Synthetic organic chemistry has come a long way in the course of the last century. At the beginning it was not much more than pure guesswork, mixing different things, heating and taking a guess what heteroaromatic might have formed. Nowadays, we have arrived at a point where it is possible to make almost any conceivable chemical structure by a rational approach, using the large toolbox of synthetic methods available today. Have we thus reached our goal? Is there nothing left to do in synthesis except improving the existing methodology?

Of course not. What we still need is a more profound understanding what is happening on the molecular level. Quite often we find ourselves faced with a synthetic problem where only one specific set of reaction conditions will work. Why this one? Nobody knows, and nobody can predict, so we have to try all possible conditions.

I would argue that the huge improvement in our understanding of reaction mechanisms and the complexity of chemical structures of today is largely related to the availability of more powerful analytical methods. A hundred years ago, melting points and elementary analysis were about the only ones, later on IR spectroscopy became available. But we all know that modern organic synthesis would be unthinkable without the help of NMR spectroscopy. Maybe a new method is just around the corner, waiting to be introduced. To gain more knowledge about mechanisms, we would need the ability to “look at” individual molecules, rather than ensembles of molecules as is the case today. A new method that could do this would definitely have a huge impact on organic synthesis.

While we observe billions of molecules at the same time with our analytics, in our mind we are still stuck with the single molecule that we draw on paper. In this way, we neglect all the interactions between molecules that can be very important for the outcome of a reaction. Take organolithium compounds as a simple example. We usually write “n-BuLi” as if it were an isolated species, although it is well-known that these compounds form clusters up to hexamers in solution, depending on the solvent and the concentration. From a theoretical point of view, it will be very important to devise models that take the interactions between molecules, molecule clusters and the solvent (more) into account.