최루성 2-Chlorobenzylidenemalononitrile 분자의 가수분해 반응성과 ADME의 예측
Hydrolysis Reactivity of 2-Chlorobenzylidenemalononitrile Molecule as Lachrymatory Material and Prediction of ADME
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시위 진압용 최루성 물질인 2-chlorobenzylidenemalononitrile 분자(S)의 가수분해 반응성과 급만성 독성을 이해하고자, MOPAC AM1 방법으로 MO함수를 계산하고, ADME 및 TOPKAT 방법으로 독성예측을 실행하고 검토하였다. 가장 안정한 입체 형태는 antiperiplanar (θ^ο= 48 및 E = 3.7378 ev.) 형이었고 MO함수의 에너지(ev.)는 εHOMO: −10.0422 ev. 및 εLUMO: −0.9215 ev.이었다. 경계궤도함수(FMO:Frontier molecular orbital) 상호작용으로부터 친핵성 첨가반응(A)과 친전자성 첨가반응(B)이 경쟁적으로(AB) 일어남을 나타내었다. 또한, 중성에서는 친핵성 첨가-제거반응(Ad_(Nu)-E) 메카니즘으로 가수분해반응이 일어나며 분해 생성물은 2-chlorobenzaldehyde 및 malononitrile이었다. ADME 및 TOPKAT에 의한 독성 예측결과, 대체로 분자(S)보다 malononitrile이 높은 독성을 나타내는 경향이었다.
Abstract
To understand on the hydrolysis reactivity of 2-chlorobenzylidenemalononitrile (S) molecule as riot control agent and chronic (or acute) toxicity of hydrolysis products, MO (Molecular orbital) calculation by MOPAC AM1 method, toxicity predictions by ADME and TOPKAT were performed and discussed quantitatively. The most stable stereo conformer of the molecule (S) was antiperiplanar (θ^o = 48, E = 3.7378 ev.) form, and the calculated MO functions were εHOMO= −10.0422 ev. and εLUMO = −0.9215 ev., respectively. Therefore, from FMO (Frontier molecular orbital) interactions, it is showed that the nucleophilic addition (A) and electrophilic addition (B) reactions occurs (A ≤ B) competitively. In the neutral, hydrolysis of the molecule (S) proceeds through an nucleophilic addition-elimination (Ad_(Nu)-E) and hydrolysis products were 2-chlorobenzaldehyde and malononitrile. Based on the predicted toxicity by ADME and TOPKAT, generally, it was shown that malononitrile had higher tendency than the molecule (S).
참고문헌 (33)
- LH Horsley, "Advanced in Chemistry Series, No. 6", pp.73~ (1952)
- JJ Li., "Name Reactions: A Collection of Detailed Reaction Mechanism. (2nd Ed.)", pp.220~221 (2003), Springer-Verlag
- H Hu, "The Use of Chemical Weapons: Conducting an Investigation Using Survey Epidemiology", J. Am. Medical Association, 262, pp.640~654 (1989)
- ST Bhattacharya, "CS gas? Implications for the anaesthetist", Anaesthesia, 48, pp.896~905 (1993)
- Olajos, EJ, "Riot Control Agents: Pharmacology, Toxicology, Biochemistry and Chemistry", J Appl Toxicol, 21, pp.355~391 (2001)
- RC Malhotra, "Chemistry and toxicity of tear gas", Def Sci J, 37, pp.281~296 (1987)
- EJ Olajos, "Riot control agents: pharmacology, toxicity, biochemistry and chemistry", J Appl Toxicol, 21, pp.355~391 (2003)
- SW Park, "A study on the hydrolysis and analysis of o-chlorobenzylidenemalononitrile", Anal Sci Tech, 5, pp.443~454 (1992)
- I Fleming, "Frontier Orbitals and Organic Chemical reactions", pp.34~85 (1976), John Wiley & Sons
- SK Balani, "Strategy of utilizing in-vitro and in-vivo ADME tools for lead optimizat ion and drug candidate selection", Curr. Top Med. Chem, 5, pp.1033~1038 (2005)
- 김해중, "Crystal Violet 염료 분자의 가수분해 및 자유 라디칼 반응성에 관한 분자 궤도론적 이해", 과학수사학, 5(3), pp.220~227 (2011), 한국과학수사학회
- Tripos Inc., "Sybyl Molecular Modeling and QSAR Software on CD-Rom. (Ver. 8.0)", Theory and Manual., ~ (2008)
- JJ Stewart, "MOPAC: A Semiempirical Molecular Orbital Program", J. Comp.-Aided Mol. Design, 4, pp.1~150 (1990)
- R Benigini, "Quantitative structure-activity relationships of mutagenic and carcinogenic aromatic amines", Chem. Rev., 100, pp.3697~3714 (2000)
- S Patai, "The Chemistry of Functional Groups. Supplement E", pp.215~278 (1980), John Wiley & Sons
- F Frank, "The Solvent Properties of Water, In Water; A Comprehensive Treatise. Vol. 2; Water in Crystalline Hydrates Aqueous Solutions of Simple Nonelectrlytes", pp.1~54 (1973), Plenum Press
- J March, "Addition to Carbon-Carbon Multiple Bonds. In Advanced Organic Chemistry; Reactions, Mechanism, and Structure.(4th Ed.)", pp.734~758 (1992), John Wiley & Sons
- G Klopman, "Chemical Reactivity and Reaction Paths", pp.55~165 (1974), John Wiley & Sons
- TR Kim, "Kinetics and mechanism of the hydrolysis of an arylmethylenemalononitrile", J. Korean Chem. Soc, 17, pp.130~135 (1973)
- ND Sung, "Kinetics and mechanism of alkaliehydrolysis of cinnamonitrile", Res. Rep. Agri. Sci. Tech, 10, pp.354~364 (1983)
- J Hine, "Acid-Base Catalysis. In Physical Organic Chemistry (2nd Ed.)", pp.112~122 (1962), McGraw-Hill Book Company, Inc.
- NS Isaacs., "Physical Organic Chemistry", pp.579~583 (1987), Longman Scientific& Technical
- M Huce, "Nucleophilic Addition-Electrophilic Coupling with a Carbanion Interm-ediate. Comp. Org. Synth", pp.237~268 (1991), Pergamon Oxford
- -Bicycl ooctane and of the Perhydroindan Series, "J. Org. Chem.", 1974, 1612~1615
- NN Kruas, "Taxonomic analysis of perceived risk: Modeling individ-ual and group perceptions within homogeneous hazard domains", Risk analysis, 8, pp.435~455 (1988)
- PD John, "Reviews: Role of albumin in human physiology and pathophysiology", J. Parenter. Enteral. Nutr., 15, pp.207~211 (1991)
- CW Rim, "Acute mammalian toxicity of o-chlorobenzylidene-malononitrile(CS)", Korean J. Toxicol, 5, pp.49~52 (1989)
- Health Council of the Netherlands, "Committee on Updating of Occupational Expo-sure Limits. 2-Chlorobenzylidenemalononitrile; Health-based Reassessment of Administrative Occupational Exposure Limits", Health Council of the Netherlands, ~ (2004)
- S Wang, "Applications of computers to toxicological research", Chem. Res. Toxicol, 6, pp.748~753 (1993)
- ND Sung, "Papent pending for domestic & foreign", ~ (2012)