Cu2+, Zn2+, and Ni2+ Complexes of C2-Symmetric Pseudopeptides with an Aromatic Central Spacer

Article abstract of DOI:10.1021/acs.inorgchem.6b01066

Two new tetradentate C₂-symmetric pseudopeptidic ligands derived from Val and Phe containing two amino and two amido groups and a central o-substituted aromatic spacer have been prepared. Their complexes with Cu²⁺, Zn²⁺, a

Full text of DOI:10.1021/acs.inorgchem.6b01066

Article
pubs.acs.org/IC
Cu2+, Zn2+, and Ni2+ Complexes of C2‑Symmetric Pseudopeptides
with an Aromatic Central Spacer
Lingaraju Gorla, Vicente Martí-Centelles, Lena Freimuth, Belen Altava,* M. Isabel Burguete,
́
and Santiago V. Luis*
́ ́ ́
Departamento de Química Inorganica y Organica, Universitat Jaume I, Av. de Vicent Sos Baynat, s/n, 12071, Castellon, Spain
S
* Supporting Information
ABSTRACT: Two new tetradentate C2-symmetric pseudo-
peptidic ligands derived from Val and Phe containing two
amino and two amido groups and a central o-substituted
aromatic spacer have been prepared. Their complexes with
Cu2+, Zn2+, and Ni2+ have been studied by potentiometry,
UV−vis spectrophotometry, FT-IR, and ESI-MS. The presence
of the aromatic spacer provides Cu2+ complexes with stability
constants several orders of magnitude higher than those
observed for related ligands containing aliphatic central
spacers. Besides, the formation of [MH−2L] complex species
is favored. Crystal structures for the corresponding Cu2+ and
Ni2+ have been obtained, revealing the metal atom in an
essentially square-planar geometry, although, in several
instances, the oxygen atom of an amide carbonyl of a second complex species can act as a fifth coordination site. In the case
of Zn2+, the only crystal structure obtained displays a square-pyramidal arrangement of the metal center. Finally, preliminary
experiments show the catalytic activity of some of these complexes, in particular, Zn2+ complexes, for epoxide ring-opening with
using aniline as the nucleophile in a ligand accelerated process.
molecular machines,18 as organogelators,19 acting as “in vivo”
INTRODUCTION
■
fluorescent pH probes,20 and as ligands for the preparation of
enantioselective catalysts.21
Metal chelation is involved in many biological processes. Thus,
copper is responsible for the normal function of many tissues,
including immune, nervous, and cardiovascular systems.1
Moreover, in recent years, metal-related drugs have gained
much importance in medicinal chemistry. They are currently in
use as medicines for the treatment of diabetes, cardiovascular
diseases, and cancer and as anti-inflammatory and antimicro-
bial.2−5 A large variety of ligands have been explored in
coordination chemistry,6−8 and the inclusion of amino acid
residues in their structure is an important strategy, not only for
their strong coordinating ability for a variety of metal ions but
also because they provide coordination environments similar to
those found in metalloproteins with multiple binding sites.9 In
this context, amino acid derived open-chain and macrocyclic
compounds have recently drawn much attention in very
different fields like synthetic,10 bioorganic,11 medicinal,12 and
supramolecular chemistry,13 or in catalysis.14 In this context,
symmetrical tetracoordinated Schiff base metal complexes
derived from amino acids, containing aromatic central spacers,
have been studied as catalysts for Et2Zn addition reactions and
as chiral porphyrin mimics.15 Furthermore, recent contributions
from our group have shown how minimalistic pseudopeptides
derived from simple natural amino acids, with the general
structures I−III (Chart 1), can have important applications,16
and have been reported as chiral solvating agents or selective
receptors for substrates of biological relevance,17 as minimalistic
Regarding metal complexation, our group has recently
studied the coordination ability of some C2-symmetrical
bis(amino amides) derived from amino acids with the general
structure I and possessing an aliphatic central spacer
(−(CH2)n−) toward Cu2+ and Zn2+ ions.22 The obtained
results revealed that both the nature of the constituent amino
acid (R in I) and the length of the aliphatic spacer (n in
−(CH2)n−) were of importance in determining the complexes
formed and their stability. Taking this into account, the
substitution of the flexible aliphatic central spacer in I by a rigid
aromatic spacer derived from o-diaminobenzene seems to be a
logical step forward for a proper understanding of the
coordination properties of this family of ligands. This aromatic
spacer should not only provide a geometrically more defined
coordination environment but also induce a modification of the
acidity of the N−H of the amide group and, accordingly, of its
involvement in the coordination to metal centers.
In this context, here we present the synthesis, character-
ization, and study of a family of bis(amino amide) ligands I
derived from L-valine and L-phenylalanine and having an
aromatic central spacer based on o-diaminobenzene, as well as
Received: May 2, 2016
© XXXX American Chemical Society
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Chart 1. General Structures for Pseudopeptides
a
Scheme 1. Synthesis of Chiral Bis(amino amide) Ligands
a
Reagents: (i) Et3N, ClCOOEt, o-phenylenediamine, −10 °C, 2 h, then rt, 24 h, THF, 39−57%; (ii) H2/Pd-C, MeOH, rt, 8 h, 53−66%.
Table 1. Logarithms of Stepwise Basicity Constants of Ligands 5−8 Determined at 298 K
a
c
df
,
cg
,
e
e
reaction
5
7
8
5
6
b
H + L ⇌ HL
8.13(3)
6.89(3)
7.94(1)
6.96(1)
7.57(1)
6.70(1)
7.09(9)
7.17(3)
6.21(3)
H + HL ⇌ H2L
7.08(9)
a
b
c
d
Charges omitted for clarity. Values in parentheses are the standard deviations in the last significant figure. 0.1 M NaCl. 0.15 M NaClO4 (ref
e
f
g
22a). 0.1 M NaCl/CH3CN 7/3 v/v. ref 22a. ref 22b.
the analysis of their binding ability toward Cu2+, Zn2+, and Ni2+.
Moreover, preliminary studies on the catalytic properties of
some of the complexes prepared have been carried out.
potentiometric studies in 0.1 M NaCl/CH3CN 7/3 v/v, the
value used for pKw was determined to be 14.6.27 The constants
previously obtained in 0.1 M NaCl for the related valine and
phenylalanine bis(amino amides) with an ethylenic central
spacer 7 and 8 (Chart 2) have also been included for
comparison.22
RESULTS AND DISCUSSION
■
Syntheses. Open-chain pseudopeptides 5 and 6 derived
from L-valine and L-phenylalanine, respectively, could be easily
prepared starting from the corresponding N-Cbz protected
amino acid (1 and 2) through the initial formation of the
corresponding N-protected bis(amino amide) (3 and 4) by
reaction with o-phenylenediamine and its N-deprotection by
hydrogenolysis, following previously reported procedures for
related compounds (Scheme 1).23 Overall yields for the
preparation of compounds 5 and 6 after the final deprotection
step were in the 53−66% range. These bis(amino amides) were
fully characterized by 1H NMR, 13C NMR, FT-IR, and ESI-MS
techniques (Figures S1−S6).
Chart 2. Pseudopeptidic Ligands (7−8) Related to
Compounds 5 and 6 Containing an Ethylenic Central Spacer
Acid−Base Properties. The proper determination of the
acid−base properties of nitrogenated compounds is essential
for understanding their coordination properties.24,25 Thus, the
protonation constants of bis(amino amides) 5 and 6 were
determined by potentiometric titrations. Although compound 5
was soluble enough to carry out the corresponding studies in
0.1 M NaCl, the low solubility of 6 in this medium required the
use of a mixed solvent (0.1 M NaCl/CH3CN 7/3 v/v) for the
corresponding studies. All the titrations were carried out as is
fully described in the Experimental Section, at 298 K, using 0.1
M NaCl or 0.1 M NaCl/CH3CN 7/3 v/v as the supporting
electrolyte to maintain a constant ionic strength. The stepwise
stability constants for the protonation of these pseudopeptidic
derivatives obtained following this methodology and using the
program HYPERQUAD26 are presented in Table 1. For the
The comparison of the constants obtained in 0.1 M NaCl for
ligands 5 and 7 derived from Val reveals that the substitution of
the ethylenic spacer by the aromatic one seems to have no
effect on the observed basicity in water. Even in the case of the
second protonation constant, the values are comparable,
indicating that, in both cases, an appropriate separation of the
two positive charges in the diammonium salt occurs. The
change in the solvent system to 0.1 M NaCl/CH3CN 7/3 v/v is
accompanied, for ligand 5, by a reduction in the first basicity
constant of about 1 order of magnitude that does not happen
for the second protonation constant. As a result, the two
stepwise protonation constants for 5 are very close, which is
remarkable. This can suggest that, in the nonprotonated
compound, for this solvent mixture, the amino nitrogen atoms
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Figure 1. Distribution diagrams for the protonated species of compounds 5 and 6 (0.1 mM) as a function of pH in 0.1 M NaCl/CH3CN 7/3 v/v at
298 K. Charges have been omitted for clarity.
1
Figure 2. H NMR chemical shift variation against pH for selected signals in compound 5, 1 mM in D2O/CD3CN 7/3 v/v.
Table 2. Logarithms of the Formation Constants (log β) for the Cu2+ Complexes with Pseudopeptidic Ligands at 298 K
a
c
df
,
cg
,
e
e
reaction
5
7
8
5
6
b
Cu + L ⇌ CuL
Cu + L ⇌ CuH−1L + H
8.48(9)
0.17(1)
6.09(4)
0.67(1)
8.83(4)
4.8(1)
9.24(3)
5.03(2)
1.11(1)
Cu + L ⇌ CuH−2L + 2H
−6.48(1)
−6.27(1)
−0.69(3)
−0.54(3)
a
b
c
d
Charges omitted for clarity. Values in parentheses are the standard deviations in the last significant figure. 0.1 M NaCl. 0.15 M NaClO4 (ref
22a). 0.1 M NaCl/CH3CN 7/3 v/v. ref 22a. ref 22b.
e
f
g
are involved in strong hydrogen bonding that needs to be
broken for the first protonation to occur. As in the case of the
pseudopeptides containing an ethylenic spacer,22 the change in
the side chain from isopropyl to benzyl produces a reduction in
the overall basicity of 6 relative to 5. Most likely, this reflects
the interference of the aromatic rings of the side chains with the
solvation of the ammonium ions. However, the first
protonation constants for 5 (log KH1 7.09) and 6 (log KH1
7.17) are very close, and only the second protonation constant
is higher for 5 than for 6 (log KH2 7.08 and 6.21, respectively).
This again suggests a particular behavior of 5 in its first
protonation in this solvent mixture. The importance of the
amino acid side chain on the solvation and hydrogen-bonding
networks has been demonstrated in the study of dynamic
processes in related pseudopeptides.18
The distribution diagrams for 5 and 6 in the mixed solvent
(Figure 1; see Figure S7 for the distribution diagram of 5 in 0.1
M NaCl) revealed the presence of HL+ species at pH 7 for both
ligands (being the major species for 6) while H2L2+ species
predominate for the pH regions below 7 (ligand 5) and 6
(ligand 6), being the only species present below pH 5 and 4,
respectively. Neutral L species start to predominate for both
ligands at pH > 7.
The protonation of ligand 5 was also monitored by 1H NMR
spectroscopy,28 using a solvent mixture similar to the one used
for potentiometric titrations (ligand 5, 1 mM in D2O/CD3CN
7/3 v/v) (see Figure S8). Although the signal for the hydrogen
atom at the chiral carbon atom partly overlaps with the water
solvent signal at pH regions close to 7, this signal experiments a
significant downfield shift between pH 8 and pH 6 (Δδ > 0.7
ppm), in good agreement with potentiometric data. Moreover,
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Table 3. Logarithms of the Formation Constants (log β) for the Complexes of Zn2+ with Pseudopeptidic Ligands at 298 K
a
c
d
e
e
reaction
5
7
5
6
Zn + L ⇌ ZnL
4.05(1)
3.81(4)
b
Zn + L ⇌ ZnH−2L + 2H
−12.22(8)
−12.44(1)
−10.01(1)
−10.45(3)
a
b
c
d
Charges omitted for clarity. Values in parentheses are the standard deviations in the last significant figure. 0.1 M NaCl. 0.15 M NaClO4 (ref
22a). 0.1 M NaCl/CH3CN 7/3 v/v.
e
Figure 3. Distribution diagrams for ligands 5 (a) and 6 (b) with Cu2+ as a function of pH in 0.1 M NaCl/CH3CN 7/3 v/v, at 298 K. Charges have
been omitted for clarity. [L] = [Cu2+] = 0.1 mM.
Figure 4. Distribution diagrams for ligands 5 (a) and 6 (b) with Zn2+ as a function of pH in 0.1 M NaCl/CH3CN 7/3 v/v, at 298 K. Charges have
been omitted for clarity. [L] = [Zn2+] = 0.1 mM.
similar trends are observed for the shifts of other signals as
shown in Figure 2.
for 7, being present at pH regions around neutrality.22a In this
regard, the corresponding distribution diagrams differ signifi-
cantly and the relative importance of the neutral [CuH−2L]
species was very different (Figure S9 for the distribution
diagram of 5 with Cu2+ in 0.1 M NaCl). For 7, this complex
species starts to be formed at pH values slightly below 6,
becoming the major species in the basic region from ca. pH > 7.
On the contrary, for 5, the [CuH−2L] species is formed at pH
values slightly below 4 and becomes predominant above pH 4.
For compound 5, the free cation is only the major species at the
very acidic regions below pH 4, while for 7 predominates below
pH 6.22a
As mentioned above, the comparison of 5 and 6 required a
mixed solvent (0.1 M NaCl/CH3CN 7/3 v/v). When
comparing the data for 5 in both solvents, it can be observed
that the dicationic complex [CuL]2+ is slightly more stable in
the mixed solvent, but the neutral complex [CuH−2L] is 1 order
of magnitude less stable. This can be associated with the
presence of CH3CN in the solvent mixture that could
participate to a higher extent in the coordination to the
[CuL]2+ species. On the other hand, the mixed solvent can
reduce the basicity of the amide groups. This allows the
observation of [CuH−1L]+ as an important species that
becomes predominant at ca. pH 5.5 (Figure 3). In any case,
the values of the stability constants continue being several
orders of magnitude higher than those measured for ligand 7,
Determination of the Cu2+ and Zn2+ Complexes
Formation Constants. Because of the interest in developing
metal-containing model systems for metalloproteins, and taking
into account our previous experience in this field, the copper,
zinc, and nickel complexes of the new ligands were investigated
to explore their coordination chemistry. The interaction of
ligands 5 and 6 with Cu2+ and Zn2+ was studied by
potentiometric titrations in 0.1 M NaCl and 0.1 M NaCl/
CH3CN 7/3 v/v over the 2−12 pH range at 298 K. The
stability constants for the formation of complexes were
determined for a 1:1 metal−ligand ratio. As in the case of the
protonation constants, accurate results for 6 could only be
obtained in the mixed solvent because of its limited solubility in
water. Results obtained are presented in Tables 2 and 3, and the
corresponding distribution diagrams are displayed in Figures 3
and 4. The values obtained previously for the related ligands 7
and 8 have also been included for comparison.22a
As seen in Table 2, the comparison between ligands 5 and 7
in 0.1 M NaCl highlights the importance of the central spacer.
The stability of the complexes detected is several orders of
magnitude higher in the case of the ligand with the central
aromatic spacer (5). Moreover, for 5, only two complex species
(nondeprotonated and bisdeprotonated) were detected, while
the monodeprotonated [CuH−1L]+ species was also detected
D
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containing a central ethylenic spacer, in water. In this mixed
solvent, the values of the formation constants were slightly
lower for ligand 5 (i.e., log K = 8.83 and 9.24, respectively, for
[CuL]2+), which can reflect similar phenomena than in the case
of the protonation constants. The corresponding distribution
diagrams (Figure 3) display similar trends for both ligands and
are in line with the distribution diagram observed for 5 in 0.1 M
NaCl (Figure S9) except for the presence of the [CuH−1L]+
complex species that predominate around pH 5. Thus, the
[CuH−2L] species start to be formed at pH values above 4 and
become the major species above pH 6. On the other hand, the
[CuL] species are present at pH values around 4 and are
particularly relevant for ligand 6. According to this, free Cu2+
species are only predominant at the very acidic pH regions,
below pH 3.5 for 5 and below pH 3 for 6.
color from blue to purple for the two Cu2+ complexes and from
green to yellow for the Ni2+ complexes, while, as could be
expected, colorless complexes were formed in the case of Zn2+.
Moreover, their formation could be followed by FT-IR
experiments by a significant shift of the CO band to lower
frequencies (i.e., 1551 cm−1 for 9a against 1661 cm−1 for 5,
Figure S10), confirming the deprotonation of the amide
group.22
In order to gain a more detailed insight into the nature of the
metal complexes formed with ligands 5 and 6, UV−vis
spectroscopic studies were carried out, in the case of Cu2+, by
selecting preferentially those pH regions at which one of the
complex species is dominant. For this purpose, the pH of a 0.1
mM solution (50 mL) of the ligand and Cu(OAc)2 in 0.1 M
NaCl/CH3CN 7/3 v/v was adjusted to ca. 2 by the addition of
50 μL of concentrated HCl. This sample was titrated exactly
under the same conditions used for the potentiometric
titrations described above using a 0.1 M NaOH solution in
water. Aliquots of 2 mL were taken for UV−vis analysis at the
selected pH values, and the resulting spectra are presented in
Figure 5a,b. In the more acidic pH regions where the presence
of [CuL]2+ or the uncomplexed cation is relevant, an ill-defined
broad band with the maximum above 700 nm is observed. This
band has been traditionally assigned to the d−d transitions
associated with octahedral Cu2+ complexes, although different
data suggest that free Cu2+ can be pentacoordinated instead of
hexacoordinated.29a In this context, it is important to bear in
mind that currently there is a strong debate of the actual
coordination number (five-coordinated or six-coordinated) of
many Cu2+ complex species of different nature.29 This band is
more clearly visible for ligand 5 in MeOH (Figure 5c),
displaying at acidic pH values an intense band with its
maximum above 800 nm (i.e., 880 nm at pH 1.6). The
formation of deprotonated [CuH−xL] complexes is accom-
panied by an important bathochromic shift for this transition
that appears as an intense band slightly above 500 nm (at pH >
10, 505, and 510 nm for 5 and 6, respectively). This is in good
agreement with the predominance of square-planar or square-
pyramidal geometries.15,30
A similar study was carried out in the case of the Zn2+ cation
(Table 3). As has been observed for most nitrogenated ligands
and in particular for those related to 5 and 6, the Zn2+
complexes are significantly less stable than those for Cu2+
with formation constants several orders of magnitude lower. In
this case, no appreciable differences were obtained as a
consequence of the change in the central spacer. Similar values
were calculated in water for the formation constants of the
[ZnH−2L] species for 5 and 7, being this one the only complex
species detected. The corresponding distribution diagrams were
also very similar, with the neutral complex species being formed
at basic pH values and becoming the major species at about pH
8 (Figure S9).22a
In the mixed solvent, ligands 5 and 6 displayed a very similar
behavior, with the formation of [ZnL] and [ZnH−2L] complex
species. Interestingly, [ZnL] species are only detected in this
medium, revealing a higher stability of these complexes. The
formation constants observed for the [ZnH−2L] species are 2
orders of magnitude greater in this medium. This trend
separates from the one observed for copper complexes and
most likely can be related to the specific behavior of Zn2+ in
water. The corresponding distribution diagrams are shown in
Figure 4. For both ligands, the neutral complexes [ZnH−2L]
start to be formed at pH values above 6 and become the
dominant species in both systems at pH > 7.5, while the
[ZnL]2+ species predominate at neutrality and the Zn2+ ion
starts to be the dominant zinc species slightly below pH 6. The
slow kinetics usually associated with Ni2+ complexes hindered
their study by potentiometric techniques.
The complex species formed by 5 and 6 with Cu2+ and Zn2+
were also studied by mass spectrometry in methanol at the
acidic and basic regions. Again, the slow kinetics associated with
Ni2+ precluded an appropriate study of the corresponding
complexes. The ESI-MS technique allows the detection in a
solution of species at low concentration, and this makes it
attractive to analyze complexation processes.31 This confirmed
the formation of deprotonated complex species even at acidic
pH regions. Thus, for instance, the ESI-MS spectrum, in the
positive mode of analysis, of the Cu2+-5 system at pH 4 showed
a major peak corresponding to [5 + H]+ at 307 and a peak at
368 corresponding to the one expected for the [CuH−1L]+
species. Full isotopic analysis showed a perfect agreement
between simulated and experimental mass spectra (Figure S11).
It must be noted that the peak at 368 can also correspond to
the ion [CuH−2L + H]+ taking into consideration that the
[CuH−2L] species is neutral and for being observed in the ESI-
MS+ mode requires the interaction with an additional positively
charged species (H+, Na+, K+, or other species depending on
experimental conditions). This was confirmed by the
observation of a smaller peak, with the correct isotopic pattern,
at 406 corresponding to the [CuH−2L + K]+ species.
Spectroscopic and Mass Spectrometry Studies. The
[MH−2L] complexes of 5 and 6 with Cu2+, Zn2+, and Ni2+ were
synthesized in MeOH with the addition of 2 equiv of KOH
(Scheme 2). The process was accompanied by a change in
Scheme 2. Synthesis of Metal Complexes Derived from
Bis(amino amides) 5 and 6
The observation of the bisdeprotonated complex species
[MH−2L]+ is easier at basic pH values. Thus, for Zn2+
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Figure 5. UV−vis spectra in 0.1 M NaCl/CH3CN 7/3 v/v for the systems: (a) Cu2+-5, (b) Cu2+-6, and (c) for Cu2+-5 in MeOH (ca. 0.1 mM in the
ligand and in Cu(OAc)2) at different pH values.
Table 4. Selected Bond Distances and Angles for Metal Complexes 9a−c and 10a,c
complex
M−N distance (Å)
molecule A
molecule B
N−M−N angle
molecule A
molecule B
9a
Cu1−N1
Cu1−N2
Cu1−N3
Cu1−N4
Zn1−N1
Zn1−N2
Zn1−N3
Zn1−N4
Ni1−N1
Ni1−N2
Ni1−N3
Ni1−N4
Cu1−N1
Cu1−N2
Cu1−N3
Cu1−N4
Ni1−N1
Ni1−N3
1.985
2.013
1.912
1.918
2.124
2.123
2.062
2.039
1.915
1.906
1.833
1.827
2.004
2.023
1.918
1.922
1.909
1.829
2.004
1.979
1.905
1.907
N1−Cu1−N2
N2−Cu1−N4
N3−Cu1−N4
N3−Cu1−N1
N1−Zn1−N2
N2−Zn1−N4
N3−Zn1−N4
N3−Zn1−N1
N1−Ni1−N2
N1−Ni1−N3
N3−Ni1−N4
N4−Ni1−N2
N1−Cu1−N2
N1−Cu1−N3
N3−Cu1−N4
N4−Cu1−N2
N1−Ni1−N3
N3−Ni1−N3
N1−Ni1−N1
107.2
83.7
106.8
84.8
84.3
84.2
9a
9a
84.3
9a
84.8
9b
102.8
79.2
9b
9b
78.9
9b
79.7
9c
1.912
1.921
1.827
1.827
1.990
2.005
1.907
1.899
100.3
86.5
101.2
85.9
86.3
86.6
105.5
85.1
84.5
84.8
9c
9c
86.6
9c
86.5
10a
10a
10a
10a
10c
10c
10c
108.57
84.63
83.67
83.48
86.66
86.44
100.28
complexes formed with 5, the ESI-MS+ measured at pH 9.1
showed a peak at 345 corresponding to [5 + K]+ and a peak at
407 corresponding to the [ZnH−2L + K]+ species (Figure S11).
Peaks with the correct isotopic pattern were also observed at
439 and 505 corresponding to the formation of the [ZnH−2L +
K + CH3OH]+ and [ZnH−2L + K + 2NaOH + H2O]+ clusters.
Single-Crystal X-ray Diffraction Studies. The presence
of the rigid aromatic central spacer significantly enhanced the
possibility of obtaining crystals of good quality for diffraction
studies. In many instances, crystals were formed directly in the
samples obtained from potentiometric titrations at basic pH
values. X-ray quality single crystals for the complexes were
grown by layering an ethanolic solution of the pseudopeptidic
ligand over an aqueous solution of Cu(OAc)2, Zn(OAc)2, and
Ni(OAc)2, respectively. Thus, suitable crystals for X-ray
diffraction analysis were obtained, in the case of ligand 5, for
the three [MH−2L] complexes 9a−c. For ligand 6, appropriate
crystals were obtained for the ligand itself and for its Cu2+ and
Ni2+ complexes, 10a, and 10c. For the [MH−2L] complexes, the
main features of the corresponding X-ray structures are shown
in Table 4 (see also Tables S1, S2, and S4−S7).
The crystallographic structure for the free ligand 6 is shown
in Figure 6 (see also Tables S2 and S3). Four independent
molecules (A−D) participate in the asymmetric unit. The
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which the two amide groups show an antidisposition in two
planes displaying 33.8° and 37° angles, leading to the formation
of hydrogen bonds with adjacent molecules located in opposite
directions. Besides, the aromatic groups of the side chains
display edge-to-face arrangements with neighboring aromatic
rings from other side chains or from the central spacer. These
π−π interactions are characterized by the presence of H···Car
distances < 3 Å (up to 2.86 Å) representing %vdWH,C < 100.33
In the case of the [CuH−2L] complex formed by ligand 5
(9a), two [CuH−2L] units form the asymmetric unit in the
crystalline structure (Figure 7a). In one of those units, the
coordination environment around the copper presents a slightly
distorted square-pyramidal geometry in which the square base
is formed by the four nitrogen atoms of a bisdeprotonated
ligand. The oxygen atom from a carbonyl group of the second
molecule provides the fifth axial coordination, being the Cu−O
distance (2.663 Å) significantly longer that those corresponding
to Cu−N distances that range from 1.912 to 2.013 Å. The
copper atom is essentially located in the plane defined by the
four nitrogen atoms, although a small distortion is observed
with the Cu-plane distance being 0.047 Å. The O−Cu−N
angles defined are 82.3° and 82.7° for the amide nitrogen atoms
and 104.2° and 100.6° for the amino nitrogen atoms. The bite
angles for the five chelate rings range from 83.7° to 84.8°,
indicative of a tight chelation. In concordance, the Namine−Cu−
Namine bite angle is 107.2°. The coordination geometry around
the Cu2+ for the second molecule is square-planar, with the
copper atom located at 0.015 Å from the plane defined by the
four nitrogen atoms. In this case, the Cu−N distances range
from 1.905 to 2.004 Å, slightly shorter as could be expected
from the absence of the fifth donor atom. The bite angles for
the five chelate rings range from 84.2° to 84.8°, in this case,
with the Namine−Cu−Namine bite angle being 106.7°. In both
molecules, the Cu−Namide distances are shorter than the ones
corresponding Cu−Namine, being 1.911 and 1.995 Å on average,
respectively. The latter was previously observed for analogous
Cu−pseudopeptidic complexes and was attributed to the
anionic coordination from the deprotonated Namide donors
instead of the neutral donation from the Namine groups.22b
The unit cell for complex 9a contains four of such pairs of
[CuH−2L] units, and besides, two water molecules are present
for each [CuH−2L] unit. These water molecules play a key role
Figure 6. Schematic representation of the hydrogen bond network in
the packing of the free ligand 6 (a) and the molecular structure of the
two conformations present for ligand 6 (b).
presence of the aromatic central unit preorganizes the
molecules in U-shaped conformations. Molecules B and C
have the corresponding U-shapes aligned in the same direction,
while molecules A and D are oriented in the opposite direction.
Two main conformations are observed. For molecules A and D,
one of the amide groups is coplanar with the central aromatic
ring (8.8° C−C−N−H torsion angle) and the second one is
almost perpendicular (83.1° and 91.1° C−C−N−H torsion
angles for A and D, respectively). In molecules B and C, none
of the amide groups is coplanar with the aromatic ring, defining
torsion angles ranging from 31.9° to 56.5°. All the amide
groups display the expected almost perfect anticoplanar
arrangement with O−C−N−H torsion angles between 170.8°
and 177.9°. Amide N−H fragments are always oriented toward
the cavity defined by the molecular cleft, facilitating the
convergence of the nitrogen atoms (three for B and C and the
four for A and D) on this cleft.32 This also favors the
participation of the oxygen atoms of the carbonyl groups in the
formation of an extensive network of intermolecular hydrogen
bonding, in particular, in the case of molecules B and C for
Figure 7. Molecular structure for complexes 9a (a) and 9c (b) in their crystal structures.
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in the hydrogen-bonding network present in the crystal
structure (Figure S12). For the [CuH−2L] unit containing the
square-pyramidal copper ion, each of the oxygen atoms of the
deprotonated amide groups acts as hydrogen bond acceptor
with one molecule of water and one amino group of a different
molecule and only one of its amino groups acts as a hydrogen
donor with a third water molecule. For the square-planar
[CuH−2L] unit, the noncoordinated amide carbonyl is
hydrogen bonded to a water molecule while the amino groups
form hydrogen bonds with the oxygen atoms from the amide
groups of two different molecules and one of them also acts as
hydrogen donor with a water molecule.
The crystal structure of the Ni2+ complex with the
bisdeprotonated ligand 5 (9c) displays some common features
with the one analyzed for the Cu2+ complex 9a. The
asymmetric unit for complex 9c (Figure 7b) is also formed
by two [NiH−2L] units defining almost perpendicular main
planes (87.6°). In one of these units, the nickel presents an
almost perfect square-planar geometry. The four Ni−N
distances are 1.827 Å for both Ni−Namide and 1.912 and
1.921 Å for Ni−Namine. The three bite angles for the chelate
rings are very close to 86°, higher than in the case of Cu2+. The
Ni atom is located at 0.013 Å from the plane defined by the
nitrogen atoms. In the second [NiH−2L] unit, the nickel atom
displays a more distorted square-planar geometry becoming
intermediate with the one for a square-pyramidal coordination.
In this regard, the oxygen atom of one amide group of the other
unit is located at 2.970 Å from the nickel atom. Besides this
long distance, it must be noted that the oxygen atom is
significantly displaced from the vertical, defining OCuN angles
of 100.9° and 109.8° for the amide nitrogen atoms and 69.1°
and 78.4° for the amino nitrogen atoms. The unit cell for
complex 9c contains eight [NiH−2L] units, grouped in four
pairs, and eight water molecules. Moreover, an extensive
network of intermolecular hydrogen-bonding interactions can
be observed between the O atoms of the carbonyl groups and
the H atom of the amine groups and/or the water molecules.
The amino groups also participate as hydrogen bond donors
with water molecules (Figure S13).
In the case of the Zn complex (9b), only one [ZnH−2L]
species contributes to the asymmetric unit (Figure 8) along
with a molecule of isopropanol. In the corresponding molecular
structure, the Zn atom displays a distorted square-pyramidal
geometry in which the square base is formed by the terminal
amine and the deprotonated amide nitrogen atoms of the
ligand 6. The oxygen atom from the carbonyl group of a second
molecule occupies the apical coordination position of the
square-pyramidal geometry. The metal center lies above the
mean plane of the coordinated nitrogens by 0.603 Å. The Zn−
Namine distances average 2.123 Å and the Zn−Namide 2.051 Å,
being the Zn−O distance 1.996 Å. The distortion in the square-
pyramidal geometry is clearly reflected in the O−Zn−N angles
present. The two angles involving the Namide atoms are 116.1°
and 114.4°, while the two involving the Namine atoms are 99.5°
and 100.3°. The bite angles for the three chelate rings are very
similar and slightly below 80° (79.7°, 79.2°, and 78.9°),
providing a Namine−Cu−Namine bite angle of 102.8°. Four
independent [ZnH−2L] units and four i-PrOH molecules define
the unit cell. The association of contiguous [ZnH−2L] units
through O−Zn bonds provides the formation of unidimen-
sional polymeric chains. The contiguous units are not parallel,
but their main plains, as defined by the aromatic carbons and
the four nitrogen atoms, are tilted by ca. 41° and the aromatic
Figure 8. Molecular structure for complex 9b. The arrangement of two
consecutive molecular units is displayed to highlight the interaction of
the oxygen atom of one amide of the first [ZnH−2L] unit with the Zn
atom of the second one.
fragments are located at opposite sites. The i-PrOH molecules
play a key role in defining the intermolecular interactions
leading to the stabilization of the three-dimensional structure
observed in the crystal packing. Each i-PrOH molecule acts as
hydrogen bond acceptor with one hydrogen atom of the NH2
group closer to the carbonyl group bound to Zn (NH···O
distance 2.189 Å) of a [ZnH−2L] unit and is also within a short
distance of one hydrogen atom of the second NH2 group of the
same unit (2.390 Å). Besides, it acts as a hydrogen bond donor
with the oxygen atom of the amide carbonyl not bound to Zn
of a [ZnH−2L] unit belonging to a second chain. As i-PrOH
molecules associated with consecutive units are located at
opposite sides of the chain, this defines a 3D hydrogen bond
network (Figure S14).
The effect of the substitution of the valine fragment by the
one corresponding to phenylalanine can be analyzed comparing
the molecular structures of complexes 9a and 10a (Figures 7a
and 9a). Also, in the case of 10a, two [CuH−2L] units are
Figure 9. Molecular structure for complexes 10a (a) and 10c (b) in
their crystal structures.
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involved in the asymmetric unit (Figure 9a). The coordination
environments of the two copper ions are very similar to those
described in 9a, with the metal coordinated to the four nitrogen
atoms of ligand 6 in a formal square-planar geometry.
same molecule with the CarH···Centroid shorter distance being
3.434 Å.
Catalytic Studies. Different metal complexes of pseudo-
peptidic ligands have shown to be catalytically active for a
variety of organic transformations.14,15,21,34 In this regard, the
ring-opening of epoxides with an amine as the nucleophile is an
important, but challenging, route for the synthesis of β-amino
alcohols.35,36 Some of the existing methods have limitations,
including the failure of less basic amines to open epoxides
under ambient conditions, the requirement of high catalyst
loading, the need of using air- and moisture-sensitive catalysts,
nonenvironmentally friendly solvents, or long reaction times.37
Taking this into account and in order to obtain information on
the potential catalytic activity of the considered metal
complexes, preliminary studies were carried out on the use of
the corresponding Cu2+, Zn2+, and Ni2+ complexes with ligands
5 and 6 for the ring-opening of cyclohexene oxide with aniline
using water and EtOH as environmentally friendly solvents
(Scheme 3).38
Again, the Cu−Namide distances are slightly shorter than these
for Cu−Namine, being 2.006 and 1.912 Å on average,
respectively. Bite angles are very similar to those found in 9a.
Also, in this case, one of the carbonyl groups of one molecule is
oriented toward the metal center of the second one, suggesting
an actual five coordinated distorted square-pyramidal arrange-
ment. Nevertheless, the resulting Cu−O distance is significantly
larger now (2.835 vs. 2.663 Å) and the disposition is similar to
that found for the Cu2+ complex of the Phegly-derived ligand
containing an ethylenic central spacer.22b The square-planar
geometry is essentially coplanar with the aromatic central
spacer with the angles between the corresponding mean planes
being 1.4° and 7.5° in both units. The two deprotonated amide
moieties are more coplanar in 10a than in 9a, with angles
between their mean planes of 4.3° and 7.2° instead of the
values of 14.6° and 18.5° found in 9a. The presence of the
additional aromatic units in 10a is important to define the
resulting packing (Figure S15). The dispositions of the two
[CuH−2L] units of the asymmetric unit are different in 9a and
10a. In 10a, the two central aromatic spacers and the aromatic
unit of one side chain converge, displaying edge-to-face
dispositions in which the shorter H−C distances are 3.137
and 3.148 Å between the central spacers and 2.977 and 3.072 Å
between the aromatic side chain and the central spacer of the
second molecule (in this case, the shorter H−centroid distance
is 2.984 Å).
Scheme 3. Epoxide Ring-Opening Reaction Studied
The results obtained are summarized in Table 5. In general,
better yields were obtained using water as a solvent. It must be
Table 5. Yields Obtained in the Epoxide Ring-Opening
The change in the component amino acid is more relevant in
the crystal structure of the corresponding Ni2+ complexes. For
complex 10c, all the [NiH−2L] units present the same
molecular structure displaying a perfect C2 symmetry (Figure
9b). As a matter of fact, only half a unit is required to define the
asymmetric unit, with the unit cell involving five [NiH−2L]
structures (Figure S16). The coordination environment around
the nickel shows a perfect square-planar geometry with the Ni
atom in the plane defined by the four nitrogen atoms (Ni−
plane distance is 0.000 Å) and Ni−Namide and Ni−Namine
distances being 1.829 and 1.909 Å, respectively. Bite angles
are very similar to those found in 9c. The aromatic ring of the
spacer and the four nitrogen atoms, along with the metal
center, define essentially a single plane (deviation is 1.2°). In
the molecular structure, the two aromatic rings of the side
chains partly cover the space above and below the plane defined
by the four nitrogen atoms and the Ni and this seem to
preclude a close approaching of an additional [NiH−2L] unit as
to allow the additional coordination of the oxygen of one amide
carbonyl to the metal, as observed in 9c. In the packing, each
[NiH−2L] unit has two additional units located close to its NH2
fragments, displaying NH···O distances of 2.387 Å. The main
plain of both molecules is almost perpendicular to the one of
the first unit (85.9°), one being located above this plane and
the second one located below and maintaining the C2 symmetry
defined by the C2 axis of the first [NiH−2L] unit. Aromatic
interactions are important. Each of the aromatic rings of the
side chain of this first unit shows an edge-to-face arrangement
with the central aromatic spacer one of these contiguous units
with the CarH···Car shorter distance being 2.853 Å. This
aromatic side chain also shows a displaced face-to-face
arrangement with one of the aromatic side chains of the
a
Reaction between Cyclohexene Oxide and Aniline
b
entry
ligand
metal
solvent
yield
1
2
5
5
6
6
5
5
6
6
5
5
6
6
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Cu(OAc)2
Zn(OAc)2
Ni(OAc)2
Cu(OAc)2
Zn(OAc)2
Ni(OAc)2
EtOH
H2O
12.2
33.5
26.6
54.4
30.8
56.8
25.3
81.4
46.8
69.6
18.4
65.6
5.6
3
EtOH
H2O
4
5
EtOH
H2O
6
7
EtOH
H2O
8
9
EtOH
H2O
10
11
12
13
14
15
16
17
18
19
20
EtOH
H2O
H2O
H2O
34.9
64.9
3.9
H2O
EtOH
EtOH
EtOH
EtOH
H2O
15.7
4.1
15.9
26.2
a
Reaction conditions: 5 mol % of ligand and 5 mol % of M(OAc)2, 16
b
h, rt. Isolated yields.
noted that, in water, the background reaction in the absence of
any catalyst is relatively important (entry 20).35b The addition
of Zn(OAc)2 slightly accelerates this reaction (entry 14), but on
the contrary, the addition of Cu(OAc)2 seems to inhibit the
process (entry 13), most likely through the strong coordination
of copper to the amino groups. The addition of Ni(OAc)2
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accelerates the process to a significant extent. The formation of
the corresponding complexes with ligands 5 and 6 led to an
acceleration of the reaction for both Zn2+ and Cu2+ complexes,
while for Ni2+ complexes seem to have no effect. Again the slow
kinetics observed for the formation of nickel complexes can be
important in this regard. This is interesting for future
applications as reveals this to be a ligand accelerated process
for copper and zinc complexes. In any case, copper complexes
were less active than zinc complexes. For both metals,
complexes formed with ligand 6 derived from Phe were more
active than those from ligand 5 derived from Val (compare
entries 2 and 4, 6 and 8). The best results were obtained using
ligand 6 and Zn(OAc)2 (81.4% yield, entry 8). Unfortunately,
no enantiomeric excesses were detected in any case. Though, as
mentioned above, the number of reports regarding the opening
of epoxides by amines is quite limited, the present results are
comparable or even better, in terms of activity, than results
previously reported for the opening of cyclohexane oxide with
aniline. Thus, for instance, the use of n-Bu3P as catalyst has
been reported to afford a 78% of the amino alcohol after 12 h
using a 10% loading of phosphine, and related results were
obtained with the addition of tertiary amines.39 To analyze
those results, however, it is very important to understand the
crucial role played by the pH of the aqueous medium for this
reaction, basic conditions favoring the process: 45 h is required
at pH 7, in the absence of catalyst, to obtain a 90% yield at 30
°C, whereas just 25 h is required, for the same yield, at pH =
8.35b In this regard, it is worth mentioning that pH values in the
6−7 range were always obtained, in our case, for the
experiments in Table 5. The use of metal complexes has
been explored using Lewis acid−surfactant-combined catalysts,
but this has been preferentially applied to the opening of highly
hydrophobic epoxides particularly well suited for this
approach.40 In this case, for instance, using a combination of
Zn(OTf)2 (10%), dodecyl sulfate (10%), and a bipyridine
ligand (12%), a 97% yield was obtained after 22 h, being the
yield lower with copper, while nickel was essentially inactive, in
line with the differences observed in our case when changing
the metal. Significant decreases in catalytic activity were
observed upon reduction of the catalyst loading or the
concentration, best results being obtained with the use of
Sc3+.40a
(9b), Ni-5 (9c), and Ni-6 (10c) were obtained. In the case of
Cu2+ and Ni2+, the square-planar geometry dominates, with the
metal located essentially in the plane defined by the four
nitrogen atoms of the ligand. This square-planar geometry is in
agreement with the spectroscopic data obtained in solution for
the Cu2+ complexes. In most cases, however, the oxygen of an
amide carbonyl group of a second ligand is located at a short
distance and acts as a fifth donor in these complexes. In the
crystal obtained for 9b, the Zn atom displays a clear square-
pyramidal geometry coordinated to the four nitrogen atoms of
a ligand and to the carbonyl oxygen of a second ligand. As
observed in other C2-symmetric pseudopeptidic ligands, the
nature of the side chain of the component amino acid plays an
important role in the fine-tuning of the properties of the
corresponding complexes, affecting both the stability constants
and the structural arrangement presented. Thus, for instance,
the presence of the aromatic side chains in ligand 6 makes more
difficult the coordination of the carbonyl group of the second
ligand to the metal center in complexes 10a and 10c.
Finally, preliminary experiments reveal the capacity of some
of the former complexes to act as catalysts for the ring-opening
of the cyclohexene epoxide using aniline as the nucleophile in
water. Interestingly, the results show that this is a ligand
accelerated catalytic process and Zn2+ complexes act as more
efficient catalysts, in particular, 10b formed in the presence of
ligand 6, than the related Cu2+ complexes. Unfortunately, the
catalytic reaction took place without any observed enantiomeric
induction, although the studied Zn2+ complexes seem to
present a higher catalytic activity than other systems studied for
this reaction.
EXPERIMENTAL SECTION
■
All reagents and solvents were obtained from commercial sources and
used as received unless otherwise stated. Deionized water was used
from a “Milli-Q Integral Water Purification System” by Millipore.
Microanalyses were performed on an elemental analyzer equipped
with an oxygen module. Rotatory power was determined with a digital
polarimeter (Na: 589 nm). Melting points were measured using a
standard apparatus and are uncorrected.
1H NMR Experiments. 1H spectra were recorded on a Varian
INOVA 500 spectrometer (500 and 125 MHz for H and 13C NMR,
1
respectively). The solvent signal was used as a reference standard.
Electromotive Force Measurements and UV−vis Experi-
ments. The potentiometric titrations were carried out at 298 K using
0.1 M NaCl or 0.1 M NaCl/CH3CN 7/3 v/v as the supporting
electrolyte. The experimental procedure (buret, potentiometer, cell,
stirrer, microcomputer, etc.) has been fully described elsewhere.41 The
acquisition of the emf data was performed with the computer program
CrisonCapture. The reference electrode was a Ag/AgCl electrode in
saturated KCl solution. The glass electrode was calibrated as a
hydrogen-ion concentration probe by titration of previously stand-
ardized amounts of HCl with CO2-free NaOH solutions, and the
equivalence point was determined by the Gran’s method,42 which gives
the standard potential, E°′, and the ionic product of water 13.78,
whereas, in the case of the water/ACN mixture used, this value was
14.6.27 The computer program HYPERQUAD26 was used to calculate
the protonation and stability constants, and the HySS43 program was
used to obtain the distribution diagrams. The pH range investigated
was 2.0−12.0, and the concentration of the metal ions and of the
ligands 0.1 mM with M2+:L molar ratios as 1:1. 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
■
The substitution of an aliphatic central spacer by an aromatic
spacer derived from o-diaminobenzene in pseudopetidic
structures I affords tetradentate ligands 5 and 6, providing
some interesting properties in their interaction with Cu2+, Zn2+,
and Ni2+. Potentiometric studies reveal that the stability of the
complexes formed with Cu2+ is several orders of magnitude
higher when compared to those formed by the related ligand
containing an ethylenic central spacer. This is particularly
relevant for the formation of the [CuH−2L] species, leading, as
shown in the corresponding distribution diagrams, to the
formation of such species even in relatively acidic regions. The
preorganization of the ligands in a U-shaped conformation
favored by the o-substitution of the aromatic spacer and the
increase in acidity of the amido groups bound to the aromatic
fragments can be responsible for this behavior. The differences
are, however, less relevant for Zn2+ complexes. The rigidity of
the central aromatic spacer also seems to facilitate obtaining
crystals suitable for X-ray diffraction. Crystal structures for
ligand 6 and [MH−2L] complexes Cu-5 (9a), Cu-6 (10a), Zn-5
UV−vis absorption spectra were recorded using a Hewlett-Packard
8453 device, using solutions of 0.1 mM at different pH values
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containing 1:1 M2+:L molar ratios. Additional experiments were
carried out in 0.1 M NaCl solutions. Only minimal differences were
observed in this case.
(%) for C16H26N4O2·0.5 H2O: C, 60.9; H, 8.6 N, 17.8. Found: C, 61.5;
H, 8.1; N, 17.4.
Compound 4. Prepared using the same protocol described for 3 but
starting from Cbz-Phe-OH. Yield 39% (4.39 g, 6.55 mmol); mp 201−
203 °C; [α]2D5 + 4.84 (c = 0.01, DMSO); IR (ATR) 3302, 3256, 3062,
2918, 1652, 1527, 1255 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 9.55
(s, 2H), 7.65 (d, J = 7.4 Hz, 1H), 7.49 (s, 1H), 7.32−7.02 (m, 10H),
4.93 (dd, J = 51.5, 12.6 Hz, 4H), 4.44 (s, 2H), 3.01−2.84 (m, 2H); 13C
NMR (75 MHz, DMSO-d6) δ 171.1, 138.3, 137.3, 130.8, 129.7, 128.7,
128.5, 128.1, 127.9, 126.8, 125.8, 125.3, 65.9, 57.3, 37.6; Anal. Calcd
(%) for C40H38N4O6·0.5 H2O: C, 70.7; H, 5.8; N, 8.2. Found: C, 70.4;
H, 5.6; N, 7.9.
Compound 6. Prepared using the same protocol described for 5 but
starting from 4. Yield 53% (0.33 g, 0.81 mmol); mp 110−113 °C;
[α]2D5 + 111.13 (c = 0.01, CHCl3); IR (ATR) 3373, 3298, 3026, 2918,
1671, 1509, 1452 cm−1; 1H NMR (500 MHz, CDCl3) δ 9.47 (s, 1H),
7.61 (dd, J = 5.9, 3.6 Hz, 2H), 7.32 (dd, J = 20.0, 12.5 Hz, 4H), 7.27−
7.20 (m, 6H), 3.76 (dd, J = 9.2, 4.1 Hz, 2H), 3.34 (dd, J = 13.7, 4.0 Hz,
2H), 2.80 (dd, J = 13.7, 9.2 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ
172.8, 137.4, 129.8, 129.3, 128.8, 126.8, 126.0, 124.5, 56.9, 40.9;
HRMS (ESI-TOF)+ Calcd for C24H26N4O2 (M + H+) 403.2134.
Found 403.2139; Anal. Calcd (%) for C24H26N4O2·0.2 H2O: C, 71.0;
H, 6.6; N, 13.8. Found: C, 70.9; H, 6.3; N, 13.5.
Mass Spectrometry. Mass spectra were recorded on a Q-TOF
Premier mass spectrometer with an orthogonal Z-spray electrospray
interface (Micromass, Manchester, U.K.) either by electrospray
positive mode (ES+) or by electrospray negative mode (ES−). The
desolvation gas, as well as nebulizing gas, was nitrogen at a flow of 700
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
mode, 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.44
IR Spectroscopy. FT-IR spectra were acquired on a JASCO 6200
equipment with a MIRacle single reflection ATR diamond/ZnSe
accessory. The raw IR spectral data were processed with the JASCO
spectral manager software.
Crystallography. Single crystals of ligand 6 and complexes 9a−c
and 10a, 10c were obtained. A suitable crystal was selected and
measured on a single crystal X-ray diffractometer. Using Olex2,45 all
the structures were solved with the ShelXS 201446 structure solution
program using Direct Methods and refined with the ShelXL 201446
refinement package using Least Squares minimization. The programs
MERCURY47 and PyMOL48 were used to prepare artwork
representations. Crystallographic data and refinement parameters are
summarized in Table 4 and Tables S1 and S2. Hydrogen bonds for the
compounds are grouped in Tables S3−S7. Crystallographic details are
available in the Supporting Information in CIF format: CCDC
numbers 1474242 (9b), 1474243 (10a), 1474244 (6), 1474245 (10c),
1474246 (9c), 1474247 (9a).
Synthesis of Compounds. Compound 3. Cbz-Val-OH (10.0 g,
39.0 mmol) and triethyl amine (5.48 mL, 39.0 mmol) were dissolved,
under a nitrogen atmosphere, in dry THF (200 mL). The reaction
mixture was cooled with an ice bath and NaCl to −10 °C. Previously
cooled ethyl chloroformate (3.84 mL, 39.0 mmol) was then added
dropwise, and the reaction mixture was stirred for 30 min at −10 °C.
Afterward, 1,2-phenylenediamine (2.13 g, 19.5 mmol) dissolved in 25
mL of dry THF was added dropwise, avoiding any increase of the
temperature. After stirring for an additional 2 h at this temperature, it
was left to warm up to room temperature, the stirring being continued
for 24 h. The white precipitate formed was filtered, washed with water,
and vacuum-dried. Yield 57% (6.53 g, 11.4 mmol); mp 206−208 °C;
[α]2D5 + 3.08 (c = 0.01, DMSO); IR (ATR) 3289, 2961, 1690, 1652,
1594, 1533, 1497, 1454 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 9.44
(s, 2H), 7.52 (s, 2H), 7.46 (d, J = 7.5 Hz, 2H), 7.38−7.27 (m, 10H),
7.18 (dd, J = 5.9, 3.5 Hz, 2H), 5.11−5.01 (m, 4H), 4.01 (t, J = 7.2 Hz,
2H), 2.09 (d, J = 6.4 Hz, 2H), 0.91 (t, J = 6.0 Hz, 12H); 13C NMR (75
MHz, DMSO-d6) δ 170.9, 156.7, 137.2, 130.5, 128.8, 127.9, 125.2,
65.9, 61.5, 30.5, 19.4, 18.6; Anal. Calcd (%) for C32H38N4O6: C, 66.9;
H, 6.7; N, 9.8. Found: C, 66.3; H, 6.5; N, 9.8.
Compound 5. To a solution of compound 3 (1.20 g, 2.09 mmol) in
dry MeOH in a two-neck round-bottom flask was added 10 mol % of
the catalyst (5 wt % Pd on activated carbon). The system was purged
to remove the air and connected to a H2 atmosphere (H2 balloon) and
stirred at room temperature for 8 h. The gray suspension turned black,
and the precipitate was filtered off through a Celite bed and washed
with MeOH. Evaporation of the solvent under vacuum yielded
compound 5 as a white solid. Yield 66% (0.420 g, 1.37 mmol); mp
70−72 °C; [α]2D5 − 15.34 (c = 0.01, CHCl3); IR (ATR) 3298, 2959,
2930, 2872, 1661, 1599, 1506, 1465 cm−1; 1H NMR (500 MHz,
CDCl3) δ 9.55 (s, 2H), 7.61 (dd, J = 5.9, 3.6 Hz, 2H), 7.19 (dd, J =
6.0, 3.5 Hz, 2H), 3.39 (s, 2H), 2.44−2.33 (m, 2H), 1.07 (d, J = 7.0 Hz,
6H), 0.93 (d, J = 6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 173.5,
130.0, 126.0, 124.5, 61.0, 31.4, 19.7, 16.3; HRMS (ESI-TOF)+ Calcd
for C16H26N4O2 (M + H+) 307.2134. Found 307.2131; Anal. Calcd
General Procedure for the Synthesis of Cu2+ Complexes.
Complex 9a. A solution of Cu(OAc)2 (1 equiv) in MeOH (ca. 10−2
M) was added to a solution of compound 5 (1 equiv) in MeOH (ca.
10−2 M). After stirring the mixture for 30 min at room temperature,
KOH (ca. 2 equiv) 1 M in methanol was added, and the solution was
maintained at room temperature overnight. The precipitate formed
was isolated by filtration and washed with dichloromethane, to yield a
purple powder. Yield 73% (0.10 g, 0.28 mmol); (IR) ATR 3600−3000,
2963, 2960, 1591, 1537, 1469, 1395 cm−1; Anal. Calcd (%) for
C16H24N4O2Cu·H2O: C, 49.8; H, 6.8; N, 14.5. Found: C, 49.3; H, 6.8;
N, 14.4.
Complex 10a. Yield 84% (0.076 g, 0.16 mmol); (IR) ATR 3600−
3000, 2963, 1594, 1541, 1471 cm−1; Anal. Calcd (%) for C24H24-
N4O2Cu: C, 62.1; H, 5.2; N, 12.1. Found: C, 62.1, H, 5.3, N, 12.0.
General Procedure for the Synthesis of Zn2+ Complexes.
Complex 9b. A solution of Zn(OAc)2 (1 equiv) in MeOH (ca. 10−2
M) was added to a solution of compound 5 (1 equiv) in MeOH (ca.
10−2 M). After stirring the mixture for 30 min at room temperature,
KOH (ca. 2 equiv) 1 M in methanol was added, and the solution was
maintained at room temperature overnight. The precipitate formed
was isolated by filtration and washed with dichloromethane to yield a
white solid. Yield 54% (0.434 g, 1.17 mmol); (IR) ATR 3600−3000,
1591, 1523, 1473 cm−1; Anal. Calcd (%) for C16H24N4O2Zn·3 H2O:
C, 45.3; H, 7.1; N, 13.2. Found C, 45.6; H, 6.8; N, 13.1.
Complex 10b. Yield 41% (0.14 g, 0.31 mmol); (IR) ATR 3352−
3308, 3248, 3144, 2963, 2960, 1591, 1537, 1469, 1395 cm−1; Anal.
Calcd (%) for C24H24N4O2Zn·0.1 H2O: C, 61.6; H, 5.2; N, 12.0.
Found C, 61.3, H, 5.3; N, 11.8.
General Procedure for the Synthesis of Ni2+ Complexes.
Complex 9c. To a solution of Ni(OAc)2 (1 equiv) in MeOH (ca. 10−2
M) was added to a solution of compound 5 (1 equiv) in MeOH (ca.
10−2 M). After stirring the mixture for 30 min at room temperature,
KOH (ca. 2 equiv) 1 M in methanol was added, and the solution was
maintained at room temperature overnight. The precipitate formed
was isolated by filtration and washed with dichloromethane to yield a
yellow solid. Yield 67% (0.091 g, 0.25 mmol); (IR) ATR 3396−3274,
2961, 1594, 1551, 1494 cm−1; Anal. Calcd (%) for C16H24N4O2Ni·
C2H5OH: C, 52.8; H, 7.4; N, 13.7. Found: C, 52.8; H, 7.3; N, 13.7.
Complex 10c. Yield 78% (0.067 g, 0.14 mmol); (IR) ATR 3281−
3026, 2940, 2918, 1597, 1551, 1476, 1452, 1275 cm−1; Anal. Calcd
(%) for C24H24N4O2Ni·H2O: C, 60.4; H, 5.5; N, 11.7. Found: C, 60.6,
H, 5.3, N, 11.7.
Typical Procedure for Ring-Opening of Epoxide Reaction. In
an oven-dried 5 mL vial, the bis(amino amide) (0.05 mmol) and the
metal acetate (0.05 mmol) were dissolved in 2 mL of solvent, and the
vial was closed. After 30 min stirring, cyclohexene oxide (103 μL, 1.0
mmol) was added. After 1 h stirring at room temperature, aniline (92
K
DOI: 10.1021/acs.inorgchem.6b01066
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
μL, 1.0 mmol) was added, and the mixture stirred for 16 h. The
solvent was evaporated to dryness, and the residue was dissolved in
water (5 mL) and extracted with DCM (3 × 5 mL). The organic
phases were collected and dried over anhydrous MgSO4 and
evaporated to give pure 2-phenyl amino cyclohexanol. 1H NMR
(500 MHz, CDCl3) δ 7.22−7.11 (m, 2H), 6.80−6.63 (m, 3H), 3.38−
3.32 (m, 1H), 3.15 (ddd, J = 11.2, 9.2, 4.0 Hz, 1H), 2.20−2.03 (m,
2H), 1.83−1.63 (m, 2H), 1.47−1.21 (m, 3H), 1.06 (ddd, J = 24.1,
12.8, 3.7 Hz, 1H).
(7) (a) Miyake, H.; Kojima, Y. Coord. Chem. Rev. 1996, 148, 301−
314. (b) Wende, C.; Ludtke, C.; Kulak, N. Eur. J. Inorg. Chem. 2014,
̈
2014, 2597−2612. (c) Quintanova, C.; Keri, R. S.; Chaves, S.; Santos,
M. A. J. Inorg. Biochem. 2015, 151, 58−66. (d) Skalamera, D.; Sanders,
E.; Vianello, R.; Marsavelski, A.; Pevec, A.; Turel, I.; Kirin, S. I. Dalton
Trans. 2016, 45, 2845−2858.
(8) (a) Karlin, K. Science 1993, 261, 701−708. (b) Roat-Malone, R.
M. Bioinorganic Chemistry: A Short Course, 2nd ed.; John Wiley &
Sons, Inc.: Hoboken, NJ, 2007. (c) Gray, H. B.; Stiefel, E. I.; Valentine,
J. S.; Bertini, I. Biological Inorganic Chemistry: Structure and Reactivity,
1st ed.; University Science Books: Sausalito, CA, 2007. (d) Gramage-
Doria, R.; Armspach, D.; Matt, D. Coord. Chem. Rev. 2013, 257, 776−
816. (e) Bistri, O.; Reinaud, O. Org. Biomol. Chem. 2015, 13, 2849−
2865.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.6b01066.
(9) (a) Hechavarría Fonseca, M.; Konig, B. Adv. Synth. Catal. 2003,
̈
345, 1173−1185. (b) Green, B. J.; Tesfai, T. M.; Xie, Y.; Margerum, D.
W. Inorg. Chem. 2004, 43, 1463−1471. (c) Tesfai, T. M.; Green, B. J.;
Margerum, D. W. Inorg. Chem. 2004, 43, 6726−6733. (d) Prell, J. S.;
Flick, T. G.; Oomens, J.; Berden, G.; Williams, E. R. J. Phys. Chem. A
2010, 114, 854−860. (e) Dokorou, V. N.; Milios, C. J.; Tsipis, A. C.;
Haukka, M.; Weidler, P. G.; Powell, A. K.; Kostakis, G. E. Dalton
Trans. 2012, 41, 12501−12513. (f) Dennis, C. R.; Swarts, J. C.;
Margerum, D. W. React. Kinet., Mech. Catal. 2012, 107, 27−38.
(g) Dong, J.; Wang, Y.; Xiang, Q.; Lv, X.; Weng, W.; Zeng, Q. Adv.
Synth. Catal. 2013, 355, 692−696.
1
Characterization of the compounds 5 and 6, H NMR
titration of compound 5 at different pH values,
potentiometric distribution diagrams, FT-IR spectrosco-
py, ESI-MS spectra, X-ray crystallographic data (PDF)
Crystallographic data for 6, 9a, 9b, 9c, 10a, and 10c
(CIF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: luiss@uji.es (S.V.L.).
*E-mail: altava@uji.es (B.A.).
■
(10) (a) Locardi, E.; Stockle, M.; Gruner, S.; Kessler, H. J. Am. Chem.
̈
Soc. 2001, 123, 8189−8196. (b) Gibson, S. E.; Lecci, C. Angew. Chem.,
Int. Ed. 2006, 45, 1364−1377. (c) White, C. J.; Yudin, A. K. Nat. Chem.
2011, 3, 509−524. (d) Lewandowski, B.; De Bo, G.; Ward, J. W.;
Papmeyer, M.; Kuschel, S.; Aldegunde, M. J.; Gramlich, P. M. E.;
Heckmann, D.; Goldup, S. M.; D’Souza, D. M.; Fernandes, A. E.;
Leigh, D. A. Science 2013, 339, 189−193.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(11) (a) Fernandez-Lopez, S.; Kim, H.-S.; Choi, E. C.; Delgado, M.;
Granja, J. R.; Khasanov, A.; Kraehenbuehl, K.; Long, G.; Weinberger,
D. A.; Wilcoxen, K. M.; Ghadiri, M. R. Nature 2001, 412, 452−455.
(b) Kubik, S. Chem. Soc. Rev. 2009, 38, 585−605. (c) Klemm, K.;
■
This research work was supported by the Spanish MINECO
(CTQ2015-68429-R), Generalitat Valenciana (PROMETEO/
2012/020), and PPI-UJI (P1-1B-2013-38). L.G. thanks
Generalitat Valenciana for a Santiago Grisolia fellowship
(GRISOLIA 2012/015). The support of the SCIC for the
different instrumental techniques at Universitat Jaume I is
acknowledged.
́ ́ ̌ ́
Radic Stojkovic, M.; Horvat, G.; Tomisic, V.; Piantanida, I.; Schmuck,
C. Chem.Eur. J. 2012, 18, 1352−1363.
(12) (a) Hu, X.; Nguyen, K. T.; Verlinde, C. L. M. J.; Hol, W. G. J.;
Pei, D. J. Med. Chem. 2003, 46, 3771−3774. (b) Loughlin, W. A.;
Tyndall, J. D. A.; Glenn, M. P.; Fairlie, D. P. Chem. Rev. 2004, 104,
6085−6118. (c) Silva, G. A.; Czeisler, C.; Niece, K. L.; Beniash, E.;
Harrington, D. A.; Kessler, J. A.; Stupp, S. I. Science 2004, 303, 1352−
1355.
REFERENCES
■
(1) (a) Multhaup, G.; Schlicksupp, A.; Hesse, L.; Beher, D.; Ruppert,
T.; Masters, C. L.; Beyreuther, K. Science 1996, 271, 1406−1409.
(b) Sen, C. K.; Khanna, S.; Venojarvi, M.; Trikha, P.; Ellison, E. C.;
Hunt, T. K.; Roy, S. Am. J. Physiol. Heart Circ. Physiol. 2002, 282,
H1821−H1827. (c) Grubman, A.; White, A. R. Expert Rev. Mol. Med.
2014, 16, e11. (d) Scheiber, I. F.; Mercer, J. F. B.; Dringen, R. Prog.
Neurobiol. 2014, 116, 33−57. (e) Bellingham, S. A.; Guo, B.; Hill, A. F.
Biol. Cell 2015, 107, 389−418.
(13) (a) Choi, K.; Hamilton, A. D. Coord. Chem. Rev. 2003, 240,
101−110. (b) Wu, Y.-D.; Gellman, S. Acc. Chem. Res. 2008, 41, 1231−
1232. (c) Nowick, J. S. Acc. Chem. Res. 2008, 41, 1319−1330.
(d) Suzuki, M.; Hanabusa, K. Chem. Soc. Rev. 2009, 38, 967−975.
(e) Brea, R. J.; Reiriz, C.; Granja, J. R. Chem. Soc. Rev. 2010, 39, 1448−
1456. (f) Ke, D.; Zhan, C.; Li, A. D. Q.; Yao, J. Angew. Chem., Int. Ed.
2011, 50, 3715−3719. (g) Das, D.; Maiti, S.; Brahmachari, S.; Das, P.
K. Soft Matter 2011, 7, 7291−7303.
(2) (a) Fricker, S. P. Dalton Trans. 2007, 4903−4917. (b) Mjos, K.
D.; Orvig, C. Chem. Rev. 2014, 114, 4540−4563. (c) Medici, S.; Peana,
M.; Nurchi, V. M.; Lachowicz, J. I.; Crisponi, G.; Zoroddu, M. A.
Coord. Chem. Rev. 2015, 284, 329−350.
(3) (a) Crichton, R. R.; Dexter, D. T.; Ward, R. J. Coord. Chem. Rev.
2008, 252, 1189−1199. (b) Ward, R. J.; Dexter, D. T.; Crichton, R. R.
Curr. Med. Chem. 2012, 19, 2760−2772.
(14) (a) Merschky, M.; Schmuck, C. Org. Biomol. Chem. 2009, 7,
́
4895−4903. (b) Weselinski, Ł.; Słyk, E.; Jurczak, J. Tetrahedron Lett.
2011, 52, 381−384. (c) Paradowska, J.; Pasternak, M.; Gut, B.; Gryzło,
B.; Mlynarski, J. J. Org. Chem. 2012, 77, 173−187.
(15) (a) Dangel, B.; Clarke, M.; Haley, J.; Sames, D.; Polt, R. J. Am.
Chem. Soc. 1997, 119, 10865−10866. (b) Dangel, B. D.; Polt, R. Org.
Lett. 2000, 2, 3003−3006. (c) 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.
(16) (a) Luis, S. V.; Alfonso, I. Acc. Chem. Res. 2014, 47, 112−124.
(17) (a) Galindo, F.; Becerril, J.; Isabel Burguete, M.; Luis, S. V.;
Vigara, L. Tetrahedron Lett. 2004, 45, 1659−1662. (b) Alfonso, I.;
Burguete, M. I.; Galindo, F.; Luis, S. V.; Vigara, L. J. Org. Chem. 2009,
(4) (a) Cini, R.; Tamasi, G.; Defazio, S.; Hursthouse, M. B. J. Inorg.
Biochem. 2007, 101, 1140−1152. (b) Marzano, C.; Pellei, M.; Tisato,
F.; Santini, C. Anti-Cancer Agents Med. Chem. 2009, 9, 185−211.
(5) (a) Sousa, I.; Claro, V.; Pereira, J. L.; Amaral, A. L.; Cunha-Silva,
L.; de Castro, B.; Feio, M. J.; Pereira, E.; Gameiro, P. J. Inorg. Biochem.
2012, 110, 64−71. (b) Dorotikova, S.; Koziskova, J.; Malcek, M.;
Jomova, K.; Herich, P.; Plevova, K.; Briestenska, K.; Chalupkova, A.;
Mistrikova, J.; Milata, V.; Dvoranova, D.; Bucinsky, L. J. Inorg. Biochem.
2015, 150, 160−173.
́
74, 6130−6142. (c) Altava, B.; Burguete, M. I.; Carbo, N.; Escorihuela,
J.; Luis, S. V. Tetrahedron: Asymmetry 2010, 21, 982−989. (d) Martí-
Centelles, V.; Izquierdo, M. A.; Burguete, M. I.; Galindo, F.; Luis, S. V.
Chem.Eur. J. 2014, 20, 7465−7478. (e) Faggi, E.; Moure, A.; Bolte,
(6) Sonmez, M.; Levent, A.; S
30, 655−660.
̧
ekerci, M. Russ. J. Coord. Chem. 2004,
̈
L
DOI: 10.1021/acs.inorgchem.6b01066
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
M.; Vicent, C.; Luis, S. V.; Alfonso, I. J. Org. Chem. 2014, 79, 4590−
4601.
(18) (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. (c) Faggi, E.; Luis, S.
V.; Alfonso, I. RSC Adv. 2013, 3, 11556−11565.
(19) (a) Becerril, J.; Burguete, M. I.; Escuder, B.; Galindo, F.; Gavara,
R.; Miravet, J. F.; Luis, S. V.; Peris, G. Chem.Eur. J. 2004, 10, 3879−
3890. (b) Becerril, J.; Escuder, B.; Miravet, J. F.; Gavara, R.; Luis, S. V.
Eur. J. Org. Chem. 2005, 2005, 481−485. (c) Wadhavane, P. D.; Galian,
R. E.; Izquierdo, M. A.; Aguilera-Sigalat, J.; Galindo, F.; Schmidt, L.;
Burguete, M. I.; Perez-Prieto, J.; Luis, S. V. J. Am. Chem. Soc. 2012,
134, 20554−20563. (d) Rubio, J.; Martí-Centelles, V.; Burguete, M. I.;
Luis, S. V. Tetrahedron 2013, 69, 2302−2308.
(20) (a) 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. (b) Wadhavane, P. D.; Izquierdo, M. A.; Lutters, D.; Burguete,
M. I.; Marin, M. J.; Russell, D. A.; Galindo, F.; Luis, S. V. Org. Biomol.
Chem. 2014, 12, 823−831.
Escorihuela, J.; Galindo, F.; García-Verdugo, E.; Luis, S. V.; Vicent, M.
J. Tetrahedron Lett. 2003, 44, 6891−6894. (c) Xiong, Y.; Huang, X.;
Gou, S.; Huang, J.; Wen, Y.; Feng, X. Adv. Synth. Catal. 2006, 348,
538−544. (d) Burguete, M. I.; Collado, M.; Escorihuela, J.; Luis, S. V.
Angew. Chem., Int. Ed. 2007, 46, 9002−9005. (e) Xu, Z.; Daka, P.;
Wang, H. Chem. Commun. 2009, 6825−6827. (f) Albada, H. B.; Rosati,
̀
F.; Coquiere, D.; Roelfes, G.; Liskamp, R. M. J. Eur. J. Org. Chem.
2011, 2011, 1714−1720.
(35) (a) Barbaro, P.; Bianchini, C.; Sernau, V. Tetrahedron:
Asymmetry 1996, 7, 843−850. (b) Azizi, N.; Saidi, M. R. Org. Lett.
2005, 7, 3649−3651. (c) Bonollo, S.; Fringuelli, F.; Pizzo, F.; Vaccaro,
L. Green Chem. 2006, 8, 960−964.
(36) (a) Sekar, G.; Singh, V. K. J. Org. Chem. 1999, 64, 287−289.
(b) Yadav, J. S.; Reddy, A. R.; Narsaiah, A. V.; Reddy, B. V. S. J. Mol.
Catal. A: Chem. 2007, 261, 207−212. (c) Shivani; Pujala, B.;
Chakraborti, A. K. J. Org. Chem. 2007, 72, 3713−3722. (d) Bhanushali,
M. J.; Nandurkar, N. S.; Bhor, M. D.; Bhanage, B. M. Tetrahedron Lett.
2008, 49, 3672−3676. (e) Li, Y.; Tan, Y.; Herdtweck, E.; Cokoja, M.;
Kuhn, F. E. Appl. Catal., A 2010, 384, 171−176. (f) Pujala, B.; Rana,
̈
S.; Chakraborti, A. K. J. Org. Chem. 2011, 76, 8768−8780. (g) Narsaiah,
A. V.; Wadavrao, S. B.; Reddy, A. R.; Yadav, J. S. Synthesis 2011, 2011,
485−489. (h) Lu, H.-F.; Sun, L.-L.; Le, W.-J.; Yang, F.-F.; Zhou, J.-T.;
Gao, Y.-H. Tetrahedron Lett. 2012, 53, 4267−4272. (i) Pathare, S. P.;
Akamanchi, K. G. Tetrahedron Lett. 2013, 54, 6455−6459.
(21) Adrian
́
, F.; Burguete, M. I.; Fraile, J. M.; García, J. I.; García, J.;
chez, M.
García-Espana, E.; Luis, S. V.; Mayoral, J. A.; Royo, A. J.; San
́
̃
C. Eur. J. Inorg. Chem. 1999, 1999, 2347−2354.
(22) (a) Blasco, S.; Burguete, M. I.; Clares, M. P.; García-Espana, E.;
̃
Escorihuela, J.; Luis, S. V. Inorg. Chem. 2010, 49, 7841−7852.
(b) Martí, I.; Ferrer, A.; Escorihuela, J.; Burguete, M. I.; Luis, S. V.
Dalton Trans. 2012, 41, 6764−6776. (c) Wadhavane, P. D.; Gorla, L.;
Ferrer, A.; Altava, B.; Burguete, M. I.; Izquierdo, M. A.; Luis, S. V. RSC
Adv. 2015, 5, 72579−72589.
(37) (a) Schneider, C.; Sreekanth, A. R.; Mai, E. Angew. Chem. 2004,
116, 5809−5812. (b) Tschop, A.; Marx, A.; Sreekanth, A. R.;
̈
Schneider, C. Eur. J. Org. Chem. 2007, 2007, 2318−2327.
(38) Bonollo, S.; Lanari, D.; Vaccaro, L. Eur. J. Org. Chem. 2011,
2011, 2587−2598.
(23) Marti-Centelles, V.; Kumar, D. K.; White, A. J. P.; Luis, S. V.;
Vilar, R. CrystEngComm 2011, 13, 6997−7008.
(39) (a) Fan, R.-H.; Hou, X.-L. J. Org. Chem. 2003, 68, 726−730.
(b) Wu, J.; Xia, H.-G. Green Chem. 2005, 7, 708−710.
(40) (a) Azoulay, S.; Manabe, K.; Kobayashi, S. Org. Lett. 2005, 7,
4593−4595. (b) Bonollo, S.; Fringuelli, F.; Pizzo, F.; Vaccaro, L.
Synlett 2008, 2008, 1574−1578. (c) Kokubo, M.; Naito, T.; Kobayashi,
S. Tetrahedron 2010, 66, 1111−1118.
(24) Martell, A. E.; Motekaitis, R. J. Coord. Chem. Rev. 1990, 100,
323−361.
(25) García-Espana, E.; Díaz, P.; Llinares, J. M.; Bianchi, A. Coord.
̃
Chem. Rev. 2006, 250, 2952−2986.
(26) Gans, P.; Sabatini, A.; Vacca, A. Talanta 1996, 43, 1739−1753.
(41) García- Espana, E.; Ballester, M.-J.; Lloret, F.; Moratal, J. M.;
̃
́
(27) Herrador, M. A.; Gonzal
́
ez, A. G. Talanta 2002, 56, 769−775.
Faus, J.; Bianchi, A. J. Chem. Soc., Dalton Trans. 1988, 101−104.
(42) (a) Gran, G. Analyst 1952, 77, 661−671. (b) Rossotti, F. J. C.;
Rossotti, H. J. J. Chem. Educ. 1965, 42, 375−378.
(28) (a) Bianchi, A.; Escuder, B.; García-Espana, E.; Luis, S. V.;
Marcelino, V.; Miravet, J. F.; Ramirez, J. A. J. Chem. Soc., Perkin Trans.
̃
2 1994, 1253−1259. (b) Aguilar, J. A.; García-Espana, E.; Guerrero, J.;
̃
(43) Alderighi, L.; Gans, P.; Ienco, A.; Peters, D.; Sabatini, A.; Vacca,
A. Coord. Chem. Rev. 1999, 184, 311−318.
(44) (a) MassLynx Software, version 4.0; Waters/Micromass UK
Limited: Milford, MA, 2002. (b) Moco, S.; Bino, R. J.; Vorst, O.;
Verhoeven, H. A.; de Groot, J.; van Beek, T. A.; Vervoort, J.; de Vos,
C. H. R. Plant Physiol. 2006, 141, 1205−1218.
(45) Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.;
Puschmann, H. J. J. Appl. Crystallogr. 2009, 42, 339−341.
(46) Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Crystallogr.
2008, 64, 112−122.
(47) Macrae, C. F.; Bruno, I. J.; Chisholm, J. A.; Edgington, P. R.;
McCabe, P.; Pidcock, E.; Rodriguez-Monge, L.; Taylor, R.; van de
Streek, J.; Wood, P. A. J. Appl. Crystallogr. 2008, 41, 466−470.
(48) Delano, W. L. The PyMOL Molecular Graphics System;
Luis, S. V.; Llinares, J.; Ramírez, J.; Soriano, C. Inorg. Chim. Acta 1996,
246, 287−294. (c) Aran
́
, V. J.; Kumar, M.; Molina, J.; Lamarque, L.;
Navarro, P.; García-Espana, E.; Ramírez, J. A.; Luis, S. V.; Escuder, B. J.
̃
Org. Chem. 1999, 64, 6135−6146.
(29) (a) Pasquarello, A.; Petri, I.; Salmon, P. S.; Parisel, O.; Car, R.;
́
́
Toth, E.; Powell, D. H.; Fischer, H. E.; Helm, L.; Merbach, A. E.
Science 2001, 291, 856−859. (b) Frank, P.; Benfatto, M.; Hedman, B.;
Hodgson, K. O. Inorg. Chem. 2008, 47, 4126−4139. (c) Zitolo, A.;
Chillemi, G.; D’Angelo, P. Inorg. Chem. 2012, 51, 8827−8833.
(d) Constable, E. C.; Housecroft, C. E.; Price, J. R.; Zampese, J. A.
CrystEngComm 2010, 12, 3163−3171. (e) Bukharov, M. S.; Shtyrlin,
V. G.; Mamin, G. V.; Stapf, S.; Mattea, C.; Mukhtarov, A. S.; Serov, N.
Y.; Gilyazetdinov, E. M. Inorg. Chem. 2015, 54, 9777−9784.
(30) (a) Autzen, S.; Korth, H.-G.; Boese, R.; de Groot, H.; Sustmann,
R. Eur. J. Inorg. Chem. 2003, 2003, 1401−1410. (b) Pauly, M. A.;
Erwin, E. M.; Powell, D. R.; Rowe, G. T.; Yang, L. Polyhedron 2015,
102, 722−734.
Schrodinger, LLC: Cambridge, MA. http://www.pymol.org.
̈
̌ ́
(31) (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. (d) Beattie, J.
W.; White, D. S.; Bheemaraju, A.; Martin, P. D.; Groysman, S. Dalton
Trans. 2014, 43, 7979−7986.
(32) (a) Rebek, J. Science 1987, 235, 1478−1484. (b) Rebek, J. Acc.
Chem. Res. 1990, 23, 399−404.
́
(33) (a) Dance, I. New J. Chem. 2003, 27, 22−27. (b) Alvarez, S.
Dalton Trans. 2013, 42, 8617−8636. (c) White, N. G.; Serpell, C. J.;
Beer, P. D. Cryst. Growth Des. 2014, 14, 3472−3479.
́ ́
(34) (a) Alcon, M. J.; Iglesias, M.; Sanchez, F.; Viani, I. J. Organomet.
Chem. 2000, 601, 284−292. (b) Burguete, M. I.; Collado, M.;
M
DOI: 10.1021/acs.inorgchem.6b01066
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