are
longer lived and better characterized spectroscopically.
[d]
2-
3-
4-
75
–
60
–
61
–
90
–
54
Cl
98
[d]
2-
3-
4-
52
56
68
14
–
–
–
–
–-
12
–
–
NO2
These include FeIII
O species.[54]
ACHTUNGTRENNUNG ACHTUNGTRENNUGN
(OOH),[49–51] FeIII(OOR),[29,52,53] and FeIV=
[a] UV/Vis yields have been calculated using e=2300 LmolÀ1 cmÀ1 for all
salicylate complexes. [b] – indicates no reaction. [c] Duplicate runs
agreed within 5%. [d] The ortho- and ipso-hydroxylation products form
concurrently, and their absorption bands partially overlap, so it is impos-
sible to independently evaluate the yield of each product from UV/Vis
data.
In the present work, the reactivities of non-heme iron
complexes 1 and 2 are compared in the carboxylate-directed
regioselective hydroxylation of various substituted benzoic
acids. Both complexes promote efficient ortho-hydroxylation
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Chem. Eur. J. 2009, 15, 13171 – 13180

Iron-Promoted ortho- and/or ipso-Hydroxylation of Benzoic Acids
FULL PAPER
comes of the hydroxylation reactions were conveniently
monitored in solution by UV/Vis spectroscopy following the
appearance of the intense visible absorption bands of the
ACHTUNGTRENNUNG
ironACHTUNGTRENNUNG(III)-salicylate products (see Table S1 in the Supporting
Information). The maxima of these absorption bands de-
pended on the electronic nature of the substituent, consis-
tent with the assignment of this absorbance as a phenolate-
parameters are compared with that of [FeIII
cylate)]+[37] in Table S4.
ACHTUNGTREN(NUGN TPA)(5-Cl-sali-
to-ironACHTUNGTRENNUNG(III) charge transfer transition. As expected, elec-
tron-donating groups caused the lmax of the salicylate com-
plex to red-shift, whereas electron-withdrawing groups had
the opposite effect (see Table S1 in the Supporting Informa-
tion). For example, the lmax of 590 nm for [FeIII-
Salicylic acids were the main products of the reactions
with benzoic acid and 3-substituted derivatives. For complex
1, 90–95% yields of salicylate products were found for ben-
zoic acid, 3-methylbenzoic acid and 3-chlorobenzoic acid
with respect to the iron complex, while the yields were 50–
60% for 2 (Table 1). In most cases, salicylic acid yields de-
termined by NMR spectroscopy agreed reasonably well with
ACHTUNGTRENNUNG
(BPMEN)(salicylate)]+ was red-shifted to 695 nm in the cor-
responding 3- or 5-methoxysalicylate derivatives (Figure 1
the amounts of corresponding ironACTHNUGTRNEUNG(III)–salicylate complexes
in solution determined from UV/Vis data (Table 1 and
Table S1 in the Supporting Information; see Experimental
Section for details). The product yields were significantly
lower for nitro-substituted substrates, presumably because
of the lower reactivity of electron-poor nitrobenzoic acids
and losses during the workup (which accounts for the yields
determined by NMR spectroscopy). A similarly low yield of
the ortho-hydroxylation of 3-methoxybenzoic acid by 1
(52%) was obtained, which can be attributed to over-oxida-
tion of the electron-rich salicylate product by H2O2. In sup-
port, adding a smaller amount of H2O2 (2 equivalents rela-
tive to iron complex) increased the yield of the correspond-
ing salicylate (57%); this was also true for the ortho-hydrox-
ylation of 3-methylbenzoic acid by 2 (62%).
Figure 1. Visible spectra of oxidation products derived from benzoic
(g), 3-methoxybenzoic (b) and 2-methoxybenzoic acids (c) in the
reactions of 1 (0.5 mm), the appropriate acid (1 mm), and H2O2 (1.5 mm)
in CH3CN at 208C. The different absorbances of hydroxylation products
are primarily caused by different product yields (see also Table 1).
For 3-substituted benzoic acids, there were two available
positions for ortho-hydroxylation, which would generate 3-
1
and/or 5-substituted salicylic acids. H NMR analysis of the
and Table S1 in the Supporting Information). The extinction
coefficients were determined for representative salicylate
products of the reaction with 1 showed that the 5-substituted
salicylic acid was the major product over 3-substituted
isomer, 3:1 for 5-methylsalicylic acid and 4:1 for 5-chlorosa-
licylic acid (see Figure S2 in the Supporting Information).
The preference for the 5-substituted isomer was not surpris-
ing on the basis of steric effects; the hydroxylation of the
para-position with respect to substituent should be sterically
less demanding than the incorporation of a hydroxyl group
between two existing substituents. Similarly, a 3:1 selectivity
in favor of 5-methoxysalicylic acid was observed with com-
plex 2 and 3-methoxybenzoic acid.
complexes
([FeIII
G
e590
=
=
=
2300 LmolÀ1 cmÀ1
2100 LmolÀ1 cmÀ1
;
;
(TPA)(5-Cl-salicylate)]+,
ACHTUNGTRENNUNG
e560
AHCTUNGTRENNUNG
(TPA)(5-MeO-salicylate)]+, e650
2100 LmolÀ1 cmÀ1) and were assumed to be similar for all
ortho-hydroxylation products. Crystal structures of [FeIII-
(TPA)(5-MeO-salicylate)]+
(Figure 2)
and
[FeIII-
Our studies showed that 1/H2O2 was more reactive than 2/
H2O2 (Table 1), effecting ortho-hydroxylation of a larger
range of benzoic acids. In particular, 1/H2O2 was able to
convert electron-deficient nitrobenzoic acids to the corre-
sponding salicylates. However, 3,5-dinitrobenzoic acid was
completely unreactive. Unlike 1/H2O2, 2/H2O2 displayed a
more limited scope of aromatic ortho-hydroxylation. The re-
activity differences between 1 and 2 suggest that the oxidant
produced by 1 is more powerful than that of 2. This notion
is consistent with the observed higher yield of oxidation
products for 1 compared to 2 in the hydroxylation of cyclo-
hexane.[45]
ACTHNUTRGNEUNG
Figure 2. ORTEP representation of [FeIII(TPA)(5-MeO-salicylate)]+. Hy-
drogen atoms have been omitted for clarity.
Chem. Eur. J. 2009, 15, 13171 – 13180
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13173

E. V. Rybak-Akimova, L. Que Jr. et al.
Oxidative decarboxylation leading to ipso-hydroxylation:
The remarkable ability of mononuclear iron(II) complexes 1
and 2 to efficiently and selectively hydroxylate benzoic acids
to their corresponding salicylic acids using H2O2 has some
limitations. Surprisingly, some benzoic acids with electron
donating substituents did not afford salicylate products,
even in the reactions involving 1 (Scheme 2). For example,
thoxybenzoic acid, suggesting that phenol product originates
from ipso-hydroxylation reaction in the presence of hydro-
gen peroxide and not from decarboxylation of 2-methoxy-
1
benzoic acid during the work-up. H NMR analysis of ex-
tracted phenols corroborates the GC analysis (the protocol
is described in the Experimental Section). These phenol
products resulted from oxidative decarboxylation of 2-me-
thoxy- and 2,6-dimethylbenzoic acids followed by ipso-hy-
droxylation (Scheme 2). Coordination of the phenolate
ACTHNUTRGNEUNG
products to [FeIII(BPMEN)]3+ then generated the observed
green chromophores, the identities of which were confirmed
by independent spectroscopic experiments described below.
In the presence of excess H2O2, phenolates undergo further
oxidation; this overoxidation is responsible for the transient
nature of the observed green complexes under certain con-
ditions.
Scheme 2. Conversion of benzoic acids to salicylates and phenolates by 1
or 2.
Resonance Raman spectra of the green chromophores
supported their formulation as FeIII(L)
ACTHNUTRGNEUNG(OAr) species, show-
the reaction of 1, the electron-rich 2-methoxybenzoic acid,
and H2O2, in a 1/2/3 ratio did not afford the corresponding
salicylate complex but instead generated a transient green
species. At room temperature, this green intermediate
formed upon mixing and decayed in 5 s, but its lifetime
could be significantly extended at À408C. Its UV/Vis spec-
trum showed a lmax at 760 nm (Figure 1), distinctly different
from the characteristic spectrum of independently generated
ing vibrational features in the 500–1600 cmÀ1 region that are
characteristic of FeIII–phenolate complexes.[29,56–58] For the 2-
methoxybenzoic acid experiment, four modes were affected
when H218O2 was used instead of H216O2 (Table 2). The
619 cmÀ1 band can be assigned to the Fe–OAr vibration by
analogy to a band with the same frequency found in the
Raman spectrum of the phenyl-hydroxylated product from
ACTHNUTRGNEUNG
FeII(6-Ph-TPA) and tBuOOH.[29] The other three vibrations
[FeIII
(BPMEN)(6-MeO-salicylate)]+
complex
(lmax
=
are associated with phenolate C O and ring deformation
modes.[59,60] Similar assignments can be made for the 18O-iso-
tope-sensitive vibrations observed for the green chromo-
phore from the 2,6-dimethylbenzoic acid experiments
(Table 2). These results also proved that the phenolate
oxygen originated from H2O2.
À
608 nm). Moreover, a similar but not identical green species
could also be observed after addition of H2O2 to a mixture
of 2,6-dimethylbenzoic acid and 1 (see Figure S3 in the Sup-
porting Information). Since both ortho positions of 2,6-di-
methylbenzoic acid were occupied, the green complex could
not result from an ortho-hydroxylation reaction. Yields of
phenolate products were determined by GCMS after appro-
priate workup as detailed in the Experimental Section.
Quenching the reactions with 1-methylimidazole followed
by acetylation and GC-MS analysis allowed us to identify
the organic products as 2-methoxyphenol and 2,6-dimethyl-
phenol, respectively, which were obtained in 70% and 20%
yields from the reaction mixtures of 1/benzoic acid/H2O2 in
a 1/2/3 ratio. In a control experiment, no phenol was ob-
served by GCMS after acetylation work-up of the 1/2-me-
To provide further evidence for our description of the ob-
served intermediates as FeIII-phenolate species, the [FeIII-
AHCTUNGTRENNUNG
(BPMEN)(2-MeO-phenolate)]2+ complex was independent-
ly prepared from reaction of 1, 2-methoxyphenol and
1 equiv of CeIV salt (see Figure S4 in the Supporting Infor-
mation), and its Raman spectrum was recorded (see Fig-
ure S5 in the Supporting Information). The spectrum exhib-
ited exactly the same features observed for the reaction of
1, 2-methoxybenzoic acid and H2O2, confirming the identity
of the observed hydroxylated complex (Figure 3). Thus the
Table 2. Raman vibrations of iron
Species/Complex
ACHTUNGTRENNUNG
Raman shift [cmÀ1] (D-18O)
(C-H) (C-O)
Ref.
n
G
d
E
n
N
nACTHNGUTERNN(UG C=C)
A
G
619 (À7)
893 (À22)
881 (À15)
1160
1267 (À3), 1288 (À10),
1312
1225 (À10) 1265 (À4)
1488, 1578
this
work
this
R
542 (À3),
560 (À4)
621 (À16)
1404, 1444, 1589
work
[FeIIITpPh2*OBz]
861
961 (À19)
G
1254 (À9), 1273,
1298 (À4)
1451, 1480, 1559,
1598, 1606
1408, 1483, 1555,
1573, 1596
1454, 1478, 1565,
1596
1501, 1602
[28]
ortho-hydroxylated FeIII
N
626, 642,
662
614, 633
1127, 1160
1249, 1279, 1297,
1314
[29]
[57]
[56]
meso-[Fe
E
827, 893
1050, 1112,
1154
1168
1270, 1366
U
568 (À10)
1272
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Chem. Eur. J. 2009, 15, 13171 – 13180

Iron-Promoted ortho- and/or ipso-Hydroxylation of Benzoic Acids
FULL PAPER
of the aromatic ring, yielding
ortho-hydroxylated
products
(salicylates).
Mechanistic insights: The simi-
lar reactivity profiles of com-
plexes
1
and
2
suggest
a
common reaction mechanism
(Scheme 3) for aromatic hy-
droxylations promoted by these
two non-heme iron complexes.
The regioselectivity of these re-
actions, which results in the in-
corporation of an -OH group
either next to or in place of the
carboxylate substituent, indi-
cates
a metal-based oxidant,
rather than hydroxyl radical
that would derive from metal
À
promoted O O bond homolysis
of H2O2. Reactivity trends sug-
gest that the oxidant is electro-
philic. Coordination of aromatic
carboxylic acids to 1 or 2 posi-
tions the aromatic ring in the
immediate vicinity of the
redox-active metal center. Iso-
Figure 3. Resonance Raman spectra of the green complexes generated in acetonitrile at À408C by mixing 1, 2-
methoxybenzoic acid and hydrogen peroxide (A) and 1, 2,6-dimethylbenzoic acid and hydrogen peroxide (B).
Spectra in black were obtained with H216O2, whereas spectra in gray were obtained with H218O2. Spectra were
acquired on frozen samples at 77 K with 647 nm excitation. Solvent peaks were denoted with *.
green chromophores in these reactions are FeIII–phenolate
complexes that formed by oxidative decarboxylation of ben-
zoic acid substrates and subsequent ipso-hydroxylation.
Further experiments established that ipso-hydroxylation
extended beyond the two examples described above. This
transformation depended on the nature of the iron complex
(1 vs. 2), the electronic properties of substituents on the
benzoic acid, and their position with respect to -COOH
group (Table 1). ipso-Hydroxylation could be observed for
benzoic acids with either electron donating or electron with-
drawing substituents in the 2- or 4-position, but not for 3-
substituted benzoic acids where only ortho-hydroxylation
was found. For some substrates, both ortho- and ipso-hy-
droxylation were observed (Table 1).
Despite their differences towards ortho-hydroxylation,
both complexes 1 and 2 behaved similarly towards ipso-hy-
droxylation. Substituents that increase electron density in
the ipso position with respect to carboxylate group promot-
ed decarboxylation leading to ipso-hydroxylation. Blocking
the sites for ortho-hydroxylation by placing substituents in
2- and/or 6-positions with respect to carboxylate, also fa-
vored ipso-hydroxylation. Meta-substituted benzoic acids
studied in this work did not afford ipso-hydroxylation prod-
ucts. Electron-withdrawing (NO2, Cl) meta substituents dras-
tically decreased electron density in the ipso-position and
prevented the electrophilic attack by the metal-based oxi-
dant, hampering the ipso-hydroxylation process. On the
other hand, strong electron donating substituents (MeO)
meta with respect to carboxylate preferentially underwent a
competing electrophilic attack at the most electron-rich site
tope substitution studies provide additional insight into pos-
sible hydroxylation mechanisms. Experiments with the deu-
terated substrate, [D5]-PhCOOH, exhibited no significant H/
D kinetic isotope effect on the rates of ortho-hydroxylation
with H2O2 in the presence of complex 1. Competition ex-
periments also showed no preference of 1 in reacting with
À
either protio or deuterio isotopomers, so C H bond break-
ing on the phenyl ring cannot be a rate limiting step in this
transformation.[36] Similarly small H/D KIE values (ꢀ1)
were also reported for other aromatic oxidations promoted
by biological and synthetic iron centers,[8,27,29,61–64] and inter-
preted in terms of either a rate-limiting formation of an
iron–oxo intermediate[29] or a rate-limiting electrophilic
attack of the aromatic ring by a metal-based oxidant (a pro-
cess that is typically characterized by only a small but in-
verse isotope effect).[27,61,62,65,66]
18O-labeling experiments with H218O2 unambiguously
showed the incorporation of one oxygen atom into the phe-
nolate or salicylate product derived from the oxidations of
benzoic acids, underscoring the fact that hydrogen peroxide
is the sole source of the oxygen atom incorporated into the
products. This conclusion applies to both ortho-hydroxyl-
ation and decarboxylation/ipso-hydroxylation, as determined
by mass spectrometry (see Figure S6 and Figure S7 in the
Supporting Information) and/or resonance Raman spectros-
copy (Figure 3). Thus the metal-based oxidant must derive
from the combination of the iron catalyst and H2O2.
An obvious starting point with respect to the identity of
the metal-based oxidant is an FeIII OOH intermediate. Such
À
species have been observed for both 1[47,48] and 2.[50,51] Al-
Chem. Eur. J. 2009, 15, 13171 – 13180
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13175

E. V. Rybak-Akimova, L. Que Jr. et al.
Scheme 3. Mechanisms of ortho-hydroxylation and ipso-hydroxylation by 1 and 2.
though 1 afforded higher yields of aromatic hydroxylation
spectra). Subsequent addition of 3-methoxybenzoic acid to
this intermediate elicited a new band at 650 nm that is asso-
ciated with the formation of the corresponding salicylate
complex (Figure 4, solid-line spectra). Reversing the order
of addition of the oxidant and the substrate also generated
the same chromophore at 650 nm, but the 540 nm absorp-
than 2 (Table 1), the FeIII OOH intermediate of 2 can be
À
obtained in much higher yield and is thus better character-
ized. While the hydroperoxo intermediate of 1 was observed
by low-temperature EPR spectroscopy,[48] its optical signa-
ture remains to be identified. We thus focused on experi-
ments with 2 in our efforts to identify the active oxidant(s)
in aromatic hydroxylation with H2O2.
tion feature of the FeIII OOH species was much less pro-
À
nounced (see Figure S8 in the Supporting Information). Sim-
ilar spectral changes were observed in parallel experiments
for 2-methoxybenzoic acid (see Figure S9 and Figure S10 in
As previously reported, the reaction of 2 and excess H2O2
in CH3CN at À408C gave the corresponding FeIII OOH in-
À
the Supporting Information). The FeIII OOH intermediate
À
termediate (2a) with a lmax at 540 nm (Figure 4, dashed-line
would thus appear to be involved in the aromatic hydroxyl-
ation.
Scheme 3 illustrates the various possible roles of the
FeIII OOH intermediate (1b or 2b) in this reaction, where
À
it could either be the oxidant itself or the precursor thereof.
A similar mechanistic landscape was discussed previously
for olefin epoxidation and cis-dihydroxylation with H2O2/1
or 2.[43,44] Three pathways were considered for the evolution
of the FeIII OOH intermediate. The hydroperoxo ligand
À
could attack the carboxylate of the bound benzoic acid to
generate an acylperoxoiron
ACHTUNGTRENNUNG
Scheme 3). Formation of such an acetylperoxoironAHCTUNGTRENNUNG
cies has been detected[48] in a mixture of 1, acetic acid, and
H2O2, but the yield was very low. In addition, Nam and co-
workers[37] reported the self-hydroxylation of peroxybenzoic
acids in the presence of 2 to form salicylate products. This
pathway however requires the formation of a doubly labeled
salicylate product from labeled H2O2 (Scheme 3). Since only
singly labeled salicylate is observed in the 18O-labeling ex-
periments, this pathway can be excluded as the mechanistic
Figure 4. Spectral changes observed in the reaction of 2 (1 mm) with
3 equiv H2O2 and 12 equiv 3-methoxybenzoic acid at À408C. Dashed
lines represent spectra obtained immediately after mixing 2 and H2O2
and after 9 min. Solid lines correspond to spectra obtained subsequent to
the addition of 3-methoxybenzoic acid (taken at 10, 20, 50, 90, 150, and
210 min after addition of the acid).
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Iron-Promoted ortho- and/or ipso-Hydroxylation of Benzoic Acids
FULL PAPER
option for the aromatic hydroxylations under our experi-
mental conditions.
acterized by a variety of spectroscopic methods,[75] indirect
evidence supporting participation of non-heme FeV–oxo in-
termediates in oxidations of alcohols,[76] olefins,[43,76,77] and
arenes[33,74,78] continues to accumulate. The coordination of
the carboxylate cis to the oxo moiety in the putative oxoir-
on(V) oxidant 1e or 2e[77] positions the aromatic ring well
for the attack of the oxo group at the carbon atom ortho to
the carboxylate function. Such an attack would form a six-
membered ring in the transition state, facilitating formation
of the product complex with a bidentate salicylate. Such di-
rected reactivity was reported for an iron catalyst closely re-
lated to 1 by Chen and White.[79] The substrates that are
consistently ortho-hydroxylated are those with substituents
meta to the carboxylate functionality; in no case is ipso-hy-
droxylation observed. In addition, higher yields of salicylate
products are obtained for substituents that enhance electron
density at the carbon ortho or para to the substituent. The
one exception is 3-methoxybenzoic acid, but the lower yield
of salicylate is likely to result from over-oxidation.
A second option for the evolution of the FeIII OOH inter-
À
À
mediate is O O bond homolysis, which would afford
[(TPA)FeIV=O]2+ and hydroxyl radical (1d or 2d in
Scheme 3). The oxidative power of the FeIV=O species has
been demonstrated in several iron-promoted oxidation reac-
tions,[27,54,67–70] including aromatic hydroxylation of anthra-
cene.[27] In fact, FeIV=O complexes were also detected in the
reactions of 1 or 2 with hydrogen peroxide and acetic
acid.[44,48] However, a detailed study on 2-catalyzed olefin
epoxidation[44] clearly excluded [(TPA)FeIV=O]2+ as the oxi-
dant in this transformation. Similarly, even though we found
that meta-chlorobenzoic acid was ortho-hydroxylated by 2
and H2O2 (Table 1), [(TPA)FeIV=O]2+ did not effect the
ortho-hydroxylation of meta-chlorobenzoic acid.[37] Even the
more reactive electron-rich substrates (3-methoxybenzoic
acid for ortho-hydroxylation, and 2-methoxybenzoic acid for
ipso-hydroxylation) were not oxidized by independently
generated [(TPA)FeIV=O]2+ (see Figure S11 and Figure S12
in the Supporting Information). These observations conclu-
sively eliminate FeIV=O as a probable oxidant in these aro-
matic hydroxylation reactions. Furthermore, since hydroxyl
radicals are known to attack benzoic acid, affording a statis-
tical mixture of o-, m, and p-hydroxylated products,[71] the
observed regioselectivity of aromatic hydroxylation with
H2O2/1 or 2 excludes the participation of OH-radicals.
In contrast, ipso-hydroxylation products are formed for
benzoic acids with ortho or para substituents. The observa-
tion of ipso-hydroxylation products can most easily be ra-
tionalized by postulating formation of a coordinated arylcar-
boxyl radical (1 f or 2 f) that undergoes spontaneous loss of
CO2,[44,80] affording an aryl radical that immediately re-
bounds with the oxoiron(IV) center to form the phenolate
À
product. The radical may derive from O O bond homolysis
With the arguments presented above, only two possible
of the precursor [FeIII
(OOH)
R
pathways remain for the FeIII OOH intermediate en route
or 2b) or intramolecular electron transfer from the coordi-
nated carboxylate to the oxoiron(V) center in 1e or 2e, in
both cases generating the carboxyl radical and an oxo-
iron(IV) center. Oxidative decarboxylation is precedented
in the reaction of phenylacetic acid with 2 and H2O2, where
benzyl radical is formed and then trapped by O2 to yield
benzaldehyde as the observed product.[44] Unlike the reso-
nance-stabilized benzyl radical, the phenyl radical would be
expected to be short-lived and undergo rapid oxygen re-
bound. The fact that ortho-substituted benzoic acids are con-
verted mainly to ipso-hydroxylation products suggests that
steric factors may promote this reactivity mode, but the ob-
servation of low yields of phenols derived from electron-
poor substrates (such as nitro-benzoic acids) indicate that
electronic factors also contribute to the efficiency of ipso-
hydroxylation. Since certain substrates can yield both ortho-
and ipso-hydroxylation products, these reactions must pro-
ceed via competing pathways. The factors governing the out-
come of this competition include relative electron density in
the ortho- and ipso-positions, and steric accessibility of the
ortho sites.
À
to the observed aromatic hydroxylation products
(Scheme 3): either direct electrophilic attack of the organic
À
substrate, or heterolytic cleavage of the O O bond to gener-
ate a formally FeV=O species[43,44,72] that attacks the iron-
bound benzoic acid. The limited existing data on the reactiv-
[40]
ity of FeIII OOH species indicate that these appear to be
À
sluggish oxidants.[73] In particular, the decay of [(TPA)FeIII-
(OOH)]2+ at À458C was shown not to depend on thioani-
sole or cyclohexene concentration,[73] although such sub-
strates were oxidized by the combination of 2 and H2O2 at
higher temperatures. We thus favor the carboxylic acid-as-
À
sisted O O bond heterolysis pathway leading to an unob-
served FeV=O oxidant, which was postulated by Mas-Bal-
lestꢁ and Que in the efficient 2-catalyzed epoxidation of ole-
fins by H2O2 in the presence of acetic acid.[44] Although it
may be argued that a direct electrophilic attack of the aro-
matic ring by 2b is plausible, particularly for benzoic acids
with electron donating substituents, the broad scope of both
ortho- and ipso-hydroxylation reactions promoted by 1 and
2 suggests that a highly electrophilic intermediate is likely to
be involved, which we propose is 1e or 2e. A similar oxi-
dant has been proposed for the 2-catalyzed self-hydroxyl-
ation of aryl peroxyacids,[37] for the intramolecular hydroxyl-
ation of the aromatic ring covalently appended to the
analog of 1,[33] and for the ortho-hydroxylation of benzyl al-
cohol by another aminopyridine iron complex.[74] Although
only one non-heme iron(V)–oxo complex has been directly
observed at low temperature as a transient species and char-
The reactivity data summarized in Table 1 show that 1 hy-
droxylates a broader range of substrates and often affords
higher yields of hydroxylated products compared to 2,
strongly suggesting that a more powerful oxidant is generat-
ed in the case of the former. This notion is supported by the
higher yields of cyclohexane oxidation products in the reac-
tions of H2O2 with 1 or 2.[45] Perhaps the three pyridine li-
gands in 2 (versus two in 1) better stabilize the higher iron
Chem. Eur. J. 2009, 15, 13171 – 13180
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E. V. Rybak-Akimova, L. Que Jr. et al.
UV/Vis studies of aromatic hydroxylation reactions: ortho- and ipso-Hy-
droxylation of various aromatic acids in the presence of 1 or 2 were per-
formed by mixing the iron complex (0.5 mm–1 mm) with aromatic acid
(2 equiv) in acetonitrile in a glove box and then adding hydrogen perox-
ide (3 equiv) at room temperature. Spectroscopic experiments with [FeII-
oxidation states required for the oxidation reactions. Indeed
IV
FeIII OOH and Fe =O intermediates of 2 have been found
À
to be stable enough to accumulate at low temperature and
be characterized by a number of spectroscopic meth-
ods.[50,51,54] In contrast, corresponding species of 1 are thus
far only fleetingly observed.[47,48]
AHCTUNTGRENUNG(N TPA)AHCTUNRTGEG(NNNU CH3CN)2]ACHTGUNTREN(NUGN OTf)2 were performed on a 1 mm solution of 2 in ace-
tonitrile in a 1 cm quartz cuvette precooled at À408C. Hydrogen perox-
ide (3 equiv, 87 mL of 0.07m) was added to a solution containing the iron
complex and an excess amount (12 equiv) of 3-methoxybenzoic acid. In
In summary, highly regioselective hydroxylation of a
broad range of substituted aromatic acids with hydrogen
peroxide in the presence of 1 or 2 proceeds readily at room
temperature. The hydroxylation occurs exclusively in the vi-
cinity of the anchoring carboxylate functional group: ortho-
hydroxylation affords salicylates, and ipso-attack results in
decarboxylation and ipso-hydroxylation, yielding phenolates.
A similar proximity effect can be postulated for the highly
ACTHNUTRGNEUNG
other experiments the metastable [(TPA)FeIII(OOH)]2+ species was gen-
erated by adding H2O2 (3 equiv) to the solution of 2 (1 mm) at À408C.
The [(TPA)FeIV=O]2+ species was generated at À408C in acetonitrile by
adding CH3CO3H (1 equiv, 0.03 mL of 0.07m) to the solution of 2 (1 mm)
according to the published procedure.[54]
Identification of ipso- and ortho-hydroxylation products by NMR spec-
troscopy: For the identification of hydroxylated products, 1 (0.12 mmol,
72 mg) was dissolved in acetonitrile (20 mL) under argon atmosphere in
a glove box and mixed with substituted benzoic acid (1 equiv). A further
H2O2 (1.5 equiv) was added to the prepared mixture. The solution was
stirred for 20–30 min. In the next step, complex was decomposed by
treating with aqueous Na2EDTA solution (20 mL, 5% solution) followed
by addition of concentrated HCl (final pH was about 0). Organic prod-
ucts were extracted with ethyl acetate (3ꢃ20 mL) and the extract was
dried over MgSO4. Evaporation of solvent resulted in brown residues
À
selective hydroxylation of tertiary C H bonds on carbons
gamma to the carboxylate functionality in what Chen and
White call the carboxylate-directed method to form five-
membered lactone rings.[79] An electrophilic, metal-based
oxidant must be involved in carboxylic-acid directed aro-
matic hydroxylation. FeIV=O species are unreactive in aro-
1
matic hydroxylations described herein. FeIII OOH is defi-
À
(soluble in chloroform) that were analyzed by H NMR spectroscopy.
Identification of ipso-hydroxylation products by GCMS: A mixture of
complex 1 or 2 (1 mm) and aromatic acid (2 equiv) in acetonitrile was
prepared under argon. H2O2 (3 equiv vs. iron) was delivered into 1 mL of
the mixture upon vigorous stirring. The reaction was quenched with 1-
methylimidazole (0.1 mL) over 30 min followed by the addition of acetic
anhydride (1 mL) to esterify the products. Naphthalene or nitrobenzene
was added as an internal standard. Organic products were extracted with
chloroform or dichloromethane (1–2 mL) and subjected to the GC and
GCMS analysis. All experiments were run at least in duplicate (runs
agreed within 5%), the reported data is the average of these reactions.
nitely involved in the hydroxylation pathways, most likely
À
via intramolecular acid-assisted O O bond heterolysis,
yielding transient, highly reactive FeV=O species whose
nature has yet to be established.
Experimental Section
Resonance Raman studies and labeling experiments: 2-Methoxybenzoic
or 2,6-dimethylbenzoic acid (1.5 equiv vs. iron) and H2O2 (3 equiv) were
added to a solution of 1 (1 mm) in acetonitrile. The mixture was analyzed
Materials and methods: All chemicals and solvents were purchased from
Aldrich, Acros Organics or Fisher Scientific and were used without addi-
tional purification unless otherwise noted. CH3CN solvent was dried over
CaH2 before use. H218O2 (90% 18O-enriched, 2% solutions in H216O) was
obtained from Cambridge Isotope Laboratories Inc. (Andover, MA).
by resonance Raman spectroscopy. Alternatively, the [FeIII
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
phenol (2 mm) in acetonitrile, and also analyzed by Raman spectroscopy.
Labeling experiments were carried out using acetonitrile solution of
H218O2 prepared from stock solution (2% solution of H218O2 in H216O,
90% 18O-enriched). The resulting green solutions were frozen 2–3 min
after addition of the oxidant (H2O2 or (NH4)2CeACHTNUGTRNEGNU(NO3)6) at 77 K using a
gold-plated copper cold finger in thermal contact with a dewar containing
liquid N2. No photobleaching was observed upon repeated scans.
ACHTUNGTRENNUNG(BPMEN)ACHTUNGTRENG(NU CH3CN)2]ACHTNUGERTNNUNG CAHTNUGTRNE(NUGN TPA)-
The complexes [FeII (ClO4)2 (1) and [FeII
A
ACHTUNGTRENNUNG
to the published procedures.[45, 54] UV/Vis spectra were acquired on a
JASCO V-570 spectrophotometer or a Hewlett–Packard (Agilent) 8452
diode array spectrophotometer over a 190–1100 nm range. In some ex-
periments, quartz cuvettes were cooled to the desired temperature in a
liquid nitrogen cryostat by Unisoku Co. Ltd. (Osaka, Japan). ESI-MS
spectra were obtained on a Finnigan LTQ mass spectrometer or a Bruker
Biotof-II mass spectrometer under conditions of a spray chamber voltage
of 4000 Volt and a dry gas temperature of 2008C. GCMS experiments
were carried out using a Shimadzu GC-17 A gas chromatograph (Rtx-
xLB column) with a GCMS-QP 5050 mass detector or using an HP 6890
gas chromatograph (HP-5 column, 30 m) with an Agilent 5973 mass de-
tector. NMR spectra were recorded on a Bruker DPX-300 spectrometer
or a Varian Unity 500 spectrometer at ambient temperature. Chemical
shifts (ppm) were referenced to the residual protic solvent peaks. Reso-
nance Raman spectra were collected on an Acton AM-506 spectrometer
(1200 groove grating) using a Kaiser Optical holographic super-notch fil-
ters with a Princeton Instruments liquid-N2-cooled (LN-1100PB) CCD
detector with a 4 cmÀ1 spectral resolution. The 647.1 cmÀ1 laser excitation
line was obtained with a Spectra Physics BeamLok 2060-KR-V krypton
ion laser. The Raman frequencies were referenced to indene. Baseline
corrections (polynomial fits) were carried out using Grams/32 Spectral
Notebase Version 4.04 (Galactic). Time-resolved spectra of rapid hydrox-
ylation reactions were acquired with TgK Scientific (formerly HiTech
Schientific, Salisbury, Wiltshire, UK) SF-61DX2 cryogenic Stopped-flow
system equipped with J&M Diode array (Spectralytics).
Crystallographic studies: Each crystal was placed onto the tip of a
0.1 mm diameter glass capillary and mounted on a CCD area detector
diffractometer for a data collection at 173(2) K.[81] A preliminary set of
cell constants was calculated from reflections harvested from three sets
of 20 frames. These initial sets of frames were oriented such that orthog-
onal wedges of reciprocal space were surveyed. This produced initial ori-
entation matrices determined from 67 reflections for [FeIII
salicylate)]+ and 44 reflections for [FeIII(TPA)(salicylate)]+. The data col-
ACHTUNGTREN(NUNG TPA)(5-MeO-
AHCTUNGTRENNUNG
lection was carried out using MoKa radiation (graphite monochromator)
with a frame time of 60 s and a detector distance of 4.9 cm. A randomly
oriented region of reciprocal space was surveyed to the extent of one
sphere and to a resolution of 0.84 ꢄ. Four major sections of frames were
collected with 0.308 steps in w at four different f settings and a detector
position of À288 in 2q. The intensity data were corrected for absorption
and decay (SADABS).[82] Final cell constants were calculated from 2717
(for
[FeIII
(TPA)(5-MeO-salicylate)]+)
and
2950
(for
[FeIII
-
AHCTUNGTRENNUNG
(TPA)(salicylate)]+) strong reflections from the actual data collection
after integration (SAINT).[83] Please refer to Table S2-S3 for additional
crystal and refinement information. The structure was solved and refined
by using Bruker SHELXTL.[84] The space groups for [FeIII
ACTHNUGRTENUNG(TPA)(5-MeO-
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Chem. Eur. J. 2009, 15, 13171 – 13180

Iron-Promoted ortho- and/or ipso-Hydroxylation of Benzoic Acids
FULL PAPER
salicylate)]+ and [FeIII
G
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Acknowledgements
This work was supported by the US Department of Energy (Grants DE-
FG02–06ER15799 to E.V.R.-A. and DE-FG02–03ER15455 to L.Q.). The
NMR facility, the ESI-MS spectrometer, and rapid kinetic instrumenta-
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