12 Principles of Green Chemistry
Learn the 12 principles of green chemistry that can make greener chemicals, processes or products. Read commentary on each principle from leading scientists.
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American Chemical Society
It is better to prevent waste than to treat or clean up waste after it has been created.

Contributed by Berkeley W. Cue, Jr., Ph.D., BWC Pharma Consulting, LLC.

In their publication “Green Chemistry, Theory and Practice” in 1998, Anastas and Warner introduced their 12 principles. My view is the first principle, often referred to as the prevention principle, is the most important and the other principles are the “how to’s” to achieve it

An often-used measure of waste is the E-factor, described by Roger Sheldon, which relates the weight of waste coproduced to the weight of the desired product. More recently, the ACS Green Chemistry Institute Pharmaceutical Roundtable (ACS GCIPR) has favored process mass intensity, which expresses a ratio of the weights of all materials (water, organic solvents, raw materials, reagents, process aids) used to the weight of the active drug ingredient (API) produced. This is an important roundtable focus because of the historically large amount of waste coproduced during drug manufacturing—more than 100 kilos per kilo of API in many cases. However, when companies apply green chemistry principles to the design of the API process, dramatic reductions in waste are often achieved, sometimes as much as ten-fold. So, it is important to extend the impressive results achieved by the ACS GCIPR to all parts of the drug industry, especially the biopharma and generic sectors, as well as to other sectors of the chemical enterprise where synthetic chemistry is used to produce their products.

More Resources & Examples:

Process Mass Intensity Tool

2012 PGCCA Winner: Codexis, Inc. and Professor Yi Tang, University of California, Los Angeles “An Efficient Biocatalytic Process to Manufacture Simvastatin”

2002 PGCCA Winner: Pfizer, Inc. “Green Chemistry in the Redesign of the Sertraline Process”

Pharma Strives for Green Goals, Stephen K. Ritter, Chemical & Engineering News, 90(22), May 28, 2012.

Articles Cited:

The E Factor: fifteen years on; R.A. Sheldon; Green Chem. 2007, (9), pp 1273-1283, DOI: 10.1039/B713736M

Using the Right Green Yardstick: Why Process Mass Intensity Is Used in the Pharmaceutical Industry to Drive More Sustainable Processes; Concepcion Jimenez-Gonzalez, Celia S. Ponder, Quirinus B. Broxterman, and Julie B. Manley; Org. Process Res. Dev., 2011, 15 (4), pp 912–917, DOI: 10.1021/op200097d.

Wherever practicable, synthetic methods should be designed to use and generate substances that possess little or no toxicity to human health and the environment.

Contributed by David J. C. Constable, Ph.D., Director, ACS Green Chemistry Institute®

When you think about it, this is a two-part principle divided by the first two words, “wherever practicable.” Saying those two words implies that it may not be practical or possible to avoid using substances that are toxic, and this is, if you will, the get out of jail card most chemists use to try to avoid applying this principle to their work. Let’s face it; chemists use toxic substances all the time because reactive chemicals afford reactions that are kinetically and thermodynamically favorable. And unless—and until—replacement chemicals along with new synthetic protocols are developed, inherently toxic materials will continue to be used. But it’s easier to say that it isn’t practicable and dispense with any thought about the chemical choices that are made.

It’s not that adhering to this principle is particularly difficult to do; it’s more that chemists are disinterested in doing it. For the synthetic organic chemist, effecting a successful chemical transformation in a new way or with a new molecule or in a new order is what matters. I have heard such arguments, as “all the other stuff in the flask is just there to make the transformation possible so it really doesn’t matter,” or “you have to be realistic and focus on the science.” Saying these things implies that the only science that matters is activating a carbon atom to functionalize it, or adding a ligand to a catalyst, etc., etc. This principle is asking chemists to broaden their definition of what constitutes good science.

What many have shown over and over again is that toxicity and the attendant hazard and risk associated with a chemical reaction is directly related to all the other “stuff” in a flask. In fact, the chemistry or chemical transformation in a synthesis generally impacts the overall toxicity profile (and most other measures of sustainability and green) of a product or process the least, except in those cases where we deliberately are producing a molecule that is toxic or biologically active by design. That is certainly the case for many molecules that are synthesized as in the pharmaceutical or agriculture chemical business—the molecules are toxic and/or have other effects on living organisms by design.

The chemicals and materials used in effecting chemical transformations matter and chemists need to pay more attention to the choices they make about what goes into the flask. It’s easy to discount all the other “stuff” and focus all our energy on the synthetic pathway that delivers the desired product. But when we ignore all the other “stuff,” we pay a high price and it’s a price we need to stop paying.

Occasionally, chemists do produce molecules that have toxic or other hazardous effects, and the next principle will have something to say about designing safer molecules.

Chemical products should be designed to preserve efficacy of function while reducing toxicity.

Contributed by Nicholas D. Anastas, Ph.D., U.S. Environmental Protection Agency- New England

Minimizing toxicity, while simultaneously maintaining function and efficacy, may be one of the most challenging aspects of designing safer products and processes. Achieving this goal requires an understanding of not only chemistry but also of the principles of toxicology and environmental science. Highly reactive chemicals are often used by chemists to manufacture products because they are quite valuable at affecting molecular transformations. However, they are also more likely to react with unintended biological targets, human and ecological, resulting in unwanted adverse effects. Without understanding the fundamental structure hazard relationship, even the most skilled molecular magician enters the challenge lacking a complete toolkit.

Mastering the art and science of toxicology requires innovative approaches to chemical characterization that state that hazard is a design flaw and must be addressed at the genesis of molecular design. The intrinsic hazard of elements and molecules is a fundamental chemical property that must be characterized, evaluated and managed as part of a systems-based strategy for chemical design.

Now is the ideal time to develop a comprehensive and cooperative effort between toxicologists and chemists, focused on training the next generation of scientists to design safer chemicals in a truly holistic and trans-disciplinary manner through innovative curricular advancements. The field of toxicology is evolving rapidly, incorporating and applying the advancements made in molecular biology to reveal the mechanisms of toxicity. Elucidation of these pathways serve as the starting point for articulating design rules that are required by chemists to guide their choices in a quest to make safer chemicals. We are at the dawn of a new sunrise, poised to illuminate the path forward to a safer, healthier and more sustainable world.

More Resources and Examples

Anastas, N. Green Toxicology, 2012 in: Green Techniques for Organic Synthesis and Medicinal Chemistry, W. Zhang and B. Cue, eds., J Wiley.

Anastas, N.D. and J.C. Warner. 2005. Incorporating Hazard Reduction as a Design Criterion in Green Chemistry, Chem. Health. Safety, March/April, 3-15.

Green Chemistry Metrics: Measuring and Monitoring Sustainable Processes, 2009, A. Lapkin and D. Constable eds., J. Wiley.

Green Chemistry Education: Changing the Course of Chemistry, 2009, ACS Symposium Series 1011, P.T. Anastas, I. Levy and K.E. Parent, eds. J. Wiley

Designing Safer Chemicals, 1996, S. DeVito and R. Garrett eds., ACS Symposium Series 640.

US EPA, 2013, http://epa.gov/ncct/Tox21/ (accessed 3/3/13)

Disclaimer:

Although these references are given to provide additional information that may be useful or interesting, EPA is not responsible for, and cannot attest to the accuracy of, the content of these articles.

The use of auxiliary substances (e.g., solvents, separation agents, etc.) should be made unnecessary wherever possible and, innocuous when used.

Dr. Concepcíon (Conchita) Jiménez-González, Director, Operational Sustainability, GlaxoSmithKline

It was a green chemistry conference and the very famous synthetic chemist had just received a question about why he had chosen a solvent that was without question a very poor choice. You have to be realistic, chemists know intuitively what's best, and solvents don't matter. It's the chemistry that counts. I've heard this kind of remark repeatedly over many years, despite the fact that it goes against the spirit and letter of Principle 5.

Solvents and mass separation agents of all kinds matter a lot to the chemistry not to mention the chemical process and the overall "greenness" of the reaction. In many cases, reactions wouldn't proceed without solvents and/or mass separation agents. To say that they don't matter, or that it's only the chemistry that counts is not just a logical fallacy, it's chemically incorrect. Solvents and separation agents provide for mass and energy transfer and without this, many reactions will not proceed.

It has also been shown that solvents account for 50 – 80 percent of the mass in a standard batch chemical operation, depending on whether you include water or you don't. Moreover, solvents account for about 75% of the cumulative life cycle environmental impacts of a standard batch chemical operation.

Solvents and mass separation agents also drive most of the energy consumption in a process. Think about it for a moment. Solvents are alternately heated, distilled, cooled, pumped, mixed, distilled under vacuum, filtered, etc. And that's before they may or may not be recycled. If they're not recycled, they are often incinerated.

Solvents are also the major contributors to the overall toxicity profile and because of that, compose the majority of the materials of concern associated with a process. On average, they contribute the greatest concern for process safety issues because they are flammable and volatile, or under the right conditions, explosive. They also generally drive workers to don personal protective equipment of one kind or another.

We will always need solvents, and with many things in chemical processes, it's a matter of impact trading. Optimize a solvent according to one green metric and many times, there are three others that don't look so good. The object is to choose solvents that make sense chemically, reduce the energy requirements, have the least toxicity, have the fewest life cycle environmental impacts and don't have major safety impacts.

Solvents and separation agents do matter and despite one or more famous synthetic organic chemists may think. It is possible to make better choices, and that is what application of this principle should promote.

Energy requirements should be recognized for their environmental and economic impacts and should be minimized. Synthetic methods should be conducted at ambient temperature and pressure.

By Dr. David Constable, Director, ACS Green Chemistry Institute®

In recent years I've begun to talk about the green chemistry and engineering's "forgotten principles," and Design for Energy Efficiency is one of them. Amongst synthetic organic chemists, no consideration is given to temperature or pressure. The chemist just follows a protocol to get a reaction to go to completion and to separate the desired product at as high a yield as possible. Energy, from the chemist’s perspective, is irrelevant and for all intents and purposes, free. Just put the plug in the wall or the heating coil around the flask, or get the liquid nitrogen out of the dewar.

For those that do think about energy, most if not all the attention that energy gets from chemists is devoted to heating, cooling, separations, electrochemistry, pumping and reluctantly, to calculations related to thermodynamics (e.g., Gibbs Free Energy). The attention is not in minimizing or considering where energy comes from or if it matters what form is used, it's just a given that we need to heat or cool or shove electrons into the reaction to make or break bonds. In reflecting on my own training as a chemist, I never was asked to convert any heating, cooling, pumping or electrochemical requirements to a cost for electricity, steam or some other utility. That may be done in chemical engineering, but not in chemistry.

Energy is a key issue for the 21st century. A majority of the energy that is produced is based, and will continue to be based on fossil fuels. And most of the energy that is delivered to the point of use is lost in conversion and transmission. What this means is that if you look at the life cycle of energy production, and you look at how much energy is actually available for useful work at the point of need, it is less than 1 or 2 percent of the energy that was originally available in the fossil fuel. It is also true that most fossil fuel energy is used for transportation services of one kind or another and the second biggest use is in space heating and cooling. There are a tremendous number of opportunities for chemists to change this energy use profile, but it is my experience that very few chemists see themselves as being a part of either transportation or the built environment.

If you think about where most chemists are trained around energy, and certainly chemical engineers are, it's around ∆H in the Gibbs Free Energy equation. Heats of formation, heats of vaporization, enthalpy, exothermic reactions, etc; these are what we think about. The interesting thing is that nature largely works with ∆S and weak forces of interaction. You don’t see a tree doing photosynthesis at reflux using a solvent, or a cell membrane is not extruded at the melt temperature of something like polystyrene.

There is so much more to energy and engaging chemists in thinking about energy than asking them to run reactions at ambient temperature and pressure. Reactions themselves are rarely where a majority of energy is used; most is used in solvent removal to set up for the next reaction, or to remove one solvent and replace it with another, or to isolate the desired product, or to remove impurities. Apart from hydrogenations or reactions that are oxygen or moisture sensitive, most reactions are done at atmospheric pressure. This doesn't mean that energy isn't important, it is just important in areas where most chemists are not focused.

Once again, thinking about more than one part of the reaction or the process during the design of a new molecule is critical not only from the standpoint of energy, but also from many different angles. Energy—like thinking about how to arrange a synthesis to have the fewest number of steps, or use the lowest cost starting materials or any other aspect of interest to the synthetic or process chemist—is just another design parameter. Historically it has not been seen as that, but we can no longer afford to design new molecules in the absence of a detailed and extended consideration of how energy will be used.

A raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable.

By Dr. Richard Wool, Professor of Chemical and Biomolecular Engineering and Director of the Affordable Composites from Renewable Materials program, University of Delaware.

The concept of making all our future fuels, chemicals and materials from feedstocks that never deplete is an interesting concept which at first glance seems impracticable. Mankind currently removes fossil fuels, coal, oil and natural gas from the ground and extracts minerals for profit until they are exhausted. In particular, our fossil fuels for carbon-based chemicals and materials are being rapidly depleted in a predictable manner with the expected rise of global populations and expanding energy intensive economies on several continents. The impacts on human health and the environment are significant and present major challenges for our scientists and leaders in the next 50 years.

Can we address these global problems by using Green Chemistry Principal #7? Yes, we will get our feedstock, as if by magic, from “thin air” and it will be renewable. The carbon in the air is in the form of carbon dioxide CO2 and methane CH4 and is removed by photosynthetic processes powered by the sun to form plants, trees, crops, algae, etc., which collectively we call “biomass”.

Nature produces about 170 billion tons of plant biomass annually, of which we currently use about 3.5 percent for human needs. It is estimated that about 40 billion tons of biomass, or about 25 percent of the annual production, would be required to completely generate a bio-based economy. The technical challenge in the use of such renewable feedstocks is to develop low energy, non-toxic pathways to convert the biomass to 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 Principal #7, all carbon footprints by design should be positive such that C(in) >> C(out). This leads in a natural way to the reduction of global warming gasses impacting our current climate change. We should also insure that the new chemicals and materials derived from renewable resources are non-toxic or injurious to human health and the biosphere.

In 2002, the U.S. Department of Energy in their Vision for Bioenergy and Bio-based Products in the United States stated:

“By 2030, a well-established, economically viable, bioenergy, and bio-based products industry is expected to create new economic opportunities for rural America [globalization through localization], protect and enhance the environment, strengthen the U.S. energy independence, provide economic security, and deliver improved products to consumers.”

In the past 10 years, significant advances have been made in the development of fuels, chemicals and materials from renewable feedstocks. These for example, have included biodiesel from plant oils and algae, bioethanol and butanol from sugars and lignocellulose, plastics, foams and thermosets from lignin and plant oils, and even electronic materials from chicken feathers. In terms of Green Chemistry Principal #7, our future is bright and laced with optimism due to the ongoing fruitful collaborations between several disciplines involving biotechnology, agronomy, toxicology, physics, engineering and others, where new fuels, chemicals and materials are being derived from renewable feedstock from “thin air” with minimal impact on human health and the environment.

Additional Resource

Vision for Bioenergy and Biobased Products in the United States - Updated 2006

Unfortunately, hydrogen does not react with ketones to any extent under normal conditions. For this, we need a catalyst such as palladium-on-charcoal. A catalyst is defined as “a substance that changes the velocity of a reaction without itself being changed in the process”. It lowers the activation energy of the reaction but in so doing it is not consumed. This means that in principle at least, it can be used in small amounts and be recycled indefinitely, that is it doesn’t generate any waste. Moreover, molecular hydrogen is also the least expensive reductant and, for this reason, catalytic hydrogenations are widely applied in the petrochemical industry, where the use of other reductants is generally not economically viable. It is only in the last two decades, however, following the emergence of green chemistry, that catalysis has been widely applied in the pharmaceutical and fine chemical industries, with the goal of minimizing the enormous amounts of waste generated by the use of stoichiometric inorganic reagents. This involves the use of the full breadth of catalysis: heterogeneous, homogeneous, organocatalysts and, more recently, Nature’s own exquisite catalysts: enzymes. The latter are particularly effective at catalyzing highly selective processes with complex substrates under mild conditions and, hence, are finding broad applications in the pharmaceutical and allied industries. Moreover, they are expected to play an important role in the transition from a chemical industry based on non-renewable fossil resources to a more sustainable bio-based economy utilizing renewable biomass as the raw material, yet another noble goal of green chemistry.

More Resources and Examples

R.A. Sheldon, I. Arends and U. Hanefeld, Green Chemistry and Catalysis, Wiley-VCH, Weinheim, 2007 (ISBN 978-3-527-30715-9)

R.A. Sheldon, Fundamentals of green chemistry: efficiency in reaction design, Chem. Soc. Rev. 41 (2012) 1437-1451.

R.A. Sheldon, E Factors, green chemistry and catalysis: An odyssey Chem. Commun. (2008) 3352-3365.

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.

Contributed by Rich Williams, Founder and President at Environmental Science & Green Chemistry Consulting, LLC

Green chemistry practitioners aspire to optimize the commercial function of a chemical while minimizing its hazard and risk. Hazard, the capability to cause harm, is an inherent characteristic arising, like function, from a chemical’s stereochemistry (the content and arrangement of atoms). Green chemistry principles 3, 4, 5, and 12 guide designers to reduce the hazards of chemicals. Principle 10, however, guides the design of products that degrade after their commercial function in order to reduce risk or the probability of harm occurring. Risk is a function of both a molecule’s inherent hazard AND exposure – contact between a chemical and a species. Degradation can eliminate significant exposure, thereby minimizing risk regardless of the hazard of the chemical involved.

Exposure to persistent chemicals can be significant as a result of global dispersion enabled by properties such as volatility or sorption to particles and partitioning into organisms based on properties such as fat solubility. Regulators have established criteria (half-lives in water, soil, air) that define persistence within frameworks used to identify chemicals as PBT (Persistent, Bioaccumulative, Toxic).

A green chemistry objective is to design out molecular features responsible for hazardous characteristics and risk. Trade-offs, or alternative approaches, must be evaluated when the molecular features to be designed in for commercial function overlap with those to be designed out to reduce hazard and risk.

Biodegradation, hydrolysis, and photolysis can be designed into chemical products. In the same way that mechanistic toxicology knowledge is essential to identify and design out molecular features that are the basis for hazards, an understanding of the mechanisms of degradation and persistence are required to design in chemical features that promote degradation and eliminate features that promote persistence. Many persistent compounds are extensively chlorinated. Halogens such as chlorine are electron withdrawing, thereby inhibiting the enzyme systems of microbes because aerobic microbial degradation favors electron rich structures.

Prediction methods that can guide the design of molecular architecture expected to degrade include rules of thumb linking structural features to degradability or persistence, databases of existing knowledge, models that evaluate biodegradability or PBT attributes, and experimental testing. All of these tools can be adapted to individual chemical sectors and specific objectives.

Understanding the anticipated release and transport pathways for a chemical informs the selection of an effective design strategy. Degradation must occur within the relevant environmental compartment(s) and at a meaningful rate. Domestic wastewater typically passes through a vigorous bioreactor within wastewater treatment plants (WWTP). The consumer product industry has designed molecules for removal within these bioreactors. In the early 1960’s, industry transitioned from non-biodegradable branched surfactants, which caused extensive foaming and other health problems in surface waters receiving WWTP effluent, to biodegradable linear alkyl benzene sulfonate based detergents – an approach to innovative design that continues today.

Tools currently exist to enable the implementation of principle 10, but advances in mechanistic understandings linking molecular features to hazards and degradability will enable more comprehensive application of green chemistry to control hazard and risk. Effective communication across disciplines is also essential to provide designers with knowledge they can factor into the complexities of product design. Because of regulatory and business constraints, many product design decisions must be made relatively early. Predictive decision-making tools must provide confidence about hazard and risk in a way that is aligned with the timing and magnitude of development decisions, and most importantly, while there is still flexibility to alter a molecular design or product formulation.