Synthesis, Resolution, and Absolute Configuration of a Phosphine-Based Hemicryptophane Cage with an Endo Phosphorus Lone Pair and Formation of the Corresponding Gold Complex.

The synthesis, characterization, and chiroptical properties of a new class of hemicryptophanes combining a phosphine moiety and a cyclotriveratrylene unit are reported. The synthesis was short and efficient. The racemic mixture of the cage was resolved by chiral high-performance liquid chromatography (HPLC), giving access to enantiopure molecular cages, whose absolute configurations could be assigned by electronic circular dichroism (ECD) spectroscopy. These new phosphines were then reacted with gold in order to make the corresponding enantiopure gold complexes. The X-ray structure reveals an endohedral functionalization of the cage with the gold metal entrapped in the heart of the cavity, leading to a Vbur of 58%. Moreover, the chirality of the cyclotriveratrylene unit was found to control the chiral arrangement of the aryl group linked to the phosphorus atom, located at the opposite side of the cavity.

Straightforward Access to Chiral Phosphangulene Derivatives.

Polycyclic aromatic hydrocarbons including heteroatoms have found a wide range of applications, for instance, in supramolecular chemistry or material science. Phosphangulene derivatives are P-containing polycyclic aromatic hydrocarbons presenting a concave aromatic surface suitable for building supramolecular receptors. However, the applications of this convenient building block have been strongly hampered by a difficult and multistep preparation requiring several protection-deprotection sequences along with the use of harmful reagents. Here, we report a straightforward, protecting-group-free, three-step, and hundred-milligram-scale synthesis of a chiral phosphangulene oxide derivative via a triple phospho-Fries rearrangement. This compound was easily resolved by chiral HPLC and further functionalized, giving rise to versatile chiral phosphangulene derivatives. Following this strategy, chiral phosphangulene oxides with low symmetry were synthesized. Molecular crystal structures revealed a variety of molecular organization in the solid. This opens the way to wider use of this compound as a building block for cages or new materials.

Probing the Importance of Host Symmetry on Carbohydrate Recognition.

The design of molecular cages with low symmetry could allow for more specific tuning of their properties and better mimic the unsymmetrical and complex environment of protein pockets. However, the added value of lowering symmetry of molecular receptors has been rarely demonstrated. Herein, C3 - and C1 -symmetrical cages, presenting the same recognition sites, have been synthesized and investigated as hosts for carbohydrate recognition. Structurally related derivatives of glucose, galactose and mannose were found to have greater affinity to the receptor with the lowest symmetry than to their C3 -symmetrical analogue. According to the host cavity modelling, the C1 symmetry receptor exhibits a wider opening than its C3 -symmetrical counterpart, providing easier access and thus promoting guest proximity to binding sites. Moreover, our results show the high stereo- and substrate selectivity of the C1 symmetry cage with respect to its C3 counterpart in the recognition of sugars.

Sequential Formation of Heteroternary Cucurbit[10]uril (CB[10]) Complexes.

The globular and monocationic guest molecule trimethyl-azaphosphatrane (AZAP, a protonated Verkade superbase) was shown to form a host:guest 1 : 1 complex with the cucurbit[10]uril (CB[10]) macrocycle in water. Molecular dynamics calculations showed that CB[10] adopts an 8-shape with AZAP occupying the majority of the internal space, CB[10] contracting around AZAP and leaving a significant part of the cavity unoccupied. This residual space was used to co-include planar and monocationic co-guest (CG) molecules, affording heteroternary CB[10]⋅AZAP⋅CG complexes potentially opening new perspectives in supramolecular chemistry.

Energy-Efficient Iodine Uptake by a Molecular Host⋠Guest Crystal.

Recently, porous organic crystals (POC) based on macrocycles have shown exceptional sorption and separation properties. Yet, the impact of guest presence inside a macrocycle prior to adsorption has not been studied. Here we show that the inclusion of trimethoxybenzyl-azaphosphatrane in the macrocycle cucurbit[8]uril (CB[8]) affords molecular porous host⋅guest crystals (PHGC-1) with radically new properties. Unactivated hydrated PHGC-1 adsorbed iodine spontaneously and selectively at room temperature and atmospheric pressure. The absence of (i) heat for material synthesis, (ii) moisture sensitivity, and (iii) energy-intensive steps for pore activation are attractive attributes for decreasing the energy costs. 1 H NMR and DOSY were instrumental for monitoring the H2 O/I2 exchange. PHGC-1 crystals are non-centrosymmetric and I2 -doped crystals showed markedly different second harmonic generation (SHG), which suggests that iodine doping could be used to modulate the non-linear optical properties of porous organic crystals.

Hemicryptophane Cages with a C1-Symmetric Cyclotriveratrylene Unit.

Two new hemicryptophanes combining a cyclotriveratrylene unit with either an aminotrisamide or a tris(2-aminoethyl)amine (tren) moiety have been synthesized. Although a conventional synthesis approach was used, the molecular cages obtained are devoid of the expected C3 symmetry. NMR analyses and X-ray crystal structure determination showed that these hemicryptophanes exhibited C1 symmetry due to the unusual arrangement of the substituents of the cyclotriveratrylene unit. This unprecedented arrangement is related to a change in the regioselectivity of the Friedel-Crafts reactions that led to the CTV cap. This constitutes an original approach to access enantiopure chiral molecular cages with low symmetry.

The Chloroazaphosphatrane Motif for Halogen Bonding in Solution.

Chloroazaphosphatranes, the corresponding halogenophosphonium cations of the Verkade superbases, were evaluated as a new motif for halogen bonding (XB). Their modulable synthesis allowed for synthetizing chloroazaphosphatranes with various substituents on the nitrogen atoms. The binding constants determined from NMR titration experiments for Cl-, Br-, I-, AcO-, and CN- anions are comparable to those obtained with conventional iodine-based monodentate XB receptors. Remarkably, the protonated azaphosphatrane counterparts display no affinity for anions under the same conditions. The strength of the XB interaction is, to some extent, related to the basicity of the corresponding Verkade superbase. The halogen bonding abilities of this new class of halogen donor motif were also revealed by the Δδ(31P) NMR shift observed in CD2Cl2 solution in the presence of triethylphosphine oxide (TEPO). Thus, chloroazaphosphatranes constitute a new class of halogen bond donors, expanding the repertory of XB motifs mainly based on CAr-I bonds.

Highly Selective Fluoride Recognition by a Small Tris-Urea Covalent Cage.

A highly selective recognition of fluoride was achieved through the design of a small hemicryptophane cage (3) presenting a southern tris-urea hosting moiety. The resulting host-guest complex has been characterized by electrospray ionization-high-resolution mass spectrometry, 1H and 19F NMR, and X-ray diffraction techniques. In particular, X-ray diffraction analysis of [3·F-] reveals that the encapsulation of one fluoride, within 3, occurs through NH···F- H-bonding with the six NH residues of the tris-urea ligand. An association constant of 1200 M-1 was extracted from 1H NMR titration experiments, indicating that efficient fluoride binding also occurs in solution. Finally, in sharp contrast with previously reported urea-based hemicryptophane hosts, the small preorganized cavity found in 3 allows for an exclusive selectivity for fluoride over other competing halides.

Enantiopure encaged Verkade's superbases: Synthesis, chiroptical properties, and use as chiral derivatizing agent.

Verkade's superbases, entrapped in the cavity of enantiopure hemicryptophane cages, have been synthesized with enantiomeric excess (ee) superior to 98%. Their absolute configuration has been determined by using electronic circular dichroism (ECD) spectroscopy. These enantiopure encaged superbases turned out to be efficient chiral derivatizing agents for chiral azides, underlining that the chirality of the cycloveratrylene (CTV) macrocycle induces different magnetic and chemical environments around the phosphazide functions.

Positive Cooperative Effect in Ion-Pair Recognition by a Tris-urea Hemicryptophane Cage.

The synthesis of a hemicryptophane cage combining a CTV unit with a C3 symmetrical moiety bearing three urea functions is reported. This host was found to bind anions with higher binding constants than other previously reported hemicryptophanes. Due to its heteroditopic character this cage proved to be an efficient ion-pair receptor. The best cooperativity effect was observed for the tetramethylammonium bromide (TMABr) salt, which was confirmed and rationalized by DFT calculations.

Endohedral Functionalized Cage as a Tool to Create Frustrated Lewis Pairs.

A frustrated Lewis pair (FLP) system was obtained by confinement of the Lewis base partner, a Verkade's superbase, in a molecular cavity. Whereas the model superbase lacking cavity displayed no catalytic activity in Morita-Baylis-Hillman (MBH) reactions, when associated to titanium (IV) chloride, the encaged superbase turns out to be an efficient catalyst under the same conditions. The crucial role of the endohedral functionalized cage on catalytic performance was further demonstrated by the fact that model superbases with bulky substituents were much less efficient to produce active catalysts, as well as by inhibition and substrate selection experiments. 31 P NMR spectroscopy and mass spectrometry experiments evidenced that no interaction between the Lewis acidic and basic partners occurred when the superbase was capped by a cycloveratrylene (CTV) unit, thus creating a true FLP active system.

Insights into the Complexity of Weak Intermolecular Interactions Interfering in Host-Guest Systems.

The recognition properties of heteroditopic hemicryptophane hosts towards anions, cations, and neutral pairs, combining both cation-π and anion-π interaction sites, were investigated to probe the complexity of interfering weak intermolecular interactions. It is suggested from NMR experiments, and supported by CASSCF/CASPT2 calculations, that the binding constants of anions can be modulated by a factor of up to 100 by varying the fluorination sites on the electron-poor aromatic rings. Interestingly, this subtle chemical modification can also reverse the sign of cooperativity in ion-pair recognition. Wavefunction calculations highlight how short- and long-range interactions interfere in this recognition process, suggesting that a disruption of anion-π interactions can occur in the presence of a co-bound cation. Such molecules can be viewed as prototypes for examining complex processes controlled by the competition of weak interactions.

Azaphosphatrane organocatalysts in confined space: cage effect in CO(2) conversion.

The endohedral functionalization of a molecular cage by an azaphosphatrane unit has allowed for the creation of highly engineered catalytic cavities for efficient conversion of CO2 into cyclic carbonates. Strong structure/activity/stability correlations have been demonstrated by careful adjustment of the size, shape, and electronic properties of the hemicryptophane host.

Catalytic activity of an encaged Verkade's superbase in a base-catalyzed Diels-Alder reaction.

Organocatalysis in a confined space has been performed through encapsulation of a proazaphosphatrane superbase in a hemicryptophane host. The resulting catalyst displays good to high catalytic activity in the base-catalyzed Diels-Alder reactions investigated. A comparison with the model superbase, which lacks a cavity, shows much higher diastereomeric excess with the encaged proazaphosphatrane for the reaction of 3-hydroxy-2-pyrone with N-methylmaleimide. The use of an encaged superbase as organocatalyst is unprecedented and highlights how the confinement may impact the stereoselectivity.

Improved hemicryptophane hosts for the stereoselective recognition of glucopyranosides.

Four new enantiomerically and diastereomerically pure hemicryptophane hosts (M-SSS-2/P-SSS-2 and M-RRR-2/P-RRR-2 pairs) were designed for the recognition of sugar derivatives. Their absolute configuration was determined from the circular dichroism spectra and DFT calculations. The host molecules were then used for the stereoselective recognition of glucopyranosides. Binding constants were obtained from (1)H NMR titration experiments showing an increase of affinity for this class of receptors, associated with an improved diastereo- and enantio-differentiation.

Ditopic Covalent Cage for Ion-Pair Binding: Influence of Anion Complexation on the Cation Exchange Rate.

A new hemicryptophane host with a ditopic molecular cavity combining a cyclotriveratrylene (CTV) unit with a tris-urea moiety was synthesized. The complexation of halides, tetramethylammonium (TMA+) cation, and ion pairs was investigated. A positive cooperativity was observed, since halides display a higher binding constant when a TMA+ cation is already present inside the cage. When TMA+ was complexed alone, a decrease of temperature from 298 K to 230 K was required to switch from a fast to a slow exchange regime on the NMR time scale. Nevertheless, the prior complexation of a halide guest in the lower part of the host resulted in significant decrease of the exchange rate of the subsequent complexation of the TMA+ cation. Under these conditions, the 1H NMR signals characteristic of a slow exchange regime were observed at 298 K. Addition of an excess of salts, increases the ionic strength of the solution, restoring the fast exchange dynamics. This result provides insight on how the exchange rate of a cation guest can be modulated by the complexation of a co-guest anion.

Azaphosphatranes as structurally tunable organocatalysts for carbonate synthesis from CO2 and epoxides.

Three azaphosphatranes were used as organocatalysts for the synthesis of cyclic carbonates from CO2 and epoxides. They proved to be efficient single-component, metal-free catalysts for the reaction of simple or activated epoxides (styrene oxide, epichlorohydrin, glycidyl methyl ether) with CO2 under mild reaction conditions, displaying high stability and productivity over several days of reaction. Substitution patterns on the catalyst were shown to affect activity and stability. Kinetic analysis allowed investigation of the reaction mechanism.

Superbases in confined space: control of the basicity and reactivity of the proton transfer.

Endohedral functionalization of the molecular cavity of host molecules is in high demand in many areas of supramolecular chemistry. When highly reactive species are incarcerated in the confined space of a molecular cavity, deep changes of their chemical properties are expected. Here, we show that the superbasic properties of proazaphosphatranes can be improved in the confined space of the molecular cavity of hemicryptophane hosts. A general and modular procedure is described to prepare supramolecular superbases with various cavity sizes. The rate of proton transfer is strongly dependent on the shape and size of the inner cavity of the designed superbasic structure. Kinetic and thermodynamic data are strongly correlated to the space available around the basic center as revealed by the X-ray molecular structures analyses.

Chiral discrimination of ammonium neurotransmitters by C3-symmetric enantiopure hemicryptophane hosts.

Enantiopure hemicryptophanes efficiently discriminate chiral ammonium neurotransmitters. The ephedrine and norephedrine molecules associate with hemicryptophane hosts to form 1:1 and 1:2 host-guest complexes. Binding constants are determined by fitting the ¹H nuclear magnetic resonance (NMR) titration curves to give ß1 and ß2 values, which are used to characterize the diastereomeric and enantiomeric discriminating potentials of the hosts.

Absolute configuration and enantiodifferentiation of a hemicryptophane incorporating an azaphosphatrane moiety.

The hemicryptophane racemate (±)-1 was optically resolved by semipreparative HPLC on Chiralpak IC column. The absolute configuration of each isolated enantiomer was established from the analysis of their electronic circular dichroism spectra. Enantiodifferentiation of the chiral cationic cage (±)-1 was evidenced in solution using Δ-TRISPHAT as chiral solvating agent, and the diastereomeric associations were observed in (1)H and (31)P NMR spectra.