Potassium formate as a small molecule switch: Controlling oxidation-reduction behaviour in a two-step sequence

Article abstract of DOI:10.1039/c3cc00126a

A one-pot reaction sequence is described in which the addition of one compound allowed switching between simultaneously occurring oxidation and reduction reactions.

Full text of DOI:10.1039/c3cc00126a

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Potassium formate as a small molecule switch:
controlling oxidation–reduction behaviour in a
two-step sequence†
Cite this: Chem. Commun., 2013,
49, 3143
Received 6th January 2013,
Accepted 21st February 2013
Jorgen S. Willemsen, Jan C. M. van Hest and Floris P. J. T. Rutjes*
DOI: 10.1039/c3cc00126a
www.rsc.org/chemcomm
A one-pot reaction sequence is described in which the addition of
one compound allowed switching between simultaneously occur-
ring oxidation and reduction reactions.
In the past decade, multi-step one-pot procedures have attracted
increasing interest of the chemical community.1 Combining multiple
transformations in one reaction vessel renders sequences more cost-
effective as fewer work-up and purification steps are required. Multi-
step one-pot procedures are therefore considered to contribute to a
more sustainable way of producing chemicals. A major challenge in
the design of multi-step sequences is the compatibility of the involved
substrates, intermediates and reagents or catalysts.
Scheme 1 One-pot oxidation–reduction sequence.
A particular challenge is seen in reactions in which opposing or acts on the intermediate product leading to both the starting
counteracting reagents or catalysts (acid–base, oxidator–reductor) material and the final product. We have shown that by introducing
are used simultaneously.2 Incompatibilities between opposing a specific reagent, the reaction can be efficiently steered into one
catalysts have been resolved by immobilization on insoluble direction by ‘switching-off’ the oxidation and simultaneously
polymers3 or encapsulation in sol–gels.4 Such behaviour is advanta- ‘switching on’ the reduction, with all catalysts present from the
geously used in for example dynamic kinetic resolutions and related start of the reaction. This is the first example of a reagent-mediated
procedures5 in which secondary alcohols are racemised via the switch between two counteracting catalytic systems, which can now
corresponding ketones through a redox equilibrium induced by a be efficiently performed in one pot in the desired sense.
single catalyst. A remarkable case has been described by Kroutil
The two-step sequence involves the aqueous enzymatic oxida-
et al., in which racemisation and reduction were performed stepwise tion of p-methoxybenzyl alcohol (1) to anisaldehyde (2), which in
using a single alcohol dehydrogenase (ADH). Switching between the presence of valinamide (3) is in equilibrium with iminium
non-selective oxidation and enantioselective reduction occurred by intermediate 4 (Scheme 1). For the enzymatic oxidation laccase
removal of the co-substrate acetone and addition of i-propanol.6
was selected because of its outstanding oxidative performance
In a different strategy, enantioselectivity has been achieved via on benzylic systems and its broad substrate selectivity.8 The
chemical oxidation by a metal-catalyst, and simultaneous reduction iminium ion 4 reacts further in an iridium-catalyzed reductive
by ADH in the same reaction vessel.7 As shown in this approach, amination with formate as the hydride source to yield amine 5.
performing multistep reactions in a consecutive manner does not However, since the latter product is readily oxidized by laccase,
per se require the adaptation of the catalysts or reactants used.
and benzaldehyde is also prone to reduction by the iridium
In this communication, we describe a model one-pot reaction catalyst, this process does not lead to any product formation
system with counteracting catalysts, in which the oxidant acts on when carried out in a single vessel. The major challenge there-
the starting compound and the final product, while the reductant fore was to limit the undesired reverse reactions.
In order to tackle the problem, we initially analysed the partial
reactions involved in more detail. Laccase belongs to the class of
oxidoreductases and is capable of performing oxidations at the
expense of O2 with water as the only byproduct. Because of its
Institute for Molecules and Materials, Radboud University Nijmegen,
Heyendaalseweg 135, 6525 AJ NIjmegen, The Netherlands.
E-mail: F.Rutjes@science.ru.nl; Fax: +31 243653393; Tel: +31 243653202
stability and non-toxic waste, laccase is also widely applied in
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc00126a
industry.9 Laccase readily oxidised anisyl alcohol (1) to aldehyde 2
c
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Table 2 Compatibility of the reductive amination with the reactants of the oxidationa
Entry Additive
Conversion after 8 hb (%)
1
2
3
4
—
100
100
64
TEMPO (0.3 equiv.)
Laccase (25.0 U)
Laccase (25 U) + TEMPO (0.3 equiv.)
Scheme 2 Laccase-mediated oxidation of anisyl alcohol (1).
3
a
b
Conditions: 5 equiv. 2, 10 equiv. HCO2K, 0.05 equiv. 6. Conversions
in oxygenated citric acid buffer at pH 5 in 92% yield (Scheme 2). We
selected an activated alcohol10 to keep the reactions short. In
addition, 0.3 equivalents of TEMPO were used as an electron carrier,
which appeared crucial for the oxidation to proceed.10,11
determined by RP-HPLC.
tolerable negative influence on the yield. The work of Arends et al.
revealed that the rhodium analogue of complex 6 shows a significant
decrease in activity in the presence of various enzymes due to
complexation of the metal center.14 In our hands the activity loss
was limited, because a higher complex/enzyme ratio was used. In the
presence of both laccase and TEMPO (entry 4), an initial yield of 8%
was observed after 4 h, which gradually decreased to provide only
traces of product 5 after 7 h, indicating that the product had reacted
with another compound.
Fabbrini and coworkers showed that benzylic amines can be
oxidized to iminium ions by the oxidized TEMPO species, resulting in
the corresponding aldehydes in aqueous media.11b Likewise, the
alkylated valinamide 5 may be rapidly oxidized via the iminium
intermediate to aldehyde 2 and valinamide 3 in the presence of laccase
and TEMPO. A competition experiment with alcohol 1 and amine 5
confirmed that the amine is more easily oxidised at pH 5.0 to aldehyde
2 than anisyl alcohol (1) (Scheme 4). At the time amine 5 was fully
oxidised to aldehyde 2, 63% of anisyl alcohol (1) was still left.
Competitive experiments at lower pH also gave a higher rate for
the amine oxidation (pH 4.5–3.5) or resulted in laccase inactivation
(pH 3.0–2.5).‡
The latter results underline that it is impossible to conduct both
transformations simultaneously, and that in a one-pot system
the products revert to the starting materials. We then chose to
adjust the procedure, prompted by the observed inhibition of laccase
by HCO2K (Table 1, entry 4). To test whether laccase could be
inactivated and oxidation of amine 5 would be suppressed, the
reductive amination was performed in the presence of laccase,
TEMPO and 25 equivalents of HCO2K. Indeed, 88% of the desired
product was formed, showing that HCO2K could be used as a switch
between the oxidation and the reduction.
The reducing agent in our sequence was iridium complex 6
(Scheme 3), which has been successfully applied in aqueous reduc-
tive amination reactions.12 The catalyst is based on related iridium
complexes which catalyse transfer hydrogenation reactions as has
been documented by Fukuzumi et al.13 The reductive amination of 2
with (S)-valinamide (3) to give the stable product 5 proceeded in 92%
yield under similar conditions in buffer at pH 5 at 40 1C (Scheme 3).
Thus, iridium complex 6 was capable of reducing the intermediate
iminium ion 4 in the presence of HCO2K as the hydride source. An
excess of anisaldehyde (2) was used, because it was partially reduced
to anisyl alcohol (1) in a competing reaction.
Next, the compatibility of the oxidation conditions with each of
the reactants of the reductive amination was examined (Table 1).
The presence of either valinamide (3, entry 2) or iridium complex
6 (entry 3) was tolerated. Contrarily, a 64 mM concentration of
HCO2K (1 equiv.) almost completely inhibited the enzymatic
activity, while 32 mM HCO2K (0.5 equiv.) resulted in only a small
decrease in yield. To investigate whether this inhibition is rever-
sible, we removed HCO2K by filtration over a spin-filter, after
which the recovered laccase was tested in the oxidation of alcohol 1.
Formation of aldehyde 2 was indeed observed, showing that laccase
is only reversibly inactivated by HCO2K.
The same approach was used for the reductive amination
(Table 2), which revealed that the reaction was not hampered by
TEMPO (entry 2). The presence of laccase (entry 3) did have a
After establishing the possibility to switch between the two
different reactions, we set out to optimize the one-pot oxidation–
reduction process (Scheme 5). Reaction in the absence of laccase
(Table 3, entry 1) did not lead to any product formation. Without
Scheme 3 Aqueous reductive amination of anisaldehyde (2).
Table 1 Compatibility of the enzymatic oxidation with the reactants of the
reductive aminationa
Scheme 4 Competitive oxidation of amine 5 and alcohol 1.
Entry
Additive
Conversion after 8 hb (%)
1
2
3
4
5
—
92
91
96
2
Valinamide (3) (0.66 equiv.)
Iridium complex 6 (5 mol%)
HCO2K (64 mM)
HCO2K (32 mM)
84
a
b
Conditions: 25 U laccase, 0.3 equiv. TEMPO. Conversions deter-
mined by RP-HPLC.
Scheme 5 One-pot two-step sequence with opposing catalysts.
c
3144 Chem. Commun., 2013, 49, 3143--3145
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Table 3 One-pot two-step sequence optimization
Entry Laccase (U) Ir-cat (mol%) HCO2K (equiv.) Time for oxidation (h) Alcohol conversiona,b (equiv.) Total reaction time (h) Conversiona (%)
1
2
3
4
5
6
7
8
0.0
25.0
25.0
25.0
5
5
5
5
5
5
1
0.5
0.2
1
1
1
10
0.5
100
25
10
10
24
12.5
12.5
13
16.5
22
23
17
23
41
0.00
5.00
4.46
4.61
4.44
4.32
3.67
3.78
4.50
3.78
3.51
2.36
10
24
20
20
20
65
50
71
136
88
65
41
0
0
18
29
2.50
32
2.50
2.50
2.50
2.50
2.50
2.50
2.50
2 Â 2.5
64
10
80 (40)c
70
10
10
9
61
10
11d
12e
3 Â 2.5
81
10
91 (50)c
78 (62)c
10
41
a
b
c
Conversions determined by RP-HPLC. With respect to valinamide 3. Isolated yields are given in brackets. Isolated yields were lower due to
d
e
losses during the extraction procedure. Two times more concentrated. Four times more concentrated.
inhibition of laccase – in the presence of small amounts of HCO2K – reductive amination with valinamide (4). The reaction sequence was
no desired product was formed either (entry 2). If 100 equivalents of performed subsequently in which it was crucial to inhibit the laccase
HCO2K were added, laccase was successfully inhibited (entry 3) albeit with an excess of HCO2K. At the same time, the reductive amination
that only 18% of the desired compound was obtained. The low yield started. The reaction conditions were fine-tuned and led to a
was the result of a second, fast competing reduction, the aldehyde maximum conversion of 91% and a maximum isolated yield of
being reduced to alcohol 2. The iminium ion is formed in an 62%. This is the first example in which a compound acts as a switch
unfavourable equilibrium reaction in water, and a fast reduction between two opposing reactions in a one-pot procedure.
mainly results in aldehyde reduction. Decreasing the reduction rate
should afford more product 5 because more time is available to set
the equilibrium. Indeed, when 25 equivalents of HCO2K were used
(entry 4), the yields significantly increased. A further enhancement
was achieved by using 10 equivalents of HCO2K (entry 5). In this case,
a ten-fold lower amount of laccase was used as otherwise the enzyme
would not be inhibited efficiently and oxidation of compound 5
Notes and references
‡ Details of the competitive oxidation under various pH values can be
found in the ESI.†
1 (a) A. Bruggink, R. Schoevaart and T. Kieboom, Org. Process Res.
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2 J. H. Schrittwieser, J. Sattler, V. Resch, F. G. Mutti and W. Kroutil,
would occur. Remarkably, the oxidation of the alcohol was only
slightly slower in entry 5 compared to that in entries 2–4. When
HCO2K was added in two portions of 2.5 equivalents a yield of 64%
was observed. To summarize, by using the appropriate amount of the
‘switching’ compound, the yield was increased from traces to 64%.
We continued the optimisation by varying the amount of catalyst
6 (entries 7–9). The presence of 0.5 or 1 mol% catalyst gave high
yields of 70 and 80%, respectively, while 0.2 mol% catalyst led to a
disagreeable reaction time of 136 h and a lower yield. In entry 10,
optimised amounts of both HCO2K (2.5 equiv.) and iridium complex
6 (1 mol%) were used. However, a comparable yield was obtained in
the example in which HCO2K was added in one batch (entry 7).
A last strategy involved using more concentrated reactions,
thereby increasing the concentration of iminium ion 4. Indeed, a
high yield of 91% (entry 11) was obtained if the reaction was
performed twice as concentrated. Contrarily, 78% (entry 12) was
found with a four times more concentrated reaction mixture. In
the latter case, the enzymatic oxidation appeared to be slow and
far from completion, explaining the lower yield. Probably the high
concentration of reagents hampered the laccase activity.
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Preliminary experiments to apply this switch concept to
substituted benzylic alcohols indicated that in each of these cases
extensive experimentation was required, which is considered to be
beyond the scope of this communication.
A successful two-step reaction sequence with counteracting
catalysts in water was performed. An enzymatic oxidation was
combined with a reducing metal catalyst in one-pot. First, anisyl
alcohol (2) was oxidised to anisaldehyde (3), which reacted in a
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 3143--3145 3145