Synthesis and Determination of Acid Dissociation Constants in Dimethyl Sulfoxide–Water Hydroorganic Solvent of 5,5-Diphenylpyrrolidine N-Aroylthiourea Derivatives

Abstract

Novel 5,5-diphenylpyrrolidineN-aroylthioureas, containing 4-methylbenzoyl, 2-chlorobenzoyl,2,4-dichlorobenzoyl, and2-naphthoyl, were synthesized and their structural analysis was performed using ¹H nuclear magnetic resonance (NMR), ¹³C NMR, Fourier transform infrared spectroscopy, mass spectrometry (MS), and high-resolution MS (HRMS) techniques. The acid dissociation constants of the 5,5-diphenylpyrrolidineN-aroylthiourea derivative compounds were determined using Hyperquad computer program for data obtained using potentiometric titration method in 25% (v/v) dimethyl sulfoxide–water hydroorganic solvent in the presence of 0.1 mol×L^-1 ionic strength of NaCl and in the acidic medium at 25±0.1°C, using sodium hydroxide base as a titrant. Two acid dissociation constants were obtained for 3a, 3b, and 3d, and it was suggested that they were related to N-H and enol groups. Furthermore, three acid dissociation constants obtained for 3a indicated that they were related to N-H, enthiol, and enol groups, and four acid dissociation constants obtained for 3c suggested that they were related to N-H, enthiol, enol, and carboxyl groups.

Keywords

• Acid dissociation constant,Aroylthiourea,5-Diphenylpyrrolidine,Potentiometric titration

References

1. 1. Ilardi EA, Vitaku E, Njardarson JT. Data-mining for sulfur and fluorine: An evaluation of pharmaceuticals to reveal opportunities for drug design and discovery. J. Med. Chem. APR 2014; 57: 2832–2842. DOI: 10.1021/jm401375q
2. 2. Saeed A, Qamar R, Fattah TA, Flörke U, Erben MF. Recent developments in chemistry, coordination, structure and biological aspects of 1-(acyl/aroyl)-3-(substituted)thioureas. Res. Chem. Intermediat. MAY 2017; 43: 3053-3093. DOI: 10.1007/s11164-016-2811-5
3. 3. Saeed A, Flörke U, Erben MF. A review on the chemistry, coordination, structure and biological properties of 1-(acyl/aroyl)-3-(substituted) thioureas. J. Sulfur. Chem. MAY 2014; 35: 318-355. DOI: 10.1080/17415993.2013.834904
4. 4. Koch KR. New chemistry with old ligands: N-alkyl- and N,N-dialkyl-N′-acyl(aroyl)thioureas in co-ordination, analytical and process chemistry of the platinum group metals. Coord. Chem. Rev. JUN-JUL 2001; 216-217: 473-488. DOI: 10.1016/S0010-8545(01)00337-X
5. 5. Erşen D, Ülger M, Mangelinckx S, Gemili M, Şahin E, Nural, Y. Synthesis and anti(myco)bacterial activity of novel 5, 5-diphenylpyrrolidine N-aroylthiourea derivatives and a functionalized hexahydro-1H-pyrrolo[1, 2-c]imidazole. Med. Chem. Res. SEP 2017; 26: 2152-2160. DOI 10.1007/s00044-017-1907-9
6. 6. Gemili M, Sari H, Ulger M, Sahin E, Nural Y. Pt (II) and Ni (II) complexes of octahydropyrrolo [3, 4-c] pyrrole N-benzoylthiourea derivatives: Synthesis, characterization, physical parameters and biological activity. Inorg. Chim. Acta. JUL 2017; 463: 88-96. DOI: 10.1016/j.ica.2017.04.026
7. 7. Saeed A, Zaib S, Pervez A, Mumtaz A, Shahid M, Iqbal, J. Synthesis, molecular docking studies, and in vitro screening of sulfanilamide-thiourea hybrids as antimicrobial and urease inhibitors. Med. Chem. Res. AUG 2013; 22: 3653-3662. DOI: 10.1007/s00044-012-0376-4
8. 8. Koca İ, Özgür A, Er M, Gümüş M, Coşkun KA, Tutar Y. Design and synthesis of pyrimidinyl acyl thioureas as novel Hsp90 inhibitors in invasive ductal breast cancer and its bone metastasis. Eur. J. Med. Chem. OCT 2016; 122: 280-290. DOI: 10.1016/j.ejmech.2016.06.032

9. 9. Saeed S, Rashid N, Jones PG, Ali M, Hussain R. Synthesis, characterization and biological evaluation of some thiourea derivatives bearing benzothiazole moiety as potential antimicrobial and anticancer agents. Eur. J. Med. Chem. APR 2010; 45: 1323–1331. DOI: 10.1016/j.ejmech.2009.12.016
10. 10. Saeed A, Shah MS, Larik FA, Khan SU, Channar PA, Flörke U, Iqbal J. Synthesis, computational studies and biological evaluation of new 1-acetyl-3-aryl thiourea derivatives as potent cholinesterase inhibitors. Med. Chem. Res. AUG 2017; 26: 1635–1646. DOI: 10.1007/s00044-017-1829-6
11. 11. Saeed A, Khan MS, Rafique H, Shahid M, Iqbal J. Design, synthesis, molecular docking studies and in vitro screening of ethyl 4-(3-benzoylthioureido) benzoates as urease inhibitors. Bioorg. Chem. FEB 2014; 52: 1-7. DOI: 10.1016/j.bioorg.2013.10.001
12. 12. Nural Y, Kilincarslan R, Dondas HA, Cetinkaya B, Serin MS, Grigg R, Ince T, Kilner C. Synthesis of Ni (II), Pd (II) and Cu (II) metal complexes of novel highly functionalized aroylaminocarbo-N-thioyl pyrrolidines and their activity against fungi and yeast. Polyhedron. SEP 2009; 28: 2847-2854. DOI: 10.1016/j.poly.2009.06.028
13. 13. Binzet G, Arslan H, Flörke U, Külcü N, Duran N. Synthesis, characterization and antimicrobial activities of transition metal complexes of N, N-dialkyl-N′-(2-chlorobenzoyl) thiourea derivatives. J. Coord. Chem. AUG 2006; 59: 1395-1406. DOI: 10.1080/00958970500512633
14. 14. Yeşilkaynak T, Muslu H, Özpınar C, Emen FM, Demirdöğen RE, Külcü, N. Novel thiourea derivative and its complexes: Synthesis, characterization, DFT computations, thermal and electrochemical behavior, antioxidant and antitumor activities. J. Mol. Struct. AUG 2017; 1142: 185-193. DOI: 10.1016/j.molstruc.2017.04.049
15. 15. Sacht C, Datt MS. Synthesis and characterisation of mixed-ligand platinum (II)–sulfoxide complexes, [PtCl (DMSO)(L)], for potential use as chemotherapeutic agents (HL= N, N-dialkyl-N′-(3-R-benzoyl) thiourea). Polyhedron. JUN 2000; 19: 1347-1354. DOI: 10.1016/S0277-5387(00)00419-8
16. 16. Yaseen S, Rauf MK, Zaib S, Badshah A, Tahir MN, Ali MI, Imtiaz-un-Din, Iqbal J, Shahid M. Synthesis, characterization and urease inhibition, in vitro anticancer and antileishmanial studies of Co (III) complexes with N, N, N′-trisubstituted acylthioureas. Inorg. Chim. Acta. MAR 2016; 443: 69-77. DOI: 10.1016/j.ica.2015.12.027
17. 17. Li S, Cao X, Chen C, Ke S. Novel salicylic acid-oriented thiourea-type receptors as colorimetric chemosensor: synthesis, characterizations and selective naked-eye recognition properties. Spectrochim Acta A. OCT 2012; 96: 18-23. DOI: 10.1016/j.saa.2012.04.102
18. 18. Alkherraz AM, Lusta ZI, Zubi AE. Synthesis and use of thioureaderivative (1-phenyl-3-benzoyl-2-thiourea) for extraction of cadmium ion. Int. J. Chem. Mol. Nucl. Mater. Metall. Eng. 2014; 8: 108-110.
19. 19. Luckay RC, Sheng X, Strasser CE, Raubenheimer H, Safin DA, Babashkina MG, Klein A. Competitive bulk liquid membrane transport and solvent extraction of some metal ions using RC(S)NHP(X)(OiPr)2(X=O, S) as ionophores. Formation of the polynuclear complex of [Ag(N≡C–NP(S)(OiPr)2)]n. Dalton Trans. 2009; 39: 8227–8236. DOI: 10.1039/b910650b
20. 20. Li X, Li J. Recent advances in the development of MMPIs and APNIs based on the pyrrolidine platforms. Mini reviews in medicinal chemistry. AUG 2010; 10: 794-805. DOI: 10.2174/138955710791608334
21. 21. Pandey G, Banerjee P, Gadre SR. Construction of enantiopure pyrrolidine ring system via asymmetric [3+2]-cycloaddition of azomethine ylides. Chem. Rev. OCT 2006; 106: 4484-4517. DOI: 10.1021/cr050011g
22. 22. Felpin FX, Lebreton J. Recent advances in the total synthesis of piperidine and pyrrolidine natural alkaloids with ring‐closing metathesis as a key step. Eur. J. Org. Chem. SEP 2003; 2003: 3693-3712. DOI: 10.1002/ejoc.200300193
23. 23. Hensler ME, Bernstein G, Nizet V, Nefzi A. Pyrrolidine bis-cyclic guanidines with antimicrobial activity against drug-resistant Gram-positive pathogens identified from a mixture-based combinatorial library. Bioorg. Med. Chem. Lett. OCT 2006; 16: 5073-5079. DOI: 10.1016/j.bmcl.2006.07.037
24. 24. Arun Y, Bhaskar G, Balachandran C, Ignacimuthu S, Perumal PT. Facile one-pot synthesis of novel dispirooxindole-pyrrolidine derivatives and their antimicrobial and anticancer activity against A549 human lung adenocarcinoma cancer cell line. Bioorg. Med. Chem. Lett. MAR 2013; 23: 1839-1845. DOI: 10.1016/j.bmcl.2013.01.023
25. 25. Arun Y, Saranraj K, Balachandran C, Perumal PT. Novel spirooxindole–pyrrolidine compounds: Synthesis, anticancer and molecular docking studies. Eur. J. Med. Chem. MAR 2014; 74: 50-64. DOI: 10.1016/j.ejmech.2013.12.027
26. 26. Mokale SN, Dube PN, Bhavale SA, Sayed I, Begum A, Nevase MC, Shelke VR, Mujaheed A. Synthesis, in-vitro screening, and docking analysis of novel pyrrolidine and piperidine-substituted ethoxy chalcone as anticancer agents. Med. Chem. Res. MAY 2015; 24: 1842-1856. DOI: 10.1007/s00044-014-1266-8
27. 27. Nájera C, Sansano JM. 1,3-Dipolar cyclo additions: applications to the synthesis of antiviral agents. Org. Biomol. Chem. 2009; 7: 4567-4581. DOI: 10.1039/b913066g
28. 28. Martín-Rodríguez M, Nájera C, Sansano JM, De Cózar A, Cossío FP. Chiral gold(I) vs chiral silver complexes as catalysts for the enantioselective synthesis of the second generation GSK hepatitis C virus inhibitor. Beilstein J. Org. Chem. JUL 2011; 7: 988-996. DOI: 10.3762/bjoc.7.111
29. 29. Mazák K, Noszál B. Advances in microspeciation of drugs and biomolecules: Species-specific concentrations, acid-base properties and related parameters. J. Pharm. Biomed. Anal. OCT 2016; 130: 390-403. DOI: 10.1016/j.jpba.2016.03.053
30. 30. Babic´, S.; Horvat, A.J.M.; Pavlovic´, D.M.; Kasˇtelan-Macan, M. Determination of pKa values of active pharmaceutical ingredients. Trends in Analytical Chemistry. DEC 2007; 26: 1043–1061. DOI: 10.1016/j.trac.2007.09.004
31. 31. Roda G, Dallanoce C, Grazioso G, Liberti V, De Amici M. Determination of acid dissociation constants of compounds active at neuronal nicotinic acetylcholine receptors by means of electrophoretic and potentiometric techniques. Anal. Sci. JAN 2010; 26: 51-54.
32. 32. Aslan N, Erden PE, Doğan A, Canel E, Kılıç E. Protonation constants of some alanyl dipeptides in mixed aqueous organic solvents. J. Solution Chem. FEB 2016; 45: 299-312. DOI: 10.1007/s10953-016-0444-3
33. 33. Dohoda D, Tsinman K, Tsinman O, Wang H, Tam KY. Spectrophotometric pKa determination of ionizable pharmaceuticals: Resolution of molecules with weak pH-dependent spectral shift. Pharmaceut. Biomed. Anal. OCT 2015; 114: 88–96. DOI: 10.1016/j.jpba.2015.05.009
34. 34. Shelley JC, Cholleti A, Frye LL, Greenwood JR, Timlin MR, Uchimaya M. Epik: a software program for pKa prediction and protonation state generation for drug-like molecules. J. Comput. Aided. Mol. Des. DEC 2007; 21: 681–691. DOI: 10.1007/s10822-007-9133-z
35. 35. Grover M, Singh B, Bakshi M, Singh S. Quantitative structure–property relationships in pharmaceutical research–Part 1. Pharma. Sci. Technol. To. 2000; 3: 28-35. DOI: 10.1016/S1461-5347(99)00214-X
36. 36. Onufriev A, Case DA, Ullmann GM. A novel view of pH titration in biomolecules. Biochemistry. MAR 2001; 40: 3413-3419. DOI: 10.1021/bi002740q
37. 37. Şanli S, Altun Y, Şanli N, Alsancak G, Beltran JL. Solvent effects on pKa values of some substituted sulfonamides in acetonitrile-water binary mixtures by the UV-spectroscopy method. J. Chem. Eng. Data. NOV 2009; 54: 3014-3021. DOI: 10.1021/je9000813
38. 38. Nural Y, Döndaş HA, Sarı H, Atabey H, Belveren S, Gemili M. Determination of acid dissociation constants (pKa) of bicyclic thiohydantoin-pyrrolidine compounds in 20% ethanol-water hydroorganic solvent. Int. J. Anal. Chem. 2014; 2014: Article ID 634194, 6 pages. DOI: 10.1155/2014/634194
39. 39. Atabey H, Sari H. The effects of ionic strength and temperature on the dissociation constants of adefovir and cidofovir used as antiviral drugs. Turk. J. Chem. 2014; 38: 806-814. DOI: 10.3906/kim-1309-39
40. 40. Mumcu A, Küçükbay H. Determination of pKa values of some novel benzimidazole salts by using a new approach with 1H NMR spectroscopy. Magnetic Resonance in Chemistry, DEC 2015; 53: 1024-1030. DOI: 10.1002/mrc.4294
41. 41. Ersen D, Gemili M, Sarı H, Nural Y. Acid dissociation constants of 5,5-diphenylpyrrolidine N-aroylthioureas and stability constants of their Pt(II) and Ni(II) complexes in acetonitrile-water hydroorganic solvent. CBU J. of Sci. 2017; 13: 125-138. DOI: http://dx.doi.org/10.18466/cbujos.302657
42. 42. Arslan H, Külcü N, Florke U. Synthesis and characterization of copper(II), nickel(II) and cobalt(II) complexes with novel thiourea derivatives. Transit. Met. Chem. OCT 2003; 28: 816-819. DOI: 10.1023/A:1026064232260
43. 43. Pettit, L.D. Academic Software, Sourby Farm, Timble, Otley, LS21 2PW, UK, 1992.
44. 44. Mussini PR, Mussini T, Rondinini S. Reference value standards and primary standards for pH measurements in D2O and aqueousorganic solvent mixtures: New accessions and assessments (Technical Report). Pure Appl. Chem. MAY 1997; 69: 1007-1014. DOI: 10.1351/pac199769051007
45. 45. Rondinini S, Mussini PR, Mussini T. Reference value standards and primary standards for pH measurements in organic solvents and water+ organic solvent mixtures of moderate to high permittivities. Pure Appl. Chem. NOV 1987; 59: 1549-1560. DOI: 10.1351/pac198759111549
46. 46. Gans P, Sabatini A, Vacca A. Investigation of equilibria in solution. Determination of equilibrium constants with the HYPERQUAD suite of programs. Talanta. OCT 1996; 43: 1739-1753. DOI: 10.1016/0039-9140(96)01958-3
47. 47. Schröder B, Schröder U, Dietze F, Beyer L. Protonation, complexation and thermochemical behaviour of N-benzoylthiocarbamic-O-alkylester anions in solution. Inorg. Chem. Commun. AUG 2001; 4: 398-401. DOI: 10.1016/S1387-7003(01)00231-3
48. 48. Binzet G, Zeybek B, Kılıç, E, Külcü N, Arslan H. Determination of the ionization constants of some benzoyl thiourea derivatives in dioxane-water mixture. Journal of Chemistry. 2013; 2013, Article ID 201238, 7 pages. DOI: 10.1155/2013/201238
49. 49. Atabey H, Sari H, Al-Obaidi FN. Protonation equilibria of Carminic acid and stability constants of its complexes with some divalent metal ions in aqueous solution. J. Solution Chem. JUN 2012; 41: 793-803. DOI: 10.1007/s10953-012-9830-7