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研究生:李泰徵
研究生(外文):Tai-Chen Li
論文名稱:苯亞甲基苯胺與偶氮苯衍生物在酸催化光化學反應上之研究
論文名稱(外文):Study on Acid-Catalyzed Photochemical Reactions of Benzylideneaniline and Azobenzene Derivatives
指導教授:何東英何東英引用關係
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:化學研究所
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2005
畢業學年度:93
語文別:中文
論文頁數:142
中文關鍵詞:光化學偶氮苯苯亞甲基苯胺
外文關鍵詞:Photochemical ReactionsBenzylideneanilineAzobenzene
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本篇論文主要是在研究苯亞甲基苯胺與對位烴基偶氮苯衍生物的光化學反應,以及所得到之產物在藥性上之應用。
在苯亞甲基苯胺研究部分,我們利用含有飽和鹽酸的無水N,N-二甲基甲醯胺或N,N-二甲基乙醯胺作為溶劑進行照光反應,得到一新的光烴化反應,即N,N-二甲基甲醯胺的氮上甲基加成在苯亞甲基苯胺上,並且有相當不錯之產率,由以往文獻之探討我們知道此類化合物的光烴化反應都與自由基和電子轉移有關,因此我們推測我們的反應為醯胺經由照光得到自由基的中間體並且轉移一個電子給質子化後激發態的苯亞甲基苯胺,最後自由基的結合而得到我們新反應的產物。
對位烴基偶氮苯研究部分,我們知道偶氮苯及其衍生物在溶劑中照光只會進行順反異構化反應,而我們利用對位烴基偶氮苯在含有1.2 M鹽酸的醇類中進行照光反應,我們得到一個新的光環化加成反應,其產物為10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine為架構之衍生物,其可能的反應機構為對位烴基偶氮苯上其中一個氮先被質子化,再經由合環反應得到一個含有兩個氮的四環過渡態,此時氮去攻打醇類並脫去一分子的水,並且在經過一連串的開環合環反應最後得到我們新的環化加成產物。
Dibenzo[b,e][1,4]diazepine為主架構之衍生物,在以往的文獻報導中往往是具有生物藥性之化合物,因此我們將對位烴基偶氮苯照光所得之環化加成產物做藥性測試,結果發現我們的產物具有抗乙醯膽鹼酵素及抗預-膽鹼酵素之能力,而目前具有此能力之藥物常常被用來治療阿茲海默氏症、肌肉無力症、失智症等與神經傳導有關之病症。
This work mainly studies on the photochemical reaction of benzylideneaniline and azobenzene derivatives, we also studies on the pharmaceutical chemistry of the product from our new reaction.
In benzylideneaniline part, when anhydrous DMF (or DMAC) with saturated hydrogen chloride as a solvent, benzylideneaniline derivatives and analogues can undergo a novel photoalkylation, there have a new carbon-carbon bond formation between benzylideneaniline and N-methyl from DMF (or DMAC). The mechanism of photoalkylation in Schiff’s base has been considered about radical intermedium or single electron transfer in the pass, and therefore we proposed the mechanism of our reaction, involved DMF (or DMAC) transfer an electron to the protonated and excited benzylideneaniline derivatives by irradiation, and finally the combination of radical intermediums to obtain a new series of products.
In azobenzene part, when ethanol as a solvent, azobenzene derivative can undergo a new photocycloaddition to obtain 10,11-dihydro-5H- dibenzo[b,e][1,4]diazepine derivatives by 1.2 M hydrochloric acid catalyzed. The mechanism of this reaction may be proposed for the azobenzene derivatives become trans structure after getting proton, and then may become the four member ring transition state, including two nitrogen atoms. The nitrogen atom attract to ethanol in the transition state, the four member ring was open, then cyclized to obtain 10,11-dihydro- 5H-dibenzo[b,e][1,4]diazepine derivatives.
The synthesis of 10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine deriva- tives and their activity as acetylcholinesterase and pseudocholinesterase inhibitors are described. The drug with that ability is usually in treatment of Alzheimer, myasthenis gravis and some diseases about the neuromuscular transmission.
目錄
目錄.......................... I
摘要.......................... V
第一章、Benzylideneaniline............... 1
一、Benzylideneaniline 的光化學反應......... 1
1、Schiff’s base................. 1
2、苯亞甲基苯胺(Benzylideneaniline)之特性....2
a. 幾何結構與UV 吸收光譜...........2
b. 質子化(protonation)的影響......... 3
3、Schiff’s base(C-N Double bond)的光化學反應.. 3
a. 光自變色(Photochromism).......... 4
b. 光還原反應(Photoreduction)......... 4
c. 光烴化反應(Photoalkylation)......... 6
d. 光環化反應(Photocyclization).........8
4、Schiff’s base salt 藉由電子轉移的加成反應.... 9
5、醯胺類的光化學反應............. . 11
a. 利用Hydroxyl radical 引發醯胺自由基..... 12
b. 直接照射醯胺產生自由基.......... 13
6、酸催化之光化學反應.......... ...14
二、結果與討論.................18
1、照光起始物的合成.............. 18
2、照光條件之測試............... 20
3、DMF 照光產物之鑑定.............. 22
a. 以NMR 變溫實驗觀察變化.......... 22
b. 不同溶劑( DMSO-d6 vs MeOD vs CDCl3 )下氫譜之
比較.....................25
4、其他條件的測試-確認是否為酸催化光化學反應..26
5、以DMAC 取代DMF 的照光反應........27
6、DMF 與DMAC 照光結果比較......... 29
7、DMAC 照光產物之鑑定.............30
8、以類似的醯胺作為反應之試劑.........32
9、Benzal Part 與aniline part 之取代基的影響....34
10、反應機構的探討...............35
a. 酸對benzylideneaniline 衍生物的影響..... 36
b. 利用Rehm-Weller equatuon 計算∆G...... 39
11、可能之反應機構...............41
第二章Azobenzene.................. 42
一、Azobenzene 之光化學反應........... 42
1、偶氮苯(Azobenzene).............42
2、偶氮苯cis-trans 異構化反應(cis-trans isomerization) 42
3、光環化反應Photocyclization.......... 44
4、氫化偶氮苯(hydrazobenzene)......... 45
二、Dibenzo[b,e][1,4]diazepine............50
三、結果與討論:.................54
1、照光起始物之合成.............. 55
2、照光條件測試................ 57
3、光環化加成反應結果............. 59
4、產物鑑定.................. 62
5、醇類對反應之影響.............. 65
6、加入其它取代基對反應的影響......... 66
7、反應機構的推測............... 67
8、驗證推測之反應機構............. 68
第三章藥性測試................... 72
一、神經傳導物質................. 72
1、乙醯膽鹼(Acetylcholine ACh) ......... 72
2、膽鹼酵素(Cholinesterase ChE).........73
a. 乙醯膽鹼酵素(Acetylcholinesterase AChE) ... 73
b. 預-膽鹼酵素(Pseudo-cholinesterase PChE) ... 74
3、膽鹼酵素(Cholinesterase ChE)在臨床上之作用. 74
4、膽鹼抑制劑(Cholinesterase inhibitors)......75
5、膽鹼酵素(Cholinesterase ChE)活性之測試... 75
二、實驗方法:..................76
1、各試劑之配製................ 76
2、紅血球上乙醯膽鹼酵素(Acetylcholinesterase AChE)之
測試......................76
3、血清上預-膽鹼酵素(Pseudo-cholinesterase PChE)之測
試.......................77
4、膽鹼抑制劑(Cholinesterase inhibitors)之測試.. 77
三、藥性結果...................77
結論......................... 80
第四章實驗部分................... 81
1、儀器部分................... 81
2、第一章化合物之合成.............. 83
a. 照光起始物之合成.............. 83
b. 所需之溶劑.................. 90
c. 測量氧化還原電位-CV 實驗........... 91
d. 照光產物之合成................ 92
2、第二章化合物之合成.............. 99
a. 照光起始物之合成.............. 99
b. 照光產物之合成............... 108
3.、第三章藥性測試................ 119
a. Inhibition of acetylcholinesterase ........ 121
a. Inhibition of Pseudo-cholinesterase ....... 129
附錄......................... 143
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