Provider: - Institution: - Data provided by Europeana Collections- Biginellijevom reakcijom, pripravljeni su razliĉito supstituirani derivati 3,4-dihidropirimidinona. Koristeći modelni derivat ...124-I-b provedena su opsežna preliminarna ispitivanja u svrhu pronalaska odgovarajućih uvjeta aromatizacije sintetiziranih derivata. Opseg preliminarnih ispitivanja potkrepljuje literaturno poznatu ĉinjenicu kako se ovaj tip spojeva vrlo teško aromatizira. Rezultat istraţivanja u sklopu ove doktorske disertacije urodio je ĉetirima novim, do sad nepoznatim metodama aromatizacije 3,4-dihidropirimidinona. Efikasna, brza i selektivna metoda aromatizacije razvijena je uz molekularni jod i kalijev t-butoksid u suhom tetrahidrofuranu pri sobnoj temperaturi (konverzija 80 % - 100 %). Ispitan je i predloţen mehanizam aromatizacije koji upućuje na nastanak t-butilhipojodita kao aktivne vrste pri reakciji aromatizacije. Aromatizacija 3,4-dihidropirimidinona uz t-butilhidro-peroksid, molekularni jod i kalijev t-butoksid u t-butilacetatu, pri temperaturi povrata otapala, modificirana je, katalitiĉka verzija prethodno opisane metode ĉiji je mehanizam dehidrogenacije također predloţen. Zabilježena je konverzija reaktanata u produkte od vrlo visokih 98 % - 100 %. Niz supstituiranih derivata oksidiran je i efikasnom metodom uz t-butilhidroperoksid i kalijev hidroksid uz kalijev jodid kao katalizator. Reakcije su provedene u metanolu pri sobnoj temperaturi (konverzija 98 % - 100 %). Derivati 4-aril-pirimidin-2(1H)-ona dehidrogenirani su u odgovarajuće 4-aril-pirimidin-one metodom uz tetracijanoetilen u acetonitrilu pri povišenoj temperaturi. Aromatizacijom razliĉito supstituiranih derivata ovom metodom postignuta je maksimalna konverzija reaktanata u produkte (100 %). U završnoj fazi istraživanja provedena je i vezana sinteza prva tri koraka pri sintezi rosuvastatin kalcija na 17 razliĉito supstituiranih derivata 3,4-dihidropirimidinona. Ova sinteza ukljuĉuje aromatizaciju 3,4-dihidropirimidinona, aktivaciju dobivenog pirimidinona na položaju 2 azaheterocikliĉke jezgre te reakciju supstitucije tako pripremljenog produkta s odgovarajućim nukleofilom. Sva tri stupnja nadogradnje provedena su u jednoj reakcijskoj tikvici, bez izolacije međuprodukata, uz iskorištenje od 12 % - 71 %.- Differently substituted 3,4-dihydropyrimidinones were prepared using a three component Biginelli reaction. By using a model compound 124-I-b, extensive preliminary research was done in order to find a new appropriate 3,4-dihydropyrimidinone aromatization method. A wide range of reaction conditions, reagents, catalysts and solvents were examined. The scope of the preliminary examination supports the literature known fact that this kinds of compounds are very difficult to be aromatized. The research in the context of this PhD thesis has resulted in four new, so far unknown methods of 3,4-dihydropyrimidinone aromatization. Efficient, rapid and selective aromatization method was developed using molecular iodine and potassium t-butoxide in dry tetrahydrofuran at room temperature (conversion 80 % - 100 %). 3,4-Dihydropyrimidinone aromatization mechanism was proposed. It includes the formation of t-butil hypoiodite as an active species during aromatization. The second aromatization method is catalytic modification of the previously described method - aromatization of 3,4-dihydropyrimidinones using t-butyl hydroperoxide, molecular iodine and potassium t-butoxide in t-butyl acetate at reflux temperature (conversion 98 % - 100 %). The series of differently substituted derivatives were oxidized using on efficient method that includes t-butyl hydroperoxide as an oxidant, potassium hydroxide as a base and potassium iodide as a catalyst. Reactions were carried out in methanol at room temperature (conversion 98 % - 100 %). In the last aromatization method, the 4-aryl-pyrimidin-2(1H)-one derivatives were dehydrogenated to the corresponding 4-aryl-pyrimidine-ones using tetracyanoethylene in acetonitrile at elevated temperatures (conversion 100 %). The final stage was one pot synthesis of the first three steps in the synthesis of rosuvastatin calcium. This synthesis includes 3,4-dihydropyrimidinone aromatization, the activation of dehydrogenated product and a substitution reaction with an appropriate nucleophile. All three stages were carried out in a single reaction flask without isolation of intermediates. The corresponding products were obtained in a yield of 12 % - 71 %, depending on the derivative.- All metadata published by Europeana are available free of restriction under the Creative Commons CC0 1.0 Universal Public Domain Dedication. However, Europeana requests that you actively acknowledge and give attribution to all metadata sources including Europeana
Provider: - Institution: - Data provided by Europeana Collections- Na temelju prethodno konstruirane ljestvice elektrofugalnosti, temeljene na benzhidrilnome
sustavu, te izmjerenih konstanti brzine ...solvolize, a prema LFER jednadžbi reaktivnosti log k
= sf(Nf + Ef), određene su nukleofugalnosti raznih izlaznih skupina. Pri tome parametar
elektrofugalnosti, Ef, definira heterolitičku reaktivnost kationskog dijela supstrata, a parametri
nukleofugalnosti, Nf i sf, definiraju reaktivnost izlazne skupine u kombinaciji s otapalom u
kojem se provodi solvoliza. Različito supstituiranim fenolatima, benzoatima i alifatskim
karboksilatima određena je nukleofugalnost u raznim otapalima, čime je nadopunjena
postojeća ljestvica nukleofugalnosti novim izlaznim skupinama.
Nadalje, istraženi su utjecaji strukturnih i solvatacijskih efekata na reaktivnost izlaznih
skupina. Tako je utvrđeno da supstituenti utječu na solvolitičku reaktivnost benzoata
induktivnim efektom i efektom polja te da polarnost otapala može uvjetovati relativne
doprinose ovih elektronskih efekata za različita mjesta supstitucije na prstenu.
Unatoč razlikama u strukturama i stabilizacijskim efektima koji utječu na solvolitičku
reaktivnost istraženih supstrata, ovaj LFER model pokazuje održivost i konzistentnost u
koreliranju solvolitičke reaktivnosti i strukture.
Uz eksperimentalne metode pokazana je i mogućnost proširenja ljestvice nukleofugalnosti na
temelju korelacije eksperimentalnih i kvantno-kemijskih podataka reaktivnosti.- On the basis of the established electrofugality scale developed for the benzhydrylium system
and measured solvolytic rate constants, it is possible to define nucleofugalities of various
leaving groups according to the LFER equation log k = sf(Nf + Ef). Electrofugality parameter
(Ef) defines heterolytic reactivity of the cationic part of substrates, whereas nucleofugality
parameters (Nf and sf) define the reactivity of a leaving group in the combination with
employed solvent.
Following syntheses of benzhydrylium derivates, nucleofugalities of variously substituted
phenolates, benzoates and other carboxylates in combinations with different solvents have
been determined. Hereby, the existing nucleofugality scale is supplemented with new leaving
groups different in type and structure.
In addition, impacts of structural and solvation effects on both nucleofugalities of leaving
groups and overall heterolytic reactivities of substrates undergoing solvolysis have been
investigated. Despite the differences in the structures and stabilization effects that govern the
solvolytic reactivities of invastegated substrates, this LFER model demonstrates both
sustainability and consistency in relating the solvolytic reactivity with a structure.
In order to supplement the nucleofugality scale with new data, the possibilities of correlating
the experimental free energies of activation with activation energies afforded by quantumchemical
models have been investigated.- All metadata published by Europeana are available free of restriction under the Creative Commons CC0 1.0 Universal Public Domain Dedication. However, Europeana requests that you actively acknowledge and give attribution to all metadata sources including Europeana
Provider: - Institution: - Data provided by Europeana Collections- All metadata published by Europeana are available free of restriction under the Creative Commons CC0 1.0 Universal Public Domain ...Dedication. However, Europeana requests that you actively acknowledge and give attribution to all metadata sources including Europeana
Provider: - Institution: - Data provided by Europeana Collections- All metadata published by Europeana are available free of restriction under the Creative Commons CC0 1.0 Universal Public Domain ...Dedication. However, Europeana requests that you actively acknowledge and give attribution to all metadata sources including Europeana
Provider: - Institution: - Data provided by Europeana Collections- All metadata published by Europeana are available free of restriction under the Creative Commons CC0 1.0 Universal Public Domain ...Dedication. However, Europeana requests that you actively acknowledge and give attribution to all metadata sources including Europeana
Provider: - Institution: - Data provided by Europeana Collections- All metadata published by Europeana are available free of restriction under the Creative Commons CC0 1.0 Universal Public Domain ...Dedication. However, Europeana requests that you actively acknowledge and give attribution to all metadata sources including Europeana
Provider: - Institution: - Data provided by Europeana Collections- All metadata published by Europeana are available free of restriction under the Creative Commons CC0 1.0 Universal Public Domain ...Dedication. However, Europeana requests that you actively acknowledge and give attribution to all metadata sources including Europeana
Provider: - Institution: - Data provided by Europeana Collections- All metadata published by Europeana are available free of restriction under the Creative Commons CC0 1.0 Universal Public Domain ...Dedication. However, Europeana requests that you actively acknowledge and give attribution to all metadata sources including Europeana
Provider: - Institution: - Data provided by Europeana Collections- All metadata published by Europeana are available free of restriction under the Creative Commons CC0 1.0 Universal Public Domain ...Dedication. However, Europeana requests that you actively acknowledge and give attribution to all metadata sources including Europeana
Provider: - Institution: - Data provided by Europeana Collections- All metadata published by Europeana are available free of restriction under the Creative Commons CC0 1.0 Universal Public Domain ...Dedication. However, Europeana requests that you actively acknowledge and give attribution to all metadata sources including Europeana
