Stereochemical control of H2O2 dismutation by Hangman porphyrins

Article abstract of DOI:10.1039/b616884a

Incorporation of a disparate set of aryl groups appended to the meso-positions of Hangman porphyrin xanthene architectures dramatically impacts the ability of such systems to catalyze the disproportionation of H ₂O₂ via the catalase

Full text of DOI:10.1039/b616884a

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Stereochemical control of H2O2 dismutation by Hangman porphyrins{
Joel Rosenthal, Leng Leng Chng, Stephen D. Fried and Daniel G. Nocera*
Received (in Berkeley, CA, USA) 17th November 2006, Accepted 3rd May 2007
First published as an Advance Article on the web 23rd May 2007
DOI: 10.1039/b616884a
Incorporation of a disparate set of aryl groups appended to the
meso-positions of Hangman porphyrin xanthene architectures
dramatically impacts the ability of such systems to catalyze the
disproportionation of H2O2 via the catalase reaction.
Oxygen activation by heme-iron centers is exploited by Nature for
cellular energy production.1–4 We have captured the fundamental
O–O bond breaking reactivity that drives this energy liberating
process using a Hangman porphyrin xanthene (HPX) construct.5
The Hangman motif is embodied by the positioning of an acid-
base group above a (P)FeIII–OH (P = porphyrin) platform via a
xanthene or dibenzofuran spacer. For such systems, the catalase
and epoxidation reactivities of the protoporphyrin IX based class
of proteins is emulated by using an acid functionality to unmask a
high-valent metal-oxo via a proton-coupled electron transfer
(PCET) process.6 We have shown that optimization of the pKa
Scheme 1 (a) (i) Phenyllithium, C6H12–THF; (ii) DMF, H2O; (iii)
of the pendent acid group for Hangman architectures dramatically
impacts the efficacy of PCET reactions,7 but little is known about
neopentyl glycol, benzenesulfonic acid, toluene, D; (b) (i) phenyllithium,
C6H12–THF; (ii) CO2; (iii) trifluoroacetic acid, water; (c) methanol,
how the basal steric and electronic properties of the iron porphyrin
H2SO4, D; (d) (i) pyrrole, aryl aldehyde (Ar–CHO), BF3?OEt2, CHCl3; (ii)
platform impacts PCET reactivity. To address this issue, we now
DDQ; (iii) AcOH, H2SO4, H2O, D.
report a set of Hangman derivatives (1–3) that incorporate
pendent aryl groups with varying stereochemical and electronic
deliver freebase Hangman 8. Hydrolysis under acidic conditions is
properties and assess which of these are paramount to the PCET
necessary to convert the ester hanging group to the desired
activation of O–O bonds at the Hangman platform.
carboxylic acid functionality.{
The crystal structure of the freebase precursor of 3{ is shown in
Fig. 1. The structure is similar to other porphyrin Hangman
derivatives.9 Noteworthy structural features include the geometry
of the xanthene spacer, which is canted by roughly 78u with respect
to the porphyrin plane. Additionally, the xanthene pillar is slightly
bent at the sp3 hybridized carbon on the aromatic backbone by
nearly 15u. Similar distortions have been observed for other
porphyrin xanthene architectures.9–11
The strategy for the synthesis of porphyrin Hangman complexes
1–3 that is outlined in Scheme 1 borrows from that already
described.8 The protected xanthene acetal (5) is prepared from the
symmetric xanthene dibromide (4) by lithiation and reaction with
DMF to generate the bromoxanthene aldehyde, followed by
subsequent condensation with neopentyl glycol. Lithiation of 5
followed by reaction with CO2 and deprotection of the masked
aldehyde with trifluoroacetic acid generates 6. Esterification of the
pendent carboxylic acid with methanol in the presence of H2SO4
provides aldehyde 7, which can then be reacted with a variety of
aryl aldehydes and pyrrole under standard Lindsey conditions to
Department of Chemistry, 6-335, Massachusetts Institute of Technology,
Cambridge, MA 02139, USA. E-mail: nocera@mit.edu
{ Electronic supplementary information (ESI) available: Tables for X-ray
structure determination of the freebase precursor to 3, and time course of
the H2O2 dismutation for all compounds studied. See DOI: 10.1039/
b616884a
Fig. 1 Crystal structure of the freebase precursor to 3. Ellipsoids shown
at the 50% probability level.
2642 | Chem. Commun., 2007, 2642–2644
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with H2O2 to generate O2 and then reaches a plateau. While the
mesityl derivative (1) consumes all available H2O2 within several
minutes, catalysts 2 and 3 begin to level off after roughly
90 seconds, producing roughly 150 and 135 turnovers over the
course of the initial five minutes, respectively.
Table 1 Reactivity data for H2O2 disproportionation
Compound
TOF/min21a
TON (% conversion)b
FeCl(TMP)
FeCl(TMP)c
0.2 ¡ 0.1
2.4 ¡ 0.4
102.3 ¡ 5.3
22.3 ¡ 1.3
27.2 ¡ 1.4
162 ¡ 14 (30%)
236 ¡ 16 (44%)
533 ¡ 8 (98%)
160 ¡ 15 (31%)
147 ¡ 6 (27%)
b
1
2
3
a
Catalyst decomposition via oxidative processes may account for
the lower TON observed for 2 and 3. However, iron porphyrins
are generally robust oxidation catalysts,17 especially those
incorporating fluorinated aryl groups on the porphyrin periphery
such as Hangman 3.18,19 Accordingly, it is unlikely that the
Hangman derivatives with fluorinated and dimethoxyphenyl
groups would undergo oxidative degradation in the same way
and at comparable rates. Another potential pathway for catalyst
deactivation centers on the fact that heme-iron porphyrins may
dimerize to generate diiron(III)-m-oxo complexes. Porphyrins with
ancillary 2,6-dimethoxyphenyl and pentafluorophenyl groups at
the macrocycle meso-positions have been shown to form
diiron(III)-m-oxo dimers.20–24 Moreover, both iron(III) chloride
5,10,15,20-(2,6-dimethoxylphenyl)porphyrin and iron(III) chloride
5,10,15,20-(pentafluorophenyl)porphyrin are virtually inactive
H2O2 dismutase catalysts.I Conversely, tetraarylporphyrins with
mesityl groups are too sterically encumbered to dimerize via a
diiron(III)-m-oxo linker. Indeed, mesityl appended porphyrins are
one of the few cases in which a monomeric iron(III) hydroxide
porphyrin derivative can be isolated and studied.20 In line with this
reasoning, FeCl(TMP) catalyzes H2O2 dismutation with lower
initial TOF, as compared to Hangman derivatives 2 and 3, but it
remains active over longer time durations (Table 1, Fig. S1{). This
is presumably because the mesityl groups prevent m-oxo formation,
which results in the formation of similar amounts of O2 as
compared to 2 and 3 over the course of 60 minutes. Evidence for
the deactivation of 2 and 3 by m-oxo dimerization was obtained
from mass spectrometric analysis of Hangman porphyrins 1–3 in
the presence of water and hydroxide. For the mesityl appended
Hangman, only MS signals associated with the monomer are
observed; however, for both 2 and 3, dimerization products are
observed.
TOF recorded over initial 30 seconds of reaction. After 60 minute
c
reaction time. Addition of one equivalent PhCO2H.
The disproportionation of H2O2 to generate 0.5 and 1.0 equiva-
lents of O2 and H2O, respectively, is an important PCET process
that is catalyzed by a wide variety of metalloproteins and
enzymes.12 With Hangman compounds 1–3 in hand, the structural
and electronic factors that influence the O–O bond activation of
the catalase transformation within the Hangman manifold can be
assessed.
As shown in Table 1, the TON recorded for 1 surpasses 500 in
less than 5 minutes for the Hangman complex, whereas the redox
only porphyrin, FeCl(TMP) (TMP = 5,10,15,20-tetramesitylpor-
phyrin), shows low activity for the disproportionation.§ The
addition of external acid (PhCO2H) enhances the TON observed
for the control system, but the activity remains far below that
observed for 1 in which intramolecular proton transfer from the
pendent acid group converts a putative metal-bound hydroper-
oxide into a compound I type intermediate via a proton driven
heterolytic O–O bond scission (Scheme 2).5,13 This compound I
species oxidizes a second equivalent of H2O2 to generate O2 and an
equivalent of H2O.
We next probed the effect that modulation of the electronic and
steric properties of the porphyrin ligand has on catalase activity.
The redox chemistry of tetraarylporphyrins is perturbed signifi-
cantly by altering the electronic properties of the ancillary aryl
+
?
groups. For instance, the P /P reduction potential of zinc(II)
porphyrins shifts significantly along the series Ar
dimethoxyphenyl (E1/2 = 0.71 V vs. SCE)14 , mesityl (E1/2
= 2,6-
=
0.98 V)15 , pentafluorophenyl (E1/2 = 1.20 V).16" Notwith-
standing, the disparate electronic properties of 1–3 are not reflected
in dramatic reactivity differences for H2O2 dismutation. As shown
by the TOF and conversion percentages provided in Table 1, both
the electron rich and poor Hangman systems (2 and 3, respectively)
are less efficient dismutase catalysts as compared with the parent
mesityl-based Hangman platform (1). Inspection of the reaction
profiles for each of the catalysts of Table 1 (see Fig. S1 of ESI{)
shows that each of the Hangman systems initially reacts rapidly
As shown in Scheme 2, diiron(III)-m-oxo dimerization subverts
catalase activity by sending the system off the catalytic pathway.
For the case of the mesityl Hangman (1), this equilibrium lies
exclusively to the right (monomer) and, as a result, the initial TOF
and total TON after 60 minutes of reaction time are large. By
contrast, this equilibrium should lie far toward the left for
Hangman derivatives with 2,6-dimethoxyphenyl or pentafluoro-
phenyl substituents (2 and 3). This cycle explains our observations,
since the initial TOF values recorded for 2 and 3 are relatively
high, as compared to control compounds lacking a pendent acid
group. However, this initial activity diminishes in time. Conversion
of the iron(III) Hangman systems to diiron(III)-m-oxo dimers
during the course of the catalase reaction ultimately leads to
catalyst deactivation, thus accounting for the relatively low TON
at longer reaction times.
In summary, while it is possible to tune the electronic properties
of Hangman porphyrin architectures by incorporating a disparate
set of aryl groups about the macrocycle periphery, steric effects
associated with the prevention of diiron(III)-m-oxo dimerization are
crucial to the efficacy of such systems in catalyzing oxygen
activation chemistry. Also of note is the realization that the
proximal hydrogen-bonding network enforced by the Hangman
Scheme 2
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§ Hydrogen peroxide disproportionation reactions: dismutation reactions
were performed at room temperature in a sealed (PTFE septum) 10 mL
reaction vial equipped with a magnetic stirbar and a capillary gas delivery
tube linked to a graduated burette filled with water. The reaction vial was
charged with 1 mmol of the iron porphyrin catalyst, 25 mmol of 1,5-
dicyclohexylimidazole, 1.5 mL of CH2Cl2, and 0.5 mL of CH3OH. The
solution was stirred for 5–10 minutes to ensure gas pressure equilibration.
An aliquot of 10.4 M (30%) aqueous H2O2 (0.11 mL) was added to the
reaction mixture via syringe, and the reaction mixture was stirred
vigorously. The time was set to zero immediately after addition of H2O2.
The conversion of the reaction was monitored volumetrically, and the
TON for produced O2 (n) was calculated through the perfect gas equation
pV = nRT, assuming that p = 1 atm. The identity of the oxygen gas was
confirmed independently by the alkaline pyrogallol test.
motif is not sufficient in and of itself to stabilize a monomeric
iron(III) hydroxide porphyrin.6 Indeed, in addition to a hydrogen-
bonding manifold, decoration of the porphyrin periphery with aryl
groups with the appropriate stereoelectronic properties is required
for the development of highly active and robust systems for O–O
bond activation and oxidation catalysis.
This work was supported by the National Institutes of Health
(GM 47274). J. R. thanks the Fannie and John Hertz Foundation
for a doctoral fellowship. The authors thank Dr D. R. Manke for
assistance with crystallography and D. Wright for uplifting
achievements.
" All oxidation potentials recorded in CH2Cl2 vs. SCE using tetrabuty-
lammonium perchlorate (TBAP) or tetrabutylammonium hexafluoropho-
sphate (TBAPF6) as the electrolyte.
Notes and references
I Control H2O2 disproportionation experiments employing iron(III)
chloride 5,10,15,20-(2,6-dimethoxylphenyl)porphyrin and iron(III) chloride
5,10,15,20-(pentafluorophenyl)porphyrin both result in the production of
negligible amounts of O2 under the conditions described above.§
{ The synthesis of Hangman porphyrins 1 and 2 and synthetic precursor 7
have been reported previously.3,6 The synthesis of Hangman porphyrin 3
was accomplished as follows: a mixture of xanthene aldehyde 7 (0.10 g,
0.25 mmol), pentafluorobenzaldehyde (0.735 g, 3.75 mmol) and pyrrole
(0.275 mL, 4.0 mmol) in chloroform (425 mL) was purged with nitrogen
for 45 min, after which a portion of BF3?OEt2 (0.168 mL, 1.32 mmol) was
added via syringe. The solution was stirred at room temperature under
nitrogen in the dark for 1 h and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(0.68 g, 3.0 mmol) was added to the reaction. After stirring for an
additional hour under nitrogen, the solvent was removed under reduced
pressure. The dark residue was redissolved in dichloromethane (100 mL)
containing 2% triethylamine and filtered through celite. The filtrate was
loaded directly onto a silica gel column and eluted with dichloromethane
until no more porphyrinic product was detected by analytical TLC. Further
purification by column chromatography on silica was accomplished using
hexanes and dichloromethane (5 : 2) as the eluent to give the porphyrin
ester as a violet microcrystalline solid (87 mg, 31% yield based on starting
aldehyde). The purified porphyrin ester (80 mg, 0.0676 mmol) was
dissolved in a mixture of acetic acid (20 mL) and sulfuric acid (5 mL).
Water (6.0 mL) was added to the green solution and the reaction was
refluxed under N2 in the dark for 7 days. The reaction was cooled to room
temperature and extracted with 50 mL of dichloromethane. The organic
layer was washed with water, dried over Na2SO4, and the solvent was
removed by rotary evaporation. Purification by column chromatography
on silica was accomplished using dichloromethane as the eluent to provide
the freebase precursor to Hangman porphyrin 3 as a purple solid in near
quantitative yield. 1H NMR (500 MHz, CDCl3, 25 uC): d = 8.91 (m, 5H),
8.79 (d, J = 7 Hz, 2H), 8.09 (d, J = 4 Hz, 1H), 7.98 (d, J = 4 Hz, 1H), 7.72
(d, J = 4 Hz, 1H), 7.62 (d, J = 4 Hz, 1H), 1.99 (s, 6H), 1.57 (s, 9H), 1.25 (s,
9H), 22.76 (s, 2H). HRESIMS (MH+) calcd for C62H39F15N4O3 m/z =
1173.2855; found, 1173.2854.
Iron insertion into the freebase Hangman described above was
accomplished as follows: a combination of the freebase Hangman (60 mg,
0.51 mmol), FeBr2 (350 mg), and CH3CN (30 mL) was refluxed under
nitrogen for 8 h, opened to air, and brought to dryness under vacuum. The
solids were redissolved in dichloromethane (100 mL) and washed with
water (4 6 75 mL). The organic layer was stirred with 20% HCl (50 mL)
for 75 min, washed with water (5 6 100 mL), and taken to dryness. The
resulting residue was purified by column chromatography on silica gel,
eluting first with dichloromethane to remove less polar impurities and then
with 5% methanol in dichloromethane to elute the product. Following
concentration of the product under reduced pressure, the dark brown
material was re-treated with HCl as described above to furnish 3 as a
brown powder (48 mg, 84% yield). HRFABMS ([M 2 Cl]+) calcd for
C71H70N4O3Fe m/z = 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%.
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Crystal data: freebase precursor to 3: C62H39F15N4O3, M = 1172.97,
orthorhombic, space group Pca21, a = 23.784(3), b = 14.5290(16), c =
3
16.258(2) A, U = 5618.1(12) A , Z = 4, Dc = 1.387 Mg m23, T = 183(2) K,
m = 0.120 mm21, wR2 = 0.1842 (5035 independent reflections), R1 = 0.0708
[I . 2s(I)]. CCDC 628103. For crystallographic data in CIF or other
electronic format, see DOI: 10.1039/b616884a
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2644 | Chem. Commun., 2007, 2642–2644
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