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Chapter 1
1.1 INTRODUCTION
During the twentieth century chemistry changed for ever the way we live.
Perhaps the greatest perceived benefits, to the general public, have come
from the pharmaceuticals industry with developments of painkillers, anti-
biotics, heart drugs and, more recently, Viagra. However, it is difficult to
think of an important facet of modern life which has not been transformed
by products of the chemical and related industries, for example:
1
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2 Chapter 1
500
3
g 400 -j
.-
300 I
g! 200
%
Published on 01 January 2002 on http://pubs.rsc.org | doi:10.1039/9781847551009-00001
-
%t 100 ’
0 : I 1
UK EU USA Japan
Figure 1.1 Chemical industry turnover
use up fossil fuels?’ and ‘how much “waste” or pollution can we safely
release to the environment?’ Whilst there are no agreed answers to these
questions there is general agreement to develop more renewable forms of
energy and to reduce pollution.
The Natural Step, an international movement, started in Sweden,
dedicated to helping society reduce its impact on the environment has
developed four system conditions for sustainability:
Materials from the Earth’s crust (e.g. heavy metals) must not system-
atically increase in nature.
Persistent substances produced by society (e.g. DDT, CFCs) must not
systematically increase.
The physical basis for the Earth’s productive natural cycles must not
be systematically deteriorated.
There must be fair and efficient use of resources with respect to
meeting human needs.
This approach recognizes that the Earth does have a natural capacity for
dealing with much of the waste and pollution which society generates; it is
only when that capacity is exceeded that our lifestyle becomes unsustain-
able.
During the early 1990s the US Environmental Protection Agency (EPA)
coined the phrase Green Chemistry ‘To promote innovative chemical
technologies that reduce or eliminate the use or generation of hazardous
substances in the design, manufacture and use of chemical products.’ Over
the last 10 years Green Chemistry has gradually become recognized as
both a culture and a methodology for achieving sustainability. The 12
Principles of Green Chemistry (Box 1.1) help show how this can be
achieved. Many of these 12 principles, e.g. catalysis and increased use of
renewable resources, are expanded on in later chapters. When looking at
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4 Chapter 1
continued on p . 5
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2. Atom Economy
Synthetic methods should be designed to maximize the incorporation of all
materials used in the process into the final product.
8. Reduce Derivatives
Unnecessary derivatization (use of blocking groups, protectiodde-protection,
and temporary modification of physicalkhemical processes) should be mini-
mized or avoided if possible, because such steps require additional reagents
and can generate waste.
9. Catalysis
Catalytic reagents (as selective as possible) are superior to stoichiometric
reagents.
6 Chapter 1
X+Y=P+U (1.1)
continued on p . 7
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0
Benzene oxidation //
'0
Formula weights
78 4 5 x 3 2 = 144 98
YOatom economy = 1OOx 981(78 + 144) = 100x98/222 = 44.1%
Butene oxidation 0
Formula weights
56 3 x 3 2 = 96 98
% atom economy = 1OOx 98/(56 + 96) = 1OOx 981152 = 64.5%
8 Chapter 1
Rearrangement Substitution
Published on 01 January 2002 on http://pubs.rsc.org | doi:10.1039/9781847551009-00001
Addition Elimination
Diels- Alder Wittig
Other concerted reactions Grignard
UV light is used to generate RCOO. radicals and the reaction proceeds via
an intermolecular free radical route rather than through nucleophilic attack
as in the conventional process. The selectivity of these reactions may be
improved by imposing steric control through carrying out the reactions in
zeolite or cyclodextrin cages.
Another valuable rearrangement reaction that is usually ‘catalysed’ by
stoichiometric amounts of catalyst is the Beckmann rearrangement
(Scheme 1.4)- This reaction is used commercially for converting cyclohex-
anone oxime into caprolactam, a key intermediate for nylon 6; 20% oleum
is the usual catalyst. A wide range of heterogeneous catalysts have been
explored, which avoid the need for using oleum. In particular, certain
J
OAICI, OH RCO’
I I
COR COR
10 Chapter 1
zeolites, notably [B]-MFI, have been shown to give excellent yields (up to
94% in fluidized-bed reactors), and good stability and ease of regenera-
tion.
One other 100% atom economic rearrangement is worth mentioning
Published on 01 January 2002 on http://pubs.rsc.org | doi:10.1039/9781847551009-00001
sulfuric acid is used, but there are also many examples of supported acid
catalysts such as FeCl, on silica being used. The mechanism involves
protonation of one of the hydroxyl groups followed by loss of water, alkyl
migration to give the more stable carbocation and final regeneration of the
proton (Scheme 1.5). All compounds in which a carbocation can be
generated a to a carbon atom bearing a hydroxyl group may undergo
similar rearrangements.
Another way of expressing this is that the most stable carbocation will be
formed (Scheme 1.6).
The Michael reaction involving addition to carbon-carbon double bonds
containing an electron-withdrawing group is catalysed by base. A variety
Published on 01 January 2002 on http://pubs.rsc.org | doi:10.1039/9781847551009-00001
R
)c- + H-Br - R
R
F C H , + Br- - R
kCH,
Br
Carbocation stability: 3" > 2" =- 1"
Catalyst =
& c o 2 y y e . 0 2 H
/ / / /
Me0 Me0
12 Chapter I
industrial use; for example hardeners for epoxy resins are made by
reaction of maleic anhydride with dienes such as 2-methyl- 1,4-butadiene.
The diene needs to be able to adopt the S-cis conformation in order to react,
e.g. no reaction is observed for 2,4-hexadiene because of steric hindrance.
I
Published on 01 January 2002 on http://pubs.rsc.org | doi:10.1039/9781847551009-00001
-t OH + HCI
+ 36.5)= 83.7%
+ H20
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BuO-K+
from an alkyl halide and a phosphine. In the presence of base this loses
HX to form an ylide (Scheme 1.15). This highly polar ylide reacts with a
carbonyl compound to give an alkene and a stoichiometric amount of a
phosphine oxide, usually triphenylphosphine oxide.
It is the formation of this material which makes the reaction have a low
atom economy and, owing to the cost of disposal (usually by conversion to
calcium phosphate and disposal as hazardous waste), has limited its
commercial usefulness to high value products. Several methods have been
developed to recycle (Ph)3P0 into (Ph)3P but these have proved more
complex than might be expected. Typically the oxide is converted to the
chloride which is reduced by heating with aluminium. Overall this
recovery is expensive and also produces significant amounts of waste.
- /=\ph + (Ph),PO
16 Chapter 1
is only one of many examples where we have learned through ‘trial and
error’ of the toxic nature of chemicals. This is not a criticism of the early
chemical industry since there was little knowledge regarding toxicity or
how to measure it. It may be argued that industry at the time did not take
adequate precautions to prevent exposure of workers to chemicals with
unknown hazards. However, this must be viewed in relation to the attitude
of the pioneering society at the time to risk in all walks of life. Following
discovery that a material was toxic, the ‘natural’ way to deal with it was to
somehow prevent workers from coming into contact with the material. This
philosophy led to the second factor in how we dealt with toxicity until
recently, namely one of limiting exposure. More and more elaborate ways of
limiting exposure have been developed over the years, including use of
breathing apparatus and handling of chemicals remotely.
A hazard can be defined as a situation which may lead to harm, whilst
risk is the probability that harm will occur. From the point of view of
harm being caused by exposure to a chemical, Equation 1.3 is applicable.
As stated above our traditional approach to reducing the risk of some harm
being caused has been to limit the exposure by some physical means, or by
introduction of systems and working practices. Whilst this has worked
relatively well, no control measure or system can be 100% perfect. The
alternative way to minimize risk, which is the Green Chemistry approach, is
to reduce the hazard. This approach gets to the root cause of the problem and
is based on the principle of ‘what you don’t have can’t harm you’. Recent
legislation is starting to reflect this change of approach. The COSHH
(Control Of Substances Hazardous to Health) regulations require that
assessments be made of all laboratory and production work where potentially
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compounds may be left in the product at the end of the reaction and
purification stages. This is completely unacceptable for any product
destined for ingestion by humans. Replacement of organotin compounds
has therefore been the subject of much recent research. One possible
alternative is to use an easily oxidized sulfide which could transfer an
electron to an electrophile to give a radical anion (Equation 1.4). This in
turn could fragment to give an organic radical.
I H,O/acetone
m ms ms
ms = methanesulphonyl Wheland Intermediate
aspidosperrnidine ms
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radicals the reaction is thought to proceed via attack by the radical on the
liberated TTFfBF4- complex. In this particular case the reaction is thought
to go via the Wheland intermediate, which, owing to steric hindrance of
the top face, controls the stereochemistry of the hydrolysis reaction.
Published on 01 January 2002 on http://pubs.rsc.org | doi:10.1039/9781847551009-00001
Aflatoxi n Safrole
20 Chapter I
REVIEW QUESTIONS
1. There are a number of past and present commercial routes to phenol
using benzene as a feed stock. Outline two such processes, writing
balanced equations for the reactions involved. Compare the two
Published on 01 January 2002 on http://pubs.rsc.org | doi:10.1039/9781847551009-00001
cial viability.
3. Give an example of an s N 1 and an sN2 reaction, explaining the
mechanism and calculating the atom economy of the reaction.
Suggest alternative synthetic routes to your products that are more
atom economic.
4. Show how styrene can be prepared using the following reactions
somewhere in your synthetic procedure, (a) Hofmann elimination, (b)
Grignard reaction, (c) Diels- Alder reaction. Compare the atom
economies of each process. Identify any issues raised by using this
approach to determine the most efficient synthetic route.
FURTHER READING
F?T. Anastas and J.C. Warner, ‘Green Chemistry Theory and Practice’,
Oxford University Press, Oxford 1998.