Macrocycle equilibrium

Macrocyclization equilibrium data from metathesis reactions of cycloolefins are compared with predictions of a novel, simple RIS scheme for polyalkenes with at least three single bonds between adjacent double bonds. The predictions agree with experiment within the combined experimental errors, supporting the conformational models and confirming that macrocyclization equilibrium has indeed been established in the metathesis reactions. 

In addition to the above thermodynamic conditions for ring formation, the kinetics of the reactions must be considered. Thus, for a reaction to take place the two ends of the polymer chain must be in the correct conformation for sufficient time for the new bond to form. The kinetic factor for cyclization is proportional to Rg, so the net effect of the thermodynamic and kinetic factors is that rings are not favoured between n = 8 and k = 11. Suter (1989) has considered the theoretical approaches of Jacobsen and Stockmayer and compared theoretical and experimental values for macrocyclization equilibrium constants. This has also been performed for Monte Carlo as well as rotational-isomeric-state calculations for the statistical conformations of cyclic esters (decamethylene fiimarates and maleates) and agreement with experimental molar cyclization equilibrium constants found (Heath et al, 2000). 

Flory, P.J., Semiyen, J. A., 1966. Macrocyclization equilibrium constants and the statistical configuration of poly(dimethylsiloxane) chains. J. Am. Chem. Soc. 88, 3209-3212. 

Such modifications can be produced either in the kinetic aspects (proton transfer) or in the equilibrium constant. Both effects are mediated by intramolecular hydrogen bonds. For instance, Navarro et al. (93MI69) showed that the rate of proton transfer between the two nitrogen atoms of pyrazole (annular tautomerism) is considerably reduced in macrocycles containing oxygen or nitrogen atoms in the macroring. 

In the context of Scheme 11-1 we are also interested to know whether the variation of K observed with 18-, 21-, and 24-membered crown ethers is due to changes in the complexation rate (k ), the decomplexation rate (k- ), or both. Krane and Skjetne (1980) carried out dynamic 13C NMR studies of complexes of the 4-toluenediazo-nium ion with 18-crown-6, 21-crown-7, and 24-crown-8 in dichlorofluoromethane. They determined the decomplexation rate (k- ) and the free energy of activation for decomplexation (AG i). From the values of k i obtained by Krane and Skjetne and the equilibrium constants K of Nakazumi et al. (1983), k can be calculated. The results show that the complexation rate (kx) does not change much with the size of the macrocycle, that it is most likely diffusion-controlled, and that the large equilibrium constant K of 21-crown-7 is due to the decomplexation rate constant k i being lower than those for the 18- and 24-membered crown ethers. Izatt et al. (1991) published a comprehensive review of K, k, and k data for crown ethers and related hosts with metal cations, ammonium ions, diazonium ions, and related guest compounds. 

Table 1 Equilibrium constants log K for the protonation of macrocyclic diamines [4] in water and methanol at 25°C.

When the neutral macrocycles [64] were dissolved in solvents other than water, equilibria between the neutral forms and betaine structures were also found. In ethanol, the equilibrium between a phenol and a betainic... 

Complex stability constants are most often determined by pH-potentiometric titration of the ligand in the presence and absence of the metal ion.100 This method works well when equilibrium is reached rapidly (within a few minutes), which is usually the case for linear ligands. For macrocyclic compounds, such as DOTA and its derivatives, complex formation is very slow, especially for low pH values where the formation is not complete, therefore a batch method is... 

The equilibrium constants, obtained by NMR spectroscopic methods, showed a strong dependence on both the macrocycles and the diorganozinc compounds. Polydentate nitrogen donor ligands, particularly triazacyclononanes, form much stronger complexes than cryptands and crown ethers. 

Two possible roles for the metal ion in a template reaction have been delineated (Thompson Busch, 1964). First, the metal ion may sequester the cyclic product from an equilibrium mixture such as, for example, between products and reactants. In this manner the formation of the macrocycle is promoted as its metal complex. The metal ion is thus instrumental in shifting the position of an equilibrium - such a process has been termed a thermodynamic template effect. Secondly, the metal ion may direct the steric course of a condensation such that formation of the required cyclic product is facilitated. This process has been called the kinetic template effect. 

As has been mentioned previously, the approach to equilibrium can often be slow for macrocyclic complex formation indeed, equilibrium may take days, weeks or even months to be established. This may give rise to experimental difficulties in conventional titration procedures. Under such circumstances, it is usually necessary to carry out batch determinations in which a number of solutions, corresponding to successive titrations points, are prepared and equilibrated in sealed flasks. The approach to equilibrium of each solution can then be monitored at will. 

For such a mechanism, the overall second-order formation rate constant is given by the product of the first-order constant ktx and the equilibrium constant Kos. The characteristic solvent exchange rates are thus often useful for estimating the rates of formation of complexes of simple monodentate ligands but, as mentioned already, in some cases the situation for macrocyclic and other polydentate ligands is not so straightforward. 

The k pathway is three times faster in D+/D20 than in H+/H20 for la. The reverse kinetic isotope effect suggests that the rate-limiting event for the k pathway could involve protonation of an amido-nitrogen or an N-Fe bond, forming the stronger N-H bond as the weaker N-Fe bond is cleaved. The k 3 pathway is rationalized as involving pre-equilibrium peripheral protonations of the TAML macrocycle (Scheme 1). The dependence of obs on [H + ] is then given by Eq. (4), which corresponds... 

Fig. 22 Macrocyclisation equilibrium constants for macrocyclic formats [30] in CH2C12 in the presence of Et2OBF3 as a catalyst (V) m = 1 (O) m = 2 (A) m= 3 (U)m = 4. (Reproduced with permission from Yamashita et al., 1980)...

The most dramatic rate retardations of proton transfers have been observed when the acidic or basic site is contained within a molecular cavity. The first kinetic and equilibrium studies of the protonation of such a basic site were made with large ring bicyclic diamines [72] (Simmons and Park, 1968 Park and Simmons, 1968a). It was also observed (Park and Simmons, 1968b) that chloride ion could be trapped inside the diprotonated amines. The binding of metal ions and small molecules by macrocyclic compounds is now a well-known phenomenon (Pedersen, 1967, 1978 Lehn, 1978). In the first studies of proton encapsulation, equilibrium and kinetic measurements were made with several macrobicyclic diamines [72] using an nmr technique. 

---