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

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-crystals (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 demonstrates 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.


Introduction
Co-crystal, i.e. multi-component molecular crystals, are of an interest to pharmaceutical and agrochemical companies as possible 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. Active ingredients often have many functional groups capable of hydrogen bonding, which makes this approach somewhat challenging.
We have previously investigated the polymorphism and solvate formation of an agrochemical active, thiophanate-ethyl (TE, diethyl 4,4'-(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 2,2'-bipyridine, 4,4'-bipyridine and 1,2-bis(4-pyridyl)ethane. Inspired by the success, we wanted to investigate whether the N-H···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 2,2'-bipyridine and make an arrangement also seen in several isomorphous solvates of TE.

Powder X-ray diffraction
For powder X-ray diffraction (PXRD) analysis the original compounds and the slurries were pressed to a zero background silicon plate and measured on a PANalytical X'Pert Pro system in reflection mode with CuKα1-radiation. A 2θ-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].

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 CuKα radiation (λ = 1.54178 Å). Absorption correction was performed with Denzo-SMN 1997 [9]. The structures were solved using direct methods, refined, and expanded by using Fourier techniques with the SHELX-97 software package [10]. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were placed in idealized positions or found from the electron density map (hydrogen bonding N-H hydrogens), and included in structure factor calculations. The N-H 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 structures were drawn with Mercury 2.4 [11]. Crystal data and refinement parameters are presented in Table 1. To verify the identity of the isomorphic co-crystals, cross refinement of the differing C/N in di(2-pyridyl)ketone and 2benzoylpyridine were done resulting in higher R-values and too small/large ellipsoids.

Hydrogen bonded co-crystals
The isomorphic di(2-pyridyl ketone) (TE1) and 2-benzoylpyridine (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 pairing of two donors and acceptors is often seen. The two N-H hydrogen 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 adjacent   The PXRD patterns measured from the slurry samples, except 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 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 4,4'-bipyridine [5], which only 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 4,4'-bipyridine, however, has a Z' of 3 and is likely polymorphic, so a similar hydrogen bonding arrangement for TE4, but with different packing, is still likely.

Biphenyl
In order to explore the effect of general molecular shape vs. the effect of the N-H···N synthon we crystallized TE with biphenyl. The arrangement (Fig. 5) in the biphenyl co-crystal (TE5), however, is different to that of the 2,2'-bipyridine co-crystal [5] even though the ratio of TE to guest (2:1) is the same. The main hydrogen bonding network of TE molecules is the same with chains of TE connected with a R2,2(8) motif consisting of two N-H···S=C hydrogen bonds. The chains pack parallel to each other with the aid of π-π interactions between the TE benzene rings with ring centroid to centroid distances of 3.81 Å. There are also weak hydrogen bonds from the C=O of TE to one of the benzene ring hydrogen atoms in an adjacent chain. The biphenyl molecules are located 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 single crystal structure.

Conclusions
Five novel co-crystal forms of TE with a selected group of pyridine 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 functionalities, 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 2,2'-bipyridine, for which TE builds a packing arrangement containing channels 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 N-H···S=C hydrogen bonds. These chains, which are also seen in most of the polymorphs of TE [3], can organize to leave in hydrophobic cavities that the guests can fill.
The non-hydrogen bonding guest molecules, like biphenyl, likely act as templates for the packing of the chains. The strong N-H···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 containing a thioamide group (-C(=S)-N(H)-), which is seen in agrochemical and pharmaceutical actives.

Supplementary material
CCDC 838991 -838994 contain the supplementary crystallographic data for this paper. These data can be