Mehanizam reakcije kloriranja 5-fluorouracila

master's thesis

• Title (english): Reaction mechanism of 5-fluorouracil chlorination
• Author: Tana Tandarić
• Mentor: Valerije Vrček (mentor)
• Committee member: Valerije Vrček (predsjednik povjerenstva)
• Committee member: Davor Šakić (član povjerenstva)
• Committee member: Tin Weitner (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of organic chemistry); Zagreb
• Defense date and country: 2016-04-07, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Medical Biochemistry

Abstract

Pojava lijekova u okolišu u posljednjih je dvadesetak godina postala goruća ekološka tema. Jedan od takvih farmaceutika je 5-fluorouracil (5-FU), antimetabolit koji se nalazi u okolišu u koncentracijama i do 63 ng/L. Eksperimentalno je pokazano da se tijekom postupka kloriranja, koji predstavlja jednu od najučestalijih metoda obrade otpadnih voda, 5-FU pregrađuje u klorhidrinski produkt 3a. Strukturne karakteristike dobivenog spoja određene su 1H, 19F i 13C NMR spektroskopijom. Kvantnokemijskim metodama istražen je reakcijski mehanizam kloriranja 5-FU. Korišten je M062X funkcional uz 6-311+G(d) bazni skup. Solvatacijski efekti opisani su implicitnim SMD solvatacijskim modelom, te korištenjem optimalnog broja eksplicitnih molekula otapala (H2O). Pokazano je da dolazi do kloriranja na C5 položaju u pirimidinskom prstenu 5-FU. Dvostupanjska reakcija u kojoj u prvom koraku dolazi do adicije Cl+ na anion 1-N1, uz nastanak iminskog intermedijera 4, određena je kao najvjerojatniji reakcijski mehanizam. Energijska barijera za reakciju adicije kloronijevog iona (preko prijelaznog stanja TSI) iznosi 106,8 kJ/mol. U drugom reakcijskom koraku dolazi do adicije vode na iminski intermedijer (Gǂ = 26,7 kJ/mol) uz nastanak klorhidrinskog produkta 3a. Rezultati dobiveni kvantno-kemijskim metodama u skladu su s eksperimentalno dobivenim podacima. Dobiveni rezultati ključni su za poznavanje ekološke sudbine 5-FU.

Abstract (english)

In the last twenty years, the occurence of pharmaceuticals in enviroment has become a burning ecological issue. One of these pharmaceuticals is 5-fluorouracil (5-FU), antimetabolite drug which has been found in the enviroment in concentrations up to 63 ng/L. In this work, it is experimentaly shown that during the chlorination process, which is one of the most common method for wastewater treatment, the 5-FU yields chlorohydrine product 3a. Structural characteristics of 3a are determined using 1H, 19F i 13C NMR spectroscopy. Reaction mechanism of chlorination of 5-fluorouracil is investigated using quantum chemistry methods. M062X functional with 6-311+G(d) basis set is applied. The solvent effects are described by the implicit SMD solvation model, using the optimal number of the explicit solvent molecules (H2O). It has been shown that 5-FU is chlorinated at the C5 position in the pyrimidine ring. The two steps reaction in which the first step is the addition of Cl+ on 1-N1 anion, yielding the imine intermediate 4, is determined as the most possible reaction mechanism. The energy barrier which corresponds to the addition of chloronium ion (through the transition state structure TSI) is 106,8 kJ/mol. The addition of water on the imine intermediate (Gǂ = 26,7 kJ/mol), which results in the chlorohydrine 3a, is the second reaction step. The results obtained with quantum chemical methods are in agreement with experimental data. Results of these study play a key role in predicting the ecological fate of 5-FU.

• Keywords: 5-flurouracil; hipoklorasta kiselina; NMR spektroskopija; računalna kemija
• Keywords (english): 5-fluorouracil; hypochlorous acid; NMR spectroscopy; computational chemistry
• Language: croatian
• URN:NBN: urn:nbn:hr:163:937517
• Study programme: Title: Medical biochemistry; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: magistar/magistra medicinske biokemije (magistar/magistra medicinske biokemije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2016-12-02 14:37:29