What would Woodward say?: Giants of chemistry in the year 2011

Science progresses by leaps and bounds, but it's not easy to chart its progress. Metrics can only do so much to quantify scientific developments.

Yet there are periods when it's clear that the rate of progress in certain scientific fields is phenomenal. For instance, nobody can deny that physics underwent an earth-shattering transformation in the first thirty odd years of the twentieth century, perhaps the greatest it ever experienced. With relativity and quantum mechanics completely changing our view of nature, a physicist who had been flash-frozen in 1900 and resurrected in 1930 would have found the state of his science almost surreal. Similarly, biology completely changed itself and our view of life between 1950 and 2000.

What about chemistry, and especially chemistry in the last few decades? While any quantification of chemical progress is ultimately subjective, it would be an amusing and instructive exercise to ask what some of the pioneers of chemical science would have felt about the state of their discipline if they had been flash-frozen just before they died and brought back to life in the year 2011. Viewing today's world through the eyes of these men and women could be a good way to discover exactly how much their field has changed.

Let's step into a time machine then and bring back four distinguished scientists into the modern age, each of whom gained lasting fame in a distinct and key area of chemistry. Robert Burns Woodward, Linus Pauling, Irving Langmuir and Alfred Werner were all giants of chemistry. Let's imagine the reaction of each one of them to modern day chemical science, especially in their own field. How about starting with you, Prof. Woodward...

1. What would Woodward say?

"It's quite something to be transported to the year 2011 and I am glad that the technology of time travel has developed rapidly enough to make this possible. When I died in 1979 I had already pioneered the synthesis of complex molecules. I am somewhat disappointed that the state of that science, while consistently strong, has not seen any fundamental transformations in the nature of the molecules being synthesized. Using more primitive and time-intensive methods, I am confident that I could have synthesized in 1980 almost any molecule which my colleagues are synthesizing in 2011. I am however very impressed by two major advances which I did not foresee during my lifetime.

The first is the staggering growth of organometallic chemistry. With my role in the discovery of ferrocene I consider myself a founder of the field, but I could not possibly have seen such tremendously useful applications of palladium catalyzed reactions, asymmetric epoxidations and olefin metathesis. I offer my most enthusiastic congratulations to the pioneers of these novel methods. As an aside, I am also quite taken by how efficient and routine asymmetric synthesis has become. My synthesis of reserpine is considered one of the first examples of stereoselective syntheses, but the total synthesis of the same molecule by my friend Gilbert Stork in 2006 seems so much more sophisticated and rich with applications of conformational analysis and stereocontrol.

If I am impressed with the development of organometallic chemistry, I am floored by the rise of chemical biology and chemical genetics. By the time I died there were already many very competent biochemists around, but there was no concerted application of chemical synthesis to an understanding of biology. This was partly because we lacked an understanding of biological systems that was made possible by the phenomenal developments in molecular biology that followed my death. It's quite amazing to witness the routine study and manipulation of complex biological pathways using intricately designed molecules. I can only see a bright future for these ideas in chemistry and medicine, and am glad that my student Stuart Schreiber has been one of the pioneers in the field.

Well, that was nice. But I need to go back now and spend my last few days working on ideas for organic superconductors."

2. What would Pauling say?

"How wonderful to be here! Having been fortunate enough to have lived for the first 93 years of one of the most important centuries that we humans have lived in, I still could not make it to 2011 to witness the achievements of chemistry in the twenty years since my death.

Many people consider me the greatest chemist of the twentieth century and I did indeed cross disciplinary boundaries with impunity, having worked significantly in theoretical chemistry, organic chemistry, biochemistry and medicine. So there is a lot of ground to cover.

Let me start by looking at progress in the field which I am most known for. By the time I died, computers had already become prominent in molecular orbital calculations, although I could not possibly have foreseen how fast and small they would become. I am glad that computational chemistry has turned into an independent field of chemistry. It still seems almost as challenging as it was then to apply theoretical methods to complicated systems and especially biological systems, but I feel gratified by the development of 'mixed' methods such as quantum mechanics-molecular mechanics (QM/MM) which simplify calculations without sacrificing accuracy. I must especially congratulate my last student, Martin Karplus, for pioneering the applications of theoretical methods to biological systems. I see a continuing bright future in this area, along with further developments in computer science that would allow us to tackle complex systems. I am especially gratified that these methods have brought computation to the masses, so that even non-specialists can now do detailed calculations and get useful answers.

As someone who is considered to be one of the founders of molecular biology, I was fortunate to have lived long enough to witness the rise of recombinant DNA technology. But like Prof. Woodward I too am very impressed with the rapid growth of chemical genetics in the last twenty years. I am very happy that chemists have taken my ideas about molecular recognition to heart and that they continue to use these ideas to develop new drugs and antibodies against diseases. I am also awed by the sheer amount of information coming out of genetic sequencing, and as someone who described the first genetic disease at a molecular level (sickle cell anemia), I am proud that scientists are now routinely exploring the molecular basis of genetic disease as an aid to develop personalized drugs. As a chemist, I would however caution against putting too much faith in the data itself and actually looking at the molecular events.

Overall then, I am very pleased to witness this growth of science. However I must also reinforce my commitment to peace (after all I did win a Nobel Peace Prize) and emphasize that this growth should serve both the most and the least fortunate among us. We do science not just for ourselves but for others"

2. What would Langmuir say?

"It's somewhat amusing for me to realize that I am almost as famous for my description of "pathological science" and pseudoscience as I am for my eponymous isotherm. But let's stick to the actual science. I died in 1957 and I was awarded a Nobel Prize for surface chemistry in 1932. I cannot even begin to express my amazement at the phenomenal advances in surface and related sciences since my death which have partially been honored with the Nobel prize in 2007.

When I died I could not have imagined in my wildest dreams that someday we could have instruments that could literally map a surface atom by atom, sensitively rolling over the contours of a molecular landscape the way a finger might roll over a bed of marbles. The invention of the scanning tunneling and atomic force microscopes have given us a tactile view of the atomic world that is beyond anything we could have dreamt of in 1957. I am fascinated by the emergence of the entirely new discipline of nanoscience which was only being imagined in 1957 (Author's note: For instance Richard Feynman gave his famous talk about nanotechnology in 1959). I can only assume that this amazing molecular manipulation of matter will continue and will pay dividends in both pure and applied science.

Speaking of pure science, before I leave I feel a strong urge to step on my soapbox and lament its decline. Anyone who thinks that high-quality basic science cannot be sustained in industry should only cite my example. I spent my entire career at GE and yet become the first industrial scientist to win a Nobel Prize in chemistry. When I scan the history books I find many other industrial labs like IBM and especially Bell Labs that were hotbeds of prizewinning scientific talent; for crying out loud, the scanning tunneling microscope that we mentioned was developed at IBM and its developers won the Nobel Prize.

How times have changed! Former industrial labs like Bell Labs are now either non-existent or are mere shadows of their former selves. As my own example demonstrates, basic science in industry was one of the things that made this country great, and its decimation can only lead to a great decline in America's scientific health. Let me say this out loud; a nation which lionizes short-term profits at the cost of long-term investment in curiosity-driven basic science is on its way to scientific mediocrity. I dearly hope that the next generation reverses this damning trend.

On these dual notes- positive regarding the state of nanoscience but negative regarding the state of scientific research- I must now take your leave."

4. What would Werner say?

"I died in 1919, so the world that is being presented to me in 2011 is in every way beyond recognition. But let me stick to my field. I am often called the "father of coordination chemistry" but I would be lying if did not say that I barely recognize my children. At the same time I am as proud as any parent can be that my field has progressed beyond its original borders and become a vast and productive enterprise.

I merely demonstrated the existence of several inorganic complexes and postulated the concepts of primary and secondary valences and isomerism. But I had little inkling about the precise nature of bonding in these complexes. Now I see that it was about the time that I died that Irving Langmuir and Gilbert Lewis were developing ideas about the shared chemical bond. I am of course very impressed by the contribution of Linus Pauling who pioneered ideas about electroneutrality and the partial covalent character of ionic bonds. It is truly astonishing how much our knowledge of chemical bonds has developed.

However it is to scientists like Hans Bethe, John van Vleck, Carl Ballhausen and Leslie Orgel that I must doff my hat. These scientists delineated the precise nature of bonding in coordination complexes. How wonderful it is to read about the relatively simple rules that predict the coordination number of a ligand, the propensity of certain ligands to bond to certain metals, and whether a complex is high spin or low spin. I can see that my tentative ideas have been placed on a sound theoretical footing.

Ultimately however, I am astonished by the application of coordination chemistry in industry and biology. It cannot be anything but gratifying to know that EDTA can be used to mitigate lead poisoning and that other ligands can be used to mop up chemical spills. And it seems that my studies have ultimately been a part of the entire field of bioinorganic chemistry where ideas about coordination complexes are used to study the interaction of metal ions with proteins.

I feel humbled that I played a role in the development of such an important and major area of chemistry, and I feel confident that this field will thrive. I go back to my own times with the reassurance that my children will continue to instruct, grow and proliferate."

And so we can all hope and strive so that the intellectual children of these four and countless other chemists will instruct, grow and proliferate.

Who are the greatest chemistry teachers?

In April 2009, Physics Today celebrated the life of physicist John Archibald Wheeler with a special issue. Not only was Wheeler one of the great scientific minds of the twentieth century, but he was also a legendary teacher who influenced an entire generation of physicists. As one of the articles in the issue notes, Wheeler supervised more PhD theses at Princeton University than any professor in the history of the department. His graduate students included Richard Feynman and Kip Thorne. But the real impact of Wheeler's mentorship is obvious from an even more striking fact- he supervised more senior undergraduate theses than anyone else. And even when he became a world-famous physicist, Wheeler still taught the freshman physics course. The article concludes by suspecting that Wheeler's influence as a mentor probably exceeds even his great influence as a scientist.

This got me thinking. Who are the great teachers of chemistry? As in the case of the greatest chemist discussion, the answer seems to be easier to answer in case of physics. A roster of great twentieth-century physicist-teachers immediately brings to mind the names of Arnold Sommerfeld, Niels Bohr, Max Born, Ernest Rutherford, Robert Oppenheimer, Isidor Rabi, Wheeler and many others. What great scientists would populate a similar list of outstanding chemist-teachers?

Fist let's lay out the criteria for being a great teacher. Simply supervising a large number of PhD students may be important but is not enough since PhD students are usually essential for research and are also lamentably often utilized as cheap labor. Undergraduate teaching will definitely count highly on the list since it usually takes a genuine love of teaching to divert precious time toward elementary courses. Then there's the matter of pedagogy, often displayed through first-rate textbooks. Great chemists who made concerted efforts to educate through the writing of timeless textbooks will also count.

But ultimately, nothing counts as much as inspiring students and immersing them in the philosophy of your subject, giving them a sense of the "taste" of the discipline, communicating to them the excitement of doing research and asking questions that will stay with them throughout their careers. A great teacher who may not be ideally suited for classroom teaching will still make the list if he invites his students for long walks and afternoon tea to engage them in informal and intense discussions about science. For instance, Robert Oppenheimer almost never taught an undergraduate class and his lectures were often opaque to everyone but the best students. Yet he managed to create the finest school of modern physics in the United States in the 30s and 40s, largely because of his immense charisma and brilliance and the sense of truly working at the frontier of physics that he communicated to his students. After classes, Oppenheimer would often invite his students out for dinner and spend the evening listening to classical music and discussing physics. As Hans Bethe put it:

Probably the most important ingredient Oppenheimer brought to his teaching was his exquisite taste. He always knew what were the important problems, as shown by his choice of subjects. He truly lived with those problems, struggling for a solution, and he communicated his concern to the group

So who then are the great chemist-teachers? As usual this represents a limited collection of my personal favorites. Incidentally, the greatest chemist of the twentieth century was also one of its greatest teachers. When Linus Pauling was teaching undergraduates at Caltech and could not find a satisfactory textbook, he wrote his own. "General Chemistry" is still in print and still quite readable. With E. Bright Wilson, Pauling also wrote "Introduction to Quantum Mechanics", the first modern quantum chemistry textbook. And then there's of course the momentous "The Nature of the Chemical Bond" which was known not only for its science but for its superb pedagogy. Pauling's lecture demonstrations to undergraduates were also well-known. A student of his described how Pauling would rapidly juggle a lump of sodium in his hands and talk at length about sodium's vigorous reaction with water, all the while warily eyeing a beaker of water on the table. The lump would then "accidentally" fall into the beaker. While everyone including Pauling ducked, nothing would happen, and Pauling would nonchalantly add, "But its reaction with alcohol is much less violent". Another chemist who taught through explosions and colors was Hubert Alyea at Princeton. Sadly, the art of the lecture demonstration seems to be lost to modern chemical education.

Speaking of textbooks, one cannot forget the author as great teacher. Sadly many of them are now forgotten and deserve to be resurrected. For some reason British authors especially stand out as marvelous pedagogical expositors in the classical tradition. A true gem for instance is "Valence" by Oxford theoretical chemist Charles Coulson whose crystal clear treatment of quantum chemistry has stood the test of time. A fair number of students who trained with Coulson later became outstanding theoretical chemists in their own right. I would place him high on the list. Then there's Stuart Warren, coauthor of my favorite organic chemistry textbook who also wrote one of the definitive books on retrosynthetic analysis. And there's the little known and under-appreciated "Guidebook to Mechanism in Organic Chemistry" by Peter Sykes which in my opinion is the most devastatingly concise and clear treatment of the subject ever written. In Sykes's hands, nucleophilic substitution sounds like a well-crafted violin sonata.

Among American authors I would name Morrison and Boyd, not famous scientists but authors of an outstanding organic chemistry text (which unfortunately was not updated). Ernest Eliel's book taught stereochemistry to a generation of organic chemists and I have always had it on my shelf. There's F. Albert Cotton's definitive textbook on inorganic chemistry; Cotton was also known as a prolific trainer of PhDs. And there's biochemistry volumes by Albert Lehninger and Lubert Stryer which are both pillars of authority and clarity in their field.

In the early part of the century the center of scientific excellence was in Europe. The great European chemists Svante Arrhenius and Walther Nernst were both extremely influential as mentors. So were Robert Robinson and Leopold Ruzicka. Harvard chemist Theodore William Richards who won the Nobel Prize for his accurate determination of atomic weights deserves special mention; his students included G N Lewis, Roger Adams and James Bryant Conant. Lewis himself was the most influential chemist of his time and imparted his style of thinking to many outstanding chemists, including Glenn Seaborg.

Let's talk about the latter half of the century. Robert Burns Woodward did not teach undergraduate courses and in fact in his later years was known to be pre-occupied with his own research to the detriment of his students. Yet Woodward's influence was so towering that his students adopted his style merely by being around him. In his earlier years he was known as a great teacher, especially by way of his famous Thursday seminars which used to last into the night. Woodward's students have populated the corridors of organic chemistry and the impact of his way of doing chemistry is undeniable. So is E J Corey's. I don't know if Corey taught undergraduates, but he has trained hundreds of students and postdocs who have carried his science all around the world and the sheer reach of Corey's chemistry and philosophy is probably greater than of any organic chemist in history. A traditional pilgrimage to Corey's lab for a postdoc was like a mandatory pilgrimage to one of the great European centers of physics in the early twentieth century. Corey qualifies as a great guide in spite of some unfortunate stories from his lab.

Caltech chemist Jack Roberts also stands out for two things- training students like George Whitesides, and writing some great books; one of the earliest accounts of MO calculations for American students, a first-rate organic textbook co-authored with Marjorie Caserio and an excellent volume on NMR basics. Another great mentor is Ronald Breslow who has trained three generations of chemists that have filled up the top ranks of academic chemistry; Nobel laureate Robert Grubbs for instance got his PhD with Breslow. Finally I want to note Dudley Herschbach who was also known for teaching introductory chemistry at Harvard and who willingly accepted the responsibility of being the c0-master of a dorm.

We could go on. There are of course many who I have not noted, and I invite others to offer their own examples. Sadly this list is fundamentally unfair since it leaves out outstanding college professors who are not very well-known as scientists. Such a list would be especially valuable.

In an age where universities are increasingly weighing the value of professors based almost exclusively on their grant-winning capabilities, it's worth reminding our institutions that fifty years ago teaching was taken as seriously as research. And as the above examples demonstrate, there is absolutely no discrepancy between being a world-class scientist and a world-class teacher. Teaching introductory chemistry and being a Nobel laureate are not diametrically opposed concepts. In many ways mentorship goes much further than research ideas. It's a lesson worth remembering.

Is the age of traditional organic synthesis over?

The Skeptical Chymist pointed me to a list of top 10 chemists from 2000-2010 produced by ISI /Thomson Reuters. I am copying the list from the Chymist's post:

"The data given is all from ISI/Web of Science: papers published, citations and 'impact' (citations per paper). I'll give you the top ten here:
Charles M. LIEBER; Harvard University (74 papers, 17,776 citations, 240.22 c/p)
Omar M. YAGHI; University of California Los Angeles (90, 19,870, 220.78)
Michael O’KEEFFE; Arizona State University (73, 12,910, 176.85)
K. Barry SHARPLESS; Scripps Research Institute (60, 9,754, 162.57)
A. Paul ALIVISATOS; University of California Berkeley (93, 14,589, 156.87)
Richard E. SMALLEY†; Formerly Rice University (60, 9,217, 153.62)
Hongjie DAI; Stanford University (88, 12,768, 145.09)
Xiaogang PENG; University of Arkansas (59, 8,548, 144.88)
Valery V. FOKIN; Scripps Research Institute (54, 6,853, 126.91)
Peidong YANG; University of California Berkeley (95, 11,167, 117.55)"

The most striking thing about this list for me is the lack of hard-core organic chemists in there. There are two bona fide synthetic chemists (Sharpless and Fokin) and no total synthesis people. Almost any such list from the 50s through the 90s would have been dominated by organic chemists engaged in methodology and total synthesis. Of course, as an enabling discipline synthesis is still key for all the research carried out by these heavy hitters. Organic synthesis will still be ubiquitously embedded in key chemical innovations. Organic chemists will still make important contributions and their syntheses will continue to be works of art imbued with elegance and economy. But organic chemistry as seen and practiced for forty exciting years by the old guard seems to be distinctly on the wane. I can almost sense a sigh and the wistful note of nostalgia.

Instead, what obviously dominates the list is nanotechnology and materials science. The materials range from pure inorganic materials to organic-inorganic hybrids to biomaterials. Materials science has clearly reigned during the past decade and will probably dominate the chemical landscape even more in the future. I suspect that other lists using different indices will come up with a similar smattering, perhaps with some more core biological chemists thrown in.

Perhaps the old guard of organic synthesis can seek respite in Tennyson's immortal lines:

"Though much is taken, much abides; and though

We are not now that strength which in old days

Moved earth and heaven; that which we are, we are;

One equal temper of heroic hearts,

Made weak by time and fate, but strong in will

To strive, to seek, to find, and not to yield.

It's been a fantastic run, but it's time we moved on.

How can we make the International Year of Chemistry successful?

2011 has been designated by the UN as the "International Year of Chemistry". As a community of chemists, for us the question is simple: What can we do to make this year successful and enhance the public's appreciation of chemistry? Here are three core aspects of chemistry which I think should be constantly highlighted:

1. Explain to the public the essential nature and unique philosophy of chemistry: As a field, chemistry is inherently more challenging to pitch to the public compared to physics or biology. If you are a physicist and you say to a layman that you are investigating the Big Bang, you don't have to say anything more to get his or her attention. A biologist who works on human evolution will get similar nods. But what about chemists? One of the reasons for the relatively dim public appreciation of chemical science was mentioned before; it is because the field apparently lacks "big ideas" that people can instantly latch on to (but see below). But what chemistry may lack in terms of the grand picture, it more than compensates for in terms of its identity as a "central science" and the sheer number of explanations and applications that it lends to almost every other discipline, from physics and biology to art and engineering. No other field does this in such a palpable way. In this sense chemistry is akin to engineering, but much more fundamental.

The chemist more than any other kind of scientist is a discerning arbiter of patterns and a patterner of chaos. One of the most striking manifestations of this quality is in the beautiful structures that chemists draw and encounter every single day. Chemists look at structures the way artists look at mosaics of colors and architects look at geometric patterns of tiles. What other kind of scientist spends his or her professional workday doodling and evaluating lines, rings and their myriad intersections? In its ability for visualization and pattern analysis, chemistry comes closer to art than any other science, and the public needs to appreciate this supremely important aspect of the discipline.

But it is in its ability to make new things which never existed before that chemistry is wholly unique. In the last few years synthesis and especially total synthesis have taken some flak as somewhat self-serving activities geared toward factory-style publication and the nurturing of slave labor, but it cannot be denied that synthesis is what makes chemistry different from all other disciplines. No other science can boast the creation of new substances that have improved every facet of human life, from the conquest of disease to the feeding of the poor. Of course chemistry also led to poison gas and nerve gas but this was true of other disciplines too. The fact remains that chemistry has modeled and sculpted the material world familiar to the layman more than any other science. Other fields provided valuable input to the principles behind synthesis, but the end products were those of chemistry alone, shining examples of the very ability of human beings to create, manipulate and improve. In the future chemistry promises us improved materials for alternative energy and designer drugs and biomolecules for treating disease. Convince the layman of the enduring centrality of synthesis, and you would have convinced him or her of the essential value of chemistry.

2. Push the origin of life as chemistry's "big idea": We mentioned above that chemistry seems to suffer from a lack of big ideas as compared to physics and biology and that this is partly responsible for its lackluster public perception. But as I indicated in my last post, there is actually a problem as big as any other which is primarily within the domain of chemistry. This is the origin of life within its broader framework of self-assembly. God must have been a molecular self-assembler, because without self-assembly the first components of life could not bond to each other and the first cells could not form and segregate their cargo, sparking the interactions and reactions that led to replication and metabolism. Darwin solved the second problem of what happens when life gets started, but not the first one of how it all began. Again, other sciences will continue to contribute to the unraveling of this problem, but the first step was uniquely chemical. A narrating of the origin of life as a quintessentially chemical question would also lead to a general exposition on self-assembly (important in diseases caused by protein misfolding) as well as a spirited homily on the central importance of weak interactions and hydrogen bonding.

3. Emphasize the crucial connections of chemistry with medicine and materials science again, and again and again...: It's official. The biggest practical contributions of chemistry to the betterment of human life have undoubtedly been in the discovery of new drugs and new materials. It is remarkable that every one of us benefits from these tangibles at every moment of day and night and yet fails to recognize the essential role that chemistry played in their creation. Since almost all of us know someone who has been afflicted or taken by a terrible malady, one would think that the public would be singing chemistry's praises for saving lives. Yet most people seem to think that it's doctors who discover new medicines. Quiz people about great medical advances and they would enthusiastically tell you about Alexander Fleming and Jonas Salk, but not about Gerhard Domagk or Gertrude Elion. This perception has got to change. Chemists are as responsible as doctors, if not more, for most of the live-saving drugs developed in the past century and will be responsible for many more in the coming one. The era of rational drug discovery was essentially ushered in by chemistry, and it will likely bring us novel advances in the form of designer proteins and small molecules as selective drugs against new threats. The public needs to know this crucial function of chemistry, and it can only be accomplished by drilling the facts into the public's mind eloquently and ad nauseam.

The other field where chemistry promises world-changing discoveries is in materials science and nanotechnology, especially as applied to energy. With climate change looming on the horizon, the next generation of breakthrough solar cells or other technologies may change the lives of millions, dramatically reduce our carbon footprint and impact the international geopolitical landscape. A central player in this seismic shift will undoubtedly be chemistry. The public now thinks very highly of nanotechnology but very few people realize that chemists have been practicing nanotechnology since their discipline gradually emerged from the shadows of alchemy. Polymers have revolutionized our lives as much as anything else. In the future polymers will contribute in novel ways such as drug delivery vehicles and smart materials in electronics engineering and space science. Organic electronics is another lucrative area of polymer science which will pay huge dividends in improving communications technology, leading to improvements in everything from healthcare to education. As the world inches closer to potentially devastating climate change and its global and social repercussions, chemistry will undoubtedly play its important role in saving the planet.

By bridging all other disciplines, enabling human progress and knitting the tapestry of the material universe, chemistry encircles the world. This is our chance to let everyone know.

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