ABSTRACT Music and chemistry are seldom mentioned in the same breath, yet the physical and mathematical principles underpinning both disciplines are deeply intertwined. Here, we explore several points of contact between the two fields, centered on their shared language of frequency, time, and modulation. The analogy between vibrato and the time‐dependent frequency fluctuations experienced by molecules in condensed‐phase environments is not merely qualitative: both are governed by the same equations of motion for a frequency‐modulated oscillator, and their spectral consequences are quantitatively described by the Kubo lineshape model. The ensemble‐averaged free induction decay (FID) is the direct spectroscopic analogue of the combined sound of an instrumental section, and its Fourier transform yields the absorption lineshape. Two‐dimensional (2D) optical spectroscopies can be understood as tools for reading the molecular score , directly measuring the frequency fluctuation correlation function (FFCF) through the waiting‐time evolution of the 2D lineshape. Finally, we discuss how chemical structures have been mapped onto musical compositions, and how NMR FIDs have been used as musical material. These examples illustrate that the relationship between music and chemistry reflects a deeper unity in the way oscillatory phenomena are described and interpreted across both disciplines.
ABSTRACT Bicyclo[1.1.1]pentane (BCP) derivatives are important motifs in medicinal chemistry as they are three‐dimensional bioisosteres of para‐substituted arenes. Herein, we describe the development of a safer and more scalable Curtius rearrangement of a BCP monoacid mono‐methyl ester under continuous‐flow conditions. Optimization of the reaction parameters and a chromatography‐free purification protocol enabled isolation of the target protected amino acid in high yield and excellent purity. On extended operation, the process delivered a projected daily productivity of 978 g/day.
ABSTRACT In this work, we propose molecular‐level crystallization mechanisms, based on non‐classical nucleation theory, using theoretical supramolecular energetic and topological data. The interactions calculated by computational tools were verified and energetically classified by density functional theory (DFT), and their contribution at the contact point was analyzed using quantum atom‐in‐molecule theory (QTAIM). The proposed mechanisms follow the model developed by our research group, in which crystallization is proposed to begin with the most stabilizing cluster interactions (C─H⋯H─C and C─H⋯C are common to both compounds, in addition to O⋯O type interactions for p ‐Br and I⋯I and C─H⋯I for p ‐I), potentially leading to the formation of supramolecular chains (1D). Next, the approximation of these chains, guided by C─H⋯C, C─H⋯X and C⋯X interactions, is proposed to result in supramolecular (2D) layers. Finally, the association between layers, predominantly driven by C─H⋯X type interactions, is proposed to give rise to three‐dimensional structures (3D mesocrystals). Additionally, the isostructuralism between the compounds was evaluated, and it was investigated whether the proposed crystal growth is consistent with the final supramolecular structure, the unit cell, and the crystal habit.
ABSTRACT Raman spectroscopy is widely used in drug development and delivery due to its label‐free and non‐destructive character. Reliable application to drug delivery systems requires unambiguous assignment of Raman bands from both the drug and the carrier material. Here, we establish the Raman spectral signatures of docetaxel (DTX)‐loaded polymeric micelles (nanoparticles, NPs) based on Pluronic F‐127, Soluplus, and a mixed Soluplus–TPGS system. DTX was nanoformulated to improve its aqueous solubility and therapeutic performance. In vitro FT‐Raman measurements (1064 nm excitation) were performed on pure polymers, unloaded micelles, and DTX‐loaded formulations. Detailed band assignments of the pure drug and nanocarriers were carried out and systematically compared with the loaded systems. Four characteristic DTX marker bands at 617, 1003, 1601, and 3072 cm − 1 were clearly identified in Soluplus and Soluplus–TPGS nanoparticles, providing spectroscopic evidence of drug incorporation. Linear least‐squares spectral decomposition enabled estimation of the relative Raman contributions of drug and carrier. The results demonstrate a higher loading capacity for Soluplus—TPGS mixed nanoparticles compared to pure Soluplus systems and establish a chemically rigorous Raman reference framework for future label‐free studies of drug–polymer nanocarriers.
ABSTRACT Reaction of KO t Bu with haloarenes in arene solvent leads to the formation of biaryls through radical intermediates, and we recently (2026) showed that the radical chemistry is initiated by the formation of benzynes. Our original studies (2014) compared the reactivity of iodobenzene and 2‐iodo‐ m ‐xylene; the latter substrate cannot form o ‐benzynes. Whereas iodobenzene led to the formation of biaryls (40%), for 2‐iodo‐ m ‐xylene this was suppressed almost to 0%. However, in the intervening time, we came to suspect that the iodoxylene was not an ideal substrate due to the potential reactivity of the Ar‐Me groups both to base and to hydrogen atom abstraction reactions. We have now examined two new substrates where the Ar‐Me groups are replaced by Ar‐Ph groups. These substrates cause much more efficient initiation of radical chemistry, arising from the formation of p ‐ and m ‐ benzynes through the reaction of iodobenzenes with base. Importantly, these substrates allow assessment of the role of the Ar‐Me groups in 2‐iodo‐ m ‐xylene in suppressing radical chemistry.
ABSTRACT The epothilones are a family of natural products from myxobacteria, whose major representatives epothilone A and B were first isolated in 1987 at the Gesellschaft für Biotechnologische Forschung in Germany. Their discovery was never published, however, until they were found to be microtubule‐stabilizing agents at Merck Research Laboratories in the US in 1995, and thus, to possess a taxol‐like mode of action. Within a short period of time, this finding turned epothilones into widely pursued targets for total synthesis and lead structures for anticancer drug discovery, with several major pharmaceutical companies becoming involved in the hunt for epothilone‐derived anticancer drugs. These efforts eventually led to two approved drugs for breast cancer treatment, out of a total of 9 epothilone‐type structures that entered clinical trials. In this review, I will summarize some of the key aspects of the (semi)synthetic chemistry of epothilones that have transpired from a wealth of synthetic work on natural epothilones and the synthesis of a multitude of analogs. Particular emphasis is placed on those compounds that have entered clinical trials. In addition, I will also discuss the development history of these compounds, including some non‐scientific aspects that are perhaps less known and appreciated in the scientific community.
ABSTRACT The escalating crisis of antimicrobial resistance (AMR) necessitates the exploration of unconventional therapeutic scaffolds. Metalloantibiotics, including those based on rhenium, have emerged as a promising, albeit underdeveloped, class of drug candidates. This review provides an analysis of the research on rhenium complexes as antimicrobial agents, tracing their origins from the well‐established anticancer and radiopharmaceutical applications of the compounds. We focus predominantly on the versatile fac ‐[Re(CO) 3 ] + core, which constitutes the majority of reported antimicrobial complexes, while also examining recent research into higher oxidation state species. We detail the key structural motifs of these antibiotic complexes and correlate them with their observed antimicrobial efficacy, particularly against high‐priority Gram‐positive pathogens like methicillin‐resistant Staphylococcus aureus (MRSA). The proposed mechanisms of action are also discussed, as are chemical modifications of the fac ‐[Re(CO) 3 ] + core that have allowed an understanding of the key molecular features required for antimicrobial efficacy.
ABSTRACT The diverse array of diterpenoid natural products stems from the ease of manipulating the promiscuity of diterpene cyclases. These enzymes are able to generate a vast array of structurally distinct diterpene skeletons from a common precursor, such as geranylgeranyl diphosphate, through subtle modifications in their active sites. Even minor amino acid substitutions can reshape the contour of the active site or alter the stabilization of key carbocation intermediates, leading to the emergence of new product profiles. This capacity for functional plasticity allows diterpene cyclases to rapidly explore chemical space, providing a rich assortment of scaffolds for development and persistence via natural selection. As a result, gene duplication followed by neofunctionalization of diterpene cyclases has driven the expansion of terpenoid repertoires across plant lineages, contributing to ecological diversification and specialized metabolic functions such as defense, communication, and adaptation to environmental stress. Here we will focus on the understudied bryophyte terpenome from structural diversification at the molecular level to regulation of biosynthetic pathways at the macroorganism level.
N‐Heterocyclic carbenes (NHCs) have emerged as powerful and versatile surface‐modifiers, forming robust and tunable metal–organic interfaces. Their controlled generation and attachment remain central to advancing NHC‐based surface chemistry, as free carbenes are reactive species. This mini‐review highlights current strategies for generating NHCs under conditions compatible with surface functionalization, including direct deprotonation of azolium salts, thermal activation of stable CO 2 and bicarbonate adducts, and emerging electrochemical methods. Here, the structure–reactivity relationships governing precursor stability and activation behavior, and their implementation in vacuum and solution environments, are discussed. Techniques used to study the modified surfaces are also briefly presented. Together, these developments provide a foundation for designing clean, well‐defined NHC monolayers, enabling new opportunities in various domains, including catalysis, sensing, and molecular electronics.
Bipyrrolidines are important chiral diamines with application in organocatalysis and the synthesis of ligands for transition metal complexes. Conventionally, these compounds are prepared by a photochemical dimerization of pyrrole, however, the method is not stereoselective, the isolation of stereopure products is tedious, and the method is difficult to apply to substituted bipyrrolidines. In this manuscript, it is shown that alpha-amino acid-substituted bipyrrolidines can be prepared in moderate to good yields by an intramolecular diamination reaction promoted by electrophilic iodinating agents. If amino acids with a sterically-demanding side chain such as valine or phenylalanine are used, high diastereoselectivities have been observed. The resulting N,N'-amino acid substituted bipyrrolidines could function after deprotection as tetradentate transition metal ligands.
This study elaborates on traceless tags for the thiol-mediated uptake (TMU) of amine-containing substrates of interest (SOIs). Traceless tags typically contain linkers that can be enzymatically cleaved to trigger the release of SOIs in their native form. To trace SOI release inside cells, the dual function of asparagusic acid (AspA) derivatives to enable TMU and to track the Golgi apparatus is explored. We tested two of the most popular cleavable linkers based on esterases and quinone reductases. Conjugated to AspA through alkyloxycarbonyloxymethyl (AOCOM) linkers, fluorescent SOIs entered cells by TMU and spread in the cytosol with or without a brief stop in the Golgi, depending on the structure. FRET probes further demonstrated that after arrival in the Golgi, SOIs are released from AspA into the lumen, where they linger before spreading to the cytosol and beyond. Quinone-based trimethyl locks (TML) are also compatible with TMU, but reductive cleavage after TMU appears to be slower in the Golgi. These results validate AOCOM and TML linkers for constructing traceless TMU tags for amine-containing SOIs and introduce AspA probes as dynamic-covalent chemistry tools to trace traceless tags inside cells and to track Golgi lumen and Golgi membranes simultaneously with separately visualizable fluorescent probes.
Advancing the synthetic and constitutional knowledge of alkali-metal amides, here we report the synthesis and structural authentication of a family of alkali-metal N-phenyl-1-naphthylamides (1Li, 1Na, and 1K) obtained from the deprotonation of the parent amine by an alkali-metal alkyl base in hexane and using biorenewable 2-methyltetrahydrofuran (2-MeTHF) as a Lewis donor. The aggregation and degree of donor-solvation of these complexes differ depending on the nature of the alkali-metal. Furthermore, the lithium N-phenyl-1-naphthylamide complex 1Li can undergo further metalation on the peri position of the naphthyl ring using either nBuLi or nBuNa as a base to give complexes 2LiLi, and 2LiNa, respectively. X-ray crystallographic studies established the molecular structures of these complexes in which both alkali-metals are chelated by a novel C,N-dianionic bidentate ligand. Quenching of 2LiLi, and 2LiNa with D2O provided further evidence supporting that the NH, C(peri)-H di-metalation has occurred.
In many of their applications, polymeric materials are expected to withstand mechanical loads, yet the molecular-scale processes that govern how stress localizes, redistributes, and ultimately leads to damage remain difficult to probe directly. Mechanophore-based mechanochromic systems offer a powerful approach to address this challenge by converting mechanical input into optical signals detectable with spectroscopic and microscopic techniques. In this Perspective, we highlight recent progress in the use of mechanophores as probes for imaging mechanical processes in solid-state polymers. We discuss how mechanophore activation can reveal molecular damage, stress localization, and time-dependent deformation processes, and how emerging reversible and multiplexed, or multimodal systems extend mechano-imaging to lower stress regimes. Finally, we outline key challenges for the field, including the development of new mechanophore scaffolds for quantitative mechano-imaging and scalable reporter systems suitable for real materials and structural health monitoring. Together, these advances position mechanophore-based mechano-imaging as a promising framework for interrogating and ultimately controlling the distribution and dissipation of mechanical energy in polymeric materials.
Metal-free halide perovskites have recently emerged as promising candidates for optoelectronic applications. However, their synthesis has largely depended on water-based single-crystal growth that limits material diversity, scalability, and practical implementation. Here, we present a mechanochemical route to synthesize N,N-diazabicyclo[2.2.2]octonium (H-DABCO)-based halide perovskites from the (DABCO)(NH4)X3 (X = I, Br) compositions. The structural properties were confirmed by X-ray diffraction and solid-state nuclear magnetic resonance spectroscopy. Thin films were prepared from mechanosynthetic powders by spin-coating and characterized by in-situ grazing incidence wide-angle scattering measurements, as well as by UV-vis absorption and steady-state photoluminescence spectroscopy. This mechanosynthetic strategy provides a scalable, environmentally friendly pathway to broaden the scope of metal-free perovskites and advance their potential in sustainable optoelectronic technologies.
The use of green solvents is a key element in making chemical processes more sustainable. In this work, three biobased solvents, diformyl xylose (DFX), dipropyl xylose (DPX), and n-butyl tetrahydrofurfuryl ether (Solvinol), were tested as cosolvents in the Suzuki-Miyaura reaction using micellar catalysis in water (TPGS-750-M system). 2% DPX gave > 99% conversion and 86% yield, while 2% DFX reached 86% conversion and 82% yield. Solvinol required 15% loading to give similar results. DFX was easily removed in the aqueous phase upon work-up, while DPX and Solvinol were more difficult to remove due to their poor water solubility and high boiling points. These results demonstrate the potential of biomass-derived solvents as green alternatives to classical organic solvents. The overall environmental efficiency of the various processes was assessed via our internal methodology. Their efficiency at low loadings supports their use in more sustainable and environmentally friendly processes.
Chiral organic molecules with pronounced chiroptical responses are of significant interest for applications ranging from bioimaging to optoelectronic devices. Herein, we report comprehensive chiroptical investigations of a compact [2.2]paracyclophane (PCP)- based macrocycle and its open precursor. While the synthesis of the structure was reported by the group of Michael Haley, chiroptical investigations were still missing. The rigid PCP core acts as a chiral template, inducing helical twisting within the conjugated diacetylene framework. Owing to its low atomic count, the compact macrocycle represents an attractive model system for combined experimental and computational studies, enabling fast DFT and TD-DFT calculations. The macrocycle and its open synthetic precursor were synthesized, structurally characterized, and, in both cases, enantiomers were separated on a chiral stationary phase HPLC. Absolute configurations were assigned through TD-DFT calculations. Optical measurements reveal enhanced conjugation and redshifted emission upon macrocyclization. Electric circular dichroism (ECD) spectra exhibit multiple intense cotton bands. Both macrocycle and open precursor display exceptionally high circularly polarized luminescence (CPL) dissymmetry factors, with glum around 10-2. Despite moderate CPL brightness, limited by the compounds' quantum yields, these results demonstrate the strong chiral amplification imparted by the PCP. The presented scaffold provides a versatile platform for probing structure-property relationships in chiral conjugated macrocycles.
Rhenium disulfide (ReS2) crystallizes in a distorted 1T ' lattice with triclinic symmetry arising from Re & horbar;Re dimerization, which produces in-plane anisotropic properties and a dense set of Raman-active modes with mixed atomic displacements. Prior conventional Raman microscopy studies in this material showed strong dependence of absolute and relative intensities of some Raman bands on the mutual orientation of the optical electric field and the in-plane crystalline axii. In the presented study, we show strongly enhanced (at least 10 times over the far field background) tip-enhanced Raman scattering (TERS) response from 1-4 L ReS2 on gold, which not only enables high spatial resolution in the TERS maps, but also remains, to a great extent, indifferent to the in-plane orientation of the ReS2 crystals. We attribute this orientation indifference to the fact that in the gap mode TERS configuration, the optical electric field is normal to the crystal plane. Additionally, we demonstrate in our TERS spectra the presence of low-frequency bands, the spectral position of which correlates with the local crystal layer number and matches very well previously published conventional Raman data, which allows a straightforward nanospectroscopic assessment of the layer number even in sub-micron-sized crystals.
The AlphaFold confidence measures are related to conformation distribution of the protein. Proteome-wide analyses of predicted local distance difference test (pLDDT) and predicted aligned error (PAE) reveal that proteomes are predominantly ordered on residue level and predominantly disordered on the level of conformation. The fraction of residues in intrinsically disordered regions (IDRs) and the fuzziness of intrinsically folded regions (IFRs) increased upon the evolutionary transition from prokaryotes to eukaryotes, while residual structure in IDRs decreased. All proteins of an organism can be arranged along these three disorder dimensions in a proteome order-disorder (POD) plot. POD plots reveal that proteomes populate the whole order-disorder continuum. Fuzziness of IFRs tends to increase with their number in a protein and a distinct subset of intrinsically disordered proteins (IDPs) is a general feature of proteomes.
The multiphasic semi-batch ring-opening polymerization of propylene oxide was investigated with respect to mass-transfer limitations at the solid-liquid and liquid-catalyst interfaces, and their impact on the polydispersity and viscosity of the resulting polypropylene glycol. To enable this analysis, a method for determining polymerization rate constants was developed based on modelling the time-dependent propylene oxide concentration during continuous dosage. The method's applicability was validated through activation-energy determination. The results show that polymerization is primarily governed by mass-transfer limitations at the liquid-catalyst interface, while gas-liquid transport limitations, though present, have minimal influence on the final polymer properties.
