Polymorph-specific chlorination of maleic-hydrazide

Article abstract of DOI:10.1016/S0022-2860(02)00525-2

The reaction of chlorination of maleic-hydrazide (1) with POC13 is specific to the substrate polymorph. Chlorination of either the triclinic polymorph of maleic-hydrazide (1), denoted MH1, or the monoclinic polymorph MH2 leads to a single product of 3,6-dichloropyridazine (2), while chlorination of the monoclinic polymorph MH3 under the same conditions results in two products: 3,6-dichloropyridazine (2) and 6-chloro-3-pyridazinone (3). The structural differences between polymorphs and their topochemical chlorination in phosphorus oxychloride are discussed. The crystal structure of 6-chloro-3-pyridazinone (3) monohydrate, determined in this study by X-ray diffraction, is built of ribbons of hydrogen-bonded 3 and water molecules. It has been established that the chlorination of ground crystals of polymorph MH3 yields exclusively the dichloropyridazine, which suggests that the crystal habit of MH3, the size of crystallites and the lower solubility of MH3 than MH1 and MH2 are the main reasons for the different course of the reaction.

Full text of DOI:10.1016/S0022-2860(02)00525-2

Journal of Molecular Structure 647 (2003) 203–210
www.elsevier.com/locate/molstruc
Polymorph-specific chlorination of maleic-hydrazide
a,
Andrzej Katrusiak , Anna Katrusiak
b,1
*
a
´
Department of Crystallography, Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 Poznan, Poland
b
´
Department of Organic Chemistry, Karol Marcinkowski University of Medical Sciences, Gruwaldzka 6, 60-780 Poznan, Poland
Received 25 January 2002; revised 23 July 2002; accepted 23 July 2002
Abstract
The reaction of chlorination of maleic-hydrazide (1) with POCl3 is specific to the substrate polymorph. Chlorination of either
the triclinic polymorph of maleic-hydrazide (1), denoted MH1, or the monoclinic polymorph MH2 leads to a single product of
3,6-dichloropyridazine (2), while chlorination of the monoclinic polymorph MH3 under the same conditions results in two
products: 3,6-dichloropyridazine (2) and 6-chloro-3-pyridazinone (3). The structural differences between polymorphs and their
topochemical chlorination in phosphorus oxychloride are discussed. The crystal structure of 6-chloro-3-pyridazinone (3)
monohydrate, determined in this study by X-ray diffraction, is built of ribbons of hydrogen-bonded 3 and water molecules. It
has been established that the chlorination of ground crystals of polymorph MH3 yields exclusively the dichloropyridazine,
which suggests that the crystal habit of MH3, the size of crystallites and the lower solubility of MH3 than MH1 and MH2 are the
main reasons for the different course of the reaction.
q 2003 Elsevier Science B.V. All rights reserved.
Keywords: Polymorphism; Chlorination; Maleic-hydrazide
1. Introduction
The reactivities of polymorphs are of particular
interest as they demonstrate the appreciable extent to
which supramolecular aggregation and intermolecu-
lar interactions can modify properties of substances.
The interdependence between crystal structure and
properties defies general description and is not well
understood. Since properties vary, polymorphism of
substances is of crucial importance for materials
science and for technological applications, especially
in the pharmaceutical industry. The pharmaceutical
aspects of polymorphism can be exemplified by the
properties of paracetamol [5,6], for which three
polymorphic forms have been reported [7–9]. It is to
be expected that the physical and chemical proper-
ties of polymorphs arise from their different
structures, either in the bulk of the crystal or on its
surface. The chemical reactions involving
3,6-Dichloropyridazine (2) is the indispensable
substrate for syntheses of various pyridazine deriva-
tives, for example tetr- or triazolopyridazines [1,2]; it
can be obtained in the well-known chlorination
reaction of 6-hydroxy-3-pyridazinone (1) with phos-
phorus oxychloride [3,4]. We observed that occasion-
ally the chlorination of 1 yielded not only compound
2, but a mixture of 2 and 6-chloro-3-pyridazinone (3)
(Scheme 1). We have ascertained that the chlorination
path depends on which polymorph of compound 1 is
used for the reaction.
*
Corresponding author..
E-mail address: katran@amu.edu.pl (A. Katrusiak).
E-mail address: akatrus@eucalyptus. usoms. poznan. pl .
0022-2860/03/$ - see front matter q 2003 Elsevier Science B.V. All rights reserved.
PII: S0022-2860(02)00525-2

204
A. Katrusiak, A. Katrusiak / Journal of Molecular Structure 647 (2003) 203–210
DMSO or CDCl3 with TMS as internal standard. The
compounds were separated by column chromatog-
raphy on silica gel, 230–400 mesh ASTM, using
acetone/hexane mixture (3:2).
2.1. 3,6-Dichloropyridazine (2)
100.0 g (0.67 mol) of 6-hydroxy-3-pyridazinone
MH1 or MH2 (1) with 200.0 cm3 of phosphorus
oxychloride was refluxed for 3 h on the water bath.
The reaction mixture was poured into water with ice,
alkalized with ammonia and extracted with chloro-
form. The extracts were washed with water, dried
(MgSO4) and evaporated. The residue was crystal-
lized from hexane, and identified as compound 2 by
comparing with literature data [3,4]: m.p. 62–63 8C.
Yield 41%.
Scheme 1.
a crystalline substrate, termed topochemical reaction
[10], are particularly likely to be affected by
polymorphism.
2.2. 3,6-Dichloropyridazine (2) and 6-chloro-3-
pyridazinone (3)
Three polymorphs of maleic-hydrazide (1) have
ꢀ
been reported so far: a triclinic form, space group P1;
Analogously we obtained a mixture of com-
pounds 2 and 3, using 100.0 g of 6-hydroxy-3-
pyridazinone MH3. The residue from the chloro-
form extract was isolated by column chromatog-
raphy; fractions were collected, evaporated and
identified as compounds 2 and 3. Identification of
compound 2 was by comparison with literature data
[3,4], yield 30%. Identification of compound 3: m.p.
130–131 8C, crystallized from water. Analysis: For
C4H3CIN2 (114.54)-Calcd.: 24.46%N, 41.94%C,
2.64%H; found: 24.21%N, 42.01%C, 2.59%H. 1H
NMR (ppm, DMSO): 6.98, 7.02 (1H, C-8, d), 7.27,
7.30 (1H, C-7, d), J ¼ 9.83 Hz, 12.43 (1H, –OH,
s). Yield 21%.
denoted MH1 [11], and two monoclinic forms: MH2,
space group P21=c [12], and MH3, space group P21=c
[13]. In all three polymorphs the molecules are
present in the lactim–lactam form of 6-hydroxy-3-
pyridazinone (1), and the same pattern of hydrogen
bonds is formed. In this study we analysed the
distortions of the hydrogen-bonded aggregates, as
well as the crystal packing and crystal morphology,
for their possible influence on the course of the
chlorination. We also determined the crystal structure
of 6-chloro-3-pyridazinone (3) monohydrate and the
pattern of hydrogen bonds formed in this structure.
Because it has several known polymorphic forms (two
new phases of maleic-hydrazide have been identified
recently [14]) with structural differences limited only
to the arrangement of the rigid planar molecules,
maleic-hydrazide appears to be a convenient model
system for studying structure-property relations in
polymorphs.
2.3. X-ray analysis
6-Chloro-3-pyridazinone (3) was recrystallized
as monohydrate from water forming small colour-
less elongated plates. The crystal data, summarized
in Table 1, were measured using a KM-4 CCD
diffractometer equipped with a sealed X-ray tube
and graphite monochromator. The structure was
solved straightforwardly by direct methods [15].
The anisotropic refinements [16] showed that the
chlorine and water oxygen atoms, like all other
non-hydrogen atoms located on a mirror plane, are
2. Experimental
Melting points were determined on a Boetius
apparatus and are uncorrected. 1H NMR spectra were
recorded on a Varian spectrometer at 300 MHz in

A. Katrusiak, A. Katrusiak / Journal of Molecular Structure 647 (2003) 203–210
205
Table 1
range from 4 to 608. The samples were ground in the
mortar to the average grain size of 5m.
Crystal data and structure refinement for 6-chloro-3-pyridazinone
monohydrate
Empirical formula
Formula weight
C4H3ClN2O·H2O
148.55
3. Results and discussion
Temperature
293(2) K
˚
0.71073 A
Wavelength
3.1. Polymorphism of maleic-hydrazide (1)
Crystal system, space group
Unit cell dimensions
othorhombic, Pnma
˚
a ¼ 6.3361(16) A
˚
b ¼ 6.467(2) A
It is a common feature of the polymorphs of
maleic-hydrazide that they are all built of mol-
ecules hydrogen-bonded into ribbons, as shown in
Fig. 1. The pattern of hydrogen bonds is identical
in the polymorphs: the hydroxyl and carbonyl
oxygens are linked by short hydrogen bonds
forming chains, which in turn are linked by pairs
of NH- -O hydrogen bonds into ribbons. The main
structural differences between the polymorphs are
due to the mutual arrangement of the ribbons, their
distortions and symmetry elements relating the
ribbons (the internal symmetry of the ribbons is
identical in all three polymorphs [13]). It appeared
initially that the most important features relevant
for the presently considered chlorination were the
distortions of the ribbons and their interactions. It
was postulated that the strain within the ribbons
and the interactions of the ribbons in the crystal
lattice were interdependent and resulted in the
comparable energies of the polymorphs, enabling
˚
c ¼ 15.589(2) A
3
˚
Volume
638.8(3) A
Z, Calculated density
Absorption coefficient
F(000)
4, 1.545 g/cm3
0.521 mm21
304 e
0.3 £ 0.2 £ 0.1 mm3
Crystal size
Theta range for data collection
Limiting indices
4.14–29.678
26 # h # 8, 28 # k # 8,
221 # l # 19
Reflections collected/unique
Completeness to u ¼ 29.67
Data/restraints/parameters
Goodness-of-fit on F 2
4630/903 [Rint ¼ 0.0858]
92.4%
903/0/76
1.019
Final R indices [I . 2sI]
R indices (all data)
R1 ¼ 0.0557, wR2 ¼ 0.0543
R1 ¼ 0.0604, wR2 ¼ 0.0692
23
˚
0.141 and 20.197 e A
Largest diff. peak and hole
strongly elongated along [010]. After allowing
these two atoms to shift away from the plane, the
reliability factors R significantly decreased. Various
possibilities of lower crystal symmetries without
the mirror plane and other disorder models were
tried using the R-factor test [17]. Finally the
structure was refined in space group Pnma with
the disordered chlorine atom, to account for its
thermal ellipsoid strongly elongated perpendicular
to the mirror plane. The water oxygen atom
appeared clearly disordered on both sides of the
mirror plane. The nature of the disorder, the crystal
symmetry and its transformations are being studied
and will be reported elsewhere. All H-atoms were
located from DF maps and refined with isotropic
temperature factors. The final atomic coordinates
are listed in Table 2. The crystal data and
experimental details have been deposited in the
Cambridge Crystallographic Database Centre as a
supplementary publication No. CCDC 175761.
X-ray powder diffractograms were recorded using
an upgraded and computer-controlled HZG-3 dif-
fractometer with filtered Cu Ka radiation in the 2u
Table 2
Atomic coordinates ( £ 104) and equivalent isotropic displacement
2
3
˚
parameters (A £ 10 ) for 6-chloro-3-pyridazinone monohydrate.
Ueq is defined as one third of the trace of the orthogonalized Uij
tensor
x
y
z
U(eq)
N(1)
2362(6)
820(7)
2500
5103(3)
4390(2)
4330(3)
3625(2)
5134(3)
5867(3)
5813(3)
6734(1)
3107(4)
3960(20)
5170(20)
6440(60)
2630(80)
3300(40)
51(1)
49(1)
N(2)
2500
C(3)
2966(8)
2500
47(2)
O(3)
3809(5)
2500
72(1)
C(4)
4005(10)
2881(10)
682(8)
2500
54(2)
C(5)
2500
57(2)
C(6)
2500
50(2)
Cl(6)
O(1W)
H(2)
2832(3)
7923(8)
2720(40)
3092(13)
2500
90(4)
59(4)
260(60)
5380(70)
3700(120)
7860(180)
6850(110)
10(10)
23(12)
160(30)
250(70)
80(30)
H(4)
2500
H(5)
2500
H(1W)
H(2W)
2500
2500

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A. Katrusiak, A. Katrusiak / Journal of Molecular Structure 647 (2003) 203–210
Fig. 1. Molecules of maleic-hydrazide (1), in the lactam–lactim form hydrogen bonded into ribbons, as observed in three polymorphic
structures. Hydrogen bonds are indicated by the dashed lines.
the concomitant (i.e. simultaneous) crystallization
of MH1 and MH3 [13]. The yields of the
chlorinations of MH1, MH2 and MH3 suggested
that the reaction proceeded best of MH2 where the
ribbons are most strained, and least effectively for
Table 3
˚
Bond lengths (A) and angles (8) for 6-chloro-3-pyridazinone
monohydrate, as well as the distances between the disordered atoms
MH3, where the ribbons are nearly ideally planar.
It was established very recently that it is even
possible to break the NH- -O hydrogen bonds in
MH2 simply by lowering the temperature. This
unusual transformation is currently being described
in full detail elsewhere [14], however, it provides
additional evidence that the NH- -O bonds in MH2
are weaker than in MH1 or MH3. It is thus
plausible that the weakness of the NH- -O bonds
promotes the chlorination.
N(1)–C(6)
1.290(5)
1.341(5)
1.363(6)
0.87(3)
N(1)–N(2)
N(2)–C(3)
N(2)–H(2)
C(3)–O(3)
1.222(6)
1.415(7)
1.347(7)
0.87(4)
C(3)–C(4)
C(4)–C(5)
C(4)–H(4)
C(5)–C(6)
1.396(8)
1.03(9)
C(5)–H(5)
C(6)–Cl(6)
Cl(6)–Cl(6a)
1.732(5)
0.29(5)
3.2. Crystal structure of 6-chloro-3-pyridazinone
monohydrate (3·H2O)
O(1W)–O(1Wa)
O(1W)–H(1W)
O(1W)–H(2W)
C(6)–N(1)–N(2)
N(1)–N(2)–C(3)
O(3)–C(3)–N(2)
O(3)–C(3)–C(4)
N(2)–C(3)–C(4)
C(5)–C(4)–C(3)
C(4)–C(5)–C(6)
N(1)–C(6)–C(5)
N(1)–C(6)–Cl(6)
C(5)–C(6)–Cl(6)
N(1)–C(6)–Cl(6a)
C(5)–C(6)–Cl(6a)
Cl(6)–C(6)–Cl(6a)
H(1W)–O(1W)–H(2W)
0.765(17)
0.84(11)
0.83(6)
115.2(4)
The structure of 3·H2O studied by X-ray
diffraction in order to determine the tautomeric
form of the molecules, lactim or lactam, and to
establish whether strong intermolecular interactions
between molecules 3 lead to aggregation that could
prevent their full chlorination. Only solvated 3·H2O
crystals were obtained. Molecules 3 are present in
the lactam form in the solid state, as evidenced by
the location of the H-atom at N2 and by the
molecular dimensions listed in Table 3. Crystals of
3·H2O are built of ribbon aggregates of hydrogen-
bonded molecules of 3 and water, as shown in
Fig. 2. Each molecule 3 is hydrogen bonded to
three water molecules, and each water molecule is
127.8(4)
119.8(4)
126.3(5)
113.9(5)
120.3(6)
118.5(6)
124.3(5)
115.3(4)
120.2(4)
115.3(4)
120.2(4)
9.6(18)
94(7)
a
Symmetry transformation used to generate equivalent atoms: x,
1=2 2 y; z.

A. Katrusiak, A. Katrusiak / Journal of Molecular Structure 647 (2003) 203–210
207
Fig. 2. Hydrogen-bonded ribbon aggregates of 6-chloro-3-pyridazinone monohydrate (3·H2O). At room temperature, water molecules are
disordered on both sides of the mirror plane on which the 6-chloro-3-phridazinone molecules are located in the crystal structure.
hydrogen-bonded to three molecules of 3. The
dimensions of the hydrogen bonds are listed in
Table 4. The crystal structure of crystals 3·H2O
indicates that the N(1)–N(2)–C(3)· · ·O(3) side of
the molecule is more hydrophilic that the hydro-
phobic C(4)· · ·C(5)–C(6)–C1 moiety. This property
would also suggest that, where appropriately
oriented at the surface of the crystal, molecules 3
may exhibit a similar anisotropy in interactions
with POCl3 that may either favour or prevent full
chlorination.
the crystals. Therefore we ground samples of the
polymorphs and repeated the chlorination for the
ground 1. For both MH1 and MH3 chlorination
yielded exclusively dichloropyridazine. X-Ray pow-
der diffractograms of the ground samples have shown
that they contained either a mixture of polymorphs
Table 4
Dimensions of hydrogen bonds in the structure of 6-chloro-3-
pyridazinone monohydrate
˚ ˚
D· · ·A (A) H· · ·A (A) D–H· · ·A (8)
D–H· · ·A
3.3. X-ray powder and reactivity study of the ground
polymorphs
N(2)–H(2)· · ·O(1W)
2.741(6)
1.89(4)
2.05(12)
2.00(7)
167.8(9)
147(7)
151(3)
O(1Wa)–H(1Wa)· · ·O(3) 2.784(6)
O(1Wb)–H(2Wb)· · ·O(3) 2.756(6)
a
The above hypothesis would imply that the
chlorination reaction proceeds at the surface of
Symmetry code: 1=2 þ x; 1=2-y; 1=2-z:
Symmetry code: 1 þ x; y, z.
b

208
A. Katrusiak, A. Katrusiak / Journal of Molecular Structure 647 (2003) 203–210
Fig. 3. Orientation of the hydrogen-bonded ribbon of maleic-hydrazide molecules in crystal structure and the morphology of polymorph MH2.
MH1 and MH3, or only the polymorph MH3. This
shows that the size of the grains and possible defects
induced by grinding in the strained grains control the
chlorination reaction for polymorph MH3. These
factors have no effect on the chlorination of
polymorphs MH1 and MH2 (for average crystals
size of about 1 mm). These conclusions are further
supported by the different orientations of the H-
bonded ribbons relative to the faces of the poly-
morphs. In polymorph MH2 the ribbons are perpen-
dicular to the largest faces (100) of the crystals
(Fig. 3), while in MH3 the ribbons are parallel to the
largest faces (001), as illustrated in Fig. 4. Thus
mainly the ends of the H-bonded ribbons are exposed
on the surface of the crystals of polymorph MH2,
while the surfaces of crystals MH3 are mainly ‘paved’
with the hydrophobic edges of the ribbons.
proceed differently and give different products due
to the topochemical character of these reactions. The
analyses of the crystal structures of the polymorphs
of maleic-hydrazide (1) and of the monochlorinated
product (3) suggest that the different courses of
reaction are related to the habits of the crystals of
the polymorphs, to the structures of their surfaces,
and to their size. Interestingly, the reactions
correlate with the structure of the hydrogen-bonded
aggregates: full chlorination proceeds in polymorph
MH2, where the ribbons are most strained and likely
to break into separate OH- -O bonded chains with
both oxygens equally exposed, whereas in the
polymorph most resistant to chlorination, MH3, the
ribbons are planar and the NH- -O hydrogen bonds
are least strained. It is also characteristic that in
polymorph MH2, for which full chlorination is
easiest, the H-bonded ribbons are perpendicular to
the largest crystal faces, while in polymorph MH3,
the most resistant to dichlorination, these faces are
the smallest. Thus it is also plausible that full
chlorination proceeds along the ribbons, which is
4. Conclusion
It is plausible that chlorinaion reactions of
polymorphs of maleic-hydrazide (1) in POCl3

A. Katrusiak, A. Katrusiak / Journal of Molecular Structure 647 (2003) 203–210
209
Fig. 4. Orientation of the hydrogen-bonded ribbon of maleic-hydrazide molecules in the crystal structure of polymorph MH3, and morphologies
of its crystals. Twinning of the MH3 crystals have been indicated [13].
consistent with the observation of the slow and
difficult chlorination of MH3. Chlorination in POCl3
may also be related to the solubility of MH1, MH2
and MH3. Thus it is possible that chlorination
proceeds only on the crystal surface for polymorph
MH3, while crystals of polymorphs MH1 and MH2
are first dissolved, and then chlorination proceeds
for 1 molecules isolated in POCl3.
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