Olefin Metathesis Reaction as a Locking Tool for Macrocycles and Mechanomolecules Construction

Introduction

The metathesis reaction has emerged as one of the most powerful tool for the formation of C-C bonds in organic chemistry and materials science. This prominent role has been awarded with the Nobel Prize in Chemistry 2005 "for the development of the metathesis method 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 starts with the formation of a metal-carbene species, which evolves to a metallacyclobutane by a [2+2]-cycloaddition reaction and which then cycloreverts, giving rise to a 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. Moreover, the ring-opening metathesis polymerization (ROMP) and the acyclic diene metathesis polymerization (ADMET) are attractive methods to synthesize functional polymers and copolymers with preorganized architectures.

In particular, the reaction effectiveness as a locking tool for the efficient construction of complex cyclic targets, such as calixarene-based macrocycles or polymers containing these privileged moieties, and mechanically interlocked structures (MIMs), arises from the intrinsic high functional groups specificity and good stability of the alkene-moieties, and from the reactivity of Ru-based catalysts. Specially, a significant advantage in the MIMs construction, in terms of increasing the post-modification yields during the template-directed synthesis, has emerged. Despite this, the disadvantage is the control over the stereochemistry of the newly double bond formed and the finding of appropriate reaction conditions to maximize the yields and minimize the formation of by-products. The development of a wide variety of well-defined Ru-alkylidene catalysts contributed to build up the above-mentioned macromolecular architectures by olefin metathesis. Among the most investigated catalysts, the 1st and the 2nd generation Grubbs catalysts (namely, G1ST and G2ND)as well as the phosphine-free 2nd generation Hoveyda-Grubbs catalyst (HG2ND) have been extensively employed (chart 1). Key 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 until February 2018, focuses on the synthetic approaches of complex structures, from macrocycles to mechanomolecules, by several olefin metathesis transformations. We have organized it in chapters by classes of cavitand and molecular-level compounds so that the reaction conditions used can be compared. Since the choice of the catalyst, solvent, temperature, concentration, and reaction time is crucial in these processes, we summarize on the base of structural similarities the reaction conditions successfully used.

Synthetic applications of intra- and inter-molecular metathesis reaction to construct calixarene-based macrocycles

Calixarenes and resorcarenes are macrocyclic molecules containing phenolic rings bridged by methylene groups renowned for their ability to form inclusion complexes or act as molecular scaffolds (chart 2). These macrocycles are studied in areas such as catalysis, molecular recognition, drug delivery, sensing and devices. Elaborate molecular and supramolecular chemistry of these versatile molecules have been developed in order to extend their application into previously unexplored fields. Very complex synthetic routes, including the preparation of suitable templates to be covalently or non-covalently linked to the reactant species, have been required to build up sophisticated architectures. In particular, the preorganization of the starting macrocycle, with an increased rigidity of its scaffold, has been essential to obtain bridged-ring structures by intra- or inter-molecular cyclizations.

In particular, olefin metathesis reaction proved to be a very efficient route to achieve the synthesis of several novel cage and huge calixarene- or resorcarene-based macrocycles with more than 100 atoms and high-molecular-weight polymers.

Olefin metathesis locking of calixarene-based macrocycles

Early example in using RCM reaction for the preparation of bridged-ring calix[4]arenes was reported by McKervey et al. in the 1998’s. In particular, the cone isomer 1a, in which the diphenol-diether groups are all-cis in the lower part of the macrocycle, was submitted to olefin metathesis using 4-8 mol% of the G1ST catalyst (scheme 2a). The reaction afforded the bridged compound 2a (57%) as a mixture of E/Z isomers. Accordingly, the conformationally more flexible dimethyl ether 1b underwent intra-molecular metathesis to give 2b as an E/Z isomeric mixture in 62% yield. When the calix[4]arene alkenyl ether 3 was used as substrate, the reaction gave only the single inter-molecular metathesis product 4 in 53% yield due to the higher steric strain associated with a shorter intramolecular bridge on the lower rim (scheme 1b). Intra-molecular RCM macrocyclization also occurred for the substrates 5a-c, in which the two distal alkene and the ester moieties are all in the cone conformation, affording the bridged 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 the cone isomer 7, a precursor with four alkene groups on the lower rim (scheme 3). The dimeric compound 8 (65%) was obtained as the main product, coming from a combination of inter-molecular and intra-molecular metathesis reaction, along with the monomeric ones 9-10.

Moreover, the authors envisaged the RCM macrocyclization in two different solvent systems, starting from the upper rim p-allyl calix[4]arene 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%), whereas in dichloromethane the only product isolated was the trimer 15 arising from macrocyclization of the linear trimer 13.

On the contrary, the tetraester analougue 11b under similar reaction conditions yielded the single monomeric product 16 in 76% yield.

In order to evaluate how calixarene conformation can affect the metathesis products distribution, the authors carried out the reaction on substrates 17 and 19 (scheme 6), both as 1,3-alternate isomers. The intra-molecular cyclization products 18 and 20 were selectively obtained in 76% (as Z geometrical isomer) and in 95% (as 1:1 mixture of geometrical 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 afford the desired alkene-bridged calix[4]arene monomers and, further, the ROMP reaction with cyclooctene (COE) and norbornene (NBE) to give the corresponding polymers. Accordingly, the ring closure by RCM of cone isomers 21-23, bearing tert-butyl or adamantyl (Ad) groups at the upper rim and featuring terminal short alkene chains at the lower rim, in the presence of G1ST catalyst led to the formation of the corresponding alkene-bridged calixarenes 24-26 in excellent yields (85%-100%).

Notably, the length of the bridge strictly determined the single configuration (either trans or cis) of the newly cyclic olefin obtained. It was also observed how the methylation reaction of the trans isomers (24 and 26) caused a conformational instability affording a dynamic mixture of 1,3-alternate (27a-alt and 28a-alt), partial cone (27b-paco) and cone (28b-cone) conformers.

With regard to the polymerization step, the alkene-bridged macrocycles thus obtained were submitted to ROMP reaction in the presence of COE and/or NBE comonomers by utilizing different G2ND catalyst loadings and reaction times.

The conformational properties of calixarene scaffold proved to be key determinants of polymer mechanical features. Accordingly, the shorter-bridged macrocycle 24 showed enhanced ROMP reactivity compared to the longer-bridged calixarene 25, due to the higher ring strain. An high-molecular-weight copolymer P(24), with a better calixarene incorporation was thus achieved using catalyst/monomer loadings of 1/300. The resulting polymer proved to be an elastomer at room temperature, due to the semicrystalline nature of the polycyclooctene domain, with a melting temperature (Tm) of 44 В°C and a subambient glass at the transition temperature (Tg) of 9 В°C. In this case, ROMP reaction showed probably higher reactivity and calixarene incorporation, suggesting how the macrocycle conformations can affect the polymerization rate. In particular, the monomers in the 1,3-alternate conformation were less reactive with respect to the others, yielding lower calixarene incorporation, probably due to the less accessible double bond to the catalyst. Additionally, the steric indrance of adamantyl group made the monomer bulkier and less reactive.

The synthesis of more complex calixarene-based macrocycles, such as multi-macrocyles, was accomplished using the metathesis reaction via reversible noncovalent bonds methodology. The tetratosylurea calix[4]arenes were successfully used as leading substrates to rearrange the calix[4]arenes containing four or eight П‰-alkenyl groups in an heterodimeric way. Taking into account the ability of the 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 the presence of G1ST catalyst (scheme 9). After hydrogenation, the corresponding multi-macrocyclic derivatives 31a,b and 32a,b were obtained in good yields (65-90%).

As an extention of their work, Bӧhmer et al. reported the preparation of huge macrocycles 8 up to 100 atoms using the above-mentioned template strategy. Thus, the RCM of calixarene 29 in an heterodimeric complex (scheme 10) with the tetraurea calixarene derivatives afforded, after hydrogenation and template removal, the tetramacrocyclic derivatives 34 in good yields (60-95% after purification). Subsequent hydrolysis of the four urea moieties in acetic acid yielded the macrocycles 35 (yield > 50%). The 1H NMR spectral data of such compounds were in agreement with cone and flattened cone conformations, respectively.

Olefin metathesis locking of resorcarene-based macrocycles

Wei et al. published interesting results on that resorcarene-encapsulated gold nano-clusters (GN) can be engaged in nondesorptive shells by using olefin metathesis reaction. Previously, despite the capability of resorcarene scaffold 36 to stabilize gold nanoparticle dispersions 36-GN in mesitylene solution (1mM), the authors showed how increasing the solvent polarity or diluting the resorcarene concentration the macrocycles desorption occurred rapidly. In order to convert the fragile surfactant layer into a robust, nondesorptive shell, they reasoned that the resorcarene coating 36-GN was sufficiently dense to promote the inter-molecular cross-linking by olefin metathesis transformation. Accordingly, when 36-GN dispersion was treated with 30 mol% of G1ST catalyst, cross-linked resorcarene shells and, therefore, particles 35-P with enhanced toughness were obtained.

Botta et al. performed a Lewis acid-catalysed synthesis of newly resorcarene stereoisomers, in which the П‰-unsaturated function on the long alkyl chains allowed their incorporation into oligomeric architectures via olefin metathesis ligation. Reaction of undecenyl resorcarenes 37a and 37b afforded different metathesis products upon exposure to Grubbs catalyst. In particular, the chair stereoisomer, which featured the simple arrangement of the four alkyl chains, was chosen as a suitable substrate to set up the best reaction conditions, changing the substrate concentrations and catalyst loadings. An intermediate substrate concentration (namely 3.0 Г— 10-3 M) and a G2ND catalyst loading of 10 mol% were selected, since they allowed the formation of cyclic alkenes by both intra- and inter-molecular metathesis (namely, bicyclic alkene 38 and dimer 39).

According to the literature, bicyclic alkene occured by two almost contemporary RCM reaction while, as clearly demonstrated by submitting 37a to the same reaction condition, the dimer was formed by ROCM reaction of two molecules of 37a. Since the series of [2+2] cycloadditions and retro[2+2]cycloadditions that make up the pathways of ruthenium-catalized metathesis reactions was well-established, the mechanistic aspects of alkene metathesis was explored. Accordingly, Botta et al. described the detection of a Ru-carbene-resorcarene complex produced, as a key intermediate, during the progress of olefin metathesis reaction carried out on bicyclic olefin 38 with G1ST catalyst. Although the olefin metathesis reaction on the chair stereoisomer 37a was carried out with the G2ND catalyst, for the investigation of mechanistic pathway involved in the dimer 39 formation from 38, the G1ST was used. NMR techniques were able to identify the complex 38[Ru] as a key intermediate in the ROCM sequence of reactions, giving definitive proof of the previously hypothesized mechanism. The analytical approach in combination with organic reaction skills enabled the development of a quantitative NMR protocol for the characterization of the reaction outcome.

On the other hand, in the case of the cone conformer 37b, the proximity of the four side chains allowed the synthesis of both intra- and inter-molecular peculiar metathesis products.

The major product double-spanned resorc[4]arene 41 showed a strong propensity to self-assembly in the solid state as a supramolecular trio of heterochiral dimers.

Beside highly strained and unstrained olefins, macrocycles themselves proved to be suitable substrates for macrocyclization reactions, according to a ROCM mechanism, and the appropriate substrate/catalyst ratios can be relevant for the modulation of the macrocycle size.

Synthetic applications of intra- and inter-molecular metathesis reaction to construct mechanomolecules

Over the years, the design and synthesis of mechanically interlocked molecules (MIMs), in which the components are non-covalently bonded, have generated great interest not only due to their fascinating architecture, but especially for their potential applications. Notably, their use ranges from chemistry and biology, as catalysts and drug delivery systems, to materials research, as molecular motors and switches [azides]. Various types of MIMs such as catenanes, based on interconnected not directly bonded rings, rotaxanes, based on a ring threaded over an acyclic ligand with the bulky groups at each end, and knots, based on mono continuous ’threads’ differently intertwined, were reported.