Synthesis of non-aggregating chlorins and isobacteriochlorins from meso-tetrakis(pentafluorophenyl)porphyrin: A study using 1,3-dipolar cycloadditions under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2014.01.049

The 1,3-dipolar cycloaddition of meso-tetrakis(pentafluorophenyl)porphyrin and its nickel complex, with the bulky azomethine ylide dipole was studied under mild conditions, and yielded chlorin and isobacteriochlorin derivatives self-prevented from aggregation. The reactions were performed at room temperature or 0 C, and we were able to establish a set of reaction conditions to obtain only the chlorin or the isobacteriochlorin. These compounds were evaluated in solution, and no aggregation was observed at less than 25 mM (～30 mg mL^-1) using ¹H NMR experiments.

Full text of DOI:10.1016/j.tetlet.2014.01.049

Tetrahedron Letters 55 (2014) 1491–1495
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Tetrahedron Letters
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Synthesis of non-aggregating chlorins and isobacteriochlorins
from meso-tetrakis(pentafluorophenyl)porphyrin: a study using
1,3-dipolar cycloadditions under mild conditions
Juliana M. de Souza a, Francisco F. de Assis a, Carla M. B. Carvalho a, José A. S. Cavaleiro b,
Timothy J. Brocksom a, Kleber T. de Oliveira a,
⇑
a Departamento de Química, Universidade Federal de São Carlos—UFSCar, Rodovia Washington Luiz, km 235, SP 310, 13.565-905 São Carlos, SP, Brazil
b Department of Chemistry and QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
The 1,3-dipolar cycloaddition of meso-tetrakis(pentafluorophenyl)porphyrin and its nickel complex, with
the bulky azomethine ylide dipole was studied under mild conditions, and yielded chlorin and isobacte-
riochlorin derivatives self-prevented from aggregation. The reactions were performed at room tempera-
ture or 0 °C, and we were able to establish a set of reaction conditions to obtain only the chlorin or the
isobacteriochlorin. These compounds were evaluated in solution, and no aggregation was observed at less
than 25 mM (ꢀ30 mg mLÀ1) using 1H NMR experiments.
Received 13 December 2013
Revised 8 January 2014
Accepted 14 January 2014
Available online 20 January 2014
Keywords:
Chlorin
Ó 2014 Elsevier Ltd. All rights reserved.
Isobacteriochlorin
1,3-Dipolar cycloaddition
Non-aggregation
Photosensitizer
Introduction
all cases, the highly reactive dipole is generated by treating an
aldehyde and an amino acid, with a decarboxylation step, in tolu-
Porphyrinoid compounds (Fig. 1) have attracted increasing
attention due to the wide range of applications that these com-
pounds present, and for the synthetic challenges of obtaining com-
pounds with improved photophysical properties.1–5
ene or chlorobenzene, at reflux temperatures, and with an excess
of more than 100 equiv of the dipole precursors. This is necessary
because the dipole is partially decomposed under these conditions.
It has been reported that the same kind of dipoles can be gen-
erated starting from different precursors, and using milder reaction
conditions, lower temperatures, and less equivalents of dipole pre-
cursor.19,20 The use of a Bronsted acid, commonly TFA, is necessary
to promote the conversion of the dipole precursor to the 1,3-di-
pole. We envisioned the application of such a 1,3-dipolar cycload-
dition to a porphyrin system, thus obtaining much milder reaction
conditions and better selectivity. We have attempted to control the
products formed in the reaction, by tuning the temperature and
equivalents of dipole precursor. In addition, we also propose to
Reductions or similar transformations at the porphyrin core are
important to furnish chlorins and bacteriochlorins, that show use-
ful photophysical properties for a number of applications, such as
PDT treatments.2,3,6–9 Cycloaddition reactions are also a powerful
tool for obtaining these derivatives, since they allow the formation
of new carbon–carbon bonds and inhibit re-oxidation reactions
leading back to the porphyrin core. In the case of the Diels–Alder
reaction, porphyrins can react as dienes or dienophiles to obtain
chlorin derivatives.10–13 Another interesting approach is the use
of 1,3-dipolar cycloadditions reactions. Cavaleiro’s laboratory has
explored the reactivity of meso-tetrakis(pentafluorophenyl)por-
phyrin (TPFPP) to act as a dipolarophile with azomethine ylides.14
These authors reported the synthesis of chlorin and isobacterio-
chlorin derivatives under such methodology. However, the bacte-
riochlorins were only obtained when the preformed chlorin was
used as substrate, under the same reaction conditions.11,15–18 In
NH
N
N
N
N
NH
N
N
NH
N
N
HN
NH HN
HN
HN
Porphyrin
Chlorin
bacteriochlorin
isobacteriochlorin
⇑
Corresponding author. Tel.: +55 16 3351 8083; fax: +55 16 3351 8350.
E-mail address: kleber.oliveira@ufscar.br (K.T. de Oliveira).
Figure 1. Core structures of a porphyrin and derivatives.
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2014.01.049

1492
J. M. de Souza et al. / Tetrahedron Letters 55 (2014) 1491–1495
Table 1
produce low aggregation compounds by the use of the bulky ben-
zyl azomethine ylide as the 1,3-dipole, which should avoid aggre-
gation in solution.
Yields in the reaction of 4 and 1, with TFA, at 25 °Ca–d,22
Entry
Equiv of 1
Recovered 4 (%)
Product 6 (%)
8 (%)
1
2
3
4
5
6
5
80.3
63.0
53.0
46.0
36.6
—
10.0
22.4
36.6
40.0
45.8
Traces
—
Traces
5.3
6.1
12.4
65.5
10
15
20
25
30
Results and discussions
The dipole precursor 1 was prepared from benzylamine and
(chloromethyl)trimethylsilane, followed by reaction with aqueous
formaldehyde in methanol.17
a
In all experiments 30 mg (29.1
Anhydrous CH2Cl2 was used as the solvent and the final volume for all the reac-
tions was 7.5 mL.
2 Equiv of TFA was used in all the reactions.
lmol) of porphyrin 4 was used.
Initially, we used porphyrin 3 (TPFPP) as the dipolarophile, and
depending upon the reaction conditions three different products
were obtained. One of these exhibited a visible spectrum which
is characteristic for chlorin 5, and for the other two we detected
the typical bands of isobacteriochlorins, corresponding to a mix-
ture of compounds 7 and 9 (Scheme 1). The compounds 5 and 7
were isolated and characterized by 1H NMR and UV–vis analyses
(Figs. S12-S13, S57 and S59—Supporting information); compound
9 was isolated as a trace product, and characterized only by UV–
vis spectra (Fig. S61—Supporting information). However, a number
of non-porphyrinoid impurities remained after exhaustive purifi-
cation steps, involving column chromatography and preparative
thin layer chromatography. As a consequence, only very small
amounts of pure chlorin 5 and the other derivatives were obtained.
In all these experiments no bacteriochlorin derivatives could be
detected.
b
c
d
Reaction time was 2 h in all cases.
of 1), a mixture of all three compounds was obtained. Finally, using
30 equiv of dipole precursor 1, we observed the total consumption
of 4, and the isobacteriochlorin 8 was isolated as the major product
in 65.5% yield. When dipole precursor 1 was used in more than
10 equiv, we observed the formation of a second isobacteriochorin
10, always as traces.
We also performed some reaction tests at 0 °C, and in these con-
ditions a very low conversion rate of 4 was observed after 2 h.
When 50 equiv of 1 was employed, only the chlorin 6 was obtained
in 16.8% yield and most of the starting materials were recovered
(76.0%). Using smaller quantities of dipole precursor insignificant
amounts of chlorin 6 and recovery of starting compound took
place.
Thus, we decided to test the use of the Ni(II) complex 4 as sub-
strate,21 and this approach has afforded much better results. With
Ni(II)–TPFPP (4), it was possible to obtain the products with no
impurities after one column and one preparative TLC (CH2Cl2/hex-
anes, 7:3). Table 1 summarizes all these results for the reactions
between 4 and 1, at 25 °C and 2 h reaction time.
All the reactions described in Table 1 were performed starting
from 30 mg (29.1
also performed some tests starting with 10 mg (9.7
l
mol) of 4 at the concentration of 3.9 mM. We
mol) of 4
l
and maintaining the same concentration, but we found some diffi-
culties to reproduce the yields because of the small scale.
Compounds 6 and 8 were fully characterized using 1H, 13C, and
2D NMR analyses (see Supporting information), as well as HRMS
The use of 5–10 equiv of 1 leads to the recovery of starting
material 4, and chlorin 6 in low yields. Under these conditions,
the formation of isobacteriochlorin 8 was observed just as traces
or not observed at all. For intermediate conditions (15–25 equiv
Ar
M
N
N
N
Ar
Ar
N
Ar
3 M= 2H
4 M= Ni
Ph
Ph
TFA
CH2Cl2
N
TMS
N
O
2
1
Ph
Ph
Ph
Ph
Ar
M
Ph
Ar
H
H
Ar
H
H
N
N
N
H
N
N
H
N
H
N
H
H
Ar
H
N
N
N
N
N
N
N
Ar
M
+
Ar
Ar
+ Ar
Ar
M
N
N
N
Ar
Ar
Ar
9 M= 2H
10 M= Ni
5 M= 2H
6 M= Ni
7 M= 2H
8 M= Ni
F
F
F
Ar=
F
F
Scheme 1. Cycloadducts from 3 or 4 under mild conditions.

J. M. de Souza et al. / Tetrahedron Letters 55 (2014) 1491–1495
1493
(MALDI-TOF). For compound 6, we observed the presence of two
broad triplets at 2.51 and 3.01 ppm, corresponding to the methy-
lene groups of the pyrrolidine ring, as well as a broad signal at
4.86 ppm corresponding to the hydrogens of the ring junction. A
sharp singlet for the methylene hydrogens of the benzyl group is
also observed at 3.45 ppm, and all the eleven aromatic hydrogens
can be found between 7.13 and 8.35 ppm. No signals were ob-
served at the negative region of the spectrum, demonstrating that
the metal was not removed during the cycloaddition reaction. In
since it is less symmetric. This analysis is based upon previous
publications from Cavaleiro’s laboratory.11 Planning on future
PDT studies, we have successfully removed nickel from compounds
6 and 8 (see Supporting information) by using CH2Cl2 and H2SO4.
Here we have demonstrated that metallation is a very important
approach to access the mono and bis adducts, and that there is
no difficulty to obtain metal free derivatives for potential uses in
PDT studies.
the case of compound
8
four triplets (2.20 ppm, 2.29 ppm,
Aggregation studies
2.66 ppm, 2.84 ppm) were observed corresponding to the four
methylene groups of the two pyrrolidine rings. Also, we observed
a singlet at 3.40 ppm corresponding to the methylene groups of
the benzyl groups, and a multiplet between 4.24 and 4.39 ppm cor-
responding to the hydrogens of the ring junctions. All the fourteen
aromatic hydrogens were observed between 7.09 and 7.68 ppm.
The relative stereochemistry of isobacteriochlorin 8 was deter-
mined by 19F NMR analysis. In the spectrum, there are 4 signals
(À135.66 ppm, À135.10 ppm, À138.06 ppm, and À138.22 ppm),
corresponding to the o-F atoms of the pentafluorophenyl substitu-
ents. Only a trans relative configuration between the two pyrroli-
dine rings can allow such a pattern, due to the higher symmetry
of 8 (Fig. 2). For the cis isomer 10, 6 signals should be expected
We have demonstrated in recent publications that porphyri-
noids presenting a ‘L-shape’ structure, are self-prevented from
aggregation in solution.23–25 The presence of bulky moieties in a
perpendicular orientation to the porphyrinoid core prevents the
occurrence of
p-stacking interactions, and thus the occurrence of
molecular aggregates. We have demonstrated the lack of aggrega-
tion for chlorin 6 and isobacteriochlorin 8 using 1H NMR analysis
(Fig. 2 and Fig. S60 in the Supporting information), as aggregation
in solution directly affects the aromatic ring anisotropy, resulting
in variations in the chemical shift (0.1–0.5 ppm), and also drastic
loss of signal resolution. It is also known that the probability of for-
mation of aggregates increases along with the concentration,
0.8 x 10-3 molL-1
1.6 x 10-3 molL-1
3.2 x 10-3 molL-1
6.4 x 10-3 molL-1
12 x 10-3 molL-1
25 x 10-3 molL-1
Figure 2. 1H NMR aggregation study for chlorin 6 in CDCl3.

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J. M. de Souza et al. / Tetrahedron Letters 55 (2014) 1491–1495
Figure 3. UV–vis aggregation study for chlorin 6 (left) and isobacteriochlorin 8 (right) in CHCl3.
especially above 4 mM.20 For compounds 6 and 8 even at 25 mM,
aggregation was not substantially observed.
8. Ogikubo, J.; Worlinsky, J. L.; Fu, Y.-J.; Brückner, C. Tetrahedron Lett. 2013, 54,
1707–1710.
9. Sakuma, S.; Otake, E.; Torii, K.; Nakamura, M.; Maeda, A.; Tujii, R.; Akashi, H.;
Ohi, H.; Yano, S.; Morita, A. J. Porphyrins Phthalocyanines 2013, 17, 331–342.
10. DiNello, R. K.; Dolphin, D. J. Org. Chem. 1980, 45, 5196–5204.
11. Tomé, A. C.; Lacerda, P. S. S.; Neves, M. G. P. M. S.; Cavaleiro, J. A. S. Chem.
Commun. 1997, 1199–1200.
12. Silva, A. M. G.; Tomé, A. C.; Neves, M. G. P. M. S.; Cavaleiro, J. A. S. Tetrahedron
2000, 41, 3065–3068.
13. de Oliveira, K. T.; Silva, A. M. S.; Tomé, A. C.; Neves, M. G. P. M. S.; Neri, C. R.;
Garcia, V. S.; Serra, O. A.; Iamamoto, Y.; Cavaleiro, J. A. S. Tetrahedron 2008, 64,
8709–8715.
Complementary UV–vis studies were also carried out for com-
pounds 6 and 8 (Fig. 3), and the results are in agreement with
the NMR data. In UV–vis studies the concentrations are obviously
much lower than in the 1H NMR analyses, but confirm that com-
pounds 6 and 8 possess a low-aggregation character in the solu-
tion, as can be observed by the linearity of the wavelength
versus the concentration (insets at Fig. 3).
14. Silva, A. M. G.; Tomé, A. C.; Neves, M. G. P. M. S.; Silva, A. M. S.; Cavaleiro, J. A. S.
Chem. Commun. 1999, 1767–1768.
15. Tomé, A. C.; Lacerda, P. S. S.; Silva, A. M. G.; Neves, M. G. P. M. S.; Cavaleiro, J. A.
S. J. Porphyrins Phthalocyanines 2000, 4, 532–537.
Conclusions
16. Silva, A. M. G.; Tomé, A. C.; Neves, M. G. P. M. S.; Silva, A. M. S.; Cavaleiro, J. A. S.
J. Org. Chem. 2005, 70, 2306–2314.
17. Silva, A. M. G.; Tomé, A. C.; Neves, M. G. P. M. S.; Silva, A. M. S.; Cavaleiro, J. A. S.
J. Org. Chem. 2002, 67, 726–732.
18. Silva, A. M. G.; Lacerda, P. S. S.; Tomé, A. C.; Neves, M. G. P. M. S.; Silva, A. M. S.;
Cavaleiro, J. A. S.; Makarova, E. A.; Lukyanets, E. A. J. Org. Chem. 2006, 71, 8352–
8356.
We have prepared chlorin and isobacteriochlorin derivatives 5
to 8, under mild and improved conditions by using the 1,3-dipolar
cycloaddition reaction. These products are self-prevented from
aggregation in solution, proving the relevance of the studies devel-
oped here.
19. Terao, Y.; Kotaki, H.; Imai, N.; Achiwa, K. Chem. Pharm. Bull. 1985, 33, 896–898.
20. Padwa, A.; Dent, W. J. Org. Chem. 1987, 52, 235–244.
21. Kadish, K. M.; Araullo-McAdams, C.; Han, B. C.; Franzen, M. M. J. Am. Chem. Soc.
1990, 112, 8364–8368.
22. Representative procedure for the synthesis of chlorin 6 and isobacteriochlorin 8: To
a mixture containing 7.5 mL of anhydrous CH2Cl2 and 30 mg of porphyrin 4
Acknowledgments
The authors thank the São Paulo Research Foundation (FAPESP)
for fellowships (2012/14328-5 and 2012/24096-4) and financial
support (2011/13993-2 and 2013/065324), and also CNPq and
CAPES. Thanks are also due to Professor E.R. Filho and Dr. D. Ferre-
ira for MALDI measurements. J.A.S.C. thanks FCT-Lisbon’ for Re-
search Unit-QOPNA funding.
(29.1
(molar equiv depending on the experiment) and trifluoroacetic acid (TFA)
(58.2 mol). After 2 h, the reaction was extracted with a saturated solution of
lmol) at 25 °C and under argon atmosphere were added compound 1
l
NaHCO3 (20 mL) and dichloromethane (3 Â 20 mL). The organic phase was
dried over anhydrous Na2SO4 and concentrated under reduced pressure at
40 °C. Purifications were performed by silica flash column chromatography
using CH2Cl2/Hexanes (7:3) as eluent and then by preparative TLC using the
same eluent.
Supplementary data
Compound 6:
1H NMR: (CDCl3, 400.15 MHz) d (ppm): 2.51 (br t, 2H, J = 7.0 Hz), 3.01 (br t, 2H,
J = 8.4 Hz), 3.45 (s, 2H), 4.89–4.82 (m, 2H), 7.30–7.13 (m, 5H), 8.35–8.02 (m,
6H). 13C NMR: (CDCl3, 100.4 MHz) d (ppm): 49.5, 59.4, 60.1, 95.5, 106.9, 114.0,
114.2, 114.4, 127.6, 128.0, 128.4, 128.7, 129.0, 133.0, 136.2, 136.7, 137.4, 138.9,
139.3, 140.4, 140.8, 143.3, 143.9, 144.7, 146.3, 147.0, 147.1, 157.0.
19F NMR: (CDCl3, 376.52 MHz) d (ppm): À161.3 to À161.1 (m, 4F), À160.8 (t,
2F, J = 22.1 Hz), À159,9 (t, 2F, J = 22.1 Hz), À151.8 (t, 2F, J = 22.1 Hz), À151.5 (t,
2F, J = 22.1 Hz), À137.4 to À137.1 (m, 6F), À134.8 (d, 2F, J = 22.1 Hz). HRMS
(MALDI-TOF): calcd for [M+H]+, C53H20F20N5Ni+, 1164.0747; found: 1164.0729.
Compound 8:
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.01.
049.
References and notes
1. de Oliveira, K. T.; Momo, P. B.; de Assis, F. F.; Brocksom, T. J. Curr. Org. Synth.
2014, 11. accepted review (Upcoming Articles).
1H NMR: (CDCl3, 400.15 MHz) d (ppm): 2.13 (br t, 2H, J = 7.7 Hz), 2.22 (br t, 2H,
J = 7.7 Hz), 2.59 (br t, 2H, J = 8.1 Hz), 2.77 (br t, 2H, J = 8.1 Hz), 3.32 (s, 4H),
4.25–4.17 (m, 4H), 7.04–7.01 (m, 5H), 7.20–7.17 (m, 7H), 7.64 (br s, 2H). 13C
NMR: (CDCl3, 100.4 MHz) d (ppm): 47.0, 50.1, 59.2, 59.7, 60.4, 91.6, 98.3, 112.6,
113.4, 113.6, 113.7, 114.0, 114.2, 121.7, 127.5, 128.4, 128.9, 129.0, 135.7, 136.7,
137.4, 139.2, 140.4, 143.0, 143.5, 143.9, 144.3, 144.7, 146.0, 146.4, 146.9, 147.1,
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151.8, 164.0. 19F NMR: (CDCl3, 376.52 MHz)
J = 22.4 Hz, J = 7.5 Hz), À161.0 (dt, 2F, J = 22.4 Hz, J = 7.5 Hz), À160.3 (dt, 2F,
d
(ppm): À161.4 (dt, 2F,
J = 22.4 Hz, J = 7.5 Hz), À159.3 (dt, 2F, J = 22.4 Hz, J = 7.5 Hz), À152.6 (t, 1F,

J. M. de Souza et al. / Tetrahedron Letters 55 (2014) 1491–1495
1495
J = 22.4 Hz), À152.3 (t, 2F, J = 22.4 Hz), À150.7 (t, 1F, J = 22.4 Hz), À138.2 (dd,
2F, J = 22.4 Hz, J = 7.5 Hz), À138.1 (dd, 2F, J = 22.4 Hz, J = 7.5 Hz), À135.0 (dd,
2F, J = 22.4 Hz, J = 7.5 Hz), À134.7 (dd, 2F, J = 22.4 Hz, J = 7.5 Hz). HRMS
(MALDI-TOF): calcd for [M+H]+, C62H31F20N6Ni+, 1297.1639; found: 1297.1671.
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