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

molecules 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,

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