What is chemical intuition?

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 for instance was regarded as the outstanding intuitionist of his age, a man whose grasp of physical reality unaided by mathematical analysis was unmatched. Yet I agree 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 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. 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 natural product synthesis or list the biological properties that a potential drug can have by simply working through the math. As 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 statistican 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. It is the art of asking the simple, decisive question that goes 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 I have noticed:

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. There is an unforgettably direct connection between the smell of cis-3-hexenol and that of freshly cut grass. Once you smell both independently 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.

I remember an anecdote about the chemist Harry Gray (an expert among other things on colored coordination complexes) who once deflated the predictions of some sophisticated quantum chemical 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 unto death of countless factors that rally either for or against the free energy of a system. 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 interactions and solvent influences. This is 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. The same goes for some other parameters like Van der Waals radii and bond lengths. Linus Pauling was lying in bed with a cold when he managed to build accurate models of the protein alpha helix, largely based on his unmatched feel for such numbers.

A striking case of insights acquired through thinking about energetics is illustrated by a story that Roald Hoffmann narrates in a recent issue of "American Scientist". Hoffmann was theoretically investigating the conversion of graphene to graphane, which is the saturated counterpart of graphene, 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 per CH group than the equivalent number of benzenes. What happened to all that discussion of unsaturation in aromatic rings contributing to unusual stability that we learnt in college? 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.

Another example that comes to my mind is an old paper by my PhD advisor which refuted an observation indicating that a group in cyclohexane was purportedly axial. In this case unlike the one above, the intuitive and commonly held principle- that substituents in cyclohexanes are equatorial- turned out to be the right one, again based on some relatively simple NMR-assisted computational energetic analysis. On the other hand, the same kind of thinking also led to the discovery that the C-F groups in substituted difluoro-piperidines are axial! Sometimes intuition leads to counter intuition, and sometimes it asserts itself.

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 ten 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 involve not missing the forest for the trees and always thinking of basic principles of structure and reactivity in the bigger sense.

This also often involves keeping in touch with other fields of chemistry since an organic chemist never knows when a basic fact from his college inorganic 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 when specialization has become so intense that it can sometimes lead to condescension toward fields other than your own. Part of the lesson also involves collaboration; what you don't have you can at least partially borrow.

Ultimately if we want to develop chemical intuition, it is worth remembering that all our favorite molecules, whether metals, macrocyles or metalloproteases, are all part of the same chemical universe, obeying the same rules even if in varied contexts. Ultimately, no matter what kind of molecule we are interrogating, Wir sind alle chemikers, every single one of us.