Nanette M. Wachter-Jurcsak
Associate Professor of Chemistry
Degrees: PHD, 1995, Univ Connecticut; MS, 1990, Old Dominion Univ; BS, 1982, St Lawrence Univ
Bio: Research Interests: 1. Synthesis of Furoxans and Evaluating Their Potential as NO-Releasing Pharmaceuticals
Nitric oxide (NO) is an important intercellular signaling molecule and plays a role in a variety of biological processes. NO is a relatively stable molecular free radical produced in biological systems that is capable of scavenging harmful free radicals in vivo. Nitric oxide has many physiological roles; NO serves as a chemical messenger and is involved in the immune, nervous and cardiovascular systems. NO regulates blood vessel dilation, serves as a neurotransmitter, and is involved in the immune response and the regulation of cell death (apoptosis). Recently, 1,2,5-oxadiazole-2-oxides (furoxans, Figure 1) have been shown to release NO in the presence of thiol cofactors. Furoxan derivatives, therefore, may serve therapeutically as NO-generators in vivo. Our research focuses on the synthesis of symmetrically substituted 3,4-dibenzoyl-1,2,5-oxadiazole-2-oxides and, in collaboration with Dr. Nirode, investigating the ability of these compounds to serve as nitric oxide-releasing pharmaceutical agents.1 A combination of spectroscopic techniques are used to characterize the heterocyclic products.
Figure 12. Solvent Effects on Inter- and Intramolecular Hydrogen Bonding in Conjugated Systems.
Hydrogen bonds play an important role in the conformations of biomolecules and are essential to many biochemical reactions. Proton nuclear magnetic resonance spectroscopy is ideal for investigating hydrogen bonds. When hydrogen bonding occurs, the chemical shift of the proton involved in bonding appears further downfield. Low temperature NMR, in particular, is useful for probing hydrogen bonds in solution because proton exchange is slowed. Hydroxyl protons involved in strong intramolecular hydrogen bonding interactions also exchange slowly.
We have measured the 1H NMR spectra of 2'- and 4'-hydroxyacetophenones, 2'- and 4'-hydroxychalcones, and 4-N,N-dimethylamino-2'- and 4'-hydroxychalcones in a variety of deuterated polar aprotic, weakly polar and nonpolar sovents at varying temperatures.2 Ortho-Hydroxyacetophenone and 2'-hydroxychalcones are capable of intramolecular hydrogen bonding between the ortho-hydroxy group and the carbonyl oxygen. In both nonpolar and polar environments, the signal for the phenolic hydrogen 4-N,N-dimethylamino-2'-hydroxychalcone (DMAHC) appears far downfield (>13 ppm) and shifts further downfield as the temperature is lowered.2a Moderately polar and polar aprotic solvents stabilize intramolecular charge transfer and thus enhance resonance-assisted intramolecular hydrogen bonding (RAHB) in DMAHC. As the vibrational energies of the molecules decrease with decreasing temperature, solvent contraction and the degree of solvent molecule reorganization stabilizes charge polarization in the polar solute and supports resonance-assisted intramolecular hydrogen bonding. On the otherhand, para-hydroxyacetophenone and chalcones are not capable of intramoleuclar hydrogen bonding but can participate in solute-solute and solute-solvent intermolecular interactions. While the chemical shift for the phenolic hydrogen of 4'-hydroxyacetophenone and 4'-hydroxychalones does not appear as far downfield, the magnitudes of the temperature dependent proton chemical shifts are much greater than those observed for the ortho-hydroxy isomers. We are continuing to investigate solvent effects on intermolecular hydrogen bonding in these systems by variable temperature proton NMR.3. Reactivity of 2-Pyridinylcarboxaldehyde in Claisen-Schmidt Condensation Reactions.
While investigating the properties of 4-substituted and heteroaromatic chalcones, prepared by base-catalyzed condensation of appropriate aromatic carboxaldehydes with acetophenone, we encountered an unanticipated kinetic effect on the reactions involving 2-pyridinecarboxaldehyde and 2-quinolinecarboxaldehyde with acetophenone (Scheme 2).3 When 2-pyridinecarboxaldehyde is treated with two equivalents of either the lithium, sodium, or potassium enolates of acetophenone, the reaction proceeds rapidly at room temperature and high yields (+90%) of 1,5-diphenyl-3-(2-pyridinyl)-1,5-pentanedione are achieved. Similar treatment of 2-quinolinecarboxaldehyde with two equivalents of the sodium enolate of acetophenone results in precipitation of 1,5-diphenyl-3-(2-quinolyl)-1,5-pentanedione from the reaction. Lewis bases have been shown to catalyze aldol reactions by altering the aggregation state, and thereby the reactivity, of the metal enolate.4 Our results suggest that interaction between the pyridinyl aldolate and metal ion is significant for systems containing 2-pyridinyl or 2-quinolyl ring systems.
1 Nirode, W. F.; Luis, J. M.; Wicker, J. F.; Wachter, N. M. Bioorg. Med. Chem Lett., 2006, 16(8), 2299-2301.2 (a) Wachter-Jurcsak, N.; Detmer, C.A. Org. Lett. 1999, 1(5), 795-8. (b) Brack, T. L.; Conti, S.; Radu, C.;Wachter-Jurcsak, N. Tetrahedron Lett. 1999, 40, 3995-3998.3 (a) Wachter-Jurcsak, N.; Redin, K.J. Chem. Educ. 2001, 78, 1264-1265. (b) Wachter-Jurcsak, N.; Radu, C.; Redin, K. Tetrahedron Lett. 1998, 39, 3903-3906. (c) Wachter-Jurcsak, N.; Zamani, H.J. Chem. Educ. 1998, 76, 653-654.4 (a) Hall, P.L.; Harrison, A.T.; Fuller, D.J.; Collum, D.B.J. Am. Chem. Soc. 1991, 113, 9575-85. (b) Willard, P.G.; Hintze, M.J.J. Am. Chem. Soc. 1990, 112, 8602-4. (c) Willard, P.G.; Salvino, J.M. Tetrahedron Lett. 1985, 26, 3931-4.