Provjera valjanosti kinetičkog modela biokatalitičke sinteze fluoriranog cijanoalkohola u različitim tipovima reaktora

master's thesis

• Title (english): Validation of a kinetic model for the biocatalytic synthesis of fluorinated cyanoalcohol in different reactor modes
• Author: Ana-Katarina Marić
• Mentor: Zvjezdana Findrik Blažević (mentor)
• Committee member: Zvjezdana Findrik Blažević (predsjednik povjerenstva)
• Committee member: Marija Vuković Domanovac (član povjerenstva)
• Committee member: Dragana Vuk (član povjerenstva)
• Granter: University of Zagreb; Faculty of Chemical Engineering and Technology; Zagreb
• Defense date and country: 2022-09-14, Croatia
• Scientific / art field, discipline and subdiscipline: TECHNICAL SCIENCES; Chemical Engineering

Abstract

Optički čisti spojevi od velike su važnosti u farmaceutskoj indrustriji, uz sve veći interes za fluorirane spojeve. Za sintezu kiralnih gradivnih elemenata često se koriste enzimi halogenhidrin-dehalogenaze (HHDH), koje mogu primiti brojne anionske nukleofile, od cijanida, cijanata, tiocijanata do azida i nitrita. U njihovoj prisutnosti dolazi do reakcije otvaranja epoksidnog prstena, što dovodi do stvaranja β-substituiranog alkohola. Osnova ovog rada je biokatalitička reakcija, točnije HHDH-katalizirana reakcija otvaranja epoksidnog prstena rac-2-(4-fluorofenil)oksirana cijanidnim ionima. Uz željeni produkt (S)-3-(4-fluorofenil)-3-hidroksipropannitril, ovom reakcijom stvara se i neželjeni (R)-3-(4-fluorofenil)-3-hidroksipropannitril te rac-2-(4-fluorofenil)-1,2-etandiol. Prethodno je razvijen matematički model ove sinteze kombinacijom kinetičkih jednadžbi i reaktorskog modela. U svrhu validacije modela, provedena je serija eksperimenata u kotlastom reaktoru s različitim početnim koncentracijama epoksida, NaCN i HHDH. U eksperimentima inkubacije uočena je deaktivacija enzima ovisna o početnoj koncentraciji epoksida. Operacijska stabilnost matematički je opisana i uključena u model. Nadalje, porastom koncentracije epoksida, stabilnost enzima opada, dok cijanidni nukleofil nema značajan utjecaj na stabilnost enzima. Eksperimentalni podaci pokazuju zadovoljavajuće slaganje s ranije razvijenim matematičkim modelom. Također, matematičko modeliranje pokazalo je kako je sinteza u kotlastom reaktoru/kotlastom reaktoru s ponavljajućim dodatkom epoksida (repetitivnom šaržnom reaktoru) optimalan način proizvodnje danog spoja.

Abstract (english)

Optically pure compounds are of great significance in the pharmaceutical industry, with the increasing interest in fluorinated compounds. One important enzyme group often employed in synthesizing various chiral building blocks are halohydrin dehalogenases (HHDHs) that can accept numerous anionic nucleophiles from cyanide, cyanate, thiocyanate to azide and nitrite. In their presence the ring-opening reaction of epoxide occurs, leading to β-substituted alcohol formation. The foundation of this work lies in a biocatalytic reaction, precisely HHDH-catalysed rac-2-(4-fluorophenyl)oxirane ring-opening reaction mediated by cyanide ions. Besides the desired (S)-3-(4-fluorophenyl)-3-hydroxypropanenitrile, this reaction yields an undesired (R)-3-(4-fluorophenyl)-3-hydroxypropanenitrile and rac-2-(4-fluorophenyl)-1,2-ethanediol. Mathematical model was earlier developed by coupling kinetic equations with reactor model. A series of different batch experiments varying in initial concentrations of epoxide, NaCN and HHDH were conducted with aim of model validation. Enzyme deactivation influenced by the initial epoxide concentration was observed within incubation experiments. Operational stability decay was mathematically described and included in the model. Furthermore, with the increase in the epoxide concentration, enzyme stability decreased, while the cyanide nucleophile did not have a significant effect on the stability of the enzyme. Experimental data has shown a satisfactory match with an earlier developed mathematical model. Moreover, mathematical modeling has shown that synthesis in batch/repetitive batch reactor is the optimal pathway for production of this compound.

• Keywords: biokataliza; enzimska kinetika; halogenhidrin-dehalogenaze; optički čisti spoj; matematičko modeliranje
• Keywords (english): biocatalysis; enzyme kinetics; halohydrin dehalogenases; optically pure compound; mathematical modeling
• Language: croatian
• URN:NBN: urn:nbn:hr:149:638536
• Project: Number: IP-2018-01-4493; Title: Enzimska sinteza fluoriranih kiralnih građevnih blokova; Acronym: EnzyFluor; Leader: Maja Majerić-Elenkov; Jurisdiction: Croatia; Funder: HRZZ; Funding stream: IP
• Study programme: Title: Applied Chemistry - Graduate study; specializations in: Environmental chemistry and green technologies, Advanced materials and technologies, Applied organic chemistry; Course: Advanced materials and technologies; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra primijenjene kemije (magistar/magistra primijenjene kemije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access; Embargo expiration date: 2023-10-01
• Created on: 2023-03-19 18:06:09