Cu2+ recognition by N,N′-benzylated bis(amino amides)

Article abstract of DOI:10.1039/c6dt04756d

Two new C₂-symmetric N,N′-benzylated bis(amino amides) have been synthesised and their interaction with different transition metals studied using a variety of techniques including UV-Vis and CD spectroscopy or ESI-MS. The determination of the c

Full text of DOI:10.1039/c6dt04756d

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Cu2+ recognition by N,N'-benzylated bis(amino amideDsO)I: 10.1039/C6DT04756D
View Article Online
Lingaraju Gorla, Vicente Martí-Centelles, Belén Altava,* M. Isabel Burguete and
Santiago V. Luis*
Departamento de Química Inorgánica y Orgánica, Universitat Jaume I, Avda. Sos Baynat s/n.,
12071 Castellón, Spain, Tel: +34 964728239, Fax: +34 964728214; E-mail: altava@uji.es,
luiss@uji.es
KEYWORDS: pseudopeptides, metal complexes, metal recognition, crystal structures
Abstract: Two new C2-symmetric N,N'-benzylated bis(amino amides) have been
synthesised and their interaction with different transition metals studied using a variety
of techniques including UV-Vis and CD spectroscopy or ESI-MS. The determination of
the corresponding stability constants with Cu2+ has been possible, in H2O/CH3CN 7/3
v/v, for one of these ligands (4) using potentiometric titrations. The results obtained
reveal that N-benzylation affords significant changes to their properties and is
accompanied by an appreciable decrease in the corresponding complexation stability
constants. However, this, along with the low kinetics associated to Ni2+, facilitates the
recognition of Cu2+ by 4 that can be followed by the naked-eye up to the submillimolar
range. Very interestingly, the chiral nature of this ligand provides an intense and well
defined CD curve for the corresponding Cu2+ complex, very sensitive to the
coordination geometry, facilitating the analysis of this interaction even at the M range.
The formation by both ligands (3 and 4) of square planar complexes with Cu2+ and Ni2+
displaying a 1:1 stoichiometry was confirmed by their X-Ray crystal structures.
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DOI: 10.1039/C6DT04756D
Introduction
The design, preparation and study of organic ligands able to interact with specific
transition metals are of great current interest for the relevant role of these metals in
different areas of chemistry and biology. These ligands can be useful for the selective
extraction, removal or sensing of biologically and environmentally important species.1
Transition metals are not only required for biological functions but also have great
potential for industrial applications. Among the various transition metal ions, Cu2+ plays
important roles in living systems as a nutrient trace element present in the active sites of
some key enzymes, but, at the same time, it is also associated with some serious human
physiological dysfunctions such as Alzheimer’s and Prion type neurodegenerative
diseases, amyotrophic lateral sclerosis, Wilson’s disease etc.2 The selective interaction
with Cu2+ has allowed the development of sensing systems through the quantification of
photophysical signals,3 including molecular probes providing logistics of naked-eye
detection through a colour change for visual perception.4, 3e
In this regard, nitrogen binding sites are commonly used as donor atoms for ligand
design,5 and different amino acid derivatives have been shown to bind metals forming
stable complexes and the results are of interest to understand the interaction of proteic
structures with metals.6 Recent contributions from our group have revealed that C2-
symmetrical bis(amino amides) derived from amino acids form stable complexes with
Cu2+, Zn2+ and Ni2+ ions.7 These results have highlighted the importance of different
structural factors for this interaction and suggested that the presence of aromatic rings at
different positions can be a key structural element. In particular, the inclusion of benzyl
and related groups can be very relevant for the properties of the resulting ligands as has
been reported for catalytic applications,6a-c and more recently in cascade-systems for the
recognition of dicarboxylates.8 Herein, we present the synthesis of two new open-chain
N,N'-benzylated bis(amino amide) ligands derived from L-phenylalanine (3) and L-
valine (4) and the study of their acid-base properties as well as their metal complexation
capacity, in particular for Ni2+ and Cu2+ using a variety of techniques.
Results and discussion
Synthesis, characterization and acid-base properties of the ligands
Scheme 1 displays the general synthetic pathway for the preparation of ligands 3 and 4.
Bis(amino amides) 1 and 2, derived from L-phenylalanine and L-valine, were prepared
from the corresponding N-Cbz protected amino acid N-hydroxysuccinimide ester, via
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coupling with 1,3-diaminopropane and final N-deprotection using HBr/AcOH. Then,
DOI: 10.1039/C6DT04756D
compounds 1 and 2 were subjected to a reductive amination process, using
benzaldehyde in methanol and then sodium borohydride, to afford ligands 3 and 4 in
good yields.10 A central spacer containing three methylene groups was selected as
previous results had shown that this spacer is very well suited to favour the formation of
strong 1:1 metal complexes with the bisdeprotonated ligand.7a,b
Scheme 1. Synthesis of ligands 3 and 4. i) DME, 20 h, r.t., 70–80 %; ii) HBr/AcOH 8 h, NaOH, r.t., 60–
70 %; iii) benzaldehyde, methanol, 2 h, r.t; iv) sodium borohydride, 18 h, r.t., 70–80 %.
Ligands 3 and 4 were fully characterised using standard techniques (1H-NMR, 13C-
NMR, ESI-MS, and FT-IR), and crystals suitable for single-crystal X-ray diffraction
analysis were obtained in the case of 3.
Figure 1. X-ray crystal structure of ligand 3.
The crystal lattice for 3 (ESI, Figure S1) highlights the potential of this ligand to self-
associate through well-defined directional supramolecular interactions and the
importance of the aromatic rings in this regard. Interestingly, one of the benzyl side
chains is folded over the central spacer in such a way that all the nitrogen bound
hydrogen atoms are located at relatively short distances of this aromatic ring (<4.2 Å for
the shortest N-H····CAr distance) in particular for one of the amino groups (2.906 Å).
The importance of the interactions N-H····Ar in peptide-like molecules has been
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highlighted in several examples of pseudopetidic minimalistic molecular rotors. The
DOI: 10.1039/C6DT04756D
most prominent feature for the crystal organization is that a defined set of H-bonds
induces a global parallel disposition of the molecules (a -sheet-like arrangement) with
carbonyl groups from the two amides of each molecule located in anti-position (Figure
1), and H-bonding to the amide groups of two additional molecules located at the two
opposite sites. A different pattern was observed for the analogous compound with a
shorter aliphatic spacer, displaying a syn disposition of the carbonyl amide groups and
both aromatic side chains oriented in opposite directions.8
The proper determination of the acid–base properties of polyamines is essential for
understanding their coordination properties.12,13 The protonation constants of bis(amino
amides) 3 and 4 were determined by potentiometric titrations. The presence of CH3CN
as co-solvent was required to guarantee the solubility of the ligands and all the titrations
were carried out at 298.1 K, using 0.1 M NaCl in H2O/CH3CN 7/3 v/v to maintain a
constant ionic strength. The obtained stepwise stability constants for the protonation of
pseudopeptidic ligands 3 and 4, using the program HYPERQUAD,14 are presented in
Table 1. For the potentiometric studies in this solvent mixture, Kw was determined to be
14.6 in good agreement with literature data.15 The starting bis(amino amides) 1 and 2
had been studied previously in 0.15 or 0.10 M NaCl.7a,b To facilitate a proper
comparison, the acid-base properties of 2 in 0.1 M NaCl in H2O/CH3CN 7/3 v/v were
also determined.
Table 1. Logarithms of the stepwise basicity constants of ligands 1-4 determined at 298.1 ± 0.1 K.b
Reaction a
1c,f
2d,g
2e
3e
4e
H + L ⇌ HL
H + HL ⇌ H2L
7.57(1)
6.70(1)
8.01(5)
6.96(7)
7.77(8)
7.11(8)
6.77(7)
5.15(1)
6.74(9)
6.73(9)
a
b
Charges omitted for clarity. Values in parentheses are the standard deviations in the last significant
figure. c determined in 0.1 M NaCl. determined in 0.15 M NaCl. 0.1 M NaCl in H2O/CH3CN 7/3 v/v.
data taken from reference 7b. g data taken from reference 7a.
d
e
f
As expected, the double N-benzyl substitution decreased the basicity of the resulting
bis(amino amides), (i.e. log KH1 7.77 for 2 against log KH1 6.74 for 4). Regarding the
effect of the amino acid residue, the values of the first protonation constants for 3 (log
KH1 6.77) and 4 (log KH1 6.74) were very close, while for the second protonation
constant the value obtained for 3 (log KH2 5.15) was more than one order of magnitude
lower than the one for 4 (log KH2 6.73) (Table 1). The similar values for the two
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DOI: 10.1039/C6DT04756D
protonation constants of 4 are remarkable. In ,-alkyldiamines, the difference between
the two protonation constants decreases with the length of the spacer as a consequence
of the reduction in the electrostatic repulsion between the two protonated sites, but
remains essentially constant after pentamethylenediamine ( log K ≈ 0.9), which has
been associated to statistical factors.12b The situation, however, is more complex when
additional heteroatoms or functional groups are present as has been observed for large
polyamines and polyazacycloalkanes.12b,16 Thus, for 1,5,9,13,17,21-hexaazaheneicosane
containing propylenic spacers, identical log K values have been reported for the first
two protonation steps.16a The same situation was observed for the macrocycle [32]aneN6
displaying two 1,5,9-triazanonane subunits separated by two heptamethylene chains.16b,c
Very close constants have also been found for the two first protonation constants ( log
K ≤ 0.2) in [24]aneN6,16d [27]aneN9,16e and [36]aneN12.16f These results cannot be only
explained by the changes in the statistical factors associated to large polyamines and
hydrogen bonding and entropic contributions have to be considered. A similar situation
had been previously observed, always in mixed solvents, in a few C2-symmetric
pseudopeptides,7d,17 Solvent effects are important on protonation constants and in the
case of some polyamines it has been shown that these effects can differ for the first and
the second protonation steps.18 For one of the pseudopeptides previously studied,
changing the solvent provided a strong reduction of the first protonation constant ( log
K = -1.04) while the second one slightly increased ( log K = 0.19).7d The comparison
of the protonation constants for the reference compound 2 in the two solvent systems in
Table 1 reveals a related trend, suggesting that the same can apply here. This could
reflect the involvement of the amino groups in strong hydrogen bonding in the non-
protonated compound that has to be broken for the first protonation to occur. The
importance of intramolecular hydrogen bonds in diamides,19 the role of aromatic
fragments on the solvation and hydrogen bonding in pseudopeptidic structures,11 and
the resulting effects on the acid-base properties of the groups involved,19b have been
studied in detail. Overall the situation is reminiscent of the one found in polytopic
systems displaying positive cooperativity,20 in particular ditopic allosteric systems for
which binding of the first guest requires a reorganization of the whole system that
facilitates the binding of the second guest.21 A relevant example is a tetramide-crown
ether system in which hydrogen bonding inhibits anion binding that is then “switched
on” through an initial cation complexation.22
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The distribution diagrams (ESI, Figure S2) revealed the presence of H2LD2O+I:a10s.10t3h9e/C6DT04756D
predominant species at pH values lower than 5 and 4 for ligands 3 and 4 respectively
while the neutral species were predominant for both ligands at pH > 8. The most
relevant difference is related to the monoprotonated species HL. The lower value of the
second protonation constant for 3 is reflected in the presence of HL as a more important
species at pH values close to neutrality, being the major species at pH 6.
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Interaction of ligands 3 and 4 with M2+species
Synthesis and characterization of Cu2+ and Ni2+ complexes
The corresponding Cu2+ and Ni2+ complexes derived from ligands 3 and 4 were
synthesised in basic MeOH (Scheme 2) allowing the generation of the neutral metal
complexes 5 and 6. This was evidenced by the change of colour from blue to orange for
the copper complexes 5a and 6a and from green to maroon for the nickel complexes 5b
and 6b. Moreover, the formation of the complexes could be followed by FT-IR through
the significant shift of the C=O band to lower frequencies when the complexes were
formed (i.e. 1551 cm-1 for 6a against 1629 cm–1 for 4, ESI, Figure S3) indicative of the
deprotonation of the N-H amide groups.6h
Scheme 2. Synthesis of the metal complexes derived from bis(amino amides) 3 and 4.
UV-Vis and CD studies
The higher solubility of the metal complexes from ligand 4 in polar protic solvents
allowed the corresponding spectroscopic studies in MeOH/H2O 80/20 v/v. No
significant differences were observed for the UV-Vis spectra of the copper complexes
of 4 in this solvent and in H2O/CH3CN (7/3 v/v). Initially, 1.2 equivalents of ligand 4
were added (200 L of a 30 mM solution, MeOH/H2O 80/20 v/v) to a set of vials
containing the acetate salts for Cu2+, Zn2+, Ni2+ and the chloride salts for Co2+and Cd2+
in the same solvent (2.5 mM, 2 mL) and the corresponding UV-Vis spectra were
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analysed (ESI, Figure S4). The pH of all the solutions was close to neutralitDyOaI:n10d.10t3h9e/C6DT04756D
addition of the ligand only afforded slight pH changes (ESI, Table S2). For Cu2+, ann
intense peak at 490 nm and a small one at 750 nm were observed, along with a purple
colour in the solution. For Ni2+, two small absorption peaks at 400 and 650 nm were
present. Only a very weak absorption at 500 nm was observed for Co2+.23 As expected,
no absorption peaks between 400 to 800 nm were observed for Zn2+ and Cd2+ and the
resulting solutions remained colourless (ESI, Figure S4).
For the Cu2+∙4 system a large increase was observed on the molar absorption
coefficients for the bands of the ligand at low wavelengths, characteristic of charge-
transfer processes when large interactions between the molecular orbitals of the ligand
and those of the metal occur.23 Besides, the two absorption peaks at 490 nm 750 nm
suggest the coexistence of two coordination geometries for the metal, probably square
planar and octahedral respectively.24 For the Ni2+∙4 system, the initial absorption peaks
observed around 400 and 650 nm suggested an octahedral structure,25 but when the UV-
Vis spectrum was again measured after 24 hours, a new peak at 460 nm, usually
associated to square planar Ni2+ complexes,26 was detected in agreement with the slow
kinetics associated to this metal cation (ESI Figure S4).27 For Co2+, the small absorption
at 500 nm suggests the occurrence of an octahedral structure.25a
Upon addition of ca. 2 equiv. of a 0.1 M NaOH solution in water to these M2+∙4 systems
(ca. 2.3 mM in the metal), pH values of 9.1-9.8 were obtained (ESI, Table S2) and for
Cu2+ the color became more intense. For this system, the UV-Vis (ESI, Figure S4)
showed the disappearance of the band at 750 nm and the increase in the intensity of the
absorption at 490 nm ( = 123 M-1 cm-1) suggesting the quantitative formation of a
square planar complex (ESI Figures S4 and S5). The stoichiometry of the complex
formed by 4 and Cu2+ was determined to be 1:1 (ligand:metal) from the Job plot of its
absorbance at 490 nm as a function of the molar fraction of added Cu2+ in MeOH/H2O
(ESI, Figure S6).28,29 The titration of Cu2+ solutions with increasing amounts of 4
provided a gradual increase in the intensity of the absorption at 490 nm and a decrease
of the one at 750 nm. The isoemissive point around 640 nm was better defined under
basic conditions. The non-linear fitting of the titration curves (1:1 stoichiometry)
provided apparent constants (Kapp) of 562 M−1 and 3350 M-1 in the absence and
presence of base (ESI, Figure S7).28 Similar trends were obtained when CuCl2 and
CuNO3 were used instead of Cu(OAc)2 as the source of Cu2+ (ESI, Figure S8).
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Considering the chiral nature of the ligand, the complexation of 4 with theDOdIi:f1f0e.1r0e3n9/tC6DT04756D
metal ions was also studied by CD. For this purpose, a 2.5 mM solution (MeOH/H2O
80/20 v/v) containing an equimolecular mixture of 4 and the corresponding M2+ and two
equivalents of base was kept stirring for 24 hours. The CD of the free ligand 4 displayed
a negative band centered at 240 nm (Figure 2a). Very interestingly, in the presence Cu2+
(Figure 2b, black line) a strong negative split-Cotton effect (-, +) was observed with a
minimum at 529 nm (∆ = - 0.44 cm2 mol-1) and a maximum at 448 nm (∆ = 0.23 cm2
mol-1), and passing through zero at 481 nm, which is the max for the UV band for the
square planar complex. In the absence of added base, an additional weaker positive CD
band was observed for the Cu2+∙4 system in the 600-800 nm region (ESI, Figure S13) in
agreement with the coexistence of two complex species and highlighting the very
different 3D chiral environments present in them. This behaviour was not detected for
other metals. Only for Ni2+, a weak Cotton effect (minimum at 463 nm, maximum at
284 nm) was observed (Figure 2b). Additional CD signals were always observed below
350 nm most likely related to metal-ligand charge transfer or to intraligand
transitions.23,30
20
4: Cu2+
40
4: Ni2+
4: Co2+
4: Zn2+
4: Cd2+
(a)
(b)
Ligand 4
10
0
20
0
-10
-20
-30
-20
-40
300
400
500
600
700
300
400
500
600
700
Wavelength (nm)
Wavelength (nm)
Figure 2. (a) CD spectra for ligand 4 in basic media (2 equiv. of NaOH). (b) CD spectra for ligand 4 in
2+
basic media (2 equiv. of NaOH) in the presence of 1 equivalent of different M metals. In all cases the
solvent was MeOH/H2O 80/20 (v/v) and the concentration of the metal and the ligand 2.5 mM.
Taking into account that most molecular designs for the detection of Cu2+ involve the
inclusion of sensitive chromogenic or fluorescent units like Rhodamine, naphthalimide,
squarylium, fluorescein, etc,3,4,31 the optical response obtained for Cu2+∙4 complexes, in
particular in CD, is remarkable. Nevertheless, the approximated LOD value calculated
for the naked-eye detection was ca. 0.25 mM (ESI, Figure S9),32 while the use of UV-
Vis spectra provided LOD values in the 79 - 91 M range, depending on the
experimental conditions (ESI, Figures S10 to S12). Although the naked-eye detection
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can compare well with some reported sensors (M – mM range in many cases)D,OthI: 1e0.U103V9/-C6DT04756D
Vis LOD values are significantly higher than those in sensors containing chromogenic
fragments.31 It is worth noting that the strong CD Cotton effect observed allowed to
obtain lower LOD values of 43 M and 28 M under neutral and basic conditions
respectively by using the variation of the amplitude of the Cotton effect (CD =
CD440nm-CD520nm) (ESI, Figures S13 and S14),33 No interference by the other metals
assayed was observed in any of the cases (ESI, Figure S15).
ESI-MS studies for the metal complexes
574.3
100
[CuH-2L+H+AcOH]+
[CuH-1L+AcOH]+
576.3
%
227.4
[CuH-2L+H]+
[CuH-1L]+
453.5
577.4
600
227.9
514.4
257.8
250
454.3
516.3
m/z
900
0
100
150
200
300
350
400
450 500
550
650
700
750
800
850
Figure 3. ESI+-MS of compound 4 (5 mM) in the presence of 1 equiv. of Cu(OAc)2 in MeOH/H2O 80/20,
v/v.
ESI-MS experiments with ligand 4 supported its preferential binding to Cu2+. The ESI+-
MS in the presence of 1 equiv. of Cu(AcO)2, displayed peaks at 514.4 and at 574.3, the
latter being the base peak, associated to [CuH-2L+H]+ and [CuH-2L+H+AcOH]+ or to
[CuH-1L]+ and [CuH-1L+AcOH]+ and supporting a 1:1 complexation (Figure 3). For
Ni2+, Cd2+, Co2+, Zn2+ ions, the corresponding peaks associated to [MH-1L]+ species
were not observed, although the peak for the [MH-1L+AcOH]+ species was present for
Zn2+ and Ni2+. However, for Ni2+, the intensity of this peak was 30 % of the base peak
while for Zn2+ its intensity was < 2 % (ESI, Figure S16). For Co2+ and Cd2+ very minor
peaks (< 2 %) corresponding to [2L+M]2+ and [L+M+Cl]+ species were observed.
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Potentiometric studies for Cu2+ complexes
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DOI: 10.1039/C6DT04756D
Finally, the interaction of ligand 4 with Cu2+ was studied by potentiometric titrations
over the 2-12 pH range. The stability constants for the formation of complexes were
determined for a 1:1 metal-ligand ratio, using NaCl 0.1 M in H2O/CH3CN 7/3 v/v to
maintain a constant ionic strength and at 298.1 K. Although the same solvent mixture
used for spectroscopic measurements was also assayed here (MeOH/H2O 80/20 v/v), its
use was not satisfactory and led to non-stable measurements in some instances. The
results obtained are presented in Table 2 and the corresponding distribution diagrams
are displayed in Figure S17 (ESI). The interaction of the starting bis(amino amide) 2
with Cu2+ was also studied by potentiometric titrations using the same medium to
provide a proper comparison. The solubility problems associated to ligand 3 complexes
again precluded carrying out accurate potentiometric titrations. When comparing the
values obtained for 2 in both solvents it can be seen that the solvent plays, in this case,
an important role. The formation of complex species seems to be favoured in the mixed
solvent,7a although the effects coming from the stronger competition of Na+ in the
medium of greater salinity need to be also considered.
As can be seen in Table 2, significant differences can be observed associated to the N-
benzylation. The most general and remarkable observation was the lower stability of the
non-deprotonated, mono and di-deprotonated complex species for compound 4. This is
easily analysed using the representation of the log Keff values vs. pH (Figure 4). For the
neutral [CuH−2L] species from 4 the formation constant (log  = -6.29) was more than
three orders of magnitude lower than the related one for ligand 2 (log  = -2.97). In
spite of this, these neutral complex species were predominant around pH 7 for 2 and 4,
though [CuH−2L] starts to be formed at slightly higher pH values for 4. This confirms
the formation of [CuH−2L] species at physiologic pH for 4 (ESI, Figure S17). On the
other hand, the relative importance of [CuH−1L] and [CuL] species is reversed for both
ligands. For 4, the [CuH−1L] species is more important at pH values around 6, while it is
a minor species in the case of 2, and [CuL] is relatively important for 2 at pH values
close to 5, whereas it is very minor for 4. The distribution diagram obtained for 4
reveals that at neutral pH values at least two species are present, [CuH−2L] and
[CuH−1L], which is in good agreement with the observations obtained from
spectroscopic experiments suggesting the coexistence of square planar and octahedral
Cu2+ species. The decrease observed in the stability of the Cu2+ complexes upon
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benzylation of the terminal amino groups of 2 is higher than that observeDdOIf: o10r.10t3h9e/C6DT04756D
benzylation of some linear polyamines, where the magnitudes of the stability constants
were 1-2 orders of magnitude lower,23c although for a triethylenetetramine bearing
anthracene and benzophenone instead of phenyl units an additional decrease in ca. five
logarithmic units has been reported.13g
Table 2. Logarithms of the formation constants (log ) for the Cu2+ complexes with ligands 2 and 4 at
298.1 ± 0.1 K.b
Reactiona
2c,d
2e
4e
Cu +L ⇌ CuL
5.99(3)
0.53(1)
-6.66(1)
6.99(7)
1.53(7)
-2.97(1)
4.39(9)
-0.66(3)
-6.29(1)
Cu + L ⇌ CuH-1L + H
Cu + L ⇌ CuH-2L + 2H
a
b
Charges omitted for clarity. Values in parentheses are the standard deviations in the last significant
figure. c determined in 0.15 M NaCl. d data taken from reference 7a. e 0.1M NaCl in H2O/CH3CN 7/3 v/v.
16
14
Cu2+·2
12
10
8
Cu2+·4
6
4
2
0
5
7
9
11
13
pH
Figure 4. Plot of the effective conditional constants v. pH for the systems Cu2+·2 and Cu2+·4 in 0.1 M
NaCl in H2O/CH3CN 7/3 v/v, at 298.1 ± 0.1 K.
Single-crystal X-ray diffraction studies
The formation of the corresponding bisdeprotonated complexes of 3 and 4 with Cu2+
and Ni2+ and their stoichiometry and geometry were confirmed by X-ray
crystallography. Crystals suitable for single-crystal X-ray diffraction analysis were
obtained for all the metal complexes by the layering of a methanolic solution of the
pseudopeptidic ligand over a basic aqueous solution of Cu(OAc)2 and Ni(OAc)2. The X-
ray crystal structures of the copper complexes 5a and 6a are presented in Figure 5. X-
ray diffraction data confirm the formation of the metal complexes with a 1:1
stoichiometry.
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DOI: 10.1039/C6DT04756D
Figure 5. X-ray crystal structures of Cu2+ complexes 5a (a) and 6a (b). Ellipsoids represented at the 50%
probability level.
The Cu2+ cation in 5a is coordinated by two amine groups and two deprotonated amide
groups, in a distorted square-planar geometry, and displays a torsion angle of 13.8°
between the Namine–Cu–Namide planes. The Cu–Namide distances are slightly shorter than
the Cu–Namine ones, being 1.921 and 2.052 Å on average, respectively.7b The N–Cu–N
angles contained in the two five-membered rings Namine–Cu–Namide are ca. 13° smaller
than those contained in the Namide–Cu–Namide six-membered ring, as expected for a
smaller ring size with a tighter environment. The Cu2+ cation in 6a is also coordinated
by two amine groups and two deprotonated amide groups, in a distorted square-planar
geometry, but displays a torsion angle of 29.9°. Again the Cu–Namide distances are
slightly shorter than the ones for Cu–Namine, being 1.912 and 2.034 Å on average,
respectively, and both slightly shorter than in 5a. The N–Cu–N angles contained in the
two five-membered rings (Namine–Cu–Namide) are ca. 14° smaller than those in the six
member ring (Namide–Cu–Namide).
The X-ray crystal structures for the Ni2+ complexes 5b and 6b are presented in Figure 6.
Also for 5b and 6b the Ni2+ cation is coordinated by two amine groups and two
deprotonated amide groups, in a distorted square-planar geometry displaying torsion
angles of 12.9° and 14.8° respectively. In both complexes the Ni–Namide distances are
slightly shorter than the corresponding Ni–Namine and the N–Ni–N angles contained in
the five-membered rings are smaller than the angles contained in the six-membered ring
(ca. 15° for 6b).
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Figure 6. X-ray crystal structure of complexes 5b (a) and 6b (b). Ellipsoids represented at the 50%
probability level.
Conclusions
N-benzylation of the terminal amino nitrogen atoms in C2-symmetric pseudopeptides
containing an aliphatic central spacer provides significant changes in their properties as
ligands. Thus, the solubility in water of 3 and 4 and that for their respective metal
complexes decreases, in particular for the phenylalanine derivative (3), which precludes
a more detailed analysis of its coordination chemistry. The corresponding spectroscopic,
spectrometric and potentiometric studies could be carried out with the valine derivative
4, in particular in aqueous mixed solvents, revealing that these bis(amino amides) are
able to provide efficient tetradentate coordination for metal cations, in particular Cu+2.
The resulting Cu2+ and Ni2+ bisdeprotonated complexes seem to represent the most
important complex species for both cations, even at slightly acidic pH regions at least
for the system Cu2+4. The complexes display 1:1 stoichiometries and square planar
arrangements around the metal centre, as suggested by spectroscopic data and
confirmed by the corresponding X-Ray structures. The presence of the additional benzyl
groups in the terminal amino groups can significantly reduce the stability of the
corresponding metal complexes, as has been observed when comparing the stability
constants obtained potentiometrically for the system Cu2+4 and those obtained for the
non-benzylated analogue 2. The observed decrease in the stability constants for Cu2+ is
significantly higher than the one observed in the case of benzylated linear polyamines.
This, however, facilitates the observation of a defined spectroscopic response to the
interaction of 4 with Cu2+, in particular at short times. It must be noted that the
corresponding Cu2+ complexes display very strong bisigned CD signals that can be used
advantageously to observe and characterize the formation of such complexes, achieving
LOD values of 28 μM while using UV-Vis measurements the value was 80-90 .
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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.
General procedure for the synthesis of N,N'-benzylated bis(amino amides).
Compound 3
Compound 1 (3.01 g, 8.17 mmol) was dissolved in methanol (50 mL) and added to a
solution of benzaldehyde (2.013 mL, 17.97 mmol) in methanol (10 mL) in a 100 mL
two necked round bottom flask, under a nitrogen atmosphere. After stirring at room
temperature for 3 h, the reaction mixture was treated with 50 mL of a methanolic
solution of NaBH4 (1.24 g, 32.68 mmol) and further stirred overnight. The solvent was
evaporated and the crude product was dissolved in basic water (pH=10-11) and
extracted with CHCl3 (3x50 mL). The organic phase was dried over anhydrous MgSO4,
and vacuum evaporated. The final pure product was obtained after washing with hexane
as a white solid (3.418 g, 6.23 mmol, 76 % Yield): mp 101-103 ºC; [α]D25 = -83.57(c =
0.01, CHCl3); IR (ATR) 3343, 3321, 2936, 1636, 1528, 1452cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.46 (t, J = 6.2 Hz, 2H), 7.24 – 7.13 (m, 7H), 7.09 (d, J = 7.0 Hz, 2H), 7.03 (d,
J = 6.6 Hz, 2H), 3.66 (d, J = 13.4 Hz, 2H), 3.49 (d, J = 13.4 Hz, 2H), 3.31 (dd, J = 9.2,
4.4 Hz, 2H), 3.11 (dt, J = 15.3, 5.7 Hz, 4H), 2.69 (dd, J = 13.8, 9.3 Hz, 2H), 1.51 – 1.47
(m, 2H); 13C NMR (126 MHz, CDCl3) δ 173.3, 137.2, 129.2, 128.7, 128.5, 128.2, 127.4,
126.9, 63.1, 52.5, 39.0, 35.7, 29.8; HRMS (ESI-TOF)+ Calcd for C35H41N4O2 (M+H)+:
549.3230; found 549.3235; Anal. Calcd for C35H40N4O2: C, 76.6; H, 7.4; N, 10.2.
Found: C, 76.2; H, 7.1; N, 10.0.
Compound 4
o
25
2.380 g, 8.74 mmol, 87 % Yield; mp 87-89 C; [α]D = -46.27(c = 0.01, CHCl3); IR
1
(ATR) 3301, 2958, 2940, 2933, 2898, 2877, 1629, 1546 cm-1; H NMR (500 MHz,
CDCl3) δ 7.52 (s, 2H), 7.33 (s, 6H), 3.80 (d, J = 13.0 Hz, 2H), 3.66 (d, J = 13.1 Hz, 2H),
3.35 – 3.24 (m, 4H), 2.97 (d, J = 3.8 Hz, 2H), 2.12 (d, J = 5.6 Hz, 2H), 1.67 – 1.62 (m,
2H), 0.94 (dd, J = 29.5, 6.6 Hz, 12H); 13C NMR (126 MHz, CDCl3) δ 174.1, 139.8,
128.5, 128.2, 127.2, 77.3, 77.0, 76.77, 68.1, 53.5, 35.7, 31.4, 30.3, 19.7, 17.9; HRMS
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+
+
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(ESI-TOF) Calcd for C27H41N4O2 (M + H) : 453.3230, found 453.3227; Anal. Calcd
for C27H40N4O2: C, 71.7; H, 8.9; N, 12.4; O, 7.07. Found: C, 71.5; H, 8.7; N, 12.2.
General procedure for the synthesis of M2+ complexes
Compound 3 (100 mg, 0.182 mmol) was dissolved in dry MeOH (5 mL) in a 25 mL
round bottom flask and maintained under a nitrogen atmosphere. Cu(OAc)2 (36.38 mg,
0.182 mmol) dissolved in dry MeOH (5 mL) was then added and the mixture stirred for
30 min at room temperature. 1 M KOH in methanol (3.3 mL, 0.364 mmol) was added
and the solution was maintained at room temperature overnight. The precipitate formed
was filtered and washed with cold dichloromethane to afford the corresponding metal
complex.
Complex 5a
70.6 mg, 0.116 mmol, 64 % Yield; FT-IR: 3500-3000, 2920, 1571, 1454, 1392 cm-1;
Anal. Calcd. (%) for C35H38N4O2Cu∙2H2O: C, 65.1, H, 6.6, N, 8.7; found: C, 65.1, H,
6.5, N, 8.5.
Complex 5b
73.5 mg, 0.121 mmol, 67 % Yield; FT-IR: 3600-3000, 2931, 1573, 1452, 1398
cm-1; Anal. Calcd. (%) for C35H38N4O2Ni∙2H2O: C, 65.5, H, 6.6, N, 8.7; found: C,
65.4, H, 6.2, N, 8.6.
Complex 6a
47.7 mg, 0.093 mmol, 42 % Yield; FT-IR: 3600-3000, 1592, 1551, 1396 cm-1; Anal.
Calcd. (%) for C27H38N4O2Cu∙1.5 H2O: C, 59.9, H, 7.6, N, 10.4; found: C, 59.5, H, 7.4,
N, 10.2.
Complex 6b
51.2 mg, 0.101 mmol, 45.5 % Yield; FT-IR: 3600-3000, 1649, 1569, 1453 cm-1; Anal.
Calcd. (%) for C27H38N4O2Ni∙3.5 H2O: C, 56.7, H, 7.9, N, 9.8; found: C, 56.3, H, 8.1,
N, 9.7.
Electromotive force measurements
The potentiometric titrations were carried out at 298.1 K using 0.1 M NaCl as the
supporting electrolyte. The experimental procedure (burette, potentiometer, cell, stirrer,
micro-computer, etc.) has been fully described elsewhere.34 The acquisition of the emf
data was performed with the computer program CrisonCapture. The reference electrode
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was an Ag/AgCl electrode in saturated KCl solution. The glass electrode was calibrated
as a hydrogen-ion concentration probe by titration of previously standardized amounts
of HCl with CO2-free NaOH solutions and the equivalence point determined by the
Gran’s method,35 which gives the standard potential, E°′, and the ionic product of water
13.78, whereas in the case of the H2O/CH3CN mixture used this value was 14.6.15 The
computer program HYPERQUAD was used to calculate the protonation and stability
constants,14 and the HySS29 program was used to obtain the distribution diagrams.36
The pH range investigated was 2.0-12.0 and the concentration of the metal ions and the
ligands 0.1 mM, with 1:1 M2+:L molar ratios. 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.
1H NMR experiments
The 1H spectra were recorded on a Varian INOVA 500 spectrometer (500 and 125 MHz
for 1H and 13C NMR, respectively). The solvent signal was used as a reference standard.
UV-Vis and CD measurements
UV-Vis absorption spectra were recorded using a Hewlett-Packard 8453 device. All
measurements were performed at room temperature and spectra were recorded from 200
to 900 nm. For metal titration experiments, a M2+ solution in MeOH/H2O 80/20 (2.5
mM) and a solution of compound 4 (30 mM) in the same solvent mixture were used and
aliquots of the ligand solution were gradually added to the metal solution using a
micropipette. After equilibration, the corresponding absorptions were measured. For
job-plot measurements stock solutions of compound 4 (5 mM in MeOH/H2O 80/20) and
Cu(OAc)2 (5 mM in MeOH/H2O 80/20) were prepared and mixed in variable
proportions so that the final volume of the mixture was maintained constant to 1 mL.
After equilibration, the absorbance at 490 nm of each solution was independently
measured. A plot of absorbance against the mole fraction of Cu2+ was used to determine
the metal–ligand ratio.
CD experiments were performed using a JASCO J-810 spectrometer. All measurements
were performed at room temperature and spectra were recorded from 200 nm to 900 nm
with 1.0 nm step and 1.0 nm bandwidth and the scanning speed was 200 nm per minute.
LOD values were calculated using the relation
Detection limit = 3σ/k
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where σ is the standard deviation of the blank measurements,32 and k is the slope
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between the absorbance for UV and mdeg for CD versus [L]. For such experiments, the
UV-Vis and CD spectra of the solvent (blank) were measured 10 times and the standard
deviation of the measurements was determined. The slope was obtained from the plot of
absorbance at 490 nm for UV-Vis or from the amplitude of the Cotton effect (CD =
CD440nm-CD520nm) vs. the concentration of ions.
Mass spectrometry
Mass spectra were recorded on a Q-TOF Premier mass spectrometer with an orthogonal
Z-spray electrospray interface (Micromass, Manchester, UK) by electrospray positive
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 of the source block and desolvation temperatures
were set to 120 °C and 150 °C. A capillary voltage of 3.5 kV was used in the positive
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.37
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 4 and complexes 5a - 6b were obtained. A suitable crystal was
selected and measured on a single crystal X-Ray diffractometer. Using Olex2,38 all the
structures were solved with the ShelXS 2014 structure solution program using Direct
Methods and refined with the ShelXL 2014 refinement package using Least Squares
minimization.39 The program MERCURY was used to prepare artwork
representations.40 Crystallographic data and refinement parameters are summarized in
Table S1 (ESI). Cambridge Crystallographic Data Centre files 1481178 (3), 1481179
(5a), 1481180 (5b), 1481181 (6a), 1481182 (6b) contain the supplementary
crystallographic data for this paper.
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Acknowledgements
Financial support from Spanish MINECO (CTQ2015-68429-R), Generalitat Valenciana
(PROMETEO/2016/071) and PPI-UJI (P1-1B-2013-38) is gratefully acknowledged.
L.G. thanks Generalitat Valenciana for a Grisolia fellowship (GRISOLIA 2012/015).
The support of the SCIC at the Universitat Jaume I for instrumental techniques is
acknowledged.
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