One-pot synthesis of aldoximes from alkenes: Via Rh-catalysed hydroformylation in an aqueous solvent system

Article abstract of DOI:10.1039/d0gc03141k

Aldoxime synthesis directly starting from alkenes was successfully achieved through the combination of hydroformylation and subsequent condensation of the aldehyde intermediate with aqueous hydroxylamine in a one-pot process. The metal complex Rh(acac)(CO)2 and the water-soluble ligand sulfoxantphos were used as the catalyst system, providing high regioselectivities in the initial hydroformylation. A mixture of water and 1-butanol was used as an environmentally benign solvent system, ensuring sufficient contact of the aqueous catalyst phase and the organic substrate phase. The reaction conditions were systematically optimised by Design of Experiments (DoE) using 1-octene as a model substrate. A yield of 85% of the desired linear, terminal aldoxime ((E/Z)-nonanal oxime) at 95% regioselectivity was achieved. Other terminal alkenes were also converted successfully under the optimised conditions to the corresponding linear aldoximes, including renewable substrates. Differences of the reaction rate have been investigated by recording the gas consumption, whereby turnover frequencies (TOFs) >2000 h-1 were observed for 4-vinylcyclohexene and styrene, respectively. The high potential of aldoximes as platform intermediates was shown by their subsequent transformation into the corresponding linear nitriles using aldoxime dehydratases as biocatalysts. The overall reaction sequence thus allows for a straightforward synthesis of linear nitriles from alkenes with water being the only by-product, which formally represents an anti-Markovnikov hydrocyanation of readily available 1-alkenes.

Full text of DOI:10.1039/d0gc03141k

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ARTICLE
One-pot synthesis of aldoximes from alkenes via Rh-catalysed
hydroformylation in an aqueous solvent system
M. Terhorsta, C. Plassb, A. Hinzmannb, A. Guntermannb, T. Jolmesa, J. Röslera, D. Pankea, H. Grögerb,
Received 00th January 20xx,
Accepted 00th January 20xx
D. Vogta, A. J. Vorholtc, T. Seidensticker*a
DOI: 10.1039/x0xx00000x
Aldoxime synthesis directly starting from alkenes was successfully achieved through the combination of hydroformylation
and subsequent condensation of the aldehyde intermediate with aqueous hydroxylamine in a one-pot process. The metal
complex Rh(acac)(CO)2 and the water-soluble ligand sulfoxantphos were used as the catalyst system, providing high
regioselectivities in the initial hydroformylation. A mixture of water and 1-butanol was used as an environmentally benign
solvent system, ensuring sufficient contact of the aqueous catalyst phase and the organic substrate phase. The reaction
conditions were systematically optimised by Design of Experiments (DoE) using 1-octene as a model substrate. A yield of
85 % of the desired linear, terminal aldoxime ((E/Z)-nonanal oxime) at 95 % regioselectivity was achieved. Other terminal
alkenes were also converted successfully under the optimised conditions to the corresponding linear aldoximes, including
renewable substrates. Differences of the reaction rate have been investigated by recording the gas consumption, whereby
turnover frequencies (TOFs) > 2000 h-1 were observed for 4-vinylcyclohexene and styrene, respectively. The high potential
of aldoximes as platform intermediates was shown by their subsequent transformation into the corresponding linear nitriles
using aldoxime dehydratases as biocatalysts. The overall reaction sequence thus allows for a straightforward synthesis of
linear nitriles from alkenes with water being the only by-product, which formally represents an anti-Markovnikov
hydrocyanation of readily available 1-alkenes.
challenge, since, in both reactions, the selective synthesis of
primary or secondary amines is complicated by multiple
substitutions at the nitrogen centre (Figure 1).
Introduction
The direct formation of C-N bonds starting from non-
functionalised base chemicals is still a challenging task. The
involved reactions are often lacking selectivity or by- as well as
side-products are formed whereby unnecessary waste is
generated. In this regard, homogeneous catalysis can help to
reduce energy costs and waste formation, yet it remains
challenging to produce primary aliphatic amines as value
products.1,2 One way of increasing selectivity is the initial
synthesis of oxygen-containing platform chemicals from base
chemicals and the subsequent substitution of oxygen in C-O
bonds with nitrogen, as performed for instance in catalytic
reactions, like alcohol amination or reductive amination.1 Both
types of reaction are based on the condensation of carbonyl
compounds with either ammonia, primary or secondary
amines. The reactive site is thus predetermined, resulting in
excellent regioselectivity. However, chemoselectivity remains a
A potent, but yet underrepresented class of intermediates on
the way towards nitrogen-containing platform chemicals are
oximes. The C-N bond formation is performed employing a
simple condensation reaction between hydroxylamine and a
carbonyl compound. With this, high regioselectivity is
maintained as well as multiple substitutions at the nitrogen
centre are avoided, potentially resulting in excellent
chemoselectivity. Moreover, oximes are incredibly versatile in
their follow-up chemistry, since, for instance, amines or amides
are accessible by hydrogenation3 and rearrangement,4
respectively (Figure 1). Recently, some of us have shown the
very high potential of aldoximes as precursors for the
corresponding nitriles via biocatalysis using aldoxime
dehydratases with unprecedented selectivities under very mild
conditions.5
Aldoximes are typically produced by reacting hydroxylamine (or
a corresponding precursor) with the corresponding aldehyde.4,6
Consequently, non-functionalised base chemicals initially have
to be converted to aldehydes, which are then typically isolated
and purified prior to the subsequent reaction, such as aldoxime
formation. Hydroformylation is the state-of-the-art technology
for atom-efficient synthesis of aldehydes by reacting readily
available alkenes with syngas (CO/H2) to aldehydes employing
homogeneous Rh- or Co-catalysts.7
a. TU Dortmund University, Department for Biochemical and Chemical Engineering,
Laboratory of Industrial Chemistry, Emil-Figge-Straße 66, 44227 Dortmund,
Germany.
b. Bielefeld University, Faculty of Chemistry, Chair of Industrial Organic Chemistry
and Biotechnology, Universitätsstraße 25, 33615 Bielefeld, Germany.
c. MPI for Chemical Energy Conversion, Department of Molecular Catalysis, Group
Multiphase Catalysis, Stiftstrasse 34-36, 45470 Mülheim an der Ruhr, Germany.
*Dr. Thomas Seidensticker, mail: thomas.seidensticker@tu-dortmund.de,
phone: + 49 231 7552310, web: www.tc.bci.tu-dortmund.de
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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one-pot approach. This might be because, in conventional
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DOI: 10.1039/D0GC03141K
organic syntheses, hydroxylamine is applied as a salt, e. g.
chloride or hydroxylammonium sulfate, and thus requires
activation by bases.4,6 The latter may harm the catalytic
hydroformylation and lead to undesired consecutive reactions
of the intermediate aldehyde. In addition, the application of the
hydrochloride is disadvantageous in terms of sustainability and
atom-efficiency, since stoichiometric amounts of salt are
formed as waste, which may also cause issues with corrosion of
the autoclave. Aqueous hydroxylamine solution, which is also
commercially available, thus seems superior for producing
(ald)oximes in a more sustainable and atom efficient manner.
As we have gained experience in both, aqueous biphasic
hydroformylation15,16 and in combining two or more catalytic
transformations in a tandem (catalytic) system,17 we now strive
for the connection of hydroformylation and oxime formation in
a one-pot approach (Scheme 1) using aqueous hydroxylamine.
To achieve sufficient mixing and to ensure contact of the
organic and the aqueous phase, the use of short-chain alcohols
proved to be effective.15,18,19 To provide high regioselectivity
towards the commonly more valuable linear product together
with effective immobilisation of the catalyst in the aqueous
phase, sulfoxantphos appears to be a viable option as a ligand.
The immobilisation possibly enables spontaneous separation of
the two phases after the reaction and, thus, simple isolation of
the aldoxime seems feasible. 1-Octene was chosen as the model
substrate for this one-pot reaction (Scheme 1), as it was used in
a similar investigation of our groups for the synthesis of
nonanitrile and 2-methyl octanenitrile.20
Figure
1:
Comparison
of
reductive
amination,
alcohol
amination,
hydroaminomethylation and the objective of this work concerning consecutive
reactions.
A compelling approach to intensify (catalytic) syntheses and
thereby increase sustainability is the merger of synthetic steps,
elegantly enabled by in situ formation of one of the reactive
intermediates.8 The combination of several reaction steps
without purifications of intermediate products has the potential
to drastically reduce the number of unit operations and thereby
decrease energy consumption and waste generation, while at
the same time feedstock utilisation is increased. Homogeneous
transition metal-catalysed hydroformylation has proven its
ability in many examples to be linked to numerous follow-up
reactions, including the formation of C-N-bonds.9 Most
importantly, this is due to the rich follow-up chemistry of
aldehydes and the ability of homogeneous Rh-complexes to
catalyse many different reactions, including hydrogenations, for
instance.
Results and Discussion
Initial investigations
We first checked whether both reaction steps could be carried
out independently from each other to achieve the general
objective of combining two reaction steps in a one-pot reaction.
Thus, we studied, if the condensation of the aldehyde and
hydroxylamine in the green solvent system21 water / 1-butanol
is practicable. Therefore, we applied 1.5 eq aqueous
hydroxylamine solution, based on previous investigations on
oxime formation,3,22 and 1 eq of nonanal. Within 20 min, the
oxime was obtained in nearly quantitative yield, confirming that
even in the presence of water condensation takes place almost
instantaneously (cf. SI).
By combining hydroformylation with subsequent aldoxime
formation, C-N bond formation from unfunctionalised alkenes
in
a one-pot fashion would be possible, similar to a
trifluoromethyloximation.10 The, to the presented work, related
hydroaminomethylation (HAM), which is the tandem-catalytic
combination of hydroformylation with reductive amination in
the presence of respective amines, also forms C-N linkages from
alkenes in a single preparative step.11 In comparison to HAM,
hydroformylation/aldoxime formation may open broader
follow-up chemistry. Nitriles, primary amines and amides are
readily accessible from aldoximes through dehydration,5,12
hydrogenation3,13
and
Beckmann-rearrangement,14
respectively. Furthermore, HAM with ammonia and primary
amines typically produces mixtures of primary, secondary and
tertiary amines and neither amides nor nitriles can be
synthesised by HAM.
Scheme 1: One-pot approach for the synthesis of aldoximes from alkenes by combining
hydroformylation with the condensation of the intermediate aldehyde with
hydroxylamine and possible consecutive reactions of the aldoxime.
To the best of our knowledge, hydroformylation has, however,
never been combined with subsequent aldoxime formation in a
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Next, hydroformylation of 1-octene in water/1-butanol solvent
was performed as an individual reaction (without the addition
of NH2OH (aq.)). Towards this end, reaction conditions
developed for the hydroformylation of methyl 10-undecenoate
were applied.19 Within 3 h, a yield of 80 % of the linear nonanal
was achieved. This proofs that both reactions, hydroformylation
and aldoxime formation, can be carried out independently in
the chosen green solvent mixture.
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DOI: 10.1039/D0GC03141K
It was expected that besides the typical side-products of
hydroformylation (hydrogenated substrate, isomerised
substrate, aldol condensates), also products from consecutive
reactions of the oxime group (nitriles, amides, amines) would
be observed. Besides, hydroxylamine might unfavourably affect
the regioselectivity in the hydroformylation step. Despite all
these concerns, the initial one-pot reaction already showed a
promising yield of the linear oxime of 20 % after 2 h by simply
adding 1.5 eq. NH2OH (aq.) (for further information, see SI). This
yield is significantly lower than the yield in the hydroformylation
reaction without addition of hydroxylamine carried out before
(cf. SI, 80 %). However, it is still very promising, taking into
account that the conditions were not yet optimised for the
intended one-pot reaction. All side-products observed in this
initial one-pot reaction were analysed and quantified and
revealed the overall reaction network (Scheme 2).
Besides the linear and branched hydroformylation products
nonanal (2a) and 2-methyl octanal (4a), respectively, all typical
side-products of the hydroformylation of 1-octene (1a), i.e.
octene isomers (7a), octane (6a) and aldol products (8a), were
observed. It is noteworthy that the hydroxylamine shows no
influence on the regioselectivity of carbonylation, even under
these non-optimised conditions. The ratio of linear to branched
products (aldoximes 3a+5a and aldehydes 2a+4a) is 95:5,
comparable to the ratio reported in the literature for
sulfoxantphos in hydroformylation reactions.23 Additionally,
small amounts of products from consecutive reactions of
nonanal oxime (3a) were identified, namely nonanitrile (10a)
and nonanamide (11a).
Scheme 2: Reaction network of the one-pot hydroformylation/aldoxime formation of
1-octene (1a) for nonanal oxime (3a) formation including all observed by-products.
All reactions were carried out for 1.5 h, allowing us to identify
significant changes in the reaction rate and selectivity at
medium conversion. After careful evaluation of the results (cf.
SI), it became apparent that low temperatures favour the
chemoselectivity of the reaction by reducing the isomerisation.
High pressures affect the regioselectivity as well as the yield of
the reaction to a reasonable extent. A possible explanation
could be the increased availability of the gases in the liquid
phase.
To validate the results of the optimisation, we performed a
reaction on a small scale (25 mL) over 4 h under these
conditions. We observed a 95 % conversion of 1-octene (1a)
with a yield of the desired nonanal oxime (3a) of 82 %.
Regioselectivity towards the linear products was 95 %, and
chemoselectivity (yield of oximes 3a+5a) for the one-pot
hydroformylation/aldoxime formation was 88 %. Side
reactions, like aldol condensation (Y8a = 3 %), hydrogenation
(Y6a = 2 %) or isomerisation (Y7a = 7 %) of 1-octene, as well as
consecutive reactions of the oxime (Y9a = <1 %, Y10a = <1 %)
were effectively suppressed or reduced. We assumed, based on
the initial results, that the hydroformylation is the rate-
determining step of the overall reaction. The reaction was
scaled-up to a 350 mL autoclave, equipped with a gas-impeller
stirrer and baffles to validate this hypothesis, (cf. SI).
Optimisation via Design of Experiments (DoE)
The complexity of the reaction network shows that optimisation
is necessary to guide the reaction towards the desired linear
nonanal oxime 3a. Hence, we carried out a Design of
Experiments (DoE) to determine critical parameters, influencing
the rate and selectivity of the reaction (Table 1).
Table 1: Parameter ranges for DoE optimisation of the one-pot
hydroformylation/aldoxime formation of 1-octene and optimised parameters for high
yield and regioselectivities.
lowest
value
90
20
1/2
middle
value
120
40
1/1
highest
value
150
60
2/1
optimised
value
100
We herein focused on parameters known to cause significant
changes in the catalytic performance of the hydroformylation
step,24 since both regioselectivity and rate of the desired
reaction sequence depend on this step.
Furthermore, the amount of hydroxylamine used was varied
because it remains to be seen whether hydroxylamine has a
significant influence on the catalysis in terms of activity and
selectivity. The mass of water and 1-butanol (both 1.8 g) and the
amount of 1-octene (6.7 mmol) was kept constant throughout
this investigation. A central composite face-centred (CCF)
model was chosen, resulting in 68 reactions, that were each
carried out twice (centre point 5 times), giving a total count of
141 reactions.
parameter
temperature [°C]
pressure [bar]
60
1/1
CO / H2 ratio [-]
hydroxylamine /
1-octene ratio [-]
rhodium/sulfoxant-
phos ratio [-]
rhodium loading
(based on 1-octene)
[mol%]
1
2
3
2.5
1/1
1/5
1/10
1/5
0.05
0.275
0.5
0.5
Constant parameters: n1-octene = 6.7 mmol, mwater = 1.8 g, m1-butanol = 1.8 g, t = 1.5 h.
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organic product phase. Thus, separation of the catalyst from the
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aldoxime for straightforward isolation is hampered.
The chemoselectivity of the Rh/sulfoxantphos system for
terminal double bonds was used to selectively convert only the
terminal double bond of 4-vinylcyclohexene (1g) to the linear
oxime in 82 % yield on a small scale (cf. SI). Styrene (1h) also
gave high yields of the aldoximes in small scale, with the
expected regioselectivity of linear and iso-oximes (34 % linear,
53 % iso) that was earlier observed for the parent ligand
xantphos.25 The iso-oxime 5h is the main product, but the
selectivities indicate that sulfoxantphos can shift the
regioselectivity towards the linear hydroformylation product.
The selectivity towards the linear product 3h was improved
Figure 2: Reaction profile of the one-pot hydroformylation/aldoxime formation of from 4 % with TPP26 to 34 % with sulfoxantphos.
1-octene (1a) for nonanal oxime (3a) formation after optimization via DoE. Conditions:
Rh(acac)(CO)2 (0.5 mol%), sulfoxantphos (2.5 mol%), 134 mmol 1-octene, 335 mmol
hydroxylamine (2.5 eq, as 50 w% aqueous solution), cRh,aq = 0.015 mol/L, cligand,aq = 0.074
Further extending the scope, substrates with oxygen-containing
functional groups were tested. Difunctional products as
potential polymer precursors are thus accessible. Depending on
the consecutive chemistry of the oxime group, even different
classes of polymers seem possible. In this regard, functionalised
molecules based on renewables, like the terpenol
dihydromyrcenol (1i) and the oleochemical methyl 10-
undecenoate (1k) are of interest since they are already
produced on a large scale.27 Dihydromyrcenol, containing a
tertiary alcohol function, yielded 68 % of the linear oxime,
which is comparable to the results achieved with 1-decene. The
reaction well tolerates the tertiary alcohol function. For methyl
10-undecenoate, a yield of 41 % to the linear oxime was
observed. Herein, consecutive reactions of the oxime group to
the corresponding nitrile in 34 % yield and the amide in 12 %
yield were observed, resulting in a cumulated yield of 87 %,
concerning the hydroformylation step. Hence, the carboxylic
acid ester group is well tolerated; however, apparently favours
the formation of consecutive products. Eugenol (1j) can be used
as pharmaceutical active compound28 and modification with
nitrogen-containing functional groups may improve its
effectiveness. Surprisingly, a yield of the linear oxime of only
15 % was obtained. Again, consecutive reactions to the
corresponding nitrile and amide were observed in a yield of
41 % and 27 %, respectively. The combined hydroformylation
yield (3j + 5j + 9j + 10j) is, as with the other functionalised
substrates, still high at 83 %.
mol/L, T = 100 °C, p = 60 bar, Vtotal = 110 mL. aconversion/yield determined via GC-FID
using n-decane as internal standard.
The reaction profile (Figure 2) reveals that the condensation
takes place immediately after the aldehyde is formed since no
aldehyde intermediates were detectable. Aldol condensates
(8a) and nonanamide (10a) were only formed in traces (<0.5%).
After 3 h reaction time, no significant changes in the yields of
the products occur. The conversion at this point is at 95% with
a yield of the linear nonanal oxime 3a of 87%. Excellent
chemoselectivity towards the desired one-pot reaction of 95%
was achieved. Consequently, a scale-up of the reaction is
possible without losses in selectivity or reaction rate. It is
noteworthy that the baffles and gas-impeller stirrer used did
not positively affect the rate of the reaction.
Small scale substrate variation
By application of other 1-alkenes of different chain lengths
(1-hexene (1b), 1-decene (1c) and 1-dodecene (1d)) under the
optimised reaction conditions in small scale (cf. SI), the yields
decrease with increasing chain length. This fact was expected,
considering that the reaction rates depend on the solubility of
the substrate in the polar aqueous phase. Internal alkenes such
as cyclooctene (1e) and 4-octene (1f) were not converted with
reasonable rates as expected for the Rh/sulfoxantphos catalyst
system. The substitution of sulfoxantphos with TPPTS
(Tri(sodium-3-sulfonatophenyl)phosphane) might enhance the
hydroformylation of internal alkenes.15 The application of
TPPTS, however, increases the polarity of the aqueous phase
(large excess of the monodentate, trisulfonated ligand to be
applied for reasonable regioselectivity and to avoid Rh-losses
into the organic phase). Neither cyclooctene (1e) nor 4-octene
(1f) were converted successfully (cf. SI). Presumably, this is
caused by the reduced solubility of the alkene in the aqueous
phase due to its increased polarity.
Consequently, functional groups are well tolerated by
hydroformylation. However, the reaction conditions developed
for 1-octene do not necessarily provide the best results for all
applied substrates. Nevertheless, the increased formation of
nitrile or amide shows high potential to integrate a subsequent
reaction step into the designed reaction sequence.
Large scale substrate variation (monitoring of gas consumption)
Reaction profiles were recorded by monitoring the gas
consumption in a 350 mL autoclave to get a more detailed
insight into the different reactivities and to minimise the
possibility for consecutive reactions (see SI for details on the
experimental setup). As soon as no significant gas consumption
was detected, the reaction was stopped to minimise aldoxime
conversion to nitriles and amides. After the reaction, the
organic phase was separated from the aqueous catalyst phase
On the contrary, the non-sulfonated TPP (triphenyl phosphane)
catalyses the one-pot hydroformylation/aldoxime formation
effectively (cf. SI), since the reaction takes place in the organic
phase without mass transfer or solubility limitations. However,
after the reaction, the catalyst and the product are both in the
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Figure 3: Conversion of selected substrates in the combined hydroformylation/aldoxime formation one-pot-reaction, evaluated by gas consumption curves. Conditions: Rh(acac)(CO)2
(0.5 mol%), sulfoxantphos (2.5 mol%), 134 mmol substrate, 335 mmol hydroxylamine (2.5 eq, as 50 w% aqueous solution), cRh,aq = 0.015 mol/L, cligand,aq = 0.074 mol/L, T = 100 °C,
pconst. = 60 bar, Vtotal = 105 - 120 mL. [a]combined yield of all hydroformylations products measured via GC-FID using decane as internal standard after reaction normalized to the
measured gas consumption.
by decantation and analysed via GC-FID. The gas consumption turnover frequency (TOF) at 20 % conversion towards
in the gas reservoir was then normalised to the summarised hydroformylation products was determined (TOF20) to compare
yield of all hydroformylation products (2+3+4+5+8+9+10). The the reaction rate of the various substrates. In Figure 3, the gas
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consumption curves of 1-octene (1a), 1-hexene (1b), 1-decene already showed the benefit of combining transition metal
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DOI: 10.1039/D0GC03141K
(1c), 1-dodecene (1d), 4-vinylcyclohexene (1g), styrene (1h), catalysis and biocatalysis for various processes. Hence, we
dihydromyrcenol (1i), eugenol (1j) and methyl-10-undecenoate wanted to demonstrate in a conclusive investigation that the
(1k) are shown. As expected, the reaction rate decreases with generated aldoximes can be converted into the corresponding
increasing chain lengths of the different 1-alkenes. The nitriles by utilisation of enzymes as biocatalysts.
maximum TOF20 was observed for 1-hexene (1518 h-1), while for Therefore, selected aldoximes were synthesised using
1-dodecene TOF20 was only half as high (855 h-1). The time to previously described reaction conditions for the one-pot
reach 90 % yield of hydroformylation products is 1 h for hydroformylation/aldoxime formation. After the reaction, the
1-hexene and 1-octene, whereas 1-decene and 1-dodecene organic product phase was easily separated from the aqueous
require reaction times above 2 h and 3 h, respectively. The yield catalyst phase containing the excess of NH2OH by decantation.
of the linear oxime exceeds 80 % only for 1-octene. This finding After evaporation of 1-butanol and column chromatography of
is a result of the optimisation by DoE, since conditions were the residue, we dehydrated the aldoximes in the presence of an
optimised only for this specific substrate. Hence, the reaction aldoxime dehydratase, following the same procedure applied in
conditions are not in the optimal range for other substrates and a previous publication of our joint research, in which the
consecutive reactions of the oxime group, hydrogenation and formation of nonanitrile and 2-methyloctanenitrile was
isomerisation are more likely to happen. Longer reaction time focussed upon (Figure 4).20
and lower reaction rates in case of 1-decene and 1-dodecene All terminal oximes derived from 1-alkenes were effectively
also contribute to this, since it increases the probability of transformed into the corresponding linear nitriles. The oxime
consecutive reactions and side-reactions. We now assume that derived from eugenol could not be converted, whereas the
the consecutive and side reactions take place simultaneously to oxime generated from dihydromyrcenol was successfully
the hydroformylation/aldoxime formation. Another factor in converted, and a yield of the nitrile of 83 % was observed.
support of this assumption is that side products were observed Remarkably, the nitriles can be produced under conditions
to a much smaller extend for 4-vinylcyclohexene (1f) and optimised for nonanal oxime in very short reaction time. In
styrene (1g) as substrates (Figure 3, middle curves). The TOF20 general, when utilising enzymes as biocatalysts, the activity is
exceeds 2000 h-1 in both cases, and the reaction time required highly dependent on the 3-dimensional structure of the
to reach 90 % yield of hydroformylation products is <1 h.
substrate. Hence, structures similar to the already known
The consumption curves for dihydromyrcenol (1h) and eugenol aliphatic terminal oximes show the best activities. Literature
(1i) differ from the previously obtained results. At first, a high values indicate that many of the substrates can be converted
conversion rate towards the hydroformylation products is quantitatively by choosing longer reaction times.20,32,33
observed, changing into an almost linear progression after 1 h.
A further flattening of the consumption curves after 2.5 h was
observed in both cases. The TOF20 for dihydromyrcenol
(1179 h-1) is slightly higher than the TOF20 for 1-decene
(1041 h-1). The reaction rate for the conversion of eugenol is the
highest of all three oxygen functionalised substrates, which may
be attributed to the comparatively good water solubility
(2.46 g Laq-1)29. Methyl 10-undecenoate on the other hand (1j) is
an oleochemical and thus not well miscible with water. Hence,
the TOF20 observed (727 h-1) is comparatively low. Since all
three reactions were conducted over a relatively long time, the
simultaneously happening, consecutive reactions of the
aldoxime group occur to a much greater extent. Control of the
selectivity towards a single product (oxime, nitrile or amide)
bears enormous potential that will be unravelled in ongoing
research.
Application of oximes in biocatalytic nitrile synthesis
Aromatic, as well as aliphatic nitriles, already have a broad
range of chemical and industrial application areas.30 The
selective synthesis of linear nitriles through simple dehydration
of aldoximes has substantial advantages considering
sustainability aspects compared to conventional methods, like
hydrocyanation (poor regioselectivities, toxic substrate) or their
synthesis starting from carboxylic acids and ammonia (high
temperatures and pressures needed). Recently, the sustainable,
selective and energy-efficient nitrile synthesis using oxime-
dehydratases gained considerable attention.31,32,33 Some of us
Figure 4: Conversion of selected aldoximes into nitriles using oxime dehydratases (Oxds).
Conditions: KPi buffer 50 mM, pH = 7, 33 mg mL-1 whole cell suspension (BWW, bio wet
weight), i-PrOH (10% (V/V)), substrate concentration 10 mM, 30 °C, 15 min, extraction
,
with EtOAc, yield determined via GC-FID, [a] literature: >99 %, t = 1 h[13] [b] >99 % at
50 mM, t = 3 h, [c] no quantitative measurement, best enzyme selected by GC area
[d] literature: >99 %, 5 mM, t = 3 h32 [e] literature-known, OxdFG, 200 mM, t = 2 h33
,
.
6 | J. Name., 2012, 00, 1-3
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Figure 5: Anti-Markovnikov hydrocyanation of 1-octene through one-pot hydroformylation/aldoxime formation and subsequent biocatalytic dehydration.
We also tried higher substrate loading of 100 mM and did not reaction steps (two of them in a one-pot process) in 85 % overall
observe inhibition of the enzymes (for more detailed yield and 95 % regioselectivity in only 2 h, with water as the only
information, see SI). We are convinced that this additional by-product.
investigation underlines the enormous potential of oxime
chemistry.
Thus, the combination of homogeneous transition metal
Conflicts of interest
There are no conflicts to declare.
catalysis, biocatalysis and the combination of two reactions
within a one-pot process, running in a green solvent system,
Acknowledgements
allows linear nitriles to be generated in a sustainable way Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) -
directly from terminal alkenes. For instance, 1-octene can be TRR 63 "Integrierte chemische Prozesse in flüssigen
transformed to nonanitrile in 85% overall yield (Figure 5), Mehrphasensystemen" (Teilprojekt A11)
–
56091768.
whereby nonanal oxime was isolated as intermediate.
Funded by the Deutsche
German Research Foundation)
Chemical Processes in Liquid
(subprojects A11, D3) - 56091768. We thankfully acknowledge
Umicore AG & Co. KG for donation of the rhodium precursors.
The authors thank Paulo Wohlfahrt and Aoi Itakura for the
synthesis of substrates.
Forschungsgemeinschaft
(DFG,
-
TRR 63 "Integrated
Multiphase
Systems”
Conclusions
For the first time, the effective combination of
hydroformylation and aldoxime formation in a one-pot reaction
was achieved, yielding aldoximes directly from alkenes in a
single preparative step. An excessive salt formation has been
bypassed by application of aqueous hydroxylamine. The
utilisation of sulfoxantphos as the ligand was found to be
purposeful, as it allows the selective synthesis of linear products
and immobilises the catalyst in an aqueous phase. A solvent
system, composed of the green solvents water and 1-butanol,
was key to success, as it enables sufficient contact of the
aqueous catalyst phase and organic substrate phase. Using 1-
octene as the model substrate, conditions were successfully
optimised via Design of Experiments (DoE), yielding >85 % of the
desired, linear oxime. The reaction conditions were successfully
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