Site-selective C20-fluorinations of chlorophyll-a derivatives using N-fluorobenzenesulfonimide and their optical properties

Article abstract of DOI:10.1016/j.tet.2020.131722

Site-selective fluorinations at the C20 position of methyl pyropheophorbides-a, which is derived from naturally occurring chlorophyll(Chl)-a, were achieved by using N-fluorobenzenesulfonimide (NFSI). All the synthetic Chl-a derivatives possessing a variety of the C3-substituents (vinyl, ethyl, formyl, acetyl, hydroxymethyl, and 1-hydroxyethyl groups) were mono-fluorinated to produce the corresponding 20-fluoro-chlorins as isolated products. These fluorinated products were characterized by 1D/2D NMR, visible absorption, and fluorescence emission spectroscopy. Owing to the strong electronegativity of the C20-fluorine atom, their red-most Qy absorption and fluorescence emission bands were bathochromically shifted except for the C3-acetyl substitutes. This study showed not only tolerance of the chlorin π-skeleton and C3-substituents to NFSI but also potential availability of the fluorinated Chl library.

Full text of DOI:10.1016/j.tet.2020.131722

Tetrahedron 76 (2020) 131722
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Site-selective C20-fluorinations of chlorophyll-a derivatives using N-
fluorobenzenesulfonimide and their optical properties
*
Shin Ogasawara, Kohei Nakano, Hitoshi Tamiaki
Graduate School of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, 525-8577, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 October 2020
Received in revised form
Site-selective fluorinations at the C20 position of methyl pyropheophorbides-a, which is derived from
naturally occurring chlorophyll(Chl)-a, were achieved by using N-fluorobenzenesulfonimide (NFSI). All
the synthetic Chl-a derivatives possessing a variety of the C3-substituents (vinyl, ethyl, formyl, acetyl,
hydroxymethyl, and 1-hydroxyethyl groups) were mono-fluorinated to produce the corresponding 20-
fluoro-chlorins as isolated products. These fluorinated products were characterized by 1D/2D NMR,
visible absorption, and fluorescence emission spectroscopy. Owing to the strong electronegativity of the
C20-fluorine atom, their red-most Qy absorption and fluorescence emission bands were bathochromi-
21 October 2020
Accepted 23 October 2020
Available online 28 October 2020
Keywords:
Methyl pyropheophorbide-a
Substitution effect
cally shifted except for the C3-acetyl substitutes. This study showed not only tolerance of the chlorin p-
skeleton and C3-substituents to NFSI but also potential availability of the fluorinated Chl library.
Visible absorption spectra
© 2020 Elsevier Ltd. All rights reserved.
1
. Introduction
bioisosteres, which are used for medicines [13e16] and molecular
probes [17e19]. Although fluorine has a similar atomic size as
hydrogen, it possesses the strongest electronegativity of all the
elements, which has been accounted to “a small atom with a big
ego” [20]. Thus, the replacement of hydrogen with fluorine pro-
vides a derivative with a similar molecular size and conformation as
the intact one, and the fluorinated derivative exhibits specific
biochemical properties. We previously reported fluorinated Chl-a
analogues by electrophilic fluorinating reagents, which have almost
the same optical properties and enzymatic reactivities as the intact
3
Naturally occurring chlorophyll(Chl)-a (Fig. 1, R ¼ vinyl,
7
20
R ¼ methyl, R ¼ H) and its analogues are one class of the most
common functional pigments in photosynthetic organisms. These
pigments play key roles in the primary step of photosynthesis,
including photoenergy harvesting, excited-energy migration,
charge separation, and electron transfer [1,2]. Considering the
specific photofunctions, various kinds of semi-synthetic Chl-a de-
rivatives that regulate their optical properties have been developed
to apply dye-sensitized solar cells [3] and photodynamic therapy
2
Chl-a, while they showed different epimerization (C13 -stereo-
[
4]. To regulate the optical properties of Chls, natural photosyn-
chemical inversion) behavior under basic conditions and pheo-
phytinization (removal of the central magnesium) under acidic
conditions [21]. Here, we report the simple C20-fluorinations of
Chl-a derivatives that possess different types of the C3-substituents
with the commercially available and electrophilic fluorination re-
agent, N-fluorobenzenesulfonimide (NFSI), to expand the variations
of fluorinated Chl-a derivatives. The C3-intact and C20-fluorinated
products were characterized by 1D/2D NMR and mass spectros-
copies, and their optical properties were evaluated by electronic
absorption and fluorescence emission data.
thetic organisms biochemically substitute a vinyl group at the C3
position of Chl-a with other peripheral substituents to produce a
3
series of Chl-a analogues: Chl-d (R ¼ formyl), bacterio(B)Chls-a/b
3
3
(
R ¼ acetyl), BChls-c/d/e (R ¼ 1-hydroxyethyl) [5]. Thus, most of
the semi-synthetic Chl-a derivatives that possess different types of
the C3-substituents have been synthesized [6e11]. Although the
C3-substituted Chl-a derivatives have been further modified at
other positions, their optical properties are primarily dependent on
the C3-substituents [12]. Thus, studies of the C3-(un)substituted
Chls-a are important in Chl chemistry.
Fluorination of biomolecules has been developed to afford
2. Experimental
2.1. General
*
Corresponding author.
E-mail address: tamiaki@fc.ritsumei.ac.jp (H. Tamiaki).
All the reagents were purchased and used without further
https://doi.org/10.1016/j.tet.2020.131722
040-4020/© 2020 Elsevier Ltd. All rights reserved.
0

S. Ogasawara, K. Nakano and H. Tamiaki
Tetrahedron 76 (2020) 131722
þ
found: m/z ¼ 569.2923, calcd for C34
H38FN
4
O
3
: MH , 569.2922.
2
.3.3. Methyl 20-fluoro-pyropheophorbide-d (20F-3)
Black solid; mp ¼ 224.5e225.5 C; H NMR (400 MHz, CDCl
ꢁ
1
3 H
) d /
ppm ¼ 11.57 (1H, s, 3-CHO), 10.54 (1H, s, 5-H), 9.61 (1H, s, 10-H),
2
5
4
.36, 5.27 (each 1H, d, J ¼ 20 Hz, 13 -H
2
), 4.85e4.78 (1H, m, 18-H),
), 3.75 (2H, q,
), 3.61 (3H, s, 12-CH ), 3.35
), 2.70e2.60, 2.35e2.19 (each 2H, m, 17-CH CH ), 1.79
), ꢀ2.73 (1H, s,
.41e4.38 (1H, m, 17-H), 3.88 (3H, d, J ¼ 3 Hz, 2-CH
3
2
J ¼ 8 Hz, 8-CH
2
), 3.74 (3H, s, 17 -COOCH
3
3
(
(
3H, s, 7-CH
3H, d, J ¼ 7 Hz, 18-CH
3
2
2
1
3
), 1.73 (3H, t, J ¼ 8 Hz, 8 -CH
3
19
NH) [Another NH was invisible.]; F NMR (376 MHz, CDCl
ppm ¼ ꢀ140.38 (br-s, 20-F); VIS (CH Cl max/nm ¼ 697 (relative
intensity, 0.67), 637 (0.07), 562 (0.25), 527 (0.14), 423 (1.00), 397
3 F
) d /
2
2
) l
Fig. 1. Molecular structures of natural (B)Chls: R ¼ hydrocarbon chain.
(
0.93), 337 (0.37), 306 (0.35); HRMS (APCI) found: m/z ¼ 569.2559,
þ
calcd for C33
H34FN
4
O
4
: MH , 569.2559.
purification. Methyl pyropheophorbide-a (Pyro-a, 1) was obtained
from Spirulina algae (see below). Flash column chromatography
2
.3.4. Methyl 3-devinyl-20-fluoro-3-hydroxymethyl-
(
0
FCC) was performed with silica gel (Merck Kieselgel 60,
.040e0.063 mm). H and F NMR spectra in CDCl were recorded
3
pyropheophorbide-a (20F-4)
1
19
Black solid; mp ¼ 232e233 C; 1H NMR (400 MHz, CDCl
ꢁ
3 H
) d /
2
), 5.31,
on a JEOL JNM-ECA-600 (600 and 564 MHz, respectively) or JNM-
AL400 spectrometer (400 and 376 MHz, respectively). Residual
ppm ¼ 9.67 (1H, s, 5-H), 9.59 (1H, s, 10-H), 5.98 (2H, s, 3-CH
2
5
4
.22 (each 1H, d, J ¼ 20 Hz, 13 -H
2
), 4.81e4.75 (1H, m, 18-H),
), 3.71 (3H, s,
), 3.57 (1H, d, J ¼ 4 Hz, 2-CH ), 3.32
), 2.67e2.57, 2.32e2.20 (each 2H, m, 17-CH CH ), 1.76
), ꢀ0.32, ꢀ2.88
each 1H, s, NH ꢂ 2) [The 3 -OH was invisible.]; F NMR (376 MHz,
/ppm ¼ ꢀ144.06 (br-s, 20-F); VIS (CH Cl max/nm ¼ 667
relative intensity, 0.46), 609 (0.05), 543 (0.11), 512 (0.10), 410
CHCl
3
(
d
H
¼ 7.26 ppm) was used as an internal reference, while C
6 6
F
.35e4.33 (1H, m, 17-H), 3.75 (2H, q, J ¼ 8 Hz, 8-CH
2
(
d
F
¼ ꢀ164.9 ppm) was used as an external reference. Electronic
2
1
7 -COOCH
3H, s, 7-CH
3H, d, J ¼ 7 Hz, 18-CH
3
), 3.61 (3H, s, 12-CH
3
2
absorption spectra, fluorescence emission spectra, and fluorescence
(
(
(
3
2
2
quantum yields were measured with Hitachi U-3500, Hitachi F-
1
3
), 1.72 (3H, t, J ¼ 8 Hz, 8 -CH
3
4
500, and Hamamatsu Photonics C9920-03G apparatuses, respec-
1
19
tively. High resolution mass spectra (HRMS) were recorded on a
Bruker micrOTOF II spectrometer: atomic pressure chemical ioni-
zation (APCI) and positive mode in an MeCN solution.
CDCl
3
)
d
F
2
2
) l
(
(
1.00), 382 (0.61), 323 (0.19); HRMS (APCI) found: m/z ¼ 571.2715,
þ
calcd for C33
H36FN
4
O
4
: MH , 571.2715.
2.2. Synthesis of 1e6
According to previous reports [22e25], Pyro-a (1) was obtained
by the acidic treatment of extracts from commercially available
dried Spirulina algae containing Chl-a and successive pyrolysis in
,4,6-collidine. Pyro-a derivatives 2e6 were given from 1 by well-
2
.3.5. Methyl 20-fluoro-bacteriopheophorbide-d (20F-5)
ꢁ
1
Black solid; mp ¼ 127e128 C; H NMR (400 MHz, CDCl
3 H
) d /
1
1
ppm (3 R:3 S ¼ 1:1) ¼ 10.02/10.00 (1H, s, 5-H), 9.58/9.57 (1H, s, 10-
2
H), 6.51/6.49 (1H, q, J ¼ 8/7 Hz, 3-CH), 5.31/5.28, 5.21/5.20 (each 1H,
established synthetic methods [26]: see details in section 3.1.
2
d, J ¼ 20 Hz,13 -H
2
), 4.79e4.73 (1H, m,18-H), 4.35e4.29 (1H, m, 17-
2
H), 3.75 (2H, q, J ¼ 8 Hz, 8-CH
3H, s, 12-CH
), 3.55/3.54 (3H, d, J ¼ 4 Hz, 2-CH
CH ), 2.68e2.57, 2.36e2.12 (each 2H, m, 17-CH
2
), 3.70 (3H, s, 17 -COOCH
3
), 3.61/3.60
2
.3. Synthesis of 20F-1e6
(
3
3
), 3.31 (3H, s, 7-
3
2
1
CH
2
), 2.19/2.18
3
), 1.72 (3H,
C20-Unsubstituted chlorins 1e6 (100
mmol) was dissolved in
(
3H, d, J ¼ 7 Hz, 18-CH
3
), 1.76/1.74 (3H, d, J ¼ 7 Hz, 3 -CH
tetrahydrofuran (THF, 15 mL), to which NFSI (1.0 equiv.) was added.
The mixture was stirred at room temperature (rt) under N in the
1
1
t, J ¼ 8 Hz, 8 -CH ), ꢀ2.93 (1H, s, NH) [Another NH and the 3 -OH
3
19
2
were invisible.];
F
NMR (376 MHz, CDCl
)
F
d /ppm
Cl ) l /
2 2 max
3
dark for 1 h. After evaporating the solvent, the residual mixture was
1
1
(
3 R:3 S ¼ 1:1) ¼ ꢀ144.55/ꢀ144.65 (br-s, 20-F); VIS (CH
nm ¼ 666 (relative intensity, 0.42), 608 (0.05), 543 (0.11), 512 (0.10),
10 (1.00), 326 (0.21); HRMS (APCI) found: m/z ¼ 585.2872, calcd
purified by FCC with AcOEt/hexane [¼ 1/5 (v/v)] and precipitation
2 2
from CH Cl and hexane to give C20-fluorinated chlorins 20F-1e6:
4
see their spectral data below.
þ
4 4
for C34H38FN O : MH , 585.2872.
2.3.1. Methyl 20-fluoro-pyropheophorbide-a (20F-1)
See ref. [21,27,28].
2.3.6. Methyl 3-acetyl-3-devinyl-20-fluoro-pyropheophorbide-a
(
20F-6)
2
.3.2. Methyl 20-fluoro-mesopyropheophorbide-a (20F-2)
Black solid; mp ¼ 116e117 C; H NMR (600 MHz, CDCl
Black solid; mp ¼ 178e179 ꢁC; 1H NMR (400 MHz, CDCl
3 H
) d /
ꢁ
1
3
)
d
H
/
ppm ¼ 9.94 (1H, s, 5-H), 9.64 (1H, s, 10-H), 5.36, 5.27 (each 1H, d,
2
ppm ¼ 9.45 (1H, s, 10-H), 9.34 (1H, s, 5-H), 5.29, 5.21 (each 1H, d,
J ¼ 20 Hz, 13 -H
H), 3.76 (2H, q, J ¼ 8 Hz, 8-CH
d, J ¼ 3 Hz, 2-CH ), 3.60 (1H, s,12-CH
), 2.70e2.58, 2.36e2.20 (each 2H, m, 17-CH
2
), 4.85e4.79 (1H, m, 18-H), 4.40e4.38 (1H, m, 17-
2
2
J ¼ 20 Hz, 13 -H
2
), 4.78e4.74 (1H, m, 18-H), 4.34e4.32 (1H, m, 17-
), 3.65 (2H, q, J ¼ 8 Hz, 8-CH ), 3.64
), 3.62 (3H, s, 12-CH
), 3.42 (3H, d, J ¼ 4 Hz, 2-
), 3.25 (3H, s, 7-CH ), 2.65e2.57, 2.28e2.19 (each 2H, m, 17-
CH
), 1.78 (3H, d, J ¼ 7 Hz, 18-CH
), 1.68 (3H, t, J ¼ 8 Hz, 8 -CH
2
), 3.74 (3H, s, 17 -COOCH
), 3.32 (3H, s, 7-CH
CH
), ꢀ0.34, ꢀ2.88 (each
/ppm ¼ ꢀ141.68 (br-s,
max/nm ¼ 681 (relative intensity, 0.37), 621
(0.10), 552 (0.18), 518 (0.16), 413 (1.00), 391 (0.85), 331 (0.45), 309
3
), 3.72 (3H,
), 3.30 (3H,
2
), 1.78 (3H,
H), 3.84 (2H, q, J ¼ 8 Hz, 3-CH
2
2
3
3
3
2
1
(
3H, s, 17 -COOCH
3
3
s, 3 -CH
d, J ¼ 7 Hz,18-CH
3
2
1
CH
CH
CH
3
2
3
3
3
), 1.73 (3H, t, J ¼ 8 Hz, 8 -CH
3
1
19
2
3
), 1.72 (3H, t, J ¼ 8 Hz, 3 -
), ꢀ0.15(1H, s, NH) [Another NH
/ppm ¼ ꢀ145.50 (br-s,
max/nm ¼ 662 (relative intensity, 0.42), 605
0.06), 543 (0.10), 512 (0.10), 411 (1.00), 324 (0.20); HRMS (APCI)
1H, s, NH ꢂ 2); F NMR (376 MHz, CDCl
3 F
) d
1
3
20-F); VIS (CH Cl
2
2
) l
19
was invisible.]; F NMR (564 MHz, CDCl
2
(
3 F
) d
0-F); VIS (CH Cl
2
2
)
l
(0.42); HRMS (APCI) found: m/z ¼ 583.2715, calcd for C34
4 4
H36FN O :
þ
MH , 583.2715.
2

S. Ogasawara, K. Nakano and H. Tamiaki
Tetrahedron 76 (2020) 131722
3
. Results and discussion
[25,29,31], followed by oxidation with N-methylmorpholine N-ox-
ide (NMO) in the presence of tetrapropylammonium perruthenate
(TPAP) to produce methyl 3-acetyl-3-devinyl-pyropheophorbide-a
3.1. Synthesis
(6) [step (vi)] [29,32].
Pyro-a (1) was synthesized via pyrolysis of methyl pheo-
As shown in Scheme 1 and Table 1, fluorinations of the five
phorbide-a, which was prepared from the treatment of Spirulina
algae extracts containing Chl-a with acidic methanol [22e25,29]. In
our previous report [21], the fluorination reaction conditions of 1
possessing the C3-vinyl group with the use of NFSI was already
optimized, and the corresponding product 20F-1 was given in 43%
Pyro-a derivatives, 2e6, using NFSI afforded their C20-fluorinated
adducts, 20F-2e6, without modification of their C3-substituents
[step (i)]. One of the electrophilic fluorination reagents, NFSI that
predominantly reacted at the C20 position, was likely due to the
lower steric hindrance and higher electron density among the meso
(C5, C10, and C20) positions. In fact, most of the available meso-
substituted Chl-a derivatives were C20-substituted ones [33,34].
Notably, the site-selective fluorination occurred under mild and
easy conditions by simple stirring with commercially available NFSI
(1.0 equiv.) in THF at rt for 1 h.
[step (i) in Scheme 1]. The fluorination exclusively occurred at the
C20 position, and the C3-vinyl group was not modified by the ac-
tion of NFSI. Thus, the same conditions were applied to the fluori-
nations of Pyro-a derivatives 2e6 possessing other C3-
substituents.
All the above Pyro-a derivatives were synthesized using pre-
viously reported procedures [26]. The C3-vinyl group of 1 was
selectively hydrogenated on Pd/C to yield methyl mesopyr-
opheophorbide-a (2) [step (ii)] [22,24,29]. The C3-vinyl group of 1
Table 1
C20-Fluorination yields of 1 and its C3-substituted derivatives 2e6 to 20F-1e6.a
was oxidized by using OsO
pyropheophorbide-d (3) that possesses the C3-formyl group [step
iii)] [24], followed by the selective reduction of the C3-formyl
group of 3 using tBuNH ∙BH [30] to afford methyl 3-devinyl-3-
4 4
and NaIO [30] to produce methyl
Product
C3-Substituent
Yield/%
(
20F-1
eCH¼CH
2
43
34
42
28
44
21
20F-2
20F-3
20F-4
20F-5
eCH CH
eCHO
eCH OH
eCH(OH)CH
eCOCH
2
3
2
3
hydroxymethyl-pyropheophorbide-a (4) [step (iv)] [24]. The hy-
2
1
dration of the C3-vinyl group of 1 produced a 1:1 (3 R/S)-epimeric
3
mixture of methyl 3-devinyl-3-(1-hydroxyethyl)pyropheo-
20F-6
3
phorbide-a (5, methyl bacteriopheophorbide-d) [step (v)]
a
Stirring with NFSI (1.0 equiv.) in THF at rt for 1 h.
Scheme 1. C3-Functionalization of Pyro-a (1) to its derivatives 2e6 and their C20-fluorinations to 20F-1e6: (i) NFSI, THF; (ii) H
2
, Pd/C, THF; (iii) OsO
4
, NaIO
4
, aq. AcOH, THF; (iv)
tBuNH
2
∙BH
3
, CH
2
Cl
2
; (v) a. HBr, AcOH, b. H
2
O, c. CH
2
N
2
, Et
2
O, CH
2
Cl
2
; (vi) TPAP, NMO, CH
2 2
Cl .
3

S. Ogasawara, K. Nakano and H. Tamiaki
Tetrahedron 76 (2020) 131722
1
In the H NMR spectra, the C20-H proton peaks of all 1e6 dis-
3.2. Optical properties
2 2
The synthetic C20-fluorinated chlorins 20F-1e6 in CH Cl
appeared after their fluorination reactions, and broad peaks
assigned to be C20-F were found in their 19F NMR spectra (see
Figs. S1eS10). It is noted that the C2-CH
3
protons of 20F-1e6 were
showed similar electronic absorption spectral shapes as in the
corresponding C20-unsubstituted 1e6 (Fig. 3). All spectra gave
Qy(0,0)/(0,1), Qx(0,0)/(0,1) and Soret maxima from longer to shorter
wavelengths. Owing to the strong electron-withdrawing C20-
fluorine, the red-most Qy(0,0) absorption maxima of 20F-1e5
were shifted to longer wavelengths by 3e5 nm than those of 1e5
(see also Table 2). By contrast, that of C3-acetylated 20F-6 was
hypsochromically shifted to a shorter wavelength by 2 nm than that
of 6. Owing to the slightly longer bond length of C20eF (ca. 1.4 Å)
than that of C20eH (ca. 1.1 Å) and/or the aforementioned
found as doublet peaks (J ¼ 3e4 Hz) on the lower magnetic field
side (þ0.11 to þ0.26 ppm) than those of C20-unsubstituted 1e6
(
Fig. 2). Downfield shifts of the chemical shifts were due to the
electron-withdrawing of the C20-fluorine. The splitting of the
inherent singlet C2-CH proton signal was induced by through-
space (TS) coupling between the C2-CH proton and C20-fluorine:
3
3
1
a specific hydrogen bond between C2 eH and C20-F could be
formed. Energy-minimized molecular models by MMþ/PM3 cal-
culations [28] showed that the estimated distances between the H
and F atoms in 20F-1e6 were all almost the same, ca. 2.6 Å (see
Fig. S11), which is comparable to the distances proposed from the
above observed JHeF [35].
1
…
1
C2 eH F20 hydrogen bonding, the mobility of the C2-methyl
group of 20F-6 was suppressed to induce steric repulsion against
the neighboring bulky C3-acetyl group. For the sterically
demanding conformation, the less
p-conjugation of the acetyl
group with the chlorin moiety induced a blue-shift of its Qy(0,0)
absorption maximum. This observation is consistent with our
Fig. 2. Specific 1H NMR spectra (4.0e3.2 ppm) of Pyro-a (1) and its C3-substituted derivatives 2e6 (black) as well as their C20-fluorinated products 20F-1e6 in CDCl
(red).
3
4

S. Ogasawara, K. Nakano and H. Tamiaki
Tetrahedron 76 (2020) 131722
Fig. 3. Electronic absorption (left) and fluorescence emission spectra (right, excitation at the Soret maxima) of 1e6 (black) and 20F-1e6 in CH
2
Cl
2
(red). All spectra were normalized
at the most intense maxima.
Table 2
effectively than the Qy bands, as reported previously [37].
There were two types of changes between 1e6 and 20F-1e6
with respect to the major Soret absorption maxima. One was the
blue-shifts by the C20-fluorination of 1/3/6 to 20F-1/3/6 that
2 2
Optical properties of 1e6 and 20F-1e6 in CH Cl .
Compound
l
maxa/nm
Soret Qx(0,1) Qx(0,0) Qy(0,1) Qy(0,0)
l
emb/nm
Dc/cm
ꢀ1
, F
d/%]
[
possessed the
acetyl), and the other was the non-shifts by the C20-fluorination of
/4/5 to 20F-2/4/5 that possessed the non-conjugative C3-
p-conjugative C3-substituents (vinyl, formyl, and
1
415
413
411
411
429
422
410
410
410
410
418
412
510
515
504
512
522
527
506
512
505
512
515
518
540
545
537
543
555
562
536
543
537
544
548
551
610
614
602
605
633
637
606
609
605
607
624
624
668
671
657
662
694
697
662
667
661
666
683
681
673 [111, 22]
676 [110, 24]
660
665
701 [144, 18]
702 [102, 26]
667 [113, 21]
671
665 [100, 22]
669 [67, 22]
2
2
2
3
2
4
2
5
2
6
2
0F-1
0F-2
0F-3
0F-4
0F-5
0F-6
2
[69, 23]
[68, 26]
substituents (ethyl, hydroxymethyl, and 1-hydroxyethyl). In com-
parison of 1/3/6 with 20F-1/3/6, the blue-shifts of the major Soret
absorption maxima by the 20-fluorination gradually increased in
the order of 1 / 20F-1 (2 nm; C3-vinyl), 6 / 20F-6 (6 nm; C3-
acetyl), and 3 / 20F-3 (7 nm; C3-formyl), corresponding with
the order of the electronegativity of the C3-substituents: 2.79 (vi-
nyl) < 2.86 (acetyl) < 2.87 (formyl) [38].
[89, 22]
693 [211, 16]
692 [233, 19]
The changes in all the fluorescence emission spectra of Pyro-a
and its derivatives before and after the C20-fluorination showed a
similar tendency as those of the red-most Qy(0,0) absorption bands
(Fig. 2 and Table 2). The Stokes shifts of 20F-1 and 2 were compa-
rable to those of 1 and 2, while those of 20F-3e5 were approxi-
a
b
c
l
max, electronic absorption maximum (ca. 10
mM).
lem, fluorescence emission maximum excited at the Soret maximum (ca. 1
m
M).
e7
D
F
, Stokes shift ¼ [1/
l
max[Qy(0,0)] e 1/
lem]ꢂ10
.
d
, fluorescence quantum yield excited at the Soret maximum (ca. 1 mM).
ꢀ1
mately 20e40 cm reduced from those of 3e5 (Table 2). These
results suggested that the C20-fluorines in 20F-3e5 maintained
their molecular conformations substantially. By contrast, the Stokes
previous report for a similar C20-bromination [36]. In the case of
the Qy(0,1) absorption maxima of 20F-1e5, all of those moved to
ꢀ1
2
e4 nm longer wavelengths than those of 1e5 (Table 2), while the
shift of 20F-6 was larger by 22 cm than that of 6 (Table 2) because
of the increase in the steric repulsion among the C20-fluorine, C2-
methyl, and C3-acetyl as mentioned above. The quantum yields of
20F-1, 2, 4, and 6 were slightly higher (1e3%) than those of 1, 2, 4,
and 6, and the quantum yield of 20F-5 was the same as that of 5
Qy(0,1) absorption maximum of 20F-6 was the same as that of 6.
The Qx(0,0)/(0,1) absorption maxima of 20F-1e6 showed larger
bathochromic shifts from those of 1e6 than the shifts of Qy maxima
(
Table 2) because the C20-substituents affected the Qx bands more
5

S. Ogasawara, K. Nakano and H. Tamiaki
Tetrahedron 76 (2020) 131722
(
Table 2). In the case of 20F-3, its quantum yield was higher by 8%
[6] M. Taniguchi, J.S. Lindsey, Chem. Rev. 117 (2017) 344e535, https://doi.org/
1
0.1021/acs.chemrev.5b00696.
7] M. Doi, H. Tamiaki, Tetrahedron Lett. 60 (2019) 150934, https://doi.org/
0.1016/j.tetlet.2019.07.025.
[8] N. Funayama, H. Tamiaki, Tetrahedron Lett. 60 (2019) 63e67, https://doi.org/
0.1016/j.tetlet.2018.11.057.
than that of 3. Although the reason for these quantum yield changes
is still unclear, the C20-fluorinations of the Pyro-a derivatives did
not inhibit their fluorescence emission efficiencies.
[
1
1
[
9] K. Ohashi, Y. Kinoshita, H. Tamiaki, Photochem. Photobiol. 95 (2019) 755e761,
4
. Conclusion
https://doi.org/10.1111/php.13044.
[
[
10] T. Takahashi, S. Ogasawara, S. Echizen, Y. Shinozaki, H. Tamiaki, Org. Biomol.
Chem. 17 (2019) 5490e5495, https://doi.org/10.1039/c9ob00130a.
11] T. Nakano, H. Tamiaki, ChemPhotoChem (2020) 338e346, https://doi.org/
Fluorinations of Pyro-a derivatives possessing different kinds of
the C3-substituents were achieved by the electrophilic fluorination
reagent, NFSI, which was selectively substituted at the C20 position.
Commercially available NFSI is a relatively safe and easy to handle
fluorination reagent, and the fluorination reactions for the Pyro-a
derivatives proceeded at rt for a short period. The mild fluorination
showed that the reactive C3-substituents was tolerant to NFSI. In all
the fluorinated products, TS spinespin coupling between the C20-
10.1002/cptc.202000012.
[12] H. Tamiaki, M. Kunieda, Photochemistry of chlorophylls and their synthetic
analogs, in: K.M. Kadish, K.M. Smith, R. Guilard (Eds.), Handbook of Porphyrin
Science, vol. 11, World Scientific, Singapore, 2011, pp. 223e290, https://
doi.org/10.1142/9789814322386_0003.
[13] K. Müller, C. Faeh, F. Diederich, Science 317 (2007) 1881e1886, https://
doi.org/10.1126/science.1131943.
[14] W.K. Hagmann, J. Med. Chem. 51 (2008) 4359e4369, https://doi.org/10.1021/
jm800219f.
1
fluorine and C2 -hydrogen nuclei resulted in a doublet peak for the
[15] D. O’Hagan, H. Deng, Chem. Rev. 115 (2015) 634e649, https://doi.org/
10.1021/cr500209t.
[16] N.A. Meanwell, J. Med. Chem. 61 (2018) 5822e5880, https://doi.org/10.1021/
acs.jmedchem.7b01788.
1
1
C2 -H in the H NMR spectra and a broad peak for the C20-F in the
19
F NMR spectra. The TS coupling between the fluorine and proton
suggested their interaction, which partially affected their visible
absorption and fluorescence properties that primarily depended on
their C3-substituents. This type of steric effect on the physical
properties must be considered for C20-fluorinated chlorins,
although the electronic effect of the fluorine is important. Thus, the
C20-fluorine affects the molecular configurations and polarity.
Fluorinations of Chl-a derivatives, including Pyro-a derivatives,
will expand their functions with more Chl-a derivative varieties.
[
[
[
[
[
[
[
[
17] E.N.G. Marsh, Y. Suzuki, ACS Chem. Biol. 9 (2014) 1242e1250, https://doi.org/
10.1021/cb500111u.
18] C.M. Tressler, N.J. Zondlo, Biochemistry 56 (2017) 1062e1074, https://doi.org/
10.1021/acs.biochem.6b01020.
19] M. Cheng, C. Guo, M.L. Gross, Angew. Chem. Int. Ed. 59 (2020) 5880e5889,
https://doi.org/10.1002/anie.201907662.
20] G.C. Tsui, J. Hu, Asian J. Org. Chem. 8 (2019) 566e567, https://doi.org/10.1002/
ajoc.201900271.
21] S. Ogasawara, K. Nakano, H. Tamiaki, Eur. J. Org. Chem. 2020 (2020)
5537e5543, https://doi.org/10.1002/ejoc.202000887.
22] K.M. Smith, D.A. Goff, D.J. Simpson, J. Am. Chem. Soc. 107 (1985) 4946e4954,
https://doi.org/10.1021/ja00303a021.
Declaration of competing interest
23] L. Ma, D. Dolphin, Tetrahedron 52 (1996) 849e860, https://doi.org/10.1016/
0040-4020(95)00944-2.
24] H. Tamiaki, M. Amakawa, Y. Shimono, R. Tanikaga, A.R. Holzwarth,
K. Schaffner, Photochem. Photobiol. 63 (1996) 92e99, https://doi.org/10.1111/
j.1751-1097.1996.tb02997.x.
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
[25] H. Tamiaki, S. Takeuchi, S. Tsudzuki, T. Miyatake, R. Tanikaga, Tetrahedron 54
1998) 6699e6718, https://doi.org/10.1016/S0040-4020(98)00338-X.
(
[26] H. Tamiaki, S. Machida, K. Mizutani, J. Org. Chem. 77 (2012) 4751e4758,
https://doi.org/10.1021/jo300442t.
Acknowledgements
[27] T.J. Michalski, E.H. Appelmann, M.K. Bowman, J.E. Hunt, J.R. Norris,
T.M. Cotton, L. Raser, Tetrahedron Lett. 31 (1990) 6847e6850, https://doi.org/
This work was partially supported by Japan Society for the
Promotion of Science (JSPS) KAKENHI Grant Number JP17H06436
in the Scientific Research on Innovative Areas “Innovation for Light-
1
0.1016/S0040-4039(00)97187-9.
[
28] Y. Kureishi, H. Tamiaki, J. Porphyr. Phthalocyanines 2 (1998) 159e169, https://
doi.org/10.1002/(SICI)1099-1409(199803/04)2:2<159::AID-JPP62>3.0.CO;2-
Q.
29] H. Tamiaki, S. Yagai, T. Miyatake, Bioorg. Med. Chem. 6 (1998) 2171e2178,
https://doi.org/10.1016/S0968-0896(98)00154-0.
30] H. Tamiaki, S. Miyata, Y. Kureishi, R. Tanikaga, Tetrahedron 52 (1996)
4
Energy Conversion (I LEC)” (to HT).
[
[
[
[
[
[
[
[
[
[
Appendix A. Supplementary data
12421e12432, https://doi.org/10.1016/0040-4020(96)00740-5.
31] K.M. Smith, G.M.F. Bissert, M.J. Bushell, J. Org. Chem. 45 (1980) 2218e2224,
https://doi.org/10.1021/jo01299a036.
32] H. Tamiaki, T. Miyatake, R. Tanikaga, Tetrahedron Lett. 38 (1997) 267e270,
https://doi.org/10.1016/S0040-4039(96)02278-2.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131722.
33] J. Li, P. Zhang, N.N. Yao, L.L. Zhao, J.J. Wang, Y.K. Shim, Tetrahedron Lett. 55
References
(
2014) 1086e1089, https://doi.org/10.1016/j.tetlet.2013.12.093.
34] H. Tamiaki, N. Ariki, S. Yasuda, T. Miyatake, T. Oba, Tetrahedron 70 (2014)
768e9775, https://doi.org/10.1016/j.tet.2014.11.032.
[
[
1] N. Nelson, W. Junge, Annu. Rev. Biochem. 84 (2015) 659e683, https://doi.org/
0.1146/annurev-biochem-092914-041942.
2] T. Mirkovic, E.E. Ostroumov, J.M. Anna, R. Van Grondelle, Govindjee,
G.D. Scholes, Chem. Rev. 117 (2017) 249e293, https://doi.org/10.1021/
acs.chemrev.6b00002.
9
1
35] J.C. Hierso, Chem. Rev. 114 (2014) 4838e4867, https://doi.org/10.1021/
cr400330g.
36] H. Tamiaki, N. Ariki, H. Sugiyama, Y. Taira, Y. Kinoshita, T. Miyatake, Tetra-
hedron 69 (2013) 8412e8421, https://doi.org/10.1016/j.tet.2013.07.060.
37] Y. Kamatani, Y. Kitagawa, H. Tamiaki, Tetrahedron Lett. 59 (2018) 978e981,
https://doi.org/10.1016/j.tetlet.2018.01.052.
[
[
[
3] S. Duan, Q. Zhou, A. Li, X.-F. Wang, S. Sasaki, H. Tamiaki, Sol. RRL 4 (2020)
2000162, https://doi.org/10.1002/solr.202000162.
4] A.A. Ryan, M.O. Senge, Photochem. Photobiol. Sci. 14 (2015) 638e660, https://
doi.org/10.1039/c4pp00435c.
5] D.A. Bryant, C.N. Hunter, M.J. Warren, J. Biol. Chem. 295 (2020) 6888e6925,
https://doi.org/10.1074/jbc.REV120.006194.
38] N. Inamoto, S. Masuda, Chem. Lett. 11 (1982) 1003e1006, https://doi.org/
1
0.1246/cl.1982.1003.
6