#RobSelects preprint of the week #ChemRxiv: Methylbutyl boronate salt as methylation reagent in Suzuki-Miyaura cross couplings. #catalysis https://doi.org/10.26434/chemrxiv.15001572/v1

A Generalized Theory for the Structural and Spatial Mapping of Energy, Entropy, and Free Energy | ChemRxiv Systems in which the free energy density is nonuniform in space are familiar: the surface tension of a water droplet and the surface energy of a solid are good examples. Some such cases can be treated with prior theory, notably inhomogeneous solvation ...

Gilson and Kurtzman (2026) A Generalized Theory for the Structural and Spatial Mapping of Energy, Entropy, and Free Energy. #ChemRxiv #preprint #TheoChem #PhysChem #CompChem #cheminformatics #chemsky 🧪
doi.org/10.26434/che...

"Detecting and controlling #mirrorlife is especially difficult because almost all diagnostic tests and tools are designed to find regular life forms"

The good news is that we have figured out an assay for mirror life - see our #ChemRxiv #preprint
chemrxiv.org/doi/full/10....

#ChemSky #Biology

COMPANY NEWS: Leading Preprint Server #ChemRxiv Joins Wiley’s Newly Launched Research Exchange #Preprints (via @wiley.com) newsroom.wiley.com/press-releas... #publishing #scholcomm

🎊Check out our latest preprint "Sampling a GDB-20 Database of 32 Trillion Drug-Like Molecules by Generative Artificial Intelligence" by @yebuehler.bsky.social , Sacha Javor, and Jean-Louis Reymond in #ChemRxiv!
👉Read it here: chemrxiv.org/doi/full/10....
@reymondgroup.bsky.social #chemical_space

Excited to share our latest work on Helical PAHs! 🌪️
We show how the migration of Clar’s aromatic sextets dictates stiffness, dynamics, and optical properties. A story of "π-cramped" structures and tunable gaps.
doi.org/10.26434/che...
#ChemRxiv #helicene #chirality

'Mirror life' - life of the opposite chirality to our own - poses a distant, yet serious, #biosecurity threat. In this #ChemRxiv preprint, we set out molecules emitting ciruclarly polarised light can be used to identify and screen against #mirrorlife threats.

chemrxiv.org/doi/full/10....

#RobSelects preprint of the week #ChemRxiv: Photochemical conversion of aryl azides into pyridines via triplet aryl nitrenes. #orgchem https://doi.org/10.26434/chemrxiv-2026-jn9zb

Synthesis of microbial-derived octadecanoids The gut microbiome is increasingly being shown to exert multiple biological effects upon the host. This activity can occur via the production of microbial-derived metabolites. Gut bacteria have been demonstrated to convert dietary polyunsaturated fatty acids (PUFAs) into oxygenated metabolites called oxylipins, which can exert potent lipid mediator functions. The products derived from C-18 fatty acids are collectively known as octadecanoids and have been shown to associate with multiple disorders including allergy and metabolic dysregulation. To study the role of these compounds, there is a need to prepare sufficient quantities for functional investigations. This study presents the successful synthesis of 17 octadecanoids possessing a hydroxy group (n=9) or a ketone (n=8) on the carbon on the 10- or 13-positions. The products of these two series were prepared for the linoleic acid (LA), α-linolenic acid (ALA) and γ- linolenic acid (GLA) pathways. The new synthetic strategies developed here provided 17 putative microbial metabolites of C-18 PUFAs with high purities, in 5-13 steps and overall yields from 1.5-37%. To study the biological formation of these compounds, the parent PUFAs (LA, ALA, GLA) were fed to cultures of Enterococcus faecalis U150 and Lactobacillus acidophilus CCUG 5917, and the octadecanoid products were measured by chiral supercritical fluid chromatography coupled to tandem mass spectrometry (SFC-MS/MS). The compounds containing a hydroxy group on the 10- or 13-position are racemic, forming 9 enantiomeric pairs. Accordingly, of the 17 compounds synthesized, 9 were chiral and 8 were achiral resulting in 26 compounds in total. An additional 7 commercial bacteria-derived octadecanoids were measured, to provide a screen of 33 compounds. Generally, PUFA supplementation resulted in selective formation of the associated octadecanoids. Of the 33 studied compounds, 16 were observed to be formed by E. faecalis and 13 by L. acidophilus. These findings demonstrate the bacteria species-specific formation of octadecanoids, which may have ramifications for associated biological response in the host.

(ChemRxiv) Synthesis of microbial-derived octadecanoids: The gut microbiome is increasingly being shown to exert multiple biological effects upon the host. This activity can occur via the production of microbial-derived metabolites. Gut bacteria have been demonstrated… (RSS) #chemrxiv #MassSpecRSS

A direct LC–MS/MS method for simultaneous quantitation of bisphenol S, propylparaben, monobutyl phthalate, and their metabolites in human urine Accurate biomonitoring of non-persistent endocrine-disrupting chemicals (EDCs) requires robust quantitative methods for reliable human exposure and risk assessment. Building on previous work showing that direct measurement of bisphenol A and its conjugated metabolites in human urine reveals substantial underestimation in commonly used indirect, hydrolysis-based approaches, this study addresses the broader need for direct assays of other short-lived EDCs. Here, a direct liquid chromatography–tandem mass spectrometry method is developed and validated for the simultaneous quantification of bisphenol S (BPS), propylparaben (PP), monobutyl phthalate (MBP), and their major glucuronide and sulfate conjugates in human urine, and its performance is systematically compared with that of indirect enzymatic hydrolysis–based methods. Chromatographic separation was achieved on a C18 column with gradient elution, and detection employed negative electrospray ionization in multiple reaction monitoring mode. The method exhibited excellent linearity (r² > 0.995), low limits of detection (≤0.1 ng/mL for all analytes except BPS glucuronide), and high precision (CV ≤ 7%) and accuracy (relative error ≤ 10%), fulfilling the U.S. FDA bioanalytical validation criteria. Solid-phase extraction provided quantitative and reproducible recoveries with minimal matrix effects and no detectable carryover. Comparison with indirect enzymatic hydrolysis demonstrated close agreement for BPS and PP but revealed concentration-dependent underestimation of MBP (down to ~65% recovery at higher concentrations) using the indirect method. Application of the validated method to urine samples from 30 second-trimester pregnant women showed that glucuronidated forms accounted for >90% of total analyte concentrations and that total BPS, PP and MBP levels exceeded contemporary National Health and Nutrition Examination Survey (NHANES) estimates. Our findings demonstrate that direct approaches can provide more accurate EDC biomonitoring data, highlighting the need to reevaluate exposure estimates derived from indirect methods in population studies.

(ChemRxiv) A direct LC–MS/MS method for simultaneous quantitation of bisphenol S, propylparaben, monobutyl phthalate, and their metabolites in human urine: Accurate biomonitoring of non-persistent endocrine-disrupting chemicals (EDCs) requires robust quantitative… (RSS) #chemrxiv #MassSpecRSS

Native Charge Detection Mass Spectrometry of Kilobase-Scale Messenger RNAs Charge detection mass spectrometry (CDMS) enables direct measurement of mass and charge for individual ions and overcomes fundamental limitations of conventional electrospray mass spectrometry for large, heterogeneous biomolecules. Messenger RNAs (mRNAs) represent a particularly challenging analytical target, as transcripts often span thousands of nucleotides, exhibit substantial heterogeneity, and form higher-order oligomers that are difficult to assess using existing workflows. Here, we optimize and evaluate native CDMS for intact analysis of long mRNAs and conduct systematic comparison of positive and negative analysis polarities. Using a panel of commercially available mRNAs ranging from approximately 1,000 to 4,500 nucleotides, we demonstrate that native CDMS enables direct, and accurate mass measurement of intact mRNAs alongside various process-related impurities (truncations, dimers etc.). Collisional activation improves mass accuracy by reducing adduct heterogeneity while preserving the ability to resolve impurity populations. Across all constructs, CDMS provides quantitative access to charge distributions that scale with transcript length and respond predictably to activation, denaturation, and polarity, offering insight into ion charging behavior and charge accommodation for large RNAs. Negative polarity measurements generally access higher charge states than positive polarity, particularly for the largest transcripts, improving sensitivity and relative size discrimination, while intact mass accuracy remains comparable between polarities when appropriate ion transmission strategies are employed. Together, these results establish native CDMS as a versatile and information-rich platform for intact mRNA characterization, providing simultaneous access to mass, charge, and impurity information that complements existing analytical methods and supports emerging needs in RNA biotherapeutic development.

(ChemRxiv) Native Charge Detection Mass Spectrometry of Kilobase-Scale Messenger RNAs: Charge detection mass spectrometry (CDMS) enables direct measurement of mass and charge for individual ions and overcomes fundamental limitations of conventional electrospray mass… (RSS) #chemrxiv #MassSpecRSS

Let’s Get Cyclic – Influence of Head-to-Tail Cyclisation of Lanmodulin-inspired peptides on Lanthanide Affinity and Structure Over the recent years lanthanide-binding proteins such as lanmodulin, a naturally lanthanide-binding EF-hand protein from Methylorubrum extorquens AM1, as well as protein-inspired lanthanide-binding peptides have become of increasing interest for the development of separation and recycling methods for rare earth elements. For the first time, a set of head-to-tail cyclised lanmodulin-inspired peptides and their complexation behaviour towards lanthanides was comprehensively examined in aqueous media using time-resolved laser induced fluorescence spectroscopy (TRLFS), isothermal titration calorimetry (ITC), nuclear magnetic resonance (NMR) and circular dichroism (CD) spectroscopies, complemented by molecular dynamic (MD) simulations and advanced mass spectrometry methods. Results obtained from this multi-method approach evidence that the head-to-tail cyclisation can indeed increase the lanthanide-affinity in natural sequences and positively impact the pre-organisation of the metal-free peptide while limiting the amount of formed complex species in comparison to linear analogues. Furthermore, the impact of minimal sequence alterations by inserting glycine is shown to be useful in NMR experiments for probing alterations in the local environment of neighbouring amino acids potentially involved in coordination. Lastly, KD values for the peptides with the whole Ln series (except Pm) and the actinide curium are presented.

(ChemRxiv) Let’s Get Cyclic – Influence of Head-to-Tail Cyclisation of Lanmodulin-inspired peptides on Lanthanide Affinity and Structure: Over the recent years lanthanide-binding proteins such as lanmodulin, a naturally lanthanide-binding EF-hand protein from… (RSS) #chemrxiv #MassSpecRSS

Oxyanion Isotopologue Analysis of Natural Samples by Electrospray-Orbitrap: Method, Validation and Clumped Isotopes Traditional gas-source, sector-field isotope ratio mass spectrometers are not optimally designed to analyse non-volatile molecular solutes such as oxyanions or organics. Tedious preparation steps – often requiring micromole-scale samples – break chemical bonds, meaning only elemental isotope ratios can be extracted. Recent advances in mass spectrometry point towards a novel isotopic technique: soft electrospray ionisation coupled to a high-resolution Orbitrap mass spectrometer (ESI-Orbitrap). Widely accessible and commonly used for bioanalysis, this combination permits high mass resolution analysis on intact molecules in liquid solutions, currently requires tens of nanomoles of sample, provides simultaneous multi-isotopologue analysis, and – in theory – permits clumped isotope measurements. In this study, we (i) present procedures for the preparation of natural aqueous samples for ESI-Orbitrap, nitrate and sulphate isotopologue analysis and subsequent data treatment; (ii) provide improved ESI-Orbitrap stability metrics; (iii) validate ESI-Orbitrap performance for nitrate and sulphate singly-substituted isotopologues in natural samples, relative to traditional isotopic methods; (iv) report measurements of previously inaccessible nitrate clumped isotopes; and (v) discuss the present limitations of ESI-Orbitrap for isotopologue analysis and avenues for optimisation. We find that ESI-Orbitrap exhibits matrix sensitivity and isotopic drift over periods exceeding 30 minutes. However, we demonstrate that careful purification of ice core and aerosol samples, application of sample-reference bracketing and performance of linear calibrations allow accurate ESI-Orbitrap measurements of δ15N-NO3-, δ18O-NO3-, Δ17O-NO3-, δ34S-SO42-, and Δ17O-SO42-, achieving 0.4 – 1.3 ‰ precision while consuming only 20 nmol nitrate or 10 nmol sulphate. Using ESI-Orbitrap no-M0 analysis, we also measure the previously-inaccessible nitrate clumped isotope values Δ15N18O-NO3- and Δ18O18O-NO3- in ice core samples with uncertainties of 2.3 ‰ and 3.3 ‰, respectively. We outline avenues for improving the sensitivity, accuracy and precision of ESI-Orbitrap isotopologue measurements, and consider how our method could be adapted to additional analytes in different sample matrices.

(ChemRxiv) Oxyanion Isotopologue Analysis of Natural Samples by Electrospray-Orbitrap: Method, Validation and Clumped Isotopes: Traditional gas-source, sector-field isotope ratio mass spectrometers are not optimally designed to analyse non-volatile molecular solutes… (RSS) #chemrxiv #MassSpecRSS

Quantitative Host Cell Protein Analysis of Antibody-Based Protein Therapeutics using the Orbitrap Astral Mass Spectrometer Host cell proteins (HCPs) are endogenous proteins generated in cellular production systems alongside the biotherapeutic of interest. Removal of HCPs is crucial as they can be detrimental to product efficacy and patient safety. Due to its ability to determine individual HCP concentrations, liquid chromatography tandem mass spectrometry is increasingly utilised as an orthogonal method to ELISA for HCP monitoring. For protein biotherapeutics like monoclonal antibodies, their dynamic range makes detection of low-level HCPs difficult. The Orbitrap Astral MS has the potential to overcome such challenges, offering significant improvements in protein identifications in complex sample matrices while simultaneously reducing analysis times. Here, we utilise the Orbitrap Astral MS to perform HCP analysis on 37 protein biotherapeutics. The use of a short 60 samples-per-day separation method, dramatically reduced analysis time without sacrificing HCP identifications. 544 HCPs were detected across the cohort and 63.60% of those found to be quantifiable in at least one product using Hi3 quantitation. Functional analysis revealed that most detected HCPs had functions related to catalysis or binding, predominately catalytic activity (46%, 97 gene IDs) or protein binding (44%, 91 gene IDs). Over 80% of quantifiable HCPs were detected at concentrations below 10 ng/mg, ~9% below concentrations of 1 ng/mg. These included HCPs considered as “high-risk” by the Biophorum Development Group. This study shows how the Orbitrap Astral MS can improve detection of low-level HCPs while significantly reducing analysis times, allowing for rapid and more informed understanding of a products HCP content.

(ChemRxiv) Quantitative Host Cell Protein Analysis of Antibody-Based Protein Therapeutics using the Orbitrap Astral Mass Spectrometer: Host cell proteins (HCPs) are endogenous proteins generated in cellular production systems alongside the biotherapeutic of interest.… (RSS) #chemrxiv #MassSpecRSS

A photochemical strategy for pyrazole to imidazole conversion Heteroaromatic scaffolds are central to modern medicinal chemistry. Methods that can reconfigure the core heterocycle of a molecule while preserving its substitution pattern would greatly streamline analogue synthesis and bioisosteric replacement. Yet, direct heterocycle-to-heterocycle interconversions remain rare. Here we report a photochemical strategy that converts pyrazoles into imidazoles in a single step with broad functional-group tolerance and full retention of peripheral substitution. The reaction is effective across densely substituted and annulated systems and extends to pyrazolo[1,5-a]azines, a class of high-value heteroaromatics that have never previously been reconfigured. We show that selective photoexcitation of the pyrazole unit enables clean, predictable rearrangement even in the presence of competing absorption pathways. Mechanistic studies support an N–N bond homolysis pathway in which solvent-dependent conformational changes govern the reactivity of the ensuing biradical intermediates. This photochemical strategy is readily translated to continuous flow, confirming its potential for scalable applications. Overall, this work establishes a practical platform for direct core reconfiguration, providing modular access to imidazole analogues of pyrazoles that are otherwise difficult to prepare or very expensive.

#RobSelects preprint of the week #ChemRxiv: Photochemical isomerization of N-substituted pyrazoles to imidazoles. #orgchem https://doi.org/10.26434/chemrxiv-2026-68vcj

High performance interface for boosting ion transmission in native mass spectrometry and beyond. Electrospray ionization (ESI)-based native mass spectrometry (MS) has been extensively used to study non-covalent protein complexes and their structural aspects in the gas phase. As such it has a stable place in the portfolio of modern structural biology and biopharmaceutical analysis techniques. It is also promising as an approach to deliver pro-teins and their assemblies into the gas phase for single particle experiments at advanced light sources such as free electron lasers and synchrotrons. Here we report on a novel radiofrequency ion transfer interface enabling gas flow laminarization at low pressure for efficient capture, focusing, thermalization, trapping and gating of ions into a mass analyser, boosting up to 19-fold the observable signal intensities especially for notoriously challenging multi-megadalton assemblies such as in-tact viral capsids. The new ion transfer interface offers unique opportunities for interdisciplinary approaches intersecting native MS-guided structural biology, molecular and cluster physics as well as (bio)analytical applications. Additionally, when combined with sensitive detection of individual particles, this technology could eventually also open new avenues in clinical diagnostics, enabling for example the analysis of viruses at very low concentrations directly from dilute patient-derived samples as well as viral therapeutic vectors along the biopharmaceutical production chain, thereby helping to un-lock the full potential of native MS.

(ChemRxiv) High performance interface for boosting ion transmission in native mass spectrometry and beyond.: Electrospray ionization (ESI)-based native mass spectrometry (MS) has been extensively used to study non-covalent protein complexes and their structural aspects… (RSS) #chemrxiv #MassSpecRSS

Native Charge Detection Mass Spectrometry of Kilobase-Scale Messenger RNAs Charge detection mass spectrometry (CDMS) enables direct measurement of mass and charge for individual ions and overcomes fundamental limitations of conventional electrospray mass spectrometry for large, heterogeneous biomolecules. Messenger RNAs (mRNAs) represent a particularly challenging analytical target, as transcripts often span thousands of nucleotides, exhibit substantial heterogeneity, and form higher-order oligomers that are difficult to assess using existing workflows. Here, we optimize and evaluate native CDMS for intact analysis of long mRNAs and conduct systematic comparison of positive and negative analysis polarities. Using a panel of commercially available mRNAs ranging from approximately 1,000 to 4,500 nucleotides, we demonstrate that native CDMS enables direct, and accurate mass measurement of intact mRNAs alongside various process-related impurities (truncations, dimers etc.). Collisional activation improves mass accuracy by reducing adduct heterogeneity while preserving the ability to resolve impurity populations. Across all constructs, CDMS provides quantitative access to charge distributions that scale with transcript length and respond predictably to activation, denaturation, and polarity, offering insight into ion charging behavior and charge accommodation for large RNAs. Negative polarity measurements generally access higher charge states than positive polarity, particularly for the largest transcripts, improving sensitivity and relative size discrimination, while intact mass accuracy remains comparable between polarities when appropriate ion transmission strategies are employed. Together, these results establish native CDMS as a versatile and information-rich platform for intact mRNA characterization, providing simultaneous access to mass, charge, and impurity information that complements existing analytical methods and supports emerging needs in RNA biotherapeutic development.

(ChemRxiv) Native Charge Detection Mass Spectrometry of Kilobase-Scale Messenger RNAs: Charge detection mass spectrometry (CDMS) enables direct measurement of mass and charge for individual ions and overcomes fundamental limitations of conventional electrospray mass… (RSS) #chemrxiv #MassSpecRSS

O-glycosylation affects proteolysis of the native tear peptidome immune response and participating in antimicrobial activity. The biological function of these native peptides is governed by their biochemical properties including peptide length, charge, and hydrophobicity. Accordingly, the production of native peptides within the tear film is tightly regulated through a complex interplay between circulating proteases and the proteolytic susceptibility of the protein substrate. Though glycosylation has been shown to regulate the proteolysis of specific proteins in vitro, the extent to which endogenous cleavage motifs are mediated by proximal O-glycans remains unexplored in a more complex sample. Furthermore, the existence and identity of native tear peptides bearing O-glycans has yet to be elucidated, largely due to the high analytical complexity of tear fluid and the difficulty in characterizing O-glycosylated peptides. To address this gap, we leveraged advances in mass spectrometry (MS) to provide the first observation of circulating tear O-glycopeptides, detailing their biochemical properties and overall glycan compositions. Beyond systematic profiling of the O-glycopeptidome, we employed site-specific glycoproteomic analysis followed by molecular dynamics to investigate the interplay between O-glycan proximity and proteolysis. Here, we observed that O-glycans preferentially occupy glycosites distal from the N-/C-terminus, thereby influencing distinct cleavage motifs and peptide backbones. Finally, we showed in silico that O-glycosylation can mediate the solvent accessibility of proximal cleavage residues, thus providing a structural basis for these observations. Taken together, this study defines the proteolytic landscape at the ocular surface and highlights a potential role for tear fluid O-glycans.

(ChemRxiv) O-glycosylation affects proteolysis of the native tear peptidome: immune response and participating in antimicrobial activity. The biological function of these native peptides is governed by their biochemical properties including peptide length, charge, and… (RSS) #chemrxiv #MassSpecRSS

A direct LC–MS/MS method for simultaneous quantitation of bisphenol S, propylparaben, monobutyl phthalate, and their metabolites in human urine Accurate biomonitoring of non-persistent endocrine-disrupting chemicals (EDCs) requires robust quantitative methods for reliable human exposure and risk assessment. Building on previous work showing that direct measurement of bisphenol A and its conjugated metabolites in human urine reveals substantial underestimation in commonly used indirect, hydrolysis-based approaches, this study addresses the broader need for direct assays of other short-lived EDCs. Here, a direct liquid chromatography–tandem mass spectrometry method is developed and validated for the simultaneous quantification of bisphenol S (BPS), propylparaben (PP), monobutyl phthalate (MBP), and their major glucuronide and sulfate conjugates in human urine, and its performance is systematically compared with that of indirect enzymatic hydrolysis–based methods. Chromatographic separation was achieved on a C18 column with gradient elution, and detection employed negative electrospray ionization in multiple reaction monitoring mode. The method exhibited excellent linearity (r² > 0.995), low limits of detection (≤0.1 ng/mL for all analytes except BPS glucuronide), and high precision (CV ≤ 7%) and accuracy (relative error ≤ 10%), fulfilling the U.S. FDA bioanalytical validation criteria. Solid-phase extraction provided quantitative and reproducible recoveries with minimal matrix effects and no detectable carryover. Comparison with indirect enzymatic hydrolysis demonstrated close agreement for BPS and PP but revealed concentration-dependent underestimation of MBP (down to ~65% recovery at higher concentrations) using the indirect method. Application of the validated method to urine samples from 30 second-trimester pregnant women showed that glucuronidated forms accounted for >90% of total analyte concentrations and that total BPS, PP and MBP levels exceeded contemporary National Health and Nutrition Examination Survey (NHANES) estimates. Our findings demonstrate that direct approaches can provide more accurate EDC biomonitoring data, highlighting the need to reevaluate exposure estimates derived from indirect methods in population studies.

(ChemRxiv) A direct LC–MS/MS method for simultaneous quantitation of bisphenol S, propylparaben, monobutyl phthalate, and their metabolites in human urine: Accurate biomonitoring of non-persistent endocrine-disrupting chemicals (EDCs) requires robust quantitative… (RSS) #chemrxiv #MassSpecRSS

Native multi-dimensional (SEC/CZE/SID) protein complex identification and topology characterization (Native MudPIT) Here, we demonstrate pilot development of native multi-dimensional protein complex identification and topology characterization (Native MudPIT) in complex biological samples via coupling native size exclusion chromatography (SEC), online native capillary electrophoresis-mass spectrometry (nCE-MS), surface-induced dissociation (SID), and multi-level proteomics. With semi-manual data interpretation because optimized algorithms do not yet exist for this approach, the Native MudPIT approach enabled the detection of 124 native endogenous protein complexes with masses up to 1.5 MDa from fractions of a whole cell lysate, identified 46 protein complexes in a discovery mode, and provided topological information for 39 protein complexes. The Native MudPIT approach is expected to be broadly applicable for characterizing protein complexes in cells, tissues, and biological fluids.

(ChemRxiv) Native multi-dimensional (SEC/CZE/SID) protein complex identification and topology characterization (Native MudPIT): Here, we demonstrate pilot development of native multi-dimensional protein complex identification and topology characterization (Native… (RSS) #chemrxiv #MassSpecRSS

DiploPhos: A Hemilabile Bisphosphine for Sterically Hindered Ni-Catalyzed Suzuki–Miyaura Couplings Pharmaceutically relevant Suzuki–Miyaura cross-couplings (SMCs) often require designer phosphine ligands and palladium loadings above 1 mol% to couple Lewis basic, sterically congested substrates. Recent work has demonstrat-ed that nickel is an attractive alternative to palladium for facile SMCs, but further ligand development is required for Ni catalysis to rival Pd for more challenging couplings. We applied prior work on monophosphine ligand design for Ni to develop a bisphosphine, DiploPhos, that outperforms state-of-the-art ligands for Ni to achieve sterically hin-dered Ni SMCs. Catalyst speciation studies revealed the hemilabile nature of DiploPhos, which improves reactivity relative to stronger chelating ligands but also leads to the formation of less-active DiploPhos-bridged aggregates. Lew-is basic functionality (present on substrates or additives) was found to promote the disaggregation of these species and led to increased SMC yields. This observation is contrary to most other systems in which Lewis basic substrates inhibit Ni-catalyzed SMC reactions. Ligand exchange studies demonstrated that despite its hemilability, DiploPhos is more resistant to displacement by heterocycles than similar bisphosphines. Together, these properties led to best-in-class reactivity for sterically hindered, Lewis base-rich Ni SMCs.

#RobSelects preprint of the week #ChemRxiv: Designing a hemilabile bisphosphine ligand for sterically hindered nickel-catalyzed Suzuki-Miyaura cross couplings. #catalysis https://doi.org/10.26434/chemrxiv-2025-q7td5

Molecular Maxwell Demons as Information Catalysts for Post-Hoc Multi-Condition Mass Spectrometry We present a theoretical and computational framework for virtual mass spectrometry based on Molecular Maxwell Demons (MMDs) operating as information catalysts. Building on the biological Maxwell demon framework, we demonstrate that mass spectrometry data contain categorical state information that is fundamentally independent of experimental conditions. MMDs implement dual filtering architectures - where the input philtre represents experimental parameters (temperature, collision energy, ionisation method) and the output philtre enforces physical realisability through hardware coherence constraints - to drastically amplify transition probabilities from potential molecular states (approximately 10 to the power of 12 configurations) to actual measured observables (approximately 10 to the power of 3 spectral features), achieving probability enhancement factors of p_MMD divided by p_0 approximately equal to 10 to the power of 8 to 10 to the power of 15. The key insight is that the MMD input filter can be reconfigured post-hoc to apply different experimental conditions to the same underlying categorical state, enabling virtual experiments without physical re-measurement. We introduce S-entropy coordinates as sufficient statistics for platform-independent molecular representation, forming a 14-dimensional feature space that compresses infinite molecular configurational information into finite, optimality-preserving coordinates. Our framework grounds virtual measurements in physical reality through an 8-scale hardware oscillation hierarchy (CPU clock, memory bus, network latency, GPU streams, disk I/O, LED modulation, display refresh, system interrupts) that maps biological oscillatory scales to computational substrates. We validate the framework on datasets spanning multiple instrument types and demonstrate: (1) post-hoc experimental condition modification (temperature, collision energy, ionisation method) with high agreement to physical validation experiments; (2) virtual multi-instrument analysis enabling simultaneous TOF, Orbitrap, FT-ICR, and IMS projections from single measurements; (3) retrospective method optimization reducing physical experimentation by approximately 95 percent while maintaining identification confidence. This work establishes MMDs as reconfigurable information catalysts that transform mass spectrometry from a fixed-condition measurement paradigm to a flexible post-hoc analytical completion tool, with immediate applications in method development, retrospective data mining, and cross-platform metabolomics.

(ChemRxiv) Molecular Maxwell Demons as Information
Catalysts for Post-Hoc Multi-Condition Mass
Spectrometry: We present a theoretical and computational framework for virtual mass spectrometry based on Molecular Maxwell Demons (MMDs) operating as information catalysts.… (RSS) #chemrxiv #MassSpecRSS

🚀🚀 Big news for the #metabolomics & #massspec community! 🚀

Right as we step into 2026!

👉 Check out our #preprint 📜 on #ChemRxiv here:
🌶️ Trends In Computational Metabolomics In The Past Five Years (2021–2025): chemrxiv.org/engage/chemr...
🖥️ All tools listed on GitHub: github.com/enveda/compu... 📊

Anthraquinone-based fluorophore as electrostatic complexation-driven turn-on probe for Cardiolipin detection in model membranes Cardiolipin (CL), being a mitochondria-specific phospholipid, is known to play a pivotal role in cellular respiration, and its levels are intricately connected to various neurodegenerative disorders. Owing to the simplicity compared to mass spectrometry-based lipidomics, optical detection of CL is an attractive option; however, only two probes, namely TTAPE-Me and 10- nonyl acridine orange (NAO), are currently available. Herein, we report the use of an anthraquinone-based fluorophore 1 as a turn-on sensor for CL in phospholipid membranes. 1 exhibited a robust fluorescence turn-on response upon selective binding to CL, with up to 5.8- fold enhancement in dioleoyl phosphatidylcholine (DOPC) vesicles and 5.1-fold in dipalmitoyl phosphatidylcholine (DPPC) vesicles. Based on the results from anisotropy, temperature studies, and salt dependence studies, it was concluded that the formation of an electrostatic complex was the driving factor behind the observed fluorescence enhancement. Mechanistic investigations, including anisotropy, salt-dependence, and temperature studies, revealed that electrostatic complex formation underlies the observed fluorescence enhancement. Interestingly, the probe also showed a high degree of selectivity toward CL compared to other biologically relevant analytes. These findings establish compound 1 as a promising optical probe for quantitative cardiolipin detection, providing an alternative to existing fluorophores.

(ChemRxiv) Anthraquinone-based fluorophore as electrostatic complexation-driven turn-on probe for Cardiolipin detection in model membranes: Cardiolipin (CL), being a mitochondria-specific phospholipid, is known to play a pivotal role
in cellular respiration, and its… (RSS) #chemrxiv #MassSpecRSS

Cryogenic Gas-Phase IR Spectroscopy on a Commercial Ion Mobility-Mass Spectrometry Platform The combination of gas-phase infrared (IR) spectroscopy with ion mobility spectrometry and mass spectrometry provides detailed, multi-dimensional structural information that facilitates the identification of unknown analytes. The instrumentation for performing these measurements is typically home-built and requires substantial expertise to operate. Here, we demonstrate messenger-tagging IR spectroscopy on a modified Synapt G2-S ion mobility-mass spectrometer. Messenger-tagging is performed in a commercially available cryogenic ion trap inserted between the exit of the transfer cell and the TOF pusher assembly and tagged ions are excited by IR light before MS measurement. We report the adjustments to the timing cycle and voltage gradient in the Synapt G2-S necessary for efficient trapping and messenger-tagging in the cryogenic trap. The capabilities of this instrument are demonstrated by measuring IM-MS-IR data for leucine enkephalin, a benchmark standard in mass spectrometry. The ability to selectively transmit ions of specific mobility enables the separation and subsequent IR spectroscopy of the isomeric trisaccharides cellotriose and melezitose. These data demonstrate the first implementation of messenger-tagging IR spectroscopy in a widely used, commercially available IM-MS system. The user-friendly implementation of these techniques overcomes a significant barrier to the widespread incorporation of orthogonal IR spectroscopy measurements in existing IM-MS workflows and will aid in distinguishing unknown molecules in untargeted -omics measurements.

(ChemRxiv) Cryogenic Gas-Phase IR Spectroscopy on a
Commercial Ion Mobility-Mass Spectrometry Platform: The combination of gas-phase infrared (IR) spectroscopy with ion mobility spectrometry and mass spectrometry provides detailed, multi-dimensional structural… (RSS) #chemrxiv #MassSpecRSS

Browsing FAIR Transformation Product Information with FAIR-TPs Considering transformation products (TPs) in environmental studies remains a huge challenge for scientists, from identification in samples via mass spectrometry through to inclusion in chemical regulation. This article introduces FAIR-TPs, a website to browse openly-available TP data collated from literature sources. The data is sourced from several community-contributed environmental datasets on the NORMAN Suspect List Exchange (NORMAN-SLE), plus a dataset from ChEMBL available through PubChem, with links to templates and contact details to encourage further community contributions. The data is compiled regularly using an open source workflow, archived and versioned on Zenodo under a CC-BY license, then processed and displayed on FAIR-TPs. FAIR-TPs currently contains 11,190 reactions involving 9,435 compounds from 11 sources. A graph-based representation of the transformations (compounds as nodes, reactions as edges) is stored in a Neo4j database as a Directed Graph and made publicly accessible online through a Django Web Application. Users can retrieve the shortest directed pathways between predecessors (parents) and successors (transformation products/metabolites), search by SMARTS substructures, or explore local reaction neighbourhood data on individual compounds. Interactive network visualizations provide ways for users to view multi-step transformations in a smooth, user-friendly interface, while exploring transformation pathways. The compound/reaction metadata provides links to further information about the chemicals and data sources. Key statistics, including number of reactions/compounds, top compounds, reaction types, mass differences are summarised from the current dataset. FAIR-TPs is designed to be a public resource to support suspect and non-target screening workflows, helping scientists identify data gaps and interpret complex transformation reactions. The FAIR-TPs website is openly available at https://fairtps.lcsb.uni.lu.

(ChemRxiv) Browsing FAIR Transformation Product Information with FAIR-TPs: Considering transformation products (TPs) in environmental studies remains a huge challenge for scientists, from identification in samples via mass spectrometry through to inclusion in chemical… (RSS) #chemrxiv #MassSpecRSS

Native Top-Down Mass Spectrometry combined with High-Resolution Charge Variant Analysis of Trastuzumab Originator and Biosimilars Comprehensive characterisation of monoclonal antibody (mAb) charge heterogeneity is essential for ensuring product quality, maintaining batch consistency, and supporting biosimilar development. Charge variant analysis (CVA) is widely used to separate acidic and basic proteoforms from the main species. However, cation-exchange chromatography coupled to mass spectrometry provides limited information and cannot localise the post-translational modifications (PTMs) responsible for mAb heterogeneity. Here, we present the coupling of pH-gradient CVA with native top-down mass spectrometry (TD-MS) for proteoform-specific analysis of trastuzumab. Individual charge variants were chromatographically separated under native conditions and directly fragmented on the chromatographic timescale using higher-energy collision dissociation (HCD), electron-transfer dissociation (ETD), and ultraviolet photodissociation (UVPD). The addition of proton-transfer charge reduction (PTCR) helped to reduce spectral congestion and enhanced the detection of high-mass fragment ions, resulting in improved sequence coverage. This workflow enabled the complete sequencing of complementarity-determining region (CDR) 3 and the direct identification and insights on the location of key PTMs at the intact-protein level, including deamidation, succinimide, and N-terminal pyroGlu, on individual proteoforms. Comparison of five trastuzumab samples (originator and biosimilars) demonstrated high reproducibility in fragmentation patterns, sequence coverage, and variant assignment, highlighting the robustness of the method. Although limitations remain due to the challenges of fragmentating intact mAbs under native conditions, this work establishes a proof of concept for CVA native TD-MS characterisation of mAbs to complement bottom-up and middle-down analyses and has potential for broad applicability on antibody-based biopharmaceuticals, from characterisation to biosimilarity evaluation.

(ChemRxiv) Native Top-Down Mass Spectrometry combined with High-Resolution Charge Variant Analysis of Trastuzumab Originator and Biosimilars: Comprehensive characterisation of monoclonal antibody (mAb) charge heterogeneity is essential for ensuring product quality,… (RSS) #chemrxiv #MassSpecRSS

Guiding Principles for Differential Electrochemical Mass Spectrometry in Dual Thin-Layer Cell: From Aqueous to Organic Electrolytes Differential electrochemical mass spectrometry (DEMS) enables real time detection of volatile products formed at an electrode. However, its application in organic solvents is hindered by their volatility and by solvent-induced swelling or permeation of the membrane that defines the liquid/vacuum interface, compromising stable product transfer to the mass spectrometer. Here, we show that a rational optimization of the membrane interface together with the operating conditions in a dual thin-layer flow cell enables extending the application of DEMS to volatile organic electrolytes. Starting from the hydrogen evolution reaction (HER) on polycrystalline platinum (Pt) in 0.5 M HClO₄ aqueous electrolyte as a model system, we systematically examined how flow rate, membrane properties, that is porosity and thickness, and the inclusion of a cold trap influence gas transport efficiency in the DEMS cell. Next, we selected acetonitrile, one of the most widely used solvents in organic chemistry, as a stringent test case due to its high volatility and swelling effect on PTFE membranes, and evaluated the methodology for both HER and OER. The systematic variation of key DEMS parameters in aqueous media provided the basis to rationally select conditions most likely to enable reliable analyte detection in this demanding solvent. Our results provide practical design guidance for the controlled operation of DEMS with a dual thin-layer flow cell and demonstrate that rationally selected parameters successfully enable its application even in challenging non-aqueous environments.

(ChemRxiv) Guiding Principles for Differential Electrochemical Mass Spectrometry in Dual Thin-Layer Cell: From Aqueous to Organic Electrolytes: Differential electrochemical mass spectrometry (DEMS) enables real time detection of volatile products formed at an electrode.… (RSS) #chemrxiv #MassSpecRSS

Mycotoxin field trial uncovers first Aflatoxin B1 occurrence in maize in Lower Austria Climate change is driving the migration of crop pests and pathogens into new regions, posing significant threats to food security and safety. Aflatoxins, toxic metabolites produced by Aspergillus flavus, are of particular concern due to their carcinogenic properties. This study reports the first detection of aflatoxin B1 (AFB1) in maize grown in Tulln, Lower Austria, a region where such contamination has not been previously observed. The data were collected as part of the BOKU TTox-Monitor trial, a long-term monitoring trial to study the impact of climate change on the (co-)occurrence of mycotoxins. In 2024, 24 maize varieties were cultivated and analysed for fungal metabolites using liquid chromatog-raphy-tandem mass spectrometry (LC-MS/MS). AFB1 was detected in one plot at concentrations ranging from 4.47 to 29.49 µg/kg, and the presence of A. flavus was confirmed through mycological analysis. The unusually hot and dry condi-tions in 2024, coupled with severe corn borer infestation, likely created an optimal environment for A. flavus infection and aflatoxin production. While most samples were below regulatory limits for other mycotoxins, significant variability in contamination levels was observed across varieties. This finding supports predictions that aflatoxin contamination will become a growing concern in central Europe as climate change progresses, and underscores the need for long-term monitoring, research, and mitigation strategies to address this emerging food safety threat.

(ChemRxiv) Mycotoxin field trial uncovers first Aflatoxin B1 occurrence in maize in Lower Austria: Climate change is driving the migration of crop pests and pathogens into new regions, posing significant threats to food security and safety. Aflatoxins, toxic metabolites… (RSS) #chemrxiv #MassSpecRSS

Abiotic transformation of radiolabelled 6-PPD and 6-PPDQ in water and in presence of nitrogen/air/ozone and light N-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylendiamine (6-PPD) and one of its oxidation products, 6-PPD quinone (6-PPDQ) are environmental contaminants released from tire and road wear particles (TRWP). The abiotic transformation of both compounds by hydrolysis and in contact with atmosphere with and without oxygen species and light was studied, following OECD-guidelines and using radiolabelled test substances. This allowed for mass balances including transformation products, those identified by liquid chromatography-mass spectrometry and those remaining unidentified. 6-PPD was effectively degraded by hydrolysis at neutral and basic pH (DT50 5 – 12 h at 25°C), with 4-HDPA being the major reaction intermediate. 6-PPDQ remained below 0.2 % of the applied radioactivity (AR) of 6-PPD, except at very acidic conditions and low temperature (10°C) with an intermediate yield of 7.5 % AR. In contact with atmosphere 6-PPD was transformed by direct photolysis (DT50 14 h). Direct reaction with ozone was slow (DT50 3.5 d) but degradation by OH-radicals (ozone/light) was very fast (DT50 3.7 h). A diverse set of products was formed; 6-PPDQ was determined in some cases, with a maximum intermediate yield of 1.3 % AR and decreasing again with ongoing oxidation of 6-PPD (to levels ≤ 0.6 % AR). 6-PPDQ is not susceptible to pure hydrolysis (DT50 > 1000 d at pH7, mean 490 d in 12 natural waters) and very limited to direct photolysis (DT50 56 d). On the contrary, reactivity towards reactive oxygen species (air/ozone and light) is in the same range as for 6-PPD (DT50 2 – 7 h). Oxidative transformation of 6-PPDQ proceeds via opening of the quinone-ring, with 20 - 50 % AR recorded as CO2 within 2 d. For 6-PPDQ oxidation in the presence of light only 50 – 80 % of AR could be recovered. This study with 14C-labelled test substances provides solid information on the abiotic transformation of both, 6-PPD and 6-PPDQ, and supports environmental risk assessment.

(ChemRxiv) Abiotic transformation of radiolabelled 6-PPD and 6-PPDQ in water and in presence of nitrogen/air/ozone and light: N-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylendiamine (6-PPD) and one of its oxidation products, 6-PPD quinone (6-PPDQ) are environmental… (RSS) #chemrxiv #MassSpecRSS