Computational study of the Sonogashira cross-coupling reaction
Date
2012-10-10
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Abstract
Suur hulk keemilisi reaktsioone toimub katalüsaatorite kaasabil ning reaktsiooni selektiivsuse ja kiiruse suurendamiseks on efektiivsemate katalüsaatorite leidmine äärmiselt tähtis. Orgaanilises sünteesis on katalüsaatoritena leidnud laialdast kasutust siirdemetallid, mis on võimelised katalüüsima ka uute süsinik-süsinik sidemete moodustumist. Alates ristkondensatsioonireaktsioonide avastamisest 1970. aastate esimesel poolel on siirdemetallid leidnud väga laialdast rakendust, eriti pallaadiumi alarühma metallid. Selektiivne C-C sidemete tekitamise võimalus on tugevalt mõjutanud orgaanilist keemiat, kuna võimaldab molekuli fragmente omavahel ühendades sünteesida soovitud keemilisi ühendeid.
Sonogashira ristkondensatsioon, mida esmakordselt kirjeldati 1975. aastal, on pallaadiumi poolt katalüüsitud süsinik-süsinik sideme tekkereaktsioon, mille tulemusena saadakse orgaanilistest halogeniididest ja ühe asendusrühmaga alküünidest diasendatud alküüne. Antud reaktsioon võimaldab suhteliselt väikestest molekulidest väga spetsiifiliselt ja efektiivselt konstrueerida konjugeeritud π-elektronsüsteemiga alküüne, mis on tihti bioaktiivsetes ainetes esinevad fragmendid ning tähtsad ka farmaatsiatööstuses, agrokeemias ja materjaliteaduses.
Hoolimata Sonogashira ristkondensatsiooni laialdasest kasutamisest on nimetatud reaktsiooni mehhanismi vähe uuritud ning sedagi eelkõige orgaanilise sünteesi käigus saadud tulemustest lähtuvalt. Samas on selle reaktsiooni mehhanismi mõistmine väga oluline efektiivsemate katalüsaatorite väljatöötamiseks. Kaasaegsed kvantkeemilised meetodid pakuvad laialdasi võimalusi reaktsioonimehhanismide uurimiseks ning sellest lähtuvalt on antud töös modelleeritud Sonogashira ristkondensatsiooni tihedusfunktisonaali teooria abil.
Töö tulemusena saadud reaktsioonimehhanism on oluliselt keerukam, kui senini kirjanduses avaldatud analoogid, koosnedes neljast etapist: oksüdatiivne liitumine, cis-trans isomerisatsioon, deprotoneerumine (transmetalleerimine) ning redutseeriv elimineerumine. Nimetatud etappides esineb mitmeid konkureerivaid reaktsiooniteid, mille valik võib sõltuda nii reaktsioonisegus olevatest lisanditest kui ka katalüsaatori ja lähteainete valikust. Antud töös leitud reaktsioonimehhanism on heaks lähtepunktiks nii analoogsete ristkondensatsioonireaktsioonide eksperimentaalseks ja arvutuslikus uurimiseks, aga ka Sonogashira ristkondensatsiooni optimaalsete reaktsioonitingimuste leidmiseks.
A large number of chemical reactions proceeds in the presence of catalyst. To improve the selectivity and rate of the reaction, design of more effective catalysts is very important. Transition metals have been found an extensive use in the field of organic synthesis as catalysts because among the other reactions they are capable of catalyzing the formation of carbon-carbon bonds. Since the discovery of cross-coupling reactions in the first half of the 1970s, metals in the subgroup of palladium have been/are widely used as catalysts. The possibility of selective formation of C-C bonds has strongly influenced organic chemistry, allowing the synthesis of desired molecules by combining suitable precursor fragments. The Sonogashira cross-coupling, which was first described in 1975, is a palladium-catalyzed carbon-carbon bond formation reaction that is used to synthesize bisubstituted alkynes from organic halides and monosubstituted alkynes. This reaction allows the effective and fairly easy way to combine relatively small molecules to form alkynes with conjugated π-electron system, which are common fragments in bioactive substances and also important for pharmaceutical industry, agrochemistry, and material sciences. Despite the wide use of the Sonogashira cross-coupling, the reaction mechanism has not been thoroughly studied and most of the information on this topic in literature is based on the data of organic synthesis. The deeper understanding of the rection mechanism is necessary for the development of more effective catalysts. Modern methods of computational chemistry offer a wide range of possibilities for the investigation of reaction mechanism, therefore, in the present thesis the Sonogashira cross-coupling is modeled by means of the density functional theory. The obtained reaction mechanism is more complex than the previously reported analogues and is composed of four steps: oxidative addition, cis-trans isomerization, deprotonation (transmetalation), and reductive elimination. These steps incorporate multiple competing pathways, which depend on a number of additives in the reaction mixture, as well as the reactants and catalyst. The mechanism, described in this thesis, is a good starting point for both experimental and computational studies of similar cross-coupling reactions, as well as to find optimal reaction conditions for the Sonogashira cross-coupling.
A large number of chemical reactions proceeds in the presence of catalyst. To improve the selectivity and rate of the reaction, design of more effective catalysts is very important. Transition metals have been found an extensive use in the field of organic synthesis as catalysts because among the other reactions they are capable of catalyzing the formation of carbon-carbon bonds. Since the discovery of cross-coupling reactions in the first half of the 1970s, metals in the subgroup of palladium have been/are widely used as catalysts. The possibility of selective formation of C-C bonds has strongly influenced organic chemistry, allowing the synthesis of desired molecules by combining suitable precursor fragments. The Sonogashira cross-coupling, which was first described in 1975, is a palladium-catalyzed carbon-carbon bond formation reaction that is used to synthesize bisubstituted alkynes from organic halides and monosubstituted alkynes. This reaction allows the effective and fairly easy way to combine relatively small molecules to form alkynes with conjugated π-electron system, which are common fragments in bioactive substances and also important for pharmaceutical industry, agrochemistry, and material sciences. Despite the wide use of the Sonogashira cross-coupling, the reaction mechanism has not been thoroughly studied and most of the information on this topic in literature is based on the data of organic synthesis. The deeper understanding of the rection mechanism is necessary for the development of more effective catalysts. Modern methods of computational chemistry offer a wide range of possibilities for the investigation of reaction mechanism, therefore, in the present thesis the Sonogashira cross-coupling is modeled by means of the density functional theory. The obtained reaction mechanism is more complex than the previously reported analogues and is composed of four steps: oxidative addition, cis-trans isomerization, deprotonation (transmetalation), and reductive elimination. These steps incorporate multiple competing pathways, which depend on a number of additives in the reaction mixture, as well as the reactants and catalyst. The mechanism, described in this thesis, is a good starting point for both experimental and computational studies of similar cross-coupling reactions, as well as to find optimal reaction conditions for the Sonogashira cross-coupling.
Description
Väitekirja elektrooniline versioon ei sisalda publikatsioone.
Keywords
orgaaniline süntees, katalüsaatorid, siirdemetallid, reaktsioonimehhanismid, tihedusfunktsionaali teooria, organic synthesis, catalysts, transition metals, reaction mechanisms, density functional theory