Enantioselective Synthesis and Physicochemical Properties of Libraries of 3‐Amino‐ and 3‐Amidofluoropiperidines

The enantioselective syntheses of 3‐amino‐5‐fluoropiperidines and 3‐amino‐5,5‐difluoropiperidines were developed using the ring enlargement of prolinols to access libraries of 3‐amino‐ and 3‐amidofluoropiperidines. The study of the physicochemical properties revealed that fluorine atom(s) decrease(s) the pK_a and modulate(s) the lipophilicity of 3‐aminopiperidines. The relative stereochemistry of the fluorine atoms with the amino groups at C3 on the piperidine core has a small effect on the pK_a due to conformationnal modifications induced by fluorine atom(s). In the protonated forms, the C?F bond is in an axial position due to a dipole–dipole interaction between the N?H⁺ and C?F bonds. Predictions of the physicochemical properties using common software appeared to be limited to determine correct values of pK_a and/or differences of pK_a between cis‐ and trans‐3‐amino‐5‐fluoropiperidines.     

Computation of the influence of chemical substitution on the pK a of pyridine using semiempirical and ab initio methods

The physical properties of chemicals are strongly influenced by their protonation state, affecting, for example, solubility or hydrogen-bonding characteristics. The ability to accurately calculate protonation states in the form of pK _as is, therefore, desirable. Calculations of pK _a changes in a series of substituted pyridines are presented. Computations were performed using both ab initio and semiempirical approaches, including free energies of solvation via reaction-field models. The selected methods are readily accessible with respect to both software and computational feasibility. Comparison of calculated and experimental pK _as shows the experimental trends to be reasonably reproduced by the computations with root-mean-square differences ranging from 1.22 to 4.14 pK _a units. Of the theoretical methods applied the best agreement occurred using the second-order M?ller–Plesset/6-31G(d)/isodensity surface polarized continuum solvation model, while the more computationally accessible Austin model 1/Solvent model 2 (SM2) approach yielded results similar to the ab initio methods. Analysis of component contributions to the calculated pK _as indicates the largest source of error to be associated with the free energies of solvation of the protonated species followed by the gas-phase protonation energies; while the latter may be improved via the use of higher levels of theory, enhancements in the former require improvements in the solvation models. The inclusion of alternate minimum in the computation of pK _as is also indicated to contribute to differences between experimental and calculated pK _a values. Received: 27 April 1999 / Accepted: 27 July 1999 / Published online: 2 November 1999     

PKA17—A Coarse-Grain Grid-Based Methodology and Web-Based Software for Predicting Protein pK a Shifts

We have developed and tested PKA17, a coarse-grain grid-based model for predicting protein pK _a shifts. Our pK _a predictor is currently deployed via a website interface. We have carried out parameter fitting using 442 Asp, Glu, His, Lys, and Arg residues for which experimental results are available in the literature. PROPKA software has been used for benchmarking. The average unsigned error and root-mean-square deviation (RMSD) have been found to be 0.628 and 0.831 pH units, respectively, for PKA17. The corresponding results with PROPKA are 0.761 and 1.063 units. We have assessed the robustness of the developed PKA17 methodology with a number of tests and have also explored the possibility of using a combination of PROPKA and PKA17 calculations in order to improve the accuracy of predicted pK _a values for protein residues. We have also once again confirmed that protein acidity constants are influenced almost entirely by residues in the immediate spatial proximity of the ionizable amino acids. The resulting PKA17 software has been deployed online with a web-based interface at http://users.wpi.edu/~jpcvitkovic/pka_calc.html . © 2019 Wiley Periodicals, Inc.     

Imidazoline‐N‐oxyl: A DFT Study of Its Protonation Reaction

Imidazoline‐based nitroxides are developed as pH probes. Their pK_a values vary over a wide range (from 1 to 11), depending on the substituents attached to the five‐membered cyclic nitroxide. Density functional calculations using the PBE1PBE method at the 6‐31+G(d,p) level, combined with natural bond orbital (NBO), frontier molecular orbital (FMO), geometry, Mulliken charge, and thermodynamic analyses, are carried out to disclose the effects involved in the changes in pK_a. The studies show that the decrease of seven pK_a units from pyrrolidine ( 11 ) to imidazoline‐N‐oxyl 8 is due to the inductive electron‐withdrawing capacity of the nitroxyl group. On the other hand, by combining both the inductive and mesomeric electron‐withdrawing capacities of the NO₂ group with delocalization of the lone pair on the amino N atom of the π system of the vinyl linker, the pK_a of 4.5 of 8 was increased by around three units to 7.8 for 1 / 2 .     

Docking flexible ligands in proteins with a solvent exposure- and distance-dependent dielectric function

Physics-based force fields for ligand–protein docking usually determine electrostatic energy with distance-dependent dielectric (DDD) functions, which do not fully account for the dielectric permittivity variance between ~2 in the protein core and ~80 in bulk water. Here we propose an atom–atom solvent exposure- and distance-dependent dielectric (SEDDD) function, which accounts for both electrostatic and dehydration energy components. Docking was performed using the ZMM program, the AMBER force field, and precomputed libraries of ligand conformers. At the seeding stage, hundreds of thousands of positions and orientations of conformers from the libraries were sampled within the rigid protein. At the refinement stage, the ten lowest-energy structures from the seeding stage were Monte Carlo-minimized with the flexible ligand and flexible protein. A search was considered a success if the root mean square deviation (RMSD) of the ligand atoms in the apparent global minimum from the x-ray structure was <2 Å. Calculations on an examining set of 60 ligand–protein complexes with different DDD functions and solvent-exclusion energy revealed outliers in most of which the ligand-binding site was located at the protein surface. Using a training set of 16 ligand–protein complexes, which did not overlap with the examining set, we parameterized the SEDDD function to minimize the RMSD of the apparent global minima from the x-ray structures. Recalculation of the examining set with the SEDDD function demonstrated a 20% increase in the success rate versus the best-performing DDD function.     

Determination of acidity constants of pyridines,imidazoles, and oximes by capillary electrophoresis

The acidity constant in the form of pK_a is one of the most important physicochemical quantities. There are prediction tools available for calculating the pK_a, but they only deliver precise calculated values for a relatively small set of chemicals. For complex structures with multiple functional groups in particular, the error in the predicted pK_a is high due to the application domain of the corresponding models. Thus, we aim to enlarge the dataset of experimentally determined pK_a values using capillary electrophoresis. We, therefore, selected various pyridines, imidazoles, and oximes to determine the pK_a values using the internal standard approach and the classical method. Especially oximes were not investigated in the past, and predictions for them include larger errors. Thus, our experimentally determined values could contribute to an improved understanding of various functional groups impacting the pK_a values and serve as additional datasets to develop improved pK_a prediction tools.     

Computing ionization states of proteins with a detailed charge model

A convenient computational approach for the calculation of the p K_as of ionizable groups in a protein is described. The method uses detailed models of the charges in both the neutral and ionized form of each ionizable group. A full derivation of the theoretical framework is presented, as are details of its implementation in the UHBD program. Application to four proteins whose crystal structures are known shows that the detailed charge model improves agreement with experimentally determined pK_as when a low protein dielectric constant is assumed, relative to the results with a simpler single-site ionization model. It is also found that use of the detailed charge model increases the sensitivity of the computed pK_as to the details of proton placement. © 1996 by John Wiley & Sons, Inc.     

Density functional theoretical study of pKa of RCOOH (RH,CH3, and C2H5) using the combination of the extended clusters‐continuum model

The accurate pK_a determinations for three carboxylic acids have been investigated using the combination of the extended clusters‐continuum model at B3LYP/6‐31+g(d,p) and B3LYP/6‐311++g(d,p) levels. To take into account of the effect of the water combined with carboxylic acids in different positions, eleven molecular clusters were considered. Among these clusters, the one involving the carboxylic acid wrapped up with water molecules and saturated with hydrogen bonds (four hydrogen bonds around ? COOH) leads to the best B3LYP pK_a results compared to the experimental data. For those clusters saturated with hydrogen bonds, when n = 3 (the number of water molecules), the average absolute errors between the calculated pK_a results and experimental data of these three carboxylic acids were 0.19 (0.23) and 0.12 (0.22) pK_a at B3LYP/6‐31+g(d,p)//PCM (IEFPCM) and B3LYP/6‐311++g(d,p)//PCM (IEFPCM) levels, respectively; when n = 4, they are 0.53 (1.23) and 1.09 (1.03) pK_a, respectively. On the basis of the above results, the molecular cluster saturated with four hydrogen bonds formed by three waters and one carboxylic acid molecule was the chief existence in the carboxylic acid solution. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2012     

A reliable and efficient first principles‐based method for predicting pKa values. 4. organic bases

The ionization (dissociation) constant (pK_a) is one of the most important properties of a drug molecule. It is reported that almost 68% of ionized drugs are weak bases. To be able to predict accurately the pK_a value(s) for a drug candidate is very important, especially in the early stages of drug discovery, as calculations are much cheaper than determining pK_a values experimentally. In this study, we derive two linear fitting equations (pK_a = a × ΔE + b; where a and b are constants and ΔE is the energy difference between the cationic and neutral forms, i.e., ΔE = E_neutral?E_cationic) for predicting pK_as for organic bases in aqueous solution based on a training/test set of almost 500 compounds using our previously developed protocol (OLYP/6‐311+G**//3‐21G(d) with the the conductor‐like screening model solvation model, water as solvent; see Zhang, Baker, Pulay, J. Phys. Chem. A 2010 , 114, 432). One equation is for saturated bases such as aliphatic and cyclic amines, anilines, guanidines, imines, and amidines; the other is for unsaturated bases such as heterocyclic aromatic bases and their derivatives. The mean absolute deviations for saturated and unsaturated bases were 0.45 and 0.52 pK_a units, respectively. Over 60% and 86% of the computed pK_a values lie within ±0.5 and ±1.0 pK_a units, respectively, of the corresponding experimental values. The results further demonstrate that our protocol is reliable and can accurately predict pK_a values for organic bases. © 2012 Wiley Periodicals, Inc.     

SAMPL6: calculation of macroscopic p<Emphasis Type="Italic">K</Emphasis><Subscript>a</Subscript> values from ab initio quantum mechanical free energies

Macroscopic pK_a values were calculated for all compounds in the SAMPL6 blind prediction challenge, based on quantum chemical calculations with a continuum solvation model and a linear correction derived from a small training set. Microscopic pK_a values were derived from the gas-phase free energy difference between protonated and deprotonated forms together with the Conductor-like Polarizable Continuum Solvation Model and the experimental solvation free energy of the proton. pH-dependent microstate free energies were obtained from the microscopic pK_as with a maximum likelihood estimator and appropriately summed to yield macroscopic pK_a values or microstate populations as function of pH. We assessed the accuracy of three approaches to calculate the microscopic pK_as: direct use of the quantum mechanical free energy differences and correction of the direct values for short-comings in the QM solvation model with two different linear models that we independently derived from a small training set of 38 compounds with known pK_a. The predictions that were corrected with the linear models had much better accuracy [root-mean-square error (RMSE) 2.04 and 1.95 pK_a units] than the direct calculation (RMSE 3.74). Statistical measures indicate that some systematic errors remain, likely due to differences in the SAMPL6 data set and the small training set with respect to their interactions with water. Overall, the current approach provides a viable physics-based route to estimate macroscopic pK_a values for novel compounds with reasonable accuracy.     

Laser raman and infrared spectrum of poly-p-xylylene

The dipole moments μ_ab of some forty complexes between substituted phenols and substituted pyridines were determined, using the Onsager relation. The dipole increment Δμ, vector difference between μ_ab and the dipole moments μ_a and μ_b of the components, show a coherent evolution with the pK_a of the donor and of the acceptor and with the complexation enthalpy, when such orientations of the molecules which correspond to a hydrogen bond between the O-H group of the phenol and the lone pair of electrons of the nitrogen atom of the base are chosen. This evolution with respect to the ΔpK_a is given by a unique curve for all the complexes. This shows that the difference in pK_a between the donor and the acceptor is the main factor determining Δμ for these complexes. This curve presents a sigmoidal aspect in agreement with a model assuming a tautomeric equilibrium between two forms of the hydrogen bond: A-H·B ? A^?·H⁺-B. The corresponding equilibrium constant K_s was computed for the complexes lying in the transition region and obeys the linear relation, log K_s = 0.7pK_a-2.25. The data also permit the evaluation of the angle θ_a between the O-H direction and the dipole moment of the 3,4-dinitrophenol. This angle is of the order of magnitude of 70°, showing the presence of appreciable amounts of different rotamers around the C-O direction in the complexes composed of this acid with pyridines.     

Determination of acidity constants,ionic mobilities,and hydrodynamic radii of carborane-based inhibitors of carbonic anhydrases by capillary electrophoresis

Capillary electrophoresis (CE) has been applied for determination of the thermodynamic acidity constants (pK_a) of the sulfamidoalkyl and sulfonamidoalkyl groups, the actual and limiting ionic mobilities and hydrodynamic radii of important compounds, eight carborane-based inhibitors of carbonic anhydrases, which are potential new anticancer drugs. Two types of carboranes were investigated, (i) icosahedral cobalt bis(dicarbollide)(1-) ion with sulfamidoalkyl moieties, and (ii) 7,8-nido-dicarbaundecaborate with sulfonamidoalkyl side chains. First, the mixed acidity constants, pK_a^mix, of the sulfamidoalkyl and sulfonamidoalkyl groups of the above carboranes and their actual ionic mobilities were determined by nonlinear regression analysis of the pH dependences of their effective electrophoretic mobility measured by capillary electrophoresis in the pH range 8.00−12.25, at constant ionic strength (25 mM), and constant temperature (25°C). Second, the pK_a^mix were recalculated to the thermodynamic pK_as using the Debye–Hückel theory. The sulfamidoalkyl and sulfonamidoalkyl groups were found to be very weakly acidic with the pK_as in the range 10.78−11.45 depending on the type of carborane cluster and on the position and length of the alkyl chain on the carborane scaffold. These pK_as were in a good agreement with the pK_as (10.67−11.27) obtained by new program AnglerFish (freeware at https://echmet.natur.cuni.cz ), which provides thermodynamic pK_as and limiting ionic mobilities directly from the raw CE data. The absolute values of the limiting ionic mobilities of univalent and divalent carborane anions were in the range 18.3−27.8 TU (Tiselius unit, 1 × 10⁻⁹ m²/Vs), and 36.4−45.9 TU, respectively. The Stokes hydrodynamic radii of univalent and divalent carborane anions varied in the range 0.34−0.52 and 0.42−0.52 nm, respectively.     

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.     

EFFECT OF THE BROMINE ATOM UPON THE DISSOCIATION CONSTANTS OF BROMOPYRIDINES,BROMOQUINOLINES AND 4-BROMOISOQUINOLINE IN THEIR LOWEST EXCITED SINGLET AND TRIPLET STATES*

Abstract— The lowest excited singlet-state dissociation constants (pK^S_a) of bromosubstituted pyridines, quinolines, and isoquinolines were determined from the pH-dependent shifts in their electronic absorption spectra. The lowest excited triplet-state dissociation constants (pK^T_a) of bromosubstituted quinolines and 4-bromoisoquinoline were obtained from the shifts of the 0–0 phosphorescence bands measured in rigid aqueous solution at 77 K. The pK^S_a values indicate that the basicity of these brominated nitrogen heterocycles is increased in the lowest excited singlet state by 2 to 10 orders of magnitude as compared with the ground state. The pK^T_a values are found to be significantly different from the corresponding ground-state pK_a values, indicating that the basicity of bromoquinolines is increased in the lowest excited triplet state by 1.7 to 3.0 pK units. The enhancement of the excited singlet-and triplet-state basicity of brominated nitrogen heterocycle derivatives as compared with the unsuhstituted parent compounds is attributed to the increased electron-donor conjugative interactions of the bromine atom pπ orbitals with π orbitals in the lowest excited singlet and triplet state.     

Conformational analysis of vitamin K<Subscript>1</Subscript> model molecule: a theoretical study

Isomerism, conformations, and molecular structure of a model molecule of vitamin K₁ with a truncated side chain have been studied by the density functional theory calculations using B3LYP method and double- and triple-ζ correlation consistent basis sets. The conformations of two possible (E and Z) isomers, formed by the rotations around three single C–C bonds closest to the naphthoquinone ring, have been studied. The lowest energy conformers are stabilized by additional hydrogen bonds between hydrogen atoms of the side chain and an oxygen atom in the naphthoquinone subunit. It is interesting to note that the structure of the energetically preferred conformer of the E-isomer (3c) has been found to be similar to the solid state structures of phylloquinones in the photosystem I of cyanobacterium Synechococcus elongatus. The excited electronic states of two lowest energy conformers have also been investigated.     

The molecular structure of N-methylsuccinimide studied by gas-phase electron diffraction (GED) and quantum-chemical methods

The molecular structure of N-methylsuccinimide was studied by the GED method at a nozzle temperature of 69–73°C. Anharmonic vibrational corrections to thermal-average r _a bond lengths, Δ(r _a − r _e), were calculated using the quadratic and cubic force constants from B3LYP/6-31G(df, p) calculations. The molecular skeleton was found to be planar within measurement errors. Some structural effects were likely caused by the conjugation of the N atom with two C=O bonds. The equilibrium geometric parameters derived from the experimental data and those from MP2/cc-pVTZ(seg-opt) calculations were in close agreement.     

Conformation dependence of pKa’s of the chromophores from the purple asFP595 and yellow zFP538 fluorescent proteins

Two members of the green fluorescent protein family, the purple asFP595 and yellow zFP538 proteins, are perspective fluorescent markers for use in multicolor imaging and resonance energy-transfer applications. We report the results of quantum based calculations of the solution pK_a values for selected protonation sites of the denatured asFP595 and zFP538 chromophores in the trans- and cis-conformations in order to add in the interpretation of photo-physical properties of these proteins. The pK_a values were determined from the theromodynamic cycle based on B3LYP/6-311++G(2df, 2p) calculations of the gas phase free energies of the molecules and the B3LYP/6-311++G(d, p) calculations of solvation energies. The results show that the pK_a’s of the protonation sites of the chromophore from asFP595 noticeably depend on the isomer conformation (cis- or trans-), while those of zFP538 are much less sensitive to isomerization.     

CE determination of the thermodynamic pKa values and limiting ionic mobilities of 14 low molecular mass UV absorbing ampholytes for accurate characterization of the pH gradient in carrier ampholytes-based IEF and its numeric simulation

Fourteen low molecular mass UV absorbing ampholytes containing 1 or 2 weakly acidic and 1 or 2 weakly basic functional groups that best satisfy Rilbe's requirement for being good carrier ampholytes (ΔpK_a = pKa_monoanion ‒ pKa_monocation < 2) were selected from a large group of commercially readily available ampholytes in a computational study using two software packages (ChemSketch and SPARC). Their electrophoretic mobilities were measured in 10 mM ionic strength BGEs covering the 2 < pH < 12 range. Using our Debye-Hückel and Onsager-Fuoss laws-based new software, AnglerFish (freeware, https://echmet.natur.cuni.cz/software/download ), the effective mobilities were recalculated to zero ionic strength from which the thermodynamic pK_a values and limiting ionic mobilities of the ampholytes were directly calculated by Henderson-Hasselbalch equation-type nonlinear regression. The tabulated thermodynamic pK_a values and limiting ionic mobilities of these ampholytes (pI markers) facilitate both the overall and the narrow-segment characterization of the pH gradients obtained in IEF in order to mitigate the errors of analyte ampholyte pI assignments caused by the usual (but rarely proven) assumption of pH gradient linearity. These thermodynamic pK_a and limiting mobility values also enable the reality-based numeric simulation of the IEF process using, for example, Simul (freeware, https://echmet.natur.cuni.cz/software/download ).     

Physicochemical Properties of 1,2-Diacylhydrazines Derived from Aliphatic Carboxylic Acids

The solubility and resistance to oxidation and hydrolysis of 1,2-diacylhydrazines derived from acetic, propionic, butyric, and valeric acids were studied in view of possible application of these compounds for concentrating nonferrous metals. The pK ₁ and pK ₂ values of the 1,2-diacylhydrazines were determined. The stability of conformers and the electron density distribution in the coordination-active moiety were estimated by SCF MO LCAO semiempirical calculations in the MNDO-PM3 approximation.     

The modified hartree-fock self-consistent field equation

The electron density at the pyridine nitrogen atom and the π-electron density of the pyridine ring were calculated by the CNDO /2-MO method assuming standard bond lengths and angles. The indices were found to correlate with the pK_a values of pyridine derivatives and with the electronic substituent constants of the Hammett type. The correlations were best for four-substituted pyridines, making the routine CNDO /2-MO calculations useful for studies of quantitative relations between structure and biological activity of the compounds.