Exploiting Chirality in Confined Nanospaces.

Spatial organization using confinement has been of great interest since the early ages of supramolecular chemistry. Application such as sensing, catalysis and delivery are continuously emerging. This minireview highlights the evolution of chiral supramolecular cages (CSC) applications in the fields of catalysis, sensing and chiroptical properties. More in detail, beside the description of the strategies adopted for the preparation of chiral supramolecular cages, either of purely organic supramolecular architectures or prepared using metal-ligand coordination bonds, recent findings on their applications, with particular attention to stereodynamic systems, are presented to highlight the recent scientific interests and the future opportunities.

Programmed guest confinement via hierarchical cage to cage transformations.

Taking inspiration from Nature, where (bio)molecular geometry variations are exploited to tune a large variety of functions, supramolecular chemistry has continuously developed novel systems in which, as a consequence of a specific stimulus, structural changes occur. Among the different architectures, supramolecular cages have been continuously investigated for their capability to act as functional hosts where guests can be released in a controlled fashion. In this paper, a novel methodology based on the use of phenanthrenequinone is applied to selectively change the binding properties of a tris(2-pyridylmethyl)amine TPMA-based cage. In particular, subcomponent substitution has been used to change structural cage features thus controlling the inclusion ratio of competing guests differing in size or chirality.

Combining Imine Condensation Chemistry with [3,3] Diaza-Cope Rearrangement for One-Step Formation of Hydrolytically Stable Chiral Architectures.

Dynamic covalent chemistry (DCC) has, in recent years, provided valuable tools to synthesize molecular architectures of increasing complexity. We have also taken advantage of imine DCC chemistry to prepare TPMA-based supramolecular cages for molecular recognition applications. However, the versatility of this approach has as a major drawback the intrinsic hydrolytic lability of imines, which hampers some applications. We present herein a synthetic strategy that combines the advantages of a thermodynamic-driven formation of a supramolecular structure using imine chemistry, together with the possibility to synthetize chiral hydrolytically stable structures through a [3,3]-sigmatropic rearrangement. A preliminary mechanistic analysis of this one-pot synthesis and the scope of the reaction are also discussed.

Fluorescence detected circular dichroism (FDCD) of a stereodynamic probe.

The use of chiroptical techniques in combination with stereodynamic probes is becoming one of the leading strategies for chiral sensing. While in most of the reported studies circular dichroism (CD) is the adopted spectroscopic technique, examples regarding the use of vibrational CD (VCD), circularly polarized luminescence (CPL), and Raman optical activity (ROA) are emerging as innovative tools. In this communication, an anthracene-decorated tris(2-pyridylmethyl)amine zinc complex (TPMA) is reported for its capability to act as a chiral sensor using either CD or fluorescence detected circular dichroism (FDCD). The latter technique offers the unique possibility to determine the enantiomeric excess of a series of carboxylic acids at sensor concentrations down to 0.1 µM. Limitations and possibilities opened by the use of this methodology, in particular regarding the specificity of the probe in the presence of another contaminant, are discussed.

Chiroptical Enhancement of Chiral Dicarboxylic Acids from Confinement in a Stereodynamic Supramolecular Cage.

The fundamental implications that chirality has in science and technology require continuous efforts for the development of fast, economic, and reliable quantitative methods for enantiopurity assessment. Among the different analytical approaches, chiroptical techniques in combination with supramolecular methodologies have shown promising results in terms of both costs and time analysis. In this article, a tris(2-pyridylmethyl)amines (TPMA)-based supramolecular cage is able to amplify the circular dichroism (CD) signal of a series of chiral dicarboxylic acids also in the presence of a complex mixture. This feature has been used to quantify tartaric acid in wines and to discriminate different matrixes using principal component analysis (PCA) of the raw CD data.

Elucidating Sulfide Activation Mode in Metal-Catalyzed Sulfoxidation Reactivity.

Interest in the catalytic activation of peroxides, together with the requirement of stereoselectivity for the production of enantiopure sulfoxides, has made sulfoxidation the ideal playground for theoretical and experimental physical organic chemists investigating oxidation reactivity. Efforts have been dedicated for elucidating the catalytic pathway regarding these species and for dissecting out the dominant factors influencing the yield and stereochemistry. In this article, Ti(IV) and Hf(IV) aminotriphenolate complexes have been prepared and investigated as catalysts in the presence of peroxides in sulfide oxidation. Experimental results have been combined with theoretical calculations obtaining detailed mechanistic information on oxygen transfer processes. The study revealed that steric issues are mainly responsible for the formation of intermediates in the oxidation pathway. In particular, we could highlight the occurrence of a blended situation where the steric effects of sulfides, ligands, and oxidants influence the formation of different intermediates and reaction pathways.

Helicity control of a perfluorinated carbon chain within a chiral supramolecular cage monitored by VCD.

Confinement within supramolecular systems is the leading technology to finely tune guest functional properties. In this communication we report the synthesis of a chiral supramolecular cage able to bias the helicity of a perfluorinated carbon chain hosted within the cage. We monitor the phenomenon of chiral induction by Vibrational Circular Dichroism (VCD) experiments complemented by DFT calculations over the possible conformers.

Chiral recognition via a stereodynamic vanadium probe using the electronic circular dichroism effect in differential Raman scattering.

Intermolecular interactions sensitive to chirality occur in many biological events. We report a complex formation between a versatile vanadium-based probe and a chiral co-ligand monitored via the combination of electronic circular dichroism (ECD) and Raman scattering. This "ECD-Raman" effect was discovered relatively recently and can be measured using a Raman optical activity (ROA) spectrometer. Simulated spectra based on experimental ECD and degree of circularity (DOC) values agree with the observed ones. Sensitive recognition of the chiral enantiopure co-ligand is thus enabled by a combination of resonance of the excitation light with the diastereoisomeric complex, co-ligand complexation, circular dichroism, and polarized Raman scattering from the achiral solvent. Relatively dilute solutions could be detected (10-4 mol dm-3), about 1000× less than is necessary for conventional ROA detection of the pure co-ligand and comparable to concentrations needed for conventional ECD spectroscopy. The results thus show that differential ECD-Raman measurements can be conveniently used to monitor molecular interactions and molecular spectroscopic properties.

Straight from the bottle! Wine and juice dicarboxylic acids as templates for supramolecular cage self-assembly.

Two imine based supramolecular cages are able to self-assemble in the presence of a complex mixture like wine or fruit juices. Taking advantage of templating agents present in these mixtures the systems are able to form and to selectively encapsulate dicarboxylic systems present in the mixtures. This capability has been exploited to develop molecular systems able to report the enantiomeric excess and composition of (a)chiral dicarboxylic acids in fruit juices and wines using 1H-NMR.

Dissection of the Polar and Non-Polar Contributions to Aromatic Stacking Interactions in Solution.

Aromatic stacking interactions have been a matter of study and debate due to their crucial role in chemical and biological systems. The strong dependence on orientation and solvent together with the relatively small interaction energies have made evaluation and rationalization a challenge for experimental and theoretical chemists. We have used a supramolecular cage formed by two tris(pyridylmethyl)amines units to build chemical Double Mutant Cycles (DMC) for the experimental measurement of the free energies of π-stacking interactions. Extrapolating the substituent effects to remove the contribution due to electrostatic interactions reveals that there is a substantial contribution to the measured stacking interaction energies which is due to non-polar interactions (-3 to -6 kJ mol-1 ). The perfectly flat nature of the surface of an aromatic ring gives π-stacking an inherent advantage over non-polar interactions with alkyl groups and accounts for the wide-spread prevalence of stacking interactions in Nature.

Tripodal gold(i) polypyridyl complexes and their Cu+ and Zn2+ heterometallic derivatives. Effects on luminescence.

Three gold(i) tripodal complexes containing the tris(2-pyridylmethyl)amine (TPA) ligand coordinated to Au-PR3 moieties (PR3 = 1,3,5-triaza-7-phosphatricyclo[3.3.1.13.7]decane, PTA (1), 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane, DAPTA (2) and triphenylphosphane (3)) were prepared together with a cage-like structure containing triphosphane 1,1,1-tris(diphenylphosphinomethyl)ethane (4). The luminescence of these complexes has been studied and they show a red shift upon the formation of heterometallic complexes by reaction with Zn(NO3)2, CuCl and [Cu(CH3CN)4]BF4. The different coordination motifs of the Zn2+ and Cu+ heterometallic species and the resulting changes in the recorded absorption, emission and NMR spectra were analysed and supported by TD-DFT calculations.

Organic Polyradicals as Redox Mediators: Effect of Intramolecular Radical Interactions on Their Efficiency.

The spin-spin interactions between unpaired electrons in organic (poly)radicals, especially nitroxides, are largely investigated and are of crucial importance for their applications in areas such as organic magnetism, molecular charge transfer, or multiple spin labeling in structural biology. Recently, 2,2,6,6-tetramethylpiperidinyloxyl and polymers functionalized with nitroxides have been described as successful redox mediators in several electrochemical applications; however, the study of spin-spin interaction effect in such an area is absent. This communication reports the preparation of a novel family of discrete polynitroxide molecules, with the same number of radical units but different arrangements to study the effect of intramolecular spin-spin interactions on their electrochemical potential and their use as oxidation redox mediators in a Li-oxygen battery. We find that the intensity of interactions, as measured by the d1/d electron paramagnetic resonance parameter, progressively lowers the reduction potential. This allows us to tune the charging potential of the battery, optimizing its energy efficiency.

Tris-pyridylmethylamine (TPMA) complexes functionalized with persistent nitronyl nitroxide organic radicals.

The chance to have persistent organic radicals in combination with metals has attracted much interest since it offers the possibility of having new functional molecules with multiple open-shell elements. In this study, we report the synthesis of two tripodal tris(2-pyridyl)methylamine ligands (TPMA) functionalized with nitronyl nitroxide persistent radicals. The newly formed ligands have been used to coordinate zinc(ii), copper(ii), iron(ii) and cobalt(ii). The resulting complexes have been investigated by means of electron paramagnetic resonance (EPR), ESI-MS, FT-IR spectroscopy and X-ray diffraction. An electron reduction of the N-O radical moiety has been observed, depending on the metal used for the formation of the complex and the reaction conditions. We have observed small differences in the EPR spectra depending on the meta or para position of the radical moiety in the complex structure and some antiferromagnetic interactions between the paramagnetic M(ii) ions and the radical species.

Testing the vibrational exciton and the local mode models on the instructive cases of dicarvone, dipinocarvone, and dimenthol vibrational circular dichroism spectra.

The vibrational circular dichroism (VCD) spectra of dicarvone (1), dipinocarvone (2), and dimenthol (3) have been recorded in the range 900-3200 cm-1 , encompassing the mid-infrared (mid-IR), the CO stretching, and the CH-stretching regions. For compound 3 also, the fundamental and the first overtone OH stretching regions have been investigated by IR/NIR absorption and VCD. Density functional theory (DFT) calculations allow one to interpret the IR and VCD spectra and to confirm the configuration/conformational studies previously conducted by X-ray diffraction. The most intense VCD signals are associated with the vibrational normal modes involving symmetry-related groups close to the CC bond connecting covalently the two molecular units. The vibrational exciton (VCDEC) model is fruitfully tested on the VCD data of compounds 1 and 2 for the spectroscopic regions at ~1700 cm-1 , and the local mode model is tested on compound 3 at ~3500 and ~6500 cm-1 . For compounds 1 and 2 also, ECD spectra are reported, and the exciton mechanism is tested also there, and connections to the VCDEC model are examined.

Hetero-Coencapsulation within a Supramolecular Cage: Moving away from the Statistical Distribution of Different Guests.

Beside sensing and delivery, another peculiar property arising from confinement in discrete molecular hosts comes from the possibility to have in close proximity, and in defined position, two different molecules (hetero-coencapsulation). This phenomenon can be tuned considering steric and electronic properties of the guests. In this work, a study on the parameters affecting homo- and hetero-coencapsulation processes within a supramolecular cage is reported. In particular, different benzoate guests were bound within a supramolecular cage containing two metal-binding sites and the experimental binding thermodynamics measured. Unexpectedly, from competition experiments it was observed that the maximum concentration of hetero-coencapsulation is achieved if a weakly binding guest is used to partially displace a strongly binding guest.

A Diastereodynamic Probe Transducing Molecular Length into Chiroptical Readout.

Nature takes advantage of molecular conformational changes to express functions such as signaling across cellular membranes or allosteric protein activation. At the synthetic level, molecular recognition events have been used to induce conformational changes able to trigger functions such as catalysis or sensing. In this context, transduction of stereochemical information has been the leading strategy. In particular, stereodynamic elements have been extensively employed to amplify and/or transduce chiral information. In this article, we report a chiral supramolecular cage with two stereodynamic units, which invert their helicities according to the length of the molecular guest confined within the system. Interestingly, achiral information is transduced by the supramolecular system to different diastereomeric states that have opposite chiroptical absorptions. This is the first example in which it is possible to produce a continuous modulation of the chiroptical output of a system by varying a physical achiral molecular property (viz. molecular dimension). This phenomenon can be exploited for the establishment of novel methods to program conformational control, for the development of innovative sensors and/or for transduction of molecular properties into chiroptical information.

Supramolecular cages as differential sensors for dicarboxylate anions: guest length sensing using principal component analysis of ESI-MS and 1H-NMR raw data.

Dynamic covalent libraries (DCLs) have been widely used in the development of differential sensors. Inspired by recent studies which use supramolecular recognition systems for sensing, we report the use of a tris(-pyridylmethyl)amine (TPMA)-based supramolecular cage as a differential sensor for dicarboxylate anions. In particular, a library of molecular cages constituted by linkers differing in size and flexibility was allowed to equilibrate toward a series of guests differing in molecular size. The differential system was able to discriminate a series of dicarboxylates depending on their chain length. This differentiation was evaluated through the application of the Principal Component Analysis (PCA) method using interpolated and raw data obtained from ESI-MS. Interestingly, while the 1H NMR spectra of the differential system did not allow for the discrimination of the analytes by the naked eye, PCA of the raw data from the spectra revealed information on the chain length of the guest and also on the odd-even character of the carbon chain.

Extending substrate sensing capabilities of zinc tris(2-pyridylmethyl)amine-based stereodynamic probe.

Tripodal metal complexes have been widely used for catalysis and more recently also for molecular recognition applications. Their ability in recognition and signal amplification of chiral substrates is because of the setup of the ligand around the metal in a propeller shape. Within this subject, we have recently reported tris(2-pyridylmethyl)amine- and triphenolamine-based complexes for the determination of the enantiomeric excess of various substrates. Herein, we show the versatility of the zinc tris(2-pyridylmethyl)amine-based stereodynamic probe by performing a detailed study of the imine formation process, by the extension of the sensing capabilities to other chiral compounds. A principal component analysis study of the system together with TD-DFT studies highlights the molecular origin of the observed chiroptical properties.

Supramolecular cage encapsulation as a versatile tool for the experimental quantification of aromatic stacking interactions.

The widespread presence of aromatic stacking interactions in chemical and biological systems, combined with their relatively small energetic contribution, have led to a plethora of theoretical and experimental studies for their quantification and rationalization. Typically, π-π aromatic interactions are studied as a function of substituents to gather information about the interaction mechanism. While experiments suggest that aromatic interactions are dominated by local electrostatic contacts between π-electron density and CH groups, theoretical work has raised the possibility that direct electrostatic interactions between local dipoles of the substituents may play a role. We describe a supramolecular cage that binds two aromatic carboxylates in a stacked geometry such that the aromatic substituents are remote in space. Chemical Double Mutant Cycles (DMCs) were used to measure fifteen different aromatic stacking interactions as a function of substituent (NMe2, OMe, Me, Cl and NO2). When both aromatic rings have electron-withdrawing nitro substituents, the interaction is attractive (-2.8 kJ mol-1) due to reduced π-electron repulsion. When both aromatic rings have electron-donating di-methylamino substituents, the interaction is repulsive (+2.0 kJ mol-1) due to increased π-electron repulsion. The results show that aromatic stacking interactions are dominated by short range electrostatic contacts rather than substituent dipole interactions.

Binding Profiles of Self-Assembled Supramolecular Cages from ESI-MS Based Methodology.

Confined molecular environments have peculiar characteristics that make their properties unique in the field of biological and chemical sciences. In recent years, advances in supramolecular capsule and cage synthesis have presented the possibility to interpret the principles behind their self-assembly and functions, which has led to new molecular systems that display outstanding properties in molecular recognition and catalysis. Herein, we report a rapid method based on ESI-MS to determine the binding profiles for linear saturated dicarboxylic acids in a series of different cages. The cages were obtained by self-assembly of modified tris(pyridylmethyl)amine (TPMA) complexes and diamines chosen to explore variations in their size and flexibility. This methodology has provided information on how small changes in the structures of the host and guest can contribute to recognition events. Moreover, it was possible to study molecular systems that contain paramagnetic metals, which are not suitable for classical binding-constant determination by 1 H NMR spectroscopy.