Green Chemistry and its

Role for Sustainability

By

Dr. S.SYED SHAFI

Professor and Director(P&D)
Department of Chemistry
Thiruvalluvar University
Serkkadu, Vellore- 632 115
16.10.2019

Chemistry can be learned with pleasure not with pressure 1

GREEN CHEMISTRY
• Green Chemistry is the utilization of a set of principles that reduces or
eliminates the use or generation of hazardous substances in the design,
manufacture and application of chemical products .
• Green Chemistry is a recent approach to design of energy efficient
processes and the best form of waste disposal.
• The awareness among the organic chemists to practice green chemical
routes for organic transformations is significantly increasing in the place
of mineral acids, mild solid acids or clays are used. The reactions are
carried out in organized media or in green solvents.

“We can’t solve problems by using the same kind of thinking we used when we created them “ - Albert Einstein

2
GREEN CHEMISTRY IS ABOUT
• Waste Minimization at Source
• Use of Catalysts in place of Reagents
• Using Non-Toxic Reagents
• Use of Renewable Resources
• Improved Atom Efficiency
• Use of Solvent Free or Recyclable Environmentally Benign Solvent systems

“Great dreams of great dreamers are always transcended “– Dr.A.P.J Abdul Kalam

3
Green Chemistry
• Green chemistry is the use of chemistry for pollution prevention
• Design of chemical products and processes that are more environmentally
benign
• Reduction or elimination of the use or generation of hazardous substances
associated with a particular synthesis or process
• Green chemistry looks at pollution prevention on the molecular scale and
is an extremely important area of Chemistry due to the importance of
Chemistry in our world today and the implications it can show on our
environment
• The Green Chemistry program supports the invention of more
environmentally friendly chemical processes which reduce or even
eliminate the generation of hazardous substances
“Science without religion is lame, Religion without science is blind “ – Albert Einstein

4
Importance of Green Chemistry
• With the increase in production and use of chemical compounds, man has
become more exposed to the deterious effects. It is clear that the knowledge of
toxicology is essential for the management and prevention of the adverse effects
and toxicity of chemicals.
• 2 billion lbs. of chemicals were released to air, land and water (USEPA) in 1994
• Data includes only 365 of 70,000 chemicals available in commerce
• Environmental and hazardous wastes operations => economic burden
• environmental expenditures : cost of doing business
• 100-150 billion $ / year for remediation in US alone
• shift financial resources from costs to research & development
• Promise of Green Chemistry to lower overall costs associated with environmental
health and safety
5
Green chemistry a tool
Sustainable
• As human beings development Industrial
the goal ecology
--- we are part of
the environment
Green
• The way in which Chemistry
A tool
we interact with our
environment
influences the
quality of our lives
Green chemistry, lies at the heart of the industrial ecology
6
Green chemistry, is also called Benign
chemistry or clean chemistry for
sustainability
• Refers to the field of chemistry dealing with

1- Synthesis (the path to making chemicals)

2- Processing (the actual making of chemicals)

3- Use of chemicals that reduce risks to humans and impact on the

environment
“Give me a firm place to stand and I will move the earth” - Archimedes

7
Green Chemistry Is About...

Waste

Materials

Hazard

Risk
Energy

Cost

8
Why do we need Green Chemistry ?
• Chemistry is undeniably a very prominent part of our daily lives.
• Chemical developments also bring new environmental problems and
harmful unexpected side effects, which result in the need for
‘greener’ chemical products.
• A famous example is the pesticide DDT.
• Hundreds of tons of hazardous waste are released to the air, water
and land by industry every hour of every day. The chemical industry is
the biggest source of such waste.
• In recent years, pollution control board regulated to reduce harmful
emissions , effluents and workers safety.

9
The 12 Principles of Green Chemistry (1-4)
1. Prevention
• It is better to prevent waste than to treat or clean up waste after it has been created.
2. Atom Economy
• Synthetic methods should be designed to maximise the incorporation of all materials
used in the process into the final product.
3. Less Hazardous Chemical Synthesis
• Wherever practicable, synthetic methods should be designed to use and generate
substances that possess little or no toxicity to people or the environment.
4. Designing Safer Chemicals
• Chemical products should be designed to effect their desired function while
minimising their toxicity.

10
The 12 Principles of Green Chemistry (5-8)
5. Safer Solvents and Auxiliaries
• The use of auxiliary substances (e.g., solvents or separation agents) should be made
unnecessary whenever possible and innocuous when used.
6. Design for Energy Efficiency
• Energy requirements of chemical processes should be recognised for their environmental and
economic impacts and should be minimised. If possible, synthetic methods should be
conducted at ambient temperature and pressure.
7. Use of Renewable Feedstocks
• A raw material or feedstock should be renewable rather than depleting whenever technically
and economically practicable.
8. Reduce Derivatives
• Unnecessary derivatization (use of blocking groups, protection/de-protection, and temporary
modification of physical/chemical processes) should be minimised or avoided if possible,
because such steps require additional reagents and can generate waste.

11
The 12 Principles of Green Chemistry (9-
12)
9. Catalysis
• Catalytic reagents (as selective as possible) are superior to stoichiometric reagents.
10. Design for Degradation
• Chemical products should be designed so that at the end of their function they break
down into innocuous degradation products and do not persist in the environment.
11. Real-time Analysis for Pollution Prevention
• Analytical methodologies need to be further developed to allow for real-time, in-
process monitoring and control prior to the formation of hazardous substances.
12. Inherently Safer Chemistry for Accident Prevention
• Substances and the form of a substance used in a chemical process should be chosen
to minimise the potential for chemical accidents, including releases, explosions, and
fires.

12
“It is better to prevent waste than to treat or
clean
up waste after it is formed”
Chemical
Process

13
“Energy requirements should be recognized for their environmental impacts
and should be minimized. Synthetic methods should be conducted at ambient
pressure and temperature”

Heating
Cooling GLOBAL WARMING
Stirring
Distillation
Compression
Pumping
Separation

Energy Requirement Burn fossil CO2 to

(electricity) fuel atmosphere

14
“A raw material of feedstock should be renewable
rather than depleting wherever technically and
economically practical”

Non-renewable Renewable

15
16
Resource Depletion
• Renewable resources can be made increasingly viable technologically
and economically through green chemistry.

Biomass Carbondioxide
Nanoscience

Solar Waste utilization

17
Examples of green chemistry
• If the chemical reaction of the type
A+B P+W

• Find alternate A or B to avoid W

Disinfection of water:
• Disinfection of water by chlorination. Chlorine oxidizes the pathogens
there by killing them, but at the same time forms harmful chlorinated
compounds.
O or
3
• A remedy is to use another oxidant, such as supercritical
water
oxidation

18
Production of allyl alcohol
• Traditional route: Alkaline hydrolysis of allyl chloride, which generates the product and
hydrochloric acid as a by-product
CH2=CHCH2Cl + H2O CH2=CHCH2OH + HCl

problem product

• Greener route, to avoid chlorine: Two-step using propylene (CH2=CHCH3), acetic acid (CH3COOH)
and oxygen (O2)
CH2=CHCH3 + CH3COOH + 1/2 O2 CH2=CHCH2OCOCH3 + H2O

CH2=CHCH2OCOCH3 + H2O CH2=CHCH2OH + CH3COOH

• Added benefit: The acetic acid produced in the 2nd reaction can be recovered and used again for
the 1st reaction, leaving no unwanted by-product.
19
Production of styrene
• Traditional route: Two-step method starting with benzene, (which is
carcinogenic) and ethylene to form ethylbenzene, followed by
dehydrogenation to obtain styrene
CH2CH3
catayst
+ H2C=CH2

ethylbenzene
• Greener route: To avoid benzene, start with xylene (cheapest source of
aromatics and environmentally safer than benzene).
CH2-CH3 CH=CH2
catayst

styrene
ethylbenzene

• Another option, still under development, is to start with toluene (benzene

ring with CH3 tail).
20
Use of auxiliary substances
• “The use of auxiliary substances (e.g. solvents, separation agents,
etc.) should be made unnecessary wherever possible, and innocuous
when used”

21
Poly lactic acid (PLA) for plastics
production

22
Polyhydroxyalkanoates (PHA’s)

23
Ibuprofen
• Ibuprofen is a common analgesic and anti-inflammatory drug used
widely.
• About 30 million lb of ibuprofen are synthesized annually by Boots
method. It will produce more than 35 million lb of waste product.
• The greener synthesize by BHC (Boots and Hoechst-Celanese
Company) can dramatically reduce this waste product generation.

“To Know, is to know that you know nothing. That is the meaning of true knowledge” - Socrates

24
Ibuprofen Synthesis Classic Route
AcOH
• Demand: 13,000 TPY
HCl, AcOH, Al Waste HCl

• Developed in 1960 Ac2O

ClCH2CO2Et H2O / H+

• 6 steps reaction AlCl3

NaOEt

COCH3

EtO2C
O OHC

NH2OH

H2O / H+

N OHN
HO2C

NH3 25
Ibuprofen Synthesis Classic Route
• Atomic Economy: 32%
• If this synthesis were to be used today, the amount of by-products per
year:

MORE WASTE THAN PRODUCT!!!

26
Boots & Hoechst Synthesis of Ibuprofen –
Green Route
Developed to improve production:
* 3 steps
* No solvents
* Catalytic vs. stoichiometric reagents
* Recycling, reuse and recovery of byproducts and reagents (acetic
acid>99%; HF >99.9%)
AcOH

HF H2 / Ni CO, Pd
Ac2O

O HO HO2C 27
Boots & Hoechst Synthesis of Ibuprofen –
Green Route


Atomic Economy 77%
Faster
More % yield
Less waste produced

“Wisdom begins in wonder” - Socrates

28
Ibuprofen

29
Pregabalin
• Pregabalin, marketed under the brand name Lyrica among others, is a
medication used to treat epilepsy, neuropathic pain, fibromyalgia, and
generalized anxiety disorder.
• Its use for epilepsy is as an add-on therapy for partial seizures with or
without secondary generalization in adults.
• Some off-label uses of pregabalin include restless leg syndrome,
prevention of migraines, social anxiety disorder, and alcohol
withdrawal.
• When used before surgery it does not appear to affect pain after
surgery but may decrease the use of opioids.
30
Green Chemistry in Process Dev.
• Pregabalin (Lyrica®) is a Drug for the treatment of Neuropathic Pain
• Launched in the US in September 2005
• Sales $1.16 billion (2006), $1.8 billion (2007)

31
Medicinal Chemistry Pregabalin Synthesis

 10 steps, 33% overall yield

 Cost was 6x target
 Silverman et al. Synthesis, 1989, 953. (racemic synthesis)
 Yuan et al., Biorg. Med. Chem. Lett., 1991, 34, 2295 (chiral
synthesis shown on slide).

32
Pregabalin (Lyrica®) Launch Process
CN
CHO NH2

EtO2C CO2Et CO2H (S)-Mandelic

acid

NH2

Efficient synthesis of racemic Pregabalin CO2H

25-29 % overall
Final Step Classical Resolution
> 99.5 % ee
Wrong enantiomer difficult to recycle
E-Factor 86
Chemistry Published (Org. Process R and D, 1997, 1, 26)
33
Asymmetric Hydrogenation Route
OCO2Et
CN CN Pd(OAc)2, PPh3 CN
CHO +
CO (300psi)
1% CO2Et

CN (Me-DuPHOS)-Rh CN NH2
0.05% mol CO2H
CO2t-BuNH3 45 psi, 18h CO2-t-BuNH3+
97.7% ee 61% (42% overall)
99.8%
Higher yield (42% overall)
Original Catalyst (Me-DuPHOS-Rh, S/C ratio 2700)
Licensed chiral ligand expensive BF4-
Rh
Much improved environmental profile but similar cost to
resolution route. P P

Chemistry Published (2004JACS5966) (2003JOC5731)

(S)-[Rh-Trichickenfootphos] 34
 Enzymatic Resolution of CNDE
(CH3)2CHCH2 CN Enzyme (CH3)2CHCH2 CN (CH3)2CHCH2 CN
Water
+ _
pH = 7
EtO2C CO2Et 25oC EtO2C CO2Et O2C CO2Et

Racemic R-Diester S-Monoester

Diester Organic Soluble Water Soluble

 Enzymatic hydrolysis of Cyano diester enabled early resolution of

chiral center
 Enzyme screen revealed 2 (S)-selective
hits with E>200:
 Thermomyces lanuginosus lipase (Novozymes)

 Rhizopus delemar lipase (Amano)

35
Biocatalytic Kinetic Resolution Route
CN
recycling of R-1
NaOEt, 100% EtO2C CO2Et
R-1, 85 % ee
CN
+
EtO2C CO2Et
CN H2O CN H2, Ni
racemic CNDE 1 NH2
H2O
765g/L of total volume -
O2C CO2Et CO2Et H2O CO2H
Lipolase
(3.25 Kg/L of H2O) (S)- CNE Step 3 Pregabalin
Step 1 (S)- CNDE acid Step 2
85-90% 90-95%
>98 % ee
@ 45% conversion 99% purity, >99.7% ee
overall 40-45% yields
Biocatalytic with low (~0.8%) protein loading after one recycling

Resolution at first step (wrong enantiomer can be recycled)

High throughput; simple operations
All 4 reactions conducted in water
Enzymatic Step scaled up to 10, 000 Kg scale
E-Factor improved from 86 to 17
36
Pregabalin Summary
 Launched in the US in September 2005
 Treatment of Neuropathic pain
 Sales in 2006 $ 1.16 billion
 Sales in 2007 $ 1.8 billion
 New enzymatic chemistry successfully
scaled up to 10 tonnes scale.
 Process was switched to the enzymatic
route in 3Q2006
 By making the switch to optimal route very early in the product lifetime, Pfizer ensures close to
maximum benefits to the environment.
 Chemistry has been published Martinez et al. (OPRD, 2008, 11, 392).

37
Atorvastatin
• Atorvastatin, marketed under the trade name Lipitor among others, is
a member of the drug class known as statins, which are used primarily
as a lipid-lowering agent and for prevention of events associated with
cardiovascular disease.
• Like all statins, atorvastatin works by inhibiting HMG-CoA reductase,
an enzyme found in liver tissue that plays a key role in production of
cholesterol in the body.

“An expert is a person who has made all the mistakes that can be made in a very narrow field” – Neils Bohr

38
New Process for Atorvastatin (Lipitor®)
OH O OH O O
OH OH O
NC NC
O O NC
O

hydroxynitrile hydroxyketone cis diol

N OH
O O O
H N OH
O
NC
O

OH TBIN

F
Atorvastatin

 The reduction of hydroxyketone to cis diol is a key step that sets the
stereochemistry for atorvastatin. This step has now been converted from
a chemical reduction to a biocatalytic reduction
39
Comparison of Chemical and Biocatalytic
Reactions
Chemical Route
NaBH4
Et3B
THF/MeOH/HOAc
OH O O cryogenic temp OH OH O
NC NC
O O
Biocatalytic Route
enzyme
aqueous buffer
ambient temperature

Chemical process is slow: 80 hours for 6 x methanol distillations to

remove the boron based waste. Enzymatic reaction takes <24 hours
with a relatively simple work-up.
 Quality: Enzymes are highly selective, giving improved cis: trans ratio.
 Triethyl Borane: pyrophoric and toxic

 NaBH4: Safety hazard. H2 source.

 Multiple solvents and low temperature requirement eliminated

40
Co-factor Recycling Systems
Substrate Coupled Co-factor Regeneration

OH O O OH OH O
NC NC
O O
ketoester cis diol

NADH
alcohol
dehydrogenase NAD
+ Greener
Option
acetone isopropanol

Enzyme Coupled Co-factor Regeneration

OH O O OH OH O
alcohol
NC dehydrogenase NC
O O
ketoester cis diol

NADPH NADP+ High Levels

of Aqueous
gluconic acid glucose Waste 41
glucose
dehydrogenase
 Environmental Benefits

The total organic waste for the

reduction step will be reduced by
3.4 million L / annum (65%
reduction)

 Liquid Nitrogen usage of 3

million L / annum is eliminated

 Large Savings in energy use

and processing time.

42
The major uses of GREEN CHEMISTRY
• Energy
• Global Change
• Resource Depletion
• Food Supply
• Toxics in the Environment

“ Time is a drug. Too much of it kills you “ - Terry

43
Energy
The vast majority of the energy generated in the world today is from
non-renewable sources that damage the environment.
•Carbon dioxide
• Depletion of Ozone layer
• Effects of mining, drilling, etc.,
• Toxics Green Chemistry will be essential in
•Developing the alternatives for energy generation (photovoltaic,
hydrogen, fuel cells, biobased fuels, etc.,) as well as continue the path
toward energy efficiency with catalysis and product design at the
forefront.
44
Global Change
• Concerns for climate change, oceanic temperature, stratospheric
chemistry and global distillation can be addressed through the
development and implementation of green chemistry technologies.

“No sanction can stand against ignited minds” - Dr.A.P.J.Abdul Kalam

45
Resource Depletion
• Due to the over utilization of non-renewable resources, natural
resources are being depleted at an unsustainable rate.
• Fossil fuels are a central issue.
• Renewable resources can be made increasingly viable technologically
and economically through green chemistry.
• Biomass
• Nanoscience & technology
• Solar
• Carbon dioxide
• Chitin
• Waste utilization

46
Food Supply
• While current food levels are sufficient, distribution is inadequate
• Agricultural methods are unsustainable
• Future food production intensity is needed.
• Green chemistry can address many food supply issues

Green chemistry is developing:

• Pesticides which only affect target organisms and degrade to innocuous by-
products.
• Fertilizers and fertilizer adjuvants that are designed to minimize usage
while maximizing effectiveness.
• Methods of using agricultural wastes for beneficial and profitable uses.
47
Toxics in the Environment
• Substances that are toxic to humans, the biosphere and all that
sustains it, are currently still being released at a cost of life, health and
sustainability.
• One of green chemistry’s greatest strengths is the ability to design for
reduced hazard.

“Everything is theoretically impossible ,until it is done” – Robert A.Heinlein

48
Pollution Prevention Hierarchy

Prevention & Reduction

Recycling & Reuse

Treatment

Disposal

49
Greener approach in Organic Synthesis
• Ionic liquid mediated reactions

• Neat reactions

• Water mediated reactions

• Microwave assisted reactions

50
Ionic Liquid Mediated Reactions
• Organic derivatives of pentavalent iodine have found wide
• application as oxidizing reagents in the synthesis of biologically
• important complex organic molecules
• o-Iodoxy benzoic acid (IBX) and Dess–Martin periodinane (DMP)are of
particular interest due to their mild, selective, efficient and eco-
friendly properties and operational simplicity
O OH AcO OAc
I I OAc
O O

O O

IBX DMP 51
Ionic Liquid Mediated Reactions
• o-Iodoxybenzoic acid (IBX) has gained great popularity as a mild oxidant for
the oxidation of alcohols to aldehyde. However, it is virtually insoluble in
all organic solvents except in DMSO. Henceforth, development of a
procedure with suitable solvent for mild and efficient oxidation of alcohols
using IBX will be of great interest in synthetic organic chemistry.
• A considerable interest has been manifested in the use of room
temperature ionic liquids (RTILs) as a promising substitute for volatile
organic solvents (VOC). They are highly polar yet weakly coordinating and
dissolve a wide range of organic and organometallic compounds. We
conceived ionic liquid as solvent for the oxidation of alcohols using IBX. To
our delight, IBX dissolved completely in ionic liquid 1-butyl-3-methyl-
imidazolium choride (bmimCl) and the oxidation reactions proceeded
smoothly to completion giving the products in excellent yield

52
Scheme
• Benzyl alcohol and substituted benzyl alcohols gave excellent yield of the
corresponding benzaldehydes. No over oxidations to benzoic acid was
observed.
O OH
I
O

OH O
1 O
R1 R
2 R1 2
R
[bmim] Cl
RT

• IBX, despite being a mild and inexpensive oxidizing agent, suffers from a lack
of proper solvent system for the oxidation reaction. Use of environmentally
benign ionic liquid as solvent shows that primary and secondary alcohols can
be oxidized to aldehyde and ketone respectively with no over oxidation to the
acid at room temperature in excellent yields. We hope that our protocol will
widen the use of IBX in organic synthesis 53
Friedländer Synthesis of Quinolines using
Lewis acidic Ionic Liquid
• The Friedländer condensation is still considered as the most popular method,
which provides rapid access to quinolines and related aza aromatic compounds.
In continuation of our interest in the application of room temperature ionic
liquids (RTILs) in organic synthesis, we reinvestigated the Friedländer synthesis of
quinolones by using bmimCl(1-butyl-3-methyl imidazolium chloride):ZnCl2 melt
(1:2 molar ratio) that can act both as a solvent and catalyst on account of its high
polarity and Lewis acidity
O Ph O
O O bmimCl:ZnCl2
Ph OEt
+ OEt RT, 24 hr.
NH2 N

54
Neat Reactions
• Cleaner reactions
• Higher yields of the products without employing any purification
steps like column chromatography or recrystalisation
• Simple experimental procedure
• SnCl2·2H2O - An Alternative to Lewis Acidic Ionic Liquids

“ The only true wisdom is in knowing you know nothing “ - Socrates

55
Synthesis of small library of 3,4-
dihydropyrimidin-2(1H)-ones catalyzed by
SnCl2.2H2O

R1 H

O O O R1
NH2 SnCl2.2H2O
+ NH
HN X Room temp
O N X
R
R

56
Hantzsch 1,4-dihydropyridine synthesis
R2
CHO NH2
neat N
R1 + R2 R1

CHO NH2
neat
N
+

CAN EtO2C
EAA
H3C N

57
Water Mediated reactions
• The beneficial effect of water as a reaction medium for Diels-Alder reactions was first
described in 1939 but was not generally recognized for more than 40 years. In the early
1980’s, Breslow and coworkers reported that the [4+2] cycloaddition of cyclopentadiene
to methyl vinyl ketone is accelerated by a factor of 700 when carried out in water
compared with isooctane. This rate enhancement, paralleled by an increase of the
endo/exo selectivity from 80:20 to 96:4 was ascribed to a hydrophobic association of the
diene with the dienophile in water.
• Loh and coworkers have reported that indium trichloride catalyzes the Diels-Alder
reaction between cyclopentadiene and ethyl acrylates in water, and have shown that the
catalyst can be easily recovered from water and reused after the reaction has been
completed.The authors have used 20 mol % of indium trichloride for reaction and
obtained corresponding cycloaddition product in 86 – 89 % yield with 9:1 endo/exo ratio.
• Water Tolerable Lewis acids that secure low toxicity high catalytic activity has been
reported but owing to their high cost they cannot be used on industrial scale
• CeCl3 .7H2O-NaI combination that is relatively non-toxic and inexpensive is also reported

58
Michael addition of indoles in aqueous media
has been reported very recently using
aluminium dodecylsulphate

O
O
Al S . 3HO
O 2
O
-
3

59
Water Mediated Synthesis of Quinolines
–
A New Green Approach to the
Friedländer Annulation
• Treatment of o-amino substituted aromatic ketones with dicarbonyl
compounds in the presence of potassium bisulphate in water :
ethanol (8:2) at reflux temperature resulted in the formation of
various 2,3,4-trisubstituted quinolones (scheme-1) in excellent yield
without the application of purification methods.

O O
KHSO4
+ Water:Ethanol(8:2)
NH2 Reflux, 3h N

60
Microwave Assisted Synthesis
• The development of the technology for organic Chemistry has
been rather slow compared to inorganic, computational and
combinatorial chemistry
• This slow uptake of the technology has been principally attributed to
its lack of controllability and reproducibility, safety aspects and a
generally low degree of understanding of the basics of microwave
dielectric heating

“ Never memorize something that you can look up” – Albert Einstin

61
Why Microwave assisted synthesis?
• Short reaction times
• Easy work-up procedure
• Reaction may be carried out in the presence of solvent
• Solvent free technique is facilitated
• Ease of synthesis of libraries of compounds
• The availability of commercial microwave equipment intended for
organic chemistry

62
Microwave assisted synthesis of furfurylidine
derivatives via Aldol and Knoevenagal
condensation
O O
O CHO O O
NaOH, Ethanol
+
MW, 1-2min,
( )n 80-100% yield ( )n

O
O
O CHO CH3 NaOH, Ethanol O
+ MW, 2 min,
X 85-95% yield
X

O CHO
NaOH, Ethanol O X
+ NC CH2 X
MW, 1 min,
85-90% yield CN

G. Babu and P.T. Perumal, Synth Commun., 1997, 27, 3677.

63
Synthesis of quinoline derivatives
3
R
2 2
R R
R1 R
3 InCl3/SiO2 R
R + 1
MW R
NH2 N
O 55_ 87 % Yields

InCl3/SiO2
R + R
MW
NH2 N
H

64
Conclusion

Green chemistry Not a solution

to all environmental problems But
the most fundamental approach to
preventing pollution.

“If the facts don’t fit the theory , change the facts “ – Albert Einstein
65
 “Learn from yesterday ,live for today, hope for tomorrow.
The important thing is to not stop questioning “ - Albert Einstein

66