molecules Article Study on the Influence of Chirality in the Threading of Calix[6]arene Hosts with Dialkylammonium Axles Carmen Talotta 1, Gerardo Concilio 1, Paolo Della Sala 1 , Carmine Gaeta 1 , Christoph A. Schalley 2,3,* and Placido Neri 1,* 1 Dipartimento di Chimica e Biologia “A. Zambelli”, Università di Salerno, Via Giovanni Paolo II 132, I-84084 Fisciano, Italy; [email protected] (C.T.); [email protected] (G.C.); [email protected] (P.D.S.); [email protected] (C.G.) 2 Institut für Chemie und Biochemie, Freie Universität, Arnimallee 20, 14195 Berlin, Germany 3 School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China * Correspondence: [email protected] (C.A.S.); [email protected] (P.N.) Academic Editors: Mario Berberan-Santos and Paula M. Marcos Received: 19 October 2020; Accepted: 12 November 2020; Published: 15 November 2020 Abstract: The influence of chirality in calixarene threading has been studied by exploiting the “superweak anion approach”. In particular, the formation of chiral pseudo[2]rotaxanes bearing a classical stereogenic center in their axle and/or wheel components has been considered. Two kind of pseudo[2]rotaxane stereoadducts, the “endo-chiral” and “exo-chiral” ones, having the stereogenic center of a cationic axle inside or outside, respectively, the calix-cavity of a chiral calixarene were preferentially formed with specifically designed chiral axles by a fine exploitation of the so-called “endo-alkyl rule” and a newly defined “endo-α-methyl-benzyl rule” (threading of a hexaalkoxycalix[6]arene with a directional (α-methyl-benzyl)benzylammonium axle occurs with an endo-α-methyl-benzyl preference). The obtained pseudorotaxanes were studied in solution by 1D and 2D NMR, and in the gas-phase by means of the enantiomer-labeled (EL) mass spectrometry method, by combining enantiopure hosts with pseudoracemates of one deuterated and one unlabeled chiral axle enantiomer. In both instances, there was not a clear enantiodiscrimination in the threading process with the studied host/guest systems. Possible rationales are given to explain the scarce reciprocal influence between the guest and host chiral centers. Keywords: calixarenes; threading; chirality; barfate salts; pseudorotaxane; chiral axles; chiral wheels. 1. Introduction Over the past two decades, there has been a great scientific interest for the synthesis of mechanomolecules [1], such as rotaxanes and catenanes [2–4]. Mechanomolecules have found many applications in very different topics, such as nanoelectronics [5–7], molecular machines [2,3,8–10], and catalysis [11–13]. The mechanical bond [1], as a building element of rotaxane and catenane architectures, is usually obtained by template-directed synthesis [14] based on the threading of a linear molecule (axle) through a macrocyclic component (wheel). The most convenient synthetic routes are the threading-followed-by-stoppering, the clipping, and the slipping methods [1,14] that exploit weak intermolecular interactions (hydrogen bond, halogen bond, π-stacking, cation-π, or metal coordination) to assemble the molecular components. The peculiar stereochemical features of mechanomolecules are one of the most fascinating aspects of these architectures. In particular, the chirality within such supramolecular architectures [15,16] is of special interest, because it is relevant for enantioselective recognition and sensing [17], asymmetric catalysis [13,18–20], and unidirectional molecular motors [21–23]. The simplest way to obtain chiral Molecules 2020, 25, 5323; doi:10.3390/molecules25225323 www.mdpi.com/journal/molecules Molecules 2020, 25, x FOR PEER REVIEW 17 of 21 Molecules 2020, 25, 5323 2 of 21 obtain chiral rotaxanes and catenanes is to introduce a classical stereogenic element in one their componentrotaxaness to andgive catenanes a chiral is to axle introduce and/ aor classical a chiral stereogenic wheel element (Figure in one 1A their) [1 components6,24,25]. Another to give more sophisticateda chiral approach axle and/or ais chiral given wheel by “mechanical (Figure1A) [ 16 ,chirality”24,25]. Another [26– more30] ( sophisticatedFigure 1B) in approach which is chirality given arises from theby combination “mechanical chirality” of achiral [26– 30“directional”] (Figure1B) in elements which chirality spatially arises fromrestricted the combination by the mechanical of achiral bond. “directional” elements spatially restricted by the mechanical bond. Of course, the first approach is Of course, the first approach is more convenient from the synthetic point of view, because a difficult more convenient from the synthetic point of view, because a difficult resolution step, on an appropriate resolutionpreparation step, on scale, an can appropriate be avoided bypreparation resorting to suitablescale, enantiopurecan be avoid moietiesed by available resorting from theto suitable enantiopurechiral pool.moieties available from the chiral pool. Figure 1.Figure Chiral 1. Chiralcatenanes catenanes and androtaxanes rotaxanes.. Chirality Chirality arising arising from ( A(A) classical) classical chiral chiral elements elements and and (B) “mechanical(B) “mechanical chirality” chirality” with achiral with achiral “directional” “directional” elements. elements. Over the past ten years, our group has shown that the threading of scarcely preorganized Overcalix[6]arene the past macrocyclesten years, (e.g.,our 1group, Scheme has1) withshow dialkylammoniumn that the threading axles (e.g., of scarcely2+) occurs preorganized in + 3 calix[6]areneCDCl3 macrocycleswhen the ammonium (e.g., 1 linear, Scheme system 1) iswith coupled dialkylammonium with the weakly coordinating axles (e.g., barfate 2 ) occurs anion in CDCl F when thetetrakis[3,5-bis(tri-fluoromethyl)phenyl]borate ammonium linear system is coupled [B(Ar with)4]− “superweak the weakly anion” coordinating [31–35]. This method barfate anion tetrakis[3,5was- defined,bis(tri-fluoromethyl)phenyl]borate in short, as the “superweak anion [B(Ar approach”F)4]− [“superweak31–34]. Interestingly, anion” we [3 also1–3 observed5]. This method was defined,that the in threading short, as of the alkylbenzylammonium “superweak anion cations approach” may result [31– in34] two. Interestingly, different stereoisomeric we also observed pseudorotaxanes [32], in which the alkyl or the benzyl moiety is hosted inside the calixarene that thecavity. threading These haveof alkylbenzylammonium been termed as “endo-alkyl” cations or “endo -benzyl”may result isomers, in respectivelytwo different (Scheme stereoisomeric1). pseudorotaxanesThe endo-alkyl [32 “orientational], in which the mechanostereoisomer” alkyl or the benzyl is usuallymoiety preferred is hosted [32 inside], thus the leading calixarene to the cavity. These havedefinition been of termed the so-called as “endo “endo--alkylalkyl rule”:” or “threadingendo-benzyl of a directional” isomers, alkylbenzylammonium respectively (Scheme axle through 1). aThe endo- alkyl “orhexaalkoxycalix[6]areneientational mechanostereoisomer occurs with an endo”-alkyl is usually preference preferred[36]. [32], thus leading to the definition of the so-calledA full“endo exploitation-alkyl ofrule”: the “ endothreading-alkyl rule” of withina directional the “superweak alkylbenzylammonium anion approach” has axle led tothrough a several interesting examples of stereoprogrammed calixarene-based pseudorotaxanes, to their integrative hexaalkoxycalix[6]areneself-sorting [36], and occurs to the synthesiswith an ofendo the corresponding-alkyl preference rotaxane [36 and]. catenane mechanomolecules [37,38]. A full exploitationThe threading of athe tertiary “endo ammonium-alkyl rule” axle within [39] has the led to“superweak the first examples anion of approach” dissymmetric has led to several calixarene-basedinteresting examples pseudo[2]rotaxanes of stereoprogrammed (Scheme1, lower right) calixarene obtained- bybased combination pseudorotaxane of two achirals, to their integrativecomponents. self-sorting In detail, [36], thisand peculiar to the chirality synthesis was generatedof the correspond by the structuraling rotaxane directionality and of catenane mechanomoleculescalix[6]arene macrocycle[37,38]. which led to differentiate the two benzyl units of the prochiral tertiary ammonium axle [39]. Interestingly, this represents an example of a dissymmetric pseudorotaxane in Thewhich threading an atomic ofstereogenic a tertiary center ammonium is generated axle by [ the39] threading has led ofto an the axle first with examples a directional of wheel. dissymmetric calixarene-based pseudo[2]rotaxanes (Scheme 1, lower right) obtained by combination of two achiral components. In detail, this peculiar chirality was generated by the structural directionality of calix[6]arene macrocycle which led to differentiate the two benzyl units of the prochiral tertiary ammonium axle [39]. Interestingly, this represents an example of a dissymmetric pseudorotaxane in which an atomic stereogenic center is generated by the threading of an axle with a directional wheel. Molecules 2020, 25, 5323 3 of 21 Molecules 2020, 25, xx FORFOR PEERPEER REVIEWREVIEW 1717 of of21 21 F3C CF3 t t Bu t F3C CF3 But But Bu Bu - But B F3C CF3 O O F3C CF3 O O - O O F [B(Ar )4] Anion N 1 N H H R H - - + F + F 2 [B(Ar )4] 3 [B(Ar )4] But But t t t t t t t Bu Bu Bu t t t Bu t Bu t t Bu Bu Bu Bu Bu t t Bu Bu t t t t t Bu Bu Bu Bu Bu Bu Bu Bu But But + HO O + O H O O H O O O N R N HO O O H O O O O H O R O O ON O O N OO O R R R R R R R R R R R Endo-Alkyl Stereoisomer Endo-Benzyl Stereoisomer Highly