The effect of incremental addition of acid (TFA) was monitored by 1 H NMR spectroscopy in CDCl3 for (Z)-1. It resulted in downfield shifts of all pyridyl proton signals, indicative of protonation (Fig. and Supplementary section 4). When a solution containing excess TFA (32 equiv.) was then left to equilibrate, the 1 H NMR signals for the protonated species (Z)-1 . H + disappeared and a new set of signals emerged (Fig. and Supplementary section 5). A NOEdiff. experiment revealed a through-space interaction between the olefinic proton (Hf) and the 3-oxindole NH-proton (He) (Supplementary Fig. ), supporting formation of the E isomer. Furthermore, the NOESY spectrum of (E)-1 . H + indicated that the olefinic proton (Hf) is in close proximity to an N-heterocyclic proton (Hj), while no coupling was observed with the pyridinium proton (Hk) (Supplementary Fig. ). Very likely, hydrogen bonding between the pyridinium and carbonyl group leads to a fixed orientation of the N-heterocycle as was predicted by DFT calculations. Gratifyingly, within a day, nearly quantitative isomerization to the E isomer was observed, i.e., a mixture enriched to 95% in (E)-1 . H + was obtained at thermal equilibrium. When the amount of TFA was lowered, however, the E/Z ratio decreased (Supplementary Figs. 23-24), even while protonation of 1 was established. A possible explanation was sought in pyridinium-trifluoroacetate ion-pair formation (Supplementary section 4), which could compete with the stabilizing intramolecular hydrogen bond formation. This ionpair is proposed to be solvated in the presence of larger amounts of TFA, explaining the difference in conversion to the E isomer. Further, increasing the amount of TFA accelerated isomerization (Supplementary section 5-6), hinting at an acid-catalyzed process. A similar observation was made previously for other conjugated olefins, including stilbene derivatives. The Z isomer could be regained by basification of the solution. When Et3N was added (48 equiv.) to an equilibrated sample of 1 in the presence of TFA (32 equiv.), most pyridyl proton signals now shifted back upfield (Hg, Hh, Hi, Fig. and Supplementary Fig. ), indicative of deprotonation. Over the course of several days, (E)-1 fully isomerized back to (Z)-1, hence completing the thermal acid/base-controlled switching cycle as outlined in Fig. .