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

Article abstract of DOI:10.1107/S0108270110045099

Details of the structures of two conformational polymorphs of the title compound, C₁₂H₁₇N₂OS⁺·Cl ^-, are reported. In form (I) (space group P1), 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 R₄ ²(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 R₄ ²(12) (N - H...Cl) hydrogen-bonded rings.

Full text of DOI:10.1107/S0108270110045099

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
on the detection and quantification of urinary metabolites or
metabolite fragments such as the free base of (1) (Mutlib et al.,
1992). We report here the conformational polymorphism of
(1), which occurs in two crystalline forms, viz. (I) and (II).
ISSN 0108-2701
Polymorphism in 2-(4-hydroxy-2,6-
dimethylanilino)-5,6-dihydro-4H-
1,3-thiazin-3-ium chloride
Julio Gutierrez,a Rodney Eisenberg,b Gabrielle
Herrensmith,a Thomas Tobin,a Tonglei Lic and Sihui
Longc*
Our analysis establishes that form (I) is triclinic (space
group P1) and form (II) monoclinic (space group P21/c), with
one formula unit in the asymmetric unit in each case. Views of
forms (I) and (II) are given in Figs. 1 and 2, respectively. In
both forms, imine atom N3 is protonated, and in both forms
the six-membered heterocyclic ring has a half-chair confor-
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
˚
mation, with atom C5 0.704 (2) A from the S1/C2/N3/C4/C6
˚
plane in form (I) and 0.699 (2) A from the same plane in form
(II). The C2—N2 and C2—N3 bond lengths in (I) are
˚
1.3296 (16) and 1.3180 (16) A, respectively, and the corre-
˚
sponding values in (II) are 1.328 (2) and 1.322 (2) A. These
dimensions are entirely consistent with delocalization of the
Correspondence e-mail: slong0@email.uky.edu
Received 18 October 2010
Accepted 3 November 2010
Online 6 November 2010
Details of the structures of two conformational polymorphs of
the title compound, C12H17N2OS+ꢀClꢁ, are reported. In form
(I) (space group P1), 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—Hꢀ ꢀ ꢀCl and O—Hꢀ ꢀ ꢀCl) hydrogen-bonded rings
and R22(18) (N—Hꢀ ꢀ ꢀO) hydrogen-bonded rings. In form (II),
the chains are formed by centrosymmetric R42(18) (N—Hꢀ ꢀ ꢀCl
and O—Hꢀ ꢀ ꢀCl) hydrogen-bonded rings and by R42(12) (N—
Hꢀ ꢀ ꢀCl) hydrogen-bonded rings.
Figure 1
The molecular structure of form (I) of (1), showing the atom-numbering
scheme. Displacement ellipsoids are drawn at the 50% probability level.
Comment
Polymorphism, the phenomenon of a given molecule existing
in more than one crystal structure, is a normal observation for
organics (McCrone, 1965). Polymorphism is of great impor-
tance 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 (Bern-
stein, 2002, 1987). 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 ꢀ-2 agonist tranquilizer widely used in equine medicine.
Optimal regulatory control of the use of xylazine is dependent
Figure 2
The molecular structure of form (II) of (1), showing the atom-numbering
scheme. Displacement ellipsoids are drawn at the 50% probability level.
Acta Cryst. (2010). C66, o593–o595
doi:10.1107/S0108270110045099
# 2010 International Union of Crystallography o593

organic compounds
Figure 4
The crystal packing of form (II). [For details of symmetry codes, see
Table 2; additionally, (iii) 1 + x, y, z.]
hydrogen-bond donors from different neighbouring cations,
viz. O4—H4, imine N3—H3 and amino N2—H2 (details in
Figure 3
The crystal packing of form (I). (For details of symmetry codes, see
Table 1.)
1
1
Table 2). There is a 12-membered ring [centred at (12, , )]
2
2
involving the N2—H2 and N3—H3 groups and the chloride
ion, with descriptor R24(12) (details in Table 2). This dimer is
then connected via N2—H2ꢀ ꢀ ꢀCl1 and O4—H4ꢀ ꢀ ꢀCl1ii
hydrogen bonds (Table 2) to generate 18-membered rings
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)
the E isomer and form (II) the Z isomer, or as conformational
isomers (with C2—N3 considered as the double bond). As
seen in Figs. 1 and 2 (which have been drawn to have similar
orientations of the six-membered heterocyclic rings), the
principal difference between the two forms is in the orienta-
tion of the 4-hydroxy-2,6-dimethylanilino moiety with respect
to the heterocyclic ring. In form (I), the S1—C2—N2—C11
torsion angle is ꢁ176.54 (9)ꢂ, while in form (II) the corre-
sponding value is 3.0 (2)ꢂ.
1
2
1
2
1 1
2 2
[centred at (0, , ), (1, , ), etc.] with descriptor R24(18), the
same as in form (I). 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 config-
urational/conformational variation in the two forms gives rise
to differences in packing and hydrogen-bond arrangements in
the crystal structures.
Experimental
3,5-Dimethyl-4-isothiocyanatophenol (1.70 g, 9.50 mmol) was dis-
solved 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). Crystals (m.p. 503 K, from differential scanning calorim-
etry) from methanol and ethanol were found to be the same and were
designated as form (I), and those from propan-2-ol were form (II).
Due to the conformational difference between the cations
in the two polymorphs, the packing patterns are dissimilar. In
polymorph (I) (Fig. 3), hydrogen bonds between the proton-
ated imine NH group and the phenol O atom (N3—H3ꢀ ꢀ ꢀO4i;
see Table 1 for details) link two cations to form an 18-
1
1
membered ring dimer centred at (12, , ), with the hydrogen-
2
2
bonded ring graph-set descriptor R22(18) (Bernstein et al.,
1995). 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) to form a second set of 18-membered rings, but this
time with hydrogen-bond descriptor R24(18), lying about
inversion centres at (0, 21, 21), (1, 21, 12), etc. This gives rise to a one-
dimensional chain along the a axis of the triclinic cell.
Polymorph (I)
Crystal data
C12H17N2OS+ꢀClꢁ
ꢂ = 70.8388 (6)ꢂ
3
˚
Mr = 272.79
Triclinic, P1
a = 6.9961 (1) A
V = 658.17 (2) A
Z = 2
˚
Mo Kꢀ radiation
ꢃ = 0.44 mmꢁ1
T = 90 K
0.30 ꢃ 0.20 ꢃ 0.10 mm
˚
b = 7.9421 (1) A
˚
c = 13.0864 (2) A
In form (II) (Fig. 4), the cations are interconnected through
hydrogen bonds between the chloride ion and all three
ꢀ = 73.3925 (6)ꢂ
ꢁ = 84.1579 (6)ꢂ
o594 Gutierrez et al. Two polymorphs of C12H17N2OS+ꢀClꢁ
Acta Cryst. (2010). C66, o593–o595
ꢄ

organic compounds
Table 1
Hydrogen-bond geometry (A, ) for polymorph (I).
Table 2
Hydrogen-bond geometry (A, ) for polymorph (II).
ꢂ
ꢂ
˚
˚
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
N2—H2ꢀ ꢀ ꢀCl1
N3—H3ꢀ ꢀ ꢀO4i
O4—H4ꢀ ꢀ ꢀCl1ii
0.88
0.88
0.84
2.28
2.12
2.17
3.1244 (11)
2.8143 (13)
2.9913 (10)
161
136
165
N2—H2ꢀ ꢀ ꢀCl1
N3—H3ꢀ ꢀ ꢀCl1i
O4—H4ꢀ ꢀ ꢀCl1ii
0.86
0.86
0.82
2.33
2.57
2.28
3.1245 (17)
3.2437 (17)
3.0579 (14)
154
136
159
Symmetry codes: (i) ꢁx þ 1; ꢁy þ 1; ꢁz þ 1; (ii) ꢁx; ꢁy þ 1; ꢁz þ 1.
Symmetry codes: (i) ꢁx þ 1; ꢁy þ 1; ꢁz þ 1; (ii) ꢁx; ꢁy þ 1; ꢁz þ 1.
Data collection
(Sheldrick, 2008); software used to prepare material for publication:
SHELXL97 and local procedures.
Nonius KappaCCD area-detector
diffractometer
Absorption correction: multi-scan
(SCALEPACK; Otwinowski &
Minor, 1997)
5923 measured reflections
2981 independent reflections
2762 reflections with I > 2ꢄ(I)
Rint = 0.017
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.
Tmin = 0.881, Tmax = 0.958
Refinement
R[F2 > 2ꢄ(F2)] = 0.028
wR(F2) = 0.072
S = 1.03
156 parameters
H-atom parameteꢁrs3 constrained
˚
Áꢅmax = 0.32 e A
Áꢅmin = ꢁ0.28 e A
ꢁ3
˚
2981 reflections
Polymorph (II)
Crystal data
C12H17N2OS+ꢀClꢁ
3
˚
V = 1370.02 (5) A
Z = 4
Mr = 272.79
Monoclinic, P21=c
Mo Kꢀ radiation
ꢃ = 0.42 mmꢁ1
T = 90 K
0.50 ꢃ 0.20 ꢃ 0.10 mm
˚
a = 11.8877 (2) A
˚
b = 9.2120 (2) A
˚
c = 12.6673 (3) A
ꢁ = 99.0242 (10)ꢂ
Data collection
Nonius KappaCCD area-detector
diffractometer
Absorption correction: multi-scan
(SCALEPACK; Otwinowski &
Minor, 1997)
6046 measured reflections
3141 independent reflections
2389 reflections with I > 2ꢄ(I)
Rint = 0.031
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.
Tmin = 0.818, Tmax = 0.959
References
Refinement
R[F2 > 2ꢄ(F2)] = 0.042
wR(F2) = 0.112
S = 1.10
157 parameters
H-atom parameteꢁrs3 constrained
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˚
Áꢅmax = 0.50 e A
ꢁ3
˚
3141 reflections
Áꢅmin = ꢁ0.31 e A
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Koike, K., Chiba, H., Shinohara, S., Kanemasa, T., Iwamoto, Y., Takahashi,
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Med. Chem. Lett., 17, 3925–3929.
All H atoms were found in difference Fourier maps and were
˚
subsequently placed in idealized positions, with O—H = 0.82 A,
2
N—H = 0.86 A, Csp —H = 0.93 A, and Csp —H = 0.97 A for CH2 H
3
˚
˚
˚
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˚
atoms and 0.96 A 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);
cell refinement: DENZO-SMN (Otwinowski & Minor, 1997); data
reduction: DENZO-SMN; program(s) used to solve structure:
SHELXS97 (Sheldrick, 2008); program(s) used to refine structure:
SHELXL97 (Sheldrick, 2008); molecular graphics: XP in SHELXTL
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122.
Two polymorphs of C12H17N2OS+ꢀClꢁ o595
ꢄ
Acta Cryst. (2010). C66, o593–o595
Gutierrez et al.