Učinkovita sinteza substituiranih cinolinov preko vmesnih diazonijevih soli

Siljanovska, Ana (author), Košmrlj, Janez (mentor)

V magistrskem delu smo se ukvarjali z razvojem metode za sintezo substituiranih cinolinov katalizirano s p-toluensulfonsko kislino. Optimizirano metodo smo uporabili za sintezo različno substituiranih cinolinov, ki smo jih karakterizirali s pomočjo tehnik jedrske magnetne resonance, masne spektrometrije visoke ločljivosti ter visokotlačne tekočinske kromatografije. Začeli smo z ravojem metode za diazotiranje anilinov, z elektronprivlačnimi substituenti na aromatskem obroču, s terc-butil nitritom kot virom dušika ter p-toluensulfonsko kislino, ki je služila kot vir protonov, njena deprotonirana oblika pa je obenem kasneje služila kot stabilizirajoči anion diazonijeve soli. Izolirani diazonijevi tozilati so stabilni dlje časa brez izgub reaktivnosti. Slednje smo potrdili z reakcijo azo spajanja z elektronsko bogatima aromatskima sistemoma do usteznih azo barvil. Optimizirane pogoje diazotiranja smo nato uporabili na elektronsko bogatih anilinov, natančneje 1,2-benzodiaminu in 2-izopropenil anilinu, ki sta po pričakovanjih reagirala do cikličnih produktov. V nadaljevanju smo raziskali ciklizacijo o-vinilanilinov do ustreznih cinolinov. Za to smo najprej iz ustreznih anilinov pripravili serijo o-vinilanilinov z različnimi substituenti in fenilacetilenov. Reakcijo smo izvajali v prisotnosti heterogenega katalizatorja montmorilonit K-10 v odsotnosti topila. Tako dobljene o-vinilaniline smo nadalje ciklizirali v želene cinolinske produkte. Optimizacijo postopka smo naredili na modelni reakciji s spremljanjem vplivov narave in količine kisline, topila ter reakcijskega časa na konverzijo izhodnega anilina v produkt. Diazotiranje takšnih vinilnih sistemov v prisotnosti terc-butil nitrita in katalitskih količin p-toluensulfonske kisline vodi do nastanka substituiranih cinolinov. Poleg tega nas je zanimal mehanizem reakcije, s pomočjo katerega bi pojasnili katalitsko delovanje kisline. S pomočjo teoretičnih izračunov na osnovi gostotnega funkcionala ter preliminarnarnih kinetičnih meritev smo predlagali mehanizem reakcije, ki v ključni stopnji poteka preko tvorbe diazonijeve soli. Prav tako smo ugotovili, da p-toluensulfonska kislina v katalitski količini služi kot prenašalec protona med dvema tavtomernima oblikama intermediatov. Izračunan mehanizem nam je dal tudi vpogled v postopek diazotiranja anilinov z organskim nitritom, ki je precej drugačen od do sedaj uveljavljenih.

• Language: Slovenian
• Keywords: diazonijev tozilat, azo barvilo, o-vinilanilin, cinolin, p-toluensulfonska kislina
• Work type: Master's thesis/paper
• Typology: 2.09 - Master's Thesis
• Organization: FKKT - Faculty of Chemistry and Chemical Technology
• Year: 2020
• PID: 20.500.12556/RUL-119123
• COBISS.SI-ID: 27825667
• Publication date in RUL: 03.09.2020

Secondary language

• Language: English
• Title: Efficient synthesis of substituted cinnolines via diazonium salt intermediate

Abstract

The aim of this work was the development of an efficient method for the synthesis of substituted cinnolines using catalytic amounts of p-toluenesulfonic acid. The optimized method was used for the synthesis of a series of substituted cinnolines, which were characterized by means of nuclear magnetic resonance, mass spectrometry and high-pressure liquid chromatography. We have developed a simple method for diazotization of weakly basic anilines in the presence of p-toluensulfonic acid, which acts as proton donor and stabilizing anion, and tert-butyl nitrite as nitrogen source. The isolated diazonium tosylates show great stability over a longer period of time without loss of reactivity. The latter was confirmed by azo coupling reaction with activated arenes yielding azo dyes. The optimized diazotization reaction conditions were further used on electron rich anilines, i.e. 1,2-benzodiamine and 2-isopropenylaniline. As expected, the two reactive anilines yielded cyclic products. Furthermore, we investigated the cyclization of different o-vinylanilines to cinnolines. For that purpose, a series of substituted o-vinylanilines was synthesised from the corresponding anilines and phenylacetilenes. The reaction takes place in the presence of heterogeneous catalyst montmorillonite K-10 in the absence of solvent. The synthesized o-vinylanilines were additionally converted into the cyclic cinnolines. A model reaction was used to optimize acid loadings, solvent nature and reaction times. Applying the optimized conditions to o-vinylanilines in the presence of tert-butyl nitrite and catalytic amounts of p-toluensulfonic acid leads to the formation of substituted cinnolines. Moreover, the reaction mechanism of the described transformation was studied. Employing a solution state density functional theory simulations as well as preliminary kinetic studies gave strong support towards a reaction mechanism that proceeds via the diazonium salt formation. Additionally, it was suggested that p-toluensulfonic acid acts as a catalytic proton shuttle between two tautomeric intermediates. This mechanistic study has also offered insight into diazotization of anilines by using organic nitrite, which is fundamentaly different from previously described reactions.

• Keywords: diazonium tosylate, azo dye, o-vinylaniline, cinnoline, p-toluenesulfonic acid