Proton-coupled O-O activation on a redox platform bearing a hydrogen-bonding scaffold

Article abstract of DOI:10.1021/ja028548o

Porphyrin architectures bearing a hydrogen-bonding scaffold have been synthesized. The H-bond pendant allows proton-coupled electron transfer (PCET) to be utilized as a vehicle for effecting catalytic O-O bond activation chemistry. Suzuki cross-coupling reactions provide a modular synthetic strategy for the attachment of porphyrins to a rigid xanthene or dibenzofuran pillar bearing the H-bond pendant. The resulting HPX (hanging porphyrin xanthene) and HPD (hanging porphyrin dibenzofuran) systems permit both the orientation and acid-base properties of the hanging H-bonding group to be controlled. Comparative reactivity studies for the catalase-like disproportionation of hydrogen peroxide and the epoxidation of olefins by the HPX and HPD platforms with acid and ester hanging groups reveal that the introduction of a proton-transfer network, properly oriented to a redox-active platform, can orchestrate catalytic O-O bond activation. For the catalase and epoxidation reaction types, a marked reactivity enhancement is observed for the xanthene-bridged platform appended with a pendant carboxylic acid group, establishing that this approach can yield superior catalysts to analogues that do not control both proton and electron inventories.

Full text of DOI:10.1021/ja028548o

Published on Web 01/17/2003
Proton-Coupled O-O Activation on a Redox Platform Bearing
a Hydrogen-Bonding Scaffold
Christopher J. Chang, Leng Leng Chng, and Daniel G. Nocera*
Contribution from the Department of Chemistry, 6-335, Massachusetts Institute of Technology,
77 Massachusetts AVenue, Cambridge, Massachusetts 02139-4307
Received September 14, 2002 ; E-mail: nocera@mit.edu
Abstract: Porphyrin architectures bearing a hydrogen-bonding scaffold have been synthesized. The H-bond
pendant allows proton-coupled electron transfer (PCET) to be utilized as a vehicle for effecting catalytic
O-O bond activation chemistry. Suzuki cross-coupling reactions provide a modular synthetic strategy for
the attachment of porphyrins to a rigid xanthene or dibenzofuran pillar bearing the H-bond pendant. The
resulting HPX (hanging porphyrin xanthene) and HPD (hanging porphyrin dibenzofuran) systems permit
both the orientation and acid-base properties of the hanging H-bonding group to be controlled. Comparative
reactivity studies for the catalase-like disproportionation of hydrogen peroxide and the epoxidation of olefins
by the HPX and HPD platforms with acid and ester hanging groups reveal that the introduction of a proton-
transfer network, properly oriented to a redox-active platform, can orchestrate catalytic O-O bond activation.
For the catalase and epoxidation reaction types, a marked reactivity enhancement is observed for the
xanthene-bridged platform appended with a pendant carboxylic acid group, establishing that this approach
can yield superior catalysts to analogues that do not control both proton and electron inventories.
and reductases such as hydrogenase30-33 and nitrogenase,34,35
to name a few.
Introduction
Many fundamental small-molecule transformations in nature
require the coupled transport of both proton and electron
equivalents to effect bond-making and bond-breaking catalysis.
Consummate examples include the photoinduced oxidation of
water to oxygen by photosystem II1-5 and the chemically
diametric reduction of oxygen to water by cytochrome c
oxidase.6-14 In addition to these enzymes, proton-coupled
electron transfer (PCET) events continue to emerge in the
structure/function relations of a broad range of other natural
systems such as copper-based oxidases,15-17 flavin- and pyr-
roloquinoline-dependent enzymes,18,19 non-heme iron proteins,20-29
Within the interiors of the complex tertiary structures of these
oxidases and reductases, noncovalent hydrogen-bonding inter-
actions are paramount to dynamically regulating the active site
for PCET reactivity. Heme-dependent proteins featuring a
conserved iron protoporphyrin IX cofactor are exemplary in their
structural control of PCET. Figure 1 compares the active-site
structures of peroxidases, catalases, and the cytochrome P450
monooxygenases, highlighting the structural parallels at the
distal side of the heme pocket where O-O activation occurs.
Through the targeted use of amino acid side chains and/or
solvent water as proton shuttles, these proteins react with oxygen
or hydrogen peroxide to generate highly reactive iron-oxo
species within their active-site cavities. Such hydrogen-bonding
groups participate in directed acid-base chemistry to provide
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10.1021/ja028548o CCC: $25.00 © 2003 American Chemical Society

Proton-Coupled O−O Activation
A R T I C L E S
Figure 1. Comparison of proposed proton-activated O-O bond cleavage for iron-oxo heme formation in (a) peroxidases, (b) catalases, and (c) cytochrome
P450 monooxygenases.
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A R T I C L E S
Chang et al.
bioconjugates, we have taken the alternative approach of
molecular design by chemical synthesis. We have sought to
combine acid-base and redox functionalities onto a single
molecular platform. Such simple constructs, in principle, allow
for the systematic control of structural and electronic variables
through targeted synthetic modification. Initial efforts have
explored the assembly of donor-acceptor redox pairs via
hydrogen-bonding interfaces,73-75 such as that afforded from
the association of an amidinium and carboxylate.76-81 This salt-
bridge interface combines the dipole of an electrostatic ion-
pair interaction with a hydrogen-bonding scaffold, allowing us
to investigate how proton motion within a hydrogen-bonded
interface affects the charge, energetics, and polarity of the
electron transport chain.
Whereas such systems have been invaluable in elucidating
mechanistic details of PCET, they are not suitable scaffolds for
exploring PCET as it pertains to small-molecule activation
chemistry. Proximate acid-base and redox sites are presented
in a side-to-side arrangement, thus orienting the PCET func-
tionalities orthogonal to the catalytic bond-making and bond-
breaking processes required to occur at the metal center. To
direct PCET toward the metal coordination site of catalytic
small-molecule activation, we sought to create constructs where
proton and electron delivery are confined to a face-to-face
arrangement.
rocyclic subunits. Replacement of one of the porphyrin redox
subunits with a proton donor converts these cofacial Pacman
systems into hybrid proton/redox shuttle platforms. We have
recently shown that a xanthene anchor may be used to “hang”
a hydrogen-bond functionality over a redox-active metallopor-
phyrin platform.88,89 These Hangman architectures are simplified
constructs of biomolecules with engineered distal sites inasmuch
as the platforms capture control of both the proton and electron
transfer but without the need for secondary and tertiary protein
structure to impose a proton network among structured water
or protonated amino acid side chains.
In this report, we describe the synthesis, characterization, and
catalytic O-O bond activation chemistry of Hangman porphyrin
platforms. Suzuki cross-coupling methods provide a smooth
synthetic inroad toward the preparation of Hangman systems
based on xanthene (HPX ) hanging porphyrin xanthene) and
dibenzofuran (HPD ) hanging porphyrin dibenzofuran) scaf-
folds. These simple constructs allow for precise control over
the functional nature of the hydrogen-bonding group in terms
of proton-donating ability and arrangement in relation to the
metalloporphyrin redox site. We have evaluated the catalytic
O-O bond activation reactivity of a systematic set of HPX and
HPD compounds with varying hydrogen-bonding and proton-
transfer abilities. Two catalytic reactivities, catalase-like oxygen
evolution and cytochrome P450-type epoxidation, of simple
redox-only porphyrin analogues with similar steric and electronic
properties have been compared to the Hangman templates. Our
findings reveal that catalytic oxidation reactivity can be dramati-
cally enhanced with a single well-positioned acid-base func-
tionality and engender divergent chemical reactivity for a single
redox cofactor.
Results
Along these lines, we have recently demonstrated that
xanthene and dibenzofuran spacers can organize two redox
cofactors along the desired face-to-face reaction coordinate.82-87
In these DPX (diporphyrin xanthene) and DPD (diporphyrin
dibenzofuran) cofacial constructs, neighboring porphyrins dis-
play an extensive range of vertical pocket size dimensions and
flexibilities with minimal lateral displacements between mac-
Hangman Porphyrins Bridged by Xanthene (HPX) and
Dibenzofuran (HPD). An approach akin to that used for the
assembly of cofacial DPX and DPD Pacman porphyrins may
be employed to create asymmetric cofacial porphyrin architec-
tures that are the subject of this report. A rigid xanthene or
dibenzofuran scaffold provides the anchor point on which to
affix a hydrogen-bonding group above the metal center of a
porphyrin motif (HPX ) hanging porphyrin xanthene, HPD )
hanging porphyrin dibenzofuran). As observed for the cofacial
Pacman constructs, substitution of the six-membered center ring
of xanthene with the five-membered one of dibenzofuran allows
for a large span of vertical distances between ditopic sites.85
The HPX and HPD complexes are delivered according to the
methods outlined in Scheme 1. We have exploited the finesse
of metal-catalyzed Suzuki cross-coupling reactions to afford a
facile and modular synthetic entry toward the preparation of
these cofacial platforms. Notably, the Suzuki routes augment
the Lindsey-type syntheses that have been previously used to
produce a library of porphyrin architectures bearing function-
alized xanthene spacers.88
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G. In Electron Transfer in Chemistry; Balzani, V., Ed.; Wiley-VCH:
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The appropriate xanthene and dibenzofuran bridge precursors
are readily available from dihalide starting materials. Regio-
selective monolithiation of Rebek’s xanthene dibromide 1 with
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G. Chem. Commun. 2000, 1355-1356.
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Proton-Coupled O−O Activation
A R T I C L E S
Scheme 1. Synthesis of Hangman Porphyrins HPX and HPDa
a (a) (1) Phenyllithium, cyclohexane/THF, (2) CO2 gas; (b) methanol, H2SO4, reflux; (c) (1) phenyllithium, cyclohexane/THF, (2) CO2 gas; (d) (1) 6,
Na2CO3, Pd(PPh3)4, DMF/water, reflux, (2) 6 N HCl; (e) (1) Mn(OAc)2‚4H2O or FeBr2, DMF or THF/benzene, reflux, (2) aq NaCl/HCl or aq NaOH.
HPX and HPD platforms provide a set of well-defined molecular
scaffolds for systematic examination of proton-coupled O-O
bond activation.
Transition-metal complexes of the HPX and HPD systems
are readily available from direct reaction with the appropriate
metal salt. Iron insertion into HPX porphyrins 7 and 8 with
FeBr2 followed by treatment with HCl affords the corresponding
chloroiron(III) porphyrin complexes FeCl(HPX-CO2H) (10) and
FeCl(HPX-CO2Me) (11) in excellent yields (89% and 92%,
respectively). Compounds 10 and 11 were fully characterized
by elemental and high-resolution mass spectral analyses. Other
metal insertions proceed with equal success. For example, the
analogous chloromanganese(III) complexes MnCl(HPX-CO2H)
(14) and MnCl(HPX-CO2Me) (15) are prepared in excellent
yields (90% and 93%, respectively) by reactions of 7 and 8
with Mn(OAc)2‚4H2O under Alder conditions, followed by
workup with NaCl and HCl. Complexes 14 and 15 gave
satisfactory high-resolution mass spectral and elemental analy-
ses. The chloroiron(III) FeCl(HPD-CO2H) (16) and chloroman-
ganese(III) MnCl(HPD-CO2H) (17) complexes of HPD are
synthesized in a similar way to their HPX congeners in 85%
and 90% yield, respectively.
phenyllithium followed by quenching with CO2 and acid workup
furnishes carboxylic acid 2 in 75% yield. Reaction of 2 with
H2SO4 in methanol affords methyl ester 3 in high yield (93%).
4,6-Dibromodibenzofuran 4 undergoes a similar monolithiation
sequence with phenyllithium, CO2, and acid to give monoacid
5.
Trimesitylporphyrin boronate 6 is a versatile transmetalating
agent for the preparation of HPX and HPD porphyrins.90,91
Metal-catalyzed cross-couplings of 6 with halide compounds
2, 3, or 5 proceed smoothly under typical Suzuki reaction
conditions using a Pd(PPh3)4/NaCO3 catalyst system. Previously
synthesized xanthene-bridged porphyrins bearing a pendant
carboxylic acid H2(HPX-CO2H) (7) or methyl ester H2(HPX-
CO2Me) (8) group are prepared in 72% and 69% yields,
respectively. For comparison, macrocycle 8 is prepared in 22%
yield under standard Lindsey conditions.88 Dibenzofuran-bridged
porphyrin H2(HPD-CO2H) (9) is synthesized in 67% yield from
5 and 6. With the ability to control both the protic capability
(carboxylic acid versus ester) and orientation (xanthene versus
dibenzoufuran) of the distal hydrogen-bonding functionality, the
Metalation of 7 and 8 followed by basic workup supplies
the monomeric iron(III) hydroxide porphyrins FeOH(HPX-
CO2H) (12) and FeOH(HPX-CO2Me) (13) in 92% and 90%
yield, respectively. The sterically demanding mesityl groups
prevent the formation of bisiron(III) µ-oxo dimers.92,93 Satisfac-
tory elemental and high-resolution mass spectral analyses
accompanied 12 and 13. The former has been recently charac-
(90) Hyslop, A. G.; Kellett, M. A.; Iovine, P. M.; Therien, M. J. J. Am. Chem.
Soc. 1998, 120, 12676-12677.
(91) Deng, Y.; Chang, C. K.; Nocera, D. G. Angew. Chem., Int. Ed. 2000, 39,
1066-1068.
(92) Cheng, R.; Latos-Grazynski, L.; Balch, A. L. Inorg. Chem. 1982, 21, 2412-
2418.
(93) Calderwood, T. S.; Bruice, T. C. Inorg. Chem. 1985, 25, 3722-3724.
9
J. AM. CHEM. SOC. VOL. 125, NO. 7, 2003 1869

A R T I C L E S
Chang et al.
Figure 2. Differential scanning calorimetry (DSC) scan of a solid sample
of FeOH(HPX-CO2H) (12) under nitrogen.
terized by single-crystal X-ray analysis.89 The structure is unique
because it is the first monomeric iron(III) hydroxide porphyrin
to be analyzed by single-crystal X-ray diffraction analysis,94
and more significantly, it displays the unprecedented feature of
a single structured water molecule. The water is suspended
above the heme platform by ditopic hydrogen bonds formed
with the distal xanthene carboxylic acid and the terminal
hydroxide ligand of the porphyrin. To further probe the
properties of the water encapsulated within the hydrogen-bonded
scaffold, differential scanning calorimetric (DSC) measurements
were undertaken on solid samples of 12. DSC scans exhibit an
endothermic peak with an onset of 270 °C (Figure 2). Thermal
gravimetric measurements coupled to in situ infrared absorption
detection confirm that this peak corresponds to a dehydration
process. The heat flow associated with the dehydration is 21.8
J/g; integration yields a binding energy of 5.8 kcal/mol for the
water to the HPX platform. This value attests to the strength of
the matched hydrogen-bonding network established by the
oxygen atoms of the ditopic metalloporphyrin and the distal
carboxylic acid of the Hangman scaffold.
Figure 3. Absorption spectra of high-valent ferryl-HPX complexes
analogous to compounds I and II of heme oxygenases. Spectrum (a) was
obtained by oxidation of a 10-5 M solution of FeCl(HPX-CO2H) (10) with
1.5 equiv of PhIO in dichloromethane at -78 °C. Spectrum (b) was obtained
by oxidation of a 10-5 M solution of FeOH(HPX-CO2H) (12) with 1.2
equiv of mCPBA in THF at -61 °C.
and HPD complexes presages an oxidation chemistry derived
from O-O bond activation chemistry.
Catalase-like Disproportionation of Hydrogen Peroxide.
Peroxide species offer a direct starting point from which to
examine the effects of hydrogen bonding and proton transfer
on O-O bond activation chemistry. In nature, catalase enzymes,
the majority of which are heme-based, dismutate intracellular
hydrogen peroxide to oxygen and water according to the
following stoichiometry:96
Chemical Generation of High-Valent Ferryl HPX and
HPD Derivatives. We sought to provide direct evidence for
the formation of high-valent species in order to establish the
suitability of the HPX and HPD platforms to effect oxidation
reactions. To this end, iron-oxo complexes of the HPX and HPD
frameworks analogous to compounds I and II of heme enzymes
were prepared at low temperature and spectroscopically inter-
rogated (Figure 3). Chemical oxidation to afford the ferryl
porphyrin (compound II) or ferryl porphyrin cation radical
(compound III) species is dependent on the axial ligand, solvent,
and reaction temperature. Reactions of iron(III) hydroxide
complexes 12 and 13 with mCPBA in THF at -61 °C furnish
deep red solutions with identical absorption spectra characteristic
of neutral iron(IV)-oxo porphyrins, displaying a Soret band at
418 nm (ꢀ ) 170 000 M-1 cm-1) and a Q-band centered at 555
nm.93,95 In contrast, treatment of the chloroiron(III) derivatives
10, 11, and 16 with PhIO in dichloromethane at -78 °C occurs
with the formation of emerald green species, which exhibit
absorption spectra consistent with their assignment as iron(IV)-
oxo porphyrin cation radicals.67 These spectra exhibit broadened,
blue-shifted Soret bands of decreased molar absorptivity (λmax
∼ 406 nm, ꢀ ∼ 70 000 M-1 cm-1) with accompanying weak,
tailing absorptions at 600-700 nm indicative of porphyrin cation
radicals. The successful preparation of high-valent ferryl HPX
2H2O2 catalase8 O2 + 2H2O
(1)
Because the 2:1 H2O2:O2 ratio is characteristic of dismutation,
we investigated the H2O2:O2 mass balance of eq 1 for the activity
of HPX carboxylic acid 10 with H2O2 under buffered, biphasic
conditions (dichloromethane/aqueous phase, pH 7) in the
presence of 1,5-dicyclohexylimidazole at 25 °C. The dioxygen
stoichiometry was established by monitoring the release of gas
with a buret. Figure 4 displays the yield of O2 as a function of
the initial H2O2 concentration in the aqueous layer in the
presence of 500 µM 10. Oxygen is obtained with a linear
dependence on the initial concentration of H2O2. The slope of
the regression line (0.45 ( 0.03) agrees well with the value of
0.5 expected for a catalase-like stoichiometry per eq 1.
A systematic evaluation of catalytic catalase reactivities for
the iron HPX and HPD complexes was carried out under the
above-mentioned buffered, biphasic conditions. The porphyrin
FeCl(TMP) served as a redox-only model compound for baseline
comparison. The catalytic results in terms of the turnover
numbers (TON) displayed in Figure 5 are striking. Complex
10, containing a xanthene bridge and a carboxylic acid group,
is the most reactive, producing almost an order of magnitude
(94) The structure of a monomeric iron(III)-hydroxide complex of a sterically
encumbered porphodimethene has been reported: Buchler, J. W.; Lay, K.
L.; Lee, Y. J.; Scheidt, W. R. Angew. Chem., Int. Ed. Engl. 1982, 21, 432.
(95) Gold, A.; Jayaraj, K.; Doppelt, P.; Weiss, R.; Chottard, G.; Bill, E.; Ding,
X.; Trautwein, A. X. J. Am. Chem. Soc. 1988, 110, 5756-5761.
(96) Nicholls, P.; Fita, I.; Loewen, P. C. AdV. Inorg. Chem. 2001, 51, 51-106.
9
1870 J. AM. CHEM. SOC. VOL. 125, NO. 7, 2003

Proton-Coupled O−O Activation
A R T I C L E S
Table 1. Epoxidation of Olefins Catalyzed by Manganese
Complexes 14, 15, 17, and MnCl(TMP)a
Substrate
Styrene (% yield) Cis-cyclooctene(% yield)
Catalyst
MnC1(HPX-CO2H) (14)
MnC1(HPX-CO2Me) (15)
MnC1(HPD-CO2H) (17)
MnC1(TMP)
70 ( 2
38 ( 2
4 ( 1
4 ( 2
6 ( 1
92 ( 6
42 ( 5
5 ( 1
5 ( 1
9 ( 2
MnC1(TMP) + 1 equiv PhCOOH
a Standard catalytic reaction conditions are given in the Experimental
Section. Yields were determined by analysis of the epoxide products by
GC-MS.
Figure 4. Oxygen release from H2O2 dismutation catalyzed by 10 at 25
°C in a biphasic dichloromethane/pH 7 phosphate buffer medium.
Figure 5. Turnover numbers (TON) for oxygen release from H2O2
dismutation catalyzed by iron complexes 10, 11, 16, and FeCl(TMP). In
the graph, TMP denotes FeCl(TMP), and TMP* denotes FeCl(TMP) + 1
equiv of benzoic acid.
Figure 6. Time-course plot for the epoxidation of cis-cyclooctene with
hydrogen peroxide catalyzed by 14 (2), 15 (9), and MnCl(TMP) (b). The
addition of 1 equiv of benzoic acid to MnCl(TMP) shows no detectable
enhancement in catalytic epoxidation reactivity.
more oxygen (436 ( 22 TON) than any of the catalysts
surveyed. Simple replacement of the “hanging” carboxylic acid
group with a methyl ester leads to a significant decrease in
catalytic activity (48 ( 3 TON for 11). Similarly, fixing the
carboxylic acid group to the vertically widened dibenzofuran
scaffold gives catalytic activities (12 ( 2 for 16) comparable
to those of the baseline compound FeCl(TMP) (2 ( 2).
Several control experiments were performed to verify the
foregoing findings. Negligible oxygen evolution is observed in
the absence of catalyst or in the presence of catalyst without
the axial 1,5-dicyclohexylimidazole ligand. Furthermore, the
external addition of 1 equiv of the molecular analogue of the
hanging group, either benzoic acid or methyl benzoate, to FeCl-
(TMP) fails to yield an increase in catalytic catalase activity.
Taken together, the data suggest that the protic nature of the
hydrogen-bonding group and its orientation are critically
important to the efficient activation of the O-O bond by 10.
Olefin Epoxidation. The success of the HPX-CO2H system
to enhance relative catalase-like activity provided a compelling
imperative to extend the reactivity of the Hangman platforms
to other processes contingent on O-O bond activation. We
targeted the catalytic epoxidation of olefins (eq 2) using
hydrogen peroxide as a terminal oxidant for the following
reasons. First, the reaction parallels the peroxide shunt cycle36,37,43
of cytochrome P450 and peroxidase enzymes while building
on the results of the observed biomimetic catalase activity.
Second, hydrogen peroxide is a green oxidant, yielding water
as the sole byproduct of catalysis.
Initial catalytic olefin epoxidation studies with the iron
Hangman porphyrins using a H2O2/1,5-dicyclohexylimidazole
system were unsuccessful, owing to the electron-rich nature of
both the porphyrin and the axial ligand.97 We thus turned our
attention to the reactivity of the manganese HPX and HPD
derivatives 14, 15, and 17, with MnCl(TMP) as the standard
baseline compound. The common olefins styrene and cis-
cyclooctene were chosen as substrates. Table 1 lists the product
yields for olefin epoxidation with H2O2 catalyzed by the
manganese complexes at 0.2 mol % catalyst loading, and Figure
6 presents a time-course plot for the epoxidation reactions
catalyzed by 14, 15, and MnCl(TMP). Epoxide products are
formed in >95% selectivity with little to no allylic oxidation
side products, indicating that the involvement of radical species
such as HO‚ and HOO‚ are unlikely.67,98 The results for
epoxidation reactivity of the manganese derivatives follow the
same general trend observed for the iron-mediated catalase
reactions. Complex 14 bearing a protic carboxylic acid group
on a xanthene platform is the most active, affording styrene
and cis-cyclooctene oxides in 70% (350 ( 10 TON) and 92%
(460 ( 30 TON) yields, respectively. These values are almost
twice as high as those obtained for the ester derivative 15 (191
( 8 TON for styrene, 208 ( 22 TON for cis-cyclooctene).
Under these conditions, both HPD complex 17 and MnCl(TMP)
yield significantly less epoxide product upon reaction with either
styrene or cis-cyclooctene (<10%, <50 TON). As observed for
(97) Nam and co-workers have used a combination of electron-deficient
imidazole co-ligands and electron-rich iron(III) porphyrins to catalyze olefin
epoxidation with H2O2: Nam, W.; Lee, H. J.; Oh, S.-Y.; Kim, C.; Jang, H.
G. J. Inorg. Biochem. 2000, 80, 219-225.
(98) Sheldon, R. A. Metalloporphyrins in Catalytic Oxidations; Marcel Dek-
ker: New York, 1994.
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A R T I C L E S
Chang et al.
the catalase reactions, negligible olefin epoxidation is detected
in the absence of catalyst or in the presence of catalyst without
axial ligand. Furthermore, the external addition of 1 equiv of
either benzoic acid or methyl benzoate to MnCl(TMP) fails to
yield an increase in epoxide product. Last, we also examined
the stereochemistry of the epoxidation of cis-stilbene by 14.99-102
The high cis-epoxide/trans-epoxide ratio of 6 ( 1 obtained is
consistent with a predominant oxomanganese(V) porphyrin
oxidizing agent.103-106
address the complexities of homolytic versus heterolytic O-O
bond cleavage pathways in protic and aprotic solvents114,115 and
demonstrate remarkable spectator ligand effects in metallopor-
phyrin-catalyzed oxidation reactions.116,117 In no case, however,
has the simple metalloporphyrin model system been designed
to intramolecularly control the proton inventory for small-
molecule activation reactivity.118-126 In doing so per a Hangman
strategy, catalytic bond-making and bond-breaking chemistry
on the metalloporphyrin redox platform is significantly en-
hanced. These systems isolate the key proton-shuttle attribute
of the distal heme cleft in a tunable synthetic platform by
scaffolding a single hydrogen-bonding group over a heme core.
This small-molecule approach affords the ability to control the
acid-base properties of the hydrogen-bonding functionality by
direct synthetic modification. Moreover, the spatial orientation
of this hydrogen-bonding distal group in relation to the porphyrin
redox platform can be modified by choice of either the xanthene
or dibenzofuran scaffold.
Structure-reactivity relationships of the HPX and HPD
frameworks in catalase-like hydrogen peroxide dismutations and
peroxide-mediated olefin epoxidations reveal that both the nature
and spatial orientation of the hydrogen-bonding group are critical
for selective and efficient catalytic chemistry. Substitution of
an aprotic hydrogen-bonding ester group for the protic car-
boxylic acid on the HPX platform results in catalyst architectures
with significantly diminished activity for the former. Moreover,
the catalytic studies reveal that the arrangement of acid-base
and redox sites is also vital for oxidation reactivity. From the
previously reported structure of 12, the monomeric iron(III)
derivative of the HPX-CO2H ligand has the unique ability to
juxtapose two oxygen atoms between proton (carboxylic acid)
and electron (metalloporphyrin) shuttle sites. Thus, the HPX
template provides a geometrically matched microcavity for the
binding and activation of peroxide and other reactive oxygen
species.
Discussion
Specific and efficient catalytic oxidation chemistry in heme-
dependent proteins is made possible by the ability of these
enzymes to exquisitely balance proton and electron inventories.
In particular, the distal side of the heme is crucial for providing
a suitable microenvironment surrounding the open coordination
site of the heme for the binding of peroxides, molecular oxygen,
and other small-molecule substrates and controlling their
subsequent catalytic chemistry as derived from coupled proton
and electron transfer. For peroxidases, catalases, and the
cytochrome P450 monooxygenases, such PCET events facilitate
the selective heterolytic cleavage of O-O bonds via the pull
effect to form high-valent iron-oxo porphyrin species such as
compound I [ferryl (FeIVdO) species paired with a porphyrin
cation radical] for further reaction with external substrates.36-39
The key O-O cleavage step itself is driven by proton activation
of a hydroperoxide intermediate, which occurs by a hydrogen-
bonding shuttle derived from proximate amino acids and/or
directed water.
The reaction chemistry of these natural enzymes emphasizes
the importance of managing proton inventory in catalytic
oxidation processes. Heretofore, metalloporphyrins employed
as models for heme-mediated oxidation chemistry have, for the
most part, focused on either modifying the redox or steric
properties of the macrocycle itself or changing the electronic
identity of the proximal axial ligand.98,107 Few intermolecular
small-molecule model systems have emerged that attend to
issues surrounding the pull effect. Notable exceptions include
Traylor’s studies of the general acid-base effects of added
imidazole in the catalytic oxidation of phenols using iron
porphyrins and peracid or hydroperoxide oxidants108-110 and
Bruice’s reports of the effects of imidazole and pH on similar
O-O cleavage reactions catalyzed by metalloporphyrins in
aqueous solution.111-113 More recently, Nam and co-workers
The divergent oxidation reactivities displayed by the Hang-
man systems can be grouped into a unified mechanistic model
that falls within the framework of natural heme enzyme
reactivity. The proposed catalytic pathway for the O-O
reactivity of the most active xanthene-bridged HPX-CO2H
platform is shown in Scheme 2. Reaction of H2O2 with the
porphyrin in the presence of an axial ligand results in a putative
(113) Bruice, T. C.; Balasubramanian, P. N.; Lee, R. W.; Smith, J. R. L. J. Am.
Chem. Soc. 1988, 110, 7890-7892.
(114) Nam, W.; Lim, M. L.; Moon, S. K.; Kim, C. J. Am. Chem. Soc. 2000,
122, 10805-10809.
(99) Groves, J. T.; Stern, M. K. J. Am. Chem. Soc. 1988, 110, 8628-8638.
(100) Bortolini, O.; Meunier, B. J. Chem. Soc., Perkin Trans. 2 1984, 1967-
1970.
(115) Nam, W.; Han, H. J.; Oh, S.-Y.; Lee, Y. J.; Choi, M.-H.; Han, S.-Y.;
Kim, C.; Woo, S. K.; Shin, W. J. Am. Chem. Soc. 2000, 122, 8677-
8684.
(101) Battioni, P.; Renaud, J. P.; Bartoli, J. F.; Reina-Artiles, M.; Fort, M.;
Mansuy, D. J. Am. Chem. Soc. 1988, 110, 8462-8470.
(102) Castellino, A. J.; Bruice, T. C. J. Am. Chem. Soc. 1988, 110, 158-162.
(103) Jin, N.; Bourassa, J. L.; Tizio, S. C.; Groves, J. T. Angew. Chem., Int.
Ed. 2000, 39, 3849-3851.
(116) Nam, W.; Jin, S. W.; Lim, M. H.; Ryu, J. Y.; Kim, C. Inorg. Chem. 2002,
41, 3647-3652.
(117) Nam, W.; Lim, M. H.; Oh, S.-Y.; Lee, J. H.; Lee, H. J.; Woo, S. K.;
Kim, C.; Shin, W. Angew. Chem., Int. Ed. 2000, 39, 3646-3649.
(118) For some seminal studies describing hydrogen-bonded porphyrins for the
binding and transport of dioxygen and carbon monoxide, see refs 119-
126.
(104) Jin, N.; Groves, J. T. J. Am. Chem. Soc. 1999, 121, 2923-2924.
(105) Nam, W.; Kim, I.; Lim, M. H.; Choi, H. J.; Lee, J. S.; Jang, H. G. Chem.
Eur. J. 2002, 8, 2067-2071.
(119) Chang, C. K.; Kondylis, M. P. J. Chem. Soc., Chem. Commun. 1986,
316-318.
(106) Gross has recently characterized oxomanganese(V) corroles: Gross, Z.;
Golubkov, G.; Simkovich, L. Angew. Chem., Int. Ed. 2000, 39, 4045-
4047.
(107) Kadish, K. M.; Smith, K. M.; Guilard, R. The Porphyrin Handbook;
Academic Press: San Diego, CA, 2000; and references therein.
(108) Traylor, T. G.; Lee, W. A.; Stynes, D. V. J. Am. Chem. Soc. 1984, 106,
755-764.
(109) Traylor, T. G.; Ciccone, J. P. J. Am. Chem. Soc. 1989, 111, 8413-8420.
(110) Traylor, T. G.; Xu, F. J. Am. Chem. Soc. 1990, 112, 178-186.
(111) Lee, W. A.; Bruice, T. C. J. Am. Chem. Soc. 1985, 107, 513-514.
(112) Zipplies, M. F.; Lee, W. A.; Bruice, T. C. J. Am. Chem. Soc. 1986, 108,
4433-4445.
(120) Chang, C. K.; Liang, Y.; Aviles, G.; Peng, S.-M. J. Am. Chem. Soc. 1995,
117, 4191-4192.
(121) Collman, J. P.; Fu, L. Acc. Chem. Res. 1999, 32, 455-463.
(122) Momenteau, M.; Reed, C. A. Chem. ReV. 1994, 94, 659-698.
(123) Gerothanassis, I. P.; Momenteau, M.; Loock, B. J. Am. Chem. Soc. 1989,
111, 7006-7012.
(124) Wuenschell, G. E.; Tetreau, C.; Lavalette, D.; Reed, C. A. J. Am. Chem.
Soc. 1992, 114, 3346-3355.
(125) Walker, F. A.; Bowen, J. J. Am. Chem. Soc. 1985, 107, 7632-7635.
(126) Tani, F.; Matsu-Ura, M.; Nakayama, S.; Naruta, Y. Coord. Chem. ReV.
2002, 226, 219-226.
9
1872 J. AM. CHEM. SOC. VOL. 125, NO. 7, 2003

Proton-Coupled O−O Activation
A R T I C L E S
Scheme 2. Proposed Pathway for Proton-Assisted Metal-Oxo Formation and Substrate Oxidation by HPX Hangman Porphyrins
metal hydroperoxide complex. The bound HO2- species is then
converted into an oxoiron(IV) porphyrin cation radical or an
oxomanganese(V) intermediate by proton transfer and subse-
quent heterolytic O-O bond cleavage. The high-valent metal-
oxo species generated are sufficiently reactive to oxidize
substrates. Alternatively, protonation activates the hydroperoxide
for direct reaction with substrates prior to O-O bond cleavage.
Increasing the distance between the ditopic sites by use of a
dibenzofuran-based HPD scaffold affords a catalyst that has
comparable performance to a simple tetramesitylporphyrin
counterpart, despite the presence of a pendant protic hydrogen-
bonding group. It is tempting to suggest that the control of
proton transfer in these catalytic cycles avoids homolytic
cleavage or other peroxide decomposition pathways, and ongo-
ing mechanistic work is aimed at addressing such issues.
The pull-based mechanism provides a working model for
assessing the relative reactivities of the Hangman platforms by
inspection of the key metal-hydroperoxide intermediate. The
HPX-CO2H system, which exhibits the highest reactivity, has
the capacity to stabilize binding of the oxidant by hydrogen
bonding, while the carboxylic acid group provides an intramo-
lecular shuttle to deliver proton equivalents for oxidation
chemistry. The ester derivative HPX-CO2Me can also stabilize
a bound HO2- species via hydrogen bonding through its hanging
carbonyl group but is unable to offer an internal pathway for
protons. Finally, the comparable activities of the HPD-CO2H
and TMP series suggest that hydrogen bonding and intramo-
lecular proton transfer are inefficient in the former, owing to
the splayed arrangement of redox and acid-base sites.
competitive analogues of existing catalysts but to demonstrate
how the addition of proton control can enhance the reactivity
of a redox cofactor. To this end, the catalytic processes of the
catalase-like disproportionation of hydrogen peroxide and the
epoxidation of olefins have been compared for the HPX and
HPD systems and redox-only porphyrin platforms. For both
cases, a marked activity enhancement is observed for the
xanthene-bridged platform with a pendant carboxylic acid group
(HPX-CO2H), which features a geometrically matched site
between proton and electron sources. The reactivity data
establish that this Hangman approach can yield superior catalysts
to analogues that do not manage both proton and electron
inventories.
The results have significant implications from the perspectives
of both biological enzymes and catalyst design. First, the ability
to achieve efficient catalase or epoxidation reactivity with a
single metalloporphyrin-based scaffold is evocative of natural
heme-dependent proteins that employ a conserved protopor-
phyrin IX cofactor to effect a myriad of chemical reactivities.
In terms of synthetic catalyst design, the Hangman strategy
demonstrates that the addition of proton control to a redox
platform can enhance its catalytic performance. The importance
of hydrogen bonding for controlling oxygen activation has been
emphasized recently with the stoichiometric reactions of oxygen
and water within tripodal non-heme cavities.127-133 The Hang-
man approach described here is distinguished by its ability to
use a hydrogen-bond network to actively deliver protons to drive
(127) MacBeth, C. E.; Golombek, A. P.; Young, V. G., Jr.; Tang, C.; Kuczera,
K.; Hendrich, M. P.; Borovik, A. S. Science 2000, 289, 938-941.
(128) Gupta, R.; MacBeth, C. E.; Young, V. G., Jr.; Borovik, A. S. J. Am. Chem.
Soc. 2002, 124, 1136-1137.
Concluding Remarks
(129) Hammes, B. S.; Young, V. G., Jr.; Borovik, A. S. Angew. Chem., Int. Ed.
1999, 38, 666-669.
The present work represents an initial study to utilize PCET
as a mechanistic framework for exploring small-molecule
activation chemistry. Our findings clearly indicate that the
introduction of a single proton-shuttle group onto a redox-active
platform in simple chemical model systems can significantly
affect the activation of O-O bonds for disparate catalytic
processes. We stress here that our aim is not to create
(130) Wada, A.; Ogo, S.; Nagatomo, S.; Kitagawa, T.; Watanbe, Y.; Jitsukawa,
K.; Masuda, H. Inorg. Chem. 2002, 41, 616-618.
(131) Ogo, S.; Wada, S.; Watanbe, Y.; Iwase, M.; Wada, A.; Harata, M.;
Jitsukawa, K.; Masuda, H.; Einaga, H. Angew. Chem., Int. Ed. 1998, 37,
2102-2104.
(132) Garner, D. K.; Allred, R. A.; Tubbs, K. J.; Arif, A. M.; Berreau, L. M.
Inorg. Chem. 2002, 41, 3533-3541.
(133) Berreau, L. M.; Mahapatra, S.; Halfen, J. A.; Young, V. G., Jr.; Tolman,
W. B. Inorg. Chem. 1996, 35, 6339-6342.
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A R T I C L E S
Chang et al.
for 30 min, and washed with water (7 × 25 mL). The organic layer
was separated and dried over Na2SO4, and the solvent was removed
by rotary evaporation. Purification by column chromatography (silica
gel, 2:1 hexanes/dichloromethane to dichloromethane) followed by
recrystallization from dichloromethane/methanol solutions delivered 7
as a royal purple powder (50 mg, 72% yield). Complex 7 obtained by
this synthetic method gave comparable high-resolution mass spectral
and elemental analyses to batches prepared by Lindsey cyclizations.
5-[4-(5-Methoxycarbonyl-2,7-di-tert-butyl-9,9-dimethylxanthenyl)]-
10,15,20- trimesitylporphyrin, H2(HPX-CO2Me) (8). Under a nitrogen
atmosphere, solids 3 (30 mg, 0.065 mmol), 6 (68 mg, 0.080 mmol),
Na2CO3 (25 mg), and Pd(PPh3)4 (15 mg, 0.0130 mmol) were combined
in a 50-mL Schlenk flask. DMF (10 mL) and deionized water (1 mL)
were added, and the mixture was heated at reflux overnight under
nitrogen. The reaction was taken to dryness and the residue was
redissolved in dichloromethane (25 mL), stirred with 6 N HCl (25 mL)
for 30 min, and washed with water (7 × 25 mL). The organic layer
was separated and dried over Na2SO4, and the solvent was removed
by rotary evaporation. Purification by column chromatography (silica
gel, 2:1 hexanes/dichloromethane) delivered 8 as a royal purple powder
(47 mg, 69% yield). Complex 8 obtained by this synthetic method gave
comparable high-resolution mass spectral and elemental analyses to
batches prepared by Lindsey cyclizations.
catalytic oxygen activation processes. We anticipate that the
further development of hybrid architectures containing both
acid-base and redox functionalities will lead to new advances
in catalysis. In this vein, current work is directed at the synthesis
of platforms that will permit, by transient absorption spectros-
copy, direct mechanistic investigations of the proton-coupled
O-O activation process and platforms that will expand the scope
of multielectron PCET reactions associated with catalytic bond-
making and bond-breaking chemistry.
Experimental Section
Materials. Silica gel 60 (70-230 and 230-400 mesh, Merck) and
aluminum oxide 60 (EM Science) were used for column chromatog-
raphy. Analytical thin-layer chromatography was performed on JT
Baker IB-F silica gel (precoated sheets, 0.2 mm thick) or JT Baker
IB-F aluminum oxide (precoated sheets, 0.2 mm thick). Solvents for
synthesis were reagent-grade or better and were dried according to
standard methods.134 4,5-Dibromo-2,7-di-tert-butyl-9,9-dimethylxan-
thene 1,135 4,6-dibromodibenzofuran 4,136 and 4-bromo-6-hydroxycar-
bonyldibenzofuran 5136 were prepared according to literature procedures.
The reference porphyrins FeCl(TMP) and MnCl(TMP) are available
by published protocols.107 The preparation of zinc(II) 5,10,15-trimesityl-
20-(4′,4′,5′,5′-tetramethyl[1′,3′,2′] dioxaborolan-2′-yl)porphyrin (6) will
be detailed in a future report. All other reagents were used as received.
4-Hydroxycarbonyl-5-bromo-2,7-di-tert-butyl-9,9-dimethylxan-
thene (2). Phenyllithium (1.2 mL, 1.8 M solution in cyclohexane) was
added over a period of 10 min to a solution of xanthene dibromide 1
(1.00 g, 2.08 mmol) in dry THF (40 mL) cooled to -78 °C under a
nitrogen atmosphere. After the mixture was stirred at -78 °C under
nitrogen for 1 h, CO2 gas was bubbled into the lithiate at a rapid rate
until the yellow color of the solution had faded. The mixture was then
allowed to warm to room temperature and stirred overnight. The
reaction was quenched with 2 N HCl (15 mL) and the organic solvent
was removed by rotary evaporation. The resulting white precipitate
was filtered and washed with water. Purification by column chroma-
tography (silica gel, dichloromethane) delivered 2 as a white powder
(0.7 g, 75% yield). 1H NMR (500 MHz, CDCl3, 25 °C): δ ) 8.18 (d,
J ) 4 Hz, 1H, ArH), 7.66 (d, J ) 4 Hz, 1H, ArH), 7.50 (d, J ) 4 Hz,
1H, ArH), 7.40 (d, J ) 4 Hz, 1H, ArH), 1.68 (s, 6H, CH3), 1.37 (s,
9H, CH3), 1.35 (s, 9H, CH3).
4-Methoxycarbonyl-5-bromo-2,7-di-tert-butyl-9,9-dimethylxan-
thene (3). A solution of acid 2 (1.0 g, 2.53 mmol) in methanol (50
mL) and H2SO4 (2 mL) was refluxed for 4 h. The solvent was removed
in vacuo, water (20 mL) was added to the residue, and the resulting
precipitate was filtered. The solid was redissolved in dichloromethane
(50 mL), washed with 15% HCl and water, dried over Na2SO4, and
taken to dryness by rotary evaporation. Purification by column
chromatography (silica gel, dichloromethane) provided ester 3 as a white
powder (0.96 g, 93% yield). 1H NMR (500 MHz, CDCl3, 25 °C): δ )
7.72 (d, J ) 4 Hz, 1H, ArH), 7.55 (d, J ) 4 Hz, 1H, ArH), 7.46 (d, J
) 4 Hz, 1H, ArH), 7.32 (d, J ) 4 Hz, 1H, ArH), 4.02 (s, 3H, CH3),
1.64 (s, 6H, CH3), 1.35 (s, 9H, CH3), 1.33 (s, 9H, CH3).
5-[4-[6-(Hydroxycarbonyl)dibenzofuranyl]]-10,15,20-trimesitylpor-
phyrin, H2(HPD-CO2H) (9). Under a nitrogen atmosphere, a mixture
of 6-bromo-4-dibenzofurancarboxylic acid (5) (42 mg, 0.144 mmol),
6 (135 mg, 0.159 mmol), Na2CO3 (49 mg, 0.462 mmol), and Pd(PPh3)4
(25 mg, 0.0216 mmol) were combined in a Schlenk flask. DMF (20
mL) and deionized water (2 mL) were added, and the mixture was
refluxed for 19 h under nitrogen. The solvent was removed and the
residue was redissolved in dichloromethane (30 mL) and stirred with
6 N HCl (20 mL) for 30 min. The organic layer was separated and
washed with 20% aqueous Na2CO3 (20 mL) followed by water (2 ×
50 mL). The solvent was evaporated and the residue was purified by
column chromatography (silica gel, 2:1 hexanes/dichloromethane to
1:1 ethyl acetate/dichloromethane) to afford 9 as a purple solid (85
1
mg, 67% yield). H NMR (300 MHz, CDCl3, 25 °C): δ ) 8.66 (m,
8H), 8.41 (m, 2H), 8.30 (dd, J1 ) 7.6 Hz, J2 ) 1.3 Hz, 1H), 8.06 (dd,
J1 ) 7.8 Hz, J2 ) 1.3 Hz, 1H), 7.85 (t, J ) 7.6 Hz, 1H), 7.52 (t, J )
7.8 Hz, 1H), 7.30 (s, 1H), 7.29 (s, 1H), 7.26 (s, 4H), 2.65 (s, 3H), 2.62
(s, 6H), 1.91 (s, 3H), 1.88 (s, 9H), 1.87 (s, 6H), -2.46 (s, 2H).
HRESIMS (MH+) m/z calcd for C60H51N4O3 875.3956, found 875.3969.
FeCl(HPX-CO2H) (10). A combination of 7 (218 mg, 0.21 mmol),
FeBr2 (270 mg), and DMF (35 mL) was refluxed under nitrogen for 2
h, opened to air, and brought to dryness under vacuum. The solids
were redissolved in dichloromethane (100 mL) and washed with water
(4 × 75 mL). The organic layer was stirred with 20% HCl (50 mL)
for 75 min, washed with water (5 × 100 mL), and taken to dryness.
The resulting residue was purified by column chromatography (silica
gel, dichloromethane to 5% methanol/dichloromethane), and retreated
with HCl as described above to furnish 10 as a brown powder (211
mg, 89% yield). HRFABMS ([M - Cl]+) m/z calcd for C71H70N4O3-
Fe, 1082.4797; found, 1082.4773. Anal. Calcd for C71H70ClN4O3Fe:
C, 76.23; H, 6.31; N, 5.01. Found: C, 76.44; H, 6.19; N, 4.82.
FeCl(HPX-CO2Me) (11). In a drybox, 8 (50 mg, 0.048 mmol), 2,6-
lutidine (0.1 mL), FeBr2 (100 mg), and THF (15 mL) were loaded in
a 100-mL flask equipped with a condenser. The reaction was refluxed
under nitrogen for 5 h, opened to air, and brought to dryness under
vacuum. The residue was purified by column chromatography (silica
gel, dichloromethane to 10% methanol/dichloromethane), redissolved
in dichloromethane (50 mL), and stirred with 20% HCl (25 mL) for 1
h. The organic layer was washed with water (5 × 50 mL) and taken to
dryness. The resulting residue was purified by column chromatography
(silica gel, dichloromethane to 5% methanol/dichloromethane), and
retreated with HCl as described above to furnish 11 as a brown powder
(50 mg, 92% yield). HRFABMS ([M - Cl]+) m/z calcd for C72H72N4O3-
5-[4-(5-Hydroxycarbonyl-2,7-di-tert-butyl-9,9-dimethylxanthenyl)]-
10,15,20- trimesitylporphyrin, H2(HPX-CO2H) (7). Under a nitrogen
atmosphere, solids 2 (30 mg, 0.067 mmol), 6 (68 mg, 0.080 mmol),
Na2CO3 (25 mg), and Pd(PPh3)4 (15 mg, 0.0130 mmol) were combined
in a 50-mL Schlenk flask. DMF (10 mL) and deionized water (1 mL)
were added, and the mixture was heated at reflux overnight under
nitrogen. The reaction was taken to dryness and the residue was
redissolved in dichloromethane (25 mL), stirred with 6 N HCl (25 mL)
(134) Armarego, W. L. F.; Perrin, D. D. Purification of Laboratory Chemicals,
4th ed.; Butterworth-Heinmann: Oxford, U.K., 1996.
(135) Nowick, J. S.; Ballester, P.; Ebmeyer, F.; Rebek, J., Jr. J. Am. Chem.
Soc. 1990, 112, 8902-8906.
(136) Schwartz, E. B.; Knobler, C. B.; Cram, D. J. J. Am. Chem. Soc. 1992,
114, 10775-10784.
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1874 J. AM. CHEM. SOC. VOL. 125, NO. 7, 2003

Proton-Coupled O−O Activation
A R T I C L E S
Fe, 1096.4954; found, 1096.4969. Anal. Calcd for C72H72ClN4O3Fe:
C, 76.35; H, 6.41; N, 4.95. Found: C, 76.70; H, 6.72; N, 4.62.
FeOH(HPX-CO2H) (12). A combination of 7 (218 mg, 0.21 mmol),
FeBr2 (270 mg), and DMF (35 mL) was refluxed under nitrogen for 2
h, opened to air, and brought to dryness under vacuum. The solids
were redissolved in dichloromethane (100 mL) and washed with water
(4 × 75 mL). The organic layer was stirred with 20% HCl (50 mL)
for 75 min, washed with water (5 × 100 mL), and taken to dryness.
The resulting residue was purified by column chromatography (silica
gel, dichloromethane to 1% methanol/dichloromethane), redissolved
in toluene (100 mL), and stirred with 0.5 M NaOH (100 mL) for 12 h.
The organic layer was washed with water (3 × 50 mL) and dried over
Na2SO4. Removal of the solvent followed by recrystallization from
pentane afforded analytically pure 12 as a brown microcrystalline
powder (212 mg, 92% yield). HRFABMS ([M - OH]+) m/z calcd for
C71H70N4O3Fe, 1082.4797; found, 1082.4824. Anal. Calcd for
C76H85N4O5Fe: C, 76.68; H, 7.20; N, 4.71. Found: C, 76.78; H, 7.19;
N, 4.69.
found, 1095.4973. Anal. Calcd for C72H72ClN4O3Mn: C, 76.41; H, 6.41;
N, 4.95. Found: C, 76.32; H, 6.32; N, 5.05.
FeCl(HPD-CO2H) (16). Iron insertion into the free base porphyrin
was achieved by a standard literature procedure. A mixture of 9 (15
mg, 0.0171 mmol), FeBr2 (37 mg, 0.171 mmol), and anhydrous DMF
(3.5 mL) was refluxed under nitrogen for 2 h, opened to air, and brought
to dryness under vacuum. The residue was redissolved in dichloro-
methane (10 mL) and washed with water (3 × 30 mL). The organic
layer was stirred with 20% HCl (4 mL) for 75 min, washed with water
(3 × 30 mL), and taken to dryness. The residue was purified by column
chromatography (silica gel, dichloromethane to 10% methanol/di-
chloromethane), redissolved in dichloromethane (10 mL), and stirred
with 4 N HCl (1.5 mL) overnight. The organic layer was separated,
washed with water (3 × 40 mL), dried over Na2SO4, and evaporated.
The iron complex 16 was isolated as a brown powder (14 mg, 85%
yield). HRESIMS ([M - Cl]+) m/z calcd for C60H48N4O3Fe, 928.3070;
found, 928.3064.
MnCl(HPD-CO2H) (17). A solution of 9 (15 mg, 0.0171 mmol)
and Mn(OAc)2‚4H2O (30 mg) in DMF (5 mL) was refluxed in air for
3 h. The reaction was cooled to room temperature and taken to dryness.
The residue was taken up in a 1:1 mixture of dichloromethane/water
(25 mL). The organic layer was separated, washed with water (3 × 25
mL), and stirred with a 5:1 mixture of saturated aqueous NaCl and
HCl (24 mL) for 90 min. The organic layer was decanted, and the
solvent was removed under vacuum. The remaining solid was purified
by column chromatography (silica gel, dichloromethane to 5% methanol/
dichloromethane) and retreated with aqueous NaCl and HCl as described
above. The organic phase was separated, washed with water (3 × 25
mL), dried over Na2SO4, and taken to dryness. Recrystallization from
dichloromethane and hexanes afforded pure 17 as a green solid (15
mg, 90% yield). HRESIMS ([M - Cl]+) m/z calcd for C60H48N4O3-
Mn, 927.3101; found 927.3093.
Physical Measurements. 1H NMR spectra were collected in CDCl3
or toluene- d8 (Cambridge Isotope Laboratories) at the MIT Department
of Chemistry Instrumentation Facility (DCIF) on either a Mercury 300
or an Inova 500 spectrometer at 25 °C. All chemical shifts are reported
in the standard δ notation in parts per million; positive chemical shifts
are to higher frequency from the given reference. Absorption spectra
were obtained on either a Cary-17 spectrophotometer modified by On-
Line Instruments (OLIS) to include computer control or a Spectral
Instruments 440 Series spectrophotometer. Differential scanning cal-
orimetry (DSC) was carried out on a Perkin-Elmer Pyris 1 differential
scanning calorimeter. Samples were run under a nitrogen atmosphere.
Thermal gravimetric analyses with in situ infrared detection were
performed on a Perkin-Elmer 3000 TG-IR system. High-resolution mass
spectral analyses were carried out at the University of Illinois Mass
Spectrometry Laboratory or the MIT Department of Chemistry
Instrumentation Facility. Elemental analyses were carried out at
Quantitative Technologies, Inc. (Whitehouse, NJ) and Michigan State
University.
FeOH(HPX-CO2Me) (13). In a drybox, 8 (50 mg, 0.040 mmol),
2,6-lutidine (0.1 mL), FeBr2 (100 mg), and THF (15 mL) were loaded
in a 100-mL flask equipped with a condenser. The reaction was refluxed
under nitrogen for 5 h, opened to air, and brought to dryness under
vacuum. The residue was purified by column chromatography (silica
gel, dichloromethane to 10% methanol/dichloromethane), redissolved
in dichloromethane (50 mL), and stirred with 20% HCl (25 mL) for 1
h. The organic layer was washed with water (5 × 50 mL) and taken to
dryness. The resulting solid was redissolved in toluene (50 mL) and
stirred with 0.5 M NaOH (50 mL) for 12 h. The organic phase was
washed with water (3 × 50 mL) and dried over Na2SO4, and the solvent
was removed by rotary evaporation. Recrystallization from pentane
furnished analytically pure 13 as a brown powder (48 mg, 90% yield).
HRFABMS ([M - OH]+) m/z calcd for C72H72N4O3Fe, 1096.4954;
found, 1096.4982. Anal. Calcd for C77H87N4O5Fe: C, 76.79; H, 7.28;
N, 4.65. Found: C, 76.74; H, 7.36; N, 4.72.
MnCl(HPX-CO2H) (14). A solution of 7 (103 mg, 0.10 mmol) and
Mn(OAc)2‚4H2O (220 mg) in DMF (15 mL) was refluxed in air for 3
h. The reaction was cooled to room temperature and taken to dryness.
The remaining residue was taken up in a 1:1 mixture of dichlo-
romethane/water (50 mL). The organic layer was separated, washed
with water (3 × 75 mL), and stirred with a 5:1 mixture of saturated
aqueous NaCl and HCl (72 mL) for 90 min. The organic layer was
decanted, and the solvent was removed under vacuum. The remaining
solid was purified by column chromatography (silica gel, dichloro-
methane to 5% methanol/dichloromethane) and retreated with aqueous
NaCl and HCl as described above. The organic phase was separated,
washed with water (3 × 75 mL), dried over Na2SO4, and taken to
dryness. Recrystallization from dichloromethane and hexanes afforded
pure 14 as a forest green microcrystalline powder (101 mg, 90% yield).
HRFABMS ([M - Cl]+) m/z calcd for C71H70N4O3Mn, 1081.4828;
found, 1081.4833. Anal. Calcd for C71H70ClN4O3Mn: C, 76.29; H, 6.31;
N, 5.01. Found: C, 76.37; H, 6.14; N, 4.93.
Hydrogen Peroxide Disproportionation Reactions. Dismutation
reactions were performed at room temperature in a 5 mL conical
reaction vial with a side port, equipped with a magnetic spinvane stir
bar and a capillary gas delivery tube linked to a graduated buret filled
with water. The reaction vial was charged with 1 µmol of the iron
porphyrin, 25 µmol of 1,5-dicyclohexylimidazole, 4 µmol of benzyl-
dimethyltetradecylammonium chloride, 2 mL of dichloromethane, and
1 mL of phosphate buffer, pH 7. The solution was stirred to ensure
gas pressure equilibration. An aliquot of 30% H2O2 (0.11 mL) was
added to the reaction mixture via syringe through the side port. The
oxygen evolution was measured by use of a buret. The identity of the
oxygen gas was confirmed independently by the alkaline pyrogallol
test.137
MnCl(HPX-CO2Me) (15). A solution of 8 (103 mg, 0.098 mmol)
and Mn(OAc)2‚4H2O (220 mg) in DMF (15 mL) was refluxed in air
for 3 h. The reaction was cooled to room temperature and taken to
dryness. The remaining residue was taken up in a 1:1 mixture of
dichloromethane/water (50 mL). The organic layer was separated,
washed with water (3 × 75 mL), and stirred with a 5:1 mixture of
saturated aqueous NaCl and HCl (72 mL) for 90 min. The organic
layer was decanted, and the solvent was removed under vacuum. The
remaining solid was purified by column chromatography (silica gel,
dichloromethane to 5% methanol/dichloromethane) and retreated with
aqueous NaCl and HCl as described above. The organic phase was
separated, washed with water (3 × 75 mL), dried over Na2SO4, and
taken to dryness. Recrystallization from dichloromethane and hexanes
afforded pure 15 as a hunter green powder (102 mg, 93% yield).
HRFABMS ([M - Cl]+) m/z calcd for C72H72N4O3Mn, 1095.4985;
(137) Duncan, I. A.; Harriman, A.; Porter, G. Anal. Chem. 1979, 51, 2206-
2208.
9
J. AM. CHEM. SOC. VOL. 125, NO. 7, 2003 1875

A R T I C L E S
Chang et al.
Olefin Epoxidation Reactions. Epoxidations were carried out at
room temperature in air in a 5 mL conical reaction vial equipped with
a magnetic spinvane stir bar and a Teflon-lined screw cap. The reaction
vial was charged with 1 µmol of the manganese porphyrin, 500 µmol
of styrene or cis-cyclooctene, 20 µmol of 1,5-dicyclohexylimidazole,
2.75 µmol of n-dodecane (standard), and 2 mL of dichloromethane.
The solution was stirred, and at regular intervals of 1 h, an aliquot of
0.23 mL of 30% H2O2 (2940 µmol, pH adjusted at 4-4.5 with 1%
aqueous NaOH) was added to the reaction mixture. The reactions were
stopped after 3 h. An aliquot of the reaction mixture was then withdrawn
for gas chromatographic (GC) analyses with n-dodecane as a standard.
Product analyses for the styrene and cis-cyclooctene epoxidation
reactions were performed on a Hewlett-Packard 5890 series II gas
chromatograph with a Hewlett-Packard-1 nonpolar column (30 m).
Retention times for the epoxides prepared in our catalytic reactions
are identical to those of authentic samples. Epoxidation of cis-stilbene
was carried out as described by Groves and Stern99 and Mansuy and
co-workers.101
Acknowledgment. C.J.C. kindly thanks the National Science
Foundation and the MIT/Merck Foundation for predoctoral
fellowships. We also thank D. Papoutsakis and J. Madden for
their help with the DSC measurements and C.-Y. Yeh and J. T.
Groves for helpful discussions. The National Institutes of Health
(GM 47274) provided funding for this work.
JA028548O
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1876 J. AM. CHEM. SOC. VOL. 125, NO. 7, 2003