Thermodynamics of sublimation and solvation for bicyclo-derivatives of 1,3-thiazine

Article abstract of DOI:10.1016/j.tca.2013.07.005

Temperature dependencies of saturated vapor pressure of novel bicyclo-derivatives of 1,3-thiazine with methoxy- and carbonyl-substituents have been obtained by method of transference by means of an inert gas carrier. Thermodynamic functions of sublimation

Full text of DOI:10.1016/j.tca.2013.07.005

Thermochimica Acta 569 (2013) 61–65
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Thermochimica Acta
journal homepage: www.elsevier.com/locate/tca
Thermodynamics of sublimation and solvation for bicyclo-derivatives
of 1,3-thiazine
Marina V. Ol’khovicha, Svetlana V. Blokhinaa,∗, Angelica V. Sharapovaa,
German L. Perlovicha, Alexey N. Proshinb
a Institute of Solution Chemistry, Russian Academy of Sciences, 1 Akademicheskaya Street, 153045 Ivanovo, Russia
b Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Temperature dependencies of saturated vapor pressure of novel bicyclo-derivatives of 1,3-thiazine with
methoxy- and carbonyl-substituents have been obtained by method of transference by means of an
inert gas carrier. Thermodynamic functions of sublimation have been calculated. Correlations between
thermodynamic functions of sublimation and thermophysical properties of the substances and molecular
descriptors have been established. The enthalpies of solvation of compounds were calculated using the
measured values of enthalpies of sublimation and of standard enthalpies of solution in hexane and buffer.
Received 29 March 2013
Received in revised form 3 July 2013
Accepted 4 July 2013
Available online 12 July 2013
Keywords:
Drug-like bicyclo-derivatives
Vapor pressure
Sublimation
© 2013 Elsevier B.V. All rights reserved.
Solvation
Thermodynamics
Molecular descriptors
1. Introduction
connection between structural, crystallochemical, kinetic and
energetic properties of molecules [5]. Nowadays, databases con-
The effectiveness of drug compounds is dependent on solubility
in an aqueous environment of an organism, the kinetics of disso-
lution and membrane permeability [1]. The key challenge of the
present day pharmaceutical chemistry is to increase solubility of
substances of high biological activity. One can achieve the desired
goal by increasing solubility through structural modification of a
compound resulting in the decrease in crystal lattice energy with-
out sacrificing its pharmacological properties [2]. Enthalpy of sub-
limation is the most important property of a solid state of organic
compound. It represents not only the extent of intermolecular
interactions in a crystalline form but is responsible for the manner
in which molecules interact when dissolved [3]. Studies on solubil-
ity and sublimation properties of the compounds permit calculation
of solvation characteristics which provide meaningful information
about the nature of interaction between the drug compound and
the solvents simulating various biological environments [4].
In addition the information about an organic substance’s
sublimation enthalpy is of prime importance for understanding
physics and chemistry of the solid state. Data on saturated vapor
pressure and sublimation enthalpies are critical for revealing the
taining vapor pressure of substances and volatile low molecular
weight compounds are mainly represented. Crystalline compounds
with the sophisticated molecule structure and low saturated vapor
pressure are scarcely presented in the databases because of exper-
imental problems connected with limited volatility and stability
of these compounds.
Bicyclic non-aromatic derivatives with atoms of oxygen, nitro-
gen and sulfur in heterocycles are classified among the compounds
widely used in medicine to treat oncological, cardiovascular and
neuro-degenerative diseases [6,7]. Earlier it has been shown that
isothiourea derivatives possess neuroprotecting and cognitive-
stimulating properties [8].
This paper seeks to study the sublimation and solvation of
some novel heterocyclic spiro-derivatives of 1,3-thiazine and to
analyze the thermodynamic characteristics of the sublimation
and solvation processes. It continues our recent works [9,10]
on physicochemical behavior of pharmaceutically relevant spiro-
compounds.
2. Experimental
2.1. Materials
∗
Three
novel
bicyclo-compounds
were
studied:
N-
(1);
Corresponding author. Tel.: +7 4932 351545; fax: +7 4932 336246.
E-mail address: svb@isc-ras.ru (S.V. Blokhina).
(1-Thia-3-aza-spiro[5.5]undec-2-en-2-yl)-benzamide
0040-6031/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.tca.2013.07.005

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M.V. Ol’khovich et al. / Thermochimica Acta 569 (2013) 61–65
(4-methoxy-phenyl)-(1-Thia-3-aza-spiro[5.5]undec-2-en-2-
yl)-amine (2); and 1-[4-(1-Thia-3-aza-spiro[5.5]undec-2-
en-2-ylamino)-phenyl]-ethanone (3). These substances were
synthesized by reaction of the appropriate isothiocyanate with
2-cyclohex-2-enyl-ethylamine followed by cyclization of the
intermediate thiourea under acidic conditions in the final bicyclic
product [11]. The structure and purity of studied compounds
has been characterized by 1H NMR spectroscopy and elemental
analysis [10]. Purity of the spiro-derivates was 0.98 (mass fraction).
Fig. 1. Molecular structure of bicyclo-derivatives of 1,3-thiazine.
2.2. Apparatus and procedure
Temperatures and enthalpies of fusion of the compounds under
investigation have been determined using a Perkin-Elmer Pyris
1 DSC differential scanning calorimeter (Perkin-Elmer Analytical
Instruments, Norwalk, CT, USA) with Pyris software for Win-
dows NT. DSC runs were performed in an atmosphere of flowing
20 cm3 min−1 dry helium gas of high purity 0.99996 (mass frac-
tion) using standard aluminum sample pans and a heating rate of
2 K min−1. The accuracy of weight measurements was 0.005 mg.
The DSC was calibrated with an indium sample from Perkin-Elmer
(P/N 0319-0033). The value determined for the enthalpy of fusion
corresponded to 28.48 J g−1 (reference value 28.45 J g−1). The fusion
temperature was 429.5 0.1 K (determined from at least ten mea-
surements). The enthalpy of fusion at 298 K was calculated by the
following equation [12]:
identified. Under this flow rate, the saturated vapor pressure is
independent of the flow rate and, thus, thermodynamic equilibrium
is realized.
The saturated vapor pressures were measured five times at each
temperature with the standard deviation no more than 5%. Because
the saturated vapor pressure of the compounds investigated is low,
it may be assumed that the heat capacity change of the vapor with
temperature is so small that it can be neglected. The experimentally
determined vapor pressure data may be described in the following
way:
B
ln(p) = A +
(2)
T
The value of the sublimation enthalpy is calculated by the
Clausius–Clapeyron equation:
ꢀlcrHm◦ (298.15) = ꢀlcrHm◦ (Tfus) − ꢀlcrSm◦ (Tfus)(Tfus − 298.15)
(1)
ꢀ
ꢁ
∂(ln p)
∂(1/T)
ꢀgcrHm◦ (T) = −R
(3)
where the difference between the heat capacities of the melt and
solid states was approximated by the fusion entropy (as an upper
estimate).
whereas the sublimation entropy at the given temperature T was
calculated from the following relation:
Sublimation experiments were carried out by the transport
method. This method consists in passing a stream of an inert gas
over a sample at the constant flow rate and temperature, the rate
being low enough to practically achieve saturation of the carrier gas
with the substance’s vapor. The vapor was condensed and the subli-
mated quantity determined. The vapor pressure over the sample at
this temperature can be calculated from the amount of sublimated
material and the volume of the inert gas used.
(ꢀcgrH◦ (T) − ꢀgcrGm◦ (T))
ꢀgcrSm◦ (T) =
(4)
m
T
with ꢀgcrGm◦ (T) = −RT ln(p/p0), where p0 is the standard pressure
of p0 = 1.013 × 105 Pa.
For experimental reasons sublimation data are obtained at
elevated temperatures. However, in comparison with effusion
methods, the temperatures are much lower, which makes extrap-
olation to room conditions easier. In order to further improve the
extrapolation to room conditions, we estimated the heat capacities
Details of the technique are given in the literature [13]. The inert
gas (nitrogen) from tank flows through a column packed with sil-
ica to adsorb any water from the gas. The stabilization of the gas
temperature occurs in a thermostated water bath. The stability of
the gas flow with precision better than 0.01% is realized by use of
mass flow controller MKS type 1259CC-00050SU. The inert gas of
constant temperature and velocity passes then to the glass tube,
which is placed in the air thermostat. Three zones of the glass tube
can be distinguished to starting zone for stabilizing of the inert gas;
the transitional zone in which sublimation process occurs; ensuring
slow sublimation of the substance investigated; the finishing zone
in which the inert gas together with the sublimated substance is
overheated by 4–5 K, controlled by platinum resistance thermome-
ter. The temperature of the air thermostat is kept constant with a
precision of 0.01 K by means of the temperature controller PID type
650 H UNIPAN equipped with a resistance thermometer. The fin-
ishing zone is coupled with the condenser built from glass helix,
placed (outside the thermostat) located in a Dewar vessel filled
with a liquid nitrogen. To avoid a humidity adsorption from the air,
a condenser is connected to a vessel filled with CaCl2.
(
crCp◦,m-value) of the crystals using the additive scheme proposed
by Chickos and Acree [15]. Heat capacity was introduced as a cor-
rection for the recalculation of the sublimation enthalpy ꢀgcrHm◦
according to the equation:
ꢀgcrHm◦ (298.15) = ꢀgcrHm◦ (T) + ꢀHcor = ꢀcgrHm◦ (T)
+ (0.75 + 0.15crCp◦,m) · (T − 298.15)
(5)
3. Results and discussion
The objects of investigation are three novel compounds of
various bicyclo-derivatives of 1,3-thiazines. The general central
fragment of molecules is given in Fig. 1. Structural formula of radi-
cals and some of the physicochemical parameters of the substances
are shown in Table 1. All investigated compounds have a common
central fragment and various substituents with a phenyl ring and
methoxy- and carbonyl-groups in their structure.
The temperatures and enthalpies of fusion of spiro-derivatives
have been measured by DSC (Table 1). Only fusion peaks are regis-
tered on DSC curves, indicating stability and the absence of phase
transitions of the substances in the temperature ranges studied. The
experimental enthalpies of fusion increase from the first substance
The equipment was calibrated using benzoic acid. The standard
value of the sublimation enthalpy obtained was ꢀgcrHm◦ = 90.5
0.3 kJ mol−1. This is in good agreement with the value recom-
mended by IUPAC (ꢀgcrHm◦ = 89.7 0.5 kJ mol−1) [14].
From the experimentally determined pressure–flow rate rela-
tionship, the optimal flow rate of 1.2–1.8 dm3 h−1 has been

M.V. Ol’khovich et al. / Thermochimica Acta 569 (2013) 61–65
63
Table 1
The structural formula of the radical and physicochemical parameters of the spiro-compounds.
Compound
–R
Tfus (K)
ꢀcl rHm◦ (Tfus) (kJ mol−1
)
ꢀlcrSm◦ (Tfus) (J mol−1 K−1
)
Vw (Å3)
ꢁEa/˛
O
1
403.4 0.2
27.9 0.5
69.2 2.5
257.2
0.157
O
2
3
388.5 0.2
436.6 0.2
29.3 0.5
32.5 0.5
75.4 2.5
74.4 2.5
264.6
273.0
0.177
0.187
CH3
O
CH3
contribution to endothermic process of sublimation ꢀgcrHm◦
>
to the third one, signaling stabilization of the crystalline state of the
compounds.
T ꢀgcrS◦ . We used ꢂH and ꢂTS parameters to quantitatively evaluate
m
The temperature dependence of saturated vapor pressure of
the compounds measured by the method of transference is pre-
sented in Table 2. As one can see from Table 2, compound 2 with
methoxyphenyl group has the highest values of saturated vapor
pressure. Introducing the phenylcarbonyl fragment to the struc-
ture of spiro-derivatives 1 and 3 leads to a decrease in the vapor
pressure compared to the compound 2. The substances arranged
according to a decrease in vapor pressure at 373 K are in the order:
2 > 1 > 3 (Fig. 2).
enthalpy and entropy terms (Table 3). Calculation of ꢂH and
ꢂTS parameters showed that the sublimation energy of all the
compounds studied is determined 65% enthalpy and 35% entropy.
In a series of 1, 2, 3 compounds one observes an increase in
Gibbs energy and its enthalpy and entropy components. From the
patterns of change in the thermodynamic functions we conclude
that the increase in Gibbs energy is due to the dominant influence
of the enthalpy increase.
The enthalpy of vaporization of the substances ꢀgHm◦ has been
calculated by Eq. (1). Linear correlation of the enthalpiles of sublima-
tion and vaporization of the spiro-derivatives allows us to conclude
that intermolecular interactions both in crystal and liquid states are
of an identical character (Fig. 3).
Thermodynamic functions of sublimation for spiro-derivatives
at 298.15 K (Table 3) were calculated on the basis of temper-
ature dependences of vapor pressure. Analysis of sublimation
enthalpy values indicates that among all the spiro-derivatives
investigated compound 1 with phenylcarbonyl radical has the low-
est enthalpy value. Introduction oxygen-containing substituents
into para-position of compounds 2 and 3 benzene ring causes an
increase in their ꢀgcrHm◦ as compared to compound 1. Values of
Sublimation process can be described by contributions of van
der Waals forces, free volume effects, interaction of induced
dipoles and by the tendency to form hydrogen bonds. The contrib-
utions of these various effects to the thermodynamic functions of
sublimation are of an additive character [16]. Dispersion interaction
energy is determined mainly by values of electron polarizability
and van der Waals radii of contacting links of molecules. In this
connection, matching of sublimation enthalpies with molecular
volumes of the substances is of interest. Van der Waals molecular
volumes (Vw) of the compounds in a crystalline phase have been
calculated with GEPOL [17] using Kitaigorodsky’s atomic radii [18]
and are presented in Table 1.
ꢀgcrH◦ for the compounds studied are increased in the sequence:
m
1 < 2 < 3.
For the compounds studied compensation effects are realized.
The correlation equation can be presented as ꢀgcrH◦m◦ (298.15) =
49.0 + 1.2T ꢀgcrSm◦ (298.15) (R = 0.9962). Positive ꢀgcrHm and ꢀcgrSm◦
values point out the following: the enthalpy factor counteracts
sublimation while entropy factor favors the process. The enthalpy
constituent of the Gibbs energy introduces the dominating
Fig. 3. Enthalpy of vaporization ꢀgHm◦ (298.15) versus enthalpy of sublimation
Fig. 2. Plot of vapor pressure ln(p) (Pa) against reciprocal temperature for the spiro-
compounds: 1 (ꢀ); 2(᭹); and 3(ꢁ).
l
ꢀgcrHm◦ (298.15).

64
M.V. Ol’khovich et al. / Thermochimica Acta 569 (2013) 61–65
Table 2
The experimental values of sublimation vapor pressures of the spiro-compounds.
1
2
3
T (K)
P × 103 (Pa)
T (K)
P × 103 (Pa)
T (K)
P × 103 (Pa)
353.15
354.15
357.15
360.15
363.15
366.15
368.15
371.15
373.15
375.15
377.15
378.15
380.15
381.15
383.15
386.15
0.0022
0.0023
0.0031
0.0038
0.0048
0.0058
0.0068
0.0089
0.0106
0.0128
0.0140
0.0151
0.0185
0.0200
0.0226
0.0287
353.15
355.15
358.15
360.15
362.15
365.15
367.15
369.15
371.15
373.15
375.15
377.15
381.15
0.0034
0.0047
0.0065
0.0095
0.0115
0.0164
0.0217
0.0273
0.0363
0.0428
0.0523
0.0663
0.0973
373.15
375.15
377.15
379.15
381.15
383.15
385.15
386.15
387.15
388.15
390.15
391.15
392.15
393.15
394.15
396.15
397.15
0.0041
0.0053
0.0068
0.0088
0.0113
0.0146
0.0187
0.0215
0.0252
0.0287
0.0344
0.0372
0.0446
0.0503
0.0550
0.0728
0.0797
Standard uncertainty for temperature u(T) = 0.01 K; and relative standard uncertainty for pressure ur(p) = 0.05. ln(P[Pa]) = (40.3 0.63) − (16,236 231)/T.
ln(P[Pa]) = (23.9 0.30) − (10,623 110)/T. ln(P[Pa]) = (43.4 0.43) − (18,238 169)/T
Table 3
Thermodynamic characteristics of sublimation of the spiro-compounds.
Compound
ꢀgcrGm◦ 298.15
ꢀgcrHm◦ (T) (kJ mol−1
)
crCp◦,m (J mol−1 K−1
)
ꢀgcrHm◦ (298.15)
(kJ mol−1
ꢀgcrSm◦ (298.15)
ςH (%)a
ςTS (%)b
(
)
(kJ mol−1
)
)
(J mol−1 K−1
)
1
2
3
57.6 0.6
63.7 0.8
71.6 1.2
88.3 0.9
135.0 1.9
151.6 1.4
344.7
394.1
372.3
92.0 0.9
139.1 1.9
156.0 1.4
115.0 3.4
252.8 4.7
283.1 8.2
62.6
66.8
64.9
37.3
33.2
35.1
The ςH = ꢀgcrHm◦ (298.15)/(ꢀcgrHm◦ (298.15) + TꢀgcrSm◦ (298.15)) × 100%.
a
The ςTS = TꢀgcrSm◦ (298.15)/(ꢀcgrHm◦ (298.15) + TꢀgcrSm◦ (298.15)) × 100%.
b
Fig. 4 shows the growth in the Gibbs energy of compounds
ability of the molecule to create hydrogen bonds (on the entalpic
scale) reduced to polarizability. The descriptors were calculated
by means of the program package HYBOT [19]. In this program,
molecular fragments are defined as atom centered concentric envi-
ronments. The fragment consists of a central atom and neighboring
atoms connected within a predefined sphere size (the number of
bonds between the central and edge atoms). For each atom in a frag-
ment, the information on the atom and bond type, charge, valency,
cycle type, and size is coded into fixed-length variables, which are
subsequently used to define a pseudorandom hash value for this
fragment. Statistical criteria of correlation equations with ꢁEa/˛
as an independent variable were the best ones in comparison with
other descriptors. The sublimation enthalpies as functions of ꢁEa/˛
are presented in Fig. 4. These data allow us to establish the main
reasons for the increase in the Gibbs energy of sublimation in the
order 1–2–3. This increase is caused by a number of molecular fac-
tors: first, the strengthening of the van der Waals interactions upon
increasing the molecular volume and polarizability; second, the for-
mation of intermolecular hydrogen bonds in the crystal lattice upon
increasing the acceptor ability of the molecules.
with an increase in molecular volumes of molecule Vw. Apart from
non-specific interactions, molecules of spiro-derivatives studied
are able to form hydrogen bonds owing to the presence of a
secondary amino- and carboxyl-groups in their structure. Proton-
donor and proton-acceptor nature of functional groups makes it
possible to presume that crystalline state of the compounds may
be defined as that of a molecular crystal with hydrogen bonds. In
view of this fact, while carrying out comparative thermodynamic
analysis, we used ꢁEa/˛ descriptor (Table 1). ꢁEa/˛ is sum acceptor
Previously, we have obtained the temperature dependencies
of solubilities of the compounds in hexane and buffer by using
the isothermal saturation method and calculated thermodynamic
functions of solution [9]. To characterize the energy of interaction
between compounds and solvents on the basis of experimental data
on the solubility and sublimation, the following thermodynamic
functions of solvation have been determined:
◦
◦
298
sub
ꢀYsolv = ꢀYsol − ꢀY
(6)
Fig. 4. Correlations between the sublimation Gibbs energies ꢀgcrGm◦ (298.15) and van
der Waals volume Vw (᭹) and descriptor ꢁEɑ/˛ (ꢀ).
where Y is one of the thermodynamic functions of G, H and S
(Table 4).

M.V. Ol’khovich et al. / Thermochimica Acta 569 (2013) 61–65
65
Table 4
Thermodynamic parameters of solubility and solvation of the spiro-compounds in hexane and buffer 7.4 at 298.15 K.
Compound
X2 (mol. frac.)
ꢀsolG◦ (kJ mol−1
)
ꢀsolH◦ (kJ mol−1
)
ꢀsolS◦ (J mol−1 K−1
)
ꢀsolvG◦ (kJ mol−1
)
ꢀsolvH◦ (kJ mol−1
)
ꢀsolvS◦ (J mol−1 K−1
)
Hexane
1
2
3
1.53 × 10−4
1.82 × 10−4
1.93 × 10−5
21.8
21.3
26.9
30.3 0.5
29.9 0.7
32.8 1.1
28.5 1.0
28.9 1.2
19.7 0.5
−35.8
−42.4
−44.7
−61.7
−109.2
−123.4
−86.5
−223.9
−264.1
Buffer 7.4
1
2
3
1.61 × 10−6
9.70 × 10−6
1.22 × 10−6
33.0
28.6
33.7
14.0 0.8
4.3 0.4
11.8 0.8
−63.7 5.0
−81.5 9.0
−73.8 4.1
−24.6
−35.1
−37.8
−78.0
−134.8
−144.2
−179.1
−334.3
−356.9
As follows from the data, the solvation processes of all com-
pounds in hexane and buffer are exothermic and determined by
the enthalpy term in the Gibbs energy. Negative values of enthalpy
and entropy of solvation of these substances indicate excess energy
of crystal lattices compounds over the energy values of dissolu-
tion. Gibbs energies of solvation in hexane are lower than those in
buffer – an evidence of much stronger solvent–solute interaction in
a polar solvent. One can assume this increase to be associated with
the formation of hydrogen bonds between water molecules and
hydrogen of the amine group as well as with oxygen of carbonyl
group of the spiro-derivatives. Data on changes in the enthalpy
and entropy of solvation establish a relationship of the interaction
energy of spiro-derivatives with solvents and ordering of their sol-
vation shells. Irrespective of the chemical nature of the solvents
used, one observes the increase solvation in the series of com-
pounds from the first to the third due to growth of intermolecular
interaction with hexane and buffer.
Acknowledgment
This work was supported by the RFBR grant (No. 12-03-00019-
ɑ).
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Temperature dependencies of saturated vapor pressure of novel
bicyclo-derivatives of 1,3-thiazine with methoxy- and carbonyl-
substituents have been obtained by transport method by means
of an inert gas carrier. Thermodynamic functions of sublimation
have been calculated. It has been found out that the compound
with methoxyphenyl group have the largest values of saturated
vapor pressure at 373 K. Introduction of a phenylcarbonyl frag-
ment into the structure of spiro-derivatives causes a decrease in
saturated vapor pressure. The analysis of sublimation enthalpy val-
ues showed that introduction of oxygen-containing substituents
into the para-position of a benzene ring of spiro-derivatives causes
the growth in their values as compared to a compound with non-
substituted phenyl group. The main reasons for the increase in
the Gibbs energy of sublimation are the strengthening of the van
der Waals interactions upon increasing the molecular volume and
polarizability and the formation of intermolecular hydrogen bonds
in the crystal lattice upon increasing the acceptor ability of the
molecules. The enthalpies of solvation of the compounds studied
were calculated using the measured values of the enthalpies of sub-
limation and standard enthalpies of solution in hexane and buffer.
Data on the changes in the enthalpies and entropies of solvation
allow us to establish a relationship between the energy of interac-
tion of spiro-derivatives with the solvents and the ordering of their
solvation shells.
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