Understanding the unique reactivity patterns of nickel/JoSPOphos manifold in the nickel-catalyzed enantioselective C–H cyclization of imidazoles

The 3d transition metal-catalyzed enantioselective C–H functionalization provides a sustainable strategy for the construction of chiral molecules. A better understanding of the catalytic nature of the reactions and the factors controlling the enantioselectivity is important for rational design of more efficient systems. Herein, the mechanisms of Ni-catalyzed enantioselective C–H cyclization of imidazoles are investigated by density functional theory (DFT) calculations. Both the π-allyl nickel(ii)-promoted σ-complex-assisted metathesis (σ-CAM) and the nickel(0)-catalyzed oxidative addition (OA) mechanisms are disfavored. In addition to the typically proposed ligand-to-ligand hydrogen transfer (LLHT) mechanism, the reaction can also proceed via an unconventional σ-CAM mechanism that involves hydrogen transfer from the JoSPOphos ligand to the alkene through P–H oxidative addition/migratory insertion, C(sp²)–H activation via σ-CAM, and C–C reductive elimination. Importantly, computational results based on this new mechanism can indeed reproduce the experimentally observed enantioselectivities. Further, the catalytic activity of the π-allyl nickel(ii) complex can be rationalized by the regeneration of the active nickel(0) catalyst via a stepwise hydrogen transfer, which was confirmed by experimental studies. The calculations reveal several significant roles of the secondary phosphine oxide (SPO) unit in JoSPOphos during the reaction. The improved mechanistic understanding will enable design of novel enantioselective C–H transformations.

Several unique reactivity patterns of the Ni/JoSPOphos manifold, including facile hydrogen transfer via the two-step oxidative addition/migratory insertion and C(sp²)–H activation via an unconventional σ-CAM mechanism, were disclosed in this work.     

Allylic C(sp3)–H alkylation via synergistic organo- and photoredox catalyzed radical addition to imines

A new catalytic method for the direct alkylation of allylic C(sp³)–H bonds from unactivated alkenes via synergistic organo- and photoredox catalysis is described. The transformation achieves an efficient, redox-neutral synthesis of homoallylamines with broad functional group tolerance, under very mild reaction conditions. Mechanistic investigations indicate that the reaction proceeds through the N-centered radical intermediate which is generated by the allylic radical addition to the imine.

A new catalytic method for the direct alkylation of allylic C(sp³)–H bonds from unactivated alkenes via synergistic organo- and photoredox catalysis is described.     

Biomimetic hydrogen-bonding cascade for chemical activation: telling a nucleophile from a base

Hydrogen bonding-assisted polarization is an effective strategy to promote bond-making and bond-breaking chemical reactions. Taking inspiration from the catalytic triad of serine protease active sites, we have devised a conformationally well-defined benzimidazole platform that can be systematically functionalized to install multiple hydrogen bonding donor (HBD) and acceptor (HBA) pairs in a serial fashion. We found that an increasing number of interdependent and mutually reinforcing HBD–HBA contacts facilitate the bond-forming reaction of a fluorescence-quenching aldehyde group with the cyanide ion, while suppressing the undesired Brønsted acid–base reaction. The most advanced system, evolved through iterative rule-finding studies, reacts rapidly and selectively with CN⁻ to produce a large (>180-fold) enhancement in the fluorescence intensity at λ_max = 450 nm.

Biomimetic cascade hydrogen bonds promote covalent capture of a nucleophile by polarizing the electrophilic reaction site, while suppressing non-productive acid–base chemistry as the competing reaction pathway.     

Catalytic asymmetric synthesis of 3,2′-pyrrolinyl spirooxindoles via conjugate addition/Schmidt-type rearrangement of vinyl azides and (E)-alkenyloxindoles

A catalytic asymmetric conjugate addition/Schmidt-type rearrangement of vinyl azides and (E)-alkenyloxindoles was realized. It afforded a variety of optically active 3,2′-pyrrolinyl spirooxindoles with high yields (up to 98%), and excellent diastereo- and enantioselectivities (up to 98% ee, >19 : 1 dr), even at the gram-scale in the presence of a chiral N,N′-dioxide–nickel(ii) complex. In addition, a possible catalytic cycle and transition state model were proposed to rationalize the stereoselectivity.

Lewis acid catalyzed asymmetric synthesis of 3,2′-pyrrolinyl spirooxindole skeletons via conjugate addition/Schmidt-type rearrangement of vinyl azides and (E)-alkenyloxindoles.     

Palladium-catalyzed synthesis of β-hydroxy compounds via a strained 6,4-palladacycle from directed C–H activation of anilines and C–O insertion of epoxides

A palladium-catalyzed C–H activation of acetylated anilines (acetanilides, 1,1-dimethyl-3-phenylurea, 1-phenylpyrrolidin-2-one, and 1-(indolin-1-yl)ethan-1-one) with epoxides using O-coordinating directing groups was accomplished. This C–H alkylation reaction proceeds via formation of a previously unknown 6,4-palladacycle intermediate and provides rapid access to regioselectively functionalized β-hydroxy products. Notably, this catalytic system is applicable for the gram scale mono-functionalization of acetanilide in good yields. The palladium-catalyzed coupling reaction of the ortho-C(sp²) atom of O-coordinating directing groups with a C(sp³) carbon of chiral epoxides offers diverse substrate scope in good to excellent yields. In addition, further transformations of the synthesized compound led to biologically important heterocycles. Density functional theory reveals that the 6,4-palladacycle leveraged in this work is significantly more strained (>10 kcal mol⁻¹) than the literature known 5,4 palladacycles.

The combined experimental and computational study on palladium-catalyzed regioselective C–H functionalization of O-coordinating directing groups with epoxides is described.     

Automatic discovery of photoisomerization mechanisms with nanosecond machine learning photodynamics simulations

Photochemical reactions are widely used by academic and industrial researchers to construct complex molecular architectures via mechanisms that often require harsh reaction conditions. Photodynamics simulations provide time-resolved snapshots of molecular excited-state structures required to understand and predict reactivities and chemoselectivities. Molecular excited-states are often nearly degenerate and require computationally intensive multiconfigurational quantum mechanical methods, especially at conical intersections. Non-adiabatic molecular dynamics require thousands of these computations per trajectory, which limits simulations to ∼1 picosecond for most organic photochemical reactions. Westermayr et al. recently introduced a neural-network-based method to accelerate the predictions of electronic properties and pushed the simulation limit to 1 ns for the model system, methylenimmonium cation (CH₂NH₂⁺). We have adapted this methodology to develop the Python-based, Python Rapid Artificial Intelligence Ab Initio Molecular Dynamics (PyRAI²MD) software for the cis–trans isomerization of trans-hexafluoro-2-butene and the 4π-electrocyclic ring-closing of a norbornyl hexacyclodiene. We performed a 10 ns simulation for trans-hexafluoro-2-butene in just 2 days. The same simulation would take approximately 58 years with traditional multiconfigurational photodynamics simulations. We generated training data by combining Wigner sampling, geometrical interpolations, and short-time quantum chemical trajectories to adaptively sample sparse data regions along reaction coordinates. The final data set of the cis–trans isomerization and the 4π-electrocyclic ring-closing model has 6207 and 6267 data points, respectively. The training errors in energy using feedforward neural networks achieved chemical accuracy (0.023–0.032 eV). The neural network photodynamics simulations of trans-hexafluoro-2-butene agree with the quantum chemical calculations showing the formation of the cis-product and reactive carbene intermediate. The neural network trajectories of the norbornyl cyclohexadiene corroborate the low-yielding syn-product, which was absent in the quantum chemical trajectories, and revealed subsequent thermal reactions in 1 ns.

Photochemical reactions are widely used by academia and industry to construct complex molecular architectures via mechanisms that are often inaccessible by other means.     

Pd-catalyzed cross-electrophile Coupling/C–H alkylation reaction enabled by a mediator generated via C(sp3)–H activation

Transition-metal-catalyzed cross-electrophile C(sp²)–(sp³) coupling and C–H alkylation reactions represent two efficient methods for the incorporation of an alkyl group into aromatic rings. Herein, we report a Pd-catalyzed cascade cross-electrophile coupling and C–H alkylation reaction of 2-iodo-alkoxylarenes with alkyl chlorides. Methoxy and benzyloxy groups, which are ubiquitous functional groups and common protecting groups, were utilized as crucial mediators via primary or secondary C(sp³)–H activation. The reaction provides an innovative and convenient access for the synthesis of alkylated phenol derivatives, which are widely found in bioactive compounds and organic functional materials.

A cascade Pd-catalyzed cross-electrophile coupling and C–H alkylation reaction of 2-iodo-alkoxylarenes with alkyl chlorides has been developed by using an ortho-methoxy or benzyloxy group as a mediator via C(sp³)–H activation.     

Monoaurated vs. diaurated intermediates: causality or independence?

Diaurated intermediates of gold-catalysed reactions have been a long-standing subject of debate. Although diaurated complexes were regarded as a drain of active monoaurated intermediates in catalytic cycles, they were also identified as the products of gold–gold cooperation in dual–activation reactions. This study shows investigation of intermediates in water addition to alkynes catalysed by [(IPr)Au(CH₃CN)(BF₄)]. Electrospray ionisation mass spectrometry (ESI-MS) allowed us to detect both monoaurated and diaurated complexes in this reaction. Infrared photodissociation spectra of the trapped complexes show that the structure of the intermediates corresponds to α-gold ketone intermediates protonated or aurated at the oxygen atom. Delayed reactant labelling experiments provided the half life of the intermediates in reaction of 1-phenylpropyne (∼7 min) and the kinetic isotope effects for hydrogen introduction to the carbon atom (KIE ∼ 4–6) and for the protodeauration (KIE ∼ 2). The results suggest that the ESI-MS detected monoaurated and diaurated complexes report on species with a very similar or the same kinetics in solution. Kinetic analysis of the overall reaction showed that the reaction rate is first-order dependent on the concentration of the gold catalyst. Finally, all results are consistent with the reaction mechanism proceeding via monoaurated neutral α-gold ketone intermediates only.

Reaction kinetics and detected α-gold ketone intermediates reveal that gold-mediated hydration of alkynes does not rely on dual activation.     

The site-selectivity and mechanism of Pd-catalyzed C(sp2)–H arylation of simple arenes

Control over site-selectivity is a critical challenge for practical application of catalytic C–H functionalization reactions in organic synthesis. Despite the seminal breakthrough of the Pd-catalyzed C(sp²)–H arylation of simple arenes via a concerted metalation–deprotonation (CMD) pathway in 2006, understanding the site-selectivity of the reaction still remains elusive. Here, we have comprehensively investigated the scope, site-selectivity, and mechanism of the Pd-catalyzed direct C–H arylation reaction of simple arenes. Counterintuitively, electron-rich arenes preferably undergo meta-arylation without the need for a specifically designed directing group, whereas electron-deficient arenes bearing fluoro or cyano groups exhibit high ortho-selectivity and electron-deficient arenes bearing bulky electron-withdrawing groups favor the meta-product. Comprehensive mechanistic investigations through a combination of kinetic measurements and stoichiometric experiments using arylpalladium complexes have revealed that the Pd-based catalytic system works via a cooperative bimetallic mechanism, not the originally proposed monometallic CMD mechanism, regardless of the presence of a strongly coordinating L-type ligand. Notably, the transmetalation step, which is influenced by a potassium cation, is suggested as the selectivity-determining step.

The transmetalation step, not the C–H activation step, is suggested as the selectivity-determining step in Pd-catalyzed C–H arylation of simple arenes.     

Thermal effects – an alternative mechanism for plasmon-assisted photocatalysis

Recent experiments claimed that the catalysis of reaction rates in numerous bond-dissociation reactions occurs via the decrease of activation barriers driven by non-equilibrium (“hot”) electrons in illuminated plasmonic metal nanoparticles. Thus, these experiments identify plasmon-assisted photocatalysis as a promising path for enhancing the efficiency of various chemical reactions. Here, we argue that what appears to be photocatalysis is much more likely thermo-catalysis, driven by the well-known plasmon-enhanced ability of illuminated metallic nanoparticles to serve as heat sources. Specifically, we point to some of the most important papers in the field, and show that a simple theory of illumination-induced heating can explain the extracted experimental data to remarkable agreement, with minimal to no fit parameters. We further show that any small temperature difference between the photocatalysis experiment and a control experiment performed under external heating is effectively amplified by the exponential sensitivity of the reaction, and is very likely to be interpreted incorrectly as “hot” electron effects.

A simple Arrhenius-based theory of heating, rather than “hot electrons”, can reproduce some high-profile photocatalysis experimental results to remarkable accuracy. Flaws in temperature measurement may have led to wrong conclusions.     

Tubularenes

We report the synthesis and characterization of conjugated, conformationally rigid, and electroactive carbon-based nanotubes that we term tubularenes. These structures are constructed from a resorcin[n_b]arene base. Cyclization of the conjugated aromatic nanotube is achieved in one-pot eight-fold C–C bond formation via Suzuki–Miyaura cross-coupling. DFT calculations indicate a buildup of strain energy in excess of 90 kcal mol⁻¹. The resulting architectures contain large internal void spaces >260 ų, are fluorescent, and able to accept up to 4 electrons. This represents the first scaffolding approach that provides conjugated nanotube architectures.

First scaffolding approach to obtain tubular-shaped contorted aromatic architectures.     

Iron-catalyzed remote functionalization of inert C(sp3)–H bonds of alkenes via 1,n-hydrogen-atom-transfer by C-centered radical relay

As an alternative approach to traditional C–H activation that often involved harsh conditions, and vicinal or primary C–H functionalization, radical relay offers a solution to these long-held problems. Enabled by 1,n (n = 5, 6)-hydrogen atom transfer (HAT), we use a most prevalent moiety, alkene, as the precursor to an sp³ C-centered radical to promote selective cleavage of inert C(sp³)–H bonds for the generation of azidotrifluoromethylated molecules. Mild conditions, broad scope and excellent regioselective control (>20 : 1) are observed in the reactions. Deuterium labelling studies disclose the kinetic characteristics of the transformations and verify a direct 1,n-HAT pathway. The key to this C-centered radical relay is that iron plays a dual role as a radical initiator and terminator to incorporate the azide functionality through radical oxidation via azido–ligand-transfer. The methods and the later derivatization promise expeditious synthesis of CF₃-containing organic azides, γ-lactam and triazoles that are widely used in designing new fluorescent tags and functional materials.

Remote functionalization of inert C(sp³)–H bonds is described via iron-catalyzed sp³ C-centered radical relay.     

1,2-Addition and cycloaddition reactions of niobium bis(imido) and oxo imido complexes

The bis(imido) complexes (BDI)Nb(N^tBu)₂ and (BDI)Nb(N^tBu)(NAr) (BDI = N,N′-bis(2,6-diisopropylphenyl)-3,5-dimethyl-β-diketiminate; Ar = 2,6-diisopropylphenyl) were shown to engage in 1,2-addition and [2 + 2] cycloaddition reactions with a wide variety of substrates. Reaction of the bis(imido) complexes with dihydrogen, silanes, and boranes yielded hydrido-amido-imido complexes via 1,2-addition across Nb-imido π-bonds; some of these complexes were shown to further react via insertion of carbon dioxide to give formate-amido-imido products. Similarly, reaction of (BDI)Nb(N^tBu)₂ with tert-butylacetylene yielded an acetylide-amido-imido complex. In contrast to these results, many related mono(imido) Nb BDI complexes do not exhibit 1,2-addition reactivity, suggesting that π-loading plays an important role in activating the Nb–N π-bonds toward addition. The same bis(imido) complexes were also shown to engage in [2 + 2] cycloaddition reactions with oxygen- and sulfur-containing heteroallenes to give carbamate- and thiocarbamate-imido complexes: some of these complexes readily dimerized to give bis-μ-sulfido, bis-μ-iminodicarboxylate, and bis-μ-carbonate complexes. The mononuclear carbamate imido complex (BDI)Nb(NAr)(N(^tBu)CO₂) (12) could be induced to eject tert-butylisocyanate to generate a four-coordinate terminal oxo imido intermediate, which could be trapped as the five-coordinate pyridine or DMAP adduct. The DMAP adducted oxo imido complex (BDI)NbO(NAr)(DMAP) (16) was shown to engage in 1,2-addition of silanes across the Nb-oxo π-bond; this represents a new reaction pathway in group 5 chemistry.

Another slice of pi: the addition of a second π-donor ligand engenders 1,2-addition and [2 + 2] cycloaddition reactivity across Nb-imido and Nb-oxo bonds.     

Catalytic asymmetric synthesis of N-substituted tetrahydroquinoxalines via regioselective Heyns rearrangement and stereoselective transfer hydrogenation in one pot

N-Substituted tetrahydroquinoxalines (37 examples) were step-economically obtained in good yield (<97%) and ee (<99%) with readily available substrates. The reaction proceeds through an interesting regioselective Heyns rearrangement/enantioselective transfer hydrogenation in one pot. The substrate scope and the reaction mechanism were systematically investigated.

N-Substituted tetrahydroquinoxalines were step-economically obtained in good yield and ee with readily available substrates.     

Chiral Lewis acid-bonded picolinaldehyde enables enantiodivergent carbonyl catalysis in the Mannich/condensation reaction of glycine ester

A new strategy of asymmetric carbonyl catalysis via a chiral Lewis acid-bonded aldehyde has been developed for the direct Mannich/condensation cascade reaction of glycine ester with aromatic aldimines. The co-catalytic system of 2-picolinaldehyde and chiral Yb^III-N,N′-dioxides was identified to be efficient under mild conditions, providing a series of trisubstituted imidazolidines in moderate to good yields with high diastereo- and enantioselectivities. Enantiodivergent synthesis was achieved via changing the sub-structures of the chiral ligands. The reaction could be carried out in a three-component version involving glycine ester, aldehydes, and anilines with equally good results. Based on control experiments, the X-ray crystal structure study and theoretical calculations, a possible dual-activation mechanism and stereo-control modes were provided to elucidate carbonyl catalysis and enantiodivergence.

The catalytic asymmetric Mannich/condensation of glycine ester with aldimines was achieved by merging chiral N,N′-dioxide/Yb^III complex Lewis acid catalysis/carbonyl catalysis under mild condition.     

trans-Hydroboration–oxidation products in Δ5-steroids via a hydroboration-retro-hydroboration mechanism

Herein, we report for the first time a “trans-hydroboration–oxidation product” isolated and characterized under traditional hydroboration–oxidation conditions using cholesterol and diosgenin as substrates. These substrates are excellent starting materials because of the rigidity and different structural environments around the double bond. Further investigations based on experimental evidence, in conjunction with theoretical studies, indicate that the formation of this trans-species occurs via a retro-hydroboration of the major product to generate the corresponding Δ⁶-structure and the subsequent hydroboration by the β-face. Besides, the corresponding Markovnikov type products have been isolated in synthetically useful yields. The behavior of the reaction under a range of temperatures is also investigated.

A trans-product is isolated and characterized under traditional hydroboration–oxidation conditions using Δ⁵-steroids as substrates. Experimental and theoretical studies indicate that the trans-species occurs via a retro-hydroboration mechanism.     

A step-economic and one-pot access to chiral Cα-tetrasubstituted α-amino acid derivatives via a bicyclic imidazole-catalyzed direct enantioselective C-acylation

C^α-Tetrasubstituted α-amino acids are ubiquitous and unique structural units in bioactive natural products and pharmaceutical compounds. The asymmetric synthesis of these molecules has attracted a lot of attention, but a more efficient method is still greatly desired. Here we describe the first sequential four-step acylation reaction for the efficient synthesis of chiral C^α-tetrasubstituted α-amino acid derivatives from simple N-acylated amino acids via an auto-tandem catalysis using a single nucleophilic catalyst. The synthetic efficiency is improved via a direct enantioselective C-acylation; the methodology affords the corresponding C^α-tetrasubstituted α-amino acid derivatives with excellent enantioselectivities (up to 99% ee). This step-economic, one-pot, and auto-tandem strategy provides facile access to important chiral building blocks, such as peptides, serines, and oxazolines, which are often used in medicinal and synthetic chemistry.

The first four-step sequential reaction for the synthesis of C^α-tetrasubstituted chiral α-amino acid derivatives via auto-tandem catalysis has been developed.     

Palladium-catalyzed hydroalkylation of methylenecyclopropanes with simple hydrazones

A palladium-catalyzed hydroalkylation reaction of methylenecyclopropanes via highly selective C–C σ-bond scission was achieved under mild conditions, in which simple hydrazones served as carbanion equivalents. This method featured good functional group compatibility, affording high yields of C-alkylated terminal alkenes.

A palladium-catalyzed hydroalkylation of methylenecyclopropanes via selective C–C σ-bond scission was achieved, in which simple hydrazones served as carbanion equivalents. This method affords high yields of C-alkylated terminal alkenes with good functional group compatibility.     

Aerosol-assisted route to low-E transparent conductive gallium-doped zinc oxide coatings from pre-organized and halogen-free precursor

Thermal control in low-emission windows is achieved by the application of glazings, which are simultaneously optically transparent in the visible and reflective in the near-infrared (IR). This phenomenon is characteristic of coatings with wide optical band gaps that have high enough charge carrier concentrations for the material to interact with electromagnetic radiation in the IR region. While conventional low-E coatings are composed of sandwiched structures of oxides and thin Ag films or of fluorinated SnO₂ coatings, ZnO-based glazing offers an environmentally stable and economical alternative with competitive optoelectronic properties. In this work, gallium-doped zinc oxide (GZO) coatings with properties for low-E coatings that exceed industrial standards (T_visible > 82%; R_{2500 nm} > 90%; λ_(plasma) = 1290 nm; ρ = 4.7 × 10⁻⁴ Ω cm; R_sh = 9.4 Ω·□⁻¹) are deposited through a sustainable and environmentally friendly halogen-free deposition route from [Ga(acac)₃] and a pre-organized zinc oxide precursor [EtZnOⁱPr]₄ (1) via single-pot aerosol-assisted chemical vapor deposition. GZO films are highly (002)-textured, smooth and compact without need of epitaxial growth. The method herein describes the synthesis of coatings with opto-electronic properties commonly achievable only through high-vacuum methods, and provides an alternative to the use of pyrophoric ZnEt₂ and halogenated SnO₂ coatings currently used in low-emission glazing and photovoltaic technology.

A pre-organised and halogen-free ZnO precursor is used to deposit GZO coatings via aerosol-assisted CVD with properties that exceed industrial standards for low-E coatings and photovoltaics.     

Uncovering an oxide ion substitution for the OH− + CH3F reaction

Theoretical investigations on chemical reactions allow us to understand the dynamics of the possible pathways and identify new unexpected routes. Here, we develop a global analytical potential energy surface (PES) for the OH⁻ + CH₃F reaction in order to perform high-level dynamics simulations. Besides bimolecular nucleophilic substitution (S_N2) and proton abstraction, our quasi-classical trajectory computations reveal a novel oxide ion substitution leading to the HF + CH₃O⁻ products. This exothermic reaction pathway occurs via the CH₃OH⋯F⁻ deep potential well of the S_N2 product channel as a result of a proton abstraction from the hydroxyl group by the fluoride ion. The present detailed dynamics study of the OH⁻ + CH₃F reaction focusing on the surprising oxide ion substitution demonstrates how incomplete our knowledge is of fundamental chemical reactions.

Reaction dynamics simulations on a high-level ab initio analytical potential energy surface reveal a novel oxide ion substitution channel for the OH⁻ + CH₃F reaction.