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研究生： 吳祈慧
Wu, Chi-Hui
論文名稱： 合成水溶性氮轉移試劑並探討其穩定性及反應性
Synthesis of Water-Soluble N-Transfer Reagents and Investigations on Their Stability and Reactivity
指導教授： 周鶴軒
Chou, Ho-Hsuan
學位類別： 碩士
Master
系所名稱： 理學院 - 化學系
Department of Chemistry
論文出版年： 2021
畢業學年度： 109
語文別： 中文
論文頁數： 119
中文關鍵詞： 水溶性氮轉移試劑 、重氮化合物 、重氮鹽 、聚乙二醇
外文關鍵詞： Water-soluble N-transfer reagent, Diazo compound, Diazonium Salt, Polyethylene glycol
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    • 近年來重氮化合物的廣泛應用性備受矚目，其合成方法也隨之蓬勃發展，但過去文獻指出水相下合成重氮化合物是相當困難的，因為大多的使用條件或有機試劑都為非極性分子，在高極性的水溶液中溶解度相當差，無法被廣泛應用在適合生物體系的緩衝或中性水溶液下進行有效的合成反應。本實驗室發展出新穎的氮轉移試劑，此試劑為重氮鹽化合物，它會先與胺基化合物形成三氮烯化合物，接著加入鹼使之裂解，形成內醯胺化合物和重氮化合物。當重氮基對位為醚類時，重氮鹽的穩定性會大幅提升。本篇研究中，我們延伸甲基醚側鏈為聚乙二醇(polyethylene glycol, PEG)，可以在保有醚類穩定性的同時，又具備生物兼容(biocompatible)的水溶特性，希望能做到在水相下進行氮轉移反應。
    有機化合物在進行水相反應時會遇到兩個問題：溶解度與穩定度，當我們使用水溶性氮轉移試劑在進行水相氮轉移反應時，雖然重氮鹽的溶解度提升，但依然會遇到重氮鹽在鹼性較強的環境下易脫除氮氣之問題，於是透過改變添加反應物的手法及實驗參數改善重氮鹽的穩定度，減少還原副產物及染料的生成。雖然我們改善了重氮鹽的溶解度與穩定度，但卻忽略了水溶性重氮鹽反應性差的問題，使其在進行水相氮轉移反應時無法完全與胺基化合物形成三氮烯化合物而造成氮轉移產率偏低，若未來能找到提升水溶性重氮鹽反應性的方法，使重氮鹽在冰浴下可完全和胺類化合物形成三氮烯化合物，就可使氮轉移反應在含水量高的混合溶劑或水相中的產率提升。

    The diverse applications of diazo compounds have attracted great attention in recent years. Chemists have developed many synthetic protocols in the organic solvent system. However, the poor solubility of nonpolar organic reagents in polar aqueous solution resulted the difficulty on synthesizing diazo compounds in aqueous phase. Recently, our laboratory has developed a diazonium salt as a novel N-transfer reagent, which could transfer applied amino acid derivatives into the in situ generated triazene intermediates and then eventually degraded into the lactam and corresponding diazo products. Furthermore, the stability of the diazonium salt would be greatly improved when there is an alkoxy group at the para-position. Based on the previous study, we extended the side chain of methyl ether to the polyethylene glycol (PEG). It could not only maintain the stability of alkoxy group, but also provide the water-soluble and biocompatible properties.
    Although the solubility of N-transfer reagents was improved, their reactivity was suppressed at the same time. The unreacted reagents would slowly expel nitrogen and finally degrade in the basic solution. The disadvantage could be solved while we changed the addition series of reactants and experimental parameters. However, the yield of N-transfer reaction was still unsatisfied due to the poor reactivity of water-soluble diazonium salts and insoluble triazene intermediates. If we can find a way to improve the reactivity of water-soluble diazonium salts, the yield of N-transfer reaction may be enhanced. We hoped that we could achieve N-transfer reaction in aqueous phase.

    摘要 I 誌謝 VII 目錄 VIII 圖目錄 X 表目錄 XI 流程目錄 XII 第一章 前言 1 1.1 重氮化合物 1 1.1.1 α-羰基重氮化合物 2 1.1.2 α-羰基重氮化合物的合成 2 1.1.3 α-羰基重氮化合物的應用 4 1.1.4 α-羰基重氮化合物在生物體上的應用 6 1.2 重氮鹽化合物 7 1.2.1 重氮鹽化合物的合成與應用 7 1.3 三氮烯化合物 9 1.3.1 三氮烯化合物的應用 9 1.4 水相重氮化反應 10 1.5 研究動機 11 第二章 結果與討論 13 2.1 實驗設計與原理 13 2.2 水溶性氮轉移試劑的合成 14 2.3 水溶性氮轉移試劑的物性 22 2.4 水溶性氮轉移試劑的氮轉移反應 25 2.5 優化水溶性氮轉移試劑的氮轉移反應 31 2.6 探討水溶性氮轉移反應副產物問題 38 第三章 結論 41 第四章 實驗步驟 42 4.1 General Information 42 4.1.1 Materials 42 4.1.2 Methods 42 4.1.3 Machines 42 4.2 Synthesis of compounds 2-6 43 4.2.1 General Procedure A for the synthesis of compounds 2b-d 43 4.2.2 Synthesis of compound 3a 46 4.2.3 General Procedure B for the synthesis of compounds 3b-d 46 4.2.4 General Procedure C for the synthesis of compounds 4a-d 49 4.2.5 General Procedure D for the synthesis of compounds 5a-d 52 4.2.6 General Procedure E for the synthesis of compounds 6a-d 55 4.3 Synthesis of compounds 7a-c, 9, 21-23 59 4.3.1 General Procedure F for Diazo Synthesis 59 4.4 Synthesis of compounds 11-12 64 4.5 Synthesis of compounds 13, 14 65 4.6 Synthesis of compounds 15-18 67 4.6.1 General Procedure G for the synthesis of compounds 15c-d 67 4.6.2 General Procedure H for the synthesis of compounds 16c-d 69 4.6.3 General Procedure I for the synthesis of compounds 17c-d 70 4.6.4 General Procedure J for the synthesis of compounds 18c-d 71 4.7 Synthesis of compounds 19c-d 73 第五章 參考文獻 75 第六章 核磁共振光譜 78

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