Synthesis of α,β- and β-Unsaturated Acids and Hydroxy Acids by Tandem Oxidation, Epoxidation, and Hydrolysis/Hydrogenation of Bioethanol Derivatives

Article abstract of DOI:10.1002/anie.202002049

We report a reaction platform for the synthesis of three different high-value specialty chemical building blocks starting from bio-ethanol, which might have an important impact in the implementation of biorefineries. First, oxidative dehydrogenation of ethanol to acetaldehyde generates an aldehyde-containing stream active for the production of C₄ aldehydes via base-catalyzed aldol-condensation. Then, the resulting C₄ adduct is selectively converted into crotonic acid via catalytic aerobic oxidation (62 % yield). Using a sequential epoxidation and hydrogenation of crotonic acid leads to 29 % yield of β-hydroxy acid (3-hydroxybutanoic acid). By controlling the pH of the reaction media, it is possible to hydrolyze the oxirane moiety leading to 21 % yield of α,β-dihydroxy acid (2,3-dihydroxybutanoic acid). Crotonic acid, 3-hydroxybutanoic acid, and 2,3-dihydroxybutanoic acid are archetypal specialty chemicals used in the synthesis of polyvinyl-co-unsaturated acids resins, pharmaceutics, and bio-degradable/ -compatible polymers, respectively.

Full text of DOI:10.1002/anie.202002049

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
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Accepted Article
Title: Synthesizing α,β- and β-Unsaturated Acids and Hydroxy
Acids via Tandem Oxidation, Epoxidation, and Hydrolysis/
Hydrogenation of Bioethanol-Derivatives
Authors: Daniel Santhanaraj, Maria P Ruiz Ramiro, Mallik R
Komarneni, Tu Pham, Gengnan E. Li, Daniel E. Resasco, and
Jimmy Alexander Faria Albanese
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202002049
Angew. Chem. 10.1002/ange.202002049
Link to VoR: http://dx.doi.org/10.1002/anie.202002049
http://dx.doi.org/10.1002/ange.202002049

10.1002/anie.202002049
Angewandte Chemie International Edition
COMMUNICATION
a b
b
Synthesizing , - and - Unsaturated Acids and Hydroxy Acids
via Tandem Oxidation, Epoxidation, and
Hydrolysis/Hydrogenation of Bioethanol-Derivatives**
D. Santhanaraj, M. P. Ruiz, M. R. Komarneni, T. Pham, G. Li, D. E. Resasco, and J. Faria*
Abstract: We report a reaction platform for the synthesis of three
different high-value specialty chemical building blocks starting from
bio-ethanol, which might have an important impact in the
implementation of biorefineries. First, oxidative dehydrogenation of
ethanol to acetaldehyde generates an aldehyde-containing stream
active for the production of C4 aldehydes via base-catalyzed aldol-
condensation. Then, the resulting C4 adduct is selectively converted
into crotonic acid via catalytic aerobic oxidation (90 % yield). Using a
sequential epoxidation and hydrogenation of crotonic acid leads to
70 % yield of b-hydroxy acid (3-hydroxybutanoic acid). By controlling
the pH of the reaction media, it is possible to hydrolyze the oxirane
environmentally friendly and sustainable bio-based and
biodegradable polymers.[2] Polyhydroxyalkanoates (PHAs) are a
class of biodegradable isotactic polymers synthesized by
bacteria.[3] Until now, these family of polymer building blocks have
been synthesized using genetically modified micro-organisms or
enzymes. [4] However, the production cost of PHAs is nearly four
times larger than its petroleum-based counterparts (c.a. PHAs[5]
and Polypropylene[6] prices are 5-6 and 1-2 $/Kg, respectively).
This is due to the high cost of raw materials costs, low conversion
rates, the complex purification of the fermentation broths, and the
large amounts of biomass waste generated (c.a. 5 Kg of raw
material per 1 Kg of product), and low conversion rates.[7]
moiety leading to 34
% yield of a,b-dihydroxy acid (2,3-
dihydroxybutanoic acid). Crotonic acid, 3-hydroxybutanoic acid, and
2,3-dihydroxybutanoic acid are archetypal specialty chemicals used
in the synthesis of polyvinyl-co-unsaturated acids resins,
pharmaceutics, and bio- degradable/-compatible polymers,
respectively.
Catalytic conversion routes of biomass-derived feedstocks to
short b-hydroxy acids (e.g. lactic acid) have shown higher
productivities and atom-efficiency at industrially relevant
operating conditions,[8] but their application has been limited to
short chain (C3) molecules. Inspired by nature, we have
developed a new catalytic cascade process that mimics the step-
wise coupling of C2 units that occurs during the biosynthesis of
PHA in bacteria. Accordingly, we have used base-catalyzed aldol-
condensation followed by tandem oxidation, epoxidation and
hydrogenation or hydration (Scheme 1). This catalytic cascade
route has allowed us to generate medium-chain a,b-unsaturated
acids (crotonic acid), a,b-dihydroxy acids (2,3-dihydroxybutanoic
acid), and b-hydroxy acids (3-hydroxybutyric acid), which are
emerging specialty chemicals and building blocks.
Polymers play a key role in the creation of a myriad of materials
that have contributed to the development of our modern society.
The current use of plastics, however, is not sustainable in the long
term due to its dependence on non-renewable fossil fuels and the
environmental pollution caused by plastic waste.[1] This dilemma
has triggered intensive research in the development of
*
Prof. J. Faria
Faculty of Science and Technology, Catalytic Processes and
Materials group
MESA+ Institute for Nanotechnology
University of Twente
Enschede, 7522 NB (The Netherlands)
E-mail: j.a.fariaalbanese@utwente.nl
Dr. D. Santhanaraj,a Dr. M. R. Komarneni, Dr. T. Pham,[c] G. Li Prof.
D. E. Resasco
School of Chemical, Biological and Materials Engineering
University of Oklahoma
Norman, OK 73019 (USA)
Dr. D. Santhanaraj,a Present Address: Department of Chemistry
Loyola College
Chennai 600-30
India
Prof. M. P. Ruiz
Faculty of Science and Technology, Sustainable Process
Technology group
University of Twente
Enschede, 7522 NB (The Netherlands)
Scheme 1. Integrated catalytic production of unsaturated, mono-
and di-hydroxy acids from bioethanol, via tandem oxidative
dehydrogenation (a), aldol-condensation (b), oxidation (c),
epoxidation (d), and hydrolysis (e) or hydrogenation (f). If R is
equal to H, then species involved are; (1) ethanol, (2)
acetaldehyde, (3) crotonaldehyde, (4) crotonic acid, (5) 3-
methyloxirane-2-carboxylic acid, (6) 2,3-dihydroxybutanoic acid,
(7) 3-hydroxybutanoic acid.
**
This work was supported by the financial support provided by the
Centro para el Desarrollo Tecnológico Industrial (CDTI) and the
Agencia IDEA (Spain).
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.202002049
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COMMUNICATION
The process of converting ethanol into unsaturated and mono-
and di-hydroxy acids starts with the catalytic dehydrogenation of
ethanol to acetaldehyde (Scheme 1a). This step was
accomplished in a flow reactor at 250 °C using SiO2-supported 10
wt. % Cu and 5 wt. % Ni catalysts (see Table S1). When the
reaction was performed at conversions below 20 %. in the
presence of oxygen, the observed rates were 0.67 ± 0.06 and
Hydrotalcite, Al-Beta zeolite, which along with the Mg-B catalyst
previously employed have shown the highest C4 productivities
among all the catalysts investigated, with productivities of 8.3,
23.4, and 24.2 mmol of C4*gcat-1*min-1, respectively, at 50-60%
conversion level and 180 °C (Table S2). Notably, on the 7.5 wt. %
B-MgO and Al-Beta catalysts the yield of C4 unsaturated
aldehydes reached 60-70 mol. C. % at levels of conversion (80-
0.46 ± 0.02 gEtOH*gcat-1*h-1 on the Cu and Ni catalysts, respectively. 90 %).
At these conditions the selectivity on both catalysts in the
presence of oxygen was c.a. 100 %, which is in agreement with
previous kinetic studies performed on Cu-SiO2, Cu-ZnO and Cu-
Al2O3 catalysts that indicated that selectivities to acetaldehyde
80 % can be obtained below 20 % conversion.[9,10] The unreacted
ethanol could either recycled back for further reaction or kept in
the product mixture for conducting the aldol-condensation step
(Fig. S9).
To selectively convert the C2 aldehydes into the corresponding C4
coupling products (Scheme 1b) we have developed a number of
catalytic systems based on basic K/Na- X, Y,[11] and MgO-
K/NaX,[12] zeolites as well as B-doped MgO oxides.[13] The Mg-Al
The subsequent conversion of the C4 adduct to the corresponding
b-hydroxy acid is rather challenging as the dehydration towards
the C4 a,b-unsaturated acid is thermodynamically and kinetically
more favorable under the reaction conditions required for the
oxidation.[14] To circumvent this limitation, we employed a tandem
oxidation-epoxidation sequence. First, to accomplish aerobic
oxidation step we employed two distinct types of Ru catalysts
supported on reducible metal-oxides (5 wt.% RuCoxCeyOz) and a
microporous titanosilicate catalysts (ETS-4) (Table 1). When the
reaction was performed on the CoxCeyOz catalyst without Ru the
conversion of crotonaldehyde was ~66 % and the yield to crotonic
acid was 54% after 6 hours of reaction in decalin.
Table 1. Product selectivity and conversions obtained during aerobic oxidation reaction of crotonaldehyde to crotonic acid at 38 bar of
synthetic air using 200 mg of catalyst in decalin.
Catalyst
Reaction time
(h)
Temperature (°C)
Solvent
Conversion (%)
Crotonic acid yield
(%)
STY
(mol*g-1*h-1)
CoxCeyOz
6
6
100
100
100
100
80
Decalin
Decalin
Water
66
92
78
67
66
48
70
85
54
92
9
0.03
0.09
0.15
1.53
0.91
0.96
6.07
11.33
RuCoxCeyOz
RuCoxCeyOz
RuCoxCeyOz
RuCoxCeyOz
RuCoxCeyOz
ETS-4
6
6
GVL
54
5
6
Water
6
60
Water
2
6
100
100
Decalin
Acetic Acid
58
85
ETS-4€
0.75
Note: RuCoCeO2 refers to 5 wt. % Ru supported on CoxCeyOz oxide. STY refers to the site time yield calculated as the moles of product per mol of catalyst per unit of time.
Addition of 5 wt. % Ru to the CoxCeyOz led to a significant
improvement in the selectivity and activity of the catalyst that
resulted in conversion values of c.a. 92 % and yield to crotonic
acid of 100 %. The high activity and selectivity of this reaction
could be attributed to the cooperative interaction between Ru and
Ce sites on the CoO(OH) surface that facilitate the oxidation of
the Co2+ to Co3+, which are believed to be the active sites for the
aerobic oxidation of aldehydes to acids via radical chain
reaction.[15–17]
oxidation of the acyl radical with oxygen leads to an acylperoxy
that abstracts a hydrogen from another aldehyde to yield a
peracid and another acyl radical. This peracid undergoes
protonation to carboxylic acid, water, and oxidized Co3+ sites.
[15,16,18] Due to the Lewis character of the Co centers it is possible
that water competes with the acylperoxy radicals for the
coordination sphere of the Co3+ cations. This competition in
combination with the quenching of chain-propagating radicals in
aqueous phase, could explain the lower rates of reaction
observed in water. Decreasing temperature from 100 °C to 80 and
60 °C did not improve the selectivity of the reaction in aqueous
environments (Table 1). Instead, the selectivity to crotonic acid
monotonically decreased as the temperature decreased,
indicative of low activation barriers for the secondary reactions in
the aqueous phase.
Notably, when the reaction was performed in water using the
RuCoxCeyOz the croton aldehyde conversion and crotonic acid
yield decreased substantially to ~ 63 % and 8 %, respectively (Fig.
1). Kinetic and mechanistic studies have shown that the oxidation
of aliphatic aldehydes starts with the reaction of the carbonyl
aldehyde group and the Co3+ sites to form acyl radicals, protons
with the concomitant reduction of the cobalt sites to Co2+. The
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By changing the solvent to a dipolar aprotic organic solvent such
as g-valerolactone (GVL) we observed similar conversion as that
obtained in water (c.a. 67 %), while the yield to crotonic acid
increased to 54 % (Fig. 1). The differences in yield in the two
solvent environments was caused by the activation of acid
catalyzed condensation reactions. In the aqueous phase crotonic
acid can partly dissociate (crotonic acid pKa = 4.69[19] and water
proton affinity 681.9 kJ/mol[20]), lowering the pH of the reaction
media and activating the vinylic bonds of the crotonaldehyde and
crotonic acid. Furthermore, acid catalyzed aldol-condensation of
the crotonaldehyde could also be enhanced at low pH. For this
reason, often oxidation reactions in aqueous environments are
performed in alkaline media.[17]
and HPLC for quantification. The results showed that before
reaction only the crotonic acid can be detected by C13-NMR (Fig.
S2). After 3h of reaction at pH 2.9 additional chemical shifts
appeared in the C13-NMR spectra that corresponded to the
formation of the epoxide (3-methyloxirane-2-carboxylic acid) and
a,b-dihydroxy acid (2,3-dihydroxybutanoic acid). At pH 2.9 the
molar fraction of epoxide was lower (22 mol. %) than that of the
a,b-dihydroxy acid (37 mol. %) (Fig. 2). The high yields to the di-
hydroxy acid (37 %) in the acidic environment can be ascribed to
the hydrolysis of epoxide ring (Table S3). The exact mechanism
of this reaction, step e in Scheme 1, is still under debate. Early
work on kinetic isotope effects on the hydrolysis of ethylene oxide
showed that there are two possible mechanisms (SN1 and
SN2).[21–23] In both mechanisms, the first step is the protonation of
the epoxide oxygen in a fast equilibrium step.[21,24] The second
step is either the decomposition of the conjugated acid followed
by rapid reaction of the carbonium ion with water (SN1
mechanism) or the bimolecular substitution of the conjugated acid
with water (SN2 mechanism).[25] A similar strategy is applied
industrially for the production of ethylene glycol from ethylene
oxide, although at higher temperature (200 °C).[26]
To reduce the rate of a,b-dihydroxy acid formation we decided to
increase the pH to 6.4 by adding KOH to the reaction mixture (Fig.
2). The C13-NMR results indicated that the two main species
present in the reaction mixture after 3 h of reaction were crotonic
acid and the epoxide. At these conditions, the conversion of
crotonic acid increased to 89% and the yield of 3-methyloxirane-
2-carboxylic acid and 2,3-dihydroxybutanoic acid were 76 and
22 %, respectively (see Table S3). Previous reports indicate that
increasing the pH beyond 7 leads to faster rates of hydrolysis,[21,24]
which in our case would have led to higher selectivity to 2,3-
dihydroxybutanoic acid. These results indicate that nearly neutral
pH can effectively reduce the rate of epoxide hydrolysis
increasing the selectivity towards the epoxide adduct.
Figure 1: Crotonaldehyde conversion and crotonic acid yield
obtained on different solvents during the aerobic oxidation
reaction of crotonaldehyde at 38 bar of synthetic air and 80 °C
using 200 mg of RuCoxCeyOz in decalin.
The results of crotonaldehyde aerobic oxidation to crotonic acid
using the ETS-4 indicated that on decalin it is possible to achieve
c.a. 58 % yield at 70 % conversion, which is similar to the results
obtained on the CoxCeyOz catalyst. Notably, when the solvent was
changed to acetic acid, the conversion and yield significantly
increased resulting in quantitative production of crotonic acid (c.a.
91 mol. C %) in the presence of 50 mg of catalyst. This
enhancement led to STY that were two orders of magnitude
higher (11.3 mol*g-1*h-1) than those obtained in the Ru CoxCeyOz
catalyst in decalin (0.09 mol*g-1*h-1). The higher yield and activity
of this reaction could be attributed to the formation of peracetic
acid. During aerobic oxidation the partially uncoordinated Ti
cations can act as Lewis acid sites that activate the formation of
peroxide species. These species can be selective oxidizing
agents for the conversion of the crotonaldehyde to crotonic acid.
Detailed batch reaction experiments were performed for several
reaction times, using only 50 mg of ETS-4 catalyst. About 84 %
of conversion was obtained during the first three hours of reaction
(Fig. S1). At this point the rate of the reaction plateaued. Notably,
at this point the selectivities achieved were c.a. 92-100 %.
Figure 2. Molar distribution obtained at different initial pH (6.4 and
2.9) after 0.5 h of the epoxidation reaction of crotonic acid (0.255
mol/L) at 65 °C and atmospheric pressure using 77 mg of WO3
catalyst synthesized by combustion. The volume of H2O2 was 230
µL of H2O2 at a concentration of 10 vol. %.
Then, we studied the selective epoxidation of crotonic acid over
Sharpless-like catalysts based on tungsten oxide catalysts in the
presence of diluted hydrogen peroxide as oxidant at 65 °C (step
d in Scheme 1). We employed C13-NMR for product identification
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The performance of the WO3 catalyst prepared using the
combustion method was compared with commercial WO3 (Sigma-
Aldrich), and SBA-15 doped with WO3 prepared by incipient
wetness impregnation (Fig. 3). The molar distribution after 0.5 h
of reaction indicates that with the WO3 combustion catalyst it was
possible to obtain up to 54 mol. % of the epoxide (3-
methyloxirane-2-carboxylic acid), while in the case of commercial
WO3 and WO3-SBA-15 catalysts these values decreased to 15
and 7 %, respectively. With all the catalysts, formation of the a,b-
dihydroxy acid (2,3-dihydroxybutanoic acid) was low due to the
near neutral pH employed during reaction.
The HPLC analysis of the product mixture obtained from the
homogeneous reduction of isolated 3-methyloxirane-2-carboxylic
acid in aqueous solution indicated that this reaction step can be
readily accomplished with very high chemo-selectivity (c.a. 100%)
at 40 % conversion. These promising results served as basis for
the evaluation of the second set of experiments using the un-
purified 3-methyloxirane-2-carboxylic acid in the presence of 34
bar of H2 and 5 wt.% Ru/C catalyst. The reaction mixture was
composed of crotonic acid, 3-methyloxirane-2-carboxylic acid,
and 2,3-dihydroxybutanoic acid (Table 2).
Table 2. Concentration of reactant and products in the
hydrogenation of crotonic acid epoxidation product on 50 mg of 5
wt. % Ru/C after 2 h of reaction at 180 °C, 34 bar of hydrogen and
800 rpm of agitation in a total volume of 100 ml.
Composition
Feed
(mol*L-1)
Product
(mol*L-1)
Conversion
(%)
Yield (%)
0.14
0.21
0
0
100
100
0
0
OH
O
0.036
0.036
0.14
0.19
100
0
0
100
-
H3C
OH
OH
0
0
OH
O
0
H3C
OH
Figure 3. Molar distribution obtained after the reaction of crotonic acid (0.255
mol/L) epoxidation at pH 6.4 and 65 °C and atmospheric pressure after 0.5
hours using 50 mg of catalysts and 230 µL of H2O2 at 10 vol. %.
After reaction, the crotonic acid and 3-methyloxirane-2-carboxylic
acid were quantitatively hydrogenated towards butanoic acid and
3-hydroxy-butanoic acid, respectively. In contrast, the a,b-
dihydroxy acid (2,3-dihydroxybutanoic acid) remained unreacted
after the reaction. Notably, the chemoselectivity of the
hydrogenation of 3-methyloxirane-2-carboxylic acid towards 3-
hydroxy-butanoic acid was 100%.
Significantly lower conversions were obtained for the commercial
WO3 and WO3-SBA-15, which only yielded 16 and 7 %,
respectively (see Table S4). Here, it was observed that WO3
prepared using the combustion method achieved rates of c.a. 9
mol*h-1*mol of WO3, while in the case of WO3 supported on SBA-
15 and commercial WO3 catalysts the rates were 6.1 and 2.3
mol*h-1*mol of WO3, respectively. Diffuse reflectance UV-vis
characterization of the as-prepared catalysts indicated that in the
WO3 catalyst the UV-visible absorption edge was shifted towards
higher wavelengths in comparison to the WO3 commercial, which
can be assigned to isolated tetrahedral and small oligomers WOx
(Fig. S3). In contrast, the UV-vis spectrum of WO3-SBA-15
catalyst showed an absorption maximum at 230 nm in
combination with a superimposed shoulder at c.a. 260 nm, which
can be assigned to isolated tetrahedral and small oligomers WOx.
Previous kinetic and spectroscopic studies reported by C.
Hammond et al.[28] on epoxidation of cyclooctene in 1-butanol
using W-Zn/SnO2 catalyst showed that the most active and stable
species during epoxidation of cyclooctene was not the isolated
Wiv species, but instead the polymeric and bulk WO3 phases. This
could explain the higher activity of the WO3 prepared by
combustion.
In summary, the utilization of tandem oxidation, epoxidation,
followed by epoxy-ring activation by either hydrolysis or
hydrogenation offers a flexible platform for the production of
specialty chemical building blocks from biomass-derived ethanol
derivatives. This strategy allows for the selective conversion of
bio-ethanol to crotonic acid, 3-hydroxy butanoic acid, and 2,3-
dihydroxyacid at high carbon yields (62, 21, and 29 %,
respectively). Our preliminary cost analysis indicates that it is
possible to obtain crotonic acid, 3-methyloxirane-2-carboxylic
acid, 3-hydroxy butanoic acid with costs of c.a. 2.8, 3.1, and 3.1
$/Kg, respectively, for an ethanol cost of 1 $/liter (Tables S7-10
and Fig. S10).
We have successfully demonstrated that using an intermediate
step of epoxidation of the unsaturated acid it is possible to
selectively produce b-hydroxy acids and a,b-dihydroxy acids,
which are otherwise inaccessible via direct oxidation of the aldol-
adduct. We envision that the heterogeneous catalytic cascade
approach that we have developed here can serve as a basis for
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COMMUNICATION
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Keywords: Bioethanol • unsaturated acids • hydroxy-acids
polyhydroxyalkanoates • chemical building blocks • tandem
chemistry
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10.1002/anie.202002049
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
We have developed a flexible chemical
platform for the conversion of
bioethanol into three distinct specialty
chemical building blocks, including:
crotonic acid (i), 3-hydroxy butanoic
acid (ii), and 2,3-dihydroxyacid (iii) at
high yields (62, 21, and 29,
respectively), which can serve as basis
for the production of numerous high-
value chemical building blocks from
bio-ethanol.
D. Santhanaraj, M. P. Ruiz,, M. R.
Komarneni, T. Pham, D. E. Resasco,
and J. Faria*
Page 1 – Page 4
Synthesis of
a
,
b
-Unsaturated Acids, -
-Hydroxy
Dihydroxy Acids and
b
Acids via Tandem Aldehyde
Oxidation and Vinyl Epoxidation of
Bioethanol-Derivatives
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