Silver and Palladium Complexes Containing Ditopic N‑Heterocyclic Carbene–Thione Ligands

The mixed donor N-heterocyclic carbene (NHC)/thione ligand precursors [1-(3-R-2<i>H</i>-imidazol-1-yl-2-thione)­methyl-3-R-2<i>H</i>-imidazol-2-ium]­X, [H<b>CS</b>^<b>R</b>]­X (R = methyl, benzyl; X = Br, I), have been utilized to prepare a range of silver and palladium complexes. The coordination of <b>CS</b>^<b>R</b> to silver­(I) salts has been explored, providing dimeric complexes of the type [AgX­(<b>CS</b>^<b>R</b>)]₂ (where R = methyl, benzyl; X = Br, I). Structural characterization of [AgX­(<b>CS</b>^<b>Bn</b>)]₂ revealed a bidentate coordination mode for the mixed donor ligand and dinuclear structures where the silver centers are bridged by two bromido centers. Palladium complexes bearing one or two <b>CS</b>^<b>R</b> ligands have additionally been prepared either directly, utilizing [Pd­(OAc)₂] as precursor, or via transmetalation strategies. The dicationic complexes [Pd­(<b>CS</b>^<b>R</b>)₂]­[X]₂ and neutral complexes [PdX₂(<b>CS</b>^<b>R</b>)] (where R = methyl, benzyl; X = Br, I, PF₆) have been synthesized and fully characterized. The <b>CS</b>^<b>R</b> ligand in the aforementioned complexes does not undergo transformation of the NHC unit to a urea function, which had been found to occur in the previously reported copper complexes. Palladium complexes containing both NHC/thione and bis-phosphine ligands were also prepared. Complexes of the type [Pd­(<b>CS</b>^<b>Me</b>)­(L₂)]­[X]₂ and [PdX­(<b>CS</b>^<b>Me</b>)­(L₂)]­[X] (where L₂ = dppe, dppp; X = Br, OAc, I, PF₆) were obtained. The presence of the bis-phosphine appears to destabilize the coordination of the NHC/thione ligand and as a consequence leads to its elimination from the complex

Elucidation of Drug Metabolite Structural Isomers Using Molecular Modeling Coupled with Ion Mobility Mass Spectrometry

Ion mobility-mass spectrometry (IM-MS) in combination with molecular modeling offers the potential for small molecule structural isomer identification by measurement of their gas phase collision cross sections (CCSs). Successful application of this approach to drug metabolite identification would facilitate resource reduction, including animal usage, and may benefit other areas of pharmaceutical structural characterization including impurity profiling and degradation chemistry. However, the conformational behavior of drug molecules and their metabolites in the gas phase is poorly understood. Here the gas phase conformational space of drug and drug-like molecules has been investigated as well as the influence of protonation and adduct formation on the conformations of drug metabolite structural isomers. The use of CCSs, measured from IM-MS and molecular modeling information, for the structural identification of drug metabolites has also been critically assessed. Detection of structural isomers of drug metabolites using IM-MS is demonstrated and, in addition, a molecular modeling approach has been developed offering rapid conformational searching and energy assessment of candidate structures which agree with experimental CCSs. Here it is illustrated that isomers must possess markedly dissimilar CCS values for structural differentiation, the existence and extent of CCS differences being ionization state and molecule dependent. The results present that IM-MS and molecular modeling can inform on the identity of drug metabolites and highlight the limitations of this approach in differentiating structural isomers

Photoinitiated Polymerization-Induced Self-Assembly in the Presence of Surfactants Enables Membrane Protein Incorporation into Vesicles

Photoinitiated polymerization-induced self-assembly (photo-PISA) is an efficient approach to predictably prepare polymeric nanostructures with a wide range of morphologies. Given that this process can be performed at high concentrations and under mild reaction conditions, it has the potential to have significant industrial scope. However, given that the majority of industrial (and more specifically biotechnological) formulations contain mixtures of polymers and surfactants, the effect of such surfactants on the PISA process is an important consideration. Thus, to expand the scope of the methodology, the effect of small molecule surfactants on the PISA process, specifically for the preparation of unilamellar vesicles, was investigated. Similar to aqueous photo-PISA findings in the absence of surfactant molecules, the originally targeted vesicular morphology was retained in the presence of varying concentrations of non-ionic surfactants, while a diverse set of lower-order morphologies was observed for ionic surfactants. Interestingly, a critical micelle concentration (CMC)-dependent behavior was detected in the case of zwitterionic detergents. Additionally, tunable size and membrane thickness of vesicles were observed by using different types and concentration of surfactants. Based on these findings, a functional channel-forming membrane protein (OmpF porin), stabilized in aqueous media by surfactant molecules, was able to be directly inserted into the membrane of vesicles during photo-PISA. Our study demonstrates the potential of photo-PISA for the direct formation of protein–polymer complexes and highlights how this method could be used to design biomimicking polymer/surfactant nanoreactors