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ConspectusOrganic chemistry has undoubtedly had a profound impact on humanity. Day in and day out, we find ourselves constantly surrounded by organic compounds. Pharmaceuticals, plastics, fuels, cosmetics, detergents, and agrochemicals, to name a few, are all synthesized by organic reactions. Very often, these reactions require a catalyst in order to proceed in a timely and selective manner. Lewis acids and organocatalysts are commonly employed to catalyze organic reactions and are considered to enhance the frontier molecular orbital (FMO) interactions. A vast number of textbooks and primary literature sources suggest that the binding of a Lewis acid or an iminium catalyst to a reactant (R1) stabilizes its LUMO and leads to a smaller HOMO(R2)-LUMO(R1) energy gap with the other reactant (R2), thus resulting in a faster reaction. This forms the basis for the so-called LUMO-lowering catalysis concept. Despite the simplicity and popularity of FMO theory, a number of deficiencies have emerged over the years, as a consequence of these FMOs not being the operative factor in the catalysis. LUMO-lowering catalysis is ultimately incomplete and is not always operative in catalyzed organic reactions. Our groups have recently undertaken a concerted effort to generate a unified framework to rationalize and predict chemical reactivity using a causal model that is rooted in quantum mechanics. In this Account, we propose the concept of Pauli repulsion-lowering catalysis to understand the catalysis in fundamental processes in organic chemistry. Our findings emerge from state-of-the-art computational methods, namely, the activation strain model (ASM) of reactivity in conjunction with quantitative Kohn-Sham molecular orbital theory (KS-MO) and a matching energy decomposition analysis (EDA). The binding of the catalyst to the substrate not only leads to a stabilization of its LUMO but also induces a significant reduction of the two-orbital, four-electron Pauli repulsion involving the

Metal-only Lewis pairs (MOLPs) based on zinc electrophiles are particularly interesting due to their relevance to Negishi cross-coupling reactions. Zinc-based ligands in bimetallic complexes also render unique reactivity to the transition metals at which they are bound. Here we explore the use of sterically hindered [Pt(PtBu3)2] (1) to access Pt/Zn bimetallic complexes. Compounds [(PtBu3)2Pt → Zn(C6F5)2] (2) and [Pt(ZnCp*)6] (3) (Cp* = pentamethylcyclopentadienyl) were isolated by reactions with Zn(C6F5)2 and [Zn2Cp*2], respectively. We also disclose the cooperative reactivity of 1/ZnX2 pairs (X = Cl, Br, I, and OTf) toward water and dihydrogen, which can be understood in terms of bimetallic frustration.

The use of the exceptionally bulky tris-2-(4,40 -di-tert-butylbiphenylyl) phosphine ligand allows the isolation and complete characterization of the first dicoordinate gold(I)–ethylene adduct, filling a missing fundamental piece on the organometallic chemistry of gold. Besides, the bonding situation of this species has been investigated by means of state-of-the-art Density Functional Theory (DFT) calculations indicating that p-backdonation plays a minor role compared with tricoordinate analogues

Low‐valent cobalt complexes equipped with chiral ligands can efficiently promote highly enantioselective (3+2) cycloadditions of alkyne‐tethered alkylidenecyclopropanes. The annulation allows to assemble bicyclic systems containing five‐membered rings in good yields and with excellent enantiomeric ratios. We also present a mechanistic discussion based on experimental and computational data, which support the involvement of CoI/CoIII catalytic cycles

Metal-only Lewis pairs (MOLPs) based on zinc electrophiles are particularly interesting due to their relevance to Negishi cross-coupling reactions. Zinc-based ligands in bimetallic complexes also render unique reactivity to the transition metals at which they are bound. Here we explore the use of sterically hindered [Pt(PtBu3)2] (1) to access Pt/Zn bimetallic complexes. Compounds [(PtBu3)2Pt→Zn(C6F5)2] (2) and [Pt(ZnCp*)6] (3) (Cp* = pentamethylcyclopentadienyl) were isolated by reactions with Zn(C6F5)2 and [Zn2Cp*2], respectively. We also disclose the cooperative reactivity of 1/ZnX2 pairs (X = Cl, Br, I, OTf) towards water and dihydrogen, which can be understood in terms of bimetallic frustration

The use of the exceptionally bulky tris-2-(4,40-di-tert-butylbiphenylyl) phosphine ligand allows the isolation and complete characterization of the first dicoordinate gold(I)–ethylene adduct, filling a missing fundamental piece on the organometallic chemistry of gold. Besides, the bonding situation of this species has been investigated by means of state-of-the-art Density Functional Theory (DFT) calculations indicating that p-backdonation plays a minor role compared with tricoordinate analogues

A new method that allows the complete control of the regioselectivity of the hydrobromination reaction of alkenes is described. Herein, we report a radical procedure with TMSBr and oxygen as common reagents, where the formation of the anti-Markovnikov product occurs in the presence of parts per million amounts of the Cu(I) species and the formation of the Markovnikov product occurs in the presence of 30 mol % iron(II) bromide. Density functional theory calculations combined with Fukui’s radical susceptibilities support the obtained results.

Low-valent cobalt complexes equipped with chiral ligands can efficiently promote highly enantioselective (3+2) cycloadditions of alkyne-tethered alkylidenecyclopropanes. The annulation allows to assemble bicyclic systems containing five-membered rings in good yields and with excellent enantiomeric ratios. We also present a mechanistic discussion based on experimental and computational data, which support the involvement of Co/Co catalytic cycles.

The redox-assisted C(sp)–C(sp3) bond activation of alkylnitriles coordinated to osmium(II) dihydride fragments has been performed with an osmium(VI) polyhydride to liberate alkanes and generate dinuclear complexes formed by two osmium(IV) polyhydride moieties linked by only one CN bridge. In addition, the bonding situation in these novel dinuclear species has been computationally studied.

Bacteria use adaptive immune systems encoded by CRISPR and Cas genes to maintain genomic integrity when challenged by pathogens and mobile genetic elements1,2,3. Type I CRISPR–Cas systems typically target foreign DNA for degradation via joint action of the ribonucleoprotein complex Cascade and the helicase–nuclease Cas34,5, but nuclease-deficient type I systems lacking Cas3 have been repurposed for RNA-guided transposition by bacterial Tn7-like transposons6,7. How CRISPR- and transposon-associated machineries collaborate during DNA targeting and insertion remains unknown. Here we describe structures of a TniQ–Cascade complex encoded by the Vibrio cholerae Tn6677 transposon using cryo-electron microscopy, revealing the mechanistic basis of this functional coupling. The cryo-electron microscopy maps enabled de novo modelling and refinement of the transposition protein TniQ, which binds to the Cascade complex as a dimer in a head-to-tail configuration, at the interface formed by Cas6 and Cas7 near the 3′ end of the CRISPR RNA (crRNA). The natural Cas8–Cas5 fusion protein binds the 5′ crRNA handle and contacts the TniQ dimer via a flexible insertion domain. A target DNA-bound structure reveals critical interactions necessary for protospacer-adjacent motif recognition and R-loop formation. This work lays the foundation for a structural understanding of how DNA targeting by TniQ–Cascade leads to downstream recruitment of additional transposase proteins, and will guide protein engineering efforts to leverage this system for programmable DNA insertions in genome-engineering applications.

Recognition of a start codon by the initiator aminoacyl-tRNA determines the reading frame of messenger RNA (mRNA) translation by the ribosome. In eukaryotes, the GTPase eIF5B collaborates in the correct positioning of the initiator Met-tRNAiMet on the ribosome in the later stages of translation initiation, gating entrance into elongation. Leveraging the long residence time of eIF5B on the ribosome recently identified by single-molecule fluorescence measurements, we determine the cryoEM structure of the naturally long-lived ribosome complex with eIF5B and Met-tRNAiMet immediately before transition into elongation. The structure uncovers an unexpected, eukaryotic specific and dynamic fidelity checkpoint implemented by eIF5B in concert with components of the large ribosomal subunit.

Nitrones have a well-recognized capacity as spin-traps and are considered powerful free radical scavengers, which are two important issues in hypoxia-induced oxidative stress and cell death in brain ischemia. Consequently, nitrones have been proposed as therapeutic agents in acute ischemic stroke (AIS). In this paper, we update the biological and pharmacological characterization of ISQ-201, a previously identified cholesteronitrone hybrid with antioxidant and neuroprotective activity. This study characterizes ISQ-201 as a neuroprotective agent against the hypoxia-induced ischemic injury. Transitory four-vessel occlusion and middle cerebral artery occlusion (tMCAO) were used to induce cerebral ischemia. Functional outcomes were determined using neurofunctional tests. Infarct area, neuronal death, and apoptosis induction were evaluated. In addition, ISQ-201 reactivity towards free radicals was studied in a theoretical model. ISQ-201 significantly decreased the ischemia-induced neuronal death and apoptosis, in a dose-dependent manner, showing its therapeutic effect when administered up until 6 h after post-ischemic reperfusion onset, effects that remained after 3 months from the ischemic episode. Furthermore, ISQ-201 significantly reduced infarct volume, leading to recovery of the motor function in the tMCAO model. Finally, the theoretical study confirmed the reactivity of ISQ-201 towards hydroxyl radicals. The results reported here prompted us to suggest ISQ-201 as a promising candidate for the treatment of AIS.