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Since its introduction by Cravatt and colleagues in 1999, activity‐based protein profiling (ABPP) has become widely utilized throughout academia, government, and industry laboratories to study enzymes spanning numerous gene families in a multitude of biological systems. As a variation of ABPP, competitive ABPP provides a powerful approach to characterize the binding behavior of small molecule probes and clinical drugs throughout the functional proteome. The power and flexibility of competitive ABPP are exemplified by a wide range of creative adaptions which increase assay throughput, enable diverse detection schemes, and support the implementation of this approach within a hybrid target‐based screening platform. We review major developments in competitive ABPP through a compare‐contrast format to provide a useful introduction to this enabling technology for scientists in chemical biology and drug discovery. [ABSTRACT FROM AUTHOR]

Electrophilic aromatic substitution reactions are of profound importance for the synthesis of biologically active compounds and other advanced materials. They represent an important means to activate specific aromatic C–H bonds without requiring transition-metal catalysts. Surprisingly, few stereoselective variants are known for electrophilic aromatic substitutions, which limits the utility of these classical reactions for stereoselective synthesis. While many electrophilic aromatic substitutions lead to achiral products (due to the planar nature of aromatic rings), there are important examples where chiral products are produced, including desymmetrization reactions of aromatic cyclophanes and of prochiral substrates with multiple aromatic rings. This Synpacts article now illustrates how chiral arms, when placed precisely above and underneath delocalized carbocations, can act as chiral auxiliaries to convert classical electrophilic aromatic substitution reactions into powerful diastereo- and enantioselective transformations. [ABSTRACT FROM AUTHOR]

This account describes the latest developments in the field of chirality-assisted synthesis (CAS). CAS has emerged as a versatile method to control the shapes of π-conjugated macromolecules and supramolecular assemblies. With CAS, the sequence and chirality of the monomeric building blocks dictates the shape and functions of the resulting macromolecules in a programmable fashion. Supramolecular materials with special functions, e.g. the ability to encapsulate macrocycles, can be created with CAS. CAS has been utilized to synthesize a variety of shape-defined nanoscale structures, including polyaromatic strips, helices, molecular claws, and very large hydrogen-bonded closed-shell capsules. Applications, challenges, and future directions of the growing CAS field are discussed in light of the unique shape-control abilities CAS has to offer. [ABSTRACT FROM AUTHOR]

Crystal-packing forces can have a significant impact on the relative stabilities of different molecules and their conformations. The magnitude of such effects is, however, not yet well understood. Herein we show, that crystal packing can completely overrule the relative stabilities of different stereoisomers in solution. Heating of atropoisomers (i.e. 'frozen-out' conformational isomers) in solution leads to complex mixtures. In contrast, solid-state heating selectively amplifies minor (<25 mole %) components of these solution-phase mixtures. We show that this heating strategy is successful for compounds with up to four rotationally hindered σ bonds, for which a single stereoisomer out of seven can be amplified selectively. Our results demonstrate that common supramolecular interactions-for example, [methyl⋅⋅⋅π] coordination and [C−H⋅⋅⋅O] hydrogen bonding-can readily invert the relative thermodynamic stabilities of different molecular conformations. These findings open up potential new avenues to control the folding of macromolecules. [ABSTRACT FROM AUTHOR]

Crystal-packing forces can have a significant impact on the relative stabilities of different molecules and their conformations. The magnitude of such effects is, however, not yet well understood. Herein we show, that crystal packing can completely overrule the relative stabilities of different stereoisomers in solution. Heating of atropoisomers (i.e. 'frozen-out' conformational isomers) in solution leads to complex mixtures. In contrast, solid-state heating selectively amplifies minor (<25 mole %) components of these solution-phase mixtures. We show that this heating strategy is successful for compounds with up to four rotationally hindered σ bonds, for which a single stereoisomer out of seven can be amplified selectively. Our results demonstrate that common supramolecular interactions-for example, [methyl⋅⋅⋅π] coordination and [C−H⋅⋅⋅O] hydrogen bonding-can readily invert the relative thermodynamic stabilities of different molecular conformations. These findings open up potential new avenues to control the folding of macromolecules. [ABSTRACT FROM AUTHOR]

Chirality-assisted synthesis (CAS) embodies a powerful strategy for the creation of chiral molecules with well-defined shapes and large cavities. In this communication, we show that C-shaped molecular receptors created with this approach bind to stacks of amphipathic perylenediimide (PDI) dyes. Evidence from 1H NMR titrations, DOSYNMR studies, and all-atom molecular dynamics simulations indicates that - in the preferred supramolecular binding mode - such polyaromatic strips specifically recognize stacked PDI dimers in solution. These results represent a key step toward the controlled self-assembly of dye molecules inside chiral cavities of shape-persistent, polyaromatic strips. [ABSTRACT FROM AUTHOR]

We report a general synthetic route toward helical ladder polymers with varying spring constants, built with chirality‐assisted synthesis (CAS). Under tension and compression, these shape‐persistent structures do not unfold, but rather stretch and compress akin classical Hookean springs. Our synthesis is adaptable to helices with different pitch and diameter, which allowed us to investigate how molecular flexibility in solution depends on the exact geometry of the ladder polymers. Specifically, we showed with molecular dynamic simulations and by measuring the longitudinal 1H NMR relaxation times (T1) for our polymers at different Larmor frequencies, that increasing the helix diameter leads to increased flexibility. Our results present initial design rules for tuning the mechanical properties of intrinsically helical ladder polymers in solution, which will help inspire a new class of robust, spring‐like molecular materials with varying mechanical properties. [ABSTRACT FROM AUTHOR]

We report a general synthetic route toward helical ladder polymers with varying spring constants, built with chirality‐assisted synthesis (CAS). Under tension and compression, these shape‐persistent structures do not unfold, but rather stretch and compress akin classical Hookean springs. Our synthesis is adaptable to helices with different pitch and diameter, which allowed us to investigate how molecular flexibility in solution depends on the exact geometry of the ladder polymers. Specifically, we showed with molecular dynamic simulations and by measuring the longitudinal 1H NMR relaxation times (T1) for our polymers at different Larmor frequencies, that increasing the helix diameter leads to increased flexibility. Our results present initial design rules for tuning the mechanical properties of intrinsically helical ladder polymers in solution, which will help inspire a new class of robust, spring‐like molecular materials with varying mechanical properties. [ABSTRACT FROM AUTHOR]

The electrochemical oxidation of ferrocenes having an H- or Li-terminated ethynyl group has been studied, especially as it relates to their covalent anchoring to carbon surfaces. The anodic oxidation of lithioethynylferrocene (1-Li) results in rapid loss of Li+ and formation of the ethynyl-based radical FeCp(η5-C5H4)(C=C), (1, Cp = η5-C5H5), which reacts with the electrode. Chemically modified electrodes (CMEs) were thereby produced containing strongly bonded, ethynyl-linked monolayers and electrochemically controlled multilayers. Strong attachments of ethynylferrocenes to gold and platinum surfaces were also possible. The lithiation/anodic oxidation process is a mirror analogue of the diazonium/cathodic reduction process for preparation of aryl-modified CMEs. A second method produced an ethynylferrocene-modified electrode by direct anodic oxidation of the H-terminated ethynylferrocene (1-H) at a considerably more positive potential. Both processes produced robust modified electrodes with well-defined ferrocene-based surface cyclic voltammetry waves that remained unchanged for as many as 104 scans. Ferrocene derivatives in which the ethynyl moiety was separated from the cyclopentadienyl ring by an ether group showed very similar behavior. DFT calculations were performed on the relevant redox states of 1-H, 1-Li, and 1, with emphasis on the ferrocenyl vs ethynyl character of their high valence orbitals. Whereas the HOMOs of both 1-H and 1-Li have some ethynyl character, the SOMOs of the corresponding monocations are strictly ferrocenium in makeup. Predominant ethynyl character returns to the highest valence orbitals after loss of Li+ from [1-Li]+ or loss of H+ from [1-H]2+. These anodic processes hold promise for the controlled chemical modification of carbon and other electrode surfaces by a variety of ethynyl or alkynyl-linked organic and metal-containing systems. [ABSTRACT FROM AUTHOR]

Chirality-assisted synthesis (CAS) is a general approach to control the shapes of large molecular strips. CAS is based on enantiomerically pure building blocks that are designed to strictly couple in a single geometric orientation. Fully shape-persistent structures can thus be created, even in the form of linear chains. With CAS, selective recognition between large host and guest molecules can reliably be designed de novo. To demonstrate this concept, three C-shaped strips that can embrace a pillar[5]arene macrocycle were synthesized. The pillar[5]arene bound to the strips was a better host for electron-deficient guests than the free macrocycle. Experimental and computational evidence is provided for these unique cooperative interactions to illustrate how CAS could open the door towards the precise positioning of functional groups for regulated supramolecular recognition and catalysis. [ABSTRACT FROM AUTHOR]

Chirality-assisted synthesis (CAS) is a general approach to control the shapes of large molecular strips. CAS is based on enantiomerically pure building blocks that are designed to strictly couple in a single geometric orientation. Fully shape-persistent structures can thus be created, even in the form of linear chains. With CAS, selective recognition between large host and guest molecules can reliably be designed de novo. To demonstrate this concept, three C-shaped strips that can embrace a pillar[5]arene macrocycle were synthesized. The pillar[5]arene bound to the strips was a better host for electron-deficient guests than the free macrocycle. Experimental and computational evidence is provided for these unique cooperative interactions to illustrate how CAS could open the door towards the precise positioning of functional groups for regulated supramolecular recognition and catalysis. [ABSTRACT FROM AUTHOR]

Selective monofunctionalization of substrates with distant, yet equally reactive functional groups is difficult to achieve, as it requires the second functional group to selectively modulate its reactivity once the first functional group has reacted. We now show that mechanically interlocked catalytic rings can effectively regulate the reactivity of stoppering groups in rotaxanes over a distance of about 2 nm. Our mechanism of communication is enabled by a unique interlocked design, which effectively removes the catalytic rings from the substrates by fast dethreading as soon as the first reaction has taken place. Our method not only led to a rare example of selective monofunctionalization, but also to a "molecular if function". Overall, the study presents a way to get distant functional groups to communicate with each other in a reaction‐history‐dependent manner by creating linkers that can ultimately perform logical operations at the molecular level. [ABSTRACT FROM AUTHOR]

Selective monofunctionalization of substrates with distant, yet equally reactive functional groups is difficult to achieve, as it requires the second functional group to selectively modulate its reactivity once the first functional group has reacted. We now show that mechanically interlocked catalytic rings can effectively regulate the reactivity of stoppering groups in rotaxanes over a distance of about 2 nm. Our mechanism of communication is enabled by a unique interlocked design, which effectively removes the catalytic rings from the substrates by fast dethreading as soon as the first reaction has taken place. Our method not only led to a rare example of selective monofunctionalization, but also to a "molecular if function". Overall, the study presents a way to get distant functional groups to communicate with each other in a reaction‐history‐dependent manner by creating linkers that can ultimately perform logical operations at the molecular level. [ABSTRACT FROM AUTHOR]

Enantioselective electrophilic aromatic nitration methodology is needed to advance chirality‐assisted synthesis (CAS). Reported here is an enantioselective aromatic nitration strategy operating with chiral diester auxiliaries, and it provides an enantioselective synthesis of a C3v‐symmetric tribenzotriquinacene (TBTQ). These axially‐chiral structures are much sought‐after building blocks for CAS, but they were not accessible prior to this work in enantioenriched form without resolution of enantiomers. This nitration strategy controls the stereochemistry of threefold nitration reactions from above the aromatic rings with chiral diester arms. Dicarbonyl‐to‐arenium chelation rigidifies the reaction systems, so that remote stereocenters position the ester‐directing groups selectively over specific atoms of the TBTQ framework. Closely guided by computational design, a more selective through‐space directing arm was first predicted with density functional theory (DFT), and then confirmed in the laboratory, to outperform the initial structural design. This enantio‐ and regioselective TBTQ synthesis opens a new pathway to access building blocks for CAS. [ABSTRACT FROM AUTHOR]

Enantioselective electrophilic aromatic nitration methodology is needed to advance chirality‐assisted synthesis (CAS). Reported here is an enantioselective aromatic nitration strategy operating with chiral diester auxiliaries, and it provides an enantioselective synthesis of a C3v‐symmetric tribenzotriquinacene (TBTQ). These axially‐chiral structures are much sought‐after building blocks for CAS, but they were not accessible prior to this work in enantioenriched form without resolution of enantiomers. This nitration strategy controls the stereochemistry of threefold nitration reactions from above the aromatic rings with chiral diester arms. Dicarbonyl‐to‐arenium chelation rigidifies the reaction systems, so that remote stereocenters position the ester‐directing groups selectively over specific atoms of the TBTQ framework. Closely guided by computational design, a more selective through‐space directing arm was first predicted with density functional theory (DFT), and then confirmed in the laboratory, to outperform the initial structural design. This enantio‐ and regioselective TBTQ synthesis opens a new pathway to access building blocks for CAS. Through‐space directed nitrations controlled by remote stereocenters create bowl‐shaped polyaromatic structures with axial chirality in an enantioselective manner. Nitration occurs in a regio‐ and stereoselective manner on multiple reaction sites, as a distinct pattern of electron‐donating carbonyl groups are positioned above delocalized arenium cations directly underneath. [ABSTRACT FROM AUTHOR]

Exciton Coupling, Hookean Molecular Springs, Model-Free Analysis, Single-Handed Ladder Polymers, Time-Dependent Density Functional Theory Keywords: Exciton Coupling; Hookean Molecular Springs; Model-Free Analysis; Single-Handed Ladder Polymers; Time-Dependent Density Functional Theory EN Exciton Coupling Hookean Molecular Springs Model-Free Analysis Single-Handed Ladder Polymers Time-Dependent Density Functional Theory 1 1 1 12/07/22 20221212 NES 221212 B Molekulare Spiralfedern b aus chiralen Leiterpolymeren expandieren und kontrahieren ohne Entfaltung bei Raumtemperatur. In ihrer Zuschrift (e202209772) zeigen Severin T. Schneebeli und Mitarbeiter, dass sich solche spiralförmigen Leiterpolymere in Lösung wie klassische Hooke'sche Federn mit einstellbaren Federkonstanten verhalten können. [Extracted from the article]

Keywords: Exciton Coupling; Hookean Molecular Springs; Model-Free Analysis; Single-Handed Ladder Polymers; Time-Dependent Density Functional Theory EN Exciton Coupling Hookean Molecular Springs Model-Free Analysis Single-Handed Ladder Polymers Time-Dependent Density Functional Theory 1 1 1 12/07/22 20221212 NES 221212 B Helical molecular springs b built from chiral ladder polymers expand and contract without unfolding at room temperature. In their Communication (e202209772), Severin T. Schneebeli and co-workers show that in solution such helical ladder polymers can act like classical Hookean springs with adjustable spring constants. Exciton Coupling, Hookean Molecular Springs, Model-Free Analysis, Single-Handed Ladder Polymers, Time-Dependent Density Functional Theory. [Extracted from the article]

Pillararene macrocycles are embraced by C‐shaped molecular strips in a manner analogous to the way a five‐sided bolt head fits into a pentagonal wrench. In their Communication on page 12722 ff., S. T. Schneebeli, J. Li et al. describe the synthesis of these large, shape‐persistent molecular tweezers as single enantiomers by using chirality‐assisted synthesis. In the presence of pillararenes and viologens, the molecular strips form ternary complexes that are stabilized by cooperative supramolecular interactions. [ABSTRACT FROM AUTHOR]

C ‐ förmige molekulare Streifen umgreifen Pillararen ‐ Makrocyclen so ähnlich wie ein Schraubenschlüssel einen Schraubenkopf. In der Zuschrift auf S. 12963 ff. beschreiben S. T. Schneebeli, J. Li et al., wie diese molekularen Pinzetten durch chiralitätsunterstützte Synthese in Form von reinen Enantiomeren erhalten werden. In Gegenwart von Pillararenen und Viologenen bilden die molekularen Streifen ternäre Komplexe, die durch kooperative supramolekulare Wechselwirkungen stabilisiert werden. [ABSTRACT FROM AUTHOR]

Molekulare Kranausleger liefern in stereoselektiver Weise Nitroniumionen zu spezifischen Stellen in konkaven polyaromatischen Systemen. S. T. Schneebeli und Mitarbeiter beschreiben in ihrer Zuschrift auf S. 1047, wie die ersten enantioselektiven Nitrierungsreaktionen mithilfe solcher Kranausleger erreicht wurden. Die Ergebnisse stellen einen Durchbruch dar, da sie es ermöglichen, eine der ältesten Reaktionen nun in enantioselektiver Weise durchzuführen. [ABSTRACT FROM AUTHOR]

Molecular crane arms deliver nitronium ions to specific locations of concave polyaromatic systems in a stereoselective manner. In their Communication on page 1035 ff., S. T. Schneebeli and co‐workers describe how the first enantioselective aromatic nitration reactions have been achieved with the help of such crane arms. These findings represent a breakthrough in terms of enabling one of the oldest reactions to finally be carried out in an enantioselective manner. [ABSTRACT FROM AUTHOR]