Resorc arene

Abstract. Due to the nonplanarity of the basic In-metacyclophane system, calixarenes and resorc-arenes can be transformed into molecules with inherent chirality. Various attempts to achieve this goal are reviewed. Special emphasis is given to derivatives with Cn-symmetry, including derivatives of spherand calixarenes and other calixarene-like macrocycles. 

Cavitands are originally host compounds based on the resorc[4]arene [35] platform obtained from the condensation of resorcinol with aldehyde [36,... 

The cavitands are essentially synthesized from their resorc[4]arene precursors which are readily obtained by resorcinol condensation with aldehydes. The main feature comes from the different configurations that are expected for this tetrameric species and the relative thermodynamical stability of each isomer, which has been widely investigated by several authors. In addition, the conformational mobility of the resorc[4]arene molecules will depend on substitution at the upper and lower rims [28, 36, 40, 41]. The first attempt to synthesize a phosphorus bridged cavitand was to treat resorc[4]arene la (1, R=CH3) with phenylphosphonic dichloride or phenylphosphonothioic dichloride. Only inseparable isomer mixtures were obtained and isolation of the desired cavitands was not possible [42]. The first isolated phosphorylated resorcinol-based cavitand was described in 1992 by Markovsky et al., who prepared compound D from la and four equivalents of o-phenylenechlorophos-phate in the presence of triethylamine [43, 44]. For this compound, a tautomeric temperature and solvent dependent equilibrium exists between the spirophosphorane structure and the cyclic phosphate form (Scheme 4). 

The general synthetic route for the preparation of bridged phosphorus cavitand is outlined in Scheme 5. From the resorc[4]arene, bearing various substituents at the lower rim, the cyclization step, which leads to the formation of the four fused eight-membered rings, was performed with three-co-ordinated and four-coordinated phosphorus reagent to give respectively tet-ra-phosphite, tetra-phosphonite, and tetra-phosphate or tetra-phosphonate derivatives. 

The tetra-bridged phosphatocavitands lOa-j (Scheme 11) were obtained by reaction of the corresponding resorc[4]arene with R0P(0)Cl2 (R=aromatic or alkyl group) in acetone in presence of triethylamine as base. In most cases, several isomers due to the different orientation of the P=0 bonds were formed in variable amounts, whereas the iiii and 0000 stereoisomers were not, or only in trace amounts [58-62]. Usually, the iiio isomer is the most abundant compound and the strereoselectivity of the reaction was essentially attributed to the preference of the host molecule to fill the cavity with at... 

Following this strategy, the stereoselective synthesis of the HU stereoisomer of novel tetra-phosphonatocavitands having lower rim functionality has been reported [66, 67]. Cavitands 12c-12f were respectively synthesized from functionalized resorc[4]arenes Ic-lf. The addition of 1-decanethiol to 12f in the presence of 9-borabicyclo[3.3.1]nonane (9-BBN) in THF afforded cavitand 12g in 80 % yield (Scheme 15). 

The use of thiophosphonic chloride reagent did not give clear results and more importantly, the stereoselectivity of the reaction is difficult to control. For instance, the reaction of C6H5P(S)Cl2 with the resorc[4]arene Ic afforded a mixture of isomers of 13, which have been only partially purified by col-... 

In the tetra-bridged phosphocavitands containing four donor P(0)R groups, the P=0 bonds can adopt the inward (f) or outward (o) orientations relatively to the molecular cavity. Only the ini isomer with the four P=0 groups oriented inwards can benefit from both cooperativity of P=0 binding and r-in-teractions with the aromatic cavity of the resorc[4]arene framework [19, 63]. The complexation properties of new iiii tetra-phosphonatocavitands 12b-12d and 12g towards metal ions were characterized by extraction of the metal picrate from water to chloroform solution containing the host compound (Fig. 4). 

We will use the name resorc[4]arene to design the tetrameric product obtained from the condensation of resorcinol and aldehyde also named resorcinarene or resorcino-larene... 

The name cavitand refers to the rigidified bridged resorc[4]arene. lUPAC name for the tetra-briged phosphorus cavitand 5,9,13,17-tetra-R-l,21,23,25-tetrakis-R -2,20 3,19-... 

Fox, 0. D., Dailey, N. K., Harrison, R. G., Structure and small molecule binding of a tetranuclear iron(II) resorc[4]arene-based cage complex. Inorg. Chem. 1999, 38, 5860-5863. 

Pfeiffer, J. and Schurig, V. (1999) Enantiomer Separation of Amino Acid Derivatives on a New Polymeric Chiral Resorc[4]arene Stationary Phase by Capillary Gas Chromatography, J. Chromatogr. A 840, 145-150. 

Although nowadays the term calixarene tends to be used for all [l ]-meta-cyclophanes, this chapter will deal with [l ]-metacyclophanes bearing phenolic OH groups in the intraannular (endo, e.g. calix[ ]arenes) or extraannular (exo, e.g. resorc[4]arenes) position. 

The acid-catalysed reaction of resorcinol with aldehydes leads to cyclic tetra-mers which are grouped in the class of resorc[4]arenes (exo-calixarenes).3 This reaction is quite general with respect to the aldehyde and to the starting resorcinol, which can bear several substituents in the 2-position.15 Niederl and Hogberg showed in a typical example, the synthetic procedure by which an ethanol solution of resorcinol, acetaldehyde and 37% hydrochloric acid maintained at 80 °C for 16 h, afforded 75% of the all cis C-methylresorc[4]arene. A shorter reaction time leads to the kinetic stereoisomer (trans,cis,trans,cis).16 This procedure is general for many aldehydes (Scheme 7.4), but the use of formaldehyde is limited to some special cases.17... 

Bis-resorcarenes, Cahxresordnols methylene-bridged 1383 synthesis of 1381-1384 Resorc[4]arenes 320, 322 Resorcarene-sugar clusters 1418 Resorcinol benzoates, Fries rearrangement of 645... 

A novel synthesis of parent resorc[4]arene and its partial alkyl ethers, J. Stursa, H. Dvorakova, J. Smidrkal, H. Petrickova and J. Moravcova, Tetrahedron Lett., 2004, 45, 2043. 

Scheme 4-7 Reinhoudt s calix[4]arene/resorc[4]arene carceplex 15 guest.

Harrison, R.G. Metal-assembled cobalt(II) resorc[4]arene-... 

Figure 8 Normal (<4A) and deep (>4A) cavitands derived from the rigidification of the resorc[4]arene (4) and calix[4]arene (5) structures with the schematic representation of their cuplike structure.

Similarly, the interaction between a resorc[4]arene cavi-tands and tip-immobilized (tetraorganyl) ammonium guests was studied. The flexible polymer linker ensured that the interaction took place as an identifiable single-molecule interaction. As shown in Figure 10, the most probable rupture force depended logarithmically on the loading rate, in accordance with the Kramers-Bell-Evans model. Ammonium and trimethyl substituted ammonium could be well differentiated. 

Resorc[4]arenes as Preorganized Synthons for Surface Recognition and Host-Guest Chemistry... 

The Construction of the Resorc[4]arene Scaffold by Lewis Acid-Mediated Tetramerization of 2,4-Dimethoxycinnamates... 

The acid-catalyzed condensation between resorcinol and an aliphatic or aromatic aldehyde (Scheme 8.1) represents the classical approach to the preparation of the resorc[4]arene nucleus [1-3], Although the reaction is carried out by heating the reagents to reflux, each aldehyde requires different optimal conditions, while unsubstituted resorcinol is the mostly used counterpart. 

Additional discussions on the chemistry of resorc[4]arene scaffold can be found... 

Our group became interested in the synthesis of these macrocycles, when the resorc[4]arene octamethyl ether 2 (R = Me) was produced by a tetramerization reaction (Scheme 8.2) of ( )-2,4-dimethoxycinnamic acid ester 1 (R = Me) under carefully controlled reaction conditions employing BF3-Et20 as a Lewis acid catalyst [4, 5]. Indeed, this simple reaction allows the design and preparation of several new structures, each one with new physical-chemical features that opened up new research avenues in the field of molecular recognition. 

Depending on the reaction conditions and the nature of the ester side chain in the cinnamates, the resorc[4]arenes can adopt different conformational states, namely, 1,2-altemate, 1,3-altemate, or flattened-cone). In particular, when ( )-2,4-dimethoxycinnamic acid methyl ester 1 was reacted with BF3 Et20 at room temperature, only the 1,2-altemate 2a and flattened-cone 2b stereoisomers were obtained in a 2 3 ratio and 75 % overall yield. In the 1,2-altemate conformation, the assignment of the 12- and 16-OMe signals, by INEPT experiments in conjunction with DIF NOE measurements, allowed to establish the correct stereochemistry at C(14). On the other hand, the presence in the H- and C-NMR spectra of only one signal for both external (H-5) and internal (H-28) aromatic protons and the related carbons, as well as a similar pattern for the methoxy group and the aliphatic... 

In 2013, the tetramerization of ( )-2,4-dimethoxycinnamic acid < -undecenyl ester 10 has been reported by our group (Scheme 8.4). The reaction afforded, under usual reaction conditions, the three stereoisomers 11a, 11b, and 11c, which were assigned as the 1,2-altemate, cone and chair conformations, respectively [8]. The conformation in solution of resorc[4]arenes 11a (1,2-altemate with Cs symmetry) and 11b (cone with C4V symmetry) were assigned by the distributiOTi pattern of the NMR spectral data, whereas the chair conformation of 11c was confirmed by X-ray diffraction analysis, which also showed a peculiar self-assembly behavior in the crystal lattice, forming intercalated hydrophilic and hydrophobic layers (6—7 A thickness) as a consequence of strong CH-jr interactions. 

The undecenyl resorc[4]arene 11c, which featured the simplest pattern of substituents, was afterward submitted to olefin metathesis reactions (see Sect. 8.4). 

Scheme 8.5 Amido-resorc[4]arenes 13a-c from 2,4-dimethoxycmnamic acid amides such as 12...

Notably, not only the 2,4-dimethoxycinnamates underwent the BF3-Et20 mediated tetramerization reaction, and this has proved the versatility of the reaction. In fact, also 2,4-dimethoxycinnamic acid amides such as 12 (Scheme 8.5), derived from the mixed anhydride of 2,4-dimethoxycinnamic acid with 1- or d-vaUne ethyl ester, upon treatment with BF3-Et20 yielded the amido-resorc[4]arenes 13a-C which proved to be chiral for the presence of four axial pendants containing the chiral valine residue [9]. A novel flattened-partial cone conformation was isolated for the first time from the reaction mixture, together with three other stereoisomers (namely, 1,2-altemate, flattened-cone, and chair). The flattened-cone stereoisomer, which was identified by molecular modeling as the most stable, proved to form as minor product in kinetic conditions, and to become the main component of the reaction mixture under more drastic conditions (namely, substrate/ BF3 Et20 = 1 400 M ratio). The chiral amido-resorc[4]arenes 13a-c were obtained in enantiomerically pure forms, as checked by enantioselective HPLC. 

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