20.500.12556/DKUM-67419 Calorimetric insight into coupling between functionalized primary alkyl halideand vinylic organocuprate reagent experimental determination of reaction enthalpies in the synthesis of (R)-ethyl 3-(tert-butyldimethylsilyloxy)hex-5-enoate - a key lactonized statinside chain precursor The first calorimetric study of coupling between organocuprate, derived from Grignard reagent (vinyl magnesium chloride), and primary alkyl halide (e.g. (S)-ethyl 3-(tert-butyldimethylsilyloxy)-4-iodobutanoate) has been conducted. This transformation is paramountly important for efficient preparation of (R)-ethyl 3-(tert-butyldimethylsilyloxy)hex-5-enoate – a key lactonized statin side chain precursor. The results obtained give thorough calorimetric insight into this complex low-temperature synthesis as well as a new understanding of the suggested reductive elimination of the final intermediates in the coupling reaction. Namely, the surprising unexpected spontaneous three-step exothermal event has been observed during controlled progressive heating of the mixture of the final intermediates to the room temperature. This phenomenon confirms that coupling between functionalized primary alkyl halide and vinylic organocuprate reagent is not a simple $S_N2$ substitution reaction. The presented study provides among others the first reported values of reaction enthalpies and corresponding adiabatic temperature rises of reaction mixture for all exothermic events that occurred in the (R)-ethyl 3-(tert-butyldimethylsilyloxy)hex-5-enoate synthesis. The obtained results ensure consequential thermal process safety knowledge which can be incorporated into safe process scale-up as well as design of reactor system with sufficient cooling capacity for industrial production of (R)-ethyl 3-(tert-butyldimethylsilyloxy)hex-5-enoate. Moreover, the results provide a basic guidance for other organocuprate coupling reaction systems. Predstavljena je prva kalorimetrična študija reakcije med organobakrovim prekurzorjem, pripravljenim iz vinilmagnezijevega klorida, in primarnim alkilhalidom ((S)-etil 3-(terc-butildimetilsilil)-4-iodobutanoatom). Reakcija omogoča učinkovito pripravo (R)-etil 3-(terc-butildimetilsilil)heks-5-enoata, ki je ključni gradnik laktonzirane statinske stranske verige. Rezultati pridobljeni s kalorimetrično študijo omogočajo poglobljeno razumevanje te kompleksne nizko-temperaturne sinteze kot tudi novo razumevanje predpostavljene reduktivne eliminacije končnega intermediata v reakcijskem zaporedju. Opažen je bil presenetljiv nepričakovan spontan tri-stopenjski eksotermni pojav med kontroliranim postopnim segrevanjem zmesi končnega intermediata v reakcijskem mediju na sobno temperaturo. Ta pojav potrjuje dejstvo, da reakcija med primarnimi alkilhalidi in vinilnimi organobakrovimi reagenti ni enostavna $S_N2$ substitucija. Opravljena študija podaja, med drugim, tudi vrednosti reakcijskih entalpij in odgovarjajočih adiabatnih temperaturnih dvigov reakcijske zmesi za vse eksotermne pojave, ki so se zgodili med sintezo (R)-etil 3-(terc-butildimetilsilil)heks-5-enoata. Pridobljeni rezultati nam omogočajo razširitev znanja o procesih z intenzivnim sproščanjem toplote, ki ga lahko uspešno uporabimo pri varnem načrtovanju povečav tehnoloških procesov v organski sintezi in projektiranju reaktorskih sistemov z zadostno hladilno kapaciteto pri industrijski proizvodnji (R)-etil 3-(terc-butildimetilsilil)heks-5-enoata. Nadalje, rezultati študije lahko dajo osnovne smernice za podobne reakcije med organobakrovimi prekurzorji pripravljenimi iz Grignardovih reagentov in alkilhalidi. Grignard reagents organocuprates coupling reaction reaction calorimetry statins Grignardov reagent reakcija spajanja reakcijska kalorimetrija statini true false true Angleški jezik Slovenski jezik Znanstveno delo 2017-08-17 11:13:37 2017-08-17 11:15:03 2022-08-01 13:57:08 2019-07-11 16:19:44 2010 0 0 str. 66-76 št. 1 Letn. 57 2010 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 1318-0207 547 14086149 1428828 1318-0207 URN:SI:UM:DK:5GERP0DC Acta_Chimica_Slovenica_2010_Casar,_Tramsek,_Gorsek_Calorimetric_Insight_into_Coupling_between_Functionalized_Primary_Alkyl_Halide_and_Vi.pdf Acta_Chimica_Slovenica_2010_Casar,_Tramsek,_Gorsek_Calorimetric_Insight_into_Coupling_between_Functionalized_Primary_Alkyl_Halide_and_Vi.pdf 1 DF4C4C556868E764BECDDD80CC6397C6 1d2b17314cf9c9d35f5c49819dbe1e6735c1d3dd50258a464bb878ea08542038 8559cf8d-7c0e-11eb-bb7a-00155d0001ca 20.500.12556/dkum/0d209463-66b7-4dd6-829c-fb061b6edf02 https://dk.um.si/Dokument.php?lang=slv&id=115427 http://acta-arhiv.chem-soc.si/57/57-1-066.pdf 1 https://dk.um.si/Dokument.php?lang=slv&id=115426 Fakulteta za kemijo in kemijsko tehnologijo 0 0 0