Molecular Face-Rotating Polyhedra: Chiral Cages Inspired by Mathematics.

ConspectusMolecular polyhedral cages, notable for their enclosed inner cavities, can possess varying degrees of symmetry, spanning from regular Platonic polyhedra to lower symmetry forms that may display chirality. Crafting chiral molecular cages typically involves using building blocks containing stereogenic elements or arranging achiral components in a manner that lacks mirror and inversion symmetries. Achieving precise control over their chirality poses both significance and challenges.In this Account, we present an overview of our research endeavors in the realm of chiral molecular polyhedral cages, drawing inspiration from Buckminster Fuller's "Face-Rotating Polyhedra (FRP)". Mathematically, FRP introduce a unique form of chirality distinguished by a rotating pattern around the center of each face, setting it apart from regular polyhedra.Molecular FRP can be constructed using two types of facial building blocks. The first includes rigid, planar molecules such as truxene and triazatruxene, which exhibit either clockwise or counterclockwise rotations in two dimensions. The second category involves propeller-like molecules, e.g., tetraphenylethylene, 1,2,3,4,5-penta(4-phenylaldehyde)pyrrole, and tridurylborane, displaying dynamic stereochemistry.The synthesis of FRP may potentially yield a diverse array of stereoisomers. Achieving high stereoselectivity becomes feasible through the selection of building blocks with specific substitution patterns and rigidity. Prominent noncovalent repulsive forces within the resulting cages often play a pivotal role in the dynamic covalent assembly process, ultimately leading to the formation of thermodynamically stable FRP products.The capacity to generate a multitude of stereoisomers, combined with the integration of chiral vertices, has facilitated investigations into phenomena such as chiral self-sorting and the "sergeant and soldiers" chiral amplification effect in FRP. Even the inclusion of one chiral vertex significantly impacts the stereochemical configuration of the entire cage. While many facial building blocks establish a stable rotational pattern in FRP, other units, such as tridurylborane, can dynamically transition between P and M configurations within the cage structures. The kinetic characteristics of such stereolabile FRP can be elucidated through physicochemical investigations.Our research extends beyond the FRP concept to encompass mathematical analysis of these structures. Graph theory, particularly the coloring problem, sheds light on the intricate facial patterns exhibited by various FRP stereoisomers and serves as an efficient tool to facilitate the discovery of novel FRP structures. This approach offers a fresh paradigm for designing and analyzing chiral molecular polyhedral cages, showcasing in our work the synergy between mathematics and molecular design.

Enantioselective Self-Assembly of a Homochiral Tetrahedral Cage Comprising Only Achiral Precursors.

How Nature synthesizes enantiomerically pure substances from achiral or racemic resources remains a mystery. In this study, we aimed to emulate this natural phenomenon by constructing chiral tetrahedral cages through self-assembly, achieved by condensing two achiral compounds-a trisamine and a trisaldehyde. The occurrence of intercomponent CH⋅⋅⋅π interactions among the phenyl building blocks within the cage frameworks results in twisted conformations, imparting planar chirality to the tetrahedrons. In instances where the trisaldehyde precursor features electron-withdrawing ester side chains, we observed that the intermolecular CH⋅⋅⋅π forces are strong enough to prevent racemization. To attain enantioselective self-assembly, a chiral amine was introduced during the imine formation process. The addition of three equivalents of chiral amino mediator to one equivalent of the achiral trisaldehyde precursor formed a trisimino intermediate. This chiral compound was subsequently combined with the achiral trisamino precursor, leading to an imine exchange reaction that releasing the chiral amino mediator and formation of the tetrahedral cage with an enantiomeric excess (ee) of up to 75 %, exclusively composed of achiral building blocks. This experimental observation aligns with theoretical calculations based on the free energies of related cage structures. Moreover, since the chiral amine was not consumed during the imine exchange cycle, it enabled the enantioselective self-assembly of the tetrahedral cage for multiple cycles when new batches of the achiral trisaldehyde and trisamino precursors were successively added.

Highly selective Cu2+ detection with a naphthalimide-functionalised pillar[5]arene fluorescent chemosensor.

Ligand 1, a rim-differentiated pillar[5]arene macrocycle modified with five naphthalimide groups through click chemistry, serves as an effective ratiometric fluorescent chemosensor for Cu2+. In contrast to the monomeric naphthalimide control compound 2, which shows only monomer emission, ligand 1 demonstrates dual emission characteristics encompassing both the monomer and excimer of the naphthalimide moieties. The binding properties of ligand 1 toward 15 different metal ions were systematically investigated in CH2Cl2/CH3CN (v/v, 1 : 1) by UV-vis and fluorescence spectroscopy. Remarkably, ligand 1 exhibits exceptional selectivity for Cu2+ ions. Upon complexation with Cu2+, the excimer emission of ligand 1 diminishes, concomitant with an enhancement of its monomer emission. The binding ratio for 1·Cu2+ was determined to be 1 : 1, with an association constant of (3.39 ± 0.40) × 105 M-1 calculated using a nonlinear least-squares curve-fitting method. Furthermore, the limit of detection (LOD) was found to be 185 ± 7 nM. Our results from 1H NMR titration, high-resolution mass spectrometry analysis and density functional theory calculations of 1·Cu2+ suggest synergistic coordination between Cu2+ and the triazole groups on ligand 1.

Tunable Supramolecular Ag+-Host Interactions in Pillar[n]arene[m]quinones and Ensuing Specific Binding to 1-Alkynes.

We developed an improved, robust synthesis of a series of pillar[6]arenes with a varying number (0-3) of quinone moieties in the ring. This easy-to-control variation yielded a gradually less electron-rich cavity in going from zero to three quinone units, as shown from the strength of host-guest interactions with silver ions. Such macrocycle-Ag2 complexes themselves were shown to display an unprecedented, sharp distinction between terminal alkynes, which strongly bound to such complexes, and internal alkynes, internal alkenes and terminal alkenes, which do hardly bind.

Chiral Molecular Cage with Tunable Stereoinversion Barriers.

The manipulation of chirality in molecular entities that rapidly interconvert between enantiomeric forms is challenging, particularly at the supramolecular level. Advances in controlling such dynamic stereochemical systems offer opportunities to understand chiral symmetry breaking and homochirality. Herein, we report the synthesis of a face-rotating tetrahedron (FRT), an organic molecular cage composed of tridurylborane facial units that undergo stereomutations between enantiomeric trefoil propeller-like conformations. After resolution, we show that the racemization barrier of the enantiopure FRT can be regulated in situ through the reversible binding of fluoride anions onto the tridurylborane moieties. Furthermore, the addition of an enantiopure phenylethanol to the FRT can effectively induce chirality of the molecular cage by preferentially binding to one of its enantiomeric conformers. This study presents a new paradigm for controlling dynamic chirality in supramolecular systems, which may have implications for asymmetric synthesis and dynamic stereochemistry.

Palladium-Mediated C(sp3)-H Bond Activation of N-Methyl-N-(pyridin-2-yl)benzamide: Direct Arylation/Alkylation and Mechanistic Investigation.

Herein, we present a facile synthetic methodology to produce a range of N-(CH2-aryl/alkyl)-substituted N-(pyridin-2-yl)benzamides via palladium-mediated C(sp3)-H bond activation. The N-methyl-N-(pyridin-2-yl)benzamide precursor was first reacted with palladium(II) acetate in a stoichiometric manner to obtain the key dinuclear palladacycle intermediates, whose structures were elucidated by mass spectrometric, NMR spectroscopic, and X-ray crystallographic studies in detail. The subsequent C(sp3)-H bond functionalizations on the N-methyl group of the starting substrate show facile productions of the corresponding N-(CH2-aryl/alkyl)-substituted N-(pyridin-2-yl)benzamides with good functional group tolerance. A plausible mechanism was proposed based on density functional theory calculations in conjunction with kinetic isotope effect experiments. Finally, the synthetic transformation from the prepared N-(CH2-aryl)-N-(pyridin-2-yl)benzamides through debenzoylation to N-(CH2-aryl)-2-aminopyridine was successfully demonstrated.

Water-soluble terphen[3]arene macrocycle: a versatile reversal agent of neuromuscular blockers.

Herein we report the design and synthesis of a terphen[n]arene derivative functionalised with sulfate acid ester groups. This water-soluble terphen[3]arene host effectively encapsulates a multitude of neuromuscular blocking agents (NMBAs) with high affinity, showing great potential as a NMBAs reversal agent in pharmaceutical research.

Macrocycle with Equatorial Coordination Sites Provides New Opportunity for Structure-Diverse Metallacages.

Reported here is the synthesis of a macrocycle with equatorial coordination sites for the construction of self-assembled metallacages. The macrocycle is prepared via a post-modification on the equator of biphen[n]arene. Utilizing this macrocycle as a ligand, three prismatic cages and one octahedral cage were synthesized by regulating the geometric structures and coordination number of metal acceptors. The multi-cavity configuration of prismatic cage was revealed by single-crystal structure. We prove that a macrocycle with equatorial coordination sites can be an excellent building block for synthesizing structure-diverse metallacages. Our results provide a typical example and a general method for the design and synthesis of metallacages.

Handcuff-like metallo-pseudorotaxanes consisting of tiara[5]arene wheels and dimeric silver trifluoroacetate axles.

The complexation between tiara[5]arene (T[5]) and silver trifluoroacetate affords a binuclear metallo-pseudorotaxane on account of multiple endo-cavity AgI η2-arene interactions. Furthermore, two such enantiomeric [(CF3CO2Ag)2⊂T[5]] complexes are bridged by an extra (CF3CO2Ag)2 dimer through exo-wall AgI η2-arene coordination, resulting in a unique handcuff metallo-bis-pseudorotaxane structure in the solid state.

Synthesis of Highly Luminescent Chiral Nanographene.

Chiral nanographenes with both high fluorescence quantum yields (ΦF ) and large dissymmetry factors (glum ) are essential to the development of circularly polarized luminescence (CPL) materials. However, most studies have been focused on the improvement of glum , whereas how to design highly emissive chiral nanographenes is still unclear. In this work, we propose a new design strategy to achieve chiral nanographenes with high ΦF by helical π-extension of strongly luminescent chromophores while maintaining the frontier molecular orbital (FMO) distribution pattern. Chiral nanographene with perylene as the core and two dibenzo[6]helicene fragments as the wings has been synthesized, which exhibits a record high ΦF of 93 % among the reported chiral nanographenes and excellent CPL brightness (BCPL ) of 32 M-1 cm-1 .

Synthesis and Mechanistic Investigation of Bipyrazolo[1,5-a]pyridines via Palladium-Catalyzed Cross-Dehydrogenative Coupling of Pyrazolo[1,5-a]pyridines.

The synthesis of a range of 3,3'-bipyrazolo[1,5-a]pyridine derivatives via direct cross-dehydrogenative coupling of pyrazolo[1,5-a]pyridine precursors is herein presented. This simple and efficient methodology involving palladium(II)-catalyzed C-H bond activation showed good functional group tolerance and product yield (up to 94%). Through the mechanistic insights gained from both kinetic isotope effect experimental studies and density functional theory calculations, a plausible reaction mechanism was outlined. Furthermore, subsequent derivatizations of the resulting 7,7'-diaryl-3,3'-bipyrazolo[1,5-a]pyridines, executed by performing palladium-mediated ortho C-H bond activation followed by hypervalent iodine-induced chlorination, rendered this series of compounds more extended π-conjugation and twisted conformations. Our study on these bipyrazolo[1,5-a]pyridine-based luminogens provides new opportunities for tailor-made organic luminescent materials.

Dynamic combinatorial libraries of a dimercapto-pillar[5]arene.

We report the synthesis and dynamic covalent chemistry (DCvC) of an A1/A2-dimercapto-functionalized pillar[5]arene (Di-SH-P5). The introduction of thiol moieties into this macrocyclic host makes it an effective building block for making a dynamic combinatorial library (DCL), giving rise to a set of cyclic trimers with intriguing host-guest properties as the dominant constituents.

Sulfur-Phenolate Exchange: SuFEx-Derived Dynamic Covalent Reactions and Degradation of SuFEx Polymers.

The products of the SuFEx reaction between sulfonimidoyl fluorides and phenols, sulfonimidates, are shown to display dynamic covalent chemistry with other phenols. This reaction was shown to be enantiospecific, finished in minutes at room temperature in high yields, and useful for both asymmetric synthesis and sustainable polymer production. Its wide scope further extends the usefulness of SuFEx and related click chemistries.

A trefoil knot self-templated through imination in water.

The preparation of topologically nontrivial molecules is often assisted by covalent, supramolecular or coordinative templates that provide spatial pre-organization for all components. Herein, we report a trefoil knot that can be self-assembled efficiently in water without involving additional templates. The direct condensation of three equivalents of a tetraformyl precursor and six equivalents of a chiral diamine produces successfully a [3 + 6] trefoil knot whose intrinsic handedness is dictated by the stereochemical configuration of the diamine linkers. Contrary to the conventional wisdom that imine condensation is not amenable to use in water, the multivalent cooperativity between all the imine bonds within the framework makes this trefoil knot robust in the aqueous environment. Furthermore, the presence of water is proven to be essential for the trefoil knot formation. A topologically trivial macrocycle composed of two tetraformyl and four diamino building blocks is obtained when a similar reaction is performed in organic media, indicating that hydrophobic effect is a major driving force behind the scene.

"Rim-Differentiated" Pillar[6]arenes.

A "rim-differentiated" pillar[6]arene (RD-P[6]) was obtained successfully, with the assistance of a dimeric silver trifluoroacetate template, among eight different constitutional isomers in a direct and regioselective manner. The solid-state conformation of this macrocycle could switch from the 1,3,5-alternate to a truly rim-differentiated one upon guest inclusion. This highly symmetric RD-P[6] not only hosts metal-containing molecules inside its cavity, but also can form a pillar[6]arene-C60 adduct through co-crystallization on account of donor-acceptor interactions. The development of synthetic strategies to desymmetrize pillararenes offers new opportunities for engineering complex molecular architectures and organic electronic materials.

Rim-differentiated Co-pillar[4+1]arenes.

A series of rim-differentiated Co-pillar[4+1]arenes featuring penta-substituted "upper" rims and mono-functionalisable "lower" rims was successfully synthesised and fully characterised. These novel pillar[5]arene-based scaffolds with clickable moieties and extra synthetic handles are versatile platforms for self-assembled molecular architectures and biological applications.

Hollow and highly diastereoselective face-rotating polyhedra constructed through rationally engineered facial units.

Molecular face-rotating polyhedra (FRP) exhibit complex stereochemistry, rendering it challenging to manipulate their assembly in a stereoselective manner. In our previous work, stereocontrolled FRP were gained at the cost of losing the confined inner space, which hampers their host-guest interactions and potential applications. Through a rational design approach, herein we demonstrate the successful construction of hollow FRP with high diastereoselectivity. Whereas the [4 + 4] imine condensation of meta-formyl substituted C 3h-symmetric TAT-m and C 3-symmetric Tri-NH2 led to the formation of all feasible FRP-12 diastereoisomers; the para-substituted constitutional isomer, TAT-p, exclusively assembled into a pair of homo-directional enantiomeric FRP-13-CCCC/AAAA with a cavity size larger than 600 Å3. Detailed structural characterizations and theoretical investigations revealed the thermodynamic landscape of FRP assembly can be effectively shaped by modulating the van der Waals repulsive forces among the facial building blocks. Our work provided a novel strategy towards stereospecific assembly of pure organic cages, opening up new opportunities for further applications of these chiral materials.

On the Stability and Formation of Pillar[n]arenes: a DFT Study.

The increased use of both pillar[5]arenes and pillar[6]arenes, stimulated by increasingly efficient syntheses of both, has brought forward the question as to what drives the intermediates in this Friedel-Crafts ring formation to form a pillar[5]arene, a pillar[6]arene, or any other sized macrocycle. This study sets out to answer this question by studying both the thermodynamics and kinetics involved in the absence and presence of templating solvents using high-end wB97XD/6-311G(2p,2d) DFT calculations.

B,N-Embedded Double Hetero[7]helicenes with Strong Chiroptical Responses in the Visible Light Region.

The development of helicene molecules with significant chiroptical responses covering a broad range of the visible spectrum is highly desirable for chiral optoelectronic applications; however, their absorption dissymmetry factors (gabs) have been mostly lower than 0.01. In this work, we report unprecedented B,N-embedded double hetero[7]helicenes with nonbonded B and N atoms, which exhibit excellent chiroptical properties, such as strong chiroptical activities from 300 to 700 nm, record high gabs up to 0.033 in the visible spectral range, and tunable circularly polarized luminescence (CPL) from red to near-infrared regions (600-800 nm) with high photoluminescence quantum yields (PLQYs) up to 100%. As revealed by theoretical analyses, the high gabs values are related to the separate molecular orbital distributions owing to the incorporation of nonbonded B and N atoms. The new type of B,N-embedded double heterohelicenes opens up an appealing avenue to the future exploitation of high-performance chiroptical materials.

Spontaneous and induced chiral symmetry breaking of stereolabile pillar[5]arene derivatives upon crystallisation.

Stereolabile pillar[5]arene (P[5]) derivatives, which are dynamic racemic mixtures in solution on account of their low inversion barriers, were employed as platforms to study chiral symmetry breaking during crystallisation. In the solid state, we showed that crystal enantiomeric excess of a conglomerate-forming P[5] derivative can be obtained by handpicking and Viedma ripening without the intervention of external chiral entities. On the other hand, in the presence of ethyl d/l-lactate as both optically-active solvents and chiral guests, the handedness of P[5] derivative crystals, either forming racemic compounds or conglomerates upon condensation, can be directed and subsequently inverted in a highly controllable manner.