Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane.

Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly found para-substituted benzene rings in drug design1. The utility of these cage structures derives from their superior pharmacokinetic properties compared with their parent aromatics, including improved solubility and reduced susceptibility to metabolism2,3. A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesized by ring-opening of the interbridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions4. By contrast, scaffolds mimicking meta-substituted arenes are lacking because of the challenge of synthesizing saturated isosteres that accurately reproduce substituent vectors5. Here we show that bicyclo[3.1.1]heptanes (BCHeps), which are hydrocarbons for which the bridgehead substituents map precisely onto the geometry of meta-substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on a multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally relevant carbon- and heteroatom-substituted BCHeps, including pharmaceutical analogues. Comparison of the absorption, distribution, metabolism and excretion (ADME) properties of these analogues reveals enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this meta-arene analogue as an sp3-rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a new surrogate for meta-substituted benzene rings for implementation in drug discovery programmes.

Chemical Bonding and the Role of Node-Induced Electron Confinement.

The chemical bond is the cornerstone of chemistry, providing a conceptual framework to understand and predict the behavior of molecules in complex systems. However, the fundamental origin of chemical bonding remains controversial and has been responsible for fierce debate over the past century. Here, we present a unified theory of bonding, using a separation of electron delocalization effects from orbital relaxation to identify three mechanisms [node-induced confinement (typically associated with Pauli repulsion, though more general), orbital contraction, and polarization] that each modulate kinetic energy during bond formation. Through analysis of a series of archetypal bonds, we show that an exquisite balance of energy-lowering delocalizing and localizing effects are dictated simply by atomic electron configurations, nodal structure, and electronegativities. The utility of this unified bonding theory is demonstrated by its application to explain observed trends in bond strengths throughout the periodic table, including main group and transition metal elements.

Mechanistic Insights into the Origins of Selectivity in a Cu-Catalyzed C-H Amidation Reaction.

The catalytic transformation of C-H to C-N bonds offers rapid access to fine chemicals and high-performance materials, but achieving high selectivity from undirected aminations of unactivated C(sp3)-H bonds remains an outstanding challenge. We report the origins of the reactivity and selectivity of a Cu-catalyzed C-H amidation of simple alkanes. Using a combination of experimental and computational mechanistic studies and energy decomposition techniques, we uncover a switch in mechanism from inner-sphere to outer-sphere coupling between alkyl radicals and the active Cu(II) catalyst with increasing substitution of the alkyl radical. The combination of computational predictions and detailed experimental validation shows that simultaneous minimization of both Cu-C covalency and alkyl radical size increases the rate of reductive elimination and that both strongly electron-donating and electron-withdrawing substituents on the catalyst accelerate the selectivity-determining C-N bond formation process as a result of a change in mechanism. These findings offer design principles for the development of improved catalyst scaffolds for radical C-H functionalization reactions.

Beyond Strain Release: Delocalization-Enabled Organic Reactivity.

The release of strain energy is a fundamental driving force for organic reactions. However, absolute strain energy alone is an insufficient predictor of reactivity, evidenced by the similar ring strain but disparate reactivity of cyclopropanes and cyclobutanes. In this work, we demonstrate that electronic delocalization is a key factor that operates alongside strain release to boost, or even dominate, reactivity. This delocalization principle extends across a wide range of molecules containing three-membered rings such as epoxides, aziridines, and propellanes and also applies to strain-driven cycloaddition reactions. Our findings lead to a "rule of thumb" for the accurate prediction of activation barriers in such systems, which can be easily applied to reactions involving many of the strained building blocks commonly encountered in organic synthesis, medicinal chemistry, polymer science, and bioconjugation. Given the significance of electronic delocalization in organic chemistry, for example in aromatic π-systems and hyperconjugation, we anticipate that this concept will serve as a versatile tool to understand and predict organic reactivity.

Visible Light Photoredox-Catalyzed Decarboxylative Alkylation of 3-Aryl-Oxetanes and Azetidines via Benzylic Tertiary Radicals and Implications of Benzylic Radical Stability.

Four-membered heterocycles offer exciting potential as small polar motifs in medicinal chemistry but require further methods for incorporation. Photoredox catalysis is a powerful method for the mild generation of alkyl radicals for C-C bond formation. The effect of ring strain on radical reactivity is not well understood, with no studies that address this question systematically. Examples of reactions that involve benzylic radicals are rare, and their reactivity is challenging to harness. This work develops a radical functionalization of benzylic oxetanes and azetidines using visible light photoredox catalysis to prepare 3-aryl-3-alkyl substituted derivatives and assesses the influence of ring strain and heterosubstitution on the reactivity of small-ring radicals. 3-Aryl-3-carboxylic acid oxetanes and azetidines are suitable precursors to tertiary benzylic oxetane/azetidine radicals which undergo conjugate addition into activated alkenes. We compare the reactivity of oxetane radicals to other benzylic systems. Computational studies indicate that Giese additions of unstrained benzylic radicals into acrylates are reversible and result in low yields and radical dimerization. Benzylic radicals as part of a strained ring, however, are less stable and more π-delocalized, decreasing dimer and increasing Giese product formation. Oxetanes show high product yields due to ring strain and Bent's rule rendering the Giese addition irreversible.

Redox Reorganization: Aluminium Promoted 1,5-Hydride Shifts Allow the Controlled Synthesis of Multisubstituted Cyclohexenes.

An efficient synthesis of cyclohexenes has been achieved from easily accessible tetrahydropyrans via a tandem 1,5-hydride shift-aldol condensation. We discovered that readily available aluminium reagents, e.g. Al2 O3 or Al(Ot Bu)3 are essential for this process, promoting the 1,5-hydride shift with complete regio- and enantiospecificity (in stark contrast to results obtained under basic conditions). The mild conditions, coupled with multiple methods available to access the tetrahydropyran starting materials makes this a versatile method with exceptional functional group tolerance. A wide range of cyclohexenes (>40 examples) have been prepared, many in enantiopure form, showing our ability to selectively install a substituent at each position around the newly forged cyclohexene ring. Experimental and computational studies revealed that aluminium serves a dual role in facilitating the hydride shift, activating both the alkoxide nucleophile and the electrophilic carbonyl group.

Single photon double and triple ionization of allene.

Double and triple ionization of allene are investigated using electron-electron, ion-ion, electron-electron-ion and electron-electron-ion-ion (ee, ii, eei, eeii) coincidence spectroscopies at selected photon energies. The results provide supporting evidence for a previously proposed roaming mechanism in H3+ formation by double ionization. The lowest vertical double ionization energy is found to be 27.9 eV, while adiabatic double ionization is not accessed by vertical ionization at the neutral geometry. The triple ionization energy is found to be close to 50 eV in agreement with theoretical predictions. The doubly charged parent ion is stable up to about 2 eV above the threshold, after which dissociations by charge separation and by double charge retention occur with comparable intensities. Fragmentation to H+ + C3H3+ starts immediately above the threshold as a slow (metastable) decay with 130.5 ± 9.9 ns mean lifetime.

Electrophilic Activation of [1.1.1]Propellane for the Synthesis of Nitrogen-Substituted Bicyclo[1.1.1]pentanes.

Strategies commonly used for the synthesis of functionalised bicyclo[1.1.1]pentanes (BCP) rely on the reaction of [1.1.1]propellane with anionic or radical intermediates. In contrast, electrophilic activation has remained a considerable challenge due to the facile decomposition of BCP cations, which has severely limited the applications of this strategy. Herein, we report the electrophilic activation of [1.1.1]propellane in a halogen bond complex, which enables its reaction with electron-neutral nucleophiles such as anilines and azoles to give nitrogen-substituted BCPs that are prominent motifs in drug discovery. A detailed computational analysis indicates that the key halogen bonding interaction promotes nucleophilic attack without sacrificing cage stabilisation. Overall, our work rehabilitates electrophilic activation of [1.1.1]propellane as a valuable strategy for accessing functionalised BCPs.

Highly Active Halogen Bonding and Chalcogen Bonding Chloride Transporters with Non-Protonophoric Activity.

Synthetic anion transporters show much promise as potential anti-cancer agents and therapeutics for diseases associated with mis-regulation of protein anion channels. In such applications high activity and anion selectivity are crucial to overcome competing proton or hydroxide transport which dissipates cellular pH gradients. Here, highly active bidentate halogen bonding and chalcogen bonding anion carriers based on electron deficient iodo- and telluromethyl-triazole derivatives are reported. Anion transport experiments in lipid bilayer vesicles reveal record nanomolar chloride transport activity for the bidentate halogen bonding anion carrier, and remarkably high chloride over proton/hydroxide selectivity for the chalcogen bonding anionophore. Computational studies provide further insight into the role of sigma-hole mediated anion recognition and desolvation at the membrane interface. Comparison with hydrogen bonding analogues demonstrates the importance of employing sigma-hole donor motifs in synthetic anionophores for achieving both high transport activity and selectivity.

A Novel Automated Screening Method for Combinatorially Generated Small Molecules.

A main challenge in the enumeration of small-molecule chemical spaces for drug design is to quickly and accurately differentiate between possible and impossible molecules. Current approaches for screening enumerated molecules (e.g., 2D heuristics and 3D force fields) have not been able to achieve a balance between accuracy and speed. We have developed a new automated approach for fast and high-quality screening of small molecules, with the following steps: (1) for each molecule in the set, an ensemble of 2D descriptors as feature encoding is computed; (2) on a random small subset, classification (feasible/infeasible) targets via a 3D-based approach are generated; (3) a classification dataset with the computed features and targets is formed and a machine learning model for predicting the 3D approach's decisions is trained; and (4) the trained model is used to screen the remainder of the enumerated set. Our approach is ≈8× (7.96× to 8.84×) faster than screening via 3D simulations without significantly sacrificing accuracy; while compared to 2D-based pruning rules, this approach is more accurate, with better coverage of known feasible molecules. Once the topological features and 3D conformer evaluation methods are established, the process can be fully automated, without any additional chemistry expertise.

autodE: Automated Calculation of Reaction Energy Profiles- Application to Organic and Organometallic Reactions.

Calculating reaction energy profiles to aid in mechanistic elucidation has long been the domain of the expert computational chemist. Here, we introduce autodE (https://github.com/duartegroup/autodE), an open-source Python package capable of locating transition states (TSs) and minima and delivering a full reaction energy profile from 1D or 2D chemical representations. autodE is broadly applicable to study organic and organometallic reaction classes, including addition, substitution, elimination, migratory insertion, oxidative addition, and reductive elimination; it accounts for conformational sampling of both minima and TSs and is compatible with many electronic structure packages. The general applicability of autodE is demonstrated in complex multi-step reactions, including cobalt- and rhodium-catalyzed hydroformylation and an Ireland-Claisen rearrangement.

Synthesis of Cyclo[18]carbon via Debromination of C18Br6.

Cyclo[18]carbon (C18, a molecular carbon allotrope) can be synthesized by dehalogenation of a bromocyclocarbon precursor, C18Br6, in 64% yield, by atomic manipulation on a sodium chloride bilayer on Cu(111) at 5 K, and imaged by high-resolution atomic force microscopy. This method of generating C18 gives a higher yield than that reported previously from the cyclocarbon oxide C24O6. The experimental images of C18 were compared with simulated images for four theoretical model geometries, including possible bond-angle alternation: D18h cumulene, D9h polyyne, D9h cumulene, and C9h polyyne. Cumulenic structures, with (D9h) and without (D18h) bond-angle alternation, can be excluded. Polyynic structures, with (C9h) and without (D9h) bond-angle alternation, both show a good agreement with the experiment and are challenging to differentiate.

Atropisomerism in Diarylamines: Structural Requirements and Mechanisms of Conformational Interconversion.

In common with other hindered structures containing two aromatic rings linked by a short tether, diarylamines may exhibit atropisomerism (chirality due to restricted rotation). Previous examples have principally been tertiary amines, especially those with cyclic scaffolds. Little is known of the structural requirement for atropisomerism in structurally simpler secondary and acyclic diarylamines. In this paper we describe a systematic study of a series of acyclic secondary diarylamines, and we quantify the degree of steric hindrance in the ortho positions that is required for atropisomerism to result. Through a detailed experimental and computational analysis, the role of each ortho-substituent on the mechanism and rate of conformational interconversion is rationalised. We also present a simple predictive model for the design of configurationally stable secondary diarylamines.

The Fluorination of C-H Bonds: Developments and Perspectives.

This Review summarizes advances in fluorination by C(sp2 )-H and C(sp3 )-H activation. Transition-metal-catalyzed approaches championed by palladium have allowed the installation of a fluorine substituent at C(sp2 ) and C(sp3 ) sites, exploiting the reactivity of high-oxidation-state transition-metal fluoride complexes combined with the use of directing groups (some transient) to control site and stereoselectivity. The large majority of known methods employ electrophilic fluorination reagents, but methods combining a nucleophilic fluoride source with an oxidant have appeared. External ligands have proven to be effective for C(sp3 )-H fluorination directed by weakly coordinating auxiliaries, thereby enabling control over reactivity. Methods relying on the formation of radical intermediates are complementary to transition-metal-catalyzed processes as they allow for undirected C(sp3 )-H fluorination. To date, radical C-H fluorinations mainly employ electrophilic N-F fluorination reagents but a unique MnIII -catalyzed oxidative C-H fluorination using fluoride has been developed. Overall, the field of late-stage nucleophilic C-H fluorination has progressed much more slowly, a state of play explaining why C-H 18 F-fluorination is still in its infancy.

Amino-oxetanes as amide isosteres by an alternative defluorosulfonylative coupling of sulfonyl fluorides.

Bioisosteres provide valuable design elements that medicinal chemists can use to adjust the structural and pharmacokinetic characteristics of bioactive compounds towards viable drug candidates. Aryl oxetane amines offer exciting potential as bioisosteres for benzamides-extremely common pharmacophores-but are rarely examined due to the lack of available synthetic methods. Here we describe a class of reactions for sulfonyl fluorides to form amino-oxetanes by an alternative pathway to the established SuFEx (sulfonyl-fluoride exchange) click reactivity. A defluorosulfonylation forms planar oxetane carbocations simply on warming. This disconnection, comparable to a typical amidation, will allow the application of vast existing amine libraries. The reaction is tolerant to a wide range of polar functionalities and is suitable for array formats. Ten oxetane analogues of bioactive benzamides and marketed drugs are prepared. Kinetic and computational studies support the formation of an oxetane carbocation as the rate-determining step, followed by a chemoselective nucleophile coupling step.

Synthesis of α-Quaternary Bicyclo[1.1.1]pentanes through Synergistic Organophotoredox and Hydrogen Atom Transfer Catalysis.

Bicyclo[1.1.1]pentanes (BCPs) are important in drug design as sp3-rich bioisosteres of arenes and tert-butyl groups; however, the preparation of BCPs with adjacent quaternary carbons is barely known. We report a facile synthesis of α-quaternary BCPs using organophotoredox and hydrogen atom transfer catalysis in which α-keto radicals, generated through oxidation of ß-ketocarbonyls, undergo efficient addition to [1.1.1]propellane. The BCP products can be transformed into a variety of useful derivatives, including enantioenriched BCPs featuring α-quaternary stereocenters.

Direct catalytic asymmetric synthesis of α-chiral bicyclo[1.1.1]pentanes.

Bicyclo[1.1.1]pentanes (BCPs) are important motifs in contemporary drug design as linear spacer units that improve pharmacokinetic profiles. The synthesis of BCPs featuring adjacent stereocenters is highly challenging, but desirable due to the fundamental importance of 3D chemical space in medicinal chemistry. Current methods to access these high-value chiral molecules typically involve transformations of pre-formed BCPs, and can display limitations in substrate scope. Here we describe an approach to synthesize α-chiral BCPs involving the direct, asymmetric addition of simple aldehydes to [1.1.1]propellane, the predominant BCP precursor. This is achieved by combining a photocatalyst and an organocatalyst to generate a chiral α-iminyl radical cation intermediate, which installs a stereocenter simultaneously with ring-opening of [1.1.1]propellane. The reaction proceeds under mild conditions, displays broad scope, and provides an array of α-chiral BCPs in high yield and enantioselectivity. We also present a theoretical model for stereoinduction in this mode of photoredox organocatalysis.

Transmembrane anion transport mediated by halogen bonding and hydrogen bonding triazole anionophores.

Transmembrane ion transport by synthetic anionophores is typically achieved using polar hydrogen bonding anion receptors. Here we show that readily accessible halogen and hydrogen bonding 1,2,3-triazole derivatives can efficiently mediate anion transport across lipid bilayer membranes with unusual anti-Hofmeister selectivity. Importantly, the results demonstrate that the iodo-triazole systems exhibit the highest reported activity to date for halogen bonding anionophores, and enhanced transport efficiency relative to the hydrogen bonding analogues. In contrast, the analogous fluoro-triazole systems, which are unable to form intermolecular interactions with anions, are inactive. The halogen bonding anionophores also exhibit a remarkable intrinsic chloride over hydroxide selectivity, which is usually observed only in more complex anionophore designs, in contrast to the readily accessible acyclic systems reported here. This highlights the potential of iodo-triazoles as synthetically accessible and versatile motifs for developing more efficient anion transport systems. Computational studies provide further insight into the nature of the anion-triazole intermolecular interactions, examining the origins of the observed transport activity and selectivity of the systems, and revealing the role of enhanced charge delocalisation in the halogen bonding anion complexes.

Rationalizing the diverse reactivity of [1.1.1]propellane through σ-π-delocalization.

[1.1.1]Propellane is the ubiquitous precursor to bicyclo[1.1.1]pentanes (BCPs), motifs of high value in pharmaceutical and materials research. The classical Lewis representation of this molecule places an inter-bridgehead C-C bond along its central axis; 'strain relief'-driven cleavage of this bond is commonly thought to enable reactions with nucleophiles, radicals and electrophiles. We propose that this broad reactivity profile instead derives from σ-π-delocalization of electron density in [1.1.1]propellane. Using ab initio and DFT calculations, we show that its reactions with anions and radicals are facilitated by increased delocalization of electron density over the propellane cage during addition, while reactions with cations involve charge transfer that relieves repulsion inside the cage. These results provide a unified framework to rationalize experimental observations of propellane reactivity, opening up opportunities for the exploration of new chemistry of [1.1.1]propellane and related strained systems that are useful building blocks in organic synthesis.