IndexIntroductionCalixarene-based olefin macrocycle blocking metathesisSynthetic applications of intra- and inter-molecular metathesis reaction to build mechanomolecules IntroductionThe metathesis reaction has emerged as one of the most powerful tools for CC bond formation in organic chemistry and materials science. This leading role was rewarded with the 2005 Nobel Prize in Chemistry "for the development of the method of metathesis in organic synthesis" shared by three chemists: Yves Chauvin, Robert H. Grubbs and Richard R. Schrock. The mechanism originally proposed by Chauvin et al. is generally accepted and begins with the formation of a metal-carbene species, which evolves into a metallacyclobutane via a [2+2] cycloaddition reaction and which then cycloreverts, giving rise to new olefin and metal-carbene species. In the specific case of olefin metathesis transformations (Scheme 1), cross-metathesis (CM) and ring-closing metathesis (RCM) are routinely used for the synthesis of small molecules and macrocyclic systems. Furthermore, ring-opening metathesis polymerization (ROMP) and acyclic diene metathesis polymerization (ADMET) are attractive methods to synthesize functional polymers and copolymers with preorganized architectures. Say no to plagiarism. Get a tailor-made essay on "Why Violent Video Games Shouldn't Be Banned"? Get an original essay In particular, the effectiveness of the reaction as a blocking tool for the efficient construction of complex cyclic targets, such as calixarene-based macrocycles or polymers containing them privileged moieties and mechanically interlocked structures (MIMs), stems from the intrinsic specificity of the high functional groups and the good stability of the alkene fractions and the reactivity of the Ru-based catalysts. In particular, a significant advantage emerged in the construction of MIMs, in terms of increased post-modification yields during model-directed synthesis. Despite this, the disadvantage is the control over the stereochemistry of the newly formed double bond and the search for adequate reaction conditions to maximize yields and minimize the formation of by-products. The development of a wide variety of well-defined Ru-alkylidene catalysts has helped build the aforementioned macromolecular architectures via olefin metathesis. Among the most studied catalysts, the first and second generation Grubbs catalysts (i.e., G1ST and G2ND), as well as the second generation phosphine-free Hoveyda-Grubbs catalyst (HG2ND) have been widely used (Graph 1). The main advantages of these catalysts are their tolerance to a range of functional groups and reaction conditions and their stability to air and moisture. The present review, which covers the literature up to February 2018, focuses on synthetic approaches of complex structures, from macrocycles to mechanomolecules, via different metathesis transformations of olefins. We have organized it into chapters by classes of cavitands and compounds at the molecular level so that we can compare the reaction conditions used. Since the choice of catalyst, solvent, temperature, concentration and reaction time is crucial in these processes, we summarize the successfully used reaction conditions on the basis of structural similarities. Synthetic applications of the intra- and intermolecular metathesis reaction to construct calixarene-based macrocycles calixarenes and resorcarenes are macrocyclic molecules containing phenolic rings linked by methylene groups renowned fortheir ability to form inclusion complexes or act as molecular scaffolds (Graph 2). These macrocycles are studied in areas such as catalysis, molecular recognition, drug delivery, sensing and devices. The elaborate molecular and supramolecular chemistry of these versatile molecules was developed in order to extend their application to previously unexplored fields. Very complex synthetic routes were required to build sophisticated architectures, including the preparation of suitable templates to bind covalently or non-covalently to the reacting species. In particular, the preorganization of the initial macrocycle, with increased rigidity of its scaffold, was essential to obtain bridging ring structures via intra- or inter-molecular cyclizations. In particular, the olefin metathesis reaction has proven to be a very efficient way to achieve the synthesis of several new cages and huge calixarene or resorciene-based macrocycles with more than 100 atoms and high molecular weight polymers. Blocking olefin metathesis of calixarene-based macrocyclesThe first example in the use of the RCM reaction for the preparation of ring-bridged calyxes [4]arenes was reported by McKervey et al. in the 98s. In particular, cone isomer 1a, in which the diphenol-diether groups are all cis at the bottom of the macrocycle, was subjected to olefin metathesis using 4–8 mol% of the G1ST catalyst (Scheme 2a). The reaction provided the bridging compound 2a (57%) as a mixture of E/Z isomers. Accordingly, the conformationally more flexible dimethyl ether 1b was subjected to intramolecular metathesis to give 2b as an isomeric E/Z mixture in 62% yield. When calix[4]arene alkenyl ether 3 was used as the substrate, the reaction produced only the single intermolecular metathesis product 4 in 53% yield due to the larger steric strain associated with a shorter intramolecular bridge at the bottom edge (scheme 1b). RCM intramolecular macrocyclization also occurred for substrates 5a–c, where the two distal portions of alkenes and esters are all in the cone conformation, giving the bridging products 6a (79%), 6b (35%), and 6c (76 %), respectively, each as a mixture of E/Z isomers. The application of RCM ligation was extended to cone isomer 7, a precursor with four alkene groups at the bottom edge (Scheme 3). As the main product, the dimeric compound 8 (65%) was obtained, coming from a combination of intermolecular and intramolecular metathesis reactions, together with the monomeric ones 9-10. Furthermore, the authors predicted macrocyclization of RCM in two different solvent systems, starting from the p-allyl calix[4]arene top-edge substrate 11a. In particular, the reaction carried out in benzene led to the formation of dimer 12 (25%), trimer 13 (20%) and cyclodimer 14 (5%), while in dichloromethane the only isolated product was trimer 15 deriving from macrocyclization of the linear trimer 13. In contrast, the tetraester analogue 11b under similar reaction conditions produced the single monomeric product 16 in 76% yield. To evaluate how the conformation of calixarene can influence the distribution of metathesis products, the authors performed the reaction on substrates 17 and 19 (Scheme 6), both as 1,3-alternative isomers. The intramolecular cyclization products 18 and 20 were selectively obtained in 76% (as a Z geometric isomer) and 95% (as a 1:1 mixture of geometric isomers), respectively. A combination of RCM-ROMP was successfully reported by Yang and Swager for the synthesis of calix[4]arene-based polymers. The synthetic strategy involved the RCM reaction to obtain the desired calix[4]arene monomers with alkene bridges and,furthermore, the ROMP reaction with cyclooctene (COE) and norbornene (NBE) to provide the corresponding polymers. Consequently, ring closure by RCM of the 21-23 cone isomers, bearing tert-butyl or adamantyl (Ad) groups on the upper edge and characterized by short terminal alkene chains on the lower edge, in the presence of the G1ST catalyst has led to the formation of the corresponding 24-26 alkene-bridged calixarenes in excellent yields (85%-100%). In particular, the length of the bridge strictly determined the single configuration (trans or cis) of the new cyclic olefin obtained. It was also observed how the methylation reaction of the trans isomers (24 and 26) caused a conformational instability providing a dynamic mixture of 1,3-alternating conformers (27a-alt and 28a-alt), partial cone (27b-paco ) and cone (28b-cone). Regarding the polymerization step, the thus obtained alkene-bridged macrocycles were subjected to the ROMP reaction in the presence of COE and/or NBE comonomers using different G2ND catalyst loadings and reaction times. The conformational properties of the calixarene scaffold proved to be key determinants of the mechanical characteristics of the polymers. Accordingly, the shorter-bridged macrocycle 24 showed greater ROMP reactivity than the longer-bridged calixarene 25, due to the higher ring tension. A high molecular weight P(24) copolymer was thus obtained, with improved incorporation of calixarene, using catalyst/monomer loadings of 1/300. The resulting polymer was found to be an elastomer at room temperature, due to the semicrystalline nature of the polycyclooctene domain, with a melting temperature (Tm) of 44 °C and a subambient glass at the transition temperature (Tg) of 9 °C. In this case, the ROMP reaction likely showed increased reactivity and incorporation of calixarene, suggesting how macrocycle conformations may influence the rate of polymerization. In particular, the monomers in the 1,3-alternating conformation were less reactive than the others, giving rise to a lower incorporation of calixarene, probably due to the less accessible double bond with the catalyst. Furthermore, the steric indrance of the adamantyl group made the monomer bulkier and less reactive. The synthesis of more complex calixarene-based macrocycles, such as multi-macrocils, has been achieved using the metathesis reaction via reversible noncovalent bonding methodology. Tetratosylurea calix[4]arenes have been successfully used as major substrates to rearrange calix[4]arenes containing four or eight П‰-alkenyl groups in a heterodimeric manner. Taking into account the ability of tetraurea calix[4]arenes to form supramolecular dimeric capsules (Chem.Commun., 2004, 1268“1269), the RCM reaction was carried out in apolar solvent using a mixture of 29 and 30a (or 30b) in presence of the G1ST catalyst (diagram 9). After hydrogenation, the corresponding multi-macrocyclic derivatives 31a,b and 32a,b were obtained in good yields (65–90%). As an extension of their work, Bö§hmer et al. reported the preparation of massive macrocycles of 8 to 100 atoms using the above-mentioned template strategy. Thus, the RCM of calixarene 29 in a heterodimeric complex (scheme 10) with the tetraurea derivatives calixarene provided, after hydrogenation and removal of the template, the tetramacrocyclic derivatives 34 in good yields (60–95% after purification ). Subsequent hydrolysis of the four urea moieties in acetic acid produced macrocycles 35 (>50% yield). The 1H NMR spectral data of these compounds were in agreement with the cone and flattened cone conformations, respectively. Blocking olefin metathesis of resorciene-based macrocyclesWei et al. they have.