(Hetero)arene-fused boroles: a broad spectrum of applications

(Hetero)arene-fused boroles are a class of compounds containing a 5-membered boron diene-ring. Based on their molecular framework, the (hetero)arene-fused boroles can be considered as boron-doped polycyclic antiaromatic hydrocarbons and are thus of great interest. Due to the vacant p_z orbital on the 3-coordinate boron atom, the antiaromaticity and strain of the 5-membered borole ring, (hetero)arene-fused boroles possess strong electron accepting abilities and Lewis acidity. By functionalization, they can be tuned to optimize different properties for specific applications. Herein, we summarize synthetic methodologies, different strategies for their functionalization, and applications of (hetero)arene-fused boroles.

(Hetero)arene-fused boroles, ‘antiaromatic’ 2n-electron π-systems, more stable and more functionalizable than boroles, offer greater potential for a variety of applications.     

Recent advances of group 14 dimetallenes and dimetallynes in bond activation and catalysis

Since the first heavy alkene analogues of germanium and tin were isolated in 1976, followed by West''s disilene in 1981, the chemistry of stable group 14 dimetallenes and dimetallynes has advanced immensely. Recent developments in this field veered the focus from the isolation of novel bonding motifs to mimicking transition metals in their ability to activate small molecules and perform catalysis. The potential of these homonuclear multiply bonded compounds has been demonstrated numerous times in the activation of H₂, NH₃, CO₂ and other small molecules. Hereby, the strong relationship between structure and reactivity warrants close attention towards rational ligand design. This minireview provides an overview on recent developments in regard to bond activation with group 14 dimetallenes and dimetallynes with the perspective of potential catalytic applications of these compounds.

This minireview highlights the recent advances in small molecule activation and catalytic applications of homonuclear dimetallenes, dimetallynes and interconnected bismetallylenes of heavier group 14 elements.     

Rhodium catalysed C-3/5 methylation of pyridines using temporary dearomatisation

Pyridines are ubiquitous aromatic rings used in organic chemistry and are crucial elements of the drug discovery process. Herein we describe a new catalytic method that directly introduces a methyl group onto the aromatic ring; this new reaction is related to hydrogen borrowing, and is notable for its use of the feedstock chemicals methanol and formaldehyde as the key reagents. Conceptually, the C-3/5 methylation of pyridines was accomplished by exploiting the interface between aromatic and non-aromatic compounds, and this allows an oscillating reactivity pattern to emerge whereby normally electrophilic aromatic compounds become nucleophilic in the reaction after activation by reduction. Thus, a set of C-4 functionalised pyridines can be mono or doubly methylated at the C-3/5 positions.

Electron poor pyridines can be activated by reduction and then methylated at C3/5 using formaldehyde.     

Strain visualization for strained macrocycles

Strain has a unique and sometimes unpredictable impact on the properties and reactivity of molecules. To thoroughly describe strain in molecules, a computational tool that relates strain energy to reactivity by localizing and quantifying strain was developed. Strain energy is calculated local to every coordinate in the molecule and areas of higher strain are shown experimentally to be more reactive. Not only does this tool directly compare strain energy in parts of the same molecule, but it also computes total strain to give a full picture of molecular strain energy. It is freely available to the public on GitHub under the name StrainViz and much of the workflow is automated to simplify use for non-experts. Unique insight into the reactivity of curved aromatic molecules and strained alkyne bioorthogonal reagents is described within.

Strain has a unique and sometimes unpredictable impact on the properties and reactivity of molecules.     

A bifunctional iminophosphorane squaramide catalyzed enantioselective synthesis of hydroquinazolines via intramolecular aza-Michael reaction to α,β-unsaturated esters

An efficient synthesis of enantioenriched hydroquinazoline cores via a novel bifunctional iminophosphorane squaramide catalyzed intramolecular aza-Michael reaction of urea-linked α,β-unsaturated esters is described. The methodology exhibits a high degree of functional group tolerance around the forming hydroquinazoline aryl core and wide structural variance on the nucleophilic N atom of the urea moiety. Excellent yields (up to 99%) and high enantioselectivities (up to 97 : 3 er) using both aromatic and less acidic aliphatic ureas were realized. The potential industrial applicability of the transformation was demonstrated in a 20 mmol scale-up experiment using an adjusted catalyst loading of 2 mol%. The origin of enantioselectivity and reactivity enhancement provided by the squaramide motif has been uncovered computationally using density functional theory (DFT) calculations, combined with the activation strain model (ASM) and energy decomposition analysis (EDA).

The activation of both aromatic and aliphatic ureas as N-centered nucleophiles in intramolecular Michael addition reactions to α,β-unsaturated esters was achieved under bifunctional iminophosphorane squaramide superbase catalysis.     

Catalytic asymmetric multiple dearomatizations of phenols enabled by a cascade 1,8-addition and Diels–Alder reaction

A direct catalytic asymmetric multiple dearomatization reaction of phenols was disclosed, which provides expedient access to a series of architecturally complex polycyclic compounds bearing four stereogenic centers in high enantiopurity. The key to achieve such a transformation is the combination of a dearomative 1,8-addition of β-naphthols to para-quinone methides generated in situ from propargylic alcohols and a subsequent intramolecular dearomative Diels–Alder reaction. Noteworthily, this protocol enrichs not only the diversity of dearomatized products but also the toolbox of dearomatization strategies.

The first chiral phosphoric acid catalyzed asymmetric multiple dearomatizations of phenols for the synthesis of bridged polycyclic compounds are reported.     

Acyl metalloids: conformity and deviation from carbonyl reactivity

Once considered as mere curiosities, acyl metalloids are now recognized for their utility in enabling chemical synthesis. This perspective considers the reactivity displayed by acylboron, -silicon, -germanium, and tellurium species. By highlighting the role of these species in various transformations, we demonstrate how differences between the comprising elements result in varied reaction outcomes. While acylboron compounds are primarily used in polar transformations, germanium and tellurium species have found utility as radical precursors. Applications of acylsilanes are comparatively more diverse, owing to the possibility to access both radical and polar chemistry.

Originally considered as fundamental curiosities, acyl metalloids have proven to be useful tools in synthesis. This perspective aims to highlight the modes of reactivity accessible to boron, silicon, germanium and tellurium species.     

Recent advances in low oxidation state aluminium chemistry

The synthesis and isolation of novel low oxidation state aluminium (Al) compounds has seen relatively slow progress over the 30 years since such species were first isolated. This is largely due to the significant challenges in isolating these thermodynamically unstable compounds. Despite challenges with isolation, their reactivity has been widely explored and they have been utilized in a wide range of processes including the activation of strong chemicals bonds, as ligands to transition metals and in the formation of heterobimetallic M–M compounds. As such, attempts to isolate novel low oxidation state Al compounds have continued in earnest and in the last few years huge advances have been made. In this review we highlight the remarkable recent developments in the low oxidation state chemistry of aluminium and discuss the variety of new reactions these compounds have made possible.

Documenting the synthesis and isolation of novel low oxidation state aluminium (Al) compounds, which until recently has seen relatively slow progress over the 30 years since such species were first isolated.     

Synthetic half-reactions

This perspective on reactivity introduces Synthetic Half-Reactions (SHRs) as a way to analyze chemical transformations. SHRs denote either an uphill transformation leading to a higher energy state or a downhill transformation leading to a lower energy state. Using well-established processes, I show how the matching of different classes of SHRs offers a tool to classify chemical transformations. This raises the possibility to discover new processes by finding underappreciated combinations of endergonic and exergonic steps.

This perspective on reactivity introduces Synthetic Half-Reactions (SHRs) as a way to analyze chemical transformations.     

Photoresponsive molecular tools for emerging applications of light in medicine

Light-based therapeutic and imaging modalities, which emerge in clinical applications, rely on molecular tools, such as photocleavable protecting groups and photoswitches that respond to photonic stimulus and translate it into a biological effect. However, optimisation of their key parameters (activation wavelength, band separation, fatigue resistance and half-life) is necessary to enable application in the medical field. In this perspective, we describe the applications scenarios that can be envisioned in clinical practice and then we use those scenarios to explain the necessary properties that the photoresponsive tools used to control biological function should possess, highlighted by examples from medical imaging, drug delivery and photopharmacology. We then present how the (photo)chemical parameters are currently being optimized and an outlook is given on pharmacological aspects (toxicity, solubility, and stability) of light-responsive molecules. With these interdisciplinary insights, we aim to inspire the future directions for the development of photocontrolled tools that will empower clinical applications of light.

This perspective article explores the current state of light-controlled molecular tools for medical therapy and imaging and offers an outlook on clinical application scenarios and optimisation strategies.     

Exploiting the radical reactivity of diazaphosphinanes in hydrodehalogenations and cascade cyclizations

The remarkable reducibility of diazaphosphinanes has been extensively applied in various hydrogenations, based on and yet limited by their well-known hydridic reactivity. Here we exploited their unprecedented radical reactivity to implement hydrodehalogenations and cascade cyclizations originally inaccessible by hydride transfer. These reactions feature a broad substrate scope, high efficiency and simplicity of manipulation. Mechanistic studies suggested a radical chain process in which a phosphinyl radical is generated in a catalytic cycle via hydrogen-atom transfer from diazaphosphinanes. The radical reactivity of diazaphosphinanes disclosed here differs from their well-established hydridic reactivity, and hence, opens a new avenue for diazaphosphinane applications in organic syntheses.

Unprecedented radical reactivity of diazaphosphinanes was explored to implement efficient hydrodehalogenations and cascade cyclizations.     

Fully fused boron-doped polycyclic aromatic hydrocarbons: their synthesis,structure–property relationships,and self-assembly behavior in aqueous media

Planarized triarylboranes are attracting increasing attention not only as models of boron-doped graphenes, but also as promising materials for organic optoelectronics. In particular, polycyclic aromatic hydrocarbon (PAH) skeletons with embedded boron atom(s) in the inner positions are of importance in light of their high chemical stability and π-stacking ability derived from their planar geometries. Herein, we disclose a robust synthesis of such fully fused boron-doped PAHs and their self-assembly behavior in aqueous media to explore their potential utility in biological applications. The synthesis using in situ-generated planar diarylboranes as a key precursor afforded a series of fully fused boron-doped PAHs, even including an amphiphilic derivative with hydrophilic side chains. These compounds exhibited red emission in solution, and slight structural modification resulted in increased fluorescence brightness. While these compounds showed relatively low Lewis acidity compared to their partially ring-fused counterparts, their Lewis acidities were slightly increased in polar solvents compared to those in nonpolar solvents. In addition, their B–N Lewis acid–base adducts, even those with a strong, charge-neutral Lewis base such as N,N-dimethylaminopyridine (DMAP), exhibited photo-dissociation behavior in the excited state. The amphiphilic derivative showed significant spectral changes with increased water content in DMSO/H₂O mixed media and formed sheet-like aggregates. The disassembly and assembly processes of the aggregates were externally controlled by the addition of DMAP and an acid, accompanied by a change in the fluorescence intensity.

A series of fully fused boron-doped polycyclic aromatic hydrocarbons is synthesized. Self-assembly of an amphiphilic derivative can be controlled by addition of a Lewis base or an acid in aqueous media.     

How metallylenes activate small molecules

We have studied the activation of dihydrogen by metallylenes using relativistic density functional theory (DFT). Our detailed activation strain and Kohn–Sham molecular orbital analyses have quantified the physical factors behind the decreased reactivity of the metallylene on going down Group 14, from carbenes to stannylenes. Along this series, the reactivity decreases due to a worsening of the back-donation interaction between the filled lone-pair orbital of the metallylene and the σ*-orbital of H₂, which, therefore, reduces the metallylene–substrate interaction and increases the reaction barrier. As the metallylene ligand is varied from nitrogen to phosphorus to arsenic a significant rate enhancement is observed for the activation of H₂ due to (i) a reduced steric (Pauli) repulsion between the metallylene and the substrate; and (ii) less activation strain, as the metallylene becomes increasingly more predistorted. Using a rationally designed metallylene with an optimal Group 14 atom and ligand combination, we show that a number of small molecules (i.e. HCN, CO₂, H₂, NH₃) may also be readily activated. For the first time, we show the ability of our H₂ activated designer metallylenes to hydrogenate unsaturated hydrocarbons. The results presented herein will serve as a guide for the rational design of metallylenes toward the activation of small molecules and subsequent reactions.

Quantum chemical analyses reveal how model metallylene catalysts activate H₂. This is the first step towards the rational design of metallylenes for the activation of small molecules and subsequent reactions.     

Ligand-protected gold/silver superatoms: current status and emerging trends

Monolayer-protected gold/silver clusters have attracted much interest as nano-scale building units for novel functional materials owing to their nonbulk-like structures and size-specific properties. They can be viewed as ligand-protected superatoms because their magic stabilities and fundamental properties are well explained in the framework of the jellium model. In the last decade, the number of ligand-protected superatoms with atomically-defined structures has been increasing rapidly thanks to the well-established synthesis and structural determination by X-ray crystallography. This perspective summarizes the current status and emerging trends in synthesis and characterization of superatoms. The topics related to synthesis include (1) development of targeted synthesis based on transformation, (2) enhancement of robustness and synthetic yield for practical applications, and (3) development of controlled fusion and assembly of well-defined superatoms to create new properties. New characterization approaches are also introduced such as (1) mass spectrometry and laser spectroscopies in the gas phase, (2) determination of static and dynamic structures, and (3) computational analysis by machine learning. Finally, future challenges and prospects are discussed for further promotion and development of materials science of superatoms.

This perspective summarizes the current status and emerging trends in synthesis and characterization of ligand-protected gold/silver superatoms.     

Reversible OH-bond activation and amphoterism by metal–ligand cooperativity of calix[4]pyrrolato aluminate

Most p-block metal amides irreversibly react with metal alkoxides when subjected to alcohols, making reversible transformations with OH-substrates a challenging task. Herein, we describe how the combination of a Lewis acidic square-planar-coordinated aluminum(iii) center with metal–ligand cooperativity leverages unconventional reactivity toward protic substrates. Calix[4]pyrrolato aluminate performs OH-bond activation of primary, secondary, and tertiary aliphatic and aromatic alcohols, which can be fully reversed under reduced pressure. The products exhibit a new form of metal–ligand cooperative amphoterism and undergo counterintuitive substitution reactions of a polar covalent Al–O bond by a dative Al–N bond. A comprehensive mechanistic picture of all processes is buttressed by isolation of intermediates, spectroscopy, and computation. This study delineates how structural constraints can invert thermodynamics for seemingly simple addition reactions and invert common trends in bond energies.

The combination of structural constraint and metal–ligand cooperativity in calix[4]pyrrolato aluminate inverts common trends of bond energies and enables reversible OH-bond activation.     

Boronic acid based dynamic click chemistry: recent advances and emergent applications

Recently, reversible click reactions have found numerous applications in chemical biology, supramolecular chemistry, and biomedical applications. Boronic acid (BA)-mediated cis-diol conjugation is one of the best-studied reactions among them. An excellent understanding of the chemical properties and biocompatibility of BA-based compounds has inspired the exploration of novel chemistries using boron to fuel emergent sciences. This topical review focuses on the recent progress of iminoboronate and salicylhydroxamic–boronate constituted reversible click chemistries in the past decade. We highlight the mechanism of reversible kinetics and its applications in chemical biology, medicinal chemistry, biomedical devices, and material chemistry. This article also emphasizes the fundamental reactivity of these two conjugate chemistries with assorted nucleophiles at variable pHs, which is of utmost importance to any stimuli-responsive biological and material chemistry explorations.

Fundamental progress, current developments, and rapidly growing applications of iminoboronate and salicylhydroxamic–boronate conjugate esters are deliberated.     

Understanding the Reactivity of Planar Polycyclic Aromatic Hydrocarbons: Towards the Graphene Limit

The Diels–Alder reactivity of maleic anhydride towards the bay regions of planar polycyclic aromatic hydrocarbons was explored computationally in the DFT framework. The process becomes more and more exothermic and the associated activation barriers become lower and lower when the size of the system increases. This enhanced reactivity follows an exponential behavior that reaches its maximum for systems having 18–20 benzenoid rings in their structures. This peculiar behavior was analyzed in detail by using the activation strain model of reactivity in combination with energy decomposition analysis. The influence of the change in the aromaticity of the polycyclic compound during the process on the respective activation barriers was also studied.     

Phosphorus-ylides: powerful substituents for the stabilization of reactive main group compounds

Phosphorus ylides are 1,2-dipolar compounds with a negative charge on the carbon atom. This charge is stabilized by the neighbouring onium moiety, but can also be shifted towards other substituents thus making ylides strong π donor ligands and hence ideal substituents to stabilize reactive compounds such as cations and low-valent main group species. Furthermore, the donor strength and the steric properties can easily be tuned to meet different requirements for stabilizing reactive compounds and for tailoring the properties and reactivities of the main group element. Although the use of ylide substituents in main group chemistry is still in its infancy, the first examples of isolated compounds impressively demonstrate the potential of these ligands. This review summarizes the most important discoveries also in comparison to other substituents, thus outlining avenues for future research directions.

The application of ylide substituents as strong donor ligands for the stabilization of reactive main group compounds with unusual properties and reactivities is discussed.     

Activatable molecular agents for cancer theranostics

Theranostics that integrates diagnosis and treatment modalities has attracted great attention due to its abilities of personalized therapy and real-time monitoring of therapeutic outcome. Such a theranostic paradigm requires agents to simultaneously possess the capabilities of targeting, imaging, and treatment. Activatable molecular agents (AMAs) are promising for cancer theranostics, as they show a higher signal-to-noise ratio (SNR), real-time detection of cancer-associated biomarkers, lower normal tissue toxicity, and a higher therapeutic effect. This perspective summarizes the recent advancements of AMAs, which include imaging-guided chemotherapy, imaging-guided photodynamic therapy, and imaging-guided photothermal therapy. The molecular design principles, theranostic mechanisms, and biomedical applications of AMAs are described, followed by a discussion of potential challenges of AMAs in cancer theranostics.

Activatable molecualr agents that intergrate diagnosis and treatment modalities have attracted great attention due to its abilities of personalized therapy and real-time monitoring of therapeutic outcome.     

Salient features of the aza-Wacker cyclization reaction

The intramolecular aza-Wacker reaction has unparalleled potential for the site-selective amination of olefins, but it is perhaps underappreciated relative to other alkene oxidations. The first part of this review makes the distinction between classical and tethered aza-Wacker cyclization reactions and summarizes examples of the latter. The second portion focuses on developments in asymmetric aza-Wacker cyclization technology. The final part of the review summarizes applications of all classes of aza-Wacker cyclization reactions to natural product assembly.

The aza-Wacker cyclization reaction is a powerful strategy for alkene amination.