Beyond Ethanol:
Synthesis and Commercialization of High Value
Bioproducts in Future Biorefineries
University of Nebraska Research Faculty Retreat
May 15, 2007
1
Petroleum Refining Value-Add Chain
90% of volume
60% of value-add
transportation fuels
10% of volume
40% of value-add
chemicals
polymers
petroleum
methanol ethene
benzene toluene xylenes
propene butadiene
2
Renewable Refining Value-Add Chain
biofuels
starch cellulose
hemicellulose
plant oils
glucose
xylose arabinose
glycerol
catalysts
microbes
chemicals
polymers
3
Aromatics from Petroleum
O
OH
HO2C
NH
caprolactam
HO
CO2H
adipic acid
HO
OH
phloroglucinol
OH
OH
HO
OH
phenol
HO
HO
catechol
apionol
OH
benzene
OH
HO
OH
OH
OH
pyrogallol
HO
hydroquinone
resorcinol
4
Aromatics from Renewables
O
NH
caprolactam
HO
CO2H
adipic acid
HO
OH
phloroglucinol
OH
OH
HO
glucose
xylose
arabinose
glycerol
phenol
HO
HO
catechol
OH
HO2C
OH
apionol
OH
OH
HO
OH
OH
OH
pyrogallol
HO
hydroquinone
resorcinol
5
Aromatics from Renewables
Economic Considerations:
lower cost, stable pricing for feedstock carbon
U.S. wet-milled glucose:
U.S. dry-milled glucose:
Brazilian glucose:
U.S. cellulosic glucose:
$0.19/kg
$0.13/kg
$0.11/kg
$0.09/kg
 increased margins for chemicals and polymers
6
Aromatics from Renewables
Chemical Considerations:
new chemicals and new chemistries
 improved performance
7
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)
OH
O
OH
OH
O
OH
HO
OH
D-glucose
OH
HO
OH
HO
OH
OH
D-xylose
OH
HO
OH
OH
L-arabinose
glycerol
nonvolatile and nontoxic
consumption of CO2
8
Phloroglucinol Platform
Target Rationale:
OH
HO
OH
phloroglucinol
1.
Elevated oxygen content.
2.
Requires a single enzyme for
biosynthesis from malonyl-CoA.
3.
Low toxicity: LD50 = 4,000 mg/kg
4.
Unique electrophilic and nucleophilic reactivity.
O
HO
OH
keto tautomer
9
Phloroglucinol Platform
OH
HO
1
Pharmaceuticals, $7.5M market
2
Energetic Materials, $4.5M market
3
Resorcinol, $360M market
OH
phloroglucinol
current market price: $55.00/kg
2007 manufacturing cost: $32.50/kg
2009 manufacturing cost:
$2.65/kg
Adhesive Resins, $3.3B market
4
Formaldehyde-based
Formaldehyde-free
10
Phloroglucinol
Existing Route to Phloroglucinol
CH3
CO2H
NO2
CH3
a
O2N
NO2
b
O2N
NO2
NO2
toluene
c
H2N
NH2
d
HO
NH2
TNT
OH
OH
phloroglucinol
Problems
• explosion risk
• toxic waste
• “red water”
• chromium salts
• multiple steps
(a) HNO3, H2SO4; (b) Na2Cr2O7, H2SO4; (c) Fe°, HCl; (d) H2SO4
Synthesis of Phloroglucinol from Renewables
OH
HO
OH
O
OH
a
OH
HO
OH
glucose
OH
Advantages
• nontoxic glucose
• no toxic waste
• single step
phloroglucinol
(a) E. coli W3110serA(DE3)/pJA3.131A
11
Phloroglucinol
Phloroglucinol as an Active Pharmaceutical Ingredient: $7.5M Market
OH
OH
CH3O
O
N
HO
OH
HO
Spasfon
(antispasmodic)
OH
CH3O
OCH3
Buflomedil
(vasodilator)
• Spasfon (anti-spasmodic): $58M total sales
• Buflomedil (vasodilator): $16M total sales
• High-value market opportunity for phloroglucinol
• Manufacturer (Cephalon) seeking alternative suppliers
• Annual demand: 40 - 60 tons of phloroglucinol
• GMP manufacture required
12
Energetic Materials
OH
HO
OH
OH
NH2
OEt
O2N
NO2
O2N
NO2
O2N
NO2
HO
OH
EtO
OEt
H2N
NH2
NO2
phloroglucinol
NO2
NO2
TATB
1,3,5-triamino-2,4,6-trinitrobenzene
TATB is used in fuze and booster systems.
Advantages of TATB:
• 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-1,3,5trinitro-1,3,5-triazine (RDX) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX).
Phloroglucinol is the starting material for TATB manufacture.
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.
13
Resorcinol
Manufacturing Route from Renewables
• Renewable feedstocks
OH
HO
OH
O
OH
a
OH
b
• Short synthetic sequence
OH
HO
OH
glucose
• Nontoxic glucose
OH
OH
phloroglucinol
resorcinol
(a) E. coli W3110serA(DE3)/pJA3.131A; (b) H2, Rh/Al2O3
• 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
14
Resorcinol
INDSPEC Manufacturing Route
SO3H
a
b
SO3Na NaHSO ONa
3
c
SO3H
benzene
benzene-1,3disulfonic acid
OH
ONa
SO3Na
disodium benzene1,3-disulfonate
Challenges
• benzene
• high temperature
• salt byproduct
d
disodium
resorcinate
OH
resorcinol
(a) SO3; (b) NaOH; (c) NaOH fusion, 350 °C; (d) H2SO4
H
O
Sumitomo Manufacturing Route
a
OH
b
benzene
m-diisopropylbenzene
d
OH
DC
O
OH
HHP
HO
H
O
O
O
DHP
O
H
H
O
O
OH
AP
c
O
OH
resorcinol
Challenges
• benzene
• yield issue
• detonation risk
acetone
d
(a) propylene, HZSM-12; (b) O2, NaOH; (c) H2SO4, heat; (d) H2SO4, H2O2
15
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
$80
M
$29
M
$54
M
$198
M
tires
wood adhesives
UV protection
other
16
Resorcinol Market
Manufacturers
Volume
Market Size
INDSPEC
~20K mt
$130M
Sumitomo
~18K mt
$117M
Mitsui
~15K mt
$98M
Other Manufacturers
~2K mt
$13M
17
Resins
Phenol-Formaldehyde Adhesive Resins
O
H
Problems:
OH
OH
n
H
• rising phenol prices
• rising resorcinol prices
• rising methanol prices
formaldehyde
phenol
phenol-formaldehyde polymer
• formaldehyde toxicity
Resorcinol-Formaldehyde Adhesive Resins
H
OH
OH
O
n
H
HO
HO
formaldehyde
resorcinol
resorcinol-formaldehyde polymer
18
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
19
Resins
Phloroglucinol-Formaldehyde Adhesive Resins
O
H
OH
OH
n
OH
H
HO
HO
OH
Phloroglucinol Advantage:
• curing temperature and time
• lower formaldehyde outgassing
• adhesive properties
formaldehyde
phloroglucinol
phloroglucinol-formaldehyde
polymer
Phloroglucinol-Aldehyde Adhesive Resins
O
R
R
OH
OH R
n
OH
H
HO
OH
HO
R
aldehyde
phloroglucinol
Phloroglucinol Advantage:
• formaldehyde-free
• 100% biobased
• adhesive properties
phloroglucinol-aldehyde
polymer
20
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
21
Resins Market
$222M
$422M
$472M
Wood Adhesive
$1,342M
Foundry
Insulation
Laminate
$883M
Abrasives
22
Resins Market
Application
Major Buyers
Manufacturers
Volume
Wood 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
23
High Performance Polymers
Lexan SLX
isoterephthate-resorcinol
segment
O
O
polycarbonate segment
O
O
O
O
O
O
O
O
O
H3C CH3
• Amorphous polycarbonate copolymer.
• Photoisomerizes to a benzophenone.
• Maintains gloss and is scratch resistant.
• Targeted as a replacement for paint in the automotive industry.
24
High Performance Polymers
Zylon
HO
OH
H2N
NH2
CO2H
HO2C
N
N
O
O
Zylon
• Synthesized using polyphosphoric acid catalysis.
• Zylon is the strongest commercially available fiber.
• Zylon’s tensile strength is greater than that of Kevlar.
25
Aromatics from Renewables
O
NH
caprolactam
HO
CO2H
adipic acid
HO
OH
phloroglucinol
OH
OH
HO
glucose
xylose
arabinose
glycerol
phenol
HO
HO
catechol
OH
HO2C
OH
apionol
OH
OH
HO
OH
OH
OH
pyrogallol
HO
hydroquinone
resorcinol
26
Caprolactam Manufacture
cyclohexane
a
b
c
d
benzene
O
NOH
e
cyclohexanone
• Benzene toxicity
O
f
• Cost of petroleum
• Waste streams
NH
caprolactam
cyclohexanone
oxime
OH
phenol
(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
NC
b
CN
c
H2N
O
CN
NH
• HCN toxicity
• Cost of petroleum
(a) HCN, Ni; (b) H2, Raney Ni/NH3; c) H2O/NH3, 300-360°C, TiO2 or Al2O3
27
Caprolactam
Caprolactam, $8.8B Market
Problems
Volume: 4M mt
Costs driven up by benzene prices
Price: ~$2.20 / kilogram
Large volumes of ammonium sulfate waste
Primary Applications
• Nylon-6 textile, resin, film, filament
Primary Manufacturers
• BASF
• DSM
• Honeywell
• China Petrochemical Development
• Ube Industries
• Sumitomo Chemical
• Bayer
• Others
Buyers: Various
Solutions
Chemical synthesis of caprolactam from
glucose-derived lysine
Enables “renewable” structural material
Reduction of salt waste streams
28
Synthesis of Caprolactam from Renewables
•Shielded from benzene price fluctuation
•Significant reduction in waste
•Enables “renewable” fiber
OH
O
a
CO2
NH3
Cl
OH
HO
OH
glucose
NH2
NH3
OH
lysine
b
O
O
c
NH
NaCl
NH
NH3
aminocaprolactam
caprolactam
(a) microbial synthesis; (b) cyclization; (c) catalytic hydrodenitrogenation
29
Lysine Supply
Major producers currently building capacity
Market size
1200
Ajinomoto
290
1000
ADM
160
800
CJ
110
BASF
90
Global Bio-Chem (China)
Degussa / Shandong (China)
145 – 290
120
2.5
2
1.5
600
1
400
0.5
200
0
0
2001
2002
2003
2004
2005
2006
30
Price ($ / kg)
Capacity (kmt / y)
Marke Size (K mt)
Major Lysine Producers
Price
Aromatics from Renewables
O
NH
caprolactam
HO
CO2H
adipic acid
HO
OH
phloroglucinol
OH
OH
HO
glucose
xylose
arabinose
glycerol
phenol
HO
HO
catechol
OH
HO2C
OH
apionol
OH
OH
HO
OH
OH
OH
pyrogallol
HO
hydroquinone
resorcinol
31
Synthesis of Aromatics from Renewables
OH
HO
OH
O
OH
OH
b
a
OH
OH
phloroglucinol
HO OH
glucose
OH
resorcinol
(a) E. coli W3110serA(DE3)/pJA3.131A; (b) H2, Rh/Al2O3
CO2H
OH
OH
O
OH
HO
OH
glucose
a
b
HO
HO
OH
PCA
OH
catechol
(a) microbial synthesis; (b) H2O, 290°C.
32
Vanillin Manufacture
O
HO
a
b
CH3O
OH
OH
catechol
O
OH
O
OH
c
CH3O
HO
O
d
CH3O
CH3O
OH
OH
4-hydroxy-3-methoxy- 4-hydroxy-3-methoxymandelic acid
glyoxylic acid
guaiacol
H
OH
vanillin
(a) MeOH, H3PO4; (b) glyoxylic acid, NaOH; (c) O2; (d) H+
Catechol Manufacture
OH
a
b
OH
c
HO
benzene
cumene
O
phenol
OH
hydroquinone
OH
catechol
acetone
(a) propene, Hn+2PnO3n+1, 200 atm, 200 °C; (b) O2; 90-120 °C; (c) 60-70% H2O2, H3PO4/HClO4.
33
Synthesis of Aromatics from Renewables
OH
HO
OH
O
OH
HO
OH
CO2H
a
b
HO
OH
OH
OH
OH
glucose
quinic acid
hydroquinone
(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.
34
Synthesis of Aromatics from Renewables
OH
CO2H
OH
O
OH
HO
OH
glucose
a
b
HO
OH
OH
shikimic acid
OH
phenol
(a) microbial synthesis; (b) H2O, 330 °C.
Shikimic Acid
Extracted from star anise in China.
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.
35
Synthesis of Aromatics from Renewables
Generic Approach:
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.
36
Polyhydroxybenzenes
OH
CO2H
OH
O
b
a
OH
HO OH
glucose
HO
OH
OH
gallic acid
HO
OH
OH
pyrogallol
(a) E. coli KL7/pSK6.161; (b) E. coli RB791serA::aroB/pSK6.234.
Gallic Acid:
Isolated from a wasp carapace in China.
Powerful antioxidant.
Most favorable toxicological profile of the largevolume antioxidants (BHA, BHT, TBHQ) .
37
Polyhydroxybenzenes
OH
OH
HO
OH
HO
OH
OH
myo-inositol
a
HO
OH
HO
O
OH
myo-2-inosose
OH
b
HO
OH
OH
apionol
(a) Gluconobacter oxydans ATCC 621; (b) H+, H2O.
apionol:
Natural product found in trace quantities in wood grain distillate.
Powerful antioxidant.
myo-inositol:
A supplement used in aquaculture and animal feed applications.
Can be derived from phytic acid or microbially synthesized from glucose.
38
Aromatics from Renewables
O
NH
caprolactam
HO
CO2H
adipic acid
HO
OH
phloroglucinol
OH
OH
HO
glucose
xylose
arabinose
glycerol
phenol
HO
HO
catechol
OH
HO2C
$
Green
OH
apionol
OH
Performance
OH
HO
OH
OH
OH
pyrogallol
HO
hydroquinone
resorcinol
39