MODULE 4: GREEN CHEMISTRY AND SYNTHESIS OF DRUGS

INTRODUCTION:

WHAT IS GREEN CHEMISTRY?

‘Green Chemistry’ is essentially a way of thinking rather than a new branch of chemistry. It
involves pulling together tools, techniques and technologies that can help chemists and
chemical engineers in research, development and production to develop more eco-friendly
and efficient products and processes, which may also have significant financial benefits.

A new but straightforward definition of Green Chemistry is

“The use of chemistry for pollution prevention by means of a proper design of
chemical products and processes that reduce or eliminate the use and generation of
hazardous substances.”
(Anastas & Warner, 1998)

THE PRINCIPLES OF GREEN CHEMISTRY

Chemists and chemical engineers applying green chemistry look at the entire life cycle of a
product or process, from the origins of the materials used for manufacturing to the ultimate
fate of the materials after they have finished their useful life. By using such an approach,
scientists have been able to reduce the impacts of harmful chemicals in the environment.

Anastas and Warner have developed the Twelve Principles of Green Chemistry to aid one
in assessing how green a chemical, a reaction or a process is.
1. Prevention : It is better to prevent waste than to treat or clean up waste after it
is formed.
The ability of chemists to redesign chemical transformations to minimize the
generation of hazardous waste is an important first step in pollution prevention. By
preventing waste generation, the hazards associated with waste storage,
transportation and treatment are minimized.
2. Atom Economy: Synthetic methods should be designed to maximize the
incorporation of all materials used in the process into the final product,
resulting in few if any wasted atoms.
Atom Economy is a concept, developed by Barry Trost of Stanford University that
evaluates the efficiency of a chemical transformation. Similar to an yield calculation,
“atom economy is a ratio of the total mass of atoms in the desired product to
the total mass of atoms in the reactants”. Choosing transformations that
incorporate most of the starting materials into the product is more efficient and
minimizes waste.
3. Less Hazardous Chemical Synthesis: Wherever practicable, synthetic
methodologies should be designed to use and generate substances that
possess little or no toxicity to human health and the environment.
The goal is to use less hazardous reagents whenever possible and design
processes that do not produce hazardous by-products. Often a range of reagent
choices exist for a particular transformation. This principle focuses on choosing
reagents that pose the least risk and generate only benign by-products.
4. Designing safer chemicals: Chemical products should be designed to preserve
efficacy of function while reducing toxicity.
Toxicity and ecotoxicity are properties of the product. New products can be designed
that are inherently safer, while highly effective for the target application. In academic
laboratories this principle should influence the design of synthetic targets and new
products..
5. Safer solvents & auxiliaries :The use of auxiliary substances (e.g. solvents,
separation agents, etc.) should be made unnecessary whenever possible and,
innocuous when used. Solvent use leads to considerable waste.
Reduction of solvent volume or complete elimination of the solvent is often possible.
In cases where the solvent is needed, less hazardous replacements should be
employed. Purification steps also generate large sums of solvent and other waste
(chromatography supports, e.g.). Avoid purifications when possible and minimize the
use of auxiliary substances when they are needed.
6. Design for energy efficiency: Energy requirements should be recognized for
their environmental and economic impacts and should be minimized.
Synthetic methods should be conducted at ambient temperature and
pressure.
The energy costs associated with extremes in temperature and pressure should be
minimized.
7. Use of Renewable Feedstocks: A raw material feedstock should be renewable
rather than depleting whenever technically and economically practical.
Examples of renewable feedstocks include agricultural products or the wastes of
other processes. Examples of depleting feedstocks include raw materials that are
mined or generated from fossil fuels (petroleum, natural gas or coal).
8. Reduce Derivatives: Unnecessary derivatization (blocking group, protection/
deprotection, temporary modification of physical/chemical processes) should
be avoided whenever possible, because such steps require additional
reagents and can generate waste.
Synthetic transformations that are more selective will eliminate or reduce the need
for protecting groups. In addition, alternative synthetic sequences may eliminate the
need to transform functional groups in the presence of other sensitive functionality.
 9. Catalysis: Catalytic reagents (as selective as possible) are superior to
stoichiometric reagents.
Catalysts can serve several roles during a transformation. They can enhance the
selectivity of a reaction, reduce the temperature of a transformation, enhance the
extent of conversion to products and reduce reagent-based waste (since they are not
consumed during the reaction). By reducing the temperature, one can save energy
and potentially avoid unwanted side reactions.
10. Design for degradation: Chemical products should be designed so that at the
end of their function they do not persist in the environment and break down
into innocuous degradation products.
It is very important that the chemical products that are synthesised should be
biodegradable and the degradation products should not possess any toxicity in the
environment .
11. Real time analysis for pollution prevention: Whenever possible, analytical
methodologies should be developed and used to allow for real-time, in-
process monitoring and control to minimize the formation of hazardous
substances.
It is always important to monitor the progress of a reaction to know when the reaction
is complete or to detect the emergence of any unwanted by-products.
12. Safer Chemistry for Accident prevention : Substances and form of substances
used in a chemical process should be chosen to minimize the potential for
chemical accidents, including releases, explosions and fires.
Risks associated with these types of accidents can sometimes be reduced by
altering the form (solid, liquid or gas) or composition of the reagents.

As it has been shown, Green Chemistry offers an interesting framework for chemists and
engineers to design “environmentally friendly” processes and products; the twelve
principles are useful as guidelines.
Goals of Green Chemistry
 Exploit green advantage for the production of bio-based chemicals and fuels.
 Invent reactions that reduce production of greenhouse gases.
 Adapt to work in environmentally benign solvents such as supercritical CO2 or
ionic liquids.
 Harvest electricity, a renewable energy, for chemical synthesis.
 Evolve enzymes for chemical synthesis of fine chemicals and pharmaceuticals.
 Convert biomass, e.g. lignin, to synthetic intermediates and fuels.
 Develop manufacturing methods using biocatalysis.
 Convert complex lignocellulosics to homogeneous thermoplastics.
 Evaluate whether new process really are green.

GREEN CHEMISTRY PRINCIPLES WITH EXAMPLES:

1. Prevention of waste:

 Hundreds of tonnes of hazardous waste are

released into the air, water, and land by
industry every hour of every day. The chemical
industry is the biggest source of such waste.
 Ten years ago less than 1% of commercial
substances in use were classified as
hazardous, but it is now clear that a much
higher proportion of chemicals presents a
danger to human health or to the environment.
 The relatively small number of chemicals
formally identified as being hazardous was due
to very limited testing regulations, which effectively allowed a large number of
chemicals to be used in everyday products without much knowledge of their toxicity
and environmental impact.
 It has caused local authorities and governments to force the legislation to restrict the
disposal of waste containing these toxic substances.
 Thus, legislation will increasingly force industry and the users of chemicals to change
– both through substitution of hazardous substances in their processes or products
and through the reduction in the volume and hazards of their waste.
 The costs of waste to a chemical manufacturing company are high and diverse and,
for the foreseeable future, they will get worse.
 These costs and other pressures are now evident throughout the supply chain for a
chemical product – from the increasing costs of raw materials, as petroleum
becomes more scarce and carbon taxes penalize their use, to a growing awareness
amongst end-users of the risks that chemicals are often associated with, and the
 need to disassociate themselves from any chemical in their supply chain that is
recognized as being hazardous (e.g. phthalates, endocrine disrupters,
polybrominated compounds, heavy metals, etc.)

2. Atom Economy
 One of the fundamental and most important principle of Green Chemistry is that of
atom economy.
 This essentially is a measure of how any atoms of the reactants end up in the final
product and how many end up in by product or waste.
 By far the most common way to judge the efficiency of reaction is to calculate the
yield (percentage yield i.e. actual weight of final desirable end product).
 In order to focus greater attention on waste by-products that are formed during a
synthesis, Barry Trost of Stanford University developed the concept of atom
economy.
 Thus this concept deals with the question: How many of the atoms of the reactants
are incorporated into the final desired product and how many are wasted by
incorporation into by-products?
 In general organic chemists consider yields of 90% or better as excellent while 20%
or less are poor.
 The real benefit of atom economy is that it can be calculated at the reaction planning
stage from a balanced reaction equation.

Measures of Reaction Efficiency:

Percentage yield= (actual yield/theoretical yield) X 100

% Atom Economy = Relative molecular mass desired products X 100

Relative molecular mass of all reactants
Examples of atom economic reactions:

Synthesis of Maleic Anhydride

Maleic anhydride can be produced by following two different synthetic routes:

Benzene oxidation
O

+ 4.5 O2 + 2 CO2 + 2H2O

O
formula 78 4.5 x 32 = 144 98
weight

% atom economy = 98 x 100 = 44.1%

(78+144)

Butene Oxidation

+ 3O2 + 3 H2O

formula 56 3 x 32 = 96 98
weight

% atom economy = 98 x 100 = 64.5%

(56+96)
 Comparison of the two routes is interesting since both reaction occur under similar
reaction conditions of 4000C in presence of a promoted V2O5 catalyst.
 It is evident that Butene oxidation is considerably more atom efficient and avoids
wasting of two carbon atoms as CO2.
 Thus Butene oxidation becomes more obvious route since it is more atom economic
and involved simple separation technology.
3. Less Hazardous Chemical Synthesis:
 The synthetic routes for chemical products should be designed in such a way that it
avoids the use of hazardous chemicals.
 Moreover, the generation of hazardous wastes from chemical processes should be
reduced in order to avoid problems with waste disposal.

Example: Synthesis of Indigo dye.

Conventional route uses hazardous Aniline:

Green route uses L-Tryptophan and enzymes:

Naphthalene
Dioxygenase Oxidation
4. Design Safer Chemicals:
 Chemists must aim to produce chemical products that fulfil their role, be that medical,
industrial, or otherwise, but which also have minimal toxicity to humans.
 The design of safer chemical targets requires a knowledge of how chemicals act in our
bodies and in the environment.

Example: The use of many insecticides like DDT, gamaxane, aldrin etc..which are found to
be toxic to human health and the environment is curtailed and alternatives like biological
pesticides and insecticides are more in use.

5. Safer Solvents and Auxiliaries:

 Many chemical reactions require the use of solvents or other agents (petroleum
based organic solvents) in order to facilitate the reaction.
 These solvents have a number of hazards associated with them, such as
flammability and volatility. Solvents such as acetone, benzene, ether are highly
inflammable , chloroform, carbon tetrachloride are volatile and hazardous to human
health and environment.
 Solvents might be unavoidable in most processes, but they should be chosen to
reduce the energy needed for the reaction, should have minimal toxicity, and should
be recycled if possible.
Example:
a) For dry-cleaning of fabrics, toxic solvent like perchloroethylene is now replaced
by liquid carbondioxide.
b) The use of green solvents such as ionic liquids and supercritical carbondioxide in
chemical synthesis which are much more safer solvents than the organic
solvents.

6. Design for Energy Efficiency:

 Where it is possible, it is better to minimise the energy used to create a chemical
product, by carrying out reactions at room temperature and pressure.
Examples:
a) The use of catalysts has the advantage of lowering the energy requirement of
a reaction.
b) Microwave radiations and ultrasound assisted chemical reactions require less
energy.
7. Use of Renewable Feedstocks:
 The perspective of this principle is largely towards petrochemicals: chemical
products derived from crude oil. These are used as starting materials in a range of
chemical processes, but are non-renewable, and can be depleted.
 Processes can be made more sustainable by the use of renewable feedstocks, such
as chemicals derived from biological sources.

Example: Synthesis of Adipic Acid

Conventional route using Benzene: (carcinogenic)

Green route using D-Glucose: (absolutely safe)

The green route of synthesis of adipic acid from D-glucose (renewable feedstock-
cornstarch) replaces the use of benzene (from depleting feedstock-petroleum) as
starting material and avoids the production of hazardous waste such as N2O.
8. Reduce Derivatives:
 Protecting, deprotecting, blocking groups or any temporary modifications are often
done in chemical synthesis, as they can prevent alteration of certain parts of a
molecule’s structure during a chemical reaction, whilst allowing transformations to be
carried out on other parts of the structure.
 However, these steps require extra reagents, and also increase the amount of waste
a process produces.
 Alternative reagents are to be used which are more selective and hence reduce
additional steps of derivatisation.

Example : Synthesis of Ibuprofen

Old route synthesis of Ibuprofen: (Atom economy = 40%)

2-methylpropyl benzene

ibuprofen

Green route synthesis of Ibuprofen: (Atom economy = 77%)

2-
methylpropyl
benzene
ibuprofen
  Old route (Boots synthesis) of synthesis for ibuprofen is a six step process using
many stochiometric reagents which cannot be recovered. Large amount of waste is
generated in this synthesis. The atom economy of this synthesis is 40 %.
 Green route (BHC synthesis) of synthesis for ibuprofen is a three step process which
uses catalysts that can be recovered and reused. Less amount of waste is generated
in this process. The atom economy of this synthesis is 77 %.

9. Catalysis:
 The use of catalysts can enable reactions with higher atom economies.
 Catalysts are used in small amounts and can carry out a single reaction many times.
 Catalysts are recovered and reused in reactions.
 Catalytic reactions are faster and hence require less energy.
 Catalytic reactions minimize generation of waste.

10. Design for Degradation:

 Ideally, chemical products should be designed so that, once they have fulfilled their
purpose, they break down into harmless products and don’t have negative impacts
on the environment.
 Persistent organic pollutants are products which don’t break down and can
accumulate and persist in the environment; they are typically halogenated
compounds, with DDT being the most famous example.
 Where possible, these chemicals should be replaced in their uses with chemicals
that are more easily broken down by water, UV light, or biodegradation.
Example: The use of biodegradable plastics made from cellulose and starch are
alternatives to plastic packaging materials such as polystyrene.

11. Real Time Pollution Prevention:

 Monitoring a chemical reaction as it is occurring can help prevent release of
hazardous and polluting substances due to accidents or unexpected reactions.
 With real time monitoring, warning signs can be spotted, and the reaction can be
stopped or managed before such an event occurs.
Example: In the synthesis of ethylene glycol, if reactions conditions are not monitored
properly, then toxic substances are produced at high temperatures.
12. Safer Chemistry for Accident Prevention:
 Working with chemicals always carries a degree of risk. However, if hazards are
managed well, the risk can be minimised.
 This principle clearly links with a number of the other principles that discuss
hazardous products or reagents.
 Where possible, exposure to hazards should be eliminated from processes, and
should be designed to minimise the risks where elimination is not possible.

Example: Synthesis of Carbaryl

Conventional synthesis using Methyl isocyanate:

Green synthesis without using Methyl isocyanate:

GREEN FUEL:

What is Biodiesel ?

Biodiesel is mono-alkyl esters of fatty acids derived from vegetable oils or animal
fats via a catalytic reaction called as transesterification.

In simple terms, biodiesel is the product you get when a vegetable oil or animal fat is
chemically reacted with an alcohol to produce a new compound that is known as a
fatty acid alkyl ester. A catalyst such as sodium or potassium hydroxide is required.
Glycerol is produced as a byproduct.

100 lbs of oil + 10 lbs of methanol 100 lbs of biodiesel + 10 lbs of glycerol

Biodiesel can be made from feedstocks such as:

1. Vegetable oils such as corn oil, canola (an edible variety of rapeseed) oil,
cottonseed oil, mustard oil, palm oil, soyabean oil etc, Jatropha seed oil.
2. Restaurant waste oils such as frying oils.
3. Animal fats such as beef tallow or pork lard.
4. Trap grease (from restaurant grease traps), float grease (from waste water
treatment plants), etc.

It is obvious that biodiesel is not going to completely replace petroleum-based diesel

fuel in the near future. If all of the vegetable oil and animal fat were used to produce
biodiesel, we could only replace about 15% of the current demand for on-highway
diesel fuel.

Biodiesel Synthesis:

Transesterification process is the reaction of a triglyceride (fat/oil) with an

alcohol to form mono alkyl esters (biodiesel) and glycerol.
 Transesterification process:
1. In this process, vegetable oils or animal fats is reacted with methanol in the
presence of a catalyst, usually a strong alkali like sodium hydroxide.
2. Methanol reacts with the oils/fats to form biodiesel and a by-product glycerol.
3. In most production methanol or ethanol is the alcohol used (methanol produces
methyl esters, ethanol produces ethyl esters) and is base catalysed by either
potassium or sodium hydroxide. Potassium hydroxide has been found to be
more suitable for the ethyl ester biodiesel production, either base can be used
for the methyl ester.
4. The reaction between the fat or oil and the alcohol is a reversible reaction and
so the alcohol must be added in excess to drive the reaction towards the right
and ensure complete conversion.
5. A successful transesterification reaction is signified by the separation of the
monoalkyl ester and glycerol layers after the reaction time. The heavier, by-
product, glycerol settles out and may be sold as it is or it may be purified for
use in other industries, e.g. the pharmaceutical, cosmetics etc.
6. It is the most economical process requiring only low temperatures and
pressures and producing a 98% conversion yield.

Properties of Biodiesel:
1. High calorific value : 40KJ/g
2. Cetane value : 45-70
3. Boiling point : 315-350°C
4. Specific gravity : 0.87-0.89
5. Low sulphur and aromatics content

Advantages of Biodiesel:
1. Biodiesel is a renewable energy source made from animal fat and veg-
etable oil unlike the fossil diesel.
2. Biodiesel is a‘carbon neutral’ fuel as the oil crop grown absorbs the same
amount of CO2 as is released when the fuel is combusted.
3. Biodiesel produces less greenhouse gases on burning when compared to fossil
diesel.
4. Biodiesel is rapidly biodegradable and completely non-toxic, meaning
spillages represent far less of a risk than fossil diesel spillages.
5. Biodiesel has a higher flash point (150 ºC) than fossil diesel and so is safer fuel.
6. Biodiesel has a higher cetane rating than diesel, which means combustion is
more efficient.
7. Biodiesel can be used in 100% (B100) or in blends with fossil diesel.
Biodiesel can be used in existing diesel engines with little or no modifications at
all and can replace fossil fuels to become the most preferred primary transport
 energy source. It improves engine lubrication and increases engine life since it
is virtually sulphur free.

Disadvantages of Biodiesel:
1. Biodiesel fuel is about one and a half times more expensive than fossil diesel
fuel.
2. Biodiesel gives out slightly higher emissions of nitrogen oxides than fossil
diesel.
3. Biodiesel may clog fuel filters as it cleans dirt from the engines.
4. Biodiesel gels in cold weather as it depends on the oil or fat that was used to
make it.

GREEN SOLVENTS:
Organic solvents (derived from petroleum) have a major part in many chemical processes.
Enormous amounts of toxic and inflammable solvents are used every day. Tons of waste
residues from organic solvents are released into the environment that lead to pollution.
Organic solvents, such as DMSO, DMF, acetone as well as benzene, toluene and
chlorinated solvents are still being used in many chemical processes in large amounts.
Prolonged exposure to these solvents have harmful impact on health such as damage to
respiratory, nervous systems and cause cancer.

Green chemistry aims in using "green solvents" that are environmental friendly alternatives
to the petrochemical solvents for chemical processes. Green solvent are characterised by
low toxicity, convenient accessibility and the possibility of reuse as well as great efficiency.

Water, supercritical fluids, ionic liquids, non-toxic liquid polymers are some of the green
solvents that are now being used in chemical processes.

ENVIRONMENTALLY DEGRADABLE PLASTICS:

Biodegradable plastics are plastics which decompose to water and carbon dioxide by the
actions of microorganisms and are safely returned to the natural biosphere as organic
carbon. Biodegradable plastics are derived from non-petroleum based commercial
wrappings, for example starch-based packaging which can be derived from corn or
potatoes.
In contrast to plastic, starch is a natural polymer increasingly used to make
environmentally-friendly packaging materials. Starch consists of spiral chains of sugars and
these chains can break down into small sugar molecules that dissolve in water. This natural
breakdown, or biodegradation, is accelerated by substances known as enzymes (we say it
is enzyme catalysed).

Examples of Biodegradable Plastics: Eco plastics

Polyhydroxyalkanoate (PHA): a biodegradable polymer produced by bacteria, which has

similar properties to polypropylene.
Polylactide (PLA): a biodegradable polymer which is derived from lactic acid, which can be
broken down in our bodies and therefore has valuable biomedical applications.

GREEN CHEMISTRY APPROACH:

The Green Chemistry approach of “benign by design” should, when applied at the design
stage, help assure the sustainability of new products across their full lifecycle and minimize
the number of mistakes we make.

Much of the research effort relevant to Green Chemistry has focused on chemical
manufacturing processes. Here we can think of Green Chemistry as directing us towards
the “ideal synthesis”
It is particularly important to seek to apply Green Chemistry throughout the lifecycle of a
chemical product. Scientists and technologists need to routinely consider lifecycles when
planning new synthetic routes, when changing feedstocks or process components, and,
fundamentally, when designing new products. Many of the chemical products in common
use today were not constructed for end-of-life nor were full supply-chain issues of resource
and energy consumption and waste production necessarily considered.

"Green chemistry" has already turned maize into biodegradable plastics, developed non-
toxic solvents and dramatically reduced the toxic byproducts from the manufacture of
popular pharmaceuticals like ibuprofen. It is vital to the production of Toyota's new electric
cars, made in part from kenaf, an annual grass plant.
 18

DBIT/FE/ENGINEERINGCHEMISTRY-II/GREEN CHEMISTRY