Unclicking the Click: Metal‐Assisted Mechanochemical Cycloreversion of Triazoles Is Possible

The mechanochemical cycloreversion of 1,2,3‐triazole compounds, which serve as unusually stable building blocks in materials and biomolecular chemistry as a result of mild “click chemistry”, remains puzzling. We show that the hitherto discussed straight‐forward retro‐click mechanism of the 1,4‐disubstituted isomer, even if Cu^I catalyzed, can be ruled out in view of more favorable activation free energies of destructive pathways. In stark contrast, the 1,5‐regioiomer can undergo cycloreversion under rather mild mechanochemical conditions owing to its favorable response to the external force in conjunction with standard Ru^II catalysis.     

The First Synthesis of the Sterically Encumbered Adamantoid Phosphazane P4(NtBu)6: Enabled by Mechanochemistry

All reported attempts to synthesize the tert‐butyl‐substituted adamantoid phosph(III)azane P₄(N^tBu)₆ have failed, leading to the classification of this molecule as inaccessible and a literature example of steric control in chemistry of phosphorus‐nitrogen compounds. We now demonstrate that this structure is readily accessible by a solvent‐free mechanochemical milling approach, highlighting the importance of mechanochemical reaction environments in evaluating chemical reactivity.     

Mechanical Reversibility of Strain‐Promoted Azide–Alkyne Cycloaddition Reactions

Mechanophores, that is, molecules that show a defined response to force, are crucial building blocks of mechanoresponsive materials. The possibility of mechanically induced cycloreversion for a series of triazoles formed via strain‐promoted azide–alkyne cycloaddition reactions was investigated by density functional theory calculations, and these triazoles were compared to the 1,4‐ and 1,5‐regioisomers formed in the reaction of an azide with a terminal alkyne. We show that cycloreversion is in principal possible and that the pulling geometry is the most important parameter that determines the probability of cycloreversion. We further compared triazole stability to the mechanical stability of polymers that are frequently used as force transducers in mechanochemical experiments and identified DIBAC (azadibenzylcyclooctyne) as a promising mechanophore for future applications.     

Cycloreversion of acylquadricyclane to acylnorbornadiene promoted by metal oxides

The very mild, stable, immobilized, and inexpensive metal oxides effectively catalyzed the cycloreversion of methyl 2,4-dimethyl 6,7-diphenyl-5-propionyltetracyclo[3.2.0.0^2,−7.04,6] heptan-1-carboxylate (1).     

Mechanochemistry in Portugal—A Step towards Sustainable Chemical Synthesis

In Portugal, publications with mechanochemical methods date back to 2009, with the report on mechanochemical strategies for the synthesis of metallopharmaceuticals. Since then, mechanochemical applications have grown in Portugal, spanning several fields, mainly crystal engineering and supramolecular chemistry, catalysis, and organic and inorganic chemistry. The area with the most increased development is the synthesis of multicomponent crystal forms, with several groups synthesizing solvates, salts, and cocrystals in which the main objective was to improve physical properties of the active pharmaceutical ingredients. Recently, non-crystalline materials, such as ionic liquids and amorphous solid dispersions, have also been studied using mechanochemical methods. An area that is in expansion is the use of mechanochemical synthesis of bioinspired metal-organic frameworks with an emphasis in antibiotic coordination frameworks. The use of mechanochemistry for catalysis and organic and inorganic synthesis has also grown due to the synthetic advantages, ease of synthesis, scalability, sustainability, and, in the majority of cases, the superior properties of the synthesized materials. It can be easily concluded that mechanochemistry is expanding in Portugal in diverse research areas.     

Visible-Light-Mediated Click Chemistry for Highly Regioselective Azide–Alkyne Cycloaddition by a Photoredox Electron-Transfer Strategy

Click chemistry focuses on the development of highly selective reactions using simple precursors for the exquisite synthesis of molecules. Undisputedly, the Cu^I-catalyzed azide–alkyne cycloaddition (CuAAC) is one of the most valuable examples of click chemistry, but it suffers from some limitations as it requires additional reducing agents and ligands as well as cytotoxic copper. Here, we demonstrate a novel strategy for the azide–alkyne cycloaddition reaction that involves a photoredox electron-transfer radical mechanism instead of the traditional metal-catalyzed coordination process. This newly developed photocatalyzed azide–alkyne cycloaddition reaction can be performed under mild conditions at room temperature in the presence of air and visible light and shows good functional group tolerance, excellent atom economy, high yields of up to 99 %, and absolute regioselectivity, affording a variety of 1,4-disubstituted 1,2,3-triazole derivatives, including bioactive molecules and pharmaceuticals. The use of a recyclable photocatalyst, solar energy, and water as solvent makes this photocatalytic system sustainable and environmentally friendly. Moreover, the azide–alkyne cycloaddition reaction could be photocatalyzed in the presence of a metal-free catalyst with excellent regioselectivity, which represents an important development for click chemistry and should find versatile applications in organic synthesis, chemical biology, and materials science.     

Synthesis of Biologically Relevant 1,2,3- and 1,3,4-Triazoles: From Classical Pathway to Green Chemistry

Green Chemistry has become in the last two decades an increasing part of research interest. Nonconventional «green» sources for chemical reactions include micro-wave, mechanical mixing, visible light and ultrasound. 1,2,3-triazoles have important applications in pharmaceutical chemistry while their 1,2,4 counterparts are developed to a lesser extent. In the review presented here we will focus on synthesis of 1,2,3 and 1,2,4-triazole systems by means of classical and « green chemistry » conditions involving ultrasound chemistry and mechanochemistry. The focus will be on compounds/scaffolds that possess biological/pharmacophoric properties. Finally, we will also present the formal cycloreversion of 1,2,3-triazole compounds under mechanical forces and its potential use in biological systems.     

N-Formylsaccharin: A Sweet(able) Formylating Agent in Mechanochemistry

The acylation of amines has always attracted a deep interest as a synthetic route due to its high versatility in organic chemistry and biochemical processes. The purpose of this article is to present a mechanochemical acylation procedure based on the use of acyl-saccharin derivatives, namely N-formylsaccharin, N-acetylsaccharin, and N-propionylsaccharin. This protocol furnishes a valuable solvent-free alternative to the existing processes and aims to be highly beneficial in multi-step procedures due to its rapid and user-friendly workup.     

Formation of hairy cellulose nanocrystals by cryogrinding

Cellulose - From a green chemistry perspective, cryogrinding of cellulose fibers conducted under mild conditions is introduced as a rapid, facile, and scalable methodology for the mechanochemical...     

Mechanochemical Encapsulation of Fullerenes in Peptidic Containers Prepared by Dynamic Chiral Self‐Sorting and Self‐Assembly

Molecular capsules composed of amino acid or peptide derivatives connected to resorcin[4]arene scaffolds through acylhydrazone linkers have been synthesized using dynamic covalent chemistry (DCC) and hydrogen‐bond‐based self‐assembly. The dynamic character of the linkers and the preference of the peptides towards self‐assembly into β‐barrel‐type motifs lead to the spontaneous amplification of formation of homochiral capsules from mixtures of different substrates. The capsules have cavities of around 800 ų and exhibit good kinetic stability. Although they retain their dynamic character, which allows processes such as chiral self‐sorting and chiral self‐assembly to operate with high fidelity, guest complexation is hindered in solution. However, the quantitative complexation of even very large guests, such as fullerene C₆₀ or C₇₀, is possible through the utilization of reversible covalent bonds or the application of mechanochemical methods. The NMR spectra show the influence of the chiral environment on the symmetry of the fullerene molecules, which results in the differentiation of diastereotopic carbon atoms for C₇₀, and the X‐ray structures provide unique information on the modes of peptide–fullerene interactions.     

Click Mechanochemistry: Quantitative Synthesis of “Ready to Use” Chiral Organocatalysts by Efficient Two‐Fold Thiourea Coupling to Vicinal Diamines

Mechanochemical methods of neat grinding and liquid‐assisted grinding have been applied to the synthesis of mono‐ and bis(thiourea)s by using the click coupling of aromatic and aliphatic diamines with aromatic isothiocyanates. The ability to modify the reaction conditions allowed the optimization of each reaction, leading to the quantitative formation of chiral bis(thiourea)s with known uses as organocatalysts or anion sensors. Quantitative reaction yields, combined with the fact that mechanochemical reaction conditions avoid the use of bulk solvents, enabled solution‐based purification methods (such as chromatography or recrystallization) to be completely avoided. Importantly, by using selected model reactions, we also show that the described mechanochemical reaction procedures can be readily scaled up to at least the one‐gram scale. In that way, mechanochemical synthesis provides a facile method to fully transform valuable enantiomerically pure reagents into useful products that can immediately be applied in their designed purpose. This was demonstrated by using some of the mechanochemically prepared reagents as organocatalysts in a model Morita–Baylis–Hillman reaction and as cyanide ion sensors in organic solvents. The use of electronically and sterically hindered ortho‐phenylenediamine revealed that mechanochemical reaction conditions can be readily optimized to form either the 1:1 or the 1:2 click‐coupling product, demonstrating that reaction stoichiometry can be more efficiently controlled under these conditions than in solution‐based syntheses. In this way, it was shown that excellent stoichiometric control by mechanochemistry, previously established for mechanochemical syntheses of cocrystals and coordination polymers, can also be achieved in the context of covalent‐bond formation.     

Mechanochemical Preparations of Anion Coordinated Architectures Based on 3-Iodoethynylpyridine and 3-Iodoethynylbenzoic Acid

The halogen bond has previously been explored as a versatile tool in crystal engineering and anion coordination chemistry, with mechanochemical synthetic techniques having been shown to provide convenient routes towards cocrystals. In an effort to expand our knowledge on the role of halogen bonding in anion coordination, here we explore a series of cocrystals formed between 3-iodoethynylpyridine and 3-iodoethynylbenzoic acid with halide salts. In total, we report the single-crystal X-ray structures of six new cocrystals prepared by mechanochemical ball milling, with all structures exhibiting C≡C−I⋅⋅⋅X⁻ (X=Cl, Br) halogen bonds. Whereas cocrystals featuring a pyridine group favoured the formation of discrete entities, cocrystals featuring a benzoic acid group yielded an alternation of halogen and hydrogen bonds. The compounds studied herein were further characterized by ¹³C and ³¹P solid-state nuclear magnetic resonance, with the chemical shifts offering a clear and convenient method of identifying the occurrence of halogen bonding, using the crude product obtained directly from the mechanochemical ball milling. Whereas the ³¹P chemical shifts were quickly able to identify the occurrence of cocrystallization, ¹³C solid-state NMR was diagnostic of both the occurrence of halogen bonding and of hydrogen bonding.     

Predetermined Chirality at Metal Centers

Asymmetric synthesis in coordination chemistry was described very clearly by Smirnoff in 1920, but, contrary to the development in organic chemistry, it was almost completely neglected for several decades. The interest in chirality in coordination chemistry (see the stereoview of [Ru(bpy)₃]²⁺) has increased rapidly in recent times as a consequence of developments in several fields where chirality is important (polynuclear systems, supramolecular structures, and enantioselective catalysis). Here we show many examples of how, through the choice of ligand, the configuration of a metal center or the chirality of a helicate can be predetermined.     

A Gram‐Scale Batch and Flow Total Synthesis of Perhydrohistrionicotoxin

The total synthesis of the spiropiperidine alkaloid (?)‐perhydrohistrionicotoxin (perhydro‐HTX) 2 has been accomplished on a gram scale by employing both conventional batch chemistry as well as microreactor techniques. (S)‐(?)‐6‐Pentyltetrahydro‐pyran‐2‐one 8 underwent nucleophilic ring opening to afford the alcohol 10 , which was elaborated to the nitrone 13 . Protection of the nitrone as the 1,3‐adduct of styrene and side‐chain extension to the unsaturated nitrile afforded a precursor 17 , which underwent dipolar cycloreversion and 1,3‐dipolar cycloaddition to give the core spirocyclic precursor 18 that was converted into perhydro‐HTX 2 . The principal steps to the spirocycle 18 have successfully been transferred into flow mode by using different types of microreactors and in a telescoped fashion, allowing for a more rapid access to the histrionicotoxins and their analogues by continuous processing.     

A New Insight into the Stereoelectronic Control of the Pd0-Catalyzed Allylic Substitution: Application for the Synthesis of Multisubstituted Pyran-2-ones via an Unusual 1,3-Transposition

Pyran-2-ones 3 undergo a novel Pd⁰-catalyzed 1,3-rearrangement to afford isomers 6 . The reaction proceeds via an η²-Pd complex, the pyramidalization of which (confirmed by quantum chemistry calculations) offers a favorable antiperiplanar alignment of the Pd−C and allylic C−O bonds ( C ), thus allowing the formation of an η³-Pd intermediate. Subsequent rotation and rate-limiting recombination with the carboxylate arm then gives isomeric pyran-2-ones 6 . The calculated free energies reproduce the observed kinetics semi-quantitatively.     

Tuning the Photocatalytic Performance of Ruthenium(II) Polypyridine Complexes Via Ligand Modification for Visible-Light-Induced Phosphorylation of Tertiary Aliphatic Amines

Tuning the redox potential of commonly available photocatalyst to improve the catalytic performance or expand its scope for challenging synthetic conversions is an ongoing demand in synthetic chemistry. Herein, the excited state properties and redox potential of commercially available [Ru(bpy)₃]²⁺ photocatalyst were tuned by modifying the structure of the bipyridine ligands with electron-donating/withdrawing units. The visible-light-mediated photoredox phosphorylation of tertiary aliphatic amines was demonstrated under mild conditions. A series of cross-dehydrogenative coupling reactions were performed employing the Ru^II complexes as photocatalyst giving the corresponding α-aminophosphinoxides and α-aminophosphonates via carbon-phosphorus (C−P) bond formation.     

Mechanochemical tools in the synthesis of organometallic compounds

In response to rising environmental concerns, chemistry is experiencing a considerable change in both concepts and practices to adopt more efficient and sustainable technologies. One of the alternative technologies that offer many advantages over the conventional solution-based techniques is mechanochemistry which utilizes mechanical energy to induce chemical reactions. Despite the fact that mechanochemistry has reached high significance in the creation of advanced materials, such as alloys, ceramics, electrode materials, and nanocomposites, in the field of small molecule synthesis its potential remains largely untapped. This review highlights the opportunities and prospects of different mechanochemical tools in the synthesis of organometallic compounds, including transition metal complexes with N-heterocyclic carbene, arene, and cyclopentadienyl ligands, monometallacyclic and pincer derivatives, as well as main group metal compounds (e.g., allyl complexes and the Grignard reagents). Many important organometallic transformations such as C–H bond metalation, transmetalation, and oxidative addition can be successfully implemented under mechanochemical conditions in a highly productive and energy-saving manner. Furthermore, the postmodification of metal-containing species upon grinding or milling is shown to be a powerful route to both new discrete metal complexes and different supramolecular architectures (metal-containing organic cages, macrocylces, networks).     

Nitrile Synthesis with Aldoxime Dehydratases: A Biocatalytic Platform with Applications in Asymmetric Synthesis,Bulk Chemicals,and Biorefineries

Nitriles comprise a broad group of chemicals that are currently being industrially produced and used in fine chemicals and pharmaceuticals, as well as in bulk applications, polymer chemistry, solvents, etc. Aldoxime dehydratases catalyze the cyanide-free synthesis of nitriles starting from aldoximes under mild conditions, holding potential to become sustainable alternatives for industrial processes. Different aldoxime dehydratases accept a broad range of aldoximes with impressive high substrate loadings of up to >1 Kg L⁻¹ and can efficiently catalyze the reaction in aqueous media as well as in non-aqueous systems, such as organic solvents and solvent-free (neat substrates). This paper provides an overview of the recent developments in this field with emphasis on strategies that may be of relevance for industry and sustainability. When possible, potential links to biorefineries and to the use of biogenic raw materials are discussed.     

Applying Mechanochemistry for Bottom‐Up Synthesis and Host–Guest Surface Modification of Semiconducting Nanocrystals: A Case of Water‐Soluble β‐Cyclodextrin‐Coated Zinc Oxide

Mechanochemistry has recently emerged as an environmentally friendly solventless synthesis method enabling a variety of transformations including those impracticable in solution. However, its application in the synthesis of well‐defined nanomaterials remains very limited. Here, we report a new bottom‐up mechanochemical strategy to rapid mild‐conditions synthesis of organic ligand‐coated ZnO nanocrystals (NCs) and their further host–guest modification with β‐cyclodextrin (β‐CD) leading to water‐soluble amide‐β‐CD‐coated ZnO NCs. The transformations can be achieved by either one‐pot sequential or one‐step three‐component process. The developed bottom‐up methodology is based on employing oxo‐zinc benzamidate, [Zn₄(μ₄‐O)(NHOCPh)₆], as a predesigned molecular precursor undergoing mild solid‐state transformation to ZnO NCs in the presence of water in a rapid, clean and sustainable process.     

Mechanochemical Suzuki-Miyaura Cross-Coupling with Natural Deep Eutectic Solvent as Liquid-Assisted Grinding Additive: Merging Two Fields for a Greener Strategy

The use of volatile solvents for organic synthesis is nowadays questioned due to their negative impact on the environnement. To develop sustainable and environmentally friendly methodologies, we propose to combine two green chemistry concepts: the use of bioinspired solvents: natural deep eutectic solvents (NaDES), and mechanochemistry. Using the Suzuki-Miyaura coupling as a model reaction, we described an efficient mechanochemical method with NaDES as a LAG (liquid-assisted grinding) additive with short reaction times and without any ligand or additional heating. A mechanochemical extraction was also used to reduce the amounts of extraction solvents and the total time of the synthesis process.