Protomer Formation Can Aid the Structural Identification of Caffeine Metabolites

The structural annotation of isomeric metabolites remains a key challenge in untargeted electrospray ionization/high-resolution mass spectrometry (ESI/HRMS) metabolomic analysis. Many metabolites are polyfunctional compounds that may form protomers in electrospray ionization sources and therefore yield multiple peaks in ion mobility spectra. Protomer formation is strongly structure-specific. Here, we explore the possibility of using protomer formation for structural elucidation in metabolomics on the example of caffeine, its eight metabolites, and structurally related compounds. It is observed that two-thirds of the studied compounds formed high- and low-mobility species in high-resolution ion mobility. Structures in which proton hopping was hindered by a methyl group at the purine ring nitrogen (position 3) yielded structure-indicative fragments with collision-induced dissociation (CID) for high- and low-mobility ions. For compounds where such a methyl group was not present, a gas-phase equilibrium could be observed for tautomeric species with two-dimensional ion mobility. We show that the protomer formation and the gas-phase properties of the protomers can be related to the structure of caffeine metabolites and facilitate the identification of the structural isomers

Biphasic pKa Values

A novel approach – termed here as biphasic pKa values – is presented for quantifying the acidity/basicity of lipophilic compounds embedded in water-immiscible media (membranes or solutions) at equilibrium with aqueous solution. In this approach the hydrogen ion activity is determined in the aqueous phase, while the concentration ratio of protonated and deprotonated forms of acid/base is measured in the lipophilic phase with any suitable technique. The approach has been demonstrated on the example of biphasic pKa values of some lipophilic indicator bases in the octanol:water system, measured using UV-Vis spectrophotometry. The measurement is straightforward if the counterion identity and concentration and overall ionic strength in the aqueous phase are included in the standard state definition. Biphasic pKa values are envisaged to be useful for characterizing lipophilic indicators, synthetic receptors, phase transfer catalysts and other implements that are used in hydrophobic media (e.g. in sensor membranes) in contact with water. This work is licensed under a Creative Commons Attribution 4.0 International License

Inducing a pH-dependent conformational response by competitive binding to Zn2+ of a series of chiral ligands of disparate basicity

Molecules that change shape in response to environmental conditions are central to biological molecular communication devices and their synthetic chemical analogues. Here we report a molecular system in which a series of chiral anionic ligands of differing basicity are selectively protonated according to the pH of the medium. A cationic circular dichroism (CD) reporter complex responds to anion binding by selecting one of two alternative enantiomeric conformations. Exploiting the principle that less basic anions have, in general, weaker electrostatic interactions than more basic anions, a set of three chiral acids with large (>5 unit) pK(a) differences and differing configurations were sequentially deprotonated in acetonitrile by addition of base, allowing the most basic anion in the mixture at any time to bind to the reporter complex. A characteristic CD output resulted, which changed in sign as the next-most basic anion was revealed by the next deprotonation in the series. Four cycles of switching between three ligand-bound states were achieved with minimal changes in signal magnitude, by alternating addition of base and acid. The pH-dependent conformational response was used to transduce a signal by appending to the binding site a 2-aminoisobutyric acid (Aib) oligomer, whose M or P helical conformation depended on the chirality of the bound ligand, and was reported by a remote (13)C-labelled NMR reporter group. The multicomponent system thus converts a pH signal into a programmable conformational response which induces a remote spectroscopic effect

Theoretical Study on Fluorinated Derivatives of Sulfolane, Cyclopentanone, and Gamma-Butyrolactone

In this paper, fluorinated compounds based on sulfolane, cyclopentanone, and gamma-butyrolactone are studied computationally, focusing on their applicability in electrochemical devices and acid–base-related studies. Candidates for solvents with (1) high polarity, (2) good electrochemical stability, and (3) low basicity were searched for. Some of the compounds are studied here for the first time. Electrochemical stabilities, dielectric constants, boiling points, basicities, and lipophilicities were estimated using DFT and COSMO-RS methods with empirical corrections. The effect of fluorination on these properties as well as the bond parameters was studied. The possible synthesis routes of the proposed compounds are outlined. Some molecules display a combination of estimated properties favorable for a solvent, although none of the studied compounds are expected to surpass acetonitrile and propylene carbonate by the width of the electrochemical stability window

pKaH values and θH angles of phosphanes to predict their electronic and steric parameters

Phosphanes have numerous important uses and at the same time are an important class of organic bases with basicities spanning more than 30 orders of magnitude. In many cases, their behaviour in specific applications depends strongly on their basicity. Basicities (pKaH values) of many phosphanes have been published but are scattered across different reports and there are prominent gaps in the availability of data. In this report, we present an extensive set of pKaH data of a most diverse set of phosphanes, both newly measured/calculated and collected from the literature. We demonstrate that pKaH values can serve as an alternative to Tolman electronic parameters (TEP values) in evaluating the electronic properties of phosphanes. Additionally, we suggest two easily obtainable parameters for assessing the steric properties of phosphaneswithout need for sophisticated calculations or preparation of metal-ligand complexes

Synthesis and Physico-Chemical Properties of 2-SF5-(Aza)Indoles, A New Family of SF5-Heterocycles

Structural diversity in heterocyclic chemistry is key to unlock new properties and modes of action. In this regard, heterocycles embedding emerging fluorinated substituents hold great promises. Herein is described a strategy to access 2-SF5- (aza)indoles for the first time. The sequence relies on the radical addition of SF5Cl to the alkynyl p-system of 2-ethynyl anilines followed by a cyclization reaction. A telescoped sequence is proposed making this strategy very appealing and reproducible on gram scale. Downstream functionalizations are also demonstrated, allowing an easy diversification of N- and C3-positions. Ames test, pKa, logP and DSC measurements of several fluorinated 2-Rfindoles are also disclosed. These studies highlight the strategic advantages that a C2-pentafluorosulfanylated motif impart to a privileged scaffold such as indole

Hydrogen-Bond Donicity in DMSO and Gas Phase and Its Dependence on Brønsted Acidity

The hydrogen-bond (HB) donicity of various HB donors, expressed as standard Gibbs free energy of HB formation with chloride ion, was studied experimentally in dimethyl sulfoxide (DMSO) and computationally in DMSO and the gas phase. Acidity and HB donicity data in the gas phase and DMSO have been obtained for 77 HB donors from different compound families. Applicability of two computational methods (SMD and COSMO-RS) for calculation of solvation contribution to reaction free energy in DMSO was evaluated and discussed. The quality of calculated Gibbs free energies of solvation was assessed using the correlation between HB strengths in solvent and in the gas phase. The investigation of the relationships between HB donicity and Brønsted acidity showed that in the gas phase the correlation is good, and within structurally uniform compound groups both acidity and donicity are described well by substituent constants. The same correlation in DMSO is less distinct. Bidentate HB donors are characterized by higher HB donicity than could be expected from their acidity in both media, and therefore, these HB donors have an important advantage in anion binding applications, e.g., in catalysis

Tris(benzophenoneimino)phosphane and related compounds

The dataset includes files supporting the article named "Tris(benzophenoneimino)phosphane and related compounds". Monocrystal XRD data, calculated .cosmo files, calculated pKaH values for related and correlation compounds, gas-phase geometry optimization and frequency calculation files, and NMR files are given

Systematic Optimization of Liquid–Liquid Extraction for Isolation of Unidentified Components

We present a systematic approach for predicting the best solvents for selective extraction of components with unknown structure from complex mixtures (e.g., natural products)a tool promising dramatic simplification of extraction process optimization. Its key advantage is that identification of the component(s) is unnecessaryprediction is based on a small set of experimental distribution coefficients (obtained using a combination of shake-flask extraction and chromatographic analysis) rather than structure-based descriptors. The methodology is suitable for the very common situations in practice where the desired compound needs to be separated from unknown impurities (i.e., selectively extracted from the mixture), as well as for large-scale and high-throughput work. The proof-of-concept methodology was developed and evaluated using an extensive set of experimental distribution data of lignin-related compounds obtained in this work