Mechanistic Investigation into Single-Electron Oxidative Addition of Single-Atom Cu(I)-N4 Site: Revealing the Cu(I)-Cu(II)-Cu(I) Catalytic Cycle in Photochemical Hydrophosphinylation.

Understanding the valency and structural variations of metal centers during reactions is important for mechanistic studies of single-atom catalysis, which could be beneficial for optimizing reactions and designing new protocols. Herein, we precisely developed a single-atom Cu(I)-N4 site catalyst via a photoinduced ligand exchange (PILE) strategy. The low-valent and electron-rich copper species could catalyze hydrophosphinylation via a novel single-electron oxidative addition (OA) pathway under light irradiation, which could considerably decrease the energy barrier compared with the well-known hydrogen atom transfer (HAT) and single electron transfer (SET) processes. The Cu(I)-Cu(II)-Cu(I) catalytic cycle, via single-electron oxidative addition and photoreduction, has been proven by multiple in situ or operando techniques. This catalytic system demonstrates high efficiency and requires room temperature conditions and no additives, which improves the turnover frequency (TOF) to 1507 h-1. In particular, this unique mechanism has broken through the substrate limitation and shows a broad scope for different electronic effects of alkenes and alkynes.

Enhanced Reactivities of Iron(IV)-Oxo Porphyrin Species in Oxidation Reactions Promoted by Intramolecular Hydrogen-Bonding.

High-valent iron-oxo species are one of the common intermediates in both biological and biomimetic catalytic oxidation reactions. Recently, hydrogen-bonding (H-bonding) has been proved to be critical in determining the selectivity and reactivity. However, few examples have been established for mechanistic insights into the H-bonding effect. Moreover, intramolecular H-bonding effect on both C-H activation and oxygen atom transfer (OAT) reactions in synthetic porphyrin model system has not been investigated yet. In this study, a series of heme-containing iron(IV)-oxo porphyrin species with or without intramolecular H-bonding are synthesized and characterized. Kinetic studies revealed that intramolecular H-bonding can significantly enhance the reactivity of iron(IV)-oxo species in OAT, C-H activation, and electron-transfer reactions. This unprecedented unified H-bonding effect is elucidated by theoretical calculations, which showed that intramolecular H-bonding interactions lower the energy of the anti-bonding orbital of iron(IV)-oxo porphyrin species, resulting in the enhanced reactivities in oxidation reactions irrespective of the reaction type. To the best of the knowledge, this is the first extensive investigation on the intramolecular H-bonding effect in heme system. The results show that H-bonding interactions have a unified effect with iron(IV)-oxo porphyrin species in all three investigated reactions.

Diborodichloromethane as Versatile Reagent for Chemodivergent Synthesis of gem-Diborylalkanes.

The development of boron reagents is crucial for synthetic chemistry. Herein, we present a scalable and practical synthesis of diborodichloromethane (DBDCM) through the reaction of trichloromethyllithium with bis(pinacolato)diboron (B2 pin2 ). The resulting DBDCM reagent serves as a basic synthetic unit for the construction of various structurally diverse gem-diborylalkanes through controllable C-Cl functionalizations. Moreover, we have developed consecutive tetra-functionalizations of DBDCM for the construction of diverse tertiary and quaternary carbon containing molecules. The use of isotopically enriched 13 C-chloroform and 10 B2 pin2 enables the synthesis of isotopically enriched 13 C-DBDCM and 10 B-DBDCM reagents, which are beneficial for the convenient synthesis of carbon-13 and boron-10 molecules.

Modular and diverse synthesis of amino acids via asymmetric decarboxylative protonation of aminomalonic acids.

Stereoselective protonation is a challenge in asymmetric catalysis. The small size and high rate of transfer of protons mean that face-selective delivery to planar intermediates is hard to control, but it can unlock previously obscure asymmetric transformations. Particularly, when coupled with a preceding decarboxylation, enantioselective protonation can convert the abundant acid feedstocks into structurally diverse chiral molecules. Here an anchoring group strategy is demonstrated as a potential alternative and supplement to the conventional structural modification of catalysts by creating additional catalyst-substrate interactions. We show that a tailored benzamide group in aminomalonic acids can help build a coordinated network of non-covalent interactions, including hydrogen bonds, π-π interactions and dispersion forces, with a chiral acid catalyst. This allows enantioselective decarboxylative protonation to give α-amino acids. The malonate-based synthesis introduces side chains via a facile substitution of aminomalonic esters and thus can access structurally and functionally diverse amino acids.

Palladium/Norbornene-Catalyzed Direct Vicinal Di-Carbo-Functionalization of Indoles: Reaction Development and Mechanistic Study.

Methods that can simultaneously install multiple different functional groups to heteroarenes via C-H functionalizations are valuable for complex molecule synthesis, which, however, remain challenging to realize. Here we report the development of vicinal di-carbo-functionalization of indoles in a site- and regioselective manner, enabled by the palladium/norbornene (Pd/NBE) cooperative catalysis. The reaction is initiated by the Pd(II)-mediated C3-metalation and specifically promoted by the C1-substituted NBEs. The mild, scalable, and robust reaction conditions allow for a good substrate scope and excellent functional group tolerance. The resulting C2-arylated C3-alkenylated indoles can be converted to diverse synthetically useful scaffolds. The combined experimental and computational mechanistic study reveals the unique role of the C1-substituted NBE in accelerating the turnover-limiting oxidative addition step.

Stereoselective C-O silylation and stannylation of alkenyl acetates.

Facile formation of carbon-heteroatom bonds is a long-standing objective in synthetic organic chemistry. However, direct cross-coupling with readily accessible alkenyl acetates via inert C‒O bond-cleavage for the carbon-heteroatom bond construction remains challenging. Here we report a practical preparation of stereoselective tri- and tetrasubstituted alkenyl silanes and stannanes by performing cobalt-catalyzed C‒O silylation and stannylation of alkenyl acetates using silylzinc pivalate and stannylzinc chloride as the nucleophiles. This protocol features a complete control of chemoselectivity, stereoselectivity, as well as excellent functional group compatibility. The resulting alkenyl silanes and stannanes show high reactivities in arylation and alkenylation by Hiyama and Stille reactions. The synthetic utility is further illustrated by the facile late-stage modifications of natural products and drug-like molecules. Mechanistic studies suggest that the reaction might involve a chelation-assisted oxidative insertion of cobalt species to C‒O bond. We anticipate that our findings should prove instrumental for potential applications of this technology to organic syntheses and drug discoveries in medicinal chemistry.

Electrooxidative Activation of B-B Bond in B2 cat2 : Access to gem-Diborylalkanes via Paired Electrolysis.

This report describes the unprecedented electrooxidation of a solvent (e.g., DMF)-ligated B2 cat2 complex, whereby a solvent-stabilized boryl radical is formed via quasi-homolytic cleavage of the B-B bond in a DMF-ligated B2 cat2 radical cation. Cyclic voltammetry and density functional theory provide evidence to support this novel B-B bond activation strategy. Furthermore, a strategy for the electrochemical gem-diborylation of gem-bromides via paired electrolysis is developed for the first time, affording a range of versatile gem-diborylalkanes, which are widely used in synthetic society. Notably, this reaction approach is scalable, transition-metal-free, and requires no external activator.

Electroreduction Enables Regioselective 1,2-Diarylation of Alkenes with Two Electrophiles.

Precisely introducing two similar functional groups into bulk chemical alkenes represents a formidable route to complex molecules. Especially, the selective activation of two electrophiles is in crucial demand, yet challenging for cross-electrophile-coupling. Herein, we demonstrate a redox-mediated electrolysis, in which aryl nitriles are both aryl radical precursors and redox-mediators, enables an intermolecular alkene 1,2-diarylation with a remarkable regioselectivity, thereby avoiding the involvement of transition-metal catalysts. This transformation utilizes cyanoarene radical anions for activating various aryl halides (including iodides, bromides, and even chlorides) and affords 1,2-diarylation adducts in up to 83 % yield and >20 : 1 regioselectivity with more than 80 examples, providing a feasible approach to complex bibenzyl derivatives.

Unraveling the Structure and Reactivity Patterns of the Indole Radical Cation in Regioselective Electrochemical Oxidative Annulations.

Oxidation-induced strategy for inert chemical bond activation through highly active radical cation intermediate has exhibited unique reactivity. Understanding the structure and reactivity patterns of radical cation intermediates is crucial in the mechanistic study and will be beneficial for developing new reactions. In this work, the structure and properties of indole radical cations have been revealed using time-resolved transient absorption spectroscopy, in situ electrochemical UV-vis, and in situ electrochemical electron paramagnetic resonance (EPR) technique. Density functional theory (DFT) calculations were used to explain and predict the regioselectivity of several electrochemical oxidative indole annulations. Based on the understanding of the inherent properties of several indole radical cations, two different regioselective annulations of indoles have been successfully developed under electrochemical oxidation conditions. Varieties of furo[2,3-b]indolines and furo[3,2-b]indolines were synthesized in good yields with high regioselectivities. Our mechanistic insights into indole radical cations will promote the further development of oxidation-induced indole functionalizations.

Triflylpyridinium Enables Rapid and Scalable Controlled Reduction of Carboxylic Acids to Aldehydes using Pinacolborane.

Building up new and efficient methods for the controlled conversion of carboxylic acids to aldehydes is important. Herein, we report a rapid, modular and scalable method for the conversion of carboxylic acids to aldehydes using pinacolborane at ambient temperature, in which a triflylpyridinium reagent is used. The conversion of carboxylic acid to intermediate acylpyridinium by triflylpyridinium is new. A binary pyridine-coordinated boronium complex is generated after reduction. The unprecedented reduction of the acylpyridinium by HBpin opens up a practically direct synthesis of aldehydes from carboxylic acids. Theoretical studies indicate that the reduction of acylpyridinium requires a lower activation free energy than that of the product aldehyde. The synthetic advantage of this protocol is further highlighted by the scalable synthesis of aldehyde via continuous flow process. Configuration retention for chiral acids are presented in those syntheses.

Iridium-Catalyzed Intramolecular ß-C-H Alkenylation of Ketones with Alkynes via a Hydride-Transfer Approach.

Direct functionalization of carbonyl ß C-H bonds without using directing groups has not been a trivial task, and it is even more challenging to realize the corresponding atom-economical transformations with common alkenes or alkynes as the coupling partner. Here, we describe the development of an iridium-catalyzed intramolecular direct ß-alkenylation of ketones with regular alkynes. The reaction is redox neutral, avoids strong acids or bases, and tolerates various functional groups. The combined experimental and computational mechanistic studies reveal a hydride-transfer pathway, involving ketone α,ß-desaturation, iridium-hydride-mediated alkyne insertion, conjugate addition, and α-protonation.

Remote Enantioselective [4 + 1] Annulation with Copper-Vinylvinylidene Intermediates.

The first copper-catalyzed enantioselective [4 + 1] annulation of yne-allylic esters with 1,3-dicarbonyl compounds was realized through an elegant remote stereocontrol strategy. The very remote ε regioselective nucleophilic substitution was developed by employing a novel chiral copper-vinylvinylidene species from the new C4 synthon yne-allylic esters. Thus, greatly diverse spirocycles were obtained with ample scope and excellent levels of chemo-, regio-, and enantioselectivities. Moreover, detailed mechanistic studies suggest an yne-allylic substitution and Conia-ene cascade pathway on the remote stereochemical induction progress.

Cascade cyclization of alkene-tethered acylsilanes and allylic sulfones enabled by unproductive energy transfer photocatalysis.

Developing photo-induced cascade cyclization of alkene-tethered acylsilanes is challenging, because acylsilanes are unstable under light irradiation. Herein, we report that the energy transfer from excited acylsilanes to a photocatalyst that possesses lower triplet energy can inhibit the undesired decomposition of acylsilanes. With neutral Eosin Y as the photocatalyst, an efficient synthesis of cyclopentanol derivatives is achieved with alkene-tethered acylsilanes and allylic sulfones. The reaction shows broad substrate scope and the synthetic potential of this transformation is highlighted by the construction of cyclopentanol derivatives which contain fused-ring or bridged-ring.

From N-H Nitration to Controllable Aromatic Mononitration and Dinitration-The Discovery of a Versatile and Powerful N-Nitropyrazole Nitrating Reagent.

Nitroaromatics are tremendously valuable organic compounds with a long history of being used as pharmaceuticals, agrochemicals, and explosives as well as vital intermediates to a wide variety of chemicals. Consequently, the exploration of aromatic nitration has become an important endeavor in both academia and industry. Herein, we report the identification of a powerful nitrating reagent, 5-methyl-1,3-dinitro-1H-pyrazole, from the N-nitro-type reagent library constructed using a practical N-H nitration method. This nitrating reagent behaves as a controllable source of the nitronium ion, enabling mild and scalable nitration of a broad range of (hetero)arenes with good functional group tolerance. Of note, our nitration method could be controlled by manipulating the reaction conditions to furnish mononitrated or dinitrated product selectively. The value of this method in medicinal chemistry has been well established by its efficient late-stage C-H nitration of complex biorelevant molecules. Density functional theory (DFT) calculations and preliminary mechanistic studies reveal that the powerfulness and versatility of this nitrating reagent are due to the synergistic "nitro effect" and "methyl effect".

Switchable Radical Carbonylation by Philicity Regulation.

Carbonylation reactions involving CO as readily available C1 synthons have become one of the most important tools for the construction of carbonyl compounds from feedstock chemicals. Despite numerous catalytic methods for carbonylation reactions proceeding via ionic or radical pathways, an inherent limitation to these methods is the need to control switchable single and double carbonylative formation of value-added products from the same and simple starting materials. Here, we describe a new strategy that exploits photoredox catalysis to regulate the philicity of amine coupling partners to drive switchable radical carbonylation reactions. In double carbonylation, amines were first transformed into nitrogen radical cations by single-electron transfer-oxidation and coupled with CO to form carbamoyl radicals, which further underwent radical cross-coupling with the incipient cyanoalkyl acyl radicals to afford the double carbonylation products. Upon the addition of stoichiometric 4-dimethylaminopyridine (DMAP), DMAP competitively traps the initially formed cyanoalkyl acyl radical to form the relatively stabilized cyanoalkyl acyl-DMAP salts that engaged in the subsequent substitution with the nucleophilic amines to produce the single carbonylation products. The reaction proceeded smoothly with excellent selectivity in the presence of various amine nucleophiles at room temperature, generating valuable amides and α-ketoamides in a versatile and controlled fashion. Combined experimental and computational studies provided mechanistic insights into the possible pathways.

Catalytic Asymmetric Vinylogous and Bisvinylogous Propargylic Substitution.

Distinct regio- and enantioselectivity control in copper-catalyzed vinylogous and bisvinylogous propargylic substitution has been accomplished by using a novel chiral N,N,P ligand. The developed method provides an efficient and selective approach to an array of highly enantioenriched alkynyl unsaturated carbonyl compounds. Salient features include excellent functional group tolerance and broad substrate scope. The synthetic utility of the developed method is further demonstrated by a gram-scale synthesis and by application to a range of transformations including enantioselective synthesis of unique challenging compounds.

Assessing the urban road waterlogging risk to propose relative mitigation measures.

Road waterlogging has become a significant issue in developed cities due to the rapid urbanization in China. It is necessary to accurately identify the risk of waterlogging in urban roads and propose appropriate mitigation measures. This study considered urban waterlogging as a landscape ecological process. The road waterlogging risk was simulated and estimated using the Minimum Cumulative Resistance model under natural drainage conditions. The results indicate that: 1) The Minimum Cumulative Resistance model effectively assesses the waterlogging risk for each road segment. The roads in and around the central city have relatively higher waterlogging risks. The overall length of high-risk roads is 918.7 km, accounting for 31.3 % of the total. 2) There are 448 potential runoff paths and 448 inflow sites. The city's center and its north and south sides are the primary locations of the high-risk runoff paths and the inflow sites. 3) Road waterlogging is significantly more affected by the land-use types of High density residential and Industrial under rainfall intensities of a-year, 2-year, 3-year, and 5-year return periods. And the effects of various land-use types on waterlogging vary with the rainfall intensity. Using landscape ecology theory to analyze the risk of road waterlogging is a novel method to address urban waterlogging issues. This approach provides a more accurate approach to identifying the urban waterlogging risks and can be applied to developed cities suffering from waterlogging to help decision-makers devise the most effective mitigation measures.

Photoinduced Copper-Catalyzed Asymmetric C(sp3 )-H Alkynylation of Cyclic Amines by Intramolecular 1,5-Hydrogen Atom Transfer.

The development of a mild and general method for C(sp3 )-H functionalization of cyclic amines has been an ongoing challenge. In this work, we describe the copper-catalyzed enantioselective C(sp3 )-H alkynylation of unactivated cyclic 2-iodo-benzamide under photo-irradiation by intramolecular 1,5-hydrogen atom transfer (HAT). The employment of a new bisoxazoline diphenylamine ligand, in conjunction with 1,1'-bi-2-naphthol, which significantly improved the reduction potential of the copper complex, was the key to success of this chemistry. Mechanistic and computational studies supported that the new copper complex served the dual role as a photoredox and coupling catalyst, the reaction went through a radical process, and the intramolecular 1,5-HAT process was involved in the rate-limiting step. Apart from the broad substrate scope including unprecedented benzocyclic amines, this method also showed excellent diastereoselectivity in 2-monosubstituted cyclic amines via substrate control.

Dual-resolving of positional and geometric isomers of C=C bonds via bifunctional photocycloaddition-photoisomerization reaction system.

The biological functions of lipids largely depend on their chemical structures. The position and configuration of C=C bonds are two of the essential attributes that determine the structures of unsaturated lipids. However, simultaneous identification of both attributes remains challenging. Here, we develop a bifunctional visible-light-activated photocycloaddition-photoisomerization reaction system, which enables the dual-resolving of the positional and geometric isomerism of C=C bonds in lipids when combines with liquid chromatography-mass spectrometry. The dual-pathway reaction mechanism is demonstrated by experiments and density functional theory calculations. Based on this bifunctional reaction system, a workflow of deep structural lipidomics is established, and allows the revealing of unique patterns of cis-trans-isomers in bacteria, as well as the tracking of C=C positional isomers changes in mouse brain ischemia. This study not only offers a powerful tool for deep lipid structural biology, but also provides a paradigm for developing the multifunctional visible-light-induced reaction.

Diastereoselective Transfer of Tri(di)fluoroacetylsilanes-Derived Carbenes to Alkenes.

Stereoselective cyclopropanation reaction of alkenes is usually achieved by metal complexes via singlet-metal-carbene intermediates. However, previous transition-metal-catalyzed cyclopropanation of alkenes with acylsilanes afforded low diastereoselectivity. Herein, we report the first visible-light-induced transition-metal-free cyclopropanation reaction of terminal alkenes with trifluoroacetylsilanes and difluoroacetylsilanes. Both aromatic and aliphatic alkenes as well as electron-deficient alkenes are suitable substrates for the highly cis-selective [2+1] cyclization reaction. A combination of experimental and computational studies identified triplet carbenes as being key intermediates in this transformation. The gram scale reaction and late-stage functionalization demonstrated the synthetic potential of this strategy.