While major advances in transition metal catalyzed reactions have been made, it remains a continuing challenge to chemists to produce structures of high molecular complexity in a single synthetic operation from readily available starting materials. Clearly, one way this goal can be met is by combining two or more reactions in a single operation, i.e. a tandem sequence. We have discovered an expedient synthesis of cross-conjugated trienes using a transition metal catalyzed allenic Alder-ene reaction. We have also shown that these trienes are then amenable to subsequent Diels-Alder [4 + 2] cycloaddition reactions (eq. 1). Investigations pertaining to alternative cycloaddition reactions (i.e. [4 + 3] and [4 + 4] will be the topic of this project (eq. 2)
Ref:  A Rhodium(I)-Catalyzed Formal Allenic Alder-ene Reaction for the Rapid and Stereoselective Assembly of Cross-Conjugated Trienes, Kay M. Brummond, Hongfeng Chen, Peter Sill, Lingfeng You, J. Am. Chem. Soc. In Press.  [12/04]

Our current research has involved exploring the use of the highly branched, dendritic polymer based on the natural amino acid lysine.  This polymer has the lysine residues joined via amide bonds at both the a- and e- amino groups. It’s rate of biodegradation is somewhat slow.  We wish to explore similar dendritic polymers  where the monomer is a lysine esterified to the natural metabolite glycolic acid.  This polymer will contain ester groups between residues and its rate of biodegradation should be correspondingly faster.  If too fast, lactic acid can be substituted.  The potential uses of the polymer will range from drug delivery, to tissue engineering, to gene therapy.  [12/04]

Synthesis and Measurements of New Fluorous Reagents

Recently developed techniques for "fluorous synthesis" unite the reaction and separation processes in organic reactions (Refs. 1,2). Molecules bearing fluorous (highly fluorinated) tags can be separated from organic (non-tagged) molecules by fluorous liquid-liquid or solid-liquid extraction. And molecules bearing different fluorous tags can be separated from each other by fluorous chromatography. However, because the field is very young, there are relatively few fluorous reagents available to pair with the new separation techniques. Last year, undergraduate coworkers developed new fluorous carbobenzyloxy  (^FCbz) groups, protected both natural and unnatural amino acids with these groups, and used the protected amino acids in innovative new techniques like quasiracemic synthesis. That work is now being readied for publication. This year’s project will involve the synthesis of a new fluorous reagent or protecting group and the study of its use in representative organic transformations.
(1) A. Studer; S. Hadida; R. Ferritto; S. Y. Kim; P. Jeger; P. Wipf; D. P. Curran, Science 1997, 275, 823-826.  (2) Luo, Z. Y.; Zhang, Q. S.; Oderaotoshi, Y.; Curran, D. P. "Fluorous mixture synthesis: A fluorous-tagging strategy for the synthesis and separation of mixtures of organic compounds" Science 2001, 291, 1766-1769  [12/04]

Professor Joseph J. Grabowski

Recently, we have demonstrated two major advances in the construction of 5-membered rings by intramolecular carbometallation of alkenes.  1. Reductive lithiation of phenyl thioethers by aromatic radical-anions is the most versatile method of generating the organolithiums for that purpose.  2. An oxyanionic function allylic or homoallylic to the alkene has a powerful accelerating effect on the cyclization and controls the stereochemistry.  The project is to apply these two findings to the development of novel enantioselective syntheses of 5·5 fused ring nitrogen heterocycles.  A number of biologically important alkaloids contain these general ring structures.  In the following schemes, LDMAN and LDBB are aromatic radical-anions.  Reasonable assumptions are made about some of the steps.  The deprotonation step in Scheme 1 is well established by Peter Beak.  The reductive lithiation in the absence of THF in Scheme 1 has recently been pioneered in our lab.  It is necessary because of the ability of alkyllithiums to deprotonate THF at room temperature.  The first goal is to prepare 6 and measure its enantiomeric excess.  We have compound 3 in hand.  If time permits, a start on the preparation of 10 may be made.  [12/04]

Measuring Relative Rates of Microwave-Accelerated and Conventional Organic Synthesis

In recent years, powerful single-mode microwaves have found an increasing number of applications in organometallic chemistry and drug discovery. Many organic solvents are transparent for microwave radiation, and in these cases that dipolar starting materials and intermediates are directly responsible for absorption of microwave energy, and a dielectric heating mechanism is operative.  Rate acceleration is particularly effective when the polarity is enhanced from ground to transition state.  We have found that transition metals such as alkenylzirconocene and -zinc species are surprisingly stable in the microwave environment under elevated temperature and pressure and thus offer an attractive opportunity for a synthetically advantageous use of this technology.  Carbon-carbon bond formations of the type shown below will be studied and new experimental applications of microwave reactors will be developed.  [12/04]

Measuring the Structure of the Phenol Dimer:  High Resolution Electronic Spectroscopy Compared to ab initio Calculations.

Molecules can interact together leading either to the formation of a new molecule or to a molecular cluster.  In the former, covalent bonds are formed while in the latter, weaker noncovalent interactions come into play.  Noncovalent interactions are very important in chemistry and physics, and are of key importance in biology.  In this project, high resolution electronic spectroscopy in the gas phase (1)  will be used to determine the structure of the phenol dimer, a species in which two different types of noncovalent bonding play a role, hydrogen bonding between the OH groups of the two molecules, and dispersive interactions between the two aromatic rings.  The final, equilibrium structure of the dimer is determined by a competition between these two types of interactions.  Previously, the structure of this dimer has been measured by the low resolution rotational coherence technique (2).  Our experiments will provide a refined structure, which will further be compared to the results of  recent ab initio calculations (3)  [1/05]
(1) W.A. Majewski, et al., Laser Techniques in Chemistry, ed. A.B. Myers and T.R. Rizzo, John Wiley and Sons, 1995, p.101.  (2) L.L. Connell, et al., J. Chem. Phys. 96 (1992) 2585.  (3) P. Hobzda, et al., Chem. Phys. 283 (2002) 331.

Biomolecules in the Gas Phase.

The behavior of living systems is intimately related to the properties of the molecules from which they are constructed, especially their three-dimensional shapes.  This project is directed towards exploring this relationship.  High resolution laser techniques will be used to study the rotational motions of large biomolecules in the gas phase from which information about their shapes will be determined. Specific activities in this project, which is largely laboratory based, will be to participate in on-going experiments of this type that are being conducted by Ms. Jessica Thomas, a graduate student in the Pratt research group.  Currently, she is working on the b-sheet model system Ac-Phe-OMe and its dimer, (Ac-Phe-OMe)₂.  It is believed that the geometries of these two species are b-sheet related, representing (if true) the first observation of such a system in the gas phase.  Jessica’s experiments will test this hypothesis to determine whether or not it is true.  The interested undergraduate student(s) will learn the fundamentals of operation of the key instruments in this experiment, including the high resolution laser, a molecular beam machine, and high speed data acquisition systems.  Gaining familiarity with these equipments, and the physical principles upon which they are based, is an important part of this research experience.  Next, the student will participate in the experiments as a member of the research team.  If the experiments are successful, he/she will then contributed to the analysis of the results and to their presentations at research group meetings that will be held periodically during the term.  Publication of the final results in a peer-reviewed journal is a distinct possibility. [1/05]
Refs.  “Structure of the protected amino acid Ac-Phe-OMe and its dimer.   A beta-sheet model system in the gas phase”,  M. Gerhards and C. Unterburg, Physical Chemistry and Chemical Physics 4, 1760-1765 (2002).  “Structure of a beta-sheet model system in the gas phase.  Analysis of the C=O stretching vibrations”, M. Gerhards, C. Unterburg, and A. Gerlach, Physical Chemistry and Chemical Physics 4, 5563-5565 (2002).

Measuring electron transfer between electrodes and biomolecules

Measuring electron tunneling between molecules

Electron transfer reactions constitute a fundamental chemical process and are of intrinsic importance in biology, chemistry, and the emerging field of nanotechnology.  Biological processes such as photosynthesis and respiration rely on electron transfer between molecular subsystems that interact through a collection of covalent and noncovalent linkages. Our group is using supermolecules that contain electron donor and electron acceptor units to investigate how electrons tunnel from one side of a molecule to another and between two molecules.  The diagram illustrates the architecture of such a molecule in which the electron tunnels from the donor to the acceptor through a pendant moiety.  We are probing how the electron tunneling probability depends the motion of the pendant group in the cleft and the rotation of dipolar solvent molecules.  An REU student will investigate how the electron transfer rate constant depends on the frictional coupling between the tunneling barrier and the solvent.  [1/05] 
[A.M. Napper, N. J.Head, A.M. Oliver, M. J. Shephard, M. N. Paddon-Row, I. Read, and D. H. Waldeck “Use of U-shaped Donor-Bridge-Acceptor Molecules to Study Electron Tunneling Through Non-bonded Contacts” J. Am. Chem. Soc, 2002, 124, 10171-10181.

Measuring the structure of the Glycine Receptor

You will use overexpressed Glycine Receptor, a large membrane protein that is involved in electrical signaling between the nerve/nerve synapse.  You will incorporate spin labels at specific sites on this protein and use Fourier Transform electron spin resonance spectroscopy (a technique analogous to NMR) to measure the distance between labeled sites.  The data will provide constraints, which ultimately will lead to the development of a model for the structure of the the Glycine Receptor, in order to understand how signaling occurs between nerve-cells.  [2/05] 

Measuring Cellular Proteome Changes in Microtubule Stabilizer-Treated Cancer Cells

We are exploring how an important class of anticancer drugs, microtubule stabilizers (the clinically used Taxol and Taxotere, and investigational agents, e.g., (+)-discodermolide, (-)-laulimalide and their derivatives) alters the proteome in cancer cells. Proteomics, a multi-method analytical chemistry platform for measuring changes in protein levels and post-translational modifications, has recently been implemented in our labs. The methods and tools to be used include cell culture, difference 2D gel electrophoresis (a.k.a. DiGE), fluorescence image analysis, solution-phase isoelectric focusing, liquid and sample handling robotics, multidimensional nanoflow HPLC, isotope-coded affinity tagging, electrospray ionization ion trap mass spectrometry (MDLC-ESI-MS), matrix-assisted laser desorption time of flight mass spectrometry (MALDI-TOF-MS) and its tandem form for sequence analysis, MALDI-TOF/TOF-MS/MS (see figure).  [2/05]

Professor Kenneth D. Jordan

Professor Kazunori Koide

Professor Paul Floreancig

Electrochemistry of Biological Polyions at Polarized Liquid/Liquid Interfaces.

Measuring Dopamine and its Metabolites in the Brain

New antennae for the development of luminescent lanthanide complexes - Project 1

     Coordination  of the lanthanide ion to an organic molecule that absorbs UV light and efficiently converts the resulting energy to the metal ion is an essential requirement to construct luminescent lanthanide complexes.  This combination of absorption and energy transfer from the ligand is called an “antenna effect.”  The antenna effect  was discovered in 1942, yet only a small set of organic molecules have been used as antennae for the sensitization of the various lanthanide cations emitting in the visible (Sm³⁺, Eu³⁺, Tb³⁺, Dy³⁺) and in the near-infrared (Nd³⁺, Yb³⁺) ranges.
     We propose here to systematically investigate and test several potential ligands of the family of flavanoids as antennae.  The molecules are natural products (present in beverage and food such as green tea or vegetables) that have oxygen donor ligands suitable for the forming a strong bond between the ligand and the lanthanide cation.   So far, these have not been explored for their ability to sensitize lanthanide cations.  Some examples of flavanoids to be tested in this project are depicted in the figure.  This project includes the comparison between the results obtained experimentally and the prediction obtained by computational methods (using the CAChe software). [3/05]

New antennae for the development of luminescent lanthanide complexes - Project 2

     Medical and biological assays targeted at protein detection require highly sensitive detection methods for low concentrations of analytes.  It is also necessary to be able to perform many analyses in a short period of time and without preliminary purification of the sample.  Lanthanide complexes are ideal candidates  since their emission can be easily discriminated from complex mixtures of molecules. The very long luminescence lifetimes of these lanthanide complexes allow for an easy discrimination between signal and fluorescent background noise through time-resolved measurements
     We also propose to use dendrimer ligands as antenna.   The end-branches of the dendrimers have been functionalized with a naphthalamide type groups in order act as an antenna for the lanthanide cations.  The amide groups in the dendrimer core have the ability to bind several luminescent lanthanide cations. [3/045

Synthesis and Characterization of Near-Infrared Emitting Lanthanide Complexes - Project 3

The goal of this project is to synthesize and to study the spectroscopic properties of a planar tetradentate ligand and its corresponding complexes with luminescent lanthanide ions. The project will involve the synthesis of the ligand as well as the characterization of the lanthanide species formed in solution and will utilized a variety of spectroscopic techniques including FT-IR, NMR, UV-Vis absorption, mass spectroscopy, fluorescence, and phosphorescence. The possibility exists for advanced characterization techniques such as X-ray crystallography or quantum yield and luminescent measurements using xenon pulsed lamp and laser excitation. This ligand has been targeted due to its potential to effectively act as an antenna for lanthanide ion excitation. This research project would expand upon recent studies of other ligands of this family.  [3/05]

Cadmium Selenide Nanocrystals as Antenna for Luminescent Tb(III) - Project 4

Photographs taken of a series of aliquots of CdSe:Tb nanocrystals collected at different growth times. Samples are displayed from shortest growth time (15 sec) on the left to the longest growth time (4 hrs) on the right. The top image reveals the absorption of visible light, whereas the bottom image reveals the emission which results from illumination with UV light (354 nm). This image demonstrates the changes in photophysical properties that occur as the nanocrystals increase in size.

Biological assays involving luminescent molecules have become more prevalent due to their high sensitivity and moderate cost. With this comes an increasing demand for luminescent reporters possessing more advanced properties such as strong resistance to photobleaching and the ability to be discriminated from background fluorescence. Through the bridging of semiconductor nanocrystals with lanthanide cations, we hope to form molecules possessing desirable complementary and unique luminescence properties. We have recently shown that it is possible to incorporate luminescent lanthanide cations into CdSe semiconductor nanocrystals. This project will involve studying a number of coating procedures in an attempt to render our nanocrystals water soluble for use in biological assays.  [3/05]