Development of mechanochemical synthesis of amides, ureas and triazoles

Fokus ovog doktorskog rada bio je razjasniti mehanizam mehanokemijske priprave različito supstituiranih amida i urea reakcijom acil-azida i amina, te razjasniti mehanizam Huisgenovih 1,3-cikloadicija kataliziranih bakrovim(I) ionima provedenih u mehanokemijskim uvjetima. Ispitan je utjecaj supstituenata i aditiva na tijek reakcije nukleofilne supstitucije amina i acil-azida korištenjem in situ Ramanove spektroskopije tijekom mljevenja. Iz dobivenih rezultata zaključeno je kako je reakcija nukleofilne supstitucije provedena u mehanokemijskim uvjetima katalizirana bazom, a korak u kojem dolazi do deprotonacije ima ključnu ulogu u ovim reakcijama. U reakcijama provedenim mljevenjem uspješno su izolirani amidni derivati, dok su ureidni derivati dobiveni isključivo reakcijama u otopini. Ispitan je utjecaj bakra i njegovih soli kao katalizatora na iskorištenje Huisgenove 1,3-cikloadicije terminalnih alkina i aril-azida u otopini i mehanokemijskim postupcima. Iz dobivenih rezultata zaključeno je kako reaktivnost p-supstituiranih aril-azida, u obje metode, pada u nizu I>Br>Cl>H. Korištenjem Ramanove spektroskopije in situ ispitan je utjecaj bakra i njegovih soli na nastajanje 1,2,3-triazolnog prstena u mehanokemijskim reakcijama.This work emphasizes the comparation of the mechanochemical and solvent synthesis of amides and ureas carried out without the use of metals as a catalyst, and Huisgen's 1,3-dipolar cycloaddition of azide and terminal alkyne in presence of cooper as a catalyst. Nucleophilic substitution reactions are investigated on the model system of acyl azide and primary amines in the presence of various additives under different reaction conditions using in situ Raman spectroscopy. The nucleophilic substitution reaction under mechanochemical conditions is base catalyzed, akin to catalysis in solution. Mechanochemical reaction as a product provide amide derivatives, while by reactions in solution are obtained only ureas. The mechanism of Huisgen copper-catalyzed mechanochemical reaction and the efficiency of copper catalysts with Cu(0), Cu(I) and Cu(II) oxidation states is clarified by means of in situ Raman spectroscopy. From the obtained results, it was concluded that the reactivity of p-substituted aryl azide, in solution and mechanochemical procedures, follows the sequence I> Br> Cl> H

Development of mechanochemical synthesis of amides, ureas and triazoles

Fokus ovog doktorskog rada bio je razjasniti mehanizam mehanokemijske priprave različito supstituiranih amida i urea reakcijom acil-azida i amina, te razjasniti mehanizam Huisgenovih 1,3-cikloadicija kataliziranih bakrovim(I) ionima provedenih u mehanokemijskim uvjetima. Ispitan je utjecaj supstituenata i aditiva na tijek reakcije nukleofilne supstitucije amina i acil-azida korištenjem in situ Ramanove spektroskopije tijekom mljevenja. Iz dobivenih rezultata zaključeno je kako je reakcija nukleofilne supstitucije provedena u mehanokemijskim uvjetima katalizirana bazom, a korak u kojem dolazi do deprotonacije ima ključnu ulogu u ovim reakcijama. U reakcijama provedenim mljevenjem uspješno su izolirani amidni derivati, dok su ureidni derivati dobiveni isključivo reakcijama u otopini. Ispitan je utjecaj bakra i njegovih soli kao katalizatora na iskorištenje Huisgenove 1,3-cikloadicije terminalnih alkina i aril-azida u otopini i mehanokemijskim postupcima. Iz dobivenih rezultata zaključeno je kako reaktivnost p-supstituiranih aril-azida, u obje metode, pada u nizu I>Br>Cl>H. Korištenjem Ramanove spektroskopije in situ ispitan je utjecaj bakra i njegovih soli na nastajanje 1,2,3-triazolnog prstena u mehanokemijskim reakcijama.This work emphasizes the comparation of the mechanochemical and solvent synthesis of amides and ureas carried out without the use of metals as a catalyst, and Huisgen's 1,3-dipolar cycloaddition of azide and terminal alkyne in presence of cooper as a catalyst. Nucleophilic substitution reactions are investigated on the model system of acyl azide and primary amines in the presence of various additives under different reaction conditions using in situ Raman spectroscopy. The nucleophilic substitution reaction under mechanochemical conditions is base catalyzed, akin to catalysis in solution. Mechanochemical reaction as a product provide amide derivatives, while by reactions in solution are obtained only ureas. The mechanism of Huisgen copper-catalyzed mechanochemical reaction and the efficiency of copper catalysts with Cu(0), Cu(I) and Cu(II) oxidation states is clarified by means of in situ Raman spectroscopy. From the obtained results, it was concluded that the reactivity of p-substituted aryl azide, in solution and mechanochemical procedures, follows the sequence I> Br> Cl> H

Development of mechanochemical synthesis of amides, ureas and triazoles

Fokus ovog doktorskog rada bio je razjasniti mehanizam mehanokemijske priprave različito supstituiranih amida i urea reakcijom acil-azida i amina, te razjasniti mehanizam Huisgenovih 1,3-cikloadicija kataliziranih bakrovim(I) ionima provedenih u mehanokemijskim uvjetima. Ispitan je utjecaj supstituenata i aditiva na tijek reakcije nukleofilne supstitucije amina i acil-azida korištenjem in situ Ramanove spektroskopije tijekom mljevenja. Iz dobivenih rezultata zaključeno je kako je reakcija nukleofilne supstitucije provedena u mehanokemijskim uvjetima katalizirana bazom, a korak u kojem dolazi do deprotonacije ima ključnu ulogu u ovim reakcijama. U reakcijama provedenim mljevenjem uspješno su izolirani amidni derivati, dok su ureidni derivati dobiveni isključivo reakcijama u otopini. Ispitan je utjecaj bakra i njegovih soli kao katalizatora na iskorištenje Huisgenove 1,3-cikloadicije terminalnih alkina i aril-azida u otopini i mehanokemijskim postupcima. Iz dobivenih rezultata zaključeno je kako reaktivnost p-supstituiranih aril-azida, u obje metode, pada u nizu I>Br>Cl>H. Korištenjem Ramanove spektroskopije in situ ispitan je utjecaj bakra i njegovih soli na nastajanje 1,2,3-triazolnog prstena u mehanokemijskim reakcijama.This work emphasizes the comparation of the mechanochemical and solvent synthesis of amides and ureas carried out without the use of metals as a catalyst, and Huisgen's 1,3-dipolar cycloaddition of azide and terminal alkyne in presence of cooper as a catalyst. Nucleophilic substitution reactions are investigated on the model system of acyl azide and primary amines in the presence of various additives under different reaction conditions using in situ Raman spectroscopy. The nucleophilic substitution reaction under mechanochemical conditions is base catalyzed, akin to catalysis in solution. Mechanochemical reaction as a product provide amide derivatives, while by reactions in solution are obtained only ureas. The mechanism of Huisgen copper-catalyzed mechanochemical reaction and the efficiency of copper catalysts with Cu(0), Cu(I) and Cu(II) oxidation states is clarified by means of in situ Raman spectroscopy. From the obtained results, it was concluded that the reactivity of p-substituted aryl azide, in solution and mechanochemical procedures, follows the sequence I> Br> Cl> H

Investigations of Thermally Controlled Mechanochemical Milling Reactions

Mechanochemical milling reactions have received much attention recently as a green and highly efficient path toward various relevant materials. Control over the fundamental reaction parameters in the milling procedure, such as temperature and pressure of the reactor, is still in its infancy, and the vast majority of milling reactions are done by controlling just the basic parameters such as frequency and milling media weight. We demonstrate here how milling under controlled, prolonged, and variable heating programs accomplished in a new milling reactor introduces a new level of mechanochemical reactivity beyond what can be achieved by conventional mechanochemical or solution procedures and also reduces the time and energy costs of the milling process. The methodology is demonstrated on four varied systems: C–C bond-forming Knoevenagel condensation, selective C–N bond formation for amide/urea synthesis, selective double-imine condensation, and solid-state formation of an archetypal open metal-organic framework, MOF-74. The potential of this methodology is best demonstrated on the one-pot selective synthesis of four complex products containing combinations of amide, amine, or urea functionalities from the same and simple acyl azide and diamine reactants. Principal control over this enhanced reactivity and selectivity stemmed from the application of specific heating regimes to mechanochemical processing accomplished by a new, in-house developed mechanochemical reactor. As even a moderate increase in temperature strongly affects the selectivity and the rate of mechanochemical reactions, the results presented are in line with recent challenges of the accepted theories of mechanochemical reactivity

Solvent-free copper-catalyzed click chemistry for the synthesis of novel N-heterocyclic hybrids based on quinolone and 1, 2, 3-triazole

Copper-catalyzed mechanochemical click reactions have been successfully implemented to provide novel 6-phenyl-2- (trifluoromethyl)quinolones with phenyl-1, 2, 3- triazole moiety at O-4 of quinolone core. Milling procedures utilizing CuI and brass milling balls proved to be more efficient than one using Cu(OAc)2, as a copper source. While solvent-free milling methods were unaffected by the presence of the p-substituted azides, solvent-based conventional methods were strongly dependent on electronic structure of azides. In situ Raman monitoring of the milling processes using the Cu(0) catalysts in form of brass milling media enabled direct insight into the reaction pathway of mechanochemical CuAAC reactions indicating that the catalysis is most likely conducted on the surface of milling balls

Solid-State Supramolecular Assembly of Salicylic Acid and 2-Pyridone, 3-Hydroxypyridine or 4-Pyridone

Mechanochemical milling of equimolar mixtures of salicylic acid with three hydroxy derivatives of pyridine provided three new phases. With 2-hydroxypyridine, which is in fact present as 2-pyridone, a discrete cocrystal supramolecular assembly is formed. 3-hydroxypyridine and salicylic acid formed a salt and an extended network of hydrogen bonds while the product of the reaction of 4-hydroxypyridine (present as 4-pyridone) and salicylic acid remained structurally uncharacterized. All three hydroxypyridines retain the tautomeric form as in their respective pure phases upon cocrystal formation. Where possible, reaction profiles have been extracted from in situ monitoring via Rietveld refinement to show direct product formation which could be well described using the first-order reaction rate law. This work is licensed under a Creative Commons Attribution 4.0 International License

Isotope Labeling Reveals Fast Atomic and Molecular Exchange in Mechanochemical Milling Reactions

Using tandem in situ monitoring and isotope-labeled solids, we reveal that mechanochemical ball-milling overcomes inherently slow solid-state diffusion through continuous comminution and growth of milled particles. This process occurs with or without a net chemical reaction and also occurs between solids and liquid additives that can be practically used for highly efficient deuterium labeling of solids. The presented findings reveal a fundamental aspect of milling reactions and also delineate a methodology that should be considered in the study of mechanochemical reaction mechanisms

Experimental and Theoretical Study of Selectivity in Mechanochemical Cocrystallization of Nicotinamide with Anthranilic and Salicylic Acid

Selectivity in mechanochemical cocrystal formation between nicotinamide and anthranilic acid or salicylic acid was studied using tandem in situ reaction monitoring by powder X-ray diffraction (PXRD) and Raman spectroscopy. Selectivity was probed by offering a competing cocrystal coformer to a previously prepared cocrystal or under competitive reaction conditions where all cocrystal coformers, in different stoichiometric ratios, were introduced together in the starting reaction mixture. Reaction paths were dependent on the starting mixture composition, and we find that the formation of intermediates and the final product can be predicted from solid-state ab initio calculations of relative energies of possible reaction mixtures. In some cases, the quantitative assessment revealed different reaction profiles derived from PXRD and Raman monitoring, directly indicating, for the first time, different mechanochemical reactivity on the molecular and the bulk crystalline level of the reaction mixture