My Introduction to the Scientific Method – as actually practised

It is often said if you can’t explain something to a six-year-old, you don’t understand.

I am not convinced, but maybe I don’t understand. Anyway, I thought I would follow from my previous post with an account of my PhD thesis. It started dramatically. My young supervisor gave me a choice of projects but only one looked sensible. I started that, then found the answer just published. Fortunately, only month wasted, but I had no project and supervisor was off on vacation. Head of Department suggested I find myself a project, so I did. There was a great debate going on whether the electrons in cyclopropane could delocalize into other parts of a molecule. To explain, carbon forms bonds at an angle of 109.5 degrees, but the three carbons of cyclopropane have to be formally at 60 degrees. In bending them around, the electrons come closer together and the resultant electric repulsions mean the overall energy is higher. The higher energy difference is called strain energy. One theory was the strain energy could be relieved if the electrons could get out and spread themselves over more space. Against that, there was no evidence of single bonds being able to do this.

My proposal was to put a substituted benzene ring on one corner, and an amine on the other. The idea was, amines are bases and react with acid, and when they do that the electrons on the amine are trapped. If the cyclopropane ring could delocalize electrons there was one substituent I could put on the benzene ring that would have different effects on that basicity depending on whether the cyclopropane ring did delocalize electrons or not. There was a test through something called the Hammett equation. My supervisor had published on this, but this would be the first time the equation might be used to do something of significance. Someone had tried that scheme with carboxylic acids, but with an extra carbon atom they were not very responsive and there were two reports with conflicting answers. My supervisor, when he came back, was not very thrilled with this proposal, but his best alternative was to measure the rates of a sequence of reactions for which I had found a report that said the reaction did not go. So he agreed. Maybe I should have been warned. Anyway, I had some long-winded syntheses to do.

When it came to reaching the end-position, my supervisor went to North America on sabbatical, and then sequentially looking for a new position in North America, so I was on my own. The amine results did not yield the desired result because the key substituent, a nitro group, reacted with the amine very quickly. That was a complete surprise. I could make the salt, but the solution with some amine quickly discoloured. However, in a fleeting visit my supervisor made a useful suggestion: react the acids in toluene with a diazo compound. While the acids previously had been too similar in properties in water, it turned out that toluene greatly amplified the differences. The results were clear: the cyclopropane ring did not delocalize electrons.

However, all did not go well. The quantum mechanical people who had shown the extreme stability of polywater through electron delocalization turned their techniques to this problem and asserted it did. In support, they showed that the cyclopropane ring stabilized adjacent positive charge. However, if the strain energy arose through increased electron repulsion, a positive charge would reduce that. There would be extra stability with a positive charge adjacent, BUT negative charge would destabilize it. So there were two possible explanations, and a clear means of telling the difference.

Anions on a carbon atom are common in organic chemistry. All attempts at making such an anion adjacent to a cyclopropane ring failed. A single carbon atom with two hydrogen atoms, and a benzene ring attached forms a very stable anion (called a benzyl anion). A big name replaced one of the hydrogen atoms of a benzyl anion with a cyclopropane ring, and finally made something that existed, although only barely. He published a paper and stated it was stabilized by delocalization. Yes, it was, and the stabilization would have come from the benzene ring. Compared with any other benzyl anion it was remarkably unstable. But the big names had spoken.

Interestingly, there is another test from certain spectra. In what is called an n->π* transition (don’t worry if that means nothing to you) there is a change of dipole moment with the negative end becoming stronger close to a substituent. I calculated the change based on the polarization theory, and came up with almost the correct answer. The standard theory using delocalization has the spectral shift due to the substituent in the opposite direction.

My supervisor, who never spoke to me again and was not present during the thesis write-up, wrote up a paper on the amines, which was safe because it never showed anything that would annoy the masses, but he never published the data that came from his only contribution!

So, what happened? Delocalization won. A review came out that ignored every paper that disagreed with its interpretation, including my papers. Another review dismissed the unexpected spectral shift I mentioned by saying “it is unimportant”. I ended up writing an analysis to show that there were approximately 60 different sorts of observation that were not in accord with the delocalization proposition. It was rejected by review journals as “This is settled” (that it was settled wrongly was irrelevant) and “We do not publish logic analyses.” Well, no, it seems they do not, and do not care that much.

The point I am trying to make here is that while this could be regarded as not exceptionally important, if this sort of wrong behaviour happens to one person, how much happens across the board? I believe I now know why science has stopped making big advances. None of those who are established want to hear anyone question their own work. The sad part is, that is not the only example I have.

A personal scientific low point.

When I started my PhD research, I was fairly enthusiastic about the future, but I soon got disillusioned. Before my supervisor went on summer holidays, he gave me a choice of two projects. Neither were any good, and when the Head of Department saw me, he suggested (probably to keep me quiet) that I find my own project. Accordingly, I elected to enter a major controversy, namely were the wave functions of a cyclopropane ring localized (i.e., each chemical bond could be described by wave interference between a given pair of atoms, but there was no further wave interference) or were they delocalized, (i.e. the wave function representing a pair of electrons spread over more than one pair of atoms) and in particular, did they delocalize into substituents? Now, without getting too technical, I knew my supervisor had done quite a bit of work on something called the Hammett equation, which measures the effect or substituents on reactive sites, and in which, certain substituents that had different values when such delocalization was involved. If I could make the right sort of compounds, this equation would actually solve a problem.

This was not to be a fortunate project. First, my reserve synthetic method took 13 steps to get to the desired product, and while no organic synthesis gives a yield much better than 95%, one of these struggled to get over 35%, and another was not as good as desirable, which meant that I had to start with a lot of material. I did explore some shorter routes. One involved a reaction that was published in a Letter by someone who would go on to win a Nobel prize. The very key requirement to get the reaction to work was omitted in the Letter. I got a second reaction to work, but I had to order special chemicals. They turned up after I had submitted my thesis. They travelled via Hong Kong, where they got put aside and forgotten. After discovering that my supervisor was not going to provide any useful advice on chemical synthesis, he went on sabbatical, and I was on my own. After a lot of travail, I did what I had set out to do, but an unexpected problem arose. The standard compounds worked well and I got the required straight line set with minimum deviation, but for the key compound at one extreme of the line, the substituent at one end reacted quickly with the other end in the amine form. No clear result.

My supervisor made a cameo appearance before heading back to North America, where he was looking for a better paying job, and he made a suggestion, which involved reacting carboxylic acids that I already had in toluene. These had already been reported in water and aqueous alcohol, but the slope of the line was too shallow to be conclusive. What the toluene did was to greatly amplify the effect. The results were clear: there was no delocalization.

The next problem was the controversy was settling down, and the general consensus that there was such delocalization. This was based on one main observational fact, namely adjacent positive charge was stabilized, and there were many papers stating that it must on theoretical grounds. The theory used was exactly the same type of programs that “proved” the existence of polywater. Now the interesting thing was that soon everybody admitted there was no polywater, but the theory was “obviously” right in this case. Of course I still had to explain the stabilization of positive charge, and I found a way, namely strain involved mechanical polarization.

So, where did this get me? Largely, nowhere. My supervisor did not want to stick his head above the parapet, so he never published the work on the acids that was my key finding. I published a sequence of papers based on the polarization hypothesis, but in my first one I made an error: I left out what I thought was too obvious to waste the time of the scientific community, and in any case, I badly needed the space to keep within page limits. Being brief is NOT always a virtue.

The big gain was that while both explanations explained why positive charge was stabilized, (and my theory got the energy of stabilization of the gas phase carbenium ion right, at least as measured by another PhD student in America) the two theories differed on adjacent negative charge. The theory involving quantum delocalization required it to be stabilized too, while mine required it to be destabilized. As it happens, negative charge adjacent to a cyclopropane ring is so unstable it is almost impossible to make it, but that may not be convincing. However, there is one UV transition where the excited state has more negative charge adjacent to the cyclopropane ring, and my calculations gave the exact spectral shift, to within 1 nm. The delocalization theory cannot even get the direction of the shift right. That was published.

So, what did I learn from this? First, my supervisor did not have the nerve to go against the flow. (Neither, seemingly, did the supervisor of the student who measured the energy of the carbenium ion, and all I could do was to rely on the published thesis.) My spectral shifts were dismissed by one reviewer as “not important” and they were subsequently ignored. Something that falsifies the standard theory is unimportant? I later met a chemist who rose to the top of the academic tree, and he had started with a paper that falsified the standard theory, but when it too was ignored, he moved on. I asked him about this, and he seemed a little embarrassed as he said it was far better to ignore that and get a reputation doing something more in accord with a standard paradigm.

Much later (I had a living to earn) I had the time to make a review. I found over 60 different types of experiment that falsified the standard theory that was now in textbooks. That could not get published. There are few review journals that deal with chemistry, and one rejected the proposal on the grounds the matter was settled. (No interest in finding out why that might be wrong.) For another, it exceeded their page limit. For another, not enough diagrams and too many equations. For others, they did not publish logic analyses. So there is what I have discovered about modern science: in practice it may not live up to its ideals.