Molecular Recognition with Enantiopure Alleno-Acetylenic Cage Receptors

Abstract

The study of synthetic model systems and biological counterparts has developed an extraordinary symbiosis, helping to decipher important chemical phenomena observed in nature. This Thesis is dedicated to the understanding of molecular recognition processes of neutral achiral and chiral small molecules by enantiopure receptors. Despite the progress in the design and construction of enantiopure receptors, examples of optically pure systems that effectively differentiate chiral neutral small molecules are still rare. The general notion prevails that strong directional interactions between the host and the guest are required. In order to question this idea, we constructed enantiopure alleno-acetylenic cage (AAC) receptors that bind molecules purely based on dispersion interactions largely in the absence of directional interactions. Subsequently, we extended our molecular recognition studies to halogen-bonding and hydrogen-bonding interactions. In the second chapter, we describe the synthesis and properties of enantiopure alleno-acetylenic cage (AAC) receptors. AACs are constructed from a methylene-bridged resorcin[4]arene core to which four homochiral alleno-acetylenes with OH termini are attached to, giving access to both (P)4- and (M)4 configured AACs. Detailed analysis of the structure-property relationship of the receptor allowed to identify important conformational features of the receptor, enabling quantification of guest uptake and release: the receptors undergoes solvent-dependent binary conformational switching accompanied by strong changes in the associated electronic circular dichroism (ECD) spectra with ΔΔɛ = 882 M–1 cm–1 at 𝜆�������� = 304 nm, allowing for a sensitive spectroscopic readout of the conformational changes. In the closed cage conformation, the OH-termini of the alleno-acetylenic arms form a cyclic four-fold hydrogen-bonding array, creating a highly confined cavity. The directional nature of the H-bonding array – clockwise for (P)4-configured AACs and counter-clockwise for (M)4-configured AACs – was identified to contribute to the unprecedentedly large change in chiroptical properties of the assembly. A general method to obtain single crystals of the solid-state inclusion complexes was developed and relies on the guest-induced switching of the receptor from its open state (in CH3CN/H2O 9:1) to the closed state upon encapsulation of guest molecules. The combination of a highly shape-persistent, confined chiral cavity, capable of guest encapsulation, together with the spectroscopic and crystallographic readout for cage inclusion, made the AAC receptors ideal model system to study chiral recognition. We first investigated the molecular recognition of achiral and chiral cyclic alkanes, where complexation is purely based on non-directional dispersion interactions. X-ray co-crystal structures revealed a size adaptability of the receptor towards the guest, thereby optimizing the packing coefficient of the ensemble. At the optimal packing coefficient of ∼55%, the enantiopure receptor showed complete selectivity towards (±)-trans-1,2-dimethylcyclohexane, where the (P)4-configured host solely bound the (R,R)-configured guest, and the (M)4-configured receptor exclusively bound the (S,S)-configured guest. X-ray co-crystal structures of the host-bound guests revealed the exclusive complexation of their higher-energy diaxial conformation, with the diaxial dihedral angle deviating strongly from the commonly accepted value of 180° down to 146°. Subsequent theoretical investigations demonstrated negligible influence of the host on the guest structures. We validated the utility of the host for the structural elucidation of the (di)axial conformations of cyclohexane derivatives by expanding the series of guest molecules to monohalo- and (±)-trans-1,2 dihalocyclohexanes. The molecular structures of the host–guest complexes, obtained through single-crystal X-ray diffraction, showed the guests exclusively bound in their axial and diaxial chair conformation, with dihedral angles ϑa,a (X-C(1)-C(2)-H/X) deviating substantially from 180°. Increasing deviation from this angle was observed for the monohalocyclohexanes (up to 25°) to (±)-trans-1,2-dihalocyclohexanes (up to 33°). Substantial bond-length and bond-angle alteration in the carbon scaffold was assumed to reduce the strain caused by the 1,3-diaxial interactions of the guests in their diaxial conformation. Solution complexation studies supported the exclusive complexation of the guests in their (di)axial chair conformation, where slow host–guest exchange allowed for full characterization of the guest in the interior of the host. Theoretical analysis of the isolated guest molecules showed close agreement of the complexed and the isolated guest structures, validating the utility of the AACs to capture single conformers of derivatives of cyclohexane for their structural elucidation. X-ray co-crystal structures of the host-guest complexes further revealed a yet hardly studied halogen-bonding contact: the C–X⋯⫴ contact. Theoretical studies on the C–X⋯⫴ interaction substantiated its halogen-bonding character. Solution binding constants, along with the theoretical calculations on the conformational energies (A-values) of the guests, indicated a contribution of the C–Br⋯⫴ halogen-bonding contact of ΔΔG F→Br = – 0.9 kcal mol–1. The C–X⋯⫴ contact appeared to majorly influence the enantioselectivity of the enantiopure receptor towards the chiral guests, with increased enantioselectivity with increased halogen-bonding strength (Cl < Br). The overall enantioselectivity towards (±)-trans-1,2-dihalocyclohexanes was lower compared to (±) trans-1,2-dimethylcyclohexanes (complete enantioselectivity). This finding was counter-intuitive considering the stronger and directional nature of halogen-bonding contacts compared to the non directional, purely dispersion interactions, of (±)-trans-1,2-dimethylcyclohexanes with the host. It is in stark contrast to established concepts for enantioselective complexation of optically pure receptors with chiral guests, where more directional interactions were considered to enhance selectivity. We explained this observation with the much higher polarizability of chlorine and bromine compared to the methyl substituents. Inspired by a crystal structure of the AAC receptor encapsulating one water molecule and two acetonitrile molecules, we expanded our series of guest molecules to cyclic and acyclic alcohols. The alcohol series formed strong directional interactions between the alcohol groups of the guest and the hydrogen-bonding array of the host. Generally, the introduction of an alcohol group increased the binding affinities of the guest to the receptors in solution by ∼3–4 kcal mol–1, resulting in kinetically stable host–guest complexes on the NMR time scale. Solution studies, along with structural information obtained from X-ray co-crystal structures, enabled the conformational analysis of the host-bound guests. Noteworthy was the substantial increase in binding affinity from cycloheptane to endo-tropine with a difference in binding affinitiy of ΔΔG 293 K = –6.1 kcal mol–1 (Ka = 7.0·106 M–1 in n-octane at 293 K), allowing to detect endo-tropine with AACs in the part per billion regime. The directional hydrogen-bonding interactions of the guest to the receptors generated various hydrogen bonding motifs (4-fold to 5-fold and 6-fold), which were strongly dependent on the alcohol guest encapsulated in the interior of the host. The host–guest-complex appeared to retain some directionality of the hydrogen-bonding array, despite the disruptive nature of the directional hydrogen-bonding interactions of the guest with the host. In a collaboration with Dr. Fischer and Prof. Carreira (ETHZ), supported by theoretical studies by T. Husch and Prof. Reiher (ETHZ), we studied the enantioselective binding of various acyclic alkyl and alkyl halide alcohols, undergoing dispersion and halogen-bonding interactions. The formation of diastereoisomeric complexes of the enantiopure hosts with the chiral guests enabled us to assess the enantioselectivity of the receptors towards the guests in solution and in the solid state. X-ray co-crystal structures gave insight into the conformation of the guests complexed to the interior of the host. In the following chapter, we describe the modular synthesis of enantiopure alleno-acetylenic cage receptors with increased surface polarity and solubility in aqueous medium. This new class of receptors revealed conformational switching from an open to a closed form upon guest complexation. The structural similarity of the hydrophobic cavity of the more polar AACs soluble in aqueous medium with the apolar AAC receptors, make them ideal to study the thermodynamic differences of enantioselective complexation in apolar and aqueous solvent systems. The last chapter gives a brief overview on the synthesis and chiroptical properties of covalently capped alleno-acetylenic cage receptors, accessed through intramolecular oxidative dimerization. The covalent AACs showed strong absorption properties towards circulary polarized light, with hardly any temperature dependencies. X-ray co-crystal structure of the covalent (P)4- and (M)4-configured AACs gave insights into the volume of the cavity for molecular recognition studies. Molecular recognition studies on the covalent receptor systems are ongoing.