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  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

The Objectives  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) Provide students with an opportunity to:

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

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, N Ac S, S N 2 (Mitsunobu), peptide synthesis, N Ar S, synthesis of ethers, enolates, use of protecting groups, spectroscopy, molecular modeling, scientific communication – parallels the chemistry introduced in class

Our target

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

Synthesis

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 ,

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)

Technology Connection #1 1.Is this pathway S N 2 or N Ar S? 2.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)?

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.

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

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

Example NMR data

NMR Expansions

Example Mass Spec and LC data M+1 at amu

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

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 13 C-NMR, 13 C-DEPT, and 1 H- 1 H-COSY  Adjust # of equivalents and observe changes  MECHANISMS  Must determine how much analysis is to be completed for “publication”

Communicating results Poster Formal Report Questions to Ponder

Pictures

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