Synthesis of 20-iodochlorophyll derivatives and their properties including reactivity, electronic absorption, and self-aggregation

Article abstract of DOI:10.1016/j.tet.2014.11.032

Methyl 20-iodopyropheophorbides-a possessing several substituents at the 3-position were prepared by treatment of the corresponding 20-unsubstituted chlorophyll-a derivatives with iodine and [bis(trifluoroacetoxy)iodo]benzene in chloroform and water at room temperature. The sterically demanding 20-iodination was clean, efficient, and regioselective without alteration of the 3-substituents, and also highly reproducible. The resulting 20-iodides were so reactive that they were readily transformed into 20-acetylchlorin (Pd-catalyzed cross-coupling) and 20-unsubstituted chlorin (acidic deiodination). Electronic absorption spectra in dichloromethane showed that the 20-iodination shifted the maxima to longer wavelengths in their monomeric states. Zinc complexes of 3¹-hydroxy-20-iodo-13¹-oxochlorins self-aggregated in non-polar organic solvents to give red-shifted and broadened absorption bands, similarly as in the corresponding 20-unsubstituted molecules, which are good models of the main light-harvesting antenna systems in photosynthetic green bacteria.

Full text of DOI:10.1016/j.tet.2014.11.032

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Tetrahedron 70 (2014) 9768e9775
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 20-iodochlorophyll derivatives and their properties
including reactivity, electronic absorption, and self-aggregation
,
a,
Hitoshi Tamiaki a , Nobutaka Ariki b, Satoru Yasuda c, Tomohiro Miyatake b, Toru Oba c
*
a Graduate School of Life Sciences, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan
b Department of Materials Chemistry, Faculty of Science and Technology, Ryukoku University, Otsu, Shiga 520-2194, Japan
c Department of Material and Environmental Chemistry, Graduate School of Engineering, Utsunomiya University, Utsunomiya, Tochigi 321-8585, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 October 2014
Received in revised form 9 November 2014
Accepted 10 November 2014
Available online 14 November 2014
Methyl 20-iodopyropheophorbides-a possessing several substituents at the 3-position were prepared by
treatment of the corresponding 20-unsubstituted chlorophyll-a derivatives with iodine and [bis(tri-
fluoroacetoxy)iodo]benzene in chloroform and water at room temperature. The sterically demanding 20-
iodination was clean, efficient, and regioselective without alteration of the 3-substituents, and also
highly reproducible. The resulting 20-iodides were so reactive that they were readily transformed into
20-acetylchlorin (Pd-catalyzed cross-coupling) and 20-unsubstituted chlorin (acidic deiodination).
Electronic absorption spectra in dichloromethane showed that the 20-iodination shifted the maxima to
longer wavelengths in their monomeric states. Zinc complexes of 31-hydroxy-20-iodo-131-oxochlorins
self-aggregated in non-polar organic solvents to give red-shifted and broadened absorption bands,
similarly as in the corresponding 20-unsubstituted molecules, which are good models of the main light-
harvesting antenna systems in photosynthetic green bacteria.
Keywords:
Electrophilic iodination
J-aggregate
Pyropheophorbide
Substitution effect
Visible absorption spectrum
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
oligomeric BChls-c/e in natural cells showed more red-shifted
maxima than the corresponding BChls-d/f, so the former are
Most photosynthetically active chlorophyllous pigments are
porphyrinoids possessing a substituent at only one of the four
meso-positions, the 15-position.1 In contrast, bacteriochloro-
phylls-c and e (BChls-c and e) are additionally substituted with
a methyl group at another meso-position, the 20-position (left
drawing of Fig. 1). In diethyl ether, 20-methylated BChls-c and e
have electronic absorption bands at longer wavelengths than the
corresponding 20-unsubstituted BChls-d and f, respectively.2 The
red-shifted absorption maxima in their monomeric states are
primarily due to the steric effect of the 20-methyl group, which
interacts with the neighboring 2- and 18-methyl groups to dis-
more effective for absorbing longer wavelength light and trans-
ferring the energy to BChl-a than the latter.4,5 The 20-
methylation is thus useful for some bacteria living in natural
environments.
A variety of semi-synthetic 20-substituted Chl derivatives are
available in the literature.6,7 For example, methyl mesopyro-
pheophorbide-a (1b) derived from naturally occurring Chl-a was
modified to its 20-substituted compounds (central drawing of
Fig. 1): R20¼alkyl,8,9 alkenyl,9 alkynyl,9e11 aryl,8,12,13 acyl,9 cyano,14
nitro,14,15 halogen substituents,9,16e18 and so on.
The iodination of porphyrinoids has been reported in some
manuscripts. Zinc complexes of 5,15-diarylporphyrins (none of b-
tort the chlorin
p
-system.3 In green photosynthetic bacteria,
BChls-c, d, e, and f self-assembled to form large J-aggregates and
gave more bathochromically shifted absorption bands than their
monomeric bands described above. Such J-aggregates efficiently
absorb dim light and the harvested light energy is transferred to
nearby BChl-a pigments. Similar to the monomeric states,
substitution and half of meso-substitution, M¼Zn and R10¼R20¼H
in right drawing of Fig. 1) in chloroform were treated with iodine in
the presence of silver hexafluoride and pyridine at room temper-
ature to give their meso-mono- and di-iodinated products as major
and minor products, respectively.19 The reaction of 5,10,15-
triarylporphyrin free bases (M¼H2, R10¼Ar, and R20¼H in right
drawing of Fig. 1) with iodine and (difluoroiodo)benzene (PhIF2,
one of the hypervalent iodine reagents) in dichloromethane at
room temperature afforded their 20-iodo-products.20 A mixture of
* Corresponding author. Fax: þ81 77 561 2659; e-mail address: tamiaki@fc.
ritsumei.ac.jp (H. Tamiaki).
http://dx.doi.org/10.1016/j.tet.2014.11.032
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

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Fig. 1. Molecular structures of naturally occurring BChls-c (R7¼R20¼Me), d (R7¼Me, R20¼H), e (R7¼CHO, R20¼Me), and f (R7¼CHO, R20¼H) (left), methyl 20-(un)substituted
mesopyropheophorbides-a prepared by modifying Chl-a (center, R20¼H for 1b), and synthetic meso-substituted porphyrinoids (right).
iodine and [bis(trifluoroacetoxy)iodo]benzene (BTI), PhI(OCOCF3)2,
is known to be a convenient electrophilic iodinating reagent for
aromatic compounds.21 The iodination of 5,15-diphenylporphyrin
with I2 and BTI in CHCl3 at room temperature gave meso-mono-
(major) and
dination occurred at the meso-position and the second proceeded
at the 20-position, the mass peaks expected for the singly io-
dinated molecule at m/z¼676 [¼550 (1b)þ127 (I)e1 (H)], and
red-shifted absorption maxima: 410/656 (1b)/418/670 nm in
CH2Cl2 (see also Section 2.3). The obtained spectral data in-
dicated that the product was 20-iodinated compound 2b. The
isolated yield fluctuated in each reaction and varied from nearly
0 to about 50%. To improve the reaction, strictly dry conditions
were applied (especially, use of anhydrous chloroform), but the
fluctuation continued. When wet conditions (addition of water)
were examined reversely, the desired product was always ob-
b
,meso-disubstituted products (minor).22 The first io-
at the b-position, and the selectivity was confirmed by the b-io-
dination of 5,10,15-triarylporphyrins with I2 and BTI.23 In the
presence of pyridine, the reaction of a 5,15-diarylporphyrin with I2
and BTI in CHCl3 at room temperature gave predominantly its
meso,meso-diiodo-product.24 It is noted that the
b- or meso-bromo-
tained and the yield increased. Reaction of 1b (10
mmol) with
atom in porphyrins was substituted with an iodo-atom to yield the
I2 (10 mol) and BTI (12.5 mol) in CHCl3 (10 ml) and H2O (2 ml)
m
m
corresponding iodoporphyrins.25,26
at room temperature for 30 min gave 2b in 92% yield after FCC.
The aqueous biphasic reaction was effective for the 20-
iodination.
Electrophilic
iodination
at
the
meso-position
of
2,3,7,8,12,13,17,18-octaethylporphyrin failed when treated with I2
and BTI.22,27 The inaccessibility is due to the sterically demanding
iodine atom and the steric hindrance around the meso-position
near the two ethyl groups. Chlorin chromophores possessing the
C17eC18 single bond showed a high reactivity at the 15- and 20-
The 31-hydroxy-substituted compound of 1b, methyl bacterio-
pheophorbide-d (1c), was converted to its 20-iodinated product 2c
by the same procedures as in 1b/2b (vide supra). The reaction
time for full consumption of 1c (1 h) was double that for 1b and the
yield of 2c (90%) was comparable to that of 2b. Similarly, 1d pos-
sessing an acetyl group at the 3-position was iodinated for 3 h to
give 2d in 81% yield. The slight decrease of the yield was ascribable
to less electrophilic reactivity at the 20-position of 1d bearing the
electron-withdrawing 3-acetyl group. The reaction times for con-
sumption of all the starting materials 1bed were dependent on the
3-substituents and increased in the order of 1b (3-CH2CH3)<1c [3-
CH(OH)CH3]<1d (3-COCH3). Electron-withdrawing groups at the 3-
position suppressed the electrophilic iodination at the 20-position:
group electronegativity¼2.48 (CH2CH3)<2.60 [CH(OH)CH3]<2.86
(COCH3).32
positions, so some b-substituted chlorin compounds were exam-
ined as substrates for iodination. A 2-unsubstituted and 18-
substituted chlorin in CHCl3 was iodinated at the 20-position by
I2 and BTI in the presence of pyridine at room temperature.28 The
iodination of a few chlorins (pyropheophorbides and purpur-
imides) possessing substituents at 2-, 15-, and 18-positions was
applied by either I2 and BTI or N-iodosuccinimide and trifluoro-
acetic acid in CHCl3, but their 20-iodochlorins were problemati-
cally18,29,30 or less produced.31
Here we report efficient synthesis of methyl 20-
iodopyropheophorbides possessing several substituents at the 3-
position with a high reproducibility. We discuss their chemical
reactivities and iodo-substitution effect on electronic absorption
bands in monomeric and self-aggregated states.
Under the same reaction conditions except for the reaction
times as in 1b/2b, 3-formyl-1e and 3-hydroxymethyl-chlorins
1f were iodinated to 2e (78%) and 2f (91%), respectively. The 3-
formyl group slightly suppressed the yield of 1e to 2e, which
was consistent with the result for the reaction of 1d to 2d. As
expected, the reaction times enhanced with an increase of the
electronegativity of the 3-substituents: 30 min/2.48 (1b, 3-
CH2CH3)<1 h/2.59 (1f, 3-CH2OH)<3 h/2.86 (1e, 3-CHO). The
groups at the 3-position of methyl pyropheophorbides 1bef
slightly affected the present iodination but the corresponding 20-
iodochlorins 2bef were obtained in good yields without alter-
ation of the 3-substituents.
2. Results and discussion
2.1. Synthesis of methyl 20-iodopyropheophorbides
Methyl mesopyropheophorbide-a (1b), one of the chloro-
phyll-a derivatives, was used as a substrate for 20-iodination,
because 1b had an ethyl group at the 3-position instead of the
reactive 3-vinyl group in methyl pyropheophorbide-a (1a) (see
Scheme 1). Treatment of 1b with I2 and BTI in CHCl3 at room
temperature gave a complex reaction mixture. After its careful
purification with flash column chromatography (FCC) on silica
gel, one product was separated and analyzed by 1H NMR, MS, and
visible spectroscopy. The isolated product gave no proton signal
2.2. Reaction of methyl 20-iodopyropheophorbides
Palladium-catalyzed cross-coupling of 20-iodochlorin 2b with
a tin reagent was first examined to confirm the reactivity of the 20-

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H. Tamiaki et al. / Tetrahedron 70 (2014) 9768e9775
Scheme 1. Synthesis of methyl 3-substituted 20-iodopyropheophorbides 2bef from methyl pyropheophorbide-a (1a) through electrophilic iodination of the corresponding methyl
3-substituted pyropheophorbides 1bef: (i) H2, PdeC/acetone; (ii) HBr/AcOH, H2O, CH2N2/Et2O; (iii) OsO4eNaIO4/THFeH2O; (iv) MeN(O)(CH2CH2)2OePr4NRuO4/CH2Cl2; (v)
tBuNH2BH3/CH2Cl2; (vi) C6H5I(OCOCF3)2eI2/CHCl3eH2O. The isolated yields are shown.
iodine substituent. Under standard Stille coupling reaction condi-
tions,9 2b was reacted with tributyl(1-ethoxyvinyl)tin and the re-
action mixture was then treated with p-toluenesulfonic acid to give
a hydrolyzed (and isomerized) product of the initial adduct, 20-
acetylchlorin 4b (Scheme 2). In the previous report,9 20-
bromochlorin 5b was transformed to 4b (57%) by the same pro-
cedure. The chemical yield of 2b/4b was 1.5 times larger than that
of 5b/4b, indicating that 20-iodochlorin 2b was more reactive
than 20-bromochlorin 5b. This is consistent with the fact that iodo-
substituted aromatics were superior as substrates of Pd-catalyzed

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H. Tamiaki et al. / Tetrahedron 70 (2014) 9768e9775
9771
Scheme 2. Transformation of 20-halogen atom into acetyl group by Pd-catalyzed re-
action (Migita-Kosugi-Stille coupling): (i) CH2]C(OEt)SnBu3ePd(PPh3)4/THF (reflux),
then 4-MeC6H4SO3H$H2O/CH2Cl2.
Scheme 3. Quantitative zinc-metallation of methyl 31-hydroxylated 20-
iodopyropheophorbides 2c/f to 3c/f: (i) Zn(OAc)2$2H2O/C5H5N.
cross-coupling reactions to the corresponding bromo-substituted
ones.33
deiodinated under the conventional metallation conditions (vide
supra). When the dichloromethane solution of 2b was stirred in the
presence of p-toluenesulfonic acid (7 equiv) at room temperature,
the complete conversion to 1b was observed within 15 min. Under
the same conditions, debromination of the corresponding 20-
bromo-analog 5b did not proceed any longer and reflux in ben-
zene for 1 day was necessary for full debromination of 5b/1b.9
The sterically demanding 20-iodides 2 possessing 2- and 18-
methyl groups were more chemically labile than the correspond-
ing 20-bromides.
Secondary alcohol 2c was oxidized by an N-oxide with a per-
ruthenate catalyst [step (iv) in Scheme 1]9 to afford corre-
sponding ketone 2d (52%). The value was smaller than the yield
of the oxidation of 20-unsubstituted 1c to 1d (75%). The sup-
pression is ascribable to the electron-withdrawing effect of the
20-iodine atom and also the following undesired reaction. In the
reaction mixture, 20-unsubstituted form 1d of desired product
2d was observed in a small amount. Under the oxidation con-
ditions, the substitution of the 20-iodine atom with a hydrogen
atom partially occurred. This is contrast with no removal of
20-bromine atom for the same oxidation of the corresponding
20-bromo analog.9 The undesired substitution of 20-I to 20-H
and no alteration of 20-Br were supported by the above obser-
vation that the 20-I was more reactive than the 20-Br. In the
transformation of 1c to 2d, the route through 1d (the oxidation at
the 3-substituent followed by the 20-iodination) was better in
total chemical yield than that via 2c (the 20-iodination and
successive oxidation at the 3-substituent): 75%ꢀ81%¼61%>47%¼
90%ꢀ52%.
2.3. Electronic absorption spectra of methyl 20-
iodopyropheophorbides
In
a
diluted dichloromethane solution of methyl 20-
iodopyropheophorbides 2bef as well as methyl 20-unsubstituted
pyropheophorbides 1bef, two intense electronic absorption
bands were observed at around 400 and 700 nm (Fig. 2), which
were called Soret and Qy bands, respectively.6,9 Both the main
bands were accompanied by some vibrational components with
a relatively low intensity at the shorter wavelength region. At the
region between Soret and Qy bands, some less intense bands were
visible and were called Qx bands. It is noted that the main Qx band
[Qx(0,0)] and its vibrational component Qx(0,1) of 20-iodochlorins
2bef were relatively more and less intense, respectively, than those
of the corresponding 20-unsubstituted 1bef.
The 20-iodination red-shifted all the absorption maxima and
the values for the main Soret, Qx, and Qy bands are summarized in
Table 1. Except for 3-acetylchlorins 1d/2d, the Qx and Qy maxima
moved to longer wavelengths by about 600 and 300 cme1, re-
spectively. Based on previous reports for the 20-substitution of
other chlorophyll derivatives,3,9,35 the red shifts were primarily
Aldehyde 2e was reduced by a borane complex [step (v) in
Scheme 1]34 to give corresponding primary alcohol 2f (80%) after
stirring at room temperature for 30 min. The yield and reaction
time were almost the same as those in the reduction of 20-
unsubstituted aldehyde 1e to 1f (82% and 30 min) and no deiodi-
nation was observed during the reduction. The 20-iodine atom did
not disturb the reduction, while it did part of the above oxidation.
When 1e was a starting material, 2f was more accessible through 1f
(the first reduction and the second iodination) than via 2e (the
reverse procedures) from the viewpoints of yields and reaction
times.
Zinc metallation of 2f was applied by a standard method.35
Treatment of 2f in dichloromethane with zinc acetate dihydrate
in methanol gave no desired zinc complex 3f, but the zinc complex
of 1f exclusively. Under the weak acidic conditions, deiodination of
2f to 1f would occur predominantly (vide infra) before desired
zinc-metallation of 2f to 3f. Reaction of 2f with zinc acetate in
pyridine36 afforded 3f quantitatively without the 20-deiodination
(Scheme 3). The basic conditions no longer induced the undesired
deiodination. Similarly, 2c was smoothly zinc-metallated to 3c.
Since 2c was a 1:1 mixture of 31R- and S-epimers, zinc complex 3c
was an epimeric mixture and both the epimeric mixtures were
used for the following optical measurements (see Sections 2.3
and 2.4).
ascribable to the distortion of chlorin p-systems produced by steric
repulsion between the 20-iodine atom and its neighbor 2/18-
methyl groups. The red-shift values of Soret and Qy maxima in
1d/2d were smaller than those of the others, while those of the
former Qx bands (Dl¼340 cme1) were about half of those of the
latter. The observation can be explained as follows. The substitution
of a large iodine atom at the 20-position restricted the rotational
conformation of its neighbor 2-methyl group and one of the pro-
tons in the conformationally fixed 2-methyl group strongly inter-
acted with the 3-acetyl group. The 3-carbonyl group was thus
rotated from the chlorin p-plane to substantially deconjugate with
chlorin moiety. The deconjugated blue-shift was compensated with
the conventional red-shift by the 20-iodination to give small red-
shifts of the main Soret and Qy maxima in 1d/2d. Since the Qx
bands were less affected by the 3-substituents,6 they moved
Although zinc insertion of the central position of the previous
iodoporphyrinoids (see Introduction section) succeeded with
treatment of zinc acetate in methanol,22e24,28 2f was readily