Synthesis of a pyridine-fused porphyrinoid: Oxopyridochlorin

Article abstract of DOI:10.1039/b819284g

The treatment of 3,5-dibenzoylporphyrins with ammonium acetate provided novel oxopyridochlorins as the first examples of pyridine-fused porphyrinoids, which displayed absorption bands reaching into the near IR region and an ability to sensitize singlet ox

Full text of DOI:10.1039/b819284g

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COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Synthesis of a pyridine-fused porphyrinoid: oxopyridochlorinw
Sumito Tokuji,a Yuji Takahashi,b Hideyuki Shinmori,*b Hiroshi Shinokubo*a
and Atsuhiro Osuka*a
Received (in Cambridge, UK) 30th October 2008, Accepted 28th November 2008
First published as an Advance Article on the web 6th January 2009
DOI: 10.1039/b819284g
The treatment of 3,5-dibenzoylporphyrins with ammonium
acetate provided novel oxopyridochlorins as the first examples
of pyridine-fused porphyrinoids, which displayed absorption
bands reaching into the near IR region and an ability to sensitize
singlet oxygen effectively.
mass ion peak of 3Zn was observed at m/z = 1142.5698 (calc.
for C76H80N5OZn = 1142.5649 [M + H]+) in its high
resolution electrospray ionization time-of-flight mass spec-
trum. The 13C NMR spectrum displayed a distinct signal at
191.17 ppm, indicating the presence of a carbonyl group. The
1H NMR spectrum exhibited six doublet signals due to the six
pyrrolic b-protons. Compared with other non-fused porphyrins,
such as 2Zn, these outer b-protons appear in a substan-
tially upfield-shifted region between 7.99 and 7.47 ppm. This
finding indicates weak aromaticity in 3Zn, because the fused
pyridine moiety tends to retain its local aromaticity. Such
decreased ring currents in porphyrinic macrocycles have also
The introduction of fused p-conjugated segments into por-
phyrins is expected to create a variety of conjugated porphyrin
systems that could exhibit unique optical and electrochemical
properties.1 This is a reflection of the flexible electronic
properties of porphyrins that respond to such perturbations.
As an interesting example, the fusion of a benzene ring to the
periphery of the 3,4,5-positions of porphyrins causes disrup-
tion to the cyclic electronic conjugation of the porphyrin,
hence forming benzochlorins that exhibit considerably per-
turbed optical properties.2 Various benzochlorins have been
studied as photosensitizers for photodynamic therapy (PDT)
owing to their red-shifted absorption bands (670–680 nm),
which is favorable for better photoexcitation with light pene-
trating tissues. More preferably, the pigment should be absor-
bent in the near infrared region of 750–900 nm, which is called
the ‘‘therapeutic window’’ due to the minimum absorbance of
biological tissue in this range.
1
been observed in the H NMR spectra of benzochlorins.3 In a
similar manner, Ni-pyridochlorin and the free base, 3Ni and
3H, were also synthesized in 65 and 40% yield, respectively.
The inner NH protons of 3H were observed in a particularly
down-field region at 7.34 and 7.08 ppm, again indicating a
weakened diatropic ring current.
Final structural elucidation was accomplished by single
crystal X-ray diffraction analyses,z which showed the presence
of pyridine and carbonyl moieties in 3Zn, 3H and 3Ni (Fig. 1).
While 3Zn and 3H display relatively planar structures charac-
terized by mean-plane deviations of 0.145 and 0.099 A, 3Ni
shows a more distorted saddle-like structure with a mean-
plane deviation of 0.412 A. The dihedral angles of the phenyl
substituents with respect to the pyridine moiety are 38.6
and 31.61 for 3Ni, which are smaller than those of 3Zn
In this Communication, we wish to report the synthesis of
novel pyridine-fused porphyrins, oxopyridoporphyrins 3. This
work was motivated by our recent finding that zinc(II) dehydro-
purpurin 1Zn was efficiently prepared from meso-bromo-
porphyrin under palladium catalysis, and was converted into
3,5-dibenzoylporphyrin 2Zn by photochemical oxidative clea-
vage of the outer CQC double bond.3 Oxopyridoporphyrins 3
are, to the best of our knowledge, the first examples of pyridine-
fused porphyrins. Interestingly, oxopyridochlorins 3 exhibit
absorption bands in the therapeutic window that are further
red-shifted upon protonation.
The treatment of 3,5-dibenzoylporphyrin 2Zn with ammo-
nium acetate at 130 1C in toluene/AcOH for 2 d furnished
oxopyridochlorin 3Zn in 60% yield (Scheme 1). The parent
a Department of Chemistry, Graduate School of Science, Kyoto
University, Sakyo-ku, Kyoto 606-502, Japan.
E-mail: osuka@kuchem.kyoto-u.ac.jp.
E-mail: hshino@apchem.nagoya-u.ac.jp; Fax: +81 75-753-3970;
Tel: +81 75-753-4008
b Division of Medicine and Engineering Science, Interdisciplinary
Graduate School of Medical and Engineering, University of
Yamanashi, 4-3-11 Takeda, Kofu 400-8511, Japan.
E-mail: shinmori@yamanashi.ac.jp; Tel: +81 55-220-8566
w Electronic supplementary information (ESI) available: Experimental
procedures, spectra and further crystallographic data. CCDC
707381–707383. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b819284g
Scheme 1 The synthesis of oxopyridochlorins 3Zn, 3H and 3Ni.
Reaction conditions: (a) air, light; (b) HCl; (c) Ni(acac)2; (d) NH4OAc,
toluene/AcOH, 130 1C, 2 d.; (e) NaBH4, CH2Cl2/MeOH; (f) air.
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group occurs to form an oxopyridoporphyrin. A similar
spontaneous oxidation has been reported for a benzochlorin.2g
In our case, 3Zn can be reduced with NaBH4 quantitatively to
afford 4Zn, which is oxidized back to 3Zn upon standing in the
air for 4–5 h.
Fig. 2(a) shows the UV/vis absorption spectra of 2Zn, 3Zn,
3H and 3Ni measured in CH2Cl2. While the absorption
spectrum of 2Zn has the typical features of porphyrins,
involving a sharp Soret band at 433 nm, and Q-bands at 558
and 599 nm, those of oxopyridochlorins are strikingly altered.
The metal complexes 3Zn and 3Ni exhibit split Soret bands at
403 and 477 nm, 405 and 480 nm, and structured Q-bands at
753 and 767 nm, respectively. Free base 3H shows a narrowly
split Soret band at 414 and 448 nm, and differently structured
Q-bands at 690 and 785 nm. Interestingly, the absorption
spectra of our oxopyridoporphyrins cover over 800 nm, deeply
entering the therapeutic window. The absorption spectrum of
4Zn shows a Soret band at 449 nm, and Q-bands at 638 and
696 nm, which indicates the importance of the carbonyl group
in the red-shifted absorption spectra of 3.
Since pyridochlorins 3 bear an external basic nitrogen site,
protonation at this site would be expected to change their
electronic structure. To investigate this possibility, we exa-
mined the effects of protonation on the absorption spectrum of
3Ni with acids, including TFA, aqueous HCl and methane-
sulfonic acid (MSA). As shown in Fig. 2(b), protonation
caused changes in the intensities of the split Soret band and
a distinct red shift of the Q-bands.
Fig. 1 X-Ray crystal structures of oxopyridochlorin. Top and side
views of (a) 3Zn, (b) 3Ni, and (c) 3H. 3,5-Di-tert-butyl groups and
hydrogen atoms are omitted for clarity.
The electrochemical properties of our oxopyridochlorins
were also examined by cyclic voltammetry (0.1 M Bu4NPF6 as
(60.8 and 45.5 or 58.11; one phenyl group is slightly disor-
dered) and 3H (60.2 and 39.01), suggesting that the distorted
structure of 3Ni leads to the mitigation of steric hindrance
among the peripheral groups. In addition, a distinct bond
length alternation is observed among C–C and C–N bonds in
the X-ray crystal structures of 3Zn, 3H and 3Ni, in line with
the observed weakened aromaticity.
A plausible mechanism for the formation of 3 is shown in
Scheme 2. Cyclization of a dihydropyridine moiety, A,
followed by the elimination of water, gives cationic species
B, and the subsequent nucleophilic attack of water furnishes
pyridine moiety C. Finally, aerobic oxidation of the hydroxyl
Fig. 2 (a) The UV/vis absorption spectra of 2Zn (red), 3Zn (blue), 3H
(violet) and 3Ni (green) in CH2Cl2. (b) Changes in the UV/vis
absorption spectra of 3Ni in CH2Cl2 with no acid (red), TFA (blue),
HCl (green) and MSA (violet).
Scheme 2 A plausible mechanism for the formation of oxopyrido-
chlorins.
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Crystal data for 3Hꢂ(methanol): C77H85N5O2, M = 1112.50, mono-
clinic, space group P21/c (no. 14), a = 19.251(5), b = 20.011(6),
c = 18.977(7) A, a = 90, b = 111.030(11), g = 901, V = 6824(4) A3,
T = 123(2) K, Z = 4, Dc = 1.124 g cmꢁ3, R1 = 0.0952 for 11 302
observed reflections with [I 4 2s(I)] and wR2 = 0.3085 for all 48 936
unique reflections, GOF = 1.034. Some unassigned electron density
due to severely disordered solvent was removed using the utility
SQUEEZE in the PLATON software package.6 CCDC 707381.w
Crystal data for 3Niꢂ3(dichloroethane): C82H91Cl6N5NiO, M =
1434.01, triclinic, space group P-1 (no .2), a = 14.341(5), b =
15.957(6), c = 17.625(5) A, a = 73.134(11), b = 82.737(12),
the electrolyte, glassy carbon and Ag/AgClO4 as the working
and reference electrodes, respectively, relative to internal
ferrocene/ferrocenium, in CH2Cl2). One-electron oxidation and
reduction waves were observed at 0.43 and ꢁ1.55 V for 2Zn, and
0.36 and ꢁ1.21 V for 3Zn, which leads to estimations of the
HOMO–LUMO gap as 1.98 and 1.57 eV, respectively, in
accordance with their absorption spectra. Similar measurements
revealed the one-electron oxidation and reduction potentials of
3Ni as being 0.51 and ꢁ1.18 V.
g = 69.420(11)1, V = 3864(2) A3, T = 123(2) K, Z = 2, Dc
=
1.232 g cmꢁ3, R1 = 0.0941 for 13 165 observed reflections with
[I 4 2s(I)] and wR2 = 0.2782 for all 29 611 unique reflections,
GOF = 1.048. CCDC 707382.w
Finally, the ability to sensitize the generation of singlet
oxygen was examined by means of the photooxidation of
1,3-diphenylisobenzofuran (DPBF)4 using a xenon lump
equipped with a light filter (4490 nm). Photoirradiation of a
toluene solution of 3Zn or 3H containing DPBF caused clear
absorption spectral changes associated with DPBF oxidation,
which were monitored by the absorbance changes at 416 nm.
Oxopyridochlorins 3Zn and 3H were found to be considerably
robust under these irradiation conditions. The quantum yields
of singlet oxygen formation for 3Zn and 3H in toluene were
determined to be 0.79 and 0.52, respectively, compared to a
reference value (0.73) for tetraphenylporphyrin (TPP).5
In summary, oxopyridochlorins, new pyridine-fused por-
phyrins, have been synthesized efficiently from dibenzoyl-
porphyrins. These oxopyridochlorins displayed weakened
diatropic ring currents as a consequence of their fused pyridine
moiety, as well as their absorption spectra tailing in the near
infrared region, entering significantly the therapeutic window.
Interestingly, protonation of the nitrogen atom in the fused
pyridine ring causes substantial changes in their UV/vis
absorption spectra, thus underscoring the effectiveness of the
peripheral and conjugated coordination site for controlling the
whole porphyrinic p-system by external stimuli. The use of
these pigments for photodynamic therapy is encouraged
because of their abilities to sensitize the generation of singlet
oxygen, despite their low-lying excited states. Moreover, the
red-shift observed in the presence of a Brønsted acid is very
interesting for photodynamic therapy applications, since it is
well known that solid tumors develop regions of acidic
interstitial pH.
For 3Zn and 3Ni, some disorder features were found in certain
substituents and solvent molecules, and appropriately restrained
(see ESIw).
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Notes and references
z Crystal data for 3Znꢂ2(methanol): C78H87N5O3Zn, M = 1207.90,
triclinic, space group P-1 (no. 2), a = 10.549(15), b = 16.88(3), c =
20.16(3) A, a = 87.34(6), b = 85.64(6), g = 74.93(6)1, V = 3455(9)
A3, T = 123(2) K, Z = 2, Dc = 1.161 g cmꢁ3, R1 = 0.0675 for 11 672
observed reflections with [I 4 2s(I)] and wR2 = 0.2001 for all 14 994
unique reflections, GOF = 1.050. CCDC 707383.w
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1030 | Chem. Commun., 2009, 1028–1030