On the Web edited by
William F. Coleman Wellesley College Wellesley, MA 02481
Synthesis and Testing of Molecules of Medical Interest William F. Coleman Department of Wellesley College; Wellesley, Massachusetts 02481
[email protected] w This paper contains enhanced objects available on the Internet at http://pubs.acs.org/jchemeduc. n
JCE Featured Molecules for June 2010 Four articles in this issue offer new ways of introducing students to molecules of importance in the field of medicinal chemistry (1-4). This is done through a variety of synthetic routes, including the use of microwave radiation and reactions on solid supports, multiple chromatographic and spectroscopic methods, an introduction to computational conformational chemistry, and several methods for assessing the biological activity of the compounds that are prepared. Molecules from each of these papers are added to the collection this month, as listed in Table 1. Structures of two of the species discussed in these papers are shown in Figure 1 and 3D, rotatable images in MOL format of all the molecules are available in the HTML version of this paper. Featured molecules from past issues are available in the molecule collection at the JCE Digital Library (5). James T. Fletcher and Grit Boriraj describe the synthesis, characterization, and assay for a benzodiazepine derivative that is related to that found in Valium and Xanax (1). All of these species are included in the molecule collection. A theme that runs through the four papers is the synthesis of a backbone structure and one or more derivatives. Students could easily explore the effect of substituents on the detailed geometry of the backbone. Lawrence L. W. Cheung, Sarah A. Styler, and Andrew P. Dicks give us an experiment involving the synthesis of two derivatives of 1,4-dihydropyridine, and connect the products to several related substances used as calcium channel blockers. The synthetic route makes use of a very old (1881) reaction, the Hantzsch reaction, which is receiving renewed interest as more emphasis is being placed on green chemistry. In their online supporting information, the authors show optimized structures for the channel blockers lacidipine and nifedipine at the AM1 level. They note that the phenyl substituent in the 4 position of the dihydropyridine ring lies above and pointing away from the backbone. An interesting computational problem for students in physical chemistry would be to compute the barrier to rotation for this ring as the energy of the minimum energy structure having the substituent ring over the dihydropyridine ring is very similar at the AM1 level. At the PM6 level, the structure with the substituent over the backbone ring is slightly lower in energy. At the HF-631-G(d) level, calculations again indicate that only a few kcal/mol separate the energies of these two conformations. Thibault Coursindel, Jean Martinez, and Isabelle Parrot employ microwave radiation and reactants on solid supports to 654
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Figure 1. Molecules of medical interest: Valium (1) and penicillin (4).
prepare a small library of molecules related to hydantoin. Structures of hydantoin and several derivatives have been included in the collection. This experiment offers another entree into a discussion of sustainable chemistry and the role of solidstate reactions in reducing chemical waste. Ragnhild D. Whitaker, Laura M. Truhlar, Deniz Yuksel, David R. Walt, and Mark D. Williams continue the theme of medically related molecules in an experiment describing the synthesis of a wide range of penicillin derivatives and the testing of the substances for antimicrobial activity. Structures for a model penicillin with a methyl terminal group, penicillin-G, and the starting material 6-aminopenicillanic acid are in the molecule collection. Crystal structures of many penicillin derivatives are available in the primary literature and students should be urged to compare the structures found there to those resulting from calculation at the Hartree-Fock level (631-G(d) in all cases). All of these experiments should engage students in organic and biochemistry courses. The procedures produce important molecules, many of which are analogs of molecules that students are familiar with from their everyday lives. Such experiments may well have a beneficial effect on the way students see their chemical life blending into the rest of their lives. All of the experiments have at least one feature that would allow for introducing ideas of sustainable chemistry, and having students consider the tie-ins between chemistry and economics, something that many of them are interested in, and a subject that a
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Vol. 87 No. 6 June 2010 pubs.acs.org/jchemeduc r 2010 American Chemical Society and Division of Chemical Education, Inc. 10.1021/ed100351t Published on Web 04/23/2010
On the Web Table 1. Molecules from June 2010 Articles Added to the JCE Featured Molecules Collection Article in June 2010 Issue
Featured Molecule
Benzodiazepine Synthesis and Rapid Toxicity Assay (1)
2,3-Dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine: HF-631-G(d) level Valium: HF-631-G(d) level Valium: PM6 level Xanax: HF-631-G(d) level
Rapid and Convenient Synthesis of the 1,4-Dihydropyridine Privileged Structure (2)
Diludine: HF-631-G(d) level Lacidipine: PM6 level Nifedipine: HF-631-G(d) level Nifedipine: PM6 level Nifedipine, ring rotated: HF-631-G(d) level Nifedipine, ring rotated: PM6 level
Microwave-Assisted Hydantoins Synthesis on Solid Support (3)
HMR 1794: HF-631-G(d) level Hydantoin: HF-631-G(d) level Phenytoin: HF-631-G(d) level Spiro-thiohydantoin: HF-631-G(d) level
Synthesis and Biological Testing of Penicillins: An Investigative Approach to the Undergraduate Teaching Laboratory (4)
6-Amino-penicillanic acid: PM6 level Penicillin (model): PM6 level Penicillin (model): HF-631-G(d) level Penicillin G: HF-631-G(d) level
number of chemistry students choose as a minor or second concentration. Literature Cited 1. Fletcher, J. T.; Boriraj, G. Benzodiazepine Synthesis and Rapid Toxicity Assay. J. Chem. Educ. 2010, 87, DOI: 10.1021/ ed100185n. 2. Cheung, L. L. W.; Styler, S. A.; Dicks, A. P. Rapid and Convenient Synthesis of the 1,4-Dihydropyridine Privileged Structure. J. Chem. Educ. 2010, 87, DOI: 10.1021/ed100171g.
r 2010 American Chemical Society and Division of Chemical Education, Inc.
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3. Coursindel, T.; Martinez, J.; Parrot, I. Microwave-Assisted Hydantoins Synthesis on Solid Support. J. Chem. Educ. 2010, 87, DOI: 10.1021/ed100169f. 4. Whitaker, R. D.; Truhlar, L. M.; Yuksel, D.; Walt, D. R.; Williams, M. D. Synthesis and Biological Testing of Penicillins: An Investigative Approach to the Undergraduate Teaching Laboratory. J. Chem. Educ. 2010, 87, DOI: 10.1021/ed100194v. 5. JCE Featured Molecules from June 2002 through December 2009 are available at the JCE Digital Library, http://www.jce.divched.org/ JCEWWW/Features/MonthlyMolecules/ (accessed Apr 2010).
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