Water-Soluble Pendant Copolymers Bearing Pro line and Permethylated β-Cyclodextrin: pH-Dependent Catalytic Nanoreactors

To achieve efficient proline-based catalysis in water, proline has been supported in the past to porous and hydrophobic solid resins leading to heterogeneous systems. These solid resins provide a hydrophobic environment to the active centers, mimicking what happens in natural enzymes. However, a more realistic mimetic approach would be to carry out the aldol reaction in a homogeneous way, maintaining the hydrophobic environment, using for example properly designed noncross-linked polymer carriers. In this work, we report the synthesis and aqueous catalytic evaluation of a linear copolymer bearing both pendant proline and permethylated beta-cyclodextrin (beta-CD) groups. It was designed on the basis that the presence of the hydrophobic cavity of the beta-CD could bring aromatic substrates into close proximity to the surrounding catalytic proline residues through host-guest interactions. The compound is water-soluble and catalyzes aldol reactions in this medium without the need for any extra organic solvent. We employed a model reaction between cylohexanone and p-nitrobenzaldehyde, and we observed a decrease of the reaction rate when a competing aromatic compound, known to form a strong inclusion complex with beta-CD, was added. The copolymeric catalyst showed a pH-dependent behavior. At pH 7, the copolymer is found in solution as extended single chains with negative charge, catalyzing the reaction in a fast and nonstereoselective mode. At the isoelectric point (pH 3.8) where the positive and negative charges of the zwitterionic proline are canceled by forming charge complexes, the copolymer forms multichain hydrophobic nanoaggregates most probably stabilized by the permethylated beta-CD. Although the reaction inside these "nanoreactors" is slower, it exhibits high stereoselectivity. It is proposed that the observed stereoselectivity is caused by the exclusion of water from the core of these homogeneous entities.