Silver complexes of peptidomimetic polyazapyridinophanes. The influence of the bonding cavity size and the nature of side chains

Article abstract of DOI:10.1039/b512762a

Several peptidomimetic macrocycles containing a pyridine spacer and ring sizes ranging from 15 to 17 have been efficiently synthesized starting from valine and phenylalanine. The complexes formed have been investigated by potentiometry and NMR. Log K values show that phenylalanine derivatives 8 are consistently more stable than valine derivatives 7, whilst macrocycles with ring sizes of 16 members are the most appropriate for the complexation. The NMR data, in combination with molecular modeling, allow rationalization of the structure of the complexes formed and the participation of the aromatic rings from the side chain of phenylalanine in π-Ag⁺ interactions to be discarded. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b512762a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Silver complexes of peptidomimetic polyazapyridinophanes. The influence
of the bonding cavity size and the nature of side chains
Ignacio Alfonso,a Isabel Burguete,a Santiago V. Luis,*a Juan F. Miravet,a Piotr Seligerb and Ewa Tomalb
Received 12th September 2005, Accepted 19th December 2005
First published as an Advance Article on the web 18th January 2006
DOI: 10.1039/b512762a
Several peptidomimetic macrocycles containing a pyridine spacer and ring sizes ranging from 15 to 17
have been efficiently synthesized starting from valine and phenylalanine. The complexes formed have
been investigated by potentiometry and NMR. Log K values show that phenylalanine derivatives 8 are
consistently more stable than valine derivatives 7, whilst macrocycles with ring sizes of 16 members are
the most appropriate for the complexation. The NMR data, in combination with molecular modeling,
allow rationalization of the structure of the complexes formed and the participation of the aromatic
rings from the side chain of phenylalanine in p-Ag+ interactions to be discarded.
Ag(III) and possess sufficient stability in vivo, have a high potential
Introduction
for being used in chemotherapy treatments.12
The design and synthesis of novel supramolecular ligand archi-
Here we present our studies directed to the preparation of
tectures is closely connected to promising application options in
several peptidomimetic polyazapyridinophanes and the study of
different areas.1 Up to now, a large number of macrocyclic and
their complexes with Ag(I) revealing that aromatic side groups
spherical ligands as well as their open-chain counterparts have
in the constituent aminoacids can have a significant role in
been synthesised and characterised and applications found in sep-
determining the stability of such complexes, even if those aromatic
aration processes, sensing and analyte detection, materials science,
rings are not directly involved in the coordination to the metal.
catalysis, biomedical uses and developmentof nanoscopicdevices.2
One important topic in supramolecular chemistry, originating
from a biomimetic approach, has been the use of aromatic units
of different kinds to build up complex molecular architectures
and supramolecular assemblies characterised by p-electronic
interactions.3 In this context, polyazacyclophanes represent a very
interesting class of macrocyclic receptors being able to interact
with either cationic or anionic guests.4 One of the most attractive
structural features of polyazamacrocycles and, in general, of
receptors containing amine groups, is the possibility of using the
nitrogen atoms to introduce sidearms of different classes. Those
sidearms can substantially affect the properties of the receptor,5 in
particular when they contain additional donor functionalities or
its introduction changes the lipophilic/lipophobic balance.6
Silver(I) complexes of organic ligands derived from arene donors
have a large potential for the construction of organometallic solid-
state devices such as electrical conductors, photoactive switches,
chemical sensors, etc.7 The highly active field of the synthesis of
novel families of compounds containing aromatic units, including
diarylalkanes (-alkenes and -alkynes), cyclophanes, deltaphanes,
cylindrophanes, etc. provides the desired molecular diversity for
this purpose.8–10 The use of the appropriate arene ligands contain-
ing several aromatic subunits gives the possibility of assembling
silver(I) in complex architectures in which the metal centre can
form part of a polymeric linear structure or be encapsulated within
a 3D network.7,11 Additionally, metal complexes that contain
Results and discussion
Synthesis of receptors
The synthesis of peptidomimetic cyclophanes such as 1 and 2
has been recently described by our group and takes place very
efficiently owing to the high degree of preorganization of open-
chain pseudopeptidic precursors 5.13 Preliminary studies have
shown, however, that compounds such as 1 and 2, under neutral
conditions, do not have a high affinity for metal cations for the
limited number of strong donor atoms available for coordination.
Thereby, the substitution of the benzene aromatic ring in 1 or
2 by a 2,6-substituted pyridine ring could greatly contribute to
improve the stability of the resulting metal complexes.
Chart 1
aDepartment of Inorganic and Organic Chemistry, UAMOA, University
Jaume I/CSIC, 12071, Castello´n, Spain. E-mail: luiss@mail.uji.es;
Fax: +34 964728214; Tel: +34 963728239
Accordingly, the synthesis of the corresponding macrocyclic
pyridinophanes (7 and 8) was carried out following the general
procedure used for the preparation of 1–2 and related systems
(Scheme 1).13,14
bDepartment of General and Inorganic Chemistry, University of Ło´dz´, 90-
136, Ło´dz´, Poland
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of the aromatic side-chains in the three-dimensional coordination
to the metal center through p interactions.15
In order to gain some information on the geometrical constrains
in the involvement of the phenyl groups of the side chains in the
coordination to a metal center sitting in the cavity, we carried out
different theoretical calculations. In this context, three different
basic conformations can be considered as defined in figure 1. For
the in–in conformation, the two phenyl rings are expected to be
bent towards the macrocyclic ring. According to the C2 symmetry
of the molecule, each one of the aromatic rings should be situated
on opposite sides of the cavity to provide a complete encapsulation
of a metal cation sitting in the cavity. For the in–out conformation,
only one aromatic ring is bent over the cavity, while the second
one is pointing outwards. Finally, for the third conformation, out–
out, both phenyl rings are pointing outwards, not providing any
possible interaction with a metal cation in the macrocyclic cavity.
Fig. 1 General description of the three different phenyl rings dispositions
around the cavity of the ligand (in–in, in–out, out–out).
Scheme 1 (i) DCC, N-hydroxysuccinimide, THF; (ii) H2N(CH2)nNH2,
DME; (iii) HBr/AcOH; (iv) aq. NaOH, (v) 2,6-bis(bromomethyl)-
pyridine, K2CO3/CH3CN.
Monte Carlo random conformational search (MMFF94 force
field as implemented in Spartan Pro) showed that these receptors
are very flexible, as confirmed by the large number of minima
obtained. However, some interesting trends can be pointed out.
Although the most favorable conformations for the phenylalanine
derivatives set the side chains pointing out of the macrocyclic
cavity, some conformers with this Ph residue folded to the
main cyclic structure are also energetically accessible. Thus, for
compound 8b (n = 3) the lowest energy minimum as well as
the one with the folded residue are depicted in figure 2. The
computed difference of energy is only 0.9 kcal mol−1, supporting
the theoretical possibility of coexisting populations of these
conformations at room temperature. Besides, if some additional
stabilization were acting, such as p-cation interactions, it would
be clearly easy to obtain conformations of this kind.
Table 1 Results obtained for the synthesis of polyazapyridinophanes
Entry
Compound
n
R
Yield (%)a
1
2
3
4
5
6
7a
7b
7c
8a
8b
8c
2
3
4
2
3
4
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH2Ph
CH2Ph
CH2Ph
62
50
63
62
56
65
a Yields refer to isolated products after chromatographic purification.
As can be seen in Table 1, the different pyridinophanes were
obtained, as pure compounds after chromatographic purification,
in 50–65% yields, bearing in mind that purification step responsible
for a significant decrease in the final yields. Nevertheless, these
yields are comparable to those obtained for related systems such
as 1, and the synthetic methodology does not require the use of
high dilution techniques. This is in good agreement with the fact
that the U-turn preorganization of the open-chain compounds 5
and 6 seems to be at the origin of this easy macrocyclization.13c
According to the goals of our work, we considered two main
structural variations for the design of macrocyclic receptors 7 and
8. First, three different sizes were selected for the macrocyclic
cavity through a variation in the number of methylene groups in
the central aliphatic spacer. Thus, the synthesized pyridinophanes
contained 15 (n = 2, 7a and 8a), 16 (n = 3, 7b and 8b) and 17 (n =
4, 7c and 8c) membered rings. The second point for molecular
diversity was the nature of the side chain. In this regard, the two
starting amino acids selected were valine and phenylalanine, as
this provides a macrocyclic species of C2 symmetry containing
Fig. 2 Minimum energy conformers: in–out (left) and out–out (right) for
compound 8b.
Study of the interaction with Ag+. Potentiometric studies
Taking the former considerations into account, the interaction
of receptors 7 and 8 with the Ag+ cation was studied by poten-
tiometric titrations using a Ag+ ion selective electrode. The low
solubility of some of the ligands precluded an accurate analysis of
the complexes formed in water. Nevertheless, conditional stabililty
constants for AgL complex formation could be determined in
=
=
either aliphatic (R CH(CH3)2, 7) or aromatic (R CH2Ph, 8) side
chains. This could allow us to explore the possible participation
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Table 2 Logarithms of the stability constants for the formation of the
AgL complexes for ligands 7 and 8 in MeOH, determined at 298.1 K in
0.05 M (C2H5)4NClO4
that some kind of p-cation interactions are involved in complex
formation.
NMR studies
Ligand
n
R
Log Ka
In order to analyse this possible participation of aromatic rings
in more detail, an NMR analysis of the corresponding complexes
7a
7b
7c
8a
8b
8c
2
3
4
2
3
4
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH2Ph
CH2Ph
CH2Ph
5.68(3)
5.82(2)
5.50(2)
6.46(3)
6.55(2)
5.72(3)
1
was undertaken. In this regard, the H and 15N NMR spectra of
AgL species in CD3OD were recorded and studied.
In the case of the 15N NMR spectroscopy, all the assignments
1
were made on the basis of 2D H–15N correlation experiments
a Standard deviation on the last significant figure are given in parenthesis.
1
(gHMBC pulse sequence).16 Fig. 3 shows the long range H–15N
correlation spectra obtained for different L : Ag+ stoichiometries
using compound 7c as the ligand and AgNO3 as the source for the
silver(I) ion. The assumed atom numbering for H and N signals is
depicted in figure 4.
MeOH. Table 2 gathers the values for the stability constants
determined in MeOH at 298.1 K in 0.05 M (C2H5)4NClO4.
The emf measurements excluded the formation of complexes
with stoichiometries differing from the 1 : 1 ligand : metal ratio.
The same conclusion was obtained with ESI-MS experiments. In
all cases, the only peaks detected correspond to the formation of
the corresponding Ag+·L complexes with no indication for the
formation of complexes with other stoichiometries.
According to the data in Table 2, it can be observed that, in both
cases, valine and phenylalanine derivatives, the highest stability
constants are obtained for the macrocyclic receptors that possess
a 16 membered ring (7b and 8c, n = 3), even if differences with
receptors having other ring sizes are small in some cases. On the
other hand, it seems that the presence of the aromatic side groups
Fig. 4 Structure of 7c with the corresponding atom numbering.
=
(8, R CH2Ph) provides an additional stabilization factor for the
complexes formed. The magnitude of this stabilization, almost
As can be seen in the figure, only three different signals, corre-
sponding to the three different kinds of nitrogen atoms: pyridine
an order of magnitude for receptors 8a and 8b, could suggest
Fig. 3 Long range 1H–15N correlation spectra (HMBC) obtained in CD3OD for 7c-AgNO3 at different ligand : metal ratios: (a) 1 : 0, (b) 2 : 1, (c) 1 : 1,
(d) 1 : 2.
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(N1), amine (N2) and amide (N3) are observed for all complex-
ation stages. This indicates that complexation–decomplexation
equilibria are fast on the NMR time scale. The peak at ca. −80 ppm
for the free ligand can be assigned to the nitrogen atom from
the pyridine subunit (N1). During complexation, this signal is
shifted more than 20 ppm upfield and reaches a shift value of
almost −105 ppm when the complexation ratio is 1 : 1. No further
changes in this shift were observed when an excess of Ag+ ions
was added, confirming the 1 : 1 stoichiometry of the complexes
formed. Only very small changes are detected, however, for the
signals corresponding to the other nitrogen atoms. Signals for the
amine nitrogen (N2) appear at −346 and −348 ppm, while the
ones for the amide nitrogen (N3) are observed at −263 ppm for
the free ligand and are upfield shifted to −258 ppm when the
complex is formed. This indicates that only the pyridine nitrogen
atom (N1) is directly involved in the coordination to the silver
cation. Participation of the amide groups seems to occur, but data
suggest that this should happen through the involvement of the
oxygen carbonyl atoms. Accordingly, 13C NMR spectra of silver
complexes showed a downfield shift of the carbonyl signals (Dd 2.2
and 0.7 ppm for 7c·Ag and 8a·Ag, respectiveley) supporting this
proposal for the mode of interaction. The NMR data also reveal
that deprotonation of the N–H amide group does not take place.
Similar trends were observed for the other macrocycles studied.
The 1H NMR spectra also provided some interesting informa-
tion. A representative example is given in Fig. 5 which shows the
1H NMR spectra in CD3OD for the free ligand 7c (lower trace)
and its 1 : 1 complex with Ag(NO3) (upper trace).
the complex. This is particularly significant for the methyl signals
of the isopropyl group (Dd = 0.14 ppm) and for protons H5 on
the butylenic spacer (Dd = 0.34 ppm). Even for H1 and H1ꢀ the
anisochrony is incremented in the complex (Dd = 0.09 ppm). In
the case of H5, one of the resulting signals remains essentially
unshifted, whilst the second one is more shielded, shifting from
ca. 3.2 to 2.9 ppm. Also protons H6 show a clear shielding in the
complex shifting from about 1.5 to about 1.2 ppm, but in this case
no splitting is observed, perhaps because of the partial overlapping
with the signal corresponding to one of the methyl groups. Most
likely, the shielding of some of the butylenic protons takes place
as a consequence of the involvement of amide oxygen atoms in the
coordination to the metal that locates the electron density of the
carbonyl group in close proximity of those hydrogen atoms.
In the case of the macrocycles 8 derived from phenylalanine,
having phenyl groups at the side chain, the NMR did not provide
any indication of the involvement of this aromatic ring in the
coordination to the metal centre. As can be observed in Fig. 6, for
8c, a significant downfield shift is observed, in the aromatic region
for pyridine protons HP1 and HP2, but the shifts corresponding
to the protons of the aromatic side chain remain essentially
unchanged. The same is observed in the case of the 13C NMR
spectra. No changes in the signals corresponding to the phenyl
group are detected when the complex is formed.
Fig. 6 Aromatic region of the 1H NMR spectra of compound 8c as free
ligand (a) and in the presence of AgNO3 for 2 : 1 (b) and 1 : 1 (c) L : metal
ratios, in CD3OD.
For a proposal of the Ag complex with the peptidomimetic
macrocycle, some molecular modeling has been also undertaken.
The optimized geometry at the HF/3-21G* level of theory for a 16-
membered ring receptor is shown in figure 7. As side chains seem
not to directly interact with the cation, they have been omitted
for computational simplicity. A nitrate counterion has been used
for completing the coordination sphere of the metal center.
Interestingly, the Ag atom is very close to the pyridine nitrogen as
well as to the amide carbonyls, but not to the benzylic nitrogens,
supporting the observed 15N chemical shift changes. In addition
to that, the carbonyl groups set their anisotropy cones pointing
to H5 protons, suggesting an explanation for the shielding of one
of the corresponding diastereotopic protons on that position. The
optimized geometry set the metal atom on top of the macrocyclic
main plane, almost equidistant to pyridine nitrogen and amide
carbonyls (see distances in figure 7). This arrangement would make
Fig. 5 1H NMR spectra for the free (a) and complexed (b) (1 : 1
ligand:metal ratio) 7c in CD3OD.
In the region corresponding to the pyridine protons, all of the
investigated compounds showed a downfield shift of both signals
(HP1 and HP2) (Dd 0.15–0.25 ppm) upon complexation. A more
significant downfield shift was even observed for the benzylic like
protons H1 and H1ꢀ that in the free ligand (for 7c) appear as two
doublets at 3.6 and 4.0 ppm and experience downfield shifts of
0.25–0.45 ppm when the complex is formed.
Less distinct trends are observed for the other protons, but
the presence of a rather rigid structure for the complex is clearly
indicated by the comparison of the spectra of L and AgL species.
Thus, for 7c, a splitting of some of the signals is observed for
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Synthesis of 7a. Compound 5a (0.5 g, 1.29 mmol), anhy-
drous K2CO3 (1.77 g, 12.9 mmol), tetrabutylammonium bromide
(0.210 g, 0.65 mmol) and 2,6-bis(bromomethyl)pyridine (0.335 g,
1.29 mmol) were placed in a flask containing dry CH3CN (175 mL)
and were refluxed for 12 h under argon atmosphere. The reaction
mixture was filtered and the solvent was evaporated under reduced
pressure. The crude product was dissolved in CHCl3 (50 mL)
and extracted with aqueous 0.01 M NaOH (3 × 50 mL). The
organic phase was dried over anhydrous MgSO4 and the solvent
was evaporated under reduced pressure. The product was purified
by silica flash chromatography using MeOH/CH2Cl2 (1 : 40) as the
eluent to give◦0.437 g of 3a in the form of a white solid. Yield 62%;
mp. 190–192 C; IR (KBr) m 3300, 3087, 2952, 1634, 1551 cm−1; 1H
NMR (500 MHz, CD3OD) d 0.93 (d, 6H, J = 6.9 Hz), 0.99 (d,6H,
J = 6.9 Hz), 2.04 (m, 2H), 2.98 (d, 2H, J = 5.5 Hz), 3.22 (m, 4H),
3.647 (d, 2H, J = 13.5 Hz), 4.07 (d, 2H, J = 13.5 Hz), 7.25 (d,
2H, J = 7.7 Hz), 7.88 (t, 1H, J = 7.7 Hz); 13C NMR (125 MHz,
CD3OD) d 18.5, 19.8, 32.6, 32.6, 40.2, 55.9, 56.0, 56.1, 69.9, 122.8,
122.9, 138.5, 138.7, 161.0, 177.3; ESI-MS m/z = 362.3 (M + H+),
384.2 (M + Na+). Anal. Calcd. for C19H31N5O2 C, 63.1; H, 8.6; N,
19.4. Found C, 62.7; H, 9.0; N, 19.2.
Fig. 7 Proposed model of coordination of Ag cation to 16-membered-ring
pepetidomimetic pyridinophane (HF/3-21G*). Selected distances to the
metal centre (dashed lines) are given in angstroms.
both faces of the receptor chemically inequivalent, suggesting
an explanation for the increased anisochrony of diasterotopic
methylene signals upon complex formation. Finally, space filling
view of the optimized geometry showed how the Ag cation fits
nicely inside the 16-membered ring macrocyclic cavity.
Synthesis of 7b. This compound was obtained as described
◦
above starting from 5b. Yield 50%; mp. 221–224 C; IR (KBr) m
3288, 3074, 2952, 1634, 1538 cm−1; 1H NMR (500 MHz, CD3OD)
d 0.967 (d, 6H, J = 6.8 Hz), 0.99 (d, 6H, J = 6.8 Hz), 1.66 (m, 2H),
1.99 (m, 2H, 2.95 (d, 2H, J = 5.9 Hz), 3.12 (m, 2H), 3.22 (m, 4H),
3.65 (d, 2H, J = 14.1 Hz), 4.06 (d, 2H, J = 14.1 Hz), 7.29 (d, 2H,
J = 7.7 Hz), 7.71 (t, 1H, J = 7.7 Hz); 13C NMR (125 MHz,
CD3OD) d 18.9, 19.8, 29.8, 32.5, 37.2, 55.4, 55.4, 70.0, 122.5,
122.6, 138.8, 139.0, 160.8, 176.9; ESI-MS m/z = 376.2 (M + H+).
Anal. Calcd. for C20H33N5O2 C, 64.0; H, 8.9; N, 18.7. Found C,
64.2; H, 9.3; N, 18.7.
Conclusions
C2 symmetric macrocyclic peptidomimetics can be easily and
efficiently synthesised according to our general methodology.
Those ligands are able to form some interesting 1 : 1 complexes
with Ag+ in CH3OH that involve the coordination of only the
pyridine nitrogen atoms. Neither the amine nor the amide nitrogen
atoms seems to participate in the coordination to the metal cation.
Instead, the oxygen atoms of the amide moiety are properly located
to participate in the coordination to silver, so that complexation
takes places without deprotonation of the amide hydrogen atom.
As could be expected, the strength of the complexes formed
is dependent on the size of the macrocyclic cavity. For both,
valine and phenylalanine derivatives (7 and 8 respectively) the
16 member macrocyclic ring size is the most suited for complex
formation. Nevertheless, differences observed in log K values,
between macrocycles with ring sizes of 15, 16 and 17 members,
are small. More significant, almost one order of magnitude in
some cases, are the variations in log K values detected when the
isopropyl substituent at the side chain is changed to phenyl. NMR
experiments ruled out the direct participation of phenyl groups
through p-cation interactions. In this regard, those differences
could be related to the different roles that both substituents may
play in either defining the solvation spheres of the ligands and
complex cations or affecting the steric environment about the
macrocycle cores.
Synthesis of 7c. This compound was obtained as described
◦
above starting from 5c. Yield 63%; mp. 228–231 C; IR (KBr) m
3299, 3076, 2957, 1638, 1549 cm−1; 1H NMR (500 MHz, CD3OD)
d 0.98 (t, 12H, J = 7.3 Hz), 1.47 (m, 4H),2.00 (m, 2H), 2.92 (d, 2H,
J = 5.8 Hz), 3.20 (m, 4H), 3.68 (d, 2H, J = 14.2 Hz), 4.01 (d, 2H,
J = 14.2 Hz), 7.36 (d, 2H, J = 7.7 Hz), 7.73 (t, 1H, J = 7.7 Hz);
13C NMR (125 MHz, CD3OD) d 17.8, 19.9, 26.3, 31.2, 38.1, 55.4,
68.9, 121.0, 137.5, 159.3, 173.0; ESI-MS m/z = 390.0 (M + H+),
412.5 (M + Na+); Anal. Calcd. For C21H35N5O2 C, 64.8; H, 9.1;
N, 17.9. Found C, 64.6; H, 9.4; N, 17.5.
Synthesis of 8a. This compound was obtained as described
◦
above starting from 6a. Yield 62%; mp. 173–175 C; IR (KBr) m
3290, 3085, 2930, 1634, 1552 cm−1; 1H NMR (500 MHz, CD3OD)
d 2.78 (m, 2H), 3.08–3.22 (m, 6H), 3.43 (dd, 2H, J = 5.8, 8.2 Hz),
3.61 (d, 2H, J = 13.5 Hz), 3.88 (d, 2H, J = 13.5 Hz), 7.14 (d, 2H,
J = 7.7 Hz), 7.22–7.28 (m, 10H), 7.63 (t, 1H, J = 7.7 Hz); 13C
NMR (125 MHz, CD3OD) d 40.1, 54.6, 65.2, 122.9, 127.76, 129.6,
130.2, 138.8, 139.1, 160.5, 176.5; ESI-MS m/z = 458.5 (M + H+),
480.5 (M + Na+); Anal. Calcd. For C27H31N5O2 × H2O C, 68.2;
H, 7.0; N, 14.7. Found C, 68.6; H, 7.3; N, 14.7.
Experimental
General procedure for the preparation of the macrocycles
Synthesis of 8b. This compound was obtained as described
◦
All of the bis(aminoamide) derivatives (5a–c and 6a–c) used
throughout our synthetic sequence were obtained as previously
described.13c
above starting from 6b. Yield 56%; mp. 176–178 C; IR (KBr) m
3311, 3080, 2953, 1635, 1546 cm−1; 1H NMR (500 MHz, CD3OD)
d 1.58 (s, 4H), 2.84 (m, 2H), 2.94–317 (m, 10H), 3.47 (m, 2H), 3.66
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(d, 2H, J = 14.1 Hz), 3.90 (d, 2H, J = 14.1 Hz), 7.16–7.30 (m,
12H), 7.66 (t, 1H, J = 7.7 Hz); 13C NMR (125 MHz, CD3OD) d
29.0, 37.6, 40.1, 54.2, 64.8, 122.8, 127.8, 129.6, 130.4, 139.1, 160.2,
176.0; ESI-MS m/z = 472.2 (M + H+), 494.2 (M + Na+); Anal.
Calcd. For C28H33N5O2 C, 71.3; H, 7.1; N, 14.9. Found C, 71.4; H,
7.2; N, 14.9.
Molecular modeling
For the molecular modeling studies, a PC version of Spartan Pro
program was used. To obtain the minima of energy, the conformer
distribution calculation option available in Spartan Pro was used.
With this option, an exhaustive Monte Carlo search without
constraints was performed for every structure. The torsion angles
were randomly varied and the obtained structures fully optimized
using the MMFF94 force field. Thus, 100 minima of energy within
an energy gap of 10 kcal mol−1 were generated. These structures
were analyzed and ordered considering the relative energy, being
the repeated geometries eliminated. For the Ag complex, the
geometry was fully optimized at the HF/3-21G* level of theory
implemented in Spartan Pro. Frequencies analysis showed that it
is a minimum of energy.
Synthesis of 8c. This compound was obtained as described
◦
above starting from 6c. Yield 65%; mp. 192–196 C; IR (KBr) m
3306, 3078, 2942, 1634, 1557 cm−1; 1H NMR (500 MHz, CD3OD)
d 1.42 (br, s 4H), 2.82 (m, 2H), 3.06 (m, 2H), 3.40 (m, 2H) 3.64
(d, 2H, J = 14.1 Hz), 3.88 (d, 2H, J = 14.1 Hz), 7.18 (d, 2H,
J = 7.7 Hz), 7.22–7.30 (m, 10H), 7.65 (t, 1H, J = 7.7 Hz); 13C
NMR (125 MHz, CD3OD) d 27.2, 39.2, 40.2, 54.3, 65.1, 122.0,
127.7, 129.4, 130.2, 138. 8, 139.0, 160.2, 175.9; ESI-MS m/z =
486.3 (M + H+), 508.2 (M + Na+); Anal. Calcd. For C28H33N5O2
C, 71.7; H, 7.3; N, 14.4. Found C, 71.8; H, 7.4; N, 14.4.
Acknowledgements
Financial support from the Spanish Ministerio de Ciencia y
Tecnolog´ıa (BQU2003-09215-C03-02) Bancaixa-UJI (P1B2004-
38) and Generalitat Valenciana (GRUPOS 04/031) is gratefully
acknowledged. P.S. thanks the University Jaume I for a postdoc-
toral fellowship. I. A. thanks MCYT for personal financial support
(Ramo´n y Cajal Program).
NMR Measurements
1
The H, and 13C spectra were recorded on Varian INOVA 500
1
spectrometer operating at 500 MHz for H and 125.75 MHz for
13C. The NMR experiments involving 15N were recorded on a
Varian INOVA 500 spectrometer equipped with a 5 mm tunable,
broadband, inverse-detection probe. The spectrometer operates
References
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The studies were carried out in solutions containing 5–15 mg of
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EMF measurements
The potentiometric titration were carried out at 298.1 0.1 K us-
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the following system:
Ag0|0.01 M AgNO3 (MeOH) + 0.04 M (C2H5)4NClO4 (MeOH)
ꢁ 0.05 M (C2H5)4NClO4 (MeOH) ꢁ cAg + (MeOH)
+ 0.05 M (C2H5)4NClO4 (MeOH) ꢁAg0
The specific measurements were performed in the system:
Ag0|0.01 M AgNO3 (MeOH) + 0.04 M (C2H5)4NClO4 (MeOH)
ꢁ 0.05 M (C2H5)4NClO4 (MeOH) ꢁ c0 (MeOH) + cAg
L
+ (MeOH) + 0.05 M (C2H5)4NClO4 (MeOH) |Ag0
where c0L is the concentration of the ligand at the beginning of the
titration, and cAg is the concentration of the standard solution of
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L
to 5 × 10−3 M. The results reproducibility was 0.20 mV. The
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