臺灣博碩士論文加值系統

　　近年來釕金屬錯化合物在催化劑以及抗癌藥物上的發展以及釕金屬氫化物在二氧化碳活化的方面都有很大的潛力，因此我們合成並鑑定了一系列含有 N,O 的雙牙酮胺配位基 OCPhCHCMeNHPh、酚胺配位基OHPh-[2-N=CH(tolyl)]、彰化師範大學林美惠老師實驗室所提供含 N,O 的雙牙吲唑衍生物配位基，及N,N 雙牙吡咯衍生物配位基 NHC4H3CH2NMe2 與芳烴釕化合物及釕金屬氫化物結合所形成對應的釕金屬錯化物。
　　將各種 N,O 雙牙酮胺配位基、酚胺配位基、吲唑衍生物配位基與芳烴釕金屬錯化合物 [Ru(η6-p-cymene)Cl2]2 反應，合成出八種新的釕金屬錯化合物：[Ru(η6-p-cymene)(OCPhCHCMeNPh)Cl] (2) {Ru(η6-p-cymene)[OCPhCHCMeN(Ph-2-OMe)]Cl} (3) {Ru(η6-p-cymene)[OCPhCHCMeN(Ph-2,6-iPr2)]Cl} (4) {Ru(η6-p-cymene)[OPh-(2-N=CH(tolyl))]Cl} (5) {Ru(η6-p-cymene)[OPh-(2-N=CH(naphthyl))]Cl} (6) {Ru(η6-p-cymene)[N(CPhNNMe)CHOPhNEt2]Cl} (7) [Ru(η6-p-cymene)(NPhCNCHCOPh)Cl] (8)，以及用吡咯衍生物配位基與釕金屬氫化物 RuH(Cl)(CO)(PPh3)3 反應，合成出 3 種新的釕金屬氫化物：[RuH(CO)(PPh3)2(NC4H3CH2NMe2)] (10) [RuH(CO)(PPh3)2(NC4H3CH2NHtBu)] (11) {RuH(CO)(PPh3)2[NC4H3CH2N(CH2CH2)2NPh]} (12)，並經由1H、13C NMR光譜以及 X-ray 單晶繞射儀鑑定其特性。
　　錯化合物 3 在醇類胺化的催化反應中有良好的催化活性，抗癌效果方面則是錯化合物 4 最好，而釕金屬氫化物 12 在作為 DCPD 與 CO2 進行 hydroformylation 的催化反應中有不錯的選擇性。

Ruthenium based organometallic compounds are potential anticancer drugs and can also act as catalysts for hydroamination. A series of mononuclear arene ruthenium compounds incorporating N,O and N,N-bidentate ligands were synthesized and their catalytic reactivity for alcohol amination and anticancer effects against human hormone-refractory metastatic prostate cancers (HRMPCs) were examined. Compounds [Ru(η6-p-cymene)(OCPhCHCMeNPh)Cl] (2), {Ru(η6-p-cymene)[OCPhCHCMeN(Ph-2-OMe)]Cl} (3), {Ru(η6-p-cymene)[OCPhCHCMeN(Ph-2,6-iPr2)]Cl} (4), {Ru(η6-p-cymene)[OPh-(2-N=CH(tolyl))]Cl} (5), {Ru(η6-p-cymene)[OPh-(2-N=CH(naphthyl))]Cl} (6), {Ru(η6-p-cymene)[N(CPhNNMe)CHOPhNEt2]Cl} (7), and [Ru(η6-p-cymene)(NPhCNCHCOPh)Cl] (8) were obtained from the reactions of [Ru(η6-p-cymene)Cl2]2 (1) with corresponding ligands in relatively high yield where cymene is 4-isopropyltoluene. Ruthenium hydride compounds [RuH(CO)(PPh3)2(NC4H3CH2NMe2)] (10), [RuH(CO)(PPh3)2(NC4H3CH2NHtBu)] (11), and {RuH(CO)(PPh3)2[NC4H3CH2N(CH2CH2)2NPh]} (12) were obtained by reacting RuH(Cl)(CO)(PPh3)3 and corresponding pyrrolyl ligands. All the new ruthenium compounds were characterized by 1H and 13C NMR spectroscopy. In addition, the molecular strucrures of 2-6 and 10-12 were also determined by X-ray crystaography.
The cell toxicity test of compounds 2-8 toward PC-3 and DU-145 are measured showing that compounds 3-6 have higher toxicity than cis-platin. Compounds 2-8 have also used as catalysts for the alcohol amination and the results are presented in the thesis.

中文摘要　　　　I
英文摘要 II
謝誌 III
目錄 IV
圖次 VI
表次 VIII
式次 IX
第一章 緒論
第一節 釕金屬錯化合物做為催化劑的應用 1
第二節 釕金屬錯化合物做為抗癌藥物的應用 5
第三節 釕金屬氫化物 (Ruthenium hydride) 活化二氧化碳的研究 6
第四節 配位基的介紹 9
第二章 結果與討論 13
第一節 釕金屬錯化物 1-12 合成鑑定與討論 13
　　2-1-1 [(Ru(η6-p-cymene)Cl2]2 (1) 13
　　2-1-2 [Ru(η6-p-cymene)(OCPhCHCMeNPh)Cl] (2) 14
　　2-1-3 {Ru(η6-p-cymene)[OCPhCHCMeN(Ph-2-OMe)]Cl} (3) 17
　　2-1-4 {Ru(η6-p-cymene)[OCPhCHCMeN(Ph-2,6-iPr2)]Cl} (4) 19
　　2-1-5 {Ru(η6-p-cymene)[OPh-(2-N=CH(tolyl))]Cl} (5) 22
　　2-1-6 {Ru(η6-p-cymene)[OPh-(2-N=CH(naphthyl))]Cl} (6) 24
　　2-1-7 [Ru(η6-p-cymene)(L1)Cl] (7) 26
　　2-1-8 [Ru(η6-p-cymene)(L2)Cl] (8) 27
　　2-1-9 RuH(Cl)(CO)(PPh3)3 (9) 28
　　2-1-10. [RuH(CO)(PPh3)2(NC4H3CH2NMe2)] (10) 28
2-1-11 [RuH(CO)(PPh3)2(NC4H3CH2NHtBu)] (11) 32
　　2-1-12 {RuH(CO)(PPh3)2[NC4H3CH2N(CH2CH2)2NPh]} (12) 36
第二節 釕金屬錯化合物 2-8 對醇類胺化催化的結果與討論 40
第三節 釕金屬氫化物 10-12 對二氧化碳活化的測試 43
第四節 釕金屬錯化合物 2-8 對激素難治性前列腺癌之抗癌活性測試 44
第三章 結論 46
第四章 實驗部分 47
第一節 一般實驗 47
第二節 物理性質的測量 48
第三節 配位基的合成 49
第四節 釕金屬錯化合物的合成 50
第五節 釕金屬錯化合物 2-8 對醇類胺化催化反應 59
第六節 釕金屬氫化物 10-12 對二氧化碳活化的測試 59
第七節 釕金屬錯化合物對激素難治性前列腺癌的抗癌活性測試 59
參考文獻 61
附錄 X-ray data 66

[1] Conley, B. L.; Pennington-Boggio M. K.; Boz, E.; Williams, T. J. Chem. Rev. 2010, 110, 2294-2312.
[2] Nguyen, S. T.; Johnson, L. K.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1992, 114, 3974-3975.
[3] Hamid, M. H. S. A.; Slatford, P. A.; Williams, J. M. J. Adv. Synth. Catal. 2007, 349, 10, 1555-1575.
[4] McGrady, J. E. Angew. Chem. Int. Ed. 2000, 39, 3077-3079.
[5] Nicholls, J. N.; Vargas, M. D. Inorg. Synth. 1989, 26, 280-285.
[6] Murahashi, S. I. Ruthenium in Organic Synthesis, 1st ed.; Wiley-VCH: Weinheim, Germany, 2005.
[7] (a) Brown, C. J.; Toste, F. D.; Bergman, R. G.; Raymond, K. N. Chem. Rev. 2015, 115, 3012-3035. (b) Süss‐Fink, G.; Faure, M.; Ward, T. R. Angew. Chem. Int. Ed. 2002, 41, 99-101. (c) Wang, Z. J.; Clary, K. N.; Bergman, R. G.; Raymond, K. N.; Toste, F. D. Nat. Chem. 2013, 5, 100-103. (d) Therrien, B. Eur. J. Inorg. Chem. 2009, 17, 2445-2453.
[8] (a) Zelonka, R. A.; Baird. M. C. Can. J. Chem. 1972, 50, 3063-3072. (b) Bennett, M. A.; Huang, T. N.; Matheson, T. W.; Smith, A. K.; Ittel, S.; Nickerson, W. Inorg. Synth. 1982, 21, 74-78. (c) Winkhaus, G.; Singer, H. J. Organomet. Chem. 1967, 7, 487-491.
[9] (a) Zhang, B.; Wang, H.; Lin, G. Q.; Xu, M. H. Eur. J. Org. Chem. 2011, 22, 4205-4211. (b) Baratta, W.; Ballico, M.; Zotto, A. D.; Herdtweck, E.; Magnolia, S.; Peloso, R.; Siega, K.; Toniutti, M.; Zangrando, E.; Rig P. Organometallics 2009, 28, 4421-4430. (c) Noyori, R.; Ohkuma, T. Angew. Chem. Int. Ed. 2001, 40, 40-73.
[10] Bacchi, A.; Cantoni, G.; Pelagatti, P. CrystEngComm 2013, 15, 6722-6728.
[11] (a) Aznar, R.; Grabulosa, A.; Mannu, A.; Muller, G.; Sainz, D.; Moreno, V.; Lorenzo, J. Organometallics 2013, 32, 2344-2362. (b) Yuan, J.; Sun, Y.; Yu, G. A.; Zhao, C.; She, N. F.; Mao, S. L.; Liu, S. H. Dalton Trans. 2012, 41, 10309-10316. (c) Özdemir, I.; Demir, S.; Çetinkaya, B.; Toupet, L.; Castarlenas, R.; Fischmeister, C.; Dixneuf, P. H. Eur. J. Inorg. Chem. 2007, 18, 2862-2869.
[12] (a) Hamid, M. H. S.; Slatford, P. A.; Williams, J. M. Adv. Synth. Catal. 2007, 349, 1555-1575. (b) Hamid, M. H. S.; Allen, C. L.; Lamb, G. W.; Maxwell, A. C.; Maytum, H. C.; Watson, A. J.; Williams, J. M. J. Am. Chem. Soc. 2009, 131, 1766-1774. (c) Marichev, K. O.; Takacs, J. M. ACS Catal. 2016, 6, 2205-2210.
[13] (a) Acton, Q. A. Platinum Compounds-Advances in Research and Application, Scholarly Ed, UK, 2013. (b) Varennikov, E.; Yedemsky, L. Platinum: Compounds, Production and Applications, Nova Science Publishers, USA, 2013.
[14] (a) Pinedo, H. M.; Schornagel, J. H. Platinum and Other Metal Coordination Compounds in Cancer Chemotherapy 2, Springer Science & Business Media, Germany, 1996. (b) Kelland, L. R.; Farrell, N. P. Platinum-Based Drugs in Cancer Therapy, Humana. Press. Inc, USA, 2000.
[15] (a) Lippert, B. Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug, Wiley-VCH: Weinheim, Germany, 1999. (b) Wood, R. D.; S.; Lange, S. S. Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 2864-2865. (c) Dasari, S.; Tchounwou, P. B. Eur. J. Pharmacol. 2014, 740, 364-378. (d) Shaili, E. Sci. Prog. 2014, 97, 20-40.
[16] (a) Kostova, I. Curr. Med. Chem. 2006, 13, 1085-1107. (b) Lentz, F.; Drescher, A.; Lindauer, A.; Henke, M.; Hilger, R. A.; Hartinger, C. G.; Scheulen, M. E.; Dittrich, C.; Keppler, B. K.; Jaehde, U. Anti-Cancer. Drugs 2009, 20, 97-103. (c) Ang, W. H.; Casini, A.; Sava, G.; Dyson, P. J. J. Organomet. Chem. 2011, 696, 989-998. (d) Bergamo, A.; Sava, G. Dalton Trans. 2011, 40, 7817-7823. (e) Antonarakis, E. S.; Emadi, A. Cancer. Chemoth. Pharm. 2010, 66, 1-9.
[17] (a) Trondl, R.; Heffeter, P.; Kowol, C. R.; Jakupec, M. A.; Bergerbd, W.; Keppler, B. K. Chem. Sci. 2014, 5, 2925-2932. (b) Levina, A.; Mitra, A.; Lay, P. A. Metallomics 2009, 458-470.
[18] (a) Rademaker-Lakhai, J. M.; Bongard, D. V. D.; Pluim, D.; Beijnen, J. H.; Schellens, J. H. Clin. Cancer. Res. 2004, 10, 3717-3727. (b) Mestroni, G.; Alessio, E.; Sava, G. International Patent 1998, PCT C07F 15/00, A61 K 31/28, WO 98/0043.
[19] (a) Lentz, F.; Drescher, A.; Lindauer, A.; Henke, M.; Hilger, R. A. Anti-cancer Drugs 2009, 20, 97-103. (b) Henke, M. M.; Richly, H.; Drescher, A.; Grubert, M.; Alex, D. Int. J. Clin. Pharmacol. Ther. 2009, 47, 58-60.
[20] (a) Hayward, R. L.; Schornagel, Q. C.; Tente, R.; Macpherson, J. S.; Aird, R. E. Cancer Chemoth. Pharm. 2005, 55, 577-583. (b) Aird, R. E.; Cummings, J.; Ritchie, A. A.; Muir, M.; Morris, R. E. Br. J. Cancer 2002, 86, 1652-1657.
[21] (a) Bergamo, A.; Masi, A.; Dyson, P. J.; Sava, G. Int. J. Oncol. 2008, 33, 1281-1289. (b) Scolaro, C.; Bergamo, A.; Brescacin, L.; Delfino, R.; Cocchietto, M. J. Med. Chem. 2005, 48, 4161-4171. (c) Vock, C. A.; Scolaro, C.; Phillips, A. D.; Scopelliti, R.; Sava, G. J. Med. Chem. 2006, 49, 5552-5561.
[22] (a) Meggers, E.; Atilla-Gokcumen, G. E.; Bregman, H.; Maksimoska, J.; Mulcahy, S. P. Synlett. 2007, 8, 1177-1189. (b) Smalley, K. S.; Contractor, R.; Haass, N. K.; Kulp, A. N.; Atilla-Gokcumen, G. E. Cancer Res. 2007, 67, 209-217.
[23] (a) Arakawa, H.; Aresta, M.; Armor, J. N.; Barteau, M. A.; Beckman, E. J.; Bell, A. T.; Domen, K. Chem. Rev. 2001, 101, 953-996. (b) Peters, M.; Köhler, B., Kuckshinrichs, W.; Leitner, W.; Markewitz, P.; Müller, T. E. ChemSusChem 2011, 4, 1216-1240. (c) Cokoja, M.; Bruckmeier, C.; Rieger, B.; Herrmann, W. A.; Kühn, F. E. Angew. Chem. Int. Ed. 2011, 50, 8510-8537. (d) Aresta, M.; Dibenedetto, A. Dalton Trans. 2007, 28, 2975-2992. (e) Sakakura, T.; Choi, J. C.; Yasuda, H. Chem. Rev. 2007, 107, 2365-2387. (f) Behr, A. Angew. Chem. Int. Ed. 1988, 27, 661-678.
[24] Wesselbaum, S.; Moha, V.; Meuresch, M.; Brosinski, S.; Thenert, K. M.; Kothe, J.; Leitner, W. Chem. Sci. 2015, 6, 693-704.
[25] Langer, R.; Diskin‐Posner, Y., Leitus, G.; Shimon, L. J.; Ben‐David, Y.; Milstein, D. Angew. Chem. Int. Ed. 2011, 50, 9948-9952.
[26] Pasha, F. A.; Bendjeriou-Sedjerari, A.; Abou-Hamad, E.; Huang, K. W.; Basset, J. M. Chem. Commun. 2016, 52, 2577-2580.
[27] Jana, A.; Roesky, H. W.; Schulzke, C.; Döring, A. Angew. Chem. Int. Ed. 2009, 121, 1126-1129.
[28] (a) Chantler, V. L.; Chatwin, S. L.; Jazzar, R. F.; Mahon, M. F.; Saker, O.; Whittlesey, M. K. Dalton Trans. 2008, 19, 2603-2614. (b) Abdur‐Rashid, K.; Guo, R.; Lough, A. J.; Morris, R. H.; Song, D. Adv. Synth. Catal. 2005, 347, 571 -579. (c) Stahl, T.; Hrobárik, P.; Königs, C. D. F.; Ohki, Y.; Tatsumi, K.; Kemper, S.; Oestreich, M. Chem. Sci. 2015, 6, 4324-4334. (d) Nagaraja, C. M.; Nethaji, M.; Jagirdar, B. R. Indian J. Chem. 2010, 49, 167-170. (e) Phanopoulos, A.; Brown, N. J.; White, A. J.; Long, N. J.; Miller, P. W. Inorg. Chem. 2014, 53, 3742-3752.
[29] Bhattacharya, S.; Boone, S. R.; Fox, G. A.; Pierpont, C. G. J. Am. Chem. Soc. 1990, 112, 1088-1096.
[30] Hiroi, Y.; Komine, N.; Komiya, S.; Hirano, M. Org. Lett. 2013, 15, 2486-2489.
[31] Occhipinti, G.; Bjørsvik, H. R.; Törnroos, K. W.; Jensen, V. R. Organometallics 2007, 26, 5803-5814.
[32] Matsinha, L. C.; Malatji, P.; Hutton, A. T.; Venter, G. A.; Mapolie, S. F.; Smith, G. S. Eur. J. Inorg. Chem. 2013, 24, 4318-4328.
[33] Phillips, A. D.; Zava, O.; Scopelitti, R.; Nazarov, A. A.; & Dyson, P. J. Organometallics 2010, 29, 417-427.
[34] Mandal, S.; Samanta, S.; Mondal, T. K.; Goswami, S. Organometallics 2012, 31, 5282-5293.
[35] Rakowski DuBois, M.; Parker, K. G.; Ohman, C.; Noll, B. C. Organometallics 1997, 16, 2325-2334.
[36] McComas, C. C.; Ziller, J. W.; Van Vranken, D. L. Organometallics 2000, 19, 2853-2857.
[37] Cox, M.; Lehninger, A. L.; Nelson, D. R. Principles of biochemistry, Wiley Online Library, Germany, 1982.
[38] Jusélius, J.; Sundholm, D. Phys. Chem. Chem. Phys. 2000, 2, 2145-2151.
[39] Hsiao, C.S.; Wang, T. Y.; Datta A.; Liao, F. X.; Hu, C. H.; Huang, J. H.; Lee, T. Y. J. Organomet. Chem. 2012, 718, 82-88.
[40] (a) Lien, Y.; Chang, Y.; Chuang, N.; Datta, A.; Chen, S.; Hu, C.; Huang, W.; Lin, C.; Huang, J. H. Inorg. Chem. 2010, 49, 136-143. (b) Hsueh, L. F.; Chuang, N. T.; Lee, C. Y.; Datta, A.; Huang, J. H.; Lee, T. Y. Eur. J. Inorg. Chem. 2011, 36, 5530-5537.
[41] Lin, M. H.; Liu, H. J.; Lin, W. C.; Kuo, C. K.; Chuang, T. H. Org. Biomol. Chem. 2015, 13, 11376.
[42] (a) Ahmad, N.; Levison, J. J.; Robinson, S. D.; Uttley, M. F. Triphenylphosphine complexes of transition metals. Inorganic Syntheses 1974, 15, 45-63. (b) Levison, J. J.; Robinson, S. D. J. Chem. Soc. (A) 1970, 2947-2954.
[43] Lin, T. H.; Das, K.; Datta, A.; Leu, W. J.; Hsiao, H. C.; Lin, C. H.; Huang, J. H. J. Organomet. Chem. 2016, 807, 22-28.