Determination of the binding constants of propeller-like metal complexes of picolinaldehyde-2-pyridylhydrazone

Article abstract of DOI:10.1016/j.ica.2018.12.026

Herein, we determined the binding constants for transition metal complexes of Cu²⁺, Co²⁺, Fe²⁺, Ni²⁺, and Zn²⁺ ions formed with the ligand picolinaldehyde-2-pyridylhydrazone (PapyH) using the Benesi-Hildebrand method. Stoichiometry 2:1 (ligand: metal) was previously determined by the Job's method and confirmed by single-crystal X-ray diffraction finding a propeller-like structure of the [Fe(Papy)₂] compound. PapyH and the metal complexes were characterized by ¹H NMR and UV-Vis spectroscopy, respectively. The Cu²⁺ complex exhibited the highest stability constant, which was confirmed by competitive reaction of different metal ions with the ligand PapyH.

Full text of DOI:10.1016/j.ica.2018.12.026

Accepted Manuscript
Research paper
Determination of the binding constants of propeller-like metal complexes of
picolinaldehyde-2-pyridylhydrazone
Christian C. Carmona-Vargas, Sandra L. Aristizábal, María I. Belalcázar,
Richard F. D'Vries, Manuel N. Chaur
PII:
S0020-1693(18)31543-3
https://doi.org/10.1016/j.ica.2018.12.026
ICA 18693
DOI:
Reference:
Inorganica Chimica Acta
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 October 2018
12 December 2018
12 December 2018
Please cite this article as: C.C. Carmona-Vargas, S.L. Aristizábal, M.I. Belalcázar, R.F. D'Vries, M.N. Chaur,
Determination of the binding constants of propeller-like metal complexes of picolinaldehyde-2-pyridylhydrazone,
Inorganica Chimica Acta (2018), doi: https://doi.org/10.1016/j.ica.2018.12.026
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Determination of the binding constants of propeller-like metal
complexes of picolinaldehyde-2-pyridylhydrazone
Christian C. Carmona-Vargasa,#, Sandra L. Aristizábala,#, María I. Belalcázara, Richard F.
D’Vriesb, and Manuel N. Chaura*
a Departamento de Química, Facultad de Ciencias Naturales y Exactas, Universidad del Valle, AA 25360,
Cali, Colombia.
b Facultad de Ciencias Básicas, Universidad Santiago de Cali, Cali, Colombia.
E-mail: manuel.chaur@correounivalle.edu.co
Abstract
Herein, we determined the binding constants for transition metal complexes of Cu2+, Co2+, Fe2+,
Ni2+, and Zn2+ ions formed with the ligand picolinaldehyde-2-pyridylhydrazone (PapyH) using the
Benesi-Hildebrand method. Stoichiometry 2:1 (ligand: metal) was previously determined by the
Job’s method and confirmed by single-crystal X-ray diffraction finding a propeller-like structure of
the [Fe(Papy)2] compound. PapyH and the metal complexes were characterized by 1H NMR and
UV-Vis spectroscopy, respectively. The Cu2+ complex exhibited the highest stability constant,
which was confirmed by competitive reaction of different metal ions with the ligand PapyH.
Keywords: Binding constants; Benesi-Hildebrand method, hydrazones, Job's method, metal
complexes.
# These authors contributed equally to this work.

1. Introduction
The nature of non-covalent binding has led to the formation of complex molecular architectures
through weak interactions (hydrogen bonding, coordinating bonds) between a host and a guest,
which is indeed the basis of many biological processes. Therefore, the measurement of
thermodynamic parameters like binding constant(s) K, and Gibbs free energy (G) in host-guest
complexation chemistry, as well as the stoichiometry of metal: ligand binding, is an important
step in the characterization and understanding of the formation of metal complexes [1]. In
addition, metal ion-ligand coordination equilibria are one of the processes of great importance in
the construction of metallo-supramolecular entities and in the development of smart materials
[2], biomedical applications [3], and even in constitutional dynamic chemistry, a subfield of
supramolecular chemistry [4].
Within the field of supramolecular chemistry, Schiff bases, especially, hydrazone compounds
have been widely exploited as building blocks in the assembly of metallo-architectures [5,6] due
to their ability to form metal complexes, besides their straightforward synthesis [7] and
modularity. The coordinating ability of hydrazones is possible thanks to the nucleophilic
character of the nitrogen atoms of the triatomic structure C=N-N of the azomethine group [8].
Hydrazone-based metal complexes can be found in several fields like biological chemistry [9],
materials science [10], molecular brakes [11], chemosensors [12], molecular logic circuits [13],
photoelectrochemical switches [14], among others.
One of the simplest pyridine-based hydrazone ligands reported is picolinaldehyde-2-
pyridylhydrazone commonly known as PapyH [15]. Since its first synthesis it has received
attention for being a chelating ligand for transition metal ions due to the size of its tridentate
coordination pocket [16] and affinity of the metal ions for electron donor nitrogen atoms.
Additionally, the acidic proton of the NH group present in this hydrazone has allowed structural
modifications by base deprotonation without losing the metal ion center [17]. In addition, the
study of the magnetic and electrochemical properties of its complexes has allowed the
estimation of some of their acidity constants [18]. However, the study of the binding constants
and the stability in competing media of PapyH-based metal complexes is a far less explored.
Therefore, herein we report the synthesis, structural characterization and determination of the
binding constants of a series of PapyH-based metal complexes using the Benesi-Hildebrand
method [19] and the Job’s method [20], one of the most popular methods for determination of
stoichiometry [1,21]. Also, this work can serve as an approach to do a quantitative analysis of

the strength of the coordinate bonds present in molecular systems containing the PapyH
backbone.
2. Experimental section
2.1. Materials and general methods
All chemicals were used as received from the commercial sources without further purification.
1
Solution H (400 MHz) and 13C (100 MHz) Nuclear Magnetic Resonance (NMR) spectra were
recorded with a Bruker Ultra Shield spectrometer at 25 °C, using CDCl3. Chemical shifts were
quoted in ppm relative to tetramethylsilane, using residual solvent peaks as reference. The
1
following notation is used for the H NMR spectral splitting patterns: singlet (s), doublet (d),
triplet (t), multiplet (m). Ultraviolet-Visible (UV-Vis) spectroscopy spectra were recorded on a
UV–1700 PharmaSpec Shimadzu spectrophotometer. FT-IR spectra were taken in a Shimadzu
FT-IR 8400 and the elemental analyses were obtained using a Thermo-Finnigan Flash EA1112
CHN (Elemental Microanalysis Ltd, Devon, UK) elemental analyzer.
2.2. PapyH synthesis
Picolinaldehyde-2-pyridylhydrazone was synthesized according to literature [16]. 2-
pyridinecarboxaldehyde (1.0 equiv) was added to a solution of 2-hydrazinopyridine (1.0 equiv) in
ethanol. After the reaction mixture was heated under reflux for 3 hours, a yellow precipitate was
collected on a Büchner funnel. The hydrazone obtained in 85% yield, and was recrystallized
from ethanol. m.p.: 181-182 °C. 1H NMR (400 MHz, CDCl3) δ/ppm = 9.57 (s, 1H, NH), 8.56 (d, J
= 4.2 Hz, 1H), 8.19 (d, J = 4.1 Hz, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.91 (s, 1H, HC=N), 7,69 – 7.63
(m, 2H), 7.63 (s, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.19 (ddd, J = 7.8, 4.9, 0.9 Hz, 1H), 6.82 (dd, J =
8.0, 1.0 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ/ppm = 156.6, 154.3, 149.3, 147.4, 139.4, 138.3,
136.3, 122.9, 119.8, 116.3, 107.7 ppm. λmax = 340 nm.
2.3. Job's method of continuous variations
Solutions of PapyH and metal salts of Cu2+, Co2+, Fe2+, Ni2+, and Zn2+ were prepared in methanol
at 3.0x10-5 mol·L-1. Subsequently, these solutions were mixed varying the concentration of the
ligand and the metal ion with a final volume of 2.0 mL. UV-Vis spectra and therefore absorbance
values were recorded for each mixture after 24 hours.
2.4. General procedure for the synthesis of metal complexes

To a solution of the free ligand PapyH (2.0 equiv) in methanol was added 1.0 equiv. of the metal
salt MCl2·6H2O (M = Cu2+, Co2+, Fe2+, Ni2+, and Zn2+). After stirring for 45 minutes, the solution
was left to crystallize by slow evaporation at room temperature. The resulting complexes were
characterized by UV-Vis spectroscopy and X-ray diffraction.
2.5. Determination of the stability constants using the Benesi-Hildebrand method
To a solution of the ligand PapyH in methanol at 3.0x10-5 mol·L-1 was added 10 µL of a solution
of the respective metal ion in methanol (3.0x10-5 mol·L-1) until completing the addition of 100 µL,
and from 100 µL up to 1500 µL. The UV-Vis spectra were collected upon addition and after 24 h,
when equilibrium was reached. The results were plotted as absorbance vs. ligand concentration,
and the K values were determined using equation 5. (see supporting information for
mathematical details).
2.6. Single crystal X-ray diffraction (SCXRD)
Single crystal X-ray diffraction data of the compound [Fe(Papy)2] were collected at room
temperature (293 K) on a Rigaku XTALAB-MINI diffractometer using MoKα radiation (0.71073 Å)
monochromated by graphite. The cell determination and the final cell parameters were obtained
on all reflections using the software CrystalClear [22]. Data integration and scaled was carried
out using the software CrystalClear [22] and CrysAlisPro [23]. The structures were solved and
refine with SHELXS-2013 software [24], included in WinGX [25] and Olex2 [26]. Non-hydrogen
atoms of the molecule were clearly resolved and full-matrix least-squares refinements of these
atoms with anisotropic thermal parameters were performed. Besides, hydrogen atoms were
stereochemically positioned and refined by the riding model. ORTEP diagrams for all structures
were prepared with Diamond; Diamond and Mercury programs were used in the preparation of
the artwork and the polyhedral representations [27,28]. Crystallographic information file was
deposited in CCDC under the code 1869252.
2.7. Competitive reactions of metal ions for PapyH
A 1:1 solution of two different metal ions (2.0 equiv) was added to a solution of PapyH (3.0x10-5
mol·L-1) in methanol (1.0 equiv). The UV-Vis spectra were collected upon addition and after 24 h
when equilibrium was reached to observe the selectivity of the ligand in a competing media.

3. Results and discussion
3.1. Job’s plot analysis
One of the main reasons to prepare metal complexes with pyridyl hydrazones is that such
ligands can be obtained easily from pyridine hydrazines and the corresponding
pyridinecarboxaldehyde. The ligand PapyH was prepared according to a methodology previously
reported [16] by a condensation of an equimolar amount of 2-pyridinecarbaldehyde with 2-
hydrazinopyridine affording the ligand PapyH in 85% yield. The 1H NMR and 13C NMR spectra of
this compound exhibited all the expected signals with the correct integration ratios (see
supporting information, Figures S1 and S2). On the other hand, the azomethine group present in
hydrazones is an isomorphic equivalent of a terpyridine, therefore, this ligand has the ability to
coordinate different transition metal ions through the electron donor capacity of the sp2 orbitals in
the involved nitrogen atoms (Scheme 1).
Scheme 1. Synthesis of the ligand PapyH and its metal complexes.
Initially, the formation of metal complexes of PapyH with M2+ (M = Cu, Co, Fe, Ni, Zn) was
studied through Job’s method [29]. For the Job’s experiments (Figure 1), plots of the absorbance
against mole fraction of the ligand were prepared and the stoichiometry obtained at the
interception of two slopes showed that the formation for all complexes occurs in a ratio ligand:
metal ion of 2:1 (see supporting information). An octahedral structure is formed, where a cation
is bound to six nitrogen atoms of the two pockets of the PapyH ligands (Scheme 1). In the case
of the Co2+ complex, there was a little deviation in the stoichiometry found by the Job’s plot,

therefore, crystals of this compound were obtained and analysed by XRD confirming the
stoichiometry 2:1. However, due to the low quality of the crystals it is not possible to fully refine
the X-ray data and thus to report its structure (see supporting information).
0.20
0.6
0.16
0.12
0.08
0.04
0.00
0.0
0.2
0.4
0.6
0.8
1.0
Molar Fraction
Figure 1. (left) UV-Vis titration of PapyH ligand with a solution of Cu2+ ions in methanol. (right) Job’s plot
for the determination of the stoichiometry of the Cu2+ complex in methanol at 473 nm.
Thereafter, the metal complexes were prepared by following the pathway described in scheme
1. PapyH was treated with MCl2 salts in molar ratio 2:1 ligand: metal ion in methanol to yield
dark red solutions for Co2+ and Fe2+ ions, a dark green solution for Cu2+ ions, and yellow
solutions for Ni2+ and Zn2+ ions.
Single crystals of the compound [Fe(Papy)2] were obtained by the addition of two equivalents of
KOH; in order to avoid the Fe(II) to Fe(III) oxidation, and by slow evaporation of a solution of this
metal complex in methanol. The obtained dark red crystals were fully characterized by X-ray
diffraction. The crystallographic data and refinement details are shown in Table S1 (supporting
information) and the ORTEP representation of the asymmetric unit is presented in the Figure 2.

Figure 2. ORTEP representation of the asymmetric unit of the [Fe(Papy)2] compound. Thermal ellipsoids
are drawn a 50% probability level and the hydrogen atoms are removed for clarity.
[Fe(Papy)2] crystallizes in the P-1 triclinic space group with one propeller-like molecule as the
asymmetric unit. In this case, two molecules of the deprotonated picolinaldehyde-2-
pyridylhydrazone ligand are joined to the metal center, forming a distorted octahedral polyhedron
(Figure 3a). The distortion of the polyhedron is due to the short N2-Fe1 = 1.848(6) Å and N6-Fe1
= 1.856(6) Å bond lengths resulting from a strong electrostatic interaction of the nitrogen atom
with the cation along the equatorial position. In contrast, the distances range from 1.962(5) to
1.975(4) Å for the remaining four polyhedral positions. In this compound, the negative charge of
the deprotonated ligand is delocalized around the N-N=C entity, allowing a strong interaction
with the cation through the nitrogen atoms.
The complex units are joined by C-H···π = 3.829 (2) and π···π = 3.808(2) interactions along the
[010] and [100] directions, respectively (Figure 3b). These interactions give rise to
supramolecular layers in the (110) plane.

Figure 3. a) Polyhedral representation, b) view along the [001] direction of the supramolecular layers and
c) view along the [010] direction of the crystal for the compound [Fe(Papy)2].
3.2. Absorption spectra
The absorption spectra given in Figure 4 show that the ligand PapyH has an intense band at 340
nm that can be attributed to the π→π* transitions in the C=N bond and the pyridine rings. This
band exhibits a hypochromic shift when the Zn2+ metal complex is formed. Additionally, the
n→π* transition between the d orbitals of the metal centre and the π* orbitals of the pyridine
rings of the ligand leads to the band around 450 nm (Figure 4). Moreover, the isosbestic point at
395 nm is evidence for the absence of intermediates in the conversion of the free ligand to the
metal complex.

Figure 4. Change on the UV-Vis spectra of PapyH with the addition of a Zn2+ methanolic solution.
In addition, the absorption spectra of the PapyH-based metal complexes show moderately
intense bands between 260-380 nm (UV region) that can be attributed to ligand-centred π→π*
transitions of the pyridine rings (Figure 5). The broad bands between 400-500 nm (visible region)
can be attributed to metal to ligand charge transfer (MLCT) processes. Additionally, for the Fe2+
complex can be observed between 500-600 nm two additional bands with low extinction
coefficient that can be attributed to d-d transitions.

1.0
0.8
0.6
0.4
0.2
0.0
Co2+
Cu2+
Fe2+
Ni2+
250 300 350 400 450 500 550 600
Wavelength (nm)
Figure 5. UV-Vis spectra of PapyH-based metal complexes in methanol at 3.0x10-5 mol.L-1.
3.3. Determination of the binding constants by the Benesi-Hildebrand method
The binding or stability constant (K) quantifies the binding strength between a metal ion and a
ligand in the formation of a coordination complex [30]. The determination of this thermodynamic
constant K is based on a simple equilibrium model between the metal (M) and the ligand (L) in
the complex formation eqn (1).
(1)
(2)
(3)
(4)
Where [M]0 and [L]0 are variables that can be fixed; [M], [L] and [ML] depend on the equilibrium,
and a and b are the stoichiometry numbers for the ligand and metal ion, respectively. There are
several analytical methods that allow the determination of K from equation (4), however, the
Benesi-Hildebrand method is by far the most used one for 1:1 stoichiometries. For 1:2 or larger
stoichiometries some difficulties and ambiguous conclusions have been reported [19], especially
in those cases where the formation of the complex goes through more than one step. In our

case, titration of the ligand with M2+ ions monitored by UV-Vis spectroscopy (Figure 4) suggests
the occurrence of a single equilibrium as evidenced by the isosbestic points. With this in mind
and the stoichiometry 2:1 (determined by the Job’s method), we proceeded to obtain an
equation for the determination of K (see supporting information for the algebraic details).
(5)
Equation (5) allows us to obtain K from the plot of
vs
(see supporting information). Table
1 organizes the binding constants for all the complexes synthesized in this work.
Table 1. Binding constants for the transition metal complexes with PapyH
Molar extinction
coefficient
ε (x104 M-1cm-1)
Ionic
Free
Binding
constant
Wavelength
(nm)
radiusa
energyb
Transition
metal cation
K(x1010 M-2)
(pm)
(kJ·mol-1)
Cu2+
Co2+
Fe2+
Zn2+
Ni2+
475
485
450
454
454
4.76
4.73
2.73
2.41
4.74
4.91
2.72
2.17
2.15
2.07
72
-39.6
75
-24.8
78
-19.7
74
-19.1
69
-18.5
a) Taken from ref [31]. Values for M2+ ions in an octahedral coordination.
b) Calculated from G° = -RTln(K°) with T = 300 K and R = 8.314 JK-1mol-1
The results show that the metal ion with highest affinity for the ligand PapyH is the Cu2+ ion, like
in other imine and hydrazone-based ligands [32,33], which can be attributed to the additional
stabilization given by Jahn-Teller distortions in the Cu2+ complex [34,35]. On the other hand, it
can be observed that the binding constants for the other transition metal ions are similar and
lower than the K value of Cu2+ complex. Maybe, the chelate effect of the PapyH ligand is higher
with the Cu2+ ion due to its small atomic radius in comparison with the other metal cations [35].
Even so, all studied complexes exhibited large binding constants (~1010 M-2).

3.4. Competitive reactions of metal ions with PapyH
The binding constant is one of the most important characteristics of metal complexes and it is
related to the chelate effects [36], which has been involved in fields like catalysis [37], and
chemical biology [38]. The measure of the stability of a metal complex through the binding
constant gives information about the affinity of the ligand PapyH for different metal ions. For
example, when the free ligand PapyH was exposed to a mixture of first-row transition metal ions,
we observed by UV-Vis spectroscopy that there is a tendency to form the band corresponding to
the Cu2+ complex, indicating that PapyH has a preference to form a metal complex with Cu2+
ions (Figure 6). As it was expected according to the values of the binding constants found
before, the Cu2+ complex has the highest K value of 4.91 x1010 M-2. In addition, we carried out
experiments of competitive reactions with other first-row transition metal ions, and we found the
tendency to form the Cu2+ complex (see supporting information Figures S23-S26).
On the other hand, the binding constants found in this work are higher in comparison with other
values of binding constants previously reported in the literature with Schiff base ligands
[32,39,40], therefore, PapyH is a very good chelating ligand of the transition metal ions tested
here.
1.0
Cu2+
Cu2+ - Co2+
Cu2+ - Fe2+
0.8
Cu2+ - Ni2+
Cu2+ - Zn2+
0.6
0.4
0.2
0.0
250 300 350 400 450 500 550 600 650
Wavelength (nm)
Figure 6. Absorption spectra in methanol of metal complexes formed with PapyH ligand in the presence of
different metal cations at 3.0x10-5 mol.L-1.
The binding constant has a narrow relationship with the estimation of the spontaneity of a
chemical process described by the Gibbs free energy (G). From the data shown in Table 1 it

can be concluded one more time that the Cu2+ complex formation with PapyH is
thermodynamically the most favourable among the transition metal ions used, with a G = -
39.63 kJ.mol-1. It is important to highlight that the mixtures of the ligand with different metal ions
were prepared and allowed to stand up to 24 hours before measuring the absorption spectra.
4. Conclusions
Using the Job’s plot and the Benesi-Hildebrand method it was possible to establish the
stoichiometry of PapyH based metal complexes. In addition, thanks to the crystallization of the
Fe2+ compound was possible to confirm the 2:1 stoichiometry of the PapyH based metal
complexes with a propeller-like structure. The [Fe(Papy)2] compound crystallizes in the P-1
triclinic space group, with one molecule per asymmetric unit.
On the other hand, we determined the binding constants for the formation of each metal
complex, where we found that the ligand PapyH has a strong preference for Cu2+ ions over the
other transition metal ions tested in a competitive reaction media. The determination of the
binding constant of metal complexes based on PapyH opens the window toward the potential
application of a simple hydrazone ligand as PapyH in the molecular recognition of Cu2+ ions in
mixtures containing other first-row transition metal ions.
Acknowledgments
Authors are grateful to the Vicerrectoría de Investigaciones and the Centro de Excelencia en
Nuevos Materiales (CENM) from the Universidad del Valle (Colombia) for their generous
financial support. C.C.C and M.N.C are grateful for the contributions from El Departamento
Administrativo de Ciencia, Tecnología e Innovación (COLCIENCIAS) for the grant “Jovenes
investigadores para la Paz” special grant No FP44842-407-2017. R.F.D acknowledges to
Dirección General de Investigaciones (DGI-USC) for their economic support. The authors would
also like to thank to Mario Macias to facilitate the measurements of Co2+ compound.
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GRAPHICAL ABSTRACT
We determined the binding constants for transition metal complexes of Cu2+, Co2+, Fe2+, Ni2+, and
Zn2+ ions formed with the ligand picolinaldehyde-2-pyridylhydrazone (PapyH). Stoichiometry 2:1
(ligand: metal) was confirmed by single-crystal X-ray diffraction finding a propeller-like structure of
the [Fe(Papy)2] compound. PapyH and the metal complexes were characterized by 1H NMR and
UV-Vis spectroscopy respectively. The Cu2+ complex exhibited the highest stability constant,
which was confirmed by competitive reaction of different metal ions with the ligand PapyH.

Highlights
 Synthesis of novel PapyH based metal complexes of Cu2+, Co2+, Fe2+, Ni2+ and
Zn2+.
 The formation of all metal complexes occurs in a ratio ligand: metal ion of 2:1
 Cu2+ exhibits the highest binding constant among the metal ions tested with K =
4.91 x1010 M-2.
 X-ray crystal structure of the [Fe(Papy)2] complex was determined.