Catalyst control of selectivity in the C–O bond alumination of biomass derived furans

Non-catalysed and catalysed reactions of aluminium reagents with furans, dihydrofurans and dihydropyrans were investigated and lead to ring-expanded products due to the insertion of the aluminium reagent into a C–O bond of the heterocycle. Specifically, the reaction of [{(ArNCMe)₂CH}Al] (Ar = 2,6-di-iso-propylphenyl, 1) with furans proceeded between 25 and 80 °C leading to dearomatised products due to the net transformation of a sp² C–O bond into a sp² C–Al bond. The kinetics of the reaction of 1 with furan were found to be 1st order with respect to 1 with activation parameters ΔH^‡ = +19.7 (±2.7) kcal mol⁻¹, ΔS^‡ = −18.8 (±7.8) cal K⁻¹ mol⁻¹ and ΔG^‡_{298 K} = +25.3 (±0.5) kcal mol⁻¹ and a KIE of 1.0 ± 0.1. DFT calculations support a stepwise mechanism involving an initial (4 + 1) cycloaddition of 1 with furan to form a bicyclic intermediate that rearranges by an α-migration. The selectivity of ring-expansion is influenced by factors that weaken the sp² C–O bond through population of the σ*-orbital. Inclusion of [Pd(PCy₃)₂] as a catalyst in these reactions results in expansion of the substrate scope to include 2,3-dihydrofurans and 3,4-dihydropyrans and improves selectivity. Under catalysed conditions, the C–O bond that breaks is that adjacent to the sp²C–H bond. The aluminium(iii) dihydride reagent [{(MesNCMe)₂CH}AlH₂] (Mes = 2,4,6-trimethylphenyl, 2) can also be used under catalytic conditions to effect a dehydrogenative ring-expansion of furans. Further mechanistic analysis shows that C–O bond functionalisation occurs via an initial C–H bond alumination. Kinetic products can be isolated that are derived from installation of the aluminium reagent at the 2-position of the heterocycle. C–H alumination occurs with a KIE of 4.8 ± 0.3 consistent with a turnover limiting step involving oxidative addition of the C–H bond to the palladium catalyst. Isomerisation of the kinetic C–H aluminated product to the thermodynamic C–O ring expansion product is an intramolecular process that is again catalysed by [Pd(PCy₃)₂]. DFT calculations suggest that the key C–O bond breaking step involves attack of an aluminium based metalloligand on the 2-palladated heterocycle. The new methodology has been applied to important platform chemicals from biomass.

Non-catalysed and catalysed reactions of aluminium reagents with furans, dihydrofurans and dihydropyrans were investigated and lead to ring-expanded products due to the insertion of the aluminium reagent into a C–O bond of the heterocycle.     

Plasmonic O2 dissociation and spillover expedite selective oxidation of primary C–H bonds

Manipulating O₂ activation via nanosynthetic chemistry is critical in many oxidation reactions central to environmental remediation and chemical synthesis. Based on a carefully designed plasmonic Ru/TiO_2−x catalyst, we first report a room-temperature O₂ dissociation and spillover mechanism that expedites the “dream reaction” of selective primary C–H bond activation. Under visible light, surface plasmons excited in the negatively charged Ru nanoparticles decay into hot electrons, triggering spontaneous O₂ dissociation to reactive atomic ˙O. Acceptor-like oxygen vacancies confined at the Ru–TiO₂ interface free Ru from oxygen-poisoning by kinetically boosting the spillover of ˙O from Ru to TiO₂. Evidenced by an exclusive isotopic O-transfer from ¹⁸O₂ to oxygenated products, ˙O displays a synergistic action with native ˙O₂⁻ on TiO₂ that oxidizes toluene and related alkyl aromatics to aromatic acids with extremely high selectivity. We believe the intelligent catalyst design for desirable O₂ activation will contribute viable routes for synthesizing industrially important organic compounds.

Room-temperature O₂ dissociation and spillover, as driven by plasmonic Ru on oxygen-deficient TiO₂, expedite the selective oxidation of primary C–H bonds in alkyl aromatics for synthesizing industrially important organic compounds.     

Characterization and reactivity study of non-heme high-valent iron–hydroxo complexes

A terminal Fe^IIIOH complex, [Fe^III(L)(OH)]²⁻ (1), has been synthesized and structurally characterized (H₄L = 1,2-bis(2-hydroxy-2-methylpropanamido)benzene). The oxidation reaction of 1 with one equiv. of tris(4-bromophenyl)ammoniumyl hexachloroantimonate (TBAH) or ceric ammonium nitrate (CAN) in acetonitrile at −45 °C results in the formation of a Fe^IIIOH ligand radical complex, [Fe^III(L˙)(OH)]⁻ (2), which is hereby characterized by UV-visible, ¹H nuclear magnetic resonance, electron paramagnetic resonance, and X-ray absorption spectroscopy techniques. The reaction of 2 with a triphenylcarbon radical further gives triphenylmethanol and mimics the so-called oxygen rebound step of Cpd II of cytochrome P450. Furthermore, the reaction of 2 was explored with different 4-substituted-2,6-di-tert-butylphenols. Based on kinetic analysis, a hydrogen atom transfer (HAT) mechanism has been established. A pK_a value of 19.3 and a BDFE value of 78.2 kcal/mol have been estimated for complex 2.

One-electron oxidation of an Fe^III–OH complex (1) results in the formation of a Fe^III–OH ligand radical complex (2). Its reaction with (C₆H₅)₃C˙ results in the formation of (C₆H₅)₃COH, which is a functional mimic of compound II of cytochrome P450.     

FLP-type nitrile activation and cyclic ether ring-opening by halo-borane nonagermanide-cluster Lewis acid–base pairs

Even though homoatomic nine-atom germanium clusters are known for two decades, their chemical properties are still rarely investigated. We now discovered that Zintl ion main group-element clusters possess a reactive lone pair of electrons, and we show a new pathway to bind ligands with functional groups to the [Ge₉] cluster core through Ge–C bond formation. We report on the reactivity of [Ge₉{Si(TMS)₃}₂]²⁻ (TMS = trimethylsilyl) towards a series of Lewis acidic bromo-boranes. The reaction of [Ge₉{Si(TMS)₃}₂]²⁻ and DAB^o-tol–Br (DAB = 1,3,2-diazaborolidine; o-tol = 2-methylphenyl) resulted, depending on the reaction protocol, either in the formation of [Ge₉{Si(TMS)₃}₂DAB^o-tol]⁻ (1a) with direct Ge–B interactions, or in [Ge₉{Si(TMS)₃}₂(CH₂)₄O–DAB^o-tol]⁻ (2a) featuring a ring-opened thf moiety. Ring opening reactions occur for all bulkier DAB^R–Br [R: o-xyl (2,6-dimethylphenyl), Mes (2,4,6-trimethylphenyl), Dipp (2,6-diisopropylphenyl)], DAB(ii)^Dipp–Br and acyclic (ⁱPr₂N)₂BBr without Ge–B bond formation as shown for the structural characterization of the ring-opened products of thf (3, 4) and trimethylene oxide (5). In contrast to thf, the activation of CH₃CN requires the simultaneous presence of Lewis-acid and Lewis-basic reactants allowing the formation of [Ge₉{Si(TMS)₃}₂CH₃C N–DAB^Mes]⁻ (6a). Within the presented compounds, 3 and 4 show an unusual substitution pattern of the three ligands at the [Ge₉] core in the solid state. The [Ge₉] cluster/borane systems correspond to intermolecular frustrated Lewis pairs (FLPs), in which the [Ge₉] cluster with several lone pairs represents the Lewis base, and the borane is the Lewis acid.

The reactivity of the lone pairs in polyhedral Zintl anions is shown by the reaction of the bis-silylated cluster [Ge₉{Si(TMS)₃}₂]²⁻ accomplishing cyclic-ether ring-opening or nitrile activation according to a FLP-like mechanism with bromo-boranes.     

Synthesis of unstrained Criegee intermediates: inverse α-effect and other protective stereoelectronic forces can stop Baeyer–Villiger rearrangement of γ-hydroperoxy-γ-peroxylactones

How far can we push the limits in removing stereoelectronic protection from an unstable intermediate? We address this question by exploring the interplay between the primary and secondary stereoelectronic effects in the Baeyer–Villiger (BV) rearrangement by experimental and computational studies of γ-OR-substituted γ-peroxylactones, the previously elusive non-strained Criegee intermediates (CI). These new cyclic peroxides were synthesized by the peroxidation of γ-ketoesters followed by in situ cyclization using a BF₃·Et₂O/H₂O₂ system. Although the primary effect (alignment of the migrating C–R_m bond with the breaking O–O bond) is active in the 6-membered ring, weakening of the secondary effect (donation from the OR lone pair to the breaking C–R_m bond) provides sufficient kinetic stabilization to allow the formation and isolation of stable γ-hydroperoxy-γ-peroxylactones with a methyl-substituent in the C6-position. Furthermore, supplementary protection is also provided by reactant stabilization originating from two new stereoelectronic factors, both identified and quantified for the first time in the present work. First, an unexpected boat preference in the γ-hydroperoxy-γ-peroxylactones weakens the primary stereoelectronic effects and introduces a ∼2 kcal mol⁻¹ Curtin–Hammett penalty for reacquiring the more reactive chair conformation. Second, activation of the secondary stereoelectronic effect in the TS comes with a ∼2–3 kcal mol⁻¹ penalty for giving up the exo-anomeric stabilization in the 6-membered Criegee intermediate. Together, the three new stereoelectronic factors (inverse α-effect, misalignment of reacting bonds in the boat conformation, and the exo-anomeric effect) illustrate the richness of stereoelectronic patterns in peroxide chemistry and provide experimentally significant kinetic stabilization to this new class of bisperoxides. Furthermore, mild reduction of γ-hydroperoxy-γ-peroxylactone with Ph₃P produced an isolable γ-hydroxy-γ-peroxylactone, the first example of a structurally unencumbered CI where neither the primary nor the secondary stereoelectronic effect are impeded. Although this compound is relatively unstable, it does not undergo the BV reaction and instead follows a new mode of reactivity for the CI – a ring-opening process.

Protecting stereoelectronic effects prevent Baeyer–Villiger rearrangement and stabilize γ-OX-γ-peroxylactones (X = H, OH), the previously elusive non-strained Criegee intermediates.     

Fluorescent probe for the imaging of superoxide and peroxynitrite during drug-induced liver injury

Drug-induced liver injury (DILI) is an important cause of potentially fatal liver disease. Herein, we report the development of a molecular probe (LW-OTf) for the detection and imaging of two biomarkers involved in DILI. Initially, primary reactive oxygen species (ROS) superoxide (O₂˙⁻) selectively activates a near-infrared fluorescence (NIRF) output by generating fluorophore LW-OH. The C C linker of this hemicyanine fluorophore is subsequently oxidized by reactive nitrogen species (RNS) peroxynitrite (ONOO⁻), resulting in cleavage to release xanthene derivative LW-XTD, detected using two-photon excitation fluorescence (TPEF). An alternative fluorescence pathway can occur through cleavage of LW-OTf by ONOO⁻ to non-fluorescent LW-XTD-OTf, which can react further with the second analyte O₂˙⁻ to produce the same LW-XTD fluorescent species. By combining NIRF and TPEF, LW-OTf is capable of differential and simultaneous detection of ROS and RNS in DILI using two optically orthogonal channels. Probe LW-OTf could be used to detect O₂˙⁻ or O₂˙⁻ and ONOO⁻ in lysosomes stimulated by 2-methoxyestradiol (2-ME) or 2-ME and SIN-1 respectively. In addition, we were able to monitor the chemoprotective effects of tert-butylhydroxyanisole (BHA) against acetaminophen (APAP) toxicity in living HL-7702 cells. More importantly, TPEF and NIRF imaging confirmed an increase in levels of both O₂˙⁻ and ONOO⁻ in mouse livers during APAP-induced DILI (confirmed by hematoxylin and eosin (H&E) staining).

Drug-induced liver injury (DILI) is an important cause of potentially fatal liver disease.     

Nickel-catalyzed C–O/N–H,C–S/N–H,and C–CN/N–H annulation of aromatic amides with alkynes: C–O,C–S,and C–CN activation

The Ni-catalyzed reaction of ortho-phenoxy-substituted aromatic amides with alkynes in the presence of LiO^tBu as a base results in C–O/N–H annulation with the formation of 1(2H)-isoquinolinones. The use of a base is essential for the reaction to proceed. The reaction proceeds, even in the absence of a ligand, and under mild reaction conditions (40 °C). An electron-donating group on the aromatic ring facilitates the reaction. The reaction was also applicable to carbamate (C–O bond activation), methylthio (C–S bond activation), and cyano (C–CN bond activation) groups as leaving groups.

The Ni-catalyzed reaction of ortho-phenoxy-substituted aromatic amides with alkynes in the presence of LiO^tBu as a base results in C–O/N–H annulation with the formation of 1(2H)-isoquinolinones.     

Tuning phenoxyl-substituted diketopyrrolopyrroles from quinoidal to biradical ground states through (hetero-)aromatic linkers

Strongly fluorescent halochromic 2,6-di-tert-butyl-phenol-functionalised phenyl-, thienyl- and furyl-substituted diketopyrrolopyrrole (DPP) dyes were deprotonated and oxidised to give either phenylene-linked DPP1˙˙ biradical (y₀ = 0.75) with a singlet open shell ground state and a thermally populated triplet state (ΔE_ST = 19 meV; 1.8 kJ mol⁻¹; 0.43 kcal mol⁻¹) or thienylene/furylene-linked DPP2q and DPP3q compounds with closed shell quinoidal ground states. Accordingly, we identified the aromaticity of the conjugated (hetero-)aromatic bridge to be key for modulating the electronic character of these biradicaloid compounds and achieved a spin crossover from closed shell quinones DPP2q and DPP3q to open shell biradical DPP1˙˙ as confirmed by optical and magnetic spectroscopic studies (UV/vis/NIR, NMR, EPR) as well as computational investigations (spin-flip TD-DFT calculations in combination with CASSCF(4,4) and harmonic oscillator model of aromaticity (HOMA) analysis). Spectroelectrochemical studies and comproportionation experiments further prove the reversible formation of mixed-valent radical anions for the DPP2q and DPP3q quinoidal compounds with absorption bands edging into the NIR spectral region.

By variation of spacer aromaticity, a spin crossover from thienylene/furylene-linked quinones DPP2q/DPP3q to phenylene-bridged biradical DPP1˙˙ (y₀ = 0.75) with a singlet open shell ground state (ΔE_ST = 19 meV) was achieved.     

Magnesium–halobenzene bonding: mapping the halogen sigma-hole with a Lewis-acidic complex

Complexes of the Lewis base-free cations (^MeBDI)Mg⁺ and (^tBuBDI)Mg⁺ with Ph–X ligands (X = F, Cl, Br, I) have been studied (^MeBDI = HC[C(Me)N-DIPP]₂ and ^tBuBDI = HC[C(tBu)N-DIPP]₂; DIPP = 2,6-diisopropylphenyl). For the smaller β-diketiminate ligand (^MeBDI) only complexes with PhF could be isolated. Heavier Ph–X ligands could not compete with bonding of Mg to the weakly coordinating anion B(C₆F₅)₄⁻. For the cations with the bulkier ^tBuBDI ligand, the full series of halobenzene complexes was structurally characterized. Crystal structures show that the Mg⋯X–Ph angle strongly decreases with the size of X: F 139.1°, Cl 101.4°, Br 97.7°, I 95.1°. This trend, which is supported by DFT calculations, can be explained with the σ-hole which increases from F to I. Charge calculation and Atoms-In-Molecules analyses show that Mg⋯F–Ph bonding originates from electrostatic attraction between Mg²⁺ and the very polar C^δ+–F^δ− bond. For the heavier halobenzenes, polarization of the halogen atom becomes increasingly important (Cl < Br < I). Complexation with Mg leads in all cases to significant Ph–X bond activation and elongation. This unusual coordination of halogenated species to early main group metals is therefore relevant to C–X bond breaking.

Complexes of a highly Lewis acidic Mg cation and the full series of Ph–X (X = F, Cl, Br, I) have been structurally characterized. The Mg⋯X–Ph angle decreases with halogen size on account of the growing halogen σ-hole.     

Characterization and chemical reactivity of room-temperature-stable MnIII–alkylperoxo complexes

While alkylperoxomanganese(iii) (Mn^III–OOR) intermediates are proposed in the catalytic cycles of several manganese-dependent enzymes, their characterization has proven to be a challenge due to their inherent thermal instability. Fundamental understanding of the structural and electronic properties of these important intermediates is limited to a series of complexes with thiolate-containing N₄S⁻ ligands. These well-characterized complexes are metastable yet unreactive in the direct oxidation of organic substrates. Because the stability and reactivity of Mn^III–OOR complexes are likely to be highly dependent on their local coordination environment, we have generated two new Mn^III–OOR complexes using a new amide-containing N₅⁻ ligand. Using the 2-(bis((6-methylpyridin-2-yl)methyl)amino)-N-(quinolin-8-yl)acetamide (H^6Medpaq) ligand, we generated the [Mn^III(OO^tBu)(^6Medpaq)]OTf and [Mn^III(OOCm)(^6Medpaq)]OTf complexes through reaction of their Mn^II or Mn^III precursors with ^tBuOOH and CmOOH, respectively. Both of the new Mn^III–OOR complexes are stable at room-temperature (t_1/2 = 5 and 8 days, respectively, at 298 K in CH₃CN) and capable of reacting directly with phosphine substrates. The stability of these Mn^III–OOR adducts render them amenable for detailed characterization, including by X-ray crystallography for [Mn^III(OOCm)(^6Medpaq)]OTf. Thermal decomposition studies support a decay pathway of the Mn^III–OOR complexes by O–O bond homolysis. In contrast, direct reaction of [Mn^III(OOCm)(^6Medpaq)]⁺ with PPh₃ provided evidence of heterolytic cleavage of the O–O bond. These studies reveal that both the stability and chemical reactivity of Mn^III–OOR complexes can be tuned by the local coordination sphere.

A pair of room-temperature-stable Mn^III–alkylperoxo complexes were characterized and shown to oxidize PPh₃. Thermal decomposition studies provide evidence of both homolysis and heterolysis of the Mn^III–alkylperoxo O–O bond.     

Triarylamine-based porous coordination polymers performing both hydrogen atom transfer and photoredox catalysis for regioselective α-amino C(sp3)–H arylation

Direct functionalization of C(sp³)–H bonds in a predictable, selective and recyclable manner has become a central challenge in modern organic chemistry. Through incorporating different triarylamine-containing ligands into one coordination polymer, we present herein a heterogeneous approach to the combination of hydrogen atom transfer (HAT) and photoredox catalysis for regioselective C–H arylation of benzylamines. The different molecular sizes and coordination modes of the ligands, tricarboxytriphenylamine (H₃TCA) and tris(4-(pyridinyl)phenyl)amine (NPy3), in one coordination polymer consolidate the triarylamine (Ar₃N) moiety into a special structural intermediate, which enhances the chemical and thermal stability of the polymers and diminishes structural relaxation during the catalytic process. The inherent redox potentials of Ar₃N moieties prohibit the in situ formed Ar₃N˙⁺ to earn an electron from C(sp³)–H nucleophiles, but allow the abstraction of a hydrogen atom from C(sp³)–H nucleophiles, enabling the formation of the C(sp³)˙ radical and the cross-coupling reaction to proceed at the most electron-rich sites with excellent regioselectivity. The new heterogeneous photoredox HAT approach skips several interactions between transient species during the typical synergistic SET/HAT cycles, demonstrating a promising redox-economical and reagent-economical heterogeneous platform that has not been reported for α-amino C–H arylation to form benzylamine derivatives. Control experiments based on monoligand coordination polymers suggested that the mixed-ligand approach improved the photochemical and photophysical properties, providing important insight into rational design and optimization of recyclable photocatalysts for rapid access to complex bioactive molecules and late-stage functionalized pharmaceuticals.

The efficiency of photosensitization and hydrogen atom transfer (HAT) catalysis is balanced in a recyclable heterogeneous manner by the modification of the N-central conformation in Cd-MIX.     

Boron tribromide as a reagent for anti-Markovnikov addition of HBr to cyclopropanes

Although radical formation from a trialkylborane is well documented, the analogous reaction mode is unknown for trihaloboranes. We have discovered the generation of bromine radicals from boron tribromide and simple proton sources, such as water or tert-butanol, under open-flask conditions. Cyclopropanes bearing a variety of substituents were hydro- and deuterio-brominated to furnish anti-Markovnikov products in a highly regioselective fashion. NMR mechanistic studies and DFT calculations point to a radical pathway instead of the conventional ionic mechanism expected for BBr₃.

Anti-Markovnikov hydrobromination of cyclopropanes was achieved using boron tribromide and water as the bromine and proton sources, respectively.

The Lewis acidic nature of organoboranes is well understood, but the participation of BR₃ in free-radical processes was largely overlooked until 1966.¹ Since the discovery of the potential of organoborane species to undergo radical reactions, many novel and synthetically useful transformations were developed.² Trialkylboranes (BR₃) can easily undergo bimolecular homolytic substitution (S_H2) at the boron atom to generate alkyl radicals (Scheme 1A). It was found that alkoxyl, dialkylaminyl, alkylthiyl and carbon-centered radicals, triplet ketones, and triplet oxygen can all initiate the radical reaction by substituting one of the alkyl groups of trialkylboranes to liberate alkyl radicals.³ BEt₃/O₂ is arguably the most studied organoborane radical-initiating system, with the peroxyl radical being the key to propagate the reaction. Apart from being a radical initiator, BEt₃, along with trace amount of O₂, can also undergo conjugate addition to unsaturated ketones and aldehydes; addition to ethenyl- and ethynyloxiranes, azidoalkenes, and imines; and addition–elimination to nitroalkenes and nitroarenes, styryl sulfones, sulfoxides and sulfinimides.³ However, apart from changing BEt₃ to other trialkylboranes or catecholborane to carry out similar radical reactions, the radical-reaction potential of other organoboranes remains underexplored, given the ease and mild conditions under which they initiate radical chains, often with trace amount of O₂ in air at low temperature. The application of such a mild radical-initiation system to stereoselective radical reactions would drastically change the reaction outcome especially when intermediates and products are thermally unstable.⁴Open in a separate windowScheme 1Classical radical reactions with trialkylboranes and our work on radical bromination using BBr₃.Halogenation is an important class of transformations and the resultant halogenated products can easily be manipulated to give a wide range of functional molecules.⁵ While trihaloboranes have been employed as halogenating or haloborating agents, their role in reactions is either ambiguous or thought to be exclusively Lewis acidic.⁶ To date, the use of trihaloboranes as a halogen radical donor has not been reported. With BR₃/O₂ being a versatile radical-initiator and conjugate-addition system, we envisioned that a suitable halogenated-borane might work similar to that of trialkylboranes in the generation of reactive, yet stable enough halogen radicals for selective halogenation reactions (Scheme 1B).Trialkylboranes readily undergo S_H2 reactions because the formation of stronger B–X (e.g. B–O) bonds via substitution is highly exothermic.³ The BDEs (B–C) of BMe₃, BEt₃, BⁿPr₃, BⁱPr₃, and BⁿBu₃ range from 344 to 354 kJ mol⁻¹ at 298 K, while their typical autoxidation products, B(OH)₃, B(OMe)₃, and B(OEt)₃, have BDEs (B–O) ranging from 519 to 522 kJ mol⁻¹ at 298 K.⁷ We hypothesized that organohaloboranes (BX_aR_3−a, X = halogen) with BDEs (B–X) similar to trialkylboranes would be a halogen radical donor from a thermodynamic viewpoint. As the common trihaloboranes (BX₃) BF₃, BCl₃ and BBr₃ have BDEs (B–X) of 644.3, 442.3 and 367.1 kJ mol⁻¹ at 298 K, respectively, BBr₃ was the logical option for our purpose.⁸ Although the BDE (B–I) of BI₃ is the lowest among all trihaloboranes and found to be 278.2 kJ mol⁻¹ at 0 K,⁹ it was not considered suitable as I₂ has proven to be a very efficient radical quencher in such reactions,¹⁰ and even rigorously purified BI₃ invariably contains a trace amount of I₂.¹¹Compared to activated cyclopropanes,¹² oxidative functionalization of unactivated cyclopropanes gives a wide range of useful molecules that are otherwise not readily accessible, and protocols for the Markovnikov-selective functionalization of unactivated cyclopropanes have been reported.^13–20 Halolyses of cyclopropanes to give 1,3-dihaloalkanes by molecular halogens are also documented although the reactions commonly suffer from the formation of side products via electrophilic aromatic halogenation.²¹ In contrast, obtaining products with anti-Markovnikov regioselectivity has been considered as one of the top challenges in industry.^22–30 Anti-Markovnikov functionalization of unactivated cyclopropanes mostly relies on photo-initiated radical processes with generally poor regioselectivity and limited scope.^31–36 To the best of our knowledge, anti-Markovnikov hydrohalogenation of cyclopropanes has not been reported.Very recently, an anti-Markovnikov hydroboration for unactivated cyclopropanes has been reported using boron tribromide and phenylsilane.³⁷ The reaction was carried out under inert and anhydrous conditions, and mechanistic studies pointed to an ionic mechanism with Lewis acid–base interactions. We show that with a simple twist in the reaction conditions, which is to introduce oxygen, a drastically different reaction outcome and mechanism could be realized. We now report the study and application of BBr₃ as a radical Br donor for the anti-Markovnikov addition of HBr to cyclopropanes.With all these considerations in mind, we initially envisioned that BBr₃/O₂ as a suitable system to generate bromine radicals, and cyclopropylbenzene (1a) as the model substrate to capture them. The radical reaction might then be terminated by another halogen radical from reagents such as N-chlorosuccinimide or N-iodosuccinimide. Unfortunately, messy mixtures were obtained for all entries (see the ESI, Scheme S1^†). On the other hand, a simple proton source, H₂O, was found to be effective in terminating the radical species. In the control experiment with only BBr₃ and cyclopropylbenzene (1a) (Scheme 2, entry 1), the anti-Markovnikov hydrobrominated product 2a was obtained in 24% yield, together with the formation of Markovnikov product 3a (trace) and dibrominated cyclopropane 4a (11%). We reasoned that the proton source was the trace amount of moisture in commercial BBr₃ solution.Open in a separate windowScheme 2Reaction optimization. Conditions: reactions were carried out under ambient conditions and quenched by saturated NaHCO₃ solution. Yields were measured by ¹H NMR with CH₂Br₂ as the internal standard. ^a24% of 1a was recovered. ^b6% of 1a was recovered.Although it is well known that boron-based Lewis acids are moisture sensitive,³⁸ counter-intuitively, the addition of 1.5 equivalents of H₂O had a positive impact on the yield of 2a, which was dramatically improved to 80% (Scheme 2, entry 2). Excess water led to a reduction in the yield of 2a and the regioselectivity (Scheme 2, entry 3). Replacing water with ethanol as the proton source resulted in a significant drop in reaction efficiency (Scheme 2, entry 4). In contrast, bulkier alcohols such as i-PrOH or t-BuOH (Scheme 2, entries 5 and 6) and less nucleophilic alcohols such as CF₃CH₂OH (Scheme 2, entry 7) gave comparable performance to that of water.Further study revealed that achieving anti-Markovnikov addition of HBr to cyclopropanes in conventional systems is not a trivial task (Scheme 3). For instance, no reaction was observed when 1a was treated with HBr in either aqueous or water/AcOH co-solvent systems at room temperature.²⁹ Heating both reactions only yielded the Markovnikov product 3a in 16–23% yield, and no anti-Markovnikov product 2a was detected. The classical radical bromination protocol with BBr₃/H₂O₂ only furnished dibrominated product 4a in 29% yield. Similar to the uniqueness of BR₃/O₂ in several aforementioned radical reactions,⁴ the incapability of these control experiments in producing 2a as a product contrasted starkly with our BBr₃/O₂ conditions, which generated a reactive yet selective bromine radical.Open in a separate windowScheme 3Reactions of cyclopropane (1a) with hydrobromic acid.Next, we expanded the substrate scope to other unactivated cyclopropanes using either water or t-BuOH as the proton source (Scheme 4). Electron-neutral, deficient and sterically bulky substrates 1a–1g gave the desired anti-Markovnikov products 2a–2g in good yields and regioselectivity. Cyclopropanes with electron-deficient substituents including nitriles (1j–n) and ester (1o) also worked well with excellent regioselectivity. This protocol also exhibits high chemoselectivity towards cyclopropanes. Aryl methyl ether (2i), which is known to be easily cleaved by BBr₃ even at low temperature, remained intact under our reaction conditions.³⁹ Due to the tendency of aryl vinyl ketones to polymerize, they are known to be unsuitable for 1,4-conjugate additions mediated by trialkylboranes.⁴⁰ Nevertheless, aryl cyclopropyl ketones (1h–i) were converted into the corresponding products in high yields, and polymerization was not observed. 1,1-Disubstituted (1p) and simple alkyl (1q) cyclopropanes were also compatible to give products 2p and 2q. When cyclopropyl carboxylic acid (1r) was used as the substrate, the unstable product 2r was detected using HRMS and crude ¹H NMR, and γ-butyrolactone was obtained ultimately through cyclization upon a basic work-up procedure. Indene-derived cyclopropyl substrate 1s was also compatible to give 2s. Scaled-up reactions were also performed on selected examples (2a, 2h, 2o, and 2r) and excellent regioselectivities were still obtained.Open in a separate windowScheme 4Reaction scope of anti-Markovnikov hydrobromination of cyclopropanes. Conditions: reactions were carried out with 1 (0.2 mmol) unless stated otherwise. Exact reaction conditions for each substrate are stated in the ESI.^†at-BuOH was used as the proton source. ^bH₂O was used as the proton source. ^c4% of 3b was detected. ^d5% of 3c was detected. ^e7% of 3b was detected. ^fThe reaction was conducted on a 1 mmol scale. ^gThe reaction was conducted on a 2 mmol scale. ^hThe product cyclized quickly upon work-up and the yield was measured on the basis of the cyclized product γ-butyrolactone.Cyclopropanes 1t–1y with secondary and tertiary alcohols also gave the corresponding anti-Markovnikov products in excellent yields and with high regioselectivities (Scheme 5). The structure of 2x was confirmed unambiguously by X-ray crystallography.⁴¹ The hydroxyl groups in the substrates were converted into bromides simultaneously by the action of BBr₃ to give a series of useful dibromides.⁴² We were interested in whether alcohol-containing substrates can be hydrobrominated in the absence of an external proton source. To our delight, 1t was able to undergo anti-Markovnikov hydrobromination to give 2t with only a slight drop in yield (76%), and 2u was produced in quantitative yield. The hydroxyl groups in 1x and 1y appear to be crucial because a sluggish reaction was observed for 1-phenyl-2-methylcyclopropane that bears no hydroxyl substituent.Open in a separate windowScheme 5Reaction scope of anti-Markovnikov hydrobromination of cyclopropanes with hydroxyl substituents. Conditions: reactions were carried out with 1 (0.2 mmol). Exact reaction conditions for each substrate are stated in the ESI.^†aReaction was conducted in the absence of water. ^bDiastereoselectivity was determined by a ¹H NMR experiment on the crude mixture.By substituting H₂O and t-BuOH with D₂O and t-BuOD, deuteriobrominations were also carried out and the corresponding mono-deuterium-labeled compounds were obtained smoothly (Scheme 6). Our protocol offered excellent regio-control in the mono-deuteriation to give 2-D. Unactivated (1a and 1e) and activated cyclopropanes (1j–k, 1m, and 1o) with various substituents worked well and excellent levels of deuterium incorporation were achieved.Open in a separate windowScheme 6Reaction scope of anti-Markovnikov deuteriobromination of cyclopropanes. Conditions: reactions were carried out with 1 (0.2 mmol) unless stated otherwise. Exact reaction conditions for each substrate are stated in the ESI.^†aThe % D incorporation was determined based on the integration of the residual proton signal in ¹H NMR. ^bThe reaction was conducted on a 1 mmol scale. ^ct-BuOH was used as the deuterium source. ^dD₂O was used as the deuterium source.The conversion of products 2 into primary alcohols and amines through nucleophilic substitution proved straightforward. For instance, alcohol 5a and amine 5b were readily prepared from 2a with high conversion (Scheme 7). As the direct synthesis of primary alcohols and amines through anti-Markovnikov hydration and hydroamination has proven to be challenging,²² our protocol provides useful precursors for the synthesis of these highly desired compounds.Open in a separate windowScheme 7Synthetic utilities of 2a.We envision a radical reaction pathway between BBr₃ and O₂, but given the Lewis acidity of BBr₃ and Lewis basicity of H₂O and alcohols, an acid-mediated pathway cannot be ruled out.³⁸ However, such a pathway appears highly unlikely, as the treatment of cyclopropanes with aqueous HBr yielded no anti-Markovnikov product 2 (Scheme 3). Several control experiments were performed to further probe the reaction mechanism.The addition of a radical scavenger, BHT or TEMPO, in slight excess of BBr₃ completely shut down the formation of anti-Markovnikov product 2a, and a significant amount of Markovnikov product 3a was detected (Scheme 8A). The addition of the acceptor olefin acrylonitrile completely suppressed the reaction. The absence of light had no impact on the reaction, thereby eliminating the possibility of a photo-triggered pathway. The presence of oxygen was crucial for both the yield and the regioselectivity. The reaction proceeded smoothly to give the desired product 2a (80%) in open air. In contrast, the yield of anti-Markovnikov product 2a dropped to 14% and that of the Markovnikov product 3a increased to 17% when the reaction was conducted with degassed CH₂Cl₂ and 1a. Deuteriobromination of 1g was also conducted with t-BuOD as the deuterium source (Scheme 8B). Other than the benzylic deuteriation product 2g-D (25%), a substantial amount of 2g-D′ (75%) was obtained. In contrast, no aromatic deuteriation was observed when phenanthrene (6) was used as the substrate under the same conditions. The formation of 2g-D′ could be attributed to the isomerization of benzylic radical species (also see the ESI, Fig. S1^†). This preliminary evidence pointed at a radical mechanism, although a carbocation intermediate cannot be ruled out completely.Open in a separate windowScheme 8Control experiments.Consistent with literature reports on BR₃,^43,44 the reactivity of BBr₃ towards homolytic debromination decreases sharply along the series BBr₃, BBr₂OR, and BBr(OR)₂ as a consequence of π-bonding between oxygen and boron. With 0.5 equiv BBr₃, only 21% of 2a was obtained even with a prolonged reaction time of 24 h. These data indicated that only the first equivalent of Br from BBr₃ is crucial for the reactivity, and contribution from the possible BBr_a(OR)_3−a byproducts should be insignificant.A series of ¹H and ¹¹B NMR experiments were conducted to gain further insight. Upon mixing BBr₃ with 1a in the absence of O₂ and a proton source, both 1a and BBr₃ were mostly consumed, and a new ¹¹B signal at 64 ppm (see the ESI, Fig. S2^†) emerged as a singlet, which is characteristic of an alkyldihaloborane species.^45,46 From ¹H NMR, it is clear that 1a is ring-opened (see the ESI, Fig. S4^†), and the species has a similar NMR pattern to a hydroborated cyclopropane, which has been reported as a reaction intermediate in literature examples (see the ESI, Fig. S3^†).³⁷ Direct bromoboration of alkynes or allenes with BBr₃ is well documented.^47,48 While this new species cannot be clearly identified, it is speculated that it could be the direct bromoboration product or hydroxyboration product. Nevertheless, it is clear that the interaction between BBr₃ and 1a does not lead to the anti-Markovnikov product 2a in the absence of O₂ and a proton source.When i-PrOH and BBr₃ were mixed in CD₂Cl₂ under air, the ¹¹B signal of BBr₃ (39 ppm) disappeared and a new signal at 25.0 ppm emerged. A new proton signal at −2.68 ppm also appeared in the ¹H NMR study of the same sample. The two new signals (25.0 ppm in ¹¹B NMR and −2.68 ppm in ¹H NMR) diminished gradually upon the addition of 1a and the amount of anti-Markovnikov product 2a increased accordingly (see the ESI, Fig. S5^†). On the other hand, a new ¹¹B NMR signal at 18.9 ppm (but no signal at 25.0 ppm) was observed when the same mixture was prepared in the absence of O₂ and attributed to the formation of the Lewis adduct between i-PrOH and BBr₃ (see the ESI, Fig. S6^†). Thus, it is reasonable to propose that the active species, responsible for initiating the anti-Markovnikov hydrobromination of cyclopropanes, was formed only in the presence of O₂.A DFT computational study was also performed to shed light on the mechanism (Fig. 1). While there are no reports on radical reactions triggered by BBr₃/O₂, we speculate that the reaction mechanism might be analogous to the classical BR₃/O₂ system in which the putative peroxy-boron species A is generated⁴⁹ at the initiation stage of the radical process (Fig. 1A) and corresponds to the new NMR signals (25.0 ppm in ¹¹B NMR and −2.68 ppm in ¹H NMR).^3,50,51 Based on the calculated energy profile, species A is capable of brominating cyclopropane 1a through a radical mechanism to give B (Fig. 1B). It is also calculated that A and A′ could be in equilibrium, but species A (ΔG = −7.6 kcal mol⁻¹) was found to be a more competent Br donor than A′ (ΔG = 0.6 kcal mol⁻¹) in the halogen atom transfer (XAT), potentially due to the intramolecular hydrogen bond that stabilizes the by-product I (Fig. 1C). It was also calculated that BBr₃ can reversibly react with water to give adduct C (¹¹B NMR signal = 18.9 ppm). Species C is unable to serve as a Br radical donor to brominate cyclopropane 1a (ΔG = 69.6 kcal mol⁻¹).Open in a separate windowFig. 1Reaction mechanism. (A) Plausible reaction pathways. (B) Calculated free energy profile of the anti-Markovnikov hydrobromination of 1a at the ωB97X-D/6-311++G(d,p), SMD(CH₂Cl₂)//ωB97X-D/6-31+G(d,p) level of theory. (C) Potential competing pathways.However, species C is capable of acting as a hydrogen radical donor to species B, furnishing the desired product 2a. This result is in alignment with the proposal in the literature in which trialkylborane-ROH complexes (R = H, Me) might act as H-donors as a result of the weakened O–H bond.⁵² Species D, which is formed from species C after the hydrogen atom transfer (HAT), was calculated to be a competent Br radical donor to brominate cyclopropane 1a to give B, thereby propagating the radical chain. Thus, we propose that oxygen is required only in the initiation stage for the generation of species A, while species C and D are responsible for propagation. Indeed, the reaction was sluggish under an inert atmosphere, while the re-introduction of oxygen into a system initially free of oxygen triggered the anti-Markovnikov hydrobromination (see the ESI, Scheme S2^†). The HAT from species A to 1a was also explored computationally, but species A could not be optimized as a stable energy minimum. Species C may also serve as a hydrogen radical donor and react with cyclopropane 1a to give species D and E, which would go on to produce the Markovnikov product 3a. However, this hydrogen atom transfer reaction is endergonic by 31.2 kcal mol⁻¹ (Fig. 1C), making it a minor pathway compared to the competing hydrogen atom transfer from C to B that gives D and 2a (Fig. 1A). This result is consistent with the experimental observation that the Markovnikov product 3a became dominant when the reaction was conducted under an inert atmosphere (Scheme 8A).In the ¹H NMR study of the reaction using 1a, apart from 2a, 3a and 4a (Scheme 2), a trace amount of allylbenzene was detected initially and diminished over time. We speculate that the allylbenzene (Fig. 1A, species G) might be formed through the zwitterionic species F as proposed in the recent studies by Wang and Shi.^37,53 The eventual disappearance of allylbenzene could be attributed to the radical bromination to give species H and the subsequent formation of 2a.In a deuterium labeling experiment with 1a as the substrate and D₂O as the deuterium source, we observed exclusive deuterium incorporation at the benzylic carbon to give product 2a-D, potentially through the C(1) radical species B1 (Scheme 9, eqn (1)). However, the deuterium incorporation pattern is vastly different when using allylbenzene instead of 1a, for which C(2) deuterated product 2a-D′ was obtained predominately (Scheme 9, eqn (2)) (also see the ESI, Fig. S7^†). The formation of 2a-D′ from allylbenzene may proceed through the C(2) radical species H1. A small amount of 2a-D (9%) was also detected in the reaction with allylbenzene, attributed to the slow 1,2-hydrogen shift⁵⁴ converting H1 to the more stable benzylic radical B1. These results suggest that the 1,2-hydrogen shift between the radical species H and B (Fig. 1A) should be much slower than the radical protonation process, implying that allylbenzene is unlikely to be the key intermediate in the reaction.Open in a separate windowScheme 9Mechanistic insights from deuteriobromination.     

Trioxatriangulenium (TOTA+) as a robust carbon-based Lewis acid in frustrated Lewis pair chemistry

We report the reactivity between the water stable Lewis acidic trioxatriangulenium ion (TOTA⁺) and a series of Lewis bases such as phosphines and N-heterocyclic carbene (NHC). The nature of the Lewis acid–base interaction was analyzed via variable temperature (VT) NMR spectroscopy, single-crystal X-ray diffraction, UV-visible spectroscopy, and DFT calculations. While small and strongly nucleophilic phosphines, such as PMe₃, led to the formation of a Lewis acid–base adduct, frustrated Lewis pairs (FLPs) were observed for sterically hindered bases such as P(^tBu)₃. The TOTA⁺–P(^tBu)₃ FLP was characterized as an encounter complex, and found to promote the heterolytic cleavage of disulfide bonds, formaldehyde fixation, dehydrogenation of 1,4-cyclohexadiene, heterolytic cleavage of the C–Br bonds, and interception of Staudinger reaction intermediates. Moreover, TOTA⁺ and NHC were found to first undergo single-electron transfer (SET) to form [TOTA]·[NHC]˙⁺, which was confirmed via electron paramagnetic resonance (EPR) spectroscopy, and subsequently form a [TOTA–NHC]⁺ adduct or a mixture of products depending the reaction conditions used.

Frustration at carbon! Herein, we present a frustrated Lewis pair system derived from a water stable carbon-based Lewis acid, trioxatriangulene (TOTA⁺), and a variety of Lewis bases, which successfully promotes bond cleavage and molecule fixation.     

Manganese vacancy-confined single-atom Ag in cryptomelane nanorods for efficient Wacker oxidation of styrene derivatives

Single-atom catalysts provide a pathway to elucidate the nature of catalytically active sites. However, keeping them stabilized during operation proves to be challenging. Herein, we employ cryptomelane-type octahedral molecular sieve nanorods featuring abundant manganese vacancy defects as a support, to periodically anchor single-atom Ag. The doped Ag atoms with tetrahedral coordination are found to locate at cation substitution sites rather than being supported on the catalyst surface, thus effectively tuning the electronic structure of adjacent manganese atoms. The resulting unique Ag–O–MnO_x unit functions as the active site. Its turnover frequency reaches 1038 h⁻¹, one order of magnitude higher than for previously reported catalysts, with 90% selectivity for anti-Markovnikov phenylacetaldehyde. Mechanistic studies reveal that the activation of styrene on the ensemble site of Ag–O–MnO_x is significantly promoted, which can accelerate the oxidation of styrene and, in particular, the rate-determining step of forming the epoxide intermediate. Such an extraordinary electronic promotion can be extended to other single-atom catalysts and paves the way for their practical applications.

Manganese vacancy-confined single-atom Ag in cryptomelane nanorods efficiently catalyses Wacker oxidation of styrene derivatives.     

Ion-molecule reactions catalyzed by a single gold atom

We report that Au atoms within van der Waals complexes serve as catalysts for the first time. This was observed in ionization-induced chemistry of 1,6-hexanediol–Au and 1,8-octanediol–Au complexes formed in superfluid helium nanodroplets, where the addition of Au atom(s) made C₂H₄⁺ the sole prominent product in dissociative reactions. Density functional theory (DFT) calculations showed that the Au atom significantly strengthens all of the C–C bonds and weakens the C–O bonds in the meantime, making the C–C bonds stronger than the two C–O bonds in the ionized complexes. This leads to a preferential cleavage of the C–O bonds and thus a strong catalytic effect of the Au atoms in the reactions.

Single Au atoms within van der Waals complexes are found to serve as catalysts in ionisation-induced chemistry for the first time.     

Iron-catalyzed α-C–H functionalization of π-bonds: cross-dehydrogenative coupling and mechanistic insights

The deprotonation of propargylic C–H bonds for subsequent functionalization typically requires stoichiometric metal alkyl or amide reagents. In addition to the undesirable generation of stoichiometric metallic waste, these conditions limit the functional group compatibility and versatility of this functionalization strategy and often result in regioisomeric mixtures. In this article, we report the use of dicarbonyl cyclopentadienyliron(ii) complexes for the generation of propargylic anion equivalents toward the direct electrophilic functionalization of propargylic C–H bonds under mild, catalytic conditions. This technology was applied to the direct conversion of C–H bonds to C–C bonds for the synthesis of several functionalized scaffolds through a one-pot cross dehydrogenative coupling reaction with tetrahydroisoquinoline and related privileged heterocyclic scaffolds. A series of NMR studies and deuterium-labelling experiments indicated that the deprotonation of the propargylic C–H bond was the rate-determining step when a Cp*Fe(CO)₂-based catalyst system was employed.

[Cp*Fe(CO)₂]⁺ facilitates the α-deprotonation of unsaturated C–C bond for propargylic and allylic C–H functionalization. Mechanistic studies reveal insights into the superior performance of the electron-rich and hindered ligand on iron.     

Ni(0)-promoted activation of Csp2–H and Csp2–O bonds

A dinickel(0)–N₂ complex, stabilized with a rigid acridane-based PNP pincer ligand, was studied for its ability to activate C(sp²)–H and C(sp²)–O bonds. Stabilized by a Ni–μ–N₂–Na⁺ interaction, it activates C–H bonds of unfunctionalized arenes, affording nickel–aryl and nickel–hydride products. Concomitantly, two sodium cations get reduced to Na(0), which was identified and quantified by several methods. Our experimental results, including product analysis and kinetic measurements, strongly suggest that this C(sp²)–H activation does not follow the typical oxidative addition mechanism occurring at a low-valent single metal centre. Instead, via a bimolecular pathway, two powerfully reducing nickel ions cooperatively activate an arene C–H bond and concomitantly reduce two Lewis acidic alkali metals under ambient conditions. As a novel synthetic protocol, nickel(ii)–aryl species were directly synthesized from nickel(ii) precursors in benzene or toluene with excess Na under ambient conditions. Furthermore, when the dinickel(0)–N₂ complex is accessed via reduction of the nickel(ii)–phenyl species, the resulting phenyl anion deprotonates a C–H bond of glyme or 15-crown-5 leading to C–O bond cleavage, which produces vinyl ether. The dinickel(0)–N₂ species then cleaves the C(sp²)–O bond of vinyl ether to produce a nickel(ii)–vinyl complex. These results may provide a new strategy for the activation of C–H and C–O bonds mediated by a low valent nickel ion supported by a structurally rigidified ligand scaffold.

A structurally rigidified nickel(0) complex was found to be capable of cleaving both C(sp²)–H and C(sp²)–O bonds.     

Ruthenium-catalyzed cascade C–H activation/annulation of N-alkoxybenzamides: reaction development and mechanistic insight

A highly selective ruthenium-catalyzed C–H activation/annulation of alkyne-tethered N-alkoxybenzamides has been developed. In this reaction, diverse products from inverse annulation can be obtained in moderate to good yields with high functional group compatibility. Insightful experimental and theoretical studies indicate that the reaction to the inverse annulation follows the Ru(ii)–Ru(iv)–Ru(ii) pathway involving N–O bond cleavage prior to alkyne insertion. This is highly different compared to the conventional mechanism of transition metal-catalyzed C–H activation/annulation with alkynes, involving alkyne insertion prior to N–O bond cleavage. Via this pathway, the in situ generated acetic acid from the N–H/C–H activation step facilitates the N–O bond cleavage to give the Ru-nitrene species. Besides the conventional mechanism forming the products via standard annulation, an alternative and novel Ru(ii)–Ru(iv)–Ru(ii) mechanism featuring N–O cleavage preceding alkyne insertion has been proposed, affording a new understanding of transition metal-catalyzed C–H activation/annulation.

A highly selective ruthenium-catalyzed C–H activation/annulation through a pathway involving N–O bond cleavage prior to alkyne insertion is developed.     

Intramolecular Csp3–H/C–C bond amination of alkyl azides for the selective synthesis of cyclic imines and tertiary amines

The intramolecular Csp³–H and/or C–C bond amination is very important in modern organic synthesis due to its efficiency in the construction of diversified N-heterocycles. Herein, we report a novel intramolecular cyclization of alkyl azides for the synthesis of cyclic imines and tertiary amines through selective Csp³–H and/or C–C bond cleavage. Two C–N single bonds or a C N double bond are efficiently constructed in these transformations. The carbocation mechanism differs from the reported metal nitrene intermediates and therefore enables metal-free and new transformation.

A novel intramolecular cyclization of alkyl azides for the synthesis of cyclic imines and tertiary amines has been developed. The aliphatic C–H or C–C bond was selectively cleaved with the efficient formation of two C–N single bonds or a C N double bond.