Green Chemistry

Mass metrics

Most reactions are inherently wasteful because not all the atoms of the reactants can be incorporated into the product (e.g. by-products are formed). Additional waste may occur because the reaction is incomplete, or require additional substances (solvents, catalysts, etc.). Waste is a central theme of Green Chemistry, and often the first step to improving a reaction is to measure the waste. These calculations are known as Green Chemistry metrics or mass metrics.

The basis of a good metric in green chemistry is that it is clearly defined, simple, and it must stimulate informed actions. The following metrics describe material utilisation (and conversely waste) and are best applied to early stage, low volume chemistry. Later, combinations of more advanced measurements that incorporate energy use, environmental impact, hazard assessment, etc. will need to be introduced. This is elegantly organised in the framework designed by McElroy et al. (2015). 

Metrics

Atom Economy is the percentage obtained by dividing the mass of the atoms in the desired product by the mass of the atoms in the reactants (Trost, 1991). It does not factor in whether the reaction is complete or not or if auxiliary substances are required. Yet it remains a useful guide to the inherent wastefulness of a reaction. The optimum Atom Economy is 100%, where all the atoms in the reactants are theoretically incorporated into the product.

The E-factor  (or environmental factor) represents the total mass of waste generated in a process compared to the mass of the desired product(s) (Sheldon, 2017), In an ideal scenario, the E-factor would be zero. However, the pharmaceutical industry relies on complex, multi-step chemistry and it is not uncommon for the E-factor of active pharmaceutical ingredient (API) manufacturing to be comfortably over 100!

GlaxoSmithKline (GSK) pioneered the concept of reaction mass efficiency (RME), which quantifies the efficiency of a reaction by dividing the mass of the product obtained by the total mass of reactants (Jimenez-Gonzalez et al., 2011). RME goes beyond Atom Economy by incorporating the completion of the reaction and if excess reactants were added to account for by-products or decomposition. RME does not include solvents and other auxiliaries like E-factor does.

 The ACS Green Chemistry Institute Pharmaceutical Roundtable has embraced Process Mass Intensity (PMI) as its designated mass metric and has created an online tool to estimate PMI, aiding the design of more environmentally sustainable chemistry. PMI is defined as the total mass of materials required to produce a specified mass of product, encompassing reactants, reagents, solvents used in reaction and purification, and catalysts (Monteith et al., 2020). It should be noted that PMI is equal to E-factor + 1, so only one is necessary to describe a reaction. The ideal PMI equals one, which represents zero waste and all materials integrated into the product.