What does mercury being liquid at room temperature have to do with Einstein's theory of relativity?

Image: Wikipedia Commons

One of the great moments in twentieth century science came when Paul Dirac married quantum mechanics with Einstein's Special Theory of Relativity to produce relativistic quantum mechanics. Dirac's theory did many things - predict electron spin and the positron, analyze atomic collisions, jump-start the revolution in quantum electrodynamics - but it also had very significant repercussions for chemistry. However these repercussions did not become known for another few decades because it turned out that for solving most problems in chemistry you could neglect relativistic effects. Figuring out chemical bonding, predicting the thermodynamic properties of molecules and rates of chemical reactions, understanding the molecular glue that holds proteins together; all these problems succumbed to calculation without chemists worrying about relativity.

All except one problem, that is. And it deals with a question that every child since antiquity has asked: Why is mercury liquid at room temperature? Mercury - the only metal with this property - has beguiled and fascinated men for centuries; a glittering substance that flows with studied gravity, supports the weight of coins, magically seems to dissolve other metals and resists all attempts to scoop it up. A substance that can aid health when calibrated inside a thermometer and can kill when it accumulates in living tissues. But the one quality of mercury that is apparent to everyone who has even the slightest acquaintance with it is its liquid nature.

Why is this so? It turns out that sometimes simple observations in science can have complicated although very interesting explanations, and this is one of those cases. Fortunately the crux of the matter is simple, and it has received its most complete and satisfying treatment in a recent paper published in the journal Angewandte Chemie. But first let's go back to the basics. Mercury is a metal, which means that it occupies the middle of the periodic table along with other metals like gold, zinc and cadmium. In fact it is in the same group as zinc and cadmium, and yet it couldn't be more different from them. Zinc and cadmium are not liquids at room temperature and they crystallize in a different form from mercury. In addition mercury is right next to gold, and yet their properties are utterly dissimilar.

Recall from college chemistry that atomic orbitals come in different flavors; s, p, d and f orbitals are distinguished by different quantum numbers and different "shapes". Metals are characterized by significantly occupied d orbitals. In addition, filled orbitals imply special stability. The singular fact that distinguishes mercury from its neighbors is that it has a filled outermost 6s atomic orbital. This means that the electrons in the orbital are happily paired up with each other and are reluctant to be shared among neighboring mercury atoms. Where the theory of relativity comes in is in accounting for subtle changes in the masses of the electrons in mercury and the atomic radii which nonetheless have profound effects on the physical properties of the metal.

According to special relativity, the apparent mass of an object increases as its velocity approaches the speed of light. From Niels Bohr's theory of atomic structure we know that the velocity of an electron is proportional to the atomic number of an element. For light elements like hydrogen (atomic number 1) the velocity is insignificant compared to the speed of light so relativity can be essentially ignored. But for the 1s electron of mercury (atomic number 80) this effect becomes significant; the electron approaches about 58% of the speed of light, and its mass increases to 1.23 times its rest mass. Relativity has kicked in. Since the radius of an electron orbit in the Bohr theory (orbital to be precise) goes inversely as the mass, this mass increase results in a 23% decrease in the orbital radius. This shrinkage makes a world of difference since it results in stronger attraction between the nucleus and the electrons, and this effect translates to the outermost 6s orbital as well as to other orbitals. The effect is compounded by the more diffuse d and f orbitals insufficiently shielding the s electrons. Combined with the filled nature of the 6s orbital, the relativistic shrinkage makes mercury very reluctant indeed to share its outermost electrons and form strong bonds with other mercury atoms.

The bonding between mercury atoms in small clusters thus mainly results from weak Van der Waals forces which arise from local charge fluctuations in neighboring atoms rather than the sharing of electrons. But all this was conjecture; someone had to do the rigorous calculations, treating every electron in the element relativistically and calculating the relevant properties. In this case the relevant property is the heat capacity of a substance which dramatically changes during a phase transition, say from solid to liquid. The question was simple; using the most state-of-the-art calculations, could you predict the temperature at which mercury melts as indicated by a sudden change in heat capacity? In a paper published in Angewandte Chemie this month, chemists from New Zealand, Germany and France have provided a result which is the most complete one to date. They actually simulated the melting of mercury using quantum molecular dynamics, solving the Schrodinger equation, calculating forces and velocities from quantum mechanics and allowing the atomic clusters to sample different geometric orientations randomly. They carried out the calculations first by excluding relativity and then by including it, and the results were unambiguous; when relativistic effects were taken into account, the melting point of mercury dropped from 355 kelvin to 250 kelvin, in excellent agreement with experiment and accompanied by a sudden change in the heat capacity.

The liquid nature of mercury is not the only thing that the special theory explains. It also explains why gold is yellow while silver is white. In this case, the splitting of orbitals and the lower energy of the 6s orbital results in gold absorbing blue light and emitting yellow and red. Since the 6s level is higher in silver, the energy required to excite an electron corresponds to the UV region instead of the visible region; consequently silver appears devoid of colors from the visible region of the spectrum.

I always feel a twang of pleasure when I come across studies like this. There are few things more satisfying than the successful application of our most cherished and accurate theories to explaining life's most humdrum and yet fascinating phenomena. That's what science is about.

References:

1. Evidence for Low-Temperature Melting of Mercury owing to Relativity; F. Calvo et al. Angew. Chem. Intl. Ed. Engl. 2013, 10.1002/anie.201302742

2. Why is Mercury Liquid? L. Norrby, J. Chem. Ed. 1991, p. 110.

3. Relativistic Effects in Chemistry, D. McKelvey, J. Chem. Ed. 1983, p. 112

This post was first published on the Scientific American Blog Network.

A particularly heinous crime: Neurology professor poisons neurologist wife

From Science Careers comes this account of a heartbreaking and especially twisted crime. A professor of neurology at the University of Pittsburgh, Robert Ferrante, has been charged with poisoning his 41-year-old wife with cyanide, an ancient poison that never seems to lose its allure. The wife was also a neurologist at the university. What really stunned me was this part:

"Authorities say that Ferrante poisoned Klein by mixing cyanide with creatine, CBSNews reports. According to Ferrante's online biography, his work "has provided the basis for human trials" using creatine. Klein consumed the drink because Ferrante told her it would help them conceive a child."

It takes a special kind of heartless monster to do that.

I cannot easily find references about using creatine to facilitate conception; since it's used as a nutritional supplement for muscle building and strength, Ferrante could have used a very simple argument to convince his wife to drink the deadly concoction. Apparently he obtained the cyanide through a lab member using a university credit card. One wonders if his associate ever suspected what a neurologist would need 250 grams of cyanide for (unfortunately chemists can obtain quantities of cyanide quite easily; I have seen half a pound of cyanide sitting in a chemical cabinet). Ferrante also seems to have performed the initial experiments within open sight of lab personnel:

He asked for the "best and purest cyanide he could get" to be delivered the next day, the witness said.

In addition, the affidavit continued, Mr. Ferrante asked that the chemical be purchased using a separate credit card not typically used in the lab.

A witness told investigators that particular card is a "last choice for purchases" and that it was the first time Mr. Ferrante had used it. Out of 145 chemicals bought by the lab, the only one purchased not related to a project or grant was the cyanide.

The same day the chemical arrived, another person in the lab witnessed Mr. Ferrante obtain a large container of creatine, measure it, mix it with water and sucrose and then drink it.

Early on April 17, Mr. Ferrante asked the witness to measure out more of the creatine, and they then placed it in a bag.

That day, according to the report, Mr. Ferrante and Klein exchanged text messages in which she said she would begin ovulating the next day. Mr. Ferrante told her to take creatine.

"I'm serious," he texted. "It will make a huge difference. I am certain of it."

When paramedics arrived at the couple's home to treat Klein the night she collapsed, according to the affidavit, they noted a 1-gallon resealable plastic bag containing a white substance along with a small glass vial in the kitchen, where Klein was found on the floor.

The report also says that out of the 250 grams of cyanide, 8.3 grams were missing. The lethal dose of cyanide is pegged at 200 milligrams on many websites; the exact dose and duration of action depends on factors like the contents of the stomach, with a higher secretion of stomach acid facilitating poisoning. In any case, if Ferrante is indeed guilty, then from the description it seems that he has left ample evidence. 

I can never understand what can possibly cause someone to put their entire life, career and reputation on the line and exhaust all other avenues of domestic conflict resolution, no matter how complicated their personal lives are (in this case a divorce might have been a simple solution). In any case, there's not much use speculating right now since Ferrante has not been officially convicted yet. But if he is indeed guilty of what he has been charged with, I cannot possibly think of subjecting him to anything other than the harshest possible punishment that is feasible for this kind of a crime.

Memo to chemists: Move away from the molecule

Megacities of the future - with their heterogeneous population and large-scale problems - will challenges the imagination of chemists (Image: Bldg Blog)

Harvard 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 latest rumination is 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. 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, 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.

First published on the Scientific American Blog Network.

Where's the chemistry lobby?

Veteran chemistry blogger Derek Lowe's takedown of the nonsensical Buzzfeed article about eight "chemicals" that you should stay away from was an excellent rejoinder to what was essentially a pile of sensationalized opinions disseminated by someone who does not bother reading up on basic science, but it also gave me a sinking feeling that is encapsulated by the following basic existential question.

How long can we chemists do this?

Over the last few years bloggers like SeeArrOh, Derek, Chembark and others have regularly pointed out instances of the growing epidemic of science and fact-free chemophobia that abounds on the Internet. In fact most of it is not even chemophobia, it's just plain ignorance of basic science. But as far as the sheer amount of chemistry-related nonsense floating around goes, all this worthy debunking is no more than a drop in the ocean. Those who don't understand science and chemistry are going to keep foisting the same falsehoods on us ad nauseum. The problem is that even if chemistry bloggers decided to debunk no more than 10% of the nonsense that goes around, they will be at it all day and night. The pile of anti-chemistry garbage that dots the landscape of the internet and print media is like a Hydra. You debunk one head and ten grow in its place. Plus the fundamental challenge in countering half-baked science is well-known: it takes only a few minutes to throw around unsubstantiated claims and link to random secondary and tertiary sources, but it takes dedicated time and effort to trawl through the primary sources, analyze the data and come up with a reasoned refutation. For instance it took me almost an hour to go through all the sources alluded to in a post about flame-retardants in couches and to write a post countering the claims. In fighting anti-chemistry forces chemists face a challenge similar to that faced by evolutionists fighting creationists. It takes only a minute for a creationist to make a statement like "There are no transitional fossil forms" but it takes time for an evolutionist to then go into the details and counter with the list of known transitional forms. Whether it's creationism or chemophobia, time is inherently biased against the responders. There is essentially no realistic possibility that a group of dedicated chemistry bloggers who are doing this in their free time are ever going to get around to refuting more than a fraction of all this fear-mongering, fact-free antiscientific piffle.

About the only remedy that I can see to counter this chemophobia and spread of ignorance is a dedicated chemistry lobby. The United States, after all, is the land of lobbies. So why not have a chemistry lobby? The task of the chemistry lobby would be simple; to have a dedicated group of chemists and people who actually care about the benefits of chemistry make a concerted effort to combat misinformation and ignorance, using every print, online and social outlet available, directing their efforts so that they reach every imaginable kind of citizen, from the man on the street to Congressmen on the Hill. The lobby would include contributions from chemistry researchers, teachers, students, policy makers and regulators. They could join hands with the American Chemical Society and any other organization that wants to further the cause of chemistry; in my personal opinion, while the ACS has done some admirable work in improving the public image of chemical science, it's efforts have been sorely lacking in proportion to the work that actually needs to be done.

Anyone who actually understands chemistry at a basic level would be welcome to contribute. The chemistry lobby could have their own TV channel, radio program and newsletter. Perhaps they could start a series that does for chemistry what "Cosmos" did for astronomy, replete with a charismatic and credible Sagan-like figure (Roald Hoffmann could fit the bill quite well). They could run campaigns to educate people about the facts and benefits of chemistry while admitting upfront to the misuse that chemistry has been put to over the years; they should also underscore the fact that misuse of chemistry has been no different from misuse of any other technology developed by flawed human beings. Their task would not be to whitewash the evils of the chemical, agricultural and pharmaceutical industries but point out the good that the industry has done in people's lives on a deep level. Chemistry largely underpins modern civilization, and it would be the task of the chemistry lobby to educate people about this fundamental fact.

The chemistry lobby would not solicit financial contributions from industry. Members of the lobby are probably going to be painted as industry shills by their opponents anyway, so it would not help being funded by massive contributions from industry. Instead the organization I am envisioning would be a non-profit group akin to the National Center for Science Education (NCSE), funded mainly by member contributions and grants. The National Center for Chemical Education (NCCE - as sound a name for the lobby as any other) would do to counter chemophobia what the NCSE has done to combat creationism. The official mission of the NCSE is to keep evolution in the class and creationism out of it. The mission of the NCCE would be to keep chemistry in the public arena and chemophobia out of it. Just like the NCSE does is not the official spokesperson of any university, atheist organization or political or social group, the NCCE would not be the official spokesperson of any body. It might support or reject the views of specific organizations, but official affiliation would be eschewed. At the same time it could fund the activities of specific bloggers, professors or citizens whose efforts to educate the general populace about chemistry are especially noteworthy. The NCCE could also fund studies and surveys designed to simply find out more about what people think about chemistry and its various incarnations in our lives.

The NCSE had done an immense amount of good over the decades to combat the forces of darkness that threaten to invade the school curriculum. At the same time they have take no official position against religion, and have in fact emphasized their respect for people's personal religious beliefs. The NCCE would similarly debunk basic ignorance of chemistry and fear-mongering without insulting the real concerns that environmentalists and parents have. It is only by taking a stand against objective falsehoods while still respecting the emotional reactions that concerned citizens have about the growth of technology that we can make a dent in fostering dialogue between disparate factions and bridging the gulf of our differences. I look forward to the day when the when a rational, effective and expansive chemistry lobby starts to achieve this goal.

Thanksgiving

When the Protein Data Bank releases a much-awaited protein structure which shows you *exactly* what you wanted to see, it's much like looking at a newly written Mozart symphony. There is a purpose to every single atom and water molecule, a rhythm to every single bond and interaction, a graceful yet deliberate elegance to every single curve of a loop, to every turn of an alpha helix, to the meandering pleats of every beta sheet.

The structure contains precisely the right number of interacting parts, not a single one more or less. Only this time the composer is nature, and the conductor is evolution. Looking at the structure you cannot help but get the feeling that nature has lifted a corner of her great veil for you to gaze in awe and appreciation at the edifice.

I don't say it enough, but today I feel grateful and humbled to be a scientist, to be granted the privilege of being able to sit in my modest little corner of the universe and revel in a movement from this grand performance.

Good luck to B.R.S.M!

B.R.S.M. is off to the US for a postdoc. And he does Woodward Wednesdays. What's not to like.

1. What is your message for BRSM?
It's the only time in your life when (unless you have a family) your only responsibility will be research; no teaching, no exams. Make the most of it while it lasts.

2. What is one postdoc survival tip you would give to BRSM?
Time is of the essence. While it's essential to have fun during your postdoc, you should hit the ground running and start making plans for job applications, grant proposals etc. right away.

3. Do you have a fun story you could share from your postdoc and/or US academic experience?
There was the time when a naive rotation student referred to the abbreviated name of a dye in her powerpoint presentation. Some of us wanted to know the structure, but before we had second thoughts and could stop her, she had already done a Google image search. Turns out the abbreviated dye name was also the name of a porn star. I thought she was going to faint with embarrassment (the rotation student, that is; porn stars never faint with embarrassment).

4. A survival tip for living in the US?
Unless you are living in a city, get a car. You don't want to add to your hectic postdoc schedule by walking in the heat/cold or waiting for the bus that never shows up.

5. What would you like to see on BRSM blog in the future?
More Woodward Wednesdays, naturally.

6. Anything else?

Live long and reflux!

Chemistry, fluid dynamics and an awful radioactive mess

When it comes to handling radioactive waste the Hanford site in western Washington state is the opposite of a role model. Ever since its reactors started producing the plutonium which was used in the Nagasaki bomb, Hanford has been generating waste with little foresight and responsibility. It has the dubious honor of being the most contaminated radioactive site in the country.

Scientific American has an article which gives an idea of how truly awful the problem is. It's not just that there's a lot of waste or that it's everywhere. It seems like the waste basically conforms to the devil's definition of the word "heterogeneous" and takes a form representing the average nuclear chemist's version of hell:

"Overall, the waste tanks hold every element in the periodic table, including half a ton of plutonium, various uranium isotopes and at least 44 other radionuclides—containing a total of about 176 million curies of radioactivity. This is almost twice the radioactivity released at Chernobyl, according to Plutopia: Nuclear Families, Atomic Cities, and the Great Soviet and American Plutonium Disasters, by Kate Brown, a history professor at the University of Maryland, Baltimore County. The waste is also physically hot as well as laced with numerous toxic and corrosive chemicals and heavy metals that threaten the integrity of the pipes and tanks carrying the waste, risking leakage. 

The physical form of the waste causes problems, too. It’s very difficult to get a representative sample from any given tank because the waste has settled into layers, starting with a baked-on “hard heal” at the bottom, a layer of salt cake above that, a layer of gooey sludge, then fluid, and finally gases in the headspace between the fluid and the ceiling. Most of the radioactivity is in the solids and sludge whereas most of the volume is in the liquids and the salt cake."

"Plutopia", by the way, is a very interesting book. In any case, the waste problem at Hanford looks like it will engage the services of every conceivable kind of chemist, engineer and fluid dynamics expert that I can imagine.

"All of these considerations contribute to the overall problem, which can be summed up in one word: flow. To get to the glass log stage the waste has to travel through an immense labyrinth of tanks and pipes. It has to move at a fast enough clip to avoid pipe and filter clogs as well as prevent solids from settling. This is quite a challenge given the multiphasic nature of the waste: solids, liquids, sludge and gases all move differently. The waste feed through the system will be in the form of a “non-Newtonian slurry”—a mixture of fluids and solids of many different shapes, sizes and densities. If the solids stop moving, problems ensue."

The article also talks about two serious concerns; the possibility that enough plutonium in the waste could build up to trigger a chain reaction (although one which in bomb parlance would be a "fizzle") and the possibility that the heat and radiation could split water up and lead to a buildup of hydrogen. For now these concerns are about unlikely events and are secondary in any case to the much more important problems of Sludge Management and the Battle against Viscosity. Just tells you how important it is to nip problems with reactor waste in the bud before they turn into a godforsaken headache for future generations.

On synthesis, design and chemistry's outstanding philosophical problems

Chemists need to move from designing structure - exemplified by this synthetic receptor - to designing function (Image: Max Planck Institute).

Yesterday I wrote a post about a perspective by multifaceted chemist George Whitesides in which he urged chemists to broaden the boundaries of their discipline and think of big picture problems. But the article spurred me to think a bit more about a question which I (and I am sure other chemists) have often thought about; what’s the next big challenge for chemistry?

And when I ask this question I am not necessarily thinking of specific fields like energy or biotechnology or food production. Rather, I am thinking of the next outstanding philosophical question confronting chemistry. By philosophical question I don’t mean an abstract goal which only armchair thinkers worry about. The philosophical questions in a field are those which define the field’s big problems in the most general sense of the term. For physicists it might be understanding the origin of the universe, for biologists the origin of life. These problems can also be narrowly defined questions that nonetheless expand the understanding and scope of a field; for instance in the early twentieth century physicists were struggling to make sense of atomic spectra, which turned out to be important for the development of quantum theory. It’s also important to note that the philosophical problems of a field change over time, and this is one reason why chemists should be aware of them; you want to move with the times. If you were a “chemist” in the sixteenth century the big question was transmutation. In the nineteenth century when chemistry finally was cast in the language of elements and molecules the big question became theconstitution of molecules in the form of atomic arrangements.

Synthesis is no longer chemistry’s outstanding general problem

When I think about the next philosophical question confronting chemistry I also feel a sense of despondency. That’s because I increasingly feel that the great philosophical question that chemists are going to face in the near future is emphatically not one whose answer they will locate in the all-pervasive activity that always made chemistry unique: synthesis. What always set chemistry apart was its ability to make new molecules that never existed before. Through this activity chemistry has played a central role in improving our quality of life.

The point is, synthesis was the great philosophical question of the twentieth century, not the twenty-first. Now I am certainly not claiming that synthesizing a complex natural product with fifty rotatable bonds and twenty chiral centers is even today a trivial task. I am also not saying that synthesis will cease to be a fruitful source of solutions for humanity’s most pressing problems, such as disease or energy; as a tool the importance of synthesis will remain undiminished. What I am saying is that the general problem of synthesis has now been solved in an intellectual sense (as an aside, this would be consistent with the generally pessimistic outlook regarding total synthesis seen on many blogs.)

The general problem of synthesis was unsolved in the 30s. It was also unsolved in the 50s. Then Robert Burns Woodward came along. Woodward was a wizard who made molecules whose construction had defied belief. He had predecessors, of course, but it was Woodward who solved the general problem by proving that one could apply well-known principles of physical organic chemistry, conformational analysis and spectroscopy to essentially synthesize any molecule. He provided the definitive proof of principle. All that was needed after that was enough time, effort and manpower. If chemistry were computer science, then Woodward could be said to have created a version of the Turing Machine, a general formula that could allow you to synthesize the structure of any complex molecule, as long as you had enough NIH funding and cheap postdocs to fill in the specific gaps. Every synthetic chemist who came after Woodward has really developed his or her own special versions of Woodward’s recipe. They might have built new models of cars, but their Ferraris, Porches and Bentleys – as elegant and impressive as they are – are a logical extension of Woodward and his predecessor’s invention of the internal combustion engine and the assembly line.

A measure of how the general problem of synthesis has been solved is readily apparent to me in my own small biotech company which specializes in cyclic peptides, macrocycles and other complex bioactive molecules. The company has a vibrant internship program for undergraduates in the area. To me the most remarkable thing is to see how quickly the interns can bring themselves up to speed on the synthetic protocols. Within a month or so of starting at the bench they start churning out these compounds with the same expertise and efficiency as chemists with PhDs. The point is, synthesizing a 16-membered ring with five stereocenters has not only become a routine, high-throughput task but it’s something that can be picked up by a beginner in a month. This kind of synthesis might have easily fazed a graduate student twenty years ago and taken up a good part of his or her PhD project. The bottom line is that we chemists have to now face an uncomfortable fact: there are still a lot of unexpected gems to be found in synthesis, but the general problem is now solved and the incarnation of chemical synthesis as a tool for other disciplines is now essentially complete.

Functional design and energetics are now chemistry’s outstanding general problems

So if synthesis is no longer the general problem, what is? My own field of medicinal chemistry and molecular modeling provides a good example. It may be easy to synthesize a highly complex drug molecule using routine techniques, but it is impossible, even now, to calculate the free energy of binding of an arbitrary simple small molecule with an arbitrary protein. There is simply no general formula, no Turing Machine that can do this. There are of course specific cases where the problem can be solved, but the general solution seems light years away. And not only is the problem unsolved in practice but it is also unsolved in principle. Sure, we modelers have been saying for over twenty years that we have not been able to calculate entropy or not been able to account for tightly bound water molecules. But these are mostly convenient questions which when enunciated make us feel more emotionally satisfied. There have certainly been some impressive strides in addressing each of these and other problems, but the fact is that when it comes to calculating the free energy of binding, we are still today where we were in 1983. So yes, the calculation of free energies – for any system – is certainly a general problem that chemists should focus on.

But here’s the even bigger challenge that I really want to talk about: We chemists have been phenomenal in being able to design structure, but we have done a pretty poor job in designing function. We have of course determined the function of thousands of industrial and biological compounds, but we are still groping in the dark when it comes to designing function. Here are a few examples: Through combinatorial techniques we can now synthesize antibodies that we want to bind to a specific virus or molecule, but the very fact that we have to adopt a combinatorial, brute force approach means that we still can’t start from scratch and design a single antibody with the required function (incidentally this problem subsumes the problem of calculating the free energy of antigen-antibody binding). Or consider solar cells. Solid-state and inorganic chemists have developed an impressive array of methods to synthesize and characterize various materials that could serve as more efficient solar materials. But it’s still very hard to lay out the design principles – in general terms – for a solar material with specified properties. In fact I would say that the ability to rapidly make molecules has even hampered the ability to think through general design principles. Who wants to go to the trouble of designing a specific case when you can simply try out all combinations by brute force?

I am not taking anything away from the ingenuity of chemists – nor am I refuting the belief that you do whatever it takes to solve the problem – but I do think that in their zeal to perfect the art of synthesis chemists have neglected the art of de novo design. Yet another example is self-assembly, a phenomenon which operates in everything from detergent action to the origin of life. Today we can study the self-assembly of diverse organic and inorganic materials under a variety of conditions, but we still haven’t figured out the rules – either computational or experimental – that would allow us to specific the forces between multiple interacting partners so that these partners assembly in the desired geometry when brought together in a test tube. Ideally what we want is the ability to come up with a list of parts and the precise relationships between them that would allow us to predict the end product in terms of function. This would be akin to what an architect does when he puts together a list of parts that allows him to not only predict the structure of a building but also the interplay of air and sunlight in it.

I don’t know what we can do to solve this general problem of design but there are certainly a few promising avenues. A better understanding of theory is certainly one of them. The fact is that when it comes to estimating intermolecular interactions, the theories of statistical thermodynamics and quantum mechanics do provide – in principle – a complete framework. Unfortunately these theories are usually too computationally expensive to apply to the vast majority of situations, but we can still make progress if we understand what approximations work for what kind of systems. Psychologically I do think that there has to be a general push away from synthesis and toward understanding function in a broad sense. Synthesis still rules chemical science and for good reason; it's what makes chemistry unique among the sciences. But that also often makes synthetic chemists immune to the (well deserved) charms of conformation, supramolecular interactions and biology. It’s only when synthetic chemists seamlessly integrate themselves into the end stages of their day job that they will learn better to appreciate synthesis as an opportunity to distill general design principles. Let the synthetic chemist interact with the physical biochemist, the structural engineer, the photonics expert; let him or her see synthesis through the requirement of function rather than structure. Whitesides was right when he said that chemists need to broaden out, but another way to interpret his statement would be to ask other scientists to channel their thoughts into synthesis in a feedback process. As chemists we have nailed structure, but nailing design will bring us untold dividends and will help make the world a better place.

First published on the Scientific American Blog Network.

George Whitesides on the responsibility of chemists and the future of chemistry

Catching up on a few articles I had missed, I came across a characteristically deep and wide-ranging essay called "Assumptions" by George Whitesides about science, its future and our responsibility as scientists. It's a very general and kaleidoscopic essay not restricted to chemistry, but the bits about chemistry, its role in understanding the major problems confronting humanity and chemists' responsibility in extending the scope of chemical science are quite thought-provoking:

Chemistry, by its culture, has been almost blindly reductionist. I am repeatedly reminded that “Chemists work on molecules”, as if to do anything else was suspect. Chemists do and should work on molecules, but also on the uses of molecules, and on problems of which molecules may be only a part of the solution. If chemists move beyond molecules to learn the entire problem—from design of surfactants, to synthesis of colloids, to MRI contrast agents, to the trajectories of cells in the embryo, to the applications of  regenerative medicine—then the flow of ideas, problems, and solutions between chemistry and society will animate both. 

Whitesides is clearly making a plea for chemists to become even more interdisciplinary than what they already are, to pursue not just the development of the solution but its application and integration; his own group provides a remarkable example of chemists, physicists, biologists and engineers working together on highly multidisciplinary problems. It's quite clear that to achieve this interdisciplinary expertise we have to completely break down the traditional barriers between synthesis, structure determination, biology and materials (in this world the professor who rejected my biochemical literature seminar topic because it "did not include any synthesis" would be an anachronism). The next paragraph makes clear the role of the "central science"

As a technology, chemistry has built the foundation from which many of the discoveries of “biology” or “microelectronics” or “brain science” (or “planetary exploration”, for that matter) have grown. There would be no genomics without chemical methods for separating fragments of DNA, and for synthesizing primers and probes, and for separating restriction endonucleases into pure activities. There would be no nuclear ICBMs without methods of refining plutonium, and making explosive lenses. There would be no drugs without synthesis and mass spectroscopy. There would be no interplanetary probes without fuels, and carbon/carbon rocket throat nozzles, and silicon single crystals. 

And here's something about what the future of chemistry should be:

Those are the past. What about the future? Chemistry is, still, everywhere: It must be! It is the science of the real world. But to remain a star in the play rather than a stagehand, it must open its eyes to new problems. It is impossible that the human life span will increase dramatically without manipulation of the molecules of the human organism, but understanding this problem will require more than manipulating molecules. Communication between the living and non-living will require engineering a molecular interface between them, but designing this interface will require understanding the nature of “information” in organisms and in computers, and how to translate between them. A society that uses information technology to interweave all its parts requires new systems for generating, distributing, and storing power, but batteries will be only one part of these systems.  

Chemistry has always been the invisible hand that builds and operates the tools, and sustains the infrastructure. It can be more. We think of ourselves as experts in quarrying blocks from granite; we have not thought it our job to build cathedrals from them. Whether we choose to focus on the molecules, materials, and tools that are at the beginnings of discovery, or bring our particular, unique understanding of the world to bear on unraveling the problems at the end, is for us to decide.  I believe that everything from methane to sentience is chemistry, and that we should reexamine our own assumptions concerning the boundaries of our field. Examining the broader assumptions that follow may provide some stimulus to do so.  

Indeed, examining the "broader assumptions" of their field in the broadest sense of the term is what chemists should do. The first paragraph presents a fair sampling of the myriad problems in which chemistry can play a central role. They involve everything from engineering interfaces between computers or electronics and human brains to harnessing the power of chemistry in generating, storing, interconverting and deploying energy in all its forms. I strongly think that the future of chemistry lies in recasting itself as an informational science in the broadest sense. At the level of biology chemistry has already manipulated information in the form of sequencing and genomics; synthetic biology will take this capability to a whole new level. But there are other areas in which chemistry can serve to manipulate information, and part of what Whitesides is doing is challenging chemists to become informational scientists in hitherto unexplored areas like energy and transportation.

The essay ends with a systems-level view of chemistry that every chemist should keep in mind, even as she works in her narrow world of natural products, zeolites, ROMP or kinases.

Because chemistry contributes broadly to the foundations of technology, it is particularly difficult to guess its future impact: a new chemical reaction might be used to make a cancer therapeutic, or a chemical weapon. Some of the opportunities that seem within the reach of investigation, if not within the reach of solution—technologies that might substantially prolong life, or develop new forms of life, or lead to sentient systems that rival us in intelligence—will do both good and harm. At minimum, those of us whopursue these problems should accept an obligation to explain to our fellow citizens fully and clearly what we are doing, and why, and (to the limited extent we can) with what possible outcomes. Humankind will do what it will do, but at least everyone should understand—in so far as is possible—what the choices are, and what the consequences might be. Chemistry, if it takes more interest in (and responsibility for) the full scope of programs—from molecules, to applications, and to influence on society—may be able to use the very breadth of its connections to technology to help in this explanation.

Whitesides Image: Boston.com

Splenda and - wait for it - DDT? You've got to be kidding me

Just when you think the perpetrators of chemophobia (actually this particular case makes chemophobia look like a knight in shining armor) cannot outdo themselves, someone seems to hit a new high.

This time it's "alternative" "medicine" "physician" Joseph Mercola. In a diatribe against Splenda he tosses out this gem:

"Splenda—"Made from Sugar" But More Similar to DDT...

That's right.

The catchy slogan "Made from sugar so it tastes like sugar" has fooled many, but chemically, Splenda is actually more similar to DDT than sugar."

There is no mention of how exactly Splenda is even remotely close to DDT in structure, function or any other conceivable parameter for that matter. I really shouldn't have to do this but here are the structures of the two molecules.

Why in the name of merciful Odin would these be considered similar? Because both of them have chlorines and we all know that chlorine is a toxic gas used in World War 1? I would say then that they share even more hydrogens than chlorines, and hydrogen is of course an inflammable gas, which can only mean that both Splenda and DDT have got to explode when consumed.

Naturally this goes beyond chemophobia and handily ends up way inland in the territory of unadulterated twaddle. Read the entire page if you are craving for that migraine and nausea which you have been longing for. I haven't read the whole thing, and who could blame me for this? A quick look through some of the references reveals the usual egregious howlers (studies extrapolated from rats who have been fed unrealistic doses of the material for an abnormally long period of time etc.) and I have no reason to believe that a more detailed look won't accomplish the same thing.

It strains my imagination to contemplate how even the loopiest of quacks could actually write something like this, let alone sincerely believe it. It's one of those very few times when freedom of speech starts sounding like a bad idea.

H/T: The promising "Chemicals are your Friends" page on Facebook, via Stuart Cantrill.