Co-crystals of an agrochemical active - A pyridine-amine synthon for a thioamide group

Article abstract of DOI:10.1016/j.molstruc.2011.10.004

Five novel co-crystals of thiophanate-ethyl (TE), an agrochemical active, with di(2-pyridyl)ketone (1), 2-benzoylpyridine (2), 3-benzoylpyridine (3), 4-phenylpyridine (4) and biphenyl (5) were found and crystal structures of four of them (TE1-TE3, TE5) so

Full text of DOI:10.1016/j.molstruc.2011.10.004

Journal of Molecular Structure 1006 (2011) 566–569
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Co-crystals of an agrochemical active – A pyridine-amine synthon
for a thioamide group
⇑
E. Nauha, M. Nissinen
Department of Chemistry, Nanoscience Center, University of Jyväskylä, P.O. Box 35, FIN-40014 Jyväskylä, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
Five novel co-crystals of thiophanate-ethyl (TE), an agrochemical active, with di(2-pyridyl)ketone (1), 2-
benzoylpyridine (2), 3-benzoylpyridine (3), 4-phenylpyridine (4) and biphenyl (5) were found and crystal
structures of four of them (TE1–TE3, TE5) solved by single crystal X-ray diffraction. Three of the co-crys-
tals (TE1–TE3) form by way of a reliable pyridine-amine hydrogen bond synthon and one (TE5) because
of close packing effects. The fifth co-crystal was identified by X-ray powder diffraction. The work demon-
strates the usage of a reliable supramolecular synthon for crystal engineering, while concurrently
reminds that the close packing of even very similar molecules cannot be fully predicted.
Ó 2011 Elsevier B.V. All rights reserved.
Received 16 August 2011
Received in revised form 3 October 2011
Accepted 3 October 2011
Available online 8 October 2011
Keywords:
Co-crystal
Synthon
Agrochemical
Thioamide
X-ray diffraction
1. Introduction
supramolecular structures with azaheterocycles. Ellis et al. [7] used
the same approach for a number of thiocarbamide derivatives and
Co-crystal, i.e. multi-component molecular crystals, are of an
interest to pharmaceutical and agrochemical companies as possi-
ble new and improved dosage forms [1]. The primary method of
designing new co-crystals is the use of reliable supramolecular
synthons [2], which are mainly composed of hydrogen bonds. Ac-
tive ingredients often have many functional groups capable of
hydrogen bonding, which makes this approach somewhat chal-
lenging.
found that they formed many 2:1 co-crystals with bipyridine-type
molecules. As agrochemical and pharmaceutical actives are often
quite complicated molecules with a number of functionalities,
we wanted to see if the pyridine-amine synthon would work well
for such systems.
2. Experimental
We have previously investigated the polymorphism and solvate
formation of an agrochemical active, thiophanate-ethyl (TE, diethyl
4,40-(o-phenylene)bis(3-thioallophanate)) (Scheme 1), which was
found to have four polymorphs and seven solvate forms [3]. TE
and an analogous thiophanate-methyl [4] both have a hydrogen
bonded pyridine solvate. They have also been found to make
co-crystals [5] with 2,20-bipyridine, 4,40-bipyridine and 1,2-bis
(4-pyridyl)ethane. Inspired by the success, we wanted to investi-
gate whether the NAHꢀ ꢀ ꢀN hydrogen bond could be used further
for co-crystal design and screened with a series of azaheterocycles
(1–4) (Scheme 1) containing a pyridine moiety. Biphenyl (5)
(Scheme 1) was selected as a comparison to investigate if it would
take the place of 2,20-bipyridine and make an arrangement also
seen in several isomorphous solvates of TE.
2.1. Slurries and crystallizations
TE (99% Chem Service), biphenyl (99% Merck), 4-phenylpyridine
(97% Aldrich), 2-benzoylpyridine (99% Aldrich), 3-benzoylpyridine
(97% Aldrich), di(2-pyridyl)ketone (99% Aldrich), distilled water
and solvents of analytical purity (min 99%) were used in the crys-
tallization and slurry experiments. Screening was started with
slurries (50 mg of TE and 25–150 mg of azaheterocycle/biphenyl
depending on solubility and starting from a ratio of 1:1) in 2 ml
of 1:4 MeCN:water, which were mixed for 1 month in RT. Evapora-
tion crystallizations of the slurry samples in 1:1 MeCN:water or in
MeCN (in the case of 2-benzoylpyridine) resulted in single crystals
suitable for crystal structure determination for samples of TE with
(1), (2), (3) and (5).
Piotrkowska et al. [6] found dithiooxamide, a simpler com-
pound that has some of the same functionalities as TE and TM, to
be a convenient substrate for construction of two component
2.2. Powder X-ray diffraction
⇑
For powder X-ray diffraction (PXRD) analysis the original com-
pounds and the slurries were pressed to a zero background silicon
Corresponding author. Tel.: +358 50 428 0804; fax: +358 14 617 412.
E-mail address: maija.nissinen@jyu.fi (M. Nissinen).
0022-2860/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2011.10.004

E. Nauha, M. Nissinen / Journal of Molecular Structure 1006 (2011) 566–569
567
refinement parameters are presented in Table 1. To verify the iden-
tity of the isomorphic co-crystals, cross refinement of the differing
C/N in di(2-pyridyl)ketone and 2-benzoylpyridine were done
resulting in higher R-values and too small/large ellipsoids.
O
O
H
H
O
O
N
S
H
H
N
S
N
N
3. Results and discussion
(TE)
N
3.1. Hydrogen bonded co-crystals
N
O
The isomorphic di(2-pyridyl ketone) (TE1) and 2-benzoylpyri-
dine (TE2) co-crystals have a ratio of 1:1 TE:(1)/(2). The structures
exhibit a complicated array of single and bifurcated hydrogen
bonds (Fig. 1), unlike in the other TE structures [3,5], where a pair-
ing of two donors and acceptors is often seen. The two NAH hydro-
gen atoms that participate in a S(6) intramolecular motif [12] are
not further hydrogen bonded. However, the C@O acceptors of the
same motif are additionally involved in hydrogen bonding to adja-
cent bifurcated NAH donors. The C1,1(4) and C1,1(11) motifs start-
ing from the bifurcated NAH donors combine to build double
chains of TE molecules running in the direction of the crystallo-
graphic b-axis. When CAH donors are taken into account, one of
the C@S sulfurs and ether oxygen atoms also participate in hydro-
gen bonding within the TE chains. The azaheterocycles (1) and (2)
are connected to one arm of TE with the pyridine-amine synthon.
In addition, the C@O in (1) and (2) have a weak hydrogen bond
to the methyl groups of TE of the adjacent chains. In TE1 the other
pyridine nitrogen of (1) is, however, not involved in hydrogen
bonding.
N
N
O
O
N
(2)
(3)
(4)
(1)
(5)
Scheme 1. Molecular structures of TE, di(2-pyridyl)ketone (1), 2-benzoylpyridine
(2), 3-benzoylpyridine (3), 4-phenylpyridine (4) and biphenyl (5).
plate and measured on a PANalytical X’Pert Pro system in reflection
mode with Cu Ka1-radiation. A 2h-angle range of 3–35° and a step
time of 60 s were used with step resolution of 0.0167°. Figures
were drawn with X’Pert HighScore Plus [8].
2.3. Single crystal X-ray diffraction
The single crystal X-ray diffraction data was collected on Nonius
Kappa CCD-diffractometer with Apex II detector at 173 K, using
graphite-monochromated Cu K
a
radiation (k = 1.54178 Å). Absorp-
In TE 3-benzoylpyridine (TE3) co-crystal the ratio of TE to
3-benzoylpyridine (3) is 1:2. The 3-benzoylpyridine molecules
are hydrogen bonded to both arms of the TE molecule in a second
level D2,2(12) motif (Fig. 2a) containing the pyridine-amine syn-
thon. The assembly is very symmetrical, but the symmetry is not
tion correction was performed with Denzo-SMN 1997 [9]. The
structures were solved using direct methods, refined, and ex-
panded by using Fourier techniques with the SHELX-97 software
package [10]. All non-hydrogen atoms were refined anisotropi-
cally. Hydrogen atoms were placed in idealized positions or found
from the electron density map (hydrogen bonding NAH hydro-
gens), and included in structure factor calculations. The NAH
hydrogen atoms found in the electron density map were restrained
to a distance of 0.91 Å for TE1 and TE2 to give the best fit to the
X-ray data and to ensure stable refinement. Pictures of the struc-
tures were drawn with Mercury 2.4 [11]. Crystal data and
crystallographic on
a larger scale. There are weak aromatic
CAHꢀ ꢀ ꢀO@C hydrogen bonds between adjacent 3-benzoylpyridine
molecules as well as from the C@O of TE to the 3-benzoylpyridine
molecules. A weak CAHꢀ ꢀ ꢀS@C hydrogen bond strengthens the pyr-
idine-amine hydrogen bond. If all the weak hydrogen bonds are
taken into account the molecules build up chains (Fig. 2b) that
elongate in the direction of the crystallographic a-axis.
Table 1
Crystal data and refinement parameters.
TE1ekn035
TE2ekn042
TE3ekn033
TE5ekn034
Chemical formula
C
14H18N4O4S2
C14H18N4O4S2
C12H9NO
553.65
Monoclinic
P21/c
C14H18N4O4S2
2(C12H9NO)
736.85
Monoclinic
P21/c
C14H18N4O4S2
C11H8N2O
554.64
Monoclinic
P21/c
0.5(C12H10
447.54
Triclinic
P ꢁ 1
)
Mr
Crystal system
Space group
Temperature (K)
a (Å)
b (Å)
c (Å)
173
173
173
173
12.7612 (7)
8.3916 (4)
26.3679 (14)
90
112.022 (3)
90
2617.6 (2)
4
2.26
12.8497 (5)
8.5996 (3)
26.0775 (9)
90
112.182 (2)
90
2668.4 (2)
4
2.20
10.4541 (4)
26.8015 (11)
13.1925 (6)
90
102.607 (2)
90
3607.2 (3)
4
1.80
8.8861 (1)
10.0077 (2)
12.7746 (3)
85.098 (2)
78.793 (1)
79.930 (1)
1095.65 (4)
2
a
(°)
b (°)
c
(°)
V (Å3)
Z
l
(mmꢁ1
)
2.49
Crystal size (mm)
Tmin, Tmax
No. of meas., indep. and obs. [I > 2r(I)] reflections
0.15 ꢂ 0.05 ꢂ 0.05
0.728, 0.896
6507, 4031, 2035
0.137
0.079, 0.214, 1.03
4031
345
4
0.39, ꢁ0.36
0.12 ꢂ 0.10 ꢂ 0.06
0.778, 0.879
7725, 4631, 3414
0.069
0.050, 0.126, 1.05
4631
357
4
0.24, ꢁ0.29
0.30 ꢂ 0.08 ꢂ 0.06
0.614, 0.900
11,459, 6233, 3761
0.107
0.064, 0.164, 1.02
6233
484
0
0.32, ꢁ0.28
0.22 ꢂ 0.22 ꢂ 0.20
0.610, 0.635
5449, 3754, 3396
0.085
0.046, 0.126, 1.03
3754
285
0
0.29, ꢁ0.28
Rint
R[F2 > 2
r
(F2)], wR(F2), S
No. of reflections
No. of parameters
No. of restraints
D
qmax
,
D
qmin (e Åꢁ3
)

568
E. Nauha, M. Nissinen / Journal of Molecular Structure 1006 (2011) 566–569
The PXRD patterns measured from the slurry samples, except
determined structure of TE2 indicates the formation of another
crystal form that, however, did not crystallize as suitably sized
and quality single crystals when the slurry sample was used for
the single crystal experiments. No single crystals for the TE co-
crystal with 4-phenylpyridine (TE4) were acquired, but the PXRD
pattern of the slurry sample was of neither 4-phenylpyridine nor
any of the known TE forms, indicating the formation of a co-crystal
(Fig. 4). Hydrogen bonding wise the co-crystal (TE4) is expected to
be similar to the TE co-crystal with 4,40-bipyridine [5], which only
for the 2-benzoylpyridine, matched well with the calculated
powder diffraction patterns of the determined structures (Fig. 3).
The reason for the mismatch between the slurry powder and the
Fig. 1. Hydrogen bonding chains in the di(2-pyridyl ketone) (TE1) and 2-benzoyl-
pyridine (TE2) co-crystals with CAH hydrogen atoms removed for clarity. (In the
web version C1,1(4) motif hydrogen bonds are in blue, C1,1(11) motif hydrogen
bonds in green and other hydrogen bonds in red.)
Fig. 3. Experimental slurry PXRD patterns and calculated PXRD patterns of co-
crystals TE1, TE2 and TE3.
Fig. 2. (a) Strong hydrogen bonding and (b) the weakly hydrogen bonded chains in
the 3-benzoylpyridine (TE3) co-crystal with non-hydrogen bonding hydrogen
atoms removed for clarity. (In the web version strong hydrogen bonds in red, weak
CAHꢀ ꢀ ꢀO@C hydrogen bonds in green and weak CAHꢀ ꢀ ꢀS@C hydrogen bonds in
blue.)
Fig. 4. PXRD patterns of 4-phenylpyridine (4), the TE4 slurry sample, TE and the
calculated PXRD pattern of the TE co-crystal with 4,40-bipyridine.

E. Nauha, M. Nissinen / Journal of Molecular Structure 1006 (2011) 566–569
569
uses one of the pyridine functional groups for hydrogen bonding to
TE. The PXRD patterns of these were compared, but they are not
similar (Fig. 4). The TE co-crystal with 4,40-bipyridine, however,
has a Z0 of 3 and is likely polymorphic, so a similar hydrogen bond-
ing arrangement for TE4, but with different packing, is still likely.
between the chains in discrete cavities with no clear interactions
to the TE molecules. The PXRD pattern of the slurry sample
(Fig. 6) still contained peaks of pure biphenyl (5), but otherwise
the pattern matched well with the pattern calculated from the sin-
gle crystal structure.
4. Conclusions
3.2. Biphenyl
Five novel co-crystal forms of TE with a selected group of pyri-
dine containing molecules and a structurally similar biphenyl were
found and the crystal structures of four of these solved with single
crystal X-ray diffraction. Co-crystal design using the pyridine-
amine synthon works well for TE, even though it has other function-
alities, which could hinder formation of the desired synthon. The
packing of the biphenyl co-crystal, however, could not be predicted
even though the shape of the molecule is very similar to 2,20-bipyr-
idine, for which TE builds a packing arrangement containing chan-
nels of guest also seen in a number of isomorphic solvates [3]. If no
strong hydrogen bonding, like the pyridine amine synthon, to a
guest is formed, TE builds chains connected via a R2,2(8) motif of
two NAHꢀ ꢀ ꢀS@C hydrogen bonds. These chains, which are also seen
in most of the polymorphs of TE [3], can organize to leave in hydro-
phobic cavities that the guests can fill. The non-hydrogen bonding
guest molecules, like biphenyl, likely act as templates for the pack-
ing of the chains. The strong NAHꢀ ꢀ ꢀN synthon breaks the formation
of these chains and is a determining factor in the formation of the
co-crystal structures of TE. The pyridine-amine synthon was found
to be very useful in the design of co-crystals for molecules contain-
ing a thioamide group (AC(@S)AN(H)A), which is seen in agro-
chemical and pharmaceutical actives.
In order to explore the effect of general molecular shape vs. the
effect of the NAHꢀ ꢀ ꢀN synthon we crystallized TE with biphenyl.
The arrangement (Fig. 5) in the biphenyl co-crystal (TE5), however,
is different to that of the 2,20-bipyridine co-crystal [5] even though
the ratio of TE to guest (2:1) is the same. The main hydrogen bond-
ing network of TE molecules is the same with chains of TE
connected with a R2,2(8) motif consisting of two NAHꢀ ꢀ ꢀS@C
hydrogen bonds. The chains pack parallel to each other with the
aid of
p–p interactions between the TE benzene rings with ring
centroid to centroid distances of 3.81 Å. There are also weak hydro-
gen bonds from the C@O of TE to one of the benzene ring hydrogen
atoms in an adjacent chain. The biphenyl molecules are located
Supplementary material
CCDC 838991–838994 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or
from the Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033).
Fig. 5. Hydrogen bonding in the biphenyl co-crystal (TE5) with two biphenyl
molecules between the chains shown in space fill style and CAH hydrogen atoms
removed for clarity.
Acknowledgements
We would like to thank the Academy of Finland (Proj. no.
116503) and the University of Jyväskylä for funding this work.
References
[1] P. Wishweshwar, J.A. McMahon, M.J. Zaworotko, Crystal engineering of
pharmaceutical co-crystals, in: E.R.T. Tiekink, J.J. Vittal (Eds.), Frontiers in
Crystal Engineering, John Wiley & Sons, England, 2006, pp. 25–46.
[2] G.R. Desiraju, Angew. Chem. Int. Ed. Eng. 34 (1995) 2311, doi:10.1002/
anie.199523111.
[3] E. Nauha, A. Ojala, M. Nissinen, H. Saxell, CrystEngComm 13 (2011) 4956,
doi:10.1039/C1CE05077J.
[4] E. Nauha, H. Saxell, M. Nissinen, E. Kolehmainen, A. Schäfer, R. Schlecker,
CrystEngComm 11 (2009) 2536, doi:10.1039/b905511h.
[5] E. Nauha, E. Kolehmainen, M. Nissinen, CrystEngComm 13 (2011) 6531,
doi:10.1039/C1CE05730H.
[6] B. Piotrkowska, A. Wasilewska, M. Gdaniec, T. Polonski, CrystEngComm 10
(2008) 1421.
[7] C.A. Ellis, M.A. Miller, J. Spencer, J. Zukerman-Schpector, E.R.T. Tiekink,
CrystEngComm 11 (2009) 1352.
[8] PANalytical B.V., 2.2b, 2006.
[9] Z. Otwinowski, D. Borek, W. Majewski, W. Minor, Acta Cryst. A59 (2003) 228,
doi:10.1107/S0108767303005488.
[10] G.M. Sheldrick, Acta Cryst. A64 (2008) 112.
[11] C.F. Macrae, P.R. Edgington, P. McCabe, E. Pidcock, G.P. Shields, R. Taylor, M.
Towler, J. van de Streek, J. Appl. Cryst. 39 (2006) 453, doi:10.1107/
S002188980600731X.
[12] M.C. Etter, J.C. MacDonald, Acta Cryst. B46 (1990) 256;
J. Bernstein, R.E. Davis, L. Shimoni, N-L. Chung, Angew. Chem. Int. Ed. Engl. 34
(1995) 1555.
Fig. 6. PXRD patterns of biphenyl (5), TE, the TE5 slurry with peaks of (5) visible,
and the calculated pattern from the structure.