The
reaction mechanism for this reaction and the related
Skraup synthesis is a matter of debate. A 2006 study proposes a fragmentation-recombination mechanism based on
carbon isotope scrambling experiments. In this study 4-isopropylaniline
1 is reacted with a mixture (50:50)of ordinary
pulegone and the 13C-enriched isomer
2 and the reaction mechanism is outlined in
scheme 2 with the labeled carbon identified with a red dot. The first step is a
nucleophilic conjugate addition of the
amine with the
enol to the amine ketone
3 in a
reversible reaction. This intermediate then fragments to the
imine 4a and the saturated
cyclohexanone 4b in a non-reversible reaction and both fragments recombine in a
condensation reaction to the
conjugated imine
5. In the next step
5 reacts with a second aniline molecule in a nucleophilic conjugate addition to imine
6 and subsequent
electrophilic addition and proton transfer to leads to
7.
elimination of one aniline molecule through
8 and rearomatization leads to final product
9. Because α-amino protons are not available in this model compound the reaction is not taken to the fully fledged quinoline. The fragmentation to
4a and
4b is key to this mechanism because it explains the isotope scrambling results. In the reaction only half the
pulegone reactant (
2) is labeled and on recombining a labeled imine fragment can react with another labeled ketone fragment or an unlabeled fragment and likewise a labeled ketone fragment can react with a labeled or unlabeled imine fragment. The resulting product distribution is confirmed by
mass spectrometry of the final product 9. ==See also==