Intermolecular contacts in the crystal structures of specifically varied halogen and protonic group substituted azines

Article abstract of DOI:10.1039/c7ce00548b

A series of azines featuring differently halogen and protic group substituted pyridine, pyrimidine and pyridazine compounds have been synthesized and studied in terms of their crystal structures in order to develop a better understanding of the links between structural conditions and molecular packing behavior. Complemented by the structure results of related compounds known from the literature, intermolecular contact relationships connected to the present substance types were found, having potential use in future crystal engineering of similar compounds. This primarily involves the formation of N?I contacts aside from specific halogen?halogen and hydrogen bond type interactions.

Full text of DOI:10.1039/c7ce00548b

View Article Online
View Journal
CrystEngComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: J. Hübscher, W.
Seichter and E. Weber, CrystEngComm, 2017, DOI: 10.1039/C7CE00548B.
This is an Accepted Manuscript, which has been through the
Volume 18 Number 1 7 January 2016 Pages 1–184
Royal Society of Chemistry peer review process and has been
accepted for publication.
CrystEngComm
Accepted Manuscripts are published online shortly after
www.rsc.org/crystengcomm
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
HIGHLIGHT
Tiddo J. Mooibroek, Antonio Frontera et al.
Towards design strategies for anion–π interactions in crystal engineering
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
rsc.li/crystengcomm

Page 1 of 21
CrystEngComm
View Article Online
DOI: 10.1039/C7CE00548B
Intermolecular contacts in the crystal structures of specifically varied halogen
and protonic group substituted azines
Jörg Hübscher, Wilhelm Seichter and Edwin Weber
Abstract
A series of azines featuring differently halogen and protic group substituted pyridine, pyrimidine and
pyridazine compounds have been synthesized and studied in terms of crystal structures in order to
develop a better understanding of the links between structural condition and molecular packing
behavior. Complemented by the structure results of related compounds known from the literature,
intermolecular contact relationships connected to the present substance types were found, having a
potential use in the future crystal engineering of similar compounds. This primarily involves the
formation of N∙∙∙I contacts aside from specific halogen∙∙∙halogen and hydrogen bond type
interactions.
Institute of Organic Chemistry, Technical University Bergakademie Freiberg,
Leipziger Straße 29, D-09596 Freiberg, Sachsen, Germany.
E-Mail: edwin.weber@chemie.tu-freiberg.de
1
† Electronic supplementary informaꢀon (ESI) available: H and 13C NMR spectra of compound 3. The
crystallographic information files have been deposited with the Cambridge Structural Database.
CCDC 1538316 – 1538319.

CrystEngComm
Page 2 of 21
View Article Online
DOI: 10.1039/C7CE00548B
Introduction
The tailoring of organic crystal structures to meet the requirements of intended applications is an
objective of highest current interest being termed ´crystal engineering`.1-4 A commonly agreed fact is
that understanding the principles of intermolecular aggregation patterns represents the basis for
this.5 Aside from hydrogen bonding patterns such as coming from carboxylic or amide functional
groups,6,7 nowadays deemed rather predictable and thus being classified as robust supramolecular
synthons,8 there is a number of non-traditional hydrogen bonding interactions, e.g. C-H∙∙∙X9,10 C-
H∙∙∙π,11,12 and other types of intermolecular interactions including halogen∙∙∙halogen,13,14 S∙∙∙S15,16 or
nitro group contacts17,18 that still have questions, although in particular halogen-involved interactions
are already shown to significantly contribute to application-related advantages19-21. Moreover, a
certain degree of uncertainty is attached in the case when different modes of association between
oligo functional molecules compete involving an unbalanced number or strength of donors and
acceptors being met with the molecular structure.22-24 Thus, understanding the effects attributable to
this kind of interference of interactions give rise to undeniable importance for the general
applicability of crystal engineering.25 Azines such as pyridine, pyrimidine or pyridazine they all have
only N-acceptors but no strong donor moiety, and therefore tend to form cyclic or chain-type
synthons generated from weak C-H∙∙∙N hydrogen bonding.26 Hence, the azine nitrogen may compete
with other existing acceptors for the contact to a donor group being present as an additional
substituent, and it seems even possible to disrupt a traditional synthon pattern.27-30
To investigate these property relationships closer, we became interested in the solid state
structures of a series of azines that were synthesized featuring the ring elements of pyridine,
pyrimidine as well as pyridazine and having available additional substituents including chlorine,
iodine, terminal acetylenic and hydroxyl groups in different positional arrangement. The concrete
structures covered in this paper and being discussed in connection with the problem raised primarily
are focused on the compounds 1, 4, 5 and 6 specified in Scheme 1 but include also the reference
compounds 7-15 (Scheme 2) known from the literature potentially providing further guidance for
relationships.
Results and discussion
Preparation of compounds
The 2,6-dichloro-4-iodo substituted pyridine 1 was obtained from 2,6-dichloropyridine via
deprotonation with n-BuLi followed by reaction with iodine and being separated from positional
isomeric 2,6-dichloro-3-iodopyridine (2) as a byproduct.31 The separation process can run easily by
fractional crystallization since 1 is less soluble in ethanol compared to the constitutional isomer 2. In
addition, completeness of the crystallization of 1 can be detected by means of their form of
crystallization because 1 yields well developed crystals, while the compound isomer 2 precipitates
only as an amorphous powder. Reaction of 2 with trimethylsilylacetylene (TMSA) under Sonogashira-
Hagihara condition32 yielded 3. Basic cleavage of the blocking TMS group from 3 using KOH in
acetonitrile led to 4 which, however, caused problems in the bulk isolation and chemical analysis
because of instability of 4 but is proven to be formed owing to the structural analysis of a single
crystal that was found in the reaction product. The 2-chloro-5-iodo substituted pyrimidine 5 was
prepared by reaction of 2-hydroxy-5-iodopyrimidine with phosphoroxychloride and
diisopropylethylamine.31 Similarly, reaction of pyridazin-3,6-diol with phosphoroxychloride resulted
in a mixture of 6-chloro-3-hydroxypyridazine [6-chloropyridazin-3(2H)-one] (6) (cf. Scheme 3) and

Page 3 of 21
CrystEngComm
View Article Online
DOI: 10.1039/C7CE00548B
3,6-dichloropyridazine which could be separated from each other by column chromatography
yielding 6 in 8 %.
X-ray structural study
Relevant crystallographic data and information concerning possible intermolecular interactions in the
crystal structures being studied are summarized in Tables 1 and 2. Molecular structures and packing
diagrams of the compounds 1, 4-6 are presented in Figures 1-3.
The dichloro iodo substituted pyridine 1 crystallizes from ethanol as colorless plates in the
orthorhombic space group Pnma with one molecule in the asymmetric part of the unit cell (Fig. 1a).
Due to the presence of the strongly electron withdrawing chlorine substituents and assisted by the
negative induction effect coming from the nitrogen atom on one side of the molecule and supported
by the iodine atom on the other side being conductively polarizable, the molecule comes up to a high
dipole moment corresponding with the found structural data. Based on this inhomogeneity of
charge, a number of distinct intermolecular contacts are determined starting with a strongly marked
I∙∙∙N interaction33 (I1∙∙∙N1) propagating along the crystallographic c-axis (Fig. 2a). A reason for this
particular interaction should be the high electron density located at the nitrogen atom and the
relatively low electron density at the iodine atom, giving rise to a so-called σ–hole there.34 Moreover,
bifurcated Cl∙∙∙I contacts35 (Cl1∙∙∙I1, Cl2∙∙∙I1) are observed including the two chlorine atoms of one
molecule and the iodine atom of a neighboring molecule that superimpose in antiparallel fashion one
to another to form a plane. Crosslinking of the chains is via Cl∙∙∙Cl contacts of the ´head-on` type (type
I).36 The layers generated in this way along the crystallographic B-plane are stacked along the b-axis
with the aid of π∙∙∙π37,38 (cg1∙∙∙cg1) and Cl∙∙∙π interactions39,40 (Cl1∙∙∙cg1, Cl2∙∙∙cg1) to yield a highly
crosslinked packing of the molecules.
The dichloroethynyl substituted pyridine 4 differs from 1 in the absence of the iodine feature
in the 4-position of the pyridine ring but has an ethynyl group attached to the 3-position of the
heterocycle. The compound crystallizes in the space group P21/n containing one molecule in the
asymmetric part of the unit cell (Fig. 1b). As ascribed above for 1, the molecular structure of 4 is
perfectly planar. However, although as for 1 two chlorine atoms are present, the molecules of 4 use
only one of them for the formation of intermolecular contacting (Fig. 2b). This includes a ´head-on`
(type I) Cl∙∙∙Cl (Cl2∙∙∙Cl2) interaction and a C-H∙∙∙Cl contact10 being effective between the protonic
hydrogen of the acetylenic group and the chlorine atom (C7-H7∙∙∙Cl2). According to this, the crystal of
4 is constructed of infinite zigzag-strands of C-H∙∙∙Cl bonded molecules which are connected among
each other by weak Cl∙∙∙Cl contacts resulting in the formation of a three-dimensional aggregate
structure.
Crystallization of 2-chloro-5-iodopyrimidine (5) yields colorless rods of the space group Pnma
with one molecule in the asymmetric part of the unit cell (Fig. 1c). The bond lengths within the
aromatic ring display no significant deviations from those found in the crystal structure of 2-
chloropyrimidine.41 The crystal of 5 is constructed of molecular sheets extending parallel to the
crystallographic B-plane. Although the molecule lacks strong donors, the crystal structure is stabilized
by a close network of non-covalent intermolecular bonding. As illustrated in Fig. 3a, within the 2D-
network the iodine atom acts as a bifurcated donor for I∙∙∙N interaction, while a second molecule
provides its chlorine atom to form an I∙∙∙Cl contact. The second nitrogen atom takes part in the
formation of a C-H∙∙∙N hydrogen bond.9 According to the given pattern of molecular connection, two
3
3
different supramolecular ring motifs are present following the graph set R3 (11) and R2 (7).42,43
Interlayer interaction is accomplished by π∙∙∙π arene stacking with a center-to-center distance of
3.817(3) Å between interacting aromatic rings.

CrystEngComm
Page 4 of 21
View Article Online
DOI: 10.1039/C7CE00548B
Colorless crystals of the chlorohydroxypyridazine derivative 6 which have been isolated by
chromatographic purification from a product mixture with 3,6-dichloropyridazine show the space
group P21/n with one molecule in the asymmetric part of the unit cell (Fig. 1d). The planar molecule
featuring a α–hydroxyazine formula structure is subject to a lactam-lactim tautomerism44 (Scheme 3),
where in the solid state the balance is on the side of the lactam tautomer. This by itself is a
remarkable behavior since in the lactam formulation the molecule abandons aromatic nature but
possibly allows the molecule to form an H-bridge (N2-H2A∙∙∙O1) mediated stabile dimer being
available in the present structure. In the packing construction, the dimers are connected by Cl∙∙∙Cl
´head-on` (type I) contacts to form infinite strands (Fig. 3b). Furthermore, Cl∙∙∙π [(Cl∙∙∙cg1) 3.440(2) Å,
symmetry 1+x, y, z] as well as O∙∙∙π interactions12 [d(O∙∙∙Cg) 3.649(2) Å, symmetry -1+x, y, z]stabilize
the crystal structure. In the course of this, each of the molecules acts as a donor of the one and an
acceptor of the other type of interaction with reference to the stacking direction.
Structure comparison involving related compounds
In order to clear up an even more profound influence measure of structural amendments with
reference to the present compound types including different substitution, it seems appropriate to
draw a comparison with structurally related compounds represented in the literature. Molecular
formula of respective compounds, namely 7-15 being specified with CCDC Refcodes, are provided in
Scheme 2.
Regarding the halogen-trisubstituted pyridines 1, 8, 10 and 11, they all are formally derived
from 4-iodopyridine (7)45 as the parent compound, with 1, 8,46 1047 and 1148 being the 2,6-dichloro,
3,5-dichloro, 3,5-dibromo and 3,5-diiodo derivatives of 7, respectively. Owing to both the 4-
iodopyridine structural unit and the symmetry property (point group C2v) the molecules have in
common, also their crystal structures are expected to show certain common structural features. In
the crystal structure of 7,45 linear strands of I∙∙∙N connected molecules are typical of the
supramolecular aggregation with no other directional interactions existing between the strands (Fig.
4a). Another peculiar fact is the uniform alignment of the molecules in this structure.
The tendency to form strand-like aggregation of molecules is also shown in the crystal
structures of the two chlorine-substituted isomers 1 (Fig. 2a) and 8 (Fig. 4b). In both these cases, the
molecular strands using ´head-on` (type I) Cl∙∙∙Cl contacts provide layers with an almost identical
structure, illustrating that the position of the chlorine substituents at the heterocyclic ring do not
have an impact on the packing behavior of the molecules or the intermolecular interaction pattern.
In contrast, replacement of the chlorine atoms by the softer bromine or iodine atoms as in 10 and 11,
respectively, indicates discernible impact on the coordination property of the molecules in the
crystalline state. The bromine compound 10 shows a layer-like packing of the molecules (Fig. 4e)
corresponding to the structure of 8. Furthermore, the iodine atom in 10 serves to link the molecules
of neighboring layers via I∙∙∙Br contacts35 counteracting a stacking of molecules typical of aromatic
rings. The presence of the iodine atoms in 11 (Fig. 4f) leads to a packing structure that fundamentally
differs from those of 8 and 10. Though the crystal structure of 11 is also characterized by a layer-like
packing structure, the iodine atoms in the meta-position relating to the nitrogen atom prevent the
strand formation typical of the above-mentioned structures. Instead, the molecules within a layer are
linked via a dense network of halogen-involved interactions comprising I∙∙∙N,49 ´side-on` (type II) I∙∙∙I36
and C-H∙∙∙I50 contacts. The large overlapping area between the molecules of neighboring layers points
to the presence of π∙∙∙π arene interactions37,38 stabilizing the crystal structure in the direction of the
layer normal.

Page 5 of 21
CrystEngComm
View Article Online
DOI: 10.1039/C7CE00548B
The crystal structure of 2,3-dichloro-4-iodopyridine (9)46 being a constitutional isomer of both
1 and 8 features a complex pattern of non-covalent interactions (Fig. 4d). Different to the molecular
species with an inherent mirror symmetry, the molecules of 9 are linked to yield a three-dimensional
intermolecular network being formed by C-H∙∙∙Cl hydrogen bridges and halogen-involved contacts of
I∙∙∙N and I∙∙∙Cl type.
The meta-positioned ethynyl groups of the pyridine derivatives 4 and 1248 represent a
specific linking element. In the case of the parent compound 3-ethynylpyridine (12), the ethynyl
hydrogen atom serves to form zigzag-shaped strands of C-H∙∙∙N connected molecules which,
however, do not arrange to layers (Fig. 4g). In contrast, the acceptor activity of the pyridine nitrogen
in the crystal structure of 2,6-dichloro-3-ethynylpyridine (4) (Fig. 2b) obviously gets lost. Instead, one
of the chlorine atoms participate in the linkage of the molecules by means of C-H∙∙∙Cl and Cl∙∙Cl
contacts to generate a three-dimensional intermolecular network.
The pyrimidine derivative 5 differs from the 2-chloropyrimidine (13),41 which is known from
the literature, by the presence of an additional iodine atom. Its ability to form coordination explains
the difference of the two crystal structures. In the crystal of 13, the molecules are linked via C-H∙∙∙N
hydrogen bond type interactions and Cl∙∙∙Cl contacts to give corrugated layers (Fig. 4h). The crystal of
the iodine containing compound 5, however, is composed of plane layers within which the molecules
are linked via I∙∙∙N, I∙∙∙Cl and C-H∙∙∙N interactions (Fig. 3a).
Regarding the solid state structure, the hydroxypyridazine 6 as well as a big number of
related compounds of this type exclusively occur in the lactam tautomer form (cf. Scheme 3).
Selected compounds that make least limited sense to allow a comparison with 6 focus on the two
hydrates 1451 and 15,52 though 6 does not exist as a hydrate. As already pointed out above, in the
crystal structure of 6 (Fig. 3b), the link behavior of the molecule is determined by the donor-acceptor
nature of the O=C-N-H unit giving rise to the formation of inversion symmetry dimers being
connected strand-like with the aid of Cl∙∙∙Cl contacts. In contrast, however, the water molecules in
the structures of the hydrates 14 and 15 exert the decisive influence on the molecular network being
formed. So results a packing and coordination property of the molecules different from 6.
Nevertheless, these compounds demonstrate structural similarity in their crystals. In 14, the
coordination active chlorine atom causes a two-dimensional networking of the molecules where the
ribbon-type aggregates being induced by the water molecules are connected via weak C-H∙∙∙Cl
hydrogen bridge interactions to form molecular layers (Fig. 4i). The same linking pattern is found in
the crystal structure of the corresponding methyl-substituted analogous compound 15 involving the
heterocycle and the water molecule to give rise to a ribbon-type aggregate structure (Fig. 4j).
Conclusions
Based on the findings with the crystal structures of the azines 1, 4-6 that have been synthesized
targeted and studied in order to obtain information on the intermolecular contact property and
complemented by the structural results of the comparative compounds 7-15, known from the
literature, correlations become visible making possible the following conclusions.
In all the present azines comprising an iodine atom substituted to the heterocyclic ring, a N∙∙∙I
contact is always found in the crystal structure as a guiding principle showing this kind of interaction
an unrivaled intermolecular linking pattern. In particular, this is expressed in the cases of 1, 7-9 and
10 where the 4-iodine substitution of the pyridine basic body creates a linear aggregation in the
molecular packing as the prime substructure. Depending on the type and arrangement of additional
substituents including chlorine, bromine or further iodine atoms, strands, layer-like or three-

CrystEngComm
Page 6 of 21
View Article Online
DOI: 10.1039/C7CE00548B
dimensional network structures are formed making use of second-rate inter-halogen or hydrogen
bond type contacts such as shown for corresponding compounds in the Figures of 2a and 4.
Considering the ethynyl-substituted pyridines 4 and 12, an unexpected finding is that the
C≡C-H∙∙∙N hydrogen bond typical of 12 is suppressed in favor of a C≡C-H∙∙∙Cl interaction in the
structure of 4 illustrating a remarkable competitive behavior between the two interaction modes.
With reference to the pyrimidines 5 and 13, the observed packing modes basically meet the
expectations. Similar facts apply for the packing structure of the pyridazine 6 which is strongly
determined by the predominance of the lactamic dimer formation. As regards the hydrated
pyridazines 14 and 15 in comparison with 6, the included water molecules understandably give rise
to a transformed hydrogen-bonded ring pattern and network structure differing from the simple
dimer formation.
In summary, in view of the general significance of the heterocycles represented here, the
present findings and conclusions are likely to run help position for specific tasks of crystal
engineering involving related compounds, e.g. as a structural unit of an active pharmaceutical
ingredient, an electro-optic crystal,53 or self-assembly coating material.54
Experimental
General remarks
The melting points were measured using a microscope heating stage (Thermovar, Reichert-Jung). The
IR spectrum was determined on a Nicolet FT-IR 510 spectrometer as KBr pellet (wavenumbers given
1
in cm-1). H and 13C NMR spectra were obtained using a Bruker Avance 500 at 500.1 (1H) and 125.8
MHz (13C) with TMS as internal standard. Chemical shifts for proton and carbon resonances are given
in ppm (δ). Mass spectra were recorded on a Hewlett-Packard 5890 Series II/MS 5989A. Elemental
analyses were carried out with a Hanau vario MICRO cube. For column chromatography, silica gel
(63-100 µm, Merck) and for TLC analysis, aluminum sheets precoated with silica gel 60 F254 (Merck)
were used. Solvents were purified by standard procedures.
Starting compounds 2-hydroxy-5-iodopyrimidine55,56 and pyridazin-3,6-diol57,58 were
prepared as described in the literature. 2,6-Dichloropyridine was purchased from Aldrich.
Synthesis
2,6-Dichloro-4-iodopyridine (1) and 2,6-dichloro-3-iodopyridine (2). To a solution of 2,6-
dichloropyridine (7.50 g, 50 mmol) in 85 ml of dry THF, cooled to -75oC under argon, n-BuLi (32 ml, 51
mmol, 1.6
M in n-hexane) was added slowly via syringe. After stirring the solution for 45 min at -75
oC, iodine (13.0 g, 50 mmol) dissolved in 24 ml dry THF was added dropwise. The resulting mixture
was stirred for 15 min at -75oC. After warming up to room temperature, the product solution was
washed with aqueous solution of sodium thiosulfate (10 proc., 43 ml) followed by water. The organic
phase was separated, dried (Na2SO4) and the solvent evaporated to yield 1 and 2 as a mixture of
compounds. Fractional crystallization from dry ethanol gave 4.1 g (30%) colorless crystalline plates of
1 and 6.1 g (45%) of 2 as a white amorphous powder.

Page 7 of 21
CrystEngComm
View Article Online
DOI: 10.1039/C7CE00548B
1: Mp 162oC and spectroscopic analytical data correspond to the data given in the
literature.31,59
2: Mp 75oC (lit.60 Mp 76-77oC). NMR data: δH (CDCl3) 8.07 (1H, d, PyH-4, JHH = 8.1 Hz), 7.02
(1H, d, PyH-3, JHH = 8.1 Hz). δC (CDCl3) 153.8 (PyC-2), 150.5 (PyC-6), 131.5 (PyC-4), 124.0 (PyC-5), 92.4
(PyC-3). MS data (GC-MS): calc. for C5H2Cl2IN (272.86), found: 272 m/z [M-H]+.
2,6-Dichloro-3-[(trimethylsilyl)ethynyl]pyridine (3). 2,6-Dichloro-3-iodopyridine (2) (6.1 g,
22.1 mmol) and trimethylsilylacetylene (TMSA) (2.3 g, 23.0 mmol) were dissolved in a degassed
mixture of dry diisopropylamine and THF (125 ml each). To this solution, the catalyst being composed
of triphenylphosphine (2 mol-%), copper(I) iodide (3 mol-%) and trans-dichlorobis-
(triphenylphosphine)palladium(II) (2 mol-%), was added. The mixture was stirred at room
temperature away from light for 10 h, then filtered over Celite and evaporated. Purification by
column chromatography yielded 2.0 g (38%) of a white light-sensitive solid. Mp 37oC. NMR data: δH
(CDCl3) 7.73 (1H, d, PyH-5, JHH = 8.1 Hz), 7.23 (1H, d, PyH-4, JHH = 8.1 Hz), 0.28 (9H, s, Me). δC (CDCl3)
151.8 (PyC-6), 149.1 (PyC-2), 143.3 (PyC-4), 122.4 (PyC-5), 119.1 (PyC-3), 104.6 (C≡C-Py), 98.1 (C≡C-
Si), 0.4 (CH3). IR data: νmax 2167 w (C≡C). MS data (GC-MS): calc. for C10H11Cl2NSi (243.00), found: 243
[M]+. Anal. calc. for C10H11Cl2NSi: C, 49.38; H, 4.53; N, 5.76, found: C, 49.51; H, 4.56; N, 5.77%.
2,6-Dichloro-3-ethynylpyridine (4). To the TMS-protected acetylene 3 (1.22 g, 5.0 mmol)
dissolved in 50 ml acetonitrile, 15 ml of 5
M
aqueous KOH solution was added at 0oC. The mixture
was stirred for 15 min at this temperature and then extracted with diethyl ether. On evaporation of
the solvent a residue was obtained which caused preparative difficulties of product separation for
ordinary chemical compound analysis. Fortunately, however, very few single crystals that have
formed could be isolated and analyzed by X-ray diffraction study correctly showing the structure of 4.
2-Chloro-5-iodopyrimidine (5). To a stirred suspension of 2-hydroxy-5-iodopyrimidine (5.0 g,
23 mmol) in dry acetonitrile (30 ml), phosphoroxychloride (4.6 g, 30 mmol) was added in one batch
followed dropwise by an equimolar amount of diisopropylamine. The mixture was heated under
reflux for 20 h. After cooling down to 40oC, the solution was quenched via pouring into double the
volume of water. Both the precipitate which formed and also the filtrate were extracted with ethyl
acetate. To the combined organic phases, a fifth volume equivalent water was added and the two-
phase mixture evaporated until the boiling temperature was 85oC. On cooling down, the product
precipitated and was isolated to yield 4.85 g (90%) of a white solid. Mp 133oC and spectroscopic
analytical data correspond to the data given in the literature.31,55
6-Chloropyridazin-3(2H)-one (6). A suspension of 3,6-pyridazindiol (17.1 g, 150 mmol) in
phosphoroxychloride (71 ml) was stirred at 90oC for 4 h. Then, the excess phosphoroxychloride was
distilled off under reduced pressure and the remaining residue neutralized by the addition of diluted
aqueous sodium hydroxide. From the solution which has formed, the product was extracted with
ethyl acetate to give a mixture of 6 together with 3,6-dichloropyridazine. Separation into the two
compounds was effected via column chromatography on SiO2 and elution with n-hexane/ethyl
acetate (2:1, v/v) to yield 1.50 g (8%) 6 (Mp 125oC, lit.61 Mp 138-140oC) and 13.6 g (60%) of 3,6-
dichloropyridazine (Mp 68oC, lit.58 Mp 68-69oC). NMR data (DMSO-d6) of 6: δH 13.18 (1H, s, NH), 7.50
(1H, d, PyH-5, JHH = 9.9 Hz), 6.67 (1H, d, PyH-4, JHH = 9.9 Hz), δC (DMSO-d6) 159.7 (PyC-3), 137.4 (PyC-
6), 134.8 (PyC-5), 132.6 (PyC-4).

CrystEngComm
Page 8 of 21
View Article Online
DOI: 10.1039/C7CE00548B
Å
X-ray structure determination
Single crystals of 1, 4, 5 and 6 suitable for X-ray diffraction study were obtained by slow evaporation
of the solvent from a solution of the respective compound. The intensity data of the compounds
were collected on a Kappa APEX II diffractometer (Bruker AXS) with graphite monochromated MoKα
radiation (λ
= 0.71073 Å) at 100(2) or 153(2) K. Cell parameters were refined with SAINT62 using all
observed reflections. Data reduction was performed with SAINT and corrected for background,
Lorentz, and polarization effects. Preliminary structural models were derived by application of direct
methods63 and were refined by full-matrix least-squares calculation based on F2 for all reflections.64
All hydrogen atoms were included in the models in calculated positions and were refined as
constrained to bonding atoms. The crystal data and experimental parameters are summarized in
Table 1. Crystallographic data for the structures in this paper have been deposited with the
Cambridge Crystallographic Date Centre as supplementary publication numbers CCDC 1538316 (1),
1538317 (4), 1538318 (5), 1538319 (6).
Acknowledgements
Financial support from the European Union (European Regional Development Fund) and from
Ministry of Science and Art of Saxony (Cluster of Excellence “Structure Design of Novel High-
Performance Materials via Atomic Design and Defect Engineering [ADDE]”) is gratefully
acknowledged by JH and EW.
References
1
2
3
4
Crystal Engineering, ed. G. R. Desiraju, J. J. Vittal and A. Ramanan, Imperial College Press,
London, 2012.
Organic Crystal Engineering, ed. J. J. Vittal, M. J. Zaworotko and E. R. T. Tiekink, Wiley,
New York, 2010.
Making Crystals by Design: Methods, Techniques and Applications, ed. D. Braga and F.
Creponi, Wiley-VCH, Weinheim, 2007.
Design of Organic Solids, Topics in Current Chemistry, ed. E. Weber, Springer-Verlag,
Berlin, Heidelberg, 1998, vol. 198.
5
6
G. Resnati, E. Boldyreva, P. Bombicz and M. Kawano, IUCrJ, 2015, 2, 675-690.
P. Rodriguez-Cuamatzi, O. I. Arillo-Flores, M. I. Bernal-Uruchurtu and A. Höpfl, Supramol.
Chem. 2007, 19, 559-578.
7
D. N. Chin, J. A. Zerkovski, J. C. MacDonald and G. M. Whitesides, in Organic Molecular
Assemblies in the Solid State, ed. J. K. Whitesell, Wiley, Chichester, 1999, pp. 185-253.
G. R. Desiraju, Angew. Chem. Int. Ed. Engl. 1995, 34, 2311-2327.
G. R. Desiraju and T. Steiner, The Weak Hydrogen Bond. In Structural Chemistry and
Biology, Oxford University Press, New York, 1999.
8
9
10 P. K. Thallapally and A. Nangia, CrystEngComm, 2001, 3, 114-119.
11 M. Nishio, Y Umezawa, K. Honda, S. Tsuboyama and H. Suezawa, CrystEngComm, 2009,
11, 1757-1788.

Page 9 of 21
CrystEngComm
View Article Online
DOI: 10.1039/C7CE00548B
12 M. Nishio, Y. Umezawa, H. Suezawa and S. Tsuboyama, in The Importance of Pi-
Interactions in Crystal Engineering, Frontiers in Crystal Engineering, ed. E. R. T. Tiekink
and J. Zukerman-Schpector, Wiley, Chichester, 2012, pp. 1-39.
13 A. Mukherjee, S Tothadi and G. R. Desiraju, Acc. Chem. Res. 2014, 47, 2514-2524.
14 P. Metrangolo, G. Resnati, T Pilati and S. Biella, in Halogen Bonding, Structure and
Bonding, ed. P. Metrangolo and G. Resnati, Springer-Verlag, Berlin, Heidelberg, 2008, vol.
126, pp. 101-136.
15 F. Katzsch and E. Weber, CrystEngComm, 2015, 17, 2737-2753.
16 R. Gleiter, D. B. Werz and B. J. Rausch, Chem. - Eur. J. 2003, 9, 2676-2683.
17 M. Daszkiewicz, CrystEngComm, 2013, 15, 10427-10430.
18 A. Sikorski and D. Trzybinski, J. Mol. Struct. 2013, 1049, 90-98.
19 B. Li, S.-Q. Zang, L.-Y. Wang and T. C. W. Mak, Coord. Chem. Rev. 2016, 308, 1-21.
20 J. S. Ovens and D. B. Leznoff, Chem. Mater. 2015, 27, 1465-1478.
21 M. K. Panda, S. Ghosh, N. Yasuda, T. Moriwaki, G. D. Mukherjee, C. M. Reddy and P.
Naumov, Nat. Chem. 2015, 7, 65-72.
22 F. Katzsch, D. Eißmann and E. Weber, Struct. Chem. 2012, 23, 245-255.
23 M. Stein, R. Berger, W. Seichter, J. Hulliger and E. Weber, J. Fluorine Chem. 2012, 135,
231-239.
24 A. Nangia, in Organic Crystal Engineering, ed. E. R. T. Tiekink, J. J. Vittal and M. J.
Zaworotko, Wiley, Chichester, 2010, pp. 151-189.
25 G. R. Desiraju, Angew. Chem. Int. Ed. 2007, 46, 8342-8356.
26 K. Biradha and L. Rajput, in Organic Crystal Engineering, ed. E. R. T. Tiekink, J. J. Vittal and
M. J. Zaworotko, Wiley, Chichester, 2010, pp. 215-238.
27 Ö. Almarsson and M. J. Zaworotko, Chem. Commun. 2004, 1889-1896.
28 M. Khan, V. Enkelmann and G. Brunklaus, Cryst. Growth Des. 2009, 9, 2354-2362.
29 S. Long and T. Lin, Cryst. Growth Des. 2009, 9, 4993-4997.
30 S. Gomathi and P. T. Muthiah, Acta Cryst. 2013, E69, o1235.
31 J. Hübscher, W. Seichter, T. Gruber, J. Kortus and E. Weber, J. Heterocyclic Chem. 2015,
52, 1062-1074.
32 K. Sonogashira, Y Tohda and N. Hagihara, Tetrahedron Lett. 1975, 16, 4467-4470.
33 P. Metrangolo, F. Meyer, T. Pilati, D. M. Proserpio and G. Resnati, Chem. Eur.-J. 2007, 13,
5765-5772.
34 P. Politzer, J. S. Murray and T. Clark, Phys. Chem. Chem. Phys. 2013, 15, 11178-11189.
35 V. R. Pedireddi, D. S. Reddy, B. S. Goud, D. C. Graig, A. D. Rae and G. R. Desiraju, J. Chem.
Soc., Perkin Trans. 2 1994, 2353-2360.
36 F. F. Awwadi, R. D. Willett, K. A. Peterson and B. Twawley, Chem. Eur.-J. 2006, 12, 8952-
8960.
37 L. M. Salonen, M. Ellermann and F. Diederich, Angew. Chem. Int. Ed. 2011, 50, 4808-
4842.
38 C. R. Martinez and B. L. Iverson, Chem. Sci. 2012, 3, 2191-
39 M. D. Prasanna and T. N. G. Row, Cryst. Eng. 2000, 3, 135-154.
40 D. Schollmeyer, O. V. Shishkin, T. Rühl and M. O. Vysotsky, CrystEngComm 2008, 10, 715-
723.
41 S. Furberg, J. Grøgaard and B. Smedsrud, Acta Chem. Scand. 1979, B33, 715-724.
42 M. C. Etter, J. C. MacDonald and J. Bernstein, Acta Cryst. 1990, B46, 256-262.
43 J. Bernstein, R. E. Davies, L. Shimoni and N.-L. Chang, Angew. Chem. Int. Ed. 1995, 34,
1555-1573.
44 L. Antonov, Tautomerism – Methods and Theories, Wiley-VCH, Weinheim, 2013.
45 B. Ahrens and P. G. Jones, Acta Cryst. 1999, C55, 1308-1310.

CrystEngComm
Page 10 of 21
View Article Online
DOI: 10.1039/C7CE00548B
46 K. Snégaroff, T. T. Nguyen, N. Marquise, Y. S. Halauko, P. J. Harford, T Roisnel, V. E.
Matulis, O. A. Ivashkevich, F. Chevallier, A. E. H. Wheatly, P. C. Gros and F. Mongin, Chem.
Eur.-J. 2011, 17, 13284-13297.
47 R. Suzuki, H. Yanuma, T. Hayashi, H. Yamada and T. Usuki, Tetrahedron 2015, 71, 1851-
1862.
48 T. Usuki, H. Yamada, T. Hayashi, H. Yanuma, Y. Koseki, N. Suzuki, Y. Masuyama and Y. Y.
Lin, Chem. Commun. 2012, 48, 3233-3235.
49 G. R. Desiraju and R. Harlow, J. Am. Chem. Soc. 1989, 111, 6757-6764.
50 D. A. Dickie, D. Abeysekera, I. D. McKenzie, H. A. Jenkins and J. A. C. Clyburn, Cryst. Eng.
2003, 6, 79-86.
51 A. Katrusiak and A. Katrusiak, J. Mol. Struct. 2003, 647, 203-210.
52 A. S. Blake and H. MacNab, Acta Cryst. 1996, C52, 2622-2627.
53 J. Hulliger, H. Bebie, S. Kluge and H. Quintel, Chem. Mater. 2002, 14, 1523-1529.
54 R. Bertini, P. Metrangolo, A. Moiana, E. Perez, T. Pilati, G. Resnati, I. Rico-Lattes and A.
Sassi, Adv. Mater. 2002, 14, 1197-1201.
55 B. W. Arantz and D. J. Brown, J. Chem. Soc. C, 1971, 1889-1891.
56 C. Péez-Balado, D. Ormerod, W. Aelterman and N. Mertens, Org. Process Res. Dev. 2007,
11, 237-240.
57 H. Feuer, E. H. White and J. E. Wyman, J. Am. Chem. Soc. 1958, 80, 3790-3792.
58 R. Sun, Y Zhang, F. Bi and Q. Wang, J. Agric. Food Chem. 2009, 57, 6356-6361.
59 M. Schlosser, C. Bobbio and T. Ransis, J. Org. Chem. 2005, 70, 2494-2502.
60 E. Marzi, A. Bigi and M. Schlosser, Eur. J. Org. Chem. 2001, 2001, 1371-1376.
61 R. Schönbeck and D. J. Kloimstein, Monatshefte Chemie 1968, 99, 15-81.
62 Bruker (2010), SAINT-NT and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.
63 G. M. Sheldrick, SHELXS-97: Program for Crystal Structure Solution; University of
Göttingen, Germany, 1997.
64 G. M. Sheldrick, SHELXL-97: Program for Crystal Structure Refinement; University of
Göttingen, Germany, 1997.
Captions to Figures and Schemes
Scheme 1. Formula structures of compounds studied in this paper.
Scheme 2. Chemical formula structures including CSD refcodes of azines represented in literature.
Scheme 3. Lactam-lactim tautomerism of the α-hydroxypyridazine 6.
Figure 1. Perspective views of the molecular structures of 1, 4, 5 and 6. Displacement ellipsoids are
drawn at the 50% probability level.

Page 11 of 21
CrystEngComm
View Article Online
DOI: 10.1039/C7CE00548B
Figure 2. Packing diagrams of 1 (a) and 4 (b). Nitrogen atoms are displayed as blue, chlorine as green
and iodine atoms as violet circles. Broken lines represent hydrogen bonds, Hal∙∙∙Hal and Hal∙∙∙N
interactions.
Figure 3. Packing illustrations of 5 (a) and 6 (b). Nitrogen atoms are displayed as blue, oxygen as red,
chlorine as green and iodine atoms as violet circles. Broken lines represent hydrogen bonds, Hal∙∙∙Hal
and Hal∙∙∙N interactions. In (a) particular ring systems of intermolecular contacts are specified by
color highlighting.
Figure 4. Schematic representations of structure motifs showing the packing and coordination
behavior of the reference compounds 7-15.
Table of Contents Entry
Discussed intermolecular interaction modes of differently halogen and protonic group substituted
azines represent a gain in experience to crystal engineering.

CrystEngComm
Page 12 of 21
View Article Online
DOI: 10.1039/C7CE00548B
Formula structures of compounds studied in this paper.
43x30mm (300 x 300 DPI)

Page 13 of 21
CrystEngComm
View Article Online
DOI: 10.1039/C7CE00548B
Chemical formula structures including CSD refcodes of azines represented in literature.
78x91mm (300 x 300 DPI)

CrystEngComm
Page 14 of 21
View Article Online
DOI: 10.1039/C7CE00548B
Lactamꢀlactim tautomerism of the αꢀhydroxypyridazine 6.
39x32mm (300 x 300 DPI)

Page 15 of 21
CrystEngComm
View Article Online
DOI: 10.1039/C7CE00548B
Perspective views of the molecular structures of 1, 4, 5 and 6. Displacement ellipsoids are drawn at the 50%
probability level.
72x83mm (300 x 300 DPI)

CrystEngComm
Page 16 of 21
View Article Online
DOI: 10.1039/C7CE00548B
Packing diagrams of 1 (a) and 4 (b). Nitrogen atoms are displayed as blue, chlorine as green and iodine
atoms as violet circles. Broken lines represent hydrogen bonds, Hal···Hal and Hal···N interactions.
109x160mm (300 x 300 DPI)

Page 17 of 21
CrystEngComm
View Article Online
DOI: 10.1039/C7CE00548B
Packing illustrations of 5 (a) and 6 (b). Nitrogen atoms are displayed as blue, oxygen as red, chlorine as
green and iodine atoms as violet circles. Broken lines represent hydrogen bonds, Hal···Hal and Hal···N
interactions. In (a) particular ring systems of intermolecular contacts are specified by color highlighting.
116x181mm (300 x 300 DPI)

CrystEngComm
Page 18 of 21
View Article Online
DOI: 10.1039/C7CE00548B
128x126mm (300 x 300 DPI)

Page 19 of 21
CrystEngComm
View Article Online
DOI: 10.1039/C7CE00548B
Schematic representations of structure motifs showing the packing and coordination behavior of the
reference compounds 7-15.
51x22mm (300 x 300 DPI)

CrystEngComm
Page 20 of 21
Table 1. Crystallographic and structure refinement data of the compounds studied
Compound
1
4
5
6
Empirical formula
C5H24N1Cl2I1
C7H3N1Cl2
C4H2N2Cl1I1
C4H3N2O1Cl1
Formula weight
Crystal system
Space group
a (Å)
b (Å)
c (Å)
273.88
Orthorhombic
Pnma
13.4092(4)
6.7578(2)
7.9577(2)
90.0
90.0
90.0
721.10(4)
4
172.00
Monoclinic
P21/n
3.8613(1)
11.4201(2)
16.0731(3)
90.0
95.936(1)
90.0
704.97(3)
4
240.43
Orthorhombic
Pnma
14.8774(3)
6.7419(2)
6.1893(1)
90.0
90.0
90.0
620.80(2)
4
130.53
Monoclinic
P21/n
4.1254(1)
10.6052(3)
11.9696(3)
90.0
96.020(2)
90.0
520.79(2)
4
α
β
γ
(°)
(°)
(°)
V (Å3)
Z
F(000)
504
2.523
5.084
344
1.621
0.827
440
2.572
5.473
264
1.665
0.613
Dc (Mg m-3)
ꢀ
(mm-1)
Data collection
Temperature (K)
100(2)
153(2)
153(2)
153(2)
No. of collected reflections
13425
16341
10081
10674
3.0 – 35.4
2.5 – 32.4
2.7 – 34.1
-23/18, -10/10, -8/9
1366
2.6 – 30.1
-5/5, -14/14, -16/16
1530
within the θ-limit (°)
Index ranges ±h, ±k, ±l
No. of unique reflections
Rint
-20/21, -10/10, -11/12 -5/5, -17/17, -24/24
1734
0.0211
2526
0.0192
0.0209
0.0200
Refinement calculations: full-matrix
least- squares on all F2 values
Weighting expression w a
[σ2(Fo2)+(0.0155P)2 +
[σ2(Fo2)+(0.0293P)2 +
[σ2(Fo2)+(0.0199P)2 +
[σ2(Fo2)+(0.0426P)2 +
0.3969P)-1
55
0.2111P)-1
91
0.5996P)-1
49
0.1473P)-1
77
No. of refined parameters
1630
2264
1201
1359
No. of F values used [I>2
Final R-Indices
σ(I)]
0.0149
0.0359
1.095
0.0238
0.0650
1.075
0.0188
0.0488
1.152
0.0268
0.0772
1.032
R(=Σ|ꢁF| / Σ|Fo |)
wR on F2
S (=Goodness of fit on F2)
Final ꢁρmax/ꢁρmin (e Å-3)
0.76/-0.58
0.40/-0.21
0.83/-1.70
0.36/-0.35
a
P =(Fo2 + 2Fc2)/3

Page 21 of 21
CrystEngComm
View Article Online
DOI: 10.1039/C7CE00548B
Table 2. Geometric parameters for nonꢀcovalent interactions in the crystal structures of the compounds
studied.
Atoms involved
Symmetry
Distance
Angle
DꢀH···A
CꢀCl···Cl
D···A
C···Cl
C···A
H···A
Cl···Cl
I···A
DꢀH···A
CꢀCl···Cl
CꢀI···A
CꢀI···A (A = N, Cl)
Cg···Cga
Cg···Cg
1
C(2)ꢀH(2)···Cl(2)
C(1)ꢀCl(1)···Cl(2)
C(5)ꢀCl(2)···Cl(1)
C(3)ꢀI(1)···N(1)
C(5)ꢀCl(2)···Cg
0.5+x, y, 1.5ꢀz
0.5+x, y, 0.5ꢀz
ꢀ0.5+x, y, 0.5ꢀz
x, y, 1+z
3.883(2)
4.966(2)
4.958(2)
5.167(2)
3.463(2)
2.99
3.404(2)
3.404(2)
3.086(2)
161.7
149 (1)
148 (1)
180(1)
ꢀx, 1ꢀy, 1ꢀz
4
C(7)ꢀH(7)···Cl(2)
C(5)ꢀCl(2)···Cl(2)
Cg···Cg
1.5+x, 0.5ꢀy, 0.5+z
ꢀ1ꢀx, 1ꢀy, 1ꢀz
1+x, y, z
3.766(2)
5.144(2)
3.861(2)
2.88
3.543(2)
156.4
152.4(2)
5
C(2)ꢀH(2)···N(2)
C(1)ꢀI(1)···N(1)
C(1)ꢀI(1)···Cl(1)
Cg···Cg
x, y, ꢀ1+z
3.487(3)
5.491(3)
4.283(3)
3.817(3)
2.58
3.473(3)
3.638(3)
165.1
162(1)
93(1)
0.5+x, y, 1.5ꢀz
0.5+x, y, 2.5ꢀz
ꢀx, ꢀy, 2ꢀz
6
N(2)ꢀH(2A)···O(1)
C(1)ꢀCl(1)···Cl(1)
Cg···Cg
2ꢀx, 1ꢀy, 1ꢀz
ꢀx, 1ꢀy, ꢀz
1+x, y, z
2.766(1)
5.054(1)
4.125(1)
1.87
3.504(2)
177.0
148(1)
a
Cg means centre of the aromatic ring. 1, 4: Ring: N1,C1...C5; 5, 6: Ring: N1,N2,C1…C4.