Polymorphism control in the mechanochemical and solution-based synthesis of a thermochromic Schiff base

Article abstract of DOI:10.1039/c5ce01445j

Three crystal forms of a thermochromic Schiff base, namely 1-{3-[(2-hydroxy-3-methoxy-benzylidene)-amino]-phenyl}-ethanone, derived from o-vanillin and 3-aminoacetophenone, were obtained by conventional solution-based methods. Two out of the three polymorphs were synthesized by mechanochemical syntheses, under solvent-free conditions. Herein, we report a study of the dependence of the composition of solvent, the crystallization temperature and impurities on the outcome of the synthesis of Schiff base polymorphs. We report the important role of seed crystals in directing the supramolecular organization of the product of a covalent solvent-free reaction towards the intended polymorphic outcome as well. All obtained polymorphs were investigated by means of thermal analysis, single crystal X-ray diffraction, ex situ and in situ powder X-ray diffraction and IR spectroscopy. The polymorphs display interesting and remarkably different molecular packing arrangements governed by C-H?O interactions leading to two-dimensional networks in forms I and III, and a three-dimensional networks in form II.

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Polymorphism control in mechanochemical and solution based
synthesis of a thermochromic Schiff base
Marija Zbačnik*, Ivana Nogalo, Dominik Cinčić and Branko Kaitner
Received 00th January 20xx,
Accepted 00th January 20xx
Three crystal forms of a thermochromic Schiff base derived from o-vanillin and 3-aminoacetophenone, namely 1-{3-[(2-
-hydroxy-3-methoxy-benzylidene)-amino]-phenyl}-ethanone, were obtained by conventional solution-based methods. Two
polymorphs out of three were synthesized by mechanochemical syntheses, under solvent-free conditions. Herein, we
report a study of the dependence of the composition of solvent, the crystallization temperature and impurities on the
outcome of the synthesis of Schiff base polymorphs. As well, we report the important role of seed crystals in directing the
supramolecular organization of the product of covalent solvent-free reaction towards the intended polymorphic outcome.
All obtained polymorphs were investigated by means of thermal analysis, single crystal X-ray diffraction, and ex-situ and in-
situ powder X-ray diffraction and IR spectroscopy. The polymorphs display interesting and remarkably different molecular
packing governed by C–H∙∙∙O interactions leading to two-dimensional networks in forms I and III, and three-dimensional
networks in form II.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
There is a continuous strong interest in understanding the from o-vanillin (ovan) and 3-aminoacetophenone (3aa). N-
phenomenon of identical molecular specie occupying different substituted imines, also known as Schiff bases, can be
crystalline arrangements, i.e. polymorphism.1 Different effortlessly obtained by the condensation reaction of primary
surroundings of molecules in the solid state significantly amines with carbonyl compounds.7 During the past two
influences the physicochemical properties of the compound decades they have been widely used as ligands in coordination
(colour, solubility, stability, bioavailability, etc.) although the chemistry of transition metals.8 Besides, the imines (and their
chemical composition is the same.2 Thus, for the design of coordination compounds) have attracted particular interest
functional materials the ability to control the solid-state due to their biological and pharmacological activities.9 Solid-
assembly of molecules into crystals is of considerable state thermochromism and photochromism are an another
importance.3 The conventional methods to control characteristic of these compounds leading to their application
polymorphism, as well as the screening of different crystal in various areas of materials science.2a-d,10,11 Schiff bases are
forms of a compound, are based on a systematic exploration of usually obtained by either condensation from a solution, or,
all possible crystallization conditions, such as by varying more recently, by neat grinding (NG), liquid-assisted grinding
solvent or temperature.4 However, polymorph screening by (LAG) or accelerated ageing.11-14 Mechanochemical synthesis is
solvent-free methods are mainly based on melt crystallization actually faster and more convenient than the conventional
or sublimation.5 An overview of literature on polymorphic solvent-based method since it avoids large quantities of
transformations and their control under solvent-free solvent and heating.15 Furthermore, the solid-state
conditions reveals that many studies were based on condensation of solid amines and aldehydes can occur readily
compression, grinding or grinding in the presence of seed simply by mixing solid reactants and without excessive input of
crystals.6
mechanical energy.11,14 Such reactions have shown great
The compound we were interested in is an imine derived potential as efficient technique for imine synthesis and can be
accelerated by gas-phase catalysts, very high humidity or
organic solvent vapours.14
Herein, we report conventional solution-based synthesis of
three Schiff base (compound 1) polymorphs and the study of
the dependence of the composition of solvent, the
crystallization temperature and impurities on the outcome of
the polymorph synthesis. As well, we report the synthesis of
two polymorphs out of three under solvent-free conditions.
We were inspired to pursue mechanochemical experiments in
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our study by a recent report of our group,13 where we
described mechanochemical
Scheme 1 Synthetic methods used to obtain compound 1 and its polymorphic forms.
see ESI). Orange single crystals used for single crystal X-ray
diffraction experiments were obtained by slow evaporation of
mother liquor in cases where only one polymorphic form was
obtained (see Experimental section and ESI).
synthesis of a Schiff base and described simultaneous covalent
solvent-free synthesis and polymorphism control using neat
grinding and seeding-assisted grinding (SEAG), i.e. neat grinding in
the presence of seed crystals of the desired product. All reactants
and polymorphs obtained by crystallization from solution, NG, LAG
Mechanochemical syntheses
and SEAG were characterised by means of powder X-ray diffraction Left hand side of Scheme 1 represents the outcomes of
grinding experiments. Equimolar quantities of ovan and 3aa
were ground in an agate mortar under normal laboratory
conditions (at RT, 40-50 % relative humidity). The required
grinding time in the agate mortar was determined empirically
when the colour of the reaction mixture stopped changing (see
ESI). After 40 s of NG the reaction mixture starts to change its
colour and after 60 s an orange paste appears. The paste starts
to solidify after 2 min of grinding. After 3.5 min an orange
powder was obtained. As revealed by PXRD, the reaction
(PXRD), differential scanning calorimetry (DSC) and Fourier-
transform infrared spectroscopy (FTIR). In-situ PXRD experiments
on monitoring of ageing reaction of the aldehyde and amine used
as purchased and ground before the contact were performed as
well.
Results and discussion
Solution based syntheses
resulted in the formation of 1 as form I (Figure 1). LAG
We first attempted the solution based synthesis of compound
1
by condensation reaction of equimolar quantities of ovan
and 3aa (Scheme 1) in boiling ethanol (EtOH). The 3aa
ethanolic solution is blurry and was in some cases filtered
using three different filtering papers and then added to the
ovan solution. The resulting mixture was left at 25 °C (RT) or
8 °C (LT). The results of the solution based syntheses are
presented in Table 1 and Figure 1. Form I was obtained both
at RT and LT and its formation is not very reliant on the
filtration whereas a certain/variable water amount should be
present in ethanol. Form II was obtained only by LT
crystallization and only if the solution of 3aa was filtered.
Crystallization experiment at RT, when the concentration of
water in ethanol is very low, leads to the formation of form III
.
In two different crystallization experiments forms I and II
appear as concomitant polymorphs. The measured PXRD
patterns of all polymorphs are in good agreement with those
calculated from single crystal data, thus confirming that all
products were obtained as pure single phases (Figure 1, and
2 | J. Name., 2012, 00, 1-3
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A paste is present as an intermediate phase in all performed
mechanochemical syntheses of compound . A recent study of
Table 1 Outcome of the synthesis of three polymorphic forms of ovan3aa.
1
Type of filtering
paper◊
Obtained
our group showed that the reaction pathway does not have to
be the same when grinding and when reactants are merely put
in close contact and the reaction mixture is left to age.11 For
that reason, we performed similar in-situ PXRD monitoring
experiments of ageing reaction using (i) reactants as purchased
and (ii) pre-ground reactants to assure smaller size of particles
and bigger reaction surface to check if the particle size
influences the way of product formation. In both cases,
Type of ethanol
Temperature
polymorph
Filtration not
performed
Student grade
(21N)
96 %
Absolute
96 %
I
Absolute
96 %
III
25 °C
White ribbon
(615)
Absolute
96 %
I
Blue ribbon
(619)
polymorph I was obtained (see ESI). The difference in using (i)
Absolute
96 %
and (ii) is in the reaction rate. When the reactants are used as
purchased i.e. the particle size is bigger, the intensities of the
maxima of the reactants deteriorate severely in the first 10
minutes after they were put into close contact but remain
present even after 3 hours (see ESI). On the other hand, the
diffraction maxima of the pre-ground reactants are present in
PXRD patterns for 30 minutes and afterwards cannot be found
meaning that they are either overlaid by maxima of the
product or all maxima can be attributed only to the product
Student grade
(21N)
I + II
I
Absolute
96 %
White ribbon
(615)
II
Absolute
96 %
8 °C
I
II
Absolute
1:1‡
1:2‡
Blue ribbon
(619)
I + II
2:1‡
◊ 21/N – weight 80 g/m2, thickness 0.28 mm, filtration speed 10 s; 615 – weight
70 g/m2, thickness 0.16 mm, filtration speed 22 s; 619 – weight 75 g/m2,
thickness 0.17 mm, filtration speed 22 s
(polymorph I). The severe deterioration in the intensity of the
diffraction after 30 min is present for 10 minutes and points to
amorphization of the reaction mixture. Afterwards solid
particles of polymorph I start to grow and diffract in a liquid
(paste-like) intermediate phase. This is in good agreement
‡ Volume raꢀo of ethanol, 96 % and disꢀlled water.
experiments were performed in two ways: (i) by adding a small
amount of ethanol (96 %) in the reactants before grinding and
(ii) by adding a small amount of ethanol (96 %) in the paste. In
both experiments the synthesis quantitatively afforded form
(see ESI). Encouraged by DSC and polymorph interconversion
experiments and the fact that form and form III are in the
I
I
monotropic relationship we turned to SEAG experiments. We
expected that, by adding a small amount of seed crystals of
polymorph III, we can direct the polymorphic outcome of a
mechanochemical covalent synthesis towards that same form.
Indeed, SEAG of 3aa and ovan for 6 min in the presence of a
small quantity of seed crystals of form III led to the formation
of compound
1 as form III. The attempt to prepare form II by
SEAG experiment was unsuccessful. As revealed by PXRD,
grinding of 3aa and ovan in the presence of a small amount of
seed crystals of form II provided compound
SEAG experiment with form II was expected to result with
form because the fact that form II converts spontaneously
into form if left standing in organic solvent vapour or by
1 but as form I.
I
I
kneading with a drop of organic solvent (see ESI). For SEAG
experiments with form III the reaction mixture remains as
powder for 1 minute as in case of NG, although to some extent
moister. The intermediate paste is somewhat denser, stickier
and with more solid phase in the liquid and it starts to solidify
after 3 min of grinding. When seeds of polymorph II are used a
paste forms in 20 s after the addition and it starts to solidify
after 2 min of grinding. In both experiments the orange
powder product is obtained after 6 min.
Fig. 1 PXRD patterns of (a) o-vanillin, (b) 3-aminoacetophenone, (c) calculated
Synthesis by ageing of the reaction mixture – In-situ PXRD
pattern of form I, (d) I prepared by neat grinding, (e) I obtained from ethanol (96
%, filtration not performed) at 25 °C, (f) calculated pattern of form II, (g) II
obtained from ethanol (96 %, white ribbon filtering paper used for filtration of
3aa solution) at 8 °C, (h) calculated pattern of form III, (i) III obtained by means
monitoring
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of seeding-assisted grinding and (j) III obtained from ethanol (absolute, filtration
performed using student grade filtering paper) at 25 °C.
three polymorphs undergo exothermic decomposition after
approximately 220 °C (see ESI).After performing DSC
experiments, we have explored the interconversion of
polymorphs from their mixtures. Three combinations of
polymorph mixtures in mass ratio of 1:1 were ground in a
mortar in the presence of small quantity of organic solvent:
acetone (ace), acetonitrile (MeCN), ethanol, cyclohexanol
(ChxOH) and water. The results of kneading experiments were
monitored ex-situ by means of PXRD just after the solvent
evaporated and after 3 weeks (see ESI). Form II converts into
with the formation of the paste-like intermediate phase in the
grinding experiment and with the proposed route (via an
intermediate liquid or paste-like phase).11
Polymorph interconversion experiments
In quest for the information on the transformation conditions
of polymorphs and routes to convert one form to the other to
be able to control their interconversion, we performed three
different methods described below (Scheme 2).
form I from a mixture of I and II in all cases except when ace
was used probably because acetone evaporates fast. When
form II is in a mixture with form III it converts rapidly into pure
form III if MeCN or EtOH are used, but if ace is used it converts
The results of DSC experiments performed on recrystallized
material are presented in Figure 2. Polymorph I starts to melt
at 103 °C while polymorph III has a melting onset of 118 °C.
The DSC curve of polymorph II has three significant peaks. For
that reason, samples of form II were heated from 25 °C to 82,
101, 106 and 116 °C, keeping samples for 2 minutes at those
temperatures and then cooling them back to 25 °C. PXRD
measurements were performed on the obtained material (see
into form
I
with time. Apparently there is no conversion of
, on the other
form II in presence of ChxOH or water. Form
I
hand, if in mixture with III rapidly converts to form III in MeCN
but it takes three weeks for that conversion if EtOH or ChxOH
are used to assist grinding. No polymorph conversion in this
mixture was observed if water is used.
ESI). Polymorph II undergoes
polymorphic transition into form III already starting from 82
°C. The same DSC experiments were done for form and III
Samples of form were heated up to 98 and 100 °C while
a temperature induced
Finally, we have performed vapour digestion experiments.
Samples of all three polymorphs were put in open test tubes
which were then put in glass vials containing ethanol (96 % or
absolute), closed and left at RT. As revealed by PXRD, crystals
I
.
I
samples of from III up to 80, 95 and 108 °C. PXRD
measurements were performed on the obtained material and
both polymorphs stay in the form in which they are at room
temperature. All
of form II convert spontaneously into form
three hours. On the other hand, there is no influence of
ethanol vapour to neither form nor form III in the same
period of vapour digestion (see ESI).
I in the period of
I
Molecular and crystal structure of polymorphs
Single crystal X-ray analysis of three crystal forms of 1 revealed
conformational differences in molecules. The acetophenone
group of the amine moiety and the hydroxy and methoxy
groups of the aldehyde moiety are on the opposite side in
molecules of forms
the same side in molecules of form II. All four molecules (form
has two independent molecules in the asymmetric unit) of
I and III. Meanwhile, these groups are on
I
Scheme 2 Polymorph interconversion experiments and transformation conditions.
these three forms are almost planar. The angles between the
aromatic subunits of the molecules are approx 5°, 4° and 2° in
forms I, II and III, respectively. The view of the molecular
overlap shows the mentioned similarities and differences
(Figure 3a). The enol-imine tautomer was detected for all
three crystal forms from the molecular geometry
consideration, where the N1–C7 and C2–O1 bond lengths are
in good agreement with analogous values of corresponding
Schiff bases (see ESI)8a,16, as well as from δF maps calculated in
the domain of N1–C7–C1–C2–O1 chelate rings (see ESI). A
close analysis of the two-dimensional fingerprint plots derived
from the Hirshfield surfaces of the molecule of all polymorphs,
revealed weak hydrogen bonds, Figure 3. The polymorphs
display interesting and remarkably different molecular packing
Fig. 2 DSC curves of form
I (black), II (red) and III (blue). Onset temperature of a
peak is indicated as te value.
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3.371 Å). Polymorph III crystallizes with four molecules per
unit cell. The molecules are connected into chains along the
[100] direction via C–H∙∙∙O interactions between neighbouring
molecules. In each molecule carbonyl oxygen acts as a
bifurcated acceptor of C–H∙∙∙O hydrogen bonds with C6∙∙∙O3
and C7∙∙∙O3 contacts of 3.356 A and 3.417 A, respectively. The
chains thus formed are connected via C–H∙∙∙O interactions,
between benzene rings and hydroxy groups of neighbouring
molecules (C13∙∙∙O1 contacts of 3.441 Å), into sheets which are
stacked along the b axis. Compound
1 fulfils the requirements
of the molecule to be able to show reversible
thermochromism2a-d,10,11 i.e. it is derived from an o-hydroxy
aldehyde so there is a possibility of proton transfer via
intramolecular O∙∙∙N hydrogen bond and the molecules have
the ability to change their geometry under crystal packing
Fig. 3 Compound 1: a) overlapped molecular structures (both molecules of Form
I
– pink, Form II – blue, Form III – violet); two-dimensional fingerprint plots of
Form I (b), Form II (c) and Form III (d) (marked corresponding regions: red arrows
for C∙∙∙C contacts, black arrows for H∙∙∙H contacts, red circle for C-H∙∙∙C contacts
and black circle for C-H∙∙∙O contacts).
governed by C–H∙∙∙O interactions (Figure 4) leading to two-
dimensional networks in forms
dimensional network in form II. All three forms crystallize in
orthorhombic system, form in general position of Pna21 space
group and forms II and III in P212121. Polymorph crystallizes
I and III, and a three-
I
I
with two molecules in the asymmetric unit and with eight
molecules per unit cell. The molecules are connected into zig-
zag chains along the [001] direction via Car–H∙∙∙Omethoxy and C–
H∙∙∙Ocarbonyl interactions (C213∙∙∙O12 of 3.469 Å and C27∙∙∙O13
of 3.487 Å). The chains thus formed interact by C–H∙∙∙O
interactions between methyl and carbonyl groups of
neighbouring molecules with C114∙∙∙O13 and C214∙∙∙O23
contacts of 3.564 Å and 3.578 Å, respectively. The sheets thus
formed are further stacked along the b axis. Polymorph II
crystallizes with four molecules per unit cell. The analysis of
crystal packing indicated C–H∙∙∙Ocarbonyl interactions between
neighbouring molecules. The C7∙∙∙O3 contacts of 3.571 Å leads
to the formation of chains along the [010] direction. The
adjacent chains are further connected into 3-D network via C–
H∙∙∙O interactions between methyl and methoxy groups of
neighbouring molecules (C13∙∙∙O2 contacts of 3.411 Å) and via
C∙∙∙C contacts between benzene rings of neighbouring
molecules (C5∙∙∙C7 contacts of 3.341 Å and C1∙∙∙C8 contacts of
Fig. 4 The crystal structure of polymorphic forms I–III of 1: chains of hydrogen
bonded molecules, via C–H∙∙∙O interactions, and assemblies of hydrogen-bonded
chains into layers.
influences. Nevertheless, all molecules of all three
polymorphic forms of
1 are almost planar (2-5°) and are
present as enol-imines in the solid state at room temperature.
Still, small amounts of recrystallized material of all three
polymorphs of
1 were put into glass testing tubes which were
then submerged into liquid nitrogen. All three samples
reversibly change their colour upon cooling from different
shades of orange to different shades of yellow as can be seen
from Figure 5. Structural and/or other reasons for solid state
thermochromism were not thoroughly revised for the purpose
of this paper.
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Fig. 5 Pictures of polymorphs of ovan3aa at room and liquid nitrogen temperature showing solid state thermochromism.
Reactants were dissolved in boiling absolute EtOH and the 3aa
solution was filtered using student grade filtering paper and
then poured into the boiling solution of ovan. The resulting
mixture was left semi-closed overnight at 25 °C.
Experimental
Synthesis
All reagents, solvents and filtering papers were purchased
from commercial sources and used as received.
A rod-like single crystal of form
harvested from crystals grown in mother liquor of solution-
based synthesis of when filtration wasn’t performed, 96 %
I used for SCXRD was
1
General procedure for solution-based syntheses
ethanol was used as solvent and crystallization was performed
at RT. A needle-like crystal used for SCXRD analysis of form II
was taken from ones developed by solution-based synthesis of
All solution based syntheses were performed using equimolar
quantities of reactants i.e. 0.153 g (1 mmol) of o-vanillin
dissolved in
2
mL and 0.135
g
(1 mmol) of 3-
1
when filtration of 96 % ethanol solution of 3aa was done
aminoacetophenone in 5 mL of corresponding boiling solvent.
Single crystals suitable for SCXRD of three different
polymorphs were obtained by crystallization from the mother
liquor. The details on filtering paper used are in ESI, Table S2.
using white ribbon and crystallization was performed at LT. A
brick-like single crystal of form III was collected form crystals
grown by slow evaporation of absolute EtOH at RT when
student grade filtering paper was used to eliminate impurities
present in the solution of 3aa used for solution-based
Solution-based syntheses of compound 1, form I
synthesis of 1.
Form I was obtained from boiling ethanol (96 % or absolute)
mixture of o-vanillin and 3-aminoacetophenone solutions left
overnight at 25 °C when 3aa solution is not filtered or was
filtered using student grade, white and blue ribbon filtering
paper prior to the addition to the ovan solution and then the
resulting mixture was left semi-closed overnight at 25 °C.
The same polymorphic form was obtained at 8 °C when 3aa
solution (96 %, absolute EtOH) was filtered using blue ribbon
filtering paper and student grade filtering paper for filtration
of 3aa dissolved in absolute ethanol.
General procedure for mechanochemical syntheses
All manual grinding experiments were performed in an agate
mortar at room temperature and 40-50 % relative humidity.
Equimolar quantities of o-vanillin (0.153 g, 1 mmol) and
3-aminoacetophenone (0.135 g, 1 mmol) were ground for 40 s
when the reaction mixture started to change its colour and
after 60 s an orange paste appeared. The paste started to
solidify after 2 min of grinding. After 3.5 min an orange
powder containing form
I was obtained. The same quantities
of reactants were used for LAG experiments where 40 μL of
EtOH, 96 %, was added at the beginning and in another case in
Solution-based syntheses of compound 1, form II
When the reactants were dissolved in boiling 96 % or absolute
EtOH and 1:1 volume ratio of 96 % EtOH and distilled water
and the 3aa solution was filtered using white ribbon and blue
the paste-like intermediate phase. Form I of compound 1 was
again obtained however it takes 2.5 min and 3.5 min,
respectively, for the reaction mixture to start to solidify and 8
min and 9 min, respectively, for the grinding process to finish.
Form III was obtained by grinding o-vanillin (0.153 g, 1 mmol),
seed crystals of form III (48 mg, 0.2 mmol) for 2.5 minutes and
then 3-aminoacetophenone (0.135 g, 1 mmol) was added. The
reaction mixture was ground for another 60 s when an orange
ribbon filtering paper, respectively, form II of compound
1 was
obtained. Each time the resulting mixture was left semi-closed
overnight at 8 °C.
Solution-based syntheses of compound 1, form III
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paste forms. By further grinding the paste gradually solidifies. polymorphs are thermochromic and display different
After 5.5 min from 3aa addition an orange dry powder of form molecular packing governed by C–H∙∙∙O interactions leading to
III was obtained.
two-dimensional networks in forms I and III, and three-
dimensional networks in form II. The molecules of all three
X-Ray Diffraction Measurements
polymorphic forms are almost planar (2-5°) and are present as
Crystal and molecular structures were determined at 298 K for enol-imines in the solid state at room temperature.
polymorphs II and III and at 200 and 110 K for polymorph The present study also highlights the efficiency of
using SCXRD on an Oxford Diffraction Xcalibur Kappa CCD X-ray mechanochemistry in the polymorphism control in the solid
I
diffractometer with graphite-monochromated MoKα
(
λ
=
state. Two out of the three polymorphs were synthesized by
0.71073 Å) radiation (for details see ESI).17 The data mechanochemical syntheses, under solvent-free conditions. A
concerning the results of the crystallographic experiments are paste is present as an intermediate phase in all performed
listed in Tables S4 to S7. In order to monitor the efficacy of the mechanochemical syntheses of compound 1. We have shown
synthetic method used and to qualitatively identify the and confirmed our previously reported study13 that seeding-
products powder X-ray diffraction (PXRD) experiments were assisted grinding can be used as an efficient approach for
performed on a PHILIPS PW 1840 X-ray diffractometer with simultaneous
covalent
solvent-free
synthesis
and
CuKα1 (1.54056 Å) radiation at 40 mA and 40 kV. Scattered polymorphism control. We have shown the important role of
intensities were measured with a scintillation counter. The seed crystals in directing the supramolecular organization of
angular range (2θ) was from 5 to 45° with steps of 0.02° and the product towards the intended polymorphic outcome. The
the measuring time was 0.5 s per step in the case of the ex-situ described results are important in the context of solid-state
experiments. In the case of the in-situ monitoring of the synthesis, as well as supramolecular and materials chemistry,
contact
reaction, and could have a significant implication for the future aspects
the angular range (2
θ
) was selected according to diffraction of the solvent-free synthesis and polymorphism control in the
maxima of the reactants from 10.0 to 20.0° with steps of 0.02°, solid state.
and the measuring time was 0.5 s per step for reactants used
as purchased. Measurements were repeated in 40 cycles. In
Acknowledgements
the case of the in-situ monitoring of the contact reaction when
reactants were separately ground prior to contact, the angular
This research was supported by the Ministry of Science,
Education and Sport of the Republic of Croatia (Grant No. 119-
1193079-3069).
range (2θ) was also selected according to the diffraction
maxima of reactants from 11.5 to 15.0° with steps of 0.02°,
and the measuring time was 0.5 s per step. Measurements
were repeated in 110 cycles. The data collection and analysis
were performed using the program package Philips X'Pert (for
details see ESI).18
References
1
(a) J. Bernstein, R. J. Davey and J.-O. Henck, Angew. Chem.,
Int. Ed., 1999, 38, 3441; (b) J. D. Dunitz and Bernstein, J. Acc.
Chem. Res., 1995, 28, 193; (c) A. Nangia, Acc. Chem. Res.,
2008, 41, 595; (d) G. R. Desiraju, Angew. Chem., Int. Ed.,
Thermal study
The measurements were performed on a Mettler Toledo
TGA/SDTA and DSC823e module in sealed aluminium pans (40
μL), heated in flowing nitrogen (200 mL min−1) at a rate of 10
°C min−1. The data collection and analysis was performed using
the program package STARe Software V10.00 (for details see
ESI).19
2007, 46, 8342; (e) J. Bernstein, Cryst. Growth Des., 2011, 11
,
632; (f) A. J. Cruz-Cabeza and J. Bernstein, Chem. Rev., 2014,
114, 2170.
(a) N. Blagden and R. J. Davey, Cryst. Growth Des., 2003, 3,
2
867; (b) A. D. Bond, R. Boese and G. R. Desiraju, Angew.
Chem. Int. Ed., 2007, 46, 618; (c) K. Johmoto, A. Sekine and
H. Uekusa, Cryst. Growth Des., 2012, 12, 4779; (d) D. E.
Braun, T. Gelbrich, R. K. R. Jetti, V. Kahlenberg, S. L. Price and
FT-IR spectroscopy
U. J. Griesser, Cryst. Growth Des., 2008,
6, 1977; (e) A.
Infrared spectra were recorded on a PerkinElmer Spectrum
Two FTIR spectrophotometer using the KBr pellet method. The
data collection and analysis was performed using the program
package PerkinElmer Spectrum 10.4.2.279.20 Spectra and the
table with characteristic stretching bands are listed in ESI.
Carletta, J. Dubois, A. Tilborg and J. Wouters, CrystEngComm,
2015, 17, 3509; (f) F. Robert, A. D. Naik, F. Hidara, B. Tinant,
R. Robiette, J. Wouters and Y. Garcia, Eur. J. Org. Chem,
2010, 621; (g) M Kitamura, Cryst. Growth Des., 2004, 6, 1153;
M Rubčić, N. Galić, I. Halasz, T. Jednačak, N. Judaš, J. Plavec,
P. Šket and P. Novak, Cryst. Growth Des., 2014, 14, 2900; (h)
I. Weissbuch, V. Y. Torbeev, L. Lieserowitz and M. Lahav,
Angew. Chem. Int. Ed., 2005, 44, 3226; (i) A. D. Bond, K. A.
Solanko, S. Parsons, S. Redder and R. Boese, CrystEngComm,
2011, 13, 399.
Conclusions
In summary, we have obtained three crystal forms of a Schiff
base derived from o-vanillin and 3-aminoacetophenone by
conventional solution-based methods. We demonstrated that
the composition of solvent, the crystallization temperature
and impurities present in reagents can significantly affect the
supramolecular outcome of the synthesis of imine. The
3
(a) M. J. Zaworotko, Cryst. Growth Des., 2007, 7, 4; (b) L. R.
MacGillivray, J. Org. Chem., 2008, 73, 3311; (c) J. A. R. P.
Sarma and G. R. Desiraju, Acc. Chem. Res., 1986, 19, 222; (d)
D. Braga and F. Grepioni, Angew. Chem., Int. Ed., 2004, 43
,
4002; (e) D. Cinčić, T. Friščić and W. Jones, Chem. Mater.,
2008, 20, 6623; (f) J. L. C. Rowsell and O. M. Yaghi, Angew.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Please do not adjust margins
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Page 8 of 9
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DOI: 10.1039/C5CE01445J
ARTICLE
Journal Name
Chem., Int. Ed., 2005, 44, 4670; (g) T. Friščić and L. R. 11 M. Zbačnik and B. Kaitner, CrystEngComm, 2014, 16, 4162.
MacGillivray, Chem. Commun., 2009, 773; (h) C. B. Aakeröy, 12 (a) J. Schmeyers, F. Toda, J. Boy and G. Kaupp, J. Chem. Soc.,
A. M. Beatty and B. A. Helfrich, J. Am. Chem. Soc., 2002, 124
14425.
(a) I. Weissbuch, V. Y. Torbeev, L. Leiserowitz and M. Lahav,
Angew. Chem., Int. Ed., 2005, 44, 3226; (b) A. J. Alvarez, A.
Singh and A. S. Myerson, Cryst. Growth Des., 2009, 9, 4181;
,
Perkin Trans. 2, 1998, 989; (b) G. Rothenberg, A. P. Downie,
C. L. Raston and J. L. Scott, J. Am. Chem. Soc., 2001, 123
,
4
8701; (c) O. Dolotko, J. W. Wiench, K. W. Dennis, V. K.
Pecharsky and V. P. Balema, New J. Chem., 2010, 34, 25; (d)
G. Kaupp and J. Schmeyers, Angew. Chem., Int. Ed. Engl.,
1993, 32, 1587.; (e) V. Stilinović, D. Cinčić, M. Zbačnik and B.
Kaitner, Croat. Chem. Acta, 2012, 85, 485; (f) O. Dolotko, J.
W. Wiench, K. W. Dennis, V. K. Pecharsky and V. P. Balema,
New J. Chem., 2010, 34, 25; (g) K. Tanaka and F. Toda, Chem.
Rev., 200, 100, 1025; (h) R. Kuroda, K. Higashiguchi, S.
(c) M. Kitamura, Cryst. Growth Des., 2004, , 1153; (d) R. C.
4
Kelly and N. Rodríguez-Hornedo, Org. Process Res. Dev.,
2009, 13, 1291; (e) K. Užarević, M. Rubčić, I. Đilović, Z. Kokan,
D. Matković-Čalogović and M. Cindrić, Cryst. Growth Des.,
2009,
H. ter Horst, H. J. M. Kramer and P. J. Jansens, Cryst. Growth
Des., 2006, , 955.
(a) B. Sarma, P. Sanphui and A. Nangia, Cryst. Growth Des.,
2010, 10, 2388; (b) I. Halasz, Cryst. Growth Des., 2010, 10
2817; (c) A. Alberola, O. P. Clements, R. J. Collis, L. Cubbitt, C.
9, 5327; (f) C. P. M Roelands, S. Jiang, M. Kitamura, J.
Hasebe and Y. Imai, CrystEngComm, 2004,
Chadwick, R. Davey and W. Cross, CrystEngComm, 2007, 9,
6, 463; (i) K.
6
5
6
732.
13 D. Cinčić, I. Brekalo and B. Kaitner, Cryst. Growth Des., 2012,
12, 44
,
M. Grant, R. J. Less, R. T. Oakley, J. M. Rawson, R. W. Reed 14 D. Cinčić, I. Brekalo and B. Kaitner, Chem. Commun., 2012,
and C. M. Robertson, Cryst. Growth Des., 2008,
Yu, J. Am. Chem. Soc., 2003, 125, 6380.
(a) T. P. Shakhtshneider and V. V. Boldyrev, Drug Dev. Ind.
Pharm., 1993, 19, 2055; (b) T. N. Drebushchak, A. A. Ogienko
and E. V. Boldyreva, CrystEngComm, 2011, 13, 4405; c) A. V.
Trask, N. Shan, W. D. S. Motherwell, W. Jones, S. Feng, R. B.
H. Tan and K. J. Cerpenter, Chem. Commun., 2005, 880; (d) H.
G. Brittain, J. Pharm. Sci., 2002, 91, 1573; (e) M. Chierotti, L.
Ferrero, N. Garino, R. Gobetto, L. Pellegrino, D. Braga, F.
8, 155; (d) L.
48, 11683.
15 (a) S. L. James, C. J. Adams, C. Bolm, D. Braga, P. Collier, T.
Friščić, F. Grepioni, K. D. M. Harris, G. Hyett, W. Jones, A.
Krebs, J. Mack, L. Maini, A. Guy Orpen, I. P. Parkin, W. C.
Shearouse, J. W. Steedk and D. C. Waddelli, Chem. Soc. Rev.,
2012, 41, 413 and references therein; (b) T. Friščić, D. G.
Reid, I. Halasz, R. S. Stein, R. E. Dinnebier and M. J. Duer,
Angew. Chem., Int. Ed., 2010, 49, 712; (c) T. Friščić, Chem.
Soc. Rev., 2012, 41, 3493; (d) G. Springuel, K. Robeyns, B.
Norberg, J. Wouters and T. Leyssen, Cryst. Growth Des.,
2014, 14, 3996; (e) D. Cinčić and T. Friščić, CrystEngComm,
2014, 16, 10169.
Grepioni and L. Maini, Chem.
Linol, T. Morelli, M.-N. Petit and G. Coquerel, Cryst. Growth
Des., 2007, , 1608; (g) A. Hédoux, Y. Guinet, L. Paccou, F.
−Eur. J., 2010, 16, 4347; (f) J.
7
Danède and P. Derollez, J. Pharm. Sci., 2013, 102, 162; (h) V. 16 F. H. Allen, O. Kennard, D. G. Watson, L. A. Brammer and G.
Mazel, C. Delplace, V. Busignies, V. Faivre, P. Tchoreloff and Orpen, J. Chem. Soc. Perkin Trans. II, 1987, S1.
N. Yagoubi, Drug Dev. Ind. Pharm., 2011, 37, 832; (i) S. Y. Lin, 17 Oxford Diffraction, CrysAlis CCD and CrysAlis RED. Version
Pharm. Res., 2014, 31, 1619; (j) Y. Hu, A. Erxleben, B. K. 1.170, Oxford Diffraction Ltd, Wroclaw, Poland, 2003.
Hodnett, B. Li, P. McArdle, Å. C. Rasmuson and A. G. Ryder, 18 (a) Philips X'Pert Data Collector 1.3e, Philips Analytical B. V.
Cryst. Growth Des., 2013, 13, 3404.
H. Schiff, Ann. Chim., 1864, 131, 118.
(a) A. Blagus, D. Cinčić, T. Friščić, B. Kaitner and V. Stilinović,
Netherlands, 2001; (b) Philips X'Pert Graphic & Identify 1.3e
Philips Analytical B. V. Netherlands, 2001; (c) Philips X'Pert
Plus 1.0, Philips Analytical B. V. Netherlands, 1999.
7
8
Maced. J. Chem. Chem. Eng, 2010, 29, 117; (b) D. Cinčić and 19 STARe Software V10.00., Mettler-Toledo AG, 1993-2011.
B. Kaitner, CrystEngComm, 2011, 13, 4351; (c) C. Baleizão, H. 20 PerkinElmer Spectrum v10.4.2.279, PerkinElmer (2014),
Garcia, Chem. Rev., 2006, 106, 3987.
PerkinElmer Ltd, United Kingdom.
9
(a) B. Chattopadhyay, S. Basu, P. Chakraborty, S. K.
Choudhuri, A. K. Mukherjee and M. Mukherjee, J. Mol.
Struct., 2009, 932 90; (b) K. M. Khan, M. Khan, M. Ali, M.
Taha, S. Rasheed, S. Perveen and M. I. Choudhary, Bioorg.
Med. Chem., 2009, 17, 7795; (c) V. Vrdoljak, I. Đilović, M.
Rubčić, S. Kraljević Pavelić, M. Kralj, D. Matković–Čalogović, I.
Piantanida, P. Novak, A. Rožman and M. Cindrić, Eur. J. Med.
Chem., 2010, 45, 38; (d) T. Rosu, E. Pahontu, C. Maxim, R.
Georgescu, N. Stanica, G. L. Almajan and A. Gulea,
Polyhedron, 2010, 29, 757; (e) S. Sathiyaraj, K. Sampath, R. J.
Butcher, R. Pallepogu and C. Jayabalakrishnan, Eur. J. Med.
Chem., 2013, 64, 81.
10 Thermochromism is defined as a reversible colour change
caused by a temperature change by H. Bouas-Laurent and H.
Durr, Pure Appl. Chem., 2001, 73, 639–665. Among the
organic compounds that exhibit reversible thermochromic
properties in the solid state, o-hydroxy aromatic Schiff bases
are particularly important. The reasons for their chromic
behaviour are still under investigation.
(a) E. Hadjoudis, and I. M. Mavridis, Chem. Soc. Rev., 2004,
33, 579; (b) J. Harada, T. Fujiwara and K. Ogawa, J. Am.
Chem. Soc., 2007, 129, 16216; (c) F. Robert, A. D. Naik, B.
Tinant, R. Robiette and Y. Garcia, Chem. Eur. J., 2009, 15
,
4327; (d) F. Robert, P.-L. Jacquemin, B. Tinant and Y. Garcia,
CrystEngComm, 2012, 14, 4396; (e) B. Kaitner and M.
Zbačnik, Acta Chim. Slov., 2012, 59, 670; (f) D. A. Safin, M.
Bolte and Y. Garcia, CrystEngComm, 2014, 16, 8786.
8 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5CE01445J
Polymorphism control in mechanochemical and solution based synthesis of
a thermochromic Schiff base
Marija Zbačnik*, Ivana Nogalo, Dominik Cinčić and Branko Kaitner
Laboratory of General and Inorganic Chemistry, Department of Chemistry, Faculty of Science,
University of Zagreb, Horvatovac 102a, HR-10002 Zagreb, Croatia
E-mail: mzbacnik@chem.pmf.hr
Fax: +385 1 4606 341
Phone: +385 1 4606 379
Abstract
Three crystal forms of a thermochromic Schiff base derived from o-vanillin and
3-aminoacetophenone were obtained by conventional solution-based methods. Two
polymorphs out of three were synthesized by mechanochemical syntheses, under solvent-free
conditions.
Graphical abstract