Regioselective bromination tactics in the de novo synthesis of chlorophyll b analogues

Article abstract of DOI:10.1021/jo9002954

The ability to introduce substituents at designated sites about the perimeter of the chlorin or 13¹-oxophorbine macrocycle is essential for fundamental studies related to chlorophylls. A chlorin is a dihydroporphyrin, whereas a 13¹-oxophorbine is a chlorin containing an annulated oxopentano ring spanning positions 13 and 15. 13 ¹-Oxophorbines bearing auxochromes at the 7-position of the macrocycle are valuable targets given their resemblance to chlorophyll a or b, which contains the 13¹-oxophorbine skeleton and bears a 7-methyl or 7-formyl group, respectively. A rational route to 7-substituted 13¹ oxophorbines was developed that relies on a new method for regioselective bromination. Under neutral conditions, a 13-acetyl-10-mesitylchlorin (FbC-M ¹⁰A¹³) undergoes bromination (with 1 molar equiv of NBS in THF) both in ring B (7-position) and at the 15-position (42% versus 28% isolated yield), thereby thwarting installation of the isocyclic ring (ring E, spanning the 13-15 positions). Under acidic conditions (10% TFA in CH ₂C1₂), ring B is deactivated, and bromination occurs preferentially at the 15-position (87% yield). The capability for preferential 15-bromination is essential to install the isocyclic ring, after which bromination can be directed to the 7-position of ring B (neutral conditions, 86% yield). The ability to suppress bromination in ring B (under acidic media) has been exploited in syntheses of sparsely substituted analogues of chlorophyll b. The analogues contain a 7-substituent (acetyl, formyl, or TIPS-ethynyl), a 10-mesityl group, and the 18,18-dimethyl group as the only substituents in the 13¹-oxophorbine skeleton. The three analogues exhibit absorption spectral features that closely resemble those of free base analogues of chlorophyll b. Taken together, the facile access to chlorins and 13 ¹-oxophorbines bearing substituents at distinct sites should enable fundamental spectroscopic studies and diverse applications.

Full text of DOI:10.1021/jo9002954

VOLUME 74, NUMBER 9
May 1, 2009
Copyright 2009 by the American Chemical Society
Regioselective Bromination Tactics in the de Novo Synthesis of
Chlorophyll b Analogues
Chinnasamy Muthiah, Dorothe´e Lahaye, Masahiko Taniguchi, Marcin Ptaszek, and
Jonathan S. Lindsey*
Department of Chemistry, North Carolina State UniVersity, Raleigh, North Carolina 27695-8204
jlindsey@ncsu.edu
ReceiVed February 10, 2009
The ability to introduce substituents at designated sites about the perimeter of the chlorin or
131-oxophorbine macrocycle is essential for fundamental studies related to chlorophylls. A chlorin is a
dihydroporphyrin, whereas a 131-oxophorbine is a chlorin containing an annulated oxopentano ring
spanning positions 13 and 15. 131-Oxophorbines bearing auxochromes at the 7-position of the macrocycle
are valuable targets given their resemblance to chlorophyll a or b, which contains the 131-oxophorbine
skeleton and bears a 7-methyl or 7-formyl group, respectively. A rational route to 7-substituted 131-
oxophorbines was developed that relies on a new method for regioselective bromination. Under neutral
conditions, a 13-acetyl-10-mesitylchlorin (FbC-M10A13) undergoes bromination (with 1 molar equiv of
NBS in THF) both in ring B (7-position) and at the 15-position (42% versus 28% isolated yield), thereby
thwarting installation of the isocyclic ring (ring E, spanning the 13-15 positions). Under acidic conditions
(10% TFA in CH2Cl2), ring B is deactivated, and bromination occurs preferentially at the 15-position
(87% yield). The capability for preferential 15-bromination is essential to install the isocyclic ring, after
which bromination can be directed to the 7-position of ring B (neutral conditions, 86% yield). The ability
to suppress bromination in ring B (under acidic media) has been exploited in syntheses of sparsely
substituted analogues of chlorophyll b. The analogues contain a 7-substituent (acetyl, formyl, or TIPS-
ethynyl), a 10-mesityl group, and the 18,18-dimethyl group as the only substituents in the 131-oxophorbine
skeleton. The three analogues exhibit absorption spectral features that closely resemble those of free
base analogues of chlorophyll b. Taken together, the facile access to chlorins and 131-oxophorbines bearing
substituents at distinct sites should enable fundamental spectroscopic studies and diverse applications.
10.1021/jo9002954 CCC: $40.75
Published on Web 04/09/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3237–3247 3237

Muthiah et al.
oxophorbine),15 which spans positions 13 and 15 (Chart 1). The
resulting chlorins typically have relatively few substituents about
the perimeter of the macrocycle. The availability of chlorins
bearing substituents at designated sites has enabled a set of
fundamental spectroscopic studies.1,8,16-23 Such sparsely sub-
stituted chlorins require considerable synthetic investment for
preparation yet are distinct from the chlorins obtained by
derivatization of porphyrins or by semisynthetic modification
of chlorophylls.24-37
CHART 1
A next challenge in chlorin chemistry entails the introduction
of multiple substituents at designated sites, primarily to examine
the impact on spectral properties, but also to achieve molecular
designs required for specific applications. For example, the 131-
oxophorbines that we recently prepared contained substituents
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Tetrahedron 2007, 63, 3826–3839.
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2007, 63, 3840–3849.
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5842.
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J. Org. Chem. 2007, 72, 7736–7749.
(15) Laha, J. K.; Muthiah, C.; Taniguchi, M.; Lindsey, J. S. J. Org. Chem.
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(16) Muthukumaran, K.; Loewe, R. S.; Kirmaier, C.; Hinden, E.; Schwartz,
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M.; Laha, J. K.; Ptaszek, M.; Lindsey, J. S.; Bocian, D. F.; Holten, D. Photochem.
Photobiol. 2007, 83, 1110–1124.
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M.; Laha, J. K.; Ptaszek, M.; Lindsey, J. S.; Bocian, D. F.; Holten, D. Photochem.
Photobiol. 2007, 83, 1125–1143.
Introduction
A deep understanding of the effects of substituents on the
spectral and photophysical properties of chlorins is essential for
applications ranging from artificial photosynthesis to photomedi-
cine. The long-wavelength absorption band ranges from 610
nm in a magnesium chlorin lacking any pyrrole substituents,1
to 642 nm in chlorophyll b, to 661 nm in chlorophyll a.2
Chlorophyll a bears methyl groups at positions 2, 7, and 12; an
8-ethyl group; a 3-vinyl group; and a keto group at position 13
(which is integral to the isocyclic ring spanning the 13-15
positions). Chlorophyll b differs from chlorophyll a only in the
presence of a 7-formyl rather than a 7-methyl group (Chart 1).3,4
To better understand the effects of distinct substituents at
specific positions, we have for some time been working to
develop rational methods for preparing stable, synthetically
tailorable chlorins, wherein each chlorin (dihydroporphyrin)
bears a geminal dimethyl group in the reduced, pyrroline ring.
The geminal dimethyl group blocks adventitious dehydrogena-
tion and thereby affords a more stable chlorin. In this regard,
we now have routes to access every peripheral site of the chlorin
macrocycle, including the 2, 3, 5, 7, 8, 10, 12, 13, 15, 17, 18,
and 20-positions5-14 and also can install the isocyclic ring (131-
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D.; Bocian, D. F.; Lindsey, J. S. Photochem. Photobiol. 2007, 83, 1513–1528.
(23) Stromberg, J. R.; Marton, A.; Kee, H. L.; Kirmaier, C.; Diers, J. R.;
Muthiah, C.; Taniguchi, M.; Lindsey, J. S.; Bocian, D. F.; Meyer, G. J.; Holten,
D. J. Phys. Chem. C 2007, 111, 15464–15478.
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Raton, 1991; pp 145-209.
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347.
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Guilard, R., Eds.; Academic Press: San Diego, 2000; Vol. 1, pp 201-237.
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(32) Montforts, F.-P.; Glasenapp-Breiling, M. Fortschr. Chem. Org. Naturst.
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(1) Taniguchi, M.; Ptaszek, M.; McDowell, B. E.; Boyle, P. D.; Lindsey,
J. S. Tetrahedron 2007, 63, 3850–3863.
(2) Strain, H. H.; Thomas, M. R.; Katz, J. J. Biochim. Biophys. Acta 1963,
75, 306–311.
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1991; pp 3-30.
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Org. Chem. 2000, 65, 3160–3172.
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393–425.
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Chem. 2000, 65, 7919–7929.
(7) Taniguchi, M.; Ra, D.; Mo, G.; Balasubramanian, T.; Lindsey, J. S. J.
Org. Chem. 2001, 66, 7342–7354.
(8) 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.
(9) Taniguchi, M.; Kim, M. N.; Ra, D.; Lindsey, J. S. J. Org. Chem. 2005,
70, 275–285.
(34) Senge, M. O.; Wiehe, A.; Ryppa, C. In Chlorophylls and Bacteriochlo-
rophylls. Biochemistry, Biophysics, Functions and Applications; Grimm, B., Porra,
R. J., Ru¨diger, W., Scheer, H., Eds.; Advances in Photosynthesis and Respiration;
Springer: Dordrecht, The Netherlands, 2006; Vol. 25, pp 27-37.
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(36) Galezowski, M.; Gryko, D. T. Curr. Org. Chem. 2007, 11, 1310–1338.
(37) Silva, A. M. G.; Cavaleiro, J. A. S. In Progress in Heterocyclic
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3238 J. Org. Chem. Vol. 74, No. 9, 2009

Bromination Tactics in Chlorin Chemistry
at the 5- and 10-positions but no substituents at the ꢀ-pyrrole
positions.15 On the other hand, a set of 7-substituted chlorins
did not contain the isocyclic ring.14
One synthetic approach is to build into the acyclic precursors
to the chlorin those groups or synthetic handles that are destined
for specific sites on the chlorin macrocycle. A complementary
approach is to construct the chlorin macrocycle and employ
selective derivatization to introduce the desired substituents.
Both approaches have been employed; the former is more
versatile yet requires the more extensive synthesis. The deriva-
tization approach has relied on bromination followed by
substitution of positions 7, 8, 15, and 20, whereas position 17
has been selectively oxidized.8,9,12,14,15,19 Access to all other
positions has required introduction of a group or synthetic handle
at the outset of the synthesis. The bromination of chlorins is an
approach that dates primarily to the work of Woodward, who
showed that the two meso positions flanking the pyrroline ring
are more reactive toward electrophilic substitution than the other
two meso positions.38 The chlorins deuterated by Woodward,
and brominated by a number of subsequent groups,39-44
contained a full complement of ꢀ-substituents. Accordingly, the
issue of competing bromination at ꢀ-sites in chlorins has been
relatively unexamined. Our own studies have shown that the
pattern of bromination of chlorins at the 7, 8, 15, and 20
positions is highly influenced by steric effects of neighboring
substituents.9,14 Our results are consistent with those of Varamo
et al. where the bromination of a 10,20-diarylchlorin afforded
a mixture of the 15-bromo- and 7,15-dibromochlorins.45 The
chief results concerning regioselective bromination that are
pertinent to the present paper are described here.
A completely unsubstituted chlorin macrocycle is anticipated
to undergo bromination preferentially at the meso-sites flanking
the pyrroline ring (i.e., 15- and 20-positions), followed by the
ꢀ-sites in the ring trans to the pyrroline ring (ring B, the 7- and
8-positions) (Figure 1). This exact study has not actually been
performed owing to the lack of access, and expected instability,
of the fully unsubstituted chlorin (u-FbC) lacking geminal
dimethyl substitution (or other stabilizing motif) in the pyrroline
ring. The expectation is supported on the basis of results from
diverse chlorins, including the following data obtained with
sparsely substituted chlorins.
(i) A chlorin (FbC) bearing substituents only in the pyrroline
ring, namely the stabilizing 18,18-dimethyl group, undergoes
regioselective bromination at the 15-position; the 20-position
is hindered by the adjacent gem-dimethyl group.12
(ii) A similar chlorin wherein the 15-position is substituted
with a phenyl group (FbC-P15) undergoes bromination equally
at the 7- and 8-positions.14
FIGURE 1. Preferred sites of bromination of free base chlorins under
neutral conditions.
the 7-position; the 8-position is hindered by the flanking 10-
aryl group.14
(iv) An analogous chlorin bearing a p-tolyl group at the
5-position (FbC-T5P15) rather than the 10-position undergoes
bromination preferentially at the 8-position; the 7-position is
now hindered by the flanking 5-aryl group.14
(v) A chlorin bearing aryl groups at the 5- and 10-positions,
and a 13-acetyl group, undergoes bromination selectively at the
15-position, which constitutes a key step in the installation of
the isocyclic ring.15 The results in i-v illustrate the overlay of
steric factors on fundamental electronic preferences.
(iii) A similar chlorin also bearing a p-tolyl group at the 10-
position (FbC-T10P15) undergoes bromination preferentially at
ˇ
(38) Woodward, R. B.; Skaric´, V. J. Am. Chem. Soc. 1961, 83, 4676–4678.
(39) Bonnett, R.; Gale, I. A. D.; Stephenson, G. F. J. Chem. Soc. C 1966,
1600–1604.
In this paper, we describe the development of conditions that
provide an additional level of control for the regioselective
bromination of chlorin macrocycles. Such conditions are
exploited in the synthesis of sparsely substituted chlorins that
bear desirable patterns of substituents, including analogues of
chlorophyll b. The motivation for preparing sparsely substituted
analogues is to be able to understand the effects of individual
substituents at designated sites on the spectral properties of
chlorins.
(40) Kenner, G. W.; McCombie, S. W.; Smith, K. M. J. Chem. Soc., Perkin
Trans. 1 1973, 2517–2523.
(41) Michalski, T. J.; Appelman, E. H.; Bowman, M. K.; Hunt, J. E.; Norris,
J. R.; Cotton, T. M.; Raser, L. Tetrahedron Lett. 1990, 31, 6847–6850.
(42) Kureishi, Y.; Tamiaki, H. J. Porphyrins Phthalocyanines 1998, 2, 159–
169.
(43) Kelley, R. F.; Tauber, M. J.; Wasielewski, M. R. J. Am. Chem. Soc.
2006, 128, 4779–4791.
(44) Sasaki, S.-I.; Mizoguchi, T.; Tamiaki, H. J. Org. Chem. 2007, 72, 4566–
4569.
(45) Varamo, M.; Loock, B.; Maillard, P.; Grierson, D. S. Org. Lett. 2007,
9, 4689–4692.
J. Org. Chem. Vol. 74, No. 9, 2009 3239

Muthiah et al.
SCHEME 1
SCHEME 2
TABLE 1. Bromination of FbCa
NBS
(equiv)
position of
substitutionb (%)
entry
solvent
1
2
3
4
5
6
THF
THF
THF
THF
1
2
3
4
1
2
15 (67%)c
15,7 and 15,8 (1:1 ratio)d
15,7,8 (62%)e
15,7,8 (48%)f
Results and Discussion
CH2Cl2/TFA (10:1)
CH2Cl2/TFA (10:1)
15 (62%)g
15,20 (51%)h
I. Synthesis of Sparsely Substituted Chlorophyll b
Analogues. A. Prelude. The anticipated retrosynthetic analysis
for the sparsely substituted chlorophyll b analogues is shown
in Scheme 1. A key reaction sequence entails synthesis of a
10-aryl-13-bromochlorin (FbC-M10Br13), which is subjected to
installation of the isocyclic ring (13-acetylation, 15-bromination,
and intramolecular R-arylation) followed by 7-bromination and
Pd-mediated coupling to introduce substituents at the 7-position.
The zinc chelates of both the 13-bromochlorin (ZnC-M10Br13)
and the 13-acetylchlorin (ZnC-M10A13) are known compounds
that were previously prepared in modest quantities (72 mg, 26%;
25 mg, 53%).10 Streamlined procedures to prepare the known
zinc chlorin ZnC-M10Br13 (431 mg, 45% yield from acyclic
precursors46) and the new free base chlorin FbC-M10A13 (301
mg, 85% yield) are described in the Supporting Information.
Treatment of FbC-M10A13 with 1 equiv of NBS in THF at
room temperature for 1.5 h afforded a mixture of two bromo-
chlorins in 42% and 28% yield. NMR analysis (1H NMR,
NOESY, COSY) of the isolated products showed that the major
component was the 7-substituted bromochlorin FbC-Br7M10A13
and the minor component was the 15-substituted bromochlorin
FbC-M10A13Br15. Similar reaction at -78 °C afforded the
a All reactions were carried out at room temperature. b On the basis of
1H NMR data. c Reference 12. d Not isolated. e A trace of
dibromochlorin was also formed (LD-MS). f Inseparable mixture of tri-
and tetrabromochlorins was formed (1H NMR and LD-MS). g A trace of
15,20-dibromochlorin was also formed (LD-MS). h A trace of
monobromochlorin was also isolated.
7-bromochlorin FbC-Br7M10A13 exclusively in 76% yield.
These results were at first surprising because our prior synthesis
of the oxophorbine had used the same conditions to achieve
15-bromination. However, those earlier studies had used,
unwittingly, a 5,10-diarylchlorin (FbC-T5M10A13, Figure 1). The
aryl substituents at the 5- and 10-positions hinder the flanking
7- and 8-positions and in so doing result in substitution at the
15-position despite the steric hindrance of the 13-acetyl moiety.
The failure to achieve selective 15-bromination of FbC-M10A13
(Scheme 2) prompted further studies of the bromination of
chlorins.
B. Bromination Studies of a Benchmark Chlorin. We have
previously reported that the electrophilic bromination of chlorin
FbC (bearing the 18,18-dimethyl substituents but no other
groups) proceeds selectively at the 15-position (entry 1, Table
1).12 To confirm our expectations about the second-, third-, and
fourth-most reactive site in the chlorin macrocycle, we reex-
amined the bromination of FbC using increasing amounts of
(46) Ptaszek, M.; Bhaumik, J.; Kim, H.-J.; Taniguchi, M.; Lindsey, J. S.
Org. Process Res. DeV. 2005, 9, 651–659.
3240 J. Org. Chem. Vol. 74, No. 9, 2009

Bromination Tactics in Chlorin Chemistry
CHART 2
SCHEME 3
NBS (Table 1). Treatment of FbC with 2 equiv of NBS in THF
at room temperature afforded an inseparable, nearly equimolar
mixture of two dibromochlorins (entry 2), which upon NMR
analysis (1H NMR, COSY, NOESY) were identified as the 7,15-
dibromochlorin FbC-Br7,15 and the 8,15-dibromochlorin FbC-
Br8,15. Treatment with 3 molar equiv of NBS afforded the
expected 7,8,15-tribromochlorin FbC-Br7,8,15 in 61% yield (entry
3). When 4 molar equiv of NBS was employed, the only isolable
product was tribromochlorin FbC-Br7,8,15, which was ac-
companied by an inseparable mixture of tri- and tetrabromo-
chlorins (entry 4). In cases where products were not isolable,
1
the reaction mixture was examined by H NMR spectroscopy
and laser desorption mass spectrometry in the absence of a
matrix (LD-MS).47
On the other hand, treatment of FbC at room temperature
with 1 molar equiv of NBS under acidic conditions, achieved
in the solvent CH2Cl2/TFA (10:1), afforded the 15-monobro-
mochlorin FbC-Br15 (entry 5), and a trace of dibromochlorin
FbC-Br15,20. Treatment with 2 equiv of NBS gave the 15,20-
dibromochlorin FbC-Br15,20 in 51% yield (entry 6), with no
detectable quantity of the 7- or 8-substituted product. The
motivation for this experiment was the hypothesis that an acidic
medium, upon protonation of the free nitrogens (Chart 2), would
preferentially deactivate ring B. This expectation was indeed
borne out. Evidence in support of protonation of at least one if
not both free nitrogens in the chlorin stems from absorption
spectroscopy. FbC undergoes a hypsochromic shift of the long-
wavelength Qy(0,0) band upon acidification in toluene.1 Similar
features were observed for the chlorins examined herein.
Spectral data for chlorins FbC and FbC-M10A13 in CH2Cl2 with
and without TFA are presented in the Supporting Information.
To our knowledge, all prior reports of chlorin bromination
under acidic conditions concern macrocycles bearing a full
complement of ꢀ-substituents (e.g., chlorophyll a derivatives)38-44
where the distinctions between neutral and acidic conditions
would not be manifested. In summary, the order of reactive sites
for bromination of chlorin FbC under neutral conditions is 15
> 7,8 > 20, whereas that under acidic conditions is 15 > 20 >
7,8. The ability to suppress the reactivity of the ꢀ-pyrrole sites
of ring B merely by altering the solvent composition (neutral
versus acidic) affords a versatile tactic for introducing substit-
uents in chlorin and oxophorbine macrocycles. The resulting
change in regioselectivity provides a solution to the synthesis
of sparsely substituted chlorophyll b analogues (vide infra).
C. Bromination of More Elaborate Chlorins. To further
develop our understanding of regioselective bromination, we
also examined the bromination of several more highly substi-
tuted chlorins or 131-oxophorbines (Scheme 3). Thus, a chlorin
bearing both a 13-bromo group and a 10-mesityl group (FbC-
M10Br13) was employed in a lengthy study of bromination. The
chief results are that neutral bromination conditions (NBS in
THF, CHCl3, or CH2Cl2) afford predominantly the 7,13-
dibromochlorin FbC-M10Br7,13, whereas acidic bromination
affords the 13,15-dibromochlorin FbC-M10Br13,15 in 60% yield
with only traces of chlorins containing two or more bromo atoms
(see the Supporting Information for a table of data). Treatment
of the 3,13-diacetylchlorin FbC-A3M10A13 with NBS under
neutral conditions at -78 °C gave the 7-bromo product FbC-
A3Br7M10A13 in 68% yield, an expected regiochemical outcome
given the similar result upon low temperature bromination of
FbC-M10A13 (vide supra).
Treatment of the 5,10-diaryl-substituted oxophorbine FbOP-
T5M10 with 1 equiv of NBS in THF at room temperature for
1.5 h afforded the 20-bromooxophorbine FbOP-T5M10Br20 in
61% yield. Thus, for a 5,10-disubstituted oxophorbine, the order
of reactivity is 20 > 7, 8 even under neutral conditions. On the
other hand, the absence of the steric effect of the 5-aryl unit
affords less clean results. Thus, FbOP-M10 under the standard
acidic bromination conditions [1 equiv of NBS in CH2Cl2/TFA
(10:1) at room temperature for 1.5 h] afforded a mixture of
products including the expected FbOP-M10Br20 as the main
product (accompanied by a small amount of an inseparable,
unidentified monobromochlorin), a significant quantity of start-
ing material (separable in 40% yield), and a small amount of
(47) Baillargeon, V. P.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 452–461.
J. Org. Chem. Vol. 74, No. 9, 2009 3241

Muthiah et al.
TABLE 2. Derivatization of 7-Bromooxophorbine FbOP-Br7M10
R-arylation15 under Pd-mediated conditions gave the desired 131-
oxophorbine FbOP-M10 in 77% yield. In a streamlined reaction
sequence, acidic bromination of FbC-M10A13 afforded the crude
15-bromochlorin (10 mM), which upon treatment under the
standard conditions for R-arylation [(PPh3)2PdCl2 (20 mol%)
and Cs2CO3 (50 mM) in toluene at reflux] afforded the 131-
oxophorbine FbOP-M10 in 58% overall yield. This method
provides facile access to the 131-oxophorbine lacking a 5-sub-
stituent. Bromination of FbOP-M10 under neutral conditions
with 1 molar equiv of NBS in THF at room temperature for
2 h gave the 7-bromo-131-oxophorbine FbOP-Br7M10 in 86%
yield. As expected, the 20-position is hindered owing to the
presence of the gem-dimethyl group, the 15-position is blocked,
and the 8-position is sterically hindered by the 10-substituent,
leaving the 7-position as the most accessible site.
SCHEME 4
The structure of FbOP-Br7M10 was confirmed by NOESY
(see the Supporting Information). The position of the adjacent
ꢀ-proton (H8) shifted from 8.42 to 8.41 ppm in going from
FbOP-M10 to FbOP-Br7M10, whereas the adjacent meso proton
(H5) shifted from 9.35 to 9.57 ppm. In general, the introduction
of a ꢀ-bromo atom causes hardly any effect on the adjacent
ꢀ-H, whereas the neighboring meso-H undergoes a chemical
shift of 0.2 ppm, making the identification of ꢀ-bromochlorins
(3, 7, 13 position, etc.) relatively straightforward. Prior 7-sub-
stituted chlorins prepared in the same manner have been
analyzed by X-ray crystallography.14
E. Derivatization of 7-Bromo-131-oxophorbines. The 7-bro-
mo-131-oxophorbine FbOP-Br7M10 was derivatized with po-
tential auxochromes such as acetyl and formyl groups (Table
2). The formyl group was introduced to mimic chlorophyll b.
The coupling of FbOP-Br7M10 (20 mM) and tributyl(1-
ethoxyvinyl)tin (80 mM) in the presence of 20 mol % of
(PPh3)2PdCl2 in THF for 20 h followed by hydrolysis with 10%
aqueous HCl gave 7-acetylchlorin FbOP-A7M10 in 76% yield
(entry 1). The synthesis of formylchlorins13 has been achieved
by Pd-mediated carbonylation. Similar treatment of FbOP-
Br7M10 (10 mM) with sodium formate (25 mM) in the presence
of (PPh3)2PdCl2 (20 mol %) and PPh3 (20 mol %) in DMF at
108 °C under an atmosphere of CO48 afforded the 7-formyl-
oxophorbine FbOP-F7M10 in 34% yield. Upon use of Bu3SnH
an unidentified dibromooxophorbine (separable). While the
acidic bromination of FbOP-M10 did not give particularly clean
results, the neutral bromination (vide infra) was quite clean.
D. Bromination Tactics in a Route to Chlorophyll b
Analogues. Bromination of 13-acetylchlorin FbC-M10A13 under
acidic conditions [NBS in CH2Cl2/TFA (10:1) at room temper-
ature for 1.5 h] gave the 15-bromochlorin FbC-M10A13Br15 in
87% yield (Scheme 4). The 7-bromochlorin was not observed
in this reaction, and only a trace of the 15,20-dibromochlorin
was identified (1H NMR, LD-MS). Subsequent ring closure via
(48) Srinivasan, N.; Haney, C. A.; Lindsey, J. S.; Zhang, W.; Chait, B. T. J.
Porphyrins Phthalocyanines 1999, 3, 283–291.
3242 J. Org. Chem. Vol. 74, No. 9, 2009

Bromination Tactics in Chlorin Chemistry
TABLE 3. Absorption Spectral Properties of 13-Substituted Chlorins and 7-Substituted 131-Oxophorbinesa
λB
λQy(0,0)
[fwhm] (nm)
∆Qy(0,0)
b
b
c
d
compd
[fwhm] (nm)
∆B (cm-1
)
(cm-1
)
IB/IQy(0,0)
ΣB/ΣQy(0,0)
FbC-M10e
400 [34]
398 [36]
415 [36]
413 [58]
638 [9]
2.5
2.1
1.9
1.7
7.9
7.0
5.5
6.3
FbC-M10Br13
FbC-M10A13
FbOP-M10
130
-900
-790
645 [10]
659 [12]
656 [11]
-170
-500
-430
FbOP-Br7M10
FbOP-E7M10
FbOP-A7M10
FbOP-F7M10
425 [40]
434 [32]
440 [21]
442 [20]
-680
-1200
-1500
-1600
656 [12]
660 [11]
654 [11]
653 [11]
0
-90
50
2.3
2.6
4.1
4.5
7.1
7.7
10
70
14
Pheo af
408.5 [54]
432.5 [18]
667.5 [18]
656.5 [18]
2.0
4.6
4.4
7.8
Pheo bf
-1350
250
b
a In toluene at room temperature unless noted otherwise. The shift of the band relative to that of the parent chlorin (FbC-M10) or parent
oxophorbine (FbOP-M10). c Ratio of the intensities of the B and Qy(0,0) bands. d Ratio of the integrated intensities of the B band (360-450 nm for
FbC-M10, FbC-M10Br13, and Pheo a; 360-480 nm for all other compounds) and Qy(0,0) band (615-665 nm for FbC-M10 and FbC-M10Br13; 625-700
nm for Pheo a and Pheo b; 630-690 nm for all other compounds). e Absorption data from ref 1 (in toluene). f Absorption data for pheophytin a and
pheophytin b in diethyl ether.49
and a stoichiometric amount of Pd(PPh3)4, the yield of 7-formyl-
ation was increased to 78% (entry 2). Reaction with (triisopro-
pylsilyl)acetylene gave the 7-ethynyl-substituted oxophorbine
FbOP-E7M10 in 67% yield (entry 3).
II. Spectroscopic Studies. The chlorins and oxophorbines
1
were characterized by H NMR spectroscopy, LD-MS, high-
resolution mass spectrometry (FAB-MS or ESI-MS), absorption
spectroscopy, and, where permitted by solubility and sample
size, 13C NMR spectroscopy. The spectral properties of the free
base 13-acetylchlorin and 131-oxophorbines are listed in Table
3, accompanied by those of the benchmark free base chlorin
(FbC-M10)1 lacking any 13-substituent, and free base derivatives
(i.e., pheophytins, abbreviated Pheo a and Pheo b)49 of
chlorophyll a and chlorophyll b. The corresponding absorption
spectra of the synthetic chlorins are displayed in Figure 2.
The spectral properties of the 13-acetylchlorin (FbC-M10A13)
or the 131-oxophorbine (FbOP-M10) are similar to those
observed previously for analogous compounds that contain an
additional 3-substituent or 5-aryl substituent, respectively.10,15,20,21
Both compounds contain a 13-keto group, which functions as
an auxochrome to cause the following effects versus the
benchmark free base chlorin FbC-M10: (i) a 13-15 nm
bathochromic shift of the B band, (ii) a 18-21 nm bathochromic
shift of the Qy(0,0) band, and (iii) a hyperchromic effect on the
Qy(0,0) band.10,15 The hyperchromic effect is assessed by the
ratio of the intensities of the B versus Qy(0,0) bands, IB/IQy(0,0)
(which is a long-established metric in chlorin chemistry2), or
by the ratio of the integrated absorbances (ΣB/ΣQy(0,0)). The latter
is a more accurate measure when the full-width at half-maximum
(fwhm) of either band changes substantially upon substitution,
as is the case here: the fwhm of the entire B band for FbC-
M10A13 is 36 nm, while that of FbOP-M10 is 58 nm. By such
FIGURE 2. Absorption spectra in toluene at room temperature of 13-
substituted chlorins and 131-oxophorbines (normalized at the B bands).
The label and the color in the graph are as follows. (A): FbC-M10 (a,
black), FbC-M10Br13 (b, blue), FbC-M10A13 (c, lime), FbOP-M10 (d,
red). (B): FbOP-M10 (d, red), FbOP-Br7M10 (e, lime), FbOP-E7M10
(f, blue), FbOP-A7M10 (g, purple), FbOP-F7M10 (h, black).
measures the Q-band gains relative strength of 1.2-1.5-fold,
as shown in Table 3. The only noticeable differences in the
spectra of the two compounds occur in the visible region, where
the Qx(0,0) band of FbOP-M10 shows further bathochromic
shifts with stronger intensity compared to that of FbC-M10A13
(see spectra in the Supporting Information).
7-position of oxophorbines affords a quite different outcome
(Figure 2B). The presence of a 7-acetyl or 7-formyl group in a
131-oxophorbine causes a significant bathochromic shift of the
B band (27 nm for FbOP-A7M10, 29 nm for FbOP-F7M10)
versus that of FbOP-M10. On the other hand, the position of
the Qy(0,0) band is essentially unchanged (2-3 nm hypsochro-
mic shift) yet the relative intensity is profoundly decreased
Whereas the presence of the oxophorbine ring in FbOP-M10
versus the chlorin benchmark FbC-M10 causes bathochromic
shifts of both the B and Qy bands and a hyperchromic effect on
the Qy(0,0) band, the introduction of auxochromes at the
(49) Zass, E.; Isenring, H. P.; Etter, R.; Eschenmoser, A. HelV. Chim. Acta
1980, 63, 1048–1067.
J. Org. Chem. Vol. 74, No. 9, 2009 3243

Muthiah et al.
regioselective bromination (acidic conditions) at the 15-position.
The resulting 131-oxophorbine, obtained upon Pd-mediated
R-arylation to form the isocyclic ring, undergoes regioselective
bromination (neutral conditions) at the 7-position. Although most
prior brominations of chlorins employed acidic conditions,39-44
the use of chlorins bearing a full complement of ꢀ-substituents
hid this otherwise new aspect of the chemistry of chlorins.
Subsequent derivatization affords analogues of chlorophyll b.
The analogues are sparsely substituted given that the only
substituents other than that at the 7-position are (i) the geminal
dimethyl group in the pyrroline ring and (ii) the mesityl group
at the 10-position.
The presence of the keto group at the 13-position in FbOP-
M10 causes a bathochromic shift and a relative increase in the
intensity of the Qy(0,0) band. On the other hand, the introduction
of an acetyl or formyl group at the 7-position in FbOP-M10
causes a bathochromic shift and sharpening of the B band, leaves
the position of the Qy(0,0) band essentially unchanged, and
affords a significant relative decrease in Qy(0,0) intensity. The
ability to install the isocyclic ring and selectively brominate
the chlorin macrocycle should facilitate a range of fundamental
studies. The ability to achieve spectral features similar to those
of free base chlorophylls in structurally simpler molecular
architectures bodes well for applications ranging from artificial
photosynthesis to photomedicine.
Experimental Section
A. Bromination Studies. Practical Aspects Concerning the
Bromination of Chlorins. The bromination of chlorins described
herein for synthetic applications generally occurs with high regio-
selectivity. Still, the main product often is accompanied by a small
amount of other isomers, overbrominated chlorins, and unreacted
chlorin. The amount of the undesired side products varies for
different chlorins, and the identity of chlorins formed as byproducts
typically has not been fully determined due to the small amount of
isolated material. In most cases, the reaction mixture was separable
by column chromatography. The composition of the reaction
mixture depends on the amount of brominating agent used. The
ratio of dibromochlorins and unreacted starting chlorins can slightly
vary for a given starting material from reaction to reaction, due to
the small inaccuracy in measurement of the amount of brominating
agent. In some instances, a 0.10 M stock solution of NBS in an
appropriate solvent was used where specified for bromination to
facilitate more accurate measurements. The addition of solid NBS
typically was performed all-at-once whereas the stock solution of
NBS was added over 10–30 sec for reactions on the scale of
0.01–0.06 mmol (or longer for larger reactions). The bromination
studies were performed using free base chlorins rather than zinc
complexes because (1) free base chlorins form narrow, well-resolved
bands on silica gel whereas zinc complexes tend to streak upon
chromatography and (ii) prior results12 concerning the bromination
of Zn(II) chlorins afforded side products which may include dimers
of chlorins.
Dibromination of FbC under Neutral Conditions: 1:1
Mixture of FbC-Br7,15 and FbC-Br8,15. A solution of FbC12 (24.0
mg, 0.0705 mmol) in THF (35 mL) was treated with NBS (25.1
mg, 0.140 mmol). The resulting reaction mixture was stirred at room
temperature for 1.5 h. The reaction mixture was diluted with CH2Cl2
(∼50 mL) and quenched by the addition of saturated aqueous
NaHCO3. The organic layer was separated, dried (Na2SO4), and
concentrated. Column chromatography of the resulting solid [silica,
hexanes/CH2Cl2 (4:1) then hexanes/CH2Cl2 (1:1)] provided the
dibromochlorin (first fraction, purple) and a trace of monobromo-
chlorin (second fraction, green). The dibromochlorin was rechro-
matographed [silica, hexanes/CH2Cl2 (1:1)] to afford a purple solid
FIGURE 3. Absorption spectra at room temperature of natural versus
synthetic 131-oxophorbines (normalized at the B bands). (A) Absorption
spectra of pheophytin a (dashed) and FbOP-M10 (solid). (B): Absorp-
tion spectra of pheophytin b (dashed) and FbOP-F7M10 (solid). The
pheophytins are in diethyl ether, whereas the synthetic analogues are
in toluene.
(2.5-2.7-fold) as illustrated by the change in the IB/IQy(0,0) ratio
from 1.7 to 4.1 (FbOP-A7M10) or 4.5 (FbOP-F7M10). The
altered IB/IQy(0,0) ratio stems in part from the sharpening (nearly
one-third decrease in fwhm) of the B band upon introduction
of the 7-acetyl or 7-formyl group. Thus, the general trend with
auxochromes at the 7-position of 131-oxophorbines is to
bathochromically shift and sharpen the B band, leaving the
Qy(0,0) band relatively unchanged in position but significantly
decreased in relative intensity.
A key outcome of our work with sparsely substituted chlorins
is the realization that the placement of essential groups at
designated sites about the perimeter of the chlorin macrocycle
can afford suitable analogues of chlorophylls. Figure 3 compares
the absorption spectra49 of pheophytins a and b with oxophor-
bines FbOP-M10 and FbOP-F7M10. Pheophytin a incorporates
a 7-methyl substituent, whereas pheophytin b is equipped with
a 7-formyl group. In each case, the spectral features are relatively
well matched, both in terms of position and relative intensity
of absorption, despite the absence of the 3-vinyl group
characteristic of the naturally occurring oxophorbines.
Conclusions
New regioselective bromination tactics have opened a rational
route to 131-oxophorbines bearing 7-conjugative groups. The
route entails preparation of a 13-acetylchlorin, which undergoes
3244 J. Org. Chem. Vol. 74, No. 9, 2009

Bromination Tactics in Chlorin Chemistry
1
(23.1 mg, 66%): H NMR δ -2.97 (brs, 1H), -2.77 (brs, 1H),
chlorin was rechromatographed [silica, hexanes/CH2Cl2 (2:1)] to
afford a purple solid (17.8 mg, 51%): 1H NMR δ -2.73 (brs, 1H),
-2.63 (brs, 1H), 2.26 (s, 6H), 4.75 (s, 2H), 8.83 (d, J ) 4.4 Hz,
1H), 8.87 (d, J ) 4.4 Hz, 1H), 9.04 (d, J ) 4.4 Hz, 1H), 9.10 (d,
J ) 4.4 Hz, 1H), 9.25 (d, J ) 4.4 Hz, 1H), 9.41 (d, J ) 4.4 Hz,
1H), 9.55 (s, 1H), 9.63 (s, 1H); 13C NMR δ 29.7, 49.1, 60.5, 96.6,
96.7, 107.7, 108.8, 126.5, 126.6, 128.7, 133.0, 133.5, 135.2, 136.2,
138.3, 140.0, 152.0, 153.0, 162.2, 171.9 (one carbon resonance was
not apparent); LD-MS obsd 496.5; FAB-MS obsd 496.1002, calcd
496.9898 [(M + H)+, M ) C22H18Br2N4]; λabs (toluene) 402, 648
nm.
2.03 (s, 6H), 4.61 (s, 2H), 8.81 (s + d, 2H), 8.88 (dd, J ) 2.0, 4.4
Hz, 1H), 8.95 (d, J ) 4.4 Hz, 0.5H), 9.05-9.08 (m, 1H), 9.12 (d,
J ) 4.4 Hz, 0.5H), 9.16 (s, 1H), 9.38 (d, J ) 4.4 Hz, 1H), 9.75 (s,
1H); LD-MS obsd 497.8, calcd 498.2131 (C22H18Br2N4); λabs
(toluene) 403, 638 nm.
Tribromination of FbC under Neutral Conditions: 7,8,15-
Tribromo-17,18-dihydro-18,18-dimethylporphyrin (FbC-Br7,8,15).
A solution of FbC (50.6 mg, 0.148 mmol) in THF (74 mL) was
treated with NBS (79.3 mg, 0.445 mmol). The resulting reaction
mixture was stirred at room temperature for 1 h. The reaction
mixture was diluted with CH2Cl2 (∼50 mL) and quenched by the
addition of saturated aqueous NaHCO3. The organic layer was
separated, dried (Na2SO4), and concentrated. Column chromato-
graphy of the resulting solid [silica, hexanes then hexanes/CH2Cl2
(4:1)] provided a tribromochlorin (first fraction, blue) and a
dibromochlorin (second fraction, greenish blue). The tribromochlo-
rin was rechromatographed [silica, hexanes/CH2Cl2 (4:1)] to afford
a purple solid (53.2 mg, 62%): 1H NMR δ -3.05 (brs, 1H), -2.88
(brs, 1H), 2.05 (s, 6H), 4.62 (s, 2H), 8.82 (s, 1H), 8.88 (dd, J )
2.0, 4.4 Hz, 1H), 9.04 (dd, J ) 2.0, 4.4 Hz, 1H), 9.13-9.15 (m,
2H), 9.63 (s, 1H), 9.65 (s, 1H); LD-MS obsd 575.9; FAB-MS obsd
574.9063, calcd 574.9083 [(M + H)+, M ) C22H17Br3N4]; λabs
(toluene) 406, 637 nm.
Attempted Tetrabromination of FbC under Neutral Condi-
tions. A solution of FbC (46.2 mg, 0.136 mmol) in THF (68 mL)
was treated with NBS (96.8 mg, 0.544 mmol). The resulting reaction
mixture was stirred at room temperature for 1 h. The reaction
mixture was diluted with CH2Cl2 (∼50 mL) and quenched by the
addition of saturated aqueous NaHCO3. The organic extract was
washed with water and brine, dried (Na2SO4), and concentrated.
Column chromatography of the resulting solid [silica, hexanes then
hexanes/CH2Cl2 (4:1)] provided a mixture of tribromo and tetra-
bromochlorins (first fraction, purple) and a tribromochlorin (second
fraction, blue). The latter was rechromatographed [silica, hexanes/
CH2Cl2 (2:1)] to afford the tribromochlorin FbC-Br7,8,15 as a purple
solid (37.5 mg, 48%). The characterization data (1H NMR, LD-
MS, FAB-MS, UV-vis) were consistent with those for the product
obtained as described in the tribromination procedure.
Monobromination of 13-Acetylchlorin FbC-M10A13. A solution
of FbC-M10A13 (44.7 mg, 0.0893 mmol) in THF (45 mL) was
treated with NBS (15.9 mg, 0.0893 mmol) at room temperature
for 1.5 h. CH2Cl2 was added. The mixture was washed with
saturated aqueous NaHCO3 solution. The organic layer was
separated, dried (Na2SO4), and concentrated. The resulting solid
was chromatographed [silica, hexanes/CH2Cl2 (3:7)] to give two
fractions, each of which contained a chlorin. The first fraction was
confirmed to be FbC-Br7M10A13 (21.7 mg, 42% of total yield),
and the second fraction was confirmed to be FbC-M10A13Br15 (14.8
mg, 28% of total yield). Data for 13-acetyl-7-bromo-17,18-dihydro-
1
10-mesityl-18,18-dimethylporphyrin (FbC-Br7M10A13): H NMR
δ -1.41 (brs, 1H), -1.16 (brs, 1H), 1.86 (s, 6H), 2.02 (s, 6H),
2.63 (s, 3H), 3.06 (s, 3H), 4.58 (s, 2H), 7.25 (s, 2H), 8.37 (s, 1H),
8.74 (s, 1H), 8.85 (d, J ) 4.4 Hz, 1H), 8.90 (s, 1H), 9.14 (d, J )
4.4 Hz, 1H), 9.75 (s, 1H), 10.07 (s, 1H); LD-MS obsd 577.3; FAB-
MS obsd 578.1692, calcd 578.1681 (C33H31BrN4O); λabs (toluene)
418, 656 nm. Data for 13-acetyl-15-bromo-17,18-dihydro-10-
1
mesityl-18,18-dimethylporphyrin (FbC-M10A13Br15): H NMR δ
-1.47 (brs, 2H), 1.84 (s, 6H), 2.04 (s, 6H), 2.61 (s, 3H), 3.07 (s,
3H), 4.57 (s, 2H), 7.24 (s, 2H), 8.39 (d, J ) 4.4 Hz, 1H), 8.48 (s,
1H), 8.72-8.74 (brs, 2H), 8.85 (d, J ) 4.4 Hz, 1H), 9.10 (d, J )
4.4 Hz, 1H), 9.54 (s, 1H); 13C NMR δ 21.4, 21.6, 31.4, 34.8, 46.6,
55.3, 95.2, 95.3, 106.2, 123.7, 125.3, 126.0, 128.0, 129.4, 130.8,
132.9, 133.3, 133.9, 137.0, 137.3, 137.6, 138.1, 139.0, 142.1, 152.3,
154.7, 162.7, 178.0, 202.4; LD-MS obsd 578.5; FAB-MS obsd
578.1692, calcd 578.1681 (C33H31BrN4O); λabs (toluene) 406, 649
nm.
Neutral Bromination at Low Temperature of a 13-Acetylchlo-
rin: 13-Acetyl-7-bromo-17,18-dihydro-10-mesityl-18,18-dimeth-
ylporphyrin (FbC-Br7M10A13). A solution of FbC-M10A13 (17.0
mg, 0.0339 mmol) in THF (16 mL) was treated with NBS (340
µL, 0.100 M THF solution) at -78 °C for 1.5 h. CH2Cl2 was added.
The mixture was washed with saturated aqueous NaHCO3. The
organic layer was separated, dried (Na2SO4), and concentrated. The
resulting solid was dissolved in a minimum amount of CH2Cl2 and
chromatographed [silica, hexanes/CH2Cl2 (3:7)] to give a purple
solid (13.5 mg, 76%); 13C NMR (75 MHz) δ 21.4, 21.6, 30.0, 31.0,
46.9, 51.9, 95.2, 98.0, 103.7, 121.4, 123.1, 125.7, 128.1, 129.3,
130.0, 13.2, 130.7, 132.3, 136.7, 137.0, 137.7, 138.3, 139.1, 143.2,
149.6, 150.1, 165.3, 178.6, 197.2; LD-MS obsd 578.4; FAB-MS
obsd 578.1692, calcd 578.1681 (C33H31BrN4O); λabs (toluene) 418,
656 nm. This sample gave a somewhat poor quality 1H NMR
spectrum and hence was converted to the zinc chelate for further
characterization.
Monobromination of FbC under Acidic Conditions: 15-Bromo-
17,18-dihydro-18,18-dimethylporphyrin (FbC-Br15). A solution of
FbC (18.4 mg, 0.0542 mmol) in CH2Cl2/TFA [27 mL, (10:1), 2
mM chlorin concentration] was treated with NBS (0.542 mL, 0.100
M in CH2Cl2) by syringe over a 30 s period. The resulting reaction
mixture was stirred at room temperature for 1 h. The reaction
mixture was diluted with CH2Cl2 (∼50 mL) and quenched by the
addition of saturated aqueous NaHCO3. The organic layer was
separated, and the aqueous phase was extracted with CH2Cl2. The
combined organic extract was washed with water and brine, dried
(Na2SO4), and concentrated. Column chromatography of the result-
ing solid [silica, hexanes/CH2Cl2 (2:3)] afforded a dibromochlorin
(first fraction, purple) and the title compound (second fraction,
greenish blue). The latter was rechromatographed [silica, hexanes/
1
CH2Cl2 (1:1)] to afford a brown solid (12.1 mg, 62%). The H
NMR, 13C NMR, LD-MS, FAB-MS, and absorption spectra were
consistent with the reported data for FbC-Br15.12
Dibromination of FbC Under Acidic Conditions: 15,20-Di-
bromo-17,18-dihydro-18,18-dimethylporphyrin (FbC-Br15,20). A
solution of FbC (23.8 mg, 0.0699 mmol) in CH2Cl2/TFA [35 mL
(10:1)] was treated with NBS (25.0 mg, 0.140 mmol). The resulting
reaction mixture was stirred at room temperature for 1 h. The
reaction mixture was diluted with CH2Cl2 (∼50 mL) and quenched
by the addition of saturated aqueous NaHCO3. The organic layer
was separated, and the aqueous phase was extracted with CH2Cl2.
The combined organic extract was washed with water and brine,
dried (Na2SO4), and concentrated. Column chromatography of the
resulting solid [silica, hexanes/CH2Cl2 (4:1) then hexanes/CH2Cl2
(1:1)] gave the title dibromochlorin (first fraction, purple) and a
monobromochlorin (second fraction, greenish blue). The dibromo-
Zn(II)-13-Acetyl-7-bromo-17,18-dihydro-10-mesityl-18,18-di-
methylporphyrin (ZnC-Br7M10A13). A solution of FbC-Br7M10A13
(13.4 mg, 0.0231 mmol) in CHCl3 (4.0 mL) was treated with a
solution of Zn(OAc)2 ·2H2O (76.1 mg, 0.346 mmol) in methanol
(1.0 mL). The reaction mixture was stirred at room temperature
for 16 h. CH2Cl2 was added. The reaction mixture was washed
with saturated aqueous NaHCO3. The organic layer was separated,
dried (Na2SO4), and concentrated. The resulting residue was
chromatographed (silica, CH2Cl2) to afford a green solid (11.4 mg,
1
77%): H NMR (THF-d8) δ 1.87 (s, 6H), 2.01 (s, 6H), 2.59 (s,
3H), 2.83 (s, 3H), 4.50 (s, 2H), 7.26 (s, 2H), 8.18 (s, 1H), 8.52 (s,
1H), 8.67 (d, J ) 4.4 Hz, 1H), 8.87 (s, 1H), 9.00 (d, J ) 4.4 Hz,
1H), 9.45 (s, 1H), 9.78 (s, 1H); 13C NMR (THF-d8) δ 21.6, 21.7,
J. Org. Chem. Vol. 74, No. 9, 2009 3245

Muthiah et al.
29.6, 31.1, 46.4, 51.2, 95.1, 98.8, 105.4, 117.3, 124.6, 128.7, 129.3,
130.0, 134.6, 135.1, 136.5, 138.4, 139.5, 139.6, 142.5, 145.4, 145.5,
149.4, 151.1, 157.1, 160.4, 173.8, 196.1; LD-MS obsd 642.4; ESI-
MS obsd 640.0801, calcd 640.0810 (C33H29BrN4OZn); λabs (toluene)
423, 631 nm.
MS obsd 666.1998, calcd 666.1994 (C40H35BrN4O); λabs (toluene)
423, 670 nm.
Acidic Bromination of a 10-Aryl-131-oxophorbine. A solution
of FbOP-M10 (12.0 mg, 0.0241 mmol) in CH2Cl2/TFA [9.9 mL
(10:1)] was treated with NBS (0.241 mL, 0.0241 mmol, 0.100 M
solution in CH2Cl2). The resulting deep-green mixture was stirred
at room temperature for 1 h. Saturated aqueous NaHCO3 was added,
and vigorous stirring for 5 min afforded a purple reaction mixture.
The organic layer was separated, dried (Na2SO4), and concentrated.
Column chromatography (silica, CH2Cl2) afforded a trace of
unidentified chlorin (first fraction, green), unidentified dibromo-
chlorin (second fraction, green), FbOP-M10Br20 (third fraction,
green-purple), and unreacted starting material (fourth fraction,
purple). Concentration of the third fraction gave a green solid (7.0
mg, 50%) consisting of FbOP-M10Br20 contaminated with ∼15%
of unidentified chlorin: 1H NMR δ -1.64 (brs, 1H), 1.25 (brs, 1H),
1.88 (s, 6H), 2.26 (s, 6H), 2.58 (s, 2H), 4.39 (s, 2H), 5.16 (s, 2H),
7.21-7.22 (m, 2H), 8.41 (d, J ) 4.4 Hz, 1H), 8.64 (s, 1H), 8.72
(d, J ) 4.4 Hz, 1H), 9.09-9.11 (m, 1H), 9.34-9.36 (m, 1H), 9.52
(s, 1H); LD-MS obsd 576.4; ESI-MS obsd 576.1519, calcd
576.1525 (C33H29BrN4O); λabs (toluene) 418, 437 (sh), 666 nm.
B. Synthesis. 13-Acetyl-15-bromo-17,18-dihydro-10-mesityl-
18,18-dimethylporphyrin (FbC-M10A13Br15). A sample of FbC-
M10A13 (77.0 mg, 0.154 mmol) was dissolved in CH2Cl2 (70 mL)
and treated with TFA (7 mL) to give a 2 mM chlorin concentration.
The chlorin solution was treated with NBS (27.4 mg, 0.154 mmol)
at room temperature for 1.5 h. CH2Cl2 was added. The mixture
was treated with saturated aqueous NaHCO3 and stirred for 5 min.
The organic layer was separated, dried (Na2SO4), and concentrated.
The resulting solid was dissolved in a minimum amount of CH2Cl2
and chromatographed [silica, hexanes/CH2Cl2 (3:7)] to give a trace
of unidentified chlorin and the title compound (purple solid, 78
mg, 87%). The data (1H NMR, 13C NMR, LD-MS, ESI-MS, and
Neutral Bromination at Low Temperature of a 3,13-Diacetyl-
chlorin: 3,13-Diacetyl-7-bromo-17,18-dihydro-10-mesityl-18,18-
dimethylporphyrin (FbC-A3Br7M10A13). A solution of FbC-
A3M10A13 (8.50 mg, 0.0156 mmol) in THF was treated with NBS
(156 µL, 0.100 M solution in THF, 0.0156 mmol) at -78 °C for
1.5 h. CH2Cl2 was added. The mixture was washed with saturated
aqueous NaHCO3. The organic layer was separated, dried (Na2SO4),
and concentrated. The resulting solid was dissolved in CH2Cl2 and
chromatographed (silica, hexanes then CH2Cl2) to give a purple
1
solid (6.6 mg, 68%): H NMR δ -1.36 (brs, 2H), 1.84 (s, 6H),
2.02 (s, 6H), 2.62 (s, 3H), 3.05 (s, 3H), 3.27 (s, 3H), 4.60 (s, 2H),
7.25 (s, 2H), 8.35 (s, 1H), 8.82 (s, 1H), 8.92 (s, 1H), 9.31 (s, 1H),
10.08 (s, 1H), 10.85 (s, 1H); LD-MS obsd 620.5; FAB-MS obsd
620.1785, calcd 620.1787 (C35H33BrN4O2); λabs (toluene) 428, 678
nm.
Acidic Bromination of a 13-Bromochlorin: 13,15-Dibromo-17,18-
dihydro-10-mesityl-18,18-dimethylporphyrin (FbC-M10Br13,15). A sample
of FbC-M10Br13 (20 mg, 0.037 mmol) was treated with a CH2Cl2/
TFA mixture [18.7 mL, (9:1)]. Protonation of the chlorin was
observed by UV-vis spectroscopy, as seen by the disappearance
of the Qy(0,0) band at 643 nm and formation of a new band at 619
nm. Then 1.4 mL (0.037 mmol) of a fresh NBS solution (26.3 mM
in CH2Cl2) was added dropwise to the green solution. The reaction
mixture was stirred at room temperature. The progress of the
bromination reaction was followed by TLC analysis (by taking a
small aliquot of the reaction mixture and quenching it with
triethylamine). After 40 min, acetone was added (3 mL) and the
reaction was quenched with triethylamine (2.8 mL) at 0 °C,
whereupon the reaction mixture turned from green to purple pink.
The organic layer was washed with saturated aqueous NaHCO3
and water, dried (Na2SO4), and filtered. The filtrate was concen-
trated. The dark purple residue obtained was dissolved in a hexanes/
CH2Cl2 solution (4:1) and chromatographed [silica, hexanes/CH2Cl2
(4:1)] slowly. Some tribromochlorin species eluted first followed
by the title compound and closely thereafter by the starting material.
The title compound was concentrated to afford a dark purple solid
λ
abs) were essentially identical to those reported above.
10-Mesityl-18,18-dimethyl-131-oxophorbine (FbOP-M10). Fol-
lowing a reported procedure,15 a mixture of FbC-M10A13Br15 (77.0
mg, 0.133 mmol), Cs2CO3 (217 mg, 0.665 mmol), and (PPh3)2PdCl2
(18.6 mg, 0.0266 mmol) was refluxed in toluene (13.5 mL) for
20 h in a Schlenk flask. The reaction mixture was concentrated.
The resulting crude solid was dissolved in a minimum amount of
CH2Cl2 and chromatographed [silica, hexanes/CH2Cl2 (1:4) then
CH2Cl2] to afford FbC-M10A13 (first fraction, ∼17%; debromination
apparently occurred upon Pd-coupling) and the title compound
1
(13.6 mg, 60%): H NMR (300 MHz) δ -1.66 (br, 2H), 1.81 (s,
1
6H), 2.01 (s, 6H), 2.60 (s, 3H), 4.62 (s, 3H), 7.23 (s, 2H), 8.38 (d,
J ) 3.9 Hz, 1H), 8.68 (s, 1H), 8.73 (d, J ) 4.5 Hz, 1H), 8.76 (s,
1H), 8.84 (d, J ) 4.8 Hz, 1H), 9.07 (d, J ) 4.8 Hz, 1H), 9.56 (s,
1H); ESI-MS obsd 615.0755, calcd 615.0753 [(M + H)+, M )
C31H29N4Br2]; λabs (CH2Cl2) 415, 508, 534, 598, 650 nm.
(second fraction, greenish blue solid, 51.2 mg, 77%): H NMR δ
-1.41 (s, 1H), 1.13 (s, 1H), 1.91 (s, 6H), 2.00 (s, 6H), 2.60 (s,
3H), 4.26 (s, 2H), 5.13 (s, 2H), 7.24 (s, 2H), 8.42 (d, J ) 4.4 Hz,
1H), 8.58 (s, 1H), 8.59 (s, 1H), 8.66 (d, J ) 4.4 Hz, 1H), 8.80 (dd,
J ) 2.0, 4.4 Hz, 1H), 9.00 (dd, J ) 2.0, 4.4 Hz, 1H), 9.35 (s, 1H);
13C NMR δ 21.3, 21.6, 31.0, 47.7, 48.5, 48.7, 94.8, 104.2, 106.3,
115.9, 126.0, 126.6, 128.1, 130.5, 132.6, 132.9, 133.0, 135.6, 138.0,
138.2, 138.8, 139.5, 143.6, 149.7, 153.0, 154.6, 157.2, 177.5, 195.9;
LD-MS obsd 498.4; ESI-MS obsd 499.2492, calcd 499.2493 [(M
+ H)+, M ) C33H30N4O]; λabs (toluene) 413, 656 nm.
Neutral Bromination of a 5,10-Diaryl-131-oxophorbine: 20-
Bromo-10-mesityl-18,18-dimethyl-131-oxo-5-p-tolylphorbine (FbOP-
T5M10Br20). A solution of FbOP-T5M10 (15.4 mg, 0.0261 mmol)
in THF (13.0 mL) was treated with NBS (261 µL, 0.100 M THF
solution) at room temperature for 1.5 h. CH2Cl2 was added. The
mixture was washed with saturated aqueous NaHCO3. The organic
layer was separated, dried (Na2SO4), and concentrated. The solid
was dissolved in a minimum amount of CH2Cl2 and chromato-
graphed [silica, hexanes then hexanes/CH2Cl2 (1:4)], which provided
a trace of an unidentified chlorin (first fraction, greenish blue) and
a second fraction (green). The latter was rechromatographed [silica,
hexanes/CH2Cl2 (1:4)] to afford a green solid (10.2 mg, 61%): 1H
NMR (300 MHz) δ -1.54 (s, 1H), 1.22 (s, 1H), 1.88 (s, 6H), 2.27
(s, 6H), 2.56 (s, 3H), 2.66 (s, 3H), 4.38 (s, 2H), 5.14 (s, 2H), 7.21
(s, 2H), 7.48 (d, J ) 8.2 Hz, 2H), 7.91 (d, J ) 8.2 Hz, 2H), 8.20
(d, J ) 4.4 Hz, 1H), 8.25 (d, J ) 4.4 Hz, 1H), 8.60 (s, 1H), 8.63
(dd, J ) 2.0, 4.4 Hz, 1H), 9.25 (dd, J ) 2.0, 4.4 Hz, 1H); 13C
NMR (75 MHz) δ 21.4, 21.5, 21.7, 29.2, 49.1, 51.3, 52.2, 95.9,
100.0, 105.7, 117.1, 122.2, 126.2, 127.2, 127.7, 128.1, 131.3, 131.8,
133.5, 133.8, 134.3, 135.4, 137.7, 138.3, 138.8, 139.3, 140.7, 142.7,
148.9, 153.8, 154.7, 157.3, 173.5, 195.6; LD-MS obsd 666.3; FAB-
Streamlined Procedure for Installing the Isocyclic Ring: 10-
Mesityl-18,18-dimethyl-131-oxophorbine (FbOP-M10). A solution
of FbC-M10A13 (218 mg, 0.435 mmol) in CH2Cl2 (200 mL) was
treated with TFA (20 mL) followed by NBS (77.5 mg, 0.435 mmol)
at room temperature. After 1.5 h, CH2Cl2 was added. The mixture
was washed with saturated aqueous NaHCO3. The organic layer
was separated, dried (Na2SO4), and concentrated. The crude solid
was used in the next step. Following a reported procedure,15
a
mixture of the crude solid, Cs2CO3 (709 mg, 2.17 mmol), and
(PPh3)2PdCl2 (61.0 mg, 0.0870 mmol) was refluxed in toluene (43
mL) for 20 h in a Schlenk flask. The reaction mixture was
concentrated. The resulting crude solid was dissolved in a minimum
amount of CH2Cl2 and chromatographed [silica, CH2Cl2/hexanes
(1:1) then CH2Cl2] to afford the starting material FbC-M10A13 (first
fraction, 32%; from unreaction upon bromination and/or debromi-
nation upon Pd coupling) and the title compound (second fraction,
3246 J. Org. Chem. Vol. 74, No. 9, 2009

Bromination Tactics in Chlorin Chemistry
greenish blue solid, 126 mg, 58%) with characterization data (1H
NMR, 13C NMR, LD-MS, FAB-MS, λabs) consistent with those
reported above.
allowed to cool to room temperature, treated with Bu3SnH, and
stirred for 15 min. The reaction mixture was filtered through a short
Celite column. The filtrate was concentrated. The resulting solid
was chromatographed (silica, CH2Cl2) to afford a purple solid (7.1
7-Bromo-10-mesityl-18,18-dimethyl-131-oxophorbine (FbOP-
Br7M10). A solution of FbOP-M10 (122 mg, 0.244 mmol) in THF
(120 mL) was treated with NBS (43.5 mg, 0.244 mmol) at room
temperature for 2 h. CH2Cl2 and saturated aqueous NaHCO3 were
added. The organic layer was separated, dried (Na2SO4), and
concentrated. The resulting crude solid was dissolved in a minimum
amount of CH2Cl2 and chromatographed [silica, hexanes then
hexanes/CH2Cl2 (3:7)] to afford a purple solid (122 mg, 86%): 1H
NMR δ -1.49 (s, 1H), 0.83 (s, 1H), 1.87 (s, 6H), 2.03 (s, 6H),
2.57 (s, 3H), 4.28 (s, 2H), 5.11 (s, 2H), 7.22 (s, 2H), 8.41 (s, 1H),
8.56 (s, 1H), 8.63 (s, 1H), 8.85 (dd, J ) 2.0, 4.4 Hz, 1H), 9.10 (dd,
J ) 2.0, 4.4 Hz, 1H), 9.57 (s, 1H); 13C NMR δ 21.3, 21.6, 31.0,
47.8, 48.5, 48.7, 95.4, 101.6, 106.7, 116.7, 121.6, 125.9, 127.0,
128.2, 131.1, 132.5, 133.2, 135.1, 138.2, 138.5, 138.8, 139.3, 144.0,
149.8, 150.4, 150.5, 158.0, 178.0, 195.6; LD-MS obsd 577.1; ESI-
MS obsd 577.1588, calcd 577.1597 [(M + H)+ M ) C33H29BrN4O];
λabs (toluene) 425, 656 nm.
1
mg, 78%): H NMR δ -1.13 (brs, 1H), 1.24 (brs, 1H), 1.88 (s,
6H), 2.01 (s, 6H), 2.59 (s, 3H), 4.24 (s, 2H), 5.07 (s, 2H), 7.24 (s,
2H), 8.55 (s, 1H), 8.58 (s, 1H), 8.78 (dd, J ) 2.0, 4.4 Hz, 1H),
8.93 (s, 1H), 9.10 (dd, J ) 2.0, 4.4 Hz, 1H), 10.33 (s, 1H), 10.90
(s, 1H); LD-MS obsd 526.9; ESI-MS obsd 527.2435, calcd
527.2441 [(M + H)+, M ) C34H30N4O2]; λabs (toluene) 442, 652
nm.
10-Mesityl-18,18-dimethyl-131-oxo-7-[2-(triisopropylsilyl)ethy-
nyl]phorbine (FbOP-E7M10). Samples of FbOP-Br7M10 (10.7 mg,
0.0185 mmol) and (triisopropylsilyl)acetylene (12.5 µL, 0.0555
mmol) were coupled using Pd2(dba)3 (3.4 mg, 0.0037 mmol) and
P(o-tol)3 (7.5 mg, 0.024 mmol) in toluene/triethylamine (5:1, 12
mL) at 60 °C under argon. After 24 h, the reaction mixture was
concentrated under reduced pressure. The resulting residue was
dissolved in a minimum amount of CH2Cl2 and chromatographed
[silica, hexanes/CH2Cl2 (1:4)] to afford a greenish blue solid (8.4
mg, 67%): 1H NMR δ -1.33 (brs, 1H), 1.14 (brs, 1H), 1.30-1.36
(m, 21H), 1.87 (s, 6H), 2.02 (s, 6H), 2.57 (s, 3H), 4.26 (s, 2H),
5.10 (s, 2H), 7.21 (s, 2H), 8.45 (s, 1H), 8.53 (s, 1H), 8.58 (s, 1H),
8.81 (d, J ) 4.4 Hz, 1H), 9.00 (d, J ) 4.4 Hz, 1H), 9.68 (s, 1H);
LD-MS obsd 679.0; ESI-MS obsd 679.3823, calcd 679.3826 [(M
+ H)+, M ) C44H50N4OSi]; λabs (toluene) 434, 660 nm.
7-Acetyl-10-mesityl-18,18-dimethyl-131-oxophorbine (FbOP-
A7M10). Following a procedure for Stille coupling with chlorins,10
a mixture of FbOP-Br7M10 (12.0 mg, 0.0207 mmol), tributyl(1-
ethoxyvinyl)tin (28.0 µL, 0.0828 mmol), and (PPh3)2PdCl2 (3.0 mg,
0.0041 mmol) was refluxed in THF (1.0 mL) for 18 h in a Schlenk
flask. The reaction mixture was treated with 10% aqueous HCl (1.0
mL) at room temperature for 1 h. CH2Cl2 was added, and the
organic layer was separated. The organic layer was washed
(saturated aqueous NaHCO3, water, and brine), dried (Na2SO4), and
concentrated. The resulting solid was dissolved in a minimum
amount of CH2Cl2 and chromatographed (silica, hexanes then
CH2Cl2) to afford a purple solid (8.5 mg, 76%): 1H NMR δ -1.45
(s, 1H), 1.17 (s, 1H), 1.90 (s, 6H), 2.01 (s, 6H), 2.60 (s, 3H), 2.97
(s, 3H), 4.24 (s, 2H), 5.07 (s, 2H), 7.25 (s, 2H), 8.53 (s, 2H), 8.77
(d, J ) 4.4 Hz, 1H), 8.83 (s, 1H), 9.10 (d, J ) 4.4 Hz, 1H), 10.50
(s, 1H); LD-MS obsd 540.2; ESI-MS obsd 541.2589, calcd
541.252598 [(M + H)+, M ) C35H32N4O2]; λabs (toluene) 439, 654
nm.
Acknowledgment. This research was supported by a grant
from the Chemical Sciences, Geosciences and Biosciences
Division, Offıce of Basic Energy Sciences, Offıce of Science,
U.S. Department of Energy (DE-FG02-96ER14632). Mass
spectra were obtained at the Mass Spectrometry Laboratory for
Biotechnology at North Carolina State University. Partial
funding for the Facility was obtained from the North Carolina
Biotechnology Center and the National Science Foundation.
Supporting Information Available: Table of bromination
results; synthesis of ZnC-M10Br13 and FbC-M10A13; additional
spectral data; characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
7-Formyl-10-mesityl-18,18-dimethyl-131-oxophorbine (FbOP-
F7M10). Following a procedure for formylation with CO,47 a mixture
of FbOP-Br7M10 (10.0 mg, 0.0173 mmol) and Pd(PPh3)4 (20.0 mg,
0.0173 mmol) was dried in a Schlenk flask for 30 min. DMF/toluene
[1.0 mL (1:1)] was added, and CO was bubbled slowly through
the reaction mixture at 70 °C. After 3 h, the reaction mixture was
JO9002954
J. Org. Chem. Vol. 74, No. 9, 2009 3247