The deliberate release of Novichok nerve agents represents one of the most critical chemical security threats of the 21st century. Conventional detection technologies such as gas chromatography-mass spectrometry, ion mobility spectrometry, and Fourier-transform infrared spectroscopy require sophisticated instrumentation and controlled facilities, limiting their applicability for rapid field monitoring. Here, we present a machine learning-integrated colorimetric optical sensor array that uses commercially available dyes to enable rapid and selective detection of multiple authentic Novichok agents in a portable format. By combining colorimetric imaging data under visible and UV illumination with supervised learning, we identified an optimized four-dye array that discriminates four Novichok species with 100% classification accuracy across micromolar concentrations. The analytical working range was 10-500 mu M with an calculated limit of detection of ca. 10 mu M, as determined from Delta E00 signal-to-noise analysis. Importantly, the platform requires only minimal sample volumes, inexpensive reagents, and simple optical readouts that can be acquired with a smartphone, underscoring its potential for real-world deployment. To the best of our knowledge, this work provides the first demonstration of an accessible sensor array capable of authentic Novichok detection and establishes a benchmark dataset for future research in chemical threat monitoring and defense-oriented sensing technologies.

Boronic acids are notable for their ability to reversibly bind 1,2- and 1,3-diols in protic media. The utility of this reversible, selective, and covalent interaction has been exploited widely in supramolecular assemblies. However, little work has been done to explore the solvent dependence of boronic acid-diol condensations. Herein, we report an evaluation of association constants for commonly used phenylboronic acids and diols in different solvents. To this end, we employed UV-visual spectroscopy to monitor the extent of complexation using indicator-displacement assays in a series of host-guest titrations. We report multivariable correlations of the binding affinities to various solvent parameters and interpret the lessons thereof. By evaluating these binding affinities, we aim to (1) support the future design of supramolecular assemblies incorporating boronic acids and diols and (2) understand how solvent characteristics influence the association strength.

Array-based differential sensing is inspired by a mammal's sense of taste and smell. The human sense of touch is also array-based; using mechanosensors in the skin that differentiate surfaces by their surface chemistry. Inspired by this, we aimed to develop a rationally biased and randomized oligomer sensor array which differentiates bulk solids by their surface chemistry. Column chromatography mimics this aspect of the sense of touch, as it is traditionally used to physically separate molecules in solution by the strength of their noncovalent interactions with the stationary phase. In this report, we differentiated column chromatography stationary phases (the analyte) by the retention time (the sensor's analytical response) of a vast library of oligomers with statistically biased but random monomer compositions (the sensor array). The use of unsupervised principal component analysis (PCA) validated our sensor array design by differentiating five surfaces with tight replicate clustering and a high degree of cross-reactivity.

The field of molecular information storage has recently expanded to include abiotic sequence-defined polymers. While robust methods have been developed, there is a current bottleneck in the throughput of this work as information density is increased. Herein, we introduce an automated workflow in which a commercial peptide synthesizer composed of a single XYZ liquid-handling robot was adapted to both synthesize and sequence sequence-defined oligourethanes. Our sequencing method was improved to cut down the number of samples required for each oligomer from 13 to one. Additionally, we introduce the use of desorption electrospray ionization mass spectrometry as our analysis method for sequencing, which allowed for simplified and increased speed of data acquisition. Finally, we created a Python script that is able to reconstruct the sequence information from the MS data in an automated fashion. We demonstrate this new workflow by encoding and decoding a quote from the late Maya Angelou: "When you learn, teach, when you get, give".

Green fluorescent protein (GFP) chromophores are widely studied as fluorescent moieties for sensing and imaging applications. Herein, we present a straightforward synthetic strategy that involves the reaction of glycine amides with 1,3-diketones to form imidazolones through an unusual molecular fragmentation and recombination pathway. Mechanistic investigations, including crossover experiments, inspired a competing strategy that incorporates exogenous ketones into the products, yielding fluorescent GFP chromophore analogues. This method holds the potential for fluorescent labeling of glycine-terminated peptides.

The growing demand for data storage has driven research into alternative storage media. Although DNA has proven effective, synthetic sequence-defined polymers (SDPs) offer tailored information-encoding potential. Despite advances in SDP chemodiversity, sequencing methods remain limited, primarily relying on tandem mass spectrometry. To address this, we developed an electrochemical sequencing technique for sequence-defined oligourethanes (SDOs), incorporating four ferrocene-based monomers. Our method combines controlled chain-end degradation with differential pulse voltammetry (DPV) to yield unique voltammograms specific to each sequence. Coupled with kinetic modeling and principal component analysis (PCA), this approach enables accurate sequence identification. We automated this process with a Python program that decodes sequences by comparing experimental DPV data to predicted profiles and thereby successfully demonstrated the encoding and decoding of an 11-character password. The technique expands the toolbox for sequencing SDPs and opens new possibilities for molecular data storage.

The sequencing of peptides via N-terminal amino acid removal is a classic reaction termed Edman degradation. This method involves repeated treatment of the N-terminal amino group of a peptide with phenyl isothiocyanate (PITC), followed by treatment with trifluoroacetic acid. Spurred by the need for an alternative non-acid-based chemistry for next-generation protein sequencing technologies, we developed a base-induced N-terminal degradation method. Several N-terminal derivatization reagents carrying supernucleophiles were tested. After rounds of iterative designs, compound DR3, with a N-hydroxysuccinimide as a leaving group and hydrazinecarboxamide as the supernucleophile, demonstrated the highest yield for the peptide derivatization step and the most efficient elimination of the N-terminal amino acid in just 1% of a hydroxide salt. The method successfully removed all 20 amino acids at the N-terminus in high yield. The technique demonstrates compatibility with oligonucleic acids, which differs from Edman degradation due to their inherent sensitivity to acidic environments. To demonstrate the practical application of our approach, we sequenced amino acids sequentially from a peptide, effectively determining the sequence of an unknown peptide. Notably, our methodology was successfully applied to mixtures of peptides derived from protein samples, where a significant fraction of the peptides derivatized with DR3 underwent elimination of their N-terminal amino acid upon addition of base. Overall, although our method does not outperform Edman degradation in efficiency, it serves as a valuable alternative in cases where base-induced cleavage is advantageous, particularly for preserving acid-sensitive functionalities.

The selective modification of natural protein templates has emerged as a powerful tool for investigating the protein structure and function as well as for designing therapeutic bioconjugates. While significant progress has been made in modifying protein side chains and terminal groups, backbone modifications remain underexplored due to the inherent inertness of amide bonds and the challenge of achieving site specificity. Despite the critical role of the backbone in the protein function, its selective chemical modification under physiological conditions has proven to be difficult. With this research, we introduce a site-specific, chemoselective, and two-step strategy for protein backbone modification via thiol/amine coupling and cyclization reactions driven by the release of volatile methyl mercaptans via a small-molecular conjugate acceptor, operating on small-molecule cysteine mimics, peptides, and proteins. This approach leverages the unique reactivity of the conjugate acceptor to first couple a cysteine residue, followed by intramolecular cyclization with an adjacent amide, forming a five-membered heterocyclic unit under aqueous conditions without requiring catalysts or heating. Additionally, molecular dynamics simulations reveal that the resulting rigid structure induces a local backbone torsion, hydrogen bond disruption, and altered side-chain orientation, thereby influencing protein folding. Preliminary investigations further explore the consequent changes in the protein thermal stability and enzymatic activity induced by backbone modification. More importantly, the process is accompanied by a fluorescence turn-on signal, enabling the real-time in situ monitoring of the modification process. Thus, this unique strategy offers a new platform for backbone-specific chemical modifications, paving the way for potential protein and peptide functional studies, fluorogenic labeling, and the development of novel bioconjugates.

A bis-pyridinium calix[4]pyrrole derivative has been synthesized and investigated for its supramolecular interactions with nerve agent surrogates. The receptor promotes the degradation of organophosphorus nerve agent surrogates by facilitating the release of fluoride and cyanide leaving groups. The released anions are subsequently detected via fluorescence response, enabling dual functionality in degradation and sensing. The binding interactions and mechanistic insights were elucidated through NMR spectroscopy, fluorescence titration, and computational studies, confirming the receptor’s role in modulating leaving group dissociation. These findings contribute to the development of supramolecular strategies for chemical defence and environmental detoxification. A bis-pyridinium calix[4]pyrrole derivative promotes the degradation of organophosphorus nerve agent surrogates by facilitating the release of fluoride and cyanide leaving groups. The released anions are subsequently detected via fluorescence response, enabling dual functionality in degradation and sensing. This supramolecular approach provides insights into molecular recognition and chemical detoxification strategies.

This JOCSynopsis underscores the pivotal role of 5-exo-trig and 6-exo-trig cyclization pathways in directing ring-closure reactions, with a focus on their application to the modification of biotic polymers, including amino acid labeling and N-terminal capping strategies in peptide stapling. This work extends these cyclizations to the degradation of both abiotic and biotic polymers. It also explores instances where degradation occurs through less favorable cyclization pathways, highlighting the complexity and context-dependence of these transformations. Additionally, it showcases the use of 5-exo-trig cyclization in reversible click chemistry, emphasizing its role in the design of dynamic materials. These insights are exemplified by systems such as a Meldrum's acid-derived conjugate acceptor, which can undergo reversible "click" and "declick" processes, paving the way for the development of polymers with tunable and responsive properties.

Nanocrystal gel networks can be responsive, tunable materials, but deliberately designing their structure and controlling their properties have been challenging. By employing reversibly bonded molecular linkers, gelation can be realized under conditions predicted by thermodynamics. But, simulations have offered the only microscopic insights, with no experimental means to monitor linking leading to gelation. Here, we introduce a metal coordination linkage with a distinct optical signature allowing us to quantify linking in situ and establish the structural and thermodynamic basis for assembly. Due to coupling between linked indium tin oxide nanocrystals, their infrared absorption shifts abruptly at a chemically tunable gelation temperature. We quantify bonding spectroscopically and use molecular dynamics simulations to understand bonding motifs as a function of temperature, revealing that gel formation is governed by reaching a critical number of effective links that extend the nanocrystal network. Microscopic insights from our colorimetric linking chemistry enable switchable gels based on equilibrium thermodynamic principles, opening the door to rational design of programmable nanocrystal net-work assemblies.

Chemically fuelled reactions are central to supramolecular chemistry, enabling transient assemblies, molecular machines, and non-equilibrium states. Yet, the term fuel remains inconsistently defined. In this perspective, we explore what qualifies as a fuel through the lens of classical physics and thermodynamics, distinguishing between any exergonic reactants - termed a 'trivial fuel' - and those that actively maintain a system away from equilibrium. We propose that a chemically fuelled reaction involves a coupled process: a primary transformation (R -> P) linked to a separate fuel-to-waste (F -> W) reaction. This coupling imparts a kinetic asymmetry, displacing the system from equilibrium and generating a non-equilibrium steady state (NESS). By analysing reaction-free energy landscapes and drawing analogies to Newtonian mechanics, we offer a unified framework for interpreting fuels as reagents that supply energy to resist equilibration. Co-authored by Stefan Borsley, this piece compares definitions from leaders in the field and emphasises the importance of mechanistic clarity in describing fuelled systems. While we acknowledge differing views, we find value in retaining the term fuel for its conceptual richness and evocative power. We hope this discussion stimulates more precise thinking - and creative chemistry - in the design of future fuelled systems.

Circular dichroism (CD)-based enantiomeric excess (ee) determination assays are optical alternatives to chromatographic ee determination in high-throughput screening (HTS) applications. However, the implementation of these assays requires calibration experiments using enantioenriched materials. We present a data-driven approach that circumvents the need for chiral resolution and calibration experiments for an octahedral Fe(II) complex (1) used for the ee determination of α-chiral primary amines. By computationally parameterizing the imine ligands formed in the assay conditions, a model of the CD response of the Fe(II) assembly was developed. Using this model, calibration curves were generated for four analytes and compared with experimentally generated curves. In a single-blind ee determination study, the ee values of unknown samples were determined within a 9% mean absolute error, which rivals the error observed using experimentally generated calibration curves.

The analysis of the absolute configuration, enantiomeric composition, and concentration of chiral compounds are frequently encountered tasks across the chemical and health sciences. Chiroptical sensing methods can streamline this work and allow high-throughput screening with remarkable reduction of operational time and cost. During the last few years, significant methodological advances with innovative chirality sensing systems, the use of computer-generated calibration curves, machine learning assistance, and chemometric data processing, to name a few, have emerged and are now matched with commercially available multi-well plate CD readers. These developments have reframed the chirality sensing space and provide new opportunities that are of interest to a large group of chemists. This review will discuss chirality sensing strategies and applications with representative small-molecule CD sensors. Emphasis will be given to important milestones and recent advances that accelerate chiral compound analysis by outperforming traditional methods, conquer new directions, and pioneering efforts that lie at the forefront of chiroptical high-throughput screening developments. The goal is to provide the reader with a thorough understanding of the current state and a perspective of future directions of this rapidly emerging field.

Sequence-defined polymers (SDPs) are currently being investigated for use as information storage media. As the number of monomers in the SDPs increases, with a corresponding increase in mathematical base, the use of tandem-MS for de novo sequencing becomes more challenging. In contrast, chain-end degradation routines are truly de novo, potentially allowing very large mathematical bases for encoding. While alphabetic scripts have a few dozen symbols, logographic scripts, such as Chinese, can have several thousand symbols. Using a new in situ consecutive click reaction approach on an oligourethane backbone for writing, and a previously reported chain-end degradation routine for reading, we encoded/decoded a confucius proverb written in Chinese characters using two encoding schemes: Unicode and Zhèng Mă. Unicode is an internationally standardized arbitrary string of hexadecimal (base-16) symbols which efficiently encodes uniquely identifiable symbols but requires complete fidelity of transmission, or context-based inferential strategies to be interpreted. The Zhèng Mă approach encodes with a base-26 system using the visual characteristics and internal composition of Chinese characters themselves, which leads to greater ambiguity of encoded strings, but more robust retrievability of information from partial or corrupted encodings. The application of information-encoded oligourethanes to two different encoding systems allowed us to establish their flexibility and versatility for data storage. We found the oligourethanes immensely adaptable to both encoding schemes for Chinese characters, and we highlight the expected tradeoff between the efficiency and uniqueness of Unicode encoding on the one hand, and the fidelity to a scripts' particular visual characteristics on the other.

We report new photoluminescent switching systems achieved through pH-induced intramolecular oxa-Michael conjugate addition reactions. Ratiometric absorbance and fluorescence emission were observed across conjugate acceptors triggered by pH, resulting in specific pseudo pK a values. The effect of substituents on the pseudo pK a’s was investigated, showing increased values from electron-withdrawing to electron-donating groups. Inspired by the physiologically related pK a, a fluorescent probe was designed, successfully distinguishing cancer cells from normal cells through live cellular imaging.

Lysine dimethylation (Kme(2)) is a crucial post-translational modification (PTM) that regulates biological processes and is implicated in diseases. There is significant interest in globally identifying these methylation marks. Unfortunately, this remains challenging due to the lack of robust technologies for selectively labeling Kme(2). To address this, we present a chemical method named tertiary amine coupling by oxidation (TACO). This method selectively modifies Kme(2) to aldehydes using Selectfluor and a base. The resulting aldehydes from Kme(2) were then functionalized using reductive amination, thiolamine, and oxime chemistry. We successfully demonstrated the versatility of TACO in selectively labeling Kme(2) peptides and proteins in complex cell lysate mixtures with varying payloads, including affinity tags and fluorophores. We further showed the application of TACO chemistry for the identification of Kme(2) sites at a single-molecule level by fluorosequencing. We discovered novel 30 Kme(2) sites, in addition to previously known 5 Kme(2) sites, by proteomics analysis of TACO-modified nuclear extracts. Our work establishes a unique strategy for covalently modifying Kme(2), facilitating the global identification of low-abundance Kme(2)-PTMs and their sites within complex cell lysate mixtures.