Steric control in the synthesis of p-benziporphyrins. formation of a doubly n-confused benzihexaphyrin macrocycle

Article abstract of DOI:10.1021/ol9016222

The use of 1,4-phenylene-containing tripyrrane analogs provides a general route to expanded p-benziporphyrins. The course of macrocyclization shows a striking dependence on the steric bulk of meso substituents.

Full text of DOI:10.1021/ol9016222

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3930-3933
Steric Control in the Synthesis of
p-Benziporphyrins. Formation of a
Doubly N-Confused Benzihexaphyrin
Macrocycle
Marcin Ste¸pien´,* Bartosz Szyszko, and Lechosław Latos-Graz˙yn´ski*
Wydział Chemii, Uniwersytet Wrocławski, ul F. Joliot-Curie 14,
50-383 Wrocław, Poland
ms@wchuwr.pl; llg@wchuwr.pl
Received July 15, 2009
ABSTRACT
The use of 1,4-phenylene-containing tripyrrane analogs provides a general route to expanded p-benziporphyrins. The course of macrocyclization
shows a striking dependence on the steric bulk of meso substituents.
Benziporphyrins are a class of porphyrinoids combining
pyrrolic and phenylene rings into a macrocyclic structure.1
p-Benziporphyrins, which contain 1,4-linked phenylene units
are of particular interest, as they exhibit coordinating abilities
of porphyrins while providing nontrivial examples of mac-
rocyclic aromaticity (Figure 1). For instance, in the generic
p-benzi[18]porphyrin(1.1.1.1) (1), the electronic structure of
the benzene ring is so strongly affected by macrocyclic
1
conjugation that the H NMR shifts of the inner (21,22-H)
and outer phenylene protons (2,3-H) differ by 5.36 ppm,
(1) For general reviews see: (a) Ste¸pien´, M.; Latos-Graz˙yn´ski, L. Acc.
Figure 1. Macrocyclic cores of p-benziporphyrin (1) and A,D-di-
Chem. Res. 2005, 38, 88–98. (b) Ste¸pien´, M.; Latos-Graz˙yn´ski, L.
Aromaticity and Tautomerism in Porphyrins and Porphyrinoids. Topics in
Heterocyclic Chemistry Volume 19. Aromaticity in Heterocyclic Compounds;
Springer: Berlin/Heidelberg, 2009; pp 83-153. For related recent work,
see, for example: (c) Sim, E.-K.; Jeong, S.-D.; Yoon, D.-W.; Hong, S.-J.;
Kang, Y.; Lee, C.-H. Org. Lett. 2006, 8, 3355–3358. (d) Reddy, J. S.; Anand,
V. G. Chem. Commun. 2008, 1326–1328.
p-benzi[28]hexaphyrin(1.1.1.1.1.1) (2).
which is indicative of a macrocyclic ring current.2 Simul-
taneously, the phenylene ring retains much of its benzenoid
character, as evidenced by X-ray structural data and the
(2) Ste¸pien´, M.; Latos-Graz˙yn´ski, L. J. Am. Chem. Soc. 2002, 124, 3838–
3839.
10.1021/ol9016222 CCC: $40.75
Published on Web 08/10/2009
 2009 American Chemical Society

conformational flexibility of the macrocycle observable by
NMR spectroscopy.
symmetry (4a,d-f) or reactivity patterns (4b,c). To achieve
complete reduction of diketones 3, it was necessary to use
LiAlH4 in refluxing THF as milder reduction conditions were
not effective in our hands.
Furthermore, the recently reported A,D-di-p-benzi[28]-
hexaphyrin(1.1.1.1.1.1) (2) provided an unprecedented ex-
ample of conformational switching between Hu¨ckel and
Mo¨bius aromaticity.3 Since the original proposal of Heil-
bronner, Mo¨bius aromaticity has been the subject of intense
theoretical and computational investigation,4 but synthetic
examples of Mo¨bius aromatics are still rare, compound 2
being only the second documented case.5 The switching
mechanism in 2 relies on the internal rotations of phenylene
rings, which act as topology selectors.
Unfortunately, the available syntheses of benziporphyrins,
while preparatively convenient, are often low-yielding and
produce mixtures of products.2,3a Here we show an improved
route to the expanded p-benziporphyrin 2, which provides
enhanced yields and superior selectivity. We also report on
a doubly N-confused benziporphyrinoid, whose formation
is dependent on the steric demand of meso substituents.
p-Benziporphyrins are normally synthesized from di-
carbinols of the general formula 4, according to a Lindsey-
type protocol.6 To date, when used for porphyrinoid syn-
thesis, dicarbinols 4 have been prepared by two routes: (1)
from terephthalaldehyde and a Grignard reagent2 and (2)
from 1,4-dibromobenzene via lithium-halogen exchange
followed by aldehyde addition.3a Both of these two ap-
proaches involve the use of air-sensitive reagents, which
makes them less convenient for large-scale work. In many
instances, these two routes can be replaced with a synthesis
shown in Scheme 1, which, to our knowledge, has not been
Dicarbinols 4 were subsequently reacted with an excess
of pyrrole to yield tripyrrane analogues 5, which were
subjected to a Lindsey macrocyclization with benzaldehyde
followed by oxidation with 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ, Scheme 2). In the case of the mesityl
derivative 5d, the reaction indeed provided hexaphyrin 2d
as the only isolable macrocyclic product (11%). This result
is an improvement over the original condensation between
4d, pyrrole, and benzaldehyde.3a The latter method provided
a mixture of products, from which 2d could be isolated in
6% yield. Additionally, by using tripyrrane analogue 5e, the
new duryl-substituted derivative 2e was prepared for the first
time. Unfortunately, this compound is unstable during
chromatography, which is a reason for the low isolated yield
(ca. 3%). Interestingly, we were unable to isolate any
expanded benziporphyrins from reactions involving tripyr-
rane analogs 5a-c, which afforded only small amounts of
the respective p-benziporphyrins. This observation indicates
that the presence of ortho-substituents on the meso-aryl
groups is required for effective ring closure.
To our surprise, when 5f was condensed with benzalde-
hyde, we observed no formation of the expected hexaphyrin
2f. Instead, a new macrocycle, 6f, was isolated with yields
up to 14%. This reactivity is more general, as the mesityl
analogue 6d forms in small amounts during the synthesis of
2d. The macrocyclic system of 6, which can be named 8,23-
dioxo-7,22-diaza-33,37-dicarba-A,D-di-p-benzi[28]hexaphyrin-
(1.1.1.1.1.1) using the standard porphyrinoid nomenclature,
differs from the structure of 2 by the presence of two
N-confused rings (B and E, Scheme 2).8 These two rings
are oxidized at the free R-pyrrolic positions (8 and 23),
providing two lactam functionalities.9
Scheme 1
The isolation of an isomerically pure doubly N-confused
system is of interest because such molecules are normally
obtained from predesigned N-confused precursors rather than
via direct ꢀ-condensation of nonconfused units.10 In the case
(5) (a) For the first example, see: Ajami, D.; Oeckler, O.; Simon, A.;
Herges, R. Nature 2003, 426, 819–821. Subsequent work on Mo¨bius
porphyrinoids: (b) Pacholska-Dudziak, E.; Skonieczny, J.; Pawlicki, M.;
Szterenberg, L.; Ciunik, Z.; Latos-Graz˙yn´ski, L. J. Am. Chem. Soc. 2008,
130, 6182–6195. (c) Tanaka, Y.; Saito, S.; Mori, S.; Aratani, N.; Shinokubo,
H.; Shibata, N.; Higuchi, Y.; Yoon, Z. S.; Kim, K. S.; Noh, S. B.; Park,
J. K.; Kim, D.; Osuka, A. Angew. Chem., Int. Ed. 2008, 47, 681–684. (d)
Park, J. K.; Yoon, Z. S.; Yoon, M.-C.; Kim, K. S.; Mori, S.; Shin, J.-Y.;
Osuka, A.; Kim, D. J. Am. Chem. Soc. 2008, 130, 1824–1825. (e) Sankar,
J.; et al. J. Am. Chem. Soc. 2008, 130, 13568–13579. (f) Saito, S.; Shin,
J.-Y.; Lim, J. M.; Kim, K. S.; Kim, D.; Osuka, A. Angew. Chem., Int. Ed.
2008, 47, 9657–9660. (g) Kim, K. S.; Yoon, Z. S.; Ricks, A. B.; Shin,
J.-Y.; Mori, S.; Sankar, J.; Saito, S.; Jung, Y. M.; Wasielewski, M. R.;
Osuka, A.; Kim, D. J. Phys. Chem. A 2009, 113, 4498–4506. (h) Tokuji,
S.; Shin, J.-Y.; Kim, K.-S.; Lim, J.-M.; Youfu, K.; Saito, S.; Kim, D.; Osuka,
A. J. Am. Chem. Soc. 2009, 131, 7240–7241.
systematically explored.7 The present method consists of a
Friedel-Crafts reaction between terephthaloyl chloride and
an appropriate arene, followed by a reduction of the resulting
diketone with lithium aluminum hydride. For this method
to work efficiently, the arene must be sufficiently active
toward acylation. Additionally, the formation of regioisomers
has to be avoided by choosing arenes with appropriate
(6) Lindsey, J. S. Synthesis of meso-Substituted Porphyrins. In The
Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard, R., Eds.;
Academic Press: San Diego, 2000; Vol. 1, Chapter 2, pp 45-118.
(7) The majority of compounds 3 and 4 were previously obtained by a
variety of methods, usually not related to the one described here. For details
and references, see the Supporting Information.
(3) (a) Ste¸pien´, M.; Latos-Graz˙yn´ski, L.; Sprutta, N.; Chwalisz, P.;
Szterenberg, L. Angew. Chem., Int. Ed. 2007, 46, 7869–7873. For reviews,
see: (b) Herges, R. Nature 2007, 450, 36–37. (c) Yoon, Z. S.; Osuka, A.;
Kim, D. Nature Chem. 2009, 1, 113–122.
(4) (a) Heilbronner, E. Tetrahedron Lett. 1964, 5, 1923–1928. For a
review of conceptual and synthetic advances, see: (b) Herges, R. Chem.
ReV. 2006, 106, 4820–4842.
(8) N-Confusion in porphyrin chemistry: (a) Furuta, H.; Maeda, H.;
Osuka, A. Chem. Commun. 2002, 1795–1804. (b) Harvey, J. D.; Ziegler,
C J. Coord. Chem. ReV. 2003, 247, 1–19.
Org. Lett., Vol. 11, No. 17, 2009
3931

Scheme 2
of 6, two pyrrole rings undergo N-confusion during macro-
rings B and E, respectively (NH···O distance of 1.95 Å).
The NH···O distances between the two inverted pyrroles equal
2.51 Å, suggesting that the transannular interaction between
rings B and E is insignificant. The phenylene rings are tilted
at an angle of 46° relative to the macrocyclic plane. Apart
from the phenylene rings, which show only a slight quinoidal
distortion from the regular benzene structure, the macrocyclic
system exhibits bond length alternation, in accord with the
expected antiaromatic character of 6f.
The conformation of 6f observed in the solid state is
largely preserved in solution, as confirmed by proton
magnetic resonance spectroscopy (Figure 3, top). The mac-
rocycle is moderately paratropic, in line with its [28]annu-
lenoid formulation, leading to observable shielding of the
peripheral protons in the molecule. In particular, the signals
at 5.61 and 5.49 ppm were identified as corresponding to
the ꢀ-pyrrolic protons of rings C/F, whereas the signal at
4.81 ppm was assigned to the lone ꢀ proton of the flipped
rings B/E. Accordingly, the downfield signals at 10.83 and
14.12 ppm were assigned to the inner NH signals of rings
B/E and C/F, respectively. The large downfield shift of the
C/F NH signal combines the deshielding effects of paratro-
picity and strong intramolecular hydrogen bonding. The
observed four-bond couplings between pyrrolic ꢀ and NH
signals are consistent with the different connectivity patterns
of the regular pyrrolic unit (C/F) and the R-oxidized
N-confused unit (B/E).
cyclization (as previously observed in several singly N-
confused porphyrinoids11). The isolated isomer is one of the
three possible doubly N-confused structures that can be
obtained in the absence of pyrrole scrambling.
Compound 6f is only formed efficiently in the presence
of excess DDQ (3 equiv per 1 mol of 5f). The use of 1.5
equiv of DDQ, which is a sufficient amount for the formation
of 2, provides only traces of 6f. However, we were unable
to identify any intermediate oxidation products from the
resulting mixture.
In the solid state,12 compound 6f adopts a quasiplanar
conformation, with the N-confused rings inverted toward the
center of the macrocycle (Figure 2). This conformation,
which is significantly different from the figure-eight structure
2, is stabilized by two intramolecular hydrogen bonds linking
amine hydrogens of rings C and F with lactam oxygens of
At room temperature, the phenylene rings (A/D) are
represented by an AA′BB′ spin system at 7.87 and 7.74 ppm.
This spectral pattern corresponds to fast phenylene libration,
which rapidly exchanges positions of the “outer” and “inner”
protons. The libration is a very fast process, and conse-
quently, decoalescence of the phenylene signals can only
observed below 190 K (dichloromethane-d2, 600 MHz). In
a supercooled solution at 160 K, two broad overlapping
signals are observed at ca. 9.4 and 9.3 ppm, corresponding
to the inner phenylene protons, whereas the outer protons
give rise to a signal of double intensity at 6.24 ppm. Such
differentiation of chemical shifts corresponds to that observed
for pyrrolic rings, and is characteristic of a paratropic system.
Figure 2. X-ray rystal structure of 6f with vibrational ellipsoids at
the 50% probability level. Solvent molecules, hydrogen atoms, and
disorder in one of the Tep substituents are not shown for clarity.
Intramolecular hydrogen bonds are shown as dotted lines. The side
view at the bottom shows the orientation of the phenylene rings.
Compound 6f has a deep red color in solution. The
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Org. Lett., Vol. 11, No. 17, 2009

macrocycles. Unexpectedly, further increase of the steric bulk
results in the formation of a doubly N-confused system 6,
which shares the basic structural outline with 2 but no longer
adopts a figure-eight conformation. While the yield of the
macrocyclization leading to 2 has seen only a moderate
improvement relative to the three-component condensation,3a
the present procedure provides a more convenient access to
the Hu¨ckel-Mo¨bius macrocycle 2, given the better scal-
ability of the dicarbinol synthesis and the absence of
macrocyclic byproducts in the cyclization step. We believe
that the methodology reported herein may find use in the
synthesis of other phenylene-containing porphyrinoids.
Acknowledgment. Financial support from the Ministry
of Science and Higher Education (Grant No. N N204
013536). We thank Prof. Tadeusz Lis (University of Wrocław)
for an X-ray diffraction measurement.
Supporting Information Available: Synthetic procedures,
X-ray crystallographic information, and spectral data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL9016222
1
Figure 3. Top: H NMR spectrum of 6f (CDCl3, 600 MHz, 300
(9) For related chemistry, see: (a) Schmidt, I.; Chmielewski, P. J.
Tetrahedron. Lett. 2001, 42, 6389. (b) Srinivasan, A.; Ishizuka, T.; Osuka,
A.; Furuta, H. J. Am. Chem. Soc. 2003, 125, 878–879. (c) Srinivasan, A.;
Ishizuka, T.; Furuta, H. Angew. Chem., Int. Ed. 2004, 43, 876–879. (d)
Srinivasan, A.; Ishizuka, T.; Maeda, H.; Furuta, H. Angew. Chem., Int. Ed.
2004, 43, 2951–2955.
K). The assignment was made on the basis of 2D NMR data. Atom
numbering corresponds to that given in Scheme 2. Arrows indicate
fast phenylene rotation. The alkyl region, containing signals of the
ethyl groups, is not shown. Bottom: The electronic spectrum of 6f
(CH2Cl2, 298 K).
(10) Multiply N-confused porphyrinoids: (a) Furuta, H.; Maeda, H.;
Osuka, A. J. Am. Chem. Soc. 2000, 122, 803–807. (b) Furuta, H.; Maeda,
H.; Osuka, A. J. Org. Chem. 2000, 65, 4222–4226. (c) Araki, K.;
Winnischofer, H.; Toma, H. E.; Maeda, H.; Osuka, A.; Furuta, H. Inorg.
Chem. 2001, 40, 2020–2025. (d) Maeda, H.; Osuka, A.; Furuta, H. J. Am.
Chem. Soc. 2003, 125, 15690–15691. (e) Sessler, J. L.; Cho, D.-G.; Ste¸pien´,
M.; Lynch, V.; Waluk, J.; Yoon, Z. S.; Kim, D. J. Am. Chem. Soc. 2006,
128, 12640–12641.
electronic spectrum of 6f (Figure 3, bottom) consists of
several broad overlapping bands and is characterized by the
absence of a dominant Soret-like absorption. The spectrum
changes insignificantly upon addition of several equivalents
of trifluoroacetic acid. This behavior is expected, since 6f
contains no imine nitrogen sites that could be protonated.
In this paper, we have shown that the reactivity patterns
leading to expanded benziporphyrins are highly dependent
on meso-substitution. It was found that the presence of
o-methyl groups on the meso substituents flanking the
phenylene is a prerequisite to the formation of expanded
(11) (a) Furuta, H.; Asano, T.; Ogawa, T. J. Am. Chem. Soc. 1994, 116,
767–768. (b) Chmielewski, P. J.; Latos-Graz˙yn´ski, L.; Rachlewicz, K.;
Głowiak, T. Angew. Chem., Int. Ed. Engl. 1994, 33, 779–781. (c) Pacholska,
E.; Latos-Graz˙yn´ski, L.; Szterenberg, L.; Ciunik, Z. J. Org. Chem. 2000,
65, 8188–8196. (d) Sprutta, N.; Latos-Graz˙yn´ski, L. Org. Lett. 2001, 3,
1933–1936.
(12) Crystal data for 6f: C94H96N4O2·4CH2Cl2, Mw ) 1653.45, mono-
clinic, space group P21/c (no. 14), a ) 14.7357(4) Å, b ) 17.0703(3) Å,
c ) 17.6198(4) Å, ꢀ ) 105.354(3)°, V ) 4273.94(17) Å3, Z ) 2, Dcalcd
1.285 g/cm3, T ) 100 K, R ) 0.0552, Rw ) 0.1291, GOF ) 0.913 .
)
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