Intramolecular hydrogen bonding as a synthetic tool to induce chemical selectivity in acid catalyzed porphyrin synthesis

Article abstract of DOI:10.1039/c2cc31228j

A straightforward procedure based on the formation of intramolecular hydrogen bonds to impart selectivity in the preparation of multi-functionalized porphyrins has been developed. To illustrate the concept, the synthesis of a biomimetic artificial photosy

Full text of DOI:10.1039/c2cc31228j

View Online / Journal Homepage / Table of Contents for this issue
This article is part of the
Porphyrins &
Phthalocyanines
web themed issue
Guest editors: Jonathan Sessler, Penny Brothers and
Chang-Hee Lee
All articles in this issue will be gathered together
online at
www.rsc.org/porphyrins

Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 4558–4560
www.rsc.org/chemcomm
COMMUNICATION
Intramolecular hydrogen bonding as a synthetic tool to induce chemical
selectivity in acid catalyzed porphyrin synthesiswz
Jackson D. Megiatto Jr., Dustin Patterson, Benjamin D. Sherman, Thomas A. Moore,*
Devens Gust* and Ana L. Moore*
Received 17th February 2012, Accepted 2nd March 2012
DOI: 10.1039/c2cc31228j
A straightforward procedure based on the formation of intra-
molecular hydrogen bonds to impart selectivity in the prepara-
tion of multi-functionalized porphyrins has been developed. To
illustrate the concept, the synthesis of a biomimetic artificial
photosynthetic model able to undergo electron and proton
transfer reactions upon irradiation is reported.
Photosystem II (PSII), we have designed biomimetic artificial
photosynthetic models able to undergo electron transfer (ET)
and proton-coupled electron transfer (PCET) reactions that
mimic the photo-redox processes occurring between the
primary electron donor chlorophyll complex (P680) and the
6
-His190). In one of our
Tyrosine
z
-Histidine-190 pair (Tyr
z
designs (Fig. 1), a high-potential 5,15-bis(pentafluorophenyl)-
porphyrin (PF10, the primary electron donor) bears a benzoic
The rich chemical and spectroscopic properties of porphyrins have
prompted their study and application across many scientific fields.
Much of this popularity is due in large part to the development of
relatively efficient and specific synthetic protocols that allow for
the preparation of a huge number of functionalized porphyrin
acid functionality (for attachment of the complex to a TiO2
nanoparticle, which serves as the primary acceptor) and a
0
2
-(2 -hydroxyphenyl)benzimidazole (Bi-PhOH) group (the
secondary electron donor). The Bi-PhOH moiety is specifically
designed to feature an intramolecular hydrogen bond between
the phenolic oxygen and the nitrogen lone pair of the benz-
imidazole residue, such that the oxidation of the phenol occurs
with the transfer of the phenolic proton to the benzimidazole
1
molecules. As a result, complex nanostructures composed of
2a–d
porphyrin subunits, such as large multiporphyrin arrays,
2e–g
polymers,
2h,i 2j–l
dendrimers, mechanically-linked systems, and
2m,n
molecular machines,
have been reported. In the field of
residue (Fig. 1). Therefore, the Bi-PhOH unit mimics the
artificial photosynthesis, porphyrins offer useful alternatives to
the synthetically demanding and relatively unstable chlorophylls
found in nature, and have been extensively investigated as com-
6
function of the Tyr
Bi–PhOH–PF10–TiO
transfer and then proton-coupled electron transfer reactions
z
-His190 pair of PSII. Irradiation of the
2
assembly triggers sequential electron
3
ponents of antenna devices and reaction center models.
+
ꢁ
that yield the final charge separated state BiH ꢀPhO ꢀ
The formation of a porphyrin molecule typically involves a
condensation reaction between pyrrole and aldehyde derivatives
in organic solvent, at room temperature, and under acid
ꢁ
ꢀ
2
PF ꢀTiO . This state is characterized by a cationic benz-
10
imidazole group, a phenoxyl radical, a neutral porphyrin, and
5a
4a–c
catalysis.
2
an electron on the semiconducting TiO nanoparticle (Fig. 1).
Despite the mild conditions, this protocol is not
This final charge separated state is thermodynamically capable
of water oxidation, rendering the system an attractive candidate
for application in water splitting photoelectrochemical systems.
The preparation of the multi-functionalized porphyrin core
of this photosynthetic model presents several substantial
synthetic challenges. In the first place, it includes a phenol
group, which usually is not compatible with standard porphyrin
compatible with some functional groups. For example, formyl,
phenol, amine, terminal ethynyl, carboxylic acid, and acyclic
acetal functionalities fail to afford porphyrins under the
4c
classical conditions. The formation of porphyrins containing
such groups usually requires the use of protecting groups or
further synthetic elaboration of suitable porphyrin precursors.
However, these strategies render the synthesis longer and
inefficient. In cases where multi-functionalized porphyrins are
required, the synthesis becomes challenging if not impossible.
One particular example in this regard comes from our own
4c
protocols. Secondly, the typical synthesis of a benzimidazole
5a,b
work. In our efforts
to gain insight into the photophysics of
Center for Bio-Inspired Solar Fuel Production, Department of
Chemistry and Biochemistry, Arizona State University, Tempe,
AZ 85287. E-mail: tmoore@asu.edu, gust@asu.edu, amoore@asu.edu
w This article is part of the ChemComm ‘Porphyrins and phthalo-
cyanines’ web themed issue.
z Electronic supplementary information (ESI) available: A complete
description about all the experimental details and spectra is provided.
See DOI: 10.1039/c2cc31228j
Fig. 1 A molecular triad photosynthetic model composed of three
covalently linked redox-active subunits which mimic the photo-redox
processes in Photosystem II.
4
558 Chem. Commun., 2012, 48, 4558–4560
This journal is c The Royal Society of Chemistry 2012

group involves the condensation of ortho-phenylenediamine
favor the formation of this intramolecular hydrogen bond, the
carbonyl lone pair of the ortho-formyl group would not be
available for acid activation, whereas the formyl group at the
para position would have unencumbered reactivity, resulting in
the selective formation of the desired porphyrin 5.
and carbonyl compounds such as formyl, carboxylic acid, or
7
activated esters. This means that the formation of the benz-
imidazole group at the position required for our purpose
demands the preparation of a porphyrin precursor containing
a meso phenol group bearing one of the ‘‘problematic’’
carbonyl functionalities at its ortho position. In addition,
perfluorinated porphyrins are known to easily undergo nucleo-
Noncovalent interactions such as hydrogen bonds are extre-
10b
mely sensitive to their chemical environment.
In order to
exploit their full capabilities, optimization of their thermo-
dynamic and kinetic stability is crucial. Usually, this process
involves extensive laboratory tests, where parameters such as
solvent polarity, concentration, and temperature are scrutinized
to determine the most favorable balance for a specific interaction.
In the case of 2, concentration has little influence because the
hydrogen bond is formed via an intramolecular interaction.
However, polar protic solvents and high temperature can poten-
8
philic substitution, restricting even further the reaction
conditions that might be used to circumvent the synthetic
challenges imposed by our design. Fourthly, the carboxylic
acid functional group needed for anchoring to the TiO
2
nanoparticle precludes the use of redox reactions to introduce
any of the suitable carbonyl functional groups cited above for
the formation of the benzimidazole moiety. Finally, the
5a,b
12
energetics of our photosynthetic model
demands a free
tially promote the disruption of this interaction. Fortunately,
base porphyrin, which can coordinate transition metal ions.
Therefore, transition-metal catalyzed reactions need to be
avoided in the synthetic strategy to prevent the coordination
the usual conditions for the porphyrin formation (high dilution
in a nonpolar aprotic solvent and reaction at room temperature)
provide favorable conditions for stabilizing the intramolecular
hydrogen bond in 2. Therefore, the key selectivity needed for the
success of the strategy depicted in Scheme 1 would likely be
9
of metal ions into the porphyrin core.
Although the use of protecting groups or several additional
synthetic steps could solve some of these issues, we decided to
pursue a different approach based on contemporary concepts
4c
afforded under the conditions of the Lindsey method,
a
standard protocol for porphyrin synthesis. Moreover, the bulky
tert-butyl group at the C-3 position in 2, originally introduced in
our design to prevent dimerization of eventual photo-generated
1
0a
applied to organic synthesis, such as atom economy, supra-
0b
1
molecular assistance to covalent synthesis,
1
and organo-
0c
13
catalysis.
To prepare our photosynthetic model, we
phenoxyl radicals, provides a steric shield against external
envisioned the straightforward synthetic strategy depicted in
Scheme 1 which does not involve any re-functionalization or
the manipulation of protecting groups. This method is
molecules that might compete for the hydrogen bond, resulting
in further stabilization.
To verify this hypothesis, compound 2, 5-(pentafluorophenyl)-
5a
dipyrromethane 3, and methyl-4-formylbenzoate 4 were
1
1
grounded on first preparing the phenol derivative 2, which
bears two formyl functionalities, one at the para position for
the porphyrin condensation reaction and the other at the ortho
position for further formation of the benzimidazole component.
The key advantage that substantially reduces the number of
synthetic steps needed to form the final compound 9 lies in the
selective condensation of the formyl group at the para position
of 2 to yield the porphyrin intermediate 5. We reasoned that the
intramolecular hydrogen bond between the phenolic proton
and the ortho-formyl residue in 2 would create an asymmetry in
the reactivity of the two carbonyl groups towards acid catalyzed
condensation reactions. By adjusting the reaction conditions to
4c
allowed to react under Lindsey conditions. In a typical
experiment, the starting materials were dissolved in freshly
distilled chloroform under a nitrogen atmosphere, boron-
3 2
trifluoride etherate (BF OEt ) was added, and the reaction
mixture was stirred for 1 h at room temperature. The resulting
dark red porphyrogenic mixture was oxidized with 2,3-di-
chloro-5,6-dicyano-1,4-benzoquinone (DDQ) for 12 h at room
temperature, yielding a black crude mixture. Filtration
through a silica pad to remove tar and polymeric byproducts
followed by concentration under reduced pressure afforded a
deep purple-reddish solid. Purification by column chromato-
2
graphy (SiO , hexanes/dichloromethane as eluent) yielded three
porphyrin fractions (23% total porphyrin yield). The target
porphyrin 5 corresponded to the second fraction eluted (11%
yield), while the first (7% yield) and third (5% yield) fractions
were unambiguously identified as porphyrins 6 and 7 (Scheme 1),
respectively. No other porphyrin product was observed in the
crude mixture, indicating that the ortho-formyl group did not
undergo side reactions under the conditions investigated. The
exclusive formation of porphyrins 5, 6, and 7 from the condensa-
tion attests to the efficacy of the intramolecular hydrogen bond
for preventing activation of the ortho-formyl group in 2 by the
Scheme 1 Synthetic strategy based on the use of an intramolecular
hydrogen bond to direct the selective acid condensation of formyl
groups for the preparation of a multi-functionalized porphyrin photo-
synthetic model. (a) hexamethylene tetraamine, trifluoroacetic acid,
3 2
BF OEt catalyst under proper conditions and demonstrates the
successful selectivity of our strategy.
1
3
H NMR analysis in CDCl (Fig. 2) provided clear evidence
for the selective formation of target porphyrin 5. The strong
downfield shifted peak of the phenolic proton resonance from
the usual region (5–6 ppm) to 12.20 ppm gives unmistakable
evidence for the presence of the intramolecular hydrogen bond
reflux, 24 h; (b) chloroform, BF
followed by oxidation with DDQ for 12 h at room temperature;
c) ortho-phenylenediamine, nitrobenzene, reflux, 12 h; (d) trifluoroacetic
3
ꢂOEt
2
, room temperature, 1h,
(
acid/hydrochloric acid (1 : 2, v/v), reflux, 24 h.
This journal is c The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 4558–4560 4559

provides a clear example of the usefulness of this approach.
Although we have investigated the effectiveness of this approach
only for the O–H—OQC hydrogen bond type, we believe that
this methodology can be extended to other hydrogen bond
12
synthons, opening up the possibility of preparing even more
complex porphyrins and photosynthetic models. These possibi-
lities are under current investigation.
This work was supported as part of the Center for Bio-
Inspired Solar Fuel Production, an Energy Frontier Research
Center funded by the U.S. Department of Energy, Office of
Science, Office of Basic Energy Sciences under Award Number
DE-SC0001016.
Notes and references
1
3
Fig. 2 H NMR spectra of porphyrin 5 (400 MHz, CDCl , 25 1C).
1
The Porphyrin Handbook, ed. K. M. Kadish, K. Smith and
R. Guilard, Academic Press, New York, 1999.
The peak marked with an asterisk is due to residual protons in the
solvent. TMS = tetramethylsilane.
2
(a) C. Maeda, T. Kamada, N. Aratani and A. Osuka, Coord.
Chem. Rev., 2007, 251, 2743–2752; (b) Z. S. Yoon, M. C. Yoon and
D. Kim, J. Photochem. Photobiol., C, 2005, 6, 249–263;
in 5. Assignment of this peak to the phenolic group is
(
c) R. W. Wagner, T. E. Johnson and J. S. Lindsey, J. Am. Chem.
supported by its absence in the spectrum after addition of a
Soc., 1996, 118, 11166–11180; (d) G. Kodis, Y. Terazono,
K. Bhushan, J. Zaks, C. Madden, A. L. Moore, T. A. Moore,
G. R. Fleming and D. Gust, J. Am. Chem. Soc., 2011, 133,
2916–2922; (e) T. Hyakutake, I. Okura, K. Asai and H. Nishide,
J. Mater. Chem., 2008, 18, 917–922; (f) P. A. Liddell, M. Gervaldo,
J. W. Bridgewater, A. E. Keirstead, S. Lin, T. A. Moore,
A. L. Moore and D. Gust, Chem. Mater., 2008, 20, 135;
3
few drops of deuterated methanol to the CDCl solution. The
formyl proton resonance appears at 10.12 ppm, confirming no
side reactions with this group. The porphyrinic core is revealed
by the resonance of the pyrrolic protons at 8.93, 8.87, and
8
.80 ppm as well as by the peak at ꢀ2.75 ppm attributed to the
inner NH protons. The two doublets observed at 8.39 and
.20 ppm are meta-coupled (J = 2.0 Hz) and therefore
assigned to the protons H2 and H6 . The aromatic doublet
at 8.45 ppm (J = 8.3 Hz) is coupled to the broad triplet peak
at 8.28 ppm and corresponds to H
(g) B. J. Brennan, M. J. Kenney, P. A. Liddell, B. R. Cherry,
J. Li, A. L. Moore, T. A. Moore and D. Gust, Chem. Commun.,
8
2
011, 47, 10034–10036; (h) W. S. Li and T. Aida, Chem. Rev., 2009,
09, 6047–6076; (i) S. Fukuzumi, K. Saito, K. Ohkubo, T. Khoury,
0
0
1
Y. Kashiwagi, M. A. Absalom, S. Gadde, F. D’Souza, Y. Araki,
0 0/H
0 0 and H
0 0/H
0 0
,
O. Ito and M. J. Crossley, Chem. Commun., 2011, 47, 7980–7982;
j) J. D. Megiatto Jr., R. Spencer and D. I. Schuster, Org. Lett.,
009, 11, 4152–4155; (k) J. A. Faiz, V. Heiz and J.-P. Sauvage,
3
5
2
6
(
2
respectively. MALDI-TOF spectrometry corroborated the
proposed structure for porphyrin 5, showing an ion peak at
+
Chem. Soc. Rev., 2009, 38, 422–442; (l) J. D. Megiatto Jr.,
S. Abwandner, G. de Miguel and D. M. Guldi, J. Am. Chem.
Soc., 2010, 132, 3847–3861; (m) P. Thordarson, E. J. A. Bijsterveld,
A. E. Rowan and R. J. M. Nolte, Nature, 2003, 424, 915–918;
(
30 10 4 4
m/z) 952.46 (M) (calculated 952.21 for C51H F N O ).
Compound 5 was successfully converted into 9 through reac-
tion with ortho-phenylenediamine in nitrobenzene under reflux to
give 8 (ref. 7) followed by acid hydrolysis of the carboxymethyl
ester group with a 70% overall yield. Electrochemical investigation
of 8 in benzonitrile revealed two (quasi)reversible anodic processes
at + 1.28 V and + 1.50 V (vs. NHE) which are attributed to the
one electron oxidation of the phenol group and the first oxida-
tion of the porphyrin core, respectively. These values indicate
(
n) A. H. F. Sourav Saha, J. F. Stoddart, S. Impellizzeri, S. Silvi,
M. Venturi and A. Credi, J. Am. Chem. Soc., 2007, 129,
12159–12171.
3 T. A. Moore, A. L. Moore and D. Gust, Acc. Chem. Res., 2009, 42,
890–1898.
(a) P. J. Rothemund, J. Am. Chem. Soc., 1936, 58, 625–627;
b) A. D. L. Adler, F. R. Finarelli, J. D. Goldmacher and
1
4
5
(
J. Assour, J. Org. Chem., 1967, 32, 476–476; (c) J. S. Lindsey,
Acc. Chem. Res., 2010, 43, 300–311.
that once the artificial photosynthetic model 9 is attached to TiO
2
(a) G. F. Moore, M. Hambourger, M. Gervaldo, O. G. Poluektov,
T. Rajh, D. Gust, T. A. Moore and A. L. Moore, J. Am. Chem.
Soc., 2008, 130, 10466–10467; (b) G. F. Moore, M. Hambourger,
G. Kodis, W. Michl, D. Gust, T. A. Moore and Ana L. Moore,
J. Phys. Chem. B, 2010, 114, 14450–14457.
J. P. McEvoy and G. W. Brudvig, Chem. Rev., 2006, 106, 4455–4483.
M. R. Grimmett, Imidazole and benzimidazole synthesis, Academic
Press, San Diego, 1997.
´
F. C. Santosa, A. C. Cunhab, M. C. B. V. de Souza, A. C. Tomea,
M. G. P. M. S. Nevesa, V. F. Ferreira and J. A. S. Cavaleiro,
Tetrahedron Lett., 2008, 49, 7268–7270.
R. W. Wagner, Y. Ciringh, C. Clausen and J. S. Lindsey, Chem.
Mater., 11, 2974–2983.
0 (a) S. Fustero, M. Sanchez-Rosello and C. del Pozo, Pure Appl.
Chem., 2010, 82, 669–677; (b) S. J. Rowan, S. J. Cantrill, G. R.
L. Cousins, J. K. M. Sanders and J. F. Stoddart, Angew. Chem.,
Int. Ed., 2002, 41, 898–952; (c) L. A. J. Shagufta, H. Shabbir and
E. V. Anslyn, Chem. Soc. Rev., 2010, 39, 3621–3632.
1 J. F. Larrow and E. N. Jacobsen, J. Org. Chem., 1994, 59, 1939–1942.
2 G. A. Jeffrey, An Introduction to Hydrogen Bond, Oxford
University Press, New York, 1997.
nanoparticles, the phenoxyl radical (at B 1.3 V vs. NHE)
should have sufficient driving force for the oxidation of water
5a,b
0.82 V vs. NHE, pH = 7).
(
Furthermore, the presence of an
intramolecular hydrogen bond in the benzimidazole-phenol
group renders the phenol oxidation process reversible, opening
up the possibility of using this system as a redox active relay as
part of a photoanode in a water splitting device.
6
7
8
9
In summary, we report an approach to the synthesis of
multi-functionalized porphyrins wherein proper incorporation
of noncovalent interactions in the synthetic design induces
advantageous selectivity in this complex chemical transformation.
The heart of the methodology centers on the fine-tuning of
formyl chemical reactivity through formation of a neutral
intramolecular O–H—OQC hydrogen bond, which effectively
prevents activation of the carbonyl moiety by acid catalysts.
The preparation of a multicomponent artificial photosynthetic
model that can mimic certain aspects of Photosystem II
1
1
1
13 A. I. Prokof’ev, Russ. Chem. Rev., 1999, 68, 727–736.
4
560 Chem. Commun., 2012, 48, 4558–4560
This journal is c The Royal Society of Chemistry 2012