Venugopal Rao VEERAMANENI, Ph.D.

Indus BioSciences (P) Ltd.

• Green Chemistry: Introduction
– What is Green Chemistry?
– Why we need to know? (Why Green Chemistry is
important?)
– Where we can apply?
– How many types of Alternatives?
– Case Studies
• Green Chemistry – Water as a Solvent
– Introduction
– Applications
• Advantages & Conclusions
 Green chemistry is the design of chemical products and
processes that reduce or eliminate the generation of
hazardous substances.

 Green chemistry seeks to reduce the hazards associated

with chemical process not just by preventing exposure or
release, but by reducing the intrinsic hazards.

 Green Chemistry Efficiently Utilizes (Preferably

Renewable) Raw Materials, Eliminates Waste and Avoids
the Use of Toxic and/or Hazardous Reagents and
Solvents in Manufacture and Application of Chemicals
Products.
 To Introduce, Educate and Promote the Application of Green
Chemistry in Colleges/Institutes
 Key Philosophy: Voluntary Restraint is Better than Enforced
Constraint
 Green Chemistry Includes Protection of the Environment and
Worker Safety
 Information and Influencing the Green Chemistry Research Agenda

 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

Growing 3% per year Doubling

every 25 years
 Increasing Supply Chain
Petrochemical Pressures and
Costs Uncertainties Increasing
Increasing Demands of
Energy Cots Emerging
Nations

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

Effective Mass Yield

 = Product (Kg)/Hazardous Reagents X 100

Carbon Efficiency
 =Mass of Carbon in Product/Mass of Carbon in Reactants X 100

Reaction Mass Efficiency

=Mass of Product/Mass of Reactants X 100
Environmental (E) Factor:
The first general metric for green chemistry remains one of the best,
which proposed by Roger Sheldon
The E-factor calculation is defined by the ratio of the mass of waste per
unit of product.
E-Factor = Raw Materials (Kg) – Desired Product (Kg) /Product Out (Kg)

E-Factors in the Chemical Industry

Industry Product E Factor

Segment Tonnage (Waste/Product)
Oil Refining 106 -108 <0.1
Bulk Chemicals 104 -106 <1-5
Fine Chemicals 102-104 5-50
Pharmaceuticals 10-103 25-100
Effective Mass Yield
Effective mass yield is defined as the percentage of the mass of the
desired product relative to the mass of all non-benign materials used
in its synthesis. Hudlicky et al. suggests the following equation
Effective Mass Yield (%) = Mass of Products x 100 /Mass of Non-
Benign Reagents

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

Reaction Mass Efficiency:

 Developed by GSK, the reaction mass efficiency takes into account
atom economy, yield and stoichiometry
From a generic reaction where A + B → C
Reaction Mass Efficiency = Molecular weight of product C X Yield
 Green Reagents
 Aqueous Phase Reaction
 Solvent free Reaction
 Solid Phase Organic
Synthesis
 Reactions in Ionic Liqueds
 Renewable Feedstocks
 Biodegradable Products
 Non-Covalent
Derivatization
 Atom –Efficient Reactions
 Biocatalysis
 Polymer-Supported
Reagents
 Use of protecting groups
 Enzyme Mediated
Reactions
 Ultrasound-Assisted
Reactions
 Microwave Induced
Reactions
 Microbial Oxidations
 Supercritical Fluid
Intermediates
 Ambient Processing
Sertraline-Active Ingredient in Zoloft (Treatment for Depression)
Pfizer’s Conventional 3 step process Reduced to a Single Step
NMe NHMe NHMe

Pd/C, H2 D-Mandelic Sertraline

TiCl4/MeNH2 acid mandelate
Tolene/Hexane THF
Cl Cl Cl
O Cl Isolated Cl Isolated Cl
Cl
OH NHMe
NHMe
Cl NMe
MeNH2
EtOH
D-Mandelic Sertraline
Cl acid mandelate
Cl Pd/CaCO3
EtOH Cl
Cl
Cl Cl
Cl
Cl
Not Isolated
Solvent use reduced from 60,000 to 6,000 gallons per ton of sertraline
Eliminated the use of 440 metric tons of titanium dioxide per year
Eliminating the use 150 metric tons of 35% hydrochloric acid per year
Eliminating the use of 100 metric tons of 50% sodium hydroxide per year
 Sertraline Process – Solvent Waste/Kg

Methanol
Ethyl acetate
Ethanol
THF
Hexane
Toluene
Methylene chloride

232 L/kg 98 L/kg 81 L/kg 26 L/kg 8 L/kg

Discovery Route 1st Commercial 2nd Commercial 3rd Commercial Chiral Tetralone
 Sildenafil useful for the treatment male impotency
 Old synthetic route is having 10 linear steps
 Potentially toxic materials in the final reaction
 Multiple crystalizations are needed to get pure compound
 Difficulties in Scale up process.

Old Synthetic Route: O OEt

O O O
N Cl
O N N N H2N
HO HO H2N N O
N N N
SOCl2 SnCl
Pr HNO3 EtOH
NH4OH H2N
O2N O2N O
Pr Pr Pr
O Pr O OEt HN N
O
N N
H2N OEt HN N
O N N N
EtO OEt HN N
N Pr
N N
H Pr N O S O
Pr
Pr N

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

 Pd/C & H2 Used for reduction of nitro to amine instead of SnCl/EtOH

 During Sulfonation, thionyl chloride used to convert sulfonic acid
(intermedite) to Sulfonyl chloride
 Sulfonamide formation was performed in aq. NaOH
 CDI used in the formation of amide (coupling) instead of Oxalyl chloride
 Cyclization reaction worked well in the presence of KOBut
 How the amount of waste produced in the manufacture
(L of waste/kg of product) has decreased over the past 13 years.

Pyridine
Toluene
t-Butanol
2-Butanone
Ethyl Acetate
Ether
Methanol
Ethanol
Acetone
Methylene Chloride

1816 L/kg 139 L/kg 31 L/kg 10 L/kg

Medicinal Optimized Commercial Route Commercial Route
Chemistry Med. Chemistry (1997) following solvent
1990 1994 recovery
 Ibuprofen (Pain Killer,) discovered in 1961
Traditional Synthesis (by Boots) involves 6 steps.
And atom utilization is only 40%
O CO2Et
CHO
O

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

 Catalytic amount of Hydrofluoric acid used instead of AlCl3. Catalyst

Reused in Next Batch.
 Acetic acid is by product in first step, was converted to Ac2O (99% of
recovered)
 Carbanion Chemistry Carbocation Chemistry
Addition of Boronic acid
B(OH)2 CHO OH
Mukaiyama Aldol Reaction
OH O
Rh(acac)/CO2/dppf OSiMe3 CHO
Cat. Yb(OTf)3
50oC/Organic/Water
H2O/THF 91%
Organometallics, 1997, 16, 4229 Dry THF 10%

Phenylation Acc. Chem. Res., 2002, 35, 209

SnCl3 CHO OH
Lewis Catalyzed Asymmetric Reaction
OH O
Catalyst
CHO OSiMe3
100oC/Water Cu(OTf)2
71%
O
JACS., 2000, 122, 9538 & 2001, 123, 7451 O
N N H2O/THF: 81% Yield, 81% ee (Syn)
Dry EtOH: 10% Yield, 41% ee (syn)
MDC: 11% Yield, 20% ee (syn)
Selective Alkylation
OH OH Acc. Chem. Res., 2002, 35, 209
a b
CHO
Br
Boron Catalyzed Reaction OH O
In, Water "b" Aduct
"a" Aduct CHO OSiMe3
Ph2BOH
J. Amer. Chem. Soc., 2003, 125, 2958
Ph
H2O: 90% Yield, 92:8 (Syn/Anti)
DMF- 72h, 65%; 100:0; THF-72h, 20%; 100:0 Et2O: Trace; MDC: Trace;
MDC & Neat- No Reaction; Water -72h, 90%; Neat: 24% Yield, 90:10 (Syn/Anti)

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

Pure Applied Chem, 2000, 1327

Oxidations & Reductions Brominations
Oxidative Coupling of 2-Naphthol Bromination of trans-stilbene
Br
Ru(OH)x/Al2O3 OH

Oxygen/Water/ OH Method 1: HBr in H2O

OH
100oC/98% Br
Method 2: NaBr/NaBrO3/H2O

J.Am. Chem. Soc., 2005, 127, 6632 Bromination of acetanilide)

NHCOCH3
NHCOCH3

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

Amides from Nitrile Using RuOH Sujuki-Maiyura Coupling

O
Cl B(OH)2 Na2PdCl4
Ru(OH)x/Al2O3 N
R N R NH2 Phosphine Ligand
Water Water, K2CO3 N
R=Alkyl, Aryl, Vinyl; 80-99%
Green Chem. 2009, 9, 1287
Angew. Chem. Int. Ed., 2004, 43, 1576
Sujuki Coupling
Olefins with Boronic
Acids B(OH) Cl B(OH)2 K PO
2
3 4
R
Rh Cat.TPPDS
Catalyst
Na2CO3/H2O Water R
80% Yield

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

Micheal Addition Formation of ethers

NO2 SH Ph NO2 Ph NO2 OH R1X, Catalyst O
R1
aq. NaOH
Ph S Ph S Syn
Anti 10hrs/22-85%
ACN/TEA - 1hr, 85% yield; 34:66 (anti/syn) R R
H2O/NaHCO3 - 30min, 95% yield; 73:27 (anti/syn)

J. Braz. Chem. Soc., 2001, 12, 135 Adv. Synth. Catal., 2002, 344 (3+4), 370

Esterification Synthesis of bridgehead azaheterocycles

Ph(CHOH)CH3 O
methylimidazole O
O
TEMDA, KOH, H2O Br X
O N
Cl 92% X B-CD/H2O
Ph
OR in presence of 50-55oC N
DBSA/Water 81% yield N NH2
5-25min/65-85%
Adv. Synth. Catal. 2006, 2057 ARKIVOC 2008 (XV), 88-89
 Miscellaneous Reactions
C-C Bond Formation Aldehyde-Amine Condensation
O
O NH2 Ph
OAc O N
CO2Et
CO2Et
Pd(PPh3)4 Cat.
Benzene/Acid Cat./Several hrs; 47-95%
Triton X-100 Cat. Water/Neat/1-3 hrs; 86-98%
K2CO3/H2O
Green Chemistry, 2000, 2, 272
Triton X 100=4-octylphenol polyethoxylate
Synthesis of Chapraninone
Dehydration Reaction
S
OMe OMe
CHO CHO H
DBSA Cat. CHO
S

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

One Pot Wittig Reactions

NC BrCH2CN CO2Et
O BrCH2CO2Et
Ph3P/LiOH/LiCl
Ph3P/LiOH/LiCl
Water/15min-120min
Water/5min-120min
86-99%
71-97%

Syn. Comm. 2006, 36 (20), 2939

 Miscellaneous Reactions

Green Chemistry, 2008, 10, 939

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

Chem. Com, 2003, 1977-1986

OH O OH 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

Toluene -16% ; ACN -27% ; MeOH – 56%

Toluene -120h; ACN – 84h; MeOH – 18h; Neat – 73%; Water – 100%
DMSO – 36h; Neat – 48h; Water – 10 min

Angew. Chem. Int. Ed., 2005, 44, 3275

3,4-dihydro-2H-benzo[b]thiazine-3-ones
Used as Key Ingredient in NCE’s
Growth Hormone Releasing Activity
N
S Anti Bacterials
O S
N
N HN
N OH N
NH2 N O
H
O O US20070004710
O
US20060142264
OMe

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

Anti Cancer Agent O

NH

Cardio Vasculor Agent O O NH

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

N Water, 80 0C, 1.0 hr NH2

Water, MW, 4 - 5 min N
H O O
H

2 1 2

Entry Product R Yield (%)

A B C
1 2a H 94 96 96
2 2b Methyl 60 65 77
3 2c Dimethyl 62 65 71
4 2d Ethyl 68 67 73
5 2e Propyl 53 59 61
6 2f Isopropyl 51 62 65
7 2g Hexyl 39 42 57
8 2h Phenyl 63 69 74
A: Conventional, B: Using Parallel synthesizer, C: Microwave irradiation.
 1,2,3,4-tetrahydro-2-quinoxalinones
MW Assisted Aqueous Phase Synthesis
H H
N R NH2
BrCH(R)CO2Et, NaOH BrCH(R)CO2Et, DMF N R

N
H O
Water, 80 0C, 1.0 hr NH2
Water, MW, 4 - 5 min N
H O

4 3 4

Entry Product R Yield (%)

A B
1 4a H 74 79
2 4b Methyl 69 75
3 4c Dimethyl 49 73
4 4d Ethyl 65 73
5 4e Propyl 68 76
6 4f Isopropyl 59 68
7 4g Phenyl 63 75
A: Parallel synthesizer, B: Microwave irradiation.
 Synthesis Must be Fine Tuned to the Nature
 Procedures are not only Green but Often also Better and Cheaper
 Competitive Advantage Beneficial in Reducing Costs/Risks and
Provide Greater Manufacturing Flexibility
 Green Chemistry Reducing Local Pollution and Can Make Your
Community A Cleaner, Safer Place
 Water is Cheapest, Safe and Green Solvent
 No inflammable, Explosive, Mutagenic, Carcinogenic
 Synthetic Utility:- Simple operation and Efficiency
 Would Be The 21st Century Be A Century of Organic Reaction in
WATER???!!!
 Every Chemist’s Wish….But A Strive To Fulfill It Is Compulsory
 Only in this Way can Chemists Pride Themselves as Human
Benefactors
 A Decline of the Public Anxiety and Improvement in Public Image
Towards Chemistry, Chemicals and Related Items.