Amphiphilic zinc phthalocyanine dendrimers by the Click Chemistry approach

Article abstract of DOI:10.1142/S1088424611003161

A series of new zinc phthalocyanine dendrimers with an increasing branched shell of oligoethylene glycol end groups has been synthesized. Owing to the presence of these hydrophilic termini at the dendrimer surface, all compounds are highly soluble in a wi

Full text of DOI:10.1142/S1088424611003161

Journal of Porphyrins and Phthalocyanines
J. Porphyrins Phthalocyanines 2011; 15: 364–372
DOI: 10.1142/S1088424611003161
Published at http://www.worldscinet.com/jpp/
Amphiphilic zinc phthalocyanine dendrimers by the Click
Chemistry approach
◊
Uwe Hahn* and Tomás Torres*
Departamento de Química Orgánica (Modulo 01), Facultad de Ciencias, Universidad Autónoma de Madrid,
Cantoblanco, 28049 Madrid, Spain
th
Dedicated to Professor John A. Shelnutt on the occasion of his 65 birthday
Received 22 January 2011
Accepted 13 March 2011
ABSTRACT: A series of new zinc phthalocyanine dendrimers with an increasing branched shell of
oligoethylene glycol end groups has been synthesized. Owing to the presence of these hydrophilic
termini at the dendrimer surface, all compounds are highly soluble in a wide range of solvents including
water. The monodispersity of the amphiphilic dendrimers has been unambiguously evidenced by both
NMR and MS techniques. UV-vis experiments point out that the tendency of the central phthalocyanine
chromophore to aggregate in polar protic solvents is not significantly reduced regardless of the dendritic
shell surrounding the macrocyclic chromophore.
KEYWORDS: phthalocyanines, dendrimers, Click Chemistry, hydrophilic systems.
the latter is viable when aiming at non-aggregated water-
INTRODUCTION
soluble scaffolds. Phthalocyanines as functional units have
Phthalocyanines feature some remarkable properties
also been in the centre of dendrimers [5]. Dendritic systems
originating not last from the exceptionally high absorp-
described in the literature dealing with an overall hydro-
tion that lies typically in the visible region of the UV-vis
philic character for instance with charged exterior cre-
spectrum between 630 to 750 nm [1, 2]. This so-called
ated by charged surfaces with e.g. carboxylate moieties of
Q-band is the reason that makes such chromophores
Fréchet- [6] or Newkome-type [7], or with neutral terminal
valuable in different fields of science and technology [3].
oligoethylene chains [8]. A particular feature that is pro-
The particular interest in hydrophilic phthalocyanines
vided by neutral end groups is that they offer the incentive
arises from the prospective use in fields like biomedicine
of conducting examination of the materials properties in
or photobiology for instance as photosensitizers in pho-
both common organic solvents as well as aqueous media.
todynamic therapy [2d, 4].
In line with aforementioned statements, placing den-
Similar to the synthesis of phthalocyanines in general,
dritic wedges in either peripheral or axial positions con-
the preparation of hydrophilic phthalocyanine derivatives
firms the general trend of aggregation and non-aggregated
can be accomplished by two fundamental approaches, i.e.
species, respectively. As part of the research on neutral
placing hydrophilic moieties in the peripheral or the axial
hydrophilic dendritic topologies, we have recently reported
positions, respectively. Whereas the former has been dem-
on the in-depth study of either water-soluble free-base
onstrated to not suppress the phenomenon of aggregation,
phthalocyanine- or perylene-derived dendrimers as potent
electron-donor or -acceptor moieties [9]. Non-covalent
immobilization onto single-wall carbon nanotubes

SPP full member in good standing
*
Correspondence to: Tomás Torres, email: tomas.torres@
led to the formation of nanostructures for which well-
characterized radical ion pair states were evidenced. Like-
wise, coordination of dendritic oligoethylene-terminated
uam.es, tel: +34 91497-4151, fax: +34 91497-3966 and Uwe
Hahn, email: uwe.hahn@uam.es
Copyright © 2011 World Scientific Publishing Company

AꢀPꢁIPꢁIꢂIC zIꢃC PꢁꢄꢁAꢂOCꢅAꢃIꢃꢆ DꢆꢃDꢇIꢀꢆꢇS ꢈꢅ ꢄꢁꢆ CꢂICk CꢁꢆꢀISꢄꢇꢅ APPꢇOACꢁ
365
pyridine based ligands in the axial positions of a ruthe-
Herein, we describe the high yield synthesis of a series
of monodisperse zinc phthalocyanine-centered dendrim-
ers encapsulated within an amphiphilic environment. The
corresponding phthalonitrile precursors have been pre-
pared with a triazole linking motif as introduced through
the Click Chemistry approach. Owing to the presence
of the hydrophilic triethylene glycol monomethyl ether
nium phthalocyanine centerpiece allowed for the investi-
gation by photophysical means [10]. The results provided
clear indication that these monodisperse and non-
aggregated phthalocyanines are capable of efficiently
generating singlet oxygen in organic media as reactive spe-
cies for potential applications in photodynamic therapy.
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
O
O
N
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
O
N
N
O
O
N
N
N
O
N
O
N
N
O
O
O
O
O
O
O
O
N ZnN
O
N
N
O
O
O
O
N
N
N
N
O
N
N
N
N
O
O
N
O
N
N ZnN
N
N
O
O
O
O
O
O
O
N
N
O
O
O
N
N
O
N
N
O
N
O
O
O
O
O
O
O
O
O
O
O
N N
O
O
O
N
O
ZnPc1
ZnPc2
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
O
O
N
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
N
N
N
N
N
N
O
N
Zn
N
O
O
O
N
N
O
O
O
O
N
N
O
O
O
O
N
O
O
O
O
O
O
O
O
O
O
O
O
N
O
O
O
O
O
O
O
N
O
O
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
ZnPc3
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Chart 1. Chemical structures of amphiphilic zinc phthalocyanine dendrimers ZnPc1–3
Copyright © 2011 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2011; 15: 365–372

366
U. ꢁAꢁꢃ AꢃD ꢄ. ꢄOꢇꢇꢆS
peripheral groups, examination of the basic photophysi-
cal properties in both common organic solvents as well
as aqueous media became attainable. The difference
between this series of zinc phthalocyanines and structur-
ally related free-base phthalocyanines will be discussed.
added and the aqueous phase extracted several times with
CH Cl . The organic phase was washed once with brine
2
2
and water, dried with Na SO and the solvent removed
2
4
under reduced pressure. The crude product was purified
as outlined in the following text.
Compound PN1. Prepared from dendritic azide 4
(
250.0 mg, 0.546 mmol), 3 (99.5 mg, 0.546 mmol),
sodium ascorbate (10.8 mg, 55 µmol) and CuSO4
6.8 mg, 27.3 µmol) in water and THF (v/v 1:1, 10 mL).
Gradient flash column chromatography (SiO , CH Cl /
EXPERIMENTAL
(
General
2
2
2
MeOH 100:1 to 20:1) gave PN1 as a highly viscous liq-
All reagents used were purchased from commercial
sources without further purification. Dendritic azides 4–6
were prepared according to a procedure as previously
described in the literature [9, 11]. Solvents were dried
using standard techniques prior to use. All reactions were
performed in standard glassware under an inert argon
atmosphere. Reactions were monitored by thin-layer
chromatography using TLC plates precoated with silica
gel 60F254 (Merck). Column chromatography was carried
out on Merck silica gel 60, 40–63 µm (230–400 mesh).
Gel permeation chromatography was performed using
Biorad, Biobeads SX-1 and dichloromethane as eluent.
1
uid (341.1 mg, 98%). H NMR (300 MHz, CDCl ): δ,
3
ppm 3.38 (s, 6 H, CH ), 3.52 (m, 4 H, CH ), 3.60–3.75
3
2
(
m, 12 H, CH ), 3.82 (t, J = 5 Hz, 4 H, CH ), 4.06 (t, J =
2
2
5
6
7
Hz, 4 H, CH ), 5.24 (s, 2 H, CH ), 5.40 (s, 2 H, CH ),
2 2 2
.01 (d, J = 2 Hz, 2 H, H ), 6.47 (t, J = 2 Hz, 1 H, H ),
ar
ar
.32 (m, 2 H; H ), 7.54 (s, 1 H; Htriazole), 7.71 (dd, J = 3
ar
1
Hz, J = 1 Hz, 1 H; H ). H NMR (300 MHz, DMSO-d ):
ar
6
δ, ppm 3.30 (s, 6 H, CH ), 3.41 (m, 4 H, CH ), 3.44–3.60
3
2
(
m, 12 H, CH ), 3.70 (t, J = 5 Hz, 4 H, CH ), 4.03 (t, J = 5
2
2
Hz, 4 H, CH ), 5.33 (s, 2 H, CH ), 5.51 (s, 2 H, CH ), 6.45
2
2
2
(
d, J = 2 Hz, 2 H, H ), 6.47 (t, J = 2 Hz, 1 H, H ), 7.56
a
r
a
r
(
m, 2 H; H ), 7.88 (s, 1 H; Htriazole), 8.06 (dd, J = 3 Hz,
1
13
ar
H and C NMR spectra were recorded using Bruker
1
3
J = 1 Hz, 1 H; H ). C NMR (100 MHz, CDCl ): δ, ppm
ar
3
Avance 300 MHz instruments; the solvent signal was
used for internal calibration. Mass spectra were recorded
using a MS-50 from A.E.I., Manchester, GB (EI), a
Concept 1H from Kratos Analytical Ltd., Manchester,
GB (FAB), and a MALDI-TofSpec-E from MICRO-
MASS, GB (MALDI). UV-vis spectra were recorded on
a Hewlett-Packard 8453 diode-array spectrophotometer
instrument.
5
1
1
4.1, 58.7, 62.3, 67.4, 69.3, 70.3, 70.4, 70.5, 71.7, 101.3,
06.9, 107.4, 115.0, 115.4, 117.1, 119.4, 120.1, 123.3,
35.1, 136.0, 142.0, 160.2, 161.1. MALDI-TOF-MS: m/z
+
(%) 640.3 ([M + H] , 100).
Compound PN2. Prepared from dendritic azide 5
470.0 mg, 0.473 mmol), 3 (86.1 mg, 0.473 mmol),
(
sodium ascorbate (9.4 mg, 47 µmol) and CuSO (5.9 mg,
4
2
4 µmol) in water and THF (v/v 1:1, 10 mL). Gradient
flash column chromatography (SiO , CH Cl /MeOH
2
2
2
Synthesis
1
00:1 to 20:1) gave PN2 as a highly viscous liquid
1
Compound 3. A solution of 4-nitrophthalonitrile
(513.7 mg, 92%). H NMR (300 MHz, CDCl ): δ, ppm
3.32 (s, 12 H, CH ), 3.52 (m, 8 H, CH ), 3.60–3.75 (m,
3
(1, 300 mg, 1.73 mmol), 2-propyn-1-ol (2, 97 mg, 1.73
3
2
mmol) and K CO (502 mg, 3.64 mmol) in N,N’-dim-
24 H, CH ), 3.79 (t, J = 5 Hz, 8 H, CH ), 4.05 (t, J = 5 Hz,
2
3
2
2
ethylformamide (10 mL) was heated to reflux for 15
h. After cooling to rt, the mixture was poured onto ice
water and extracted with CH Cl . The organic phase was
8 H, CH ), 4.88 (s, 4 H, CH ), 5.22 (s, 2 H, CH ), 5.40
2 2 2
(s, 2 H, CH ), 6.38 (t, J = 2 Hz, 2 H, H ), 6.40 (d, J =
2
ar
2 Hz, 2 H, H ), 6.48–6.52 (m, 5 H, H ), 7.28–7.37 (m,
2
2
ar
ar
washed several times with water, dried with Na SO and
the solvent removed under reduced pressure. Purification
2 H; H ), 7.58 (s, 1 H; Htriazole), 7.66 (dd, J = 3 Hz, J = 1
2
4
ar
1
3
Hz, 1 H; H ). C NMR (100 MHz, CDCl ): δ, ppm 54.1,
ar
3
by flash column chromatography (SiO ; CH Cl ) gave 3
58.8, 62.4, 67.4, 69.5, 69.8, 70.3, 70.4, 70.6, 71.7, 101.0,
102.0, 105.9, 107.1, 107.4, 115.1, 115.5, 117.1, 119.6,
120.1, 123.5, 135.2, 136.3, 138.6, 142.1, 160.0, 160.2,
2
2
2
1
as colorless solid (298.9 mg, 95%). H NMR (300 MHz,
CDCl ): δ, ppm 2.61 (t, J = 2 Hz, 1 H, C≡CH), 4.81 (d,
3
+
J = 2 Hz, 2 H, CH ), 7.29 (dd, J = 9 Hz, J = 3 Hz, 1 H,
161.2. MALDI-TOF-MS: m/z (%) 1198.5 ([M + Na] ,
2
+
H ), 7.36 (d, J = 3 Hz, 1 H, H ), 7.74 (d, J = 9 Hz, 1 H,
32), 1176.5 ([M + H] , 100).
ar
ar
1
3
H ). C NMR (100 MHz, CDCl ): δ, ppm 56.7, 76.3,
Compound PN3. Prepared from dendritic azide 6
(330.0 mg, 160 µmol), 3 (32.0 mg, 176 µmol), sodium
ar
3
7
1
7.9, 108.4, 115.2, 115.6, 117.6, 120.0, 120.2, 135.3,
+
60.5. EI-MS: m/z (%) 181.0 ([M] , 100).
ascorbate (3.2 mg, 16 µmol) and CuSO (2.0 mg, 8 µmol)
4
General procedure for the preparation of the den-
in water and THF (v/v 1:1, 10 mL). Gradient flash column
chromatography (SiO , CH Cl /MeOH 100:1 to 15:1)
dronized phthalonitriles PN1–3. To a solution of the
corresponding dendritic azide 4–6 (1 equiv.) and 3 (1
or 1.1 equiv.) in a mixture of water and THF (v/v 1:1)
2
2
2
gave PN3 as a highly viscous liquid (338.0 mg, 94%).
1
H NMR (300 MHz, CDCl ): δ, ppm 3.37 (s, 24 H, CH ),
3
3
was added sodium ascorbate (0.1 equiv.) and then CuSO
3.55 (m, 16 H, CH ), 3.58–3.76 (m, 48 H, CH ), 3.86 (t,
4
2
2
-1
(
0.05 equiv.) dissolved in water (c = 0.1 mmol mL ).
J = 5 Hz, 16 H, CH ), 4.10 (t, J = 5 Hz, 16 H, CH ), 4.96
2 2
The resulting mixture was stirred at rt for 2 d. Water was
(s, 12 H, CH ), 5.19 (s, 2 H, CH ), 5.46 (s, 2 H, CH ), 6.44
2
2
2
Copyright © 2011 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2011; 15: 366–372

AꢀPꢁIPꢁIꢂIC zIꢃC PꢁꢄꢁAꢂOCꢅAꢃIꢃꢆ DꢆꢃDꢇIꢀꢆꢇS ꢈꢅ ꢄꢁꢆ CꢂICk CꢁꢆꢀISꢄꢇꢅ APPꢇOACꢁ
367
(
t, J = 2 Hz, 6 H, H ), 6.55 (t, J = 2 Hz, 2 H, H ), 6.58–6.64
(br m, 4 H, H ), 8.50 (br s, 4 H, Htriazole), 9.04 (br m, 4 H,
ar
ar
Pc
(
7
m, 13 H, H ), 7.27–7.37 (m, 2 H; H ), 7.56 (s, 1 H; Htriazole),
H ), 9.28 (br m, 4 H, H ). MALDI-TOF-MS: m/z (%)
9061 ([M + H] , 100).
ar
ar
Pc
Pc
13
+
.68 (dd, J = 3 Hz, J = 1 Hz, 1 H; H ). C NMR (100
ar
MHz, CDCl ): δ, ppm 54.1, 58.9, 62.4, 67.4, 69.6, 69.9,
3
7
1
1
0.5, 70.6, 70.7, 71.8, 101.0, 101.6, 102.2, 106.0, 106.2,
07.1, 107.5, 115.1, 115.6, 117.2, 119.5, 120.1, 123.5,
RESULTS AND DISCUSSION
35.2, 136.4, 138.8, 138.9, 142.1, 160.0, 160.2, 161.2.
+
MALDI-TOF-MS: m/z (%) 2272.0 ([M + H] , 100).
General procedure for the preparation of the den-
dritic zinc phthalocyanines ZnPc1–3. A mixture of den-
dritic phthalonitrile PN1–3 (4 equiv.) and zinc acetate (1.1
equiv.) in dimethylaminoethanol (DMAE) was heated to
reflux for 18 h. After this time, the intense green colored
solution was cooled to rt and the solvent evaporated to
dryness. The residue was dissolved in a small quantity of
CH Cl , filtered and purified by size exclusion chroma-
Synthesis
Dendrimers are synthetic macromolecules with a
tree-like well-defined branched structure [12, 13]. The
modification of these peculiar and most often flexible
architectures has been an active area of research through-
out the last two decades [12, 13]. By far the most often
used method for the construction of dendritic phtha-
locyanines is the approach via pre-functionalization
of the corresponding phthalontrile by a fractal species
which is subsequently subjected to cyclotetramerization
[5–8]. This way, the synthesis of peripherally substituted
phthalocyanine dendrimers can be achieved as has been
demonstrated by numerous examples. As mentioned
before, the rational design of dendritic ligands bearing a
single functional unit in the focal point can be used for
the orthogonal assembly onto e.g. ruthenium or silicon
phthalocyanines. However, also the postmodification of
a previously synthesized phthalocyanine precursor by
dendritic units could be envisaged. Nonetheless, this
approach has been considered to a lesser degree presum-
ably as a result of the problem of steric hindrance that
might be encountered upon functionalization with the
first dendrons. This might ultimately hamper the access
of the residual functional units and will in most cases
lead to ill-defined dendrimers rather than monodisperse
nanoarchitectures.
The strategy pursued herein relies on pre-functional-
izing the phthalonitrile with the corresponding branched
moiety. The covalent linker chosen to covalently con-
nect the two precursors is the triazole ring structure. This
approach is well-known as Click Chemistry and origi-
nates from the reaction of an alkyne and an azide cata-
lyzed by copper(II) ions and has first been introduced and
exploited in the 1970s by Huisgen [14]. This particular
motif has experienced a dramatic revival during recent
years not last due to the fact that target structures can
be produced in a vast number of cases in up to quantita-
tive yields. It is not surprising that the “click” methodol-
ogy has also been used for the construction of regularly
shaped dendritic nanoarchitectures [15]. Likewise, this
approach has also been employed in the modification of
phthalocyanines [16].
2
2
tography on Biobeads, BioRad S-X1 (eluent: CH Cl ).
2
2
Compound ZnPc1. Prepared from dendritic phthalo-
nitrile PN1 (54.2 mg, 84.7 µmol) and zinc acetate (5.1 mg,
2
3.3 µmol) in DMAE (1.5 mL). ZnPc1 was obtained as
1
intense green solid (22.4 mg, 37%). H NMR (300 MHz,
DMSO-d ): δ, ppm 3.33 (s, 24 H, CH ), 3.39 (m, 16 H,
6
3
CH ), 3.44–3.56 (m, 48 H, CH ), 3.68 (t, J = 5 Hz, 16 H,
2
2
CH ), 4.05 (t, J = 5 Hz, 16 H, CH ), 5.63 (s, 8 H, CH ),
2
2
2
5
.72 (s, 8 H, CH ), 6.49 (t, J = 2 Hz, 4 H, H ), 6.59 (t,
2
a
r
J = 2 Hz, 8 H, H ), 7.70 (m, 4 H, H ), 8.56 (s, 4H, Htriazole),
ar
Pc
1
3
8
.73 (m, 4 H, H ), 8.99 (m, 4 H, H ). C NMR (100
Pc Pc
MHz, CDCl ): δ, ppm 53.0, 58.0, 62.0, 67.2, 68.8, 69.6,
3
6
9.7, 69.9, 71.2, 100.5, 106 (br, C ), 106.7, 106.8, 117
Pc
(
br, C ), 123 (br, C ), 125.0, 131 (br, C ), 131.2, 138.1,
Pc Pc Pc
1
40 (br, C ), 143.2, 151–153 (br, C ), 159.9. MALDI-
Pc Pc
+
TOF-MS: m/z (%) 2621.1 ([M + H] , 44).
Compound ZnPc2. Prepared from dendritic phthalo-
nitrile PN2 (183.0 mg, 155.6 µmol) and zinc acetate (9.4
mg, 42.8 µmol) in DMAE (1.0 mL). ZnPc2 was obtained
1
as intense green highly viscous liquid (78.5 mg, 42%). H
NMR (300 MHz, DMSO-d ): δ, ppm 3.34 (s, 48 H, CH ),
6
3
3
.39 (m, 32 H, CH ), 3.45–3.57 (m, 96 H, CH ), 3.70
2
2
(
br s, 32 H, CH ), 4.05 (br s, 32 H, CH ), 5.00 (m, 16 H,
2
2
CH ), 5.67 (s, 8 H, CH ), 5.78 (s, 8 H, CH ), 6.44 (m, 8
2
2
2
H, H ), 6.55 (m, 16 H, H ), 6.65 (s, 4 H, H ), 6.69 (m, 8
ar
ar
ar
H, H ), 7.88 (br s, 4 H, H ), 8.58 (s, 4 H, Htriazole), 9.04
ar
Pc
1
3
(
br s, 4 H, H ), 9.28 (br s, 4 H, H ). C NMR (100 MHz,
Pc Pc
CDCl ): δ, ppm 53.0, 58.0, 62.2, 67.1, 68.8, 69.2, 69.5,
3
6
1
1
9.7, 69.9, 71.2, 100.3, 101.4, 105.9, 106.0, 106 (br, CPc),
07.1, 118 (br, C ), 123 (br, C ), 125.0, 131 (br, C ),
Pc
Pc
Pc
31.3, 138.1, 138.9, 139.0, 140 (br, C ), 143.1, 151–153
Pc
(
4
br, C ), 159.5, 159.6, 159.7. MALDI-TOF-MS: m/z (%)
766.1 ([M + H] , 100).
Pc
+
Compound ZnPc3. Prepared from dendritic phtha-
lonitrile PN3 (130.0 mg, 60.0 µmol) and zinc acetate
3.8 mg, 17.3 µmol) in DMAE (1.0 mL). ZnPc3 was
obtained as intense green highly viscous liquid (51.3 mg,
By implementing the triazole moiety as linker between
the dendrimer part and the central macrocycle, a consid-
erable expansion of the dendrimer structures has been
obtained. However, the triazole unit itself has no sig-
nificant impact on the materials properties of the target
molecules as will be shown below. Such hollow cavities
might be especially interesting for hosting small guest
(
1
3
9
9%). H NMR (300 MHz, DMSO-d ): δ, ppm 3.16 (br s,
6
6 H, CH ), 3.22–3.74 (br m, 320 H, CH ), 4.01 (br s, 64
3
2
H, CH ), 4.97 (br s, 48 H, CH ), 5.58 (br m, 16 H, CH ),
2
2
2
6
.42 (br m, 24 H, H ), 6.43–6.73 (m, 60 H, H ), 7.80
a
r
a
r
Copyright © 2011 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2011; 15: 367–372

368
U. ꢁAꢁꢃ AꢃD ꢄ. ꢄOꢇꢇꢆS
molecules within the interior of the flexible dendrimer
structure which have demonstrated their value when
aiming at for instance drug delivery [17]. In particular
lipophilic guest molecules could penetrate through the
uncharged dendrimer shell to be accommodated close
to the hydrophobic centre of the overall amphiphilic
structure.
that this copper ion-catalyzed reaction led to the very
high yielding or virtually quantitative formation of the
dendritic phthalonitriles PN1–3 irrespective of the den-
dron size. With the dendritically modified phthalonitriles
PN1–3 of first to third generation in hands, the corre-
sponding cyclotetramerizations have been conducted in
the presence of zinc acetate as metal template. The tar-
get dendrimers ZnPc1–3 have hence been obtained as
intense green products in reasonably good yields of 37 to
42% for the preparation of phthalocyanines after purifi-
cation by size exclusion chromatography.
The first precursor PN1 bearing the terminal alkyne
moiety has been obtained in 95% yield through ipso-
substitution of 4-nitrophthalonitrile (1) with propargyl
alcohol (2) in the presence of K CO as base. On the
2
3
other hand, dendrons carrying triethylene glycol monom-
ethyl ether end groups and a benzylic bromide function
at the centre were obtained following a literature proce-
dure [8–11]. Subjection to a reaction with sodium azide
then readily formed the corresponding azide derivatives
Structural characterization
Owing to the appended oligoethylene glycol peripheral
moieties present in all fractal structures studied herein,
it turned out that the entire series showed good solubil-
ity in common organic solvents such as CH Cl , CHCl
or THF, thus facilitating spectroscopic characterization
by NMR, UV-vis, and MS techniques. Furthermore, all
4
–6 in quantitative yields [9]. The aforementioned highly
reliable and high yielding Click Chemistry reaction under
formation of a triazole ring structure was then performed
for all azides of different generations. Indeed, it was found
2
2
3
(
i)
(ii)
O N
2
CN
CN
O
CN
CN
N
N
N
O
CN
CN
1
3
PN1-3
Scheme 1. Preparation of dendritic phthalonitriles PN1–3 with terminal oligoethylene glycol chains (light spheres represent
polyarylether branching units, dark spheres represent triethylene glycol monoethyl ether end groups). Reagents and conditions:
(
i) 2-propyn-1-ol (2), K CO , DMF, reflux, 15 h (95%); (ii) dendritic azide 4–6, sodium ascorbate (10 mol.%), CuSO (5 mol.%),
2
3
4
THF - H O (v/v 1:1), rt, 2d (PN1: 98%, PN2: 92%, PN3: 94%)
2
N N
N
O
N
N
N
N
N
N
N
N
(i)
O
CN
CN
N
O
N Zn N
N
N
O
N
N
N
PN1-3
N
O
N
N N
ZnPc1-3
Scheme 2. Preparation of zinc phthalocyanine dendrimers ZnPc1–3 with terminal oligoethylene glycol chains (light spheres repre-
sent polyarylether branching units, dark spheres represent triethylene glycol monoethyl ether end groups). Reagents and conditions:
(
i) zinc acetate, DMAE, reflux, 18 h (ZnPc1: 37%, ZnPc2: 42%, ZnPc3: 39%)
Copyright © 2011 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2011; 15: 368–372

AꢀPꢁIPꢁIꢂIC zIꢃC PꢁꢄꢁAꢂOCꢅAꢃIꢃꢆ DꢆꢃDꢇIꢀꢆꢇS ꢈꢅ ꢄꢁꢆ CꢂICk CꢁꢆꢀISꢄꢇꢅ APPꢇOACꢁ
369
dendrimers ZnPc1–3 could be readily dissolved in water.
to the corresponding phthalonitrile. Similar effects have
been found for the respective larger second and third gen-
eration dendrimers. It could be added that a significant
broadening has been observed on passing from ZnPc1 to
The increasing amount of hydrophilic surface moieties
leads to the creation of an amphiphilic environment in
which the hydrophobic core is embedded in the interior,
thus generating a shielding effect. However, it is impor-
tant to note that solubilisation of ZnPc1 in aqueous media
only proceeds slowly and no high concentrations can be
reached. Elucidation of both series of phthalonitrile and
phthalocyanine structures was easily possible as all sig-
nals of the various parts of the dendrimers appeared in
specific regions and did thus assist the assignment of
sets of signals. Figure 1 displays the proton spectra of
1
ZnPc3 in the H NMR spectra. This observation could be
ascribed to significant changes in the relaxation time T2
as a result of the large increase in molecular weight. This
is a typical phenomenon frequently observed for large
1
3
dendritic assemblies. The respective C NMR spectra
confirmed the general trend and showed analogous shifts
for the corresponding carbon atoms.
Structural elucidation of both series PN1–3 and
ZnPc1–3 has also been conducted under the use of mass
spectrometry. The dendritic phthalonitriles gave clean
spectra as obtained by the MALDI-TOF-MS technique
with the target mass as base peak in all cases. Likewise,
also the structures of the branched zinc phthalocyanines
were unequivocally determined by their corresponding
MALDI-TOF-MS spectra. The spectra gave clear evi-
dence with the observed signals that could be explic-
itly ascribed to the ion mass peaks of ZnPc1–3. This is
in strong contrast with findings reported in the litera-
ture for structurally related free-base phthalocyanines
[8b]. In these cases, the MS spectra as obtained under
similar conditions as for ZnPc1–3 gave rise to clus-
ters and aggregates. Moreover, the significant cleavage
of remote benzylic sites as mentioned by McKeown
et al. does not coincide with the results as observed for
ZnPc1–3.
PN1 and ZnPc1 as recorded in DMSO-d thus allowing
6
direct comparison of the corresponding shifts. Accord-
ingly, apart from the multiplets at 7.70, 8.73, and 8.99
ppm that can be recognized as fingerprints for the various
inseparable phthalocyanine isomers as formed during the
cyclotetramerization reaction, the single signals obtained
for the triazole protons are indicative of the structural
integrity. Upon metal-assisted phthalocyanine formation,
these protons are shifted by approx. 0.2 ppm as a result of
the strong influence as exerted by the macrocycle. Also
the two sets of methylene protons adjacent to the triazole
motif encounter similar shifts of 0.2 or 0.3 ppm shifts.
Furthermore, the aromatic signals of the inner shell of
the dendritic branches are inverted in appearance. All the
other protons that are not in close proximity to the phthal-
ocyanine core do not experience a strong shift rather than
showing minor changes in chemical shifts with respect
1
Fig. 1. H NMR spectra of (a) PN1 and (b) ZnPc1 recorded in DMSO-d
6
Copyright © 2011 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2011; 15: 369–372

370
U. ꢁAꢁꢃ AꢃD ꢄ. ꢄOꢇꢇꢆS
Fig. 2. MALDI-TOF-MS spectra of (a) ZnPc1, (b) ZnPc2 and (c) ZnPc3
UV-visible absorption spectroscopy
The absorption spectra of the series of
ZnPc1–3 dendrimers have been recorded
using three categories of solvents, i.e. in
chloroform (Fig. 3a) as moderately polar
solvent, in THF (Fig. 3b) as polar aprotic
solvent and in water (Fig. 3c) as polar pro-
tic environment. For the former two, the
spectral features are almost identical for
the respective dendritic generation and are
dominated by well-defined Q-bands cen-
tred at λmax = 682 nm in chloroform and
λmax = 678 nm in THF, respectively. How-
ever, it is important to note two trends: (i)
lower Q-band absorption coefficients in
chloroform when compared to THF and
(
ii) decreasing absorption upon going to
larger generation species in a given sol-
vent. These effects presumably result from
a certain degree of intra- or intermolecu-
lar aggregation that is noticeable between
ZnPc1 and ZnPc2 and more pronounced
when switching to ZnPc3. The two addi-
tional maxima located at around λmax
=
6
82 nm and 280 nm can be assigned to the
B-band and the dimethoxybenzene moi-
eties of the dendrimer skeleton. Whereas
the former remains at constant intensity
the latter increases in intensity on passing
to the larger generation species. Another
feature that indicates intra- or intermo-
lecular aggregation is the appearance of
the rather broad absorption in the region
between B- and Q-band that again ascends
with increasing dendrimer generation.
Fig. 3. UV-vis spectra of ZnPc1–3 in (a) CHCl , (b) THF and (c) H O
3
2
Copyright © 2011 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2011; 15: 370–372

AꢀPꢁIPꢁIꢂIC zIꢃC PꢁꢄꢁAꢂOCꢅAꢃIꢃꢆ DꢆꢃDꢇIꢀꢆꢇS ꢈꢅ ꢄꢁꢆ CꢂICk CꢁꢆꢀISꢄꢇꢅ APPꢇOACꢁ
371
As expected, the behavior drastically changes upon
The considerable expansion of the dendrimer interior
as obtained by the triazole spacer moieties may lead to
the formation of hollow cavities that might be exploited
in e.g. drug delivery applications. The overall amphiphilic
structure as generated by the outer water-soluble groups
and the internal lipophilic phthalocyanine core could
assist the accommodation of lipophilic guest molecules.
Likewise, the preparation of asymmetric dendrimers car-
rying a specific function in a predetermined position is
currently underway. With this implemented functional
moiety the use in specific bioorganic or medicinal appli-
cations can be envisaged thereby e.g. addressing specific
target positions in cells.
switching to polar protic medium. The spectra in water
show many facets archetypical of aggregation phenom-
ena in this kind of dyes, i.e. broad Q-bands with lower
absorption coefficients than the typical monomer phtha-
locyanines. This phenomenon results from the coplanar
association under formation of dimers, trimers, and higher
oligomers, respectively [24]. Also imparting bulky sub-
stituents in the peripheral positions can help to reduce the
formation of such aggregates, but still aggregation has to
be considered. Accordingly, a broadening of the Q-band
with maxima at λmax = 641 and 684 nm, respectively,
has been obtained with significant decrease in intensity
as a result of the aggregation phenomenon. The B-band
for the whole series experiences a slight hypsochromi-
cal shift to be centred at λmax = 345 nm. As observed for
the measurements conducted in organic solutions, also
in water an additional broad band in the region between
B- and Q-band appears thus giving further proof for a
pronounced aggregation behavior in the case of the higher
generation dendrimer derivatives. It can be added that for
the three dendritic species presented herein aggregation
is an effect that apperas to be generation-independent,
i.e. the Q-band has basically same intensities along the
whole series. On the contrary, the absorption coefficients
of the dendritic branches remain virtually unaffected and
increase in intensity within ZnPc1–3.
Acknowledgements
The MEC (Spain) is gratefully acknowledged for
financial support and a “Ramón y Cajal” research con-
tract to U.H.
REFERENCES
1. a) Handbook of Porphyrin Science, Vol. 1–5, Kadish
KM, Smith KM and Guilard R. (Eds.) World Sci-
entific: Singapore, 2010. b) Handbook of Porphy-
rins and Phthalocyanines, Vol. 16–20, Kadish KM,
Smith KM and Guilard R. (Eds.) Academic Press:
New York, 1999.
2. a) Bottari G, de la Torre G and Torres T. Chem. Rev.
2
010; 110: 6768–6816. b) Torres T. Angew. Chem.
CONCLUSION
Int. Ed. 2006; 45: 2834–2837. c) Claessens CG, de la
Torre G and Torres T Chem. Commun. 2007; 2000–
2015. d) Claessens CG, Hahn U and Torres T. Chem.
Rec. 2008; 8: 75–97. e) de la Torre G, Bottari G, Hahn
U and Torres T. Struct. Bond. 2010; 135: 1–44.
A new series of monodisperse zinc phthalocyanine-
centered dendrimers ZnPc1–3 encapsulated within an
amphiphilic environment has been presented. Dendritic
modification of the phthalonitrile precursor was accom-
plished through the Click Chemistry approach under
formation of the triazole ring structure motif. These
dendritic benzodinitriles as obtained in excellent yields
for all steps of the synthetic protocol were then involved
in cyclotetramerization reactions to furnish the three
monodisperse ZnPc1–3 dendrimers in good yields for
such macrocyclic compounds. All structures have been
unequivocally identified by both NMR and MS tech-
niques. Owing to the presence of the hydrophilic trieth-
ylene glycol monomethyl ether peripheral groups, the
whole series of dendrimers is soluble in both common
organic solvents and aqueous media. UV-vis absorption
spectra in different types of solvents evidenced in organic
solvents the typical features as usually obtained for inde-
pendent phthalocyanines. However, along the series the
Q-band absorption coefficients decreased thus indicating
a certain degree of intra- or intermolecular aggregation.
Experiments conducted in aqueous medium confirm the
general trend that steric isolation of the macrocycle by
bulky peripheral substituents is not effective in polar pro-
tic solvents as shown by broad Q-bands with significant
lower absorption coefficients.
3. Rio Y, Rodríguez-Morgade MS and Torres T. Org.
Biomol. Chem. 2008; 6: 1877–1894.
4. a) Handbook of Porphyrin Science, Vol. 4, Kadish
KM, Smith KM and Guilard R. (Eds.) World Scien-
tific: Singapore, 2010.
5. Li WS and Aida T. Chem. Rev. 2009; 109:
6047–6076.
6. a) Nishiyama N, Morimoto Y, Jang WD and
Kataoka K. Adv. Drug Deliver. Rev. 2009; 61: 327–
338. b) Ng DKP. C. R. Chimie 2003; 6: 903–910.
c) Nishiyama N, Iriyama A, Jang WD, Miyata K,
Itaka K, Inoue Y, Takahashi H, Yanagi Y, Tamaki Y,
Koyama H and Kataoka K. Nat. Mater. 2005; 4: 934–
941. d) Choi CF, Huang JD, Lo PC, Fong WP and
Ng DKP. Org. Biomol. Chem. 2008; 6: 2173–2181.
7. a) Kimura M, Sugihara Y, Muto T, Hanabusa K,
Shirai H and Kobayashi N. Chem. Eur. J. 1999; 5:
3495–3500. b) Kimura M, Nakada K, Yamaguchi
Y, Hanabusa K, Shirai H and Kobayashi N. Chem.
Commun. 1997; 1215–1216.
8. a) Brewis M, Helliwell M, McKeown NB, Reynolds
S and Shawcross A. Tetrahedron Lett. 2001; 42:
Copyright © 2011 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2011; 15: 371–372

372
U. ꢁAꢁꢃ AꢃD ꢄ. ꢄOꢇꢇꢆS
8
13–816. b) Brewis M, Helliwell M and McKeown
and Moorhouse AD. Chem. Soc. Rev. 2007; 36:
1249–1262. c) Huisgen R. Angew. Chem. Int. Ed.
1963; 2: 565–598.
NB. Tetrahedron 2003; 59: 3863–3872.
. Hahn U, Engmann S, Oelsner C, Ehli C, Guldi
DM and Torres T. J. Am. Chem. Soc. 2010; 132:
9
15. a) Franc G and Kakkar AK. Chem. Soc. Rev. 2010;
39: 1536–1544. b) Villalonga-Barber C, Micha-
Screttas M, Steele BR, Georgopoulos A and Demet-
zos C. Curr. Top. Med. Chem. 2008; 8: 1294–1309.
16. For recent examples see: a) Campidelli S, Balles-
teros B, Filorama A, Diaz Diaz D, de la Torre G,
Torres T, Rahman GMA, Ehli C, Kiessling D,
Werner F, Sgobba V, Guldi DM, Cioffi C, Prato M
and Bourgoin J-P. J. Am. Chem. Soc. 2008; 130:
11503–11509. b) Juricek M, Kouwer PHJ, Rehak J,
Sly J and RowanAE. J. Org. Chem. 2009; 74: 21–25.
c)ChenX,ThomasJ,GangopadhyayP,NorwoodRA,
Peyghambarian N and McGrath DV. J. Am. Chem.
Soc. 2009; 131: 13840–13843. d) Albert-Seifried S,
Finlayson CE, Laquai F, Friend RH, Swager TM,
Kouwer PHJ, Juricek M, Kitto HJ, Valster S, Nolte
RJM and Rowan AE. Chem. Eur. J. 2010; 16:
10021–10029.
6
392–6401.
1
1
1
0. Hahn U, Setaro F, Ragàs X, Nonell S, Gray-Weale
A and Torres T. Phys. Chem. Chem. Phys. 2011; 13:
3
1. Stephan H, Juran S, Born K, Comba P, Geipel G,
385–3393.
Hahn U, Werner N and Vögtle F. New J. Chem.
2
008; 32: 2016–2022.
2. a) Newkome GR, Moorefield CN and Vögtle F.
Dendrimers and Dendrons, Wiley-VCH: Wein-
heim, 2001. b) Dendrimers and Other Dendritic
Polymers, Fréchet JMJ and Tomalia DA. (Eds.)
John Wiley & Sons: Chichester, 2001. c) Vögtle F,
Richardt G and Werner N. Dendrimer Chemistry,
Wiley-VCH: Weinheim, 2009.
1
1
3. a) Topics in Current Chemistry, Dendrimers V, Vol.
2
28 (and previous volumes I-IV), Schalley CA
and Vögtle F. (Eds.) Springer: Heidelberg, 2003.
b) Astruc D, Boisselier E and Ornelas C. Chem.
Rev. 2010; 110: 1857–1959. c) Newkome GR and
Shreiner CD. Polymer 2008; 49: 1–173.
17. a) Astruc D, Boisselier E and Ornelas C. Chem. Rev.
2010; 110: 1857–1959. b) MenjogeAR, Kannan RM
and Tomalia DA. Drug Discov. Today 2010; 15:
171–185. c) Medina SH and El-Sayed MEH. Chem.
Rev. 2009; 109: 3141–3157.
4. a) Kolb HC, Finn MG and Sharpless KB. Angew.
Chem. Int. Ed. 2001; 40: 2004–2021. b) Moses JE
Copyright © 2011 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2011; 15: 372–372