Design and synthesis of porphyrins bearing rigid hydrogen bonding motifs: Highly versatile building blocks for self-assembly of polymers and discrete arrays

Article abstract of DOI:10.1021/jo010108c

Two aldehydes, 2,6-diacetamido-4-formylpyridine (7) and 1-butyl-6-formyluracil (11), are used to synthesize five pyridyl and four uracyl meso-subsituted porphyrins. With these complementary porphyrin building blocks, it is possible to build various types of multi-porphyrin supramolecules with different spatial relationships in predefined geometries. The formation and properties of self-complementary dimers and a dosed tetrameric square are presented as a basis of comparison to the latter system in the solid state. An X-ray structure of 5,10-bis(4-tert-butylphenyl)-15,20-bis-(3,5-diacetamido-4-pyridyl)porphyrin confirms its molecular structure and reveals a hydrogen-bonded supramolecular organization mediated by water molecules.

Full text of DOI:10.1021/jo010108c

J . Org. Chem. 2001, 66, 6513-6522
6513
Design a n d Syn th esis of P or p h yr in s Bea r in g Rigid Hyd r ogen
Bon d in g Motifs: High ly Ver sa tile Bu ild in g Block s for
Self-Assem bly of P olym er s a n d Discr ete Ar r a ys
Xinxu Shi,† Kathleen M. Barkigia,‡ J ack Fajer,‡ and Charles Michael Drain*,†
Department of Chemistry and Biochemistry, Hunter College of the City University of New York,
695 Park Avenue, New York, New York 10021, and Energy Sciences and Technology Department,
Brookhaven National Laboratory, Upton, New York 11973-5000
Received J anuary 29, 2001
Two aldehydes, 2,6-diacetamido-4-formylpyridine (7) and 1-butyl-6-formyluracil (11), are used to
synthesize five pyridyl and four uracyl meso-subsituted porphyrins. With these complementary
porphyrin building blocks, it is possible to build various types of multi-porphyrin supramolecules
with different spatial relationships in predefined geometries. The formation and properties of self-
complementary dimers and a closed tetrameric square are presented as a basis of comparison to
the latter system in the solid state. An X-ray structure of 5,10-bis(4-tert-butylphenyl)-15,20-bis-
(3,5-diacetamido-4-pyridyl)porphyrin confirms its molecular structure and reveals a hydrogen-
bonded supramolecular organization mediated by water molecules.
In tr od u ction
assembly of both polymers and discrete arrays with
various structures in high yields by appropriate combina-
tions of the molecular building blocks.
Self-assembly into specifically designed structures
involves the spontaneous association of molecules through
intermolecular interactions.1 The ability to control the
supramolecular organization of molecular entities by
nonconvalent interactions remains a challenging goal in
materials science,1b because of our still imperfect ability
to predictably design supramolecular structures in solu-
tion and in the solid state. Due to their key role in many
important biological systems, the self-assembly of por-
phyrin derivatives has attracted considerable attention
because of their photoelectric properties, their potential
use as components of nanometer scale photonic devices,
and as novel functional materials.2 In addition to the free
bases, the functionality (luminescence, redox, electronic,
etc.) of these large, rigid aromatic macrocycles may be
altered or fine-tuned by formation of various metal
derivatives. For these reasons, porphyrins and metallo-
porphyrins are particularly attractive molecular species
to incorporate into supramolecular assemblies with spe-
cial built-in properties or functions. Much effort has been
applied to the design and synthesis of covalent porphy-
rinic arrays analogous to those found in nature for charge
separation, electron transport,3 and signal or energy
transduction.4 Formation of multiple hydrogen bonds
between complementary molecular components is widely
used in the fabrication of supramolecular assemblies
because of their strength, directionality, specificity, and
reversibility. Preparation of monomeric hydrogen bond
recognition unit-bearing chromophores allows the self-
Designed porphyrin arrays have been formed by hy-
drogen bonding,5,6 axial metallo-porphyrin coordination,7,8
and coordination of exocyclic ligands.9 Several topologi-
cally complex structures such as catenanes and rotaxanes
have utilized porphyrins.10,11 Porphyrins have been in-
corporated into lipid membranes to form photo transis-
(4) For examples of various types of discrete multiporphyrinic
covalent arrays: (a) Lin, V. S.-Y.; DiMagno, S. G.; Therien, M. J .
Science 1994, 264, 1105-1111. (b) Wagner, R. W.; Seth, J .; Yang, S.
I.; Kim, D.; Bocian, D. F.; Holten, D.; Lindsey, J . S. J . Org. Chem. 1998,
63, 5042-5049. (c) Lindsey, J . S.; Gust, D.; Moore, T. A.; Moore, A. L.;
Weghorn, S. J .; J ohnson, T. E.; Lin, S.; Liddell, P. A.; Kuciauskas, D.
J . Am. Chem. Soc. 1999, 121, 8604-8614. (d) Aratani, N.; Osuka, A.;
Kim, Y. H.; J eong, D. H.; Kim, D. Angew. Chem., Int. Ed. 2000, 39,
1458-1462. (e) Khoury, R.; J aquinod, L.; Nurco, D. J .; Pandey, R. K.;
Senge, M. O.; Smith, K. M. Angew. Chem, Int. Ed. Engl. 1996, 35,
2496-2499. (f) Burrell, A. K.; Officer, D. L. Synlett 1998, 1297-1307.
(g) Osuka, A.; Yamazaki, I.; Nakano, A.; Yamazaki, T.; Nishimura, Y.
Angew. Chem., Int. Ed. 1998, 37, 3023-3027. (h) Li, J .; Lindsey, J . S.
J . Org. Chem. 1999, 64, 9101-9108. (i) Anderson, S.; Anderson, H. L.;
Sanders, J . K. M. J . Chem Soc., Perkin Trans. 1 1995, 2247-2254 and
references therein.
(5) For examples of discrete multiporphyrinic arrays formed by
hydrogen bonding: (a) Drain, C. M.; Fischer, R.; Nolen, E. G.; Lehn,
J .-M. J . Chem. Soc., Chem. Commun. 1993, 243-245. (b) Drain, C.
M.; Russell, K. C.; Lehn, J .-M. J . Chem. Soc., Chem. Commun. 1996,
337-338 (c) Ikeda, C.; Nagahara, N.; Motegi, E.; Yoshioka, N.; Inoue,
H. Chem. Commun. 1999, 1759-1760. (d) Balaban, T. S.; Eichhoffer,
A.; Lehn, J .-M. Eur. J . Org. Chem. 2000, 4047-4057.
(6) For examples of porphyrin hydrogen bonding in solid-state
networks: (a) Dahal, S.; Goldberg, I. J . Phys. Org. Chem. 2000, 13,
1-6. (b) Bhyrappa, P.; Wilson, S. R.; Suslick, K. S. J . Am. Chem. Soc.
1997, 119, 8492-8502. (c) Diskin-Posner, Y.; Dahal, S.; Goldberg, I.
Angew. Chem., Int. Ed. Engl. 2000, 39, 1288-1291.
(7) For examples of discrete axial coordination arrays: (a) Stibrany,
R. T.; Vasudevan, J .; Knapp, S.; Potenza, J . A.; Emge, T.; Schugar, H.
J . J . Am. Chem. Soc. 1996, 118, 3980-3981. (b) Knapp, S.; Vasudevan,
J .; Emge, T.; Arison, B. H.; Potenza, J . A.; Schugar, H. J . Angew. Chem.,
Int. Ed. Engl. 1998, 37, 2368-2370. (c) Sanders, J . K. M.; Bampos,
N.; Mak, C. C. Chem. Commun. 1999, 1086-1086. (d) Chi, X.; Guerin,
A. J .; Haycock, R. A.; Hunter, C. A.; Sarson, L. D. Chem. Commun.
1995, 2563-2565.
(8) For examples of axial coordination polymers or networks: (a)
Fleischer, E. B.; Shachter, A. M. Inorg. Chem. 1991, 30, 3763-3769.
(b) Abrahams, B. F.; Hoskins, B. F.; Robson, R. J . Am. Chem. Soc.
1991, 113, 3606-3607. (c) Kumar, R. K.; Balasubramanian, S.;
Goldberg, I. Mol. Cryst. Liq. Cryst. 1998, 313, 105-114. (d) Goldberg,
I. Chem. Eur. J . 2000, 6, 3863-3870.
* To whom correspondence should be sent. Fax: (212) 772-5332.
E-mail: Cdrain@shiva.hunter.cuny.edu.
† City University of New York.
‡ Brookhaven National Laboratory.
(1) (a) Lehn, J .-M. Angew. Chem., Int. Ed. Engl. 1990, 29, 1304-
1319. (b) Dagani, R. Chem., & Eng. News 1998, 76, 35-46.
(2) Lindsey, J . S. New J . Chem. 1991, 15, 153-180.
(3) For reviews on reaction center models see: (a) Wasielewski, M.
R. In The Photosynthetic Reaction Center; Deisenhofer, J ., Norris, J .,
Eds.; Academic Press: New York, 1993; Vol. 2, pp 465-511. (b) Gust,
D.; Moore, T. A. In The Porphyrin Handbook; Kadish, K., Smith, K.,
Guilard, R., Eds.; Academic Press: New York, 2000; Vol. 8, pp 153-
190.
10.1021/jo010108c CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/30/2001

6514 J . Org. Chem., Vol. 66, No. 20, 2001
Shi et al.
tors12 and have been used in read-write devices13 and as
receptors.14 Several recent reviews on self-assembly of
various molecules, including porphyrins, put the present
work into context.15 One conclusion that may be drawn
from these numerous studies is that the nature of the
chemical linkerscovalent, coordination, or hydrogen
bondsis just as important to the function of the array
as the topology of the chromophores. Thus, porphyrinic
squares formed by metal ion coordination have substan-
tially different photophysical properties than porphyrin
squares formed via hydrogen bonding.9 For example, if
fluorescence is a desired property of the material, say for
a ns luminescent switch, then hydrogen bonding is
preferred over metal ion coordination or acetylenic link-
ers, because these later reduce the quantum yield by
heavy atom effects and energy or electron transfer,
respectively. While there is an ever increasing number
of discrete porphyrin arrays mediated by metal ion
coordination, there are few discrete arrays mediated by
hydrogen bonding.5,6
The primary objective of this work is to develop
synthetic strategies for two sets of porphyrin building
blocks bearing rigidly linked peripheral complementary
triple hydrogen bonding moieties (Figure 1), and the
heretofore unknown aldehydes. The issue of a general
synthesis of porphyrins bearing complex heterocyclic
substituents is yet unresolved, vide infra. These can be
joined into a variety of discrete nanostructures with
remarkable control and precision.1 By mixing these
complementary synthons in organic solvents with ac-
curately controlled stoichiometry, the directed triple
hydrogen bonding moiety makes it possible to form
various types of rigid multi-porphyrin arrays with dif-
ferent, designed spatial relationships. Low molecular
weight polymers with somewhat tunable size, depending
on the thermodynamics of binding, and molecular orga-
nization into higher order structures are also possible.16
F igu r e 1. Interactions between two porphyrin building blocks
via complementary hydrogen bonding. Assemblies containing
more than two uracyl groups will have one or more isomeric
forms.
The use of free base or metalloporphyrin building blocks
enables the fabrication of arrays with predetermined
metalation states. These building blocks also provide
hydrogen-bonded pathways through which energy or
electron transfer might be facilitated.17 In addition, an
X-ray study of a 5,15 disubstituted pyridyl derivative
reveals an unexpected new mode of hydrogen-bonded
supramolecular aggregation mediated by adventitious
water molecules.
Resu lts a n d Discu ssion
The syntheses of two aldehydes 717c and 11 are shown
in Schemes 1 and 2. The direct amination of 4-methylpy-
ridine, 1, with sodium amide in a tetralin solution affords
2,6-diamino-4-methylpyridine, 2, in 65% yield. This factor
of 2 increase in yield over previous methods18 is largely
due to milder reaction conditions (slowly heating by
stages) and workup (hydrolysis with ethanol). 2,6-Diac-
etamido-4-methylpyridine, 3, is made through acylation
of 2 with acetic anhydride. The oxidation of compound 3
with peracetic acid yields 2,6-diacetamido-4-methylpy-
ridine-1-oxide, 4. Refluxing 4 in acetic anhydride results
in the oxidation of the methyl group by a transfer of the
intermediate 1-acetoxy group19 to yield 2-diacetimido-6-
acetamido-4-acetoxymethylpyridine 5. Selective hydroly-
sis of one acetate of the imide and the ester group of 5
(9) For examples of discrete arrays formed by exocyclic ligand
coordination: (a) Drain, C. M.; Lehn, J .-M. J . Chem. Soc., Chem.
Commun. 1994, 2313-2315. (b) Drain, C. M.; Nifiatis, F.; Vasenko,
A.; Batteas, J . Angew. Chem., Int. Ed. 1998, 37, 2344-2347. (c) Yuan,
H.; Thomas, L.; Woo, L. K. Inorg. Chem. 1995, 36, 2808-2817. (d)
Slone, R. V.; Hupp, J . T. Inorg. Chem. 1997, 36, 5422-5423. (e) Stang,
P. J .; Fan, J .; Olenyuk, B. Chem. Commun. 1997, 1453-1454. (f) Fan,
J .; Whiteford, J . A.; Olenyuk, B.; Levin, M. D.; Stang, P. J .; Fleischer,
E B. J . Am. Chem. Soc. 1999, 121, 2741-2752.
(10) For examples of hybrid arrays: (a) Burrell, A. K.; J ones, B. M.;
Hall, S. B.; Officer, D. L.; Reid, D. C. W.; Wild, K. Y. J . Incl. Phenom.
Macrocycl. Chem. 1999, 35, 185-190. (b) Anderson, S.; Anderson, H.
L.; Sanders, J . K. M. Acc. Chem. Res. 1993, 26, 469-475. (c) Anderson,
S.; Anderson, H. L.; Bashall, A.; McPartin, M.; Sanders, J . K. M. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1096-1099. (d) Funatsu, K.; Kimura,
A.; Imamura, T.; Ichimura, A.; Sasaki, Y. Inorg. Chem. 1997, 36, 1626-
1653.
(11) For example: (a) Hungerford, G.; Auweraer, M. V.; Chambron,
J .-C.; Heitz, V.; Sauvage, J .-P.; Pierre, J .-L.; Zurita, D. Chem. Eur. J .
1999, 5(7), 2089-2100. (b) Feiters, M. C.; Fyfe, M. C. T.; Martinez-
Diaz, M.-V.; Menzer, S.; Nolte, R. J . M.; Stoddart, J . F.; van Kan, P. J .
M.; Williams, D. J . J . Am. Chem. Soc. 1997, 119, 8119-8120.
(12) (a) Drain, C. M.; Mauzerall, D. Bioelectrochem. Bioenerg. 1990,
24, 263-268. (b) Drain, C. M.; Mauzerall, D. Biophys. J . 1992, 63,
1544-1555. (c) Drain, C. M.; Christensen, B.; Mauzerall, D. Proc. Natl.
Acad. Sci., USA 1989, 86, 6959-6962.
(13) (a) Fox, M. A.; J ones, W. E.; Watkins, D. M. Chem. Eng. News
1993, 38-48. (b) Liu, C.; Pan, H.; Fox, M. A.; Bard, A. J . Science 1993,
261, 897-899.
(14) Hayashi, T.; Miyahara, T.; Koide, N.; Kato, Y.; Masuda, H.;
Ogoshi, H. J . Am. Chem. Soc. 1995, 119, 7281-7290.
(15) (a) Stang, P. J .; Olenyuk, B. Acc. Chem. Res. 1997, 30, 502-
518. (b) Burrell, A. K.; Wasielewski, M. R. J . Porph. Phthal. 2000, 4,
401-406. (c) Suslick, K. S.; Rakow, N. A.; Kosal, M. E.; Chou, J .-H. J .
Porph. Phthal. 2000, 4, 407-413. (d) Philp, D.; Stoddart, J . F. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1154-1196. (e) Linton, B.; Hamilton,
A. D. Chem. Rev. 1997, 97, 1669-1680.
(16) (a) Lehn, J .-M. Chem. Eur. J . 2000, 6, 2097-2102. (b) Berl, V.;
Krische, M. J .; Huc, I.; Lehn, J .-M.; Schmutz, M. Chem. Eur. J . 2000,
6, 1938-1946.
(17) For example: (a) Sessler, J . L.; Wang, B.; Harriman, A. J . Am.
Chem. Soc. 1995, 117, 704-714. (b) Sessler, J . L.; Wang, B.; Harriman,
A. J . Am. Chem. Soc. 1993, 115, 10418-10419. (c) The synthesis of
aldehyde similar to 7 from 2,6-dihydroxyisonicotinic acid in lesser
yields, and an deca substituted porphyrin with one diacetamidopyridyl
group was heuristically described in: Osuka, A.; Yoneshima, R.;
Shiratroi, H.; Okada, T.; Taniguchi, S.; Mataga, N. J . Chem. Soc.,
Chem. Commun. 1998, 1567-1568. (d) Vollmer, M. S.; Wurthner, F.;
Effenberger, F.; Emele, P.; Meyer, D. U.; Stumpfig, T.; Port, H.; Wolf,
H. C. Chem. Eur. J . 1998, 4(2), 260-269. (e) de Rege, P. J . F.; Williams,
S. A.; Therien, M. J . Science 1995, 269, 1409-1413. (f) Smeets, S.;
Asokan, C. V.; Motmans, F.; Dehaen, W. J . Org. Chem. 2000, 65, 5882-
5885.
(18) (a) There are two different melting points reported in this
reference: one for the recrystallized material and one for sublimed
material, which reverted to the lower melting point on standing.
Bernstein, J .; Stearns, B.; Shaw, E.; Lott, W. A. J . Am. Chem. Soc.
1947, 69, 9, 1151-1158. (b) Leffer, M. T. In Organic Reactions; Adams,
R., Bachmann, W. E., Fieser, L. E., J ohnson, J . R., Snyder, H. R., Eds.;
J ohn Wiley and Sons: New York, 1941; Vol. 1, pp 91-104. (c) Shreve,
R. N.; Riechers, E. H.; Rubenkoenig, H.; Goodman, A. H. Ind. Eng.
Chem. 1940, 32, 173-178. (d) 2,6-diamino-4-isoropylpyridine is made
in 53% using 4-isopropylpyridine and sodium amide in tetralin K. K.
Kogyo, J apanese Patent: Kokai. Tokyo Koho 80 76, 861, 10, J une 1980
(CA 93-204, 467n).
(19) Adams, R.; Miyano, S. J . Am. Chem. Soc. 1954, 76, 2785-2786.

Design and Synthesis of Porphyrins
J . Org. Chem., Vol. 66, No. 20, 2001 6515
Sch em e 1
chemical shift of ∼0.1 ppm, which is consistent with the
expected inductive and geometric effects, Supporting
Information.
The synthesis of the complementary 1-butyl-6-formyl-
uracil, 11, from 6-formyluracil, 8, is substantially differ-
ent than that of the known 1-butyl-5-formyluracil5a
(Scheme 2). Unlike the 5-formyl derivative,21a the
6-formyluracil21b does not alkylate preferentially at the
1-position so must be protected as the acetal, alkylated,
and deprotected. Trimethyl orthoformate in methanol/
methylene chloride and 8 were refluxed for 10 h in the
presence of the p-toluenesulfonic acid to form the
6-(dimethoxymethyl)uracil in 86% yield.22a The dimethyl
acetal was alkylated with n-butylbromide catalyzed by
K2CO3 in DMSO at room temperature for 72 h to form
the 1-butyl-6-(dimethoxymethyl)uracil (37% based on
n-butylbromide)23 and two byproducts. The 1-butyl-6-
(dimethoxymethyl)uracil could not be converted to its
corresponding aldehyde under a variety of aqueous acid
conditions, so a Lewis acid, BBr3, in CH2Cl2 was used to
cleave the dimethyl acetal22b at -78 °C in 87% yield. In
dry solvents the uracil vinyl proton can be observed as
two peaks, possibly as a consequence of self-complemen-
tary hydrogen bonding of 11.
Sch em e 2
Both sets of porphyrin building blocks were prepared
by the Adler24 synthesis (Schemes 3 and 4) and modifica-
tions thereof.25 Using a mixture of two different alde-
hydes results in a mixture of six porphyrins in yields that
are weighted by the reactivity, the solubility, and the
relative amounts of the aldehydes.8a,9a,25 All three of these
can be exploited to obtain maximum yields of the desired
porphyrins, vide infra. Since the polarities of the six
porphyrins are very different, they are readily separated
by column chromatography. The mixed aldehyde condensa-
tion8a,25 was chosen for several reasons. (1) Heterocyclic
aldehydes and/or those bearing Lewis bases are generally
not tolerated or have poor yields using the Lindsey por-
phyrin syntheses26 as well as most of the [n + (4 - n)]
coupling reactions. (2) The five compounds containing the
heterocycles are all needed as building blocks for the self-
assembled arrays. (3) The Adler24 synthesis and its
modifications25 are quite amenable to large scale, mul-
tigram reactions without significant sacrifice in yields or
complications in purification. (4) All the porphyrins and
isomers can be well characterized by the 1H NMR spectra
in the aromatic region, especially by the pyrrole â-H.
with K2CO3 in a methanol/water solution affords the 2,6-
diacetamido-4-hydroxymethylpyridine, 6. The alcohol 6
is oxidized with PCC (on alumina) under ultrasound
conditions to yield 2,6-diacetamido-4-formylpyridine, 7,
where yields as high as 65% are observed in small-scale
oxidation reactions. Starting from 2, the 26-32% overall
yield of this synthetic route (Scheme 1) is reasonable
because of the inexpensive starting materials and the
easy scale-up. Other routes to this aldehyde are not
successful because of the substantial electronic effects at
the 4 position. For example, the 2,6-diamino-3-formylpy-
ridine isomer can be synthesized by the formylation of
2,6-diaminopyridine by a Vilsmeyer reaction.20 Com-
pletely optimized structure calculations using Gaussian
98 (B3LYP/6-311**) on aldehyde 7 indicate that both
the acetamido and aldehyde groups are coplanar with the
pyridine ring, with the amide oxygen atoms pointing
toward the ring. These calculations also suggest that
there is some hydrogen bonding between the amide
oxygen atoms and the pyridyl hydrogens, and one of the
pyridyl hydrogens is near enough to hydrogen bond with
the aldehyde oxygen. The difference in the chemical shifts
for the two pyridyl protons is calculated (GIAO) to be
0.220 ppm in the gas phase, and that measured in
chloroform-d is <0.07 ppm. Interestingly, the pyridyl
protons sense the formation of the self-complementary
hydrogen bond dimer of II, manifested as a small
(21) (a) Brossmer, R.; Ziegler, D. Tetrahedron Lett. 1966, 5253-5256.
(b) Zee-Cheng, K.-Y.; Cheng, C. C. J . Heterocycl. Chem. 1967, 4 (1)
163-165. (c) Demuynck, M.; DeClercq, P.; Vandewalle, M. J . Org.
Chem. 1979, 26, 4863-4866.
(22) (a) Botta, M.; DeAngelis, F.; Corelli, F.; Menichincheri, M.;
Nicoletti, R.; Marongiu, M. E.; Pani, A.; Colla, P. L. Arch. Pharm. 1991,
324, 203-207. (b) Demuynck, M.; DeClercq, P.; Van de Walle, M. J .
Org. Chem. 1979, 44, 4863-4866. (c) Adams, L. L.; Luzzio, F. A. J .
Org. Chem. 1989, 54, 5387-5390.
(23) Brown, D. T.; Eisinger, J .; Leonard, N. J . J . Am. Chem. Soc.
1968, 90, 7302-7306.
(24) Adler, A. D.; Longo, F. R.; Finarelli, J . D.; Goldmacher, J .;
Assour, J .; Korsakoff, L. J . Org. Chem. 1967, 32, 476-480.
(25) (a) Little, R. G.; Anton, J . A.; Loach, P. A.; Ibers, J . A. J .
Heterocycl. Chem. 1975, 12, 343-349. (b) Walker, F. A.; Balke, V. L.;
McDermott, G. A. Inorg. Chem. 1982, 21, 3342-3348. (c) Milgrom, L.
R. J . Chem. Soc., Perkin Trans. 1 1984, 1483-1487. (d) J ohnstone, R.
A. W.; Nunes, M. L. P. G.; Pereira, M. M.; Gonsalves, A. M. d’A. R.;
Serra, A. C. Heterocycles 1996, 43, 1423-1436. (e) Drain, C. M.; Gong,
X. Chem. Commun. 1997, 2117-2118.
(26) (a) Lindsey, J . S.; Schreiman, I. C.; Hsu, H. C.; Kearney, P. C.;
Marguerettaz, A. M. J . Org. Chem. 1987, 52, 827-836. (b) Gryko, D.;
Lindsey, J . S. J . Org. Chem. 2000, 65, 2249-2252. (c) Rao, P. D.;
Dhanalekshmi, S.; Littler, B. J .; Lindsey, J . S. J . Org. Chem. 2000,
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6516 J . Org. Chem., Vol. 66, No. 20, 2001
Shi et al.
Sch em e 3
Thus, with ample quantities of the two aldehydes in
hand, a number of porphyrin syntheses were explored:
three different reaction solvents, acetic acid, propionic
acid, and a mixture of nitrobenzene/acetic acid were tried
each with and without zinc acetate as a possible tem-
plating agent. All these conditions give good results with
7, but 11 was more problematic.
To increase the yield of the four porphyrin building
blocks bearing both heterocyclic and alkylphenyl groups,
we adopted three measures: (i) increasing the relative
amount of the heterocyclic aldehydes, (ii) decreasing the
concentration of the reaction mixture (0.05 M), (iii) for
the uracyl porphyrin building blocks, changing the
reactant addition order whereby the 4-tert-butylbenzal-
Sch em e 4

Design and Synthesis of Porphyrins
J . Org. Chem., Vol. 66, No. 20, 2001 6517
dehyde was added 10 min after adding the pyrrole rather
than adding two aldehydes together. During the course
of this investigation only one method for the synthesis
of the tetrauracylporphyrin was discovered, namely using
acetic acid and nitrobenzene as reaction solvents25d with
zinc acetate (Scheme 4.). The 5.1% yield of XII is
consistent with previous Adler synthesis25a considering
that it bears a nonaromatic heterocycle with a sterically
hindering substituent next to the aldehyde.
for VIII, the phenyl protons are observed as multiplets
rather than a simple AB quartet. This spectrum of VIII
shows the expected diagnostic pattern in the â-pyrrole
region for this type of derivative, where there are four
different chemical environments that should result in two
AB quartets, but only the quartet from the pyrroles
nearest the heterocycle is observed, while those on the
opposite side of the heterocycle are observed as a singlet
even on the 500 MHz instrument.
The one striking aspect of the physical properties of
both the diheterocyclic porphyrin isomers is the abnor-
mally low solubility of the 5,15-isomer compared to that
of the 5,10-isomer. In nonpolar organic solvents the
solubility of the 5,10-disubstituted porphyrins is usually
expected to be less than that of the 5,15-isomers due to
greater polarity; however, on the contrary, these 5,10-
porphyrins are found to have much greater solubility
than the 5,15-isomers. As discussed below, this anoma-
lous solubility is explained by the self-complementary
hydrogen-bond self-assembly of linear polymeric tapes vs
closed tetrameric squares.
For analytical purposes both rotamers of IX and X,
were isolated. Both the 5,15- and 5,10-compounds can
exist as RR or Râ rotamers, each with a different
symmetry, with respect to the relative orientation of the
two 1-butyl-6-uracyl groups. Thus, the chemical environ-
ments of the porphyrin faces are the same for the Râ
rotamers and different for the RR rotamers for both IX
and X. As in the mono substituted derivative, these
1
rotameric forms are readily observed in the H NMR in
the region of the two 4-tert-butylphenyl groups. A simple
doublet of doublets for the phenyl groups of the Râ
rotamers of both compounds is observed, while multiplets
for the same groups are observed for the RR rotamers.
Because the pyrrole â-H are in the porphyrin plane, the
rotameric forms of IX and X are not observed in this
region, so there are the expected four different pyrrole
resonances in X and two for IX.
While the characterization of the 3,5-diacetamido-4-
pyridylporphyrins is straightforward, the characteriza-
tion of meso-1-butyl-6-uracylporphyrins merits comment.
The four 1-butyl-6-uracyl groups are rigidly linked to the
meso-positions of the porphyrin and rotation about the
connecting bond is hindered by the butyl substituents.
Thus the 1-butyl-6-uracyl group is oriented nearly normal
to the porphyrin plane, projecting the butyl substituents
Str u ctu r a l Stu d ies
1
As an additional, unexpected example of the intrinsic
tendency of these compounds to aggregate by hydrogen
bonding, we also present an X-ray study of IV. Atom
names, displacements from planarity and an edge-on
view of the macrocycle are given in Figure 2. The
crystallographic determination provides unambiguous
identification of IV. Complete experimental details,
atomic coordinates and molecular geometry are included
in the Supporting Information. The C5-,C10-, and C20-
meso substituents are completely ordered, but the tert-
butylphenyl group at C15 exists in two discrete orienta-
tions with 75/25% occupancies. (Only the orientation of
the major component is shown in Figure 2.)
The skeleton of IV is mainly saddled with some degree
of ruffling. The Cb atoms in each of the four pyrrole rings
exhibit substantial unequal displacements from the mean
porphyrin plane that range between 0.34 and 0.48 Å (see
Figure 2). The deviations of the meso carbons are also
unequal; they are smaller at C5 and C10, 0.02 Å and
-0.07 Å, than at C15 and C20, 0.17 Å and -0.13 Å. The
edge-on view in Figure 2 further illustrates the distorted
conformation of the macrocycle, with rings B and D above
the mean plane and rings A and C below it. Note that
above or below the macrocycle. The H NMR spectra, see
Supporting Information, of the tetrauracyl compound XII
reveals that: (1) all the chemical shifts of the butyl group
are shifted upfield due to ring current effects; (2) the
methylene group next to the 1-N atom showed four sets
of multiplets rather than one triplet and the methyl
group showed four sets of triplets rather than one triplet.
This proves that the butyl groups are on the 1-positions
of the uracyl, and that there are four rotameric forms27
in a ratio of 1:3:2:1 from low to high field. The statistical
ratio for the RRRR, RRRâ, RRââ, and RâRâ rotamers would
be 1:4:2:1, respectively (R above and â below the porphy-
rin plane).28 The integral areas of the terminal methyl
group are consistent with the N-methylene, but may be
in a different order. The observed deviations from the
ideal ratios may be due to losses during the purification
process. The rotameric forms of VIII-XII result in self-
assembled supramolecular species with different isomeric
forms, but the isomers are not observed. There are also
no detectable consequences on the energetics and kinetics
of the self-assembly process since the uracyl ADA (A )
hydrogen bond acceptor, D ) hydrogen bond donor)
recognition function(s) are directed along the porphyrin
plane.29
The 1H NMR spectra of the various other uracyl
porphyrin derivatives, VIII-XI, are similarly complex
due to the presence of both 4-tert-butylphenyl and 1-bu-
tyl-6-uracyl groups and the resulting rotamers. Each
porphyrin face is different in the monouracyl porphyrin,
VIII. This results in an AB, A′B′ system, where A′, B′
represents the phenyl protons on the opposite side of the
macrocycle relative to the butyl group on the uracil. Thus
(29) (a) Beijer, F. H.; Sijbesma, R. P.; Vekemans, J . A. J . M.; Meijer,
E. W.; Kooijman, H.; Spek, A. L. J . Org. Chem. 1996, 61, 6371-6380.
(b) Beijer, F. H.; Sijbesma, R. P.; Kooijman, H.; Spek, A. L.; Meijer, E.
W. J . Am. Chem. Soc. 2000, 120, 6761-6769. (c) Beijer, F. H.;
Kooijman, H.; Spek, A. H.; Sijbesma, R. P.; Meijer, E. W. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 75-78. (d) Ercolani, G. J . Phys. Chem.. 1998,
91, 5699-5703. (e) Ercolani, G. Chem. Commun. 2001, J une advanced
web addition. Note that a ∆G of -7 to -12 kJ mol-1 corresponds to
2.8 to 4.9 kBT, thus dynamic processes are expected at room temper-
ature. Though common practice, equilibrium constants for weakly
H-bonding systems determined by NMR data are probably internally
comparable, but should be treated with caution unless the dynamics
of the system(s) are specifically addressed. Theoretical treatments of
equilibrium constants based on simple dimer interactions to predict
product distributions in larger systems that neglect cooperativity29d,
(27) Collman, J . P.; Gagne, R. R.; Reed, C. A.; Halbert, T. R.; Lang,
G.; Robinson, W. T. J . Am. Chem. Soc. 1982, 104, 4500-4502.
(28) Lindsey, J . S. In The Porphyrin Handbook; Kadish, K., Smith,
K. M., Guilard, R., Eds.; Academic Press: San Diego, CA, 2000; Vol.
1, pp 45-118 and references therein.
2
9esespecially in aromatic systems such as thesesshould also be used
with caution.

6518 J . Org. Chem., Vol. 66, No. 20, 2001
Shi et al.
F igu r e 3. Hydrogen-bonded supramolecular assembly of
porphyrin IV mediated by water. (Hydrogen bonds are shown
as dotted lines.)
The sample was crystallized from a mixture of ethyl
acetate and hexane, but the crystals do not incorporate
either of these solvents. Instead, the lattice contains 2.5
molecules of adventitious water per porphyrin. The
unexpected water molecules (O5 and O6) mediate a more
extensive supramolecular array of IV via multiple hy-
drogen bonds (Figure 3).
For simplicity, the basic porphyrin building blocks of
this array are designated as 1, 2, 3, and 4. Only molecule
I comprises the crystallographic asymmetric unit; the rest
are generated by space group operators. Molecules 1 and
2 are joined by two reciprocal O1‚‚‚N9 and two reciprocal
N5‚‚‚N10 hydrogen bonds at 3.02 Å and 3.05 Å. This
dimeric unit is further incorporated into a complex multi-
porphyrin array. O2 of molecule 1 associates with O6 (a
water molecule of solvation) with an O2‚‚‚O6 distance of
2.84 Å. O6 then hydrogen bonds to N6 of molecule 3
which is 2.99 Å from it. N7 of molecule 1 associates with
O5 (another water molecule of solvation) with N7‚‚‚O5
) 3.00 Å. O5 sits 2.82 Å away from O4 of molecule 4.
(There are additional interactions involving O7, a third
water of crystallization that is present only 50% of the
time.)
All five possible hydrogen-bond donors and acceptors
(O1, N6, N5, N7, and O2) of the C5-meso substituent
participate in the network formation, whereas only N9,
N10 and O4 of the C10-meso substituent participate, and
may thus contribute to the differences in the orientations
of the peripheral rings. The closest approach of pyrrole
ring centers (A and D) is 3.87 Å involving 1 and another
molecule not involved in the hydrogen bonding with 1.
Since the center to center distance of 1 and 2 is 12.70 Å,
they interact only at the periphery. The structure reveals
that there are no substantial π-π interactions in this
arrangement of macrocycles in the solid state. Therefore,
the degree of porphyrin distortion caused solely by
hydrogen bonding in this single-component system is
unprecedented.31 These results also indicate that the
intentional addition of water to molecules designed to
form networks or arrays mediated by hydrogen bonding
may well lead to novel aggregates, as evidenced by this
structure.
F igu r e 2. Top: Molecular structure and atom names for IV.
Thermal ellipsoids are drawn at the 50% probability level.
Peripheral hydrogens are omitted for clarity. Middle: Dis-
placements of the 24 atoms that comprise the macrocycle from
the 24 atom mean porphyrin plane in units of 0.01 Å. Bottom:
Edge-on view of the porphyrin core. Thermal ellipsoids enclose
1% probability for clarity.
such out-of-plane distortions of the porphyrin macrocycle
have been shown to have significant effects on the optical,
redox and excited-state properties of the chromophores.30
Biological systems containing porphyrinic proteins such
as those used in photosynthesis and electron transport
exploit these effects to fine-tune their reactivity and
photophysical properties.31
As observed in other saddled porphyrins,30,31 the dihe-
dral angles between the meso-substituents and the
porphyrin plane are unusually acute. They assume values
of 62° at C5, 36° at C10, 60° and 72° at C15, and 62° at
C20. The unusual dihedral angle of 36° of the C10
substitutent, compared to the nearly perpendicular angles
of 80-90° normally observed in planar aryl-substituted
porphyrins, is most likely related to its participation in
hydrogen bonds (vide infra).
(30) (a) Drain, C. M.; Gentemann, S.; Roberts, J . A.; Nelson, N. Y.;
Medforth, C. J .; J ia, S.; Simpson, M. C.; Smith, K. M.; Fajer, J .;
Shelnutt, J . A.; Holten, D. J . Am. Chem. Soc. 1998, 120, 3781-3791.
(b) Drain, C. M.; Kirmaier, C.; Medforth, C. J .; Nurco, D. J .; Smith, K.
M.; Holten, D. J . Phys. Chem. 1996, 100, 11984-11993.
(31) Shelnutt, J . A.; Song, X.-Z.; Ma, J . G.; J ia, S.-L.; J entzen, W.;
Medforth, C. J . Chem. Soc. Rev. 1998, 27, 31-41.
Self-Assem bled Squ a r es in Solu tion . The prepon-
1
derance of evidence from H NMR, UV-visible, ESI-MS,
light scattering, and osmometry suggests that IV self-

Design and Synthesis of Porphyrins
J . Org. Chem., Vol. 66, No. 20, 2001 6519
Sch em e 5
versus the expected ∼13 kJ mol-1 for the alkyl substi-
tuted derivative in the same solvent.29 AM1 calculations
indicate that the presence of a phenyl group on the 4
position of the 2,6-diacetamidopyridyl moiety increases
F igu r e 4. Formation of closed tetrameric squares. (A) The
self-complementary association of IV in CDCl3 is compared to
(B) the complementary association of a 1:1 mixture of IV and
X in THFd8.
the self-complementary H-bond enthalpy by ∼4 kJ mol-1
.
Typically, the electronic effects of the porphyrin are
greater than the phenyl group, so a further increase in
the ∆H of the self-complementary interaction(s) is ex-
pected and calculated to be ∼6 kJ mol-1 greater than the
parent recognition unit. Thus the experimental and
calculated results are qualitatively consistent. The 90°
geometry of the rigidly linked recognition groups on the
porphyrins, and the thermodynamic stability of the
self-assembled H-bond squares compared to other struc-
tures,29d ensure that the squares are formed in ∼75% in
chloroform, and ∼90% in toluene.32,33 Both experimental
and computational results show that the presence of the
phenyl has little effect on the self-complementary 1-butyl-
6-uracyl system. Calculations indicated there should be
a modest increase of ∼3 kJ mol-1 for hetero-complemen-
tary 2,6-diacetamido-4-phenylpyridine and 1-butyl-6-
phenyluracil. The H-bond strengths between the comple-
mentary porphyrins II, and VIII, are calculated to be 45
kJ mol-1, ∼7 kJ mol-1 greater than for the isolated
recognition units bearing neither porphyrin nor phenyl
substituent.29,33 Thus the porphyrin ring is expected and
observed to enhance the basicity of the pyridyl nitrogen
and therefore the H-bond strength. This is a well-
documented phenomenon in the coordination chemistry
of pyridylporphyrins.9
assembles into tetrameric squares in solvents with low
hydrogen-bonding potential by self-complementary hy-
drogen bonds.32 This is well demonstrated by fits of the
chemical shift of the amide proton versus concentration
to yield an apparent equilibrium constant, K, and the
number of molecules in the final assembly, n (Figure 4A).
If there are several products or dynamic processes, such
as the breaking apart of one or more sets of hydrogen
bonds occurring on the NMR time scale, these results will
only give rough estimates of K, but this serves as a basis
of comparison for the square formed by complementary
H-bonds, below. Analysis of the NMR data32 for the self-
complementary self-assembly of the square tetramer of
IV yields K ) 2.1 ( 1 × 109 M-3, and n ) 3.9 ( 0.3 in
chloroform. In toluene the equilibrium constants are
greater, as expected, where K is ∼2 ( 1 × 1010 M-3).
ESI-MS and vapor phase osmometry data also indicate
a tetrameric species.
The thermodynamics of these self-complementary sys-
tems in solution are discussed herein. The association
for the diacetamidopyridyl moiety is usually considered
weak,29 ∆Gdimer ranges from 4 to 13 kJ mol-1, and the
double hydrogen bond considered the dominant interac-
tion. However, the strengths of these recognition units
are substantially altered by the presence of the directly
linked porphyrin. Thus there is likely an equilibrium
between the various self-complementary interactions of
the diacetamidopyridyl groups - double, triple, qua-
The formation of a tetrameric square from two equiva-
lents each of IV and X (Scheme 5) in THF, used because
of the limited solubility of X, is indicated by similar
experiments as described above. The overall shape of the
NMR concentration vs amide chemical shift (Figure 4B)
clearly indicates a tetrameric species with n ) 4 and an
apparent equilibrium constant, see caveats vide supra,
1
druple hydrogen bonds. Van’t Hoff plots of the H NMR
data for the self-complementary dimerization of II indi-
cate ∆Hf of the dimer is ∼21 ( 5 kJ mol-1 in toluene
(33) (a) DeGrado, W. F.; Lear, J . D. J . Am. Chem. Soc. 1985, 107,
7684-7689. (b) Deranleau, D. A.; J . Am. Chem. Soc. 1969, 91, 4044-
4054. (c) Whitlock, B. J .; Whitlock, H. W. J . Am. Chem. Soc. 1990,
112, 3910-3915.
(32) Drain, C. M.; Shi, X.; Milic, T.; Nifiatis, F. Chem. Commun.
2001, 287-288.

6520 J . Org. Chem., Vol. 66, No. 20, 2001
Shi et al.
of 6 ( 3 × 1012 M-3 which is somewhat greater than that
estimated solely by equilibrium considerations from the
C1/2 data.29e Note that the C1/2 for the complementary
square is about 2-fold less than that of the self-
complementary species, and the ∆ppm for the amide
protons is a factor of 5 greater. These are all indicative
that the complementary interactions between the uracyl
and diacetamidopyridyl moieties, calculated by various
means to be ∼45 kJ mol-1, are much stronger than either
self-complementary interaction even in a solvent known
to be less favorable to H-bonding than chloroform.
Dynamic light scattering detects only species with ∼ 4
nm hydrodynamic radius between 0.04 and 0.1 mM.
Vapor phase osmometry experiments using concentra-
tions between 0.1 and 1 mM yields an average molecular
weight of 3500 ( 300 da. ESI-MS using a mixture of IV,
Co(III)IV, and X (1:1:2) shows the doubly charged tet-
ramer as well as other multimers and the monomers.
Taken together, these data indicate that the complemen-
tary tetrameric square forms in solution. Experimental
and computational work on these latter assemblies is in
progress.
cooling, the reaction mixture was filtered, and the remaining
black solid material worked up by the dropwise addition of
150 mL ethanol. 10 g of silica gel was added, and the ethanol
was removed under reduced pressure. The resultant dark solid
was added to the top of a 45 g column of silica gel and eluted
with ethyl acetate to afford 8.02 g (65%) of 2 as a white powder.
Recrystallized from chloroform, mp 85-86 °C (lit.18a 87-88 °C,
sublimed crystal, 109-111 °C). 1H NMR (CDCl3) δ 5.74 (s, 2H),
4.06 (br, s, 4H), 2.11 (s, 3H); 13C NMR (CDCl3) δ 158.3, 151.3,
99.5, 21.8; MS (ESI) m/z (MH+, 124).
2,6-Dia ceta m id o-4-m eth ylp yr id in e (3). 16.0 mL of acetic
anhydride was added to 1.5 g (12.2 mmol) of the diamine 2.
The resultant solution was stirred for 1 h and 2.35 g (93%) of
a white crystalline solid 3 was collected by filtration, mp 199-
1
201 °C. H NMR (CDCl3) δ 7.72 (s, 2H), 7.64 (br, m, 2H), 2.35
(s, 3H), 2.17 (s, 6H); 13C NMR (CDCl3) δ 168.9, 153.4, 149.9,
110.9, 25.5, 22.5; MS (ESI) m/z (MH+, 208). Anal. Calcd for
C
10H13N3O2: C, 57.97; H, 6.32; N, 20.27. Found: C, 57.84; H,
6.50; N 20.10.
2,6-Dia ceta m id o-4-m eth ylp yr id in e-1-oxid e (4). To a
solution of the diamide 3 (2.07 g, 10.0 mmol) in 10 mL acetic
acid, 3.0 mL of 32% peracetic acid was added carefully at room
temperature. The resulting solution was heated for 3 h at 50-
60 °C and 4 h at 65-70 °C. After cooling to room temperature,
adding FeSO4 solid to destroy residual oxidant, and removing
the acetic acid under reduced pressure, the residue was
recrystallized from water to yield 1.76 g (79%) of the oxide 4
Con clu sion
1
as a white powder: mp 210-211 °C. H NMR (CDCl3) δ 9.83
(s, 2H), 7.92 (s, 2H), 2.35 (s, 3H), 2.27 (s, 6H); 13C NMR (CDCl3)
δ 164.4, 137.4, 137.0, 104.1, 21.0, 17.8; MS (ESI) m/z (MH+,
224). Anal. Calcd for C10H13N3O3: C, 53.80; H, 5.87; N, 18.82.
Found: C, 53.94; H, 5.96; N, 18.90.
These two sets of complementary porphyrin building
blocks can be used for constructing diverse multi-por-
phyrin arrays in defined geometries through self-
complementary or hetero-complementary assembly. The
enthalpy of the latter is stronger by more than 2-fold,
and this ensures that the self-complementary products
are not complicating factors in the hetero self-assembly
process. The 1-butyl-6-uracyl and 3,5-diacetamido-4-
pyridyl groups can be used to form linear, square, and
junction structures in a predefined metalation state. The
ability to self-assemble nanoscaled building blocks with
precisely controlled size and composition, and to incor-
porate them into larger electronics componentsswhich
may entail secondary self-assembly steps to form hier-
archical structuresswith unique properties and functions
may have significant implications for the incorporation
of these types of molecules into photonic devices. These
studies also demonstrate that water can mediate the self-
aggregation of H-bonding species and dictate the su-
pramolecular arrangement of subunits, as it does in many
protein structures.
2-D ia c e t im id o -6-a c e t a m id o -4-a c e t o x y m e t h y lp y r i-
d in e (5). A solution of the oxide 4 (1.50 g, 6.73 mmol) in acetic
acid (3.0 mL) was added to stirred, refluxing acetic anhydride
(20 mL) over a 30-min. period. The reaction mixture was
stirred at reflux temperature for 30 h, cooled, 5.0 g silica gel
was added to the reaction mixture, and the solvent removed
under reduced pressure. The resultant dark material was
added to the top of a 20 g column of silica gel and eluted with
ethyl acetate/petroleum ether (1:1) to afford 1.49 g (72%) of 5
1
as a white powder, mp: 177-178 °C. H NMR (CDCl3) δ 8.24
(s, 1H), 7.89 (br, s, 1H), 6.93 (s, 1H), 5.17 (s, 2H), 2.29 (s, 6H),
2.21 (s, 3H), 2.20 (s, 3H); 13C NMR (CDCl3) δ172.9, 170.9,
169.2, 152.3, 151.7, 151.6, 118.0, 112.3, 64.7, 27.3, 25.5, 21.5;
MS (ESI) m/z (MH+, 308). Anal. Calcd for C14H17N3O5 C, 54.72;
H, 5.57; N, 13.67. Found: C, 54.66; H, 5.64; N, 13.71.
2,6-Dia ceta m id o-4-h yd r oxym eth ylp yr id in e (6). A solu-
tion of the acetate 5 (1.20 g, 3.9 mmol) and K2CO3 (0.59 g) in
methanol/water (10 mL, 4:1) was stirred at room temperature
for 8 h. The reaction mixture was loaded on 3.0 g silica gel.
The resultant yellow material was added to the top of a 25 g
column of silica gel and eluted with ethyl acetate/ethanol (9:
1) to afford 0.80 g (92%) of the alcohol 6 as a white powder,
Exp er im en ta l Section
1
mp 194-195 °C. H NMR (DMSO-d6) δ 9.93 (s, 2H), 7.65 (s,
Ma ter ia ls a n d Meth od s. Melting points were determined
on a Thomas-Hoover UniMelt capillary apparatus and are
uncorrected. Flash column chromatography was performed
using 230-400 mesh ASTM Merck silica gel-60. 1H and 13C
NMR spectra were recorded on J EOL 400 MHz, a Varian VXR-
300 MHz, or a Varian 500 MHz instrument. Chemical shifts
are reported in ppm relative to TMS for 1H and 13C spectra,
and coupling constants in Hz. NMR assignments are consistent
with those published previously. Agilent Technologies HP 1100
LC/MSD, and a Cary Bio-3 were used. Typical Electrospray
Ionization Mass Spectroscopy (ESI-MS) method: ∼0.05mM
solutions in acetonitrile/water (50:50) containing 1% trifluo-
roacetic acid, positive ion mode, and the fragmentor voltage
between 100 and 350 V. Elemental analysis by Schwarzkopf
Microanalytical Laboratory, Inc.
2H), 5.34 (t, 1H), 4.43 (d, 2H), 2.05 (s, 6H); 13C NMR (DMSO-
d6) δ 170.1, 156.8, 151.2, 107.5, 63.4, 25.2; MS (ESI) m/z (MH+,
224). Anal. Calcd for C10H13N3O3: C, 53.80; H, 5.87; N, 18.82.
Found: C, 53.72; H, 6.04; N 18.86.
2,6-Dia ceta m id o-4-for m ylp yr id in e (7). A solution of the
alcohol 6 (0.80 g, 3.58 mmol) in CH2Cl2 (15 mL) was treated
with NaOAc (2.85 g, 14.32 mmol) followed by portionwise
addition of pyridinium chlorochromate (PCC/Alumina, 1.15 g,
5.38 mmol). The reaction mixture was placed in a sonication
bath22c at room temperature for 1 h, at which time additional
PCC/Alumina (0.43 g, 2.01 mmol) was added. After being
sonicated an additional 3 h, the reaction mixture was loaded
on 3.0 g silica gel, added to the top of a 25 g column of silica
gel, and eluted with ethyl acetate/ethanol (9:1) to afford 0.43
1
2,6-Dia m in o-4-m eth ylp yr id in e (2). A solution of 4-meth-
ylpyridine 1 (9.31 g, 9.73 mL, 0.10 mole) in 50 mL tetralin
was added to a solution of sodium amide (9.33 g, 0.24 mole)
in 100 mL tetralin at 130∼140 °C over 6 h, afterward heated
to 195 °C and kept at this temperature for 10 h.18d After
g (54%) of the aldehyde 7, mp 223-224 °C. H NMR (DMSO-
d6) δ 10.33 (s, 2H), 9.96 (s, 1H), 8.11 (s, 2H), 2.10 (s, 6H); 13C
NMR (DMSO-d6) δ 194.1, 170.7, 152.6, 146.5, 108.9, 25.3; MS
(ESI) m/z (MH+, 222). Anal. Calcd for [C10H12N3O3]+: C, 54.05;
H, 5.44; N, 18.91. Found: C, 53.63; H, 5.27; N, 18.26.

Design and Synthesis of Porphyrins
J . Org. Chem., Vol. 66, No. 20, 2001 6521
6-(Dim eth oxym eth yl)u r a cil (9). A solution of orotalde-
hyde (8) (3.0 g, 21.42 mmol) and trimethyl orthoformate (9.08
g, 9.4 mL, 85.68 mmol) in MeOH (50 mL) and CH2Cl2 (100
mL) was refluxed for 10 h in the presence of p-toluenesulfonic
acid (0.3 g, 1.58 mmol). After the reaction mixture cooled to
room temperature, triethylamine was added to the reaction
mixture until it turned weakly basic. 5.0 g silica gel was added
to the reaction mixture and the solvent removed under reduced
pressure. The resultant yellow material was added to the top
of a 25 g column of silica gel and eluted with ethyl acetate/
ethanol (9:1) to afford 3.46 g (87%) of the acetal 9 as a white
powder, mp 185-186 °C, (lit.:22a 185-186 °C). 1H NMR (CDCl3)
δ 11.02 (br, s, 1H), 10.83 (br, s, 1H), 5.45 (s, 1H), 4.99 (s, 1H),
3.25, (s, 6H); 13C NMR (CDCl3) δ 164.9, 152.4, 151.8, 99.5, 99.1,
54.8; MS (ESI) m/z (M-H+, 185).
1-Bu tyl-6-(d im eth oxym eth yl)u r a cil (10). To a solution
of the acetal (9) (3.20 g, 17.20 mmol) in DMSO (200 mL) were
added 1-bromobutane (0.7850 g, 0.62 mL, 5.73 mmol) and
anhydrous K2CO3 (2.61 g, 18.92 mmol). The suspension was
stirred for 72 h at room temperature after which it was filtered
and the DMSO was removed in vacuo. The solid was absorbed
on 5 g silica gel, loaded on the top of a 25 g column of silica
gel, and eluted with hexane to afford 0.140 g (8.2%) of 1,3-
dibutyl-6-(dimethoxymethyl)uracil as an oil. Further elution
with ethyl acetate/hexane (1:9) afforded 0.222 g (16%) 3-butyl-
6-(dimethoxymethyl)uracil and 0.513 g (37%) of 10. Yields
reported for this compound are based on 1-bromobutane, mp:
91-92 °C. 1H NMR (CDCl3) δ 9.28 (br, s, 1H), 5.95 (s, 1H),
5.05 (s, 1H), 3.87 (t, 2H, J ) 7.7 Hz), 1.67-1.57, (m, 2H), 1.42-
1.30, (m, 2H), 0.95, (t, 3H, J ) 6.9 Hz); 13C NMR (CDCl3) δ
163.4, 152.2, 151.3, 102.7, 99.9, 54.5, 45.1, 31.7, 20.8, 14.5; MS
(ESI) m/z (MH+, 243).
pyrrole, the isolated yield is 20.6%, and the isolated amounts
are I, 0.153 g (3.5%); II, 0.261 g (5.14%); III, 0.222 g (4.11%);
IV, 0.290 g (5.36%); V, 0.149 g (2.60%); VI, 0.052 g (0.86%).
The relative amounts are II (24%), III (20%), IV (26%), and V
(11%), and the two homo-substituted porphyrins I (14.5%) and
VI (4.5%).
5-(3,5-Dia cet a m id o-4-p yr id yl)-10,15,20-t r is(4-ter t-b u -
tylp h en yl)p or p h yr in (II). 1H NMR (CDCl3) [500 MHz NMR,
50 °C] δ 9.11, 9.05 (d, 2H, J ) 5.0 Hz), 8.92 (s, 4H), 8.81 (s,
2H), 8.89 (s, 2H), 8.175, 7.785 (d, 12H, J ) 7.5 Hz), 2.298 (s,
6H), 1.637 (s, 27H), -2.761 (s, 2H); 13C NMR (DMSO-d6) δ
169.0, 156.1, 151.1, 148.4, 139.7, 135.1, 131.7-131.9, 124.2,
121.6, 121.2, 117.0, 35.7, 32.5, 25.6; MS (ESI) m/z (MH+, 898).
5,15-Bis(3,5-d ia ceta m id o-4-p yr id yl)-10,20-bis(4-ter t-bu -
tylp h en yl)p or p h yr in (III). 1H NMR (CDCl3) δ 9.27, 9.23 (dd,
8H, J ) 4.4), 9.15 (s, 4H), 8.49, 8.10 (d, 8H, J ) 8.1), 8.35 (s,
4H), 2.62 (s, 12H), 1.95 (s, 18H), -2.49 (s, 2H); MS (ESI) m/z
(MH+, 957).
5,10-Bis(3,5-d ia ceta m id o-4-p yr id yl)-15,20-bis(4-ter t-bu -
tylp h en yl)p or p h yr in (IV). 1H NMR (CDCl3) [500 MHz NMR,
50 °C] δ 8.98 (s, 2H), 8,95, 8.91 (dd, 4H, J ) 5.0 Hz), 8.89 (s,
2H), 8.77 (s, 2H), 7.90 (s, 2H), 8.17, 7.79 (d, 8H, J ) 7.5 Hz),
2.29 (s, 6H), 1.64 (s, 27H), -2.72 (s, 2H); 13C NMR (DMSO-d6)
δ 170.3, 150.9, 149.6, 138.6, 134.7,131.2∼132.6, 124.3, 121.5,
117.9, 115.8, 35.1, 31.9, 24.7; MS (ESI) m/z (MH+, 957).
5,10,15-Tr is(3,5-d ia cet a m id o-4-p yr id yl)-20-(4-ter t-b u -
tylp h en yl)p or p h yr in (V). 1H NMR (DMSO-d6) δ 10.51 (s,
6H), 8.81∼8.97 (m, 8H), 8.59 (s, 6H), 8.12, 7.77 (dd, 4H, J )
8.1), 2.16 (s, 18H), 1.51 (s, 18H), -3.10, (s, 2 H); 13C
NMR (DMSO-d6) δ 170.8, 153.5, 151.4, 150.1, 138.9, 135.2,
132.4∼132.5, 129.9, 129.2, 126.3, 124.7, 122.3, 119.2, 116.4,
35.7, 32.5, 25.4; MS (ESI) m/z (MH+, 1016).
1-Bu tyl-6-for m ylu r a cil (11). A solution of the butylacetal
10 (0.50 g, 2.07 mmol) in 20 mL of CH2Cl2 was cooled to -78
°C and treated with 1.6 mL of BBr3 and stirred for 2 h at that
temperature. The cold bath was removed and the solution was
allowed to reach room temperature. Saturated NaHCO3 (15
mL) was added until the pH reached 7-7.5. The organic layer
was removed and the aqueous layer was extracted with CH2-
Cl2. The extracts were combined and dried (with Na2SO4), and
the solvent was removed to afford 0.315 g of the aldehyde 11
as a white solid (87%), mp 146-147 °C. 1H NMR (CDCl3), δ
9.57 (s, 1H), 9.18 (br, s, 1H), 6.25 (s, 1H), 4.19 (t, 2H, J ) 7.3
Hz), 1.63-1.53, (m, 2H), 1.43-1.33, (m, 2H), 0.95, (t, 3H, J )
7.3 Hz); 13C NMR (CDCl3) δ 186.0, 162.6, 151.5, 147.6, 115.0,
44.5, 32.3, 20.5, 14.4; MS (ESI) m/z (M-H+, 195). Anal. Calcd
for C11H18N2O4: C, 55.09; H, 6.16; N, 14.28. Found: C, 55.49;
H, 6.13; N, 14.25.
5,10,15,20-Tet r a k is(1′-b u t yl-6′-u r a cyl)p or p h yr in a t o-
(Zn )(II) (XII). Pyrrole (69.5µL, 1.0 mmol), 1-butyl-6-formyl-
uracil (196 mg, 1.0 mmol) and zinc acetate (109.8 mg, 0.50
mmol) were added to a boiling mixture of acetic acid (7.5 mL)
and nitrobenzene (5.0 mL). The reaction mixture was refluxed
for 10 h while monitoring the yields spectroscopically, and then
taken to dryness under vacuum. The resulting solid was
purified by chromatography, eluting with ethyl acetate to
afford ∼5.1% 12. 1H NMR (DMSO-d6) δ 11.83 (br, s, 4H), 9.50
(m, 8H), 6.26 (s, 4H), 3.56∼3.08 (m, 8H), 1.10∼0.91 (m, 8H),
0.30∼0.08 (m, 8H), 0.00∼-0.60 (m, 12H); 13C NMR (CDCl3) δ
185.0, 163.4, 150.6, 142.3, 110.4, 41.9, 30.3, 20.9, 14.5; MS
(ESI) m/z (MH+, 1037 for ZnXII). Anal. Calcd for C52H52N12O8-
Zn: C, 60.15; H, 5.05; N, 16.18, for C52H52N12O8Zn with 1
H2O: C, 59.12; H, 5.16; N, 15.90. Found: C, 60.04; H, 5.24; N
15.92.
5,10,15,20-Tetr a k is(3,5-d ia ceta m id o-4-p yr id yl)p or p h y-
r in (VI). Pyrrole (69.5 µL, 1.0 mmol) and 2,6-diacetamido-4-
formylpyridine 7 (221 mg, 1.0 mmol) were added to boiling
propionic acid (10.0 mL). The reaction mixture was refluxed
for 2 h and then taken to dryness under vacuum. The resulting
solid was purified by chromatography on silica gel eluting with
ethanol/ethyl acetate (1:1) to yield 77.1 mg (29%) of VI. 1H
NMR (DMSO-d6) δ 10.52 (s, 8H), 8.99 (s, 8H), 8.60 (s, 8H),
2.16 (s, 24H), -3.10, (s, 2H); 13C NMR (DMSO-d6) δ170.7,
153.2, 150.1, 132.7, 119.4, 116.5, 25.4; MS (ESI) m/z (MH+,
1075). Anal. Calcd for [C56H50N16O8 plus 2 H2O] C, 60.45; H,
4.89; N, 20.16. Found: C, 60.92; H, 4.95; N, 20.01.
Dia ceta m id op yr id yl/ter t-bu tylp h en yl P or p h yr in s. 2,6-
diacetamido-4-formylpyridine 7 (2.763 g, 12.5 mmol) and 4-tert-
butylbenzaldehyde (1.63 g, 1.68 mL, 10.0 mmol) were added
to 450 mL of boiling propionic acid and then 1.56 mL (22.6
mmol) of pyrrole was added. The reaction mixture was refluxed
for 2 h at which time a 23.8% yield of the mixture of porphyrins
was detected spectroscopically. The solvent was removed under
vacuum, and the resulting solid was purified by chromatog-
raphy eluting with hexane (I), to chloroform (II), chloroform/
ethyl acetate (1:1) (III, IV), and ethyl acetate (V, VI) to get
the four porphyrins with two different motifs at the meso
positions. A second column using 10% v/v dioxane in chloro-
form is used to purify the fractions containing both III and
IV, and typically the tetrasubstituted derivatives are not
isolated as they can be made directly. Based on starting
Ur a cyl/ter t-Bu tylp h en yl P or p h yr in s. Pyrrole (0.83 mL,
12.0 mmol), 1-butyl-6-formyluracil (1.568 g, 8.0 mmol) and zinc
acetate (2.90 g, 13.2 mmol) were added to a boiling mixture of
acetic acid (90.0 mL) and nitrobenzene (60.0 mL). After 10 min.
4-tert-butylbenzaldehyde (0.652 g, 0.67 mL, 4.0 mmol) was
added to the reaction mixture and reflux continued for 10 h.
A 22.4% overall yield of the mixture of porphyrins was detected
spectroscopically in the reaction mixture. The solvent was
removed under vacuum. The resulting solid was purified by
chromatography using a solvent gradient (isolated yield, %
yield based on starting pyrrole): starting with hexane I (0.075
g, 2.37%), then chloroform VIII (0.225 g, 6.44%), then chloro-
form/ethyl acetate (1:1) IX (0.08 g, 2.21%), and X (0.10 g,
2.76%), and ethyl acetate XI (0.02 g, 0.51%), and XII (5 mg,
0.12%) to get the four uracyl/phenyl porphyrins. A second
column using a 15% v/v dioxane/chloroform solution as eluent
can be used to separate IX, X, and their rotameric forms. An
∼18%, 0.5 g, isolated yield is obtained for the collection of
porphyrins with relative yields of I, 15%; VIII, 45%; IX, 15%;
X, 20%; XI, 4%; XII, 1%. Typically the tetrasubstituted
derivatives are not isolated as they can be made directly.
5-(1′-Bu tyl-6′-u r a cyl)-10,15,20-tr is(4-ter t-bu tylp h en yl)-
1
p or p h yr in (VIII). H NMR (CDCl3) [500 MHz NMR] δ 9.11,
9.05 (dd, 4H, J ) 4.5 Hz), 8.92 (s, 4H), 8.81 (s, 1H), 8.12∼8.22,
7.81∼7.84 (m, 12H), 6.60 (s, 1H), 3.47 (t, 2H, J ) 8.0 Hz), 1.20
(m, 2H), 0.41(m, 2H), 0.08(t, 3H, J ) 7.5 Hz); 13C NMR (CDCl3)
δ 162.5, 156.9, 151.6, 151.7, 139.4, 135.1, 129.2∼132.6, 124.5,

6522 J . Org. Chem., Vol. 66, No. 20, 2001
Shi et al.
124.3, 123.56, 122.16, 110.31, 106.81, 47.62, 35.74, 32.48,
31.82, 19.94, 13.65; MS (ESI) m/z (MH+, 873).
nenberg for Gaussian 98 calculations, Dr. Michael
Blumenstein for high field NMR, Dr. Clifford Soll for
MS, and Diana Samaroo for careful reading of the
manuscript. The chemistry department infrastructure
is partially supported by NIH RCMI program GM3037,
and by the NSF for the ESI-MS. The Division of
Chemical Sciences, Geosciences and Biosciences, Office
of Basic Energy Sciences, U.S. Department of Energy,
under Contract DE-AC02-98CH10886, supported the
work at Brookhaven. We thank Dr. J onathan C. Hanson
for assistance with the crystallographic data collection
at beamline X7B of the National Synchrotron Light
Source.
5,15-Bis(1′-bu tyl-6′-u r acyl)-10,20-bis(4-ter t-bu tylph en yl)-
p or p h yr in a to(Zn )(II) (IX). 1H NMR (DMSO-d6): (IXa ) Râ
rotamer (CDCl3) 11.84 (s, 4H), 9.32, 8.83 (dd, 8H, J ) 4.8 Hz),
8.08, 7.81 (2d, 8H, J ) 8.2 Hz), 6.21 (s, 2H), 3.20∼3.32 (m,
4H), 1.56 (s, 18H), 1.05∼1.10 (m, 4H) 0.21∼0.23 (m, 4H), -0.20
(t, 6H, J ) 7.33 Hz); MS (ESI) m/z (MH+, 907).
(IXb) RR rotamer (CDCl3) 11.84(s, 4H), 9.32, 8.82 (dd, 8H,
) 4.76), 8.09, 7.77 (2d, 8H, J ) 7.3 Hz), 6.23 (s, 2H),
J
3.21∼3.34 (m, 4H), 1.54 (s, 18H), 1.03∼1.08 (m, 4H) 0.31∼0.35
(m, 4H), -0.11 (t, 6H, J ) 7.32); MS (ESI) m/z (MH+, 907).
5,10-Bis(1′-bu tyl-6′-u r acyl)-15,20-bis(4-ter t-bu tylph en yl)-
p or p h yr in a to(Zn )(II) (X). 1H NMR (DMSO-d6) 11.81 (s, 1H),
9.26, 8.79 (d, 4H, J ) 4.8 Hz), 8.75 (s, 4H), 8.12∼7.77 (m, 12H),
6.27 (s, 2H), 3.22∼3.34 (m, 2H), 1.55 (s, 27H), 1.01∼1.08 (m,
2H), 0.19∼0.26 (m, 2H), -0.18 (t, 3H, J ) 7.32 Hz); 13C NMR
(CDCl3) δ 162.00, 156.10, 151.13, 148.42, 139.75, 135.14,
131.70∼131.88, 124.21, 121.64, 121.15, 116.97, 35.68, 32.48,
25.58; MS (ESI) m/z (MH+, 907).
Su p p or tin g In for m a tion Ava ila ble: ESI-MS,1H and 13C
NMR for key intermediates and porphyrins, and a table of UV-
visible data for the porphyrins are presented. Experimental
crystallographic details, atomic coordinates, bond lengths and
angles, anisotropic thermal parameters, and schemes for
unsuccessful synthetic routes. This material is available free
of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. This work was funded by N.S.F.
CHE-9732950, PSC-CUNY-30 grants to C.M.D. We
gratefully acknowledge the help of Prof. J oseph Dan-
J O010108C