Covalent macrocycle synthesis

This chapter deals with formation of cyclic 2D and 3D structures in solution by self-assembly of two or more components using hydrogen bonds as the major interactions. Obviously, the formation of a defined supramolecular aggregate stabilized by non-covalent forces is a thermodynamically driven process which reflects a balance between enthalpy and entropy. Consequently, the product of a non-covalent macrocyclic synthesis must be evaluated and predicted in terms of thermodynamic minima in an equilibrium mixture. 

Scheme 10.2 Covalent template synthesis of an 18-membered macrocycle.

Most of the systems described in Chapter 5 contain small- or medium-sized or multinuclear benzenoid and non-benzenoid arenes. In Chapter 6, Hoger gives an overview over the mastery of the synthesis of macro- and megacycles. He shows different approaches towards shape-persistent macrocycles and carefully examines and discusses selected examples that display the advantages and disadvantages of macrocycle synthesis under kinetic and thermodynamic control. The template approach (both supramolecular and covalent) towards functionalized rings is also discussed and introduces a strong motif of supramolecular chemistry, which is much further developed but in a more polymer-oriented topic, in the next chapter. 

Cucurbituril, Its Homologues, and Derivatives, p. 390 The Diphenylmethane Moiety, p. 452 Interpenetration, p. 735 Macrocycle Synthesis, p. 830 Rotaxanes and Pseudorotaxanes. p. 1194 Self-Assembly Definition and Kinetic and Thermodynamic Considerations, p. 1248 Self-Assembly Terminology, p. 1263 Strict Self-Assembly and Self-Assembly with Covalent Modifications, p. 1372 The Template Effect, p. 1493... 

The technique is applied to link non-cyclic ligsons together to form macrocyclic systems. The ligson heteroatoms have weak donor properties, so that centres such as transition and rare earth element, alkali, and alkaline metal ions are not able to play a template role in synthesis from the relevant species. The metalloids are able to form covalent bonds to weak donors and are thus suitable for the realisation of the required reactions. Organo-element compounds of appropriate metals are used for covalent-template synthesis. These combine the coordination ability of metals and the substitution ability of organic moieties, and therefore facilitate the wide range of chemical conversions involved in template processes. The basic feature of the reactions considered here is the weakness of bonds between matrix and ligsons, so that the synthesis of the free macrocyclic compound may be completed by release of the template. 

Until now most covalent-template syntheses have been carried out to form macro-cyclic polylactones [1, 6-16]. The synthesis of tetralactones L1562-L1567 represented in Scheme 7-1 has been achieved in 30-85% yield [7, 10]. Other cyclic stannoxanes are also suitable for covalent-template synthesis of macrocyclic tetralactones, for example L1568 (Eq. 7.1) [10]. Tetralactones L1569 (Eq. 7.2) and L1570 (Eq. 7.3) are synthesised in an analogous way [10]. 

Organosilicon derivatives can be used for the covalent-template synthesis of macrocyclic polylactams [28, 29]. The method includes conversion of acyclic dia-... 

Nitrenium ions have been applied to the synthesis of macrocycles and other medicinally interesting compounds. The most successful reactions have been in cases where the nitrenium ion is covalently tethered to its intended target. Further efforts aimed at modulating the selectivity of these intermediates would increase their synthetic utility. 

A related synthesis of macrocyclic tetralactones should be mentioned here. By using covalent tin templates, macrocycles containing four lactone groups can be formed in an essentially one pot reaction (80CC176). 

Sulfonamide groups incorporated in rotaxanes enable the construction of new topological assemblies provided with mechanically and covalently bonded subunits. Methylation of a [2]rotaxane containing a sulfonamide unit in the axle revealed that the substitution reaction is not sterically hindered by the macrocycle. Similar to the synthesis of the pretzelane 96, the two sulfonamide groups of rotaxane 80m were bridged with 95 to form 100 in 71% yield (Figure 39) [46]. The additional covalent bond converts the former [2]rotaxane into a [l]rotaxane and reduces the mobility of the wheel along the axle. Rotaxanes 80m and 100 are his-... 

It was not only for the basic scientific knowledge but also for the new challenges in the synthesis and the beauty of the final structures that nearly half a century ago, chemists started to investigate intertwined macrocyclic supramolecules such as rotaxanes and catenanes [4], Earlier, when the syntheses of such structures were at their infancy, the routes to such systems were troublesome. The statistical methods [5] proved to be low-yield processes. Multistep procedures [6] involving a covalent junction which is formed between two parts that are needed to stay together until the structure is complete were not convenient as well. The use of non-covalent templates thus provided a more straightforward and high-yield approach to the problem. 

In this article the design, synthesis and d-block metal ion chemistry of some more recent examples of covalently-linked, macrocyclic ligand systems are discussed. The use of macrocyclic rings in such systems is not surprising given that the resulting macrocyclic complexes often exhibit both enhanced kinetic and thermodynamic stabilities and hence tend to retain their integrity under a variety of conditions - a lesson that nature knows well. 

The lanthanide phthalocyanine complexes, obtained by conventional methods starting from metal salts at 170-290°C and phthalonitrile (Example 26), contain one or two macrocycles for each metal atom [5,6,8,63,82,84-98]. Thus, according to Refs. 6,63, and 85, the complexes having compositions LnPc2H, XLnPc (X- is halide anion), and Ln2Pc3 (a super-complex ) were prepared from phthalonitrile as a precursor the ratio of the reaction products depends on the synthesis conditions and the metal nature. The ionic structure Nd(Pc)+Nd(Pc)2 was suggested [85] and refuted [63] for the neodymium super-complex Nd2Pc3 the covalent character of the donor-acceptor bonds in this compound and other lanthanide triple-decker phthalocyanines was proved by the study of dissociation conditions of these compounds [63]. 

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