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We describe the preparation, dynamic, assembly characteristics of vase‐shaped basket 13− along with its ability to form an inclusion complex with anticancer drug mitoxantrone in abiotic and biotic systems. This novel cavitand has a deep nonpolar pocket consisting of three naphthalimide sides fused to a bicyclic platform at the bottom while carrying polar glycines at the top. The results of 1H Nuclear Magnetic Resonance (NMR), 1H NMR Chemical Exchange Saturation Transfer (CEST), Calorimetry, Hybrid Replica Exchange Molecular Dynamics (REMD), and Microcrystal Electron Diffraction (MicroED) measurements are in line with 1 forming dimer [12]6−, to be in equilibrium with monomers 1(R)3− (relaxed) and 1(S)3− (squeezed). Through simultaneous line‐shape analysis of 1H NMR data, kinetic and thermodynamic parameters characterizing these equilibria were quantified. Basket 1(R)3− includes anticancer drug mitoxantrone (MTO2+) in its pocket to give stable binary complex [MTO⊂1]− (Kd=2.1 μM) that can be precipitated in vitro with UV light or pH as stimuli. Both in vitro and in vivo studies showed that the basket is nontoxic, while at a higher proportion with respect to MTO it reduced its cytotoxicity in vitro. With well‐characterized internal dynamics and dimerization, the ability to include mitoxantrone, and biocompatibility, the stage is set to develop sequestering agents from deep‐cavity baskets. [ABSTRACT FROM AUTHOR]

We report Pd‐catalyzed cyclotrimerization of (+)‐α‐bromoenone, obtained from monoterpene β‐pinene, into an enantiopure cyclotrimer. This C3 symmetric compound has three bicyclo[3.1.1]heptane rings fused to its central benzene with each ring carrying a carbonyl group. The cyclotrimer undergoes diastereoselective threefold alkynylation with the lithium salts of five terminal alkynes (41–63 %, de=4–83 %). The addition enabled a rapid synthesis of a small library of novel chiral cavitands that, in shape, resemble a tripod stand. These molecular tripods include a tris‐bicycloannelated benzene head attached to three alkyne legs twisted in one direction to form a nonpolar cavity with polar groups as feet. Tripods with methylpyridinium and methylisoquinolinium legs, respectively, form inclusion complexes with anti‐inflammatory and chiral drugs (R)/(S)‐ibuprofen and (R)/(S)‐naproxen. The mode of binding shows drug molecules docked in the cavity of the host through ion‐ion, cation‐π, and C−H−π contacts that, in addition of desolvation, give rise to complexes having millimolar to micromolar stability in water. Our findings open the door to creating a myriad of enantiopure tripods with tunable functions that, in the future, might give novel chemosensors, catalysts or sequestering agents. [ABSTRACT FROM AUTHOR]

In this study, we describe a synthetic method for incorporating arenes into closed tubes that we name capsularenes. First, we prepared vase‐shaped molecular baskets 4–7. The baskets comprise a benzene base fused to three bicycle[2.2.1]heptane rings that extend into phthalimide (4), naphthalimide (6), and anthraceneimide sides (7), each carrying a dimethoxyethane acetal group. In the presence of catalytic trifluoroacetic acid (TFA), the acetals at top of 4, 6 and 7 change into aliphatic aldehydes followed by their intramolecular cyclization into 1,3,5‐trioxane (1H NMR spectroscopy). Such ring closure is nearly a quantitative process that furnishes differently sized capsularenes 1 (0.7×0.9 nm), 8 (0.7×1.1 nm;) and 9 (0.7×1.4 nm;) characterized by X‐Ray crystallography, microcrystal electron diffraction, UV/Vis, fluorescence, cyclic voltammetry, and thermogravimetry. With exceptional rigidity, unique topology, great thermal stability, and perhaps tuneable optoelectronic characteristics, capsularenes hold promise for the construction of novel organic electronic devices. [ABSTRACT FROM AUTHOR]

In this study, we describe a synthetic method for incorporating arenes into closed tubes that we name capsularenes. First, we prepared vase‐shaped molecular baskets 4–7. The baskets comprise a benzene base fused to three bicycle[2.2.1]heptane rings that extend into phthalimide (4), naphthalimide (6), and anthraceneimide sides (7), each carrying a dimethoxyethane acetal group. In the presence of catalytic trifluoroacetic acid (TFA), the acetals at top of 4, 6 and 7 change into aliphatic aldehydes followed by their intramolecular cyclization into 1,3,5‐trioxane (1H NMR spectroscopy). Such ring closure is nearly a quantitative process that furnishes differently sized capsularenes 1 (0.7×0.9 nm), 8 (0.7×1.1 nm;) and 9 (0.7×1.4 nm;) characterized by X‐Ray crystallography, microcrystal electron diffraction, UV/Vis, fluorescence, cyclic voltammetry, and thermogravimetry. With exceptional rigidity, unique topology, great thermal stability, and perhaps tuneable optoelectronic characteristics, capsularenes hold promise for the construction of novel organic electronic devices. [ABSTRACT FROM AUTHOR]

The precise positioning of functional groups about the inner space of abiotic hosts is a challenging task and of interest for developing more effective receptors and catalysts akin to those found in nature. To address it, we herein report a synthetic methodology for preparing basket‐like cavitands comprised of three different aromatics as side arms with orthogonal esters at the rim for further functionalization. First, enantioenriched A (borochloronorbornene), B (iodobromonorbornene), and C (boronorbornene) building blocks were obtained by stereoselective syntheses. Second, consecutive A‐to‐B and then AB‐to‐C Suzuki–Miyaura (SM) couplings were optimized to give enantioenriched ABC cavitand as the principal product. The robust synthetic protocol allowed us to prepare (a) an enantioenriched basket with three benzene sides and each holding either tBu, Et, or Me esters, (b) both enantiomers of a so‐called "spiral staircase" basket with benzene, naphthalene, and anthracene groups surrounding the inner space, and (c) a photo‐responsive basket bearing one anthracene and two benzene arms. [ABSTRACT FROM AUTHOR]

The precise positioning of functional groups about the inner space of abiotic hosts is a challenging task and of interest for developing more effective receptors and catalysts akin to those found in nature. To address it, we herein report a synthetic methodology for preparing basket‐like cavitands comprised of three different aromatics as side arms with orthogonal esters at the rim for further functionalization. First, enantioenriched A (borochloronorbornene), B (iodobromonorbornene), and C (boronorbornene) building blocks were obtained by stereoselective syntheses. Second, consecutive A‐to‐B and then AB‐to‐C Suzuki–Miyaura (SM) couplings were optimized to give enantioenriched ABC cavitand as the principal product. The robust synthetic protocol allowed us to prepare (a) an enantioenriched basket with three benzene sides and each holding either tBu, Et, or Me esters, (b) both enantiomers of a so‐called "spiral staircase" basket with benzene, naphthalene, and anthracene groups surrounding the inner space, and (c) a photo‐responsive basket bearing one anthracene and two benzene arms. [ABSTRACT FROM AUTHOR]

The precise positioning of functional groups about the inner space of abiotic hosts is a challenging task and of interest for developing more effective receptors and catalysts akin to those found in nature. To address it, we herein report a synthetic methodology for preparing basket‐like cavitands comprised of three different aromatics as side arms with orthogonal esters at the rim for further functionalization. First, enantioenriched A (borochloronorbornene), B (iodobromonorbornene), and C (boronorbornene) building blocks were obtained by stereoselective syntheses. Second, consecutive A‐to‐B and then AB‐to‐C Suzuki–Miyaura (SM) couplings were optimized to give enantioenriched ABC cavitand as the principal product. The robust synthetic protocol allowed us to prepare (a) an enantioenriched basket with three benzene sides and each holding either tBu, Et, or Me esters, (b) both enantiomers of a so‐called “spiral staircase” basket with benzene, naphthalene, and anthracene groups surrounding the inner space, and (c) a photo‐responsive basket bearing one anthracene and two benzene arms. [ABSTRACT FROM AUTHOR]

Two limiting cases of molecular recognition, induced fit (IF) and conformational selection (CS), play a central role in allosteric regulation of natural systems. The IF paradigm states that a substrate "instructs" the host to change its shape after complexation, while CS asserts that a guest "selects" the optimal fit from an ensemble of preexisting host conformations. With no studies that quantitatively address the interplay of two limiting pathways in abiotic systems, we herein and for the first time describe the way by which twisted capsule M‐1, encompassing two conformers M‐1(+) and M‐1(−), trap CX4 (X=Cl, Br) to give CX4⊂M‐1(+) and CX4⊂M‐1(−), with all four states being in thermal equilibrium. With the assistance of 2D EXSY, we found that CBr4 would, at its lower concentrations, bind M‐1 via a M‐1(+)→M‐1(−)→CBr4⊂M‐1(−) pathway corresponding to conformational selection. For M‐1 complexing CCl4 though, data from 2D EXSY measurements and 1D NMR line‐shape analysis suggested that lower CCl4 concentrations would favor CS while the IF pathway prevailed at higher proportions of the guest. Since CS and IF are not mutually exclusive, we reason that our work sets the stage for characterizing the dynamics of a wide range of already existing hosts to broaden our fundamental understanding of their action. The objective is to master the way in which encapsulation takes place for designing novel and allosteric sequestering agents, catalysts and chemosensors akin to those found in nature. [ABSTRACT FROM AUTHOR]

Two limiting cases of molecular recognition, induced fit (IF) and conformational selection (CS), play a central role in allosteric regulation of natural systems. The IF paradigm states that a substrate "instructs" the host to change its shape after complexation, while CS asserts that a guest "selects" the optimal fit from an ensemble of preexisting host conformations. With no studies that quantitatively address the interplay of two limiting pathways in abiotic systems, we herein and for the first time describe the way by which twisted capsule M‐1, encompassing two conformers M‐1(+) and M‐1(−), trap CX4 (X=Cl, Br) to give CX4⊂M‐1(+) and CX4⊂M‐1(−), with all four states being in thermal equilibrium. With the assistance of 2D EXSY, we found that CBr4 would, at its lower concentrations, bind M‐1 via a M‐1(+)→M‐1(−)→CBr4⊂M‐1(−) pathway corresponding to conformational selection. For M‐1 complexing CCl4 though, data from 2D EXSY measurements and 1D NMR line‐shape analysis suggested that lower CCl4 concentrations would favor CS while the IF pathway prevailed at higher proportions of the guest. Since CS and IF are not mutually exclusive, we reason that our work sets the stage for characterizing the dynamics of a wide range of already existing hosts to broaden our fundamental understanding of their action. The objective is to master the way in which encapsulation takes place for designing novel and allosteric sequestering agents, catalysts and chemosensors akin to those found in nature. [ABSTRACT FROM AUTHOR]

The synergy among twelve carboxylates from two hexavalent baskets 16− assisted the encapsulation of one divalent diammonium guest 32+–62+ and the formation of ternary [3–6⊂12]10−. The reduction of basket's multivalency, by photoinduced α-decarboxylation of 16− to give 23−, intercepted the interannular cooperativity operating in the stabilization of capsulpex [3–6⊂12]10− to dramatically diminish the binding affinity towards diammonium guests. As a result, the cationic guests were released into bulk water with 23− assembling into nanoparticles. With numerous drugs carrying positive sites, the finding reported here could now be examined for their light-promoted spatiotemporal delivery. [ABSTRACT FROM AUTHOR]

In this work, we report a mechanism by which stereoisomeric and twisted capsules P/M‐1 direct their dynamic chirality in the presence of haloalkane guests. The capsule comprises a static, but twisted, cage that is linked to a dynamic tris(2‐pyridylmethyl)amine (TPA) lid at its top. From the results of experimental (NMR spectroscopy and X‐ray crystallography) and computational (DFT) studies, the TPA lid was shown to assume clockwise (+) and counterclockwise (−) folds with diastereomeric (but racemic) capsules M‐1(+) and M‐1(−) interconverting at a rapid rate (ΔG≠189K=9.1 kcal mol−1). The relative stability of the capsules was found to be a function of guest(s) residing in their interior (243/262 Å3) with small CH2Cl2 (61 Å3) yielding roughly equal population of diastereomeric inclusion complexes. Larger guests, such as CCl4 (89 Å3) and CBr4 (108 Å3), however, formed M‐1(−)⊂CX4 at the expense of M‐1(+)⊂CX4 in circa 3:1 ratio. To account for the observation, theory (DFT:M06‐2X/6–31+G*) and experiments (1H NMR spectroscopy) were used to deduce that CX4 guests become localized inside the twisted cage of the capsule by forming a C−X⋅⋅⋅π halogen bond [Nc=d/(rH+rX)=0.91–0.92] with the benzene "floor" while encountering electrostatic repulsions with closer naphthalimide boundaries. At last, the TPA lid used its central methylene hydrogens to establish, within the M‐1(−)⊂CX4, three stabilizing C−H⋅⋅⋅X−C interactions with the guest. The same C−H⋅⋅⋅X−C interactions, however, became weaker (or possibly vanished) after the conformational reorganization of the lid and the formation of less stable M‐1(+)⊂CX4 complex. On individual basis, C−H⋅⋅⋅X−C intermolecular contacts are weak and hardly detectable in the solution phase. In the case of capsule P/M‐1, however, these contacts were multivalent and altogether strong enough to direct the host's dynamic chirality. [ABSTRACT FROM AUTHOR]

Molecular baskets 16−–36−, functionalized with α-amino acids at their rim, undergo photo-induced α-decarboxylations to give amphiphilic 43−–63− assembling into nanoparticles. Nanoparticulate 43−–63− possess greater affinities for complexing OPs (akin to sarin and cyclosarin) than monomeric 16−–36−. With the ability of nanoparticles to function in urine, our study sets the stage for creating novel nanocarriers capable of spatiotemporal sequestration of nerve agents or pesticides in competitive chemical environments. [ABSTRACT FROM AUTHOR]

Discovering novel and functional photoresponsive materials is of interest for improving controlled release of molecules and scavenging toxic compounds for cleaning our environment or designing chemosensors. In this study, we report on the photoinduced decarboxylation of basket 16−, containing three glutamic acids at its rim. This concave compound is, in an aqueous environment (30 mm phosphate buffer at pH 7.0), monomeric (1H NMR DOSY, DLS) with glutamic acid residues randomly oriented about its rim (1H NMR and MM‐OPLS3). The irradiation (300 nm) of 16− leads to the exclusive removal of its α‐carboxylates to give amphiphilic 23− possessing γ‐carboxylates. The photochemical transformation is a consecutive reaction with mono‐ and bis‐decarboxylated products observed with 1H NMR spectroscopy and ESI mass spectrometry. Amphiphilic 23− is a preorganized molecule (MM‐OPLS3) that, in water, aggregates into organic nanoparticles (ca. 50–200 nm in diameter; DLS, TEM and cryo‐TEM) having a critical aggregation concentration of 12 μm (UV/Vis). As the transition of monomeric 16− into nanoparticulate 23− is triggered with light, we reasoned that stimuli‐responsive formation of the soft material lends itself to nanotechnology applications such as controlled release or scavenging of targeted compounds. Filling the basket: Photoinduced decarboxylation of molecular baskets functionalized with glutamic acids was found to, in water, give amphiphilic cavitands. These cavitands assemble into organic nanoparticles that could be used for scavenging toxic molecules, promoting chemical reactions or delivering drugs. [ABSTRACT FROM AUTHOR]

The reactivity of the C2v-symmetric pentakisadduct of C60 with azomethine ylides and conjugated dienes was studied experimentally and computationally. This derivative possesses four [6,6] double bonds, each with unique electrophilicity. The Diels-Alder reaction studied is a regiospecific, kinetically and thermodynamically guided [4 + 2] process producing [5:1]-hexaadducts with an octahedral addition pattern. The kinetically controlled Prato reaction gives a mixture of regioisomeric [5:1]-hexaadducts. The synthesis of geometrically well-defined supramolecular architectures may benefit from these new types of highly functionalized [5:1]-hexaadducts. [ABSTRACT FROM AUTHOR]

Directing the outcome of electrophilic addition reactions of norbornenes could be a challenging task. We have found that the ionic addition of bromine to dichloro-norbornene 2 is accompanied with the formation of a bromonium cation followed by anchimeric assistance of juxtaposed chlorine to give five-membered chloronium cation, which upon reacting with bromide gives norbornane 4 in >90% yield. At higher temperatures, however, the radical addition of Br 2 dominates so that dibromo compound 3 appears as the principal reaction product (72%). Stereo- and regioselective rearrangements of norbornenes, reported herein, could be of interest for the syntheses of complex haloalkanes. [ABSTRACT FROM AUTHOR]

Sequential 5-alkenyl hydantoin and pyrrolidine ring-forming reactions have been applied in the synthesis of conformationally constrained fused bicyclic scaffold. They are assembled by a three-step reaction sequence from two variable building blocks (readily available β-ketoesters and alkenyl halides) by combining a Bucherer–Bergs reaction with a final selenium-promoted intramolecular cyclization as a key step. The chemoselectivity of this bicyclic hydantoin formation is strongly influenced by experimental factors such as the solvent and the use of additives. The reaction is regiospecific giving only five-membered fused bicyclic hydantoins in good to excellent yields stemming from the nucleophilic attack of the nitrogen atom to a cyclic seleniranium ion intermediate during the cyclization step. A separable diastereomeric mixture is obtained; the products with bridgehead substituents and phenylseleno groups in cis relationships were formed predominantly. The reaction tolerates a variety of substitution at the double bond, furthermore, the presence of substituents at C(5) and N(3) position opens up the capability of generating a broad structural diversity. [ABSTRACT FROM AUTHOR]

The polydentate ligand 3-[(2-hydroxybenzylidene)amino]-2-thioxoimidazolidin- 4-one was synthesized in the intermolecular cyclocondensation reaction of 2-hydroxybenzaldehyde thiosemicarbazone and ethyl chloroacetate. A novel palladium(II) complex was obtained from cis-[Pd(DMSO)2Cl2] by nucleophilic substitution of both DMSO ligands with the iminic nitrogen and the thiolactamic sulfur from the ligand. The structures of the compounds were characterized based on their spectral data. The cytotoxic activities of the ligand and the palladium(II) complex were studied on the tumor cell lines: human colon carcinoma HCT-116 and SW-480 cells using the MTT viability test. The results showed that the investigated palladium(II) complex had a significantly greater cytotoxic effect compared to that of the ligand. [ABSTRACT FROM AUTHOR]

Invited for the cover of this issue is the group of Jovica Badjić at The Ohio State University, and colleagues. The image, by Radoslav Z. Pavlović (idea) and Jennifer F. Neal (design), depicts weak noncovalent contacts controlling the reported system's dynamic stereochemistry, which are shown as a dragon blowing fire at C−H groups. Read the full text of the article at10.1002/chem.201903006. [ABSTRACT FROM AUTHOR]

Front Cover: Multivalent C-H---Cl/Br-C Interactions Directing the Resolution of Dynamic and Twisted Capsules (Chem. Eur. J. 57/2019) On the Front Cover, these weak noncovalent contacts controlling the system's dynamic stereochemistry are shown as a dragon blowing fire at C-H groups. On the Front Cover, these weak noncovalent contacts controlling the system's dynamic stereochemistry are shown as a dragon blowing fire at C-H groups. [Extracted from the article]

We describe the design, preparation and assembly of chair-shaped molecules, comprising a tris-bicyclo[2.2.1]heptane hub that extends into three phthalimides carrying amino acids or short peptides. In water, molecular chairs stack in an antiparallel manner to give hexavalent dendritic structures, in spite of holding equal charges. The here described strategy for increasing the multivalency of peptides is easy to implement in practice, therefore holding potential for creating novel soft materials and therapeutics. [ABSTRACT FROM AUTHOR]

An efficient strategy for a four-step synthesis of angularly fused tricyclic hydantoins as suitable precursors of cis-fused bicyclic a- amino acids is developed by combining a highly diastereoselective Bucherer- Bergs reaction of 2-alkenylcycloalkanones and a regiospecific selenium-induced closure of pyrrolidine ring. This methodology was applied in a five-step synthesis of bicycloproline derivatives in high overall yield. The method could be used for the multigram preparation of free conformationally constrained bicyclic a-amino acids with two points of diversity (size of cycloalkyl ring and substituent at the pyrrolidine ring). [ABSTRACT FROM AUTHOR]

Covalent capsule 1 was designed to include two molecular baskets linked with three mobile pyridines tucked into its inner space. On the basis of both theory (DFT) and experiments (NMR and X‐ray crystallography), we found that the pyridine "doors" split the chamber (380 Å3) of 1 so that two equally sizeable compartments (190 Å3) became joined through a conformationally flexible aromatic barrier. The compartments of such unique host could be populated with CCl4 (88 Å3; PC=46 %), CBr4 (106 Å3; 56 %) or their combination CCl4/CBr4 (PC=51 %), with thermodynamic stabilities ΔG° tracking the values of packing coefficients (PC). Halogen (C−X⋅⋅⋅π) and hydrogen bonding (C−H⋅⋅⋅X) contacts held the haloalkane guests in the cavities of 1. The consecutive complexations were found to occur in a negative allosteric manner, which we propose to result from the induced‐fit mode of complexation. Newly designed 1 opens a way for probing the effects of inner conformational dynamics on noncovalent interactions, reactivity and intramolecular translation in confined spaces of hollow molecules. [ABSTRACT FROM AUTHOR]

We describe a preparative method for directing Mizoroki–Heck cyclotrimerization of enantioenriched bromonorbornenes into molecular baskets having increasingly deeper and extendable aromatic cavities. Such diastereoselective cyclotrimerizations of the bromo-olefinic substrates resulted from prevalent β migratory insertions without the formation of palladacycle intermediate(s). The facile access to multigram quantity of a new series of basket-like hosts clears the way for creating novel supramolecular materials for storage, sequestration and catalysis. [ABSTRACT FROM AUTHOR]

Tetradecanoic acid was decarboxylated by means of lead(IV) acetate (LTA) under thermal (81 °C) and photolytic (r.t.) conditions in benzene solution. The mixture of products, obtained in thermal reaction, consists of esters (acetoxyalkanes and carboxylates), tridecenes, tridecane and phenyltridecane. Additionally, tetradecane and hexacosane, under photolytic conditions, were formed. The classes of products and their distribution might be explained by presence of intermediate 1-tridecyl radical which can undergo intramolecular (result in formation of rearranged carbon centered radicals) and intermolecular stabilization pathways. Experimentally obtained results were used as input data for computational Monte Carlo simulation study of the reaction. On the basis of these results, radical rearrangements, as well as hydride shifts in tridecyl system are discussed. [ABSTRACT FROM AUTHOR]

Abstract: The rearrangements of 1-octyl, 1-decyl and 1-tridecyl intermediates obtained from thermal lead(IV) acetate (LTA) decarboxylation of nonanoic, undecanoic and tetradecanoic acid were investigated experimentally through analysis and distribution of the products. The relationships between 1,5-, 1,6- and possibly existing 1,7-homolytic hydrogen transfer in 1-octyl-radical, as well as successive 1,2-hydride shift in corresponding cation have been computed via Monte-Carlo method. Taking into account that ratios of 1,5-/1,6-homolytic rearrangements in 1-octyl- and 1-tridecyl radical are approximately the same, the simulation shows very low involvement of 1,7-hydrogen rearrangement (1,5-/1,6-/1,7-hydrogen rearrangement=85:31:1) in 1-octyl radical. [Copyright &y& Elsevier]