Direct routeDrop-in bio-basedalternatives

Fuel circleBiorefineries of the future

Direct routeDrop-in bio-basedalternatives

Fuel circleBiorefineries of the future

Agrochemical intermediates ... Leather &textile chemicals ... Electronic chemicals ...Osmium chemistry

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JULY 2010Volume 30 No. 07

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Dennis McGrew of Genomatica outlines the case for directly produced, drop-in bio-based replacements for traditional manufacturing methods

Sustainability

In the last 18 months, the chemicals industryhas made signi�cant strides toward more bio-based production. One year ago, a survey con-

ducted by Genomatica and ICIS showed that 57%of industry executives said their companies shouldreduce their exposure to the petroleum-basedcommodity market. Companies also acknowl-edged that their customers have expressed realinterest in chemicals based on renewable materi-als.

More than half of the executives in the survey,however, said that cost was the most prohibitivepart of a sustainable chemicals programme.Consumer attitudes, volatile petroleum marketsand global demand contraction have convergedfor a unique moment of interest and demand forsustainable chemicals, but cost continues to be thekey barrier to adoption.

If capacity rebounds in the next three to �veyears, as some analysts predict, it will present aninteresting opportunity to introduce new processtechnologies that use renewable feedstocks tomanufacture chemicals. These new processes candrive the start of a transformation of the chemicalsindustry.

However, helping the industry to transitionfrom petroleum-based feedstocks to renewablefeedstocks will not happen overnight. As shown inthe survey, common wisdom holds that transition-ing to a more sustainable industry will raise costsand further squeeze tight margins.

Making the industry more environmentally sus-tainable at the cost of economic viability is not anoption. Genomatica believes strongly that sustain-ability must come at a lower cost and that innova-tive biotechnology can deliver sustainable solu-tions at lower costs, especially when direct pro-duction routes eliminate as many intermediateprocessing steps as possible and the resulting

materials are equivalent to conventional ones usedtoday, enabling them to be dropped into existingdownstream value chains.

Metabolic engineering platformTo ful�ll this daunting goal of low-cost sustainabil-ity, our research teams have explored hundreds ofroutes to dozens of products. Genomatica’s coretechnologies for metabolic engineering, combinedwith our laboratory and process engineering capa-bilities, have enabled us to explore a broad port-folio of processes to generate a range of chemicalintermediates.

Early assessment and IP around platform mole-cules like succinic acid and 3HP were de-empha-sised in favour of more direct production routes toexisting, large chemical intermediates like 1,4-butanediol (BDO). Our other ongoing e�orts alsoinclude various acrylates, polyamide (PA, or nylon)intermediates, solvents and surfactants. Publishedpatent applications demonstrate the breadth ofroutes available, with development priority givento those with the best opportunity to deliverbreakthrough cost reductions of >25% over thebest available conventional technology in large,growing chemical intermediate markets.

Challenges with indirect routes In August 2004, the US Department of Energy(DOE) published a study intended to evaluate andcompare more than 300 molecules from the pointof view of technological feasibility, size of potentialmarket and interest to the chemicals industry. Itidenti�ed priorities for the top 12 chemicals ofgreatest interest.

These 12 are often called platform molecules,because they may serve as a platform for produc-ing a variety of derivatives. However, they gener-ally provide an indirect route to the chemical inter-

mediates that are large consumers of fossil fuelstoday. Such routes face several potential chal-lenges that may ultimately a�ect economics.

Unwanted by-products are often generated thatimpact not only costs, but also the process’s envi-ronmental footprint, while additional processingsteps typically require more unit operations withthe inherent added capital, energy and operatingexpense, as well as creating the potential for yieldlosses.

Finally, the chemical intermediates purportedlyderived from these platform molecules often havesubstantially larger markets than the platformchemicals themselves, requiring large infrastruc-ture investments to reach su�cient economies ofscale to make a signi�cant impact on fossil fueluse.

Unintended consequencesA concern, especially for larger-scale chemicalintermediate production, is the potential for unde-sirable co-products from indirect productionroutes. Organic acids, some considered as poten-tial platform molecules, are an example of this.

Lactic acid can be produced from bio-basedfeedstocks through fermentation but requiresdirect acidi�cation, esteri�cation and hydrolysisthrough reactive distillation to purify and providea useful chemical intermediate. Direct acidi�cationproduces large quantities of gypsum co-product,which may not be pure enough for industrial use.

As processes scale up, even a relatively minorwaste stream can become problematic, addingdisposal costs and reducing yield. Improvementsin technology may substantially reduce undesir-able co-products, but will likely not eliminate thementirely.

Platform chemical routes like organic acids maybe e�ective for some small speciality chemicals or

32 July 2010 Speciality Chemicals Magazine

Getting to the point: Direct bio-base

Fermentation

Hydrolysis

Lime

SugarsDirect

Acidi�cation Esteri�cation

Lacticacid

Water

Sulphuricacid

Gypsum

Alcohol

Water

Ester

Figure 1 - Traditional route to lactic acid

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Sustainability

niche ‘green’ markets, but for larger volumechemical intermediates like 1,4-BDO, acrylates ornylon intermediates, the waste products couldbecome problematic.

Lactic acid also shows the challenge of multipleunit operations required to isolate and purify it asa raw material for subsequent chemical conver-sion to the targeted chemical intermediates(Figure 1). Further, impurities associated with itsproduction can be problematic for downstreamproducts, a�ecting yields and separations, espe-cially as one strives for lower costs. These chal-lenges may also manifest themselves for otherorganic acids developed as platform chemicals.

Keeping it simpleWhilst platform molecules may indeed providebio-based routes to various chemical intermedi-ates, the additional necessary steps run counter tothe goal of a low-cost solution. To foster wide-spread adoption of sustainable chemicals, the newprocesses must cost less than traditional methods.

We see our direct production route to 1,4-BDO(Figure 2) as a prime example, eliminating theneed for the isolation and puri�cation of succinicacid and the subsequent high-temperature andhigh-pressure steps for BDO conversion via cat-alytic hydrogenation. We estimate that the addi-tional processing steps between succinic acid andbutanediol could add at least 20 cts/lb (€0.36/kg)to the cost of the �nal product.

In both academic journals and media outlets,there is concern that succinic acid production hasnot yet reached economic competitiveness withtraditional production methods.1,2 Most sourcessay the cost of separating and purifying it from thefermentation broth is the largest barrier to eco-nomic production for most applications.

For the large global PA market, we have �led apatent application for bio-based direct route toseveral intermediates, potentially opening up fullybio-based PA 6 and PA 6,6. We typically �lepatents on a range of routes, but pursue only themost direct ones, those that can be achieved in asingle organism and the simplest possible process.

We achieve this through metabolic engineeringand genetic modi�cation.

By contrast, many of the other approaches forpursuing bio-based nylon routes are indirect pro-duction routes through platform chemicals includ-ing lysine, a common bio-based amino acid. Forinstance, researchers at Michigan State Universityhave patented a process for converting L-lysinefrom natural materials to -caprolactam, a precur-sor to PA 6, in a handful of processing steps witha yield of about 75%. The -caprolactam is thenpolymerised into PA 6, which has a huge globalmarket.

Genomatica’s proposed routes have signi�cant-ly fewer steps and those steps are simpler, espe-cially in the separations of intermediates anddesired end-products (Figure 3).

Industrial inertia dictates that a simpler replace-ment technology will spread faster through theindustry where the simplicity leads to lower costs.Building replacement processes with the mini-mum number of unit operations for current large-market chemical intermediates is vital. Instead ofrequiring additional processing steps and addi-tional capital investments, more direct productionroute will ease adoption when compared to indi-rect methods.

Leveraging infrastructureThe e�ective and rapid transformation of thechemicals industry toward greater production ofbio-based materials will require leveraging exist-ing infrastructure to the greatest extent possible.Historically, substitutes for existing chemical inter-mediates or polymers have required substantialchanges in existing infrastructure or downstreamderivative production.

These changes can create barriers to marketadoption, extending time for speed-to-scale ofnew products and o�setting economies gainedwith bio-based production. Success critically relieson performance advantages due to these barriers.

We feel that an approach with chemically iden-tical, performance-equivalent chemicals and poly-mers at lower cost than conventional processes

will be required to drive the large-scale transfor-mation of the chemicals industry. Instead of devel-oping new markets for chemicals or requiring newinfrastructure or supply chains, direct productionof existing chemical intermediates can quicklydrop into current markets and leverage substantialdownstream infrastructure that is already in placeglobally.

At present, succinic acid serves a relatively smallworld market of about 40,000 tonnes/year.Proponents contend that the market could grow100-fold if the bio-based variety is made at a lowerprice than the petrochemical method. Whilst theglobal market for lysine is substantially larger thansuccinic acid at more than 700,000 tonnes/year, itremains far smaller than the 4,000,000tonnes/year market for caprolactam.

It is di�cult to believe that economical produc-tion of large-scale chemical intermediates can bedriven through these indirect routes, as a signi�-cant amount of capital will need to be invested forthe platform molecule, in addition to capital forconversion to target chemical intermediates.

Chemicals producers are making importantstrides to serve this sustainable market demandand allow the industry to diversify away frompetrochemical feedstocks. Several processes arenearing commercialisation, as small demonstrationfacilities start up and industry leaders, includingBASF and DSM, have announced the commer-cialisation of bio-based succinic acid in the comingyears.

However, most industry e�orts appear focusedon lower volume specialities, green niches, likedeicing �uids, and potentially new polymers, likepolybutylene succinate, rather than as a platformmolecule for the production of BDO. While thesee�orts establish more important examples of suc-cessful bio-based processes, we believe the pathto open large chemical intermediate markets isthrough drop-in, low-cost alternatives via the mostdirect production method possible.

The International Sugar Organisation’s (ISO)�rst industrial bio-products market study, ‘MarketPotential of Sugarcane & Beet Bio-products’,

Speciality Chemicals Magazine July 2010 33

o-based chemical productionFermentationSugar Acidi�cation Separations Hydrogenation

Separations BDO

FermentationSugar Separations BDO

a

b

Figure 2 - Succinic acid (a) & direct (b) routes to BDO

Sustainability

34 July 2010 Speciality Chemicals Magazine

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charts new territory in sugar cane and sugar beetmarket analysis by focusing on the emergingopportunity for sugar-derived chemicals, polymersand bioplastics. Genomatica’s sugar-based processfor producing 1,4-BDO is presented in the‘Biobased Chemicals’ section titled as a promisingtechnology.3

Aside from bio-polyethylene, which the ISOidentifies as a key bioplastics opportunity, thereport finds that of all chemicals studied BDO has“the best potential in the near term”, in part dueto the direct nature of its production in theGenomatica process and consequent lower pro-duction costs.

BDO’s large market size, it adds, combinedwith Genomatica’s process, gives bio-based BDOseveral advantages over bio-based succinic acid,which has a significantly smaller market andrequires additional conversion to create chemicalssuch as BDO, with yield losses and cost increasesin the process.

Direct to 1,4-BDOIf a process is to produce the target chemicalsdirectly, a microorganism must be engineered toproduce the chemical and serve as an effectivebiocatalyst. Driving the titre, productivity and yieldof the process are some of the most importantmetrics to produce an economically viable, sus-tainable chemical, and organism performance iscritical to success.

If the fermentation process can produce morequickly, that lowers the overall cost of production.Genomatica uses genetic engineering and adap-tive evolution to improve the rate of productionfrom fermentation processes.

Our research teams have focused on increasingtitres as we move toward commercialisation. Thisspring, they achieved an important milestone withour flagship butanediol process, achieving over 80gm/litre titres in 30 litre fermentations.Simultaneously, we are reducing by-products andseeing improved yields.

Unlike many organisms that make a targetedchemical as a by-product of their own growth, ourtechnology platform allows us to link the organ-ism’s growth to the production of the target chem-ical. We genetically knock out the pathways to theother by-products, so the organism must produceour target chemical to survive. All of theseadvances are important and our economic modelsestimate that our process is now at least cost-com-petitive with traditional methods of manufacturing.

We continue to refine the process and we areconfident that we can achieve a significant costadvantage through an even higher titre andimproved yield. In less than two and a half years,we moved from the first detectable quantities ofBDO ever shown in a fermentation to over 80gm/litre from raw sugar (sucrose). This thresholdmatches the cost of current petroleum-basedBDO production, and we are well on our way tothe next threshold, which will give us a strong costadvantage.

We find that traditional chemicals producers arebecoming more knowledgeable and comfortableabout titre and other key metrics of bio-basedchemical production. They understand the keys toviable production and recognise both ourprogress and the power of our integrated devel-opment process.

Next stepsLooking to the future, a few more key milestoneswill mark the industry’s progress toward a moresustainable future. We have scaled our flagshipBDO process up 100-fold, as part of the prepara-tion for a demonstration plant in 2011, and haverecently shown equivalent fermentation perform-ance at both 30 and 3,000 litre scales.

Our initial engagements with existing BDOconsumers and producers indicate that our bio-based BDO is promising from both analytical andapplication standpoints. Pilot-scale production andthe demonstration plant will allow for furtherlarge-scale sampling and downstream conversion

testing to demonstrate effective use in key deriva-tive products, including PBT, PTMEG and TPU.

We have also demonstrated the utility of ourorganism and process across a variety of commer-cial feedstocks, with no apparent loss in key fer-mentation performance metrics or final productquality. As with our BDO process, the growth ofthe industry will depend on continued conversionof bio-based products to end products, compati-bility with existing derivative infrastructure andcost-effective manufacturing.

A wide range of companies are innovating tomake the chemicals industry more sustainable andto allow for the use of other feedstocks. Many dif-ferent bio-based applications will find a range ofniche markets, but a truly widespread revolutionwill require lower costs and simple conversion.Direct, cost-effective production has greaterpotential to revolutionise the chemicals industry,expanding sustainability more quickly and bring-ing increased profitability at the same time.

For more information, please contact:Dennis McGrewGenomatica, Inc.10520 Wateridge CircleSan DiegoCA 92121USATel: +1 858 362 8578E-mail: dmcgrew@genomatica.com Website: www.genomatica.com

References: 1. J.B. McKinlay, C. Vieille & J.G. Zeikus, Prospectsfor a Bio-Based Succinate Industry, AppliedMicrobiology & Biotechnology 2006 , 76, 727-7402. A. Cukalovic & C.V. Stevens, Feasibility ofProduction Methods for Succinic Acid Derivatives: AMarriage of Renewable Resources & ChemicalTechnology, Biofuels, Bioproducts & BiorefiningAugust 2008 , 6, 505-5293. www.isosugar.org/PDF%20files/MECAS(09)17;%20MECAS(09)18;%20MECAS(09)19.pdf

Lysine-HCIseparationsAcidification

Ion exchangeEvaporation

NeutralisationCrystallisation

Lysine cyclisation& separationsAlkalinisationSalt, solvent &water removal

Fermentationto lysine

Deamination& -Caprolactam

recoveryAddition of KOH& NH2OSO3HAmine removal

Sublimation

Polymerisation PA6

Sugar

6-ACAseparations

pH adjustmentEvaporation

Crystallisation

Fermentationto 6-ACA

Polymerisation PA6

Sugar

a

b

Figure 3 - Lysine-based (a) & direct 6-ACA-based (b) routes to PA 6