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PERSPECTIVE www.rsc.org/ees | Energy & Environmental Science

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View Article Online / Journal Homepage / Table of Contents for this issue

Green Chemistry: A design framework for sustainability

Evan S. Beach, Zheng Cui and Paul T. Anastas*

Received 11th March 2009, Accepted 16th June 2009

First published as an Advance Article on the web 9th July 2009

DOI: 10.1039/b904997p

In this review we will highlight some of the science that exemplifies the principles of Green Chemistry, in

particular the efficient use of materials and energy, development of renewable resources, and design for

reduced hazard. Examples are drawn from a diverse range of research fields including catalysis,

alternative solvents, analytical chemistry, polymer science, and toxicology. While it is impossible for us

to be comprehensive, as the worldwide proliferation of Green Chemistry research, industrial

application, conferences, networks, and journals has led to a wealth of innovation, the review will

attempt to illustrate how progress has been made toward solving the sustainability goals of the 21st

century by engaging at the molecular level.

1. Introduction

Green Chemistry is the design of chemical products and processes

that reduce or eliminate the use and generation of hazardous

substances.1 The green chemistry approach seeks to redesign the

materials that make up the basis of our society and our

economy—including the materials that generate, store, and

transport our energy—in ways that are benign for humans and the

environment and possess intrinsic sustainability. The concepts

and practice of Green Chemistry have developed over nearly

20 years into a globe-spanning endeavor aimed at meeting the

‘‘triple bottom line’’—sustainability in economic, social, and

environmental performance.2 Many challenges still lie ahead, and

the solutions will be found not only in the discipline of chemistry

but at its interfaces with engineering, physics, and biology.3 New

developments in toxicology such as predictive toxicology and

toxicogenomics are making it ever more possible to advance the

most important concept in Green Chemistry: design.

The aphorism ‘‘an ounce of prevention is worth a pound of

cure’’ is at the heart of Principle 1 of the Twelve Principles of

Green Chemistry, a comprehensive set of design guidelines that

have guided Green Chemistry development for many years.4 The

cost of handling, treating, and disposing hazardous chemicals is

Center for Green Chemistry and Green Engineering, Yale University, 225Prospect Street, New Haven, CT 06511, United States. E-mail: [email protected]; Fax: +1 203 436 8574; Tel: +1 203 432 5215

Broader context

Green Chemistry has enormous implications for energy and the

a significant portion of energy consumed by the manufacturing

catalysis and alternatives to conventional heating in chemical proce

the chemical enterprise. Additionally, as the world shifts from fossil

of energy, the demand for infrastructure presents an opportunity to

using chemical feedstocks in an efficient and non-polluting mann

Chemistry have contributed new ideas and techniques to move towa

the future will depend on connecting diverse scientific disciplines

through design at the molecular level.

1038 | Energy Environ. Sci., 2009, 2, 1038–1049

so high that it necessarily stifles innovation: funds must be

diverted from research and development (scientific solutions) to

hazard management (regulatory and political solutions, often).

For example, in the United States, the government has estimated

that 4% of manufacturing GDP is spent on compliance with

regulations related to environmental, worker, and product

safety.5 Reviews of chemical accidents show that while the

chemical industry is safer than other manufacturing jobs, expo-

sure controls can and do fail. The consequence is injury and

death to workers, which could have been avoided by working

with less hazardous chemistry.6 Impacts on human health and

the environment from dispersal of hazardous waste are similarly

grim. The United States Environmental Protection Agency Toxic

Release Inventory Program, which only monitors 650 out of

78,000 chemicals in commerce—in one country—reported more

than 60 kg of toxic chemicals per second were released directly to

the air, land, and water in 2005. A glance at the Blacksmith

Institute ‘‘World’s Worst Polluted Places’’ shows the devastating

costs of these releases, and the monumental cleanup problems

that are faced as a result of the ‘‘treatment’’ rather than

‘‘prevention’’ approach. In Green Chemistry, prevention is the

approach to risk reduction (eqn 1):

Risk ¼ f(hazard � exposure) (1)

By minimizing the hazard portion of the equation, using

innocuous chemicals and processes, risk cannot increase

environment. As the chemical industry currently accounts for

sector (and its corresponding emissions of CO2), advances in

sses will play an important role in ensuring the sustainability of

fuels to solar, wind, hydro, and other readily renewable sources

build materials and technologies based on renewable resources,

er. Over the last 20 years, researchers in the field of Green

rd practical solutions to critical sustainability issues. Success in

through a common thread: reducing environmental impacts

This journal is ª The Royal Society of Chemistry 2009

http://dx.doi.org/10.1039/b904997p

https://pubs.rsc.org/en/journals/journal/EE

https://pubs.rsc.org/en/journals/journal/EE?issueid=EE002010

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spontaneously through circumstantial means—accidents, spills,

or disposal. This review will show how Green Chemistry has been

tremendously successful in devising ways to reduce pollution

through synthetic efficiency, catalysis, and improvements in

solvent technology. We will discuss alternative synthetic methods

that have been applied to reduce energy consumption in the

chemical industry, and we will survey bio-based feedstocks and

materials that are decreasing our reliance on depleted fossil

resources. Finally, we will consider the challenges that lie ahead in

designing safer chemicals: the establishment of a comprehensive

set of design principles and interdisciplinary cooperation to move

toward routine consideration of hazards as molecular properties

just as malleable to chemists as solubility, melting point, or color.

2. Material and energy efficiency

Several of the Twelve Principles of Green Chemistry aim to

minimize hazard by eliminating waste:

� incorporating all starting materials into a product

� avoiding protecting groups whenever possible

� favoring catalytic reagents

� using less solvent and separation agents

� reducing energy consumption

Waste reduction translates very readily into economic bene-

fits—wasted reagents are wasted money, and material that is not

Dr Evan Beach

Dr Evan Beach joined the

Center for Green Chemistry and

Green Engineering at Yale in

2007. He received his BS and

PhD in Chemistry from Carne-

gie Mellon University, where he

researched environmentally

benign catalytic oxidation

systems for water cleaning

applications. His current

research focuses on polymers,

fine chemicals, and other useful

materials from renewable feed-

stocks, with an emphasis on

productive use of byproducts

generated in biofuel production.

Dr Zheng Cui

Dr Zheng Cui is a postdoctoral

research associate in the Center

for Green Chemistry and Green

Engineering at Yale. She

received her PhD in Materials

Science from Beijing University

of Aeronautics and Astronautics

in 2008, where her thesis work

consisted of synthesis and char-

acterization of chitosan-based

proton exchange membranes for

fuel cell applications. Her

current research interests

include applications of chitosan,

lignin, and other underutilized

polymers of biological origin.


converted into product or recycled is essentially paid for twice:

once as a feedstock, and again as a waste to be disposed of.

Alternative solvents and solvent-free reactions contribute to

safer conditions for chemical workers, since many conventional

solvents are volatile, flammable, or associated with acute and

chronic health effects.7 Syntheses and processes that are carefully

designed to eliminate waste streams make questions of environ-

mental persistence and toxicity moot. Most of the Green

Chemistry success stories of the last 20 years are related to

advances in waste minimization.

This area of Green Chemistry has been aided by the devel-

opment of metrics for assessing the potential environmental

impact of a synthesis or process. For more than a century,

chemists have relied on the concept of ‘‘yield’’ almost exclusively

to gauge the success of a reaction or series of reactions.

A significant advance in accounting for chemical waste was the

concept of ‘‘atom economy’’, outlined by Trost in 1991.8 Atom

economy is a measure of how many atoms in a reagent are

incorporated into the product during a chemical transformation.

Addition reactions, for example cycloadditions or bromination

of olefins, are completely atom economical, since no atoms are

lost during the transformations. Substitution reactions result in

partial loss of atoms since the leaving group necessarily becomes

waste; Trost gives the example of methylene group transfer using

methyltriphenylphosphonium bromide, in which only 14 out of

365 Daltons are utilized productively. Elimination reactions are

intrinsically the least atom economical, since the starting mate-

rials only lose mass and all eliminated atoms become waste. Since

atom economy does not account for solvents and separation

agents, the ‘‘E-factor’’ proposed by Sheldon is a complementary

metric that accounts for all raw materials consumed but not

incorporated into the product.9,10 The E-factor reports the

amount of unit waste produced per unit product, and ideally will

equal zero. Table 1, Sheldon’s breakdown of waste generation by

chemical industry sector, highlights the need for improvements

particularly in fine chemical and pharmaceutical manufacturing.

The custom synthesis of biomolecules in the biotech sector

may yield E-factors well over 100. E-factors for nanoparticle

Dr Paul Anastas

Dr Paul Anastas is the Teresa

and John Heinz III Professor in

the Practice of Green Chemistry

for the Environment at Yale

University and serves as the

Director of the Center for Green

Chemistry and Green Engi-

neering at Yale. Trained as

a synthetic organic chemist, Dr

Anastas received his PhD from

Brandeis University. He is

credited with establishing the

field of green chemistry during

his time working for the U.S.

Environmental Protection

Agency as the Chief of the Industrial Chemistry Branch and as the

Director of the U.S. Green Chemistry Program. He has published

widely on topics of science through sustainability. (Photo credit:

Michael Marsland)

Energy Environ. Sci., 2009, 2, 1038–1049 | 1039


Table 1 Waste in various sectors of the chemical industry

Industry sectorProduction/metrictons year�1

E-factor/kg wastekg product�1

Oil refining 106–108 <0.1Bulk chemicals 104–106 <1–5Fine chemicals 102–104 5–50Pharmaceuticals 10–103 25–100

Fig. 1 A green method for preparing boronic esters. The conventional

route (top) results in stoichiometric magnesium, chloride, and alkoxide

waste, while the new route (bottom) generates only hydrogen.

Fig. 2 Hydrogen-mediated formation of carbon–carbon bonds, avoid-

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production vary greatly and some production methods can reach

100,000.11

Additional metrics such as ‘‘reaction mass efficiency’’ and

‘‘carbon efficiency’’ have been successfully adopted by the

pharmaceutical industry. The variety of metrics to choose from is

not confusing, rather, it provides ways to express waste and

efficiency information most usefully to chemists, engineers, or

business managers.12

ing stoichiometric metal waste (X ¼ NH, O).

Fig. 3 Reactive distillation and hydrogenation of glycerol to propylene

glycol; recent improvements in the catalytic process allow the reaction to

be carried out at significantly lower temperature and pressure.

2.1 Catalysis

Excessive waste generation can be attributed in part to reliance

on traditional stoichiometric reagents.13 Reductions with metals

or metal hydrides, and oxidations with metal oxides such as

permanganate and dichromate necessarily generate stoichio-

metric amounts of metal waste. Numerous conventional organic

transformations rely on mineral and Lewis acids or metal

hydroxides, creating waste streams laden with inorganic salts.

Advances in catalysis are rendering these classical methods

obsolete. The greener alternatives include catalytic hydrogena-

tion (H2), oxidation (O2 or H2O2), carbonylation, and hydro-

formylation. Transition metal catalysis has created a toolbox of

low- or zero-waste carbon–carbon bond-forming chemistry. The

power of catalysis to advance sustainable chemistry was recog-

nized by the Royal Swedish Academy of Sciences in 2005, who in

awarding the Nobel Prize in Chemistry to Chauvin, Grubbs, and

Schrock, noted that the scientists’ pioneering work in olefin

metathesis was a ‘‘great step forward for green chemistry’’.14

The three most recent U.S. Presidential Green Chemistry

Challenge Awards given to academic researchers by the

United States Environmental Protection Agency honored

breakthroughs in catalysis.15 The 2008 prize was awarded for

improvements in Suzuki coupling—a popular method for

building complex chemical structures through carbon–carbon

bond formation. Early Suzuki couplings were waste intensive;

a typical synthesis might require reaction of an aryl chloride with

a Grignard reagent followed by addition of a trialkylborate ester,

generating stoichiometric magnesium, chloride, and alkoxide

waste (Fig. 1), in addition to any waste associated with preparing

the chlorinated feedstock. The award-winning chemistry is

halogen-free, based on thermal, catalytic activation of an aryl

carbon–hydrogen bond. The only coproduct is hydrogen. The

iridium catalysts are robust and selective, allowing some

syntheses to be carried out in solvent-free conditions.16

The 2007 award recognized a powerful technique for enan-

tioselective carbon–carbon bond formation; using a rhodium or

iridium catalyst, an alkyne can be coupled to a carbonyl

compound or imine with H2 acting as the mediator.17 The allyl

alcohol or allyl amine products are valuable chiral compounds

for production of pharmaceuticals and other fine chemicals. A


conventional route to an allylamine might rely on a series of

organometallic reagents, each generating stoichiometric metal

waste. The new catalytic method completely incorporates the

starting materials into the product molecule, with no byproducts

(Fig. 2).

In 2006, the potential for catalysis to minimize another kind

of waste—wasted energy—was highlighted. As biofuels have

increased in popularity, the byproduct glycerol has flooded the

market. Industry is seeking to develop a platform of valuable

chemicals from glycerol, for example propylene glycol, which can

be obtained by dehydration of glycerol and subsequent hydro-

genation of the intermediate product (Fig. 3). The hydrogenation

step typically requires hydrogen pressures in excess of 10 MPa

and temperatures as high as 350 �C. A new process based on

a recyclable copper–chromite catalyst requires just 1.4 MPa H2

and operates at 200 �C.18,19 As of mid-2007 a facility capable of

producing 30 million kg year�1 was under construction.20

Green Chemistry has also aimed to eliminate waste caused by

catalysts themselves, including metal, solvent, and auxiliary

waste generated in catalyst quenching and separation processes.

Many strategies have been developed to improve catalyst recy-

clability. Immobilization of catalysts on inorganic or polymer

supports facilitates catalyst recovery and regeneration and

minimizes contamination of products. Catalysts have also been

designed with properties that allow them to be readily recovered

by adjusting pH or temperature.21 Porous inorganic solids for use

in heterogeneous catalysis are a good example of the green

chemistry benefits that can be achieved using new techniques.

These catalysts can be prepared with useful functionality

(Brønsted- or Lewis-acidic or redox-active metal sites) and they

can be designed so that the active sites are similar and well

separated, avoiding the common problem in heterogeneous

catalysis that different sites have a range of activities and



Fig. 4 A microporous solid catalyst converts 3-picoline to niacin in

a single step without heavy metal oxidants or organic solvents.Fig. 6 A biomimetic catalyst for stereospecific oxidation of alkanes

(X ¼ ClO4�).

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selectivities.22 Solid ‘‘single-site’’ catalysts have been designed

for shape-, regio-, and enantioselectivity, and they can be used to

carry out chemical transformations in fewer steps than conven-

tional processes and with significant reduction of waste

byproducts.23 For example niacin (3-picolinic acid) and other

useful oxygenated picolines are conventionally prepared with

selenium dioxide, permanganate, or chromic acid in multistep,

waste-intensive syntheses. In some cases 2.8 kg of inorganic

waste is generated per kg niacin. But, a microporous alumi-

nophosphate catalyst with Mn(III) sites converts 3-picoline to

niacin in just one step without organic solvents under mild

conditions (Fig. 4).24

Recyclable solid acid catalysts can eliminate hazardous waste

associated with conventional Lewis acid catalysts such as AlCl3;

industrially relevant applications include benzoylation of

benzene with a sulfated zirconia catalyst.25 Mesoporous silica has

been used to prepare a supported TEMPO catalyst that can

oxidize alcohols in air without any transition metals (Fig. 5). The

use of a TEMPO system avoids heavy metal oxidants, and the

porous solid has allowed the catalysis to take place without

transition metal promoters or high temperatures that are often

required by TEMPO chemistry.26

Nature is a source of inspiration for new catalytic chemistry.

Modeling of enzyme active sites has led to the development of

first-row transition metal complexes with simple ligands that can

carry out enzyme-like transformations. For example, non-heme

iron oxygenases were the inspiration for the first iron catalysts to

activate H2O2 to carry out stereospecific oxidation of alkanes

(Fig. 6).27 The catalysts were further shown to enable epoxidation

and cis-hydroxylation of alkenes.28 These kinds of oxidation

reactions would ordinarily be carried out with stoichiometric

organic peroxides or inorganic metal oxides, generating stoi-

chiometric waste. Hydrogen peroxide, on the other hand, can

generate only innocuous byproducts: water and oxygen. A

similar bio-inspired iron catalyst was recently discovered that is

Fig. 5 A supported TEMPO catalyst oxidizes alcohols to carbonyl

compounds without any transition metals. The chemistry requires only

catalytic amounts of NaNO2 and tetrabutylammonium bromide.


capable of selectively oxidizing one of the five tertiary C–H

bonds in artemisinin.29 In the case of complex molecules like

artemisinin, selectivity usually comes at the price of additional

synthetic steps to introduce or remove activating and protecting

groups, each of which can add to hazardous waste streams.

Ideally, further understanding of catalyst-derived selectivity will

allow chemists to transform complex molecules in predictable

ways, with a fraction of the environmental impact.30 Iron

complexes with tetraamidomacrocylic ligands (Fe–TAMLs)

have been developed to activate hydrogen peroxide with activi-

ties and lifetimes comparable to peroxidase enzymes.31 These

catalysts, which were the subject of a 1999 U.S. Presidential

Green Chemistry Challenge Award, have found applications in

a number of fields, most notably as an environmentally benign

technology for cleaning endocrine disrupting chemicals from

water.32,33

Biomimetic catalysis has also been a successful strategy in

polymer synthesis. For example, hematin can be modified with

poly(ethylene glycol) to create a ‘‘synthetic enzyme’’ that

emulates horseradish peroxidase, catalyzing the synthesis of

polyanilines, polyphenols, polypyrroles, and polythiophenes.34,35

Conventional routes to these materials can be waste-intensive;

polyaniline synthesis often entails high temperature, inorganic

oxidants, and toxic solvents, whereas enzymatic methods can be

performed in water under mild conditions.36 The hematin-based

catalyst retains the functionality of the peroxidase active site, but

is stable to a wider range of reaction conditions. The bio-inspired

synthesis can be used to produce useful materials including

conducting polymers and non-toxic industrial antioxidants, with

minimal solvent, chemical, and energy waste.37

It is often productive to take advantage of enzymes themselves

to achieve selective transformations with a minimum of reagents

and synthetic steps. For example, enzymatic synthesis of

a precursor to the drug pregabalin eliminates the need for classical

chiral resolution and multiple recrystallization steps, reducing

waste streams by 80%.38 Enzymes can be used in tandem or in

integration with chemical synthesis to prepare complex, chiral

molecules from low-value starting materials.39 The reactions are

not limited to water; useful enzymatic transformations have been

carried out in neat organic solvents and ionic liquids, and of

particular interest to green chemists are reactions in which

enzymes facilitate transformations of undissolved substrates,

including solid-to-solid chemistry.40 ‘‘BRENDA’’ (Braunschweig

Enzyme Database, http://www.brenda-enzymes.info) is the

world’s largest compendium of enzyme data, manually collected

from the primary literature, covering more than 4000 enzymes.

The database is searchable by reaction types, substrates and

products, industrial applications, structure, stability, and

numerous other parameters.41

At the cutting edge of enzyme technology is directed evolution,

a technique involving high-throughput screening of mutants.



Fig. 8 Industrial-scale hydrogenation of isophorone. In the process

using supercritical CO2, no product purification steps are required.

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Directed evolution can make enzymes more broadly useful: it

can improve stability; it can induce enzymes to accept unnatural

substrates; it can change the reaction pathway so different

products are obtained; or it can enhance the regio- or stereo-

specificity of the reactions.42 For example, in the synthesis of the

pharmaceutical atorvastatin, an enzyme’s performance was

increased 4000-fold by introduction of 35 mutations. The

enhanced enzymatic process meets a variety of green chemistry

goals including reduced solvent, safer reagents, and elimination

of wasteful purification steps.43

2.2 Alternative solvents

Solvents often account for the vast majority of mass wasted in

syntheses and processes. Many conventional solvents are toxic,

flammable, or corrosive. Their volatility contributes to air

pollution, increases the risk of worker exposure, and has led to

countless catastrophic accidents. Recovery and reuse, when

possible, is often accomplished by energy-intensive distillation

processes. Large proportions of solvent used, for example in

pharmaceutical synthesis, contribute to hazardous waste

streams, including contaminated water.44 Green chemists have

made significant progress in reducing the negative impacts of

solvent usage.45 Guides have been developed to suggest substi-

tutions for the most problematic solvents.7,46 Non-toxic and non-

flammable solvents like carbon dioxide and water have been

explored in depth, as discussed below. Poly(ethylene glycols) are

beginning to find use as safe, biodegradable solvents,47 and the

frontiers of solvent research include ‘‘smart solvents’’ with

switchable polarity that can reduce solvent waste and facilitate

recycling.48

It is often said that ‘‘the best solvent is no solvent’’. The

benefits of solvent-free chemistry often extend beyond waste

reduction and hazard avoidance. There are numerous examples

of shorter reaction times, and even enhanced activity and enan-

tioselectivity of catalysts in the absence of solvent.49 More than

1000 preparative-scale solid–solid or solid–gas syntheses are

known to give quantitative yield, and many are easily performed

on the kilogram scale. In some cases, the corresponding solution

chemistry is so difficult as to be practically impossible, for

example formation of a 1 : 1 urea–glucose complex (Fig. 7).50

CO2 has been extensively studied as an environmentally benign

solvent. It is abundant and inexpensive, often obtainable as

a waste material from other processes. Its liquid and supercritical

phases are accessible at mild temperature and pressure, and

sensitivity of some reactions to easily tunable CO2 pressure gives

chemists greater control over reaction rates and selectivity.51 The

first ‘‘green’’ application of supercritical CO2 was replacement of

the toxic solvent dichloromethane in decaffeination of coffee

beans.52 CO2 remains a useful and safe solvent for routine

Fig. 7 Solvent-free formation of a glucose–urea complex is achieved

rapidly on a large scale, replacing a wasteful 6-month crystallization

technique suitable only for milligram quantities.


extractions,53 but has also been developed as a reaction medium

for synthesis of small molecules, polymers, and nanoparticles.

There are numerous examples of homogeneous and heteroge-

neous catalysis carried out in CO2,51 and even biocatalysis is

feasible.54 Catalytic reactions in CO2 can be scaled up to indus-

trially useful processes:55 the University of Nottingham has

collaborated with Thomas Swan & Co. to construct a plant for

conducting reactions on the scale of 100 kg h�1. The first reaction

to be run was hydrogenation of isophorone to trimethylcyclo-

hexanone over a palladium catalyst (Fig. 8).56 The recent

invention of a CO2-based process for synthesizing H2O2 from H2

and O2 is a step toward making the environmentally friendly

oxidant even ‘‘greener’’; it reduces the risk of explosion and

avoids the organic solvent and anthraquinone wastes generated

by the conventional method.57 Progress in designing surfactants

and stabilizers for CO2, particularly for water-in-CO2 micro-

emulsions, will continue to expand the range of chemistry that

can be performed in CO2 to include more ionic and polar

reagents.58

Water, perhaps the most innocuous substance on the planet,

has also attracted much attention as an alternative to organic

solvents, and it can be used for an enormous variety of chemistry

including most types of carbon–carbon bond forming reactions

as well as oxidations and reductions.59–61 Lewis acid catalysis,

which is usually highly sensitive to trace moisture, can be carried

out in aqueous conditions with careful selection of metals and

ligands.62 Even dehydration reactions can be performed in

water.63 In many of these cases, the aqueous chemistry avoids

energy-intensive solvent purification and distillation steps asso-

ciated with conventional solvents. However, the relatively low

volatility of water may increase the energy needed to isolate

products or remove contaminants from solution in some

processes, making it necessary to always consider the overall

environmental impact of the chemistry.

2.3 Green analytical chemistry

One of the twelve principles of green chemistry calls for improved

monitoring of chemical syntheses and processes to prevent waste,

reduce solvent and auxiliaries, and prevent formation of

hazardous side products. This demands technologies that are

real-time, placing limits on opportunities for chemical derivati-

zation or instrument calibration and requiring that the technol-

ogies be adaptable to process equipment. A recent review

discusses progress in the field, covering nanosensors, molecular

recognition, and lab-on-a-chip capabilities that have made it

possible to monitor heat, chemical concentrations, mass, and

optical properties in-process.64 Microreactors (in which reaction

components are manipulated in channels as small as 10 mm in

diameter) are especially well suited for real-time, in-reactor

monitoring because they allow exceptionally precise control of



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reagent concentrations and other reaction conditions in both

time and space.65 For example, using in situ UV/visible or

infrared spectroscopy monitoring, microreactor flow rates can be

adjusted to optimize reaction yields.66

Analytical methodologies themselves should also adhere to the

principles of green chemistry. There is some irony in the fact that

common methods for monitoring pollutants create dangerous

waste streams; the chemical oxygen demand test used in waste-

water analysis usually relies on carcinogenic hexavalent chro-

mium as well as mercury and silver reagents.67 A recent review of

the analytical chemistry literature has found significant

improvements in ‘‘green’’ analytical methods. New techniques

for extraction reduce solvent and energy demands by using

ultrasound, microwaves, or supercritical fluids. Advances in

membrane separations, solid-phase extraction, and flow injection

analysis have reduced the environmental footprint of analytical

techniques.53 Improvements in spectroscopy have made it

possible to use research-grade instrumentation in-process or in

the field. For example, NMR spectroscopy can be used to

monitor flowing material, and low-field NMR techniques have

been developed to unobtrusively measure moisture content, fat

content, or fluorine content in solid materials without any kind

of pretreatment, separation, or purification steps.68 Low-field

NMR can determine the oil content in oilseeds at the rate of

20,000 seeds h�1, an analysis that would ordinarily be achieved

by extraction with hazardous solvents.69 The National

Environmental Methods Database maintained by the US Envi-

ronmental Protection Agency and US Geological Survey (http://

www.nemi.gov) has been updated to include ‘‘greenness’’

information in the method profiles, making it more convenient

for analytical chemists to compare the environmental impacts of

various techniques.53

2.4 Energy impacts

The chemical industry accounts for significant energy

consumption and CO2 emissions.70 In the United States, the

industry typically consumes 25–30% of the total energy used

annually by the entire manufacturing sector, and energy use has

been steadily increasing: in 2002 it was almost 1.5 PJ higher than

1991 (Fig. 9). The two categories of plastics manufacturing and

‘‘other’’ basic organic chemicals— including common monomers

and solvents—represent more than half of the chemical industry

energy use.71 Chemists often have more power over energy effi-

ciency than chemical engineers or process engineers; if a green

chemist devises a synthesis that avoids the need to accelerate

Fig. 9 Annual energy consumption by the U.S. chemical industry, not

including primary metals or coal and petroleum refinining.


a reaction with heat, control reactivity through cooling, or purify

products through distillation, crystallization, or ultrafiltration,

the potential energy savings are enormous.

Alternative techniques like microwave-, sono-, or photo-

assisted chemistry have been applied by green chemists in the last

20 years, taking advantage of advances in technology to not only

save energy but also reduce reaction times, simplify experimental

conditions, and increase the effectiveness of catalysts. In micro-

wave chemistry, it is now possible to use commercial equipment

to control all aspects of microwave heating, greatly improving

safety and reproducibility. Microwaves enable very rapid heating

and cooling, avoiding the need for prolonged residence time at

high temperature.72 Energy savings compared to conventional

heating depends on efficiency in converting electric energy to

microwave energy, as well as the characteristics of the reactor,

the amount of reaction mixture, and the capability of the

reaction components to absorb microwave energy.73 The use of

microwave heating on an industrial scale is in early stages of

research, though so far it is favorable in comparison to

conventional heating; for example, a continuous microwave

reactor has been applied in biodiesel production on the scale of

L min�1.74 Also at the forefront of microwave research is using

microwave energy to support other ‘‘green’’ techniques such as

solvent-free or aqueous chemistry and reactions using recyclable

catalysts and supports.75

Sonochemistry is the use of high frequency (20–100 kHz)

sound waves to promote chemical reactions. The collapse of

bubbles formed in solution by the sound waves results in very

high temperature and pressure, and potentially an order of

magnitude more energy available per molecule than thermal

heating.76 Unlike microwaves, sonochemistry can break chemical

bonds and access novel reaction pathways. Sound waves can also

lead to ‘‘false sonochemistry’’: effects analogous to high-speed

stirring that can also improve the efficiency of chemical reac-

tions.77 There are many examples of industrial-scale reactions

promoted by sonochemistry with increased yields in shorter

amounts of time than conventional heating. It cannot always be

assumed that sonochemistry will save energy, though in some

cases, for example methyl transesterification of triglycerides, it is

an order of magnitude more efficient in terms of mass of product

per energy consumed.78 Other methods of promoting bubble

collapse in solution are potentially far more energy efficient:

hydrodynamic cavitation, in which turbulent flow is used to

create bubbles, also promotes chemical reactions.79 In the same

transesterification study mentioned above, hydrodynamic cavi-

tation was more efficient than conventional heating by a factor

of 1000.

Photochemistry also offers alternatives to thermal processes.

Photons, unlike ordinary activating agents or catalysts, leave no

trace after they are used. In many cases, the molecular trans-

formations achieved would require additional synthetic steps.80

Absorption of photons does not necessarily depend on solvent,

so photochemistry expands the range of possible solid-to-solid

chemical reactions.81 Sunlight—the most abundant source of

energy on the planet—can be used to produce useful chemicals

on the multi-kilogram scale. Using photoreactors in Germany,

researchers have carried out photoacylation and photo-

oxygenations, producing important synthetic intermediates and

commercial fragrances in bulk with minimal consumption of



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fossil energy.82 Another example of the energy savings that can

be realized by harnessing sunlight or artificial UV light is photo-

curable resins: BASF has developed automotive primer coatings

that crosslink readily under light irradiation. The new coatings

obviate the need for energy-intensive bake ovens used to ther-

mally cure conventional primers.37 Because chemically important

UV radiation only accounts for a small percentage of solar

photons reaching the earth’s surface, continuing development of

visible-light-absorbing sensitizers will promote more effective use

of natural sunlight. Mimicry of photosynthesis, using synthetic

systems to collect light and convert the energy into a form that

can power enzymatic reactions, may soon revolutionize the way

energy is generated and used in chemical manufacturing.83

Green chemistry also has much to gain from ‘‘noncovalent

derivatization’’ techniques. Whereas chemists have traditionally

driven reactions through enthalpy—covalent bond-breaking and

bond-making reactions—nature is usually reliant on entropic

processes, with no need for high temperature conditions.

Chemists can manipulate the physical properties of materials like

melting point, solubility, vapor pressure, and diffusivity using

specific noncovalent interactions including hydrogen bonding,

p-stacking, lipophilic–lipophilic interactions, and electrostatic

interactions. While each interaction is low in energy, accumula-

tion of interactions eventually causes a system to reach a ‘‘tipping

point’’ where a dramatic shift from one state to another suddenly

occurs.84,85 Predicting and controlling this process can potentially

eliminate pollution associated with solvents and purification, and

should require only minimal energy input. Noncovalent chem-

istry has been used to control the stability of crystalline

complexes in Polaroid Instant Photography.86

3. Renewable resources

One of the major goals of green chemistry is to produce chemical

feedstocks sustainably, from annually renewable resources

instead of petroleum. Nature produces biomass on the scale of

about 180 billion metric tons year�1, of which only about 4% is

currently utilized by humans. Most (about 75%) is in the form of

carbohydrates, about 20% is lignin, and the remainder includes

fats, proteins, and terpenes.87

Currently, the major nonfood uses of carbohydrates are

production of ethanol, furfural, sweeteners, lactic acid, surfac-

tants, and pharmaceuticals (e.g. penicillin).88 However, routes

are available for converting low-value carbohydrates into a much

wider range of industrially useful products. Simple carbohy-

drates derived from starch, hemicelluloses, and cellulose can be

converted into ‘‘building block’’ compounds via biological or

chemical conversion. The US Department of Energy and Pacific

Northwest National Laboratory have identified 12 of these

intermediate chemicals that could be further exploited to

produce more than 300 small molecules, many of which are

commercially valuable feedstocks currently derived from petro-

leum feedstocks.89 Microbial conversion of glucose and other

monosaccharides to 3-dehydroshikimic acid provides routes to

useful aromatic compounds including vanillin and catechols.90

Lignin, one of the main structural components of plants and

a byproduct of the pulp and paper industry, is nature’s richest

source of aromatic carbon. Since lignin is a high molecular

weight, irregular macromolecule, production of small molecules


containing aromatic rings will require advances in catalysis to

become feasible on a large scale. One principle of Green Engi-

neering is ‘‘conserve complexity’’:91 lignin has natural complexity

that would be extraordinarily time-, material-, and energy-

intensive to reconstruct from smaller molecules. It may be most

productive to seek uses of lignin where its macromolecular

structure is beneficial. According to the US Department of

Energy, this is where the lowest-risk gains are to be made in

lignin research. Macromolecular lignin could be potentially used

to make high-strength, lightweight carbon fibers to replace steel.

Other areas of opportunity include polymer additives, resins,

adhesives, and binders.92 No matter the molecular weight range,

a platform of lignin chemicals will make the abundant natural

material much more valuable than it currently is as a combustible

waste.

Increasingly, natural oils have been used instead of petro-

chemical- or silicon-based feedstocks to develop polymers,

lubricants, surfactants, and emulsifiers. This sustainable oleo-

chemistry currently faces challenges because many vegetable oils

are also in high demand for energy and food uses.93 However, the

increasing popularity of ‘‘second-generation’’ biofuel crops like

Jatropha curcas,94 fuel from cellulosic biomass,95 and production

of oils from cultivation of algae96 are all expected to remedy

supply concerns. Waste oil, like cashew nut shell liquid from the

cashew nut-processing industry, is also a ‘‘green’’ starting mate-

rial. Glycolipids synthesized from the nut shell liquid can be

applied in soft materials, biosensors, liquid crystal displays, and

pharmaceutical delivery.97

Soy and chickens are among the sources of proteins used

productively by green chemists. Soy flour can be chemically

modified to create an adhesive that mimics the water-resistant

natural glue mussels use to attach to rocks. The new soy adhesive

is an alternative to urea–formaldehyde, the binder used in

plywood boards, and has already replaced millions of kg of the

toxic synthetic resin.98 Chicken farms produce waste feathers on

the scale of billons of kg year�1. The feathers, which are more

than 90% keratin, can be carbonized to create strong, lightweight

fibers with properties suitable for electronic circuitry. The

Affordable Composites from Renewable Sources (ACRES)

group at the University of Delaware combines the feather fibers

with soy-based resins to produce biodegradable circuit boards.

The feather–soy composites may also prove to be useful struc-

tural materials for car parts and building construction.99

The use of CO2 as a renewable source of carbon has been

recently reviewed.100 While this application of CO2 as a raw

material is not expected to significantly reduce levels of CO2 in

the atmosphere, the nontoxic, non-flammable gas is still

considered to be an environmentally friendly reagent. So far the

most successful use of CO2 as a feedstock has been in the

formation of carbonates. Dimethyl carbonate is an alternative to

the toxic chemical phosgene, used in polycarbonate and poly-

urethane synthesis.101 Ironically, dimethyl carbonate itself is

ordinarily synthesized from phosgene as well, but new syntheses

are based on CO2.102 Cyclic carbonates, useful feedstocks for

polycarbonate synthesis, can be prepared from epoxides or

directly from alkenes. The synthesis from alkenes has additional

‘‘green’’ characteristics: it is performed in water without use

of metal catalysts.103 The preparation of polycarbonates from

CO2 has been enabled by the invention of highly active



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polymerization catalysts. Among these CO2-based polymers,

poly(cyclohexene carbonate) shows promise as an alternative to

polystyrene.104 CO2 has also been used in cement–fiber

composites. The process consumes waste CO2, uses little energy,

and offers alternatives to construction materials that are

prepared by CO2-emitting processes.105

Commercial plastics are mostly prepared from fossil fuel

feedstocks, accounting for a significant portion (approx. 5%) of

annual petroleum production.106 Increasing pressures on supplies

of fossil fuels, toxicity of commonly used monomers, and poly-

mer persistence in the environment are all concerns that may be

addressed by invention of new polymer materials based on bio-

logical feedstocks. Polysaccharides have been used as a platform

for plastic materials for many decades: chemically modified

cellulose, starches, xanthan, and pullulan are employed in

a variety of applications.107 Chitin is one of the most abundant

biopolymers but also one of the most underutilized; 11 billion

metric tons are generated each year in the biosphere, but the

commercial market is on the order of 5000 metric tons. Chitosan

(deacetylated chitin) and its derivatives have already found

applications as ingredients in cosmetics and personal care

products, adsorbents for wastewater treatment, controlled-

release agents, artificial human tissue, and biodegradable food

packaging.108,109 The ease with which chitin and chitosan struc-

tures can be modified should create many opportunities for

chemists to devise new bio-based polymers with a wide range of

functional groups and mechanical properties.110

Polyester materials like polyhydroxylalkanoates (PHAs) and

poly(lactic acid) (PLA) are at present among the most commer-

cially successful renewable, biodegradable polymers. PHAs have

been commercialized by Metabolix and Archer Daniel Midlands

Co., using genetically engineered microbes to synthesize the

polymer from fermentable raw materials.37 A facility is under

construction that will be capable of producing 50 million kg

year�1 of PHA bioplastic.111 PHA can also be produced by

genetically engineered switchgrass, accounting for nearly to 4%

of the dry weight of the leaves. Thus, as biofuel-from-switchgrass

projects expand, PHAs are poised to become more prevalent.112

Large-scale production of PLA was pioneered by NatureWorks,

now jointly owned by Cargill and Teijin Ltd. of Japan. The

production process has been honored with a Presidential Green

Chemistry Challenge Award for following all Twelve Principles

of Green Chemistry: its avoids organic solvent, uses efficient

catalysis to achieve high yields, and reduces waste through

recycle streams. The process uses up to 50% less petroleum

resources compared to conventional polymers.113 Lactic acid is

conventionally derived from corn sugar but it can also be

obtained by fermentation of cellulosic waste.114 PLA may find

a broader range of applications as progress is made in developing

adequate plasticizers.115 Preparation of biocomposite materials

from PLA and agricultural wastes offers an alternative to non-

degradable, difficult-to-recycle petroleum-based resins.116,117

Optimization of the synthetic pathways to bio-based feed-

stocks and invention of new bio-based materials will reduce our

reliance on depleted petroleum resources and support the

production of fuels by biorefineries. Integrated biorefineries, in

which energy, chemicals, and food processing are combined, will

be crucial to extracting the maximum value from abundant

biomass and meeting the sustainability goals of the next


100 years.118 It has been suggested that biorefineries and

petroleum refineries can operate synergistically as well; with design

of more highly selective catalysts for hydrotreating and catalytic

cracking of bio-based feedstocks to produce alkane, olefin, and

aromatic fuels, existing infrastructure might be used to smooth the

transition to a sustainable economy.119 In the near future, biomass

will only be a partial solution to the challenge of sustainable

energy: a study by the Oak Ridge National Laboratory has noted

that in the United States, for example, renewable sources of

biomass could potentially account for 30% of current petroleum

consumption by 2030. Thus we must rely on other renewable

energy technology as well, ideally solar power.120 However,

biomass is our only non-depleting source of chemical feedstocks.

Invention and application of bio-based materials has advanced

tremendously in the last 20 years, and this will continue to be an

area of research with many opportunities for green chemists.

4. Designing safer chemicals and processes

Increasingly chemists have access to more information about

the chemicals and classes of chemicals that threaten human and

environmental health. It is relatively easy, conceptually, to

eliminate known hazards from a synthesis or process, but it is

much more difficult to be sure that the alternative will be benign.

The future of green chemistry requires that chemists take on

a more proactive role in designing for reduced hazard, to avoid

the kind of cycle that leads to accidental environmental damage,

toxicity surprises, and daunting cleanup problems:

1. A chemist synthesizes a novel chemical.

2. The chemical enters commerce and is dispersed around the

world.

3. Alarms are sounded about persistence, bioaccumulation,

toxicity, etc.

4. Legislation bans or restricts further use; remediation

programs are implemented.

5. A novel chemical is required to replace the previous

offender.

The development and routine implementation of ‘‘green’’

design principles will be crucial in the coming years, as green

chemists grapple with the phenomena of endocrine disruption,

synergism, and non-linear dose-response curves that contradict

the ancient notion that ‘‘the dose makes the poison’’.121,122

Toxicity concerns about the negative effects of ubiquitous

chemicals like organochlorine compounds,123 perfluorooctanoic

acid,124 polybrominated flame retardants,125 phthalate plasti-

cizers,126 and bisphenol A127 ensure that chemists will be pressed

to improve the safety of existing, well-established technologies

and to guarantee that emerging new fields like nanotechnology

are not derailed by safety concerns.11,128 It will be necessary for

chemists to relate molecular structure not only to intended

function, but also unintended behavior: mobility, persistence, and

fate in humans, animals, and the environment. It has been

proposed that design rules should be established based on

(in order of importance):129,130

1. Molecular toxicology that relates structural features to

mechanism of action.

a. Avoidance of toxic chemical classes or functional groups.

b. Structural blocking or relocation of toxic groups.



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2. Quantitative structure-activity relationships (QSARs) that

predict potential hazard when mechanistic data is unavailable.

3. Toxicokinetics and toxicodynamics studies to ensure safe

metabolism.

a. Planned biochemical elimination of toxic groups.

b. Facilitation of excretion.

c. Facilitation of biodegradation.

4. Decreasing bioavailability so that a chemical released into

the environment cannot pass through relevant biological

barriers.

a. Appropriate molecular size.

b. Low volatility.

c. Appropriate water solubility and lipophilicity.

d. Consideration of specific routes of absorption.

DeVito has extensively reviewed many of the design elements

that are part of this framework.131 His valuable compendium of

chemical design information includes:

� A catalog of electrophilic functional groups, the biological

nucleophiles they may react with, and the toxic effects.

� Examples of how molecular toxicology and QSARs have led

to design rules for less hazardous carboxylic acids,

nonylphenols, and other industrially important chemicals.

� Isosteric replacements (groups of atoms that have similar

characteristics but are not necessarily structurally related).

� Examples of design for safe metabolism.

At present, some of the most thoroughly laid-out design rules

for designing safer chemicals are related to biodegradability. If

a chemical does not persist beyond the end of its useful function,

it has reduced chance of exerting toxic effects on humans or

lifeforms we depend on. Small molecule biodegradability has

been recently reviewed by Boethling et al., who outline the

guidelines that can be inferred from structure-degradability

relationships, provide examples related to industrial chemistry,

and survey software and database resources.132 With the excep-

tion of natural polymers and polymers derived from renewable

resources, most high-molecular-weight molecules are extremely

resistant to microbial action. In some cases it may be possible to

impart degradability to conventional petroleum-based polymers

by derivatizing them with degradable functional groups,133

but the problem of persistent plastics remains a significant

challenge.134

Computational methods for exploring the properties of

molecules have become highly sophisticated. In particular, the

refinement of models for drug discovery and protein-small

molecule interactions is creating powerful tools for pharmaceu-

tical research—and potentially green chemists. The ability to

predict the ‘‘druglikeness’’ of molecules allows one to determine

if a molecule has favorable ADME (absorption, distribution,

metabolism, and excretion) characteristics, and gain information

about blood-brain barrier permeability, cell permeability, solu-

bility, and likely metabolites.135 A chemist designing, for

example, plasticizers for use in baby bottles might be able to use

these capabilities to prescreen candidate molecules and reject

structures with high bioavailability. One new tool for screening

potentially hazardous chemicals is ‘‘Shape Signatures’’, an

algorithm that encodes molecular shape and polarity character-

istics into simple, easy-to-compare metrics. Shape Signatures has

been applied to high-quality protein–ligand data contained in the

public Protein Data Bank, allowing chemists to screen molecules


for potential biological receptors.136 The technique has also been

used to identify novel estrogen antagonists based on similarities

to known estrogens or anti-estrogens, showing that it will be

a useful tool for identifying potential endocrine-disrupting

chemicals.137

The growing concerns about pharmaceuticals in the environ-

ment and the animal testing that is being carried out in response

may provide useful design guidelines to green chemists. Many

drug receptors are more highly conserved between mammals

and fish than between mammals and Daphnia or algae.138

Mammalian data from pharmaceutical testing can been applied

to identify drugs that may elicit chronic toxicity in fish.139 It is

also useful to run these studies in the reverse direction: using fish

to screen non-pharmaceutical chemicals for potential bioactivity

in humans. Zebrafish (Danio rerio) in particular have shown

tremendous promise as a way to accurately model human

diseases; zebrafish assays have been used to screen small mole-

cules for bioactivity including pharmaceutical properties or

mutagenicity.140,141 Using fish, Daphnia, algae, and bacterial

testing more routinely, not only in the pharmaceutical industry,

will help avert environmental disasters and build chemists’

knowledge of toxic mechanisms of action.

The future of designing safer chemicals will most likely be

linked to developments in toxicogenomics and other ‘‘omics’’

fields. Toxicogenomics is the study of the effect of a toxin on the

expression of genes on the cell level. The patterns of gene

expression offer ‘‘fingerprints’’ for different kinds of toxicological

responses, allowing chemicals to be classed according to the kind

of biological damage they are capable of. Toxicogenomic infor-

mation can be supplemented by proteomics (patterns of protein

expression) and metabolomics/metabonomics (changes in levels

of metabolites).142 Epigenetics, the study of heritable changes in

gene expression that occur without changes in DNA sequence,

will also contribute to our knowledge of mechanisms of action.143

Together, these fields that lie at the interface of toxicology,

biology, and medicine will generate a corpus of information

about specific hazards that can be linked to specific chemicals.

Elucidating design principles from ‘‘omics’’ data will be chal-

lenging, but might offer the greatest breakthroughs for green

chemists working at the cutting edge.

5. Future challenges and opportunities

The brief history of the field of Green Chemistry is marked with

extraordinary creativity and accomplishments in achieving the

dual goal of merging superior environmental and economic

performance. This has generally been accomplished, as shown

above, through the important tactic of improving a single

important element or characteristic such as toxicity, persistence,

or energy consumption. The powerful reality that is beginning to

be realized and that must be exploited in the future is that the

Principles of Green Chemistry can be approached as a unified

system. Rather than thinking of the principles as isolated

parameters to be optimized separately, one can view the princi-

ples as a cohesive system with mutually reinforcing components.

This approach will be particularly important as we strive to

understand the fundamentals of sustainability. While many of

the current approaches seek to address important elements of

sustainability, e.g., energy, or water, or food, it is important to



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recognize that all of these elements of sustainability are inextri-

cably linked. Therefore, one important strategy will be to address

these interconnected issues at the place where they all intersect:

the molecular level. While no one would argue that this makes

the challenges easy, it does become conceptually more straight-

forward through the principles of Green Chemistry.

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