With more effective ligands (152 and 153) beginning to emerge for KOtBu-catalysed
hydrogenation of benzophenone, investigations were made to identify the reaction
mechanism. The reaction solution from Figure 35 using ligand 153 was analysed by
mass spectroscopy after the reaction had taken place and both mono and fully
oxidised derivatives of the ligand as shown in Figure 36 were found to be present.
Figure 36. Ligand species identified in reaction solution by mass spectrometry.
The presence of oxidised ligand may be evidence of a transfer hydrogenation process
rather than interaction of the ketone with hydrogen gas. The ligands may transfer
RMM = 342.5 gmol-1 Found m/z 434.2 [M+H]+ RMM = 340.5 gmol-1 Found m/z = 430.5 [M+H]+ RMM = 338.4 gmol-1 Found m/z = 339.5 [M + H]+ [M+H]+
84 hydrogen from their terminal hydroxyl groups to benzophenone resulting in
oxidation of the ligand and reduction of benzophenone. The presence of the phenyl
groups adjacent to the terminal hydroxyl group may help this process with
delocalisation of the oxygen’s electron density into the aromatic ring weakening the O-H bond. Also the resulting carbonyl group in the ligand would provide increased
conjugation and hence stability making the oxidation process favourable. A proposed
mechanism for the transfer hydrogenation process is shown in Scheme 55.
Scheme 55. Proposed mechanism for the transfer of hydrogen from ligand 153 to benzophenone.
The mass spectrometry results, showing the presence of the oxidised derivatives of
the ligand, are not conclusive as ionisation and fragmentation processes occurring in
the mass spectrometer could also be the reason for the oxidised species being seen.
In order to obtain conclusive evidence for or against the hydrogen transfer process,
the hydrogenation of benzophenone with KOtBu and ligand 153 was carried out
under atmospheric nitrogen rather than pressurised hydrogen (Scheme 56). If
molecular hydrogen is not involved in the reaction, and it is indeed the ligands that
are transferring the hydrogen, conversion to benzhydrol should occur to a similar
extent as under pressurised hydrogen reported in Figure 35.
85 As shown in Scheme 56, the reaction did proceed under nitrogen and a similar
conversion to that seen in Figure 35 was obtained. This implies that molecular
hydrogen is not involved in the process and the ligands are transferring the hydrogen
to the benzophenone. Further evidence for the transfer hydrogenation process can be
seen when looking back to results obtained in Figure 35. Where the transfer
hydrogenation process from ligand to ketone is not possible, no conversion to
benzhydrol was achieved. For example with ligands 150 and 151, where the
hydroxyl component of the ligand is provided by a phenol, it is not possible to
oxidise the C-O bond and transfer hydrogen to the benzophenone, possibly due to
the formation of the potassium phenoxide salt of the ligand. Also with ligand 155
possessing no hydroxyl groups, no conversion to benzhydrol was achieved.
The hydrogen transfer process would be stoichiometric with respect to the ligand and
thus the reaction was therefore repeated with 20 and 100 mol% ligand. In order to
investigate the importance of the presence of a phenyl group adjacent to the terminal
hydroxy groups, bis-(2-hydroxyethyl)ethylenediamine (147) was used. To
investigate the importance of the tetradentate nature of the ligand, the reaction was
also carried out using 20 and 100 mol% ephedrine 158. The results are summarised
86
Table 17. Conversion to benzhydrol using 20 and 100 mol% ligand for transfer hydrogenation.
Entry Solvent Mol% KOtBu Mol% ligand Ligand Benzhydrol (%)a Time (hours) 1b 2-methyl- 2-butanol 20 20 2.1 116 2 2-methyl- 2-butanol 20 100 0.2 116 3c 2-methyl- 2-butanol 20 20 0.8 116 4 2-methyl- 2-butanol 20 100 2.4 116 a
Determined by GC analysis. b Ligand obtained from Aldrich. cEphedrine obtained from Aldrich.
The conversions obtained for Table 17, entry 1 with 20 mol% of the unsubstituted
ligand 147 are significantly lower under the absence of hydrogen than previously
seen for the same ligand (Table 15) suggesting that the absence of the phenyl groups
reduces the preference for the transfer hydrogenation process relative to reaction
with hydrogen gas. When the ligand loading was increased to 100 mol%, the
conversion to benzhydrol was significantly reduced. It is thought that this may be
due to the increased amount of ligand saturating the potassium, thereby preventing
co-ordination of the benzophenone and thus the hydrogenation process. Entries 3 and
4 of Table 17 investigate the importance of the tetradentate nature of the ligand. Use
87 suggesting tetradentate ligands are more active for the transfer hydrogenation
process, possibly exhibiting improved co-ordination to the metal centre.
Our aim in this work was to develop convenient conditions for highly active catalytic
APH of ketones using transition metal-free catalysts. The transfer hydrogenation
process found to be taking place is not deemed appropriate for further development
as a viable transition metal-free process for catalytic asymmetric ketone
hydrogenation. The process is not efficient both in terms of the synthesis of the
ligands and also because at best, half an equivalent of ligand relative to the substrate
would be required to achieve full conversion to the alcohol product. The ligands
were also found to offer no advantage to the reaction in terms of enantioselectivity.
Indeed, processes involving active non-precious metal catalysts for transfer
hydrogenation and asymmetric transfer hydrogenation such as the MSPV reduction43
are already prominent in the literature and thus further development of the KOtBu
system was not investigated.