Theoretical calculation of the pKa values of some drugs in aqueous solution

In this work, calculations of pK_a values have been performed on benzoic acid and its para‐substituted derivatives and some drugs by using Gaussian 98 software package. Gas‐phase energies were calculated with HF/6‐31 G** and B3LYP/6‐31 G** levels of theory. Free energies of solvation have been computed using the polarizable continuum model (PCM), conductor‐like PCM (CPCM), and the integral equation formalism‐PCM at the same levels which have been used for geometry determination in the gas‐phase. The results that show the calculated pK_a values using the B3LYP are better than those using the corresponding HF. In comparison to the other models, the results obtained indicate that the PCM model is a suitable solvation model for calculating pK_a values. For the investigated compounds, a good agreement between the experimental and the calculated pK_a values was also observed. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Experimentation with different thermodynamic cycles used for pKa calculations on carboxylic acids using complete basis set and Gaussian‐n models combined with CPCM continuum solvation methods

Complete basis set and Gaussian‐n methods were combined with Barone and Cossi's implementation of the polarizable conductor model (CPCM) continuum solvation methods to calculate pK_a values for six carboxylic acids. Four different thermodynamic cycles were considered in this work. An experimental value of ?264.61 kcal/mol for the free energy of solvation of H⁺, ΔG_s(H⁺), was combined with a value for G_gas(H⁺) of ?6.28 kcal/mol, to calculate pK_a values with cycle 1. The complete basis set gas‐phase methods used to calculate gas‐phase free energies are very accurate, with mean unsigned errors of 0.3 kcal/mol and standard deviations of 0.4 kcal/mol. The CPCM solvation calculations used to calculate condensed‐phase free energies are slightly less accurate than the gas‐phase models, and the best method has a mean unsigned error and standard deviation of 0.4 and 0.5 kcal/mol, respectively. Thermodynamic cycles that include an explicit water in the cycle are not accurate when the free energy of solvation of a water molecule is used, but appear to become accurate when the experimental free energy of vaporization of water is used. This apparent improvement is an artifact of the standard state used in the calculation. Geometry relaxation in solution does not improve the results when using these later cycles. The use of cycle 1 and the complete basis set models combined with the CPCM solvation methods yielded pK_a values accurate to less than half a pK_a unit. © 2001 John Wiley & Sons, Inc. Int J Quantum Chem, 2001     

Potential energy surface of the reaction of imidazole with peroxynitrite: Density functional theory study

This article presents a theoretical investigation of the reaction mechanism of imidazole nitration by peroxynitrite using density functional theory calculations. Understanding this reaction mechanism will help in elucidating the mechanism of guanine nitration by peroxynitrite, which is one of the assumed chemical pathways for damaging DNA in cells. This work focuses on the analysis of the potential energy surface (PES) for this reaction in the gas phase. Calculations were carried out using Hartree–Fock (HF) and density functional theory (DFT) Hamiltonians with double‐zeta basis sets ranging from 6‐31G(d) to 6‐31++G(d,p), and the triple‐zeta basis set 6‐311G(d). The computational results reveal that the reaction of imidazole with peroxynitrite in gas phase produces the following species: (i) hydroxide ion and 2‐nitroimidazole, (ii) hydrogen superoxide ion and 2‐nitrosoimidazole, and (iii) water and 2‐nitroimidazolide. The rate‐determining step is the formation of a short‐lived intermediate in which the imidazole C₂ carbon is covalently bonded to peroxynitrite nitrogen. Three short‐lived intermediates were found in the reaction path. These intermediates are involved in a proton‐hopping transport from C₂ carbon to the terminal oxygen of the ? O? O moiety of peroxynitrite via the nitroso (ON? ) oxygen. Both HF and DFT calculations (using the Becke3–Lee–Yang–Parr functional) lead to similar reaction paths for proton transport, but the landscape details of the PES for HF and DFT calculations differ. This investigation shows that the reaction of imidazole with peroxynitrite produces essentially the same types of products (nitro‐ and nitroso‐) as observed experimentally in the reaction of guanine with peroxynitrite, which makes the former reaction a good model to study by computation the essential characteristics of the latter reaction. Nevertheless, the computationally determined activation energy for imidazole nitration by peroxynitrite in the gas phase is 84.1 kcal/mol (calculated at the B3LYP/6‐31++G(d,p) level), too large for an enzymatic reaction. Exploratory calculations on imidazole nitration in solution, and on the reaction of 9‐methylguanine with peroxynitrite in the gas phase and solution, show that solvation increases the activation energy for both imidazole and guanine, and that the modest decrease (15 kcal mol^?1) in the activation energy, due to the adjacent six member ring of guanine, is counterbalanced by solvation. These results lead to the speculation that proton tunneling may be at the origin of experimentally observed high reaction rate of guanine nitration by peroxynitrite in solution. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005     

Fluoro‐ and Perfluoralkylsulfonylpentafluoroanilides: Synthesis and Characterization of NH Acids for Weakly Coordinating Anions and Their Gas‐Phase and Solution Acidities

Fluoro‐ and perfluoralkylsulfonyl pentafluoroanilides [HN(C₆F₅)(SO₂X); X=F, CF₃, C₄F₉, C₈F₁₇] are a class of imides with two different strongly electron‐withdrawing substituents attached to a nitrogen atom. They are NH acids, the unsymmetrical hybrids of the well‐known symmetrical bissulfonylimides and bispentafluorophenylamine. The syntheses, the structures of these perfluoroanilides, their solvates, and some selected lithium salts give rise to a structural variety beyond the symmetrical parent compounds. The acidities of representative subsets of these novel NH acids have been investigated experimentally and quantum‐chemically and their gas‐phase acidities (GAs) are reported, as well as the pK_a values of these compounds in acetonitrile (MeCN) and DMSO solution. In quantum chemical investigations with the vertical and relaxed COSMO cluster‐continuum models (vCCC/rCCC), the unusual situation is encountered that the DMSO‐solvated acid Me₂SO–H‐N(SO₂CF₃)₂, optimized in the gas phase (vCCC model), dissociates to Me₂SO‐H⁺–N(SO₂CF₃)₂^? during structural relaxation and full optimization with the solvation model turned on (rCCC model). This proton transfer underlines the extremely high acidity of HN(SO₂CF₃)₂. The importance of this effect is studied computationally in DMSO and MeCN solution. Usually this effect is less pronounced in MeCN and is of higher importance in the more basic solvent DMSO. Nevertheless, the neglect of the structural relaxation upon solvation causes typical changes in the computational pK_a values of 1 to 4 orders of magnitude (4–20 kJ mol^?1). The results provide evidence that the published experimental DMSO pK_a value of HN(SO₂CF₃)₂ should rather be interpreted as the pK_a of a Me₂SO‐H⁺–N(SO₂CF₃)₂^? contact ion pair.     

Calculating pKa values for substituted phenols and hydration energies for other compounds with the first‐order fuzzy‐border continuum solvation model

We have computed pK_a values for 11 substituted phenol compounds using the continuum Fuzzy‐Border (FB) solvation model. Hydration energies for 40 other compounds, including alkanes, alkenes, alkynes, ketones, amines, alcohols, ethers, aromatics, amides, heterocycles, thiols, sulfides, and acids have been calculated. The overall average unsigned error in the calculated acidity constant values was equal to 0.41 pH units and the average error in the solvation energies was 0.076 kcal/mol. We have also reproduced pK_a values of propanoic and butanoic acids within about 0.1 pH units from the experimental values by fitting the solvation parameters for carboxylate ion carbon and oxygen atoms. The FB model combines two distinguishing features. First, it limits the amount of noise which is common in numerical treatment of continuum solvation models by using fixed‐position grid points. Second, it uses either second‐ or first‐order approximation for the solvent polarization, depending on a particular implementation. These approximations are similar to those used for solute and explicit solvent fast polarization treatment which we developed previously. This article describes results of using the first‐order technique. This approximation places the presented methodology between the Generalized Born and Poisson‐Boltzmann continuum solvation models with respect to their accuracy of reproducing the many‐body effects in modeling a continuum solvent. © 2012 Wiley Periodicals, Inc.     

Experimental and computational study of the pKa of coumaric acid derivatives

The dissociation constant (pK_a) of a drug is a key parameter in drug discovery and pharmaceutical formulation. The hydroxy substituent has a significant effect on the acidity of hydroxycinnamic acid. In this work, the acidic constants of coumaric acids are obtained experimentally by spectrophotometry using the chemometric method and calculated theoretically using ab initio quantum mechanical method at the HF/6‐31G* level of theory in combination with the SMD continuum solvation method. Rank annihilation factor analysis (RAFA) is an efficient chemometric technique based on the elimination of the contribution of one of the chemical components from the data matrix. RAFA cannot be performed because the pure spectrum of HA^? is not available. So, two‐rank annihilation factor analysis (TRAFA) is proposed for the determination of the pK_a OF H₂A. A comparison between the pK_a values obtained previously by TRAFA for the molecules o‐coumaric acid (4.13, 9.58), m‐coumaric acid (4.48, 10.35), and p‐coumaric acid (4.65, 9.92) makes it clear that there is good agreement between the results obtained by TRAFA and ab initio quantum mechanical method.     

Ion‐Pair SN2 Reaction of OH− and CH3Cl: Activation Strain Analyses of Counterion and Solvent Effects

We have theoretically studied the non‐identity S_N2 reactions of M_nOH^(n?1)+CH₃Cl (M⁺=Li⁺, Na⁺, K⁺, and MgCl⁺; n=0, 1) in the gas phase and in THF solution at the OLYP/6‐31++G(d,p) level using polarizable continuum model (PCM) implicit solvation. We want to explore and understand the effect of the metal counterion M⁺ and solvation on the reaction profile and the stereoselectivity of these processes. To this end, we have explored the potential energy surfaces of the backside (S_N2‐b) and frontside (S_N2‐f) pathways. To explain the computed trends, we have carried out analyses with an extended activation strain model (ASM) of chemical reactivity that includes the treatment of solvation effects.     

Ab Initio and DFT Studies on CO2 Interacting with Znq+–Imidazole (q=0, 1, 2) Complexes: Prediction of Charge Transfer through σ‐ or π‐Type Models

Using first‐principles methodologies, the equilibrium structures and the relative stability of CO₂@[Zn^q+Im] (where q=0, 1, 2; Im=imidazole) complexes are studied to understand the nature of the interactions between the CO₂ and Zn^q+–imidazole entities. These complexes are considered as prototype models mimicking the interactions of CO₂ with these subunits of zeolitic imidazolate frameworks or Zn enzymes. These computations are performed using both ab initio calculations and density functional theory. Dispersion effects accounting for long‐range interactions are considered. Solvent (water) effects were also considered using a polarizable continuum model approach. Natural bond orbital, charge, frontier orbital and vibrational analyses clearly reveal the occurrence of charge transfer through covalent and noncovalent interactions. Moreover, it is found that CO₂ can adsorb through more favorable π‐type stacking as well as σ‐type hydrogen‐bonding interactions. The inter‐monomer interaction potentials show a significant anisotropy that might induce CO₂ orientation and site‐selectivity effects in porous materials and in active sites of Zn enzymes. Hence, this study provides valuable information about how CO₂ adsorption takes place at the microscopic level within zeolitic imidazolate frameworks and biomolecules. These findings might help in understanding the role of such complexes in chemistry, biology and material science for further development of new materials and industrial applications.     

Accurate pKa Calculation of the Conjugate Acids of Alkanolamines,Alkaloids and Nucleotide Bases by Quantum Chemical Methods

The pK_a of the conjugate acids of alkanolamines, neurotransmitters, alkaloid drugs and nucleotide bases are calculated with density functional methods (B3LYP, M08‐HX and M11‐L) and ab initio methods (SCS‐MP2, G3). Implicit solvent effects are included with a conductor‐like polarizable continuum model (CPCM) and universal solvation models (SMD, SM8). G3, SCS‐MP2 and M11‐L methods coupled with SMD and SM8 solvation models perform well for alkanolamines with mean unsigned errors below 0.20 pK_a units, in all cases. Extending this method to the pK_a calculation of 35 nitrogen‐containing compounds spanning 12 pK_a units showed an excellent correlation between experimental and computational pK_a values of these 35 amines with the computationally low‐cost SM8/M11‐L density functional approach.     

Active-site α-helix in papain and the stability of the ion pair RS− ··· ImH+. Ab initio molecular orbital study

Ab initio MO calculations, using both minimal (STO -3G) and extended (Roos–Siegbahn) basis sets are reported for the systems methanethiol–imidazole, methanethiol–imidazole–formaldehyde, and methanethiol–imidazole–formamide, which, together with a point-change representation of a long α-helix, form models for the active site of papain. It is shown that the large electric field exerted by the helix in the active-site region is responsible for the presence of the essential residues Cys 25 and His 159 in the form of an ion pair RS^? ··· ImH⁺, which is crucial for a recently proposed mechanism for the catalytic action of the enzyme. Also, an explanation is given for the anomalies in measured pK values for these residues. Detailed studies on the (sub)systems show that minimal basis sets lack the flexibility necessary for describing the type of proton transfer involved. We conclude that α-helices are essential parts of enzymes and that they play a significant role in the catalytic process.     

A new method of accurate pKb determinations for some organic amines

The accurate pK_b determinations for some amines have been investigated using the combination of the extended clusters‐continuum model with the polarizable continuum solvation model. The formation of molecular clusters by means of the amines wrapped up with water molecules leads to the weakness of the mutual function between the polar solvents and the amines, and, hence, the accuracy of pK_b has been enhanced by using a coherent and well‐defined approach without external approximations or experimental data. The calculations are performed at the HF/6‐311++G(d, p) level and agreed well with experimental data because electron correlation effect cancels mutually in the calculated value of ΔG which is not an absolute value, but a relative value. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2008     

Calculation of dissociation constants and chemical hardness of some biologically important molecules: A theoretical study

The gas‐phase geometries of neutral, protonated, and deprotonated forms of some biologically important molecules, alanine (Ala), glycine (Gly), phenylalanine (Phe), and tyrosine (Tyr), were optimized using density functional theory at B3LYP/6‐311++G(d) and the ab initio HF/6‐311++G(d) level of theories. The neutral and different stable ionic states of Ala, Gly, Phe, and Tyr have also been solvated in aqueous medium using polarizable continuum model for the determination of solvation free energies in the aqueous solution. The gas‐phase acidity constants of above four molecules have been also calculated at both levels of theories and found that the values calculated at HF/6‐311++G(d) method are in good agreement with experimental results. A thermodynamic cycle was used to determine the solvation free energies for the proton dissociation process in aqueous solution and the corresponding pK_a values of these molecules. The pK_a values calculated at B3LYP/6‐311++G(d) method are well supported by the experimental data with a mean absolute deviation 0.12 pK_a units. Additionally, the chemical hardness and the ionization potential (IP) for these molecules have been also explored at both the level of theories. The Tyr has less value of chemical hardness and IP at both levels of theories compared with other three molecules, Ala, Gly, and Phe. The calculated values of chemical hardness and IP are decreasing gradually with the substitution of the various functional groups in the side chain of the amino acids. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

A pH Scale for the Protic Ionic Liquid Ethylammonium Nitrate

To quantify the properties of protic ionic liquids (PILs) as acid–base reaction media, potentiometric titrations were carried out in a neat PIL, ethylammonium nitrate (EAN). A linear relationship was found between the 14 pK_a values of 12 compounds in EAN and in water. In other words, the pK_a value in EAN was found to be roughly one unit greater than that in water regardless of the charge and hydrophobicity of the compounds. It is possible that this could be explained by the stronger acidity of HNO₃ in EAN than that of H₃O⁺ in water and not by the difference in the solvation state of the ions. The pH value in EAN ranges from ?1 to 9 on the pH scale based on the pH value in water.     

Fragmentation of deprotonated cyclic dipeptides by electrospray ionization mass spectrometry

The fragmentation pathways of deprotonated cyclic dipeptides have been studied by electrospray ionization multi‐stage mass spectrometry (ESI‐MSⁿ) in negative mode. The results showed that the fragmentation pathways of deprotonated cyclic dipeptides depended significantly on the different substituents, the side chains of amino acid residues at the diketopiperazine ring. In the spectra of deprotonated cyclic dipeptides, the ion [M? H? substituent radical]^? was firstly observed in the ESI mode. The characteristic fragment ions [M? H? substituent radical]^? and [M? H? (substituent? H)]^? could be used as the symbols of particular cyclic dipeptides. The hydrogen/deuterium (H/D) exchange experiment, the high‐resolution mass spectrometry (Q‐TOF) and theoretical calculations were used to rationalize the proposed fragmentation pathways and to verify the differences between the fragmentation pathways. The relative Gibbs free energies (ΔG) of the product ions and possible fragmentation pathways were estimated using the B3LYP/6–31++G(d, p) model. The results have some potential applications in the structural elucidation and interpretation of the mass spectra of homologous compounds and will enrich the gas‐phase ESI‐MS ion chemistry of cyclic dipeptides. Copyright © 2009 John Wiley & Sons, Ltd.     

The salt–cocrystal spectrum in salicylic acid–adenine: the influence of crystal structure on proton‐transfer balance

At one extreme of the proton‐transfer spectrum in cocrystals, proton transfer is absent, whilst at the opposite extreme, in salts, the proton‐transfer process is complete. However, for acid–base pairs with a small ΔpK_a (pK_a of base ? pK_a of acid), prediction of the extent of proton transfer is not possible as there is a continuum between the salt and cocrystal ends. In this context, we attempt to illustrate that in these systems, in addition to ΔpK_a, the crystalline environment could change the extent of proton transfer. To this end, two compounds of salicylic acid (SaH) and adenine (Ad) have been prepared. Despite the same small ΔpK_a value (≈1.2), different ionization states are found. Both crystals, namely adeninium salicylate monohydrate, C₅H₆N₅⁺·C₇H₅O₃^?·H₂O, I , and adeninium salicylate–adenine–salicylic acid–water (1/2/1/2), C₅H₆N₅⁺·C₇H₅O₃^?·2C₅H₅N₅·C₇H₆O₃·2H₂O, II , have been characterized by single‐crystal X‐ray diffraction, IR spectroscopy and elemental analysis (C, H and N) techniques. In addition, the intermolecular hydrogen‐bonding interactions of compounds I and II have been investigated and quantified in detail on the basis of Hirshfeld surface analysis and fingerprint plots. Throughout the study, we use crystal engineering, which is based on modifications of the intermolecular interactions, thus offering a more comprehensive screening of the salt–cocrystal continuum in comparison with pure pK_a analysis.     

Theoretical Study of Firefly Luciferin pKa Values—Relative Absorption Intensity in Aqueous Solutions

Ground‐state vibrational analyses of firefly luciferin and its conjugate acids and bases are performed. The Gibbs free energies obtained from these analyses are used to estimate pK_a values for phenolic hydroxy and carboxy groups and the N–H⁺ bond in the N‐protonated thiazoline or benzothiazole ring of firefly luciferin. The theoretical pK_a values are corrected using the experimental values. The concentrations of these chemical species in solutions with different pH values are estimated from their corrected pK_a values, and the pH dependence of their relative absorption intensities is elucidated. With the results obtained we assign the experimental spectra unequivocally. Especially, the small peak near 400 nm at pH 1–2 in experimental absorption spectra is clarified to be due to the excitation of carboxylate anion with N‐protonated thiazoline ring of firefly luciferin. Our results show that the pK_a values of chemical species, which are contained in the aqueous solutions, are effective to assign experimental absorption spectra.     

Monohydration selectivity mechanism of alkali cations in the potassium channel of excitable biomembranes

Nonempirical quantum chemical method Hartree–Fock–Roothan LCAO SCF MO in a two-exponent Dunning basis with the use of an extended set of Gaussian functions by Huzinaga–Dunning with consideration of electron correlation according to the Meller–Plesset theory of excitations of the second order was used to study monohydrates of Li⁺, Na⁺, K⁺, and HCOO^? ions. The indicated basis was supplemented with polarization functions of d-type on the O atom and of p-type on the hydrogen atom as well as with diffusion functions of p-type on the oxygen atom. It has been found that binding energies of the water molecule with Li⁺, Na⁺ appeared to be higher and with K⁺ lower than with HCOO^? · H₂O. Potential curve shapes of K⁺ + H₂O and HCOO^? + H₂O reactions are shown to be similar. The molecular mechanism of K⁺ channel selectivity of an excitable membrane is explained on the basis of the obtained calculations.     

A universal approach for continuum solvent pK a calculations: are we there yet?

This paper reviews several pK _a calculation strategies that are commonly used in aqueous acidity predictions. Among those investigated were the direct or absolute method, the proton exchange scheme, and the hybrid cluster–continuum (Pliego and Riveros) and implicit–explicit (Kelly, Cramer and Truhlar) models. Additionally, these protocols are applied in the pK _a calculation of 55 neutral organic and inorganic acids in conjunction with various solvent models, including the CPCM-UAKS/UAHF, IPCM, SM6 and COSMO-RS, with a view to identifying a universal approach for accurate pK _a predictions. The results indicate that the direct method is unsuitable for general pK _a calculations, although moderately accurate results (MAD <3 units) are possible for certain classes of acids, depending on the choice of solvent model. The proton exchange scheme generally delivers good results (MAD <2 units), with CPCM-UAKS giving the best performance. Furthermore, the sensitivity of this approach to the choice of reference acid can be substantially lessened if the solvation energies for ionic species are calculated via the IPCM cluster–continuum approach. Reference-independent hybrid approaches that include explicit water molecules can potentially give reasonably accurate values (MAD generally ~2 units) depending on the solvent model and the number of explicit water molecules added.     

Enolate Stabilization by Anion–π Interactions: Deuterium Exchange in Malonate Dilactones on π‐Acidic Surfaces

Of central importance in chemistry and biology, enolate chemistry is an attractive topic to elaborate on possible contributions of anion–π interactions to catalysis. To demonstrate the existence of such contributions, experimental evidence for the stabilization of not only anions but also anionic intermediates and transition states on π‐acidic aromatic surfaces is decisive. To tackle this challenge for enolate chemistry with maximal precision and minimal uncertainty, malonate dilactones are covalently positioned on the π‐acidic surface of naphthalenediimides (NDIs). Their presence is directly visible in the upfield shifts of the α‐protons in the ¹H NMR spectra. The reactivity of these protons on π‐acidic surfaces is measured by hydrogen–deuterium (H–D) exchange for 11 different examples, excluding controls. The velocity of H–D exchange increases with π acidity (NDI core substituents: SO₂R>SOR>H>OR>OR/NR₂>SR>NR₂). The H–D exchange kinetics vary with the structure of the enolate (malonates>methylmalonates, dilactones>dithiolactones). Moreover, they depend on the distance to the π surface (bridge length: 11–13 atoms). Most importantly, H–D exchange depends strongly on the chirality of the π surface (chiral sulfoxides as core substituents; the crystal structure of the enantiopure (R,R,P)‐macrocycle is reported). For maximal π acidity, transition‐state stabilizations up to ?18.8 kJ mol^?1 are obtained for H–D exchange. The Brønsted acidity of the enols increases strongly with π acidity of the aromatic surface, the lowest measured pK_a=10.9 calculates to a ΔpK_a=?5.5. Corresponding to the deprotonation of arginine residues in neutral water, considered as “impossible” in biology, the found enolate–π interactions are very important. The strong dependence of enolate stabilization on the unprecedented seven‐component π‐acidity gradient over almost 1 eV demonstrates quantitatively that such important anion–π activities can be expected only from strong enough π acids.