Solubility, Model Correlation, and Solvent Effect of 2-Amino-3

Article pubs.acs.org/jced

Cite This: J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Solubility, Model Correlation, and Solvent Effect of 2‑Amino-3methylbenzoic Acid in 12 Pure Solvents Anfeng Zhu,*,† Kun Hong,*,‡ Fengxia Zhu,† Benlin Dai,† Xu Jiming,† and Wei Zhao† †

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Jiangsu Key Laboratory for Chemistry of Low-Dimensional Materials, Jiangsu Engineering Laboratory for Environment Functional Materials, Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, School of Chemistry and Chemical Engineering, Huaiyin Normal University, Huaian 223300, P.R. China ‡ National & Local Joint Engineering Research Center for Deep Utilization Technology of Rock-Salt Resource, Faculty of Chemical Engineering, Huaiyin Institute of Technology, Huaian 223003, P.R. China ABSTRACT: In this experiment, the research of solution process for 2-amino-3methylbenzoic acid in different solvents is essential for its purification. The solubility values in pure methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, acetone, acetonitrile, 2butanone, ethyl acetate, 1,4-dioxane, toluene, and cyclohexane were established with the isothermal saturation method at temperatures T = 278.15 to 318.15 K under pressure of 101.2 kPa. The solubility of 2-amino-3-methylbenzoic acid in mole fraction increased with a rise of temperature. Moreover, at a certain temperature, the order of the solubility data from high to low is 1,4-dioxane > acetone > 2-butanone > ethyl acetate > acetonitrile > methanol > ethanol > 1-propanol > 1-butanol > 2-propanol > toluene > cyclohexane. The modified Apelblat equation, λh equation, Wilson model, and NRTL model were used to correlate the experimental data. The values of root-mean-square deviation (RMSD) and relative average deviation (RAD) were not exceeding 4.51 × 10−4 and 1.87%, respectively. In order to choose the best model for 2-amino-3methylbenzoic acid, the relative applicability of these models was evaluated by Akaike Information Criterion (AIC). Furthermore, solute−solvent and solvent−solvent interactions have been studied. The mixing properties of 2-amino-3methylbenzoic acid were computed. From the analysis results, the mixing process of 2-amino-3-methylbenzoic acid was an endothermic, spontaneous, and entropy-driven process. In particular, purification, recrystallization, and formulation development of 2-amino-3-methylbenzoic acid in the industry were effected by its solubility values.

1. INTRODUCTION

its solubility data is of great significance for purification and design of the subsequent process. For selection of solvents, solvent selection is a pivotal procedure. Practicable solvents should be thermally stable, have stable physical properties, be nontoxic (environmentally safe), be noncorrosive, and be commercially available. The physical properties of the selected solvents are relatively suitable and stable. In the previous publications, 2-amino-3methylbenzoic acid obtained from the known process is purified by recrystallization in acetone and ethanol or ethanol aqueous solution.6−8 Furthermore, methanol, ethanol, 1propanol, 2-propanol, and 1-butanol were safe and widely used solvents in the chemical industry. Toluene and cyclohexane are excellent industrial solvents. Ethyl acetate, 1,4dioxane, 2-butanone, and acetonitrile are safe and common solvents to be used as extractant in industry due to high solubilization capacity. On the basis of the considerations mentioned above, in this research, the solubility of 2-amino-3methylbenzoic acid in 12 selected monosolvents was determined at the temperature ranging from 278.15 to 318.15 K. The Apelblat equation, λh equation, Wilson

2-Amino-3-methylbenzoic acid (CAS No. 4389-45-1) is an important chemical product, pharmaceutical, and organic synthesis intermediate. It is an important intermediate in the production of chlorantraniliprole.1 It can also be used as an additive for levofloxacin hydrochloride injection to make the injection more stable and safer.2 In addition, a Chinese patent No. 103435594 reports the preparation of 2-aminoquinazoline inhibitors by 2-amino-3-methylbenzoic acid.3 It has a strong inhibitory effect on polo-like kinase-1 (PLK-1) and inhibits the growth of tumor cells. With the intensification of research on PLK-1, the demand for high purity of 2-amino-3-methylbenzoic acid is increasing. In industry, two methods have been used to produce 2-amino-3-methylbenzoic acid. One is using otoluidine as raw material and then condensation.4−6 This method is too complex to manufacture on a large scale. The other one is using 3-methylbenzoic as raw material, followed by nitrification and ammoniation.7,8 This is a commercial and sample process. However, during the synthesis of 2-amino-3methylbenzoic acid, it is easy to generate 3-amino-5methylbenzoic acid due to the reaction conditions. The separation and purification of 2-amino-3-methylbenzoic acid from isomer mixtures is the first process in the whole synthesis of 2-aminoquinazoline inhibitors. Thus, systematic research on © XXXX American Chemical Society

Received: December 19, 2018 Accepted: March 12, 2019

A

DOI: 10.1021/acs.jced.8b01226 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Journal of Chemical & Engineering Data

Article

Table 1. Source and Purity of the Materials Used in the Work chemicals

molar mass g·mol−1 151.06

2-amino-3-methylbenzoic acid methanol 1-propanol 2-propanol 1-butanol ethanol toluene ethyl acetate acetonitrile 1,4-dioxane cyclohexane 2-butanone acetone

32.04 60.06 60.06 74.12 46.07 92.14 88.11 41.05 88.11 84.16 72.11 58.05

CAS no.

melting point K

melting enthalpy kJ·mol−1

density kg·m−3 (295 K)

52130−17−3

447.37a

27.30a

1254b 786.5c 805.3c 803.5c 810.9c 789.3c 871.0c 900.3c 776.8c 1033.7c 778.1c 801.4c 784.5c

67−56−1 71−23−8 67−63−0 71−36−3 64−17−5 108−88−3 141−78−6 75−05−8 123−91−1 110−82−7 78−93−3 67−64−1

source Shanghai Yuanye BioTechnology Co., Ltd. Sinopharm Chemical Reagent Co., Ltd., China.

mass fraction purity

analysis method

0.996

HPLCd

0.997 0.994 0.995 0.996 0.995 0.996 0.995 0.994 0.996 0.996 0.994 0.995

GCe GC GC GC GC GC GC GC GC GC GC GC

a Take from ref 26. bCalculated with the Advanced Chemistry Development (ACD/Laboratories) Software V11.02 (©1994−2016 ACD/ Laboratories). cTaken from ref 12. dHigh-performance liquid phase chromatograph. eGas chromatography.

mercury glass microthermometer (standard uncertainty: 0.02 K). Solid and solvent were mixed by a magnetic stirrer adequately. The liquid phase was taken out at intervals of 2 h using 2 mL of preheated syringe connected with a pore syringe filter (PTFE 0.2 μm) and then tested by the HPLC. The results showed that 12 h was enough to make the solution equilibrium for all the studied systems. Then, the magnetic stirrer was stopped, and any solid was precipitated out from the mixture. The upper equilibrium solution was taken out by a preheated syringe and transferred into a 25 mL preweighed volumetric flask with a rubber stopper. The total amount of the sample and flask was weighed by an analytic balance. It was diluted to the mark with corresponding solvent and tested by the HPLC. The experiment was carried out at about 101.2 kPa. The mole fraction solubility (xe) of 2-amino-3-methylbenzoic acid in pure solvents can be calculated with eq 1.

model, and NRTL model were used to correlate the solubility data, and the Akaike Information Criterion (AIC) was used to compare the relative applicability of these models. In addition, solvent effect was discussed. Afterward, the mixing properties for the solution process of 2-amino-3-methylbenzoic acid in pure solvents were calculated by the Wilson model.

2. EXPERIMENTAL SECTION 2.1. Materials. 2-Amino-3-methylbenzoic acid was purchased from Shanghai Yuanye Bio-Technology Co., Ltd. The content of 2-amino-3-methylbenzoic acid used in solubility measurement was 0.996 in mass fraction without further purification. All solvents were from Sinopharm Chemical Reagent Co., Ltd., China (AR grade) and used as received. The detailed information on 2-amino-3-methylbenzoic acid and the studied solvents was listed in Table 1. 2.2. Solubility Determination. The solid−liquid equilibrium was determined by using the isothermal saturation method.9,10 The temperature in this measurement ranged from T = 278.15 to 318.15 K under atmospheric pressure. The reliability of verification of the experimental apparatus was verified by determining the solubility of benzoic acid in 2propanol,11and the results are presented in Table 2. Excessive solid 2-amino-3-methylbenzoic acid was added into the glass vessel fitting with about 40 mL of each solvent. The temperature was controlled by a thermostatic watercirculator bath. The experiment temperature was shown by a

xe =

xexp

xref

100RD

278.06 288.15 293.11 303.45

0.1295 0.1578 0.1729 0.2148

0.1286 0.1595 0.1738 0.2146

0.70 −1.06 −0.52 0.09

(1)

In eq 1, the symbols m1 and m2 refer to the mass of 2-amino-3methylbenzoic acid and solvents, respectively, and the symbols M1 and M2 stand for the molar mass of 2-amino-3methylbenzoic acid and the solvents. 2.3. Analysis Method. The sample was analyzed by highperformance liquid chromatography (HPLC). A reverse-phase column with a type of LP-C18 (250 mm × 4.6 mm) was used. The HPLC column temperature was set as 303 K. The UV detection wavelength was 254 nm, which was determined by continuous UV scanning. The mobile phase was pure methanol with a flow rate of 1.0 mL·min−1. Each analysis was carried out three times, and the average value of three measurements was regarded as the final value of the analysis.

Table 2. Solubility (x) of Benzoic Acid in 2-Propanol with the Relative Deviation at 278.06K, 288.15 K, 293.11 K, and 303.45 K under 101.2 kPaa T/K

m1/M1 m1/M1 + m2 /M 2

3. RESULTS AND DISCUSSION 3.1. Solubility Data. The determined solubilities (x) of 2amino-3-methylbenzoic acid in mole fraction in methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, acetonitrile, acetone, 2-butanone, ethyl acetate, 1,4-dioxane, toluene, and cyclohexane at the temperature range from 278.15 to 318.15 K are listed in Table 3 and shown graphically in Figure 1. In addition, the van’t Hoff plots of ln(x) versus 1/T in 12 solvents

a Standard uncertainties u are u(T) = 0.02 K and u(p) = 400 Pa. Relative standard uncertainty ur is ur(x) = 0.0149. xexp, experiment data; xref, taken from ref 11; RD is the relative deviations of experimental value with the reference data.

B



Article

Table 3. Experimental Mole Fraction Solubility (x) of 2-Amino-3-methylbenzoic Acid in Different Monosolvents at the Temperature Range from T = 278.15 to 318.15 K under 101.2 kPaa,b 100x T/K

xexp

xλh

xapelblat

xWilson

xNRTL

Methanol 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 100 RAD

1.997 2.349 2.733 3.173 3.675 4.234 4.835 5.501 6.239

1.995 2.344 2.739 3.181 3.676 4.225 4.833 5.504 6.239 0.12

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 100 RAD

1.762 2.084 2.442 2.856 3.326 3.847 4.439 5.089 5.818

1.762 2.081 2.445 2.858 3.324 3.848 4.435 5.090 5.818 0.06

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 100 RAD

1.512 1.784 2.122 2.512 2.933 3.441 3.997 4.603 5.323

1.504 1.793 2.126 2.506 2.940 3.433 3.990 4.616 5.319 0.27

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 100 RAD

0.8756 1.092 1.380 1.701 2.077 2.528 3.028 3.600 4.271

0.8725 1.102 1.375 1.699 2.079 2.521 3.029 3.609 4.266 0.27

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 100 RAD

1.172 1.436 1.756 2.116 2.541 3.019 3.566 4.221 4.982

1.181 1.441 1.749 2.109 2.529 3.017 3.581 4.230 4.972 0.35

278.15 283.15

6.464 7.212

6.491 7.181

2.004 2.348 2.736 3.173 3.664 4.214 4.826 5.508 6.265 0.23

1.998 2.345 2.738 3.179 3.672 4.222 4.831 5.505 6.246 0.13

1.997 2.345 2.738 3.18 3.674 4.223 4.832 5.504 6.243 0.12

1.763 2.082 2.445 2.857 3.322 3.846 4.433 5.091 5.824 0.08

1.753 2.076 2.444 2.860 3.330 3.856 4.444 5.099 5.824 0.21

1.760 2.081 2.446 2.860 3.327 3.850 4.436 5.089 5.813 0.09

1.504 1.793 2.126 2.507 2.941 3.433 3.989 4.615 5.319 0.28

1.501 1.793 2.127 2.510 2.945 3.437 3.991 4.613 5.308 0.30

1.503 1.793 2.127 2.508 2.943 3.435 3.990 4.614 5.312 0.29

0.8846 1.105 1.370 1.686 2.061 2.502 3.018 3.619 4.315 0.83

0.8892 1.107 1.369 1.682 2.054 2.494 3.013 3.621 4.331 1.09

0.9113 1.128 1.387 1.693 2.054 2.477 2.969 3.540 4.198 1.87

1.175 1.438 1.748 2.111 2.533 3.022 3.585 4.230 4.966 0.29

1.176 1.438 1.748 2.111 2.533 3.022 3.585 4.231 4.968 0.29

1.176 1.438 1.748 2.111 2.533 3.022 3.585 4.231 4.968 0.29

6.512 7.187

6.519 7.184

6.429 7.157

Ethanol

1-Propanol

2-Propanol

1-Butanol

2-Butanone

C



Article

Table 3. continued 100x T/K

xexp

xλh

xapelblat

xWilson

xNRTL

2-Butanone 288.15 293.15 298.15 303.15 308.15 313.15 318.15 100 RAD

7.924 8.723 9.532 10.41 11.39 12.38 13.43

7.920 8.707 9.545 10.44 11.38 12.38 13.43 0.17

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 100 RAD

7.453 8.286 9.183 10.10 11.05 12.06 13.17 14.29 15.44

7.463 8.287 9.162 10.09 11.06 12.09 13.16 14.28 15.45 0.11

288.15 293.15 298.15 303.15 308.15 313.15 318.15 100 RAD

10.76 11.68 12.67 13.69 14.77 15.87 17.06

10.76 11.69 12.66 13.69 14.76 15.88 17.05 0.04

7.912 8.690 9.523 10.41 11.37 12.39 13.48 0.26

7.902 8.677 9.511 10.41 11.37 12.41 13.52 0.36

7.927 8.738 9.589 10.48 11.41 12.38 13.39 0.36

7.517 8.302 9.143 10.04 11.01 12.04 13.14 14.31 15.55 0.41

7.494 8.293 9.146 10.06 11.02 12.05 13.15 14.31 15.54 0.30

7.460 8.288 9.164 10.09 11.06 12.09 13.16 14.28 15.45 0.11

10.78 11.69 12.65 13.67 14.74 15.88 17.09 0.16

10.78 11.68 12.64 13.66 14.74 15.89 17.10 0.17

10.73 11.69 12.68 13.72 14.78 15.88 17.02 0.15

Acetone

1,4-Dioxane

Acetonitrile 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 100 RAD

2.267 2.746 3.293 3.896 4.615 5.401 6.281 7.266 8.341

2.269 2.743 3.287 3.908 4.611 5.401 6.283 7.262 8.343 0.10

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 100 RAD

2.936 3.449 4.048 4.685 5.403 6.185 7.044 8.025 9.067

2.943 3.457 4.034 4.679 5.396 6.189 7.062 8.019 9.063 0.17

278.15 283.15 288.15 293.15 298.15 303.15 308.15

0.1104 0.1446 0.1843 0.2355 0.2983 0.3821 0.4904

0.1126 0.1437 0.1834 0.2342 0.2992 0.3822 0.4881

2.288 2.749 3.280 3.890 4.586 5.377 6.270 7.274 8.398 0.41

2.265 2.739 3.284 3.906 4.611 5.405 6.291 7.276 8.363 0.18

2.283 2.745 3.280 3.893 4.591 5.383 6.276 7.277 8.392 0.32

2.957 3.460 4.028 4.665 5.378 6.173 7.054 8.029 9.103 0.35

2.945 3.456 4.030 4.674 5.390 6.184 7.061 8.026 9.084 0.21

2.945 3.456 4.031 4.675 5.392 6.186 7.062 8.023 9.074 0.19

0.1074 0.1416 0.1849 0.2393 0.3070 0.3909 0.4939

0.1102 0.1428 0.1842 0.2363 0.3021 0.3849 0.4895

0.1132 0.1444 0.1838 0.2335 0.2967 0.3775 0.4824

Ethyl Acetate

Toluene

D



Article

Table 3. continued 100x xexp

xapelblat

313.15 318.15 100 RAD

0.6195 0.7973

0.6233 0.7957 0.58

283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 100 RAD

0.008891 0.01153 0.01533 0.02035 0.02704 0.03499 0.04535 0.05784

0.008618 0.01161 0.01550 0.02051 0.02691 0.03501 0.04520 0.05793 0.84

T/K

xλh

xWilson

xNRTL

0.6197 0.7724 1.76

0.6218 0.7901 0.59

0.6208 0.8090 0.99

0.008655 0.01166 0.01556 0.02057 0.02694 0.03500 0.04511 0.05771 0.94

0.008705 0.01168 0.01554 0.02050 0.02684 0.03491 0.04511 0.05796 0.90

0.008793 0.01177 0.01562 0.02054 0.02681 0.03474 0.04470 0.05717 1.27

Toluene

Cyclohexane

a

x denotes the experimental mole fraction solubility of 2-amino-3-methylbenzoic acid at the studied temperature T; RAD denotes the relative average deviation, respectively. bStandard uncertainties u are u(T) = 0.02 K and u(p) = 400 Pa. Relative standard uncertainty ur(x) = u(x)/x,

(

1/2

)

∑i = 1 (xi − x ̅ )2 , ur(x) = 0.025. xexp, experiment data; xapelblat, calculated by the Apelblat model; xλh, calculated by the λh model; xWilson, calculated by the Wilson model; xNRTL, calculated by the NRTL model.

U (x) =

1 n(n − 1)

n

mole fraction solubility of 2-amino-3-methylbenzoic acid in different solvents from high to low is 1,4-dioxane (12.67 × 10−2, 298.15 K) > acetone (11.05 × 10−2, 298.15 K) > 2butanone (9.532 × 10−2, 298.15 K) > ethyl acetate (5.403 × 10−2, 298.15 K) > acetonitrile (4.615 × 10−2, 298.15 K) > methanol (3.675 × 10−2, 298.15 K) > ethanol (3.326 × 10−2, 298.15 K) > 1-propanol (2.933 × 10−2, 298.15 K) > 1-butanol (2.541 × 10−2, 298.15 K) > 2-propanol (2.077 × 10−2, 298.15 K) > toluene (2.983 × 10−3, 298.15 K) > cyclohexane (2.035 × 10−4, 298.15 K). Table 4 presents some properties of the studied solvents, which correspond to polarities and dielectric constants (ε). It

Figure 1. Solubility (x) of 2-amino-3-methylbenzoic acid in mole fraction in monosolvents: (a) ■, 1,4-dioxane; ●, acetone; ▲, 2butanone; ▼, ethyl acetate; ◇, acetonitrile; △, 2-propanol; (b) ◀, methanol; ◆, ethanol; ▶, 1-propanol; ★, 1-butanol; □, toluene; ○, cyclohexane. Calculated curves by the modified Apelblat equation.

Table 4. Physical Properties for the Selected Solventsa

are plotted in Figure 2. From Figure 1, it can be seen that the solubility of 2-amino-3-methylbenzoic acid increases with increasing temperature at a certain solvent. At a certain temperature, the mole fraction solubility of 2-amino-3methylbenzoic acid in 1,4-dioxane (12.67 × 10−2, 298.15 K) is the largest and in cyclohexane (2.035 × 10−4, 298.15 K) is the lowest. Figure 1 further illustrates that the order of the

solvent

polarity (water 100)

α

β

π*

δ2/1000 (J/cm3)

methanol ethanol 1-propanol 2-propanol 1-butanol acetonitrile acetone 2-butanone ethyl acetate 1,4-dioxane toluene cyclohexane

76.2 65.4 61.7 54.6 60.2 46.0 35.5 32.7 23.0 16.4 9.9 0.6

0.98 0.86 0.84 0.76 0.84 0.19 0.08 0.06 0 0 0 0

0.66 0.75 0.9 0.84 0.84 0.40 0.43 0.48 0.45 0.37 0.11 0

0.60 0.54 0.52 0.48 0.47 0.75 0.71 0.67 0.55 0.55 0.54 0

0.8797 0.5630 0.6025 0.5630 0.5333 0.5806 0.3994 0.3648 0.331 0.4194 0.3334 0.02813

a

Taken from refs 12 and 16−18.

can be found from Figure 1 and Tables 2 and 3 that, for polar protic solvents (methanol, ethanol, 1-propanol, 2-propanol, and 1-butanol), the sequence of the mole fraction solubility is in accordance with the polarities and dielectric constants (ε). The solubility values in alcohol ranked as methanol > ethanol > 1-propanol > 2-propanol > 1-butanol, and for other aprotic solvents (1,4-dioxane, toluene, cyclohexane, 2-butanol, ethyl acetate, acetonitrile, and acetone), the order of them in high to low is in accordance with the polarities and dielectric constants

Figure 2. van’t Hoff plots of ln(x) versus 1/T in different solvents: ■, 1,4-dioxane; ●, acetone; ▲, 2-butanone; ▼, ethyl acetate; ◇, acetonitrile; △, 2-propanol; ◀, methanol; ◆, ethanol; ▶, 1propanol; ★, 1-butanol; □, toluene; ○, cyclohexane. E



Article 2

(ε) except for 1,4-dioxane and acetonitrile. The polarities and dielectric constants of solvents seem to be a significant factor to affect the solubility of 2-amino-3-methylbenzoic acid in solvents, but the polarities of solvents is not the only factor to determine the solubility of 2-amino-3-methylbenzoic acid in solvents. The 1,4-dioxane molecule has a ring structure, and the 2-amino-3-methylbenzoic acid molecule also has a ring structure. Based on the principle that similar structures are more likely to be dissolved by each other, the structure similarity between 2-amino-3-methylbenzoic acid and 1,4dioxane due to ring structure enhances the solubility; thus, the solubility of 2-amino-3-methylbenzoic acid in 1,4-dioxane is highest (12.67 × 10−2, 298.15 K). On the other hand, the polarity of 2-amino-3-methylbenzoic acid molecule is much stronger than that of the cyclohexane molecule. In all solvents, the polarity of cyclohexane is the weakest. As a result, the solubility of 2-amino-3-methylbenzoic acid in cyclohexane (2.035 × 10−4, 298.15 K) is the lowest. 3.2. Solvent Effect. In order to study the effect of solvation interaction on solubility, a multiple linear regression analysis (MLRA) involving various solvent parameters has been sought. Generally, several independent modes of solute− solvent interaction have been proposed. It is customary to describe any property linearly related to the Gibbs energy (XYZ) of a solute−solvent system in terms of LSER by the following equation.13,14

tion. Otherwise, the coefficient of α and Vsδ H is negative, 100RT which indicates that HBD interaction of the solvent with the solute and the cavity term, accounted for by the Hildebrand solubility parameter, is unfavorable. Moreover, the magnitude of the coefficient of α is relatively small compared to those of β and π*; therefore, solubility of the solute is less sensitive to a variation of α. We have tried the 2

MLRA of ln x with β and π* and Vsδ H . The result is hardly 100RT affected if α is not used in the correlation equation. Thus ln(x) = −8.329 + 2.138β + 8.320π* − 4.179

(5) 2

where n = 10, R = 0.945, RSS = 1.03, and F = 52.99 In this respect, the thermodynamic property, ln(x), differs from the spectroscopic parameter; viz.,16 the negative sign of 2

the coefficient of Vsδ H indicates the solubility decreases as the 100RT self-cohesiveness (or structuredness) of the solvent increases. Thus, an increase in the solvent−solvent interaction inducing self-cohesiveness has an unfavorable influence on the solubility of the solute. 3.3. Solubility Correlation and Calculation. The solubility behavior for 2-amino-3-methylbenzoic acid in monosolvents was correlated to the λh equation,19 modified Apelblat equation,20 Wilson model,21 and NRTL model.22 λh Equation. This model is a semiempirical model proposed by Buchowski.19 This equation is expressed as eq 6. ÄÅ É ij 1 ÅÅ λ(1 − x) ÑÑÑÑ 1 yzz lnÅÅÅ1 + − Ñ = λhjjj z Ñ j T /K ÅÅÇ ÑÑÖ x Tm/K zz{ (6) k

XYZ = XYZ0 + cavity formation energy + Σsolvent− solute interaction energy

(2)

The term XYZ0 depends only on the solute. The summation in the above equation extends over all the modes of solute− solvent interaction. The Kamlet and Taft linear solvation energy relationship model, KAT-LSER, has been developed to relate the Gibbs free energy change of solvent dependent reactions, which described as eq 3.15 ln(x) = c0 + c1α + c 2β + c3π * + c4

Vsδ H2 100RT

In eq 6, x is the solubility in mole fraction. λ and h are two adjustable parameters in the λh equation, and Tm denotes the melting temperature of 2-amino-3-methylbenzoic acid in Kelvin. Modified Apelblat Equation. The modified Apelblat equation is also a semiempirical model,20 which is described as eq 7.

(3)

In this equation, α, β, and π* represent the hydrogen bond acidity, hydrogen bond basicity, and dipolarity/polarizability of the solvent, respectively. The variable δH stands for Hildebrand solubility parameter of the solute, and Vs is molar volume of solute. The solubility of 2-amino-3-methylbenzoic acid in monosolvents was examined by the KAT-LSER model at 298.15 K. Table 3 lists α, β, π*, and δ2H values for these monosolvents, which are taken from the literature.16−18 After screening and comparing one by one, it was found that the MLRA of ln(x) with the exception of 1,4-dioxane and toluene was the best. The results are described as eq 4.

ln x = A + B /(T /K) + C ln(T /K)

Vsδ H2 100RT

(7)

where x is also the solubility in mole fraction, and A, B, and C are adjustable equation parameters. Wilson Model. This model applies to the solid−liquid equilibrium system at a certain temperature and pressure, which is described as23 ln(x·γ ) =

ln(x) = −8.367 − 0.683α + 2.671β + 7.530π * − 2.207

Vsδ H2 100RT

ΔHtp ijj 1 Ttp y 1 zy ΔCp ijj Ttp jj − zzzz − − + 1zzzz jjln j R j Ttp Tz R k T T { k { ΔV (p − ptp ) − (8) RT

Here, γ donates the solute activity coefficient, and R is the universal gas constant, which is 8.314 J·K−1·mol−1. ΔV and ΔCp represent the difference of volume and heat capacity of solute between in solid phase and in liquid phase, respectively. The ΔCp in eq 8 may be neglected because of its minor importance.24 For lots of substances, the triple point temperature Ttp and corresponding enthalpy ΔHtp are hard to obtain. Therefore, the Ttp is approximately equal to the

(4)

where n = 10, R2 = 0.936, RSS = 1.01, and F = 34.03. From eq 4, the regression coefficients of β and π* were positive, which indicates that solubility increases with an increase in the value of the two parameters. Therefore, HBA interaction of the solvent with the solute and nonspecific dipolarity/polarizability interactions are favorable to dissoluF



Article

melting temperature Tm. As a result, the simplified equation can be described as eq 9.23 Δ H ij 1 1 yzz ln(xi·γi) = fus jjj − z R jk Tm/K T /K zz{

N

RMSD =

Λ 21 =

V2 i λ − λ11 yz V2 i Δλ y zz = expjjj− 12 expjjj− 12 zzz V1 RT { V1 k k RT {

V1 i λ − λ11 zy V2 i Δλ y zz = expjjj− 21 expjjj− 21 zzz V2 RT V k { k RT { 1

(10)

(11)

(12)

In eqs 10−12, x1 and x2 donate solute and solvent in mole fraction in the equilibrium liquid phase. V1 and V2 represent the molar volume of solute and solvent, respectively. Parameters Δλij are (J·mol−1) related to interaction energy between the components i and j. The parameters are independent of temperature and composition. The values of Δλij can be obtained by regressing from the experimental data. NRTL Model. This model is proposed based on the molecular local composition concept.22 The activity coefficient is given as eqs 13−16. ÅÄ ÑÉ N N N ∑ j = 1 τjiGjixj ∑i = 1 xiτijGij ÑÑÑÑ xjGij ÅÅÅÅ ln γi = +∑ N ÅÅÅτij − ÑÑ N N Å ∑i = 1 Gijxi ∑i = 1 Gijxi ÑÑÑÑ j = 1 ∑i = 1 Gijxi Å ÅÇ Ö (13)

Gji = exp( −αjiτji)

(14)

αij = αji = α

(15)

τij =

gij − gjj RT

=

AIC = −2 ln L(θ ) + 2k

(16)

where Δgij are adjustable model parameters related to interaction energy, and they can be deemed to a constant. The adjustable parameter α is related to the nonrandomness of a solution, and the range of the parameter is usually from 0.20 to 0.47. The experimental solubility of 2-amino-3-methylbenzoic acid in the selected pure solvents is correlated and calculated by using the method of nonlinear regression.25 During the regression process, the objective function is defined as F=

∑ (ln xie − ln xic)2 i=1

AIC = N ln(RSS/N ) + 2k

1 N

i |xic − xie| yz zz zz e k xi {

∑ jjjjj N

i=1

(20)

(21)

with N

RSS =

∑ (xie − xic)2 i=1

(22)

Here N is the number of observations; RSS is the residual sum of squares; and xe and xc are the experimental and calculated solubility data of 2-amino-3-methylbenzoic acid. Table 6 listed the calculated results of AIC for four models. It can be seen that, in the systems of 2-amino-3-methylbenzoic acid + solvents, the Apelblat equation is the best correlating model because the value of AIC of the Apelblat equation is lowest. 3.5. Thermodynamic Analysis. According to the Lewis− Randall rule, the mixing properties of solution can be computed. For an ideal solution, the mixing Gibbs energy, mixing enthalpy, and mixing entropy in monosolvents are expressed as28

(17)

Here ln xei and ln xci donate the logarithm of experimental solubility data and logarithm of calculated data using the model in mole fraction, respectively. In addition, relative average deviation and (RAD) and rootmean-square deviation (RMSD) are used in this work to evaluate the selected solubility models. RAD =

(19)

Here L(θ) is the maximized likelihood value for the estimated model, and k is the number of estimable parameters in the model. In the special case of least-squares estimation with normal distributed errors, apart from an additive constant, AIC can be simplified to

Δgij RT

N

Here N is the number of experimental data points, and xci and xei represent the calculated solubility values and experimental data of 2-amino-3-methylbenzoic acid, respectively. In this work, the Mathcad software was used to correlate the solubility data with models. The parameters and values were regressed and calculated by the Mathcad program. During the process of regression, the densities of the solvents presented in Table 1 are taken from ref 12. The density of 2-amino-3methylbenzoic acid is calculated with the Advanced Chemistry Development (ACD/Laboratories) Software V11.02 (1994− 2016 ACD/Laboratories), and the melting temperature (Tm) and melting enthalpy (ΔfusH) of 2-amino-3-methylbenzoic acid are taken from ref 26. The model parameters, along with the RMSD values, are presented in Table 5. What’s more, in order to demonstrate the difference between the experimental solubility and the calculated ones, the computed solubility of 2-amino-3-methylbenzoic acid with four models along with calculated RAD values are presented in Table 3. Moreover, in Table 5, the RMSD values are no more than 4.51 × 10−4. The RAD values are all less than 1.87%. Figure 3 highlights the fit quality of four models by comparing the calculated values (yaxis) and the measured values (x-axis) for 2-amino-3methylbenzoic acid in the analyzed solvents. In a word, the thermodynamic models can all be employed to correlate the solubility of 2-amino-3-methylbenzoic acid in the monosolvents. 3.4. Akaike Information Criterion of Four Models. The Akaike Information Criterion (AIC)27 was used to compare the relative applicability of these models. Generally, the model with the lowest value of AIC can be supposed to be the best-fit model. The value of AIC for the four models is given as follows

(9)

The activity coefficients ln γ are presented as eqs 10−12.21 ÄÅ ÉÑ ÅÅ ÑÑ Λ12 Λ 21 Å ÑÑ ln γ1 = −ln(x1 + Λ12x 2) + x 2ÅÅÅ − Ñ ÅÅÇ x1 + Λ12x 2 x 2 + Λ 21x1 ÑÑÑÖ

Λ12 =

∑i = 1 (xic − xie)2

(18) G


0.32 0.83 2.32 2.13 4.07 0.97 1.07 4.51 0.52 0.52 0.038 1.40 0.20 0.20 0.20 0.20 0.20 0.20 0.30 0.20 0.47 0.25 0.47 0.20 −635.50 −577.02 −1024.6 −544.97 −878.65 −319.38 −611.39 95.87 1410.70 −555.25 1556.09 −1027.55 0.68 0.92 2.53 1.04 4.08 0.96 1.21 2.75 0.31 0.59 0.017 4.17 65536.9 12392.1 −2680.8 −607.94 −2864.61 2557.81 −2035.82 −717.60 −1516.35 16981.9 918.11 −2042.41 −4985.80 −4036.49 −455.72 924.23 1724.69 −1996.44 1588.60 2321.68 8055.25 −6120.97 11207.1 −613.40

1285.8 1091.96 2794.84 499.01 3018.96 424.31 1069.83 −29.22 −384.11 1466.04 −96.68 2246.43

α λ21 10 RMSD

g21

Figure 3. Calculated solubility values using four equations as a function of the corresponding experimental solubility values for 2amino-3-methylbenzoic acid in the analyzed solvents.

Table 6. Value of the Akaike Information Criterion of the Modified Apelblat Equation, λh Equation, Wilson Model, and NRTL Model in the Selected Solvents

0.34 0.79 2.29 2.38 2.79 0.98 1.97 2.08 0.95 1.24 0.018 5.28 4434.64 4409.79 3026.72 2453.91 3482.62 3599.49 2945.40 3355.82 11041.0 4454.74 103448 2883.43

Apelblat equation λh equation Wilson model NRTL model

0.5819 0.6223 0.3807 1.1806 0.4053 0.8826 0.8357 1.0457 0.3933 0.5492 0.0470 0.5031

10 RMSD

0.22 0.79 0.73 0.51 1.80 0.91 0.94 0.56 0.19 0.49 0.015 1.43 −2318.19 −2327.99 −1209.63 −4765.62 −1306.17 −2491.21 −3291.93 −6368.72 4422.49 −2891.56 −4154.21 −2339.57

8.487 5.210 4.940 4.560

× × × ×

−7

10 10−6 10−6 10−6

N

parameters

AIC

105 105 105 105

3 2 2 2

−1950.52 −1762.00 −1767.66 −1776.06

Δmix Gid = RT (x1 ln x1 + x 2 ln x 2)

(23)

Δmix S id = −R(x1 ln x1 + x 2 ln x 2)

(24)

Δmix H id = 0

(25)

Δmix M = ME + Δmix M id

(26)

M = G , H , and S

(27)

for E

Here M stands for the excess property in real solutions. ΔmixH, ΔmixG, and ΔmixS represent the mixing enthalpy, mixing Gibbs energy, and mixing entropy, respectively. The superscript id denotes the ideal state. The mixing properties can be computed by eqs 28−30.29 GE = RT(x1 ln γ1 + x 2 ln γ2) =−RT[x1 ln(x1 + x 2 Λ12) + x 2 ln(x 2 + x1Λ 21)] (28) ÄÅ É Å ∂(GE /T ) ÑÑÑ E 2Å Å ÑÑ=x x ijjj Δλ12 Λ12 + Δλ 21Λ 21 yzzz H = −T ÅÅÅ Ñ ÅÅÇ ∂T ÑÑÑÖ 1 2jjk x1 + Λ12x 2 x 2 + Λ 21x1 zz{

ethanol 1-propanol 1,4-dioxane acetonitrile 2-butanone 1-butanol ethyl acetate 2-propanol toluene methanol cyclohexane acetone

−1.857 −4.655 −1.743 49.04 −3.759 −8.542 23.52 72.26 −188.32 13.46 −8.800 19.65

RSS

Here x1 and x2 represent the mole fraction of solute and solvent, respectively. The three mixing properties in real solution could be computed by the following equations.

1.093 1.569 0.655 −6.342 1.016 2.320 −2.703 −9.612 29.43 −1.240 2.499 −2.458

λ 10 RMSD

C B A solvent

Article

models

h

Wilson model

4

λh equation

4

Modified Apelblat equation

Table 5. Parameters of the Equations and RMSD Values for 2-Amino-3-methylbenzoic Acid in Different Monosolvents

4

g12

λ12

NRTL model

104 RMSD


(29) H



Article

Table 7. Calculated Values for ΔmixG, ΔmixH, ΔmixS, ln γ∞ 1 , and

a HE,∞ 1

ΔmixG

ΔmixH

ΔmixS

T/K

J·mol−1

J·mol−1

J· K−1·mol−1

ln γ∞ 1

kJ·mol−1

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−252.2 −290.3 −330.72 −375.5 −424.8 −477.8 −532.9 −591.6 −654.0

−121.1 −142.2 −165.1 −191.2 −220.9 −253.9 −288.7 −327.2 −369.5

0.472 0.523 0.575 0.629 0.684 0.739 0.792 0.844 0.894

−0.564 −0.517 −0.473 −0.429 −0.388 −0.347 −0.308 −0.271 −0.234

−6.065

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−222.3 −257.5 −295.4 −337.9 −384.6 −434.7 −489.5 −547.4 −609.9

−87.47 −103.4 −120.9 −141.3 −164.3 −189.6 −218.3 −249.7 −284.6

0.485 0.544 0.605 0.671 0.739 0.808 0.880 0.951 1.023

−0.431 −0.393 −0.356 −0.320 −0.286 −0.253 −0.221 −0.190 −0.160

−4.985

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−190.7 −220.8 −256.8 −297.1 −339.4 −388.5 −440.4 −495.2 −557.4

−59.34 −69.78 −82.69 −97.48 −113.3 −132.3 −152.8 −174.9 −200.9

0.472 0.533 0.604 0.681 0.758 0.845 0.933 1.023 1.121

−0.273 −0.243 −0.214 −0.186 −0.159 −0.133 −0.108 −0.084 −0.061

−3.904

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−110.6 −135.0 −166.1 −199.9 −238.3 −282.9 −330.9 −384.2 −444.5

6.012 7.461 9.330 11.36 13.65 16.26 19.04 22.03 25.29

0.419 0.503 0.609 0.721 0.845 0.987 1.136 1.297 1.477

0.282 0.277 0.271 0.266 0.260 0.255 0.250 0.245 0.240

0.778

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−147.4 −176.8 −211.4 −249.3 −292.7 −340.2 −392.9 −453.7 −521.7

−7.214 −8.472 −9.946 −11.52 −13.32 −15.26 −17.40 −19.94 −22.82

0.504 0.595 0.699 0.811 0.937 1.072 1.219 1.385 1.568

0.009 0.013 0.017 0.021 0.024 0.027 0.030 0.033 0.035

−0.482

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15

−870.6 −951.1 −1026.1 −1107.4 −1187.7 −1272.0 −1362.4 −1451.0

1.133 1.278 1.418 1.570 1.723 1.883 2.056 2.226

−2.585 −2.498 −2.417 −2.339 −2.267 −2.198 −2.133 −2.071

HE,∞ 1

Methanol

Ethanol

1-Propanol

2-Propanol

1-Butanol

2-Butanone −555.5 −589.2 −617.4 −647.1 −674.0 −701.1 −728.9 −753.9 I

−10.52



Article

Table 7. continued T/K

ΔmixG

ΔmixH

ΔmixS

J·mol−1

J·mol−1

J· K−1·mol−1

ln γ∞ 1

−1541.7

−777.7

2.401

−2.012

1.817 1.986 2.163 2.339 2.515 2.696 2.886 3.071 3.253

−2.717 −2.652 −2.589 −2.530 −2.473 −2.419 −2.367 −2.317 −2.270

−8.225

0.966 1.126 1.300 1.482 1.689 1.903 2.131 2.372 2.620

−0.743 −0.736 −0.730 −0.723 −0.718 −0.712 −0.707 −0.701 −0.696

−0.860

0.918 1.045 1.188 1.333 1.491 1.656 1.829 2.017 2.209

−1.075 −1.041 −1.010 −0.979 −0.951 −0.924 −0.898 −0.874 −0.850

−4.128

0.067 0.085 0.104 0.129 0.157 0.192 0.236 0.285 0.348

2.419 2.382 2.347 2.313 2.279 2.247 2.215 2.184 2.154

4.870

0.008 0.010 0.012 0.016 0.020 0.026 0.032 0.040

5.114 5.027 4.942 4.860 4.781 4.704 4.630 4.558

11.90

1.990 2.161 2.338 2.515 2.696 2.875 3.060

−3.174 −3.089 −3.008 −2.931 −2.858 −2.789 −2.722

−11.48

HE,∞ 1 kJ·mol−1

2-Butanone 318.15

Acetone 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−1002.1 −1094.2 −1190.3 −1285.8 −1381.9 −1480.8 −1585.0 −1686.9 −1788.1

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−287.5 −341.2 −400.7 −464.8 −538.4 −616.7 −701.4 −792.9 −889.4

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−374.7 −431.4 −495.5 −561.9 −634.3 −710.9 −792.2 −881.5 −973.1

−496.8 −531.8 −566.9 −600.1 −632.0 −663.5 −695.7 −725.3 −753.0 Acetonitrile −18.84 −22.34 −26.19 −30.26 −34.91 −39.75 −44.89 −50.31 −55.85 Ethyl Acetate −119.5 −135.5 −153.3 −171.0 −189.8 −209.0 −228.7 −249.7 −270.3 Toluene

278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−13.85 −17.70 −22.09 −27.56 −34.09 −42.47 −52.89 −64.94 −80.75

4.877 6.345 8.023 10.13 12.65 15.86 19.79 24.22 29.81 Cyclohexane

283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15

−1.094 −1.396 −1.815 −2.351 −3.040 −3.840 −4.847 −6.029

1.047 1.355 1.797 2.378 3.147 4.054 5.225 6.623 1,4-Dioxane

288.15 293.15 298.15 303.15 308.15 313.15 318.15

−1437.1 −1531.3 −1629.0 −1726.5 −1825.9 −1923.8 −2025.1

−863.6 −897.8 −931.9 −963.9 −995.0 −1023.5 −1051.7 J



Article

Table 7. continued a ΔmixG, ΔmixS, and ΔmixS denote the mixing Gibbs free energy, mixing enthalpy, and mixing entropy, respectively. γ∞ 1 denotes the infinitesimal denotes infinitesimal concentration-reduced excess enthalpy. concentration activity coefficient, and HE,∞ 1

HE − GE (30) T The Wilson model can be used to compute the activity coefficient (γ∞ 1 ) at infinitesimal concentration and reduced 30,31 excess enthalpy (HE,∞ 1 ).

values is the Apelblat equation. Moreover, the mixing Gibbs energy, mixing enthalpy, mixing entropy, reduced excess enthalpy (H1E,∞), and activity coefficient at infinitesimal concentration (γ∞ 1 ) in the monosolvents were computed. Finally, it can be concluded that the results in this research could provide guidance for industrial design and operation of crystallization processes of 2-amino-3-methylbenzoic acid.

SE =

ln γ1∞ = −ln Λ12 + 1 − Λ 21 ÄÅ É ÅÅ ∂ ln γ ∞ ÑÑÑ E, ∞ 1 Å ÑÑ H1 = RÅÅÅ Ñ ÅÅÇ ∂(1/T ) ÑÑÑÖ P ,x

■

(31)

AUTHOR INFORMATION

Corresponding Authors (32)

*Tel.: +86 517 83525085. E-mail: [email protected]. *Tel.: +86 517 83559061. E-mail: [email protected].

According to the experimental data and the values of parameters in Wilson mode, the ΔmixG, ΔmixH, ΔmixS, ln γ∞ 1 , and HE,∞ are computed and listed in Table 7. From Table 7 1 and Figure 4, we can see that the ΔmixG values are all negative.

ORCID

Anfeng Zhu: 0000-0002-8915-2216 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS The project was supported by “Six Talent Peak” high-level talents of Jiangsu Province (No. 2018XNY-004).

■

REFERENCES

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Figure 4. Calculated mixing Gibbs energy at measured solubility points based on the Wilson model: ■, 1,4-dioxane; ●, acetone; ▲, 2butanone; ▼, ethyl acetate; ◇, acetonitrile; △, 2-propanol; ◀, methanol; ◆, ethanol; ▶, 1-propanol; ★, 1-butanol; □, toluene; ○, cyclohexane.

The values decrease with the increase in temperature; besides, all the ΔmixS values are positive, and the lowest Gibbs free energy is acquired for the 1,4-dioxane system. So, the dissolution process of 2-amino-3-methylbenzoic acid is spontaneous and favorable in the selected monosolvents.

4. CONCLUSIONS In this work, the solubility data of 2-amino-3-methylbenzoic acid in 12 pure solvents were determined experimentally. It increased with increasing temperature, and at a given temperature, it ranked as 1,4-dioxane > acetone > 2-butanone > ethyl acetate > acetonitrile > methanol > ethanol > 1propanol > 1-butanol > 2-propanol > toluene > cyclohexane. The experiment solubility values were correlated by the modified Apelblat equation, λh equation, Wilson model and NRTL model. The root-mean-square deviation (RMSD) and relative average deviation (RAD) values did not exceed 4.51 × 10−4 and 1.87%, respectively. In addition, solute−solvent and solvent−solvent interactions were discussed, from solvent effect, HBA interaction of the solvent with the solute, and nonspecific dipolarity/polarizability interactions in favor of the increase of solubility. Otherwise, the cavity term, accounted for by the Hildebrand solubility parameter, is unfavorable. According to the results of Akaike Information Criterion (AIC), the best model to correlate the experiment solubility K



Article

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Solubility, Model Correlation, and Solvent Effect of 2-Amino-3

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