Mechanochemical cocrystal formation studied by in situ Raman spectroscopy.

U ovom radu mehanokemijskom sintezom u suhim uvjetima i tekućinom potpomognutim mljevenjem dobiveni su kokristali nikotinamida s benzojevom, antranilnom ili salicilnom kiselinom. Kokristali s antranilnom i benzojevom kiselinom dosad nisu bili poznati u literaturi i okarakterizirani su uz pomoć difrakcije rendgenskih zraka na praškastim uzorcima i uz pomoć Ramanove spektroskopije. Kristalne strukture dosad nepoznatih kokristala određene su iz difrakcijskih podataka. In situ Ramanovom spektroskopijom praćene su sve reakcije, a istraţio se i utjecaj dodatka male količine primarnih alkohola na brzinu i tijek reakcije.In this thesis neat grinding and liquid-assisted grinding procedures for mechanochemical synthesis of cocrystals of nicotinamide with benzoic, anthranillic or salicylic acid were investigated. Obtained cocrystals of nicotinamide with benzoic or anthranillic acid were not previously known in the literature and were charachterized using powder X-ray diffraction and Raman spectroscopy. Crystal structures were solved using powder X-ray diffraction data. In situ Raman spectroscopy was used to gain insights into the course of the reaction including the influence of small quantities of added alcohols

Mechanochemical Metathesis between AgNO3 and NaX (X = Cl, Br, I) and Ag2XNO3 Double-Salt Formation

Here we describe real-time, in situ monitoring of mechanochemical solid-state metathesis between silver nitrate and the entire series of sodium halides, on the basis of tandem powder X-ray diffraction and Raman spectroscopy monitoring. The mechanistic monitoring reveals that reactions of AgNO3 with NaX (X = Cl, Br, I) differ in reaction paths, with only the reaction with NaBr providing the NaNO3 and AgX products directly. The reaction with NaI revealed the presence of a novel, short-lived intermediate phase, while the reaction with NaCl progressed the slowest through the well-defined Ag2ClNO3 intermediate double salt. While the corresponding iodide and bromide double salts were not observed as intermediates, all three are readily prepared as pure compounds by milling equimolar mixtures of AgX and AgNO3. The in situ observation of reactive intermediates in these simple metathesis reactions reveals a surprising resemblance of reactions involving purely ionic components to those of molecular organic solids and cocrystals. This study demonstrates the potential of in situ reaction monitoring for mechanochemical reactions of ionic compounds as well as completes the application of these techniques to all major compound classes

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

Mechanistic Insights on the Mechanosynthesis of Phenytoin, a WHO Essential Medicine

In recent years, mechanochemistry has enriched the toolbox of synthetic chemists, enabling faster and more sustainable access to new materials and existing products, including active pharmaceutical ingredients (APIs). However, molecular-level understanding of most mechanochemical reactions remains limited, delaying the implementation of mechanochemistry in industrial applications. Herein, we have applied in situ monitoring by Raman spectroscopy to the mechanosynthesis of phenytoin, a World Health Organization (WHO) Essential Medicine, enabling the observation, isolation, and characterization of key molecular-migration intermediates involved in the single-step transformation of benzil, urea, and KOH into phenytoin. This work contributes to the elucidation of a reaction mechanism that has been subjected to a number of interpretations over time and paints a clear picture of how mechanosynthesis can be applied and optimized for the preparation of added-value molecules

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

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