Energy Minimization by DFT First, DFT calculations on possible isomers of hemi-indigo pyridyl derivative 1 were carried out (Supplementary section 10). For the E and the Z isomers, in their neutral and protonated states, two possible rotational isomers were considered. The energetically favored structures are depicted in Fig. alongside the relative energies. In the neutral form there is a substantial thermodynamic preference for the Z over the E isomer (G = 32.9 kJ mol -1 ) whereas, in the protonated state, the E isomer is considerably lower in energy (G = -30.5 kJ mol -1 ). These large energy differences can be mainly ascribed to stabilization by intramolecular hydrogen bonding. That is, in (Z)-1 a hydrogen bond is formed between the pyridyl nitrogen and the N-