1. Synthesis and Characterization of Aminodipyridylphosphine Oxide Iron(II) Complexes. Catalytic Application on Microwave-Assisted Amidation of Aldehydes 指導教授 : 于淑君 博士 2013 / 07 /25 1 學 生 : 蔡俊偉

2. 2 Green Chemistry 化學反應的綠色化  原子經濟反應 產品的綠色化  環境友好產品 溶劑的綠色化  無毒無害的溶劑 原料的綠色化  無毒無害的原料  可再生資源 觸媒的綠色化  無毒無害的觸媒 能源的綠色化  提升能源的效率 如微波 Chahbane, N.; Popescue, D., L.; Mitchell, D., A.; Chanda, A.; Lenoir, D.; Ryabov, A.D.; Schramm, K., W. and Collins, T., J. Green Chem. 2007, 9, 49–57.

3. Green Catalysts Solid acid catalysts – Ex, Nafion-H, SO 4 2- /ZrO2 、 SO 4 2- /TiO 2, … HPA catalysts – H 3 PMo 12 O 40, H 4 PW 11 VO 40 Zeolite catalysts – ZSM-5, X-type, Y-type Metal catalysts – heterogeneous catalysis, homogeneous catalysis Enzyme 3 Sheldon, R., A.; Arends, I., W.,C., E.; and Hanefeld, U. (2007) Green Chemistry and Catalysis, Wiley-VCH Verlag GmbH, Weinheim

4. 4 Application of Green Chemistry Sonogashira coupling timeyield (%) Conventional18h80 Microwave assisted25 min97 Epoxidation 物質動物, 途徑 Lethal Dose, 50% (LD 50 ) FeCl 3.6H 2 O 大鼠, 口服 1872 mg/ kg FeCl 2.4H 2 O 大鼠, 口服 1678 mg/ kg RuCl 3 大鼠, 口服 210 mg/kg Anilkumar, G.; Bhor, S.; et. al. Tetrahedron Asymm., 2005, 16, 3536–3561 Hasan, K.; Browne, N. and Kozak, C.,M. Green Chem., 2011, 13, 1230.

5. 5 Phosphine Ligand Phosphines are electronically and sterically tunable. Chemical waste - water bloom Air/water sensitive and thermally unstable. Metal leaching.. Expensive. Kinzel, E. J. Chem. Soc. Chem. Commun. 1986 1098.

6. The Importance of Fe(II) Iron is one of the most abundant metals on earth. (5.6% of earth’s crust. 4th most abundant element after oxygen, silicon, and aluminum. Iron is environmentally friendly metal Low toxic In body play a important role to transport oxygen (woman 2.5g ， man 4g) 60 mg/kg to iron poisoning 6

7. The Catalytic Applications of Fe(II)  Ring Opening Reactions  Kharasch Reaction  Cross-Coupling Reactions  Mukaiyama-aldol reaction  Cycloadditions  [2+1]-Cycloadditions  [2+2]-Cycloadditions  Acetalization  Diels-Alder Reaction  Sulfide Oxidations  Aminochlorination  Allylic Aminations  Baeyer-Villiger Reactions  Amidation Reaction 7

8. Amide Bond C. A. G. N. Montalbetti, V. Falque Tetrahedron, 2005, 61, 10827–10852 8

9. Application of Acyl Sulfonamides HCV NS5B polymerase allosteric inhibitors antitumor activity 9 Navitoclax S. Jana, F. Hof. J. Org. Chem. 2011, 76, 3733–3741 Hepatitis C Virus Non-structural protein 5B, NS5B

10. Acyl Sulfonamides 10 J. Chan,* K. D. Baucom, and J. A. Murry J. Am. Chem. Soc. 2007,, 129, 14106-14107 J. W. W. Chang and P. W. H. Chan*, et al. Angew. Chem. Int. Ed. 2008, 47, 1138-1140 J. W. W. Chang and P. W. H. Chan*,et.al. J. Org. Chem. 2011, 76, 4894-4904

11. 11 Motivation  Well-defined structure  Iron is environmentally friendly metal  Iron is less expensive than other transition metals. - Rh 2 (esp) 2 $ 30172 USD/mol ReagentPlus ® (Aldrich) - Ru(TTP)CO $ 20740 USD/mol reagent grade (Sigma-Aldrich) - FeCl 2. 4H 2 O $ 148 USD/mol reagent grade (Sigma-Aldrich)  Using bipyridine ligand to replace phosphine ligand in organomatallic catalysis.  Microwave to replace thermal energy

12. 80 % Synthesis of 4C-Ppy 2 and (4C-Ppy 2 ) 2 FeCl 2 IR (KBr) : py Ring stretching = 1590(s), 1426(s) cm -1 12 80 %

13. IR Spectra of 4C-Ppy 2 and (4C-Ppy 2 ) 2 FeCl 2 ν C － C (Py ring) ν C － N (Py ring) Wavenumber (cm -1 ) pyridine ring vibration ν(C = N) Δν Ln- FeCl 2 a 1650 → 166818 PdCl 2 (2-pmOpe) 2 b 1594 → 160915 11C-Ppy 2 -Cu(OTf)1570 → 159222 11C-Ppy 2 -NiBr 2 1577 → 159215 11C-Ppy 2 -Pd(OAc) 2 1574 → 158612 11C-Ppy 2 -MnCl 2 1574 → 158612 b. a. Hahn, F. E.; Langehahn, V.; Lügger, T.; Pape, T.; Le Van, D. Angew. Chem. Int. Ed. 2005, 44, 3759-3763. Zerong, L.; Zhongquan, L.; Ning, M. and Biao, W. Bull. Korean Chem. Soc. 2011, 32, 2537-3543 wavernumber

14. Iron Complexes –Catalyzed Amidation Reactions of Aldehyde with PhINTs 14 entrycatalyticYield(%) a 1 FeCl 2 ． 4H 2 O 20 2 FeCl 3 ． 6H 2 O 15 3FeCl 2 + 4C-Ppy 2 90 4FeCl 3 + 4C-Ppy 2 76 a Yields were determined by H-NMR. Reaction conditions: aldehyde (1 equiv.), PhINTs (1.5 equiv.), catalyst (0.05 equiv.), solvent = 0.67 mL, 50 o C, 3 hr

15. AA Spectrum of [CH 3 (CH 2 ) 3 N(H)P(O)(2-py) 2 ] 2 FeCl 2 15 1.467  10 -6 mol/mg Fe ppm 吸收度 30.153 60.267 90.365 120.483 150.562 mol/mg Fe 1 1.679  10 -6 2 1.653  10 -6 3 1.589  10 -6 2.487  10 -6 mol/mg Fe Calculated base on chemical formula experimental AA data

16. 16 Colorimetry of [CH 3 (CH 2 ) 3 N(H)P(O)(2-py) 2 ] 2 FeCl 2 1,10-Phenanthroline Fe 2+ + 3phen  (phen) 3 Fe(II ) Visible spectrum of (phen) 3 Fe(II) max = 510nm (4C-Ppy 2 ) 2 -FeCl 2 (3) mol/mg FeCl 2 ·4H 2 O mol/mg 理論值 a 1.48 × 10 -6 5.031 × 10 -6 AA 實驗值 1.58 × 10 -6 4.671 × 10 -6 傳統比色分析 1.42× 10 -6 3.783 × 10 -6 二價鐵純度 b 80 %81 % a.Calculated base on chemical formula b. ( 傳統比色分析 / AA 實驗值 ) × 100% Harvey, J.; Aubrey, E.; John, A. Smart, Analytical Chemistry 1955, 27, 26-29.

17. ESI-MS Spectrum of [CH 3 (CH 2 ) 3 N(H)P(O)(2-py) 2 ] 2 FeCl 2 [CH 3 (CH 2 ) 3 N(H)P(O)(2-py) 2 ] 2 FeCl 2 + = 641 (m/z) Simulated MS Data [CH 3 (CH 2 ) 3 N(H)P(O)(2-py) 2 ]FeCl 2 + = 366 (m/z) Experimental MS Data 17

18. EPR Spectrum of [CH 3 (CH 2 ) 3 N(H)P(O)(2-py) 2 ] 2 FeCl 2 18 g = 2.199 g = 2.04 (radical) 77 k, MeOH 300 k, MeOH Li Zhong-Fang, et al. Chinese Journal of Inoranic chemistry 2003, 19.7, 691-698.

19. 80 % 93 % Synthesis of 11C-Ppy 2 Lin, Y.-Y; Tsai, S.-C.; Yu, S. J. J. Org. Chem. 2008, 73, 4920-4928. 19

20. 20 Synthesis of (11C-Ppy 2 ) 2 -FeCl 2 IR (KBr) : py Ring stretching = 1588(s), 1425 (s) cm -1

21. IR Spectra of 11C-Ppy 2 and (11C-Ppy 2 ) 2 -FeCl 2 21 1575cm -1 1424cm -1 1588cm -1 1426cm -1 Wavenumber T( %) ν C － C (Py ring) ν C － N (Py ring) 2

22. AA Spectrum of [HO(CH 2 ) 11 N(H)P(O)(2-py) 2 ] 2 FeCl 2 22 1.106  10 -6 mol/mg Fe 1.937  10 -6 mol/mg Fe mol/mg Fe 1 1.324  10 -6 2 1.413  10 -6 experimental AA data Calculated base on chemical Formula

23. 23 Colorimetry of [HO(CH 2 ) 11 N(H)P(O)(2-py) 2 ] 2 FeCl 2 1,10-Phenanthroline Fe 2+ + 3phen  (phen) 3 Fe(II ) Visible spectrum of (phen) 3 Fe(II) max = 510nm (11C-Ppy 2 ) 2 -FeCl 2 (6) mol/mg FeCl 2 ·4H 2 O mol/mg 理論值 a 1.11 × 10 -6 5.031 × 10 -6 AA 實驗值 1.32 × 10 -6 4.671 × 10 -6 傳統比色分析 1.03× 10 -6 3.783 × 10 -6 二價鐵純度 b 78 %81 % a.Calculated base on chemical formula b. ( 傳統比色分析 / AA 實驗值 ) × 100% Harvey, J.; Aubrey, E.; John, A. Smart, Analytical Chemistry 1955, 27, 26-29.

24. ESI-MS Spectrum of [HO(CH 2 ) 11 N(H)P(O)(2-py) 2 ] 2 FeCl 2 [HO 3 (CH 2 ) 11 N(H)P(O)(2-py) 2 ] 2 FeCl + = 869 (m/z) 24 Simulated MS Data Experimental MS Data

25. Optimization of Reaction Conditions entryPhINTs(equiv.)temp.hourcolventconv.% 12rt18CH 2 Cl 2 87% 224018CH 2 Cl 2 95% 32406CH 2 Cl 2 85% 40.5406CH 2 Cl 2 56% 51.5406CH 2 Cl 2 88% 61.5403CH 2 Cl 2 56% 71.5403CHCl 3 89% 81.5403CH 3 CN65% 9b9b 1.54018CHCl 3 30% 101.5rt3CHCl 3 50% 25 5 mol % b. no cat.

26. entrysolventtime (hr) Polarity (P ＊ )yield a (%) 1CHCl 3 34.189 2CH 2 Cl 2 33.156 3CH 2 Cl 2 685 4CH 3 CN35.865 5CH 2 Cl 2 : Toluene = 1 : 130.5 × 3.1 + 0.5 × 2.424 6CHCl 3 : Toluene = 2 : 130.67 × 4.1 + 0.33 × 2.418 7MeOH35.120 8DMSO37.2NA 9[Bmim]Br313 a Yields were determined by H-NMR. Reaction conditions: aldehyde (1 equiv.), PhINTs (1.5 equiv.), catalyst (0.05 equiv.), solvent = 0.67 mL, 40 o C, 3 hr NA = not available 26 Reaction Conditions Screening P ＊ AB =Q A P ＊ A +Q B P ＊ B [Bmim]PF 6 dipole moment 14.89 D

27. 27 (4C-Ppy 2 ) 2 -Fe(II) Complex –Catalyzed Amidation Reactions of Aldehyde with PhINTs General reaction conditions: Aldehyde (1 equiv.), PhINTs (1.5 equiv.), Catalyst (0.05 equiv.) Solvent = 0.67 mL, 40 o C, 3 h. a Yields were determined by 1 H-NMR. b. PhINTs = 2 equiv. c 18 h

28. Summary of Fe(II) catalytic Activity EntryProduct (4C-Ppy 2 ) 2 - FeCl 2 Yield(%) a (11C-Ppy 2 ) 2 - FeCl 2 Yield(%) a EntryProduct (4C-Ppy 2 ) 2 - FeCl 2 Yield(%) a (11C-Ppy 2 ) 2 - FeCl 2 Yield(%) a 1 90 86 7 90 85 2 92 87 8 85 77 3 82 80 9 85 86 4 90 85 10 78 75 5 59 64 b 57 11 67 84 b 65 6 92 83 12 87 80 General reaction conditions: Aldehyde (1 equiv.), PhINTs (1.5 equiv.), Catalyst (0.05 equiv.) Solvent = 0.67 mL, 40 o C, 3 h. a Yields were determined by 1 H-NMR. b. PhINTs = 2.0 equiv.

29. 29 Proposed Mechanism of Amidation Reactions of Aldehyde with PhINTs J. W. W. Chang and P. W. H. Chan* J. Org. Chem. 2011, 76, 4894-4904 byproduct

30. Microwave Assisted Amidation Reactions of Aldehyde with PhINTs 30 entryM.W. power time. ( s )solventYieldDielectric loss 1300W5minCHCl 3 29%0.43 2300W5minCHCl 3 + 3drop [Bmim][PF 6 ] 20% 3300W2minDMSONo product37.12 4b4b 300W5minCHCl 3 5% 5300W5minCHCl 3 + 1 drop DMSO11%0.43+37.12 6600w7minCHCl 3 53%, 7600w7minCHCl 3 + 1 drop MeOH28%0.43+21.4 8600w7minCHCl 3 + 1 drop DI water 22%,0.43+9.89 9c9c 600w7minCHCl 3 67% 10 d 600w7minCHCl 3 87% a Yields were determined by H-NMR. Reaction conditions: aldehyde (1 equiv.), PhINTs (1.5 equiv.), catalyst (0.05 equiv.), solvent = 0.67 mL. b no cat.. c aldehyde = 0.4 mol PhINTs = 0.6 mol Fe cat. = 10 mol% solvent = 1 ml. d solvent = 0.4 mL [ Bmim][PF 6 ] dipole moment 14.82 D

31. Optimization of Reaction Conditions under Focused Microwave 31 entryM.W. power time. ( min ) aldehyde ( M)temp. ( o C) yield(%) 150 W10.53530% 2100w10.54340% 3150W10.56447% 4150W20.56352% 5150W50.56668% 150W80.56577% 6150W100.57075% 7150W10.5M+1 drop BmimBr6976% 8150W30.5M+1 drop BmimBr8388% 9150W30.5M+2 drop BmimBr12467% 10150W50.5M+1 drop BmimBr9591% 11200W10.56657% 12200W10.5 M+1 drop BmimBr11054% 13250W10.56263% 14250W20.56851% a Yields were determined by H-NMR. Reaction conditions: aldehyde = 0.2 mol (1 equiv.), PhINTs (1.5 equiv.), catalyst (0.05 equiv.), solvent CHCl 3 = 0.4 mL.

32. (4C-Ppy 2 ) 2 -Fe(II) Complex Catalyzed Amidation Reactions of Aldehyde with PhINTs 32 a Yields were determined by H-NMR. Reaction conditions: aldehyde = 0.2 mol (1 equiv.), PhINTs (1.5 equiv.), catalyst (0.05 equiv.), solvent CHCl 3 = 0.4 mL. b PhINTs (2.0 equiv)

33. 33 Summary of Fe(II) Catalytic Activity under Focused Microwave a Yields were determined by H-NMR. Reaction conditions: aldehyde = 0.2 mol (1 equiv.), PhINTs (1.5 equiv.), catalyst (0.05 equiv.), solvent CHCl 3 = 0.4 mL. b PhINTs (2.0 equiv) EntryProduct (4C-Ppy 2 ) 2 - FeCl 2 Yield(%) a (11C-Ppy 2 ) 2 - FeCl 2 Yield(%) a EntryProduct (4C-Ppy 2 ) 2 - FeCl 2 Yield(%) a (11C-Ppy 2 ) 2 - FeCl 2 Yield(%) a 1 90 807 82 73 2 93 838 86 72 3 76 649 71 63 4 86 7810 75 5 54 5011 80 b 65 b 6 90 8012 84 68

34. 34 Synthesis of the RS-Au-L1-FeCl 2 RS-Au-L1-FeCl 2 RS-Au-L1 Au-RS RS = CH 3 (CH 2 ) 7 SH

35. IR Spectra of L1, Au-L1 and Au-L1-FeCl 2 1575cm -1 1585cm -1 1426cm -1 1428cm -1 35 1575cm -1 1422cm -1 Wavenumber T (%)

36. TEM Image of RS-Au-L1-FeCl 2 Particle size distribution 7.32 ± 1.2 nm 36 Particle size distribution 2.68 ± 0.3 nm Fe RS-Au-L1 Element Weight % Atomic % Fe6.237.05 Cu70.6070.21 Au19.676.31

37. 37 RS-Au-L1-FeCl 2 Complex –Catalyzed Amidation Reactions of Aldehyde with PhINTs 30 % Particle size distribution 6.87 ± 1.4 nm

38. Summary 1.We have successfully synthesized green catalysts [4C-Ppy 2 ] 2 - FeCl 2 、 [ 11C-Ppy 2 ] 2 -FeCl 2.Their structures were studied by IR, ESI-MS, AA, EPR spectroscopies 2.We have successfully demonstrated the catalytic activity of the Fe(II) complexes for amidation reactions of aldehyde with PhINTs. 3. The Fe(II)-catalyzed amidation reactions of aldehyde with PhINTs can be further accelerated under microwave irradiation conditions. 38

39. 39

40. 4C-Ppy 2 -FeCl 2 (3)11C-Ppy 2 -FeCl 2 (6) FeCl 2. 6H 2 O AA 理論值 1.48 × 10 -6 mol/mg1.11 × 10 -6 mol/mg 5.031 × 10 -6 mol/mg AA 實驗值 1.58 × 10 -6 mol/mg1.32 × 10 -6 mol/mg 4.671 × 10 -6 mol/mg 傳統比色分析 1.42× 10 -6 mol/mg1.03× 10 -6 mol/mg 3.783 × 10 -6 mol/mg 二價鐵純度 a 80 %78 % 81 % a. ( 傳統比色分析 / AA 實驗值 ) × 100% 40

41. 41 瓦數時間焦耳 600 W7 min252000 5.5 倍 150 W5 min45000 31 倍 130 W180*601404000 傳統加熱 620 W 300 o C 6 格 呈線性 1.3 格 130W 40 o C

42. 42 (11C-Ppy 2 ) 2 -Fe(II) Complex Catalyzed Amidation Reactions of Aldehyde with PhINTs a Yields were determined by H-NMR. Reaction conditions: aldehyde = 0.2 mol (1 equiv.), PhINTs (1.5 equiv.), catalyst (0.05 equiv.), solvent CHCl 3 = 0.4 mL. b PhINTs (2.0 equiv)

43. 43

44. 44 表 3.12 用 [CH 3 (CH 2 ) 3 N(H)P(O)(2-py) 2 ] 2 FeCl 2 (3) 鐵催化劑 對於 PhINTs 競爭反應進行 amidation 反應的催化結果 entrysolventyield (%) a byproduct yield (%) a 1thermalCHCl 3 9032 2thermalCHCl 3 + 1.1 mol DI water2682 3microwaveCHCl 3 9033 4microwaveCHCl 3 + 1.1 mol DI water1076 5b5b thermalCHCl 3 + 1.1 mol DI waterNA45 6c6c thermalCHCl 3 + 1.1 mol DI waterNA80 a Yields were determined by H-NMR. Reaction conditions: aldehyde = 0.2 mol (1 equiv.), PhINTs (1.5 equiv.), catalyst (0.05 equiv.), solvent CHCl 3 = 0.67 mL (thermal) 0.4 mL (MW). b no Fe cat. C no aldehyde 1

45. Reproposed Mechanism of Amidation Reactions of Aldehyde with PhINTs 45 J. W. W. Chang and P. W. H. Chan* J. Org. Chem. 2011, 76, 4894-4904

46. 46 non classed Staudinger reaction mechanism

47. Staudinger reaction mechanism 47

48. 48 25 mL 211.5 USD 25 G 396 USD 100 mL 31.9 USD 10G 135.5USD

49. 理論值 = 0.0002 mol*0.05 = 0.00001mol 0.00001*55.845/1 5.584 × 10 -4 g (in 1ml ) CHCl 3 (ml) Aldehyde (mol) Temp./TimeAA (mg/L) 取 0.1 ml total Fe g 4C-0.2M10.240 o C/3h4.614 4.614 × 10 -4 g 4C-0.3M10.340 o C/3h6.786 6.786 × 10 -4 g 4C-0.2M10.2Rt. / 10 min4.005 4.005 × 10 -4 g 4C-0.3M10.3Rt. / 10 min3.779 3.779 × 10 -4 g 11C-0.2M10.240 o C/3h3.560 3.560 × 10 -4 g 11C-0.3M10.340 o C/3h3.615 3.615 × 10 -4 g 49

50. 50 Synthesis of Spacer-Linker Lin, Y.-Y; Tsai, S.-C.; Yu, S. J. J. Org. Chem. 2008, 73, 4920-4928. L1

51. 1 H NMR Spectra of Au NPs L1 and L1-Metal 51 RS-Au-L1-FeCl 2 RS-Au-L1 d 4 -MeOH ＊ Py N-H

52. 52 物質動物, 途徑 Lethal Dose, 50% (LD 50 ) 水大鼠, 口服 >90,000mg/kg 甲醇 大鼠, 口服 5,628 mg/kg 氯化鈉大鼠, 口服 3,000 mg/kg 維他命 A維他命 A 大鼠, 口服 2,000 mg/kg 二氯化亞鐵大鼠, 口服 1678mg /kg 三氯化鐵大鼠, 口服 1872mg/ kg 釕鹽

53. 53 (11C-Ppy 2 ) 2 -FeCl 2 Complex –Catalyzed Amidation Reactions of Aldehyde with PhINTs General reaction conditions: Aldehyde (1 equiv.), PhINTs (1.5 equiv.), Catalyst (0.05 equiv.) Solvent = 0.67 mL, 40 o C, 3 h. a Yields were determined by 1 H-NMR. b. PhINTs = 2.0 equiv.