Metal‐Free, Noncovalent Catalysis of Diels–Alder Reactions byNeutralHydrogen Bond Donors in Organic Solvents and in Water

Abstract

We examined the catalytic activity of substituted thioureas in a series of Diels-Alder reactions and 1,3-dipolar cycloadditions. The kinetic data reveal that the observed accelerations in the relative rates are more dependent on the thiourea substituents than on the reactants or solvent. Although the catalytic effectiveness is the strongest in noncoordinating, nonpolar solvents, such as cyclohexane, it is also present in highly coordinating polar solvents, such as water. In 1,3-dipolar cycloadditions, the thiourea catalysts demonstrate only very moderate selectivity for reactions with inverse electron demand. Our experiments emphasize that both hydrophobic and polar interactions can co-exist, making these catalysts active, even in highly coordinating solvents. This class of catalysts increases the reaction rates and endo-selectivities of Diels-Alder reactions, in a similar manner to weak Lewis acids, without concomitant product inhibition.

Computational design of a lipase for catalysis of the Diels-Alder reaction

“…The relative rate constants (k c1 /k u ) of all three dienophiles (∼ 10 1 − 10 2 ) correlate well to experimental rates for H-bonding molecular catalysts. [35] Moreover, they confirm the limitation of H-bond stabilization as the only means of rate enhancement; one cannot obtain more than a few kcal·mol −1 in stabilization, and thus ≤ 10 3 in k c1 /k u .…”

“…[34] These values are expected to be similar using lipase oxyanion holes, so the main concern for the viability of lipases such as CALB therefore lies in the ligandreceptor dynamics. From data on molecular catalysis reported in the literature, we can conclude that rather high catalyst concentrations are required for a reasonable activation, typically around 1-20 mol-%, [35,36,37,38] which is not possible with enzymes. Thus the binding constant between the enzyme and both substrate must be sufficiently low.…”

“…The corresponding v c1 /v u values for the most efficient organic catalyst can be estimated to approximately 10-100. [35] The dependence on the catalyst concentration clearly explains the superiority of small organic catalyst over enzymes for catalyzing the Diels-Alder reaction; organic catalysts can be, and typically are, used in concentrations > 1 M.…”

“…[22,21] Inserting the standard enzyme and substrate concentrations we obtain rate enhancements of the order 10 3 for 1 and 10 2 for 3, respectively. These values are competitive with conventional molecular catalysts, such as Schreiner-type thioureas, [35] which give modest rate enhancements of about 10, despite that they are used at much higher concentrations. However, it should be emphasized that the rate enhancements are likely to be overestimated.…”

Crystal structure of N-phenyl-2-(pyridin-4-ylcarbonyl)hydrazinecarboxamide with Z′ = 4, C13H12N4O2

“…Molecules having urea functionality have been reported in a wide range of applications, in particular, metal binding as neutral or anionic ligands [1][2][3][4][5][6]. These molecules have also been found to be useful in surfactant self-assembies [7] and photo-dimerizing agents in coumarins [8].…”