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regulation, labeling and testing for their properties (except cosmetics,
medicines, foodstuffs, pesticides, radioactive materials, etc). From 1981
onwards the European Chemicals Bureau (http://ecb.jrc.it, Ispra, Italy)
gathered data for another 20-25.000 chemical substances. It is estimated that
every year 600-800 new chemicals enter the international market. The health
and safety authorities concentrate on the 2.500-3.000 high volume chemicals
which are produced in million of tones every year.
But the new chemicals are covered by new more strict regulations and
toxicity tests in order to be approved for commercial use. But the European
system encountered many problems and in 2007 a new system REACH of
registration and evaluation was established.
REACH (Registration, Evaluation, Authorisation and Restriction of
Chemical substances) is the new European Community Regulation on
chemicals and their safe use (EC 1907/2006). The aim of REACH is to
improve the protection of human health and the environment through the
better and earlier identification of the intrinsic properties of chemical
substances. At the same time, REACH aims to enhance innovation and
competitiveness of the European Union chemicals industry.
Statistics from the American Chemical Society (ACS) showed that the
value of chemicals produced on a global scale in 2009 was in the order of
3.700 billion dollars ($). The countries with the highest production of
chemicals were: USA (689 billions $), China (549 billions $), Germany (263
billions $), France (158 billions $), Brazil (126 billions $), Great Britain (123
billions $), Italy (122 billions $), Netherlands (81 billions $), Russia (77 billions
$), etc. 7
The biggest chemical industries in yearly sales at the international
arena in 2007 [ICIS.com, The Top 100 global chemical companies, London,
www.icis.com/home/)] were: BASF (Germany, 65 billions $, sales), Dow
Chemicals (USA, 53 billions $, ), INEOS (Great Britain, 43 billions. $),
Lyondell Basell (Switzerland, 42 billions $), Formosa Plastics (32 billions $,
South Korea), Du Pont (28 billions $, USA), BAYER (Germany), Mitsubishi
(Japan), Akzo Nobel/Imperial Chemical Industries (ICI) (The Netherlands/
Great Britain), etc.
Chemical industry under the auspices of international organizations
(such as OECD, Organization of Economic Co-operation and Development,
UNEP, United Nations Environment Programme, etc) has complied with
international standards on health and safety regulations and on safer
chemical products and materials. Compared to the previous decades, all
commercial chemical substances are classified, regulated and tested for their
toxicity and their rate of biodegradation under environmental conditions. Some
chemical substances, that are known for their high toxicity but are still in use
for their properties and can not be replaced, are restricted in their use.
Chemical industries all over the world are competing for innovation and
safer products. Green Chemistry and Green Engineering provide the tools
and alternative materials, processes and systems which will change not only
the sustainability of the production of chemical materials, but also their
environmental credentials by reducing toxicity and increase recyclability.
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4.3. Old and New Synthesis of Ibuprofen
The initial synthesis, observed under the green principles, had many
disadvantages. The starting chemical could not be incorporated into the
product, producing lots of by-products and waste. The six steps of the
synthetic route was consuming chemicals and energy while lowering the yield
of the final product.
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In 1990 the company BHC after prolonged research on the subject
discovered a new synthetic route with only three steps and increased
efficiency. The atoms of the starting chemicals are incorporated into the
products of the reactions and waste is minimised. In both synthetic routes the
starting chemical is 2-methylpropylbenzene, which is produced from the
petrochemical industry. The innovation in the new method was in the second
step. A catalysts of Nickel (Raney nickel) was used thus decreasing
substantially the steps of the synthesis.9
Figure 4.2. The two synthetic routes of Ibuprofen. In the old method the
synthetic route comprised of six steps and in the second was reduced to three
steps. The efficiency of the reaction increased substantially.
In the old synthetic route, each step had a yield of 90% so that the final
product came to be 40% yield compared to the starting chemical. This
resulted in the increased production of by-products as waste. The drug was
produced annually (only in Great Britain) in 3.000 tones and we understand
that substantial amounts of chemicals were lost as waste. Energy also was
lost by the low efficiency of the reaction method. In the greener method of
three steps the final yield is 77%, whereas the Raney nickel catalyst (Nickel,
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CO/Pt) can be recycled and reused. In the old synthetic route, the AlCl 3 used
as a catalyst had to be thrown away as waste. The energy requirements of
the second method were much lower than the first.
The new synthetic route of Ibuprofen is a classic example of how
Green Chemistry ideas can influence to the better the industrial synthetic
methods, not only from the point of economic efficiency, but also from the
point of more effective science and technology methods.
65
Volfram or Tungsten (W) [Tungsten catalysts (Na2WO4 /KHSO4/ Aliquat 336
].10-12
Figure 4.4. The traditional route for the synthesis of adipic acid and the new
greener method, with less waste and recycling. In the second method W
salts are used which can be recycled. [Aliquat 336 (Stark's catalyst) is a mixture
of octyl C8 and decyl C10 chains with C8 predominating. It is a quaternary
ammonium salt used as a phase transfer catalyst and metal extraction reagent able
to dissolve metal complexes].
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iii) 6.0 g (5.5 mL) solution 30% H2O2 (carefully because it can cause burns to
the skin, wear gloves),
iv) 0.19 g KHSO4 (potassium hydrogen sulphate),
The addition of the starting chemical cyclohexene (1.0 g) can be done
after half minute of vigorous stirring to mix the reagents. A re4flux condenser
is attached to the conical flask and the mixtures is stirred, slowly in the
beginning (one minute) and more vigorously for 45 minutes. The reaction
mixture is allowed to cool for 3 minutes and the milky liquid is warmed gently
for few minutes. The tope layer is an aqueous mixture while the oily layer on
the bottom is the Aliquat 336 solvent. With the help of the pipette we transfer
carefully most of the top layer to a glass beaker and cool on ice for 10
minutes. The white liquid precipitates. Collect solid from the walls of the
beaker with the help of a glass rod. The precipitate is separated and filtered
under vacuum on a Buchner funnel. All solid crystals are collected in the
centre and washed on the filter with 2-3 mL of cold water. Recrystallization is
performed from water (1 mL for every 2.3 g of product). The mixture is boiled
to 80-100 oC, more water is added to dissolve the solid crystals, The mixture
is allowed to cool and the precipitate is filtered again on a Buchner funnel.
The solid crystals can be washed with cold water The solid is dried in a
furnace at 115 oC for 10-15 minutes. The melting point of the adipic acid can
be determined at 151-152 oC. The yield can be between 90-95 %.
The adipic acid synthesis by the two methods can be used as a good
example for the atom economy (atom or mass efficiency) of reactions in
synthetic routes.
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In this method the negative aspect is the release of nitrogen oxides. The
Yield is 93% If we take into account the mass of the atoms, for reactants and
product, we can have the following calculations:
Product mass = (6C)(12) (10H)(1) (4O)(!6) = 146 g
Reactant mass = (6C)(12) (18)(1) (9)(16) (2)(14) = 262 g
Yield or Mass efficiency of the reaction, is the ratio of product/reactants X
100 = 146/262 X 100 = 55,7%
[Reaction mass efficincy takes into account atom economy, chemical yield and
stoichiometry. The formula can take one of the two forms shown below: From a
generic reaction where A + B C Reaction mass efficiency = molecular weight of
product C yield m.w. A + (m.w. B molar ratio B/A). Simply Reaction mass
efficiency = mass of product C 100 / mass of A + mass of B. Like carbon
efficiency, this measure shows the clean-ness of a reaction but not of a process.
These metrics can present a rearrangement as very green but they would fail to
address any solvent, work-up and energy issues arising from the practical reaction].
B. The new greener method.
The preparation from cyclohexene oxidized by H2O2 in the presence of the
catalyst 2W4.22 (1%) with solvent Aliquat 336 [C3(-C817)3] S4
(1%) ].
Reference: Sato K, Aoki M, Noyori R. A green route to adipic acid: direct
oxidation of cyclohexenes with 30 percent hydrogen peroxide. Science, 281:
1646-1647, 1998; Usui Y, Sato K. A green method of oxidation of
cycloalkanones with 30% hydrogen peroxide. Green Chem 5: 373-375, 2003.
The new greener method do no produce toxic waste and its yield is 90%.
Product mass =(6C)(12) (10H)(1) (4 O)(16) (2N)(14)=146 g
Reactant mass = (6C)(12) (18H)(1) (8 O)(16) = 218 g
Reaction Mass efficiency = 146/218 X 100 = 67%.
The reaction mass efficiency of the greener method is 11% higher
than the first method.
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Figure 4.6. Maleic Anhydrites molecular formula. It is a white crystalline
substance produced annually in one million tones.
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This oxidation reaction with air as an oxidizing agent has a yield of 95%
Product mass = 2(4)(12) 2(3)(16) 2(2)(1) = 196
Reactant mass =2(6)(12) 9(2)(16) 2(6)(1) = 444
Reaction Mass efficiency = 196/344 (X 100) = 196/444 (X100) = 44.4% .
70
Industry sector Annual production (t) E-factor Waste produced (t)
6 8 5 7
Oil refining 10 -10 Ca. 0.1 10 -10
4 6 4 6
Bulk chemicals 10 -10 <15 10 -510
Figure 4.8. New equipment appeared in the market for microwave irradiation
reactions with special reflux condensers and digital indicators.
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Microwave-assisted eco-friendly organic synthesis have become a new
trend with many applications in synthesising organic chemicals. Organic
reactions under the microwave irradiation have many advantages compared
to the conventional reactions which need very high temperatures. Microwave
assisted reactions are cleaner, last only very few minutes, have high yield
and produce minimum waste.23
Microwave assisted organic synthesis has become an expanding field
in synthetic research. New publications cover the many aspects of this
greener technique and its practical applications.24-29 The scientific literature
is full of new research papers on microwave reaction mechanisms and
applications.30-34
Figure 4.9. Numerous publications in the last years cover the multiplications
of technical applications, research and methodologies in microwave assisted
organic synthesis,
72
4.8. New Green Methods in Synthetic Organic
Sonochemistry
Figure 4.10. In the last decade there are many publications on Sonochemistry
and its applications in organic synthetic routes
73
The scientific literature on sonochemistry research and applications is
by now very extended and numerous books on the subject have been
published in the last decade.38-44
URL:http://www.organic-chemistry.org/topics/greenchemistry.shtm
74
3. Organocatalytic direct -hydroxy phosphonate of aldehydes and
ketones
A simple, practical, and catalytic method for the N-formylation in the presence
of molecular iodine as a catalyst under solvent-free conditions is applicable to
a wide variety of amines. -Amino acid esters can be converted without
epimerization. J.-G. Kim, D. O. Jang, Synlett, 2010, 2093-2096.
75
7. Oxidation of sulfides with H2O2
76
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