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pKa Determination of Newly Synthesized N‑(benzothiazole-2-yl)-2(4,5-dimethyl-1-(phenylamino)-1H-imidazol-2-ylthio)acetamide Derivatives Murat Duran* and Mehmet Ç etin Canbaz Eskişehir Osmangazi University, Faculty of Science and Letters, Chemistry Department, 26480, Eskişehir, Turkey S Supporting Information *

ABSTRACT: In this work, nine drug precursors, 2-(4,5-dimethyl-1-(phenylamino)-1H-imidazol-2-ylthio)-N-(benzothiazole-2yl) acetamide derivative compounds, were newly synthesized by reacting 4,5-dimethyl-1-(phenylamino)-1H-imidazole-2(3H)thione derivatives with 2-chloro-N-(thiazol-2-yl) acetamide compounds. Structures of the synthesized compounds were confirmed by 1H NMR, FTIR (Fourier transform infrared), MS (mass spectroscopy), and elemental analysis. The acidity constants of these acetamide derivatives were determined via UV spectroscopic studies. It was found that the first protonation of these compounds occurs on the nitrogen at imidazole ring, while the second protonation of these compounds occurs on the nitrogen at benzothiazole ring. The first pKa values were found to vary between 5.91 and 8.34 while the second pKa values were varying between 3.02 and 4.72. (e.g., less than 2 or higher than 11).34 Samples, however, must possess chromophore(s) close to ionizable groups in a way that the neutral and ionized forms have different absorption spectra. The largest change in absorbance occurs at the pH corresponding to the pKa value. This work is an extension of our previous study relating to synthesis and evaluation of anticancer activities of N-(6substituted benzothiazol-2-yl)-2-(4,5-dimethyl-1-(4-substituted phenylamino)-1H-imidazol-2-ylthio)acetamide derivatives.35 The objective of this study is to synthesize similar new compounds (N-(6-substituted benzothiazol-2-yl)-2-(4,5-dimethyl-1-(4-substituted phenylamino)-1H-imidazol-2-ylthio)acetamide derivatives) and determine the pKa values of the compounds via UV−vis spectrophotometric method.

1. INTRODUCTION Heterocyclic compounds are rich sources of diverse physical, chemical, and biological properties.1,2 They are commonly used as templates to design biologically active agents in medicinal chemistry.1 Heterocycles containing the thiazole ring system exhibit a wide spectrum of biological activities. In addition to acting as antiviral and antifungal agents, these systems have been identified as a central structural element of a number of biologically active neutral products and pharmacologically active compounds.3−10 Imidazole and its derivatives form a variety of nucleophilic and general base catalysts.11 The imidazole ring is a model molecule for more complex systems and belongs to a specific area in biology, where it is involved in nucleic acids and amino acids. Many of them exhibit a wide spectrum of biological activities.12−20 The acid−base dissociation constant (pKa) of a solid drug is a vital thermodynamic parameter in the design of drug compounds as well as in the development and optimization of drug manufacturing process due to the understanding of certain chemical phenomena such as biological uptake, activity, transport, and the prediction of migration of these solutes.21−29 Therefore, development of new compounds requires accurate determination of pKa values. In pKa determination, potentiometric titration and UV−vis spectrophotometric method30 can be used. Potentiometric titration requires large volumes and a time-consuming process for the preparation of carbonate free solution. On the other hand, the UV-spectrophotometric method can be considered as a more suitable method because of the requirement of small amounts of matter and the obtainment of more accurate results.31 For the determination of acidity constant values, spectrophotometric method is commonly applied, and this method is based on the measurement of the ratio of neutral/ protonated forms of the compounds.32,33 Spectrometry is an ideal method when a substance is not enough soluble for potentiometry or when its pKa value is particularly low or high © XXXX American Chemical Society

2. EXPERIMENTAL SECTION 2.1. Synthesis and Characterization. Preparation of N(6-substituted benzothiazol-2-yl)-2-(4,5-dimethyl-1-(4-substituted phenylamino)-1H-imidazol-2-ylthio)acetamide (abbreviated as IBA) derivatives (1−9) was achieved by the sequence of reactions depicted in Figure 1. Starting materials were commercially available or synthesized according to the indicated literature methods.36−38 For the synthesis of target derivatives, 4-substituted aniline derivatives were reacted with ammoniumthiocynate in the presence of bromine and 2aminobenzothiazole derivatives (1a−c) were obtained. Afterward, 2-aminobenzothiazole derivatives (1a-c) were reacted with chloroacetylchloride, and 2a−c compounds were obtained. Treatment of 2-chlorobutanone with 4-substituted phenylhydrazines in the presence of sodium thiocynate yielded the Received: January 28, 2013 Revised: May 12, 2013 Accepted: June 3, 2013

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dx.doi.org/10.1021/ie400316r | Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX

Industrial & Engineering Chemistry Research

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Figure 1. Synthesis routes of compounds 1−9.

controlled UNICAM UV/vis UV2 double beam spectrophotometer equipped with a 1 cm path length quartz cell. Spectrophotometric Measurements. Stock solution of each IBA derivative (10−3 M) was prepared with 1:1 (v/v) ethanol/ water mixture. Afterward, sample solutions were prepared with addition of 0.5 mL stock solution to a series of 9.5 mL buffer solutions (0.05−0.2 M) in volumetric flasks of 10 mL. UV−vis spectra of the sample solutions were taken, and it was seen that they give suitable absorbance values between 0.5 and 1. All series of the sample solutions were taken into UV cells, hermetically closed, and thermostatted at 25 °C for 15 min. Then, UV−vis spectra of all compounds were recorded on spectrophotometer within the range from approximately 200 to 400 nm. Simultaneously, the corresponding absorbance values were measured at the optimum wavelength. This process was followed for the each of nine molecules (1−9).

imidazolene-2-thione derivatives (3a−c). Finally, the following reaction of the 2a−c series with the 3a−c compounds gave the 1−9 derivatives.39 See the Supporting Information for characterizations of synthesized compounds. After the synthesis of these compounds, they were recrystallized from the ethanol to determine their acidity constants. Melting points (°C, uncorrected) of the synthesized compounds were determined by using an electrothermal melting point apparatus. 1H NMR spectra were recorded with a Bruker DPX-400, 400.13 MHz high performance digital FTNMR spectrometer, in DMSO-d6 (dimethylsulfoxide) solvent including TMS (tetramethylsilane) as an internal standard. IR spectra were obtained in KBr pressed pellets via a Bruker Tensor 27 FT-IR (Fourier transform infrared) spectrometer. Mass spectra (FAB) were obtained on a VG Quattro mass spectrometer. Elemental analyses were performed on a PerkinElmer EAL 240 elemental analyzer. The compounds were checked for purity by TLC (thin layer chromatography) on silica gel 60 F254. 2.2. Procedure of Spectrophotometric pKa Measurements. Materials and Solutions. The employed buffer solutions were prepared for the pH region from (a) 0.1 M HCl−0.1 M KCl, pH = 1−2.2; (b) 0.2 M citric acid monohydrate−0.1 M NaOH, pH = 2.0−5.0; (c) 0.07 M KH2PO4−0.1 M NaOH, pH = 5.8−8.0; (d) 0.05 M borax−0.1 M HCl, pH = 8.0−9.0; (e) 0.05 M borax−0.1 M NaOH, pH = 9.3−10.7 and for full acid region from H2SO4 1−98%.40 All these materials and buffer solutions were from Merck or SigmaAldrich, and they were used as received, without further purification. Equipment. The pH values were measured by Mettler Toledo MP220 pH meter, which is furnished with a combined glass electrode, and it was calibrated at 25 °C by using standard buffers of pH 4.01, 7.00, and 9.21. In order to determine absorptiometric pKa values, UV−vis spectra of the investigated compounds were recorded at each pH using a computer

3. RESULTS AND DISCUSSION 3.1. Synthesis of Acetamide Derivatives. Synthesis Procedure of Compounds 1a−c, 2a−c and 3a−c. To synthesize the required 2-aminobenzothiazole derivatives, ammonium thiocyanate (6 mmol) was added to a solution of the related 4-aniline derivatives (3 mmol) in glacial acetic acid (50 mL). A solution of bromine (6 mmol) in acetic acid (10 mL) was added to this mixture dropwise, and the temperature was kept below 30 °C in a water bath. After the addition was complete, the reaction mixture was stirred at room temperature for 12 h. Then, the reaction mixture was poured into water, neutralized with NaHCO3, dried, and recrystallized from ethanol (1a−c). 2-Aminobenzothiazole derivatives (1a−c) (40 mmol) were dissolved in 150 mL THF (Tetrahydrofuran) and added to triethylamine (5.6 mL) in a 250 mL round-bottom flask. A dropping funnel was fitted to the flask, and 4.2 mL solution of chloroacetylchloride in THF was taken to the dropping funnel and added dropwise to the mixture. The solution was stirred at room temperature for 6 h. After the formed precipitate was B



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Figure 3. pH−εmax (at 221 nm) (a) and log I−pH (b) plots of the compound 1.

Figure 2. Absorption−wavelength spectra of compound 4: (a) recorded in 50% H2SO4 solution for the first protonation; (b) recorded in 98% H2SO4 solution for the second protonation.

into account any medium effect on the wavelength of the maximum UV absorption and the corresponding molar absorptivity. Molar absorptivity (ε) values can be calculated using Beers’ Law:

cooled and poured into water, it was filtered. The crude products were dried and recrystallized from ethanol (2a−c). Equimolar quantities of sodium thiocyanate and 2chlorobutanone (50 mmol) dissolved in acetic acid (150 mL) were mixed at ambient temperature for 20 min. Equimolar amounts of phenyl hydrazine derivatives were added to this mixture and stirred at 30 °C for 5 h. The reaction mixture was refluxed for 2 h and controlled by TLC. Then, it was quenched by water (250 mL), washed, and dried in air. The resulting solids (3a−c) were recrystallized from ethanol. Synthesis Procedure of Compounds 1−9. Equimolar quantities of 2a−c (3 mmol) in acetone (30 mL) and potassium carbonate were mixed and followed by addition of various 4,5-dimethyl-1-(phenylamino)-1H-imidazole-2(3H)thione derivatives (3a−c). The solution was stirred at room temperature for 24 h (checked by TLC). The solvent was removed under reduced pressure, and water (100 mL) and brine were added to the residue. The mixture solution was filtered and dried in air. The solid was dissolved in ethanol, and decolorizing activated charcoal was added to the solution. Then, the solution was boiled. After filtering off the charcoal by filter paper, the residue was purified by recrystallization from ethanol, and compounds 1−9 were obtained. 3.2. Determination of pKa Values. The pKa values desribe the extent of ionization of compounds with respect to pH.41 The spectrophotometric method involves the direct determination of the molar ratios of acid−base conjugate pairs in a series of buffered solutions at known pH. This method takes

A = εbc

(1)

where A is the measured absorbance, ε is the wavelengthdependent molar absorptivity coefficient, b is the path length of the sample, and c is the concentration of the compound in solution. The wavelength of the protonation occurrence was deduced from the comparison of maximum and minimum absorbance points, which are in overlap position in the recorded UV spectra of the compounds. In the wavelength of the protonation occurrence, the fully protonated form of the compound has the maximum absorbance value, while the neutral form of the compound has the mimimum absorbance. Absorption−wavelength spectra of compound 4 are given as a representative example in Figure 2. Molar absorptivity coefficient (ε) values for the selected wavelength were plotted against pH, and sigmoid curves were obtained. The ε−pH graph of the compound 1 is given in Figure 3 as a representative example. The selected wavelengths, half-protonation values, and UV absorption maxima belonging to the first protonation of the compounds are listed in Table 1, while similar data obtained for the second protonation are given in Table 2. If the molar absorptivity coefficient of the conjugated acid (protonated molecule) is shown as εca and the molar absorptivity coefficient of the pure free base is shown as εfb, the ionization ratio (I) of the compounds can be calculated from eq 2. C



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Table 1. First Protonation Values of the Compounds and Their UV−Spectral Data compd.

neutral forma (log εmax) 288 304 230 310 307 313 287 289 277

1 2 3 4 5 6 7 8 9

(4.940) (4.986) (4.706) (4.638) (4.679) (4.697) (4.662) (4.796) (4.740)

monocation formb (log εmax) 277 304 230 319 319 320 261 281 277

(4.950) (4.986) (4.706) (4.178) (4.196) (4.191) (4.215) (4.338) (4.329)

λmaxc

Ho(1/2)d

me

221.0 314.0 314.0 322.0 313.0 322.0 261.0 279.0 277.0

8.30 7.60 9.85 9.47 9.40 10.35 7.70 −7.49 15.42

0.816 0.944 0.847 0.835 0.733 0.736 0.767 −0.977 0.534

pKa1

R2f

± ± ± ± ± ± ± ± ±

0.952 0.989 0.948 0.961 0.912 0.959 0.864 0.994 0.999

6.77 7.17 8.34 7.91 6.89 7.62 5.91 7.32 8.23

0.22 0.33 0.35 0.27 0.43 0.25 0.58 0.12 0.10

a Measured in pH = 7. bMeasured in 1% or 50% H2SO4. cMeasurement of the dissociation constant on the wavelength (nm). dHalf protonation values. eSlope. fCorrelation coefficient.

Table 2. Second Protonation Values of the Compounds and Their UV−Spectral Data compd.

monocation forma (log εmax)

dication formb (log εmax)

λmaxc

Ho(1/2)d

me

1 2 3 4 5 6 7 8 9

277(4.950) 304(4.986) 230(4.706) 319(4.178) 319(4.196) 320(4.191) 261(4.215) 281(4.338) 277(4.329)

250(4.489) 303(4.327) 226(4.773) 252(4.239) 262(4.576) 252(4.474) 252(4.462) 308(4.344) 307(4.302)

304.0 305.0 226.0 250.0 262.0 252.0 252.0 309.0 307.0

8.55 8.16 9.20 15.80 −6.60 −6.90 6.38 −2.05 5.04

0.508 0.579 0.502 0.271 −0.715 −0.524 0.474 −1.938 0.692

pKa2

R2 f

± ± ± ± ± ± ± ± ±

0.758 0.873 0.997 0.628 0.753 0.909 0.937 0.894 0.910

4.34 4.72 4.62 4.28 4.71 3.62 3.02 3.97 3.49

0.37 0.72 0.50 0.50 0.62 0.40 0.36 0.38 0.33

a

Measured in 1% or 50% H2SO4. bMeasured in 98% H2SO4. cMeasurement of the dissociation constant on the wavelength (nm). dHalf protonation values. eSlope. fCorrelation coefficient.

Figure 4. Possible first and second protonation pathways of the studied molecules.

I=

(Aobs − A fb) (ε − εfb) [BH +] = = obs [B] (Aca − Aobs) (εca − εobs)

An experimental plot of log I (i.e., log [BH+]/[B]) vs pH will be equal to pKa when log I = 0; this point indicates the half protonation value. Therefore, eq 5 may be applied:

(2)

The equilibrium constant for protonation of a weak base can be expressed thermodynamically in terms of concentration and activity coefficients, as shown in (eq 3). Ka =

[BH+] γBH+ [B][H+] γBγH+

pK a = mHx1/2

where H1/2 x represents the half protonation value and m is the slope of the log I−pH plot. The linear plot of log I (changes between −1.0 and 1.0) against pH has a slope m and yielded the half protonation value as H1/2 or pH1/2 at log I = 0, as shown in Figure 3. x Consequently, all the pKa values were calculated using eq 5; corresponding pKa1 and pKa2 values belonging to the first and second protonations of the compounds are listed in Tables 1 and 2, respectively. At the same time, these tables reveal how the substitution of R1 and R2 groups affect the acidity constants.

(3)

Assuming that γBH+/γB = 1, the pKa value can be expressed as follows (eq 4): pK a = −log

[BH+] + pH [B]

(5)

(4) D



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As can be seen from the possible protonation pathways (Figure 4), these compounds can be protonated from two different centers; the first center is imidazole ring nitrogen and the second center is benzothiazole ring nitrogen. It is known that the pKa value of imidazole is 6.9542 and this value is very close to first protonation values determined from this study for the compounds 1−9. This suggests that the first protonation of these compounds occur at imidazole ring nitrogen. When we take into account the acidity constant value (6.95) of imidazole, we can see that the molecules 1, 5, and 7 have smaller acidty constant values, while the molecules 2, 3, 4, 6, 8, and 9 have higher pKa values (Table 1). Among the investigated series, compound 3 has the highest pKa value and compound 7 has the smallest value for the first protonation. The first protonation of the compounds follow the order: 7 < 1 < 5 < imidazole < 2 < 8 < 6 < 4 < 9 < 3. As a result, we can infer that molecules containing chlorine atom (3, 6, and 9) as a substituent on the R2 position, have more basic character due to increased pKa values of the compounds. On the other hand, since the methoxy substituted compounds (2, 5, and 8) have smaller pKa values compared to the chlorine substituted derivatives, methoxy substituted molecules have less basic character than the chlorine substituted molecules. This effect might be attributed to the mesomeric effect of the chlorine atom on the aryl group. The pKa value of thiazole is known as 4.51,43 and this value is very close to second protonation values of the compounds 1−9 (Table 2). This suggests that the second protonation of these compounds occur at thiazole ring nitrogen. pKa values of the compounds 1, 4, 6, 7, 8, and 9 are smaller than that of the thiazole. Only compounds 2, 3, and 5 have slightly higher pKa values according to thiazole. Second protonation and increasing basicity of the investigated acetamides follows the order: 7 < 9 < 6 < 8 < 4 < 1 < thiazole < 3 < 5 < 2. In contrary to first protonation, the presence of chlorine atom on the R1 position (7, 8, and 9) increases of acidity and leads to decrease of pKa values for the second protonation of the compounds under investigation.

AUTHOR INFORMATION

Corresponding Author

*Tel.: +90 222 239 3750. Fax: +90 222 2393578. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors wish to acknowledge to Eskisehir Osmangazi University for the use of laboratories and equipments. Special thanks go to Professor Şeref Demirayak for his valuable support during this study.

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REFERENCES

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4. CONCLUSIONS In this work, nine drug precursor acetamide derivative compounds were newly synthesized. Characterization of the compounds verified the achievement of synthesis of target molecules. Acidity constant values of newly synthesized acetamide derivatives were determined by UV−vis spectrophotometric measurements, and these pKa values were introduced to the literature. The results showed that benzothiazole ring nitrogen is protonated after the protonation of the imidazole ring nitrogen. Due to the importance of relationship between biological activity and acid−base property of the compounds, it is thought that findings obtained from this study might be helpful for the development of new drugs.

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ASSOCIATED CONTENT

S Supporting Information *

Characterization of synthesized compounds. This information is available free of charge via the Internet at http://pubs.acs. org/. E



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