There is a great variety of natural compounds that have the typical structure of a chalcone, consisting of two aromatic rings and an α, β-unsaturated carbonyl group in resonance with each other, such as 1,3-diaryl-2-propen-1 -one. The presence of this conjugation is responsible for the biological activity of these compounds, which is their main reason of interest. This structural reason is found in various types of vegetables, seeds, fruits and many other plants, from which natural substances with multiple biological activities are extracted: antioxidants, anti-inflammatory, cytotoxic, antimicrobial, antidiabetic and many other beneficial properties. Thanks to these activities, chalcones have increasingly found use in pharmaceutical principles and medicinally relevant compounds. In recent decades, numerous synthetic ways have been developed to obtain chalconic derivatives. Among the most common are certainly the Claisen-Schmidt condensation reaction, the Julia-Kochenski or Wittig olefination reactions, or cross-coupling reactions such as Suzuki-Miyaura or Heck cross coupling. This thesis proposes an innovative synthetic way for the synthesis of chalcones, which envisages the use of a solvent-free reaction as a key point. In particular, it is an aldol reaction between a ketone and an aldehyde, promoted by magnesium hydrogen sulfate (Mg (HSO4) 2) which has a dual role: first it promotes the formation of the ketone enol, then it promotes the aldol reaction thanks to the chelation of the reactants' oxygen by the Mg2 + ion. An optimization of the reaction conditions was initially carried out; since all reagents are powders, various methods of mixing the solids were examined, obtaining the highest yields using a mechanical stirring system. Once the reaction conditions were optimized, the scope was examined, applying the protocol with a large variety of reagents. The best results have been obtained with electron-rich acetophenones and electron-poor benzaldehydes, as well as with heteroaromatic derivatives, which are very promising from a medical point of view. Subsequently, the solvent-free reaction was used for the synthesis of naturally occurring chalcones, including isoliquiritigenin, butein and okanin. Initially the reaction was directly attempted using the reagents with free OH groups, but not obtaining the expected results. Therefore it was decided to use a protection / deprotection system, which allowed to obtain the natural products in interesting yields. In conclusion, an innovative protocol for the synthesis of chalcones was developed that exploits a solvent-free reaction. It is a simple, efficient and green chemistry focused procedure, which constitutes a valid alternative to the classical methods used to synthesize such compounds.
In natura esiste una grande varietà di composti naturali che presenta la struttura tipica di un calcone, costituita da due anelli aromatici e da un gruppo carbonilico α,β-insaturo in risonanza tra loro, come 1,3-diaril-2-propen-1-one. La presenza di tale coniugazione è responsabile dell’attività biologica di tali composti, che costituisce il loro principale motivo di interesse. Tale motivo strutturale si riscontra in vari tipi di vegetali, semi, frutti e molte altre piante, da cui si estraggono sostanze naturali aventi molteplici attività biologiche: antiossidanti, antinfiammatorie, citotossiche, antimicrobiche, antidiabetiche e molte altre proprietà benefiche. Grazie a tali attività, i calconi hanno trovato sempre più impiego in principi farmaceutici e composti rilevanti dal punto di vista medico. Negli ultimi decenni sono state sviluppate numerose vie sintetiche per ottenere derivati calconici. Tra le più diffuse si trovano sicuramente la reazione di condensazione di Claisen-Schmidt, le reazioni di olefinazione di Julia-Kochenski o di Wittig, oppure reazioni di cross-coupling come quella di Suzuki-Miyaura o quella di Heck. In questa tesi viene proposta una via sintetica innovativa per la sintesi di calconi, che prevede come punto chiave l’utilizzo di una reazione solvent-free. In particolare, si tratta di una reazione aldolica tra un chetone e un’aldeide, promossa dal magnesio idrogenosolfato (Mg(HSO4)2) che assume un duplice ruolo: prima favorisce la formazione dell’enolo del chetone, in seguito promuove la reazione aldolica grazie alla chelazione da parte dello ione Mg2+ degli ossigeni dei reagenti. Inizialmente è stata effettuata una ottimizzazione delle condizioni di reazione; essendo tutti i reagenti delle polveri, sono stati esaminati vari metodi di miscelazione dei solidi, ottenendo le rese più elevate usando un sistema di agitazione meccanica. Una volta ottimizzate le condizioni di reazione, ne è stato esaminato lo scopo, applicando il protocollo con una grande varietà di reagenti. I risultati migliori sono stati ottenuti con acetofenoni elettron-ricchi e con benzaldeidi elettron-povere, così come con derivati eteroaromatici, molto promettenti da un punto di vista medico. In seguito, la reazione solvent-free è stata utilizzata per la sintesi di calconi naturali, tra cui isoliquiritigenin, butein e okanin. Inizialmente la reazione è stata tentata direttamente usando i reagenti con i gruppi OH liberi, non ottenendo però i risultati attesi. Perciò è stato deciso di usare un sistema di potezione/deprotezione, che ha permesso di ottenere i prodotti naturali in rese comunque interessanti. In conclusione, è stato sviluppato un protocollo innovativo per la sintesi di calconi che sfrutta una reazione solvent-free. Si tratta di una procedura semplice, efficiente e focalizzata sulla green chemistry, che costituisce una valida alternativa ai metodi classici utilizzati per sintetizzare tali composti.
Condensazione aldolica incrociata mediata da Mg(HSO4)2 per la sintesi solvent-free di calconi
SARACI, ERVIS
2019/2020
Abstract
There is a great variety of natural compounds that have the typical structure of a chalcone, consisting of two aromatic rings and an α, β-unsaturated carbonyl group in resonance with each other, such as 1,3-diaryl-2-propen-1 -one. The presence of this conjugation is responsible for the biological activity of these compounds, which is their main reason of interest. This structural reason is found in various types of vegetables, seeds, fruits and many other plants, from which natural substances with multiple biological activities are extracted: antioxidants, anti-inflammatory, cytotoxic, antimicrobial, antidiabetic and many other beneficial properties. Thanks to these activities, chalcones have increasingly found use in pharmaceutical principles and medicinally relevant compounds. In recent decades, numerous synthetic ways have been developed to obtain chalconic derivatives. Among the most common are certainly the Claisen-Schmidt condensation reaction, the Julia-Kochenski or Wittig olefination reactions, or cross-coupling reactions such as Suzuki-Miyaura or Heck cross coupling. This thesis proposes an innovative synthetic way for the synthesis of chalcones, which envisages the use of a solvent-free reaction as a key point. In particular, it is an aldol reaction between a ketone and an aldehyde, promoted by magnesium hydrogen sulfate (Mg (HSO4) 2) which has a dual role: first it promotes the formation of the ketone enol, then it promotes the aldol reaction thanks to the chelation of the reactants' oxygen by the Mg2 + ion. An optimization of the reaction conditions was initially carried out; since all reagents are powders, various methods of mixing the solids were examined, obtaining the highest yields using a mechanical stirring system. Once the reaction conditions were optimized, the scope was examined, applying the protocol with a large variety of reagents. The best results have been obtained with electron-rich acetophenones and electron-poor benzaldehydes, as well as with heteroaromatic derivatives, which are very promising from a medical point of view. Subsequently, the solvent-free reaction was used for the synthesis of naturally occurring chalcones, including isoliquiritigenin, butein and okanin. Initially the reaction was directly attempted using the reagents with free OH groups, but not obtaining the expected results. Therefore it was decided to use a protection / deprotection system, which allowed to obtain the natural products in interesting yields. In conclusion, an innovative protocol for the synthesis of chalcones was developed that exploits a solvent-free reaction. It is a simple, efficient and green chemistry focused procedure, which constitutes a valid alternative to the classical methods used to synthesize such compounds.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/11932