Science as a messy human endeavor: The origin of the Woodward-Hoffmann rules

A 1973 slide from Roald Hoffmann displaying the 'Woodward
Challenge' - four mysterious reactions which spurred the
Woodward-Hoffmann rules

There is a remarkable and unique article written by my friend and noted historian of chemistry Jeff Seeman that has just come out in the Journal of Organic Chemistry. The paper deals with seven pivotal months in 1964 when Robert Burns Woodward and Roald Hoffmann worked out the basic structure of what we call the Woodward-Hoffmann rules. 

Organic chemists need no introduction to these seminal rules, but for non-chemists it might suffice to say that they opened the door to an entire world of key chemical reactions - both in nature and in the chemist's test tube - whose essential details had hitherto stayed mysterious. These details include the probability of such reactions occurring in the first place and the stereochemistry (geometric disposition) of their molecular constituents. The rules were probably the first significant meld between theoretical and organic chemistry - ten commandments carried down from a mountain by Woodward and Hoffmann, pointing to the discovery of the promised land.The recognition of their importance was relatively quick; In 1980 Hoffmann shared a Nobel Prize for his contributions, and Woodward would have shared it too (it would have been his second) had he not suddenly passed away in 1979.

The first paper on these rules was submitted in November, 1964 and it came out in January, 1965. Jeff's piece essentially traces the conception of the rules in the previous six months or so. The article is very valuable for the light it sheds not just on the human aspect of scientific discovery but on its meandering, haphazard nature. It is one of the best testaments to science as a process of fits and starts that I have recently seen. Even from a strictly historical perspective Jeff's article is wholly unique. He had unprecedented access to Hoffmann in the form of daylong interviews at Cornell as well as unfettered access to Hoffmann's office. He has also interviewed many other important historical figures such as Andrew Streitweiser, George Whitesides and Jack Roberts who were working in physical organic chemistry at the time: insightful and amusing quotes from all these people (such as Whitesides's reference to the demise of a computer at MIT implying that he would now have to perform calculations using an abacus or his toes) litter the account. And there are copious and fascinating images of scores of notebook pages from Hoffmann's research as well as amusing and interesting letters to editors, lists of publications, scribblings in margins and other correspondence between friends and colleagues. Anyone who knows Jeff and has worked with him will be nodding their heads when they see how thorough the job here is.

The story begins when Woodward was already the world's most acclaimed organic chemist and Hoffmann was an upcoming theoretical chemistry postdoc at Harvard. Then as now, Hoffmann was the quintessential fox whose interests knew no bounds and who was eager to apply theoretical knowledge to almost any problem in chemistry that suited his interests. By then he had already developed Extended Hückel Theory (EHT), a method for calculating energies and orbitals of molecules which was the poster child for a model: imprecise, inaccurate, semiquantitative and yet pitched at the right level so that it could explain a variety of facts in chemistry. Woodward had already been interested in theory for a while and had worked on some theoretical constructs like the octant rule. It was a marriage made in heaven.

The most striking thing that emerges from Jeff's exhaustive and meticulous work is how relatively laid back Woodward and Hoffmann's research was in a sense. Hoffmann became aware of what was called the 'Woodward challenge' early in 1964 during an important meeting; this challenge involved the then mysterious stereochemical disposition during some well-known four and six electron reactions, reactions whose jargon ("electrocyclization", conrotatory") has now turned into household banter for organic chemists. The conventional story would then have had both Woodward and Hoffmann burning the midnight oil and persisting doggedly for the next few months until they cracked the puzzle like warriors on a quest. This was far from the case. Both pursued other interests, often ended up traveling and only occasionally touching base. Why they did this is unclear, but then it's no more unclear than why humans do anything else for that matter. Once they realized that could crack the puzzle however they kicked the door open. The paper that emerged in early 1965 was so long and comprehensive that they worried about its suitability for JACS in a cover letter to the editor.

Jeff's story also touches on a tantalizing conundrum whose solution many readers would have loved to know - E. J. Corey's potential role or the lack thereof in the conception of the rules, a role Corey unambiguously acknowledged in his 2004 Priestley Medal address, setting off a firestorm. Unfortunately Corey declined to talk to Jeff about this article (although he does dispute the timing of Woodward and Hoffmann's first meeting). His side of the story may never be known.

There is a lot of good stuff in the 45-page article that is worth reading about which I can only mention in passing here. Many of the actual mechanistic and technical details would be of interest only to organic chemists. But the more general message should not be lost upon more general readers: science is a messy, almost always unheroic, haphazard process. In addition, its real story is often warped by malleable memory, shifting egos, mundane oversights and blind alleys. For a long time science was described in bestselling books and newspaper articles as a determined, heroic march to the truth. These days there is an increasing number of books aimed at uncovering science's massive storehouses of failure and ignorance. But there is a third view of science - that of a journey to the truth which is more mundane, more complex, perpetually puzzling because of its mystery and perpetually comforting because of its human nature.

In this case even Jeff's exhaustive research leaves us with kaleidoscopic questions, questions that may likely remain unanswered. These pertain to Woodward and Hoffmann's occasional indifference to what was clearly a pivotal piece of research, to Corey's claim about the reactions, to the potential cross-fertilization between whatever else Woodward and Hoffmann were doing during this time and the project in question, and to the number of insights they might have imbibed from the community at large. Jeff conjectures answers to these questions, but even his probing mind provides no comforting conclusions, probably because there are none. The quote from Roald Hoffmann with which the piece ends captures the humanity quite well.

"Life is messy. Science is not all straight logic. And all scientists are not always logical. We're just scrabbler for knowledge and understanding."

Here's to the messy scrabblers.

R B Woodward lives!: ACS Day 2

What kind of a man was Robert Burns Woodward? As a student of his says, "He was a genius. Period. If he walked into the lab and asked for your arm, you would ask, "Which one?"

So much has been said about this legend that not much can be added. But it's worth pondering his contributions. Woodward fine-honed the science of organic chemistry into a precisely rational science and we all stand on his shoulders. Whether it was structure, spectroscopy, or of course, synthesis, his contributions were unmatched. He made molecules whose construction then defied imagination, and even now challenges some of the finest minds in science. And his larger-than-life personality generated a windfall of anecdotes. His obsession with the color blue (with his tie, his office ceiling and his parking space all painted blue), his famous Thursday evening seminars which lasted into the long hours of the night, his heavy drinking which accompanied even his talks, and the talks themselves- those four hour works of art where he filled up long blackboards with exquisitely drawn, multicolor chalk structures- all are the stuff of legend. The man towered above everyone else, even by Harvard standards.

Much of this appreciation was captured by the Robert Burns Woodward symposium organized by the ACS on Monday. It was hard to miss the survivors of a heroic age of organic chemistry sitting in the front row- Jack Roberts, Sam Danishefsky, Jerry Meinwald, Ken Houk, Bill Lipscomb and of course, Roald Hoffmann. People who were looking for historical tidbits found some rare treats. For instance, there was a long video of Woodward describing the synthesis of Vitamin B12 playing outside the room. In addition, Jeff Seeman who is an acclaimed historian of chemistry managed to procure a rather singular video of Woodward (appropriately holding a glass of scotch) being carried on stage for a department function in a sedan chair hoisted on two long wooden beams, like a Pharaoh.



The chair itself was on display next to the stage. In the video, a hirsute graduate student with an unkempt beard is one of the chair-bearers. That hirsute student was Stuart Schreiber, now completely devoid of his former looks, a clean-shaven, balder than bald, world-famous scientist, dressed in his characteristic turtle-neck and sports jacket. The man was mobbed after his talk and asked to pose for photos. I am sure he hates the burden of fame.

The morning began with an endearing introduction by Hoffmann about his former mentor. He described Woodward as a "patterner of chaos" who made organic chemistry intelligible to everyone else. Then there were some fairly technical talks by Yoshito Kishi (mainly) about Cr and Ni-mediated couplings and by Tom Hoye about how Woodward influenced some of his own ideas. There were many memories of Woodward in these talks; how discussions with him used to consist of long periods of silence periodically interrupted by pencil tapping, how his attention to detail was evident in the way he used to compare IR spectra of synthetic and natural material with a pencil and magnifying glass, and how he could hold his alcohol better than anyone else.

This was followed by a lively talk by Robert Williams (Colorado State) who described the recent controversy (albeit one now laid to rest) about Gilbert Stork and the Woodward-Doering-Rabe-Kindler total synthesis of quinine. He talked essentially about Jeff Seeman's marvelous ACIE article and his own follow-up work. As Williams noted, a postdoc named Aaron Smith brought up Seeman's article in a group meeting. Williams said he was "amazed" that nobody had attempted the final conversion of quinotoxine to quinine- the last step of quinine synthesis which Rabe and Kindler were supposed to have performed and which Woodward and Doering took for granted; promptly he assigned the project to Smith (just another project that a beleaguered postdoc needs). It's worth taking a look at Williams's paper and to read about some of the obstacles he and Smith had to overcome, especially in investigating "aged" aluminum powder which gave different results. They actually used only reagents and conditions available in 1944 to make sure they could reproduce Rabe and Kindler's work.

And then, the really controversial piece by Jeff Seeman, the piece de resistance about E J Corey's "contribution" to the Woodward-Hoffman rules. The word "plagiarism" in the title of the talk guaranteed a full room. In a sense the talk was not as controversial as everyone thought since Seeman never really answered the question ("Was plagiarism involved in the development of the Woodward-Hoffmann rules?") with a simple yes or no. However, he also made it clear that it may well be impossible to answer the question this way. What was clear is that he has had only one or two chances to get E J Corey's side of the story. On the other hand, Corey himself has made his view about the matter quite clear. In his Priestley Medal acceptance speech, he quite clearly and matter-of-factly said that he gave Woodward a suggestion about electrocyclic reactions that involved looking at the symmetry of the orbitals. More provocatively, he made this point much more emotionally in two letters to Hoffmann in 1981 and 1984, where he stopped short of accusing both Hoffmann and Woodward of blatant dishonesty and plagiarism. The way Corey tells the story, he stopped by Woodward's office on an evening, Woodward asked him the question, Corey gave Woodward a suggestion, and then Woodward apparently incorporated Corey's suggestion into his own framework without giving due credit to Corey. Woodward also clearly told Hoffmann that Corey had played no role in the development of the rules. One interesting point that Seeman made was that many other organic chemists were thinking along the same lines as Woodward and Hoffmann around this time, as evidenced from publications. So perhaps the right question is; why didn't anybody else come up with the Woodward-Hoffmann rules? It's also interesting to note, as recounted by Hoffmann in his Angew Chem article, that Corey employed electrocyclic reactions to control stereochemistry in his synthesis of a compound named dihydrocostunolide, which he published a year or two after the alleged appropriation of his idea. If he was really keen on making his contribution known, why didn't he talk about the conservation of orbital symmetry in his paper? Or was he afraid it would have just made it look like he was piggybacking on the Woodward-Hoffmann concept? Many such little and not so little questions remain unanswered. There are other interesting anecdotes. According to Corey's own account, his relationship with Woodward cooled to a strictly business relationship after he thought Woodward failed to give him due credit. In spite of this, Woodward warmly recommended Corey as the top contender for the Cope Award.

Seeman also had some interesting statistics about a study he conducted regarding the assignment of credit in publications. He and a colleague polled 600 academic chemists and asked them whether there was a time when they thought they hadn't been given credit as an author on a paper. About 50% said yes. Most people also said that they had not been given credit by another faculty member from their department rather than their own advisor. It's also worth highlighting another question Seeman asked to the respondents, whether they would include someone who had contributed a key intellectual idea and nothing more either as an author or in the acknowledgments of a paper. The majority of respondents (42%) agreed that such a person should be included in the acknowledgments, although a visible number (21%) also agreed that such contributors should be listed as co-authors. These are interesting statistics. I think we have all faced situations where, in group meetings, seminars or even in casual discussions down the hall, we have provided important suggestions to a student, colleague or faculty member. However, we may then not have had anything to do with the actual execution of the idea. The question is; in what way then, if at all, should our contribution be acknowledged by the person capitalizing on our idea? Just something to ponder.

In the end as Seeman narrated, the story might never be unravelled, partly because it goes far beyond the immediate topic at hand and treads into questions about the genesis of ideas, personal ambitions, academic prestige, scientific communication, the ways in which human beings understand each other and the myriad ways in which we misunderstand each other.

Finally, does it matter? Both Woodward and Corey's place in the history of chemistry is assured beyond a shade of doubt. Whatever people's opinions about E J Corey may be, you would not find a soul who denies that he is an undisputed giant of chemistry. Woodward, Hoffmann and Corey all won their medals and had extraordinary careers. Hoffmann became known not just as a chemist but also as a man of letters, and Corey is probably the greatest chemist alive today. Yet the story will continue to intrigue us, simply because it involves so many elements of human fallibility, folly and triumph which we encounter in all aspects of the human experiment.

Does RBW still live? In more than one way, yes! Stuart Schreiber who gave the last talk on cancer therapeutics started by showing some revealing pages from his graduate school notebook with RB's scribblings. RB had drawn what we today know as graphene, and there were some figures in which he had pondered inserting nitrogen atoms into graphene. Schreiber strongly believes that RB was getting seriously interested in materials chemistry towards the end of his life, and he also reminded everyone that Nobel Prizes were won for fullerenes and conducting polymers. Had RB started to foreshadow some of this work? Would he have become the world's preeminent materials chemist after he had conquered the realm of natural products? We will never know.

What we do know for sure is that the world as a whole will always be grateful to Roald Hoffmann, E J Corey and R B Woodward for all they have done. Among the thicket of controversies, personal rivalries and ambiguous interpretations, this fact will always stand as the one bright, shining light in the dark jungle of historical analysis. Science always wins.

Woodward-Hoffman-Schmoffman?

Next week I am attending and giving a talk at the ACS National Meeting in Boston. Lots of interesting presentations, but the unusual title of one talk in particular caught my eye:

"Was plagiarism involved in the development of the Woodward—Hoffmann rules?"

Jeffrey I. Seeman Ph.D.

That sounds like fun! I am guessing the answer is going to be 'no'. It's in Room 205A/B on Monday, August 23rd.