Binding abilities of a chiral calix[4]resorcinarene: a polarimetric investigation on a complex case of study

Binding abilities of a chiral calix[4]resorcinarene: a polarimetric investigation on a complex case of study Marco Russo1 and Paolo Lo Meo*1,2 Full Research Paper Address: 1Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), University of Palermo, V.le delle Scienze ed. 17, 90128 Palermo, Italy and 2ATeNCenter, University of Palermo, V.le delle Scienze ed. 18, 90128 Palermo, Italy Email: Paolo Lo Meo* - * Corresponding author Open Access Beilstein J. Org. Chem. 2017, 13, 2698–2709. doi:10.3762/bjoc.13.268 Received: 01 September 2017 Accepted: 30 November 2017 Published: 15 December 2017 Associate Editor: H. Ritter © 2017 Russo and Lo Meo; licensee Beilstein-Institut. License and terms: see end of document. Keywords: calix[4]resorcinarene; host–guest complexes; p-nitroanilines; polarimetry; supramolecular chemistry Abstract Polarimetry was used to investigate the binding abilities of a chiral calix[4]resorcinarene derivative, bearing L-proline subunits, towards a set of suitably selected organic guests. The simultaneous formation of 1:1 and 2:1 host–guest inclusion complexes was observed in several cases, depending on both the charge status of the host and the structure of the guest. Thus, the use of the polarimetric method was thoroughly revisited, in order to keep into account the occurrence of multiple equilibria. Our data indicate that the stability of the host–guest complexes is affected by an interplay between Coulomb interactions, π–π interactions, desolvation effects and entropy-unfavorable conformational dynamic restraints. Polarimetry is confirmed as a very useful and versatile tool for the investigation of supramolecular interactions with chiral hosts, even in complex systems involving multiple equilibria. Introduction During the last decades calix[n]arenes and calix[n]resorcinarenes (CAs) have emerged as versatile supramolecular host systems for various applications [1-5], spanning from sensors [6,7] to catalysis [8,9] and drug carriers [10-13]. Unlike the more popular cyclodextrins (CDs), CAs are exclusively obtained by chemical synthesis [14-18]. Therefore, they are particularly suitable for designing tailored systems with peculiar properties and abilities. This can be generally achieved by linking suitable donor groups to the aromatic scaffold. Among the virtually countless examples available in recent literature, L-proline-modified CAs constitute an interesting subject of study [19-32]. Proline-based systems in general have been proven excellent stereoselective organocatalysts [33-40]. In particular, CA derivatives bearing proline units (on both the upper and the lower rim) have been tested as catalysts for asymmetric aldol reactions in water [28-30,33]. Similar derivatives have also been studied as hydrogelators [22,23]. Moreover, water soluble chiral calix[4]resorcinarenes have been recently de- 2698 Beilstein J. Org. Chem. 2017, 13, 2698–2709. signed and used as chiral shift reagents for NMR applications [24-27]. The possibility to introduce chiral groups onto the CA scaffold is particularly intriguing from the viewpoint of the methodologies for investigating host–guest binding equilibria. In fact, simple polarimetry has been recently demonstrated to be an appealing and versatile tool for studying the host–guest interactions that imply cyclodextrins (CDs) [41-45], as well as for a reliable evaluation of the relevant binding constants. We were interested in verifying if the same technique could be suitably applied to other classes of chiral hosts. Thus, proline-modified calixarenes or calixresorcinarenes appeared ideal testing candidates. It is also worth noting that, because of the large variety of diversely modified CA derivatives existing, the binding abilities of these macrocycles have been subjected to less systematic and thorough studies [32,46-48] as compared to other classes of hosts such as CDs. With the aim at gaining a deeper understanding of the microscopic and thermodynamic aspects of the binding phaenomena involving CAs, as well as at verifying the possibility to extend the use of polarimetry as an investigation tool to these systems, in the present work we studied the binding abilities of an easily accessible L-proline-derivatized calix[4]resorcinarene, namely 2,8,14,20-tetrapropyl-4,6,10,12,16,18,22,24-octahydroxy[5,11,17,23-(L-prolin-1-yl)methyl]calix[4]resorcinarene (CAP, Figure 1) towards a set of variously structured organic guests 1–12 (Figure 2). The host CAP was designed in analogy with a sulfonated chiral calix[4]resorcinarene (CAPS, Figure 1) already known from the literature as NMR shift reagent able to perform chiral recognition [24-27]. Guests 1–12 were selected for their diverse structural features. We considered both neutral and ionic species, in particular aliphatic and aromatic cations of different size and hydrophobic character. Moreover, some p-nitroaniline derivatives were selected, because this class of molecules have been already proven as excellent probe guests to assess the microscopic interactions controlling the binding abilities of cyclodextrins [43-45,49-53]. Figure 1: Structure of the L-proline-calix[4]resorcinarene derivatives CAP and CAPS. Figure 2: Structures of guests 1–12. 2699 Beilstein J. Org. Chem. 2017, 13, 2698–2709. Results and Discussion Synthesis and solubility properties of CAP As we mentioned previously, the synthesis of CAP was approached (see Experimental) in a similar way as the one reported for its sulfonate analogue CAPS [26], i.e., by subjecting the preformed (2,8,14,20-tetrapropyl)-(4,6,10,12,16,18,22,24octahydroxy)calix[4]resorcinarene (preCA) [54] to a Mannichtype reaction with L-proline and formaldehyde (Figure 3). Figure 3: Synthesis of CAP. The precursor preCA, in turn, was obtained by an acid-catalysed condensation between resorcinol and butyraldehyde. Of course, the main difference between the syntheses of CAP and CAPS is constituted by the choice of the starting aldehyde, namely simple butyraldehyde instead of a 3-sulfonatopropionaldehyde (which in turn must be generated in situ from commercial precursors). This derived from the need to rule out the occurrence of any possible interaction between cationic guests and the negatively charged pendant chains linked to the methylene bridges at the 2, 8, 14 and 20 positions of the macrocycle scaffold, specifically in order to address the interaction with the host cavity and, possibly, the pendant proline moieties. The structure of the final product was confirmed by NMR (see Supporting Information File 1 for details). It is worth stressing here that, owing to the hydrophobic nature of the ancillary propyl groups, CAP is sparingly soluble in water under neutral conditions, whereas its solubility significantly increases as an increasing amount of a strong base is added. Noticeably, neutral CAP possesses 16 ionizable sites (four sites per prolinylarene subunit) and 12 acidic hydrogens, k (...truncated)