Green Chemistry Metrics

This chapter provides an overview of green metrics and their historical role in promoting the development of green chemistry. Starting with the history of the field, the Twelve Principles of Green Chemistry are introduced and discussed in conjunction with a “green-by-design” approach recently applied to the synthesis of Lipitor^®. Various perspectives on synthetic efficiency are briefly outlined with reference to atom economy and E factor. These ideas are further explored in the context of three industrial processes which have received Presidential Green Chemistry Challenge Awards. The synthesis of ibuprofen is examined from the point of view of intrinsic efficiency. Using the BHC process as an example, several benefits associated with the use of catalysis are discussed, with an emphasis placed on designing atom-efficient reactions. A global perspective centered around the production of chemical waste is also outlined with reference to Merck’s commercial synthesis of Januvia^®, a medication for the treatment of type II diabetes. Finally, Pfizer’s new sertraline process is used to describe ways of improving both quantitative as well as qualitative aspects of an industrial synthesis. The chapter concludes with a brief outline of the future directions of green metrics.

The green metrics atom economy (AE) and reaction mass efficiency (RME) are introduced and discussed. Following literature definitions, examples of reactions appropriate for upper-level undergraduate students are provided to illustrate how the metrics are calculated. In the case of atom economy, important assumptions regarding reactants, solvents and reagents are identified and explained. Several examples of inherently atom-efficient and inefficient reactions are also provided. In terms of reaction mass efficiency, the focus centers on a concise mathematical breakdown of various factors which contribute to changes in RME values in the context of two well-established definitions. A view of RME as a more robust metric that better captures the materials used during a chemical transformation is developed in the context of an undergraduate Suzuki reaction. With numerous academic and industrial examples comparing traditional syntheses with modern catalytic routes, the benefits and limitations of AE and RME are considered. Along with real-world case studies, the useful and effective application of these metrics is explained using several definitions of an ideal chemical reaction as points of reference. Finally, future projections and academic work are briefly outlined in order to highlight the development of these important metrics.

The environmental (E) factor and process mass intensity (PMI) metrics are introduced and thoroughly analyzed. As indispensable green metrics widely applied throughout the chemical industry, the E factor and PMI are calculated for numerous industrial processes throughout the chapter. A perspective on waste in the context of academic research, industrial synthesis and reactivity within alternative reaction media highlights the importance of material recovery, in particular with regard to reaction solvents. The section on catalysis further expands on the question of waste reduction by considering several important points. Advantages of heterogeneous catalysis which include catalyst recycling and simple product isolation and purification are described. Issues and potential solutions encountered with homogeneous catalysts and potential solutions are also discussed. Finally, the biocatalytic synthesis of pregabalin sheds light on the notions of solvent recovery and water intensity. Limitations of the E factor (which include failure to address the nature of the waste produced) provide for an introduction to process mass intensity. After explaining the simple relationship between PMI and E factor, the chapter turns to the benefits of PMI as a more robust front-end approach for evaluating the material efficiency of a process. This idea is captured by considering the biocatalytic synthesis of Singulair.

Qualitative green metrics such as the laboratory EcoScale, its modified industrial form and other computational tools are discussed. The first half of the chapter provides the reader with an appreciation of point-based categorical analysis as a means of assessing process greenness. Using calculated values for two benzodiazepine preparations, the EcoScale approach is explained in terms of its virtues and limitations. Simplicity and flexibility are highlighted as key advantages which make the EcoScale particularly effective in evaluating the nature of process operations and materials. Discussion then shifts to a recently proposed modified version of the EcoScale which addresses several drawbacks inherent in the original method. Using a newly defined system based on rewards rather than penalties, the modified EcoScale is shown to be effective at assessing industrial processes. The second portion of the chapter discusses two additional qualitative methods which are based on computational analysis. These approaches are the environmental assessment tool for organic syntheses (EATOS) and the radial polygon approach proposed by Andraos. To highlight their illustrative power and comprehensive scope, a recent article comparing four routes to a cyclic carbamate product is considered.

An introduction to the history of life cycle assessment (LCA) is provided as a segue into a more detailed presentation of the guidelines and principles of LCA. The term “life cycle” is defined and illustrated by means of a figure which is used to describe various system boundaries that a typical LCA can evaluate. Discussion then shifts to the four stages of the LCA process identified in the international standards for conducting a life cycle analysis. These principles are connected with the principles of green chemistry in order to highlight common goals related to both fields. The theoretical portion ends with a discussion of the virtues and limitations inherent in the currently accepted methodology. This section covers the notion of “burden shifting” as well as the complexity and arbitrary nature of several components of the LCA process. The use of software packages to simplify LCA is described in the context of an approach developed at GlaxoSmithKline known as Fast Life Cycle Assessment of Synthetic Chemistry (FLASC^TM). The advantages of this software are explored by revisiting the synthesis of 7-aminocephalosporanic acid. The chapter concludes with a novel approach to teaching LCA in the context of green metrics to upper-level undergraduate students.