Organic Chemistry III

1. Organic Chemistry III Classroom: Rm 121 Time: M-3,4 and T-1,2 教授: Tien-Yau Luh 陸天堯 Rm 621 Tel. 4088 tyluh@ntu.edu.tw 助教: Jiun-Le Shih 施俊樂 Rm 617 Tel. 4087 shihjiunle@ntu.edu.tw 課程網址: http://www.ch.ntu.edu.tw/~tyluh/course/course97/index.html

3. Syllabus • Introduction • Stereochemistry and Conformational Analysis • Pericyclic Reactions and Woodward Hoffmann Rule • Frontier Molecular Orbital Theory • Linear Free Energy Relationship and Kinetic Isotope Effect • Retrosynthetic Approaches and Selected Examples on Total Synthesis

4. Reference books Eric V. Anslyn and Dennis A. Dougherty “Modern Physical Organic Chemistry”, University Science Books, 2006. Francis A. Carey and Richard J. Sundberg “Advanced Organic Chemistry” Parts A and B, 4th Ed., Kluwer/Plenum, 2000. Michael B. Smith and Jerry March “Advanced Organic Chemistry” 5th Ed., Wiley, 2001 Robert B. Grossman “The Art of Writing Reasonable Organic Reaction Mechanisms”, 2nd Ed., Springer, 2003 Stuart Warren “Organic Synthesis: The Disconnection Approach” Wiley, 1984. • Book for fun Alex Nickon and Ernest F. Silversmith “Organic Chemistry: the Name Game”, Pergamon, 1987

5. Chapter 1 Introduction • What can an organic chemist do?--representative examples • Milestones of organic chemistry • Equilibrium and Thermodynamics--a brief review • Reaction Kinetics--a brief review

6. Professions and molecules • Chemists invent molecules. • Biologists apply molecules. • Physicists study molecules. • Engineers fabricate molecules. • Public enjoys molecules. Luh, T.-Y. 2005

7. Candles-soy bean-based chemistry

8. Explosives

9. Polymer oscillator Cf. White, T. J.; Tabiryan, N. V.; Serak, S. V.; Hrozhyk, U. A.; Tondiglia, V. P.; Koerner, H.; Vaiaa R. A.; Bunning, T. J. Soft Matter 2008, 4, 1796.

10. Photochromic materials Morimoto M.; Irie, M.Chem. Commun.2005, 3895.

11. Bacteria resistance to vancomycin Lessard, I. A. D.; Walsh, C. T. Proc. Nat. Acad. Sci. USA 1999, 96, 11028.

12. 506 x 2 = 1012 Spencer, D. M.; Wandless, T. J.; Schreiber, S. L.; G. R. Crabtree, Science1993, 262, 1019.

13. DNA cleavage Glatthar, R.; Spichty, M.; Gugger, A.; Batra, R.; Damm, W.; Mohr, M.; Zipseb, H.; Giese, B. Tetrahedron 2000, 56, 4117.

14. Bergmann rearrangement Kar, M.; Basak, A. Chem. Rev. 2007, 107, 2861.

15. Bergman rearrangement Kar, M.; Basak, A. Chem. Rev. 2007, 107, 2861.

16. DNA binding Dervan, P. B.Biorg. Med. Chem. 2001, 2215.

17. Behav. Ecol. Sociobiol. doi:10.1007/s00265-008-0620-6 (2008). Nature2008, 454, 920.

18. Renaissance in chemistry • Organic Chemistry just now is enough to drive one mad. It gives me the impression of a primeval tropical forest, full of the most remarkable things; a monstrous and boundless thicket, with no way of escape, into which one may well dread to enter. F. Wöhler, 1835 • Dissymmetry is the only and distinct boundary between biological and nonbiological chemistry. Symmetrical physical or chemical force cannot generate molecular dissymmetry. Louis Pasteur, 1851

19. Renaissance in chemistry • The structure known, but not yet accessible by synthesis, is to the chemists what the unclimbed mountain, the unchartered sea, the untilled field, the unreached planet, are to other men. R.B. Woodward, 1965 • When we have faced with a problem of effecting a chemical synthesis we have sought known methods. We have not paused to think why we do not invent a new method every time. If we adopt this philosophy we are going to be extremely busy till the end of the century (2000) (a) trying to equal the enzymes, and (b) thinking of new ways of synthesis. Derek H. R. Barton, 1969 • This notion (by Pasteur) is no longer true. The recent revolutionary development in asymmetric catalysis has totally changed the approach to chemical synthesis. Ryoji Noyori, 2001

20. Chemical synthesis If a definitive history of twentieth century science is ever written, one of the highlights may well be a chapter on the chemical synthesis of complex molecules. Elias J. Corey, 1990

21. 2005 Yves Chauvin, Robert H. Grubbs, Richard R. Schrock 2001 Williams S. Knowles, Ryoji Noyori, K. Barry Sharpless 2000 Alan Heeger, Alan G. MacDiamid, Hideki Shirakawa 1996 Robert F. Curl, Jr., Harold W. Kroto, Richard E. Smalley 1994 George A. Olah 1990 Elias J. Corey 1987 Donald J. Cram, Jean-Marie Lehn, Charles J. Pedersen 1984 Bruce Merrifield 1983 Henry Taube 1981 Kenichi Fukui, Roald Hoffmann 1979 Herbert C. Brown, Georg. Wittig 1976 William Lipscomb 1975 John Cornforth, Vladimir Prelog 1973 Ernst O. Fischer Geoffrey Wilkinson 1969 Derek Barton, Odd Hassel 1965 Robert B Woodward 1963 Karl Ziegler, Giulin Natta 1961 Melvin Calvin 1957 Alexander R. Todd 1953 Hermann Staudinger 1950 Otto Diels, Kurt Alder 1947 Robert Robinson 1938 Adolf Butenandt, Leopold Ruzicka 1938 Richard Kuhn 1937 Norman Haworth, Paul Karrer 1930 Hans Fischer 1928 Adolf Windaus 1927 Heinrich Wieland 1915 Richard Wilstaetter 1913Alfred Werner 1912 Victor Grignard, Paul Sabatier 1910 Otto Wallach 1905 Adolf von Baeyer 1902 Emil Fischer Nobel prize winners related to organic and inorganic chemistry

22. A B [C][D] [A][B] Equilibria: Two typical cases [B][products] K K= = 1. [A] [reactants] K = equilibrium constant [ ] = concentration in mol L-1 K A +B K = C + D 2. If K large: reaction “complete,” “to the right,” “downhill.” How do we quantify?Gibbs free energy, ∆G°

23. ∆G° = -RT lnK = -2.3 RT logK = -1.36logK Gibbs Free Energy, ∆G° T in kelvins, K (zero kelvin = -273 °C) R = gas constant ~ 2cal deg-1 mol-1 Large K : Large negative ∆G° : downhill

24. Equilibria and Free Energy At 25ºC (298°K): ΔGº = - 1.36 logK

25. Enthalpy ∆H° and Entropy ∆S° ∆G° = ∆H° - T∆S°cal-1 deg-1 mol-1 or entropy units, or e.u. Kcal mol-1 Enthalpy ∆H° = heat of the reaction; for us, mainly due to changes in bond strengths: ∆H° = (Sum of strength of bonds broken) – (sum of strengths of bonds made)

26. Bond energies (Kcal/mol)

27. Example: + CH3CH2―H Cl―Cl CH3CH2―Cl + H―Cl 101 58 84 103 ∆H° = 159 – 187 = -28 kcalmol-1 ∆H° negative: called “exothermic” if positive: called “endothermic” ∆S° = change in the “order”of the system. Nature strives for disorder. More disorder = positive ∆S ° (makes a negative contribution to ∆G° )

28. Chemical example: CH2CH2 +HCl CH3CH2Cl 1 molecule 2 molecules ∆H° = -15.5 kcal mol-1 ∆S° = -31.3 e.u. If # of molecules unchanged, ∆S° small, ∆H° controls ( we can estimate value from bond strength tables)

29. Kinetics • Rate law and reaction mechanisms A steady state approach Example: SN1 reaction JACS 1966, 88, 2599.

30. Hammond Postulate “Early TS” “Late TS”

31. Curtin-Hammett Principle

32. Kinetic vs thermodynamic control

34. Intramolecular vs Intermolecular Reactions Intramolecular versus intermolecular reactions benefit from a far more favorable entropy of activation

35. In forming small rings, ring strain developing in the product decelerates the rate of reaction (large enthalpy of activation) that can offset the favorable entropy of activation rate acceleration.

36. Geminal dimethyl effect (Thorpe Ingold effect)