Cyclen derivatives with two trans-methylnitrophenolic pendant arms: A structural study of their copper(ii) and zinc(ii) complexes

Article abstract of DOI:10.1039/c2dt32363j

Two new cyclen derivatives, H₂do2nph and H₂cb-do2nph, containing two trans-2-methyl-4-nitrophenol pendant arms and the latter including also an ethylene cross-bridge, were prepared in good yields using the bisaminal synthetic route. The two ligands were studied comparatively regarding their metal complexation behaviour. The copper(ii) and zinc(ii) complexes of H₂do2nph and H₂cb-do2nph were studied in dimethylsulfoxide-water (9:1 v/v) solution by a range of spectroscopic techniques. Copper(ii) complexes were also studied in solid state by X-ray single crystal diffraction. These studies showed that the copper(ii) and zinc(ii) complexes of H₂do2nph exhibited a distorted square pyramidal coordination environment with the four nitrogen atoms of the cyclen ring defining the basal plane, and that one of the nitrophenolate arms did not coordinate to the metal, independently of its protonation state. On the other hand, depending on the protonation state of one of the nitrophenolic arms, the cross-bridged derivative forms copper(ii) complexes with distorted square pyramidal or octahedral geometries with one or two arms coordinated to the metal centre, respectively. In the complex with distorted octahedral geometry, the two phenolic oxygen atoms are coordinated to the metal centre in a cis-fashion. Acid-assisted dissociation assays in 1 mol dm^-3 HCl DMSO-H ₂O (9:1 v/v) solution at 298.2 K allowed one to determine the half-life of both copper(ii) complexes, which is lower for the derivative without a cross-bridge as expected, while for the other one it is quite high and in line with similar cross-bridged cyclen derivatives from the literature.

Full text of DOI:10.1039/c2dt32363j

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Cyclen derivatives with two trans-methylnitrophenolic
pendant arms: a structural study of their copper(II) and
zinc(II) complexes†
Cite this: Dalton Trans., 2013, 42, 6149
Catarina V. Esteves,a Luís M. P. Lima,a Pedro Mateus,a Rita Delgado,*a Paula Brandãob
and Vítor Félixc
Two new cyclen derivatives, H2do2nph and H2cb-do2nph, containing two trans-2-methyl-4-nitrophenol
pendant arms and the latter including also an ethylene cross-bridge, were prepared in good yields using
the bisaminal synthetic route. The two ligands were studied comparatively regarding their metal com-
plexation behaviour. The copper(II) and zinc(II) complexes of H2do2nph and H2cb-do2nph were studied in
dimethylsulfoxide–water (9 : 1 v/v) solution by a range of spectroscopic techniques. Copper(II) complexes
were also studied in solid state by X-ray single crystal diffraction. These studies showed that the copper(II)
and zinc(II) complexes of H2do2nph exhibited a distorted square pyramidal coordination environment
with the four nitrogen atoms of the cyclen ring defining the basal plane, and that one of the nitrophe-
nolate arms did not coordinate to the metal, independently of its protonation state. On the other hand,
depending on the protonation state of one of the nitrophenolic arms, the cross-bridged derivative forms
copper(II) complexes with distorted square pyramidal or octahedral geometries with one or two arms
coordinated to the metal centre, respectively. In the complex with distorted octahedral geometry, the
two phenolic oxygen atoms are coordinated to the metal centre in a cis-fashion. Acid-assisted dis-
sociation assays in 1 mol dm−3 HCl DMSO–H2O (9 : 1 v/v) solution at 298.2 K allowed one to determine
the half-life of both copper(II) complexes, which is lower for the derivative without a cross-bridge as
expected, while for the other one it is quite high and in line with similar cross-bridged cyclen derivatives
from the literature.
Received 5th October 2012,
Accepted 14th December 2012
DOI: 10.1039/c2dt32363j
www.rsc.org/dalton
derivatives has recently been particularly driven by the need to
find better ligands to chelate cations with potential use in
Introduction
Macrocyclic ligands obtained by N-functionalization of cyclen medical imaging and therapy,2 such as for magnetic resonance
(1,4,7,10-tetraazacyclododecane) continue to be especially imaging (MRI),3 for diagnosis by positron emission tomo-
interesting due to their ability to form very stable complexes graphy (PET) and single-photon emission computed tomography
with a range of important metal cations.1 Between several (SPECT),4,5 or for α- and β-radiotheraphy.5 Among transition
possible applications, the development of new cyclen metals and related ones, possible isotopes for radiotherapy are
67Cu, while important isotopes for imaging are 64Cu and 68Ga
for PET or 67Ga for SPECT.4–6
aInstituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Av. da
To be suitable for medical applications, complexes of rele-
República, 2780-157 Oeiras, Portugal. E-mail: delgado@itqb.unl.pt;
vant isotopes must exhibit a range of chemical properties such
as high thermodynamic stability, high kinetic inertness, fast
and mild complex formation, appropriate pharmacokinetics,
and preferably the possibility of coupling with targeting
biomolecules.1,2,4–6 Stable copper(II) complexes of cyclen
derivatives are usually 5- or 6-coordinate in square pyramidal,
distorted octahedral or tetragonal preferred geometries. This
means that cyclen should be appended with at least one or two
coordinating arms to fulfil the coordination demand of this
cation. Furthermore, the presence of an ethylene bridge
between opposite nitrogen atoms has demonstrated the yield
Fax: (+351) 21 441 12 77
bDepartamento de Química, CICECO, Universidade de Aveiro, 3810-193 Aveiro,
Portugal
cDepartamento de Química, CICECO, and Secção Autónoma de Ciências da Saúde,
Universidade de Aveiro, 3810-193 Aveiro, Portugal
†Electronic supplementary information (ESI) available: X-band EPR spectra of
the copper(II) complexes and the corresponding simulated ones; 1H and 13C
NMR spectra of the zinc(II) complexes; time course of the dissociation of the
copper(II) complexes; 1H, 13C and 2-D NMR spectra of the compounds and their
mass spectra. CCDC 904673–904676 for [H4do2nph](ClO4)2·H2O; [H2cb-
do2nph]·1.5H2O; [Cu(do2nph)][Cu(Hdo2nph)]ClO4·3H2O; [Cu(cb-do2nph)]·H2O
respectively. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c2dt32363j
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Scheme 1 Cyclen derivatives mentioned in this work.
of particularly inert complexes.4–6 The choice of useful
pendant arms has traditionally been focused on carboxylic
and derived moieties although a variety of other substituents
were reported, such as phosphonic and aminic among others.
Phenolic functions have been rarely appended on cyclen,7,8
while they are well known for presenting good coordi-
nation ability for copper(II) and also for harder Lewis acid
cations such as trivalent transition and lanthanide metals.9
Indeed, phenolates have been successfully used by Kimura
et al. on other macrocyclic skeletons such as cyclam (1,4,8,11-
tetraazacyclotetradecane) and 1,5,9-triazacyclododecane in the
form of a substituent of the macrocyclic framework.10–15 On
the other hand, Moore et al.16,17 and Wieghardt et al.18,19 used
methylphenolic arms N-appended on tacn (1,4,7-triazacyclono-
nane) to study complexes of trivalent metal ions such as
gallium(III) and iron(III).
With the above features in mind, we set out to develop a
range of new macrocyclic ligands containing methylphenolic
pendant arms in their structure, in order to take advantage of
their coordination ability for copper(II) and foreseeably also for
gallium(III). Our initial approach was focused on cyclen deriva-
tives with complexation properties potentially suitable for
yielding octahedral metal coordination environments.
Scheme 1 represents the selected literature cyclen derivatives
relevant for copper(II) complexation and mentioned along this
work. We have developed two new cyclen derivatives,
Scheme 2 Synthetic procedures used to obtain the compounds H2do2nph
and H2cb-do2nph. (a) 2-(Bromomethyl)-4-nitrophenol, MeCN, r.t., 8 days; (b)
N2H4–H2O, reflux, 2 h; (c) NaBH4, EtOH–H2O (9 : 1), r.t., 8 days.
H2do2nph and H2cb-do2nph (Scheme 2), both containing two coordination environments adopted in the complexes of both
opposite 2-methyl-4-nitrophenol pendant arms and one of ligands, correlating the solution structures with the ones
them including also an ethylene cross-bridge, in search for observed in solid state. The kinetic inertness of both copper(II)
enhanced coordination ability towards copper(II). The cross- complexes was also analysed in acid-assisted dissociation
bridged compound, H2cb-do2nph, was studied comparatively assays, while determination of thermodynamic stability con-
with the other one, H2do2nph, regarding their complexation stants for the complexes in solution was hampered by the very
behaviour. Copper(II) and zinc(II) complexes were studied in low overall solubility of the compounds in any feasible water-
solution and in solid state by a range of spectroscopic tech- containing media. Nonetheless, it is known that, for medical
niques and X-ray single crystal diffraction. The obtained applications, the kinetic inertness of metal complexes is more
results allowed us to make
a detailed analysis of the relevant than their thermodynamic stability.
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with a N⋯O distance of 3.335(2) Å. These weak and coopera-
tive hydrogen bonds are shown in the right view of Fig. 1.
This structure is rather similar to that found for the related
Results and discussion
Syntheses of the compounds
The compounds H2do2nph and H2cb-do2nph were prepared compound containing two additional N-methyl pendant arms
from cyclen-glyoxal according to previously reported routes as in the protonation form (H3do2nph2me)Br (see Scheme 1 for
shown in Scheme 2. Bisquaternarization of cyclen-glyoxal20 the molecular representation of the compound). In this case
with two equivalents of 2-(bromomethyl)-4-nitrophenol pro- the protonations occur at the two cyclen amines bound to the
duced the diammonium salt in nearly quantitative yield. From appended methylnitrophenolic groups and at only one of the
this, H2do2nph and H2cb-do2nph were obtained in very good nitrophenolic groups.23 The cyclen ring adopts the usual
yields, the former by deprotection with hydrazine mono- [3333] conformation as in (H4do2nph)2+, however with trans
hydrate,21 and the latter after reduction with sodium boro- N⋯N distances larger for the reported (H3do2nph2me)Br
hydride in ethanol/water.22 Both compounds proved to be only (4.37 Å between the protonated amines and 3.88 Å between the
sparingly soluble in water and almost insoluble in any other methylated amines).
solvent except DMSO, thus limiting significantly possible
The asymmetric unit of the H2cb-do2nph is composed of
studies of their chemical properties. For that reason, most one zwitterionic macrocycle (with one protonated amine in the
solutions of the compounds and their complexes prepared ring and one of the phenolic groups deprotonated) and two
throughout this work used either neat DMSO or a DMSO– water crystallisation molecules, one with occupancy of 50%. In
water mixture.
addition an ethylene linkage in the macrocyclic backbone is
disordered over two positions with different occupations as
described in the Experimental section. The molecular struc-
ture defined by a disordered component is shown in Fig. 2
together with the atomic notation scheme adopted. The single
phenol interacts with a crystallisation water molecule through
a hydrogen bond with O⋯O distances of 2.680(11) and
O–H⋯O angles of 124°.
The steric constraints imposed by the ethylene cross-bridge
influences the cavity size of H2cb-do2nph leading to N⋯N
intramolecular distances gathered in Table 1, together with
those calculated for H2do2nph2+. However, the N⋯N distances
exhibited by H2cb-do2nph, varying between 2.779(3) and 3.570(3)
Å, allow the protonation of a single nitrogen donor of the
macrocycle. Furthermore, this proton is stabilised by three
intramolecular N–H⋯N hydrogen bonds with H⋯N distances
of 1.81(5), 2.27(4) and 2.35(5) Å established with N(7), N(1) and
N(10) atoms, respectively.
Single crystal X-ray studies
Structures of the compounds. The crystal structure of
(H4do2nph)(ClO4)2·2H2O salt was built up from an asymmetric
unit composed of one (H4do2nph)2+ cation and two ClO4
−
counterions and two crystallisation water molecules. A water
molecule is disordered over two positions. The ORTEP
diagram of (H4do2nph)2+ presented in Fig. 1 with the labelling
scheme adopted shows the secondary nitrogen atoms and the
phenol groups protonated as revealed by the last difference
Fourier maps calculated along the structure refinement. The
N⋯O and O⋯O intermolecular distances found in the crystal
lattice are consistent with the existence of a 1-D dimensional
network of N–H⋯O and O–H⋯O hydrogen bonding inter-
actions between (H4do2nph)2+ cations, water crystallisation
−
molecules and ClO4 anions. The hydrogen atoms of the dis-
ordered water molecule were not considered in this analysis (see
below). In addition, the macrocyclic conformation is stabilised
by intramolecular bonding interactions including multiple
N–H⋯N hydrogen bonds with N⋯N distances ranging from
2.834(2) to 2.966(3) Å and a single N–H⋯O hydrogen bond
Structures of copper(II) complexes of H2do2nph and H2cb-
do2nph. Selected bond distances and angles in coordination
spheres of the copper(II) complexes of H2do2nph and H2cb-
do2nph are given in Table 2. The asymmetric unit of the
Fig. 1 Structural features of (H4do2nph)2+: ORTEP diagram with thermal ellipsoids drawn at 30% probability level (left view) and the macrocyclic conformation
(right view) stabilised by multiple N–H⋯N and N–H⋯O hydrogen bonds.
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Fig. 2 Perspective views of H2cb-do2nph: ORTEP diagram with the labelling scheme adopted for the nitrogen donors and thermal ellipsoids represented at 30%
probability level (left) and the macrocyclic conformation stabilised by three N–H⋯N hydrogen bonds drawn as green dashed lines (right). The disordered
–NCH2CH2N– linkage is shown in a single position for clarity.
Table 1 Intramolecular N⋯N distances (Å) on the macrocyclic backbone of
deprotonated while in the [Cu(Hdo2nph)] complex a single
phenolic group is protonated, as can be seen from their mole-
cular structures presented in Fig. 3. Both complexes exhibit
distorted square pyramidal coordination environments with
the four nitrogen atoms of the cyclen ring defining the basal
plane. The copper centre is positioned above the N4 coordi-
nation plane by 0.513(3) Å for [Cu(do2nph)] and 0.510(3) Å for
[Cu(Hdo2nph)]+, pointing towards the apical oxygen atom
from the coordinated 2-methyl-4-nitrophenol arm. Indeed,
both complexes exhibit a Cu–O apical oxygen distance, 2.079(4)
Å in [Cu(do2nph)] and 2.086(4) in [Cu(Hdo2nph)]+, shorter
than the corresponding distance between the oxygen and the
basal plane of 2.577(5) and 2.570(5) Å. The two complexes also
have equivalent equatorial Cu–N bond distances (see Table 2).
(H4do2nph)2+ and H2cb-do2nph
Ligand
(H4do2nph)2+
H2cb-do2nph
N(1)⋯N(4)
N(1)⋯N(7)
N(1)⋯N(10)
N(4)⋯N(7)
N(4)⋯N(10)
N(7)⋯N(10)
2.834(2)
3.990(2)
2.883(2)
2.966(3)
4.177(2)
2.874(2)
2.779(3)
2.868(3)
3.570(3)
2.575(3)
2.807(3)
2.779(3)
Table 2 Selected bond distances (Å) and angles (°) in the copper(II) coordi-
nation spheres of the complexes of H2do2nph and H2cb-do2nph
Complex
[Cu(do2nph)] [Cu(Hdo2nph)]+ [Cu(cb-do2nph)] Furthermore, the trigonal distortion was calculated for both
complexes using the index structural parameter (τ) as pre-
Bond lengths/Å
Cu–N(1)
Cu–N(4)
Cu–N(7)
Cu–N(10)
viously defined by Addison et al.24 The τ parameter assumes
2.035(6)
2.028(6)
2.025(5)
2.034(6)
2.079(4)
2.027(6)
2.015(6)
2.028(5)
2.027(6)
2.086(4)
2.003(4)
2.070(4)
2.010(4)
2.302(4)
values of 0 and 1 for ideal square pyramidal and trigonal
bipyramidal geometries, respectively. The τ values of 0.09 for
[Cu(do2nph)] and 0.13 for [Cu(Hdo2nph)]+ are entirely consist-
ent with a distorted square pyramidal coordination sphere.
The structures of these two copper(II) complexes compare
well with those of the related ligand, [Cu(Hdo2nph2me)]-
(ClO4),8 and of cyclen, [Cu(cyclen)(NO3)]NO3.25 These four
structures are however in contrast with those of copper(II) com-
plexes of several cyclen derivatives where instead the copper
centre tends to exhibit hexacoordinated environments, like in
[Cu(H2dota)],26,27 where the copper adopts a distorted octa-
hedral geometry, or in [Cu(do2py)]2+, which is in a distorted
triangular prismatic geometry.28
Cu–O(23)
—
Cu–O(25)
Cu–O(36)
—
—
—
—
1.963(4)
2.343(3)
Bong angles/°
N(7)–Cu–N(1)
N(4)–Cu–N(10)
N(1)–Cu–N(10)
N(4)–Cu–N(1)
N(7)–Cu–N(4)
N(7)–Cu–N(10)
O(25)–Cu–N(4)
N(10)–Cu–O(36)
O(25)–Cu–O(36)
153.5(2)
147.9(2)
86.5(3)
86.4(2)
86.5(2)
86.1(2)
—
154.9(2)
146.8(2)
86.3(2)
86.3(2)
87.2(2)
85.9(2)
—
166.77(14)
78.26(14)
81.55(14)
87.90(16)
86.00(16)
85.71(14)
177.91(17)
170.34(12)
87.64(14)
87.65(12)–
104.53(13)
—
—
—
—
N–Cu–Ocis-angles, range 95.4(2)–
94.9(2)–
110.2(2)
111.06(19)
The crystal structure is stabilised by a complex 3-D network
of N–H⋯O and O–H⋯O hydrogen bonds in which molecules
of [Cu(Hdo2nph)]+ and [Cu(do2nph)] are assembled through
the NO2 phenol substituents by water bridges composed of
complex of H2do2nph contains two copper(II) species with
different net charges, [Cu(do2nph)] and [Cu(Hdo2nph)]+, one three water molecules.
−
disordered ClO4 counterion and three crystallisation water
molecules, which is consistent with the molecular formula
The molecular structure of [Cu(cb-do2nph)] is shown in
Fig. 4 with the relevant atomic notation scheme adopted. The
[Cu(do2nph)][Cu(Hdo2nph)]ClO4·3H2O. In the complex [Cu- complex displays a distorted octahedral geometry with two
(do2nph)], the two phenolic functional groups are phenolic oxygen atoms coordinated to the metal centre in a
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Fig. 3 ORTEP views of [Cu(Hdo2nph)]+ (left) and [Cu(do2nph)] (right) with the atomic labelling scheme and thermal ellipsoids drawn at the 50% probability level.
Fig. 4 ORTEP view of [Cu(cb-do2nph)] showing thermal ellipsoids at the 50% probability level and the relevant atomic labelling scheme adopted.
cis-fashion giving an O–Cu–O angle of 87.64(14)°. The atoms oxygens,30 or the complex [Cu(cb-do2pr)] in which the equator-
O(36) and N(10) occupy the apical positions with a N–Cu–O ial plane is formed by three amines and one pendant arm
angle of 170.34(12)°, and Cu–O(36) and Cu–N(10) distances of oxygen just as found for [Cu(cb-do2nph)].31
2.343(3) and 2.302(4) Å, respectively. These distances are
Spectroscopic studies
longer than the remaining four coordination distances ranging
between 1.963(4) and 2.070(4) Å in agreement with the Jahn–
Teller effect. The Cu–N equatorial distances compare well with
those reported for the two copper complexes of H2do2nph, see
Table 2. This type of axially elongated distorted octahedral geo-
metry is the most common for cross-bridged cyclen derivatives.
Examples are the [Cu(cb-do2me)(CH3CN)2]2+ where the equa-
torial plane is instead formed by two amines and two MeCN
solvent molecules,29 the [Cu(cb-do2a)] complex in which the
equatorial plane is made of two amines and two carboxylate
Electronic and EPR spectra. Due to the low solubility in
water of the H2do2nph and H2cb-do2nph compounds and
especially of their complexes, these studies were performed in
DMSO–water (9 : 1, v/v) solution. In Table 3 are compiled the
UV-vis as well as the X-band EPR spectroscopic data of the
spectra of the copper(II) complexes.
The absorption spectrum at the 500 to 850 nm region of
the [Cu(do2nph)] complex (in its neutral form) shows a band
with maximum at 631 nm (ε = 286 cm−1 mol−1 dm3), which
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Table 3 UV-vis and X-band EPR spectroscopic data of the copper(II) complexes of H2do2nph and H2cb-do2nph
X-band EPRb,c
UV-visa
λmax/nm (εmolar/dm3 mol−1 cm−1
d
d
d
Complex
)
g1
g2
g3
A1
A2
A3
e
[Cu(H2do2nph)]2+
[Cu(Hdo2nph)]+
[Cu(do2nph)]
321 (2.1 × 104); 403 (2.1 × 103); 700 (307)
316 (1.2 × 104); 403 (2.0 × 104); 637 (261)
419 (4.1 × 104); 631 (286)
2.215
2.206
2.202
2.204
2.241
2.07
2.07
2.07
2.05
2.07
2.05
2.04
2.04
2.04
2.04
170
178
181
188
165
14
17
23
28
14
—
—
—
—
e
e
e
[Cu(Hcb-do2nph)]+
[Cu(cb-do2nph)]
320 (1.1 × 104); 403 (1.9 × 104); 617 (193)
420 (4.3 × 104); 680 (170)
10
a DMSO–H2O (9 : 1 v/v) solution, recorded at 298 K. b In DMSO–H2O (9 : 1 v/v), recorded at 90 K, microwave power 2.0 mW and frequency (ν) 9.51
GHz. c Experimental and simulated EPR spectra are presented in Fig. S1–S5 of the ESI. d Values of A × 104 in cm−1 e Values too low to be
.
accurately determined.
Fig. 5 Spectral changes of the copper(II) complexes of H2do2nph in DMSO–H2O (9 : 1 v/v): absorption spectra recorded at 0.0, 0.2, 0.4, 0.6, 0.8, 1.0, 2.0 and 7.0
equiv. of HCl (a) in the 500–850 nm region and (b) in the 265–475 nm region, (c) X-band EPR spectra in frozen solutions, (d) proposed mechanism.
tails into the low-energy region of the spectrum (Fig. 5a, blue different principal values for the g parameter of each species,
spectrum).
with g1 > (g2 + g3)/2 while the lowest g value is ≥2.04, which is
The corresponding EPR spectrum (Fig. 5c, blue spectrum) characteristic of mononuclear copper(II) complexes in dx2−y2
showed one paramagnetic species with the expected four lines ground state and elongation of the axial bonds. Distorted
at lower field. Simulation of the spectrum indicated three square pyramidal or octahedral stereochemistries are thus
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consistent with these data.32,33 The position and intensity of [Cu(Hdo2nph)]+ and [Cu(do2nph)] (Fig. 3), which showed that
the d–d transition band as well as the values of the EPR para- one of the arms does not coordinate independently of its pro-
meters obtained (see Table 3) are similar to those of copper(II) tonation state, indicating that the structures adopted by these
complexes of cyclen34 and its derivatives bearing one pendant complexes in solution and in the solid state are the same.
arm, known to possess
a distorted square pyramidal Addition of another equivalent of HCl causes only slight
geometry.35–37 The obtained crystal structure of [Cu(do2nph)] changes in the spectra of the complex, which means that the
(Fig. 3) also confirms the distorted square pyramidal geometry second nitrophenolic arm has little tendency to protonate and
of the copper centre. Addition of one equivalent of HCl has detach from the metal ion. In fact, complete formation of the
little effect in the visible absorption and EPR spectra of the [Cu(H2do2nph)]2+ species is achieved only upon addition of
complex (Fig. 5a and c), which suggests that its geometry 7 equiv. HCl (see Fig. 5).
remains essentially the same. The absorption spectra in the
The copper(II) complexes of H2cb-do2nph, on the other
265 to 475 nm region, on the other hand, showed that addition hand, revealed somewhat different features. The absorption
of up to one equivalent of HCl causes a decrease of the band spectrum at the 500 to 850 nm region of the [Cu(do2nph)]
at 419 nm to about half of its height and concomitant increase complex (in its neutral form) shows a band with maximum at
of a band at 316 nm, with an isosbestic point at 370 nm 680 nm (ε = 170 cm−1 mol−1 dm3), which tails into the low-
(Fig. 5b). This behaviour can be attributed to the protonation energy region of the spectrum (Fig. 6a). Simulation of the cor-
of one nitrophenolic group of the complex. The fact that proto- responding EPR spectrum indicated three different principal
nation of a nitrophenolic arm causes almost no changes in the values for the g parameter of each species, with g1 > (g2 + g3)/2
vis and EPR spectra of the complex suggests that one of the with the lowest g value being ≥2.04, suggesting distorted
nitrophenolic arms is never coordinated. These observations square pyramidal or octahedral stereochemistries.32,33 The
are also in agreement with the obtained crystal structures of position and low intensity of the d–d transition band as well
Fig. 6 Spectral changes of the copper(II) complexes of H2cb-do2nph in DMSO–H2O (9 : 1 v/v): absorption spectra recorded at 0.0, 0.2, 0.4, 0.6, 0.8, 1.0, 2.0 and 7.0
eq. of HCl (a) in the 500–850 nm region and (b) in the 265–475 nm region, (c) X-band EPR spectra in frozen solutions, (d) proposed mechanism.
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as the values of the EPR parameters obtained (see Table 3) are coordinated to the metal cation. An inspection of the 13C
similar to those of copper(II) complexes of cyclen derivatives spectra of both complexes (Fig. S7–S8†) showed that a higher
known to adopt a distorted octahedral geometry.28,31,37–39 The symmetry exists in solution for the complex of the cross-
crystal structure of [Cu(cb-do2nph)] (Fig. 4) also showed the bridged ligand compared to the other one. The spectrum of
copper centre in a distorted octahedral geometry. Addition of [Zn(cb-do2nph)] has only 12 signals for the 24 carbon nuclei of
one equivalent of HCl causes a blue shift of the d–d transition the ligand backbone, 7 for the two equivalent pendants and 5
band of 63 nm together with a decrease of the g1 value and an for the macrocyclic ring and bridge, indicating an effective C2
increase of the A1 value, consistent with a stronger equatorial symmetry of the complex in solution. In contrast, the spectrum
ligand field or a weaker axial ligand field, which suggest a of [Zn(do2nph)] has a total of 18 signals for the 22 carbon
change from octahedral to square pyramidal geometry.40–42 nuclei, 7 for each of the two non-equivalent pendants and
Addition of up to one equivalent of HCl to the copper(II) another 4 for the macrocyclic ring, pointing to a C1 symmetry
complex of the cross-bridged ligand, as also observed for the of the complex in solution. Overall, the features found for both
complex of H2do2nph, causes a decrease of the band at zinc(II) complexes suggest their solution structures are similar
418 nm of the absorption spectra to about half of its intensity to the ones found in the solid state for the related copper(II)
and a concomitant increase of the band at 320 nm, with an complexes (see above). Indeed, the spectrum of [Zn(cb-
isosbestic point at 373 nm (Fig. 6b). As mentioned above this do2nph)] is consistent with a distorted octahedral geometry,
behaviour can be attributed to the protonation of one nitro- while that of [Zn(do2nph)] displays a pentacoordination mode
phenol group of the complex. Thus, in the case of the H2cb- from the ligand alone, which could indicate a square pyrami-
do2nph copper(II) complex, the protonation of one nitrophenol dal geometry.
arm causes a change from octahedral to square pyramidal geo-
Kinetic stability of the copper(II) complexes
metry consistent with the detachment of one nitrophenol arm
from the coordination sphere. Addition of another equivalent
of HCl has practically no effect in the spectra of the complex
(Fig. 6, green spectra) and further additions of up to 7 equiv.
HCl showed no spectral variations, which means that the
second nitrophenolic arm has even less tendency to protonate
and detach from the metal ion than that in the case of [Cu-
(Hdo2nph)]. This behaviour is most likely related to the strong
coordination interaction of one phenolic oxygen atom on the
equatorial plane of the complex as demonstrated by the short
Cu–O(25) distance observed in the crystal structure of [Cu(cb-
do2nph)] (see Fig. 4 and Table 2).
The kinetics of the acid-assisted dissociation of the copper(II)
complexes of both H2do2nph and H2cb-do2nph was studied
under pseudo-first order conditions in 1 mol dm−3 HCl
DMSO–H2O (9 : 1 v/v) solutions at 298.2 K. The dissociation of
the complexes was monitored by following the decrease in the
visible absorption (700 nm) in the complex of H2do2nph, or
the blue shift of a UV absorption (350 nm) in the complex of
H2cb-do2nph for which the visible absorption is not
sufficiently strong in the attainable concentration range. The
half-life values found were 10.9 min and 46.1 min for the com-
plexes of H2do2nph and H2cb-do2nph, respectively, thus fol-
lowing the expected trend where complexes of cross-bridged
ligands are more inert than the complexes of non-bridged
parent macrocycles. A few half-life values can be found in the
literature for complexes of related cross-bridged cyclen deriva-
tives in 1 mol dm−3 HCl aqueous solutions at 303 K, such as
4.0 h for H2cb-do2a,30 52.0 min for cb-do2py,28 and 37.2 min
for H2cb-do2pr.31 Although these literature values are
measured at a slightly higher temperature and for a different
solvent than the ones used in our assays, it is still possible to
make a rough comparison and conclude that the complex of
H2cb-do2nph exhibits a half-life value for the HCl-assisted dis-
sociation in line with that of other reported cross-bridged
derivatives.
NMR spectra of the zinc(II) complexes of H2do2nph and
H2cb-do2nph. The 1H and 13C NMR spectra of the zinc(II)
complexes of H2do2nph and H2cb-do2nph were recorded in
DMSO-d6 solutions at 298 K, together with 2D correlation
spectra to help on the assignment. A single species was found
1
in the spectra of both complexes. The H spectra are reason-
ably well resolved at room temperature, especially in the
region 3–8 ppm where the resonances of the 2-methyl-4-nitro-
phenol pendant arms appear (see Fig. S6 in the ESI†). A full
assignment of these spectra was not attempted due to the com-
plicated resonance pattern at high field, but the involvement
of the phenolate pendants in the coordination of zinc(II) could
1
be clearly understood. The H NMR spectrum of [Zn(do2nph)]
shows two distinct sets of resonances for the aromatic protons
of the pendants, with some overlapping signals. At the same
time, the methylene protons of the pendants appear also as
two different resonances, one singlet and one quadruplet (AB
Conclusions
system). It is thus clear that the two pendant arms are non- Two new cyclen derivatives containing two trans 2-methyl-4-
equivalent and that only one of them is involved in coordi- nitrophenol pendant arms, H2do2nph and H2cb-do2nph, were
nation of the metal cation, see Fig. S6 in the ESI† (top). In con- prepared in good yields and studied comparatively regarding
trast, the spectrum of [Zn(cb-do2nph)] showed a single set of their metal complexation behaviour. Solution and solid state
resonances for the aromatic protons and only one quadruplet studies revealed that the copper(II) complex of H2do2nph exhi-
(AB system) for all the methylene protons. This indicates that bits a distorted square pyramidal coordination environment
the pendant arms are magnetically equivalent and both are with the four nitrogen atoms of the cyclen ring defining the
6156 | Dalton Trans., 2013, 42, 6149–6160
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basal plane and that one of the nitrophenolate arms does not 2D HMQC experiments (Fig. S9–S18 in the ESI†). Microana-
coordinate to the metal, independently of its protonation lyses were carried out by the ITQB/IBET Analytical Services
state. On the other hand, depending on the protonation state Unit. The electronic absorption spectra were recorded on a
of one of the nitrophenolic arms, the cross-bridged derivative UNICAM UV-vis spectrophotometer model UV-4. EPR spectra
forms copper(II) complexes with distorted square pyramidal or were recorded on a Bruker EMX 300 spectrometer equipped
octahedral geometries with one or two arms coordinated to with continuous-flow cryostat for liquid nitrogen, operating at
the metal centre, respectively. In the complex with distorted the X-band.
octahedral geometry, the two phenolic oxygen atoms are co-
Syntheses
ordinated to the metal centre in a cis-fashion. 1H and 13C NMR
spectra of the zinc(II) complexes of both ligands showed identi-
Cyclen-glyoxal trans-bis(2-methyl-4-nitrophenol) diammo-
cal features, pointing also to a distorted square pyramidal nium bromide. A solution of 2-(bromomethyl)-4-nitrophenol
coordination environment in [Zn(do2nph)] and an octahedral (1.363 g, 5.9 mmol) in MeCN (10 cm3) was added dropwise
geometry in [Zn(cb-do2nph)]. Overall, we could have a clear over 30 min to a stirred solution of cyclen-glyoxal (0.456 g,
insight of the coordination properties of copper(II) and zinc(II) 2.4 mmol) in MeCN (10 cm3). The solution was left under stir-
complexes of both ligands in solution. Furthermore, the struc- ring at r.t. for 8 days, during which time a white precipitate
tures found in solution correlate well with those determined in formed. The solid was filtered, washed with MeCN and then
the solid state. Despite the unusual solution medium used in with diethyl ether. The compound was vacuum dried and
the acid-assisted dissociation assays, the half-life found for the found pure (1.483 g, 96%); m.p. 225 °C (decomp.). 1H NMR
copper(II) complex of H2cb-do2nph shows that it is quite inert (400 MHz, DMSO-d6): δ 8.57 (2 H, d, J = 2.8 Hz, 3-H), 8.32 (2 H,
when compared to other cross-bridged cyclen derivatives.
dd, J = 9.0, 2.8 Hz, 5-H), 7.20 (2 H, d, J = 9.0 Hz, 6-H), 4.95,
It is known from the literature that copper(II) complexes of 4.74 (4 H, ABq, JAB = 13 Hz, CH2nph) 4.75 (2 H, s, CH-bis-
cyclen derivatives with two or more coordinating pendant aminal), 4.18–2.88 (16 H, m, CH2-ring) ppm. 13C NMR
arms may exhibit square pyramidal as well as octahedral geo- (100 MHz, DMSO-d6): δ 163.9 (C4), 140.0 (C1), 131.5 (C3),
metries, with the preference being dictated by the type and 128.6 (C6), 117.3 (C2), 115.1 (C5), 77.2 (CH-bisaminal), 60.0
length of the pendant groups, while the complexes of cross- (CH2nph), 56.8, 54.8, 46.5, 43.1 (C-ring) ppm.
bridged cyclen derivatives adopt most frequently distorted
H2do2nph hydrochloride. The diammonium bromide from
octahedral geometries, although square pyramidal environ- above (1 g, 1.5 mmol) was suspended in a solution of hydra-
ments cannot be discarded as seen in the present work. Here, zine monohydrate–water 1 : 1 v/v (13 cm3) and refluxed for 2 h.
we have demonstrated that two phenolic arms appended on The mixture was allowed cooled to r.t. and a yellow precipitate
cyclen derivatives resulted in chelators with a good coordi- formed which was filtered, washed with water and then with
nation ability for copper(II) and zinc(II) metal ions, especially diethyl ether. This solid was recrystallised from boiling HCl–
the cross-bridged derivative where an octahedral geometry is EtOH (1 : 1 v/v), yielding a white crystalline solid which was
preferred. The use of such a chelate structure may prove very dried in an oven at 60 °C (0.908 g, 91%): m.p. 250 °C
interesting for metal radioisotopes used in medical appli- (decomp.). 1H NMR (400 MHz, D2O) δ 8.18 (2 H, dd, J = 8.9, 2.8
cations, provided that changes are made on the ligand struc- Hz, 5-H), 8.15 (2 H, d, J = 2.8 Hz, 3-H), 7.00 (2 H, d, J = 8.9 Hz,
ture in order to increase the solubility of the complexes in 6-H), 3.68 (4 H, s, CH2nph), 3.68–2.87 (16H, NHCH2CH2N)
aqueous media. Envisaged radioisotopes are not only those of ppm. 13C NMR (100 MHz, D2O): δ 161.6 (C4), 140.4 (C1), 128. 2
copper(II), but possibly also those of gallium(III) which have (C3), 126.4 (C6), 123.3 (C2), 116.1 (C5), 51.5 (CH2nph), 47.4
identical ionic radii and invariably adopt octahedral geometry. (NHCH2), 42.5 (CH2N) ppm. Anal. calcd. for C22H30N6O6·5HCl:
The nitro groups present in the ligands can be easily trans- C, 40.3; H, 5.4; N, 12.8%. Found: C, 40.8; H, 5.2; N, 12.3%.
formed in order to increase solubility and also to bind a bio- ESI-MS (H2O–MeOH, 8 : 2) m/z: 475.0 [M + H]+.
molecule for use in targeted medical applications. We are
H2cb-do2nph hydrochloride. The diammonium bromide
currently developing modified ligands with the above aims, from above (1.490 g, 2.3 mmol) was suspended in EtOH–H2O
and the promising properties already observed for their com- 95 : 5 (150 cm3) and solid NaBH4 (0.855 g, 22 mmol) was
plexes will be disclosed in due time.
added in small portions. The mixture was left under stirring at
r.t. for 8 days, then cooled in an ice bath, acidified with 2 mol
dm−3 HCl and left stirring for another 2 h. The precipitate
thus formed was filtered, washed with EtOH and then with
diethyl ether, and dried in an oven at 60 °C (1.422 g, 92%).
M.p. 163–164 °C. 1H NMR (400 MHz, D2O) δ 8.30 (2 H, d,
Experimental
General considerations
Cyclen-glyoxal was prepared by adaptation of a literature pro- J = 2.8 Hz, 3-H), 8.24 (2 H, dd, J = 9.0, 2.8 Hz, 5-H), 7.11 (2 H,
cedure.43 All solvents and chemicals were commercially pur- d, J = 9.0 Hz, 6-H), 4.38 (4 H, s, CH2nph), 3.60–3.10 (16 H,
chased with reagent grade quality and used as supplied without NCH2CH2N-ring), 3.20 (4 H, s, NCH2CH2N-bridge) ppm.
further purification. NMR spectra were recorded on a Bruker 13C NMR (100 MHz, D2O): δ 161.9 (C4), 140.4 (C1), 128. 2 (C3),
Avance II+ 400 MHz instrument. Peak assignments are based 127.3 (C5), 120.4 (C2), 116.2 (C6), 54.3 (CH2nph), 54.2, 53.9
1
on peak integration and multiplicity for 1D H spectra and on (CH2-ring), 46.7 (CH2-bridge) ppm. Anal. calcd for
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C24H32N6O6·5HCl: C, 42.2; H, 5.5; N, 12.3%. Found: C, 42.2; H, then added to approximately 1 : 1 v/v and the solution was
5.6; N, 12.3%. ESI-MS (H2O–MeOH, 8 : 2) m/z: 501.1 [M + H]+.
allowed to evaporate slowly at r.t. Yellow single crystals were
[Cu(do2nph)]. The compound H2do2nph (99 mg, 151 µmol) obtained within two weeks.
was dissolved in MeOH–H2O 1 : 1 v/v (50 cm3), 0.95 equiv. of
Crystals of [Cu(do2nph)]. To 1 cm3 of a 2 × 10−3 mol dm−3
Cu(ClO4)2 was added, pH was rendered basic with aqueous solution of H2do2nph in MeOH–H2O (1 : 1 v/v) was added 1
KOH and the dark green solution was heated at 60 °C for 3 h. equiv. of an aqueous Cu(ClO4)2 solution. Aqueous KOH was
After cooling to r.t. the pH was neutral and the MeOH was added to neutral pH and the solution heated to 60 °C for 1 h.
removed on a rotary evaporator. A crystalline dark green solid After cooling to r.t. the pH was readjusted to neutral and the
precipitated as the mixture cooled to r.t. The solid was filtered, solution was allowed to evaporate slowly at r.t. Blue single crys-
washed with cold water and dried in an oven at 60 °C until tals grew in one week.
constant mass (70 mg, 90.3%). Anal. calcd. for C22H28CuN6O6:
C, 49.5; H, 4.9; N, 15.7%. Found: C, 49.1; H, 5.2; N, 15.6%.
Crystals of [Cu(cb-do2nph)]. Procedure similar to the one
for [Cu(do2nph)]. After a week two types of crystals formed:
[Cu(cb-do2nph)]. A procedure similar to the one described green and blue coloured crystals.
for [Cu(do2nph)] was used for H2cb-do2nph (100 mg, 146
Crystals of [Zn(cb-do2nph)]. Procedure similar to the one
µmol), producing a fine green powder (70 mg, 89.9). Anal. for [Cu(do2nph)]. After a week yellow crystals formed.
calcd. for C24H30CuN6O6: C, 51.3; H, 5.4; N, 15.0%. Found: C,
Spectroscopic studies
51.3; H, 5.3; N, 14.6%.
[Zn(do2nph)]. The compound H2do2nph (62 mg, 94 µmol) UV-vis spectra were measured at 298 K in DMSO–H2O (9 : 1 v/v)
was dissolved in MeOH (20 cm3), and 0.95 equiv. of ZnCl2 was solutions. Concentrations in the vis region were of 5.5 × 10−4
dissolved in water (20 mL) and added to the H2do2nph solu- mol dm−3 for [Cu(do2nph)] and of 3.47 × 10−4 mol dm−3 for
tion. The pH was rendered basic with aqueous KOH, the solu- [Cu(cb-do2nph)], while in the UV region they were 1.80 × 10−5
tion turned yellow and after 5 min stirring a precipitate with mol dm−3 in both cases. Aliquots of diluted HCl were added to
the same colour appeared. The mixture was heated at 70 °C these solutions until 7 equivalents of acid was present. The
during 2 days, cooled until r.t. and pH was checked as neutral. solutions used to measure the vis spectra were frozen (90 K)
Upon removal of MeOH on a rotary evaporator a light yellow and used as they were to acquire EPR spectra. X-band EPR
powder precipitated. The solid was filtered, washed with water spectroscopic measurements of the copper(II) complexes were
and diethyl ether, and dried in an oven at 60 °C until constant recorded at microwave power 2.0 mW and frequency (ν) 9.51
mass (47 mg, 97.4%). Anal. calcd for C22H28ZnN6O6: C, 49.1; GHz. EPR spectra were simulated with the SpinCount soft-
H, 5.3; N, 15.6%. Found: C, 49.2; H, 5.0; N, 15.6%. 1H NMR ware44 to obtain the relevant parameters. NMR samples of the
(400 MHz, D2O) δ 2.2–3.3 (16 H, m, ring CH2), 3.65 (2 H, s, zinc(II) complexes were prepared in DMSO-d6 at ca. 1.0 × 10−2
uncoordinated pendant CH2), 3.87, 4.16 (2 H, ABq, JAB = 12.6 mol dm−3. 1H, 13C, COSY, NOESY and HMQC spectra were run
Hz, coordinated pendant CH2), 6.25, 7.85 (2 × 1 H, d, coordi- at 298 K with the chemical shifts referenced to the solvent
nated pendant aromatics), 6.40 (1 H, d, uncoordinated residual peak (δ = 2.50 ppm on 1H and δ = 39.52 ppm on 13C).
pendant aromatic), 7.90 (3 H, m, mixed aromatics) ppm. 13C NMR
Kinetic inertness of the copper(II) complexes
(100 MHz, D2O): δ 44.0, 45.0 (2 × 1 C, ring CH2), 44.5, 51.7 (2 ×
3 C, ring CH2), 56.8 (1 C, uncoordinated pendant CH2), 61.1 The acid-assisted dissociation of the complexes of both
(1 C, coordinated pendant CH2), 119.8 (2 C, aromatic CH2), ligands with copper(II) was studied in 1 mol dm−3 HCl under
122.5, 123.8, 126.4, 126.5, 127.4, 128.4, 131.5, 131.7, 176.0, pseudo-first order conditions by addition of concentrated
176.9 (10 × 1 C, aromatic CH2) ppm.
aqueous solutions of HCl to solutions of the preformed com-
[Zn(cb-do2nph)]. A procedure similar to the one described plexes in DMSO, while keeping the final solutions at 9 : 1 (v/v)
for [Zn(do2nph)] was used for H2cb-do2nph (62 mg, 91 µmol), in DMSO–H2O. Dissociation experiments were performed at
producing a fine yellow powder (46 mg, 99.1%). Anal. calcd for 298.2 K by following the spectral absorption bands of the com-
C24H30ZnN6O6: C, 51.1; H, 5.4; N, 14.9%. Found: C, 51.3; H, plexes in the vis (H2do2nph) or UV (H2cb-do2nph) range at
5.1; N, 15.5%. 1H NMR (400 MHz, D2O) δ 2.2–3.3 (16 H, m, 700 nm and 350 nm, respectively. The concentration of the
ring CH2), 3.83, 4.41 (4 H, ABq, JAB = 12.2 Hz, coordinated pen- complexes in the experiments was at 5.3 × 10−4 mol dm−3 for
dants CH2), 6.35, 7.91, 8.00 (3 × 1 H, d, coordinated pendants H2do2nph or 2.4 × 10−5 mol dm−3 for H2cb-do2nph, without
aromatics) ppm. 13C NMR (100 MHz, D2O): δ 49.4, 55.2, 57.3, 57.7, any control of the ionic strength. Experimental data were pro-
58.5 (5 × 2 C, ring and bridge CH2), 61.8 (2 C, pendants CH2), cessed by exponential regression in order to calculate the half-
119.4, 123.0, 126.8, 129.0, 132.4, 176.4 (6 × 2 C, aromatic CH2) ppm. lives from the fitting equation.
Crystals of H4do2nph. About 2 µmol of H4do2nph hydro-
chloride was dissolved in the minimum amount of MeOH–
Crystallography
H2O (1 : 1 v/v). The solution was allowed to evaporate slowly at The single crystal X-ray data of [H4do2nph](ClO4)2·2H2O 1,
r.t. Yellow single crystals grew within a week.
H2cb-do2nph·1.5H2O 2, [Cu(do2nph)][Cu(Hdo2nph)]ClO4·
Crystals of H2cb-do2nph. About 2 µmol of H2cb-do2nph 3H2O 3, and [Cu(cb-do2nph)]·H2O 4 were collected on a CCD
hydrochloride was dissolved in the minimum amount of H2O Bruker APEX II at 150(2) K using graphite monochromatized
and aqueous KOH was added up to neutral pH. MeOH was Mo-Kα radiation (λ = 0.71073 Å). The selected crystal of each
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Table 4 Crystal data and selected refinement details for the H2do2nph and H2cb-do2nph compounds and their copper(II) complexes
[H4do2nph](ClO4)2·H2O
1
[H2cb-do2nph]·1.5H2O
2
[Cu(do2nph)][Cu(Hdo2nph)]ClO4·3H2O [Cu(cb-do2nph)]·H2O
Compound
3
4
Empirical Formula
Mw
Crystal system
Space group
a/[Å]
b/[Å]
c/[Å]
α/[°]
β/[°]
C
22H36Cl2N6O16
C24H35.N6O7.50
532.08
C44H59ClCu2N12O19
1222.56
Monoclinic
Cc
21.9871(7)
16.3897(3)
16.9181(5)
(90)
119.432(1)
(90)
5309.8(3)
4
C24H32CuN6O7
580.10
Monoclinic
711.47
Triclinic
ˉ
P1
Tetragonal
ˉ
P421c
Cc
8.6397(3)
9.7922(4)
18.6551(9)
100.664(3)
99.990(3)
100.033(2)
1492.37(11)
2
16.7755(5)
16.7755(5)
17.8638(7)
(90)
(90)
(90)
5027.2(3)
8
1.394
23.2324(10)
10.1166(5)
12.6511(6)
(90)
122.370(2)
90
2511.4(2)
4
1.534
γ/[°]
V [Å3]
Z
Dc [Mg m−3
]
1.583
0.304
1.534
0.937
μ/[mm−1
]
0.105
0.927
Reflections collected
Unique reflections
23 591
8974 [0.0215]
64 273
6773 [0.0413]
25 343
12 168 [0.0500]
22 481
7236 [0.0452]
[Rint
]
Final R indices
R1, wR2 [I > 2σ(I)]
R1, wR2 (all data)
0.0505, 0.1532 [6963]
0.0702, 0.1864
0.0622, 0.1732 [5881]
0.0724, 0.1835
0.0690, 0.1544 [9816]
0.0934, 0.1946
0.0550, 0.1540 [6325]
0.0664, 0.1680
compound was positioned at 35 mm from the CCD. The diffrac- were not revealed. All O–H hydrogen atoms were refined with
tion spots were measured with a counting time of 40 s for 4 isotropic thermal constraint of Uiso = 1.2Ueq. The hydrogen
and 60 s for remaining compounds. Data reduction of each atoms of the disordered water molecules or half occupancy
compound comprising a multi-scan absorption correction was were not taken into account in the structure refinement. Final
carried out using the SAINT-NT from Bruker AXS. The struc- R values together with pertinent crystallographic data are sum-
tures were solved with SHELXS by direct methods and refined marized in Table 4 for the H2do2nph and H2cb-do2nph com-
on F2 using full-matrix least squares with SHELXL available pounds and their metal complexes. ORTEP diagrams were
from the SHELX-97 package.45 The X-ray diffraction pattern of drawn with Ortep-3 for windows,46 and the representation of
3 was consistent with space groups Cc and C2/c. The structure [H4do2nph]2+ in stick fashion was obtained with Pymol.47
was solved in both space groups, but the structure refinement
was only successful in the non-centrosymmetric one. All non-
hydrogen atoms were refined with anisotropic thermal par-
Acknowledgements
ameters. C–H hydrogen atoms were introduced at calculated
positions and refined with Uiso = 1.2Ueq of the parent atom. In
The authors acknowledge Fundação para a Ciência e a Tecno-
logia (FCT), with co-participation of the European Community
funds FEDER, POCI, QREN and COMPETE, for the financial
support and the fellowship of C. V. Esteves under project
PTDC/QUI/67175/2006. P. Mateus and L. M. P. Lima acknowl-
edge FCT also for the postdoctoral fellowships SFRH/BPD/
79518/2011 and SFRH/BPD/73361/2010, respectively. The NMR
spectrometers are part of the National NMR Network and were
purchased in the framework of the National Program for Scien-
tific Re-equipment, contract REDE/1517/RMN/2005, with
funds from POCI 2010 (FEDER) and FCT. We also acknowledge
M. C. Almeida for providing elemental analysis and ESI-MS
data from the ITQB/IBET Analytical Services Unit.
−
the crystal structures of 1 and 3, the ClO4 counter-ion was
found disordered over two tetrahedral positions which were
included in the structure refinement with refined occupancies
of x and 1 − x, being x equal to 0.538(4) and 0.69(2), respect-
ively. The macrocyclic backbone of 2, showed one ethane
linkage disordered over two positions, which were refined with
statistical occupancies of 0.63(1) and 0.37(1), respectively. The
atomic positions of –NH2 groups of 1 were obtained from the
last difference Fourier maps and were refined with individual
isotropic temperature factors as well as the N–H hydrogen
atom of 2. The atomic coordinates of the hydrogen atoms of
each phenol group of this compound were also revealed by the
last Fourier maps while the hydrogen atom of the single
phenol group was introduced via AFIX 147 command using
the initial coordinates of the hydrogen corresponding to the
trial position determined by the maximum number of hydro-
gen bonds established in crystal packing with neighbouring
molecules namely crystallisation water molecules. The atomic
positions of the hydrogen atoms of the crystallisation water
molecules with entire occupancy were obtained from last
difference Fourier maps with exception for 2 and 4, which
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