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SPRINGER BRIEFS IN MOLECULAR SCIENCE
GREEN CHEMISTRY FOR SUSTAINABILITY
Angelo Albini
Stefano Protti
Paradigms in
Green Chemistry
and Technology
123
SpringerBriefs in Molecular Science
Series editor
Sanjay K. Sharma, Jaipur, India
More information about this series at http://www.springer.com/series/10045
Angelo Albini Stefano Protti
•
Paradigms in Green
Chemistry and Technology
123
Angelo Albini Stefano Protti
PhotoGreen Lab, Department of Chemistry PhotoGreen Lab, Department of Chemistry
University of Pavia University of Pavia
Pavia Pavia
Italy Italy
During the last decades, green chemistry has emerged as a consistent discipline,
with a set of concepts or thought patterns, including theories, research method, and
standards. Thus, the social uneasiness about the damage to the environment and
human health caused by industry, in particular chemical industry, and about the
waste of non-renewable natural resources that has been a main issue from 1950 on
has received an answer, or at least the direction to follow has been defined, through
a strictly scientific approach. “Green” is no more an eye-catching word added to the
title of a paper or a patent whenever wished, as in previous times “new” or “novel”,
but rather a precise qualification that attests the belonging to a recognized disci-
pline. Green chemistry is certainly interdisciplinary and involves contributions from
every part of science (not only chemistry), but the adherence to a firm set of
paradigms can be quantitatively assessed through a recognized green metrics.
Within the small dimensions proper to this form, this brief wishes to share with
anybody interested our view of such paradigms.
We are deeply thankful to colleagues and students in Pavia that contributed in
various ways to this text, in particular Prof. Maurizio Fagnoni and Dr. Davide
Ravelli, as well as to the Springer team.
v
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 Preserving the Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 Sustainable and Green Chemistry. . . . . . . . . . . . . . . . . . . . . . . . 5
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2 Green Metrics, an Abridged Glossary . . . . . . . . . . . . . . . . . . . . . . . 11
2.1 Environmental Parameters for a Chemical Reaction . . . . . . . . . . . 11
2.1.1 Mass Metrics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
2.1.2 Environmental Metrics . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2.1.3 Energy Metrics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
3 Activation of Chemical Substrates in Green Chemistry . . . . . . . . . . 25
3.1 Methods of Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
3.2 Carbon-Heteroatom Bond Formation . . . . . . . . . . . . . . . . . . . . . 29
3.2.1 Oxidation/Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
3.2.2 N-Acylation and Alkylation . . . . . . . . . . . . . . . . . . . . . . 36
3.2.3 O-Acylation and Alkylation . . . . . . . . . . . . . . . . . . . . . . 41
3.3 Carbon–Carbon Bond Formation . . . . . . . . . . . . . . . . . . . . . . . . 43
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
4 Renewable Resources: From Refinery to Bio-refinery . . . . . . . . . . . 63
4.1 Shifting to Renewable . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
4.2 Chemicals from the Biorefinery . . . . . . . . . . . . . . . . . . . . . . . . . 65
4.2.1 Alcohols, Glycols and Epoxides . . . . . . . . . . . . . . . . . . . 65
4.2.2 Aldehydes, Ketones and Derivatives . . . . . . . . . . . . . . . . 68
4.2.3 Carboxylic Acids and Derivatives . . . . . . . . . . . . . . . . . . 70
4.2.4 Hydrocarbons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
5 The Solvent Issue. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
vii
viii Contents
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Chapter 1
Introduction
Abstract The growing awareness that a serious damage to the environment had
been caused and valuable resources consumed stirred up the social and political
conscience and preservation of the environment became one of the key issues in the
political arena during the 1960s. What impressed more common people was the
destruction of the ecosystem by strongly toxic compounds used e.g. as pesticides in
agriculture or for new commodities, e.g. polymers. Large amounts of aggressive
products and intermediates were buried in chemical plants, and leakage from such
deposits may cause pollution of water bodies. In the following decades, the reversed
point of view was introduced, focusing on a new way of preparing useful chemicals
while avoiding to produce toxic by-products. This was tagged Green Chemistry and
found a meaningful expression in the 12 green chemistry principles.
Fireflies. During the early 1960s fireflies began to disappear because of air pollution
and, particularly in the country, of water pollution (no more blue rivers and clear
water in brooks). “This was a fast and stunning event, and after a few years, the
insects became a rather excruciating souvenir from the past. Thus, an old man who
remembered their presence couldn’t recognize in new young people what he had
been as a young man and was deprived even of such a regret” [1]. The Italian poet
Pierpaolo Pasolini commented the disappearance of fireflies as a consequence of the
large use of insecticides and weed-killers. He took this date as a turning point,
where also a reversal of old social values had occurred [1].
This was certainly not the first time that similar issues were mentioned. Indeed,
the history of man is also the history of the reckless exploitation of the environment
and the 10 thousand years during which human beings have been the dominating
profitable in the mid-1920s” [3]. Further antiknock additives were considered, such
as iron carbonyl (in afterthought not a good choice) and methanol or ethanol, but
despite the many counter indications this remained the cheapest additive. Thus, less
toxic additives from renewable sources were discarded and production began.
Attention to the troubles connected with tetraethyl lead use was revived only at the
time of the following oil crisis in the 70–80s, when another “gasoline famine”
started up again interest in the matter. As the leaded gasoline crisis abated in the fall
of 1925, Kettering noted that the search for a substitute for petroleum had become
problematic: “Many years may be necessary before the actual development of such
a substitute,” he said [4]. Many such cases may be quoted, e.g. the Eternit company
that produced asbestos-based materials in several Italian towns (Casale Monferrato,
Broni, Bagnoli), while concealing most of (known) risks related with this com-
pound [5].
Beetles and robins. In a highly successful book, Silent Spring (published in
1962), the marine biologist Rachel Carson [6] showed that the systematic use of
insecticides and weed-killers seriously contributed to destroy local ecosystems.
“Was it wise or desirable to use substances with such a strong effect on physiology
for the control of insects, especially when the control measures involve introducing
the chemical directly into the body of water?” [7]. The food chain multiplied the
effect of such toxic compounds, even when applied in a very low concentration.
“Did we really want a world with no birds singing in the morning and serious
consequences even on humans for eliminating beetles?” At the time, control
agencies did not take too seriously the situation, but biologists feared a catastrophe.
Whom had a citizen to believe? Certainly the book by Mrs. Carston greatly helped
to change the social attitude, and the preservation of the environment became a key
issue of modern social movement, in the US, in Europe and gradually all over the
word. A result was the National Environmental Policy Act (NEPA), passed by the
Congress in 1969, with the goal of creating and maintaining “conditions under
which man and nature can exist in productive harmony.” The U.S. Environmental
Protection Agency (EPA) was established the following year, and began its activity
by banning the use of DDT and other chemical pesticides.
The existence of dismissed plants where chemical waste had been buried by
companies over the previous decades and the leakage from the barrels, with
potential pollution of drinking water was another main topic [8]. As it appears from
the above, up to this moment the focus was on dismissing production of highly
toxic chemicals and cleaning up those that had been spread over the planet in
previous decades. In every case, early regulations concerning the environment were
adopted not so much on the basis of scientific reports, but rather due to the strength
of societal activism that demanded a more environment-respectful approach by
industry. Worries about the effect of man-made chemicals continued to increase,
with the identification of more subtle effects. As an example, many chemicals have
an endocrine-disrupting effect that is revealed only when tested under natural
ecological conditions, which makes it doubtful whether consistent and definitive
data on toxicology will ever be available [9].
4 1 Introduction
However, the new generation that had been educated in a time where environ-
mental awareness was growing took a more innovative path and began to think
whether it was a better choice to prevent pollution rather than have to remediate
afterwards. In 1983, an independent committee headed by Norwegian Prime
Minister Gro Harlem Brundtland was established within the U.N. General
Assembly. The main goal of such World Commission on Environment and
Development was to examine global environmental issues up to the year 2000,
while reassessing critical problems and formulating realistic proposals for solving
them. The results of this work was the Our Common Future agenda (1987), where
new, non environmental harmful, policies on which the growth of economies and
societies should be based were proposed [10]. The Brundtland Commission
expressed the first definition of sustainable development as “a process of change in
which the exploitation of resources, the direction of investments, the orientation of
technological development and any institutional change were all in harmony”, thus
enhancing “both current and future potential to meeting human needs and aspira-
tions” [10a]. The first symposium on Green Chemistry was organized in January
1993 in collaboration with the National Science Foundation (NSF) and the Council
for Chemical Research (CCR). Most of the key steps in the evolution of green
chemistry are related to the US Environmental Protection Agency (US EPA)
activity. During the 1980s pollution prevention became the priority, instead of
end-of-pipeline control, leading to the approval in 1990 of the Pollution Prevention
Act by the American Congress [10b]. Specialized groups, such as the Office of
Pollution Prevention and Toxics, established within the EPA in 1988, and inter-
national bodies such as the Organization for Economic Co-operation and
Development (OECD) favored a co-operative effort for improving existing chem-
ical processes and introducing pollution prevention. These first common efforts led
to the United Nations Conference on Environment and Development (Rio de
Janeiro, 1992) during which the “Rio declaration of environment and development”
and the Agenda 21 action program were formulated [11]. As remarked by Metzger,
scientists were urged to contribute to the best of their strength to the Agenda 21
program (see for instance chapter 35 where is highlighted “the role and the use of
the sciences in supporting the prudent management of the environment and
development for the daily survival and future development of humanity”) [12].
Most issues related to chemistry that were introduced in various parts of Agenda 21
will be examined in the following chapters. In general, the most important break-
through arising from the work by both the Brundtland commission and the Rio
meeting is the awareness that the goal should be pollution prevention rather than
pollution remediation, and the first attitude should be recognized as the most
effective strategy for environmental issues. The US Environmental Protection
Agency (EPA) staff coined the motto “benign by design” and the phrase “green
chemistry”.
1.2 Sustainable and Green Chemistry 5
In a recent paper Warner and coworkers remarked the excessive and sometimes
misleading use of terms such as “green” and “sustainable” in media and even in
scientific discussions [13] and advocated that both concepts of “sustainable
chemistry” and “green chemistry” were more clearly defined. In particular, the
former is a subsystem of sustainability, and represents a broad concept that deals
with all aspects of making and using materials and chemical compounds in the
man-built world, including safety and risk policy, remediation technologies, water
purification, alternative energy, and, obviously, green chemistry. In the definition
by Warner, the last discipline is “application agnostic in that it focuses on the
building blocks that go into the ultimate technology” [14]. Green chemistry is thus
involved in the optimization of synthesis, in the use of renewable rather than non
renewable resources (both chemicals and energy) and in the qualitative and
quantitative control of artificial materials employed and produced (as well as of the
accompanying waste) [13].
As a consequence, green chemistry involves rethinking chemical reactions and
chemical processes in such a way that scientists and engineers are enabled “to
protect and benefit the economy, people and the planet by finding creative and
innovative ways to reduce waste, conserve energy, and discover replacements for
hazardous substances”. Thus, the target is not limited to control chemical toxicity
and includes “energy conservation, waste reduction, and life cycle considerations
such as the use of more sustainable or renewable feedstock and designing for end of
life or the final disposal of the product” [15]. From the 1990s, some chemistry
practitioners began to publish studies where the environmental performance of
chemical processes was explicitly considered [14]. Later in this decade, the
advancement of green chemistry and its best known definition as “designing
chemistry for the environment” was presented by Anastas, who commented that
this “has been driven by new knowledge” [16]. The philosophy of green chemistry
was centered on minimizing waste formation (expressed by the paradigm of atom
economy) and by devising mild conditions (most often by catalytic processes). As
Clark put it, “the challenge for chemists and others is to develop new products,
processes and services that achieve the societal, economic and environmental
benefits that are now required. This requires a new approach which sets out to
reduce the materials and energy intensity of chemical processes and products,
minimize or eliminate the dispersion of harmful chemicals in the environment,
maximize the use of renewable resources and extend the durability and recyclability
of products in a way which increases industrial competitiveness” [17].
These concepts were offered in a compact and cutting way in the 12 principles of
Green Chemistry that are reported below [18, 19]. Actually, rather than principles
(“laws” or “rules”), these should be considered guidelines (indications on how to
carry out an action).
6 1 Introduction
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.
Advances in mechanistic understandings linking molecular features to hazards
and degradability will enable a more comprehensive application of green
chemistry to control the effect on the environment. Predictive decision-making
tools must provide confidence about hazard and risk in a way that is aligned
with the timing and magnitude of such decisions and, most importantly, while
there is still flexibility to alter a molecular design or product formulation [24].
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.
Real-time feedback is essential in proper functioning chemical processes in
order to avoid losing control of a process [25].
12. Inherently Safer Chemistry for Accident Prevention. Substances used in a
chemical process should be chosen to minimize the potential for chemical
accidents, including release, explosion, and fire. The adherence to the green
chemistry principles will result in a scenario that is also safer (see Fig. 1.1) [26].
This depicts the Hierarchy of Safety Controls and highlights “the difference
between focusing on the control and the hazard part of the safety definition.
Fig. 1.1 Hierarchy of safety control. Personal protective equipment must be worn every time that
it is not possible to fully avoid exposure to a hazard. Administrative and work practice control
includes include additional relief workers, exercise breaks and rotation of workers. However, the
best precaution is removing the hazard or substituting it with something that is not hazardous, and
this is the specific mission of green chemistry. If this is not feasible, engineering control must be
applied (enclosing the hazard in such a way that no exposure occurs during normal operations, or
at least reduce exposure by a suitable ventilation Reprinted with permission from Ref. [26]
8 1 Introduction
References
13. Cannon AS, Pont JL, Warner JC (2012) Green chemistry and the pharmaceutical industry. In:
Zhang W, Cue BW jr (eds) Green techniques for organic synthesis and medicinal chemistry.
John Wiley & Sons, New York
14. Cathcart C (1990) Green chemistry in the Emerald Isle. Chem Ind 5:684–687. Centi G,
Perathoner S (2003) Catalysis and sustainable (green) chemistry. Catal Today 77:287–297
15. Linthorst JA (2010) An overview: origins and development of green chemistry. Found Chem.
doi:10.1007/s10698-009-9079-4; Clark JH, Macquarrie DJ (1998) Catalysis of liquid phase
organic reactions using chemically modified mesoporous inorganic solids. Chem Commun 8:
853–860
16. Anastas PT, Williamson TC (eds) (1996) Green chemistry: designing chemistry for the
environment, ACS symposium series, vol 626. American Chemical Society, Washington
17. Clark JH (1999) Green chemistry: challenges and opportunities. Green Chem 1:1–8
18. Anastas PT, Williamson TC, Hjeresen D, Breen JJ (1999) Promoting green chemistry
initiatives. Environ Sci Technol 33:116A–119A
19. http://www.acs.org/content/acs/en.html
20. Jimenez-Gonzalez C in Ref. [19]
21. Constable D in Ref. [19]
22. Wool R in Ref. [19]
23. Dunn PJ in Ref. [19]
24. Williams R in Ref. [19]
25. Raynie D in Ref. [19]
26. Bradley S, Finster DC, Goodwin T in Ref. [19]
27. https://www.gov.uk/government/policies/improving-water-quality
Chapter 2
Green Metrics, an Abridged Glossary
Abstract Green chemistry is an aspiration, and the advancement in this field must
be recognized and quantitatively assessed. Various proposals of a green metrics
have been put forward, based on the consumption of resources, the coproduction of
waste, the environmental performance. These are briefly presented, pointing out the
specific advantages and limitation of each one. In general, such metrics must blend
high level of information supplied with accessibility. Software for several such
metrics is freely available.
What chemists strive to obtain, and what is asked from them, has traditionally been
obtaining as much as possible of the desired (saleable) compound. The key
parameters have thus been the reaction yield (RY) and the selectivity (S).
Reaction yield (RY) is the quantity of a product (usually expressed as a fraction
or a percentage) generated by a chemical reaction from a given reactant. A more
correct, but not commonly used praxis should be referring the yield to the balanced
chemical equation, thus taking into account the fact that one of the reagents is often
used in excess. Selectivity (S) is referred to the ratio of one of the products (usually
the desired one) arising from the conversion of a certain reactant with respect to the
other ones, or to the conversion of the starting material. When a chemical reaction is
carried out on industrial scale, the occupation of the available reactors must be
taken into account, through parameters such as productivity (amount of the desired
product per time unit) and space time yield (STY), defined as the amount of reaction
product formed per unit volume of the reactor per unit time.
Table 2.1 Current E-Factor value for different industrial sectors from [6]
Industrial sector Production (Tons year−1) E-factor Waste produced
(kg kg−1) (Tons year−1)
Petrochemical 106–108 ca. 0.1 106
Bulk chemicals 104–106 1–5 105
Fine chemicals 102–104 5– 50 104
Pharmaceuticals 10–103 25–100 103
A different issue is having a process that is “green”, that is one that causes as
little as possible negative effects on the environment. Although good sense will help
in judging what will be such effect, specific parameters for the assessment of the
environmental performance of chemical reactions have been proposed over the
years, with the aim of offering an objective set of metrics for making a process
“greener” and making better use both of the materials and of the energy. Proposals
have come from various laboratories, sometimes overlapping in some aspects. The
metrics are summarily listed below according to their main goals, viz. optimization
of the mass used, minimization of environmental damage and of the energy con-
sumed. The most representative parameters are summarized in Table 2.1.
As for the mass balance, the parameter Atom Economy (AE or atom utilization), has
been first defined by Trost in 1991 [1] as “the ability of a chemical process to
incorporate as many as possible of the atoms” of the starting material into the final
products, and thus to the ratio of the molecular weights (MW), see Eq. (2.1):
MW ðproductÞ
AE ¼ P ð2:1Þ
MW ðreagentsÞ
Furthermore, neither solvent nor additives (when present) appear in the chemical
equation and thus are likewise not considered. This is obviously a significant limi-
tation, and this parameter is better used in conjunction with other metrics. A simple
improvement is obtained by considering the yield of the process and introducing a
composite parameter, indicated either as the actual atom economy (AAE) or as the
reaction mass efficiency of the process (RMEKernel), defined as the ratio of the actual
mass of the products obtained with respect to the reagents used (Eq. 2.3) [5].
mass
AAE ¼ RMEKernel ¼ RY AE ¼ ð2:3Þ
mass
This concept can be extended to the global Reaction Mass Efficiency (RMEglobal
also defined by Sheldon as Material Efficiency, see Chap. 4) that takes into account
all of the materials involved in the process, viz. solvents, auxiliaries and chemicals
used for the work up procedure. This results in Eq. (2.4), with inclusion of the
stoichiometric factor SF for the reagent used in excess, viz.
P
mass excess reagents ðkgÞ
SF ¼ 1 þ P ð2:4Þ
mass stoichiometric reagents ðkgÞ
as well as of a material recovered factor (MRP) including all of the recovered and
reusable materials (starting materials used in excess and recovered at the end of the
process, solvents and auxiliaries, see Eq 2.5) [5]. All of these parameters are
fractions between 0 and 1.
MRP
RMEGlobal ¼ AAE ð2:5Þ
SF
The other way around, one may focus on the concept of waste, which is implicit
in the above parameters. Thus, any output from the reaction other than the desired
product (that is what is sold) is considered waste. The definition thus includes the
unreacted starting material, the solvent used (when not recovered), as well as any
catalyst or additive, when present. Further to be considered are other products
formed beside the desired one, viz. byproducts and coupled products (that is
compounds arising from the same pathway that yields the desired product) as well
as side-products (that in contrast are produced from the same starting materials used
for the synthesis of the target product, but arise from an entirely different mecha-
nism). Furthermore, as mentioned above, often one (or more) of the reactants is
used in stoichiometric excess with respect to the other ones. This may well increase
the yield of the desired products, but at the same time obviously increases the
amount of waste produced. Finally, any purification method used to isolate the
product from the crude reaction mixture generates a further amount of waste.
An approach to assess the greenness of a chemical process based on the waste
produced was proposed by Sheldon [6, 7] at about the same time as Trost (1992),
during the analysis of the industrial production of pharmaceutical intermediates such
14 2 Green Metrics, an Abridged Glossary
As pointed out by Sheldon (see Table 2.2), the value of E-Factor strongly
depends on the type of product and on the scale in which it is produced. Thus, in the
case of oil refining, highly evolved (catalytic) systems are used, where waste has
been minimized through a long effort. On the other hand, the large volume involved
would not make tolerable such processes if this were not the case, both because of
the environmental effect and because this would reduce the profit margins. On the
contrary, in pharmaceutical industry the tonnage produced is much lower, but the
waste produced when preparing (by multistep syntheses) and purifying highly
sophisticated materials is much larger, as apparent from the E factor (see Table 2.1).
Yet another approach makes use of the Process Mass Intensity (PMI, the
reciprocal of Reaction Mass Efficiency RMEglobal) as proposed by the Glaxo group
[9]. This is defined as the total mass of the materials required for the production of
the unit mass of desired product (Eq. 2.8):
As in the case of E, PMI takes into account the amount of (non reusable)
reactants, auxiliaries and solvents employed in the process. In the ideal situation,
the PMI value is unitary or close to it (and correspondingly, E = 0). Notice that, as it
has been pointed out (see Eq 2.9), E factor and PMI differ by a unity [9]. This is
important, since this difference corresponds to the amount of the target product
obtained in the process, that is to the actual revenue of the process (see Fig. 2.1).
PMI has been considered as a more convenient parameter than E when planning
production, because the improvement of the productivity (of the saleable product)
and not the waste reduction appears to be a more appealing target. Furthermore, the
concept of PMI better matches with the first green chemistry principle of preventing
waste production rather than having to find a way to manage it afterwards.
5
PMI
4
3 E-Factor
oduct
l e pr
eab
2 Sal
0
0 1 2 3 4 5
Fig. 2.1 PMI and E-factor differ for one unit which corresponds to the saleable product
16 2 Green Metrics, an Abridged Glossary
Since five parameters (Reaction Yield, the reciprocal of stoichiometric factor SF,
AE, RME and the material recovery parameter MRP) well account for the
“greenness” of a process, a radial pentagon has been used in order to evidence
which are the most sensitive points. Each axis ranges in value between zero and one
and in the greenest situation each parameter is equal to 1 (see for review [10]),
which results in a regular pentagon. This visual representation has been used by
Andraos for the evaluation of different processes, including aldol condensation,
Friedel Crafts acylation and cycloaddition (see in Fig. 2.2 an example involving the
synthesis of diphenylmethanol via generation of a Grignard reagent and scenarios
with different extent of reclaiming excess reagents are evaluated) [11].
It is apparent from the figure that a complete reclaiming is required for a rea-
sonable environmental performance. When applied to a multistep procedure, as
typical for Active Pharmaceutical Ingredients (APIs), the use of E-factor in the
assessment procedure has the advantage that the contribution for each step is
additive, while PMI is not, but is liable to inconsistent application, since the level of
solvent recycling, when not measured, is estimated by the evaluator (a 90 % recycling
H OH
I Mg
Et2O
2.1 Environmental Parameters for a Chemical Reaction 17
is often assumed). Thus, the use of a complete (cEF) and a simple E-factor (sEF) have
been proposed by Roschangar et al. [12] as defined in Eqs. 2.10 and 2.11.
P P P P
mðraw materialsÞ þ mðreagentsÞ þ mðsolventsÞ þ mðwaterÞ mðproductÞ
cEF ¼
mðproductÞ
ð2:10Þ
P P
mðraw materialsÞ þ mðreagentsÞ mðproductÞ
sEF ¼ ð2:11Þ
mðproductÞ
These authors suggests that cEF is applied in the post finalization stage, when
optimization of the commercial procedure is being carried out, while at an earlier
stage sEF is considered. Further determining is the choice of the starting point.
Attention is often given to the steps carried out in house, starting from a purchased
raw material, but this leaves out part of the environmental relevant processes.
Actually, if a raw material is not a commodity, its synthesis must be considered as
done especially for that particular API and included into the evaluation. It has been
observed that at present 20–50 % of chemical steps are outsourced during the early
development and 30–70 % during the late development or after commercial launch
of a product. In order to obtain a fair evaluation, it has been proposed to label as raw
materials only those that are offered in the Sigma Aldrich catalogue at a price below
100$ per mol (for the largest offered quantity). In the contrary case, the respective
synthesis must be included [12].
The conversion of the raw materials into the usually highly complex API
involves several steps, and a first appreciation of the greenness of a synthetic plan
may be obtained by checking that the number of chemical transformations required
for achieving the final complex structure is reduced. Balan [13] has proposed the
concept of ideal synthesis as shown in Eq. 2.12.
complexity per drug target is ca. 9 (7 × 1.3). The transformation GAL (tGAL) is
therefore expressed by Eq. 2.13 and the process GAL by Eq. 2.14 [12].
ðs or cÞEF
tGAL ¼ ð2:13Þ
Average complexity
GAL ðs or cÞEF
RPG ¼ ð2:15Þ
ðs or cÞ EF
A RPG > 100 % shows that the green character of the process is below the
average industrial value and would benefit from further optimization.
An increased green character of a new process can be evaluated by the reduction
of the EF, taking into account the change in complexity. Roschangar and coll
demonstrated that decreasing the amount of waste in the overall process does not
imply that the RPG doesn’t decrease in every single step [12].
E-factor and PMI are the most convenient (and the most easily calculated)
parameters for a first assessment of the sustainability of a process. As shown in the
following sections, these parameters are largely used as a benchmark in the liter-
ature. The main limitation is that these two parameters consider the mass of
chemicals involved as a “lump sum”, and no account is taken of the quality of such
chemicals and the ecological risks related to them. A first attempt to introduce this
issue in green metrics was carried out by Hudlicky [14] with the term Effective
Mass Yield defined as the fraction of the percentage of the mass of desired product
relative to the mass of all non-benign materials used in its synthesis, according to
the equation below:
This is based on the proportion of the mass of the product that arises from
non-toxic materials. “Benign” components are defined as ‘the by-products, reagents
or solvents that have no known environmental risk associated with them, for
example, water, low concentration saline solutions, dilute ethanol, autoclaved cell
mass, etc.”. However, the subjective definition of benign materials is open to
criticism.
2.1 Environmental Parameters for a Chemical Reaction 19
To date, the most extensive effort to quantify the risk related to a given process is
represented by the EATOS (Environmental Assessment Tool for Organic Syntheses)
facility. The software, developed by Eissen and Metzger in 2004, takes into account
as entries a large number of data, which are however easily available, and evaluates
a chemical synthesis through four indices, including the above mentioned mass
index (PMI) and environmental factor E-factor, as well as two environmental
quotients, the “unfriendliness” parameters Q.
Thus, the Environmental Index Input EIN = PMI × QIN, is the Potential
Environmental Impact (PEI kg−1) of chemicals used in the process. The factor QIN,
quantifies the environmental and social costs involved in the use of such chemicals
(based upon data generally available from the safety data sheet of the chemicals
employed, such as risk phrases, the reclaiming of resources involved, transport
information and cost).
Analogously, the Environmental Index Output (EIOUT = E × QOUT) is the
Potential Environmental Impact (PEI kg−1) on the ecosystem by the chemicals
produced. QOUT is calculated from data available in the Material Safety Data Sheet,
by using weighting categories such as human toxicity, chronic toxicity, and eco-
toxicology. In addition to the mass and environmental indices, the EATOS software
affords also the cost involved in the production of the desired product (expressed in
€ per kilogram of product). The above contributions well account for the envi-
ronmental effect [15].
Furthermore, an easy to use semi-quantitative assessment method was reported
by Van Aken and takes into account six different characteristics of the reaction, that
is yield, cost, safety, technical set-up, temperature and feasibility of
workup/purification procedures. In this approach, a range of penalty points is
assigned to each of these parameters. As far as the safety is concerned, hazard
warning symbols are used to quantify the penalty assigned. Such ECOSCALE
software uses a scale from 0 to 100, the latter figure representing the ideal reaction,
which the Authors defined as “Compound A (substrate) undergoes a reaction with
(or in the presence of) inexpensive compound(s) B to give the desired compound C
in 100 % yield at room temperature with a minimal risk for the operator and a
minimal impact for the environment”.
The contribution to the safety, health and environmental performances are
detailed in the analogous SHE toolbox [16]. For each chemical and reaction step
involved in the process, the SHE aspects are classed into 11 effect categories (fire
explosion, reaction decomposition, acute toxicity, chronic toxicity and air mediated
effects among others). These are not combined into a single index, but the effect of
each substance to a given effect category is individually determined. An idea of the
application of this method can be gathered from a paper by Hungerbhüler and
coworkers where a reaction carried out in a pharmaceutical industry is considered.
This is the methylation of 8-α-(tert-butyloxycarbonylamino)-6-methylergonin 1 to
compound 2, one of the six steps of the batch synthesis of building block 8-α-
amino-2,6-dimethylergolin, see Fig. 2.3 [17].
20 2 Green Metrics, an Abridged Glossary
COOMe COOMe
1. LDA, SiMe3Cl
H 2. C6H13Li, CH3I, HCl H
NMe NMe
H 76% yield H
N N 2
1
Boc Boc CH3
Fig. 2.3 Environmental performance of the materials used in the methylation of 8-α-
(tert-butyloxycarbonylamino)-6-methylergolin 1. Adapted with permission from Ref. [17a]
Importantly, none of the above described parameters takes into account the amount
of energy supplied for carrying out a chemical process [18]. This is particularly
relevant, since in some cases the advantage of using a method that is more eco-
sustainable when considering the chemicals used may be lost due to energetic costs.
Indeed, in the case of laboratory reactions, the electric energy employed can be
measured with good accuracy with easily available, cost-effective energy counters,
although only a fraction of the electric energy consumption is actually transferred to
the reaction batch. Different energy metrics have been introduced to class a
chemical process. One of first parameters defined is the Energy Efficiency (EE) that
is the ratio between the amount of the desired product obtained and the electric
energy used in a synthesis [18].
2.1 Environmental Parameters for a Chemical Reaction 21
Analogously, the specific productivity (sP) has been defined as the amount of
product (expressed in molar unit, more often used by chemists) obtained for unit of
work (in KWh), a definition suitable for any kind of activation, including irradiation
by lamps or microwave [19].
AP ¼ AR þ AW
Energy consumption ðReaction; WÞ þ Energy consumption workup ðWÞ
¼
mass product ðkgÞ
ð2:19Þ
The most used parameter is, however, the Energy-induced methane equivalents
that quantifies the energy consumed as moles of methane required to produce the
end product. For determining this value, it is assumed that electricity is exclusively
obtained from burning methane, with an efficiency, in the power plant, of 43 %.
Then, the amount of methane is calculated in mol (1 MJ = 3.052 mol methane).
Alternatively, the amount of CO2 produced for the process can be also easily
calculated.
A general, advanced approach is offered by the Life Cycle Assessment (LCA),
which follows a philosophy “from the cradle to the grave”, where every section of
the entire life of the product is assessed [20] including raw material supply, each
chemical step, the product or service itself, including its final disposal and waste
removal. This approach has been known since the early 1970s when only the
energy consumption was investigated, but only in the early 1990s the LCA as we
know it today started to emerge. Generally, LCA consists of four steps, namely
(1) Goal and definition of the scope. (2) Life Cycle Inventory Analysis, where all
the mass and energy flows of the process are recorded according to the defined
scope. (3) Life Cycle Impact Assessment, where the results of Life Cycle Inventory
process is analyzed in view of its environmental impact, including, among others,
climate change, ozone depletion, freshwater and marine eutrophication, human
toxicity and water depletion. 4) Life Cycle Interpretation, that involves pointing out
the most significant issues related to the process and their evaluation. This approach
is operated by a dedicate software regulated by the ISO standards (see the ISO
14000 series). The obtained results can be coupled with other environmental and
22 2 Green Metrics, an Abridged Glossary
Fig. 2.4 Comparison between different conditions employed for biodiesel production. Adapted
with permission from Ref. [21]