Rational or statistical routes from 1-acyldipyrromethanes to meso-substituted porphyrins. Distinct patterns, multiple pyridyl substituents, and amphipathic architectures

Article abstract of DOI:10.1021/jo800588n

(Figure Presented) New methodology is described for the synthesis of porphyrins bearing four (A₄, cis-A₂B₂, cis-ABC₂, trans-A₂B₂) or fewer (A, cis-AB, cis-A₂, trans-A)₂ meso substituents. The method entails condensation of two 1-acyldipyrromethanes in the presence of a metal salt (MgBr₂, 3 mol equiv) and a noncoordinating base (DBU, 10 mol equiv) in a noncoordinating solvent (toluene) with heating (conventional or microwave irradiation) and exposure to air. The rational synthesis of trans-A ₂B₂- or trans-A₂-porphyrins was achieved via condensation of two identical 1-acyldipyrromethanes. The statistical synthesis of various meso-substituted porphyrins was achieved via condensation of two nonidentical 1-acyldipyrromethanes. Both routes possess attractive features including (1) no scrambling, (2) good yield (up to 60%) at high concentration (100 mM) for the macrocycle-forming step, (3) reasonable scope (aryl, heteroaryl, alkyl, or no substituent), (4) short reaction time (～2 h) via microwave irradiation, (5) magnesium porphyrins as the products, which easily undergo demetalation, and (6) facile chromatographic purification. A key advantage of the statistical route is to obtain a cis-substituted porphyrin without the corresponding trans isomer. For example, reaction of an A/B-substituted 1-acyldipyrromethane and the fully unsubstituted 1-formyldipyrromethane gave the magnesium chelates of three porphyrins: the trans-A₂B₂-porphyrin, the "hybrid" cis-AB-porphyrin, and porphine (no trans-AB-porphyrin can form), which were readily demetalated and separated as the free base species. Altogether 26 1-acyldipyrromethanes and 26 target porphyrins have been prepared, including many with two different pyridyl substituents. One set of amphipathic porphyrins includes cis-A₂B₂- or cis-A₂BC-porphyrins wherein A = pentyl and B/C = pyridyl (o-, m-, p-). Taken together, the rational and statistical routes enable facile conversion of readily available 1-acyldipyrromethanes to diverse porphyrins bearing 1-4 meso substituents for which access is limited via other methods.

Full text of DOI:10.1021/jo800588n

Rational or Statistical Routes from 1-Acyldipyrromethanes to
meso-Substituted Porphyrins. Distinct Patterns, Multiple Pyridyl
Substituents, and Amphipathic Architectures
Dilek Kiper Dogutan, Marcin Ptaszek, and Jonathan S. Lindsey*
Department of Chemistry, North Carolina State UniVersity, Raleigh, North Carolina 27695-8204
jlindsey@ncsu.edu
ReceiVed March 14, 2008
New methodology is described for the synthesis of porphyrins bearing four (A4, cis-A2B2, cis-ABC2,
trans-A2B2) or fewer (A, cis-AB, cis-A2, trans-A2) meso substituents. The method entails condensation
of two 1-acyldipyrromethanes in the presence of a metal salt (MgBr2, 3 mol equiv) and a noncoordinating
base (DBU, 10 mol equiv) in a noncoordinating solvent (toluene) with heating (conventional or microwave
irradiation) and exposure to air. The rational synthesis of trans-A2B2- or trans-A2-porphyrins was achieved
via condensation of two identical 1-acyldipyrromethanes. The statistical synthesis of various meso-
substituted porphyrins was achieved via condensation of two nonidentical 1-acyldipyrromethanes. Both
routes possess attractive features including (1) no scrambling, (2) good yield (up to 60%) at high
concentration (100 mM) for the macrocycle-forming step, (3) reasonable scope (aryl, heteroaryl, alkyl,
or no substituent), (4) short reaction time (∼2 h) via microwave irradiation, (5) magnesium porphyrins
as the products, which easily undergo demetalation, and (6) facile chromatographic purification. A key
advantage of the statistical route is to obtain a cis-substituted porphyrin without the corresponding trans
isomer. For example, reaction of an A/B-substituted 1-acyldipyrromethane and the fully unsubstituted
1-formyldipyrromethane gave the magnesium chelates of three porphyrins: the trans-A2B2-porphyrin,
the “hybrid” cis-AB-porphyrin, and porphine (no trans-AB-porphyrin can form), which were readily
demetalated and separated as the free base species. Altogether 26 1-acyldipyrromethanes and 26 target
porphyrins have been prepared, including many with two different pyridyl substituents. One set of
amphipathic porphyrins includes cis-A2B2- or cis-A2BC-porphyrins wherein A ) pentyl and B/C ) pyridyl
(o-, m-, p-). Taken together, the rational and statistical routes enable facile conversion of readily available
1-acyldipyrromethanes to diverse porphyrins bearing 1-4 meso substituents for which access is limited
via other methods.
Introduction
rational synthetic routes to meso-substituted porphyrins have
been developed that rely on dipyrromethane building blocks
(Scheme 1). The routes provide access to ABCD-porphyrins
(route I),1,2 trans-A2B2-porphyrins (route II),3–5 trans-AB-
porphyrins (route III),6,7 and even porphine (route IV),8 which
Porphyrins bearing distinct patterns of meso substituents are
of interest for a broad range of applications. A number of
(1) Rao, P. D.; Dhanalekshmi, S.; Littler, B. J.; Lindsey, J. S. J. Org. Chem.
2000, 65, 7323–7344.
(2) Zaidi, S. H. H.; Fico, R. M., Jr.; Lindsey, J. S. Org. Process Res. DeV.
2006, 10, 118–134.
(5) Sharada, D. S.; Muresan, A. Z.; Muthukumaran, K.; Lindsey, J. S. J.
Org. Chem. 2005, 70, 3500–3510.
(3) Littler, B. J.; Ciringh, Y.; Lindsey, J. S. J. Org. Chem. 1999, 64, 2864–
2872.
(6) Fan, D.; Taniguchi, M.; Yao, Z.; Dhanalekshmi, S.; Lindsey, J. S.
Tetrahedron 2005, 61, 10291–10302.
(4) Rao, P. D.; Littler, B. J.; Geier, G. R., III; Lindsey, J. S. J. Org. Chem.
2000, 65, 1084–1092.
(7) Taniguchi, M.; Balakumar, A.; Fan, D.; McDowell, B. E.; Lindsey, J. S.
J. Porphyrins Phthalocyanines 2005, 9, 554–574.
10.1021/jo800588n CCC: $40.75
Published on Web 07/19/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6187–6201 6187

Dogutan et al.
SCHEME 1
lacks meso substituents altogether. Porphyrins bearing fewer than
four meso substituents also can be prepared by route II (trans-
A2-porphyrins) and route III (A-porphyrins). Such sparsely
substituted porphyrins can be further derivatized at the open
meso positions by halogenation followed by palladium-mediated
coupling reactions9 or by nucleophilic addition followed by
oxidation.10
Inspection of routes I-IV might suggest unlimited access to
porphyrins bearing any type and pattern of meso substituents.
Setting aside the generic limitation of modest yield that afflicts
almost all routes in porphyrin chemistry, at least two significant
and specific limitations remain in routes I-III: (1) Certain types
of substituent patterns, particularly for sparsely substituted
porphyrins (e.g., cis-A2, cis-AB, and A), remain difficult to
access.11 Route I, which provides versatile access to porphyrins
bearing four distinct substituents (i.e., ABCD-porphyrins), in
principle should provide access to porphyrins with fewer
numbers of substituents. However, the ABCD synthesis fails
in such cases owing to the poor reactivity of primary carbinols
in the dipyrromethane-dicarbinol (B, C substituents ) H) upon
acid-catalyzed condensation with the dipyrromethane.12 (2)
Certain types of substituents are incorporated with difficulty in
most of the routes shown in Scheme 1, including heterocyclic
groups and alkyl groups. In both cases, the conditions for acid-
catalyzed condensation (routes I, IIa, IIb, III) are either
incompatible with the substituents (heterocyclic groups) or
provide poor reactivity (alkyl groups), despite extensive studies
of acid catalysis conditions.2,12–15 The chief problem with many
nitrogen heterocycles (e.g., pyridyl) lies in the complexation of
the heterocycle with the acid catalyst, resulting in neutralization
of the acid and often precipitation of the complex. Some
improvement has been achieved by use of modified acid
catalysts but the conditions lack generality.16–19 The chief
problem with alkyl groups stems from scrambling (i.e., frag-
mentation and undesired recombination) to give a mixture of
porphyrins.1,12,20
Heterocyclic and alkyl groups are of interest for biomedical
applications and for studies in supramolecular chemistry. In this
regard, porphyrins bearing pyridyl groups21 have been used for
DNA intercalation,22–26 DNA cleavage,26,27 DNA labeling,28
(8) Dogutan, D. K.; Ptaszek, M.; Lindsey, J. S. J. Org. Chem. 2007, 72,
5008–5011.
(9) Sharman, W. M.; van Lier, J. E. J. Porphyrins Phthalocyanines 2000, 4,
441–453.
(10) Senge, M. O. Acc. Chem. Res. 2005, 38, 733–743.
(11) Wiehe, A.; Shaker, Y. M.; Brandt, J. C.; Mebs, S.; Senge, M. O.
Tetrahedron 2005, 61, 5535–5564.
(12) Geier, G. R., III; Callinan, J. B.; Rao, P. D.; Lindsey, J. S. J. Porphyrins
Phthalocyanines 2001, 5, 810–823.
(13) Geier, G. R., III; Littler, B. J.; Lindsey, J. S. J. Chem. Soc., Perkin
Trans. 2 2001, 701–711.
(14) Geier, G. R., III; Littler, B. J.; Lindsey, J. S. J. Chem. Soc., Perkin
Trans. 2 2001, 712–718.
(15) Speckbacher, M.; Yu, L.; Lindsey, J. S. Inorg. Chem. 2003, 42, 4322–
4337.
telomerase29 or acetylcholinesterase30 inhibition, prion binding,31
superoxide dismutase mimicry,32 photodynamic inactivation,33,34
(16) Gryko, D.; Lindsey, J. S. J. Org. Chem. 2000, 65, 2249–2252.
(17) Gryko, D. T.; Tasior, M. Tetrahedron Lett. 2003, 44, 3317–3321.
(18) Goncalves, D. P. N.; Ladame, S.; Balasubramanian, S.; Sanders, J. K. M.
Org. Biomol. Chem. 2006, 4, 3337–3342.
(19) Goncalves, D. P. N.; Sanders, J. K. M. Synlett 2007, 591–594.
(20) Geier, G. R., III; Lindsey, J. S. Tetrahedron 2004, 60, 11435–11444.
(21) Sliwa, W.; Zujewska, T.; Mielniczak, M. Chem. Heterocycl Compd.
1993, 617–628.
(25) Wang, K.; Zhang, Z.; Wu, L.; Li, Z. Y. Chem. BiodiVersity 2007, 4,
514–522.
(26) (a) Bigey, P.; Frau, S.; Loup, C.; Claparols, C.; Bernadou, J.; Meunier,
B. Bull. Soc. Chim. Fr. 1996, 133, 679–689. (b) Yellappa, S.; Seetharamappa,
J.; Rodgers, L. M.; Chitta, R.; Singhal, R. P.; D’Souza, F. Bioconjugate Chem.
2006, 17, 1418–1425.
(22) Bejune, S. A.; Shelton, A. H.; McMillin, D. R. Inorg. Chem. 2003, 42,
8465–8475.
(23) Wu, S.; Li, Z.; Ren, L. G.; Chen, B.; Liang, F.; Zhou, X.; Jia, T.; Cao,
X. P. Bioorg. Med. Chem. 2006, 14, 2956–2965.
(24) Shelton, A. H.; Rodger, A.; McMillin, D. R. Biochemistry 2007, 46,
9143–9154.
(27) Ishikawa, Y.; Yamakawa, N.; Uno, T. Bioorg. Med. Chem. 2007, 15,
5230–5238.
(28) Balaz, M.; Holmes, A. E.; Benedetti, M.; Proni, G.; Berova, N. Bioorg.
Med. Chem. 2005, 13, 2413–2421.
6188 J. Org. Chem. Vol. 73, No. 16, 2008

Routes from 1-Acyldipyrromethanes to meso-Substituted Porphyrins
radiosensitization,35 binding to nanoparticles,36 and assembly
into micelles,37 bilayer lipid membranes,38 molecular squares,39
arrays,40 oligomers,41,42 and light-harvesting architectures.43
Several examples have been reported of porphyrins that bear
both pyridyl and alkyl groups.23,24,44–52 Most of the porphyrins
bearing fewer than four identical pyridyl groups have been
formed by statistical reactions, which give multiple products.
The limitations posed by sparsely substituted porphyrin
architectures and heterocyclic or alkyl groups often are inter-
twined: the target porphyrin often contains one or two hetero-
cyclic or alkyl groups as required to achieve the desired polarity
and functionality, while sparse substitution is desired to maintain
a compact size and low molecular weight. To broaden access
to sparsely substituted porphyrins and porphyrins bearing
heterocyclic or alkyl groups requires consideration of new routes
to porphyrins. Several years ago we found serendipitously that
two 1-acyldipyrromethane molecules would condense under
basic metal-mediated conditions to give the corresponding trans-
A2B2-porphyrin (route IIc, Scheme 1).5 The conditions employed
a palladium reagent and KOH in refluxing ethanol and afforded
the palladium porphyrin. The 1-acyldipyrromethane condensa-
tion provided a more concise route to the trans-A2B2-porphyrin
than that of route IIb, which employs the condensation of
dipyrromethane-1-carbinol molecules. We were attracted to basic
conditions because we felt such conditions would circumvent
the twin problems of acidolysis leading to scrambling that occurs
with alkyl and other types of groups and acid-neutralization/
complexation that occurs with heterocyclic substituents. How-
ever, the formation of the palladium porphyrin represented a
limitation in scope given that removal of palladium requires
treatment of the porphyrin with strong acid.
To exploit the approach illustrated in route IIc and overcome
the fundamental limitations, we embarked on a program to
identify conditions that (i) are nonacidic, (ii) use a readily
removable and inexpensive metal, and (iii) provide broad scope.
We ultimately found that a noncoordinating solvent and base
(e.g., toluene and DBU) with a magnesium halide (MgBr2)
support the condensation to give the corresponding magne-
sium(II) porphyrins. We have already reported the use of these
conditions in the synthesis of magnesium porphine (route IV)8
and in a quite different route wherein a 1-acylbilane undergoes
intramolecular cyclization to give the magnesium porphyrin.53
The use of MgBr2 in toluene containing DBU for porphyrin
formation has some commonality with conditions used for the
insertion of magnesium into free base porphyrins.54
In this paper we report the development of the basic,
magnesium-mediated conditions for condensation of 1-acyl-
dipyrromethanes and the application of these conditions to give
diverse meso-substituted porphyrins. The paper is organized as
follows. Part 1 describes the synthesis of 26 1-acyldipyr-
romethanes with emphasis on a broad survey of functional
groups as well as a focus on alkyl and pyridyl substituents. Part
2 summarizes the key conditions for the 1-acyldipyrromethane
condensation; extensive studies are contained in Supporting
Information. Part 3 reports the application of the conditions to
the synthesis of trans-A2B2-porphyrins or trans-A2-porphyrins
(numbered 1). Part 4 describes the use of statistical reactions
wherein two nonidentical 1-acyldipyrromethanes undergo con-
densation, which has been used to gain access to sparsely
substituted porphyrins of the type cis-A2, cis-AB, and A
(numbered 2) and cis-ABC2-porphyrins containing two pentyl
groups and two nonidentical pyridyl groups (numbered 3).
Altogether 26 target porphyrins have been prepared via these
routes. Taken together, the approaches described herein support
the synthesis of diverse porphyrins bearing substituents (alkyl,
aryl, heterocyclic) in a variety of patterns.
(29) (a) Han, H. Y.; Hurley, L. H. Trends Pharmacol. Sci. 2000, 21, 136–
142. (b) Shi, D. F.; Wheelhouse, R. T.; Sun, D. Y.; Hurley, L. H. J. Med. Chem.
2001, 44, 4509–4523.
(30) Namgoong, S. K.; Lee, J. S.; Shin, J. H.; Moon, S. C.; Jung, B. H.;
Kim, H. S.; Yu, B. S. Bull. Korean Chem. Soc. 2000, 21, 264–266.
(31) Caughey, W. S.; Raymond, L. D.; Horiuchi, M.; Caughey, B. Proc.
Natl. Acad. Sci. U.S.A. 1998, 95, 12117–12122.
(32) Batinic-Haberle, I.; Spasojevic, I.; Stevens, R. D.; Bondurant, B.; Okado-
Matsumoto, A.; Fridovich, I.; Vujaskovic, Z.; Dewhirst, M. W. Dalton Trans.
2006, 617–624.
(33) Lambrechts, S. A. G.; Aalders, M. C. G.; Van Marle, J. Antimicrob.
Agents Chemother. 2005, 49, 2026–2034.
(34) Malatesti, N.; Smith, K.; Savoie, H.; Greenman, J.; Boyle, R. W. Int. J.
Oncol. 2006, 28, 1561–1569.
(35) (a) Meng, G. Z. G.; James, B. R.; Skov, K. A. Can. J. Chem. 1994, 72,
1894–1909. (b) Meng, G. G.; James, B. R.; Skov, K. A.; Korbelik, M. Can.
J. Chem. 1994, 72, 2447–2457.
(36) Mayer-Gall, T.; Birkner, A.; Dyker, G. J. Organomet. Chem. 2008, 693,
1–3.
(37) (a) Yamamura, T. Chem. Lett. 1977, 773–776. (b) Guilard, R.; Senglet,
N.; Liu, Y. H.; Sazou, D.; Findsen, E.; Faure, D.; Des Courieres, T.; Kadish,
K. M. Inorg. Chem. 1991, 30, 1898–1905.
Results and Discussion
1. Synthesis of 1-Acyldipyrromethanes. 1-Acyldipyr-
romethanes are typically prepared by formation of a dipyr-
romethane followed by acylation. In this study, we examined a
set of 1-acyldipyrromethanes possessing diverse groups (electron-
rich, electron-deficient, heteroaryl, alkyl, bulky, H) at the meso
(5-) or 1-positions. Multigram quantities of dipyrromethanes are
available by condensation of an aldehyde with excess pyrrole
in the presence of acid.55 The 14 dipyrromethanes examined
herein are shown in Chart 1. Dipyrromethanes 4a,53 4b,2 4c,55
4d,56 4e,48 4f,55 4g,55 4h,57 4i,58 4j,16 4k,16 4l,16 and 4n59 are
known; however, a more recent procedure (using InCl3)55 was
(38) Matile, S.; Berova, N.; Nakanishi, K. Chem. Biol. 1996, 3, 379–392.
(39) Lee, S. J.; Hupp, J. T. Coord. Chem. ReV. 2006, 250, 1710–1723.
(40) Fleischer, E. B.; Shachter, A. M. J. Heterocycl. Chem. 1991, 28, 1693–
1699.
(41) Fleischer, E. B.; Shachter, A. M. Inorg. Chem. 1991, 30, 3763–3769.
(42) Gerasimchuk, N. N.; Mokhir, A. A.; Rodgers, K. R. Inorg. Chem. 1998,
37, 5641–5650.
(43) Choi, M. S.; Yamazaki, T.; Yamazaki, I.; Aida, T. Angew. Chem., Int.
Ed. 2004, 43, 150–158.
(44) Bogatskii, A. V.; Zhilina, Z. I.; Vodzinskii, S. V.; Zakharova, R. M.
Russ. J. Org. Chem. 1985, 21, 649–652.
(45) Malinka, E. A.; Khutornoi, A. M.; Vodzinskii, S. V.; Zhilina, Z. I.;
Kamalov, G. L. React. Kinet. Catal. Lett. 1988, 36, 407–410.
(46) Malinka, E. A.; Kamalov, G. L.; Vodzinskii, S. V.; Melnik, V. I.; Zhilina,
Z. I. J. Photochem. Photobiol. A: Chem. 1995, 90, 153–158.
(47) Stibrany, R. T.; Vasudevan, J.; Knapp, S.; Potenza, J. A.; Emge, T.;
Schugar, H. J. J. Am. Chem. Soc. 1996, 118, 3980–3981.
(48) Rucareanu, S.; Mongin, O.; Schuwey, A.; Hoyler, N.; Gossauer, A.;
Amrein, W.; Hediger, H.-U. J. Org. Chem. 2001, 66, 4973–4988.
(49) Tomohiro, Y.; Satake, A.; Kobuke, Y. J. Org. Chem. 2001, 66, 8442–
8446.
(53) Dogutan, D. K.; Zaidi, S. H. H.; Thamyongkit, P.; Lindsey, J. S. J.
Org. Chem. 2007, 72, 7701–7714.
(54) Woodford, J. N.; Lindsey, J. S. Inorg. Chem. 1995, 34, 1063–1069.
(55) Laha, J. K.; Dhanalekshmi, S.; Taniguchi, M.; Ambroise, A.; Lindsey,
J. S. Org. Process Res. DeV. 2003, 7, 799–812.
(50) Rusakova, N. V.; Korovin, Y. V.; Zhilina, Z. I.; Vodzinskii, S. V.;
Ishkov, Y. V. J. Appl. Spectrosc. 2004, 71, 504–511.
(51) Fukuda, S.; Satake, A.; Kobuke, Y. Thin Solid Films 2006, 499, 263–
268.
(56) Wickramasinghe, A.; Jaquinod, L.; Nurco, D. J.; Smith, K. M.
Tetrahedron 2001, 57, 4261–4269.
(57) Balakumar, A.; Muthukumaran, K.; Lindsey, J. S. J. Org. Chem. 2004,
69, 5112–5115.
(52) Kitagishi, H.; Satake, A.; Kobuke, Y. Inorg. Chem. 2004, 43, 3394–
3405.
(58) Trova, M. P.; Gauuan, P. J. F.; Pechulis, A. D.; Bubb, S. M.; Bocckino,
S. B.; Crapo, J. D.; Day, B. J. Bioorg. Med. Chem. 2003, 11, 2695–2707.
J. Org. Chem. Vol. 73, No. 16, 2008 6189

Dogutan et al.
CHART 1
p-tert-butylphenyl at the 5-position and p-ethylphenyl at the
1-acyl site. The first set (6b-j) contained a p-tolyl group at the
5-position and diverse groups at the 1-acyl moiety. The second
set (6k-p) contained pyridyl groups at both positions. The third
set (6r-u) contained alkyl groups at both positions. The fourth
set (6j, 6v-z) contained the 1-formyl moiety and diverse
5-substituents. A final type of 1-acyldipyrromethane that we
sought contained both alkyl and heterocyclic groups (6q), but
this compound was not obtained in pure form. Of these 26
1-acyldipyrromethanes (Table 1), a handful are known com-
pounds (6a,53 6g,12 6j′,65 6r65).
The general procedures for preparing 1-acyldipyrromethanes
worked well for most cases, though 6d, 6f, and 6k required
additional purification, and the 5-(pyridyl)-containing 1-acyl-
dipyrromethanes gave slightly lower yields. Attempted acylation
of 5-(2-pyridyl)dipyrromethane 4j using the p-pyridyl-containing
Mukaiyama reagent 5f failed (starting material was recovered),
whereas acylation of 4j with o-pyridyl-containing Mukaiyama
reagent 5e provided the 1-acyldipyrromethane 6k in 33% yield.
Synthesis of a 1-mesitoyldipyrromethane (6i) was done by
utilizing mesitoyl chloride (entry 9). In several cases (6b and
6c) a boron complexation strategy65 was employed to facilitate
purification of the 1-acyldipyrromethane (see Supporting In-
formation). Formylation of 5-(2-pyridyl)dipyrromethane 4j via
the Grignard conditions afforded recovered starting material;
Vilsmeier conditions (POCl3/DMF) afforded only a trace amount
of product. Vilsmeier formylation of dipyrromethane 4i afforded
6y in 58% yield. We note that a number of the 1-acyldipyr-
romethanes are elaborate compounds containing three or four
distinct nitrogenous heterocycles.
2. Conditions for the 1-Acyldipyrromethane Condensa-
tion. The development of the conditions for use in the
condensation of a 1-acyldipyrromethane entailed an extensive
exploration of metal reagents, solvents, bases, concentrations
and molar ratios, and reaction duration. The standard procedure
that emerged from this study entails reaction of a 1-acyldipyr-
romethane (100 mM) in the presence of MgBr2 (3.0 mol equiv)
and DBU (10.0 mol equiv) in toluene (115 °C) with stirring
exposed to air for 12-14 h to give the target trans-A2B2-
porphyrin. Such conditions were tested with substrates that are
especially prone to acidolytic scrambling (e.g., 6a, which bears
p-tert-butylphenyl and p-ethylphenyl groups), and no scrambling
was detected. The results from this survey are listed in
Supporting Information. Three pertinent points deserve emphasis:
(1) The yield of porphyrin Mg-1a upon reaction of 6a was
47%, 69%, and 65% at 50, 100, and 200 mM, respectively, but
only 7% in the absence of toluene. The good yield at 200 mM
augurs well for scale-up applications.
used to prepare dipyrromethanes 4d and 4e. The new compound
4m was prepared in 89% yield by condensation of 1-methyl-
sulfonylpyrrole-2-carboxaldehyde60 with pyrrole in the presence
of InCl3. All of the dipyrromethanes shown in Chart 1 with the
exception of 4c and 4n were acylated; the latter were employed
in exploration of alternative routes to porphyrins (see Supporting
Information).
Acylation can be carried out by treatment at -78 °C of the
dipyrromethane-Grignard reagent with an S-2-pyridyl thioate
(Mukaiyama reagent) or acid chloride.61 The Mukaiyama
reagents (5a-k) required for the target 1-acyldipyrromethanes
were prepared by reaction of the corresponding acid chloride
with 2-mercaptopyridine. Mukaiyama reagents 5a,53 5b,61 5h,61
and 5i61 are known; 5c,61 5d,62 5g,12 and 5k63 also are known
and were prepared according to a new procedure. Formylation
can be achieved by treatment of the dipyrromethane-Grignard
reagent with phenyl formate64 or by use of the Vilsmeier reagent.
The Mukaiyama reagents and other acylating species [acid
chloride 5l, phenyl formate (5m), Vilsmeier reagent (5n)] are
shown in Table 1.
(2) Among a number of metals examined in place of MgBr2,
only Pd(CH3CN)2Cl2 afforded a significant amount of the
corresponding metalloporphyrin (37% yield).
(3) The rationale for the exposure of the reaction mixture to
air stems from the fact that the conversion of two 1-acyldipyr-
romethane molecules to a molecule of porphyrin requires an
oxidant. The balanced reaction is shown in eq 1.
Five major sets of 1-acyldipyrromethanes were prepared
following the benchmark compound (6a),53 which contained
(59) Bhaumik, J.; Yao, Z.; Borbas, K. E.; Taniguchi, M.; Lindsey, J. S. J.
Org. Chem. 2006, 71, 8807–8817.
6a + 6a + MgBr2 f Mg-1a + 2HBr + 2H2O + 2e- + 2H+
(60) Abell, A. D.; Nabbs, B. K.; Battersby, A. R. J. Am. Chem. Soc. 1998,
120, 1741–1746.
(1)
(61) Zaidi, S. H. H.; Muthukumaran, K.; Tamaru, S.-I.; Lindsey, J. S. J.
Org. Chem. 2004, 69, 8356–8365.
(62) Gerlach, H.; Oertle, K.; Thalmann, A. HelV. Chim. Acta 1977, 60, 2860–
2865.
Oxygen present in air would seem a likely source for the
oxidizing equivalents, although prior studies of related reactions,
(63) Annunziata, R.; Cinquini, M.; Cozzi, F.; Cozzi, P. G.; Consolandi, E.
Tetrahedron 1991, 47, 7897–7910.
(64) Ptaszek, M.; McDowell, B. E.; Lindsey, J. S. J. Org. Chem. 2006, 71,
4328–4331.
(65) Muthukumaran, K.; Ptaszek, M.; Noll, B.; Scheidt, W. R.; Lindsey, J. S.
J. Org. Chem. 2004, 69, 5354–5364.
6190 J. Org. Chem. Vol. 73, No. 16, 2008

Routes from 1-Acyldipyrromethanes to meso-Substituted Porphyrins
TABLE 1. Synthesis of 1-Acyldipyrromethanesa
J. Org. Chem. Vol. 73, No. 16, 2008 6191

Dogutan et al.
TABLE 1. Continued
a The acylation reactions were carried out with 5-15 mmol of reactants unless noted otherwise in the experimental section. b Reference 53. c Yield is
given after two steps (boron complexation and decomplexation). d Reference 12. e Reference 65. f Could not be purified. g Multiple products on the basis
of TLC and H NMR analyses. h Reference 65. i Reference 64. j Reference 8.
1
6192 J. Org. Chem. Vol. 73, No. 16, 2008

Routes from 1-Acyldipyrromethanes to meso-Substituted Porphyrins
which were quite limited in methods and in range of substrates
examined, were not conclusive.5,8,53
porphyrin bearing two p-pyridyl and two m-pyridyl groups
(Mg-1o). The porphyrins were obtained in 21-61% yields
(Table 2, entries 12-14). These results indicate the utility
of this approach for the synthesis of porphyrins bearing four
heterocyclic substituents. Although demonstrated in part by
the preparation of A4-porphyrins, these promising results
encouraged further study of the scope of microwave-assisted
porphyrin syntheses (vide infra).
4. Statistical Synthesis of meso-Substituted Porphyrins from
1-Acyldipyrromethanes. 1. Approach. A time-honored sta-
tistical synthesis in porphyrin chemistry entails reaction of
two aldehydes (A, B) with pyrrole, affording a mixture of
six porphyrins (A4, A3B, trans-A2B2, cis-A2B2, AB3, B4). In
such mixtures, the separation of the A3B-porphyrin is often
quite straightforward for those cases where the substituents
in aldehydes A and B have different polarity.67 However,
the separation of cis-A2B2- and trans-A2B2-porphyrins is often
exceptionally difficult. By contrast, the condensation of two
nonidentical 1-acyldipyrromethanes would at most yield only
three porphyrins, which presents a more tractable separation
problem. Two sets of condensations were examined under
microwave irradiation with a particular focus on those
substituents that are difficult to introduce via other proce-
dures, particularly heterocyclic moieties, alkyl chains or no
substituents (H).
Route to cis-AB-, cis-A2-, or A-Porphyrins. Reaction of
1-formyldipyrromethane and an AB-substituted 1-acyldipyr-
romethane is expected to afford a mixture composed of
porphine, the trans-A2B2-porphyrin, and the hybrid cis-AB-
porphyrin. Note that no trans-AB-porphyrin can form, which
would complicate separation of the target cis-AB-porphyrin.
When A ) B, the hybrid porphyrin contains the cis-A2
substitution pattern. Access to each of these architectures was
explored with 1-acyldipyrromethanes that contained two het-
erocycles (6k, 6l, 6m, 6n, 6o, and 6p). Each 1-acyldipyr-
romethane was condensed with 1-formyldipyrromethane (6z).
As one example, the reaction of 1-acyldipyrromethane 6m
(bearing two p-pyridyl groups) with 1-formyldipyrromethane
followed by treatment with TFA to demetalate the magnesium
chelates afforded the three free base porphyrins: meso-tetra-
pyridylporphyrin (1m, 14%), porphine (16%), and the hybrid
cis-A2-porphyrin bearing the two pyridyl units (2c, 27%). TLC
analysis showed the three free base porphyrins to be widely
separated. Column chromatographic separation afforded the
three porphyrins, which upon washing with hexanes and
methanol yielded the pure porphyrin as a purple powder. In
this manner, the target cis-AB- and cis-A2-porphyrins were
obtained in 9-28% yield (Table 3, entries 1-5), each of which
contains two heterocyclic substituents.
When the 1-acyldipyrromethane contains only one substituent
(A) and is condensed with 1-formyldipyrromethane, the expected
porphyrins are the trans-A2-porphyrin, porphine, and the hybrid
A-porphyrin, which contains a single meso substituent. Access
to such A-porphyrins was explored with 1-formyldipyr-
romethanes that contained one heterocycle at the 5-position (6v,
6w). In this manner, two A-porphyrins were obtained (Table 3,
entries 7 and 8; 32% and 21% yields), each of which contains
a single pyridyl substituent. It is noteworthy that relatively few
porphyrins have been prepared that contain one or two pyridyl
groups and no other substituents.18,68–70
3. Rational Synthesis of trans-A2B2-Porphyrins. Conven-
tional Heating. The standard conditions were applied to a wide
variety of 1-acyldipyrromethanes to prepare the corresponding
trans-A2B2-porphyrins. Each reaction was carried out with 100
mM 1-acyldipyrromethane and a scale ranging from 0.2 to 3.8
mmol. In each successful porphyrin synthesis, TLC analysis
(silica, CH2Cl2) of the crude reaction mixture revealed the
presence of a trace amount of free base porphyrin (close to the
solvent front), the desired magnesium porphyrin, and a trace
amount of unreacted 1-acyldipyrromethane. The results are
shown in Table 2.
The reaction of 1-acyldipyrromethane 6a, which was used
in all of the studies to develop conditions, gave the highest yield
of porphyrin (Mg-1a in 69% yield; entry 1, Table 2). Most
members of each set of 1-acyldipyrromethanes shown in Table
1 were examined for conversion to the corresponding trans-
A2B2-porphyrin. The set of 5-p-tolyl-1-acyldipyrromethanes
(6b-j) enabled identification of the effects of a particular
substituent. In general, 1-acyldipyrromethanes that possess
electron-releasing aryl substituents resulted in porphyrins (Mg-
1a, Mg-1b, Mg-1c) in relatively high yields. 1-Acyldipyr-
romethanes bearing a pyridyl substituent (o-, m-, p-) afforded
dipyridyl porphyrins Mg-1e, Mg-1f, and Mg-1g in 6%, 43%,
and 25% yield, respectively, upon use of larger excesses of
MgBr2 and DBU. Mg-1f and Mg-1g exhibited poor solubility
yet were purified by simply washing the crude reaction mixture
with methanol. 1-Formyldipyrromethane 6j gave the corre-
sponding trans-A2-porphyrin Mg-1j in 39% yield (90% purity
owing to the presence of the chlorin analogue).
A sizable number of attempted reactions did not give the
corresponding porphyrin. One surprise was the failure of a
1-acyldipyrromethane lacking a meso substituent (6j′) given the
excellent results with the transposed analogue 6j. The presence
of a bulky group (pentafluorophenyl, mesityl) at the 1-acyl
position resulted in little (Mg-1h) or no porphyrin (Mg-1i). The
1-acyldipyrromethanes bearing two pyridyl groups or two alkyl
groups also afforded little or no porphyrin. Further failures
include 1-formyldipyrromethanes bearing a pyridyl, acetal, or
ester group at the 5-position. These studies indicated only
modest scope for macrocycle formation under conventional
heating and prompted a parallel set of studies of the reactions
carried out with microwave heating.
Microwave Heating. Microwave-assisted organic reactions
have become popular for the synthesis of numerous classes
of compounds.66 We previously found that porphine can be
synthesized efficiently under microwave irradition.8 Initially,
we investigated microwave-assisted reactions under the
standard conditions (toluene, 100 mM of the 1-acyldipyr-
romethane, 3 mol equiv of MgBr2 and 10 mol equiv of DBU)
for the trials shown in Table 2 where poor yields were
obtained with conventional heating. The microwave reactions
were carried out for ∼2 h versus 12-14 h for the conven-
tional reactions. In some cases, no improvement was observed
(entries 5, 8-10, and 16-18). On the other hand, a substantial
increase in yield was observed in several cases, including
trans-A2-porphyrin 1y (A ) ethoxycarbonyl) and three
porphyrins each bearing four pyridyl groups. The latter
include two A4-porphyrins (tetra-p-pyridylporphyrin Mg-1m
and tetra-m-pyridylporphyrin Mg-1l) and a trans-A2B2-
(67) Lindsey, J. S. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M.,
Guilard, R., Eds.; Academic Press: San Diego, CA, 2000; Vol. 1, pp 45-118..
(66) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250–6284.
J. Org. Chem. Vol. 73, No. 16, 2008 6193

Dogutan et al.
TABLE 2. trans-A2B2-Magnesium Porphyrin Synthesis Directly from 1-Acyldipyrromethanesa
6194 J. Org. Chem. Vol. 73, No. 16, 2008

Routes from 1-Acyldipyrromethanes to meso-Substituted Porphyrins
TABLE 2. Continued
a The reactions were carried out with 0.1-2.3 mmol of 1-acyldipyrromethane unless noted otherwise. b NA ) not attempted. c 9 equiv of MgBr2, 35
equiv of DBU. d 3 equiv of MgBr2, 20 equiv of DBU. e 6 equiv of MgBr2, 10 equiv of DBU. f The yield was determined by absorption spectrometry.
g The free base porphyrin obtained by demetalation. h Reference 8.
Route to cis-ABC2- or cis-A2B2-Porphyrins. Amphipathic
porphyrins are of interest for organization in monolayers and
in lipid bilayers.71 We sought to exploit the present methodology
to prepare cis-A2B2-porphyrins bearing two pyridyl groups and
two pentyl groups. To our knowledge, only one example has
been reported of a cis-A2B2-porphyrin bearing pyridyl/alkyl
groups at the meso positions.44 Thus, a series of reactions was
carried out where the 1-acyldipyrromethane bearing two pentyl
substituents (6r) was condensed with a 1-acyldipyrromethane
bearing two pyridyl substituents. The resulting reactions po-
tentially afford meso-tetrapentylporphyrin, the meso-tetra-
pyridylporphyrin (A4 or trans-A2B2), and the hybrid cis-A2B2-
or cis-ABC2-porphyrin. The results are summarized in Table
4. In each case examined, the hybrid porphyrin was obtained
in yields of 7-26%, the tetrapyridylporphyrin was obtained in
yields of 5-23%, and no meso-tetrapentylporphyrin was
isolated; the two porphyrins that were isolated were widely
separated upon chromatography (see Supporting Information).
The failure to obtain the tetraalkylporphyrin was not unexpected
given that the condensation alone of the dipentyl 1-acyldipyr-
romethane 6r also fails altogether (Table 2, entry 16). In this
regard, the successful synthesis of the hybrid porphyrin is
remarkable.
In summary, this study shows that statistical condensation
of 1-acyldipyrromethanes under microwave irradiation can
provide entre´e into a class of porphyrins having limited access
with the current procedures (cis-ABC2, cis-A2B2, cis-AB, and
A). The cis-substituted porphyrins are obtained without ac-
companiment by the trans isomer, thereby facilitating purification.
Amphipathic Porphyrin. To accentuate the amphipathic
character of the dipyridyl/dipentylporphyrins, one such porphy-
rin (3c) was treated with excess methyl iodide to form the
quaternized product containing methyl pyridinium units (Scheme
2). The bis-quaternized porphyrin (3c-Me2I2) was isolated in
90% yield simply by washing with hexanes. Porphyrin 3c-Me2I2
contains two pentyl groups in a cis-configuration and two methyl
pyridinium groups in a cis-configuration, which provides an
attractive amphipathic architecture for examination in bilayer
lipid membranes. The synthetic route employed here is more
versatile than a prior route to cis-A2B2-porphyrins that were
designed for studies of bilayer lipid membranes.71
(68) Tsuda, A.; Nakamura, T.; Sakamoto, S.; Yamaguchi, K.; Osuka, A.
Angew. Chem., Int. Ed. 2002, 41, 2817–2821.
Outlook
(69) Hwang, I. W.; Kamada, T.; Ahn, T. K.; Ko, D. M.; Nakamura, T.; Tsuda,
A.; Osuka, A.; Kim, D. J. Am. Chem. Soc. 2004, 126, 16187–16198.
(70) Yao, M.; Iwamura, Y.; Inoue, H.; Yoshioka, N. Langmuir 2005, 21,
595–601.
The nonacidic, magnesium-mediated conditions described
here provide access to diverse meso-substituted porphyrins via
the condensation of two 1-acyldipyrromethane molecules. The
nonacidic nature of the conditions sidesteps acidolytic processes
(71) Hwang, K. C.; Mauzerall, D.; Wagner, R. W.; Lindsey, J. S. Photochem.
Photobiol. 1994, 59, 145–151.
J. Org. Chem. Vol. 73, No. 16, 2008 6195

Dogutan et al.
TABLE 3. Statistical cis-AB-Porphyrin Synthesis from Two Nonidentical 1-Acyldipyrromethanesa
a All reactions were carried out under microwave irradiation with 0.2 mmol of 1-acyldipyrromethane unless noted otherwise. The porphyrin was
purified by column chromatography followed by washing with hexanes. b 0.1 mmol of 1-acyldipyrromethane was used. c NI ) not isolated.
and enables the use of 1-acyldipyrromethanes that bear pyridyl
or alkyl substituents. Pyridyl substituents have been some of
the most sought after substituents yet also the most challenging
owing to their facile acid-complexation behavior. The present
method thus complements the methods shown in Scheme 1 for
gaining access to trans-A2B2- or trans-A2-porphyrins via acid-
catalyzed processes (routes I, IIa, IIb, and III). The conditions
explored here for the reaction of a 1-acyldipyrromethane are
more general than those in route IIc, which requires an expensive
palladium reagent and affords the corresponding palladium
porphyrin.
Much about mechanism remains unknown. The conversion
of two 1-acyldipyrromethanes to the porphyrin entails, in
unknown order, formation of two C-C bonds, elimination of
two molecules of water, dehydrogenation (with an unknown
oxidant), and metal complexation. The good yield at 100 or
200 mM reactions tends to suggest the formation of a magne-
sium complex with the two 1-acyldipyrromethanes early in the
process, thereby favoring intramolecular over intermolecular
reaction (i.e., cyclization over polymerization). The 1-acyl-
dipyrromethanes containing an o-pyridyl group (but not m- or
p-pyridyl) at the acyl site gave low yields of porphyrin, which
may stem from competitive coordination of magnesium by the
o-pyridyl and keto functional groups. Although early complex-
ation with magnesium would seem reasonable, magnesium
insertion into free base porphyrins is facile under these and
analogous54 reaction conditions; thus, the isolation of the
magnesium porphyrin alone is not sufficient proof of a templated
reaction process (see Supporting Information). Concerning the
course of reaction, it should be noted that each 1-acyldipyr-
romethane that bears a 5-substituent presumably exists as a pair
of enantiomers; the resulting intermediate(s) on the path to
porphyrin may be diastereomeric with different reactivities.
While studies to investigate these issues are beyond the scope
of the present work, it deserves noting that attempts to apply
these conditions to the reaction of a 1,9-diacyldipyrromethane
and a dipyrromethane gave only a trace of the corresponding
porphyrin. On the other hand, the condensation of 5-phenyl-
dipyrromethane and p-tolualdehyde gave the trans-A2B2-por-
phyrin in 20% yield, but yields upon extension to other
substrates were quite low (see Supporting Information). Thus,
at present the basic, magnesium-mediated reaction conditions
6196 J. Org. Chem. Vol. 73, No. 16, 2008

Routes from 1-Acyldipyrromethanes to meso-Substituted Porphyrins
TABLE 4. Statistical cis-ABC2-Porphyrin Synthesis from Two Nonidentical 1-Acyldipyrromethanesa
a All reactions were carried out under microwave irradiation with 0.2 mmol of each 1-acyldipyrromethane unless noted otherwise. Each porphyrin was
purified by column chromatography followed by washing with hexanes. b cis-A2B2-porphyrin. c A4-porphyrin.
appear restricted to the condensation of 1-acyldipyrromethanes,8
the cyclization of 1-acylbilanes,53 and magnesium insertion into
free base porphyrins.54
(ii-v) also employ acid catalysis conditions, which may give
poor results with pyridyl or alkyl groups.
Given the widespread acceptance of statistical routes in porphyrin
synthesis, it is surprising that few efforts other than the pioneering
work of Drain,74–76 Richert,77–79 and Boyle80,81 have been made
toward the exploitation of such routes in the development of
porphyrin libraries. The routes that have been examined rely on
(1) the reaction of a collection of aldehydes with pyrrole,74,77,78,82
(2) derivatization of a pure porphyrin,75,76,79,83,84 or (3) derivati-
zation of a mixture of porphyrins.74,78 Few combinatorial ap-
The statistical condensations described herein have afforded
entre´e into porphyrins with substituent patterns that previously
presented difficulties (including cis-A2B2 and cis-ABC2, and the
sparsely substituted analogues cis-A2, cis-AB, A), do so in each
case without concomitant formation of the trans isomer, and
are compatible with pyridyl and alkyl substituents. Statistical
condensations have long been used in porphyrin chemistry to
access a desired porphyrin architecture, typically by chromato-
graphic separation of the resulting mixture of porphyrins.67 The
most prevalent statistical routes to porphyrins include (i) two
aldehydes and pyrrole to give six porphyrins;67 (ii) two
aldehydes and a dipyrromethane (or vice versa) to give three
porphyrins;67 (iii) two dipyrromethane-1-carbinols to give three
porphyrins;72 (iv) one aldehyde, 2-hydroxymethylpyrrole, and
a dipyrromethane to give two porphyrins;73 and (v) one
aldehyde, pyrrole, and tripyrrane to give two porphyrins.73 All
of the methods that employ dipyrromethanes or tripyrranes
(74) Drain, C. M.; Gong, X. C.; Ruta, V.; Soll, C. E.; Chicoineau, P. F.
J. Comb. Chem. 1999, 1, 286–290.
(75) Chen, X.; Hui, L.; Foster, D. A.; Drain, C. M. Biochemistry 2004, 43,
10918–10929.
(76) Samaroo, D.; Vinodu, M.; Chen, X.; Drain, C. M. J. Comb. Chem. 2007,
9, 998–1011.
(77) Berlin, K.; Jain, R. K.; Tetzlaff, C.; Steinbeck, C.; Richert, C. Chem.
Biol. 1997, 4, 63–77.
(78) Berlin, K.; Jain, R. K.; Richert, C. Biotechnol. Bioeng. 1998, 61, 107–
118.
(79) Dombi, K. L.; Richert, C. Molecules 2000, 5, 1265–1280.
(80) Elgie, K. J.; Scobie, M.; Boyle, R. W. Tetrahedron Lett. 2000, 41, 2753–
2757.
(81) Shi, B. L.; Scobie, M.; Boyle, R. W. Tetrahedron Lett. 2003, 44, 5083–
5086.
(72) Wallace, D. M.; Leung, S. H.; Senge, M. O.; Smith, K. M. J. Org. Chem.
1993, 58, 7245–7257.
(82) Fagadar-Cosma, E.; Cseh, L.; Badea, V.; Fagadar-Cosma, G.; Vlascici,
D. Comb. Chem. High Throughput Screening 2007, 10, 466–472.
(83) Okuno, Y.; Ford, W. E.; Calvin, M. Synthesis 1980, 537–539.
(73) Ryppa, C.; Senge, M. O.; Hatscher, S. S.; Kleinpeter, E.; Wacker, P.;
Schilde, U.; Wiehe, A. Chem. Eur. J. 2005, 11, 3427–3442.
J. Org. Chem. Vol. 73, No. 16, 2008 6197

Dogutan et al.
SCHEME 2
(C11H15NOS). Anal. Calcd for C11H15NOS: C, 63.12; H, 7.22; N,
6.69. Found: C, 62.76; H, 7.19; N, 7.01.
Synthesis of 1-Acyldipyrromethanes (Method 2).4 A solution of
EtMgBr (38 mL, 38 mmol, 1.0 M in THF) was added slowly to a
solution of the dipyrromethane (15.0 mmol) in THF (30.0 mL)
under argon. The resulting mixture was stirred at room temperature
for 10 min, and then cooled to -78 °C. A solution of Mukaiyama
reagent (15.0 mmol) in THF (30.0 mL) was added to the reaction
mixture. The solution was stirred at -78 °C for 10 min and then
allowed to warm to room temperature. The reaction mixture was
quenched by the addition of saturated aqueous NH4Cl. The mixture
was extracted with ethyl acetate. The organic layer was washed
(water, brine), dried (Na2SO4), and filtered. The filtrate was
concentrated. The resulting product was chromatographed [silica,
CH2Cl2 (until all the unreacted dipyrromethane was eluted) f
hexanes/ethyl acetate (3:1)] to afford the corresponding 1-acyl-
dipyrromethane.
5-(4-Methylphenyl)-1-picolyldipyrromethane (6e). Following
Method 2, a solution of EtMgBr (38 mL, 38 mmol, 1.0 M in THF),
5-(4-methylphenyl)dipyrromethane (4b, 3.55 g, 15.0 mmol, in 30
mL of THF), and a solution of S-2-pyridyl picolinothioate (5e,
3.24 g, 15.0 mmol, in 30 mL of THF) afforded an oily product,
which upon chromatography [silica, CH2Cl2/ethyl acetate (7:2), 4
cm dia × 30 cm] afforded a brown powder (3.91 g, 76%): mp 54
1
°C (dec); H NMR δ 2.35 (s, 3H), 5.53 (s, 1H), 6.01-6.02 (m,
1H), 6.10-6.12 (m, 1H), 6.19-6.21 (m, 1H), 6.73-6.74 (m, 1H),
7.13- 7.18 (m, 4H), 7.39-7.42 (m, 2H), 7.82-7.86 (m, 2H),
8.02-8.12 (m, 1H), 8.17-8.18 (brs, 1H), 8.44-8.58 (brs, 1H); 13
C
NMR δ 21.3, 44.2, 107.77, 107.78, 108.7, 110.8, 118.0, 124.1,
126.3, 128.6, 129.7, 131.7 (brs), 137.2, 137.5, 138.2, 141.6, 148.2,
155.7, 171.5; FAB-MS obsd 341.1528, calcd 341.1526. Anal. Calcd
for C22H19N3O: C, 77.40; H, 5.61; N, 12.31. Found: C, 76.09; H,
5.77; N, 11.71. The elemental analysis data are consistent with the
presence of one molecule of ethyl acetate per four molecules of
product.
proaches have relied on routes that afford a more narrow set of
porphyrins.80,81 The condensation of 1-acyldipyrromethanes appears
attractive in this latter regard for two reasons: (i) the ability to focus
on selected architectures such as cis-A2B2-porphyrins, and (ii) the
tolerance of the reaction conditions toward heterocyclic substituents.
The ability to incorporate heterocyclic substituents in sparsely
substituted architectures is of interest for a number of biomedical
applications, where charged or amphipathic substituents are desired
in a compact molecular design.
Synthesis of 1-Formyldipyrromethanes (Method 3).64 A sample
of dipyrromethane (15.0 mmol) in THF (30 mL) was treated with
MesMgBr (30 mL, 30 mmol, 1.0 M in THF). After 10 min, the
mixture was cooled to -78 °C. Phenyl formate (5m, 3.27 mL, 30.0
mmol) was added in one portion. The reaction mixture was stirred
at -78 °C for 1 h. The cooling bath was removed, and stirring
was continued for 1 h. The reaction mixture was quenched by the
addition of saturated aqueous NH4Cl (∼150 mL). The organic
extract was washed (water, brine) and concentrated. The resulting
oil was dissolved in CH3CN (150 mL) and treated with 2 M aqueous
NaOH (90 mL). The resulting mixture was stirred vigorously at
room temperature for 1 h. Water (∼100 mL) was added, and the
mixture was extracted with CH2Cl2. The organic phase was washed
(saturated aqueous NH4Cl, water, brine), dried (Na2SO4), and
concentrated. The resulting dark oil was chromatographed [silica,
CH2Cl2 f CH2Cl2/ethyl acetate (10:1)] to afford the product.
1-Formyl-5-(3-pyridyl)dipyrromethane (6v). Following Method
3, reaction of 5-(3-pyridyl)dipyrromethane (4k, 1.12 g, 5.00 mmol
in 20 mL of THF), MesMgBr (10.0 mL, 10 mmol, 1.0 M in THF),
and phenyl formate (5m, 1.1 mL, 10. mmol) afforded an oily
product. Column chromatography (silica, ethyl acetate) afforded a
pure product (an orange solid, 0.304 g) and mixed fractions; the
latter were rechromatographed (silica, ethyl acetate) to afford an
additional 0.162 g of product. Total yield (0.466 g, 37%): mp
174-176 °C (dec); 1H NMR (300 MHz) (THF-d8) δ 5.49 (s, 1H),
5.65-5.67 (m, 1H), 5.86-5.88 (m, 1H), 5.95-5.98 (m, 1H),
6.63-6.66 (m, 1H), 6.80-6.82 (m, 1H), 7.18-7.22 (m, 1H),
7.44-7.49 (m, 1H), 8.49-8.42 (m, 2H two signals overlapped),
Experimental Section
Known Porphyrins. Metalloporphyrins Mg-1e,42 Mg-1m,85 and
Mg-porphine8 prepared herein are known, as are free base
porphyrins 1b,86 1e,42 1f,17 1g,12 1h,87 1j,88 1k,89 1l,90 1m,91 1r,92
1v,23 1w,18 1y,58 2c,18 and 2h.18
Synthesis of Mukaiyama Reagents (Method 1).61 A solution of
2-mercaptopyridine (5.55 g, 50.0 mmol) in THF (50.0 mL) was
treated slowly with an acid chloride (50.0 mmol). The resulting
slurry was stirred for 30 min. The precipitate was collected by
filtration and washed with hexanes (70.0 mL) in a Buchner funnel.
The filtered material was added into a biphasic solution of saturated
aqueous NaHCO3 (100 mL) and diethyl ether (100 mL). The
mixture was stirred until the foaming subsided. The organic layer
was removed, and the water layer was extracted with diethyl ether.
The combined organic extract was dried (Na2SO4) and filtered. The
filtrate was concentrated to give a solid, which was washed with
hexanes (∼20 mL) to afford the product.
S-2-Pyridyl Hexanothioate (5c). Following Method 1, a solution
of 2-mercaptopyridine (6.66 g, 60.0 mmol) in THF (60 mL) was
treated with hexanoyl chloride (8.3 mL, 60 mmol) to afford a yellow
1
liquid (12.2 g, 97%): H NMR δ 0.89-0.91 (m, 3H), 1.31-1.34
(84) (a) Chaleix, V.; Sol, V.; Guilloton, M.; Granet, R.; Krausz, P.
Tetrahedron Lett. 2004, 45, 5295–5299. (b) Biron, E.; Voyer, N. Chem. Commun.
2005, 4652–4654. (c) Schroder, T.; Schmitz, K.; Niemeier, N.; Balaban, T. S.;
Krug, H. F.; Schepers, U.; Brase, S. Bioconjugate Chem. 2007, 18, 342–354.
(85) O’Shea, D. F.; Miller, M. A.; Matsueda, H.; Lindsey, J. S. Inorg. Chem.
1996, 35, 7325–7338.
(m, 4H), 1.70-1.74 (m, 2H), 2.69 (t, J ) 7.6 Hz, 2H), 7.26-7.29
(m, 1H), 7.60- 7.62 (m, 1H), 7.71-7.76 (m, 1H), 8.61-8.62 (m,
1H); 13C NMR δ 14.0, 22.5, 25.3, 31.2, 44.4, 123.7, 130.4, 137.4,
150.5, 151.7, 196.7; FAB-MS obsd 210.0958, calcd 210.0953
6198 J. Org. Chem. Vol. 73, No. 16, 2008

Routes from 1-Acyldipyrromethanes to meso-Substituted Porphyrins
9.40 (s, 1H), 9.84-9.98 (br, 1H), 11.20-11.29 (brs, 1H); 13C NMR
(THF-d8) δ 42.8, 108.4, 111.1, 118.7, 121.2, 124.0, 131.9, 134.6,
136.4, 138.7, 142.9, 149.1, 151.1, 178.8 (signals derived from two
carbon atoms are apparently overlapped); ESI-MS obsd 252.1134,
calcd 252.1131 [(M + H)+, M ) C15H13N3O]. Anal. Calcd for
C15H13N3O: C, 71.70; H, 5.21; N, 16.72. Found: C, 71.58.; H, 5.21;
N, 16.44.
MS obsd 804.8; FAB-MS obsd 804.4073, calcd 804.4042
(C56H52MgN4); λabs 405, 426, 564, 605 nm.
Condensation of a 1-Acyldipyrromethane via Conventional
Heating at 115 °C (Method 4B). The experimental protocol for
trans-A2B2 magnesium porphyrin synthesis was carried out with
the oil bath temperature set at 115 °C while keeping the rest of the
procedure unchanged.
5,15-Bis(4-methylphenyl)-10,20-di-3-pyridylporphinatomagne-
sium(II) (Mg-1f). Following Method 4B, 6f (0.171 g, 0.500 mmol)
in toluene (5 mL) was treated with DBU (1.49 mL, 10.0 mmol, 20
mol equiv) and MgBr2 (0.276 g, 1.50 mmol, 3.0 mol equiv). The
reaction was complete in 30 min. The crude reaction mixture was
allowed to cool and then concentrated. The resulting residue was
dissolved in CH2Cl2 and filtered through a column [alumina grade
V,93 CH2Cl2/triethylamine (100:1)]. The porphyrin-containing frac-
tion was collected and concentrated. The resulting solid was treated
with methanol (5 mL), and the resulting suspension was centrifuged.
Solvent was decanted, and the remaining purple solid was collected.
This procedure (treat with methanol, centrifuge, and decant) was
repeated twice to afford a purple solid (72 mg, 43%): LD-MS 666.6,
ESI-MS obsd 667.2449, calcd 667.2455 [(M + H)+, M )
C44H32N4]; λabs (hot THF) 408, 429, 571, 614 nm. Due to extensive
Condensation of a 1-Acyldipyrromethane via Conventional
Heating at 135 °C (Method 4A). A sample of 1-acyldipyrromethane
(1.00 g) was placed in a 250 mL one-necked round-bottom flask
that was oven-dried and contained a magnetic stir bar. A Teflon
septum was attached, and toluene (∼10 to ∼25 mL) was added
via syringe. The reaction mixture was stirred at room temperature
for 1 min, whereupon DBU (10 mol equiv versus 6a) was added
dropwise via syringe under vigorous stirring. The resulting mixture
was stirred at room temperature for 5 min. The mixture darkened.
The septum was removed, and MgBr2 (3.0 mol equiv versus 6a)
was added in one portion under vigorous stirring. (Note that a dry
flask is essential, as is vigorous stirring, so that MgBr2 does not
clump as a solid on the bottom of the flask, which typically lowers
the yield of porphyrin.) The septum was replaced, and the
heterogeneous reaction mixture was stirred for 1 min at room
temperature. The flask was fitted with a reflux condenser (4 cm
dia × 30 cm) having the top end open to the atmosphere, and the
flask was placed in an oil bath preheated to 135 °C. The reaction
mixture was stirred under reflux. When porphyrin formation was
complete (on the basis of TLC analysis and absorption spectroscopy,
typically after overnight reaction), the crude reaction mixture was
allowed to cool to room temperature and then concentrated. The
resulting residue was dissolved in CH2Cl2 (2 mL) and filtered
through a column [alumina, 500 g, 4 cm dia × 30 cm, CH2Cl2 f
CH2Cl2/ethyl acetate (5:1 f 3:1), ∼1.5 L]. The grade of alumina
employed depended on the polarity of the porphyrin (see Supporting
Information). The porphyrin-containing fraction was collected and
concentrated to afford a purple solid.
1
aggregation upon attempted H NMR spectroscopy, a sample of
the magnesium porphyrin (42.5 mg, 0.0637 mmol) was demetalated
in CH2Cl2 (10 mL) by addition of TFA (1.5 mL). The resulting
crude reaction mixture was neutralized by the addition of triethyl-
amine (5.0 mL). Aqueous workup and washing with methanol
afforded the free base porphyrin 1f as a purple powder (32.5 mg,
80%): 1H NMR (300 MHz) δ -2.75 (s, 2H), 2.72 (s, 6H), 7.58 (d,
J ) 7.4 Hz, 4H), 7.73-7.77 (m, 2H), 8.12 (d, J ) 7.4 Hz, 4H),
8.52-8.56 (m, 2H), 8.82 (d, J ) 4.8 Hz, 4H), 8.97 (d, J ) 4.8 Hz,
4H), 9.06-9.08 (m, 2H), 9.50-9.51 (m, 2H); 13C NMR (75 MHz)
δ 21.7, 116.1, 121.2, 122.2, 127.7, 130.0-131.5 (brs), 131.8-132.8
(brs), 134.7, 137.8, 138.3, 139.0, 141.1, 149.3, 153.9; LD-MS 644.3,
ESI-MS obsd 645.2765 calcd 645.2761 [(M + H)+, M ) C44H32N4];
λabs 421, 517, 550, 592, 651 nm.
5,15-Bis(4-tert-butylphenyl)-10,20-bis(4-ethylphenyl)porphinato-
magnesium(II) (Mg-1a). Following Method 4A, DBU (3.64 mL,
24.4 mmol, 10.0 mol equiv versus 6a) was added dropwise to a
solution of 6a (1.00 g, 2.44 mmol, 100 mM) in toluene (24.4 mL).
MgBr2 (1.35 g, 7.32 mmol, 3.00 mol equiv) was added. The reaction
mixture was heated to reflux (oil bath temperature 135 °C) with
exposure to air for the overnight duration of the reaction. TLC
analysis (silica, CH2Cl2) showed the free base porphyrin, magne-
sium porphyrin and a trace amount of 6a (although alumina
chromatography was successful, TLC analysis on alumina did not
give a successful separation whereas that on silica resulted in better
separation). Chromatography [alumina, 500 g, 4 cm dia × 40 cm,
CH2Cl2/ethyl acetate (4:1 f 3:1)] afforded a trace (0.0040 g, 0.45%)
of free base porphyrin (1a), which eluted first and was easily
isolated apart from the title magnesium porphyrin. The dominant
magnesium porphyrin-containing fraction was isolated to give the
Condensation of a 1-Acyldipyrromethane via Microwave Ir-
radiation (Method 5, as used in Table 2). A sample of 1-acyl-
dipyrromethane (0.10 mmol) was placed in a 10 mL glass tubular
reaction vessel containing a magnetic stir bar. Toluene (1.0 mL)
and DBU (0.150 mL, 1.00 mmol) were added. The resulting mixture
was stirred to obtain a homogeneous solution and then treated with
MgBr2 (0.055 g, 0.30 mmol). The vessel was sealed with a septum
and subjected to microwave irradiation at 100 W. The protocol was
as follows: (1) heat from room temperature to 115 °C (irradiate
for 2 min), (2) hold at 115 °C (irradiate for 15 min; temperature
typically overshot to 135 °C and then stabilized after 2 min), (3)
allow to cool to room temperature (∼1 min), (4) check the reaction
mixture by TLC analysis and absorption spectroscopy, (5) repeat
steps 1-3 until porphyrin formation is complete. The reaction
mixture was transferred to a round-bottom flask (using THF, which
was HPLC grade and lacked stabilizer) and concentrated. The
resulting crude product was filtered through a column [alumina
grade V,93 CH2Cl2 f CH2Cl2/ethyl acetate (1:1) f ethyl acetate
f THF/MeOH (10:1)]. The porphyrin-containing fractions were
concentrated. The resulting porphyrin was suspended in hexanes
(5 mL). The suspension was sonicated for ∼1 min, centrifuged,
and decanted to obtain the powder. The resulting porphyrin was
suspended in methanol (5 mL) and treated likewise (sonication,
centrifugation, decantation) to afford a purple powder.
1
title compound as a purple solid (0.511 g, 52%): H NMR (THF-
d8) δ 1.54 (t, J ) 7.6 Hz, 6H), 1.62 (s, 18H), 3.02 (q, J ) 7.6 Hz,
4H), 7.56 (d, J ) 7.8 Hz, 4H), 7.73 (d, J ) 7.8 Hz, 4H), 8.10-8.15
(m, 8H), 8.77 (s, 8H); 13C NMR (THF-d8) δ 15.4, 28.9, 31.3, 34.7,
121.5, 123.1, 125.6, 131.3, 131.4, 134.9, 135.0, 141.7, 142.0, 142.8,
149.7, 149.8 (the signals of two carbons were not observed); LD-
(86) Shi, B. L.; Boyle, R. W. J. Chem. Soc. Perkin Trans. 1 2002, 1397–
1400.
5,15-Di-3-pyridyl-10,20-di-4-pyridylporphinatomagnesium(II)
(Mg-1o). Following Method 5, a sample of 6o (0.0330 g, 0.100
mmol) gave porphyrin in 45 min. Chromatography [CH2Cl2 f
CH2Cl2/ethyl acetate (1:1) f ethyl acetate f THF/MeOH (20:1)]
followed by washing the porphyrin suspension with hexanes and
methanol afforded a purple powder (14 mg, 21%): 1H NMR
(87) Suzuki, M.; Osuka, A. Org. Lett. 2003, 5, 3943–3946.
(88) Manka, J. S.; Lawrence, D. S. Tetrahedron Lett. 1989, 30, 6989–6992.
(89) Leanord, D. R.; Smith, J. R. L. J. Chem. Soc. Perkin Trans. 2 1990,
1917–1923.
(90) (a) Little, R. G. J. Heterocyclic Chem. 1981, 18, 833–834. (b) Little,
R. G.; Anton, J. A.; Loach, P. A.; Ibers, J. A. J. Heterocyclic Chem. 1975, 12,
343–349.
(91) Fleischer, E. B. Inorg. Chem. 1962, 1, 493–495.
(92) Lindsey, J. S.; Schreiman, I. C.; Hsu, H. C.; Kearney, P. C.; Marguer-
ettaz, A. M. J. Org. Chem. 1987, 52, 827–836.
(93) Li, F.; Gentemann, S.; Kalsbeck, W. A.; Seth, J.; Lindsey, J. S.; Holten,
D.; Bocian, D. F. J. Mater. Chem. 1997, 7, 1245–1262.
J. Org. Chem. Vol. 73, No. 16, 2008 6199

Dogutan et al.
(DMSO-d6) δ 7.03-7.07 (m, 2H), 7.38-7.39 (br, 4H), 7.76-7.78
(m, 2H), 7.93 (d, J ) 6.2 Hz, 4H), 7.98 (d, J ) 6.2 Hz, 4H),
8.17-8.19 (m, 6H), 8.46-8.54 (br, 2H); LD-MS obsd 640.6, ESI-
MS obsd 641.2044, calcd 641.2047 [(M + H)+, M ) C40H24MgN8];
λabs (toluene) 407, 428, 564, 604 nm.
(4 mL) was treated with DBU (0.60 mL, 4.0 mmol) and MgBr2
(0.220 g, 1.20 mmol). Chromatography [silica, THF f THF/MeOH
(10:1)] followed by washing the porphyrin with hexanes (5 mL)
afforded the title compound as a purple powder (0.016 g, 21%):
1H NMR δ -3.69 (s, 2H), 8.17-8.19 (m, 2H), 9.02-9.06 (m, 4H),
9.43-9.44 (m, 2H), 9.42-9.48 (m, 4H), 10.28 (s, 1H), 10.34 (m,
2H); 13C NMR δ 104.5, 105.2, 115.9, 129.9, 130.1, 130.7, 131.7,
132.2, 148.6, 150.2; ESI-MS obsd 388.1554, calcd 388.1556 [(M
+ H)+, M ) C25H17N5]; λabs (toluene) 402, 495, 527, 569 nm. Two
other porphyrins also were isolated, 5,15-di-4-pyridylporphyrin (1w,
0.010 g, 11%) and porphine (trace). No ESI-MS signal was observed
for 1w because of low solubility.
Statistical Condensation of Two 1-Acyldipyrromethanes via
Microwave Irradiation (Method 6). Samples of a first 1-acyldipyr-
romethane (0.20 mmol) and a second 1-acyldipyrromethane (0.20
mmol) were placed in a 10 mL glass tubular reaction vessel
containing a magnetic stir bar. Toluene (4.0 mL) and DBU (0.60
mL, 4.0 mmol) were added. The resulting mixture was stirred to
obtain a homogeneous solution and then treated with MgBr2 (0.221
g, 1.20 mmol). The vessel was sealed with a septum and subjected
to microwave irradiation at 100 W. The protocol was as follows:
(1) heat from room temperature to 115 °C (irradiate for 2 min), (2)
hold at 115 °C (irradiate for 15 min; temperature typically overshot
to 135 °C and then stabilized after 2 min), (3) allow to cool to
room temperature (∼1 min), (4) check the reaction mixture by TLC
analysis and absorption spectroscopy, and (5) repeat steps 1-3 until
porphyrin formation is complete. After porphyrin formation was
complete, the crude reaction mixture was transferred to a round-
bottom flask (using THF, which was HPLC grade and lacked
stabilizer) and concentrated. The resulting crude product was
washed (water, brine), dried (Na2SO4), and concentrated. The
resulting crude reaction mixture was dissolved in CH2Cl2 (4 mL)
and demetalated by the addition of TFA (0.032 mL). A sample of
triethylamine was added (0.020 mL). The crude reaction mixture
was washed (water, brine), dried (Na2SO4), and concentrated. The
resulting product was chromatographed [silica, CH2Cl2 f CH2Cl2/
ethyl acetate (1:3) f ethyl acetate f ethyl acetate/MeOH (10:1)].
Each porphyrin-containing fraction was concentrated. The resulting
porphyrin was suspended in hexanes (5 mL). The suspension was
sonicated for ∼1 min, centrifuged, and decanted to obtain the
powder. The resulting porphyrin was suspended in methanol (5 mL)
and treated likewise (sonication, centrifugation, decantation) to
afford a purple powder.
5,10-Dipentyl-15,20-di-4-pyridylporphyrin (3c). Following Method
6, a mixture of 6m (0.033 g, 0.10 mmol) and 6r (0.031 g, 0.10
mmol) in toluene (2 mL) was treated with DBU (0.30 mL, 2.0
mmol) and MgBr2 (0.110 g, 0.600 mmol). The reaction was
monitored with TLC analysis [silica, THF/MeOH (10:1)] and
absorption spectroscopy. Porphyrin formation was complete in ∼2
h. TLC analysis of the crude reaction mixture [silica, CH2Cl2 f
CH2Cl2/ethyl acetate (1:1) f THF/MeOH (10:1)] revealed two
green spots (Rf ) 0.32 and 0.61). The absorption spectrum of the
crude reaction mixture revealed four bands (303, 405, 425, and
564 nm). The LD-MS analysis (with POPOP) of the crude reaction
mixture indicated the presence of two porphyrins. The molecule
ion peak, m/z ) 626.9, was assigned to Mg-3c, whereas the peak
at m/z ) 640.6 was consistent with porphyrin Mg-1m. The crude
product was dissolved in CH2Cl2 and demetalated by addition of
TFA. The reaction mixture was neutralized with triethylamine.
Aqueous workup and chromatography [silica, CH2Cl2 f CH2Cl2/
ethyl acetate (1:1) f ethyl acetate/MeOH (10:1)] afforded the title
1
compound as a purple powder (0.016 g, 26%): H NMR δ -2.77
(s, 2H), 0.97 (t, J ) 7.2 Hz, 6H), 1.54-1.57 (m, 4H), 1.75-1.83
(m, 4H), 2.50-2.58 (m, 4H), 4.98-5.01 (m, 4H), 8.10 (d, J ) 5.8
Hz, 4H), 8.67-8.72 (brs, 2H), 8.79 (d, J ) 4.4 Hz, 2H), 9.00 (d,
J ) 5.8 Hz, 4H), 9.48 (d, J ) 4.4 Hz, 2H), 9.57-9.61 (brs, 2H);
LD-MS obsd 604.7, ESI-MS obsd 605.3382, calcd 605.3387 [(M
+ H)+, M ) C40H40N6]; λabs (toluene) 419, 517, 551, 595, 652
nm. 5,10,15,20-Tetra-4-pyridylporphyrin (1m) also was isolated
Note that when one of the 1-acyldipyrromethanes was 1-formyl-
dipyrromethane (6z), the order of elution typically was porphine,
the target “hybrid” porphyrin, and the porphyrin derived from
condensation of two molecules of the other 1-acyldipyrromethane.
When one of the 1-acyldipyrromethanes was 1-hexanoyl-5-pentyl-
dipyrromethane (6r), the order of elution typically was the target
“hybrid”porphyrin followed by the porphyrin derived from con-
densation of two molecules of the other 1-acyldipyrromethane; no
tetrapentylporphyrin was obtained.
1
(0.0076 g, 12%): H NMR δ -2.93 (s, 2H), 8.15-8.17 (m, 8H),
8.85-8.88 (brs, 8H), 9.06-9.08 (m, 8H); ESI-MS obsd 619.2371,
calcd 619.2353 [(M + H)+, M ) C40H26N4]; λabs (THF) 408, 429,
529, 569, 611 nm.
Quaternization Procedure to Yield 5,10-Dipentyl-15,20-bis[4-
methylpyridin-4-ium-1-yl]porphyrin Diiodide (3c-Me2I2). A solu-
tion of 3c (0.020 g, 0.033 mmol) in chloroform (3.3 mL) was treated
with excess iodomethane (0.410 mL, 6.62 mmol). The reaction
mixture was stirred at room temperature for 12 h. The reaction
mixture was concentrated, and the resulting product was washed
with hexanes (5 mL × 2) to afford the title compound as a purple
5,10-Di-3-pyridylporphyrin (2b). Following Method 6, a mixture
of 6l (0.066 g, 0.20 mmol) and 6z (0.035 g, 0.20 mmol) in toluene
(4 mL) was treated with DBU (0.60 mL, 4.0 mmol) and MgBr2
(0.220 g, 1.20 mmol). Chromatography followed by washing the
porphyrin with hexanes (5 mL) and methanol (5 mL) afforded the
1
powder (0.0264 g, 90%): H NMR (DMSO-d6) δ -2.88 (s, 2H),
1
title compound as a purple powder (0.026 g, 28%): H NMR δ
0.93 (t, J ) 7.4, 6H), 1.46-1.54 (m, 4H), 1.73-1.78 (m, 4H),
2.53-2.55 (overlapped with DMSO signal), 4.70 (s, 6H), 4.98-5.11
(m, 4H), 8.94-8.96 (m, 8H), 9.43-9.45 (m, 4H), 9.14-8.16 (m,
4H); 13C NMR (DMSO-d6) δ 14.7, 23.0, 32.6, 48.5, 113.0, 124.2,
132.9, 144.7, 157.9 (not all carbon signals were observed owing
to limited solubility); ESI-MS obsd 317.1893, calcd 317.1886 [(M
- 2I)2+, M ) C42H46I2N6]; λabs (water) 419, 525, 563, 646 nm.
Yield Calculations for Statistical Reactions (Tables 3 and 4).
The yield of porphyrin formation via condensation of equal
quantities of two nonidentical 1-acyldipyrromethanes (e.g., 0.10
mmol each) was calculated as follows: (1) the theoretical yield of
porphyrins in total was equal to one-half the sum total number of
millimoles of dipyrromethane species, (2) the actual yield in mmol
of each porphyrin was determined experimentally, and (3) the ratio
of the actual yield to the theoretical yield in total gives the reported
% yield for each component. In this manner, the sum of all % yields
can equal but not exceed 100%. Also, if each of the two
1-acyldipyrromethanes exclusively underwent homocondensation
to give the two porphyrins derived therefrom with no heterocon-
-3.47 (s, 2H), 7.73-7.78 (m, 2H), 8.50-8.52 (m, 2H), 8.90 (s,
2H), 8.96 (d, J ) 6.6 Hz, 2H), 9.06-9.08 (m, 2H), 9.38 (d, J )
6.6 Hz, 2H), 9.41-9.43 (brs, 2H), 9.44-9.47 (brs, 2H), 10.24 (s,
2H); 13C NMR δ 105.2, 115.9, 122.2, 131.1-132.9 (brs), 138.1,
141.2, 149.4, 153.9; LD-MS obsd 464.4; ESI-MS obsd 465.1819,
calcd 465.1822 [(M + H)+, M ) C30H20N6]; λabs (toluene) 409,
502, 534, 577 nm. Two other porphyrins also were isolated,
5,10,15,20-tetra-3-pyridylporphyrin (1l, 4 mg, 3%) and porphine
1
(0.0080 g, 26%). Data for 1l: H NMR (300 MHz) δ -2.84 (s,
2H), 7.68-7.72 (m, 4H), 8.05-8.11 (m, 4H), 8.19-8.21 (m, 4H),
8.84-8.8 (brs, 8H), 9.12-9.14 (brs, 4H); 13C NMR δ 117.0, 122.3,
131.2-131.8 (brs), 137.8, 141.2, 149.6, 153.9, 160.8; ESI-MS obsd
619.2355, calcd 619.2353 [(M + H)+, M ) C40H26N8]; λabs (toluene)
420, 515, 550, 592, 648 nm. The data (1H NMR, 13C NMR, FAB-
MS) for porphine were consistent with those obtained from an
authentic sample.8
5-(4-Pyridyl)porphyrin (2h). Following Method 6, a mixture of
6w (0.050 g, 0.20 mmol) and 6z (0.035 g, 0.20 mmol) in toluene
6200 J. Org. Chem. Vol. 73, No. 16, 2008

Routes from 1-Acyldipyrromethanes to meso-Substituted Porphyrins
densation to give hybrid porphyrin, the yield of each would be 50%,
again giving a total of 100%. Conversely, if exclusive heterocon-
densation occurred, the yield of hybrid porphyrin would be 100%.
the North Carolina Biotechnology Center and the National
Science Foundation.
Supporting Information Available: Survey of reaction
conditions; procedures for preparing compounds; experimental
section; and spectral data for selected compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This research was supported by the NIH
(GM36238). Mass spectra were obtained at the Mass Spec-
trometry Laboratory for Biotechnology at North Carolina State
University. Partial funding for the Facility was obtained from
JO800588N
J. Org. Chem. Vol. 73, No. 16, 2008 6201