Summary of Research Projects in the Tolman Group

Equilibrium between peroxo- and bisoxodicopper complexes.



 

Recently discovered monocopper O₂ complex.

1. Synthetic Modeling of Copper Protein Active Sites: Dioxygen Activation (Funding: NIH)

Numerous copper-containing proteins use the oxidizing power of dioxygen to perform chemically interesting and important transformations, including the selective hydroxylation of hydrocarbons. A goal of our research is to understand on a fundamental chemical level how these processes occur through the detailed study of small molecule analogs of the metalloprotein active sites. The specific questions we ask include: What are the structures, physicochemical properties, and reactivities of species resulting from the interaction of Cu(I) complexes with dioxygen? How do supporting ligand electronic and structural features influence the course of the Cu(I)/dioxygen reactions, as well as the interconversions among the various types of resulting reactive species?

In previous work, we characterized a new type of Cu/dioxygen intermediate that contains a bis(oxo)dicopper(III,III) core, and showed that it can equlibrate with a side-on (peroxo)dicopper(II,II) isomer in a process that models how the dioxygen O-O bond may be broken and formed at dimetal active sites in biology and catalysis (Figure, top). More recently, we showed that by perturbing the steric properties of supporting diketiminate ligands, monomeric 1:1 species (Figure, bottom) could be obtained which model reactive intermediates postulated to be involved in dioxygen activation at single copper sites in proteins (e.g. dopamine beta-monooxygenase). Current work is focused on expanding upon these findings, and in particular on exploring the reactivity of the 1:1 adducts with organic and metal-containing substrates.  

Review articles

Studies of the bis(oxo)/peroxo interconversion

Selected Recent  Work

 
Models of (left) CuA and (right) type 1 electron transfer sites.


 

Recently prepared analog of biosites with a type 1 center linked to a second metal ion via a histidine-cysteine linker .

2. Synthetic Modeling of Copper Protein Active Sites: Cu-Thiolate Electron Transfer Centers (Funding: NIH)

Copper-thiolate centers in biology include the binuclear, delocalized mixed-valence "CuA" site and the monocopper "Type 1" sites. The "Type 1" copper sites are ubiquitous in biology, functioning to shuttle electrons via Cu(I)/Cu(II) redox reactions that occur rapidly, often via electron transfer over long distances, and at widely varying potentials. The type 1 copper sites exhibit unusual geometries (including in some cases 3-coordinate trigonal planar), a short Cu(II)-thiolate bond, and unique spectroscopic properties (intense 600 nm absorption, small Cu hyperfine splitting in EPR spectra). As a consequence of their unusual structural and spectroscopic properties and their importance in biological electron transfer, chemists have long been interested in preparing synthetic analogs of these type 1 sites (as well as the CuA centers) in order to assess how their structures, spectral properties, and ET function are related.
 
We have prepared accurate models of the CuA center and several key members of the type 1 class of active sites (Figure, top). Detailed spectroscopic studies performed in collaboration with the Solomon group (Stanford) have provided new insights into the electronic structures of these molecules and their protein counterparts. In recent work, we have developed a ligand comprising a thiolate linked to a pyridyl donor and have shown that it can be used to construct a binuclear complex with a type 1 analog connected to a second Cu(I) site (Figure, bottom). Such units with a type 1 center connected via a histidine-cysteine linker to a second metal site are found in several biological systems. Future work is focused on the use of the new thiolate/pyridyl ligand to construct a variety of linked multimetal systems and on their physicochemical characterization.  

Modeling CuA

Models of Type 1 Sites

Catalytic cycle for Galactose Oxidase, showing two key active site species.

   
Reaction of a Cu(I)-phenolate model of reduced GAO with dioxygen to yield a novel side-on Cu(II)-superoxo complex.

3. Synthetic Modeling of Copper Protein Active Sites: The Cu-Phenolate Unit in Galactose Oxidase (Funding: NIH)

The fungal metalloenzyme galactose oxidase (GAO) has been the subject of intense research interest due to the novel structure, physical properties, and reactivity of its active site. This site contains a single Cu(II) ion coordinated to a cysteine-modified tyrosyl radical (Y272-C228) that performs two-electron redox chemistry, the oxidation of primary alcohols to aldehydes and the reduction of dioxygen to hydrogen peroxide (Figure, top). GAO  thus is an important member of the fascinating class of enzymes that use metal-radical arrays for multielectron redox catalysis. 

Our understanding of GAO catalysis has been augmented significantly by studies of synthetic model complexes. In previous work, we synthesized and characterized Cu(II)-phenolate and -phenoxyl radical complexes that model key intermediates in the enzymatic catalytic cycle. More recently, we have focused on the step whereby the reduced Cu(I) form of the enzyme reacts with dioxygen to generate hydrogen peroxide. In this new work, we have prepared Cu(I)-phenolate models of the reduced active site and have explored their reactivity with dioxygen at low temperature using spectroscopic and, in collaboration with the Zuberbühler group, stopped flow kinetic techniques. A key discovery was a novel and quite thermodynamically stable superoxo complex, which we postulated to have the structure shown in the Figure (bottom). Current work is focusing on the reactivity of this intermediate, as well as on related mechanistic issues in GAO catalysis.

Review article

       
   
Monocopper(I) complexes of nitrite (left) and nitric oxide (right).

4. Synthetic Modeling of Copper Protein Active Sites: Nitrogen Oxide Activation (Funding: NIH)

Several intriguing copper proteins function to reduce simple nitrogen oxides such as nitrite, nitric oxide, and nitrous oxide through mechanisms that are only poorly understood. In order to shed light on such mechanistic issues, we are investigating how NOx species interact with discrete Cu complexes. Previously, we characterized novel monocopper nitrite and nitric oxide complexes (Figure, top), and investigated their reactivity. In current work, we are focusing on the challenging synthesis of multicopper sulfide clusters analogous to that found in nitrous oxide reductase.

Nitrite and Nitrosyl Complexes

Ligand Development for Multicopper Cluster Synthesis

   
Carboxylate ligands used to build novel metal complexes.

5. Sterically Hindered Carboxylates for Modeling Fe and Cu Biosites (Funding: NIH, misc.; Joint with L. Que)

Multimetallic arrays in proteins that feature substantial carboxylate ligation are of special interest due to the significance of the reactions they perform and the complexity of their structures and mechanisms of action. An important subclass of such arrays are the nonheme diiron active sites of enzymes that bind and activate dioxygen. In order to model the chemistry of these sites, one must choose the appropriate ligand set (two N-donors and four carboxylates) organized to control complex nuclearity so that the desired diiron species are formed, while at the same time providing appropriate steric shielding to stabilize oxidized intermediates and inhibit undesired intermolecular processes. In a project jointly directed with Professor Larry Que, we have focused on using sterically hindered carboxylates (Figure) in which interligand steric interactions are relied upon to induce low coordination numbers and nuclearities in derived complexes, with hydrophobic shielding effects of the large organic substituents acting to stabilize reactive species and influence redox properties. In fact, by using these types of ligands, a number  of novel Fe(II) compounds have been isolated, some of which react with dioxygen to yield reactive intermediates with unusual spectroscopic features. Current work is focused on extending the use of ligands already proven to be effective in order to model other types of metalloprotein active sites, as well on the development of new types of hindered ligand systems.

Review Article

Selected Recent Work

• “Mechanistic Studies on the Formation and Reactivity of Dioxygen Adducts of Diiron Complexes Supported by Sterically Hindered Carboxylates.” Kryatov, S. V.; Chavez, F. A.; Reynolds, A. M.; Rybak-Akimova, E. V.; Que, L. Jr.; Tolman, W. B. Inorg. Chem. 2004, 43, 2141-2150.
  
• "Unusual Peroxo Intermediates in the Reaction of Dioxygen with Carboxylate-Bridged Diiron(II,II) Paddlewheel Complexes," Chavez, F. A.; Ho, R. Y. N.; Pink, M.; Young, V. G., Jr.; Kryatov, S. V.; Rybak-Akimova, E. V.; Andres, H. P.; Münck, E.; Que, L., Jr.; Tolman, W. B. Angew. Chem. Int. Ed. 2002, 41, 149-152.
• "Metal Ion Complexation by a New, Highly Sterically Hindered, Bowl-Shaped Carboxylate Ligand," Chavez, F. A.; Que, L., Jr.; Tolman, W. B. Chem. Commun. 2001, 111-112.
  
• "Conformational Tuning of Valence Delocalization in Carboxylate-Rich Diiron Complexes," Hagadorn, J. R.; Que, L., Jr.; Tolman, W. B.; Prisecaru, I.; Münck, E. J. Am. Chem. Soc. 1999, 121, 9760-9761.
  

   


Syntheses of polylactide (PLA, (a)) and a perfectly alternating copolymer (b), and the structure of a new dizince-ethoxide catalyst.

6. New Catalysts for the Polymerization of Cyclic Esters (Funding: NSF, misc.; Joint with M. Hillmyer)

The use of biorenewable resource starting  materials for the preparation of commodity polymers will lessen the undesirable environmental impact of the ubiquitous petroleum-based derivatives such as polyethylene and polypropylene. Therefore, the development of efficient, controlled, and versatile methods for the synthesis of polymers derived from renewable resources is an important objective. In this regard, the aliphatic polyester polylactide (PLA) has garnered particular interest because of its usefulness in biomedical, packaging, and engineering material applications. The cyclic dimer of lactic acid, lactide (LA), is a precursor to PLA and is derived from carbohydrate-rich renewable resources (e.g. corn). The catalytic ring-opening polymerization of lactide is a superior method for the synthesis of PLA, as it offers the capability to achieve good control over the molecular parameters of the resultant polymeric materials and is advantageous from an environmental perspective. Future technological applications of PLA (and related polyesters derived from cyclic esters analogous to lactide) depend on the ability to vary and improve its properties in a purposeful manner. We are addressing this ulitimate objective through (a) the characterization and detailed mechanistic study of discrete catalysts for the ring-opening of LA and other cyclic esters (cf. Figure), and (b) the synthesis and characterization of a new class of perfectly alternating copolymers of lactic acid and a cyclic ether component, via a route involving the ring-opening of low ring-strain cyclic ester precursors.

Review Article

Selected Recent Work

• “A Highly Active Zinc Catalyst for the Controlled Polymerization of Lactide.” Williams, C. K.; Breyfogle, L. E.; Choi, S. K.; Nam, W.; Young, V. G. Jr.; Hillmyer, M. A.; Tolman, W. B. J. Am. Chem. Soc. 2003, 125, 11350-11359.
  
• "Metalloenzyme Inspired Dizinc Catalyst for the Polymerisation of Lactide," Williams, C. K.; Brooks, N. R.; Hillmyer, M. A.; Tolman, W. B. Chem. Commun. 2002, 2132-2133.
• "Mechanistic Comparison of Cyclic Ester Polymerizations by Novel Iron(IIi)-Alkoxide Complexes: Single Vs. Multiple Site Catalysis," O'Keefe, B. J.; Breyfogle, L. E.; Hillmyer, M. A.; Tolman, W. B. J. Am. Chem. Soc. 2002, 124, 4384-4393.
• "Polymerization of Lactide by Monomeric Sn(II) Alkoxide Complexes," Aubrecht, K. B.; Hillmyer, M. A.; Tolman, W. B. Macromolecules 2002, 35, 644-650.
• "Perfectly Alternating Copolymer of  Latic Acid and Ethylene Oxide as a Plasticizing Agent for Polylactide," Bechtold, K.; Hillmyer, M. A.; Tolman, W. B. Macromolecules 2001, 34, 8641-8648.