Crystal habit modification of Cu(ii) isonicotinate-N-oxide complexes using gel phase crystallisation

Article abstract of DOI:10.1039/c8nj05036h

We report the crystallisation of three forms of the copper(ii) isonicotinate-N-oxide complex and their phase interconversion via solvent-mediated crystal-to-crystal transformation. The different forms of the copper complex have been isolated and character

Full text of DOI:10.1039/c8nj05036h

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Crystal habit modification of Cu(II) isonicotinate–
N-oxide complexes using gel phase
crystallisation†
Cite this: New J. Chem., 2018,
42, 19963
a
a
Dipankar Ghosh,a Katja Ferfolja,
Zygimantas Drabavicius,
ˇ
ˇ
Jonathan W. Steed *b and Krishna K. Damodaran
*
a
We report the crystallisation of three forms of the copper(II) isonicotinate–N-oxide complex and their
phase interconversion via solvent-mediated crystal-to-crystal transformation. The different forms of the
copper complex have been isolated and characterised by single crystal X-ray diffraction. Gel phase
crystallisation performed in hydrogels, low molecular weight gels and gels of a tailored gelator showed
crystal habit modification. Crystallisation in aqueous ethanol resulted in the concomitant formation of
blue (form-I) and green (form-II/IV) crystals while the use of a low molecular weight gel resulted in the
selective crystallization of the blue form-I under identical conditions. Comparison of the gel phase and
the solution state crystallisation in various solvent compositions reveals that the blue form-I is the
thermodynamically stable form under ambient conditions.
Received 4th October 2018,
Accepted 1st November 2018
DOI: 10.1039/c8nj05036h
rsc.li/njc
because of their versatility, stimuli-responsive properties and
often facile synthesis. Gel phase crystallisation results in the
Introduction
Supramolecular gels based on low molecular weight gelators shutdown of convection currents leading to diffusion limited
(LMWGs)1–9 have witnessed tremendous growth over the last growth, and the gel fibres can provide an active surface for
decade due to their emerging potential applications5–8 such as heterogeneous nucleation. There have been a few recent reports
dynamic behaviour, use as cell growth media, drug delivery and of crystallisation within gels based on LMWGs21,26–30 and small-
as media to control crystal growth. Gel phase crystallisation in molecule supramolecular hydrogels have been used to crystallise
hydrogels is a classical technique for inorganic compounds and pharmaceuticals such a modafinil26 and carbamazepine.21
biomolecules such as proteins.11–15 The gel environment can An inert gel matrix based on LMWGs (without drug-specific
influence the properties16–22 such as crystal habit, crystal size functionality) has been shown to influence the pharmaceutical
and polymorphism. Polymorphism depends on a number of crystallisation solid form and habit outcomes.29 Efforts have
factors including the nucleation rate, which can give rise to the also been made to develop supramolecular gel phase crystallisation
simultaneous crystallisation of two or more polymorphs with using a gelator that mimics the anticancer drug cisplatin. This
similar nucleation rates, known as concomitant polymorphism.23 resulted in the crystal habit modification of cisplatin and the
For decades, researchers have been using various techniques isolation of a novel solvate form.28 LMWGs that are structurally
such as evaporative crystallization, solution cooling, melt similar to the crystallisation substrate have been shown to give rise
crystallization and sublimation24,25 to search for polymorphic to the selective crystallisation of the metastable R polymorph of
modifications. While these methods are highly effective, they the highly polymorphic drug precursor ROY.31 The gel phase
can sometimes fail to efficiently isolate slow-nucleating forms. crystallisation of isoniazid gives rise to significant differences in
LMWGs can provide various advantages as crystal growth media the crystal habit and crystal size compared to solution control
experiments.22 In 2004, Hamilton’s group demonstrated the use
of a hydrogel medium to crystallize calcite,32 while Gunnlaugsson’s
a Department of Chemistry, Science Institute, University of Iceland, Dunhagi 3,
group reported that supramolecular gels can be used to produce
single crystal nanowires based on NaCl, KCl, and KI in a gel
medium.33 In the present work, we report the use of LMWGs as
crystallisation media for coordination compounds, which display
several crystalline forms varying in the copper coordination
environment. Specifically, we have selected the complexes of
copper(II) with isonicotinic acid–N-oxide, which exhibits three
´
107 Reykjavık, Iceland. E-mail: krishna@hi.is; Fax: +354 552 8911;
Tel: +354 525 4846
b Department of Chemistry, Durham University, South Road, Durham DH1 3LE, UK.
E-mail: jon.steed@durham.ac.uk
† Electronic supplementary information (ESI) available: Crystallisation of Cu(II)
complexes, details of gelation experiments and gel phase crystallisation, and
comparison of PXRD of form-IV. CCDC 1846767. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c8nj05036h
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by distillation over Mg turnings and iodine.66 1H-NMR and
13C-NMR spectra were recorded on a Bruker Advance 400
spectrometer. Single crystal X-ray diffraction (SCXRD) was
performed on a Bruker D8 venture, and powder X-ray diffraction
(PXRD) was carried out using a Bruker D8 Focus instrument.
The morphology of the xerogel was analysed by Scanning
Electron Microscopy (SEM) using a Leo Supra 25 Microscope.
Synthesis
3,30,300-((Benzene-1,3,5-tricarbonyl)tris(azanediyl))tris-(pyridine
1-oxide) (L-3Nox). To a solution of N1,N3,N5-tri(pyridin-3-
yl)benzene-1,3,5-tricarboxamide (0.88 g, 2.0 mmol) in hot
methanol (50 mL), m-chloroperbenzoic acid (1.86 g, 10.8 mmol)
was added in portions over a period of 15 minutes. The reaction
mixture was refluxed at 70 1C overnight. The mixture was
cooled to room temperature. The solid obtained was filtered,
washed with water followed by methanol, dried and the product
was obtained as a white powder (0.76 g, 1.6 mmol). Yield:
78.0%. 1H NMR (400 MHz, DMSO-d6) d: 10.95 (3H, s), 8.86 (3H,
s), 8.74 (3H, s), 8.05 (3H, d, J = 6.4), 7.71 (3H, d, J = 8.4), 7.46
(3H, dd, J = 8.6, 6.2). 13C NMR (100 MHz, DMSO-d6) d: 164.78,
138.10, 134.69, 134.40, 131.01, 130.51, 126.23, 116.84. HRMS
(m/z) calcd for C24H18N6O6Na: 509.118; found: 509.118 [M ꢁ Na+].
Anal. data for C24H18N6O6: calc. C, 59.26; H, 3.73; N, 17.28.
Found: C, 59.10; H, 3.82; N, 17.00.
[Cu(C6H4NO3)2(H2O)2] (form-I). 27.8 mg (0.2 mmol) of isonico-
tinic acid–N-oxide was dissolved in water (8.5 mL)/ethanol (1.5 mL)
mixture and was layered over 5 mL aqueous solution of
Cu(NO3)2ꢀ3H2O (24.1 mg, 0.1 mmol). Slow evaporation of the
mixture resulted in blue crystals of form-I in 3–4 days.34
[Cu(l-C6H4NO3)2(H2O)]n (form-II). 27.8 mg (0.2 mmol) of
isonicotinic acid–N-oxide was dissolved in ethanol (10 mL) and
layered over ethanolic solution (5 mL) of Cu(NO3)2ꢀ3H2O (24.1 mg,
0.1 mmol) and the vial was sealed. Plate shaped green crystals of
form-II were obtained in 3–4 days.36
Scheme 1 Molecular structures of three copper(II) isonicotinate–N-oxide
complexes deposited in the Cambridge Structural Database.10
forms34–36 deposited within the Cambridge Structural Database10
and these complexes can be easily isolated (Scheme 1). These
three forms of the copper(II) isonicotinate–N-oxide complex are a
discrete square planar diaqua species bound through mono-
dentate carboxylate oxygen atoms [Cu(C6H4NO3)2(H2O)2] (blue,
form-I, CSD refcode BUXDED), a square pyramidal aqua
complex involving bridging ligands bound by both carboxylate
and N-oxide oxygen atoms [Cu(m-C6H4NO3)2(H2O)]n (green, form-II,
CSD refcode BEJCID) and a trinuclear hydroxyl-bridged species
[Cu(H2O)(m-OH)2{Cu(C6H4NO3)2(H2O)2}2]ꢀ2H2O (green, form-III,
CSD refcode BULWIO), formed under basic conditions. A fourth
form of formula [{Cu(C6H4NO3)2}{Cu(C6H4NO3)NO3}2]n (green,
form-IV) is reported herein.‡ The gelators are based on the amide
N–HꢀꢀꢀO supramolecular synthon, an important class of stimuli-
responsive supramolecular gels7,37–53 with tuneable properties.
Supramolecular gels based on trimesic amide derivatives33,54–65
have been selected as gel media due to their typically very low
minimum gel concentration (MGC). The candidate gel mimicking
the pyridine N-oxide functional group of the isonicotinic acid–N-
oxide ligand is reported.
[{Cu(C6H4NO3)2}{Cu(C6H4NO3)NO3}2]n (form-IV). 27.8 mg
(0.2 mmol) of isonicotinic acid–N-oxide and 24.1 mg (0.1 mmol)
of Cu(NO3)2ꢀ3H2O were added to 2 mL of ethanol and the
mixture was heated at 85 1C in a sealed vial. Block shaped
green crystals of form-IV were obtained overnight at 85 1C. Anal.
data for C24H16Cu3N6O18: calc. C, 33.25; H, 1.86; N, 9.69. Found:
C, 33.16; H, 1.94; N, 9.70.
Experimental
Materials and methods
All starting materials were purchased from Sigma Aldrich and
were used as supplied. The tris-amide of trimesic acid with
L-valine methyl ester (Val-TMA)62 and aminopyridine54 were
synthesised following the reported procedures. The tailored
N-oxide compound was synthesised by oxidizing the pyridyl
group of tris-pyridyl trimesic amide.54 Deionized water was
used for all the experiments and absolute ethanol was obtained
Single crystal X-ray diffraction
X-ray quality single crystals of form-IV were isolated from
mother liquor, immediately immersed in cryogenic oil and then
mounted. The diffractions were collected using MoKa radiation
(l = 0.71073 Å) on a Bruker D8 Venture (Photon100 CMOS
detector) diffractometer equipped with a Cryostream (Oxford
Cryosystems) open-flow nitrogen cryostats at a temperature of
‡ Crystal data for the Cu(II)–isonicotinic acid–N-oxide complex (form-IV): 150.0(2) K. The unit cell determination, data collection, data
C24H16Cu3N6O18, FW = 867.05, monoclinic, P21/n, a = 8.892(2), b = 15.096(4),
reduction, structure solution/refinement and empirical absorption
correction (SADABS) were carried out using Apex-III (Bruker AXS:
c = 11.178(3) Å, b = 103.646(9)1, V = 3443(3) Å3, Z = 4, Dc = 1.975 cm3, F(000) = 866,
and T = 150 K. Final residuals (for 242 parameters) were R1 = 0.0218 for 3288
Madison, WI, 2015). The structure was solved by a direct method
reflections with I 4 2s(I), and R1 = 0.0218, wR2 = 0.0581, and GOF = 0.989 for all
and refined by the full-matrix least squares on F2 for all data using
3052 reflections. CCDC 1846767 contains the supplementary crystallographic
data for this paper.
SHELXTL67 and Olex268 software. All non-disordered non-hydrogen
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atoms were refined anisotropically except for the disordered oxygen Gel phase crystallisation
atom of the nitrate group, where the free variables were refined by
the FVAR instruction. All the hydrogen atoms were placed in the
calculated positions and refined using a riding model.
Crystallisation of Cu(NO3)2ꢀ3H2O and isonicotinic acid–N-oxide
was performed in the presence of hydrogelators (agarose and
gelatin) and low molecular weight gelators (LMWGs). In a
typical experiment, isonicotinic acid–N-oxide (2 equivalent)
and the gelator were dissolved together in water (for agarose
and gelatin) and then Cu(NO3)2ꢀ3H2O (1 equivalent) was added.
The solution was sonicated and left undisturbed to form the gel
and crystallise. For Val-TMA and L-3Nox, isonicotinic acid–N-
oxide and the gelator were dissolved in a polar organic solvent
(DMF or DMSO) and Cu(NO3)2ꢀ3H2O and water were added to
this mixture in the quantities given below.
Crystallisation in agarose. Isonicotinic acid–N-oxide (13.9 mg,
0.1 mmol) and agarose (6.0 mg) were dissolved in water (1 mL) by
heating, and Cu(NO3)2ꢀ3H2O (12.1 mg, 0.05 mmol) was added to
the resulting solution. X-ray quality crystals of form-I were
obtained in 2 days.
Gel phase crystallisation in Val-TMA. Isonicotinic acid–N-
oxide (27.8 mg, 0.2 mmol) and Val-TMA (40.0 mg, 4.0 wt%) were
dissolved in DMF (0.5 mL) by heating and sonicating. Water
(0.5 mL) and Cu(NO3)2ꢀ3H2O (24.1 mg, 0.1 mmol) were added to
this solution, and the mixture was left undisturbed to form
a blue gel. X-ray quality crystals of form-I were obtained in
2–3 days.
Gel phase crystallisation in L-3Nox. Isonicotinic acid–N-
oxide (27.8 mg, 0.2 mmol) and L-3Nox (8.0 mg) were dissolved
in DMSO (0.5 mL) by heating and sonicating. Water (0.5 mL)
and Cu(NO3)2ꢀ3H2O (24.1 mg, 0.1 mmol) were added to this
solution and leaving the mixture undisturbed yielded a blueish
green gel. X-ray quality single crystals of form-I were obtained
in 2 days.
Gelation properties of tailored N-oxide compounds
The gelating ability of L-3Nox was screened in various solvent
systems (see the ESI†). The gelator was soluble only in highly
polar solvents such as DMF, DMA and DMSO and gels were
formed only in DMSO/water mixtures. In a typical experiment,
the compound was dissolved in a required amount of DMSO by
heating and sonicating followed by the addition of water. The
mixture was then sonicated to form a suspension, and left
undisturbed to form a gel. The gel formation was confirmed by
the inversion test.
Minimum gelation concentration. Various amounts (1.0 to
5.0 mg) of L-3Nox gelator were taken in standard vials (7 mL)
and 0.5 mL of DMSO was added. The solution was heated and
sonicated to dissolve the compound followed by the addition of
0.5 mL water, and the resulting mixture was left undisturbed to
form the gel. After 24 hours, the gel formation was checked by
an inversion test. The lowest concentration at which the gel was
formed was recorded as the minimum gel concentration (MGC).
Gel–sol transition temperature. The required amount of
L-3Nox gelator was taken in a standard 7 mL vial and the gel
was prepared in DMSO/water (1 : 1 v/v) as per the above procedure.
After 24 hours, a small spherical glass ball weighing 92.0 mg was
placed on the gel surface, and the gel was heated gradually in an
oil bath. The temperature at which the ball touched the bottom of
the vial was recorded as the gel–sol transition temperature (Tgel).
Crystallisation experiments
Crystal-to-crystal transformation: transformation of a blue
complex (form-I) to a green polymer (form-II). Form-I (3.0 mg)
was added to absolute ethanol (10 mL) in a standard vial. The
Results and discussion
Solution phase crystallization
vial was sealed to prevent the evaporation of ethanol and left Layering an ethanolic solution of Cu(NO3)2ꢀ3H2O over an aqueous
without disturbance. Green crystals of form-II were obtained ethanolic solution (5% of water, v/v) of isonicotinic acid–N-oxide at
over the course of one week and were characterized by SCXRD. a 1 : 2 metal–ligand ratio results in the formation of a mixture of
Transformation of a green polymer (form-II) to a blue blue and green crystals over a period of three days (Fig. S1, ESI†).
complex (form-I). Water (1 mL) was added to form-II (3.0 mg). These crystals were isolated, and the structure was determined by
Excess water was avoided since form-II is sparingly soluble in single crystal X-ray diffraction. This technique shows that the
water. The transparent green crystals almost instantly turned into samples match with the reported structures, namely form-I (blue
an opaque blue material and the mixture was left undisturbed. crystals) and form-II (green crystals).34,36 Formation of the
X-ray quality blue crystals of form-I were obtained in 2–3 days and hydroxyl-bridged species form-III is not expected under these
were characterized by SCXRD.
conditions due to the absence of a base.35 Basic conditions were
Transformation of a green polymer (form-IV) to a blue not investigated because of the effect of changing pH on the
complex (form-I). Water (1 mL) was added to form-IV (3.0 mg) gelation process in LMWGs.69
in a standard vial. X-ray quality blue crystals were obtained in
2–3 days and characterized by SCXRD.
We have optimized the crystallisation conditions for these
two forms and confirmed that crystallisation depends on the
Scanning electron microscopy. The gelator (L-3Nox) was ethanol/water ratio. Form-I can be obtained in aqueous ethanol
dissolved in 0.7 mL of DMSO, the mixture was heated and containing 410% of water (v/v), whereas the green form-II is
sonicated, and 0.3 mL of water was added to form the gel. The gel formed at lower water content (o3.5% of water, v/v). Both forms
was filtered through a filter paper after 24 hours and the residue are obtained simultaneously from aqueous ethanol containing
was air-dried in a fume hood. The xerogels were gold coated and 7% water (v/v). The monoaqua form-II transforms into the
SEM was performed using a Leo Supra 25 Microscope.
diaqua form-I over three days, presumably due to the absorption
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formula [{Cu(C6H4NO3)2}{Cu(C6H4NO3)NO3}2]n, which displays
two different Cu(II) centres with distorted octahedral and
square pyramidal geometries (Fig. 2a). The oxygen atoms of
the carboxylate moiety of the isonicotinate–N-oxide ligands are
coordinated to the two Cu(II) centres in a bidentate fashion
forming an eight-membered metallo-macrocycle.
The Cu(II) centres in the metallo-macrocycle display square
pyramidal geometry with oxygen atoms of the N-oxide moiety,
the nitrate anion and two carboxylate moieties in the equatorial
site, and the axial position is coordinated to the oxygen atom
of the carboxylate moiety. The oxygen atoms of the N-oxide
moieties of isonicotinate–N-oxide in the metallo-macrocycle are
coordinated to the Jahn–Teller distorted octahedral Cu(II)
centre. In the octahedral Cu(II) centre, four isonicotinate–N-
oxide ligands are coordinated to the equatorial position of the
metal centre (two oxygen atoms of the N-oxide moiety and
two carboxylate oxygen atoms), and the axial positions are
coordinated to the oxygen atoms of the N-oxide moiety.
The oxygen atom of the N-oxide moiety displays a bridging
coordination mode and binds to the equatorial position of the
distorted octahedral and square pyramidal copper(II) centres
resulting in a complex 3-D network (Fig. 2b). Form-IV was
found to convert to form-I when immersed in water (confirmed
by single crystal X-ray diffraction).
Fig. 1 Solvent mediated crystal-to-crystal transformation of form I and
form-II.
of moisture from the mother liquor. The effect of temperature
was studied by comparing the room temperature and low
temperature (ꢁ15 1C) crystallisation for both forms. The yields
of the single crystals in both cases were low compared to room
temperature crystallisation. We have also performed low tem-
perature crystallisation for form-I and form-II and interestingly,
form-II does not disappear from the mixture even after three
weeks. The conversion of green to blue crystals prompted us
to explore the solvent-mediated solid-state transformation of
form-I and form-II. Crystals of form-I were isolated, immersed
in absolute ethanol and the crystals underwent conversion to
green form-II over five days (Fig. 1). Similarly, treating form-II
with water resulted in form-I overnight. The transformation
of form-I to form-II was found to be reversible, which was
confirmed by single crystal X-ray diffraction.
Gel phase crystallization
The existence of at least four distinct copper(II) isonicotinate–N-
oxide complexes prompted us to explore the selective crystallisation
of this system in gel media. The copper(II) isonicotinate–N-oxide
compounds were initially crystallised in gels of commercially avail-
able hydrogelators, namely agarose and gelatin. A blue gel was
obtained by dissolving Cu(NO3)2ꢀ3H2O, isonicotinic acid–N-oxide
and agarose in hot water, which subsequently produced X-ray
quality crystals of blue form-I upon cooling. Crystallisation experi-
ments performed at various concentrations of agarose, Cu(NO3)2ꢀ
3H2O and isonicotinic acid–N-oxide gave similar results; however,
experiments with low concentration of metal salt and ligand did not
yield any solid product. Crystals of isonicotinic acid–N-oxide (CSD
refcode XUCPAO) were obtained at a higher concentration of metal
salt and ligand. Experiments performed with 1 : 1 ethanol/water (v/v)
gave similar results. Use of gelatin hydrogels as the crystallization
medium resulted in blue gels, but crystals were not formed even
after several weeks. Neither gelatin nor agarose formed gels in
absolute ethanol. We then turned our attention to LMWGs based on
Val-TMA62 (Scheme 2 and ESI†).
Heating copper(II) nitrate and isonicotinic acid–N-oxide at
85 1C in ethanol in a sealed vial resulted in block-shaped green
crystals, a morphology that contrasts to the plate shaped
form-II. Single crystal X-ray analysis of the block-shaped green
crystals revealed a new coordination polymer (form-IV)‡ of the
Gel phase crystallisation was performed by mixing copper(II)
nitrate trihydrate and isonicotinic acid–N-oxide at a 1 : 2 metal–
ligand ratio with the gelator (4.0 wt%) in ethanol/water and
DMF/water (1 : 1, v/v respectively). This resulted in blue crystals
of form-I after two days (confirmed by single crystal X-ray
diffraction). The formation of form-I in this ‘generic’ supra-
molecular gel medium prompted us to investigate the crystal-
lisation of copper(II) isonicotinate–N-oxide complexes in the
tailored LMWG gel, which is structurally similar to the crystal-
lisation substrate. Recently we have shown that the tailored
LMWG gel can enable selective crystallisation31 of particular
Fig. 2 (a) Molecular structure of form-IV [{Cu(C6H4NO3)2}{Cu(C6H4NO3)-
NO3}2]n, (b) representation of crystal structure showing octahedral (purple)
and square pyramidal (green) metal centres and (c) interconnected octahedral
and square pyramidal geometry.
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Scheme 2 Chemical structure of a non-tailored gelator (Val-TMA) and a
tailored N-oxide gelator (L-3Nox).
polymorphs of the olanzapine precursor, ROY.70 We have also
reported the formation of crystalline materials in a supramolecular
gel matrix of copper(II) metallogels with pyridyl amides.71
Fig. 4 SEM image of L-3Nox xerogel at 0.5 wt% obtained from DMSO/
water (7 : 3, v/v).
The gelator design involves trimesic pyridyl amide based
compounds,7,37 which show two types of hydrogen bonding
motifs, one through a N–Hꢀ ꢀ ꢀO synthon involving the amide
moiety and the other through a N–Hꢀ ꢀ ꢀN synthon involving the
amide and the pyridyl ring nitrogen atom. Thus, a tailored gel
was designed for the copper(II) isonicotinate–N-oxide system by
modifying the pyridyl groups of trimesic amides to give N-oxides.
In this context, we prepared a tailored tris-N-oxide compound
(L-3Nox, Scheme 2) by oxidising N,N0,N00-tris(3-pyridyl)-trimesic
amide54 with m-chloroperbenzoic acid (ESI†). The gelation
properties of L-3Nox were tested in aqueous solutions of highly
polar DMSO, due to its poor solubility in other solvents. L-3Nox
formed gels in various mixtures of DMSO and water (ESI†) and
the gel formation was confirmed by an inversion test (Fig. 3). We
selected a 7 : 3 DMSO/water mixture (v/v) for L-3Nox since the gel
was transparent at this composition. The thermal stability of the
tailored gel was evaluated by analysing the temperature at which
the gel was converted into a liquid phase (Tgel). Tgel was found to
be 107 1C at 0.5 wt% and the minimum gel concentration (MGC)
was 0.15 wt% in the DMSO/water (7 : 3, v/v) mixture. Tgel and
MGC were 105 1C at 0.5 wt% and 0.3 wt% in the 1 : 1 DMSO/
water (v/v) mixture. Thus, replacing the pyridyl group with
pyridyl N-oxide has a significant effect on the MGC of L-3Nox
(0.15 wt%) compared to N,N0,N00-tris(3-pyridyl)-trimesic amide
(0.03 wt%) in the DMSO/water (7 : 3, v/v) mixture.54
Scanning electron microscopy (SEM) was performed on the
xerogel of L-3Nox to elucidate the morphology of the xerogels
(Fig. 4), which clearly indicates the fibrous nature of the gel
network, and twisted fibres were observed in L-3Nox. The
thickness of the individual fibres was found to be 20–40 nm
and these fibres combine to form bundles with thickness
ranging from 100 to 150 nm.
Gel phase crystallisation was performed by mixing copper(II)
nitrate trihydrate and isonicotinic acid–N-oxide at a 1 : 2 metal–
ligand ratio with L-3Nox gelator in DMSO/water. The mixture
was heated to give a clear green solution and left without
disturbing for 2 hours to form the gel (ESI†). The crystallisation
experiments were performed at a higher concentration of L-3Nox
gelator (greater than the MGC) to ensure gel formation. The
crystallisation experiments were also performed with varying
amounts of copper(II) nitrate trihydrate and isonicotinic acid–N-
oxide. A greenish-blue gel was formed in an hour in all cases for
L-3Nox gelator at 0.8 wt% in 1 : 1 (v/v) DMSO/water. The optimized
concentration for crystallisation was found to be 0.06 mmol of
copper(II) nitrate trihydrate and 0.12 mmol isonicotinic acid–N-
oxide. Crystals were not formed for experiments with a lower
metal–ligand concentration, whereas a concentration of 0.06 mmol
or more copper(II) nitrate trihydrate produced blue crystals (form-I)
in a week (Fig. 5c).
We have compared the morphologies of form-I crystals
obtained from the gel phase crystallisation in different gelators.
The solution phase crystallisation in an ethanol/water mixture
without a gelator resulted in block shaped crystals. Similar crystals
Fig. 3 Gels obtained from (a) agarose in water, (b) gelatin in water,
(c) Val-TMA in DMF/water (1: 1 v/v), (d) Val-TMA in ethanol and (e) L-3Nox
in DMSO/water (1: 1 v/v).
Fig. 5 Gel phase crystallisation of Cu(II) complexes from (a) agarose gel in
water (1.5 wt%), (b) Val-TMA gel at 4.0 wt% in DMF/water (1 : 1, v/v) and
(c) L-3Nox gel at 0.8 wt% in DMSO/water (1 : 1, v/v).
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Fig. 6 Images of isolated crystals from (a) solution phase, (b) agarose gel,
(c) Val-TMA gel and (d) L-3Nox gel.
of form-I were obtained in water with very low yield due to the
crystallisation of the isonicotinic acid–N-oxide ligand. The gel
phase crystallisation of the complex in an agarose gel yielded
block-shaped crystals (Fig. 6). However, plate shaped crystals were
obtained from Val-TMA and L-3Nox tailored gels indicating that
the presence of similar functional groups in the gelator plays a role
in crystal morphology. Crystallisation of copper(II) isonicotinate–N-
oxide complexes was also performed in ethanolic supramolecular
gel media. Since the tailored gelator and agarose do not form gels
in absolute ethanol or a mixture of ethanol and other solvents, the
gel phase crystallisation in ethanol was performed only with
Val-TMA gelator. Adding copper(II) nitrate to a hot solution of
isonicotinic acid–N-oxide and Val-TMA in absolute ethanol led to a
green solution, which subsequently formed a green gel. However,
crystals of Cu(II) isonicotinate–N-oxide complex were not formed
and isonicotinic acid–N-oxide crystallised due to its poor solubility
in ethanol at ambient temperature. The solubility of isonicotinic
acid–N-oxide was increased by adding a trace amount of water.
Thus, a mixture of isonicotinic acid–N-oxide (27.8 mg, 0.2 mmol)
and Val-TMA (4.0 wt%) was heated in the ethanol/water (5% water,
v/v) mixture, and copper(II) nitrate (24.1 mg, 0.1 mmol) was added
to yield a green solution and the vial was sealed. The solution
turned into a greenish blue gel in 15 minutes, and the blue colour
intensified overnight resulting in blue crystals of form-I in the gel
medium (Fig. 7a and b). Blue crystals of form-I were formed in
almost every case, with one out of 25 trails forming green crystals
of form-II, which might be due to accidental heteroseeding.
Experiments were performed under identical conditions (the same
solvent composition and the same concentration of copper(II)
nitrate and isonicotinic acid–N-oxide) without Val-TMA by adding
copper(II) nitrate to a hot solution of isonicotinic acid–N-oxide in
ethanol/water (5% water, v/v), which resulted in a green solution.
The vial was sealed, and a mixture of blue and green crystals was
formed overnight (Fig. 7c and d). X-ray single crystal diffraction of
these crystals revealed that the blue crystal belongs to form-I and
the green crystals were either form-II or form-IV. Thus, concomitant
Fig. 7 Crystallisation experiments of the copper(II) isonicotinate–N-oxide
complex in aqueous ethanol (5% water, v/v) (a) with Val-TMA gelator
(4.0 wt%) and (b) the isolated crystals. Solution phase crystallisation
(c) without gelator and (d) top view of crystals.
Conclusions
In summary, we report the crystallisation of three forms of
copper(II) isonicotinate–N-oxide (form-I, form-II and form-IV)
and their solvent-mediated interconversion. The crystal-to-
crystal transformation of a concomitant mixture of blue and green
crystals was also studied as a function of solvent concentration. We
have designed a gelator that is structurally similar to the crystal-
lisation substrate. Gel phase crystallisation of the complex was
performed in hydrogels, the gels of low molecular weight gelators
and tailored LMWG. The morphologies of the crystals obtained
from solution and from agarose gel proved to be similar to each
other while gel phase crystallisation performed in LMWGs and the
tailored gelator resulted in plate shaped crystals indicating
an influence of the gelator on the crystallization process.
Crystallisation of copper(II) isonicotinate–N-oxide complexes
in aqueous ethanol (5% water, v/v) resulted in a mixture of
blue and green crystals, whereas gel phase crystallisation in
Val-TMA gel under identical conditions resulted in only blue
crystals indicating the influence of LMWGs in selective crystal-
lisation of the thermodynamically stable form-I.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
crystallisation of different forms was observed from the solution. We thank the University of Iceland Research Fund and the
´
Science Institute for funding and Dr Sigurjur Sveinn Jonsson,
Most of the green crystals eventually turned blue over a week.
19968 | New J. Chem., 2018, 42, 19963--19970 This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2018

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19970 | New J. Chem., 2018, 42, 19963--19970 This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2018