Calix[3]Arene-Analogous Metacyclophanes: Synthesis, Structures and Properties with Inﬁnite Potential

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Review Calix[3]arene-Analogous Metacyclophanes: Synthesis, Structures and Properties with Inﬁnite Potential

Md. Monarul Islam 1 , Paris E. Georghiou 2,* , Shoﬁur Rahman 3 and Takehiko Yamato 4

1 Chemical Research Division, Bangladesh Council of Scientiﬁc and Industrial Research (BCSIR), Dhanmondi, Dhaka 1205, Bangladesh; [email protected] 2 Department of Chemistry, Memorial University of Newfoundland, St. John’s, NL A1B 3X7, Canada 3 Aramco Laboratory for Applied Sensing Research, King Abdullah Institute for Nanotechnology, King Saud University, Riyadh 11451, Saudi Arabia; [email protected] 4 Department of Applied Chemistry, Faculty of Science and Engineering, Saga University, Honjo-Machi 1, Saga 840-8502, Japan; [email protected] * Correspondence: [email protected]

Academic Editors: Mario Berberan-Santos and Paula M. Marcos Received: 24 August 2020; Accepted: 10 September 2020; Published: 14 September 2020

Abstract: Calixarene-analogous metacyclophanes (CAMs) are a special class of cyclophanes that are cyclic polyaromatic hydrocarbons containing three or more aromatic rings linked by one or more methylene bridging groups. They can be considered to be analogues of calixarenes, since, in both types of molecules, the component aromatic rings are linked by methylene groups, which are meta to each other. Since the prototype or classical calix[4]arene consists of four benzene rings each linked by methylene bridges, which are also meta to each other, it can be considered to be an example of a functionalized [1.1.1.1]metacyclophane. A metacyclophane (MCP) that consists of three individual hydroxyl-group functionalized aromatic rings linked by methylene groups, e.g., a trihydroxy[1.1.1]MCP may therefore, by analogy, be termed in the broadest sense as a “calix[3]arene” or a “calix[3]arene-analogous metacyclophane”. Most of the CAMs reported have been synthesized by fragment coupling approaches. The design, synthesis and development of functionalized CAMs, MCPs, calixarenes and calixarene analogues has been an area of great activity in the past few decades, due their potential applications as molecular receptors, sensors and ligands for metal binding, and for theoretical studies, etc. In this review article, we focus mainly on the synthesis, structure and conformational properties of [1.1.1]CAMs, i.e., “calix[3]arenes” and their analogues, which contain three functionalized aromatic rings and which provide new scaﬀolds for further explorations in supramolecular and sensor chemistry.

Keywords: calix[3]arenes; metacyclophanes; calixarene-analogous metacyclophanes; inherent chirality; host-guest chemistry

1. Introduction Cyclophanes are an important class of bridged aromatic hydrocarbons, consisting of one or more aromatic units linked by methylene group chains in such a way that the aromatic units form part of a macrocycle. A generic synthetic structure of cyclophanes in which two or more aromatic groups are linked via their ortho, meta or para positions by variably sized methylene groups is shown in Figure1. These molecules have been extensively pursued and studied for a variety of di ﬀerent considerations [1,2]. Cyclophane chemistry can be considered to have been initiated by Pellegrin [3] who, in 1899, reported the synthesis of [2.2]metacyclophane (i.e., [2,2]MCP) 1 by Wurtz coupling of 1,3-bis(bromomethyl)benzene. The real development of the chemistry of cyclophanes, however,

Molecules 2020, 25, 4202; doi:10.3390/molecules25184202 www.mdpi.com/journal/molecules Molecules 2020, 25, 4202 2 of 19 Molecules 2020, 25, x FOR PEER REVIEW 2 of 19 Molecules 2020, 25, x FOR PEER REVIEW 2 of 19 iswell-acknowledged well-acknowledged to to have have occurred occurred after after Cram Cram and and Steinberg’s Steinberg’s synthesis synthesis of of [2.2]paracyclophane [2.2]paracyclophane 2 well-acknowledged to have occurred after Cram and Steinberg’s synthesis of [2.2]paracyclophane 2 in 1951 [[4].4]. in 1951 [4].

Figure 1.1. TopTop:: GenericGeneric cyclophane cyclophane structure structure with with the theortho ortho-, meta-, meta- or-para or -substitutionpara-substitution of the of phenyl the phenyl rings Figure 1. Top: Generic cyclophane structure with the ortho-, meta- or para-substitution of the phenyl andrings where and mwhere, n and mz are, n variable.and z are Compound variable.1 isCompound [2.2]metacyclophane 1 is [2.2]metacyclophane and 2 is [2.2]paracyclophane, and 2 is rings and where m, n and z are variable. Compound 1 is [2.2]metacyclophane and 2 is where[2.2]paracyclophane,m = n = 2 and zwhere= 1. m = n = 2 and z = 1. [2.2]paracyclophane, where m = n = 2 and z = 1. On the other hand, calixarenes such as 3a–d (Figure2 2),), whichwhich cancan bebe consideredconsideredto tobe beexamples examples On the other hand, calixarenes such as 3a–d (Figure 2), which can be considered to be examples of [1n]metacyclophanes]metacyclophanes (where (where nn == 4,4, 5, 5, 6 6or or 8,8, respectively), respectively), have have also also become become an an important important class class of of [1n]metacyclophanes (where n = 4, 5, 6 or 8, respectively), have also become an important class of ofcompounds compounds since since Zincke Zincke and andZeigler’s Zeigler’s first firstreport report in 1944 in 1944of a cyclic of a cyclic tetrameric tetrameric compound compound (later compounds since Zincke and Zeigler’s first report in 1944 of a cyclic tetrameric compound (later (laterconfirmed confirmed to be to 3a be) 3afrom) from the the base-induced base-induced reaction reaction of of parapara-substituted-substituted terttert-butylphenol-butylphenol withwith confirmed to be 3a) from the base-induced reaction of para-substituted tert-butylphenol with formaldehyde [[5].5]. The importance of of this class of compounds derives from the fact thatthat calixarenescalixarenes formaldehyde [5]. The importance of this class of compounds derives from the fact that calixarenes have “basket”-“basket”- or or “cup”-like “cup”-like 3-D 3-D topologies, topologies, with with the hydroxylthe hydroxyl groups groups forming forming a narrower a narrower or “lower” or have “basket”- or “cup”-like 3-D topologies, with the hydroxyl groups forming a narrower or rim“lower” due torim the due strong to the intermolecular strong intermolecular hydrogen bonds.hydrogen The bonds. opposite The rim opposite is termed rim the is “upper” termed rimthe “lower” rim due to the strong intermolecular hydrogen bonds. The opposite rim is termed the and“upper” is wider rim dueand tois wider the steric due repulsion to the steric of therepulsionpara-substituents of the para-substituents and the orientation and the of orientation the aromatic of “upper” rim and is wider due to the steric repulsion of the para-substituents and the orientation of ringsthe aromatic although rings for the although larger calix[ forn ]arenesthe larger (n > calix[6); however,n]arenes their (n shapes> 6); however, or conformations their shapes can vary or the aromatic rings although for the larger calix[n]arenes (n > 6); however, their shapes or orconformations be more complex. can vary As or a result,be mo thesere complex. molecules As cana result, be selectively these molecules functionalized can be at selectively either rim conformations can vary or be more complex. As a result, these molecules can be selectively andfunctionalized they can serve at either as building rim and blocksthey can for serve a variety as building of applications, blocks for sucha variety as, for of applications, example, ionic such or functionalized at either rim and they can serve as building blocks for a variety of applications, such molecularas, for example, receptors. ionic Gutsche or molecular and coworkers receptors. pioneered Gutsche and and developed coworkers methodologies pioneered forand synthesizing developed as, for example, ionic or molecular receptors. Gutsche and coworkers pioneered and developed pmethodologies-tert-butylcalix[4]arene for synthesizing3a [6] (also p-tert commonly-butylcalix[4]arene and inaccurately 3a [6] referred (also commonly to simply asand “calix[4]arene”, inaccurately methodologies for synthesizing p-tert-butylcalix[4]arene 3a [6] (also commonly and inaccurately whichreferred should to simply strictly as be “calix[4]arene”, confined to the which de-tert should-butylated strictly derivative be confined of 3a), pto-tert the-butylcalix[5]arene de-tert-butylated referred to simply as “calix[4]arene”, which should strictly be confined to the de-tert-butylated 3bderivative[7], p-tert of-butylcalix[6]arene 3a), p-tert-butylcalix[5]arene3c [8], and p-tert 3b-butylcalix[8]arene [7], p-tert-butylcalix[6]arene3d [9] (recently, 3c Haase[8], and reported p-tert a- derivative of 3a), p-tert-butylcalix[5]arene 3b [7], p-tert-butylcalix[6]arene 3c [8], and p-tert- highlybutylcalix[8]arene selective and 3d high-yield [9] (recently, synthesis Haase forreported the production a highly selective of calix[8]arenes and high-yield [10]) as synthesis major products. for the butylcalix[8]arene 3d [9] (recently, Haase reported a highly selective and high-yield synthesis for the Gutsche’sproduction syntheses of calix[8]arenes were achieved [10]) as usingmajor p-tertproducts.-butylphenol Gutsche’s and syntheses formaldehyde were achieved under diusingfferent p-tert but- production of calix[8]arenes [10]) as major products. Gutsche’s syntheses were achieved using p-tert- reproduciblebutylphenol and reaction formaldehyde conditions, under which different have allowed but reproducible these compounds, reaction andconditions, derivatives which thereof, have butylphenol and formaldehyde under different but reproducible reaction conditions, which have toallowed become these easily compounds, accessible and to derivatives be widely thereof, studied. to Derivativesbecome easily of accessible3a are well-known to be widely to studied. be able allowed these compounds, and derivatives thereof, to become easily accessible to be widely studied. toDerivatives exist in four of di3aff erentare well-known major conformationally to be able to immobile exist in conformersfour different known major as conformationallycone, partial-cone, Derivatives of 3a are well-known to be able to exist in four different major conformationally 1,3immobile-alternate conformers, and 1,2-alternate knownconformers as cone, partial-cone (Figure3), 1,3 and-alternate which can, and be 1,2 selectively-alternate generated conformers and (Figure isolated 3) immobile conformers known as cone, partial-cone, 1,3-alternate, and 1,2-alternate conformers (Figure 3) byand introducing which can be diff selectivelyerent functional generated groups and onto isolated the lower by introducing rim of 3a [ 11different]. functional groups onto and which can be selectively generated and isolated by introducing different functional groups onto the lower rim of 3a [11]. the lower rim of 3a [11].

Figure 2. Basic structural motifs of calix[n]arenes 3a–d.. Figure 2. Basic structural motifs of calix[n]arenes 3a–d.

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Figure 3. General structure of p-substituted calix[4]arene (e.g., R = t-Bu) and schematic representations of its formal conformational isomers. Figure 3. General structure of p-substituted calix[4]arene (e.g., R = t-Bu) and schematic representations Figure 3. General structure of p-substituted calix[4]arene (e.g., R = t-Bu) and schematic representations of its formal conformational isomers. ofMany its formal calixarene-based conformational isomers.molecu lar receptors have been synthesized and studied, but calix[4]arenesMany calixarene-based and its derivatives molecular with receptorsamide, ketone have and been ester synthesized functionalities and studied, at the butlower calix[4]arenes rim, which Many calixarene-based molecular receptors have been synthesized and studied, but andhave its shown derivatives significant with cation amide, affinity ketone [12,13], and ester have functionalities received the at most the lower attention rim, to which date. have In general, shown calix[4]arenes and its derivatives with amide, ketone and ester functionalities at the lower rim, which significantmodifications cation of acalixarenesffinity [12, 13have], have been received via functionalization the most attention of totheir date. lower In general, or upper modifications rims. The have shown significant cation affinity [12,13], have received the most attention to date. In general, ofspirodienone calixarenes route have [14] been and via Lhtoak’s functionalization mercuration of their[15] route, lower however, or upper ar rims.e notable The exceptions spirodienone for modifications of calixarenes have been via functionalization of their lower or upper rims. The routeeffecting [14 ]the and direct Lhtoak’s modifications mercuration to the [15 ]basic route, cali however,x[4]arene are skeleton notable not exceptions specifically for involving effecting the spirodienone route [14] and Lhtoak’s mercuration [15] route, however, are notable exceptions for directfunctionalization modifications of tothe the upper basic and/or calix[4]arene lower skeletonrims, or not via specifically convergent involving fragment-based the functionalization approaches. effecting the direct modifications to the basic calix[4]arene skeleton not specifically involving the ofSince the there upper are and many/or lowerexcellent rims, reviews or via and convergent monograp fragment-basedhs that have been approaches. published Sinceon calixarenes, there are functionalization of the upper and/or lower rims, or via convergent fragment-based approaches. manyand their excellent more reviewstypical andanalogues, monographs including that havehomocalixarenes been published [16], on homooxacalixarenes calixarenes, and their [17,18], more Since there are many excellent reviews and monographs that have been published on calixarenes, typicalazacalixarenes analogues, [19] includingand hexahomoazacalixarenes homocalixarenes [16 [20],], homooxacalixarenes and other types [21,22] [17,18 the], azacalixarenes reader is referred [19] and their more typical analogues, including homocalixarenes [16], homooxacalixarenes [17,18], andto these hexahomoazacalixarenes so will not be further [20 elaborated], and other upon types he [21re.,22 Instead,] the reader for this is referred review, to we these have so willchosen not beto azacalixarenes [19] and hexahomoazacalixarenes [20], and other types [21,22] the reader is referred furtheremphasize elaborated the MCP upon skeleton here. that Instead, has been for this extensivel review,y we explored have chosen as a versatile to emphasize and stable the MCP platform, skeleton or to these so will not be further elaborated upon here. Instead, for this review, we have chosen to thatscaffold, has beenfor functionalization extensively explored and as study. a versatile In particular, and stable platform,we present or scaa specificffold, for focus functionalization upon those emphasize the MCP skeleton that has been extensively explored as a versatile and stable platform, or andfunctionalized study. In particular, MCPs, which we presentin the broadest a specific sense, focus can upon be thoseconsidered functionalized to be directly MCPs, analogous which in with the scaffold, for functionalization and study. In particular, we present a specific focus upon those broadestcalix[3]arenes sense, in can general. be considered A review to of be the directly syntheses analogous and properties with calix[3]arenes of cyclophanes in general. incorporating A review three of functionalized MCPs, which in the broadest sense, can be considered to be directly analogous with thearomatic syntheses units and is presented properties below. of cyclophanes incorporating three aromatic units is presented below. calix[3]arenes in general. A review of the syntheses and properties of cyclophanes incorporating three 2.aromatic Calixarene-Analogous units is presented MCPs below. Containing Three Aromatic Rings: Calix[3]arene Analogues

2. Calixarene-AnalogousMany reports during MCPs the past Containing few decades Three have Aromatic dealt with Rings: the modiﬁcationmodificationCalix[3]arene and Analogues studies of the properties of calix[n]arenes, particularlyparticularly those inin whichwhich n == 4,5,6 or 8, but not many have concerned Many reports during the past few decades have dealt with the modification and studies of the calix[3]arenes containing only three aromatic rings, i.e., calix[3]arenes or [1.1.1]MCPs (or [1n]MCPs),]MCPs), withproperties the exception of calix[ nof ]arenes, the hexahomoxacalix[3]arenes hexahomoxacalix[3]arenes particularly those in which in in which whichn = 4,5,6 the the or bridging bridging 8, but not groups groups many are arehave one one concerned or or more more - calix[3]arenes containing only three aromatic rings, i.e., calix[3]arenes or [1.1.1]MCPs (or [1n]MCPs), -CHCH22OCHOCH2-2 -groups groups [17,18]. [17,18]. [1.1.1]MCPs [1.1.1]MCPs cyclophanes, cyclophanes, wh whichich incorporate incorporate only only three three aromatic aromatic rings, havewith the been exception a major of focus the hexahomoxacalix[3]arenes of our group in recent years in which and the provide bridging useful groups molecular are one platforms, or more - particularlyCH2OCH2- groups for their their [17,18]. synthesis synthesis [1.1.1]MCPs and and study study cyclophanes, of of their their conformational conformational which incorporate properties properties only and andthree molecular molecular aromatic strain. strain.rings, In Inhave1982, 1982, Moshfeghbeen Moshfegh a major and and focusco-workers co-workers of our reported reportedgroup inthe the recent first ﬁrst synthesis synthesisyears and of of aprovide aseries series of ofuseful functionalized functionalized molecular [1.1.1]MCPs, [1.1.1]MCPs, platforms, i.e.,particularly p-halocalix[3]-arenes for their synthesis 4a–cc [ [23]23and] (Figure(Figure study of4 4).). their conformational properties and molecular strain. In 1982, Moshfegh and co-workers reported the first synthesis of a series of functionalized [1.1.1]MCPs, i.e., p-halocalix[3]-arenes 4a–c [23] (Figure 4).

Figure 4. General structures of the [1.1.1]metacyclophane (MCP) calixarene analogues 4a–c.

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Molecules 2020Figure, 25, 42024. General structures of the [1.1.1]metacyclophane (MCP) calixarene analogues 4a–c. 4 of 19

These compounds which contained intra-annular hydroxy groups and halogens on the para positionsThese of compounds one, two or whichall three contained of the phenyl intra-annular groups and hydroxy which groupsadopted and cone halogens type conformations, on the para positionswere obtained of one, in two69–90% or all yields three by of the phenylcyclocondensation(s) groups and which of the adopted correspondingcone type precursor conformations, mono- wereor dihalo-2,2’-dihydroxydiphenyl-methane obtained in 69–90% yields by the cyclocondensation(s)with 2,6-bis(hydroxymethyl)phenol of the corresponding, or with 4-halo-2,6- precursor mono-bis(hydroxymethyl)phenol or dihalo-2,2’-dihydroxydiphenyl-methanes [23]. The antimicrobial withproperties 2,6-bis(hydroxymethyl)phenol, of these compounds which or were with 4-halo-2,6-bis(hydroxymethyl)phenolsnamed as “phloroglucide” analogues were [23]. reported The antimicrobial but surprisingly, properties to date, of these no compoundsother studies which have werebeen reported named as with “phloroglucide” these particular analogues compounds. were reported but surprisingly, to date, no other studies have been reported with these particular compounds. 3. Homocalixarene-Analogous MCPs Containing Three Aromatic Rings: Homocalix[3]arene 3.Analogues Homocalixarene-Analogous MCPs Containing Three Aromatic Rings: Homocalix[3]arene Analogues Expanded macrocyclic calixarene-analogous metacyclophanes (CAMs) containing Expanded macrocyclic calixarene-analogous metacyclophanes (CAMs) containing polymethylene polymethylene bridging groups such as [3.1.1]MCP 7 which contains a single trimethylene (−(CH2)3−) bridging groups such as [3.1.1]MCP 7 which contains a single trimethylene ( (CH ) ) and two and two methylene bridges can be regarded as an example of an unsymmetrical− homocalix[3]arene2 3− methylene bridges can be regarded as an example of an unsymmetrical homocalix[3]arene analogous analogous MCP. Thus, 7 which can be considered to be an example of a [3.1.1]dihomocalix[3]arene- MCP. Thus, 7 which can be considered to be an example of a [3.1.1]dihomocalix[3]arene-analogous MCP analogous MCP was synthesized using the Nafion-H catalyzed cyclobenzylation of 5 and tert- was synthesized using the Nafion-H catalyzed cyclobenzylation of 5 and tert-butylphenol 6 [24,25]. butylphenol 6 [24,25]. The trimethoxy and trihydroxy derivatives of 7 were also reported. The room The trimethoxy and trihydroxy derivatives of 7 were also reported. The room temperature 1H-NMR temperature 1H-NMR spectrum of dimethoxy 7 revealed two sets of doublets for the methylene spectrum of dimethoxy 7 revealed two sets of doublets for the methylene protons which implied protons which implied that it is in an asymmetric “2-partial-cone” conformation, in which the two that it is in an asymmetric “2-partial-cone” conformation, in which the two aromatic rings linked by aromatic rings linked by the trimethylene group are anti to each other as shown in Scheme 1. the trimethylene group are anti to each other as shown in Scheme1. However, at 80 ◦C in CDBr3, However, at 80 °C in CDBr3, coalescence of the methylene protons indicates that there is coalescence of the methylene protons indicates that there is conformational ring flipping above this conformational ring flipping above this temperature. A mechanism was proposed in which two temperature. A mechanism was proposed in which two possible structures results from the alternating possible structures results from the alternating hydrogen bonding formed between one of the hydrogen bonding formed between one of the methoxy groups and the hydroxyl group. The triol methoxy groups and the hydroxyl group. The triol however was fixed in a typical cone conformation however was fixed in a typical cone conformation with all three hydroxyl groups syn to one another. with all three hydroxyl groups syn to one another.

Scheme 1. Synthesis of hydroxy[3.1.1]MCP calixarene analogue 7 and schematic representation of Scheme 1. Synthesis of hydroxy[3.1.1]MCP calixarene analogue 7 and schematic representation of interconverting 2-partial-cone conformer structures. interconverting 2-partial-cone conformer structures. Tashiro and coworkers reported the synthesis and conformational properties of the dihomocalix[3]areneTashiro and coworkers containing reported one methylenethe synthesi ands and two conformational dimethylene ( (CHproperties) ) bridges,of the − − − 2 2− i.e.,dihomocalix[3]arene trimethoxy[2.2.1]MCP containing8 and severalone methylene of its derivatives. and two [26 dimethylene] The synthesis ( of(CH8,2 which)2 ) bridges, can also i.e., be consideredtrimethoxy[2.2.1]MCP to be a dihomocalix[3]arene 8 and several of analogue,its derivatives. was found [26] The to be synthesis a 2:1 mixture of 8, ofwhich asymmetric can also and be symmetricalconsidered to atropisoisomers be a dihomocalix[3]arene8a and 8b ,analogue, respectively was (Scheme found to2). be The a 2:1 synthesis mixture wasof asymmetric accomplished and viasymmetrical the corresponding atropisoisomers dithia[3.3.1]MCP 8a and 8b, respectively precursor, (Scheme which was 2). The transformed synthesis bywas the accomplished oxidation and via the corresponding dithia[3.3.1]MCP precursor, which was transformed by the oxidation and sulfone sulfone pyrolysis-extrusion methodology under vacuum pyrolysis at 450 ◦C[27,28]. Based upon 1 theirpyrolysis-extrusion1H-NMR spectra, methodology and with theunder use vacuum of Pirkle’s pyrolysis reagent, at these450 °C molecules [27,28]. Based were shownupon their to exist H-

Molecules 2020, 25, 4202 5 of 19 Molecules 2020, 25, x FOR PEER REVIEW 5 of 19 inNMR alternate spectra, conformations and with the designateduse of Pirkle’s as 2,1-alternate reagent, these8a moleculesand 2,2-alternate were shown8b, which to exist could in alternate undergo rapidconformations interconversion. designated as 2,1-alternate 8a and 2,2-alternate 8b, which could undergo rapid interconversion.

Scheme 2. Conformers of [2.2.1]MCP dihomocalix[3]arene analogues 8–12 (R = CH CO Et). Scheme 2. Conformers of [2.2.1]MCP dihomocalix[3]arene analogues 8–12 (R = CH22CO2Et). Trihydroxy[2.2.1]MCPs 9a and 9b were obtained by the simple demethylation of 8a, but only Trihydroxy[2.2.1]MCPs 9a and 9b were obtained by the simple demethylation of 8a, but only dihydroxymethoxy[2.2.1]MCP 10 was obtained from the demethylation of 8b, the remaining methoxy dihydroxymethoxy[2.2.1]MCP 10 was obtained from the demethylation of 8b, the remaining group presumably being sterically shielded from the BBr3 attack. Treatment of the mixture of 9a and 9b methoxy group presumably being sterically shielded from the BBr3 attack. Treatment of the mixture with NaH/ethyl bromoacetate afforded only MCP 11. On the other hand, a 2:1 mixture of both MCPs of 9a and 9b with NaH/ethyl bromoacetate afforded only MCP 11. On the other hand, a 2:1 mixture 12a and 12b was obtained from similar treatment of 2,2-alternate 10. The single-crystal X-ray structures of both MCPs 12a and 12b was obtained from similar treatment of 2,2-alternate 10. The single-crystal of both 8a and 8b further confirmed their structures. Tashiro’s group had previously reported the X-ray structures of both 8a and 8b further confirmed their structures. Tashiro’s group had previously synthesis of trimethyl [2.2.2]MCPs [29]. These molecules, however, contained only intra-annular methyl reported the synthesis of trimethyl [2.2.2]MCPs [29]. These molecules, however, contained only intra- groups and thus cannot be considered to be calix[3]arene-analogous MCPs, which, of course, typically annular methyl groups and thus cannot be considered to be calix[3]arene-analogous MCPs, which, contain hydroxyl or O-alkylated functional groups in the corresponding intra-annular positions. of course, typically contain hydroxyl or O-alkylated functional groups in the corresponding intra- The efficient syntheses of larger macrocyclic MCPs in which the aromatic groups are linked annular positions. by varying larger numbers of CH groups can also be effectively accomplished using two other The efficient syntheses of −larger2− macrocyclic MCPs in which the aromatic groups are linked by non-sulfur extrusion processes, namely the low-valent zinc McMurry coupling reaction, or the TosMIC varying larger numbers of −CH2− groups can also be effectively accomplished using two other non- (p-tolylsulfonylmethyl isocyanide) [30,31] methodology that was used to great advantage by Vogtle’s sulfur extrusion processes, namely the low-valent zinc McMurry coupling reaction, or the TosMIC (p-tolylsulfonylmethyl isocyanide) [30,31] methodology that was used to great advantage by Vogtle’s

Molecules 2020, 25, 4202 6 of 19 Molecules 2020, 25, x FOR PEER REVIEW 6 of 19 group, for the synthesissynthesis ofof [3[3nn]MCPs [[32].32]. The The synthesis, conformations and and properties of several types ofof thethe largerlarger homocalix[3]arene-analogue homocalix[3]arene-analogue MCPs MCPs [33 [33–38],–38], using using TosMIC TosMIC has has been been reported reported by ourby ourgroup. group. For example, For theexample, synthesis the of thesynthesis symmetrical of all-trimethylene-bridgedthe symmetrical all-trimethylene-bridged hexahomocalix[3]arene hexahomocalix[3]areneanalogue MCP, namely tri-analoguetert-butyl-trimethoxy[3.3.3]MCP MCP, namely tri-tert-butyl-trimethoxy[3.3.3]MCP13a, was achieved via the TosMIC-NaH 13a, was achievedmediated via cyclotrimerization the TosMIC-NaH reaction mediated of 2,6-bis(bromomethyl)-4- cyclotrimerization reactiontert-butylanisole of 2,6-bis(bromomethyl)-4-14, followed by acidtert- butylanisolehydrolysis, to 14 form, followed trione 15by alongacid hydrolysis, with dione to16 formin 22% trione and 15 10% along yields, with respectively dione 16 in (Scheme 22% and3)[ 10%33], yields,although respectively better yields (Scheme of 15 (68%) 3) [33], could although be obtained better yields using of the 15 1 (68%)+ 1 coupling could be reaction obtained of bis-TosMICusing the 1 +adduct 1 coupling17 with reaction14, instead, of bis-TosMIC as shown adduct in Scheme 17 with3 14., Wol instead,ff–Kishner as shown reduction in Scheme of 3.15 Wolff–Kishnerproduced the reductiondesired tri- oftert 15-butyl-trimethoxy[3.3.3]MCP produced the desired tri-tert13a-butyl-trimethoxy[3.3.3]MCPin 86% yield. The demethylation 13a ofin 13a86%with yield. BBr The3 in demethylationdichloromethane of gave13a with the tri-BBrtert3 in-butyl-trihydroxy[3.3.3]MCP dichloromethane gave the tri-13btertin-butyl-trihydroxy[3.3.3]MCP 89% yield. The O-Alkylation 13b of 13bin 89%could yield. be achievedThe O-Alkylation in high yields of 13b with could several be achieved alkyl halides in high (RX: yields R = Et, with Pr, several and n-Bu), alkyl in halides the presence (RX: Rof = Cs Et,2CO Pr,3 andunder n-Bu), reflux in the conditions presence in of acetone, Cs2CO3 tounder predominantly reflux conditions yield thein acetone,partial-cone to predominantlyconformers of yieldderivatives the partial-cone13c–g. The conformerspartial-cone conformersof derivatives of 13c 13c–e–wereg. The formed partial-cone exclusively, conformers but, in theof 13c cases–e ofwere13f formedand 13g ,exclusively, the partial-cone but,:cone in theratio cases fell from of 13f 95:5 and to 67:33.13g, the On partial-cone the other hand,:cone whenratio fell NaH from was 95:5 used to instead 67:33. Onas the the base other to hand, form 13fwhenand NaH13g alsowas inused high instead yields as (> the95%), base the tocone formconformers 13f and 13g were also now in high exclusively yields (>95%),formed. the The cone authors conformers rationalized were theirnow exclusively results by a formed. mechanism The inauthors which rationalized ring-inversion their of oneresults of theby arings mechanism could occur in which at diff ring-inversionerent rates, leading of one to of the the formation rings could of theoccurpartial-cone at differentisomers rates, withleading the to ethyl, the propylformation and of butyl the partial-cone derivatives. isomers However, with with the ethyl, the corresponding propyl and butyl larger derivatives. ethoxycarbonylmethoxy However, with andthe correspondingN,N-diethylaminocarbonylmethoxy larger ethoxycarbonylmethoxy derivatives, and a “metal-templating” N,N-diethylaminocarbonylmethoxy effect with Cs2+ ion derivatives, and more astrongly “metal-templating” with the Na+ effection, prevents with Cs complete2+ ion and ringmore inversion. strongly Similarwith the metal-templating Na+ ion, prevents eff completeects had beenring inversion.noted previously Similar in metal-templating the case of O-alkylation effects reactions had been with noted calix[4]arenes. previously “Doubly-bridged” in the case of O derivatives-alkylation reactionsof 13b [34 with] in whichcalix[4]arenes. two of the “Doubly-bridged” hydroxy groups derivatives were capped of 13b using [34] 3,5-bis(bromomethyl)toluene, in which two of the hydroxy groupsor 1-tert -butyl-3,5-bis(bromomethyl)-benzene,were capped using 3,5-bis(bromomethyl)toluene, Cs2CO3 and acetone or 1- undertert-butyl-3,5-bis(bromomethyl)- reflux conditions in acetone, wasbenzene, deduced Cs2CO to3 also and be acetone in a partial-cone under refluxconformation. conditions in acetone, was deduced to also be in a partial- cone conformation.

Scheme 3. Hexahomocalix[3]areneHexahomocalix[3]arene analogue MCPs 13a–g and capped 13h–i.

In a a similar similar manner manner as as with with the the synthesis synthesis of 13a of 13a, the, thetetrahomocalix[3]arene-analogue tetrahomocalix[3]arene-analogue MCP, MCP, tri- terttri-tert-butyl-trimethoxy-[3.3.1]MCP-butyl-trimethoxy-[3.3.1]MCP 20a20a waswas synthesized synthesized by by a aNaH/DMF-mediated NaH/DMF-mediated cyclocondensation cyclocondensation of 1717 andand 1818 followedfollowed by by Wolff–Kishner Wolﬀ–Kishner reduction reduction of ofthe thediketone diketone intermediate intermediate 19 (Figure19 (Figure 5). The5). Theinherent inherent chirality chirality of the of resulting the resulting C1-symmetricalC1-symmetrical 20e was20e wasconfirmed conﬁrmed by its by room its room temperature temperature 1H-

Molecules 2020, 25, 4202 7 of 19 Molecules 2020, 25, x FOR PEER REVIEW 7 of 19

NMR1H-NMR spectrum spectrum with with added added Pirkle’s Pirkle’s chiral chiral shift shift reag reagent,ent, which which caused caused a asplitting splitting of of the the OMe OMe groups groups andand AB patterns corresponding to the methylene protons indicating a 2-partial-cone conformation.

Figure 5. 20a e Figure 5. SynthesisSynthesis and and conformers conformers of of tetrah tetrahomocalix[3]areneomocalix[3]arene analogue analogue MCPs 20a–e.. The demethylation of 20a using tetramethylsilyl iodide (TMSI) in acetonitrile produced the The demethylation of 20a using tetramethylsilyl iodide (TMSI) in acetonitrile produced the corresponding trihydroxy[3.3.1]MCP, 20b, as expected, but when BBr3 in dichloromethane was used, corresponding trihydroxy[3.3.1]MCP, 20b, as expected, but when BBr3 in dichloromethane was used, the partial demethylation of 20a resulted, forming only the dihydroxy[3.3.1]MCP, 20c. Upon further the partial demethylation of 20a resulted, forming only the dihydroxy[3.3.1]MCP, 20c. Upon further treatment with TMSI/MeCN, however, 20c afforded the trihydroxy[3.3.1]MCP 20b [38]. Its 1H-NMR treatment with TMSI/MeCN, however, 20c afforded the trihydroxy[3.3.1]MCP 20b [38]. Its 1H-NMR spectrum (in CDCl3) exhibits the signals for the hydroxyl groups at ~ δ 3.33 and 6.25 ppm, which is spectrum (in CDCl3) exhibits the signals for the hydroxyl groups at ~ δ 3.33 and 6.25 ppm, which is evidence for the formation of intramolecular hydrogen bonding and a cone conformation [38]. In contrast, evidence for the formation of intramolecular hydrogen bonding and a cone conformation [38]. In both the 1H-NMR spectrum and a single crystal analysis confirmed the 2-partial-cone conformation of contrast, both the 1H-NMR spectrum and a single crystal analysis confirmed the 2-partial-cone macrocycle 20c. Its 1H-NMR spectrum shows two sets of doublets at δ 3.61 and 4.36 ppm (J = 13.3 conformation of macrocycle 20c. Its 1H-NMR spectrum shows two sets of doublets at δ 3.61 and 4.36 Hz) for the ArCH2Ar methylene protons and a single peak at δ 1.72 ppm for the methoxy protons ppm (J = 13.3 Hz) for the ArCH2Ar methylene protons and a single peak at δ 1.72 ppm for the methoxy consistent with a 2-partial-cone conformation. To date, no further studies on either the computational protons consistent with a 2-partial-cone conformation. To date, no further studies on either the or supramolecular properties of these compounds have been reported. computational or supramolecular properties of these compounds have been reported. 4. Calixbenzofuran-Analogous MCPs: Calix[3]benzofuran Analogues 4. Calixbenzofuran-Analogous MCPs: Calix[3]benzofuran Analogues The demethylation of [3.3.1]MCP-dione 19 in acetonitrile with in-situ-generated TMSI produced a The demethylation of [3.3.1]MCP-dione 19 in acetonitrile with in-situ-generated TMSI produced mixture of benzofuran ring-containing products, the symmetrical 22a and unsymmetrical 23a and a new a mixture of benzofuran ring-containing products, the symmetrical 22a and unsymmetrical 23a and spirobisdihydro-furan 24 in 24, 45 and 5% yields, respectively (Figure6)[ 39]. It is presumed that the a new spirobisdihydro-furan 24 in 24, 45 and 5% yields, respectively (Figure 6) [39]. It is presumed trihydroxy-diketo intermediate 21 is first formed, and then undergoes intramolecular TMSI-mediated that the trihydroxy-diketo intermediate 21 is first formed, and then undergoes intramolecular TMSI- cyclizations to form the observed products [39–41]. Sawada and co-workers had previously reported mediated cyclizations to form the observed products [39–41]. Sawada and co-workers had previously that the treatment of tetramethoxy [2.1.2.1]MCPs with TMSI formed hemisphere-shaped calixarene reported that the treatment of tetramethoxy [2.1.2.1]MCPs with TMSI formed1 hemisphere-shaped analogues containing a dihydrobenzofuran ring [42,43]. The CDCl3 H-NMR spectrum of the calixarene analogues containing a dihydrobenzofuran ring [42,43]. The CDCl3 1H-NMR spectrum of symmetrical 22a shows the hydroxyl signal at δ 6.54 ppm, indicating intramolecular hydrogen the symmetrical 22a shows the hydroxyl signal at δ 6.54 ppm, indicating intramolecular hydrogen bonding between the hydroxyl and the oxygen of one of the benzofuran rings. The single-crystal bonding between the hydroxyl and the oxygen of one of the benzofuran rings. The single-crystal X- X-ray structure of 22a confirmed the intramolecular hydrogen bond as predicted from the 1H-NMR ray structure of 22a confirmed the intramolecular hydrogen bond as predicted from the 1H-NMR spectroscopic data, with a distance of 2.182 Å between the hydroxyl proton and one of the benzofuran spectroscopic data, with a distance of 2.182 Å between the hydroxyl proton and one of the benzofuran

Molecules 2020, 25, x 4202 FOR PEER REVIEW 88 of of 19 Molecules 2020, 25, x FOR PEER REVIEW 8 of 19 oxygens. The unsymmetrical regioisomer 23a is fixed in an asymmetrical hemispherically shaped oxygens. The unsymmetrical regioisomer 23a is fixed in an asymmetrical hemispherically shaped coneoxygens. conformation The unsymmetrical and the regioisomerspirobisdihydrofuran23a is ﬁxed 24 in anis asymmetricalpresumed to hemispherically have been formed shaped bycone a cone conformation and the spirobisdihydrofuran 24 is presumed to have been formed by a nucleophilicconformation attack and theon one spirobisdihydrofuran of the formed benzofurans24 is presumed in 22a. to have been formed by a nucleophilic nucleophilicattack on one attack of the on formed one of benzofurans the formed benzofurans in 22a. in 22a.

Figure 6. Calix[3]didibenzofuran analogue MCPs 22–24. Figure 6. Calix[3]dibenzofuran analogue MCPs 22–24.

The O-methylation-methylation ofof23a 23awith with MeI MeI/K/K2CO2CO3 3in in acetone acetone resulted resulted in in the the folding folding of the of the arene arene ring ring into The O-methylation of 23a with MeI/K2CO3 in acetone resulted in the folding of the arene ring intothe macrocyclethe macrocycle to form to theform non-symmetrical the non-symmetricalpartial-cone partial-conemethoxy[1.1.1]MCP methoxy[1.1.1]MCP23b, which 23b, iswhich evident is into the macrocycle to form the non-symmetrical partial-cone methoxy[1.1.1]MCP 23b, which is evidentfrom the from1H signals the 1H observedsignals observed for the bridge for the methylene bridge methylene hydrogen hydrogen atoms. The atoms. methoxy The methoxy group of group23b is evident from the 1H signals observed for the bridge methylene hydrogen atoms. The methoxy group ofshifted 23b is to shifted the high to fieldthe high as a singletfield as at a δsinglet1.97 ppm at δ due 1.97 to ppm its shielding due to its by shielding the benzofuran by the benzofuran rings; these of 23b is shifted to the high field as a singlet at δ 1.97 ppm due to its shielding by the benzofuran 1rings;H signals these correspond 1H signals correspond to an unsymmetrical to an unsymmetricalpartial-cone partial-conestructure as structure depicted as from depicted density from functional density rings; these 1H signals correspond to an unsymmetrical partial-cone structure as depicted from density functionaltheory (DFT)-optimized theory (DFT)-optimized energy structures. energy Its structures.1H-NMR spectraIts 1H-NMR with added spectra Pirkle’s with reagentadded revealedPirkle’s functional theory (DFT)-optimized energy structures. Its 1H-NMR spectra with added Pirkle’s reagentthe racemic revealed mixture the of racemicP- and M mixture-enantiomers of P- (Figureand M7-enantiomers). Single-crystal (Figure X-ray analysis7). Single-crystal of 23b revealed X-ray reagent revealed the racemic mixture of P- and M-enantiomers (Figure 7). Single-crystal X-ray analysisthat the macrocyclicof 23b revealed skeleton that adopts the macrocyclic a highly asymmetric skeleton hemisphere-shapedadopts a highly asymmetriccone-type conformationhemisphere- analysis of 23b revealed that the macrocyclic skeleton adopts a highly asymmetric hemisphere- shapedin which cone the-type methoxy conformation group is pointed in which upwards the methoxy and is group exo to is the pointed two benzofuran upwards rings,and is predictedexo to the from two shaped cone-type conformation in which the methoxy group is pointed upwards and is exo to the two benzofuranthe 1H-NMR rings, spectra. predicted These molecules, from the therefore,1H-NMR byspectra. adopting These curvature molecules, in their therefore, planar structures by adopting that benzofuran rings, predicted from the 1H-NMR spectra. These molecules, therefore, by adopting curvaturehave no symmetry in their planesplanar in structures their three-dimensional that have no representations, symmetry planes fit Szumna’s in theirexpanded three-dimensional definition curvature in their planar structures that have no symmetry planes in their three-dimensional representations,of inherent chirality fit Szumna’s [44,45]. Others, expanded including definition Böhmer of inherent [46,47] andchirality Mandolini [44,45]. [48 Others,], had previouslyincluding representations, fit Szumna’s expanded definition of inherent chirality [44,45]. Others, including Böhmerproposed [46,47] and studied and Mandolini inherent chirality [48], had in calixarenes.previously proposed and studied inherent chirality in Böhmer [46,47] and Mandolini [48], had previously proposed and studied inherent chirality in calixarenes. calixarenes.

Figure 7. SchematicSchematic diagram of M--23b (left) and P-23b (right). Figure Figure adapted adapted from from [39]. [39]. Figure 7. Schematic diagram of M-23b (left) and P-23b (right). Figure adapted from [39]. The DFT calculations conducted on these molecules using Gaussian-09 [49][49] showed that the The DFT calculations conducted on these molecules using Gaussian-09 [49] showed that the energy-minimized structures structures of of the the hemisphere-shaped hemisphere-shaped conecone conformersconformers were were in agreement in agreement with with the energy-minimized structures of the hemisphere-shaped cone conformers were in agreement with the observedthe observed single-crystal single-crystal X-ray X-ray structures. structures. The The DFT DFT gas gas phase phase calculations calculations using using B3LYP/6-31G(d) B3LYP/6-31G(d) observed single-crystal X-ray structures. The DFT gas phase calculations using B3LYP/6-31G(d) showed that of the regioisomers 22a and 23a, the latter of which was energetically more favored by by showed that of the regioisomers 22a and 23a, the latter of which was energetically more favored by

Molecules 2020, 25, 4202 9 of 19 Molecules 2020, 25, x FOR PEER REVIEW 9 of 19 Molecules 2020, 25, x FOR PEER REVIEW 9 of 19 3.791 kJ mole 1. The DFT calculations of the corresponding conformations of methoxy derivatives 22b 3.791 kJ mole−−1. The DFT calculations of the corresponding conformations of methoxy derivatives 22b and 23b showed that the latter was also similarly more favored by 2.358 kJ mole 1, with the methoxy and3.791 23b kJ showedmole−1. The that DFT the calculationslatter was also of the similarly correspondi more ngfavored conformations by 2.358 kJof methoxymole−−1, with derivatives the methoxy 22b groups being favored to be in exo rather than endo orientations to the benzofuran rings, as shown in groupsand 23b being showed favored that theto be latter in exo was rather also similarlythan endo more orientations favored byto the2.358 benzof kJ moleuran−1, withrings, the as methoxyshown in Figure8. Figuregroups 8. being favored to be in exo rather than endo orientations to the benzofuran rings, as shown in Figure 8.

Figure 8. Geometry-optimized structures ofof endoendo 22a22a andand endoendo 23a23a;; exoexo 22b22b andand exoexo 23b23b.. All hydrogens exceptFigure methoxy 8. Geometry-optimized and phenolicphenolic hydrogenshydrstructuresogens of areare endo omittedomitted 22a and forfor endo clarity.clarity. 23a; exo FigureFigure 22b and adaptedadapted exo 23b andand. All re-calculatedre-calculated hydrogens fromfromexcept [[39].39 methoxy]. and phenolic hydrogens are omitted for clarity. Figure adapted and re-calculated from [39]. A series of derivatives 25b–e of calix[3]benzofuran 25a were synthesized using typical electrophilic A series of derivatives 25b–e of calix[3]benzofuran 25a were synthesized using typical aromaticA series substitution of derivatives reactions to25b investigate–e of calix[3]benzofuran the inﬂuence of the25a substituents were synthesized on the conformations using typical of electrophilic aromatic substitution reactions to investigate the influence of the substituents on the theelectrophilic calix[3]benzofurans. aromatic substitution The 1H-NMR reactions spectra to of in25avestigate–e reveal the that influence they adopt of the diverse substituents conformations on the conformations of the calix[3]benzofurans. The 1H-NMR spectra of 25a–e reveal that they adopt inconformations solution and inof somethe calix[3]benzofurans. cases undergo very The fast 1 conformationalH-NMR spectra changesof 25a–e relative reveal tothat the they NMR adopt time diverse conformations in solution and in some cases undergo very fast conformational changes scale.diverse For conformations example, 25a freelyin solution interconverts and in betweensome casescone undergoand saddle veryconformers fast conformational (Figure9) in solution,changes relative to the NMR time scale. For example, 25a freely interconverts between cone and saddle butrelative the tribromocalix[3]benzofuran to the NMR time scale. For25b example,, adopts a25a rigid freelycone interconvertstype hemisphere-shaped between cone symmetrical and saddle conformers (Figure 9) in solution, but the tribromocalix[3]benzofuran 25b, adopts a rigid cone type structureconformers in the(Figure solid 9) state. in solution, The triformyl but the derivativetribromocalix[3]benzofuran25c showed fast cone25b,- saddleadoptsinterconversion a rigid cone type in hemisphere-shaped symmetrical structure in the solid state. The triformyl derivative 25c showed fast solution,hemisphere-shaped but, when the symmetrical three formyl structure groups in were the reducedsolid state. to formThe triformyl the corresponding derivative trihydroxymethyl 25c showed fast cone-saddle interconversion in solution, but, when the three formyl groups were reduced to form the derivativecone-saddle25d interconversion, the molecule in adopted solution, a bu ﬁxed-t, whencone theconformation three formyl as groups with 25b were. The reduced acylation to form of 25a theto corresponding trihydroxymethyl derivative 25d, the molecule adopted a fixed-cone conformation as formcorresponding25e once again trihydroxymethyl led to the formation derivative of a slowly-interconverting25d, the molecule adopted mixture a fixed- of cone-saddlecone conformationconformers as with 25b. The acylation of 25a to form 25e once again led to the formation of a slowly-interconverting (Tablewith 125b)[40. The]. acylation of 25a to form 25e once again led to the formation of a slowly-interconverting mixture of cone-saddle conformers (Table 1) [40]. mixture of cone-saddle conformers (Table 1) [40].

FigureFigure 9. 9. Calix[3]benzofuran Calix[3]benzofuran analogue MCPs, 25a–e andand conecone andand saddlesaddle conformers conformers of ofof 25a 25a25a [40]. [[40].40].

Molecules 2020, 25, x FOR PEER REVIEW 10 of 19

Molecules 2020, 25, 4202 10 of 19 Table 1. Influence of substituents on the conformations of benzofurans 25a–e [40].

Δ ≠ −1 ° Table 1. InﬂuenceCompound of substituents Tc onG the kJ conformations mol Cone:saddle of benzofurans(−30 C) 25a–e [40]. 25a 40 a 61.9 80:20 , 1 Compound Tc ∆G kJ mol− Cone:saddle( 30 ◦C) 25b 45 a 62.8 100:0 − 25a 40 a 61.9 80:20 a 25b 25c 45 a 28 58.662.8 40:60 100:0 a 25c 25d 28 50 a 68.258.6 100:0 40:60 25d 50 a 68.2 100:0 25e 75 b 69.0 20:80 25e 75 b 69.0 20:80 aa: CDCl3;b b: CDBr3 (300 MHz). : CDCl3; : CDBr3 (300 MHz).

SolventSolvent and and gas-phase gas-phase DFT DFT determinations determinations with with calix[3]benzofuran calix[3]benzofuran MCPs MCPs25a 25a–e–e[40 [40]] revealreveal that that bothboth the thesaddle saddleand and corresponding correspondingcone coneconformers conformers have have lower lower ground-state ground-state energies energies in in the the solvent solvent systemsystem than than in in the the gas gas phase phase (Figure (Figure 10 10).).

Figure 10. Geometry-optimized structures of the cone and saddle conformers of 25a. Similar structures Figure 10. Geometry-optimized structures of the cone and saddle conformers of 25a. Similar structures were obtained for the cone and saddle conformers of 25b–e and are not shown. were obtained for the cone and saddle conformers of 25b–e and are not shown. The calculations also show that, among the calix[3]benzofurans, the saddle conformers are energeticallyThe calculations more favored also than show their that, corresponding among thecone calix[3]benzofurans,conformers in both the solventsaddle conformers and gas-phase. are Theenergetically energy di ffmoreerences favored are inthan the their following corresponding order: 23a cone> conformers25e > 25d in> both25c > the25a solvent> 23b and> 22b gas-. Thus,phase. by The introducing energy differences the di arefferent in the groups following at order: the furan 23a > 25e moieties, > 25d > 25c their > 25asaddle > 23bconformers > 22b. Thus, becomeby introducing energetically the different more favored, groups roughly at the accordingfuran moieties, to the their increasing saddle sizeconformers of the groupsbecome energetically more favored, roughly according to the increasing size of the groups (i.e., COMe > (i.e., COMe > CH2OH > CHO), except for 25b. In the case of 25b, there may be two factors influencing theCH stability2OH > CHO), of the coneexceptconformers: for 25b. In bromine the case isof electronegative 25b, there may inbe nature two factors and also influencing has greater the electron stability densityof the cone due conformers: to multiple lone-pairsbromine is ofelectronegative electrons. A single-crystal in nature and structurealso has greater of 25b, electron however, density revealed due itto to multiple be in a cone lone-pairsconformation of electrons. in the A solid single-crystal state, but itstructure should beof noted25b, however, that it co-crystallized revealed it towith be in a a well-definedcone conformation chloroform in the molecule solid state, and but with it should disordered be noted solvent that methanol it co-crystallized molecules. with a well-defined chloroformThe cycloaddition molecule and reactionwith disordered of 17 solventand 26methanol, followed molecules. by acidic work-up afforded [3.3.3]MCPThe cycloaddition27a (Figure reaction11) which, of 17 in and turn, 26, whenfollowed treated by acidic with work-up TMSI, generated afforded [3.3.3]MCP in situ from 27a (Figure 11) which, in turn, when treated with TMSI, generated in situ from chlorotrimethylsilane/sodium iodide in CH3CN, generated, instead of the expected trihydroxy 27b, twochlorotrimethylsilane/sodium calix[3]benzofuran[3.1.1]MCP-analogues iodide in CH3CN,28a generated,and 29 in instead 52% and of 7%the yields,expected respectively trihydroxy [ 4127b]., Thetwo regioisomer calix[3]benzofuran[3.1.1]MCP-analogues of 28a, namely the unsymmetrical 28a and29 ,29 however, in 52% and could 7% notyields, be isolated,respectively although [41]. The it wasregioisomer detected inof the28a,1 Hnamely NMR the spectra unsymmetrical of the crude 29 reaction, however, mixture. could not The be1H-NMR isolated, spectrum although of it 28awas detected in the 1H NMR spectra of the crude reaction mixture. The 1H-NMR spectrum of 28a exhibits exhibits a single peak at δ = 4.09 ppm for the ArCH2Ar methylene bridge protons and the trimethylene protonsa single appeared peak at δas = 4.09 a broad ppm multiplet for the Ar atCHδ 2.012Ar methylene and 2.98 ppm. bridge The protons position and of the trimethylene hydroxyl group protons at δ δ δ 6.34appeared ppm is as consistent a broad multiplet with the existence at 2.01 ofand intramolecular 2.98 ppm. The hydrogen position bondingof the hydroxyl between group the hydroxyl at 6.34 groupppm is and consistent the oxygen with of the one existence of the benzofuran of intramolecular rings. Thehydrogen formation bonding of 30 between, which containsthe hydroxyl the spirobisdihydrofurangroup and the oxygen moiety, of one is analogousof the benzofuran to the spirobishydrofuran rings. The formation24 described of 30, which previously contains [41]. the spirobisdihydrofuran moiety, is analogous to the spirobishydrofuran 24 described previously [41].

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Figure 11. Structures of calix[3]benzofuran analogue MCPs 27–30. Figure 11. Structures of calix[3]benzofuran analogue MCPs 27–30. When 28a was treatedtreated withwith MeIMeI inin thethe presencepresence ofof KK22COCO33 inin acetoneacetone methoxy[3.1.1]MCPmethoxy[3.1.1]MCP 28b was producedWhenproduced 28a asaswas itsits treated conecone-conformer.-conformer. with MeI Thisin the is presence evident fromof K2 CO the3 11inH acetonesignals observedmethoxy[3.1.1]MCP for the bridge 28b methylenewas produced hydrogen as its atoms cone-conformer. that are split This and is appearevident asfrom a pair the of 1 H doublets signals atobserved δ = 3.793.79 andfor and the4.07 4.07 bridge ppm. ppm. Previously,methylene hydrogen wewe hadhad notednoted atoms that that that the the areO O-methylation -methylationsplit and appear of of23a 23a asunder aunder pair the ofthe samedoublets same conditions conditions at δ = 3.79 resulted resulted and 4.07 instead instead ppm. in theinPreviously, the inversion inversion we of hadof one one noted of of the the benzofuranthat benzofur the O-methylationan rings, rings, aff affordingording of 23a the theunder non-symmetrical non-symmetrical the same conditionspartial-cone partial-cone resulted23b 23b(Figure (Figureinstead6). Thus,6).in theThus, theinversion sizethe ofsize of the oneof linking theof the linking methylene benzofur methylenean chains rings, can chainsaffording have can significant the have non-symmetrical significant effects on theeffects partial-cone resulting on the conformers,23b resulting (Figure whichconformers,6). Thus, are formedthe whichsize [ 41of ]. theare The linkingOformed-benzylation methylene [41]. of 28aThe chains, producedO-benzylation can have the cone significant -benzyloxy[3.1.1]MCPof 28a , effectsproduced on the 28cthe resultingwith cone no- isomerizationbenzyloxy[3.1.1]MCPconformers, beingwhich observed. 28care withformed Thisno isomerization is evident[41]. The from beingO the-benzylation 1observed.H signals This forof the is28a bridgeevident, produced methylene from the the1 hydrogenH signalscone- atomsforbenzyloxy[3.1.1]MCP the thatbridge are methylene split and 28c appear hydrogenwith no as isomerization aatoms pair ofthat doublets are being split observed. at andδ = appear3.77 This and as is a 4.45 evidentpair ppm of doubletsfrom [41]. the In at1 principle,H δ signals = 3.77 theseandfor the 4.45 molecules bridge ppm [41].methylene could In principle, adopt hydrogen three these possible atoms molecules that conformations, arecould split adopt and whichthreeappear possible are as schematicallya pair conformations, of doublets represented atwhich δ = 3.77 are in Figureschematicallyand 4.45 12 ppm. [41].represented In principle, in Figure these 12. molecules could adopt three possible conformations, which are schematically represented in Figure 12.

Figure 12. Schematic representations of the three basic possible conformers of 28 and 29.. Figure 12. Schematic representations of the three basic possible conformers of 28 and 29. Gas-phase DFT computational analysis of the three basic types of conformers of compoundscompounds 27a–30Gas-phase was undertaken DFT computational using the geometry-optimized analysis of the three st structures ructuresbasic types of of each of conformers of these conformers of compounds [41]. [41]. –1 The27a– 30 calculated was undertaken optimized-energy using the geometry-optimized didifferencesﬀerences (kJ molmol–1 st)) ructuresfor 27a– of30 eachshowed of these that, conformers of the various [41]. conformationalThe calculated isomersoptimized-energy isomers of of 27a27a––3030, ,thedifferences the conecone-shaped-shaped (kJ molstructures structures–1) for are27a are –the30 the mostshowed most favored favoredthat, energetically,of energetically, the various in intheconformational the following following order: isomers order: conecone of> 2-partial-cone 27a> 2-partial-cone–30, the cone > 1,3-alternate.-shaped> 1,3-alternate. structures For example,For are example, the the most cone the conformerfavoredcone conformer energetically, of 28a of is28a −13.4 inis 1 the13.4 following− and 23.9 order: kJ−1 mol cone− >more 2-partial-cone stable than > 1,3-alternate. its corresponding For example,2-partial-cone the coneand conformer1,3-alternate of conformers,28a is −13.4 −and 23.9 −kJ mol more stable than its corresponding 2-partial-cone and 1,3-alternate conformers, − −1 respectively.and 23.9 kJ Themol The findings ﬁndings more stable were were thanalso consistent its corresponding wi withth the 2-partial-cone experimental and evidence 1,3-alternate that theconformers, phenolic hydrogenrespectively. forms The weak findings intramolecular were also hydrogen consistent bonding with the with experimental an oxygen atom evidence of one that of the the benzofuran phenolic

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hydrogen forms weak intramolecular hydrogen bonding with an oxygen atom of one of the rings.benzofuran The distances rings. The between distances the between hydroxyl the hydrogen hydroxyl and hydrogen the benzofuran and the oxygensbenzofuran are, oxygens respectively, are, 2.014respectively, Å and 3.3742.014 Å,Å and 2.698 3.374 Å and Å, 2.698 4.253 Å Å, and and 4.253 2.010 Å, Åand and 2.010 3.493 Å and Å for 3.493 the Åcone for, 2-partial-conethe cone, 2-partial-and 1,3-alternatecone and 1,3-alternateconformers conformers of 28a. For of the 28a corresponding. For the corresponding conformers ofconformers29, the respective of 29, the distances respective are 1.836distances Å vs. are 3.277 1.836 Å, Å 2.605 vs. 3.277 Å vs. Å, 3.065 2.605 Å, Å and vs. 3.6603.065 ÅÅ, vs. and 3.836 3.660 Å. Å vs. 3.836 Å.

5. Homooxacalixarene-Analogue MCPs Containing Three Aromatic Rings: “Oxacalix[3]arene” “Oxacalix[3]arene”Analogues Analogues Hexahomotrioxacalix[3]arene 31 (Figure 1313;;R R = H), commonly also called “oxacalix[3]arene”, was firstfirst reportedreported in 1962 by Hultzsch who isolated it in less than 1% yield from the reaction of formaldehyde with p-tert-butylphenol [50], [50], and the evolution of the chemistry of this and relatedrelated analogues havehave been been well well reviewed reviewed recently recent [17,ly18 ].[17,18]. Hexahomotrioxacalix[3]arene Hexahomotrioxacalix[3]arene31 can be 31 considered can be to be an example of a [3.3.3]MCP in which the phenolic units are linked by CH OCH− bridges.− considered to be an example of a [3.3.3]MCP in which the phenolic units are linked− 2 by CH2− 2OCH2 Inbridges. 1983, DhawanIn 1983, Dhawan and Gutsche and Gutsche described described detailed detailed reproducible reproducible syntheses syntheses of 31 [51 of], 31 which [51], canwhich be conductedcan be conducted in relatively in relatively large-scale. large-scale. Hampton Ha andmpton co-workers and co-workers also have describedalso have andescribed alternative an smaller-scalealternative smaller-scale acid-catalyzed acid-catalyzed procedure procedure which has which been usedhas been for the used synthesis for the synthesis of several of di severalfferent “wide-rim”different “wide-rim”para-substituted para-substituted analogues of analogues31 [52]. Shinkai’s of 31 group[52]. Shinkai’s and others group have extensively and others studied have 31extensivelyas a platform studied to 31 generate as a platform several to versatile generate hostsseveral [53 vers–56atile] since, hosts in [53–56] comparison since, within comparison the basic calix[4]arenewith the basic structure, calix[4]arene31 o structure,ffers some 31 potential offers some advantages: potential (1) advantages: its intra-annular (1) its intra-annular cavity consists cavity of a 18-memberedconsists of a 18-membered ring, whereas ring, that ofwhereas calix[4]arene that of isca alix[4]arene 16-membered is a 16-membered ring; (2) the rate ring; of ring(2) the inversion rate of forring derivatives inversion for of 31derivativesshould be of much 31 should faster be than much that faster for calix[4]arenesthan that for calix[4]arenes because of the because flexibility of the of theflexibility dimethyleneoxa of the dimethyleneoxa linkages; (3) linkages; conformational (3) conformational isomerism isomerism is much more is much simplified, more simplified, as there are as onlytheretwo are typesonly two of formal types conformationsof formal conformations possible, namely possible,cone namelyand partial-cone cone and partial-cone(Figure 13), (Figure in contrast 13), toin contrast the four to possible the four formal possible conformations formal conformati in calix[4]arenes;ons in calix[4]arenes; (4) the ethereal (4) the ringethereal oxygens ring oxygens may act cooperativelymay act cooperatively with the phenolicwith the oxygensphenolic upon oxygens binding upon with binding metal with ions; metal and (5) ions; its coneand and(5) itspartial-cone cone and conformerspartial-cone conformers can have C3v canand have/or CCs3vsymmetry, and/or Cs whichsymmetry, is particularly which is particularly useful for the useful design for of the receptors design + forof receptors biologically for relevantbiologically RNH relevant3 ammonium RNH3+ammonium ions. ions.

Figure 13. Structures of hexahomotrioxacalix[3]arene 31 (R = H) and schematic representations ofFigure the 13.cone Structuresand partial-cone of hexahomotrioxacalix[3]areneconformers of its tri- O31-functionalized (R = H) and schematic derivatives representations32 (R = alkyl);of the 33cone(R and= ethoxycarbonylmethoxy) partial-cone conformers and of 34its(R tri-= N,NO-functionalized-diethyl O-methylacetamido). derivatives 32 (R = alkyl); 33 (R= ethoxycarbonylmethoxy) and 34 (R = N,N-diethyl O-methylacetamido). In 1993, Shinkai and coworkers reported that treatment of 31 with four alkyl halides in DMF in the presenceIn 1993, ofShinkai NaH, Kand2CO coworkers3, Cs2CO3, reportedt-BuOK that or K treatment afforded the of 31 corresponding with four alkylO-methoxy, halides inO DMF-ethoxy, in Othe-n -propyloxypresence of NaH, and O K-n2CO-butyloxy3, Cs2CO derivatives3, t-BuOK or that K afforded can adopt thecone correspondingand/or partial-cone O-methoxy,conformations O-ethoxy, (FigureO-n-propyloxy 13) in varying and O- yieldsn-butyloxy ratios. derivatives They showed that can that adopt a metal cone templating and/or partial-cone and solvent conformations effect could lead(Figure to preferential13) in varying thermodynamic yields ratios. andThey/or showed a kinetic that preference a metal fortemplating the partial-cone and solventconformers effect ofcould the correspondinglead to preferential tri-O thermodynamic-alkylated derivatives. and/or Ina kinetic particular, preference tri-O-n -butylatedfor the partial-cone32 (R – nconformers-Bu) was formed of the exclusivelycorresponding with tri- theO use-alkylated of NaH derivatives. in DMF but In also particular, in a 99:1% tri- ratioO-n over-butylated the cone 32conformer (R – n-Bu) when was Csformed2CO3 inexclusively DMF was with used [the53]. use Shinkai of NaH [54– in56 ]DMF also reportedbut also thein synthesisa 99:1% ratio of the overtris- Othe-ethoxycarbonylmethoxy cone conformer when derivativeCs2CO3 in33 DMF(R = CHwas2CO used2Et) by[53]. the Shinkai reaction [54–56] of excess also ethyl reported bromoacetate the synthesis with 31 in of acetone the tris under-O- refluxethoxycarbonylmethoxy conditions with K 2derivativeCO3 or Cs 233CO (R3, =and CH that2CO2 anEt) alkali-metal by the reaction template of excess effect ethyl led exclusivelybromoacetate to thewith formation 31 in acetone of the underpartial-cone reflux conditions-33 conformer. with WithK2CO NaH3 or Cs or2COt-BuOK3, and that in THF, an alkali-metal however, a template mixture ofeffectcone ledand exclusivelypartial-cone to theproducts formation was of formed, the partial-cone with the-33cone conformer.-33 conformer With NaH being or formed t-BuOK in in only THF, a

Molecules 2020, 25, x FOR PEER REVIEW 13 of 19 MoleculesMolecules 20202020,, 2525,, 4202x FOR PEER REVIEW 1313 of 1919 however, a mixture of cone and partial-cone products was formed, with the cone-33 conformer being formedhowever, in aonly mixture a 20–22% of cone yield. and Shinkaipartial-cone was products also able was to show formed, both with a metal the cone templating-33 conformer and solvent being 20–22% yield. Shinkai was also able to show both a metal templating and solvent eﬀect for the effectformed for in theonly efficient a 20–22% formation yield. Shinkai of the was tris- alsoO-amido able to derivatives show both 34a metal(R = templatingCH2CONEt and2) from solvent the eﬃcient formation of the tris-O-amido derivatives 34 (R = CH2CONEt2) from the reactions of 31 with reactionseffect for ofthe 31 efficientwith diethylchloroacetamide formation of the tris- [55].O-amido With NaH derivatives in THF, cone34 (R-34 = was CH formed2CONEt exclusively,2) from the diethylchloroacetamide [55]. With NaH in THF, cone-34 was formed exclusively, but, with K2CO3 or but,reactions with ofK2 CO31 with3 or Csdiethylchloroacetamide2CO3 in acetone, partial-cone- [55]. With34 was NaH exclusively in THF, cone formed.-34 was With formed NaH exclusively, in DMF, a Cs2CO3 in acetone, partial-cone-34 was exclusively formed. With NaH in DMF, a lower overall yield lowerbut, with overall K2CO yield3 or (29Cs 2andCO3 26%,in acetone, respectively) partial-cone- of the34 cone was and exclusively partial-cone- formed.34 was With obtained. NaH inHowever, DMF, a (29 and 26%, respectively) of the cone and partial-cone-34 was obtained. However, with t-BuOK in THF withlower t-BuOK overall in yield THF (29 a mixture and 26%, of respectively) cone and partial-cone- of the cone34 productsand partial-cone- was formed34 was in obtained. 60 and 38% However, overall a mixture of cone and partial-cone-34 products was formed in 60 and 38% overall yield. yield.with t -BuOK in THF a mixture of cone and partial-cone-34 products was formed in 60 and 38% overall Recently, 35 the C3-symmetric N-pyridyl O-methylacetamido functionalized derivative of 31 yield.Recently, 35 the C3-symmetric N-pyridyl O-methylacetamido functionalized derivative of 31 (Figure 14) was reported to be able to selectively and cooperatively bind Ag+ and n-butylammonium (FigureRecently, 14) was 35 reported the C3 -symmetricto be able to N selectively-pyridyl O and-methylacetamido cooperatively bind functi Agonalized+ and n-butylammonium derivative of 31 ions and be controlled by the metal ion [57]. The geometries of the molecular structures were optimized ions(Figure and 14) be was controlled reported by to bethe able metal to selectively ion [57]. Theand cooperativelygeometries of bind the Agmolecular+ and n-butylammonium structures were in the gas phase using the PBE0 functional theory with the LANL2DZ basis set. The calculated optimizedions and bein controlledthe gas phase by theusing metal the ionPBE0 [57]. functiT Theonal geometries theory+ with of the theT molecular LANL2DZ+ structures basis set.T were The+ binding or interaction energies (IE) for cone-35 n-BuNH3 , cone-35 t-BuNH3 , cone-35 Ag , calculatedoptimized bindingin the gas or phaseinteraction usingT energies the PBE0 (IE)⊃ functi for cone-onal 35theory ⊃n-BuNH with⊃ 3the+, cone- LANL2DZ35 ⊃t-BuNH basis3+ ⊃, set.cone- The35 and nBuNH + [cone-35 Ag+] are 298.8 kJ mol 1, 268.3 kJ mol 1, 457.1 kJ mol 1, ⊃ + 3 + ⊂ ⊃ + −1 −⊃ +−1 − ⊃ −1 + − calculatedAg , and bindingnBuNH⊂ 31or interaction[cone-⊃35 Ag energies] are − 298.8(IE)− for kJ molcone-,35 −268.3 n-BuNH− kJ mol3 , ,cone- −457.135 kJt− mol-BuNH, and3 , cone- –525.835 and 525.8 kJ mol− , respectively, and were in agreement with the trend for the complexation data kJ·mol⊃Ag−+ ,− 1and, respectively, nBuNH· 3+ ⊂ and [cone were-35 ⊃inAg agreement+] are −298.8 with kJ molthe −trend1, −268.3 for kJthe mol complexation−1, −457.1 kJ moldata− 1determined, and –525.8 determined by the 1H-NMR spectroscopic titration experiments with the corresponding perchlorate −11 bykJ·mol the H-NMR, respectively, spectroscopic and were titration in agreement experiments with thewith trend the corresponding for+ the complexation perchlorate data saltsdetermined [57]. A salts [571 ]. A conceptualization of the complexation of nBuNH3 by the receptor cone-35 is shown in conceptualizationby the H-NMR spectroscopic of the complexation titration of experiments nBuNH3+ by with the thereceptor corresponding cone-35 is shownperchlorate in Figure salts 15.[57]. A Figure 15. conceptualization of the complexation of nBuNH3+ by the receptor cone-35 is shown in Figure 15.

Figure 14. A schematic representation showing the cooperative binding mode of 35 (shown in a cone Figure 14. A schematic representation showing the cooperative binding mode of 35 (shown in a Figure 14. A schematic representation+ showing the cooperative binding mode of 35 (shown 3in+ a cone conformation) with and without Ag complexation+ and selective binding with n-BuNH and+ t- cone conformation) with and without+ Ag complexation and selective binding with n-BuNH+ 3 and conformation)3+ with and without Ag complexation and− selective binding with n-BuNH3 and t- BuNH cations.+ The green circles represent the CONH and the hexagons represent the pyridyl t-BuNH3 cations. The green circles represent the CONH and the hexagons represent the pyridyl groups.BuNH3+ (Figurecations. take The from green [57]). circles represent the CONH−− and the hexagons represent the pyridyl groups. (Figure take from [57]). groups. (Figure take from [57]).

Figure 15. 15. Geometry-optimizedGeometry-optimized (PBE0/L (PBE0ANL2DZ)/LANL2DZ) structures structures of cone of-35cone and-35 itsand complex its complex with Ag+ with and + T + Ag+ and+ nBuNH . Left: The free cone-35, Middle: 1:1+ cone-35 Ag complex,+ and right: nFigureBuNH 15.3 . Left:Geometry-optimized The3 free cone-35 ,(PBE0/L Middle:ANL2DZ) 1:1 cone- 35structures ⊃Ag complex, of cone-35 and and right: its complex nBuNH with3 ⊂ Ag+[cone and-35 + T + ⊃ n⊃BuNH+ + [cone-35 Ag ] complex. Figure taken from⊃ + reference [57]. + ⊂ nBuNHAg ] complex.33 . ⊂Left: TheFigure free⊃ taken cone -from35, Middle: reference 1:1 [57]. cone -35 Ag complex, and right: nBuNH3 [cone-35 ⊃Ag+] complex. Figure taken from reference [57].

MoleculesMolecules 20202020, 25, 25, x, FOR 4202 PEER REVIEW 14 14of of19 19 Molecules 2020, 25, x FOR PEER REVIEW 14 of 19 Chirality is also possible with unsymmetrically substituted hexahomooxacalix[3]arenes. Araki Chirality isis alsoalso possible possible with with unsymmetrically unsymmetrically substituted substituted hexahomooxacalix[3]arenes. hexahomooxacalix[3]arenes. Araki Araki et al. et al. had previously reported the “pseudo C2-symmetric inherent chirality” of the di-O-benzylated ethad al. previously had previously reported reported the “pseudo the “ Cpseudo-symmetric C2-symmetric inherent inherent chirality” chirality” of the di- Oof-benzylated the di-O-benzylated derivative derivative 36a and the di-O-benzylated-mono-2 O-methoxy derivative (Figure 16) 36b of derivative36a and the 36a di- Oand-benzylated-mono- the di-O-benzylated-mono-O-methoxy derivativeO-methoxy (Figure derivative 16) 36b of(Figure oxacalix[3]arene 16) 36b 31of, oxacalix[3]arene 31, by O-alkylation at the lower rim of 31 and that these molecules were useful for oxacalix[3]areneby O-alkylation at31, the by lowerO-alkylation rim of 31at theand lower that theserim of molecules 31 and that were these useful molecules for the were recognition useful for of the recognition of α-amino acid derivatives [58]. theα-amino recognition acid derivatives of α-amino [58 acid]. derivatives [58].

FigureFigure 16. 16. SynthesisSynthesis of ofchiral chiral oxac oxacalixarenealixarene MCP MCP analogues analogues 36a36a–b– showingb showing the the chiral chiral atropisomers. atropisomers. Figure 16. Synthesis of chiral oxacalixarene MCP analogues 36a–b showing the chiral atropisomers. FigureFigure adapted adapted from from reference reference [58]. [58 ]. Figure adapted from reference [58]. InIn a avery very recent recent contribution, contribution, Marcos Marcos andand co-workersco-workers reportedreported their their latest latest results results with with cation cation and In a very recent contribution, Marcos and co-workers reported their latest results with cation andanion anion ditopic ditopic receptors receptors based based upon upon trisubstituted trisubstituted derivatives derivatives of 31 withof 31 lower-rim with lower-rimO-tert-butylurea, O-tert- and anion ditopic receptors based upon trisubstituted derivatives of 31 with lower-rim O-tert- butylurea,phenylthiourea phenylthiourea or phenylurea or functionalities, phenylurea whichfunctionalities, are connected which to the hexahomotrioxacalix[3]areneare connected to the butylurea, phenylthiourea or phenylurea functionalities, which are connected to the hexahomotrioxacalix[3]arenescaffold via butyl spacers. [59 scaffold] Both cone viaand butylpartial-cone spacers.conformers [59] Both cone were and obtained partial-cone with the conformers phenylurea hexahomotrioxacalix[3]arene scaffold via butyl spacers. [59] Both cone and partial-cone conformers werebut obtained only partial-cone with theproducts, phenylurea as determined but only partial-cone by solution products, NMR studies as determined and their by binding solution properties NMR were obtained with the phenylurea but only partial-cone products, as determined by solution NMR studiestowards and several their binding relevant properties anions with towards different several geometries relevant were anions assessed with different by proton geometries NMR titrations. were studies and their binding properties towards several relevant anions with different geometries were assessedThe cone byconformation proton NMR oftitrations. the trisphenylurea The cone conformation derivative was of the also tris confirmedphenylurea by derivative single-crystal was also X-ray assessed by proton NMR titrations. The cone conformation of the trisphenylurea derivative was also confirmedcrystallography by single-crystal and also provedX-ray crystallography to be the best an d anion also proved receptor, to be with the the best highest an anion affi receptor,nity being confirmed by single-crystal X-ray crystallography and also proved to be the best an anion receptor, withshown the towardhighest theaffinity trigonal being planar shown acetate toward and benzoatethe trigonal anions planar (log acetateKassoc =and4.12 benzoate and 4.00, anions respectively) (log withamongst the highest the spherical, affinity linear being and shown tetrahedral toward anions the trigonal tested. planar It also acetate proved and to be benzoate an effective anions ditopic (log Kassoc = 4.12 and 4.00, respectively) amongst the spherical, linear and tetrahedral anions tested. It also Kassoc = 4.12 and 4.00, respectively) amongst the spherical, linear and tetrahedral anions tested. It also provedreceptor to forbe severalan effective biogenic ditopic amine receptor hydrochlorides for several monoamine biogenic amine neurotransmitters hydrochlorides and monoamine trace amine proved to be an effective ditopic receptor for several biogenic amine hydrochlorides monoamine neurotransmittershydrochlorides, inand di fftraceerent amine solvents. hydrochlorides, in different solvents. neurotransmitters and trace amine hydrochlorides, in different solvents. Jabin’sJabin’s group group [60] [60 compared] compared the the binding binding of of a ase seriesries of of ammonium ammonium ions ions with with two two previously previously Jabin’s group [60] compared the binding of a series of ammonium ions with two previously reportedreported tris- tris-O-amidoO-amido derivatives, derivatives, 34 34[54][54 and] and the thetris-mediatedtris-mediated cryptand cryptand 37 previously37 previously reported reported by reported tris-O-amido derivatives, 34 [54] and the tris-mediated cryptand 37 previously reported by Yamatoby Yamato and coworkers and coworkers [61] in [10%61] inyields, 10% and yields, later and in an later improved in an improved50% yield by 50% Jabin yield and by coworkers Jabin and Yamato and coworkers [61] in 10% yields, and later in an improved 50% yield by Jabin and coworkers1 [62].coworkers Both of these [62]. Bothreceptors of these are receptorslocked in cone are locked-conformations in cone-conformations (Figure 17) and (Figure 1H-NMR 17) studies and H-NMR with [62]. Both of these receptors are locked in cone-conformations (Figure 17) and 1H-NMR studies with bothstudies formed with endo-complexes both formed endo-complexes with seventeen with different seventeen primary different ammonium primary ion ammonium guests, including ion guests, both formed endo-complexes with seventeen different primary ammonium ion guests, including biomolecules,including biomolecules, even in protic even media. in protic media. biomolecules, even in protic media.

Figure 17. Structures of hexahomotrioxacalix[3]arene-analogue-MCPs 34 and 37. Figure 17. Structures of hexahomotrioxacalix[3]arene-analogue-MCPs 34 and 37. Figure 17. Structures of hexahomotrioxacalix[3]arene-analogue-MCPs 34 and 37.

Molecules 2020, 25, 4202 15 of 19 Molecules 2020, 25, x FOR PEER REVIEW 15 of 19

The ammonium ions of each of these guests inserted deeply into the polyaromatic cavity of the The ammonium ions of each of these guests inserted deeply into the polyaromatic cavity of + host receptor molecules. The NH3 +moieties were situated very close to the 18-atom lower-rim the host receptor molecules. The NH3 moieties were situated very close to the 18-atom lower-rim macrocyclic plane, forming H-bonds with the three oxygen atoms of the macrocycle. The overall macrocyclic plane, forming H-bonds with the three oxygen atoms of the macrocycle. The overall topological complementarity between primary ammonium ions and the two cavity-based receptors topological complementarity between primary ammonium ions and the two cavity-based receptors resulted in the previously unreported complexation specificity for the primary ammonium ions over resulted in the previously unreported complexation speciﬁcity for the primary ammonium ions over the secondary, tertiary and quaternary ones that were tested in this study. The authors were able to the secondary, tertiary and quaternary ones that were tested in this study. The authors were able to take advantage of this and demonstrated selective liquid–liquid extraction of primary ammonium take advantage of this and demonstrated selective liquid–liquid extraction of primary ammonium salts from water solutions and for the selective recognition of lysine-containing peptides, with salts from water solutions and for the selective recognition of lysine-containing peptides, with obvious obvious potential for peptide sensing. Interestingly, also, 34 showed better binding than 37 potential for peptide sensing. Interestingly, also, 34 showed better binding than 37 presumably since presumably since the capping reduced the flexibility for the polyaromatic cavity to accommodate the the capping reduced the ﬂexibility for the polyaromatic cavity to accommodate the guests. guests. To date, there is only one report of a 2-naphthol ring-analogue of 31, namely oxacalix[3]naphthalene To date, there is only one report of a 2-naphthol ring-analogue of 31, namely 38, which has its naphthol units linked by -CH2OCH2- bridges and can be considered to be an example oxacalix[3]naphthalene 38, which has its naphthol units linked by -CH2OCH2- bridges and can be of a [3.3.3]metanaphthalenophane analogue of the more common [3.3.3]homooxacalixarenes described considered to be an example of a [3.3.3]metanaphthalenophane analogue of the more common above. This compound that was reported in 2001 by our group, was formed in 25% yield along [3.3.3]homooxacalixarenes described above. This compound that was reported in 2001 by our group, with its unsymmetrical regioisomer in lower yield, via a fragment-based approach in which the was formed in 25% yield along with its unsymmetrical regioisomer in lower yield, via a fragment- linear precursor underwent cyclo-condensation under acidic conditions [63] similar to those described based approach in which the linear precursor underwent cyclo-condensation under acidic conditions Hampton [51]. Only a limited study of its complexation properties with metal ions was conducted; [63] similar1 to those described Hampton [51]. Only a limited study of its complexation properties however, a H NMR study of its complexation properties with C60 fullerene was reported; additionally, with metal ions was conducted; however, a 1H NMR study of its complexation properties with C60 it formed a solid state 2:1 supramolecular complex in its cone conformation with C60 (Figure 18)[64] in fullerene was reported; additionally, it formed a solid state 2:1 supramolecular complex in its cone contrast to the 1:1 complexes observed for C60 with 31 and several derivatives thereof reported earlier conformation with C60 (Figure 18) [64] in contrast to the 1:1 complexes observed for C60 with 31 and by Tsubaki et al. [65]. several derivatives thereof reported earlier by Tsubaki et al. [65].

Figure 18. Hexahomotrioxacalix[3]naphthalene 38 and the single-crystal X-ray structure of its 2:1

complexFigure with18. Hexahomotrioxacalix[3]naphthalene fullerene-C60. Figure adapted from Reference38 and the [64 single-crystal]. X-ray structure of its 2:1 complex with fullerene-C60. Figure adapted from Reference [64]. 6. Conclusions 6. ConclusionsIn this review article, we have focused mainly upon the synthesis, structure and conformationalIn this review properties article, ofwe calixarene-analogous have focused mainly metacyclophanes,upon the synthesis, which structure contain and threeconformational aromatic rings.properties These moleculesof calixarene-analogou can be considereds metacyclophanes, to be analogues ofwhich the relatively contain less-knownthree aromatic “calix[3]arenes”. rings. These Thismolecules group ofcan molecules be considered also encompasses to be analogues homocalix[3]arenes of the relatively less-known and homooxacalix[3]arenes “calix[3]arenes”. and This can group be consideredof molecules as homocalix[3]arene- also encompasses and homocalix[3]arenes homooxacalix[3]arene-analogous and homooxacalix[3]arenes metacyclophanes. and Tocan date, be theconsidered latter, including as homocalix[3]arene- their supramolecular and homooxacalix[3]arene-analogo properties, have been the mostus extensivelymetacyclophanes. studied. To Thisdate, reviewthe latter, highlights including the origins,their supramol synthesis,ecular structural properties, aspects have including been the their most inherent extensively chirality, studied. and some This ofreview the diﬀ highlightserent modiﬁcations the origins, that synthesis, are possible structural with these aspects molecules including as a group their that inherent can lead chirality, to diverse and applicationsome of the possibilities. different modifications We have mostly that consideredare possible and with cited these the molecules more recent as literaturea group that that can has lead been to publisheddiverse application and, where possibilities. available, the We more have recently mostly publishedconsidered reviews. and cited The the supramolecular more recent literature properties that ofhas the been new published synthetic homocalix[3]arene-analogousand, where available, the more metacyclophanes, recently published which reviews. the The Yamato supramolecular group has mainlyproperties been of focused the new on, synthetic however, homocalix[3]arene have been untapped-analogous and will bemetacyclophanes, subjected to further which investigation. the Yamato group has mainly been focused on, however, have been untapped and will be subjected to further investigation.

Funding: This research received no external funding.

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Funding: This research received no external funding. Acknowledgments: M.M.I. and T.Y. thank the OTEC at Saga University for financial support. This work was performed under the Cooperative Research Program of “Network Joint Research Center for Materials and Devices (Institute for Materials Chemistry and Engineering, Kyushu University)”. S.R. would like to thank A. Alodhayb and the Deanship of Scientific Research, King Saud University, Saudi Arabia, ongoing support. Conflicts of Interest: The authors have no conflicts of interest to declare.

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