| The CuI-catalyzed azide-alkyne cycloaddition (CuAAC) has solidified its position as the quintessential 'click' reaction since its discovery in 2001. Copper-binding ligands can accelerate the ligation by several orders of magnitude, thus further increasing its utility. We employed reaction calorimetry to screen over 100 different compounds that were reported in the literature or were easily obtainable Cu-chelators. The top contenders were generally multidentate C3v-symmetric tris(heterocyclemethyl) amines, which we further tested with different substrates and showed they can impart remarkably fast rates in preparative scale reactions with catalyst loadings of 0.1% or less. We then prepared hybrid tripodal amines, each bearing a linear combination of 2-benzimidazolemethyl, 2-pyridinemethyl and 4-benzyltriazolemethyl heterocycles and investigated the effects that solvents, pH, and substrate concentration play on them. Strongly chelating ligands formed inhibitory Cu complexes in water, but in coordinating media they were able to bind CuI productively and give outstanding acceleration. Rate order studies revealed a catalytic complex that brings at least two copper ions together and aided by EPR and mass spectrometry data we were able to build the most comprehensive model of the CuAAC reaction to date. The ligand containing one benzimidazole and two pyridines (BimPy 2) was found to form the most versatile catalyst, so we immobilized it on polystyrene and polyethylene glycol resins. The resulting materials show convenient properties of rate, metal retention, and separability from soluble reaction components even in strongly coordinating solvents such as DMSO and DMF, which allows them to be reused dozens of times without the addition of extra Cu. Finally, in order to gain more information on the mechanism of the ligand-accelerated CuAAC, we prepared chiral C3 v-symmetric tris(oxazolinylmethyl) amines with i-Pr-, Bn- and Ph- substituents. Kinetic resolution experiments with pseudoracemic azides showed small rate difference (s = 1.6) in the formation of (R)- vs. (S)-triazoles. This encouraged us to seek other heterocycles that could better discriminate against starting material enantiomers and we made progress toward the synthesis of the planary chiral tris(azaferrocenylmethly) amine. |
