R. B. Woodward, general problems and the importance of timely birth

History has its own way of securing rewards for those who ride its crests. That's especially true of scientists. If we look at the greatest scientists in history, there is no doubt that being born at the right place at the right time is paramount in scientific success. One of the main reasons for this is that certain times are ripe for solving general problems, and the specific examples that are then attacked are only special cases, presumably choice fodder for 'lesser' minds.

R B Woodward, who celebrates his 100th birthday this week, is certainly a case in point. He showed us how to synthesize almost any complex molecule, and it’s not possible to see how someone could do that again. Until Woodward did it many believed that it might be impossible to synthesize molecules as complex as reserpine, chlorophyll, cholesterol and vitamin B12, and after he did it there was no doubt in anyone's mind. Now there are still undoubtedly challenges in synthetic organic chemistry, and particular examples abound, but the general problem was solved by Woodward and there is no chance that someone can solve it again. Contrast that with a field like computational chemistry, where the general problem of efficiently computing the free energy of binding of a small molecule to a protein is far from being solved.

There is no escaping the fact that you can fail to make your contribution to a scientific paradigm simply because you are born a few years too late. A great example is the golden age of physics in the twenties when people like Heisenberg, Dirac, Pauli and Schrodinger others laid the foundations of quantum mechanics. With the glaring exception of Schrodinger, all the others were in their mid twenties and in fact were born within a year or two of each other (1900-1902). Once they invented quantum theory nobody could invent it again. Dirac in particular was not only one of the founding fathers of quantum mechanics but was also the founding father of quantum electrodynamics; thus, the stunning success of that field after World War 2 by Feynman and others built on his work.

This meant that if you were unfortunate enough to be born just a few years later, say between 1906 and 1910, you would miss your chance to contribute to these developments no matter how talented you were. Examples of people in this category include Robert Oppenheimer, Hans Bethe and Edward Teller. All of them, and especially Bethe, made seminal contributions to physics, but they missed the bus on laying the foundations. They matured at a time when the main task of physicists was to apply the principles developed by men only a few years older than they were to existing problems. Bethe and others achieved great success in this endeavor but there was no way they could replicate the success of their predecessors. Quantum mechanics was perhaps a rare example since the time window during which the fortuitous confluence of brilliance, data, geographic proximity and collaboration bore copious fruit was remarkably narrow, but it does underscore the general point that the period during which one can make fundamental contributions to a field might be preciously rare. As a more recent example, think of particle physics. After the discovery of the Higgs boson, how easy would it be for someone just entering the field to make a fundamental discovery of comparable magnitude? What are the chances that a particle as important as the quark or the neutron would again be discovered? It's quite clear that while there's still plenty of important discoveries to be made in physics, one could make a good case that the age of fundamental discovery at the level of the atom might be over. That is why one cannot help but feel a bit sorry for someone like Edward Witten, perhaps the greatest mathematical physicist since Paul Dirac. If Witten had been born in 1900 he might well have formulated quantum theory or discovered the uncertainty principle, but being born in 1951, he had to be content with formulating string theory instead, a field struggling to find experimental validation.

A similar theme applies to chemistry. Woodward was heads and shoulders ahead of many of his contemporaries but he also had the advantage of being born a few years earlier. Thus, his first synthetic success came with quinine in 1944, a time when many future leaders in the field like E. J. Corey, Carl Djerassi, Samuel Danishefsky, Gilbert Stork were just entering high school or graduate school. This was still the case when Woodward synthesized two other landmarks, strychnine (1954) and reserpine (1956). Being a titan certainly entails being born with great intellectual gifts but it also benefits tremendously if you are born at the right time. Woodward matured when the conditions in organic chemistry were right for a man of his stature to revolutionize the field. The British chemist Robert Robinson and others had just described the electronic theory of organic chemistry which charted movements of electrons in organic reactions, UV and infrared spectroscopy were coming into vogue and structure determination by chemical degradation had reached its zenith. Woodward combined all these tools to invent a superb new methodology of his own and then applied it to scale hitherto unscaled peaks. He pioneered spectroscopy as an alternative to tedious chemical degradation for determining the structure of molecules and applied sound theoretical principles for making complex molecules. Another specific example is his development of the Woodward-Hoffmann rules; these are rules which allow chemists to predict the course of many key reactions that are of both of pure and applied interest. In formulating these reactions with Roald Hoffmann, Woodward again was in a rather unique position to appreciate both observations arising from his synthesis of vitamin B12 and the widespread dissemination of molecular orbital principles which were ripe for application. After he did all this that was it; while the others also made highly innovative contributions, in many ways they were duplicating his success.

This discussion also has a bearing on the frequent debate about awarding Nobel Prizes to one discipline or another. The fact is that we are very unlikely to see Nobel Prizes in organic synthesis in the future because many of the fundamental problems in the field have been solved. There has not been a general organic synthesis prize awarded since 1990 (Corey) and for good reason. Methodology has been recognized more often, but even the two  most recent methodology prizes (2005 and 2011) stem from work done about twenty years earlier. There is of course a chance that some transition metal may further the cause of efficient, high-yielding and environmentally friendly synthesis in a significant manner but these achievements are likely to be rare.

There is a very important lesson to be learnt from all this regarding the education of students in the history of science. Students should never be discouraged from studying particular scientific fields, but graduate students at the cusp of their research careers should be given a good idea of where the greatest opportunities in science lie. There’s still nothing to stop a Phil Baran (widely considered to be the brightest synthetic organic chemist of his generation) from venturing into organic synthesis, but he should do so with full knowledge of what Woodward and Corey have done before him. One way to ensure success in science is of course to work in the “hottest” fields, and while history often has its own peculiar way of defining what these are, it’s sometimes clearer which ones have passed their prime. And it’s important to drive home this point to young researchers.

The linguistic adventures of Robert Burns Woodward

Photo credit: Jeff Seeman

Everyone knows about the supreme scientific achievements of Robert Burns Woodward, but few chemists from today's generation are perhaps acquainted with Woodward's love of the English language. This omission would be easy to remedy, however: anyone who reads Woodward's famous papers on the total synthesis of strychnine, or reserpine or chlorophyll would notice his unusually well-formed sentences, injection of Latin or historic references and allusions to synthetic chemistry as a heroic endeavor. Chemistry being a science whose products and protocols are especially palpable and vivid because of their colors, smells, textures and general visual displays, it was particularly amenable to Woodwardian linguistic flourishes. 

All these qualities are now presented in a delightful paper by my friend, the noted historian of chemistry Jeff Seeman, in Angewandte Chemie. Jeff describes how Woodward's English ancestry and Anglophilic affinities propelled him to develop his love of language and a very distinct style of writing that influenced his peers (in his autobiography, Jack Roberts of Caltech has also commented on some of Woodward's unusual English pronunciation: "mole-e-cule" instead of "mall-e-cule" for instance). Woodward of course considered and practiced organic synthesis as a mix of extreme performance sport and high art, so it's only appropriate that his language matched the elegance of his synthetic creations.

Foremost among his descriptions of compounds, reagents and reactions is what I consider to be the ultimate paean ever paid to a molecule: his tribute to a lowly isothiazole ring and his eloquent description of it as a travel companion to whom one needed to bid farewell after a fateful and adventurous journey. This was from his synthesis of colchicine:

"Our investigation now entered a phase which was tinged with melancholy. Our isothiazole ring had served admirably in every anticipated capacity, and some others as well. … It had enabled us to construct the entire colchicine skeleton, with almost all of the needed features properly in place, and throughout the process, it and its concealed nitrogen atom had withstood chemical operations, variegated in nature, and in some instances of no little severity. It had mobilized its special directive and reactive capacities dutifully, and had not once obtruded a willful and diverting reactivity of its own. Now, it must discharge but one more responsibility—to permit itself gracefully to be dismantled, not to be used again until someone might see another opportunity to adopt so useful a companion on another synthetic adventure. And perform this final act with grace it did.”

Then there's the famous synthesis of strychnine, in which the use of a simple exclamation mark in the first sentence places the project on a whole new level of scientific stardom. Albert Eschenmoser who worked with Woodward on his vitamin B12 synthesis offers an appropriate tribute:

Then there are the military metaphors. Today we might be used to descriptions of complex, multistep, multi-personnel and multiyear syntheses as being akin to climbing great mountains or fighting great battles; one of Woodward's successors, K C Nicolaou, has especially enshrined such comparisons in his reviews, but it was Woodward who was the first to memorialize them. As Jeff explains, Woodward was a serious history buff, and his knowledge of a reference to the Battle of Berezina in which the French under Napoleon achieved a costly victory against the Russians made its way into a review on strychnine. More martial references emerge in his description of efforts to decipher chlorophyll (as an aside, even today, I am struck by how much of the jargon of drug discovery is war-inspired: "targets", "hits" and "campaigns" are only a few examples).

1961: Fresh from his dramatic conquest of the blood pigment, [Hans] Fischer hurled his legions into the attack on chlorophyll, and during a period of approximately fifteen years, built a monumental corpus of fact. As this chemical record, almost unique in its scope and depth, was constructed, the molecule was transformed and rent asunder in innumerable directions, and the fascination and intricacy of the chemistry of chlorophyll and its congeners was fully revealed.”

Jeff considers dozens of other examples where Woodward's facility with language was on generous display: Strychnine possessed a "tangled skein of atoms" and another molecule contained a "felicitously placed carboxyl group and a double bond of good augury". Yet another compound is a "substance precariously balanced on a precipice", presumably by virtue of its instability. Finally, Woodward's love of Latin found its way into more than a few of his papers ("sui generis", "sub judice" and "pari passu").

All this achieves a goal which Woodward may or may not have consciously had in mind: to make synthesis look like high art, supremely arduous mountaineering and inspired military strategy all at once. A memorable paragraph of his on the fundamental motivation for organic synthesis brings together many of these themes and pays a glowing tribute to the the whys of the creation of new molecules:

“The structure known, but not yet accessible by synthesis, is to the chemist what the unclimbed mountain, the uncharted sea, the untilled field, the unreached planet, are to other men. The achievement of the objective in itself cannot but thrill all chemists, who even before they know the details of the journey can apprehend from their own experience the joys and elations, the disappointments and false hopes, the obstacles overcome, the frustrations subdued, which they experienced who traversed a road to the goal. The unique challenge which chemical synthesis provides for the creative imagination and the skilled hand ensures that it will endure as long as men write books, paint pictures, and fashion things which are beautiful, or practical, or both.”

Interestingly at the end of the article, Jeff also discusses the reactions of a few reviewers of Woodward's words who were not as taken by his linguistic playfullness, who thought that his undue emphasis on unusual language often obscured the clarity of the science. I am a bit sympathetic to this view myself. Personally I love reading Woodward's papers, but that's because I am someone who enjoys literature. Others who may not be as enamored of the felicities of language, who may have a no-nonsense approach to the writing of scientific papers and who might not want to wade through the icing before they get to the cake might not appreciate Woodward's language as much. This is not an entirely unfair point: The main purpose of scientific papers is to clarify, explain and enumerate, not to decorate, bedeck and garland. 

There's also another important aspect of scientific writing that especially needs to be considered in this age, one in which science is highly international: scientific papers have to be written for an international audience, and it's not unreasonable to think that the kind of language Woodward used might make his papers harder for those whose first language is not English to understand. In Woodward's time science was a smaller community, the Internet did not exist and the total synthesis of organic molecules was an endeavor whose leading practitioners were largely confined to Europe and the United States. One did not really worry about chemists in China appreciating the meaning of words like "adumbrate", "punctilio", "apposite" and "cavil", all of which were peppered across Woodward's writings. Today we do.

Nonetheless, in case of Woodward these stratospheric incarnations of the English language work, mostly because of the profound feats in science which they herald. The synthesis of strychnine or vitamin B12 is indeed an unprecedented achievement akin to high art, so it doesn't seem out of place for such performances to be described in language that is as novel as the achievements are groundbreaking. 

One can get away with a lot if one is Robert Burns Woodward.

R B Woodward. Vitamin B12. 3.5 hours. Enough said.

Dylan Stiles (of pioneering "Tenderbutton" fame - username tender, password button in case you want a trip down memory lane) has uploaded a rare and valuable 3.5 hour lecture of the demigod of organic synthesis, R B Woodward, giving a talk on his joint total synthesis of vitamin B12 with ETH Zurich's Albert Eschenmoser.

The talk starts with a charming and funny introduction by Canadian biochemist David Dolphin who dwells on Woodward's background and achievements. Before the talk begins an assistant makes daiquiris. Yes, daiquiris. After that the master takes the reins.

This is a demonstration of intellectual prowess from another day and age, when synthesis was king and R B Woodward was Zeus with lightning bolts. There are four important observations to note here: first, that it's about vitamin B12 which at that time was the most complex organic molecule ever synthesized, second, that it starts with a neat lineup of cigarettes on the table, all of which have been smoked by the end, third, that there are daiquiris on the table and in Woodward's hand, and fourth, that the talk is a short and breezy three and a half hours long. All four of these facts attest to the force of nature that called itself Robert Burns Woodward.

The B12 synthesis involved a truly remarkable trans-Atlantic relay comprising almost a hundred postdocs and graduate students and the synthesis itself is almost a hundred steps. At the end of the talk Woodward places a series of flags on the table, each representing the country of origin of the postdocs and students who worked on the project (99 from 19 countries to be exact). Since then no one has attempted the construction, probably because of lack of interest but also likely because of lack of stamina.

As for the length, Woodward's talks were legendary, and he was known to fill entire blackboards with beautifully drawn structures - using multiple colors of chalk. He would start at the top left hand corner and finish at the bottom right hand corner. As attested to by this marathon lecture, the length of the talk was whatever Woodward wanted it to be. His colleagues started measuring lecture time in units of milli-Woodwards, with his longest talk pegged as 1 Woodward.

A former postdoc of his once said that they generated three anecdotes about Woodward: 1. He never gets drunk (as evidenced by his heavy drinking of scotch), 2. He never gets tired (as evidenced by his ability to work eighteen hours a day and make do with only 3-4 hours of sleep every night) and 3. He never perspires.

You can certainly validate the second and third anecdotes by watching this video. And let me know if you survive through to the end.

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.

The 111 Nobel Prize nominations of Robert Burns Woodward

As Nobel season dawns upon us, Stu Cantrill points me to an endlessly interesting link on the Nobel website which lists nominating information for various scientists up to 1964 (names of nominees and nominators cannot be revealed for 50 years). Since many more deserving scientists never win the prize compared to those who do this list makes for especially readable material.

For instance Carl Djerassi who never won the prize was nominated three times (only until 1964 though, so he was likely nominated many more times after that). In the peace category Franklin Roosevelt was nominated 5 times. And Lise Meitner was nominated 47 times without winning in both the physics and the chemistry categories.

The astonishing statistics are for everybody's favorite chemistry demigod R B Woodward. Woodward was nominated a record 111 times from 1937 until 1965 when he finally won. What's even more stunning though is the year of his first nomination - 1937. That can't be quite right since Woodward was 20 years old then and about to finish his PhD at MIT. Interestingly there is no name in front of the nomination so this could be a mistake. But there's little doubt that nominating even the precocious Woodward at age 20 would have been premature to say the least (Note: Woodward famously finished both college and graduate school in four years and had to drop out for one semester for neglecting other subjects). 

The more authentic nomination still comes in 1946 when he was still only 29: this time he was nominated along with his colleague Bill Doering by the astronomer Harlow Shapley. The nomination was clearly for the Woodward-Doering breakthrough synthesis of quinine. After 1946 Woodward was nominated pretty much every single year by multiple people. In fact looking at the list what's astonishing is how he didn't win the prize until 1965.

You can have more fun looking at the list and especially searching for other famous chemists who should have gotten a Nobel Prize but who never did. For instance Gilbert Newton Lewis is widely considered to be the greatest American chemist to have never won, and he was nominated 41 times so one wonders what exactly kept him from being on the list. C K Ingold, one of the fathers of physical organic chemistry, also never won and he was nominated 63 times. On the other hand, Robert Robinson with whom Ingold enjoyed a friendly rivalry was nominated 51 times but actually won.

Another interesting fact to be gained from the database is the number of times a particular Nobel Laureate nominated another scientist. In what is a testimony to his well-known generosity of spirit for instance, Niels Bohr nominated other scientists 25 times (this included multiple nominations for Lise Meitner who unfortunately never won). 

Woodward on the other hand nominated someone only once - Linus Pauling in 1949. Interestingly, Woodward had tried to apply for an instructorship at Caltech in 1942 when Pauling was the chairman of the department but as the letter below indicates, Pauling didn't seem too interested; one wonders how the course of American and Caltech chemistry would have been had both Woodward and Pauling reigned over the world of chemistry from the same department.

Source: Angew. Chem. Int. Ed. 2007, 1378

In any case, the nomination website makes for very intriguing browsing with which you can play around for a long time. The one thing it makes clear is what we already know - that the number of outstanding Nobel-caliber scientists who will never win the prize far outweighs the number who actually do. That fact should put the nature of the prize in the right perspective.

Chemical and Engineering News celebrates 90 years: How chemistry has come a long way

Chemistry is - in the true sense - the central science, reaching inside every aspect of our lives (Image: Marquette University)

Chemical and Engineering News (C&EN) is celebrating 90 years of its existence this year, and I can only imagine how perplexed and awestruck its editors from 1923 would have been had they witnessed the state of pure and applied chemistry in 2013. I still remember devouring the articles published in the magazine during its 75th anniversary, and this anniversary also offers some tasty perspectives on a diverse smattering of topics; catalysis, structural biology and computational chemistry to name a few. 

There's an article in the magazine documenting how the single-most important concept in chemistry - that of the chemical bond - has undergone a transformation; from fuzzy, to rigorously defined, to fuzzy again (although in a very different sense).

Nobel Laureate Roald Hoffmann had something characteristically insightful to say about The Bond:

"My advice is this: Push the concept to its limits. Be aware of the different experimental and theoretical measures out there. Accept that at the limits a bond will be a bond by some criteria, maybe not others. Respect chemical tradition, relax, and instead of wringing your hands about how terrible it is that this concept cannot be unambiguously defined, have fun with the fuzzy richness of the idea.”

In a bigger sense the change in chemistry during these 90 years has been no less than astounding. In 1923 the chemical industry already made up the foundations of a great deal of daily life, but there was little understanding of how to use the concepts and products of chemical science in a rational manner. Since 1923 our knowledge of both the most important aspect of pure chemistry (the chemical bond) and of applied chemistry (synthesis) has grown beyond the wildest dreams of chemistry's founders.

If we had to pinpoint two developments in chemistry during these 90 years that would truly be described as "paradigm shifts", they would be the theoretical understanding of bonding and the revolution in instrumental analysis. As I and others have argued before, chemistry unlike physics is more "Galisonian" than "Kuhnian", relying as much on new instrumental techniques as on conceptual leaps for its signal achievements.

The two most important experimental advances in chemistry - x-ray diffraction and nuclear magnetic resonance - both came from physics, but it was chemists who honed these concepts into a routine laboratory tool for the structure determination of a staggeringly diverse array of substances, from table salt to theribosome. The impact of these two developments on chemistry, biology, medicine and materials science cannot be underestimated; they cut down the painstaking task of molecular structure determination from months to hours, they allowed us to find out the nature of novel drugs, plastics and textiles and they are now used by every graduate student every single day to probe the structure of matter and synthesize new forms of it. Other developments like infrared spectroscopy, electron diffraction, atomic force microscopy and single molecule spectroscopy are taking chemistry in novel directions.

The most important theoretical development in chemistry also derived from physics, but its progress against demonstrates chemists' central role in acting as mediators between concept and application. It also serves to make a key point about reductionism and the drawbacks of trying to reduce chemistry to physics. The chemical bond is an abstract concept going back to "affinities" between atoms (which when illustrated were replete with hooks and eyes). But it was in 1923 that the great American chemist G. N. Lewis propounded the idea in terms of atoms sharing electrons. This was a revolutionary brainwave and illuminated the way for Linus Pauling, John Slater, Robert Mulliken, John Pople and others to use the newly developed machinery of quantum mechanics to fashion the qualitative principle into an accurate, quantitative tool which  - with the development of modern computing - now allows chemists to routinely calculate and predict important properties for any number of chemical substances.

Yet the ramifications of the chemical bond tempt and beguile physicists and constantly escape from their grasp when they try to define them too accurately. The above quote by Roald Hoffmann puts the problem in perspective; quintessentially chemical ideas like aromaticity, the hydrophobic effect, steric effects and polarity "fray at the edges" (in Hoffmann's words) when you try to push them to their limits and try to define them in terms of subatomic physics. Chemistry is a great example of an emergent discipline. It is derived from physics and yet independent of it, relying on fundamental definitions at its own level when progressing.

The chemical bond and other theoretical aspects of chemistry have enabled the rise of the one activity pursued by chemists of which society is an unsurpassed beneficiary - the science, art and commerce of synthesis. Every single molecule that bathes, clothes, feeds, warms, transports and heals us has been either derived from nature using chemical techniques or has been synthetically made in a chemical laboratory. The social impact of these substances is hard to underestimate; even a sampling of a few such as the contraceptive pill, antibiotics or nylon attests to the awesome power of chemistry to completely transform our lives.

In 1923 synthesis was a haphazard process and there was virtually no understanding of how we could do it rationally. All of this changed in the 1950s and 60s when a group of pioneering scientists led by the legendary organic chemist Robert Burns Woodward revolutionized the process and honed synthesis into a precisely rational science which took advantage of the course of chemical reactions, the alignment of orbitals, the development of new chemical reagents and the three-dimensional shape of molecules. Many Nobel Prizes were handed out for these groundbreaking discoveries, but none surpassed the sheer impact that synthesis will continue to have on our way of life.

As is inevitably the case for our embrace of science and technology, with progress also come problems, and chemists have had to deal with their share of issues like environmental pollution, drug side effects and the public perception of chemistry. Suffice it to say that most chemists are well aware of these and are working hard to address them. They recognize that with knowledge comes responsibility, and the responsibility they bear to mitigate the ills of the wrongful application of their science transcends their narrow professional interests and encompasses their duties as citizens.

In the new century chemistry continues to build upon its past and chemists continue to push its boundaries. Another change which the editors of C&EN would not have foreseen in 1923 is the complete integration of chemistry into other disciplines like biology, medicine and engineering and its coming into its own as the true "central science". Today chemistry deeply reaches into every single aspect of our lives. The cardinal problems facing civilization - clean and abundant food and water, healthcare, national security, overpopulation, poverty, climate change and energy - cannot be solved without a knowledge of chemistry. Simply put, a world without chemistry would be a world which we cannot imagine, and we should all welcome and integrate the growth of chemical science into our material and moral worldview.

First published on the Scientific American Blog Network.

Woodward, and the importance of being born at the right time

Woodward as a freshman at MIT (Image: CHC)

On his blog Derek has a contemplative post on the conditions necessary for seeing titans in particular fields, and whether these conditions can be replicated again. I completely concur with his viewpoint that it’s possible to discover the structure of DNA, or formulate general relativity, or revolutionize organic synthesis, just once.

Putting it another way, the question to ask is whether the general problem has been solved. Woodward is certainly a case in point...

Read the rest of the post on my Scientific American Blog

Explaining Woodward to the layman

We scientists often, and rightly so, complain that even the best of our lot are hardly known to the man on the street. How many of my non-scientific friends and relatives, even otherwise highly informed and well-educated, have heard of Hans Bethe, Robert Woodward, Ernst Mayr or even Freeman Dyson (who has written great popular books)? 

The truth is that the number of scientists who are famous enough to count in the public imagination can be counted on your fingers. I feel saddened by this fact, but also realize that this situation is not going to change anytime soon; Bob Woodward the journalist would always be more widely known than Bob Woodward the chemist. And in any case, it's much better to do your part in publicizing the achievements of great scientists than to keep on lamenting their lack of recognition.

The fact is, there are ways in which the stature of scientists can be concisely communicated to those who may be unfamiliar with their achievements. Here's one way to do it:

“We arrived at the night club and Armstrong was already playing. I introduced Bob to my friend saying, “This is Bob Woodward.” My friend turned around impatiently, shook his hand, and returned his attention to the music. I said, “Look, Bill, Bob Woodward is to organic chemistry what Louis is to the trumpet!” At that my friend turned around slowly, looked Bob in the eye, and said, “Man, you must be one hell of a chemist!” Bob said he thought that was the most sincere compliment he ever got."

Well done. Although I will say that it was Louis Armstrong who was the Robert Burns Woodward of jazz.

Reference: Blout E. Robert Burns Woodward. Biographical Memoirs of the National Academy of Sciences, 2001; 80.

Image: Wikipedia Commons

A history of metallocenes: Bringing on the hashish

Following on the heels of the comprehensive article on metal-catalyzed reactions noted by Derek, here's another one by Helmut Werner specifically about the history of ferrocene and other metallocenes. It's got lots of interesting trivia about priorities, personalities and chemical developments. The article traces early priority disputes in the discovery of ferrocene followed by an account of the rush to explore other metal-organic systems.

It's hard for us today to imagine the shock that was felt on witnessing the existence of the first sandwich compound, a complex of iron sandwiched between two cyclopentadienyl rings. Before ferrocene the division of chemistry into inorganic (especially metallic) and organic compounds was assumed to be virtually set in stone, and this was one of those classic developments that shatters the mirror between two realms. The world of transition metal-mediated chemistry that the discovery inaugurated completely transformed the academic and industrial practice of chemistry, led to several Nobel Prizes and turned out to be one of the most beneficial scientific developments of the latter half of the twentieth century. 

The novelty of the new compound is best captured by what must surely be the most memorable reply sent by a journal editor to a submitting author, this one being from Marshall Gates (the editor of JACS) to R. B. Woodward:

"We have dispatched your communication to the printer but I cannot help feeling that you have been at the hashish again. 'Remarkable' seems a pallid word with which to describe this substance"

Perhaps the most extraordinary part of the story is the candid and rather dramatic note from Woodward to the Nobel committee lamenting his exclusion from the 1973 Nobel Prize awarded to Geoffrey Wilkinson and Ernst Fischer.

"The notice in The Times of London (October 24, p. 5) of the award of this year's Nobel Prize in Chemistry leaves me no choice but to let you know, most respectfully, that you have - inadvertently, I am sure - committed a grave injustice"

Woodward went on to rather pointedly emphasize his individual contributions to the discovery, making it sound like he had done Wilkinson at least a minor favor by putting his own name last on the manuscript. 

"The problem is that there were two seminal ideas in this field-first the proposal of the unusual and hitherto unknown sandwich structure, and second, the prediction that such structures would display unusual, "aromatic" characteristics. Both of these concepts were simply, completely, and entirely mine, and mine alone. Indeed, when I, as a gesture to a friend and junior colleague interested in organo-metallic  chemistry, invited Professor Wilkinson to join me and my colleagues in the simple experiments which verified my structure proposal, his initial reaction to my views was close to derision . . . . But in the event, he had second thoughts about his initial scoffing view of my structural proposal and its consequences, and all together we published the initial seminal communication that was written by me. The decision to place my name last in the roster of authors was made, by me alone, again as a courtesy to a junior staff colleague of independent status".

Interestingly, his recollection almost completely differs from that of Wilkinson's who stated in a 1975 review that he thought of the structure right away while Woodward immediately started thinking about its reactions. It's intriguing - and probably futile - to psychoanalyze the reasons for this very public expression of disappointment, especially coming from one who was not exactly known for publicly airing his personal feelings (for instance, his Cope Award lecture is the only time Woodward really provided personal biographical details). By 1973 Woodward had already won the Nobel Prize, and while he was always known to be extraordinarily ambitious, he must have known that his place in chemical history had already been secured; at that point he had even published the landmark papers on the Woodward-Hoffmann rules. Perhaps he sincerely felt that he deserved a share of the prize; nevertheless, it's a little curious that such a towering figure in the field made it a point to convey his disappointment at not winning a prize so publicly and strongly. Whatever the reason, Woodward's note makes it clear that scientists - both famous ones and otherwise - are keen to stake their priority. They are after all human.

To be fair to the prize committee, the award was given for the more general field of organometallic chemistry that the discovery of ferrocene launched rather than for the structure of ferrocene itself. Even at the beginning Wilkinson had been more interested in the new structural class of metallocenes while Woodward had been more interested in the kind of reactions the novel compounds would undergo. After the initial finding, while Wilkinson immersed himself in investigating the interactions of other metals with similar organic systems, Woodward went back to his life's love; the chemistry of natural products. Thus, it seems sensible in retrospect to have the prize given to Wilkinson and Fischer if the purpose had been to honor a new field of chemistry. Woodward died in 1979, and I am not familiar with his later thoughts on the subject if he had any. But of course, his place in the annals of science had long been assured, and ferrocene has turned into little more than an interesting historical footnote in his list of superlative achievements.

Note: The quotes by Woodward come from an article by Thomas Zydowsky from the Northeastern Section of the ACS that I had noted in the mailing list ORGLIST...in 2001. Time flies.

Woodward on how to travel incognito

Searching aimlessly for material on R. B. Woodward online, I came across an amusing source: "Droll Science" by Robert Weber. In it I found the following droll anecdote:

At the Munich (1955) meeting of the Gesellschaft deutscher Chemiker, Woodward attracted attention as he roamed the halls carrying a big notebook in a blue silk cover on which was embroidered the structural formula of strychnine. The next day he appeared bearing a cover innocent of any embroidery. Asked a friend, "Why no structural formula?" Quipped Woodward, "Oh, I'm traveling incognito today."

The anecdote probably says more about the man than it intends to: Woodward's identity was inextricably linked to the objects of his creation, and without them, he could indeed pronounce himself incognito.

Note on the cultish status of organic synthesis: Part 1

When I was in graduate school, a friend and I used to joke that the most egotistical elitists are to be predominantly found in two fields: particle physics and the total synthesis of complex organic molecules. As with most jokes and exaggerations, this one had a shred of truth in it. We had read about the hubris arising from a belief in strict reductionism to be found among particle physicists, and we had heard of similar hubris arising from a sense of mastery over nature found among synthetic organic chemists. What physicist has not heard Paul Dirac's quote that quantum mechanics would explain "all of chemistry", and what organic chemist does not like to gossip about slave-driving synthetic chemists who think they are doing other chemists a favor by contributing to what they have proclaimed to be the highest calling in their field? There is little doubt that more than many other branches of chemistry, organic chemistry and synthesis in particular enjoy (or is it suffer from?) a cultish status.

More recently, a few comments on the "greatest chemists" post at The Skeptical Chymist again struck a chord. The writers of the post wondered whether "organic chemists are just a little insular and think that their bit of the chemistry kingdom is the only one that matters?". Another commenter reaffirmed this sentiment by saying that more than other fields of chemistry, "organic chemists have a culture of legend-making".

I agree with both these statements and I think there are three main reasons why organic synthesis has lent itself to cult-making. A major reason is the personalities, their exquisite language and metaphors, their harnessing of armies of graduate students and postdocs and the stories they loved to weave around their science. The second reason is simply the great practical utility of organic chemistry in improving the quality of life. The last and perhaps the most important reason is the continued perception of organic synthesis as the ultimate chemical science which has lifted the great veil of nature and allowed man to wrest Nature's deepest secrets from her; there is something stupendous in having a mere mortal synthesize chlorophyll from scratch. The three reasons are connected, but each brings a distinct flavor to the argument. In this post I will dwell on the perceived cult of personality in organic synthesis, and will leave the rest of the discussion for another post.

So let's talk about the personalities. At the outset let's make it clear that not all organic chemists revel in showmanship, and such generalizations can be flawed. There are of course dozens of brilliant chemists who are extremely unassuming, letting their colleagues put on the shows in papers and in lectures. Yet as we all know, belief depends as much on perception as on reality, and there is a very distinct feeling in the chemical community that synthetic organic chemists love to perform more than others.

Is this true? Well, more than most other chemists, organic chemists have surrounded themselves with stories reminiscent of tales of great human adventures, exploits, triumphs and follies. Myth-making has contributed somewhat uniquely to organic chemistry. Part of the myth-making and legend-building was engendered by a happy accident of history that inadvertently did some harm to the perception of the field- the name of this happy accident was Robert Burns Woodward. So much has been said about him that it's not worth repeating. But there was no comparable chemist in any field during his time, and as long as he lived, Woodward achieved feats that almost defied belief. It's hard to see how organic synthesis would have turned into a mythical endeavor had it not been for this singular man. Others like Corey, Djerassi, Danishefsky, Nicolaou etc. simply carried on the tradition. Harvard became the mecca of organic synthesis, and Woodward and Corey's laboratories turned into Plato's academies through which every budding intellectual in the field had to pass in order to get a stamp of respect. Even today it's remarkable how many top synthetic organic chemists in the world have trained with one of these masters. The students in turn have carried forward the legend-making and perpetuated the reputation of the field, like Homer's portraits of Hector, Achilles and the great wars they fought in.

A corollary to the legend-making is the language and the metaphors. Look up some of the most famous total synthesis papers and the authors make them sound less like synthesis and more like a combination of Tenzing and Hillary's conquest of Everest and Michelangelo's painting of the Sistine Chapel. For instance, a review on the synthesis of the CP molecules begins with stories and portraits of Thesus's pursuit of the fearsome Minotaur. Organic synthesis is portrayed as the ultimate art and adventure and organic chemists are intrepid explorers venturing into the unknown. There is no doubt that synthesis is an art and that synthetic chemists are explorers, but so are other scientists. In fact, protein crystallography probably lends itself to the mountain-climbing metaphor even more since crystallographers sometimes stake their entire careers on the relentless chase of a single structure. Yet it's organic synthesis and not other branches of chemistry which claims to be the epitome of art, science, adventure and determination. I suspect that is partly because unlike synthesis, crystallography is a more interdisciplinary activity that cannot be easily labeled as chemical.

Again, one has to inevitably partly blame Woodward. For instance, consider this masterpiece from his colchicine synthesis which makes us feel like we are reading not Woodward but Tolkien:

"Our investigation now entered a phase which was tinged with melancholy. Our isothiazole ring had served admirably in every anticipated capacity and some others as well...it had mobilised its special directive and reactive capacities dutifully, and had not once obtruded a willful and diverting reactivity of its own. Now it must discharge but one more responsibility- to permit itself gracefully to be dismantled, not to be used again until someone might see another opportunity to adopt so useful a companion on another synthetic adventure. And perform this final act of grace it did."

A more exquisite paean to a five-membered ring containing carbon, nitrogen and sulfur was never penned. No wonder synthesis acquired the status of a highly-refined art form. One wonders how the field would have been perceived had it not been for the flourishing phrases, the allusions to mountain-climbing and Greek classics and the romantic metaphors. Not everyone does this of course, but it seems to be widely prevalent among top synthetic chemists.

The power of personality also extends to power over other human beings, and this has always been a sensitive topic that has contributed to the field's reputation. In the latter half of the twentieth century, the ability to synthesize increasingly complex molecules translated to the need to amass armies of students and postdocs. Woodward's collaboration with Swiss master Albert Eschenmoser on the stunning synthesis of Vitamin-B12 is a telling example; the synthesis involved dozens of graduate students and postdocs in a kind of trans-Atlantic relay that spanned 12 years and almost a hundred steps. Who would not be swayed by such overarching ability to attract personnel, resources, time and funding? Other total synthesis chemists also typically command such a glut of labor. For a long time, organic synthesis was regarded as the ultimate character-building experience. Hard work is of course essential to success in any science, but organic synthesis seemed to require a particularly intense combination of the ability to constantly bounce back from failure and the cheerful stamina of a marathon runner. This is perhaps one of the reasons why total synthesis students in my department appeared darker and more self preoccupied than others, and it could also contribute to the perceived sense of hubris among synthetic chemists. But that is also one of the reasons why total synthesis students are highly sought-after in both academia and industry, not just for their technical abilities but for their doggedness.

Nonetheless, while synthetic activity continues to be regarded as a character-building experience, the reputation of synthetic chemists has suffered in recent years because of their reliance on cheap labor and the unusually harsh working hours that synthesis students have to endure. Synthetic chemists have been held up as slave-drivers who care little about their students' education and simply need them to serve as automatons who plug one step's intermediate into the next. There have even been rumors of students forced to compete against each other for the quickest route to the product, with the "loser" not making it to the authors' list on the paper. New students are being advised not to spend five years working in a high-profile total synthesis group if they want to have a life outside graduate school. Stories of student suicides have done nothing to improve the situation, although one wonders if such stories are also not to be found in other disciplines and are simply being highlighted because of the high-profile nature of the groups. Is this reputation deserved? I don't know, but it certainly seems to contribute to an unfavorable view of total synthesis.

Yet this view has not generally colored the status of the field. Total synthesis still commands the attention of first-rate blogs, synthesis papers still make it to highly-cited lists, and total syntheses are still enthusiastically lauded as the works of art which they undoubtedly are. While the reputation of synthesis may have suffered because of myriad factors, the power of personality and the artistic metaphors have guaranteed it a special place in the minds and souls of chemists. The ghost of Robert Burns Woodward lives on in more than one way.