Fatty alcohol synthesis from fatty acids at mild temperature by subsequent enzymatic esterification and metal-catalyzed hydrogenation

Article abstract of DOI:10.1039/d0ob01561j

Fatty alcohols are important products in chemical industry to be used in the formulation of surfactants and lubricants. This work describes a two step approach for the production of myristyl alcohol under neat conditions by combining a lipase catalyzed esterification of myristic acid and myristyl alcohol with a ruthenium catalyzed hydrogenation of the intermediate myristyl myristate. The esterification was carried out in a bubble column reactor with the commercial immobilized lipase B from Candida antarctica as a biocatalyst, while the hydrogenation was conducted under pressurized conditions being catalyzed by the homogeneous chemocatalyst Ru-Macho-BH. By investigating the reaction steps separately, comparable reaction rates were found for the esterification of short chain and long chain alcohols. Additionally, the hydrogen pressure could be reduced to 35 bar compared to the current industrial Lurgi process. Characterization of cross interactions by the reactants myristic acid and sodium myristate in the hydrogenation demonstrates that the metal catalyst was completely deactivated, even at a low amount of 0.5 mol% of myristic acid. Complete conversion of myristic acid in the esterification with equal amounts of myristic acid and myristyl alcohol was obtained, overcoming any limitation in the hydrogenation. In comparison to the Lurgi process starting also from fatty acid and fatty alcohols, the chemoenzymatic two step reaction sequence could be realized at lower reaction temperatures of 60 and 100 °C as well as lower hydrogen pressures of 35 bar. This journal is

Full text of DOI:10.1039/d0ob01561j

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Biomolecular Chemistry
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Fatty alcohol synthesis from fatty acids at mild
temperature by subsequent enzymatic
Cite this: DOI: 10.1039/d0ob01561j
esterification and metal-catalyzed hydrogenation
a
b
a
b
Kim E. Schlipköter, Tobias Betke, Joscha Kleber, Harald Gröger * and
a
Andreas Liese
*
Fatty alcohols are important products in chemical industry to be used in the formulation of surfactants
and lubricants. This work describes a two step approach for the production of myristyl alcohol under neat
conditions by combining a lipase catalyzed esterification of myristic acid and myristyl alcohol with a
ruthenium catalyzed hydrogenation of the intermediate myristyl myristate. The esterification was carried
out in a bubble column reactor with the commercial immobilized lipase B from Candida antarctica as a
biocatalyst, while the hydrogenation was conducted under pressurized conditions being catalyzed by the
homogeneous chemocatalyst Ru-Macho-BH. By investigating the reaction steps separately, comparable
reaction rates were found for the esterification of short chain and long chain alcohols. Additionally, the
hydrogen pressure could be reduced to 35 bar compared to the current industrial Lurgi process.
Characterization of cross interactions by the reactants myristic acid and sodium myristate in the hydro-
genation demonstrates that the metal catalyst was completely deactivated, even at a low amount of
0
.5 mol% of myristic acid. Complete conversion of myristic acid in the esterification with equal amounts
Received 29th July 2020,
Accepted 19th September 2020
of myristic acid and myristyl alcohol was obtained, overcoming any limitation in the hydrogenation. In
comparison to the Lurgi process starting also from fatty acid and fatty alcohols, the chemoenzymatic two
step reaction sequence could be realized at lower reaction temperatures of 60 and 100 °C as well as
lower hydrogen pressures of 35 bar.
DOI: 10.1039/d0ob01561j
rsc.li/obc
4
mation of waste. In industry, the so-called Lurgi-process
gained particular importance and therein a reduction of the
Introduction
The hydrogenation of fatty acids to their corresponding alco- intermittently formed wax esters to fatty alcohols is realized by
hols is an important industrial task due to the broad use of a more sustainable process compared to other processes.
fatty alcohols in various fields of specialty chemicals such as Harsh temperatures (230–270 °C) are required for the previous
1
surfactants and lubricants. However, direct hydrogenation of solvent free esterification of the fatty acid with a fatty alcohol.
fatty acids requires harsh reaction conditions such as, e.g., The intermediate, the wax ester, is hydrogenated by means of a
2
temperatures of >200 °C. In contrast, hydrogenation of fatty heterogeneous catalyst. In total, side products or waste as well
acid esters is being carried out at lower temperature, and a as energy consuming downstream processes are circum-
5
range of efficient homogeneous metal-catalyzed ester hydro- vented. Alternatively, esters can be prepared under mild,
2
,3
6–8
genations under mild conditions were recently reported. On solvent-free conditions utilizing a biocatalyst.
The pro-
the other hand, esters need to be prepared from a fatty acid duction of emollient esters by a biocatalytic route offers advan-
and in general short chain alcohols like methanol that, tages over conventional processes in terms of waste reduction
4
,9
however, is wasted afterwards. The ester formation typically and energy consumption.
requires harsh conditions when using a chemocatalyst or con- In this contribution a conceptually waste-free process
sumption of additional reagents leading to an increased for- sequence is reported which combines the advantages of start-
ing directly from fatty acids and same chain length fatty alco-
hols with the advantage of applying smooth hydrogenation
conditions being known for esters (Scheme 1). The process
concept is based on an initial, solvent-free esterification of a
fatty acid (exemplified for myristic acid as a C14-fatty acid)
with its corresponding fatty alcohol in the first reactor. The
a
Institute of Technical Biocatalysis, Hamburg University of Technology, Denickestr.
1
b
5, 21073 Hamburg, Germany. E-mail: liese@tuhh.de
Chair of Industrial Organic Chemistry and Biotechnology, Department Chemistry,
University of Bielefeld, post office box 100131, 33501 Bielefeld, Germany.
E-mail: harald.groeger@uni-bielefeld.de
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Scheme 1 Process concept of a less energy-intensive fatty alcohol
production.
reaction is catalyzed at mild temperature by a heterogenized
1
0,11
lipase
following
previously
developed
protocols.
Subsequently, separation of the formed ester from the
immobilized lipase by simple filtration and subsequent trans-
fer of the formed ester into a second reaction vessel for direct
hydrogenation under pressure conditions. In consequence, at
temperatures of less than 120 °C two molecules of the same
Fig. 1 Esterification of myristic acid with short chain alcohols and myr-
istyl alcohol. Conditions: T = 63 °C, myristic acid (5 g, 21.9 mmol),
Novozym 435 (1 wt% regarding myristic acid), 1 eq. alcohol, 2.6 g mole-
desired alcohol (here: C14-alcohol) are delivered within this cular sieves 3 Å, t = 120 min.
second reaction. This ester hydrogenation is catalyzed by a
1
2,13
pincer-type transition metal catalyst.
chemoenzymatic approach, sustainable, “zero-waste”
besides waste from catalysts) and economically attractive con-
By means of such a
a
(
version of myristic acid to myristyl alcohol could be realized.
Results and discussion
Initially, we focused on the biocatalytic esterification of myris-
tic acid as first step of this cascade. We started with investi-
gation of the influence of several alcohols on the reaction rate
in order to gain an insight into the impact of a longer chain
(C14-)alkyl alcohol compared to the short-chain alcohols such
as ethanol and propanol, which have been reported in
1
0,14
literature.
versions were obtained in all cases by integrating water
removal via molecular sieves, but also comparable reaction hydrogen pressures between 10 and 50 bar. Conditions: p(H
It could be demonstrated that not only full con-
Fig. 2 Hydrogenation of myristyl myristate to myristyl alcohol under
) = 10–50
bar, T = 100 °C, myristyl myristate (2.1 g, 5 mmol), c(Ru-Macho-BH) =
.5 mol%, 3 eq. myristyl alcohol, U = 250 rpm, t = 5 h, double
measurements.
2
courses under neat conditions (Fig. 1). Hence, the chain
length seemed to be of lower impact for the reaction rate of
the esterification.
0
For the second step, the Takasago-catalyst Ru-MACHO-BH
was found to reach full conversion of myristyl myristate hydro- requires 70 to 100 bar hydrogen pressure, this new approach
5
,15
genation. This catalyst tolerates the long alcohol moiety of the enables a possible hydrogen pressure reduction of 50 bar.
fatty ester and proceeds very efficiently at 100 °C, which is Considering Henry’s law, the distribution of hydrogen between
1
2,13
necessary for catalyst activation.
The conversion depen- the gas and the liquid phase is determined by the partial
dency on hydrogen pressure was investigated in replicate pressure and gives an explanation for the increase of the con-
experiments of 5 hours by application of hydrogen pressures version with increasing hydrogen pressure, a higher concen-
between 10 and 50 bar (Fig. 2). It could be shown, that even tration of hydrogen becomes available for the reaction. To
with a comparable low hydrogen pressure of 10 bar a conver- realize a two step reaction sequence, a filtration step needed to
sion of 10% could still be reached. Overall, the conversion be integrated to intermittantly separate the immobilized bioca-
increases progressively from 10% to 40% by a reaction time of talyst to prevent interactions with the Takasago-catalyst. Since
5
h when raising the hydrogen pressure from 10 to 50 bar. The myristyl alcohol was used as solvent in the pressure screening
difference in the final conversion between 25 and 50 bar is just of the hydrogenation catalyst Ru-Macho-BH, the impact of
%, which indicates a feasibility of the reaction already at a alcohol residues from the prior esterification step as critical
low pressure of 25 bar. Compared to the Lurgi process, which component in the hydrogenation can be neglected. To investi-
7
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gate, if residual non-converted myristic acid from the esterifi-
cation step could influence the activity of the Ru-Macho-BH
catalyst, conversion studies were carried out with myristic acid
as additive. In detail, amounts of 0.5 and 1 mol% of myristic
acid as well as (for comparison) sodium myristate were added
to the hydrogenation reaction with a concentration of Ru-
Macho-BH in the same range of 0.5 and 1 mol% (Fig. 3). In the
presence of myristic acid no conversion could be observed in
contrast to the addition of sodium myristate, where 16 and 3%
conversion were reached, respectively. However, all conversion
points were lower than in the experiments without its addition.
In conclusion, the chemocatalyst Ru-Macho-BH seemed to be
significantly inhibited by the acid function.
Because of the acid sensitivity of the hydrogenation catalyst,
full conversion of myristic acid is required in the preceding
esterification to prevent an additional downstream step
besides filtration of the biocatalyst. Thermodynamically
driven, to enable full conversion of the acid, a high alcohol to
acid ratio is required in the esterification. To determine the
optimal ratio of myristic acid and myristyl alcohol, also
enabling high reaction rates, different amounts of myristyl
alcohol between 35 and 82 mol% of the total mass of 120 g
reaction mixture were applied in the esterification (Fig. 4). To
simplify the experimental setup, the reactor was changed to a
bubble column reactor, because it allows by aeration with dry
air simultaneous efficient mixing of the reaction mixture and
separation of the byproduct water, which is formed during the
Fig. 4 Progress curves of the esterification in a bubble column with
different substrate ratios of myristyl alcohol and myristic acid to form
myristyl myristate as well as the time to reach 90% conversion in the
7
,10,11
esterification, enabling full conversion of myristic acid.
Fig. 4 demonstrates, that the reaction rate increased with
decreasing myristyl alcohol amount. Conversions are calcu- = 60 °C, m(total) = 120 g, c(CalB immo) = 1 wt%, V(air) = 1.5 L min− , t =
esterification depending on the myristyl alcohol amount. Conditions: T
1
300 min.
lated based on the concentration of the key component, which
was added in lower amounts, in most cases myristic acid. Full
conversion was achieved with 35 mol% myristyl alcohol at
1
20 min, with equal amounts of the acid and the alcohol after 180 min and with an excess of alcohol of 68 mol% after
hours. Exceeding 68 mol% of alcohol, full conversion could
5
not be reached during the monitored time range of 5 hours.
This substrate dependency of the activity was already reported
by previous investigations of this lipases. In this case, an
optimum of 0.6 mol mol− of myristic acid was found. To
efficiently integrate the esterification as first step in the two
step reaction sequence a compromise between highest biocata-
lyst activity and short reaction time to reach maximum conver-
sion, resulting in minimum residual acid, needs to be met. A
fast reaction requires an implementation of an acid excess in
the esterification combined with an additional downstream
process next to the filtration to separate the acid prior to char-
ging the reaction mixture to the hydrogenation. Otherwise, an
application with equal or lower amounts of myristic acid neg-
lected the second downstream process, but this implies a
longer reaction time to reach full conversion. As one aim of
this approach is to lower process costs by minimizing the
number of downstream processing steps subsequent to the
esterification, equal amounts of both substrates were chosen
for further investigations of the two step process.
1
16
Fig. 3 Influence of additives from the esterification step on the conver-
sion of the hydrogenation of myristyl myristate. Conditions: p(H
bar, T = 100 °C, c(Ru-Macho-BH) = 0.5/1 mol%, 4 eq. myristyl alcohol, t
18 h, myristic acid/sodium myristate = 0.5/1 mol%.
2
) = 50
To prove the feasibility of this chemoenzymatic reaction
sequence a two step process was carried out (Fig. 5). The con-
=
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Fig. 5 Conversion of the complete reaction sequence to produce myristyl alcohols consisting of esterification in a bubble column and hydrogen-
ation in an autoclave. Conditions: esterification: T = 70 °C, myristyl acid (50 g, 220 mmol), m(CalB immo) = 1 wt%, 1 eq. myristyl alcohol, V˙ (air) = 1.5
L min− , t = 180 min, hydrogenation: T = 100 °C, p(H2) = 35 bar, myristyl myristate (60 g, 142 mmol), c(Ru-Macho-BH) = 0.5 mol%, 3 eq. myristyl
alcohol, U = 600 rpm, t = 18 h, for both reactions 3 determinations.
1
version in the solvent-free esterification increased constantly antarctica (CalB immo, 9.100 LU g− ) was purchased by c-LEcta
and reached full conversion after 120 min. In the subsequent GmbH (Leipzig, Deutschland). Phenolphthalein (1% in
hydrogenation complete conversion could also be reached. As ethanol), n-hexane (99%) as well as potassiumhydroxide solu-
space–time yield (STY) for the esterification 590 g (L h)− was tion in ethanol (0.1 N) were used from Carl Roth GmbH & Co.
determined. Overall, a two step process for synthesis of myris- KG (Karlsruhe, Deutschland). 2-Methyltretrahydrofuran (98%)
1
1
tyl alcohol was realized, at a relative short reaction time.
as well as Ru-Macho-BH were ordered by Tokyo Chemical
Industry (TCI, Zwijndrecht, Belgium). Because of no commer-
cial availability, myristyl myristate was synthesised starting
from myristic acid and myristyl alcohol by enzyme catalyzed
esterification following the procedure below.
Conclusions
A two step chemoenzymatic approach to synthesize myristyl
alcohol could be realized successfully in a 100 g scale. In the first
reaction step an enzyme catalyzed neat esterification of myristyl
alcohol with myristic acid was carried out in a bubble column
Analysis
Esterification with different alcohol chain length and the influ-
ences of myristic acid on the hydrogenation were recorded at
−1
reactor, reaching a space–time yield of 590 g (L h) . In a sub-
sequent hydrogenation of the esterification product myristyl myris-
tate catalyzed by Ru-Macho-BH myristyl alcohol was yield.
Complete conversion of myristic acid in the first reaction step was
achieved and the immobilized lipase was be removed by filtration
to apply the obtained solution in the second chemocatalyzed reac-
tion step. It was possible to reduce the overall reaction time signifi-
cantly compared to the actual industrial process, by application of
the lipase CalB immo to catalyze the esterification and the homo-
geneous Ru-Macho-BH in the hydrogenation in contrast to the
state of the art of non-catalyzed esterification followed by a hetero-
geneously catalyzed hydrogenation. This goes along with reduction
to mild reaction conditions of 60 and 100 °C reaction temperature,
respectively, and 35 bar hydrogen pressure. However, an effective
separation of the homogeneous ruthenium catalyst, Ru-Macho-BH,
needs to be identified to enable recyclization.
5
00 MHz by a DRX 500 NMR (Bruker Cooperation). The chemi-
cal shift δ is given in ppm and referenced to the corresponding
solvent signal (CDCl ). Coupling constants are given in Hz.
3
The samples of esterification in the bubble column had
been solved in 10 mL of a 2-methyltetrahydrofuran–water-
mixture (5 : 1, volumetric) and been analysed by titration with
ethanoic KOH-solution and phenolphthalein (20 µL) until a
colour change to pink was visible.
All other samples were analyzed isothermic at 230 °C
column temperature via GC-FID (HP 5890 Series II) with an
Optima FFAP Plus column (30 m × 0.25 mm × 0.25 µm,
Macherey-Nagel) and hydrogen as a carrier gas. Typical reten-
tion times were: myristyl alcohol 1.10 min, myristic acid
2
.26 min, myristyl myristate 7.85 min.
Procedure of esterification with different alcohols
For esterification with different alcohols, myristic acid (5 g,
2
2
1.9 mmol), ethanol, propanol or tetradecanol (1 eq.,
1.9 mmol) and molecular sieves (3 Å, 2.6 g) were given into a
Experimental
Myristic acid (≥99%), myristyl alcohol (≥98%) were ordered by heat dried Schlenk flask, equipped with a thermometer on the
Merck KGgA (Darmstadt, Deutschland). Lipase B from Candida inside of the flask. The reaction mixture was heated up and
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stirred, upon which the acid started melting. After reaching a 186.9 mmol and 110 g, 514.0 mmol) were liquefied separately
temperature of 60–70 °C, CalB (Novozyme 435, 1 wt% regard- in a water bath (60 °C) and then filled in the bubble column
ing myristic acid) was added and the reaction progress was with an air flow of 1.5 L min− . After sampling, CalB immo
1
1
monitored by H-NMR-analysis of collected samples (50 µL). (1 wt% regarding the total mass) was added. Sampling
The progress calculation took place by analysis of the occurred at defined time points. At the end of the reaction,
α-methylgroups of the alcohols and esters.
CalB immo was separated by filtration through a filter paper
1
−3
3
H-NMR (500 MHz, CDCl ). 1-Ethanol: δ[ppm] = 0.87 (t, J = (270 mm, 65 g m ) at 70 °C in a heating chamber.
6
2
0
2
.9 Hz, 3H), 1.20–1.36 (m, 24H), 1.62 (tt, J = 14.4, 7.2 Hz, 2H),
.33 (t, J = 7.5 Hz, 2H), 3.72 (q, J = 7.0 Hz, 1H), ester: δ[ppm] =
Procedure of hydrogenation in two step process
.90 (t, J = 6.8 Hz, 3H), 1.28 (m, 23H), 1.63 (tt, J = 14.4, 7.2 Hz, For hydrogenation a 450 mL bench top autoclave from Parr
H), 2.30 (t, J = 7.6 Hz, 2H), 4.14 (q, J = 7.1 Hz, 2H). Instruments Company was applied. In a typical procedure myristyl
-Propanol: δ[ppm] = 0.88 (t, J = 6.9 Hz, 3H), 0.94 (t, J = 7.4 myristate (60 g, 141.5 mmol) and myristyl alcohol (3 eq., 90 g,
1
Hz, 1H), 1.17–1.40 (m, 24H), 1.53–1.71 (m, 3H), 2.34 (t, J = 7.5 420.5 mmol) were weighted in and melted. The reactands and Ru-
Hz, 2H), 3.61 (t, J = 6.6 Hz, 1H), ester: δ[ppm] = 0.88 (t, J = 6.9 Macho-BH (0.5 mol%, 707 µmol) were charged to the reactor,
Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H), 1.25–1.33 (m, 20H), 1.58–1.70 which was flushed three times with argon after closing. The
(m, 4H), 2.29 (t, J = 7.6 Hz, 2H), 4.02 (t, J = 6.7 Hz, 2H).
mixture was heated up to 100 °C, hydrogen (35 bar) was added as
1-Tetradecanol: δ[ppm] = 0.88 (t, J = 6.9 Hz, 6H), 1.27 (m, 42H), soon as 100 °C was reached and samples were withdrawn via a
1.59 (m, 4H), 2.29 (t, J = 7.5 Hz, 2H), 3.64 (t, J = 6.6 Hz, 2H), ester: sampling port over 18 h. After decrease of the hydrogen pressure
δ[ppm] = 0.88 (t, J = 6.9 Hz, 6H), 1.17–1.42 (m, 42H), 1.61 (m, 4H), of 5 bar pressure, hydrogen was added again up to 35 bar The
2.28 (t, J = 7.5 Hz, 2H), 4.05 (t, J = 6.7 Hz, 2H)
withdrawn samples were analysed by GC-analysis.
Procedure of pressure screening for hydrogenation
For the pressure screening 20 mL autoclaves equipped with mag- Conflicts of interest
netic stirrers were applied. In a standard procedure myristyl myris-
tate (2 g, 4.7 mmol) and myristyl alcohol (3 g, 14.0 mol) were
There are no conflicts to declare.
melted in the reactors at 60 °C. A time point zero sample was
taken when the mixture was liquified and Ru-Macho-BH
Acknowledgements
(
0.5 mol%, 13.8 mg, 24 µmol) added. The reactors were closed,
pressurized by hydrogen (10–50 bar) and heated to 100 °C. After
h the reaction was stopped by depressurizing the reactors and a
Harald Gröger and Tobias Betke gratefully acknowledge gener-
ous support from the German Federal Ministry of Education
and Research (BMBF) within the funding programme
5
GC sample (20 µL) was taken, while heating to 80 °C.
“
Biotechnologie 2020 +, Nächste Generation biotechnolo-
Procedure for the hydrogenation with additives
gischer Verfahren” (grant number: 031A184A).
Myristyl myristate (3.40 g, 8.00 mmol), 1-tetradecanol (6.43 g,
3
0.0 mmol) and additive (40–80 µmol, 0.5–1.0 mol%) were
charged into a stainless steel autoclave under continuous flow
of argon gas. Ru-Macho-BH (40 µmol, 0.5 mol%) was weighted
under inert gas and added to the reaction mixture. The auto-
clave was sealed and heated to 60 °C to melt the compounds.
After purging with nitrogen gas three times, the reactor was
pressurized with hydrogen gas (50 bar) and heated to 100 °C
for 18 h. At the end of the reaction the pressure was released
and the autoclave opened. The crude product was transferred
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