UndergraduateResearch Topics

August 2012

University of Cincinnati

Dr. Bruce S. Ault Office: 401 Crosley Telephone: 556-9238

Email: Bruce.Ault@uc.edu

Spectroscopic Studies of Reactive Intermediates in Reactions of Ozone Our overall research interests lie with the exploration of the mechanisms of important chemical reactions by isolating, identifying and characterizing reactive intermediates that are created and destroyed during the course the reaction. These species, which live for only fractions of a second under normal laboratory conditions, can be studied very effectively at cryogenic temperatures. We employ the matrix isolation technique, which allows for the trapping of highly reactive intermediates of interest in an argon crystal at nearly absolute zero. We use high resolution infrared spectroscopy as one of the primary techniques for identification and characterization of the reactive intermediate, along with theoretical calculations using modern computational chemistry software. While many chemical systems are amenable to study using this combination of techniques, our current interest is in two classes of reactions of O3. The first aims to resolve a long standing question in the reaction of ozone with alkenes, namely whether or not the proposed Criegee intermediate really exists. This unusual species, a carbonyl oxide, has been proposed as the second intermediate in the reaction sequence, but has never been observed. Calculations indicate that it should be present. We have developed new tools using matrix isolation to attack and solve this problem. This project has implications for atmospheric chemistry, where O3 is present from photochemical reactions and many alkenes are also present, from both anthropogenic and biogenic sources. The second study of ozonolysis reactions is an exploration of the reaction mechanism(s) of O3 with organometallic compounds. Interestingly, almost nothing is known about these reactions other than they are extremely rapid. They are of particular interest currently due to their potential use in the synthesis of metal oxide thin films for the solar energy conversion industry. We have carried out an initial study of the O3 + (CH3)2Zn system and now are broadening our approach to study the reaction of O3 with a wide range of volatile metal organic species.

Dr. Neil Ayres Office: 902 Crosley Telephone: 556-9280

Email: Neil.Ayres@uc.edu Our group uses synthetic polymer chemistry applied to areas in biotechnology. Currently we have projects investigating surface coatings for biomedical materials to improve blood compatibility and create bacteriostatic surfaces, improving protein synthesis in “in vitro compartmentalization” technology, using peptido-mimics for polymer synthesis and biological sensing applications. Students in our group gain exposure to organic and polymer chemistry, materials science, and analytical techniques. No prior experience is required, and undergraduate participation in these projects is welcomed and encouraged. Surface initiated polymerizations. Polymer brushes are assemblies of macromolecules that are tethered to a surface in a high grafting density. This forces the chains to extend away from the surface to minimize segment-segment overlap. We prepare these assemblies through a surface initiated polymerization employing a controlled/living radical polymerization technique known as atom transfer radical polymerization (ATRP). ATRP allows us to control polymer architecture including the molecular weight and formation of homopolymers and block copolymers. We are using surface initiated ATRP to create polymer coatings that will improve blood compatibility and bacteriostatic properties of current biomaterials. These projects include many aspects – from monomer and polymer synthesis, polymer characterization and analysis, and in vitro testing. Polymer synthesis employing ‘peptoid’ structures. The synthesis of peptide mimics known as ‘peptoids’ provides a powerful and versatile synthetic

tool. We are interested in employing this technology in the synthesis of novel monomers and polymers of varied architectures including highly branched comb

copolymers that will posses many potential application including therapy. Students involved in these projects will gain knowledge of organic synthesis both in solution and using solid phase techniques, polymer chemistry and analytical science. Please stop by if you like more information on these or other projects in our research group.

Dr. Michael J. Baldwin Office: 302 Crosley Telephone: 556-9225 Email: Michael.Baldwin@uc.edu

Undergraduate Research Opportunities in the Baldwin Group Our research group is interested in designing new transition metal complexes that may have useful applications, and are inspired by bioinorganic systems, but are not limited to biologically available components. For example, one project in our group uses Ni(II), which is generally unreactive with O2, to catalyze oxidation of various organic compounds using O2 as the oxidant. Catalysis of aerobic substrate oxidations like this is considered to be environmentally friendly “green chemistry”. This chemistry is accomplished by choosing ligand donor groups, oximates, which form a remarkable metal-organic redox hybrid with the nickel. This kind of redox hybrid is used in nature by various metalloenzymes, including the copper-containing galactose oxidase and amine oxidases, which catalyze the same kind of chemistry as our nickel complex. Another project in our group involves the development of bio-inspired, light-activated metal transport agents. These complexes bind Fe(III) very tightly, but release it as Fe(II) upon photolysis by an appropriate wavelength of light. Among the potential applications of these “siderophore mimics” is site-specific delivery of an activating metal to a metal dependent pharmaceutical, such as a chemotherapy agent that would be activated by the light-triggered release of an appropriate metal only at the tumor site. A typical undergraduate project in any of these areas would involve synthesis of a new ligand designed for the particular application, characterization of its metal complex (with nickel, iron, or other appropriate metal), and screening the new complex for the desired chemistry. This will provide the student with experience in organic and inorganic synthesis, a variety of spectroscopic and analytical methods, and the evaluation of useful new chemistry. Several undergraduates working on these projects have become co-authors on published papers based on their research.

Dr. Thomas L. Beck Office: 1301A Crosley Telephone: 556-4886 Email: becktl@email.uc.edu Computer modeling studies of biological membranes and ion channels: Our group is developing new methods to study ion transport through membrane proteins called ion channels. This work involves computational methods including bioinformatics, Monte Carlo methods, and molecular dynamics simulations. We are trying to understand selectivity and gating in complex channels like the chloride channel, whose structure was recently discovered by MacKinnon. An undergraduate researcher will gain extensive experience in using computers to model biological systems, an active and developing field. We also collaborate with research groups in the medical school and engineering. Computational Chemistry: We are developing a new approach for quantum chemistry, the multigrid method. We have applied these methods to calculate electron transport properties through single molecules. These molecules will have applications in the development of new molecular electronic devices. Parallel Computing: We have assembed a 64 node Beowulf cluster on which we do our calculations. An undergraduate interested in computers and computing will learn a great deal while engaged in the research projects described above.

Dr. Joseph A. Caruso Office: 507 Rieveschl Telephone: 556-9306 Email: Joseph.Caruso@uc.edu Research problems in our group are in the area of plasma spectrometry for trace element analysis. Plasmas as highly stable and sensitive elemental emission sources have gained much popularity. In fact, it has been the fastest growing analytical technique of any consequence. Our work is now focusing on the chemistry of various plasma sources as well as expanding their potential for chemical trace analysis. Expanding the plasma techniques for chemical trace analysis is a many faceted problem. Initially we need to push the state-of-the-art in detection limits, linear dynamic ranges and sensitivity. Moreover, a particular metal or non-metal species is of highest interest, since certain chemical forms of an element (oxidation state, organometal, Cl in a pesticide, etc.) are more toxic than other forms. Speciation is through gas or liquid chromatography for separation with the plasma as the sensitive and element selective chromatographic detector. In this way we can obtain a high amount of chromatographic information especially by monitoring more than one element in the eluting compound. Below are some examples of specific problems or interest. A variety of M.S. and Ph.D. problems are available in these areas. 1. Characterization of He and Ar plasmas formed as microwave discharges

Recent work in these labs shows that plasmas formed at 500 W of power have high potential to provide analyte excitation at equal or higher levels than those sources presently commercially available at 1/5 the costs. Further characterization is now imperative. Methods other than direct solution nebulization such as solid injection, flow injection, and thermal vaporization need to be studied.

2. Plasma Mass Spectrometry

Within the last 3 years, plasma source M.S. has emerged as one of the most exciting new analytical techniques for trace analysis because the analytical plasmas provide very high ion populations. By extracting these ions into a vacuum system, they are amenable to selective and sensitive M.S. detection at sub-pg detection levels. Fundamental studies plus sample introduction of halogenated substances and phosphorous and sulfur compounds (such as pesticides) are of high interest since ultimate fragmentation to Cl+, S+, P+ and Br+ lead to very low detection levels (in the fg/s levels) by our newest method of sample introduction, supercritical fluid chromatography.

3. Introduction of Aqueous Aerosols for He Plasma M.S.

Our experiments to date show excellent potential for aqueous sample introduction into He MlPs and into Ar-He ICPs operated at atmospheric pressure. Detection limits for many elements are in the low part-per-trallion range. A great advantage over Ar plasma is the accessibility to virtually all elements in the periodic table. This exciting new area of plasma research has potential for many specialized projects for plasma formation to instrumentation.

Projects involving both He and Ar plasmas are available studying flow injection methods, matrix minimization, HPLC sample introduction for speciation of As, Sn and Pb compounds, studying “soft-ionization” capabilities of the plasma and sample introduction through supercritical fluid chromatography.

Dr. William B. Connick Office: 702 Crosley Telephone: 556-0148

Email: Bill.Connick@uc.edu Undergraduate students have the opportunity to contribute in a variety of ways and to learn many different techniques in our laboratory. Generally speaking, our research involves understanding and taking advantage of how light interacts with molecules. Specifically, our studies are focused on the photochemical and electron-transfer reactions of transition metal complexes. Current projects address a wide array of problems relating to photosynthesis, solar energy, chemical sensing, information/energy storage, and catalysis. The basic ideas behind our research can be summarized as: (1) when a molecule absorbs light, an electron is excited; (2) the resulting excited molecule is more reactive than the ground-state (unexcited) molecule; (3) consequently, light can be used to cause chemical reactions to occur that would not normally be observed. No prior experience or knowledge is necessary. Please do not hesitate to stop by if you would like more detail/explanation or information on other projects. Photoinduced Two-Electron Transfer Reactions Photosynthesis is the process by which plants convert light to chemical energy: a single photon of light excites a molecule, causing the molecule to release an electron that is used to drive a desirable chemical reaction. Chemists are extremely interested in efficiently duplicating this reactivity in the laboratory, and we are pursuing a novel approach to this problem: we are designing molecules that will release two electrons when excited by light. An example of one of these molecules based on platinum is pictured to the right. One obvious benefit of this design is that these molecules will be twice as efficient as conventional one-electron systems. Even more intriguing, however, is our prediction that two-electron charge separation will be much longer-lived than one-electron charge separation. This means that we may be able to use these molecules in photo-information/energy storage systems. There opportunities for students to contribute to this research, especially in the area of synthesis of these remarkable new molecules.

Studies of Photochromic Rhodium Complexes Something that changes color when exposed to light is said to be photochromic. Recently a graduate student in our laboratory discovered a new reversible photochromic system based on a rhodium metal complex. When a blue solution containing this molecule is exposed to light, it changes to a yellow color within seconds. However, when the solution is placed in the dark for several minutes, the blue color returns. The system is remarkably robust, and we can cycle back and forth between these colors many times. Preliminary experiments suggest that the yellow color results from a photoinduced two-electron transfer reaction. Consequently, if we

can learn to control the rate of the back electron-transfer reaction (recovery of the blue color), it may be possible to use such a system in energy/information storage applications. We have only just begun to examine this chemistry, and there is an excellent opportunity for an undergraduate to help with this project.

N

Rh Rh

NN N

NN N

2+

Pt NN

N

N

N

+

Electron-transfer reactions through -stacks Currently there is a heated debate surrounding the role of -stacking interactions between base pairs in mediating long-range electron transfer through double-stranded DNA. Previously, an undergraduate in our laboratory prepared the novel -stacked bridging molecule shown below. We are interested in this type molecule because it can bridge (by bonding through the nitrogen

atoms) an electron donor (e.g., a ruthenium complex) and an electron acceptor (e.g., an iron complex). Studies of these donor-acceptor complexes will help to resolve the effect of -interactions on electron transport in DNA. Students have the opportunity to contribute to this research by helping with synthesis

and making measurements on these new compounds. Designing New Chemical Sensors Chemical sensing of biological molecules and hazardous chemicals is a fundamental problem in chemistry that has applications ranging from national security to gene therapy. We are investigating three molecular systems that will undergo a dramatic change in color and/or phosphorescence when exposed to certain analytes. One system under investigation involves Pt(diimine)X2 complexes, such as the molecule pictured to the right. These complexes are brightly emissive in fluid solution, meaning that when excited by light they emit light at lower energy, thus appearing to glow. We are currently investigating these unusual luminescent properties. Students have the opportunity to contribute to the development of these molecules for chemical sensing by carrying out synthetic work and/or making physical measurements using a state-of-the-art nanosecond laser system. Design and Construction of a Spectroelectrochemical Cell An important aspect of our research is understanding the electronic structures of the molecules with which we are working. Spectroelectrochemical studies are extremely useful in this regard since they allow us to obtain spectra (e.g., UV-visible or infrared absorption) of the reduced and oxidized forms of molecules. In addition, these spectra are essential for the identification of intermediates formed during electron-transfer reactions. In collaboration with Professors Mark, Ridgway and Heineman, a student will help to design and construct cells with optimum spectroscopic and electrochemical behavior.

NN

NN

N

N

S

SPt

Dr. Ruxandra I. Dima Office: 1302 Crosley Telephone: 556-3961 Email: Ruxandra.Dima@uc.edu Bioinformatics methods for targeted drug-design: (1) Our group is developing and applying database mining approaches and other bioinformatics methods to the determination of binding motifs at interfaces between various biological molecules; the goal of this research is to build a repository of specific and non-specific interactions between macromolecules which can be used for targeted drug-design. An undergraduate researcher will gain ample experience with databases for protein and RNA structures, protein families and motifs and will learn to design software applications to extract statistical information from such large databases. Computer modeling of biological macromolecules dynamics and function: (1) We are studying the conformational space in proteins using simplified methods that encode specific characteristics of the polypeptide chain; an example of a project is to target the metastable states that represent obligatory intermediates on the pathway of folding of a protein from a fully unfolded state to its native functional form. Knowledge of all the relevant intermediates for the reaction from the unfolded to the folded form of a molecule can be used to gain insight into the details of its function. Computational studies of aggregation in proteins associated with amyloid diseases: (1) Our group studies proteins associated with amyloid diseases to reveal the initial steps in the association process. An undergraduate researcher involved with this research will gain knowledge of realistic modeling of proteins and their cellular environment (water, ions) and of the computational packages that follow the dynamics of such systems.

Dr. Hairong Guan Office: 503 Crosley Telephone: 556-6377

Email: Hairong.Guan@uc.edu ▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬

Our research lies in the interface of Inorganic Chemistry and Organic Chemistry. We are interested in designing transition metal complexes for the synthesis of small molecules that are valuable to the chemical industry. At the mean time, we study some metal-catalyzed reactions and investigate how the metals interact with organic substrates. The information obtained not only helps us to improve the existing catalyst system, but also provides basis for rational design of new reactions catalyzed by related metal complexes. Students in our group will learn various synthetic (both inorganic and organic) techniques, particularly manipulating compounds that are moisture or air sensitive. We also expect that students will receive proper training on how to utilize all kinds of spectroscopic tools and how to think about a chemical reaction mechanistically.

The research projects are specifically designed for undergraduate students. Please feel free to contact us if you are interested and would like to know more about the details on research.

Dehydrogenation of Alcohols by Iron Catalysts

Dehydrogenation of alcohols is an important process in industry. Current technology is primarily based on precious metal catalysts and/or harsh reaction conditions that require high temperature. We have reported that a hydride derived from iron (thus inexpensive) catalyzes the hydrogenation of aldehydes and ketones with high efficiency and high chemoselectivity. The

detailed mechanistic studies on this hydrogenation system suggest that the H-atom transfer step is reversible. Dehydrogenation of alcohols, the reverse step of hydrogenation, is therefore possible if one can identify a suitable hydrogen acceptor.

Our preliminary results show that acetone serves as the desired hydrogen acceptor. In fact, it can also be used as the solvent for dehydrogenation reactions. We have successfully demonstrated two examples where secondary alcohols (1-phenylethanol and 1-phenyl-1-buten-3-ol) are efficiently dehydrogenated to give ketones in high chemical yields. Dehydrogenation of primary alcohols is also feasible. We have isolated an ester product in excellent yield from the dehydrogenation of a diol. Our future direction is to study the scope and mechanism of this catalytic system. This project is very promising, and should be suitable for undergraduate students with interest in organic synthesis.

R

O

R'

Fe

O

OCOC

H

TMS

TMS

HFe

O

COOC

TMS

TMSO

R'R H

H

+reversible

14h, 60 deg

1 mol% Fe, CH3COCH3OH

OH O

O

Catalytic Hydrofunctionalization of Olefins by First-Row Transition Metal Complexes

Olefins constitute an important feedstock in the petroleum industry. The development of catalytic hydrofunctionalization of olefins allows synthesis of a variety of value-added organic products in an efficient manner. While the existing catalyst design is focused on lanthanide- or precious-metal-based complexes, the search for catalysts containing inexpensive metals is particularly attractive. Complexes derived from late first-row transition metals (i.e., Fe, Co, Ni, and Cu) can potentially catalyze the hydrofunctionalization of olefins. Our research plan involves the synthesis of a variety of catalytically relevant inorganic complexes, and the understanding of fundamentally important elementary steps. This project provides an excellent training ground for undergraduate students who are interested in both synthesis and mechanism.

R

Nu

RNu+ NuH

Ror

Fe, Co, Ni, Cu

Dr. Anna D. Gudmundsdöttir Office: 802 Crosley Telephone: 556-3380 Email: Anna.Gudmundsdottir@uc.edu Photorelease of Fragrances

We are interested in the release of alcohols since they are used as fragrances in applications such as body care and household cleaning goods. One of the drawbacks of using volatile alcohols in fragrances is that the desired aroma is detected for only a relatively short time in applications. Thus by forming a phenyl butyric ester (1) of a volatile alcohol it is possible to release the fragrance in a controlled manner over an extended time period by exposure to light.

An undergradute project

would focus on preparing various derivatives of ester 1 and investigate if they release alcohol upon exposure to sunlight. The undergraduate student working on this project will gaine experience in carrying out simple synthesis and how to purify the starting material by column chromatography. The student will also learn to use 1H-NMR, IR and MS spectroscopy to characterize the starting materials.

Solid State Photoreaction: Green Chemistry

One of the advances of studying chemical reactions in the solid state is that it reduces the use and disposal of potentially hazardous solvents, an important consideration in this era of increased environmental awareness. Furthermore, due to the restricted motions of molecules in crystals, solid state reactions are generally more selective than their counterparts in solutions. Crystal lattices can therefore pose as an effective technique for controlling chemical reactivity. We are interested in study the reactivity of azidoarylketones in the solid state, since they can be used to make interesting heterocyclic compounds.

An undergraduate working on this project

would focus on synthesizing and characterizing various derivatives of the azidoarylketones. The photoproducts from solution and solid state photolysis of these compounds can then be isolated and characterized. Obtaining X-ray structure analysis of the staring material will allow us to connect the solid state reactivity with the structure of the starting material. By studying a series of closely related compounds we can attempt to correlate the molecular structure and the molecular packing arrangements in the crystals, a concept known as “crystal engineering”. The ultimate goal of this research is to control the regioselectivity of photochemical reactions by slight changes in the molecular structure of the substrates to obtain specific crystal lattices.

The student working on this project will gain experience in carrying out synthesis in

solutions and in the solid state. The student will have contributed to the development of using crystals as a reaction media for synthesis.

O

O

OR

OO

ROH

X X

light+

Ester 1 Fragance

Ar

O

N3

NN

O

Ar

Ar

NN

O

Ar

Ar

Ar

O

Ar

O

N

H

h

Crystals

h Solution

+ +

Dr. William R. Heineman Office: 120 Crosley Telephone: 556-9210 Email: William.Heineman@uc.edu

My research interests are primarily in electroanalytical and bioanalytical chemistry. Many of the projects are interdisciplinary in nature and involve collaborations with scientists in physical chemistry, biochemistry, engineering, and the medical sciences. Specific research areas at this time include novel chemical sensors and biosensors, microfluidic sensing systems, and capillary electrophoresis on a microchip. Some current projects are described below.

Novel spectroelectrochemical sensor - This sensor combines three levels of selectivity in one device: selective partitioning into a film, electrochemical excitation signal, and optical response signal. The sensor structure is essentially a guided wave optic that exhibits multiple internal reflection with an optically transparent electrode (OTE) deposited on it. The OTE is coated with a thin chemically-selective film that serves to enhance detection limit by preconcentrating the analyte. The evanescent field at the points of internal reflection within the guided wave optic penetrates the film so that electrochemical events within the film can be monitored optically. The research has many facets including the development of selective coatings for the sensor, instrumentation, and theory to describe the spectroelectrochemical behavior. We are pursuing applications in biomedical and environmental areas. Miniature immunosensors based on microfabrication technology - We are developing a complete system for immunoassay on a microfabricated chip (i.e., a laboratory on a chip). Projects include the development of immunoassays based on capture antibody immobilized on magnetic microbeads, the application of dendrimers to immunoassay, and electrochemical detection using interdigitated array microelectrodes. Application areas include detection of compounds of environmental importance such as herbicides, pesticides, toxins, viruses and bacteria; the analysis of samples of medical importance such as samples from neonates (premature infants) and geriatrics where sample size is limited; and forensic analysis where the amount of sample available for analysis can also be extremely small. Capillary electrophoresis on a microchip - The goal of this research is to significantly improve the determination of trace amounts of biologicals with respect to speed of analysis, selectivity, and limit of detection, versus the standard immunoassay methodology. Aptamer-based assays of polypeptides and proteins are used as illustrative chemical systems, and affinity capillary electrophoresis on a multilane plastic microchip with detection by laser induced fluorescence is the analytical technique. Analysis time is shortened from hours to minutes by the rapid, high-resolution separation of protein-photoaptamer complexes without the need for prior sample preparation. Additionally, the multilane, disposable plastic chip format provides rapid throughput due to the multiplexing of the analysis and the disposability of the low cost chips.

Dr. Patrick A. Limbach Office: 429 Rieveschl Telephone: 556-1871

Email: Pat.Limbach@uc.edu Molecular Biology Cloning and Overexpression of Ribonuclease TA The goal of this research project is to reproduce a clone for RNase TA overexpression. A student working on this project will support a senior lab member, learning the basics of molecular biology and becoming proficient in protein isolation and purification. Techniques will include gel electrophoresis, size-exclusion chromatography, and PCR. No prior research experience is required. This research project requires a minimum of a 2-quarter commitment by the student. Biochemistry RNA Methylation in HeLa cells The goal of this research project is to examine whether methionine-labeled HeLa cells can be used to study the kinetics of RNA methylation. A student working on this project will learn how to purify transfer RNAs from mammalian cells and assist a senior lab researcher in the use of mass spectrometry to characterize labeling efficiency. Due to the nature of the cell line used in this project, only juniors or seniors who have completed Organic Chemistry (Chem 203) and Cell Biology (Biol 301) or Genetics (Biol 302) will be considered. This research project requires a minimum of a 1-year commitment by the student. Isolation, Purification and Characterization of Ribonuclease U2 The goal of this research project is to isolate the cellular expressed ribonuclease U2. A student working on this project will learn how to culture the fungus, isolate RNase U2 from the extracellular matrix, purify the RNase and then test the enzyme activity on various RNA substrates. No prior research experience is required, but it is recommended that the student have completed the first year sequence in Chemistry and Biology. This research project requires a minimum of a 1-year commitment by the student. Cyclic Nucleotide Phosphodiesterase (CPD) Over-expression and Purification The goal of this research project is to over-express a 2’,3’-cyclic nucleotide phosphodiesterase (2’-CNPase) available on a clone given to our laboratory. A student working on this project will learn how to manipulate plasmids and over-express the plasmid-encoded protein in Escherichia coli. The student will learn to purify this protein and confirm its enzymatic activity. No prior research experience is required, but it is recommended that the student have completed the first year sequence in Chemistry and Biology. This research project requires a minimum of a 1-year commitment by the student. Bioanalytical Chemistry Quantitative Analysis of Media-Enriched Labeled-Nucleic Acids (MELNA) The goal of this research is to develop a new technique to identify the changes in RNA abundance in bacterial or yeast cells. This new technique involves culturing the model organism using media containing isotopicallyenriched or isotopically-depleted nutrients, which will modify the isotope composition of the resulting RNA. A student working on this project will learn various biochemical, molecular biology and analytical methods that are useful in chemistry, biology and genetics, including cell culturing, RNA isolation and mass spectrometry. No prior research experience is required, but it is recommended that the student have completed the second year sequence in Chemistry and Biology. This research project requires a minimum of a 1-year commitment by the student.

Affinity Purification of Heat-stable tRNAs The goal of this research is to use DNA-based hybridization probes for the purification of specific heat-stable tRNAs from the organism Thermus thermophilus. A student working on this project will learn various biochemical, molecular biology and analytical methods that are useful in chemistry, biology and genetics, including cell culturing, RNA isolation and mass spectrometry. No prior research experience is required, but it is recommended that the student have completed the first year sequence in Chemistry and Biology. This research project requires a minimum of a 2-quarter commitment by the student.

Dr. Vladislav A. Litosh Office: 805 Crosley

Telephone: 556-9273

Email: litoshvv@uc.edu

The Litosh group is focused on medicinal organic chemistry, and is currently pursuing

the two main projects: (1) the development of novel nanocarrier delivered cancer

chemotherapeutic agents; and (2) the development of novel cyclopropene based inhibitors

of cysteine proteases. The successful fulfillment of these goals has the promise of

providing novel, highly efficient chemotherapeutic agents against cancer, as well as

against certain viral infections (e.g. SARS) and parasites (e.g. malarial)

Each project has the following subprojects that are specifically designed for

undergraduate students. No prior experience or knowledge is necessary to participate.

Project 1. Contrary to normal cells, cancer cells undergo rapid, abnormal, and

uncontrolled division, which warrants a constant need for DNA production. Interfering

with this process therefore affects them preferentially, and represents a plausible

approach to cancer chemotherapy. Recently, pursuing the development of reversible

terminators for DNA sequencing by synthesis, we have developed base-modified

nucleotide analogs that get incorporated into a growing DNA strand by natural

polymerases better than the corresponding natural nucleotides. Since nucleosides are

readily converted into nucleotides, both in vivo and in vitro, it is hypothesized that

treatment of cancer cells with similar base-modified analogs will result in obstruction of

their DNA replication process, thus resulting in high cytostatic activity. A typical

undergraduate project will involve the synthesis of representative base-modified

pyrimidine analogs and labeling the most promising drug candidates with a compact

fluorescent dye to study their cellular uptake and intracellular distribution.

NO

OH

HO

N

NH2

O

O

X

R

dC analogs

Z

NO

OTBS

TBSO

NH

O

O

O

X

R

T analogs

Z

Y

Y

NO

OTBS

TBSO

NBoc

O

O

Br

Benzylalcohol

90-110 oC

neat

Litosh et al. Nucleic AcidsRes. 2011, 39, e39

NO

OH

HO

NH

O

O

O

X

R

Z

Y

NO

OTBS

TBSO

N

OTs

O

O

X

R

Z

Y

TBAF

TsCl/Et3N

2. TBAF

1. NH3

100 oC

Dye labeled T analogs

NO

OH

HO

NH

O

O

O

X

R

Y

N-propargyl-NBD

Pd(PPh3)4/CuIfor Z = I

HN N

ON

NO2

Ethynyl-Bimane

Pd(PPh3)4/CuIfor Z = I

Dye labeled dU analogs

NO

OH

HO

NH

O

O

O

X

R

Y

OO

Project 2. Cysteine proteases are protein processing and protein degrading enzymes

whose overexpression in human body results in serious pathological changes (e.g.

Alzheimer’s disease, multiple sclerosis, stroke, myocardial infarcts, cataract formation,

destruction of cartilage tissue, bone atrophy etc.) Other cysteine proteases play an

essential role in life cycles of some viruses (e.g. corona virus) and parasites (e.g.

malaria). Therefore, developing inhibitors of cysteine proteases is an important target for

organic and medicinal chemists. The most efficient inhibitors of cysteine proteases bear

an electrophilic “warhead”, a reactive group that covalently binds the active site cysteine

residues. Examples include species with an activated double bond (e.g. vinyl sulfones,

methylene ketones, etc.) or a three-membered ring heterocycle (e.g. epoxide or aziridine),

the latter compounds generally having greater potency. Their activity, however, is not

always restricted to cysteine proteases, often affecting aspartate and serine proteases as

well. The goal of this research proposal is to develop highly efficient and selective

inhibitors of cysteine proteases exploiting the specific reactivity of the thiol group toward

a cyclopropene system as a novel “warhead”. Initial studies on this new project will

include the use of conventional peptide syntheses to make several analogs of known

cysteine protease inhibitors, bearing cyclopropenyl "warhead" instead of the one used in

the original compound, followed by comparison of their activity and selectivity.

NHH

Ph

OH

NH

HNO

N

O

O

Ph

O

O

NHAc

H

Ph

OH

NH

HNO

NH

O

O

Ph

O

NH2

O

Ph

H

Ph

OH

NH

HNO

O

O

O

Ph

O

OH

NH

HNO

O

O

Ph

PhO

OR

Cu(OTf)L*

N2

O

O

R"

ONH2

O

NH2Ph

NH2H

Ph

OH

NH

HNO

O

O

Ph

1. NaN3

2. 80 oC

N

O

O

NHAc

HO

DCC, DIPEA

These projects will provide excellent training opportunity for undergraduate students with

interest in organic synthesis and medicinal chemistry. You will acquire synthetic,

purification skills, and learn to use the instrumentation (NMR, MS, chromatography). In

addition, you will gain experience in elucidation of structure-activity relationship.

Please contact me or stop by my office if you would like more information.

Dr. James Mack Office: 502 Crosley Telephone: 556-9249

Email: mackje@ucmail.uc.edu My research interests can be divided into two areas of research 1. Host-Guest Interactions of Fullerene Fragments 2. Green Chemistry Host-Guest Interactions of Fullerene Fragments. Fullerenes and nanotubes have unique electronic properties which potentially will play a large role in the field of nanotechnology. Since these molecules have exhibited such potential, interest has expanded to incorporate the area of fullerene fragments. Fullerene fragments, also known as bowl-shaped polyarenes, are molecules which map onto the surface of fullerenes. One such molecule is corannulene, C

20H

10, which represents 33% of a fullerene[60] molecule. Similar to

fullerenes, fullerene fragments possess an electron-poor convex shell and an electron rich concave surface. The electron-rich concave surface may exhibit strong sites for cationic binding. We are interested in synthesizing molecules which covalently link two fullerene fragments for the study of their interactions with various guests. One such target molecule in this class is a [6,6] 1,8-corannulene cyclophane with enediyne bridges. Using the enediyne bridges to connect the two fragments may allow the molecule to accommodate large guest such as fullerenes as well as small guest such as ammonium ion.

Green Chemistry. The chemical community has recently been concerned with green chemistry. These concerns have led to an increasing interest in chemical waste minimization. One of the primary sources of chemical waste is volatile organic compounds (VOCs). Many VOCs have been targets of waste minimization since the Clean Air Act Amendments of 1990. In research laboratories organic solvents generally comprise most of the waste involved in a reaction. Common practice has been to use milligram quantities of reagents and gram quantities of solvents. At the conclusion of such reactions the small amounts of reagents are recovered and the large volumes of solvent discarded. VOCs such as carbon tetrachloride and benzene both appear on several of the EPA's minimization priority lists. Carbon tetrachloride has been shown to be an ozone depletion

chemical, while benzene is a known carcinogen. Although both of these chemicals have a history of environmental disdain they are continually used in the research laboratory as well as in industrial processes, especially in the area of radical chemistry. Benzene has been cited in more than 1,400 publications as the solvent for various reactions in 2002. Likewise carbon tetrachloride, given its tag as an ozone depletion chemical and its mark up in price over the past several years has been used as a solvent in more than 400 publications in 2002. We are interested in exploring solvent-free reactions utilizing high-speed vibrational milling. HSVM is a procedure in which solid reactants (crystals or powders) are placed inside a steel vessel along with ball bearings. The vessel is sealed and placed inside the milling apparatus whereby it is vigorously agitated. The high speed agitation (60 Hz) forces the ball bearings to pulverize the reagents, causing them to react. Reactions under HSVM conditions potentially will have large impact in organic synthesis with little to no solvent waste.

Dr. Allan R. Pinhas Office: 604 Crosley Telephone: 556-9255 Email: Allan.Pinhas@uc.edu

The Conversion of an Aziridine to an Oxazolidinone in Water A couple years ago, we discovered the very easy and synthetically useful conversion of an aziridine to an oxazolidinone shown below (Hancock and Pinhas, Tetrahedron Letters, 2003, 44, 5457). The solvent for this reaction is THF.

We studied the regiochemistry and found that regardless of the alkyl group, the CO2 inserts into the less substituted bond of the aziridine. However, when an aryl group is present, it is the more substituted bond of the aziridine that reacts. In addition, we studied the stereochemistry and found,

as shown below, the reaction goes with net retention of configuration. As part of an undergraduate research project, Justin Wallace (Wallace, Hancock, Lieberman, and Pinhas, J. Chem. Ed. submitted for publication) discovered that this reaction goes readily using tap water as the solvent. We tried a number of salts and found that any iodide salt works well, but any chloride salt does not work at all.

Future work for this project involves synthesizing a number of different aziridines. Then, the student will react these compounds with I- and CO2 in water, to determine the regiochemistry and stereochemistry, and compare his/her results with our previous results in THF.

N

H3C

Ph

1) LiI

2) CO2

N O

O

H3C

Ph

NH3C

N

H3C

O1) LiI

2) CO2

CH3

Ph

Ph

CH3

H1 H2 H1 H2

O

cis cis

trans trans

N

H3C

Ph

MX / CO2

WaterN O

O

H3C

Ph

MX = LiI, NaI, CsI, NH4I, LiCl, NaCl, NH4Cl

Dr. Laura Sagle Office: 702 Crosley

Telephone: Email: saglela@uc.edu

The Sagle group has two main interests: (1) the development of surface enhanced Raman

spectroscopy as a new single molecule folding technique and (2) the development of new

bionanomaterials, mainly for biosensing. There is ample opportunity for undergraduate

students to take part in both projects.

Single Molecule Protein Folding Using SERS. Single molecule SERS is an

emerging new field that has not yet been applied towards protein folding and offers a lot

of advantages over other techniques in its ability to probe protein flexibility, carry out

site-selective folding measurements, and resolve rapidly converting intermediates.

Because proteins are associated with plasmonic nanoparticles, this technique also offers

the ability to carry out the first nanoparticle-assisted temperature-jump folding studies.

Some of the first proteins used in this new technique will be horse heart Cytochrome c,

Hemoglobin A, and the SH3 Domain. Proteins of interest will either be tethered to the

surface of a nanoparticle cluster, or trapped inside a polymer vesicle in which a gold

nanoshell is grown. As an undergraduate researcher in the group, some of the first

measurements may involve (1) comparing the spectroscopic properties of different

hollow nanoshell materials or (2) comparing the folding properties of proteins in solution

Vs proteins tethered to a nanoparticle surface.

Protein Patterning Using Colloidal Lithography. Colloidal lithography has commonly

been used for making arrays of noble metal nanoparticles on a solid substrate. Hole-

mask colloidal lithography (HCL), in which holes are generated on a thin film polymer

substrate, provides an excellent medium to pattern protein molecules on a substrate since

the holes are the same length scale as a protein molecule. HCL will be expanded to

pattern proteins in various arrays and substrates. In addition, it will be very interesting to

push the size limitations of HCL to make patterns containing single protein molecules.

Biosensing With Protein-Nanoparticle 2-D Arrays. Currently, localized surface

plasmon resonance (LSPR) based biosensors are more sensitive than other types of

biosensors, but specificity and biofouling (the binding of unwanted substances) plague

many applications. By linking plasmonic nanoparticles together with proteins to make 2-

D protein-nanoparticle arrays, these problems can be circumvented. These ‘smart’

protein‐nanoparticle arrays yield a response that is not driven by something binding to the

surface, but rather a protein binding a specific ligand and changing conformation, thus

changing the spacing between the plasmonic particles. These type of biosensors are

expected to be much more sensitive because changes in protein conformation will give

rise to differences in plasmonic coupling, which should shift the

LSPR peak maximum (or color) by hundreds of nanometers instead of only 5‐10 nm that

is typically observed by LSPR‐based biosensors currently being used. In addition, these

biosensors should have increased sensitivity and resistance to biofouling since the

response comes from a specific ligand binding to the protein and not a change in local

index of refraction. These protein‐nanoparticle arrays will be built from proteins known

to form discrete large‐scale structures both in solution and on surfaces, such as collagen,

microtubules and fibrinogen. Other proteins of interest can be attached to these

structure‐forming proteins via genetically engineered fusion proteins and nanoparticles

will be attached via covalent and noncovalent linkages. These biosensing arrays will

eventually be incorporated into microfluidic, on-chip devices for sensing of markers

associated with various diseases such as cancer and Alzheimer’s.

Dr. David B. Smithrud Office: 602 Crosley Telephone: 556-9254

Email: David.Smithrud@uc.edu Our research goals are to use the Mimetic Chemistry approach to discover and replicate the mechanisms used by proteins to recognize DNA, ligands, and other proteins with high affinity and specificity. Protein binding domains combine multiple amino acids to not only activate the side chains, but to also give stabilized pockets with extensive structure. Thus, the challenge facing synthetic chemists is the construction of stabilized-active, water-soluble pockets. The synthetic pockets and domains constructed in our research group are based on the X-ray crystallographic structures of various protein binding domains or predicted key features of these domains. Not only do these mimetics provide unique and highly active agents, but they also provide insight into protein properties. Novel artificial receptors and antibodies, based on the rotaxane architecture, have been constructed and shown to interact strongly with a variety of guests in a variety of solvents, including water. Rotaxanes are a new, exciting class of compounds whose inter-locked ring and axle are key features to many exotic nanoscale devices. In our research, the rotaxane has proven to be a highly effective method to combine and activate multiple amino acids necessary for highly selective recognition. For example, host-[2]rotaxane 1 binds fluorescein and N-acetyl-tryptophan in 98/2 (v/v) buffer to DMSO solutions with large association constants (KA = 5 x 106 M-1 and 2 x 104 M-1, respectively, Fig. 1). Template-[2]rotaxane 2 has also been constructed and its properties are being investigated. Its design mimics the hot spot and O-ring believed to be the important domains of protein binding sites. Thus, besides creating a new class of binding agents, we are investigating this fundamental property of proteins.

Figure 1. Lowest energy structures of [2]rotaxane 1 bound to N-Ac-Trp and fluorescein obtained using Monte Carlo simulations.

O

NH2+

OHO

O HO

HN

O2N

H3CO OH3CO

O

NH

O

O

O O

O

O

O

OO

NH

NH

TFA-

NH

NH2

NHH2N

O

O

NHAcTFA- +H2N

NHAc

TFA- +H2N

1

Calix[4]arene Calix[4]arene

Ring Ring N-Ac-Trp Fluorescein

Dr. Apryll M. Stalcup Office: 201 Crosley Telephone: 556-9216 Email: Apryll.Stalcup@uc.edu About the Project: Currently, the fastest growing areas of high performance liquid chromatographic (LC) separations are in the areas of biomolecule separations and liquid chromatography-mass spectrometry (LC-MS). Although the last couple of decades have seen phenomenal progress in mass spectrometry, the shortfalls inherent in the separations coupled to the mass spectrometer still present considerable barriers to accessing the full information content in biological samples. Biopolymer separations (e.g., proteins, poly-peptides, oligonucleotides) are particularly challenging because they present a variety of interaction modalities ranging from hydrophobic to polar to electrostatic. Concurrently, the chemical industry is challenged with developing "green" technologies to reduce the environmental impact of manufacturing processes. In response, ionic liquids are being explored as a promising alternative to traditional solvents. Ionic liquids are ionic substances with melting points considerably lower than typical for ionic salts; many are even liquids at or below room temperature. They are of interest because they are nonvolatile and nonflammable with high thermal stability. Typically, they consist of nitrogen-containing organic cations and inorganic anions.

Our work is integrating this emerging field of ionic liquids into novel separation strategies for biomolecular separations. We have shown previously that ionic liquids, used as auxiliary agents in capillary electrophoresis, can be very effective at separating polyphenols, the naturally occurring anti-oxidants found in red wine. These polyphenols, present as complex mixtures, are thought to be responsible for the “French Paradox” or low levels of heart disease in France despite the high levels of butter in French cuisine. Our project provides a new chromatographic approach to the analytical separation of biopolymers by offering multimodal interaction potentials that complement the various interaction modalities present in biopolymers. Simultaneously, it provides a convenient means of interrogating ionic liquid/solute interactions.

Dr. George Stan Office: 304 Crosley Telephone: 556-3049 Email: George.Stan@uc.edu Computational molecular modeling of chaperonin molecules Chaperonins are biological nanomachines that employ a spectacular mechanism to assist protein folding. During the chaperonin cycle, concerted, large scale, rigid body conformational changes, ultimately driven by ATP hydrolysis, result in a dramatically expanded chaperonin cavity serving as folding chamber. Currently, very little is known about the annealing action of eukaryotic chaperonins. Questions that we are trying to address are what are the chaperonin binding sites for substrate proteins, how does protein folding assistance take place in the absence of a change in chemical environment and how does the sequential opening of the eukaryotic chaperonin promote protein folding. We develop and apply computational molecular modeling tools, such as the widely used program CHARMM, in combination with extensive data mining of protein databases. This is an opportunity to acquire a diverse set of computational skills and apply them to problems of biomedical interest. In addition, our soon-to-be-built supercomputer cluster provides a chance to learn about designing and maintaining high-performance computers for data intensive applications.

Dr. Pearl Tsang Office: 700 Crosley

Telephone: 556-2301 Email: Pearl.Tsang@uc.edu For all the ensuing projects, the common theme of our laboratory research involves elucidating the structure versus function relationship of proteins/nucleic acids, in order to better understand how these very important biological molecules function in vivo. PDZ3 Domain of PSD-95 Protein: This research involves spectroscopic studies conducted upon a type of domain which has been implicated in a very wide range of important cell signaling pathways. These proteins appear to help different proteins assemble together and this helps coordinate them so that cell processes can occur. The PDZ domains bind to target proteins, typically via the C-terminal portion of these proteins and this helps bring different proteins together for specific interactions and events. This research specifically involves the use of biological NMR techniques to characterize the structure and monitor the mechanism by which this particular PDZ domain interacts with its targeted proteins in an attempt to understand how the domain is important to these cell signaling pathways. tRNA synthetase N-terminal domain: This research involves the study of peptides derived from the N-terminal domain of human lysyl tRNA synthetase. This synthetase extension does not exist in prokaryotic systems and its precise function is still unknown but is critical for proper enzyme functions during protein translation. The exact role of this N-terminal domain will be investigated by studying the binding properties of this domain with tRNA and DNA. This work will also involve spectroscopic studies (fluorescence, NMR and CD) to characterize where and how this domain interacts with important DNA and tRNA molecules. Graphics image of a tRNA synthetase dimer (red and blue molecules) complexed with cognate tRNA molecule (green). Envelope proteins of HIV-1: The role and function of different glycosylated proteins during the process of infection by HIV-1

virus represents an ongoing area of active research. A portion of one such HIV-1 protein is studied in our lab in order to investigate how its structural properties are pertinent to its function during infection. The research will entail use of spectroscopic and chromatographic methods aimed at characterizing the interaction of these viral proteins with anti-HIV-1 antibodies as well as host cell proteins which interact with them during the process of virus infection. This cartoon of HIV-1 infection shows the viral glycoproteins interacting with specific cell receptor proteins on the host cell membrane.

Dr. Peng Zhang Office: 124 Crosley

Telephone: 556-9222 Email: Peng.Zhang@uc.edu Nanoscience is at the unexplored frontiers of science and engineering, and it offers one of the most exciting opportunities for innovation in technology. One of the hopes for nanoscience and technology is that the combination of a number of areas - from physics and chemistry to material science and biology - will create a new area and lead to major advances both in understanding of science and in their applications in technology. Key to this new era is research across many disciplinary interfaces. As illustrated in the following diagram, the central theme of this research program is metal-enhanced spectroscopies and their applications, typically bio-related, based on various types of nanomaterials. Synthesis of nanomaterials with photon upconversion properties At present, luminescence-based assays generally provide high sensitivity, large dynamic range, and the simultaneous use of multiple fluorophores with different spectral characteristics (multiplexing). Nevertheless, greater sensitivity, improved multiplexing, and performance under extreme test conditions is continuously demanded. On the other hand, upconversion emission, i.e., the emission of light at shorter wavelength than the excitation, has been observed and studied in many lanthanide-doped bulk materials. In this effort, we intend to synthesize lanthanide-doped photon-upconverting nanoparticles. Once such upconverting nanoparticles are prepared, their surfaces can be easily modified to conjugate biomolecules of interest. Because most non-target materials under study do not possess upconversion properties, an enhanced signal-to-noise ratio is expected when these phosphor nanoparticles are used for sensing, imaging and photodynamic therapy. The ultimate goal of this project is to develop biocompatible nanomaterials for biologically related applications. Development and applications of nanocomposites as efficient SERS tags The key objective of this effort is the development of nanomaterials as surface-enhanced Raman spectroscopy (SERS) tags, with an ultimate goal of making SERS a bioimaging/analytical tool. The phenomenon of SERS has been known and studied for around 30 years. It has been observed that, adsorbed on the surfaces of some metals in a variety of morphologies and physical environments, a very large number of molecules would display significant enhancement (10^4 - 10^6) in their Raman scattering. From an analytical point of view, Raman spectroscopy offers several important advantages. It is rapid and non-destructive, yielding highly compound-specific information for chemical analysis, which leads to great potential for multi-component analysis. One limitation of conventional Raman spectroscopy is its low sensitivity. Discovery of SERS indicated that the Raman scattering efficiency could be greatly enhanced. SERS research has since drawn a lot of attention and interests as the effect was large, unexpected, and of enormous practical utility if it could be understood and exploited. There have been a variety of applications of SERS, including immunoassay, DNA detections, detection of hazardous chemicals (environmental pollutants, explosives, and chemical warfare agents), etc. Nevertheless, one of the major barriers that SERS technique has not been practiced more frequently in an analytical environment is that, the preparation of SERS substrates is far from “standardized” or reproducible. In this project, we plan to capitalize upon our recent results and advancement in near-field SERS investigation and nanoparticles synthesis, and develop nanomaterials as efficient SERS-active Raman-tags or substrates for bioimaging and trace detection of chemicals and biomolecules. Development of nanoparticle-based photosensitizers for photodynamic antibacterial therapy We are developing nanoparticles as photosensitizers to be used in photodynamic antimicrobial therapy. The particle sizes range from <10 to 100 nm. The versatility of such nanoparticle-based photosensitizers lies in the fact that the surface of these nanoparticles can be modified to have either positive or negative charges so as to be specific to a class of bacteria, or be coated with antibodies specific to a certain type of bacterium. Experiments are underway to test the efficacy of these photosensitizers towards several bacteria, such as P. fluorescens, E. coli., and S. epi.