Search

Herein, we report a study on the reactivity of three 1,3-diarylimidazolium-based fluoride reagents, with a general formula of [IPrH][F(HF)$_n$] (n = 0, 1, or 2), that tackle the challenges of limited solubility, hygroscopicity, instability, and laborious preparation procedures of nucleophilic fluoride reagents. Fluorination of 4-tert-butylbenzyl bromide reveals that trifluoride [IPrH][F(HF)$_2$] is the most selective reagent. Microwave-assisted activation coupled with the addition of sterically hindered amine DIPEA or alkali metal fluorides increases the rate of fluorination with [IPrH][F(HF)$_2$], making it an excellent reagent for the fluorination of various organic substrates. The scope of substrates includes benzyl bromides, iodides, chlorides, aliphatic halides, tosylates, mesylates, α-haloketones, a silyl chloride, acyl and sulfuryl chlorides, and a nitroarene. The exceptional stability of the air-stable and nonhygroscopic [IPrH][F(HF)$_2$] reagent is illustrated by its convenient synthesis and detailed experimental regeneration protocol using hydrofluoric acid without organic solvents.

Kemija je jednostavna znanost, jer je njezin osnovni cilj – jednostavan: različitim kemijskim postupcima od dviju ili više poznatih tvari dobiti nove materijale naprednih i poboljšanih svojstava. No, često su zamišljene pretvorbe, iako logične i smislene na papiru, u praksi povezane s brojnim poteškoćama i ograničenjima, tako da postavljene reakcije uopće ne idu ili ne daju ciljane tvari, omogućuju produkte koji su nestabilni ili nemaju željeno svojstvo, a povremeno specifični eksperimenti postaju čak i neizvedivi. Upravo iz tih razloga, brojni sintetski putevi, kako u akademskim krugovima, tako još više i u industrijskim sredinama, oslanjaju se na primjenu ekstremnih uvjeta, velikog suviška pojedinih reaktanata ili katalizatora, što često dovodi do skupih i dugotrajnih postupaka, a nerijetko i do procesa koji generiraju velike količine otpada i nečistoća potpuno neprihvatljivih za okoliš. Stoga je zahvalno da kemičari danas nisu samo ljudi u kutama i zaštitnim naočalama. Današnja moderna istraživanja uvelike se oslanjaju na predviđanja i putokaze koje im pružaju računalne metode. Uslijed strelovitog razvoja informatičkih tehnologija tijekom posljednjih 40-ak godina, računalna kemija postala je ravnopravan i nužan partner eksperimentalnim istraživanjima u svim granama te znanosti, prvenstveno zbog brzine, efikasnosti i ekonomičnosti kojima se dolazi do vrijednih rezultata. Računalne metode omogućuju izračun i predviđanje gotovo svih kemijskih i fizikalnih svojstava molekula, čak i prije nego li te molekule uopće postoje. Po svojoj točnosti, rezultati računskih simulacija usporedivi su s onima iz najsuvremenijih eksperimenata, a dobiveni uvid u neka svojstva kemijske veze i elektronske strukture molekula nije niti moguće dobiti drugim tehnikama, radi čega ovi pristupi omogućuju bolje razumijevanje fenomena uočenih eksperimentima. Računalne tehnike danas se koriste kako bi nadopunile, usmjerile i povremeno potpuno zamijenile eksperimentalna istraživanja, posebice ona vremenski i financijski zahtjevna te potencijalno opasna i ekološki neprimjerena. U ovom predavanju, kroz nekoliko ilustrativnih primjera vlastitih znanstvenih istraživanja [1–3], predstavit će se mogućnosti i korist računalnih simulacija u multidisciplinarnim istraživanjima.

V doktorskem delu smo predstavili nekatere nove sintezne metode, spojine, reagente v okviru organske kemije halogenov in halkogenov s poudarkom na načelih zelene kemije in trajnostnem razvoju. Zaradi netrajnostne rabe naravnih virov in onesnaževanja okolja se je razvilo področje, imenovano zelena kemija, ki temelji na okolju prijaznih principih. Med hal(k)ogeniranimi organskimi spojinami najdemo mnoge materiale, topila, reagente, sintone in naravne spojine ter medicinsko, industrijsko in agrokemijsko pomembne spojine. Kljub hitremu napredku na področju, se pojavljajo potrebe po sintezi obstoječih in novih motivov pod alternativnimi pogoji, ki sledijo načelom trajnostnega razvoja. Organske sulfokside smo do sulfidov reducirali na vodnem mediju 37% HCl s cenenim reagentom NaSH, ki po koncu reakcije tvori okolju nenevarne odpadne produkte. Produkt reakcije v večjem merilu smo izolirali z neposredno destilacijo. Razvili smo novo, hitro in priročno metodo oksidacije organskih sulfidov, ki pri zelenih pogojih slelektivno poteka s t-BuOCl. Pretvorbe so odvisne od temperature in topila, sulfokside in sulfone pa smo izolirali z odstranitvijo topila in hlapnih primesi. Metodo smo prenesli na večje merilo in na polimerne substrate ter raziskovali mehanizem. Prej neznane N-jodo sulfoksimine smo pripravili neposredno iz sulfidov z eno-lončnim sintetskim pristopom v zelenem topilu metanolu. Metodo smo izvedli v večjem merilu in predstavili nekatere nadaljnje pretvorbe. Organske selenide smo do selenoksidov oksidirali s 30% vodno raztopino zelenega oksidanta H2O2. Pripravili smo dva reagenta za elektrofilno selenocianiranje in -SeCN uvedli pod trajsnotnimi pogoji. 2-Amino-4H-pirane smo pod reakcijskimi pogoji brez topil s t-BuOCl regioselektivno klorofukcionalizirali do α,N-dikloroiminov in produkte izolirali z odstranjevanjem hlapnih primesi. Zlato smo raztopili v etanolu s katalitsko količino joda, 33% vodne raztopine H2O2 ter cenenim in nenevarnim ligandom. Doktorska naloga predstavlja pomemben doprinos k zeleni kemiji redoks reakcij žveplovih in selenovih organskih spojin, elektrofilnega prenosa halogenov in halkogenov ter njihovih funkcionalnih skupin, sintezi in reaktivnosti haloiminskega stukturnega motiva in recikliranja dragocenih kovin. Herein we present some novel synthetic methods, compounds and reagents in the context of halogen and chalcogen organic chemistry with emphasis on green chemistry principles and sustainable development. Due to unsustainable exploitation of natural resources and environmental pollution, green chemistry was established on environmentally friendly principles. Halogenated and chalcogenated organic compounds are important materials, solvents, reagents, synthons and natural compounds, that are used in medicine, industry, and agrochemistry. Despite quick development of this field, there is still a great need for preparation of existing and novel motifs under alternative conditions that follow sustainable development. Organic sulfoxides were deoxygenated to sulfides using 37% aqueous HCl and affordable reagent NaSH, that produce environmentally benign waste. Product of scaled-up reaction was isolated by direct distillation. New, rapid, and convenient method for oxidation of organic sulfides that selectively proceeds with t-BuOCl under green reaction conditions. Reaction was temperature- and solvent-dependent and product sulfoxides and sulfones were isolated by removal of solvent. The method was easily scalable and tested on polymeric substrate. The mechanism was explored. Previously unknown N-iodo sulfoximines were prepared from sulfides via one-pot approach in green solvent methanol. The method was scaled-up and further transformations were explored. We developed new sustainable method for oxidation of organic selenides using 30% aqueous H2O2 solution. Two reagents for electrophilic selenocyanation were prepared and -SeCN motif was introduced under sustainable conditions. 2-Amino-4H-pyrans were regioselectively chloro-functionalised with t-BuOCl under neat reaction conditions to afford α,N-dichloroimines that were isolated by removal of volatiles. Gold was dissolved in ethanol with catalytic amount of iodine, 33% aqueous H2O2 and inexpensive and non-toxic ligand. Doctoral thesis presents an important contribution to green chemistry topics of sulfur and selenium organic compound redox reactions, halogen and chalcogen functional group electrophilic transfer and synthesis, reactivity of haloimine structural motif and noble metal recycling.

V zadnjem času se krepi zavedanje, da mora boj za ohranitev človeku prijaznega okolja potekati na vseh ravneh. Temu primerno se stopnjuje tudi zanimanje in novi načini reakcij pod zelenimi pogoji. Aromatski ketoni so sestavine mnogih različnih snovi. Prisotni so v farmacevtskih izdelkih, naravnih proizvodih in sredstvih za zaščito pridelkov. V diplomi je predstavljeno Friedel-Craftsovo aciliranje polisubstituiranih in aktiviranih aromatskih spojin z enim ali dvema obročema. Substituenti so metoksi in metilne skupine. Reakcije so bile z eno izjemo izvedene brez kovinskega katalizatorja in z bistveno manj proizvedenega odpadka kot pri klasični sintezi. Ena reakcija je bila zaradi neuspeha pod zelenimi pogoji izvedena na klasičen način z etanoil kloridom in AlCl3. Nekateri nastali produkti v trenutno razpoložljivi literaturi še niso opisani. Recently, there has been a growing awareness that the fight to preserve a human-friendly environment must take place at all levels. Correspondingly, interest and new ways of reacting under green conditions are also increasing. Aromatic ketones are components of many different substances. They are present in pharmaceutical products, natural products and agrochemicals. The thesis presents Friedel-Crafts acylation of polysubstituted and activated aromatic compounds with one or two rings. Substituents are methoxy and methyl groups. With one exception, the reactions were carried out without a metal catalyst and with significantly less produced waste than in classic synthesis. One reaction was performed under traditional conditions with acetyl chloride and AlCl3 due to the failure of the reaction under green conditions. Some of the resulting products have not yet been described in the currently available literature.

V svojem diplomskem delu sem preizkušal aciliranje aktiviranih aromatov s karboksilnimi anhidridi in trifluoroocetno kislino. Trifluoroocetna kislina v reakciji nastopa kot katalizator in topilo. Reakcija je okolju prijaznejša alternativa klasičnemu aciliranju, kjer se uporablja kovinske kloride, ki jih v reakciji izgubimo, trifluoroocetno kislino pa je mogoče uporabiti ponovno. Ta način aciliranja daje solidne izkoristke na 1,3,5-trimetoksibenzenu in 2-metoksinaftalenu. Produkte, ki jih proizvedemo, je lahko očistiti, saj praktično ne dobimo stranskih produktov in drugih nečistot. In my thesis, I tested the alternative method of acylating aromatic compounds with carboxylic anhydrides and trifluoroacetic acid. Trifluoroacetic acid has a catalytic role in the reaction and it serves as a solvent. The reaction is a greener alternative to classic acylation where metal halides are used and are lost in the reaction. Contrary to metal halides, trifluoroacetic acid can be recycled and used for further reactions. This kind of acylation gives acceptable yields on 1,3,5-trimethoxybenzene and on 2-methoxynaphtalene. Synthesised products are easily purified because almost no by-products are formed in the process.

Različno substituirani 3-benzoilamino-2H-piran-2-oni z Diels–Alderjevo cikloadicijo z maleinahidridom ali N-fenilmaleimidom vodijo v nastanek biciklo[2.2.2]oktenskih sistemov. V svojem magistrskem delu opisujem izvedbo omenjenih reakcij v topilih, ki jih je možno pridobivati iz biomase. Takšna topila predstavljajo eno izmed novejših vrst topil, ki se uvrščajo pod zeleno kemijo. Uspešno sem sintetizirala več različno substituiranih biciklo[2.2.2]oktenskih produktov v para-cimenu, α-pinenu in evkaliptolu. V para-cimenu sem tudi preizkusila in optimizirala nekatere reakcije, da bi dosegale čim višje konverzije, bile čim manj energijsko potratne in tako čim bolje ustrezale principom zelene kemije. Omenjene Diels–Alderjeve reakcije sem preizkusila tudi v limonenu, kjer reakcija ni potekla, in γ-valerolaktonu, kjer so bile težave z izolacijo produkta. Produkte, ki so uspešno nastali, sem okarakterizirala s pomočjo IR, 1H NMR in MS analize. Various substituted 3-benzoylamino-2H-pyran-2-ones lead to bicyclo[2.2.2]octene derivatives upon reaction with maleic anhydride or N-phenylmaleimide via Diels–Alder cycloaddition. In this master's thesis, such reactions are described in biomass-derived solvents. This type of solvent is one of the newer types of green solvents. Various substituted bicyclo[2.2.2]octenes were synthesized in para-cymene, α-pinene and eucalyptol. Some of the reactions carried out in para-cymene were optimized to achieve high conversion rates, to be as energy efficient as possible, and to satisfy as many principles of green chemistry as possible. The aforementioned synthesis of bicyclo[2.2.2]octenes was also attempted in limonene, where the reaction did not occur and in γ-valerolactone, where problems with the isolation of the product were encountered. The successfully synthesized products were characterized by IR, 1H NMR and MS analytical methods.

Razvojem programa zelene kemije, tendencija znanstvenika i akademske zajednice je da se načela zelene kemije primjenjuju u kemijskim i biološkim procesima. Također, jedan od ciljeva je zamijeniti organska otapala alternativnim zelenim otapalima. Niskotemperaturna eutektička otapala dosad su pokazala velik potencijal za njihovu primjenu u biotransformacijama. Jedna od primjena je reakcijski medij za proizvodnju kiralnih lijekova. Prema tome, u ovom radu ispitana je aktivnost lipaza u niskotemperaturnim eutektičkim otapalima (hDES) te mogućnost korištenja hDES u enantioselektivnoj redukciji (R,S)-1-feniletiletanola uz primjenu lipaza kao biokatalizatora. Praćenjem parametara (X, VE, Vp), zaključeno je da je najaktivnija lipaza CALB u hDES-u Ty:C8. U tom sustavu je provedena kinetička (dinamička) rezolucija (R,S)-1-feniletanola te je na temelju dobivenih rezultata zaključeno da Ty:C8 moguća zamjena za organska otapala u ispitanim reakcijskim uvjetima. With the development of the green chemistry program, the tendency of scientists and the academic community is to apply the principles of green chemistry in chemical and biological processes. Also, one of the goals is to replace organic solvents with alternative green solvents. Deep eutectic solvents have so far shown great potential for their application in biotransformations. They can be used as a reaction medium for the production of chiral drugs. Therefore, in this work, the activity of lipases in deep eutectic solvents (hDES) and the possibility of using hDES in the enantioselective reduction of (R,S)-1-phenylethylethanol with the use of lipase as a biocatalyst were tested. By monitoring the parameters (X, VE, Vp), it was concluded that the most active lipase is CALB in hDES Ty:C8. In this system, the kinetic (dynamic) resolution of (R,S)-1-phenylethanol was performed, and based on the obtained results, it was concluded that Ty:C8 is a possible substitute for organic solvents in the tested reaction conditions.

Pri svojem diplomskem delu sem se osredotočil na Michaelove adicije v prisotnosti in odsotnosti topil. Izvedel sem predvsem adicije aktiviranih metilenskih spojin (Michaelovi donorji) na tako α,β-nenasičene ketone kot tudi nitroalkene (Michaelovi akceptorji), in sicer v prisotnosti katalizatorjev LiClO4 in Et3N pri sobni temperaturi ter brez prisotnosti topil. Prav tako sem sintetiziral derivat rodanina v prisotnosti vode, a brez dodanih katalizatorjev. Reakcije sem najprej izvedel v manjšem merilu in jih kasneje izvedel še v večjem merilu, če so bile v manjšem merilu uspešne. Produkte reakcij v manjšem merilu sem izoliral z ekstrakcijo in destilacijo, pri reakcijah v večjem merilu pa sem produkte očistil s prekristalizacijo. Izkoristki reakcij v manjšem merilu so bili odlični, medtem ko so bili izkoristki pri večjem merilu slabi ali kvečjemu povprečni. Na koncu sem produkte analiziral z uporabo 1H NMR spektrov, ki sem jih posnel v CDCl3 pri 300 MHz. In the thesis, I focused on Michael additions in solution or under solvent-free conditions. I mostly carried out additions of activated methylene compounds (Michael donors) onto α,β-unsaturated ketone and nitroalkenes (Michael acceptors) in the presence of the LiClO4/Et3N catalyst at room temperature under solvent-free conditions. I also synthesized a rhodanine derivative in water under catalyst-free conditions. All reactions were first carried out on a smaller scale and later - if successful on the smaller scale - also on a larger scale. I isolated the small-scale products with extraction and distillation, while purification of products on a larger scale was performed by crystallization. Reactions on a smaller scale gave products in excellent yields, while large-scale reaction yields varied from poor to average. I analyzed my products using 1H NMR spectra recorded in CDCl3 at 300 MHz.

Primjena eutektičkih otapala u kemijskim sintezama predstavlja prihvatljivu alternativu najčešće korištenim organskim otapalima koja mogu biti štetna po zdravlje i okoliš. Ovom radu cilj je ispitati i dokazati mogućnost korištenja takvih dvokomponentnih otapala u sintezi Schiffovih baza. Schiffove baze su spojevi koji nastaju kondenzacijom aldehida ili ketona i primarnih amina. Takvi se spojevi smatraju podgrupom imina i predmet su brojnih istraživanja jer pokazuju potencijalna antimikrobna, antiviralna i antikancerogena svojstva. Prvi dio rada obuhvaća optimizaciju modelne reakcije u 20 eutektičkih otapala na bazi kolin-klorida, nakon čega slijedi sinteza 20 Schiffovih baza s kinazolinonskom jezgrom pri optimalnim uvjetima. The use of deep eutectic solvents in chemical syntheses is an acceptable alternative to the most commonly used organic solvents that can be harmful to human health and environment. The aim of this research was to investigate and prove the possibility of using such two - component solvents in the synthesis of Schiff bases. Schiff bases are compounds formed by the condensation of aldehydes or ketones and primary amines. Such compounds are considered a subgroup of imines and are the subject of many research because they show potential antimicrobial, antiviral and anticancer properties. The first part of the paper includes the optimization of the model reaction in 20 choline chloride based eutectic solvents, followed by the synthesis of 20 Schiff bases with quinazolinone nucleus under optimal conditions.

Zbog sve većeg onečišćenja okoliša javlja se sve veća potreba za korištenjem ekološki prihvatljivih i energetski učinkovitijih procesa i kemikalija koji bi odgovarali principima zelene kemije. Mehanokemijska sinteza je jedna od metoda zelene kemije koja daje mogućnost sinteze novih spojeva bez korištenja otapala. U eksperimentalnom dijelu ovog završnog rada korišten je laboratorijski kuglični mlin za sintezu derivata kinazolinona koristeći tri prekursora 3-amino-2-metilkinazolin- 4(3H)-on, 3- amino-6-jod-2-metilkinazolin-4(3H)-on i 3-amino-7-klor-2-metilkinazolin)-4(3H)-on sa četiri aromatska izocijanata, fenil-izocijanat, 1- naftil-izocijanat, 4-klor-3-(trifluorometil)fenil- izocijanat i 4-nitrofenil-izocijanat. Strukture pripravljenih derivata kinazolinona potvrđene su masenom spektrometrijom.

Ubrzani rast populacije koji prati povećana potrošnja i proizvodnja dobara uzrokuje i sve veće ekološko opterećenje okoliša. U težnji da zadovolje apetite populacije, proizvodni procesi povećavaju svoje kapacitete, što posredno ima negativne učinke na okoliš. U jeku takvog brzorastućeg fenomena ubrzane proizvodnje, danas se naglasak sve više stavlja na zaštitu okoliša i zelene proizvodne i ostale procese. Uz ostale, kemijska i farmaceutska industrija primijenjuju velike količine štetnih organskih lakohlapljivih otapala, koja se na kraju procesa odlažu u otpad. Osim otapala, nastoji se racionalizirati i upotreba štetnih toksičnih katalizatora i reagenasa općenito, te dizajn samog kemijskog procesa. Današnji pristup smanjenja štetnih utjecaja u kemijskim procesima se uvelike temelji na načelima zelene kemije objavljenim od strane Paul T. Anastasa i Johna C. Warnera 1998. g. Prema načelima zelene kemije i sinteza heterocikličih spojeva se nastoji što više prilagoditi navedenim principima, a radovi mnogih autora svjedoče vrlo efikasnoj primjeni i izvrsnim rezultatima. Mnoštvo autora dokazalo je da su neki procesi zelene sinteze heterocikličkih spojeva efikasniji od konvencionalnog pristupa, što zaista utire put novoj generaciji procesa s većom efikasnošću i manjim negativnim utjecajem na okoliš.

Niskotemperaturna eutektička otapala (DES-ovi), kao zelena alternativa organskim otapalima iz neobnovljivih izvora, istraživanjima i implementacijom u enzimski kataliziranim reakcijama pokazuju svoj potencijal buduće primjene u industriji te potencijal zelene kemije kao takve. U ovom je radu primjenom računalnog programa COSMOtherm proveden probir eutektičkih otapala za kinetičku rezoluciju temeljem procjene topljivosti supstrata vinil acetata i (R,S)-1-feniletanola. U odabranim eutektičkim otapalima provedena je kinetička rezolucija te je praćena uspješnost reakcije u hidrofobnom niskotemperaturnom eutektičkom otapalu (Ty:C10) u odnosu na hidrofilno niskotemperaturno eutektičko otapalo (ChCl:U10%) te organsko otapalo etil-acetat (klasično korišteno). Vrijednosti konverzije i enantiomernog viška su se koristile za procjenu uspješnosti reakcije. Timol:dekanska kiselina (Ty:C10) dokazano je najbolje otapalo od ispitanih otapala za provedbu reakcije esterifikacije (R,S)-1-feniletanola, s najvećim udjelom konverzije od 53,04%. Enantiomerni višak je zadovoljavajuć i veći od 97% za sva tri korištena otapala. Također, enantiomerni višak (ee) je najviši za otapalo Ty:C10 i iznosi 98,80%. Deep eutectic solvents (DESs), as a green alternative to organic solvents from non-renewable sources, show their potential for future industrial applications and the potential of green chemistry through research and implementation in enzyme-catalyzed reactions. In this paper, eutectic solvents were investigated for kinetic resolution using the software program COSMOtherm based on the evaluation of the solubility of the substrates vinyl acetate and (R,S)-1-phenylethanol. Kinetic resolution was carried out in selected eutectic solvents and the success of the reaction was monitored in the hydrophobic deep eutectic solvent (Ty:C10) and compared to both hydrophilic deep eutectic solvent (ChCl:U10%) and the organic solvent ethyl acetate (classically used). Conversion and enantiomeric excess values were used to evaluate the success of the reaction. Thymol:decanoic acid (Ty:C10) proved to be the best solvent among the tested solvents for carrying out the esterification reaction of (R,S)-1-phenylethanol with the highest conversion rate of 53.04%. The enantiomeric excess is satisfactory and is more than 97% for all three solvents used. Moreover, the enantiomeric excess (ee) is highest for our most successful solvent Ty:C10 and its value is 98.80%.

Ru(II)/carboxylate/PPh$_3$ catalyst system enabled the preparation of highly conjugated pyrazine derivatives in water under microwave irradiation. Both nitrogen atoms efficiently dictated cleavage of the ortho-C–H bonds in both benzene rings of 2,3-diphenylpyrazine substrates through chelation assistance. In conformationally more flexible diphenyldihydropyrazine 1, the arylation of four ortho-C–H bonds was possible, while in the aromatic analog 2, the triarylation was the limit.

V diplomskem delu sem najprej predstavila lastnosti različnih dienov in dienofilov, ki sodelujejo v Diels–Alderjevih reakcijah, ter sam mehanizem in selektivnost [4+2] cikloadicij. V nadaljevanju se posvetim aktualni problematiki preprečevanja onesnaževanja okolja ter opišem osnovna načela zelene kemije, katere glavni cilj je izboljševanje kemijskih procesov in s tem zmanjšanje proizvodnje ter uporabe snovi, nevarnih za človeka in okolje. Pri iskanju okolju prijaznejših sinteznih poti so se razvile nove zelene metode aktivacije reakcij. V diplomski nalogi sem se osredotočila predvsem na obsevanje z mikrovalovi in uporabo visokega tlaka. Na koncu uporabo teh dveh metod predstavim na primerih Diels–Alderjevih reakcij, pri katerih so v večini primerov kot dienofili uporabljeni substituirani ciklični sistemi. The diploma work first presents the properties of different dienes and dienophiles involved in Diels–Alder reactions, as well as the mechanism and selectivity of these [4+2] cycloadditions. In the following paragraphs, the focus is on the current issue of pollution prevention and the basic principles of green chemistry, the main goal of which is to improve chemical processes and thus reduce the production and use of substances harmful to humans and the environment. In the search for more environmentally friendly synthetic pathways, new green methods of activating reactions have been developed. In my diploma work, I focused mainly on microwave irradiation and the use of high pressure. Finally, I present the use of these two methods on the examples of Diels–Alder reactions in which in most cases as dienophiles substituted cyclic systems are used.

Potreba za dizajniranjem kemijskih, farmaceutskih i biotehničkih proizvoda i procesa koji smanjuju ili potpuno uklanjaju primjenu i stvaranje škodljivih i opasnih tvari s jedinstvenim ciljem zaštite okoliša doveli su do razvoja koncepta zelene kemije koji je sve učestaliji industrijski pristup današnjice. Spomenuti pristup podrazumijeva korištenje alternativnih otapala i ekološki prihvatljivih i obnovljivih sirovina, ali i primjenu alternativnih oblika energije te provođenje organskih reakcija primjenom biokatalizatora. Shodno tome, sve je veći interes za primjenom eutektičkih otapala kao medija za biokemijsku pripravu kiralnih biološki aktivnih komponenti. U ovom je radu provedena reakcija enantioselektivne redukcije halogeniranog acetofenona u kiralni halogenirani alkohol, a spomenuta reakcija katalizirana je kvascem Saccharomyces cerevisiae, inače idealnim biokatalizatorom za industrijsku primjenu. Enantioselektivna redukcija provedena je u tri različita niskotemperaturna eutektička otapala s različitim udjelima vode. Biokatalitička reakcija redukcije u eutektičkom otapalu rezultirala je većim iskorištenjem u otapalu kolin klorid : etilen glikol s 10 %-tnim masenim udjelom vode odnosu na bioredukcije provedene u ostalim otapalima i puferu. Designing non-polluting processes and the need to design chemical, pharmaceutical and biotechnical products and processes that reduce or completely eliminate the use and production of harmful and hazardous substances, with the unique goal of environmental protection, have led to the development of green chemistry, which is an increasingly common industrial approach today. This approach involves the use of alternative solvents and environmentally friendly and renewable raw materials, but also the use of alternative forms of energy and the implementation of organic reactions using biocatalysts. Consequently, there is a growing interest in the use of eutectic solvents as a medium for the biochemical preparation of chiral biologically active components. In this work, the reaction of enantioselective reduction of halogenated acetophenone to chiral halogenated alcohol was performed, and the mentioned reaction was catalyzed by the yeast Saccharomyces cerevisiae, otherwise and ideal biocatalysts for industrial application. Enantioselective reduction was performed in three different deep eutectic solvents with different water contents. The biocatalytic reduction in deep eutectic solvents choline chloride : ethylene glycol with 10 % of water resulted in a higher yield compared to the bioreduction perfomed in the other solvents and buffer.

U okviru ovog rada provedena je sinteza i spektroskopska karakterizacija novih derivata Schiffovih baza purinskih bioizostera: benzotiazola (13a–13d, 18a–18d), benzoksazola (14a–14d, 19a–19d )i imidazo[1,2-a]piridina (15a–15d). Za pripravu ciljnih spojeva upotrijebljene su klasične metode organske sinteze i sinteza potpomognuta ultrazvučnim zračenjem. Dvostupnjevitom linearnom sintezom priređeni su amino-supstituirani prekursori benzotiazola 6, benzoksazola 7 i imidazo[1,2-a]piridin 11 iz odgovarajućih nitro derivata 4, 5 i 10. Ciljani hibridi Schiffovih baza benzotiazola, benzoksazola i imidazo[1,2-a]piridina pripravljeni su iz prethodno priređenih heterocikličkih primarnih amina i različito supstituiranih 2-hidroksibenzaldehida metodama klasične organske sinteze i motodama zelene kemije primjenom ultrazvučnog zračenja u etanolu i glicerolu. Strukture svih priređenih spojeva potvrđene su 1H i 13C NMR spektroskopijom. This paper describes synthesis and spectroscopic characterization of novel Schiff base derivatives of purine bioisosteres: benzothiazoles 13a–13d, 18a–18d, benzoxazoles 14a–14d, 19b–19c and imidazo[1,2-a]pyridines 15a–15d prepared by conventional synthetic methods and by using ultrasonic irradiation. The main amino-substituted precursors of benzothiazole 6, benzoxazole 7 and imidazo [1,2-a]pyridine 11 were prepared by two-step linear synthesis from corresponding nitro derivateves 4, 5 andi 10. Target hybrids of Schiff bases of benzothiazole, benzoxazole and imidazo[1,2-a]pyridine were synthesized from prepared heterocycle primary amines and variously substituted 2-hydroxybenzaldehydes by conventional synthetic methods and by green synthesis using ultrasonic irradiation with ethanol and glycerol as solvents. Structures of all synthesized compounds were confirmed by 1H and 13C NMR spectroscopy.

Cilj ovog rada bilo je istražiti eutektička otapala (DES), te njihovu primjenu u izolaciji bioaktivnih spojeva iz biljnog materijala. Eutektička otapala zbog svojih svojstava i lakoće pripreme sve više zamjenjuju organska otapala u industriji. Nastaju miješanjem dvaju ili više prirodnih organskih komponenata, kao što su kolin klorid, karboksilne kiseline, urea, glicerol i drugi. Važan je odabir komponenata prilikom pripreme kako bi se dobila smjesa željenih svojstva, poput viskoznosti, gustoće, električne vodljivosti, itd. Postoje razne metode pripreme DES-ova, a najčešća upotrjebljena metoda je zagrijavanje dviju čvrstih komponenata na određenoj temperaturi sve dok se ne dobije bistra otopina. Pretraživanjem dostupne literature i dosadašnjih istraživanja o eutektičnim otapalima, moguće je zaključiti da će primjena eutektičnih otapala bit sve veća. The aim of this study was to investigate deep eutectic solvents (DES) and their application in isolation of bioactive compounds from plant material. Due to their properties and easy preparation, eutectic solvents are increasingly replacing organic solvents in industry. They are formed by mixing two or more natural organic components, such as choline chloride, carboxylic acids, urea, glycerol and others. It is important to select the components during preparation to obtain a mixture of desired properties, such as viscosity, density, electrical conductivity, etc. There are various methods of preparing DESs, and the most common method used is heating two solid components at a certain temperature until clear solution is formed. By searching the available literature and previous research on eutectic solvents, it is possible to conclude that the use of eutectic solvents will be increasing.

Jodirane organske spojine imajo pomembno vlogo kot sintezni intermediati v organski kemiji ter zdravila in radioaktivni označevalci v medicini. Klasični jodirni reagenti so atomsko neekonomični in so tako s stališča zelene kemije neprimerni. Zato so bile narejene številne raziskave na področju oksidativnega jodiranja, ki omogoča 100 % atomsko ekonomičnost joda. V diplomskem delu smo raziskovali aerobno oksidativno jodiranje s sistemom I2/O2/NaNO2/H2SO4. Proučili smo vpliv in vlogo vsake komponente jodirnega sistema. I2 je vir jodovih atomov. O2 je terminalni oksidant, potreben za regeneracijo joda iz jodidnih ionov, ki nastanejo kot stranski produkt. NaNO2 v prisotnosti kisline disproporcionira na dušikove okside, ki so posredniki elektronov med jodidnimi ioni in kisikom v katalitskem ciklu regeneracije joda. Hkrati katalitski cikel lahko omogoči in situ tvorbo elektrofilnega »I+« reagenta, ki reagira z nukleofilnim organskim substratom. H2SO4 je aktivator jodiranja, saj omogoči tvorbo dušikovih oksidov iz NaNO2. Z jodirnim sistemom smo v kisikovi atmosferi pri sobni temperaturi monojodirali anizol, 4-terc-butilfenol in 4-terc-butiltoluen. Anizol se s substehiometričnimi količinami H2SO4 po 3 urah kvantitativno pretvori v monojodiran produkt 4-jodoanizol smo izolirali z 82 % izkoristkom, pri tem pa nismo potrebovali organskih topil. 4-terc-Butilfenol s sistemom ni kompatibilen zaradi stranske reakcije oksidativnega nitriranja – zaradi porabljanja NO2 se katalitski cikel ustavi in kvantitativna pretvorba v jodiran produkt ni mogoča. Po kromatografski ločbi reakcijske zmesi je bil izkoristek dobljenega jodiranega produkta 34 %. 4-terc-Butiltoluen je za jodiranje manj aktiviran, a je pretvorba kvantitativna ob povečanju količine H2SO4 in podaljšanju reakcijskega časa na 24 ur. Izkoristek jodiranja je 95 %. Metoda uporablja dostopen vir jodovih atomov I2, »zelen« oksidant O2 in poceni katalizator NaNO2. Reakcija poteka pri sobni temperaturi, reakcijski medij pa je ekološko sprejemljiv MeCN. Sistem je primeren za jodiranje aktiviranih aromatskih spojin, njegovo reaktivnost pa uravnavamo s koncentracijo H2SO4. Iodinated organic compounds have a crucial role as synthetic intermediates in organic chemistry, as well as drugs and radioactive markers in medicine. Classic iodinating agents have low atom economy and as such are unsuitable from a green chemistry perspective. Therefore, abundant research has been conducted on the field of oxidative iodination, which enables 100 % iodine atom economy. Within this Bachelor's thesis, aerobic oxidative iodination with I2/O2/NaNO2/H2SO4 system is studied. Influence and role of each component in our system was investigated. I2 is the source of iodine atoms. O2 is the terminal oxidant for iodine regeneration from iodide ions that form as a side product. Under acidic conditions, NaNO2 disproportionates to nitric oxides that act as electron mediators between iodide ions and oxygen in the catalytic cycle of iodine regeneration. Furthermore, the catalytic cycle can enable in situ formation of electrophilic »I+« reagent that reacts with nucleophilic organic substrate. H2SO4 is the activator of iodination, as it enables the formation of nitric oxides from NaNO2. Using our system, anisole, 4-tert-butylphenol and 4-tert-butyltoluene were monoiodinated at room temperature in oxygen atmosphere. Anisole is quantitatively converted to monoiodinated product in 3 hours 4-iodoanisole was isolated with 82 % yield without the use of organic solvents. 4-tert-Butylphenol is incompatible with our system due to oxidative nitration side reaction – depletion of NO2 halts the catalytic cycle, thus making quantitative conversion to iodinated product unattainable. Isolated yield of iodinated product was 34 % after chromatographic separation. Although 4-tert-butyltoluene is less activated for iodination, quantitative conversion was achieved by employing higher concentration of H2SO4 and longer reaction time (24 hours). Yield of iodination was 95 %. Our method utilizes accessible iodine atom source I2, »green« oxidant O2, and inexpensive catalyst NaNO2. Reaction is conducted at room temperature in environmentally acceptable MeCN. Our system is suitable for iodination of activated aromatic compounds, and its reactivity can be readily tuned by adjusting the concentration of H2SO4.

V zadnjih desetletjih se je zaradi pretiranega izvajanja sintez , ki so človeku in okolju neprijazne, povečalo zanimanje za razvoj novih sinteznih poti pod zelenimi pogoji. Te lahko potekajo do enostavnih ali bolj kompleksnih produktov, pri katerih za reaktante uporabimo karbonilne spojine. Produkti so lahko vse od enostavnih arom do zapletenih farmacevtsko pomembnih aktivnih učinkovin. Mnoge sinteze takšnih spojin se izvajajo v do človeka in okolja neprijaznih topilih, pri visokih temperaturah ter z nizkimi selektivnostmi in nizkimi pretvorbami reakcij. V diplomskem delu sem skušal predstaviti nekaj pomembnih konceptov ter nekaj že optimiziranih reakcij zelene kemije. Pretvorbe potekajo kot reakcije adicije, kondenzacije, reakcije v vodi, pretvorbe z mletjem in kot večkomponentne pretvorbe, vse z visokimi izkoristki, visoko selektivnostjo in pod čimbolj zelenimi pogoji. In the past decades, excessive implementation of human and environmentally unfriendly syntheses sparked increasing interest for development of newer synthetic pathways under green conditions, products taking places from simple to more complex, where reactants are carbonyl compounds. Products can range from common aromas to complex active pharmaceutical ingredients. Such syntheses are often carried in solvents that are harmful to people and environment, at high temperature, furnishing products with low yield and selectivity. In this work, I have decided to present some important concepts of already optimised reactions of green chemistry. Conversions take place as reactions of addition, condensation, reactions in water, conversion with grinding and multicomponent reactions, all with high yields and high selectivity with as green conditions as possible.

Bioaktivne sastavnice iz biljnog materijala, prvenstveno polifenoli, dobivaju sve veću pozornost zbog svojih funkcionalnih i bioloških učinaka na zdravlje čovjeka. Konvencionalne metode ekstrakcije bioaktivnih sastavnica iz biljnog materijala uključuju korištenje organskih otapala odgovornih za ekološko onečišćenje i nepovoljno djelovanje na zdravlje pojedinca. Ekstrakcija posredovana ciklodekstrinima nova je, „zelena“ i alternativna metoda ekstrakcije kojom se izbjegava korištenje štetnih i skupih organskih otapala. Ekstrakcija ciklodekstrinima temelji se na nastanku inkluzijskih kompleksa s bioaktivnim sastavnicama čime se povećava njihova topljivost u ekstrakcijskom sredstvu, a samim time i učinkovitost ekstrakcije. Primjenom ciklodekstrina dolazi do skraćenja duljine trajanja ekstrakcijskog postupka, osiguravanja kemijske stabilnosti sastavnica tijekom ekstrakcije kao i povećanja antioksidativne aktivnosti izoliranih sastavnica. Završetkom ekstrakcijskog postupka nije potrebno uklanjanje ciklodekstrina, čime je osigurano smanjenje utroška energije, vremena i novca u odnosu na ekstrakciju konvencionalnim otapalima. Ovaj rad razmatra ključne parametre uključene u proces ekstrakcije ciklodekstrinima: tip ciklodekstrina, koncentracija ciklodekstrina, temperatura i duljina trajanja ekstrakcijskog postupka te tehnika ekstrakcije. Promatranjem učinka različitih ciklodekstrina na prinos i antioksidativnu aktivnost bioaktivnih sastavnica tijekom ekstrakcije uočeno je kako β-ciklodekstrin i njegovi derivati pokazuju najbolju sposobnost inkapsulacije bioaktivnih sastavnica. Istražene su i sažete koristi ostvarene ekstrakcijom bioaktivnih sastavnica iz biljnog materijala koristeći ciklodekstrine

Fulereni i derivati fulerena dobro su istraženi u znanosti o materijalima jer pokazuju ogroman potencijal za primjenu zbog svojih jedinstvenih fizikalno-kemijskih svojstava. Funkcionalni materijali koji imaju fuleren ugrađen u strukturu obično se odlikuju povećanom stabilnošću, vodljivošću, magnetizmom ili katalitičkom aktivnošću u usporedbi s njihovim sastavnicama. Metal-organske mreže (MOF) su kristalni, porozni materijali koji su se pokazali izvrsnim matricama za uklapanje molekula gostiju. [1] Glavni problem trenutnih sintetskih strategija je nedostatak kontrole nad postupkom uklapanja s obzirom na topljivost korištenih komponenata i činjenicu da su molekule otapala i gosta u kompeticiji za uklapanje u pore MOF-ova. [2] Ovdje se kao prikladno rješenje nameće, brzi i zeleni, mehanokemijski pristup jer koristi otapalo u minimalnim količinama. Mljevenje u vibracijskom mlinu je omogućilo stehiometrijski kontrolirano uklapanje fulerena te je rezultiralo četirima kristalnim materijalima C60 @ ZIF-8 (zeolitna imidazolatna mreža) sa 15, 30, 60 i 100 mol% fulerena uklopljenog u pore sodalitnog ZIF-8 dok su otopinske sintetske strategije rezultirale minimalnim punjenjem. Fulereni uklopljeni u matricu ZIF-8 pokazuju svojstva izoliranih molekula. [3] Stoga bi ova strategija mogla poslužiti za uklapanje odabranih endofulerena u prikladne MOF-ove za upotrebu u naprednoj spintronici.

Cilj ovog rada je prikazati mogućnost primjene odabranih metoda zelene kemije u alkiliranju derivata kinazolinona i kumarina. Sinteze su provedene u mikrovalnom reaktoru i ultrazvučnoj kupelji u skladu s principima zelene kemije. Uspoređene su nekonvencionalne metode s konvencionalnom, a konačni produkti okarakterizirani su temperaturama taljenja, spektrometrijom masa i \(R_{f}\) vrijednostima. The aim of this work was to investigate the possibility of applying selected green chemistry methods in the alkylation of quinazolinone and coumarin derivatives. The syntheses were carried out in a microwave reactor and an ultrasonic bath according to the principles of green chemistry. Unconventional methods were compared with conventional ones, and the final products were characterized by melting points, mass spectrometry, and \(R_{f}\) values.

Preradom naranče, kao jednog od najviše korištenih agruma u svijetu, stvara se velika količina otpada, primarno u obliku kore. Kora naranče predstavlja veliku količinu biomase bogate biološki aktivnim spojevima koji bi se mogli izdvojiti te koristiti u prehrambenoj i farmaceutskoj industriji. U skladu s načelima zelene kemije, ključno je pronaći proces ekstrakcije bioaktivnih komponenti iz biljnih izvora koji je ekonomski održiv i prihvatljiv za okoliš. U tom smislu su se eutektička otapala pokazala kao dobra zamjena za organska otapala konvencionalno korištena u procesima ekstrakcije, koja su često hlapiva i štetna za okoliš. U ovom radu ispitano je citotoksično djelovanje ekstrakta kore naranče pripravljenog u euteltičkom otapalu kolin-klorid:glicerol s različitim udjelima vode te je istražen tip stanične smrti na HeLa i HaCaT stanicama. Najjače djelovanje pokazao je ekstrakt pripremljen u ChClGly s 30 % (v/v) vode, u odnosu na ekstrakte u puferu i ChClGly s 80 % (v/v) vode, koji nisu pokazali značajni učinak na rast stanica. Djelovanje ekstrakta pripremljenog u ChClGly s 30 % (v/v) vode ovisno je o dozi i vremenu trajanja tretmana, a može se povezati s indukcijom nekroze kod HeLa stanica te apoptoze kod HaCaT stanica. Jača citotoksičnost ekstrakata kod HeLa stanica u odnosu na HaCaT stanice ukazuje na potencijalno antitumorsko djelovanje ekstrakta kore naranče, čija je biološka aktivnost izraženija u prirodnom eutektičkom otapalu nego u konvencionalnom otapalu. As one of the most used citrus fruits in the world, orange produces a large amount of waste, mostly in the form of peels. Orange peel represents a large amount of biomass rich in bioactive compounds that could be reused in the food and pharmaceutical industry. According to green chemistry principles, it is essential to invent an extraction process that is economically acceptable and safe for the environment. According to this, deep eutectic solvents have shown to be an excellent substitute to commonly used organic solvents in extractions that are often volatile and harmful to the environment. In this paper, the cytotoxic ability of orange peel extract prepared in choline-chloride:glycerol with different water ratios has been explored, as well as the type of cell death on HeLa and HaCaT cell cultures. The extract prepared in ChClGly with 30 % (v/v) water has shown the strongest antiproliferative effects compared to the ones prepared in buffer solution and ChClGly with 80 % (v/v) water. The effect of the extract in ChClGly with 30 % (v/v) water is dose- and time-dependent, and could be connected with the induction of necrosis in HeLa cells, and apoptosis in HaCaT cells. Extracts prepared in buffer solution and ChClGly with 80 % (v/v) water have shown no significant results. The cytotoxic effect that was stronger on HeLa cells than on HaCaT cells could imply potential antitumor properties of orange peel extract whose biological activity has also been enhanced in natural deep eutectic solvents in comparison to conventional solvents.

Valorizacija otpadne kore naranĉe u sklopu koncepta biorafinerije primjer je odrţivog razvoja te predstavlja moguće rješenje za adekvatno zbrinjavanje agro-industrijskog otpada uz proizvodnju visokovrijednih proizvoda. Kako bi koncept biorafinerije u potpunosti bio u skladu s naĉelima zelene kemije, sve veći naglasak stavlja se na zamjenu konvencionalnih organskih otapala ''zelenijim'' alternativama poput primjene prirodnih eutektiĉkih otapala. U ovom radu istraţena je moguća primjena ĉetiri prirodna eutektiĉka otapala u valorizaciji naranĉine kore kao sirovine unutar koncepta biorafinerije. Ispitana otapala pokazala su se izrazito uspješnima prilikom ekstrakcije ukupnih polifenolnih spojeva, ali i kao pogodan medij za provoĊenje kinetiĉke rezolucije (R,S)-1-feniletil acetata pri ĉemu su pozitivno utjecala na enantioselektivnost biokatalizatora. S druge strane, ekstrakcija proteina i D-limonena iz naranĉine kore nije bila osobito uspješna u usporedbi s referentnim otapalima što ukazuje na potrebu za dodatnom optimizacijom odabranih otapala. Valorization of orange peel waste through biorefinery concept is an excellent example of sustainable development. It represents a potential solution for environmentally friendly management of agro-industrial waste while also allowing production of high-value products. In order for biorefinery concept to be in accordance to green chemistry principles it is very important to introduce green solvents such as natural deep eutectic solvents (NaDES) to replace conventional organic solvents. Therefore, possible use of four NaDES in biorefinery of orange peel waste has been studied. NaDES proved to be very efficient in extraction of polyphenolic compounds, and also could be considered as a suitable medium for kinetic resolution of (R,S)-1-phenylethyl acetate showing a positive impact on the enantioselectivity of biocatalyst. However, extraction of proteins and D-limonene from orange peel did not meet the desired efficiency when compared to reference solvents suggesting that further optimization of used NaDES is needed.

Gotovo svaki industrijski proces proizvodnje uključuje primjenu organskih otapala čija je uporaba odgovorna za onečišćenje okoliša te nepovoljna za zdravlje radnika i sigurnost procesa zbog svojstva toksičnosti, lake hlapljivosti, zapaljivosti i eksplozivnosti. Stoga, kako bi se ispunili zahtjevi zelene kemije za ekološkom prihvatljivošću i održivošću, traže se alternativna otapala. Eutektička otapala istaknula su se svojstvima poput niske hlapljivosti, netoksičnosti, nezapaljivosti, biorazgradivosti te jednostavnim metodama priprave. Nadalje, u polju biokatalize dehidrogenaze pokazuju veliki potencijal za dobivanje visoko vrijednih kiralnih spojeva koji se koriste u proizvodnji optički čistih lijekova. Cilj ovog rada bio je istražiti mogućnost primjene prirodnih eutektičkih otapala na bazi kolin-klorida kao medija za reakcije redukcije katalizirane dehidrogenazama. U pripravljenim otapalima određena je aktivnost alkohol dehidrogenaze te promjene u konformaciji iste. U istim otapalima također je ispitana stabilnost pripadajućih koenzima NADH/NAD+. Blago lužnata prirodna eutektička otapala koja su sadržavala etilen-glikol i ureu pokazala su stabilizirajući utjecaj na oba koenzima, no niti u jednom otapalu alkohol dehidrogenaza nije pokazala zadovoljavajuću aktivnost uz značajne promjene u konformaciji u odnosu na pufer kao referentno otapalo. Almost every industrial production process involves the use of organic solvents whose use is responsible for environmental pollution and unfavorable to workers' health and process safety, due to the properties of toxicity, volatility, flammability and explosiveness. Therefore, in order to meet the requirements of green chemistry for environmental safety and sustainability, alternative solvents are sought. Eutectic solvents stood out with properties such as low volatility, non-toxicity, non-flammability, biodegradability and simple preparation methods. Furthermore, in the field of biocatalysis, dehydrogenases show great potential for obtaining high-value chiral compounds used in the production of optically pure drugs. The aim of this study was to investigate the possibility of using natural eutectic solvents based on choline chloride as a medium for dehydrogenase-catalyzed reduction reactions. The activity of alcohol dehydrogenase and changes in its conformation was determined in the prepared solvents. The stability of the corresponding NADH/NAD+ coenzymes was also tested in the same solvents. Slightly alkaline natural eutectic solvents containing ethylene glycol and urea showed a stabilizing effect on both coenzymes, but in neither solvent did alcohol dehydrogenase show satisfactory activity with significant changes in conformation relative to buffer as reference solvent.

V diplomskem delu najprej opišem kemijske lastnosti 2H-piran-2-onov. Razčlenim vrste naravnih spojin, v katerih se pojavi izoliran ali pripojen skelet piranonov kot sestavni del spojine. Opisani so bufadienolidi, stiril-, 4-hidroksi-, 6-substituirani-2H-piran-2-oni, kumarini in kromoni. Posvetim se tudi aktualni temi zelene kemije. Njena načela usmerjajo načrtovanje kemijskih produktov in procesov tako, da se prepreči onesnaževanje ter zmanjša negativne vplive kemikalij na zdravje in okolje. Pomembna vira za raziskovanje zelenih načinov aktivacije reakcij in zelenih procesov sta obsevanje z mikrovalovi in uporaba visokega tlaka. V delu opišem sinteze 2H-piran-2-onov z reakcijami kondenzacije, z Wittigovo in Baylis‒Hillmanovo reakcijo, s povečanjem obroča, s ciklizacijo s sledečo premestitvijo, z jodolaktonizacijo in sinteze z uporabo organskih ali kovinskih katalizatorjev. V eksperimentalnem delu opišem praktično opravljeni sintezi 6-(2-furil)-3-benzoilamino- in 3-benzoilamino-6-(4-metilfenil)-2H-piran-2-ona po 'one pot' metodi, ki jo je razvil Kepe s sodelavci. This diploma work describes chemical properties of 2H-pyran-2-ones. It goes over types of naturally occurring compounds, with pyranone framework as an isolated structure or fused into a polycyclic compound. It describes bufadienolide, styryl-, 4-hydroxy-, 6-substituted-2H-pyran-2-ones, coumarins and chromones. It addresses the topica of green chemistry. Its principles direct planning of chemical products and processes in such a way as to prevent pollution and decrease negative effects of chemicals on health and environment. Important sources for research of green approaches to activate the reactions are microwave irradiation and use of high pressure. The synthesis of 2H-pyran-2-ones with the application of reactions of condensation, Wittig’s and Baylis‒Hillmans reaction, ring expansion strategy and rearrangement-cyclization, iodolactonization and use of organo or metal catalysts are described. In the experimental part a description of two synthesis, namely of 6-(2-furyl)-3-benzoylamino- and 3-benzoylamino-6-(4-methylphenyl)-2H-pyran-2-one as conducted via ‘one pot’ method developed by Keppe and co-workers, is provided.

U ovom radu opisana je sinteza novih konjugata 1,1'-disupstituiranih ferocena i kinolina povezanih 1,2,3-triazolilnom poveznicom (4a–d, 5a–d, 6a, 6b, 7a i 7b). 6-supstituirani derivati kinolona 1a–1d priređeni su Conrad-Limpachovom sintezom te su nadalje prevedeni u O- i N-propargilirane derivate kinolina, odnosno kinolona 2a–2d. Ciljani konjugati 1,1'-disupstituiranih ferocena i kinolina, odnosno kinolona 4a–d, 5a–d, 6a, 6b, 7a i 7b priređeni su bakrom(I) kataliziranom azid-alkin cikloadicijom propargiliranih derivata 2a–2d, 3a i 3b i bis-azidnih derivata ferocena u mehanokemijiskim uvjetima. Strukture novosintetiziranih spojeva potvrđene su 1H NMR i 13C NMR spektroskopijom, a naknadno će se provesti i antiproliferativna ispitivanja novosintetiziranih spojeva. In this work the syntesis of novel 1,1’-disubstituted ferrocene quinoline derivatives bridged via 1,2,3-triazole linker (4a–d, 5a–d, 6a, 6b, 7a and 7b) is described. 6-Substituted quinolone derivatives 1a–1d were prepared by the Conrad-Limpach method and further transformed to O- and N-propargylated derivatives 2a–2d. The target 1,1'-disubstituted ferrocene and quinoline or quinolone conjugates 4a–d, 5a–d, 6a, 6b, 7a and 7b were prepared by copper(I) catalysed azide-alkyne cycloaddition of propargylated derivatives 2a–2d, 3a and 3b with corresponding bis-azidoferrocene derivatives. The structures of all compounds were determined by 1H NMR and 13C NMR spectroscopy. Antiproliferative evaluations of these compounds will be performed.

The application of enzymes in chemical synthesis, due to the recent advances, has a strong impact in multiple industries, especially the pharmaceutical industry. Namely, the use of enzymes shows remarkable advantages over classical chemical catalysis and therefore it is considered a ‘green’ solution. By using novel techniques, it is possible to tailor the enzymes to adapt them for a given process. Today, several pharmaceutical companies are successfully producing valuable precursors for the production of active pharmaceutical ingredients using enzymes, some of them being statin precursors. Statins are hypolipidemics, drugs used for the prevention of cardiovascular diseases and lowering cholesterol concentration in blood. Due to challenges in the chemical synthesis of statin intermediates, the production of statin intermediates using enzyme-catalysed reactions shows some notable advantages. Therefore, research and development laboratories, combined with reaction engineering techniques, have shifted their focus towards applying biochemical catalysis for the production of statin intermediates. This work is licensed under a Creative Commons Attribution 4.0 International License., Napredak tehnologije usko je vezan uz primjenu enzima u kemijskoj sintezi. Biokataliza ima velik utjecaj na različite industrije a među njima se posebno ističe farmaceutska industrija. Primjena enzima pokazuje značajne prednosti u usporedbi s tehnikama klasične kemijske sinteze te se smatra i ‘zelenim’ rješenjem. Primjenjujući nove dostupne tehnike i tehnologije, enzime je moguće u potpunosti prilagoditi zahtjevima određenog procesa. Danas je poznato nekoliko farmaceutskih tvrtki koje uz pomoć enzima uspješno proizvode vrijedne intermedijare za proizvodnju aktivnih farmaceutskih spojeva, a u njih se ubrajaju i prekursori statina. Statini su hipolipidemici, lijekovi koji se upotrebljavaju za prevenciju kardiovaskularnih bolesti te za snižavanje koncentracije kolesterola u krvi. Metoda klasične kemijske sinteze intermedijara statina vrlo je zahtjevna te stoga njihova proizvodnja primjenom enzimski kataliziranih reakcija ima značajne prednosti. Iz tog razloga za proizvodnju intermedijara statina istraživanje i razvoj uz primjenu reakcijskog inženjerstva sve se više usmjeravaju prema primjeni biokatalize. Ovo djelo je dano na korištenje pod licencom Creative Commons Imenovanje 4.0 međunarodna.

In this dissertation, 15 natural deep eutectic solvents were successfully prepared and applied for developing an eco-friendly method for extraction of anthocyanins and lipase-catalyzed (R)-1-phenylethanol synthesis. Also, the biological activity of prepared grape pomace extracts was evaluated. With natural deep eutectic solvents efficiency of the process was increased in comparison with conventional processes. Extraction and biocatalytic process were optimised using the response surface methodology afterward laboratory-developed methods were scaled up. In both processes, the recyclation of used natural deep eutectic solvents was performed, as well as isolation and purification of the final product (anthocyanins, (R)-1-phenylethanol). U sklopu doktorske disertacije uspješno je pripremljeno i okarakterizirano 15 prirodnih eutektičkih otapala i primijenjeno za razvoj ekološki prihvatljivih metoda ekstrakcije antocijana iz komine grožđa te biokatalitičkog procesa priprave (R)-1-feniletanola pomoću lipaze. Također, evaluirana je biološka aktivnost pripremljenih polifenolnih ekstrakata u prirodnim eutektičkim otapalima. Primjenom prirodnih eutektičkih otapala u ekstrakciji polifenolnih spojeva i biokatalizi ostvarena je veća učinkovitost procesa u odnosu na konvencionalne postupke. Ekstrakcija i biokataliza su optimirani primjenom metode odzivnih površina te su laboratorijski razvijene metoda prenijete u veće mjerilo. U oba procesa razvijena je i metoda reciklacije korištenog prirodnog eutektičkog otapala, kao i izolacije i pročišćavanja produkta (antocijani, (R)-1-feniletanol).

Sulfoksidi in sulfoni ustvarjajo množico spojin, ki kažejo biološko aktivne lastnosti. Zato med farmacevtskimi spojinami najdemo veliko takih, ki vsebujejo sulfoksidno ali sulfonsko skupino. Z rastjo števila različnih žveplovih spojin pa raste tudi povpraševanje po različnih sinteznih poteh, med novejšimi pa lahko najdemo vedno več tako imenovanih zelenih poti sinteze, ki vsebujejo reaktante, ki niso obremenjujoči za okolje. V diplomskem delu sem raziskal selektivnost aerobne oksidacije aromatskih sulfidov z uporabo dušikovo(V) kislino, železovimi ioni kot katalizatorjev v fluoriranih alkoholih. Spreminjal sem vrsto in količino topila, katalizatorjev in temperaturo. Uspel sem izolirati želeni sulfoksid dibenzotiofena, dibenzo[b,d]tiofen 5-oksid, z 72% izkoristkom. Oksidacijo sem naredil tudi s substratom tiantrenom, kjer sem sulfoksid tiantren 5-oksid izoliral z 41% izkoristkom, hkrati pa je potekla tudi nadaljnja oksidacija predvsem do cis-tiantren 5,10-dioksida s 5,5% izkoristkom in trans-tiantren 5,10-dioksida s 30% izkoristkom. Sulfoxides and sulfones create a set of chemical compounds, that show biological activity. That is why we can find a lot of different pharmaceutical compounds that include either sulfoxide or sulfone group. As variety of different sulfur compounds grows everyday, there is also a growth in synthesis of such chemicals. We can find more and more different so called green routes of synthesis, which include reactants that present minimum burden to our living environment. In this undergraduate degree I studied selectivity of aerobic oxidation of aromatic sulfides with usage of nitric(V) acid and iron ions as catalysts in fluorinated alcohols. I varied solvents and their amounts, temperature and catalysts and its quantity. I succeded to obtain the wanted sulfoxide of dibenzotiophene, dibenzo[b,d]tiophene 5-oxide with a yield of 72%. Same oxidation method was also applied on thianthren which sulfoxides were isolated. Thianthren 5-oxide with a 41% yield and two thianthren dioxides cis-thianthren 5,10-dioxide with a 5,5% yield and trans-thianthren 5,10-dioxide with a 30% yield.

Implementacija načela zelene kemije upotrebom prirodnih eutektičkih otapala (NADES) u biokatalizi omogućuje unaprijeđenje procesa kroz bolju supstratnu topljivost, poboljšanu enzimsku aktivnost i stabilnost. U ovom radu utvrđuje se najpovoljnije otapalo koje može poslužiti kao reakcijski i skladišni medij za slobodnu (slLip) i imobiliziranu (imLip) C. antarctica lipazu B. U tu svrhu ispitana su tri NADES-a (ChEG, ChGly, ChGlc) sa različitim udjelima vode (10, 30 i 50 % (v/v)). Inkubacija enzima u svim otapalima 28 dana pri 25 °C, pokazala je nadmoćniju stabilnost i aktivnost imLip u odnosu na slLip. Dok slLip zadržava maksimalno 40 % rezidualne aktivnosti nakon 28 dana inkubacije (u ChGlc30%), aktivnost imLip pada sporije, pri čemu u istom periodu zadržava i do 67 % aktivnosti (u ChGly10%). Zaključno, ChGly izdvaja se kao NADES s najvećim potencijalom da postane stabilizirajući medij za lipaze. Implementation of green chemistry principles through the use of natural deep eutectic solvents (NADES) in biocatalysis can improve reaction efficiency and sustainability through better substrate solubility, improved enzyme activity and stability. To determine the best solvent to act as reaction and stabilization medium for immobilized (imLip) and free (slLip) C. antarctica lipase B, three NADES (ChEG, ChGly, ChGlc) with different water shares (10, 30 i 50 % (w/w)) have been assessed. Enzyme incubation in these solvents at 25 °C during the period of 28 days has shown greater activity and stability of imLip in regard to the slLip. While slLip maintains up to 40 % residual activity after 28 day incubation period (in ChGlc30%), imLip keeps a significantly higher value in the same period, up to 67% (in ChGly10%). Finally, ChGly steps out as the best NADES that could potentially serve as lipase stabilizing medium.

Kako bi se smanjio negativan utjecaj na okoliš, unazad nekoliko godina zelena kemija ubrzano napreduje. Blaţi uvjeti reakcije, redukcija štetnih otapala, veća iskorištenja i kraće reakcijsko vrijeme su sve prednosti zelenih metoda sinteze u odnosu na konvencionalne. Sinteza potpomognuta ultrazvukom i mehanokemijska sinteza jedne su od zelenih metoda korištenih u ovomu radu. Te metode su primijenjene za sintezu 20 različitih derivata Schiffovih baza. Schiffove baze su važna skupina spojeva jer pokazuju antiupalna, antibakterijska, antivirusna, antikancerogena, antitumorska i mnoga druga pozitivna svojstva. Željene Schiffove baze sintetizirane su iz prekurzora 3-amino-2- metilkinazolin-4(3H)-ona i različito supstituiranih aromatskih aldehida u različitom rasponu iskorištenja.

The aim of our work was to synthesise biscoumarins by condensing 4-methoxybenzaldehyde with 4- hydroxycoumarin, using ethanol as a reaction medium and applying three different „green“ methods: microwave irradiation, ultrasound irradiation and synthesis in a ball mill. The reactions were carried out: a) in catalyst-free conditions, b) using catalytic amount of molecular iodine. The results show that the usage of iodine as a catalyst enchances theses reactions, reduces the reaction time and increases yields compared to the reaction under catalyst-free conditions.

U modernom dobu gdje smo sve više okrenuti „zelenoj kemiji“ zbog osviještenosti stanja okoliša koriste se sinteze bez toksičnih i štetnih otapala za ljudsko zdravlje i okoliš. Popularizira se sve više mehanokemijska sinteza koja ne koristi toksična organska otapala poput drugih sinteza. Cilj ovog završnog rada bio je sintetizirati trostruke perovskite Ba3Fe2WO9 i Sr3Fe2WO9 mehanokemijskom sintezom pomoću planetarnog kugličnog mlina. Dobiveni uzorci analizirani su termogravimetrijskom analizom (TGA) te rentgenskom difrakcijom na prahu (PXRD).

U ovom radu cilj bio je ispitati primjenu eutektičkih otapala na bazi kolin-klorida te primjenu ultrazvuka u sintezi kvaternih derivata izonikotinamida. Teorijski dio rada obuhvaća svojstva i primjenu eutektičkih otapala i ultrazvuka u organskoj sintezi, kvaterne amonijeve spojeve, njihova svojstva, potencijalnu biološku aktivnost i primjenu istih u znanosti i industriji. Eksperimentalni dio rada obuhvaća sintezu kvaternih derivata izonikotinamida metodama po principima zelene kemije. Rezultati pokazuju kako su skoro sva ispitana eutektička otapala dobar alternativni medij za kvaternizaciju izonikotinamida i supstituiranih 2-bromacetofenona. Najveće je iskorištenje (96 %) dobiveno u reakciji kvaternizacije izonikotinamida i 2, 4-dibromacetofenona u eutektičkom otapalu ChCl : oksalna kiselina 1 : 1. Ultrazvučnom su metodom uglavnom dobivena slična iskorištenja u odnosu na konvencionalnu metodu pri čemu je u reakciji kvaternizacije izonikotinamida i 2, 4'-dibromacetofenona u eutektičkom otapalu ChCl : oksalna kiselina 1 : 1 postignuto najviše iskorištenje (94 %). In this paper, the goal was to examine the use of choline chloride-based eutectic solvents and the use of ultrasound in the synthesis of quaternized isonicotinamide derivatives. The theoretical part will discuss the properties and applications of eutectic solvents and ultrasound in organic synthesis, as well as quaternary ammonium compounds, their properties, potential biological activity and their application in science and industry. The experimental part of the paper, the synthesis of quaternized isonicotinamide derivatives, includes methods in accordance with the principles of green chemistry. The results show that almost all eutectic solvents tested are a good alternative medium for the quaternization of isonicotinamide and substituted 2-bromoacetophenones. The highest yield (96%) was obtained in the quaternization reaction of isonicotinamide and 2,4’-dibromoacetophenone in the eutectic solvent ChCl: oxalic acid 1: 1. The ultrasound method generally yielded similar yields as the conventional method, where the quaternization reaction of isonicotinamide and 2,4’-dibromacetophenone in the eutectic solvent ChCl: oxalic acid 1: 1 gave the highest yield (94%).

Mehanokemijska sinteza temelji se na reakcijama između čvrstih praškastih tvari uz primjenu mehaničke energije. S obzirom da se u mehanokemijskoj sintezi reakcije odvijaju bez otapala ili s vrlo malom količinom otapala, ova se metoda nametnula kao potencijalna ekološka i „zelena“ alternativa klasičnoj otopinskoj sintezi. Jedna od glavnih tehnika mehanokemijske sinteze jest mljevenje – proces usitnjavanja materijala djelovanjem mehaničkih sila koje su jače od unutarnjih sila vezanja čestica. Mehanokemijska sinteza može se primjenjivati u najrazličitijim područjima: organskoj sintezi, metalurgiji, proizvodnji katalizatora i sl., no ograničena je na šaržne procese u laboratorijskim mlinovima. Za širu primjenu u industrijskoj proizvodnji neophodno je pronaći načine uvećanje ove vrste sinteze te za njeno kontinuirano provođenje. U ovom radu obrađena je mogućnost primjene ekstruzije u dvopužnom ekstruderu, kao mogućoj tehnici koja objedinjuje mogućnost kontinuirane proizvodnje i velikih kapaciteta, iako mljevenje nije njihova primarna namjena. Kao i za svaki kontinuirani proces, neophodna je i mogućnost kontinuirane kontrole kvalitete proizvoda, pa je dan pregled procesnih analitičkih tehnologija koje se mogu primijeniti za bezkontaktnu analizu prašaka, s ciljem boljeg razumijevanja mehanokemijskih reakcijskih mehanizama i vođenja procesa. Mechanochemical synthesis is based on reactions between solids that take place using mechanical energy. Since in mechanochemical synthesis reactions take place without solvent or with a very small amount of solvent, this method has emerged as an ecological and "green" alternative to classical solution synthesis. One of the main techniques of mechanochemical synthesis is grinding – the process of crushing materials by the action of mechanical forces that are stronger than the internal binding forces of particles. Mechanochemical synthesis has a potential for wide range of applications, from organic synthesis to metallurgy and catalyst sythesis, but is limited to batch processing in laboratory mills. To facilitate its wider acceptance in chemical process industry, it is essential to find ways to scale-up this type of synthesis and its continuous operation. This paper deals with the possibility to apply continuous twin-screw extrusion as a way to unify both, large capacity and continuous production. As with all continuous processes, continuous product quality control is paramount. In this papers, most important process analytical tools suitable for contactless powder analysis are presented, which can be used to better understand the mechanism of mechanochemical reactions and for process control.

Mnogi industrijski procesi koriste velike količine hlapivih, zapaljivih i toksičnih organskih otapala što rezultira onečišćenjem prirode i narušavanjem ekološke ravnoteže. Prirodna eutektička otapala pripadaju novoj generaciji nehalapljivih i stabilnih otapala te su se pokazala su se kao dobra zamjena za tradicionalna organska otapala u kemijskoj i biotehnološkoj industriji. U ovom radu ispitana je mogućnost primjene nekoliko prirodnih eutektičkih otapala u enantioselektivnoj hidrolizi (R, S)-1-feniletil-acetata uz lipazu B kao biokatalizator za pripravu komercijalno zanimljivog kiralnog alkohola (R)-feniletanola. Prirodna eutektička otapala pokazala su se povoljnim otapalima za ispitivanu hidrolizu obzirom na ispitane parametre, pri čemu se otapalo kolin-klorid:etilen glikol pokazalo najpovoljnijim. Optimiranjem reakcijskih uvjeta pronađeni su optimalni uvjeti za hidrolizu, a koji se odnose na omjer enzima i supstrata, temperaturu i udio vode. Osim toga provedena je reciklacija enzima i otapala čime se pokazala mogućnost njihove ponovne upotrebe. Na temelju dobivenih rezultata može se zaključiti kako je primjena biokatalize i prirodnih eutektičkih otapala vrlo učinkovita, ekološki i ekonomski prihvatljiva metoda za proizvodnju (R)-1-feniletanola. Many industrial processes use large quantities of volatile, flammable and toxic organic solvents resulting in pollution of nature and disturbance of ecological balance. Natural deep eutectic solvents belong to the new generation of non-volatile and stabile solvents, and are intensively studied as a replacement for organic solvents in chemical and biotechnological industry. This study examines the possibility of using several natural deep eutectic solvents for enantioselective hydrolysis of (R, S)-1-phenylethyl acetate with lipase B as biocatalyst for the preparation of a commercially interesting chiral alcohol (R)-phenyethanol. All enantioselective reactions in natural deep eutectic solvents were successfully conducted according to all tested parameters, where solvent choline chloride:ethylene glycol was found to be the best choice for reaction tested. The reaction conditions were optimized according to ratio of enzyme and substrate, temperature and water content. In addition, the recycling of enzymes and solvents was carried out, demonstrating the possibility of their reuse. Based on the results obtained, it can be concluded that the application of biocatalysis and natural deep eutectic solvents could be very efficient, environmentally and economically acceptable method for the production of (R)-1-phenylethanol.

Narušavanje ekološke ravnoteže i negativan utjecaj na zdravlje ljudi samo su neke od posljedica djelovanja kemijske industrije. Temeljen na znanstvenim i ekonomskim načelima, 1990. prezentiran je koncept zelene kemije s ciljem smanjenja štetnih učinaka te povećanja održivosti i energetske učinkovitosti proizvodnih procesa. U ovom je radu prikazana primjena biotehnologije u zelenoj kemiji u kontekstu sinteze biopolimera, biogoriva te organske sinteze. Razvitak biokemijskog, genetičkog i metaboličkog inženjerstva, kao i srodnih područja, rezultirao je mnogobrojnim postignućima. Međutim, neki od izazova još su uvijek nepremostivi, stoga su edukacija i ulaganje u biotehnološka područja od neupitne važnosti. Disturbance of ecological balance along with a negative impact on human health is just some of the consequences of the chemical industry. In 1990, based on scientific and economical principles, the concept of green chemistry was presented in order to reduce harmful effects as well as increase the sustainability and energy efficiency of production processes. In this thesis, the use of biotechnology in green chemistry applied to biopolymers, biofuels and organic synthesis is presented. The development of biochemical, genetic and metabolic engineering, as well as related fields, has resulted in numerous achievements. Even so, some of the challenges are still insurmountable, hence education and investment in biotechnology areas are of indisputable importance.

Farmacevtska industrija, medicinska diagnostika, agrokemija in kemija materialov predstavljajo le nekaj področij, ki so bistveno napredovala zaradi razvoja kemije fluora in posebnih lastnosti fluoriranih spojin. Z željo po razvijanju omenjene kemije, smo razširili začetno raziskavo reaktivnosti reagentov na osnovi imidazolijevega fluorida. Najmanj reaktivnega in hkrati najbolj stabilnega izmed omenjenih reagentov (1,3-bis(2,6-diizopropilfenil)imidazolijev divodikov trifluorid ImH2F3) smo uspešno aktivirali za fluoriranje benzil bromidov. Preizkusili smo do sedaj znane aktivatorje [F(HF)n]– zvrsti iz literature in ocenili njihovo primernost za uporabo v našem sistemu. Pri fluoriranju benzilnih substratov se je sterično ovirana baza DIPEA izkazala kot ključen dodatek za hitro in selektivno fluoriranje. Isti učinek aktivacije smo dosegli le še s kalijevim in cezijevim fluoridom, litijev in natrijev fluorid pa sta neaktivna. Preučili smo vpliv vode, načina segrevanja in reakcijske skale na potek reakcije fluoriranja benzilnih substratov. Dodatek vode je imel negativen vpliv pri aktivaciji z DIPEA, nasprotno pa je kalijev fluorid omogočal fluoriranje tudi v zmesi acetonitrila in vode. Z mikrovalovnim segrevanjem smo lahko dosegli višje temperature in posledično krajše reakcijske čase. Pri prehodu na večjo skalo fluoriranja je bilo potrebno posebno pozornost nameniti koncentracijam reaktantov ali pa ustrezno skrajšati reakcijski čas. Z optimiziranim postopkom smo fluorirali širok nabor benzilnih substratov, pri čemer se je od bromida, jodida, mezilata in tozilata le klorid izkazal kot slabša izstopajoča skupina. Benzilne substrate smo fluorirali z dobrimi do odličnimi izkoristki (56–93 %). Večina preizkušenih substratov z elektron donorskimi ali elektron akceptorskimi skupinami je kompatibilna z optimiziranimi reakcijskimi pogoji. Izkoristke fluoriranja benzil kloridov smo povečali z uporabo presežka reagenta in aktivatorja. Nabor substratov smo razširili in poleg aromatskega substrata, acil ter sulfonil klorida fluorirali tudi primarni jodid, sekundarni mezilat in -bromokarbonilni spojini. Pokazali smo, da je ImH2F3 poleg reakcij fluoriranja primeren tudi kot reagent za odščito sililnih etrov. Razvili smo enostaven separacijski postopek, ki nam je poleg izolacije fluoriranega produkta omogočal tudi izolacijo preostanka reagenta. Slednjega smo uspeli regenerirati z uporabo fluorovodikove kisline ali brezvodnega vodikovega fluorida brez organskih topil. Uporaba ionske kromatografije nam je omogočila spremljanje reakcij zamenjav anionskega dela imidazolijevih soli. Pokazali smo, da je aktiviran H2F3– anion lahko dober vir nukleofilnega fluorida. Z vezavo H2F3– iona na imidazolijev strukturni element dobimo stabilen fluorirni reagent, ki se lahko uporablja na zraku, v vodnih pogojih in je hkrati enostavno obnovljiv s fluorovodikovo kislino. Pharmaceutical industry, medical diagnostics, agrochemistry and material sciences are among many different fields which have benefited tremendously from the development of fluorine chemistry and unique properties of fluorinated compounds. In order to further develop this type of chemistry we expanded initial reactivity studies of imidazolium fluoride-based reagents. Among these, the least reactive but the most stable reagent, 1,3-bis(2,6-diisopropylphenyl)imidazolium dihydrogen trifluoride (ImH2F3), was successfully activated for fluorination of benzyl bromides. We tested poly(hydrogen fluoride) species activators from the literature and evaluated their compatibility with our reaction system. Besides potassium and caesium fluoride only sterically hindered base DIPEA enabled us quick and selective fluorination of benzylic substrates. Lithium and sodium fluoride proved to be inactive. Influence of added water, heating mode and reaction scale were studied. Water is detrimental for fluorination yield when DIPEA is used as an activator while potassium fluoride allows fluorination in acetonitrile / water solvent mixture. Higher reaction temperatures and shorter reaction times can be achieved using microwave heating. Careful concentration control or reduction of reaction time are crucial for reaction scale-up. After the optimization of reaction conditions benzyl fluorides were prepared in fair to excellent yields (56–95 %) from the corresponding benzyl bromides, iodides, mesylates and tosylates. Benzylic substrates with electron donating as well as electron accepting groups are compatible with the optimized reaction conditions. Benzyl chlorides are less reactive. However, good fluorination yields with benzyl chlorides can be achieved by using excess of both ImH2F3 reagent and DIPEA. Substrate scope was expanded with one example of aromatic fluorodenitration, preparations of acyl and sulfonyl fluorides and fluorination of an aliphatic iodide, a secondary mesylate and -bromocarbonyl compounds. ImH2F3 can also be used as a mild reagent for deprotection of silyl ethers. We have developed simple protocols for isolation of fluorinated product and spent reagent. The latter can be conveniently regenerated with hydrofluoric acid or anhydrous hydrogen fluoride without the use of organic solvents. Reactions involving interconversions of imidazolium salts can be easily monitored with ion chromatography. We showed that dihydrogen trifluoride anion can be activated to serve as a good source of nucleophilic fluoride. Dihydrogen trifluoride anion forms an air-stable nucleophilic fluoride reagent with imidazolium moiety, which is suitable for fluorination in wet organic solvents and can be recycled with hydrofluoric acid.

Zelena ili održiva kemija je dio kemije koji se bavi proučavanjem i osmišljavanjem procesa koji smanjuju ili u potpunosti uklanjaju upotrebu štetnih tvari. Također proučava sintezu i analizu kemijskih proizvoda bez štetnih posljedica za okoliš. Počecima programa zelene kemije smatraju se 1990.-te godine kada su Paul Anastas i John C. Warner izdali knjigu „Zelena kemija: Teorija i praksa“. U toj su knjizi detaljno opisali Dvanaest načela zelene kemije na kojima se temelji program zelene kemije. Dvanaest načela zelene kemije temelje se na promicanju važnosti zaštite okoliša i zdravlja čovjeka. Zagovaraju nekorištenje otrovnih otapala u kemijskim sintezama i analizama i smanjeno stvaranje štetnih nuspojava iz tih procesa. Jedno od područja istraživanja i razvoja unutar zelene kemije je primjena zelene kemije u analitičkim metodama što ujedno potiče i razvoj zelene analitičke kemije. Zelena analitička kemija temelji se na Dvanaest načela zelene analitičke kemije koja su 2013. predložili i detaljno opisali Galuszka, Migaszewski i Namiénski. Zaštita okoliša i profit postižu se kroz nekoliko glavnih načela koje zagovaratelji programa zelene kemije promiču. Neka od tih načela su: kataliza, biokataliza, uporaba alternativa (obnovljive sirovine-biomasa), upotreba pogodnog reakcijskog medija (voda, ionske tekućine, superkritične tekućine) te razvoj novih sintetskih putova (fotolitičke reakcije).

Tekom diplomske naloge sem izvajala reakcije pod pogoji brez topila. Iz različnih ketonov in fenilacetilena sem v prisotnosti kalijevega terc-butoksida s trenjem v terilnici sintetizirala propargilne alkohole z dobrimi izkoristki pri sobni temperaturi. Produkte sem izolirala z ekstrakcijo in destilacijo topila ter nato izvedla še analizo z 1H NMR spektroskopijo. Spektri so bili posneti v CDCl3 pri 300 MHz. During the Diploma work I carried out reactions under solvent free conditions. From different ketones and phenylacetylene and in the presence of potassium tert-butoxide, I synthesized propargyl alcohols with good yields and at room temperature, with grinding in the mortar. I isolated the products with extraction and solvent distillation. Then I analyzed the products with 1H NMR spectroscopy. Spectra were recorded in CDCl3 at 300 MHz.