Late-stage oxidative C(sp3)-H methylation.

Frequently referred to as the 'magic methyl effect', the installation of methyl groups-especially adjacent (α) to heteroatoms-has been shown to dramatically increase the potency of biologically active molecules1-3. However, existing methylation methods show limited scope and have not been demonstrated in complex settings1. Here we report a regioselective and chemoselective oxidative C(sp3)-H methylation method that is compatible with late-stage functionalization of drug scaffolds and natural products. This combines a highly site-selective and chemoselective C-H hydroxylation with a mild, functional-group-tolerant methylation. Using a small-molecule manganese catalyst, Mn(CF3PDP), at low loading (at a substrate/catalyst ratio of 200) affords targeted C-H hydroxylation on heterocyclic cores, while preserving electron-neutral and electron-rich aryls. Fluorine- or Lewis-acid-assisted formation of reactive iminium or oxonium intermediates enables the use of a mildly nucleophilic organoaluminium methylating reagent that preserves other electrophilic functionalities on the substrate. We show this late-stage C(sp3)-H methylation on 41 substrates housing 16 different medicinally important cores that include electron-rich aryls, heterocycles, carbonyls and amines. Eighteen pharmacologically relevant molecules with competing sites-including drugs (for example, tedizolid) and natural products-are methylated site-selectively at the most electron rich, least sterically hindered position. We demonstrate the syntheses of two magic methyl substrates-an inverse agonist for the nuclear receptor RORc and an antagonist of the sphingosine-1-phosphate receptor-1-via late-stage methylation from the drug or its advanced precursor. We also show a remote methylation of the B-ring carbocycle of an abiraterone analogue. The ability to methylate such complex molecules at late stages will reduce synthetic effort and thereby expedite broader exploration of the magic methyl effect in pursuit of new small-molecule therapeutics and chemical probes.

Cu2+ coordination-induced in situ photo-to-heat on catalytic sites to hydrolyze ß-lactam antibiotics pollutants in waters.

For degradation of ß-lactam antibiotics pollution in waters, the strained ß-lactam ring is the most toxic and resistant moiety to biodegrade and redox-chemically treat among their functional groups. Hydrolytically opening ß-lactam ring with Lewis acid catalysts has long been recognized as a shortcut, but at room temperature, such hydrolysis is too slow to be deployed. Here, we found when Cu2+ was immobilized on imine-linked COF (covalent organic framework) (Cu2+/Py-Bpy-COF, Cu2+ load is 1.43 wt%), as-prepared composite can utilize the light irradiation (wavelength range simulated sunlight) to in situ heat anchored Cu2+ Lewis acid sites through an excellent photothermal conversion to open the ß-lactam ring followed by a desired full-decarboxylation of hydrolysates. Under 1 W/cm2 simulated sunlight, Cu2+/Py-Bpy-COF powders placed in a microfiltration membrane rapidly cause a temperature rising even to ~211.7 °C in 1 min. It can effectively hydrolyze common ß-lactam antibiotics in waters and even antibiotics concentration is as high as 1 mM and it takes less than 10 min. Such photo-heating hydrolysis rate is ~24 times as high as under dark and ~2 times as high as Cu2+ homogenous catalysis. Our strategy significantly decreases the interference from generally coexisting common organics in waters and potential toxicity concerns of residual carboxyl groups in hydrolysates and opens up an accessible way for the settlement of ß-lactam antibiotics pollutants by the only energy source available, the sunlight.

Exploring Aqueous Coordination Chemistry of Highly Lewis Acidic Metals with Emerging Isotopes for Nuclear Medicine.

Nuclear medicine harnesses radioisotopes for the diagnosis and treatment of disease. While the isotopes 99mTc and 111In have enabled the clinical diagnosis of millions of patients over the past 3 decades, more recent clinical translation of numerous 68Ga/177Lu-based radiopharmaceuticals for diagnostic imaging and therapy underscores the clinical utility of metal-based radiopharmaceuticals in mainstream cancer treatment. In addition to such established radionuclides, advancements in radioisotope production have enabled the production of radionuclides with a broad range of half-lives and emission properties of interest for nuclear medicine. Chemical means to form kinetically inert, in vivo-compatible species that can be modified with disease-targeting vectors is imperative. This presents a challenge for radiosiotopes of elements where the aqueous chemistry is still underdeveloped and poorly understood. Here, we discuss our efforts to date in exploring the aqueous, radioactive coordination chemistry of highly Lewis acidic metal ions and how our discoveries apply to the diagnosis and treatment of cancer in preclinical models of disease. The scope of this Account includes approaches to aqueous coordination of to-date understudied highly Lewis acidic metal ions with radioisotopes of emerging interest and the modulation of well-understood coordination environments of radio-coordination complexes to induce metal-catalyzed reactivity for separation and pro-drug applications.First, we discuss the development of seven-coordinate, small-cavity macrocyclic chelator platform mpatcn/picaga as an exemplary case study, which forms robust complexes with 44Sc/47Sc isotopes. Due to the high chemical hardness and pronounced Lewis acidity of the Sc3+ ion, the displacement of ternary ligand H2O by 18/natF- can be achieved to form an inert Sc-18/natF bond. Corresponding coordination complex natSc-18F is in vivo compatible and forms a theranostic tetrad with corresponding 44Sc/47Sc, 177Lu complexes all exhibiting homologous biodistribution profiles. Another exceptionally hard, highly Lewis acidic ion with underdeveloped aqueous chemistry and emerging interest in nuclear medicine is 45Ti4+. To develop de novo approaches to the mononuclear chelation of this ion under aqueous conditions, we employed a fragment-based bidentate ligand screening approach which identified two leads. The screen successfully predicted the formation of [45Ti][Ti(TREN-CAM)], a Ti-triscatechol complex that exhibits remarkable in vivo stability. Furthermore, the fragment-based screen also identified approaches that enabled solid-phase separation of Ti4+ and Sc3+ of interest in streamlining the isotope production of 45Ti and accessing new ways to separate 44Ti/44Sc for the development of a long-lived generator system. In addition to establishing the inert chelation of Ti4+ and Sc3+, we introduce controlled, metal-induced reactivity of corresponding coordination complexes on macroscopic and radiotracer scales. Metal-mediated autolytic amide bond cleavage (MMAAC) enables the temperature-dependent release of high-molar-activity, ready-to-inject radiopharmaceuticals; cleavage is selectively triggered by coordinated trivalent Lewis acid nat/68Ga3+ or Sc3+. Following the scope of reactivity and mechanistic studies, we validated MMAAC for the synthesis of high-molar-activity radiopharmaceuticals to image molecular targets with low expression and metal-mediated prodrug hydrolysis in vivo.This Account summarizes how developing the aqueous coordination chemistry and tuning the chemical reactivity of metal ions with high Lewis acidity at the macroscopic and tracer scales directly apply to the radiopharmaceutical synthesis with clinical potential.

Dioxygen Reduction and Bioinspired Oxidations by Non-heme Iron(II)-α-Hydroxy Acid Complexes.

ConspectusAerobic organisms involve dioxygen-activating iron enzymes to perform various metabolically relevant chemical transformations. Among these enzymes, mononuclear non-heme iron enzymes reductively activate dioxygen to catalyze diverse biological oxidations, including oxygenation of C-H and C═C bonds and C-C bond cleavage with amazing selectivity. Several non-heme enzymes utilize organic cofactors as electron sources for dioxygen reduction, leading to the generation of iron-oxygen intermediates that act as active oxidants in the catalytic cycle. These unique enzymatic reactions influence the design of small molecule synthetic compounds to emulate enzyme functions and to develop bioinspired catalysts for performing selective oxidation of organic substrates with dioxygen. Selective electron transfer during dioxygen reduction on iron centers of synthetic models by a sacrificial reductant requires appropriate design strategies. Taking lessons from the role of enzyme-cofactor complexes in the selective electron transfer process, our group utilized ternary iron(II)-α-hydroxy acid complexes supported by polydentate ligands for dioxygen reduction and bioinspired oxidations. This Account focuses on the role of coordinated sacrificial reductants in the selective electron transfer for dioxygen reduction by iron complexes and highlights the versatility of iron(II)-α-hydroxy acid complexes in affecting dioxygen-dependent oxidation/oxygenation reactions. The iron(II)-coordinated α-hydroxy acid anions undergo two-electron oxidative decarboxylation concomitant with the generation of reactive iron-oxygen oxidants. A nucleophilic iron(II)-hydroperoxo species was intercepted in the decarboxylation pathway. In the presence of a Lewis acid, the O-O bond of the nucleophilic oxidant is heterolytically cleaved to generate an electrophilic iron(IV)-oxo-hydroxo oxidant. Most importantly, the oxidants generated with or without Lewis acid can carry out cis-dihydroxylation of alkenes. Furthermore, the electrophilic iron-oxygen oxidant selectively hydroxylates strong C-H bonds. Another electrophilic iron(IV)-oxo oxidant, generated from the iron(II)-α-hydroxy acid complexes in the presence of a protic acid, carries out C-H bond halogenation by using a halide anion.Thus, different metal-oxygen intermediates could be generated from dioxygen using a single reductant, and the reactivity of the ternary complexes can be tuned using external additives (Lewis/protic acid). The catalytic potential of the iron(II)-α-hydroxy complexes in performing O2-dependent oxygenations has been demonstrated. Different factors that govern the reactivity of iron-oxygen oxidants from ternary iron(II) complexes are presented. The versatile reactivity of the oxidants provides useful insights into developing catalytic methods for the selective incorporation of oxidized functionalities under environmentally benign conditions using aerial oxygen as the terminal oxidant.

Enantioselective Radical Reactions Using Chiral Catalysts.

Benefiting from the impressive increase in fundamental knowledge, the last 20 years have shown a continuous burst of new ideas and consequently a plethora of new catalytic methods for enantioselective radical reactions. This review aims to provide a complete survey of progress achieved over this latter period. The first part of this review focuses on the use of chiral organocatalysts, and these include catalysts covalently linked to the substrate and those that interact with the substrate by weaker interactions like hydrogen bonds. The second part of the review is devoted to transition-metal redox catalysis which is organized according to increasing atomic number for the first-row transition metals (Ti, Cr, Fe, Mn, Co, Ni, Cu). Bioinspired manganese- and iron-mediated hydroxylations and oxidations are also discussed. A specific section is dedicated to the reactivity of Ru, Rh, and Ir complexes as Lewis acids with a special focus on complexes chiral at metal. Absorption of photons result in different events such as energy transfer, single-electron transfer, and hydrogen-atom transfer facilitating the formation of radicals. Organocatalysis has been successfully combined with photocatalysts, a reactivity which has opened new pathways enlarging the number of radical precursors available. The merger of photocatalysis with organo- or metalla-photocatalysis has brought novelty and allowed for the discovery of a large number of original transformations. The use of enzyme-catalyzed reactions involving radical intermediates which also largely benefit from visible-light irradiation are included in the review. This review provides a comprehensive inventory of progress in enantioselective radical reactions with a goal of detailing the reaction mechanisms involved in these transformations such that any nonspecialist could find their own creativity to invent yet unknown applications.

Insight into the Alkali Resistance Mechanism of FeMoTiOx Catalysts for NH3 Selective Catalytic Reduction of NO: Self-Defense Effects of MoOx for Alkali Capture.

The deactivation of selective catalytic reduction (SCR) catalysts caused by alkali metal poisoning remains an insurmountable challenge. In this study, we examined the impact of Na poisoning on the performance of Fe and Mo co-doped TiO2 (FeaMobTiOx) catalysts in the SCR reaction and revealed the related alkali resistance mechanism. On the obtained Fe1Mo2.6TiOx catalyst, the synergistic catalytic effect of uniformly dispersed FeOx and MoOx species leads to remarkable catalytic activity, with over 90% NO conversion achieved in a wide temperature range of 210-410 °C. During the Na poisoning process, Na ions predominantly adsorb on the MoOx species, which exhibit stronger alkali resistance, effectively safeguarding the FeOx species. This preferential adsorption minimizes the negative effect of Na poisoning on Fe1Mo2.6TiOx. Moreover, Na poisoning has little influence on the Eley-Rideal reaction pathway involving adsorbed NHx reacting with gaseous NOx. After Na poisoning, the Lewis acid sites were deteriorated, while the abundant Brønsted acid sites ensured sufficient NHx adsorption. As a benefit from the self-defense effects of active MoOx species for alkali capture, FeaMobTiOx exhibits exceptional alkali resistance in the SCR reaction. This research provides valuable insights for the design of highly efficient and alkali-resistant SCR catalysts.

Quaternary stereocentres via an enantioconvergent catalytic SN1 reaction.

The unimolecular nucleophilic substitution (SN1) mechanism features prominently in every introductory organic chemistry course. In principle, stepwise displacement of a leaving group by a nucleophile via a carbocationic intermediate enables the construction of highly congested carbon centres. However, the intrinsic instability and high reactivity of the carbocationic intermediates make it very difficult to control product distributions and stereoselectivity in reactions that proceed via SN1 pathways. Here we report asymmetric catalysis of an SN1-type reaction mechanism that results in the enantioselective construction of quaternary stereocentres from racemic precursors. The transformation relies on the synergistic action of a chiral hydrogen-bond-donor catalyst with a strong Lewis-acid promoter to mediate the formation of tertiary carbocationic intermediates at low temperature and to achieve high levels of control over reaction enantioselectivity and product distribution. This work provides a foundation for the enantioconvergent synthesis of other fully substituted carbon stereocentres.

Surficial engineering of active hydroxyls for ambient formaldehyde oxidation via enhanced Lewis acidity over Zr-doped cryptomelane materials.

Lewis acids of solid catalysts have been featured for a pivotal role in promoting various reactions. Regarding the oxidation protocol to remove formaldehyde, the inherent drawback of the best-studied MnO2 materials in acidic sites has eventually caused deficiency of active hydroxyls to sustain low-temperature activity. Herein, the cryptomelane-type MnO2 was targeted and it was tuned via incorporation of Zr metal, exhibiting great advances in not only the complete HCHO-to-CO2 degradation but also cycling performance. Zr species were existent in doping state in the MnO2 lattice, rendering lower crystallinity and breaking the regular growth of MnO2 crystallites, which thereby tripled surface area and created larger volume of smaller mesopores. Meantime, the local electronic properties of Mn atoms were also changed by Zr doping, i.e., more low-valence Mn species were formed due to the electron transfer from Zr to Mn. The results of infrared studies demonstrate the higher possession of Lewis acid sites on ZrMn, and this high degree of electrophilic agents favored the production of hydroxyl species. Furthermore, the reactivity of surface hydroxyls, as investigated by CO temperature programmed reduction and temperature programmed desorption of adsorbed O2, was obviously improved as well after Zr modification. It is speculated jointly with the characterizations of the post-reaction catalysts that the accelerated production of active hydroxyls helped rapidly convert formaldehyde into key intermediate-formate, which was then degraded into CO2, avoiding the side reaction path with undesired intermediate-hydrocarbonate-over the pristine MnO2, where active sites were blocked and formaldehyde oxidation was inhibited. Additionally, Zr decoration could stabilize Lewis acidity to be more resistant to heat degeneration, and this merit brought about advantageous thermal recyclability for cycled application.

Catalytic Enantioselective 6π Photocyclization of Acrylanilides.

Controlling absolute stereochemistry in catalytic photochemical reactions is generally challenging owing to high rates of background reactivity. Successful strategies broadly rely on selective excitation of the reaction substrate when associated with a chiral catalyst. Recent studies have demonstrated that chiral Lewis acid complexes can enable selective energy transfer from a photosensitizer to facilitate enantioselective triplet state reactions. Here, we apply this approach to the enantioselective catalysis of a 6π photocyclization through the design of an iridium photosensitizer optimized to undergo energy transfer to a reaction substrate only in the presence of a chiral Lewis acid complex. Among a group of iridium(III) sensitizers, enantioselectivity and yield closely correlate with photocatalyst triplet energy within a narrow window enabled by a modest reduction in substrate triplet energy upon binding a scandium/ligand complex. These results demonstrate that photocatalyst tuning offers a means to suppress background reactivity and improve enantioselectivity in photochemical reactions.

Strategies toward the Difunctionalizations of Enamide Derivatives for Synthesizing α,ß-Substituted Amines.

Enamide and enecarbamate derivatives containing a nucleophilic center at the ß-position from their nitrogen atom as well as a latent electrophilic site at their α-position are interesting motifs in organic chemistry. This dual reactivity─analogous that of the enamines─enables difunctionalization and increased structural complexity. Furthermore, an electron-withdrawing group on nitrogen drastically increases their stability. In that respect, enamides and enecarbamates are excellent partners for multicomponent transformations, and our research primarily focuses on these compounds in particular.Difunctionalization generally occurs through the nucleophilic addition of the enecarbamate on an electrophile to form iminium, which can subsequently react with a nucleophilic species. Although potent, such an approach is highly challenging due to the low stability of the intermediate iminium, leading to undesired hydrolysis or oligomerization. Epimerization, competitivity, and compatibility issues between the reaction partners are additional hindrances to developing these methodologies. To overcome these limitations, we described many complementary strategies.To control the enantioselectivity of these transformations, chiral phosphoric acids were found to be particularly well-suited to activate multiple reactants due to the formation of a hydrogen bonds network, allowing for an organized transition state in a chiral pocket. Interestingly, when deprotonated as phosphates, they can also play the role of ligands for Lewis acidic metals.To avoid iminium oligomerization, we successfully used stabilized α-arylated enamides. However, this approach was restricted to a simple nucleophilic addition at the ß-position. To achieve the difunctionalizations of α-unsubstituted derivatives, we explored reversibly linked nucleophile and electrophile to address their compatibility problem. Alternatively, we devised a sequential methodology for resolving the stability issue of the N-acyl iminium based on its intermediate trapping using a temporary nucleophile (alcohol or thiol). Interestingly, the trapping agent could further be displaced by the desired final α-substituent under Lewis acidic or photocatalytic activation. This led us to design new chiral and bifunctional phosphoric acid catalysts bearing chromophores to merge asymmetric organocatalysis and photochemistry.These photocatalysis studies incited us to focus on radical processes to manage original functionalizations that would not be feasible otherwise. ß-Alkylation and ß-trifluoromethylation of enecarbamates via visible-light-promoted atom transfer radical additions were successfully performed. As ß-allylations remained unattainable with the precedent methods, we eventually turned our attention to cerium(IV)-mediated oxidative single electron transfers. It allowed for singly occupied molecular orbital activation of these substrates to elicit their umpolung reactivity.Thus, the functionalization of enecarbamate derivatives appears as a valid synthetic strategy for obtaining important building blocks for agrochemical, pharmaceutical, and cosmetic industries, including diamines, haloamines, aminotryptamines, and less accessible trifluoromethylated or allylic compounds.

Asymmetric Catalytic Rearrangements with α-Diazocarbonyl Compounds.

α-Diazocarbonyl compounds serve as nucleophiles, dipoles, carbene precursors, and rare electrophiles, enabling a vast array of organic transformations under the influence of metal catalysts. Among them, rearrangement processes are attractive and provide straightforward and efficient accesses to one-carbon extension adducts or heteroatom-containing molecules. The reactions occur upon the release of dinitrogen after nucleophilic addition or before ylide formation. Although significant progress has been made for these two types of rearrangement reactions, the issue of enantiocontrol is challenging because the final optically enriched products are generated via multistep transformations and the inherent spacial arrangement of the intermediates has more or less influence on the regio- and enantioselectivity.In this Account, we collected several rearrangements of α-diazocarbonyl compounds, showcasing the efficient catalysts and tailored strategies for tackling enantioselective varieties of these two types of rearrangement reactions. Our research group initiated the catalytic asymmetric reactions of α-diazocarbonyl compounds during the development of chiral Feng N,N'-dioxide-metal complex catalysts and others. As a kind of useful chiral Lewis acid catalyst chiral N,N'-dioxide-metal complexes are favorable for the activation of various carbonyl compounds, accelerating the diastereo- and enantioselective nucleophilic addition of α-diazoesters and the sequential rearrangements in either an intermolecular or intramolecular manner. Aldehydes, acyclic and cyclic ketone derivatives, and α,ß-unsaturated ketones could participate in efficient asymmetric homologation reactions, and an obvious ligand-acceleration effect is observed in these processes. For example, the Roskamp-Feng reaction of aldehydes gives optically active ß-ketoesters through a H-shift, overwhelming the aryl group shift or oxygen attack. The shift preference and enantiocontrol in the homologation of acyclic and cyclic ketone derivatives could be under excellent control of the chiral catalysts. An unusual electrophilic α-amination of aryl/alkyl ketones and even a complicated homologation/dyotropic rearrangement/interconversion/[3 + 2] cycloaddition cascade used to construct dimeric polycyclic compounds were discovered as a result of the selection of chiral ligands and additives. On the basis of the understanding of the interaction of the functional group with N,N'-dioxide-metal complexes in catalysis and the key enantio-determining issues in ylide-based rearrangements, we designed new α-diazocarbonyl compounds by introducing a pyrazole-1-carboxyl group as the acceptor unit, which could benefit the formation of both carbenoid species and the chiral catalyst-bound ylides to deliver stereoselectivity. Taking advantage of Ni(II) or Co(II) complexes of Feng N,N'-dioxide ligands, we realized several kinds of enantioselective [2,3]-sigmatropic rearrangements, such as the Doyle-Kirmse reaction with allylic sulfides or selenides, [2,3]-Stevens rearrangements of vinyl-substituted α-diazo pyrazoleamides with thioacetates, Sommelet-Hauser rearrangements of aryl-substituted α-diazo pyrazoleamides with thioamides, and thio-Claisen rearrangements of 2-thio-indoles as well. Moreover, this strategy was shown to be applicable to highly γ-selective and enantioselective insertion into N-H bonds of secondary amines with vinyl-substituted α-diazo pyrazoleamides.

Exploring the Lewis Acidity and Reactivity of Neutral Pentacoordinate Dithienophospholes.

A series of luminescent, neutral pentacoordinate dithieno[3,2-b:2',3'-d]phosphole compounds was synthesized by [4+1] cycloaddition of o-quinones with the corresponding trivalent phospholes. The electronic and geometrical modification of the π-conjugated scaffold implemented here impacts the aggregation behavior of the species in solution. It proved successful in generating species with improved Lewis acidity of the phosphorus center that was then leveraged for small-molecule activation. Hydride abstraction from an external substrate involving the hypervalent species is followed by an intriguing P-mediated umpolung from the hydride to a proton and supports the catalytic potential of this class of main-group Lewis acids for organic chemistry. This study is a comprehensive investigation into various methods, including electronic, chemical, geometric modifications (and sometimes combinations of these approaches) to systematically improve the Lewis acidity of neutral and stable main-group Lewis acids with practical value for a range of chemical transformations.

New Opportunities in Metal-Organic Framework Catalysis: From Bifunctional to Frustrated Lewis Pairs Catalysis.

This article highlights novel prospects for metal-organic frameworks (MOFs) in heterogeneous catalysis as having frustrated Lewis acid-base pairs (FLPs) or as bifunctional acid-base solid catalysts able to activate molecular hydrogen. Starting from the extensive application MOFs as Lewis acid and Lewis base catalysts, this article uses catalytic hydrogenation to briefly summarize the efforts made to heterogenize boron and amine in MOFs to mimic molecular FLP systems. The core of this concept is based on recent findings which demonstrate the ability of two commonly used MOFs, namely UiO-66 and MIL-101, to catalyze the selective hydrogenation of polar double X=Y bonds at moderate H2 pressures below 10 bar. The influence of electron-donating, the withdrawal of substituents on the linker, and the aniline poisoning effect highlight the significance of Lewis acid sites, while density-functional theory calculations indicate the heterolytic H-H bond cleavage at the MOF metal oxo clusters. It is expected that this new perspective on MOFs as solid FLP systems will spur further research to explore and define the potential of dual sites in the catalytic activation of small molecules.

Boosting Ring Strain and Lewis Acidity of Borirane: Synthesis, Reactivity and Density Functional Theory Studies of an Uncoordinated Arylborirane Fused to o-Carborane.

Among the parent borirane, benzoborirene and ortho-dicarbadodecaborane-fused borirane, the latter possesses the highest ring strain and the highest Lewis acidity according to our density functional theory (DFT) studies. The synthesis of this class of compounds is thus considerably challenging. The existing examples require either a strong π-donating group or an extra ligand for B-coordination, which nevertheless suppresses or completely turns off the Lewis acidity. The title compound, which possesses both features, not only allows the 1,2-insertion of P=O, C=O or C≡N to proceed under milder conditions, but also enables the heretofore unknown dearomative 1,4-insertion of Ar-(C=O)- into a B-C bond. The fusion of strained molecular systems to an o-carborane cage shows great promise for boosting both the ring strain and acidity.

A Quantum-chemical Analysis on the Lewis Acidity of Diarylhalonium Ions.

Cyclic diaryliodonium compounds like iodolium derivatives have increasingly found use as noncovalent Lewis acids in the last years. They are more stable toward nucleophilic substitution than acyclic systems and are markedly more Lewis acidic. Herein, this higher Lewis acidity is analyzed and explained via quantum-chemical calculations and energy decomposition analyses. Its key origin is the change in energy levels and hybridization of iodine's orbitals, leading to both more favorable electrostatic interaction and better charge transfer. Both of the latter seem to contribute in similar fashion, while hydrogen bonding as well as steric repulsion with the phenyl rings play at best a minor role. In comparison to iodolium, bromolium and chlorolium are less Lewis acidic the lighter the halogen, which is predominantly based on less favorable charge-transfer interactions.

Carbonyl-Olefin Metathesis.

This Review describes the development of strategies for carbonyl-olefin metathesis reactions relying on stepwise, stoichiometric, or catalytic approaches. A comprehensive overview of currently available methods is provided starting with Paternò-Büchi cycloadditions between carbonyls and alkenes, followed by fragmentation of the resulting oxetanes, metal alkylidene-mediated strategies, [3 + 2]-cycloaddition approaches with strained hydrazines as organocatalysts, Lewis acid-mediated and Lewis acid-catalyzed strategies relying on the formation of intermediate oxetanes, and protocols based on initial carbon-carbon bond formation between carbonyls and alkenes and subsequent Grob-fragmentations. The Review concludes with an overview of applications of these currently available methods for carbonyl-olefin metathesis in complex molecule synthesis. Over the past eight years, the field of carbonyl-olefin metathesis has grown significantly and expanded from stoichiometric reaction protocols to efficient catalytic strategies for ring-closing, ring-opening, and cross carbonyl-olefin metathesis. The aim of this Review is to capture the status quo of the field and is expected to contribute to further advancements in carbonyl-olefin metathesis in the coming years.

Targeted NO Oxidation and Synchronous NO2 Inhibition via Oriented 1O2 Formation Based on Lewis Acid Site Adjustment.

An appealing strategy for ensuring environmental benefits of the photocatalytic NO oxidation reaction is to convert NO into NO3- instead of NO2, yet the selectivity of products remains challenging. Here, such a scenario could be realized by tailoring the exposure of Lewis acid sites on the surface of ZrO2, aiming to precisely regulate the ROS evolution process for the selective oxidation of NO into NO3-. As evidenced by highly combined experimental characterizations and density functional theory (DFT) simulations, Lewis acid sites serving as electron acceptors could induce itinerant electron redistribution, charge-carrier transfer, and further oxidation of •O2-, which promotes the oriented formation of 1O2. As a result, monoclinic ZrO2 with more Lewis acid sites exhibited an outstanding NO conversion efficiency (56.33%) and extremely low NO2 selectivity (5.04%). The ROS-based reaction process and promotion mechanism of photocatalytic performance have been revealed on the basis of ESR analysis, ROS-quenching experiments, and in situ ROS-quenching DRIFTS. This work could provide a critical view toward oriented ROS formation and advance a unique mechanism of selective NO oxidation into NO3-.

Catalytic allylic oxidation of internal alkenes to a multifunctional chiral building block.

The stereoselective oxidation of hydrocarbons is one of the most notable advances in synthetic chemistry over the past fifty years. Inspired by nature, enantioselective dihydroxylations, epoxidations and other oxidations of unsaturated hydrocarbons have been developed. More recently, the catalytic enantioselective allylic carbon-hydrogen oxidation of alkenes has streamlined the production of pharmaceuticals, natural products, fine chemicals and other functional materials. Allylic functionalization provides a direct path to chiral building blocks with a newly formed stereocentre from petrochemical feedstocks while preserving the olefin functionality as a handle for further chemical elaboration. Various metal-based catalysts have been discovered for the enantioselective allylic carbon-hydrogen oxidation of simple alkenes with cyclic or terminal double bonds. However, a general and selective allylic oxidation using the more common internal alkenes remains elusive. Here we report the enantioselective, regioselective and E/Z-selective allylic oxidation of unactivated internal alkenes via a catalytic hetero-ene reaction with a chalcogen-based oxidant. Our method enables non-symmetric internal alkenes to be selectively converted into allylic functionalized products with high stereoselectivity and regioselectivity. Stereospecific transformations of the resulting multifunctional chiral building blocks highlight the potential for rapidly converting internal alkenes into a broad range of enantioenriched structures that can be used in the synthesis of complex target molecules.

A guide to secondary coordination sphere editing.

This tutorial review showcases recent (2015-2021) work describing ligand construction as it relates to the design of secondary coordination spheres (SCSs). Metalloenzymes, for example, utilize SCSs to stabilize reactive substrates, shuttle small molecules, and alter redox properties, promoting functional activity. In the realm of biomimetic chemistry, specific incorporation of SCS residues (e.g., Brønsted or Lewis acid/bases, crown ethers, redox groups etc.) has been shown to be equally critical to function. This contribution illustrates how fundamental advances in organic and inorganic chemistry have been used for the construction of such SCSs. These imaginative contributions have driven exciting findings in many transformations relevant to clean fuel generation, including small molecule (e.g., H+, N2, CO2, NOx, O2) reduction. In most cases, these reactions occur cooperatively, where both metal and ligand are requisite for substrate activation.

Activation of aminocyclopropanes via radical intermediates.

Aminocyclopropanes are versatile building blocks for accessing high value-added nitrogen-containing products. To control ring-opening promoted by ring strain, the Lewis acid activation of donor-acceptor substituted systems is now well established. Over the last decade, alternative approaches have emerged proceeding via the formation of radical intermediates, alleviating the need for double activation of the cyclopropanes. This tutorial review summarizes key concepts and recent progress in ring-opening transformations of aminocyclopropanes via radical intermediates, divided into formal cycloadditions and 1,3-difunctionalizations.