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题名: Theoretical study of N-dealkylation of N-cyclopropyl-N-methylaniline catalyzed by cytochrome P450: insight into the origin of the regioselectivity
作者: Li, Dongmei1, 2;  Wang, Yong1;  Yang, Chuanlu3;  Han, Keli1
刊名: DALTON TRANSACTIONS
发表日期: 2009
DOI: 10.1039/b810767j
期: 2, 页:291-297
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Physical Sciences
类目[WOS]: Chemistry, Inorganic & Nuclear
研究领域[WOS]: Chemistry
英文摘要: The mechanism of N-dealkylation of N-cyclopropyl-N-methylaniline (3) catalyzed by cytochrome P450 (P450) was investigated using density functional theory. This reaction involves two steps. The first one is a C(alpha)-H hydroxylation on the N-substituent to form a carbinolaniline complex, and the second is a decomposition of the carbinolaniline to yield cyclopropanone (or formaldehyde) and N-methylaniline (or N-cyclopropylaniline). Our calculations demonstrate that the first step proceeds in a spin-selective mechanism (SSM), mostly on the low-spin (LS) doublet state. The rate-limiting C(alpha)-H activation is an isotope-sensitive hydrogen atom transfer (HAT) step. The environmental effect switches the regioselectivity of this reaction from a competition between N-decyclopropylation and N-demethylation to a clear preference for N-demethylation. This preference is consistent with former experimental studies. However, it is not in accord with the normal Delta E-BDE correlation since the BDE of C(alpha)-H on the methyl group is higher than that on the cyclopropyl group. Insight into the origin of the preference for N-demethylation reveals that tertiary amine 3 is different from normal hydrocarbons, possessing a unique pi(Ph)-pi(C-N) conjugated system. The electron delocalization effect of the pi(Ph)-pi(C-N) conjugated system in 3 makes the transition state pose a polar character, and the bulk polarity and hydrogen bonding capability of the protein pocket can exert a remarkable effect on the regioselectivity of N-dealkylation of 3. Decomposition of carbinolaniline is a water-assisted proton-transfer process in the nonenzymatic environment. The ring-intact cyclopropanone formed in the reaction sheds some light on the inability of 3 to inactivate P450 during its N-decyclopropylation.
关键词[WOS]: C-H HYDROXYLATION ;  ISOTOPE EFFECT PROFILES ;  DENSITY-FUNCTIONAL THERMOCHEMISTRY ;  SUBSTITUTED N,N-DIMETHYLANILINES ;  ALKANE HYDROXYLATION ;  ELECTRONIC-STRUCTURE ;  REACTIVITY PATTERNS ;  2-STATE REACTIVITY ;  REBOUND STEP ;  COMPOUND-I
语种: 英语
WOS记录号: WOS:000261807400010
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/141352
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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作者单位: 1.Chinese Acad Sci, Dalian Inst Chem Phys, State Key Lab Mol React Dynam, Dalian 116023, Peoples R China
2.Chinese Acad Sci, Grad Sch, Beijing 100039, Peoples R China
3.Ludong Univ, Dept Phys, Yantai 264025, Peoples R China

Recommended Citation:
Li, Dongmei,Wang, Yong,Yang, Chuanlu,et al. Theoretical study of N-dealkylation of N-cyclopropyl-N-methylaniline catalyzed by cytochrome P450: insight into the origin of the regioselectivity[J]. DALTON TRANSACTIONS,2009(2):291-297.
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