1 Beyond Ethanol: Synthesis and Commercialization of High Value Bioproducts in Future Biorefineries University of Nebraska Research Faculty Retreat May.

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Beyond Ethanol:Synthesis and Commercialization of High Value

Bioproducts in Future Biorefineries

University of Nebraska Research Faculty Retreat

May 15, 2007

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methanol ethenebenzene toluene xylenes

propene butadiene

petroleum

transportation fuels

chemicalspolymers

90% of volume 60% of value-add

10% of volume 40% of value-add

Petroleum Refining Value-Add Chain

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Renewable Refining Value-Add Chain

starch cellulosehemicellulose

plant oils

glucosexylose arabinose

glycerol

chemicalspolymers

biofuels

microbes

catalysts

4

Aromatics from Petroleum

OH

OHHO

OH

HO OH

NH

O

OH

HO

OH

OH

OH

CO2HHO2C

OHHO

HO

caprolactam phloroglucinol

apionol

pyrogallol

hydroquinoneresorcinol

catechol

adipic acid

HO

phenol

HObenzene

OH

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Aromatics from Renewables

OH

OHHO

OH

HO OH

NH

O

OH

HO

OH

OH

OH

CO2HHO2C

OHHO

HO


apionol

pyrogallol


catechol

adipic acid

HO

phenol

HO

OHglucose

xylose

arabinose

glycerol

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lower cost, stable pricing for feedstock carbon

increased margins for chemicals and polymers

Economic Considerations:

U.S. wet-milled glucose: $0.19/kg

U.S. dry-milled glucose: $0.13/kg

U.S. cellulosic glucose: $0.09/kg

Brazilian glucose: $0.11/kg

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Chemical Considerations:

new chemicals and new chemistries

improved performance

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Environmental Considerations

benzene

volatile carcinogen associated with leukemia and non-Hodgkin’s lymphoma

toxic at levels lower than the U.S. exposure limit of 1 ppm over 8 h (Science 2004, 306, 1774)

O

OHOH

OHOHHO

D-glucose

O

OHOH

OHOH

D-xylose

HO

OH

OH

HOL-arabinose

HO OHOH

glycerol

nonvolatile and nontoxic

consumption of CO2

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Phloroglucinol Platform

Requires a single enzyme for biosynthesis from malonyl-CoA.

Elevated oxygen content.1.

2.

3. Low toxicity: LD50 = 4,000 mg/kg

Target Rationale:

4. Unique electrophilic and nucleophilic reactivity.

OH

HO OHphloroglucinol

O

HO OH

keto tautomer

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Phloroglucinol Platform

Resorcinol, $360M market

Pharmaceuticals, $7.5M market1

3

4Formaldehyde-based

Formaldehyde-free

Adhesive Resins, $3.3B market

OH

HO OH

phloroglucinol

Energetic Materials, $4.5M market2

current market price: $55.00/kg

2007 manufacturing cost: $32.50/kg

2009 manufacturing cost: $2.65/kg

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Phloroglucinol

Existing Route to Phloroglucinol

Synthesis of Phloroglucinol from Renewables

Problems

• explosion risk

• toxic waste

• “red water”

• chromium salts

• multiple steps(a) HNO3, H2SO4; (b) Na2Cr2O7, H2SO4; (c) Fe°, HCl; (d) H2SO4

(a) E. coli W3110serA(DE3)/pJA3.131A

CH3

NO2

NO2

O2N

TNT

CH3

NO2

NO2

O2N

TNT

CO2HNO2

NO2

O2N NH2H2N

NH2

OHHO

OH

phloroglucinol

CH3CH3

toluene

a b c d

O

HO OHOH

OHOH

OHHO

OH

phloroglucinolglucose

a

Advantages• nontoxic glucose• no toxic waste• single step

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Phloroglucinol

OH

HO OH

OH

HO OH

Spasfon(antispasmodic)

CH3O

CH3O OCH3

NO

Buflomedil(vasodilator)

• High-value market opportunity for phloroglucinol

• Annual demand: 40 - 60 tons of phloroglucinol• GMP manufacture required

• Spasfon (anti-spasmodic): $58M total sales

• Buflomedil (vasodilator): $16M total sales

• Manufacturer (Cephalon) seeking alternative suppliers

Phloroglucinol as an Active Pharmaceutical Ingredient: $7.5M Market

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• thermally-stable, impact-insensitive energetic material

• possesses a greater density and detonation velocity relative to 2,4,6-trinitrotoluene (TNT)

• reduced shock sensitivity and increased thermal stability relative to hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX).

Energetic Materials

Advantages of TATB:

Phloroglucinol is the starting material for TATB manufacture.

TATB is used in fuze and booster systems.

Market opportunity:

• Phloroglucinol is manufactured in China, India, and Pakistan but not in the U.S.

• U.S. Department of Defense is seeking a domestic source.

NH2

H2N NH2

NO2

NO2

O2N

TATB

1,3,5-triamino-2,4,6-trinitrobenzene

OH

HO OH

OH

HO OH

NO2

NO2

O2NOEt

EtO OEt

NO2

NO2

O2N

phloroglucinol

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(a) E. coli W3110serA(DE3)/pJA3.131A; (b) H2, Rh/Al2O3

O

HO OHOH

OHOH

OHHO

OH

phloroglucinol

OH

OH

resorcinolglucose

a b

Resorcinol

Manufacturing Route from Renewables

• Renewable feedstocks

• Nontoxic glucose

• Short synthetic sequence

• Mild reaction temperatures.

• Salt waste stream minimized

• Explosion risk minimized

• Use of contract manufacturing

current market price: $ 6.50/kg

2009 manufacturing cost: $ 3.80/kg

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O

O

O

H

OH

O

OH

O

H

OH

OH

OH

OHresorcinol

DHPHHPDC

HO OO

H

O

acetone

benzene

AP

m-diisopropylbenzene

a b c

d

d

OH

OH

resorcinol

SO3H

SO3H

benzene

SO3Na

SO3Na ONa

ONa

benzene-1,3-disulfonic acid

a b c dNaHSO3

disodium benzene-1,3-disulfonate

disodiumresorcinate

Resorcinol

(a) SO3; (b) NaOH; (c) NaOH fusion, 350 °C; (d) H2SO4

INDSPEC Manufacturing Route

Sumitomo Manufacturing Route

(a) propylene, HZSM-12; (b) O2, NaOH; (c) H2SO4, heat; (d) H2SO4, H2O2

Challenges• benzene• high temperature• salt byproduct

Challenges• benzene• yield issue• detonation risk

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Resorcinol Market

Application Major Buyers

- Adhesives for tires and fiber-reinforced rubber goods

- Goodyear- Michelin- Bridgestone- Continental- Others

- Wood adhesives requiring room-temperature curing, structural integrity, waterproofing

- Hexion- Georgia-Pacific- Dynea- National Casein

- UV screening agents

- Dyestuffs

- Pharmaceuticals

- Other miscellaneous

- Akzo Nobel- ISP- Others

$198M

$54M

$29M

$80M

$198M

$54M

$29M

$80M

tires

other

UV protection

wood adhesives

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Resorcinol Market

Manufacturers Volume Market Size

INDSPEC Sumitomo Mitsui Other Manufacturers

~20K mt

~18K mt

~15K mt

~2K mt

$130M

$117M

$98M

$13M

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Resins

OH

H H

OOH

n

formaldehyde phenol phenol-formaldehyde polymer

OH

H H

OOH

n

formaldehyde resorcinol resorcinol-formaldehyde polymer

HO HO

Phenol-Formaldehyde Adhesive Resins

Resorcinol-Formaldehyde Adhesive Resins

Problems:

• formaldehyde toxicity

• rising phenol prices

• rising resorcinol prices

• rising methanol prices

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Regulation and Litigation Risk

Formaldehyde a threat • Formaldehyde classified as known human carcinogen in 2004 (International Agency

for Research on Cancer)• Companies exposed to regulation / litigation

• Danger to employees who handle phenol-formaldehyde• Danger to consumers from formaldehyde “off-gassing”

Specter of asbestos litigation• Bankruptcy (e.g., Owens Corning)

Demand for formaldehyde-free alternatives• Johns Mansville (fiber-glass insulation): now using acrylic replacement• Hexion: introduced “Ecobind adhesive resin with “low emissions” of formaldehyde• Knauff seeking replacement for phenol-formaldehyde adhesives

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Resins

Phloroglucinol-Formaldehyde Adhesive Resins

Phloroglucinol Advantage:

• adhesive properties

• curing temperature and time

• lower formaldehyde outgassing

Phloroglucinol-Aldehyde Adhesive Resins

OH

H H

OOH

n

formaldehyde phloroglucinol phloroglucinol-formaldehyde polymer

HO HO OHOH

OH

R H

OOH

n

phloroglucinol-aldehyde polymer

HO OH

RR

R

OHHO

phloroglucinolaldehyde

Phloroglucinol Advantage:

• adhesive properties

• formaldehyde-free

• 100% biobased

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Resins

Replace formaldehyde with alternative, nontoxic aldehyde

Options to source alternative aldehydes• Plant oils• Fischer-Tropsch products

• Sasol (multiple K metric tons)

• Exxon (~300K metric tons, C6 through C15 aldehydes)

• Shell (~300K metric tons, C9 through C15 aldehydes)

• Sterling Chemical (~100K metric tons, C7 through C11 aldehydes)

• BASF• Eastman

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Wood Adhesive

Foundry

Insulation

Laminate

Abrasives

$1,342M

$883M

$472M

$422M

$222M

Wood Adhesive

Foundry

Insulation

Laminate

Abrasives

$1,342M

$883M

$472M

$422M

$222M

Resins Market

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Resins Market

Application Major Buyers Manufacturers VolumeWood adhesives

- Plywood

- Oriented Strand Board (OSB)

- Laminated veneer lumber (LVL)

- Hardboard

- I-beam

- Finger-joint

- Weyerhauser

- Georgia-Pacific

- Louisiana-Pacific

- Canfor

- Hexion Specialty Chemicals

- Dynea

- Georgia-Pacific

1,239 Kt

Foundry

- Binders for sand cores

- Binders for mold production

- Foundries - HA-International

- Ashland Specialty Chemical

- Georgia-Pacific

Est. 446 Kt

Insulation

- Glass Fiber

- Waste Fiber

- Mineral Wool

- Knauf Insulation

- Johns Manville

- Owens Corning

- CertainTeed


- Dynea

- Durez

-Georgia-Pacific

- Schenectady

- Ranbar Electrical Materials

- Von Roll Isola USA

334 Kt

Laminate

- Decorative

- Industrial

- Wood products mfcts. - Hexion Specialty Chemicals

- Dynea

- Georgia-Pacific

389 Kt

Abrasive

- Grinding and finishing wheels

- Abrasive machining tools

- Scrub and scouring pads

- Sandpaper

- 3M

- Others


- Dynea

- Durez

-Georgia-Pacific

- Schenectady

- 3M (captive product)

Est. 92 Kt

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High Performance Polymers

Lexan SLX

O O

O

O

O

O

O

O

H3C CH3

O O

O

polycarbonate segmentisoterephthate-resorcinolsegment

• Amorphous polycarbonate copolymer.

• Photoisomerizes to a benzophenone.

• Maintains gloss and is scratch resistant.

• Targeted as a replacement for paint in the automotive industry.

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Zylon

• Synthesized using polyphosphoric acid catalysis.

O

N

O

N

Zylon

CO2H

HO2C

OHHO

NH2H2N

• Zylon is the strongest commercially available fiber.

• Zylon’s tensile strength is greater than that of Kevlar.

High Performance Polymers

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OH

OHHO

OH

HO OH

NH

O

OH

HO

OH

OH

OH

CO2HHO2C

OHHO

HO


apionol

pyrogallol


catechol

adipic acid

HO

phenol

HO

OHglucose

xylose

arabinose

glycerol

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Caprolactam Manufacture

benzene

NOH

cyclohexanone oxime

cyclohexanone

cyclohexane

OH

phenol

O

caprolactam

NH

Oa b

c d

e f

(a) H2, Pt; (b) i) O2, Co, ii) Cu/Zn; (c) i) propylene, Hn+2PnO3n+1, 200 atm, 200 °C; ii) O2; 90-120 °C; (d) H2, Pd; (e) i) (NH2OH)2H2SO4, ii) NH3; (f) i) H2SO4•SO3, ii) NH3.

a

CNNC

b

H2N CN

c

NHO

(a) HCN, Ni; (b) H2, Raney Ni/NH3; c) H2O/NH3, 300-360°C, TiO2 or Al2O3

• Benzene toxicity

• HCN toxicity

• Cost of petroleum

• Waste streams

• Cost of petroleum

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Caprolactam

Caprolactam, $8.8B Market

Volume: 4M mt

Price: ~$2.20 / kilogram

Primary Applications• Nylon-6 textile, resin, film, filament

Primary Manufacturers• BASF• DSM• Honeywell• China Petrochemical Development• Ube Industries• Sumitomo Chemical• Bayer• Others

Buyers: Various

Problems

Costs driven up by benzene prices

Large volumes of ammonium sulfate waste

Solutions

Chemical synthesis of caprolactam from glucose-derived lysine

Enables “renewable” structural material

Reduction of salt waste streams

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•Shielded from benzene price fluctuation

•Significant reduction in waste

•Enables “renewable” fiber

(a) microbial synthesis; (b) cyclization; (c) catalytic hydrodenitrogenation

lysine caprolactam

NH3

CO2

NH3

NH

O

O

OHOH

OHOH

HO

glucose

ca

NH3

NH

ONH2

ClNaCl

aminocaprolactam

b

Synthesis of Caprolactam from Renewables

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Lysine Supply

0

200

400

600

800

1000

1200

2001 2002 2003 2004 2005 2006M

arke

Siz

e (K

mt)

0

0.5

1

1.5

2

2.5

Pri

ce (

$ /

kg)

Market size Price

Major Lysine Producers

Ajinomoto

ADM

CJ

BASF

Global Bio-Chem (China)

Degussa / Shandong (China)

Capacity (kmt / y)

290

160

110

90

145 – 290

120

Major producers currently building capacity

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OH

OHHO

OH

HO OH

NH

O

OH

HO

OH

OH

OH

CO2HHO2C

OHHO

HO


apionol

pyrogallol


catechol

adipic acid

HO

phenol

HO

OHglucose

xylose

arabinose

glycerol

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Synthesis of Aromatics from Renewables

O

HO OHOH

OHOH

OHHO

OH

phloroglucinol

OH

OHresorcinolglucose

a b

(a) E. coli W3110serA(DE3)/pJA3.131A; (b) H2, Rh/Al2O3

catechol

HOOH

O

OHOH

OHOHHO

glucose

CO2H

HOOH

PCA

a b

(a) microbial synthesis; (b) H2O, 290°C.

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HOOH

CH3OOH OH

CH3O

HO

vanillincatechol guaiacol

CH3OOH

OH

OHO

4-hydroxy-3-methoxy-mandelic acid

CH3OOH

OH

OO

4-hydroxy-3-methoxy-glyoxylic acid

a b c d

Vanillin Manufacture

(a) MeOH, H3PO4; (b) glyoxylic acid, NaOH; (c) O2; (d) H+

OH

OHhydroquinone

OH

phenolcumenebenzene O

acetone

a b c

catechol

HOOH

(a) propene, Hn+2PnO3n+1, 200 atm, 200 °C; (b) O2; 90-120 °C; (c) 60-70% H2O2, H3PO4/HClO4.

Catechol Manufacture

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OH

OH

hydroquinone

O

OHOH

OHOH

HO

glucose

OHOH

HO CO2H

HO

quinic acid

a b

(a) microbial synthesis; (b) HOCl or Ag3PO4/K2S2O8

Quinic Acid

Isolated from Cinchona tree bark primarily in Zaire.

Starting material for the original Gilead synthesis of Tamiflu.

Biologically active component in extract of Uncaria tomentosa (cat’s claw) bark.

Cat’s claw extract stimulates the immune system and accelerates DNA repair.


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OH

phenol

a b

HOOH

CO2H

OH

shikimic acid

O

OHOH

OHOH

HO

glucose

(a) microbial synthesis; (b) H2O, 330 °C.

Starting material for the synthesis of Tamiflu.

As Tamiflu came out of clinical trials in 1998, shikimic acid cost $50,000/kg.

The manufacturing cost of microbe-synthesized shikimic acid is $20/kg.

Extracted from star anise in China.

Shikimic Acid


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Two-step syntheses: microbial catalysis followed by chemical catalysis.

The first step’s product is less toxic to microbes than the second step’s product.

The first step’s product is higher value-added relative to the second step’s product.


Generic Approach:

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Polyhydroxybenzenes

(a) E. coli KL7/pSK6.161; (b) E. coli RB791serA::aroB/pSK6.234.

Isolated from a wasp carapace in China.

Powerful antioxidant.

Most favorable toxicological profile of the large-volume antioxidants (BHA, BHT, TBHQ) .

Gallic Acid:

OHpyrogallol

HO OHO

HO OHOH

OHOH

OHgallic acidglucose

a b

CO2H

HO OH

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(a) Gluconobacter oxydans ATCC 621; (b) H+, H2O.

apionol:

Natural product found in trace quantities in wood grain distillate.

Powerful antioxidant.

Polyhydroxybenzenes

OHHO OH

OH

apionol

OH

HO

HO OH

OHOH

a

OH

HO

HO OH

OHO

b

myo-inositol myo-2-inosose

myo-inositol:

A supplement used in aquaculture and animal feed applications.

Can be derived from phytic acid or microbially synthesized from glucose.

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$

Green

Performance

OH

OHHO

OH

HO OH

NH

O

OH

HO

OH

OH

OH

CO2HHO2C

OHHO

HO


apionol

pyrogallol


catechol

adipic acid

HO

phenol

HO

OHglucose

xylose

arabinose

glycerol

1 Beyond Ethanol: Synthesis and Commercialization of High Value Bioproducts in Future Biorefineries University of Nebraska Research Faculty Retreat May.

Documents

resorcinol market slide

petroleum slide

chain slide

performance slide

formaldehyde toxicity

threat formaldehyde

phenolformaldehyde adhesives

litigation risk formaldehyde