Green chemistry metrics

Green chemistry metrics are metrics that measure aspects of a chemical process relating to the principles of green chemistry. These metrics serve to quantify the efficiency or environmental performance of chemical processes, and allow changes in performance to be measured. The motivation for using metrics is the expectation that quantifying technical and environmental improvements can make the benefits of new technologies more tangible, perceptible, or understandable. This, in turn, is likely to aid the communication of research and potentially facilitate the wider adoption of green chemistry technologies in industry.

For a non-chemist the most attractive method of quoting the improvement might be a decrease of X unit cost per kilogram of compound Y. This, however, would be an oversimplification—for example, it would not allow a chemist to visualise the improvement made or to understand changes in material toxicity and process hazards. For yield improvements and selectivity increases, simple percentages are suitable, but this simplistic approach may not always be appropriate. For example, when a highly pyrophoric reagent is replaced by a benign one, a numerical value is difficult to assign but the improvement is obvious, if all other factors are similar.^[1]

Numerous metrics have been formulated over time and their suitability discussed at great length. A general problem observed is that the more accurate and universally applicable the metric devised, the more complex and unemployable it becomes. A good metric must be clearly defined, simple, measurable, objective rather than subjective and must ultimately drive the desired behavior.

Effective Mass Yield

Effective mass yield is defined as the percentage of the mass of the desired product relative to the mass of all non-benign materials used in its synthesis. Hudlicky et al. suggests the following equation:

Effective mass yield (%) = mass of products × 100% / mass of non-benign reagents

This metric requires further definition of a benign substance. Hudlicky defines it as “those by-products, reagents or solvents that have no environmental risk associated with them, for example, water, low-concentration saline, dilute ethanol, autoclaved cell mass, etc.”. This definition leaves the metric open to criticism, as nothing is non-benign (which is a subjective term) and the substances listed in the definition have some environmental impact associated with them. The formula also fails to address the level of toxicity associated with a process. Until all toxicology data is available for all chemicals and a term dealing with these levels of “non-benign” reagents is written into the formula the effective mass yield is not the best metric for chemistry.

Carbon efficiency

Carbon efficiency is a simplified formula developed at GlaxoSmithKline (GSK).iv The mathematical representation is shown below:

Carbon efficiency (%) = amount of carbon in product × 100% / total carbon present in reactants

This metric is a good simplification for use in the pharmaceutical industry as it takes into account the stoichiometry of reactants and products. Furthermore, this metric is of interest to the pharmaceutical industry where development of carbon skeletons is key to their work.

Atom economy

Atom economy was designed in a different way to all the other metrics; most of these were designed to measure the improvement that had been made. Barry Trost conversely, designed atom economy as a method by which organic chemists would pursue “greener” chemistry. The simple definition of atom economy is a calculation of how much of the reactants remain in the final product. This is shown below:

For a generic multi-stage reaction:

1. A + B → C
2. C + D → E
3. E + F → G

Atom economy = m.w. of G × 100% / Σ (m.w. A,B,D,F)

The drawback of atom economy is that assumptions have to be made. For example, inorganic reagents (such as potassium carbonate in a Williamson ether synthesis) are ignored as they are not incorporated into the final product. Also, solvents are ignored, as is the stoichiometry of the reagents.

The atom economy calculation is a very simple representation of the “green-ness” of a reaction as it can be carried out without the need for experimental results. However, it is useful as a low atom economy at the design stage of a reaction prior to entering the laboratory can drive a cleaner synthetic strategy to be formulated.

Reaction mass efficiency

Again developed by GSK, the reaction mass efficiency takes into account atom economy, chemical yield and stoichiometry. The formula can take one of the two forms shown below:

From a generic reaction where A + B → C Reaction mass efficiency = molecular weight of product C × yield / m.w. A + (m.w. B × molar ratio B/A)

Or more simply Reaction mass efficiency = mass of product C × 100% / mass of A + mass of B

RME principle is that by the conservation of mass, the total molecular mass of the reactants is the same as the total molecular mass of the products. In an ideal chemical process, the amount of starting materials or reactants equals the amount of all products generated and no atom is wasted. However, in some processes, some of the consumed reactant atoms do not become part of the intended products. This can be a concern for raw materials that have a high cost or due to economic and environmental costs of disposal of the waste.

Like carbon efficiency, this measure shows the “clean-ness” of a reaction but not of a process, for example, neither metric takes into account waste produced. For example, these metrics could present a rearrangement as “very green” but they would fail to address any solvent, work-up and energy issues arising.

Environmental (E) factor

The first general metric for green chemistry remains one of the most flexible and popular ones. Roger A. Sheldon’s E-factor^[2] can be made as complex and thorough or as simple as required. Assumptions on solvent and other factors can be made or a total analysis can be performed.

The E-factor calculation is defined by the ratio of the mass of waste per mass of product:

E-factor = total waste / product

As examples, Sheldon included E-factor analysis of various industries:

It highlights the waste produced in the process as opposed to the reaction, thus helping those who try to fulfil one of the twelve principles of green chemistry to avoid waste production. E-factors ignore recyclable factors such as recycled solvents and re-used catalysts, which obviously increases the accuracy but ignores the energy involved in the recovery (these are often included theoretically by assuming 90% solvent recovery). The main difficulty with E-factors is the need to define system boundaries, for example, which stages of the production or product life-cycle to consider before calculations can be made.

Crucially, this metric is simple to apply industrially, as a production facility can measure how much material enters the site and how much leaves as product and waste, thereby directly giving an accurate global E-factor for the site. Table 1 shows that oil companies produce a lot less waste than pharmaceuticals as a percentage of material processed. This reflects the fact that the profit margins in the oil industry require them to minimise waste and find uses for products which would normally be discarded as waste. By contrast the pharmaceutical sector is more focused on molecule manufacture and quality. The (currently) high profit margins within the sector mean that there is less concern about the comparatively large amounts of waste that are produced (especially considering the volumes used) although it has to be noted that, despite the percentage waste and E-factor being high, the pharmaceutical section produces much lower tonnage of waste than any other sector. This table encouraged a number of large pharmaceutical companies to commence “green” chemistry programs.

By incorporating yield, stoichiometry and solvent usage the E-factor is an excellent metric. Crucially, E-factors can be combined to assess multi-step reactions step by step or in one calculation.

Comparison of metrics

A group of scientists at GSK attempted to compare the metrics currently available, with the goal of designing a metric set suitable for their business. Following lengthy comparisons of different metrics for twenty eight reaction types and comparing simple and complex costings for four different drug molecules, they came up with a number of conclusions. It was suggested that yield is still a very good metric especially for high value added chemistries such as those used in pharmaceutical synthesis, but conceded that yield does not encourage sustainable practices. Atom economy has its uses in conjunction with other metrics but is not suitable as a standalone green chemistry metric. Reaction mass efficiency combines both process and chemistry features and thereby has potential to be used optimally by chemists, process chemists and chemical engineers. The reaction mass efficiency is more likely to encourage sustainable practices as it focuses attention away from the waste and towards the use of materials. However, in terms of measuring the process and ease of use E-factors are the most effective calculation at the current time.

The EcoScale

The EcoScale is a recently developed metric tool^[3] for evaluation of the effectiveness of a synthetic reaction. It is characterized by simplicity and general applicability. Like the yield-based scale, the EcoScale gives a score from 0 to 100, but also takes into account cost, safety, technical set-up, energy and purification aspects. It is obtained by assigning a value of 100 to an ideal reaction 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 on the environment", and then subtracting penalty points for non-ideal conditions. These penalty points take into account both the advantages and disadvantages of specific reagents, set-ups and technologies. By calculating the EcoScale, a quick assessment of the "greenness" of reaction protocols is obtained, and the areas that need further attention are clearly indicated, which finally can drive improvement of reaction conditions.

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