Macrocyclization, under thermodynamic control

Scheme 4 Ring—ring equiiibria in a macrocyclization under thermodynamic control.

Since most of the DLs described in the Hterature consist of interconverting linear and cychc species, a deep knowledge of the mles governing macrocyclization under thermodynamic control is crucial to a quantitative analysis of the phenomenology related to DCC. Concepts and results described in Section 3.1 have to be taken into account when a DL is examined in quantitative terms. 

Ercolani G, Mandohni L, Mencarelli P, Roelens S. Macrocyclization under thermodynamic control. A theoretical study and its apphcation to the equihbrium cydooligome-rization of 8-propiolactone. J Hm Chem Soc. 1993 115 3901-3908. 

The use of imines as the dynamic covalent bond significantly augmented the versatility of the thermodynamic approach toward the formation of interlocked systems. Stoddart et al. reported on the synthesis of [2]rolaxanes by the clipping protocol, in which a dialdehyde was used to clip the macrocycle under thermodynamically controlled conditions (Figure 6). In this system, the driving force for the formation of rotaxane 10 is the stabilizing interaction between ammonium ions and crown ethers, which was widely exploited by Stoddart and coworkers. In the first instance, a library of macrocyclic and linear compounds was prepared on condensation of tetraethylene glycol bis(2-aminophenyl)ether 6 and 2,6-diformylpyridine 7. 

A different approach towards shape-persistent macrocydes is macrocycle preparation under thermodynamic control, i.e. if the desired structure is the most stable under the given conditions and the cydization reaction is reversible, one might be able to obtain a single macrocyclic product in quantitative yield although the reaction starts with small building blocks [41, 42],... 

The theoretical treatment for the self-assembly of a molecular entity into rings or cages occurring under thermodynamic control is based on two fundamental physicochemical quantities the effective molarity (EM) of the intramolecular interaction of the cyclic n-mer and the value of the stability constant of the intermolecular interaction (fCinter) [5]. The following formula has been derived by Ercolani and allows calculation of the minimum value of the product fCinterEM to obtain a virtually complete self-assembled macrocycle at certain monomer concentration ... 

Figure 7 Organic Magic rings . Interconversion between macrocycle and catenane under thermodynamic control...

Naturally, the question arises What accounts for the dramatic difference in yields between these processes Macrocyclization under kinetic control, as shown by the Staab example, is clearly not a favorable situation, as evidenced by the low yield of 14a. In contrast, it has been shown that when alkyne metathesis macrocyclization is under thermodynamic control, [n]cycles are the lowest-energy product [64]. ADIMAC of monomer 15a under the conditions shown in Scheme 6.8 generate [6]cycle 16 as the major product, and [5]cycle 17 as a minor product. Gel permeation chromatography (GPC) analysis confirmed that the oligomeric products (both linear and cyclic) that are initially formed in the reaction are consumed over time, and the [5-6]cycles are the major product upon completion. More dramatically, when polymer 15b was subjected to the same conditions, the major products... 

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. 

But in most macrocyclizations, thermodynamic control is not yet possible. These macrocyclizations have therefore been carried out under kinetic control, often using high dilution conditions. Typical reactions are the formation of lactams, for instance, in the second macro-cyclization during the synthesis of concave pyridines 1 by reaction of the macrocyclic diamines 8 with diacid dichIorides. or the reaction of calix[6]arene with... 

The experimental profiles in Fig. 7 impressively reflect the theoretical behaviour of Fig. 4 which is typical of a DL under fuU thermodynamic control. Moreover, the values of EM/ for the strainless macrocycles pC-CF-Y),-of each series, obtained from the plateau values of profiles such as those reported in Fig. 7, perfecdy obey the JS theory, decreasing with as predicted. Since a ring-chain equilibrium is estabHshed, during the ROP of the mentioned formais, part of the material is converted into linear species (M,-, Scheme 8) the end groups of which are supplied by the catalyst (Scheme 9). 

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