Inert Bonds Research Articles

A Reversibly Photoswitchable Zinc Metallocycle Based on Azobenzene

Photoswitchable metallocycles and cages are of special interest for a photocontrolled uptake and/or release of guest molecules. While most compounds undergo a disassembly‐re‐assembly mechanism among photoisomerization, examples for reversibly switchable compounds without decomposition are extremely rare. Furthermore, most metallocycles and cages are based on 4d and 5d metal ions that form kinetically inert bonds. We here present a dinuclear Zn(II) metallocycle that despite the usually high ligand exchange rate of Zn(II) reversibly undergoes photoisomerization without disassembly. Therefore, we prepared the novel ligand 3,3’‐Azobenz(BPA)2 (1) that is based on an azobenzene scaffold equipped with two benzylpicolylamine (BPA) moieties for metal complexation. With this ligand, the Zn(II) complexes [{ZnCl2}2(1)] (2) and the cyclic 2:2 complex [Zn2(1)2](BF4)4 (3) were prepared and characterized. The photophysical switching properties of all compounds have been assessed using NMR and UV/Vis spectroscopy as well as quantum chemical calculations by density functional theory (DFT) at the CAM‐B3LYP/D4/def2‐TZVPP level. These studies show the highly quantitative and reversible photoinduced cyclic E/Z isomerization of 1 – 3. To the best of our knowledge, 3 thus represents the only second metallocycle based on azobenzene and first one using Zn(II), which reversibly undergoes photoisomerization.

Photoinduced Radical Borylation of Robust Carbon–Heteroatom Bonds

AbstractPhotoinduced borylation has emerged as a valuable strategy for synthesizing arylboronic esters. However, photochemical transformations involving inert bonds such as C(sp2)−F bonds are still challenging. Herein, we report a straightforward and operationally simple method for the activation of various inert carbon–heteroatom bonds, enabling the synthesis of diverse arylboronic esters without the need for transition metals or catalysts. Mechanistic investigations reveal that the deprotonation of DMSO plays a pivotal role in the reaction, and the excited DMSO anion can undergo electron transfer to the aryl substrates activated by anionic sp2–sp3 diboron compounds, i. e., [FB2pin2]−, thereby facilitating the cleavage of carbon–heteroatom bonds. The reaction allows the conversion of diverse Caryl–hetero bonds in batch and flow reactors into the corresponding arylboronic esters. The products can be used in a subsequent Suzuki‐Miyaura cross‐coupling without isolation.

Modifying Proton Relay into Bioinspired Dye‐Based Coordination Polymer for Photocatalytic Proton‐Coupled Electron Transfer

AbstractProton‐coupled electron transfer (PCET) imparts an energetic advantage over single electron transfer in activating inert substances. Natural PCET enzyme catalysis generally requires tripartite preorganization of proton relay, substrate‐bound active center, and redox mediator, making the processes efficient and precluding side reactions. Inspired by this, a heterogeneous photocatalytic PCET system was established to achieve higher PCET driving forces by modifying proton relays into anthraquinone‐based anionic coordination polymers. The proximally separated proton relays and photoredox‐mediating anthraquinone moiety allowed pre‐assembly of inert substrate between them, merging proton and electron into unsaturated bonds by photoreductive PCET, which enhanced reaction kinetics compared with the counter catalyst without proton relay. This photocatalytic PCET method was applied to a broad‐scoped reduction of aryl ketones, unsaturated carbonyls, and aromatic compounds. The distinctive regioselectivities for the reduction of isoquinoline derivatives were found to occur on the carbon‐ring sides. PCET‐generated radical intermediate of quinoline could be trapped by alkene for proton relay‐assisted Minisci addition, forming the pharmaceutical aza‐acenaphthene scaffold within one step. When using heteroatom(X)−H/C−H compounds as proton‐electron donors, this protocol could activate these inert bonds through photooxidative PCET to afford radicals and trap them by electron‐deficient unsaturated compounds, furnishing the direct X−H/C−H functionalization.

Modifying Proton Relay into Bioinspired Dye-Based Coordination Polymer for Photocatalytic Proton-Coupled Electron Transfer.

Proton-coupled electron transfer (PCET) imparts an energetic advantage over single electron transfer in activating inert substances. Natural PCET enzyme catalysis generally requires tripartite preorganization of proton relay, substrate-bound active center, and redox mediator, making the processes efficient and precluding side reactions. Inspired by this, a heterogeneous photocatalytic PCET system was established to achieve higher PCET driving forces by modifying proton relays into anthraquinone-based anionic coordination polymers. The proximally separated proton relays and photoredox-mediating anthraquinone moiety allowed pre-assembly of inert substrate between them, merging proton and electron into unsaturated bonds by photoreductive PCET, which enhanced reaction kinetics compared with the counter catalyst without proton relay. This photocatalytic PCET method was applied to a broad-scoped reduction of aryl ketones, unsaturated carbonyls, and aromatic compounds. The distinctive regioselectivities for the reduction of isoquinoline derivatives were found to occur on the carbon-ring sides. PCET-generated radical intermediate of quinoline could be trapped by alkene for proton relay-assisted Minisci addition, forming the pharmaceutical aza-acenaphthene scaffold within one step. When using heteroatom(X)-H/C-H compounds as proton-electron donors, this protocol could activate these inert bonds through photooxidative PCET to afford radicals and trap them by electron-deficient unsaturated compounds, furnishing the direct X-H/C-H functionalization.

Direct site-selective C(sp<sup>3</sup>)–H functionalization of unprotected non-activated alcohols

Free alcohols are ubiquitous in nature, drugs, bulk chemicals, and various complex molecules. The abundantly available free aliphatic alcohols, being inexpensive, are sustainable starting materials in organic synthesis to construct value-added scaffolds. Direct C(sp<sup>3</sup>)–H functionalization of inert bonds in aliphatic alcoholic chain is challenging due to their inactive nature towards chemical reactions and also multiple similar C–H bonds are available for functionalization reaction at a time. Barton process, which is a classical method for generating alkoxyl radicals, has been widely used for the remote functionalization of alcoholic chain using the strategy of 1,5-hydrogen atom transfer (1,5-HAT). However, the requirement for the pre-activation of alcohols not only adds extra and tedious steps but also, these precursors are challenging to prepare and handle. Generating desired alkoxyl radicals from these precursors is a difficult task and also affects the atom economy of reactions. Numerous methods covering the C(sp<sup>3</sup>)–H functionalization of unprotected non-activated alcohols at diverse (α-, β-, γ-, δ-) positions to access functionalized alcohols are elaborated here. A precise and focused compilation will help to understand what has been established and how new methodologies can be developed for the future needs. <br> The bibliography includes 158 references.

Synthesis and Reactivity of Ruthenium(BINAP)(PPh3).

Ru(BINAP)(PPh3)HCl cleanly reacts with LiCH2TMS to give Ru(BINAP)(PPh3) (1) that has been fully characterized, including by X-ray diffraction (BINAP and TMS stand for (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and trimethylsilyl respectively). In sharp contrast with other carbonyl-free phosphine complexes of Ru(0), 1 demonstrates a strikingly high thermal stability and no propensity for intramolecular C-H activation (cyclometalation). Yet 1 coordinates acetonitrile and readily exchanges its PPh3 ligand with alkenes and dienes, thus behaving like a "masked" 16-e Ru(0) species. Electron-poor alkenes coordinate more readily than electron-rich ones, which testifies for the nucleophilic character of the Ru(0)-BINAP fragment. While being thermally stable, 1 is highly reactive and is capable of activating C-H and N-H bonds, and even of cleaving an inert N-Et bond. The combination of high reactivity and stability originates from the P,arene-chelation by the BINAP ligand, i.e., the coordinated π-arene stabilizes Ru(0) to prevent cyclometalation, yet it can slide upon substrate coordination, thereby enabling a variety of inert bond activation reactions to occur under mild conditions.

Synthesis and Reactivity of Ruthenium(BINAP)(PPh3)

AbstractRu(BINAP)(PPh3)HCl cleanly reacts with LiCH2TMS to give Ru(BINAP)(PPh3) (1) that has been fully characterized, including by X‐ray diffraction (BINAP and TMS stand for (2,2′‐bis(diphenylphosphino)‐1,1′‐binaphthyl and trimethylsilyl respectively). In sharp contrast with other carbonyl‐free phosphine complexes of Ru(0), 1 demonstrates a strikingly high thermal stability and no propensity for intramolecular C−H activation (cyclometalation). Yet 1 coordinates acetonitrile and readily exchanges its PPh3 ligand with alkenes and dienes, thus behaving like a “masked” 16‐e Ru(0) species. Electron‐poor alkenes coordinate more readily than electron‐rich ones, which testifies for the nucleophilic character of the Ru(0)‐BINAP fragment. While being thermally stable, 1 is highly reactive and is capable of activating C−H and N−H bonds, and even of cleaving an inert N−Et bond. The combination of high reactivity and stability originates from the P,arene‐chelation by the BINAP ligand, i.e., the coordinated π‐arene stabilizes Ru(0) to prevent cyclometalation, yet it can slide upon substrate coordination, thereby enabling a variety of inert bond activation reactions to occur under mild conditions.

New visible-light-driven Bi2MoO6/Cs3Sb2Br9 heterostructure for selective photocatalytic oxidation of toluene to benzaldehyde

Herein, new Bi2MoO6/Cs3Sb2Br9 heterostructure (BiMo/CSB) was investigated for the first time as a visible-light-driven photocatalyst for C(sp3)–H bond activation using molecular oxygen as a green oxidant and toluene as a model substrate. The optimized BiMo/CSB photocatalyst exhibited enhanced toluene oxidation activity (2,346 μmol g-1h−1), which was almost two- and five-fold that of pristine CSB (1,165 μmol g-1h−1) and BiMo (482 μmol g-1h−1), respectively. The improved photocatalytic performance was essentially attributed to the formation of staggered band energy lineup in the BiMo/CSB hybrid, which promoted S-scheme charge transfer across the BiMo/CSB heterointerface as supported by ultraviolet photoelectron spectroscopy (UPS), density functional theoretical (DFT), time-resolve photoluminescence (TRPL), and photoelectrochemical studies. Spin–trapping electron paramagnetic resonance (EPR) and radical scavenging studies revealed that photoinduced hole, molecular oxygen, and superoxide radical are key active species in this photocatalytic system. The developed BiMo/CSB catalyst provided good selectivity toward benzaldehyde product (94–98 %), presumably due to the inhibiting effect of benzyl alcohol on benzaldehyde oxidation. No significant change in structure and morphology was observed for the spent catalyst, however small negative shift of Sb 3d and Bi 4f binding energy was found suggesting partial reduction of Sb3+ and Bi3+. This work not only provides a new visible-light-driven photocatalyst for C(sp3)–H bond activation but also opens the doors for exploitation of the conversion and functionalization of this inert bond toward the production of high value-added organic chemicals.

Chalcogen-bridged coordination polymer for the photocatalytic activation of aryl halides

The ability to deliver electrons is vital for dye-based photocatalysts. Conventionally, the aromatic stacking-based charge-transfer complex increases photogenerated electron accessibility but decreases the energy of excited-state dyes. To circumvent this dilemma, here we show a strategy by tuning the stacking mode of dyes. By decorating naphthalene diimide with S-bearing branches, the S···S contact-linked naphthalene diimide string is created in coordination polymer, thereby enhancing electron mobility while simultaneously preserving competent excited-state reducing power. This benefit, along with in situ assembly between naphthalene diimide strings and exogenous reagent/reactant, improves the accessibility of short-lived excited states during consecutive photon excitation, resulting in greater efficiency in photoinduced electron-transfer activation of inert bonds in comparison to other coordination polymers with different dye-stacking modes. This heterogeneous approach is successfully applied in the photoreduction of inert aryl halides and the successive formation of CAr−C/S/P/B bonds with potential pharmaceutical applications.

A General Light‐Driven Organocatalytic Platform for the Activation of Inert Substrates

AbstractDue to their strong covalent bonds and low reduction potentials, activating inert substrates is challenging. Recent advances in photoredox catalysis offered a number of solutions, each of which useful for activating specific inert bonds. Developing a general catalytic platform that can consistently target a broad range of inert substrates would be synthetically useful. Herein, we report a readily available indole thiolate organocatalyst that, upon excitation with 405 nm light, acquires a strongly reducing power. This excited‐state reactivity served to activate, by single‐electron reduction, strong C−F, C−Cl, and C−O bonds in both aromatic and aliphatic substrates. This catalytic platform was versatile enough to promote the reduction of generally recalcitrant electron‐rich substrates (Ered<−3.0 V vs SCE), including arenes that afforded 1,4‐cyclohexadienes. The protocol was also useful for the borylation and phosphorylation of inert substrates with a high functional group tolerance. Mechanistic studies identified an excited‐state thiolate anion as responsible of the highly reducing reactivity.

A General Light-Driven Organocatalytic Platform for the Activation of Inert Substrates.

Due to their strong covalent bonds and low reduction potentials, activating inert substrates is challenging. Recent advances in photoredox catalysis offered a number of solutions, each of which useful for activating specific inert bonds. Developing a general catalytic platform that can consistently target a broad range of inert substrates would be synthetically useful. Herein, we report a readily available indole thiolate organocatalyst that, upon excitation with 405 nm light, acquires a strongly reducing power. This excited-state reactivity served to activate, by single-electron reduction, strong C-F, C-Cl, and C-O bonds in both aromatic and aliphatic substrates. This catalytic platform was versatile enough to promote the reduction of generally recalcitrant electron-rich substrates (Ered <-3.0 V vs SCE), including arenes that afforded 1,4-cyclohexadienes. The protocol was also useful for the borylation and phosphorylation of inert substrates with a high functional group tolerance. Mechanistic studies identified an excited-state thiolate anion as responsible of the highly reducing reactivity.

Breaking bonds and breaking rules: inert-bond activation by [(iPr3P)Ni]5H4 and catalytic stereospecific norbornene dimerization.

The facile carbon atom abstraction reaction by [(iPr3P)Ni]5H6 (1) with various terminal alkenes to give [(iPr3P)Ni]5H4(μ5-C) (2) occurs via a common highly reactive intermediate [(iPr3P)Ni]5H4 (3), which was isolated by the reaction of 1 with norbornene. Temperature dependent 1H and 31P{1H} NMR chemical shifts of 3 are consistent with a thermally populated triplet excited state only 2 kcal mol-1 higher energy than the diamagnetic ground state. Complex 3 catalyzes the dimerization of norbornene to stereoselectively provide exclusively (Z) anti-(bis-2,2'-norbornylidene).

N-Pyridylimidates as Traceless Acyl Equivalents for Directed C-O Bond Functionalization.

Directing groups are a common strategy to target traditionally inert bonds, with an easily removable directing group being ideal. Herein we disclose our method for rhodium-catalyzed C-O bond functionalization of N-pyridylimidates using a recyclable and traceless amine directing group. In addition to the substrate scope, we discuss the behavior of this class of compounds and how that behavior affects their reactivity.

Overriding the inherent alkalinity to dual phosphinito bimetallic catalyst for C(sp2)-C(sp3) formation: A combined computational and experimental study

Unraveling the catalytic reaction mechanism is a long-term challenge for developing efficient catalysts. The blooming bimetallic catalyst have enabled to activate inert bonds and realize complex C-C formation. Herein, we theoretically discover a dual-phosphinito bridged hetero-bimetallic species that verified by NMR experiments. Our results indicate only dual-phosphinito Ni-Al model can be an active catalyst in asymmetric cycloadditions via C-C activation and C-H activation, which can well rationalize the experimental observations for both reactivity and stereo-selectivity. An unprecedented tandem redox dehydrogenation mechanism was revealed to control the formation of this active species overriding the inherent basicity. Synergistic Lewis acid and eg orbital interactions, including dz2orbital reoccupation and dx2−y2 orbital recombination, were disclosed to understand both thermodynamic and kinetic advance of dual-bridged model, displaying feasible redox properties.

A nonpolar bond to hydrogen vs. lone pair: Incorporation of HPO32− and SeEO32− into a lead perrhenate framework

Two new lead perrhenate compounds, [Pb2(ReO4)2(SeO3)H2O]H2O (1) and [Pb2(ReO4)2(HPO3)H2O]H2O (2), were prepared by adding selenious or phosphorous acid to boiling concentrated solutions of lead perrhenate. Both compounds adopt the same crystal structure illustrating similar structural impact of lone pair and nonpolar hydrogen bond on one-sided coordination and formation of loose structural architectures. The crystal structure of 1 and 2, which corresponds to a novel structure type, consists of lead-perrhenate double layers interconnected by the selenite or phosphite anions into framework; the channels are filled by water molecules. We briefly discuss the chemistry of compounds containing both regular-shaped and ‘lone-pair’ or ‘inert bond’ anions.

Iron-Catalyzed Cross-Electrophile Coupling of Inert C–O Bonds with Alkyl Bromides

Iron-Catalyzed Cross-Electrophile Coupling of Inert C–O Bonds with Alkyl Bromides

Manganese Alkyl Carbonyl Complexes: From Iconic Stoichiometric Textbook Reactions to Catalytic Applications.

ConspectusThe activation of weakly polarized bonds represents a challenging, yet highly valuable process. In this context, precious metal catalysts have been used as reliable compounds for the activation of rather inert bonds for the last several decades. Nevertheless, base-metal complexes including cobalt, iron, or nickel are currently promising candidates for the substitution of noble metals in order to develop more sustainable processes. In the past few years, manganese(I)-based complexes were heavily employed as efficient catalysts for (de)hydrogenation reactions. However, the vast majority of these complexes operate via a metal–ligand bifunctionality as already well implemented for precious metals decades ago. Although high reactivity can be achieved in various reactions, this concept is often not applicable to certain transformations due to outer-sphere mechanisms. In this Account, we outline the potential of alkylated Mn(I)-carbonyl complexes for the activation of nonpolar and moderately polar E–H (E = H, B, C, Si) bonds and disclose our successful approach for the utilization of complexes in the field of homogeneous catalysis. This involves the rational design of manganese complexes for hydrogenation reactions involving ketones, nitriles, carbon dioxide, and alkynes. In addition to that, the reduction of alkenes by dihydrogen could be achieved by a series of well-defined manganese complexes which was not possible before. Furthermore, we elucidate the potential of our Mn-based catalysts in the field of hydrofunctionalization reactions for carbon–carbon multiple bonds. Our investigations unveiled novel insights into reaction pathways of dehydrogenative silylation of alkenes and trans-1,2-diboration of terminal alkynes, which was not yet reported for transition metals. Due to rational catalyst design, these transformations can be achieved under mild reaction conditions. Delightfully, all of the employed complexes are bench-stable compounds. We took advantage of the fact that Mn(I) alkyl complexes are known to undergo migratory insertion of the alkyl group into the CO ligand, yielding an unsaturated acyl intermediate. Hydrogen atom abstraction by the acyl ligand then paves the way to an active species for a variety of catalytic transformations which all proceed via an inner-sphere process. Although these textbook reactions have been well-known for decades, the application in catalytic transformations is still in its infancy. A brief historical overview of alkylated manganese(I)–carbonyl complexes is provided, covering the synthesis and especially iconic stoichiometric transformations, e.g., carbonylation, as intensively examined by Calderazzo, Moss, and others. An outline of potential future applications of defined alkyl manganese complexes will be given, which may inspire researchers for the development of novel (base-)metal catalysts.

Merging Charge Transfer into Metal-Organic Frameworks to Achieve High Reduction Potentials via Multiphoton Excitation.

Utilization of multiphotons to achieve high reduction potentials is a highly demanding but still challenging task for reductive cleavage of inert bonds. Herein, we report a new charge transfer approach that simultaneously excites the electron-rich dye and the radical anionic of the electron-deficient one for photocatalytic activation of aryl chlorides with high reduction potentials (Ered ≈ -1.9 to -2.9 V). Interactions between the tetraphenylbenzene-1,4,-diamine dyes in the large pores of metal-organic frameworks and the adsorbed 9,10-dicyanoanthracene partly endows charge transfer in the ground state. The first photoexcitation led to the formation charge separation pairs containing both radical cation and anion for second photon excitation. The possibility of modifying each absorption band of the two dyes independently innovated the resultant aryl radicals applied in various useful transformations, expanding multiphoton manifolds on both the dye scopes and reaction versions. A comparison of the catalytic performance between different structural patterns of metal-organic frameworks with the same ligand demonstrated that the incorporating of the organic dyes within the pores of the frameworks was essential to form charge-transfer species and accelerate the interesting chemical conversion.

Discovery of Electronic Structure and Interfacial Interaction Features in Catalytic Activity.

The selective transformation of inert bonds (C-H, C-O, C-C, C-F, etc.) via various catalysts is one of the most challenging areas, with applications in organic synthesis, materials science, and biological and pharmaceutical chemistry. The catalytic performance of homogeneous and heterogeneous catalysts can be rationally controlled in two ways: (i) electronic structure modulation of the active site, such as the metal center, ligands, and coordination modes, to improve the catalytic activity and stability and (ii) tuning intermolecular or interfacial interactions to promoting the reaction kinetics by accelerating the transmission of electrons between the catalyst and solvents or support. The rational design of catalysts based on adjustable features, such as metal (monometallic or bimetallic) active sites, crystal phase, ligands, solvents, and supports for inert bond activation under mild conditions remains a challenge. This Perspective summarizes the features of electronic structures, interfacial interactions, and their effects on molecular catalysis, metal-organic frameworks (MOFs), and natural mineral catalysis. The discovery of efficient catalysts could be promoted using machine-learning methods with high-performance descriptors. More attention should be paid to high-throughput quantum-chemical computations and experiments, automatic searches of chemical reaction pathways, and efficient machine-learning or deep-learning methods to accelerate catalyst design and synthesis in the future.

A Review of Modifications of Quinoline Antimalarials: Mefloquine and (hydroxy)Chloroquine.

Late-stage modification of drug molecules is a fast method to introduce diversity into the already biologically active scaffold. A notable number of analogs of mefloquine, chloroquine, and hydroxychloroquine have been synthesized, starting from the readily available active pharmaceutical ingredient (API). In the current review, all the modifications sites and reactivity types are summarized and provide insight into the chemistry of these molecules. The approaches include the introduction of simple groups and functionalities. Coupling to other drugs, polymers, or carriers afforded hybrid compounds or conjugates with either easily hydrolyzable or more chemically inert bonds. The utility of some of the compounds was tested in antiprotozoal, antibacterial, and antiproliferative assays, as well as in enantiodifferentiation experiments.