Diels-Alder reactions in water: Enforced hydrophobic interaction and hydrogen bonding

Abstract: Second-order rate constants have been measured for the Diels-Alder (DA) reactions of cyclopentadiene with dienophiles of varying hydrophobicity and hydrogen-bond acceptor capacity in water, in a series of organic solvents and in alcohol-water mixtures. The intramolecular DA reaction of N-furfuryl-N-alkylacrylamides was also investigated in the same reaction media. The often huge rate accelerations in water appear to be inherent in the activation process of the cycloaddition and do not originate from diene-dienophile association. A pseudothermodynamic analysis of the rate acceleration in water relative to 1-propanol and 1-propanol-water mixtures provides evidence for two factors dominating the rate enhancement in water: hydrogen-bond stabilization of the polarized activated complex and the decrease of the hydrophobic surface area of the reactants during the activation process. Quite generally, organic chemists think that water is not a good solvent for organic reactions. Rightly so. The often limited solubility of apolar organic compounds in water and the sensitivity of many reagents and functional groups towards water are among the factors which make more apolar and iner