Temperature-dependent thermochemical properties of the Mebicaret (2,4-dimethyl-6,8-diethylglycoluril) solutions in H2O and D2O at the ambient pressure

Thermochimica Acta 627 (2016) 48–54

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Temperature-dependent thermochemical properties of the Mebicaret (2,4-dimethyl-6,8-diethylglycoluril) solutions in H2 O and D2 O at the ambient pressure Evgeniy V. Ivanov a,∗ , Dmitriy V. Batov b,c , Vladimir V. Baranov d , Angelina N. Kravchenko d a Laboratory of Thermodynamics of Solutions of Non-electrolytes and Biologically Active Substances, G.A. Krestov Institute of Solution Chemistry, Russian Academy of Sciences, 1 Akademicheskaya Str., 153045 Ivanovo, Russian Federation b Incorporated Physicochemical Center of Solution Researches, G.A. Krestov Institute of Solution Chemistry, Russian Academy of Sciences, 1 Akademicheskaya Str., 153045 Ivanovo, Russian Federation c Department of Inorganic Chemistry, Ivanovo’s State University of Chemistry and Technology, 7 Sheremetevsky Ave., 153000 Ivanovo, Russian Federation d Laboratory of Nitrogen-containing Compounds, N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Ave., 199119 Moscow, Russian Federation

a r t i c l e

i n f o

Article history: Received 20 September 2015 Received in revised form 25 January 2016 Accepted 28 January 2016 Available online 22 February 2016 Keywords: Enthalpies of dissolution and dilution Mebicaret Ordinary and heavy water

a b s t r a c t The enthalpies of solution of Mebicaret or 2,4-dimethyl-6,8-diethyl-2,4,6,8-tatraazabicyclo[3.3.0]octane3,7-dione in ordinary (H2 O) and heavy (D2 O) water at (278.15, 279.15, 288.15, 298.15, 308.15, and 313.15) K as well as the enthalpies of dilution of its H/D isotopically distinguishable aqueous solutions at 298.15 K were measured calorimetrically. The standard (at infinite dilution) molar enthalpies and heat capacities of solution, and the enthalpic coefficients for pair (h22 ) and triplet (h222 ) interactions between hydrated solute molecules along with D2 O−H2 O solvent isotope effects (IEs) on the studied quantities were computed. The enthalpic effects of Mebicaret dissolution in H2 O and D2 O experience a negative-to-positive sign inversion nearby 303 K and 304 K, respectively, whereas the corresponding IEs were found to be wholly negative (by sign) and decreasing in magnitude with increasing temperature. The h22 values as well as IEs on them were found to be negative, too. On the contrary, the values of h222 are positive and comparable in magnitude with h22 ones. These facts indicate that the Mebicaret hydration, being enhanced in the D2 O medium, is dualistic by the nature with the prevailing hydrophilic mechanism. © 2016 Elsevier B.V. All rights reserved.

1. Introduction As a part of our continuous efforts to obtain information on the enthalpic effects caused by a dissolution/dilution of achiral N-tetraalkylated glycoluril-derivatives in the H/D isotopically distinguishable aqueous media [1–3], we report here results of a calorimetric study of 2,4-dimethyl-6,8-diethyl-2,4,6,8tatraazabicyclo[3.3.0]octane-3,7-dione (titled a Mebicaret, see Fig. 1a) solutions in ordinary (H2 O) and heavy (D2 O) water. It is known that some representatives of this class of heterocyclic compounds possess the pronounced physiological or biological activity, serving as a basis to design the promising drugs [4]. Among the N-alkyl glycoluril derivatives, tetra-substituted compounds are considered to be the most active [5,6]. Herewith it is assumed that

∗ Corresponding author. Fax: +7 4932 336237. E-mail addresses: [email protected], evi [email protected] (E.V. Ivanov). http://dx.doi.org/10.1016/j.tca.2016.01.010 0040-6031/© 2016 Elsevier B.V. All rights reserved.

their activity decreasing markedly with the decrease in the number and bulk of N-alkyl substituents [5,7]. The psychotropic pharmaceuticals Mebicar (2,4,6,8-tetramethylglycoluril, Fig. 1b) and Albicar (2,6-dimethyl-4,8-diethylglycoluril) are well-known tranquilizers and antidepressants [1–5,8–11]. Other representatives of the specified fully N-alkylated bioactive compounds, Mebicaret (see Fig. 1a) and Bicaret (2,4,6,8-tetraethylglycoluril, Fig. 1c), possessing anxiolytic and sedative activity, are much less studied [3,5,7,12]. At the same time the lack of reliable data on their thermodynamic properties in both crystalline and dissolved states does not allow identifying the peculiarities of hydration of pharmacophore (hydrophobic and proton-donor/acceptor) centers of the molecules in question. Earlier we (with some other co-authors) have carried out a number of such studies for the aqueous Mebicar [1,2,13–15] and Bicaret [3,7]. As seen in Fig. 1a–c, a Mebicaret molecule can be considered as the “intermediate” for the molecules of these two heterocyclic compounds simultaneously. Seen in this light, we consider it would

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Fig. 1. The schematically simplified structure of Mebicaret (a), Mebicar (b) or Bicaret (c) molecule with the labeling of atoms (owing to rigidity of the heterocyclic core and cis-fusion of the five-membered rings, a glycoluril’s molecule adopts the conformation of “half-open book” or “gull-wing” shape [5,8]). Here, Me = methyl group, Et = ethyl group.

be interesting to assess the influence of structure- and energyrelated changes caused by increasing in volume of nonpolar groups in one of the five-membered rings of a N-tetraalkylated glycolurilderivative on the features of its interaction in aqueous medium (including the hydration effect). Based on what is stated above, within the scope of this study, we discussed the D2 O–H2 O solvent isotope effects (hereinafter, IEs or ı) on the standard molar enthalpy, sol Ho2 , and heat o , of Mebicaret dissolution, as well as on enthalpycapacity, sol Cp,2 related (virial) coefficients of pairwise and triple interactions, h22 and h222 , between its molecules in water H/D-isotopologues. By virtue of the quantum nature of H2 O-by-D2 O replacement [16–18], such approach allows one to establish at the molecular level the role of hydrogen-bonding and hydrophobic effects in the structure-forming process which are manifested in the molar enthalpy-related characteristics of dissolution and interaction. The calorimetric experiments were performed at T = (278.15, 279.15, 288.15, 298.15, 308.15, and 313.15) K and p ∼ 0.1 MPa, the conditions under which the sol Ho2 values for Bicaret in H2 O and D2 O were derived [3] (for Mebicar in D2 O such measurements were performed at three temperatures only [1]). The enthalpies of dilution of H/D isotopically distinguishable aqueous solutions of Mebicaret, dil Hn2 , were carried out at T = 298.15 K. Immediately prior to considering the obtained results, note also that at present there is some ambiguity in naming of the title compound. So, its IUPAC name is 1,3-dimethyl-4,6-diethyltetrahydroimidazo[4,5-d]imidazole-2,5(1H,3H)-dione (Table 1). At the same time this naming does not reflect the fact of the existence of asymmetric contiguous C(1) and C(5) atoms being termed as a “glyoxalic bridge” that form the heterocyclic structure of a glycoluril molecule [5,8]. To eliminate this ambiguity, a more agreed-upon name for such glycolurils is used now in the literature [8,19,20]: bicyclic bisureas of the octane series or 2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-diones. Given this, further for simplicity, we will stick with a trivial name of the compound in question.

2. Materials and methods A detail description of chemical compounds employed in this work is given in Table 1.

Mebicaret was synthesized in accordance with the procedure [20]: by way of cyclocondensation of 4,5-dihydroxy1,3-dimethylimidazolidin-2-on with 1,3-dimethylurea under the influence of heating and stirring. The product yield was 59%. The synthesized sample was recrystallized from acetone with further drying for 24 h in vacuo at T = 320 K (to constant mass); its melting point and standard molar enthalpy of fusion determined with a differential scanning calorimeter DSC 204 F1 Phoenix were 367.7 (±0.5) K and 25.4 (± 0.5) kJ·mol−1 , respectively. In the parentheses, the expanded uncertainty with a 95% level of confidence is given. The purity of the prepared sample was checked using a high performance liquid chromatography (HPLC in Table 1). Additionally, the 1 H NMR and 13 C NMR spectra were measured on a Bruker AM 300 spectrometer in DMSO-d6 . Being derived by such way, the chemical shifts, ı/ppm, and coupling constants, J/Hz, were: 1.07 (t, 6H, Me, 3 J = 7.2), 2.81 (s, 6H, Me), 3.16 (dq, 2H, CH2 N, 2 J = 14.2, 3 J = 7.1), 3.34 (dq, 2H, CH2 N, 2 J = 14.2, 3 J = 7.1), 5.17 (s, 2H, CH) and 30.20 (C−Me), 30.03 (N−Me), 37.19 (CH2 ), 69.55 (CH), 157.83, 158.78 (C O), respectively, at T = 300 K. We have found it necessary to present the 1 H NMR and 13 C NMR spectra for the Mebicaret sample in Figs. S1 and S2, which are given as a Supplementary material. Noteworthy is the fact that the proton NMR-spectrum (Fig. S1) corresponding to the structure depicted in Fig. 1a contains two sextets, being placed in the (3.0 to 3.5) ppm region. These sextets are the multiplet-type AMX3 systems. Moreover, there are extra peaks at 2.50 ppm and 3.35 ppm being related to DMSO and H2 O, respectively (Fig. S1). Prior to calorimetric measurements, the sample of Mebicaret was additionally dried in a vacuum chamber for 48 h at T = 320 K and the residual water content in it, determined with a Karl-Fischer titration (using a Mettler Toledo C30 titrator), was about 0.007 wt.%. Before and after serial experiments, the Mebicaret sample was stored in a light-proof vacuum dessicator over P2 O5 . Water of natural isotope composition was twice distilled in a Pyrex-glass apparatus up to a specific conductivity () of 1.6·10−6 S cm−1 . Heavy water (“AstraKhim”, St. Petersburg, Russia; 99.9 at.% D;  = 1.2·10−6 S cm−1 ) was used as such. The concentration-dependent molar enthalpies of the Mebicaret dissolution in water H/D isotopologues, sol Hm 2 (m is a solution molality), were measured at the chosen temperatures and p = (99.6 ± 0.8) kPa using an automated isoperibol ampouletype calorimeter fitted with an electrical calibration before and

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Table 1 Sample description. Characteristics

Solute

H-solvent

D-solvent

Abbreviated name Molecular formula Molar mass/(g mol−1 ) a IUPAC name

Mebicaret C10 H18 N4 O2 226.2787 1,3-Dimethyl-4,6-diethyl-tetrahydroimidazo[4,5-d]imidazole2,5(1H,3H)-dione Original synthesis, being performed by the authors (Baranov & Kravchenko) 371228-04-5 >0.95b Double recrystallization from acetone with addition of diethyl ether ∼0.993b HPLC

Ordinary water H2 O 18.01528 Water

Heavy water D2 O 20.02762 [2 H]2 -Water

Local (of the natural isotope composition) 7732-18-5 – Deionization and double distillation – –

Astrakhim Co. (St-Petersburg, Russia)

Source CAS RN Initial mass fraction purity Purification method Final mass fraction purity Analysis method a b c

7789-20-0 ∼0.999c – ∼0.999c FT-IR-spectroscopy

For the absolutely pure compounds (including D2 O with the 100% deuterium content). Analyzed using the ECOM-based liquid-chromatography setup. With the (99.9 ± 0.05) at.% deuterium and the natural 18 O content (according to a manufacturer certificate).

after each experiment. A glass ampoule containing the sample was broken in a 30 cm3 titanium vessel. The detection limit of the apparatus is 10−5 K, and the temperature instability in the bath is 10−3 K in the temperature range considered. The detailed description of the instrument, its testing and procedure of experimental measurements of sol Hm 2 were set out in [21]. Prior to our serial measurements, the calorimeter was tested by measuring (in a series of 10 experiments) the enthalpies of solution of potassium chloride (KCl) in water at T = 298.15 K −1 (H O)} = (17.60 ± 0.04) kJ mol−1 being sol Hm 2 2 {m = 0.111 mol·kg and sol Ho2 ( sol H∞ ) = (17.23 ± 0.06) kJ mol−1 , respectively. The 2 agreement between our and recommended literature values, (17.584 ± 0.017) kJ mol−1 [22,23] and (17.217 ± 0.042) kJ mol−1 [24], was found to be excellent. The measurements of dil Hn2 were performed by employing the same calorimeter. The experimental procedure was described in general outline in our recent reports [3,25]. Here we will only note that the minimal enthalpic effect exceeds the declared detection limit of a calorimeter (see above) by a factor of ca. 100. The uncertainty for dil Hn2 is estimated to be no more than 5% of each experimental value being measured. Because the values of dil Hn2 have not averaged, they did not require estimation using the confidence limit (UH ). 3. Results and discussion The calorimetric measurements showed that the sol Hm 2 values in the concentration region considered do not depend on m within the experimental error at all the temperatures chosen. As a result, the values of sol Ho2 (≡ sol H∞ 2 ) were calculated as averageweighted, |sol Hm 2 |av , using a half-width confidence interval (UH ). The latter was determined by the Peters formula [3,26]. The experimental data on sol Ho2 for Mebicaret in H2 O and D2 O are listed in Table 2. According to the results presented in Table 2, the process of the Mebicaret dissolution in both ordinary and heavy water is accompanied by a heat evolution which decreases with increasing temperature at least up to ∼ 303 K for the protiated system and to ∼ 304 K for the deuterated one. When the temperature goes above these inversion points (where sol Ho2 = 0), the Mebicaret dissolution becomes increasingly endothermic. The H2 O-by-D2 O isotope substitution has a rather pronounced influence on sol Ho2 , varying this quantity by ca. 0.4 kJ mol−1 (or ∼ 5.5% of the total) at T = 278.15 K and by ca. 0.16 kJ mol−1 (or ∼ 6% of the total) at T = 313.15 K. Since the uncertainty in the ısol Ho2 (H2 O → D2 O) determination does not exceed ± 0.1 kJ mol−1 (Table 2), it will be a good plan to carry out the subsequent discussion of the IEs considered.

Fig. 2. D2 O–H2 O solvent isotope effects on the standard molar enthalpy of solution of Mebicar (triangles) [1], Mebicaret (circles) and Bicaret (squares) [3] as a function of temperature. The bars limit a half-width of 95% confidence interval for each of IEs being considered. The dashed line is the enthalpy-isotopic zero-axis.

A similar (negative-to-positive) temperature-dependent sign inversion of sol Ho2 was found previously for the solutions of Bicaret in H2 O and D2 O [3]. However in the latter cases, such “transformations” are observed at temperatures by ∼ 10 K higher than. Since the changes in sol Ho2 observed on going from H2 O to D2 O are equal to those in the standard enthalpy of solvation (hydration), solv Ho2 , upon the specified isotope substitution [1,3,16], we can predict the temperature range in which ısol(v) Ho2 (H2 O → D2 O) becomes zero, using the equation [3,27]



(ı)sol Ho2 (T ) = (ı)sol Ho2 () + bT T − 



(1)

where (ı)sol Ho2 () is the solution enthalpy in H2 O or D2 O (or corresponding IE) at a reference temperature  = 298.15 K and bT = o [3,27]. (ı)sol Cp,2 As can be seen in Fig. 2, such a hypothetical negative-to-positive inversion point for Mebicaret, being Tinv ≈ 346 K, lies between the corresponding values for Bicaret, Tinv ≈ 389 K, and Mebicar, Tinv ≈ 318 K. It is not surprising due to the significant negative difference in ısol(v) Ho2 for the first two glycoluril-derivatives over the whole temperature range studied. Obviously, the structuremaking effect (mainly due to the hydrophobic hydration) is more pronounced in aqueous solutions of Bicaret and in heavy water, on the whole. A directly opposite situation is observed for Mebicar: the specified enthalpy-isotope effect becomes decreasingly positive down to Tinv (Fig. 2). Taking it into account, one can say that there is a certain structural (hydrophilic-hydrophobic) “dualism”

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Table 2 Standard (at infinite dilution) molar enthalpies of solution, sol Ho2 /(kJ mol−1 ), of Mebicaret in ordinary and heavy water at different temperatures T and p = 99.6 kPa.a T/K

Ordinary water

278.15 279.15 288.15 298.15 308.15 313.15 a b

H2 O → D2 O

Heavy water sol Ho2 ± UH

mb

−6.95 ± 0.07 −6.67 ± 0.05 −4.17 ± 0.04 −1.47 ± 0.06 1.41 ± 0.06 2.80 ± 0.07

0.0044–0.0062 0.0050–0.0056 0.0047–0.0054 0.0040–0.0048 0.0042–0.0053 0.0037–0.0063

sol Ho2 ± UH

mb

ısol Ho2 ± UH

−7.35 ± 0.05 −7.03 ± 0.07 −4.52 ± 0.07 −1.76 ± 0.04 1.17 ± 0.06 2.64 ± 0.04

0.0041–0.0077 0.0037–0.0067 0.0033–0.0061 0.0045–0.0071 0.0047–0.0062 0.0048–0.0057

−0.40 ± 0.09 −0.36 ± 0.09 −0.35 ± 0.08 −0.29 ± 0.07 −0.24 ± 0.08 −0.16 ± 0.08

Um = ±0.0001 mol (kg solvent)−1 , UT = ±0.001 K, Up = ±0.8 kPa (level of confidence = 0.95). The molality range {mol [kg H2 O (or D2 O)]−1 } in which the sol Hm 2 values were averaged.

in the hydration behavior of Mebicaret pharmacophore groups that requires further investigation. The sign inversion in ısol(v) Ho2 is primarily caused by a faster destruction of the spatial hydrogen-bonded network of heavy water (compared to that for H2 O) under influence of the solute and temperature. Because heavy water is more structured than ordinary water, the largest changes in ısol(v) Ho2 at low temperatures (see Fig. 2) are due to the joint effects of hydrophobic hydration of the solute molecules and ability of them to form the stronger D-bonds (by ca. 1.0 kJ mol−1 [16,17,28]) with the aqueous environment. However the difference in energies of molecular vibrations (librations) and, as a consequence, in structure packings of H2 O and D2 O becomes less pronounced as the temperature increased [1,3,7,14,16,17,28–30]. The use of Eq. (1) and results given in Table 2 made it possible  o = ∂ Ho /∂T to calculate the sol Cp,2 values for Mebicaret in sol 2 p

H2 O and D2 O. A linear form of Eq. (1) assumes that these values, being equal to (278.3 ± 3.5) and (284.1 ± 4.6) J mol−1 K−1 for Mebicaret in H2 O and in D2 O, respectively, virtually do not depend on T within the chosen temperature range. The same quantities for Bicaret in ordinary and heavy water, as we have estimated recently [3], are equal to (441.3 ± 5.2) and (450.5 ± 4.7) J mol−1 K−1 , respectively, at T = 298.15 K. Hence there is more than 50% distinction with the corresponding values for Mebicaret. In this context, of special o quantity for Mebicar is also interest is the fact that the sol Cp,2 positive, running up to 60% of the Mebicaret values: (169 ± 9) and (155 ± 11) J mol−1 K−1 in ordinary and heavy water, respectively [1,2,15]. o The large and positive value of sol Cp,2 (in the water isotopologue) is usually connected with the predominating the hydrophobic hydration of a solute [31–33]. The point is that o (or partial quantity, C ¯ o ) reflects primarily the increasing sol Cp,2 p,2 structure- and energy-related changes caused by increasing the number of shorter water–water hydrogen bonds in the nearest vicinity of nonpolar groups [31]. Meanwhile, the results of computer simulation [34] show also that H bonds between water molecules surrounding amine groups of typically hydrophilic urea (U) become very similar to those around hydrophobic solutes. That is, one can observe the slight excess of shorter lengths and smaller angles for the N H· · ·O-bonding. This largely explains the fact o (U) ≈ 30 J mol−1 K−1 at T = 298.15 K although such a that hydr Cp,2 molecule contains no hydrophobic groups. Therefore, going from Mebicar to Mebicaret and further to Bicaret, the structure-making effect of a solute seems to be really enhanced due to strengthening of the hydrophobic hydration constituent, although the interaction of carbonyl oxygens via heterocomponent H(D)-bonding seems to be significant in all the cases considered [2,34,35]. This makes sense because two intermediate methylene groups are added to a solute molecule in each of the transitions considered. o (H O → D O) quantities for At the same time if the ısol Cp,2 2 2 Mebicaret and Bicaret were found to be coinciding numerically

Table 3 The integral enthalpies for dilution, dil Hn2 , of solutions of Mebicaret in ordinary and heavy water at T = 298.15 K and p = 99.6 kPa a . Mebicaret solutions in H2 O mi

b

1.4743 1.4743 1.7469 1.7469 1.7469 –

mf

b

0.0195 0.0216 0.0219 0.0231 0.0235 –

Mebicaret solutions in D2 O dil Hn2 c

mi b

mf b

dil Hn2 c

−7.8 −8.4 −14.5 −15.6 −15.7 –

0.8853 0.8853 1.2264 1.2264 1.4750 1.4750

0.0128 0.0169 0.0160 0.0175 0.0154 0.0177

−1.5 −2.2 −7.8 −8.6 −12.2 −14.2

a Um = ±0.0001 mol (kg solvent)−1 , UT = ±0.001 K, Up = ±0.8 kPa (level of confidence = 0.95). The uncertainty for dil Hn2 was estimated to be no more than 5% of each experimental value being measured (see in Experimental section). b Units: mol [kg H2 O (or D2 O)]−1 . c Units: J per kg of the solvent (H2 O or D2 O) in the solution with final concentration mf .

within the fitting error, being up to 7 J mol−1 K−1 , the introduction of Mebicar simultaneously into ordinary and heavy water leads to a radically opposite change in the enthalpy-isotopic effect when the o < 0 (Fig. 2). It is clear that the temperature is rising, i.e., ısol Cp,2 process of Mebicar hydration proceeds in a different way, with a predominantly hydrophilic character [1,3,14]. In accordance with conclusions [35–37], it may be realized by the formation of intermolecular H- or D-bonds not only through two carbonyl oxygens, but also via “glyoxalic” (bridging) C H groups (Fig. 1a,b). Herewith the possibility to form hydrogen bonds between water molecules and nitrogen atoms are sterically hindered. Besides, at least two water molecules incorporated in the hydration shell of a Mebicar molecule retain their rotation mobility, as it was observed in the case of “negative hydrophilic” hydration of U [38]. Therefore it is ◦ not surprising that ıC p,2 (H2 O → D2 O) for hydrophilic U in water (being ca. −10.4 J mol−1 K−1 [39]) has proved to be analogous (by o sign and magnitude) with ısol Cp,m of Mebicar. Returning to the Mebicaret hydration, one can assume that, unlike the aqueous Bicaret where the formation of “glyoxalic” CH· · ·OD/OH-bonds in the H/D isotopically distinguishable aqueous solutions is sterically hindered [3,7], its molecules have not lost the ability to form such bonds. Such an explanation seems quite reasonable, if one consider a Mebicaret molecule as an in half ethylated Mebicar molecule. However the “authentic” nature of the enthalpy and enthalpy-isotopic effects observed at dissolving Mebicaret still remains unclear, and to derive more detailed conclusions, the additional experimental investigations must be performed. To understand this situation more clearly, the computed values of h22 as well as h222 for Mebicaret solutions in H2 O and D2 O must be considered, too. The h22 and h222 quantities were estimated by fitting the dil Hn2 values (Table 3) with the known polynomial expansion based on the McMillan-Mayer formalism [40,41] dil Hn2 (mi → mf ) (J × kg-1 )

= h22 mf (mf − mi ) + h222 mf (m2f − m2i ) + · · ·

(2)

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where mi and mf are the initial and final solution molality, respectively. In this equation, the dil Hn2 values are attributed to kg of the solvent (H2 O or D2 O) in the solution with final concentration mf . Alternatively, Eq. (2) may be transformed into form dil Hm 2 (mi → mf ) (J × mol−1 )

= h22 (mf − mi ) + h222 (m2f − m2i ) + · · ·

(3)

where dil Hm 2 values are attributed to the mole of solute (Mebicaret). The dil Hn2 values for H/D isotopically distinguishable aqueous solutions of Mebicaret are given in Table 3. In fitting of Eq. (2), a least-squares method was used. In the fitting of this equation, a least-squares method was employed. The fitting was tried with the polynomial of increasing degree, choosing that of highest degree, for which all the coefficients are significant with respect to their own 95% confidence limit. Besides, the theoretical zero values of dil Hn2 = dil Hm 2 representing the “background” heat level (dissolution of the pure solvent in pure solvent) also were included in the fitting procedure. Being computed by Eq. (2), the h22 and h222 values for solutions of Mebicaret in H2 O and D2 O, together with the similar results for Mebicar [2] and Bicaret [3], are summarized in Table 4. The analysis of data presented in Table 4 convinces us that, unlike the situation with sol Ho2 and ısol Ho2 as a whole, the h22 values for Mebicaret and Bicaret are opposite by sign. In turn, the character of 2–2 intermolecular interactions for {H2 O (or D2 O) + Mebicar} is similar to that in aqueous Mebicaret, despite the oppositely directed temperature-dependent ısol Ho2 (H2 O → D2 O) values (Fig. 2). Noteworthy is also the fact that the homotactic pairwise interaction coefficients for U (h22 ≈ −330 J kg mol−2 in H2 O and ∼ −430 J kg mol−2 in D2 O [13]) are coincide numerically with those for the title glycoluril-derivative (Table 4). That is, by analogy

Fig. 3. Correlation between standard molar enthalpies of solution of Bicaret (1), Mebicaret (2) and Mebicar (3) and corresponding enthalpy coefficients of pair solute–solute interactions in ordinary water (䊐) and heavy water (䊏). The values of confidence interval half-width, UH (h) , are presented in Table 2 and Fig. 2.

Finally, we have found that the existing differences in the hydration behavior of Mebicaret and its N-tetraalkylated analogues are reflected in the obvious interrelation between sol Ho2 and h22 quantities for the solutes compared in the H/D isotopically distinguishable aqueous media. As seen in Fig. 3, each of such correlation dependences at T = 298.15 K is linear (within the limit of error). It can be regarded as an argument in favor of the belief that the given characteristics are thermodynamically and structurally related, at least for the solutes in question. By fitting the functions of sol Ho2 against h22 analytically, these correlations (Fig. 3) may be expressed in the form of first-order equations

sol Ho2 (H2 O) = −(2.58 ± 0.09) × 103 − (3.06 ± 0.06) h22 , sol Ho2 (D2 O)

3

= −(2.97 ± 0.80) × 10 − (2.59 ± 0.43) h22 ,

with a typically hydrophilic U (and Mebicar as well), the heterocyclic Mebicaret molecules may be interacted rather strongly with each other to form the solvent-separated pairs [42] despite the presence of four N-sited alkyl substituents in them. The H2 O-byD2 O substitution leads to enhancement of self-association of the hydrated Mebicaret molecules (ıh22 < 0 in Table 4) [13]. However in the case of aqueous Mebicar the given tendencies are substantially more pronounced. This is in agreement with the above suggestion that the hydration of Mebicaret should be treated as a superposition of two mechanisms, hydrophobic and hydrophilic, and the latter seems to be predominating. On the other hand, the positive sign at h22 in Table 4 shows that the interactions between Bicaret molecules are to be prevailingly hydrophobic by the nature. It means that an overlapping of their cospheres leads to considerable enhancement of clathrate-formation in the nearest vicinity of nonpolar groups (where the aqueous local structure becomes the more stable than that in bulk water), a factor that facilitates the separation of hydrated solute molecules [13]. This is supported by the increase in h22 at deuteration of solvent molecules (Table 4). The values of h222 for Mebicaret solutions in ordinary and heavy water are positive in sign and comparable in magnitude with h22 ones (see Table 4). Noteworthy is the unusual fact that these quantities for Mebicaret and Bicaret in both water H/D-isotopologues, as well as the ıh222 (H2 O → D2 O) quantities for all the compared glycoluril-derivatives, are very close to each other (Table 4). However it is not yet subject to a reasonable explanation.

R = 1.0,

sd = 11.1 Jmol−1

R = 0.9998,

sd = 105 J mol

(4) (5)

Based on the results presented in Fig. 3, one may confirm that interaction-related effects are more pronounced in the deuterated aqueous media. Herewith the Bicaret molecule is the most hydrophobic one, as it was emphasized in our recent works [3,7]. The introduction of Bicaret and Mebicaret (a fortiori, Mebicar) into the ordinary or heavy water leads to radically different solute–solute interactions. It can be because the molecules of the latter contain the less branched alkyl constituents and two “glyoxalic” methine groups capable of specific interaction through hydrogen-bonding with the aqueous surroundings. Using Eqs. (4) and (5), one can predict also the “range of existence” of a hypothetical glycoluril-derivative for which ıh22 (H2 O → D2 O) and ısol Ho2 (H2 O → D2 O) values are to be zero (see Fig. 3). We have found that the mean-weighted values for the “crossing-point” desired are ısol Ho2 ≈-0.41 kJ mol−1 and ıh22 ≈-400 J kg mol−2 . 4. Short summary We can conclude that the hydration process is weakened when Mebicaret is substituted by its N-tetramethylated analogue (the drug Mebicar) but the N-tetraethylated glycoluril-derivative (Bicaret) is hydrated stronger than the title solute. It is because two intermediate methylene groups are added to a solute molecule in each of the transitions considered. Going from Mebicaret to Bicaret, a hydrophobic constituent becomes the predominant one in the total enthalpy effect of solute hydration and this is enhanced in heavy water, despite the formation of stronger heterocomponent deuterium-bonds. In turn,

E.V. Ivanov et al. / Thermochimica Acta 627 (2016) 48–54

53

Table 4 Enthalpy-related homotactic interaction coefficients, h22 and h222 , for Mebicaret solutions in ordinary and heavy water with the corresponding solvent isotope effects, ıh22(222) (H2 O → D2 O), at T = 298.15 K and p = 99.6 kPa.a Solute

h22 (H2 O) b

h22 (D2 O) b

ıh22 (H2 O→ D2 O) b

h222 (H2 O)c

h222 (D2 O) c

ıh222 (H2 O→ D2 O c

Mebicaret Bicaret Mebicar

−358 ± 23 1389 ± 102 −2042 ± 68

−436 ± 39 1804 ± 164 −2663 ± 122

−78 ± 45 415 ± 193 −621 ± 140

421 ± 14 303 ± 81 903 ± 62

664 ± 30 673 ± 120 1287 ± 123

243 ± 33 370 ± 145 384 ± 138

a b c

UT = ± 0.001 K, Up = ± 0.8 kPa (all the reported uncertainties, including Uh , correspond to the 95% confidence limits). Units: J kg mol−2 . Units: J kg2 mol−3 .

unlike the aqueous Bicaret where the proton-donating ability of bridging (“glyoxalic”) protons in the H/D-isotopically distinguishable aqueous solutions is sterically hindered, the Mebicaret (a fortiori, Mebicar) molecules have not lost the ability to form such (CH· · ·OD/OH-) bonds. This is in agreement with the suggestion based on the obtained enthalpy-related characteristics that the hydration of Mebicaret is dualistic by the nature. Such a “dualism” should be treated as a superposition of two mechanisms, hydrophobic and hydrophilic, and the latter seems to be predominating. Acknowledgments The given work was supported by the Russian Foundation for Basic Researches (Grant No. 13-03-00716-a). The measurements of the solute heat fusion (melting point) and solvent density were carried out using the equipment of the “The Upper-Volga Regional Centre of Physic-chemical Researches” (being located at the G.A. Krestov Institute of Solution Chemistry of the RAS, Ivanovo, Russia). Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tca.2016.01.010. References [1] E.V. Ivanov, V.K. Abrosimov, D.V. Batov, Effect of temperature on the H/D isotope effects in the enthalpy of hydration of tetramethyl-bis-carbamide, Russ. Chem. Bull. Ed. 55 (2006) 741–743, http://dx.doi.org/10.1007/s11172006-0323-y. [2] E.V. Ivanov, D.V. Batov, Enthalpy-related interaction parameters in H/D isotopically distinguishable aqueous solutions of tetramethylurea cyclic derivatives at 298.15 K, Thermochim. Acta 523 (2011) 253–257, http://dx.doi. org/10.1016/j.tca.2011.05.019. [3] E.V. Ivanov, D.V. Batov, G.A. Gazieva, A.N. Kravchenko, V.K. Abrosimov, D2 O-H2 O solvent isotope effects on the enthalpies of bicaret hydration and dilution of its aqueous solutions at different temperatures, Thermochim. Acta 590 (2014) 145–150, http://dx.doi.org/10.1016/j.tca.2014.05.011. [4] R.G. Kostyanovsky, K.A. Lyssenko, A.N. Kravchenko, O.V. Lebedev, G.K. Kadorkina, V.R. Kostyanovsky, Crystal properties of N-alkylsubstituted glycolurils as the precursors of chiral drugs, Mendeleev Commun. 11 (2001) 134–136, http://dx.doi.org/10.1070/MC2001v011n04ABEH001469. [5] V.Z. Pletnev, I. Yu Mikhailova, A.N. Sobolev, N.M. Galitskii, A.I. Verenich, L.I. Khmel’nitskii, O.V. Lebedev, A.N. Kravchenko, L.I. Suvorova, Three-dimensional structure of psychotropically active N-polytetraalkyl derivatives of 2,4,6,8-tetra-azabicyclo[3.3.0]octanedione-3,7 series in crystal revealed by X-ray analysis, Russ. J. Bioorg. Chem. 19 (1993) 671–681. [6] M.O. Dekaprilevich, L.I. Suvorova, L.I. Khmelnitskii, 1,6-Dimethyltetrahydroimidazo[4,5-d]-imidazole-2,5(1H,6H)-dione monohydrate, Acta Cryst. C (1940), http://dx.doi.org/10.1107/ S0108270194004555. [7] E.V. Ivanov, E. Yu. Lebedeva, V.K. Abrosimov, Standard volumetric properties of tetra-N-ethylglycoluril (Bicaret) in ordinary and heavy water at temperatures from (278.15 to 318.15) K and ambient pressure, J. Chem. Eng. Data 60 (2015) 2079–2089, http://dx.doi.org/10.1021/acs.jced.5b00154. [8] E.G. Atavin, A.V. Golubinskii, A.N. Kravchenko, O.V. Lebedev, L.V. Vilkov, Electron diffraction study of molecular structure of mebicar, J. Struct. Chem. 46 (2005) 417–421, http://dx.doi.org/10.1007/s10947-006-0119-9. [9] A.V. Val’dman, I.V. Zaikonnikova, M.M. Kozlovskaya, I.E. Zimakova, A study of the spectrum of psychotropic action of Mebicar, Bull. Exp. Biol. Med. 89 (1980) 621–624, http://dx.doi.org/10.1007/BF00835799.

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