Communication
gastri, supplement their formaldehyde metabolism by
a second pathway using dismutases that are independent of
external sacrificial redox partners (Scheme 1, top right).[26–28] On
one side, these formalin disproportionating enzymes exhibit
a considerable structural and functional resemblance of gluta-
thione-independent zinc-containing dehydrogenases, with a se-
quence similarity greater 70% (Supplementary Figure 1 in the
Supporting Information).[29] As a result of a firmly immobilized
nicotinamide-dinucleotide cofactor inside the active site,[30,31]
however, initial dehydrogenation of the conjugated formalin is
accompanied by a reduction of a second formaldehyde
moiety. Hence, the deviated catalytic behavior provides both
methanol and formate from two molecules of formaldehyde
and water. Considering the analogy of NADH as biological hy-
drogen carrier and our lately described bioinspired process fea-
turing an acceptorless H2 liberation,[25] we envisioned that
modification of the organometallic species and/or the reaction
environment of our original protocol will lead to a novel ho-
mogeneously catalyzed formaldehyde-to-methanol converting
system, (Scheme 1, bottom right) yet unprecedented in the
context of abiotic C1-valorization pathways.[32,33]
Scheme 2. Proposed routes for the catalytic formaldehyde disproportiona-
tion based on H2 coupled dehydrogenation/hydrogenation pathways or the
dismutase-like catalysis by intermediary hydride species. [a] H2/HCO2H can
potentially act as reducing agents for another equivalent of formaldehyde.
Table 4) and, thus, cannot be considered as a productive path-
way. Under the assumption that free H2 is involved as redox
mediator, two hydrogen-coupled routes are feasible. As metha-
nediol has been shown to readily dehydrogenate to yield CO2
and H2, it was considered that in a closed system the direct re-
duction of CO2 to methanol might be occurring (Scheme 2,
left). However, neither precharging of the reaction vessel with
carbon dioxide nor the removal of superfluous CO2 by Ca(OH)2
resulted in measurable effects on the methanol yields (Supple-
mentary Table 5). This suggests that the direct CO2 reduction
might not be the primary mechanism for the methanol forma-
tion. Additionally, the dismutation of 13C-labelled paraformalde-
hyde was conducted under elevated pressure of 12CO2 to get
further insight into the potential role of carbon dioxide. While
the yields were not affected by the level of CO2 in the pressur-
Recently, we reported on the possibility to incorporate
a ruthenium-based formaldehyde dehydrogenase mimic into
an artificial metabolism, which nicely cooperates with metha-
nol-activating enzymes to provide a room-temperature path-
way for the MeOH to H2 conversion and showcases the poten-
tial of chemoenzymatics in the small molecule activation.[34]
However, in our crimp-top setup for the in situ gas phase anal-
ysis, the apparent turnover numbers of the H2 liberation in
aqueous phosphate buffer lagged behind the uncoupled
system, which can in parts be attributed to infavourable
metal–protein interactions, or might be related to the reversi-
bility of the process by the formalin reduction under elevated
H2 pressure. This finding served as a starting point for the redi-
rection of the catalytic profile towards a formaldehyde dismu-
tase mimic that is disclosed in this communication.
1
ized atmosphere (Supplementary Table 6), the H NMR spectro-
scopical analysis of the methanol obtained from the 13CH2O
disproportionation under 15 bar 12CO2 provided no significant
evidence of the 12CH3OH formation (Supplementary Figure 2),
suggesting that carbon dioxide was not incorporated from the
To our delight, already slight modifications of our parent
[Ru(p-cymene)Cl2]2 catalysed H2 release protocol, namely
a closed-vessel system and increased reaction temperatures,
resulted in a functional dismutase mechanism. Further optimi-
zations, with regard to the nature and stoichiometry of the ad-
ditives, led to an efficient catalytic disproportionation (Supple-
mentary Table 1–3). While initial attempts provided methanol
from paraformaldehyde in a 1:1 stoichiometry, formalin decom-
position with 1 mol% of [Ru(p-cymene)Cl2]2 at 808C in phos-
phate buffer (0.4 m, pH 6) proceeded with increased MeOH
yields (75%) as a result of the formate dehydrogenation, which
allows for the reduction of a second formaldehyde equiva-
lent.[35] For the primary disproportionation, various mechanisms
can be assumed (Scheme 2). Hence, studies aiming to eluci-
date the actual catalytic pathway have been conducted.
overlaying atmosphere by
(Scheme 3).
a
CO2 reduction pathway
In an alternative route, the methanol formation could result
from the direct reduction of formaldehyde, either by another
hydrogen-coupled process exploiting free H2 as redox media-
tor (Scheme 2, centre), or by the dismutase-like dehydrogena-
tive generation of reducing ruthenium-hydride species from
the tetrahedral formalin (Scheme 2, right). Examination of the
reaction gas phase by pressure monitoring and headspace GC-
Hydrolysis of paraformaldehyde would, in any of our propos-
als, lead to free formaldehyde in equilibrium with its hydrated
form methanediol. Initial investigations of the pH dependency
of the reaction quickly revealed that the ruthenium-independ-
ent Cannizzaro-type disproportionation appears only as a back-
ground reaction at pH values greater than 9.5 (Supplementary
Scheme 3. 13C-Labelling experiment to exclude the possibility of carbon di-
oxide as formal disproportionation intermediate.
Chem. Eur. J. 2016, 22, 11568 – 11573
11569
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