Cyclodextrins molecular reactivity

Recently, it has been found that the outcome of some cycloadditions can be altered remarkably when performed inside the cavity of cyclodextrins (288), self-assembled molecular capsules (289), or coordination cages (290). This fact intrigued us greatly and stimulated our interest in the Diels-Alder reactivity of the calixarene-like [M2(L19)(L )]+ complexes bearing unsaturated carboxylate coligands L (215). 

Carbenes can be highly reactive but modification of their chemistry through supra-molecular encapsulation by cyclodextrins, hemicarcerands, and zeolites has been discussed in a microreview.10... 

Cyclodextrins and their derivatives are already known to catalyse an enormous variety of biochemical and non-biochemical transformations. The basis of the catalysis by native (unmodified) cyciodextrins is the positioning of the reactive secondary hydroxyl groups directly at the entrance to the molecular cavity. One of the most effective reactions catalysed by cyclodextrins is the hydrolysis of aryl and phosphate esters (esterase activity). For example, the rate of hydrolysis of p-nitrophenol esters is increased by factors of up to 750 000 by /TCD. The mechanism of action of the cyclodextrin is shown in Scheme 12.2.1... 

Solubility enhancement by use of cyclodextrins is achieved for a number of drug substances, an approach of interest in formulation of drugs for topical, parenteral, and oral use (Stella and Rajewski, 1997 Loftsson and Masson, 2001 Qi and Sikorski, 2001). The solubilizing effect can be extensive even in low concentrations of cyclodextrin. The use of 0.1 M sulfobutyl-ether-P-cyclodextrin increases the solubility of prednisolone acetate and testosterone by a factor of 426 and 2020, respectively (Myrdal and Yalkowsky, 2002). Cyclodextrin encapsulation of a molecule will affect many of its physicochemical properties (Loftsson, 1995). As a result of complexation, solubility, pKa value, spectral properties, and the chemical reactivity of the included substance will change. The cyclodextrins are known to affect molecular orientation and to have an influence on rates and efficiency of electron transfer, excited state proton transfer, and rate of decomposition (Chattopadhyay, 1991 Fox, 1991 Sur et al., 2000). Cyclodextrins can also be used in combination with liposomes a cyclodextrin-liposome entity represents an even more complex environment to the drug molecule (Loukas et al., 1995). 

The problem with this system is that the molecular reactor offers very little in the way of a real practical advantage The ratio of formation of the dyes has been changed in favour of indirubin but only by reducing the overall yield of the two dyes by a factor of almost thirty and the yield of indirubin by Ihirteen times. This is almost certainly the result of complexation of indoxyl and isatin by the cyclodextrin, increasing their effective steric bulk and reducing the frequency of their productive coUisions. At the same time the rates of hydrolytic decomposition of indoxyl and isatin are largely unaffected, so these processes become more dominant. Similar effects are likely to be common with molecular reactors unless complexation increases the desired reactivity in some other way. 

Most of the work concerning the modification of carbene reactivity has been performed on cyclodextrins (CD) with reactive alkyl carbenes. Diazirines have proven to be the most convenient precursors due to the small size of the three-membered ring and the volatility of the leaving group, molecular nitrogen. Diazirines are usually obtained from the corresponding ketone in two steps in a methanolic solution of ammonia, hydroxylamine-0-sulfonic acid (HOSA) is added yielding a diaziridine which then is oxidized to the diazirine, most conveniently with iodine. 

Some encapsulation processes have limited variability with regards to payload. For example, the payload capacity of molecular encapsulation or complexation in cyclodextrins is limited by affinity equilibrium of the active molecule to the host molecule. Conversely, the payload for some of the common emulsion-based processes, such as interfacial polymerization, will remain high due to the inability to increase shell thickness set by the diffusion limits of the reactive monomers used to form the shell. While liposomes can also have a core-shell structure, their formation process and structure severely limit payload. Lipophilic active ingredients can be entrapped within the lipid bilayer of the liposome but are limited to low percentages to avoid disrupting the bilayer structure. Hydrophilic active ingredients can be entrapped in the core of the liposome, but payload is again limited by their solubility or concentration in the inner aqueous environment. 

Shell materials can be solvent-based, water-based, molten, reactive, or molecnlar. Variations of atomization, spray coating, and coextrusion are available to deposit shell or matrix materials from solvent, water, or as a molten material. For example, spray drying is snitable for encapsnlating with solvent-based or water-based matrix materials, while spray congealing nses molten fats or waxes. Fewer shell material selections are available with the emulsion-based processes. For example, complex coacervation is most often associated with the use of gelatin as the shell, and the generation of polyurea or polymelamine formaldehyde shells is associated with in situ polymerization. Further limited examples include the use of cyclodextrins for molecular complexation or phospholipids for the formation of liposomes. 

In the present paper, we report the stereoselectivity and the regulation of reactivity in molecular inclusion reactions with a-cyclodextrin. 

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