An efficient PIFA-mediated synthesis of a directly linked zinc chlorin dimer via regioselective oxidative coupling

Article abstract of DOI:10.1021/ol300969g

The synthesis of a directly linked zinc chlorin dimer was first achieved by a facile and efficient oxidative coupling of zinc chlorin monomers with phenyliodine bis(trifluoroacetate) (PIFA). The reaction shows high regioselectivity at the 20-position near the hydrogenated pyrrole ring producing selective dichlorin in 74% yield.

Full text of DOI:10.1021/ol300969g

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2746–2749
An Efficient PIFA-Mediated Synthesis of a
Directly Linked Zinc Chlorin Dimer via
Regioselective Oxidative Coupling
Qin Ouyang,†,‡ Kai-Qi Yan,† Yi-Zhou Zhu,† Cai-Hui Zhang,† Jin-Zhong Liu,†
Chen Chen,† and Jian-Yu Zheng*,†
State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, China, and College of Pharmacy, Third Military Medical University,
Chongqing 400038, China
jyzheng@nankai.edu.cn
Received April 13, 2012
ABSTRACT
The synthesis of a directly linked zinc chlorin dimer was first achieved by a facile and efficient oxidative coupling of zinc chlorin monomers with
phenyliodine bis(trifluoroacetate) (PIFA). The reaction shows high regioselectivity at the 20-position near the hydrogenated pyrrole ring producing
selective dichlorin in 74% yield.
Porphyrin and chlorin dimers have attracted significant
attention due to their numerous applications such as
artificial photosynthetic systems, sensors, and nonlinear
optical(NLO)devices.1 Inrecentyears, contributionsfrom
several research groups have resulted in the facile synthesis
of directly linked porphyrins by oxidative coupling.2 It has
been shown that the short distance and electronic interac-
tion between porphyrin units imparted predominant
photophysical properties tothe molecules, such aseffective
energy transfer and low energy absorption bands.3 Chlo-
rins are structurally more similar to natural photosynthetic
pigments than porphyrin.4 Besides their application as
models to understand the key steps of the natural photo-
synthetic mechanism, many bis-chlorin model structures
bridged by ether, ester, and CꢀC at varied distances have
recently been reported5 as effective photosensitizers for
photodynamic therapy (PDT). However, the synthesis of
† Nankai University.
‡ Third Military Medical University.
(1) For some examples of the leading reports, see: (a) Chou, J.-H.;
Kosal, M. E.; Nalwa, H. S.; Rakow, N. A.; Suslick, K. S. In The
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Nakamura, Y.; Aratani, N.; Shinokubo, H.; Takagi, A.; Kawai, T.;
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Muranaka, A.; Kobayashi, N.; Osuka, A. J. Am. Chem. Soc. 2006,
128, 4119 and references cited therein.
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T.; Kim, D.; Osuka, A. J. Am. Chem. Soc. 2005, 127, 236. (e) Maeda, C.;
Kamada, T.; Aratani, N.; Osuka, A. Coord. Chem. Rev. 2007, 251, 2743.
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phylls and Bacteriochlorophylls: Biochemistry, Biophysics, Functions and
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25, pp 79ꢀ94.
r
10.1021/ol300969g
Published on Web 05/14/2012
2012 American Chemical Society

directly linked chlorins via oxidative coupling and the
effect of the electronic interaction of the most closely
connected units has never been explored.
cation, produced via SET oxidation, coupled itself to form
the dimer.8ꢀ10 Compared to porphyrin, chlorin has a
similar conjugation path and redox properties; however,
one pyrrole ring is reduced to a pyrroline ring (Scheme 1).
Therefore, we infer that a similar oxidative coupling reac-
tion of chlorin would be realized if the oxidation of the
pyrroline ring could be avoided. In this paper, we report an
oxidative coupling method for the synthesis of a directly
linked chlorin dimer by treating Zn(II) chlorin with PIFA
in 74% yield. This coupling reaction shows high regios-
electivity at the meso-bridge position 20 in the vicinity of
the pyrroline ring over the meso-bridge position 10.
Scheme 1. Conjugation Pathway of Porphyrin and Chlorin
Scheme 2. Oxidative Reaction of Metal Chlorins
Recently, hypervalent iodine(III) reagents, such as
phenyliodine diacetate (PIDA) and phenyliodine bis-
(trifluoroacetate) (PIFA), have been widely applied as safe
and useful nonmetal oxidants in many organic reactions
for their high reactivities and selectivities.6 The coupling
reactions of a metalloporphyrin monomer which has a
meso-H can be easily and efficiently promoted by hyper-
valent iodine(III).2e This synthesis strategy has also been
used, in our group, to achieve the synthesis of chiral
diporphyrins and fused diporphyrins.7 The mechanism
for porphyrin to carry out such a reaction was previously
widely considered as involving single electron transfer
(SET) oxidation. It was thought that the porphyrin radical
Table 1. Yields of the Oxidative Reaction of Metal Chlorins
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Engl. 1996, 35, 1013. (d) Jaquinod, L.; Senge, M. O.; Pandey, R. K.;
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M.; Holten, D.; Bocian, D. F.; Lindsey, J. S. J. Org. Chem. 2010, 75,
3193.
yield/%a
entry
reactant
DDQb
PIDAc
PIFAc
1
2
3
4
5
1a
1b
1c
1d
1e
80 (3a)
50 (3b)
48 (3c)
30 (3d)
78 (3e)
N.R.
N.R.
35 (2b)
N.R.
74 (2b)
58 (3c)
54 (3d)
66 (3e)
N.R.
N.R.
a Isolated yield of 2b and 3aꢀe. b The amount of added oxidant was
1.0 equiv. c The amount of added oxidant was 0.5 equiv.
(6) For selective leading reviews, see: (a) Stang, P. J.; Zhdankin, V. V.
Chem. Rev. 1996, 96, 1123. (b) Kita, Y.; Takada, T.; Tohma, H. Pure
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2008, 386.
In our experiments, the metal chlorins, prepared via a
streamlined synthesis,11 were treated with the oxidants
DDQ (2,3-dichloro-5,6-dicyanobenzoquinone), PIDA,
and PIFA (Scheme 2). The oxidants were added to a
solution of 1aꢀe in CH2Cl2 under nitrogen. The directly
linked chlorin dimer was only obtained by the reaction of
Zn(II) chlorin with hypervalent iodine(III) reagents (Table
1, entry 2). Pd(II), Cu(II), and Ni(II) chlorins were oxi-
dized by PIFA and DDQ to the respective porphyrin
(58ꢀ66%) and were inert to PIDA. Moveover, the free
base chlorin 1a reacted with DDQ to produce a porphyrin
but was inert to hypervalent iodine(III) reagents. With the
Zn(II) chlorin 2a the oxidative coupling reaction with
(11) (a) Whitlock, H. W., Jr.; Hanauer, R.; Oester, M. Y.; Bower,
B. K. J. Am. Chem. Soc. 1969, 91, 5. (b) Balem, F.; Yanamala, N.; Klein-
Seetharaman, J. Photochem. Photobiol. 2009, 85, 471.
Org. Lett., Vol. 14, No. 11, 2012
2747

PIFA progressed very fast, and the raw material comple-
tely disappeared within 5 min. We found that addition of
0.5 equiv of PIFA promoted the reaction in high yield of 2b
(74%). This reaction could also be achieved using PIDA;
however, the yield is significantly reduced (35%). As
expected, this coupling reaction showed high regioselec-
tivity, and the 20ꢀ200 linked dimer was obtained as the
only product. Further addition of oxidants led to the
formation of a complex mixture, but not the compound
formed by coupling in the meso-position 10. Furthermore,
the Zn(II) chlorin 1b could not be oxidatively coupled to 2b
using DDQ; instead it underwent oxidative dehydrogena-
tion to the porphyrin 3b (50%, entry 2). These results
indicate that PIDA and PIFA do not oxidize the pyrroline
ring but regioselectively react with the 20-position to
generate the dimer.
Figure 2. HOMO of Zn(II) Chlorin 1b derived by calculations at
the B3LYP/6-31G(d,p) level, using the LANL2DZ effective
core potential for zinc.
with its first oxidation potential.7b,12 The electrochemical
properties of 1aꢀe and 5,15-diphenyl Zn(II) porphyrin
were studied by cyclic voltammetry in CH2Cl2 contain-
ing 0.1 M tetrabutylammonium hexafluorophosphate
(n-Bu4NPF6) as a supporting electrolyte. The Zn(II) chlo-
rin 1b underwent reversible first oxidation at 0.10 V vs
Fc/Fcþ, which was quite lower than that of other chlorins
(0.21ꢀ0.35 V) and 5,15-diphenyl Zn(II) porphyrin (0.37 V).
It suggests that Zn(II) chlorin hasthe highest reactivity and
may be easier to oxidize. This explanation was supported
by the results of the following experiment: a solution of
equivalent amounts of Zn(II) chlorin 1b and Zn(II) por-
phyrin 3b in CH2Cl2 was treated with 0.5 equiv of PIFA.
The dimer 2b was formed immediately, but Zn(II) por-
phyrin 3b remained unchanged. It implies the regioselec-
tive oxidation may result from the high reactivity between
Zn(II) chlorin and hypervalent iodine(III) reagents.
Figure 1. 1H NMR spectra of 1b and 2b in CDCl3.
Regiocontrolled synthesis of chlorin is an important
issue, since chlorin compared to porphyrin has lower
symmetry and highly reactive positions.13 In order to
understand this selectivity, a DFT calculation was per-
formed todetermine the electron density of 1b. The energy-
minimized structures are calculated with Gaussian 0314 at
the B3LYP/6-31G(d,p) level, using the LANL2DZ15 ef-
fective core potential for zinc. Zn(II) chlorin exhibited the
HOMO with electron density at all meso-positions and
nonreduced β-positions albeit in differing amounts at
various positions (Figure 2). The 20-position of chlorin,
offering a site for electrophilic reaction,16 was evaluated to
have higher electron density than the other peripheral
positions. To confirm the reactivity of the meso bridge
carbon at the 10 position, the 20-substituted meso-triphe-
nyl-2,3-chlorin with the free 10-position, prepared as
described,17 was treated with PIFA under the same condi-
tions. No dimers but several highly polar compounds were
The structure of chlorin dimer 2b was confirmed by its
NMR data and mass spectrometry. The HR-MS of 2b
showed a molecular ion peak at m/z = 1106.273, indicat-
ing a dimeric structure. The apperance of a single set of
resonances in the NMR spectrum for both chlorin mole-
cules suggested some degree of symmetry of the molecule.
A complete 1H NMR assignment for the individual pro-
tons of 1b and 2b was achieved by 2D-NMR studies.
1
Compared with monomer 1b, the H NMR spectrum of
2b exhibited a singlet at 9.60 ppm due to H-10 and the
signal of H-20 of 1b disappeared (Figure 1), indicating the
two units were joined together at position 20. Additionally,
the obvious upfield shifts of the proton signals near the
20-position, especially showing a shifting from 8.69 to
7.68 ppm due to H-18 and from 4.53 to 3.76 ppm due to
H-2, further confirmed its dimeric structure with a link at
position 20. Additionally, the interaction between H-2 and
H-18 can be found in the 1H-NOESY NMR spectrum of
2b (Supporting Information), which further confirms it
links at position 20.
(12) (a) Felton, R. H.; Linschitz, H. J. Am. Chem. Soc. 1966, 88, 1113.
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R. K.; Balasubramanian, S.; Sukumaran, D. K.; Zhang, M.; Kadish,
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The mechanism of the reaction between chlorins and
hypervalent iodine(III) may be the same as that for the
oxidative coupling of porphyrins. As described, the reac-
tivity of a metal porphyrin should have some relationship
2748
Org. Lett., Vol. 14, No. 11, 2012

Figure 3. Structure of the directly linked chlorin dimer 2a as
derived by DFT calculations.
Figure 4. UVꢀvis spectra of 1b and 2b in CH2Cl2.
observed when excessive oxidant was added. This suggests
the chlorins may only be able to couple at the meso-
position adjacent to the dihydropyrrole ring.
absorption in the near-IR region, this type of chlorin could be
useful in treating tumors that are deeply seated.
To understand the stereochemical properties of the
diaxial systems, the geometry of dimer 2a was optimized
at the B3LYP/3-21G level with no symmetry constraints,
using the Gaussian 03 program.14 For the global minimum
structure (Figure 3), the dihedral angle between the chlorin
planes in 2a was found to be 88°. Due to the steric
hindrance effect of the dihydropyrrole rings, this angle
was smaller than that in mesoꢀmeso directly linked
diporphyrin (confirmed to be 90°).18
The absorptionspectra of zinc(II) chlorin1band directly
linked zinc chlorin dimer 2b are shown in Figure 4. As
described, the long-wavelength absorption bands of both
compounds have a greatly enhanced oscillator strength at
610 nm. It is worth noting that the mesoꢀmeso directly
linked porphyrin dimers always exhibit broadened and
split Soret bands because of the exciton coupling between
the two perpendicular porphyrin moieties.18 However, the
directly linked zinc chlorin dimer 2b which had nearly
perpendicular aromatic moieties showed two slightly split
Soret band at 412 and 418 nm, as well as two remarkablely
split Q bands at 617 and 631 nm. Due to their long wavelength
In conclusion, the novel directly linked zinc chlorin
dimer was for the first time prepared through a practical
and simple oxidative coupling method with a hypervalent
iodine(III) reagent. The reaction shows a high degree of
regioselectivity at the position near the dihydropyrrole ring
to produce the directly linked zinc chlorin dimer linked in
positions 20,200. Further investigations to expand the
reaction as well as to develop the photodynamic activities
of those novel dichlorins are ongoing and will be reported
in due course.
Acknowledgment. We thank the 973 Program (2011CB-
932902) and NSFC (Nos. 21172126 and 20802038) for their
generous financial support. We are also grateful to the
computational support of Nankai University ISC.
Supporting Information Available. Experimental pro-
cedures and compound data. This material is available
free of charge via the Internet at http://pubs.acs.org.
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The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 11, 2012
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