Fig. 4: Experimental and modelled hyperspace of a Ugi-type, four-component reaction.
From: Robot-assisted mapping of chemical reaction hyperspaces and networks
a–d, Snapshots of the reaction’s four-dimensional hyperspace. The axes of each plot are initial amine, aldehyde and isocyanide concentrations for initial concentrations of pTSA indicated above each plot. Experimental yields (after 16 h at 26 °C) of product 16e are colour-coded according to the legend in d. Only 125 interpolated conditions per cube are shown for clarity (see Supplementary Information Section 4.15 and Supplementary Video 3). Green and blue stars mark two distinct yield maxima. e–h, Corresponding yield distributions of 16e predicted by a kinetic model fitted simultaneously to all experimental data (yield isosurfaces are at 0.5%, 1.0%, 1.5% and 5.0%). This model is based on a kinetic network outlined in i and further side reactions (see Supplementary Information Scheme 5). The original reaction of 16a, 16b, 16c and DMF using initiator 16d and leading to product 16e is on the yellow background. The classic Ugi mechanism is summarized by blue arrows (for details, see Supplementary Information Scheme 6). A competing oxazoline-based path (brown) was experimentally excluded (red cross). A third mechanism (magenta), potentially active at high [pTSA]0 and involving aldehyde, amine and isocyanide in a 1:1:2 ratio, did not improve model fit. The theoretical model (Supplementary Tables 19, 20, 22 and 23) comprised this entire mechanistic network of 12 reactions and 15 proton transfer steps. Best-fitted model followed the data closely while retaining pKa values (in red font) of most species within 1–2 units from literature values (black font) used as initial guess (see Supplementary Information Section 5.3). j, Experimental and modelled yield profiles at the two maxima (corners A and B in a) along [pTSA]0 confirm that yields at global/local maxima are higher than at any four-dimensional paths connecting them (see Supplementary Video 3 and Supplementary Fig. 161). Error bars correspond to 14.6% relative standard error. k, Initial concentrations at global and local maxima.
