Department of Chemistry

Metallo-radical and organo-metal substrate reactions are used in both obtaining living radical polymerization for application in block copoymer materials and energy relevant small molecule organometallic transformations.

Our NSF supported polymer program spans areas from transition metal catalyst development and block co-polymer synthesis to materials applications of nano-structured polymer arrays in membranes, sensors, and microelectronic devices. The reactivity of metal-centered radical species and organometallic derivatives are exploited in the control of radical polymerization by catalytic chain transfer and living radical polymerization. Organo-cobalt porphyrin complexes have recently been observed to mediate a highly precise living radical polymerization of acrylate monomers to form low polydispersity homopolymers and block co-polymers. This new approach to obtaining living radical polymerization occurs by a degenerative transfer pathway that involves rapid interchange of polymeric radicals in the polymer with polymeric units in the organo-cobalt porphyrin complexes. This pathway to obtain living radical polymerization is a transition metal form of degenerative transfer that we refer to as radical interchange polymerization (RIP). The expanding capabilities of living radical polymerization to provide new classes of materials required to advance issues that have significant technological relevance are exploited through an active collaboration with materials science and engineering .Two of the issues targeted as focal points for this collaboration are 1) membranes for water purification and 2) low dielectric thin films for advanced micro electric devices. New materials design strategies are determined for each of the central topics along with the requisite approaches for polymer synthesis, morphology, and property evaluation.

The DOE supported energy related research interests are centered on developing new strategies to accomplish thermodynamically and or kinetically challenging reactions such as methane activation and carbon monoxide reductive coupling and hydrogenation. Ligands are designed to achieve high selectivity through steric and electronic constraints on forming the transition states for substrate reactions .The primary focus is on group nine (Co, Rh, Ir) metal complexes where the importance of metallo-radicals is a recurring theme. Metallo-porphyrins, chlorophylls, and related macrocycles are prominent thermal and photocatalysts in biological systems and emerging as important catalyst materials for chemical manufacturing processes. The unique unique chemical and physical properties of metallo-porphyrins and macrocyclic complexes are used in producing thermal and photocatalytic cycles for small molecule reactions. Several important examples include hydrogenation of CO and CO2, activation of methane, oxidation of alkenes, photoreductions and alkene polymerization. Tethered diporphyrin ligands have been designed and synthesized that are used in forming bimetalloradical complexes of Rh(II). Bimetalloradicals provide preorganization of transition states that involve two metalloradicals and give rapid highly selective substrate reactions. Structural, kinetic-mechanistic, thermodynamic, and reactivity studies are used in characterizing intermediates, anticipating new types of reactions, and guiding strategies to produce selective catalyst materials.

Research in the Walsh group merges the fields of catalysis and organic and inorganic synthesis with the goal of achieving new catalytic and stoichiometric transformations.  

Current projects include:

Application of cation-pi interactions to facilitate activation of benzylic C–H bonds. This is exemplified by the arylation of toluene, where it was demonstrated that cation-pinteractions enable the deprotonation of toluene with relatively mild silyl amide bases (Scheme 1) and Cs+catalyzed aminobenzylation of aldehydes (Scheme 2).

The study of unusual reactivity has been an active area of recent research in the Walsh group.  These include the discovery of 2-azaallyl anions as super electron donors (SEDs).  In this chemistry, deprotonation of benzophenone ketimines generates 2-azaallyl anions (A0).  Traditionally, these species undergo two electron reactions, acting as nucleophiles.  We found that they can also undergo single electron transfer (SET) to the starting ketimine (Scheme 3) to generate a 2-azaallyl radical (A0) and a ketiminyl anion (A2).  As shown in Scheme 4, the 2-azaallyl radical can react with unactivated vinyl bromides to give vinylation products under transition metal free conditions.  The utility of this method was demonstrated in the synthesis of benzofuran derivatives (Scheme 5).  We have also found that 2-azaallyl anions react with [1.1.1]propellane to give bicyclo[1.1.1]pentane (BCPs) derived amines. The BCP group is a bioisosteres of the phenyl group, making these compounds BCP analogues of diarylmethyl amines, which are extremely important in pharmaceutical sciences (5 of the top 200 medications contain diarylmethyl amines).

Other reactive intermediates include the development of sulfenate anions [ArSO]–for dehydrocoupling of benzyl chlorides, the first catalytic synthesis of all three bonds of alkynes (see below). Application of these reactions to the synthesis of stilbene-based polymers, including novel PPVs, is an area of ongoing work.   For more information, see the research areas section of the group’s website!

We are studying the structures of biologically interesting molecules by X-ray crystallography in an effort to understand their structure-function relationships. Current projects include:

Yeast inorganic pyrophosphatase

Pyrophosphatases are essential enzymes that catalyze the hydrolysis of inorganic pyrophosphate to phosphate and, in doing so, drive the many biosynthetic reactions that yield pyrophosphate (e.g., polypeptide and polynucleotide synthesis) to completion. We have determined the refined 2.7-angstrom resolution structure of yeast inorganic pyrophosphatase, a dimeric enzyme of identical 286-residue subunits. We are presently determining the X-ray structures of selected mutant forms of this enzyme, both alone and in complex with inhibitors of this enzyme. The results of these studies, when correlated with the enzymological characteristics of the mutant enzymes, should lead to the formulation of a catalytic mechanism of inorganic pyrophosphatases as well as a greater understanding of biological phosphoryl transfer reactions in general.

Granulocyte -macrophage colony-stimulating factor (GM-CSF)

GM-CSF is a protein growth factor (cytokine) that stimulate the differentiation, proliferation, and activation of white blood cells known as granulocytes and macrophages. The therapeutic use of GM-CSF therefore holds considerable promise for the treatment of immunosuppressive conditions such as AIDS and the consequences of cancer chemotherapy. Indeed, GM-CSF is presently in clinical use to facilitate bone marrow transplantation. We have determined the refined X-ray structure of human GM-CSF to 3.0-angstrom resolution. We plan to determine the X-ray structures of selected mutant varieties of human GM-CSF in an effort to understand how GM-CSF interacts with its cell surface receptor. We also intend to determine the X-ray structure of the human GM-CSF receptor, both alone and in complex with GM-CSF. 

The x-ray structure of yeast inorganic pyrophosphatase. A 286-residue monomer unit of this homodimeric enzyme is shown with its polypeptide backbone represented in ribbon form embedded in its solvent accessible surface. The side chains of its active site residues are shown in ball-and-stick form.

Conformational Relaxation in Isolated Molecular Clusters

When molecules become electronically excited, the rearrangement of electronic charge can precipitate many types of relaxation processes. To probe details of such events, one can employ isolated molecular clusters consisting of only a few hydrogen-bonded molecules. One particularly interesting case is the cluster involving a Coumarin 151 molecule bonded to a water dimer. Two different structures have been identified in the ground state, as shown below.

Recent experiments have shown that the species shown on the left here is unstable in the excited state, and relaxes to that shown on the right on a picosecond or nanosecond time scale depending on the available energy. This corresponds to movement of the water dimer by ~10Å from one side of the molecule to another, following and yet the activation energy is only 60 cm-1. Such conformational changes have been studied by a combination of fluorescence and infrared double resonance techniques in conjunction with ionization and mass resolution.

Hydrogen-Bonded Molecular Dimers

Hydrogen-bonded dimers present important opportunities to study short-range intermolecular interactions, including modification of the electronic structure, and corelated proton or hydrogen atom transfer. Molecules such as the dimer of 4-Amino-N-methylphthalimide, shown here, reveal dramatic changes in their infrared spectra between the ground and excited states. The simple ground-state ground-state infrared spectrum reflects the high symmetry of the ground state. On the other hand, the much more complex excited-state spectrum shows evidence for a loss of symmetry resulting from changes in the acid-base properties of NH2 and >C=O groups, which may result in proton transfer across the intermolecular hydrogen bonds. These types of strongly bonded dimers are different from many other dimer systems studied so far, because both their electronic and vibrational spectra are highly structured, despite the large increase in binding energy upon electronic excitation. Femtosecond-domain experiments are planned, to follow in real time the changes in vibrational spectra, which will provide further insights into the reasons for their complexity in the excited state.

Ultrafast Electronic Relaxation of Hydrogen-Bonded Molecules Studied by Femtosecond Pump-Probe Spectroscopy

Femtosecond pump-probe experiments allow us to observe the time evolution of the first events following pulsed laser excitation, including motions in the first coordination shell of a hydrogen-bonded molecule in fluid solution. New pump-probe experiments involving the detection of ultrashort-lived fluorescence have explored spectroscopic changes of aminophthalimide molecules in hydrogen-bonding solvents on a time scale more than 10 times faster than existing data for fluorescence Stokes shifts. Both fluorescence upconversion and pump-probe methods are being used to investigate ultrafast energy transfer processes in complex molecules, in collaboration with the Regional Laser and Biomedical Technology Laboratories at Penn.

Research has recently focused on computational studies involving molecular interactions and selectivity, molecular architecture, and molecular recognition. Some of our most recent research has involved collaborations with Professors Ralph Hirschmann and Amos B. Smith, III (University of Pennsylvania) on electrostatic potentials as a means of understanding somatostatin receptor interactions, and with Professor Nobuo Tanaka (Kyoto Institute of Technology) on isotope effects in HPLC as a means of studying hydrophobic effects and interactions.

We have found substantial differences in electrostatic potential surfaces (shown in 1 and 2) between different aromatic systems such as benzene (1) vs. pyridine (2). These differences correlate nicely with binding properties of glucose-based peptidomimetics containing different aromatic substituents, and they appear to explain observed differences in binding to the somatostatin receptor.

We have studied the separation of hydrogen/deuterium isotopologue pairs by means of reversed-phase chromatographic separation in order to examine deuterium isotope effects on hydrophobic binding. The results (see Figure, where tr is the HPLC retention time) demonstrate that dispersion interactions in the hydrophobic phase are an important component of hydrophobic interactions.

We are also interested in design of extended three-dimensional structures with specific architectures and novel properties. Large molecules with architecturally complex structures and shapes, having properties designed for specific purposes, are of increasing importance in all areas of organic and bioorganic chemistry.

A major area of interest in our lab has been study of interactions, transition structures, and mechanisms, for example, mechanistic studies on deuterium and sulfur isotope effects, solvolysis reactions, E2 eliminations, mass spectra, electrical discharge reactions, acid-base catalysis, the Diels-Alder reaction, theory of transition state structural effects, and reactions of carbenes.

Previous bioorganic studies in our lab involved structures and interactions of saccharides and glycolipids utilizing 13C NMR relaxation times, hydrophobic interactions, carbene photochemical labeling of model membranes, and proteins of synaptic vesicles.

Research in the Subotnik group focuses on the intersection of static quantum chemistry methods (especially for excited states) with nonadiabatic dynamics methods (specifically surface hopping). The focus is quantifying electron transfer, energy transfer, and electronic relaxation. Applications are to almost all photo-induced processes!

Our research in inorganic chemistry, energy-storage and materials science includes synthetic studies in main-group, transition metal and materials chemistry along with physical and structural investigations of molecular, polymeric, and solid-state materials. Brief overviews of ongoing projects are presented in the following sections.

Alternative Energy Carriers: New Chemical Methods for Hydrogen Storage

The development of efficient methods for hydrogen storage is a major hurdle that must be overcome to enable the use of hydrogen as an alternative energy carrier. We are exploring the use of chemical hydrides such as ammonia borane and ammonia triborane to store and deliver large amounts of hydrogen through dehydrogenation and/or hydrolysis reactions. As depicted in the example in Figure 1, we have shown that the rate and the extent of hydrogen release from these amineboranes can be significantly increased through the use of metal catalysts, ionic liquids and/or chemical additives. We are continuing to investigate both new methods for the controlled hydrogen release from amineboranes and the development of energy-efficient methods for their regeneration from spent-fuel products.

Figure 1. Rhodium catalyzed hydrolysis of ammonia triborane

Chemical Precursors to Ultra High Temperature Aerospace Materials

The production of complex structural and electronic materials in useable forms is one of the most challenging problems of modern solid-state chemistry and materials science. Our research in this area is focused on the design, syntheses and applications of new processible molecular and/or polymeric precursors to advanced carbide, nitride and boride ceramics that allow the formation of these technologically important materials in forms that cannot be produced with conventional methods. We are especially interested in ultra high temperature materials, such as HfB2 and ZrB2 based composites, that are potentially important in hypersonic (i.e. flying faster than 5 times the speed of sound) aerospace vehicles (Figure 2). A second part of the project is focused on the formation and properties of micro- and nanostructured ceramics, including fibers, tubes and porous materials.

Figure 2. New chemical precursor systems for ultra high temperature hafnium-ceramics that were developed at Penn

Transition Metal-Promoted Reactions of Inorganic Compounds

We are developing new general, metal-catalyzed methodologies that enable the systematic, high-yield syntheses of important polyborane compounds and materials. Our goals are both to discover new types of catalytic reactions and to develop an understanding of their fundamental reaction mechanisms and controlling factors.

Figure 3. (Left) Metal-catalyzed synthesis of the poly(norbornenyldecaborane) polymer; and (Right) The crystallographically determined structure of a new dendritic decaborane (you can manipulate this molecule online at

Ionic Liquid Promoted Reactions

Ionic liquids have properties that make them attractive solvents for synthesis, including: negligible vapor pressures, thermal stability to elevated temperatures; the ability to dissolve a range of compounds, salts and gases, immiscibility with many hydrocarbons and/or water thus enabling two-phase reaction systems, weakly-coordinating anions and cations that provide a polar, inert reaction medium, and the ability to stabilize polar intermediates and/or transition states. While ionic liquids have been widely employed for organic synthesis, our recent work showing that decaborane olefin-hydroboration and alkyne-insertion reactions proceed in biphasic ionic-liquid/hydrocarbon solvents without the need of the catalysts required in conventional solvents, was the first demonstration of the unique activating effects of ionic liquids for polyborane syntheses. We are continuing to explore the scope of ionic liquid mediated polyborane reactions along with experimental and computational studies of the mechanisms by which these reactions occur.

Inorganometallic Chemistry

Because of the unusual ranges of their accessible charges and coordination geometries, polyboranes can function as versatile ligands that can stabilize transition metals in a much wider array of environments than their organic counterparts, such as the cyclopentadienide anion. We are using integrated synthetic, structural (NMR and X-ray crystallography), electrochemical, and computational (DFT/GIAO) investigations to elucidate the nature of polyborane-metal bonding. The unique properties of metallapolyborane complexes are also being exploited to design new metallocene-like complexes with chemical, optical and/or bioactivity properties of importance to solid-state and/or anticancer applications. 

Figure 4. (Left) Comparisons of the bonding modes of the cyclopentadienyl and tricarbadecaboranyl ligands; (Right) The crystallographically determined structures of new maganatricarbadecaboranyl complexes illustrating a cage-slippage reaction analogous to a cyclopentadienyl ring-slippage process

Smith's research interests encompass three diverse areas: natural product synthesis, bioorganic chemistry and materials science. To date, more than 90 architecturally complex natural products having significant bioregulatory properties have been prepared in his Laboratory. In addition, Smith, in collaboration with Ralph Hirschmann, has achieved the design and synthesis of non-peptide peptidomimetics of neuropeptideic hormone/transmitters and protease enzyme inhibitors and, also with Stephen Benkovic (Penn State), haptens for the production of catalytic antibodies capable of peptide bond formation. At Monell, in collaboration with Peter Jurs (Penn State), he pioneered the use of computerized pattern recognition techniques for the analysis of primate chemical communication. Collaborative programs at the LRSM include the chemistry and physics of novel liquid crystals and the fullerenes. To date Smith research achievements have been reported in more than 500 peer reviewed publications.

The focus of my research lies with protein nucleic acid assemblies that participate in the replication and maintenance of eukaryotic chromosome ends, called telomeres. Telomeres protect chromosome ends from gradual length erosion, prevent end-to-end fusions and recombination, and promote proper chromosome partitioning during meiosis. Telomere length deregulation and telomerase activation are early and perhaps necessary steps in cancer cell evolution. Furthermore, telomerase and telomere dysfunction are thought to contribute to replicative senescence and programmed cell aging. Despite these fundamental roles in maintaining genome integrity and cell fate, surprisingly little is known about the molecular basis of telomere synthesis by telomerase. We are interested in elucidating the mechanism of telomere replication by telomerase and understand how telomere and telomerase binding proteins regulate telomerase activity and protect chromosome ends. The lab primarily uses structural methods coupled with biophysical and biochemical techniques to study the above systems.

Telomerase Function

Telomere replication is mediated by telomerase, an RNA dependent DNA polymerase structurally similar to retroviral reverse transcriptases and viral RNA polymerases. Biochemical studies on telomerase for more than two decades have provided a wealth of information regarding telomerase function and substrate specificity. Despite this information, the biophysical mechanisms underlying telomerase architecture and function are poorly understood. Our goal is to further elucidate the molecular basis of telomere replication by telomerase using structural and biochemical approaches. The information generated here should provide novel insights into the basic mechanisms of telomere replication and length homeostasis. It will further enrich our understanding of the mechanism of DNA replication by polymerases in general. It will provide a framework to design small molecule inhibitors of telomerase that may be of therapeutic value for cancer and other diseases associated with cellular aging.

Telomerase Regulation

In recent years, a number of factors essential for telomerase regulation and telomere maintenance have been identified. The method by which telomerase and associated regulatory factors physically interact and function with each other to maintain appropriate telomere length is poorly understood. Structural and biochemical characterization of these factors, both in isolation and in complex with one another will facilitate our understanding of how the proper function of these factors impacts telomerase function and cell proliferation.

Projects in the Schelter Group involve inert atmosphere/Schlenk line synthesis of inorganic and organometallic complexes. Rigorous characterization of new compounds is achieved through X-ray crystallography, NMR, FTIR, and UV-Visible absorption spectroscopies, electrochemistry and magnetic susceptibility studies. Current projects are focused on the chemistries and electronic structure effects of the lanthanides, uranium and main group elements

Advanced Rare Earths Separations Chemistry

The rare earth elements: La-Lu, Y and Sc are used in critical renewable energy applications including wind turbine generators and hybrid electric vehicle batteries. These modern applications require pure rare earth elements that must be separated from their composite mineral sources. The Peoples Republic of China currently holds ~97% of the international rare earths market comprising nearly all aspects of the (environmentally taxing) supply chain. To develop other sources of rare earths and reduce the environmental impact of their isolation, there is a clear need for new separations chemistry that reduces the cost of industrial-scale rare earths separations. This project seeks to develop a totally new extractant strategy by harnessing the physicochemical distinctiveness of certain high-value rare earths. New designer rare earth extractants will enable selective separations chemistry for these technologically critical elements.

Capturing Heavy-Fermion Type Electron Correlations in Molecular Complexes

The intermetallic heavy-fermion materials, comprising intermediate valence f-elements such as cerium, are characterized by exotic emergent phenomena including unconventional superconductivity. Recent results on these materials suggest a common energy scale for the emergence of the superconducting state, dependent on the local magnetic interaction of f-moments with conduction electrons. Local electron correlations are also believed to underpin the high Tc superconductivity of other families of materials. Parallel studies in molecular chemistry have begun to show inorganic and organometallic complexes are capable of exhibiting the same type of mixed-valency and correlations found in the heavy-fermion materials.

This project will generalize the requirements for emergence of Kondo-like phenomena in magnetically-dilute molecular complexes. New materials will be synthesized from fundamental units of electron correlation to three-dimensional molecular phases.

Exploring the Inverse Trans Influence in the Chemistry of Uranium

Antithetical to the trans influence in transition metal chemistry, which results in a weakening of metal-ligand bonds trans to strongly-bound groups, is the inverse trans influence in the chemistry of the actinides. Semi-core p-orbital mixing with valence d- or f-orbitals gives rise to the influence, however, the presence of both orbital types in the actinide valence shell precludes its simple description. The large thermodynamic stability of the ubiquitous linear, trans-dioxo uranyl cation, UO22+ is one important consequence of this influence.

This project will develop new complexes in varying geometries and coordination environments to systematically study the inverse trans influence in the structural chemistry of uranium. These results will have direct relevance to the bio-remediation of actinide contaminated ground waters, for which the thermodynamic driving force of the influence plays an important role.