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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

Green Chemistry for Sustainability

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

ISSN 2191-5407 ISSN 2191-5415 (electronic)

SpringerBriefs in Molecular Science
ISSN 2212-9898
SpringerBriefs in Green Chemistry for Sustainability
ISBN 978-3-319-25893-5 ISBN 978-3-319-25895-9 (eBook)
DOI 10.1007/978-3-319-25895-9

Library of Congress Control Number: 2015953812

Springer Cham Heidelberg New York Dordrecht London

© The Author(s) 2016
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part
of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations,
recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission
or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar
methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this
publication does not imply, even in the absence of a specific statement, that such names are exempt from
the relevant protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this
book are believed to be true and accurate at the date of publication. Neither the publisher nor the
authors or the editors give a warranty, express or implied, with respect to the material contained herein or
for any errors or omissions that may have been made.

Printed on acid-free paper

Springer International Publishing AG Switzerland is part of Springer Science+Business Media

(www.springer.com)
Preface

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

6 Process Intensification in Organic Synthesis . . . . . . . . . . . . . . . . . . 87

6.1 Green Chemical Engineering and Green Chemistry . . . . . . . . . . . 87
6.2 Progress Intensification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
7 Conclusions and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106

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.

Keywords Environmental pollution
Sustainability
Green chemistry
12

principles

1.1 Preserving the Environment

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

© The Author(s) 2016 1

A. Albini and S. Protti, Paradigms in Green Chemistry and Technology,
SpringerBriefs in Green Chemistry for Sustainability,
DOI 10.1007/978-3-319-25895-9_1
2 1 Introduction

species have produced a consistent series of environment destructions and disasters.

Future generations have thus been robbed of a large part of the opportunities
previous generations had found available. However, the fast development of
chemical industry (and of industry in general) in the last 150 years has made these
changes proceed at a fast increasing pace and awaken in the contemporary man the
conscience that there was an actual risk that evolution couldn’t be controlled and
that the damage created was irreversible. Industry is now concerned with envi-
ronmental issues, but its attitude had not been as open-minded before. Many times a
vital choice has been arrived at on the basis of the maximal short-time profit only,
despite the unquestionable awareness of the risks that such decision involved.
An emblematic case. Consider the production of tetraethyl lead, the antiknock
agent that made the skyrocketing expansion of the car market possible in the 1920s.
Several leading scientists warned General Motors (GM) scientists of the serious
menace to human health and environment that this compound caused, due to the
toxicity (which gained to it the nickname of “loony gas”) and the risk of explosion
[2]. Actually, even as GM and Standard Oil were about to form a partnership and
greatly expand the role of this organometallic compound in the gasoline market, its
adoption was still questioned because of the risk implied. However, an internal note
of the firm in March 1923 left no doubt upon why going forward was that important.
“The way I feel about the Ethyl Gas situation is about as follows: It looks as though
we could count on a minimum of 20 % of the gas sold in the country if we advertise
and go after the business—this at three cent gross to us from each gallon sold.
I think we ought to go after it as soon as we can without being too hasty …” [3]. As
it has been commented, with gasoline sales around eight billion gallons per year,
20 % would represent two billion gallons, and three cents gross would bring in
$60 million per year. With the cost of production and distribution less than one cent
per gallon of treated gasoline, more than two thirds of this would be annual gross
profit [2]. As it turned out, these original figures were modest compared to the
market success that would come later. Furthermore, a bad accident occurred in a
plant when production was beginning and caused five casualties (to be added to
those due to toxicity), raising public attention and harsh polemics in the papers, but
General Motors and Standard Oil insisted that tetraethyl lead had no alternative as
an antiknock agent, and, in the absence of a determined resistance by the Federal
Institutions, they had this compound dominate the market by the end of the 1920s.
The situation did not change until at the beginning of the 1970s it was recognized
that combustion of tetraethyl lead produced particles of the metal and this was
dangerous for the public health, so that after a phase down, it was banned.
A study based on GM files reveals a second aspect of the controversy involving
the auto industry’s long term fuel strategy. The main target for the Research
Manager, C. F. Kettering, was protecting GM against oil shortages (then expected
to occur by the 1940s or 1950s). “His strategy was to raise engine compression
ratios with tetraethyl lead specifically to facilitate a transition to well known
alternative fuels (particularly ethyl alcohol from cellulose). However, Kettering lost
an internal power struggle with GM and Standard Oil Co. Kettering’s strategy was
discarded when oil supplies proved to be plentiful and PbEt4 turned out to be
1.1 Preserving the Environment 3

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

1.2 Sustainable and Green Chemistry

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

1. Prevention. It is better to prevent waste formation than to treat or clean up

waste after that it has been created.
2. Atom Economy. Synthetic methods should be designed to maximize the
incorporation of all materials used in the process into the final products.
The two first principles are considered in a quantitative rather than qualitative
form (see Green Metrics in Chap. 2).
3. Less Hazardous Chemical Syntheses. Wherever practicable, synthetic methods
should be designed to use and generate substances that possess little or no
toxicity to human health and the environment.
4. Designing Safer Chemicals. Chemical products should be designed to main-
tain their desired function while minimizing their toxicity.
5. Safer Solvents and Auxiliaries. The use of auxiliary substances (e.g., solvents,
separation agents, etc.) should be made unnecessary wherever possible and
innocuous when used.
The 3rd, 4th and 5th principles concern safety. It should be noticed that despite
the reservation expressed in the 3rd principle, the moral attitude must be
uncompromising. New protocols that are inherently safer must be designed and
there is no excuse for maintaining the old ones when these do not guarantee
safety. Likewise, collaboration between toxicologists and chemists is important
for designing “safer chemicals in a truly holistic and trans-disciplinary manner
through innovative curricular advancements” [20].
6. Design for Energy Efficiency. Energy requirements of chemical processes
should be recognized for their environmental and economic impacts and should
be minimized. If possible, synthetic methods should be conducted at ambient
temperature and pressure.
As it has been pointed out, this is rather a “forgotten principle”, despite the key
role of energy. The use of consistently more expensive energy must be mini-
mized, and new processes occurring under mild conditions have to be intro-
duced, following the path taught by nature [21].
7. Use of Renewable Feedstock. A raw material or feedstock should be renewable
rather than depleting whenever technically and economically practicable.
The goal is converting the biomass into useful chemicals in a manner that does
not generate more carbon than is being removed from “thin air”. The difference
between C(in) from the air and C(out) from the energy used is the carbon
footprint ΔC. Ideally, when using Principle #7, the overall carbon footprint
should be designed as positive, so that C(in) > C(out) [22].
8. Reduce Derivatives. Unnecessary derivatization (use of blocking groups,
protection/deprotection, temporary modification of physical/chemical pro-
cesses) should be minimized or avoided if possible, because such steps require
additional reagents and can generate waste. Here again, learning from nature
and enzymatic processes is a good choice [23].
9. Catalysis. Catalytic reagents (as selective as possible) are superior to stoi-
chiometric reagents.
1.2 Sustainable and Green Chemistry 7

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

Traditional chemical safety models focus primarily on the control component of

that definition”… however… “the most effective means of increasing safety is
eliminating the hazard component”. Thus, striving towards safer conditions for
workers is also striving toward a safer environment for the general public and
maintains a safer planet for mankind.
It should further be noticed that green chemistry is by definition close to
industrial chemistry, and in particular to chemical engineering, because it is from
actual industrial products that comes the main environmental damage, even though
small amount of strongly toxic substances occasionally formed may cause major
troubles [27]. The purpose of this Brief is to share with researchers and students the
paradigms, that is the organized body of notions, on which green chemistry is
based. Thus, a small number of recently reported procedures will be presented, with
limitation to cases where the environmental performance has been evaluated in a
quantitative way. Some issues that have a basic role in this field will be thus
considered, namely the use of a recognized metrics (Chap. 2), the choice of re-
newable feedstock (Chap. 3), the search for mild conditions for the activation of
substrates (Chap. 4), the choice of the solvent (Chap. 5), the relation between
process intensification and green chemistry (Chap. 6).

References

1. Pasolini P (1975) Corriere della Sera. Accessed 1 Feb 1975. http://www.corriere.it/speciali/

pasolini/potere.html
2. Kovarik B (1994) Charles F. Kettering and the 1921 discovery of tetraethyl lead. Society of
automotive engineers, fuels and lubricants division conference, Baltimore, 1994. http://www.
environmentalhistory.org/billkovarik/about-bk/research/cabi/ket-tel/#earlyw
3. “Midge” to “My dear Boss” Kettering, 2 Mar 1923, Factory correspondence, unprocessed
Midgley files, GMI. Quoted in [2]
4. New York Times, 25 Oct, section 9, p 14. Quoted in [2]
5. Frittoli E (2014) Eternit: la storia del cemento che uccide (1901–2014). http://www.panorama.
it/news/cronaca/eternit-storia-cemento-uccide-1901-2014/
6. Carstons R (1962) Silent springs, Houghton Mifflin Harcourt (2002 edition)
7. Page 49 in Ref. [6]
8. van Leeuwen FX (2000) Safe drinking water: the toxicologist’s approach. Food Chem Toxicol
38:S51–S58
9. Zala S, Penn DJ (2004) Abnormal behaviour induced by chemical pollution: a review of the
evidence and new challenges. Anim Behav 68:649–664
10. (a) Report of the World Commission on environment and development: our common future;
UN documents: gathering a body of global agreements. http://www.un-documents.net/wced-
ocf.htm. (b) Pollution prevention act of 1990. US Government Printing Office, Washington,
1995, p 617
11. Rio declaration on environment and development, United Nations publication, sales no. E.73.
II.A.14 and corrigendum, chapter I. http://www.unep.org/Documents.Multilingual/Default.
asp?documentid=78&articleid=1163
12. Metzger JO (2004) Agenda 21 as a guide for green chemistry research and a sustainable future.
Green Chem 6:G15–G16
References 9

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]
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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.

Keywords Green metrics
Mass metrics
Energy metrics
Environmental

metrics Life cycle

2.1 Environmental Parameters for a Chemical Reaction

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.

© The Author(s) 2016 11

A. Albini and S. Protti, Paradigms in Green Chemistry and Technology,
SpringerBriefs in Green Chemistry for Sustainability,
DOI 10.1007/978-3-319-25895-9_2
12 2 Green Metrics, an Abridged Glossary

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.

2.1.1 Mass Metrics

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

Convergent syntheses with two or more separate branches can be analyzed by

taking into account the amount of the reactants involved in each chemical step,
while ignoring the product intermediates [2]. A more elaborated AE expression for
multistep synthesis has been proposed by Eissen et al. [3].
A variation, of obvious significance in organic synthesis, is carbon economy (CE),
proposed by Curzons et al. [4] that is limited to the amount of carbon in the reactants
that is incorporated in the end product, according to the equation below (Eq. 2.2):

Amount of Carbon in product

CE ¼ ð2:2Þ
Amount of Carbon in reagents

As originally defined, AE is referred to the chemical equation as such, and thus to

a quantitative yield and the use of the reactants in exactly stoichiometric amounts.
2.1 Environmental Parameters for a Chemical Reaction 13

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 phloroglucinol (1,3,5-benzenetriol) [7]. This is the E-Factor (E), defined as the

ratio between the mass of waste produced for mass unit of final product (Eq. 2.6).

Mass of waste ðkgÞ

E¼ ð2:6Þ
Mass of product ðkgÞ

According to Eq. 2.6, recyclable materials such as solvents, reused reactants or

catalysts are not considered as waste and thus ignored, and the ideal value of E is 0.
Different parts contribute to the value of the total E-factor (Eglobal). In a detailed
analysis, Andraos [8] proposed a more articulated view of this parameter, defined as
the sum of different contributions deriving from the core chemical equation
(by-products, side-products, and unreacted starting materials, Ekernel), from excess
reagent (Eexcess), and from auxiliary materials used in the process, including
work-up and purification operations (Eaux).

Eglobal ¼ Ekernel þ Eexcess þ Eaux : ð2:7Þ

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

Table 2.2 A summary of the main parameters discussed in this chapter

Metrics Equation Range of values
(ideal value)
Mass metrics
Reaction yield (RY) mol ðproductÞ obtained 0 < RY < 1 (1)
mol ðproductÞ expected
Atom economy (AE) PMW ðproductÞ 0 < AE < 1 (1)
MWðreagentsÞ
Reaction mass efficiency kernel Mass of product ðkgÞ 0 < RMEkernel < 1
(RMEKernel) or actual atom Mass of reagents ðkgÞ (1)
economy (AAE)
Reaction mass efficiency global AAE  MRP
SF
0 < RMEglobal < 1
(RMEGlobal) (1)
Environmental factor (E) Mass of waste ðkgÞ 0 < E < ∞ (0)
Mass of product ðkgÞ
Process mass intensity (PMI) Mass of chemicals ðkgÞ 1 < PMI < ∞ (1)
Mass of product ðkgÞ
Environmental metrics
Effective mass yield (EMY) Mass of products ðkgÞ 1 < EMY < ∞ (∞)
Mass of non benign reagents ðkgÞ
EIN (EATOS) PMI × QIN 1 < EIN < ∞ (1)
EOUT (EATOS) E-factor × QOUT 0 < EOUT < ∞ (0)
Energy metrics
Energy efficiency (EE) Mass product (kg) 0 < EE < ∞
Energy consumption (kJ)
2.1 Environmental Parameters for a Chemical Reaction 15

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):

1 Mass of chemicals ðkgÞ

PMI ¼ ¼ ð2:8Þ
RME global Mass of product ðkgÞ

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

Mass of chemicals ðkgÞ Mass of product ðkgÞ þ mass of waste ðkgÞ

PMI ¼ ¼
Mass of product ðkgÞ Mass of product ðkgÞ
¼ Eþ1
ð2:9Þ

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

Fig. 2.2 Synthesis of

diphenylmethanol with
different extent of reclaiming
excess reagent

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.

no: of construction reactions þ no: of strategic redox reactions

% Ideality ¼
no: of reactions
ð2:12Þ

In order to standardize chemical processes across the pharmaceutical industry,

the concept of green aspiration level has been introduced. In this way, one is able to
define SMART (Specific, Measurable, Ambitious and achievable, Result-based,
Time-bound) processes as green chemistry goals for the whole field. A standard
aspirational level (GAL) is defined with reference to the average parameters of
processes examined by the ACS Green Chemistry Institute. Roschangar and
co-workers calculated the average values as cEF = 307 kg kg−1 for Phase 1 and
167 kg kg−1 for commercial projects, and sEF = 167 kg kg−1 for Phase 1 and
23 kg kg−1 for commercial projects. In average, the number of steps in these
processes is 7 with 1.3 chemical transformations per step. Thus, the average
18 2 Green Metrics, an Abridged Glossary

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 ¼ ðtGalÞ  complexity ð2:14Þ

The relative process greenness is thus defined as indicated in Eq 2.15).

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].

2.1.2 Environmental Metrics

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:

Mass of products ðkgÞ

Effective Mass Yield ¼ ð2:16Þ
Mass of non benign materials ðkgÞ

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]

2.1.3 Energy Metrics

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

mass product ðkgÞ

EE ¼ ð2:17Þ
Energy consumption ðKJÞ

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].

mol product ðmolÞ

sP ¼ ð2:18Þ
Electric work ðKWhÞ

The reverse of EE is defined as the Energetic process expenditure (AP). Energy is

consumed both during the reaction (energetic reaction expenditure, AR) and during
work up (energetic work up expenditure, AE), but often the latter contribution is
larger.

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]

evaluation methods in three-dimension graphs, with the aim of affording a complete

picture of the process. Kralish et al. analyzed different routes to biodiesel by taking
into account the nature of the feedstock, the catalyst (both acid and alkali) and the
reaction conditions (heating, microwave activation, use of supercritical fluids),
finding that supercritical processing in an intensifying continuous flow reactors is
the most favorable proposal (see Fig. 2.4). The results obtained were inserted in a
tetrahedral chart including both safety (EHS, see below), environmental (LCA) and
economic parameters (Life Cycle Cost, (LCC) that is the analysis of the cost of
goods throughout its full life cycle) [21].
In any case, despite the capability of giving a precise idea of both the envi-
ronmental and (in particular) of the energetic cost of the process, this approach has
been substantially limited to a few large scale productions and hardly applied to fine
chemistry, because of the fact that the required data are available only for a few
chemicals in inventories already present in the LCA database [22].
In order to overcome this limitation, a Simplified Life Cycle Assessment (SLCA)
has been proposed by the Society of Environmental Chemistry and Toxicology
(SETAC), where some chosen approximations (e.g. the use of data of an analogous
compounds, rather than exactly of the required one, a move that has been shown
often not too largely affect the final result) are applied to the four phases of the
traditional LCA [21]. In this way, the LCAs approach is increasingly adopted for
the optimization of synthetic routes leading to Active Pharmaceutical Ingredients
(APIs) despite the complexity of the problem, in some cases by accepting a rea-
sonable compromise. LCA should offer a realistic measure of the “greenness” of the
examined process, be easy to use and able to assess quantitatively the
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22 Aug
6456 Osborne R H
E 22
120 July
2714 Osterhardt B S
C 1
86 Dec
12269 Ostrander J
A 12
120 Mar
108 Ostrander J H
F 23
94 Aug
6326 Otis Jno
A 21
100 Sept
8768 Otto Chas
F 14
12 Apr
656 Otto Jas L, Cor Cav
E 21
47 Aug
5447 Owens Ed
G 12
49 Dec
12227 Owens Wm
I 5
7504 O’Reilly Philip Art 2 I Sept
 1
146 Sept
9319 Page O D
F 20
85 June
2825 Palmer P H
D 22
17 June
2582 Palmer F
F 27
15 Aug
6753 Pallette D Cav
K 24
86 Mar
20 Palmiter R, Cor
D 7
71 Aug
5958 Pamperin Wm
H 17
85 July
3350 Pardy E
K 15
146 Aug
5710 Parish D
E 15
128 Nov
12180 Parker F, Cor
C 27
85 June
2092 Parker I
I 17
124 July
2819 Parker Isaac
G 3
80 May
1392 Parker J
I 26
154 July
2953 Parker J
G 6
15 July
3886 Parker J Cav
F 16
Aug
4732 Parkinson A Art 4C
4
109 Nov
11956 Parks Wm
K 11
11218 Parsons W 64 Oct
E 20
76 Sept
9487 Patterson D
D 21
Aug
5880 Patterson E Art 6M
16
15 July
3440 Patterson G W “
M 17
1 Aug
6165 Patterson H Cav
- 19
85 Aug
5279 Patterson I H
F 11
85 Aug
4708 Patterson J H
G 4
39 Oct
10368 Paul P
L 8
Aug
6696 Pease Martin Cav 2C
24
22 June
2166 Peck J G “
F 19
Oct
11630 Peckins L “ 2A
28
12 Oct
11673 Pedro Francis “
E 30
15 June
1542 Pellet Ed “
I 1
July
3781 Pen R “ 2F
22
69 July
2763 Pinablin Jno
F 12
Oct
11348 Pen Chas Art 6D
23
7398 Perkey D 85 Aug
 B 31
24 Aug
7172 Perkins J P Bat
- 29
39 Oct
10562 Perry A, Cor
G 9
84 Aug
4527 Perry Jno
D 2
Sept
7866 Perry W Cav 2B
5
99 July
3721 Perry Wm
E 21
79 Nov
12182 Perry Wm
A 27
61 Aug
4517 Person A
H 2
64 July
3082 Persons W B 64
B 9
52 Aug
5224 Peters Fritz
C 10
114 July
3914 Peters J
F 25
178 Aug
5684 Peterson C
I 15
48 Sept
9120 Peterson H
B 18
100 July
3302 Pettis L P
F 14
81 Aug
5727 Petrie Josh
I 13
132 Apr
486 Phelps Martin
G 9
85 July
4235 Phillips Geo A
B 29
12481 Phillips I Cav 6E Jan 65
17
100 Sept
7637 Phillips H, S’t 64
H 2
85 July
3318 Phillips R, Cor
B 14
July
4152 Pierce Albert Art 2M
28
73 June
2459 Pierce Chas
F 25
85 Aug
5371 Pierce H, Cor
B 11
85 Aug
6027 Pierce J
D 18
8 Oct
11663 Pierce J H Cav
- 30
76 Aug
6005 Pierson J
B 17
61 Sept
9422 Pilseck E
I 21
99 May
1532 Pinmon John
I 31
97 Sept
9994 Pitts G
K 29
61 Oct
11441 Pivant M
D 25
47 Aug
6086 Place E
F 18
120 Apr
815 Plass H
G 30
146 Oct
11379 Plunkett J
A 24
9549 Polack J 85 Sept
 C 23
16 July
4432 Pollock R Cav
L 31
21 June
1843 Pomroy C “
G 11
16 Aug
4531 Ponteis G “
K 2
85 June
1830 Popple W G
B 11
15 Oct
11120 Pope Jas E Art
A 18
125 Oct
12291 Post H E
G 15
94 Jan
12425 Post J A 65
E 10
48 Aug
6385 Potter H 64
E 21
85 June
1582 Potter W H, S’t
F 3
Aug
5116 Powell Geo Art 7H
9
24 July
2948 Powers J Cav
H 6
10 July
3367 Powers J
K 15
Aug
6890 Powers O Art 6 I
21
146 Aug
5435 Pratt B F
G 12
May
1394 Presselman C Cav 4M
26
Aug
5523 Preston H G 9G
13
1096 Price David 154 May
A 14
Dec
12346 Price J, Citizen - -
27
24 Aug
6455 Pratt P Bat
- 22
132 June
1651 Priest W
E 5
10 May
1479 Pratt G B Cav
D 30
Pringler Thos W, 118 Sept
7964
Cor A 6
14 Aug
6914 Prow Jno Art
L 26
149 Sept
9668 Prowman S H
H 24
15 Sept
9937 Puff I Art
- 28
115 June
2321 Puley Daniel
I 22
132 Apr
729 Pullers U H
E 25
14 June
2395 Putnam L Art
L 24
84 May
1515 Purkey Jacob
B 31
49 July
4063 Purstle S
A 27
147 Oct
11432 Prunan L, Cor
H 24
11 Sept
9046 Quackenbuss P
K 17
8227 Quigley J 99 Sept
 I 9
10 Sept
8064 Quinn Edser Cav
B 27
July
4305 Randolph —— 9E
30
59 Oct
11648 Rafbrun W
C 30
132 Apr
512 Rafferty M
G 12
June
2534 Rafferty P Cav 5M
26
Oct
11330 Rafferty T Art 5B
23
Aug
4593 Raker L Cav 1E
3
100 July
3751 Ranch J
D 22
99 Oct
10875 Randall Jno 64
A 13
47 Aug
6503 Ralinger J
B 22
100 Aug
6794 Rangheart Jno
A 25
100 Sept
7778 Rasterfer Jno
A 4
104 July
4216 Rattery Jno
I 26
Oct
10937 Ray C Cav 3B
14
154 Oct
10246 Ray R S
A 3
125 July
4336 Raynard F
- 30
3435 Rattersboon J Art 3K July
17
86 July
2880 Ramsay Isaac
I 4
31 May
1265 Ramsay Hiram
K 21
111 June
2186 Reamer W C
B 19
July
2820 Redman J Art 3K
3
Oct
11695 Reddo D V Cav 8M
31
64 Aug
7232 Reed F A
E 30
140 Sept
8574 Reed J
H 12
13 Apr
406 Reed S G
B 6
146 Aug
6041 Reed W D
H 18
41 Oct
10232 Reed W J
I 2
14 Sept
8492 Reed Wm Art
I 11
52 Aug
7369 Reetz Jno
A 31
152 Aug
5694 Reeve G
C 5
57 June
1680 Reeves Jno
H 6
43 Oct
10467 Redmond J
C 7
10911 Regler W H Cav 22 Oct
 M 14
164 Sept
9122 Reiley P O
B 18
29 Aug
7195 Reuback C
- 29
59 Jan
12455 Rebman J 65
C 15
Sept
8431 Rencermane J R C 5B 64
11
76 Sept
9320 Randall A B
F 20
July
3352 Remson C Cav 2M
15
155 Sept
8209 Reynolds O
E 8
85 Aug
6799 Reynolds O S
E 25
Reynolds 92 Oct
10265
Samuel H 3
140 Aug
6350 Reynolds Wm
I 21
65 Aug
6546 Reidy J D
I 23
39 July
4318 Rice F, Cor
I 30
24 July
3077 Rich T D Bat
- 9
82 Dec
12289 Rich J
C 15
66 July
3561 Richey R
C 18
178 June
2427 Rider E
E 24
8005 Rhenebault R H 21 Sept
B 6
Nov
11904 Rehn W Art 7C
7
132 July
3891 Richistine C, Cor
D 24
52 Aug
5317 Richards A
D 11
41 Aug
5674 Richards A
E 14
Dec
12243 Richards A 9C
7
47 July
3682 Richards H
E 21
146 Sept
7578 Richards N J, S’t
C 2
20 July
4240 Richardson H M C
M 29
Nov
12193 Ricker M Art 2M
29
85 Sept
8155 Rickhor J
E 8
125 Apr
415 Rikel Robert
G 7
73 Jan
12382 Riley I 65
E 2
99 July
2885 Riley J 64
C 4
176 Aug
5021 Riley John
C 8
39 Aug
6347 Riley John
D 21
11163 Ripley F A 152 Oct
 C 19
42 Nov
11760 Ripp W
B 3
75 July
3514 Rising C
B 18
46 Oct
10610 Risley Geo W
G 4
132 June
2558 Ritcher F, S’t
D 27
18 Aug
7245 Ritson S Cav
E 29
115 Sept
9224 Ritzmiller Jno
- 19
99 June
1775 Roach F
F 9
85 June
1842 Roach Chas
E 11
46 June
2354 Robberger P H
B 23
122 Oct
11195 Roberson C A 64
B 20
134 June
2346 Robertson W H
B 23
96 Sept
8554 Robertson W M
B 12
39 Sept
9970 Robinson H
K 28
111 Sept
7607 Robinson A
I 2
95 July
3880 Robinson H C
I 21
115 Aug
6419 Robinson Jno
A 22
 27 Robins L, Cor 154 Mar
K 8
173 Sept
7663 Roberts A
C 3
14 Sept
7585 Rockwell N C A
D 2
85 July
8318 Rockfeller R E
D 23
15 Oct
11342 Rockfeller H Art
M 23
July
3959 Rock F “ 6F
25
July
4350 Rogers A “ 7 I
31
125 Aug
6059 Rogers A
H 18
85 Aug
5791 Rogers G, Mus
F 15
132 July
3011 Rogers Jas
H 7
85 July
4287 Rogers H C
C 30
Sept
8369 Rogers H J Art 2E
10
43 Aug
4912 Rogers M
D 6
85 Aug
7208 Rogers O S, S’t
C 29
12 Aug
6824 Rogers Thos
F 25
Nov
11772 Romer F 9A
3
8468 Rook G Art 6E Sept
 11
152 Sept
9663 Rooney Jno
G 28
132 Sept
9102 Rooney M
F 18
Sept
8922 Rooney P Art 2C
16
85 Aug
5669 Root A N
C 14
120 July
2998 Roots W T
H 7
24 June
1735 Root Legrand Bat
- 8
16 Oct
10278 Rose A
L 2
125 Sept
9550 Rosecrans J E
H 23
23 Sept
8171 Ross C Cav
A 8
111 July
3874 Ross E F
I 24
27 Aug
5591 Ross David
D 14
76 Aug
6741 Ross G
K 24
Sept
9751 Ross A Cav 1M
25
121 Nov
11963 Ross J H
G 11
Aug
5929 Rosenbarger Jno 4D
17
84 July
3616 Rosser Lewis
A 20
2924 Rosenburg J 30 July
A 5
24 Sept
8737 Rosson Chas Cav
E 14
93 Dec
12259 Roswell J
K 10
151 Apr
727 Ross Jacob
A 25
120 June
1940 Row W J
B 14
39 Aug
5097 Roth Louis
D 9
20 Sept
8504 Rothwell M, Cor Cav
M 12
12 July
3720 Rouge Wm, Bug C
F 21
11 Sept
7709 Rowbotham R C
L 3
70 Aug
5857 Rowell J E
G 16
99 July
3492 Rowell L N
H 17
Mar
59 Roberts A B, S’t Cav 8B
18
120 June
2609 Ruddin C
H 28
120 May
867 Rudler Wm
M 3
Mar
40 Rue Newton, S’t Cav 5A
13
69 Sept
8667 Runey F
H 13
12635 Russ Jno 2K Feb 65
 10
Sept
8856 Russell J, Cor Art 7A 64
15
106 Aug
5094 Ryan D
D 8
95 Sept
8599 Ryan J
E 12
22 Sept
8741 Ryan J Cav
E 14
12 Aug
7258 Ryan Owen
A 30
66 Aug
4762 Ryonch Jno
I 5
Aug
6413 Ryson Jno Art 7L
22
39 Aug
6206 Ryne J M
E 9
111 Apr
684 Rush Jno
E 23
85 Aug
7234 Sackett R S
G 29
77 June
1920 Sadley M
H 14
24 June
1880 Safford B J Bat
- 12
Nov
11870 Salsbury H Art 1M
6
16 Oct
10652 Salisbury E
D 11
13 Oct
10923 Samlett —— Cav
I 14
15 Oct
10880 Samet W
H 13
3769 Sampson J 106 July
K 22
Sanders Chas, Apr
346 Mil 9A
Cor 2
99 July
3618 Sanders J
C 23
12 Sept
9857 Sanders J Cav
A 27
July
4423 Sandford P O Art 7L
31
12 June
2341 Saughin J Cav
F 23
Sept
7740 Sawyer J “ 2L
3
22 Oct
11232 Sayles A “
E 21
85 July
3612 Seaman A, Cor
H 19
2 Oct
10856 Seaman A Art
- 13
May
1372 Sears F Cav 2H
25
Aug
6120 Seagher J 8M
19
11 July
4325 See Henry
K 30
140 Sept
8824 Seeley A J
A 15
15 Oct
11374 Seeley C B
H 24
100 July
4256 Seeley Thos
F 29
10027 Segam Ed Cav 5K Sept
 29
10 July
4204 Seigler Geo
- 29
120 Sept
7458 Seigle John R
K 1
59 Nov
11886 Selson H
C 6
40 July
3457 Serrier R
C 17
June
1746 Serine C Cav 4M
8
99 Apr
629 Settle Henry
H 19
Sept
9828 Seyman F Cav 1A
27
77 Aug
5951 Seard Louis
E 17
21 Aug
6888 Schayler J W Cav
M 26
160 Oct
10794 Schadt Theo
A 12
July
3557 Scheck B Cav 2G
18
120 July
3190 Schemerhorn H
G 12
Nov
11965 Schempp M Art 7F
11
170 July
2795 Schermashie B
A 2
Schlotesser J, 91 May
1325
S’t H 24
Oct
11515 Schlotesser J 1L
26
9578 Schmaker Jno 30 Sept
B 23
Oct
10291 Schmaley J 1G
16
39 Oct
10550 Schmeager A
A 9
39 Aug
5311 Schneider Chas
A 11
24 Sept
8595 Shockney T T Bat
- 12
Sept
8796 Schofield J 7H
15
54 June
2441 Scholl Jno
D 25
59 Oct
11422 Schriber H
I 24
Sept
7814 Schroeder G Art 7E
4
14 Sept
8550 Schrum J “
K 12
20 May
1070 Schrimer Wm
B 13
12 July
4280 Schware F Cav
K 20
66 Aug
6613 Schwick A
G 23
85 Aug
4849 Scott J C, S’t
K 6
14 Aug
6857 Scott P C Cav
G 26
Sept
8622 Scott W W “ 2F
13
8290 Sibble W 148 Sept
 G 9
July
4362 Sick R E - -
31
Aug
4557 Sickler E Art 7E
2
120 July
3210 Sickles A
D 12
40 Nov
11950 Siddell G
- 10
Dec
12284 Simmons A Art 8H
13
Simmons C G, 85 Aug
6364
S’t B 21
116 Sept
8316 Simon H
B 10
85 Aug
6284 Simons H L, S’
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155 Mar
142 Simondinger B
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99 Mar
242 Simpson D
H 30
22 Aug
6345 Sisson P V, S’t Art
M 21
50 Sept
10067 Shaab J 64
A 30
61 Mar
201 Shea Pat, Drum’r
M 28
7 Aug
4801 Shaffer M Art
- 5
66 Aug
4584 Shaffer J
E 2
103 Apr
782 Shafer H
F 28