Synthesis and photochemical properties of 12-substituted versus 13-substituted chlorins

Article abstract of DOI:10.1021/jo900706x

(Chemical Equation Presented) Understanding the effects of substituents on natural photosynthetic pigments is essential for the rational design of artificial photosynthetic systems. The long-wavelength absorption of chlorins derives from a transition that

Full text of DOI:10.1021/jo900706x

pubs.acs.org/joc
Synthesis and Photochemical Properties of 12-Substituted versus
13-Substituted Chlorins
Olga Mass,† Marcin Ptaszek,† Masahiko Taniguchi,† James R. Diers,‡ Hooi Ling Kee,§
David F. Bocian,*,‡ Dewey Holten,*,§ and Jonathan S. Lindsey*,†
†Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695-8204,
‡Department of Chemistry, University of California, Riverside, California 92521-0403, and §Department of
Chemistry, Washington University, St. Louis, Missouri 63130-4889
david.bocian@ucr.edu; holten@wuchem.wustl.edu; jlindsey@ncsu.edu
Received April 3, 2009
Understanding the effects of substituents on natural photosynthetic pigments is essential for the rational
design of artificial photosynthetic systems. The long-wavelength absorption of chlorins derives from a
transition that encompasses rings A and C, which includes the 2,3- and 12,13-positions, respectively.
Chlorophylls bear a 3-vinyl group and a 13-keto group, as well as a full complement of substituents at the
other β-pyrrole sites. Prior studies of sparsely substituted synthetic chlorins to probe the effects of
substituents yielded 3,13-substituted chlorins that contain a geminal dimethyl group in the pyrroline ring
(for stability) and a mesityl group at the 10-position. Attempts to prepare analogous chlorins lacking the 10-
mesityl substituent encountered unexpected difficulties during construction of the Eastern half precursor
(8,9-dibromo-1-formyldipyrromethane) to the 13-bromochlorin. Direct bromination of 1-formyldipyrro-
methane with 2 mol equiv of NBS at -78 °C led to an isomeric mixture of the desired 8,9-dibromodi-
pyrromethane (minor) and the unexpected 7,9-dibromodipyrromethane (major). Hence, a new rational
route was developed for the synthesis of 8,9-dibromo-1-formyldipyrromethane that entailed (i) InCl3-
catalyzed condensation of 4-bromo-2-(hydroxymethyl)pyrrole and pyrrole to give the 8-bromodipyrro-
methane, (ii) 1-formylation, and (iii) 9-bromination. Two new substituted chlorins carrying auxochromes at
the 3- and 13-positions were synthesized. The photophysical and redox properties of the 13-substituted
chlorins were compared with those of isomeric 12-substituted chlorins, synthesized previously via a 7,
9-dibromo-1-formyldipyrromethane. Such studies (static absorption and fluorescence spectroscopy, time-
resolved fluorescence spectroscopy, electrochemistry of the zinc chelates, and density functional theoretical
calculations) reveal only very slight differences between the isomeric 12- and 13-substituted chlorins.
Introduction
interest for application in solar energy conversion1 as well as
diverse biomedical fields such as polychromatic flow cyto-
metry,2 molecular imaging,3 and photodynamic therapy.4
In this regard, synthetic macrocycles that contain the chlorin
Understanding the effects of substituents on the spectral
properties of chlorophyll molecules is of fundamental im-
portance. Knowledge gained from such studies also enables
subtle tuning of the absorption bands of chlorins, which is of
(2) De Rosa, S. C.; Brenchley, J. M.; Roederer, M. Nature Med. 2003, 9,
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Holten, D. J. Phys. Chem. C 2007, 111, 15464–15478.
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Published on Web 06/11/2009
DOI: 10.1021/jo900706x
r
2009 American Chemical Society

Mass et al.
JOCArticle
chromophore and that bear relatively few substituents at
designated sites are essential for such studies to pinpoint the
effects of specific substituents.
SCHEME 1
A general route for the de novo synthesis of chlorins is
shown in Scheme 1.5-7 The synthesis employs the condensa-
tion of an Eastern half and a Western half followed by metal-
mediated oxidative cyclization. The Western half contains a
geminal dimethyl group, a key design feature that stabilizes
the hydroporphyrin macrocycle toward oxidation. The de
novo route requires far more synthetic effort than derivati-
zation of porphyrins or semisynthesis beginning with chloro-
phylls;8-21 however, the de novo route affords greater
versatility in the scope and range of substituents that can
be introduced, and is well suited to the preparation of
sparsely substituted chlorins. The de novo route has been
(5) Strachan, J.-P.; O’Shea, D. F.; Balasubramanian, T.; Lindsey, J. S. J.
Org. Chem. 2000, 65, 3160–3172.
(6) Taniguchi, M.; Ra, D.; Mo, G.; Balasubramanian, T.; Lindsey, J. S. J.
Org. Chem. 2001, 66, 7342–7354.
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S. Tetrahedron 2007, 63, 3826–3839.
(8) Flitsch, W. Adv. Heterocycl. Chem. 1988, 43, 73–126.
(9) Hynninen, P. H. In Chlorophylls; Scheer, H., Ed.; CRC Press: Boca
Raton, FL, 1991; pp 145-209.
(10) Smith, K. M. In Chlorophylls; Scheer, H., Ed.; CRC Press: Boca
Raton, FL, 1991; pp 115-143.
used to construct chlorins bearing a wide variety of substit-
uents in diverse patterns.5-7,22-35 Among various substitu-
ents and patterns, the examination of auxochromes at the 3-
and 13-positions is of interest because (i) the long-wavelength
absorption band of chlorophylls originates from a transition
that encompasses rings A and C and (ii) chlorophylls a and b
each contain auxochromes substituted in these rings, namely a
3-vinyl group and a 13-keto group.32,36-38
€
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M., Guilard, R., Eds.; Academic Press, San Diego, CA, 2000; Vol. 1, pp 201-
237.
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Smith, K. M., Guilard R., Eds.; Academic Press: San Diego, CA, 2000; Vol.
1, pp 149-199.
To probe the effects of auxochromes on the spectral
properties of chlorins, in the past few years we have reported
the synthesis of >20 chlorins that bear a 10,13-substituent
pattern (and often other substituents, particularly at the
3-position),26,27,32-35 as well as two target 3,13-substituted
chlorins that lack a 10-substituent.26 Building on the latter
chemistry, we recently intended to prepare a 13-substituted
chlorin that lacks a 10-substituent en route to the corre-
sponding fully unsubstituted 131-oxophorbine (which, like
chlorophylls, contains the 5-membered isocyclic ring span-
ning positions 13 and 15). However, this attempt was not
successful. X-ray analysis of the putative 13-acetyl-15-bro-
mochlorin (ZnC-A13Br15), the key intermediate for installa-
tion of the isocyclic ring, showed the acetyl group at the
12-position instead (ZnC-A12Br15; vide infra). Obviously,
intramolecular R-arylation27 of the 12-acetyl group with the
(15) 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.
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chlorophylls. Biochemistry, Biophysics, Functions and Applications; Grimm,
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B., Porra, R. J., Rudiger, W., Scheer, H., Eds.; Advances in Photosynthesis
and Respiration; Springer: Dordrecht, The Netherlands, 2006; Vol. 25, pp
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Chemistry; Gribble, G. W., Joule, J. A., Eds.; Elsevier: Amsterdam, The
Netherlands, 2008; Vol. 19, Chapter 2, pp 44-69.
(22) Balasubramanian, T.; Strachan, J.-P.; Boyle, P. D.; Lindsey, J. S. J.
Org. Chem. 2000, 65, 7919–7929.
(23) Taniguchi, M.; Kim, H.-J.; Ra, D.; Schwartz, J. K.; Kirmaier, C.;
Hindin, E.; Diers, J. R.; Prathapan, S.; Bocian, D. F.; Holten, D.; Lindsey, J.
S. J. Org. Chem. 2002, 67, 7329–7342.
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8190–8200.
(32) 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.
(25) Taniguchi, M.; Kim, M. N.; Ra, D.; Lindsey, J. S. J. Org. Chem.
2005, 70, 275–285.
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D. F.; Holten, D.; Lindsey, J. S. Photochem. Photobiol. 2008, 84, 786–801.
ꢀ
(26) Laha, J. K.; Muthiah, C.; Taniguchi, M.; McDowell, B. E.; Ptaszek,
M.; Lindsey, J. S. J. Org. Chem. 2006, 71, 4092–4102.
(27) Laha, J. K.; Muthiah, C.; Taniguchi, M.; Lindsey, J. S. J. Org. Chem.
2006, 71, 7049–7052.
(28) Taniguchi, M.; Ptaszek, M.; McDowell, B. E.; Lindsey, J. S. Tetra-
hedron 2007, 63, 3840–3849.
(34) Ruzie, C.; Krayer, M.; Lindsey, J. S. Org. Lett. 2009, 11, 1761–1764.
(35) Muthiah, C.; Lahaye, D.; Taniguchi, M.; Ptaszek, M.; Lindsey, J. S.
J. Org. Chem. 2009, 74, 3237–3247.
(36) 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.
(29) Taniguchi, M.; Ptaszek, M.; McDowell, B. E.; Boyle, P. D.; Lindsey,
J. S. Tetrahedron 2007, 63, 3850–3863.
(30) Muthiah, C.; Ptaszek, M.; Nguyen, T. M.; Flack, K. M.; Lindsey, J.
S. J. Org. Chem. 2007, 72, 7736–7749.
(37) Scheer, H. In Chlorophylls and Bacteriochlorophylls; Grimm, B.,
€
Porra, R. J., Rudiger, W., Scheer, H., Eds.; Advances in Photosynthesis and
Respiration; Springer: Dordrecht, The Netherlands, 2006; Vol. 25, pp 1-26.
(38) Kobayashi, M.; Akiyama, M.; Kano, H.; Kise, H. In Chlorophylls
€
and Bacteriochlorophylls; Grimm, B., Porra, R. J., Rudiger, W., Scheer, H.,
Eds.; Advances in Photosynthesis and Respiration; Springer: Dordrecht, The
Netherlands, 2006; Vol. 25, pp 79-94.
(31) Muthiah, C.; Taniguchi, M.; Kim, H.-J.; Schmidt, I.; Kee, H. L.;
Holten, D.; Bocian, D. F.; Lindsey, J. S. Photochem. Photobiol. 2007, 83,
1513–1528.
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CHART 1
SCHEME 2
for the rational synthesis of 3,13-disubstituted chlorins and
thereby overcomes the undesired regiochemistry upon dibro-
mination of the 5-unsubstituted 1-formyldipyrromethane. The
photophysical and redox properties of the resulting 3,13-
disubstituted chlorins are presented and are compared with
those from the previously synthesized 3,12-disubstituted chlorin
isomers.32,36 This work provides access to chlorins for funda-
mental studies of the effects of substituents on the spectral
properties of molecules related to the chlorophylls. This work
also sets the stage for extension to the fully unsubstituted
131-oxophorbine, which will be described in due course.
Results and Discussion
I. Bromination of Dipyrromethanes. Many studies have
been reported concerning the bromination of pyrroles,39 and
bromo-substituted dipyrrins (the oxidized counterparts of
dipyrromethanes) have longstanding use in classical por-
phyrin syntheses.40 On the other hand, the bromination of
dipyrromethanes has been less extensively investigated, par-
ticularly where nearly all pyrrole positions are open.41
Introduction of bromine atoms in dipyrromethanes plays
an important role in the synthesis of Eastern halves for the
preparation of substituted chlorins. We reported previously
that bromination of 1-formyldipyrromethanes lacking a 5-
substituent (1) or containing a 5-substituent (2) with 1 mol
equiv of NBS at -78 °C proceeded to the 9-position,
affording 1-Br9 and 2-Br9, respectively.26 This result was
expected (and confirmed here as shown in Scheme 2) given
the deactivation of the R-formyl-substituted pyrrole ring,
and the known course of electrophilic aromatic substitution
of 2-alkylpyrroles.42 On the other hand, we report here that
bromination of 1-formyldipyrromethanes with 2 mol equiv
of NBS proceeds with a more subtle outcome: the site of the
second bromination depends on the nature of the 5-substi-
tuent (R5 in Scheme 2). The key results are described below.
The bromination of 1-formyldipyrromethanes43 1 and
2 was carried out with 2 mol equiv of NBS under the same
conditions applied previously26 (2 mol equiv of NBS at
15-position cannot form the isocyclic ring. Consequently, the
two target chlorins ZnC-E3E13 and ZnC-E3A13 (and their
chlorin precursors ZnC-Br3Br13 and ZnC-E3Br13) reported
by us previously as 13-substituted chlorins26 actually are the
isomeric 12-substituted macrocycles ZnC-E3E12 and ZnC-E3A12
(and their precursors are ZnC-Br3Br12 and ZnC-E3Br12), respec-
tively (Chart 1). The structures assigned for all of the 10,13-
substituted chlorins are correct.
The synthesis of the fully unsubstituted 131-oxophorbine
remains an important objective. Because such synthesis
requires the ability to prepare the 13-acetylchlorin (lacking
the 10-substituent), and the prior error in assignments is
restricted to the 10-unsubstituted (but not 10-substituted)
chlorins,26 we carried out a lengthy study to understand how
the regiochemistry of substitution in ring C depends on the
nature of the 10-substituent. The provision for introduction
of substituents in ring C of the chlorin is set at the dipyrro-
methane stage. The dipyrromethane required for the syn-
thesis of 13-substituted chlorins carries a 1-formyl group and
two bromine atoms: the electrophilic R-carbon atom bonded
with a bromine atom serves for condensation with a Western
half, and the β-bromine atom in turn enables subsequent
modifications at the 13-site. Thus, the 12- versus 13-substitu-
tion in the chlorins originates from a change in the regio-
chemistry upon introduction of the bromine atoms in the
1-formyldipyrromethane.
(39) Artico, M. In Pyrroles. Part One; Jones, R. A., Ed.; John Wiley &
Sons, Inc.: New York, 1990; pp 329-395.
In this paper, we first describe the bromination of
1-formyldipyrrromethanes (which contain a 5-mesityl sub-
stituent or no 5-substituent) and characterize the brominated
dipyrromethane products. Note that the 5(or meso)-position
of the dipyrromethane corresponds to the 10-position of the
chlorin. This study reveals an unexpected interplay of steric
and electronic effects in controlling the regiochemistry of
dibromination of 1-formyldipyrromethanes. We next de-
scribe a new, independent synthesis of 8,9-dibromo-1-for-
myldipyrromethane, which provides the critical precursor
(40) (a) Fischer, H.; Orth, H. Die Chemie Des Pyrroles; Johnson Reprint
Corp.: New York, 1968; Vol. II, First Half. (b) Smith, K. M. In Porphyrins
and Metalloporphyrins; Smith, K. M., Ed.; Elsevier Scientific Publishing Co.:
Amsterdam, The Netherlands, 1975; pp 29-58. (c) Paine, J. B. III In The
Porphyrins; Dolphin, D., Ed.; Academic Press: New York, 1978; Vol. 1, pp
101-234.
(41) Liu, Z.; Yasseri, A. A.; Loewe, R. S.; Lysenko, A. B.; Malinovskii, V.
L.; Zhao, Q.; Surthi, S.; Li, Q.; Misra, V.; Lindsey, J. S.; Bocian, D. F. J. Org.
Chem. 2004, 69, 5568–5577.
(42) Thamyongkit, P.; Bhise, A. D.; Taniguchi, M.; Lindsey, J. S. J. Org.
Chem. 2006, 71, 903–910.
(43) Ptaszek, M.; McDowell, B. E.; Lindsey, J. S. J. Org. Chem. 2006, 71,
4328–4331.
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SCHEME 3
-78 through -20 °C). The results are shown in Scheme 3.
The bromination of 5-unsubstituted dipyrromethane 1 af-
forded the isomeric dibromodipyrromethanes 1-Br8,9 and
1-Br7,9 in the ratio 1:5, as well as trace quantities of the
monobrominated dipyrromethane 1-Br9 and the unstable
tribrominated dipyrromethane 1-Br3,7,9 (estimated 80% iso-
lated purity). The two dibromodipyrromethane isomers were
separable upon column chromatography [silica, hexanes/
CH2Cl2/ethyl acetate (7:2:1)], where dibromodipyrro-
methane 1-Br7,9 was less polar than its isomer 1-Br8,9. To
ensure that the isolated yields were not biased by selective
loss upon workup, the ratio of dibromodipyrromethane
isomers was determined on the basis of 1H NMR spectros-
copy of the crude mixture, relying on the noticeable differ-
ence in chemical shifts of the pyrrolic protons of the pair of
dibromodipyrromethane isomers (1-Br8,9 and 1-Br7,9; Fig-
ure 1). The ratio of the pair of isomers was essentially
identical in the crude reaction mixture as upon isolation in
pure form. In summary, the dibromodipyrromethane pre-
viously assigned26 as the 8,9-dibromo isomer actually is the
This study demonstrates that the regioselectivity of bromi-
nation is affected by the steric bulk of the 5-substituent. The
first bromination occurs at the 9-position for both 1 and 2. In
the case of 9-bromo-1-formyldipyrromethane (1-Br9), both
positions C-7 and C-8 are sterically accessible for the second
bromination. Position 7 is flanked by the bridging -CH2-
and H8; position 8 is flanked by the 9-bromine substituent and
H7. Consequently, the second bromination occurs preferen-
tially at the 7-position (giving 1-Br7,9). On the other hand, the
CPK projection of 9-bromodipyrromethanes (analogues of
1-Br9 lacking the 1-formyl group) shows how the bulky
5-substituent hinders the 7-position (Figure 2), thereby ex-
plaining the major direction of the second bromination in this
case to the less sterically shielded 8-position (giving 2-Br8,9).
II. Synthesis. A. 12-Acetylchlorin. The 5-unsubstituted
7,9-dibromodipyrromethane 1-Br7,9 (interpreted previously
as an 8,9-dibromodipyrromethane26) was synthesized at the
preparative level under the same conditions as in the pre-
vious work.26 Full characterization by a number of two-
dimensional NMR experiments (HH-COSY, NOESY, and
TOCSY) confirmed the position of the bromine atoms at
positions 7 and 9. Dibromodipyrromethane 1-Br7,9 was
condensed with Western half44 3 in CH2Cl2 upon treatment
7,9-dibromo isomer 1-Br7,9
.
This result prompted us to repeat the very bromination of
5-mesityldipyrromethane 2 described earlier.26 Thus, bromi-
nation of 5-mesityldipyrromethane 2 under the same condi-
tions led to the isomeric dibromodipyrromethanes 2-Br8,9
and 2-Br7,9 in the ratio 5:1, as well as very small amounts
of monobromodipyrromethane 2-Br9 and unstable tribro-
modipyrromethane 2-Br3,8,9 (Scheme 3). 7,9-Dibromodipyr-
romethane 2-Br7,9 also was less polar than its isomer, 8,
9-dibromopyrromethane 2-Br8,9, and the two dibromodi-
pyrromethanes were readily isolated (although 2-Br7,9 and
2-Br3,8,9 were isolated in estimated 90% purity). Finally,
an analogous bromination study of 1-formyl-5-phenyldi-
pyrromethane resulted in a 5:1 ratio of the 8,9-dibromo
versus 7,9-dibromodipyrromethane product (see Suppor-
ting Information), indicating that the 5-phenyl substituent
caused the same regiochemical outcome as the 5-mesityl
substituent.
with a solution of TsOH H2O in MeOH followed by Zn(II)-
3
mediated oxidative cyclization with 2,2,6,6-tetramethylpi-
peridine, Zn(OAc)2, and AgOTf open to air.7,30 Chlorin
H2C-Br12 was obtained in 8% yield. Acetylation can be
achieved by Pd-mediated coupling with tributyl(1-ethoxyvi-
nyl)tin45 followed by acidic hydrolysis. Previously we used
THF for such reactions.26,27,30,32,46 New conditions devel-
oped recently for hydroporphyrin acetylation [CH3CN/
ꢀ
DMF (3:2), C. Ruzie and J. S. Lindsey, unpublished data]
(44) Ptaszek, M.; Bhaumik, J.; Kim, H.-J.; Taniguchi, M.; Lindsey, J. S.
Org. Process Res. Dev. 2005, 9, 651–659.
(45) Kosugi, M.; Sumiya, T.; Obara, Y.; Suzuki, M.; Sano, H.; Migita, T.
Bull. Chem. Soc. Jpn. 1987, 60, 767–768.
(46) Taniguchi, M.; Cramer, D. L.; Bhise, A. D.; Kee, H. L.; Bocian, D.
F.; Holten, D.; Lindsey, J. S. New J. Chem. 2008, 32, 947–958.
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FIGURE 1. 1H NMR spectra showing diagnostic features for 7,
9- versus 8,9-dibromodipyrromethanes.
afford shorter reaction time (2.5 versus 20 h) with compar-
able if not increased yield. Application of such conditions
afforded H2C-A12 in 78% yield. Metalation of H2C-A12
readily afforded the zinc chelate ZnC-A12. Chlorin H2C-A12
was subjected to regioselective bromination (under acidic
conditions35) at the 15-position to give H2C-A12Br15 in
40% yield (Scheme 4). Two-dimensional NMR experiments
of both H2C-Br12 and H2C-A12Br15, and X-ray analysis
of H2C-A12Br15, confirmed the structures of each chlorin
(see the Supporting Information), and, therefore, the position
of bromine atoms at positions 7 and 9 in the chlorin precursor,
FIGURE 2. Optimized structures of 9-bromodipyrromethanes with
MM2 (CPK projection). The 1-formyl group was omitted in the
calculations. In each structure, the 9-bromine atom is shown at left in
red, and nitrogen is shown in yellow. 9-Bromodipyrromethane
(a) shows little or no steric differentiation of the 7- and 8-positions
toward bromination whereas for 9-bromo-5-phenyldipyrromethane
(b) and 9-bromo-5-mesityldipyrromethane (c) the steric effect of the
5-aryl substituent suppresses bromination at the neighboring 7-position.
namely dipyrromethane 1-Br7,9
.
B. 8,9-Dibromo-1-formyldipyrromethane. To overcome
the undesired regiochemical outcome upon dibromination
of 1-formyldipyrromethane 1, we developed a stepwise
synthesis of 8,9-dibromodipyrromethane 1-Br8,9. The step-
wise synthesis relies on a sequence of formylation and
bromination where each newly introduced substituent pro-
vides regioselectivity for the next reaction (Scheme 5).
The synthesis begins with 4-bromopyrrole-2-carboxalde-
hyde (4).26 Reduction of 4 with NaBH4 in THF/MeOH
(10:1) afforded the corresponding carbinol 4-OH, which
was subjected to solventless condensation with pyrrole
(20 mol equiv versus 4) in the presence of a mild Lewis acid
(InCl3) to give 5-unsubstituted 8-bromodipyrromethane 5
in 58% yield. Attempts to purify 5 by crystallization were
unsuccessful. Purification by column chromatography af-
forded 5 as a colorless oil that was fully characterized,
although the oil darkened quickly and decomposed upon
long-term storage. Dipyrromethane 5 was previously
obtained in a similar manner but with HCl catalysis, and
was not fully characterized.30 A number of prior stepwise
syntheses of sparsely substituted dipyrromethanes have
employed a similar approach, often with the use of protec-
tive groups.22,42,47-53
The standard Vilsmeier-Haack formylation54 of 5 af-
forded 1-formyl-8-bromodipyrromethane 1-Br8 in 40%
yield. Protection of the pyrrolic nitrogen atom to direct the
formylation to the 1-position is not required: the 8-bromine
atom deactivates the adjacent 9-position, and formylation
proceeded regioselectively at the most active site in the
dipyrromethane, namely the 1-position. Treatment of 1-Br8
with 1 mol equiv of NBS at -78 °C afforded 8,9-dibromo-
dipyrromethane 1-Br8,9 as the major product in 71% yield.
(48) Lee, C.-H.; Lindsey, J. S. Tetrahedron 1994, 50, 11427–11440.
(49) Noss, L.; Liddell, P. A.; Moore, A. L.; Moore, T. A.; Gust, D. J.
Phys. Chem. B 1997, 101, 458–465.
(50) Abell, A. D.; Nabbs, B. K.; Battersby, A. R. J. Org. Chem. 1998, 63,
8163–8169.
(51) Cho, W.-S.; Kim, H.-J.; Littler, B. J.; Miller, M. A.; Lee, C.-H.;
Lindsey, J. S. J. Org. Chem. 1999, 64, 7890–7901.
(52) Littler, B. J.; Miller, M. A.; Hung, C.-H.; Wagner, R. W.; O’Shea, D.
F.; Boyle, P. D.; Lindsey, J. S. J. Org. Chem. 1999, 64, 1391–1396.
(53) Balasubramanian, T.; Lindsey, J. S. Tetrahedron 1999, 55, 6771–
6784.
(47) Wallace, D. M.; Leung, S. H.; Senge, M. O.; Smith, K. M. J. Org.
Chem. 1993, 58, 7245–7257.
(54) Dogutan, D. K.; Ptaszek, M.; Lindsey, J. S. J. Org. Chem. 2007, 72,
5008–5011.
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SCHEME 4
SCHEME 5
newly synthesized 8,9-dibromodipyrromethane 1-Br8,9. Thus,
the reaction of the Eastern half 1-Br8,9 with the Western half
bearing a bromine substituent (6)26 was carried out in the
standard way,7,30 affording chlorin ZnC-Br3Br13 in 9% yield.
Sonogashira coupling with (triisopropylsilyl)acetylene in the
presence of Pd2(dba)3, P(o-tol)3, and triethylamine afforded the
bis(ethynyl)chlorin ZnC-E3E13 in 35% yield (Scheme 6).
A chlorin bearing a 3-ethynyl and 13-acetyl group was
prepared as shown in Scheme 7. Eastern half 1-Br8,9 was
condensed with ethynyl-substituted Western half 726 in CH2Cl2
upon treatment with a solution of TsOH H2O in MeOH
3
(Scheme 7). The yield upon oxidative cyclization under con-
ventional heating did not exceed 2%, whereas microwave
irradiation afforded the target chlorin ZnC-E3Br13 in 5% yield.
The Pd-mediated acetylation of ZnC-E3Br13 was carried out
in four steps including demetalation of the zinc chelate in
TFA/CH2Cl2, acetylation under conditions analogous to those
used in the preparation of H2C-A13, acidic hydrolysis in 10%
Here, the deactivation caused by the 1-formyl group prevents
bromination at the 2- and 3-positions. Dipyrromethane 1-
Br8,9 was crystalline, thus allowing purification without use
of column chromatography. The regioselectivity of bromi-
nation was established by NMR spectroscopy (HH-COSY
and NOESY experiments, see the Supporting Information).
Compound 1-Br8,9 can be stored in solid form at 4 °C for at
least 10 weeks without decomposition.
aqueous HCl, and metalation with Zn(OAc)2 2H2O. In this
manner, chlorin ZnC-E3A13 was obtained in 59% yield.
III. Chemical Characterization. The chlorins were charac-
3
1
terized by H NMR spectroscopy (including NOESY), 13C
C. 3,13-Substituted Chlorins. Two 3,13-substituted chlo-
rins bearing auxochromes were synthesized by using the
NMR spectroscopy (for 3,13-disubstituted chlorins), matrix-
assisted laser desorption mass spectrometry (using a matrix
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SCHEME 6
SCHEME 7
of 1,4-bis(5-phenyloxazol-2-yl)benzene),55 high-resolution
electrospray ionization mass spectrometry, and absorption
and fluorescence spectroscopy.56,57
X-ray structures of a number of chlorins were obtained
to verify the substitution patterns described herein as well
as several other patterns described previously (Chart 2).
Chlorin H2C-A12Br15 was prepared via the 5-unsubstituted
dipyrromethane 1-Br7,9; the product and precursor were
previously ascribed (incorrectly)26 to chlorin isomer H2C-
A13Br15 and dipyrromethane isomer 1-Br8,9, respectively.
Chlorin ZnC-Br3Br13 was prepared from 5-unsubstituted
dipyrromethane 1-Br8,9; the X-ray structure thus confirms
the integrity of the substitution pattern for the new synthetic
route to 8,9-dibromodipyrromethanes. Additional X-ray
structures of two chlorins (ZnC-M10Br13, ZnC-T5M10A13)
and an oxophorbine (H2OP-T5M10) confirm the pattern of
10,13-, 5,10,13-, and 5,10,13,15-substituents, respectively
(see the Supporting Information). The X-ray structure of
the copper chelate CuT5M10A13 has been published.27 Each
of these macrocycles was prepared previously26,27 via the
intermediacy of a 5-mesityldipyrromethane that bears the
8,9-dibromo substitution pattern, thus confirming the integ-
rity of the 8,9-dibromination of the 5-mesityldipyrro-
methane. Other X-ray structures of chlorins have validated
the reported substitution at the 7-chlorin position.30
IV. Spectroscopy. A. Optical Spectra. The electronic
ground state absorption spectra of ZnC-E3E13 and ZnC-
E3E12 are shown in Figure 3, panels A and B, respectively.
The longest wavelength absorption feature for each com-
pound is the Qy(0,0) band and corresponds to the S0 f S1
transition. This band lies at a slightly longer wavelength
for ZnC-E3E12 than ZnC-E3E13 (645 versus 643 nm).
An analogous but slightly larger shift is observed for the
(55) Srinivasan, N.; Haney, C. A.; Lindsey, J. S.; Zhang, W.; Chait, B. T.
J. Porphyrins Phthalocyanines 1999, 3, 283–291.
(56) Li, F.; Gentemann, S.; Kalsbeck, W. A.; Seth, J.; Lindsey, J. S.;
Holten, D.; Bocian, D. F. J. Mater. Chem. 1997, 7, 1245–1262.
(57) 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, 109, 20433–20443.
5282 J. Org. Chem. Vol. 74, No. 15, 2009

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CHART 2
FIGURE 3. Absorption and fluorescence spectra of ZnC-E3E13 (A)
and ZnC-E3E12 (B) in toluene. The peak wavelengths (nm) are
indicated.
near-UV Soret feature, which corresponds to a transition
from S0 to a higher singlet excited state. Both the Qy(0,0) and
Soret maxima for ZnC-E3A12 are also bathochromically
shifted from those for ZnC-E3A13 (Figure 4), and the
shifts are 2 to 4 times larger than that found for ZnC-E3E12
versus ZnC-E3E13. These results also show that incorpora-
tion of the acetyl group in place of the ethynyl group at either
the 12- or 13-position results in a shift of the Qy and Soret
absorption features to longer wavelengths compared to the
unsubstituted chlorin (Table 1), in keeping with our prior
studies of synthetic chlorins.32,36 The ratios of the peak
intensities of the Soret and Qy bands are essentially the same
for ethyne or acetyl at the 12- or 13-positions, and the same
is true for the integrated intensities of the band contours
(Table 1).
The Qy(0,0) S1 f S0 fluorescence feature for each chlorin is
shown in Figures 3 and 4. For each compound, there is very
little Stokes shift from the corresponding absorption max-
imum. This finding is in accord with prior results on a large
series of synthetic chlorins, indicating very little change in
structural or electronic characteristics of the chlorin macro-
cycle following excitation. The average Stokes shift for the
two acetyl-substituted chlorins ZnC-E3A13 and ZnC-E3A12
(∼50 cm-1) is larger than that for the ethynyl-substituted
analogues ZnC-E3E13 and ZnC-E3E12 (∼25 cm-1). This
difference may reflect in part rotation of the acetyl group
with respect to the macrocycle in the excited state; however,
given the small magnitudes of the shifts for both substituents,
this effect is not substantial.
FIGURE 4. Absorption and fluorescence spectra of ZnC-E3A13 (A)
and ZnC-E3A12 (B) in toluene. The peak wavelengths (nm) are
indicated.
B. Fluorescence Quantum Yields and Excited-State Life-
times. The fluorescence quantum yields (Φf) and singlet
excited-state lifetimes (τS) for the four substituted chlorins
are given in Table 1 along with the values for the parent
chlorin ZnC (lacking any meso or β-pyrrole substituents).
The incorporation of an ethynyl substituent at the 13-posi-
tion of ZnC-E3E13 versus the 12-position of ZnC-E3E12 gives
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Mass et al.
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modestly larger values for Φf (0.23 versus 0.18) and τS (3.7 ns
versus 3.1 ns). Similar results are obtained for the analogous
acetyl derivatives ZnC-E3A13 versus ZnC-E3A12: Φf =0.24
versus 0.22 and τS =4.6 ns versus 4.1 ns. Insights into the
origins of these differences can be seen from the common
dependence of both Φf and τS on the rate constants for S1 f
S0 spontaneous fluorescence (kf), S1 f S0 internal conversion
(kic), and S1 f T1 intersystem crossing (kisc) via eqs 1 and 2.
-1
group is placed at the 13-position compared to the 12-posi-
tion. A possible underlying cause of this effect is that anethyne
or acetyl at the 13-position results in a slightly greater extent of
electron delocalization off the macrocycle compared to the
same group located at the 12-position.
C. Electrochemistry. The incorporation of two ethyne
groups to the parent chlorin ZnC causes a significant
(∼0.1 V) shift of the first oxidation potential to more
positives values (Table 2); furthermore, with the first ethyne
τS ¼ ðkf þ kic þ kiscÞ
ð1Þ
ox
at the 3-position, the ΔE value is effectively the same
1/2
whether the second ethyne group is located at the 12- versus
13-position (+0.40 V versus +0.41 V). Basically the same is
true for 3-ethynylchlorins in which an acetyl group is placed
at the 12- or 13-position (+0.42 V or +0.44 V). Turning to
the first reduction potentials, the incorporation of two
ethynyl groups causes a substantial (∼0.25 V) shift to less
negative values; furthermore, with the first ethyne at the 3-
position, the ΔEr1e/d2 value is effectively the same whether the
second ethyne is located at the 12- or 13-position (-1.49 or -
1.48 V). Again, the same is true for the addition of an acetyl
group at the 12- or 13-position of a 3-ethynylchlorin (-1.42
or -1.41 V). Although there are insignificant differences if
the second substituent (ethyne or acetyl) is added at the 12- or
13-position, the differences in reduction potentials of the
ethynylacetylchlorins (ZnC-E3A12 or ZnC-E3A13) are ∼0.07
V less negative than those for the bis(ethynyl)chlorins (ZnC-
E3E12 or ZnC-E3E13); the corresponding oxidation poten-
tials of the former complexes are only ∼0.02 V more positive
than those of the former. Thus, the ethynylacetylchlorins are
significantly easier to reduce than the bis(ethynyl) analogues,
but are only marginally harder to oxidize.
Φf ¼ kf =ðkf þ kic þ kiscÞ
Equation 3 shows how the radiative (fluorescence) rate
constant is calculated from the measured values of Φf and τS
(Table 1).
ð2Þ
kf ¼ Φf =τS
ð3Þ
The calculated kf values are essentially the same for ZnC-
E3E12 and ZnC-E3E13 [(16 ns)-1 and (17 ns)-1, respectively]
and the same is true for ZnC-E3A13 and ZnC-E3A12 [both
(19 ns)-1]. This finding, when factored into eqs 1 and 2,
indicates that the greater Φf and τS values that result from
placement of either an ethyne or acetyl at the 13- versus
12-position must derive from a decrease in one or both of
the nonradiative rate constants (kic, kisc). The energy-gap law
would predict a slightly smaller internal-conversion rate con-
stant for analogous 13- versus 12-substituted chlorins because
the former compounds have a slightly greater S1 excited state
energy (as seen by the Qy(0,0) absorption and emission
wavelengths, Table 1). Because kisc typically dominates over
kic for chorins,32 and given that 13- versus 12-substituted
chlorins exhibit slightly larger Φf and τS values, it is likely
that the kisc values are also smaller when an ethyne or acetyl
D. DFT Calculations. The results of the density functional
theory calculations generally track the key redox and optical
properties of the chlorins under study (Figure 5). The
identical HOMO energies of ZnC-E3E12 or ZnC-E3E13 are
in accord with the finding that the first oxidation potentials
are the same to within 0.01 eV (Table 2). The identical
LUMO energies of the same two bis(ethynyl)chlorins also
are consistent with the finding that the first reduction
potentials are the same to within 0.01 eV. The calculated
TABLE 1. Photophysical Properties of Zinc Chlorinsa
λ
Q (0,0) (nm)
y
d
compd b
ZnC e
ZnC-E3E12 f 420
λ
B (nm) absn emis IB/IQ c ΣB/ΣQ Φf τs (ns) kf-1 (ns)
y
y
398
602 602 3.4
4.1 0.062 1.7
27
645 646 1.5
643 644 1.3
655 657 1.2
648 650 1.3
2.2 0.18 3.1
2.2 0.23 3.7
2.0 0.22 4.1
2.2 0.24 4.6
17
16
19
19
HOMO of ZnC-E3A13 being only 0.02 eV more negative than
ZnC-E3E13
416
ZnC-E3A12 g 428
ZnC-E3A13
420
ox
1/2
that for ZnC-E3A12 is consistent with the measured ΔE
value of the former compound being only 0.02 eV more
positive than that of the former, the values being within
experimental error for the two compounds. Similarly, the
calculated LUMO and measured ΔEr1e/d2 values are the same
for the two ethynylacetylchlorins to within 0.01 eV. The
findings from the measured redox potentials that the ethy-
nylacetylchlorins are perhaps slightly harder to oxidize but
a All samples were measured at room temperature in toluene. b For
nomenclature, see text and Chart 1. c Ratio of the peak intensities of the
B and Qy(0,0) bands. d Ratio of the integrated intensities of the B (Bx plus
By components) and Qy absorption manifolds, which includes the (0,0)
and (1,0) features. e From ref 32. f From ref 32 wherein the compound
was initially assigned as ZnC-E3E13
.
g From ref 32 wherein the
compound was initially assigned as ZnC-E3A13
.
TABLE 2. Redox Properties and Orbital Energies of Zinc Chlorins
redox potential (V)a
orbital energy (eV)
ox
1/2
red
1/2
b
c
d
compd
ZnC
ΔE
ΔE
ΔEredox
HOMO-1
HOMO
LUMO
LUMO+1
ΔEMO
ΔE0,0
+0.30e
+0.40f
+0.41
+0.42g
+0.44
-1.74e
-1.49f
-1.48
-1.42g
-1.41
2.04
1.89
1.89
1.84
1.85
-5.16
-5.31
-5.32
-5.36
-5.36
-4.79
-4.94
-4.94
-5.02
-5.04
-2.12
-2.43
-2.43
-2.58
-2.57
-1.55
-1.79
-1.75
-1.88
-1.81
2.67
2.51
2.51
2.45
2.47
2.06
1.92
1.93
1.89
1.91
ZnC-E3E12
ZnC-E3E13
ZnC-E3A12
ZnC-E3A13
aMeasured in butyronitrile/0.1 M n-BuN4PF6; potentials versus FeCp2/FeCp2+=+0.19 V. b ΔEredox=ΔE -ΔE
. .
c ΔEMO=ELUMO -EHOMO
ox
1/2
red
1/2
dΔE0,0 is the energy of the lowest singlet excited state in toluene from Table 1. e From ref 36. f The oxidation and reduction potentials reported
in ref 36, where the compound was assigned as ZnC-E3E13, were +0.40 and -1.51 V. g From ref 36 wherein the compound was initially assigned as
ZnC-E3A13
.
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FIGURE 5. Molecular orbital energies and electron-density distributions obtained from DFT calculations.
more substantially easier to reduce are also reproduced by
the differences in HOMO energies and LUMO energies,
respectively. Finally, the differences in the redox properties
of the four substituted chlorins with the parent chlorin ZnC
are qualitatively reproduced by the trends in orbital energies.
measured difference in first oxidation and reduction poten-
ox
red
tials ΔEredox = ΔE - ΔE . These two quantities in turn
1/2
1/2
match the finding of the same energy (ΔE0,0 within 0.01 eV)
of the lowest singlet excited state derived from the optical
spectra. One expects the latter result since the LUMO-
HOMO energy gap is a major contributor to the energy of
the S1 excited state, along with a somewhat smaller (40%)
contribution from the energy gap between LUMO+1 and
The calculated orbital-energy differences ΔEMO=ELUMO
-
EHOMO for ZnC-E3E12 and ZnC-E3E13 are the same.
This result matches the finding of the same value for the
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Mass et al.
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HOMO-1.58,59 The same basic agreement is found for the
ΔEMO, ΔEredox, and ΔE0,0 values for ZnC-E3A12 and
ZnC-E3A13. In addition, the calculated ΔEMO values are
slightly (∼0.05 eV) smaller for the ethynylacetylchlorins than
for the bis(ethynyl)chlorins, consistent with the similarly smal-
ler experimental ΔEredox and ΔE0,0 values for the former versus
the latter chlorins.
in toluene.56,57 Fluorescence lifetimes were obtained by using a
phase modulation technique.57 Argon-purged solutions with an
absorbance of e0.10 at the Soret-band λexc were used for the
fluorescence spectral and lifetime measurements. For fluores-
cence spectra, the excitation and detection monochromators
typically had a band-pass of 1.5 and 3.7 nm, respectively, and
spectra were obtained with use of 0.2 nm data intervals. The
emission spectra were corrected for detection-system spectral
response. Fluorescence quantum yields were determined for
argon-purged solutions of the chlorin relative to chlorophyll
a in benzene (Φf = 0.325)60 and were corrected for solvent
refractive index.
Conclusions
Reexamination of the dibromination of dipyrromethanes
1 and 2 revealed an unexpected interplay of steric and
electronic effects. In particular, the bromination of a
1-formyldipyrromethane with 2 equiv of NBS proceeds at
the 9- and 7-positions when there is no steric hindrance
owing to a 5-aryl substituent; in the presence of a 5-aryl
substituent, bromination proceeds at the 9- and 8-positions.
The 7,9-dibromination pattern provides access to 12-sub-
stituted chlorins that lack a 10-substituent.
For calculation of the integrated-intensity ratio of the Soret
and Qy absorption manifolds (ΣB/ΣQ ), the Soret region was
y
typically integrated from the red of the origin maximum
(∼450 nm) to ∼350 nm in order to encompass the Bx(0,0),
By(0,0), Bx(1,0), and By(1,0) features. Similarly, integration of
the Qy manifold encompassed the (0,0) band and the (1,0)
feature(s), but not any (2,0) contributions. For each compound,
the integration range for both the B and Qy manifolds was
chosen to attempt to best capture the associated oscillator
strength while minimizing contributions from absorption to
higher energy electronic states (e.g., the Qx bands in the case
of the Qy manifold).
Electrochemistry. The electrochemical measurements were
made in a standard three-electrode cell with Pt working
and counter electrodes and an Ag/Ag+ reference electrode.
The solvent/electrolyte was butyronitrile containing 0.1 M
n-BuN4PF6. The potentials are reported versus FeCp2/
FeCp2+=0.19 V.
A rational route has been developed to 8,9-dibromo-1-
formyldipyrromethane (1-Br8,9, lacking a 5-substituent),
which constitutes a key precursor for 13-substituted chlor-
ins lacking 10-substituents. Thus, chlorins bearing a single
substituent at the 12-position or 13-position can now be
unambiguously obtained, the former by regioselective bro-
mination of the Eastern half precursor (1-formyldipyrro-
methane), the latter by a new, stepwise synthesis of 8,
9-dibromo-1-formyldipyrromethane. It is essential to set
the regiochemistry of bromine substitution at the dipyrro-
methane stage, given that the target dibromo-1-formyldipyr-
romethane can be separated from isomers thereof as well as
from monobromo and polybromo analogues. By contrast,
the corresponding chlorin isomers are not readily separable.
The availability of both 12-substituted and 13-substituted
chlorins provided an opportunity to probe the distinctions
caused by this change in substitution pattern. The incorpora-
tion of an ethyne or acetyl group at the 12-position versus the
13-position of a 3-ethynylchlorin results in (1) essentially the
same first oxidation potential (within 0.01 eV), (2) essentially
the same first reduction potential (within 0.02 eV), (3) a small
blue shift in the Qy(0,0) absorption and emission bands
(∼2 nm for the bis(ethynyl)chlorin and ∼7 nm for the
ethynylacetylchlorin), (4) an increase in fluorescence yield
(∼30% for the bis(ethynyl)chlorin and ∼10% for the ethy-
nylacetylchlorin), and (5) an ∼15% average lengthening of
the lifetime of the lowest singlet excited state. The availability
of chlorin isomers identical in all aspects except for the
position of a substituent at the 12- or 13-position, which
grew out of an effort to understand the unexpected regio-
chemistry of bromination of 1-formyldipyrromethanes, has
provided deeper insight into the effects of substituents on the
spectral, redox, and photochemical features of analogues of
chlorophyll.
Molecular Orbital Calculations. Density functional theory
(DFT) calculations were performed as described previously,36
using the hybrid B3LYP functional and a 6-31G* basis set. The
equilibrium geometry of each complex was fully optimized by
using the complete structure and the default parameters of the
program.
Bromination of 1-Formyldipyrromethane (1). A solution of 1
(174 mg, 1.00 mmol) in anhydrous THF (10 mL) at -78 °C was
treated with NBS (348 mg, 2.00 mmol) in one batch under argon.
The reaction mixture was stirred for 1 h at -78 °C, after which the
ice bath was removed. A thermometer was placed in the reaction
mixture. The reaction mixture was allowed to warm up. Hexanes
(10 mL) and water (10 mL) were added when the temperature of
the reaction mixture reached -20 °C. The entire contents of the
reaction flask were transferred to a separatory funnel. Ethyl acetate
(20 mL) was added. The organic layer was separated, dried
(K2CO3), and concentrated without heating to afford a brown
solid. Column chromatography [silica, hexanes/CH2Cl2/ethyl ace-
tate (7:2:1)] afforded three brominated dipyrromethanes in the
following order: a trace of 3,7,9-tribromo-1-formyldipyrro-
methane (1-Br3,7,9, estimated 80% purity, 8 mg, 2%); a dominant
amount of 7,9-dibromo-1-formyldipyrromethane (1-Br7,9, 219 mg,
66%); and finally a lesser amount of 8,9-dibromo-1-formyldi-
pyrromethane (1-Br8,9, 41 mg, 12%).
The three products were examined by 1H NMR spectroscopy.
The 1H NMR data for 1-Br7,9 were consistent with those
described previously (reported as 1-Br8,9).27 The 1H NMR data
for 1-Br8,9 were consistent with those described for the com-
pound prepared by rational synthesis (vide infra). Compound
1-Br3,7,9 has not been previously described.
Experimental Section
1
Data for 1-Br3,7,9: H NMR (THF-d8) δ 3.96 (s, 2H), 6.06
Absorption and Fluorescence Spectroscopy. Static absorption
and fluorescence measurements were performed as described
previously, typically for very dilute solutions of the compounds
(m, 1H), 6.92 (m, 1H), 9.37 (s, 1H), 10.71 (br s, 1H), 11.45
(br s, 1H); ESI-MS obsd 408.8184 (M+H)+ corresponds to
407.81114 (M), calcd 407.81085 (C10H7Br3N2O).
Bromination of 1-Formyl-5-mesityldipyrromethane (2). Bro-
mination of 2 (292 mg, 1.00 mmol) was carried out in exact
(58) Gouterman, M. In The Porphyrins; Dolphin, D., Ed.; Academic
Press: New York, 1978; Vol. 3, pp 1-165.
(59) Petit, L.; Quartarolo, A.; Adamo, C.; Russo, N. J. Phys. Chem. B
2006, 110, 2398–2404.
(60) Weber, G.; Teale, F. W. J. Trans. Faraday Soc. 1957, 53, 646–655.
5286 J. Org. Chem. Vol. 74, No. 15, 2009

Mass et al.
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analogy with that of 1. Column chromatography [silica,
hexanes/CH2Cl2/ethyl acetate (7:2:1)] afforded three bromi-
nated dipyrromethanes in the following order: a trace of 3,8,
9-tribromo-1-formyl-5-mesityldipyrromethane (2-Br3,8,9, esti-
mated 90% purity, 9 mg, 2%); an amount of 7,9-dibromo-1-
formyl-5-mesityldipyrromethane (2-Br7,9, estimated 90% pur-
ity, 37 mg, 10%); and finally a dominant amount of 8,
9-dibromo-1-formyl-5-mesityldipyrromethane (2-Br8,9, 180 mg,
12-Acetyl-17,18-dihydro-18,18-dimethylporphyrin (H2C-A12).
Following a procedure for acetylation of aromatic compounds
via Stille coupling45 with modification, a mixture of H2C-Br12
(14 mg, 0.034 mmol), tributyl(1-ethoxyvinyl)tin (45.0 μL, 0.134
mmol), and (PPh3)2PdCl2 (4 mg, 0.005 mmol) was heated in
acetonitrile/DMF [3 mL, (3:2)] at 85 °C for 2.5 h. The reaction
mixture was treated with 10% aqueous HCl (3 mL) at room
temperature for 40 min and then diluted with CH2Cl2. The
organic phase was washed with saturated aqueous NaHCO3,
water, and brine. The organic layer was dried (Na2SO4), con-
centrated, and chromatographed [silica, CH2Cl2] to afford a
purple solid (10 mg, 78%): 1H NMR δ -2.29 (br s, 1H), -2.08
(br s, 1H), 2.05 (s, 6H), 3.27 (s, 3H), 4.59 (s, 2H), 8.93 (s, 1H),
8.98 (d, J =4.5 Hz, 1H), 8.99 (d, J =4.1 Hz, 1H), 9.01 (s, 1H),
9.13 (d, J =4.1 Hz, 1H), 9.20 (d, J =4.5 Hz, 1H), 9.24 (s, 1H),
9.73 (s, 1H), 10.80 (s, 1H); LD-MS obsd 381.6; ESI-MS
obsd 383.1869 (M+H)+ corresponds to 382.1797 (M), calcd
382.1794 (C24H22N4O); λabs 414, 662 nm.
1
49%). The three products were examined by H NMR spec-
1
troscopy. The H NMR data for 2-Br8,9 were consistent with
those described previously.26 Compounds 2-Br7,9 and
2-Br3,8,9 have not been previously described.
Data for 2-Br7,9: mp 66-68 °C dec; 1H NMR (THF-d8) δ 2.06
(s, 6H), 2.23 (s, 3H), 5.67-5.68 (m, 1H), 5.80 (s, 1H), 6.10 (s,
1H), 6.76 (s, 1H), 6.81 (s, 2H), 9.42 (s, 1H), 10.46 (br s, 1H), 11.31
(br s, 1H); 13C NMR (THF-d8) δ 21.1, 21.2, 39.9, 96.7, 97.4,
112.0, 113.5, 121.1, 131.1, 132.0, 134.3, 135.4, 137.1, 137.9,
139.8, 178.7; ESI-MS obsd 448.98618 (M + H)+ corresponds
to 447.97890 (M), calcd 447.97859 (C19H18Br2N2O).
Zn(II)-12-acetyl-17,18-dihydro-18,18-dimethylporphyrin (ZnC-
A12). A solution of H2C-A12 (9 mg, 0.02 mmol) in CHCl3
(4 mL) was treated with a solution of Zn(OAc)2 2H2O (78 mg,
Data for 2-Br3,8,9: mp 65 °C dec; 1H NMR (THF-d8) δ 2.06
(s, 6H), 2.23 (s, 3 H), 5.54-5.55 (m, 1H), 5.74 (s, 1H), 6.82
(s, 2H), 6.94-6.95 (m, 1H), 9.39 (s, 1H), 11.01 (br s, 1H),
11.26 (br s, 1H); ESI-MS obsd 526.8955 (M+H)+corresponds
to 525.88826, calcd 525.88910 (C19H17Br3N2O).
3
0.35 mmol) in MeOH (1 mL). The reaction mixture was stirred
for 6 h at room temperature. Then the reaction mixture was
concentrated, and the crude solid was dissolved in CH2Cl2. The
organic phase was washed with saturated aqueous NaHCO3,
water, and brine. The organic layer was dried (Na2SO4) and
concentrated. The solid was washed three times with hexanes.
The solid was dissolved in CH2Cl2 (1 mL), and hexanes (1 mL)
was added. The resulting precipitate was isolated by centrifuga-
tion (9 mg, 80%): 1H NMR (THF-d8) δ 2.05 (s, 6H), 3.14 (s, 3H),
4.56 (s, 2H), 8.70 (s, 1H), 8.74 (s, 1H), 8.79-8.80 (m, 1H), 8.92-
8.93 (m, 1H), 9.05-9.08 (m, 2H), 9.28 (s, 1H), 9.58 (s, 1H), 10.77
(s, 1H); LD-MS obsd 444.1; ESI-MS obsd 444.0928 (M+)
corresponds to 444.0934 (M), calcd 444.0929 (C24H20N4OZn)
7,9-Dibromo-1-formyldipyrromethane (1-Br7,9). Following
the procedure for dibromination of 1-formyldipyrromethanes
(described incorrectly to give 1-Br8,9),26 a solution of 1 (174 mg,
1.00 mmol) in anhydrous THF (15 mL) at -78 °C was treated
with NBS (383 mg, 2.20 mmol) in one batch under argon. The
reaction mixture was stirred for 1 h at -78 °C, after which the ice
bath was removed, and the reaction mixture was allowed to
warm up. Hexanes was added when the reaction mixture
reached -20 °C, and water was added upon reaching 0 °C.
Ethyl acetate was added. The organic layer was separated, dried
(K2CO3), and concentrated without heating to afford a brown
solid. Column chromatography [silica, hexanes/CH2Cl2/ethyl
acetate (7:2:1)] afforded a pinkish-white solid (175 mg, 52%):
mp 109-111 °C dec; 1H NMR (THF-d8) δ 3.94 (s, 2H), 5.89-
5.91 (m, 1H), 6.06 (m, 1H), 6.77-6.80 (m, 1H), 9.37 (s, 1H),
10.84 (br s, 1H), 11.17 (br s, 1H); 13C NMR (THF-d8) δ 96.2,
97.9, 110.0, 112.6, 121.6, 121.7, 128.8, 134.2, 138.9, 178.4. Anal.
Calcd for C10H8Br2N2O: C, 36.18; H, 2.43; N, 8.44. Found: C,
36.58; H, 2.50; N, 8.11.
λ
abs 418, 637 nm.
12-Acetyl-15-bromo-17,18-dihydro-18,18-dimethylporphyrin (H2C-
A12Br15). A solution of H2C-A12 (14.0 mg, 0.0368 mmol) in
CH2Cl2/TFA [18 mL (10:1)] was treated with NBS (368 μL,
0.100 M in CH2Cl2, 0.037 mmol). The reaction mixture was
stirred for 1 h at room temperature. CH2Cl2 was added, and the
mixture was washed with NaHCO3. The organic layer was dried
(Na2SO4), concentrated, and chromatographed [silica, CH2Cl2/
hexanes (2:1)] to afford a purple solid (7 mg, 40%): 1H NMR δ -
1.99 (br s, 2H), 2.03 (s, 6H), 3.25 (s, 3H), 4.58 (s, 2H), 8.75 (s,
1H), 8.76 (d, J = 4.2 Hz, 1H), 8.87 (d, J = 4.8 Hz, 1H), 8.95
(d, J = 4.2 Hz, 1H), 9.06 (d, J = 4.8 Hz, 1H), 9.44 (s, 1H), 9.48
(s, 1H), 10.63 (s, 1H); MALDI-MS obsd 460.3; ESI-MS obsd
461.09692 (M+H)+ corresponds to 460.08965 (M), calcd
460.08987 (C24H21BrN4O); λabs 418, 664 nm.
12-Bromo-17,18-dihydro-18,18-dimethylporphyrin (H2C-Br12).
A solution of 1-Br7,9 (155 mg, 0.467 mmol) and 3 (88 mg, 0.47
mmol) in anhydrous CH2Cl2 (12 mL) was treated with a solution
of TsOH H2O (445 mg, 2.34 mmol) in anhydrous methanol
3
(3 mL) under argon. The color of the reaction mixture changed
immediately to orange-red. The mixture was stirred for 30 min
under argon, then treated with 2,2,6,6-tetramethylpiperidine (970
μL, 5.15 mmol) and concentrated to dryness. The resulting brown
solid was suspended in acetonitrile (50 mL), and 2,2,6,
6-tetramethylpiperidine (1.58 mL, 9.34 mmol), Zn(OAc)2
(1.29 g, 7.01 mmol), and AgOTf (360 mg, 1.40 mmol) were added.
The resulting suspension was refluxed for 16 h exposed to air. The
reaction mixture was filtered though a silica pad, and the filtrate
was concentrated to a green solid. The solid was dissolved in
CH2Cl2 (12 mL), and the solution was stirred and treated drop-
wise with TFA (280 μL, 3.60 mmol). After 3 h the reaction mixture
was diluted with CH2Cl2 and washed (saturated aqueous NaH-
CO3, water, and brine). The organic phase was separated, con-
centrated, and chromatographed [silica, CH2Cl2/hexanes (1:2)] to
afford a green solid(15 mg, 8%): 1H NMR δ -2.45 (br s, 2H), 2.06
(s, 6H), 4.64 (s, 2H), 8.96-8.99 (m, 4H), 9.06 (d, J = 3.9 Hz, 1H),
9.10 (d, J = 3.9 Hz, 1H), 9.25 (d, J = 4.7 Hz, 1H), 9.85 (s, 1H),
9.92 (s, 1H); LD-MS obsd 417.8; ESI-MS obsd 419.0869 (M+
H)+ corresponds to 418.0796 (M), calcd 418.0793 (C22H19BrN4);
2-Bromodipyrromethane (5). A solutionof 4 (2.48 g, 14.4 mmol)
in anhydrous THF/methanol (144 mL) at 0 °C was slowly treated
with NaBH4 (8.85 g, 233 mmol) in portions. The mixture was
stirred for 2 h. Then water and ethyl acetate were added, and the
resultingmixturewasstirredfor20min. Afterthoroughextraction
with ethyl acetate, the organic layer was separated, dried
(Na2SO4), and concentrated to give a colorless oil, which was
used in the next stage without purification. The oil was dissolved in
pyrrole (20.0 mL, 287 mmol). The solution was degassed with a
stream of argon for 10 min and then treated with InCl3 (343 mg,
1.55 mmol). The mixture was stirred overnight under argon. The
mixture turned dark brown during the first hour of reaction. The
reaction mixture was quenched with 1 M NaOH (50 mL). After
extraction with ethyl acetate, the organiclayer was dried (Na2SO4)
and concentrated. The excess pyrrole was recovered under high
vacuum. The resulting crude brown oil was chromatographed
[silica, hexanes/CH2Cl2/ethyl acetate (7:2:1)] to afford a pale
1
yellow oil that turned brown upon storage (2.02 g, 58%): H
NMR δ 3.89 (s, 2H), 6.02-6.03 (m, 2H), 6.13-6.16 (m, 1H),
λabs 391, 640 nm.
J. Org. Chem. Vol. 74, No. 15, 2009 5287

Mass et al.
JOCArticle
6.58-6.59 (m, 1H), 6.65-6.66 (m, 1H), 7.66-7.84 (br s, 2H); 13
C
corresponds to 557.90238, calcd 557.90330 (C22H16Br2N4Zn);
λ
NMR δ 26.5, 96.1, 107.1, 108.7, 109.2, 117.2, 117.9, 128.2, 130.2;
ESI-MS obsd 225.00137 (M+H)+ corresponds to 223.99409 (M),
calcd 223.99491 (C9H9BrN2).
abs 405, 619 nm.
Zn(II)-13-bromo-17,18-dihydro-18,18-dimethyl-3-[2-(triisopropyl-
silyl)ethynyl]porphyrin (ZnC-E3Br13). A solution of 1-Br8,9 (117
mg, 0.350 mmol) and 7 (130 mg, 0.350 mmol) in anhydrous
CH2Cl2 (10.0 mL) was treated with a solution of TsOH H2O
8-Bromo-1-formyldipyrromethane (1-Br8). A sample of DMF
(7.00 mL) was treated with POCl3 (1.00 mL, 10.9 mmol) at 0 °C
under argon, and the mixture was stirred for 10 min. Then a
solution of 5 (1.94 g, 8.55 mmol) in DMF (25 mL) at 0 °C was
treated with the freshly prepared Vilsmeier reagent (5.62 mL)
under argon. The resulting mixture was stirred for 2 h at 0 °C.
The mixture was poured into a cooled mixture of 2 M NaOH
(120 mL) and CH2Cl2 (80 mL) at 0 °C and stirred for 20 min. The
organic phase was washed (saturated aqueous NH4Cl, water,
and brine), dried (Na2SO4), and concentrated to give a red-
brownish oil. The oil was treated with hexanes and concentrated
to give a brown solid. Column chromatography [silica, hexanes/
ethyl acetate (6:1)] afforded a brown solid. For recrystallization
the solid was dissolved in the minimal amount of warm CH2Cl2,
which upon cooling afforded pale brown crystals (868 mg,
3
(333 mg, 1.75 mmol) in anhydrous methanol (2.5 mL) under
argon. The reaction mixture changed immediately to orange-
red. The mixture was stirred for 40 min under argon, then
treated with 2,2,6,6-tetramethylpiperidine (655 μL, 3.85 mmol)
and concentrated to dryness. The resulting light brown solid was
suspended in acetonitrile (35 mL), and the mixture was placed in
an 80 mL pressurized microwave flask. The microwave appa-
ratus has been described.34 2,2,6,6-Tetramethylpiperidine (1.48
mL, 8.75 mmol), Zn(OAc)2 (966 mg, 5.25 mmol), and AgOTf
(270 mg, 1.05 mmol) were added consecutively to the solution.
The flask was inserted in a microwave reactor, and the reaction
was carried out at 81 °C for 1.5 h. The crude mixture was filtered
through a silica pad with ethyl acetate, and the filtrate was
concentrated and chromatographed [silica, CH2Cl2/hexanes
(3:2)] to afford a dark green solid (11 mg, 5%): 1H NMR
(THF-d8) δ 1.44-1.46 (m, 21H), 2.04 (s, 6H), 4.62 (s, 2H),
8.67 (s, 1H), 8.86 (s, 1H), 8.91 (s, 1H), 8.95 (s, 1H + 1H), 9.14 (s,
1H), 9.56 (s, 1H), 9.87 (s, 1H); 13C NMR (THF-d8) δ 12.7, 19.5,
31.3, 46.1, 51.6, 94.2, 95.3, 98.8, 104.4, 106.7, 108.6, 116.5, 127.0,
130.0, 130.2, 130.7, 133.2, 145.3, 147.3, 147.9, 148.5, 149.5,
152.5, 160.3, 171.3; MALDI-MS obsd 660.4; ESI-MS obsd
660.1261 (M+) corresponds to 660.1255 (M), calcd 660.1262
(C33H37BrN4SiZn); λabs 412, 632 nm.
1
40%): mp 134-135 °C dec; H NMR (acetone-d6) δ 4.02 (s,
2H), 5.93-5.95 (m, 1H), 6.08-6.09 (m, 1H), 6.73-6.75 (m, 1H),
6.89-6.90 (m, 1H), 9.41 (s, 1H), 10.6 (br s, 1H), 10.9 (br s, 1H);
13C NMR (acetone-d6) δ 27.2, 96.2, 110.0, 110.8, 118.4, 122.4,
131.0, 134.1, 140.6, 179.2; ESI-MS obsd 252.99694 (M+H)+
corresponds to 251.98966 (M), calcd 251.98983 (C10H9BrN2O).
Anal. Calcd for C10H9BrN2O: C, 47.46; H, 3.58; N, 11.07.
Found: C, 47.74, H, 3.52, N, 11.03.
8,9-Dibromo-1-formyldipyrromethane (1-Br8,9). A solution of
1-Br8 (506 mg, 2.00 mmol) in anhydrous THF (20 mL) was
treated with NBS (356 mg, 2.00 mmol) in one batch under argon
at -78 °C. The reaction mixture was stirred for 1 h at -78 °C,
after which the ice bath was removed, and the reaction mixture
was allowed to warm up. Upon reaching 5 °C, hexanes and
water were added. The mixture was extracted with ethyl acetate.
The organic layer was dried (K2CO3) and concentrated to afford
a brown solid. The solid was suspended in warm CH2Cl2, and
THF was added to achieve complete dissolution, whereupon
hexanes was added. Pale yellow crystals were obtained (476 mg,
71%): mp 104-105 °C dec; 1H NMR (acetone-d6) δ 4.03 (s, 2H),
6.03 (s, 1H), 6.10 (d, J=3.9 Hz, 1H), 6.89 (d, J=3.9 Hz, 1H),
9.41 (s, 1H), 10.9 (br s, 1H), one NH was not observed
presumably due to deuterium exchange; 13C NMR (acetone-
d6) δ 27.2, 98.2, 98.8, 110.7, 111.0, 122.4, 132.2, 133.8,
139.9, 179.1; ESI-MS obsd 330.90857 (M+H)+ corresponds
to 329.90130 (M), calcd 329.90034 (C10H8Br2N2O). Anal. Calcd
for C10H8Br2N2O: C, 36.18; H, 2.43; N, 8.44. Found: C, 36.08,
H, 2.43, N, 8.28.
Zn(II)-17,18-dihydro-18,18-dimethyl-3,13-bis[2-(triisopropyl-
silyl)ethynyl]porphyrin (ZnC-E3E13). Following a procedure for
ethynylation of chlorins via Sonogashira coupling,26 a mixture
of ZnC-Br3Br13 (38 mg, 0.068 mmol), (triisopropylsilyl)acety-
lene (95 μL, 0.41 mmol), Pd2(dba)3 (19 mg, 0.020 mmol), and
P(o-tol)3 (50 mg, 0.16 mmol) was heated in toluene/triethyla-
mine [12 mL, (3:1)] at 60 °C for 8 h, using a Schlenk line. The
reaction mixture was concentrated and chromatographed [sili-
ca, hexanes/CH2Cl2 (3:1)] to afford a green solid (18 mg, 35%):
1H NMR (THF-d8) δ 1.43-1.46 (m, 42H), 2.06 (s, 6H), 4.60
(s, 2H), 8.64 (s, 1H), 8.91 (s, 1H), 8.93 (d, J = 4.2 Hz, 1H), 8.96
(d, J = 4.2 Hz, 1H), 9.03 (s, 1H), 9.18 (s, 1H), 9.58 (s, 1H),
9.85 (s, 1H); 13C NMR (THF-d8) δ 12.7, 13.0, 19.1, 19.5,
31.4, 46.2, 51.5, 94.8, 95.0, 97.5, 98.8, 104.4, 104.7, 106.4,
109.4, 122.1, 127.0, 130.1, 130.8, 135.5, 145.7, 147.5, 148.2,
148.7, 152.7, 153.7, 160.2, 171.6, one R-carbon was not
observed owing to overlap; MALDI-MS obsd 762.8;
ESI-MS obsd 763.3585 (M+H)+ corresponds to 762.35122
(M), calcd 762.34915 (C44H58N4Si2Zn); λabs 416, 643 nm; λem
(λex=416 nm) 644 nm.
Zn(II)-13-acetyl-17,18-dihydro-18,18-dimethyl-3-[2-(triisopropyl-
silyl)ethynyl]porphyrin (ZnC-E3A13). The following procedure en-
tails zinc demetalation, Pd-mediated coupling with tributyl(1-
ethoxyvinyl)tin, acidic hydrolysis, and zinc metalation. A solu-
tion of ZnC-E3Br13 (18 mg, 0.027 mmol) in CH2Cl2 (1 mL) was
treated dropwise with TFA (42 μL, 0.54 mmol). After 5 h
CH2Cl2 was added, and the organic layer was washed (saturated
aqueous NaHCO3, water, brine), dried (Na2SO4), and concen-
trated. The resulting crude solid was used in the next step. A
mixture of crude solid, tributyl(1-ethoxyvinyl)tin (0.037 mL,
0.11 mmol), and (PPh3)2PdCl2 (3 mg, 0.004 mmol) was stirred
in acetonitrile/DMF [2.5 mL, (3:2)] at 85 °C, using a Schlenk
line. After 3.5 h the reaction mixture was treated with 10%
aqueous HCl (3.5 mL) at room temperature. The mixture was
stirred for 1 h. CH2Cl2 was added, and the organic layer was
washed (saturated aqueous NaHCO3, water, brine), dried
(Na2SO4), and concentrated. The crude solid was dissolved in
Zn(II)-3,13-dibromo-17,18-dihydro-18,18-dimethylporphyrin (ZnC-
Br3Br13). A solution of 1-Br8,9 (134 mg, 0.400 mmol) and 6 (107
mg, 0.400 mmol) in anhydrous CH2Cl2 (10.6 mL) was treated
with a solution of TsOH H2O (380 mg, 2.00 mmol) in anhy-
3
drous methanol (2.8 mL) under argon. The reaction mixture
changed immediately to orange-red. The mixture was stirred for
30 min under argon, then treated with 2,2,6,6-tetramethylpiper-
idine (746 μL, 4.40 mmol) and concentrated to dryness. The
resulting brown solid was suspended in acetonitrile (40 mL), and
2,2,6,6-tetramethylpiperidine (1.70 mL, 10.0 mmol), Zn(OAc)2
(1.10 g, 6.00 mmol), and AgOTf (308 mg, 1.20 mmol) were
added consecutively. The resulting suspension was refluxed for
22 h exposed to air. The crude mixture was filtered through a
silica pad with CH2Cl2, and the filtrate was chromatographed
[silica, CH2Cl2] to afford a green solid (21 mg, 9%): 1H NMR
(THF-d8) δ 2.04 (s, 6H), 4.61 (s, 2H), 8.65 (s, 1H), 8.86-8.87
(m, 2H), 8.95 (d, J=4.1 Hz, 1H), 9.01 (d, J=4.1 Hz, 1H), 9.14
(s, 1H), 9.57 (s, 1H), 9.73 (s, 1H); 13C NMR (THF-d8) δ 31.5,
46.4, 51.7, 94.0, 95.1, 109.1, 109.2, 115.8, 128.6, 129.4, 129.8,
133.0, 133.7, 144.6, 147.6, 147.8, 148.3, 149.3, 155.1, 159.8,
171.6; MALDI-MS obsd 557.9; ESI-MS obsd 557.9021 (M+)
CHCl3 (4 mL), and the solution was treated with Zn(OAc)2
2H2O (89 mg, 0.41 mmol) in MeOH (1 mL). The reaction
3
5288 J. Org. Chem. Vol. 74, No. 15, 2009

Mass et al.
JOCArticle
mixture was stirred for 16 h at room temperature. Then the
reaction mixture was concentrated and chromatographed [sili-
ca, CH2Cl2/hexanes (2:1)] to afford a green solid (10 mg, 59%):
1H NMR (THF-d8) δ 1.43 (s, 21H), 2.02 (s, 6H), 3.09 (s, 3H),
4.56 (s, 2H), 8.58 (s, 1H), 8.87 (s, 1H), 8.88 (d, J=3.9 Hz, 1H),
8.95 (d, J=3.9 Hz, 1H), 9.63 (s, 1H), 9.64 (s, 1H), 9.75 (s, 1H),
9.88 (s, 1H); 13C NMR (THF-d8) δ 12.7, 19.5, 29.6, 31.2, 46.2,
51.5, 95.0, 98.7, 99.1, 104.2, 105.8, 111.4, 127.5, 130.0, 130.7,
131.7, 135.2, 138.3, 143.5, 148.35, 148.42, 149.3, 150.8, 153.6,
160.4, 172,5, 196.0; MALDI-MS obsd 624.8; ESI-MS
obsd 625.2320 (M+H)+ corresponds to 624.22476 (M), calcd
05ER15661), D.F.B. (DE-FG02-05ER15660), and J.S.L.
(DE-FG02-96ER14632). Olga Mass was the recipient of a
Burroughs-Wellcome Fellowship. Mass spectra were ob-
tained at the Mass Spectrometry Laboratory for Biotechno-
logy at North Carolina State University. Partial funding for
the facility was obtained from the North Carolina Biotech-
nology Center and the National Science Foundation. We
thank Dr. Chinnasamy Muthiah for obtaining the X-ray
structures of selected chlorins.
624.22628 (C35H40N4OSiZn); λabs 420, 645 nm; λem (λex
420 nm) 650 nm.
=
Supporting Information Available: Spectral data (1H NMR
and 13C NMR) for all new chlorins including spectral assign-
ments; additional information concerning experimental proce-
dures; X-ray data for four chlorins and one 131-oxophorbine
(H2C-A12Br15, ZnC-Br3Br13, ZnC-T5M10A13, ZnC-M10Br13,
H2OP-T5M10). This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. This research was supported by grants
from the Chemical Sciences, Geosciences and Biosciences
Division, Office of Basic Energy Sciences, Office of
Science, U.S. Department of Energy to D.H. (DE-FG02-
J. Org. Chem. Vol. 74, No. 15, 2009 5289