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The ability to manipulate excited-state decay cascades using molecular structure is essential to the application of abundant-metal photosensitizers and chromophores. Ligand design has yielded some spectacular results elongating charge-transfer excited state lifetimes of Fe(II) coordination complexes, but triplet metal-centered (3MC) excited states─recently demonstrated to be critical to the photoactivity of isoelectronic Co(III) polypyridyls─have to date remained elusive, with temporally isolable examples limited to the picosecond regime. With this report, we show how strong-field donors and intramolecular π-stacking can conspire to stabilize a long-lived 3MC excited state for a remarkable 4.1 ± 0.3 ns in fluid solution at ambient temperature. Analysis of variable-temperature time-resolved absorption data using theoretical models ranging from Arrhenius to semiclassical Marcus theory, combined with computational modeling and X-ray crystallography, reveal a Jahn–Teller stabilized excited state with a high activation barrier for ground-state recovery. The net result is a chromophore with a 3MC excited-state lifetime that is orders of magnitude longer than anything yet observed for an Fe(II) complex.

Integrating an NIR fluorescent probe with a magnetic resonance imaging (MRI) agent to harvest complementary imaging information is challenging. Here, we have designed water-soluble, biocompatible, noncytotoxic, bright-NIR-emitting, sugar-functionalized, mechanically interlocked molecules (MIMs)-capped superparamagnetic ultrasmall Fe3O4NPs for targeted multimodal imaging. Dual-functional stoppers containing an unsymmetrical NIR squaraine dye interlocked within a macrocycle to construct multifunctional MIMs are developed with enhanced NIR fluorescence efficiency and durability. One of the stoppers of the axle is composed of a lipophilic cationic TPP+functionality to target mitochondria, and the other stopper comprises a dopamine-containing catechol group to anchor at the surface of the synthesized Fe3O4NPs. Fe3O4NPs surface-coated with targeted NIR rotaxanes help to deliver ultrasmall magnetic NPs specifically inside the mitochondria. Two carbohydrate moieties are conjugated with the macrocycle of the rotaxane via click chemistry to improve the water solubility of MitoSQRot-(Carb-OH)2-DOPA-Fe3O4NPs. Water-soluble, rotaxane-capped Fe3O4NPs are used for live-cell mitochondria-targeted NIR fluorescence confocal imaging, 3D and multicolor imaging in combination with T2-weighted MRI on a 9.4 T MR scanner with a high relaxation rate (r2) of 180.7 mM–1s–1. Biocompatible, noncytotoxic, ultrabright NIR rotaxane-capped superparamagnetic ultrasmall monodisperse Fe3O4NPs could be a promising agent for targeted multimodal imaging applications.

Although phenol is stable in bulk water, we report an exceptional phenomenon in which phenol is spontaneously transformed into a phenyl carbocation (Ph+) in water microdroplets. The high electric field at the air–water interface is proposed to break the phenolic Csp2–OH bond, forming Ph+, which remains in equilibrium with phenol as deciphered by mass spectrometry. We detected up to 70% conversion of phenol to Ph+in aqueous microdroplets, although catalyst-free activation of the phenolic Csp2–OH bond is challenging. This transformation is well tolerated by a wide range of electron-donating and -withdrawing substituents in phenolic compounds. The Ph+in water microdroplets could be reacted with various nucleophiles (amine, pyridine, azide, thiol, carboxylic acid, alcohol, and 18O-water), yielding the ipso-substitution products of phenol through an aromatic SN1 mechanism. Despite the fleeting life of Ph+in the bulk, this study demonstrates its unusual stability at the aqueous microdroplet surface, enabling its detection and transformation.

Given the current impact of SARS-CoV2 and COVID-19 on human health and the global economy, the development of direct acting antivirals is of paramount importance. Main protease (MPro), a cysteine protease that cleaves the viral polyprotein, is essential for viral replication. Therefore, MProis a novel therapeutic target. We identified two novel MProinhibitors, D-FFRCMKyne and D-FFCitCMKyne, that covalently modify the active site cysteine (C145) and determined cocrystal structures. Medicinal chemistry efforts led to SM141and SM142, which adopt a unique binding mode within the MProactive site. Notably, these inhibitors do not inhibit the other cysteine protease, papain-like protease (PLPro), involved in the life cycle of SARS-CoV2. SM141and SM142block SARS-CoV2 replication in hACE2 expressing A549 cells with IC50values of 8.2 and 14.7 nM. Detailed studies indicate that these compounds also inhibit cathepsin L (CatL), which cleaves the viral S protein to promote viral entry into host cells. Detailed biochemical, proteomic, and knockdown studies indicate that the antiviral activity of SM141and SM142results from the dual inhibition of MProand CatL. Notably, intranasal and intraperitoneal administration of SM141and SM142lead to reduced viral replication, viral loads in the lung, and enhanced survival in SARS-CoV2 infected K18-ACE2 transgenic mice. In total, these data indicate that SM141and SM142represent promising scaffolds on which to develop antiviral drugs against SARS-CoV2.

The stereochemical activity of lone pair electrons plays a central role in determining the structural and electronic properties of both chemically simple materials such as H2O, as well as more complex condensed phases such as photocatalysts or thermoelectrics. TlReO4is a rare example of a non-magnetic material exhibiting a re-entrant phase transition and emphanitic behavior in the long-range structure. Here, we describe the role of the Tl+6s2lone pair electrons in these unusual phase transitions and illustrate its tunability by chemical doping, which has broad implications for functional materials containing lone pair bearing cations. First-principles density functional calculations clearly show the contribution of the Tl+6s2in the valence band region. Local structure analysis, vianeutron total scattering, revealed that changes in the long-range structure of TlReO4occur due to changes in the correlation length of the Tl+lone pairs. This has a significant effect on the anion interactions, with long-range ordered lone pairs creating a more densely packed structure. This resulted in a trade-off between anionic repulsions and lone pair correlations that lead to symmetry lowering upon heating in the long-range structure, whereby lattice expansion was necessary for the Tl+lone pairs to become highly correlated. Similarly, introducing lattice expansion through chemical pressure allowed long-range lone pair correlations to occur over a wider temperature range, demonstrating a method for tuning the energy landscape of lone pair containing functional materials.

Pathways for direct conversion of indoles to oxindoles have accumulated considerable interest in recent years due to their significance in the clear comprehension of various pathogenic processes in humans and the multipotent therapeutic value of oxindole pharmacophores. Heme enzymes are predominantly responsible for this conversion in biology and are thought to proceed with a compound-I active oxidant. These heme-enzyme-mediated indole monooxygenation pathways are rapidly emerging therapeutic targets; however, a clear mechanistic understanding is still lacking. Additionally, such knowledge holds promise in the rational design of highly specific indole monooxygenation synthetic protocols that are also cost-effective and environmentally benign. We herein report the first examples of synthetic compound-I and activated compound-II species that can effectively monooxygenate a diverse array of indoles with varied electronic and steric properties to exclusively produce the corresponding 2-oxindole products in good to excellent yields. Rigorous kinetic, thermodynamic, and mechanistic interrogations clearly illustrate an initial rate-limiting epoxidation step that takes place between the heme oxidant and indole substrate, and the resulting indole epoxide intermediate undergoes rearrangement driven by a 2,3-hydride shift on indole ring to ultimately produce 2-oxindole. The complete elucidation of the indole monooxygenation mechanism of these synthetic heme models will help reveal crucial insights into analogous biological systems, directly reinforcing drug design attempts targeting those heme enzymes. Moreover, these bioinspired model compounds are promising candidates for the future development of better synthetic protocols for the selective, efficient, and sustainable generation of 2-oxindole motifs, which are already known for a plethora of pharmacological benefits.

Over the last 50 years, proposals of α-carbonyl cation intermediates have been driven by chemical intuition and indirect evidence. Recently, wide interest in α-carbonyl cation chemistry has opened new gates to prepare α-functionalized carbonyl compounds. Though these intrinsically unstable carbocations are formed under forcing conditions (e.g., in a strong acid medium), their fleeting existence prohibits direct observation or spectroscopic measurement. We report that high-speed aqueous microdroplets can directly capture α-carbonyl cation intermediates from various reactions (Friedel–Crafts arylation, deoxygenation, and azidation) upon bombarding with the corresponding reaction aliquots. The α-carbonyl cations caged in water droplets are then desorbed to the gas phase, allowing their successful measurement by mass spectrometry. This has also enabled us to simultaneously monitor the relative abundance of the associated precursor, α-carbonyl cation intermediate, and product during the progress of the reaction.

Carbon quantum dots (CQDs) represent a class of carbon materials exhibiting photoresponse and many potential applications. Here, we present a unique property that dissolved CQDs capture large amounts of molecular oxygen from the air, the quantity of which can be controlled by light irradiation. The O2content can be varied between a remarkable 1 wt % of the CQDs in the dark to nearly half of it under illumination, in a reversible manner. Moreover, O2depletion enhances away from the air–solution interface as the nearby CQDs quickly regain them from the air, creating a pronounced concentration gradient in the solution. We elucidate the role of the CQD functional groups and show that excitons generated under light are responsible for their tunable adsorbed-oxygen content. Because of O2enrichment, the photocatalytic efficiency of the CQDs toward oxidation of benzylamines in the air is the same as under oxygen flow and far higher than the existing photocatalysts. The findings should encourage the development of a new class of oxygen-enricher materials and air as a sustainable oxidant in chemical transformations.

M-N-C catalysts, incorporating non-precious-metal ions (e.g. M = Fe, Co) within a nitrogen-doped carbon support, have been the focus of broad interest for electrochemical O2reduction and aerobic oxidation reactions. The present study explores the mechanistic relationship between the O2reduction mechanism under electrochemical and chemical conditions. Chemical O2reduction is investigated via the aerobic oxidation of a hydroquinone, in which the O–H bonds supply the protons and electrons needed for O2reduction to water. Mechanistic studies have been conducted to elucidate whether the M-N-C catalyst couples two independent half-reactions (IHR), similar to electrode-mediated processes, or mediates a direct inner-sphere reaction (ISR) between O2and the organic molecule. Kinetic data support the latter ISR pathway. This conclusion is reinforced by rate/potential correlations that reveal significantly different Tafel slopes, implicating different mechanisms for chemical and electrochemical O2reduction.

G-Protein-coupled receptors (GPCRs) belong to an important family of integral membrane receptor proteins that are essential for a variety of transmembrane signaling process, such as vision, olfaction, and hormone responses. They are also involved in many human diseases (Alzheimer’s, heart diseases, etc.) and are therefore common drug targets. Thus, understanding the details of the GPCR activation process is a task of major importance. Various types of crystal structures of GPCRs have been solved either at stable end-point states or at possible intermediate states. However, the detailed mechanism of the activation process is still poorly understood. For example, it is not completely clear when the nucleotide release from the G protein occurs and how the key residues on α5 contribute to the coupling process and further affect the binding specificity. In this work we show by free energy analysis that the guanosine diphosphate (GDP) molecule could be released from the Gsprotein when the binding cavity is half open. This occurs during the transition to the Gsopen state, which is the rate-determining step in the system conformational change. We also account for the experimentally observed slow-down effects by the change of the reaction barriers after mutations. Furthermore, we identify potential key residues on α5 and validated their significance by site-directed mutagenesis, which illustrates that computational works have predictive value even for complex biophysical systems. The methodology of the current work may be applied to other biophysical systems of interest.

In past studies, spin selective transport was observed in polymers and supramolecular structures that are based on homochiral building blocks possessing stereocenters. Here we address the question to what extent chiral building blocks are required for observing the chiral induced spin selectivity (CISS) effect. We demonstrate the CISS effect in supramolecular polymers exclusively containing achiral monomers, where the supramolecular chirality was induced by chiral solvents that were removed from the fibers before measuring. Spin-selective transport was observed for electrons transmitted perpendicular to the fibers’ long axis. The spin polarization correlates with the intensity of the CD spectra of the polymers, indicating that the effect is nonlocal. It is found that the spin polarization increases with the samples’ thickness and the thickness dependence is the result of at least two mechanisms: the first is the CISS effect, and the second reduces the spin polarization due to scattering. Temperature dependence studies provide the first support for theoretical work that suggested that phonons may contribute to the spin polarization.

Herein we report the synthesis and characterization of anionic boron- and carbon-based Kekulé diradicaloids spanned by a p-phenylene bridge. In contrast to Thiele’s hydrocarbon, a closed-shell singlet system, they show an appreciable population of the triplet state at room temperature, as evidenced by both NMR and EPR spectroscopy. Moreover, en route to these anionic boron- and carbon-based hetero-diradicaloids, the formation of an isolable diamino(4-diarylboryl-phenyl)methyl radical was observed.

Considering the importance of water splitting as the best solution for clean and renewable energy, the worldwide efforts for development of increasingly active molecular water oxidation catalysts must be accompanied by studies that focus on elucidating the mode of actions and catalytic pathways. One crucial challenge remains the elucidation of the factors that determine the selectivity of water oxidation by the desired 4e–/4H+pathway that leads to O2rather than by 2e–/2H+to H2O2. We now show that water oxidation with the cobalt–corrole CoBr8as electrocatalyst affords H2O2as the main product in homogeneous solutions, while heterogeneous water oxidation by the same catalyst leads exclusively to oxygen. Experimental and computation-based investigations of the species formed during the process uncover the formation of a Co(III)–superoxide intermediate and its preceding high-valent Co–oxyl complex. The competition between the base-catalyzed hydrolysis of Co(III)–hydroperoxide [Co(III)–OOH]−to release H2O2and the electrochemical oxidation of the same to release O2via [Co(III)–O2•]−is identified as the key step determining the selectivity of water oxidation.

Self-assembly of an achiral acceptor of square-planar Pd(II) or Pt(II) ion with a symmetric donor generally yields achiral architecture or a racemic mixture of chiral assemblies. Selective formation of an enantiopure assembly in such processes is very challenging. We report here a new approach of converting a dynamic mixture of multiple homochiral assemblies to an enantiopure architecture through the interaction of a chiral guest molecule. One-pot reaction of a cationic C3-symmetric tripyridyl donor L·HNO3with cis-[(tmeda)Pd(NO3)2] (M) [tmeda = N,N,N′,N′-tetramethylethane-1,2-diamine] yielded a complex mixture of stereoisomers of a chiral octahedral cage. Surprisingly, the presence of R-BINOL as a chiral guest in the above self-assembly induced selective formation of a single enantiopure octahedral cage. S-BINOL induced formation of the other enantiomer of the cage selectively. While selective recognition of an enantiomeric guest from a racemic mixture by a chiral host is well-known, present observation of “reverse chiral recognition” where the guest molecule determines the handedness of the host leading to the formation of an enantiopure cage is noteworthy.