Carbon monoxide and hydrogen (syngas) as a C1-building block for selective catalytic methylation

Article abstract of DOI:10.1039/d0sc05404f

A catalytic reaction using syngas (CO/H₂) as feedstock for the selective β-methylation of alcohols was developed whereby carbon monoxide acts as a C1 source and hydrogen gas as a reducing agent. The overall transformation occurs through an intricate network of metal-catalyzed and base-mediated reactions. The molecular complex [Mn(CO)₂Br[HN(C₂H₄PⁱPr₂)₂]]1comprising earth-abundant manganese acts as the metal component in the catalytic system enabling the generation of formaldehyde from syngas in a synthetically useful reaction. This new syngas conversion opens pathways to install methyl branches at sp³carbon centers utilizing renewable feedstocks and energy for the synthesis of biologically active compounds, fine chemicals, and advanced biofuels.

Full text of DOI:10.1039/d0sc05404f

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Carbon monoxide and hydrogen (syngas) as a C1-
building block for selective catalytic methylation†
Cite this: DOI: 10.1039/d0sc05404f
ab
ab
Markus Holscherb and Walter Leitner
*
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Akash Kaithal,
¨
A catalytic reaction using syngas (CO/H2) as feedstock for the selective b-methylation of alcohols was
developed whereby carbon monoxide acts as a C1 source and hydrogen gas as a reducing agent. The
overall transformation occurs through an intricate network of metal-catalyzed and base-mediated
reactions. The molecular complex [Mn(CO)2Br[HN(C2H4PiPr2)2]]
1
comprising earth-abundant
Received 29th September 2020
Accepted 11th November 2020
manganese acts as the metal component in the catalytic system enabling the generation of
formaldehyde from syngas in a synthetically useful reaction. This new syngas conversion opens pathways
to install methyl branches at sp3 carbon centers utilizing renewable feedstocks and energy for the
synthesis of biologically active compounds, fine chemicals, and advanced biofuels.
DOI: 10.1039/d0sc05404f
rsc.li/chemical-science
applications for the synthesis of fuels, large volume products,
ne chemicals, and pharmaceuticals.
Background and motivation
Synthesis gas (syngas), a mixture of carbon monoxide (CO) and
hydrogen (H2), is a crucial relay between the energy and the
chemical sector. While produced mainly from fossil resources
today,1,2 it can be obtained also from other carbon feedstocks
such as biomass,3–5 recycled plastics,6 or even carbon dioxide
(CO2) combined with renewable energy.7–9 Therefore, catalytic
processes for the chemical conversion of syngas are considered
central elements in future sustainable chemical value chains. In
particular, conversion of renewable-based syngas via the
Fischer–Tropsch process10–12 or methanol synthesis13–15 is
nding wide-spread interest due to the large product volumes.
At the same time, “de-fossilized” syngas may be envisaged also
as a C1-building block in later-stages of the chemical value
chain.16,17 Hydroformylation, for example, uses syngas for the
production of commodities and ne chemicals.18–20
Results and discussion
Most recently, catalytic methods using methanol (CH3OH) for b-
methylation of alcohols have been reported by us21–23 and
others.24–29 These reactions occur via an integrated “borrowing
hydrogen” reaction sequence involving metal-catalyzed re-
We report here a novel catalytic process using syngas to
install methyl branches (H3C–) with high selectivity at existing
aliphatic carbon chains in the b-position of alcohol substrates
(Scheme 1). This transformation combines two distinct features
of Fischer–Tropsch chemistry (full deoxygenation of CO,
hydrocarbon product) and hydroformylation (chemo- and
regioselectivity, C1 building block). The reaction is catalysed by
a molecular complex comprising earth abundant and non-toxic
manganese as an active metal in the presence of a suitable base.
The transformation opens new pathways to introduce renew-
able carbon into molecular structures with potential
a
¨
Max Planck Institute for Chemical Energy Conversion, Stistraße 34-36, Mulheim a.d.
Ruhr, 45470, Germany. E-mail: walter.leitner@cec.mpg.de
b
¨
Institut fur Technische und Makromolekulare Chemie, RWTH Aachen University,
Worringer Weg 2, 52074 Aachen, Germany
Scheme 1 (a) Established processes for the conversion of syngas (CO/
H2) to fuels and chemicals. (b) Novel catalytic reaction to use syngas as
a methyl source for the b-methylation of alcohols.
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0sc05404f
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hydrogenation and de-hydrogenation in conjunction with base- >99% conversion and isolated in 86% yield by column chro-
mediated aldol-condensation/isomerization. Formaldehyde is matography (Table 1, entry 2). Lower yields were obtained at
formed as the C1 building block in situ by de-hydrogenation of lower (120 ꢀC) as well as higher (170 ꢀC) temperatures (Table 1,
methanol in these systems.21–23 Starting from syngas as the C1 entry 3 and 4) reecting a combined inuence of activity and
source would thus require to provide sufficient concentrations selectivity. Reducing the syngas pressure decreased the yield to
of formaldehyde to enter this sequence. Notably, examples for the desired methylated product drastically while conversion
catalytic generation of formaldehyde from syngas using remained relatively high (Table 1, entry 5). Increasing the
homogeneous catalysis are very scarce.30 Lately, however, the syngas pressure (CO: 8 bar, H2: 24 bar) gave similar results as
groups of Prakash as well as Checinski and Beller reported the under the conditions of entry 2 (Table 1, entry 6). When the
amine assisted hydrogenation of CO to methanol using homo- amount of NaOtBu was decreased to 1 equiv. with respect to 2a,
geneous transition metal catalysts based on ruthenium and the rate of the transformation decreased leading to 3a in 67%
manganese, respectively.31,32
yield at 82% conversion (Table 1, entry 7). Replacing the base
Based on recent progress using Mn-complexes in alkyl- with KOtBu led to high conversion but very unselective product
ation22,29,33–36 and CO/CO2 hydrogenation,32,37 we explored the formation including polymeric materials, while Cs2CO3 resul-
potential of the well-established complex [Mn(iPr- ted in no signicant activity (Table 1, entry 8 and 9).
MACHO)(CO)2Br] (iPr-MACHO ¼ HN(C2H4PiPr2)2; 1) as a cata-
Monitoring the pressure over time for the b-methylation of 2-
lyst precursor for the methylation directly from syngas. At the phenyl propanol 2a under the conditions of entry 2, Table 1,
outset, 2-phenylethanol (2a) was selected as a benchmark indicated sigmoidal reaction progress (see the ESI†). In the rst
substrate to validate the catalytic activity of 1 and to screen a set 3 hours, the pressure dropped slowly by 2.5 bar followed by
of parameters for optimization. The initial conditions involved a sharp decrease resulting in a total 12 bar pressure drop over
reacting 2a under a mixture of CO (5 bar) and H2 (15 bar) in the 7 h which continued to nally reach a stable value of a 15 bar
presence of complex 1 (1 mol%) and NaOtBu as a base (2 equiv. total pressure drop aer 16 h. The conversion/time prole ob-
with respect to 2a) in toluene as a solvent. Already under this tained by the 1H NMR analysis of the reaction mixture at
preliminary set of conditions, analysis of the liquid phase different time intervals corroborate this observation (Fig. 1).
revealed >99% conversion of 2a and the formation of the b- The reaction starts with a signicant induction period exhibit-
methylated product 3a in a yield of 65% aer 24 h at 150 ꢀC ing only 5% conversion and 4% yield to the b-methylated
(Table 1, entry 1). Alkenes and aldol-coupled products were alcohol product aer 1.5 h. The reaction rate continuously
observed in the reaction mixture indicating selectivity as the increases reaching a maximum around 50% conversion.
main optimization target. Using the closely related noble metal Subsequently, the transformation slows down but continues to
complex [RuH(CO)(BH4)(HN(C2H4PPh2)2)] as a catalyst resulted reach >99% conversion while selectivity catches up to result in
in rather unselective conversions with 25% yield of 3a only, 92% yield of the desired product 3a. The 1H NMR spectra
highlighting the superior performance of the 3d metal in the revealed the formation of small amounts phenylacetaldehye (1H
diagonal position of the periodic table in this case.
NMR ¼ 9.86 ppm, t, J ¼ 4 hz), methanediol (1H NMR ¼
The selectivity for b-methylation could be improved signi- 4.89 ppm, s), and methanol (1H NMR ¼ 3.50 ppm, s) as potential
cantly when the amount of complex 1 was increased to 2 mol%. intermediate products in the reaction (see the ESI†).
The desired product 3a was formed with a selectivity of 92% at
Table 1 MnI catalyzed b-methylation of 2a with CO and H2: influence of different reaction conditionsa
CO (bar)
H2 (bar)
Base (equiv.)
Temp. (ꢀC)
Conv. (%)
Yield (%)
1b
2
3
4
5
6
7
8
9
5
5
5
5
2.5
8
5
5
5
15
15
15
15
7.5
24
15
15
15
NaOtBu (2)
NaOtBu (2)
NaOtBu (2)
NaOtBu (2)
NaOtBu (2)
NaOtBu (2)
NaOtBu (1)
KOtBu (2)
150
150
120
170
150
150
150
150
150
>99
>99
94
>99
72
>99
82
>99
8
65
92
73
54
15
93
67
0
Cs2CO3 (1)
0
a
Reaction conditions: 2-phenylethanol 2a (0.5 mmol), Mn-complex 1 (2 mol%), CO, H2, base, and toluene (0.8 mL) were heated in a high-pressure
reactor for 24 h. Conversion and yield were calculated using 1H NMR spectroscopy. b Modied conditions: 2a (0.5 mmol), 1 (1 mol%), CO, H2, base,
and toluene (0.8 mL) were heated in a high-pressure reactor for 24 h.
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Fig.
1
Conversion/time profile based on 1H NMR of individual
experiments. Reaction conditions: 2a (0.5 mmol), Mn-complex 1
(2 mol%), CO (5 bar), H2 (15 bar), NaOtBu (1 mmol), and toluene (0.8
mL) were heated at 150 ꢀC in a high-pressure reactor for a certain time.
Scheme 2 shows a plausible reaction network to rationalize
the basic mechanism of the new catalytic process which is
consistent with the conversion/time prole of Fig. 1 and sup-
ported by the control experiments summarized in Scheme 3.38
The Mn–pincer complex catalyzed de- and re-hydrogenation
steps of the organic substrate and intermediates39–52 and the
base mediated aldol condensation are well established and the
deuterium scrambling over all three carbon centers is fully
consistent with this sequence (Scheme 3a).22,36 The high degree
of deuterium incorporation at the a- and b-position in product 4
reects rapid de- and re-hydrogenation at all stages of the
catalytic network (Scheme 3a, see the ESI, Section 5.2 and 5.3†).
The manganese-catalyzed generation of formaldehyde from CO/
H2 is unprecedented, however, and unlocks the overall mani-
fold. It can be reasonably assumed as the limiting factor in the
initial phase explaining the observed induction period. While
a direct hydrogenation pathway for CO reduction cannot be
fully excluded, we favor an indirect conversion similar to
previous reports on homogeneously catalyzed methanol
formation from syngas.31,32,53,54 These reports have identied
organic formyl species resulting from base mediated coupling
of CO and secondary amines as crucial intermediates for CO
hydrogenation. In full analogy, the alcohols used as substrates
here can be converted to formate esters in the presence of CO
and NaOtBu.53,55 This possibility was conrmed for substrate 2a
in the absence of hydrogen and a catalyst under otherwise
typical reaction conditions (Scheme 3b). In line with this
assumption, the reaction of 2-phenethyl formate 5a produced
Scheme 3 Control experiments to investigate the reaction sequence
shown in Scheme 2. Values in parentheses correspond to the pressure
of the reactive gases.
the methylated alcohol 3a in 81% yield under standard condi-
tions (Scheme 3c). Furthermore, the reaction of 2a in the pres-
ence of ethyl formate and hydrogen led to the methylated
product formation with a yield of 40% (Scheme 3d), clearly
demonstrating that formate esters can serve as a formaldehyde
source. On the other hand, when syngas was reacted under the
standard conditions but in the absence of alcohol, the reaction
resulted in only a very small amount of methanol (TON # 2) and
no formation of formaldehyde or methanediol was detected
under these conditions (Scheme 3e). These control experiments
affirmed that the presence of the alcohol substrate is necessary
to mediate the hydrogenation of carbon monoxide most likely
via formate esters as intermediates.
Having established a robust method to construct a methyl
group from syngas in the b-position of the aliphatic chain in the
benchmark substrate 2a, we set out to explore the synthetic
scope of this catalytic reaction. The methyl branch is a highly
important structural motif in biologically active products such
as pharmaceuticals and agrochemicals.56,57 Using the reaction
conditions of Table 1 entry 2 as standard procedure, various 2-
Scheme 2 Proposed reaction network for the catalytic b-methylation of alcohols using syngas (CO/H2) as a C1 source.
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arylethanol derivatives were methylated with CO and H2
addressing potential building blocks and intermediates for
biologically active products (Scheme 4, 3a–3i).
Electron donating as well as withdrawing substituents in the
phenyl ring were fully tolerated and no dehalogenation was
observed (Scheme 4, 3a–3h). Notably, pharmaceutically relevant
ibuprofen and naproxen alcohols were prepared by using this
new methodology in excellent yields of 92% and 96%, respec-
tively (Scheme 4, 3c and 3f). The sulfur containing heterocyclic
2-(thiophen-2-yl)ethanol was converted effectively and the
product 3i could be isolated in 86% yield. Aryl-substituted
longer chain aliphatic alcohols reacted also smoothly under
standard conditions providing very good to excellent yields of
the corresponding methyl-branched products (Scheme 4, 3j–
3n). Again, heteroatoms were tolerated and the pharmaceuti-
cally important amino alcohol 2-(methyl(phenyl)amino)ethan-
1-ol58 was selectively mono-methylated with a yield of 73% at
>99% conversion (Scheme 4, 3o).
Secondary alcohols of general structure 7 were used also as
substrates for selective b-methylation (Scheme 5). Using the
standard reaction conditions, 1-phenylpropan-1-ol was mono-
methylated at the b-position with 81% selectivity at full
conversion and the product was isolated in 77% yield (Scheme
5, 8a). Similarly, 1-(p-tolyl)propan-1-ol was also mono-
methylated in good yield (Scheme 5, 8b). The reaction also
Scheme 5 MnI catalyzed b-methylation of secondary alcohols 7 with
CO and H2. Reaction conditions: same as Scheme 4. aModified
conditions: 7 (0.5 mmol), Mn-complex 1 (2 mol%), CO (5 bar), H2 (15
bar), NaOtBu (1 mmol), and toluene (0.8 mL) were heated in a high
pressure reactor for 36 h. b7 (0.5 mmol), Mn-complex 1 (2 mol%), CO
(8 bar), H2 (24 bar), NaOtBu (2 mmol), and toluene (0.8 mL) were
heated in a high-pressure reactor for 36 h.
occurred readily when the reactive position was part of a 6-
membered carbocycle, installing the methyl group with a 2 : 1
preference in the trans-position to the OH group (Scheme 5, 8c).
Scheme 4 | MnI catalyzed b-methylation of aryl substituted alcohols 2 with CO and H2. Reaction conditions: 2 (0.5 mmol), Mn-complex 1
(2 mol%), CO (5 bar), H2 (15 bar), NaOtBu (1 mmol), and toluene (0.8 mL) were heated at 150 ꢀC in a high-pressure reactor for 24 h. Conversion
1
and yield were calculated using H-NMR spectroscopy. Yields in parentheses correspond to isolated yield.
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Scheme 6 MnI catalyzed b-methylation of aliphatic alcohols 9 with CO and H2. Reaction conditions: same as Scheme 4. aModified conditions: 9
(0.5 mmol), Mn-complex 1 (2 mol%), CO (8 bar), H2 (24 bar), NaOtBu (2 mmol), and toluene (0.8 mL) were heated in a high-pressure reactor at
150 ꢀC for 36 h. b9 (0.5 mmol), Mn-complex 1 (2 mol%), CO (5 bar), H2 (15 bar), NaOtBu (1 mmol), and toluene (0.8 mL) were heated at 150 ꢀC in
a high-pressure reactor for 36 h.
Di-methylation of 1-arylethanols to generate iso-propyl groups enabling the use of carbon monoxide as a renewable C1 source and
was possible under slightly adjusted conditions (see the ESI†). “green” hydrogen as a reducing agent. The catalyst system
Increasing the amount of base to 4 equiv. and reacting the comprises the earth-abundant, rst row transition metal manga-
substrates under higher pressures of CO (8 bar) and H2 (24 bar) nese in the form of an air-stable pincer complex as the metal
for 36 h allowed isolation of the di-methlyated products 8a and component. This new catalytic reaction for the installation of
8d in 70% and 48%, respectively.
methyl groups at sp3 C-centers generates water as the sole by-
Methyl branches in aliphatic carbon chains feature benecial product. The reaction shows a remarkable broad substrate scope
combustion properties in fuel components.59,60 As a possible providing very high to excellent yields for primary and secondary
synthetic pathway for the upgrading of biogenic alcohols to fuel alcohols. Potential products include fuel components or
components with improved combustion properties,61,62 we there- commodity chemicals, ne chemicals, and even pharmaceuticals.
fore focused next on the selective b-methylation of purely aliphatic Even with the resource basis of today's petrochemical industry, the
alcohols (Scheme 6). Ethanol proved to be a challenging substrate, catalytic process described herein opens new retrosynthetic path-
but a mixture of iso-butanol (46%) from di-methylation and 1- ways to important target molecules providing potential environ-
propanol (16%) from mono-methylation was obtained under 8 bar mental benets. Most intriguingly, however, the resulting novel
of CO and 24 bar of H2 at an elongated reaction time of 36 h synthetic strategies may help to unlock the potential of waste,
(Scheme 6, 10a). Longer chain aliphatic alcohols that can result in biomass, or CO2 as carbon sources for the chemical value chain in
mono-methylation only were almost quantitatively converted line with the principles of Green Chemistry.17 The general concept
under 5 bar of CO and 15 bar of H2 within 24–36 h providing good to access formaldehyde from syngas through a catalytic cycle with
selectivity and yields (Scheme 6, 10b–10f). Fatty alcohols including a molecularly dened organometallic complexes and to intercept
lauryl alcohol, and stearyl alcohol were also converted resulting in this useful building block provides a multitude of further oppor-
high yield to the corresponding b-monomethylated alcohols tunities for chemical synthesis.
(Scheme 6, 10h, and 10i). Remarkably, the unsaturated fatty
alcohol undec-10-en-1-ol was transformed into the corresponding
b-methylated product with 68% yield leaving the C]C double
Conflicts of interest
bond in the molecule intact (Scheme 6, 10g). These products may
have potential application as ne chemicals for surfactants or in
the cosmetic industry.
There are no conicts to declare.
Acknowledgements
The studies were performed as part of our activities in the
Conclusions
framework of the “Fuel Science Center” funded by the Deutsche
In conclusion, a catalytic reaction has been developed employing Forschungsgemeinscha (DFG, German Research Foundation)
syngas as raw material for the catalytic b-methylation of alcohols under Germany's Excellence StrategyꢁExzellenzcluster 2186,
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The Fuel Science Center “ID: 390919832”. A. K. thanks the
Erasmus Mundus Action 1 Programme (FPA2013-0037) “SIN-
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