Transiting from Adipic Acid to Bioadipic Acid. Part II. Biosynthetic

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Transiting from adipic acid to bio-adipic acid Part II. Biosynthetic pathways Jan C.J. Bart, and Stefano Cavallaro Ind. Eng. Chem. Res., Just Accepted Manuscript • Publication Date (Web): 18 Dec 2014 Downloaded from http://pubs.acs.org on December 18, 2014

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Industrial & Engineering Chemistry Research

Transiting from adipic acid to bio-adipic acid Part II. Biosynthetic pathways Jan C. J. Bart and Stefano Cavallaro* Dipartimento di Ingegneria Elettronica, Chimica e Ingegneria Industriale dell’Università di Messina, Viale F. Stagno D’Alcontres, 31 – 98166 Sant’Agata di MESSINA (ITALY).

ABSTRACT: Bio-based reaction pathways toward adipic acid starting from renewables such as glucose or vegetable oils are more benign than the traditional petrochemical approaches.

Various combined

fermentative/chemo-catalytic or fully enzymatic adipic acid processes are now emerging. It is reasonable to expect that high-quality bio-adipic acid can technically be introduced into the market within the next few years. This review paper describes the imminent transition from adipic acid to bio-adipic acid. Keywords: Bio-adipic acid, renewables, green chemistry, biotechnology, prospective manufacturing technologies.

*Corresponding author: Stefano Cavallaro Tel +39-090-393134 Fax: +39-090-391518 E-mail address: [email protected] (S. Cavallaro)

Contents 1. Introduction 2. Prospective manufacturing technologies of bio-adipic acid 2.1 Technology for non-commercial bio-based routes to adipic acid from glucose 2.2 Emerging bio-based adipic acid production technologies 3. Life-cycle analyses of adipic acid processes 4. Conclusions and prospects 5. References 1 ACS Paragon Plus Environment


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1. Introduction In a previous paper the current prospects for an innovative commercial petrochemical process to the commodity chemical adipic acid (AA), a monomer widely used in the production of nylon resins and fibres, as well as an important component of polyurethane resins and foams, and non-phthalate plasticisers, have been evaluated and judged unsatisfactory (1). Given the product’s production volume (approximately 2.6 Mt/y) and the waste produced by the current complicated process (although virtually no NO2 and N2O waste in case of end-of-pipe solutions), a more sustainable pathway to adipic acid synthesis is an important target of green chemistry (2). Replacement of the traditional petrochemical process route to adipic acid via cyclohexane oxidation by a biocatalytic process is hampered by: (i) the highly conservative bulk chemical industry (in connection with plant depreciation times); (ii) no shortage of benzene for chemical production; and (iii) expensive enzymes. As oil becomes increasingly scarce and expensive, biological processing of renewable raw materials in the production of chemicals using live microorganisms or their purified enzymes will become increasingly interesting. This paper examines the prospects for renovation of industrial adipic acid manufacture by biotechnological pathways.

2. Prospective manufacturing technologies of bio-adipic acid Commercial multi-step adipic acid manufacturing, via cyclohexanol from benzene, although efficient and low cost, requires improvement for a variety of reasons (1). Apart from operational complexity and safety concerns, there is the problem of resource management. Use of petrochemicals is not sustainable and greener approaches are highly wanted. It is desirable to provide a synthesis route for adipic acid which not only avoids reliance on environmentally sensitive starting materials but also makes efficient use of inexpensive, renewable resources, avoids significant energy inputs and minimises formation of toxic by-products. In the next Sections we consider manufacturing techniques of bio-adipic acid. It is becoming increasingly more interesting for industry and beneficial to the environment to engineer biological, microbial routes to adipic 2 ACS Paragon Plus Environment

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acid. Recent advances in genetic engineering are bringing forth new possibilities for biocatalysis such as the synthesis of the important bulk chemical adipic acid from renewable feedstocks. As will be seen, a bio-based chemicals industry does not necessarily imply total reliance on biotechnology and fermentation.

Fig. 1. Some basic modes of access to bio-adipic acid by fermentation processes (dashed) and chemocatalytic conversions (bold).

Figure 1 shows possible access to bio-based adipic acid. As to the various options (feedstocks), it should be pointed out that petrochemical processes based on butadiene (carbonylation or hydrogenation) lead to adiponitrile but this is not used for adipic acid but only for 1,6diaminohexane. Similarly, adiponitrile from acrylonitrile is not a pathway for adipic acid. A number of microbiological routes to adipic acid have been described. An early proposal for the preparation of adipic acid by Minoda et al. (to Nissan Chemical Industries, Ltd) consists in culturing microorganisms belonging to the Nocardia genus in a medium added with an aliphatic C6C18 (di)amine at 20-40°C at pH 6-10 for 18-72 h under aerobic conditions (3). Another early process, combining elements of biocatalysis and chemistry, entails the multi-step chemical conversion of biomass (including paper, wood, corn stalks and many low-cost renewables) into 1,6hexanediol, which is then oxidised to adipic acid by Gluconobacter oxydans, see Fig. 2 (4). While this process relies on cheap starting materials, it requires multiple chemical conversions which are carried out at elevated temperatures (100° to 350°C) and pressures and employs multiple metal catalysts including copper chromite. No further development has been reported.

Fig. 2. Process for producing adipic acid from biomass. 3 ACS Paragon Plus Environment


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After ref. (4).

As indicated in Fig. 1, bio-based production of adipic acid may proceed through precursors such as

cis,

cis-muconic

acid

(hexa-2,4-dienedioic

acid)

and

glucaric

acid

(2,3,4,5-

tetrahydroxyhexanedioic acid). These precursors may be produced by fermentation from benzoate (5) and glucose (6,7), respectively, and converted chemo-catalytically to adipic acid by hydrogenation using Pt/C or Ru10Pt2 nanoparticles (8-10). The (Ru, Pt) bimetallic catalyst is superior in its selectivity to other bimetallic nanocatalysts and to monometallic supported catalysts such as Pt and Rh. Biological conversion of aromatics to cis, cis-muconic acid in aqueous medium at room temperature is well documented. Already Maxwell (to Celanese Corp.) has provided a microbiological process for oxidation of toluene to cis, cis-muconic acid at a commercially feasible rate and concentration using a strain of Pseudomonas putida (11). Several bacteria have also been described that convert benzoic acid (5,12). The ability to produce cis,cis-muconic acid from benzoate by fermentation has been expressed by microorganisms such as Pseudomonas sp B13 (13), P. putida KT2440 (14, 15) and ATCC 12633 (16); P. putida KT2440–JD1 has the highest measured specific volumetric production (4.3 mmol gdry

cell

−1

h−1) whereas 18.5 g L−1 cis, cis-

muconate accumulated in the culture medium with a molar product yield of close to 100% (12, 14). Dissimilation of benzoate via the ortho-cleavage pathway of the key intermediate catechol proceeds via cis, cis-muconic acid to succinyl-CoA and acetyl-CoA downstream in the β-ketoadipate pathway (17), which is one of the main biodegradation pathways for aromatic compounds in aerobic soil bacteria. However, as in case of the industrial process for manufacture of adipic acid, bioconversion of petroleum-based benzoate to cis, cis-muconic acid does not address the problem of a toxic starting material (18) and of the limitation of petroleum-based feedstocks in the long run. An alternative might be provided by the use of bio-based benzoate or related aromatic compounds such

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as phenol, catechol, protocatechuic acid and 4-hydroxybenzoic acid (from lignocellulosic degradation (12, 19)). D-Glucaric acid, a top value-added chemical from biomass (20), is currently produced in low yields (< 55%) from glucose (a 30 Mt/yr chemical) or starch in a non-selective and expensive chemocatalytic process using strong oxidants such as nitric acid or NO2 (21). The technical barrier to its large-scale production is the development of efficient and selective oxidation technology to eliminate the need for nitric acid as oxidant. Both TEMPO-like nitroxide-mediated oxidation (with > 85% yield) (22) and selective photo-oxidation of glucose (23) have been proposed. Rennovia, Inc. obtains the product by air (oxygen) oxidation over Pt/SiO2 (24), see Section 3. The production of glucaric acid by microbial fermentation has been addressed only recently. A synthetic pathway in E. coli has been constructed for the conversion of glucose to D-glucaric acid (6,7). Microbial production of both cis, cis-muconic acid and glucaric acid has been addressed by fermentation and metabolic engineering (25, 26). Microbial muconic acid production by de novo biosynthetic pathways from abundant and renewable carbon sources (e.g. glucose) requires further development. As shown in Fig. 1, adipic acid is also generated as an intermediate in the degradation pathways involving cyclohexane, ε-caprolactam, adiponitrile, and long-chain aliphatic dicarboxylic acids or aldehydes. Organisms possessing nitrilase activity transform aliphatic nitriles (e.g. adiponitrile) into carboxylic acids, such as adipic acid (27). Wildtype and mutant organisms (e.g. E. coli AB2834) are able to convert renewable feedstocks such as glucose and hydrocarbons to adipic acid (28-32). In particular, wild-type organisms have been used to convert cyclohexane and cyclohexanol, and other alcohols, to adipic acid (33-35). Yeasts of the Candida and Pichia genus allow microbial production of long-chain α, ωdicarboxylic acids (C5-C16) from n-alkanes (36). Yarrowia lipolytica and Torulopsis candida are other alkane-utilising yeasts which accumulate α, ω-dicarboxylic acids (37, 38). Strains of C. tropicalis have been engineered to convert alkanes and/or fatty acids into dicarboxylic acids, including adipic acid (39, 40). Recently, more interest has been developed into the bio-based 5 ACS Paragon Plus Environment


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production of adipic acid by α-, and/or ω-oxidation of long-chain n-alkanes, alcohols, diols or fatty acid substrates using engineered yeast strains (37, 41). Saturated and unsaturated fatty acids and ωhydroxy fatty acids with different chain length are converted to the corresponding dicarboxylic acids by selective terminal oxidation (see Fig. 3). A yeast fermentation process for adipic acid production from vegetable oils and animal fats is currently under development by Verdezyne, Inc. (Carlsbad, CA), see Section 2.2. Various enzymatic pathways have been suggested to convert cyclohexanol to adipic acid (35, 4244). One enzymatic pathway for the conversion of cyclohexanol to adipic acid has been suggested as including the intermediates cyclohexanone, 2-hydroxycyclohexanone, ε-caprolactone and 6hydroxycaproic acid. Some specific enzyme activities in this pathway have been demonstrated (42). An alternate enzymatic pathway has been postulated to comprise cyclohexanone, 1-oxa-2oxocycloheptane, 6-hydroxyhexanoate and 6-oxohexanoate (43). Strains of Acinetobacter and Nocardia (44) have been reported which, when grown on cyclohexanol as the sole source of carbon, produce adipic acid as an intermediate in the metabolic pathway. Figure 3 shows a biosynthetic pathway for the conversion of cyclohexanol to adipic acid mediated by a set of enzymes isolated from Acinetobacter sp. (33, 34).

Fig. 3. Biosynthetic pathway for the conversion of cyclohexanol to adipic acid and relevant enzymes. After ref. (34).

According to the Roadmap for Biomass Technologies in the United States (45), by 2030 25% of all chemicals consumed in the United States will be produced from biomass. The production of biobased adipic acid is a sustainable alternative to benzene price swings and allows the synthesis of renewable nylon-6,6 and polyurethanes with a substantially smaller environmental footprint. Clean technologies and industrial biotechnology are keys for future economical development (46). 6 ACS Paragon Plus Environment

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However, ecological benefits of white biotechnology (also referred to as industrial biotechnology) should be accompanied by cost advantages.

The BREW report estimates potential cradle-to-gate

NREU (non-renewable energy use) savings of 30%-50% for a bio-based adipic acid process (enzyme fermentative) based on corn starch (47). The present competitive cost position of bioroutes compared to the conventional process has recently been assessed (48), see also Sections 2.2 and 3.

2.1 Technology for non-commercial bio-based routes to adipic acid from glucose Bio-based chemicals production is seen as an opportunity for the US to regain world leadership in chemicals production, i.e. to invert the decline in global share from 27% in 1999 to 19% in 2009. Several biotechnology start-up companies, such as Rennovia, Inc. (Menlo Park, CA), Verdezyne, Inc. (Carlsbad, CA), Genomatica, Inc. (San Diego, CA), Celexion LLC (Cambridge, MA), and BioAmber S.A.S. (Montreal) have developed a strong patent position regarding bio-based routes to adipic acid and purification technology. Also Asahi Kasei Kogyo (Japan) has a long-standing interest in biotechnological adipic acid manufacture (49). A variety of recombinantly engineered metabolic pathways have been designed to achieve the biosynthesis of adipate from renewable feedstock, mainly glucose (Table 1). Successful engineering of these pathways involves identifying an appropriate set of enzymes with sufficient activity and specificity, cloning their corresponding genes into a production host, optimising fermentation conditions, and assaying for product formation following fermentation. Burgard et al. (to Genomatica, Inc.) have provided non-naturally occurring microbial organisms for several adipate pathways (see Figs. 4, 5, 7 and 8) (50). In particular, E. coli, which is amenable to genetic manipulation and capable of effectively producing succinic acid under anaerobic or microaerobic conditions, has been used to engineer several exemplary pathways. For the production of adipate, the recombinant strains are cultured in a medium with a (renewable) carbon source; usually any carbohydrate (e.g. glucose, starch, cellulosic biomass), but also syngas (from biomass or waste 7 ACS Paragon Plus Environment


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gasification), alone or in combination with methanol can be used to produce acetyl-coenzyme A (acetyl-CoA) or other derived products (such as methyl tetrahydrofolate) (51).

A variety of

biosynthesised chemicals and fuels, such as adipic acid and 1-butanol may be obtained from acetylCoA at costs that are significantly advantaged over both traditional petroleum-based products and products derived from glucose or lignocellulose sugars.

The product profile from syngas

fermentations is determined by the choice of organism and experimental conditions. In addition to fermentation procedures, chemical synthesis steps are occasionally introduced. For example, an intermediate in the adipate pathway utilising 3-oxoadipate or α-ketoglutarate, hexa-2-enedioate, can be converted to adipate by chemical hydrogenation (see Figs. 5 and 7). The same holds for cis,cismuconic acid (see Fig. 6).

Table 1. Exemplary pathways for biosynthesis of adipate.

Figure 4 shows an exemplary pathway for adipate formation via a reverse degradation pathway (as described for Penicillium chrysogenum). This highly efficient pathway, which is achieved through genetically altering a microorganism for enzymatic reactions from succinyl-CoA and acetyl-CoA, can efficiently transform glucose into adipate under anaerobic conditions with a 92% molar yield (Table 2).

Fig. 4. Adipate formation via a reverse degradation pathway. After ref. (50).

Table 2. Maximum theoretical yields of adipate per mol of glucose. 8 ACS Paragon Plus Environment

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Another pathway that uses acetyl-CoA and succinyl-CoA as precursors for adipate formation passes through the metabolic intermediate 3-oxoadipate (Fig. 5). The initial two transformations in this pathway are the two terminal steps of the degradation pathway for aromatic compounds operating in the reverse direction. Specifically, the first step forms 3-oxoadipyl CoA by the condensation of succinyl- and acetyl-CoA. The second step forms 3-oxoadipate and is reported to be reversible in Pseudomonas sp. strain

B13 (54). The subsequent steps involve reduction,

dehydration and again reduction (biochemically or chemically) to form adipate. Theoretical adipate yield, oxygen requirements and associated kinetics are identical to those of the reverse adipate pathway (Table 2). Interestingly, the product yield can be increased further to 1 mole adipate per mole of glucose if chemical hydrogenation is used with 100% catalytic efficiency. The two aforementioned routes are beneficial with respect to: (i) the adipate yields; (ii) the lack of requirement for oxygen for adipate synthesis; (iii) the associated energetics; and (iv) the theoretical capability to produce adipate as the sole fermentation product. Other metabolic pathways for adipate production, such as those that pass through α-ketoadipate (see Fig. 7) or lysine, are lower yielding and require aeration for maximum production.

Fig. 5. Exemplary pathway for adipate formation via 3-oxoadipate. After ref. (50).

Since adipic acid is not produced by naturally isolated microorganisms, its production requires biosynthetic pathways in an appropriate host. Figure 6 shows schematically Frost and Draths’ exemplary pathway for synthesis of adipic acid from D-glucose via cis,cis-muconic acid (9, 29, 31, 55). This route entails introduction of three heterologous genes into E. coli that can convert 3dehydroshikimate (DHS), an intermediate in aromatic amino acid biosynthesis, into cis,cis-muconic 9 ACS Paragon Plus Environment


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acid in three enzymatic steps via catechol. The biosynthesis pathway is considerably more complex than the conventional chemical synthesis: it consists of nine steps and uses eight different enzymes. However, the first eight steps are all carried out inside the E. coli cell at 37°C, and ambient pressure. A final chemocatalytic hydrogenation step then leads to formation of adipic acid using 10 wt% Pt/C at ambient temperature and mild pressures. There are no enzymatic reactions known which convert cis-cis-muconic acid to yield adipic acid. The combined biocatalytic-catalytic pathway is economically prohibitive. The United States Environmental Protection Agency (EPA) has presented one of its 1998 Presidential Green Chemistry Challenge Awards to Frost and Draths for their microbe-based adipic acid synthesis. Yet, there are several disadvantages connected to this method as compared to the other ones: (i) lower theoretical yields (Table 2); (ii) negligible ATP yields; and (iii) the involvement of a dioxygenase, which necessitates oxygen supply to the bioreactor and precludes the option of anaerobic fermentation.

Fig. 6. Biocatalytic-chemocatalytic pathway for the synthesis of adipic acid from D-glucose via cis-cismuconic acid. After ref. (9).

Adipate synthesis may also proceed via an α-ketoadipate pathway using α-ketoglutarate as a starting point. Alpha-ketoadipate is a known intermediate in lysine biosynthesis in S. cerevisiae and this information was used to identify an additional pathway for adipic acid biosynthesis (Fig. 7). Also in this pathway the last step can be catalysed either enzymatically or chemically. Because of the loss of two CO2 molecules during the conversion of acetyl-CoA to adipate, only 67% of the glucose can be converted into adipate. This is reflected in the molar yields for this pathway under aerobic conditions (Table 2); the yields are further reduced in the absence of oxygen uptake. 10 ACS Paragon Plus Environment

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Fig. 7. Exemplary pathway for adipate synthesis via α-ketoadipate using α-ketoglutarate as a starting point. After ref. (50).

Fig. 8. Exemplary adipate synthesis pathways using α-ketoadipate as a starting point. After ref. (50).

Two more adipate synthesis pathways utilise α-ketoadipate as a precursor and pass through 2hydroxyadipyl-CoA intermediate (Fig. 8). The maximum yield of adipate from glucose via these pathways is 0.67 mol/mol (50). The maximum theoretical yields of two additional pathways (not shown), which rely on lysine degradation to form adipate, are lower in comparison to other alternatives listed in Table 2.

Fig. 9. Celexion’s adipic acid biosynthetic pathway. KDC = α-keto acid decarboxylase. ALDH = aldehyde dehydrogenase.

In another development, Baynes et al. (to Celexion, LLC) (52) have recently disclosed bioproduction of adipic acid from carbohydrate feedstocks in metabolically engineered host cells via the α-ketopimelate route. The metabolically engineered host cell can be a prokaryotic cell and may be selected from the group consisting of E. coli, C. glutanicum, B. flavum and B. lactofermentum. Figure 9 shows the corresponding adipic acid biosynthesis pathway, which also 11 ACS Paragon Plus Environment


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starts from α-ketoglutaric acid and α-ketoadipate but then diversifies from the route of Fig. 7. Adipic acid is obtained by 2-keto elongation (Coenzyme B biosynthesis) of α-ketoglutaric acid (AKG; C5 chain) to α-ketoadipic acid (AKA; C6 chain), conversion of AKA into α-ketopimelic acid (AKP; C7 chain), conversion of AKP into adipic acid semialdehyde (ASA), and finally into adipic acid. At least one of these conversions is carried out using a recombinantly expressed enzyme. Recently also Verdezyne, Inc. has claimed a biological pathway for producing adipic acid from glucose, namely via 6-hydroxyhexanoic acid (53), see Section 2.2. A proposed pathway for bio-based production of adipic acid from glucose via 2-oxoadipate is very challenging (17, 56). This latter intermediate is formed from acetyl-CoA and 2-oxoglutarate by the first three enzymatic steps of the α-aminoadipate pathway for L-lysine biosynthesis. 2Oxoadipate can be converted to adipic acid either by chemocatalytic reduction or enzymatically, but not without overcoming considerable hurdles. For bioconversion of 2-oxoadipate to the immediate adipic acid precursor 2-hexenedioate a route via 2-hydroxyadipate, 2-hydroxyadipoyl-CoA and 2hexenedioyl-CoA has recently been proposed (56). Enzymes that catalyse conversion of 2oxoadipate to (R)-2-hydroxyadipate, a critical step for adipic acid production, have been described (57) but a reductase able to catalyse the reduction of 2-hexenedioate to adipic acid is still not available. Several obstacles remain before this pathway for production of adipic acid might work with full functionality and high selectivity. The benzene-free biochemical processes to adipic acid are inherently safer and more sustainable than the industrial cyclohexane oxidation route. The prospected biocatalytic conversions of Dglucose are prototypes of environmentally designed processes, i.e. syntheses running without any hazardous reagents or starting materials from non-renewable feedstocks.

However, for most

proposed process routes scale-up and optimisation are to be resolved and cost-effective industrial application is yet to be demonstrated. It should be realised that relative market prices of chemicals derived from renewables are likely to differ considerably from these derived from fossil feedstock. This requires an economical reassessment. 12 ACS Paragon Plus Environment

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2.2 Emerging bio-based adipic acid production technologies Several US industrial biotechnology companies are actively developing adipic acid production from renewable sources as sustainable alternatives at the same or lower cost than current industrial practice. A second driver towards bio-based chemicals in the potential for reduced environmental impact. Advanced pilot or demo scale plants for conceptually different pathways to bio-based adipic acid have been developed by Rennovia, Inc. and Verdezyne, Inc.

Fig. 10. Rennovia’s feedstock plan. After ref. (58).

Rennovia’s philosophy is that high space-time yields, temperature and solvent flexibility, highcarbon efficiencies, and low costs of product isolation make chemical catalysis preferable to fermentation for many large-volume chemical manufacturing processes (58). This specialty chemical company is adapting industrial catalytic technology, already proven to be scalable and efficient in the refining and chemical industries for the conversion of biorenewable feedstock, to today’s key petrochemicals, such as adipic acid (24, 59). While Rennovia’s feedstock strategy initially concentrates on the existing carbohydrate supply chain, it also ensure that its technology is forward-compatible with emerging feedstocks (Fig. 10).Rennovia’s industrial chemistry processes for adipic acid production comprise a glucaric acid and a furan route. Hydroxy-methylfurfural (HMF) as an intermediate to adipic acid has been reported before (4), see Fig. 2.

Fig. 11. Rennovia’s renewable adipic acid multi-step process. After ref. (24). 13 ACS Paragon Plus Environment


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Figure 11 shows Rennovia’s renewable adipic acid step process based on selective catalytic oxidation of glucose to glucaric acid followed by selective catalytic hydrodeoxygenation of glucaric acid to adipic acid. In this process the pH effect and deactivation of the Pt catalyst in the first reaction step (oxidation) are of concern. Similarly, the stability and reuse of the hydrodeoxygenation catalysts require optimisation. Rennovia has employed high-throughput catalyst (HTC) synthesis and screening technology to develop new industrially-scalable heterogeneous catalysts for these process step (59, 60). The catalytic oxidation of glucose is carried out with 4% Pt/SiO2 at 90°C at increased oxygen pressure (up to 5 atm) in the presence of a solvent (water or acetic acid) and yields 66% glucaric acid after 8 h. Hydrodeoxygenation of D-glucaric acid in acetic acid/water and HBr over Pt/Rh with H2 (up to 100 atm) at 160°C yields 89% adipic acid after 3 h. A 25 lb/day lab pilot scale continuous three-phase trickle-bed reactor is being operated since 2011; targeted initial commercial production in 2015. Rennovia’s renewable adipic acid process operates below cash-costs of the petro cyclohexane process with robust advantages in both capital and operating expenses: 20% lower capital, 30% lower raw materials, 15% lower utilities and 30% lower manufacturing costs (60). Life-Cycle Assessment (LCA) analysis for adipic acid indicates greenhouse gas (GHG) emissions of current petrochemical processes of 25.7 and 9.0 kg CO2 eq/kg AA for China (80% abatement plants) and Europe (98% abatement plants), respectively, as compared to only 1.3 kg CO2 eq/kg AA for the bio-based process, or a 85% GHG emissions reduction as compared to the latter (60). The reduced carbon footprint of Rennovia’s target process compared to a state-of-art petrochemical process is achieved through a combination of renewable feedstock, lower energy usage, and avoidance of N2O by-product. Similarly, other eco-impacts (human health, ecosystem quality and resource depletion) are better than for petro-based processes (58). In PCT Int. Publ. WO 2010/144873 A1 (to Rennovia, Inc.) Boussie et al. have disclosed chemocatalytic conversion of a carbohydrate source to adipic acid products via a furanic substrate 14 ACS Paragon Plus Environment

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such as 2,5-furandicarboxylic acid (by catalytic hydrodeoxygenation) (61). The latter product is among the twelve platform chemicals targeted by the US government for production of biomass. The environmental impact and economic viability of the process have yet to be improved. Verdezyne, Inc. has developed pathways for adipic acid from sugars and triglycerides, from fats and oils, and from paraffins (53, 62). Whereas most bio-based processes under development originate from renewable sugars (see Section 2.1), Verdezyne has used proven and proprietary metabolic pathway engineering tools to develop a unique yeast fermentation process using plantbased feedstocks such as vegetable oils or their waste streams to cost-effectively produce a variety of commercial diacids, including adipic acid. To enable the production of bio-adipic acid Verdezyne, Inc. has engineered a robust industrial yeast strain and developed a fermentation and downstream purification process to recover polymer-grade bio-adipic acid in high yield and selectivity from the fermentation broth using fatty acids derived from any vegetable oil or animal fat (regardless of their fatty acid composition), including their soapstock or fatty acid distillate process waste streams, as feedstocks for the fermentation (62). These waste streams can represent up to 5% of the volume of oil processed, cost less than half the parent oil, and have no competing food use. Figures 12 and 13 show the simplified metabolic pathway from fats and oils, paraffins and sugars as carbon sources to adipic acid. Paraffins are first terminally oxidised through the ωoxidation pathway to the corresponding fatty acid substrate for the β-oxidation pathway that generates the metabolic intermediates and energy required for growth. Each cycle of degradation through the β-oxidation pathway releases a molecule of acetyl-CoA for respiration and shortens the fatty acid backbone by two carbons. The selectivity of substrate entry into the β-oxidation pathway has been engineered so that degradation does not proceed beyond the 6-carbon adipic acid. Fermentation is carried out in a two-stage fed-batch process. Coconut oil (CNO) was converted into adipic acid with highly selectively (98%). The maximum theoretical yield of the conversion is dependent upon the fatty acid chain length distribution of the feedstock (0.60 g/g for CNO or 0.69 g/g for CNO soapstock). 15 ACS Paragon Plus Environment


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Fig. 12. Adipic acid production from fats and oils by ω-oxidation and from long-chain dicarboxylic acids (DCAs) by β-oxidation. After ref. (53).

Fig. 13. Metabolic pathway for producing adipic acid from various carbon sources via 6hydroxyhexanoic acid. After ref. (53).

Advantages over the petroleum-based manufacturing processes include lower cost, sustainable feedstock supply and a smaller environmental footprint. Pilot-scale (300 L) experimentation has been completed and market development of polymer-grade bio-based adipic acid has started. Verdezyne is projecting a biochemical production facility in Malaysia, in collaboration with BiotechCorp (Kuala Lumpur) for palm oil use (63). In another industrial development, BioAmber (Plymouth, MN), a bio-succinic acid (Bio-SATM) producer (from corn via glucose/dextrose syrup), has successfully adapted its succinic acid purification technology to adipic acid (64) produced via Celexion’s metabolic pathway (see Section 2.1). Pavone (48) has compared the conventional Du Pont/Invista cyclohexane-based oxidation process to the bio-based processes developed by Verdezyne, Inc. (using genetically modified enzymes to ferment glucose to AA) and Rennovia, Inc. (using catalytic air oxidation to convert glucose to glucaric acid, followed by hydrodeoxygenation). The Rennovia process is considered to have the higher potential to be cost competitive with the conventional cyclohexane oxidation process. A significant advantage of both bio-routes is the use of glucose feedstock ($ 300/mt), as 16 ACS Paragon Plus Environment

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compared to cyclohexane ($ 1,250/mt, 2012). Significant challenges still are high feedstock selectivity and catalyst productivity (Rennovia oxidation route), and high enzyme turnover rates and satisfactory kinetics (Verdezyne enzyme fermentation route).

3. Life-cycle analyses of adipic acid processes Van Duuren et al. (12) have assessed the possibility to reduce the environmental impact of the current petroleum-based adipic acid production by comparing different carbon backbone feedstocks (petrochemical and biomass-based) for the combined biological/chemical production of adipic acid using a limited LCA study. It was considered that feedstock is one of the most important parameters in life-cycle performance of chemical production systems. The LCA comprises the biological conversion of the aromatic feedstocks benzoic acid (from oxidised toluene), impure aromatics (from Benzene-Toluene-Xylenes waste), toluene (from benzene), and phenol (from wheat stover lignin) to cis, cis-muconic acid, which is subsequently converted to adipic acid through hydrogenation. Two broth concentrations of cis, cis-muconic acid were considered (1.85 wt% and 4.26 wt%). At a cumulative energy demand (CED) of 104.2 GJ/t, and emission values of 60.2 kg N2O/t and 5.1 t CO2/t product of commercial adipic acid production, there is a large potential to reduce the environmental impact by employing bio-processing techniques based on aqueous solutions. It is to be noted that apolar compounds such as phenol and toluene are generally not well soluble in water and often toxic to whole cells. The feedstock for the carbon backbone of cis, cis-muconic acid, glucose, and sodium hydroxide, plays important roles in the total fossil fuel energy demand and GHG emission of the system. The analysis reveals a huge potential of employing impure aromatics over benzoic acid as a feedstock. However, the robustness and productivity of bacteria with impure aromatics remains to be assessed. The most sustainable option would be using the bio-based material lignin for phenols. When phenol from lignin is used as a carbon source CED decreases 30.4 to 58.4 GJ/t (29% to 57%) compared to the traditional petroleum-based production process. The bulk of the bioprocessing energy is 17 ACS Paragon Plus Environment


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attributed to the hydrogenation-evaporation process (15.1 to 35.1 GJ/t), but this can be reduced by extraction procedures. Although economic biological delignification and isolation techniques are currently not available a switch to lignin-based feedstock is foreseeable, but not at short term (65). A decrease in CO2 eq emission was achieved especially when the N2O emission in the combined biological/chemical process was restricted. At 4.26 wt% cis, cis-muconic acid, a 14.0 to 17.4 t CO2 eq/t adipic acid emissions reduction can be achieved. The environmental impact concerning the CED and CO2 eq emission of the manufacturing of the nylon-6,6 precursor adipic acid can thus be reduced by replacing the current petroleum-based chemical process with a combined biological and chemical process. Colodel et al. (66) have used LCA, Life-Cycle Costing (LCC) and the Life-Cycle Working Environment (LCWE) method for an overall assessment of the ecological, economic and social impacts of adipic acid from a renewable source (corn) versus adipic acid from crude oil. Conventional routes still outperform bio-based adipic acid. The bio-sources approach should be optimised by exploring different routes from various agricultural bio-products and by overcoming the inefficient steps in the production route. These approaches should bring down production costs and substantially improve the environmental performance of bio-source based adipic acid (especially the eutrophication impact). Adipic acid made from renewable resources requires considerably more human labour than its conventional competitor from crude oil.

4. Conclusions and prospects Promising approaches toward the bio-based production of adipic acid or its precursors from renewable carbon sources (such as glucose) have been described by several US biotechnology startup companies and offer alternatives for the traditional petroleum-based processes. Pilot plants for bio-adipic acid production have already been developed (8, 58). Adipic acid from renewable feedstock is an emerging technology promising cheaper raw materials, lower investment, lower manufacturing costs and GHG emissions reduction (no N2O generation) than the conventional 18 ACS Paragon Plus Environment

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cyclohexane oxidation process. Multiple routes to bio-based adipic acid are now available that can provide production cost advantages and which have the potential for commercialisation. Long-term advantages compared to petrochemical-based adipic acid are estimated being about 25%. It is reasonable to expect that bio-adipic acid can technically be introduced into the market within the next few years, gradually replacing old (depreciated) petro adipic acid plants.

However,

implementing such new processes while phasing out the old technology will take time, especially taking into account distortions in the market caused by N2O abatement subsidies. In time, also aromatic compounds (such as phenol, etc.) will be obtained from lignocellulosic material (12, 19). Comparison of petro- and biomass-based aromatic feedstocks for the combined biological and chemical production of adipic acid indicates a huge potential for employing aromatics obtained by delignification.



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5. References (1)

Bart, J.C.J.; Cavallaro, S. Transiting from adipic acid to bio-adipic acid. Part I. Petroleumbased processes. I&EC Res. 0000, 000, 000-000.

(2)

Chen, D.; Chen, P. Green characteristics of adipic acid production process and discussion on the green synthesis. Huaxue Gongye Yu Gongcheng Jishu 2009, 30(1), 24-6.

(3)

Minoda, T.; Oomori, T.; Narishima, H. (Nissan Chemical Industries, Ltd). Preparation of adipic acid by microorganism. Jpn. Patent JP 58149687 A, 1983.

(4)

Faber, M. (Hydrocarbon Research, Inc.). Process for producing adipic acid from biomass. U.S. Patent 4,400,468, 1983.

(5)

Mizuno, S.; Yoshikawa, N.; Seki, M.; Mikawa, T.; Imada, Y. Microbial-production of cis,cismuconic acid from benzoic acid. Appl. Microbiol. Biotechnol. 1988, 28(1), 20-5.

(6)

Lippow, S.M.; Moon, T.S.; Basu, S.; Yoon, S.H.; Li, X.; Chapman, B.A.; Robison, K.; Lipovsek, D.; Prather, K.L. Engineering enzyme specificity using computational design of a defined-sequence library. Chem. Biol. 2010, 17, 1306-15.

(7)

Moon, T.S.; Yoon, S.H.; Lanza, A.M.; Roy-Mayhew, J.D.; Prather, K.L. Production of glucaric acid from a synthetic pathway in recombinant Escherichia coli, Appl. Environm. Microbiol. 2009, 75, 589-95.

(8)

De Guzman, D. Bio-adipic acid prepares for entry. In ICIS Chemical Business, Sept. 27-Oct. 3, 2010; pp. 22-3.

(9)

Niu, W.; Draths, K.M.; Frost, J.W. Benzene-free synthesis of adipic acid. Biotechnol. Progress 2002, 18, 201-11.

(10) Thomas, J.M.; Raja, R.; Johnson, B.F.; O’Connell, T.J.; Sankar, G.; Khimyak, T. Bimetallic nanocatalysts for the conversion of muconic acid to adipic acid. Chem. Commun. 2003, 11267. (11) Maxwell, P.C. (Celanese Corp.). Production of muconic acid. U.S. Patent 4,355,107, 1982. (12) Van Duuren, J.B.J.H.; Brehmer, B.; Mars, A.E.; Eggink, G.; Martins dos Santos, V.A.P.; Sanders, J.P.M. A limited LCA of bio-adipic acid: manufacturing the nylon-6,6 precursor adipic acid using the benzoic acid degradation pathway from different feedstocks. Biotechnol. Bioengng. 2011, 108(6), 1298-1306. (13) Schmidt, E.; Knackmuss, H.J. Production of cis,cis-muconate from benzoate and 2-fluoro-cis, cis-muconate from 3-fluorobenzoate by 3-chlorobenzoate degrading bacteria, Appl. Microbiol. Biotechnol. 1984, 20, 351-5. (14) Van Duuren, J.B.J.H.; Wijte, D.; Karge, B; Martins dos Santos, V.A.P.; Yang, Y.; Mars, A.E.; Eggink, G. pH-stat fed-batch process to enhance the production of cis,cis-muconate from benzoate by Pseudomonas putida KT2440-JD1, Biotechnol. Progr. 2011, 709.


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(15) Van Duuren, J.B.J.H.; Wijte, D.; Leprince, A.; Karge, B; Puchalka, J; Wery, J.; Martins dos Santos, V.A.P.; Eggink, G.; Mars, A.E. Generation of a catR deficient mutant of P. putida KT2440 that produces cis,cis-muconate from benzoate at high rate and yield. J. Biotechnol. 2011, 156, 163-72. (16) Liu, W.H.; Cheng, T.L. Microbial production of cis-cis-muconic acid from benzoic acid. Zhongguo Nongye Huaxue Huizhi 1991, 29(4), 396-405; C.A. 1992, 116, 254023. (17) Polen, T.; Spelberg, M.; Bott, M. Toward biotechnological production of adipic acid and precursors from biorenewables. J. Biotechnol. 2013, 167(2), 75-84. (18) Nair, B. Final report on the safety assessment of benzoyl alcohol, benzoic acid, and sodium benzoate. Int. J. Toxicol. 2001, 20 (Suppl. 3), 23-50. (19) Zakzeski, J.; Weckhuysen, B.M. Lignin solubilization and aqueous phase reforming for the production of aromatic chemicals and hydrogen. ChemSusChem 2011, 4, 369-78. (20) Werpy, T.; Petersen, G. Top value added chemicals from biomass. Vol. I. Results of screening for potential candidates from sugars and synthesis gas. U.S. Dept. of Energy, 2004; http://www.osti.gov/bridge. (21) Mehltretter, C.L. D-glucaric acid, Methods. In Carbohydrate Chemistry; Whistler, R.L.; Wolfrom, M.L.; BeMiller, J.M., Eds.; Academic Press: New York, NY, 1963; Vol. 2, pp. 468. (22) Merbouth, N.; Thaburet, J.F.; Ibert, M.; Marsais, F.; Bobbitt, J.M. Facile nitroxide-mediated oxidations of D-glucose to D-glucaric acid. Carbohydr. Res. 2001, 336, 75-8. (23) Colmenares, J.C.; Magdiziarz, A.; Bielejewska, A. High-value chemicals obtained from selective photo-oxidation of glucose in the presence of nanostructured titanium photocatalysts. Bioresour. Technol. 2011, 102, 11254-7. (24) Boussie, T.R.; Dias, E.L.; Fresco, Z.M.; Murphy, V.J.; Shoemaker, J.; Archer, R.; Jiang H. (Rennovia, Inc.). Composition of matter. U.S. Patent Appl. 2011/0218318, 2011. (25) Myers, A.G.; Siegel, D.R.; Buzard, D.J.; Charest, M.G. Synthesis of a broad array of highly functionalised, enantiomerically pure cyclohexane-carboxylic acid derivatives by microbial dihydroxylation of benzoic acid and subsequent oxidative and rearrangement reactions. Org. Lett. 2001, 3, 2923-6. (26) Yu, C.; Cao, Y.; Zou, H.; Xian, M. Metabolic engineering of Escherichia coli for biotechnological production of high-value organic acids and alcohols. Appl. Microbiol. Biotechnol. 2011, 89, 573-83. (27) Petre, D.; Cerbeleaud, E.; Levy-Schil, S.; Crouzet, J. (Rhône Poulenc Chimie). Polypeptides possessing a nitrilase activity and method of converting nitriles to carboxylates by means of said polypeptides. U.S. Patent 5,629,190, 1997. (28) Frost, J.W.; Renewable feedstocks. Chem Eng. 1996, 611, 32-5.



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(29) Frost, J.W.; Draths, K.M. (Purdue Research Foundation). Synthesis of adipic acid from biomass-derived carbon sources. U.S. Patent 5,487,987, 1996. (30) Frost, J.W.; Draths, K.M. (Purdue Research Foundation). Biocatalytic synthesis of catechol from glucose. U.S. Patent 5,272,073, 1993. (31) Frost, J.W.; Draths, K.M. (Purdue Research Foundation). Bacterial cell transformants for production of cis,cis-muconic acid and catechol. U.S. Patent 5,616,496, 1997. (32) Steinbüchel, A. Microorganisms for the preparation of polymers. Chem. Labor Biotechn. 1995, 46(6), 277-8. (33) Cheng, Q.; Nagarajan, V.; Thomas, S.M. (E.I. du Pont de Nemours & Co.). Biological method for the production of adipic acid and intermediates. U.S. Patent 6,794,165, 2004. (34) Brzostowicz, P.C.; Rouviere, P.E. . (E.I. du Pont de Nemours & Co.). Genes and enzymes for the production of adipic acid intermediates. U.S. Patent Appl. 2002/0127666 A1, 2002. (35) Hasegawa, Y.; Tsujimoto, H.; Obata, H.; Tokuyama, T. The metabolism of cyclohexanol by Exophiala jeanselmei, Biosci. Biotechnol. Biochem. 1992, 56(8), 1319-20. (36) Shiio, I.; Uchio, R. Microbial production of long-chain dicarboxylic acids from n-alkanes. Part I. Screening and properties of microorganisms producing dicarboxylic acids. Agr. Biol. Chem. 1971, 35, 2033-42. (37) Smit, M.S.; Mokgoro, M.M.; Setati, E.; Nicaud, J.M. α,ω-Dicarboxylic acid accumulation by acyl-CoA oxidase deficient mutants of Yarrowia lipolytica, Biotechnol. Lett. 2005, 27, 85964. (38) Kaneyuki, H.; Ogata, K. (Mitsui Petrochemical Industries, Ltd). Method of producing dicarboxylic acids by microorganisms. U.S. Patent 3,912, 586, 1975. (39) Hara, A.; Ueda, M.; Matsui, T.; Arie, M.; Saeki, H.; Matsuda, H.; Furuhaishi, K.; Kanai, T.; Tanaka, A. Repression of fatty-acyl-CoA oxidase-encoding gene expression is not necessarily a determinant of high-level production of dicarboxylic acids in industrial dicarboxylic acidproducing Candida tropicalis, Appl. Microbiol. Biotechnol. 2001, 56, 478-85. (40) Picataggio, S.; Rohrer, T.; Deanda, K.; Lanning, D.; Reynolds, R.; Mielenz, J.; Eirich, L.D. Metabolic engineering of Candida tropicalis for the production of long-chain dicarboxylic acids. Nature Biotechnol. 1992, 10, 894-8. (41) Yang, Y.; Lu, W.; Zhang, X.; Xie, W.; Cai, M.; Gross, R.A. Two-step biocatalytic route to biobased functional polyesters from ω-carboxy fatty acids and diols. Biomacromol. 2010, 11, 259-68. (42) Tanaka, H.; Obata, H.; Tokuyama, T.; Ueno, T.; Yoshizako, F.; Nishimura, A. Metabolism of cyclohexanol by Pseudomonas species, Hakko Kogaka Kashi 1977, 55(2), 62-7. (43) Donaghue, N.A.; Trudgill, P.W. The metabolism of cyclohexanol by Acinetobacter NCIB9871. Eur. J. Biochem. 1975, 60(1), 1-7. 22 ACS Paragon Plus Environment

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(59) Boussie, T.R.; Dias, E.L.; Fresco, Z.M.; Murphy, V.J.; Shoemaker, J.; Archer, R.; Jiang, H. (Rennovia, Inc.). Production of adipic acid and derivatives from carbohydrate-containing materials. U.S. Patent Appl. 2010/0317823, 2010. (60) Diamond, G.; Murphy, V.; Boussie, T.R. Applications of high throughput experimentation to the production of commodity chemicals from renewable feedstocks. In Modern Application of High Throughput R&D in Heterogeneous Catalysis; Hagemeyer, A.; Volpe, A.F., Eds.: Bentham Science Publishers: Sharjah (UAE), 2014; pp. 288-309. (61) Boussie, T.R.; Dias, E.L.; Fresco, Z.M.; Murphy, V.J. (Rennovia, Inc.). Production of adipic acid and derivatives from carbohydrate-containing materials. PCT Int. Publ. WO 2010/144873 A1, 2010. (62) Beardslee, T.; Picataggio, S. Bio-based adipic acid from renewable oils. Lipid Technol. 2012, 24(10), 223-5. (63) http://verdezyne.com/verdezyne/News/documents/VerdezynePilotPlantReleaseBusinessFINA L.pdf, 2011. (64) Fruchey, O.S.; Manzer, L.E.; Dunuwila, D.; Keen, B.T.; Albin, B.A.; Clinton, N.A.; Dombek, B.D. (BioAmber S.A.S.). Processes for producing monoammonium adipate from fermentation broths containing diammonium adipate, monoammonium adipate and/or adipic acid, and conversion of monoammonium adipate to adipic acid, U.S. Patent Appl. 2011/0266133 A1, 2011. (65) Chakar, F.S.; Ragauskas, A.J. Review of current and future softwood kraft lignin process chemistry. Ind. Crop Prod. 2004, 20, 131-41. (66) Colodel, C.M.; Kupfer, T.; Barthel, L.-P.; Albrecht, S. R&D decision support by parallel assessment of economic, ecological and social impact - Adipic acid from renewable resources versus adipic acid from crude oil. Ecol. Econ. 2009, 68, 1590-1604.


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Table 1. Exemplary pathways for biosynthesis of adipate. Metabolic pathwaya

Reference(s)

·

Reverse adipate degradation

(50)

·

3-Oxoadipate

(50)

·

cis, cis-Muconic acid/catechol

·

α-Ketoadipate

(50)

·

Lysine degradation

(50)

·

α-Ketopimelate

(52)

·

6-Hydroxyhexanoic acid.

(53)

·

α-Aminoadipate

(17)

a

(9, 29)

Using natural occurring or genetically engineered organisms.



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Table 2. Maximum theoretical yields of adipate per mole of glucose. Metabolic pathway

· · · · · a

Anaerobic

Aerobic

Reverse adipate degradation

0.92

0.92

3-Oxoadipate

a

0.92/1.00

0.92/1.00a

cis, cis-Muconic acid/catechol

0.75/0.85a

0.00/0.00a

α-Ketoadipate

0.67/0.67a

0.45/0.40a

Lysine degradation

0.40/0.50b

0.20/0.34b

Final step enzymatic/Final step chemical hydrogenation. Using α-ketoglutarate/aspartate as starting point.

b


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Figure 1. Some basic modes of access to bio-adipic acid by fermentation processes (dashed) and chemocatalytic conversions (bold). 254x190mm (96 x 96 DPI)

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Figure 2. Process for producing adipic acid from biomass. According to ref. (4). 254x190mm (96 x 96 DPI)


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Figure 3. Biosynthetic pathway for the conversion of cyclohexanol to adipic acid and relevant enzymes. According to ref. (34). 240x116mm (300 x 300 DPI)



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Figure 4. Adipate formation via a reverse degradation pathway. According to ref. (50). 152x180mm (300 x 300 DPI)


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Figure 5. Exemplary pathway for adipate formation via 3-oxoadipate. According to ref. (50). 142x177mm (300 x 300 DPI)



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Figure 6. Biocatalytic-chemocatalytic pathway for the synthesis of adipic acid from D-glucose via cis-cismuconic acid. According to ref. (9). 245x64mm (300 x 300 DPI)


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Figure 7. Exemplary pathway for adipate synthesis via α-ketoadipate using α-ketoglutarate as a starting point. According to ref. (50). 105x171mm (300 x 300 DPI)



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Figure 8. Exemplary adipate synthesis pathways using α-ketoadipate as a starting point. According to ref. (50). 211x166mm (300 x 300 DPI)


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Figure 9. Celexion’s adipic acid biosynthetic pathway. KDC = α-keto acid decarboxylase. ALDH = aldehyde dehydrogenase. 175x145mm (300 x 300 DPI)



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Figure 10. Rennovia’s feedstock plan. According to ref. (58). 254x190mm (96 x 96 DPI)


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Figure 11. Rennovia’s renewable adipic acid multi-step process. According to ref. (24). 251x35mm (300 x 300 DPI)



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Figure 12. Adipic acid production from fats and oils by ω-oxidation and from long-chain dicarboxylic acids (DCAs) by β-oxidation. According to ref. (53). 105x249mm (300 x 300 DPI)


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Figure 13. Metabolic pathway for producing adipic acid from various carbon sources via 6-hydroxyhexanoic acid. According to ref. (53). 165x166mm (300 x 300 DPI)


Transiting from Adipic Acid to Bioadipic Acid. Part II. Biosynthetic

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