Macrocyclization, under thermodynamic

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 ... 

It is clear that the ideas of combinatorial chemistry could potentially be applied to identifying excellent matches of "hosts" and "guests", and that to achieve this requires the synthesis of libraries of macrocycles. As noted above, when cyclic oligomers are prepared under thermodynamic conditions the family of oligomers formed can equilibrate, Reactions 3 in Scheme 1, i.e. dimers can interconvert with trimers and tetramers etc. Use can be made of this to establish equilibria between cyclic oligomers of different families, i.e. to "mix" the different families, and in this way a soluble macrocyclic library may be prepared. 

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... 

The palladium-catalyzed cyclization of compound 138 amply demonstrates the utility of the Stille reaction as a macrocyclization method (see Scheme 37). This efficient ring closure is just one of many examples disclosed by J.E. Baldwin and his group at Oxford.58 Interestingly, compound 138 can be employed as a stereoisomeric mixture of vinylstannanes because both stereoisomers converge on the same cyclized product. To rationalize this result, it was suggested that the configuration of the vinylstannane moiety is conserved in the cyclization, but that the macrocycle resulting from the (Z)-vinylstannane stereoisomer isomerizes to the thermodynamically favored trans product under the reaction condi-... 

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