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Theoretical Study on the Acidities of Pyrrole, Indole, Carbazole and Their Hydrocarbon Analogues in DMSO

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Theoretical Study on the Acidities of Pyrrole, Indole, Carbazole and Their Hydrocarbon Analogues in DMSO Canadian Journal of Chemistry Theoretical study on the acidities of pyrrole, indole, carbazole and their hydrocarbon analogues in DMSO Journal: Canadian Journal of Chemistry Manuscript ID cjc-2018-0032.R1 Manuscript Type: Article Date Submitted by the Author: 13-May-2018 Complete List of Authors: Ariche, Berkane; Modelisation and computational Méthods Laboratory, Faculty of Sciences, University of Saida, Chemistry RAHMOUNI,Draft Ali; Universite Dr Tahar Moulay de Saida, Chimie Is the invited manuscript for consideration in a Special Not applicable (regular submission) Issue?: Keyword: pKa calculation, Aromaticity index, Pyrolle, DMSO, DFT https://mc06.manuscriptcentral.com/cjc-pubs Page 1 of 33 Canadian Journal of Chemistry Theoretical study on the acidities of pyrrole, indole, carbazole and their hydrocarbon analogues in DMSO Ariche Berkane, Rahmouni Ali* Modeling and Calculation Methods Laboratory, University of Saida, B.P. 138, 20002 Saida, Algeria *Corresponding author [email protected] Abstract SMD and IEF-PCM continuum solvation models have been used, in combination with three quantum chemistry methods (B3LYP,Draft M062X and CBS-QB3) to study the acidities of pyrrole, indole and carbazole as well as their hydrocarbon analogues in DMSO, following a direct thermodynamic method. Theoretical parameters such as aromaticity indices (HOMA and SA), molecular electrostatic potential (MEP) and atomic charges have been calculated using B3LYP/6-311++G(d,p) level of theory. Calculated pKa values indicate that there is generally good agreement with experimental data, with all deviations being less than the acceptable error for a directly calculated pKa values. The M062X functional combined to SMD solvation model provide the more accurate pKa values. MEP surfaces show clearly the electron density change accompanying the deprotonation process and explain the relative stability of conjugate bases. The HOMA aromaticity indices seem to be directly related to acidity strength. The collected data have been used to elucidate the pKa trends for the series of molecules under consideration. Key words: pKa Calculation, Aromaticity, Density functional theory, CBS-QB3, SMD, Electrostatic interaction. https://mc06.manuscriptcentral.com/cjc-pubs Canadian Journal of Chemistry Page 2 of 33 1. Introduction Over the past several decades, acid-base equilibrium has remained one of the key concepts in chemistry. Thus, different computational strategies have been proposed to predict accurate pKa values1,2. For efficient computations in solution, thermodynamic cycles are generally combined with high level quantum chemical calculations in the gas phase and convenient calculation level for implicit solvation models3,4. The use of thermodynamic cycles represents the traditional approach in theoretical pKa * estimations, whereby solvation free energies (∆G solv) and gas phase deprotonation free ° energy (∆G gas) are combined so as to obtain the free energy of deprotonation in solution * 5,6 (∆G soln) . The thermodynamic cycles are mainly employed due to the fact that solvation * models are adjusted to deliver accurate solvation free energies (∆G solv), but the modest levels of theory at which they are parameterizedDraft are not accurate enough to estimate deprotonation * 1 free energy in solution (∆G soln) . By applying a thermodynamic cycle, one can make use of high-level ab initio calculations or experimental data in the gas phase to enhance the accuracy * of the resulting free energy (∆G soln). Over the past few years, numerous thermodynamic cycles have been proposed in the literature1,7. The most elementary one is called direct or absolute method, which is depicted in Scheme 1. A number of alternatives to the direct method are widely employed in the literature; such as the proton exchange or isodesmic reaction scheme8, the hybrid cluster– continuum9 and the implicit-explicit models10. It should be noted that some recent proposed 11,12 approaches for pKa calculations avoid gas-phase calculations and yield accurate results . Solvation free energies of molecular and ionic species are generally calculated using continuum models. In these models, species are covered by a molecular-shaped cavity embedded in a dielectric continuum13. The interaction between the charge distribution of the solute and the dielectric continuum provides the electrostatic contribution, which is the https://mc06.manuscriptcentral.com/cjc-pubs Page 3 of 33 Canadian Journal of Chemistry dominant term of solvation free energies for polar solvent and charged solutes. Nowadays, the most common implicit solvation models are the PCM family of models (eg. IEFPCM, CPCM and IPCM1,14-18, the Minnesota solvation models, SMx (e.g., x=D19 or x=620) and the Conductor-Like Screening Models of Klamt and coworkers (e.g., COSMO21 or COSMO- RS22). Such models can be applied to a wide variety of solvents. They can estimate solvation free energies for typical neutral solutes, in either aqueous or non-aqueous solvents, accurate to within 1 kcal/mol. However, the errors incurred for ionic solutes are considerably larger and can exceed 4 kcal/mol23-25. Solvation free energies as well as acidity data in organic solvents like dimethyl sulfoxide (DMSO) are less abundant in comparison with those related to aqueous media28-30. Such information is the principal key for understanding many chemical and biochemical processes31-33, in particular the roleDraft that the specific and nonspecific solvent-solute interactions occupy in the binding between species and their target sites34. Moreover, most of the compounds screened for biological activities are soluble in DMSO at room temperature35- 37. Thus, DMSO is usually used for in vitro experimentation and in vivo administration of a wide range of hydrophobic chemical species38. In this paper, we studied theoretically the acidities of pyrrole (1), indole (2) and carbazole (3) as well as their hydrocarbon analogues 1,3-cyclopentadiene (4), indene (5) and fluorene (6) in DMSO. As shown in Table 1, the acidities in DMSO of 1, 2 and 3 increase in that order, while the acidities of 4, 5 and 6 are in the reverse order. These acidity rankings can be attributed primarily to the presence of the benzene rings and to the successive increase/decrease in the aromaticities of conjugate bases39. In addition, the fact that intrinsic acidity of nitrogen acids N-H is greater than that of carbon acids C-H, due to the greater electronegativity of nitrogen than carbon, the relatively high acidities of 4 and 5 in comparison with those of 1 and 2 are unanticipated. The main purpose of the present study is https://mc06.manuscriptcentral.com/cjc-pubs Canadian Journal of Chemistry Page 4 of 33 to examine carefully some electronic and structural proprieties such as aromaticity indices, molecular electrostatic potential, dipole moment and Mulliken atomic charges, for each compound, in order to explain acidity ranking of hydrocarbon cycles as well as nitrogen- containing heterocycles. 2. Methods All calculations have been conducted using the GAUSSIAN 09 software package41. Three quantum chemistry methods, namely the B3LYP hybrid functional42,43, the M062X Minnesota functional44 and the CBS-QB3 composite method45-47, have been used to fully optimize structures either in gas phase or in solution. The 6-311++G(d,p) basis set has been adopted for DFT calculations. The continuum solvation models SMD19 and IEF-PCM17 were used to perform solution calculations. The IEF-PCMDraft model was applied in combination with the PAULING48-49 and BONDI49 cavities to yield the IEF-PCM/PAULING and IEF- PCM/BONDI solvation free energies respectively. It is well known that CBS-QB3 method is reputed by its expensive cost and moderate estimation of pKa values. However, such a method provides accurate estimates of gas phase thermo-chemistry data7,12. The purpose of its use in the present work is, on the one hand, the comparison of his gas phase deprotonation free energies with the values obtained through DFT functionals, on the other hand, the examination of their estimated solvation free energies for each combination of cavity and continuum model. Thermodynamic cycle of Scheme 1 shows the chemical reactions for the dissociation of HA acid in the gas phase and in the solution phase. The directly estimated pKa values may be obtained via thermodynamic cycle through Eqs. 1-3. ∆∗ ͤͅ = (ĦĢğġ) (1) ')(ͥͤ) https://mc06.manuscriptcentral.com/cjc-pubs Page 5 of 33 Canadian Journal of Chemistry ∗ ° ∗ ͯ ∗ ͮ ∗ Ȱ ∆́(.*')) = ∆́(".) + ∆́(.*'1)(̻ ) + ∆́(.*'1)(͂ ) − ∆́(.*'1)(̻͂) + ͎͎͌͌͢͠ (2) ° ° ͯ ° ͮ ° ∆́(".) = ́(".)(̻ ) + ́(".)(͂ ) − ́(".)(̻͂) (3) - Where ∆G°(gas) is the gas pas deprotonation free energy. The terms ∆G*(solv)(A ) and - ∆G*(solv)(HA) correspond to the free energy change related to the solvation process of A and HA species, respectively. Given that ∆G*(solv) corresponds to the free energy change related to the solvation process (gas solution), where the solvated compound is in its equilibrium geometry in the respective phases1,7,24, all structures were optimized in the gas phase as well as in solution. The stationary points were confirmed by frequency calculations for each level of theory. The factor RTlnRȱT of Eq. 2 accounts for the correction needed to convert between standard states, since gas phase free energies are calculated with respect to a standard state of 1atm and solution phase free energiesDraft correspond to a standard state of 1 mol/L. R and ͌Ȱ are the gas constant in units of J/mol.K and L.atm/mol.K, respectively. In the absolute method, all of the above-mentioned free energies can be estimated using quantum chemistry methods, + + except G°(gas)(H ) and ∆G*(solv)(H ), due to the fact that the proton is a particular quantum + entity which contains no electrons. The calculation of G°(gas)(H ) using the standard equations of thermodynamics and the Sackur-Tetrode equation50 yields a value of 26.27 kJ/mol. While + solvation free energy of proton in DMSO, ∆G*(solv)(H ), has been determined either experimentally or using theoretical computations, several values have been proposed, the latest and more accepted value is -1114.62 kJ/mol, which is proposed by Knapp and coworkers51.
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