Abstract

Some new pyrimidine derivatives have been synthesized and their characterization was done by IR, NMR, and mass spectral data. The solubility of these synthesized compounds has been studied in methanol, N,N dimethylformamide (DMF), and carbon tetrachloride (CCl4) by gravimetrical method from 298.15 to 328.15 K under atmospheric pressure and the solubility data were correlated against temperature. The solubility is found to increase with temperature and order of solubility is DMF > methanol > CCl4. The experimental solubility data is correlated with the modified Apelblat equation. Some thermodynamic parameters such as dissolution enthalpy, Gibbs energy of dissolution, and entropy of mixing have also been calculated.

1. Introduction

The pyrimidine ring is an important structure in numerous natural products and bioactive compounds [1]. Further, the pyrimidine nucleus is present as a building block in materials science [2, 3]. Literature survey reveals that as pharmacologically active compounds, substituted pyrimidine scaffolds have become increasingly important with antimicrobial [4, 5], antimalarial [6], anticancer [7], and antimycotic activities [1].

So, it will be interesting to study their solubility in different solvents due to their various applications, which may help their uses in other fields also. Thus, in the present paper, solubility of some pyrimidine derivatives in methanol, DMF, and CCl4 from 298.15 to 328.15 K has been studied at atmospheric pressure. Some thermodynamic parameters such as dissolution enthalpy, Gibbs energy of dissolution, and entropy of mixing have also been calculated.

2. Experimental

2.1. Materials

The choice of solvent depends upon solubility and relative permeability. 2,4-Dichloropyrimidine (DCP) (CAS no.: 3934-20-1) and 4-((1H-1,2,4-triazol-1-yl)methyl)aniline (TMA) (CAS no.: 119192-10-8) used in the synthesis were purchased from Sigma-Aldrich. N,N-diisopropylethylamine (DIPEA) (CAS no.: 7087-68-5), the solvents methanol, dimethylformamide (DMF), and carbon tetrachloride (CCl4) used in the present work were of AR grade supplied by Spectrochem Pvt. Ltd. (Mumbai, India) and were purified according to the standard procedure [8]. The purity of solvents was checked by GC-MS (SHIMADZU-Model no.-QP-2010) and found to be greater than 99.0%.

2.2. Synthesis

A mixture of 2,4-dichloropyrimidine (DCP) (1.0 equi.), 4-((1H-1,2,4-triazol-1-yl)methyl)aniline (TMA), and N,N-diisopropylethylamine (DIPEA) (1.2 equi.) in n-Butanol was refluxed for 3 h. The completion of reaction was confirmed by analytical thin layer chromatography (TLC). After completion of reaction, reaction mass was cooled and the resulting solid was filtered, washed with cold water, and dried in vacuo to give crude product.

This resulting product was refluxed for 3 h with ethanolic solution of different aromatic amines (1.1 equi.) in presence of glacial acetic acid (2-3 drops). After completion of reaction, the reaction mass was cooled and the resulting solid was filtered, washed with cold ethanol, and dried in vacuo to give crude product. The obtained crude product was purified by trituration with diethyl ether and purity of all these synthesized compounds was checked by TLC (performed on aluminum coated TLC plates Gel 60 F254 (E. Merck)). The reaction scheme is given in Figure 1.


Figure 1 
The reaction scheme of pyrimidine derivatives.
2.3. Spectroscopy Study

Spectroscopic study of all the synthesized compounds was done by IR, 1H NMR, and mass spectroscopy. IR spectra were recorded on KBr discs, using FT-IR (Shimadzu Spectrophotometer Model no.-8400). 1H-NMR spectra were taken on a Bruker AVANCE II 400. In all the cases, NMR spectra were obtained in DMSO-d6 using TMS as an internal standard. The NMR signals are reported in ppm. Mass spectra were determined using direct inlet probe on a GCMS-QP-2010 mass spectrometer. Melting points of compounds were measured by Differential Scanning Calorimeter (Shimadzu-DSC-60).

2.4. Solubility Measurements

The solubility was measured by a gravimetric method [9]. For each measurement, an excess mole of compound was added to a known mole of solvent. Then, the equilibrium cell was heated to a constant temperature with continuous stirring. After at least 3 h (the temperature of the water bath approached constant value, and then the actual value of the temperature was recorded), the stirring was stopped and the solution was kept still for 2 h. A portion of this solution was filtered and by a preheated injector, 2 mL of this clear solution was taken in another weighed measuring vial (). The vial was quickly and tightly closed and weighed () to determine the mole of the sample (). Then, the vial was covered with a piece of filter paper to prevent dust contamination. After the solvent in the vial had completely evaporated at room temperature, the vial was dried and reweighed () to determine the mole of the constant residue solid (). All the moles were taken using an electronic balance (Mettler Toledo AB204-S, Switzerland) with an uncertainty of ±0.0001 g. Thus, the concentration of the solid sample in the solution, mole fraction , could be determined from where is the molar mole of compound and is the molar mole of the solvent.

At each temperature, the measurement was repeated three times and an average value is given in Table 3.

3. Results and Discussion

The physical properties of all the synthesized compounds are given in Table 1. For compound BKD-5, IR and 1H NMR spectra are shown in Figures 2 and 3, respectively.

Table 1 
Physical properties of synthesized pyrimidine derivatives.

Figure 2 
IR spectrum of compound BKD-5.

Figure 3 
1H NMR spectrum of compound BKD-5.
3.1. IR Spectra

The IR spectrum of BKD-5 is depicted in Figure 2. The IR data of BKD-5 clearly shows a –NH (secondary) stretching band at 3396 and 3196 cm−1. The IR stretching bands at 3090–2987 cm−1 and 1651–1494 cm−1 confirmed the presence of aromatic C–H and C=C in basic skeleton. The absorption band at 758 cm−1 and 1062–972 indicates presence of C–Cl and C–F stretching present in synthesized compounds and IR stretching band at 1379 cm−1 indicates presence of triazole ring in synthesized compound. The bending vibration –CH2 was observed at 1462 cm−1, respectively. The C–H symmetric stretching and asymmetric stretching absorption are observed at 2833 cm−1 and 2850 cm−1, respectively. All the IR group frequencies were suggestive of the fact that pyrimidine derivative is prepared successfully.

3.2. 1H-NMR Spectra

The proton NMR spectrum of BKD-5 is depicted in Figure 3. The peak due to residual DMSO was observed at about 3.505 ppm. It can be seen from the chemical structure of compound BKD-5 that proton of the phenyl ring attached to the carbons appeared as an appropriate multiplicity in the aromatic region at 6.463–8.698 ppm. The protons, which were present in methylene (–CH2) (attached to phenyl ring and triazole ring), appeared as a singlet at 5.421 ppm. The other two characteristic –NH groups appeared as a singlet at 10.527 ppm and 10.8 ppm.

3.3. Solubility Measurements

The solubility of the compounds in methanol, DMF, and CCl4 is summarized in Table 3 at temperatures ranging from 298.15 to 328.15 K. It is observed that for all the compounds, solubility is found to increase with temperature and order of solubility is DMF > methanol > CCl4. These solubility results are correlated with the dielectric constant and dipole moment of solvents which are given in Table 2. It is observed from Table 2 that both dielectric constant and dipole moment are higher for DMF and lower for CCl4. This is in accordance with the solubility trend in the three solvents. Thus, in present study, these properties affect the solubility. The variation of solubility in studied solvent with temperature is also shown in Figure 4.

Table 2 
Dielectric constant and dipole moment of solvents.
Table 3 
Observed mole fraction solubilities , calculated mole fraction solubilities , and relative deviation (RD) of pyrimidine derivatives in studied solvents.
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Figure 4 
Variation of mole fraction solubilities ( ) with temperature for pyrimidine derivatives, (a) in methanol, (b) in DMF, and (c) in CCl4. BKD-1 (◊), BKD-2 (Δ), BKD-3 (+), BKD-4 (○), and BKD-5 (□). Dotted lines: .

The temperature dependence of solubility of compounds in solvents is described by the modified Apelblat equation [10, 11]. Consider where is the mole fraction solubility of compound, is the absolute temperature, and , , and are constants determined by least square analysis and values of these constants are given in Table 4. The calculated solubilities are also reported in Table 3. The experimental solubility () of synthesized compounds in the studied solvents was compared with calculated solubility () and relative deviations (RD) between the experimental and calculated value are calculated by the following equation: and the values are given in Table 3.

Table 4 
Constants , , and of (2), ARD and RMSD of pyrimidine derivatives in studied solvents.

The relative average deviations (ARD) and root-mean-square deviations (RMSD) calculated by (4) are listed in Table 4. Consider where is the number of experimental points and is the solubility calculated by (2).

According to the Krug et al. [12] approach, the following modified Van’t Hoff expression was used to determine the enthalpy of solution (): where is the apparent standard enthalpy energy charge for the solution process and is the harmonic mean of the experimental temperatures, which is evaluated by the following equation: where is the number of experimental temperatures [13]. In the present case, the value obtained is 312.7505 K. The value of was obtained from the slope of the plot of versus () as shown in Figure 5 for methanol, DMF, and CCl4.

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Figure 5 
Van’t Hoff plot for pyrimidine derivatives solubility in (a) in methanol, (b) in DMF, and (c) in CCl4. BKD-1 (◊), BKD-2 (□), BKD-3 (Δ), BKD-4 (○), and BKD-5 (+).

The apparent standard Gibbs energy change for the solution process (), considering the approach proposed by Krug et al., is calculated at by the following equation: in which the intercept was from the plot of versus ().

Finally, using these evaluated and values, the entropies of solutions were obtained from equation [12, 14] All these thermodynamic parameters are given in Table 5.

Table 5 
Thermodynamic parameters of dissolution of pyrimidine derivatives in studied solvents.

It is evident from Table 5 that for all the compounds and values are positive. Further, values are also positive for all compounds in DMF and CCl4 whereas it is negative in methanol excepting BKD-1. When stronger bonds are broken and weaker bonds are formed, energy is consumed. So, becomes positive [12] which indicates endothermic dissolution of compounds [15]. The positive value of indicates that the dissolution process is not spontaneous [12, 15]. The positive entropy change indicates that the entropy of solubilization is unfavorable for solute in solution [15], whereas negative entropy is due to more order in solutions [16]. This depends on the functional groups present in the compound as well as on the solvent. The negative entropy in methanol may be due to the fact that there may be hydrogen bonding between solute and solvent molecules which may give more ordered structure in solution, whereas in DMF and CCl4, due to larger structure (in comparison to methanol), the structure may be disrupted, thus giving positive entropy.

Appendix

Spectral Data

BKD-1: IR (cm−1, KBr). 3375, 3225 (–NH (sec.) str.), 3095, 3036 (Ar–H str.), 2883 (–CH2 asym. str.), 2833 (–CH2 sym. str.), 1654–1489 (C=C str. Phenyl nucleus), 1456 (–CH2 bending vib.), 1371 (triazole ring str.), 1273 (C–N str.), 1242–1010 (C–H in plane bending, phenyl ring), 827 (C–H oop phenyl ring), 759 (C–Cl str.), 705–675 (C–H oop triazole ring), 626 (in plane pyrimidine ring bending), 422 (Out of plane pyrimidine ring bending). 1H NMR (DMSO-d6) (ppm): 5.458 (s, 2H), 6.559–6.575 (d, 1H, ), 7.308–7.329 (d, 2H, ), 7.396–7.418 (d, 2H, ), 7.518–7.538 (d, 2H, ), 7.583–7.601 (d, 2H, ) 8.019–8.037 (d, 1H, ), 8.095 (s, 1H), 8.820 (s, 1H), 10.984 (s, 1H), 11.282 (s, 1H). MS: (m/z) = 377.

BKD-2: IR (cm−1, KBr). 3394, 3217 (–NH (sec.) str.), 3088 (Ar–H str.), 3041 (–CH2 asym. str.), 2897 (–CH3 sym. str.), 2837 (–CH2 sym str.), 1647–1516 (C=C str. Phenyl nucleus), 1460 (–CH2 bending vib.), 1352 (–CH3 asy bending) 1274 (C–N str.), 1240–972 (C–H in plane bending, phenyl ring), 868–813 (C–H oop phenyl ring), 813 (C–Cl str.), 758 (C–H oop triazole ring). 1H NMR (DMSO-d6) (ppm): 2.331 (s, 3H), 5.425 (s, 2H), 6.432–6.449 (d, 1H, ), 7.161–7.181 (d, 2H, ), 7.249–7.270 (d, 2H, ), 7.342–7.363 (d, 2H, ), 7.592–7.612 (d, 2H, ), 7.930–7.947 (d, 1H, ), 8.016 (s, 1H), 8.693 (s, 1H), 10.418 (s, 1H), 10.873 (s, 1H). MS: (m/z) = 357.

BKD-3: IR (cm−1, KBr). 3391, 3213 (–NH (sec.) str.), 3059 (Ar–H str.), 2893 (–CH2 asym. str.), 1654–1506 (C=C str. Phenyl nucleus), 1462 (–CH2 bending vib.), 1388 (triazole ring str), 1273 (C–N str.), 1219–1136 (C–H in plane bending, phenyl ring), 1018 (C–F str.), 835–768 (C–H oop phenyl ring), 767 (C–H oop triazole ring). 1H NMR (DMSO-d6) (ppm): 5.36 (s, 2H), 6.2–6.214 (d, 1H, ), 7.114–7.212 (m, 4H), 7.22–7.247 (m, 1H), 7.605–7.627 (d, 2H, ), 7.721–7.765 (m, 1H), 7.963–7.981 (d, 2H, ), 8.635 (s, 1H), 8.699 (s, 1H), 9.432 (s, 1H). MS: (m/z) = 361.

BKD-4: IR (cm−1, KBr). 3311, 3203 (–NH (sec.) str.), 3107–3041 (Ar–H str.), 2951 (–CH2 asym. str.), 2883 (–CH2 sym str.), 1637–1491 (C=C str. Phenyl nucleus), 1456–1419 (–CH2 bending vib.), 1334 (triazole ring str), 1271 (C–N str.), 1230–1157 (C–H in plane bending, phenyl ring), 1107–1014 (C–F str.), 966–848 (C–H oop phenyl ring), 794–650 (C–H oop triazole ring). 1H NMR (DMSO-d6) (ppm): 5.377 (s, 2H), 6.279–6.293 (d, 1H, ), 7.222–7.257 (t, 3H, ), 7.434–7.474 (t, 1H, ), 7.686–7.707 (d, 2H, ), 7.996–8.012 (d, 2H, ), 8.068–8.083 (d, 1H, ), 8.175 (s, 1H), 8.654 (s, 1H), 9.521 (s, 2H). MS: (m/z) = 411.

BKD-5: IR (cm−1, KBr). 3396, 3196 (–NH (sec.) str.), 3090–2987 (Ar–H str.), 2850 (–CH2 asym. str.), 2833 (–CH2 sym str.), 1651–1494 (C=C str. Phenyl nucleus), 1462 (–CH2 bending vib.), 1379 (triazole ring str), 1265 (C–N str.), 1205, 1139 (C–H in plane bending, phenyl ring), 1060–972 (C–F str.), 879–819 (C–H oop phenyl ring), 758 (C–Cl str.), 680–509 (C–H oop triazole ring). 1H NMR (DMSO-d6) (ppm): 5.421 (s, 2H), 6.463–6.480 (d, 1H, ), 7.286–7.307 (d, 2H, ), 7.333–7.353 (d, 2H, ), 7.405–7.422 (d, 2H, ), 7.903–7.920 (d, 1H, ), 8.004–8.021 (d, 2H, ), 8.685–8.698 (d, 1H, ), 10.52 (s, 1H), 10.8 (s, 1H). MS: (m/z) = 395.

Nomenclature

:Concentration (mol·L−1)
:Absolute temperature (K)
:Experimental solubility ()
:Calculated mole fraction solubility ()
:Enthalpy of solution
:Gibbs energies of dissolution (kJ·mol−1)
:Entropy of solutions (kJ·mol−1)
:Universal gas constant (J·mol−1·K−1)
:Harmonic temperature (K).
Abbreviations
DCP:2,4-Dichloropyrimidine
TMA:4-((1H-1,2,4-Triazol-1-yl)methyl)aniline
DIPEA:N,N-Diisopropylethylamine
DMF:N,N-Dimethylformamide
CCl4:Carbon tetrachloride
AR:Analytical reagent
AAD:Absolute average deviations
rmsd:Root-mean-square deviations
RD:Relative deviations.

Conflict of Interests

The authors of this paper do not have a direct financial relation with the commercial identity that might lead to a conflict of interests for any of the authors.