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Cost of waste
Cost of wasted reagents
Cost of wasted energy
Cost of waste disposal
Cost of increased regulation
Green Chemistry:
Addressing the Source
&
Global Chemical
Production
Reducing
Increasing number of
Fines for Chemistry
Pollution Students
Poor Public
Increasing Image &
Costs of Waste Negative Media
Disposal Reporting
Increasing Increasing
Costs for Producer
Storing Responsibilitie
Hazardous s
New Diminishing
Substances
Legistation Supplies of
forcing testing non-
of all chemicals sustainable
Resources
D
R Diminishing Market Increasing New
I fossil Distortions Cost of Waste Increasing Requirements for
V Reserves & due to new Disposal & Energy Product testing
E Increasing Manufacturing Storage of Cost Recovery
Prices Regions Hazardous Recyclability
R
S
Chemical
Raw Materials
Manufacturing and Product use
Pre/Manufacturing
Production
B
A Reduce Dependence Employ Green
E Build up Portfolio of
C on Traditional Chemical
N Green and Sustainable
T Resources. Technology to Chemical Products that
E
I Maximize use of Improve Process can dominate future
F Renewable Local Efficiency & Reduce
O World Markets
I Resources Waste
N
T
S
S
DATA GAP
SAFTEY GAP
(Information)
(Accountability)
Business &
Consumer Choice Evidence of
Necessary & Cause & effect
Available Slandered Evidence
Information is Required for
Regulation
TECHNOLOGY GAP
(Capacity)
Intellectual &
Technical
Markets Capacity to Support Government
Buyers: No Haz. Data Green Chemistry Inability to Assess Haz.
Sellers: No Case for GC
Inability to Control Haz.
Subject Environmentally Thinking Economically Thinking
Atom Minimal by Product Formation More from Less - Incorporate
Economy Total Value of Materials
Solvent Less Solvent Waste Higher throughput, Less
reduction Energy
Reagent Catalytic, Low Stoichometry, Higher Efficiency - Higher
Optimization Recyclable Reagents, Minimize Selectivity
Us age
Convergency Due to Increased Processed Higher Efficiency - Fever
Efficiency Operations
Energy From Power Generation, Reduced Energy , Increased
Reduction Transport and Use Efficiency, Shorter Process and
Mild Conditions
Safety Non-Hazardous Materials Worker Safety and Reduced
Reduce Risk of Exposure, Down Time. Reduced Time on
Release, Explosions & Fire Special Control Measures
Green Chemistry - 12 Principles
Prevent wastes
Renewable materials
Omit derivatization steps
Degradable chemical products
Use safe synthetic methods
Catalytic reagents
Temperature, pressure ambient
In-process monitoring
Very few auxiliary substances
E-factor, maximize feed in product
Low toxicity of chemical products
Yes, it is safea
E-Factor
= Total Waste (Kg)/Product (Kg)
Atom Economy
= FW of Atoms Utilized/FW of all Reactants X 100
Atom Efficiency
= % of Yield X Atom Economy
Carbon Efficiency
=Mass of Carbon in Product/Mass of Carbon in Reactants X 100
Carbon Efficiency:
Carbon efficiency is a simplified formula developed at
GlaxoSmithKline (GSK).iv The mathematical representation
Carbon Efficiency (%) = Amount of Carbon in Product x 100 /Total
Carbon Present in the Reactant
This metric is a good simplification for use in the pharmaceutical
industry as it takes into account the stoichiometry of reactants and
products
Atom Economy
Atom economy was designed in a different way to all the other metrics;
most of these were designed to measure the improvement that had been
made. Barry Trost, conversely, designed atom economy as a method by
which organic chemists would pursue “greener” chemistry. The simple
definition of atom economy is a calculation of how much of the reactants
remain in the final product.
% Atom Economy: Atoms Utilized/Atoms Used X 100
Methanol
Ethyl acetate
Ethanol
THF
Hexane
Toluene
Methylene chloride
SO2Cl
N
Commercial/Convergent Route:
O
O
N
N H2N
H2N N O
N Pr
Pd-C/H2 OEt O N
N OEt HN N
H2N
O2N Pr N N
Pr H N
CDI H2N
O
Pr
OEt O
OEt OH OEt O O S O
OH N KOBut/tBuOH O S O
O ClSO3H OH N
SOCl2 NaOH/H2O O S O N
N
SO2Cl N
Pyridine
Toluene
t-Butanol
2-Butanone
Ethyl Acetate
Ether
Methanol
Ethanol
Acetone
Methylene Chloride
AlCl3/Ac2O
ClCH2CO2Et H3O
NaOEt
CHNOH CN CO2H
Excess AlCl3 is used old process and which gave 20,000 tones of solid
waste.
BHC Redesigned in 1990 (after patent expire in 1984)
Catalytic Synthesis, completed in 3 steps
77% Atom Utilization
O OH CO2H
HF/Ac2O H2 Pd
R-Ni CO
100:0; Water (more dilution) -24h, 85%; 1:99 Angew. Chem. Int. Ed., 2001, 40, 2816
Diels-Alder Reactions
O
Me
O
H
O
H2O
R,T
N N
H
O O O
AcO AcO
Tetrahedron Lett, 39, 1239
Toluene -144hrs, 79% ; ACN -144hrs,
N
43%; MeOH – 48hrs, 82%; Neat – 10hrs, O
82%; Water – 8hrs, 81%
H2O O
Angew. Chem. Int. Ed., 2005, 44, 3275 N
O2N
O O
Tetrahedron Lett, 36, 2645 O2N
N N
Ph CO2H
Ph CO2H
H2O
Acetonitrile
Acetonitrile –– 17%
17% ee;
ee; THF
THF --
24%
24% ee;
ee; EtOH
EtOH –– 39%
39% ee;
ee; CHCl
CHCl33 CO2H CO2H
–– 44%
44% ee;
ee; Water
Water –– 74%
74% ee
ee
J. Am. Chem. Soc. 1980, 102, 7816
J. Amer, Chem, Soc. 1999, 121, 6798
Radical Reactions
Atom transfer Radical Cyclization Radical Coupling
I I
Et3B MDC (0%); THF (0%) FeCl3 OH
MeOH (6%); EtOH (3%)
3hrs ACN (13%); DMF (13%) Water Drop OH
O O DMSO (37%); H2O (78%) OH
O O &
Grind
J.Am. Chem. Soc., 2000, 122, 11041
Textbook of Practical Organic Chemistry,
O
Radical Reductions
O OR OR
O Et3B O Hexane (10%);
H3PO4, NaBCO3
Benzene (23%)
I O 3hrs MeOH (0%);
O AIBN, H2O
H2O (69%)
98% Yield
I
I
J.Am. Chem. Soc., 2000, 122, 11041 Bull. Chem. Soc. Jpn., 2001, 74, 225
NHCOCF3
F3COCHN
OH
S S
N
BF4
S S Acetone/Water N
N2
OH
O CAN/KBr
R H2O/EtOH
ARP-Pd (cat.0 R
O2/H2O Br
R=H (97%); R=Me (99%) 85%
Journal of Chemical Education. 1996, 173,
Angew. Chem. Int. Ed., 2003, 42, 194 267
Synthesis of tetrabutylammonium tribromide
Reduction of Ketones (TBATB) and application:
OH
O Br O
OH
R TBATB
RuCl2 Cat.
Br
aq. NaCO2H Water, 15 min
90% Yield & 77% ee
Angew. Chem. Int. Ed., 2004, 43, 6731 US Patent No. 7005548, February 28, 2006
Transition Metal Catalytic Reactions
J.Am. Chem. Soc., 2001, 123, 5358 Appl. Organometal Chem, 2008, 233
Copper Catalyzed Reations
Pd Catalyzed C-N bond formation
R
N R
Cu(OTf) Cl NH2 H
N N
H
H2O, Phoshine Ligand
93% Yield
96% ee Pd2dba3/KOH, H2O
91% Yield
J. Am. Chem. Soc., 2002, 124, 5638 J.Am. Chem. Soc., 2003, 125, 6653
Miscellaneous Reactions
One pot synthesis of C-glycosidie Ketone Alkylations in the presence of Butylcalix[n]arenes:
OH
R
OH
O O
O O RX, Catalyst
HO HO
HO O aq. NaOH O
OH NaHCO3/H2O HO O 10hrs/70-94%
OH
OH 96%
Chem. Comm., 2000, 2049 Adv. Synth. Catal., 2002, 344 (3+4), 370
J. Braz. Chem. Soc., 2001, 12, 135 Adv. Synth. Catal., 2002, 344 (3+4), 370
SH Water/4hrs/40oC CO2Et
HS O O
96% Yield H CO2Na H
o
Benzene/80 C/72hrs/67%; Water/R.T/5hrs/75%
DBSA=Dodecabenzenesulfonic acid
J. Am. Chem. Soc., 1990, 112, 9436
OH
Asymmetric OH
Dihydroxylation
Water Ph
O O
O O
H
N O
Adv. Synth. Catal., 2003, 345, 576 N NH
H O
O N Catalyst
O O
N
O RCM
O Ph
Water N
H
CHO O O O
O
CO2Et Ph
O O
EAA, NH4OAc
N Anti Hepatitis C Virus;
Water H
J. Org, Chem, 2005, 70, 10765
ARKIVOC 2008 (XV), 1-8
Miscellaneous Reactions
PhCHO OH PhCHO Ph OH
Br Br Br
In/Water Ph In/Water HO Ph
O
O
HNO3
H2O2
OH
HO
OH
H2O
O
O
O Proline Cat. OH
Chem. Eur. J. 2007, 13,
HO
OH 689 – 701
Water/THF
89-99%ee (~90% Yield) Traces or No Product
O OH
CO2Me
N CO2Me
N
N R.T,
MeO2C N 120hrs
CO2Me Cl Cl
S
Treatment for CNS Damage
O O O
N O N
H H
US2005009733 O
S
H
S N
OH
Treatment of
N HyperUricemia
O
Cl N Anti Bacterial
O Me H
O N N
US20080305169 S
N US20050197326
H O
Cl
O
1,2,3,4-tetrahydro-2-quinoxalinones
Used as Key Ingredient in NCE’s
O
H
N Treatment for Breast Cancer
Histone Deacetylase Inhibitors
H N O O
N N
S
N S
O N
O H O
N O O2N
H N US20080255109
US 20070155730
H H
N N
Anti Cancer Agent
H
N
N O
US20050148586 O N
O
N HN
N N S
H
N
N O
US20060247244 O
US20060019959
3,4-dihydro-2H-benzo[b]thiazine-3-ones
Known Methods to Prepare
S.No Conditions
1. CH3CH(Br)COOH, Zuletzt, 150 oC
2. CH3CH(Br)COOEt, in AcOH; Con. HCl
3. RCH(X)COOEt; DMF, 90 – 95 Oc; R = CH3, Ph
4. CH3CH(Br)COOH; 120 – 125 oC
5. CH3CH(Cl)CONH2; K2CO3, Acetone, Refluxed for 16.0 hrs
6. i) SmI, THF; ii) RCH(Br)COOH; R = CH3, Ph
7. KOH, Methanol, 2,2,2 – trichloro-1-phenyl
8. CH3CH(Cl)CO2H; NaOH, Water; Refluxed for 4.0 hrs
9. PhCH(Br)COOH,; Zuletzt, 150 oC
10. i) PhCH(Br)COOMe, KI; ii) NaOMe, C6H6, 80 ° oC
11. PhCH(Cl)COOH,; NaOH.
12. (CH3)2C(Br)COOH; KOH, EtOH
3,4-dihydro-2H-benzo[b]thiazine-3-ones
MW Assisted Aqueous Phase Synthesis
S R SH S R
BrCH(R)CO2Et, NaOH BrCH(R)CO2Et, NaOH
2 1 2
N
H O
Water, 80 0C, 1.0 hr NH2
Water, MW, 4 - 5 min N
H O
4 3 4