Production and Characterization of a New Copper(II) Propanoate-Isonicotinamide Adduct Obtained via Slow Evaporation and using Supercritical CO2 as an Antisolvent

Article abstract of DOI:10.1021/acs.cgd.8b01034

A new adduct of isonicotinamide (INA) with copper(II) propanoate [Cu(C₃)₂] was prepared [Cu₂(C₃)₄(INA)₄] using two different methods. This type of compound shows high fungicidal activity. Solvent evaporation from ethanol rendered crystals suitable for single-crystal X-ray diffraction. Furthermore, a new semicontinuous method capable of simultaneous crystallization and micronization of the adduct using supercritical CO₂, the supercritical antisolvent technique (SAS), was also assessed. Crystals were characterized using powder X-ray diffraction, infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis coupled with mass spectrometry, scanning electron microscopy, and microelemental analysis. In the adduct, two copper(II) ions are coordinated through two bridging and two chelating carboxylates to the propanoate anions forming approximately a plane. Each metal ion is then coordinated with the pyridine nitrogen of two different INA molecules that behave as monodentate ligands. The amide groups of the INA form H-bonds with other amide and carboxylate groups forming a molecular crystal with a three-dimensional H-bond arrangement of the binuclear units. With the SAS technique, crystals 100-fold smaller than those obtained by slow evaporation were obtained, proving SAS as a suitable method for mixed-ligand complexes preparation with reduced particle size and therefore expected bioavailability enhancement.

Full text of DOI:10.1021/acs.cgd.8b01034

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Article
Production and characterization of a new Copper(II)
propanoate-Isonicotinamide adduct obtained via Slow
2
Evaporation and using Supercritical CO as an Antisolvent
Isaac A. Cuadra, Francisco J. Martinez-Casado, José A. R.
Cheda, M.I. Redondo, Concepción Pando, and Albertina Cabañas
Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b01034 • Publication Date (Web): 09 Jan 2019
Downloaded from http://pubs.acs.org on January 10, 2019
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Production and Characterization of a new
Copper(II) Propanoate-Isonicotinamide
Adduct obtained via Slow Evaporation and
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using Supercritical CO as an Antisolvent
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Isaac A. Cuadra, Francisco J. Martínez-Casado*, José A. R. Cheda, M. I. Redondo,
Concepcion Pando, Albertina Cabañas*
Dpto. Química Física, Universidad Complutense, E-28040 Madrid, Spain
*
fmarcas@gmail.com, *a.cabanas@quim.ucm.es
ABSTRACT
A new adduct of isonicotinamide (INA) with copper (II) propanoate [Cu(C ) ]
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was prepared [Cu (C ) (INA) ] using two different methods. This type of compounds
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shows high fungicidal activity. Solvent evaporation from ethanol rendered crystals
suitable for single crystal X-ray diffraction (SCXRD). Furthermore, a new
semicontinuous method capable of the simultaneous crystallization and micronization of
the adduct using supercritical CO the supercritical antisolvent technique (SAS), was also
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assessed. Crystals were characterized using powder X-ray diffraction (PXRD), infrared
spectroscopy (FTIR), differential scanning calorimetry (DSC), thermogravimetric
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analysis (TGA) coupled with mass spectrometry, scanning electron microscopy (SEM)
and micro-elemental analysis. In the adduct, two copper(II) ions are coordinated through
two bridging and two chelating carboxylates to the propanoate anions forming
approximately a plane. Each metal ion is then coordinated with the pyridine nitrogen of
two different INA molecules that behave as monodentate ligands. The amide groups of
the INA form H-bonds with other amide and carboxylate groups forming a molecular
crystal with a 3D H-bond arrangement of the binuclear units. Using the SAS technique,
crystals 100 folds smaller than those obtained by slow evaporation were obtained, proving
SAS as a suitable method for mixed-ligand complexes preparation with reduced particle
size and therefore expected bioavailability enhancement.
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. INTRODUCTION
The synthesis and behavior of copper (II) alkanoates has been widely studied
during the last decades.1-9 The paddle-wheel configuration in which the carboxylate
ligands bond both copper (II) atoms with a bridging ligand confers these compounds
interesting features. They present monotropic polymorphism and mesomorphism, as a
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hexagonal columnar discotic liquid crystal. Recent research has explored the thermal
behavior and structure of the copper(II) alkanoate series in both crystal and liquid crystal
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phases where the dimeric complex molecular units are present. Important applications
of the copper (II) alkanoates result from their magnetic properties,11, 12 and their potential
use in the production of nanoreactors.13-16 Special interest arises from their biological
activity as they have proven pharmaceutical activity in diverse fields such as
antiinflammatory, antirheumatic and antitumoral17-26 as well as fungicidal activity27-31 for
which they have been extensively studied as wood preservatives. Dimeric complexes
involving bridging carboxylate groups, like the Copper(II) propanoate (Cu(C ) ,
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hereafter), are of special interest for their fungicidal properties.27 Pyridine-4-
carboxamide, or isonicotinamide (INA, hereafter), is a pharmaceutical coformer of
common use in the co-crystal production as it possesses antitumoral, antipyretic,
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thrombolytic and antibacterial properties. It is also known to behave as a high-yielding
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supramolecularreagent. The nitrogen atom present in the pyridine readily acts as a
hydrogen bond acceptor when faced with hydrogen bond donors such as carboxylic
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acids and can even coordinate directly to the copper. The activity of the metal ions
increases with the addition of some already biologically active substances, therefore a
large number of adducts and complexes of copper(II) carboxylates with N donor ligands
such as urea, nicotinamide, papaverine, 3-hydroxypyridine, 2-aminopyridine… have
already been produced and their crystal structure solved.28, 29, 31, 35-37
In this communication we report the preparation of the new adduct formed by
Cu(C ) and INA. Single crystals were obtained by slow evaporation from an ethanol
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solution, which allowed the resolution of the crystal structure. On the other hand, this
method presents several drawbacks for the production of crystals at industrial scale.
Cooling crystallizers require temperature to have a considerable effect on solubility.
Furthermore, the slow crystal growth rate in slow evaporative crystallizers, and therefore
the long periods of time required to obtain the product, as well as the use of large amounts
of organic solvents, can make the scaling up of the process practically or economically
non-viable. Other evaporative crystallizers (APV Kestner, Swenson or Oslo-Krystal) can
present tube-scaling problems and may require a washing process after crystallization.
The utilization of supercritical CO as a solvent in the production of several metal organic
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frameworks with different organic ligands in a batch reactive crystallization process has
been investigated by López-Periago and coworkers.39, 40 More information on the
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processing of metal-organic frameworks using supercritical fluids as reaction medium or
drying agents can be found in a recent review.41
As an alternative to these processes, we investigate the feasibility of using the
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supercritical CO anti-solvent technique (SAS) in the precipitation and production of
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metal adducts with N donor ligands. The SAS technique has been previously employed
in the production of several co-crystals (multicomponent system connected by non-
covalent interactions)42-44 and presents the added advantage of the production of solvent-
free precipitates with smaller particle size (thus increasing even more the bioavailability
of the new copper adducts) in a semicontinuous process.
Carbon dioxide presents major advantages as a supercritical fluid because it is
innocuous, non-flammable and its critical point is relatively easy to reach (304 K and 7.4
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MPa). It is also considered a green solvent, thus carbon dioxide is the most commonly
used supercritical fluid. Its use in the anti-solvent technique is due to the good miscibility
with many organic solvents. Carbon dioxide diffuses in the organic solvent in which the
solutes to precipitate have been previously dissolved reducing the solvation power of the
solvent and generating supersaturation. The properties of supercritical fluids are
intermediate between those of gases and liquids and can be easily modified with slight
changes in temperature or pressure enabling the control of particle size and/or
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morphology. The solubility of the target solutes to precipitate in carbon dioxide should
be very low. The solubility values of several copper complexes in supercritical CO have
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already been measured46-50 as well as the solubility of the INA isomer nicotinamide,51
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which has already been processed by SAS at our laboratory, and their low solubility
values make them good candidates for SAS processing. Neither copper (II) alkanoates
nor INA have been processed by SAS before. The aim of this paper is to explore the
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crystal structure of the Cu(C ) -INA adduct and to study the feasibility of the SAS
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technique to produce the mentioned adduct.
2. EXPERIMENTAL SECTION
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.1. Materials. INA (C H N O) 99% was purchased from Sigma-Aldrich in its
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polymorph form I. Cu(C ) (C H CuO ) was prepared in our laboratory by direct reaction
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of copper (II) oxide (Merck pro analysis >99%) with propanoic acid (Fluka puriss.
>99.5%) in a small amount of ethanol heated under reflux at 333 K for several hours as
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described elsewhere . Absolute ethanol was purchased from Fisher Scientific. All
reactants were used with no further purification. Compressed CO (99.998%) was
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supplied by Contse S.A. (Spain).
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Cu(C ) -INA: Slow evaporation from solution and supercritical antisolvent precipitation.
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.2.1 Crystallization from solution (slow evaporation)
This procedure consisted in the grinding of Cu(C ) and INA in a 1:2 molar ratio
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respectively (1.2 mmol of Cu(C ) ) assisted with a few drops of ethanol. The powder
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obtained by grinding was dissolved in approximately 175 mL of ethanol at 333 K and
then filtered twice. After cooling, the obtained solution was covered with perforated
parafilm and left to slowly evaporate. A change of color from cyan to lighter blue was
observed. Crystals suitable for single crystal X-ray diffraction were obtained after several
weeks.
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The supercritical fluid antisolvent (SAS) technique was also used. A complete description
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of the high-pressure equipment employed can be found elsewhere. A typical experiment
is described here. Compressed CO was cooled to 272 K in a chiller and pumped into the
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system using a high pressure pump (Thar-SCF high pressure Pump P-50) at a rate of 20
g/min. The CO passed through a heat exchanger, where temperature was raised to 313
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K, before entering a 500 mL precipitation chamber. A back pressure regulator (BPR)
situated at the exit of the chamber kept the pressure in the chamber at 10 MPa throughout
the experiment. When steady conditions were reached in the precipitation chamber a 1:2
molar ratio solution in ethanol of Cu(C ) (3.3 mg/mL) and INA was injected using an
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high-performance liquid chromatography (HPLC) pump (labAlliance series III pump)
into the precipitation chamber through a 100 µm nozzle at a flow rate of 1 mL/min. The
precipitation chamber was equipped with a heating jacket to ensure that the experiment
occurs at the desired temperature of 313 K. Inside the chamber a basket with a filter (frit,
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µm) was placed in order to collect the microparticles obtained. The effluent exiting the
BPR was directed to a cyclone separator where CO was separated from the waste. After
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spraying approximately 30 mL of solution the HPLC pump was stopped and 1.5 L of CO2
at the same precipitation conditions were allowed to flow through the chamber at 20 g/min
to ensure that the product was free of ethanol. A schematic representation of the process
is illustrated in Figure 1.
Experiments were performed at 298 and 313 K and pressures of 8, 10 and 25 MPa using
ethanol as a solvent and a 1:2 molar ratio of Cu(C ) to INA. Further experiments were
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conducted at 313 K and 10 MPa using methanol. An additional experiment at 313 K and
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Solubility of Cu(C ) and INA was studied in a mixture of CO and ethanol at the
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precipitation conditions using a high-pressure view cell available at our laboratory and
following the procedure previously described.52 As required for a successful SAS
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precipitation, solubility of these compounds was very low, below 2 x 10 in mole fraction.
Figure 1. Schematic representation of the SAS equipment and process. T: temperature
control and measurement; P: pressure measurement; BPR: back pressure regulator.
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.3 Adduct characterization. Single Crystal X-ray Diffraction (SCXRD) experiments
were performed with a wavelength λ= 0.8000 Å, at 100 and 320 K at the 911-3 beamline
of Max II (Max IV Laboratory, Lund, Sweden) using a MAR225 CCD area-detector,
making phi scans while collecting the data. The oscillation range (∆ φ) used for each
image was one degree. The structure was solved and refined using the SHELXS-97 and
SHELXL-97 programs.53
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Powder X-ray Diffraction data (PXRD) for most of the compounds were collected
on reflection mode in a Panalytical X´Pert MPD X-ray diffractometer with vertical
goniometer θ-2θ. A Cu anode X-ray tube was powered at 40 kV and 40 mA (K 1.54056
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Å). Scans were measured between 5º and 60º 2θ with a step size of 0.016º 2θ and a
continuing time of 5 s per step.
The adduct obtained by slow evaporation was measured at room temperature (RT)
in transmission mode in 0.5 mm spinning capillaries at the I711 beamline of the Max II
synchrotron (MAX IV Laboratory, Lund, Sweden), with a wavelength of 0.9940 Å, and
using a Newport diffractometer equipped with a Pilatus 100 K area detector mounted 76.5
cm from the sample. The detector was scanned continuously, from 2 to 70°, in approx. 6
min, recording 125 images per ° (step size 0.008°) for each measurement. The true 2θ
position of each pixel was recalculated, yielding an average number of 100.000 pixels
contributing to each 2θ value. Integration, applying no corrections for the tilt of the
detector, provided full width at half maximum (FWHM) values of 0.03–0.08° from 0 to
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The Rietveld refinement was performed with the FullProf program,54, 55
introducing the atomic coordinates previously obtained from the single crystal data in
each case.
Fourier Transform Infrared (FTIR) spectra of the samples were obtained using the
spectrum 100 Fourier-transform infrared spectrometer from Perkin Elmer with the
universal attenuated total reflection (ATR) sampling accessory at a resolution of 4 cm-1.
-1
Samples were measured in the 4000-650 cm range.
Differential scanning calorimetry (DSC) thermograms were measured using a TA
Instruments Q 20 modulated DSC connected to a refrigerating cooling system (RCS), at
a heating rate of 5 K/min and a dry nitrogen flow of 50 mL/min. Samples were confined
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in sealed aluminum volatile pans and weighed using a MT5 Mettler microbalance (error
of ±0.001 mg). Temperature and enthalpy of the calorimeter were previously calibrated
using standard samples of In (purity > 99.999%), Sn (>99.9%) and benzoic acid
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(>99.97%). Thermogravimetric analysis (TGA) and decomposition mechanisms were
studied with a TA Instruments Q500 thermobalance equipped with an evolved gas
analysis (EGA) oven connected to a ThermoStar Omnistar GSD 301 O/301T mass
spectrometer. Samples were placed in Pt containers and heated at 10 K/min under a 100
mL/min N flow from room temperature to 773 K. Uncertainty in the temperature was
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0.1 and ±0.5 K in the DSC and TGA measurements, respectively.
Particle size and morphology of samples were examined by Scanning Electron
Microscopy (SEM) using a JEOL 6335F JSM microscope. Samples were coated with
gold in a Q150RS Rotary-Pumped Sputter Coater. SEM images were taken with an
accelerating voltage of the electron beam of 10, 15 or 20 kV.
Micro-elemental analysis of the samples was performed in a LECO CHNS-932.
Uncertainty in the measurements was ± 0.3 % for N and H and ± 0.35 % for C.
3
. RESULTS AND DISCUSSION
3.1. Crystal Structure. Large crystals of the adduct Cu (C ) (INA) with single
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crystal quality were obtained through slow solvent evaporation. The experimental
parameters, crystal sizes, and main crystallographic information obtained from the
SCXRD data at 100 K (structure II) and 320 K (structure I) are shown in Table 1.
Table 1. Crystallographic Data and Structure Refinement Parameters of Cu(C ) -INA
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adduct
Cu(C ) -(INA)
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chemical formula
formula weight (g/mol)
crystal system
CuC H N O
453.94
monoclinic
18 22 4 6
space group
P 2 /c
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crystal size (mm)
λ (Ǻ)
temperature (K) / structure
a (Ǻ)
b (Ǻ)
c (Ǻ)
α (º)
β (º)
0.060 × 0.040 × 0.030
0.8000 (1)
100 / II
320 / I
10.812 (2)
12.367 (3)
15.467 (3)
90
10.572 (2)
11.612 (2)
15.779 (3)
90
0
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103.,93 (3)
90
103.46 (3)
90
γ (º)
V (Ǻ )
3
1880.1(7)
4
2011.3(7)
4
Z
3
Dcalc (g/cm )
µ (mm )
1.604
1.499
-1
1.207
1.128
absorption correction
reflection collected
reflections with I > 2σ (I)
parameters refined/restraints
hydrogen treatment
R-factor
none
none
3844
4659
3624
3441
276/0
280/0
mixed
0.0403
0.1052
1.074
mixed
0.0427
0.1056
1.046
wR -factor
2
goodness of fit
CCDC no
1846632
1846633
Figures 2a and 2b show the structures of Cu(C ) and the Cu (C ) (INA) adduct
3
2
2
3 4
4
obtained at 100 K. The colour change from the original cyan of the Cu(C ) to a lighter
3
2
blue can be attributed to the change in the coordination of the copper from 5 (square
pyramidal) in the alkanoate to 6 (distorted octahedral) in the adduct. The paddle-wheel
structure of Cu(C ) is constructed by four bridging carboxylate ligands (µ ) which form
3
2
3
catenae in a one dimensional (1D) coordination polymer arrangement (Fig. 2a), typical
1
-9
of all the Cu(II) alkanoates. The paddle-wheels, and therefore the catenae, disappear in
the new complex where two-metal units are coordinated by two bridging (µ ) and two
2
chelating carboxylates (µ ) from the propionate anions, and four N atoms from INA
2
molecules. Each Cu ion in the binuclear unit is coordinated by four O atoms (two of them
from two different bridging carboxylates, and the other two from the chelating
carboxylate), in the plane approximately, while the N atoms are in the apical vertices of
the distorted octahedron (see Figure 2b). The INA behaves as a monodentate ligand
1
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coordinating to the copper ions through the pyridine nitrogen atom, and leaving the amide
group towards the outside of the complex, where H-bonds are then formed with other
amide and carboxylate groups. The amide-amide synthons grow linearly in the direction
of the apical vertices of the Cu octahedron. The H-bonds between the amide groups and
the chelating carboxylates are similar to those previous reported for complexes of Cu(II)
and INA33, 56 and grow perpendicular to the ones of amide-amide synthons, and laterally
with respect to the chelating carboxylate, joining different di-copper units (see Figure 2c).
Thus, the final structure results in a molecular crystal of isolated binuclear complexes
joined by H-bonds in a 3D arrangement (see Figure 2c). Hydrogen-bond interactions and
distances are summarized in Table 2.
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0
Table 2. Hydrogen-bond intermolecular distances for the Cu(C ) - INA adduct at 320
3
2
K.
Amide-Amide Synthon Distance (Ǻ)
O(6)...H(2N1)
O(5)...H(4N2)
Amide-Carboxyl
O(3)...H(2N2)
O(4)...H(4N1)
2.179 (4)
2.086 (4)
2.148 (4)
2.164 (4)
The complex crystallizes in the monoclinic system group (P 2 /c),
1
centrosymmetric, and it is worth noting that the inversion center is in the middle of the
di-copper units, so the asymmetric unit contains half of those aforementioned parts: one
Cu, two propionates and two INA molecules. Small distortions are observed in the
structures at 100 and at 320 K, mainly in the chelating carboxylate and the expected
higher thermal displacement in the alkyl chain of the propionates.
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Figure 2. a) Catena of a Cu(II) alkanoate (1D coordination polymer of double
coordination bond of paddle wheels), showing the square pyramidal coordination of the
Cu atoms; b) binuclear unit of the Cu(C ) -INA adduct, measured at 100 K, with 50%
probability ellipsoids and showing the distorted octahedric coordination around the Cu
atoms; the semi-transparent atoms have been generated by symmetry operations; c) 3D
arrangement of the units showing the H-bonds of the amide-amide and the amide-
carboxylic synthons.
3
2
The synthesis of the adduct was also attempted by the SAS technique using
supercritical CO . Experiments were performed at different temperatures and pressures,
2
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solvents and Cu(C ) to INA molar ratios. Both pressure and temperature had a significant
3
2
effect in the adduct formation by SAS. PXRD of the different samples prepared by SAS
only fit the pattern of the adduct prepared by evaporation in the experiments performed
at 313 K and 10 MPa using ethanol or methanol as solvents and the 2:1 molar ratio of
Cu(C ) to INA. At the remaining conditions, complex PXRD patterns which do not
1
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match those of the pure compounds or the adduct previously described were obtained.
PXRD of all the samples precipitated by SAS are given as supplementary material (Figure
S1).
Figure 3 compares the patterns of the products obtained by SAS at 313 K and 10
MPa for a 2:1 Cu(C ) to INA molar ratio using ethanol as solvent and that of the sample
3
2
prepared by slow evaporation (by grinding some crystals). The pattern from the grinded
crystals was fitted by Rietveld refinement using the model obtained by SCXRD. On the
other hand, the adduct prepared by SAS showed the most intense peaks of the former
sample, but clearly with much lower crystallinity. PXRD of this sample was also refined
using the Rietveld method. Similar cell parameters were obtained for the samples
prepared by SAS in ethanol and by evaporation. The fittings and data of the Rietveld
refinements for both samples are given as Supporting Information (Figure S2). For the
SAS sample, the microstructure was also studied. The average crystal domain
corresponded to a platelet, which was extremely narrow in the direction (010) (see Table
S1 in supplementary material). No sign of other crystalline phases (reactants, or new
phases) was observed by PXRD.
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Figure 3. Comparison of the diffraction patterns observed for the adduct obtained by: a)
SAS using ethanol at 313 K, 10 MPa and a 1:2 molar ratio of Cu(C ) to INA, b) slow
3
2
evaporation and c) calculation from the Rietveld refinement at room temperature.
SEM images of the precipitated adducts, commercial and SAS processed INA,
Cu(C ) prepared at our laboratory and SAS processed Cu(C ) are shown in Figure 4. In
3
2
3 2
every case, ethanol was used as a solvent. Cu(C ) prepared at our laboratory presented a
3
2
ribbon-like morphology with heterogeneous crystal sizes that can vary from 1 µm in
width and length up to 50 µm. After processing Cu(C ) by SAS, size was reduced to
3
2
small spheres of 70 nm diameter. Commercial INA presented prismatic crystals of
polydisperse size and rough surface that vary from 20 to 100 µm in thickness and 60 to
4
00 µm in length. SAS processed INA showed a platelet morphology with thickness of
2
around 7 µm and surfaces up to several 100 µm . Adduct crystals obtained by slow
evaporation presented sizes up to 150 µm wide and lengths close to 1 mm (although
crystals were crashed and fragmented and show therefore an heterogeneous size
distribution).
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Figure 4. SEM images of: a) Cu(C ) prepared at our laboratory; b) commercial INA; c)
3
2
Cu (C ) (INA) formed by slow evaporation; d) Cu(C ) processed by SAS; e) INA
2
3 4
4
3 2
processed by SAS; f) adduct formed by SAS employing a 1:2 molar ratio of Cu(C ) to
3 2
INA. SAS experiments were performed at 313 K and 10MPa using ethanol. Images b), c)
and e) are at 100x magnification; images a) and f) at 1000x and d) at 1500x magnification.
As it can be observed, the production of the adduct crystals by SAS generated
much smaller crystals (up to 100 times smaller). Supercritical CO combines liquid-like
2
densities with gas-like diffusion coefficients allowing a very rapid mixture of the liquid
and supercritical phase in the precipitation chamber. This leads to a fast supersaturation
of the solution and the precipitation of the solute. As at 313 K and 10 MPa we operate
5
7, 58
over the critical point of the mixture CO -ethanol
we can expect gas-like mixing in
2
5
9
the precipitation chamber, thus, many crystal nuclei are produced and crystal growth is
hindered. However, the small adduct particles precipitated by SAS exhibited a mixture of
different morphologies. Whilst most particles were around 3µm wide and 30 to 50 µm
long, nano-fibers and small conglomerates were also present. SEM images for the sample
precipitated from the methanol solution are given in the supporting information (Figure
S3). Morphology of the sample in this case was similar but particles were even smaller
than those precipitated from the ethanol solution. Although the only crystalline phase
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observed by PXRD was that of the adduct, the different morphologies observed in the
SAS samples by SEM could indicate the presence of amorphous impurities. The results
obtained from the microstructural analysis by XRD of the sample precipitated by SAS
using ethanol show a platelet domain (see Supporting Information), compatible with the
main particle morphology but with an average crystal domain much smaller than the
observed particle size.
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3.2. FTIR Spectroscopy. Figure 5 shows FTIR spectra of the samples. Table 3.
7
60, 61
displays the absorption peak assignments of INA, Cu(C )
and the adduct formed by
3
2
both techniques. One of the most significant bands is the carbonyl amide stretching band
-1
at 1708 cm . In pure INA the carbonyl group is bonded through H-bonds to two amide
groups of different INA molecules (distances of 2.076 and 2.088 Å), the vibration
-1
frequency of this stretching band is at 1655 cm . In the adduct though, this carbonyl
group of the INA is bonded to only one amide group forming the amide-amide synthon
shown in Figure 2 (distances of 2.179 and 2.086 Å) and consequently the frequency of
-1
this vibration blue shifts to 1708 cm . The presence of this synthon also shifts the
-1
-1
asymmetric and symmetric stretchings of the NH group from 3361 cm and 3177 cm
2
-1
-1
in the pure INA that red shift to 3296 cm and 3149 cm in the adduct respectively. These
shifts show that in the adduct a different H-bond net is present. In the Cu(C ) the
3
2
-1
carboxylate asymmetric and symmetric stretchings have a frequency of 1585 cm and
-1
1420 cm respectively. The wavenumber difference between these stretching bands (∆ν
-1
62
=
165 cm ) is in accordance with the bridging bidentate structure of the Cu(C ) . In the
3
2
-1
adduct, the asymmetric stretching of the carboxylate was observed at 1583cm and two
-1
-1
different symmetric stretching were observed at frequencies of 1420 cm and 1393 cm .
Although a smaller distance between the asymmetric and symmetric stretchings
6
3
of the carboxylate with the chelating bidentate could be expected the intramolecular
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forces between the chelating ligand and the amide group red shift the symmetric band to
-1
1
393 cm in the adduct. Other important aspect that can be observed in the spectra is the
shift in the vibration frequency of the pyridine ring breathing motion, present in the INA
-1
-1
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
3
3
3
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4
4
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4
4
4
4
4
4
4
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5
5
5
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0
1
2
3
4
5
6
7
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9
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1
2
3
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2
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at 994 cm and in the adduct at 1029 cm , due to the monodentate coordination of the
pyridine ring with the Cu (II).
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-1
Table 3. Infrared peaks (cm ) and assignments of INA, Cu(C ) and the adduct Cu(C ) -
3
2
3 2
INA: ν stretching; δ bending; γ torsion; ω wagging; tw twisting; ρ rocking.
INA
Cu(C3)2
Cu(C ) -INA
Assignment
3 2
3361 s
3177 s
3296 s
3149 s
2986 w
2964 sh
2936 w
2879 w
1708 s
1640 m
1583 s
1583 s
1555 w
ν (NH )
asy
2
νsym (NH2)
ν (CH )
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
2
2
974 m
944 m
922 w
879 w
asy
3
νsym (CH3)
νsym (CH3)
ν (CH )
asy
2
1
655 m
νasy (C=O) amide
1621 m
NH deformation amide
2
-
1
585 s
ν (COO )
asy
1
1
586 s
551 s
ν pyridine ring
ν pyridine ring
δasy (CH3)
1
511 m
473 w
1459 w
1
δasy (CH3)
1460 m
δasy (CH3)
1466 w
415 s
ν pyridine ring
νsym (COO )
ν pyridine (CC)
-
1
420 s
1420 sh
1420 sh
1
in plane pyridine (CH)
1
383 w
1371 m
299 s
243 m
1393 s
δsym (CH )
νsym (COO )
3
-
1
393 s
1369 w
1304 sh
1289 w
δsym (CH3)
ν pyridine (CC)
ω (CH2)
1311 w
1
1
278 m
ω (CH2)
1
1229 m
1219 w
1151 m
1119 m
1077 w
1077 w
1066 s
1066 s
1009 w
1000 sh
1029 m
884 w
tw (CH2)
ν pyridine (CC)
1
1
219 m
148 w
ρ (NH )
asy
2
1122 m
C-CONH amide
2
1
087 w
δ pyridine (CH)
ν (CCα)
1
1
087 w
072 s
1
γ (CH3)
δ CCC ring
1
065 m
015 w
998 w
γ (CH3)
ν (CC)
ring breathing pyridine
994 m
8
8
93 s
11 s
ν (C CO)
α
8
52 s
861 m
809 s
breathing pyridine
γ (C H )
α
2
7
7
95 m
76 m
out of plane pyridine (CH)
ring breathing pyridine(CC)
out of plane ring deformation
γ (CH2)
754 m
764 w
764 w
754 m
99 w
65 m
7
6
21 m
68 m
out of plane ring deformation
-
6
δ (COO )
δ ring (CCC)
-
6
δ (COO )
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FTIR spectra of the adducts obtained by SAS (in ethanol at 313 K, 10 MPa and a
:2 molar ratio of Cu(C ) to INA) and slow evaporation are nearly identical as can be
1
3
2
expected from the PXRD patterns. Nevertheless, SAS spectrum shows a broadening of
-1
-1
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1
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the absorption bands at 1460 and 1393 cm and two new peaks at 1321 and 839 cm
(
none of them present in the FTIR spectra of pure INA or Cu(C ) which suggest the
3 2
presence of impurities in the SAS precipitate.
Figure 5. FTIR spectra: a) adduct obtained by slow evaporation; b) adduct obtained by
SAS using ethanol at 313 K, 10 MPa and a 1:2 molar ratio of Cu(C ) to INA; c)Cu(C ) ;
3
2
3 2
d) INA.
3
.2. Thermal behavior. DSC and TGA experiments were carried out to study the
thermal behavior of the adducts obtained by SAS and slow evaporation.
Thermal analysis by DSC of the adduct obtained by evaporation after cooling at
1
0 K/min is shown in Figure 6. DSC shows in the first heating a phase transition at 235.7
K associated to the conversion of structure II obtained from SCXRD at 100 K to structure
I obtained at 320 K. Furthermore, a small change in the heat capacity of the sample at
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19.7 K was also observed. This change could be related to the rotation of the pyridine
rings in the adduct. Isostructural phase transitions are common in mixed ligand complexes
or in coordination polymers.64, 65 In fact, small changes in the coordination environment
can affect drastically some of the properties of these materials, such as those related to
the magnetic and electrical properties of transition metals.
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In contrast, no phase transition was detected at low temperature in the sample
prepared by SAS, which could be possibly related to the much smaller particle size of this
sample. The reduction of the phase transition temperature with particle size and film
thickness has been previously reported.66, 67
Figure 6. DSC of the adduct obtained by slow evaporation. Sample was cooled down from room
temperature at 10 K/min up to 183 K and then heated at 10 K/min up to 360 K.
Thermogravimetric data of the adducts prepared by evaporation and SAS are
given in Figure 7. The adduct obtained by slow evaporation had an onset temperature on
melting of 482 K. The enthalpy of fusion could not be determined using DSC because
there is a mass loss associated to the fusion process (see Figure 7a) indicating a
decomposition, possibly due to an incongruent fusion and the presence of a peritectic
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point in the binary Cu(C ) -INA phase diagram, breaking the coordination and liberating
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the two components, INA and copper(II). The INA thus sublimed/evaporated producing
the observed loss of mass. This melting temperature was intermediate between the
sublimation/evaporation temperature of commercial INA (429 K), and the decomposition
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temperature reported for Cu(C ) (503 K). On the other hand, the adduct obtained via
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SAS in ethanol at 313 K and 10 MPa with a molar ratio 1:2 Cu(C ) to INA had a more
3 2
complex thermal behavior. It firstly showed an endothermic event with onset at 394 K
followed by an exothermic event. This endo-exo event had associated a loss of mass of
ca. 25% (measured using TGA).
Figure 7. Thermal analysis data: a) TGA and DSC (5 K/min) of the adduct obtained by
slow evaporation; b) TGA and DSC (5 K/min) of the adduct obtained by SAS in ethanol
at 313 K, 10 MPa and a 1:2 molar ratio Cu(C ) to INA ; c) TGA (10 K/min) and mass
3
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spectroscopy results for 44 m/z (red), 77 m/z (green) and 104 m/z (blue) of the adduct
obtained by slow evaporation; d) TGA (10 K/min) and mass spectroscopy results for 44
m/z (red), 77 m/z (green) and 104 m/z (blue) of the adduct obtained by SAS in ethanol at
313 K, 10 MPa and a 1:2 molar ratio Cu(C ) to INA.
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Decomposition behavior in N of the crystals prepared by slow evaporation was
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studied using mass spectrometry. Short after melting (429 K) commercial INA
sublimed/evaporated and mass loss could be observed in the TGA. In the adduct,
however, INA was stabilized and there was no mass loss until the melting temperature of
the adduct was reached at 482K. INA evaporated at this temperature and the characteristic
mass to charge ratios (m/z) of the INA at 77 m/z and 104 m/z could be clearly observed
along with other decomposition molecules suggesting the liberation of INA from the
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adduct and the same pyrolysis mechanism for the Cu(C ) as suggested elsewhere. The
3
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mechanism involved a self-redox reaction with the formation of metallic copper and
radicals of the carboxylic acid, that break into CO gas and fragments of alkyl chains
2
when heated. The decomposition behavior of the adduct obtained by SAS showed the
formation of mainly CO as mass loss starts. Although the release of INA starts at 429 K
2
(
sublimation of INA), the highest concentration of INA was reached after the 482 K
melting onset of the adduct), suggesting that most of the INA in the SAS precipitate was
(
in the adduct structure. The different thermal behavior of the sample prepared by SAS
seems to be related to the much smaller particle size which seems to prompt adduct
decomposition at a much lower temperature. Similar finding have been previously
reported.68
Micro-elemental analysis of the SAS samples are given as supplementary material
(Table S2). Whilst a 4.5 C:N molar ratio was obtained in the adduct prepared by
evaporation, slightly smaller ratios close to 4 were obtained in the samples precipitated
by SAS. The lower carbon content suggests partial decomposition of the sample.
Additionally the SAS experiment performed at a 1:1 molar ratio of Cu(C ) to INA (with
3 2
large Cu(C ) excess) also yielded the same C:N ratio.
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All these data suggest that the samples obtained by both techniques have the same
crystal structure but, in the compound processed by SAS, the adduct may be mixed with
other non-crystalline phase(s). DSC and TGA analysis point in the same direction
indicating the presence of more than one compound in the precipitate obtained by SAS.
The thermal behavior of Cu(C ) processed by SAS also showed that decomposition and
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mass loss started much earlier than expected. In this case, micro-elemental analysis
showed that the carbon content of the Cu(C ) sample processed by SAS was also lower
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than the theoretical one. The partial decomposition of the alkyl chain in Cu(C ) during
3
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the SAS process yielding Cu or CuO nanoparticles cannot be ruled out. The very small
size of these nanoparticles would make very difficult their detection. We are currently
studying the preparation of Cu nanoparticles from the pyrolysis of other copper
alkanoates. Experimental data seems to indicate that the SAS process leads to a mixture
of phases where the adduct is the major component.
4
. CONCLUSION
The preparation of a mixed-ligand complex or adduct with Cu(C ) and
3
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isonicotinamide has been carried out by two very different synthetic routes: a
conventional one (slow evaporation) and a novel one which involves the use of
supercritical CO as an antisolvent. By slow solvent evaporation large crystals were
2
prepared, whilst the SAS method rendered nanocrystals of the same adduct and non-
crystalline impurities, as seen by the different characterization techniques.
The complex was thoroughly characterized by SCXRD, PXRD, DSC, TGA,
microanalysis and FTIR. The structure, solved by XRD, shows that the molecules of INA
in this mixed ligand copper complex, coordinating the metal centers, act like capping
agents breaking the catenae, typical from copper (II) carboxylates. On the other hand, the
amide groups of INA form a net of H-bonds between the isolated binuclear complexes.
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DSC and TGA data show the stability of INA in the adduct at temperatures up to 482 K.
Mass spectroscopy indicates the sublimation and decomposition of INA around this
temperature.
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Finally, the use of SAS appears as a suitable method to synthesize mixed-ligand
complexes or adducts. Furthermore, these materials are solvent-free precipitates obtained
through a single-step process. The reduction in the particle size that would lead to an
enhanced bioavailability of the adduct and the semicontinuos nature of the process are
clear advantages of the SAS method in comparison to other more conventional methods.
The reduction in particle seems to shift the phase diagram to lower temperature and leads
to a much lower decomposition temperature. Further purification strategies should be
implemented in order to remove the impurities of the SAS product. Our work opens up
the path to the study of similar metal adducts using the SAS technique.
ASSOCIATED CONTENT
Supporting Information. Crystallographic information files (cif) of Cu (C3) INA :
2
4
4
CCDC-1846632 (at 100 K), and CCDC-1846633, at 320 K, solved by SCXRD, and
CCDC-1848049 (at 298 K) solved by PXRD.
In the Supporting information file: 1) PXRD patterns of the samples precipitated by SAS
at the different conditions (Figure S1). 2) High Resolution Powder Diffraction (HRPD)
and Rietveld refinements (Figure S2); 3) Experimental parameters and structure
refinement data from PXRD for the adducts obtained by slow evaporation and SAS (Table
S1). 4) SEM images of the sample prepared by SAS at 313 K and 10 MPa using methanol
as a solvent (Figure S3). 5) Microelemental analysis of the samples prepared by
evaporation and SAS at the different conditions (Table S2). This information is available
free of charge via the Internet at http://pubs.acs.org/.
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AUTHOR INFORMATION
Corresponding Authors
Francisco J. Martínez-Casado. Email: fmarcas@gmail.com
Albertina Cabañas, Email:a.cabanas@quim.ucm.es
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Author Contributions
The manuscript was written through contributions of all authors. All authors have given
approval to the final version of the manuscript.
ACKNOWLEDGMENT
We gratefully acknowledge the financial support of the Spanish Ministry of
Science and Innovation (MICINN), research project CTQ2013-41781-P and UCM-
Santander, research project PR75/18-21583. I.A.C. thanks MICINN for its support
through a FPI grant. The authors wish to thank the beamlines I711 and I911-3 (Max II
ring, MAX IV Laboratory) and the Centers of Scientific Instrumentation at the University
Complutense of Madrid (XRD and Electron Microscopy), and their staff, for the use of
their technical facilities and help.
REFERENCES
(
1)
containing liquid crystals. Coord. Chem. Rev. 1998, 178, 1485-1499.
(2) Bird, M. J.; Lomer, T. R., Crystal and molecular structure of anhydrous copper
butyrate. Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1972, B 28, 242-
46.
3)
Giroud-Godquin, A. M., My 20 years of research in the chemistry of metal
2
(
Simonov, Y. A.; Malinovs.Ti, Crystal structure of anhydrous copper propionate
Soviet Physics Crystallography, USSR. 1970, 15, 370-371.
2
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
4)
Mrozinski, J.; Heyduk, E.; Korabik, M., Magnetism of biologically active
copper(II) carboxylates. Monomer-dimer equilibrium. Bull. Pol. Acad. Sci., Chem. 1994,
2, 169-180.
5) Riesco, M. R.; Martinez-Casado, F. J.; Cheda, J. A. R.; Yelamos, M. I. R.; da
4
(
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Silva, I.; Plivelic, T. S.; Lopez-Andres, S.; Ferloni, P., New Advances in the One-
Dimensional Coordination Polymer Copper(II) Alkanoates Series: Monotropic
Polymorphism and Mesomorphism. Cryst. Growth Des. 2015, 15, 2005-2016.
(
6)
of copper(II) alkanoates Koord. Khim. 1992, 18, 882-890.
7) Cheda, J. A. R.; Garcia, M. V.; Redondo, M. I.; Gargani, S.; Ferloni, P., Short
chain copper(II) n-alkanoate liquid crystals. Liq. Cryst. 2004, 31, 1-14.
8) Riesco, M. R.; Casado, F. J. M.; Lopez-Andres, S.; Perez, M. V. G.; Yelamos, M.
Ilina, E. G.; Troyanov, S. I.; Dunaeva, K. M., Crystalline structure and volatility
(
(
I. R.; Torres, M. R.; Garrido, L.; Cheda, J. A. R., Monotropic polymorphism in copper(II)
decanoate. Cryst. Growth Des. 2008, 8, 2547-2554.
(9)
Riesco, M. R.; Martinez-Casado, F. J.; Cheda, J. A. R.; Yelamos, M. I. R.;
Fernandez-Martinez, A.; Lopez-Andres, S., Study of the Polymorphism in Copper(II)
Decanoate through Its Phase Diagram with Decanoic Acid, and Texture of the Columnar
Thermotropic Liquid Crystal Developable Domains in This and Similar Systems. Cryst.
Growth Des. 2015, 15, 497-509.
(10) Abied, H.; Guillon, D.; Skoulios, A.; Weber, P.; Giroudgodquin, A. M.; Marchon,
J. C., Investigation of the structures of the crystalline and columnar phases of linear-chain
copper (II) alkanoates. Liq. Cryst. 1987, 2, 269-279.
(
11) Mrozinski, J., New trends of molecular magnetism. Coord. Chem. Rev. 2005, 249,
2534-2548.
12) Chung, Y. H.; Wei, H. H.; Liu, Y. H.; Lee, G. H.; Wang, Y., Reinvestigation of
(
the crystal structure and cryomagnetic behaviour of copper(II) propionates. Polyhedron.
1998, 17, 449-455.
(
13) Riesco, M. R. Estudio estructural por XRD y calorimetría de alcanoatos de cobre,
litio, y otros metales. Thesis, Universidad Complutense de Madrid, Madrid, 2015.
14) Park, S. H.; Lee, Y. J.; Huh, Y. D., Inorganic-organic chain assemblies as lamellar
(
nanoreactors for growing one-dimensional Cu(OH) and CuO nanostructures. Chem.
2
Commun. 2011, 47, 11763-11765.
2
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(
15) Nasui, M.; Mos, R. B.; Petrisor, T.; Gabor, M. S.; Varga, R. A.; Ciontea, L.,
Synthesis, crystal structure and thermal decomposition of a new copper propionate
Cu(CH CH COO) • 2H O. J. Anal. Appl. Pyrolysis 2011, 92, 439-444.
3
2
2
2
(16) Kim, Y. H.; Kang, Y. S.; Lee, W. J.; Jo, B. G.; Jeong, J. H., Synthesis of cu
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
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4
4
4
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4
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5
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0
1
2
3
4
5
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7
8
9
0
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2
3
4
5
6
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0
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2
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0
1
2
3
4
5
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0
nanoparticles prepared by using thermal decomposition of Cu-oleate complex. Mol.
Cryst. Liq. Cryst. 2006, 445, 231-238.
(17) Dillon, C. T.; Hambley, T. W.; Kennedy, B. J.; Lay, P. A.; Zhou, Q. D.; Davies,
N. M.; Biffin, J. R.; Regtop, H. L., Gastrointestinal toxicity, antiinflammatory activity,
and superoxide dismutase activity of copper and zinc complexes of the antiinflammatory
drug indomethacin. Chem. Res. Toxicol. 2003, 16, 28-37.
(18) Blahova, M.; Sokolik, J.; Tumova, I.; Svec, P., Antiinflammatory activity of
aqua(cresoxyacetato)copper(II) complexes. Pharmazie. 1999, 54, 156-156.
(19) Abuhijleh, A. L., Mononuclear and binuclear copper (II) complexes of the
antinflammatory drug ibuprofen. Synthesis, characterization and catecholase-mimetic
activity. J. Inorg. Biochem. 1994, 55, 255-262.
(
20) Blahova, M.; Tumova, I.; Sokolik, J.; Gallasova, M.; Svec, P., Antiinflamatory
activity of aqua(aryloxyacetato)copper(II) complexes. Pharmazie. 1994, 49, 373-374.
21) Frechilla, D.; Lasheras, B.; Ucelay, M.; Parrondo, E.; Craciunescu, G.;
(
Cenarruzabeitia, E., On the mechanism of the antiinflamatory activity of some copper(II)
complexes Arzneim. Forsch. 1990, 40-2, 1008-1010.
(22) Frechilla, D.; Lasheras, B.; Ucelay, M.; Parrondo, E.; Craciunescu, G.;
Cenarruzabeitia, E., Antiinflamatory activity of some copper(II) complexes. Arzneim.
Forsch. 1990, 40-2, 914-917.
(23) Okuyama, S.; Hashimoto, S.; Aihara, H.; Willingham, W. M.; Sorenson, J. R. J.,
Copper complexes of non-steroidal antiinflammatory agents: Analgesic activity and
possible opioid receptor activation. Agents Actions. 1987, 21, 130-144.
(24) Sorenson, J. R. J., Antiinflamatory, antiulcer and analgesic activities of copper
complexes offer a physiological approach to treatment of rheumatoid arthritis. Recl.: J.
R. Neth. Chem. Soc. 1987, 106, 378-378.
(
25) Arnaud, C.; Beseme, F.; Sabbagh, I.; Gallet, J. P., Antiinflamatory activity of 5
copper-complexes. C. R. Acad. Sci., Ser. III. 1986, 302, 239-242.
26) Sorenson, J. R. J., Copper complexes in biochemistry and pharmacology. Chem.
Br. 1984, 20, 1110-1113.
(
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(
27) Petric, M.; Pohleven, F.; Turel, I.; Segedin, P.; White, A. J. P.; Williams, D. J.,
Complexes of copper(II) carboxylates with 2-aminoethanol - syntheses, characterization
and fungicidal activity; crystal structure of Cu(O CC H ) (NH C H OH) . Polyhedron.
2
8
17 2
2
2
4
2
1
998, 17, 255-260.
0
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(28) Williams, C. J.; Morris, H.; Svorec, J.; Valkova, M.; Valko, M.; Moncol, J.;
Mazur, M.; Valach, F.; Melnik, M., A study of copper(II) carboxylato complexes with
the biological ligands nicotinamide and papaverine. J. Mol. Struct. 2003, 659, 53-60.
(29) Golobic, A.; Ozbolt, L.; Pohleven, F.; Leban, I.; Segedin, P., Synthesis,
characterization, crystal structures and fungicidal activity of some copper(II) carboxylates
with 3-hydroxypyridine. Acta Chim. Slov. 2006, 53, 238-244.
(30) Palanti, S.; Feci, E.; Predieri, G.; Francesca, V., Copper complexes grafted to
amino-functionalized silica gel as wood preservatives againt fungal decay: mini-blocks
and standard test. Bioresource.s 2012, 7, 5611-5621.
(31) Kozlevcar, B.; Leban, I.; Turel, I.; Segedin, P.; Petric, M.; Pohleven, F.; White,
A. J. P.; Williams, D. J.; Sieler, J., Complexes of copper (II) acetate with nicotinamide:
preparation, characterization and fungicidal activity; crystal structures of [Cu (O CCH )
3 4
2
2
(nia)] and [Cu (O CCH ) (nia) ]. Polyhedron. 1999, 18, 755-762.
2 2 3 4 2
(32) de Souza, R. A.; Stevanato, A.; Treu, O.; Netto, A. V. G.; Mauro, A. E.;
Castellano, E. E.; Carlos, I. Z.; Pavan, F. R.; Leite, C. Q. F., Antimycobacterial and
antitumor activities of Palladium(II) complexes containing isonicotinamide (isn): X-ray
structure of trans-[Pd(N ) (isn) ]. Eur. J. Med. Chem. 2010, 45, 4863-4868.
3 2
2
(33) Aakeroy, C. B.; Beatty, A. M.; Desper, J.; O'Shea, M.; Valdes-Martinez, J.,
Directed assembly of dinuclear and mononuclear copper(II)-carboxylates into infinite 1-
D motifs using isonicotinamide as a high-yielding supramolecular reagent. Dalton Trans.
2
003, 3956-3962.
(34) Bathori, N. B.; Lemmerer, A.; Venter, G. A.; Bourne, S. A.; Caira, M. R.,
Pharmaceutical Co-crystals with Isonicotinamide-Vitamin B3, Clofibric Acid, and
Diclofenac-and Two Isonicotinamide Hydrates. Cryst. Growth Des 2011, 11, 75-87.
(35) Kozlevcar, B.; Lah, N.; Zlindra, D.; Leban, I.; Segedin, P., Copper(II) benzoates
and acetates with 2-aminopyridine. Acta Chim. Slov. 2001, 48, 363-374.
(36) Kozlevcar, B.; Lah, N.; Makuc, S.; Segedin, P.; Pohleven, F., Copper(II)
carboxylates - Synthesis, structure and biological activity. IV. Fatty acid copper(II)
carboxylates with urea. Acta Chim. Slov. 2000, 47, 421-433.
2
8
ACS Paragon Plus Environment

Page 29 of 32
Crystal Growth & Design
1
2
3
4
5
6
7
8
9
(
37) Jaskova, J.; Miklos, D.; Korabik, M.; Jorik, V.; Segl'a, P.; Kalinakova, B.;
Hudecova, D.; Svorec, J.; Fischer, A.; Mrozinski, J.; Lis, T.; Melnik, M., Synthesis,
spectral and magnetic properties and crystal structures of copper(II) pyridinecarboxylates
as potential antimicrobial agents. Inorg. Chim. Acta 2007, 360, 2711-2720.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
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0
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9
0
(38) Padrela, L.; Rodrigues, M. A.; Tiago, J.; Velaga, S. P.; Matos, H. A.; de Azevedo,
E. G., Insight into the Mechanisms of Cocrystallization of Pharmaceuticals in
Supercritical Solvents. Cryst. Growth Des. 2015, 15, 3175-3181.
(39) Lopez-Periago, A. M.; Portoles-Gil, N.; Lopez-Dominguez, P.; Fraile, J.; Saurina,
J.; Aliaga-Alcalde, N.; Tobias, G.; Ayllon, J. A.; Domingo, C., Metal-Organic
Frameworks Precipitated by Reactive Crystallization in Supercritical CO . Cryst. Growth
2
Des. 2017, 17, 2864-2872.
(40) Lopez-Periago, A.; Vallcorba, O.; Domingo, C.; Ayllon, J. A., Hollow
Microcrystals of Copper Hexafluoroacetylacetonate-Pyridine Derivative Adducts via
Supercritical CO2 Recrystallization. Cryst. Growth Des. 2016, 16, 1725-1736.
(
41) Matsuyama, K., Supercritical fluid processing for metal-organic frameworks,
porous coordination polymers, and covalent organic frameworks. J. Supercrit. Fluids.
018, 134, 197-203.
42) Cuadra, I. A.; Cabañas, A.; Cheda, J. A. R.; Martinez-Casado, F. J.; Pando, C.,
2
(
Pharmaceutical co-crystals of the anti-inflammatory drug diflunisal and nicotinamide
obtained using supercritical CO as an antisolvent. J. CO Util. 2016, 13, 29-37.
2
2
(43) Cuadra, I. A.; Cabanas, A.; Cheda, J. A. R.; Pando, C., Polymorphism in the co-
crystallization of the anticonvulsant drug carbamazepine and saccharin using supercritical
CO as an anti-solvent. J. Supercrit. Fluids. 2018, 136, 60-69.
2
(44) Pando, C.; Cabañas, A.; Cuadra, I. A., Preparation of pharmaceutical co-crystals
through sustainable processes using supercritical carbon dioxide: a review. RSC Adv.
2
016, 6, 71134-71150.
(45) Machida, H.; Takesue, M.; Smith, R. L., Green chemical processes with
supercritical fluids: Properties, materials, separations and energy. J. Supercrit. Fluids.
2
011, 60, 2-15.
46) Lagalante, A. F.; Hansen, B. N.; Bruno, T. J.; Sievers, R. E., Solubilities of
copper(II) and chromium(III) β-diketonates in supercritical carbon dioxide. Inorg. Chem.
995, 34, 5781-5785.
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