Solvent-free and catalysis-free approach to the solid state in situ growth of crystalline isoniazid hydrazones

Article abstract of DOI:10.1021/cg400529s

The isonicotinoylhydrazones and their coordination compounds have antibacterial, antifungal, antitubercular, antitumor, and anticonvulsant activities. A typical method employed in the preparation of isonicotinoylhydrazones involves the usage of the volati

Full text of DOI:10.1021/cg400529s

Article
pubs.acs.org/crystal
Solvent-Free and Catalysis-Free Approach to the Solid State in Situ
Growth of Crystalline Isoniazid Hydrazones
Agata Trzesowska-Kruszynska*
Department of X-ray Crystallography and Crystal Chemistry, Institute of General and Ecological Chemistry, Lodz University of
Technology, Zeromskiego 116, 90-924 Lodz, Poland
S
* Supporting Information
ABSTRACT: The isonicotinoylhydrazones and their coordi-
nation compounds have antibacterial, antifungal, antitubercu-
lar, antitumor, and anticonvulsant activities. A typical method
employed in the preparation of isonicotinoylhydrazones
involves the usage of the volatile organic solvents during the
condensation reaction between isonicotinic acid hydrazide and
carbonyl compounds. It has been shown that the solvent-free
technique can be applied to obtain crystalline compounds.
Reaction of isoniazid with carbonyl compound under solvent-free conditions results in microcrystalline solid state isonicotinoyl-
hydrazones. The influence of solvent effect on the mechanism of condensation reaction was evaluated and the most significant
intermediates and transition states, in the gas phase and in the presence of water and methanol were resolved. The solvent has
positive effect on the reaction mechanism, but the organic solvent is unnecessary during the synthesis of crystalline
isonicotinoylhydrazones derived from aldehydes. Mixing solid/liquid reactants together without additional solvent reduce the
time of reaction and can be used to obtain microcrystalline compounds, which are synthesized for example to evaluate biological
properties.
solid such as solubility and bioavailability.37,38 The application of
INTRODUCTION
■
solvent-free method reduces the number of unit operations and
Isoniazid-related hydrazones are very important group of imines.
the amount of used solvents even if the purification or
These derivatives are of great interest owing to their biological
crystallization of the obtained product is required.
activities. The isonicotinoylhydrazones and their coordination
In this work, the experimental procedures and quantum-
compounds have potent antibacterial, antifungal, antitubercular,
mechanical calculations have been used to check and explain the
antitumor and anticonvulsant activities.1−10
possibility of obtaining nicotinoylhydrazones in crystalline form
A typical method employed in the preparation of isonicoti-
via extremely simple solventless method, in which usage of
noylhydrazones involves the usage of the volatile organic solvents
microwave radiation, high pressure, etc., is unnecessary.
during the condensation reaction between isonicotinic acid
hydrazide and carbonyl compounds, carried out by refluxing the
EXPERIMENTAL SECTION
■
mixture of substrates for several hours in the presence of an acidic
Synthesis. Equimolar quantities of isonicotinohydrazide (mp
catalyst. The solventless methods (including grinding, the usage
171 °C) (10 mmol) and the appropriate carbonyl compound (10
of poly(propyleneglycol) (PPG) or water as an alternative
mmol of 2-nitrobenzaldehyde, furan-2-carbaldehyde, 4-dimethylamino-
reaction media and microwave irradiation as the nonpolluting
method of activation) were successfully used in the synthesis of
imines,11−27 but the preparation of isonicotinoylhydrazones,
considered as an effective pharmacophore, under solvent-free
conditions was not confirmed. The mechanochemical synthe-
ses28−34 become more widely used as alternative to traditional
solution phase methodology. The mechanochemistry has been
successfully utilized to obtain nanoparticles of inorganic
compounds.35,36 Besides the absence of solvents or catalysts,
which is a distinct advantage, the solventless reactions often lead
to very pure products, allow shortening the synthesis time and
minimizing the energy consumption. These factors are especially
important in pharmaceutical industry. The active pharmaceutical
ingredients are generally crystals of small organic molecules. The
crystal size, shape, and crystal form of such compounds is crucial
because it influence the physical and chemical properties of the
benzaldehyde, 2-hydroxybenzaldehyde, 2-acetylthiophene), existing in
the liquid or solid state under normal conditions, were mixed. The
mixtures were stirred and heated on an electric hot plate, in the absence
of an addition of solvent and catalyst, until the initially watery mixtures
(from water evolving during reaction) solidified to the products. The
reaction times did not exceed 20 min (Table 1). The temperature of the
samples was monitored by thermocouple connected to computer via
Elmetron CX-505 device, and the reaction temperature was in range
56−60 °C (Table 1).
2-Nitrobenzaldehyde Isonicotinoylhydrazone (1): Orange solid;
mp 232 °C; IR (KBr, cm−1) 3650−2960 (νNH, νCH), 1680 (νCO,
δNH), 1600 (νCN, νCCring), 1560 (νNO2, νCCring), 1520 (δNH,
δCH), 1415 (δCH), 1350 (δNO2), 1290 (δCH, νCN), 1270 (δCH),
Received: April 10, 2013
Revised: July 18, 2013
© XXXX American Chemical Society
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Table 1. Experimental Details of Solvent-Free Syntheses
carbonyl compound
product
reaction temperature [°C]
reaction time [min.]
yield [%]
2-nitrobenzaldehyde (mp 45 °C)
1
2
3
4
57
60
60
56
15
15
20
20
99
99
99
99
furan-2-carbaldehyde (mp −37 °C)
4-dimethylaminobenzaldehyde (mp 74.5 °C)
2-hydroxybenzaldehyde (mp −7 °C)
790 (δCH, δNO2), 740 (δNO2); UV−vis (solid state, nm) 215 (π → π*),
270 (π→π*), 350 (π→π*); 1H NMR (DMSO-d6, δ, ppm) 12.40 (s, 1H,
NH), 8.89 (s, 1H, HCN), 8.81 (d, 2H), 8.13 (d, 2H), 7.85 (m, 3H), 7.72
(m, 1H); 12C NMR (DMSO-d6, δ, ppm) 153.2, 151.2, 147.2, 142.9, 136.6,
133.8, 131.3, 130.9, 127.6, 124.4; Anal. Calcd for C13H10N4O3 C, 57.77;
Found C, 57.83.
and subsequently completed by difference Fourier recycling. All the
non-hydrogen atoms were refined anisotropically using full-matrix, least-
squares technique on F2. The hydrogen atoms were found from
difference Fourier syntheses and treated as “riding” on their parent non-
hydrogen atoms, with assigned isotropic displacement parameters equal
to 1.5 (methyl group) or 1.2 (other atoms) times the value of equivalent
displacement parameters of the parent atoms. The geometry of
hydrogen atoms attached to carbon atoms was idealized after each
cycle of least-squares refinement. SHELXS97, SHELXL97, and
SHELXTL40 programs were used for all the calculations. Details
concerning crystal data and refinement are summarized in Table 2.
2-Furfuryl Isonicotinoylhydrazone (2): Beige solid; mp 214 °C; IR
(KBr, cm−1) 3560−3040 (νNH, νCH), 1650 (νCO, δNH), 1620
(νCN), 1535 (νCCring), 1470 (νCCring, δNH), 1410 (δCC, δNH),
1360 (δNH, δCH), 1290 (δCH, νCN), 1160 (νCN), 1030 (νNN),
950 (νCOring), 770 (δCH), 680 (δCH); UV−vis (solid state, nm) 275
1
(π→π*); H NMR (DMSO-d6, δ, ppm) 11.98 (s, 1H, NH), 8.79 (d,
2H), 8.36 (s, 1H, HCN), 7.88 (d, 1H), 7.81 (d, 2H), 6.99 (d, 1H),
6.66 (m, 1H); 12C NMR (DMSO-d6, δ, ppm) 164.3, 153.2, 152.0, 148.4,
143.2, 141.5, 125.9, 124.3, 117.1, 115.1; Anal. Calcd for C11H9N3O2 C,
61.39; Found C, 61.40.
p-(N,N-Dimethylamino)benzaldehyde Isonicotinylhydrazone
Monohydrate (3): Pale green solid; mp 186 °C; IR (KBr, cm−1)
3580−3130 (νNH, νCH, νOH), 1660 (νCO, δNH, δOH), 1610
(νCN), 1590 (νCCring), 1370 (δNH, δCH), 1315 (νCN), 1180
(νCN), 820 (δCH), 680 (δCH); UV−vis (solid state, nm) 275 (π→π*),
330 (π→π*), 400 (n→π*), 600 (n→π*); 1H NMR (DMSO-d6, δ, ppm)
11.76 (s, 1H, NH), 8.75 (d, 2H), 8.33 (s, 1H, HCN), 7.81 (d, 2H),
7.57 (d, 2H), 6.77 (d, 2H), 2.99 (s, 6H); 12C NMR (DMSO-d6, δ, ppm)
163.9, 154.5, 153.1, 152.7, 152.3, 143.7, 131.5, 124.3, 124.0, 114.6; Anal.
Calcd for C15H16N4O · H2O C, 62.92; Found C, 62.96.
Table 2. Crystal Data and Refinement Details for 5
empirical formula
formula weight
crystal system
space group
temperature [K]
unit cell dimensions
a [Å]
C12H11N3OS
245.30
triclinic
P1
̅
291.0(3)
3.9533(2)
b [Å]
10.6197(4)
14.3961(6)
74.675(2)
c [Å]
α [deg]
β [deg]
82.622(3)
Salicylaldehyde Isonicotinylhydrazone (4): Pale yellow solid; mp
243 °C; IR (KBr, cm−1) 3600−2920 (νNH, νCH, νOH), 1680 (νCO,
δNH), 1620 (νCN), 1600 (νCN, νCCring), 1480 (νCCring, δNH),
1410 (δCC, δNH, δOH), 1290 (δCH, νCN), 1270 (δCH, νOH), 1160
(νCN), 1070 (δCH), 1000 (νNN), 850 (δCH, δCCring), 770 (δCH),
690 (δCH); UV−vis (solid state, nm) 270 (π→π*), 335 (π→π*); 1H
NMR (DMSO-d6, δ, ppm) 12.29 (s, 1H, NH), 11.09 (s, 1H, OH), 8.81
(d, 2H), 8.69 (s, 1H, HCN), 7.86 (d, 2H), 7.61 (d, 1H), 7.32 (m, 1H),
6.96 (m, 2H); 12C NMR (DMSO-d6, δ, ppm) 160.3, 153.2, 151.8, 142.8,
134.6, 132.1, 124.3, 122.3, 121.5, 119.3; Anal. Calcd for C13H11N3O2 C,
64.72; Found C, 64.65.
γ [deg]
79.443(2)
volume [Å3]
570.99(4)
Z
2
absorption coefficient [mm−1
F (000)
]
2.410
256
θ range for data collection [deg]
3.19−69.56
−4 ≤ h ≤ 3
−12 ≤ k ≤ 12
−17 ≤ l ≤ 17
1.109
index ranges
goodness-of-fit on F2
In the case of a reaction between isonicotinohydrazide and 2-
acetylthiophene (mp 10 °C), for which the solventless method was
unsuccessful, the traditional method involving the heating of substrates
in the presence of a solvent was used. A 2-acetylthiophene (5 mmol) was
added to a hot solution of an isonicotinohydrazide (5 mmol) in
methanol (40 mL). The reaction mixture was heated under reflux for 2 h.
The solution was then reduced by evaporation to a half-volume and
allowed to cool. After 6 days, plate, yellow crystals of N′-(1-(2-
thienyl)ethylidene)isonicotinohydrazide (5) were formed. Yield: 76%.
2-Acetylthiophene Isonicotinoylhydrazone, C12H11N3OS (5): mp
191−193 °C; IR (KBr, cm−1) 3600−2930 (νNH, νCH), 1670 (νCO,
δNH), 1650 (νCN), 1550 (νCCring), 1410 (δCC, δNH), 1390 (δNH,
δCH), 750 (νCS), 705 (δCH); UV−vis (solid state, nm) 280 (π→π*),
330 (π→π*); 1H NMR (DMSO-d6, δ, ppm) 12.01 (s, 1H, NH), 8.78 (d,
2H), 7.79 (d, 2H), 7.65 (d, 1H), 7.56 (d, 1H), 7.10 (t, 1H), 2.31 (s, 3H);
12C NMR (DMSO-d6, δ, ppm): 161.4, 153.2, 151.8, 142.8, 140.9, 128.7,
final R indices [I > 2σ[I]]
R indices [all data]
R1 = 0.0349, R2 = 0.0962
R1 = 0.0353, R2 = 0.0966
0.214 and −0.278
largest difference peak and hole [e Å3]
Final products obtained by the solvent-free method were determined
by X-ray powder diffraction analysis. The X-ray powder diffraction
patterns were measured in reflection mode on an XPert PRO X-ray
powder diffraction system equipped with Bragg−Brentano PW 3050/65
high resolution goniometer and PW 3011/20 proportional point detector.
The CuKα1 radiation was used. The patterns were measured at 298.0 K in
the range 5−90° with the narrowest beam attenuator (0.017 mm). The 6 s
per 0.01° step procedure was used. The thicknesses of the samples were no
more than 0.01 mm. During the measurements each specimen was spun in
the specimen plane to improve particle statistics.
Theoretical Calculations. The geometric parameters of substrates
and products were employed from crystal structure data.41−50 The gas
phase and solution geometry optimization of reactants and inter-
mediates was performed at the CBS-4 M (complete basis set51,52) level
using the GAUSSIAN0353 program package. CBS-4 M is a multistep
method that involves a series of HF and MPn calculations. Since the
relatively low method (HF/3-21G) is used by CBS-4 M in geometry
optimization, the gas-phase geometry optimization of substrates and
products was performed at the B3LYP/6-31++G(d,p) level of theory.
128.0, 127.3, 124.3.
X-ray Crystallography. The crystal of compound 5 was mounted
on a KM-4-CCD automatic diffractometer equipped with CCD detec-
tor, and used for data collection. X-ray intensity data were collected with
graphite monochromated CuKα radiation (λ = 1.54178 Å), with ω scan
mode. The crystal used for data collection did not change its appearance
during measurement. Lorentz, polarization and numerical absorption39
corrections were applied. The structure was solved by direct methods
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Scheme 1. Studied Reactions of Carbonyl Compounds with Isonicotinohydrazide
The optimized geometrical parameters obtained by both methods differ
by ∼0.03 Å. Local minima and transition states were identified by the
number of imaginary frequencies. The solvent effect was included by
usage of the polarizable continuum model.54,55 The optimized geo-
metrical parameters were similar to those found from X-ray measure-
ment except 2-acetylthiophene isonicotinoylhydrazone (Supporting
Information Figure S1). The gas-phase geometry optimized molecule is
almost planar (the N−C(O)−Cpyridine−Cpyridine angle is 0.02°), whereas
in the crystal structure as well as in the implicit-solvent optimized
molecule the pyridine ring is twisted (the N−C(O)−Cpyridine−Cpyridine
angle is −49.08° (in crystal), −31.00° (in methanol as a continuous
medium) and −31.67° (in water as a continuous medium)). In general,
the optimized imine bond length is shorter than this observed in the
solid state.
can give the ambiguous results). The reaction products were
characterized by X-ray powder diffraction technique (XRD), IR,
and UV−vis spectroscopy, differential scanning calorimetry
(DCS), and elemental analysis.
The results of heating on a hot plate of solid−solid/solid−
liquid state reactants show that nicotinoylhydrazones can be
obtained by the solventless methods. In the absence of an organic
solvent, a liquid reactant acts both as a reactant and as an organic
phase. The following reactants have been used: the isoniazid
(as a source of NH2 group) and various carbonyl compounds:
2-nitrobenzaldehyde, furan-2-carbaldehyde, 4-dimethylamino-
benzaldehyde, 2-hydroxybenzaldehyde, 2-acetylthiophene
(Scheme 1). The carbonyl compounds have been selected to
exhibit different states of matter, and to possess different chemical
properties related to the structure. Generally, the known,
previously synthesized by traditional method and structurally
characterized compounds were obtained to allow the comparisons
of results with literature data.41−44 In all cases, the heating process
was carried out no longer than 20 min, and the heating did not
exceed the 60 °C. Four of five studied compounds have been
successfully obtained. The nicotinoylhydrazones are formed in
near-quantitative yield (small amount of products remains on
reaction vessels). Only one compound, the one derived from
2-acetylthiophene, could not be obtained under the above-
mentioned conditions. An increase of the reaction time to 1 h has
not led to formation of the hydrazone, and the sample did not
become solid. In general, ketones are less reactive in the nucleo-
philic addition reaction and the methyl group of acetylthiophene
sterically hinders the approach of the nucleophile, and this can
explain the observed lack of reactivity in the solid state.
Other measurements. The IR spectra (400−4000 cm−1) of the
samples prepared as KBr disks were recorded with a Jasco FT/IR-6200
spectrophotometer. The UV−vis spectra were recorded with a Jasco
V-660 spectrophotometer, in transmission mode, for the solid-state
samples pressed between two quartz plates. The differential scanning
calorimeter (DSC 200 F3 Maia, Netzsch) was used to measure the
melting points. The elemental analyses were performed using the total
organic carbon analyzer (SSM-5000A, Shimadzu). The SEM measure-
ments were performed using S-4700 scanning electron microscope
(HITACHI S-4700) equipped with energy dispersive spectrometer
(ThermoNoran). 1H NMR and 13C NMR spectra were recorded on a
Bruker Avance II Plus spectrometer at 700 MHz (1H) and 176 (13C) in
DMSO-d6 as solvent using TMS as the internal standard.
RESULTS AND DISCUSSION
■
Since the synthesis of isonicotinoylhydrazones was performed
under solvent-free conditions, the analysis methods can not
involve any dissolution of the obtained products (dissolving of
the unreacted samples may lead to reaction within a solution and
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Figure 1. The X-ray powder diffraction patterns of compounds 1−4 obtained by solventless method compared with the reference X-ray powder
diffraction patterns calculated on the basis of the single crystal structures.41−44
.
The phase homogeneity of obtained solid-state products was
confirmed by X-ray powder diffraction technique by comparison
of obtained reflection positions with the reference X-ray powder
diffraction patterns calculated on the basis of the single crystal
structures41−44 (Figure 1), although the presence of traces of
unreacted substrates cannot be excluded by this method. The
lack of the substrates in the final products was confirmed by the
absence of the band corresponding to N−H stretching vibrations
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of NH2 group in the IR spectra. The lattice constants calculated
for polycrystalline products are in agreement with those
determined for single crystals from X-ray diffraction measure-
ments.
Although it could be expected that water molecules would
be evolved during the solventless synthesis process, the
4-dimethylaminobenzaldehyde isonicotinoylhydrazone was ob-
tained in a monohydrate form similarly to the previously
reported crystal structure of this compound.31 The 2-furaldehyde
isonicotinoylhydrazone, obtained by the traditional method
including the usage of an organic solvent, crystallizes with one
or two independent molecules in the asymmetric unit (the
space group Cc56 and P21/c,42 respectively). The analysis of
the experimental X-ray powder pattern proves that the solvent-
free synthesis leads to formation of only one crystal form, that
one with two independent molecules in the asymmetric unit,
crystallizing in the P21/c space group.42 The morphology of
crystalline samples of 1−4, was evaluated using scanning electron
microscopy (SEM). The solid-state samples are composed of
aggregated irregular microparticles (Figure 2). The average size
Figure 3. Molecular structure of 5 showing the atom numbering
scheme. The displacement ellipsoids are drawn at 50% probability level
and H atoms are shown as spheres of arbitrary radii.
the steric hindrance, resulting from the presence of the methyl
group at the imine carbon atom, the NH group of a hydrazone
moiety is able to form strongly limited number of hydrogen
bonds. Molecules of 5 are assembled by the intermolecular
N2−H2N···O1i hydrogen bonds (symmetry transformation: (i)
−x − 1, −y + 1, −z + 2, N−H distance is 0.85 Å, N···O distance is
2.9633(17) Å and N−H···O angle is 168.1°) and create a dimer
forming N1R2 (8) motif60 (Figure 4). The close inspection of the
2
Figure 2. SEM images of compounds 1−4.
of the crystallites was determined by Scherrer equation after
correction of the deconvoluted reflections fwhm on the
instrumental broadening (with usage of the highly crystalline
standard). For each sample the reported value was based on 10
reflections. The average size of the crystallites is 102(3) nm for 1,
72(5) nm for 2, 177(3) nm for 3, and 133(2) for 4.
For compound 5, the composition of the reaction product
was confirmed by single crystal X-ray diffraction study. The
hydrazone molecule of 5 exists as the keto-amine tautomer with
the configuration E toward azomethine bond (Figure 3).
In contrast to previously reported crystal structures of N′-
thienylidene-isonicotinohydrazide,57−59 the hydrazone molecule
of 5 shows uncommonly large deviation from planarity, with the
dihedral angle between the weighted least-squares planes cal-
culated through all non-H atoms of the pyridine and thiophene
rings equal to 46.65(13)°. These two rings make angles of
47.42(12)° and 2.93(13)°, respectively, with the central ali-
phatic hydrazone moiety (O1−C6−N2−N3−C7). Because of
Figure 4. Dimer of 5. Dashed lines indicate hydrogen bonds.
short contacts existing in the crystal structure shows that only
one additional interaction can be classified as the hydrogen bond
(weak intramolecular C5−H5···N3 interaction, with C−H
distance of 0.93 Å, C···N distance of 2.944(2) Å and C−H···N
angle of 101.6°). The possibility of the π···π interactions between
the rings containing double and delocalized bonds were excluded
on the basis of the shortest distance between ring centroids equal
to 5.759(2) Å.
In most cases, the solvent molecules do not participate in
chemical reaction, they are used as a heat transfer and a transport
medium. The solvent in which the reaction is carried out can
stabilize or destabilize the transition state, changing the electron
distributions of the solutes because of its dielectric properties.
The results of experiments involving heating and mixing of
E
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Table 3. Calculated Gibbs Free Energies (G Obtained by the Extrapolation to the CBS) and Gibbs Free Energy Changes of a
Reaction (ΔrG0) (1 a.u. = 627.5095 kcal mol−1)
G [a.u.]
compound
medium
isonicotinohydrazide
aldehyde/ketone
hydrazone
water
ΔG0 [kcal mol−1
]
1
gas-phase
methanol
water
−471.663607
−471.689526
−471.690825
−471.663607
−471.689526
−471.690825
−471.663607
−471.689526
−471.690825
−471.663607
−471.689526
−471.690825
−471.663607
−471.689526
−471.690825
−549.365061
−549.380495
−549.381401
−342.905288
−342.91687
−342.917279
−478.822154
−478.835175
−478.835748
−420.222308
−420.243417
−420.244403
−704.777915
−704.787952
−704.78839
−944.669624
−944.702794
−944.706409
−738.205581
−738.240192
−738.242351
−874.12277
−874.154801
−874.15692
−815.534262
−815.56706
−76.368248
−76.382222
−76.382688
−76.368248
−76.382222
−76.382688
−76.368248
−76.382222
−76.382688
−76.368248
−76.382222
−76.382688
−76.368248
−76.382222
−76.382688
−5.78
−9.41
−10.59
−3.10
−10.05
−10.63
−3.30
−7.73
−8.18
−10.41
−10.25
−10.32
−3.19
−5.12
−5.34
2
3
4
5
gas-phase
methanol
water
gas-phase
methanol
water
gas-phase
methanol
water
−815.568991
−1100.078351
−1100.103423
−1100.105043
gas-phase
methanol
water
reactants showed that an organic solvent and a catalyst are not
required for the formation of various imines. In the synthesis
reaction of these compounds under solvent-free conditions, the
microwave radiation, ultrasounds or grinding can be used as a
source of energy required to overcome activation barriers. In the
case of microwave-assisted organic synthesis, the reaction rate is
accelerated due to high reaction temperature, which quickly can
be achieved during process. Grinding or simple stirring of
reactants causes their molecular motions, friction, reduction of
particle size, and heating.
by theoretical calculation and only an approximate approach can
be used.
To investigate the solvent effect on the mechanism of
condensation reaction of the studied isonicotinohydrazide with
carbonyl compounds the quantum−mechanical calculations
were performed for the single molecules of reactants, products,
the most significant intermediates, and transition states in the
gas phase and in the presence of water and methanol using
continuum solvation model. These polar solvents were used
because the methanol is the most popular solvent used in the
traditional imine synthesis process and the water is the con-
stant product of imine formation reaction. Thus the combined
approach based on calculation results performed for the gas
phase and for the water polarizable continuum model can rea-
sonably approximate the solvent-free reaction conditions in
studied systems. The comparison of single molecule energy
values of studied compounds can provide the useful information
about the reaction pathway, allows a validation of the most
popular reaction conditions (methanolic ones). The disadvant-
age of such theoretical approach is the exclusion the noncovalent
intermolecular interactions of the reaction species with the
neighboring molecules. However, it was shown for the reaction
of reversible disulfide metathesis that the inclusion of the crystal
lattice energy and the molecular conformation-related energy in
the solid state only slightly influences the energetic effect of the
reaction. These factors allow explaining the differences in
reactivity of compounds in solution and during the solvent-free
reactions, but only for metathesis reactions in which purely solid
products were formed.31 In studied reactions, the formation and
evolving of water affects the reaction state of matter and
additionally the energetic effects are distinctly larger than in
mentioned metathesis reactions.
In general, the synthesis of imines from carbonyl compounds
and primary amines includes formation of a carbinolamine
intermediate, which next undergoes rearrangement, and finally
dehydrates, forming the corresponding imine. The imine
formation requires a hydrogen transfer step and the reaction
proceeds much faster in a polar solvent. According to the results
of quantum-mechanical calculations,61−63 the relatively high
energy barrier of imine formation can be reduced by the presence
of a water molecule or molecules acting as catalyst, which
facilitate the proton transfer processes, because of their hydrogen
bonding ability. Incorporation of one or two water molecules can
decrease the strain within the cyclic transition state (the four-
membered ring becomes more stable six- or eight-membered
ring). These findings suggest that the water formation during the
reaction lowers the energy barrier, since water molecules can
participate in relaying of a proton, can increase the contact of the
substrates and thus the additional solvent is not required.
Moreover, formation of small amount of water continuously
removed during the reaction prevents the reaction from reversing
and thus the formation of the reactants from the products.
The condensation reaction mechanism has several steps. In the
reaction environment, the molecules of reactants, products, and
intermediates can be present at the same time. These molecules
can interact with each other. In the studied reaction two solid−
solid or liquid−solid reactants give the solid and liquid products,
of which the second one evaporates in the reactions conditions
(the provided energy is sufficient to remove the gradually
produced water from the reaction environment), but before the
water molecules are removed from the reaction system, they may
influence the reaction mechanism. Water is present even during
studied solid−solid reaction under solventless conditions. Be-
cause of complexity, such systems cannot be directly reproduced
The solvent effect was incorporated using the polarizable
continuum model, which includes global electrostatic solute−
solvent interactions. The initial geometric parameters of
reactants and products were employed from crystal structure
data,41−50 except the parameters of 2-furfural and salicylalde-
hyde, which were obtained from their cocrystal structures, and
2-acetylthiophene, which were obtained from the bromo-
derivative.
The calculated CBS-4 M Gibbs free energies of reaction
(ΔrG0) at room temperature are reported in Table 3. All the
F
dx.doi.org/10.1021/cg400529s | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
Figure 5. Gibbs free-energy profile (298 K) for the formation of 2-furfuryl isonicotinoylhydrazone 2 in the gas phase (black dash) and in the presence of
the methanol (solvent) treated as a polarizable continuum (blue dash). This figure includes significant geometric parameters of the reaction (distances, Å).
The values in parentheses are the energy (kcal mol−1) difference between the Gibbs free energy of transition state (TS) and a sum of isolated substrate
molecules Gibbs free energy.
calculated reaction paths were found to be exergonic. The change
of the Gibbs free energy (ΔrG0) for reaction was determined
from the standard Gibbs free energy of the individual reactants
and products. In general, the inclusion of continuum solvent−
solute interactions makes the reactions thermodynamically more
favored. The solvation effects reduce the values of Gibbs free
energy change, but do not reverse the general reactivity trend.
The exception is the 2-hydroxybenzaldehyde isonicotinohydra-
zone (4), for which the presence of solvent seems to have
negative influence on reaction equilibrium. The changes of the
Gibbs free energy (ΔrG0) for reaction in methanol and water are
very similar. The change of the Gibbs free energy of reaction does
not depend on simple molecular properties (such as dipole
moment), but it originates from the whole distribution of the
electrostatic potential of the molecule. The 2-hydroxybenz-
aldehyde isonicotinylhydrazone (4) creates the O−H···N intra-
molecular hydrogen bond (the six-membered supramolecular
ring) and such interaction can also stabilize the transition state in
the absence of the solvent. The lack of possibility of such
interaction formation among other compounds leads to more
preferred reaction in solvents than in the gas phase. In terms of
Gibbs free energy, the condensation reaction of amines and
carbonyl compounds should occur even without the presence of
additional organic solvent, also for N′-(1-(2-thienyl)ethylidene)-
isonicotinohydrazide.
of substrates and products. The inclusion of one water molecules
decreases the activation energy by about 19 kcal mol−1.61−63
For the studied reactions, the calculated Gibbs free energy
values of reactant and product molecules, as well as of the most
significant intermediates and transition states, are lowered when
the methanol solvent as a polarizable continuum is included, but
the barrier heights do not change significantly (for 2 and 3) if the
sum of Gibbs free energies of substrate molecules is included
(Supporting Information Figure S2 and Table S1). In case of
compound 4, for which the geometry of transition structures
(TS2) is different, the barrier height in methanol is higher in
comparison to this one existing in the gas-phase. The energy
profile of the studied path for compound 2 synthesis reaction is
given as example in Figure 5. Solvation effect is associated with
change of the electrostatic properties of a solute and polarization
of its electron density by the solvent. Since the studied com-
pounds are polar, they undergo larger stabilization in solution.
The solvation alters the charge of carbonyl group atoms of
aldehyde/ketone, the carbon atom becomes more positive, and
hence more reactive, whereas the oxygen atom becomes more
negative, on the basis of Breneman64 and atomic polar tensor
(APT65) derived charge values (Table 4). In general, the imine
formation proceeding via a four-membered ring transition state
(TS2) requires more energy than the carbinolamine formation
(TS1), which is consistent with the results of previous
computational studies concerning the imine formation mecha-
nism in the gas phase and in the presence of explicit solvent
molecules.61−63 In case of 2-acetylthiophene isonicotinoyl-
hydrazone (5), the proton transfer to the hydroxyl group,
resulting in the elimination of a water molecule, requires less
energy in the presence of methanol than in the gas-phase. The
geometry of transition structures is different, as for 2 and 4
(Supportign Information Figure S2), and all these differences
The inclusion of explicit water molecules have been previously
considered only for the proton transfer steps of reactions
between methylamine with formaldehyde (G2(MP2,SVP) level
of theory),63 acetaldehyde (B3LYP/6-31g(d,p) level),61 and
acetone (B3LYP/6-31g(d,p) and B3LYP/6-311+G(2d,p) levels),62
and thus only the decreasing of the energies of transition states
were observed, while the presence of water molecules possessing
the ability to form hydrogen bonds can also change the energies
G
dx.doi.org/10.1021/cg400529s | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
Table 4. Atomic Charges [a.u.]
ASSOCIATED CONTENT
* Supporting Information
■
S
ATP charge
Breneman charge
gas-phase methanol
The selected bond lengths of reactant molecules from the crystal
structures for the gas-phase optimized structures and implicit-
solvent optimized molecule−methanol and water, the optimized
structures of intermediates (Int), transition structures (TS),
substrate and product molecules for 1 and 3, the calculated Gibbs
free energy values for reactant and product molecules, as well as
for transition states and intermediates in the gas phase and in the
presence of the methanol solvent as a polarizable continuum.
This information is available free of charge via the Internet at
http://pubs.acs.org/. CCDC-892705 (5) contains the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.
html [or from the Cambridge Crystallographic Data Centre
(CCDC), 12 Union Road, Cambridge CB2 1EZ, U.K.; fax
+44(0)1223−336033; e-mail deposit@ccdc.cam.ac.uk].
compound
atom
gas-phase
methanol
1
C
O
C
O
C
O
C
O
C
O
0.784
−0.662
0.963
1.056
−0.891
1.253
0.449
−0.518
0.530
0.512
−0.609
0.584
2
3
4
5
−0.705
1.085
−0.949
1.454
−0.556
0.454
−0.664
0.492
−0.807
0.902
−1.106
1.214
−0.554
0.521
−0.670
0.588
−0.728
1.002
−0.994
1.334
−0.572
0.672
−0.681
0.729
−0.754
−1.003
−0.602
−0.700
originate from possibility of solute−solvent interactions. The
solvent modifies the electron distribution in the solute structure
and thereby its geometry. It is worth mentioning that the mo-
lecular geometry of the hydrazone 1−4, changes only marginally
in a solvent. The presence of solvent−solute interactions plays an
important role in the hydrazone synthesis from a ketone. The
electrostatic interactions reduce the reaction barrier by changing
the geometry of transition structure, possessing the methyl group
responsible for sterical hindrance. In the synthesis of hydrazones
derived from ketones the solvent has significantly more positive
effect on the reaction mechanism in comparison to these ones
derived from aldehydes.
AUTHOR INFORMATION
Corresponding Author
■
*Tel.: +48-42-631-31-37. Fax: +48-42-631-31-03. E-mail: agata.
trzesowska@p.lodz.pl.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financed by funds allocated by the Ministry of
Science and Higher Education to Faculty of Chemistry, Lodz
University of Technology, Poland (Iuventus Plus, Grant no.
IP2011 056771) and statutory sources of the Institute of General
and Ecological Chemistry, TUL. The GAUSSIAN03 calculations
were carried out in the Academic Computer Centre
CYFRONET of the AGH University of Science and Technology
CONCLUSIONS
■
The experimental and quantum-mechanical results suggest that
the additional solvent is the unnecessary component in the
synthesis of nicotinoylhydrazones, especially these ones derived
from aldehydes. The experimental procedure is not complicated
and it does not require any sophisticated laboratory equipment.
The simple heating on a hot plate of solid−solid/solid−liquid
state reactants can be routinely used to obtain new nicotinoyl-
hydrazones on laboratory scale. The energy delivered in this way
is enough to overcome activation barriers. The results of XRD
and SEM measurements showed that obtained under solvent-
free conditions isonicotinoylhydrazones form crystalline micro-
particles. It is important since these compounds are synthesized
as target structures for evaluation of biological activities, and the
size and shape of particles influences the compound properties
such as bioavailability. The one-step solvent-free method of
synthesis can be used to obtain crystalline compounds.
The water formation during the reaction lowers the energy
barrier significantly in comparison to gas phase61−63 since the
water molecules can participate in relaying a proton, increase the
contact of the substrates and thus the additional solvent is not
required. Thermochemical parameter of the formation of
isonicotinoylhydrazones, the free Gibbs energy change, indicated
that all studied compound can be obtained. Although the solvent
has positive effect on the reaction mechanism (the energy of
transition states is lowered by about 26 kcal mol−1 for 1−4),
the organic solvent is unnecessary during the synthesis of iso-
nicotinoylhydrazones derived from aldehydes. Only one com-
pound, this one derived from 2-acetylthiophene, could not be
obtained under solventless conditions. In this case, the solvent
effects are considerable in reducing the energy barriers due to the
stabilization of the transition state. In general, ketones are less
reactive in the nucleophilic addition reaction and the methyl
group of acetylthiophene sterically hinders the approach of the
nucleophile.
in Cracow, Poland (Grant No. MNiSW/SGI3700/Płod
́
zka/
040/2008).
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