Ionizing Properties of Noncovalent Organocatalysts - A Systematic Study of Hydrogen Bond Donor Catalysis
Final Report Abstract
Chiral hydrogen-bond-donor catalysts have been successfully used for the generation and stereoselective transformation of reactive carbocationic intermediates. Systematic investigations on the anion-abstraction reactions of ureas and thioureas with benzhydryl chlorides revealed that the corresponding ionization step proceeds surprisingly fast. Therefore, it is hypothesized that heterolysis reactions promoted by hydrogen-bond donors represent a fast pre-equilibrium to further nucleophilic transformations of the intermediate cations. In this case, the thermodynamics of the anion abstraction will significantly influence the turnover of the corresponding catalytic cycles. By UV/visspectrophotometric determination of equilibrium constants for the ionizations of alkoxy-substituted benzhydryl halides with ureas, thioureas, and guanidinium ions in CH2Cl2 solution, it was possible to quantify and directly compare the ionization efficiencies of these different classes of hydrogen-bonddonor catalysts. For all cases investigated, a 2:1 stochiometry of the complex between hydrogen-bond donor and halide anion were found. This 2:1 stochiometry is further reflected in the strong negative reaction entropies that were derived from a van’t-Hoff analysis for the equilibrium constants of ureaand thiourea-promoted anion abstractions. Although thioureas are generally considered as stronger hydrogen-bond donors than corresponding urea compounds, thiourea-derived catalysts were shown to be less efficient in the investigated anion abstractions. In addition, systematic competition experiments revealed that thioureas can have significant Lewis basicities, which may also have to be considered in reactions catalyzed by these compounds. The investigations of chiral amino-acid-derived hydrogen-bond donors showed more complicated scenarios for their ionizations of benzhydryl chlorides than it was found for simple N,N’- bisaryl-substituted ureas and thioureas. Due to the presence of additional hydrogen-bond-acceptor moieties (i.e., an amide carbonyl group), amino-acid-substituted hydrogen-bond-donor catalysts have a strong tendency for dimerization. This can dramatically decrease the ionization efficiencies of these compounds. However, the independent investigations of the dimerization-equilibrium constants for amino-acid-substituted hydrogen-bond donors by isothermal titration calorimetry (ITC) as well as their ionization-equilibrium constants for anion abstractions with benzhydryl chlorides by UV/vis spectroscopy provide powerful tools for the full characterization of the underlying coupled dissociation/ionization equilibria. The obtained data in this work is likely to provide a rational basis for future catalyst development and may contribute to a deeper understanding and a more efficient design of enantioselective transformations involving anion abstraction with hydrogen-bond-donor catalysts.
