SC IENCE & TECHNOLOGY
SILANEDIOL CATALYSTS TAKE THE STAGE ACS MEETING NEWS: Hydrogen-bonding organocatalysts
offer new ways to run metal-free addition reactions
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 lowcost, 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 catalyticcarbon-carbonbond-formingreactions 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
THE RESEARCHERS synthesized a se-
ries of diphenyl-substituted silanediols, including dimesityl, mesityl-fluorophenyl, and mesityl-trifluoromethylphenyl versions, and tested them in a Diels-Alder self-condense and form oligomers. Spontacycloaddition reaction. They found that neous condensation of the compounds can silanediol acidity—and catalytic activity— make a mess of catalytic reactions. can be increased by controlling crowding Working independently, Franz and around the hydroxyl groups and by incorMattson began to consider whether the porating electron-withdrawing fluorinated hydrogen-bonding ability of silanediols substituents (Chem. would lend itself to organocatalysis under Eur. J., DOI: 10.1002/ controlled conditions. chem.201101492). They envisioned that One of the UC Davis silanediols could match team’s key findings, the hydrogen-bonding stemming from its Xabilities of urea, thioray crystal structures urea, and guanidinium organocatalysts that and nuclear magnetic mimic the activating properties of amino resonance spectrosacids in peptides and enzymes. copy binding studies, is “Hydrogen-bond-mediated that silanediols self-associate catalysts are an exceptionto form dimers (Org. Lett., ally hot area for catalysis DOI: 10.1021/ol202971m). right now, so it’s exciting This cooperative hydrogen to see these creative, bonding is not observed groundbreaking new with most organocatacatalysts being devellysts, Franz said. Dimeroped,” said chemistry ization enhances the professor Scott M. ability of each silanediol Sieburth of Temple Uniunit to hydrogen bond versity. Sieburth’s group with and activate a reacstudies silanediols as protetant molecule relative to ase enzyme inhibitors, which asinglehydrogen-bonded are important in treating high silanediol molecule, she blood pressure, cancer, said. The UC Davis chemALTERNATIVE PROPOSAL A and HIV infection. ists observed that the triGiven the known prob- single molecule of Mattson’s fluoromethyl-substituted catalyst lems of silanol and silane- dinaphthylsilanediol catalyst provides yields on binds to β-nitrostyrene (top) in diol self-condensation, par with silica gel and outa manner typical of hydrogen“these are daring endeav- bonding organocatalysts. performs silica gel under Franz’s group has proposed ors for a pair of assistant solvent-free conditions. that silanediol dimer formation, professors,” Sieburth said. “Our current work is foas shown with a mesityl“Both of these research trifluoromethylphenyl silanediol cused on designing chiral groups have carefully catalysts that take advan(bottom), may be key to designed catalysts that bal- activating a reactant molecule tage of novel silanediol disuch as β-nitrostyrene. ance the steric hindrance mers as catalytically active needed to limit self-conspecies,” Franz told C&EN. densation and leave the siShe added that the study of lanol hydroxyl groups available for catalysis. homogeneous silanediol catalysis is providTheir initial results are really promising.” ing further insight regarding surface silanol In San Diego, Wilson and Franz reviewed groups in heterogeneous catalysis. their group’s initial structural studies on Meanwhile, as the Franz group’s work how silanediols form hydrogen bonds with was progressing, Mattson’s group at Ohio
STEPHEN K. RITTER, C&EN WASHINGTON
SILANEDIOLS HAVE JOINED the ranks of
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.
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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 syn-
thesized 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 singleenantiomer 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
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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. ◾
