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Held, Ingmar (2007): Allgemeine und spezielle Beiträge zur nucleophilen Acyl-Transfer-Katalyse. Dissertation, LMU München: Faculty of Chemistry and Pharmacy
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Abstract

One of the important transformations of alcohols to esters is the reaction with acetic anhydride catalysed by 4-(dimethylamino)pyridine (DMAP) in the presence of an auxiliary base like triethyl amine. Although this is a widely used reaction, several questions left unaddressed until now: the reaction mechanism of the latter transformation was not completely conceived. Since Steglich and Litvenencko found DMAP in 1969 independently as nucleophilic catalyst, there was hardly any effort to search for new nucleophilic catalysts of higher catalytic efficiency than DMAP or 4-(pyrrolidinyl)pyridine (PPY). All chiral nucleophilic catalysts are based on these structural motifs and due to their lack of catalytic efficiency, there are hitherto no examples for kinetic resolution experiments of tertiary alcohols described. In this dissertation, the following goals were achieved: With computational methods, the reaction pathway of tert-butanol with acetic anhydride in the presence of DMAP was explored. Based on these results a fast computational tool was developed to screen for more efficient nucleophilic catalysts. The best candidates were synthesised, the catalytic efficiency quantified and the best catalysts applied in the synthesis of esters. The reaction mechanism of the acetylation of tert-alcohols was explored by calculating the nucleophilic and base catalysed reaction pathway of tert-butanol with acetic anhydride in the presence of DMAP at B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level of theory. In the course of this study, a nucleophilic and base catalysed reaction pathway with DMAP as catalyst was found. The energetically lowest transition state of the base catalysed reaction pathway is 37.9 kJ mol-1 higher in energy then the energetically lowest transition state in the rate-determining step of the nucleophilic reaction path. The combination of kinetic measurements with the calculation of the nucleophilic reaction path reveals that no triethyl amine is involved in the rate-determining step of nucleophilic reaction pathway. This shows clearly that nucleophilic catalysis is the preferred and that the acetate anion is deprotonating the alcohol in the rate-determining step. Furthermore, the results of the recalculation of the nucleophilic reaction path with a different catalyst show that a higher stabilisation of the transient acylpyridinium cation has a pivotal influence on the overall reaction rate of the ester formation. Therefore, relative acetylation enthalpies (ΔH298) were calculated at B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level of theory by using an isodesmic reaction approach. In this way a large number of new nucleophilic catalysts were screened and numerous promising candidates were synthesised which have a larger negative ΔH298 value then DMAP (-82.1 kJ mol 1). The catalytic effiency of the new nucleophilic catalysts was quantified by a test reaction using 1 equiv. of 1-ethynylcyclohexanol, 2 equiv. of acetic or isobutyric anhydride and 3 equiv. triethyl amine. The conversion of 1-ethynylcyclohexyl acetate or -isobutyrate was monitored by 1H NMR spectroscopy. Pyrido[3,4-b]pyrazine- and pyrido[3,4 b]quinoxaline-derivatives show the best catalytic effiency. Especially (rac) 5,10-diethyl-5,5a,6,7,8,9a,10-octahydropyrido[3,4 b]-quinoxaline (DOPQ) shows equal to better catalytic efficiency then 6,6-tricyloaminopyridine (TCAP), which was hitherto the best nucleophilic catalyst. DOPQ can be synthesised very efficiently in a four step protocol starting from commercially available 3,4-diaminopyridine and cyclohexane-1,2-dione with an overall yield of 45 % while TCAP is only available in a five step synthesis with an overall yield of 8-13 %. The synthesis of DOPQ starts with the Schiff-base formation of 3,4-diaminopyridine and cyclohexane-1,2-dione. Reduction with LiAlH4 yields the cis-configured octahydro[3,4-b]quinoxaline, which can be alkylated without the use of any protecting group in the presence of acetic anhydride in pyridine and subsequent reduction with LiAlH4/AlCl3 to yield DOPQ. The structure of the latter compound was confirmed by X ray single crystal structure. The new catalysts were applied to an enhanced Gooßen esterification to transform sterically hindered acids to their tert-butyl esters. The reaction mechanism was explored by monitoring the substrate, intermediate and product conversions with 1H NMR spectroscopy. With this enhanced reaction protocol, it was possible to transform 1-phenylcyclohexane carboxylic acid into the tert-butyl ester under high concentration conditions at room temperature in the presence of 5 mol% DOPQ within 270 min while with the standard DCC/DMAP protocol only the anhydride of the carboxylic acid is formed. With this very mild method, it was possible to convert a variety of substrates into their tert-butyl- and benzyl esters, which are not accessible with any other method starting from the free carboxylic acid. In the case of chiral substrates no lose of stereochemical information was detected. Combination of high concentration conditions and new catalysts provide attractive reaction times of a few minutes instead of several hours with the Gooßen protocol.