Theoretical study of N-dealkylation of N-cyclopropyl-N-methylaniline catalyzed by cytochrome P450: insight into the origin of the regioselectivity

	Theoretical study of N-dealkylation of N-cyclopropyl-N-methylaniline catalyzed by cytochrome P450: insight into the origin of the regioselectivity
	Li, Dongmei 1,2; Wang, Yong 1; Yang, Chuanlu 3; Han, Keli 1
刊名	dalton transactions
	2009
期号	2 页码:291-297
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.
WOS标题词	science & technology ; physical sciences
类目[WOS]	chemistry, inorganic & nuclear
研究领域[WOS]	chemistry
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
收录类别	SCI
语种	英语
WOS记录号	WOS:000261807400010
公开日期	2015-11-17
内容类型	期刊论文
源URL	[http://159.226.238.44/handle/321008/141352]
专题	大连化学物理研究所_中国科学院大连化学物理研究所
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
推荐引用方式 GB/T 7714	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.
APA	Li, Dongmei,Wang, Yong,Yang, Chuanlu,&Han, Keli.(2009).Theoretical study of N-dealkylation of N-cyclopropyl-N-methylaniline catalyzed by cytochrome P450: insight into the origin of the regioselectivity.dalton transactions(2),291-297.
MLA	Li, Dongmei,et al."Theoretical study of N-dealkylation of N-cyclopropyl-N-methylaniline catalyzed by cytochrome P450: insight into the origin of the regioselectivity".dalton transactions .2(2009):291-297.