- link chemistry:

Most types of reactions are not simply dimerizations but proceed in an asymmetrical fashion. This means that one usually can identify two differing chemical structures, one of which will connect onto the other. So one could say that the two components which will be joined to form a link are of two opposite abstract polarities. In an ideal case of link-chemistry, these two polarity components are each attached in the same way to the skeleton structure of a MBB, for example each using up one functionalization site. In this fashion, maximum design flexibility is obtained because it becomes possible to invert the polarity of a link between two MBBs in order to try out different assembly sequences and strategies without having to change anything in the MBB skeleton structures.

As link formation has to occur in such a crowded environment, the additional difficulty arises of planning for ejection trajectories for leaving groups, if the chosen reaction generates one. Also, for reactions with mechanisms which depend on interactions with the solvent, as is the case with reactions that need movement of protons, the detailed geometrical arrangement of solvent molecules in the vicinity of the reaction site would have to be known precisely. Such data is hard to get, and it probably can not be assured that the desired solvent arrangement will be present in the crowded space where links have to be formed.

A reaction which is in many ways quite ideal is the Diels-Alder cycloaddition, shown in figure 2.

FIGURE 2: Diels-Alder cycloaddition.

The big benefits of a Diels-Alder reaction are: no leaving group is generated, nothing ionic is involved (which means that the reaction rate is little influenced by the dielectric constant of the surrounding environment), and it works in solvents from hexane to water. The two components of the Diels-Alder reaction can be viewed as two parts which simply snap together when held in sufficient proximity. The reactivity can be tailored by the appropriate attachment of electron-withdrawing and electron-supplying neighbouring functional groups (denoted as "Y" in figure 2).

But a big disadvantage is that the two reactive polarities involved, a diene and a dienophile, can not be dealt with like ordinary (heteroatomic) functional groups. Depending on the design, they are likely to end up not being symmetrically exchangeable because the two polarities most often have to be anchored differently on a MBB skeleton. Incorporating these two functionalities creates a lot of trouble as usually at least two functional group attachment sites would have to be used up, and maybe the whole skeleton structure would have to be custom-tailored around these reactands. This would violate modularity boundaries and sacrifice the flexibility gained by being able to separately design skeleton structures and the functional group decoration.

On the other hand, these functionalities offer quite some flexibility in decorating the formed cyclic adduct by additional functional groups, denoted by "Y" in figure 2, that may serve for more than just the fine-tuning of reactivity, and which could turn the links between MBBs into structure-contributing entities in their own right.