Mechanochemical reactivity inhibited,prohibited and reversed by liquid additives: examples from crystal-form screens

We demonstrate that liquid additives can exert inhibitive or prohibitive effects on the mechanochemical formation of multi-component molecular crystals, and report that certain additives unexpectedly prompt the dismantling of such solids into physical mixtures of their constituents. Computational methods were employed in an attempt to identify possible reasons for these previously unrecognised effects of liquid additives on mechanochemical transformations.

Liquid additives can exert catalytic, inhibitive or prohibitive effects on the mechanochemical formation of multi-component molecular crystals.     

Orbital energy mismatch engenders high-spin ground states in heterobimetallic complexes

The spin state in heterobimetallic complexes heavily influences both reactivity and magnetism. Exerting control over spin states in main group-based heterobimetallics requires a different approach as the orbital interactions can differ substantially from that of classic coordination complexes. By deliberately engendering an energetic mismatch within the two metals in a bimetallic complex we can mimic the electronic structure of lanthanides. Towards this end, we report a new family of complexes, [^Ph,MeTpMSnPh₃] where M = Mn (3), Fe (4), Co (5), Ni (6), Zn (7), featuring unsupported bonding between a transition metal and Sn which represent an unusual high spin electronic structure. Analysis of the frontier orbitals reveal the desired orbital mismatch with Sn 5s/5p primarily interacting with 4s/4p M orbitals yielding localized, non-bonding d orbitals. This approach offers a mechanism to design and control spin states in bimetallic complexes.

We report a series of high spin bimetallic transition metal–tin complexes. The unusual high spin configuration in a bimetallic complex is enabled by an energetic mismatch in the orbital energies, leading to lanthanide-like nonbonding interactions.     

Efficient access to materials-oriented aromatic alkynes via the mechanochemical Sonogashira coupling of solid aryl halides with large polycyclic conjugated systems

Sonogashira coupling represents an indispensable tool for the preparation of organic materials that contain C(sp)–C(sp²) bonds. Improving the efficiency and generality of this methodology has long been an important research subject in materials science. Here, we show that a high-temperature ball-milling technique enables the highly efficient palladium-catalyzed Sonogashira coupling of solid aryl halides that bear large polyaromatic structures including sparingly soluble substrates and unactivated aryl chlorides. In fact, this new protocol provides various materials-oriented polyaromatic alkynes in excellent yield within short reaction times in the absence of bulk reaction solvents. Notably, we synthesized a new luminescent material via the mechanochemical Sonogashira coupling of poorly soluble Vat Red 1 in a much higher yield compared to those obtained using solution-based conditions. The utility of this method was further demonstrated by the rapid synthesis of a fluorescent metal–organic framework (MOF) precursor via two sequential mechanochemical Sonogashira cross-coupling reactions. The present study illustrates the great potential of Sonogashira coupling using ball milling for the preparation of materials-oriented alkynes and for the discovery of novel functional materials.

Using a high-temperature ball-milling technique, a practical mechanochemical protocol for the Sonogashira cross-coupling of polyaromatic halides was achieved, which provides efficient access to materials-oriented aromatic alkynes.     

Regio- and diastereoselective reactions of chiral secondary alkylcopper reagents with propargylic phosphates: preparation of chiral allenes

The diastereoselective S_N2′-substitution of secondary alkylcopper reagents with propargylic phosphates enables the preparation of stereodefined alkylallenes. By using enantiomerically enriched alkylcopper reagents and enantioenriched propargylic phosphates as electrophiles anti-S_N2′-substitutions were performend leading to α-chiral allenes in good yields with excellent regioselectivity and retention of configuration. DFT-calculations were performed to rationalize the structure of these alkylcopper reagents in various solvents, emphasizing their configurational stability in THF.

The diastereoselective S_N2′-substitution of secondary alkylcopper reagents with propargylic phosphates enables the preparation of stereodefined alkylallenes.     

Is Cu instability during the CO2 reduction reaction governed by the applied potential or the local CO concentration?

Cu-based catalysts have shown structural instability during the electrochemical CO₂ reduction reaction (CO₂RR). However, studies on monometallic Cu catalysts do not allow a nuanced differentiation between the contribution of the applied potential and the local concentration of CO as the reaction intermediate since both are inevitably linked. We first use bimetallic Ag-core/porous Cu-shell nanoparticles, which utilise nanoconfinement to generate high local CO concentrations at the Ag core at potentials at which the Cu shell is still inactive for the CO₂RR. Using operando liquid cell TEM in combination with ex situ TEM, we can unequivocally confirm that the local CO concentration is the main source for the Cu instability. The local CO concentration is then modulated by replacing the Ag-core with a Pd-core which further confirms the role of high local CO concentrations. Product quantification during CO₂RR reveals an inherent trade-off between stability, selectivity and activity in both systems.

The stability of bimetallic AgCu and PdCu catalysts for electrochemical CO₂RR is investigated using the combination of operando and ex situ TEM. The local CO concentration is identified as the main link between activity, stability and selectivity.     

Synthesis of carbon-supported sub-2 nanometer bimetallic catalysts by strong metal–sulfur interaction

Small-sized bimetallic nanoparticles that integrate the advantages of efficient exposure of the active metal surface and optimal geometric/electronic effects are of immense interest in the field of catalysis, yet there are few universal strategies for synthesizing such unique structures. Here, we report a novel method to synthesize sub-2 nm bimetallic nanoparticles (Pt–Co, Rh–Co, and Ir–Co) on mesoporous sulfur-doped carbon (S–C) supports. The approach is based on the strong chemical interaction between metals and sulfur atoms that are doped in the carbon matrix, which suppresses the metal aggregation at high temperature and thus ensures the formation of small-sized and well alloyed bimetallic nanoparticles. We also demonstrate the enhanced catalytic performance of the small-sized bimetallic Pt–Co nanoparticle catalysts for the selective hydrogenation of nitroarenes.

The strong interactions between metal and sulfur atoms doped in a carbon matrix allow for the synthesis of supported sub-2 nanometer M–Co (M = Pt, Rh, Ir) bimetallic nanocluster catalysts.     

Hydantoin-bridged medium ring scaffolds by migratory insertion of urea-tethered nitrile anions into aromatic C–N bonds

Bicyclic or tricyclic nitrogen-containing heterocyclic scaffolds were constructed rapidly by intramolecular nucleophilic aromatic substitution of metallated nitriles tethered by a urea linkage to a series of electronically unactivated heterocyclic precursors. The substitution reaction constitutes a ring expansion, enabled by the conformationally constrained tether between the nitrile and the heterocycle. Attack of the metallated urea leaving group on the nitrile generates a hydantoin that bridges the polycyclic products. X-ray crystallography reveals ring-dependant strain within the hydantoin.

Bicyclic or tricyclic nitrogen-containing heterocyclic scaffolds were constructed rapidly by ring expanding intramolecular S_NAr on a series of electronically unactivated heterocyclic precursors.     

Cleavable and tunable cysteine-specific arylation modification with aryl thioethers

Cysteine represents an attractive target for peptide/protein modification due to the intrinsic high nucleophilicity of the thiol group and low natural abundance. Herein, a cleavable and tunable covalent modification approach for cysteine containing peptides/proteins with our newly designed aryl thioethers via a S_NAr approach was developed. Highly efficient and selective bioconjugation reactions can be carried out under mild and biocompatible conditions. A series of aryl groups bearing different bioconjugation handles, affinity or fluorescent tags are well tolerated. By adjusting the skeleton and steric hindrance of aryl thioethers slightly, the modified products showed a tunable profile for the regeneration of the native peptides.

A cleavable and tunable covalent modification approach for cysteine by aryl thioethers via a S_NAr approach was developed. The highly efficient and selective bioconjugation reactions can proceed under the mild and biocompatible conditions.     

The non-adiabatic nanoreactor: towards the automated discovery of photochemistry

The ab initio nanoreactor has previously been introduced to automate reaction discovery for ground state chemistry. In this work, we present the nonadiabatic nanoreactor, an analogous framework for excited state reaction discovery. We automate the study of nonadiabatic decay mechanisms of molecules by probing the intersection seam between adiabatic electronic states with hyper-real metadynamics, sampling the branching plane for relevant conical intersections, and performing seam-constrained path searches. We illustrate the effectiveness of the nonadiabatic nanoreactor by applying it to benzene, a molecule with rich photochemistry and a wide array of photochemical products. Our study confirms the existence of several types of S₀/S₁ and S₁/S₂ conical intersections which mediate access to a variety of ground state stationary points. We elucidate the connections between conical intersection energy/topography and the resulting photoproduct distribution, which changes smoothly along seam space segments. The exploration is performed with minimal user input, and the protocol requires no previous knowledge of the photochemical behavior of a target molecule. We demonstrate that the nonadiabatic nanoreactor is a valuable tool for the automated exploration of photochemical reactions and their mechanisms.

The nonadiabatic nanoreactor is a tool for automated photochemical reaction discovery that extensively explores intersection seams and links conical intersections to photoproduct distributions.     

Silyloxymethanesulfinate as a sulfoxylate equivalent for the modular synthesis of sulfones and sulfonyl derivatives

An efficient protocol for the modular synthesis of sulfones and sulfonyl derivatives has been developed utilizing sodium tert-butyldimethylsilyloxymethanesulfinate (TBSOMS-Na) as a sulfoxylate (SO₂²⁻) equivalent. TBSOMS-Na, easily prepared from the commercial reagents Rongalite™ and TBSCl, serves as a potent nucleophile in S-alkylation and Cu-catalyzed S-arylation reactions with alkyl and aryl electrophiles. The sulfone products thus obtained can undergo the second bond formation at the sulfur center with various electrophiles without a separate unmasking step to afford sulfones and sulfonyl derivatives such as sulfonamides and sulfonyl fluorides.

An efficient protocol for the modular synthesis of sulfones and sulfonyl derivatives has been developed utilizing sodium tert-butyldimethylsilyloxymethanesulfinate (TBSOMS-Na) as a sulfoxylate (SO₂²⁻) equivalent.     

Engineering a highly selective probe for ratiometric imaging of H2Sn and revealing its signaling pathway in fatty liver disease

Hydrogen polysulfides (H₂S_n, n > 1) have continuously been proved to act as important signal mediators in many physiological processes. However, the physiological role of H₂S_n and their signaling pathways in complex diseases, such as the most common liver disease, nonalcoholic fatty liver disease (NAFLD), have not been elucidated due to lack of suitable tools for selective detection of intracellular H₂S_n. Herein, we adopted a general and practical strategy including recognition site screening, construction of a ratiometric probe and self-assembly of nanoparticles, to significantly improve the probes'' selectivity, photostability and biocompatibility. The ratiometric probe PPG-Np-RhPhCO selectively responds to H₂S_n, avoiding interaction with biothiol and persulfide. Moreover, this probe was applied to image H₂S_n in NAFLD for the first time and reveal the H₂S_n generation pathways in the cell model of drug-treated NAFLD. The pathway of H₂S_n revealed by PPG-Np-RhPhCO provides significant insights into the roles of H₂S_n in NAFLD and future drug development.

A highly selective probe (PPG-Np-RhPhCO) used for revealing the intracellular H₂S_n signaling pathways in a nonalcoholic fatty liver disease (NAFLD) model.     

Integrating hydrogen production with anodic selective oxidation of sulfides over a CoFe layered double hydroxide electrode

Replacing the sluggish oxygen evolution reaction (OER) with oxidation reactions for the synthesis of complex pharmaceutical molecules coupled with enhanced hydrogen evolution reaction (HER) is highly attractive, but it is rarely explored. Here, we report an electrochemical protocol for selective oxidation of sulfides to sulfoxides over a CoFe layered double hydroxide (CoFe-LDH) anode in an aqueous-MeCN electrolyte, coupled with 2-fold promoted cathodic H₂ productivity. This protocol displays high activity (85–96% yields), catalyst stability (10 cycles), and generality (12 examples) in selective sulfide oxidation. We demonstrate its applicability in the synthesis of four important pharmaceutical related sulfoxide compounds with scalability (up to 1.79 g). X-ray spectroscopy investigations reveal that the CoFe-LDH material evolved into amorphous CoFe-oxyhydroxide under catalytic conditions. This work may pave the way towards sustainable organic synthesis of valuable pharmaceuticals coupled with H₂ production.

Replacing anodic OER with selective sulfide oxidation produces sulfoxide-related pharmaceutical compounds over a CoFe-LDH catalyst with enhanced HER, providing a sustainable protocol for valuable pharmaceuticals synthesis without external oxidants.     

Facilitated inversion complicates the stereodynamics of an SN2 reaction at nitrogen center

Bimolecular nucleophilic substitution (S_N2) reactions at carbon center are well known to proceed with the stereospecific Walden-inversion mechanism. Reaction dynamics simulations on a newly developed high-level ab initio analytical potential energy surface for the F⁻ + NH₂Cl nitrogen-centered S_N2 and proton-transfer reactions reveal a hydrogen-bond-formation-induced multiple-inversion mechanism undermining the stereospecificity of the N-centered S_N2 channel. Unlike the analogous F⁻ + CH₃Cl S_N2 reaction, F⁻ + NH₂Cl → Cl⁻ + NH₂F is indirect, producing a significant amount of NH₂F with retention, as well as inverted NH₂Cl during the timescale within the unperturbed NH₂Cl molecule gets inverted with only low probability, showing the important role of facilitated inversions via an FH…NHCl⁻-like transition state. Proton transfer leading to HF + NHCl⁻ is more direct and becomes the dominant product channel at higher collision energies.

Multiple-inversion, the analogue of the double-inversion pathway recently revealed for S_N2@C, is the key mechanism in S_N2 at N center undermining stereospecificity.     

Designing naphthopyran mechanophores with tunable mechanochromic behavior

Mechanochromic molecular force probes conveniently report on stress and strain in polymeric materials through straightforward visual cues. We capitalize on the versatility of the naphthopyran framework to design a series of mechanochromic mechanophores that exhibit highly tunable color and fading kinetics after mechanochemical activation. Structurally diverse naphthopyran crosslinkers are synthesized and covalently incorporated into silicone elastomers, where the mechanochemical ring–opening reactions are achieved under tension to generate the merocyanine dyes. Strategic structural modifications to the naphthopyran mechanophore scaffold produce dramatic differences in the color and thermal electrocyclization behavior of the corresponding merocyanine dyes. The color of the merocyanines varies from orange-yellow to purple upon the introduction of an electron donating pyrrolidine substituent, while the rate of thermal electrocyclization is controlled through electronic and steric factors, enabling access to derivatives that display both fast-fading and persistent coloration after mechanical activation and subsequent stress relaxation. In addition to identifying key structure–property relationships for tuning the behavior of the naphthopyran mechanophore, the modularity of the naphthopyran platform is demonstrated by leveraging blends of structurally distinct mechanophores to create materials with desirable multicolor mechanochromic and complex stimuli-responsive behavior, expanding the scope and accessibility of force-responsive materials for applications such as multimodal sensing.

Structure–activity relationships for strategic substitution of the naphthopyran mechanophore scaffold enable polymeric materials with tunable mechanochromic behavior.     

Mechanochemical generation of acid-degradable poly(enol ether)s

In an effort to develop polymers that can undergo extensive backbone degradation in response to mechanical stress, we report a polymer system that is hydrolytically stable but unmasks easily hydrolysable enol ether backbone linkages when force is applied. These polymers were synthesized by ring-opening metathesis polymerization (ROMP) of a novel mechanophore monomer consisting of cyclic ether fused bicyclohexene. Hydrogenation of the resulting polymers led to significantly enhanced thermal stability (T_d > 400 °C) and excellent resistance toward acidic or basic conditions. Solution ultrasonication of the polymers resulted in up to 65% activation of the mechanophore units and conversion to backbone enol ether linkages, which then allowed facile degradation of the polymers to generate small molecule or oligomeric species under mildly acidic conditions. We also achieved solid-state mechano-activation and polymer degradation via grinding the solid polymer. Force-induced hydrolytic polymer degradability can enable materials that are stable under force-free conditions but readily degrade under stress. Facile degradation of mechanically activated polymechanophores also facilitates the analysis of mechanochemical products.

A mechanically responsive polymer system that is hydrolytically stable without stress, but unmasks enol ether backbone linkages under force to allow facile hydrolytic degradation.     

Real-time imaging of nanoscale electrochemical Ni etching under thermal conditions

The ability to vary the temperature of an electrochemical cell provides opportunities to control reaction rates and pathways and to drive processes that are inaccessible at ambient temperature. Here, we explore the effect of temperature on electrochemical etching of Ni–Pt bimetallic nanoparticles. To observe the process at nanoscale resolution we use liquid cell transmission electron microscopy with a modified liquid cell that enables simultaneous heating and biasing. By controlling the cell temperature, we demonstrate that the reaction rate and dissolution potential of the electrochemical Ni etching process can be changed. The in situ measurements suggest that the destabilization of the native nickel oxide layer is the slow step prior to subsequent fast Ni removal in the electrochemical Ni dissolution process. These experiments highlight the importance of in situ structural characterization under electrochemical and thermal conditions as a strategy to provide deeper insights into nanomaterial transformations as a function of temperature and potential.

The combination of electrochemical analysis, temperature control and in situ TEM imaging directly probes the etching of Ni from bimetallic Ni–Pt nanoparticles.     

Ortho C–H arylation of arenes at room temperature using visible light ruthenium C–H activation

A ruthenium-catalyzed ortho C–H arylation process is described using visible light. Using the readily available catalyst [RuCl₂(p-cymene)]₂, visible light irradiation was found to enable arylation of 2-aryl-pyridines at room temperature for a range of aryl bromides and iodides.

A ruthenium-catalyzed ortho C–H arylation process is described using visible light.     

Enhancing the CO2 Electroreduction of Fe/Ni-Pentlandite Catalysts by S/Se Exchange

The electrochemical reduction of CO₂ is an attractive strategy towards the mitigation of environmental pollution and production of bulk chemicals as well as fuels by renewables. The bimetallic sulfide Fe_4.5Ni_4.5S₈ (pentlandite) was recently reported as a cheap and robust catalyst for electrochemical water splitting, as well as for CO₂ reduction with a solvent-dependent product selectivity. Inspired by numerous reports on monometallic sulfoselenides and selenides revealing higher catalytic activity for the CO₂ reduction reaction (CO₂RR) than their sulfide counterparts, the authors investigated the influence of stepwise S/Se exchange in seleno-pentlandites Fe_4.5Ni_4.5S_8-YSe_Y (Y=1–5) and their ability to act as CO₂ reducing catalysts. It is demonstrated that the incorporation of higher equivalents of selenium favors the CO₂RR with Fe_4.5Ni_4.5S₄Se₄ revealing the highest activity for CO formation. Under galvanostatic conditions in acetonitrile, Fe_4.5Ni_4.5S₄Se₄ generates CO with a Faradaic Efficiency close to 100 % at applied current densities of −50 mA cm⁻² and −100 mA cm⁻². This work offers insight into the tunability of the pentlandite based electrocatalysts for the CO₂ reduction reaction.     

Metal-free tandem carbene N–H insertions and C–C bond cleavages

A metal-free C–H [5 + 1] annulation reaction of 2-arylanilines with diazo compounds has been achieved, giving rise to two types of prevalent phenanthridines via highly selective C–C cleavage. Compared to the simple N–H insertion manipulation of diazo, this method elegantly accomplishes a tandem N–H insertion/S_EAr/C–C cleavage/aromatization reaction, and the synthetic utility of this new transformation is exemplified by the succinct syntheses of trisphaeridine and bicolorine alkaloids.

A metal-free C–H [5 + 1] annulation reaction of 2-arylanilines with diazo compounds has been achieved, giving rise to two types of prevalent phenanthridines via highly selective C–C cleavage.     

Intramolecular Friedel–Crafts alkylation with a silylium-ion-activated cyclopropyl group: formation of tricyclic ring systems from benzyl-substituted vinylcyclopropanes and hydrosilanes

A trityl-cation-initiated annulation of benzyl-substituted vinylcyclopropanes (VCPs) with hydrosilanes is reported. Two Si–C(sp³) bonds and one C(sp²)–C(sp³) bond are formed in this process where an intramolecular 6-endo-tet Friedel–Crafts alkylation of a silylium-ion-activated cyclopropane ring is the rate-determining key step. The reaction mechanism is proposed based on computations and is in agreement with experimental observations. The new reaction leads to an unprecedented silicon-containing 6/6/5-fused ring system. A phenethyl-substituted VCP derivative yields another unknown tricycle having 6/6/6 ring fusion by reacting in a related but different way involving a 6-exo-tet ring closure.

Downstream to alkene hydrosilylation, the opening of the cyclopropane ring in benzyl-substituted VCPs is interlinked with an S_EAr of the aryl group.