First phthalocyanine-β-cyclodextrin dyads

Article abstract of DOI:10.1016/j.tetlet.2006.06.068

Novel water-soluble phthalocyanine-β-cyclodextrin dyads were prepared via a statistical cross condensation of a 4-(β-cyclodextrin)phthalonitrile with known phthalonitriles.

Full text of DOI:10.1016/j.tetlet.2006.06.068

Tetrahedron Letters 47 (2006) 6129–6132
First phthalocyanine–b-cyclodextrin dyads
a
a
a
Anderson O. Ribeiro,a,b Joao P. C. Tome, Maria G. P. M. S. Neves, Augusto C. Tome,
´
´
˜
a,
b
c
*
´
´
Jose A. S. Cavaleiro, Osvaldo A. Serra and Tomas Torres
aDepartment of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
bDepartment of Chemistry, FFCLRP – University of Sao Paulo, Ribeira˜o Preto, Brazil
cDepartment of Organic Chemistry, Autonoma University of Madrid, Cantoblanco, 28049 Madrid, Spain
Received 24 April 2006; revised 6 June 2006; accepted 12 June 2006
Available online 10 July 2006
Abstract—Novel water-soluble phthalocyanine–b-cyclodextrin dyads were prepared via a statistical cross condensation of a 4-(b-
cyclodextrin)phthalonitrile with known phthalonitriles.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Recently, the syntheses of ionic9 and neutral10 water-sol-
uble phthalocyanine derivatives have been described. In
this work, we propose a new methodology to obtain sta-
ble water solutions of Pcs using a covalent linkage to the
b-cyclodextrin. Furthermore, the CD moiety promotes
good amphiphilicity character to the new compounds.
It is worth to mention that, as far as cyclodextrins and
phthalocyanines are concerned, only inclusion com-
pounds have been described. The exterior hydrophilic
properties of the CD combined with its hydrophobic
cavity in the centre allow the solubilization of these
Pcs in water.11,12a
Phthalocyanines (Pcs) have been intensively studied due
to their applications in many scientific areas,1 their use
as photosensitizers (PS) in photodynamic therapy
(PDT)2 being a most promising one. PDT uses a combi-
nation of visible light, oxygen and a photosensitizer to
cause photodamage to tumour tissues; it is strongly
dependent on the photophysical and photochemical
photosensitizer properties. The latter should exhibit
high light absorption features in the 600–800 nm region,
good selectivity to the target cells, minimal dark toxicity,
high singlet oxygen quantum yields formation, amphi-
philicity features and others.3,4
2. Synthesis
Phthalocyanines show a higher molar absorptivity
(>105 MÀ1 cmÀ1) at the adequate PDT therapeutic win-
dow in comparison with the already established drugs.5
However, most Pcs are insoluble in physiological fluids,
requiring usually hard formulations to be used.6 Differ-
ent biologically compatible delivery systems have been
described in order to solve that limitation, such as incor-
poration into liposomes, biopolymers and cyclodextrins
(CD).7,8 In that way, it is expected that these problems
could be overtaken if water-soluble phthalocyanines
can become available.
The novel phthalocyanine–b-cyclodextrin (Pc–CD)
dyads 4 and 5 were prepared in two steps (Scheme 1).
First the 4-(b-cyclodextrin)phthalonitrile 3 was synthe-
sized by coupling b-cyclodextrin 1 with 4-nitrophthalo-
nitrile 2, at room temperature in DMF, and in the
presence of K2CO3.13 Then, the Pc–CD dyads 4 and 5
were prepared by statistical cross condensation of
the cyclodextrin–phthalonitrile 3 with an excess of
phthalonitrile or 4,5-dibutoxyphthalonitrile, respec-
tively, in the presence of zinc chloride. The reactions
were carried out in refluxing N,N-dimethylaminoethanol
(DMAE) affording the desired dyads as well as the sym-
metric zinc phthalocyanine, formed by self-condensa-
tion of the non cyclodextrin–phthalonitrile. The pro-
ducts were purified by silica gel and reverse phase column
chromatography using a gradient of THF/H2O as the
Keywords: Phthalocyanines; Cyclodextrins; Water-soluble phthalo-
cyanines.
*
Corresponding author. Tel.: +351 234 370 717; fax: +351 234 370
084; e-mail: jcavaleiro@dq.ua.pt
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.068

6130
A. O. Ribeiro et al. / Tetrahedron Letters 47 (2006) 6129–6132
OH
5
OH
6
O
2
O
O
O
HO
HO
O
O
4
1
OH
OH
HO
HO
3
6
3
O
O
OH
4
OH
O
CN
CN
OH
OH
OH
HO
HO
O
OH
O
OH
O
O
O
O
5
O2N
CN
CN
i)
HO
O
HO
O
HO
HO
HO
+
β-CD
OH
O
OH
OH
O
OH
HO
OH
OH
HO
HO
2
O
O
O
O
OH
O
OH
O
OHO
OHO
HO
HO
HO
HO
CN
O
O
3
OH
OH
R
R
1
R
R
CN
ii)
OH
8
11
O
O
HO
O
HO
OH
N
N
O
OH
N
1
15
18
2
R
O
OH
HO
O
OH
N
Zn
N
N
O
O
3
R
HO
O
HO
4
N
N
OH
HO
O
OH
OH
25
22
HO
O
O
OH
O
OHO
4, R = H
HO
5, R = OBu
R
R
HO
O
OH
Scheme 1. Reagents and conditions: (i) DMF, K2CO3, rt; (ii) DMAE, ZnCl2, reflux.
eluent.14,15 The structures of dyads 4 and 5 were con-
firmed by NMR spectroscopy, UV–vis and HRMS–
MALDI-TOF.
indicating monomeric species in solution. However,
the optical features of these compounds in water differ
remarkably from those in DMSO (Fig. 1). The B-bands
are slightly shifted to shorter wavelength, whereas the
Q-bands are also blue-shifted and split in two main
absorption bands at 675–680 and 630 nm. The intensity
of these bands is much lower than the Q-band in
DMSO. It is well known that aggregation in phthalo-
cyanines, due to cofacial arrangement of the macro-
cycles, gives rise to effects in the UV–vis spectra similar
to that described above.12b In our particular case, both
monomeric and lower oligomeric (characteristic band
at 630 nm) species coexist in the aqueous solution.
The 1H NMR spectra show the resonances of the
cyclodextrin protons (d: 3–6 ppm), as well as the reso-
nances due to the phthalocyanine aromatic protons (d:
7–9 ppm). For dyad 5, the resonances of the protons of
the six butoxyl groups appear as multiplets in the high
field region.
Dyads 4 and 5 give well-defined UV–vis spectra in
DMSO, with sharp Q-bands centred at 675–680 nm,
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
300
350
400
450
500
550
600
650
700
750
300
350
400
450
500
550
600
650
700
750
800
Wavelength (nm)
(a)
(b)
Wavelength (nm)
Figure 1. UV–vis spectra of dyads 4 (—) and 5 (---) at the same concentration: (a) in DMSO (4.5 lM) and (b) in water (17 lM).

A. O. Ribeiro et al. / Tetrahedron Letters 47 (2006) 6129–6132
6131
Materials: Synthesis, Structure and Function; Cambridge
University Press: Cambridge, 1998; (c) Kadish, K. M.;
Smith, K. M.; Guilard, R. In The Porphyrin Handbook;
Academic Press: San Diego, 2003; Vols. 15–20; (d) de la
Beer’s law was obeyed for 4 and 5 in DMSO at concen-
trations lower than 5 · 10À5 mol LÀ1, and the extinction
coefficients are similar to the corresponding symmetric
Pcs in the same solvent. The solubility of dyad 4a in
water was determined as being 18 mg/mL. As expected,
the water solubility of this dyad is not very different than
that of the b-CD (18.5 mg/mL).16
´
´
´
Torre, G.; Vazquez, P.; Agullo-Lopez, F.; Torres, T.
J. Mater. Chem. 1998, 8, 1671–1683; (e) de la Torre, G.;
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´
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Vazquez, P.; Agullo-Lopez, F.; Torres, T. Chem. Rev.
2004, 104, 3723–3750.
2. Castano, A. P.; Demidova, T. N.; Hamblin, M. R.
Photodiag. Photodynamic Therapy 2004, 1, 279–293.
3. Bonnet, R.; Martinez, G. Tetrahedron 2001, 57, 9513–
9547.
4. Macdonald, I. J.; Dougherty, T. J. J. Porphyrins Phthalo-
cyanines 2001, 5, 105–129.
5. Gao, L.; Qian, X.; Zhang, L.; Zhang, Y. J. Photochem.
Photobiol. B: Biol. 2001, 65, 35–39.
6. Allen, C. M.; Sharman, W. M.; Van Lier, J. E. J.
Porphyrins Phthalocyanines 2001, 5, 161–169.
7. Nyman, E. S.; Hynninen, P. H. J. Photochem. Photobiol.
B: Biol. 2004, 73, 1–18.
MS spectra17 of 4 and 5 provided a definitive proof for
their characterization. Peaks for the corresponding
molecular ions of 4 and 5 were detected when a matrix as-
sisted laser desorption ionization time-of-flight technique
(MALDI-TOF) was used. As expected, complex isotopic
distributions were observed for the molecular ions. Both
low and high resolution MS spectra were obtained. In the
last case the corresponding monoisotopic peak was
selected for comparison with the standard. In the case
of the starting compound 3, NaI was added for improv-
ing ionization results. In compounds 4 and 5 ionization
took place better in the absence of NaI.
´
8. Lang, K.; Mosinger, J.; Wagnerova, D. M. Coord. Chem.
Rev. 2004, 248, 321–350.
9. Sharman, W. M.; van Lier, J. E. J. Porphyrins Phthalo-
cyanines 2005, 9, 651–658.
10. Alvarez-Mico, X.; Calvete, M. J. F.; Hanack, M.; Ziegler,
T. Tetrahedron Lett. 2006, 47, 3283–3286.
3. Summary and outlook
11. Ruebner, A.; Yang, Z. W.; Leung, D.; Breslow, R. Proc.
Natl. Acad. Sci. U.S.A. 1999, 96, 14692–14693.
The synthesis of covalently linked phthalocyanine–
cyclodextrin dyads has been reached for the first time.
MALDI-TOF-MS has proved to be an excellent tool
for systematically studying this kind of systems, which
otherwise are difficult to characterize. Taking into
account the solubility of the dyads in water and the
individual optical (Pc) and complexation (CD) proper-
ties of both components, this family of compounds
may be of interest as water-soluble photosensitizers for
PDT, as well as for constructing supramolecular systems
for molecular recognition, with potential applications in
optical sensing. The organization at a supramolecular
level of water-soluble phthalocyanine photoactive
assemblies18a and subphthalocyanines18b is also an
important goal to be pursued.
12. (a) Tau, P.; Ogunsipe, A. O.; Maree, S.; Mearee, M. D.;
Nyokong, T. J. Porphyrins Phthalocyanines 2003, 7, 439–
446; (b) Snow, A. W. In The Porphyrin Handbook; Kadish,
K. M., Smith, K. M., Guillard, R., Eds.; Academic Press:
San Diego, 2003; Vol. 17, pp 129–176.
13. 6-O-[4-(1,2-dicyanobenzene)]-b-cyclodextrin (3): b-Cyclo-
dextrin (1, 1.96 g, 1.70 mmol) and 4-nitrophthalonitrile (2,
0.33 g, 1.87 mmol) were stirred in dry DMF (10.0 mL) at
room temperature, under a N2 atmosphere, in the presence
of K2CO3 (0.24 g, 1.70 mmol), for 12 h. Compound 3 was
precipitated by addition of acetone; it was filtered and
recrystallized from H2O/acetone (1.9 g, 86% yield). 1H
NMR (300.13 MHz, DMSO-d6) d: 8.02 (d, J = 8.8 Hz,
1H, H-6), 7.84 (d, J = 2.5 Hz, 1H, H-3), 7.56 (dd, J = 8.8,
2.5 Hz, 1H, H-5), 6.05–5.65 (m, 14H, CD–OH-2,3), 5.15–
4.84 (m, 7H, CD–H-1), 4.67–4.57 (m, 6H, CD–CH2OH),
4.10–4.00 (m, 2H, CD–CH2O–Phth), 3.60–3.40 (m, 40H,
CD–H-2,3,4,5 and CD–CH2OH—overlapped with H2O);
13C NMR (75.47 MHz, DMSO-d6) d (CD): 55.1 (CH2O–
Phth), 60.1 (CH2OH), 72.2, 72.5, 72.9, 73.2, 78.3, 79.3,
81.5; d (phthalonitrile): 102.1, 106.0, 115.9, 116.1, 116.5,
121.5 and 121.8 (CN), 135.7; MS (MALDI-TOF,
DHB+NaI), m/z: 1283.2 [M+Na]+, 1299.2 [M+K]+.
Acknowledgements
Thanks are due to CAPES–Brazil, to the Organic
Chemistry Research Unit of the University of Aveiro,
´
and Ministerio de Educacion y Ciencia, Spain (Grant
CTQ 2005-08933 BQU), for funding. A.O.R. thanks
CAPES and J.P.C.T. thanks FCT for their post-doc
grants.
HRMS
(MALDI-TOF,
PEG+NaI):
m/z
(C50H72N2O35Na): calcd: 1283.3787. Found: 1283.3808,
m/z (C50H72N2O35K): calcd: 1299.3547. Found:
1299.3561.
14. Synthesis of Zn-phthalocyanine–cyclodextrin dyads 4 and
5. Typical procedure: a solution of compound 3 (0.30 g,
0.24 mmol), 1,2-dicyanobenzene [or 4,5-dibutoxy-1,2-dicy-
anobenzene (2.4 mmol)] and ZnCl2 (0.47 g, 1.44 mmol) in
DMAE (10.0 mL), under an inert atmosphere, was stirred
at 145 ꢁC for 12 h. The product was pre-purified by silica
gel column chromatography using THF–H2O (100:0 to
90:10) as the eluent. Then, the compound was purified by a
reverse-phase chromatography using THF–H2O (90:10) as
the eluent. Dyad 4: Yield: 70 mg (18% yield); 1H NMR
(300.13 MHz, DMSO-d6) d: 9.40–9.20 (m, 6H, H-
8,11,15,18,22,25), 8.93 (d, 1H, J = 8.3 Hz, H-4), 8.82
(d, 1H, J = 2.3 Hz, H-1), 8.24–8.14 (m, 6H, H-
9,10,16,17,23,24), 7.83 (dd, J = 8.3, 2.3 Hz, 1H, H-3),
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.06.068.
References and notes
1. (a) Leznoff, C. C.; Lever, A. B. P. In Phthalocyanines:
Properties and Applications; VCH: Weinheim, 1989, 1993,
1996; Vols. 1–4; (b) McKeown, N. B. Phthalocyanine

6132
A. O. Ribeiro et al. / Tetrahedron Letters 47 (2006) 6129–6132
6.28–5.77 (m, 14H, CD–OH-2,3), 5.14–4.56 (m, 13H, CD–
CD–CH2O–Phth), 4.15–3.60 (m, 42H, CD–H-2,3,4,5
and CD–CH2OH), 2.00–1.20 (4m, 54H, –OBu); UV–
vis (DMSO): kmax (loge) = 360 (4.91), 678 (5.25) nm;
MS (MALDI-TOF, DHB), m/z: 2140.9–2148.9 [M+]
isotopic pattern. HRMS (MALDI-TOF, PEG): m/z
(C98H132N8O41Zn): calcd: 2140.7776. Found: 2140.7825.
16. Szejtli, J. Chem. Rev. 1998, 98, 1743–1753.
17. Low resolution MS spectra were taken in a MALDI-TOF
Reflex III instrument (Bruker). 2,5-Dihydroxybenzoic acid
(DBH) was used as a matrix. High resolution MS-
MALDI-TOF spectra were taken in a MALDI-TOF–
TOF instrument (Applied Biosystems 4700 Proteomic)
using PEG (MW 1500 and 2000) as internal standard.
H-1 and CD–CH2OH), 4.42–4.35 (m, 2H, CD–CH2O–
Phth), 3.96–3.57 (m, 40H, CD–H-2,3,4,5 and CD–
CH2OH); 13C NMR (75.47 MHz, DMSO-d6) d (CD):
60.0 (CD–CH2OH), 72.2, 72.5, 73.2, 81.6, 102.0; d
(phthalocyanine): 108.0, 110.0, 111.2, 116.5, 118.1, 121.4,
122.3, 129.3, 132.0, 137.7, 139.6, 152.1, 152.5, 162.0; UV–
vis (DMSO): kmax (loge) = 350 (4.80), 675 (5,31) nm; MS
(MALDI-TOF, DHB), m/z: 1708.5–1717.5 [M+] isotopic
pattern.
HRMS
(MALDI-TOF,
PEG):
m/z
(C74H84N8O35Zn): calcd: 1708.4325. Found: 1708.4381.
15. Dyad 5: Yield: 90 mg (17%); 1H NMR (300.13 MHz,
DMSO-d6) d: 9.41 (d, J = 8.0 Hz, 1H, H-4), 9.23 (d,
J = 2.2 Hz, 1H, H-1), 9.07–8.85 (m, 6H, H-
8,11,15,18,22,25), 7.97 (dd, J = 8.0, 2.2 Hz, 1H, H-3),
6.27–5.59 (m, 14H, CD–OH-2,3), 5.20–5.00 (m, 7H, CD–
H-1), 4.59–4.48 (m, 6H, CD–CH2OH), 4.27–4.18 (m, 2H,
´
18. (a) Guldi, D. M.; Gouloumis, A.; Vazquez, P.; Torres, T.;
Georgakilas, V.; Prato, M. J. Am. Chem. Soc. 2005, 127,
´
´
5811–5813; (b) Claessens, C. G.; Gonzalez-Rodrıguez, D.;
Torres, T. Chem. Rev. 2002, 102, 835–853.