What is chemical intuition?

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Recently I read a comment by a leading chemist in which he said that in chemistry, intuition is much more important than in physics. This is a curious comment since intuition is one of those things which is hard to define but which most people who play the game appreciate when they see it. It is undoubtedly important in any scientific discipline and certainly so in physics; Einstein and Feynman for instance were regarded as the outstanding intuitionists of their age, men whose grasp of physical reality largely unaided by mathematical analysis was unmatched. Yet it seems to me that "chemical intuition" is a phrase which you hear much more than "physical intuition". When it comes to intuition, chemists seem to be more in the league of financial traders, geopolitical experts and psychologists than physicists.

 

Why is this the case? The simple reason is that in chemistry, unlike physics, armchair mathematical manipulation and theorizing can take you only so far. Most chemical systems are too complex for the kind of first-principles approaches that yield predictions in physics to an uncanny degree of accuracy; the same is true of biology. While armchair speculation and order-of-magnitude calculations can certainly be very valuable, no chemist can design a zeolite, predict the ultimate product of a complex polymer synthesis or list the biological properties that a potential drug can have by simply working through the math. As the great organic chemist R B Woodward once said of his decision to pursue chemistry rather than math, in chemistry, ideas have to answer to reality. Chemistry much more than physics is an experimental science built on a foundation of rigorous and empirical models, and as the statistician George Box once memorably quipped, all models are wrong, but some are useful. It is chemical intuition that can separate the good models from the bad ones.

How then, to acquire chemical intuition? All chemists crave intuition, few have it. It's hard to define it, but I think a good definition would be that of a quality that lets one skip a lot of the details and get to the essential result, often one that is counter intuitive. That definition reminds me of a recent book by the philosopher Daniel Dennett in which he describes an intellectual device called an "intuition pump". An "intuition pump" is essentially a shortcut - anything from a linguistic trick to a thought experiment - that allows one to skirt the usual process of rigorous and methodical analysis and get to the point. A lot of chemical thinking involves the fine art of manipulating intuition pumps. It is the art of asking the simple, decisive question that gets to the heart of the matter. As in a novel mathematical proof, a moment of chemical intuition commands an element of surprise. And as with a truly ingenious mathematical derivation, it should ideally lead us to smack our foreheads and ask why we could not think of something so simple before.

Ultimately when it comes to harnessing intuition, there can be no substitute for experience. Yet the masters of the art in the last fifty years have imparted valuable lessons on how to acquire it. Here are three that I have noticed, and I would think they would apply as much to other disciplines as to chemistry.

1. Don't ignore the obvious: One of the most striking features of chemistry as a science is that very palpable properties like color, smell, taste and elemental state are directly connected to molecular structure. For instance, there is an unforgettably direct connection between the smell of a simple molecule called cis-3-hexenol and that of freshly cut grass. Once you smell both separately it is virtually impossible to forget the connection. Chemists who are known for their intuition never lose sight of these simple molecular properties, and they use them as disarming filters that can cut through the complex calculations and the multimillion dollar chemical analysis.

Colors, smells and explosions are what often attract budding chemists to their trade at an early age, and these qualities are also precisely the ones which can be an important elements of chemical intuition. I remember an anecdote about the Caltech chemist Harry Gray (an expert among other things on colored chemical compounds) who once deflated the predictions of some sophisticated quantum mechanics calculation by simply asking what the color of the proposed compound was; apparently there was no way the calculations could have been right if the compound had a particular color. As you immerse yourself in laborious compound characterization, computational modeling and statistical significance, don't forget what you can taste, touch, smell and see. As Pink Floyd said, this is all that your world will ever be.

2. Get a feel for energetics: The essence of chemistry can be boiled down to a fight: a fight unto death of countless factors that rally either for or against the amount of useful energy - technically called the free energy - that a system can provide. In one sense all of chemistry is one big multivariable optimization problem. When you are designing molecules as anticancer agents, for hydrogen storage or solar energy conversion or as enzyme mimics, ultimately what decides whether they will work or not is energetics, how well they can stabilize and be stabilized and ultimately lower the free energy of the system. Intimate familiarity with numbers can help in these cases. Get a feel for the rough contributions made by hydrogen bonds, electrostatics, steric effects and solvent influences, essentially all the important interactions between molecules that dictate the fate of chemical systems. Often the key to improving the properties of molecules is to figure out what single interaction or combination of interactions is responsible for a particular property; you can then tweak that property by turning the knobs on the relevant factors.

Order of magnitude calculations and rough guesses are especially important for chemists working at the interface of chemistry and biology; remember, life is a game played within a 3 kcal/mol window and any insight that allows you to nail down numbers within this window can only help. Linus Pauling was lying in bed with a cold when he managed to build accurate models of protein structure, largely based on his unmatched feel for such numbers that allowed him to make educated guesses about bond lengths and angle. And every chemist can learn from the incomparable intuition of Enrico Fermi who tossed pieces of paper in the air when the first atomic bomb went off, and used the distance at which they fell to calculate a crude estimate of the yield.

A striking case of insights acquired through thinking about energetics is illustrated by a story that the Nobel Prize winning chemist Roald Hoffmann narrates in an issue of the magazine "American Scientist". Hoffmann was theoretically investigating the conversion of graphene to graphane, which is the saturated counterpart of graphene (one in which all double bonds have been converted to single ones), under high pressure. After having done some high-level calculations, his student came into his office and communicated a very counter-intuitive result; apparently graphane was more stable than the equivalent number of benzenes. This was highly counterintuitive since every chemistry student learns that so-called aromatic compounds with alternating double bonds are more stable that their single-bond analogs because of the ubiquitous phenomenon of resonance. Hoffmann could not believe the result and his first reaction was to suspect that something must be wrong with the calculation.

Then, as he himself recalls, he leaned back in his chair, closed his eyes and brought half a century's store of chemical intuition to bear on the problem. Ultimately after all the book-keeping had been done, it turned out that the result was a simple consequence of energetics; the energy gained in the formation of strong carbon-carbon bonds more than offset that incurred due to the loss of aromaticity. The fact that it took a Nobel Laureate some time to work out the result is not in any way a criticism but a resounding validation of thinking in terms of simple energetics. Chemistry is full of surprises- even for Roald Hoffmann- and that's what makes it endlessly exciting.

3. Stay in touch with the basics, and learn from other fields: This is a lesson that is often iterated but seldom practiced. An old professor of mine used to recommend flipping open an elementary chemistry textbook every day to a random page and reading a few pages from it. Sometimes our research becomes so specialized and we become so enamored of our little corner of the chemical world that we forget the big picture. Part of the lessons cited above simply involves not missing the forest for the trees and always thinking of basic principles of structure and reactivity in the bigger sense.

This also involves keeping in touch with other fields of chemistry since an organic chemist never knows when a basic fact from his college inorganic chemistry textbook will come in handy. Most great chemists who were masters of chemical intuition could seamlessly transition their thoughts between different subfields of their science. This lesson is especially important in today's age when specialization has become so intense that it can sometimes lead to condescension toward fields other than your own. A corollary of learning from other fields is collaboration; what you don't have you can at least partially borrow. As Oppenheimer used to say about afternoon tea when he was director of the Institute for Advanced Study, "Tea is where we explain to each other what we don't understand". Chemists and scientists in general need to have tea more often.

Ultimately if we want to develop chemical intuition, it is worth remembering that all our favorite molecules, whether solar energy catalysts, cancer drugs or fertilizers, are all part of the same chemical universe, obeying the same rules even if in diverse contexts. Ultimately, no matter what kind of molecule we are interrogating, "Wir sind alle chemikers", every single one of us.

This is a revised version of an older post.