Aromatic and nonaromatic pyriporphyrins

Article abstract of DOI:10.1021/ol071052x

Pyriporphyrins with three different orientations for the pyridine moiety have been prepared using a '3 + 1' strategy. The nonaromatic pyriporphyrins are stable so long as phenyl substituents are present at the meso-positions adjacent to the pyridine ring. An aromatic dihydropyriporphyrin with an external CO ₂Ph protective group has also been prepared from 2,4- pyridinedicarbaldehyde.

Full text of DOI:10.1021/ol071052x

ORGANIC
LETTERS
2007
Vol. 9, No. 15
2863-2866
Aromatic and Nonaromatic
Pyriporphyrins†
Timothy D. Lash,* Komal Pokharel, Jill M. Serling, Valerie R. Yant, and
Gregory M. Ferrence
Department of Chemistry, Illinois State UniVersity, Normal, Illinois 61790-4160
tdlash@ilstu.edu
Received May 5, 2007
ABSTRACT
Pyriporphyrins with three different orientations for the pyridine moiety have been prepared using a ‘3
+
1’ strategy. The nonaromatic
pyriporphyrins are stable so long as phenyl substituents are present at the meso-positions adjacent to the pyridine ring. An aromatic
dihydropyriporphyrin with an external CO2Ph protective group has also been prepared from 2,4-pyridinedicarbaldehyde.
Pyridine analogues of the phthalocyanines were first de-
scribed by Linstead in the 1950s,1 but the porphyrin analogue
Scheme 1. Pyriporphyrins
“pyriporphyrin” 1a eluded synthesis until very recently.2-5
Reaction of 2,6-pyridinedicarbaldehyde with a tripyrrane in
the presence of an acid catalyst was reported to give a labile
dihydropyriporphyrin, but oxidation with DDQ or chloranil
gave unstable oxophlorins or dimers instead of 1a (Scheme
1).2 In contrast, isophthalaldehyde reacted with tripyrranes
under the same type of ‘3 + 1’ conditions to give benzi-
porphyrin 1b,6,7 while related hydroxydialdehydes gave
excellent yields of the aromatic porphyrinoids 2a and 2b.4,8
The ‘3 + 1’ methodology9 has been used to prepare many
related macrocycles including azuliporphyrins10 and benzo-
carbaporphyrins.11 In recent studies, syntheses of tetraarylpy-
riporphyrins 5 and 6 were reported,5,12 and the metalation
† Part 43 in the series Conjugated Macrocycles Related to the Porphyrins.
(1) Linstead, R. P. J. Chem. Soc. 1953, 2873.
(2) Berlin, K.; Breitmaier, E. Angew. Chem., Int. Ed. Engl. 1994, 33,
219.
(3) For the synthesis of related macrocycles, see: (a) Callot, H. J.;
Schaeffer, E. Tetrahedron 1978, 34, 2295. (b) Carre´, F. H.; Corriu, J. P.;
Bolin, G.; Moreau J. J. E.; Vernhet, C. Organometallics 1993, 12, 2478.
(c) Adams, K. R.; Bonnett, R.; Burke, P. J.; Salgado, A.; Valle´s, M. A. J.
Chem. Soc., Perkin Trans. 1 1997, 1769. (d) Liu, D.; Ferrence, G. M.; Lash,
T. D. J. Org. Chem. 2004, 69, 6079. (e) Sim, E.-K.; Jeong, S.-D.; Yoon,
D.-Hong, W. S.-J.; Kang, Y.; Lee, C.-H. Org. Lett. 2006, 8, 3355.
(4) Lash, T. D.; Chaney, S. T. Chem.sEur. J. 1996, 2, 944.
(5) Mysliborski, R.; Latos-Grazynski, L.; Szterenberg, L. Eur. J. Org.
Chem. 2006, 3064.
of these systems has been investigated.13 Although one-pot
syntheses of tetraarylazuliporphyrins14 and benziporphyrins15
have been developed, these procedures could not be used in
(6) Lash, T. D. Synlett 2000, 279.
the synthesis of pyriporphyrins due to the poor reactivity
10.1021/ol071052x CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/29/2007

characteristics of the electron-deficient pyridine precursors.5
Instead, multistep procedures were required to prepare
macrocycles such as 5 and 6.5,12
11 could be trapped out as an acyl derivative 12. This
reaction was attempted by adding acetic anhydride and
triethylamine. Small amounts of Ac2O were not effective,
but when a large excess of the reagent was used (>2 mL
for 100 mg of 9), a porphyrin-like product could be detected.
However, attempts to acylate the crude reaction mixture with
other reagents such as acetyl chloride, pivaloyl chloride, or
benzoyl chloride failed to give more than trace amounts of
the corresponding acyl derivatives. The crude Ac2O-derived
product showed a strong diatropic ring current with a CH
resonance at -6 ppm and a strong Soret-type band at 426
nm in its UV-vis absorption spectrum. High-resolution EI
mass spectrometry also gave a molecular ion at m/z 506.3050,
which corresponded to the expected molecular formula for
C33H38N4O (calculated mass 506.3046). Unfortunately, 12a
proved to be rather unstable and could not be fully purified.
Phenyl chloroformate has been reported to be a superior
reagent for derivatizing dihydropyridines17 and for this reason
was selected as an alternative reagent for stabilizing the
porphyrinoid system. Reaction of the crude intermediate with
a large excess of PhOCOCl and Et3N generated the carbam-
ate derivative 12b as a major reaction product. Following
chromatography on silica and recrystallization from chloro-
form-hexanes, the porphyrin analogue was obtained as dark
purple crystals in 36% yield. The UV-vis spectrum for 12b
showed a Soret band at 420 nm and a series of Q-bands
extending to 709 nm (Figure 1). Addition of TFA gave a
In our studies, we were particularly interested in the
N-confused pyriporphyrin system 7, which has not been
investigated previously. This system could potentially form
aromatic dihydropyriporphyrin derivatives 8 with chro-
mophores similar to oxybenziporphyrin 4b.8 In addition, the
presence of external nitrogen atoms may facilitate the
formation of multicomponent molecular systems. In order
to assess the possibility of synthesizing N-confused pyri-
porphyrins, tripyrrane 9 was reacted with 2,4-pyridinedicar-
baldehyde16 in the presence of trifluoroacetic acid using the
‘3 + 1’ variant of the MacDonald condensation (Scheme
2).9 The reaction solutions rapidly turned a dark green color
Scheme 2
that was consistent with macrocycle formation. However,
attempts to oxidize the intermediate to 10 with DDQ or FeCl3
gave complex mixtures, and column chromatography af-
forded a series of green bands that yielded no stable products.
A dihydropyriporphyrin such as 11 is likely to be formed in
the initial condensation reaction, but this species and its
oxidation products appear to be highly unstable. However,
no oxidation would be required if the aromatic tautomer of
Figure 1. UV-vis spectra of pyriporphyrin 12b in 1% Et3N-
CHCl3 (red line) and trace TFA-CHCl3 (blue line).
(7) (a) Berlin, K.; Breitmaier, E. Angew. Chem., Int. Ed. Engl. 1994,
33, 1246. (b) Lash, T. D.; Chaney, S. T.; Richter, D. T. J. Org. Chem.
1998, 63, 9076. (c) Richter, D. T.; Lash, T. D. Tetrahedron 2001, 57, 3659.
(d) Miyake, K.; Lash, T. D. Chem. Commun. 2004, 178.
(8) Lash, T. D. Angew. Chem., Int. Ed. Engl. 1995, 34, 2533.
(9) (a) Lash, T. D. Chem.sEur. J. 1996, 2, 1197. (b) Lash, T. D. J.
Porphyrins Phthalocyanines 1997, 1, 29.
(10) (a) Lash, T. D.; Chaney, S. T. Angew. Chem., Int. Ed. Engl. 1997,
36, 839. (b) Lash, T. D.; Colby, D. A.; Graham, S. R.; Chaney, S. T. J.
Org. Chem. 2004, 69, 8851.
(11) (a) Lash, T. D.; Hayes, M. J. Angew. Chem., Int. Ed. Engl. 1997,
36, 840. (b) Lash, T. D.; Hayes, M. J.; Spence, J. D.; Muckey, M. A.;
Ferrence, G. M.; Szczepura, L. F. J. Org. Chem. 2002, 67, 4860.
(12) Mysliborski, R.; Latos-Grazynski, L. Eur. J. Org. Chem. 2005, 5039.
(13) Mysliborski, R.; Rachlewicz, K.; Latos-Grazynski, L. Inorg. Chem.
2006, 45, 7828.
related cation 12bH+ that retained a porphyrin-like UV-
vis spectrum with a Soret band at 431 nm. The proton NMR
spectrum of 12b in CDCl3 confirmed that this system has
highly diatropic characteristics, showing the internal CH
upfield at -6.6 ppm and the external meso-protons as four
1H singlets in the downfield region between 8.5 and 9.6 ppm
(Figure 2). Carbon-13 NMR and HRMS further confirmed
the identity of this novel aromatic porphyrinoid structure.
The synthesis of pyriporphyrins presents a challenge not
only due to the electron-withdrawing nature of the pyridine
unit and the basicity of the nitrogen, which can also poten-
tially interfere with macrocycle formation, but also because
of their limited stability. The undesired reactivity of pyri-
porphyrins appears to be associated with the meso-carbons
surrounding the pyridine unit, and meso-aryl substituents can
(14) (a) Colby, D. A.; Lash, T. D. Chem.sEur. J. 2002, 8, 5397. (b)
Lash, T. D.; Colby, D. A.; Ferrence, G. M. Eur. J. Org. Chem. 2003, 4533.
(15) (a) Stepien, M.; Latos-Grazynski, L. Chem.sEur. J. 2001, 7, 5113.
(b) Szymanski, J. T.; Lash, T. D. Tetrahedron Lett. 2003, 44, 8613. (c)
El-Beck, J. A.; Lash, T. D. Org. Lett. 2006, 8, 5263.
(16) Pastour, P.; Queguiner, G. Bull. Soc. Chim. Fr. 1968, 4117.
2864
Org. Lett., Vol. 9, No. 15, 2007

presence of TFA in CH2Cl2 and oxidized with DDQ. Follow-
ing workup, column chromatography on grade 3 basic alum-
ina, and recrystallization, the three isomeric pyriporphyrins
18a-c were isolated in 22-42% yield. N-Confused pyri-
porphyrins 18a and 18b showed no indication of a diatropic
ring current, and the UV-vis spectra were similar to the
spectrum reported for benziporphyrin 4a. The proton NMR
spectrum for 18a showed the meso-protons at 5.84 and 5.88
ppm, while the more symmetrical isomer 18b gave a 2H
singlet at 6.32 ppm. The internal CH for 18a gave a reso-
nance at 8.98 ppm compared to 7.94 ppm for 18b. Although
there are minor differences, these results are not consistent
with the presence of any macrocyclic ring currents. Addition
of TFA afforded the related dications. Although external pro-
tonation on the pyridine nitrogen is possible, the proton NMR
spectra indicate that internal protonation is favored for these
1
Figure 2. Partial 400 MHz H NMR spectrum of pyriporphyrin
12b in CDCl3 showing the upfield and downfield regions.
protect these porphyrinoids from degradation processes.
Although this consideration was beneficial in the synthesis
of pyriporphyrins 5 and 6,5,12 those studies generated the
required tripyrrane-type precursors from relatively expensive
dibromopyridines. This approach also necessitated the use
of very low-temperature metal-halogen exchange reac-
tions.12 The synthesis of 6 was particularly inefficient,
requiring several additional steps, and the final ring closure
step only occurred in 5.5% yield.5 In our investigations, we
have developed far more efficient syntheses of three isomeric
nonaromatic pyriporphyrins starting with readily available
pyridine dicarboxylic acids 13. Treatment of 13 with excess
thionyl chloride and catalytic DMF afforded the correspond-
ing diacyl chlorides, and these reacted with benzene under
Friedel-Crafts acylation conditions to give the corresponding
diketones 14 in >70% yield. These were easily reduced with
sodium borohydride in ethanol to give virtually quantitative
yields of the corresponding dicarbinols 15. At this stage, it
was necessary to generate a tripyrrane-type intermediate 16.
Reaction of 15 or the corresponding acetate derivatives with
pyrrole gave no reaction. However, Mysliborski and Latos-
Grazynski had found that mesylate derivatives could be used
to conduct this type of chemistry.12 Reaction of 15a-c with
methane sulfonyl chloride and triethylamine at 0 °C, followed
by condensation with 100 equiv of pyrrole at room temper-
ature, gave the tripyrranes 16 in 23-43% yield. Although
dialcohols 15a-c and tripyrranes 16a-c were obtained as
mixtures of diastereomers, this was of little significance in
these studies because the stereochemistry is lost in the
subsequent chemistry.
2+
compounds, as illustrated for 18bH2 in Scheme 4.12
Scheme 3
The molecular structure of 18a was confirmed by X-ray
crystallographic analysis (Figure 3). Difference Fourier maps
clearly indicated the presence of electron density consistent
with hydrogen atoms attached to the C(22) and N(24) atoms.
The macrocycle adopts a saddled geometry with the 2-aza-
benzi moiety tilted 30.7(1)° out of the N(23), N(24), N(25)
Scheme 4. Protonation and Metalation Reactions
meso-Aryl tripyrranes often give poor yields in porphyrin
syntheses because they can undergo fragmentation processes
under acid-catalyzed conditions.18 This can be overcome
using mesityl groups that sterically hinder these side reac-
tions.5,19 However, in this case, the pyridine unit provides
stabilization due to its electron-deficient characteristics, and
this beneficial property is enhanced under acidic conditions
due to protonation of the basic nitrogen atom. For this reason,
we anticipated that these tripyrrane analogues could be used
in ‘3 + 1’ MacDonald-type reactions with readily available
pyrrole dialdehydes.20 In addition, the absence of substituents
at the other two meso-positions was considered to not be
crucial for stabilizing the pyriporphyrin systems. Hence,
pyritripyrranes 16 were reacted with dialdehyde 17 in the
Org. Lett., Vol. 9, No. 15, 2007
2865

can only be explained by the presence of a weak diatropic
ring current. Further support for this interpretation comes
from the CH2 resonances of the ethyl substituents, which
shift downfield by 0.3 ppm on addition of acid, while
virtually no shift occurs for these peaks in the NMR spectra
of 18a and 18b. If one of the protonations for 18cH22+ occurs
on the pyridine nitrogen, this species can have a resonance
contributor with an 18π-electron delocalization pathway that
aids in charge delocalization (Scheme 4). Interestingly,
pyriporphyrin 6 has been shown to have similar properties
for the monoprotonated form but not for the dication.5
Pyriporphyrin 18c does show the formation of an intermedi-
ary monocation by UV-vis spectroscopy, but careful titration
of TFA into an NMR tube only gave complex poorly
resolved spectra until the dication had been fully generated.
Pyriporphyrins 18a and 18b have a carbaporphyrinoid core
that may facilitate the formation of organometallic deriv
atives.21 In a preliminary study, 18a was reacted with
Pd(OAc)2 in refluxing acetonitrile for 10 min. A nonpolar
palladium complex was isolated by column chromatography,
and following recrystallization from chloroform-hexanes,
19 was isolated in 57% yield. Hence, the new substitution
pattern present in pyriporphyrins 18 appears to be compatible
with metalation chemistry. Pd(II) complex 19 is nonaromatic
but can be protonated with TFA on the external nitrogen to
give a monocation, indicating that the meso-phenyl groups
do not prevent protonation from occurring.
Figure 3. ORTEP III drawing (50% probability level, hydrogen
atoms drawn arbitrarily small) of compound 18a viewed (a) normal
to and (b) edge on with the core N,N,N plane. Selected bond lengths
(Å): C(1)-N(2) 1.367(2), N(2)-C(3) 1.345(2), C(3)-C(4) 1.376-
(2), C(4)-C(5) 1.384(2), C(5)-C(22) 1.398(2), C(22)-C(1) 1.397-
(2), C(5)-C(6) 1.479(2), C(1)-C(21) 1.479(2). Selected bond
angles (deg): C(1)-N(2)-C(3) 117.2(2); N(2)-C(3)-C(4) 124.0-
(2), C(3)-C(4)-C(5) 119.1(2), C(4)-C(5)-C(22) 118.5(2), C(5)-
C(22)-C(1) 119.3(2), C(22)-C(1)-N(2) 121.9(2).
In conclusion, efficient syntheses of pyriporphyrins have
been developed starting from pyridine dicarboxylic acids,
and these show promise in formation of organometallic
derivatives and supramolecular assemblies. This chemistry
may also be applicable to the synthesis of other porphyrin
analogue systems with other electron-deficient subunits. In
addition, a dihydropyriporphyrin was trapped as a fully
aromatic species that resembles carbaporphyrinoid systems
such as oxybenziporphyrin.
plane. Close examination of the structure indicates this
striking feature is attributable to contact between the 6 and
21 phenyl ipso-carbon atoms and the adjacent respective
hydrogen atom attached to C(4) and N(2) lone pair of
electrons. It is expected that such steric constraints are likely
to prevent methylation and could even inhibit protonation
of the 2-azabenzi nitrogen atom. The pyridine subunit
possesses bond lengths and angles typical for an isolated
pyridine π-system. The C(1)-C(21) and C(5)-C(6) dis-
tances, C(6) distances, both 1.479(2) Å, are typical for single-
bond C(sp2)-C(sp2) interactions. These structural features
corroborate that the pyridine ring retains unperturbed aro-
maticity and is electronically isolated from the macrocycle.
The free base form of pyriporphyrin 18c also appears to
be nonaromatic, and the proton NMR spectrum in CDCl3
shows the meso-protons at 6.28, the pyridine protons at 7.94
(1H, t) and 8.14 (2H, d), and the internal NH at 10.0 ppm.
However, in this case, addition of 1 drop of TFA showed a
significant effect that was consistent with the resulting
Acknowledgment. This material is based upon work
supported by the National Science Foundation under Grant
Nos. CHE-0616555 (to T.D.L.) and CHE-0348158 (to
G.M.F.), and the Donors of the Petroleum Research Fund,
administered by the American Chemical Society. We also
thank Dr. Matthias Zeller and the Youngstown State Uni-
versity Structure & Chemical Instrumentation Facility for
collecting the low-temperature CCD X-ray data.
Supporting Information Available: Details of the X-ray
crystallographic analysis, selected experimental procedures,
and UV-vis, 1H NMR, and 13C NMR spectra are provided.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL071052X
(17) Comins, D. L.; Abdullah, A. H. J. Org. Chem. 1984, 49, 3392.
(18) Jiao, W.; Lash, T. D. J. Org. Chem. 2003, 68, 3896.
(19) Venkatraman, S.; Anand, V. G.; Pushpan, S. K.; Sankar, J.;
Chandrashekar, T. K. Chem. Commun. 2002, 462.
(20) Tardieux, C.; Bolze, F.; Gros, C. P.; Guilard, R. Synthesis 1998,
267.
2+
dication 18cH2 taking on aromatic character (Scheme 4).
(21) For examples of similar organometallic derivatives, see: (a) Lash,
T. D.; Colby, D. A.; Graham, S. R.; Ferrence, G. M.; Szczepura, L. F.
Inorg. Chem. 2003, 42, 7326. (b) Lash, T. D.; Rasmussen, J. M.; Bergman,
K. M.; Colby, D. A. Org. Lett. 2004, 6, 549.
The meso-protons shift downfield to 7.61, while the internal
NHs gave broad resonances at 6.1 (1H) and 9.6 ppm (2H).
Although dications will give some deshielding, these shifts
2866
Org. Lett., Vol. 9, No. 15, 2007