Efficient synthesis of hangman porphyrins

Article abstract of DOI:10.1021/ol902947h

Chemical equation presented A two-step synthetic method has been designed to furnish hangman porphyrins In good yields from easily available starting materials. The use of the microwave Irradiation technique has been found to be valuable for delivering the car boxy lie acid hanging group in a much simplified and less time-consuming basic ester hydrolysis (4 h vs 7 days under harsh acidic conditions). The new route facilitates the synthesis of various hangman porphyrins that previously had limited or no access.

Full text of DOI:10.1021/ol902947h

ORGANIC
LETTERS
2010
Vol. 12, No. 5
1036-1039
Efficient Synthesis of Hangman
Porphyrins
Dilek K. Dogutan, D. Kwabena Bediako, Thomas S. Teets, Matthias Schwalbe,
and Daniel G. Nocera*
Department of Chemistry, 6-335, Massachusetts Institute of Technology,
77 Massachusetts AVenue, Cambridge, Massachusetts 02139-4307
nocera@mit.edu
Received January 6, 2010
ABSTRACT
A two-step synthetic method has been designed to furnish hangman porphyrins in good yields from easily available starting materials. The
use of the microwave irradiation technique has been found to be valuable for delivering the carboxylic acid hanging group in a much simplified
and less time-consuming basic ester hydrolysis (4 h vs 7 days under harsh acidic conditions). The new route facilitates the synthesis of
various hangman porphyrins that previously had limited or no access.
The activation of many small molecules requires the coupling
of electrons to protons. In the absence of such coupling, large
reaction barriers confront the conversion of the small
molecule.1-3 The challenge to effecting proton-coupled
electron transfer (PCET) is in the management of the
disparate tunneling length scales of the electron and proton.4,5
Proton transfer is fundamentally limited to short distances,
whereas the lighter electron may transfer over much longer
distances. Hangman porphyrins manage the proton and
electron extremely well by establishing the proton transfer
distance with an acid-base group poised above the electron
transfer conduit of the porphyrin macrocycle.6,7 Electron8
or energy9 transfer to the macrocycle can be coupled to a
short proton transfer to or from substrates bound within the
hangman cleft. In this way, the hangman architecture captures
the structural and functional relationships engendered by the
amino acid residues in the distal cavities of heme hydrop-
eroxidase enzymes. For example, a threonine residue on the
distal side of cytochrome P450 (BM-3 structure) establishes
a water channel by positioning a water molecule above the
heme.10 In hangman porphyrins, the hanging group assumes
the structural role of threonine by preorganizing a water
molecule above the hangman cleft.11 Moreover, the diversity
of biological redox processes performed by the heme
enzymes is captured by hangman porphyrins. The active site
in the enzyme, Compound I (Cpd I), which is two redox
levels above FeIII with a ferryl FeIVdO and associated
radical,12-14 is furnished by the heterolytic cleavage of the
O-O bond of H2O2 or O2.12,15-18 A parallel oxygen activity
(1) Nocera, D. G. Inorg. Chem. 2009, 48, 10001
.
(2) Lewis, N. S.; Nocera, D. G. Proc. Natl. Acad. Sci. U.S.A. 2006,
103, 15729
.
(10) Haines, D. C.; Tomchick, D. R.; Machius, M.; Peterson, J. A.
Biochemistry 2001, 40, 13456.
(3) Dempsey, J. L.; Esswein, A. J.; Manke, D. R.; Rosenthal, J.; Soper,
J. D.; Nocera, D. G. Inorg. Chem. 2005, 44, 6879
(4) Hammes-Schiffer, S. Acc. Chem. Res. 2006, 39, 93
(5) Reece, S. Y.; Nocera, D. G. Annu. ReV. Biochem. 2009, 78, 673
(6) Rosenthal, J.; Nocera, D. G. Acc. Chem. Res. 2007, 40, 543
(7) Rosenthal, J.; Nocera, D. G. Prog. Inorg. Chem. 2007, 55, 483
(8) Reece, S. Y.; Hodgkiss, J. M.; Stubbe, J.; Nocera, D. G. Philos.
Trans. R. Soc. London, Ser. B 2006, 361, 1351.
(9) Hodgkiss, J. M.; Krivokapicˇ, A.; Nocera, D. G. J. Phys. Chem. B
2007, 111, 8258.
.
(11) Yeh, C.-Y.; Chang, C. J.; Nocera, D. G. J. Am. Chem. Soc. 2001,
123, 1513.
.
.
(12) Heme Peroxidases; Dunford, H. B., Ed.; Wiley: New York, 1999.
.
(13) Watanabe, Y. In The Porphyrin Handbook; Kadish, K. M., Smith
.
K. M., Guilard, R., Eds.; Academic Press: San Diego, CA, 2000; Vol. 4, p
97.
(14) Newcomb, M.; Zhang, R.; Chandrasena, R. E. P.; Halgrimson, J. A.;
Horner, J. H.; Makris, T. M.; Sligar, S. G. J. Am. Chem. Soc. 2006, 128,
4580
.
10.1021/ol902947h  2010 American Chemical Society
Published on Web 02/08/2010

is observed within the cleft of hangman porphyrins.19,20
Formation of Cpd I intermediate is accomplished by coupling
proton transfer to a 2e- heterolysis of an O-O bond. The
incorporation of the hanging group enables multifunctional
O-O activity at a single redox scaffold as is evocative of
natural heme-dependent proteins, which employ a conserved
protoporphyrin IX cofactor to affect a myriad of chemical
reactivities.
The introduction of the acid-base hanging group into the
hangman architecture is challenging. Over the years, we21-23
and others24,25 have developed methods for the facile
assembly of porphyrins onto dibenzofuran (DPD) and
xanthene (DPX) spacers. However, introduction of the
hanging group is not facile and proceeds via hydrolysis of
protected groups such as esters over long times and in low
yields.26 In this report, we describe stepwise and statistical
synthetic methods for delivering new hangman porphyrin
xanthenes (HPX). The use of microwave irradiation in the
latter route is especially effective for deprotecting the nascent
hanging group. The new methods should provide easy access
to hangman porphyrins that have heretofore limited or no
access.
metalation30 and regioselective R-bromination31 afforded
porphyrin ZnP2-F15 in 98% yield. Bis(pinacolato)diboron
was coupled with ZnP2-F15 by applying the Miyaura
reaction32 to afford porphyrin ZnP3-F15. Cross-coupling of
ZnP3-F15 with 4-hydroxycarbonyl-5-bromo-2,7-di-tert-butyl-
9,9-dimethylxanthene 4,33 under Suzuki reaction conditions,
afforded the previously reported HPX1-CO2H with a 3%
overall yield. To synthesize porphyrins in larger quantities,
shorter time periods, and fewer steps, statistical condensation
procedures were explored.
2. Statistical Synthesis of Hangman Porphyrins. The
HPX library shown in Table 1 was constructed using the
Table 1. Statistical Synthesis of Hangman Porphyrin Xanthene
(HPX) under Microwave Irradiation
1. Stepwise Synthesis of Hangman Porphyrins. Hang-
man porphyrins have the A3B motif. Scheme 1 shows the
synthesis of the HPX1-CO2H exemplar.
Scheme 1. Stepwise Synthesis of HPX1-CO2H
a Porphyrin formation was performed under modified Lindsey conditions.
The yield calculations were given based on aldehyde 5. b Overall yield for
steps a and b of Scheme 2.
statistical and more concise synthetic pathway depicted in
Scheme 2. Compound 5, which serves as a common synthon
for the construction of a variety of hangman porphyrins, was
synthesized by following reported procedures.26 In all cases,
the standard high-dilution Lindsey condition34 is employed
for the porphyrin synthesis. The acid-catalyzed condensation
of 5 with pentafluorobenzaldehyde and pyrrole afforded the
corresponding porphyrinogen. In situ 6e-/6H+ oxidation of
the latter with DDQ afforded the hangman porphyrin with a
methyl ester hanging group (HPX1-CO2Me) in 34% yield.
meso-Tetrakis(pentafluorophenyl)porphyrin F20-TPP was
also isolated as a side product in 4% yield. Single crystals
of F20-TPP were obtained by slow evaporation of hexane
and CH2Cl2. The structure (Figure S1) shows an almost
planar macrocycle with the aryl groups twisted considerably
out of plane (∼83°) owing to steric clashing.
5-Pentafluorophenyl dipyrromethane 127 and 1,9-diacyl-
dipyrromethane 228 were synthesized according to reported
procedures with slight modifications. Reduction of 2 gave
the corresponding dipyrromethane dicarbinol (2-OH), which
upon condensation29 with dipyrromethane 327 gave the
corresponding porphyrin P1-F15 in 38% yield. Subsequent
The hydrolysis of a methyl ester to the corresponding
carboxylic acid has been performed under acidic conditions.35
Org. Lett., Vol. 12, No. 5, 2010
1037

of HPX1-CO2Me using 6 N NaOH and microwave irradia-
tion was achieved in 4 h with 98% yield. The statistical
porphyrin synthesis afforded the target porphyrin HPX1-
CO2H in four steps with 29% isolated overall yield, which
is 9× higher yield than that obtained from the stepwise route
of Scheme 1. This promising result prompted us to inves-
tigate generality of Scheme 2 for the synthesis of hangman
porphyrins with meso groups of varying electronic and steric
properties.
Scheme 2
.
Statistical Synthesis of Hangman Porphyrin
Xanthene (HPX-CO2H)
The condensation reaction, step a in Scheme 2, proceeded
smoothly for all listed R1 substituents. The progress of the
microwave-induced basic hydrolysis was monitored with
thin-layer chromatography; optimized powers and irradiation
times for each reaction are given in the Supporting Informa-
tion. The reaction was allowed to proceed until all starting
porphyrin was consumed and no decomposition products
were observed. Reaction times were found to be highly
dependent on the properties of the meso substituent. Whereas
deprotection of the methyl ester was achieved in 4-6 h for
hangman porphyrins bearing electron-withdrawing meso
groups, porphyrins bearing electron-releasing meso substit-
uents required ∼16 h of microwave irradiation for complete
consumption of starting material. This slower reaction time
is likely a result of retarded nucleophilic attack by hydroxide
anion on the more electron-rich macrocycles. Zinc, manga-
nese, and cobalt insertion was promoted by microwave
irradiation;40 the metalation of the porphyrin proceeds at
>90% yield. The overall yields of hangman porphyrins
delivered via this new strategy set out in Scheme 2 are
satisfactory (see Table 1).
The reaction required refluxing HPX1-CO2Me in a mixture
of acetic acid and sulfuric acid (4:1) under N2 in the dark
for 7 days. Basic hydrolysis of a methyl ester of HPX5-
CO2Me has also been shown to afford the hangman
porphyrin with carboxylic acid hanging unit in 3 days under
reflux with argon;26 for the electron-withdrawing porphyrins
described herein (e.g., HPX1-CO2Me and HPX2-CO2Me),
no reaction was observed after 2 weeks. In an attempt to
curtail reaction times, we turned our attention to microwave
synthesis.36-39 Efficient hydrolysis of the ester functionality
Crystals of ZnHPX2-CO2H that were suitable for X-ray
analysis were obtained from hexanes/CH2Cl2 mixtures. The
structure of an isolated molecule of ZnHPX2-CO2H is
shown in Figure 1. The Zn(II) ion is elevated 0.239 Å out
of the N4 plane, and an average Zn-Npyrrole bond length of
2.05 Å is observed. The meso substituents at the 5,15
positions are twisted between 58° and 65° out of the
macrocyclic plane, whereas the aryl substituent opposite the
xanthene backbone is twisted 87°. The elevation of the Zn(II)
ion from the N4 plane and exaggerated twisting of the meso-
15 substituent can be understood when the complete structure
of ZnHPX2-CO2H is considered. As shown in Figures S2
and S3, ZnHPX2-CO2H assumes a dimeric arrangement that
is supported by a hydrogen bonding network occurring
between a trapped water molecule and the carboxylic hanging
groups. The trapped water molecule is almost equidistant to
both zinc atoms (2.39 and 2.43 Å) and is also hydrogen
(15) Veitch N. C.; Smith, A. T. AdVances in Inorganic Chemistry;
Academic Press: New York, 2001; Vol. 51, p 107
.
(16) Newcomb, M.; Chandrasena, R. E. P. Biochem. Biophys. Res.
Commun. 2005, 338, 394
(17) Davydov, R.; Chemerisov, S.; Werst, D. E.; Rajh, T.; Matsui, T.;
Ikeda-Saito, M.; Hoffman, B. M. J. Am. Chem. Soc. 2004, 126, 15960
(18) Hiner, A. N. P.; Raven, E. L.; Thorneley, R. N. F.; Garcia-Canovas,
F.; Rodriguez-Lopez, J. N. J. Inorg. Biochem. 2002, 91, 27
(19) Soper, J. D.; Kryatov, S. V.; Rybak-Akimova, E. V.; Nocera, D. G.
J. Am. Chem. Soc. 2007, 129, 5069
.
.
.
.
(20) Chang, C. J.; Chng, L. L.; Nocera, D. G. J. Am. Chem. Soc. 2003,
125, 1866
.
(21) Deng, Y. Q.; Chang, C. J.; Nocera, D. G. J. Am. Chem. Soc. 2000,
122, 410
.
(22) Chang, C. J.; Deng, Y. Q.; Shi, C. N.; Chang, C. K.; Anson, F. C.;
Nocera, D. G. Chem. Commun. 2000, 1355
(23) Chang, C. J.; Deng, Y. Q.; Heyduk, A. F.; Chang, C. K.; Nocera,
D. G. Inorg. Chem. 2000, 39, 959
(24) Kadish, K. M.; Ou, Z.; Shao, J.; Gros, C. P.; Barbe, J. M.; Jerome,
F.; Bolze, F.; Burdet, F.; Guilard, R. Inorg. Chem. 2002, 41, 3990
(25) Kadish, K. M.; Shao, J.; Ou, Z.; Fremond, L.; Zhan, R.; Burdet,
R.; Barbe, J. M.; Gros, C. P.; Guilard, R. Inorg. Chem. 2005, 44, 6744
.
.
.
.
(26) Chang, C. J.; Yeh, C.-Y.; Nocera, D. G. J. Org. Chem. 2002, 67,
bonded to carboxylic oxygen atoms with OH O-Ocarbonyl
1403
.
2
(27) Laha, J. K.; Dhanalekshmi, S.; Taniguchi, M.; Ambroise, A.;
distances of 2.78 Å. The carboxylic acid groups of the
xanthene backbones, which exhibit significant bending
Lindsey, J. S. Org. Process Res. DeV. 2003, 7, 799
(28) Rao, P. D.; Dhanalekshmi, S.; Littler, B. J.; Lindsey, J. S. J. Org.
Chem. 2000, 65, 7323
(29) Zaidi, S. H. H.; Fico, R. M., Jr.; Lindsey, J. S. Org. Process Res.
DeV. 2006, 10, 118
(30) Muresan, A. Z.; Thamyongkit, P.; Diers, J. R.; Holten, D.; Lindsey,
J. S.; Bocian, D. F. J. Org. Chem. 2008, 73, 6947
(31) Tomizaki, K.; Lysenko, A. B.; Taniguchi, M.; Lindsey, J. S.
Tetrahedron 2004, 60, 2011
.
.
(35) Rosenthal, J.; Chng, L. L.; Fried, S. D.; Nocera, D. G. Chem.
.
Commun. 2007, 2642
(36) Dogutan, D. K.; Ptaszek, M.; Lindsey, J. S. J. Org. Chem. 2008,
73, 6187.
.
.
(37) Elghamry, I.; Tietze, L. F. Tetrahedron Lett. 2008, 49, 3972.
(38) Balaban, M. C.; Chappaz-Gillot, C.; Canard, G.; Fuhr, O.; Roussel,
C.; Balaban, T. S. Tetrahedron 2009, 65, 3733.
(39) Samaroo, D.; Soll, C. E.; Todaro, L. J.; Drain, C. M. Org. Lett.
2006, 8, 4985.
(40) Dean, M. L.; Schmink, J. R.; Leadbeater, N. E.; Bru¨ckner, C. Dalton
Trans. 2008, 1341.
.
(32) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508
.
(33) Chang, C. J.; Chng, L. L.; Nocera, D. G. J. Am. Chem. Soc. 2003,
125, 1866
(34) Lindsey, J. S.; Wagner, R. W. J. Org. Chem. 1989, 54, 828
.
.
1038
Org. Lett., Vol. 12, No. 5, 2010

xanthene scaffold typically shifts the reduction potentials
cathodically by ∼200 mV. ZnHPX1-CO2H shows one
reduction wave at -1.71 V that is accompanied by a
prefeature in the initial scan at more positive potentials
(Figure S11g); this behavior is consistent with adsorption
of porphyrin on the electrode. Of greater interest are the CVs
of the Co HPX1 series of compounds (Figure S13c).
CoHPX1-CO2Me exhibits two reversible waves at -1.15
and -2.19 V vs Fc+/Fc, whereas CoHPX1-CO2H shows a
reversible initial reduction at -1.20 V. However, the second
reduction at Epeak ) -2.0 V is irreversible. The reduction of
Co(II) macrocycles in the presence of a proton is often
accompanied by Co(III) hydride formation.43 The hangman
scaffold provides a source for such a proton, and the results
suggest that the CoHPX-CO2H compounds may support
hydrogen evolution chemistry. Studies to investigate this
possibility are now underway.
The synthetic route described here is a general method
for the practical synthesis of hangman porphyrins (1) from
easily available starting materials, (2) in two steps, (3) in
good yields, and (4) with abbreviated reaction times (4-16
h). Twelve new hangman porphyrins have been prepared with
meso substituents that perturb the electronic properties of
the macrocycle. The ability to tune the electronic properties
of the hangman macrocycle by the synthetic method de-
scribed here, and obtain them in good yields, will be useful
for exploiting hangman active sites for small molecule
activation.
Figure 1. Crystal structure of ZnHPX2-CO2H showing only half
of the dimer. Thermal ellipsoids are drawn at the 50% probability
level.
(148°), are aligned on the same side of the dimer and show
a common hydrogen bonded dimeric motif with an O-O
distance of 2.66 Å. The Zn-Npyrrole metrics are consistent
with distorted square pyramidal geometry of pentacoordinate
Zn(II) porphyrin derivatives.41 The high degree of twisting
of the aryl substituent opposite the xanthene backbone is a
result of steric congestion in the dimer structure. This dimeric
array is not prevalent in all hangman structures. For instance,
as shown in Figure S4, HPX5-CO2H crystallizes as a
monomer. The proton of the carboxylic acid group forms a
six-membered ring by hydrogen bonding (d(Oxanthene···H) )
1.91 Å) to the oxygen of xanthene. This structural motif has
been observed previously for hangman amide complexes.42
Cyclic voltammograms (CVs) of F20-TPP and hangman
porphyrins in CH3CN generally show two reversible reduc-
tion waves at -1.19 to -1.37 V vs Fc+/Fc for the first
reduction and -1.65 to -1.83 V vs Fc+/Fc for the second
reduction (Figure S10f). The replacement of one pentafluo-
rophenyl meso substituent of the TPP framework by the
Acknowledgment. T.S.T. acknowledges the Fannie and
John Hertz Foundation for a predoctoral fellowship. The
developments of new synthetic methods and synthesis of the
new compounds were performed under the sole sponsorship
of Eni S.p.A under the Eni-MIT Alliance Solar Frontiers
Program, and characterization work was executed under the
Division of Chemical Sciences, Geosciences, and Bio-
sciences, Office of Basic Energy Sciences of the U.S.
Department of Energy through Grant DE-FG02-05ER15745.
Supporting Information Available: Characterization data
and detailed descriptions of the syntheses of all compounds.
X-ray crystallographic files for porphyrins (CIF) are also
provided as separate files. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL902947H
(41) Ochsenbein, P.; Bonin, M.; Schenk, K.; Froidevaux, J.; Wytko, J.;
Graf, E.; Weiss, J. Eur. J. Inorg. Chem. 1999, 1175.
(42) Chang, C.-K.; Bag, N.; Guo, B.; Peng, S.-M. Inorg. Chim. Acta
2003, 351, 261.
(43) Hu, X. L.; Brunschwig, B. S.; Peters, J. C. J. Am. Chem. Soc. 2007,
129, 8988.
Org. Lett., Vol. 12, No. 5, 2010
1039