Reaction cavity inclusion complexes

Water plays a crucial role in the inclusion process. Although cyclodextrin does form inclusion complexes in such nonaqueous solvents as dimethyl sulfoxide, the binding is very weak compared with that in water 13 Recently, it has been shown that the thermodynamic stabilities of some inclusion complexes in aqueous solutions decrease markedly with the addition of dimethyl sulfoxide to the solutions 14,15>. Kinetic parameters determined for inclusion reactions also revealed that the rate-determining step of the reactions is the breakdown of the water structure around a substrate molecule and/or within the cyclodextrin cavity 16,17). 

Only the hydrophobic and steric terms were involved in these equations. There are a few differences between these equations and the corresponding equations for cyclo-dextrin-substituted phenol systems. However, it is not necessarily required that the mechanism for complexation between cyclodextrin and phenyl acetates be the same as that for cyclodextrin-phenol systems. The kinetically determined Kj values are concerned only with productive forms of inclusion complexes. The productive forms may be similar in structure to the tetrahedral intermediates of the reactions. To attain such geometry, the penetration of substituents of phenyl acetates into the cyclodextrin cavity must be shallow, compared with the cases of the corresponding phenol systems, so that the hydrogen bonding between the substituents of phenyl acetates and the C-6 hydroxyl groups of cyclodextrin may be impossible. 

In contrast to the reactions of the cycloamyloses with esters of carboxylic acids and organophosphorus compounds, the rate of an organic reaction may, in some cases, be modified simply by inclusion of the reactant within the cycloamylose cavity. Noncovalent catalysis may be attributed to either (1) a microsolvent effect derived from the relatively apolar properties of the microscopic cycloamylose cavity or (2) a conformational effect derived from the geometrical requirements of the inclusion process. Kinetically, noncovalent catalysis may be characterized in the same way as covalent catalysis that is, /c2 once again represents the rate of all productive processes that occur within the inclusion complex, and Kd represents the equilibrium constant for dissociation of the complex. 

Reactions proceeding through S CD inclusion complexes should show competitive inhibition (Fersht, 1985) in the presence of additives which bind in the CD cavity. Such behaviour has been observed for the cleavage of mNPA by a-CD (VanEtten et al., 1967a) and by /3-CD (Tee and Hoeven, 1989), supportive of the mechanism in Scheme 2A. In sharp contrast, with many potential inhibitors, the cleavage of pNPA is not retarded to the extent expected for competitive inhibition, and in a few cases slight rate enhancements are observed (Tee and Hoeven, 1989 Tee et al., 1993b). 

Thus the boundaries of the enclosures in organized media may be of two types they may be stiff (i.e, none of the guest molecules can diffuse out and the walls do not bend), as in the case of crystals and some inclusion complexes, or flexible (i.e., some of the guest molecules may exit the cavity and the walls of the cavity are sufficiently mobile to allow considerable internal motion of the enclosed molecules), as in the case of micelles and liquid crystals. In these two extremes, free volume needed for a reaction is intrinsic (built into the reaction cavity) and latent (can be provided on demand). 

The importance of free volume within the reaction cavities in the case of inclusion complexes has also been shown by several examples. Lahav, Leiserowitz et al. have observed that irradiation of the inclusion complexes of acetophenones with deoxycholic acid yields an addition product enantio-merically pure in each case (Scheme 10) [136]. Supported by a detailed... 

Comparatively, the walls of a reaction cavity of an inclusion complex are less rigid but more variegated than those of a zeolite. Depending upon the constituent molecules of the host lattice, the guest molecules may experience an environment which is tolerant or intolerant of the motions that lead from an initial ketone conformation to its Norrish II photoproducts and which either can direct those motions via selective attractive (NB, hydrogen bonding) and/or repulsive (steric) interactions. The specificity of the reaction cavity is dependent upon the structure of the host molecule, the mode of guest inclusion, and the mode of crystallization of the host. 

Several interesting examples of solid inclusion complexes with ketone guests which undergo the Norrish II reactions have been examined. They illustrate the breadth of reaction cavity types and resultant selectivities that can be expected in such systems. 

The size of the cavity plays a crucial role on the selectivity of the reaction. For example, when the esterification was performed with p-sulfonatocalix [4]arenes, the kcaiixarene/k HBS value for histidine was indeed increased from 24 to 86. 2H NMR studies supported the formation of an inclusion complex of caiixarenes with basic amino acids, and the reaction followed Michaelis-Menten kinetics. The specific rate enhancement observed for basic amino acids His 33, Lys 34 and Arg 35 is the result of a stabilization by the anionic sulfonate groups of the cationic intermediate, which can undergo esterification (see Scheme 13.8). In contrast, the formation of Phe 36, might proceed via simple acid catalysis. 

Useful chemical reactions have been carried out in the nano-sized cavity, as illustrated by the in situ isolation of a labile cyclic siloxane trimer (Fig. 20.3.19). In the first step, three to four molecules of phenyltrimethoxysilane enter the cage and are hydrolyzed to siloxane molecules. Next, condensation takes place in the confined environment to generate the cyclic trimer SiPh(0H)0- 3, which is trapped and stabilized in a pure form. The overall reaction yields an inclusion complex [ SiPh(0H)0- 3 c Pt(bipy) 6L4](N03)i2-7H20, which can be crystallized from aqueous solution in 92% yield. The all-cis configuration of the cyclic siloxane trimer and the structure of the inclusion complex have been determined by NMR and ESI-MS. 

A simple possibility for the synthesis of esters, the reaction of an acid chloride with an alcohol, was used by Schrage and Vogtle [58] for a two-step synthesis of the macrocycle 63 from the alcohol 61 and the acid chloride 62. Compound 63, an example from the field of host/guest chemistry, forms a cavity, as studied with CPK-models, which could include planar, aromatic guests. Crystals obtained from benzene/ -heptane point to a 1 2 stoichiometry of 63 and benzene according to NMR-spectroscopic data. However, whether this is a molecular inclusion complex or just a clathrate is not yet known. 

The structure of 6-(tert-butylthio)-y0-CD was characterized by Tabushi et al. [21]. The compound of 6-O-(tert-butylthio)-y0-CD was prepared from the reaction of 6-O-(p-toluenesulfonyl)-y0-CD with tert-butylmercaptan and recrystallized in water. This is the first example of the determination of crystal structure of monosubstituted CD derivatives and the first evidence concerning the supramolecular polymer of an inclusion complex of a monosubstituted CD. The crystal structure of 6-O-(tert-butylthio)-y0-CD was arranged around the two-fold axis to yield a polymeric structure, in which the tert-butyl group is intermolecularly included in the cavity of CD (Fig. 3). 

The rotaxane 57 has been obtained by initial formation of the 4,4 -diaminostil-bene inclusion complex of 3-cyclodextrin followed by reaction with the appropriate bulky blocking moieties. For this system, the UV-Vis and induced circular dichroism (CD) spectra confirmed that the central aromatic chromophore of the linear component was embedded in the cyclodextrin cavity. 

---