We present the first comprehensive, internally consistent analysis of core-level chemical shifts for aqueous-phase solutes using Electron Spectroscopy for Chemical Analysis of Liquids (ESCAL). An absolute binding-energy calibration enables high accuracy and cross-molecule comparability. The C 1s spectra of oxygenated aliphatic compounds display functional-group-specific shifts that increase with carbon oxidation state. Although these trends depart from gas- and solid-phase behavior, highlighting solvent and hydration effects, they correlate closely with calculated core-level orbital energies, providing a useful first-order predictor. We further resolve secondary, through-bond shifts over one and two bonds, the magnitudes of which depend sensitively on specific functional-group interactions (notably carboxylic acid and ketone motifs). Such element- and oxidation-state-specific structural information establishes the principles and reference data needed to build a predictive ESCAL database for liquid-phase structural and chemical analysis. The results will be contrasted with NMR studies.

In this study, we explore a new approach for the mild and selective activation of C(sp3)-F bonds in fluorinated azidoalkanes. Our approach utilizes electrophilic azide groups, which promote fluoride elimination and enable nucleophilic addition to newly formed electrophilic sites. This method achieves rapid, high-yield transformations of (per)fluoroalkyl azides into novel sulfur-containing azides, imines, and triazoles under mild conditions and using inexpensive reagents. The reaction proceeds without metal catalysts or external energy input and displays broad functional group tolerance, including toward thiol-sensitive motifs. Mechanistic studies supported by spectroscopy and x-ray crystallography, corroborated by ab initio calculations, reveal key azide intermediates and establish the denitrogenation pathway via α,α-disubstituted species. This transformation provides a practical and scalable route for the conversion of (per)fluoroalkyl azides into nitrogen- and sulfur-functionalized scaffolds, advancing C─F activation processes.

Nonadiabatic molecular dynamics simulations aim to describe the coupled electron- nuclear dynamics of molecules in excited electronic states, beyond the celebrated Born-Oppenheimer approximation. These simulations have been applied to understand a plethora of photochemical and photophysical processes and to support the interpretation of ultrafast spectroscopy experiments at advanced light sources. As a result, the number of nonadiabatic dynamics simulations has been growing significantly over the past decade. Yet, the field remains in its infancy, and a potential user may find it difficult to approach this type of simulation, given their complexity and the number of elements that should be considered for a (hopefully) successful nonadiabatic dynamics simulation. Nonadiabatic molecular dynamics relies on several key steps: finding a level of electronic-structure theory to describe the molecule in its Franck-Condon region and beyond, describing the photoexcitation process, selecting a method to perform the nonadiabatic dynamics, and analyzing the final results before calculating observables for a more direct comparison with experiment. This Best Practices guide aims to provide a general guide for the user of nonadiabatic molecular dynamics by (i) discussing the fundamentals of nonadiabatic molecular dynamics and the various trajectory-based methods developed for molecular systems, (ii) introducing the different electronic-structure methods and concepts – adiabatic/diabatic representation, conical intersections – that can be used with nonadiabatic molecular dynamics (or for benchmarking), (iii) providing details on the various steps required to perform a nonadiabatic dynamics simulation and their practical use, as well as guided examples and a discussion on the calculation of observables, (iv) proposing a FAQ with the typical questions a user may have when performing nonadiabatic dynamics, and (v) sketching a checklist for the key practical steps when performing a (trajectory-based) nonadiabatic molecular dynamics. Each section is self-contained, but we endeavor to provide additional key references for each concept discussed, making this Guide a starting point for the interested reader to dig further into the field of nonadiabatic dynamics.

Although bilirubin photochemistry is central to neonatal jaundice phototherapy, the mechanism of bilirubin photooxidation remains unclear. Here, we use a comprehensive computational approach to investigate whether this mechanism might be initiated by photoinduced electron transfer (PET) to molecular oxygen (O2), generating superoxide (O2˙-). For this purpose, we employed a simplified bilirubin model compound-tetramethyldipyrrinone (TMD). We use a combination of multireference, coupled cluster methods, and density functional theory techniques to assess the feasibility of the TMD-O2 complex formation and PET from TMD to O2. Our results support the feasibility of PET in the TMD-O2 complex and suggest that PET could potentially initiate bilirubin photooxidation. Beyond the bilirubin case, this work underscores the need for efficient and accurate protocols to compute binding free energies of weak O2 encounter complexes with organic chromophores in solution, and it highlights the broader challenge of modeling triplet photochemistry with dense manifolds of near-degenerate states, crossings, and strongly state-specific solvent response.

The environmentally friendly refrigerant trans-1,3,3,3-tetrafluoropropene HFO1234ze(E) is a promising alternative to replace 1,1,1,2-tetrafluoroethane R134a in particle detectors and SF6 in high-voltage-engineering applications. A set of electron-molecule scattering cross sections for HFO1234ze(E) up to 300 keV is presented. Initial experimental information was obtained by means of electron-energy-loss spectroscopy, providing insight into the vibrational and electronic excitations in HFO1234ze(E). Additional information on the excited electronic states was obtained from vacuum-ultraviolet photoabsorption spectroscopy and from ab initio quantum chemistry calculations. The cross sections were refined based on electron-transport-coefficient measurements performed on a pulsed Townsend apparatus. The occurrence of an unspecific vibrational excitation is observed and its effect on the electron-transport coefficients is elaborated. The previously investigated positive synergy in the reduced critical electric field strength of SF6 and HFO1234ze(E) mixtures is discussed. The resulting cross-section set is implemented in both magboltz and degrad, allowing accurate simulations for gaseous detectors and electrical insulation technologies. The cross sections are published in the open-access database LXCat.

Aqueous radiation chemistry emerges through ultrafast proton transfer and ion-radical formation with unexplored energy-redistribution dynamics steering the subsequent reactions. We performed time-resolved disruptive probing on pure water dimer, (H_2O)_2, to disentangle the post-ionization reactions. Through kinetic-energy-resolved ion imaging, we unraveled the dynamics in the (H_2O)_2^+ ground state: at low-energy (∼0.05 eV) ultrafast proton transfer (∼19 fs) is followed by H_3O^++OH fragmentation (∼360 fs). At higher energies, proton transfer becomes hindered (∼60 fs) while the subsequent fragmentation becomes faster (∼210 fs), evolving into coupled dynamics (>0.15 eV, ∼100 fs). Moreover, we observed H_2O)_2^+ stabilization proceeding through a Zundel-like structure. This reveals how ion-radical formation in ionized hydrogen-bonded networks shapes reactivity in aqueous dynamics.

Mixed-reference spin-flip time-dependent density functional theory (MRSF-TDDFT) has recently emerged as an attractive electronic-structure method for studying photochemical processes, given that it bridges the computational efficiency of single-reference approaches with the versatility of multireference methods. In the following, we critically assess the general applicability of MRSF-TDDFT to photochemistry and identify two important limitations. First, the doubly excited configurations included in MRSF-TDDFT come at the cost of missing some singly excited configurations. Second, MRSF-TDDFT provides unreliable excited-state energies when its triplet reference─a cornerstone of the method─abruptly changes its nature, e.g., when the T1 and T2 triplet states become nearly degenerate and exchange electronic character. This change of character of the triplet reference can induce discontinuities or sharp distortions in electronic potential energy curves of the response states in unsuspected regions of the nuclear configuration space. We propose strategies and diagnostics to detect these limitations in the exploration of potential energy surfaces and nonadiabatic molecular dynamics using MRSF-TDDFT.

Charge-transfer-to-solvent (CTTS) excitations provide a chemically central route to generating hydrated electrons and initiating redox chemistry in solution, yet the earliest stage of CTTS—the formation of the excited state itself—is usually treated as instantaneous. Here we present a time-domain perspective of how CTTS character builds up during core-level photoexcitation of an aqueous metal ion. Using time-dependent configuration interaction, we simulate the coherent evolution of a dense manifold of core-excited states and track the ultrafast flow of electronic charge from the initially localized site into solvent-supported final states. We find that the dynamics evolves from a few-state, oscillatory behavior to effectively irreversible delocalization, as the charge disperses among many coupled configurations, providing a microscopic mechanism for the early-time emergence of CTTS character. Our results offer a transparent real-time interpretation of what core-level spectroscopies and core-hole-clock-type measurements can probe in solutions, outlining experimental signatures for probing the build-up of CTTS states on the core-hole-lifetime timescale. Looking ahead, attosecond and sub-femtosecond X-ray pump–probe approaches at X-ray free-electron lasers provide a realistic route to directly time-resolve the core-excited CTTS wave packets in solution.

Photoexcitation is an inherent part of any photochemical or spectroscopic experiment, yet its impact on the excited-state dynamics is often overlooked. However, it is the excited molecular state, built upon photoexcitation and shaped by the characteristics of the light source, that determines the fate of the excited molecule and its subsequent photochemical reactions. In this work, we investigate how excited molecular states are built by different laser pulses, leveraging two representations of the molecular wave function: Born-Huang expansion and exact factorization. We explore the generation of two limiting cases: a stationary molecular state with a long laser pulse and an electronic wave packet by an ultrashort (attosecond) laser pulse. The standard concepts of population transfer between electronic states, resonance condition, or sudden vertical excitation, inherent to the Born-Huang representation and used by chemists to approximate the impact of photoexcitation on molecular systems, are challenged by the exact factorization.

This Perspective is part of a Special Topic that explored the maturity of nonadiabatic molecular dynamics for predicting photochemical processes. In 2023, a prediction challenge was issued to the community of computational photochemists to simulate the photochemistry of cyclobutanone, photoexcited at 200 nm, and the resulting time-resolved mega-electronvolt ultrafast electron diffraction (MeV-UED) signal. The challenge attracted 15 theoretical predictions from more than 70 researchers, employing a wide range of strategies for electronic structure and nonadiabatic molecular dynamics to predict the time-resolved MeV-UED signal before the experiment had been conducted at SLAC (Stanford, USA). The MeV-UED instrument at Shanghai Jiao Tong University was also used to provide a second independent time-resolved MeV-UED signal for the photochemistry of cyclobutanone. This Perspective discusses the various approaches and strategies used by the participants to predict the photochemistry of cyclobutanone. This work also summarizes the strengths and weaknesses of various methods used for photoexcitation, electronic structure, nonadiabatic dynamics, and calculation of observables, as agreed by the participants during a CECAM workshop dedicated to the results of the challenge and organized in Lausanne in April 2025. This Perspective also collects all the predicted time-resolved MeV-UED signals into a single figure, together with the experimental signal. The challenge (i) demonstrated the qualitative predictive power of nonadiabatic molecular dynamics and (ii) underscored the impact of electronic-structure theory on the outcome of the excited-state dynamics and the need for its careful benchmarking. This effort allowed the community to share practical strategies to perform nonadiabatic dynamics (discussed in the present Perspective) and constitutes a "calibration" exercise for computational photochemistry.

We investigate proton sharing in biologically relevant polycarboxylic acids in aqueous solutions using liquid-jet X-ray photoelectron spectroscopy. In contrast to techniques that record time-averaged proton positions, like nuclear magnetic resonance, photoelectron spectroscopy captures instantaneous proton distribution due to its ultrafast probing time scale. The method is, therefore, uniquely sensitive to the occurrence of proton sharing in an aqueous environment, as demonstrated here. We only observe significant proton sharing dynamics in maleic acid, where its monoanionic form shows a single, delocalized peak in the carbon 1s spectrum. Conversely, succinic acid, fumaric acid, malic acid, glutaric acid, and citric acid exhibit distinct peaks corresponding to separate, localized COOH and COO- groups, instead of shared protons. Our results reveal that intramolecular proton sharing in water is rather an exception for most biologically relevant polycarboxylic acids. This highlights the importance of enzyme-driven structural changes of polycarboxylic acids associated with proton sharing during metabolic processes.

Strain-promoted azide-alkyne cycloaddition (SPAAC) is a cornerstone of bioorthogonal chemistry, offering metal-free and biocompatible ligation for applications ranging from bioconjugation to live-cell imaging. However, its relatively slow kinetics and limited selectivity hinder the simultaneous labelling of multiple targets. Here, we report on a systematic study of fluoroalkyl azides as SPAAC reagents that display enhanced reactivity with electron-rich cyclooctynes, while showing significantly reduced reactivity with electron-deficient dipolarophiles. Kinetic measurements revealed over 100-fold rate differences depending on the azide-alkyne pair, enabling orthogonal bioconjugation in both purified proteins and living cells. Quantum chemical calculations support the feasibility and qualitative trends of these SPAAC reactions while highlighting the limitations of simple frontier-orbital descriptors and inverse-electron-demand arguments. Fluorescently labelled fluoroalkyl and alkyl azide probes demonstrate the selective labeling of modified antibody trastuzumab and protein concanavalin A in vitro and the selective labelling of organelles in living cells. This dual-selectivity strategy enables orthogonal SPAAC labeling.

Cyanine dyes are widely used in bioimaging, sensing, optoelectronic, and medicinal applications due to their tunable photophysical properties. However, controlling their electronic structures and photophysical properties remains a challenge. Here we report a general synthetic route to pentamethine and heptamethine cyanines bearing C1' chain substituents that allow substantial control of their electronic, photophysical, and photochemical properties. By varying the terminal heterocycle and introducing various substituents at the 1'-position, we investigated the role of symmetry breaking and its impact on bond length alternation (BLA) and out-of-plane rotation (OPR). Our analysis shows that OPR, coupled with BLA, suppresses or hypsochromically shifts the first absorption band, thereby significantly altering the absorption properties of the studied dyes. This effect is particularly pronounced in structures with different heterocyclic end groups and bulky or electron deficient substituents at the 1'-position. Through quantum chemical calculations and spectroscopic analyses, we demonstrate how these modifications can be used to tune optical properties of these dyes across the visible region, paving the way for their further customization.

Diazidodifluoromethane was prepared from dibromodifluoromethane, sodium azide and an alkanethiolate initiator. It represents the first example of a diazidomethane that is stable enough to be used in synthesis. The stability of (poly)azidomethanes was explored with ab initio calculations. Copper(I)-catalysed azide-alkyne cycloaddition of the title azide with alkynes afforded difluoromethylene-containing bis(1,2,3-triazoles)amenable to Rh(II)-catalysed transannulation with nitriles to difluoromethylene bis(imidazoles).

ConspectusPhotochemical reactions have always been the source of a great deal of mystery. While classified as a type of chemical reaction, no doubts are allowed that the general tenets of ground-state chemistry do not directly apply to photochemical reactions. For a typical chemical reaction, understanding the critical points of the ground-state potential (free) energy surface and embedding them in a thermodynamics framework is often enough to infer reaction yields or characteristic time scales. A general working principle is that the energy profile along the minimum energy paths provides the key information to characterize the reaction. These well-developed concepts, unfortunately, rarely stretch to processes involving the formation of a nonstationary state for a molecular system after light absorption.Upon photoexcitation, a molecule is likely to undergo internal conversion processes, that is, changes of electronic states mediated by couplings between nuclear and electronic motion, precisely what the celebrated Born-Oppenheimer approximation neglects. These coupled electron-nuclear processes, coined nonadiabatic processes, allow for the molecule to decay from one electronic state to the other nonradiatively. Understanding the intricate nonadiabatic dynamics is pivotal to rationalizing and predicting the outcome of a molecular photoexcitation and providing insights for experiments conducted, for example, in advanced light sources such as free-electron lasers.Nowadays, most simulations in nonadiabatic molecular dynamics are based on approximations that invoke a near-classical depiction of the nuclei. This reliance is due to practical constraints, and the classical equations of motion for the nuclei must be supplemented by techniques such as surface hopping to account for nonadiabatic transitions between electronic states. A critical but often overlooked aspect of these simulations is the selection of initial conditions, specifically the choice of initial nuclear positions and momenta for the nonadiabatic dynamics, which can significantly influence how well the simulations mimic real quantum systems across various experimental scenarios. The conventional approach for generating initial conditions for nonadiabatic dynamics typically maps the initial state onto a nuclear phase space using a Wigner quasiprobability function within a harmonic approximation, followed by a second approximation where the molecule undergoes a sudden excitation.In this Account, we aim to warn the experienced or potential user of nonadiabatic molecular dynamics about the possible limitations of this strategy for initial-condition generation and its inability to accurately describe the photoexcitation of a molecule. More specifically, we argue that the initial phase-space distribution can be more accurately represented through molecular dynamics simulations by using a quantum thermostat. This method offers a robust framework that can be applied to large, flexible, or even solvated molecular systems. Furthermore, the reliability of this strategy can be benchmarked against more rigorous approaches such as path integral molecular dynamics. Additionally, the commonly used sudden approximation, which assumes a vertical and sudden excitation of a molecule, rarely reflects the excitation triggered by laser pulses used in actual photochemical and spectroscopic experiments. We discuss here a more general approach that can generate initial conditions for any type of laser pulse. We also discuss strategies to tackle excitation triggered by a continuous-wave laser.

Nonadiabatic molecular dynamics simulations aim to describe the coupled electron-nuclear dynamics of molecules in excited electronic states. These simulations have been applied to understand a plethora of photochemical and photophysical processes, and, as a result, the number of nonadiabatic dynamics simulations has been growing significantly over the past decade. Yet, the field remains in its infancy, and a potential user may find it difficult to approach this type of simulation, given their complexity and the number of elements that should be considered for a (hopefully) successful nonadiabatic dynamics simulation. Nonadiabatic molecular dynamics relies on several key steps: finding a level of electronic-structure theory to describe the molecule in its Franck-Condon region and beyond, describing the photoexcitation process, selecting a method to perform the nonadiabatic dynamics, and analyzing the final results before calculating observables for a more direct comparison with experiment. This Best Practices guide aims to provide a general guide for the user of nonadiabatic molecular dynamics by (i) discussing the fundamentals of nonadiabatic molecular dynamics and the various trajectory-based methods developed for molecular systems, (ii) introducing the different electronic-structure methods and concepts - adiabatic/diabatic representation, conical intersections - that can be used with nonadiabatic molecular dynamics (or for benchmarking), (iii) providing details on the various steps required to perform a nonadiabatic dynamics simulation and their practical use, as well as guided examples and a discussion on the calculation of observables, (iv) proposing a FAQ with the typical questions a user may have when performing nonadiabatic dynamics, and (v) sketching a checklist for the key practical steps when performing a (trajectory-based) nonadiabatic molecular dynamics.

Despite decades of research, our understanding of radiation damage in aqueous systems remains limited. The recent discovery of Intermolecular Coulombic Decay (ICD) following inner-valence ionization of liquid water raises interesting questions about its efficiency as a major source of low-energy electrons responsible for radiation damage. To investigate, we performed electron-electron coincidence measurements on liquid H2O and D2O using a monochromatized high-harmonic-generation light source, detecting ICD electrons in coincidence with photoelectrons from the 2a1 shell. We find that the ICD efficiency γ is below unity in both liquids and that γ(H2O)/γ(D2O) = 0.86 ± 0.03. Ab initio calculations reveal that ICD competes with proton transfer and non-adiabatic relaxation, which can close the ICD channel. A multi-scale stochastic model incorporating solvent effects reproduces these efficiencies. Our combined experimental and theoretical results suggest that the higher ICD efficiency in D2O arises from slower proton transfer and non-adiabatic transitions, highlighting the crucial role of nuclear motion in liquid-phase ICD and advancing the understanding of radiation damage.

Proton transfer underpins number of chemical and biochemical processes, yet its sub-100 fs dynamics have rarely been captured in real time. Here, we report direct and time-resolved observation of ionizing radiation-induced proton transfer in a heteroaromatic hydrate: the pyrrole-water complex. Both the electron-impact and strong-field laser experiments create a locally and doubly charged pyrrole unit (C4H5N2+), which immediately (within 60 fs) donates a proton to the adjacent H2O, generating deprotonated C4H4N+ and hydronium H3O+ cations that subsequently undergo Coulomb explosion. The electron-impact experiments directly revealed initial states and provided dynamical insights through fragment ions and electron coincidence momentum imaging. The strong-field femtosecond laser experiments tracked the ultrafast dynamics of proton transfer; complementary ab initio calculations unraveled the dynamical details. The 50-60 fs proton transfer qualifies as one of the fastest acid-base reactions observed to date. This study offers a novel perspective on radiation-induced proton transfer in hydrated biomolecules.