Synthetic chlorins bearing auxochromes at the 3- and 13-positions

Article abstract of DOI:10.1021/jo060208o

Synthetic chlorins bearing diverse auxochromes at the 3- and 13-positions of the macrocycle are valuable targets given their resemblance to chlorophylls a and b, which bear 3-vinyl and 13-keto groups. A de novo route has been exploited to construct nine z

Full text of DOI:10.1021/jo060208o

Synthetic Chlorins Bearing Auxochromes at the 3- and 13-Positions
Joydev K. Laha, Chinnasamy Muthiah, Masahiko Taniguchi, Brian E. McDowell,
Marcin Ptaszek, and Jonathan S. Lindsey*
Department of Chemistry, North Carolina State UniVersity, Raleigh, North Carolina 27695-8204
jlindsey@ncsu.edu
ReceiVed January 31, 2006
Synthetic chlorins bearing diverse auxochromes at the 3- and 13-positions of the macrocycle are valuable
targets given their resemblance to chlorophylls a and b, which bear 3-vinyl and 13-keto groups. A de
novo route has been exploited to construct nine zinc chlorins bearing substituents at the 3- and 13-
positions and two benchmark zinc chlorins lacking such substituents. The chlorins are sterically uncongested
and bear (1) a geminal dimethyl group in the reduced pyrroline ring, (2) a H, an acetyl, a
triisopropylsilylethynyl (TIPS-ethynyl), or a vinyl at the 3-position, (3) a H, an acetyl, or TIPS-ethynyl
at the 13-position, and (4) a H or a mesityl at the 10-position. The synthesis of the 13-substituted chlorins
relied on p-TsOH‚H2O-catalyzed condensation of an 8,9-dibromo-1-formyldipyrromethane (eastern half)
and 2,3,4,5-tetrahydro-1,3,3-trimethyldipyrrin (western half), followed by metal-mediated oxidative
cyclization, affording the 13-bromochlorin. Similar use of a bromo- or TIPS-ethynyl-substituted western
half provided access to 3-substituted chlorins. A 3-bromo, 13-bromo, or 3,13-dibromochlorin was further
transformed by Pd-coupling to introduce the vinyl group (via tributylvinyltin), TIPS-ethynyl group (via
TIPS-acetylene), or acetyl group (via tributyl(1-ethoxyvinyl)tin, followed by acidic hydrolysis). In the
10-mesityl-substituted zinc chlorins, the series of substituents, 3-vinyl, 13-TIPS-ethynyl, 3-TIPS-ethynyl,
13-acetyl, 3,13-bis(TIPS-ethynyl), 3-TIPS-ethynyl-13-acetyl, or 3,13-diacetyl, progressively causes (1) a
redshift in the absorption maximum of the B band (405-436 nm) and the Qy band (606-662 nm), (2)
a relative increase in the intensity of the Qy band (IB/IQ ) 4.2-1.5), and (3) an increase in the fluorescence
quantum yield Φf (0.059-0.29). The zinc chlorins bearing a 3-TIPS-ethynyl-13-acetyl or a 3,13-diacetyl
group exhibit a number of spectral properties resembling those of chlorophyll a or its zinc analogue.
Taken together, this study provides access to finely tuned chlorins for spectroscopic studies and diverse
applications.
Introduction
sition exhibited by naturally occurring chlorophylls. Indeed,
chlorophyll a exhibits a strong Qy band at 661 nm (ꢀQ ) 78 200
y
The fundamental chromophore of the chlorophylls is a chlorin,
which differs from a porphyrin in having one pyrrole ring
reduced at the â-positions. Reduction of a porphyrin to give
the chlorin enhances the intensity of the long-wavelength absorp-
tion (Qy) band.1 However, mere reduction does not account for
the intensity or redshifted position of the long-wavelength tran-
M-1cm-1),2 whereas a benchmark compound that contains only
the core magnesium chlorin chromophore (MgChlorin, Chart
1) exhibits a Qy band at 610 nm (ꢀQ ) 56 000 M-1cm-1).3
y
(1) Gouterman, M. In The Porphyrins; Dolphin, D., Ed.; Academic
Press: New York, 1978; Vol. III, pp 1-165.
10.1021/jo060208o CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/26/2006
4092
J. Org. Chem. 2006, 71, 4092-4102

Synthetic Chlorins Bearing Auxochromes
CHART 1
macrocycles. The reduction of synthetic chlorins suffers from
limited control over the pattern of substituents with respect to
the ring that undergoes reduction, and the resulting chlorins often
slowly revert via dehydrogenation to the corresponding por-
phyrin. The de novo routes to chlorins are few in number and
have been developed primarily as exercises in natural products
synthesis rather than for fundamental studies of chlorin physical
properties.
Over the past decade, we have been developing rational de
novo routes for preparing chlorins, wherein each chlorin bears
a geminal dimethyl group in the reduced pyrroline ring.11-15
The geminal dimethyl group blocks adventitious dehydrogena-
tion to give the porphyrin, thereby affording a more stable
chlorin (i.e., dihydroporphyrin) chromophore. The general
synthetic route has entailed the reaction of a 9-bromodipyr-
romethane-1-carbinol (eastern half) and a 2,3-dihydro-1,3,3-
trimethyldipyrrin11 or 2,3,4,5-tetrahydro-1,3,3-trimethyldipyr-
rin13 (western half). The use of substituted analogues of the
eastern and western halves provided access to chlorins bearing
substituents at the 2-, 5-, 8-, 10-, 12-, and 18-positions (Chart
1).11-13 Subsequent oxidation afforded the 17-oxochlorins.14
Halogenation of the chlorin or oxochlorin at the 15- or
20-position followed by Pd-mediated coupling reactions enabled
the introduction of aryl or ethynyl substituents at these meso
sites.15 Thus, access has been achieved for all sites with the
exception of positions 3, 7, and 13. It is ironic that these latter
three sites are perhaps the most important for tuning the spectral
properties of the chlorins.
In this paper, we report the synthesis of nine zinc chlorins
bearing a variety of potential auxochromic groups at the
3-position (acetyl, TIPS-ethynyl, vinyl) and 13-position (acetyl,
TIPS-ethynyl). The chlorins bear a minimum of other substit-
uents so that the effects of the 3- and 13-groups can be clearly
delineated. Taken together, this work provides the foundation
for tuning the spectral properties of chlorins in a systematic
manner and establishes methodology for gaining access to
chlorins of potential value in applications ranging from artificial
photosynthesis to photomedicine.
Naturally occurring chlorins typically contain a full complement
of substituents at the â-pyrrolic positions of the macrocycle,
including alkyl groups (2-, 8-, and 12-positions) and auxochro-
mic groups (3-, 7-, and 13-positions). Chlorophyll a and b each
bear a 3-vinyl group and an isocyclic ring spanning the 13-15
positions.4 The isocyclic ring contains a 13-keto group, which
is conjugated with the π-system of the macrocycle.
Studies to probe the effects of substituents on chlorin spectral
properties have generally employed derivatives of the naturally
occurring macrocycles. Key findings are that the 3-vinyl
substituent redshifts the Qy transition by ∼12-14 nm (versus
that of a 3-ethyl group)5,6 and the annulated 13-keto substituent
imparts a redshift of ∼20-30 nm.5,7,8 The 3-vinyl group does
not appear to cause any change in the intensity of the transition,
whereas the 13-keto substituent has a significant hyperchromic
effect.5 The introduction of conjugative substituents on the
3-vinyl group has resulted in a redshift of up to 60 nm.9 Thus,
the presence of auxochromes at the 3- and 13-positions appears
essential for realizing strong absorption in the far-red region
with chlorin chromophores.
A more thorough examination of substituent effects on chlorin
spectral properties requires the ability to prepare stable, steric-
ally uncongested chlorin macrocycles with a defined number
and pattern of substituents at the â-pyrrole and meso positions.
There are three distinct routes to chlorins, including (1)
derivatization of naturally occurring chlorins, (2) reduction of
synthetic porphyrins, and (3) de novo syntheses.10 The deriva-
tization of chlorophylls is constrained by the nearly full
complement of substituents present in the naturally occurring
Results and Discussion
(2) Strain, H. H.; Svec, W. A. In The Chlorophylls; Vernon, L. P., Seely,
G. R., Eds.; Academic Press: New York, 1966; pp 21-66.
(3) Eisner, U.; Linstead, R. P. J. Chem. Soc. 1955, 3742-3749.
(4) Scheer, H. In Chlorophylls; Scheer, H., Ed.; CRC Press: Boca Raton,
FL, 1991; pp 3-30.
I. Synthesis. Each of the target chlorins herein lacks a
substituent at the 5-position to avoid any possible steric
interaction with substituents at the 3-position. Our prior synthetic
route to chlorins employed a 9-bromodipyrromethane-1-carbinol
as the eastern half, where the substituent at the 1-position of
the eastern half becomes the 5-substituent in the chlorin. We
recently developed new methodology for chlorin synthesis that
employs a 1-formyl-9-bromodipyrromethane and a 2,3,4,5-
tetrahydro-1,3,3-trimethyldipyrrin, whereupon the chlorin lacks
a 5-substituent. The synthesis development and studies of the
fundamental properties of stable unsubstituted chlorins will be
described elsewhere. The syntheses described herein rely on
(5) Boldt, N. J.; Donohoe, R. J.; Birge, R. R.; Bocian, D. F. J. Am. Chem.
Soc. 1987, 109, 2284-2298.
(6) Smith, K. M.; Goff, D. A.; Simpson, D. J. J. Am. Chem. Soc. 1985,
107, 4946-4954.
(7) Tamiaki, H.; Miyatake, T.; Tanikaga, R. Tetrahedron Lett. 1997, 38,
267-270.
(8) Abraham, R. J.; Rowan, A. E.; Smith, N. W.; Smith, K. M. J. Chem.
Soc., Perkin Trans. 2 1993, 1047-1059.
(9) Tamiaki, H.; Kouroba, M. Tetrahedron 1997, 53, 10677-10688.
(10) (a) Pavlov, V. Y.; Ponomarev, G. V. Chem. Heterocycl. Compd.
2004, 40, 393-425. (b) Montforts, F.-P.; Glasenapp-Breiling, M. Fortschr.
Chem. Org. Naturst. 2002, 84, 1-51. (c) 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. (d) Vicente,
M. G. H. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard,
R., Eds.; Academic Press: San Diego, CA, 2000; Vol. 1, pp 149-199. (e)
Jaquinod, L. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M.,
Guilard, R., Eds.; Academic Press: San Diego, CA, 2000; Vol. 1, pp 201-
237. (f) Montforts, F.-P.; Glasenapp-Breiling, M. Prog. Heterocycl. Chem.
1998, 10, 1-24. (g) Montforts, F.-P.; Gerlach, B.; Ho¨per, F. Chem. ReV.
1994, 94, 327-347. (h) Smith, K. M. In Chlorophylls; Scheer, H., Ed.;
CRC Press: Boca Raton, FL, 1991; pp 115-143. (i) Hynninen, P. H. In
Chlorophylls; Scheer, H., Ed.; CRC Press: Boca Raton, FL, 1991; pp 145-
209.
(11) Strachan, J.-P.; O’Shea, D. F.; Balasubramanian, T.; Lindsey, J. S.
J. Org. Chem. 2000, 65, 3160-3172.
(12) Balasubramanian, T.; Strachan, J. P.; Boyle, P. D.; Lindsey, J. S. J.
Org. Chem. 2000, 65, 7919-7929.
(13) Taniguchi, M.; Ra, D.; Mo, G.; Balasubramanian, T.; Lindsey, J.
S. J. Org. Chem. 2001, 66, 7342-7354.
(14) 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.
(15) Taniguchi, M.; Kim, M. N.; Ra, D.; Lindsey, J. S. J. Org. Chem.
2005, 70, 275-285.
J. Org. Chem, Vol. 71, No. 11, 2006 4093

Laha et al.
TABLE 1. Bromination of 1-Formyldipyrromethanes
SCHEME 1
reactant
NBS equiv
product
R5
R8
yield (%)
1
1
2
2
1
2
1
2
3a
3b
4a
4b
H
H
Mes
Mes
H
Br
H
78
56
67
51
Br
this approach, using an 8-bromo derivative of the eastern half
(i.e., an 8,9-dibromo-1-formyldipyrromethane) and an 8-bromo
derivative of the western half to gain access to chlorins bearing
substituents at the 3- and 13-positions.
A. Eastern and Western Halves. The syntheses of 9-bromo
and 8,9-dibromo derivatives of 1-formyldipyrromethanes are
shown in Table 1. While the 9-bromo derivatives of 1-acyl-
dipyrromethanes are known,11-15 8,9-dibromo derivatives of
1-formyldipyrromethanes have not been previously prepared.
In this regard, a number of polyhalogenated pyrroles from
marine organisms have been identified and synthesized.16
Treatment of 1-formyldipyrromethane 117 or 217 with 1 molar
equivalent of NBS at -78 °C gave the 9-bromo derivative 3a
or 4a in 78 or 67% yield, respectively. On the other hand,
treatment of 1 or 2 with 2 molar equivalents of NBS at -78 °C
gave the 8,9-dibromo derivative 3b or 4b in 56 or 51% yield,
respectively. The regiochemistry of the 8,9-vicinal substitution
pattern in the dibromo derivatives was established by NMR
spectroscopy (HH-COSY and NOESY experiments, see Sup-
porting Information). The regioselective formation of the
dibromo product (3b, 4b) stems in part from the deactivation
of the R-formyl-substituted pyrrole ring. The first bromination
occurs at the most active site in the dipyrromethane, which is
the R-position of the adjacent pyrrole ring, and the second
bromination occurs at the vicinal â-pyrrole position.
In some instances, the 8,9-dibromodipyrromethanes 3b and
4b were found to have limited stability. A study was carried
out to more closely assess the factors that affect handling. A
solution of compound 3b (10 mM) in a solvent such as
CH2Cl2, ethyl acetate, hexanes, or mixtures thereof changed
color from pale yellow to purple over 2 h but without any
1
evidence of decomposition of 3b, as assessed by H NMR
spectroscopy. In CDCl3, the compound was stable for 24 h, but
was found to have decomposed completely after 30 h. On the
other hand, a solution of 3b in THF-d8 was very stable for 5
days. The powdered solid 3b can be stored at -20 °C for 2-3
months without decomposition. Compound 4b proved to be
somewhat less stable, decomposing almost completely in ethyl
acetate or chlorinated solvents within 18-20 h, even at 0 °C,
but was very stable in THF-d8 for 5 days. However, compound
4b also could be stored in the solid form at -20 °C for 2-3
months without decomposition. In general, we have found that
removal of the solvent during workup or column chromatog-
raphy of 3b or 4b should be done without heating, and the
samples should be stored at low temperature in the solid form.
The synthesis of an 8-bromo-substituted western half is shown
in Scheme 1. Treatment of pyrrole-2-carboxaldehyde (5) with
(16) (a) Bailey, D. M.; Johnson, R. E. J. Med. Chem. 1973, 16, 1300-
1302. (b) Bailey, D. M.; Johnson, R. E.; Salvador, U. J. J. Med. Chem.
1973, 16, 1298-1300. (c) Gilow, H. M.; Burton, D. E. J. Org. Chem. 1981,
46, 2221-2225. (d) Keifer, P. A.; Schwartz, R. E.; Koker, M. E. S.; Hughes,
R. G., Jr.; Rittschof, D.; Rinehart, K. L. J. Org. Chem. 1991, 56, 2965-
2975. (e) Cho, H.; Matsuki, S.; Mizuno, A.; Annoura, H.; Tatsuoka, T. J.
Heterocycl. Chem. 1997, 34, 87-91. (f) Olofson, A.; Yakushijin, K.; Horne,
D. A. J. Org. Chem. 1998, 63, 1248-1253. (g) He, R. H.-Y.; Jiang, X.-K.
J. Chem. Res., Synop. 1998, 786-787. (h) Armitt, D. J.; Banwell, M. G.;
Freeman, C.; Parish, C. R. J. Chem. Soc., Perkin Trans. 1 2002, 1743-
1745. (i) Hoffmann, H.; Lindel, T. Synthesis 2003, 1753-1783. (j) Patel,
J.; Pelloux-Le´on, N.; Minassian, F.; Valle´e, Y. J. Org. Chem. 2005, 70,
9081-9084.
(17) Ptaszek, M.; McDowell, B. E.; Lindsey, J. S. J. Org. Chem. 2006,
71, 4328-4331.
4094 J. Org. Chem., Vol. 71, No. 11, 2006

Synthetic Chlorins Bearing Auxochromes
TABLE 2. Effects of Substituents on Chlorin-Forming Reactions
one molar equivalent of NBS at -78 °C gave 4-bromopyrrole-
2-carboxaldehyde 618 in 55% yield after crystallization. This
method for brominating pyrrole-2-carboxaldehyde is superior
to a reported method that uses Br2.18 It should be noted that
careful handling of the crude product is required; the off-white
solid often turns reddish (irrespective of preparation using Br2
or NBS), which complicates crystallization. Following a pro-
cedure for the synthesis of 2-(2-nitroethyl)pyrroles,13 treatment
of 6 with excess nitromethane, sodium acetate, and methylamine
hydrochloride at room temperature for 16 h, followed by the
addition of NaBH4, gave 4-bromo-2-(2-nitroethyl)pyrrole (7)
in variable yield (32-48%). However, 7 was found to explode
(CAUTION), which caused us to abandon this intermediate.
We investigated the protection of the pyrrole nitrogen in
4-bromopyrrole-2-carboxaldehyde (6) with two purposes: (1)
to obtain a stable analogue of 4-bromo-2-(2-nitroethyl)pyrrole
(7), and (2) to achieve efficient palladium-coupling in the latter
part of the 8-ethynyl western half synthesis. Considering the
facile conditions for the removal of a p-toluenesulfonyl group
as well as the crystalline nature of 2-(2-nitroethyl)-N-p-
tosylpyrroles,19 the N-tosylation20 of compound 6 was carried
out. Thus, treatment of 6 with NaH for 1 h, followed by addition
of p-toluenesulfonyl chloride, gave 6-Ts as a pale yellow
crystalline solid in 68% yield. Following a reported procedure
chlorin substituentsc
for the synthesis of 2-(2-nitrovinyl)-N-p-tosylpyrroles,19
a
WHa EHb
3
13
10
chlorin
yieldd (%)
mixture of 6-Ts, excess nitromethane, and ammonium acetate
was refluxed for 3 h. The crude product was satisfactorily pure
(as evidenced by NMR spectroscopy) and was used directly in
the next step. Reduction of the crude product with NaBH4 in
the presence of Montmorillonite K1021 or silica gel22 at room
temperature afforded 2-(2-nitroethyl)-N-p-tosylpyrrole 7-Ts as
a white solid in 40 or 58% yield, respectively. A Michael
addition of 7-Ts with mesityl oxide in the presence of TBAF23
and 3 Å molecular sieves gave the detosylated pyrrole-hexanone
8 in 47% yield. The p-toluenesulfonyl group is known to be
cleaved by TBAF.24 The reduction22 of 8 with excess zinc dust
and HCOONH4 in THF at room temperature gave the 8-bromo
western half 9 in 45% yield.
For the synthesis of 3,13-unsymmetrical chlorins, we con-
sidered functionalizing the western half 9 as a means of
installing the desired auxochrome prior to the chlorin-forming
reaction. The synthesis of a western half bearing a TIPS-ethynyl
group at the 8-position is shown in Scheme 1. The Michael
addition13 of 7-Ts and mesityl oxide was carried out using CsF
in anhydrous CH3CN at 65 °C, affording nitrohexanone 8-Ts
in 30% yield along with a substantial amount of N-detosylated
product 8 (∼30%). CsF also is known to cause detosylation.25
A similar reaction at room temperature for 16 h gave a similar
product distribution. Commonly used bases22 for Michael
additions such as tetramethylguanidine or DBU did not give
any trace of 8-Ts. The reductive cyclization of 8-Ts in the
presence of excess zinc dust and HCOONH4 in THF at room
11
9
11
9
10
11
9
4a
4a
4b
4b
4b
3a
3b
3b
H
Br
H
H
H
Mes ZnC-M10
42
37
26
30
11
16
26
7
Mes ZnC-Br3M10
Br Mes ZnC-M10Br13
Br
Br Mes ZnC-Br3M10Br13
tsTIPS Br Mes ZnC-E3M10Br13
H
Br
H
Br
H
H
H
ZnC
ZnC-Br3Br13
ZnC-E3Br13
10
tsTIPS Br
a Western half with no substituent (11, Y ) H) or a substituent at the
8-position (9, 10). b Eastern half. c Numbering of chlorins is shown in Chart
1. d Isolated yield.
temperature gave N-tosyl western half 9-Ts in 74% yield.
Sonogashira coupling of 9-Ts with (triisopropylsilyl)acetylene
was carried out under conditions that have been used with
pyrrolic compounds (20 mol % each of (PPh3)2PdCl2 and CuI
in THF and diisopropylamine),26 affording 10-Ts in 54% yield.
The selective detosylation27 in the presence of the TIPS group
was achieved by stirring a mixture of 10-Ts, HSCH2COOH,
and LiOH in anhydrous DMF at 65 °C for 5 h, affording TIPS-
ethynyl western half 10 in 72% yield.
B. Chlorin Formation. The general chlorin-forming reaction
entails an acid-catalyzed condensation of a 9-bromo-1-formyl-
dipyrromethane species (eastern half) and a 2,3,4,5-tetrahydro-
1,3,3-trimethyldihydrodipyrrin species (western half), followed
by zinc-mediated oxidative cyclization, as shown in Table 2.
The conditions were drawn in part from those employed by
Battersby in the synthesis of copper chlorins.23 Thus, a stirred
suspension of an eastern half (3a, 3b, 4a, 4b, in slight excess)
and a western half with a substituent at the 8-position (9, 10)
or no substituent (11) in anhydrous CH2Cl2 was treated with a
solution of p-TsOH‚H2O in anhydrous MeOH under argon,
(18) Anderson, H. J.; Lee, S.-F. Can. J. Chem. 1965, 43, 409-414.
(19) Hamdan, A.; Wasley, J. W. F. Synth. Commun. 1985, 15, 71-74.
(20) Tietze, L. F.; Kettschau, G.; Heitmann, K. Synthesis 1996, 851-
857.
(21) Bahulayan, D.; Das, S. K.; Iqbal, J. J. Org. Chem. 2003, 68, 5735-
5738.
(22) Ptaszek, M.; Bhaumik, J.; Kim, H.-J.; Taniguchi, M.; Lindsey, J.
S. Org. Process Res. DeV. 2005, 9, 651-659.
(23) Battersby, A. R.; Fookes, C. J. R.; Snow, R. J. J. Chem. Soc., Perkin
Trans. 1 1984, 2725-2732.
(26) (a) Alvarez, A.; Guzma´n, A.; Ruiz, A.; Velarde, E.; Muchowski, J.
M. J. Org. Chem. 1992, 57, 1653-1656. (b) Bergauer, M.; Hu¨bner, H.;
Gmeiner, P. Bioorg. Med. Chem. Lett. 2002, 12, 1937-1940.
(27) Haskins, C. M.; Knight, D. W. Tetrahedron Lett. 2004, 45, 599-
601.
(24) Yasuhara, A.; Sakamoto, T. Tetrahedron Lett. 1998, 39, 595-596.
(25) Eisch, J. J.; Behrooz, M.; Dua, S. K. J. Organomet. Chem. 1985,
285, 121-136.
J. Org. Chem, Vol. 71, No. 11, 2006 4095

Laha et al.
SCHEME 2
SCHEME 3
affording a clear reddish-brown solution over 30-45 min.
Workup afforded a yellow-brown foamlike solid, which was
treated with Zn(OAc)2, 2,2,6,6-tetramethylpiperidine, and
AgOTf in CH3CN at reflux exposed to air for 18-24 h. The
chlorin was obtained by silica column chromatography. This
route provided access to chlorins bearing H, Br, or TIPS-ethynyl
at the 3-position and H or Br at the 13-position in yields ranging
from 7 to 42%. In the chlorin-forming reactions with ethynyl
western half 10, two chlorins in ∼2:1 ratio were isolated from
the crude mixture, of which the major product was the desired
chlorin and the minor chlorin was not identified. Each target
chlorin was characterized by absorption spectroscopy, 1H NMR
spectroscopy, LD-MS, and high-resolution mass spectrometry.
C. Chlorin Derivatization. (i) 3-Substituted Chlorins. The
syntheses of 3-vinylchlorin ZnC-V3M10 and 3-ethynylchlorin
ZnC-E3M10 are shown in Scheme 2. Stille coupling of ZnC-
Br3M10 and tributyl(vinyl)tin was carried out under conditions
that have been employed with porphyrin substrates (10 mol %
of (PPh3)2PdCl2 in THF at reflux),28 affording ZnC-V3M10 in
66% yield. Sonogashira coupling of ZnC-Br3M10 and (triiso-
propylsilyl)acetylene was carried out under conditions that have
been used with chlorins [Pd2(dba)3 and P(o-tol)3 in toluene/
TEA (5:1)],15 affording ZnC-E3M10 in 52% yield. The latter
conditions for Sonogashira coupling proceed under mild condi-
tions and avoid the use of copper altogether, which can
transmetalate with the zinc chelate.
of which upon acidic hydrolysis unveils the acetyl group.
Exploratory studies showed that the yield of the coupling step
was higher with the free-base chlorin versus the zinc chlorin.
Because the acidic hydrolysis would cause demetalation, thereby
requiring reinsertion of zinc(II), we went ahead and demetalated
the precursor zinc bromochlorins and performed the coupling
on the free-base bromochlorin. Thus, chlorin ZnC-M10Br13 was
demetalated with TFA in CH2Cl2 at room temperature. The
crude free-base chlorin was subjected to Stille coupling with
tributyl(1-ethoxyvinyl)tin in the presence of 20 mol % of
(PPh3)2PdCl2 in THF for 20 h. Subsequent hydrolysis of the
reaction mixture with 10% aqueous HCl gave a crude product
that on metalation with Zn(OAc)2‚2H2O gave chlorin ZnC-
M10A13 in 53% overall yield. Sonogashira coupling of ZnC-
M10Br13 with (triisopropylsilyl)acetylene in the presence of
Pd2(dba)3 and P(o-tol)3 gave 13-ethynylchlorin ZnC-M10E13 in
71% yield.
(iii) 3,13-Substituted Chlorins. The syntheses of 3,13-
diethynylchlorins ZnC-E3E13 and ZnC-E3M10E13 are shown in
Scheme 4. Sonogashira coupling of ZnC-Br3M10Br13 with
(triisopropylsilyl)acetylene in the presence of 20 mol % of
(PPh3)2PdCl2 and CuI gave 3,13-diethynylchlorin ZnC-E3M10E13
in 42% yield, along with the formation of an unknown mono-
ethynyl chlorin (∼15% yield). The same coupling of ZnC-
Br3Br13 or ZnC-Br3M10Br13 with (triisopropylsilyl)acetylene,
using the superior copper-free conditions [Pd2(dba)3 and P(o-
(ii) 13-Substituted Chlorins. The syntheses of 13-acetyl-
chlorin ZnC-M10A13 and 13-ethynylchlorin ZnC-M10E13 are
shown in Scheme 3. The key step entails Pd-mediated coupling
of a bromochlorin with tributyl(1-ethoxyvinyl)tin,29 the product
(28) DiMagno, S. G.; Lin, V. S.-Y.; Therien, M. J. J. Org. Chem. 1993,
58, 5983-5993.
(29) Kosugi, M.; Sumiya, T.; Obara, Y.; Suzuki, M.; Sano, H.; Migita,
T. Bull. Chem. Soc. Jpn. 1987, 60, 767-768.
4096 J. Org. Chem., Vol. 71, No. 11, 2006

Synthetic Chlorins Bearing Auxochromes
SCHEME 4
SCHEME 5
bromo-3-ethynylchlorins ZnC-E3Br13 and ZnC-E3M10Br13
(Scheme 5). Thus, demetalation of ZnC-E3Br13 or ZnC-
E3M10Br13, Stille coupling of the corresponding crude product
with tributyl(1-ethoxyvinyl)tin, acidic workup, and zinc meta-
lation gave ZnC-E3A13 or ZnC-E3M10A13 in 53 or 23% overall
yield, respectively.
1
II. Spectroscopy. A. NMR Spectroscopy. H NMR spec-
troscopy provides valuable information about the chlorin
substitution patterns. A general description of chlorin spectral
features, and complete spectral assignments for the meso and
â-pyrrole protons of selected 3- and 13-substituted chlorins are
shown in the Supporting Information.
B. Absorption and Fluorescence Spectroscopy. The spectral
properties of interest in the chlorins include the position,
intensity, and full-width at half-maximum (fwhm) of both the
short-wavelength absorption band (B) and the long-wavelength
absorption band (Qy), the fluorescence emission spectrum and
fluorescence quantum yield (Φf), and the Stokes shift (∆ν)
between absorption and emission. The intensities of the B and
Qy transitions can be assessed by the measured molar absorption
coefficients; however, comparisons of such values often are
somewhat unreliable given the experimental variability encoun-
tered upon handling small quantities of materials. A traditional
method in the chlorophyll field employs the ratio of the
intensities of the B and Qy bands for a given compound (IB/IQ
ratio), which obviates reliance on molar absorption coef-
ficients.30 For a wide variety of applications, bathochromic and
hyperchromic shifts of the Qy band are desired (i.e., shifted to
longer wavelength and increased in intensity), given that the
position and intensity of the long-wavelength transition plays a
dominant role in determining photochemical properties.
The spectral properties of the zinc chlorins are listed in Table
3. The spectral properties of the nine new substituted chlorins
can be compared with those of chlorophyll a (Chl a),30-33 its
tol)3], gave 3,13-diethynylchlorin ZnC-E3E13 or ZnC-E3M10E13
in 53 or 75% yield, respectively.
The synthesis of 3,13-diacetylchlorin ZnC-A3M10A13 also is
shown in Scheme 4. Demetalation of chlorin ZnC-Br3M10Br13
with TFA in CH2Cl2 at room temperature afforded the crude
free-base chlorin, which was subjected to Stille coupling with
tributyl(1-ethoxyvinyl)tin in the presence of 20 mol % of
(PPh3)2PdCl2 in THF for 30 h. Hydrolysis of the reaction
mixture with 10% aqueous HCl, followed by metalation with
Zn(OAc)2‚2H2O, gave chlorin ZnC-A3M10A13 in 37% overall
yield.
The syntheses of 3-ethynyl-13-acetylchlorins ZnC-E3A13 and
ZnC-E3M10A13 were carried out using the protocol described
above for the installation of the 13-acetyl group with the 13-
(30) Strain, H. H.; Thomas, M. R.; Katz, J. J. Biochim. Biophys. Acta
1963, 75, 306-311.
J. Org. Chem, Vol. 71, No. 11, 2006 4097

Laha et al.
TABLE 3. Spectral Properties of Chlorinsa
b
d
λ
B (fwhm)
in nm
λ
Qy (fwhm)
in nm
∆νQ
λem
∆υe
y
c
f
compound
ZnC-M10
log ꢀB
log ꢀQ
(cm-1
)
IB/IQ
(nm)
(cm-1
)
Φf
y
405 (13)
413 (18)
413 (16)
416 (16)
418 (18)
423 (18)
428 (21)
436 (21)
399 (14)
420 (19)
428 (31)
423 (38)
429 (39)m
433 (39)m
5.45
5.18
5.26
5.14
5.17
4.97
4.79
4.72
5.38
5.08
4.81
5.09
5.05
5.01
606 (12)
621 (16)
626 (11)
627 (12)
632 (14)
646 (12)
652 (16)
662 (18)
603 (13)
645 (12)
655 (17)
653 (18)
661 (17)m
666 (19)m
4.81
4.66
4.92
4.73
4.84
4.76
4.62
4.54
4.84
4.93
4.75
4.96
4.93
4.89
0
400
530
550
680
1020
1160
1400
0
1080
1320
4.2
3.3
2.2
2.6
2.1
1.6
1.5
1.5
3.2
1.4
1.2
1.38
1.3
609
625
628g
630
636
649
656
668
605
648h
660
657k
666n
671m
80
100
50
80
100
70
90
110
50
0.059
0.078
0.16
ZnC-V3M10
ZnC-M10E13
ZnC-E3M10
ZnC-M10A13
ZnC-E3M10E13
ZnC-E3M10A13
ZnC-A3M10A13
ZnC
0.11
0.22
0.24
0.25
0.29
0.062
0.18
ZnC-E3E13
ZnC-E3A13
Zn-Pheo ai,j
Chl ai,l
70
120
90k
110m
110m
0.22
0.23k
0.32o
0.325o
Chl ap,q
1.294
a In toluene at room temperature, unless noted otherwise. b The redshift of the Qy band relative to that of the parent chlorin (ZnC-M10 or ZnC). c Ratio
of the intensities of the B and Qy bands. d Excitation was performed at the λmax of the B band. e Stokes shift. f Determined in toluene at room temperature
with λexc at the B-band maximum using chlorophyll a as a standard (Φf ) 0.322), unless noted otherwise (see Supporting Information). g Shoulder at 689
nm. h Shoulder at 705 nm. i In diethyl ether. j Absorption data from ref 35. The absorption spectrum is essentially identical in CHCl3.34 k Reference 37. We
calculated the Φf value using data from ref 37 and chlorophyll a as a standard. A value of Φf ) 0.17 in diethyl ether/petroleum ether has been reported.36
l Absorption data from ref 30. m This work. n Data from PhotochemCAD version 2.33 o Reference 31. p In benzene. q Absorption data from ref 32.
zinc analogue (Zn-Pheo a),34-37 as well as two benchmark zinc
chlorins lacking 3- and 13-substituents (ZnC-M10 and ZnC).
Each benchmark, ZnC or ZnC-M10, exhibits a B band at 399
or 405 nm, a Qy band at 603 or 606 nm, and IB/IQ ratio of 3.2
or 4.2, respectively. Inspection of the table shows the progressive
redshift in absorption properties upon introduction of vinyl,
TIPS-ethynyl, and/or acetyl groups. Indeed, each chlorin with
a single 3- or 13-substituent (vinyl, TIPS-ethynyl, or acetyl)
exhibits a B band in the region of 413-418 nm and a Qy band
in the range from 621 to 632 nm. Thus, a single substituent at
the 3- or 13-position redshifts the Qy band by 400-680 cm-1
(∼15-26 nm), compared to the benchmark chlorin ZnC-M10.
The presence of substituents at both 3- and 13-positions results
in a B band in the region 423-436 nm, and a Qy band in the
range from 646 to 662 nm; the total redshift of the Qy band is
1000-1400 cm-1 (∼40-56 nm). The largest effect of a single
substituent was observed with the acetyl group (ZnC-M10A13),
and the most pronounced redshift with two substituents was
observed with two acetyl groups (ZnC-A3M10A13).
the unsubstituted parent compound ZnC-M10 to 1.5 in ZnC-
A3M10A13. The redshift and changing band intensities (IB/IQ
ratio) are displayed in the normalized absorption spectra of
chlorins in the 10-mesityl-substituted family (Figure 1, upper
panel). Note that ZnC-E3M10 and ZnC-M10E13 exhibit nearly
identical spectra; only the data for the former are displayed.
Analogous redshifts and changing band intensities were observed
in the 10-unsubstituted family of chlorins (Figure 1, lower
panel). It is noteworthy that the measured molar absorption
coefficient for the B band tends to decline upon substitution
with groups affording redshifted spectra, but is not fully com-
pensated by a commensurate increase in the intensity of the Qy
band. For example, the spectrum of ZnC-A3M10A13 closely
resembles that of chlorophyll a in terms of shape and position,
but is ∼2-fold weaker in intensity. We have no explanation for
this apparent discrepancy. A more full discussion concerning
absorption intensity is provided in the Supporting Information,
including a figure showing overlaid absorption spectra plotted
on the basis of measured molar absorption coefficients.
The fluorescence emission spectra are typical of chlorins, with
strong (0,0) bands and much weaker (0,1) and (0,2) emission
bands. The fluorescence quantum yields were measured in
degassed toluene at room temperature, using chlorophyll a as a
standard (Φf ) 0.322). The values increased from 0.059 or 0.062
for ZnC-M10 or ZnC, respectively, to 0.25 or 0.22 for the
3-TIPS-ethynyl-13-acetylchlorins ZnC-E3M10A13 or ZnC-
E3A13. The most emissive chlorin was the 3,13-diacetylchlorin
ZnC-A3M10A13, which exhibited Φf ) 0.29. The increase in
fluorescence quantum yield generally paralleled the redshift and
relative intensification of the Qy band. In general, the rate
constant for radiative emission is directly proportional to the
oscillator strength of the transition. It should be noted, however,
that the oscillator strength of the Qy band is given by the
The redshift of absorption maxima is accompanied by a
relative increase in the intensity of the Qy band versus that of
the B band. Thus, the band intensity ratio changed from 4.2 in
(31) Weber, G.; Teale, F. W. J. Trans. Faraday Soc. 1957, 53, 646-
655.
(32) Seely, G. R.; Jensen, R. G. Spectrochim. Acta 1965, 21, 1835-
1845.
integrated band area38 (approximated by the product of ꢀQ
×
y
fwhm) rather than the molar absorption coefficient. This is
pertinent here given the variation in fwhm of the Qy bands,
which ranges from 11 to 18 nm across the series of chlorins. A
deeper understanding of the effect of auxochromic groups on
the fluorescence yield requires knowledge of the excited-state
(33) Dixon, J. M.; Taniguchi, M.; Lindsey, J. S. Photochem. Photobiol.
2005, 81, 212-213.
(34) Boucher, L. J.; Katz, J. J. J. Am. Chem. Soc. 1967, 89, 4703-4708.
(35) Jones, I. D.; White, R. C.; Gibbs, E.; Denard, C. D. J. Agric. Food
Chem. 1968, 16, 80-83.
(36) Dvornikov, S. S.; Knyukshto, V. N.; Solovev, K. N.; Tsvirko, M.
P. Opt. Spektrosk. 1979, 46, 385-388.
(37) Agostiano, A.; Catucci, L.; Colafemmina, G.; Scheer, H. J. Phys.
Chem. B 2002, 106, 1446-1454.
(38) Strickler, S. J.; Berg, R. A. J. Chem. Phys. 1962, 37, 814-822.
4098 J. Org. Chem., Vol. 71, No. 11, 2006

Synthetic Chlorins Bearing Auxochromes
the presence of the geminal dimethyl group in the pyrroline
ring of the synthetic chlorins prepared herein lowers the
symmetry, but the geminal dimethyl group is not expected to
perturb the π-system and, hence, should have little effect on
the spectral properties. The 3- and 13-positions each reside in
a pyrrole ring aligned along the Qy axis; the former is distal,
whereas the latter is proximal to the pyrroline ring. In one case
where a comparison could be made, the magnitude of the effect
caused by a substituent at the 3-position was found to be quite
similar to that at the 13-position: ZnC-E3M10 and ZnC-M10E13
exhibited nearly identical Qy band positions (627 nm, 626 nm).
Additional comparisons are required to more fully understand
the effects of auxochromes at the two locations proximal (2
and 13) versus distal (3 and 12) to the pyrroline ring. Such
comparisons are now possible with the synthetic methodology
described herein for preparing substituted chlorins.
Conclusions
A new route has been established for the de novo synthesis
of sterically uncongested, stable chlorins bearing substituents
at the 3- and 13-positions. The motivation for introducing
auxochromes at the 3- and 13-positions stems from chlorophylls
a and b, which bear 3-vinyl and 13-keto groups. This work
complements studies of derivatives of naturally occurring
chlorins, which typically contain a full set of â-pyrrolic
substituents and are less malleable synthetically. The use of one
or two acetyl, TIPS-ethynyl, or vinyl groups at these positions
enables fine-tuning of the absorption and fluorescence properties
of the chlorins. The spectral redshift imparted by a single group
is substantial [3-vinyl (400 cm-1), 3- or 13-TIPS-ethynyl (∼540
cm-1), 13-acetyl (680 cm-1)], and the effect of two such groups
is nearly additive [3,13-bis(TIPS-ethynyl) (1020 cm-1), 3-TIPS-
ethynyl-13-acetyl (1160 cm-1), 3,13-diacetyl (1400 cm-1)]. The
redshift is accompanied by (1) a relative increase in the Qy band
intensity versus the B band intensity, and (2) an increase in the
fluorescence quantum yield. The use of 3,13-bis(TIPS-ethynyl),
3-TIPS-ethynyl-13-acetyl, or 3,13-diacetyl groups affords chlo-
rins with absorption spectral (shape and position, but not
intensity) properties and fluorescence properties that rival those
of chlorophyll a. It is noteworthy that ethynes do not occur in
natural chlorophylls; however, ethynes are particularly attractive
in their ease of introduction, potent auxochromic effect, and
amenability toward synthetic elaboration. Ethynes have been
employed extensively in porphyrin chemistry,28,39 but have been
relatively little examined with hydroporphyrins.15,40 The syn-
thetic approaches described herein should enable a much broader
examination of substituents for tuning the spectral and photo-
chemical properties of chlorins. The ability to prepare 3,13-
substituted chlorins also complements the work of Balaban et
al., who have employed synthetic porphyrins or derivatives of
chlorophylls in exploring the effects of substituents on porphy-
rinic self-assembly processes leading to light-harvesting archi-
tectures.41
FIGURE 1. Absorption spectra in toluene at room temperature of zinc
chlorins (normalized at the B bands). Upper panel: The 10-mesityl-
chlorins (label, color in graph) and their Qy bands include ZnC-M10
(a, black), 606 nm; ZnC-V3M10 (b, violet), 621 nm; ZnC-E3M10 (c,
blue), 627 nm; ZnC-M10A13 (d, green), 632 nm; ZnC-E3M10E13 (e,
lime), 646 nm; ZnC-E3M10A13 (f, orange), 652 nm; and ZnC-A3M10A13
(g, red), 662 nm. The IB/IQ ratio decreases from 4.2 to 1.5 in the series.
Lower panel: The 10-unsubstituted chlorins (color in graph) and their
Qy bands include ZnC (black), 603 nm; ZnC-E3E13 (blue), 645 nm;
and ZnC-E3A13 (red), 655 nm. The IB/IQ ratio decreases from 3.2 in
ZnC to 1.2 in ZnC-E3A13.
FIGURE 2. The Qy axis in chlorins.
dynamics, including excited singlet-state lifetimes. Regardless,
the absorption spectral properties (shape and position) and
fluorescence spectral properties of the 3,13-bis(TIPS-ethynyl)-
chlorins (ZnC-E3M10E13, ZnC-E3E13), 3-TIPS-ethynyl-13-
acetylchlorins (ZnC-E3M10A13, ZnC-E3A13), and 3,13-diace-
tylchlorin ZnC-A3M10A13 resemble those of chlorophyll a or
its zinc analogue Zn-Pheo a.
A final point concerns the effect of auxochromes substituted
in ring A versus ring C. In chlorins, the Qy band is polarized
along the N-N axis containing pyrrole rings A and C (Chart 1
and Figure 2).1 A chlorin nominally has C2V symmetry,1 in which
case the 2- and 13-positions are symmetrically equivalent, and
the 3- and 12-positions are symmetrically equivalent. In practice,
Experimental Section
Monobromination: 9-Bromo-1-formyl-5-mesityldipyrrometh-
ane (4a). Following a reported procedure,11 a solution of 2 (43.5
(39) Lin, V. S.-Y.; DiMagno, S. G.; Therien, M. J. Science 1994, 264,
1105-1111.
(40) Hindin, E.; Kirmaier, C.; Diers, J. R.; Tomizaki, K.-Y.; Taniguchi,
M.; Lindsey, J. S.; Bocian, D. F.; Holten, D. J. Phys. Chem. B 2004, 108,
8190-8200.
J. Org. Chem, Vol. 71, No. 11, 2006 4099

Laha et al.
mg, 0.149 mmol) in dry THF (4 mL) at -78 °C under argon was
treated with NBS (26.5 mg, 0.149 mmol) and stirred for 30 min.
Hexanes (4 mL) and water (4 mL) were added, and the cooling
bath was removed. The mixture was allowed to warm to room
temperature. The mixture was extracted with ethyl acetate. The
organic phase was dried (MgSO4) and filtered. The filtrate was
concentrated to give a brown solid that was chromatographed [silica,
hexanes/ethyl acetate (9:1 f 3:1)]. The product was recrystallized
(EtOH/H2O, 4:1) to afford light brown crystals (37 mg, 67%):
mp 159 °C (dec); 1H NMR (THF-d8) δ 2.05 (s, 6H), 2.22 (s,
3H), 5.49-5.52 (m, 1H), 5.74 (s, 1H), 5.80-5.85 (m, 1H),
5.89-5.92 (m, 1H), 6.76-6.78 (m, 1H), 6.80 (s, 2H), 9.38 (s, 1H),
10.45 (br s, 1H), 11.09 (br s, 1H); 13C NMR δ 22.2, 31.9, 41.5,
98.4, 110.7, 111.4, 112.2, 121.9, 131.9, 134.5, 135.3, 136.2, 138.0,
139.2, 143.6, 179.2; FAB-MS obsd, 370.0664; calcd, 370.0681
(C19H19BrN2O).
(water and brine) and dried (Na2SO4). Concentration followed by
crystallization (ethyl acetate/hexanes) afforded pale yellow crystals
(6.75 g, 68%): mp 83-85 °C; 1H NMR δ 2.43 (s, 3H), 7.09 (d, J
) 2.0 Hz, 1H), 7.35 (d, J ) 8.3 Hz, 2H), 7.57 (d, J ) 2.0 Hz, 1H),
7.81 (d, J ) 8.3 Hz, 2H), 9.94 (s, 1H); 13C NMR δ 22.0, 101.8,
125.4, 127.8, 127.9, 130.6, 133.5, 134.7, 146.7, 178.5. Anal. Calcd
for C12H10BrNO3S: C, 43.92; H, 3.07; N, 4.27; S, 9.77. Found:
C, 43.92; H, 3.02; N, 4.26; S, 9.84.
4-Bromo-2-(2-nitroethyl)-N-p-tosylpyrrole (7-Ts). Following
a reported procedure,19 a mixture of 6-Ts (7.50 g, 22.8 mmol),
nitromethane (21.6 mL, 405 mmol), and ammonium acetate (1.18
g, 15.3 mmol) was refluxed for 3 h. The reaction mixture was
concentrated under reduced pressure. The residue was dissolved
in ethyl acetate, and the solution was washed with aqueous
NaHCO3, water, and brine and then dried (Na2SO4). Removal of
the solvent gave a brown solid that was used directly in the next
step. Following a published procedure,22 a solution of the crude
product in CHCl3 (195 mL) and 2-propanol (65 mL) was treated
with silica (26.3 g). The resulting suspension was treated in three
portions with NaBH4 (1.65 g, 45.6 mmol) under vigorous stirring
at room temperature. The reaction mixture was stirred for ∼1.5 h
and monitored by TLC. The reaction mixture was filtered. The filter
cake was washed several times with CH2Cl2. The organic solution
was washed with water and brine. The organic layer was dried
(NaSO4), concentrated, and subjected to high vacuum to remove
traces of 2-propanol. The resulting residue was subjected to column
chromatography [silica, hexanes/CH2Cl2/ethyl acetate (8:1:1)] to
afford a pale yellow solid (4.95 g, 58%): mp 126-128 °C;
1H NMR (300 MHz) δ 2.44 (s, 3H), 3.38 (t, J ) 7.0 Hz, 2H),
4.60 (t, J ) 7.0 Hz, 2H), 6.09 (d, J ) 2.0 Hz, 1H), 7.31 (d, J ) 2.0
Hz, 1H), 7.35 (d, J ) 8.3 Hz, 2H), 7.68 (d, J ) 8.3 Hz, 2H); 13C
NMR δ 21.9, 25.3, 74.3, 100.9, 117.3, 122.5, 127.0, 129.5, 130.7,
135.4, 146.2. Anal. Calcd for C13H13BrN2O4S: C, 41.84; H, 3.51;
N, 7.51. Found: C, 41.88; H, 3.50; N, 7.29. An alternative
preparation using Montmorillonite K10 is described in the Sup-
porting Information.
Dibromination: 8,9-Dibromo-1-formyldipyrromethane (3b).
A solution of 1 (270 mg, 1.55 mmol) in dry THF (15.5 mL) at
-78 °C under argon was treated with NBS (552 mg, 3.17 mmol).
The reaction mixture was stirred for 1 h at -78 °C. Hexanes and
water were added at -20 °C, and the mixture was allowed to warm
to 0 °C. The organic layer was separated, dried (K2CO3), and
concentrated at ambient temperature. The resulting brown solid was
purified by column chromatography [silica, hexanes/CH2Cl2/
ethyl acetate (7:2:1)], affording a purple solid (290 mg, 56%): mp
1
109-111 °C (dec); H NMR (THF-d8) δ 3.93 (s, 2H), 5.89 (s,
1H), 6.05-6.07 (m, 1H), 6.78-6.79 (m, 1H), 9.37 (s, 1H), 10.81
(br s, 1H), 11.16 (br s, 1H); 13C NMR (THF-d8) δ 26.0, 96.3, 98.0,
110.1, 112.7, 121.7, 128.9, 134.3, 139.0, 178.5. Anal. Calcd for
C10H8Br2N2O: C, 36.18; H, 2.43; N, 8.44. Found: C, 36.58; H,
2.50; N, 8.11. Note: A significant amount (∼30%) of the starting
1-formyldipyrromethane 1 was recovered in this reaction. Com-
pound 3b can be stored in solid form at -20 °C for 2-3 months
without decomposition but is susceptible to decomposition in
solution, particularly in CDCl3. All handling in solution, including
during solvent removal, should be done without heating.
4-Bromopyrrole-2-carboxaldehyde (6). A solution of pyrrole-
2-carboxaldehyde (5, 4.75 g, 50.0 mmol) in dry THF (200 mL)
was cooled to -78 °C under argon. NBS (8.90 g, 50.0 mmol) was
added, and the reaction mixture was stirred for 1 h at -78 °C.
Hexanes and water were added, and the reaction mixture was
allowed to warm to 0 °C. The organic phase was extracted with
hexanes and dried (Na2SO4). Crystallization of the crude mixture
using hexanes/THF afforded white crystals (4.83 g, 55%): mp 120-
6-(4-Bromo-1H-pyrrol-2-yl)-4,4-dimethyl-5-nitrohexan-2-
one (8). Following a reported procedure,23 a solution of TBAF‚
3H2O (2.64 g, 8.36 mmol) in anhydrous DMF (25 mL) was stirred
in the presence of 3 Å molecular sieves (8 g) for 30 min at
room temperature under argon. The stirred suspension was treated
with a solution of 7-Ts (1.56 g, 4.18 mmol) and mesityl oxide
(4.80 mL, 42.0 mmol) in anhydrous DMF (15 mL). The mixture
was stirred at room temperature for 3 h. The reaction mixture
was filtered through filter paper. The filtrate was concentrated
under reduced pressure. The resulting residue was dissolved in
ethyl acetate. The organic solution was washed with water, dried
(Na2SO4), and chromatographed [silica, CH2Cl2] to give a viscous
liquid (623 mg, 47%): 1H NMR (300 MHz) δ 1.09 (s, 3H), 1.22
(s, 3H), 2.14 (s, 3H), 2.40 (d, J ) 17.6 Hz, 1H), 2.58 (d, J ) 17.6
1
121 °C [lit.18 122-123 °C]; H NMR δ 6.95 (m, 1H), 7.12 (m,
1H), 9.45 (s, 1H), 9.65-9.85 (br s, 1H); 13C NMR δ 99.0, 123.0,
127.0, 132.8, 179.3. Anal. Calcd for C5H4BrNO: C, 34.51; H, 2.32;
N, 8.05. Found: C, 34.50; H, 2.26; N, 7.75. Note: Careful handling
of the crude mixture is required. Evaporation of the solvent during
workup should be done without heating. The use of ethyl acetate
or any chlorinated solvent was avoided during workup or crystal-
lization. The crystallization of the crude mixture was carried out
by dissolving the off-white solid in THF by warming (40-50 °C),
followed by addition of hexanes. The crude off-white solid very
often turns a reddish color, which subsequently prevents crystal-
lization. In that case, a small silica-pad filtration of the crude mixture
is required before crystallization.
4-Bromo-2-formyl-N-p-tosylpyrrole (6-Ts). Following a re-
ported procedure,20 a stirred suspension of NaH (865 mg, 36.0
mmol) in THF (200 mL) was treated with 6 (5.22 g, 30.0 mmol)
at room temperature. When the evolution of gas had ceased, the
mixture was stirred for 1 h before treating with p-toluenesulfonyl
chloride (6.30 g, 33.0 mmol). After 16 h, the conversion was
complete, as monitored by TLC. The reaction mixture was quenched
by adding saturated aqueous NH4Cl. Ethyl acetate was added, and
the organic layer was separated. The organic layer was washed
2
Hz, 1H), 2.97 (AB, J ) 15.2 Hz, 1H), 3.28 (ABX, J ) 15.2 Hz,
2
3
3J ) 11.6 Hz, 1H), 5.11 (ABX, J ) 11.6 Hz, J ) 3.5 Hz, 1H),
5.97-5.99 (m, 1H), 6.62-6.64 (m, 1H), 8.10-8.18 (br s, 1H);
13C NMR δ 24.3, 24.5, 26.8, 32.0. 36.9, 51.6, 94.4, 96.2, 110.0,
117.8, 127.3, 207.7; FAB-MS obsd, 316.0432; calcd, 316.0423
(C12H17BrN2O3). Note: Compound 8 (neat or in solution) changes
color from yellow to black over time (1-2 days) at room
temperature, indicating partial decomposition.
6-(4-Bromo-N-p-tosylpyrrol-2-yl)-4,4-dimethyl-5-nitrohexan-
2-one (8-Ts). Following a reported procedure,13 CsF (3.17 g, 20.9
mmol) was freshly dried by heating at 100 °C under vacuum for 1
h and then cooled to room temperature under argon. A solution of
7-Ts (2.60 g, 6.96 mmol) and mesityl oxide (8.16 mL, 71.0 mmol,
10 molar equiv) in dry acetonitrile (61 mL) was transferred by
cannula to the flask containing CsF. The mixture was stirred at 65
°C for 18 h. The reaction mixture was filtered through a pad of
silica, and the filter cake was washed with ethyl acetate. The filtrate
was concentrated under reduced pressure. Column chromatography
[silica, hexanes/CH2Cl2/ethyl acetate (7:2:1)] of the crude product
(41) Balaban, T. S.; Tamiaki, H.; Holzwarth, A. R. Top. Curr. Chem.
2005, 258, 1-38.
4100 J. Org. Chem., Vol. 71, No. 11, 2006

Synthetic Chlorins Bearing Auxochromes
afforded a brown solid (0.980 g, 30%): mp 103-104 °C; 1H NMR
δ 1.11 (s, 3H), 1.24 (s, 3H), 2.13 (s, 3H), 2.40 (AB, J ) 17.8 Hz,
1H), 2.43 (s, 3H), 2.55 (AB, J ) 17.8 Hz, 1H), 3.18 (AB, J )
16.2 Hz, 1H), 3.36 (ABX, J ) 16.2 Hz, J ) 11.8 Hz, 1H), 5.14
(AB, J ) 11.8 Hz, 1H), 6.00-6.02 (m, 1H), 7.22-7.24 (m, 1H),
7.34 (AB, J ) 8.2 Hz, 2H), 7.64 (AB, J ) 8.2 Hz, 2H); 13C NMR
δ 21.9, 23.7, 24.4, 26.4, 31.8. 36.9, 51.0, 93.5, 101.0, 117.0, 122.4,
126.8, 130.2, 130.6, 135.6, 146.0, 206.3; FAB-MS obsd, 471.0596;
calcd, 471.0589 (C19H23BrN2O5S).
at room temperature for 30 min. The reaction mixture was washed
(10% NaHCO3, water, brine), dried (Na2SO4), and concentrated,
yielding a brown solid. The solid was dissolved in CH3CN (20
mL), and the resulting solution was treated with 2,2,6,6-tetrameth-
ylpiperidine (0.340 mL, 2.00 mmol), Zn(OAc)2 (370 mg, 2.00
mmol), and AgOTf (154 mg, 0.600 mmol). The resulting suspension
was refluxed for 14 h exposed to air. The crude mixture was
concentrated and chromatographed [silica, CH2Cl2], affording a
green solid (45 mg, 37%): 1H NMR δ 1.85 (s, 6H), 2.01 (s, 6H),
2.60 (s, 3H), 4.50 (s, 2H), 7.23 (s, 2H), 8.37 (d, J ) 4.1 Hz, 1H),
8.50 (s, 1H), 8.55 (d, J ) 4.4 Hz, 1H), 8.60 (d, J ) 4.4 Hz, 1H),
8.68 (s, 1H), 8.77 (s, 1H), 8.88 (d, J ) 4.1 Hz, 1H), 9.73 (s, 1H);
LD-MS obsd, 598.3; ESI-MS obsd, 598.0720; calcd, 598.0711
(C31H27BrN4Zn); λabs 408, 614 nm.
Chlorin Vinylation: Zn(II)-17,18-Dihydro-10-mesityl-18,18-
dimethyl-3-vinylporphyrin (ZnC-V3M10). Following a procedure
for Stille coupling with porphyrins,28 a mixture of ZnC-Br3M10
(20 mg, 0.033 mmol), Bu3SnCHdCH2 (20 µL, 0.068 mmol), and
(PPh3)2PdCl2 (3.0 mg, 0.0042 mmol) was refluxed in THF (2 mL)
for 14 h using a Schlenk line. The reaction mixture was concentrated
and chromatographed [silica, CH2Cl2], affording a blue solid (12
mg, 66%): 1H NMR δ 1.86 (s, 6H), 2.02 (s, 6H), 2.60 (s, 3H),
4.50 (s, 2H), 5.85 (d, J ) 10.8 Hz, 1H), 6.47 (d, J ) 17.5 Hz, 1H),
7.23 (s, 2H), 8.19 (dd, J ) 17.5, 10.8 Hz, 1H), 8.33 (d, J ) 4.1
Hz, 1H), 8.50 (d, J ) 4.4 Hz, 1H), 8.52 (s, 1H), 8.55 (d, J ) 4.4
Hz, 1H), 8.62 (s, 1H), 8.81 (d, J ) 4.1 Hz, 1H), 8.83 (s, 1H), 9.68
(s, 1H); LD-MS obsd, 546.7; FAB-MS obsd, 546.1739; calcd,
546.1762 (C33H30N4Zn); λabs 413 (log ꢀ ) 5.18), 621 (4.66) nm;
λem ) 625 nm.
Chlorin Ethynylation: Zn(II)-17,18-Dihydro-10-mesityl-
18,18-dimethyl-3-[2-(triisopropylsilyl)ethynyl]porphyrin
(ZnC-E3M10). Following a procedure for Sonogashira coupling with
chlorins,15 a mixture of ZnC-Br3M10 (18 mg, 0.030 mmol),
(triisopropylsilyl)acetylene (14 µL, 0.060 mmol), Pd2(dba)3 (4.2 mg,
0.0045 mmol), and P(o-tol)3 (11 mg, 0.036 mmol) was heated at
60 °C in toluene/triethylamine (5:1, 12 mL) using a Schlenk line.
After 7 h, (triisopropylsilyl)acetylene (14 µL, 0.060 mmol), Pd2-
(dba)3 (4.2 mg, 0.0045 mmol), and P(o-tol)3 (11 mg, 0.036 mmol)
were added to the reaction mixture. After 18 h, the reaction mixture
was concentrated and chromatographed [silica, hexanes/CH2Cl2 (2:
1)], affording a green solid (11 mg, 52%): 1H NMR δ 1.38 (m,
18H), 1.40 (m, 3H), 1.85 (s, 6H), 2.01 (s, 6H), 2.60 (s, 3H), 4.51
(s, 2H), 7.22 (s, 2H), 8.36 (d, J ) 4.1 Hz, 1H), 8.50-8.54 (m,
2H), 8.60 (d, J ) 4.1 Hz, 1H), 8.67 (s, 1H), 8.80-8.85 (m, 2H),
9.88 (s, 1H); LD-MS obsd, 700.5; FAB-MS obsd, 700.2930; calcd,
700.2940 (C42H48N4SiZn); λabs 416 (log ꢀ ) 5.14), 627 (4.73) nm;
λem ) 630 nm.
Chlorin Acetylation: Zn(II)-13-Acetyl-17,18-dihydro-10-
mesityl-18,18-dimethylporphyrin (ZnC-M10A13). The standard
procedure entails (1) zinc demetalation, (2) Pd-mediated coupling
with tributyl(1-ethoxyvinyl)tin, (3) acidic hydrolysis of the coupled
product, and (4) zinc metalation, as described in detail as follows.
A solution of ZnC-M10Br13 (50 mg, 0.083 mmol) in CH2Cl2 (1.0
mL) was treated dropwise with TFA (0.13 mL, 1.6 mmol) over 2
min. The solution was stirred at room temperature for 2 h. CH2Cl2
was added, and the organic layer was washed (saturated aqueous
NaHCO3, water, brine) and then dried (Na2SO4). The crude mixture
was concentrated and used in the next step. Following a procedure
for the replacement of a bromo group with an acetyl group on an
aromatic substrate,29 a mixture of the crude product, tributyl(1-
ethoxyvinyl)tin (49 µL, 0.14 mmol), and (PPh3)2PdCl2 (10 mg,
0.014 mmol) was refluxed in THF (7 mL) for 20 h using a Schlenk
line. The reaction mixture was treated with 10% aqueous HCl (4
mL) at room temperature for 2 h. CH2Cl2 was added, and the
organic layer was separated. The organic layer was washed
(saturated aqueous NaHCO3, water, brine), dried (Na2SO4), and
concentrated. The resulting residue was dissolved in CHCl3 (5 mL).
The solution was treated with Zn(OAc)2‚2H2O (320 mg, 1.45
mmol) in MeOH (2 mL), and the reaction mixture was stirred
3
2
Western Half Formation: 8-Bromo-2,3,4,5-tetrahydro-1,3,3-
trimethyldipyrrin (9). Following a refined procedure,22 a stirred
suspension of 8 (350 mg, 1.10 mmol) and HCOONH4 (1.04 g, 16.5
mmol) in THF (4.4 mL) was treated portionwise with Zn dust (1.07
g, 16.5 mmol) for 15 min. The reaction mixture was stirred
vigorously for 3 h at room temperature. Ethyl acetate was added,
and the reaction mixture was filtered through filter paper. The filtrate
was washed (half saturated aqueous NaHCO3, water, brine), dried
(Na2SO4), and chromatographed (silica, ethyl acetate), affording a
1
yellow solid (135 mg, 45%): mp 83-84 °C; H NMR δ 0.92 (s,
3H), 1.11 (s, 3H), 2.03 (s, 3H), 2.28 (AB, J ) 16.8 Hz, 1H), 2.38
2
3
(AB, J ) 16.8 Hz, 1H), 2.54 (ABX, J ) 14.9 Hz, J ) 11.8 Hz,
2
3
1H), 2.69 (ABX, J ) 11.8 Hz, J ) 2.5 Hz, 1H), 3.56-3.62 (m,
1H), 5.85-5.94 (m, 1H), 6.63-6.69 (m, 1H), 9.72-10.01 (br s,
1H); 13C NMR δ 20.7, 23.0, 27.3, 27.8, 42.0, 54.4, 80.2, 95.2, 108.2,
116.5, 132.8, 175.1. Anal. Calcd for C12H17BrN2: C, 53.54; H, 6.37;
N, 10.41. Found: C, 53.15; H, 6.32; N, 10.11. Note: Continued
reaction for g5 h often results in the significant formation of a
side product.
8-[2-(Triisopropylsilyl)ethynyl]-2,3,4,5-tetrahydro-1,3,3-tri-
methyl-N11-p-tosyldipyrrin (10-Ts). A mixture of 9-Ts (0.560 g,
1.32 mmol), (triisopropylsilyl)acetylene (0.590 mL, 2.65 mmol),
(PPh3)2PdCl2 (186 mg, 0.265 mmol), diisopropylamine (0.930
mL, 6.63 mmol), and CuI (50.0 mg, 0.262 mmol) was refluxed in
THF (6 mL) for 20 h using a Schlenk line. The reaction mixture
was concentrated and chromatographed [silica, hexanes/ethyl acetate
(1:1)], affording a viscous liquid (375 mg, 54%): 1H NMR (300
MHz) δ 0.87 (s, 3H), 1.05-1.07 (m, 24H), 1.97 (s, 3H), 2.26 (AB,
J ) 16.8 Hz, 1H), 2.35 (AB, J ) 16.8 Hz, 1H), 2.40 (s, 3H), 2.60
2
3
2
(ABX, J ) 16.2 Hz, J ) 10.1 Hz, 1H), 2.86 (ABX, J ) 16.2
3
Hz, J ) 3.8 Hz, 1H), 3.68-3.70 (m, 1H), 6.28-6.30 (m, 1H),
7.28 (d, J ) 8.1 Hz, 2H), 7.46-7.47 (m, 1H), 7.68 (d, J ) 8.1 Hz,
2H); 13C NMR δ 11.5, 18.8, 20.7, 21.8, 23.0, 27.2, 28.0, 42.4, 54.6,
77.9, 91.1, 100.5, 108.6, 116.2, 125.9, 127.3, 130.3, 134.1, 136.0,
145.4, 175.2. FAB-MS obsd, 525.2966; calcd, 525.2971 [(M + H)+,
M ) C30H45N2O2SSi].
8-[2-(Triisopropylsilyl)ethynyl]-2,3,4,5-tetrahydro-1,3,3-tri-
methyldipyrrin (10). Following a reported procedure,27 a stirred
suspension of 10-Ts (230 mg, 0.438 mmol) and LiOH (53.0
mg, 2.20 mmol) in anhydrous DMF (2 mL) was treated with
HSCH2COOH (77.0 µL, 1.10 mmol) at room temperature. The
reaction mixture was stirred for 5 h at 65 °C under argon. Ethyl
acetate was added, and the resulting mixture was washed (water,
brine), dried (Na2SO4), concentrated, and chromatographed [silica,
hexanes/ethyl acetate (1:1)], affording a white solid (118 mg,
72%): mp 110-112 °C; 1H NMR (300 MHz) δ 0.92 (s, 3H), 1.10-
1.12 (m, 24H), 2.03 (s, 3H), 2.28 (AB, J ) 16.8 Hz, 1H), 2.37
2
3
(AB, J ) 16.8 Hz, 1H), 2.51 (ABX, J ) 14.9 Hz, J ) 11.8 Hz,
2
3
1H), 2.68 (ABX, J ) 14.9 Hz, J ) 2.8 Hz, 1H), 3.56-3.59 (m,
1H), 6.01-6.03 (m, 1H), 6.90-6.92 (m, 1H), 9.90-9.93 (br s, 1H);
13C NMR δ 11.6, 18.9, 20.6, 23.0, 27.3, 27.7, 42.0, 54.4, 80.1,
87.2, 103.7, 104.0, 109.4, 121.9, 131.8, 175.6. Anal. Calcd for
C23H38N2Si: C, 74.53; H, 10.33; N, 7.56. Found: C, 74.25; H,
10.29; N, 7.49.
Chlorin Formation: Zn(II)-3-Bromo-17,18-dihydro-10-mesi-
tyl-18,18-dimethylporphyrin (ZnC-Br3M10). A solution of 4a
(75 mg, 0.20 mmol) and 9 (54 mg, 0.20 mmol) in distilled CH2Cl2
(6 mL) was treated with a solution of p-TsOH‚H2O (0.19 g, 1.0
mmol, 5 mol equiv relative to the western half 9) in distilled
methanol (2 mL) under argon. The red reaction mixture was stirred
J. Org. Chem, Vol. 71, No. 11, 2006 4101

Laha et al.
overnight at room temperature. Concentration followed by chro-
matography of the crude mixture [silica, CH2Cl2/hexanes (1:1)]
gave a green solid (25 mg, 53%): 1H NMR δ 1.82 (s, 6H),
2.00 (s, 6H), 2.60 (s, 3H), 2.72 (s, 3H), 4.47 (s, 2H), 7.20 (s, 2H),
8.30 (d, J ) 4.4 Hz, 1H), 8.48 (s, 1H), 8.68 (d, J ) 4.4 Hz, 2H),
8.81 (s, 1H), 8.96 (d, J ) 4.4 Hz, 1H), 9.38 (s, 1H), 9.55 (s, 1H);
LD-MS obsd, 560.7; ESI-MS obsd, 562.1700; calcd, 562.1711
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: Experimental procedures;
molar absorption coefficient determination method and spectral
graph; fluorescence yield determination method; and spectral data
for selected compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(C33H30N4OZn); λabs 418 (log ꢀ ) 5.17), 632 (4.84) nm; λem
636 nm.
)
Acknowledgment. This research work was supported by the
NIH (GM36238). Mass spectra were obtained at the Mass
JO060208O
4102 J. Org. Chem., Vol. 71, No. 11, 2006