鐵-硫-亞硝基化合物：合成、反應性及其在生化擬態雙亞硝基鐵化合物之應用

Iron-Thiolate Nitrosyl Complexes: Synthesis, Reactivity andApplication of the Biomimetic Dinitrosyl Iron Complexes

謝忠宏(Chung-Hung Hsieh)

指導教授 ： 廖文峯

國立清華大學/理學院/化學系/博士(2008年)

摘要

較強σ-電子提供，π-電子接受的配位基，如PPh3、PPh3-3-SO3Na或Ph2P(CH2)5PPh2與[Fe(μ-SC6H4-o-COOH)(NO)2]2 (1)反應，可以引發化合物1上橋接的thiolatet產生還原脫去。經由紅外線/紫外線-可見光光譜儀及單晶X光繞射結構的鑑定，此反應可以各別得到一系列不具有電子順磁共振訊號，電子組態為{Fe(NO)2}10的化合物：單核化合物[(PPh3)2Fe(NO)2] (2)、具水溶性的化合物[(PPh3-3-SO3Na)2Fe(NO)2] (4)以及双核的化合物[Fe2(-μ-PPh2(CH2)5PPh2-)2(NO)4] (3)。將化合物3以[NO][BF4]氧化可以得到具有電子順磁共振訊號的双核{Fe(NO)2}9-{Fe(NO)2}9陽離子化合物[Fe2(-μ-PPh2(CH2)5PPh2-)2(NO)4][BF4]2 (32+)，若進一步將化合物32+與不同的thiolates反應，如[SC7H4SN]-、[SPh]-或[SEt]-，會得到不同電子組態的双亞硝基鐵化合物[PPN][(SC7H4SN)2Fe(NO)2]或化合物3。由此現象可以判斷thiolate的還原能力及其配位的方式，將會影響到此反應其間的相戶轉換。双核化合物[Fe(μ-SC7H4SN)(NO)2]2 (5)具有橋接的thiolate分別以硫和氮兩端鍵結在鐵上亦被合成出來，其中兩個鐵的距離為4.0Å。將化合物5與不同的親核基反應，如PMe3、imidazole、[PhCOO]-、[OPh]-、[SC7H4SN]-或[N3]-，可以得到具有電子順磁共振訊號的陰離子{Fe(NO)2}9双亞硝基鐵化合物。此外，前驅物[(CO)2Fe(NO)2][BF4] (12)的鑑定與使用也提供一個新的方法合成陰離子双亞硝基鐵化合物。藉由以上所得到之化合物，可以將其分類為具有硫/氮/氧配位的陰離子{Fe(NO)2}9双亞硝基鐵化合物、中性的{Fe(NO)2}9双亞硝基鐵化合物以及磷配位的{Fe(NO)2}9陽離子双亞硝基鐵化合物。而具有維生素H的配位基N,N'-[dithiobis(4,1-phenylene)]bis{5-[(3aS,6aR)-2-oxohexa-hydro- 1H-thieno[3,4-d]imidazol-4-yl]pentanamide} ([(SC6H4-o-NHCO(CH2)4Biotin)2]; Ligand 1)和化合物 [Fe(μ-SC6H4-o-NHCO(CH2)4Biotin)(NO)2]2 (17)也被合成出來，並使用核磁共振光譜、紅外線/紫外線-可見光光譜儀、元素分析及質譜儀將其鑑定。在HABA螢光取代法的測試中，分別有平均3.19個Ligand 1鍵結上以及3.64個化合物17鍵結上的維生素H可與抗生物素蛋白結合。
水溶性化合物[Na•3THF][Fe(SC6H4-o-S)2]2 (18)被合成出來與鑑定，將化合物18的陽離子置換後可得到化合物[PPN]2[Fe(SC6H4-o-S)2]2 (20)。將化合物20與一氧化氮反應後再進一步與氧氣反應，可以得到具有disulfinate {Fe(NO)}6電子組態的化合物[PPN]2[(NO)Fe(SO2C6H4-o-SO2)(μ-SC6H4-o-S)]2 (25)。以[SC6H4-o-NH2]-將化合物25還原生成具有{Fe(NO)}7電子組態的 [PPN]2[(NO)Fe(SO2C6H4-o-SO2)(SC6H4-o-S)] (26)其Fe-N-O角度為165.7o。化合物20被用來做為合成[PPN][(Cl)Fe(S-C6H4-o-S)(S,SCN(CH3)2)] (27)、[(NO)Fe (S-C6H4-o-S)(S,SCN(CH3)2)] (30)及[PPN][(NO)Fe(S-C6H4-o-S)(S, SCN(CH3)2)] (31)的前驅物。化合物27與一氧化氮反應可以得到化合物30，藉由光照在有[Cl]-的存在之下，化合物30會轉變回化合物27。將化合物30以[SPh]-還原，可生成具有{Fe(NO)}7電子組態的 {Fe(NO)}7化合物31其Fe-N-O角度為150.8o。當化合物30及31分別與氧氣反應時，化合物30會產生無法鑑定的不溶於溶劑的黃色物質，然而化合物31則會被氧化並轉變回化合物30。所以很明顯的，配位基dithiocarbamate以及1,2-benzenedithiolate所提供電子的能力的不同，在硫活化氧氣的反應上扮演重要的角色。此外，化合物18 與 20可將在氫氧化鈉水溶液中的氰甲烷轉換為乙醯胺。在動物的活體實驗中，化合物18的生理食鹽水溶液以股靜脈注射的方式注入Wister公白鼠中，其血壓會上升約10毫米汞柱。
三核鐵簇合物[(ON)Fe(μ-S,S-C6H4)]3 (23)及其氧化態化合物[(ON)Fe(μ-S,S-C6H4)]3[PF6] (24)被合成出來且經由紅外線光譜儀、單晶X光繞射結構、X光吸收光譜、電子順磁共振及磁性的分析與鑑定。在磁性以及電子順磁共振光譜中指出，化合物23有一未成對電子(Stotal = 1/2)，但在化合物24中並不具有未成對電子(Stotal = 0)。此外，在結構的解析，化合物23的Fe(1)上具有較短的Fe-Fe、Fe-N和Fe-S鍵。紅外線光譜儀則顯示一氧化氮stretching頻率在化合物23中為1751 cm-1及化合物24中為1821, 1857 cm-1 (KBr)。化合物23的X光吸收及電子順磁共振光譜表示Fe(1)的部份可以適當的被描述為{Fe(1)NO}7。

關鍵字

一氧化氮 ； 金屬酵素 ； 双亞硝基鐵化合物 ； 氰水解酵素 ； 亞硝基化 ； 一氧化氮補捉劑

並列摘要

Addition of the stronger ?-donating and ?-accepting phosphine ligands, PPh3, PPh3-3-SO3Na or Ph2P(CH2)5PPh2, triggered the reductive elimination of bridged thiolates of RRE [Fe(μ-SC6H4-o-COOH)(NO)2]2 (1) to yield the EPR-silent neutral {Fe(NO)2}10 [(PPh3)2Fe(NO)2] (2), the water-soluble {Fe(NO)2}10 [(PPh3-3-SO3Na)2Fe(NO)2] (4), and the dimeric {Fe(NO)2}10-{Fe(NO)2}10 DNICs [Fe2(-μ-PPh2(CH2)5PPh2-)2(NO)4] (3), respectively. Complex 2-4 were characterized by IR, UV-vis, and single-crystal X-ray diffraction. Oxidation of complex 3 by 2 equiv of [NO][BF4] resulted in the formation of EPR-active cationic {Fe(NO)2}9-{Fe(NO)2}9 dimeric complex [Fe2(-μ-PPh2(CH2)5PPh2-)2(NO)4][BF4]2 (32+). Reaction of complex 32+ with thiolates ([PPN][SC7H4SN], [PPN][SPh] or [PPN][SEt]) yields anionic {Fe(NO)2}9 complex [PPN][(SC7H4SN)2Fe(NO)2] (6) and neutral {Fe(NO)2}10 complex 3. These results unambiguously illustrate one aspect of how the reducing ability and the binding mode of the thiolate ligands functions to regulate the conversion of cationic {Fe(NO)2}9 into anionic {Fe(NO)2}9 or neutral {Fe(NO)2}10 DNICs upon the reaction of complex 32+ and thiolates.
Dimeric {Fe(NO)2}9 dinitrosyl iron complex (DNIC) [Fe(μ-SC7H4SN)(NO)2]2 (5) with S and N atoms of the anionic [-SC7H4SN-]– ligand bound to two separate {Fe(NO)2}9 cores, respectively, shows the Fe…Fe distance of 4.0 Å. A straightforward reaction of complex 5 and nucleophiles (PMe3, imidazole, [PhCOO]-, [OPh]-, [SC7H4SN]- or [N3]-) led to the EPR-active {Fe(NO)2}9 DNICs in THF. In addition, the precursor [(CO)2Fe(NO)2][BF4] (12) provided a new method for synthesizing several kinds of DNICs with different ligations, such as [(SC5H5N)2Fe(NO)2]- (13), [(NO2)2Fe(NO)2]- (15), [(NO3)2Fe(NO)2]- and [(OPh)2Fe(NO)2]- (16). All these {Fe(NO)2}9 DNICs can be classified into the anionic {Fe(NO)2}9 DNICs with S/N/O ligation, the neutral {Fe(NO)2}9 DNIC with one thiolate and one neutral imidazole ligation, and the cationic {Fe(NO)2}9 DNICs with the neutral P-containing coordinated ligands. Moreover, the biotinylated ligand, N,N'-[dithiobis(4,1-phenylene)]bis{5-[(3aS,6aR)-2-oxohexa-hydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamide} ([(SC6H4-o-NHCO(CH2)4Biotin)2]; Ligand 1) and biotinylated RRE [Fe(μ-SC6H4-o-NHCO(CH2)4Biotin)(NO)2]2 (17) were synthesized and identified by NMR, IR, UV-vis. EA and ESI-MS. The HABA assay shows that the average 3.19 (Ligand 1) and 3.64 (complex 17) biotinylated parts bind to avidin.
The water-soluble iron-thiolate NO trapping agent/scavenger [Na•3THF][Fe(SC6H4-o-S)2]2 (18) was synthesized and characterized. Reaction of complex 18 and [PPN][Cl] resulted in the formation of [PPN]2[Fe(SC6H4-o-S)2]2 (20) via cation exchange. Nitrosylation and the subsequent sulfur oxygenation of complex 20 yielded the dimeric disulfinate {Fe(NO)}6 complex [PPN]2[(NO)Fe(SO2C6H4-o-SO2)(μ-SC6H4-o-S)]2 (25). Reduction of complex 25 by [PPN][SC6H4-o-NH2] resulted in the formation of {Fe(NO)}7 complex [PPN]2[(NO)Fe(SO2C6H4-o-SO2)(SC6H4-o-S)] (26) with a bent Fe-N-O bond angle of 165.7o. Complex 20 was adopted as the precursor to synthesize complexes [PPN][(Cl)Fe(S-C6H4-o-S)(S,SCN(CH3)2)] (27), [(NO)Fe(S-C6H4-o-S)(S,SCN(CH3)2)] (30) and [PPN][(NO)Fe(S-C6H4-o-S)(S, SCN(CH3)2)] (31) with mixed [S-C6H4-o-S]2- and [S,SCN(CH3)2]- coordinated ligands. Nitrosylation of complex 27 led to the formation of complex 30. Photolysis of complex 30 in the presence of [PPN][Cl] led to the formation of complex 27. Reduction of {Fe(NO)}6 complex 30 by [PPN][SPh] resulted in the formation of {Fe(NO)}7 complex 31 with a bent Fe-N-O bond angle of 150.8o. Upon addition of O2 into a CH2Cl2 solution of complex 30 or 31, respectively, the yellow decomposition occurred for complex 30, while, complex 30 was reobtained from O2 oxidation of complex 31. Obviously, the deficient electronic density surrounding the iron center resulting form the less electron-donating anionic dithiocarbamate ligand retards the sulfur oxygenation of 1,2-benzenedithiolate to yield the iron-thiolate sulfinate nitrosyl complex. Moreover, the solvent dependent complexes 18 and 20 can convert acetonenitrile to acetamide in the presence of NaOH. This result implicates that the substrate nitrile coordinating to the catalytic metal center of active site is a key step of nitrile hydrolysis to amide. In the animal model studies, the aqueous solution of complex 18 was injected to the right femoral vein as the NO trapping agent/scavenger to male Wistar rats, which increased the blood pressure around 10 mmHg.
The neutral trinuclear iron-thiolate nitrosyl, [(ON)Fe(μ-S,S-C6H4)]3 (23), and its oxidation product, [(ON)Fe(μ-S,S-C6H4)]3[PF6] (24), were synthesized and characterized by IR, X-ray diffraction, X-ray absorption, EPR and magnetic measurement. The five-coordinated square pyramidal geometry around each iron atom in complex 23 remains intact when complex 23 is oxidized to yield complex 24. Magnetic measurements and EPR results show that there is only one unpaired electron in complex 23 (Stotal = 1/2) and no unpaired electron (Stotal = 0) in 24. The detailed geometric comparisons between complexes 23 and 24 provide the understanding of the role that the unpaired electron plays in the chemical bonding of this trinuclear complex. Significant shortening of the Fe-Fe, Fe-N and Fe-S distances around Fe(1) is observed when complex 23 is oxidized to 24. This result implicates that the removal of the unpaired electron does induce the strengthening of the Fe-Fe, Fe-N and Fe-S bonds in Fe(1) fragment. A significant shift of the ?NO stretching frequency from 1751 cm-1 (23) to 1821, 1857 cm-1 (24) (KBr) also indicates the strengthening of the N-O bonds in complex 24. The EPR, X-ray absorption and magnetic measurements lead to the conclusion that the unpaired electron in complex 23 is mainly allocated in Fe(1) fragment and was best described as {Fe(1)NO}7.

並列關鍵字

Nitric Oxide ； metalloenzyme ； DNICs ； nitrile hydratase ； nitrosyl ； NO trapping agent

參考文獻

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