Temperature-controlled conformational switching of squaramides enabled by side-chain hydrogen bonding

Precise control of local conformational bias is essential for constructing stimulus-responsive aromatic architectures. Amide-derived scaffolds such as squaramides are particularly attractive targets, as their moderate rotational barriers allow thermodynamic tuning without irreversible locking. Here we demonstrate that introduction of a hydrogen-bond-accepting side chain enables thermodynamic programming of squaramide conformations. The triethylene glycol (TEG) substituent of squaramide 1c bearing a pyrene moiety induces reversible temperature-dependent switching between (trans, trans) and (cis, trans) forms, which can be quantified by variable-temperature NMR and van't Hoff analysis (ΔH° = -1.87 kcal mol^-1, ΔS° = -8.2 cal mol^-1 K^-1). In contrast, N-n-propyl analogue 1b lacking a hydrogen-bond-accepting functionality exists exclusively in (cis, trans) form under identical conditions, establishing the minimal structural requirement for switching. A diphenyl analogue 1d without π-extension retains thermally reversible behavior, demonstrating that π-surface enlargement is not essential, but modulates conformational bias. These results establish a side-chain-enabled design principle for thermodynamically programmable aromatic conformations.