Reaction selectivity comes in many different forms (regio-, chemo, stereo-, you name it). Factors that affect various types of selectivity are, should we say, complicated… Temperature is the oldest and most reliable way of achieving selectivity because of a direct relationship between it and the kinetic barrier of a given reaction. Here is a paper in JACS that came out quite a few years ago. In it, Chang and colleagues prepare a library of substituted triazines using nucleophilic aromatic substitution. The point of the paper is not the chemistry used by the authors. Indeed, the cornerstone of the process has been worked out in other labs before this paper. In Chang’s example, it is all about how they ran their synthesis. The authors achieved high levels of selectivity by sequentially ramping up temperature. In my view, this is quite remarkable. For the life of me, I cannot think of another example that approaches this one in terms of simplicity and clarity of execution of three distinct operations! Check it out: 0 oC, 60 oC, 120 oC… If you read the experimental section, you will note that base is added only in the last two iterations (the 0 oC step does not involve added DIPEA). You have to admit that a system that allows this type of control is special. The flip side (there is always one, isn’t there?) is that this kind of aromatic substitution has been beaten to death in library development, making the resulting class of compounds over-represented in many collections. However, this should not take anything away from the value of the present process. It would be good to have more examples of this kind of reactions as they would allow one to take a common scaffold and sequentially decorate it like a Christmas tree with all sorts of appendages using… temperature as the enabling parameter.