Abstract: Asymmetric organocatalysis is a rapidly developing area,1 with (L)-proline and its derivatives playing a prominent role as efficient and selective small molecule catalysts for an increasing number of homogeneous reactions, including important carbon-carbon bond-forming reactions such as aldol and Michael reactions.2,3 While immobilized forms of asymmetric organocatalysts have been known and used,4 the advantages of these materials over their homogeneous counterparts have remained largely limited to filtration and ease-of-recovery. The beneficial effect of confinement on enantioselectivity has been demonstrated previously in heterogeneous organometallic catalysts5-14 as well as in homogeneous organometallic systems,15,16 yet this effect remains to be proven for asymmetric organic catalysts. One of the complicating factors for studying the effect of confinement in heterogeneous inorganic-oxide catalysts is the varied surface chemistry of inorganic oxide materials, which is intrinsically due to the presence of a variety of defect site environments. These differences in turn lead to differing chemical interactions between the active site and the solid surface, which can affect catalysis, independent of effects arising due to confinement at the active site. Because proof of confinement effects in heterogeneous catalysis requires comparisons across different materials, it is difficult to separate the effect of confinement on catalysis from specific active site-surface chemical interactions in any two materials being compared. A promising solution to this apparent dilemma is the exhaustive capping of accessible defect sites within the two materials being compared. While exhaustive capping fails to completely eliminate all active site-surface interactions,17 it minimizes potential differences in surface chemistry between any capped materials being compared. Thus it then becomes possible to rigorously ascribe differences between two materials with differing porosity to confinement rather than potential differences in active site-surface interactions. Our goal here is to develop a general synthetic method that will permit the confinement of a class of asymmetric organocatalyst active sites as isolated species in hydrophobic silica. These attributes are necessary in order to study the effect of confinement on organic catalysis. We have specifically targeted the class of proline amide18-20 catalysts as a general structural motif for our heterogeneous catalyst system, because the amide hydrogens present in the catalyst possess the ability to hydrogen bond to reaction substrates, which has been shown to be an important interaction for controlling catalyst enantioselectivity.19 Our approach is to design and synthesize proline amide catalysts covalently attached to silica via a propylamine tether. We use the technique of bulk silica imprinting21 for the synthesis of isolated active sites within confined and hydrophobic environments. The hydrophobic environment is synthesized via exhaustive capping with TMSCl/TMSI and results in a saturation coverge of TMS-capped silanols as described previously.21 A conceptual illustration of our desired catalyst is shown in Figure 1. Accomplishing the synthesis of the conceptual material shown in Figure 1 requires demonstrating the imprinting of secondary amines in bulk, microporous silica as well as the synthesis of a chiral active site with bulk silica imprinting.
Template and target information: secondary amines