A sustainable synthetic route for biobased 6-hydroxyhexanoic acid, adipic acid and ?-caprolactone by integrating bio- And chemical catalysis

Article abstract of DOI:10.1039/d0gc01454k

A green route for the production of 6-carbon polymer building blocks 6-hydroxyhexanoic acid, adipic acid and ?-caprolactone from 1,6-hexanediol, a hydrogenation product of biobased 5-hydroxymethylfurfural is reported. Gluconobacter oxydans oxidized 1,6-hexanediol completely to adipic acid, and selectively at pH 6-7 to 6-hydroxyhexanoic acid, which was converted to ?-caprolactone by catalytic cyclization. This journal is

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DOI: 10.1039/D0GC01454K
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A sustainable synthetic route for biobased 6-hydroxyhexanoic
acid, adipic acid and ε-caprolactone by integrating bio- and
chemical catalysis
Received 00th January 20xx,
Accepted 00th January 20xx
Sang-Hyun Pyo a,*, Ji Hoon Park b, Vanessa Srebny a, and Rajni Hatti-Kaul a
DOI: 10.1039/x0xx00000x
A green route for production of 6-carbon polymer building
Fossil based AA and ε-CL are already well-established
blocks 6-hydroxyhexanoic acid, adipic acid and ε- products. AA, the aliphatic dicarboxylic acid is an essential
caprolactone from 1,6-hexanediol, a hydrogenation product commodity chemical for commercial manufacturing of Nylon-
of
biobased
5-hydroxymethylfurfural
is
reported. 6,6 and polyurethanes, and is now also used as a component
Gluconobacter oxydans oxidized 1,6-hexanediol completely in the biodegradable polyester poly(butylene adipate
to adipic acid, and selectively at pH 6-7 to 6-hydroxyhexanoic terephthalate) (PBAT). It is produced almost exclusively from
acid, which was converted to ε-caprolactone by catalytic cyclohexane, derived from petroleum benzene in an inefficient
cyclization.
oxidation process which releases N2O, a potent greenhouse
gas (Scheme S1) [19]. A selective synthetic method for AA, 1,6-
Decoupling industrial production from fossil resources is HD, and 1,6-hexanediamine (1,6-HMD) via adipic aldehyde
drawing increasing attention as contribution of fossil based diacetal obtained by double-n-selective hydroformylation of
greenhouse gas emissions to climate change is becoming a 1,3-butadiene has been described [15]. Different approaches
global concern [1-5]. Biobased 5-hydroxymethylfufural (HMF) for producing biobased AA have been reported in recent
is projected to be an important platform for functional years. Gilkey et. al. reported up to 89% yield of AA from
building blocks for fuel, chemical and polymer industry, thanks tetrahydrofuran-2,5-dicarboxylic acid prepared from FDCA, by
to the presence of reactive aldehyde and alcohol groups and metal-free selective hydrogenolysis in a propionic acid solvent
the furan ring. Hence, the past decade has seen intensive at 160 °C. Several metabolic engineering approaches have
research in process development for its production from C6- been proposed for production of AA from sugars and lipids,
sugar monomers and cellulose [6,7]. Further conversion of often with low yields [20,21].
HMF
to
polymer
building
blocks
including
5-
hydroxymethylfurancarboxylic acid (HMFCA) and 2,5-
furandicarboxylic acid (FDCA) by oxidation, 1,6-hexanediol
(1,6-HD) by catalytic hydrogenation [8,9], as well as levulinic
acid by hydration, have gained considerable attention [7,10-
13].
Production of biobased 1,6-HD allows access to other
valuable C6-products like 6-hydroxyhexanoic acid (6-HHA),
adipic acid (AA) and ε-caprolactone (ε-CL), with applications
both as platform chemicals and as building blocks for
important polymers [1,3,14-16] (Scheme 1). Production of 1,6-
HD by direct hydrogenations of HMF using double layered
catalysts of Pd/SiO2 and Ir–ReOx/SiO2 (with 57.8% yield) [9],
and Pd/ZrP (43% yield) [17], and by hydrogenation of a HMF
derivative, tetrahydrofuran dimethanol using Pt-WOx/TiO2
(70% yield) [18] have been reported.
O
O
HO
[O]
[H2]
O
O H
O H
HO
HO
H
Biocat.
1,6-HD
6-HHA
NH3
5-HMF
IEx
NH2
[O]
Biocat.
IEx, MS
H2
N
1,6-HMD
O
O H
O
O H
O
HO
O
NH3
NH
O
HO
O H
O H
HO
Fructose
(Biomass, e.g. glucose,
fructose, sucrose)
O
Caprolactam
ε-CL
AA
Scheme 1. An integrated microbial-chemical route for the
production of biobased 6-hydroxyhexanoic acid (6-HHA),
adipic acid (AA), and ε-caprolactone (ε-CL) via 5-
hydroxymethylfurfural (5-HMF) and 1,6-hexanediol (1,6-HD.
Biocat: biocatalyst; IEX: ion exchange catalyst. The route can
be extended to ε-caprolactam and 1,6-hexamethylenediamine
(1,6-HMD) through amination (dotted arrows) [8,15].
a. Biotechnology, Department of Chemistry, Center for Chemistry and Chemical
Engineering, Lund University, SE-22100 Lund, Sweden
b. Center for Environment & Sustainable Resources, Korea Research Institute of
Chemical Technology (KRICT), Daejeon, Republic of Korea
* Corresponding author, E-mail: Sang-Hyun.Pyo@biotek.lu.se (S.-H. Pyo)
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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COMMUNICATION
Green Chem.
The oxidation of 1,6-HD to 6-HHA DrOeqI:u10ir.1e0s3V9oie/Dxwi0dAGratiCctli0eo1On4n5l4ionKef
ε-CL, used primarily in the production of biodegradable
poly(caprolactone), is industrially produced at a multi-10 000 only one hydroxyl group to carboxylic acid group via an
ton scale per year by the UCC process [16,22,23], in which aldehyde intermediate, while AA is produced as the end
cyclohexanone is oxidized by using stoichiometric amounts of product by complete oxidation of both hydroxyl groups
peracetic acid, with associated drawbacks of toxicity, ecology, (Scheme 2 and S2).
and safety [23].
1,6-HD was efficiently transformed to ε-CL using methyl
isobutylketone (MIBK) as oxidant and a catalyst system
([{Ru(cymene)Cl2}2] and 1,1’-bis(diphenylphosphino)
ferrocene)) by Oppenauer oxidation [8]. However, the
stoichiometric amounts of the reduction product of MIBK, 4-
methyl-2-pentanol was formed, hence direct dehydrogenation
of 1,6-HD to caprolactone without the use of an oxidant would
be much preferred, but to date selectivities are too low [8].
Baeyer–Villiger monooxygenase (BVMO) enzymes
including the preferred cyclohexanone monooxygenase
G. oxydans
(A)
O
O
< pH 5
O H
O H
O H
HO
HO
HO
X
O
> pH6
1,6-Hexanediol
Mycobacterium
6-Hydroxyhexanoic acid
Adipic acid
(B)
MS16
O
O
O H
O H
O H
X
HO
HO
HO
O
1,6-Hexanediol
6-Hydroxyhexanoic acid
Adipic acid
(CHMO) from Acinetobacter calcoaceticus, catalyse the Scheme 2. Synthesis of adipic acid by microbial selective
oxidation of cyclohexanone to ε-CL in the presence of O2 oxidation of 1,6-hexanediol via 6-hydroxyhexanoic acid.
[23,24], however the system suffers from low productivity and
stability of the CHMO, which is also subject to substrate and
product inhibition [23]. To overcome the inhibition, a direct
ring-opening oligomerization of ε-CL by Candida antarctica at 81ꢁ% yield and 93ꢁ% selectivity (with AA as by-product) was
lipase A was reported, which resulted in the formation of achieved by the use of
more than 20 g/L of oligo-ε-CL from 200 mM cyclohexanol hydrotalcite-supported N,N-dimethyldodecylamine N-oxide
[23]. (DDAO)-capped bimetallic Au–Pd nanoparticles
In an earlier report, selective oxidation of 1,6-HD to 6-HHA
Kara et al. reported the oxidative lactonization of 1,6-HD (Au40Pd60-DDAO/HT) as catalyst [26]. Besides the noble metal
to ε-CL with 26% yield catalyzed by horse liver alcohol catalysts, the reaction required the use of an oxidant (H2O2)
dehydrogenase in a two-liquid phase system [24]. In a and a base. In contrast, biocatalysis can be performed under
subsequent study,
a convergent bi-enzymatic cascade milder reaction conditions without the use of oxidant and
involving BVMO and an alcohol dehydrogenase was designed provide higher product selectivity [11,31]. Biotransformation
to produce 3 molar equivalents of ε-CL from cyclohexanone of 1,6-HD to AA using Gluconobacter oxydans subsp. oxydans
(two equivalents) and 1,6-HD (one equivalent) in one pot has been reported earlier, but only limited information was
process [25]. The BVMO catalysed processes are however still provided on experimental details and results [32]. The acetic
dependent on the petroleum-based cyclohexanone. Buntara acid bacteria G. oxydans are also known for performing
et al. have reported a novel process to caprolactam and ε-CL selective oxidations [11]. G. oxydans DSM 50049 was recently
through 1,6-HD from HMF [8].
reported to selectively oxidize the aldehyde group of HMF to
6-HHA has potential applications in dermopharmaceutical, form 5-hydroxymethylfuran carboxylic acid (HMFCA) under pH
cosmetic and polymer sectors, especially for the production of control at 7 [11].
poly(caprolactone) [16,26]. The classical synthetic route of 6-
The same strain when used for oxidation of 1,6-HD,
HHA includes metal-catalyzed reduction of AA at 523ꢀK with oxidized both the hydroxyl groups of the diol to carboxylic acid
300ꢀbar H2 [16,27], and is also formed as a by-product by ring groups to give AA via 6-HHA as intermediate (Figure 1, Figure
opening and oxidation of caprolactone in the AA production S1) (Scheme 2A). 1,6-HD at a concentration of 84.6 mM in 100
[26,28]. Recently, a multi-enzyme cascade reaction for the mM phosphate buffer pH 7 was completely oxidized to AA
production of 6-HHA was reported, involving whole cells of within 36 hours. Although slower conversions were observed
Escherichia coli co-expressing an alcohol dehydrogenase and a with higher concentration of 1,6-HD, the amounts of AA
CHMO for oxidation of cyclohexanol to ε-CL, which was ring- produced were linearly increased without exhibiting any
opened to 6-HHA using C. antarctica lipase B [29]. A route to substrate or product inhibition, which resulted in higher
biobased 6-HHA is via the selective oxidation of 1,6-HD, overall oxidation rate and efficiency with the same amount of
however the selective oxidation of primary aliphatic diols cells (Figure S1).
becomes difficult as the length of the carbon chain between
the two hydroxyl groups increases [30].
Since the aldehyde intermediate was observed in low
concentration or not observed at all during the initial reaction
In this study, we present a new synthetic route for time, aldehyde dehydrogenase activity in the bacteria was
generating biobased 6-HHA, AA and ε-CL from 1,6-HD most likely higher than that of the alcohol dehydrogenase; the
produced from HMF, by integrating bio- and chemical catalysis risk of biocatalyst inactivation by accumulation of the toxic
(Scheme 1,2). This value chain can be extended further to aldehyde could thus be avoided. During the course of the
caprolactam and 1,6-HMD.
reaction, pH of the medium was decreased from initial pH 7 to
4.3.
2 | J. Name., 2012, 00, 1-3
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Green Chemistry
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Green Chem.
COMMUNICATION
(Figure 2); 100% conversion of 42.3 mM 1,6-HD, at initial
reaction pH of 7, was achieved with 100% produVcitewseArlteiccletiOvniltinye.
DOI: 10.1039/D0GC01454K
However, with increasing concentration of 1,6-HD, the
conversion rate and product amount were significantly
decreased although still maintaining the selectivity (Figure 2).
The enzymes involved are most likely subject to substrate
inhibition, hence bioprocess engineering such as fed batch
mode of reaction and in situ recovery of product could be the
solution to reduce the inhibition and to improve the
productivity.
Figure 2. Selective oxidation of 1,6-HD to 6-HHA at 30 C by
Mycobacterium sp. MS16. Conversion of 1,6-HD (%, ♦) at initial
diol concentrations of 42.3, 84.6, 126.9 and 169.2 mM,
respectively, and content of 6-HHA (mg/mL, ●) formed at 36 h
reaction time.
Since the oxidative activity of the responsible enzymes in G.
oxydans and Mycobacterium sp. might depend on the reaction
pH, the degree of substrate conversion and product profiles
were also determined with initial pH at 5 instead of pH 7
(Figure 3). G. oxydans oxidized 1,6-HD to AA via 6-HHA, while
Mycobacterium sp. exhibited very low activity with 18%
conversion mainly to AA with 6-HHA as a minor product. It
seems therefore that the lower pH is more favourable for
adipic acid formation in both cases. While the reaction efficiency
seems to be slightly increased at pH 5 with G. oxydans cells as
catalyst, both the reaction efficiency and the product profiles were
altered in case of Mycobacterium sp. Especially the oxidation of
1,6-HD was negatively affected in the latter case.
Figure 1. Oxidation of (A) 42.3 mM, (B) 84.6 mM, (C) 126.9
mM and (D) 169.2 mM 1,6-hexanediol to adipic acid via 6-
hydroxyhexanoic acid by G. oxydans 50049 at 30 C. The initial
pH of the reaction was 7. The symbols indicate conversion (%)
of 1,6-HD (♦), and content (%) of 6-HHA (■) and AA (▲) in the
reaction.
Figure 3. Comparison of pH effect on the oxidation of 84.6
mM 1.6-HD at 12 h and 24 h at pH 5 by G. oxydans DSM 50049
and Mycobacterium sp. MS16, respectively.
Meanwhile, selective (incomplete) oxidation of 1,6-HD to
6-HHA was achieved by Mycobacterium sp. MS16 (Scheme 2B)
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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COMMUNICATION
hese observations provide the basis for a unique
approach for controlling the selectivity of the microbial
oxidation reaction using G. oxydans by simple switching of pH,
one of the key parameters in biotransformation. In further
investigations, reactions with shorter and longer aliphatic diols
will be run to determine if their oxidation to the
corresponding hydroxyl-carboxylic acids and di-acids could be
achieved by controlling the reaction pH.
Green Chem.
[34-36]. Based on Lewis versus Brönsted contribuVtiieownAsr,ticFleriOendlineel
T
Crafts reactions are better performed with zeolites, whereas
DOI: 10.1039/D0GC01454K
the etherification of alkenes with light alcohols is essentially
performed with cation exchange resins in the H+ form.
Although the two catalysts could individually convert 6-HHA to
ε-CL and also a by-product ε-formyloxyhexanoic acid (ε-FOHA),
(Table 1), the combination of two catalysts enhanced the
formation of cyclic product, ε-CL with 74.4% selectivity at
98.3% 6-HHA conversion (Table 1, Entry 11).
This method provides a useful approach for the direct
lactonization of ω-hydroxy acid without activation of acid to
ester or anhydrous form. With both the catalysts, the
conversion of 6-HHA and selectivity of cyclization to ε-CL
increased with increasing amount of molecular sieves (Figure
S2). The molecular sieves most likely promote the cyclization
process through scavenging of H2O resulting from the
dehydration. In our previous report, we have successfully
demonstrated the use of molecular sieves for cyclization of
polyols including 1,3-type diols such as 1,3-propanediol and 2-
methyl-1,3-propanediol, and trimethylolpropane in reaction
with dimethylcarbonate to form cyclic carbonates [37]. ε-
FOHA could be formed by the reaction between formyl group
of DMF and hydroxyl group of 6-HHA in the acidic
environment. The formation of ε-FOHA was increased with
decrease in the amount of molecular sieves, and the highest
amount was formed when no molecular sieves were used
(Table 1, entry 2).
Further studies with oxidation of 1,6-HD using G. oxydans
revealed shift in the selectivity from AA to 6-HHA by
controlling the pH at 6-7 (Scheme 2A). As seen in Figure 4,
addition of 1,6-HD in a fed-batch mode (total amount 250 mg)
over a period of 100 hours led to quantitative production of 6-
HHA while showing no product inhibition (Figure 4).
Comparing with the productivity (4.39 mmol h-1 mgdcw-1) in the
selective oxidation of the aldehyde group in HMF (16 mg/L,
126.8 mM) to form HMFCA under similar conditions (about 4
mg/mL cell dry weight and 6 h reaction time) [11], lower
productivity (1.34 mmol h-1 mgdcw-1) was observed in the
oxidation of 1,6-HD (10 mg/mL, 84.6 mM) to 6-HHA at 6 h of
reaction (Figure 4). This is most likely due to the higher
substrate concentration and the two-step oxidation of alcohol
to acid via aldehyde in the present work. The extremely high
selectivity of the reaction provides a definite advantage over
the metal catalysed oxidation of 1,6-HD reported earlier [26].
Table 1. One-pot cyclization and esterification of
hydroxyhexanoic acid (6-HHA) to ε-caprolactone (ε-CL) by
combination of two acidic heterogeneous catalysts. Reaction
conditions: 0.38 mmol 6-HHA in 1.5 mL DMF at 140 C using
given amounts of molecular sieves (MS) and cation exchange
resin DR-2030. ε-Formyloxyhexanoic acid (ε-FOHA) was
a
b
formed as a byproduct (Figure S5). Analyzed by GC. Overall
isolated yield (mol/mol) from 1,6-HD through 6-HHA by
integrating bio- and chemical catalysis.
Selectivity (%) a
Time Conversion
MS
(g)
IEx
(mg)
Entry
(h)
(%) a
ε-CL
43.5
47.4
51.0
61.3
51.3
53.9
64.1
63.1
62.2
73.1
ε-FOHA
14.0
46.3
30.3
17.4
18.4
22.8
15.8
17.8
12.2
15.5
Figure 4. Continuous selective oxidation of 1,6-HD to 6-HHA by
G. oxydans DSM 50049 at 30 C with pH control at pH 6.5-7 in
a reaction volume of 10 mL in a 50 mL bioreactor. Symbols:
accumulated 6-HHA amount (mg, ■), 1,6-HD content (mg, ▲),
and pH (♦). Arrows indicate addition of 50 mg 1,6-HD at 0, 24,
44, 60 and 72 h, respectively.
1
0.5
0
0
20
20
20
20
9
77.9
50.5
60.3
86.6
90.0
88.9
90.5
90.8
94.6
97.0
2
50
3
0.25
0.5
0.5
0.5
0.75
0.75
1
25
4
50
5
100
100
75
Finally, conversion of 6-HHA to ε-CL was investigated. In
general, lactonization to a ring of more than 7-carbons from
ω-hydroxy acids or esters is not efficient, since inter-molecular
esterification occurs as the main reaction [33]. Lactonization
of ethyl 6-hydroxyhexanoate to ε-CL with quantitative yield
was achieved in a flow reactor with a fixed-bed catalyst
hydrous zirconium (IV) oxide at 250 C [33], while direct
lactonization of the acid form, 6-HHA is still rare. We made use
of molecular sieves (4Å, zeolites composed of sodium
aluminosilicate) and acidic ion exchange resin for performing
the catalytic lactonization of 6-HHA in dimethylformamide
(DMF) at 130-160 C (Table 1). Molecular sieves (zeolites) and
cation exchange resins may be considered as recyclable and
“green” Brönsted and/or Lewis acid heterogeneous catalysts
6
20
9
7
8
75
20
9
9
50
10
1
100
9
74.4
11
1.5
50
6
98.3
12.5
(67.2)b
Interestingly, the synthesis of ε-FOHA is rare, and its formation
as a co-product has been reported during production of 6-HHA
from the peroxides of cyclohexanone, formed by reaction of
cyclohexanone with hydrogen peroxide, using concentrated
4 | J. Name., 2012, 00, 1-3
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Green Chemistry
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COMMUNICATION
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required to find optimal processes.
Conclusions
We have demonstrated a new facile process to produce
industrially important 6-carbon chemicals such as 6-HHA, AA
and ε-CL from renewable resources, and which can be further
valorized to caprolactam and 1,6-HMD, and their polymers.
The biobased synthetic route, highly selective and controlled
oxidation of diol to ω-hydroxy acid or dicarboxylic acid, and
catalytic cyclization of ω-hydroxy acid can be a valuable model
for an environmentally friendly synthetic process for
chemicals and polymers by integrating biotechnology and
chemical synthesis.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was performed within the research program,
Sustainable Plastics and Transition Pathways (STEPS) at Lund
University supported by the Swedish Foundation for Strategic
Environmental Research (Mistra) (grant no. 2016/1489), and
was also supported by the Swedish Research Council VR (grant
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COMMUNICATION
Green Chem.
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View Article Online
DOI: 10.1039/D0GC01454K
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Green Chemistry
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DOI: 10.1039/D0GC01454K
A sustainable synthetic route for biobased 6-hydroxyhexanoic
acid, adipic acid and ε-caprolactone by integrating bio- and
chemical catalysis
Table of contents entry
Green synthetic route and possible utilization of biobased 6-carbon polymer building blocks
6-hydroxyhexanoic acid, adipic acid and ε-caprolactone from biomass via 1,6-hexanediol, a
hydrogenation product of biobased 5-hydroxymethylfurfural.