Design, synthesis, and photophysical characterization of water-soluble chlorins

Article abstract of DOI:10.1021/jo7026728

(Chemical Equation Presented) The use of chlorins as photosensitizers or fluorophores in a range of biological applications requires facile provisions for imparting high water solubility. Two free base chlorins have been prepared wherein each chlorin bears a geminal dimethyl group in the reduced ring and a water-solubilizing unit at the chlorin 10-position. In one design (FbC1-PO ₃H₂), the water-solubilizing unit is a 1,5-diphosphonopent-3-yl ("swallowtail") unit, which has previously been used to good effect with porphyrins. In the other design (FbC2-PO ₃H₂), the water-solubilizing unit is a 2,6-bis(phosphonomethoxy)phenyl unit. Two complementary routes were developed for preparing FbC2-PO₃H₂ that entail introduction of the protected phosphonate moieties either in the Eastern-half precursor to the chlorin or by derivatization of an intact chlorin. Water-solubilization is achieved in the last step of each synthesis upon removal of the phosphonate protecting groups. The chlorins FbC1-PO₃H₂ and FbC2-PO₃H₂ are highly water-soluble (>10 mM) as shown by ¹H NMR spectroscopy (D₂O) and UV-vis absorption spectroscopy. The photophysical properties of the water-soluble chlorins in phosphate-buffered saline solution (pH 7.4) at room temperature were investigated using static and time-resolved absorption and fluorescence spectroscopic techniques. Each chlorin exhibits dominant absorption bands in the blue and the red region (λ = 398, 626 nm), a modest fluorescence yield (Φ_f ≈ 0.11), a long singlet excited-state lifetime (τ = 7.5 ns), and a high yield of intersystem crossing to give the triplet state (Φ_isc = 0.9). The properties of the water-soluble chlorins in aqueous media are comparable to those of hydrophobic chlorins in toluene. The high aqueous solubility combined with the attractive photophysical properties make these compounds suitable for a wide range of biomedical applications.

Full text of DOI:10.1021/jo7026728

Design, Synthesis, and Photophysical Characterization of
Water-Soluble Chlorins
K. Eszter Borbas,† Vanampally Chandrashaker,† Chinnasamy Muthiah,† Hooi Ling Kee,‡
Dewey Holten,*,‡ and Jonathan S. Lindsey*,†
Department of Chemistry, North Carolina State UniVersity, Raleigh, North Carolina 27695-8204, and
Department of Chemistry, Washington UniVersity, St. Louis, Missouri 63130-4889
jlindsey@ncsu.edu; holten@wustl.edu
ReceiVed December 15, 2007
The use of chlorins as photosensitizers or fluorophores in a range of biological applications requires
facile provisions for imparting high water solubility. Two free base chlorins have been prepared wherein
each chlorin bears a geminal dimethyl group in the reduced ring and a water-solubilizing unit at the
chlorin 10-position. In one design (FbC1-PO3H2), the water-solubilizing unit is a 1,5-diphosphonopent-
3-yl (“swallowtail”) unit, which has previously been used to good effect with porphyrins. In the other
design (FbC2-PO3H2), the water-solubilizing unit is a 2,6-bis(phosphonomethoxy)phenyl unit. Two
complementary routes were developed for preparing FbC2-PO3H2 that entail introduction of the protected
phosphonate moieties either in the Eastern-half precursor to the chlorin or by derivatization of an intact
chlorin. Water-solubilization is achieved in the last step of each synthesis upon removal of the phosphonate
protecting groups. The chlorins FbC1-PO3H2 and FbC2-PO3H2 are highly water-soluble (>10 mM) as
shown by 1H NMR spectroscopy (D2O) and UV-vis absorption spectroscopy. The photophysical properties
of the water-soluble chlorins in phosphate-buffered saline solution (pH 7.4) at room temperature were
investigated using static and time-resolved absorption and fluorescence spectroscopic techniques. Each
chlorin exhibits dominant absorption bands in the blue and the red region (λ ) 398, 626 nm), a modest
fluorescence yield (Φf ≈ 0.11), a long singlet excited-state lifetime (τ ) 7.5 ns), and a high yield of
intersystem crossing to give the triplet state (Φisc ) 0.9). The properties of the water-soluble chlorins in
aqueous media are comparable to those of hydrophobic chlorins in toluene. The high aqueous solubility
combined with the attractive photophysical properties make these compounds suitable for a wide range
of biomedical applications.
Introduction
One particular challenge has entailed rendering the large,
hydrophobic tetrapyrrole macrocycles soluble in aqueous media.
A handful of naturally occurring porphyrins have moderate
A large number of areas of photomedicine and clinical
diagnostics can benefit from the availability of porphyrinic
molecules that are suitably tailored with regard to photochemical
attributes, solubility, and tethers for coupling to other molecules.
The chief applications encompass photodynamic therapy,1
optical imaging,2 flow cytometry,3 and combinatorial barcoding.4
(1) (a) Sternberg, E. D.; Dolphin, D.; Bru¨ckner, C. Tetrahedron 1998,
54, 4151-4202. (b) Pandey, R. K.; Zheng, G. In The Porphyrin Handbook;
Kadish, K. M., Smith, K. M., Guilard, R., Eds.; Academic Press: San Diego,
CA, 2000; Vol. 6, pp 157-230. (c) Bonnett, R. Chemical Aspects of
Photodynamic Therapy; Gordon and Breach Science Publishers: Amster-
dam, 2000. (d) Detty, M. R.; Gibson, S. L.; Wagner, S. J. J. Med. Chem.
2004, 47, 3897-3915. (e) Nyman, E. S.; Hynninen, P. H. J. Photochem.
Photobiol. B: Biol. 2004, 73, 1-28.
† North Carolina State University.
‡ Washington University.
10.1021/jo7026728 CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/15/2008
J. Org. Chem. 2008, 73, 3145-3158
3145

Borbas et al.
CHART 1
aqueous solubility, but the presence of a full complement of
functional groups renders selective synthetic modification rather
difficult. Synthetic porphyrins offer the possibility of gaining
control over the substitution pattern. Traditional approaches for
imparting water solubility to synthetic porphyrins have relied
on sulfonation of meso-aryl substituents or quaternization of
meso-pyridyl groups.5 Although modestly water-soluble, many
such compounds still tend to aggregate and precipitate from
solution over time.
A second challenge lies in the use of porphyrinic compounds
that absorb strongly in the red or near-infrared region of the
spectrum. The red or infrared region is of great interest owing
to the deep tissue penetration afforded by light in this spectral
region,6 and the availability of this comparatively underutilized
spectral region for diverse labeling applications.7 Chlorins and
bacteriochlorins absorb strongly in the red and near-infrared
regions, respectively.8 However, water-soluble derivatives of
chlorins and bacteriochlorins have generally not been available,
though a number of naturally occurring compounds have polar
side chains.9 Chlorin e6 (I)10 is a readily accessible derivative
of chlorophyll a and contains three ionizable carboxylic acid
groups, one of which is thrust over the plane of one face of the
molecule (Chart 1). The presence of three carboxylic acid groups
along with substituents at nearly all the other peripheral positions
of the macrocycle can impede synthetic manipulation, though
a number of water-soluble analogues have been prepared.11-13
Purpurinimides (II), which are also derived from chlorophylls,
afford a single site for derivatization, but the designs employed
to date have resulted in a hydrophobic macrocycle bearing an
appended polar group.14,15 Synthetic chlorins have typically
relied on the presence of up to four substituted meso-aryl groups
to impart polarity;16-21 examples include chlorins III17 and
(2) (a) Licha, K. Top. Curr. Chem. 2002, 222, 1-29. (b) Berg, K.; Selbo,
P. K.; Weyergang, A.; Dietze, A.; Prasmickaite, L.; Bonsted, A.; Engesaeter,
B. Ø.; Angell-Petersen, E.; Warloe, T.; Frandsen, N.; Høgset, A. J. Microsc.
2005, 218, 133-147.
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9, 112-117. (b) Perfetto, S. P.; Chattopadhyay, P. K.; Roederer, M. Nat.
ReV.: Immun. 2004, 4, 648-655. (c) Chattopadhyay, P. K.; Price, D. A.;
Harper, T. F.; Betts, M. R.; Yu, J.; Gostick, E.; Perfetto, S. P.; Goepfert,
P.; Koup, R. A.; De Rosa, S. C.; Bruchez, M. P.; Roederer, M. Nat. Med.
2006, 12, 972-977.
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635. (b) Krutzik, P. O.; Nolan, G. P. Nat. Methods 2006, 3, 361-368.
(5) Hambright, P. In The Porphyrin Handbook; Kadish, K. M., Smith,
K. M., Guilard, R., Eds.; Academic Press: San Diego, CA, 2000; Vol. 3,
pp 129-210.
(6) Dawson, J. B.; Barker, D. J.; Ellis, D. J.; Grassam, E.; Cotterill, J.
A.; Fisher, G. W.; Feather, J. W. Phys. Med. Biol. 1980, 25, 695-709.
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F.; Holten, D.; Lindsey, J. S. New J. Chem. 2008, 32, DOI: 10.1039/
b717803d.
(8) Gouterman, M. In The Porphyrins; Dolphin, D., Ed.; Academic
Press: New York, 1978; Vol. 3, pp 1-165.
IV16,20 shown in Chart 1. Access to such synthetic chlorins
typically entails reduction of the corresponding porphyrin.22 To
fulfill the promise of chlorins in photomedical applications,
versatile and compact molecular designs are required that afford
both water solubility and synthetic malleability.
Recently we reported the synthesis and characterization of a
series of highly water-soluble porphyrins for applications in flow
cytometry,23,24 fluorescence imaging,23,24 and molecular brachy-
therapy25 (Figure 1). The macrocycles were equipped with a
(9) Montforts, F.-P.; Glasenapp-Breiling, M. Fortschr. Chem. Org.
Naturst. 2002, 84, 1-51.
(10) (a) Hynninen, P. H. In Chlorophylls; Scheer, H., Ed.; CRC Press:
Boca Raton, FL, 1991; pp 145-209. (b) Pavlov, V. Y.; Ponomarev, G. V.
Chem. Heterocyc. Compds. 2004, 40, 393-425.
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2005, 46, 4161-4164.
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12, 6331-6340.
(13) Hargus, J. A.; Fronczek, F. R.; Vicente, M. G. H.; Smith, K. M.
Photochem. Photobiol. 2007, 83, 1006-1015.
(14) Zheng, G.; Graham, A.; Shibata, M.; Missert, J. R.; Oseroff, A. R.;
Dougherty, T. J.; Pandey, R. K. J. Org. Chem. 2001, 66, 8709-8716.
(15) Pandey, S. K.; Zheng, X.; Morgan, J.; Missert, J. R.; Liu, T.-H.;
Shibata, M.; Bellnier, D. A.; Oseroff, A. R.; Henderson, B. W.; Dougherty,
T. J.; Pandey, R. K. Mol. Pharm. 2007, 4, 448-464.
(16) Losev, A. P.; Nichiporovich, I. N.; Bachilo, S. M.; Egorova, G. D.;
Volkovich, D. I.; Solov’yov, K. N. J. Appl. Spectroscopy 1995, 62, 311-
320.
3146 J. Org. Chem., Vol. 73, No. 8, 2008

Water-Soluble Chlorins
swallowtail motifs with respect to the plane of the porphyrin
macrocycle was established with EPR spectroscopy of porphyrin
1
cation radicals (for hydrophobic swallowtail motifs),26 and H
NMR spectroscopy and molecular modeling for the polar-
terminated swallowtail derivatives.23,24 The porphyrin-alkyl-
diphosphonate solutions were found to be stable at room
temperature for extended periods of time (>1 year) when
shielded from light, and aggregation or precipitation was not
observed.23,24 A similar solubilizing unit bearing carboxylic acid
termini was recently reported for bis- and tris-porphyrin arrays.27
Only two chlorin-phosphonates have been reported previously,
an analogue of deuteroporphyrin wherein the carboxylic acids
have been replaced with phosphonic acids,28 and a synthetic
chlorin bearing a 4-phosphonophenyl unit at the chlorin 10-
position.29
In this paper, we describe the synthesis of a chlorin bearing
a phosphonate-terminated swallowtail motif. The chlorin mac-
rocycle was synthesized by a route developed recently,30 and
makes use of a swallowtail-substituted dipyrromethane24 that
was employed in the synthesis of the analogous swallowtail
porphyrins. The success of the diphosphonate-terminated swal-
lowtail motif prompted the design of a diphosphonate-substituted
aryl motif. The latter was investigated in an effort to achieve
increased versatility of design and synthesis. Two routes were
investigated for the synthesis of meso-2,6-bis(phosphonoalkoxy)-
phenyl-substituted chlorins. The photophysical properties of
chlorins of both types were investigated in aqueous solution to
assess the potential of the chlorins for use in photomedical and
diagnostic applications. Taken together, this work provides the
foundation for the synthesis of water-soluble chlorins for a range
of biological applications.
FIGURE 1. (A) Newman projection showing the alkyl chains of the
swallowtail motif above and below the plane of the tetrapyrrole
macrocycle. (B) Water-soluble porphyrin-alkyldiphosphonates prepared
previously for bioconjugation.23,24 (C) Water-soluble porphyrin-alkyl-
diphosphates prepared for targeted molecular brachytherapy.25
Results and Discussion
I. Molecular Design. The key design feature for both the
swallowtail-chlorin and the aryl-chlorin is the positioning of
nonhydrolyzable ionic groups (i.e., phosphonates) over both
faces of the chlorin macrocycle. The objective for the aryl-
chlorin was to identify a diphosphonate-substituted aryl unit that
would behave comparably to the alkyl swallowtails but may be
more accessible. Extensive use has been made of o-substituted
meso-aryl groups to encumber one or both faces of porphyrins
for solubilization in organic media31,32 and to obtain receptors,
catalysts and enzyme mimics.33-35 Much less work has been
devoted to meso-aryl groups bearing ionic groups appended to
symmetrically branched diphosphonate- or diphosphate-termi-
nated alkyl chain (‘swallowtail motif’), which resulted in
solubility in pure water at concentrations of up to 20 mM. The
origin of the high solubility stems from the projection of the
alkyl groups above and below the plane of the macrocycle.26
The alkyl groups block access to the π faces of the macrocycle;
moreover, the polar terminal groups are ionized (phosphate or
phosphonate) in aqueous media and are expected to suppress
aggregation by electrostatic repulsion. The conformation of the
(17) Griffiths, S. J.; Heelis, P. F.; Haylett, A. K.; Moore, J. V. Cancer
Lett. 1998, 125, 177-184.
(18) Murugesan, S.; Shetty, S. J.; Srivastava, T. S.; Samuel, A. M.;
Noronha, O. P. D. J. Photochem. Photobiol. B: Biol. 2002, 68, 33-38.
(19) Garcia, G.; Sol, V.; Lamarche, F.; Granet, R.; Guilloton, M.;
Champavier, Y.; Krausz, P. Bioorg. Med. Chem. Lett. 2006, 16, 3188-
3192.
(20) Kruk, M. M.; Braslavsky, S. E. J. Phys. Chem. A 2006, 110, 3414-
3425.
(21) Varamo, M.; Loock, B.; Maillard, P.; Grierson, D. S. Org. Lett.
2007, 9, 4689-4692.
(26) Thamyongkit, P.; Speckbacher, M.; Diers, J. R.; Kee, H. L.;
Kirmaier, C.; Holten, D.; Bocian, D. F.; Lindsey, J. S. J. Org. Chem. 2004,
69, 3700-3710.
(27) Inaba, Y.; Ogawa, K.; Kobuke, Y. J. Porphyrins Phthalocyanines
2007, 11, 406-417.
(28) Wedel, M., Walter, A.; Montforts, F.-P. Eur. J. Org. Chem. 2001,
1681-1687.
(29) Muthukumaran, K.; Loewe, R. S.; Ambroise, A.; Tamaru, S.-I.; Li,
Q.; Mathur, G.; Bocian, D. F.; Misra, V.; Lindsey, J. S. J. Org. Chem.
2004, 69, 1444-1452.
(22) (a) Vicente, M. G. H. In The Porphyrin Handbook; Kadish, K. M.,
Smith, K. M., Guilard, R., Eds.; Academic Press, San Diego, CA, 2000;
Vol. 1, pp 149-199. (b) Jaquinod, L. In The Porphyrin Handbook; Kadish,
K. M.; Smith, K. M.; Guilard, R., Eds.; Academic Press, San Diego, CA
2000; Vol. 1, pp 201-237. (c) Galezowski, M.; Gryko, D. T. Curr. Org.
Chem. 2007, 11, 1310-1338.
(30) Ptaszek, M.; McDowell, B. E.; Taniguchi, M.; Kim, H.-J.; Lindsey,
J. S. Tetrahedron 2007, 63, 3826-3839.
(31) Wagner, R. W.; Lindsey, J. S.; Turowska-Tyrk, I.; Scheidt, W. R.
Tetrahedron 1994, 50, 11097-11112.
(32) Loewe, R. S.; Tomizaki, K.-Y.; Youngblood, W. J.; Bo, Z.; Lindsey,
J. S. J. Mater. Chem. 2002, 12, 3438-3451.
(23) Borbas, K. E.; Mroz, P.; Hamblin, M. R.; Lindsey, J. S. Bioconjugate
Chem. 2006, 17, 638-653.
(33) (a) Collman, J. P.; Fu, L. Acc. Chem. Res. 1999, 32, 455-463. (b)
Collman, J. P.; Boulatov, R.; Sunderland, C. J.; Fu, L. Chem. ReV. 2004,
104, 561-588.
(24) Borbas, K. E.; Kee, H. L.; Holten, D.; Lindsey, J. S. Org. Biomol.
Chem. 2008, 6, 187-194.
(34) Suslick, K. S. In The Porphyrin Handbook; Kadish, K. M., Smith,
K. M., Guilard, R., Eds.; Academic Press: San Diego, CA, 2000; Vol. 4,
pp 41-63.
(25) Yao, Z.; Borbas, K. E.; Lindsey, J. S. New J. Chem. 2008, 32, 436-
451.
J. Org. Chem, Vol. 73, No. 8, 2008 3147

Borbas et al.
SCHEME 1
SCHEME 2
the 2- and 6-positions. Jux has employed the 2,6-bis(bromo-
methyl)-4-tert-butylphenyl unit at the four meso-positions of
an A4-porphyrin, which upon derivatization with 4-tert-butylpy-
ridine gave the octa-pyridinium porphyrin.36 Jux and co-workers
extended this approach to include alkylation of the 2,6-bis-
(bromomethyl)-4-tert-butylphenyl unit in a trans-A2B2-porphy-
rin37,38 or A4-porphyrin39 with diethyl malonate followed by
saponification, thereby yielding a facially encumbered porphyrin
bearing eight or sixteen carboxylate groups, respectively. Our
prior success in achieving solubilization of a porphyrin upon
use of a single diphosphonate-terminated swallowtail unit, and
the attractive features of the Jux designs, prompted us to focus
on a 2,6-bis(phosphonomethoxy)aryl unit. A key issue was
whether a single such meso-aryl group also would impart the
desired water solubility to the chlorin.
The swallowtail and aryl solubilizing units could be intro-
duced most straightforwardly at the 10-position of the chlorins
(Scheme 1). The 10-position is easily accessible during de noVo
chlorin synthesis given that the substituent is derived from an
aldehyde via an intermediate dipyrromethane (Eastern half). In
future designs, elaboration of the chlorin architecture can be
achieved at the 5-position by use of a 1-acyldipyrromethane,40
at the 15-position through electrophilic bromination followed
by palladium coupling reactions,41,42 or at other sites by
preparation of substituted Eastern or Western halves.43-45
II. Synthesis. A. Swallowtail-Chlorins. We have previously
reported the preparation of a swallowtail-aldehyde bearing
TBDMS protecting groups for the terminal alcohol groups and
application of the swallowtail-aldehyde in dipyrromethane
synthesis.23 It was expected that the TBDMS groups would not
resist the acid catalysis conditions used in the chlorin-forming
macrocyclization.30 Therefore, a benzyl ether protecting group
was investigated (Scheme 2). Selective protection of one
(35) Chen, Y.; Fields, K. B.; Zhang, X. P. J. Am. Chem. Soc. 2004, 126,
14718-14719.
(36) Jux, N. Org. Lett. 2000, 2, 2129-2132.
(37) Guldi, D. M.; Zilbermann, I.; Anderson, G.; Li, A.; Balbinot, D.;
Jux, N.; Hatzimarinaki, M.; Hirsch, A.; Prato, M. Chem. Commun. 2004,
726-727.
(38) Jee, J.-E.; Eigler, S.; Hampel, F.; Jux, N.; Wolak, M.; Zahl, A.;
Stochel, G.; van Eldik, R. Inorg. Chem. 2005, 44, 7717-7731.
(39) Jee, J.-E.; Eigler, S.; Jux, N.; Zahl, A.; van Eldik, R. Inorg. Chem.
2007, 46, 3336-3352.
(40) (a) Strachan, J.-P.; O’Shea, D. F.; Balasubramanian, T.; Lindsey,
J. S. J. Org. Chem. 2000, 65, 3160-3172. (b) Taniguchi, M.; Ra, D.; Mo,
G.; Balasubramanian, T.; Lindsey, J. S. J. Org. Chem. 2001, 66, 7342-
7354.
(41) Taniguchi, M.; Kim, M. N.; Ra, D.; Lindsey, J. S. J. Org. Chem.
2005, 70, 275-285.
(42) Taniguchi, M; Ptaszek, M; McDowell, B. E.; Lindsey, J. S.
Tetrahedron 2007, 63, 3840-3849.
(43) Laha, J. K.; Muthiah, C.; Taniguchi, M.; McDowell, B. E.; Ptaszek,
M.; Lindsey, J. S. J. Org. Chem. 2006, 71, 4092-4102.
(44) Laha, J. K.; Muthiah, C.; Taniguchi, M.; Lindsey, J. S. J. Org. Chem.
2006, 71, 7049-7052.
(45) Muthiah, C.; Ptaszek, M.; Nguyen, T. M.; Flack, K. M.; Lindsey,
J. S. J. Org. Chem. 2007, 72, 7736-7749.
hydroxy function of ethylene glycol gave 2-benzyloxyethanol
(1), which underwent OH f I exchange upon treatment with
I2/PPh3/imidazole to give 2-benzyloxy-1-iodoethane (2). Both
1 and 2 are known compounds,46 for which improved syntheses
were recently reported47 that are nearly identical to those we
developed (see Supporting Information). Deprotonation of CH3-
CN with LDA followed by bis-alkylation with 2 was employed
(46) Ludeman, S. M.; Bartlett, D. L.; Zon, G. J. Org. Chem. 1979, 44,
1163-1166.
(47) Schomaker, J. M.; Bhattacharjee, S.; Yan, J.; Borhan, B. J. Am.
Chem. Soc. 2007, 129, 1996-2003.
3148 J. Org. Chem., Vol. 73, No. 8, 2008

Water-Soluble Chlorins
SCHEME 3
to obtain nitrile 3a; however, the product obtained upon column
chromatography contained di-, mono- and trialkylated nitriles
3a, 3b and 3c in approximately 4:1:1 ratio, respectively, as
1
shown by H NMR analysis. The reduction of the mixture of
nitriles in CH2Cl2 at -78 °C using DIBALH gave the desired
aldehyde 4 in pure form after column chromatography.
Treatment48 of 4 with excess pyrrole in the presence of InCl3
gave the 5-substituted dipyrromethane 5 in 58% yield after
column chromatography. Vilsmeier formylation49 of dipyr-
romethane 5 at 0 °C followed by workup with aqueous NaOH
and chromatographic separation gave the 1-formyldipyr-
romethane 6 as a pale yellow oil in 55% yield. The facile
separation enabled removal of the diformylated side-product
without resort to use of dialkyl-tin complexation,49,50 a process
that is specific for the diformyl species. The simpler separation
explains the superior yield of 6 compared to that of 10 (Vide
infra). Bromination of the remaining R-pyrrolic position fol-
lowing standard procedures [NBS, THF, -78 °C]30,43 afforded
Eastern half 7 in excellent yield after column chromatography.
Eastern half 7 was condensed with unsubstituted tetrahy-
drodipyrrin 851 in a two-step one-flask synthesis30 to furnish
bis(benzyloxy)swallowtail-chlorin ZnC1-OBn in 28% yield as
a dark green solid after column chromatography on silica
(Scheme 3). In some preparations, laser desorption mass
spectrometry (LD-MS) and UV-vis analysis of the crude
product showed the presence of unmetalated species, although
the major product was always the zinc chlorin. The presence
of small quantities of free base chlorin was not a problem given
that quantitative demetalation occurs in the subsequent step of
the synthesis, which entails cleavage of the benzyl protecting
groups. Alternatively, uniform products could be obtained by
remetalation with zinc acetate (in CH2Cl2/MeOH, 5:1, 18 h) or
by demetalation with TFA in CH2Cl2 (1:2, 3 h). An example of
the latter procedure yielding FbC1-OBn is shown in Scheme 3.
Cleavage of the benzyl protecting groups was initially
attempted under hydrogenation conditions. However, direct
hydrogenolysis (H2, Pd/C) and catalytic transfer hydrogenation
(NH4HCO2, THF, Pd/C) both proved sluggish and gave only
partially deprotected products. Furthermore, partial reduction
of the chlorin to give the bacteriochlorin was observed upon
UV-vis absorption analysis of the reaction mixture. Quantitative
and rapid debenzylation occurred upon treatment of ZnC1-OBn
in dry CHCl3 with excess TMS-I. After simple aqueous-
organic workup, the product (FbC1-OH) was suitable for use
in the subsequent step. Clean samples could be obtained upon
chromatography either on neutral alumina or silica using CH2-
Cl2/MeOH as the eluent.
with aqueous NaHCO3. All methods for phosphonoester cleav-
age with trialkylsilyl halides stem from the seminal work of
Rabinowitz52 (for subsequent elaboration see ref 29 and 53).
The resulting crude FbC1-PO3H2 was obtained as a clear, dark
green solution. Purification on C-18-modified silica followed
by freeze-drying from water yielded FbC1-PO3H2 as a dark
green, voluminous solid.
B. Aryl-Chlorins. The target was a chlorin bearing a 2,6-
diphosphonate-substituted aryl group at the 10-position. The first
route relied on preparation of a dimethoxyphenyl-substituted
chlorin, which is then transformed into the diphosphonate
derivative. The second route entailed the preparation of the
diphosphonate-substituted benzaldehyde, which carries the
phosphonate groups (in protected form) through all steps leading
to the chlorin. The latter route circumvents manipulations of
the chlorin macrocycle, which are typically carried out at low
concentrations and with small amounts of reactants. Both routes
are described below.
Hydroxy-bromine exchange following reported procedures23,28
yielded the dibrominated chlorin FbC1-Br in excellent yield
(93% yield over two steps from ZnC1-OBn). The Arbuzov
reaction with P(OCH3)3 in THF (to ensure complete dissolution
of FbC1-Br) provided chlorin-alkyldiphosphonate FbC1-
PO3Me2 in moderate yield. Straightforward cleavage of the
methyl protecting groups was achieved by treatment of FbC1-
PO3Me2 with TMS-Br in dry CHCl3 followed by neutralization
(48) Laha, J. K.; Dhanalekshmi, S.; Taniguchi, M.; Ambroise, A.;
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(49) Ptaszek, M.; McDowell, B. E.; Lindsey, J. S. J. Org. Chem. 2006,
71, 4328-4331.
(50) Tamaru, S.-I; Yu, L.; Youngblood, W. J.; Muthukumaran, K.;
Taniguchi, M.; Lindsey, J. S. J. Org. Chem. 2004, 69, 765-777.
(51) Ptaszek, M.; Bhaumik, J.; Kim, H.-J.; Taniguchi, M.; Lindsey, J.
S. Org. Process Res. DeV. 2005, 9, 651-659.
(52) Rabinowitz, R. J. Org. Chem. 1963, 28, 2975-2978.
(53) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons, Inc.: New York, 1999; pp 666-
670.
J. Org. Chem, Vol. 73, No. 8, 2008 3149

Borbas et al.
SCHEME 4
temperature, followed by aqueous-organic workup. The result-
ing crude Eastern half was condensed with tetrahydrodipyrrin
8 (Western half) in the presence of p-TsOH‚H2O under argon,
affording a clear reddish-brown solution over 40-50 min. The
reaction mixture was neutralized (with 2,2,6,6-tetramethylpip-
eridine), concentrated, and exposed to metal-mediated oxidative
cyclization with Zn(OAc)2 and AgOTf in refluxing CH3CN
exposed to air. The resulting zinc chlorin ZnC2-OMe was
obtained in 40% yield after silica column chromatography.
Demetalation with TFA afforded the free base chlorin FbC2-
OMe in 92% yield. Demethylation using excess BBr3 followed
by alkylation of the crude product using (EtO)2P(O)CH2OTf54
yielded chlorin-aryldiphosphonate FbC2-PO3Et2 in 38% yield
after column chromatography. Hydrolysis of the phospho-
noesters followed by preparative reverse-phase column chro-
matography afforded water-soluble chlorin-aryldiphosphonate
FbC2-PO3H2 in excellent yield.
Route 2. As a more straightforward means to access FbC2-
PO3H2, we considered the introduction of the phosphonate
groups into the aryl aldehyde precursor of the chlorin. In
addition, a modified route30,45 to the chlorin was employed that
relies on a 9-formyltetrahydrodipyrrin (Western half)55 and a
1-bromodipyrromethane (Eastern half). The synthesis of the
target chlorin began with the preparation of known31 2,6-
dihydroxybenzaldehyde (Scheme 5). Treatment56 of 2,6-dihy-
droxybenzaldehyde (obtained from 2,6-dimethoxybenzaldehyde
in 54% yield)31 with (EtO)2P(O)CH2OTf in CH3CN in the
presence of K2CO3 gave aryl-diphosphonate 11 in 81% yield.
The condensation48 of 11 with pyrrole in the presence of InCl3
afforded dipyrromethane 12 in 88% yield. Following a stream-
lined procedure for chlorin formation,30,45 treatment of 12 with
1 equiv of NBS at -78 °C gave a mixture of the R-bromo-
dipyrromethane 12-r-Br, the R,R′-dibromodipyrromethane, and
1
the unreacted dipyrromethane (5:2:1 on the basis of H NMR
spectroscopy). Given the expected inert nature of the 1,9-
dibromodipyrromethane in the condensation step, the crude
sample of 12-r-Br was condensed with formyltetrahydrodipyr-
rin 1355 under the standard conditions of p-TsOH‚H2O catalysis.
The putative tetrahydrobiladiene-ab formed was subjected to
metal-mediated oxidative cyclization (2,2,6,6-tetramethylpi-
peridine, Zn(OAc)2 and AgOTf in refluxing CH3CN in the
presence of air) for 16 h, affording the zinc chelate of the 10-
arylchlorin ZnC2-PO3Et2 in 42% yield. Demetalation of ZnC2-
PO3Et2 with p-TsOH‚H2O afforded the free base chlorin FbC2-
PO3Et2 in 72% yield. The free base chlorin FbC2-PO3Et2
prepared in this manner agreed in all respects with the sample
of FbC2-PO3Et2 prepared as shown in Scheme 4.
The route shown in Scheme 5 to obtain the 10-arylchlorin
FbC2-PO3Et2 has the following noteworthy features compared
to that of Scheme 4: (i) the synthesis of FbC2-PO3Et2 was
achieved in 4 steps rather than 5; (ii) the reactions were
performed under milder conditions; and (iii) the overall isolated
yield of FbC2-PO3Et2 was greater (12% versus 2.6% starting
from 2,6-dimethoxybenzaldehyde).
C. Chemical Characterization. The hydrophobic chlorins
were characterized by 1H NMR spectroscopy, laser-desorption
mass spectrometry in the absence of a matrix (LD-MS),57 high-
Route 1. The synthesis begins with the preparation of a
dipyrromethane (9) bearing the 2,6-dimethoxyphenyl substituent
(Scheme 4). Condensation48 of commercially available 2,6-
dimethoxybenzaldehyde with excess pyrrole in the presence of
InCl3 afforded dipyrromethane 9 as a yellowish brown solid in
76% yield following column chromatography. Vilsmeier formy-
lation49 of 9 was carried out followed by removal of the diformyl
(54) Phillion, D. P.; Andrew, S. S. Tetrahedron Lett. 1986, 27, 1477-
1480.
(55) Kim, H.-J.; Dogutan, D. K.; Ptaszek, M.; Lindsey, J. S. Tetrahedron
2007, 63, 37-55.
(56) Jurecka, P.; Vojtisek, P.; Novotny, K.; Rohovec, J.; Lukes, I. J.
Chem. Soc., Perkin Trans. 2 2002, 1370-1377.
49,50
byproduct by complexation with Bu2SnCl2
whereupon
1-formyldipyrromethane 10 was obtained as a red solid in 26%
yield. Following a streamlined procedure for chlorin synthesis,30
10 was brominated by treatment with 1 equiv of NBS at low
3150 J. Org. Chem., Vol. 73, No. 8, 2008

Water-Soluble Chlorins
SCHEME 5
FIGURE 2. Interconversion of two rotamers of FbC1-PO3H2. Other
conformations are possible upon rotation of the swallowtail group such
that the tertiary proton (at the swallowtail branch point) is positioned
slightly above or below the face of the macrocycle (not shown).
PO3H2, FbC2-PO3H2) displayed excellent solubility in aqueous
1
solution (at least 10 mM), enabling H NMR analysis in D2O,
1
although the H NMR spectrum of FbC1-PO3H2 displayed
broad peaks. We attribute the signal broadening to the presence
of two rotamers (Vide infra), and partial deprotonation of the
phosphonate groups, giving rise to multiple species. The addition
of small amounts of pyridine-d5 to the D2O solution of FbC1-
PO3H2 did not improve the spectral quality. The spectrum of
FbC2-PO3H2 in D2O was sharp with all peaks readily assigned
(except for NH and OH owing to exchange). 31P NMR analysis
of the D2O solution of FbC1-PO3H2 gave a cluster of four peaks
centered at 23.0 ppm and a cluster of four peaks centered at
30.2 ppm, to be compared with two peaks for FbC1-PO3Me2
(centered at ∼34.1 ppm in CDCl3), a single peak for FbC2-
PO3H2 (10.35 ppm, in D2O), a single peak for FbC2-PO3Et2
(16.7 ppm, in CDCl3) and a single peak for ZnC2-PO3Et2 (14.0
ppm, in THF-d8). The data can be compared with that of the
following compounds: CH3PO3H2 (29.8 ppm),58 HOCH2PO3H2
(22.6 ppm),58 and CH3P(O)(OEt)2 (29.4 ppm),58 and related
alkylphosphonic acids.59 The chemical shift of phosphorus is
reported to be sensitive to ionization state.60 Further 31P NMR
studies, including variable-temperature measurements, were
performed of the swallowtail-chlorins (see Supporting Informa-
tion).
Each swallowtail-chlorin described herein exists as a dia-
stereomeric mixture of rotamers. The origin of the rotamers is
a consequence of the orientation of the two alkyl groups and
tertiary proton at the branch point of the swallowtail substituent
(Figure 2). The tertiary proton projects toward one or the other
of the flanking â-pyrrole protons, either H8 (ring B) or H12 (ring
(58) Mark, V.; Dungan, C. H.; Crutchfield, M. M.; van Wazer, J. R. In
Top. Phosphorus Chem. Grayson, M., Griffith, E. J., Eds.; John Wiley &
Sons, Inc.: New York, 1967; Vol. 5, pp 227-457.
resolution FAB-MS or ESI-MS spectrometry, UV-vis absorp-
tion spectroscopy, and where permitted by solubility and sample
size, 13C NMR spectroscopy. Chlorin FbC1-Br gave a poor
quality H NMR spectrum in a range of solvents (THF-d8,
CDCl3, CD3OD, and mixtures thereof), presumably due to
(59) (a) Maier, L. Z. Anorg. Allg. Chem. 1972, 394, 117-124. (b) van
Wazer, J. R.; Callis, C. F.; Shoolery, J. N.; Jones, R. C. J. Am. Chem. Soc.
1956, 78, 5715-5726. (c) Tebby, J. C. In Phosphorous-31 NMR Spectros-
copy in Stereochemical Analysis; Verkade, J. G., Quin, L. D., Eds.; VCH
Publishers: Deerfield Beach, FL, 1987; pp 1-60. (d) Loewe, R. S.;
Ambroise, A.; Muthukumaran, K.; Padmaja, K.; Lysenko, A. B.; Mathur,
G.; Li, Q.; Bocian, D. F.; Misra, V.; Lindsey, J. S. J. Org. Chem. 2004, 69,
1453-1460.
1
aggregation. The deprotected chlorin-diphosphonates (FbC1-
(60) (a) Moedritzer, K. Inorg. Chem. 1967, 6, 936-939. (b) Broeren,
M. A. C.; de Waal, B. F. M.; van Genderen, M. H. P.; Sanders, H. M. H.
F.; Fytas, G.; Meijer, E. W. J. Am. Chem. Soc. 2005, 127, 10334-10343.
(57) Srinivasan, N.; Haney, C. A.; Lindsey, J. S.; Zhang, W.; Chait, B.
T. J. Porphyrins Phthalocyanines 1999, 3, 283-291.
J. Org. Chem, Vol. 73, No. 8, 2008 3151

Borbas et al.
pyrrole ring (ring D in Figure 2). The standard convention8
places the saturated pyrrole ring along the x-axis; this choice
places the central protons of the free base chlorin along the
y-axis. Within Gouterman’s four-orbital model, the near-UV
(Bx and By) and visible (Qx and Qy) transitions of the chlorin
are derived primarily from linear combinations of the electronic
configurations resulting from one-electron promotions among
the frontier molecular orbitals.
The near-UV Soret (B) absorption contains overlapping
Bx(0,0) and By(0,0) components. The peak wavelength of the
most intense Soret feature for each chlorin (398 nm, FbC1-
PO3H2; 399 nm, FbC2-PO3H2) is listed in Table 1 along with
the maxima of the other features in the absorption spectra. The
longest-wavelength feature in each spectrum is the Qy(0,0) band
(626 nm, FbC1-PO3H2; 628 nm, FbC2-PO3H2); this is the
origin transition from the ground to lowest-energy singlet excited
state. Table 1 also shows the ratio of the peak intensities of the
B(0,0) and Qy(0,0) bands. This ratio has been used extensively
as a first-order gauge of the variation in Qy intensity among
chlorins, and typically is more reliable than trends based on
molar absorption coefficients (determined with tiny quantities
of material).43,61 For both chlorins, the peak intensity of the
Qy(0,0) band is roughly 7-fold lower than that of the Soret
maximum (Table 1). A weaker Qy(1,0) vibronic component lies
in the vicinity of 580 nm, which is ∼1400 cm-1 above the Qy
origin band. The most prominent of the features between the B
and Qy manifolds is the Qx(1,0) band (501 nm, FbC1-PO3H2;
498 nm, FbC2-PO3H2). This vibronic satellite is more intense
than the Qx(0,0) origin transition at ∼530 nm.
FIGURE 3. Normalized absorption (solid) and fluorescence (dashed)
spectra of FBC1-PO3H2 (A) and FBC2-PO3H2 (B) in PBS at room
temperature.
C). Rings B and C are not equivalent to each other owing to
their location with respect to the reduced ring (ring D) of the
chlorin macrocycle. The rotamers were typically observed in
ratios of 40:60 to 25:75 (depending on the end-groups of the
1
swallowtail motif) by H NMR spectroscopy. The diagnostic
Although the absorption spectra of water-soluble chlorins
FbC1-PO3H2 and FbC2-PO3H2 contain all the main charac-
teristics of the spectra for typical hydrophobic chlorins, there
are several modest differences. To facilitate such comparisons,
Table 1 also lists the properties of two synthetic chlorins (FbC3
and FbC4) that we have studied recently in the nonpolar organic
solvent toluene (Chart 2).61,62 Chlorin FbC3 contains no
substituents other than the chemically stabilizing geminal
dimethyl groups in the reduced pyrrole ring (also present in
FbC1-PO3H2 and FbC2-PO3H2). Chlorin FbC4 differs from
FbC3 by the addition of a 10-mesityl group. Thus, the closest
comparison is between FbC4 and FbC2-PO3H2; the 10-aryl
group of the latter chlorin bears the terminal phosphonate groups
that impart water solubility.
features were the inner NH protons, the CH2 moiety of the
reduced ring, and the meso-protons (particularly H5), whereas
other regions of the spectrum were quite complex. In particular,
the aromatic region consisted of a large number of signals, only
some of which could be unambiguously assigned after extensive
gCOSY and NOESY experiments. NOESY experiments con-
ducted on ZnC1-OBn were inconclusive concerning the AB
versus CD direction of orientation of the tertiary proton of the
swallowtail motif. 31P NMR spectra also were consistent with
the presence of two rotamers. HPLC analysis of a pure sample
of FbC1-PO3H2 showed two peaks (74:26 ratio), which were
attributed to the two rotamers. By contrast, aryl-chlorin FbC2-
PO3H2, for which rotamers are not expected, gave a single peak.
Analogous effects of the swallowtail group on the 1H NMR
features also were observed previously with the swallowtail-
porphyrins (e.g., those displayed in Figure 1).23 However, unlike
the chlorins, the two halves of the porphyrin macrocycle
disposed about the 5,15-axis are identical with each other
(ignoring NH tautomers in the free base porphyrins); thus, no
isomers were present. The energy of activation for rotation about
the C-C bond that joins the swallowtail branch carbon and the
meso carbon of the free base swallowtail-porphyrin was
estimated by variable temperature 1H NMR spectroscopy to be
Inspection of Table 1 indicates that the Soret maximum of
FbC2-PO3H2 is red-shifted by 3 nm from that of FbC4 (an
∼190 cm-1 downshift in energy), while the Qy(0,0) band is blue-
shifted by 9 nm (an ∼225 cm-1 upshift in energy). These small
spectral differences are accompanied by a change in the relative
intensities of the two bands. In particular, the B(0,0)/Qy(0,0)
peak-intensity ratio is 6.7 for FbC2-PO3H2 and 2.7 for FbC4
(Table 1). Thus, the presence of the phosphonate groups in
FbC2-PO3H2 results in an ∼60% reduction of the relative
Qy(0,0) intensity. This difference does not require the presence
of a 10-aryl core in the water-solubilizing entity. This point
follows because FbC1-PO3H2, which utilizes instead a diphos-
phonate-terminated aliphatic swallowtail motif, has a B(0,0)/
68-70 kJ‚mol-1 23
.
III. Photophysical Characterization. A. Absorption Spec-
tra. The electronic ground-state absorption spectra of water-
soluble chlorins FbC1-PO3H2 and FbC2-PO3H2 in phosphate-
buffered saline (PBS) solution at room temperature are shown
in Figure 3 (solid lines). The spectra for the two compounds
are very similar to one another and exhibit the standard features
observed for typical metal-free chlorins in organic solvents. The
main features are x or y polarized due to the directional
inequivalence that results primarily from saturation of one
(61) Kee, H. L.; Kirmaier, C.; Tang, Q.; Diers, J. R.; Muthiah, C.;
Taniguchi, M.; Laha, J. K.; Ptaszek, M.; Lindsey, J. S.; Bocian, D. F.;
Holten. D. Photochem. Photobiol. 2007, 83, 1110-1124.
(62) Kee, H. L.; Kirmaier, C.; Tang, Q.; Diers, J. R.; Muthiah, C.;
Taniguchi, M.; Laha, J. K.; Ptaszek, M.; Lindsey, J. S.; Bocian, D. F.;
Holten, D. Photochem. Photobiol. 2007, 83, 1125-1143.
3152 J. Org. Chem., Vol. 73, No. 8, 2008

Water-Soluble Chlorins
TABLE 1. Summary of Photophysical Propertiesa
absorbance
emission
f
g
B(0,0)
(nm)
Qx (1,0)
(nm)
Qy(0,0)
(nm)
B(0,0)b/
Qy(0,0)
Qy(0,0)
(nm)
[(kf)-1
(ns)
]
[(knr)-1
]
(ns)
c
e
compound
solvent
Φf
τ
d (ns)
Φisc
FbC1-PO3H2
FbC2-PO3H2
FbC3
PBS
PBS
toluene
toluene
398
399
398
396
501
498
492
499
626
628
633
637
7.3
6.7
2.4
2.7
629
631
633
637
0.12
0.11
0.20
0.22
7.7
7.5
9.0
10
0.9
0.9
0.9
0.9
64
68
46
45
8.8
8.4
11
FbC4
11
a Measurements at room temperature. Data for FbC3 and FbC4 are from refs 61 and 62. b Peak-intensity ratio of the B(0,0) and Qy(0,0) bands. c Fluorescence
quantum yield of compound (5%. d Singlet excited-state lifetime (5%. e Intersystem crossing (triplet) yield (10%. f Radiative rate constant for decay of
the Qy excited-state determined from eq 3. g Net nonradiative rate constant for decay of the Qy excited-state determined from eq 4.
CHART 2
water-soluble chlorins are roughly 40% lower than the values
for parent chlorin FbC3 (0.20) and its 10-mesityl analogue
FbC4 (0.22) in toluene, and the lifetimes are reduced roughly
20% (Table 1).
The yields of intersystem crossing to give the triplet excited
state (Φisc) for both water-soluble chlorins FbC1-PO3H2 and
FbC2-PO3H2 are the same as for the two benchmark hydro-
phobic chlorins FBC3 and FBC4 within experimental uncer-
tainty (0.9 ( 0.1). This value is comparable to those reported
for the unsubstituted chlorin (0.78)63 and tetrakis(m-hydroxy-
phenyl)chlorin (0.89)64 in organic solvents, but is somewhat
larger than that for tetrakis(4-sulfonatophenyl)chlorin (0.48)20
in aqueous media.
C. Excited-State Decay Pathways and Rates. The modest
differences in photophysical properties of the water-soluble and
hydrophobic chlorins can be analyzed with the aid of eqs 1-4.
τ ) (kf + knr)-1
Φf ) kf ÷ (kf + knr)
kf ) Φf ÷ τ
(1)
(2)
(3)
(4)
Qy(0,0) intensity ratio of 7.3, which is only slightly larger than
that for FbC2-PO3H2.
knr ) (1 - Φf) ÷ τ
In summary, these comparisons along with the other absorp-
tion spectral data in Table 1 indicate the following: (i) Starting
with the parent chlorin FbC3, the incorporation of a 10-mesityl
group to give FbC4 results in a small (4 nm) red shift and small
(10%) decrease in the relative intensity of the Qy(0,0) band;
this trend continues upon the incorporation of additional meso-
aryl rings.61,62 (ii) Starting with the parent chlorin FbC3, the
incorporation of a diphosphonate-bearing water-solubilizing
group at the 10-position, based on either an aromatic or aliphatic
core, leads to a small (5-7 nm) blue shift and a modest (60%)
decrease in the relative Qy intensity. This modest absorption-
intensity decrease is paralleled by differences in the Qy excited-
state fluorescence yield and decay characteristics described
below, with the common link being the radiative transition
probability.
B. Fluorescence Spectra, Quantum Yields, and Lifetimes.
The Qy excited-state fluorescence spectra of chlorins FbC1-
PO3H2 and FbC2-PO3H2 are shown in Figure 3 (dashed lines).
For each compound, the main feature is the Qy(0,0) band and
the weaker feature at longer wavelength is the Qy(0,1) vibronic
satellite. The Qy(0,0) peak for each chlorin is shifted 3 nm from
the corresponding absorption maximum (Table 1), which
In these equations, the Qy excited-state lifetime (τ) and
fluorescence yield (Φf) are expressed in terms of the rate
constants for radiative (spontaneous fluorescence) decay (kf) and
nonradiative decay (knr). Here, knr ) (kic + kisc) is the sum of
the rate constants for internal conversion to the ground state
and intersystem crossing to the triplet excited state. On the basis
of eqs 3 and 4 and the measured fluorescence yields and excited-
state lifetimes, the last two columns of Table 1 list the values
of (kf)-1 and (knr)-1 expressed in nanoseconds.
The calculated radiative rates kf for water-soluble chlorins
FbC1-PO3H2 and FbC2-PO3H2 in aqueous media are reduced
by ∼25% from those for the hydrophobic chlorins FbC and
FbC-M10 in toluene. This factor is somewhat smaller than the
∼60% reduction factor obtained above for the relative Qy
absorption intensities of the water-soluble versus hydrophobic
reference chlorins. However, the effects are in the same direction
and the agreement is good considering experimental uncertain-
ties. The connection between these two observables is the direct
proportionality of the Einstein coefficients for spontaneous
fluorescence and induced absorption. Thus, the modest diminu-
tion of the Qy absorption intensity and fluorescence yield upon
incorporation of the water-solubilizing motifs used in FbC1-
PO3H2 and FbC2-PO3H2 go hand in hand.
corresponds to a Stokes shift of ∼75 cm-1
.
The fluorescence quantum yields (Φf) for deoxygenated
FbC1-PO3H2 and FbC2-PO3H2 in PBS are 0.12 and 0.11,
respectively. The corresponding lifetimes of the lowest-energy
excited singlet state (Qy), measured by fluorescence methods,
are τ ) 7.7 and 7.5 ns. The fluorescence yields for the two
(63) Gradyushko, A. T.; Sevchenko, A. N.; Solovyov, K. N.; Tsvirko,
M. P. Photochem. Photobiol. 1970, 11, 387-400.
(64) Bonnett, R.; Charlesworth, P.; Djelal, B. D.; Foley, S.; McGarvey,
D. J.; Truscott, T. G. J. Chem. Soc., Perkin Trans. 2 1999, 325-328.
J. Org. Chem, Vol. 73, No. 8, 2008 3153

Borbas et al.
Several factors could contribute to the modest reductions in
radiative absorption and fluorescence decay rates, and small
shifts in spectral positions, for the chlorins upon incorporation
of a water-solubilization motif. One is a purely electronic effect
owing to the attachment at the meso position of the alkyl or
aryl substituent for water solubilization. Such substituent effects
can modulate the relative energies of the frontier molecular
orbitals of the chlorin and thereby the energies and oscillator
strengths of the optical transitions.61,62 However, the fact that
the water-solubilizing motifs based on 10-aryl and 10-alkyl cores
give such similar effects suggests that purely inductive or
conjugative effects are likely not the sole source of the effects
on the radiative probabilities. A second factor involves slight
distortion of the chlorin macrocycle by the solubilizing groups,
with resulting electronic consequences. However, our studies
of the effects of the swallowtail motif on the electronic properties
of porphyrin analogues indicates that such structural-based
perturbations are not likely to be substantial.26 A third factor
derives from the partial ionization of the phosphonate groups
at the pH (7.4) of the PBS buffer. Calculations have shown
that the presence of a charge 3-4 Å above a bacteriochlorin
can shift the energies of the frontier molecular orbitals and
thereby alter the optical spectra.65 Such charge-induced pertur-
bations likely play a role, along with the other factors described
above, in the small spectral shifts and modest changes in
radiative transition probabilities caused by the water-solubilizing
groups utilized in FbC1-PO3H2 and FbC2-PO3H2.
In principle, a reduction in kf may also transform into a change
in the Qy excited-state lifetime. However, the effect is expected
to be much smaller than that on the quantum yield. This
difference arises because of the following: (i) The values of τ
and Φf depend markedly differently on kf (eq 1 versus 2). (ii)
The net nonradiative decay rate knr dominates over kf in
determining the excited-state lifetime for the chlorins (via eq
1). This latter point is indicated by the fact that the fluorescence
accounts for a small fraction of the Qy excited-state decay for
FbC1-PO3H2 and FbC2-PO3H2, as well as for FbC3 and
FbC4, as is reflected in the fluorescence yields (Table 1). (iii)
There may be a small increase in the net nonradiative rate knr
for the water-soluble versus hydrophobic chlorins (Table 1) that
partially offsets the effect of a diminution in kf (eq 1). The net
result is that the Qy excited-state lifetimes (∼7.5 ns) for water-
soluble chlorins FbC1-PO3H2 and FbC2-PO3H2 are only ∼20%
shorter than those for the hydrophobic chlorins FbC3 and FbC4
(Table 1).
PO3H2, rotation about the single methylene group between the
aryl oxygen and the phosphonate moiety also enables confor-
mational freedom, as does limited torsional motion about the
carbon-carbon bond between the chlorin meso-carbon and the
aryl unit.
(2) The pKa values expected for the phosphonic acid moieties
can be gauged by comparison with similar reference com-
pounds: n-propylphosphonic acid exhibits pK1 ) 2.49 and pK2
) 8.18; hydroxymethylphosphonic acid exhibits pK1 ) 1.91
and pK2 ) 7.15.66 Thus, at pH 7.4 each phosphonic acid group
is expected to bear 1-2 negative charges owing to ionization.
The presence of two phosphonate moieties in each solubil-
izing unit creates further structural diversity in aqueous solution,
given that the two phosphonates on opposite sides of the chlorin
macrocycle can have predominant charge combinations of
-1/-1, -1/-2, and -2/-2. The multiplicity of charge states
and the conformational motion of each solubilizing unit is
expected to give rise to a distribution of molecular species in
solution. The collection of such chlorin-diphosphonates may
give rise to a small spread of properties in a given solution.
In summary, the modest differences in photophysical proper-
ties of the water-soluble porphyrins compared to hydrophobic
analogues in organic solvents may arise from (1) small changes
in electronic structure due to a different pattern of substituents,
(2) a difference in electronic/physical structure due to electronic/
steric effects of the water-solubilizing entity, particularly if the
terminal (e.g., phosphonate) group extends over the face of the
macrocycle and is ionized, (3) the charged character of the
water-solubilizing group upon ionization, and (4) differences
in the media used to solubilize and study the molecules. On
this latter point, the photophysical properties of hydrophobic
porphyrins normally vary minimally with solvent characteristics,
particularly free base species for which axial ligation of the
solvent to the central metal is not relevant. The same is likely
true of the water-soluble versus hydrophobic porphyrins, except
for the potentially significant role that the medium plays in the
ionization state of the water-solubilizing entity. However, solvent
effects alone would not appear to underlie the systematic
differences in photophysical properties (Qy absorption strength,
Φf, τ) connected by the radiative rate. The distributions of
rotamers and ionization states associated with the water-
solubilizing entities most likely give rise to a spread of properties
for a given chlorin in a given medium. Regardless, the
photophysical properties of the water-soluble chlorins studied
here are quite similar to those of the hydrophobic analogues.
It should be noted that more detailed analysis of spectroscopic
results beyond the scope of the present paper would take into
account the structures of the chlorin-diphosphonates that are
present in aqueous solution. A distribution of structures is
expected owing to the conformations of the solubilizing units
and the ionization of each of the two phosphonate moieties in
each solubilizing unit:
(1) Considerable conformational motion is available to the
phosphonate moieties for each type of chlorin-diphosphonate,
FbC1-PO3H2 and FbC2-PO3H2. In the swallowtail-chlorin
FbC1-PO3H2, two rotamers are present (Vide supra). In
addition, rotation about the two methylene groups between the
branch point and the phosphonate moiety of the swallowtail
unit can result in the projection of the phosphonate directly over
or away from the chlorin macrocycle. In the aryl-chlorin FbC2-
Conclusions and Outlook
Two designs have been developed to achieve high aqueous
solubility of relatively compact, sparsely substituted chlorins.
Both designs rely on the projection of charged, phosphonate
substituents above and below the plane of the chlorin macro-
cycle, thereby suppressing π-π interaction between chlorin
macrocycles. The core unit in each design is either a pentyl
group in a swallowtail architecture or a 2,6-dimethoxyphenyl
unit. The diphosphonate-terminated swallowtail unit provides
the most compact design, yet requires a more lengthy synthesis.
The diphosphonate-substituted aryl unit can be introduced either
by derivatization of a 2,6-dihydroxyphenyl-substituted chlorin
or by use of a diphosphonate-substituted benzaldehyde as a
precursor to the chlorin.
(65) Hanson, L. K.; Fajer, J.; Thompson, M. A.; Zerner, M. C. J. Am.
Chem. Soc. 1987, 109, 4728-4730.
(66) Freedman, L. D.; Doak, G. O. Chem. ReV. 1957, 57, 479-523.
3154 J. Org. Chem., Vol. 73, No. 8, 2008

Water-Soluble Chlorins
ns time course) with the time constant fixed at the fluorescence
lifetime. In the second method, the triplet bleaching was measured
directly at a long (∼20 ns) time delay. The triplet yields obtained
using the different methods were averaged.
The chlorins bearing deprotected phosphonates (FbC1-
PO3H2, FbC2-PO3H2) are soluble at >10 mM in water. The
swallowtail unit used herein (pent-3-yl) provides a two-atom
linker between the carbon attached to the chlorin meso-carbon
whereas the aryl unit used herein provides a 3-atom linker; both
designs afford water solubility. The water-soluble chlorins in
aqueous media exhibit photophysical features that are compa-
rable to those of hydrophobic chlorins in toluene. The water-
soluble chlorins exhibit only small perturbations to the optical
spectral positions, a modest diminution in the intensity of the
long-wavelength absorption band and the fluorescence yield (Φf
≈ 0.1), and little change in the lifetime of the lowest singlet
excited singlet state, which remains quite long (τ ≈ 7.5 ns).
The long lifetime may prove very attractive for applications in
optical imaging. The fluorescence features are similar to those
of the tetrakis(4-sulfonatophenyl)chlorin (IV, Chart 1) at pH
7.4, which exhibits Φf ) 0.086 and τ ) 8.5 ns.16,20 The
collective photophysical properties are quite attractive in
conjunction with aqueous solubility in the millimolar range.
Furthermore, recent insights into the effects of auxochromes
on the photophysical properties of synthetic chlorins61,62 should
allow tuning of the characteristics of the water-soluble chlorins
for a variety of applications.
1,5-Dibenzyloxy-3-cyanopentane (3). A solution of HMPA
(11.0 mL) and LDA (15.2 mL of a 2.0 M solution in THF/hexanes/
ethylbenzene) in dry THF (23 mL) at -78 °C under argon was
treated with CH3CN (1.62 mL, 31.6 mmol). The solution was stirred
for 30 min, whereupon 2 (6.86 g, 26.2 mmol) in THF (23 mL)
was added dropwise. Stirring was continued for 2 h, after which a
second portion of LDA (15.2 mL) was added. The solution was
stirred for 30 min, whereupon a second portion of 2 (6.86 g, 26.2
mmol) in THF (23 mL) was added dropwise. The reaction was
allowed to proceed for 2 h. Saturated aqueous NH4Cl was added,
and the mixture was allowed to reach room temperature. Diethyl
ether was added, the phases were separated, and the aqueous layer
was extracted with diethyl ether. The organic extract was washed
with water and brine, dried over Na2SO4, and concentrated. Column
chromatography [silica, hexanes/diethyl ether (3:1)] afforded a
colorless liquid (8.94 g, 4:1:1 mixture of 3a:3b:3c). The following
data from analysis of the mixture are for 3a: 1H NMR (300 MHz)
δ 1.84-1.94 (m, 4H), 3.08-3.13 (m, 1H), 3.63-3.70 (m, 4H), 4.53
(s, 4H), 7.32-7.34 (m, 10H); ESI-MS obsd 310.17995, calcd
310.18016 [(M + H)+, M ) C20H23NO2]. The sample was used
without further purification.
1,5-Dibenzyloxy-3-formylpentane (4). A solution of 3 (8.94 g,
4:1:1 mixture of 3a:3b:3c) in dry CH2Cl2 (134 mL) at -78 °C
under argon was treated with DIBALH (50.8 mL of a 1.0 M solution
in CH2Cl2), and the reaction was allowed to proceed for 1 h. Water
(6.3 mL) was added, and the mixture was allowed to reach room
temperature. Aqueous NaOH (6.3 mL, 2.5 M solution) was added,
and stirring was continued for 15 min. Water (12.6 mL) was added,
and the suspension was stirred for 15 min. A large amount of Na2-
SO4 was added. The resulting mixture was filtered. The filtrate was
concentrated under reduced pressure, and chromatographed [silica,
hexanes/diethyl ether (85:15)] to afford a colorless liquid (3.94 g,
56%): 1H NMR (300 MHz) δ 1.75-1.84 (m, 2H), 1.98-2.05 (m,
2H), 2.60-2.64 (m, 1H), 3.51 (t, J ) 6.2 Hz, 4H), 4.47 (s, 4H),
7.26-7.36 (m, 10H), 9.66 (d, J ) 1.8 Hz, 1H); 13C NMR (75 MHz)
δ 29.5, 47.0, 67.9, 73.3, 127.87, 127.89, 128.6, 138.4, 204.5; ESI-
MS obsd 335.1620, calcd 335.1617 [(M + Na)+, M ) C20H24O3].
5-(1,5-Dibenzyloxypent-3-yl)dipyrromethane (5). Following a
standard procedure,48 aldehyde 4 (762 mg, 2.44 mmol) was
dissolved in pyrrole (17.4 mL, 0.250 mol), and the solution was
flushed with argon for 10 min. InCl3 (56.0 mg, 0.0670 mmol) was
added, and the reaction was allowed to proceed for 3 h. The reaction
was quenched by addition of powdered NaOH (301 mg, 7.53
mmol). The mixture was stirred for 45 min. The mixture was
filtered. The filtrate was concentrated under reduced pressure.
Chromatography [silica, hexanes/CH2Cl2/ethyl acetate (7:2:1)]
afforded a pale yellow oil (604 mg, 58%): 1H NMR (300 MHz) δ
1.46-1.53 (m, 2H), 1.74-1.83 (m, 2H), 2.40-2.48 (m, 1H), 3.49-
3.59 (m, 4H), 4.37 (d, J ) 4.5 Hz, 1H), 4.49 (s, 4H), 6.00 (app s,
2H), 6.13-6.14 (m, 2H), 6.56 (app s, 2H), 7.30-7.35 (m, 10H),
8.51 (br, 2H); 13C NMR (75 MHz) δ 32.4, 37.1, 40.8, 45.3, 69.5,
73.4, 106.8, 108.3, 116.4, 127.9, 128.0, 128.7, 131.9, 138.5, 149.9;
FAB-MS obsd 428.2476, calcd 428.2464 (C28H32N2O2).
Experimental Section
Photophysical Measurements. The photophysical properties of
FbC1-PO3H2 and FbC2-PO3H2 were investigated at room tem-
perature using 1× PBS (phosphate-buffered saline; 137 mM NaCl,
2.7 mM KCl, 10 mM Na3PO4, pH 7.4) as the solvent. Static
absorption and fluorescence measurements were performed using
dilute (µM) solutions, as described previously.67,68 Fluorescence
lifetimes were obtained using a phase modulation technique.67
Argon-purged solutions with an absorbance of e0.10 at the Soret-
band excitation wavelength were used for the fluorescence spectral
and lifetime measurements. For fluorescence spectra, the excitation
and detection monochromators had a band-pass of 1.5 and 3.3 nm,
respectively, and spectra were obtained using 0.2 nm data intervals.
The fluorescence spectra were corrected for detection-system
spectral response. Fluorescence quantum yields were determined
using argon-purged solutions and several excitation wavelengths
for FbC1-PO3H2 (387, 398, 405, 501 nm) and FbC2-PO3H2 (387,
399, 405, 498 nm) relative to chlorophyll a in benzene [Φf )
0.325],69 H2TPP in toluene [Φf ) 0.09],63 and FbC3 in toluene
[Φf ) 0.20],61 and the results were averaged. Yields of the lowest
excited triplet state (ΦT) were obtained using a transient-absorption
technique similar to that described previously.70,71 The extent of
bleaching of the ground-state Qx(1,0) band at ∼500 nm (relative
to the featureless transient absorption) due to the lowest singlet
excited-state was measured immediately following a 130 fs flash
in either the Soret (418 nm) or Qy (583) bands. The amplitude of
this signal was compared to that due to the lowest triplet excited
state, which was derived from two methods. In the first method,
the triplet bleaching signal was taken as the long-time asymptote
of the fitted exponential singlet-excited-state bleaching decay (4
5-(1,5-Dibenzyloxypent-3-yl)-1-formyldipyrromethane (6). A
sample of POCl3 (212 µL, 2.32 mmol) was added to DMF (1.41
mL) cooled in an ice-water bath under argon. The solution was
stirred for 10 min to form the Vilsmeier reagent. A solution of 5
(604 mg, 1.41 mmol) in DMF (4.65 mL) at 0 °C under argon was
treated with 1.06 mL of the Vilsmeier reagent. Stirring was
continued for 1.5 h. The solution was quenched at 0 °C by addition
of aqueous sodium hydroxide (50 mL of 2.5 M solution). The
resulting mixture was poured into ethyl acetate. The phases were
separated. The organic extract was washed with water and brine,
dried (Na2SO4), and concentrated. Chromatography [silica, hexanes/
ethyl acetate (2:1)] gave a pale brown oil (354 mg, 55%): 1H NMR
(67) Kee, H. L.; Kirmaier, C.; Yu, L.; Thamyongkit, P.; Youngblood,
W. J.; Calder, M. E.; Ramos, L.; Noll, B. C.; Bocian, D. F.; Scheidt, W.
R.; Birge, R. R.; Lindsey J. S.; Holten, D. J. Phys. Chem. B 2005, 43,
20433-20443.
(68) Li, F.; Gentemann, S.; Kalsbeck, W. A.; Seth, J.; Lindsey, J. S.;
Holten D.; Bocian, D. F. J. Mater. Chem. 1997, 7, 1245-1262.
(69) Weber, G.; Teale, F. W. J. Trans. Faraday Soc. 1957, 53, 646-
655.
(70) Tait, C. D.; Holten, D. Photobiochem. Photobiophys. 1983, 6, 201-
209.
(71) Magde, D.; Windsor, M. W.; Holten, D.; Gouterman, M. Chem.
Phys. Lett. 1974, 29, 183-188.
J. Org. Chem, Vol. 73, No. 8, 2008 3155

Borbas et al.
(300 MHz) δ 1.40-1.48 (m, 2H), 1.69-1.78 (m, 2H), 2.47-2.49
(m, 1H), 3.42-3.60 (m, 4H), 4.41 (d, J ) 5.4 Hz, 1H), 4.44-4.55
(m, 4H), 5.96 (app s, 1H), 6.11-6.16 (m, 2H), 6.55 (d, J ) 1.2
Hz, 1H), 6.87-6.89 (m, 1H), 7.26-7.36 (m, 10H), 8.90 (br, 1H),
9.34 (s, 1H), 10.06 (br, 1H); 13C NMR (75 MHz) δ 32.18, 32.23,
37.1, 41.4, 68.8, 69.2, 73.4, 73.6, 107.6, 108.5, 110.7, 117.1, 128.0,
128.1, 128.2, 128.7, 128.8, 130.0, 132.1, 138.25, 138.34, 143.1,
178.5, 203.9; FAB-MS obsd 456.2424, calcd 456.2413 (C29H32N2O3);
Anal. Calcd C, 76.29; H, 7.06; N, 6.14. Found C, 76.34; H, 7.16;
N, 6.00.
5-(1,5-Dibenzyloxypent-3-yl)-1-bromo-9-formyldipyr-
romethane (7). Following a standard procedure,30,43 a solution of
6 (338 mg, 0.741 mmol) in anhydrous THF (7.6 mL) at -78 °C
under argon was treated with NBS (127 mg, 0.713 mmol), and the
reaction was allowed to proceed for 1 h. Water and ethyl acetate
were added, and the mixture was allowed to warm to 0 °C. The
phases were separated. The organic extract was washed with water,
dried (Na2SO4), and concentrated. Chromatography [silica, hexanes/
ethyl acetate (3:1)] gave a pale brown oil (307 mg, 78%): 1H NMR
(300 MHz) δ 1.42-1.49 (m, 2H), 1.64-1.77 (m, 2H), 2.45-2.50
(m, 1H), 3.42-3.56 (m, 4H), 4.32 (d, J ) 6.0 Hz, 1H), 4.45-4.55
(m, 4H), 5.86 (app s, 1H), 6.00 (app s, 1H), 6.15 (app s, 1H), 6.88
(s, 1H), 7.26-7.34 (m, 10H), 9.27 (s, 1H), 9.52 (br, 1H), 10.40 (s,
1H); 13C NMR (75 MHz) δ 32.0, 32.1, 36.9, 41.9, 68.5, 69.0, 73.4,
73.6, 96.8, 109.5, 110.3, 111.1, 128.0, 128.1, 128.2, 128.7, 128.8,
131.7, 132.2, 138.1, 138.3, 143.2, 178.7, 217.3; FAB-MS obsd
534.1507, calcd 534.1518 (C29H31N2O3Br); Anal. Calcd C, 65.05;
H, 5.84; N, 5.23. Found C, 64.94; H, 5.91; N, 5.03.
0.0095 mmol) in CH2Cl2 (1 mL) was treated with TFA (0.5 mL)
for 3 h at room temperature. The sample was diluted with CH2Cl2,
and neutralized with small portions of dilute aqueous NaHCO3.
The layers were separated, and the aqueous phase was extracted
with CH2Cl2. The organic extract was washed with water, dried
(Na2SO4), and concentrated. Chromatography [silica, hexanes/CH2-
Cl2 (1:4)] yielded a dark green solid (5.5 mg, 93%): 1H NMR (300
MHz) δ -2.27 (s, 0.45H), -2.17 (s, 0.55H), -1.58, -1.52 (2s,
1H), 2.05 (s, 6H), 2.95-3.04 (m, 2H), 3.22-3.30 (m, 3H), 3.38-
3.42 (m, 3H), 4.09-4.21 (m, 4H), 4.63 (s, 2H), 5.51-5.67 (m,
1H), 7.17-7.26 (m, 10H), 8.83-9.02 (m, 5H), 9.22 (app s, 1H),
9.35 (d, J ) 3.6 Hz, 0.55H), 9.46 (d, J ) 3.9 Hz, 0.45H), 9.54 (s,
1H), 9.82, 9.85 (2s, 1H); 13C NMR (75 MHz) δ 29.9, 31.4, 38.8,
39.2, 41.5, 46.4, 52.1, 52.3, 69.5, 69.6, 73.1, 94.0, 96.6, 96.9, 99.2,
106.9, 107.45, 122.7, 123.3, 124.0, 124.3, 126.0, 126.9, 127.6,
127.9, 128.4, 128.7, 129.9, 130.1, 133.1, 133.4, 133.9, 134.4, 137.5,
137.7, 138.7, 140.1, 141.5, 148.2, 162.7; LD-MS obsd 622.5; ESI-
MS obsd 623.33876, calcd 623.33805 [(M + H+), M ) C41H42N4O2];
λabs (CH2Cl2) 356, 401, 501, 582, 635 nm; λem (λexc 401 nm) 639,
680 (shoulder) nm.
17,18-Dihydro-10-(1,5-dihydroxypent-3-yl)-18,18-dimethylpor-
phyrin (FbC1-OH). A solution of ZnC1-OBn (46 mg, 0.067
mmol) in anhydrous CHCl3 (3 mL) under argon was treated with
TMS-I (60 µL). Stirring was continued for 1 h. The reaction
mixture was diluted with CH2Cl2. The solid residue was dissolved
in a small volume of MeOH. Water was added to the solution, and
the phases were separated. The aqueous layer was extracted three
times with CH2Cl2 containing 5% MeOH. The organic extract was
washed with water. The organic phase was dried (Na2SO4) and
Zinc(II)-10-(1,5-Dibenzyloxypent-3-yl)-17,18-dihydro-18,18-
dimethylporphyrin (ZnC1-OBn). Following a standard proce-
dure,30,43 a solution of 7 (1.02 g, 1.90 mmol) and 8 (362 mg, 1.90
mmol) in anhydrous CH2Cl2 (52 mL) under argon was treated
dropwise with a solution of p-TsOH‚H2O (1.80 g, 9.46 mmol) in
anhydrous methanol (12.9 mL). The mixture was stirred at room
temperature for 50 min. 2,2,6,6-Tetramethylpiperidine (3.23 mL,
19.1 mmol) was added, and the mixture was stirred for 5 min. The
mixture was concentrated in vacuo without heating. The residue
was suspended in CH3CN (194 mL), and the sample was treated
with 2,2,6,6-tetramethylpiperidine (8.08 mL, 47.8 mmol), Zn(OAc)2
(5.24 g, 28.8 mmol) and AgOTf (1.46 g, 5.68 mmol). The reaction
mixture was heated at reflux for 22 h open to the air. The reaction
mixture was concentrated. Column chromatography [silica, hexanes/
CH2Cl2 (1:1), then CH2Cl2] yielded a dark green solid (366 mg,
28%). Carrying out the reaction on smaller scale (0.15 mmol of 8)
1
concentrated. H NMR analysis of the crude product showed the
disappearance of the benzylic (CH2 and CH) signals. The sample
could be used without further purification. Samples of analytical
purity could be obtained upon chromatography [neutral alumina,
CH2Cl2/MeOH (0f10%)]. Evaporation of the solvents afforded a
1
dark green solid (29 mg, 97%). H NMR analysis revealed the
presence of two interconverting rotamers (∼2:3 ratio). Data for the
major rotamer: 1H NMR (300 MHz) δ -2.19 (s, 1H), -1.58 (br,
1H), 1.99 (s, 6H), 2.67-2.71 (m, 2H), 2.85-3.04 (m, 2H), 3.36-
3.46 (m, 4H), 4.46 (s, 2 H), 5.33 (m, 1H), 8.72-8.96 (m, 5H),
9.15 (app s, 2H), 9.46-9.47 (m, 1H), 9.76 (s, 1H). Data for the
minor rotamer: 1H NMR (300 MHz) δ -2.29 (s, 0.4H), -1.58
(br, 1H), 2.01 (s, 6H), 2.67-2.71 (m, 2H), 2.85-3.04 (m, 2H),
3.36-3.46 (m, 4H), 4.54 (s, 2H), 5.45 (m, 1H), 8.72-8.96 (m,
5H), 9.30-9.31 (m, 1H), 9.40-9.41 (m, 1H), 9.46-9.47 (m, 1H),
9.76 (s, 1H). The rotamers were not distinguished by the following
methods: 13C NMR δ (75 MHz) 30.0, 31.3, 38.1, 38.5, 43.7, 43.9,
46.4, 46.6, 52.1, 52.2, 61.7, 94.2, 96.8, 97.0, 107.0, 107.4, 122.9,
123.5, 123.6, 124.1, 124.3, 124.7, 125.9, 126.1, 128.8, 129.0, 129.1,
130.0, 130.4, 133.1, 133.5, 133.6, 134.0, 134.4, 137.1, 137.6, 140.0,
141.6, 141.7, 147.8, 148.3, 151.0, 152.0, 162.2, 162.9, 175.8, 176.0;
LD-MS obsd 441.5; ESI-MS obsd 443.24418, calcd 443.24415 [(M
+ H)+, M ) C27H30N4O2]; λabs (CH2Cl2) 356, 393, 403, 501, 635
nm; λem (λexc 403 nm) 637, 680 (shoulder), 700 nm (shoulder).
10-(1,5-Dibromopent-3-yl)-17,18-dihydro-18,18-dimethylpor-
phyrin (FbC1-Br). A suspension of crude FbC1-OH (from 0.173
mmol of ZnC1-OBn) in CH2Cl2 (36 mL) in an ice-water bath
was treated with CBr4 (162 mg, 0.488 mmol). The mixture was
stirred for 10 min, after which PPh3 (254 mg, 0.977 mmol) was
added. Stirring was continued for 30 min with cooling, and for 10
h thereafter at room temperature. Water was added to the reaction
mixture, and the phases were separated. The aqueous layer was
extracted with CH2Cl2. The organic extract was washed with water,
dried (Na2SO4), and concentrated. Chromatography (silica, CH2-
Cl2) yielded a dark green solid that was poorly soluble in common
organic solvents (CH2Cl2, CHCl3, MeOH, THF) (90.9 mg, 93%
1
resulted in yields of up to 40%. H NMR analysis revealed the
presence of two interconverting rotamers. Data for the major
rotamer: 1H NMR (300 MHz) δ 2.02 (s, 6H), 2.75-2.82 (m, 2H),
3.08-3.26 (m, 6H), 3.93-4.03 (m, 4H), 4.74 (s, 2H), 5.31-5.42
(m, 1H), 6.88-7.01 (m, 4H), 7.01-7.09 (m, 6H), 8.53 (s, 1H),
8.61-8.66 (m, 2H), 8.70 (d, J ) 4.2 Hz, 1H), 8.86 (d, J ) 4.5 Hz,
1H), 9.02 (d, J ) 4.2 Hz, 1H), 9.18 (d, J ) 4.5 Hz, 1H), 9.46 (d,
J ) 4.2 Hz, 1H), 9.51 (s, 1H). Data for the minor rotamer: 1H
NMR (300 MHz) δ 2.02 (s, 6H), 2.75-2.82 (m, 2H), 3.08-3.26
(m, 4H), 3.93-4.03 (m, 4H), 4.74 (s, 2H), 5.31-5.42 (m, 1H),
6.88-7.01 (m, 4H), 7.01-7.09 (m, 6H), 8.56 (s, 1H), 8.61-8.66
(m, 2H), 8.75 (d, J ) 4.5 Hz, 1H), 8.92 (d, J ) 4.2 Hz, 1H), 9.06
(d, J ) 4.2 Hz, 1H), 9.31 (d, J ) 4.5 Hz, 1H), 9.39 (d, J ) 5.1 Hz,
1H), 9.59 (s, 1H). The rotamers were not distinguished by the
following methods: 13C NMR (75 MHz) δ 31.1, 31.2, 39.2, 39.3,
40.5, 41.3, 45.4, 45.6, 50.3, 50.4, 69.1, 69.3, 72.4, 72.5, 94.1, 96.7,
96.8, 109.1, 109.4, 125.6, 126.3, 126.8, 127.1, 127.2, 127.4, 127.7,
128.2, 128.3, 128.6, 131.1, 131.5, 133.0, 138.3, 144.5, 144.8, 145.7,
146.0, 147.1, 147.9, 149.2, 151.0, 153.9, 154.2, 154.3, 158.5, 159.2,
171.1; LD-MS obsd 684.4 (major), 621.7 (trace), 549.9 (trace); ESI-
MS obsd 684.24345, calcd 684.24372 (C41H40N4O2Zn); λabs (CH2-
Cl2) 384 (shoulder), 402, 501, 560, 604 nm; λem (λexc 402 nm) 610,
660 (shoulder) nm.
1
over two steps). H NMR analysis revealed the presence of two
interconverting rotamers (∼1:3 ratio): 1H NMR (300 MHz) δ
-2.38 (s, 0.25H), -2.24 (s, 0.75H), -1.85 (s, 0.25H), -1.56 (s,
0.75H), 2.05 (s, 6H), 3.16-3.40 (m, 6H), 3.60-3.73 (m, 2H), 4.63
10-(1,5-Dibenzyloxypent-3-yl)-17,18-dihydro-18,18-dimeth-
ylporphyrin (FbC1-OBn). A sample of ZnC1-OBn (6.5 mg,
3156 J. Org. Chem., Vol. 73, No. 8, 2008

Water-Soluble Chlorins
(s, 2H), 5.45-5.72 (m, 1H), 8.87-9.87 (m, 9H). The rotamers were
not distinguished by the following methods: LD-MS obsd 565.4;
ESI-MS obsd 567.07571, calcd 567.07535 [(M + H)+, M ) C27H28-
Br2N4]; λabs (CH2Cl2) 404, 502, 584, 635 nm; λem (λexc 404 nm)
638 nm.
romethanes,50 the crude oil was dissolved in CH2Cl2 (35 mL) and
treated with TEA (3.19 mL, 2.30 mmol) and Bu2SnCl2 (2.30 g,
7.60 mmol) for 30 min at room temperature. The solvent was
removed. The resulting oil was chromatographed [silica, hexanes/
ethyl acetate (19:1) f hexanes/ethyl acetate (3:2) containing 1%
1
TEA] to afford a dark red solid (612 mg, 26%): mp 138 °C; H
17,18-Dihydro-18,18-dimethyl-10-[1,5-bis(dimethylphospho-
no)pent-3-yl]porphyrin (FbC1-PO3Me2). A solution of FbC1-
Br (90.4 mg, 0.160 mmol) in THF (3 mL) and P(OCH3)3 (27 mL)
was heated at reflux for 24 h. The sample was concentrated. The
residue was dissolved in a small volume of CH2Cl2, and washed
with water and dilute NaHCO3. The organic layer was concentrated
and chromatographed [silica, CH2Cl2/MeOH (0 f 5%)] to afford
a dark green solid (29 mg, 29%): 1H NMR (300 MHz) δ -2.36,
-2.27 (2s, 1H), -1.63, -1.55 (2s, 1H), 1.27-1.50 (m, 2H), 1.84-
1.97 (m, 2H), 2.05 (s, 6H), 2.93-3.02 (m, 2H), 3.21-3.28 (m,
2H), 3.42-3.54 (m, 12H), 4.63 (s, 2H), 5.17-5.24 (m, 1H), 8.86-
9.09 (m, 5H), 9.23 (s, 1H), 9.34 (d, J ) 4.5 Hz, 1H), 9.48-9.54
(two d, 1H), 9.84, 9.86 (2s, 1H); 31P NMR (162 MHz) δ 34.1 (two
peaks); LD-MS obsd 625.8; ESI-MS obsd 627.25005, calcd
627.24958 [(M + H)+, M ) C31H40N4O6P2]; λabs (CH2Cl2) 357
(shoulder), 404, 501, 635 nm; λem (λexc 404 nm) 638, 701 (shoulder)
nm.
17,18-Dihydro-18,18-dimethyl-10-[1,5-diphosphonopent-3-yl]-
porphyrin (FbC1-PO3H2). A solution of FbC1-PO3Me2 (11.0 mg,
0.0176 mmol) in anhydrous CHCl3 (1 mL) under argon was treated
with TMS-Br (100 µL). Stirring was continued for 1 h. MeOH (1
mL) was added to the reaction mixture, and stirring was continued
for 30 min. The sample was concentrated, and the residue was
dissolved in dilute aqueous NaHCO3 (3 mL). The solution was
chromatographed [C-18 silica, H2O/MeOH (0 f 50%)] to afford
a dark green solution. The sample was concentrated to dryness,
and the residue was dissolved in water. The solution was filtered
through a plug of cotton wool. The filtrate was freeze-dried, yielding
a dark green, fluffy solid (9.9 mg, 99%): 1H NMR (D2O, 60 °C,
300 MHz) δ 0.98-1.06 (br, 4H), 1.62-1.85 (br, 2H), 2.20-2.50
(br, 2H), 3.13-3.31 (br, 2H); 3.59-3.62 (br, 4H), 5.57 (br, 1H),
7.89-8.32 (m, 4H), 8.90-9.22 (m, 3H), 9.85 (br 1H), 10.16 (br
1H); 31P NMR (D2O, 162 MHz) δ 23.0 (cluster of four peaks),
30.2 (cluster of four peaks); ESI-MS obsd 571.18665, calcd
571.18698 [(M + H)+, M ) C27H32N4O6P2]; λabs (H2O, pH 7) 398,
501, 627 nm, λem (λexc 398 nm) 632, 692 nm; tR ) 22.75 min
(major), 23.76 min (minor).
NMR (400 MHz) δ 3.74 (s, 6H), 5.90-5.94 (m, 1H), 6.08-6.14
(m, 2H), 6.15 (s, 1H), 6.62 (d, J ) 8.4 Hz, 2H), 6.67-6.71 (m,
1H), 6.83-6.87 (m, 1H), 7.22 (t, J ) 8.4 Hz, 1H), 8.82 (brs, 1H)
9.07 (brs, 1H), 9.33 (s, 1H); 13C NMR (100 MHz) δ 33.0, 56.4,
105.7, 107.6, 108.0, 109.4, 117.5, 117.8, 122.3, 129.0, 130.2, 131.5,
144.6, 158.0. 178.1; FAB-MS obsd 310.1323, calcd 310.1317
(C18H18N2O3).
Zinc(II)-17,18-Dihydro-10-(2,6-dimethoxyphenyl)-18,18-di-
methylporphyrin (ZnC2-OMe). Following a streamlined proce-
dure,30 a solution of 10 (399.5 mg, 1.287 mmol) in dry THF (13
mL) at -78 °C under argon was treated portionwise with NBS
(229.0 mg, 1.287 mmol). The reaction mixture was stirred for 1 h
at -78 °C. The cooling bath was removed, and the reaction mixture
was allowed to warm to 0 °C. Ethyl acetate was added. The organic
layer was washed with water, dried (Na2SO4), and concentrated.
The resulting crude bromo-formyldipyrromethane was dissolved
in anhydrous CH2Cl2 (38 mL), and 8 (244.8 mg, 1.287 mmol) was
added. The solution was treated dropwise with a solution of
p-TsOH‚H2O (1.22 g, 6.43 mmol) in anhydrous methanol (9 mL)
under argon. The resulting red reaction mixture was stirred at room
temperature for 50 min. A sample of 2,2,6,6-tetramethylpiperidine
(2.18 mL, 12.9 mmol) was added. The reaction mixture was
concentrated. The resulting solid was suspended in CH3CN (128
mL) and subsequently treated with 2,2,6,6-tetramethylpiperidine
(5.46 mL, 32.1 mmol), Zn(OAc)2 (3.54 g, 19.3 mmol), and AgOTf
(992 mg, 3.86 mmol). The resulting suspension was refluxed for
18 h exposed to air. The crude mixture was filtered through a pad
of silica (CH2Cl2). The filtrate was concentrated and chromato-
graphed [silica, hexanes/CH2Cl2 (1:2) f CH2Cl2] to afford a purple
solid (283.3 mg, 40%): 1H NMR (400 MHz) δ 2.02 (s, 6H), 3.55
(s, 6H), 4.52 (s, 2H), 6.98 (d, J ) 8.4 Hz, 2H), 7.68 (t, J ) 8.4 Hz,
1H), 8.48 (d, J ) 4.4 Hz, 1H), 8.59 (s, 1H), 8.62 (d, J ) 4.4 Hz,
1H), 8.65-8.71 (m, 2H), 8.74 (d, J ) 4.4 Hz, 1H), 8.85 (d, J )
4.4 Hz, 1H), 9.06 (d, J ) 4.4 Hz, 1H), 9.60 (s, 1H); LD-MS obsd
539.4; FAB-MS obsd 538.1332, calcd 538.1347 (C30H26N4O2Zn);
λabs (toluene) 406, 607 nm.
17,18-Dihydro-10-(2,6-dimethoxyphenyl)-18,18-dimethylpor-
phyrin (FbC2-OMe). A solution of ZnC2-OMe (119 mg, 0.219
mmol) in CH2Cl2 (5 mL) was treated dropwise with TFA (507 µL,
6.58 mmol) over a 3 min period. The solution was stirred at room
temperature for 3 h. CH2Cl2 was added, and the organic layer was
washed (saturated aqueous NaHCO3 and water) and then dried (Na2-
SO4). The organic layer was concentrated and chromatographed
[silica, hexanes then hexanes/CH2Cl2 (1:1)] to afford a purple solid
(96.5 mg, 92%): 1H NMR (400 MHz) δ -2.25 (brs, 1H), -1.95
(brs, 1H), 2.05 (s, 6H), 3.52 (s, 6H), 4.63 (s, 2H), 6.99 (d, J ) 8.4
Hz, 2H), 7.70 (t, J ) 8.4 Hz, 1H), 8.56 (d, J ) 4.4 Hz, 2H), 8.74
(d, J ) 4.4 Hz, 1H), 8.78 (d, J ) 4.4 Hz, 1H), 8.80 (s, 1H), 8.92
(d, J ) 4.4 Hz, 1H), 8.98 (s, 1H), 9.20 (d, J ) 4.4 Hz, 1H), 9.81
(s, 1H); 13C NMR (100 MHz) δ 31.3, 46.4, 52.2, 56.2, 94.2, 96.6,
104.4, 107.2, 113.5, 119.4, 122.7, 123.7, 127.8, 130.2, 131.3, 132.7,
133.9, 135.8, 139.6, 140.4, 150.9, 153.7, 160.6, 162.7, 174.5; LD-
MS obsd 476.9; ESI-MS obsd 477.2295, calcd 477.2285 [(M +
H)+, M ) C30H28N4O2]; λabs (toluene) 402, 639 nm.
10-[2,6-Bis(diethylphosphonomethoxy)phenyl]-17,18-dihydro-
18,18-dimethylporphyrin (FbC2-PO3Et2). A solution of FbC2-
OMe (56.2 mg, 0.117 mmol) in anhydrous CH2Cl2 (6 mL) under
argon was treated with BBr3 (2.3 mL, 2.3 mmol, 1 M solution in
CH2Cl2). The mixture was stirred at room temperature for 12 h.
The reaction mixture was diluted with CH2Cl2 (40 mL)and saturated
aqueous NaHCO3. The organic layer was separated, dried (Na2-
SO4), and concentrated. The resulting solid was dissolved in CH3-
CN (8 mL). The solution was treated with K2CO3 (355 mg, 2.57
5-(2,6-Dimethoxyphenyl)dipyrromethane (9). Following a
reported procedure,48 a mixture of pyrrole (139 mL, 2.00 mol) and
2,6-dimethoxybenzaldehyde (1.66 g, 10.0 mmol) under argon was
treated with InCl3 (221 mg, 1.00 mmol) at room temperature for
1.5 h. The reaction mixture was treated with powdered NaOH (2.0
g, 50 mmol). The mixture was stirred for 45 min and filtered. The
filtrate was concentrated, and unreacted pyrrole was recovered. The
residue was purified by column chromatography [silica, hexanes/
CH2Cl2/ethyl acetate (7:2:1)] to afford a yellowish brown solid (2.14
g, 76%, 92% purity by GC): mp 93-94 °C: 1H NMR (400 MHz)
δ 3.75 (s, 6H), 5.93 (s, 2H), 6.08-6.16 (m, 2H), 6.19 (s, 1H), 6.61-
6.68 (m, 4H), 7.20 (t, J ) 8.4 Hz, 1H), 8.52 (brs, 2H); 13C NMR
(100 MHz) δ 32.7, 56.6, 106.0, 107.8, 116.3, 119.7, 128.3, 133.1,
158.3; FAB-MS obsd 282.1380, calcd 282.1368 (C17H18N2O2).
1-Formyl-5-(2,6-dimethoxyphenyl)dipyrromethane (10). Fol-
lowing a reported procedure,49 anhydrous DMF (10 mL) was treated
with POCl3 (1.50 mL, 16.4 mmol) at 0 °C under argon, and the
resulting solution was stirred for 10 min to give the Vilsmeier
reagent. A solution of 9 (2.14 g, 7.57 mmol) in DMF (25 mL) at
0 °C under argon was treated with the freshly prepared Vilsmeier
reagent (5.6 mL, 8.0 mmol), and the resulting solution was allowed
to stir for 1.5 h at 0 °C. Saturated aqueous sodium acetate (80 mL)
was added, and the reaction mixture was stirred for 4 h at room
temperature. The mixture was extracted with ethyl acetate. The
organic layer was washed (brine), dried (Na2SO4), and filtered. The
filtrate was concentrated to obtain a dark red oil. Following a
procedure for the dialkyltin complexation of 1,9-diacyldipyr-
J. Org. Chem, Vol. 73, No. 8, 2008 3157

Borbas et al.
mmol) and (EtO)2P(O)CH2OTf (702 mg, 2.34 mmol). The reaction
mixture was refluxed for 12 h. The mixture was concentrated. The
residue was dissolved in CH2Cl2 and chromatographed [silica, CH2-
Cl2 f CH2Cl2/MeOH (49:1)] to afford a greenish purple solid (34.2
mg, 38%): 1H NMR (400 MHz) δ -2.36 (brs, 1H), -2.06 (brs,
1H), -0.34 (t, J ) 7 Hz, 6H), -0.15 (t, J ) 7 Hz, 6H), 2.08 (s,
6H), 2.23-2.55 (m, 6H), 2.58-2.81 (m, 2H), 4.16 (d, J ) 10.4
Hz, 4H), 4.66 (s, 2H), 7.07 (d, J ) 8.4 Hz, 2H), 7.74 (t, J ) 8.4
Hz, 1H), 8.50 (d, J ) 4.4 Hz, 1H), 8.72 (d, J ) 4.4 Hz, 1H), 8.79
(d, J ) 4.4 Hz, 1H), 8.87 (d, J ) 4.4 Hz, 1H), 8.93 (s, 1H); 8.96
(d, J ) 4.4 Hz, 1H), 9.00 (s, 1H), 9.22 (d, J ) 4.4 Hz, 1H), 9.78
(s, 1H); 31P NMR (162 MHz) δ 16.71; LD-MS obsd 748.7; ESI-
MS obsd 749.2865, calcd 749.2863 [(M + H)+, M ) C38H46N4O8P2];
λabs (toluene) 403, 638 nm.
17,18-Dihydro-18,18-dimethyl-10-[2,6-bis(phosphonometh-
oxy)phenyl]porphyrin (FbC2-PO3H2). A solution of FbC2-
PO3Et2(21.3 mg, 0.0284 mmol) in anhydrous CHCl3 (1 mL) under
argon was treated with TMS-Br (250 µL, 1.89 mmol). The solution
was stirred for 1 h at room temperature. The solution was
concentrated, and the residue was dissolved in MeOH (2 mL). The
solution was stirred at room temperature for 1 h. Evaporation of
the solvent yielded a dark green solid, which was dissolved in dilute
aqueous NaOH (2 M). The solution was chromatographed (C-18
silica, water/MeOH gradient) to obtain a blue solid (17.2 mg,
95%): 1H NMR (400 MHz, D2O) δ 2.05 (s, 6H), 3.84-3.95 (m,
4H), 4.71 (s, 2H), 7.35 (d, J ) 8.0 Hz, 2H), 7.90 (t, J ) 8.0 Hz,
1H), 8.79 (d, J ) 4.4 Hz, 1H), 9.00 (d, J ) 4.4 Hz, 1H), 9.08 (d,
J ) 4.4 Hz, 1H), 9.11 (d, J ) 4.4 Hz, 1H), 9.18-9.25 (m, 2H),
9.29 (s, 1H), 9.41 (d, J ) 4.4 Hz, 1H), 10.09 (s, 1H); 13P NMR
(D2O, 162 MHz) δ 10.35; ESI-MS obsd 637.1620, calcd 637.1611
[(M + H)+, M ) C30H30N4O8P2]; λabs (pH 7, H2O) 399, 628 nm;
tR ) 27.20 min.
2,6-Bis(diethylphosphonomethoxy)benzaldehyde (11). Fol-
lowing a reported procedure,56 a suspension of 2,6-dihydroxyben-
zaldehyde (401 mg, 2.90 mmol) and K2CO3 (1.60 g, 11.5 mmol)
in CH3CN (20 mL) was refluxed for 30 min. The reaction mixture
was allowed to cool to room temperature. A solution of (EtO)2P-
(O)CH2OTf (2.09 g, 6.96 mmol) in CH3CN (12 mL) was added,
and the mixture was refluxed for 2.5 h. The reaction mixture was
concentrated, and CH2Cl2 was added. The organic layer was washed
with water, dried (Na2SO4), and concentrated. The residue was
purified by column chromatography (silica, CH2Cl2 f CH2Cl2/
methanol (7:3)] to give a colorless gummy oil. The product was
dissolved in ethyl acetate, filtered to remove any residual silica
gel, and the filtrate was concentrated (1.03 g, 81%): 1H NMR
(THF-d8, 400 MHz) δ 1.30 (t, J ) 7.2 Hz, 12H), 4.15-4.23 (m,
8H), 4.36 (d, J ) 10 Hz, 4H), 6.84 (d, J ) 8.0 Hz, 2H), 7.13 (t, J
) 8.8 Hz, 1H), 10.5 (s, 1H); 13C NMR (THF-d8, 100 MHz) δ 17.0,
63.3, 65.0, 107.3, 136.0, 162.0, 162.2, 187.6; ESI-MS obsd
439.1284, calcd 439.1281 [(M + H)+, M ) C17H28O9P2].
5-[2,6-Bis(diethylphosphonomethoxy)phenyl]dipyrrometh-
ane (12). Following a reported procedure,48 a mixture of pyrrole
(32.0 mL, 460 mmol) and 11 (1.01 g, 2.30 mmol) was treated under
argon with InCl3 (51.0 mg, 0.230 mmol) at room temperature for
1.5 h. The reaction mixture was diluted with CH2Cl2, and saturated
aqueous NaHCO3 was added. The organic layer was separated, dried
(Na2SO4), and concentrated with recovery of unreacted pyrrole. The
residue was purified by column chromatography [silica, hexanes
f CH2Cl2/methanol (19:1)] to obtain a yellow gummy oil. Storage
at -20 °C afforded a yellowish brown solid (1.12 g, 88%): mp
104-106 °C: 1H NMR (THF-d8, 400 MHz) δ 1.26 (t, J ) 7.2 Hz,
12H), 3.88-4.34 (br m, 12H), 5.84-5.86 (m, 4H), 6.22 (s, 1H),
6.52-6.54 (m, 2H), 6.74 (brs, 2H), 7.13 (t, J ) 8.8 Hz, 1H), 10.0
(brs, 2H); 13C NMR (THF-d8, 100 MHz) δ 17.0, 34.2, 63.3, 65.0
(br), 107.3, 107.4, 117.3, 122.5, 128.5, 132.8, 158.7 (br); ESI-MS
obsd 555.20041, calcd 555.20197 [(M + H)+, M ) C25H36N2O8P2].
Zn(II)-10-[2,6-Bis(diethylphosphonomethoxy)phenyl]-17,18-
dihydro-18,18-dimethylporphyrin (ZnC2-PO3Et2). Following a
streamlined procedure,30,45 a solution of 12 (204 mg, 0.367 mmol)
in dry THF (6.5 mL) at -78 °C under argon was treated with NBS
(65.5 mg, 0.367 mmol). The reaction mixture was stirred for 1 h at
-78 °C. The cooling bath was removed, and the reaction mixture
was allowed to warm to ∼ -30 °C. Ethyl acetate was added. The
organic layer was washed with water, dried (Na2SO4), and
concentrated. The resulting crude bromo-dipyrromethane was
dissolved in anhydrous CH2Cl2 (8 mL), and 13 (80.1 mg, 0.367
mmol) was added. The solution was treated dropwise with a solution
of p-TsOH‚H2O (349 mg, 1.83 mmol) in anhydrous methanol (2
mL) under argon. The resulting red reaction mixture was stirred at
room temperature for 35 min. A sample of 2,2,6,6-tetramethyl-
piperidine (685 µL, 4.02 mmol) was added. The reaction mixture
was concentrated. The resulting solid was suspended in CH3CN
(37 mL) and was subsequently treated with 2,2,6,6-tetramethyl-
piperidine (1.55 mL, 9.17 mmol), Zn(OAc)2 (1.01 g, 5.50 mmol),
and AgOTf (283 mg, 1.10 mmol). The resulting suspension was
refluxed for 16 h exposed to air. The crude mixture was filtered
through a pad of silica [CH2Cl2/ethyl acetate (1:2)]. The filtrate
was chromatographed [silica, CH2Cl2 f CH2Cl2/ethyl acetate (1:
2)] to afford a green solid (128 mg, 42%): 1H NMR (THF-d8, 400
MHz) δ 0.12 (t, J ) 7.0 Hz, 6H), 0.17 (t, J ) 7.0 Hz, 6H), 2.04 (s,
6H), 2.65-2.90 (m, 8H), 4.11 (d, J ) 10 Hz, 4H), 4.54 (s, 2H),
7.20 (d, J ) 8.0 Hz, 2H), 7.70 (t, J ) 8.8 Hz, 1H), 8.35 (d, J ) 4.4
Hz, 1H), 8.53 (s, 2H), 8.61 (d, J ) 4.4 Hz, 2H), 8.72 (d, J ) 4.4
Hz, 1H), 8.74 (d, J ) 4.4 Hz, 1H), 9.02 (d, J ) 4.4 Hz, 1H), 9.54
(s, 1H); 13C NMR (THF-d8, 100 MHz) δ 15.97, 15.99, 16.02, 16.05,
31.4, 46.2, 51.4, 62.30, 62.32, 62.36, 63.38, 63.0, 64.6, 94.4, 96.7,
106.6, 109.4, 115.1, 122.4, 127.5, 127.6, 128.5, 128.6, 130.5, 132.8,
133.0, 146.8, 147.1, 147.5, 148.6, 154.0, 154.6, 159.3, 160.6, 160.8,
170.7; 31P NMR (THF-d8, 162 MHz) δ 14.0; LD-MS obsd 810.4;
ESI-MS obsd 810.19150, calcd 810.19204 (C38H44N4O8P2Zn); λabs
(toluene) 408, 608 nm.
10-[2,6-Bis(diethylphosphonomethoxy)phenyl]-17,18-dihydro-
18,18-dimethylporphyrin (FbC2-PO3Et2). Following a reported
procedure,25 a solution of ZnC2-PO3Et2 (40.0 mg, 0.219 mmol)
in CH2Cl2 (15 mL) was treated with p-TsOH‚H2O (543 mg, 6.58
mmol) at room temperature for 1 h. The reaction mixture was
diluted with CH2Cl2 and washed with saturated aqueous NaHCO3
solution. The organic layer was separated, dried (Na2SO4), and
concentrated. The resulting residue was chromatographed [silica,
CH2Cl2 f CH2Cl2/MeOH (98:2)] to afford a greenish purple solid
(26.2 mg, 72%): 1H NMR (400 MHz) δ -2.36 (brs, 1H), -2.06
(brs, 1H), -0.34 (t, J ) 7.0 Hz, 6H), -0.15 (t, J ) 7.0 Hz, 6H),
2.08 (s, 6H), 2.23-2.55 (m, 6H), 2.58-2.81 (m, 2H), 4.16 (d, J )
10 Hz, 4H), 4.66 (s, 2H), 7.07 (d, J ) 8.0 Hz, 2H), 7.74 (t, J ) 8.8
Hz, 1H), 8.50 (d, J ) 4.4 Hz, 1H), 8.72 (d, J ) 4.4 Hz, 1H), 8.79
(d, J ) 4.4 Hz, 1H), 8.87 (d, J ) 4.4 Hz, 1H), 8.93 (s, 1H); 8.96
(d, J ) 4.4 Hz, 1H), 9.00 (s, 1H), 9.22 (d, J ) 4.4 Hz, 1H), 9.78
(s, 1H); 13C NMR (THF-d8, 100 MHz) δ 15.42, 15.48, 15.5, 15.6,
31.5, 47.2, 52.8, 62.09, 62.16, 62.23, 63.0, 64.7, 95.2, 97.3, 106.5,
107.7, 113.8, 120.8, 123.7, 124.5, 128.5, 128.6, 131.2, 132.2, 133.4,
135.1, 136.7, 140.6, 141.6, 152.1, 154.6, 160.6, 160.7, 163.7, 175.5;
LD-MS obsd 748.7; ESI-MS obsd 749.28592, calcd 749.28636 [(M
+ H)+, M ) C38H46N4O8P2]; λabs (toluene) 403, 638 nm.
Acknowledgment. This work 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
the North Carolina Biotechnology Center and the NSF.
Supporting Information Available: Variable-temperature 31P
NMR spectroscopic results for the swallowtail-chlorins; procedures
for preparing compounds 1 and 2; spectral data for selected
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO7026728
3158 J. Org. Chem., Vol. 73, No. 8, 2008