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Volume 66 
Part 12 
Pages o593-o595  
December 2010  

Received 18 October 2010
Accepted 3 November 2010
Online 6 November 2010

Polymorphism in 2-(4-hydroxy-2,6-dimethylanilino)-5,6-dihydro-4H-1,3-thiazin-3-ium chloride

aMaxwell H. Gluck Equine Center, University of Kentucky, Lexington, KY 40546, USA,bFrontier Biopharm, PO Box 614, Richmond, Kentucky 40475, USA, and cDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA
Correspondence e-mail: slong0@email.uky.edu

Details of the structures of two conformational polymorphs of the title compound, C12H17N2OS+·Cl-, are reported. In form (I) (space group P[\overline{1}]), the two N-H groups of the cation are in a trans conformation, while in form (II) (space group P21/c), they are in a cis arrangement. This results in different packing and hydrogen-bond arrangements in the two forms, both of which have extended chains lying along the a direction. In form (I), these chains are composed of centrosymmetric R42(18) (N-H...Cl and O-H...Cl) hydrogen-bonded rings and R22(18) (N-H...O) hydrogen-bonded rings. In form (II), the chains are formed by centrosymmetric R42(18) (N-H...Cl and O-H...Cl) hydrogen-bonded rings and by R42(12) (N-H...Cl) hydrogen-bonded rings.

Comment

Polymorphism, the phenomenon of a given molecule existing in more than one crystal structure, is a normal observation for organics (McCrone, 1965[McCrone, W. C. (1965). Physics and Chemistry of the Organic Solid State, Vol. 2, edited by D. Fox, M. M. Labes & A. Weissberge, pp. 725-767. New York: Interscience.]). Polymorphism is of great importance in pharmaceuticals, as well as in materials science, because individual forms may have different physicochemical properties which can potentially lead to new formulations or new materials. Conformational polymorphism, a branch of polymorphism, is particularly interesting since it provides ideal cases for structure-property relationship studies (Bernstein, 2002[Bernstein, J. (2002). Polymorphism in Molecular Crystals. New York: Oxford University Press.], 1987[Bernstein, J. (1987). Organic Solid State Chemistry, Vol. 32, edited by G. R. Desiraju, pp. 471-518. Amsterdam: Elsevier.]). Conformational polymorphism arises from intrinsic molecular flexibility and is the result of a compromise between inter- and intramolecular interactions.

The free base of the title compound, (1), is the principal metabolite fragment recovered from equine urine after enzymatic hydrolysis of xylazine [N-(2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiazin-2-amine], which is a relatively short-acting [alpha]-2 agonist tranquilizer widely used in equine medicine. Optimal regulatory control of the use of xylazine is dependent on the detection and quantification of urinary metabolites or metabolite fragments such as the free base of (1) (Mutlib et al., 1992[Mutlib, A. E., Chui, Y. C., Young, L. M. & Abbott, F. S. (1992). Drug Metab. Dispos. 20, 840-848.]). We report here the conformational polymorphism of (1), which occurs in two crystalline forms, viz. (I)[link] and (II)[link].

[Scheme 2]

Our analysis establishes that form (I)[link] is triclinic (space group P[\overline{1}]) and form (II)[link] monoclinic (space group P21/c), with one formula unit in the asymmetric unit in each case. Views of forms (I)[link] and (II)[link] are given in Figs. 1[link] and 2[link], respectively. In both forms, imine atom N3 is protonated, and in both forms the six-membered heterocyclic ring has a half-chair conformation, with atom C5 0.704 (2) Å from the S1/C2/N3/C4/C6 plane in form (I)[link] and 0.699 (2) Å from the same plane in form (II)[link]. The C2-N2 and C2-N3 bond lengths in (I)[link] are 1.3296 (16) and 1.3180 (16) Å, respectively, and the corresponding values in (II)[link] are 1.328 (2) and 1.322 (2) Å. These dimensions are entirely consistent with delocalization of the C2=N2 double bond over the N2-C2-N3 moiety, as shown in structures (1a) and (1b) in the scheme below. Thus, the two cations could either be considered as configurational isomers (with C2-N2 considered as the double bond), with form (I)[link] the E isomer and form (II)[link] the Z isomer, or as conformational isomers (with C2-N3 considered as the double bond). As seen in Figs. 1[link] and 2[link] (which have been drawn to have similar orientations of the six-membered heterocyclic rings), the principal difference between the two forms is in the orientation of the 4-hydroxy-2,6-dimethylanilino moiety with respect to the heterocyclic ring. In form (I)[link], the S1-C2-N2-C11 torsion angle is -176.54 (9)°, while in form (II)[link] the corresponding value is 3.0 (2)°.

[Scheme 1]

Due to the conformational difference between the cations in the two polymorphs, the packing patterns are dissimilar. In polymorph (I)[link] (Fig. 3[link]), hydrogen bonds between the protonated imine NH group and the phenol O atom (N3-H3...O4i; see Table 1[link] for details) link two cations to form an 18-membered ring dimer centred at ([{1 \over 2}], [{1 \over 2}], [{1 \over 2}]), with the hydrogen-bonded ring graph-set descriptor R22(18) (Bernstein et al., 1995[Bernstein, J., Davis, R. E., Shimoni, L. & Chang, N.-L. (1995). Angew. Chem. Int. Ed. Engl. 34, 1555-1573.]). This dimer is further connected through hydrogen bonds between the chloride ion and the hydroxy O4-H4 and secondary N2-H2 groups of neighbouring cations (details in Table 1[link]) to form a second set of 18-membered rings, but this time with hydrogen-bond descriptor R42(18), lying about inversion centres at (0, [{1 \over 2}][{1 \over 2}]), (1, [{1 \over 2}][{1 \over 2}]), etc. This gives rise to a one-dimensional chain along the a axis of the triclinic cell.

In form (II)[link] (Fig. 4[link]), the cations are interconnected through hydrogen bonds between the chloride ion and all three hydrogen-bond donors from different neighbouring cations, viz. O4-H4, imine N3-H3 and amino N2-H2 (details in Table 2[link]). There is a 12-membered ring [centred at ([{1 \over 2}][{1 \over 2}][{1 \over 2}])] involving the N2-H2 and N3-H3 groups and the chloride ion, with descriptor R42(12) (details in Table 2[link]). This dimer is then connected via N2-H2...Cl1 and O4-H4...Cl1ii hydrogen bonds (Table 2[link]) to generate 18-membered rings [centred at (0, [{1 \over 2}], [{1 \over 2}]), (1, [{1 \over 2}], [{1 \over 2}]), etc.] with descriptor R42(18), the same as in form (I)[link]. In this way, a one-dimensional chain is developed along the a axis of this monoclinic cell.

Our work has thus shown that the two crystalline forms discovered for (1) can be considered as either configurational or conformational isomers, due to the delocalization of the amine lone-pair of electrons over three atoms. The configurational/conformational variation in the two forms gives rise to differences in packing and hydrogen-bond arrangements in the crystal structures.

[Figure 1]
Figure 1
The molecular structure of form (I)[link] of (1), showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.
[Figure 2]
Figure 2
The molecular structure of form (II)[link] of (1), showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.
[Figure 3]
Figure 3
The crystal packing of form (I)[link]. (For details of symmetry codes, see Table 1[link].)
[Figure 4]
Figure 4
The crystal packing of form (II)[link]. [For details of symmetry codes, see Table 2[link]; additionally, (iii) 1 + x, y, z.]

Experimental

3,5-Dimethyl-4-isothiocyanatophenol (1.70 g, 9.50 mmol) was dissolved in dry dichloromethane (20 ml) and 3-aminopropanol (1.70 ml, 22.18 mmol) was added. The reaction mixture was refluxed overnight with stirring. The solution was then cooled to room temperature and the solvent removed under reduced pressure to give the crude product. Concentrated hydrochloric acid solution (8 ml) was added to the crude product and the resulting solution was refluxed overnight with stirring. The solution was poured into 10% NaOH (50 ml) and stirred for 3 h. The final product (yield 2.0 g, 90.9%) was precipitated using Dowex resin H+ form (pH = 1) (Kai et al., 2007[Kai, H., Morioka, Y., Tomida, M., Takahashi, T., Hattori, M., Hanasaki, K., Koike, K., Chiba, H., Shinohara, S., Kanemasa, T., Iwamoto, Y., Takahashi, K., Yamaguchi, Y., Baba, T., Yoshikawa, T. & Takenaka, H. (2007). Bioorg. Med. Chem. Lett., 17, 3925-3929.]). Crystals (m.p. 503 K, from differential scanning calorimetry) from methanol and ethanol were found to be the same and were designated as form (I)[link], and those from propan-2-ol were form (II)[link].

Polymorph (I)[link]

Crystal data
  • C12H17N2OS+·Cl-

  • Mr = 272.79

  • Triclinic, [P \overline 1]

  • a = 6.9961 (1) Å

  • b = 7.9421 (1) Å

  • c = 13.0864 (2) Å

  • [alpha] = 73.3925 (6)°

  • [beta] = 84.1579 (6)°

  • [gamma] = 70.8388 (6)°

  • V = 658.17 (2) Å3

  • Z = 2

  • Mo K[alpha] radiation

  • [mu] = 0.44 mm-1

  • T = 90 K

  • 0.30 × 0.20 × 0.10 mm

Data collection
  • Nonius KappaCCD area-detector diffractometer

  • Absorption correction: multi-scan (SCALEPACK; Otwinowski & Minor, 1997[Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307-326. New York: Academic Press.]) Tmin = 0.881, Tmax = 0.958

  • 5923 measured reflections

  • 2981 independent reflections

  • 2762 reflections with I > 2[sigma](I)

  • Rint = 0.017

Refinement
  • R[F2 > 2[sigma](F2)] = 0.028

  • wR(F2) = 0.072

  • S = 1.03

  • 2981 reflections

  • 156 parameters

  • H-atom parameters constrained

  • [Delta][rho]max = 0.32 e Å-3

  • [Delta][rho]min = -0.28 e Å-3

Table 1
Hydrogen-bond geometry (Å, °) for polymorph (I)[link]

D-H...A D-H H...A D...A D-H...A
N2-H2...Cl1 0.88 2.28 3.1244 (11) 161
N3-H3...O4i 0.88 2.12 2.8143 (13) 136
O4-H4...Cl1ii 0.84 2.17 2.9913 (10) 165
Symmetry codes: (i) -x+1, -y+1, -z+1; (ii) -x, -y+1, -z+1.

Polymorph (II)[link]

Crystal data
  • C12H17N2OS+·Cl-

  • Mr = 272.79

  • Monoclinic, P 21 /c

  • a = 11.8877 (2) Å

  • b = 9.2120 (2) Å

  • c = 12.6673 (3) Å

  • [beta] = 99.0242 (10)°

  • V = 1370.02 (5) Å3

  • Z = 4

  • Mo K[alpha] radiation

  • [mu] = 0.42 mm-1

  • T = 90 K

  • 0.50 × 0.20 × 0.10 mm

Data collection
  • Nonius KappaCCD area-detector diffractometer

  • Absorption correction: multi-scan (SCALEPACK; Otwinowski & Minor, 1997[Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307-326. New York: Academic Press.]) Tmin = 0.818, Tmax = 0.959

  • 6046 measured reflections

  • 3141 independent reflections

  • 2389 reflections with I > 2[sigma](I)

  • Rint = 0.031

Refinement
  • R[F2 > 2[sigma](F2)] = 0.042

  • wR(F2) = 0.112

  • S = 1.10

  • 3141 reflections

  • 157 parameters

  • H-atom parameters constrained

  • [Delta][rho]max = 0.50 e Å-3

  • [Delta][rho]min = -0.31 e Å-3

Table 2
Hydrogen-bond geometry (Å, °) for polymorph (II)[link]

D-H...A D-H H...A D...A D-H...A
N2-H2...Cl1 0.86 2.33 3.1245 (17) 154
N3-H3...Cl1i 0.86 2.57 3.2437 (17) 136
O4-H4...Cl1ii 0.82 2.28 3.0579 (14) 159
Symmetry codes: (i) -x+1, -y+1, -z+1; (ii) -x, -y+1, -z+1.

All H atoms were found in difference Fourier maps and were subsequently placed in idealized positions, with O-H = 0.82 Å, N-H = 0.86 Å, Csp2-H = 0.93 Å, and Csp3-H = 0.97 Å for CH2 H atoms and 0.96 Å for methyl H atoms. All H atoms were allowed for as riding, with Uiso(H) = 1.5Ueq(parent atom) for hydroxy and methyl H atoms, and 1.2Ueq(parent atom) for all others.

For both compounds, data collection: COLLECT (Nonius, 2002[Nonius (2002). COLLECT. Nonius BV, Delft, The Netherlands.]); cell refinement: DENZO-SMN (Otwinowski & Minor, 1997[Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307-326. New York: Academic Press.]); data reduction: DENZO-SMN; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); molecular graphics: XP in SHELXTL (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); software used to prepare material for publication: SHELXL97 and local procedures.


Supplementary data for this paper are available from the IUCr electronic archives (Reference: FG3203 ). Services for accessing these data are described at the back of the journal.


Acknowledgements

Published as paper No. 392 from the Equine Pharmacology, Therapeutics and Toxicology Program at the Maxwell H. Gluck Equine Research Center and Department of Veterinary Science, University of Kentucky. Published as Kentucky Agricultural Experiment Station Article No. 10-14-123 with the approval of the Dean and Director, College of Agriculture and the Kentucky Agricultural Experimental Station. This work was made possible by research support from The National Horsemen's Benevolent and Protective Association and the Alabama, Arizona, Arkansas, Canada, Charles Town (West Virginia), Florida, Iowa, Indiana, Kentucky, Louisiana, Michigan, Minnesota, Nebraska, Ohio, Oklahoma, Ontario (Canada), Oregon, Pennsylvania, Tampa Bay Downs (Florida), Texas, Washington State, and West Virginia Horsemen's Benevolent and Protective Associations and the Florida Horsemen's Charitable Foundation, the Oklahoma Quarter Horse Racing Association and the Neogen Corporation. The authors also thank Charlie Hughes for his assistance during the synthesis and Dr Sean Parkin for helpful discussions.

References

Bernstein, J. (1987). Organic Solid State Chemistry, Vol. 32, edited by G. R. Desiraju, pp. 471-518. Amsterdam: Elsevier.
Bernstein, J. (2002). Polymorphism in Molecular Crystals. New York: Oxford University Press.
Bernstein, J., Davis, R. E., Shimoni, L. & Chang, N.-L. (1995). Angew. Chem. Int. Ed. Engl. 34, 1555-1573.  [CrossRef] [ChemPort] [ISI]
Kai, H., Morioka, Y., Tomida, M., Takahashi, T., Hattori, M., Hanasaki, K., Koike, K., Chiba, H., Shinohara, S., Kanemasa, T., Iwamoto, Y., Takahashi, K., Yamaguchi, Y., Baba, T., Yoshikawa, T. & Takenaka, H. (2007). Bioorg. Med. Chem. Lett., 17, 3925-3929.  [CrossRef] [PubMed] [ChemPort]
McCrone, W. C. (1965). Physics and Chemistry of the Organic Solid State, Vol. 2, edited by D. Fox, M. M. Labes & A. Weissberge, pp. 725-767. New York: Interscience.
Mutlib, A. E., Chui, Y. C., Young, L. M. & Abbott, F. S. (1992). Drug Metab. Dispos. 20, 840-848.  [PubMed] [ChemPort]
Nonius (2002). COLLECT. Nonius BV, Delft, The Netherlands.
Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307-326. New York: Academic Press.
Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.  [CrossRef] [details]


Acta Cryst (2010). C66, o593-o595   [ doi:10.1107/S0108270110045099 ]