Azacalix[2]arene[2]triazine-based receptors bearing carboxymethyl pendant arms on nitrogen bridges: Synthesis and evaluation of their coordination ability towards copper(ii)

Article abstract of DOI:10.1039/c3ob42047g

For functional nitrogen-bridged calix(hetero)aromatic platforms to be further used in the design of more sophisticated receptors, the azacalix[2]arene[2]triazine nitrogen bridges were functionalised with methyl bromoacetate. Three new macrocycles with four N-methyl ester pendant arms were straightforwardly prepared in good yields from the undecorated azacalix[2]arene[2]triazine precursors with chlorine, dimethylamine or dihexylamine substituted triazines. These intermediate macrocycles exhibited different reactivity towards the nucleophilic replacement, which was rationalized from the computed electrostatic potential for these molecules. Subsequently, the N-methyl ester appendages were hydrolyzed with each dialkylamine derivative providing a single macrocycle with four carboxylic groups. In contrast, the hydrolysis of the dichlorinated azacalix[2]arene[2] triazine analogue yielded a mixture of three isomeric macrocycles having two N-methyl esters and two carboxylmethyl pendant arms and the triazine chlorine atoms replaced by hydroxyl groups. The coordination ability of two macrocycles with four carboxylic groups for transition metals was evaluated with copper(ii) by UV-vis titrations. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3ob42047g

Organic &
Biomolecular Chemistry
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Azacalix[2]arene[2]triazine-based receptors
bearing carboxymethyl pendant arms on nitrogen
bridges: synthesis and evaluation of their
coordination ability towards copper(II)†
Cite this: Org. Biomol. Chem., 2014,
12, 589
João M. Caio,a,b Teresa Esteves,b Silvia Carvalho,a Cristina Moiteiro*b and
Vítor Félix*a
For functional nitrogen-bridged calix(hetero)aromatic platforms to be further used in the design of more
sophisticated receptors, the azacalix[2]arene[2]triazine nitrogen bridges were functionalised with methyl
bromoacetate. Three new macrocycles with four N-methyl ester pendant arms were straightforwardly
prepared in good yields from the undecorated azacalix[2]arene[2]triazine precursors with chlorine, di-
methylamine or dihexylamine substituted triazines. These intermediate macrocycles exhibited different
reactivity towards the nucleophilic replacement, which was rationalized from the computed electrostatic
potential for these molecules. Subsequently, the N-methyl ester appendages were hydrolyzed with each
dialkylamine derivative providing a single macrocycle with four carboxylic groups. In contrast, the hydro-
lysis of the dichlorinated azacalix[2]arene[2]triazine analogue yielded a mixture of three isomeric macro-
cycles having two N-methyl esters and two carboxylmethyl pendant arms and the triazine chlorine atoms
replaced by hydroxyl groups. The coordination ability of two macrocycles with four carboxylic groups for
transition metals was evaluated with copper(II) by UV-vis titrations.
Received 13th October 2013,
Accepted 11th November 2013
DOI: 10.1039/c3ob42047g
www.rsc.org/obc
versatile building block straightforwardly obtained from the
highly reactive cyanuric chloride, which is commercially avail-
Introduction
1,3,5-Triazine derivatives have found widespread application able as a low-cost material.1a
in medicinal chemistry, herbicides, catalysis, textiles, dyestuffs
The intermolecular interactions mentioned above have also
and optical bleaches, among others.1 In the area of supramole- inspired the supramolecular chemistry community for the
cular chemistry, the 1,3,5-triazine derivatives have been exten- design of macrocyclic receptors containing a 1,3,5-triazine
sively used as
a
central building unit of sophisticated ring4,5 as the recognition entity of charged3,6 or neutral
architectures including organic and inorganic–organic hybrid substrates7–9 with biological relevance. These receptors
frameworks.1a,2 Moreover, the 1,3,5-triazine-based compounds include several macrocyclic platforms decorated with 1,3,5-tri-
containing both donor and acceptor hydrogen binding sites azine units such as classical calixarenes10–12 or common
are able to form self-assemblies by a network of complemen- cyclam derivatives.13 Alternatively, the triazine units are in-
tary intermolecular hydrogen bonds eventually assisted by corporated into the macrocyclic framework as illustrated by
π-interactions.3 It is also noteworthy that 1,3,5-triazine is a azacalix[2]arene[2]triazine derivatives where four aromatic
units composed of two phenyl and two triazine rings are com-
monly arranged in a 1,3-alternate fashion. These azacalix[n]-
heteroarenes were originally reported by Wang et al.14 and are
promptly obtained by two successive SNAr coupling reactions
between electrophilic-activated cyanuric chloride units and
nucleophilic 1,3-phenyldiamine derivatives. The same group
also showed that the replacement of the N-bridged hydrogen
atoms by bulky groups such as alkyl, methyl, benzyl or p-methoxy-
phenyl substituents leads to the fine tuning of azacalix[2]arene-
[2]triazine cavity size and shape due to the perturbation caused
by these substituents on the conjugation state of the nitrogen
bridging atoms.15 Besides the appendage of substituents at the
aDepartamento de Química, CICECO and Secção Autónoma de Ciências da Saúde,
Universidade de Aveiro, 3810-193 Aveiro, Portugal. E-mail: vitor.felix@ua.pt;
Fax: +351 234 370 084
bDepartamento de Química e Bioquímica and Centro de Química e Bioquímica,
Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa,
Portugal. E-mail: cmmoiteiro@fc.ul.pt; Fax: +351 217 500 088
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra,
IR data, MS (ESI) spectra, HRMS (ESI) data of all compounds, UV-vis titration
data for 4 and 5 and crystallographic data of 1, 2 and 12 including the corres-
ponding ORTEP diagrams and CIF files. CCDC 957200, 957201 and 957202.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob42047g
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nitrogen bridges, the azacalix[2]arene[2]triazine platform can
be easily functionalized through the replacement of the two
labile triazine chlorine atoms or by the introduction of the
binding units at phenyl rings.8,15
In spite of the chemical versatility, the inherent hydrogen
bonding capacity and π acidic character of the azacalix[2]arene-
[2]triazine scaffold, as aforementioned, the use of this entity
remains almost unexplored concerning the design of func-
tional synthetic receptors for charged or neutral guest species.
In contrast, the dichlorinated tetraoxacalix[2]arene[2]triazine
macrocycle is able to host inorganic polyatomic anions with
different geometries through the anion–π interactions estab-
lished with both electron deficient triazine rings,16 while the
SNAr replacement of both chlorine atoms by chelating pyridine
amines leads to macrocycles with highly selective coordination
ability for copper(II).17 On the other hand, binding studies
with azacalix[2]arene[2]triazine derivatives are limited.
Recently, macrocycles incorporating this platform were
obtained by functionalization of the upper rim with L-alanine
units, and their molecular recognition ability towards aromatic
carboxylate anions was evaluated by our groups.6 Furthermore,
a HPLC stationary phase based on tetraazacalix[2]arene[2]tri-
azine-modified silica gel was prepared and further used in the
separation of various polycyclic aromatic hydrocarbons, nitro-
benzene, organic bases, phenols, and inorganic anions.18 This
platform anchored to a silica supporter was also applied as an
SPE sorbent for the extraction of trace-level tobacco-specific
N-nitrosamines in plasma matrices.19
Pursuing our research line in exploring the azacalix[2]arene-
[2]triazine as a platform for the appendage of binding units,
herein, we report the functionalization of the nitrogen bridges
with ester methyl groups leading to a new series of macro-
cycles 1–5. The ester groups were hydrolyzed and the coordi-
nation ability of the carboxylic acid derivatives 4 and 5 was
evaluated for transition metals with copper(II). The recog-
nition capability of these receptors for neutral substrates is
illustrated with the X-ray crystal structure of macrocycle 1 with
the diglycolic acid.
Scheme 1 Two synthetic pathways (a and b) devised for the synthesis
of N,N,N,N-tetracarboxymethylazacalix[2]arene[2]triazine 1.
The synthetic route (a), requires the functionalization of
starting materials m-phenylenediamine 6 and the trimer 7,
with methyl bromoacetate before the macrocyclization reac-
tion. The trimer 7 was previously obtained by the reaction of 6
with two high reactive cyanuric chloride molecules, as earlier
described by Wang et al.14 The derivatization of the starting
material 6 was undertaken using different bases (Cs2CO3 or
K2CO3), temperatures (room or 65 °C) and solvents (DMF, CH3CN
or THF). In these experimental conditions, the intermediates 8
and 9 were always obtained together with several secondary pro-
ducts, as it was impossible to separate them from the crude reac-
tion mixture. In spite of the separation failing, and in order to
obtain 1 through the synthetic pathway (a), we have decided to
continue the reaction between the crude products 8 and 9.
However, the formation of the macrocycle 1 was not observed,
which led us to definitively leave this synthetic approach.
Alternatively, in the synthetic route (b), the macrocyclic plat-
form azacalix[2]arene[2]triazine 10 was synthetized from the
coupling reaction between 6 and the trimer 7 in 58% yield
using experimental conditions slightly modified from those
previously reported by Wang et al.14 Afterwards, the N–H brid-
ging groups of 10 were functionalized with methyl bromo-
acetate (10 eq.) in CH3CN/Cs2CO3, yielding the target
N-tetramethyl ester macrocycle 1 in 59% yield. The insertion of
four methyl ester appendages at the nitrogen bridges was con-
firmed by the 1H NMR spectrum through the absence of a
singlet corresponding to the four N–H bridges at δ 10.00 ppm
and the occurrence of two new singlets at δ 4.47 and 3.75 ppm
assigned to four methylene and methoxy groups, respectively.
Furthermore, the four N-methyl ester-bridging groups were
corroborated by the 13C NMR spectrum with a resonance at δ
169.7 ppm and by the IR spectroscopy through a band at
1750 cm−1 assigned to carbonyl groups. The ESI-MS spectrum
showed a [M + H]+ ion peak at m/z 727 and an adduct ion
[M + Na]+ at m/z 749 was also consistent with the existence of 1.
The subsequent MS2 spectrum of the [M + H]+ showed the loss
Results and discussion
Synthesis
In order to prepare the azacalix[2]arene[2]triazine derivative 1,
two synthetic strategies were initially intended as shown in
Scheme 1.
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of CH3OH, one and two fragments of C(OH)+OCH3 from with methyl bromoacetate in the presence of Cs2CO3 using
N-methyl ester arms. The presence of two chlorine-substi- different equivalents (10 to 20 eq.) of these two reagents
tuted triazines was confirmed by [M + 2]+ and [M + 4]+ ion (Scheme 2). The target 3, with two dihexylamine chains, was
peaks with relative intensities 64/10, reflecting the natural successfully obtained from 12 in 42% yield when 16 equi-
isotope distribution pattern of chlorine 35Cl/37Cl. The structure valents of both Cs2CO3 and methyl bromoacetate were used.
1
of 1 was further established by single crystal X-ray diffraction, The formation of 3 was confirmed through the H NMR spec-
which revealed the existence of an unexpected dimethyl di- trum, showing a multiplet at δ 4.35 ppm and a singlet at
glycolate molecule associated with 1, vide infra. The dimethyl δ 3.69 ppm assigned to the methylene and methoxy groups
diglycolate is a side reaction product eventually derived from respectively, both from the four N-methyl ester arms. In agree-
the basic assisted self-condensation of two methyl bromo- ment, the ESI-MS spectrum performed in positive ion mode
acetate molecules along the appending reaction.
showed a [M + H]+ ion peak at m/z 1026 and an adduct ion
Aiming at the potential use of tetra-carboxylic acid deriva- [M + Na]+ at 1048. Furthermore, the macrocycle 3 exhibits a
tives as eventual intermediates in organic synthesis, the lipo- fragmentation pattern similar to 1.
philicity of the azacalix[2]arene[2]triazine platform was
In contrast, the intermediate 11 did not afford the macro-
changed, replacing the chlorine atoms of the triazine rings by cyle 2 using equivalent reaction conditions. Thus, the reactivity
two dialkylamines with different alkyl size chains (dimethyl- of 12 seems to be related with the higher solubility of this
amine or dihexylamine). The substitution of two electron-with- intermediate in acetonitrile, considering that 11 and 12 have
drawing groups by two electron-donating groups leads comparable reactivity towards the nucleophilic substitution
necessarily to azacalix[2]arene[2]triazine derivatives with reaction as later discussed. It is noteworthy that the insertion
different reactivity on the nitrogen bridges.
of the N-methyl ester appendages was successful only when
Bearing in mind these considerations, the syntheses of the acetonitrile was used as a solvent.
ester macrocyles 2 and 3 were undertaken following two syn-
Alternatively, in the second synthetic route (Scheme 3), the
thetic pathways. In the first route (Scheme 2), the appending macrocycles 2 and 3 are obtained directly from the N-tetra-
reaction of methyl ester arms was preceded by the preparation methyl ester derivative 1. Thus, 2 was prepared by the reaction
of the dialkyl amine derivatives 11 and 12 through the replace- of 1 with dimethylamine in the presence of K2CO3 and DMF at
1
ment of the triazine chlorine atoms of 10 by dimethyl- and 70 °C in a yield of 82%. The H NMR spectrum of 2 compared
dihexylamine, respectively. The success of these two nucleo- with 1 shows a new singlet at δ 3.05 ppm assigned to four
philic reactions was corroborated by the 1H NMR spectra of 11 NCH3 methyl groups. The ESI-MS spectrum exhibits a [M + H]+
and 12, displaying chemical shifts between δ 3.63–3.10, ion peak at m/z 745 consistent with the molecular formula of
1.71–1.20 and 0.94–0.93 ppm assigned to NCH2, –(CH2)4– alkyl 2. The structure of 2 was further corroborated by single crystal
12 and CH3 terminal chains respectively. The formation of 11 X-ray diffraction, vide infra. Compound 3 was also obtained
was confirmed by ESI-MS spectrum with a [M + H]+ ion peak at using identical experimental conditions in a yield of 51%,
m/z 457 while the evidence of 12 was obtained by TOF-MS exhi- which represents a slight improvement relative to the synthetic
biting a [M]+ ion peak at m/z 737. In addition, the structure of approach outlined in Scheme 2. Therefore, these experimental
12 was definitively established by single crystal X-ray structure results seem to indicate that the NH bridging units in the
determination, vide infra.
undecorated macrocyle 10 are more reactive towards the
In order to obtain the target macrocycles 2 and 3, the inter- nucleophilic substitution than the dialkylamine substituted
mediates 11 and 12 were subsequently reacted in acetonitrile triazines 11 and 12. Further insights into the reactivity of N–H
bridging groups were obtained from the calculation of the
electrostatic potential on the surfaces of 10–12 using the
Hartree–Fock computational analysis as follows.
Scheme 3 Synthesis of 2 and 3 directly from 1 after the insertion of
Scheme 2 Synthesis of the target macrocycle 3 preceded by the repla-
cement of both chlorine atoms of 10 by dialkylamines.
carboxymethyl pendant arms on nitrogen bridges of the parent macro-
cyle 10.
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Electronic structure calculations
the base-catalyzed nucleophilic substitution of the hydrogen
nitrogen bridging atoms by four methyl ester pendant arms.
The Vs,max and Vs,min values were calculated at HF/6-311+G**
from the structures of 10–12 previously optimized at the same
level of theory with Gaussian 0923 and are gathered in Table 1.
The three macrocycles exhibit four well-defined positive
regions drawn in red on the electrostatic potentials mapped on
the electron densities of 10–12, shown in Fig. 1 with maxima
depicted as red dots positioned at short distances from the
hydrogen atoms of the nitrogen bridges (ca. 1.21 Å). Further-
more, the four Vs,max values for 10 are higher than for 11 and
12, indicating that the former macrocycle is more acidic on the
nitrogen bridges due to the electron withdrawing promoted by
both chlorine-substituted triazine rings. In agreement, the
macrocycle 10 has a negative region located inside the macro-
cyclic cavity with two close Vs,min values of only −35.5 and
−35.4 kcal mol−1 and depicted by the two cyan dots in Fig. 1
(top). In contrast, the dialkylamine substituents on both triazine
rings make the calix framework electron rich and consequently
the two minima shown in Fig. 1 for 11 (middle) and 12
(bottom) are more negative than for 10 (see Table 1). In other
words, 11 and 12 are more basic in the centre of the macrocyclic
cavity and less acidic on the four N–H bridging groups.
The electrostatic potential computed on a molecule’s electron
density surface (Vs) provides an effective tool to evaluate non-
covalent interactions, which are largely electrostatic in
nature.20 In particular, the most positive values (Vs,max) and
the most negative values (Vs,min) of Vs have been shown to cor-
relate well with hydrogen-bond acidity and basicity respecti-
vely.21,22 Therefore, we decided to assess the Vs,max and Vs,min
for macrocycles 10–12 in order to rationalize their reactivity in
Table 1 Vs,max (left) and Vs,min (right) values (kcal mol−1). On the 0.001
electron per bohr3 density surfaces of 10–12
10
11
12
44.6, −35.5
44.2, −35.4
43.8
35.5, −49.9
35.3, −49.7
34.5
35.8, −50.7
35.4, −50.4
34.1
43.8
34.4
33.9
This analysis is entirely consistent with the experimental
reactivity observed for 10–12. In macrocycle 10, with higher
Vs,max values, the hydrogen N-bridging atoms are more easily
released than in 11 and 12, and consequently, 10 is more reac-
tive towards base-catalysed nucleophilic substitution. By con-
trast, the macrocycles 11 and 12 with similar local maxima
potentials have similar acidities, hence identical nucleophilic
reactivities are expected. Therefore, the non-reactivity of 11
seems to be dictated by its poor solubility in acetonitrile.
Single crystal X-ray structures of 1, 2 and 12
The structure of the association between 1 and dimethyl digly-
colate with a stoichiometry 1 : 1 observed in the solid state is
presented in Fig. 2. This association has a 2-fold crystallo-
graphic axis running through the oxygen atom of the ether
diglycolate linkage. The macrocyle exhibits the usual 1,3-alter-
nate conformation24 with four methyl acetate arms located
Fig. 2 Association between 1 and dimethyl diglycolate in solid state is
shown in the left plot with the neutral substrate through the C–H⋯O
hydrogen bonds and C–H⋯π interactions, which are drawn as purple
dashed lines. The plot at the right emphasizes the almost parallel dispo-
sition of the two phenyl rings in 1,3-alternate conformation together
with Hortho⋯Hortho and Hmeta⋯Hmeta distances drawn as yellow and cyan
teal dashed lines, respectively.
Fig. 1 Electrostatic potential mapped on the molecular electron
density surface (0.001 electrons bohr−3) for 10 (top), 11 (middle) and 12
(bottom). The colour scale ranges from blue (−50.8 kcal mol−1) to red
(44.0 kcal mol−1). The red and cyan dots correspond to the location of
V
s,max and Vs,min values respectively.
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Fig. 3 Molecular structure of 2 illustrating the spatial disposition of the
four methyl ester pendant arms relatively to the N4 bridge plane (left)
and the nonparallel disposition of two phenyl rings relatively to each
other (right). Remaining details as given in Fig. 2.
below the macrocyclic plane defined by the four nitrogen
bridges, henceforth denominated as the N4 bridging plane.
The substrate is positioned over the narrow rim of azacalix[2]-
arene[2]triazine with C–H⋯O distances between two ortho-
hydrogen atoms of both phenyl rings and the ether oxygen
atom of dimethyl diglycolate of 2.80 Å. Furthermore, one
hydrogen of each methylene group points to an electron
deficient triazine ring at a C–H centroid ring distance of
2.87 Å. These distances, drawn in Fig. 2 (left plot) as purple
dashed lines, seem to indicate that the association is stabilized
by weak C–H⋯O hydrogen bonds and C–H⋯π interactions,
apart from the other electrostatic interactions derived from
crystal packing.
Fig. 4 Different structural features of the solid state structure of 12:
molecular diagram in the top shows the two CHCl3 solvent molecules
positioned above and below the macrocycle with C–H groups at dis-
tances from the plane defined by the azacalix[2]arene[2]triazine scaffold
consistent with the existence of C–H⋯π interactions, which are
depicted as red dashed lines (the yellow dot is the centroid defined by
the nitrogen bridging atoms); view in the bottom shows 12 in space
filling model emphasizing the ladder type conformation and the short
distance between ortho phenyl protons.
The asymmetric unit of 2 consists of one macrocycle,
shown in Fig. 3, and one THF solvent crystallization molecule.
As observed for 1, the macrocycle 2 exhibits a 1,3-alternate con-
formation, but with tetramethyl ester pendant arms showing a
different spatial disposition. In 2, a carboxylate methoxy group
located above (+) the N4 plane is followed by another posi-
tioned below this plane (−), leading to a conformation type
+-+- (Fig. 3, right), whereas in 1, as a consequence of the
dimethyl diglycolate position, the conformation adopted is −−
(Fig. 2, left).
It is noteworthy that the two 1,3-alternate conformations of
these two macrocycles correspond to different shapes, as is
evident from the structural comparison presented in ESI
(Table S1†). Indeed, the two phenyl rings in 1 are almost paral-
lel (see Fig. 2, right) with distances between the ortho (the
azacalix[2]arene[2]triazine derivatives (as revealed by a search
on CSD)24 with the two phenyl rings adopting an almost anti-
parallel disposition with a dihedral angle of 2.5°. The two
ortho hydrogen atoms are facing each other, giving a shorter
Hortho⋯Hortho distance of 2.75 Å when compared with the
corresponding distances in 1 (4.49 Å) and 2 (3.70 Å). The tri-
azine rings are nearly coplanar with the N4 bridging plane con-
sistent with ϕ angles of 2.8 and 4.3°, whereas the phenyl rings
intercept this plane at a Ω angle of 25.8 and 28.2° leading to a
ladder type conformational shape, as depicted in the perspec-
tive view presented in Fig. 4 (bottom). An unusual flattened
partial cone conformation was also observed for the related
tetraoxacalix[2]arene[2]triazine derivative bearing benzyloxy
and methyl ester substituents on both benzene rings, while for
an analogous macrocycle, in which these bulky groups are
replaced by tert-butyl groups, this conformation coexists in the
solid state, as a major component, with the common 1,3-alter-
nate conformation.25 In contrast to 12, in these molecules the
phenyl rings adopt a spatial disposition roughly perpendicular
to the O4 bridging plane with Ω angles of 86.0 and 85.1° for
the former and second macrocyle, respectively.
hydrogen atoms between the nitrogen bridges, Hortho⋯Hortho
)
and meta hydrogen atoms (Hmeta⋯Hmeta) of 4.49 and 4.80 Å,
respectively. In contrast in 2, the Hortho⋯Hortho distances of
3.70 Å are markedly shorter than the Hmeta⋯Hmeta distances of
6.77 Å showing the existence of a wider rim. Furthermore, in 2
the phenyl rings intercept the N4 plane at dihedral angles (Ω)
of 68.3 and 71.4°, while in 1 the phenyl rings are roughly per-
pendicular to this plane with Ω angles of 88.4°. In contrast, in
both compounds, the triazine rings are tilted relatively to the
N4 plane by comparable dihedral angles (ϕ) of 33.7° for 1 and
35.2 and 36.0° for 2.
Another intriguing structural feature in 12 is the location of
the two crystallographically independent solvent molecules
above and below the macrocycle, with the corresponding C–H
groups at distances of 2.19 and 2.57 Å from the N4 bridging
plane. These distances suggest the existence of C–H⋯π inter-
actions between the acidic C–H chloroform groups and π elec-
tron azacalix[2]arene[2]triazine rich system promoted by the
The asymmetric unit of 12 is composed of three discrete
molecules, one of macrocyle and two CHCl3 solvent crystalliza-
tion molecules as shown in Fig. 4. It is noteworthy that
the macrocyle exhibits an unprecedented conformation for
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N-dihexylamine substituents on triazine rings and the almost
flattened conformation. Indeed, the ladder type conformation
is converted into the 1,3-alternate one when 12 is optimised in
the gas-phase at the HF/6-311+G** level of theory. Therefore,
the ladder conformation type observed in the crystal structure
is governed by a delicate balance between the electronic nature
of azacalix[2]arene[2]triazine scaffold and packing effects.
The N–C bridges distances have comparable values in the
three macrocycles following the usual pattern exhibited by aza-
calix[2]arene[2]triazine, i.e. the distances to triazine rings are
shorter than those to phenyl rings in agreement with a double
sp2/sp3 hybridization state for nitrogen bridging atoms
(Table S1†). Nevertheless, the distances of a second set in 12
are systematically 0.02 Å shorter than the corresponding ones
in 1 and 2, indicating a more efficient electron delocalization
through the azacalix[2]arene[2]triazine scaffold in 12, in agree-
ment with the different conformational shape adopted by this
macrocycle when compared with 1 and 2.
Scheme 5 Tetracarboxylic acids derivatives 4 and 5 obtained respecti-
vely from 2 and 3 azacalix[2]arene[2]triazine methyl ester analogues.
confirmed by the absence of the isotopic [M + 2]+ and [M + 4]+
ion peaks in the positive ion mode ESI-MS spectrum.
Subsequently, the hydrolysis of 1 was also undertaken in
acidic medium of HCl (6 or 10 N). Under these reaction con-
ditions a water-soluble product was obtained, suggesting the
formation of the tetra-carboxylic acid. Unfortunately, all
attempts to isolate this compound were unsuccessful, even as
a hydrochloric salt.
Hydrolysis of the N-tetramethyl ester pendant arms
In contrast to what happened with 1, all four methyl ester
groups of 2 and 3 were hydrolyzed with KOH in the THF–
MeOH solvent mixture leading to the target compounds 4 and
5, which were obtained in good yields of 74% and 98%,
respectively (Scheme 5), after acidification. The formation of
these two macrocycles was attested by the absence of the
methyl ester protons from the corresponding precursors in
their 1H NMR spectra. In agreement, the ESI-MS spectra
carried out in negative ion mode showed [M − H]− and
[M + Na − 2H]− peaks at m/z 687 and 709 for 4 respectively,
and 968 and 990 for 5 in the same order.
In order to obtain suitable ligands for metal coordination the
hydrolysis of the methyl ester pendant arms was carried out
using either basic or acidic conditions. Firstly, the saponifica-
tion of 1 was performed in THF–MeOH (1 : 1) solvent system
using KOH or LiOH aqueous solutions as strong bases. In both
reaction conditions, a mixture of three possible isomeric com-
pounds 13, bearing two carboxylic groups and two methyl
ester groups, adjacent to the phenyl or triazine rings or in
alternate positions, was obtained (Scheme 4) in ca. 62% yield
after acidification of the reaction mixture with HCl (6 N) at
pH = 1. The substitution of the chlorine atoms of both triazine
moieties by hydroxyl groups was also observed. The presence
of two methyl ester groups was confirmed in the 1H NMR
spectrum with the singlet at δ 3.82 ppm integrating to six
protons of two methoxy groups. The 13C NMR spectrum
showed two resonances at δ 170.5 and 171.3 ppm, indistin-
guishably assigned to the ester and acid carbonyl groups.
Further experimental evidence for the partial hydrolysis of the
methyl ester groups was acquired through the negative ion
ESI-MS technique with the appearance of the [M − H]− ion
peak at m/z 661 and [M + Na − 2H]− adduct at m/z 683 in agree-
ment with the existence of a mixture of isomeric compounds
13 having two carboxyl and two methyl ester pendant arms.
The replacement of chlorine atoms by two hydroxyl groups was
Coordination studies
The coordination ability of the macrocycles 4 and 5 for tran-
sition metals was investigated with copper(II) through the UV-vis
spectroscopy. The four carboxylic groups of both macrocycles
can be deprotonated depending on the medium pH. Therefore,
in order to avoid the formation of species with different proto-
nation states only the fully protonated (acid) and the fully
deprotonated (basic) forms of both were evaluated. In addition,
due to solubility reasons, the acid form was investigated in dry
methanol and the basic form in water at pH ≈ 11. The spectra
of the macrocycles and their metal complexes were recorded
and are presented in ESI as Fig. S43–S46.† The corres-
ponding UV-vis absorption bands are summarized in Table 2.
In both solvents the UV-vis spectra of free ligands 4 and 5
display absorption bands typical of ILCT transitions. Further-
more when a CuCl2 solution is added to solutions of 4 and 5,
new absorption bands appear in the spectra, which correspond
to the ligand field d–d and LMCT transitions. The d–d bands
have very low intensities when compared with the remaining
ones. The ILCT bands do not suffer a substantial wavelength
shift with the coordination of Cu2+ to both macrocycles.
The stoichiometry of the complexes formed between the
Cu2+ and the macrocycles 4 and 5, in the acid form, was
Scheme 4 Hydrolysis of N-methyl ester appendages of 1 in basic
conditions.
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eventually composed of nitrogen bridging atoms and carboxy-
late oxygen donor atoms. Unfortunately the Cu2+ complexes of
4 and 5 did not afford suitable crystals for single crystal
X-ray diffraction determination, and further coordination
studies on these complexes are beyond of the scope of this
work. To the best of our knowledge, and in contrast with tetra-
oxacalix[2]arene[2]triazine derivatives,17 this preliminary
coordination study is the first one reported on azacalix[2]arene-
[2]triazine based artificial receptors.
Equivalent titration studies with both macrocycles, in their
basic forms, were not possible to be undertaken due to the for-
mation of precipitated hydroxo complexes in the presence of
high amounts of metal.
Table 2 UV-vis absorption bands for the d–d, LMCT and ILCT tran-
sitions of 4 and 5 and their copper(II) complexes with λmax in nm
Species
Solvent
d–d
LMCT
ILCT
4
H2O
CH3OH
—
—
—
—
351
237.2, 242.8, 249.2, 255.4, 261.5,
268.3, 272 (sh)b
4·Cu2+
H2O
CH3OH
nda
675
421
341.5
351
238.2, 243.2, 249.2, 255.4, 261.5,
268.3, 272 (sh)b
5
H2O
CH3OH
—
—
—
—
242.5
238.2, 246.3, 252.0, 259.6, 266.5,
272 (sh)b
5·Cu2+
H2O
CH3OH
636
654
336.1
371.5
242.5
238.2, 246.3, 252, 259.6, 266.5,
272 (sh)b
Conclusions
a The band was not observed by solubility reasons. b sh means
shoulder.
Two synthetic approaches to afford azacalix[2]arene[2]triazine
macrocycles armed on the nitrogen bridges with four methyl
ester groups were explored. However, our studies showed that
the macrocycle 1 is only successfully obtained from the un-
decorated azacalix[2]arene[2]triazine 10 platform, after the
determined using the mole ratio method in methanol at 20 °C.
The addition of increasing amounts of Cu2+ to the solution of
4 or 5 leads to an intensity decrease of the absorption bands
between 260 and 270 nm till 1 equivalent of metal is added as
shown in Fig. 5. From this stage, no change in the absorbance
was observed, which indicates a 1 : 1 metal : ligand stoichio-
metry (Fig. 5). Moreover, a band at ca. 300–400 nm, attributed
to the LMCT as earlier described, is present throughout the
titrations. The stability constants of Cu2+ complexes were
determined from the titration data using the HypSpec soft-
ware26 and log K values of 6.70 0.2 for 4 and 6.65 0.2 for 5
were estimated. These values indicate that both macrocycles
are able to coordinate the metal centre with equivalent
strengths, thus affording complexes with coordination spheres
macrocyclization process. Afterwards,
1 can be straight-
forwardly used to prepare the macrocycles 2 and 3 by the single
SNAr replacement of the chlorine atoms by dimethylamine and
dihexylamine respectively. Otherwise, these two macrocycles
can be obtained from the corresponding dialkyl azacalix[2]-
arene[2]triazine intermediates 11 and 12, but this synthetic
pathway is less efficient. The four N–H bridged atoms in 11
and 12 are less acidic than in 10 and, in agreement with the
computed Vs,max values, the nitrogen bridges of 11 and 12 are
less reactive to the base catalyzed nucleophilic substitution.
The hydrolysis of all four N-methyl ester pendant arms was
only successfully achieved when strong basic conditions were
used to afford the target macrocycles 4 and 5 from 2 and 3
respectively. In contrast, in 1, the two chlorinated triazine ring
positions are still reactive, and then, concomitantly with the
random hydrolysis of two methyl ester groups, the nucleo-
philic substitution of both triazine chlorine atoms by hydroxyl
groups occurs.
The preliminary coordination studies showed that the
macrocycles 4 and 5 are able to form Cu2+ complexes under
either basic or acidic conditions. The search for neutral recep-
tors based on the azacalix[2]arene[2]triazine platform able to
recognise cations and anions continues to progress at our
laboratories.
Experimental section
General remarks
Fig. 5 Titration of 4 and 5 in dry methanol with CuCl2 by means of
UV spectroscopy: UV-vis spectra of 4 (7.96 × 10−6 M – top left) and 5
(1.35 × 10−5 M – bottom left) recorded at 20 °C by the addition of
increasing amount of CuCl2; absorbance variation versus Cu2+ equiva-
lents added at λmax 261.5 nm for 4 (top right) and at λmax 266.5 nm for 5
(bottom right).
All reagents were used as supplied without further purifi-
cation. All solvents were purified and dried before use accord-
ing to standard methods.27 Melting points were determined
with a Reicher Model Thermovar melting-point apparatus
without further correction. LRMS spectra were obtained on a
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Bruker Daltonic Esquire 3000 Ion Trap Mass Spectrometer (0.97 mmol). The mixture was stirred for 24 h at 70 °C. After-
with ESI-ITD-MS/MS positive or negative ion mode while wards, ethyl ether was added to the crude reaction and the
HRMS (ESI) measurements were performed on a Bruker resulting organic phase was washed with water. The organic
Daltonics ApexQe FTICR Mass Spectrometer equipped with a phase was evaporated under reduced pressure to give the
combined Apollo II electrospray/MALDI ion source and a 7 T required macrocyle.
actively shielded superconducting magnet. 1H, 13C (APT) and
Di(dimethylamino)azacalix[2]arene[2]triazine, 11. A general
2D NMR (HMQC and COSY) spectra were recorded on a Bruker reaction of 10 with dimethylamine gave 11 (107 mg, 51%
CXP400 spectrometer operating at 400 MHz using one of the yield), m.p. > 350 °C; 1H NMR (400 MHz, DMSO-d6, 25 °C): δ =
following deuterated solvents: DMSO-d6 (99.9%), acetone-d6 or 8.77 (s, 4H, NH), 7.80 (s, 2H), 7.09 (t, J = 7.9 Hz, 2H), 6.76–6.60
CDCl3. All chemical shifts are given in ppm and using tetra- (m, 4H), 3.10 (s, 12H) ppm; 13C NMR (101 MHz, DMSO-d6, 25 °C):
methylsilane as an internal reference. UV-vis spectra were δ = 165.0, 164.6, 139.6, 128.2, 116.4, 116.3, 35.5 ppm; ESI-MS
recorded with a Shimadzu UV-2450 spectrophotometer.
m/z 479 [M + Na]+; 457 [M + H]+; MS2 (M + H)+ m/z 412 [M + H
N,N′-Bis(dichloro-s-triazinyl)-m-phenylenediamine, 7, was − HN(CH3)2]+, 387.
prepared as previously described by Wang et al.14
Di(dihexylamino)azacalix[2]arene[2]triazine, 12. A general
Azacalix[2]arene[2]triazine, 10. As mentioned above this reaction of 10 with dihexylamine afforded 12 as a white solid
macrocyle was obtained using an experimental procedure (258 mg, 76% yield), m.p. > 350 °C; 1H NMR (400 MHz, CDCl3,
slightly different from that previously reported by Wang et al.14 25 °C): δ 8.24 (s, 2H), 7.03 (t, 2H, J = 7.70 Hz), 6.45 (br, s, 4H),
The diamine 6 (1.11 mmol, 0.12 g) and the trimer 7 6.67 (s, 4H), 3.40 (t, 8H, J = 6.75 Hz), 1.58–1.52 (m, 8H), 1.25 (s,
(1.11 mmol, 0.45 g), previously dissolved in acetone (98 mL), 24H), 0.83 (t, J = 6.75 Hz, 12H) ppm; 13C NMR (101 MHz,
were simultaneously added dropwise at the same rate to a solu- CDCl3, 25 °C): δ 164.9, 146.0, 128.9, 115.3, 110.7, 46.4, 31.7,
tion of diisopropylethylamine (0.46 mL, 2.75 mmol) in acetone 27.9, 26.7, 22.7, 14.1 ppm; TOF-MS m/z 737 [M + H]+; 369
(224 mL) at 65 °C for 8 h. The reaction mixture was stirred [M + H − 2 × HN(CH2)5CH3)2]+.
under nitrogen at room temperature for the subsequent 7 days
Di(dimethylamino)-N,N,N,N-tetracarboxymethylazacalix[2]-
leading to a white precipitate, which was filtered and washed arene[2]triazine 2. A reaction of 1 (0.46 mmol) with dimethyl-
with water and then with acetone. The intermediate macro- amine (0.97 mmol) following the general procedure earlier
cycle 10 was obtained (278 mg, 57%.) as a white solid, m.p. described to prepare 11 and 12, afforded 2 (281 mg; 82%) as a
>350 °C; 1H NMR (400 MHz, DMSO-d6, 25 °C): δ = 10.00 (s, 4H), white solid, m.p. 206–209 °C, after purification through the
7.75 (s, 2H), 7.22 (t, J = 7.9 Hz, 2H), 6.79 (d, J = 7.5 Hz, 4H) flash chromatography using 3 : 1 cyclohexane–acetone as an
ppm; 13C NMR (101 MHz, DMSO-d6, 25 °C): δ = 168.0, 164.3, eluent. IR (KBr) νmax 2935 (C–H), 1751 (CvO ester), 1541, 1458
137.9, 128.9, 118.8, 118.1 ppm.
(CC Ar), 1203 (C–N), 1198 (C–O ester) cm−1 1H NMR
;
N,N,N,N-Tetracarboxymethylazacalix[2]arene[2]triazine, 1. (400 MHz, CDCl3, 25 °C): δ 7.16–7.10 (m, 4H), 7.00 (dd, J = 7.9,
Methyl bromoacetate (3.28 mmol, 0.3 mL) was added to a dis- 1.6 Hz, 4H), 4.39–4.28 (m, 8H), 3.71 (s, 12H), 3.05 (s, 12H)
persion of 10 (0.41 mmol, 0.18 g) in CH3CN (3.5 mL) contain- ppm; 13C NMR (101 MHz, CDCl3, 25 °C): δ 171.3, 165.5, 165.1,
ing Cs2CO3 (4.1 mmol, 1.34 g). The reaction was carried out at 144.5, 130.7, 129.3, 126.0, 52.7, 51.8, 35.8 ppm; ESI-MS m/z
65 °C under stirring for 3 h. Subsequently, CHCl3 was added 767 [M + Na]+; 745 [M + H]+; MS2 (M + H)+ m/z 685 [M + H −
to the reaction crude and the organic phase was successively CH3OCOH]+; 625 [M + H − 2 × CH3OCOH]+; 565 [M + H − 3 ×
washed with an aqueous solution of HCl 10%, and a solution CH3OCOH]+.
of NaHCO3 and brine. The organic phase was dried with mag-
Di(dihexylamino)-N,N,N,N-tetracarboxymethyl azacalix[2]-
nesium sulfate and concentrated under vacuum. The macro- arene[2]triazine, 3. The macrocycle was prepared following two
cycle 1 was purified by flash chromatography using as an alternative synthetic pathways as described above. In the route
eluent cyclohexane–acetone (3 : 2). A white solid was obtained depicted in Scheme 3, the macrocyle 3 was produced by the
(180 mg, 59% yield), m.p. 170–172 °C; IR (KBr) νmax 1749 reaction of 1 with dihexylamine, (0.97 mmol) using the general
(CvO ester), 1568, 1498, 1473 (CC Ar), 1200 (C–O ester), 802 procedure described above to synthesize 11 and 12. The flash
1
(C–Cl) cm−1; H NMR (400 MHz, CDCl3, 25 °C): δ = 7.20–7.14 chromatography of crude reaction using as an eluent cyclo-
(m, 2H), 7.04 (s, 4H), 7.02–7.01 (m, 2H), 4.47 (s, 8H), 3.75 (s, hexane–acetone (3 : 1) provided the macrocycle 3 (240 mg.
12H) ppm; 13C NMR (101 MHz, CDCl3, 25 °C): δ = 169.7, 169.4, 51%) as a white solid, m.p. 150–153 °C; IR (KBr) νmax 2937
165.7, 143.4, 130.0, 129.1, 127.4, 52.3, 51.5 ppm; ESI-MS m/z (C–H), 2918 (C–H), 2850 (C–H), 1736 (CvO ester), 1541, 1458
749 [M + Na]+; 731 [M + H + 4]+; 729 [M + H + 2]+; 727 [M + H]+; (CC Ar), 1199 (C–N), 1194 (C–O ester) cm−1
;
1H NMR
MS2 (M + H)+ m/z 695 [M + H − CH3OH]+; 667 [M + H − C(OH)- (400 MHz, CDCl3, 25 °C): δ = 7.15–7.10 (m, 4H), 6.99 (dd, J =
OCH3]+; 631 [M + H − (C(OH)OCH3 + HCl)]; 607 [M + H − 2 × 7.8, 1.6 Hz, 4H), 4.35 (q, J = 17.1 Hz, 8H), 3.69 (s, 12H), 3.40 (tt,
C(OH)OCH3]+; HRMS (ESI) calcd for C30H29Cl2N10O8+ [M + H]+: J = 17.0, 8.5 Hz, 8H), 1.60–1.47 (m, 8H), 1.36–1.28 (m, 24H),
727.1469, found 727.1510.
0.91 (t, J = 6.7 Hz, 12H) ppm; 13C NMR (101 MHz, CDCl3,
25 °C): δ = 171.2, 165.6, 164.4, 144.6, 130.9, 129.2, 126.2, 52.4,
51.7, 47.4, 31.9, 28.1, 26.8, 22.8, 14.1 ppm; ESI-MS m/z 1048
General procedure for the synthesis of 11 and 12
To a solution of 10 (0.46 mmol, 0.2 g) and K2CO3 (1.24 mmol, [M + Na]+; 1025 [M + H]+; MS2 (M + H)+ m/z 965 [M + H −
0.171 g) in DMF (14 mL) was added
a
dialkylamine CH3OCOH]+; 905 [M + H − 2 × CH3OCOH]+.
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Compound 3 was also prepared by the synthetic route (400 MHz, acetone-d6, 25 °C): δ = 7.21–7.02 (m, 8H), 4.54–4.24
described in Scheme 2 as follows: to a dispersion of 12 (m, 8H), 3.58–3.44 (m, 8H), 1.63 (s, 8H), 1.40–1.24 (m, 24H),
(0.41 mmol, 0.302 g) in CH3CN (3.5 mL) having Cs2CO3 0.89 (t, J = 6.4 Hz, 12H) ppm; 13C NMR (101 MHz, acetone-d6,
(6.56 mmol, 2.14 g) was added methyl bromoacetate 25 °C): δ = 171.7, 166.5, 165.2, 145.7, 131.6, 130.0, 126.5, 53.0,
(6.56 mmol, 0.6 mL). The reaction mixture was stirred at 50 °C 48.1, 32.5, 27.6, 23.4, 14.4 ppm; ESI-MS m/z 990 [M + Na −
for 3 h. The macrocycle 3 was obtained (176 mg, 42% yield) 2H]−; 968 [M − H]−; MS2 (M − H)− m/z 924 [M − H − CO2]−; 880
after work-up as described above for 1.
[M − H − (COHOHCH2 + CO)]−; 836 [M − H − (COHOHCH2 +
CO + CO2)]−; 792 [M − H − 2 × (COHOCH3 + CO)]−; HRMS (ESI)
General procedure for the hydrolysis of the N-tetramethyl ester
macrocycles
+
calcd for C50H73N12O8 [M + H]+: 969.5596, found 969.5652;
elemental analysis calcd (%) for C50H72N12O8·2H2O·CH3OH: C
To a solution of 1, 2 or 3 (0.146 mmol) in THF–MeOH 59.05, H 7.77, N 16.20; found: C 59.42, H 7.53, N 15.82.
(1.42 mL/1.42 mL) an aqueous solution of KOH (5.40 mmol,
0.302 g) in 0.46 mL of water was added. The mixture was
UV-vis spectrophotometric measurements
stirred for 24 h at room temperature and the solvents were The metal complexes in water were prepared by addition of
removed under vacuum. The crude reaction was dissolved in copper(II) chloride salt (0.4 eq.) to a solution of 4 or 5 (1.38 ×
water (3.6 mL) and the acidification of the solution to pH 1 10−3 or 3.09 × 10−3 M). The pH was maintained around 11
with 10% HCl triggered the precipitation of the macrocycle using a standard solution of KOH. The lower concentration
requested.
solutions allowed the measurement of the absorption bands in
Dihidroxy-N,N-dicarboxymethyl-N,N-dicarboxylazacalix[2]arene- the ultraviolet region, while for more concentrated solutions
[2]triazine, 13. A mixture of isomeric macrocycles having two the absorption bands were measured in the visible region.
carboxylic and two methyl esters was obtained from 1 using
Titrations were performed by addition of small amounts of
the general hydrolysis procedure as a white solid (60 mg, yield the chloride copper(II) salt to 4 and 5 in their acid forms in a
of 62%); IR (KBr) νmax 1701 (CvO acid), 1578, 1527 (CC Ar), dry methanol solution at 293.2 0.1 K. The copper(II) salt in
1367 (C–N), 1207 (C–O acid) cm−1; 1H NMR (400 MHz, DMSO-d6, dry methanol solution was standardized as described in ref.
25 °C): δ = 12.71 (s, 2H), 7.25 (t, J = 7.9 Hz, 2H), 7.03 (dd, J = 28. The concentration of each macrocycle was determined by
10.0, 2.1 Hz, 6H), 4.31 (dd, J = 34.6, 17.6 Hz, 8H), 3.82 (s, 6H) the method of continuous variation.29
ppm; 13C NMR (101 MHz, DMSO-d6, 25 °C): δ = 171.3, 170.5,
The stability constants of 4 and 5 Cu2+ complexes were
166.7, 144.1, 130.2, 129.7, 126.3, 54.1, 52.6 ppm. ESI-MS m/z calculated by fitting the corresponding spectrophotometric
683 [M + Na − 2H]−; 661 [M − H]−; MS2 (M − H)− m/z 617 [M − titration data with the HypSpec program.26 The molar absor-
H − CO2]−; 573 [M − H − (COHOHCH2 + CO)]−; 529 [M − H − bance of free macrocycles in methanol and in water solutions
(COHOHCH2 + CO + CO2)]−; 485 [M − H − 2 × (COHOCH3 + was measured in a separate experiment and kept constant for
CO)]−.
all subsequent determinations. The errors quoted are the stan-
Di(dimethylamino)-N,N,N,N-tetracarboxymethylazacalix- dard deviations of the overall stability constants given directly
[2]arene[2]triazine, 4, was straightforwardly prepared through by the program for the input data, which include all the experi-
the general procedure of hydrolysis from 2 as a white solid mental points from all titration curves.
(109 mg; 74% yield), m.p. 278–281 °C; IR (KBr) νmax 2922
X-ray crystallography
(O–H), 1707 (CvO acid), 1587, 1545 (CC Ar), 1245 (C–N), 1203
(C–N) cm−1; 1H NMR (400 MHz, DMSO-d6, 25 °C): δ = 7.21–7.02 Single crystal X-ray diffraction data for 1, 2 and 12 were col-
(m, 8H), 4.54–4.24 (m, 8H), 3.05 (s, 12H) ppm; 13C NMR lected on a Bruker SMART APEX II diffractometer with a CCD
(101 MHz, DMSO-d6, 25 °C): δ = 171.7, 166.5, 165.2, 145.7, 131.6, area detector using graphite monochromatized Mo-Kα radi-
130.0, 126.5, 53.0, 35.8 ppm. ESI-MS m/z 709 [M + Na − 2H]−; ation (λ = 0.71073 Å) at 150(2) K. The frames were integrated
687 [M − H]−; MS2 (M − H)− m/z 643 [M − H − N(CH3)2]−; 599 with the SAINT-Plus software package,30 and the intensities
[M − H − (COHOHCH2 + CO)]−; 555 [M − H − (COHOHCH2 + were corrected for polarization and Lorentz effects. Absorption
CO + CO2)]−; 511 [M − H − 2 × (COHOCH3 + CO)]−; HRMS corrections for all data sets were applied via the multi-scan
+
(ESI) calcd for C30H33N12O8 [M + H]+: 689.2466, found procedure using the SADABS31 from the same graphical suite.
689.2517; elemental analysis calcd (%) for C30H32N12O8·3H2O: The structures were solved by a combination of direct methods
C 48.52, H 5.16, N 22.63 C; found: C 48.87, H 5.10, N 23.00.
with subsequent difference Fourier syntheses and refined by
Di(dihexylamino)-N,N,N,N-tetracarboxymethylazacalix[2]arene- full matrix least squares on F2 using the SHELX-97 suite,32 and
[2]triazine, 5. This macrocycle was obtained from 3 by the final refinements were carried out with SHELXL-2013.32 Aniso-
general hydrolysis procedure. After acidification with HCl, the tropic thermal displacements were used for all non-hydrogen
crude reaction was extracted with dichloromethane. Sub- atoms. The hydrogen atoms were inserted at geometrical posi-
sequently, this organic phase was dried with magnesium tions with Uiso = 1.2 Ueq. to those to which they are attached.
sulfate, filtered and concentrated under vacuum. The macro- Crystal data and refinement details for the three macrocycles
cycle 5 was provided (99 mg; 98% yield) as a white solid, are summarized in Table S2 given in the ESI.† Molecular dia-
m.p. 257–258 °C; IR (KBr) νmax 2922 (O–H), 1716 (CvO acid), grams were drawn with PYMOL.33 Crystal data for the
1541, 1458 (CC Ar), 1238 (C–N), 1201 (C–N) cm−1
;
1H NMR structures have been deposited with the Cambridge
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Crystallographic Data Centre, CCDC: 957200, 1, 957201, 2, and
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and the wave functions for these molecules were generated by
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The authors are grateful for funding from QREN-FEDER,
through the Operational Program Competitiveness Factors –
COMPETE, and National Funds through the FCT under project
PTDC/QUI-QUI/101022/2008 and Pest-OE/QUI/UI0612/2013.
J.M.C. and S.C. thank FCT for PhD scholarship SFRH/BD/
66789/2009 and postdoctoral grant SFRH/BPD/42357/2007
respectively. We also acknowledge Paula Branco from ASAE for
the mass spectra.
23 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone,
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