20-(N-Methylpyridiniumyl)ethynylated chlorophyll-a derivative with an intense Qx absorption band at a green to orange region

Article abstract of DOI:10.1016/j.tetlet.2018.01.052

Methyl 20-substituted mesopyropheophorbides-a were prepared by the chemical modification of natural chlorophyll-a via palladium-catalyzed cross-coupling reactions. The 20-ethynylation and further 2-pyridylation showed bathochromic shifts in their visible absorption bands as well as hyperchromic effects of the Qx bands in a diluted chloroform solution. The protonation and methylation at the nitrogen atom of the 20²-pyridyl group induced much larger shifts and effects, especially giving red-shifted and intensified Qx bands.

Full text of DOI:10.1016/j.tetlet.2018.01.052

Accepted Manuscript
20-(N-Methylpyridiniumyl)ethynylated chlorophyll-a derivative with an in-
tense Qx absorption band at a green to orange region
Yusuke Kamatani, Yuichi Kitagawa, Hitoshi Tamiaki
PII:
S0040-4039(18)30087-X
https://doi.org/10.1016/j.tetlet.2018.01.052
TETL 49639
DOI:
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
13 December 2017
12 January 2018
19 January 2018
Please cite this article as: Kamatani, Y., Kitagawa, Y., Tamiaki, H., 20-(N-Methylpyridiniumyl)ethynylated
chlorophyll-a derivative with an intense Qx absorption band at a green to orange region, Tetrahedron Letters (2018),
doi: https://doi.org/10.1016/j.tetlet.2018.01.052
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20-(N-Methylpyridiniumyl)ethynylated
chlorophyll-a derivative with an intense Qx
absorption band at a green to orange region
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a
b
a,*
Yusuke Kamatani , Yuichi Kitagawa , Hitoshi Tamiaki

1
Tetrahedron Letters
20-(N-Methylpyridiniumyl)ethynylated chlorophyll-a derivative with an intense Qx
absorption band at a green to orange region
Yusuke Kamatani a, Yuichi Kitagawa b, Hitoshi Tamiaki a, 
a Graduate School of Life Sciences, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan
b Division of Materials Chemistry, Faculty of Engineering, Hokkaido University, Sapporo, Hokkaido 060-8628, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Methyl 20-substituted mesopyropheophorbides-a were prepared by the chemical modification of
natural chlorophyll-a via palladium-catalyzed cross-coupling reactions. The 20-ethynylation
and further 2-pyridylation showed bathochromic shifts in their visible absorption bands as well
as hyperchromic effects of the Qx bands in a diluted chloroform solution. The protonation and
methylation at the nitrogen atom of the 202-pyridyl group induced much larger shifts and effects,
especially giving red-shifted and intensified Qx bands.
Available online
Keywords:
2018 Elsevier Ltd. All rights reserved.
Cationic chlorophyll
Cross-coupling reaction
Pyropheophorbide
Visible absorption spectrum
Chlorophylls (Chls) are photosynthetically active pigments,
which absorb sunlight efficiently and are useful for light-
harvesting processes in phototrophic cells.1 Chls exhibit intense
absorption bands at red and blue-to-purple regions, called Qy and
Soret bands, respectively.2 Between these bands, weak Qx
bands are usually observed in their absorption spectra. Chl
derivatives have intense Qy bands at a red region where the
transparency of human cells is high, so they are promising for the
pigments in photodynamic therapy (PDT) of tumors giving
reactive oxygen species via their photosensitization.3 Since Chls
are lipophilic, the enhancement of their water-solubilities is
requisite for their practical use as PDT sensitizers and a variety
of hydrophilic substituents have been introduced into the
molecules. Some cationic functional groups including
Migita-Kosugi-Stille coupling product in dichloromethane was
treated with tetrabutylammonium fluoride in THF at room
temperature [step (iv)]8 to afford 20-ethynyl-chlorin 1b in a 22%
isolated yield for the two steps. The copper-free Sonogashira
coupling reaction8,9 of mono-substituted acetylene 1b with 2-
bromopyridine gave 20-(2-pyridylethynyl)chlorin 1c [38%, step
(v)]. 2-Substituted pyridine 1c was N-methylated by
iodomethane in refluxing acetonitrile to 20-(N-
methylpyridinium-2-yl)ethynyl-chlorin iodide 1e [63%, step
(vi)]. Trifluoroacetic acid was added to a chloroform solution of
1c to give initially mono-cationic compound 1d protonated on
the 20-pyridine group [step (vii)]. Its further addition produced
species protonated at the inner nitrogen atom(s) of the chlorin
moiety. This selective protonation is ascribable to the different
basicities of the imino groups and is consistent with the previous
observation for the related pyridylated chlorins.10
oligoarginine led to high cell penetration.4 Therefore, we have
prepared several cationic Chl derivatives by the chemical
modification of naturally occurring Chl-a. During this project,
we prepared a Chl-a derivative possessing a cationic group in the
20-substituent and unexpectedly found its intense Qx band.
Here we report the synthesis of metal-free Chl-a derivatives
bearing (un)substituted ethynyl groups at the 20-position and
their visible absorption spectra in a diluted solution.
In chloroform, 1a showed a visible absorption spectrum
characteristic of metal-free Chl-a derivatives (Fig. 1A),2 giving
intense Qy and Soret maxima (max) at 657 and 411 nm,
respectively, as well as relatively small Qx bands at 536 and 505
nm (Table 1). The introduction of an ethynyl group at the 20-
position of 1a to 1b shifted Qy, Qx, and Soret bands to longer
Chl-a was obtained from cyanobacterial cells5 and modified to
methyl mesopyropheophorbide-a (1a) according to reported
procedures [step (i) of Scheme 1].5,6 The reaction of 1a with
pyridinium perbromide in dichloromethane at room temperature
gave 20-bromo-chlorin regioselectively in an 81% yield [step
(ii)].6,7 The bromide in refluxing tetrahydrofuran (THF) was
reacted with tributyl(trimethylsilylethynyl)tin in the presence of
wavelengths and broadened the Qx bands (Figs. 1A/B): max
657  673, 536  555, and 411  417 nm for Qy(0,0),
Qx(0,0), and Soret maxima, respectively. The Qx(0,0) band
=
increased in intensity upon the 20-ethynylation of 1a to 1b (Fig.
1F). The substitution with a 2-pyridyl group at the terminus of
the 20-ethynyl moiety of 1b to 1c further red-shifted the visible
absorption maxima and enhanced the Qx(0,0) peak intensity
(Figs. 1B/C): max[Qy(0,0)/Qx(0,0)/Soret] = 673/555/417 (1b) 
tetrakis(triphenylphosphine)palladium(0) [step (iii)],8 and the
———
 Corresponding author. Tel.: +81-77-561-2765; fax: +81-77-561-3729; e-mail: tamiaki@fc.ritsumei.ac.jp (H. Tamiaki)

2
Tetrahedron Letters
677/568/422 nm (1c). The bathochromic shifts of max in the
so the (b c ) configuration is heavily admixed with the (b c )
1 2 2 1
order of 1a, 1b, and 1c were ascribable to the elongated -
conjugation of the 20-substituents. The red shifts are consistent
with reported data.11
configuration, resulting in a weak Qx band.14 The elongated -
conjugation of the 20-substituents reduced the energy gaps in the
above four configurations, inducing red shifts of the Qy, Qx, and
Soret bands. This effect also changed the -conjugation
symmetry of 20-substituted 1b and 1c to allow the Qx band
The protonation of the pyridyl group of 1c to 1d moved max
to longer wavelengths (Figs. 1C/D):
formed by the (b c ), (b c ), and (b c ) configurations, thereby
relaxing the mixing degree between the (b c ) and (b c )
configurations and resulting in a relatively intense Qx band
(Tables S2–S3). The mixing degree of the (b c ) configuration
of 1c was greater than that of 1b, which originated from the
longer -conjugation length. This theoretical explanation
supports the observation that the Qx(0,0) bands increased in the
order of 1a, 1b, and 1c. In addition, the protonation and N-
methylation of the 2-pyridyl group at the 202-position resulted in
the stronger orbital mixing between the pyridine and chlorin
moieties than that of 1c (Fig. S1). These strong orbital mixing
further affected the electronic characteristics of Chl-a derivatives
1d/e, which intensified the Qx absorption bands.
1 2
2 1
2 2

max[Qy(0,0)/Qy(0,1)/Qx(0,0)/Soret] = 677/620/568/422 (1c) 
1 2
2 1
687/631/573/427 nm (1d). The Qx bands increased by the
protonation and the Qx(0,0) peak intensity of 1d was comparable
to the Qy(0,0) intensity. The N-methylation of the pyridyl group
of 1c to 1e induced larger red shifts of max than the
corresponding protonation (Table 1):
2 2

max[Qy(0,0)/Qy(0,1)/Qx(0,0)/Soret] = 702/647/582/439 nm (1e).
It is noted that the Qx(0,0) intensity of 1e was apparently larger
than the Qy(0,0) intensity (Fig. 1E). The red shifts would be
partially due to the electron-withdrawing effect of the 202-
substituents.
To clarify the effect of elongated -conjugation at the 20-
position on the electronic absorption properties, density
Methyl 20-(N-methylpyridinium-2-yl)ethynyl-
functional theory (DFT) calculations were performed using the
Gaussian 03 program.12 First, the optimized structures of 1a, 1b,
and 1c were calculated at the B3LYP/6-31G(d) level, and their
molecular orbitals (MOs) and MO energy diagrams are shown in
Fig. 2. Time-dependent (TD)-DFT calculations at the same level
were also performed for the optimized structures. The
calculated spectral features were in good agreement with the
experimentally obtained data (Tables S1–S3). The spectroscopic
properties of the absorption bands can be qualitatively explained
mesopyropheophorbide-a iodide (1e) was prepared by modifying
natural Chl-a.15 The synthetic cationic species in chloroform
showed a Qy maximum at a longer wavelength than 700 nm, a
relatively intense Qx band at a green to orange region, and a
broadened Soret band with an absorption edge at around 500 nm.
The visible absorption spectrum was unique, compared with
those of conventional Chl derivatives.2 The Qx peak was more
intense than the Qy peak, which has not yet been observed, to our
best knowledge, for any compounds possessing a chlorin -
system with a characteristically intense Qy band. The wide
range of visible absorption bands would make 1e an efficient
absorber of visible light including a light-harvesting pigment.
by Gouterman's four-orbital model using four MOs (b , b , c ,
1
2
2
and c ) and four electronic configurations, (b c ), (b c ), (b c ),
1
2 2
1 2
2 1
and (b c ).13 The energy difference between the (b c ) and
1 1
1 2
(b c ) configurations is relatively small for 20-unsubstituted 1a,
2 1
Scheme 1. Synthesis of methyl 20-(un)substituted mesopyropheophorbide-a 1a–e by modifying naturally occurring Chl-a: (i) H2SO4 / MeOH,
collidine reflux, H2–Pd(C) / Me2CO; (ii) C5H5NH+Br3– / CH2Cl2; (iii) Me3SiCCSnBu3–Pd(PPh3)4 / THF; (iv) Bu4NF / THF–CH2Cl2; (v) 2-
BrC6H4N–Pd2(PhCH=CHCOCH=CHPh)3–(2-MeC6H4)3P / PhMe–NEt3; (vi) MeI / MeCN; (vii) CF3CO2H / CHCl3. The synthetic details are
described in ESI.

3
120
100
80
60
40
20
0
100
80
1a [20-H]
1b [20-CCH]
A
C
E
B
D
F
60
40
20
0
300
400
400
400
500
600
700
800 300
400
500
600
700
800
120
100
80
1c [20-CCPy]
1d [20-CCPyH+]
120
80
40
0
60
40
20
0
300
500
600
700
800 300
400
500
600
700
800
50
40
30
20
10
1e [20-CCPyMe+]
60
40
20
0
0
300
500
600
700
800
520
560
600
640
Wavelength /nm
Figure 1. Visible absorption spectra of methyl 20-(un)substituted mesopyropheophorbide-a 1a–e in chloroform (A–E). Panel F shows their
spectra around the Qx region.

4
Tetrahedron
Figure 2. MO energy diagrams and MOs of 1a (a), 1b (b), and 1c (c).
Table 1. Visible absorption maxima max (nm) of methyl 20-(un)substituted mesopyropheophorbide-a 1a–e in chloroform (ca. 10–5 M)a
Compound
Soret
Qx
Qy
[20-substituent]
(0,1)
(0,0)
(0,1)
(0,0)
1a [H]
396, 411 (232)
≈400, 417 (250)
≈403, 422 (270)
≈405, 427 (307)
405, 439 (156)
505 (21)
521 (17)
≈530 (17)
≈535 (29)
≈540 (30)
536 (21)
555 (40)
568 (52)
573 (93)
582 (116)
602 (19)
616 (20)
620 (24)
631 (37)
647 (39)
657
673
677
687
702
1b [CCH]
1c [CCPy]
1d [CCPyH+]
1e [CCPyMe+]
aThe values in parentheses indicate the absorption intensities (%) relative to the Qy(0,0) maximum.
Acknowledgments
References and notes
We thank Ms. Ayaka Wada of Ritsumeikan University for her
experimental assistance. This work was partially supported by
JSPS KAKENHI Grant Numbers JP24107002 and JP17H06436
in Scientific Research on Innovative Areas.
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Supplementary data (synthetic details and DFT data of Chl-a
derivatives 1) associated with this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2017.
8.
9.
Click here to remove instruction text...
10. Yamamoto, Y.; Tamiaki, H. Dyes Pigments 2015, 118, 159–165.
Highlights
20-(1-Methylpyridinium-2-yl)ethynylated
chlorophyll-a derivative was prepared.
The cationic species showed unique wide range of
visible absorption bands.
Its redmost Qy maximum in chloroform was
situated at > 700 nm.
Unexpectedly, its Qx peak was more intense than
the corresponding Qy peak.
The absorption edge of its broadened Soret band
was at around 500 nm.