Agnieszka Szumna

A New Macrocyclic Polylactam-Type Neutral Receptor for Anions − Structural Aspects of Anion Recognition

A macrocyclic ligand containing four amide functionalities was synthesised and its complexes with various anions (F−, Cl−, AcO−, H2PO4−, and p-NO2C6H4O−) were investigated in solution and in the solid state. NMR titration experiments (carried out in [D6]DMSO), X-ray studies and electrospray mass spectrometry (ESI MS) were employed for determination of stoichiometry and selectivity. The results in solution indicated predominant formation of 1:1 complexes for all anions studied. However, the existence of a 2:1 complex of 1 with bidentate AcO− anion as a minor species was also detected. X-ray crystal structure determination provided evidence that the Cl− anion is too bulky to be included in the cavity of the 18-membered tetralactam ring [Kass(Cl−; DMSO) = 65 M−1], but that F− fits well [Kass(F−; DMSO) = 830 M−1]. The binding mode of AcO− anion consists of formation of four hydrogen bonds to only one of the carboxylate oxygen atoms (employing the syn-anti lone pairs of AcO−). The selectivity of the receptor towards AcO− anion [Kass(AcO−; DMSO) = 2640 M−1] is discussed in terms of a favourable arrangement of hydrogen-bond donors. The limited extent of formation of a 2:1 (1/AcO−) complex is attributed to unfavourable interactions between two receptor molecules.

Anion-sealed single-molecule capsulesElectronic supplementary information (ESI) available: Experimental details. See http://www.rsc.org/suppdata/cc/b3/b301511d/

A new approach to anion recognition utilizing electrostatic and hydrogen bonding interactions has been demonstrated by placement of the whole ion-pair in a molecular capsule.

Dynamic Formation of Hybrid Peptidic Capsules by Chiral Self‐Sorting and Self‐Assembly

Owing to their versatility and biocompatibility, peptide-based self-assembled structures constitute valuable targets for complex functional designs. It is now shown that artificial capsules based on β-barrel binding motifs can be obtained by means of dynamic covalent chemistry (DCC) and self-assembly. Short peptides (up to tetrapeptides) are reversibly attached to resorcinarene scaffolds. Peptidic capsules are thus selectively formed in either a heterochiral or a homochiral way by simultaneous and spontaneous processes, involving chiral sorting, tautomerization, diastereoselective induction of inherent chirality, and chiral self-assembly. Self-assembly is shown to direct the regioselectivity of reversible chemical reactions. It is also responsible for shifting the tautomeric equilibrium for one of the homochiral capsules. Two different tautomers (keto-enamine hemisphere and enol-imine hemisphere) are observed in this capsule, allowing the structure to adapt for self-assembly.

Chiral encapsulation by directional interactions.

The complexation of chiral guests in the cavity of dimeric self-assembled chiral capsule 1(2) was studied by using NMR spectroscopy and X-ray crystallography. Capsule 1(2) has walls composed of amino acid backbones forming numerous directional binding sites that are arranged in a chiral manner. The polar character of the interior dictates the encapsulation preferences towards hydrophilic guests and the ability of the capsule to extract guests from water into an organic phase. Chiral discrimination towards hydroxy acids was evaluated by using association constants and competition experiments, and moderate de values were observed (up to 59 %). Complexes with one or two guest molecules in the cavity were formed. For 1:1 complexes, solvent molecules are coencapsulated; this influences guest dynamics and makes the chiral recognition solvent dependent. Reversal of the preferences can be induced by coencapsulation of a nonchiral solvent in the chiral internal environment. For complexes with two guests, filling of the capsules internal space can be very effective and packing coefficients of up to 70 % can be reached. The X-ray crystal structure of complex 1(2) superset((S)-6)(2) with well-resolved guest molecules reveals a recognition motif that is based on an extensive system of hydrogen bonds. The optimal arrangement of interactions with the alternating positively and negatively charged groups of the capsules walls is fulfilled by the guest carboxylic groups acting simultaneously as hydrogen-bond donors and acceptors. An additional guest molecule interacting externally with the capsule reveals a possible entrance mechanism involving a polar gate. In solution, the structural features and dynamic behavior of the D(4)-symmetric homochiral capsule were analyzed by variable-temperature NMR spectroscopy and the results were compared with those for the S(8)-symmetric heterochiral capsule.

Making a Right or Left Choice: Chiral Self-Sorting as a Tool for the Formation of Discrete Complex Structures

This review discusses chiral self-sorting-the process of choosing an interaction partner with a given chirality from a complex mixture of many possible racemic partners. Chiral self-sorting (also known as chiral self-recognition or chiral self-discrimination) is fundamental for creating functional structures in nature and in the world of chemistry because interactions between molecules of the same or the opposite chirality are characterized by different interaction energies and intrinsically different resulting structures. However, due to the similarity between recognition sites of enantiomers and common conformational lability, high fidelity homochiral or heterochiral self-sorting poses a substantial challenge. Chiral self-sorting occurs among natural and synthetic molecules that leads to the amplification of discrete species. The review covers a variety of complex self-assembled structures ranging from aggregates made of natural and racemic peptides and DNA, through artificial functional receptors, macrocyles, and cages to catalytically active metal complexes and helix mimics. The examples involve a plethora of reversible interactions: electrostatic interactions, π-π stacking, hydrogen bonds, coordination bonds, and dynamic covalent bonds. A generalized view of the examples collected from different fields allows us to suggest suitable geometric models that enable a rationalization of the observed experimental preferences and establishment of the rules that can facilitate further design.

Cyclochiral conformers of resorcin[4]arenes stabilized by hydrogen bonds

Cyclochiral resorcinarenes, that maintain their cyclochirality by means of hydrogen bonds, were synthesized by a sequence of reactions involving the Mannich reaction, removal of the N,O-acetal bridge and subsequent N-substitution with an RCO group. During this study it was found that ethyl nitroacetate is a mild and very efficient agent for N,O-acetal bridge removal. The resulting resorcinarenes 4a-j exist in cyclochiral/inherently chiral kite conformations (resembling 4-bladed propellers) that are stabilized by eight hydrogen bonds (in both solid state and solution). It is shown that the cycloisomerization process is characterized by the relatively high racemization barrier (14.6-18.5 kcal mol(-1) as determined by 2D EXSY) and thus it can be concluded that the transformation of one cycloconformer into the other requires the simultaneous rupture of all eight hydrogen bonds. For derivatives with additional stereogenic centers two cyclodiastereoisomeric conformations were detected (diastereomeric excess in the range of 72% up to >95%). The experimental results are additionally supported by AM1 semi-empirical calculations.

Hybrid [n]Arenes through Thermodynamically Driven Macrocyclization Reactions

Hybrid [n]arenes, the class of medium-sized macrocyclic compounds consisting of different alkoxybenzene units, were obtained by a simple, one-pot, direct condensation of two different alkoxybenzenes with formaldehyde catalyzed by a Brønsted acid (trifluoroacetic acid). We have shown that, under Brønsted acid catalysis, this reaction is reversible and therefore governed by the relative stability of the products. The main macrocyclic products are hybrid [n]arenes consisting of four alkoxybenzene units of [2 + 2] or [3 + 1] stoichiometry. However, an unusual [3 + 2] hybrid macrocycle was also obtained as a main product of the condensation between 1,4-dimethoxybenzene, 1,3,5-trimethoxybenzene, and formaldehyde. The stability of the hybrid products and the reversibility of the reaction were further confirmed by a scrambling experiment, involving pillar[5]arene and per-O-methylated resorcin[4]arene. The scrambling experiment has given hybrid macrocycles in yields comparable with those obtained in condensation reactions. NMR spectra and X-ray structures of hybrid [n]arenes indicate that 1,2- and 1,3-dialkoxybenzene units are flexible parts of macrocyclic rings. However, the 1,4-dialkoxybenzene units present considerable steric hindrance, resulting in the formation of isomers and inherently chiral macrocycles due to inhibited rotation. The recognition properties toward various organic cations were also determined. Highly selective recognition of the N-methylpyridinium cation was observed for the [3 + 2] hybrid macrocycle.

Water co-encapsulation in an inverted molecular capsule

Comparison of water-free and water-mediated recognition processes within a synthetic resorcinarene-based self-assembled capsule shows that water can change the stoichiometry of binding as well as the selectivity and it can substantially restrict guest dynamics within the binding site.

Mechanochemical Encapsulation of Fullerenes in Peptidic Containers Prepared by Dynamic Chiral Self‐Sorting and Self‐Assembly

Molecular capsules composed of amino acid or peptide derivatives connected to resorcin[4]arene scaffolds through acylhydrazone linkers have been synthesized using dynamic covalent chemistry (DCC) and hydrogen-bond-based self-assembly. The dynamic character of the linkers and the preference of the peptides towards self-assembly into β-barrel-type motifs lead to the spontaneous amplification of formation of homochiral capsules from mixtures of different substrates. The capsules have cavities of around 800 Å(3) and exhibit good kinetic stability. Although they retain their dynamic character, which allows processes such as chiral self-sorting and chiral self-assembly to operate with high fidelity, guest complexation is hindered in solution. However, the quantitative complexation of even very large guests, such as fullerene C60 or C70 , is possible through the utilization of reversible covalent bonds or the application of mechanochemical methods. The NMR spectra show the influence of the chiral environment on the symmetry of the fullerene molecules, which results in the differentiation of diastereotopic carbon atoms for C70 , and the X-ray structures provide unique information on the modes of peptide-fullerene interactions.

Inherently Chiral Iminoresorcinarenes through Regioselective Unidirectional Tautomerization

Tetraformylresorcin[4]arene is obtained in 48% yield via a chromatography-free Duff reaction. The formylated resorcinarene reacts easily with primary aliphatic and aromatic amines. The resulting imines exist exclusively in keto-enamine forms. Owing to a system of intramolecular hydrogen bonds, the reaction selectively leads to regioisomers with C4 symmetry. They possess an inherent chirality due to a propeller-like skeleton. For chiral amines, inherently chiral diastereoisomers are observed.