1
Beyond Ethanol:Synthesis and Commercialization of High Value
Bioproducts in Future Biorefineries
University of Nebraska Research Faculty Retreat
May 15, 2007
2
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
3
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
5
Aromatics from Renewables
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
HO
OHglucose
xylose
arabinose
glycerol
6
Aromatics from Renewables
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
7
Aromatics from Renewables
Chemical Considerations:
new chemicals and new chemistries
improved performance
8
Aromatics from Renewables
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
9
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
10
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
16
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
- Hexion Specialty Chemicals
- 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
- Hexion Specialty Chemicals
- 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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Aromatics from Renewables
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
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
28
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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Aromatics from Renewables
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
HO
OHglucose
xylose
arabinose
glycerol
32
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
34
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.
Synthesis of Aromatics from Renewables
35
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
Synthesis of Aromatics from Renewables
36
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.
Synthesis of Aromatics from Renewables
Generic Approach:
37
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
38
(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.
39
Aromatics from Renewables
$
Green
Performance
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
HO
OHglucose
xylose
arabinose
glycerol