Chemical engineers and chemists have always been actively developing heterogeneous catalysts for the economical and large-scale production of products. Yet as the major challenges facing catalysis in this century shift towards unprecedented levels of high catalyst selectivity, including enantioselectivity, we and others within the community are investigating new methods for synthesizing heterogeneous catalysts to meet this challenge. In the chiral products market alone, for example, growth can be observed in the following figures: revenues were 7 billion U.S. dollars for 2002 and are estimated to be 9 and 15 billion U.S. dollars by 2004 and 2009, respectively.

How can we take the historical success of heterogeneous catalysis and apply it to emerging challenges that require exceptionally high catalyst selectivity within the biorenewables, pharmaceuticals, and fine chemicals arenas? Among the many approaches that are available for tackling this question, our research group has turned to biological catalysts for inspiration, which have evolved to be able to accomplish this task.

How can we incorporate the essence of biological catalyst active sites into synthetic heterogeneous catalysts that will also function in a highly active and selective manner? Of the many important general features of biological catalysts, we have chosen to focus on two that we believe are essential for function: active site isolation and confinement. These two aspects have in general been difficult to incorporate into synthetic heterogeneous catalysts because of the tendency of active sites to aggregate and the lack of materials synthesis methodologies that permit confinement of isolated active sites in solids.

Our approach synthesizes isolated active sites in synthetic heterogeneous catalysts by using cookie-cutter-type molecular templating approaches. These approaches permit synthesis of uniform active sites containing well-defined atomic connectivity and organization within the site and a controlled chemical environment that confines and surrounds it. This allows us to systematically investigate the active site, using synthesis as a tool, and study the most important factors that influence heterogeneous catalyst activity and selectivity.

Our research has thus far impacted two active areas of synthetic heterogeneous catalysis: i) organic catalysis with amines anchored on silica and ii) metal-oxide catalysis with titanium on silica. We have also begun a third area involving the imprinting of bulk silica using nanoparticle templates, which has applications in the synthesis of metal shells for heterogeneous catalysis. All three of our research areas are schematically represented here and described in further detail below. A fallout of our materials research program is that our isolated and confined nanoscale active sites for catalysis can often be applied for the design of functional materials with desired electronic/optical properties in other fields, including physical chemistry.

Imprinting of Amines in Bulk Silica via Thermolysis

The environment surrounding amine active-sites in biological catalysts can strongly affect the amine pKa and its activity as a base catalyst. We have aimed to extend this type of environmental control to synthetic heterogeneous organic catalysts. Our goal has been to investigate how the composition of the framework surrounding isolated amines immobilized on silica can influence their reactivity. We synthesized catalysts consisting of isolated amines in bulk hydrophilic (i.e. amines that are surrounded by silanols) and hydrophobic (i.e. amines that are surrounded by trimethylsilyl functional groups) silica, and compared these with conventional amine-silica materials, which consist of clustered amines on silica. Our results demonstrate that isolated amines on silica can be several orders of magnitude more active as catalysts compared with conventional materials under identical conditions and that the acidity of the surrounding framework can be critical to base catalysis in reactions involving an enolate mechanism.

Amines on silica have been used as heterogeneous base catalysts for reactions such as Knoevenagel condensation, Michael addition, aldol condensation, and Henry reaction. The synthesis of conventional amine-on-silica catalysts consists of contacting an aminosilane molecule with porous silica and allowing for hydrolysis and condensation of the aminosilane on the silica surface. This typically leads to a material that contains clustered amines and relatively few free silanol groups on the silica surface, which become consumed during aminosilane anchoring.

Imprinting of amines in bulk silica can be used to synthesize isolated amines in silica, but bulk silica imprinting has been limited to frameworks that have a hydrophobic surface (trimethylsilyl functionality). In addition, bulk silica imprinting has been limited to microporous material frameworks. As a result, isolated amines anchored within bulk, microporous silica, although accessible for catalysis, have been strongly mass-transport limited.

To overcome these limitations, we developed new methods for synthesizing bulk imprinted silica. For circumventing mass-transport limitations, we incorporated mesoporosity into bulk imprinted silica, by relying on a two-step acid-base-catalyzed sol-gel hydrolysis and condensation, which was originally developed for silicates without an organic component. We successfully applied this for the synthesis of bulk, mesoporous imprinted silica consisting of isolated anchored amines (probed via fluorescence using a custom-synthesized probe molecule that was used for the first time for this purpose). Our approach is schematically summarized here.

To overcome limitations of framework hydrophobicity in bulk imprinted silica, we developed a method for synthesizing bulk imprinted silica via thermolytic deprotection. The difficulty with using a thermally-labile group for imprinting required design of the protecting group. It must be robust and stable enough to withstand the high acidity/basicity and ionic strength present during mesoporous silica synthesis conditions, yet the group must be easily removable upon mild heating later during deprotection. This delicate balance has been difficult to achieve while avoiding deprotection during silica synthesis. Our group has relied on a carbamate protecting group that is derived from a tertiary alcohol and isocyanate for solving these technical problems. We subsequently used bulk silica imprinting via thermolytic deprotection for synthesizing isolated amines within the well-defined chemical environments that are described above.

The role of acidic silanols in the Knoevenagel condensation reaction using amine-on-silica catalysts has remained as an open question. Early mechanisms, which were later supported by the experimental data of other investigators, point to a potential role for silanols. However, the very fact that the conventional amine-on-silica material, which is commercially available from Aldrich – contains few free silanols suggests that silanols are not required for Knoevenagel condensation catalysis.

We rigorously investigated this question by using imprinting to change the environment surrounding anchored amine catalysts without concurrently changing other properties of the catalyst. Our results unequivocally demonstrate the strong cooperative role that silanols and anchored amines have in a combined acid-base bifunctional mechanism for catalyzing the Knoevenagel condensation reaction. We have characterized the acidity of these silanols by using salicylaldehyde as a sensitive and relevant probe molecule of amine density and chemical environment. We have also investigated closely related systems such as the thermolysis reaction itself in order to elucidate the accessibility and importance of the silanols’ acidity.

We have also applied our “optimization of environment surrounding catalyst active site” approach described above to other classes of reactions, such as the Pd-catalyzed Suzuki coupling reaction. In this case, effects of environment were also observed, albeit in smaller magnitude than for the Knoevenagel condensation (~ 3 fold rate enhancements between hydrophobic and hydrophilic).

Single-Step Immobilization of Calixarenes onto Solid Surfaces: Synthesis of Cal Silica

Calixarenes have been successfully anchored onto solid surfaces for the synthesis of chromatographic stationary phases during the past ten years. However, calixarene immobilization has never been accomplished previously without the use of an organic tether, which requires organic synthesis for attachment between calixarene and silica. Our method of calixarene anchoring obviates the need for organic tether and thereby significantly decreases the difficulty and cost of immobilizing calixarene macrocycles on silica. Importantly, from the perspective of functional application, our method of calixarene anchoring selectively produces the cone conformer of the calixarene, which is the most desired for binding neutral organic guests via non-covalent interactions, and metal ions via strategically organized phenolic oxygens on the lower rim. The former capability is used for demonstrating our anchored calixarenes as adsorption active sites.

Our approach for calixarene immobilization is inspired by homogenous multicavitands (characterized using single-crystal X-ray diffraction), which comprise stable linkages between a tetrahedral silicon atom and three calixarene phenolic oxygens on the lower rim. We hypothesized that it may be possible to replace one of the two calixarenes in multicavitands, which makes a single-point attachment to the silicon atom, with a silica surface. Our hypothesis proved to be correct, and the resulting heterogeneous analogs of multicavitand molecules can be synthesized using the silica activation methodology that we developed as shown here.

silica was fully characterized using a host of analytical techniques. Among these, thermogravimetric analysis showed that the degree of calixarene coverage corresponded to a calixarene-on-silica weight fraction of 0.141 – or equivalently – to a calixarene area of about 4 nm² on the silica surface. These coverages are the highest reported for immobilized calixarenes and correspond to a full monolayer under the irreversible binding conditions of calixarene to the silica surface.

We have characterized the calixarene binding sites in silica by using volatile organic molecules as guests in water and have quantitatively followed the adsorption via spectrophotometry. There is a distinct saturation of the adsorption isotherm of toluene from aqueous solution, which corresponds to a single adsorbed toluene per calixarene. This is the precise stoichiometry predicted from X-ray crystallography for calixarene:toluene host:guest complexes. This result provided indirect proof that the calixarene was anchored in the cone conformation, with open and accessible binding pockets, as in multicavitand molecules. This conformation results from the restriction imposed by the tridentate binding of a silicon atom on the calixarene lower rim during immobilization. We have also successfully bound other guests such as phenol, benzene, toluene, and nitrobenzene into the calixarene cavity, and showed that the cavity can discriminate between various guest molecules in the expected manner. In addition, we have shown that the binding of guests to calixarene pockets can be reversible via thermal desorption spectroscopy.

Grafted Calixarenes as Single-Site Surface Organometallic Catalysts

Because of the absence of organic tether between calixarene and inorganic oxide support in Cal silica, our method of calixarene immobilization is unique in that it offers intimate electronic and steric contact between calixarene and support surface via a single metal atom, which is not possible to accomplish with conventional calixarene-on-silica materials. We wished to exploit this feature in implementing the calixarene in Cal silica as a surface organometallic ligand for catalytically active transition metal atoms. Because titanium is known to be isostructural with silicon in a tetrahedral oxo environment, we hypothesized that the silicon atom connecting calixarene to silica in Cal silica can readily be substituted with titanium. The resulting heterogeneous catalyst consists of an isolated atom of titanium within a ligand sphere defined from the top by a calixarene and from the bottom by the silica surface. Working in collaboration with the group of Prof. Enrique Iglesia (joint student Justin M. Notestein), we developed an approach for the synthesis and characterization of this catalyst. The following important conclusions were made. Grafted metallocalixarenes: a) form isolated tetrahedral Ti-oxo sites on the surface of an inorganic oxide, b) are stable under storage in ambient air, c) are single-site heterogeneous epoxidation catalysts that are uninhibited by competitive binding of alcohol byproducts, something that many epoxidation catalysts are unable to accomplish, and d) retain their calixarene ligand and immobilized coordination geometry under reaction conditions.

Relying on the metallocalixarene building-block shown here, which was previously synthesized and characterized via single-crystal X-ray diffraction, we developed a route for its immobilization and for synthesis of a Ti-containing material that is isostructural with Cal Silica. Even before performing catalysis, we observed several signs that the structure of the anchored metallocalixarene was preserved during immobilization.

¹³C CP/MAS NMR spectroscopy showed evidence of a weak interaction between the Ti metal center and the methoxy group on the calixarene; this interaction is predicted by the structure of the molecular precursor from single-crystal X-ray diffraction studies. Next, UV-vis absorption spectra of the catalyst showed a single edge energy (corresponding to ligand to metal charge transfer), regardless of the site coverage on the material. This was the first indication that the material synthesized behaved as a single site material. Finally, cyclohexene epoxidation catalysis, which was used as a model reaction, showed a rate of catalysis to be independent of Ti-coverage on the catalyst. This latter trait is an accepted hallmark of a single-site catalyst. The stability of Ti-calixarene connectivity in our materials before and after catalysis was proven using multiple analytical methods involving repeated catalytic runs (for probing catalyst deactivation and formation of catalytically inactive species), solid-state NMR spectroscopy, UV-vis spectroscopy, and elemental analysis. The role of the sterically bulky calixarene in our heterogeneous catalyst is to serve as an organized, rigid multi-dentate ligand, ensuring titanium isolation and confinement within a pseudo-tetrahedral environment. Our research group is currently synthesizing controlled electronic and steric environments around the metal centers in this class of materials, by relying on the calixarene as a tunable ligand that can be synthetically changed to directly affect the metal center.

Synthesis of Nanoparticle Building Blocks for Bulk Silica Imprinting

We have initiated a program in the synthesis of imprinted silica using gold nanoparticles as templates. Our goal is to use these sites for the nucleation of metal shells for catalysis. A different type of templating approach has already been successfully implemented, albeit on a length scale at least ten-fold larger, for synthesizing catalytically-active Pd metal shells as active heterogeneous catalysts. We have successfully synthesized the required imprint for this area – consisting of thiols organized on the surface of colloidal gold, and we have successfully coated these imprints with silica for the synthesis of a core-shell gold@silica nanoparticle, as shown here. In developing the required synthetic approach for accomplishing this, we have answered rather long-standing questions relating to the mechanism of protected thiol adsorption and deprotection on gold surfaces. These include unequivocally proving that protected thiols can adsorb onto gold surfaces in the protected form – a hypothesis that had remained in the literature for 7 years before.