Macrocyclization rates

Templates based on ether tethers also have been examined. Improvements in product yield may be anticipated from the reduced steric congestion in the cyclization step due to the substitution of an -O linkage for a -CH2 linkage [43]. In addition, such oxygenated tethers might serve as crown-ether type substrates, sequestering ions that in turn serve to promote macrocyclization. The beneficial effect on macrocyclization rates by complex-ation of this type has precedent in the work of Mandolini and Illuminati [44]. 

As a final example we consider noncovalent molecular complex formation with the macrocyclic ligand a-cyclodextrin, a natural product consisting of six a-D-glucose units linked 1-4 to form a torus whose cavity is capable of including molecules the size of an aromatic ring. Table 4-3 gives some rate constants for this reaction, where L represents the cyclodextrin and S is the substrate ... 

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. 

The importance of the relationship between the macrocycle cavity and the binding of two reagents is shown by the cycloadditions of cyclopentadiene with diethyl fumarate and ethyl acrylate in aqueous solution. The presence of jS-CD strongly accelerates the first cycloaddition, while it slows down the reaction rate of the second, probably because the cavity favors the binding of two molecules of either diene or dienophile [65c]. 

Gonzalez and Holt (1981) have shown how macrocyclic lactones can be made conveniently in microemulsion media. Thus, intramolecular e.sterification of (o-hydroxy alkanoic acids can be carried out with a very small amount of acid catalysts like p-toluene sulphonic acid, and rates are markedly higher as compared to simple media. 

Rate constant for the exchange of a particular coordinated water molecule. b RRSS form of macrocycle. c Five-coordinate RSRS form of macrocycle. d The two inequivalent H20 exchange at different rates. 

Electrocatalysis employing Co complexes as catalysts may have the complex in solution, adsorbed onto the electrode surface, or covalently bound to the electrode surface. This is exemplified with some selected examples. Cobalt(I) coordinatively unsaturated complexes of 2,2 -dipyridine promote the electrochemical oxidation of organic halides, the apparent rate constant showing a first order dependence on substrate concentration.1398,1399 Catalytic reduction of dioxygen has been observed on a glassy carbon electrode to which a cobalt(III) macrocycle tetraamine complex has been adsorbed.1400,1401... 

The effect of steric crowding on the rates of reaction of the Ni1 tetraaza macrocycle complex [Ni(dmc)]+ with organic halides and hydroperoxides has also been examined. Reaction with this complex was found to be about 104 times slower than with the corresponding [Ni(tmc)]+ complex.2329... 

Although these results have been interpreted in terms of a specific interaction between catalyst and substrate, the precise catalytic mechanism has not been firmly established. Indeed, the possibility that binding outside of the cavity of 16 leads to effective rate accelerations cannot be eliminated. Nevertheless, these preliminary results suggest that macrocyclic amines may surpass their progenitors, the cycloamyloses, in catalytic efficiency, and indicate a potentially fruitful direction for future research. 

In the preceding chapter, thermodynamic aspects of macrocycle complexation were treated in some detail. In this chapter, kinetic aspects are discussed. Of course, kinetic and thermodynamic factors are interrelated. Thus, in terms of a simple complexation reaction of the type given below (charges not shown), the stability constant (/CML) may be expressed directly as the ratio of the second-order formation constant (kf) to the first-order dissociation rate constant (kd) ... 

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. 

Chelate ring formation may be rate-limiting for polydentate (and especially macrocyclic) ligand complexes. Further, the rates of formation of macrocyclic complexes are sometimes somewhat slower than occur for related open-chain polydentate ligand systems. The additional steric constraints in the cyclic ligand case may restrict the mechanistic pathways available relative to the open-chain case and may even alter the location of the rate-determining step. Indeed, the rate-determining step is not necessarily restricted to the formation of the first or second metal-macrocycle bond but may occur later in the coordination sequence. 

The need for multiple desolvation of the metal ion in some systems may provide a barrier to complex formation which is reflected by lower formation rates - especially for inflexible macrocycles such as the porphyrins. Because of the high energies involved, multiple desolvation will be unlikely to occur before metal-ion insertion occurs rather, for flexible ligands, solvent loss will follow a stepwise pattern reflecting the successive binding of the donor atoms. However, because of the additional constraints in cyclic systems (relative to open-chain ones), there may be no alternative to simultaneous (multiple) desolvation during the coordination process. 

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