Co-crystal formation between 2-amino-4,6-dimethylpyrimidine and new p-xylylene-bis(thioacetic) acid

Article abstract of DOI:10.1039/c4ce01567c

Novel p-xylylene-bis(thioacetic) acid (p-XBTA) and its co-crystals with 2-amino-4,6-dimethylpyrimidine (DMP) have been synthesized and characterized by single-crystal X-ray diffraction, infrared spectroscopy and thermal analysis methods (TG/DSC). Depending on the crystallization conditions, three different multicomponent crystal forms have been isolated with various chemical compositions and stoichiometries of the co-formers. The ATR-FTIR spectra of the co-crystals display the stretching vibration bands for the co-formers with associated shifts confirming the formation of new phases. DSC and TG were used to reveal the relative stabilities of new solids compared to those of the co-formers.

Full text of DOI:10.1039/c4ce01567c

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yszczek, L. mazur and B. Tarasiuk, CrystEngComm, 2014, DOI: 10.1039/C4CE01567C.
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Co-crystals formation between 2-amino-4,6-dimethylpyrimidine and new p-xylylene-
bis(thioacetic) acid
A. Ostasza, R. Łyszczeka, L. Mazura, B. Tarasiukb
b
aDepartment of General and Coordination Chemistry, Department of Organic Chemistry,
Faculty of Chemistry, Maria Curie-Skłodowska University, M.C. Skłodowska Sq. 2, 20-031
Lublin, Poland;
email: a.ostasz@poczta.umcs.lublin.pl
Abstract
Novel p-xylylene-bis(thioacetic) acid (p-XBTA) and its co-crystals with 2-amino-4,6-dimethyl
pyrimidine (DMP) have been synthesized and characterized by the single crystal X-ray
diffraction, infrared spectroscopy and thermal analysis methods (TG/DSC). Depending on the
crystallization conditions, three different multicomponent crystal forms have been isolated
with various chemical compositions and stoichiometries of the co-formers. The ATR-FTIR
spectra of co-crystals display the stretching vibrations bands for the co-formers with
associated shifts confirming the formation of a new phases. DSC and TG were used to reveal
the relative stabilities of new solids compared to those the co-formers.
Introduction
Preparation of new compounds with tailor-made properties can be exploited for
many purposes such as host-guest compounds,1, 2 nonlinear optical materials,3, 4 organic
conductors5 or coordination polymers.6, 7
.
Co-crystals represent a class of compounds that could be reasonably described as
long known but little studied. Less than 1% of structurally characterized molecular organics
are co-crystals.8 In 2012 year, 46 authors of article in Crystal Growth@Design proposed the
1

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definition of co-crystals consistent with the scientific literature: co-crystals are solids that are
crystalline single phase materials composed of two or more different molecular and/or ionic
compounds generally in a stoichiometric ratio which are neither solvates nor simple salts.9
Co-crystals offer huge opportunities for the pharmaceutical industry. Co-crystallization can
improve final product properties such as solubility, melting point, crystallinity, hydroscopicity
and stability.10
Pyrimidines and aminopyrimidine derivatives are biologically important compounds
that manifest themselves in nature as components of nucleic acids. The functions of nucleic
acids are explicitly determined by hydrogen-bonding patterns including base pairing, which
is responsible for genetic information transfer. Their interactions with carboxylic acids are
involved in protein-nucleic acid recognition and drug-protein recognition processes. Co-
crystals of aminopyrimidine with carboxylic acids represent model systems where the
hydrogen bonded supramolecular motifs can be studied in detail.11 Some co-crystal
structures of pyrimidine and aminopyrimidine derivatives have been reported earlier.12 The
primary motif in their crystals is the pyrimidine-carboxylic acid dimer through the
13
ͦ
predominant ͌ (8) synthon, involving the O-H∙∙∙N and N-H∙∙∙O hydrogen bonds.
ͦ
Subsequent levels of aggregation form either a linear (LHT) or cyclic heterotetramer (CHT) or
heterotrimer (HT) or other preferred stable synthons.10,11 There are is 33 carboxylic acid:
DMP molecular complexes (22 co-crystals and 11 salts) which have been described in the
literature so far.14 The dominant synthon observed in their structures is a LHT one (67% of
existing structures). It is worth noting that co-2 is probably the first example of hydrated
form of carboxylic acid: DMP co-crystal, reported so far, as confirmed by the CSD14 data
search.
Fig. 1 Presentation of the percentage distribution of types of synthons in the existing structures
of DMP and carboxylic acids (LHT- linear heterotetramer, CHT- cyclic heterotetramer, HT-
heterotrimer)14
2

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In this paper the synthesis, structural and some physicochemical properties of p-
xylylenebis-(thioacetic) acid (p-XBTA) are presented. The crystal structure of p-XBTA has not
been reported in literature so far. The acid is derived from a xylylene molecule and contains
two carboxylic groups as well as flexible thioaliphatic spacers. As such, this is a potential
ligand for construction of coordination polymers. The aim of this study was to explore the
capacity of (p-XBTA) (Scheme 1b) to form supramolecular assemblies with 2-amino-4,6-
dimethyl-pyrimidine (DMP) (Scheme 1a) base as well as to check the influence of synthesis
conditions on structure and composition of the resulting co-crystals.
Scheme 1. Molecular structures of a) 2-amino-4,6-dimethylpyrimidine (DMP) and
b) p-xylylenebis-(thioacetic) acid (p-XBTA)
Experimental
Synthesis
The co-crystal former, p-xylylenebis(thioacetic) acid, was synthesized in four stages (Scheme
2). In the first stage p-bis(bromomethyl)benzene (mp15 145 °C) was obtained by the action of
bromine on p-xylene. The resulting compound was heated in ethanol with thiourea. The salt
of p-diisothiouronium was subjected to basic hydrolysis and then the resulting p-phenylene-
bis(methanethiol) was condensed with chloroacetic acid in the alkaline medium.
p-Bis(bromomethyl)benzene
p-Xylene (10.6 g, 0.10 mol) was dissolved in tetrachloromethane (100 ml) and 0.5 g of
dibenzoyl peroxide was added. The mixture was heated under reflux and bromine (35.5 g,
0.22 mol) was added to a solution of tetrachloromethane dropwise within 20 min. The
reaction mixtures were stirred for 5 h and irradiated with UV-lamp. The solvent evaporated
under reduced pressure, and the reaction mixtures were crystallized three times from
methanol and cyclohexane ( 70:30, v/v). The residue (13.7 g, 52%) was sufficiently pure. mp
145.5 oC (ref. 15 mp 145 °C)
Anal. Calc. for C8H8Br2 (263.96): C 36.40; H 3.05. Found: C 36.43; H 3.08, 1H NMR (CDCI3):
4.65 (4H, s, -C6H4CH2Br), 7.39-8.11 (4H, m, C6H4-H).
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p-Benzene-bis(methanethiol)
Thiourea (9.5 g, 0.125 mol) was added to a solution of α,α′-dibromo-p-xylene (13.2 g, 0.05
mol) in acetone (200 ml). The mixture was heated to reflux for 1 h, and then cooled to room
temperature. A precipitate of bis(thiouronium) salt was filtered off, and dried under high
vacuum. The solid was dissolved in 3M NaOH (100 ml), the mixture was heated to reflux for
3 h, and the solution was neutralized to pH ~2 with hydrochloric acid. Dithiol was extracted
into methylene chloride, the organic solution was washed with water, dried over anhydrous
Na2SO4, and evaporated. The residue (7.4 g, 87%) was sufficiently pure. mp 46 oC (ref. 16 mp
46-47 oC).
Anal. Calc. for C8H10S2 (170.30): C 56.42; H 5.92. Found: C 56.43; H 5.89, 1H NMR (CDCI3):
1.72 (2H, s, -SH), 4.15 (4H, s, -C6H4CH2S), 7.38-8.15 (4H, m, -C6H4-H,).
p-Xylylenebis(thioacetic) acid
To the mixture of 8.0 g of sodium hydroxide dissolved in 150 ml of ethanol and 100 ml of
water, 8.5 g of 1,4-benzene-bis(methanethiol) (0.05 mol) was added. To this mixture stirred
at room temperature, a solution of 9.5 g (0.1 mol) of chloroacetic acid in 50 ml of water was
added and the reaction mixture was refluxed for 4 hours, cooled to 0 oC and acidified to pH 1
with hydrochloric acid. Crystallization of the crude product from ethanol gave 11.7 g (82 %
yield) of pure compound p-xylylene-bis(thioacetic) acid in the form of white powder. Mp 149 -
150 oC (ref.17 149 oC).
1H NMR (CDCI3): 3.15 (4H, s, -SCH2CO), 3.85 (4H, s, -ArCH2S), 7.38-8.15 (4H, m, ArH, ), 10.20
(2H, s, -COOH). Anal. Calc. for C12H14O4S2 (286.37): C 50.33; H 4.93; S 22.39. Found: C 50.43;
H 4.89; S 22.40.
p-XBTA acid synthesized in four steps was obtained as polycrystalline powder. To prepare
single crystals suitable for X-ray diffraction, recrystallization of crude p-xylylene-
bis(thioacetic) acid from a methanol solution was attempted and thus its structure was
determined.
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Scheme 2. Schematic representation of four-steps synthesis of p-xylylene-bis(thioacetic) acid (p-
XBTA) (p-xylylene was the initial reactant)
Co-crystals synthesis
Co-crystals were prepared by mixing the solutions of 2-amino-4,6-
dimethylpyrimidine, with the solution of p-xylylene-bis(thioacetic) acid at the molar ratio
2:1, respectively.
(co-1) p-XBTA (DMP)2 p-XBTA (0.040g, 0.14 mmol) was dissolved in DMF (5ml). DMP
(0.034g, 0,28 mmol) was dissolved in 5ml DMF. Next, the two solutions were combined and
stirred for 5 min. Slow evaporation of the solution at room temperature yielded plate-like
single crystals
(co-2) p-XBTA (DMP)2⋅2H2O The ethanol-water (v=20 ml : v=10 ml) mixture was added
to p-XBTA (0.040g, 0.14 mmol) and the obtained solution was heated at 70˚C and stirred. To
DMP (0.034g, 0,28 mmol) there was added the ethanol: water (v=20 ml : v=10 ml) mixture,
and the solution was heated at 70˚C while stirring. The two solutions were combined and
stirred for 5 min. Colorless needle-like single crystals were obtained after a few days by slow
evaporation at room temperature.
p-XBTA (0.040g, 0.14 mmol) and DMP (0.034g, 0,28 mmol) were dissolved in DMSO
(4 ml). After a few weeks, needle-like single crystals of co-2 were harvested.
(co-3) p-XBTA DMP Propan-2-ol (15 ml) was added to p-XBTA (0.040g, 0.14 mmol)
and the obtained solution was heated at 70˚C while stirring. The same solvent (propan-2-ol,
(15 ml)) was added to DMP (0.034g, 0.28 mmol) and solution was heated (up to 70˚C) and
mixed. The two solutions were combined and stirred for 5 min. Colorless plate-like single
crystals were obtained after a few days of slow evaporation at room temperature.
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The same procedure was repeated for the synthesis of co-3 in acetonitrile and ethyl acetate
solvents. The amounts of added co-formers and the solvent volumes were the same as for
the 2-propanol solution.
Changing the molar ratio of DMP : p-XBTA to 3:1 does not affect the final products. Using the
same of solvents and their quantity afforded the same three forms of co-crystals as in the
case molar ratio 2:1.
ATR-FTIR
Attenuated total reflectance ATR-FTIR spectra were recorded over the range of 4000 - 600
cm-1 on the Nicolet 6700 FTIR spectrometer equipped with a universal ATR attachment with
a ZnSe crystal.
X-ray analysis
The crystallographic measurements were performed on an Oxford Diffraction
Xcalibur CCD diffractometer with the graphite-monochromated Mo Kα radiation (λ = 0.71073
Å). Data sets were collected at 100 K using the ω scan technique, with an angular scan width
of 1.0°. The programs CrysAlis CCD and CrysAlis Red18 were used for data collection, cell
refinement, and data reduction. A multi-scan absorption correction was applied. The
structures were solved by direct methods using SHELXS-9719 and refined by the full-matrix
least squares on F2 using SHELXL-97.19 Calculations were carried out with the WinGX package
program.20 All non-H atoms were refined with anisotropic displacement parameters. All H
atoms in p-XBTA and co-3 were located from the difference-Fourier maps and refined
isotropically. In co-1 hydrogens attached to aromatic carbon atoms were placed at
calculated positions and included in the refinement in the riding model approximation with
Uiso(H) = 1.2Ueq(C). All remaining ones were found in the difference-Fourier maps and refined
isotropically. In turn, in co-2 (C)H atoms were placed at calculated positions and refined
using the ‘riding model’. Water, hydroxyl and amine H-atoms were found in the difference-
Fourier maps and refined with isotropic displacement parameters. The summary of crystal
data, experimental details, and refinement results are listed in Table 1. The selected bond
distances and angles are presented in Table S1 (Supplementary Materials). The molecular
plots were drawn with Mercury.21 The CIF files for each refinement are available from the
Supporting Information or can be retrieved from the Cambridge Crystallographic Data Centre
(CCDC) (deposition numbers CCDC 1014647-1014650).
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Table 1. Summary of crystallographic data and refinement details for p-XBTA acid and its co-crystals.
Compound
p-XBTA
co-1
co-2
co-3
Chemical formula C12H14O4S2
C12H14O4S2⋅2(C6H9N3)
532.68
C12H14O4S2⋅2(C6H9N3)⋅2H2O C12H14O4S2⋅C6H9N3
Formula weight
Crystal system
Space group
a (Å)
286.35
568.71
819.03
monoclinic
C2/c
monoclinic
P21/c
monoclinic
P21/c
orthorhombic
Cmca
9.4633(4)
17.637(2)
20.968(3)
32.932(3)
b (Å)
c (Å)
12.6496(4)
10.8834(4)
104.267(4)
1262.64(8)
4
4.8355(5)
15.593(2)
96.07(1)
1322.3(2)
2
4.7107(5)
14.401(2)
95.31(1)
1416.4(3)
2
7.9668(5)
15.2754(8)
90
β
(°)
V (Å3)
4007.7(5)
8
Z
T (K)
100(2)
100(2)
100(2)
100(2)
Crystal colour and colourless prism
shape
colourless plate
colourless needle
colourless plate
Dcalc (g cm-3)
(mm-1)
1.506
0.425
2837
1452
0.0204
1358
110
1.338
0.243
8987
3027
0.0562
2354
187
1.333
0.237
9304
3235
0.0654
2308
190
1.357
0.294
5299
2326
0.0337
1617
174
ꢀ
Refl. collected
Refl. unique
R(int)
Refl. with I>2σ(I))
Refined
parameters
GooF on F2
R1 (I>2σ(I))
wR2 (all data)
1.153
1.041
1.105
0.902
0.0320
0.0841
-0.20/0.55
0.0579
0.1565
-0.29/0.57
0.0651
0.1534
-0.31/0.43
0.0351
0.0758
-0.19/0.37
/ e·Å−3
Thermal analysis
The thermal behaviour of the compounds was investigated with the aid of a Setsys 16/18
(Setaram) thermal analyzer, registering the TG, DSC and DTG curves. The samples (5 mg)
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were heated in a ceramic crucible in the temperature range 30 - 700°C in the flowing air
atmosphere (v = 1 dm3 h-1) with a heating rate of 10°C min-1.
Results and discussion
Analysis of co-crystals 1, 2 and 3 via infrared spectroscopy
Infrared spectroscopy is a reliable technique to ascertain the formation of co-crystals.
Usually, formation of co-crystals is reflected in their IR spectra by shifting characteristic
stretching vibrations (ν) bands of co-formers. A comparison of the νs bands of shifts gave an
estimate of the relative strengths of the hydrogen bonds formed between the functional
groups.22 The detailed peaks assignment for the free co-formers and each co-crystal is given
in Table S2 (Supplementary Materials). The analysis of the ATR-FTIR spectra of the
compounds prepared in this study confirms formation of co-crystals in all cases. In general,
contribution of D-H group (where D is an atom being of proton donor) in hydrogen bonds or
other weak interactions during co-crystal formation decreases the frequency and intensity of
stretching vibrations while bandwidth is increased. These observations have remained true
for most of the hydrogen bonded systems.23-25
The crystal structures of co-crystals 1, 2 and 3 are stabilized via hydrogen bonds
where strong hydrogen bonding groups such as COOH, NH2, H2O as well as pyridine N-atoms
are preferred, so vibrations of these functional groups are associated with the largest shifts
in the ATR-FTIR spectra compared to those of co-formers. The co-crystals display the
stretching frequency bands for both co-formers with associated shifts confirming the
formation of a new phase (Figs 2a, 2b).
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Fig. 2 ATR-FTIR spectra of p
-XBTA, DMP and co-1, co-2, co-3 in the ranges: a) 3500-2500 cm-1 and b)
1800-650 cm-1
The ATR-FTIR spectrum of
strongest submaxima at 2656 and 2549 cm-1. These absorption peaks are derived from
stretching vibrations of hydrogen bonded hydroxyl groups
(OH)24, from carboxylic groups
and the C−H stretching modes (C-H) from methylene groups and aromatic ring. Such bands
p
-XBTA shows broad band in the range 3200-2400 cm-1 with the
ν
ν
bear out on association of acid molecules in the crystal structure.
As can be seen from Fig. 2a , these bands are not visible in the spectra of co-crystals. Only in
co-2, there is a band at 3449 cm-1 which can be assigned to stretching vibrations ν(OH) of
water molecules.26 The most intense band in the ATR-FTIR spectrum of the acid occurring at
1686 cm-1 is associated with the carbonyl stretching vibrations ν(C=O) of COOH groups. This
band “almost” disappear in co-1 and co-2 while in co-3, ν(C=O) band has a medium intensity
(Fig. 3). The changes in the intensity of such bands can be explained by participation of C=O
groups in hydrogen bonds. The following difference observed among the spectrum of
XBTA and its co-crystals is connected with shift of the band at 1280 cm-1 related to vibrations
of -COOH groups ( (C-O)+
(OH)) to higher frequencies (1311, 1315 and 1302 cm-1 for co-1,
p-
ν
β
co-2 and co-3, respectively). Additionally, in the spectrum of free acid, strong band at 916
cm-1 can be observed due to out-of-plane deformation vibrations of carboxylic OH group.26 In
the spectra of co-crystals this band disappears.
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Fig.3 ATR-FTIR spectra of co-1 and co-2 (monoclinic form) and co-3 (orthorhombic form) in the
range 1800-650 cm-1
The ATR-FTIR spectrum of free DMP exhibits two bands at 3394 and 3306 cm-1
assigned to the asymmetric νasym(NH2) and symmetric νsym(NH2) stretching vibrations of
amine group. This group is involved in N-H…N hydrogen bonds with different geometry.27 In
all co-crystals spectra, shifts of these bands to lower frequencies are observed. The greatest
shift of νasym(NH2) bands is observed in the case of co-3 where the strongest N-H∙∙∙Ocar
hydrogen bonds appear. The infrared stretching vibrations with the associated shifts (in
brackets) in comparison with DMP are given in Table 2.
Table 2 Infrared stretching vibrations for amine NH2 groups in free DMP and co-crystalsa
Peak assignment
DMP
3394
Co-1
3332(-62)
Co-2
3324(-70)
Co-3
3311(-83)
amine ν(NH2)asym(cmꢀ1)
N-H…O(carb)/3.002
N-H…N(pyrim)/3.060
N-H…O(carb)/2.947
N-H…O(H2O)/3.077
N-H…O(carb)/2.854
(D…A distance/ Ǻ)
amine ν(NH2)sym(cmꢀ1)
3306
3170(-136)
3192(-114)
3180(-126)
aThe values given in the brackets are the frequency shifts in comparison with the corresponding groups in the co-
former DMP
X-ray crystallography
Molecular and crystal structure of p-XBTA
The title compound crystallizes in the monoclinic C2/c space group (Table 1) with a
half of molecule in the asymmetric unit. The compound is a flexible symmetric dicarboxylic
acid which bears two S atoms in the aliphatic side-chains of benzene ring. The
centrosymmetric molecule of p-XBTA, with the inversion centre at the mid-point of the
aromatic ring, is non-planar (Fig. 4a). The thioacetic moieties are strongly twisted away from
the plane of xylylene unit due to sp3 hybridization of sulphur and methylene carbon atoms.
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The orientation of the central moiety in relation to the carboxylic group is defined by the C1-
C2-S1-C3 torsion angle (Table S1, Supplementary Materials). In -XBTA atom C1 adopts a -
p
synclinal (-sc) orientation with respect to xylylene C3. In turn, the thioacetic S1 atom is -
anticlinal (-ac) with respect to hydroxyl O1 and anticlinal (+ac) to phenyl C5 atom. The
dihedral angle between the best planes of benzene ring and carboxylic group is 58.0(1)°. Due
to symmetry, the carboxylic groups adopt trans-coplanar configuration with respect to the
phenyl unit. Twisting of the carboxylic group from the plane of the central ring is also
observed in other phenylacetic acids.28-30 The bent conformation of the aliphatic side-chains
is stabilized via intramolecular, three-centre C5-H5…O2, C3-H3a…O2 hydrogen bonding
(Table 3, Fig. 4a). The carboxylic groups in p-XBTA adopt the syn conformation and the O1-
C1-O2 angle of 123.7(1)° is typical of protonated carboxylic acids.31 All remaining bond
lengths and angles (Table S1, SM) are in accordance with the standard values.32
The supramolecular network of
p
-XBTA is built up from centrosymmetric hydrogen-
ͦ
ͦ
bonded dimers with ͌ (8) ring motif (Fig. 4b). This ͌ (8) homosynthon is favoured over
ͦ
ͦ
catemar motif in benzenecarboxylic acids.31 The acid molecules form infinite 1-D chains
extending along the [101] direction, in which the molecules are linked to each other via
strong, linear hydrogen bonds of O−H∙∙∙O type (Table 3). Along with strong hydrogen bonds,
weak interactions contribute to self-assembly processes in p-XBTA. These contacts can be
observed between one of H-atoms of the methylene group of acetic moiety and O-atom the
carboxylic groups as well as between sulphur atom and Car−H donor of benzene ring. As can
be seen from Figs 4b and 4c, the former C2-H2b…O1 (symmetry code: 1/2-x, 1/2-y, 2-z)
interactions link adjacent [101] molecular chains into (-111) layers, whereas the latter
C5−H5…S1 (1/2-x, 1/2+y, 3/2-z) contacts lead to folded (-202) molecular layers. The combination
of the motifs gives a complex 3-D supramolecular architecture (Fig. 4d).
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Fig. 4 (a) Molecular structure of p-XBTA with the atom labelling scheme. (b) (c) Hydrogen-
bonded molecular layers, parallel to (-111) and (-202) crystallographic planes, respectively.
(d) Crystal packing in view along the a-axis. Displacement ellipsoids are drawn at the 50%
probability level. Dashed lines indicate hydrogen bonds.
Table 3. Geometries of proposed hydrogen bonds
Bond
Symmetry
operations
D−H /Å
H⋅⋅⋅A /Å
D−H⋅⋅⋅A /Å
p-XBTA
<D−H⋅⋅⋅A/°
0.83(2)
0.93
0.97
0.96
0.93
1.85(2)
2.64
2.59
2.62
2.98
2.677(2)
3.407(2)
3.212(2)
3.543(2)
3.903(2)
180(1)
140
122
162
137
1-x, 1-y, 2-z
x, y, z
x, y, z
1/2-x, 1/2-y, 2-z
1/2-x, 1/2+y, 3/2-z
O1−H1o⋅⋅⋅O2
C5−H5⋅⋅⋅O2
C3−H3a⋅⋅⋅O2
C2−H2b⋅⋅⋅O1
C5−H5⋅⋅⋅S1
co-1
0.90
0.85
0.93
0.97
0.80
0.93
1.69
2.17
2.70
2.68
2.28
2.43
2.580(2)
3.002(2)
3.365(2)
3.284(2)
3.060(3)
3.283(3)
168
169
129
121
167
153
x, y, z
x, y, z
O1−H1o⋅⋅⋅N1
N2−H21⋅⋅⋅O2
C5−H5⋅⋅⋅O1
C3−H3a⋅⋅⋅O1
N2−H22⋅⋅⋅N3
C9−H9⋅⋅⋅O2
x, y, z
x, y, z
-x, 2-y, 1-z
x, 3/2-y, -1/2+z
co-2
0.99
1.60
2.583(3)
2.947(4)
3.077(4)
2.892(3)
2.776(3)
174
x, 1/2-y, 1/2+z
x, 1/2-y, -1/2+z
-x, -1/2+y, 1/2-z
x, y, z
O1−H1o⋅⋅⋅N1
N2−H21⋅⋅⋅O2
N2−H22⋅⋅⋅O1w
O1w−H1w⋅⋅⋅N3
O1w−H2w⋅⋅⋅O1w
0.89(3)
0.90(4)
0.88(4)
0.76(3)
2.06(4)
2.20(4)
2.02(4)
2.05(3)
173(1)
165(1)
168(1)
159(1)
-x, 1/2+y, 1/2-z
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0.97
0.93
0.93
2.69
3.332(4)
3.605(3)
3.349(3)
124
127
161
x, y, z
C3−H3a⋅⋅⋅O1
C5−H5⋅⋅⋅S1
C9−H9⋅⋅⋅O2
2.96
2.46
1-x, 1/2+y, 3/2-z
x, 1+y, z
co-3
1.02(3)
0.90(2)
0.93(2)
0.99(2)
0.95(2)
1.60(3)
1.96(2)
2.61(2)
2.97(2)
2.92(2)
2.611(2)
2.854(1)
3.381(2)
3.800(2)
3.809(2)
171(1)
172(1)
141(1)
142(1)
156(1)
x, 1/2 -y, -1/2+z
x, 1/2-y, 1/2+z
x, y, z
O1−H1o⋅⋅⋅N1
N2−H21⋅⋅⋅O2
C10−H10c⋅⋅⋅O2
C3−H3b⋅⋅⋅S1
C2−H2a⋅⋅⋅S1
x, 1/2+y, 3/2-z
x, -1/2+y, 3/2-z
Crystal structure of p-XBTA (DMP)2 (co-1
)
The crystal structure of p-XBTA (DMP)2 belongs to the monoclinic P21/c space group. The
asymmetric unit of co-1 contains a half of acid molecule and one molecule of 2-amino-4,6-
dimethylpyrimidine (Fig. 5a). The bond distances in the carboxylic groups of the acid (C1-O1:
1.310(3) Å; C1-O2: 1.225(3) Å) as well as those in the pyrimidine ring (C7-N1: 1.361(3) Å; C7-
N3: 1.359(3) Å) confirm that both co-formers are in their neutral form in the crystal. The
overall geometry of the acid in co-1 is quite similar to that observed in
relative orientation of –COOH group with respect to the central moiety. As indicated from
the O1-C1-C2-S1 torsion angle (91.1(2) ) the hydroxyl O1 atom in co-1 is +ac with respect to
p-XBTA except for the
°
the S1 atom, vs the -ac conformation (torsion angle: -97.1(1)°) observed in the crystal of the
pure acid. The dihedral angle between the best planes of benzene ring and carboxylic group
is 41.2(2)°. Another conformational difference between the molecules results from small
rotation around the C3-C4 bond (Table S1, SM). Opposite orientation of the carboxylic group
is induced by hydrogen-bonding patterns. Every acid molecule in co-1 is connected with two
DMP molecules through the pairs of hydrogen bonds: Ocar−H∙∙∙Npyr and Npyr−H∙∙∙Ocar with a
ͦ
graph set of ͌ (8) (Table 3, Fig. 5a). Additionally, the observed self-association of the base
ͦ
ͦ
molecules is observed due to preferences of DMP for formation of homosynthon ͌ (8) via
ͦ
N-H∙∙∙N hydrogen bonds (Fig. 5b). In the current structure, characteristic discrete motifs
composed of a pair DMP molecules and two acid can be distinguished (Fig. 5b). The same
association mode was observed in some others, previously reported co-crystals of DMP with
different monocarboxylic acids 12, 33-36 as well as with glutaric, adipic11 or terephthalic acid.37, 38
The translation related heterotetramers (LHT) form molecular tapes parallel to (212) crystallo-
graphic plane. The adjacent tapes are packed to form 2-D layers stabilized via weak C11-
H11b⋅⋅⋅πpyr (dC11⋅⋅⋅πcent=3.451(2) Å, dH11b⋅⋅⋅πcent=2.60 Å, <C11-H11b⋅⋅⋅πcent=157°; symmetry code:
x, y+1, z) interactions and π-stacking contacts (Fig. 5d) involving almost coplanar pyrimidine
rings and carboxylic groups. The other non-covalent forces stabilizing the 3-D network of co-1
are weak interactions of CCH2-H⋅⋅⋅O type (Table 3, Fig. 5c) occurring between the adjacent
perpendicular layers.
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Fig.5 Part of the crystal structure of co-1 showing: (a) molecular structure of co-formers
linked via strong O1-H1o…N1 and N2-H21…O2 hydrogen bonds; (b) linear heterotetramer
(LHT) stabilized by strong hydrogen bonds; (c) crystal packing in view along the b-axis; (d)
crystal packing in view along the a-axis. Dashed lines indicate hydrogen bonds.
Co-crystal description of p-XBTA (DMP)2⋅2H2O (co-2)
p-Xylylene-bis-(thioacetic) acid and 2-amino-4,6-dimethylpyrimidine form a 1:2 co-
crystal of the formula p-XBTA (DMP)2⋅2H2O (co-2) (Fig. 6a) during crystallization from DMSO
or ethanol-water mixture. The hydrate crystallizes in the monoclinic P21/c space group, with
a half of p-XBTA, one DMP and one water molecule in the asymmetric unit. Inclusion of the
water molecules into the crystal does not entail any significant changes in the overall
geometry of the acid compared to that observed in co-1. The only noticeable conformational
changes result from small rotation around S1-C2 and C3-C4 bonds (Table S1, SM). Much
more visible differences are in supramolecular association modes. The most characteristic
motif observed in co-2 is a trimer composed of two DMPs and one acid molecule through
ͦ
the predominant ͌ (8) heterosynthons (Fig. 6b). Each acid molecule is connected with two
ͦ
adjacent 2-amino-4,6-dimethylpyrimidine molecules via a pair of hydrogen bonds:
ͦ
Ocar−H∙∙∙Npyr and Npyr−H∙∙∙Ocar creating a ͌ (8) ring motif (Table 3, Figs 6b,c). It is worth
ͦ
noting that each DMP molecule is engaged only once in formation of the above motif. The
other pyrimidine nitrogen atom participates in Ow-H∙∙∙Npyr hydrogen bonds. Additionally, the
amine group is involved in N-H∙∙∙Ow interactions with another water molecule (Table 3).
Water molecules play the crucial role in the architecture of the studied co-crystal. As can be
seen from the crystal packing view along the b-axis (Fig. 6c), they serve as a ‘molecular glue’
filling a free space between the adjacent trimeric motifs. Hydrogen-bonded water molecules
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are propagated along the b-axis forming 1-D helical chains (Fig. 6d) with a distance between
the neighbouring oxygen atoms equal to 2.776(3) Å. Chains of water molecules are
accommodated between columns of 2-amino-4,6-dimethylpyrimidines. Apart from strong
hydrogen bonds the 3-D structure of co-2 is stabilized by weak intermolecular Car−H⋅⋅⋅S and
Cpyr−H⋅⋅⋅Ocar interactions (Table 3, Fig. 6c).
Fig. 6 (a) Molecular structure of co-formers in co-2 linked via strong hydrogen bonds; (b)
hydrogen-bonding patterns; (c) crystal packing in view along the b-axis; (d) helical chains of
water molecules in view along a-axis. Dashed lines indicate hydrogen bonds.
Crystal structure of p-XBTA DMP (co-3
)
The orthorhombic form of p-XBTA DMP crystallizes in the Cmca space group. This co-crystal
can be grown from the acetonitryle, ethyl acetate or propan-2-ol solvents. The asymmetric
unit of co-3 comprises a half of the acid and a half of 2-amino-4,6-dimethylpyrimidine
molecule (Fig. 7a). Each acid molecule is associated with two base molecules through two
pairs of hydrogen bonds: Ocar−H∙∙∙Npyr and Namine−H∙∙∙Ocar (Table 3, Fig. 7b) which form
ͦ
characteristic heterosynthons ͌ (8). The same heterotrimeric (HT) motif was found in co-
ͦ
crystals of DMP with cinnamic acid,39 3-phenylacrylic acid,12 3,5- and 3,4-dimethylbenzoic
acids.36 The trimeric units are repeated along the a-axis forming infinite chains. The DMP
molecules in such a motif are coplanar. On the contrary, reflected through a mirror plane p-
XBTA molecules are not coplanar; the best-planes of their phenyl rings form an angle of
19.0(1)°. The crystal packing view along the a axis (Fig. 7c) shows that chains are arranged
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into the (010) molecular layers stabilized by weak CCH3−H⋅⋅⋅Ocar hydrogen bonds. Interlayer
stabilization is provided by cyclic CCH −H⋅⋅⋅S interactions (Table 3, Fig. 7d).
2
Fig. 7 (a) Molecular structure of co-formers in co-3 linked via strong O1-H1o…N1 and N2-
H2a…O2 hydrogen bonds; (b) heterotrimer (HT) stabilized by strong hydrogen bonds; (c)
crystal packing in view along the b-axis; (d) crystal packing in view along the a-axis. Dashed
lines indicate hydrogen bonds.
Thermal analysis
Detailed TG/DSC experiments were carried out for each co-crystal to study the
thermal behaviour in comparison with that of co-formers. The TG and DSC curves for DMP,
p
-XBTA and co-crystals are presented in Figures 8 and 9. As can be seen from the TG curves,
thermal decomposition of obtained co-crystals is entirely different from that of co-formers.
Additionally, diverse chemical composition and crystal structures of co-crystals give rise to
different ways of their thermal decomposition. The DSC curves for all compounds showed a
single endothermic effect corresponding to the melting points (DMP: 153.0°C;
p-XBTA:
153.0°C; co-1: 152.5°C; co-2: 150.2°C; co-3: 156.7°C). The melting point of co-crystals was
distinct from either of the individual components confirming the formation of new phases.
Very small differences in the melting point values between the co-crystals and co-formers
are due to the same melting point ranges of both single components. The presence of water
molecules in co-2 was confirmed by thermal analysis. The co-2 hydrate, showed two
endothermic effects where the first (110°C) is connected with loss of water molecules. The
TG curve confirmed the effect of a loss of water (∼5.9% of the total weight) that matched
approximately to one water molecule in the asymmetric unit (Fig. 9). The analysis of the
melting points of all co-crystals reveals that the orthorhombic co-3 displays an improved
thermal stability over the free DMP component, while both monoclinic forms (co-1 and co-2)
remain nearly the same showing decreased thermal stability compared to that of DMP.
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Fig. 8 TG (a) and DSC (b) curves of
p-XBTA, DMP and co-1, co-2, co-3
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Fig. 9 TG and DSC curves of co-2
Conclusions
New flexible thiocarboxylic acid and its co-crystals with DMP were synthesized
and characterized thoroughly by single crystal XRD, TG, DSC and ATR-FTIR. Depending on the
solvent used for crystallization, three different forms of co-crystals have been isolated. The
acid molecules are connected via pairs of O−H∙∙∙O hydrogen bonds into the 1-D infinite
chains which are further associated into the 3-D supramolecular network.
In all three forms of co-crystals acid binds with the DMP via N-H∙∙∙O and O-H∙∙∙N hydrogen
bonds. In co-1, the formation of linear heterotetramer is observed. Notably, co-2 represents
the first example of hydrated form of the co-crystal of 2-amino-4,6-dimethyl pyrimidine with
carboxylic acid. In the above-mentioned co-crystal form, pair of water molecules linked
trimeric moieties composed of two DMP and one acid molecule. The hydrated form co-2 was
formed from the C2H5OH/H2O mixture or DMSO solvent. Water as a good hydrogen bonds
donor competes with p-XBTA acid in interaction with the DMP base forming O-H(water)⋅⋅⋅N
connection.
The water molecules in hydrated co-crystal play the role of ‘molecular glue’ filling the free
space in the crystal. Formation of hydrated co-crystal from the DMSO solvent can be
explained by slow evaporation of this solvent and absorption of the moisture from the air.
The crystal structure of co-3 consists of heterotrimers. The hydrogen bonding
supramolecular synthons observed in the structures are consistent with the fact that the
strong acceptors prefer strong donors and the weak acceptors prefer the weak donors.
The analysis of the melting points of all co-crystals reveals that the orthorhombic
form of co-3 displays an improved thermal stability.
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In conclusion, this work indicates that p-xylylene-bis(thioacetic) acid is a good
participant in hydrogen-bonding networks for the formation of acid-base molecular co-crystals.
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329x128mm (96 x 96 DPI)