pKa Values Research Articles

Effect of pH and Buffer Capacity of Physiological Bicarbonate Buffer on Precipitation of Drugs.

The purpose of this study was to investigate the effect of the pH and buffer capacity (β) of physiological bicarbonate buffer solutions (BCB) on drug precipitation. The precipitation profiles of poorly soluble drugs in BCB were evaluated by using a pH-shift precipitation test. Phosphate buffer solutions (PPB) were used for comparison. Two weakly acidic drugs (pKa: 4.9 and 7.0) and two weakly basic drugs (pKa: 6.1 and 8.3) were used as model drugs. The bulk phase pH value (pHbulk) and β values were set to cover the physiological range in the small intestines (pH: 5.5 to 7.5, β: 2.2 to 17.6 mM/ΔpH). A floating lid was used to maintain the pHbulk of BCB to avoid CO2 loss. It was also applied to PPB to align the experimental conditions. Each drug was completely dissolved in HCl (pH 3.0, for weakly basic drugs) or NaOH (pH 11.0, for weakly acidic drugs) solutions (450 mL, 50 rpm, 37 °C). The pHbulk value was then shifted to the neutral pH region by adding a 10-fold concentrated buffer solution (50 mL, final volume of 500 mL). The initial total drug concentration (neutral + ionized species) was set so that the concentration and supersaturation ratio of the neutral species were the same under all pHbulk conditions. The solid forms of the precipitates were determined by powder X-ray diffraction and differential scanning calorimetry. In BCB, as pHbulk was increased above (for weakly acidic drugs) or decreased below (for weakly basic drugs) the drug pKa value, the precipitation of the free form solid became slower. As β was increased, drug precipitation in BCB became faster. Drug precipitation in PPB was faster than that in BCB and less affected by pHbulk and β. In BCB, at pHbulk at which a drug is ionizable, the surface pH of the precipitating particles can differ from pHbulk because of the slow hydration process of CO2. In conclusion, pHbulk and β affected the precipitation of weakly acidic and basic drugs in BCB. As BCB is a physiological buffer in the small intestine, it should be used for precipitation studies of weakly acidic and basic drugs.

Toward Explicit Solvation for Simulations of Electrocatalytic Reactions: AIMD for pKa and Redox Potentials of Transition Metal Compounds and Catalyst Models.

In this work, we study the possibility to extend electronic structure simulations for electrocatalysis by explicit solvation models. In previous work, we proposed a simulation scheme that explicitly includes the effects of pH and electrochemical potential in density functional theory (DFT) simulations with implicit solvation. Based on calculations of protonation and oxidation reactions, the pH and electrochemical potential can be included given appropriate reference values. In this work, we compute the pKa values and oxidation potentials for a series of transition metal aquo complexes and compare the results including implicit, explicit static and explicit dynamic (AIMD) models for the aqueous solvent and compare vs experimental pKa and redox potential data. This allows the construction of a pKa/redox potential scale that can in principle be extrapolated to the simulation of other transition metal-based materials. An explicit dynamic solvent model is then proposed and applied to a model system for iridium oxide-based catalysts for the oxygen evolution reaction. We outline the advantages and disadvantages of the different approaches and demonstrate that, at the expense of a larger computational effort, the microsolvation environment of a given model can be described in a robust way using a limited amount of solvent molecules and AIMD. Especially for reactions in which water is solvent and reactant like the oxygen evolution reaction (OER) or oxygen reduction reaction (ORR), this model provides a more detailed and complete description that can be exploited in mechanistic studies.

Design, Synthesis, and Anti‐Glioma Activity Evaluation of Dehydroabietic Acid Derivatives

AbstractDehydroabietic acid (DHAA) is a common natural product with a broad range of biological activities. In previous research, our group identified a range of dehydroabietic acid derivatives with strong anti‐glioma activity. In order to search for better anti‐glioma drugs candidates, new chalcone derivatives A1‐A10 and B1‐B10 were designed and synthesized in this study. The antiproliferative activity of these derivatives against U87 glioma cells was tested by CCK‐8 assay, in which A10 has the best IC50 value of 11.39 µM. Scratch and cloning studies further confirmed that A10 strongly inhibited the proliferation and colony‐forming activity of U87 cells. The antiproliferative activity of A10 on U87 cells showed some concentration dependence manner and the pKa values of A10 were within the desirable range of anti‐gliomas drugs. In addition, molecular docking revealed hydrogen bonding interaction was formed between A10 and the target protein. These results suggest that A10 may be a promising DHAA‐derived lead compound that deserves further strategic optimization in search of the anticancer candidates against glioma.

CUTTING-EDGE DEVELOPMENTS IN HPLC FOR IDENTIFYING PROCESS IMPURITIES: A REVIEW ON METHOD OPTIMIZATION AND VALIDATION

High-Performance Liquid Chromatography (HPLC) is a widely utilized column chromatography technique in biochemistry and analytical sciences for the separation, identification, and quantification of active compounds. Renowned as a leading separation technology, HPLC plays a pivotal role in detecting, separating, and quantifying pharmaceutical drugs. The development and validation of HPLC methods are essential in novel drug discovery, development, manufacturing, and various human and animal studies. This review highlights the comprehensive processes involved in the development and validation of HPLC methods. Method development is influenced by factors such as the chemical structure of molecules, synthetic pathways, solubility, polarity, pH, pKa values, and the activity of functional groups. Validation, as per ICH Guidelines, encompasses key parameters including accuracy, precision, specificity, linearity, range, limits of detection and quantification, robustness, and system suitability testing.

Photoacids and Photobases: Applications in Functional Dynamic Systems.

Brønsted photoacids and photobases are a unique class of molecules that undergo a major change in their pKa values between their ground and excited states, resulting in donating or accepting a proton, respectively, but only after light excitation. This property of photoacids/photobases makes them an attractive tool for light-gating various dynamic processes. Here, we review the use of this property to manipulate functional dynamic systems with light. We discuss how a proton transfer event that can happen upon light excitation from a photoacid to a chemical moiety of a certain system or, vice versa, from the system to a photobase, can result in a shift in the equilibrium of the system, resulting in some dynamicity. We detail various systems, including self-assembly processes of nanostructures, self-propulsion of droplets, catalysis for hydrogen evolution or CO2 capturing, nanotechnological devices based on enzymatic processes, and changes in proton-conducting ionophores and materials. We detail the basic guidelines for using Brønsted photoacids and photobases in a desired system and conclude with the current technological gaps in further using these molecules.

KaMLs for Predicting Protein pKa Values and Ionization States: Are Trees All You Need?

Despite its importance in understanding biology and computer-aided drug discovery, the accurate prediction of protein ionization states remains a formidable challenge. Physics-based approaches struggle to capture the small, competing contributions in the complex protein environment, while machine learning (ML) is hampered by the scarcity of experimental data. Here, we report the development of pKa ML (KaML) models based on decision trees and graph attention networks (GAT), exploiting physicochemical understanding and a new experiment pKa database (PKAD-3) enriched with highly shifted pKa's. KaML-CBtree significantly outperforms the current state of the art in predicting pKa values and ionization states across all six titratable amino acids, notably achieving accurate predictions for deprotonated cysteines and lysines─a blind spot in previous models. The superior performance of KaMLs is achieved in part through several innovations, including the separate treatment of acid and base, data augmentation using AlphaFold structures, and model pretraining on a theoretical pKa database. We also introduce the classification of protonation states as a metric for evaluating pKa prediction models. A meta-feature analysis suggests a possible reason for the lightweight tree model to outperform the more complex deep learning GAT. We release an end-to-end pKa predictor based on KaML-CBtree and the new PKAD-3 database, which facilitates a variety of applications and provides the foundation for further advances in protein electrostatic research.

KaMLs for Predicting Protein pKa Values and Ionization States: Are Trees All You Need?

Despite its importance in understanding biology and computer-aided drug discovery, the accurate prediction of protein ionization states remains a formidable challenge. Physicsbased approaches struggle to capture the small, competing contributions in the complex protein environment, while machine learning (ML) is hampered by scarcity of experimental data. Here we report the development of pKa ML (KaML) models based on decision trees and graph attention networks (GAT), exploiting physicochemical understanding and a new experiment pKa database (PKAD-3) enriched with highly shifted pKa's. KaML-CBtree significantly outperforms the current state of the art in predicting pKa values and ionization states across all six titratable amino acids, notably achieving accurate predictions for deprotonated cysteines and lysines - a blind spot in previous models. The superior performance of KaMLs is achieved in part through several innovations, including separate treatment of acid and base, data augmentation using AlphaFold structures, and model pretraining on a theoretical pKa database. We also introduce the classification of protonation states as a metric for evaluating pKa prediction models. A meta-feature analysis suggests a possible reason for the lightweight tree model to outperform the more complex deep learning GAT. We release an end-to-end pKa predictor based on KaML-CBtree and the new PKAD-3 database, which facilitates a variety of applications and provides the foundation for further advances in protein electrostatics research.

Unraveling Ofloxacin Behavior in Aqueous Environments: Molecular Dynamics of Colloidal Formation and Surface Adsorption Mechanisms.

Ofloxacin, a commonly prescribed antibiotic, raises serious environmental concerns due to its persistence in aquatic systems. This study offers new insights into the environmental behavior of ofloxacin and its interactions with carbon-based adsorbents with the aim of enhancing our understanding of its removal mechanisms via adsorption processes. Using a comprehensive computational approach, we analyzed the speciation, pKa values, and solubility of ofloxacin across various pH conditions, accounting for all four microspecies, including the often-overlooked neutral form. Our findings indicate that clustering of ofloxacin in water is influenced not only by solubility but also by electrostatic repulsion, dipole creation, and π-π interactions. At extreme pH levels, clustering is primarily driven by Coulombic forces and strong π-π interactions between different ofloxacin molecules. Density functional theory (DFT) was employed to optimize the molecular structures, and molecular dynamics (MD) simulations explored interactions among ofloxacin, water, and carbon surfaces. Hybrid Reverse Monte Carlo (HRMC) simulations were used to determine the disordered structure of an activated carbon cloth (ACC), specifically, KIP1200 (Dacarb company, France), for use in MD simulations. KIP1200 contains a small amount of oxygen (less than 2%), which supports our assumption of a predominantly carbon-based structure. Surface interactions were found to vary significantly depending on the ofloxacin form. The neutral form exhibited strong π-π interactions with flat surfaces, whereas the zwitterionic form displayed a greater affinity for curved surfaces. On KIP1200, adsorption was pH-dependent: acidic conditions enhanced adsorption due to reduced repulsion, while adsorption decreased under basic conditions. The aromatic rings in ofloxacin, combined with the high electronegativity of its fluorine atoms, played a critical role in facilitating adsorption through π-π interactions. These results deepen our understanding of ofloxacin microspecies, colloid formation, and adsorption mechanisms under diverse conditions.

Comparative Analysis of pK a Predictions for Arsonic Acids Using Density Functional Theory-Based and Machine Learning Approaches.

Arsonic acids (RAsO(OH)2), prevalent in contaminated food, water, air, and soil, pose significant environmental and health risks due to their variable ionization states, which influence key properties such as lipophilicity, solubility, and membrane permeability. Accurate pK a prediction for these compounds is critical yet challenging, as existing models often exhibit limitations across diverse chemical spaces. This study presents a comparative analysis of pK a predictions for arsonic acids using a support vector machine-based machine learning (ML) approach and three density functional theory (DFT)-based models. The DFT models evaluated include correlations to the maximum surface electrostatic potential (V S,max), atomic charges derived from a solvation model (solvation model based on density), and a scaled solvent-accessible surface method. Results indicate that the scaled solvent-accessible surface approach yielded high mean unsigned errors, rendering it less effective. In contrast, the atomic charge-based method on the conjugated arsonate base provided the most accurate predictions. The ML-based approach demonstrated strong predictive performance, suggesting its potential utility in broader chemical spaces. The obtained values for pK a from V S,max show a weak prediction level, because the way of predicting pK a is related only to the electrostatic character of the molecule. However, pK a is influenced by many factors, including the molecular structure, solvation, resonance, inductive effects, and local atomic environments. V S,max cannot fully capture these different interactions, as it gives a simplistic view of the overall molecular potential field.

Rhodamine-functionalized carbon dots with pH-regulated FRET efficiency for ratiometric fluorescence sensing and imaging of extremely alkaline pH.

Aratiometric fluorescent nanoprobe (CDs-Rho), synthesized through the simple covalent amide linkage between carbon dots (CDs) and pH-sensitive rhodamine dye (Rho), was designed for the precise sensing and imaging of extremely alkaline environments. The sensing mechanism involves the opposite pH-dependent fluorescence changes in CDs and Rho, respectively, coupled with pH-regulated FRET efficiency from CDs to Rho. The nanoprobe features a wide pH response window from pH 7.0 to 12.0 with a pKa value of 11.3 and shows high sensitivity, robust anti-interference capability, and high reversibility. Moreover, the significant shifts in emission wavelength following the pH fluctuations result in two well-separated emission signals, thus ensuring the visualization of reversible and distinct color changes (from green to red) during in vivo fluorescence imaging. This work furnished a facile protocol that contributes to the advancement of a novel method for the accurate sensing and imaging of extreme alkaline environments.

5'-Amino-Formyl-Thieno[3,2-b]thiophene End-Label for On-Strand Synthesis of Far-Red Fluorescent Molecular Rotors and pH-Responsive Probes.

The ability to label synthetic oligonucleotides with fluorescent probes has greatly expanded their nanotechnological applications. To continue this expansion, it is essential to develop approachable, modular, and tunable fluorescent platforms. In this study, we present the synthesis and incorporation of an amino-formyl-thieno[3,2-b]thiophene (AFTh2) handle at the 5'-position of DNA oligonucleotides. The 5'-AFTh2 end-label participates in both on-strand Knoevenagel and heterocyclization reactions, yielding far-red hemicyanines and pH-responsive probes with pKa values in the biological regime. The Knoevenagel products, designated 5'-ATh2Btz and 5'-ATh2Ind, demonstrate excitation maxima beyond 640 nm with brightness up to ∼50,000 M-1 cm-1. Notably, 5'-ATh2Btz demonstrates strong topology sensitivity, allowing it to probe transitions from duplex- to single-strand (SS)/G-quadruplex (GQ) topologies with an ∼9-fold increase in fluorescence in the absence of quenchers. In contrast, the heterocyclization product, 5'-ATh2BIM, displays visible excitation and emission and is weakly fluorescent in basic solution. Upon lowering the pH from ∼8 to 5, this probe undergoes an unprecedented 400-fold light-up. Additionally, attaching 5'-ATh2BIM to a polymorphic GQ allows for a shift in pKa by ∼1.5 pH units simply by changing topology. The performance of the probes has been demonstrated in various contexts, including GQs, i-motifs, duplexes, and SS oligonucleotides. Their performance should facilitate the development of new DNA-based sensing platforms.

MEDOC: A Fast, Scalable, and Mathematically Exact Algorithm for the Site-Specific Prediction of the Protonation Degree in Large Disordered Proteins.

Intrinsically disordered regions are found in most eukaryotic proteins and are enriched with positively and negatively charged residues. While it is often convenient to assume that these residues follow their model-compound pKa values, recent work has shown that local charge effects (charge regulation) can upshift or downshift side chain pKa values with major consequences for molecular function. Despite this, charge regulation is rarely considered when investigating disordered regions. The number of potential charge microstates that can be populated through acid/base regulation of a given number of ionizable residues in a sequence, N, scales as ∼2N. This exponential scaling makes the assessment of the full charge landscape of most proteins computationally intractable. To address this problem, we developed "multisite extent of deprotonation originating from context" (MEDOC) to determine the degree of protonation of a protein based on the local sequence context of each ionizable residue. We show that we can drastically reduce the number of parameters necessary to determine the full, analytical Boltzmann partition function of the charge landscape at both global and site-specific levels. Our algorithm applies the structure of the q-canonical ensemble, combined with novel strategies to rapidly obtain the minimal set of parameters, thereby circumventing the combinatorial explosion of the number of charge microstates even for proteins containing a large number of ionizable amino acids. We apply MEDOC to several sequences, including a global analysis of the distribution of pKa values across the entire DisProt database. Our results show differences in the distribution of predicted pKa values for different amino acids and good agreement with NMR-measured pKa values in proteins.

Computational Explorations of Th4+ First Hydrolysis Reaction Constants: Insights from Ab Initio Molecular Dynamics and Density Functional Theory Calculations.

The fundamental hydrolysis behavior of tetravalent actinide cations (An4+) with a high charge is crucial for understanding their solution chemistry, particularly in nuclear fuel reprocessing and environmental behavior. Using Th4+ as a reference of the An4+ series, this work employed both the periodic model and the cluster model to calculate the first hydrolysis reaction constant (pKa1) of the Th4+ aqua ion and conducted a detailed evaluation of these approaches. In the periodic model, ab initio molecular dynamics (AIMD) simulations of Th4+ in the explicit solvation environment are conducted, using metadynamics and constrained molecular dynamics to calculate pKa1 values. Metadynamics simulations with sufficient sampling yielded a value of 5.02, aligning with the experimental values (4.12-4.97). Moreover, AIMD results reveal further Grotthuss-type proton transfers and changes in the solvent structures, which are important for accurately modeling the hydrolysis process. In the cluster model, density functional theory calculations are performed on isolated hydrate clusters to obtain pKa1 values, describing solvation effects through the cluster-continuum model. Based on insights from the periodic models, particularly regarding further proton transfer, the cluster model was modified and tested using different functionals and similar cations (La3+and Ac3+). The pKa1 values obtained in the cluster model also show good agreement with the experimental values. The current computational approaches provide a comprehensive understanding of Th4+ hydrolysis and a reference framework for studying the hydrolysis of other lanthanide and actinide ions.

Comprehensive Chemical Analysis of the Methyl 3-Nitrogen-2,3-Dideoxysaccharides Derivatives with d-ribo-Configuration: Synthesis, Reactivity of HIV-1 Reverse Transcriptase Inhibitors.

This study extends previous research, particularly focusing on patented scientific objects No. ID: PL 240 353 B1, investigating the physicochemical properties of the methyl 3-azido- and 3-amino-2,3-dideoxysaccharides with a nucleoside scaffold similar to 3'-azidothymidine (AZT). The study utilizes multiwavelength spectrophotometric and potentiometric methods to evaluate the ionization of the saccharide units in aqueous solutions. pKa values, obtained from two independent methods, reveal significant sugar ionization effects on UV spectra with varying pH levels. Stability constants for divalent metal ion complexes (Cu2+ and Ni2+) with the saccharide isomers indicate that complex stoichiometries and stabilities are highly dependent on the configuration of sugar ring substituents. Spectrophotometric results show a descending order of CT-DNA-binding affinity: BRNH2OMe > BRN3OMe > ARN3OMe > ARNH2OMe, suggesting varied interaction strengths. Molecular docking of models of synthesized O-glycosides confirmed their potential as reverse transcriptase inhibitors. Among the derivatives tested, the compound BRN3OMe displays the highest interaction with the enzyme active site residues and DNA, suggesting it may possess the greatest efficacy. Our reported results highlight the promising inhibitory properties of novel O-glycosides against HIV reverse transcriptase, supporting their potential development as antiviral agents.

Comparative photocatalytic degradation of cationic rhodamine B and anionic bromocresol green using reduced ZnO: A detailed kinetic modeling approach.

The photocatalytic degradation of rhodamine B (RhB), a cationic dye, and bromocresol green (BCG), an anionic dye, was investigated using oxygen vacancy-enriched ZnO as the catalyst. These dyes were selected due to their differing charges and molecular structures, allowing for a deeper exploration of how these characteristics impact the degradation process. The catalyst was prepared by reducing ZnO with 10% H2/Ar gas at 500°C, and the introduction of oxygen vacancies was confirmed using various characterization techniques. A detailed kinetic model was developed to track dye degradation, accounting for adsorption and photocatalytic degradation simultaneously, both in solution and on the catalyst surface. The model incorporated the effect of pH on adsorption by considering the dissociation behavior of the dyes and their respective pKa values. The study revealed that degradation primarily occurs on the catalyst surface at acidic pH, while at basic pH, degradation is more pronounced in the solution. DFT calculations supported these findings, showing that the electrostatic potential of the dyes shifts depending on pH, influencing their interaction with hydroxyl radicals or the catalyst surface. Quantum yield calculations indicate peak values of 6.32 10-5 molecules per photon for RhB at pH 11, and 4.20 10-5 for BCG at pH 3.

PKa Matching Enables Quantum Proton Delocalization in Acid-1-Methylimidazole Binary Mixtures.

Short hydrogen bonds (SHBs), characterized by donor-acceptor heteroatom separations below 2.7 Å, are prevalent in condensed-phase systems. Recently, we identified SHBs in nonaqueous binary mixtures of acetic acid and 1-methylimidazole (MIm), where electronic and nuclear quantum effects facilitate extensive proton delocalization. In this work, we explore the conditions favoring SHB formation in binary acid-base mixtures and propose that the difference in pKa values between the acid and base, measured in a nonaqueous, aprotic solvent like DMSO, is a key determinant. Using MIm as a model base, we perform electronic structure calculations to systematically analyze pKa matching across 97 acid-MIm pairs in DMSO solutions. Through a combination of first-principles simulations and infrared spectroscopy, we confirm the formation of SHBs and the delocalization of protons in benzoic acid-MIm and salicylic acid-MIm binary mixtures. Our results demonstrate that pKa matching can significantly alter proton behavior in nonaqueous systems, transforming acid-base interactions from conventional proton transfer to quantum mechanical proton delocalization. This work establishes DMSO as a valuable alternative to water for assessing pKa matching and highlights the importance of hydrogen bond networks in modulating these conditions. By elucidating the impact of electronic and nuclear quantum effects, our results provides insights for designing organic mixtures that leverage SHBs for advanced material applications.

Tailoring the Multi‐Protolytic Equilibrium of Tin Porphyrins as Promising Molecular Catalyst for the Two‐Electron Oxidation of Water in Artificial Photosynthesis

AbstractTwo‐electron oxidation of water to form hydrogen peroxide is an alternative approach to overcome the photon‐flux density problem as the bottleneck subject in artificial photosynthesis associated with molecular systems for photochemical water splitting. Tin‐porphyrin complexes show promising activity and selectivity for the two‐electron water‐oxidation pathway. A key aspect of the reaction mechanism of these systems is the attack of OH−/H2O to the activated axial oxygen atom as the reaction center of the one‐electron oxidized species to form O−O bond, which is feasible when an odd electron is localized on axial oxygen. DFT calculations show that the spin of the odd electron is mostly localized on the axial oxygen atoms when they are in deprotonated states; hence, their pKa determine the applicability of these systems under the pH conditions adopted. The milder pH conditions are most preferable. To explore the conditions the effect of various porphyrin ring substituents on the pKa of the protonation–deprotonation process in A4 and A3B tin‐porphyrin complexes have been studied here by spectrophotometric titration. Tetra‐fluorophenyl (Sn−F4), tetra‐chlorophenyl (Sn−Cl4), and tetra‐methoxycarbonylphenyl (SnTCPPMester)‐substituted Sn−A4 porphyrins have pKa1 values of 10.1 (Sn−F4), 9.8 (Sn−Cl4), and 6.7 (SnTCPPMester), which are in the increasing order of the electron‐withdrawing effect, ‐F (σp=0.06)<‐Cl (0.23)<‐COOMe (0.45). For A3B (A=fluorophenyl or chlorophenyl, B=methoxycarbonylphenyl) Sn‐porphyrins, pKa1 shifts to the smaller value (Sn−F3Mester: 9.4, Sn−Cl3Mester: 6.6), improving the pH range of the active species from basic to ambient pH. This study shows how the pH range of the active species can be effectively tailored by choosing the meso‐substituents.

Aqueous Solubility of Sodium and Chloride Salts of Glycine─"Uncommon" Common-Ion Effects of Self-Titrating Solids.

Although glycine is the simplest of the amino acids, its solution and solid-state properties are far from straightforward. The aqueous solubility of glycine plays an important role in various applications, including nutrition, food products, biodegradable plastics, and drug development. There is evidence that glycine in subsaturated pH 3-8 solutions forms a dimer, as suggested by several techniques. However, what takes place below pH 3 and above pH 8 in saturated solutions has been sparsely explored and is thought to exhibit complex properties. Although the solubility measurements in the pH 0-13 range have been reported by several groups, the interlaboratory variance between the data below pH 3 and above pH 8 has been high. In a couple of cases, there appears to be no pH dependence on solubility across the wide pH range, even though the reported glycine pKa values are 2.34 and 9.61. The solubility of the salt forms of glycine is largely uncharacterized. The solubility products of the simplest salts, glycine hydrochloride and sodium glycinate, appear not to have been published. In this study, five series of precision solubility measurements of glycine and its salts were performed at 25 °C, covering the range of pH -0.4 to 12.4, where in each case, just enough glycine was added to reach saturation. We have developed an equilibrium model to rationalize the complicated salt regions. Elemental analysis of isolated solids from saturated solutions supports the speciation model. At least three different salt forms have been indicated in acidic solutions and one salt form in alkaline solutions. Solubility products are reported here. The presence of a water-soluble cationic dimer is also proposed. Data analysis was performed with the aid of the pDISOL-X computer program. Activity corrections based on the Stokes-Robinson hydration theory have been implemented in saturated solutions with ionic strength in some cases exceeding 5 M. Although salt solubility is not a constant, since it depends on two independently controlled reactant concentrations, the salt solubility product is commonly expected to be a constant. However, in the glycine salt region below pH 3, our solubility measurements demonstrate that the solubility products depend on the total amount of added glycine in a saturated solution. We view this as an "uncommon" common-ion effect.

Xanthine Nucleosides with Pyrazolo[3,4-d]pyrimidine Skeleton: Functionalization with Halogen Atoms, Clickable Side Chains, Pyrene, and iEDDA Cycloadducts, and Impact of Ionic Forms on Photophysical Properties.

Xanthine nucleosides play a significant role in the expansion of the four-letter genetic code. Herein, 7-functionalized 8-aza-7-deazaxanthine ribo- and 2'-deoxyribonucleosides are described. 2-Amino-6-alkoxy nucleosides were converted to halogenated 8-aza-7-deazaxanthine nucleosides by deamination followed by hydroxy/alkoxy substitution. 8-Aza-7-deaza-7-iodo-2'-deoxyxanthosine served as an intermediate in Suzuki-Miyaura, Sonogashira, and Stille reactions. Alkynyl and vinyl side chains as well as fluorescent tags were introduced. Pyrene conjugates were derived by copper(I)-catalyzed cycloaddition. Inverse-electron-demand Diels-Alder reaction of 8-aza-7-deaza-7-vinyl-2'-deoxyxanthosine with 3,6-dipyridyl-tetrazine proceeded with a second-order rate constant of 0.042 L M-1 s-1. X-ray analysis of 8-aza-7-deaza-7-vinyl-2'-deoxyxanthosine displayed two conformers with a syn conformation. Crystal packing is stabilized by xanthine base pairs. UV spectroscopy confirmed the sensitivity of 7-functionalized 8-aza-7-deazaxanthine nucleosides to pH changes. Halogen and alkynyl substituents decrease pK values, and vinyl, pyrene, or benzofuran leads to an increase. Fluorescence measurements of 8-aza-7-deaza-7-benzofuran-2'-deoxyxanthosine disclosed solvatochromism and enhanced fluorescence when the pH or the viscosity of the solvent is increased. Nucleoside pyrene conjugates connected by a linear linker displayed monomer emission, and two pyrene residues connected by a dendritic linker exhibited excimer emission. According to their fluorescence properties and sensitivity to pH changes, the functionalized 8-aza-7-deazaxanthine nucleosides expand the class of nucleosides applicable to fluorescence detection for diagnostic and therapeutic purposes.

Exploring acidity-dependent PCET pathways in imino-bipyridyl cobalt complexes.

The electrochemical proton reactivity of transition metal complexes has received intensive attention in catalyst research. The proton-coupled electron transfer (PCET) process, influenced by the coordination geometry, determines the catalytic reaction mechanisms. Additionally, the pKa value of a proton source, as an external factor, plays a crucial role in regulating the proton transfer step. Understanding the effects of variations in the pKa values of Brønsted acids on the PCET process is therefore essential. This study compares the PCET pathways of two high-spin cobalt (Co) complexes with contrasting exchange coupling interactions under acidic conditions with high and low pKa values. These findings reveal how proton reduction reactions in high-spin Co complexes are affected by the internal factor of the spin state, as well as an external factor related to the proton source. The corresponding reaction mechanisms are also proposed based on these observations.