Two Simple and Highly Efficient Variants of the Griffith-Ley Oxidation of Alcohols

Article abstract of DOI:10.1002/cctc.202000413

The Griffith-Ley oxidation of alcohols to aldehydes and ketones is performed with either RuCl₃ ? (H₂O)_x or a highly stable, well-defined ruthenium catalyst and with cheap trimethylamine N-oxide (TMAO) as the oxygen source. The use of n-heptane as the solvent, which forms a second phase with TMAO and a part of the alcohol, allows the reactions to be performed with a minimum amount of catalyst. This results in high local concentrations and thus to very rapid conversions. Detailed quantum chemical calculations suggest, that the Griffith-Ley oxidation not necessarily requires high oxidation states of ruthenium but can also proceed with Ru^II/Ru^IV species.

Full text of DOI:10.1002/cctc.202000413

The European Society Journal for Catalysis
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Accepted Article
Title: Two simple and highly efficient variants of the Griffith-Ley
oxidation of alcohols
Authors: Pascal Weingart, Patrick Hütchen, Angelo Damone,
Maximilian Kohns, Hans Hasse, and Werner R. Thiel
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ChemCatChem
10.1002/cctc.202000413
FULL PAPER
Two simple and highly efficient variants of the Griffith-Ley
oxidation of alcohols
[a]
[a]
[b]
[b]
[b]
Pascal Weingart, Patrick Hütchen, Angelo Damone, Maximilian Kohns, Hans Hasse, Werner
[a]
R. Thiel*
[a]
Dipl.-Chem. P. Weingart, Dipl.-Chem. P. Hütchen, Prof. Dr. W. R. Thiel
Fachbereich Chemie
Technische Universität Kaiserslautern
Erwin-Schrödinger-Str. 54, 67663 Kaiserslautern, Germany
E-mail: thiel@chemie.uni-kl.de
[b]
Dr.-Ing. A. Damone, Jun.-Prof. Dr.-Ing. M. Kohns, Prof. Dr.-Ing. Hans Hasse
Lehrstuhl für Thermodynamik
Fachbereich Maschinenbau und Verfahrenstechnik
Technische Universität Kaiserslautern
Erwin-Schrödinger-Str. 44, 67663 Kaiserslautern, Germany
Supporting information for this article is given via a link at the end of the document.
Abstract: The Griffith-Ley oxidation of alcohols to aldehydes and
ketones is performed with either RuCl (H O) or a highly stable, well-
defined ruthenium catalyst and with cheap trimethylamine N-oxide
TMAO) as the oxygen source. The use of n-heptane as the solvent,
reactions stopped at yields between 40 and 70% with these
oxygen sources. Pyridine N-oxide and some of its derivatives
turned out to be inactive.
3
2
x
(
In their work Sharpless and co-workers pointed out that “The
mechanism of these oxidations probably involves formation of a
ruthenium alkoxide which undergoes β-elimination to produce the
carbonyl compound and a ruthenium hydride. The ruthenium
hydride (or its equivalent) could be oxidized by the amine-N-oxide
which forms a second phase with TMAO and a part of the alcohol,
allows the reactions to be performed with a minimum amount of
catalyst. This results in high local concentrations and thus to very
rapid conversions. Detailed quantum chemical calculations suggest,
that the Griffith-Ley oxidation not necessarily requires high oxidation
[
4a]
and then the cycle could be repeated.” According to this, the
reaction can be considered at least partially as a reversion of a
transfer hydrogenation of ketones or aldehydes. Bäckvall et al.
proved that a transfer dehydrogenation of alcohols is in principle
II IV
states of ruthenium but can also proceed with Ru /Ru species.
possible with acetone as the hydrogen acceptor and (PPh
[5]
3
)
3
RuCl
2
Introduction
or Shvo’s catalyst. In contrast to this, high reaction states were
[
postulated in the literature to drive the Griffith-Lay oxidation.
2,6]
Historically, stoichiometric quantities of hazardous chromium(VI)
or manganese(VII) compounds were used to oxidize alcohols to
In course of a study on the oxidation of alcohols from natural re-
sources, we were looking for catalyst systems giving optimum
yields and selectivities in the dehydrogenation of alcohols to
aldehydes and ketones in the presence of a reasonably priced
oxdizing agent. We therefore revived the protocol of Sharpless
and co-workers under these basic conditions. In addition, we
wanted to elucidate by means of quantum chemical calculations
whether the Sharpless concept of a mechanism based on ruthe-
nium species in low oxidation states is energetically possible.
Accordingly, the manuscript is structured in two sections, one
focusing on the experiments carried out to optimize catalyst and
reaction conditions and a second one which is devoted to DFT
calculations.
[
1]
ketones and aldehydes. This changed in 1987 when W. P.
Griffith and co-workers found that tetraalkylammonium perruthe-
nate(VII) in combination with N-methylmorpholine N-oxide con-
verts alcohols into the corresponding ketones and aldehydes in a
[
2]
highly selective manner. Since this reaction is rather tolerant to
functional groups and requires only low concentrations of the
catalyst, it has reached widespread applications in organic syn-
[3]
thesis.
However, the history of this reaction dates back to 1976, when
Sharpless and co-workers published a rarely cited short commun-
ication wherein they described the performance of a series of
ruthenium compounds and different N-oxides in the oxidation of
[4]
alcohols. In contrast to the 1987 report of Griffith, the authors
focused on ruthenium species in the oxidation states 0-IV. Some
of them were inactive such as (RuO
2
·(H
(PPh
showed rather good activities. The reactions were
2
O)
x
,
Ru(acac)
3
,
RuCl
RuCl
3
3
(NO)(PPh
3
)
2
) but others like RuCl
2
3
)
3
, Ru
3
(CO)12 and
·(H O)
2
x
performed in acetone or DMF at room temperature and gave
yields between 65 and 100% after a reaction time of 2 h with a
catalyst loading of 0.84 mol-% and two equiv. of N-methylmorpho-
line N-oxide. Only a few alcohols (cholesterol, 1-nonen-4-ol, β-3-
indolylethanol) turned out to be unreactive under the given
conditions. The authors also investigated the use of other N-
oxides than N-methylmorpholine N-oxide but stated that the
1
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ChemCatChem
10.1002/cctc.202000413
FULL PAPER
Results and Discussion
Catalysis
ation process with RuCl
3
·(H
2
O)
x
as the catalyst. Comparing ent-
ries 2 and 5 or entries 3 and 6 clearly proves this statement: The
yield of acetophenone is higher at the lower temperatures. A
further decrease of the reaction temperature to 40 °C (entry 8)
then leads to a slightly poorer yields. Table 1 makes clear, that
the deactivation process is rapid, since there is almost no im-
provement of the yield after 10 min of reaction time. However, the
oxidation process at lower temperatures must therefore be even
faster than the deactivation, otherwise high yields would not be
feasible.
Since RuCl
available, it was the catalyst of choice from the very beginning.
Sharpless and co-workers reported that RuCl (H O) was approx.
0% less active than RuCl (PPh and Ru (CO)12. However, the
costs for RuCl ·(H O) are by a factor of six lower than for tetra-
alkylammonium perruthenate(VII) and by factor of five lower than
for RuCl (PPh based on the ruthenium content. Ru (CO)12 has
almost the same price as RuCl ·(H O) but the later one is much
3 2 x
(H O) is by far the cheapest source of ruthenium
3
2
x
2
2
3
)
3
3
3
2
x
2
3
)
3
3
For the evaluation of the substrate scope, the conditions of entry
3
2
x
5
in Table 1 were applied. Samples were taken after 10 min of
simpler to handle. Concerning the cost of the N-oxide, pyridine N-
oxide is the cheapest. We therefore reinvestigated the application
of this N-oxide under the conditions of Sharpless and found low
reactivity as reported. In addition, other low-prized oxygen sour-
ces such as acetone (Oppenauer-type oxidation), dioxygen, hy-
drogenperoxide and TBHP (tert-butylhydroperoxide) gave no con-
reaction time. Scheme 1 summarizes the results.
Table 1. Evaluation of the reaction conditions for the oxidation of 1-
[a]
phenylethanol with RuCl (H
3
2
O)
x
as the catalyst.
3
[b]
version. Among the N-oxides with sp -hybridized nitrogen atoms,
yield [%] after t [min]
cat.
equiv.
temp.
[°C]
entry
trimethylamine N-oxide (TMAO) dihydrate is the cheapest relative
to the molecular mass. Highly volatile trimethylamine would be the
sole by-product, which can easily be recovered and in principle
be reoxidized to TMAO in processes larger than lab-scale exper-
iments.
[
mol-%]
TMAO
1
0
30
30
60
40
[c]
1
2
3
4
5
6
7
8
9
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
2
60
80
80
80
26
98
76
59
3
2
98
98
TMAO is well known for the in-situ activation of catalysts by oxid-
78
79
[
7]
ative decarbonylation of metal carbonyl complexes. However, it
has hardly been investigated as an alternative hydrogen acceptor
resp. oxygen donor in catalytic oxidation reactions so far. In 1990,
Maumy et al. published a copper mediated oxidation of benzylic
1.1
3
59
59
60
60
60
40
40
40
>99
95
64
97
84
57
>99
96
>99
96
[
8]
alcohols with TMAO as the oxygen source. It proceeds with
copper alcoholates that have to be preformed in-situ. Good yields
of the corresponding aldehydes and ketones are obtained in the
presence of four equivalents of TMAO. In 1997, Ley and co-wor-
kers reported the oxidation of alcohols with TMAO with 20 mol-%
of a polymer supported perruthenate reagent as a heterogeneous
2
1.1
3
65
67
>99
89
>99
90
2
[9]
catalyst. In the presence of molecular sieves and 1.0 equiv. of
TMAO they were able to convert 1-phenylethanol to acetophen-
one within 18 h at room temperature in 60% yield. Pearson and
co-workers published in 2005 the first iron catalyzed oxidation of
10
1.1
62
63
[
a] Reaction conditions: 1-phenylethanol (1 mmol), 1 mL of solvent, 100 µL
of tetradecane (internal standard); [b] yields determined by GC; [c] with
TMAO·(H O) instead of TMAO.
[
10]
alcohols with TMAO as the hydrogen acceptor. They reported
2
2
the oxidation of various allylic and benzylic alcohols by using 30
4
mol-% of (η -cyclohexadiene)Fe(CO)
3
as the catalyst with 3.0
equiv. of TMAO in benzene at room temperature. Substrate con-
versions varied between 87% and 98% after 10 h of reaction time.
In the year 2012, Woo and co-workers were the first to report a
gold catalyzed oxidative dehydrogenation of dibenzylamine using
[
11]
TMAO as the oxidant. By reacting 1 mmol of pure gold powder
and 0.066 mmol of TMAO with 0.012 mmol of Bn NH they could
reach 77% of the imine product within 24 h in CD CN at 60 °C.
With RuCl ·(H O) as the catalyst, 1-phenylethanol as the sub-
2
3
3
2
x
strate and TMAO as the oxygen source, a short series of experi-
ments was carried out to optimize the reaction conditions (Table
1). Among all solvents that were tested, DMF gave the best
results.
Entry 1 (Table 1) shows, that the presence of larger amounts of
water are detrimental for the performance of the process, since
2 2
the use of TMAO·(H O) distinctly reduces the yield of the product.
The dihydrate is much cheaper than pure TMAO, but there is no
problem to remove the water by azeotropic distillation with toluene
[
12]
or DMF. The most important information that can be drawn from
Table 1 is, that there must be a temperature dependent deactiv-
2
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ChemCatChem
10.1002/cctc.202000413
FULL PAPER
catalyst 1 in this second phase. I this is true, the catalyst is sur-
rounded by high local concentrations of the oxidizing agent and
the alcohol, which explains the very high conversions even with
catalyst loadings being as low as 0.1 mol-% (Scheme 1). At the
end of the reaction, the tiny droplets containing the main amount
of the catalyst still show the typical strawberry-red color of catalyst
1. Obviously aliphatic alcohols give poorer results with 1 as the
catalyst than aromatic ones. Here, the second polar phase is not
formed, since these substrates are well soluble in n-heptane. To
prove this theory, a small amount (200 µL) of DMF was added to
create the second polar phase. This leads to distinctly higher
yields of carbonyl compounds (cyclohexanone, 46; 2-hexanone,
47; octanal, 48%). Prolonging the reaction time to 30 min for the
aliphatic substrates does not further improve the outcome of the
reaction. Recovering the polar phase by decantation of the
heptane phase allows a reuse of the catalyst. After filling the vial
with another charge of n-heptane, internal standard, TMAO and
1-phenylethanol, still a conversion of about 50% could be
achieved. It has to be mentioned here, that some water is formed
during the first experiment, which is known to hamper complete
conversions. This was not removed from the polar phase.
DFT calculations
Scheme 1. Carbonyl products derived from alcohol oxidation. The yields were
To get a deeper insight in the mechanism, quantum chemical
calculations including a solvent model for DMF were carried out
with a model species A (Scheme 3) which is structurally closely
determined by GC and the reaction time was 10 min in all cases. Reaction
conditions: substrate (1 mmol), 0.5 mol-% of RuCl
Me NO (2 eq.), DMF (1 mL) or n-heptane (3 mL, yields in italics), 100 µL of
tetradecane (internal standard), 60 or 80 °C.
3 2 x
·(H O) or 0.1 mol-% of 1,
3
n
related to catalyst 1. We left the butyl groups and changed the
allylic side chains into methyl groups to facilitate the search for
energetic minima. Ethanol was taken as the model alcohol, since
the oxidation of primary aliphatic alcohols resulting in aldehyde
formation is harder to achieve than the oxidation of secondary
alcohols leading to ketones or primary benzylic alcohols. The
calculated barriers can therefore be considered as are an upper
bound for other substrates.
Performing the reaction in an alkane as the solvent instead of
DMF would simplify the product separation at the end of the
reaction. For this, we applied ruthenium complex 1 (Scheme 2),
which we recently developed for the transfer hydrogenation of
[
13]
ketones, aldehydes and imines. Compound 1 is highly active in
these conversions.
In order to simplify the entrance into the mechanistic discussion,
we have divided the presentation of our results in four parts that
are summarized in Scheme 3 in a shortened form. They will be
discussed below in more detail. The catalytic cycle of the alcohol
oxidation starts with the catalyst activation and ends up with the
catalyst regeneration. For the actual oxygen transfer, two alter-
native mechanistic routes, the oxo and the hydrido pathway, were
II
IV
II
found, both including a Ru → Ru → Ru sequence but differing
in their elemental steps. After the activation of catalyst A, which
ends with the chloridoethanolatoruthenium(II) intermediate E, the
oxo pathway follows the addition of TMAO and the formation of a
ruthenium(IV) oxo species. It is completed with the abstraction of
a β-hydrogen atom from the alcoholato ligand and the dissociation
of acetaldehyde. β-Hydrogen abstraction is in contrast the first
step in the hydrido pathway where it is followed by the generation
of a hydridooxoruthenium(IV) species. This pathway is completed
by a 1,2-hydrogen shift leading to the same hydroxochloridoruthe-
nium(II) species I as the oxo pathway. Regeneration of E pro-
ceeds via an OH/OEt exchange. The overall oxidation of ethanol
to acetaldehyde according to Scheme 3 was calculated to be
exothermic by ∆H = -38.61 kcal/mol and exergonic by ∆G = -53.42
kcal/mol. The four parts of the calculated mechanism shall in the
following be discussed in more detail.
Scheme 2. Molecular structure of catalyst 1.
Since Sharpless et al. postulated the ruthenium catalyzed oxid-
ation of alkoholes to ketones resp. aldehydes with N-oxides to be
[
4]
a reversion of the transfer hydrogenation, it seemed worth to
investigate compound 1 for the oxidation reaction, too. In addition,
there are no other oxidizable ligands in 1 than the phosphine
ligand, which speaks for a structural motif that should be rather
stable under the reaction conditions.
According to the butyl and allyl substituents of its ligand, it is well
soluble in almost all organic solvents, only in non-polar hydro-
carbons it is sparingly soluble. Since TMAO is only poorly soluble
in alkanes too, the ternary mixture of TMAO, n-heptane and the
substrate separates in a two-phase system with a tiny amount of
a polar phase, having the red color of catalyst 1. According to the
solubilities in polar/non-polar solvents of the components taking
part in the catalysis it seems reasonable to assume that most of
the TMAO and a part of the alcohol are concentrated together with
3
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ChemCatChem
10.1002/cctc.202000413
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Supporting Information). Due to the low difference in energy
between Ba and Bb, we calculated both isomers Ca and Cb that
are formed by addition of ethanol. Isomer Ca with the ethanol
ligand in the trans-position to the pyridine ring is slightly lower in
energy than Cb having the ethanol ligand in the cis-position to
pyridine. An alternative sequence wherein ethanol is deproton-
ated prior to the addition to the ruthenium(II) site might be possible,
too. However, we believe, that according to the low acidity of
ethanol and the rather low basicity of the bases trimethylamine
and trimethylamine N-oxide, the ethanolate concentration in the
solution is not high enough for this pathway. By coordination to
the ruthenium(II) site, the acidity of ethanol will increase by
several orders of magnitude. Elimination of HCl from the interme-
diate ethanol adduct was calculated with one molecule of trime-
thylamine as the base.
In the real catalytic system, the base requested for the elimination
3
of HCl can either be TMAO or NMe . Their concentrations will
change during the course of the reaction. We therefore have
investigated the interaction between the weaker base TMAO and
a primary alcohol (here n-propanol) in DMF solutions with mole-
cular dynamics simulations (for details see the Supporting Inform-
ation). The analysis of the local concentrations of TMAO around
the alcohol from the simulation results reveals a high affinity
between the oxygen atom of TMAO and the proton of the alcohol
OH group, even at low concentrations of TMAO. These results
support both hypotheses: TMAO can act as a base in the early
3
state of the transformation (low NMe concentration) and an
excess of TMAO is beneficial.
The reaction enthalpy ∆∆H for the formation of the hydrogen
bound trimethylamine adducts Da and Db is close to 0.0 kcal/mol,
while the final 16VE chloridoethanolatoruthenium(II) complex Ea
is comparable in its ∆∆G value with the dichlorido complex A. Ea
has a trans-orientation of the ethanolato and the chlorido ligand.
However, there are two other possible isomers having the ethan-
olato and the chlorido ligand in cis-orientation to each other, one
with the ethanolato ligand trans to the pyridine ring (Eb), the other
with the chlorido ligand trans to pyridine (not shown in Figure 1).
The latter was not included in the calculations, since this geometry
prevents the transformation of the ethanolato ligand in both of the
following steps (see below). Calculations showed that Eb is by
more than 11 kcal/mol higher in energy than Ea. Calculation of
the equilibrium constant for the reaction Ea ⇌ Eb by taking the
Scheme 3. Summary of the calculated reaction mechanism including catalyst
activation and regeneration and two alternative pathways for the oxygen
transfer (oxo and hydrido pathway). The labelling of the species (A, E, …) refers
to the discussion below. To allow a straightforward overview on the mechanism,
a series of intermediates, other stereoisomers and all calculated transition
states are omitted. Bottom: Reaction equation summing up the oxidation of
ethanol to acetaldehyde with TMAO as the oxygen source.
6
∆G values of the two isomers gives K = 6.37·10 . In a first sum-
mary, the energy requested for the formation of the chloridoethan-
olatoruthenium(II) complex Ea from the dichloridotriphenylphos-
phine)ruthenium(II) complex A is low.
Catalyst activation. For binding any substrate, a free coordin-
ation site has to be generated at the ruthenium centre. Therefore,
the activation of A starts with the dissociation of triphenylphos-
phine, which is endothermic by +8.37 but exergonic by -11.21
kcal/mol (Figure 1). These values are calculated without the pre-
sumably occurring, exothermic oxidation of triphenylphosphine in
the presence of trimethylamine N-oxide. In the intermediate 16VE
ruthenium(II) complex Ba the two chlorido ligands end up in trans-
geometry. An isomer Bb wherein the two chlorido ligands are
found in cis-orientation to each other (one chlorido ligand in trans-
position to the pyridine donor) was calculated to be another local
minimum and is approx. 7 kcal higher in energy than Ba (see the
4
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Figure 1. Catalyst activation: calculated molecular structures and energies; all energies in kcal/mol; full lines connect isomer Ba and the following intermediates,
dashed lines connect isomer Bb and the following intermediates; ∆∆H values are given in violet, ∆∆G values in blue; enlarged drawings of the molecular
structures are depicted in the Supporting Information.
Oxo pathway. The early formation of an oxoruthenium(IV) inter-
mediate is the central step of the oxo pathway. It starts from Ea
resp. Eb (Figure 2). The addition of TMAO to these intermediates
is as expected endergonic (∆G) due to the bond formation but
almost thermoneutral with respect to ∆H. Isomer Fb having the
TMAO ligand in the trans-position to the chlorido ligand is slightly
more stable than the isomer Fa with the TMAO ligand in the trans-
position to the pyridine site. This can be explained by the fact that
chloride is a poorer σ-donor than pyridine. The following two
transition states TSFa→Ga and TSFb→Gb leading to the formation of
the oxoruthenium(IV) intermediates Ga and Gb are by about 15-
first one, which therefore is the compound, that the catalyst regen-
eration sequence starts with (see below) The stereoisomer with
the chlorido ligand in trans-position to the pyridine site was not
calculated, since the addition of ethanol to this stereoisomer (see
catalyst regeneration below) would result in a geometry, where
the intramolecular transfer of a proton from the ethanol ligand to
the hydroxido ligand is not possible.
Hydrido pathway. In the hydrido pathway, a hydridoruthenium(II)
complex is generated prior to the oxidation of the ruthenium site
(Figure 3). It starts with a β-hydride elimination from the ethanol-
ato ligand in Ea (see Figure 1) leading to the hydridoruthenium(II)
complex Ja bearing a π-coordinated acetaldehyde moiety in the
‡
‡
1
7 (∆G ) resp. 17-19 kcal/mol (∆H ) higher in energy than their
precursors Fa and Fb. Each of these values is not too high to fit
well to the rapid catalytic conversions we observe at 80 °C. The
two resulting isomeric 18VE chloridoethanolatooxoruthenium(IV)
products Ga and Gb are considerably lower in energy than
complex Ea, the sequence starts with. The next step, the
intermolecular transfer of a hydride from the ethanolato to the oxo
ligand via the two cyclic, five-membered transition states TSGa→Ha
and TSGb→Hb should also proceed rapidly, since the according
barriers for both isomers are very low. Two isomeric chlorido-
hydroxidoruthenium(II) complexes Ha and Hb each containing a
σ-bound acetaldehyde ligand are formed in a strongly exothermal
and exergonic reaction. The according isomers having π-bound
acetaldehyde ligands were not calculated. Due to the results
shown in the hydrido pathway (see below), we expect them to be
slightly lower in energy than the σ-bound isomers. Dissociation of
acetaldehyde results in the formation of a chloridohydroxido-
ruthenium(II) complex again existing as three stereoisomers. The
stereoisomer Ia with the chlorido and the hydroxido ligand in
trans-orientation to each other and the stereoisomer Ib with the
hydroxido ligand in trans-position to the pyridine site were include-
ed in the calculations. The latter is much higher in energy than the
‡
trans-position to the chlorido ligand. The ∆∆G value for the
according transition state TSEa→Ja was calculated to be 11.46
kcal/mol higher than ∆∆G of the starting compound Ea. An
alternative pathway starting from isomer Eb with the ethanolato
ligand in the trans-position to the pyridine site (not shown in Figure
3) is energetically not feasible. This process would lead to a
hydridoruthenium(II) complex with a π-coordinated acetaldehyde
moiety in trans-position to the pyridine site and the hydrido ligand
in trans-position to the chlorido ligand. By scanning the reaction
coordinate of this mode of hydride transfer, we found a local
minimum for a complex with a strong β-agostic Ru-H interaction
that is connected to the starting geometry with a local transition
state. However, a further approach of the β-hydrogen atom to the
ruthenium(II) center does not lead to the desired formation of a π-
coordinated acetaldehyde ligand. Probably this route is not
possible due to steric reasons that prevent the acetaldehyde to
coordinate in the position between the two N-methyl groups. The
reaction therefore proceeds via complex Ka, wherein the acetal-
dehyde is now σ-coordinated to the ruthenium(II) site. ∆∆H for Ja
→ Ka is slightly positive while ∆∆G is slightly negative, which
matches the larger degree of freedom of the σ-coordinated
5
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Figure 2. Oxo pathway: calculated molecular structures and energies; all energies in kcal/mol; full lines connect isomer Ea and the following intermediates,
dashed lines connect isomer Eb and the following intermediates; ∆∆H values are given in violet, ∆∆G values in blue; enlarged drawings of the molecular
structures are depicted in the Supporting Information.
compared to the π-coordinated acetaldehyde ligand. Dissociation
of acetaldehyde generates chloridohydridoruthenium(II) comple-
xes, which can appear in three isomeric structures: a) La, wherein
the hydrido ligand is coordinated in the trans-position to the pyrid-
ine donor, b) Lb, wherein the chlorido ligand is found in the trans-
position to the pyridine donor, and c) Lc with the hydrido and the
chlorido ligand being in trans-orientation to each other. Isomer Lc
is not a stable minimum on the energy hypersurface and relaxes
either to La or to Lb. However, the energy that is required to bring
the chlorido and the hydrido ligand in trans-orientation to each
other is only about 5 kcal/mol higher in energy than Lb. This result
was obtained by scanning the according coordinate (angle Cl-Ru-
H). Lb is energetically largely favored over La (∆∆H: 21.32, ∆∆G:
enthalpy than Ma-Mc. The chloridohydridooxoruthenium(II) inter-
mediates Na-Nc differ largely in their energies. According to the
strong trans-influences of both, the hydrido and the oxo ligand,
intermediate Nb is energetically unfavorable since these two
ligands are oriented in trans-position to each other. In addition,
this is the only orientation of the oxo and hydrido ligand that does
not allow a direct insertion of the oxo ligand into the Ru-H bond,
which will occur in the following step. However, instead of being a
“dead end” of the reaction sequence, Nb might be converted into
Na or Nc by dissociation of the chlorido ligand and its re-
coordination in an appropriate orientation. The energetics of this
process was not calculated. The barriers related to the two
transition states TSNa→Ia and TSNc→Ia are rather low. Interestingly,
the oxo ligand moves to the hydrido ligand and not vice versa.
Species Ia is identical to the final compound of the Ru=O pathway
as described above. For a second isomer Ib see the discussion
above (oxo pathway).
21.72 kcal/mol), which can be explained by the high σ-donor
strength of the hydrido ligand, preferring no strong σ-donor in the
trans-position. These two isomers directly provide a free site for
the coordination of TMAO, which leads to the six-coordinated
ruthenium(II) complexes Ma and Mb. This addition is strongly exo-
thermal for La → Ma and endergonic for Lb → Mb which is due
to the trans-influence of the hydrido ligand. However, we also
included the third isomer Mc (TMAO trans to pyridine) into our
calculations since the orientation of the ligands in Mb does not
give access to a hydrido ligand in cis-orientation to an oxo ligand.
Catalyst regeneration. Both, the Ru=O and the Ru-H pathway
end up with the chloridohydroxidoruthenium(II) complexes Ia and
Ib. In the final part of the reaction sequence, the catalyst regener-
ation (Figure 4), the hydroxido ligand has to be exchanged against
an ethanolato ligand leading back to the central chloridoethanol-
atoruthenium(II) intermediates Ea and Eb from which the Ru=O
and the Ru-H pathway started. Since the energetic differences
between the isomers from the a- and the b-series are small, only
3
Loss of NMe produces the corresponding chloridohydridooxoru-
thenium(IV) species Na-Nc. The three according transition states
‡
TSMa→Na-TSMc→Nc are by ∆∆H = 34.6-29.11 kcal/mol higher in
6
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Figure 3. Hydrido pathway: calculated molecular structures and energies; all energies in kcal/mol; full lines connect isomer Ea and the following intermediates,
dashed and dotted lines connect other structurally related isomers; ∆∆H values are given in violet, ∆∆G values in blue; enlarged drawings of the molecular
structures are depicted in the Supporting Information.
the a-series was calculated here. Addition of ethanol to the 16VE
complex Ia gives the 18 VE intermediate Oa, in a slightly
exothermal but endergonic reaction. The hydrogen bond formed
between the ethanol OH group and the oxygen atom of the
hydroxo ligand paves the way for the generation of an ethanolato
and a water ligand which proceeds via the low laying transition
state TSOa->Pa. The energetic data given for the resulting aqua-
chloridoethanolatoruthenium(II) complex Pa are slightly higher
than for TSOa->Pa, which is contradictory at a first glance. However,
the computational optimization of the structures is done on the E
hypersurface and an imaginary frequency prove that TSOa->Pa is
really a transition state. Dissociation of water in an almost thermo-
neutral reaction regenerates Ea.
complexes Ma and Ga (for a graphical explanation see the Sup-
porting Information). No transition states could be located for
these reactions by using the QST2 or QST3 keyword in the
GAUSSIAN optimization. Additional attempts to localize the
transition state by performing scans along the critical reaction
coordinates also failed. The energies of these calculations raised
far above those of the highest transition states found for the two
pathways discussed above. This can be explained by the charges
of the hydrogen atom that is transferred and the oxygen atom at
TMAO that has to accept this hydrogen atom. Both are negatively
polarized, they are nucleophiles. Or in other words: the oxygen
atom only gains sufficient electrophilicity (oxenoid character)
3
when it has lost the NMe moiety and is coordinated as an oxido
ligand to ruthenium(IV).
At the moment, there is no experimental evidence for one of the
species discussed above, despite the equilibrium of phosphine
dissociation, the sequence starts with. However, oxidoruthe-
nium(IV) species have been postulated as intermediates in water
On the basis of the DFT calculations, it is not possible to decide
whether the hydrido or the oxo pathway is the route that leads to
‡
the product. The barrier of the oxo pathway is at ∆∆G = 30.26
‡
and ∆∆H = 23.15 kcal/mol for TSFb→Gb, the highest barrier of the
[14]
‡
‡
oxidation processes.
hydrido pathway is at ∆∆G = 20.37 and ∆∆H = 29.11 kcal/mol
for TSMa→Na with respect to compound A. So in terms of the free
energy the hydrido pathway should be the preferred route, in
terms of enthalpy it’s the oxo pathway. However, the low barriers
of activation found here make clear, that high oxidation state
ruthenium species may not necessarily be required for this type
of oxidation. In classical transfer hydrogenation reactions, M-H
intermediates are formed. Therefore, at least a part of the hydride
In addition to the calculations discussed above, we also investig-
ated four alternatives for a direct transfer of a hydrogen atom to
TMAO, which avoid the oxidation to ruthenium(IV): On one side
the hydrogen abstraction from the ethanolato ligand of the chlor-
idoethanolatoruthenium(II) complex Ea or from the chloridohy-
dridoruthenium(II) complex Lc by uncoordinated TMAO. On the
other side the direct transfer of a hydrogen atom to TMAO in
7
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10.1002/cctc.202000413
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Figure 4. Catalyst regeneration pathway: calculated molecular structures and energies; all energies in kcal/mol; ∆∆H values are given in violet, ∆∆G values in
blue; enlarged drawings of the molecular structures are depicted in the Supporting Information.
route fits to the proposal of Sharpless et al., that the ruthenium
catalysed oxidation of alcohols with N-oxides as the oxygen
source can be considered as something like a reversion of a
Experimental Section
hydrogenation reaction.
General information: Purification and drying of solvents was carried out
according to standard methods. Synthesis and catalysis were performed
under an atmosphere of nitrogen although the ruthenium catalysts are not
Conclusion
sensitive towards oxygen and moisture. References and NMR data
belonging to the synthesis of compound 1 are deposited in the Supporting
We here have reported two easily applicable and highly efficient
Information.
ways to use the ruthenium catalysed Griffith-Ley oxidation for the
generation of a wide variety of aldehydes and ketones with very
Catalytic reactions. All catalytic experiments were performed in crimp top
low catalyst loadings at short reaction times. The use of a non-
vials purchased from VWR International GmbH with a total volume of 20
polar solvent that dissolves the alcohol and the product but not
the catalyst and the oxygen source, which then form a second
polar phase together with a part of the alcohol can be taken as a
paradigm for other (oxidation) reactions. In addition, quantum
chemical calculations showed that at least for catalyst 1, there are
alternative pathways for the Griffith-Ley oxidation that do not
require ruthenium in high oxidation states but involve ruthenium
species in the oxidation states +II and +IV. Based on these
calculations we can propose two possible mechanisms
proceeding with ruthenium species in the oxidation states +II and
mL. The catalyst and TMAO were weighed and filled in the vials, a magnet
stirrer was added and the vials were sealed with ptfe septa followed by
three cycles of 15 min of evacuation and purging with dry nitrogen. Solvent
and internal standard were added by use of syringes. The vials were
placed in an aluminum heating block with normed boreholes preheated to
the reaction temperature. Then the substrate was added by use of a
syringe. Samples were taken with single use syringes and cannula (Braun
GmbH) and were analyzed with a Clarus 580 GC equipped with a FID-
detector or a Varian 3900 GC-MS (2100T). GC columns: FS-OV-1701-CB-
0.25 (30 m, d = 0.25 mm, CS Chromatographie Service GmbH).
+
IV, that differ in the order of the oxygen and hydrogen transfer
Hazard note: Leaving the solvent and carrying out the experiments with
the alcohol as the only liquid component led to explosions of the vials!
Even when an excess of alcohol was used and the vial is not closed, the
mixtures started to burn heavily after some seconds of initialization.
steps. Oxidoruthenium(IV) intermediates take part in this process,
which are reduced back to ruthenium(II) by hydride transfer. The
direct transfer of a hydride to TMAO, either coordinated or un-
coordinated is energetically unfavourable. We believe that our
results fit well to the role that is addressed to oxoruthenium(IV)
species in the water oxidation and maybe will enhance the interest
in deeper investigations on other oxidation processes with this
element.
Quantum chemical calculations: The calculations on the mechanism of
the oxidation of alcohols to ketones and aldehydes were carried out with
[
15 ]
the program Gaussian16
using the B3LYP gradient corrected
exchange-correlation functional [16] in combination with the 6-31+G* basis
set for C, H, N, O, Cl [17] obtained from the EMSL/PNNL Basis Set
8
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Exchange site.[18] For ruthenium, the according Stuttgart RSC 1997 ECP
basis set was applied.[19] The influence of the solvent DMF was included
in the calculations by performing PCM calculations using the CPCM
polarizable conductor calculation model.[20] Temperature was set to 358.15
Acknowledgements
The authors gratefully acknowledge financial support by the EU-
INTERREG project BIOVAL.
1
K (85 °C). Full geometry optimizations were carried out in C symmetry
using analytical gradient techniques and the resulting structures were
confirmed to be true minima by diagonalization of the analytical Hessian
Matrix. The thermodynamic corrections were obtained from the frequency
calculations. In most cases scans along the internal reaction coordinate
were carried out to locate the transition state. The starting geometry of
compound 1 for the calculations was taken from a solid-state structure.
Keywords: alcohol • oxidation • ruthenium • mechanism • DFT
calculation
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Entry for the Table of Contents
High yields and selectivities are achieved by using low-valent ruthenium(II) catalysts for the oxidation of alcohols to carbonyl
compounds. DFT calculations give an insight into a possible mechanism.
1
0
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