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Physical Organic Chemistry in the 21st Century
A Q1 Progress Report
by Ian H. Williams
In 1997, a collection of twenty personal perspectives from eminent chemists was published in Pure and Applied Chemistry to mark the centenary of physical organic chemistry [1]. This Symposium in Print, entitled Physical Organic Chemistry in the 21st Century (POC21C), was organized by the IUPAC Commission on Physical Organic Chemistry, which was chaired at that time by Tom Tidwell, who contributed a historical prologue in which he suggested Stieglitz’s 1899 proposal of carbocations as reaction intermediates as (unwittingly) having given birth to the discipline. The principal authors were Edward Arnett, Daniel Bellus, Ron Breslow, Fulvio Cacace, Jan Engberts, Marye Anne Fox, Ken Houk, Keith Ingold, Alan Katritzky, Ed Kosower, Meir Lahav, Teruaki Mukaiyama, Oleg Nefedov, George Olah, John Roberts, Jean-Michel Savéant, Helmut Schwarz, Andrew Streitwieser, Frank Westheimer, and Akio Yamamoto. Tidwell noted that, whereas they were not all known as physical organic chemists, yet they had all used the tools of this discipline in their work and were able to comment upon the utility of physical organic chemistry for the practice of other areas of chemistry as well. The theme that ran through all the essays was that the future of the field lay in an interdisciplinary approach, that physical organic chemists would use all the tools available to them, and that they would not be fettered to narrow views.
A quarter of a century later, it is timely to reflect briefly upon what has happened in the intervening 25 years. Is physical organic chemistry still alive? Does it serve a useful purpose any longer? Have the predicted directions for future research been followed? What unexpected developments have there been?
Glossary of Physical Organic Chemistry
2022 sees the publication in Pure and Applied Chemistry of the Glossary of Terms used in Physical Organic Chemistry (IUPAC Recommendations 2021) [2], a major update of the 1994 version and the result of a lengthy project involving a task group, led by Charles Perrin, under the auspices of the IUPAC Subcommittee on Structural and Mechanistic Chemistry. Besides the redrafting and improvement of entries for many existing terms, the updated Glossary contains numerous new entries. Among these are terms relating to biological chemistry (e.g. catalytic antibody, molecular recognition), computational chemistry (e.g. activation strain model, bifurcation, coarctate), materials chemistry (e.g. ionic liquid, nanomaterial, photochromism), supramolecular chemistry (e.g. dendrimer, self-assembly), techniques (dynamic NMR, FRET, high-throughput screening), and fundamental concepts (e.g. frustrated Lewis acid-base pair, halogen bond, organocatalysis). The task group was strongly of the opinion that an up-to-date compendium of terms is an essential tool for use by all chemists and not a superfluous extravagance of interest to a small minority. The introduction to the updated glossary includes a pertinent quote from Lavoisier:
(As it is words that preserve ideas and convey them, it follows that one cannot improve language without improving science, nor improve science without improving language.”) If this observation was true in 1789, it is certainly no less true today: all interdisciplinary endeavours depend upon clear understanding of language and terminology across whatever disciplinary borders are being crossed.
What’s in a name?
During the time of Charlie Perrin’s chairmanship of the Commission on Physical Organic Chemistry, not only did it become a Subcommittee (of IUPAC Division III, Organic and Biomolecular Chemistry), but “physical organic” was replaced by “structural and mechanistic” in its name. Why? Several of the contributors to POC21C had commented to the effect that, as the techniques employed in physical organic chemistry would become generally accepted as the routine way of approaching problems in chemical reactivity, so the need for a special name for a distinct subdiscipline would disappear. The name might be evanescent, but the influence would be transcendent: developments in physical organic chemistry belong to all of chemistry. As structure and mechanism are common themes throughout the whole of chemistry, so the change of name for the Subcommittee was a deliberate move away from being regarded as a (possibly dying) niche area to something of wide and vital significance.
In 2005 the UK Engineering and Physical Sciences Research Council (EPSRC) held a workshop to bring together the academic and industrial chemistry community to discuss the way forward for physical organic chemistry, which was defined as “studies of the dynamics, reactions and interactions of organic molecules and systems leading to quantitative understanding of the interplay between structure, function and reactivity.” This led to a focused funding initiative in the years that followed, but also—indirectly—to the Organic Reaction Mechanisms Group (a special interest group within the Royal Society of Chemistry) confidently renaming itself as the Physical Organic Chemistry Group!
The definition of physical organic chemistry suggested by EPSRC would probably be acceptable to many, except—perhaps—for its inclusion of the word “organic.” Several of the POC21C authors had noted the fruitful application of “physical-organic” techniques to other areas beyond the traditional realm of organic chemistry. Undoubtedly there are reasons why the pioneering kinetic studies of Lapworth, Orton, and Lowry at the start of the 20th century involved investigations of organic rather than inorganic reactions, not least that their observed rates were compatible with the timescales of the experimental techniques they employed. It was entirely natural that Hammett should coin the phrase “physical organic chemistry” and use this as the title of his influential 1940 book, and that Ingold should entitle his 1953 monograph as Structure and Mechanism in Organic Chemistry. However, in 2022 it is much less obvious why the discipline should take its name from the interface of only one of the several possible branches of chemistry.
What’s happened since 1997?
An important function of the Subcommittee on Structural and Mechanistic Chemistry is to maintain the continuity of the biennial International Conference on Physical Organic Chemistry (ICPOC). Covid19 interrupted the regular pattern, but the rescheduled 25th edition of ICPOC is now due to take place in July 2022 in Hiroshima, Japan [3]. Since 1998, plenary lectures at these meetings have covered a very wide range of topics. Biological, computational, materials, and supramolecular chemistry, along with “traditional” physical organic chemistry, have been represented in roughly equal proportions, accounting for over 70% of the lectures, while organometallic mechanisms, radicals, and new techniques have made up most of the balance. Of course, some lecture topics cannot be simply categorised as they are in themselves multidisciplinary: for example, there have been numerous presentations of joint experimental and computational work. Essentially all the topics mentioned by the POC21C contributors have featured during this period.
So what developments were not explicitly foreseen by that group of “seers” in 1997? One notable example is the field of asymmetric organocatalysis (see Figure 1), for which the 2021 Nobel Prize in Chemistry was awarded jointly to Benjamin List and David MacMillan, whose seminal but independent papers were published in 2000 [4,5]. Although some could quibble that this development was merely the application of well-known principles of covalent catalysis, by either nucleophiles or electrophiles (as enunciated 60 years ago by Bender [6] and Jencks [7]) to asymmetric synthesis, many might enviably muse “why didn’t I think of that?” Does it matter that this hugely significant development came from synthetic chemists rather than physical organic chemists? No, of course not! This is an example of the assimilation of ideas and techniques, that were once the preserve of specialists, into “mainstream” organic chemistry and chemistry in general which was indeed foreseen as a welcome consequence of maturity.
Figure 1. Asymmetric organocatalysis of Diels-Alder cycloaddition by a chiral nucleophile.
Whilst reflecting on Nobel Prizes in Chemistry, it may be noted that about half of the awards since 1997 have been made for developments involving advances in structure and mechanism, broadly construed, and which therefore may be considered as falling within the wide scope of physical organic chemistry. Possibly none of these Nobel laureates would describe themselves as a physical organic chemist, but that is irrelevant. However, perhaps more than a few of them might acknowledge that their work was influenced to some extent by consideration of the “dynamics, reactions, and interactions of…molecules and systems leading to quantitative understanding of the interplay between structure, function and reactivity.”
What about any other developments that were not predicted by the POC21C contributors? Any selection is bound to be subjective, but I venture to suggest a couple. First, the realization that many thermal reactions do not behave according to transition-state theory but instead follow non-statistical dynamics [8]. Unexpected results may arise in experiments due to the presence of a specific features on the potential-energy surface governing a chemical reaction. For example, a bifurcation occurring after the transition state has been traversed, or a shallow energy-minimum in which vibrational energy is not equilibrated before a transient intermediate may proceed to alternative products. Computational simulations of reaction dynamics are required to reveal the causes of these effects, which may be found, for example, in gas-phase SN2 reactions and in pericyclic reactions in solution.
My second personal choice is the application of experimental measurements of multiple kinetic isotope effects, in combination with computational modelling and organic synthesis, to characterize the transition-state structure of an enzyme-catalysed reaction, which enables the design and generation of transition-state analogues as effective enzyme inhibitors and successful therapeutic drugs (Figure 3) [9].
Figure 3. Application of kinetic isotope effects (KIEs), computational modeling and organic synthesis in drug design. (Adapted from ref. 9.)
(Adapted from V.L. Schramm, Annu. Rev. Biochem. 80:703–732, 2011)
Textbooks and teaching
One of the 1997 POC21C contributors (Arnett) commented that “the modern sophomore organic chemistry textbook may be regarded as an unqualified triumph of physical organic chemistry!.” [10] By this he meant that most of the current textbooks were organised around the fundamentals of structure and mechanism. This remains the case with today’s generation of textbooks, but with varying degrees of success. For several years I used an excerpt from one modern text as a revision exercise for students to spot the errors in the printed account of the kinetics of nucleophilic substitution reactions! There is a danger that the insights of physical organic chemistry might become assimilated too much within mainstream organic chemistry as to be unrecognisable, and they may then be treated with a lack of rigour and due diligence. Two very different modern textbooks [11,12], which both attempt to build upon a solid foundation of physical organic chemistry, certainly avoid that danger, but the field is now so broad that each is inevitably selective in its range of included topics.
It has often been recognised that physical organic chemistry is not always taught as a distinct component of undergraduate degree courses and that, when it is taught, it is not always done so by specialists. When I was appointed to a lectureship in Bath, over thirty years ago, I was asked to introduce physical organic chemistry into the curriculum. I relished this challenge and thoroughly enjoyed teaching my own idiosyncratic selection of topics to students at all levels. For most of time, I was less concerned that they should remember specific details than that they would have been encouraged to think logically and critically about data and its significance. Earlier in this article, I mentioned the importance of language in science, and reflected on the possible unimportance of the name by which physical organic chemistry is known. In my opinion, the essential characteristic of those who practise the discipline is the willingness and ability to communicate across the language barrier that too often separates different communities within chemistry and its allied subjects. Historically, the divide was between physical chemists and organic chemists, and may have involved more than just jargon and terminology; other, deeper differences were also exposed. Nowadays the challenge remains to use appropriate language to enable quantitative understanding of the interplay between structure, function, and reactivity to be gained in the study of reactions and interactions of molecules and systems, not only in organic chemistry, but also in biological, materials, supramolecular, and other developing branches of chemistry. I hope that the updated Glossary of Physical Organic Chemistry will help many in this endeavour.
A last word
See full text for references
I close with a personal anecdote. A junior colleague, with a background in synthetic organic chemistry, once came to me to discuss some recent research observations. After some time, and with the whiteboard full of structures and diagrams exploring concepts of physical organic chemistry, he turned and exclaimed, “Now this is real science!”
Ian H. Williams <i.h.williams@bath.ac.uk> is Emeritus Professor of Chemistry at the University of Bath, UK. He is Chair of the IUPAC Subcommittee on Structural and Mechanistic Chemistry, an Associate Member of the Organic and Biomolecular Chemistry Division (Div III), and a former editor of Advances in Physical Organic Chemistry. ORCID.org/0000- 0001-9264-0221
Cite: https://doi.org/10.1515/ci-2022-0203
Header img. A post-transition-state bifurcation on a potential-energy surface may give rise to nonstatistical dynamical effects. (Reproduced from A.E. Litovitz, I. Keresztes, B.K. Carpenter, J. Am. Chem. Soc. 130:12085-94, 2008.)
