Impact of non-ideality on reconstructing spatial and temporal variations in aerosol acidity with multiphase buffer theory

Aerosol acidity is a key parameter in atmospheric aqueous chemistry and strongly influences the interactions of air pollutants and the ecosystem. The recently proposed multiphase buffer theory provides a framework to reconstruct long-term trends and spatial variations in aerosol pH based on the effective acid dissociation constant of ammonia (Ka,NH3∗). However, non-ideality in aerosol droplets is a major challenge limiting its broad applications. Here, we introduced a non-ideality correction factor (cni) and investigated its governing factors. We found that besides relative humidity (RH) and temperature, cni is mainly determined by the molar fraction of NO3- in aqueous-phase anions, due to different NH4+ activity coefficients between (NH4)2SO4- and NH4NO3-dominated aerosols. A parameterization method is thus proposed to estimate cni at a given RH, temperature and NO3- fraction, and it is validated against long-term observations and global simulations. In the ammonia-buffered regime, with cni correction, the buffer theory can reproduce well the Ka,NH3∗ predicted by comprehensive thermodynamic models, with a root-mean-square deviation ∼ 0.1 and a correlation coefficient ∼ 1. Note that, while cni is needed to predict Ka,NH3∗ levels, it is usually not the dominant contributor to its variations, as ∼ 90 % of the temporal or spatial variations in Ka,NH3∗ are due to variations in aerosol water and temperature.

Water-Activated Semiquinone Formation and Carboxylic Acid Dissociation in Melanin Revealed by Infrared Spectroscopy

Eumelanin is a widespread biomacromolecule pigment in the biosphere and has been widely investigated for numerous bioelectronics and energetic applications. Many of these applications depend on eumelanin’s ability to conduct proton current at various levels of hydration. The origin of this behavior is connected to a comproportionation reaction between oxidized and reduced monomer moieties and water. A hydration-dependent FTIR spectroscopic study on eumelanin is presented herein, which allows for the first time tracking the comproportionation reaction via the gradual increase of the overall aromaticity of melanin monomers in the course of hydration. We identified spectral features associated with the presence of specific “one and a half” C𝌁O bonds, typical for o-semiquinones. Signatures of semiquinone monomers with internal hydrogen bonds and that carboxylic groups, in contrast to semiquinones, begin to dissociate at the very beginning of melanin hydration were indicated. As such, we suggest a modification to the common hydration-dependent conductivity mechanism and propose that the conductivity at low hydration is dominated by carboxylic acid protons, whereas higher hydration levels manifest semiquinone protons.

Recent Developments of Computational Methods for pKa Prediction Based on Electronic Structure Theory with Solvation Models

The protonation/deprotonation reaction is one of the most fundamental processes in solutions and biological systems. Compounds with dissociative functional groups change their charge states by protonation/deprotonation. This change not only significantly alters the physical properties of a compound itself, but also has a profound effect on the surrounding molecules. In this paper, we review our recent developments of the methods for predicting the Ka, the equilibrium constant for protonation reactions or acid dissociation reactions. The pKa, which is a logarithm of Ka, is proportional to the reaction Gibbs energy of the protonation reaction, and the reaction free energy can be determined by electronic structure calculations with solvation models. The charge of the compound changes before and after protonation; therefore, the solvent effect plays an important role in determining the reaction Gibbs energy. Here, we review two solvation models: the continuum model, and the integral equation theory of molecular liquids. Furthermore, the reaction Gibbs energy calculations for the protonation reactions require special attention to the handling of dissociated protons. An efficient method for handling the free energy of dissociated protons will also be reviewed.

An Investigation of Some Aspects of the Coordination Chemistry of Synthetic Macroheterocyclic Ligands

<p>The preparation of a range of fully saturated, unsubstituted pentaazamacrocycles is described. The macrocycles vary in ring size from fifteen to twenty members, and comprise every possible arrangement of dimethylene and trimethylene linkages between five nitroqens in a monocyclic arrangement. A new linear homologue of tetraethylene pentamine with trimethylene linkages between nitrogens is also reported. The copper(II) and nickel(II) complexes of these amines have been prepared; the conductivity and spectral properties have been determined in order to investigate their stereochemistry. The nickel(II) complexes of the two largest macrocycles appear to be five-coordinate both in the solid state and in solution. The remainder of the complexes are either five-coordinate (as the perchlorate salts in the solid state or in non-coordinating solvents) or six-coordinate (with a coordinated nitrate). Cobalt(III) complexes of the fifteen to eighteen membered macrocycles have been prepared with a variety of ligands occupying the sixth coordination site. Ligand field parameters have been derived from the electronic spectra of the complexes. The stereochemistry of the complexes and their behaviour on ligand substitution have been investigated principally by 13C n.m.r. Only a few of the numerous possible isomers of each species were formed. The structures of [Co(1, 4, 7, 10, 14-pentaazacycloheptadecane) Cl]Br0.33 Cl1.67. H2O and [Co(1, 4, 7, 11, 15-pentaazacyclooctadecane)Br]Br2, which were determined by single-crystal x-ray diffraction studies, are described. The spontaneous aquation rates of the bromo complexes have been investigated semi-quantitatively, and found to span many orders of magnitude. The most labile bromo complex [Co(1, 4, 8, 11, 15-pentaazacyclooctadecane)Br]Br2 spontaneously aquates in a matter of seconds at room temperature. The increasing strain and steric crowding caused by successive replacement of five-membered chelate rings by six-membered chelate rings, or by simply altering the sequence of five- and six-membered chelate rings is manifested in a progressive increase in the instability of the complexes. In the case of the nineteen- and twenty-membered macrocycles, this crowding and strain results in the formation of stable five-coordinate cobalt(II) complexes; for these ligands, no stable complexes were formed with the smaller cobalt(III) cation. The acid-dissociation kinetics of the copper(II) complexes have been examined in nitric acid at 298 K. A variable temperature study has also been performed on the complex of l, 4, 7, 10, 14-pentaazacycloheptadecane in order to determine the activation parameters. The complexes are labile by comparison with most tetraazamacrocyclic complexes. The dissociation reactions are first-order in complex concentration, but the acid-dependence varies. The observed rate constant is second-order in hydrogen ion concentration for the complex of 1, 4, 7, 10, 13-pentaazacyclopentadecane, first-order in hydrogen ion concentration for 1, 4, 7, 10, 14-pentaazacycloheptadecane and takes the form kobs = a[H+]2/(l+b[H+]2) for the complex of 1, 4, 7, 10, 13-pentaazacyclohexadecane. For the remainder of the complexes, the observed rate constant takes the form kobs = (c[H+] + d[H+]2)/(e + [H+]). Possible mechanisms that are consistent with the above behaviour are presented.</p>

An Investigation of Some Aspects of the Coordination Chemistry of Synthetic Macroheterocyclic Ligands

<p>The preparation of a range of fully saturated, unsubstituted pentaazamacrocycles is described. The macrocycles vary in ring size from fifteen to twenty members, and comprise every possible arrangement of dimethylene and trimethylene linkages between five nitroqens in a monocyclic arrangement. A new linear homologue of tetraethylene pentamine with trimethylene linkages between nitrogens is also reported. The copper(II) and nickel(II) complexes of these amines have been prepared; the conductivity and spectral properties have been determined in order to investigate their stereochemistry. The nickel(II) complexes of the two largest macrocycles appear to be five-coordinate both in the solid state and in solution. The remainder of the complexes are either five-coordinate (as the perchlorate salts in the solid state or in non-coordinating solvents) or six-coordinate (with a coordinated nitrate). Cobalt(III) complexes of the fifteen to eighteen membered macrocycles have been prepared with a variety of ligands occupying the sixth coordination site. Ligand field parameters have been derived from the electronic spectra of the complexes. The stereochemistry of the complexes and their behaviour on ligand substitution have been investigated principally by 13C n.m.r. Only a few of the numerous possible isomers of each species were formed. The structures of [Co(1, 4, 7, 10, 14-pentaazacycloheptadecane) Cl]Br0.33 Cl1.67. H2O and [Co(1, 4, 7, 11, 15-pentaazacyclooctadecane)Br]Br2, which were determined by single-crystal x-ray diffraction studies, are described. The spontaneous aquation rates of the bromo complexes have been investigated semi-quantitatively, and found to span many orders of magnitude. The most labile bromo complex [Co(1, 4, 8, 11, 15-pentaazacyclooctadecane)Br]Br2 spontaneously aquates in a matter of seconds at room temperature. The increasing strain and steric crowding caused by successive replacement of five-membered chelate rings by six-membered chelate rings, or by simply altering the sequence of five- and six-membered chelate rings is manifested in a progressive increase in the instability of the complexes. In the case of the nineteen- and twenty-membered macrocycles, this crowding and strain results in the formation of stable five-coordinate cobalt(II) complexes; for these ligands, no stable complexes were formed with the smaller cobalt(III) cation. The acid-dissociation kinetics of the copper(II) complexes have been examined in nitric acid at 298 K. A variable temperature study has also been performed on the complex of l, 4, 7, 10, 14-pentaazacycloheptadecane in order to determine the activation parameters. The complexes are labile by comparison with most tetraazamacrocyclic complexes. The dissociation reactions are first-order in complex concentration, but the acid-dependence varies. The observed rate constant is second-order in hydrogen ion concentration for the complex of 1, 4, 7, 10, 13-pentaazacyclopentadecane, first-order in hydrogen ion concentration for 1, 4, 7, 10, 14-pentaazacycloheptadecane and takes the form kobs = a[H+]2/(l+b[H+]2) for the complex of 1, 4, 7, 10, 13-pentaazacyclohexadecane. For the remainder of the complexes, the observed rate constant takes the form kobs = (c[H+] + d[H+]2)/(e + [H+]). Possible mechanisms that are consistent with the above behaviour are presented.</p>

Quantitation of reduced IL-33 levels in human serum: mitigating interference from endogenous binding partners

Aim: IL-33 is a potential therapeutic target but commercially available assays for the quantitation of systemic IL-33 have poor reliability. Results: In commercial IL-33 kits, interference from endogenous binding partners (e.g., soluble ST2) causes under-quantitation. Mitigating this required acid dissociation and addition of the detection reagent simultaneously with the capture step. This enabled detection of total, reduced (active) levels of IL-33 in human serum (LLOQ 6.25 pg/ml). Conclusion: Acid treatment of serum samples dissociates IL-33 from endogenous binding partners, increasing soluble ST2 tolerance to >1000 ng/ml. The modified method was specific for reduced endogenous IL-33. Analysis of over 300 samples from individuals with and without asthma and with different smoking status revealed no difference in serum IL-33.

Exploring the Assembly of Resorc[4]arenes for the Construction of Supramolecular Nano-Aggregates

Many biologically active compounds feature low solubility in aqueous media and, thus, poor bioavailability. The formation of the host-guest complex by using calixarene-based macrocycles (i.e., resorcinol-derived cyclic oligomers) with a good solubility profile can improve solubilization of hydrophobic drugs. Herein, we explore the ability of resorc[4]arenes to self-assemble in polar solutions, to form supramolecular aggregates, and to promote water-solubility of an isoflavone endowed with anti-cancer activity, namely Glabrescione B (GlaB). Accordingly, we synthesized several architectures featuring a different pattern of substitution on the upper rim including functional groups able to undergo acid dissociation (i.e., carboxyl and hydroxyl groups). The aggregation phenomenon of the amphiphilic resorc[4]arenes has been investigated in a THF/water solution by UV–visible spectroscopy, at different pH values. Based on their ionization properties, we demonstrated that the supramolecular assembly of resorc[4]arene-based systems can be modulated at given pH values, and thus promoting the solubility of GlaB.

Asymmetric protonation of glutamate residues drives a preferred transport pathway in EmrE

EmrE is an Escherichia coli multidrug efflux pump and member of the small multidrug resistance (SMR) family that transports drugs as a homodimer by harnessing energy from the proton motive force. SMR family transporters contain a conserved glutamate residue in transmembrane 1 (Glu14 in EmrE) that is required for binding protons and drugs. Yet the mechanism underlying proton-coupled transport by the two glutamate residues in the dimer remains unresolved. Here, we used NMR spectroscopy to determine acid dissociation constants (pKa) for wild-type EmrE and heterodimers containing one or two Glu14 residues in the dimer. For wild-type EmrE, we measured chemical shifts of the carboxyl side chain of Glu14 using solid-state NMR in lipid bilayers and obtained unambiguous evidence on the existence of asymmetric protonation states. Subsequent measurements of pKa values for heterodimers with a single Glu14 residue showed no significant differences from heterodimers with two Glu14 residues, supporting a model where the two Glu14 residues have independent pKa values and are not electrostatically coupled. These insights support a transport pathway with well-defined protonation states in each monomer of the dimer, including a preferred cytoplasmic-facing state where Glu14 is deprotonated in monomer A and protonated in monomer B under pH conditions in the cytoplasm of E. coli. Our findings also lead to a model, hop-free exchange, which proposes how exchangers with conformation-dependent pKa values reduce proton leakage. This model is relevant to the SMR family and transporters comprised of inverted repeat domains.

Automated High Throughput pKa and Distribution Coefficient Measurements of Pharmaceutical Compounds for the SAMPL8 Blind Prediction Challenge

The goal of the SAMPL (Statistical Assessment of the Modeling of Proteins and Ligands) challenge is to improve the accuracy of current computational models to estimate free energy of binding, deprotonation, distribution and other associated physical properties that are useful for the design of new pharmaceutical products. New experimental datasets of physicochemical properties provide opportunities for prospective evaluation of computational prediction methods. Here, aqueous pKa and a range of bi-phasic logD values for a variety of pharmaceutical compounds were determined through a streamlined automated process to be utilized in the SAMPL8 physical property challenge. The goal of this paper is to provide an in-depth review of the experimental methods utilized to create a comprehensive data set for the blind prediction challenge. The significance of this work involves the use of high throughput experimentation equipment and instrumentation to produce acid dissociation constants for twenty-three drug molecules, as well as distribution coefficients for eleven of those molecules.