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Title

Building Addressable Libraries: Site-Selective Cu(I) Reactions On Microelectrode Arrays

Date of Award

Spring 5-15-2012

Author's School

Graduate School of Arts and Sciences

Author's Department

Chemistry

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Microelectrode arrays have great potential as a platform for building and studying addressable molecular libraries. To do this, we need the ability to conduct chemical reactions on specific electrodes in the arrays and then analyze the binding of the resulting molecules to biological receptors.

As part of a larger effort to develop the synthetic chemistry that can be utilized on the arrays, a new Cu(I)-catalyst system was converted into a "site-selective" method. The effort proved very fruitful, and the use of Cu(I) on the arrays has allowed for the addition of nine new synthetic reactions to our arsenal of chip-based synthesis tools. In addition, we have developed a new TOF-SIMS cleavable linker for characterizing the molecules made. The overall strategy places a Cu(II)-reagent in solution, and then reduces it at selected electrodes in the array in order to generate the active Cu(I)-species just where it is needed. The resulting active species then catalyzes the reaction of choice. The reactions developed include a "click"-reaction between terminal alkynes and azides and a series of coupling reactions between aryl and vinyl halides with amine, alcohol, and thiol nucleophiles. In all of the reactions, oxygen is used as a confining reagent so the transformations occur only at the selected electrodes. It accomplishes this by reoxidizing any Cu(I) in the solution above the array before it can migrate to a remote site.

In addition to this work, a series of small peptides have been synthesized for testing the analytical capabilities of the arrays. The initial targets for ligand-receptor interactions were RGD peptides are recognized by integrin receptors. Previous research in the lab utilized a well-known technique, a hetero-Michael reaction, to place such peptides onto the arrays. However, recent research in the group has demonstrated that a Cu(I)-catalyzed reaction between an aryl bromide functionalized polymer surface and a thiol labeled peptide provides a superior method for accomplishing this task.

Language

English (en)

Chair and Committee

Kevin D Moeller

Committee Members

Joshua A Maurer, John-Stephen A Taylor, John R Bleeke, Garland R Marshall, Kendall J Blumer

Comments

Permanent URL: https://doi.org/10.7936/K7DB7ZRH

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