Confinement induced thermodynamic and kinetic facilitation of some Diels–Alder reactions inside a CB[7] cavitand

The effect of geometrical confinement on the Diels–Alder reactions between some model dienes viz. furan, thiophene, cyclopentadiene, benzene, and a classic dienophile, ethylene has been explored by performing density functional theory‐based calculations. The effect of confinement has been imposed by a rigid macrocyclic molecule cucurbit[7]uril (CB[7]). Results indicate that all the reactions become thermodynamically more favorable at 298.15 K temperature and one atmospheric pressure inside CB[7] as compared to the corresponding free gaseous state reactions. Moreover, the rate constants associated with the reactions experience manifold enhancement inside CB[7] as compared to the “unconfined” reactions. Suitable contribution from the entropy factor makes the concerned reactions more facile inside CB[7]. The energy gap between the frontier molecular orbitals of the dienes and dienophiles decrease inside CB[7] as compared to that in the free state reactions thereby allowing facile orbital interactions. The nature of interaction as well as bonding has been analyzed with the help of atoms‐in‐molecules, noncovalent interaction, natural bond orbital as well as energy decomposition analyses. Results suggest that all the guests bind with CB[7] in an attractive fashion. Primarily, noncovalent interactions stabilize the host–guest systems. © 2017 Wiley Periodicals, Inc.     

CuII‐Containing 1‐Aminocyclopropane Carboxylic Acid Oxidase Is an Efficient Stereospecific Diels–Alderase

In the context of developing ecofriendly chemistry, artificial enzymes are now considered as promising tools for synthesis. They are prepared in particular with the aim to catalyze reactions that are rarely, if ever, catalyzed by natural enzymes. We discovered that 1‐aminocyclopropane carboxylic acid oxidase reconstituted with Cu^II served as an efficient artificial Diels–Alderase. The kinetic parameters of the catalysis of the cycloaddition of cyclopentadiene and 2‐azachalcone were determined (K_M=230 μm , k_app=3 h^?1), which gave access to reaction conditions that provided quantitative yield and >99 % ee of the (1S,2R,3R,4R) product isomer. This unprecedented performance was rationalized by molecular modeling as only one docking pose of 2‐azachalcone was possible in the active site of the enzyme and this was the one that leads to the (1S,2R,3R,4R) product isomer.     

Side‐chain polypseudorotaxanes by threading cucurbit[7]uril onto poly‐N‐n‐butyl‐N′‐(4‐vinylbenzyl)‐4,4′‐bipyridinium bromide chloride: Synthesis,characterization, and properties

A novel side‐chain polypseudorotaxanes P4VBVBu/CB[7] was synthesized from poly‐N‐n‐butyl‐N′‐(4‐vinylbenzyl)‐4,4′‐bipyridinium bromide chloride (P4VBVBu) and cucurbit [7]uril (CB[7]) in water by simple stirring at room temperature. CB[7] beads are localized on viologen units in side chains of polypseudorotaxanes as shown by ¹H NMR, IR, XRD, and UV–vis studies, and it is considered that the hydrophobic and charge‐dipole interactions are the driving forces. TGA data show that thermal stability of the polypseudorotaxanes increases with the adding of CB[7] threaded. DLS data show that P4VBVBu and CB[7] could form polypseudorotaxanes, and the average hydrodynamic radius of the polypseudorotaxanes increases with increasing the concentration of CB[7]. The typical cyclic voltammograms indicate that the oxidation reduction characteristic of P4VBVBu is remarkably affected by the addition of CB[7] because of the formation of polypseudorotaxanes and the shielding effects of CB[7] threaded on the viologen units of polypseudorotaxanes. With the increase of the concentration of KBr or K₂SO₄, the formation of the polypseudorotaxanes was inhibited due to the shielding effects of both Br^? or SO to viologen ion and K⁺ to CB[7] by UV–vis. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 2135–2142, 2010     

Complexation and Fluorescence of Tricyclic Basic Dyes Encapsulated in Cucurbiturils

Tricyclic basic dyes (proflavine, acridine orange, pyronine, pyronine Y, oxonine, thionine and methylene blue) often form one‐to‐one or two‐to‐one complexes with CB[7] and CB[8], respectively. In the case of pyronine Y, the complexes with CB[7] and CB[8] have a one‐to‐one and three‐to‐one stoichiometry, respectively. The binding constants for CB[7] complexes range from 3.07×10⁶ to 1.70×10⁷ m ^?1. In the case of CB[8], the association constant varies between 3.24×10¹³ and 2.50×10¹⁶ m ^?2. Overall, these binding constants are four orders of magnitude higher than those reported for the same dyes in β and γ‐cyclodextrins. Formation of the host–guest complexes leads to an increase in the fluorescence quantum yields in the case of CB[7], while the dimeric or trimeric dye encapsulated in CB[8] are remarkably less fluorescent than the same dye in diluted solutions.     

Irreversible endo‐Selective Diels–Alder Reactions of Substituted Alkoxyfurans: A General Synthesis of endo‐Cantharimides

The [4+2] cycloaddition of 3‐alkoxyfurans with N‐substituted maleimides provides the first general route for preparing endo‐cantharimides. Unlike the corresponding reaction with 3H furans, the reaction can tolerate a broad range of 2‐substitued furans including alkyl, aromatic, and heteroaromatic groups. The cycloaddition products were converted into a range of cantharimide products with promising lead‐like properties for medicinal chemistry programs. Furthermore, the electron‐rich furans are shown to react with a variety of alternative dienophiles to generate 7‐oxabicyclo[2.2.1]heptane derivatives under mild conditions. DFT calculations have been performed to rationalize the activation effect of the 3‐alkoxy group on a furan Diels–Alder reaction.     

Uptake of Hydrocarbons in Aqueous Solution by Encapsulation in Acyclic Cucurbit[n]uril‐Type Molecular Containers

The ability of two water‐soluble acyclic cucurbit[n]uril (CB[n]) type containers, whose hydrophobic cavity is defined by a glycoluril tetramer backbone and terminal aromatic (benzene, naphthalene) sidewalls, to act as solubilizing agents for hydrocarbons in water is described. ¹H NMR spectroscopy studies and phase‐solubility diagrams establish that the naphthalene‐walled container performs as well as, or better than, CB[7] and CB[8] in promoting the uptake of poorly soluble hydrocarbons into aqueous solution through formation of host–hydrocarbon complexes. The naphthalene‐walled acyclic CB[n] container is able to extract large hydrocarbons from crude oil into aqueous solution.     

Programming A Molecular Relay for Ultrasensitive Biodetection through 129Xe NMR

A supramolecular strategy for detecting specific proteins in complex media by using hyperpolarized ¹²⁹Xe NMR is reported. A cucurbit[6]uril (CB[6])‐based molecular relay was programmed for three sequential equilibrium conditions by designing a two‐faced guest (TFG) that initially binds CB[6] and blocks the CB[6]–Xe interaction. The protein analyte recruits the TFG and frees CB[6] for Xe binding. TFGs containing CB[6]‐ and carbonic anhydrase II (CAII)‐binding domains were synthesized in one or two steps. X‐ray crystallography confirmed TFG binding to Zn²⁺ in the deep CAII active‐site cleft, which precludes simultaneous CB[6] binding. The molecular relay was reprogrammed to detect avidin by using a different TFG. Finally, Xe binding by CB[6] was detected in buffer and in E. coli cultures expressing CAII through ultrasensitive ¹²⁹Xe NMR spectroscopy.     

Determination of L‐Cystine by a New Sensitive Cucurbit[7]uril/palmatine Probe

In the presence of cucurbit[7]uril (CB[7]), the CB[7] could react with palmatine, which served as a sensitive fluorescence probe, to form host‐guest stable complexes and the fluorescence intensity of the complexes was greatly enhanced. The fluorescence intensity decreased linearly with an increasing number of L‐cystine in the inclusion system. The experimental results show that there exists a competition between L‐cystine and palmatine for the CB[7] hydrophobic cavity and L‐cystine occupies the space of CB[7] cavity, leading palmatine molecules to be forced to reside in the aqueous environment. Based on the fluorescence quenching of the CB[7]/palmatine complexes resulting from complex formation between CB[7] and L‐cystine, a spectrofluorimetric method for the determination of L‐cystine in aqueous solution in the presence of CB[7] was developed. The linear relationship between the corresponding values of the fluorescence quenching ΔF and L‐cystine concentration was obtained in the range of 6.0 to 1.5×10³ ng·mL^?1, with a correlation coefficient (r) of 0.9996. The detection limit was 2.0 ng·mL^?1. The application of the present method to the determination of L‐cystine in tablets gave satisfactory results. This paper also discussed the mechanism of the fluorescence indicator probe.     

Unravelling RNA–Substrate Interactions in a Ribozyme‐Catalysed Reaction Using Fluorescent Turn‐On Probes

The Diels–Alder reaction is one of the most important C?C bond‐forming reactions in organic chemistry, and much effort has been devoted to controlling its enantio‐ and diastereoselectivity. The Diels–Alderase ribozyme (DAse) catalyses the reaction between anthracene dienes and maleimide dienophiles with multiple‐turnover, stereoselectivity, and up to 1100‐fold rate acceleration. Here, a new generation of anthracene‐BODIPY‐based fluorescent probes was developed to monitor catalysis by the DAse. The brightness of these probes increases up to 93‐fold upon reaction with N‐pentylmaleimide (NPM), making these useful tools for investigating the stereochemistry of the ribozyme‐catalysed reaction. With these probes, we observed that the DAse catalyses the reaction with >91 % de and >99 % ee. The stereochemistry of the major product was determined unambiguously by rotating‐frame nuclear Overhauser NMR spectroscopy (ROESY‐NMR) and is in agreement with crystallographic structure information. The pronounced fluorescence change of the probes furthermore allowed a complete kinetic analysis, which revealed an ordered bi uni type reaction mechanism, with the dienophile binding first.     

Cucurbituril‐Modulated Supramolecular Assemblies: From Cyclic Oligomers to Linear Polymers

Employing bis(p‐sulfonatocalix[4]arenes) (bisSC4A) and N′,N′′hexamethylenebis(1‐methyl‐4,4′‐bipyridinium) (HBV⁴⁺) as monomer building blocks, the assembly morphologies can be modulated by cucurbit[n]uril (CB[n]) (n=7, 8), achieving the interesting topological conversion from cyclic oligomers to linear polymers. The binary supramolecular assembly fabricated by HBV⁴⁺ and bisSC4A units, forms an oligomeric structure, which was characterized by NMR spectroscopy, atomic force microscopy (AFM), transmission electron microscopy (TEM), dynamic light scattering (DLS), isothermal titration calorimetry (ITC), and gel permeation chromatography (GPC) experiments. The ternary supramolecular polymer participated by CB[8] is constructed on the basis of host–guest interactions by bisSC4A and the [2]pseudorotaxane HBV⁴⁺@CB[8], which is characterized by means of AFM, DLS, NMR spectroscopy, thermogravimetric analysis (TGA), UV/Vis spectroscopy, and elemental analysis. CB[n] plays vital roles in rigidifying the conformation of HBV⁴⁺, and reinforcing the host–guest inclusion of bisSC4A with HBV⁴⁺, which prompts the formation of a linear polymer. Moreover, the CB[8]‐participated ternary assembly could disassemble into the molecular loop HBV²⁺@CB[8] and free bisSC4A after reduction of HBV⁴⁺ to HBV²⁺, whereas the CB[7]‐based assembly remained unchanged after the reduction. CB[8] not only controlled the topological conversion of the supramolecular assemblies, but also improved the redox‐responsive assembly/disassembly property practically.     

Investigation of Diels–Alder Reaction of 7‐Substituted 4‐Styrylcoumarins with Symmetrical Dienophiles Leading to 3,4‐Annulated Coumarins

The thermal [4 + 2] cycloaddition reaction of 7‐substituted 4‐styrylcoumarins with N‐phenylmaleimide and tetracyanoethylene in nitrobenzene under reflux conditions rapidly gives 3,4‐annulated coumarins as the Diels–Alder adducts. The position of the surviving double bond was determined on the basis of NMR and supported by energies of the possible structures. The effects of the 7‐substituent and the solvent on the reaction were studied.     

Turning Cucurbit[8]uril into a Supramolecular Nanoreactor for Asymmetric Catalysis

Chiral macromolecules have been widely used as synthetic pockets to mimic natural enzymes and promote asymmetric reactions. An achiral host, cucurbit[8]uril (CB[8]), was used for an asymmetric Lewis acid catalyzed Diels–Alder reaction. We achieved a remarkable increase in enantioselectivity and a large rate acceleration in the presence of the nanoreactor by using an amino acid as the chiral source. Mechanistic and computational studies revealed that both the amino acid–Cu²⁺ complex and the dienophile substrate are included inside the macrocyclic host cavity, suggesting that contiguity and conformational constraints are fundamental to the catalytic process and rate enhancement. These results pave the way towards new studies on asymmetric reactions catalyzed in confined achiral cavities.     

Diels–Alder Reactions of Novel (1′‐Arylallylidene)cyclopropanes with Heterodienophiles

Palladium‐catalyzed cross‐coupling of various aryl iodides with bicyclopropylidene provided isolable (1′‐arylallylidene)cyclopropanes, which reacted with a number of carbonyl compounds in the presence of Eu(fod)₃ under high pressure to furnish oxaspiro[2.5]octene derivatives in moderate to good yields (22–69 %). The reactions of the allylidenecyclopropanes with two azo compounds as dienophiles afforded diazaspiro[2.5]octenes in high yields (82 and 99 %) even at ambient pressure. When treated with nitrosobenzene, two of the allylidenecyclopropanes gave the Diels–Alder adducts in up to 83 and 40 % yield. 2,5‐Diiodo‐p‐xylene coupled twice with bicyclopropylidene, and the product underwent a twofold Diels–Alder reaction with nitrosobenzene to produce the bis(spirocyclopropaneoxazine) derivative in 88 % yield. This overall transformation can be brought about in a one‐pot, two‐step operation by addition of the nitrosoarene to the reaction mixture immediately after formation of the allylidenecyclopropanes to furnish various 5‐oxa‐4‐azaspiro[2.5]oct‐7‐ene derivatives in 22–77 % yield. The coupling of methyl bicyclopropylidenecarboxylate with 2,6‐dimethylphenyl iodide produced a mixture of very stable regioisomeric allylidenecyclopropane derivatives in 90 % yield. The reaction of this mixture with N‐phenyltriazolinedione gave a corresponding mixture of the spirocyclopropanated heterobicycles in 61 % yield.     

Study on δ‐form complex in syndiotactic polystyrene–organic molecules systems. IV. Formation of complexes with a mixture of solvents and structural changes during the sorption of solvents by syndiotactic polystyrene mesophase membranes

The syndiotactic polystyrene (sPS) δ form was crystallized from mixtures with different compositions of p‐chlorotoluene–chlorobenzene (p‐CT–CB) and p‐chlorotoluene–1,1,2‐trichloroethane (p‐CT–TCE). The presence of the δ form and TTGG helical conformation was confirmed by Fourier transform infrared and wide‐angle X‐ray diffraction (WAXD) analyses. In sPS/p‐CT–CB and sPS/p‐CT–TCE δ‐form membranes, the relative absorbance (RA) of the p‐chlorotoluene (p‐CT) solvent peak was very high even at very low concentrations of p‐CT in comparison with the RA of higher concentrations of chlorobenzene (CB) or 1,1,2‐trichloroethane (TCE) in the mixtures. However, the RAs of both CB and TCE solvent peaks decreased with decreasing concentrations of CB and TCE in the mixtures. A negligible decrease in the RA of the TTGG helical content was observed with a decreasing concentration of CB or TCE. The WAXD results showed that the 2θ peak positions of the [010] and [ 10] planes of the sPS/p‐CT–CB and sPS/p‐CT–TCE δ‐form membranes appeared in the same position and were almost equal to those of the sPS–p‐CT δ‐form membrane. The mesophases of the sPS–p‐CT [p‐CT (A‐M)] and sPS–TCE [TCE (A‐M)] membranes were used for the sorption studies with different concentrations of various solvents. The sorption amount of aromatic solvents by both p‐CT (A‐M) and TCE (A‐M) mesophase membranes was higher than that of aliphatic solvents, regardless of the size, shape, and nature of the molecular cavity. The 2θ peak of the [010] plane of the sPS membranes slowly approached the original δ‐form value when the sPS mesophase membranes were immersed in various solvents of different concentrations for 48 h. The shifting of the 2θ peak of the [010] plane to the original δ form depended on the nature and concentration of the immersion solvents. © 2005 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 43: 2380–2387, 2005     

Cucurbit[7]uril⋅Guest Pair with an Attomolar Dissociation Constant

Host?guest complexes between cucurbit[7] (CB[7]) or CB[8] and diamantane diammonium ion guests 3 or 6 were studied by ¹H NMR spectroscopy and X‐ray crystallography. ¹H NMR competition experiments revealed that CB[7]? 6 is among the tightest monovalent non‐covalent complexes ever reported in water with K_a=7.2×10¹⁷ M ^?1 in pure D₂O and 1.9×10¹⁵ M ^?1 in D₂O buffered with NaO₂CCD₃ (50 mM ). The crystal structure of CB[7]? 6 allowed us to identify some of the structural features responsible for the ultratight binding, including the distance between the NMe₃⁺ groups of 6 (7.78 Å), which allows it to establish 14 optimal ion‐dipole interactions with CB[7], the complementarity of the convex van der Waals surface contours of 6 with the corresponding concave surfaces of CB[7], desolvation of the C?O portals within the CB[7]? 6 complex, and the co‐linearity of the C₇ axis of CB[7] with the N⁺???N⁺ line in 6 . This work further blurs the lines of distinction between natural and synthetic receptors.     

Stereoselection in the diels–alderase ribozyme: A molecular dynamics study

The Diels‐Alderase ribozyme is an in vitro‐evolved ribonucleic acid enzyme that catalyzes a [4 + 2] cycloaddition reaction between an anthracene diene and a maleimide dienophile. The ribozyme can in principle be used to selectively synthesize only one product enantiomer, depending on which of the two entrances to the catalytic pocket, “front” or “back”, the substrate is permitted to use. Here, we investigate stereoselection and substrate recognition in the ribozyme by means of multiple molecular dynamics simulations, performed on each of the two substrates individually in the pocket, on the reactant state, and on the product state. The results are consistent with a binding mechanism in which the maleimide likely binds first followed by the anthracene, which enters preferentially through the front door. The free energy profiles for anthracene binding indicate that the pre‐(R,R)‐enantiomer conformation is slightly preferred, in agreement with the experimentally observed small enantiomeric excess of the (R,R)‐enantiomer of the product. The reactant state is stabilized by the simultaneous presence of both substrates bound to their binding sites in the hydrophobic pocket as well as by stacking interactions between them. © 2012 Wiley Periodicals, Inc.     

Total Synthesis of (+)‐Machaeriols B and C and of Their Enantiomers with a Cannabinoid Structure

An efficient and concise synthesis of the biologically interesting (+)‐machaeriol B ( 2 ) and its enantiomer 5 was accomplished from O‐phenylhydroxylamine ( 7 ) in four steps (Scheme 2). In addition, the first total synthesis of natural (+)‐machaeriol C ( 3 ) and its enantiomer 6 was achieved from the readily available ester 15 in eight steps (Scheme 4). The key strategies in the syntheses of 2 and 5 involved benzofuran formation through a [3,3]‐sigmatropic rearrangement and trans‐hexahydrodibenzopyran formation by a domino aldol‐type/hetero‐Diels–Alder reaction. In the case of 3 and 6 , the key steps were stilbene formation by a Horner–Wadsworth–Emmons reaction and trans‐hexahydrodibenzopyran formation by domino reactions.     

Cucurbit[7]uril Complexation Drives Thermal trans–cis‐Azobenzene Isomerization and Enables Colorimetric Amine Detection

Complexation of yellow diaminoazobenzenes 1 and 3 inside cucurbit[7]uril (CB[7]) results in the formation of purple‐colored CB[7] ? cis‐ 1? 2 H⁺ and CB[7] ? cis‐ 3? 2 H⁺ complexes, respectively. The high binding affinity and selectivity displayed by CB[7] toward 1 and 3 pays the >10 kcal mol^?1 thermodynamic cost for this isomerization. We investigated the behavior of these complexes as a function of pH and observed large pK_a shifts and high pH responsiveness, which are characteristic of cucurbit[n]uril molecular containers. The remarkable yellow to purple color change was utilized in the construction of an indicator displacement assay for biologically active amines 4 – 10 . This indicator displacement assay is capable of quantifying the pseudoephedrine ( 5 ) content in Sudafed tablets over the 5–350 μM range.     

Supramolecular Polymerization Promoted and Controlled through Self‐Sorting

A new method in which supramolecular polymerization is promoted and controlled through self‐sorting is reported. The bifunctional monomer containing p‐phenylene and naphthalene moieties was prepared. Supramolecular polymerization is promoted by selective recognition between the p‐phenylene group and cucurbit[7]uril (CB[7]), and 2:1 complexation of the naphthalene groups with cucurbit[8]uril (CB[8]). The process can be controlled by tuning the CB[7] content. This development will enrich the field of supramolecular polymers with important advances towards the realization of molecular‐weight and structural control.     

DFT Studied Hetero‐Diels–Alder Cycloaddition for the Domino Synthesis of Spiroheterocycles Fused to Benzothiazole and Chromene/Pyrimidine Rings in Aqueous Media

Structurally diverse spiroheterocycles; spiro[pyrimido[2,1‐b ]benzothiazole‐3,3′‐chromene]‐2′,4′‐dione, spiro[pyrimido[2,1‐b ]benzothiazole‐3,5′‐pyrimidine]‐2′,4′,6′‐trione, and spiro[pyrimido[2,1‐b ]benz‐thiazole‐3,2′‐cyclohexane]‐1′,3′‐dione have been synthesized by an environmentally benign, efficient, and facile one‐pot pseudo‐four component reaction of 2‐aminobenzothiazoles with aromatic aldehydes and cyclic β‐diketones in aqueous medium. The process involves hetero‐Diels–Alder cycloaddition and provides facile access to spiroheterocycles fused with potentially interesting biologically active scaffolds. The configuration of hetero‐Diels–Alder cycloadduct has been ascertained through density functional theory calculations.