Issue Date: April 9, 2012
Silanediol Catalysts Take The Stage
Silanediols have joined the ranks of metal-free alternatives for catalyzing addition reactions. At the American Chemical Society national meeting in San Diego last month, two research groups recounted their discovery and initial study of the organocatalysts, which take advantage of hydrogen bonding to activate organic molecules for addition reactions.
Although the work is still in its infancy, the researchers said, the experimental findings suggest that chemists should consider silanediols when looking for low-cost, low-toxicity, air-stable replacements for transition-metal catalysts.
Representing one group, graduate student Sean O. Wilson and assistant chemistry professor Annaliese K. Franz of the University of California, Davis, described their efforts to decipher the mechanism of silanediol catalysis. They reported that hydrogen bonding between silanediols forms dimers, which appear to be the active catalyst species in addition reactions.
Representing the second group, graduate student Andrew G. Schafer and assistant chemistry professor Anita E. Mattson of Ohio State University reported that silanediols can match the talents of existing organocatalysts in addition reactions. Their work includes the synthesis of a racemic silanediol catalyst that could lead to enantioselective reactions.
Silanediols have intrigued chemists for years. Drug designers like to incorporate the motif into their molecules because diol carbon analogs are rare and the acidic silanediol group binds to target drug receptors more tightly than other hydrogen-bonding molecules do. In addition, acidic silanol groups on the surface of materials such as silica gel are known to promote heterogeneous catalytic carbon-carbon bond-forming reactions via hydrogen-bonding networks.
However, working with soluble silanols and silanediols is a tricky business, the researchers pointed out, because the chemicals typically are unstable and tend to self-condense and form oligomers. Spontaneous condensation of the compounds can make a mess of catalytic reactions.
Working independently, Franz and Mattson began to consider whether the hydrogen-bonding ability of silanediols would lend itself to organocatalysis under controlled conditions. They envisioned that silanediols could match the hydrogen-bonding abilities of urea, thiourea, and guanidinium organocatalysts that mimic the activating properties of amino acids in peptides and enzymes.
“Hydrogen-bond-mediated catalysts are an exceptionally hot area for catalysis right now, so it’s exciting to see these creative, groundbreaking new catalysts being developed,” said chemistry professor Scott M. Sieburth of Temple University. Sieburth’s group studies silanediols as protease enzyme inhibitors, which are important in treating high blood pressure, cancer, and HIV infection.
Given the known problems of silanol and silanediol self-condensation, “these are daring endeavors for a pair of assistant professors,” Sieburth said. “Both of these research groups have carefully designed catalysts that balance the steric hindrance needed to limit self-condensation and leave the silanol hydroxyl groups available for catalysis. Their initial results are really promising.”
In San Diego, Wilson and Franz reviewed their group’s initial structural studies on how silanediols form hydrogen bonds with carbonyl compounds. They gave presentations at symposia organized by the Division of Organic Chemistry, the Division of Catalysis Science & Technology, and the Women Chemists Committee, which awarded Franz a WCC Rising Star Award.
The researchers synthesized a series of diphenyl-substituted silanediols, including dimesityl, mesityl-fluorophenyl, and mesityl-trifluoromethylphenyl versions, and tested them in a Diels-Alder cycloaddition reaction. They found that silanediol acidity—and catalytic activity—can be increased by controlling crowding around the hydroxyl groups and by incorporating electron-withdrawing fluorinated substituents (Chem. Eur. J., DOI: 10.1002/chem.201101492).
One of the UC Davis team’s key findings, stemming from its X-ray crystal structures and nuclear magnetic resonance spectroscopy binding studies, is that silanediols self-associate to form dimers (Org. Lett., DOI: 10.1021/ol202971m). This cooperative hydrogen bonding is not observed with most organocatalysts, Franz said. Dimerization enhances the ability of each silanediol unit to hydrogen bond with and activate a reactant molecule relative to a single hydrogen-bonded silanediol molecule, she said. The UC Davis chemists observed that the tri-fluoromethyl-substituted catalyst provides yields on par with silica gel and outperforms silica gel under solvent-free conditions.
“Our current work is focused on designing chiral catalysts that take advantage of novel silanediol dimers as catalytically active species,” Franz told C&EN. She added that the study of homogeneous silanediol catalysis is providing further insight regarding surface silanol groups in heterogeneous catalysis.
Meanwhile, as the Franz group’s work was progressing, Mattson’s group at Ohio State was testing silanediols to see how they stack up against established organocatalysts. During a symposium organized by the Division of Organic Chemistry in San Diego, Schafer described using dinaphthylsilanediol to catalyze the Friedel-Crafts addition of substituted indoles to substituted β-nitrostyrenes in dichloromethane solvent (Org. Lett., DOI: 10.1021/ol2021115).
When the silanediol binds and activates β-nitrostyrene it renders the alkene double bond susceptible to nucleophilic attack by indole, Schafer suggested. In control experiments the researchers found that dinaphthylsilanediol provides better yields than conventional urea and thiourea organocatalysts and that it works better than diphenylsilanediol or triphenylsilanol.
To show that the silanediol group is key to reactivity, they tried the reaction with dimethoxysilane, which can’t function as a hydrogen-bond donor and resulted in a poor yield. In addition, solvents with hydrogen-bonding capabilities—such as tetrahydrofuran, ethyl acetate, and acetonitrile—compete with the silanediol and disrupt its catalytic activity, Schafer said.
Mattson’s group subsequently turned to a chiral binaphthylsilanediol to develop asymmetric catalytic reactions. The binaphthyl scaffold is analogous to binaphthol (BINOL) and binaphthyl phosphine (BINAP) groups that are used as chiral ligands for transition-metal-catalyzed asymmetric syntheses.
Schafer reported how the team synthesized the racemic binaphthylsilanediol and successfully tested it in the addition of 5-methoxyindole to β-nitrostyrene to yield a racemic addition product. The Ohio State researchers are attempting to resolve the racemic silanediol to generate a single-enantiomer catalyst for enantioselective addition reactions, he said.
The UC Davis and Ohio State groups are now working to verify the mechanism of silanediol catalysis. For example, for indole addition to β-nitrostyrene the groups have seen different results. It may be that more than one reaction pathway is at work. Mattson noted that her group’s preliminary kinetic data suggest that only one silanediol molecule is involved in the rate-determining step, rather than a dimer. “Perhaps the silanediol catalysts can operate solo or cooperatively, depending on the catalyst and reaction conditions,” she suggested.
“Franz’s and Mattson’s efforts in studying the chemistry of silanediols as hydrogen-bond-donor catalysts, even if emergent, have already in my mind defined a new area of research at the interface of organic and main-group chemistry,” commented chemistry professor François P. Gabbaï of Texas A&M University. Gabbaï’s group uses main-group elements such as boron to create compounds with molecular-recognition properties.
“Their work presented at the ACS meeting hints that silanediol catalysis could be part of the future for many types of reactions,” Gabbaï continued. “It’s reasonable to envision that other acidic main-group compounds that so far have been regarded as laboratory curiosities could also turn out to be useful organocatalysts. These two researchers should be commended for having the courage to be original in their early careers.
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