Coordination of Cu2+ Ions to C 2 Symmetric pseudopeptides derived from valine

Article abstract of DOI:10.1021/ic100748g

The acid-base and coordination properties of a family of pseudopeptidic ligands with C₂ symmetry derived from valine (4a-e) have been studied using a variety of techniques as a model for metal coordination in peptides and proteins. The Cu²⁺ cation has been selected for coordination studies, although, for comparison, some results for Zn²⁺ are also presented. Good agreement has been obtained between the results obtained by potentiometric titrations, spectroscopic analysis, and mass spectrometry (ESI) studies. These results highlight the potential for the use of ESI MS for characterizing the nature of the complex species formed. Clearly, the Cu ²⁺ complexes are much more stable than the Zn²⁺ complexes. While the role of the aliphatic spacer seems to be very minor in the case of the Zn²⁺ complexes, revealing the ability of this cation to accommodate different coordination environments, this role is critical in the case of Cu²⁺. Different complexes with 1:1 or 2:2 Cu²⁺:L stoichiometries can be formed according to the length of the spacer and the basicity of the media. This is fully illustrated by the resolution of the X-ray structures of two different Cu²⁺ complexes corresponding to the ligands containing a spacer with two methylene groups (ligand 4a, complex 6a [Cu₂(H_-1L)₂](ClO₄)₂ with a 2:2 stoichiometry) and a propylene spacer (4b, complex 5b [CuH_-2L] CH₃CH₂OH with a 1:1 stoichiometry).

Full text of DOI:10.1021/ic100748g

Inorg. Chem. 2010, 49, 7841–7852 7841
DOI: 10.1021/ic100748g
Coordination of Cu2þ Ions to C2 Symmetric Pseudopeptides Derived from Valine
‡
†
‡
,‡
Salvador Blasco, M. Isabel Burguete, M. Paz Clares, Enrique Garcıa-Espana,* Jorge Escorihuela,† and
~
´
Santiago V. Luis*,†
†
´
ꢀ
ꢀ
Departamento de Quımica Inorganica y Organica, Universitat Jaume I, Avda. Sos Baynat s/n.,
‡
ꢀ
´
ꢀ
12071 Castellon, Spain, and Instituto de Ciencia Molecular (ICMOL), Departamento de Quımica Inorganica,
ꢀ
ꢀ
ꢀ
Universidad de Valencia, C/Catedratico Jose Beltran 2, 46980 Paterna (Valencia), Spain
Received April 19, 2010
The acid-base and coordination properties of a family of pseudopeptidic ligands with C2 symmetry derived from valine
(4a-e) have been studied using a variety of techniques as a model for metal coordination in peptides and proteins. The Cu2þ
cation has been selected for coordination studies, although, for comparison, some results for Zn2þ are also presented. Good
agreement has been obtained between the results obtained by potentiometric titrations, spectroscopic analysis, and mass
spectrometry (ESI) studies. These results highlight the potential for the use of ESI MS for characterizing the nature of the
complex species formed. Clearly, the Cu2þ complexes are much more stable than the Zn2þ complexes. While the role of the
aliphatic spacer seems to be very minor in the case of the Zn2þ complexes, revealing the ability of this cation to accommodate
different coordination environments, this role is critical in the case of Cu2þ. Different complexes with 1:1 or 2:2 Cu2þ:L
stoichiometries can be formed according to the length of the spacer and the basicity of the media. This is fully illustrated by
the resolution of the X-ray structures of two different Cu2þ complexes corresponding to the ligands containing a spacer with
two methylene groups (ligand 4a, complex 6a [Cu2(H-1L)2](ClO4)2 with a 2:2 stoichiometry) and a propylene spacer
(4b, complex 5b [CuH-2L] CH3CH2OH with a 1:1 stoichiometry).
3
Introduction
have been involved in the preparation and study of a broad
family of pseudopeptides with C2 symmetry. Open-chain
pseudopeptides such as 4 have been used as building blocks
for the construction of macrocyclic structures. The corre-
sponding macrocyclization processes have been based on the
preorganization induced by conformational elements5 or con-
figurational factors6 or through the use of anionic templates.7
Some of those systems are able to display interesting features
such as their behavior as organogelators,8 acting as “in vivo”
fluorescent pH probes,9 as selective receptors for substrates of
Coordination chemistry in metalloproteins is dominated
by amino acids since amino acid side chains and backbone
heteroatoms entail the majority of ligands available to
coordinate to metal ions.1 The design of new small-molecule
ligands to model such challenging structural and/or func-
tional motifs is essential for new developments in bioinor-
ganic chemistry.2 Although many model complexes use non-
amino acid ligands that mimic various aspects of the ligand
environment found in the protein, there is no doubt that the
development of new ligands based on the presence of amino
acid subunits is a fundamental approach in this area.3,4
Thus, a large number of pseudopeptidic structures have
been designed in recent years for multiple purposes, and we
ꢀ
(5) (a) Adrian, F.; Burguete, M. I.; Luis, S. V.; Miravet, J. F.; Querol, M.;
~
Garcıa-Espana, E. Tetrahedron Lett. 1999, 40, 1039–1040. (b) Becerril, J.;
´
~
Bolte, M.; Burguete, M. I.; Galindo, F.; García-Espana, E.; Luis, S. V.; Miravet,
J. F. J. Am. Chem. Soc. 2003, 125, 6677–6686.
(6) (a) Bru, M.; Alfonso, I.; Burguete, M. I.; Luis, S. V. Tetrahedron Lett.
2005, 46, 7781–7785. (b) Alfonso, I.; Bolte, M.; Bru, M.; Burguete, M. I.; Luis,
S. V. Chem.;Eur. J. 2008, 14, 8879–8891.
*To whom correspondence should be addressed. E-mail: luiss@qio.uji.es
(S.V.L.), enrique.garcia-es@uv.es (E.G.-E.).
(7) (a) Bru, M.; Alfonso, I.; Burguete, M. I.; Luis, S. V. Angew. Chem., Int.
Ed. 2006, 45, 6155–6159. (b) Alfonso, I.; Bolte, M.; Bru, M.; Burguete, M. I.;
Luis, S. V.; Rubio, J. J. Am. Chem. Soc. 2008, 130, 6137–6144.
(1) Roat-Malone, R. M. Bioinorganic Chemistry: A Short Course, 2nd ed.;
John Wiley & Sons, Inc.: Hoboken, NJ, 2007.
(2) Karlin, K. D. Science 1993, 261, 701–708.
(3) (a) Sigel, H.; Martin, R. B. Chem. Rev. 1982, 82, 385–426. (b) Lucet, D.; Le
Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2580–2627. (c) Fache, F.;
Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. Rev. 2000, 100, 2159–2231. (d)
(8) (a) Becerril, J.; Escuder, B.; Miravet, J. F.; Gavara, R.; Luis, S. V. Eur.
J. Org. Chem. 2005, 481–485. (b) Becerril, J.; Burguete, M. I.; Escuder, B.; Luis,
S. V.; Miravet, J. F.; Querol, M. Chem. Commun. 2002, 738–739. (c) Becerril, J.;
Burguete, M. I.; Escuder, B.; Galindo, F.; Gavara, R.; Miravet, J. F.; Luis, S. V.;
Peris, G. Chem.;Eur. J. 2004, 3879–3890. (d) Burguete, M. I.; Galindo, F.;
Gavara, R.; Izquierdo, M. A.; Lima, J. C.; Luis, S. V.; Parola, A. J.; Pina, F.
Langmuir 2008, 24, 9795–9803. (e) Burguete, M. I.; Izquierdo, M. A.; Galindo,
F.; Luis, S. V. Chem. Phys. Lett. 2008, 460, 503–506.
€
Hechavarría-Fonseca, M.; Konig, B. Adv. Synth. Catal. 2003, 345, 1173–1185. (e)
Kizirian, J.-C. Chem. Rev. 2008, 108, 140–205. (f) Prell, J. S.; Flick, T. G.; Oomens, J.;
Berden, G.; Williams, E. R. J. Phys. Chem. A. 2010, 114, 854–860.
(4) (a) Burke, S. K.; Xu, Y.; Margerum, D. W. Inorg. Chem. 2003, 42, 5807–
5817. (b) Green, B. J.; Tesfai, T. M.; Margerum, D. W. Inorg. Chem. 2004, 43, 1463–
1471. (c) Green, B. J.; Tesfai, T. M.; Margerum, D. W. Dalton Trans. 2004, 3508–3514.
(d) Tesfai, T. M.; Green, B. J.; Margerum, D. W. Inorg. Chem. 2004, 43, 6726–6733.
(9) Galindo, F.; Burguete, M. I.; Vigara, L.; Luis, S. V.; Kabir, N.;
Gavrilovic, J.; Russell, D. A. Angew. Chem., Int. Ed. 2005, 44, 6504–6508.
r
2010 American Chemical Society
Published on Web 08/03/2010
pubs.acs.org/IC

7842 Inorganic Chemistry, Vol. 49, No. 17, 2010
Blasco et al.
Scheme 1. Synthesis of Chiral Bis(Amino Amide) Ligands Derived
Table 1. Stepwise and Cumulative Basicity Constants of Compounds 4a-e
Determined in 0.15 M NaClO4 at 298.1 K
from Valinea
reactiona
4a
4bb
4c
4d
4e
H þ L a HL
7.94(1)c 8.008(5) 8.126(3) 8.111(4) 8.16(1)
HþHL a H2L 6.96(1)
6.956(7) 7.319(4) 7.312(4) 7.367(1)
a Charges omitted. b Determined in 0.15 M NaCl. c Values in par-
entheses are standard deviations in the last significant figure.
a Reagents: (i) DCC, N-hydroxysuccinimide, THF, rt. (ii) H2NCH2-
(CH2)nCH2NH2, DME, rt. (iii) HBr/AcOH. (iv) NaOHaq
.
biological relevance,10 as minimalistic molecular machines,11
or as ligands for the preparation of enantioselective catalysts,
of particular efficiency in the case of the enantioselective
addition of dialkylzinc to aromatic aldehydes.12 On the other
hand, the self-assembly of this kind of compound in the solid
state has also given rise to the observation of some remarkable
crystalline structures and nanoassembled morphologies with
relevance for the understanding of structural parameters in
proteins and related systems.13
Here, we present the study of the acid-base properties of
some valine-derived open-chain pseudopeptides of this class
(4a-e), as well as the analysis of their binding ability toward a
cation playing a key role in bioinorganic chemistry such as
Cu2þ. Some data for Zn2þ are also presented. Interesting varia-
tions in the complexes formed are observed as a consequence of
the modification of the aliphatic spacer. The structure of some
of those complexes has been determined by X-ray crystal-
lography. The combination of a set of different complementary
techniques including pH-metric titrations, ESI-MS, UV-vis
spectroscopy, and X-ray diffraction analysis has allowed the
achievement of an in depth knowledge of these systems.
Figure 1. Distribution diagram for the protonated species of 4a in 0.15 M
NaClO4 at 298.1 K.
Acid-base properties of compounds 4 were studied by the
use of pH-metric titrations. All thetitrationswerecarriedout
as has been fully described,16 at 298.1 K using 0.15 M
NaClO4 to maintain a constant ionic strength. The program
PASAT was used for data acquisition.17 The program
HYPERQUAD18 was employed for calculating the stability
constants, and the program HYSS was used to obtain the
distribution diagrams.19 The stepwise and cumulative stabi-
lity constants for the protonation of receptors 4, obtained in
this way, are presented in Table 1.
All the compounds show two stepwise basicity con-
stants within the pH range of the study (2-11) that
correspond to the protonation processes of the primary
amino groups. Although there is a very slight increase in
basicity following the increase in the number of methy-
lene groups in the bridge separating the amide groups, the
most noticeable aspect is, however, the resemblance of the
stepwise basicity constants for all these compounds. The
separation between positive charges is high enough to
make the basicity of all these compounds very close
between them.20 Accordingly, very similar distribution
diagrams for the protonated species were obtained for all
receptors 4. As an example, the distribution diagram for
the smaller compound, 4a, is presented in Figure 1. The
distribution diagrams for all protonations are collected in
Figure S2 of the Supporting Information.
Results and Discussion
Equilibrium Studies on Ligand Protonation and on the For-
mation of Cu2þ and Zn2þ Complexes. EMF Measurements.
The synthesis of the receptors was carried out following pre-
viously reported procedures, as is outlined in Scheme 1.5
Acid-Base Behavior. The study of the acid-base proper-
ties of the receptors is essential for a proper understanding of
the coordination properties of nitrogenated compounds.14,15
(10) (a) Burguete, M. I.; Galindo, F.; Izquierdo, M. A.; Luis, S. V.; Vigara, L.
Tetrahedron 2007, 63, 9493–9500. (b) Alfonso, I.; Burguete, M. I.; Galindo, F.; Luis,
S. V.; Vigara, L. J. Org. Chem. 2009, 74, 6130–6142. (c) Burguete, M. I.; Galindo, F.;
Luis, S. V.; Vigara, L. J. Photochem. Photobiol. A 2010, 209, 61–67.
(11) (a) Alfonso, I.; Burguete, M. I.; Luis, S. V. J. Org. Chem. 2006, 71,
2242–2250. (b) Alfonso, I.; Burguete, M. I.; Galindo, F.; Luis, S. V.; Vigara, L. J.
Org. Chem. 2007, 72, 7947–7956.
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(16) (a) Garcıa-Espana, E.; Ballester, M.-J.; Lloret, F.; Moratal, J. M.;
Faus, J.; Bianchi, A. J. Chem. Soc., Dalton Trans. 1988, 101–104. (b)
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Burguete, M. I.; García-Espana, E.; Lopez-Diago, L.; Luis, S. V.; Miravet, J. F.;
Sroczynski, D. Org. Biomol. Chem. 2007, 5, 1935–1944.
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(12) (a) Adrian, F.; Burguete, M. I.; Fraile, J. M.; Garcı
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a, J. I.; Garcı
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(17) Fontanelli, M.; Micheloni, M. Program for the automatic control of
the microburette and the acquisition of the electromotive force readings.
Proceedings of the I Spanish-Italian Congress on Thermodinamics of Metal
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Espana, E.; Luis, S. V.; Mayoral, J. A.; Royo, A. J.; Sanchez, M. C. Eur. J.
Inorg. Chem. 1999, 2347–2354. (b) Burguete, M. I.; Escorihuela, J.; Luis, S. V.;
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Lledos, A.; Ujaque, G. Tetrahedron 2008, 64, 9717–9724.
Complexes, Peníscola, Castellon, Spain, 1990.
(13) (a) Alfonso, I.; Bolte, M.; Bru, M.; Burguete, M. I.; Luis, S. V.
CrystEngComm 2009, 11, 735–738. (b) Alfonso, I.; Bru, M.; Burguete, M. I.;
García-Verdugo, E.; Luis, S. V. Chem.;Eur. J. 2010, 16, 1246–1255. (c)
Becerril, J.; Bolte, M.; Burguete, M. I.; Escorihuela, J.; Galindo, F.; Luis, S. V.
CrystEngComm 2010, 12, 1722-1725.
(18) Gans, P.; Sabatini, A.; Vacca, A. Talanta 1996, 43, 1739–1753.
(19) Alderighi, L.; Gans, P.; Ienco, A.; Peters, D.; Sabatini, A.; Vacca, A.
Coord. Chem. Rev. 1999, 184, 311–318.
(20) (a) Sarnesky, J. E.; Surprenant, H. L.; Molen, F. K.; Reiley, C. N.
Anal. Chem. 1975, 47, 2116–2124. (b) Frassineti, C.; Ghelli, S.; Gans, P.;
Sabatini, A.; Moruzzi, M. S.; Vacca, A. Anal. Biochem. 1995, 231, 374–382. (c)
Frassineti, C.; Alderighi, L.; Gans, P.; Sabatini, A.; Vacca, A. Anal. Bioanal.
Chem. 2003, 376, 1041–1052.
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Article
Inorganic Chemistry, Vol. 49, No. 17, 2010 7843
Chart 1. Proton Assignment for NMR Studies
Figure 2. Minimum energy conformers calculated for nonprotonated
(L), monoprotonated (HL), and diprotonated (H2L) 4a.
Table 2. Protonation Induced Observed Shifts in the δ Values for the Different
Hydrogen Atoms of 4a in D2O at 303 K, Working at 500 MHz
both amino groups are protonated, most likely to achieve
an extended conformation in order to minimize electro-
static repulsions.
pD
Δδ HA
Δδ HB
Δδ Hc
12.67
9.96
8.55
7.63
6.53
4.86
2.82
0.00
0.07
0.15
0.30
0.37
0.33
0.00
0.13
0.41
0.62
0.73
0.68
0.00
0.00
0.02
0.03
0.10
0.04
In this regard, molecular modeling calculations to get
further information and better analyze this process were also
performed.23 The structures of the local minima obtained for
each protonated state were in good agreement with the pro-
cess suggested by NMR data. To obtain the corresponding
energy minima by molecular modeling, the conformer dis-
tribution calculation option available in Spartan 04 was
used.24 With this option, an exhaustive Monte Carlo search
without constraints was performed for every structure. The
torsion angles were randomly varied and the obtained struc-
tures fully optimized using the MMFF force field. Thus, 100
minima of energy within an energy gap of 10 kcal/mol were
generated for each protonated state of the different receptors.
These structures were analyzed and ordered considering their
relative energy, the repeated geometries being eliminated.
Similar results were obtained for all the ligands. Although a
significant number of different conformations are obtained
within the considered energy gap, all of them maintain some
common structural elements and confirm the predominance
of very different conformations for monoprotonated (HL)
and diprotonated (H2L) species. This can be observed for the
minimum energy conformers of 4a depicted in Figure 2. Both
the nonprotonated (L) and the monoprotonated (HL) spe-
cies present folded conformations, while the diprotonated
(H2L) species presents an extended conformation in order to
minimize electrostatic repulsions. The folded arrangement
for the nonprotonated and monoprotonated system favors
their stabilization through intramolecular H-bonding and
additional electrostatic interactions.
The protonation process can also be monitored
through the use of H NMR spectroscopy. NMR spec-
1
troscopy can give interesting information regarding pro-
tonation sequences, in particular, when the nitrogen
atoms bearing the protons present different chemical
environments.21 It is well established that upon protona-
tion of polyamine compounds, the hydrogen nuclei
attached to the carbon in the R position to the nitrogen
atom bearing the proton are those exhibiting the largest
downfield changes in their chemical shift.22 Therefore, to
obtain further information about the protonation se-
1
quence of the compounds, the H NMR spectra of the
ligands versus pD were recorded. For all the cases, the
protonation of the amino groups is accompanied, as
could be expected, by a significant downfield shift of the
proton Hb (see Chart 1) attached to the stereogenic
carbon atom and also by a smaller downfield shift of
the proton Ha of the isopropyl group. The protonation
also has a minor effect on the shift of protons Hc located
at the spacer.
As an example, the Δδ values obtained for 4a at
different pD values, taking the spectrum at pH 12.7 as
the reference, are given in Table 2. It is worth mentioning
that for the three studied protons (for signals of protons
HA, HB, and HC), the δ values steadily increase on going
from basic to acidic regions, reaching a maximum around
pD = 5 in correspondence with the completion of the
second protonation. At more acidic pH regions, a slight
decrease in the corresponding Δδ values is observed. This
suggests that in order to minimize electrostatic repulsions,
a significant conformational change takes places when
Determination of the Cu2þ Complexes Formation Con-
stants. Because of the interest in developing copper-
containing model systems for metalloproteins,25 and taking
into account our previous experience in this field, for instance
in the study of simplified HCA models,26 the synthesis and
study of copper and zinc complexes of those compounds was
carried out. In this regard, Cu2þ complexes could be easily
obtained by the reaction of one equivalent of the bis(amino
amide) ligands 4 and one equivalent of Cu2þ acetate in basic
(21) (a) Dagnall, S. P.; Hague, D. N.; McAdam, M. E. J. Chem. Soc.,
Perkin Trans. 2 1984, 1111–1114. (b) Hague, D. N.; Moreton, A. D. J. Chem.
Soc., Perkin Trans. 2 1994, 265–270. (c) Bianchi, A.; Escuder, B.; García-
~
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(23) (a) Burguete, M. I.; Escuder, B.; Garcıa-Espana, E.; Luis, S. V.;
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Espana, E.; Luis, S. V.; Marcelino, V.; Miravet, J. F.; Ramírez, J. A. J. Chem. Soc.,
Miravet, J. F. J. Org. Chem. 1994, 59, 1067–1071. (b) Altava, B.; Bianchi, A.;
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Perkin Trans. 2 1994, 1253–1259. (d) Aguilar, A.; García-Espana, E.; Luis, S. V.;
Llinares, J. M.; Miravet, J. F.; Ramírez, J. A.; Soriano, C. Inorg. Chim. Acta 1996,
246, 287–294. (e) Aran, V. J.; Kumar, M. J.; Molina, J.; Lamarque, L.; Navarro, P.;
García-Espana, E.; Ramirez, J. A.; Luis, S. V.; Escuder, B. J. Org. Chem. 1999,
64, 6135–6146.
(22) (a) Dagnall, S. P.; Hague, D. N.; McAdam, M. E. J. Chem. Soc.,
Perkin Trans. 2 1984, 435–440. (b) Alderighi, L.; Bianchi, A.; Biondi, L.; Calabi,
L; De Miranda, M.; Gans, P.; Ghelli, S.; Losi, P.; Paleari, L.; Sabatini, A.; Vacca,
A. J. Chem. Soc., Perkin Trans. 2 1999, 2741–2745. (c) Bencini, A.; Bianchi, A.;
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Bazzicalupi, C.; Burguete, M. I.; García-Espana, E.; Luis, S. V.; Miravet, J. F.
Supramol. Chem. 1997, 8, 287–299. (c) Albelda, M. T.; Frías, J. C.; García-
~
Espana, E.; Luis, S. V. Org. Biomol. Chem. 2004, 2, 816–820.
~
(24) Spartan 04; Wavefunction, Inc.: Irvine, CA. For MMFF force field
calculations, see: Halgren, T. A. J. Comput. Chem. 1996, 17, 490-519 and
following papers in this issue.
(25) Stephens, J. C.; Khan, M. A.; Houser, R. P. Inorg. Chem. 2001, 40,
5064–5065.
(26) (a) Altava, B.; Burguete, M. I.; Luis, S. V.; Miravet, J. F.; Garcı
´
a-
~
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García-Espana, E.; Micheloni, M.; Ramírez, J. A. Coord. Chem. Rev. 1999, 188,
Espana, E.; Marcelino, V.; Soriano, C. Tetrahedron 1997, 53, 4751–4762. (b)
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97–156. (d) Aguilar, J.; Díaz, P.; Escartí, F.; García-Espana, E.; Gil, L.; Soriano,
Andres, S.; Escuder, B.; Domenech, A.; García-Espana, E.; Luis, S. V.; Marcelino,
V.; Llinares, J. M.; Ramírez, J. A.; Soriano, C. J. Phys. Org. Chem. 2001, 14,
495–500.
C.; Verdejo, B. Inorg. Chim. Acta 2002, 39, 307–316. (e) Albelda, M. T.; Frias,
J. C.; García-Espana, E. Encycl. Supramol. Chem. 2007, 1:1, 1.
~

7844 Inorganic Chemistry, Vol. 49, No. 17, 2010
Blasco et al.
Table 3. Logarithms of the Formation Constants for the Cu2þ Complexes of Ligands 4a-e Determined in 0.15 M NaClO4 at 298.1 K
reactiona
4a
4bb
4c
4d
4e
Cu þ L a CuL
6.09(4)c
5.99(3)
7.03(1)
12.64(2)
-0.04(2)
-6.61(1)
5.61(2)
-7.07(1)
-6.56(2)
6.76(1)
12.51(4)
-0.23(2)
-9.89(3)
5.74(3)
-7.00(2)
-9.66(4)
7.14(2)
12.67(6)
-0.04(2)
-9.78(3)
5.53(5)
-7.19(2)
-9.74(3)
Cu þ L þ H a CuHL
Cu þ L a CuH-1L þ H
Cu þ L a CuH-2L þ 2H
CuL þ H a CuHL
0.67(1)
-6.48(1)
0.53(1)
-6.66(1)
CuL a CuH-1L þ H
CuH-1L a CuH-2L þ H
-5.42(4)
-7.15(2)
-5.46(3)
-7.19(1)
a Charges omitted for clarity. b Determined in 0.15 M NaCl. c Values in parentheses are standard deviations in the last significant figure.
the monodeprotonated species predominates in solution can-
not be distinguished. For the largest two ligands (4d and 4e),
there is a greater separation between the deprotonation of the
first and second amide groups that occurs at more basic pH
values (Figure 3, top). See the Supporting Information for the
distribution diagrams for 4b, 4c, and 4e.
Coordination of Cu2þ to the shortest ligands induces a
drop in basicity of the amide groups of over 5 orders of mag-
nitude. As a matter of fact, the nondeprotonated [CuL]2þ
species do not predominate at any pH value, being only
major species in solution complexes with deprotonated amide
groups. At this point, some concern can exist with regard to
the structure of the [CuH-1L]þ species for 4a, since in the
solid state it presented a polymeric structure.
The behavior of the two largest ligands is represented by
the distribution diagram shown at the top of Figure 3. In this
case, the [CuL]2þ species prevails in a narrow 6-7 pH win-
dow, and although the inductive effects generated by the
metal are still very important, the amide groups, particularly
the second one, deprotonate at higher pH values.
Determination of the Zn2þ Complexes’ Formation Con-
stants. For the sake of comparison, a similar study to that
reported above for Cu2þ was carried out for the determina-
tion of the Zn2þ complexes’ formation constants. The stabi-
lity constants for the formation of Zn2þ complexes were
determined by potentiometic titrations in water using
0.15 M NaClO4 to maintain constant the ionic strength and
a temperature of 298.1 K and are presented in Table 4.
Significant differences can be observed when the data in
Table 4 are compared with those obtained for Cu2þ com-
plexes. The most remarkable observation is the low stability
of the Zn2þcomplexes formed. Although lower values of the
stability constants are expected when the Zn2þ complexes are
compared with those of Cu2þ for a given ligand, the values
obtained are even some orders of magnitude lower than
those reported for the Zn2þ complexes of other tetraden-
tated ligands.27 As a matter of fact, only the formation of
[ZnH-2L] complex species is observed above pH 8. As in the
case of Cu2þ complexes, ligands 4 can be grouped in two
categories. For receptors 4a,b containing the shortest spacers
(see the Supporting Information for the corresponding
distribution diagrams), only the [ZnH-2L] species are essen-
tially detected above pH 8; a minor contribution of [ZnL] is
also observed for 4a (L1). For the ligands 4c-e (L3-L5)
containing longer spacers, some additional complex species
are detected at the 5-9 pH window, although, in all cases,
those species are always very minor. The fact that the length
Figure 3. Distribution diagrams for the systems Cu2þ-4a (bottom) and
Cu2þ-4d (top) determined in 0.15 M NaClO4.
methanol to afford bright-colored solids. The interaction of
Cu2þ and ligands 4 was systematically studied by potentio-
metric titrations in aqueous solution over the 2-11 pH range.
The stability constants for the formation of Cu2þ complexes
have been determined in water using 0.15 M NaClO4 to
maintain a constant ionic strength and a temperature of
298.1 K. The results obtained are presented in Table 3.
All the compounds in this series show a similar speciation
with the formation of a nondeprotonated [CuL]2þ species
and two deprotonated species [CuH-1L]þ and [CuH-2L].
Apart from these species, a monoprotonated [CuHL]3þ spe-
cies has also been detected for the compounds with longer
hydrocarbon chains between the coordination sites (4c-e).
According to the general structure of compounds 4, it seems
reasonable to assume that the formation of monocationic
[CuH-1L]þ and neutral [CuH-2L] species takes place
through deprotonation of the N-H amide functional
groups. This was further inferred from their infrared and
visible electronic spectra and supported by the two crystal
structures solved by X-ray diffraction (see below). The values
of the constants in Table 3 and the distribution diagrams
(Figure 3, bottom) show that the three shortest ligands, 4a,
4b, and 4c, undergo deprotonation of the amido groups at
relatively low pH values. Moreover, for 4c, both deprotona-
tions proceed in a cooperative way, so that a pH range where
ꢀ
(27) (a) Lamarque, L.; Navarro, P.; Miranda, C.; Aran, V. J.; Ochoa, C.;
~
Escartı, F.; Garcıa-Espana, E.; Latorre, J.; Luis, S. V.; Miravet, J. F. J. Am.
´ ´
Chem. Soc. 2001, 123, 10560–10570. (b) Burguete, M. I.; Escuder, B.; García-
~
Espana, E.; Luis, S. V.; Miravet, J. F. Tetrahedron 2002, 58, 2839–2846.

Article
Inorganic Chemistry, Vol. 49, No. 17, 2010 7845
Table 4. Logarithms of the Formation Constants for the Zn2þ Complexes of Receptors 4a-e Determined in 0.15 M NaClO4 at 298.1 K
reactiona
4a
4bb
4c
4d
4e
Zn þ L a ZnL
3.09(6)c
11.08(3)
-4.9 (1)
-12.14(1)
7.99(4)
3.50(3)
10.86(3)
-5.1(1)
3.99(2)
11.32(5)
-4.53(8)
-12.08(1)
7.32(4)
-8.52(7)
-7.55(8)
Zn þ L þ H a ZnHL
Zn þ L a ZnH-1L þ H
Zn þ L a ZnH-2L þ 2H
ZnL þ H a ZnHL
-12.44(1)
-12.64(1)
-12.22(1)
7.36(3)
ZnL a ZnH-1L þ H
ZnH-1L a ZnH-2L þ H
-8.1(1)
-7.2(1)
-8.63(9)
-7.1(1)
a Charges omitted for clarity. b Determined in 0.15 M NaCl. c Values in parentheses are standard deviations in the last significant figure.
Scheme 2. Synthesis of Cu2þ Complexes Derived from Ligands 4
of the spacer seems to affect only to a minor extent the
formation of the corresponding Zn2þ complexes is in good
agreement with the results reported for those ligands as cata-
lysts for the Et2Zn addition to aldehydes.12b In this case, it
has been shown that catalytic results are essentially indepen-
dent of the spacer. Those results suggest that Zn2þ is able to
easily accommodate the changes forced in its coordination
sphere by the modification of the spacer. Nevertheless, this
must be taken with caution, as the catalytic experiments have
been carried out in hexanes and other organic solvents
Spectroscopic and Spectrometric Studies on the Forma-
tion of Cu2þ and Zn2þ Complexes. Spectroscopic Studies.
In order to gain more detailed insight into the nature of the
complex species formed by receptors 4 (L) and Cu2þ and
Zn2þ, a spectroscopic study was carried out, taking ad-
vantage of the data provided by the distribution diagrams
formerly obtained. In the case of Cu2þ, both UV-visible
and IR spectroscopies were used; while in the case of Zn2þ
only IR spectroscopy could be applied. In both cases, this
study was completed by the use of mass spectrometry (ESI-
MS), as will be discussed below.
,
Figure 4. Complex formationin MeOH fromreceptors 4 and Cu(OAc)2
under neutral conditions (top) and after the addition of two equivalents of
KOH (bottom).
pseudopeptidic structures. The complexes formed by Cu2þ
in methanolic solution under neutral conditions show, in all
cases, a blue coloration that sharply changes when a base is
added to afford solutions with colors ranging from red-
orange to violet depending on the ligand used, as shown in
Figure 4. The most significant spectroscopic data for those
complexes obtained under basic conditions are gathered in
Table 5. The preferential formation, under basic conditions,
of [CuH-2L] complex species derived from the double
deprotonation of the ligand at both amide groups, was
confirmed by UV-visible titrations. For this purpose, the
reactants, the corresponding receptor 4 and Cu2þ acetate,
were mixed (0.6 mM and 0.6 mM, respectively, in MeOH)
in a spectrophotometric cell. Aliquots of a base (KOH in
MeOH) were added stepwise. For the formation of metallic
complexes 5 (or 6), deprotonation of the amide group of
ligands 4 is needed. Since there are two amide groups in 4,
then two equivalents of the base, relative to Cu2þ, would be
required to form the final complex. As shown in Figure 5,
the reaction of one equivalent of 4 with one equivalent of
Cu2þ is complete after the addition of exactly two equiva-
lents of KOH, according to UV-vis spectroscopy data.
As mentioned before, Cu2þ complexes can be obtained by
reaction of one equivalent of 4 and one equivalent of Cu2þ
acetate in basic methanol (KOH). The structures postulated
in Scheme 2 are presented according to experimental evi-
dence. Upon complexation, the carbonyl frequency (FT-IR)
shifts from 1663 cm-1 in compounds 4 to 1566 cm-1 in com-
plexes 5, indicating the participation of the deprotonated
amide group in the coordination to Cu2þ in agreement with
the data obtained by potentiometry and with related sys-
tems.28 The same shifts in the carbonyl band are also ob-
served for the formation of Zn2þ complexes, although in this
case colorless complexes are obtained.
Besides the chelate complexes 5 (CuH-2L), other struc-
tures like the ones represented in 6 (Cu2(H-2L)X4) can
also be considered. In this case, a variety of ligands can
stand for X, including donor atoms (N, O) from other
(28) (a) Wagler, T. R.; Fang, Y.; Burrows, C. J. J. Org. Chem. 1989, 54,
1584–1589. (b) Dangel, B.; Clarke, M.; Haley, J.; Sames, D; Polt, R. J. Am.
Chem. Soc. 1997, 119, 10865–10866. (c) Weeks, C. L.; Turner, P.; Fenton, R. R.;
Lay, P. A. J. Chem. Soc., Dalton Trans. 2002, 931–940. (d) Burguete, M. I.;
Galindo, F.; Luis, S. V.; Vigara, L. Dalton Trans. 2007, 4027–4033. (e) Shakya,
R.; Jozwiuk, A.; Powell, D. R.; Houser, R. P. Inorg. Chem. 2009, 48, 4083–4088.

7846 Inorganic Chemistry, Vol. 49, No. 17, 2010
Blasco et al.
Figure 5. Change ofthe absorbance (439 nm) in MeOH ofa mixture of4a (left) or 4d (right) (0.6 mM) and Cu(OAc)2 (0.6 mM) uponthe additionof KOH.
Figure 6. UV-vis spectra in water for the Cu2þ-4a and Cu2þ-4d systems at different pH values (see insets) in the 400-800 nm region.
Table 5. Spectroscopic Data for the Cu2þ-4 Complexes Obtained in Methanol
shown in Figure 6. At pH = 6.8, a region for which depro-
tonated [CuH-xL](2-x)þ species only account for about 30%
of the total copper concentration and [CuL]2þ species are still
predominant in solution (ca. 50%), the spectrum shows a
broad band with its maximum at 668 nm. When a pH value
of 8.1 is reached by adding NaOH, the band shifts to 578 nm,
and this corresponds, at the distribution diagram, with the
presence of [CuH-1L]þ as the major species (ca. 85%) along
with [CuL]2þ and [CuH-2L] as minor species (below 5%
each). Finally, at pH=12, the maximum of the band is fur-
ther shifted to 553 nm, corresponding to the presence of
[CuH-2L] as the only species in solution. A similar analysis
can be carried out for the other ligands, and the correspond-
ing spectra are presented in the Supporting Information. It is
worth mentioning that for the receptors containing the shor-
test spacers, 4a-c, the UV-vis spectra confirm, as observed
in the distribution diagrams, that deprotonated complexes
[CuH-xL](2-x)þ start forming even without the addition of a
base, at pH values of 6-7. For those cases (pH ≈ 6-7),
broader bands are observed that can be deconvoluted into
two bands: a more intense one centered about 650 nm and a
minor one centered at 500 nm, which allows for a rough
estimate of a participation below 10% of the total for those
species.
under Basic Conditions
compound
λ
max (nm) ε (M-1 cm-1
)
λ
max (nm)a
υ
(CdO) (cm-1
)
5a
5b
5c
5d
5e
439
437
455
440
445
60
132
75
75
75
502
496
510
553
518
1566
1567
1567
1566
1566
a Determined in water.
The spectroscopic properties of the Cu2þ complexes
formed do not differ greatly from methanol to water. On
the other hand, the corresponding distribution diagrams pro-
vide a very useful tool to rationalize the changes observed
with the pH of the medium. In the UV-vis spectra, all com-
plexes exhibit intense ligand to metal charge transfer transi-
tions (LMCT) in the range of 200-315 nm. In the regions
where the uncomplexed cation or [CuL]2þ complexes pre-
dominate, the maxima for the band corresponding to d-d
transitions are in the 640-690 nm range, characteristic of
octahedral Cu2þ complexes, while for regions where depro-
tonated complexes [CuH-xL](2-x)þ are the major species, the
maxima are bathochromically shifted to 490-560 nm, sug-
gesting geometries ranging from square-planar to square-
pyramidal.29 This is well illustrated by the comparison of the
UV-vis spectra obtained in water for the system Cu2þ-4d as
The stoichiometry of the Cu2þ complexes in methanol
was determined by the continuous variations method
(Job plot).30 For this purpose, different solutions of the
(29) Polt, R.; Kelly, B. D.; Dangel, B. D.; Tadikonda, U. B.; Ross, R. E.;
Raitsimring, A. M.; Astashkin, A. V. Inorg. Chem. 2003, 42, 566–574. (b)
Autzen, S.; Korth, H.-G.; Boese, R.; De Groot, H.; Sustmann, R. Eur. J. Inorg.
Chem. 2003, 1401–1410.
(30) (a) Schneider, H. J.; Yatsimirsky, A. Principles and Methods in
Supramolecular Chemistry; Wiley: New York, 2000. (b) Job, P. Ann. Chim.
1928, 9, 113–203.

Article
Inorganic Chemistry, Vol. 49, No. 17, 2010 7847
Figure 7. Job plot for ligands 4a and 4d and Cu(OAc)2 in methanol.
Figure 8. ESIþ MS spectra for Cu2þ and ligand 4a at pH = 6.5 (top) and at pH = 12.1 (bottom) in water.
corresponding ligand containing different molar frac-
tions of the Cu2þ salt were prepared with the total concen-
tration kept constant at 3 ꢀ 10-5 M. The molar fraction
of the metal salt varied in the 0.1-0.9 range. As is illus-
trated for 4a and d in Figure 7, the Job plots showed
maxima centered at a molar ratio of 0.5, indicative of a 1:1
ligand/metal stoichiometry.
Mass Spectrometry Analysis. In order to obtain addi-
tional information on the molecularity of the complexes
formed, the different solutions prepared for obtaining the
UV-vis spectra of Cu2þ species, at different pH values,
were also examined by mass spectrometry.31 In this
respect, ESI-MS is a very useful technique, since it allows
the detection of species at very low concentrations.32 For
this purpose, the ESI technique in the positive mode of
analysis was used. Again, similar results were obtained
either in methanol or in water.33
For the shortest ligand 4a, at pH values of 6.8-7.0, the
observed base peak appears at 320.1 (Figure 8). This mass
corresponds to the one expected for the monocationic [Cu-
H-1L]þ species, which largely predominates in this pH
region. Nevertheless, a careful analysis of the isotopic pattern
of the cluster at 320.1 reveals that it is formed through the
participation of the doubly charged dimer [[CuH-1L]2]2þ
along with [CuH-1L]þ (see inset of Figure 8).
The second most intense fragment (ca. 40%) is the one at
380.1 that can be attributed to the [[CuL]þAcO]þ monoca-
tion. This corresponds with the presence at this pH of the
[CuL]2þ species as a minor component (see distribution dia-
gram in Figure 3). A third peak of lower intensity (20%)
appears at 639.2 and can be assigned to the monocationic
heterodimer [[CuH-1L][CuH-2L]]þ in accordance with the
presence at this pH of ca. 25% of the fully deprotonated
complex [CuH-2L]. This is also reflected in the observation
of the corresponding homodimeric species [[CuH-2L]2þ
Na]þ at 677.2 and the peaks at 342.1 and 358.1 for [Cu-
H-2L]þNa]þ and [CuH-2L]þK]þ, respectively. It is inter-
esting to note that those peaks are almost absent at pH=
6.9, while they reach an intensity of 20-30% at pH = 7,
(31) Gao, J.; Reibenspies, J. H.; Zingaro, R. A.; Woolley, F. R.; Martell,
A. E.; Clearfield, A. Inorg. Chem. 2005, 44, 232–241.
ꢁꢀ
(32) (a) Schug, K.; Frycak, P.; Maier, N. M.; Lindner, W. Anal. Chem.
2005, 77, 3660–3670. (b) Di Tullio, A.; Reale, S.; De Angelis, F. J. Mass
Spectrom. 2005, 40, 845–865. (c) Baytekin, B.; Baytekin, H. T.; Schalley, C. A.
Org. Biomol. Chem. 2006, 4, 2825–2841.
(33) It is important to note that in order to optimize the ESI-MS results,
some methanol was added to the purely aqueous solutions where the
complexes were prepared and being used for the UV-visible analyses. No
additional solvents were, however, added to the purely methanolic solutions.

7848 Inorganic Chemistry, Vol. 49, No. 17, 2010
Blasco et al.
in correspondence with the sharp increase in the concentra-
tion of the bis-deprotonated complex in this region. Addi-
tional fragments, corresponding either to the free ligand or
to clusters derived from deprotonated complexes and in-
cluding other species such as NaOAc or H2O (i.e., 402.1 for
[[CuH-1L]þNaAcO]þ), are also detected. At a pH around
12, the situation is simpler. Here, only the [CuH-2L] species
are present in the distribution diagram and are, essentially,
the only species detected in MS. The base peak appears at
342.1, corresponding to the monocationic [[CuH-2L]þNa]þ
species (NaOH was used as the base). In addition, a frag-
ment at 281.2 for the free ligand [LþNa]þ (ca. 45%) and a
minor peak, with an intensity below 20%, at 661.2, corre-
sponding to the monocationic homodimer [[CuH-2L]2þ
Na]þ is also observed. Some additional fragments corre-
sponding to other clusters can be identified, but in all cases
their relative intensities fall below 10%.
are [CuL]2þ (ca. 60%) and [[CuH-1L]þ (ca. 20%). In good
agreement with this, the base peak at this pH value appears
at 422.1, corresponding to the monocation [[CuL]þAcO]þ
and the dication [[CuL]þAcO] 2þ. The second, more im-
2
portant peak is observed for the [CuH-1L]þ species at 362.2
(58%) involving also [[CuH-1L]2]2þ species. Rather inter-
estingly, for this ligand, the ESIþ-MS presents small peaks
that can be assigned to mononuclear Cu2þ complexes con-
taining two ligand fragments. So, the MS contains peaks at
662.4 (17%) and 722.4 (<10%) that can be assigned,
respectively, to the species [CuþLþH-1L]þ and [[CuL2]þ
AcO]þ. A cluster at 783.4 (<10%) containing two copper
atoms, according to the isotopic pattern, can be associated
with the [[CuH-1L]2þAcO]þ species. Very similar peaks are
observed at pH = 8, where [CuH-1L]þ largely predomi-
nates (ca. 85%), with a minor contribution from [CuL]2þ
(ca. 10%). At this pH, however, the peak at 362.2 contains a
very important contribution from the dimeric cluster [[Cu-
H-1L]2]2þ. It is worth mentioning that at pH = 12, essen-
tially no peaks assignable to the expected [CuH-2L] species
are detected, with the exception of the [[CuH-2L]þNa]þ
peak at 384.1. Instead, the peaks associated with the free
ligand are the most important, along with some smaller
peaks than can be assigned to species derived from the
[CuH-1L]þ complex. This seems to indicate either a much
lower stability of the [CuH-2L] complexes for this ligand or,
alternatively, the presence of complexes of a polymeric
nature that cannot be transferred to the vapor phase without
destroying their structure. In this case, the influence of the
solvent appears to be very important, and in the case of the
complexes formed in methanol, the corresponding peaks for
[[CuH-2L]þK]þ (400.1, 100%) or for the corresponding
dimer [[CuH-2L]2þK]þ (763.3 ) are observed. This change
in the nature of the complexes formed by the ligands with
the larger spacers is confirmed by the fact that for the ligand
4e no peaks corresponding to Cu2þ complexes could be
detected either in water or in methanol.
Thus, although complex clusters containing several
molecules of the corresponding bis-deprotonated copper
complex are observed for ligands 4a-c along with the
peaks attributed to the molecular complexes, the absence
of such molecular peaks for 4d,e suggest that, in parti-
cular in water, polymeric complexes are predominant for
the larger ligands. It must be also noted that, in general,
the trend toward the formation of dimeric or oligomeric
complexes seems to be larger for [CuH-1L]þ species in the
case of ligands 4a-c and in particular for the first one.
The structures of the Zn2þ species, at different pH values,
were then examined by mass spectrometry. In this case, the
experiment could not be carried out in water because of the
slow precipitation of the corresponding species. Accordingly,
all the mass spectra were obtained in methanol. The much
lower stability constants for Zn2þ complexes were clearly
reflected in the results obtained by ESI MS. Thus, by the use
of the positive detection mode (ESI-MSþ), the species de-
rived from [ZnH-2L] could not be observed under any con-
ditions. This is reasonable since the observation of the peak
involves protonation or interaction with an additional cation
(i.e., Naþ or Kþ), which is enough to destroy the complex.
Accordingly, only peaks derived from [L] are observed at
basic pH. At pH values closer to neutrality (pH=8), [ZnL]2þ
species are observed. As shown in the distribution diagram,
[ZnL]2þ complex species are present in the pH window 5-9,
The ESIþ-MS spectra obtained from methanolic solu-
tions provide the same information, although they are
slightly more complex, as under those conditions, the for-
mation of complex aggregates is favored (see the Supporting
Information).
Similar trends are observed for 4b. At pH values of 6.5-
6.6, the [CuH-1L]þ complex species is predominant and the
corresponding base peak appears at 334.1 along with the
related heterodimer [[CuH-1L][CuH-2L]]þ at 670.3. In this
case, the peak at 334.1 also contains, according to the isoto-
pic pattern, significant amounts of the homodimer [[CuH-1
-
L]2]2þ. In addition, peaks corresponding to the free ligand,
[CuL]2þ, and [CuH-2L] species are also very significant,
which reflects the variety of species found in the distribution
diagram at this pH value (see Figure S8, Supporting Infor-
mation). Smaller clusters for [[CuH-2L]2þNa]þ (691.2) or
with the general composition [[CuH-2L]xþMM0]2þ, where
M and M0 can be either Naþ or Kþ, are also observed, for up
to values of x = 7. From pH 7 to 12, only peaks derived from
[CuH-2L] are detected. The base peak is the expected [[Cu-
H-2L]þNa]þ species, and the dimer [[CuH-2L]2þNa]þ only
accounts for less than 20% of the intensity of the base peak.
Again, as shown by the isotopic pattern, this peak also
contains a contribution from the doubly charged cluster
[[CuH-2L]4þNa2]2þ. Very small peaks corresponding to
higher order clusters [[CuH-2L]xþNa2]2þ are also detected.
For ligand 4c at pH = 6.3, [CuL]2þ species are the most
important ones according to the distribution diagram, and
the base peak in the ESI-MS at 408.1 corresponds to the
[[CuL]þAcO]þ species. The peak assigned to [CuH-1L] at
348.1 is also important (90%), and of minor importance are
the peaks for [[CuH-2L]þK]þ at 386.1 and the dimer [[Cu-
H-1L]2þAcO]þ at 755.3. At pH = 7, [CuL], [CuH-1L], and
[CuH-2L] species coexist, but [CuL] is very minor. Accord-
ingly, the three most relevant peaks are those for [CuH-1L]þ
at 348.1 (100%), [[CuH-2L]þNa]þ at 370.1 (80%), and
[[L]þNa]þ at 309.2 (70%). Small peaks for the complex
clusters [[CuH-2L]xþMM0]2þ can be observed. At pH =
12, the MS is very similar to the one at pH = 7, but the peak
assigned to [[CuH-2L]þNa]þ is the base peak, while the
2þ
peak at 348.2 seems to correspond mainly to [CuH-1L]2
.
In methanol, under basic conditions, the two more signifi-
cant peaks appear at 386.1 for [[CuH-2L]þNa]þ and at
735.2 for [[CuH-2L]2þNa]þ.
In the case of the receptor with a spacer containing five
methylene groups, 4d, the predominant species at pH = 6.5

Article
Inorganic Chemistry, Vol. 49, No. 17, 2010 7849
Figure 9. ESI-MSþ spectra for Zn2þ and ligand 4b at pH = 8 (top) and ESI-MS- at pH = 12 (bottom), both in methanol.
although those species are very minor. It must be noted that
under those conditions (methanolic solutions at pH = 8),
essentially the same spectra were obtained for compounds 4
independently of the aliphatic spacer. The most intense frag-
ment is the one attributed to the monocation [[ZnL]þAcO]þ.
The species [[ZnL2]þAcO]þ is also detected. A peak of lower
intensity (10%) can be assigned to the species [[ZnL]þ
2AcOþNa]þ. Additional fragments, corresponding either
to the free ligand (i.e., [LþK]þ or [2LþK]þ) or to [ZnL]2þ
clusters are also detected. The situation is different for ESI-
MS-. In this case, ionization can take place by an additional
deprotonation, and the neutral [ZnH-2L] species is trans-
formed in the monoanionic [ZnH-3L]- species that can be
detected. Thus, at pH=12, the fragments observed for com-
pounds 4 correspond to the monoanionic deprotonated
ligand ([H-1L]) and to the [ZnH-3L]-species. The observed
trends in ESI-MS are illustrated in Figure 9 for 4b.
X-Ray Diffraction Studies. Crystals of good quality for
X-ray diffraction studies were obtained for the corre-
sponding Cu2þ complexes of ligands 4a and 4b, but at
different pH values (7 and 12, respectively). The struc-
tures obtained nicely confirm the formation of complexes
with very different environments for the copper atoms, in
good agreement with the results obtained with the former
techniques.
primary amines and to the two deprotonated amide nitro-
gen groups (Figure 10).
As expected, the Cu-amide nitrogen distances (ave-
rage 1.92 A) are shorter than the Cu-amine ones (average
1.99 A). The most important structural parameters for the
structure are gathered in Table 6.
Although all the N-Cu-N angles are close to 90°, it can
be noticed that the angle of the six-membered chelate ring
involving the two deprotonated amide groups is broader
than the angles of the five-membered chelate rings involving
amide and primary amine nitrogens. This is a well-known
feature in complexes having alternated five-membered and
six-membered chelate rings and represents a strain-free con-
formation in which the metal-ligand interactions are
maximized.34 Finally, the angle involving the primary amines
in both complexes is in between the previous ones (Table 6).
The two isopropyl groups of each are oriented toward diffe-
rent sides of the coordination plane. It is interesting to
remark that the different units and ethanol molecules are
interconnected between them through a hydrogen bond net-
work. Bifurcated hydrogen bonds are formed between the
carbonyl oxygen atom O31 and secondary nitrogen atoms
N1 and N11 of identical units (O31-N1, 2.79 A; O31-N11,
3.03 A); the other carbonyl oxygen atom of this unit (O91)
connects with a nitrogen of a different unit (O91-N11A,
2.84 A). Hydrogen bonds are also formed between the etha-
nol molecules and the carbonyl oxygen atom C31A of the
second unit. Figure 11 depicts the hydrogen bond network
formed.
Crystal Structure of [Cu(H-24b)] CH3CH2OH (5b).
Crystals of 5b were grown by evaporating solutions of
Cu(AcO)2 H2O and 4b at pH = 12 in ethanol. The crystal
3
3
structure revealed the formation of a mononuclear neutral
complex with a 1:1 ligand/metal stoichiometry. The struc-
ture of 5b consists of two practically equivalent [CuH-2L]
neutral complex units and ethanol molecules coming from
the crystallization solvent. In each unit, the copper atoms
are coordinated with square-planar geometry to the two
Crystal Structure of [Cu2(H-14a)2](ClO4)2 (6a). Crys-
tals of 6a were grown by evaporating water solutions of
(34) Fawcett, T. G.; Rudich, S. M.; Toby, B. H.; Lalancette, R. A.;
Potenza, J. A.; Scugar, H. J. Inorg. Chem. 1980, 19, 940–945.

7850 Inorganic Chemistry, Vol. 49, No. 17, 2010
Blasco et al.
Figure 12. Molecular diagram of the [CuH-14a]22þ subunit. Ellipsoids
at the 50% probability level. Hydrogen atoms and solvent molecules have
been omitted for clarity.
Figure 10. Molecular diagram for one out of the two [Cu(H-24b)] units
present in 5b. Ellipsoids at 50% probability level. Hydrogen atoms and
solvent molecules have been omitted for clarity.
Table 7. Selected Bond Lengths (A) and Angles (deg) for Compound 6a
Bond Distances
Cu(1)-N(2A)
Cu(1)-O(4C)
Cu(1)-N(6A)
Cu(1)-N(6C)
1.922(8)
1.979(8)
1.983(8)
1.998(9)
Cu(2)-N(2D)
Cu(2)-O(4B)
Cu(2)-N(6B)
Cu(2)-N(6D)
Cu(2)-O(4D)
1.917(10)
2.039(7)
1.989(8)
1.999(10)
2.415(8)
Bond Angles
N(2A)-Cu(1)-O(4C)
N(2A)-Cu(1)-N(6A)
O(4C)-Cu(1)-N(6C)
N(6A)-Cu(1)-N(6C)
N(2D)-Cu(2)-O(4B)
97.0(4) O(4B)-Cu(2)-N(6B)
83.1(3) N(6B)-Cu(2)-N(6D)
82.8(3) N(6B)-Cu(2)-O(4D)
81.8(3)
97.1(3)
83.0(3)
97.5(3) N(6D)-Cu(2)-O(4D) 108.2(4)
98.4(4) N(2D)-Cu(2)-O(4D)
N(2D)-Cu(2)-N(6D) 83.2(4) O(4B)-Cu(2)-O(4D)
96.0(5)
98.9(3)
According to ESI-MS experiments, a mixture of the mono-
cationic species [CuH-1L1]þ and the dicationic dimer
[CuH-1L1]22þ are responsible for the base peak. In gen-
eral, [CuH-1L1]þ species tend to be detected as dimeric
fragments.
The crystal structure of 6a consists of a zigzag chain in
which different [CuH-1L1]22þ dicationic dinuclear units are
interconnected through coordinative bonds between Cu(2)
and one oxygen atom of a deprotonated amide group of
a neighbor unit (see Figures S12 and S13, Supporting
Information).
Figure 11. Schematic representation of the hydrogen bond network
formed in compound [Cu(H-24b)] CH3CH2OH (5b).
3
Table 6. Selected Bond Lengths (A) and Angles (deg) for Compound 5ba
Bond Distances
Each [CuH-1L]22þ moiety contains two monodeproto-
nated ligands presenting an extended conformation and
involving the coordination to two metal ions. The torsion
angles in the chains that coordinate both metal sites are
N2A-C1A-C1B-N2B, 173.7(8); C1A-C1B-N2B-
C3B, 96.1(12); N2D-C1D-C1C-N2C, 174.6(10); and
C1D-C1C-N2C-C3C, 128.5(19) (Figure 12).
Cu(1)-N(1)
Cu(1)-N(4)
Cu(1)-N(8)
Cu(1)-N(11)
1.982(2)
1.924(2)
1.916(2)
1.991(2)
Cu(1A)-N(1A)
Cu(1A)-N(4A)
Cu(1A)-N(8A)
Cu(1A)-N(11A)
1.989(2)
1.932(3)
1.912(2)
2.002(2)
Bond Angles
In this basic unit, one copper atom, Cu(1), is coordinated
in a square planar arrangement to two terminal primary
amino groups of each ligand (N6A and N6C), to a nitrogen
atom of a deprotonated amido group (N2A), and to the
oxygen atom of a carbonyl group (O4C) of a neutral amide
group of the other ligand (Figure 12).35 As shown in Table 7,
N(1)-Cu(1)-N(4) 84.73(9) N(1A)-Cu(1A)-N(4A) 82.37(11)
N(1)-Cu(1)-N(11) 92.67(9) N(1A)-Cu(1A)-N(11A) 95.74(10)
N(4)-Cu(1)-N(8) 98.56(10) N(4A)-Cu(1A)-N(8A) 97.71(10)
N(8)-Cu(1)-N(11) 83.91(10) N(8A)-Cu(1A)-N(11A) 84.15(10)
a Data for the two slightly different [CuH-24b] complexes found in
the asymmetric unit are presented.
Cu(ClO4)2 6H2O and 4a at an initial pH of 7. The crystal
3
structure consists of [CuH-1L2]22þ cations and perchlo-
rate counteranions. As shown in the distribution diagram
included in Figure 4 (bottom), at this pH a species of
[CuH-1L1]þ stoichiometry predominates in solution.
(35) This type of chelating binding mode for amino acids is relatively
common and, in particular, has been reported for copper(II) amino acid
species: (a) Castellano, E. E.; Piro, O. E.; Casado, N. M. C.; Brondino, C. D.;
Calvo, R. J. Chem. Crystallogr. 1998, 28, 61–68. (b) Tan, X. S.; Fujii, Y.; Sato,
T.; Nakano, Y.; Yashiro, M. Chem. Commun. 1999, 881–882.

Article
Inorganic Chemistry, Vol. 49, No. 17, 2010 7851
the shortest Cu-N distance is the one with the deprotonated
amino group (Cu(1)-N(2A), 1.922(8) A). The bite angles
are narrower than 90° when donor atoms of the same ligand
are implicated and wider when donor atoms of the different
ligands are implicated in the formation of the chelate rings
(Table 7).
The second copper atom, Cu(2), displays a square-bipyr-
amidal coordination geometry with significant axial distor-
tion. The equatorial plane is defined by the nitrogen atom of
a deprotonated amido group (N2D), which displays again
the shortest Cu-N bond distance, two nitrogens of the
terminal primary amino groups (N6B and N6D), and an
oxygen atom (O4B) belonging to the carbonyl group of the
nondeprotonated amine group.
The first one confirms the monomeric nature and the forma-
tion of the expected deprotonated complex according to the
general structure 5, giving place to a square planar arrange-
ment around the copper atom. The second structure obtained
for 4a at pH ≈ 7 reveals the presenceof complex species with a
general composition [CuH-1L]þ but involving dimeric
[CuH-1L]22þ subunits with one square planar and one square
pyramidal copper atom. Apical coordination of this second
Cu with the carbonyl oxygen atom of another dimeric unit
allows propagating the chain into a polymeric structure. In
both cases, an extensive H-bonding network also involving
the addition of anions or solvent molecules completes the
interactions in the crystal.
The axial position is occupied by a carbonyl oxygen
of a deprotonated amide belonging to a neighbor ligand
molecule in the chain (Cu(2)-O(4D), 2.415(8) A). Cu(2)
is displaced 0.228 A from the mean plane defined by the
equatorial donor atoms toward the apical position. As
previously commented upon, this axial coordination is
the way in which the chain propagates, the angles between
the mean coordination planes of the zigzag disposed
dinuclear coordination [[CuH-1L]2]2þ fragments being
79.6°. The chains are interconnected by bifurcated hydro-
gen bonds forming layers. The hydrogen bonds are
established between the oxygen atom O4A of the depro-
tonated amide group and the primary amine nitrogens
N6A and N6C (O4A-N6A, 2.919(13) A; O4A-N6C,
3.051(11) A; see the Supporting Information).
Experimental Section
Electromotive Force Measurements. The potentiometric titra-
tions were carried out at 298.1 K using 0.15 M NaClO4 as a
supporting electrolyte. The experimental procedure (buret,
potentiometer, cell, stirrer, microcomputer, etc.) has been fully
described elsewhere. The acquisition of the EMF data was
performed with the computer program PASAT.17 The reference
electrode was a Ag/AgCl electrode in saturated KCl solution.
The glass electrode was calibrated as a hydrogen-ion concentra-
tion probe by the titration of previously standardized amounts
of HCl with CO2-free NaOH solutions and the equivalent point
determined by Gran’s method,36 which gives the standard
potential, E°0, and the ionic product of water [pKw = 13.73(1)].
The computer program HYPERQUAD16 was used to calculate
the protonation and stability constants, and the HySS17 program
was used to obtain the distribution diagrams. The pH range
investigated was 2.5-11.0, and the concentration of the metal
ions and of the ligands ranged from 1 ꢀ 10-3 to 5 ꢀ 10-3 M with
Cu2þ/L molar ratios varying from 2:1 to 1:2. The different titration
curves for each system (at least two) were treated either as a single
set or as separated curves without significant variations in the
values of the stability constants. Finally, the sets of data were
merged together and treated simultaneously to give the final
stability constants.
Conclusions
Pseudopeptidic ligands 4a-e are able to form complexes of
very different structures with metal ions such as Cu2þ and
Zn2þ. A combination of pH-metric titrations, spectroscopic
studies, and ESI-MS experiments has been carried out to
analyze the complex formation. Two critical factors deter-
mining the final structure are the nature of the aliphatic
spacer connecting the amino acid subunits and the pH value
at which the complex is formed. Important differences can be
found between Zn2þ and Cu2þ complexes. In the case of
Zn2þ, the complexes, as expected, display much lower stabi-
lity constants, but the most remarkable feature is that the
length of the spacer seems to have a very minor influence
on the nature of the complexes formed. While for Zn2þ the
only complex species formed to a significant extent is the
[ZnH-2L] species, for Cu2þ the situation is more complex.
Bis-deprotonated [CuH-2L] species are the most stable com-
plex species formed at basic pH values. The formation of
those species is particularly important for the ligands with the
shortest spacers (4a-c) for which deprotonation does not
require very basic media. Monoprotonated [CuH-1L]þ com-
plexes are always detected at lower pH values, although the
participation of dimeric and oligomeric species with the gene-
ral composition [CuH-1L]x seems to be very important, in
particular for the shorter ligand 4a and for the larger ligands
4d,e. In this regard, a clear, different behavior seems to be pre-
sent when comparing ligands 4a-c with 4d,e. For the larger
ligands, the formation of monomeric [CuH-2L] complexes is,
apparently, not favored, and, instead, oligomeric/polymeric
structures predominate. The crystals structures of the
Mass Spectrometry. Mass spectra were recorded on a hybrid
QTOF I (quadrupole-hexapole-TOF) mass spectrometer with
an orthogonal Z-spray-electrospray interface (Micromass,
Manchester, U.K.) using either the electrospray positive mode
(ESþ) or the electrospray negative mode (ES-). The desolvation
gas as well as nebulizing gas was nitrogen at a flow of 700 L/h
and 20 L/h, respectively. The temperature of the source block
was set to 120 °C and the desolvation temperature to 150 °C.
A capillary voltage of 3.5 and 3.3 kV was used in the positive
and negative scan modes, respectively. The cone voltage was
typically set to 20 V to control the extent of fragmentation of the
identified ions. Sample solutions were infused via syringe
pump directly connected to the ESI source at a flow rate of
10 mL/min. The observed isotopic pattern of each intermediate
perfectly matched the theoretical isotope pattern calculated
from their elemental composition using the MassLynx 4.0
program.
NMR Measurements. The 1H spectra were recorded on a
Varian VNMR System 500 MHz spectrometer operating at 500
MHz. The solvent signal was used as a reference standard.
Adjustments to the desired pH were made using drops of DCl
or NaOD solutions. The pD was calculated from the measured
pH values using the correlation pH = pD - 0.4.37
(36) (a) Gran, G. Analyst (London) 1952, 77, 661–671. (b) Rossotti, F. J.;
Rossotti, H. J. Chem. Educ. 1965, 42, 375–378.
(37) (a) Glasoe, P. K.; Long, F. A. J. Phys. Chem. 1960, 64, 188–190. (b)
Covington, A. K.; Paabo, M.; Robinson, R. A.; Bates, R. G. Anal. Chem. 1968,
40, 700–706.
solid complexes [Cu(H-2L)] CH3CH2OH (L=4b) and [Cu2-
3
(H-1L)2](ClO4)2 (L = 4a) confirm the former observations.

7852 Inorganic Chemistry, Vol. 49, No. 17, 2010
Blasco et al.
Table 8. Crystallographic Data for [Cu2(H-14a)2](ClO4)2 (6a) and [Cu(H-24b)]
CH3CH2OH (5b)
diffractometer and that of the complex from ligand 4b with a
Siemens CCD three-circle diffractometer. In both cases, Mo KR
radiation (λ = 0.71073 A) was used. The space groups were P21 and
P212121 for 6a and 5b, respectively. A total of 11 791 and 46 978
reflections were measured in the hkl ranges (-17, -12, -17) to (17,
9, 18) and (-13, -14, -46) to (13, 14, 46) between θ limits 1.5 < θ
< 27.4° and 2.0 < θ < 28.4° for 6a and 5b, respectively. The struc-
ture was solved by the Patterson method using the program
SHELXS-86,38 running on a Pentium 100 computer. Isotropic least-
squares refinement was performed by means of the program
SHELXL-97.39 The location of hydrogen atoms was inferred from
neighboring sites. Crystal data, data collection parameters, and
results of the analyses are listed in Table 8. During the final stages
of the refinement, the positional parameters and the anisotropic
thermal parameters of the non-hydrogen atoms were refined. The
hydrogen atoms were refined with a common thermal parameter.
Absolute structure was checked with Flack’s parameter,40 which
resulted in 0.020(10) for 5b and -0.02(4) for 6a. Molecular plots
were produced with the ORTEP41 and MERCURY programs.42
See the Supporting Information for crystallographic data in electro-
nic format.
3
6a
5b
empirical formula
fw
cryst size, mm
cryst syst/s.g.
space group
T K
λ(Mo KR) (A)
a, A
b, A
C
24H50Cl2Cu2N8O12
C15H32CuN4O3
379.99
840.70
0.15 ꢀ 0.1 ꢀ 0.1
monoclinic
P21
293(2)
0.71073
13.4170(6)
9.8305(4)
14.0594(7)
90
100.920(2)
90
1820.80(14)
2
1.533
0.35 ꢀ 0.28 ꢀ 0.12
orthorhombic
P212121
173(2)
0.71073
10.191(2)
10.771(2)
35.070(5)
90
c, A
R, deg
β, deg
90
90
γ, deg
V, A3
3849.5(12)
8
1.311
1.153
1624
Z
dcalc, g/cm3
abs coeff (mm-1
F (000)
)
1.381
876
reflecns collected
unique reflns
restraints
params
11791
7064
46
433
46978
8918
3
429
Acknowledgment. Financial support from Ministerio de
ꢀ
Ciencia e Innovacion (CTQ2009-14366-C02-01) and Bancaja-
R1
wR2
GooF
0.0806
0.2805
1.04
0.038
0.082
1.03
UJI (P1-1B2009-59) and Fondos Europeos de Desarrollo Re-
gional (FEDER) is gratefully acknowledged. Dr. C. Vicent of
the SCIC (UJI) is warmly acknowledged for his help with MS
analyses.
Crystallographic Analysis. [CuH-14a]2(ClO4)2 (6a). Crys-
tals of 6a suitable for X-ray analysis were obtained in 40% yield
by slow evaporation of water solutions containing 4a (0.017 g,
Supporting Information Available: NMR titration for 4a,
distribution diagrams, UV-vis spectra, Job plots, and ESIþ-MS
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
0.03 mmol) and Cu(ClO4)2 6H2O (0.011 g, 0.03 mmol) adjusted
3
to pH 7. Anal. Calcd for C24H50Cl2Cu2N8O12: C, 34.29; H, 5.99;
N, 13.33. Found: C, 34.45; H, 5.75; N, 13.22.
(38) Sheldrick, G. M.; Kruger, C.; Goddard, R. Crystallographic Com-
puting; Clarendon Press: Oxford, England, 1985; p 175.
(39) Sheldrick, G. M SHELXL-97; Institut f€ur Anorganische Chemie,
Caution! Perchlorate salts of compounds containing organic
ligands are potentially explosive and should be handled with care.
[CuH-24b] CH3CH2OH (5b). Yellow crystals of 5b suitable
€
€
University of Gottingen: Gottingen, Germany, 1997. (b) Sheldrick, G. M Acta
Crystallogr. 2008, A64, 112.
3
for X-ray diffraction analysis were obtained by slow evapora-
tion in an open vessel of ethanol solutions containing 4b and
(40) Flack, H D Acta Crystallogr. 1983, A39, 876.
Cu(OAc) H2O in a 1:1 molar ratio (0.05 mol dm-3 con-
(41) Johnson, C. K. ORTEP; Report ORNL-3794, Oak Ridge National
Laboratory: Oak Ridge, TN, 1971.
(42) MERCURY 1.3 for Windows Me/2000/XP: (a) Taylor, R.; Macrae,
C. F. Acta Crystallogr. 2001, B57, 815–827. (b) Bruno, I. J.; Cole, J. C.;
Edgington, P. R.; Kessler, M. K.; Macrae, C. F.; McCabe, J.; Pearson, J.; Taylor, R.
Acta Crystallogr. 2002, B58, 389–397.
3
centrations) and at pH 12. Anal. Calcd for C15H32CuN4O3: C,
47.41; H, 8.49; N, 16.72. Found: C, 47.59; H, 8.46; N, 16.99.
Analysis of the single crystals of the complex from ligand 4a was
carried out with an Enraf-Nonius KAPPA CCD single-crystal