Core-modified, meso-alkylidenyl porphyrins and their expanded analogues: A new family of nonplanar porphyrinoids

Article abstract of DOI:10.1021/jo070872k

(Chemical Equation Presented) New core-modified, meso-alkylidenyl porphyrinoids bearing multiple exocyclic double bonds were synthesized and characterized. The synthesis was accomplished using a typical "3 + 1"-type condensation approach. Stable exocyclic

Full text of DOI:10.1021/jo070872k

Core-Modified, meso-Alkylidenyl Porphyrins and Their Expanded
Analogues: A New Family of Nonplanar Porphyrinoids
Seung-Doo Jeong,† Seong-Jin Hong,† Kee Jong Park,† Sihyun Ham,‡ Jonathan L. Sessler,§
Vincent Lynch,§ and Chang-Hee Lee*,†
Department of Chemistry and Institute of Basic Science, Kangwon National UniVersity,
Chun-Chon 200-701 Korea, Department of Chemistry and Biochemistry, UniVersity of Texas at Austin,
Austin, Texas 78712, and Department of Chemistry, Sookmyung Women’s UniVersity,
Seoul 140-742, Korea
Chhlee@kangwon.ac.kr
ReceiVed April 27, 2007
New core-modified, meso-alkylidenyl porphyrinoids bearing multiple exocyclic double bonds were
synthesized and characterized. The synthesis was accomplished using a typical “3 + 1”-type condensation
approach. Stable exocyclic tautomers bearing double bonds at the meso positions, as well the corresponding
endocyclic tautomers, were isolated in the case of both thiabenziporphyrin and thiapyriporphyrin products
prepared in the course of this study. On the other hand, only the exocyclic tautomer was isolated in the
case of the congeneric oxapyriporphyrin and oxabenziporphyrin. Expanded analogues of the exocyclic
forms of oxabenziporphyrin and thiabenziporphyrin were also isolated as minor products. A single-
crystal X-ray diffraction analysis of the expanded thiabenziporphyrin (20) revealed that all four pyrrole
rings displayed an inverted geometry, presumably reflecting the strong hydrogen-bonding extant between
the pyrrole N-H proton and the carbonyl group of the malonate moiety in the solid state. On the other
hand, the expanded oxabenziporphyrin (14) was found to possess a severely distorted geometry with
only one pyrrole ring being inverted. Careful analysis of the structure revealed that the solid-state geometry
of the expanded macrocycles correlates well with the internal angle defined by the 2- and 5 substituents
and the centers of the furan (14) or thiophene (20) subunits.
Introduction
in areas such as photomedicine,1 supramolecular chemistry,2 and
materials science.3 Within the cadre of this generalized effort,
core-modified porphyrins, such as carbaporphyrinoids4 and their
metal complexes,5 pyridine-containing porphyrinoids,6 and thia-
Many structural analogues of porphyrins such as isomeric
porphyrins, aromatic or nonaromatic porphyrin analogues, and
expanded porphyrins have been prepared over the last few
decades and studied extensively due to their diverse applications
(1) (a) Sessler, J. L.; Hemmi, G.; Mody, T. D.; Murai, T.; Burrell, A.;
Young, S. W. Acc. Chem. Res. 1994, 27, 43. (b) Sessler, J. L.; Miller, R.
A. Biochem. Pharmacol. 2000, 59, 733.
(2) Sessler, J. L.; Gale, P. A.; Cho, W. S. Synthetic Anion Receptor
Chemistry; Royal Society of Chemistry: Cambridge, 2006; pp 131-166.
* Corresponding author. Tel.: 82-33-250-8490; fax: 82-33-253-7582.
† Kangwon National University.
‡ Sookmyung Women’s University.
§ University of Texas at Austin.
10.1021/jo070872k CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/07/2007
6232
J. Org. Chem. 2007, 72, 6232-6240

Core-Modified, meso-Alkylidenyl Porphyrins
SCHEME 1. Tautomeric Equilibrium between Exocyclic Form and Endocyclic Form of meso-Alkylidenyl Porphyrinoids
bonds at the meso positions, were reported in 1976.11 Ni(II)
SCHEME 2. Retrosynthetic Analysis of Target Compound 4
complexes of a different system, 5,10,15,20-tetraisopropylpor-
phyrin-containing exocyclic methylenes, were reported in
1998.12 Oxidation products of meso-tetrakis(3,5-di-t-butyl-4-
hydroxyphenyl)porphyrin also contain exocyclic double bonds,13
as does tetra-meso-methyleneporphyrinogen.14 Unfortunately,
however, these species are relatively unstable. Most recently,
cumulene-type, quinonoidal metalloporphyrins were reported by
Anderson et al.,15 with the compounds in question showing
promising optoelectronic properties. These interesting properties
and the rather unusual conjugation of meso-alkylidenyl por-
phyrins has led us to attempt the synthesis of novel porphy-
rinoids bearing stable exocyclic double bonds at multiple meso
positions. We were also motivated by an appreciation that
or oxa-porphyrinoids,7 have stimulated particular interest due
benziporphyrinoids or pyriporphyrinoids bearing exocyclic
to their unique physicochemical properties. They provide a
double bonds at more than one meso position would constitute
means for better understanding the electronic features of the
useful model compounds for exploring the interplay between
porphyrinoid macrocycles. For instance, it was found that the
benziporphyrins and pyriporphyrins8,9 bearing a benzene or
pyridine subunit as a part of the core structure did not exhibit
porphyrin-like macroaromatic properties due to the disruption
of the overall conjugation pathway. However, it was observed
that the presence of tautomerizable functional groups can
facilitate aromaticity in some cases.10 These observations have
provided a stimulus to prepare and study new kinds of
porphyrinoid macrocycles, and this has resulted in many
examples being described in recent years. In spite of this
progress, porphyrinoids bearing multiple meso-alkylidenyl
double bonds have attracted relatively little attention, with only
a handful of examples having been reported in the literature.
The first such systems, the so-called xanthoporphyrinogens,
structural analogues of porphyrin bearing exocyclic double
global aromaticity, molecular geometry, and substituent effects.
With such considerations in mind, we report here the synthesis,
characterization, and spectroscopic properties of new core-
modified porphyrinoids bearing alkylidenyl double bonds at
multiple meso positions. The presence of the exocyclic double
bond at the meso position(s) serves to disturb the full conjuga-
tion of the macrocycle, leading to systems that are rather
destabilized. Nonetheless, in several cases, different tautomers
were found to coexist, albeit with differing levels of apparent
stability.
Results and Discussion
Benziporphyrin is a well-recognized nonaromatic macrocycle.
Its lack of global or total macrocyclic aromaticity is ascribed
to a conjugation pathway that is interupted by a fully incorpo-
rated six-membered, 1,3-linked benzene moiety.8 To the extent
such rationalizations are correct, we considered it likely that
the presence of exocyclic double bonds combined with a
benziporphyrin-like incoporated six-membered ring would give
rise to porphyrinoid macrocycles with π-frameworks that are
further destabilized and hence even more distorted from
planarity. Further, if restrictions to the conformational flexibility
could be imposed via the introduction of bulky substituents at
the meso positions, we considered it likely that an even greater
(3) Chandrashekar, T. K.; Venkatraman, S. Acc. Chem. Res. 2003, 36,
676-691.
(4) (a) Lash, T. D. Synlett 2000, 279-295. (b) Lash, T. D. The Porphyrin
Handbook; Kadish, K., Smith, K. M., Guilard, R., Eds.; Academic Press:
San Diego, 2000; Vol. 2, pp 125-199.
(5) (a) Venkatraman, S.; Anand, V. G.; Pushpan, S. K.; Sankar, J.;
Chandrashekar, T. K. Chem. Commun. 2002, 462-463. (b) Stepien, M.;
Latos Grazynski, L.; Lash, T. D.; Szterenberg, L. Inorg. Chem. 2001, 40,
6892-6900. (c) Lash, T. D.; Miyake, K. Chem. Commun. 2004, 178-179.
(6) Berlin, K.; Breitmaier, E. Angew. Chem., Int. Ed. Engl. 1994, 33,
219-220.
(7) Hung, C. H.; Lin, C. Y.; Lin, P. Y.; Chen, Y. J. Tetrahedron Lett.
2004, 45, 129-132.
(11) Sheldrick, W. S. J. Chem. Soc., Perkin Trans. 2 1976, 453-456.
(12) Nelson, N. Y.; Medforth, C. J.; Khoury, R. G.; Nurco, D. J.; Smith,
K. M. Chem. Commun. 1998, 1687-1688.
(8) (a) Berlin, K.; Breitmaier, E. Angew. Chem., Int. Ed. Engl. 1994,
33, 1246-1247. (b) Lash, T. D.; Chaney, S. T.; Richter, D. T. J. Org. Chem.
1998, 63, 9076-9088.
(13) Milgrom, L. R.; Hill, J. P.; Yahioglu, G. J. Heterocycl. Chem. 1995,
32, 97-101.
(9) Kozyrev, A. N.; Alderfer, J. L.; Dougherty, T. J.; Pandey, R. K.
Angew. Chem., Int. Ed. 1999, 38, 126-128.
(14) Otto, C.; Breitmaier, E. Liebigs Ann. Chem. 1991, 1347-1348.
(15) Blake, I. M.; Rees, L. H.; Claridge, T. D. W.; Anderson, H. L.
Angew. Chem., Int. Ed. 2000, 39, 1818-1821.
(10) (a) Lash, T. D. Angew. Chem., Int. Ed. Engl. 1995, 34, 2533-2535.
(b) Lash, T. D.; Chaney, S. T. Chem.sEur. J. 1996, 2, 944-948.
J. Org. Chem, Vol. 72, No. 16, 2007 6233

Jeong et al.
SCHEME 3. Synthetic Scheme for Oxabenziporphyrins and Oxapyriporphyrins
level of distortion could be attained. In the limit, all vestiges of
global conjugation might be destroyed with the consequence
that various tautomers involving endo or exocyclic double bonds
would become chemically distinct in terms of isolation on the
laboratory time scale. In other words, under these latter limiting
conditions, the different forms illustrated by generalized struc-
tures 1-3 would no longer be interconvertible and could be
potentially isolated as stable constitutional isomers as shown
in Scheme 1. If the substituents on the meso-methyl/methylene/
methine groups (including R in structures 1,-3) are not only
bulky but also electron withdrawing, it should lead to a further
stabilization of the individual tautomeric forms.
With such considerations in mind, we designed a new class
of porphyrin analogues, represented by the general structure 4,
that should be amenable to synthesis using the so-called
modified “3 + 1” method, as shown retrosynthetically in
Scheme 2.16
Tripyrrane analogues of generalized structure 5 are core
building blocks in porphyrin analogue chemistry; likewise, the
furan and thiophene diols 6 are well-known precursors in this
area.17 Further, as shown in Scheme 3, the 2,6-bisvinyl benzene
derivative 7 and the 2,6-bisvinylpyridine derivative 8 could be
obtained readily via a Knoevenagel condensation of diethyl
malonate with 2,6-pyridinedicabaldehyde or isophthalaldehyde,
respectively.18 A subsequent acid-catalyzed addition of pyrrole
served to convert 7 or 8 to the corresponding tripyrrane
analogues 9 and 10. Many different catalysts and conditions
were tested in an effort to optimize the addition of pyrrole to
the vinylic double bonds of 7 and 8, and it was found that the
yield of the desired product dramatically depends on the catalyst
applied. For example, the best yield of 9 was obtained when
InCl3 was used as the catalyst. On the other hand, the highest
yield of 10 was obtained when trifluoroacetic acid was employed
as a catalyst. This difference was rationalized in terms of
pyridine being able to coordinate to the In(III) center, with the
resulting complex presumably not being activated sufficiently
to undergo electrophilic substitution at the methylene R-carbon.
Metal coordination could also be inhibitory as the result of steric
hindrance. Such limitations would not be operative in the case
of TFA-mediated catalysis, even under conditions where the
pyridine nitrogen atom is protonated.
All the addition reactions proved regiospecific and afforded
a single regioisomer, namely, the R,R′-dipyrryl derivatives 9
and 10. However, proton NMR spectral analysis revealed the
formation of diastereomeric mixtures; these were used directly
in the ensuing condensations without further purification since
the ring-forming reaction was expected to lead to the formation
of achiral products. The carbinols 11 required for the condensa-
tion were synthesized by treating furan with n-butyllithium,
followed by reaction with benzaldehyde.19 Once all the needed
building blocks were in hand, the bispyrrole-functionalized
precursors 9 and 10 were condensed, respectively, with carbinol
11 as shown in Scheme 3. Specifically, the reaction pair
consisting of 9 and 11 was dissolved in acetonitrile and treated
with trifluoroacetic acid followed by oxidation with DDQ; this
afforded the desired oxabenziporphyrin 12 in 20% yield. An
expanded analogue of this macrocycle bearing four exocyclic
double bonds, 14, was also isolated in a small amount (∼2%);
presumably, it was formed from the condensation of two
molecules of 9 with two molecules of carbinol 11. In contrast,
a similar condensation involving 10 and 11 afforded only the
oxapyriporphyrin 13 in 19% yield with no isolable quantities
of putative expanded congeners being obtained.
Compounds 12-14 were not expected to exhibit global
aromatic properties. Both the R-carbon of the diethyl malonate
group and the meso carbon are sp2-hybidized; thus, the benzene
(pyridine), the pyrrole, and the two ethoxycarbonyl groups were
expected to reside above or below the mean plane of the
macrocycle. Further, in 12 and 13, the benzene (or pyridine)
moiety would presumably be tilted significantly so as to reduce
the steric congestion that would otherwise originate from the
two diethyl malonate groups and the exocyclic double bonds.
The observation of the pyrrole N-H resonance at 8.09 ppm in
the 1H NMR spectrum, which is a typical chemical shift value
for simple pyrrole N-H protons, is fully consistent with the
suggested lack of extended conjugation. Moreover, the 13C NMR
(16) (a) Lee, C. H.; Kim, H. J.; Yoon, D. W. Bull. Korean Chem. Soc.
1999, 20, 276-280. (b) Sessler, J. L.; Genge, J. W.; Urbach, A.; Sanson,
P. Synlett 1996, 187-188. (c) Lash, T. D. Chem.sEur. J. 1996, 2, 1197-
1200. (d) Boudif, A.; Momenteau, M. J. Chem. Soc., Perkin Trans. 1 1996,
1235-1242.
(17) (a) Chadwick, D. J.; Willbe, C. J. Chem. Soc. Perkin Trans. 1 1977,
887-893. (b) Nagarajan A.; Ka, J. W.; Lee, C. H. Tetrahedron 2001, 57,
7323-7330.
(18) Hong, S. J.; Lee, M. H.; Lee, C. H. Bull. Korean Chem. Soc. 2004,
25, 1545-1550.
(19) Arumugam, N.; Ka, J. W.; Lee, C. H. Tetrahedron 2001, 57, 7323-
7330 and references therein.
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Core-Modified, meso-Alkylidenyl Porphyrins
SCHEME 4. Synthetic Scheme for Thiapyriporphyrins
SCHEME 5. Synthesis of Thiabenziporphyrin 19 and a Higher Homologue, 20
SCHEME 6. Conversion of Exocyclic Thiapyriporphyrin 16 to Its Endocyclic Isomer, 17
spectrum of 12 and 13 showed features corresponding to 22
total carbon signals, a finding that is in accord with the proposed
high symmetry for these macrocycles.
shown in Scheme 5. The reaction afforded only the exocyclic
product 19 and none of the endocyclic analogue, at least after
workup and purification. Thus, the thiapyriporphyrins 16 and
17 were the only tautomeric pair that could be isolated cleanly
from the present set of condensations.
Similar condensations of 10 with 15 were carried out using
conditions identical to those used to generate 12. However, in
this case, the reaction afforded a mixture of three different
products, namely, 16-18 in yields of 10, 2, and 2%, respec-
tively, as shown in Scheme 4. This is noteworthy because two
stable tautomeric products, specifically 16 and 17, were formed.
These two tautomers, which were isolated by column chroma-
tography over silica gel, proved stable in organic solvents. Thus,
both tautomers could be fully characterized using regular
spectroscopic methods.
The two tautomers 16 and 17 showed unique signals in their
respective proton NMR spectra. For example, the pyrrole NH
resonance was observed at 8.63 ppm in 16, whereas, as expected,
no pyrrole NH signal was seen in the case of 17. Instead, a
signal ascribable to the R-protons of the diethyl malonate groups
was observed at 5.18 ppm as a singlet. However, when
macrocycle 16 was treated with a strong base (EtOH/EtO-),
conversion to 17 was observed along with extensive decomposi-
tion (Scheme 6). On the other hand, treatment of 17 with a base
did not produce observable quantities of 16 and, instead, resulted
Condensation of 9 with 15 also resulted in the formation of
19, as well as a small amount of the higher homologue 20 as
J. Org. Chem, Vol. 72, No. 16, 2007 6235

Jeong et al.
FIGURE 1. Ortep rendered structures of (a) oxabenziporphyrin 12 and (b) oxapyriporphyrin 13 highlighting their structural similarity. The top
alkylidenyl double bonds exhibit a distorted geometry with the dihedral angle looking down the CdC double bond being 19.8° in panel a and 21.0°
in panel b, respectively.
FIGURE 2. Ortep rendered single-crystal X-ray diffraction structures of (a) expanded oxabenziporphyrin 14 and (b) expanded thiabenziporphyrin
20. Note that all four pyrrole rings in panel b adopt an inverted conformation due to the intramolecular hydrogen bonding between pyrrole N-H
and carbonyl group, while in panel a, three pyrrole rings are inverted, and one pyrrole ring is involved in hydrogen-bonding interactions with a
carbonyl group residing within the cavity.
only in extensive decomposition. Thus, it was possible to effect
partial interconversion between these two tautomers using
chemical means.
The UV-vis absorption spectrum of oxabenziporphyrin 12
recorded in CH2Cl2 revealed two dominant peaks at λmax at 390
(ꢀ ) 3.6 × 104) and 530 nm (ꢀ ) 2.2 × 104). The oxapyri-
porphyrin 13 also showed two dominant absorption features at
389 (ꢀ ) 2.7 × 104) and 534 nm (ꢀ ) 1.6 × 104) in its spectrum
FIGURE 3. Effective angle between 2 and 5 substituents in the furan
and thiophene subunits of 14 and 20, as calculated from the corre-
sponding solid-state structures.
when it was recorded under identical conditions. Similar
spectral features were seen for thiapyriporphyrin 16, a species
that also displayed λmax at 382 (ꢀ ) 4.0 × 104) and 555 nm
(ꢀ ) 1.7 × 104) in CH2Cl2. On the other hand, 17, the endocyclic
tautomer of 16, exhibited red-shifted absorption features with
The puckered geometry of 12 and 13 appears to have its origin
in the steric congestion arising from the two diethyl malonyl
groups and the benzene or pyridine rings, as well as the
electronic effect of the malonate carbonyl groups. Presumably,
as a consequence of these effects, both molecules adopt a
conformationally locked structure that precludes any
appreciable conjugation between the respective six π-electron
subunits (benzene or pyridine) with the rest of the π-electron
periphery.
λ
max at 395 (ꢀ ) 3.9 × 104) and 560 nm (ꢀ ) 1.4 × 104), again
in CH2Cl2.
Single-crystal X-ray diffraction structural studies of oxaben-
ziporphyrin 12 and oxapyriporphyrin 1320 revealed that both
porphyrins adopt severely puckered geometries. The benzene
(or pyridine) moiety was found to lie almost perpendicular to
the mean plane of the macrocycle (Figure 1). The lengths of
the double bonds appended to the meso positions were found
to be 1.381 and 1.389 Å, respectively.
6236 J. Org. Chem., Vol. 72, No. 16, 2007

Core-Modified, meso-Alkylidenyl Porphyrins
SCHEME 7. Reaction of 2,5-Bisvinylthiophene Derivative with Pyrrole
SCHEME 8. “3 + 1” Condensation Product of 24 with 15
Expanded macrocycles 14 and 20 were also subject to single-
With the synthesis of the benzene and pyridine-containing
meso-alkylidenyl porphyrins 12, 13, 16, and 19 accomplished,
efforts were made to prepare congeneric systems containing a
five-membered ring. Toward this end, 2,5-bisvinylthiophene 21
was reacted with pyrrole in the presence of InCl3 in the hopes
of obtaining open chain precursors analogous to 9 and 10.
However, in contrast to what was seen in the case of reactions
involving the benzene and pyridine derivatives 7 and 8, the
reaction resulted in the formation of retro-Knoevenagel products,
such as 22. Lowering the reaction temperature to 0 °C afforded
the thiophene-functionalized dipyrromethane 23 (Scheme 7).
crystal X-ray diffraction analysis.19,20 Figure 2 shows the
resulting structures with the hydrogen atoms omitted for clarity.
As can be seen from an inspection of this figure, the expanded
oxabenziporphyrin 14 adopts a severely disordered conforma-
tion. Three pyrrole rings (N1, N2, and N4) are inverted and are
involved in hydrogen-bonding interactions with the carbonyl
functions of the malonate groups. One pyrrole ring (N3) is not
inverted, and instead, one of the malonate groups resides close
to the cavity. On the other hand, the crystal structure of 20
reveals a molecule with near perfect C2V symmetry where all
four pyrrole rings are inverted and forming hydrogen bonds with
the malonate carbonyls. Support for the proposed intramolecular
hydrogen-bonding interactions came from the proton NMR
spectra, with significant downfield shifts for the pyrrolic N-H
resonances being observed; these signals were seen at 11.61
ppm in 20 and 11.10 ppm in 18.
Given this lack of success, precursor 24, bearing a single
ethoxycarbonyl group on each methylene bridge, was prepared;
it was synthesized by condensing the corresponidng carbinol
with pyrrole as shown in Scheme 8. Condensing 24 with diol
15 in the usual manner then provided porphyrin 25 bearing a
single ethyl acetate group on the meso positions.
Careful analysis of the solid-state structure reveals that the
bond angle (cf. Figure 3 for a schematic definition) about the
2,5-substituted furan in 14 is 133.0°, while the corresponding
angle in the thiophene subunit of 20 is 157.8°. These values
provide support for the notion that thiophene is better able to
accommodate the formation of a larger macrocycle without
being subject to undue angle strain.
The introduction of a single ethoxycarbonyl substituent on
each of the meso-methylene groups was expected to reduce the
steric congestion about these positions, leading to the prediction
that in the case of 25, the analogous alkylidenyl porphyrin 26
would not be formed. Indeed, no evidence of the latter species
was observed, with the aromatic porphyrin 25 being the sole
product isolated when precursors 15 and 24 were subject to
condensation according to the conditions of Scheme 5. This
result stands in contrast to what was seen in the case of the
(20) Sim, E. K.; Jeong, S. D.; Yoon, D. W.; Hong, S. J.; Kang, Y.; Lee,
C. H. Org. Lett. 2006, 8, 3355-3358.
J. Org. Chem, Vol. 72, No. 16, 2007 6237

Jeong et al.
phenyl- and pyridine-containing systems described earlier in this
paper and provides support for the notion that an appropriate
combination of factors is needed to obtain the nonaromatic
alkylidenyl products. On the basis of the present study, two such
leading factors are (i) the presence of a subunit, such as a 1,3-
linked benzene ring, that disrupts the conjugation pathway and
(ii) a highly hindered exocyclic meso-methylene substituent.
Unfortunately, a full distinction between these two effects is
not currently possible. In particular, the exact effect of the size
of the exocyclic meso-methylene substituent is difficult to
quantify at present. This is because attempted syntheses of the
meso-ethylaceto-substituted version of 9, the key intermediate
required for a synthesis of an alkylidenyl porphyrin analogous
to 26 (e.g., 27), proved to be unsuccessful. Attempts to prepare
such a product via the reaction of 1,3-bis(2-ethoxycarbonyl-
vinyl)-benzene with pyrrole in the presence of various acids
(BF3, TFA, In(III), K-10 clay, Pd(II), trifluoromethane sulfonic
acid, etc.) resulted only in extensive decomposition of the
pyrrole with, in particular, no meso-(mono-ethoxycarbonyl)
analogues of 9 being obtained.
of monomeric units, and metal complexation). Work along these
lines is currently in progress.
Experimental Section
Pyrrole was distilled at atmospheric pressure from CaH2.
Compounds 7-11, 15, and 21 were synthesized using slight
modifications of published procedures.18,19
6,21-Bis(diethoxycarbonylmethylidene)-11,16-diphenyl-24-
oxabenziporphyrin (12), Expanded Macrocycle (14).21-26 Com-
pounds 9 (0.11 g, 0.2 mmol) and 11 (0.062 g, 0.22 mmol) were
dissolved in CH3CN (20 mL) with stirring. TFA (0.040 mL, 0.52
mmol) was then added. The whole mixture was stirred for 24 h at
25 °C. At this juncture, DDQ (0.14 g, 0.62 mmol) and TEA (0.10
mL, 0.72 mmol) were added. The mixture was stirred for 1 h and
extracted with CH2Cl2 after adding brine (40 mL). The organic layer
was collected and dried (Na2SO4) before the solvent was removed
in vacuo. The mixture was chromatographed over silica gel, eluting
with CH2Cl2/EtOAc (19:1) to afford a crude mixture of 12 and 14.
Final purification of 12 and 14 was accomplished by repeated
column chromatography over silica gel adopting EtOAc/hexanes
1:2 as the eluent. Compound 12 was eluted first followed by 14.
1
For 12: Yield: 0.032 g (20%); H NMR (400 MHz, CDCl3) δ
8.02 (br s, 2H), 7.49-7.20 (m, 14H), 6.71-6.68 (m, 2H), 6.18 (s,
2H), 5.77-5.75 (m, 2H), 4.29 (q, J ) 7.13 Hz, 4H), 4.06 (q, J )
7.11 Hz, 4H), 1.29 (t, J ) 7.13 Hz, 6H), 1.13 (t, J ) 7.11 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 167.6, 164.1, 154.6, 143.4, 138.4,
135.2, 132.2, 131.5, 128.7, 128.6, 128.3, 127.9, 126.5, 124.9, 120.3,
115.5, 115.2, 108.1, 51.6, 50.9, 13.9, 13.9; MALDI-TOF MS Calcd
for C48H42N2O9 exact mass 790.29, found 790.34. For 14: Yield:
Conclusion
We have demonstrated that meso-alkylidenyl porphyrins,
bearing multiple exocyclic double bonds at the meso positions,
can be synthesized using a simple “3 + 1” condensation.
Introduction of bulky electron-withdrawing groups at the meso
positions in combination with conjugation-disrupting core
modifications permits the isolation and characterization of what
would otherwise be expected to be rather unstable tautomeric
forms. The resulting structures are all nonaromatic and are
characterized by puckered geometries. The distortion is most
apparent near the bridging six-membered ring (benzene or
pyridine in the present case), while the other parts of the
porphyrinoids exhibit features consistent with a partially
conjugated electronic structure. In one particular case, it was
found that both an exocyclic tautomer 16 and the corresponding
endocyclic tautomer 17 could be isolated from the same reaction
sequence and independently characterized. The former could
be transformed to the latter by treatment with a strong base,
albeit not with complete conversion.
In the case of the expanded macrocycles, the thiophene-
containing system 20 was characterized by a high degree of
symmetry and thiophene subunits that were tilted well off the
mean macrocycle plane. In this structure, all four pyrrole rings
are inverted, and the pyrrolic N-H protons form hydrogen
bonds with the carbonyl groups on the exocyclic malonate
substituents. In contrast, the furan-derived macrocycle 14 is
characterized by a rather distorted and irregular structure. The
differences in structure between 20 and 14 are seen to correlate
with the bite angle between the 2 and 5 substituents of the
thiophene and furan subunits. Thus, to the extent that conclu-
sions may be drawn from this kind of solid-state information,
it appears as if the incorporation of thiophene, rather than furan,
within these kinds of systems favors the formation of larger
macrocycles since less angle strain is imposed during the course
of the ring-forming process.
1
0.0062 g (2%); H NMR (400 MHz, CDCl3) δ 12.29 (br s, 1H),
11.58 (br s, 3H), 7.41-7.16 (m, 32H), 6.30 (s, 4H), 6.17-6.15
(m, 4H), 4.03-3.78 (m, 16H), 1.21-0.76 (m, 24H); 13C NMR (100
(21) Crystal data for 14 : C97H86N4O18, triclinic, space group P1h, a )
16.3452(3) Å, b ) 17.9863(3) Å, c ) 18.0871(4) Å, R ) 66.749(1)°, â )
85.227(1)°, γ ) 63.118(1)°, V ) 4330.46 Å3, T ) 153(2) K, Z ) 2, GOF
on F2 ) 0.995, R1 (I > 2σ(I)) ) 0.0676, wR2 ) 0.1406. Crystal data for
20: C112H120N4O16S2, triclinic, space group P1h, a ) 13.3598(3) Å, b )
18.5652(4) Å, c ) 23.1445(6) Å, R ) 71.668(1)°, â ) 84.352(1)°, γ )
77.554(1)°, 5318.2(2) Å3, T ) 153(2) K, Z ) 2, GOF on F2 ) 1.202, R1
(I > 2σ(I)) ) 0.1714, wR2 ) 0.1831. Crystals grew as dark, almost black
prisms by slow evaporation from hexanes. The data crystal was a prism
that had approximate dimensions of 0.22 mm × 0.20 mm × 0.07 mm. The
data were collected on a Nonius Kappa CCD diffractometer using a graphite
monochromator with Mo KR radiation (λ ) 0.71073Å). A total of 313
frames of data was collected using ω-scans with a scan range of 1.3° and
a counting time of 204 s per frame. The data were collected at 153 K using
an Oxford Cryostream low temperature device. Data reduction was
performed using DENZO-SMN.22 The structure was solved by direct
methods using SIR9723 and refined by full-matrix least-squares on F2 with
anisotropic displacement parameters for the non-H atoms using SHELXL-
97.24 The hydrogen atoms were calculated in ideal positions with isotropic
displacement parameters set to 1.2 × Ueq of the attached atom (1.5 × Ueq
for methyl hydrogen atoms). A molecule of what appears to be n-hexane
was found to be disordered near the center of the macrocycle. In addition,
sandwiched between adjacent molecules of the macrocycle that were related
by 1 - x, 1 - y, and -z, there were additional disordered solvent molecules.
All solvate molecules were severely disordered. Therefore, the contribution
to the scattering by the solvate was removed by use of the utility, SQUEEZE,
in PLATON98.25 PLATON98 was used as incorporated in WinGX.26
(22) Otwinowski, Z.; Minor, W. Methods in Enzymology; Carter, C. W.,
Jr., Sweets, R. M., Eds.; Academic Press: San Diego, 1997; Vol. 276, pp
307-326.
(23) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna,
R. SIR97, A Program for Crystal Structure Solution. J. Appl. Crystallogr.
1999, 32, 115-119.
(24) Sheldrick, G. M. SHELXL97; Program for the Refinement of Crystal
Structures; 1994, University of Gottingen, Germany.
(25) Spek, A. L. PLATON, A Multipurpose Crystallographic Tool;
Utrecht University: Utrecht, The Netherlands, 1998.
(26) Farrugia, L. J. WinGX 1.64, An Integrated System of Windows
Programs for the Solution, Refinement, and Analysis of Single-Crystal X-ray
Diffraction Data. J. Appl. Crystallogr. 1999, 32, 837-838.
The synthetic approach presented here may allow for
systematic studies of the interplay between global, macrocycle-
based aromaticity and distortion in heterocyclic aromatic
systems. A further potential benefit of the synthetic approach
described here is that it should be amenable to future modifica-
tion through (e.g., further expansion of ring size, self-assembly
6238 J. Org. Chem., Vol. 72, No. 16, 2007

Core-Modified, meso-Alkylidenyl Porphyrins
MHz, CDCl3) δ 166.27, 156.36, 131.19, 128.71, 127.96, 126.50,
108.70, 61.10, 60.84, 13.95; MALDI-TOF MS Calcd for C96H84N4O18
exact mass 1580.58, found 1581.62.
6,21-Bis(diethoxycarbonylmethylidene)-11,16-di(p-tolyl)-24-
thiabenziporphyrin (19) and Expanded Macrocycle (20). Com-
pounds 9 (0.33 g, 0.60 mmol) and 15 (0.21 g, 0.66 mmol), NH4Cl
(0.29 g, 0.54 mmol), TFA (0.15 mL, 1.88 mmol), DDQ (0.47 g,
2.09 mmol), and TEA (0.33 mL, 2.39 mmol) were used to prepare
these products using a procedure identical to that used for the
synthesis of 16. The crude product mixture was chromatographed
over silica gel, eluting first with CH2Cl2/EtOAc (9:1) during the
first purification and then with EtOAc/hexanes (1:3) during a
follow-up chromatographic purification step; this allowed isolation
of two different products (19 and 20). For 19: Yield: 0.038 g (8%);
1H NMR (400 MHz, CDCl3) δ 8.56 (br s, 2H), 7.56 (t, J ) 7.62
Hz, 1H), 7.44 (s, 1H), 7.40 (d, J ) 7.62 Hz, 2H), 7.22-7.15 (m,
8H), 6.75-6.73 (m, 2H), 6.57 (s, 2H), 6.02-6.00 (m, 2H), 4.45-
4.28 (m, 4H), 4.11-4.03 (m, 4H), 2.38 (s, 6H), 1.35 (t, J ) 7.12
Hz, 6H), 1.14 (t, J ) 7.09 Hz, 6H); 13C NMR (100 MHz, CDCl3)
δ 167.6, 163.6, 141.5, 138.2, 137.3, 136.7, 136.4, 135.3, 132.6,
131.3, 130.6, 129.0, 128.9, 128.8, 128.1, 122.5, 120.1, 116.8, 114.6,
61.8, 60.9, 21.3, 13.9; MALDI-TOF MS Calcd for C50H46N2O9S
exact mass 834.30, found 834.57. For 20: Yield: 0.013 g (1%);
1H NMR (400 MHz, CD2Cl2) δ 11.61 (br s, 4H), 7.34-7.22 (m,
24H), 7.18-7.14 (m, 4H), 6.54 (s, 4H), 6.02 (m, 4H), 4.04-3.87
(m, 16H), 2.42 (s, 12H), 1.19-1.04 (m, 24H); 13C NMR (100 MHz,
CDCl3) δ 166.3, 144.1, 138.1, 137.7, 130.6, 129.3, 128.8, 126.4,
123.9, 123.0, 116.3, 61.3, 60.9, 53.4, 31.9, 30.2, 29.7, 29.4, 22.7,
21.3, 14.2, 14.1, 14.0, 13.9, 1.0; MALDI-TOF MS Calcd for
6,21-Bis(diethoxycarbonylmethylidene)-11,16-diphenyl-24-ox-
apyriporphyrin (13). Compounds 10 (0.10 g, 0.19 mmol) and 11
(0.059 g, 0.21 mmol), TFA (0.050 mL, 0.65 mmol), DDQ (0.13 g,
0.57 mmol), and TEA (0.10 mL, 0.72 mmol) were used to prepare
this product using a procedure identical to that used to prepare 12.
The mixture was chromatographed over silica gel, eluting with CH2-
Cl2/EtOAc (19:1) during the first purification and then with EtOAc/
hexanes (1:2) during subsequent purifications. Yield: 0.028 g
(19%); 1H NMR (300 MHz, CDCl3) δ 8.09 (brs, 2H), 7.76 (t, J )
7.76 Hz, 1H), 7.40 (d, J ) 7.76 Hz, 2H), 7.38-7.26 (m, 10H),
6.74-6.17 (m, 2H), 6.17 (s, 2H), 5.80-5.78 (m, 2H), 4.29 (q, J )
7.13 Hz, 4H), 4.07 (q, J ) 7.10 Hz, 4H), 1.28 (t, J ) 7.13 Hz,
6H), 1.15 (t, J ) 7.10 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
167.6, 163.4, 156.1, 154.4, 142.1, 138.3, 136.46, 135.5, 131.5,
128.3, 127.9, 126.3, 123.6, 121.2, 115.7, 115.6, 108.1, 61.7, 61.0,
14.0, 13.9; MALDI-TOF MS Calcd for C47H41N3O9 exact mass
791.28, found 791.34.
6,21-Bis(diethoxycarbonylmethylidene)-11,16-di(p-tolyl)-24-
thiapyriporphyrin (16), 6,21-Bis(diethylmalonyl)-11,16-di(p-
tolyl)-24-thiapyriporphyrin (17), and Expanded Macrocycle
(18). Compound 10 (0.32 g, 0.59 mmol) and diol 15 (0.23 g, 0.70
mmol) were dissolved in CH3CN (60 mL) with stirring. NH4Cl
(0.31 g, 0.59 mmol) and TFA (0.16 mL, 2.05 mmol) were then
added. The whole mixture was stirred for 4.5 h at 25 °C before
DDQ (0.46 g, 2.05 mmol) and TEA (0.24 mL, 2.34 mmol) were
added successively. The resulting mixture was stirred for 1 h and
extracted with CH2Cl2 after adding brine (50 mL). The organic layer
was collected and dried (Na2SO4) before the solvent was removed
in vacuo. The resulting solid contained all three compounds.
Column chromatography over silica gel while eluting with CH2-
Cl2/EtOAc (19:1) afforded 17 as a fast moving fraction. The other
fractions were not separated clearly, and thus, further column
chromatographic purifications were performed. The mixture of 16
and 18 can be separated by repeated column chromatography over
silica gel using EtOAc/hexanes 1:2 as the eluent. Compound 16
was eluted first followed by 18. For 16: Yield: 0.047 g (10%); 1H
NMR (300 MHz, CDCl3) δ 8.63 (br s, 2H), 7.86 (t, J ) 7.76 Hz,
1H), 7.42 (d, J ) 7.76 Hz, 2H), 7.24-7.16 (m, 8H), 6.75-6.72
(m, 2H), 6.61 (s, 2H), 6.07-6.05 (m, 2H), 4.41-4.28 (m, 4H),
4.09 (q, J ) 7.10 Hz, 4H), 2.39 (s, 6H), 1.31 (t, J ) 7.13 Hz, 6H),
1.16 (t, J ) 7.10 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 167.4,
162.8, 155.8, 140.6, 138.2, 136.7, 136.6, 136.5, 135.2, 132.7, 130.6,
130.5, 129.0, 124.0, 122.5, 121.4, 116.7, 114.8, 61.8, 61.0, 21.3,
14.0, 13.9; MALDI-TOF MS Calcd for C49H45N3O9S exact mass
835.29, found 834.83. For 17: Yield: 0.008 g (2%); 1H NMR (300
MHz, CDCl3, 25 °C) δ 7.73 (t, J ) 7.76 Hz, 1H), 7.30-7.21 (m,
8H), 7.19 (d, J ) 7.76 Hz, 2H), 6.81-6.77 (m, 4H), 6.79 (s, 2H),
4.39-4.22 (m, 4H), 4.13 (q, J ) 6.82 Hz, 4H), 2.42 (s, 6H), 1.29
C100H92N4O16S2 exact mass 1668.59, found 1670.61.
2,5-Bis[bis(pyrrol-2-yl)methyl]thiophene (22). Indium(III) chlo-
ride (0.13 g, 0.56 mmol) was added to a solution of 2,5-bis(2,2-
diethoxycarbonylvinyl)thiophene 21 (0.18 g, 0.43 mmol) and
pyrrole (1.2 mL, 17.07 mmol). The mixture was stirred for 2 h at
room temperature. At this point, the mixture was combined with
brine (10 mL) and extracted with CH2Cl2. The organic layer was
collected and dried (Na2SO4) before the solvent was removed in
vacuo. The resulting solid was purified by column chromatography
over silica gel (CHCl3/EtOAc/hexanes ) 8:1:1) to obtain product
1
22. Yield: 0.13 g (82%); H NMR (300 MHz, CDCl3) δ 7.99 (br
s, 4H), 6.72 (s, 2H), 6.70-6.68 (m, 4H), 6.16-6.13 (m, 4H), 6.03
(m, 4H), 5.65 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 143.7, 130.8,
124.0, 116.5, 116.4, 107.3, 107.2, 106.0, 105.9, 38.2; EI MS Calcd
for C22H20N4S exact mass 372.14, found 372.14.
2-(2,2-Diethoxycarbonylvinyl)-5-[bis(pyrrole-2-yl)methyl] (23).
2,5-Bis(2,2-diethoxycarbonylvinyl)thiophene 21 (0.09 g, 0.22 mmol),
pyrrole (0.6 mL, 8.53 mmol), and indium(III) chloride (0.06 g, 0.28
mmol) were treated in the same way as in the synthesis of 22 except
the reaction temperature employed was 0 °C. Yield: 0.05 g (74%);
1H NMR (300 MHz, CDCl3) δ 8.06 (br s, 2H), 7.23 (s, 1H), 7.20
(d, J ) 3.73 Hz, 1H), 6.82 (d, J ) 3.73 Hz, 1H), 6.68-6.66 (m,
2H), 6.16-6.13 (m, 2H), 6.02 (m, 2H), 5.67 (s, 1H), 4.33-4.22
(m, 4H), 1.32-1.27 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 166.7,
164.7, 153.7, 135.5, 135.4, 135.2, 131.3, 126.7,122.0, 118.2, 109.0,
107.8, 62.3, 62.0, 39.9, 14.6, 14.3; EI MS Calcd for C21H22N2O4S
exact mass 398.13, found 398.00.
2,5-Bis[(R-ethoxycarbonylmethyl-R-(pyrrole-2-yl))methyl]-
thiophene (24). 3-[5-(2-Ethoxycarbonyl-1-hydroxyethyl)-thiophen-
2-yl]-3-hydroxypropionic acid ethyl ester (0.9 g, 2.85 mmol) was
dissolved in neat pyrrole (5 mL, 72 mmol), and then BF3·OEt2 (1.24
mL, 9.8 mmol) was added. The mixture was stirred for 5 h at room
temperature. The reaction was quenched by the addition of aqueous
NaOH (0.1 N) and extracted with CH2Cl2. The organic layer was
collected and washed with water and dried (Na2SO4). The solvent
was removed in vacuo, and the resulting solid was purified by
column chromatography over silica gel (eluent: CH2Cl2/EtOAc )
19:1). Yield 0.72 g (71%). 1H NMR (300 MHz, CDCl3) δ 8.32 (br
s, 2H), 6.66-6.64 (m, 4H), 6.11-6.08 (m, 2H), 5.97 (s, 2H) 4.70
(t, J ) 7.31 Hz, 2H), 4.09 (q, J ) 7.14 Hz, 4H), 3.07-2.89 (m,
4H), 1.19 (t, J ) 7.14, 6H); 13C NMR (100 MHz, CDCl3) δ 144.8,
132.8, 124.2, 124.2, 117.3, 108.1, 105.4, 60.8, 41.7, 41.7, 36.1; EI
MS Calcd for C22H26N2O4S exact mass 414.16, found 414.00.
1
(t, J ) 7.14 Hz, 6H), 1.12 (t, J ) 7.12 Hz, 6H); H NMR (400
MHz, CDCl3, 0 °C) δ 7.80 (t, J ) 7.75 Hz, 1H), 7.33-7.28 (m,
8H), 7.25 (d, J ) 7.75 Hz, 2H), 6.85-6.82 (m, 4H), 6.84 (s, 2H),
5.18 (s, 2H), 4.40-4.35 (m, 2H), 4.29-4.24 (m, 2H), 4.16-4.08
(m, 4H), 2.44 (s, 6H), 1.39 (t, J ) 7.12 Hz, 6H), 1.15 (t, J ) 7.11
Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 167.5, 166.3, 163.6, 158.4,
155.0, 153.3, 147.0, 146.6, 139.6, 135.2, 135.0, 134.1, 130.9, 129.7,
128.6, 128.0, 123.4, 62.0, 61.5, 21.4, 13.9, 13.8; MALDI-TOF MS
Calcd for C49H45N3O9S exact mass 835.29, found 834.91. For 18:
1
Yield: 0.016 g (2%); H NMR (400 MHz, CDCl3) δ 11.10 (br s,
4H), 7.69 (t, J ) 7.70 Hz, 2H), 7.35 (d, J ) 7.70 Hz, 4H), 7.26-
7.20 (m, 16H), 7.10-6.83 (m, 4H), 6.52 (s, 4H), 6.02 (m, 4H),
4.12-4.06 (m, 16H), 2.40 (s, 12H), 1.15 (t, J ) 7.07 Hz, 12H),
1.09 (t, J ) 6.97 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 167.0,
156.7, 142.7, 141.9, 138.6, 137.7, 135.5, 133.0, 130.9, 130.6, 129.8,
129.3, 129.1, 128.8, 123.7, 122.9, 116.0, 114.2, 61.4, 60.9, 29.7,
21.3, 14.0, 13.9; MALDI-TOF MS Calcd for C98H90N6O16S2 exact
mass 1670.59, found 1672.26.
J. Org. Chem, Vol. 72, No. 16, 2007 6239

Jeong et al.
5,20-Bis(ethoxycarbonylmethyl)-10,15-di(p-tolyl)-21,23-dithi-
aporphyrin (25). Compounds 24 (0.21 g, 0.51 mmol) and 9 (0.17
g, 0.51 mmol) were dissolved in CH3CN (51 mL), and TFA (0.069
mL, 0.93 mmol) was added. The mixture was stirred for 30 min at
room temperature. At this point, DDQ (0.34 g, 0.15 mmol) was
added, and the reaction mixture was stirred an additional 1 h. The
reaction was quenched by adding saturated aqueous NaHCO3 (70
mL) and extracted with CH2Cl2. The organic layer was collected
and dried (Na2SO4) before the solvent was removed in vacuo. The
resulting solid was purified by preparative TLC (eluent: EtOAc/
hexanes ) 1:2). Yield 0.067 g (19%); 1H NMR (400 MHz, CDCl3)
δ 10.27 (s, 2H), 9.62 (s, 2H) 9.26-9.25 (d, J ) 4.6 Hz, 2H), 8.75-
8.73 (d, J ) 4.6 Hz, 2H), 8.09-8.07 (d, J ) 7.83 Hz, 4H), 7.61-
7.59 (d, J ) 7.83 Hz, 4H), 5.97 (s, 4H), 4.19-4.14 (q, J ) 7.10,
4H), 2.70 (s, 6H), 1.13-1.09 (t, J ) 7.07, 6H) 13C NMR (100
MHz, CDCl3) δ 171.5, 157.1, 156.4, 148.1, 147.6, 138.1, 137.9,
135.6, 135.4, 134.34, 134.1, 133.2, 132.0, 128.2, 125.5, 124.2, 61.5,
40.8, 34.2, 30.3, 29.7, 21.5, 14.1; MALDI-TOF MS Calcd for
C42H38N2O4S2 exact mass 698.21, found 697.26.
Acknowledgment. This work was supported by a grant from
the Korean Research Foundation (KRF-2005-202-C00204). The
Vascular System Research Center (VSRC) at KNU is acknowl-
edged for support. The work in Austin was supported by the
National Science Foundation (Grant CHE 0515670 to J.L.S.).
Supporting Information Available: Synthetic details of all
compounds, spectroscopic data, and single-crystal X-ray data. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
JO070872K
6240 J. Org. Chem., Vol. 72, No. 16, 2007