A terrible year for academic organic chemistry

In the last one year, academic chemistry has lost Jack Roberts, Jerome Berson, George Olah, Gilbert Stork and now Ron Breslow. The last two in just one week. 

It's been a terrible loss. All these chemists were world-renowned pioneers in their areas who laid the foundations of much of what graduate students now learn in their textbooks and what professional chemists apply in their laboratories. They were the last torch bearers of the golden age of organic chemistry, the age which laid the foundations of the three pillars of organic chemistry: structure, reactivity and synthesis.

Jack Roberts pioneered NMR spectroscopy in the United States. He should really have received a Nobel Prize for this contribution in my opinion. But in addition to this, he was also one of the foremost practitioners of molecular orbital theory and made very significant contributions to conformational analysis and carbocation chemistry.

Jerome Berson was another important physical organic chemist who also wrote what I consider to be a very unique contribution to the history of science - a book titled "Chemical Creativity", that traces creativity in the work of leading chemists, from Hückel to Woodward.

George Olah was the father of modern carbocation chemistry and an inventor of superacids that allow us to stabilize carbocations. He contributed massively to work that is used in the petrochemical industry and, along with Martin Saunders, delivered the coup de grace that settled the famous non-classical cation controversy for good.

Gilbert Stork about whom much has been written since he passed away just a few days ago was one of the most original synthetic organic chemists of the 20th century. His work on enamine alkylations, radical cyclizations and other key reactions is now part of the textbooks, and so are his several elegant natural product syntheses.

And now Ronald Breslow. Primarily known as a physical organic chemist, Breslow was one of the most versatile chemists of the 20th century whose contributions ranged across the entire chemical landscape. He is famous for many things; for discovering the simplest aromatic system - the cyclopropenium ion, for d-orbital conjugation, for very intriguing work on chemistry in aqueous solvents, for building artificial enzymes, for inventing the marketed drug SAHA (the first histone deacetylase inhibitor) and for exploring the origin of chirality during the origin of life. How many chemists can claim that kind of oeuvre?

Breslow received pretty much every award for science there is out there except the Nobel Prize - the National Medal of Science, membership in the National Academy of Sciences and presidency of the ACS among others. He also saw his share of controversies, although the chemical community always came out wiser for learning from them. 

Most notably, in an age when senior professors are often criticized for using graduate students and postdocs as cheap labor, Breslow was an extraordinary educator. Among his students and postdocs are Robert Grubbs, Robert Bergman and Larry Overman. There is probably not a continent on which some student of his is not doing chemistry. More than once during his talks, he made a pitch for hiring the student or postdoc who had done the work. Breslow belonged to an older, more gentlemanly generation of professors who would make calls to get their students jobs.

I last heard Breslow speak only one year ago at an ACS meeting. Before that I had heard him speak at an ACS meeting about ten years ago. The remarkable thing is that between those ten years he did not seem to have aged, displaying the same boyish enthusiasm and curiosity for chemistry that was always his hallmark. When he received the Priestley Medal in 1999, one of his students said the same thing: "He just doesn't seem to age, certainly not intellectually. Talking to him now is like talking to him 30 years ago. He's got the same enthusiasm, the same excitement about chemistry."

We are all poorer for the loss of Breslow and these other pioneers, but the best thing is that they will be part of the textbooks as long as there is a science of chemistry.

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.

George Whitesides to chemists: Move away from the molecule

This is an updated version of a post I wrote about an article by George Whitesides that exhorted chemists to move beyond the molecule. It was provoked in part by several recent discussions I have had about how chemists can have a broader impact on other disciplines as well as on the public appreciation of their own discipline.

Chemist George Whitesides probably does not consider himself a philosopher of chemistry, but he is rapidly turning into one with his thought-provoking pronouncements on the future of the field and its practitioners. His most recent rumination on the topic was a piece in the Annual Reviews of Analytical Chemistry provocatively titled "Is the Focus on Molecules Obsolete?" where he uses analytical chemistry as an excuse to really pontificate on the state and progress of chemical science. Along the way he also has some valuable words of advice for aspiring chemists.

Whitesides's main message to young chemists is to stop focusing on molecules. Given the nature of chemistry this advice may seem strange, even blasphemous. After all it's the molecule that has always been the heart and soul of chemical science. And for chemists, the focus on molecules has manifested itself through two important activities - structure determination and synthesis. The history of chemistry is essentially the history of finding out the structure of molecules and of developing new and efficient methods of making them. Putting these molecules to new uses is what underpins our modern world, but it was really a secondary goal for most of chemistry's history. Whitesides tells us that the focus of the world's foremost scientific problems is moving away from composition to use, from molecules to properties. Thus the new breed of chemists should really focus on creating properties rather on creating molecules. The vehicle for Whitesides's message is the science and art of analytical chemistry which has traditionally dealt with developing new instrumentation and methods for analyzing the structure and properties of molecules.

Of course, since properties depend on structures, Whitesides is not telling us to abandon our search for better, cleaner and more efficient techniques of synthesis. Rather, I see what he is saying as a kind of "platform independence". Let's take a minute to talk about platform independence. As the physicist Leo Kadanoff has demonstrated, you can build a computer by moving around 1s and 0s or by moving around buckets of water, with full buckets essentially representing 1s and empty ones representing 0s. Both models can give rise to computing. Just like 1s and 0s simply turn out to be convenient abstract moving parts for building computers, similarly a certain kind of molecule should be seen as no more than a convenient vehicle for creating a particular property. 

For practical applications that property can be anything from "better stability in whole blood" to "efficient capture of solar energy" to "tensile strength". The synthesis of whatever molecular material gives rise to particular properties is important, but it should be secondary; a convenient means to an end that can be easily replaced with another means. As an example from his own childhood, Whitesides describes a project carried out in his father's company in which his job was to determine the viscosities of different coal-tar blacks. The exact kind of coal-tar black was important, but what really counted was the property - viscosity - and not the molecular composition.

A focus on properties is accompanied by one on molecular systems instead of on individual molecules, since often it's a collection of different, diverse molecules rather than of a single type that gives rise to a desired property. What kind of problems will benefit from a molecular systems approach? Whitesides identifies four critical ones; health care, environmental management, national security and megacity management. We have already been living with the first three challenges, and the fourth one looms large on the horizon.

Firstly, health care. Right now most of the expenditure on health care, especially in the United States, is on end-of-life care. Preventative medicine and diagnostics are still relegated to the sidelines. One of the most important measures to drive down the cost of healthcare will be to focus on prevention, thus avoiding the expensive, all-out war that is often waged - and lost - on diseases like cancer during their end stages. Prevention and diagnostics are areas where chemistry can play key roles. We still lack methods that can quickly and comprehensively analyze disease markers in whole blood, and this is an area where analytical and other kinds of chemists can have a huge impact. And no method of diagnostics is going to be useful if it's not cheap, so it's obvious that chemistry will also have to struggle to minimize material cost, another goal which it has traditionally been good at addressing, especially in industry.

Secondly, the environment. We live in an age when the potentially devastating effects of climate change and biodiversity loss demand quick and comprehensive action. Included in this response will be the ability to monitor the environment, and to relate local monitoring parameters to global ones. Just like we still lack methods to analyze the composition of complex whole blood, we also lack methods to quickly analyze and compare the composition of the atmosphere, soil and seawater in different areas of the world. Analyzing heterogeneous systems with different phases like the atmosphere is a tricky and quintessentially chemical problem, and chemists have their work cut out in front of them to make such routine analysis a reality.

Thirdly, national security. Here chemists will face even greater challenges, since the solutions are as much political and social as they are scientific. Nonetheless, science will play an important role in the resolution of scores of challenges that have to be met to make the world more secure; these include quickly analyzing the composition of a suspicious liquid, solid or gas, unintrusively finding out whether a particular individual has spent time in certain volatile parts of the world or has been handling certain materials, and using techniques to track the movements of suspicious individuals in diverse locations. Chemistry will undoubtedly have to interface with other disciplines in addressing these problems and questions of privacy will be paramount, but there is little doubt that chemists have traditionally not participated much in such endeavors and need to step up to the plate in order to address what are obviously important security issues.

Fourthly, megacities. As we pick up speed and move into the second decade of the twenty-first century, one of the greatest social challenges confronting us is how to have very large, heterogeneous populations ranging across diverse levels of income and standards of living co-existing in peace over vast stretches of land. This is the vision of the megacity whose first stirrings we are already witnessing around the world. Among the problems that megacities will encounter will be monitoring air, water and food quality (vida supra). A task like analyzing the multiple complex components of waste effluent, preferably with a readout that quantifies each component and assesses basic qualities like carcinogenicity would be invaluable. There is no doubt that chemists could play an indispensable role in meeting such challenges.

The above discussion of major challenges makes Whitesides's words about moving away from the molecule clear. The problems encompassing health care, national security and environmental and megacity management involve molecules, but what they really are are collages resulting from the interaction of molecules with other scientific entities, and with the interaction of chemists with many other kinds of professional scientists and policy makers. In one sense Whitesides is simply asking chemists to leave the familiar environment of their provincial roots and diversify. What chemists really need to think of is molecules embedded in a broad context involving other disciplines and human problems.

Part of the challenge of addressing the above issues will be the proper training of chemists. The intersection of chemistry with social issues and public policy demands interdisciplinary and general skills, and Whitesides urges chemists to be trained in general areas rather than specialized subfields. Courses in applied mathematics and statistics, public policy, urban planning, healthcare management and environmental engineering are traditionally missing from chemistry curricula, and chemists should branch out and take as many of these as is possible within a demanding academic environment. It is no longer sufficient for chemists to limit themselves to analysis and synthesis if they want to address society's most pressing problems. And at the end of it they need not feel that a movement away from the molecule is tantamount to abandoning the molecule; rather it is an opportunity to press the molecule into interacting with the human world on a canvas bigger than ever before.

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.

Cryo-electron microscopy: A prime example of a tool-driven scientific revolution

Last week I had the immense pleasure again of having lunch with Freeman Dyson in Princeton. One of the myriad topics on the platter of intellectual treats on the table was the idea of science as a tool-driven rather than as an idea-driven scientific revolution. The framework was fleshed out in detail by Harvard historian of science Peter Galison in his highly readable book "Image and Logic" and was popularized by Dyson in his own book and article. I wrote a post on that particular paradigm last year.

Since physics had profited immensely from idea-driven revolutions in the 20th century (most notably relativity and quantum theory) that were enshrined by Thomas Kuhn in his idea of paradigm shifts, it took physicists some time to appreciate how tools like the cyclotron, the cloud chamber, the CCD and the laser have played an equal part in their revolutionary history. But as I told Dyson, chemists on the other hand have absolutely no problem accepting the idea of tool-driven revolutions. Chemistry more than physics is an experimental science where first principles theories are often too complicated to put into practice. Chemists have thus benefited much more from experimental toys rather than fancy theorizing, and in no other case has the ascendancy of such toys been more prominent than in the case of x-ray crystallography and NMR spectroscopy. It's hard to overstate how much these two techniques have revolutionized not just our understanding of the world of molecules but of other domains, like biology and engineering. Last year's Nobel Prize for microscopy was likewise a fitting tribute to the supremacy of tools in chemical and biological research.

Now a new technique joins the arsenal of structural weapons, and I have little doubt that it too is going to be part of a revolution - cryo-electron microscopy. ACS has a nice article on how much the technique has advanced in the last decade and how prominently it is poised to be applied to structural problems that have been recalcitrant to the old approaches. During the last few years use of the technique has skyrocketed: as this Nature article compellingly describes, cryo-EM can acquire structures of ribosomes in weeks or months that took Nobel Prize-winning scientists years to solve. And as the article says, even this revolution has benefited from a crucial tool-within-a-tool.

Over the years, gradual progress in computational power and microscope quality has yielded higher and higher resolution structures. Up until the past few years, most cryo-EM structures clocked in at well above 10-Å resolution, about the size of an amino acid. Between 2002 and 2012, only 14 structures determined by EM crossed the 4-Å threshold, dipping a toe in high-resolution territory. But a true breakthrough came in 2012 when a new toy—the direct electron detector—opened the gates, allowing for a flood of high-resolution cryo-EM structures. In 2014 alone, 27 structures have reached sub-4-Å resolution, and scientists keep pushing the boundaries. “The direct electron detector has been the biggest game changer for the electron microscopy field,” says Melanie D. Ohi of Vanderbilt University.

The direct electron detector joins a long list of specialized instruments like the Bunsen burner, the Kirchhoff spectroscope, the scintillation counter and the Geiger counter, all of which proved to be key appendages of the larger technologies which they were enabling. A good counterpart to the direct electron detector would be the CCD which revolutionized tools like cameras and telescopes and which was awarded a Nobel Prize a few years ago.

Cryo-EM will almost certainly make a big splash in the world of drug discovery in the upcoming decades. However, better experimental tools alone won't suffice for this revolution. It's sometimes underappreciated how important software and hardware were in enabling the routine application of NMR and crystallography to tough biological problems in drug design. The advent of cryo-EM similarly opens up attractive opportunities for the development of specialized software and hardware that can handle the often fuzzy, low-resolution images coming out of cryo-EM. This will especially be important for multiprotein assemblies like modular enzymes and ribosomes where multiple solutions exist for a given dataset and where computational model building will be paramount. 

As the technique proliferates, so will the data that it unearths. Someone will have to then make sense of this data, and scientific and financial rewards will await those who have the courage and foresight to found companies making specialized software for analyzing cryo-EM images. The founding of these companies with their custom hardware and software will itself be a paean to the tool-driven revolution in science, in this case one led by the computer. One tool both piggybacking on and enabling another tool, that's how science progresses.

Added: Here's a nice application of cryo-EM in resolving crystals of the protein alpha-synuclein that are essentially 'invisible'.

Image source

How Linus Pauling almost gave Matt Meselson tellurium breath

Matt Meselson

Linus Pauling was the greatest chemist of the twentieth century. Matt Meselson devised the ingenious Meselson-Stahl experiment and almost single-handedly convinced Nixon and Kissinger to get rid of chemical and biological weapons (a feat for which he more than almost anyone else deserves a long overdue Nobel Prize).

But Meselson almost did not get around to doing these things, partly because Linus Pauling once came a step away from dooming him to a joyless existence of social expulsion when he was Pauling's graduate student. Here's the story as recounted fondly by Meselson at a Pauling anniversary celebration.

"That fall, in 1953, it came time for me to have a research problem, so I went to see Linus in his office in the Crellin Lab, and he took a rock down off of a shelf near his desk and announced that this was a tellurium mineral -- he had worked on tellurium minerals, years earlier -- and that this would have an interesting crystal structure. The discussion went something like this:

LP: Well, Matt, you know about tellurium, the group VI element below selenium in the periodic chart of the elements?
Me: Uh, yes. Sulfur, selenium, tellurium ...
LP: I know that you know how bad hydrogen sulfide smells. Have you ever smelled hydrogen selenide?
Me: No, I never have.
LP: Well, it smells much worse than hydrogen sulfide.
Me: I see.
LP: Now, Matt, Hydrogen telluride smells as much worse than hydrogen selenide as hydrogen selenide does compared to hydrogen sulfide.
Me: Ahh ...
LP: In fact, Matt, some chemists were not careful when working with tellurium compounds, and they acquired a condition known as "tellurium breath." As a result, they have become isolated from society. Some have even committed suicide.
Me: Oh.
LP: But Matt, I'm sure that you would be careful. Why don't you think it over and let me know if you would like to work on the structure of some tellurium compounds?"

The breadth of Carl Djerassi's scientific work

One measure of the diversity of Carl Djerassi's work can be gained from a simple diversity analysis of the top 50 of his most cited papers - he wrote more than 1200. The articles range from pure synthetic methodology to novel natural product isolation and structure determination to marine steroid biosynthesis to circular dichroism to artificial intelligence to mechanistic organic chemistry.

Here's a sampling based on a listing of those top 50 in Scifinder. And this of course does not even consider his very substantial second career in the arts and humanities. A towering intellect and a role model for the rest of us to emulate. 

Mass spectrometry in structural and stereochemical problems. XXXII. Pentacyclic triterpenes

• By Budzikiewicz, H.; Wilson, J. M.; Djerassi, Carl
• From Journal of the American Chemical Society (1963), 85(22), 3688-99.  |  Language: Unavailable, Database: CAPLUS

Minor and trace sterols in marine invertebrates.  26.  Isolation and structure elucidation of nine new 5α,8α-epidoxy sterols from four marine organisms

• By Gunatilaka, A. A. Leslie; Gopichand, Yalamanchili; Schmitz, Francis J.; Djerassi, Carl
• From Journal of Organic Chemistry (1981), 46(19), 3860-6.  |  Language: English, Database: CAPLUS

Structure and the optical rotatory dispersion of saturated ketones

• By Moffitt, William; Woodward, R. B.; Moscowitz, A.; Klyne, W.; Djerassi, Carl
• From Journal of the American Chemical Society (1961), 83, 4013-18.  |  Language: Unavailable, Database: CAPLUS

Organic sulfur compounds. VI. Cyclic ethylene and trimethylene hemithioketals

• By Djerassi, Carl; Gorman, Marvin
• From Journal of the American Chemical Society (1953), 75, 3704-8.  |  Language: Unavailable, Database: CAPLUS

Oxidations with ruthenium tetroxide

• By Djerassi, Carl; Engle, Robert R.
• From Journal of the American Chemical Society (1953), 75, 3838-40.  |  Language: Unavailable, Database: CAPLUS

Steroids from sponges

• By Sheikh, Younus M.; Djerassi, Carl
• From Tetrahedron (1974), 30(23/24), 4095-103.  |  Language: English, Database: CAPLUS

Biosynthetic studies of marine lipids.  41.  Sponge sterols:  origin and biosynthesis

• By Djerassi, Carl; Silva, Christopher J.
• From Accounts of Chemical Research (1991), 24(12), 371-8.  |  Language: English, Database: CAPLUS

Brominations with pyridine hydrobromide perbromide, C5H5N.HBr.Br2

• By Djerassi, Carl; Scholz, Caesar R.
• From Journal of the American Chemical Society (1948), 70, 417-18.  |  Language: Unavailable, Database: CAPLUS

Mechanism of hydride reduction of 1-alkyn-3-ols

• By Grant, Barbara; Djerassi, Carl
• From Journal of Organic Chemistry (1974), 39(7), 968-70.  |  Language: English, Database: CAPLUS

Applications of artificial intelligence for chemical inference.  I.  Number of possible organic compounds.  Acyclic structures containing carbon, hydrogen, oxygen, and nitrogen

• By Lederberg, Joshua; Sutherland, Georgia L.; Buchanan, Bruce G.; Feigenbaum, Edward A.; Robertson, Alexander V.; Duffield, Alan M.; Djerassi, Carl
• From Journal of the American Chemical Society (1969), 91(11), 2973-6.  |  Language: English, Database: CAPLUS

Structure of the antibiotic methymycin

• By Djerassi, Carl; Zderic, John A.
• From Journal of the American Chemical Society (1956), 78, 6390-5.  |  Language: Unavailable, Database: CAPLUS

Carbon-13 nuclear magnetic resonance spectra of acyclic aliphatic amines

• By Eggert, Hanne; Djerassi, Carl
• From Journal of the American Chemical Society (1973), 95(11), 3710-18.  |  Language: English, Database: CAPLUS

Alkaloids. LII. The alkaloids from Vallesia dichotoma

• By Walser, A.; Djerassi, Carl
• From Helvetica Chimica Acta (1965), 48(2), 391-404.  |  Language: German, Database: CAPLUS

Carl Djerassi (1923-2015): Chemist, writer, polymath, cultural icon

R B Woodward, Vladimir Prelog and Carl Djerassi on the beach at a conference in Riga, Latvia. Photo signed by Djerassi and generously gifted to the author by Prof. Jeffrey Seeman, University of Richmond.

Very few scientists of the 20th century have had as much of both a scientific as well as a cultural impact on the world as Carl Djerassi. It is a measure of how many things Djerassi excelled at that even his amazing purely scientific career seems like a distant horizon. While most scientists are quite happy to become world-renowned in their narrow subfield of science, Djerassi polished off multiple fields of chemistry and then reinvented himself as a notable playwright and writer. And he did all this after significantly contributing to one of the greatest social revolutions of the 20th century, if not of all time - safe, affordable and easily accessible contraception for women. Very few technical inventions in history contributed to giving women control over their lives the way the pill did. Scientists are usually not cultural icons, and the wrong people often are, but Djerassi definitely deserves to be one.

On his 90th birthday, my friend, the noted historian of chemistry Jeff Seeman summarized a few of Djerassi's astonishing contributions and honors:

He has published more than 1,200 scientific papers, 350 in the Journal of the American Chemical Society.

He is a chemical “father of the Pill.”

He has published three autobiographies, one memoir, five novels, two nonfiction books, 11 plays, two collections of poetry, three collections of essays and short stories, and one art book.

He has made significant contributions, in cash and in kind, to charitable causes and artistic endeavors.

He has received the National Medal of Science and the National Medal of Technology.

He has been awarded the Priestley Medal, the first Wolf Prize in Chemistry, and many other awards, as well as 32 honorary doctorates.

He has been recognized by Austria with a postage stamp issued in his honor.

He is in constant demand as a lecturer around the world.

He will turn 90 on Oct. 29.

Yet, Carl Djerassi has never been fully satisfied.

I first encountered Djerassi's work when as an undergraduate I studied the octant rule that he, R B Woodward, Bill Moffit and others pioneered to study the configuration of steroids. Nobody really uses it anymore since more sophisticated methods like NMR spectroscopy have superseded it, but as I came to know more about Djerassi's contributions, it amazed me that the same man who published the octant rule also pioneered the use of mass spectrometry in natural products chemistry, unraveled the biosynthesis of several key steroids and alkaloids and also published some of the first papers on the applications of artificial intelligence in organic chemistry. His 1200 papers span the breadth of the discipline, and among younger chemists only Clark Still comes to my mind as someone who had the same diversity of contributions.

Djerassi's autobiography ("Steroids Made It Possible") which is edited by Jeff is wonderful and a real treat. In it he talks about a variety of scientific and private topics, ranging from the letter to Eleanor Roosevelt that got him a college scholarship to his experiments with mescaline to his accidental grin in the photo showing Richard Nixon awarding him the National Medal of Science (he hated Nixon and in fact was on Nixon's silly "enemies" list, but Nixon said something funny right at the moment the photo was taken). The book also contains painful ruminations such as the one about his daughter's struggle with addiction and her suicide. Djerassi was nothing but upfront about his life, both in this memoir as well as his subsequent two books, the latest of which just came out and which I haven't read yet. 

His writings are also studded with sketches of great chemists like R B Woodward, Gilbert Stork, Bill Johnson and E J Corey, most of whom Djerassi counted among his close friends and colleagues. In some sense, a journey through his science is a journey through the development of postwar organic chemistry in its golden age. And speaking of R B Woodward, Djerassi managed to become the highest cited chemist of the 60s - at a time when his friend had already staked his claim as the the greatest organic chemist of the century and continued to publish seminal papers. That's no small feat.

Djerassi was of course also a noted playwright, reinventing himself during the second half of his life and crafting the play "Oxygen" with his fellow chemist Roald Hoffmann for instance. He was a great example of someone who bridged C P Snow's two cultures, inculcating and displaying a wide storehouse of knowledge ranging from philosophy and art to literature and science. His shares in Syntex Corporation where he researched steroids also made him a wealthy man and allowed him to do this. It also enabled him to retire early, amass an enviable private art collection and spend part of every year in London and other parts of Europe writing and giving talks. His fiction is well worth reading, and his characters are as interesting and honest as the science he pioneered.

Most laymen will of course always know Djerassi as one of the fathers of the contraceptive pill, although those of us who are aware of his chemical contributions appreciate that it was but one part of his prolific career. As many of us also know, Djerassi was a favorite on Nobel Prize lists for a long time, and as they did with many other scientists, the Nobel Prize committee did themselves a disservice by not awarding him one. But Djerassi's career more than that of most others indicates the irrelevance of prizes, as honorable as they may be. In that sense Djerassi is like Gandhi. His work was beyond prizes, and considering the social revolution that The Pill brought about, he will always stand not only as one of the scientific greats of the 20th century but as one of its most important human beings. RIP.