Two polymorphic forms of the oxathiin systemic fungicide active carboxine

Two polymorphic crystal forms of 6-methyl-N-phenyl-2,3-dihydro-1,4-oxathiine-5-carboxamide) were isolated from a truncated, (12 solvent), polymorph screen on pure lyophillized material. Crystals of form 1 were obtained from all solvents included in the screen with the exception of methanol. As isolated from acetonitrile the crystals are triclinic, space group P with Z′ = 2. Crystals of form 2, which were isolated from methanol only are monoclinic, space group I2/a with Z′ = 1.


Chemical context
6-Methyl-N-phenyl-2,3-dihydro-1,4-oxathiine-5-carboxamide, (Carboxine or Carboxin) 1, is a systemic fungicide from the oxathiin class of agents. This class of agents was discovered in 1964 (von Schmeling & Kulka, 1966) and was notable in that they were among the first fungicides that were known to exhibit translocation i.e. the ability to move from the leaves to other tissues in the plant. This unique property has made them particularly effective for protection against rusts and smuts. In particular 1, which is marketed under the trade name VITAVAX 1 , has itself demonstrated high specificity against the fungal class Basideomycetes, Deuteromycetes and Phycomycetes (Edgington et al., 1966;Edgington & Barron, 1967;Snel et al., 1970). There is currently no report of any crystal structure of this important fungicide in the literature although the material has been reported to be dimorphic based upon the observation of two distinct melting points, 91.5-92.5 C and 98-100 C (Worthing, 1979). As part of an ongoing program into the preparation of co-crystal forms of agrichemical active materials to enhance or adapt their physicochemical properties (Eberlin & Frampton, 2017), it was pertinent to investigate the possible crystal structures of this active material. Given that there is just one hydrogen-bond donor and three possible acceptor groups it was deemed necessary to probe the nature of the hydrogen-bonding interactions present in the two distinct forms, thus directing the choice of prospective coformers for a screen. In this paper we report the single crystal X-ray structures of the two reported dimorphic forms of Carboxine 1 at 100 K. ISSN 2056-9890

Structural commentary
Colourless block-shaped crystals of form 1 were obtained from acetonitrile. The crystal structure of form 1 of Carboxine is triclinic, Space group P1, with two independent molecules in the asymmetric unit, (Z '= 2). For clarity, each independent molecule is labelled with suffix A or B. Figs. 1 and 2 show displacement ellipsoid plots for the two molecules, A and B. Hydrogen-bond distances and angles are given in Table 1. The molecule contains two rotational degrees of freedom such that the phenyl and oxathiin rings can rotate with respect to the central carboxamide core. The phenyl ring defined by atoms C1-C6 and the carboxamide core defined by atoms C6, N1, C7, O1 and C8 are almost planar. A calculated least-squares plane through the six atoms of the phenyl ring and through the five atoms of the carboxamide core gave r.m.s. deviations from planarity and a calculated dihedral angle between them as follows; Molecule A, 0.0016 Å , 0.0278 Å , 24.80 (6) , respectively; molecule B, 0.0020 Å , 0.0040 Å , 43.06 (5) , respectively. It is interesting to note that the carboxamide core for Molecule A is significantly less planar than that of Molecule B with atom N1A displaced from the mean plane by À0.0481 (6) Å . The orientation of the oxathiin moiety with respect to the carboxamide core also differs for each molecule in the asymmetric unit with the torsion angle O1-C7-C8-S1 having values of 33.1 (2) and 143.4 (1) for molecules A and B, respectively. Fig. 3 shows an overlay of the two molecules in the asymmetric unit (Molecule A in violet and Molecule B in green), showing the differences in their conformations; the overlay was constructed based on the six atoms of the phenyl ring only (r.m.s. deviation = 0.0034 Å ) using the Structure Overlay routine in Mercury (Macrae et al., 2008). A DSC of the material from this crystallization experiment gave a single sharp melting endotherm, (onset 97.4 C, peak 98.2 C).
Colourless lath-shaped crystals of form 2 were obtained by slow evaporation from methanol. The crystal structure of form 2 is monoclinic, space group I2/a with a single molecule in the asymmetric unit, (Z '= 1). Fig. 4 shows a displacement ellipsoid plot and the hydrogen-bond distance and angle is given in View of molecule B of the asymmetric unit of form 1 with the atom labelling scheme. Displacement ellipsoids are drawn at the 50% probability level. Table 1 Hydrogen-bond geometry (Å , ) for form 1.

Figure 3
View of the structure overlay of molecule A (violet) and molecule B (green) from the form 1 structure.

Figure 1
View of molecule A of the asymmetric unit of form 1 with the atom labelling scheme. Displacement ellipsoids are drawn at the 50% probability level.

Figure 4
View of molecule 1 of the asymmetric unit of form 2 with the atom labelling scheme. Displacement ellipsoids are drawn at the 50% probability level. ring and carboxamide core as described above for the form 1 structure show that these two groups are closer to being coplanar than in the form 1 structure, with r.m.s. deviations from planarity and a calculated dihedral angle between the planes being 0.0064 Å , 0.0154 Å and 9.59 (6) , respectively. The O1-C7-C8-S1 torsion angle for the form 2 structure is 47.3 (2) . A DSC of the form 2 material is shown in Fig. 5. It shows a sharp melting endotherm, (onset 90.1 C, peak 91.1 C), followed by an exothermic recrystallization event, (onset 92.1 C, peak 92.5 C) to form 1, which subsequently gives a sharp melting endotherm (onset 97.5 C, peak 98.4 C). From this we deduce that form 1 is the most thermodynamically stable of the two forms, which is also supported by the higher density of form 1 over form 2, 1.431 g cm À3 versus 1.316 g cm À3 , respectively. We also note that if crystals of form 2 are left in the methanol mother liquor for a period of time they will spontaneously convert to the form 1 polymorph.

Supramolecular features
The packing of molecules in the crystal structure of form 1 is governed by the formation of two infinite hydrogen-bonded chains, which run parallel to the crystallographic a axis, Fig. 6. These two chains are formed from discrete Molecule A and Molecule B moieties respectively. The hydrogen-bonding interactions are through the amide -NH to carbonyl O for both chains with DÁ Á ÁA distances of 2.957 (1) and 2.978 (1) Å for the A and B chains, respectively. The N-HÁ Á ÁO hydrogen bond angles for both chains are significantly reduced from 180 to $150 (2) in both chains. The crystal packing found in form 2 is also governed by the formation of an infinite amide -NH to carbonyl O hydrogen-bonded chain, which again runs parallel to the crystallographic a axis of the unit cell, Fig. 7. The DÁ Á ÁA distance for this chain is significantly shorter than that found in the form 1 structure at 2.868 (2) Å and the N-HÁ Á ÁO hydrogen bond angle for this chain is $178 (2) , which is closer to the expected linear value. The closest example to the title compound is the direct dioxide, (-SO 2 ), analogue KABFEA (Brown & Baughman, 2010). A further close example is one where the phenyl group has been substituted at the 4-and 5-positions with a chloro and isopropyl benzoate group, respectively, SOHZUK (Silverton et al., 1991). Structure ZANDUQ (Kulkarni, 2017) is a chromene-substituted oxathiin and structure XEQPEO View of the crystal packing of form 1 as viewed approximately down the a axis. The N-HÁ Á ÁO hydrogen bonds are shown as dotted lines (see Table 1 and text).

Figure 7
View of the crystal packing of form 2 as viewed down the b axis. The N-HÁ Á ÁO hydrogen bonds are shown as dotted lines (see Table 2 and text).

Figure 5
Differential scanning calorimetry thermogram of form 2. (Caputo et al., 1999) is an example of a chiral sulfoxide oxathiin with a single phenyl substituent. The remaining example, TUHDUV is a fused oxathiin (Moge et al., 1996) synthesized in order to incorporate an oxygen atom into tetrathiafulvalene.

Synthesis and crystallization
Crystals of form 1 and form 2 of Carboxine were isolated from a truncated polymorph screen based on the recrystallization of lyophillized amorphous material from twelve different solvent or solvent water mixtures. Carboxine (Sigma Aldrich, 99.9%, Lot # SZBC023XV), was analyzed by X-ray powder diffraction and DSC as received prior to commencing the polymorph screen. The data demonstrated the starting material to be highly crystalline with a single sharp melting endotherm, (onset 97.4 C, peak 98.2 C). This material was assigned as form 1. The polymorph screen consisted of approximately 50 mg of lyophillized Carboxine being dispensed per vial along with approximately 40 volumes of the appropriate solvent or solvent/water mixture (ca 2 ml) at room temperature. For the vials that gave clear solutions, these were filtered through a 4 mm filter to remove any potential seeds that may have remained in the solution. Samples that did not dissolve were kept as a slurry. The vials were placed in a platform shaker incubator (Heidolph Titramax/Inkubator 1000) and subjected to a series of heat-cool cycles under shaking from room temperature (RT) to 50 C (8 h cycles; heating to 50 C for 4 h and then cooling to RT for a further 4 h) for a maximum of 48 h. The resulting solutions were then allowed to evaporate slowly. Samples that crystallized by saturation crystallization were filtered and the resultant filtrate was then allowed to evaporate to dryness. Samples that did not crystallize were allowed to evaporate to dryness. All solid materials obtained from the screen were analyzed by X-ray powder diffraction. Of the twelve vials in the polymorph screen, eleven demonstrated an X-ray powder diffraction pattern that was identical to that of the starting material (form 1) whereas the material from the twelfth vial gave a pattern that was completely different. Suitable single-crystal samples were selected, form 1 from vial 9, (acetonitrile) and form 2 from vial 8 (methanol). A DSC of the form 2 crystalline material was also measured. It should be noted that in the course of this study, it was discovered that if the crystals of form 2 were allowed to remain in the methanol mother liquor, they will over a period of time convert to yield the form 1 structure. A list of solvents and the results of the truncated polymorph screen are given in the supporting information.

Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.