Essays 1 DOI: 10.1002/ijch.201800016 2 3 4 Complex Organic Synthesis: Structure, Properties, and/or 5 Function? 6 7 [a] 8 George M. Whitesides 9 10 In 1956 – the year R. B. Woodward’s famous Perspective[1] addition to performing research, university research groups 11 was published – I was a senior in high school. The next year, have the important obligation to teach students what they need 12 when I started college and joined a research group, it was still to know for their intended careers. Is the training that students 13 all the (I thought, hopefully and in anticipation, “we”) organic currently receive in organic synthesis the one that best 14 chemistry graduate students talked about. The vision was so prepares them for their future (and which may possibly be 15 astonishing, and the ambition so grand, that it was transfixing. entirely different than their research director’s past)? 16 It clearly marked the transformation of the field of synthesis 17 from one state into something entirely different – one marked 18 by disciplined, elegant, complexity. I never actually met “Organic Synthesis:” What Is It? 19 Woodward (other than secondarily, through one of his 20 postdocs, to let me know of his intense displeasure at my use The phrase “Organic Synthesis” is a complicated one, and 21 of his IR spectrometers in the middle of the night), but I did means different things to different people. It is always risky, 22 go to Woodward group seminars, where I learned humility, as semantically, to use a single phrase to describe many different 23 well as new definitions of “endurance” and bladder control things. Arguably, the phrase “organic synthesis” is an umbrella 24 (these seminars were – or seemed – very, very long to that includes an enormous range of activities: the marvelously 25 someone who understood very little of what was going on). optimized processes used in production of fuels and commod- 26 Still, it was impossible for me not to share the feeling of the ity polyolefin film, the generation of monoclonal antibodies 27 birth of a new field. and of C60, the synthesis of palytoxin, the manufacture of 28 I did not become a “synthetic organic chemist,” but almost Simvastatin, the synthesis of the liquid crystals used in 29 all the research that my colleagues and I have done (and do) displays, and the many, many other types of organic 30 involves organic synthesis. The ability to put together compounds produced synthetically. It is all “organic synthesis? 31 molecules – bit-by-bit, simple or complex – is one of Using a single phrase for everything risks ambiguity. For 32 chemistry’s great accomplishments, and a source of amaze- specificity in this Perspective, I propose to use a particular 33 ment to those in many other fields of science. More than one nomenclature: I will call the broad activity of synthesizing 34 physicist has told me that s/he cannot believe that it is possible organic compounds at all scales, of all structural complexities, 35 to manipulate bonds between individual atoms with the skill and by any methods – that is, without limit on target or 36 that organic chemists do. When I look at a complex structure method: the putting together of molecules – “organic syn- 37 assembled in a beautifully organized campaign, I also am thesis,” and will specify the particular sub-activity of putting 38 amazed. That said, all fields of science morph with time. The together complex structures – often (at least historically), 39 phrase “organic synthesis” has come to mean “synthesis of natural products, in the style defined by Woodward, Barton, 40 structurally complex natural products”, or, perhaps, “synthesis Eschenmoser, Stork, and others – as “Organic Synthesis.” 41 of complicated molecules with pharmaceutical activity.” I suggest that it is appropriate – in light of the indisputable 42 Nature, and relevance to healthcare, define the targets, and past successes of the field described by the phrase “Organic 43 provide the utilitarian justification for the effort.[2] Is there (or Synthesis” – to raise three questions about its future. i) Is the 44 should there be) more to it than that? particular skill of synthesizing complex molecular structures a 45 Will this style of organic synthesis – a style that science (in the sense that it generates new concepts and new 46 emphasizes technical proficiency and complexity rather than theory), an art (albeit one with an underlying aesthetic 47 simplicity, breadth, and utility – persist? Natural products, and structure easily – but sometimes only – perceptible to experts, 48 selected, specific types of transformations, provide endless without regard to generality or utility?), or a craft (requiring 49 technically interesting problems – in structure, in synthetic great skill, but relying more on empirical expertise than on 50 design, in development of reagents – but does their solution theory)? Fields of science tend to move toward “theory” as 51 justify the effort that goes into them? Are there other types of they mature. ii) Is Organic Synthesis better described as an 52 problems that need the skills of experts in synthesis, and other invaluable enabling technology (making possible the synthesis 53 types of opportunity than those that have historically been [3] 54 most exhaustively studied? [a] G. M. Whitesides 55 Aside from the technical focus, there is another issue. Department of Chemistry and Chemical Biology 56 Much of complex organic synthesis goes on in universities. In Harvard University Isr. J. Chem. 2018, 58, 142 –150 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 142 Essays 1 of new drugs and specialty chemicals), or as an intellectual practical applications, and jobs for chemists and chemical 2 structure within which to ask questions about the nature of engineers. 3 molecular structure, the synthetic methods and designs needed The situation has now changed. One can argue (or at least 4 to build them, and the purposes they can serve? iii) Should many skilled synthetic chemists have told me) that almost any 5 students understand all of it (or as much of it as humanly natural product can be synthesized, given enough time and 6 possible, since it encompasses an immense amount of effort. Both the pharmaceutical industry and NIH – at least 7 empirical information), or just parts of what is now known, those parts that focused on oncology–have shifted their focus 8 combined with ideas from other fields? Is “all of it” as from cytotoxic agents (where synthetic chemistry had a very 9 presently practiced enough, or is there more – and different – important role to play) to biopharmaceuticals (which are 10 that they should (or perhaps, must) know for the future? predominately proteins). At the other end of the scale (in 11 The answers to these kinds of questions are never clear- terms of quantities required), the commodity and fine- 12 cut, but important to the future of one of the most remarkable chemical industries – with a few exceptions – turned away 13 skills in science. The characteristics of scientists and engineers from new classes of products and from research (although they 14 who are working on different parts of the synthetic spectrum retained some interest in new processes). The resulting decline 15 are often quite specialized and almost non-overlapping. in innovation has been justified (or dictated) both by financial 16 Complex Organic Synthesis has a large element of empiricism constraints and market opportunities. Companies that retained 17 and pattern recognition, and experimental precedent is more a strong interest in technical discovery (for example, DuPont) 18 important than theory: the details count! In designing large- were unable to demonstrate that “Research and Development” 19 scale industrial production facilities, both the product and the was an investment (reflected in revenues and profits) rather 20 pathway to it are often already known, but the quantitative than simply an expense. 21 engineering detail is critical. In materials science, the design Structure, Properties, or Function? Throughout this 22 and production of a new photoresist (for example) requires productive period, if one were to ask a synthetic chemist what 23 knowledge of synthesis (including methods often not consid- she or he did, the answer would usually have been some form 24 ered or included in Organic Synthesis), a deep understanding of “I make molecules.” That is, the intellectual emphasis was 25 of mechanism, and an acute appreciation of the complex on molecular structure. In large-scale industrial chemistry, of 26 technical needs of those using the composition to prepare course, properties (adhesion strength, corrosion resistance, 27 microchips. Although all are different – in fact, so different as tensile modulus) were often practically more important than 28 to be almost unrecognizable as parts of the same field – all structure. But for both, “function” – the ability of the 29 involve the formation of bonds between atoms in molecules, molecules to do something – was largely left to others. A key 30 the designs of synthetic processes, and the execution of question for the future of synthesis will be “is the target of the 31 complex operations. synthetic program a structure, a material with properties, or a 32 The style and scope of modern organic synthesis stems solution to a problem in function?” If “function” is the 33 from World War II, which had four lasting influences on objective, then the simplest (or perhaps simply least expen- 34 organic synthesis. i) The first was the ability to carry out very sive) synthesis – not the most elegantly complicated – that 35 large-scale conversions of petroleum to fuels. These conver- provides this function will be the best. It is not what 36 sions also produced a wide range of other molecules that Woodward had in mind.