A.D. Mašulovi ´c , J.M. Lad¯arevi ´c , L.D. Radovanovi ´c et al.
Journal of Molecular Structure 1237 (2021) 130419
formation in Alzheimer’s disease [21], as well as key intermediates
in the synthesis of pyridine, quinolone, quinolizidine and indolizine
alkaloids [13]. The biological activity of these compounds can be
closely related to the existence of the amide bond, similar to
those connecting amino acids in protein molecules [22]. Also, 4,6-
disubstituted-3-cyano-2-pyridones presenting both pyridines and
nitriles found an application in obtaining pigments, commercial
dyes and additives for fuels and oils [23]. Bearing in mind the 2-
pyridone molecule architecture, it has been shown that the amino
unit, traditionally being a hydrogen-bond acceptor, is in fact a
hydrogen-bond donor, because of the conjugation of the lone pair
on the amino N atom to the aromatic ring. On the other hand,
the 2-pyridone exhibits one more tautomeric form, the hydrox-
ypyridine molecule, which can be either a bond donor on the ba-
sis of the O atom, or an acceptor on the basis of O and N atoms
2. Experimental section
2.1. General
All commercially available reagents, used without further pu-
rification, were purchased from either Fluka (Germany), Lach-ner
(Czech Republic) or Sigma-Aldrich (Germany). Thin layer chro-
matography (TLC) was performed on silica UV254, Machereg-Nagel
0.2 mm precoated plates, a trichlormethane methanol mixture
99:1 was used. Products were visualized under UV light at 254
and 365 nm. Melting points were determined in capillary tubes
on an automated melting point system Stuart SMP30. FT-IR spectra
were recorded on a Nicolet iS10 (ATR) spectrophotometer. 1H and
13C NMR spectra were recorded on a Bruker Ascend 400 apparatus
(400 and 100 MHz, respectively) in deuterated dimethyl sulfoxide
[
23,24]. Pyridones and pyridone derivatives are suggested as stable
(DMSO-d ), using tetramethylsilane (TMS) as an internal standard.
6
hydrogen bond dimers with versatile molecules in supramolecu-
lar chemistry whose aggregation patterns through hydrogen bonds
are structured as cyclic dimers, one-dimensional chains or three-
dimensional assemblies [11,25,26]. The 2-pyridone dimer is found
to be governed by an antiparallel N–H · · · O hydrogen bond form-
All spectroscopic measurements were carried out at room temper-
ature (25 °C). MS was performed on Quadrupole ion trap mass
spectrometer, LCQ Advantage (Thermo Fisher Scientific, USA) with
Surveyor HPLC system (Thermo Fisher Scientific, USA).
2
2
ing a R (8) ring as a motif [27]. Despite the existence of a strong
2.2. Synthesis and crystal growth
N–H · · · O hydrogen bond, the supramolecular architecture of sub-
stituted pyridone moieties is affected by secondary interactions,
such as weaker hydrogen bonds as well as π–stacking interactions.
The variety of structural motifs arises from altering substituents in
the moieties [24,26]. To the best of our knowledge, little is known
about substituted pyridone hydrates and their crystal structures
have not been reported as zwitterionic hydrates so far.
All investigated compounds were synthesized according to a
modified two step procedure [35]. Step one implies the reac-
tion of commercially obtained 2-chloracetamide, diluted in N,N-
dimethylformamide (DMF), and corresponding pyridine, wherein
amides were acquired (Scheme 1). The second step is comprised
of amides reacting with ethyl acetoacetate in methanol, under re-
flux, wherein pyridones 1 and 2 were obtained and recrystallized
from ethanol.
Based on the above scientific background and considering wide
applicability, a pyridine scaffold is introduced in the pyridone
moieties. Pyridine, as a highly deficient aromatic moiety, is an
interesting building block due to its ability to establish a vari-
ety of non-covalent interactions. Moreover, the pyridine salts are
found to have remarkable biological activity [9,28] and salts in
general are found to exhibit a tendency towards including water
molecules into their crystal structure, resulting in co-crystals [1].
Co-crystals are widely applicable as magnetic materials [29], lu-
minescent polymorphs [30,31] and solids of special optical prop-
erties [32], whereas water co-crystals have a tendency of dif-
ferent supramolecular formation prominence in pharmaceuticals
Hydrates suitable for X-ray diffraction analysis were obtained
from ethanol by slow evaporation during two weeks at room tem-
perature. The molecular structures and purities of 1 · 2H O and
2
1
13
2 · 4H O were confirmed using melting points, FT-IR, H and
C
2
NMR spectroscopy and MS. Atoms in the compounds 1 · 2H O and
2
2 · 4H O are labeled as depicted in Fig. 1 for the purpose of easier
2
manipulation with obtained results.
2.2.1. Synthesis of
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
4 -methyl-2 -oxo-1 ,2 -dihydro-[1,3 -bipyridin]-1-ium-6 -olate
[
1,2]. It should be appointed that pharmaceuticals are often found
dihydrate– 1 · 2H O
2
in the zwitterionic form [2]. Zwitterions are proven to interlock
quite well into crystal packing, forming dimers that stabilize the
molecular architecture. Besides the strong hydrogen bonds be-
tween molecules the repeating structural segment is to be based
on nonspecific interactions [4,6,33,34]. The introduction of water
channels into the molecular network leads to a more stable struc-
ture, wherein zwitterions are found to incorporate water molecules
into the architecture, leading to water channels [1,3,6].
Primarily, the synthesis of corresponding amide was car-
ried out according to literature procedure [35] shown in the
Scheme 1 the pathway (a). 1-(2-Amino-2-oxoethyl)-pyridinium-
chloride (0.42 mol, 25 g) is diluted in 54 mL of DMF. Pyridine
(0.28 mol, 21.15 g) is added to the solution and mixture was
heated to 110 °C for one hour. After cooling, the obtained crude
product is slurred in acetone. Further filtration and recrystalliza-
tion from ethanol gives 15 g of white crystalline 1-(2-amino-2-
oxoethyl)-pyridinium chloride. The obtained amide (0.1 mol, 15 g)
was then diluted in 114.1 mL of methanol and then 11.14 mL
ethyl acetoacetate is added along with sodium hydroxide solution
(35.8 g sodium hydroxide, 90.5 mL water). The reaction mixture
is stirred under reflux for three hours. The synthesis course was
monitored by TLC analysis. The crude product was recrystallized
from ethanol (yield 78%). The compound was further dissolved in
In this context, the synthesis of two pyridone based zwitte-
rion hydrates and the evolution of their crystal structures is pre-
sented. Compounds have been characterized by melting points, At-
tenuated Total Reflectance-Fourier transform infrared spectroscopy
(
FT-IR), 1H and 13C nuclear magnetic resonance (NMR) and mass
spectroscopy (MS) as well as single-crystal X-Ray analysis. Herein,
a comparative study in terms of theoretical calculation of the lat-
tice energy of the crystal, using the PIXEL method, which gives
an insight into a quantitative evaluation of interactions partitioned
into Coulombic, disperse, repulsion and polarization contributions
is presented. Both crystals have been compared in terms of synthe-
sis, lattice energies and energies associated with molecular pairs
extracted from their supramolecular architecture. Their DFT molec-
ular geometries have been thoroughly analysed through the influ-
ence of dipole moments, intramolecular interactions, solvent and
torsion angle influence.
ethanol and slow evaporation was allowed, whereas 1 · 2H O is ac-
2
quired. Golden crystals: m.p. > 300 °C; 1H NMR (400 MHz, DMSO-
d ): δ=9.81 (s, 1H; N–H), 8.87 (d, J = 8 Hz, 2H; pyridinium), 8.52
6
(t, J = 6 Hz, 1H; pyridinium), 8.08 (t, J = 6 Hz, 2H; pyridinium),
13
4.90 (s, 1H; C4), 1.78 ppm (s, 3H; CH );
C NMR (100 MHz,
3
DMSO-d ): δ=164.10 (C5), 159.16 (C1), 148.6 (C6, C10), 145.3 (C3),
6
144.3 (C8), 127.7 (C7, C9), 112.34 (C2), 96.56 (C4), 17.98 ppm (CH );
3
FT-IR (ATR): ν ˜=1582 (vs), 1623 (vs) (C=O), 3353 (m) (N–H),
−1
+
3339 (m) cm
(O–H); MS (ESI): m/z calcd. for C11
H
N O +H :
2
10
2
2