Nature-Inspired Photocatalytic Azo Bond Cleavage with Red Light.

The emerging field of photoredox catalysis in mammalian cells enables spatiotemporal regulation of a wealth of biological processes. However, the selective cleavage of stable covalent bonds driven by low-energy visible light remains a great challenge. Herein, we report that red light excitation of a commercially available dye, abbreviated NMB+, leads to catalytic cleavage of stable azo bonds in both aqueous solutions and hypoxic cells and hence a means to photodeliver drugs or functional molecules. Detailed mechanistic studies reveal that azo bond cleavage is triggered by a previously unknown consecutive two-photon process. The first photon generates a triplet excited state, 3NMB+*, that is reductively quenched by an electron donor to generate a protonated NMBH•+. The NMBH•+ undergoes a disproportionation reaction that yields the initial NMB+ and two-electron-reduced NMBH (i.e., leuco-NMB, abbreviated as LNMB). Interestingly, LNMB forms a charge transfer complex with all four azo substrates that possess an intense absorption band in the red region. A second red photon induces electron transfer from LNMB to the azo substrate, resulting in azo bond cleavage. The charge transfer complex mediated two-photon catalytic mechanism reported herein is reminiscent of the flavin-dependent natural photoenzyme that catalyzes bond cleavage reactions with high-energy photons. The red-light-driven photocatalytic strategy offers a new approach to bioorthogonal azo bond cleavage for photodelivery of drugs or functional molecules.

Transition-Metal-Catalyzed C-C Bond Formation from C-C Activation.

ConspectusC-C single bonds are ubiquitous in organic compounds. The activation and subsequent functionalization of C-C single bonds provide a unique opportunity to synthesize conventionally inaccessible molecules through the rearrangement of carbon skeletons, often with a favorable atom and step economy. However, the C-C bonds are thermodynamically and kinetically inert. Consequently, the activation of C-C bonds is particularly attractive yet challenging in the field of organic chemistry. In the past decade, we sought to develop efficient strategies to carry out transition-metal-catalyzed diverse C-C cleavage/C-C forming reactions and to obtain some insights into the intrinsic reactivities of different C-C bonds. With our efforts, readily available alcohols, carboxylic acids, and ketones served as suitable substrates for the catalytic C-C coupling reactions, which are reviewed in this Account. In 2009, we observed a Ni-catalyzed cross coupling of aryl nitriles with arylboronic esters through C-CN cleavage. Encouraged by these results, we are interested in transition-metal-catalyzed C-C bond activation. Due to their broad availability, we then turned our attention to C-C cleavage of carboxylic acids. Rhodium-catalyzed decarbonylative coupling of carboxylic acids with (hetero)arenes was then achieved through oxidative addition of in situ formed, more reactive mixed anhydrides to Rh(I) without the need for oxidants that are commonly required for the decarboxylative coupling of carboxylic acids. Subsequently, the decarbonylation of more challenging unstrained aryl ketones was realized under Rh catalysis assisted by N-containing directing groups. Following this work, a group exchange of aryl ketones with carboxylic acids was achieved through 2-fold C-C bond cleavage. By employing the chelation strategy, Rh-catalyzed C-C bond activation of secondary benzyl alcohols was also accomplished through ß-carbon elimination of the rhodium alcoholate intermediates. The competing oxidation of secondary alcohols to ketones via ß-hydrogen elimination of the same intermediates was suppressed as thermodynamically favorable five-membered rhodacycles are formed after ß-carbon elimination. Different types of transformations of alcohols, including the Heck-type reaction with alkenes, cross coupling with arylsilanes, and Grignard-type addition with aldehydes or imines, have been achieved, showing the great potential of secondary alcohols in the formation of C-C bonds. These C-C bond-forming reactions are complementary to traditional cross couplings of aryl halides with organometallic reagents. However, these transformations produce small molecules as byproducts. To improve the atom economy, we then investigated C-C bond transformations of strained-ring cyclic compounds. Ni-catalyzed intermolecular cyclization of benzocyclobutenones with alkynes was recently achieved via the uncommon cleavage of the C1-C8 bond by employing a removable blocking strategy. Rh-catalyzed intramolecular annulation of benzocyclobutenols with alkynes was also achieved. In summary, our developments demonstrate the great potential of transition-metal-catalyzed C-C bond activation for the formation of new C-C bonds. To further expand the synthetic utility of C-C bond activation, more efforts are required to expand the substrate scope and to achieve earth-abundant metal-catalyzed transformations.

Jellyfish-type Dinuclear Hafnium Azido Complexes: Synthesis and Reactivity.

Di- and multinuclear hafnium complexes bridged by ligands have been rarely reported. In this article, a novel 3,5-disubstituted pyrazolate-bridged ligand LH5 with two [N2 N]2- -type chelating side arms was designed and synthesized, which supported a series of dinuclear hafnium complexes. Dinuclear hafnium azides [LHf2 (µ-1,1-N3 )2 (N3 )2 ][Na(THF)4 ] 3 and [LHf2 (µ-1,1-N3 )2 (N3 )2 ][Na(2,2,2-Kryptofix)] 4 were further synthesized and structurally characterized, featuring two sets of terminal and bridging azido ligands like jellyfishes. The reactivity of 3 under reduction conditions was conducted, leading to a formation of a tetranuclear hafnium imido complex [L1 Hf2 (µ1 -NH)(N3 ){µ2 -K}]2 5. DFT calculations revealed that the mixed imido azide 5 was generated via an intramolecular C-H insertion from a putative dinuclear HfIV -nitridyl intermediate.

Direct Incorporation of Dinitrogen into an Aliphatic C-H Bond.

The activation of dinitrogen (N2) and direct incorporation of its N atom into C-H bonds to create aliphatic C-N compounds remains unresolved. Incompatible conditions between dinitrogen reduction and C-H functionalization make this process extremely challenging. Herein, we report the first example of dinitrogen insertion into an aliphatic Csp3-H bond on the ligand scaffold of a 1,3-propane-bridged [N2N]2--type dititanium complex. Mechanistic investigations on the behaviors of dinuclear and mononuclear Ti complexes indicated the intramolecular synergistic effect of two Ti centers at a C-N bond-forming step. Computational studies revealed the critical isomerization between the inactive side-on N2 complex and the active nitridyl complex, which is responsible for the Csp3-H amination. This strategy maps an efficient route toward the future synthesis of aliphatic amines directly from N2.

Neutral Boryl Radicals in Mixed-Valent B(III) Br-B(II) Adducts.

The general strategies to stabilize a boryl radical involve single electron delocalization by π-system and the steric hinderance from bulky groups. Herein, a new class of boryl radicals is reported, with intramolecular mixed-valent B(III) Br-B(II) adducts ligated by a cyclic (alkyl)(amino)carbene (CAAC). The radicals feature a large spin density on the boron center, which is ascertained by EPR spectroscopy and DFT calculations. Structural and computational analyses revealed that the stability of radical species was assisted by the CAAC ligand and a weak but significant B(III)Br-B(II) interaction, suggesting a cooperative avenue for stabilization of boryl radicals. Two-electron reduction of these new boryl radicals provides C-H insertion products via a borylene intermediate.

Distance-Triggered Distinct Aryl Migrations on Azidodiboranes.

Derived from structurally similar precursors, two different azidodiboranes went through distinct aryl migration reactions triggered by different boron-boron separation distances. Biphenylene based diborane with a shorter boron-boron distance underwent heterolateral aryl migration to form a seven-membered azadiborepin, while xanthrene based diborane with a longer boron-boron distance afforded a stable bis-azidoborane scaffold. The pyrolysis of such a bis-azidoborane led to eight-membered oxazadiborocine through homolateral aryl migration and subsequent [3+2] cycloaddition. Density functional theory (DFT) calculations unveiled that the boron-boron separation distances were the intrinsic factors for the distinct migrations.

(n-Bu)4NBr-Promoted N2 Splitting to Molybdenum Nitride.

Splitting of N2 via six-electron reduction and further functionalization to value-added products is one of the most important and challenging chemical transformations in N2 fixation. However, most N2 splitting approaches rely on strong chemical or electrochemical reduction to generate highly reactive metal species to bind and activate N2, which is often incompatible with functionalizing agents. Catalytic and sustainable N2 splitting to produce metal nitrides under mild conditions may create efficient and straightforward methods for N-containing organic compounds. Herein, we present that a readily available and nonredox (n-Bu)4NBr can promote N2-splitting with a Mo(III) platform. Both experimental and theoretical mechanistic studies suggest that simple X- (X = Br, Cl, etc.) anions could induce the disproportionation of MoIII[N(TMS)Ar]3 at the early stage of the catalysis to generate a catalytically active {MoII[N(TMS)Ar]3}- species. The quintet MoII species prove to be more favorable for N2 fixation kinetically and thermodynamically, compared with the quartet MoIII counterpart. Especially, computational studies reveal a distinct heterovalent {MoII-N2-MoIII} dimeric intermediate for the N≡N triple bond cleavage.

Nitrogen fixation and transformation with main group elements.

Nitrogen fixation is essential for the maintenance of life and development of society, however, the large bond dissociation energy and nonpolarity of the triple bond constitute a considerable challenge. The transition metals, by virtue of their combination of empty and occupied d orbitals, are prevalent in the nitrogen fixation studies and are continuing to receive a significant focus. The main group metals have always been considered incapable in dinitrogen activation owing to the absence of energetically and symmetrically accessible orbitals. The past decades have witnessed significant breakthroughs in the dinitrogen activation with the main group elements and compounds via either matrix isolation, theoretical calculations or synthetic chemistry. The successful reactions of the low-valent species of the main group elements with inert dinitrogen have been reported via the π back-donation from either the d orbitals (Ca, Sr, Ba) or p orbitals (Be, B, C…). Herein, the significant achievements have been briefly summarized, along with predicting the future developments.

Direct conversion of N2 and O2: status, challenge and perspective.

As key components of air, nitrogen (N2) and oxygen (O2) are the vital constituents of lives. Synthesis of NO2, and C-N-O organics direct from N2 and O2, rather than from an intermediate NH3 (known as the Haber-Bosch process), is tantalizing. However, the extremely strong N≡N triple bond (945 kJ mol-1) and the nonpolar stable electron configuration of dinitrogen lead to its conversion being extensively energy demanding. The further selective synthesis of high-value C-N-O organics directly from N2, O2 and C-containing molecules is attractive yet greatly challenging from both scientific and engineering perspectives. Enormous efforts have been dedicated to the direct conversion of N2 and O2 via traditional and novel techniques, including thermochemical, plasma, electrochemical, ultrasonic and photochemical conversion. In this review, we aim to provide a thorough comprehension of the status and challenge of the direct conversion of N2, O2 and C-containing molecules (particularly N2 and O2). Moreover, we will propose some future perspectives to stimulate more inspiration from the scientific community to tackle the scientific and engineering challenges.

Recent progress in the oxidative coupling of unactivated Csp3-H bonds with other C-H bonds.

The oxidative coupling between two carbon-hydrogen (C-H) bonds offers the most straightforward pathway to construct C-C bonds from hydrocarbons without pre-functionalization, exhibiting high step- and atom-economy. This article features the recent advances in the oxidative coupling of unactivated Csp3-H with different hybrid C-H bonds, including Csp-H, Csp2-H and Csp3-H bonds. The substrate scope, proposed mechanism and application of these reactions are summarized, intending to provide insights toward developing novel and efficient protocols for Csp3-C bond construction.

Skeleton Reorganization of Substituted Benzocyclobutenols through Rh-Catalyzed C-C Bond Cleavage Manipulated by Hydrogen Transfer.

Although transition-metal-catalyzed C-C bond activation has been investigated extensively, C-C bond cleavage manipulated by hydrogen transfer has been unexplored. In this work, we disclose a skeleton reorganization of alkene-tethered benzocyclobutenols through Rh-catalyzed C-C bond cleavage coupled with intra- and intermolecular hydrogen transfer. The reaction pathway was well-tuned by the catalytic systems. As a result, divergent benzofurans bearing 4-ß-hydroxy or 4-ß-keto moieties were synthesized under pH- and redox-neutral conditions.

Site-Selective C-C Cleavage of Benzocyclobutenones Enabled by a Blocking Strategy Using Nickel Catalysis.

Controlling the chemo- and regioselectivity of transition-metal-catalyzed C-C activation remains a great challenge. The transformations of benzocyclobutenones (BCBs) usually involve the cleavage of C1-C2 bond. In this work, an unprecedented highly selective cleavage of C1-C8 bond with the insertion of alkynes is achieved by using blocking strategy via Ni catalysis, providing an efficient method for synthesis of 1,8-disubstituted naphthalenes. Notably, the blocking group could be readily removed after the transformation.

Intramolecular Oxidative Coupling between Unactivated Aliphatic C-H and Aryl C-H Bonds.

Direct oxidative coupling of different inert C-H bonds is the most straightforward and environmentally benign method to construct C-C bonds. In this paper, we developed a Pd-catalyzed intramolecular oxidative coupling between unactivated aliphatic and aryl C-H bonds. This chemistry showed great potential to build up fused cyclic scaffolds from linear substrates through oxidative couplings. Privileged chromane and tetralin scaffolds were constructed from readily available linear starting materials in the absence of any organohalides and organometallic partners.

Synthesis of arylamines and N-heterocycles by direct catalytic nitrogenation using N2.

Ammonia and nitric acid are two key platform chemicals to introduce nitrogen atoms into organic molecules in chemical industry. Indeed, nitric acid is mostly produced through the oxidation of ammonia. The ideal nitrogenation would involve direct use of dinitrogen (N2) as a N source to construct N-containing organic molecules. Herein, we report an example of direct catalytic nitrogenation to afford valuable diarylamines, triarylamines, and N-heterocycles from easily available organohalides using dinitrogen (N2) as the nitrogen source in a one-pot/two-step protocol. With this method, 15N atoms are easily incorporated into organic molecules. Structurally diversified polyanilines are also generated in one pot, showing great potential for materials chemistry. In this protocol, lithium nitride, generated in situ with the use of lithium as a reductant, is confirmed as a key intermediate. This chemistry provides an alternative pathway for catalytic nitrogenation to synthesize highly valuable N-containing chemicals from dinitrogen.

Silylamido supported dinitrogen heterobimetallic complexes: syntheses and their catalytic ability.

Molybdenum dinitrogen complexes supported by monodentate arylsilylamido ligand, [Ar(Me3Si)N]3MoN2Mg(THF)2[N(SiMe3)Ar] (5) and [Ar(Me3Si)N]3MoN2SiMe3 (6) (Ar = 3,5-Me2C6H3) were synthesized and structurally characterized, and proved to be effective catalysts for the disproportionation of cyclohexadienes and isomerization of terminal alkenes. The 1H NMR spectrum suggested that the bridging nitrogen ligand remains intact during the catalytic reaction, indicating possible catalytic ability of the Mo-N=N motif.

Direct transformation of dinitrogen: synthesis of N-containing organic compounds via N-C bond formation.

N-containing organic compounds are of vital importance to lives. Practical synthesis of valuable N-containing organic compounds directly from dinitrogen (N2), not through ammonia (NH3), is a holy-grail in chemistry and chemical industry. An essential step for this transformation is the functionalization of the activated N2 units/ligands to generate N-C bonds. Pioneering works of transition metal-mediated direct conversion of N2 into organic compounds via N-C bond formation at metal-dinitrogen [N2-M] complexes have generated diversified coordination modes and laid the foundation of understanding for the N-C bond formation mechanism. This review summarizes those major achievements and is organized by the coordination modes of the [N2-M] complexes (end-on, side-on, end-on-side-on, etc.) that are involved in the N-C bond formation steps, and each part is arranged in terms of reaction types (N-alkylation, N-acylation, cycloaddition, insertion, etc.) between [N2-M] complexes and carbon-based substrates. Additionally, earlier works on one-pot synthesis of organic compounds from N2 via ill-defined intermediates are also briefed. Although almost all of the syntheses of N-containing organic compounds via direct transformation of N2 so far in the literature are realized in homogeneous stoichiometric thermochemical reaction systems and are discussed here in detail, the sporadically reported syntheses involving photochemical, electrochemical, heterogeneous thermo-catalytic reactions, if any, are also mentioned. This review aims to provide readers with an in-depth understanding of the state-of-the-art and perspectives of future research particularly in direct catalytic and efficient conversion of N2 into N-containing organic compounds under mild conditions, and to stimulate more research efforts to tackle this long-standing and grand scientific challenge.

Fe(ii)-Catalyzed alkenylation of benzylic C-H bonds with diazo compounds.

We report herein an alkenylation of benzylic C(sp3)-H bonds with diazo compounds via carbon cation intermediates with DDQ as the oxidant in the presence of a catalytic amount of Fe(ii). Diphenylmethane, toluene, benzyl methyl sulfide and their derivatives could be applied as substrates to afford the tetra-substituted olefin products, which may serve as useful building blocks in organic synthesis.

Upgrading Cross-Coupling Reactions for Biaryl Syntheses.

Transition-metal catalyzed cross-coupling reactions have emerged as a powerful tool for constructing biaryl compounds. Aryl halides and aryl metallic reagents (typically prepared from aryl halides) are used as coupling partners. It would be desirable to replace either aryl halide or aryl metallic reagents used in cross-couplings reactions with more readily available surrogates. Oxidative dehydrogenative cross-coupling between two different "inert" aryl C-H bonds represents an ideal system that would revolutionize cross-coupling chemistry. Furthermore, cross-coupling reactions might be improved by developing new catalytic protocols based on cheap transition-metal catalysts or even transition-metal-free systems to decrease costs and avoid the use of heavy metal and noble transition metals. It would be desirable to promote both catalytic systems and replace either or both coupling partners. We have used different strategies to improve cross-coupling reactions for constructing biaryls, which we categorized into four groups as follows. First, we focused on developing methodologies to be applied to easily produced and naturally abundant arenol-based electrophiles in cross-coupling via C-O activation. We have extended coupling partners to aryl carboxylates and arenols. Direct application of arenes as surrogates for organohalides and organometallic reagents avoids the tedious preparation of these reagents from arenes and considerably reduces the cost of starting materials. We have also explored cross-coupling reactions of arenes with various organometallic reagents, such as arylboronic acids, arylsilanes, and aryl Grignard reagents. Second, we summarize oxidative cross-coupling reactions based on C-H activation with aryl metallic reagents. On the basis of the reactivity patterns of different organometallic reagents, we adapted different catalytic systems to achieve effective cross-coupling reactions. Third, we improved a well-developed cross-coupling between arenes and organohalides through a strategy of replacing one coupling partner and using a new catalytic system. We have applied earth-abundant transition metals, such as Fe, and Co, and even developed transition-metal-free catalytic systems. Finally, our ultimate goal is to construct biaryls by cross dehydrogenative arylation between two different arenes. Owing to the structural similarity of both arenes, in particular two substituted benzenes, the greatest challenges are not only achieving regio- and chemo-selective C-H activation reactions but also matching both the reactivities and selectivities of both substrates to avoid homocouplings of either arene. Through our efforts, we have developed and applied four different strategies by introducing directing groups, controlling electronic and steric properties, and using dual directing strategies. We hope our studies will stimulate interest and new thinking on cross-couplings reactions for building carbon-carbon bonds from readily available and inexpensive chemicals from basic petroleum chemistry and nature.