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π-Stacking effects on acid capacity of p-aminobenzoic acid

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Abstract

Acidity changes of p-aminobenzoic acid (pABA) after π-stacking with substituted benzenes (SB) have been investigated using quantum mechanical calculations at the M06-2X/6-311++G(d,p) level of theory. In addition to benzene derivatives that are usually used as a model for aromatic amino acids (AA), two amino acids, tryptophan (TRP) and histidine (HIS), with different cyclic structures were also considered in this work. All substituents enhance the stacking interactions, in which enhancement is higher for electron-withdrawing substituents (EWSs). The stacking interaction (in presence of all substituents) enhances the acidity (3.42 for Br). Natural energy decomposition analysis (NEDA) shows that the polarization interactions (POL) have the largest contribution in the binding energies (ΔE) of neutral and anionic complexes, while the electrostatic effects (ES) are in better correlation with ΔE. The ΔE values are linearly dependent on the sum of electron densities (ΣρBCP) calculated at the bond critical points (BCPs) between the rings and the ΣρRCP values calculated at the ring critical points (RCPs) in the neutral and anionic SB||pABA complexes. An excellent correlation was found between the ΔE values and a combination of electrostatic (σmeta), resonance/induction (σpara), and dispersion/polarizability (molar refractivity, MR) substituent constant terms. There are good relationships between pKa and the global minimum and maximum of electrostatic potential around the O (∑Vmin-O) and H (Vmax-H) atoms, and the results of natural population analysis (NPA). Therefore, the electrostatic and charge transfer effects play a major role in acidity.

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References

  1. Matherl LH (2001) Molecular and cellular biology of the human reduced folate carrier. Prog Nucleic Acid Res Mol Biol 67:131–162

    Article  Google Scholar 

  2. Hevener KE, Yun MK, Qi J, Kerr ID, Babaoglu K, Hurdle JG, Lee RE (2009) Structural studies of pterin-based inhibitors of dihydropteroate synthase. J Med Chem 53:166–177

    Article  CAS  Google Scholar 

  3. Li C, Liang X, Wen K, Li Y, Zhang X, Ma M, Yu X, Yu W, Shen J, Wang Z (2018) Class-Specific Monoclonal Antibodies and Dihydropteroate Synthase in Bioassays Used for the Detection of Sulfonamides. Anal Chem 91:2392–2400

    Article  CAS  Google Scholar 

  4. Dawadi S, Kordus SL, Baughn AD, Aldrich CC (2017) Synthesis and analysis of bacterial folate metabolism intermediates and antifolates. Org Lett 19:5220–5223

    Article  CAS  PubMed  Google Scholar 

  5. Mutch CA, Ordonez AA, Qin H, Parker M, Bambarger LE, Villanueva-Meyer JE, Blecha J, Carroll V, Taglang C, Flavell R, Sriram R (2018) [11C] Para-Aminobenzoic Acid: A Positron Emission Tomography Tracer Targeting Bacteria-Specific Metabolism. ACS Infect Dis 30:1067–1072

    Article  CAS  Google Scholar 

  6. Pan X, Zheng Y, Chen R, Qiu S, Chen Z, Rao W, Chen S, You Y, Lü J, Xu L, Guan X (2019) Cocrystal of Sulfamethazine and p-Aminobenzoic Acid: Structural Establishment and Enhanced Antibacterial Properties. Cryst Growth Des 194:2455–2460

    Article  CAS  Google Scholar 

  7. Laborda P, Zhao Y, Ling J, Hou R, Liu F (2018) Production of antifungal p-aminobenzoic acid in Lysobacter antibioticus OH13. J Agric Food Chem 663:630–636

    Article  CAS  Google Scholar 

  8. Tripathi GN, Su Y (1996) Spectroscopic and kinetic properties of the radical zwitterion and related intermediates in the one-electron oxidation of p-aminobenzoic acid. J Am Chem Soc 118:2235–2244

    Article  CAS  Google Scholar 

  9. Garg RK, Sarkar D (2016) Polymorphism control of p-aminobenzoic acid by isothermal anti-solvent crystallization. J Cryst Growth 454:180–185

    Article  CAS  Google Scholar 

  10. Hao H, Barrett M, Hu Y, Su W, Ferguson S, Wood B, Glennon B (2011) The use of in situ tools to monitor the enantiotropic transformation of p-aminobenzoic acid polymorphs. Org Process Res Dev 161:35–41

    Google Scholar 

  11. Rosbottom I, Ma CY, Turner TD, O’Connell RA, Loughrey J, Sadiq G, Davey RJ, Roberts KJ (2017) Influence of solvent composition on the crystal morphology and structure of p-Aminobenzoic acid crystallized from mixed ethanol and nitromethane solutions. J Cryst Growth 17:4151–4161

    Article  CAS  Google Scholar 

  12. Turner TD, Caddick S, Hammond RB, Roberts KJ, Lai X (2018) Kinetics of the Aqueous-Ethanol Solution Mediated Transformation between the Beta and Alpha Polymorphs of p-Aminobenzoic Acid. J Cryst Growth 18:1117–1125

    Article  CAS  Google Scholar 

  13. Kamali N, Erxleben A, McArdle P (2016) Unexpected effects of catalytic amounts of additives on crystallization from the gas phase: depression of the sublimation temperature and polymorph control. Cryst Growth Des:162492–162495

  14. Black JF, Davey RJ, Gowers RJ, Yeoh A (2015) Ostwald's rule and enantiotropy: polymorph appearance in the crystallisation of p-aminobenzoic acid. Cryst Eng Commun 17:5139–5142

    Article  CAS  Google Scholar 

  15. John KA, Cogswell ME, Campbell NR, Nowson CA, Legetic B, Hennis AJ, Patel SM (2016) Accuracy and usefulness of select methods for assessing complete collection of 24‐hour urine: a systematic review. J Clin Hypertens 18:456–467

    Article  CAS  Google Scholar 

  16. Roberts SB, Morrow FD, Evans WJ, Shepard DC, Dallal GE, Meredith CN, Young VR (1990) Use of p-aminobenzoic acid to monitor compliance with prescribed dietary regimens during metabolic balance studies in man. AJCN 51:485–488

    CAS  Google Scholar 

  17. Pliego Jr JR (2003) Thermodynamic cycles and the calculation of pKa. Chem Phys Lett 367:145–149

    Article  CAS  Google Scholar 

  18. da Silva CO, da Silva EC, Nascimento MA (2003) Comment on ‘Thermodynamic cycles and the calculation of pKa’[Chem. Phys. Lett. 367 (2003) 145]. Chem Phys Lett 381:244–245

    Article  CAS  Google Scholar 

  19. Kelly CP, Cramer CJ, Truhlar DG (2006) Adding explicit solvent molecules to continuum solvent calculations for the calculation of aqueous acid dissociation constants. J Phys Chem A 110:2493–2499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sutton CC, Franks GV, da Silva G (2012) First principles pKa calculations on carboxylic acids using the SMD solvation model: effect of thermodynamic cycle, model chemistry, and explicit solvent molecules. J Phys Chem B 116:11999–12006

    Article  CAS  PubMed  Google Scholar 

  21. Zhang S, Zhang T, Tang S (2016) Determination of the Hammett Acidity Functions of Triflic Acid/Ionic Liquid Binary Mixtures by the 13C NMR-Probe Method. J Chem Eng Data 61:2088–2097

    Article  CAS  Google Scholar 

  22. Zhang X, Zhang R, Liu H, Meng X, Xu C, Liu Z, Klusener PA (2016) quantitative characterization of Lewis acidity and activity of chloroaluminate ionic liquids. Ind. Eng. 55:11878–11886

    Article  CAS  Google Scholar 

  23. Liptak MD, Shields GC (2001) Accurate pKa calculations for carboxylic acids using complete basis set and Gaussian-n models combined with CPCM continuum solvation methods. J Am Chem Soc 123:7314–7319

    Article  CAS  PubMed  Google Scholar 

  24. Ou SC, Pettitt BM (2019) Free Energy Calculations Based on Coupling Proximal Distribution Functions and Thermodynamic Cycles. J Chem Theory Comput 15:2649–2658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dávila YA, Sancho MI, Almandoz MC, Blanco SE (2013) Solvent Effects on the Dissociation Constants of Hydroxyflavones in Organic–Water Mixtures. Determination of the Thermodynamic p K a Values by UV–Visible Spectroscopy and DFT Calculations. J Chem Eng Data 58:1706–1716

    Article  CAS  Google Scholar 

  26. Gao D, Svoronos P, Wong PK, Maddalena D, Hwang J, Walker H (2005) pKa of Acetate in Water: A Computational Study. J Phys Chem A 109:10776–10785

    Article  CAS  PubMed  Google Scholar 

  27. Ho J, Coote MLA (2010) universal approach for continuum solvent pKa calculations: are we there yet? Theor Chem Acc 125:3

    Article  CAS  Google Scholar 

  28. Qin Z, Dong D, Yao M, Yu Q, Sun X, Guo Q, Zhang H, Yao F, Li J (2019) Freezing-Tolerant Supramolecular Organohydrogel with High Toughness, Thermoplasticity, Healable and Adhesive Property. ACS Appl Mater Interfaces 11:21184–21193

    Article  CAS  PubMed  Google Scholar 

  29. Mitchell MO, Means J (2018) Cation−Π Interactions in Biochemistry: A Primer. J. Chem. Educ 95:2284–2288

    Article  CAS  Google Scholar 

  30. Heller BA, Gindt YM (2000) A biochemical study of noncovalent forces in proteins using phycocyanin from Spirulina. J Chem Educ 77:1458

    Article  CAS  Google Scholar 

  31. Wang S, Guo G, Lu X, Ji S, Tan G, Gao L (2018) Facile soaking strategy toward simultaneously enhanced conductivity and toughness of self-healing composite hydrogels through constructing multiple noncovalent interactions. ACS Appl Mater Interfaces 10:19133–19142

    Article  CAS  PubMed  Google Scholar 

  32. Meli M, Engel H, Laor D, Gazit E, Colombo G (2019) Mechanisms of metabolite amyloid formation: computational studies for drug design against metabolic disorders. ACS Med Chem Lett 10:666–670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Fu HL, Po C, Leung SY, Yam VW (2017) Self-Assembled Architectures of Alkynylplatinum (II) Amphiphiles and Their Structural Optimization: A Balance of the Interplay among Pt··· Pt, π–π Stacking, and Hydrophobic–Hydrophobic Interactions. ACS Appl Mater Interfaces 9:2786–2795

    Article  CAS  PubMed  Google Scholar 

  34. Waters ML (2002) Aromatic interactions in model systems. Curr Opin Chem Biol. 6:736–741

    Article  CAS  PubMed  Google Scholar 

  35. Hunter CA, Lawson KR, Perkins J, Urch CJ (2001) Aromatic interactions. J Chem Soc Perkin Trans 2:651–669

    Article  Google Scholar 

  36. Hunter CA, Sanders JK (1990) The nature of. pi.-. pi. interactions. J Am Chem Soc 112:5525–5534

    Article  CAS  Google Scholar 

  37. Kang M, Zhang P, Cui H, Loverde SM (2016) π–π stacking mediated chirality in functional supramolecular filaments. Macromolecules. 49:994–1001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lee EC, Kim D, Jurecˇka P, Tarakeshwar P, Hobza P, Kim KS (2007) Understanding of assembly phenomena by aromatic− aromatic interactions: benzene dimer and the substituted systems. J Phys Chem A 111:3446–3457

    Article  CAS  PubMed  Google Scholar 

  39. Quiñonero D, Frontera A, Deyà PM, Alkorta I, Elguero J (2008) Interaction of positively and negatively charged aromatic hydrocarbons with benzene and triphenylene: Towards a model of pure organic insulators. Chem Phys Lett 460:406–410

    Article  CAS  Google Scholar 

  40. Escudero D, Frontera A, Quinonero D, Deya PM (2008) Interplay between edge-to-face aromatic and hydrogen-bonding interactions. J Phys Chem A 112:6017–6022

    Article  CAS  PubMed  Google Scholar 

  41. Zaccheddu M, Filippi C, Buda F (2008) Anion− π and π− π Cooperative Interactions Regulating the Self-Assembly of Nitrate− Triazine− Triazine Complexes. J Phys Chem A 112:1627–1632

    Article  CAS  PubMed  Google Scholar 

  42. Li Z, Guo T, Hu Y, Qiu Y, Liu Y, Wang H, Li Y, Chen X, Song J, Yang H (2019) A Highly Effective π–π Stacking Strategy To Modify Black Phosphorus with Aromatic Molecules for Cancer Theranostics. ACS Appl Mater Interfaces 11:9860–9871

    Article  CAS  PubMed  Google Scholar 

  43. Rashkin MJ, Waters ML (2002) Unexpected substituent effects in offset π− π stacked interactions in water. J Am Chem Soc 124:1860–1861

    Article  CAS  PubMed  Google Scholar 

  44. Sinnokrot MO, Valeev EF, Sherrill CD (2002) Estimates of the ab initio limit for π− π interactions: The benzene dimer. J Am Chem Soc 124:10887–10893

    Article  CAS  PubMed  Google Scholar 

  45. Akher FB, Ebrahimi A, Mostafavi N (2017) Characterization of π-stacking interactions between aromatic amino acids and quercetagetin. J Mol Struct 1128:13–20

    Article  CAS  Google Scholar 

  46. Akher FB, Ebrahimi A (2015) π-stacking effects on the hydrogen bonding capacity of methyl 2-naphthoate. J Mol Graph Model 61:115–122

    Article  CAS  PubMed  Google Scholar 

  47. Kruse H, Banas P, Šponer J. (2018) Investigations of stacked DNA base-pair steps: highly accurate stacking interaction energies, energy decomposition, and many-body stacking effects. J Chem Theory Comput 15:95–115

    Article  PubMed  CAS  Google Scholar 

  48. Yusuff N, Doré M, Joud C, Visser M, Springer C, Xie X, Herlihy K, Porter D, Tour BB (2012) Lipophilic Isosteres of a π–π Stacking Interaction: New Inhibitors of the Bcl-2-Bak Protein–Protein Interaction. ACS Med Chem Lett 3:579–583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Burley SK, Petsko GA (1985) Aromatic-aromatic interaction: a mechanism of protein structure stabilization. Science 229:23–28

    Article  CAS  PubMed  Google Scholar 

  50. Burley SK, Petsko GA. (1988) Weakly polar interactions in proteins. In Advances in protein chemistry. AP 39:125-189

  51. Nandy R, Subramoni M, Varghese B, Sankararaman S (2007) Intramolecular π-stacking interaction in a rigid molecular hinge substituted with 1-(pyrenylethynyl) units. J Org Chem 72:938–944

    Article  CAS  PubMed  Google Scholar 

  52. Rezac J, Greenwell C, Beran GJ (2018) Accurate Noncovalent Interactions via Dispersion-Corrected Second-Order Møller–Plesset Perturbation Theory. J Chem Theory Comput 14:4711–4721

    Article  CAS  PubMed  Google Scholar 

  53. Tsuzuki S, Honda K, Uchimaru T, Mikami M, Tanabe K (2002) Origin of attraction and directionality of the π/π interaction: model chemistry calculations of benzene dimer interaction. J Am Chem Soc 124:104–112

    Article  CAS  PubMed  Google Scholar 

  54. Lee H, Dehez F, Chipot C, Lim HK, Kim H (2019) Enthalpy–Entropy Interplay in π-Stacking Interaction of Benzene Dimer in Water. J Chem Theory Comput 15:1538–1545

    Article  CAS  PubMed  Google Scholar 

  55. Ramanathan N, Sankaran K, Sundararajan K (2017) Nitrogen: A New Class of π-Bonding Partner in Hetero π-Stacking Interaction. J Phys Chem A 121:9081–9091

    Article  CAS  PubMed  Google Scholar 

  56. Bogdanov AM, Acharya A, Titelmayer AV, Mamontova AV, Bravaya KB, Kolomeisky AB, Lukyanov KA, Krylov AI (2016) Turning on and off photoinduced electron transfer in fluorescent proteins by π-stacking, halide binding, and Tyr145 mutations. J Am Chem Soc 138:4807–4817

    Article  CAS  PubMed  Google Scholar 

  57. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery Jr JA, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas O, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09 Revision A.02. Gaussian Inc, Wallingford CT

    Google Scholar 

  58. Bissantz C, Kuhn B, Stahl M (2010) A medicinal chemist’s guide to molecular interactions. J Med Chem 53:5061–5084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zhao Y, Truhlar DG (2008) The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor Chem Acc 120:215–241

    Article  CAS  Google Scholar 

  60. Boys SF, Bernardi FD (1970) The calculation of small molecular interactions by the differences of separate total energies. Some procedures with reduced errors. Mol Phys 19:553–566

    Article  CAS  Google Scholar 

  61. Marenich AV, Cramer CJ, Truhlar DG (2009) Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. J Phys Chem B 113:6378–6396

    Article  CAS  PubMed  Google Scholar 

  62. Bader RF. (1990) International Series of Monographs on Chemistry. Atoms in Molecules, A Quantum Theory. 22.

  63. Biegler-Konig F, Schonbohm J, Bayles D (2001) Software news and updates-AIM2000-A program to analyze and visualize atoms in molecules. J Comput Chem 22:545–559

    Article  Google Scholar 

  64. Reed AE, Curtiss LA, Weinhold F (1988) Intermolecular interactions from a natural bond orbital, donor-acceptor viewpoint. Chem Rev 88:899–926

    Article  CAS  Google Scholar 

  65. Glendening ED, Reed AE, Carpenter JE, Weinhold F (1990) NBO 3.0 program manual. Theoretical Chemistry Institute, University of Wisconsin, Madison, WI

    Google Scholar 

  66. Schenter GK, Glendening ED (1996) Natural energy decomposition analysis: The linear response electrical self energy. J Phys Chem 100:17152–17156

    Article  CAS  Google Scholar 

  67. Glendening ED (1996) Natural energy decomposition analysis: Explicit evaluation of electrostatic and polarization effects with application to aqueous clusters of alkali metal cations and neutrals. J Am Chem Soc 118:2473–2482

    Article  CAS  Google Scholar 

  68. Lu T, Chen F (2012) Multiwfn: a multifunctional wavefunction analyzer. J Comput Chem 33:580–592

    Article  PubMed  CAS  Google Scholar 

  69. Watt M, Hardebeck LK, Kirkpatrick CC, Lewis M (2011) Face-to-face arene− arene binding energies: dominated by dispersion but predicted by electrostatic and dispersion/polarizability substituent constants. J Am Chem Soc 133:3854–3862

    Article  CAS  PubMed  Google Scholar 

  70. Hansch C, Rockwell SD, Jow PY, Leo A, Steller EE (1977) Substituent constants for correlation analysis. J Med Chem 20:304–306

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank the Computational Quantum Chemistry Laboratory for computational facilities.

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We thank the University of Sistan and Baluchestan for financial supports.

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  1. Department of Chemistry, Computational Quantum Chemistry Laboratory, University of Sistan and Baluchestan, P.O. Box 98135-674, Zahedan, Iran

    Ebrahim Khalilinia & Ali Ebrahimi

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Khalilinia, E., Ebrahimi, A. π-Stacking effects on acid capacity of p-aminobenzoic acid. Struct Chem 31, 1707–1716 (2020). https://doi.org/10.1007/s11224-020-01530-y

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