Khalid Baig Mirza defends his Ph.D. thesis at Drexel University on December 6, 2010 (advisor JC Bradley). He first discusses Open Notebook Science and his contribution to the sodium hydride oxidation controversy. Then he describes the UsefulChem project, involving the use of the Ugi reaction as an approach to synthesizing new anti-malarial agents, including a few unexpected side reactions and challenges. Finally he presents an overview of the ONS Solubility Challenge and its application to organic synthesis.

1. Khalid Baig Mirza Advisor : Prof. Jean-Claude Bradley Drexel University Prof Frank Ji (Chair) , Prof. Susan A. Varnum, Prof. Sally Solomon, Prof Peter Wade, Prof. Louis Scerbo, Prof. Jun Xi

6. Wang’s ketones...

8. Green: 1-phenylethanol Blue: acetophenone Red: product HNMR Overlay PPM

9. Green: acetophenone Blue:1-phenylethanol Red: product IR Overlay

11. Lewis E., G.; J. Org. Chem ; 30; 7; 2433–2436 (1965) Scientific communication through social networks- Blog

17. Proposed mechanism for the dehydration of adrenaline to DOPAL

18. Ugi reaction The reaction did not produce the desired Ugi product

20. A Mechanistic Insight

21. Imine kinetics a- Alicia Holsey, b- James Giammarco, c- Sean Gardner 0.1043 c CD3OD 5-methylfurfurylamine 3,4,-dihydroxybenzaldehyde 0.008 b CD3OD t-butyl amine piperonal 0.1552 a CD3OD 5-methylfurfurylamine piperonal 0.07 a CDCl3 5-methylfurfurylamine piperonal 0.106 CD3OD 5-methylfurfurylamine veratraldehyde 0.01 CDCl3 5-methylfurfurylamine veratraldehyde Imine formation rate constant 1/(M*min) solvent amine aldehyde

22. Ugi reaction

25. Furfuryl Cleavage The unusual elimination was seen in Ugi products containing the N-furfuryl group.

26. Reactivity of furan derivatives acidic media Butin, A.,V; Stroganova, T.; Lodina, I., V.; Krapivin, G., D.; Tet. Lett; 42; 10; 2031-2033; (2001) Reissert modification-indole synthesis

27. Furan ring opening with lewis acid Piancatelli, G.; Scettri, A.; David, G.; D’Auria, M.; Tetrahedron; 34; 18; 2775-; (1978)

28. 1, 6-Hoffman elimination of quaternary amines Appropriately substituted quaternary ammonium hydroxides undergo loss of trimethyl amine across a furan or thiophene to unusual cyclic conjugated trienes, there dimmers and polymers Winberg, H., E.; Fawcett, F., S.; Mochel, W.,E.; Thebald, W., C.; J. Amer. Chem .Soc ; 82; 6; 1428-1435; (1959)

30. k = 0.9x10-3 min-1 k = 0.9x10 -3 min -1

31. k = 1.2x10 -3 min -1

32. k = 0.9x10 -3 min -1

33. Proposed mechanism for furfuryl cleavage

34. No methyl group- The cleavage is a thousand times slower than the methyl furfuryl analogs cleavage under the same conditions k= 4x10 -6 min -1 A different mechanism needed... Non-methylated furfuryl analog cleavage

35. Mechanism for the furfuryl cleavage for the non methylated analog

41. Results of the Optimization study Statistical analysis: Prof. Kevin Owens

47. Ugi reaction precipitation trends Correlation in terms of isocyanide Carboxylic acid – boc-glycine 35 % 0 0 107 tosylmethyl isocyanide 11 23 215 t-butyl isocyanide 4 5 120 n-butyl isocyanide 13 10 77 cyclohexyl isocyanide 7 3 43 benzyl isocyanide 0 0 13 2-morpholinoethyl isocyanide 0 0 4 2-chloro-6-methyl phenyl isocyanide 0 0 38 1-pentyl isocyanide 0 0 32 1,1,3,3-tetramethylbutyl isocyanide Percent precipitation number of product precipitations Number of reaction Isocyanide

49. Anti-malarial activity results

53. Solubility issues 0.14 toluene 17 0.104 methanol 16 0.07 hexane 15 0.44 ethyl acetate 14 0.1 ethanol 13 0.1 diethyl ether 12 0 dichloromethane 11 0.03 cyclopentane 10 0.07 cyclohexane 9 0.04 chloroform 8 0.66 benzene 7 0.153 acetonitrile 6 1.29 THF 5 0.77 DMSO 4 1.25 DMF 3 0.07 2-propanol 2 0.02 1,1,2-trichlorotrifluoroethane 1 Ave. (M) Solvent Solubility of phenanthrene-9-carboxaldehyde 0 toluene 16 0.014 methanol 15 0 hexane 14 0.06 ethanol 13 0.02 diethyl ether 12 0.07 dichloromethane 11 0 cyclopentane 10 0 cyclohexane 9 0.03 chloroform 8 0 carbon tetrachloride 7 0 benzene 6 0 acetonitrile 5 0.55 THF 4 2.067 DMSO 3 1.88 DMF 2 0.06 2-propanol 1 Ave. (M) Solvent Solubility of 1-pyrenebutyric acid

57. Hemiacetal of 4-nitrobenzaldehyde in methanol (3:1 aldehyde: hemiacetal ratio) Solute- Solvent reaction

58. 2-chloro-5-nitrobenzaldehyde in methanol (2:3 aldehyde: hemiacetal ratio) Solute- Solvent reaction

65. Books published..