A Research Project in the Second Semester Organic Chemistry LaboratoryTimm A. KnoerzerNazareth College

NERM 2004Rochester, NY

The ProblemStudents are usually not engaged in problem solving or critical thinking while in the laboratoryNo 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 reactionsLimited integration of technologyLittle exposure to structurally sophisticated molecules

The ObjectivesDo what real organic chemists do (perform a multi-step, multi-week project that requires students to plan, adapt, modify, improvise)Learn modern/advanced chemical techniquesUse technology to support and explain experimental outcomesLearn 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 ProjectObjective: To generate a diverse small molecule library of benzothiazine/amino acid/isothiocyanate hybridsContext: Students are active participants in generating new compounds and in rehearsing critical synthetic transformationsNovelty: 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 ProjectStrategy: Combinatorial chemistry in conjunction with the synthesis of key nitrocinnamic acid starting materialsSchedule: 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

Our target

Combinatorial strategyTotal AA = 3, total NCA = 2, total SCN = 2

3 x 2 x 2 = 12 total compounds in this librarySolid-phase parallel synthesis

Synthesis

Synthesis

Nitrocinnamic Acid SynthesisWe have used this scheme to construct 13 novel substituted 2-nitrocinnamic acidsMcDonald, E; Suksamrarn, A. J. Chem. Soc., Perkin Trans. 1 1978, 440-446.

Project DesignPowerPoint introduction to projectStudents select synthetic units:(2-3) amino acids(2) nitrocinnamic acids (1-2) phenyl isothiocyanatesmay also select linkerStudents 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 productsStudents must decide if synthetic products are pure enough to continue if not they must purify (e.g. chromatography)

Technology Connection #1Is 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)?

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 ResultsHere surface value = +20 in range of 60 to +26Here surface value = +13 in range of 60 to +26

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

Example NMR data

NMR Expansions

Example Mass Spec and LC dataM+1 at 478.4 amu

More Mass Spec and LC dataM+1 at 483.2 amu391 = loss of NH-Ph348 = leftover starting material (incomplete rxn)

Further Study and ExtensionsDesign TLC system to monitor the course of the Mitsunobu reaction and to perform subsequent column chromatographic purificationDetermine how to obtain solid products that are free of solventFurther confirmation of products by 13C-NMR, 13C-DEPT, and 1H-1H-COSYAdjust # of equivalents and observe changesMECHANISMSMust determine how much analysis is to be completed for publication

Communicating resultsPosterFormal ReportQuestions to Ponder

Pictures

Pictures

AcknowledgementsDr. 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 ONeil, Ashanti Tolbert)Graduate students in the the Miller groupTerry OConnellOrganic chemistry students 2002-2004