Cyclodextrins aromatic substitution

The large effects of naturally occurring cyclodextrins and their derivatives, which act as miniature reaction vessels, on the ratios of products from some electrophilic aromatic substitution reactions have been restated.6... 

Further insight came from our study of other aromatic substitution reactions. When we blocked the para position of anisole in compound 65, we saw that ortho chlorination was blocked by binding with a-cyclodextrin, so the only reaction was from the substrate that was in free solution, not that which was bound. However, with p-cresol (66) there was still, of course, ortho chlorination but now it was catalyzed by the a-cyclodextrin. When p-cresol binds to the cyclodextrin, the polar phenol or phenoxide group will be out of the cavity, bringing the ortho positions within reach of the cyclo-... 

Selective Aromatic Substitution Directed by Cyclodextrin Complexing... 

Since this early work, other laboratories have reported selective aromatic substitution reactions in cyclodextrin cavities. In most cases the cyclodextrin does not serve as a template, but simply blocks some otherwise reactive spots. These cases have been reviewed [30]. 

We are extending these studies and looking at ways in which com-plexing forces can orient a reagent and its substrate. We published a related work a year ago (14), a study of the effect of a-cyclodextrin on aromatic substitution. Table IX shows that when anisole is chlorinated with aqueous HOCl, it produces a 60/40 ratio of p- to o-chloroanisole. However, in the presence of a-cyclodextrin this ratio climbs, and it is... 

Friedrich Cramer did the first work in this area, and early work was done by Myron Bender. In Bender s studies, a bound ester reacted with a hydroxyl group on the rim of the cyclodextrin to undergo a transesterification, with reasonable geometric selectivity and some rate acceleration. This was followed up with substrates better designed to be accelerated by such a process, and this will be the first part of the review. Then there are some reactions in which cyclodextrin promotes a process but is not itself transformed, and the first example of this was work we reported on selective aromatic substitution, the second section of this review. I also describe the use of cyclodextrins to catalyse Diels-Alder reactions, in which both the diene and the dienophile can bind into the cyclodextrin cavity in water and in water-like solvents. 

Catalytic Reactions in Cyclodextrin Cavities Aromatic Substitution... 

R. Breslow, P. Campbell, Selective aromatic substitution within a cyclodextrin mixed complex, J. Am. Chem. Soc., 1969, 91, 3085. 

R. Breslow, R Campbell, Selective aromatic substitution within a cyclodextrin mixed complex, J. Am. Chem. Soc., 1969, 91, 3085 R. Breslow, P. Campbell, Selective aromatic substitution by hydrophobic binding of a substrate to a simple cyclodextrin catalyst, Bioorg. Chem., 1971,... 

An interesting case of a cathodic substitution is the EuCh-mediated reduction of oxygen that reacts with aliphatic CH bonds. The selectivity of 1-H 2-H 3-H being 1 6 19 was attributed to a radical intermediate, while in the aromatic substitution the preferred ortho- and para-substitution points to an electrophilic oxygen species [96]. In the FeCls-mediated oxygenation of n-hexane in a fuel cell, the addition of a- and /3-cyclodextrins improved the selectivity toward oxygenation of the terminal CHs-groups due to inclusion of the -hexane in the cyclodextrin cavity [97]. 

Previously (10,13), the authors succeeded in selective syntheses of 4-hydroxybenzoic acids from phenols and carbon tetrachloride, using 3-cyclodextrin (3-CyD) as catalyst. With the use of 3-CyD catalyst, a side reaction, carboxylation at the ortho-position, was largely suppressed, and 4-hydroxybenzoic acids were synthesized in selectivity larger than 95 %. In addition, various aromatic substitution and addition reactions were achieved in virtually 100 % selectivity and high yields in the presence of CyDs as catalyst (9-13). Selective catalyses involve regioselectivity, regulation of molecular sizes of intermediates and products, and/or protection of unstable products (9-13). 

We found that an external chlorinating reagent preferentially passed the chlorine to the template cyclodextrin first, and that the cyclodextrin then relayed the chlorine on to the substrate. Furthermore, this was a catalytic process, and occurred faster than chlorination in the absence of the template. The mechanism involved was established by detailed studies, including reaction kinetics. Modification of the cyclodextrin, and its incorporation into a polymer, have led to the production of highly selective catalysts for this aromatic substitution reaction [22]. In other laboratories an electrochemical adaptation of our reaction has also been made, in which the cyclodextrin molecule is attached to the electrodes [23]. 

The application of cyclodextrins to biomimetic chemistry was orignated by F. Cramer in 1965, followed by R. L. Letsinger, H. Morawetz, M. L. Bender, and further extended by R. Breslow and I. Tabushi. R. Breslow, leader of a group at Columbia University, was the first to show that selective aromatic substitution can take place with the a-cyclodextrin system (174). He found that treatment of anisole (10" M) in water at room temperature with HOCl (10 M) in the presence of an excess of a-cyclodextrin resulted in 96% chlorination at the para position of the anisole ring. 

The radical site of the intermediates in the dimerization reaction is stabilised by resonance and examples have been noted where dimerization occurs by substitution onto the aromatic ring. This is the major reaction course for the reduction of 1-acetylnaphthalene [3 ] which yields 1 in alkaline solution by a radical-ion radical coupling. In the reduction of acetophenone, small amounts of related reaction products, 2 and two diastereomers of 3, can be detected. The yields of these compounds are increased by the reduction of acetophenone encapsulated in a cyclodextrin [32],... 

Analytical Properties (i-Cyclodextrin (cycloheptamylose) normal phase separation of positional isomers of substituted benzoic acids reverse phase separation of dansyl and napthyl amino acids, several aromatic drugs, steroids, alkaloids, metallocenes, binapthyl crown ethers, aromatics acids, aromatic amines, and aromatic sulfoxides this substrate has seven glucose units and has a relative molecular mass of 1135 the inside cavity has a diameter of 0.78 nm, and the substrate has a water solubility of 1.85 g/ml, although this can be increased by derivatization Reference 13-28... 

Two measures to reproduce the key aspects of the enzyme have had some success to use an aromatic thiol and to block attack on the iron by building organic frameworks over the metal. Other approaches, illustrated in Fig. 4.10, include substituting iron with manganese, which is less sensitive to aerial oxidation, and to tether a cyclodextrin to the porphyrin so that the organic substrate could be positioned correctly for oxidation. 

Aqueous a-cyclodextrin solutions seem to be generally applicable for TLC separation of a wide variety of substituted aromatics on polyamide thin-layer stationary sheet (13-14). In most cases, the compounds moved as distinct spots and their R, values were dependent on the concentration of the cyclodextrin in tne mobile phase. In a given family of compounds, (o-, m-, and p-nitrophenols, for example) the isomer with the largest stability constant for a-cyclodextrin complex formation had the larger value. In general, the para-substituted isomers have larger R values than the meta-isomers, which in turn have larger R values than the ortho substituted ones. 

Nitrile oxide cycloaddition with mono- and trisubstituted alkenes affords almost exclusively 5-mono- and 4,5,5-trisubstituted isoxazolines, respectively, the regioselectivity being determined by steric effects. Reverse regioselectivity in nitrile oxide cycloaddition to terminal alkenes has been reported <1997CC1517> for example, 4-A t/-butylbenzoni-trile oxide was forced to reverse alignment for the cycloaddition by formation of the inclusion complex 470 with /3-cyclodextrin. Under these conditions, 90% of the 3,4-disubstituted cycloadducts were obtained, whereas in the absence of cyclodextrin the aromatic nitrile oxide afforded only the 5-substituted isoxazoline. 

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