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A Research Project in the Second Semester Organic Chemistry Laboratory

A Research Project in the Second Semester Organic Chemistry Laboratory. Timm A. Knoerzer Nazareth College NERM 2004 Rochester, NY. The Problem. Students are usually not engaged in problem solving or critical thinking while in the laboratory

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A Research Project in the Second Semester Organic Chemistry Laboratory

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  1. A Research Project in the Second Semester Organic Chemistry Laboratory Timm A. Knoerzer Nazareth College NERM 2004 Rochester, NY

  2. The Problem • Students are usually not engaged in problem solving or critical thinking while in the laboratory • No connection of work from week to week (does not simulate the real world; the “one and done” scenario) • Chemistry not done in context (scientifically relevant) • Student do not always learn about modern chemical techniques and reactions • Limited integration of technology • Little exposure to structurally sophisticated molecules

  3. The Objectives Provide students with an opportunity to: • Do what real organic chemists do (perform a multi-step, multi-week project that requires students to plan, adapt, modify, improvise) • Learn modern/advanced chemical techniques • Use technology to support and explain experimental outcomes • Learn relevant chemistry (connected to what students are learning in class and are interested in) • Summarize and communicate the work (report and poster)

  4. Synopsis of The Project • Objective: To generate a diverse small molecule library of benzothiazine/amino acid/isothiocyanate hybrids • Context: Students are active participants in generating new compounds and in rehearsing critical synthetic transformations • Novelty: Synthesize a heterocycle that has limited precedence in the chemical literature (unknown utility) • Relevance: To ultimately explore the binding potential of these compounds toward various molecular recognition targets (receptors, enzymes, and other proteins) = bioorganic chemistry

  5. Synopsis of The Project • Strategy: Combinatorial chemistry in conjunction with the synthesis of key nitrocinnamic acid starting materials • Schedule: Spring semester -- Begins in week 5; ends in week 14 (total of 9 weeks) • Topics: carbonyl addition, NAcS, SN2 (Mitsunobu), peptide synthesis, NArS, synthesis of ethers, enolates, use of protecting groups, spectroscopy, molecular modeling, scientific communication – parallels the chemistry introduced in class

  6. Our target

  7. Combinatorial strategy Solid-phase parallel synthesis Total AA = 3, total NCA = 2, total SCN = 2 3 x 2 x 2 = 12 total compounds in this library

  8. Synthesis

  9. Synthesis

  10. Nitrocinnamic Acid Synthesis We have used this scheme to construct 13 novel substituted 2-nitrocinnamic acids McDonald, E; Suksamrarn, A. J. Chem. Soc., Perkin Trans. 11978, 440-446.

  11. Project Design • PowerPoint introduction to project • Students select synthetic units: • (2-3) amino acids • (2) nitrocinnamic acids • (1-2) phenyl isothiocyanates • may also select linker • Students are responsible for generating enough synthetic material to complete project (need ~20 mg of the final compound) • Students are responsible for using analytical and spectroscopic methods to confirm products • Students must decide if synthetic products are pure enough to continue – if not they must purify (e.g. chromatography)

  12. Technology Connection #1 • Is this pathway SN2 or NArS? • Why does the conversion occur para to the nitro group rather than meta upon exposure of the starting 4,5-dimethoxy compound to 20% KOH (aq)?

  13. Molecular Modeling (Spartan) The red line represents the energy of the transition state (kcal/mol) and the green line represents the charge on the incoming OH nucleophile.

  14. More Modeling Results Here surface value = +20 in range of –60 to +26 Here surface value = +13 in range of –60 to +26

  15. Technology Connection #2 How can you confirm the identity/purity of your products?

  16. Example NMR data

  17. NMR Expansions

  18. Example Mass Spec and LC data M+1 at 478.4 amu

  19. More Mass Spec and LC data M+1 at 483.2 amu “391” = loss of NH-Ph “348” = leftover starting material (incomplete rxn)

  20. Further Study and Extensions • Design TLC system to monitor the course of the Mitsunobu reaction and to perform subsequent column chromatographic purification • Determine how to obtain solid products that are free of solvent • Further confirmation of products by 13C-NMR, 13C-DEPT, and 1H-1H-COSY • Adjust # of equivalents and observe changes • MECHANISMS • Must determine how much analysis is to be completed for “publication”

  21. Communicating results Poster Formal Report Questions to Ponder

  22. Pictures

  23. Pictures

  24. Acknowledgements • Dr. Benjamin Miller (U of R Medical School Center for Future Health) • Dr. Paula Satterly-Childs • Nazareth College summer research students (Jessica Goodman, Jennifer Cahoon, Christina Gallis, Ed O’Neil, Ashanti Tolbert) • Graduate students in the the Miller group • Terry O’Connell • Organic chemistry students 2002-2004

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