Allgemeine und spezielle Beiträge zur nucleophilen Acyl-Transfer-Katalyse

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.