Solvatomorphism in (E)-2-(2,6-dichloro-4-hydroxybenzylidene) hydrazinecarboximidamide

Article abstract of DOI:10.1107/S0108270111023845

The structures of orthorhombic (E)-4-(2-{[amino(iminio)- methyl]amino}vinyl)-3,5-dichlorophenolate dihydrate, C₈H₈- Cl₂N₄O·2H₂O, (I), triclinic (E)-4-(2-{[amino(iminio)methyl]- amino}vinyl)-3,5-dichlorophenolate methanol disolvate, C₈H₈-Cl₂N₄O· 2CH₄O, (II), and orthorhombic (E)-amino[(2,6-dichloro- 4-hydroxystyryl)amino]methaniminium acetate, C₈H₉-Cl ₂N₄O⁺·C₂H₃O ₂^-, (III), all crystallize with one formula unit in the asymmetric unit, with the molecule in an E configuration and the phenol H atom transferred to the guanidine N atom. Although the molecules of the title compounds form extended chains via hydrogen bonding in all three forms, owing to the presence of different solvent molecules, those chains are connected differently in the individual forms. In (II), the molecules are all coplanar, while in (I) and (III), adjacent molecules are tilted relative to one another to varying degrees. Also, because of the variation in hydrogenbond- formation ability of the solvents, the hydrogen-bonding arrangements vary in the three forms.

Full text of DOI:10.1107/S0108270111023845

organic compounds
Acta Crystallographica Section C
Crystal Structure
gaunabenz, an antiprion drug for the treatment of neurode-
generative disorders in mammals and also a potent tranquilizer
Communications
ISSN 0108-2701
Solvatomorphism in (E)-2-(2,6-di-
chloro-4-hydroxybenzylidene)-
hydrazinecarboximidamide
used to sedate horses (Fluck et al., 1983). In this report, we
describe three crystal structures of (1) which include two
solvates, (I) and (II), and one acetate salt, (III) (Fig. 1).
Julio Gutierrez,a Rodney Eisenberg,b Gabrielle
Herrensmith,a Thomas Tobin,a Tonglei Lic and Sihui
Longc*
aMaxwell H. Gluck Equine Center, University of Kentucky, Lexington, KY 40546,
USA, bFrontier Biopharm, PO Box 614, Richmond, KY 40475, USA, and
cDepartment of Pharmaceutical Sciences, College of Pharmacy, University of
Kentucky, Lexington, KY 40536, USA
Correspondence e-mail: longsihui@yahoo.com
Received 22 February 2011
Accepted 17 June 2011
Online 6 July 2011
Our analysis establishes that (I) is orthorhombic (space
group Pbca) (Fig. 2), (II) is triclinic (space group P1) (Fig. 3)
and (III) is again orthorhombic (space group Pbca) (Fig. 4),
with one formula unit in the asymmetric unit in each case. In
the water, (I), and methanol, (II), solvates, (1) exists as a
zwitterion with the phenol proton transferred to the guanidine
N atom. In the acetate salt, (III), (1) is protonated by the
acetic acid and is thus positively charged. The molecules in the
three forms are all in the E configuration and are nearly flat.
Without considering the participation of the solvent mol-
ecules, all three forms show the same C(11) hydrogen-bonding
The structures of orthorhombic (E)-4-(2-{[amino(iminio)-
methyl]amino}vinyl)-3,5-dichlorophenolate dihydrate, C8H8-
Cl2N4Oꢀ2H2O, (I), triclinic (E)-4-(2-{[amino(iminio)methyl]-
amino}vinyl)-3,5-dichlorophenolate methanol disolvate, C8H8-
Cl2N4Oꢀ2CH4O, (II), and orthorhombic (E)-amino[(2,6-di-
chloro-4-hydroxystyryl)amino]methaniminium acetate, C8H9-
Cl2N4O+ꢀC2H3O2ꢁ, (III), all crystallize with one formula unit
in the asymmetric unit, with the molecule in an E configura-
tion and the phenol H atom transferred to the guanidine N
atom. Although the molecules of the title compounds form
extended chains via hydrogen bonding in all three forms,
owing to the presence of different solvent molecules, those
chains are connected differently in the individual forms. In
(II), the molecules are all coplanar, while in (I) and (III),
adjacent molecules are tilted relative to one another to
varying degrees. Also, because of the variation in hydrogen-
bond-formation ability of the solvents, the hydrogen-bonding
arrangements vary in the three forms.
Comment
Solvatomorphism, the counterpart of polymorphism and
sometimes called pseudopolymorphism, deals with systems
with different crystal structures of the same substance asso-
ciated with various amounts or types of solvent molecules
(Brittain, 2010; Seddon, 2004; Desiraju, 2004; Bernstein, 2005;
Nangia, 2006). Unlike polymorphs, solvatomorphs not only
have different molecular arrangements but also possess
diverse molecular compositions due to the presence of solvent
molecules. Like polymorphism, solvatomorphism is also
commonly observed in organics and is of great significance in
pharmaceuticals and materials. (E)-2-(2,6-Dichloro-4-hydroxy-
benzylidene)hydrazinecarboximidamide, (1), is a metabolite of
Figure 1
Representative crystals of (I), (II) and (III).
o310 # 2011 International Union of Crystallography
doi:10.1107/S0108270111023845
Acta Cryst. (2011). C67, o310–o314

organic compounds
Figure 2
The molecular structure of (I), showing the atom-numbering scheme.
Displacement ellipsoids are drawn at the 50% probability level.
Figure 4
The molecular structure of (III), showing the atom-numbering scheme.
Displacement ellipsoids are drawn at the 50% probability level.
Figure 3
The molecular structure of (II), showing the atom-numbering scheme.
Displacement ellipsoids are drawn at the 50% probability level.
Figure 5
Crystal packing of (I) (top), (II) (middle) and (III) (bottom) without
considering the solvent molecules and acetate counter-ion.
pattern in the graph-set concept (Bernstein et al., 1995), i.e.
one-dimensional chains based on the hydrogen bond between
the phenol O atom and a guanidine NH group [for example,
i
1
1
N12—H12Bꢀ ꢀ ꢀO1 in (I); symmetry code: (i) x, ꢁy + , z + ]
2
2
1
3
(Tables 1–3). The relative positions of the molecules in the
chains differ, however, with molecules in the chain of (II) in
the same plane, and molecules in the chains of (I) and (III)
tilted toward each other to different degrees as indicated by
the dihedral angles between the arene rings on adjacent
molecules in the three forms: ca 22ꢂ for (I), 0ꢂ for (II) and 55ꢂ
for (III) (Fig. 5).
symmetry code: (ii) ꢁx + 1, y ꢁ , ꢁz + ]. When the second
2
2
water molecule (O2W) acts as a hydrogen-bond donor, it links
two adjacent host molecule chains through hydrogen bonds
with O1; when it works as a hydrogen-bond acceptor, it forms
hydrogen bonds with the other water molecule and N9—H9 of
the host molecule (N9—H9ꢀ ꢀ ꢀO2Wi). Overall, the crystal
structure can be viewed as parallel one-dimensional chains of
the host molecules along the a axis bridged by water molecules.
Form (II) contains two equivalents of another solvent
molecule, i.e. methanol. The O—H group of methanol simi-
larly participates in hydrogen bonds as both a donor and
acceptor (Fig. 7). The first methanol molecule connects two
adjacent chains by using the O15—H15 group as a hydrogen-
bond donor to O1 of the host molecule from one chain and
meanwhile utilizing O15 as a hydrogen-bond acceptor to
accept H atoms from both N9 and N12 of the host molecule
from another chain [N9—H9ꢀ ꢀ ꢀO15i and N12—H12Bꢀ ꢀ ꢀO15i;
symmetry code: (i) ꢁx + 2, ꢁy + 2, ꢁz + 1] (Table 2). The
second methanol molecule forms hydrogen bonds with O1 as a
Since compound (1) is associated with different guest
molecules in the three forms, the packing is distinct in each
case because of different hydrogen-bonding patterns. In (I),
there are two equivalents of water, and water is both a
hydrogen-bond donor and acceptor (Fig. 6). When acting as a
hydrogen-bond donor, one water molecule (O1W) forms
hydrogen bonds with both O1 of the host molecule and O2W
of the other water molecule [O1W—H2W1ꢀ ꢀ ꢀO2Wiii;
1
1
symmetry code: (iii) x ꢁ , ꢁy + , ꢁz + 1] (Table 1); while
2
2
serving as a hydrogen-bond acceptor, O1W accepts H atoms
from both N11 and N12 from the guanine group of the host
molecule [N11—H11Aꢀ ꢀ ꢀO1Wii and N12—H12Aꢀ ꢀ ꢀO1Wii;
C8H8Cl2N4Oꢀ2H2O, C8H8Cl2N4Oꢀ2CH4O and C8H9Cl2N4O+ꢀC2H3O2
o311
ꢁ
ꢃ
Acta Cryst. (2011). C67, o310–o314
Gutierrez et al.

organic compounds
Figure 6
1
2
1
2
1
2
1
2
The crystal packing of (I); for details of symmetry codes see Table 1. Additionally: (iv) x, ꢁy + , z ꢁ ; (v) x + , ꢁy + , ꢁz + 1.
Figure 7
The crystal packing of (II); for details of symmetry codes see Table 2. Additionally: (iv) x, y ꢁ 1, z ꢁ 1; (v) x + 1, y + 1, z + 1.
Figure 8
1
2
1
2
The crystal packing of (III); for details of symmetry codes see Table 3. Additionally: (iv) x, ꢁy + 12, z ꢁ ; (v) ꢁx + 2, y ꢁ , ꢁz + 23; (vi) ꢁx + 32, ꢁy, z + 21.
donor and N11 as an acceptor [N11—H11Aꢀ ꢀ ꢀO16ii; symmetry
code: (ii) x, y + 1, z + 1]. Similar to (I), the crystal structure of
(II) also can be considered as parallel one-dimensional chains
of (1) linked by methanol molecules.
In the 1:1 organic acetate salt (III), compound (1) is
protonated at O1. Both O atoms of the acetate act as
hydrogen-bond acceptors (Fig. 8). O15 accepts hydrogen
bonds from O1 and N11 from different cations [O1—
H1ꢀ ꢀ ꢀO15i and N11—H11Aꢀ ꢀ ꢀO15ii; symmetry codes: (i)
1
2
ꢁx + 32, ꢁy, z ꢁ ; (ii) ꢁx + 2, y + 21, ꢁz + 32] and O16 also accepts
hydrogen bonds from N9 and N12 of two different cations
(N9—H9ꢀ ꢀ ꢀO16 and N12—H12Aꢀ ꢀ ꢀO16ii). Thus, one acetate
o312 Gutierrez et al. C8H8Cl2N4Oꢀ2H2O, C8H8Cl2N4Oꢀ2CH4O and C8H9Cl2N4O+ꢀC2H3O2
Acta Cryst. (2011). C67, o310–o314
ꢁ
ꢃ

organic compounds
Table 1
Hydrogen-bond geometry (A, ) for (I).
anion bridges three chains through hydrogen bonding with
one cation in each chain. These undulating chains also run
parallel in space.
ꢂ
˚
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
Attempts were made to obtain good-quality crystals of an
unsolvated and/or a neutral form of (1) without success. A
Cambridge Structural Database (CSD, version 5.32; Allen,
2002) search resulted in six structurally related hits, none of
which was found to form multiple solvates. Among them, the
complex chloro(ꢀ-resorcylidene aminoguanidine)copper(II)
tetrahydrate (refcode RIYMIV; Onuska et al., 1996) is similar
to (III) with the O atom protonated and a hydrogen bond
existing between the O atom and a guanine N atom, leading to
one-dimensional chains. In N-(2,4-dimethoxybenzylidene-
amino)guanidinium dihydrogenphosphate (refcode DAY-
HOB; Dinc¸er et al., 2005), 7-amino-5-(p-tolyl)-4-phenyl-2-
(p-methoxyphenyl)-3,4-dihydroimidazo[1,5-b]pyridazine (ref-
code LORRAL; Kolos et al., 1999), 2,4,6-trimethoxybenzyl-
ideneaminoguanidinium chloride (refcode MELBIO; Bats &
Hoffmann, 2000) and (4-methoxy-3-nitrobenzylideneamino)-
guanidinium chloride (refcode RIGKOI; Ring et al., 2007), the
corresponding O atom is methylated. The chain structure is
replaced by a dimer based on two hydrogen bonds between
methoxy O and guanine N atoms [graph-set notation R22(22)]
in DAYHOB, and no hydrogen bonds form between the
corresponding atoms in the other three compounds. In
2-methyl-4-hydroxybenzaldehyde 2-imidazolin-2-yl-hydra-
zone hydrochloride monohydrate (refcode FAJHED; Atfani
et al., 1986), the O atom is protonated as in (III), and the two N
atoms in the guanine group are integrated into a five-
membered ring. Again, a one-dimensional chain similar to that
in (III) is observed. Thus, it seems this hydrogen-bonding
motif is a common feature of (E)-2-(4-hydroxybenzyl-
idene)hydrazinecarboximidamides and is likely due to the
relatively high strength of the N—Hꢀ ꢀ ꢀO interaction.
N9—H9ꢀ ꢀ ꢀO2Wi
0.88
0.88
0.88
0.88
1.99
2.05
2.96
2.13
2.863 (3)
2.829 (3)
3.817 (3)
2.888 (3)
2.854 (3)
2.800 (3)
2.751 (3)
2.616 (3)
2.819 (3)
169
147
166
143
N11—H11Aꢀ ꢀ ꢀO1Wii
N11—H11Bꢀ ꢀ ꢀCl2
N12—H12Aꢀ ꢀ ꢀO1Wii
N12—H12Bꢀ ꢀ ꢀO1i
O1W—H1W1ꢀ ꢀ ꢀO1
O1W—H2W1ꢀ ꢀ ꢀO2Wiii
O2W—H1W2ꢀ ꢀ ꢀO1
O2W—H2W2ꢀ ꢀ ꢀO1iii
0.88
1.98
175
0.84 (2)
0.80 (2)
0.82 (2)
0.82 (2)
1.96 (2)
1.97 (2)
1.83 (2)
2.00 (2)
178 (4)
166 (3)
158 (3)
171 (3)
1
2
1
2
1
2
3
2
1
1
Symmetry codes: (i) x; ꢁy þ ; z þ ; (ii) ꢁx þ 1; y ꢁ ; ꢁz þ ; (iii) x ꢁ ; ꢁy þ ,
2
2
ꢁz þ 1.
Compound (I)
Crystal data
3
˚
C8H8Cl2N4Oꢀ2H2O
V = 2532.51 (9) A
Z = 8
Mr = 283.12
Orthorhombic, Pbca
Mo Kꢁ radiation
ꢂ = 0.52 mmꢁ1
T = 90 K
0.40 ꢄ 0.10 ꢄ 0.03 mm
˚
a = 6.8802 (1) A
b = 16.7892 (4) A
˚
c = 21.9240 (5) A
˚
Data collection
Nonius KappaCCD diffractometer
Absorption correction: multi-scan
(SCALEPACK; Otwinowski &
Minor, 1997)
5390 measured reflections
2898 independent reflections
1692 reflections with I > 2ꢃ(I)
Rint = 0.061
Tmin = 0.820, Tmax = 0.985
Refinement
R[F2 > 2ꢃ(F2)] = 0.053
wR(F2) = 0.142
S = 1.05
2898 reflections
167 parameters
6 restraints
H atoms treated by a mixture of
independent and constrained
refinement
ꢁ3
˚
Áꢄmax = 0.66 e A
ꢁ3
˚
Áꢄmin = ꢁ0.41 e A
Our work has thus shown that compound (1) can form at
least two solvated crystalline forms and salt formation with
acids should be expected as indicated by the existence of an
acetate salt. Owing to the presence of different solvents or
acids, the crystals have diverse packing and hydrogen-bond
arrangements.
Compound (II)
Crystal data
C8H8Cl2N4Oꢀ2CH4O
ꢅ = 107.4271 (9)ꢂ
3
˚
V = 718.02 (2) A
Z = 2
Mr = 311.17
Triclinic, P1
˚
a = 7.0255 (1) A
b = 10.0683 (2) A
Mo Kꢁ radiation
ꢂ = 0.46 mmꢁ1
T = 90 K
0.40 ꢄ 0.30 ꢄ 0.20 mm
Experimental
˚
˚
c = 11.7580 (2) A
Compound (1) was synthesized according to a modified literature
procedure (Li et al., 2010; Holzer et al., 1992; Gug et al., 2010). To a
solution of HCl (20%, 1 ml) in ethanol (17 ml) was added 2,6-di-
chloro-4-hydroxybenzaldehyde (0.5g, 2.62 mmol), followed by the
slow addition of a solution of aminoguanidine bicarbonate in H2O
(3 ml). After liberation of CO2, the solution was heated to reflux and
then cooled to room temperature. An aqueous solution of 40% KOH
(8.5 ml) was then added and the solution was refluxed for 10 min.
Afterward, the solution was left stirring overnight at room
temperature. To quench the reaction, the pH was adjusted to 7 using
5 M NaOH. NaHCO3 (15 ml) and dichloromethane (15 ml) were
added and the mixture was stirred for 30 min. The product precipi-
tated as an orange powder. Crystals of (I), (II) and (III) were grown
from solutions of (1) in acetone, methanol and acetic acid, respec-
tively.
ꢁ = 112.3416 (8)ꢂ
ꢀ = 93.9597 (9)ꢂ
Data collection
Nonius KappaCCD diffractometer
Absorption correction: multi-scan
(SCALEPACK; Otwinowski &
Minor, 1997)
6495 measured reflections
3269 independent reflections
2673 reflections with I > 2ꢃ(I)
Rint = 0.027
Tmin = 0.837, Tmax = 0.913
Refinement
R[F2 > 2ꢃ(F2)] = 0.035
wR(F2) = 0.095
S = 1.06
176 parameters
H-atom parameteꢁrs3 constrained
˚
Áꢄmax = 0.34 e A
ꢁ3
˚
3269 reflections
Áꢄmin = ꢁ0.33 e A
C8H8Cl2N4Oꢀ2H2O, C8H8Cl2N4Oꢀ2CH4O and C8H9Cl2N4O+ꢀC2H3O2
o313
ꢁ
ꢃ
Acta Cryst. (2011). C67, o310–o314
Gutierrez et al.

organic compounds
Table 2
Hydrogen-bond geometry (A, ) for (II).
reduction: DENZO-SMN (Otwinowski & Minor, 1997); program(s)
used to solve structure: SHELXS97 (Sheldrick, 2008); program(s)
used to refine structure: SHELXL97 (Sheldrick, 2008); molecular
graphics: XP in SHELXTL (Sheldrick, 2008); software used to
prepare material for publication: SHELXL97 and local procedures.
ꢂ
˚
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
O15—H15ꢀ ꢀ ꢀO1
0.84
0.84
0.88
0.88
0.88
0.88
0.88
1.83
1.83
2.02
1.89
2.23
1.99
2.57
2.6640 (18)
2.6464 (17)
2.8109 (18)
2.7665 (19)
2.969 (2)
171
163
149
173
142
167
127
O16—H16ꢀ ꢀ ꢀO1
N9—H9ꢀ ꢀ ꢀO15i
N12—H12Aꢀ ꢀ ꢀO1ii
N12—H12Bꢀ ꢀ ꢀO15i
N11—H11Aꢀ ꢀ ꢀO16ii
N11—H11Bꢀ ꢀ ꢀO16iii
Published as paper No. 394 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 Horse-
men’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.
2.8596 (19)
3.1702 (19)
Symmetry codes: (i) ꢁx þ 2; ꢁy þ 2; ꢁz þ 1; (ii) x; y þ 1; z þ 1; (iii) ꢁx þ 1; ꢁy þ 1,
ꢁz þ 1.
Table 3
Hydrogen-bond geometry (A, ) for (III).
ꢂ
˚
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
O1—H1ꢀ ꢀ ꢀO15i
N11—H11Aꢀ ꢀ ꢀO15ii
N12—H12Aꢀ ꢀ ꢀO16ii
N12—H12Bꢀ ꢀ ꢀO1iii
0.84
0.88
0.88
0.88
0.88
1.70
1.91
2.04
1.96
2.05
2.5336 (19)
2.730 (2)
2.900 (2)
2.828 (2)
2.868 (2)
175
153
167
168
153
N9—H9ꢀ ꢀ ꢀO16
3
2
1
2
1
2
3
2
1
1
Symmetry codes: (i) ꢁx þ ; ꢁy; z ꢁ ; (ii) ꢁx þ 2; y þ ; ꢁz þ ; (iii) x; ꢁy þ ; z þ .
2
2
Compound (III)
Crystal data
C8H9Cl2N4O+ꢀC2H3O2
ꢁ
3
˚
V = 2576.41 (8) A
Z = 8
Mo Kꢁ radiation
ꢂ = 0.51 mmꢁ1
T = 90 K
Mr = 307.14
Orthorhombic, Pbca
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: SQ3285). Services for accessing these data are
described at the back of the journal.
˚
a = 15.9630 (1) A
˚
b = 7.4060 (2) A
˚
c = 21.7930 (3) A
0.40 ꢄ 0.20 ꢄ 0.10 mm
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¨
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¨
¨
¨
¨
˚
Áꢄmax = 0.38 e A
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˚
2952 reflections
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2
3
˚
˚
˚
˚
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846.
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.
2
˚
quently placed in idealized positions, with N—H = 0.88 A, Csp —H =
3
0.95 A and Csp —H = 0.98 A for methyl H atoms. For (I), the water
˚
˚
˚
H atoms were refined with restraints of O—H = 0.82 (2) A and
˚
Hꢀ ꢀ ꢀH = 1.30 (3) A. Isotropic displacement parameters for all H
atoms were fixed at Uiso(H) = 1.5Ueq(parent atoms) for hydroxy and
methyl H atoms and 1.2Ueq(parent atoms) for all others.
Ring, J. R., Parkin, S. & Crooks, P. A. (2007). Acta Cryst. C63, o392–o394.
Seddon, K. R. (2004). Cryst. Growth Des. 4, 1087.
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122.
For all compounds, data collection: COLLECT (Nonius, 1998); cell
refinement: SCALEPACK (Otwinowski & Minor, 1997); data
o314 Gutierrez et al. C8H8Cl2N4Oꢀ2H2O, C8H8Cl2N4Oꢀ2CH4O and C8H9Cl2N4O+ꢀC2H3O2
Acta Cryst. (2011). C67, o310–o314
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