Three Candidates, Two Peaks: Addressing Conflicting Assignments of Fentanyl Protomers with DMS-UVPD.

Fentanyl and its analogs, many of which share the piperidine-4-carboxamide core, consistently exhibit two distinct peaks when detected as the protonated ion on the various low-field IMS platforms (one major, one minor). These peaks, widely presumed to arise from prototropic isomers (i.e.

Unsymmetrical Imidazopyrimidine-Based Ligand and Bimetallic Complexes.

With bimetallic catalysts becoming increasingly important, the development of electronically and structurally diverse binucleating ligands is desired. This work describes the synthesis of unsymmetric ligand 2,7-di(pyridin-2-yl)imidazo[1,2-]pyrimidine () that is achieved in four steps on a multigram scale in an overall 54% yield. The ability of to act as a scaffold for the formation of bimetallic complexes is demonstrated with the one-step syntheses of the dicopper complex [Cu()(μ-OH)(CFCOO)] (), the dipalladium complex [Pd()(μ-OH)(CFCOO)](CFCOO)·CFCOOH (), and the dimeric dinickel complex [Ni()(μ-Cl)ClMeOH][2Cl] () in good yields (79-92%).

Protomers of the green and cyan fluorescent protein chromophores investigated using action spectroscopy.

The photophysics of biochromophore ions often depends on the isomeric or protomeric distribution, yet this distribution, and the individual isomer contributions to an action spectrum, can be difficult to quantify. Here, we use two separate photodissociation action spectroscopy instruments to record electronic spectra for protonated forms of the green (HBDI) and cyan (Cyan) fluorescent protein chromophores. One instrument allows for cryogenic ( = 40 ± 10 K) cooling of the ions, while the other offers the ability to perform protomer-selective photodissociation spectroscopy.

Bridging the Gap between Differential Mobility, Log , and Log Using Machine Learning and SHAP Analysis.

Aqueous solubility, log , and the water-octanol partition coefficient, log , are physicochemical properties that are used to screen the viability of drug candidates and to estimate mass transport in the environment. In this work, differential mobility spectrometry (DMS) experiments performed in microsolvating environments are used to train machine learning (ML) frameworks that predict the log and log of various molecule classes. In lieu of a consistent source of experimentally measured log and log values, the OPERA package was used to evaluate the aqueous solubility and hydrophobicity of 333 analytes.

MobCal-MPI 2.0: an accurate and parallelized package for calculating field-dependent collision cross sections and ion mobilities.

Ion mobility spectrometry (IMS), which can be employed as either a stand-alone instrument or coupled to mass spectrometry, has become an important tool for analytical chemistry. Because of the direct relation between an ion's mobility and its structure, which is intrinsically related to its collision cross section (CCS), IMS techniques can be used in tandem with computational tools to elucidate ion geometric structure. Here, we present MobCal-MPI 2.

Chemical Transformations Can Occur during DMS Separations: Lessons Learned from Beer's Bittering Compounds.

While developing a DMS-based separation method for beer's bittering compounds, we observed that the argentinated forms of humulone tautomers (i.e., [Hum + Ag]) were partially resolvable in a N environment seeded with 1.

First-Principles Modeling of Preferential Solvation in Mixed-Modifier Differential Mobility Spectrometry.

Differential mobility spectrometry (DMS) separates ions based on mobility differences between high and low electric field conditions. To enhance resolution, solvents such as water and acetonitrile are often used to modify the collision environment and take advantage of differing dynamic clustering behavior between analytes that coelute in hard-sphere environments (., N).

Argentination: A Silver Bullet for Cannabinoid Separation by Differential Mobility Spectrometry.

As the legality of cannabis continues to evolve globally, there is a growing demand for methods that can accurately quantitate cannabinoids found in commercial products. However, the isobaric nature of many cannabinoids, along with variations in extraction methods and product formulations, makes cannabinoid quantitation by mass spectrometry (MS) challenging. Here, we demonstrate that differential mobility spectrometry (DMS) and tandem-MS can distinguish a set of seven cannabinoids, five of which are isobaric: Δ-tetrahydrocannabinol (Δ-THC), Δ-THC, exo-THC, cannabidiol, cannabichromene, cannabinol, and cannabigerol.

The hitchhiker's guide to dynamic ion-solvent clustering: applications in differential ion mobility spectrometry.

This article highlights the fundamentals of ion-solvent clustering processes that are pertinent to understanding an ion's behaviour during differential mobility spectrometry (DMS) experiments. We contrast DMS with static-field ion mobility, where separation is affected by mobility differences under the high-field and low-field conditions of an asymmetric oscillating electric field. Although commonly used in mass spectrometric (MS) workflows to enhance signal-to-noise ratios and remove isobaric contaminants, the chemistry and physics that underpins the phenomenon of differential mobility has yet to be fully fleshed out.

Improved First-Principles Model of Differential Mobility Using Higher Order Two-Temperature Theory.

Differential mobility spectrometry is a separation technique that may be applied to a variety of analytes ranging from small molecule drugs to peptides and proteins. Although rudimentary theoretical models of differential mobility exist, these models are often only applied to small molecules and atomic ions without considering the effects of dynamic microsolvation. Here, we advance our theoretical description of differential ion mobility in pure N and microsolvating environments by incorporating higher order corrections to two-temperature theory (2TT) and a pseudoequilibrium approach to describe ion-neutral interactions.

Protonation-Induced Chirality Drives Separation by Differential Ion Mobility Spectrometry.

Upon development of a workflow to analyze (±)-Verapamil and its metabolites using differential mobility spectrometry (DMS), we noticed that the ionogram of protonated Verapamil consisted of two peaks. This was inconsistent with its metabolites, as each exhibited only a single peak in the respective ionograms. The unique behaviour of Verapamil was attributed to protonation at its tertiary amino moiety, which generated a stereogenic quaternary amine.

Predicting differential ion mobility behaviour using machine learning.

Although there has been a surge in popularity of differential mobility spectrometry (DMS) within analytical workflows, determining separation conditions within the DMS parameter space still requires manual optimization. A means of accurately predicting differential ion mobility would benefit practitioners by significantly reducing the time associated with method development. Here, we report a machine learning (ML) approach that predicts dispersion curves in an N2 environment, which are the compensation voltages (CVs) required for optimal ion transmission across a range of separation voltages (SVs) between 1500 to 4000 V.

"Thermometer" Ions Can Fragment Through an Unexpected Intramolecular Elimination: These Are Not the Fragments You Are Looking For.

Benzylpyridinium analogs are effective thermometer ions since monitoring the formation of the benzylium fragment produced from heterolytic cleavage of the C-N bond can be linked to the ion's internal energy. In this study, three -substituted benzylpyridinium ions containing ethoxy (OEt), isopropoxy (OPr) and -butoxy (OBu) substitutents were synthesized and evaluated as chemical thermometers. Intriguingly, the product ion spectra of the three benzylpyridinium ions were dominated by / 107 instead of the anticipated benzylium species.

Determining Collision Cross Sections from Differential Ion Mobility Spectrometry.

The experimental determination of ion-neutral collision cross sections (CCSs) is generally confined to ion mobility spectrometry (IMS) technologies that operate under the so-called low-field limit or those that enable empirical calibration strategies (e.g., traveling wave IMS; TWIMS).

The Charge-State and Structural Stability of Peptides Conferred by Microsolvating Environments in Differential Mobility Spectrometry.

The presence of solvent vapor in a differential mobility spectrometry (DMS) cell creates a microsolvating environment that can mitigate complications associated with field-induced heating. In the case of peptides, the microsolvation of protonation sites results in a stabilization of charge density through localized solvent clustering, sheltering the ion from collisional activation. Seeding the DMS carrier gas (N) with a solvent vapor prevented nearly all field-induced fragmentation of the protonated peptides GGG, AAA, and the Lys-rich Polybia-MP1 (IDWKKLLDAAKQIL-NH).

How Hot Are Your Ions in Differential Mobility Spectrometry?

Ions can experience significant field-induced heating in a differential mobility cell. To investigate this phenomenon, the fragmentation of several -substituted benzylpyridinium "thermometer" ions (R = OMe, Me, F, Cl, H, CN) was monitored in a commercial differential mobility spectrometer (DMS). The internal energy of each benzylpyridinium derivative was characterized by monitoring the degree of fragmentation to obtain an effective temperature, , which corresponds to a temperature consistent with treating the observed fragmentation ratio using a unimolecular dissociation rate weighted by a Boltzmann distribution at a temperature .

Augmenting Basin-Hopping With Techniques From Unsupervised Machine Learning: Applications in Spectroscopy and Ion Mobility.

Evolutionary algorithms such as the basin-hopping (BH) algorithm have proven to be useful for difficult non-linear optimization problems with multiple modalities and variables. Applications of these algorithms range from characterization of molecular states in statistical physics and molecular biology to geometric packing problems. A key feature of BH is the fact that one can generate a coarse-grained mapping of a potential energy surface (PES) in terms of local minima.

A parallelized molecular collision cross section package with optimized accuracy and efficiency.

Ion mobility-based separation prior to mass spectrometry has become an invaluable tool in the structural elucidation of gas-phase ions and in the characterization of complex mixtures. Application of ion mobility to structural studies requires an accurate methodology to bridge theoretical modelling of chemical structure with experimental determination of an ion's collision cross section (CCS). Herein, we present a refined methodology for calculating ion CCS using parallel computing architectures that makes use of atom specific parameters, which we have called MobCal-MPI.

A Flexible Synthesis of Ga-Labeled Carbonic Anhydrase IX (CAIX)-Targeted Molecules via CBT/1,2-Aminothiol Click Reaction.

We herein describe a flexible synthesis of a small library of Ga-labeled CAIX-targeted molecules via an orthogonal 2-cyanobenzothiazole (CBT)/1,2-aminothiol click reaction. Three novel CBT-functionalized chelators (⁻) were successfully synthesized and labeled with the positron emitter gallium-68. Cross-ligation between the pre-labeled bifunctional chelators (BFCs) and the 1,2-aminothiol-acetazolamide derivatives ( and ) yielded six new Ga-labeled CAIX ligands with high radiochemical yields.

The structures and properties of anionic tryptophan complexes.

The physicochemical properties of [Trp-H] and [TrpCl] (n = 1, 2) have been investigated in a combined computational and experimental infrared multiple dissociation (IRMPD) study. IRMPD spectra within the 850-1900 cm region indicate that deprotonation is localized on the carboxylic acid moiety in [Trp-H] clusters. A combination of hydrogen bonding and higher order charge-quadrupole interactions appear to influence cluster geometries for all investigated systems.

Early-Stage Incorporation Strategy for Regioselective Labeling of Peptides using the 2-Cyanobenzothiazole/1,2-Aminothiol Bioorthogonal Click Reaction.

Herein, we describe a synthetic strategy for the regioselective labeling of peptides by using a bioorthogonal click reaction between 2-cyanobenzothiazole (CBT) and a 1,2-aminothiol moiety. This methodology allows for the facile and site-specific modification of peptides with various imaging agents, including fluorophores and radioisotope-containing prosthetic groups. We investigated the feasibility of an early-stage incorporation of dipeptide into targeting vectors, such as and , during solid-phase peptide synthesis.

Early-Stage Incorporation Strategy for Regioselective Labeling of Peptides using the 2-Cyanobenzothiazole/ 1,2-Aminothiol Bioorthogonal Click Reaction.

Invited for this month's cover picture is the group of Dr. Yann Seimbille at the Life Sciences Division at TRIUMF (Canada). The cover picture shows how a simple and innovative methodology based on the bioorthogonal click reaction between 2-cyanobenzothiazole and 1,2-aminothiol has been elaborated to facilitate the labeling of peptide biovectors.

Correction to "Assessing Physicochemical Properties of Drug Molecules via Microsolvation Measurements with Differential Mobility Spectrometry".

[This corrects the article DOI: 10.1021/acscentsci.6b00297.

Assessing Physicochemical Properties of Drug Molecules via Microsolvation Measurements with Differential Mobility Spectrometry.

The microsolvated state of a molecule, represented by its interactions with only a small number of solvent molecules, can play a key role in determining the observable bulk properties of the molecule. This is especially true in cases where strong local hydrogen bonding exists between the molecule and the solvent. One method that can probe the microsolvated states of charged molecules is differential mobility spectrometry (DMS), which rapidly interrogates an ion's transitions between a solvated and desolvated state in the gas phase (i.

B(CF)-Catalyzed transfer 1,4-hydrostannylation of α,β-unsaturated carbonyls using iPr-tricarbastannatrane.

Tris(pentafluorophenyl)borane, B(CF), has been found to be an effective catalyst to access the hydridoborate anion, [N(CHCHCH)Sn][HB(CF)], via hydride abstraction from the hypercoordinated tin reagent, iPr-tricarbastannatrane. This process has been applied to the B(CF)-catalyzed transfer 1,4-hydrostannylation of electron-deficient olefins, namely benzylidene barbituric acids. Insights into the mechanism have been obtained via a series of H, H, B, C, and Sn NMR spectroscopy, mass spectrometry, and labeling experiments.