To gain more insight into the pyridine-dependent disparities in the reaction outcome, DFT calculations were conducted on the quinoline-forming reaction at the 6-311++G(d,p)/SMD(dichloroethane)//B3LYP-D3/6-31G(d,p) level (Fig. ). In the case of electron-poor Py 1 , the pathway from transient dinitrilium intermediate INT-II to pyridine adducts INT-III,III′ is energetically unfavourable. The energetic barrier for the nucleophilic addition of alkyne 6 to mono-pyridine adduct INT-III towards transition state TS-Alk is comparable to that for the intramolecular cyclization via TS-7 and the subsequent spontaneous contraction en route to ddc dication 7, thereby leading to the low yield of TEQ 8a associated with 7. Indeed, 7 was obtained in acceptable yield (73%) under milder conditions at room temperature in the absence of alkyne 6 (Fig. ). The formation of 7 appeared to be kinetically irreversible, which was empirically supported by an unsuccessful attempt to transform 7 into 8a upon exposure to the optimized reaction conditions using alkyne 6 and Py 3 (Fig. . More detailed data are summarized in Supplementary Section 3)). On the other hand, using the more electron-rich pyridines Py Single crystals of racemic TEQ 8a were grown in DMSO, and a crystallographic analysis revealed a C2-symmetric saddle-shaped architecture with a central hollow surrounded by four pyridyl nitrogen atoms that are aligned in an almost coplanar fashion (torsion angle: 5.9°) (Fig. ). Each quinoline unit deviates only slightly from the fitted plane (mean distance: 0.023 Å; standard deviation: 0.018) and is concatenated with an averaged torsion angle of 69.2°. The analysis of the NCI plot revealed the absence of any significant repulsive interactions between the quinoline units (Fig. ) . Optimizing the geometry of S4-symmetric non-substituted TEQ 9 using DFT calculations reproduced an almost identical architecture. A StrainViz analysis of 9 and enthalpic evaluation (∆Hf = +5.0 kcal×mol -1 ) of hypothetical homodesmotic reactions implied that TEQ adopts its saddle-shaped architecture with only a marginal amount of strain (Fig. , Supplementary Fig. ) . The highly rigid nature of the TEQ architecture was corroborated by the high calculated flipping barrier of 9 (53.8 kcal×mol -1 ), which is significantly larger than that of 1,1′-binaphthol (empirical: 39.6 kcal×mol -1 ; racemization t1/2 = 1.15 h at 250 °C) , a chiral ligand widely used in organic synthesis (Fig. ). This result strongly suggests a potential use of TEQs as chiral ligands, and more specifically, as a new class of chiral non-planar tetradentate nitrogen ligands that emulate porphyrin chemistry. To determine the empirical flipping barrier of the TEQ architecture, C2-symmetric rac-TEQ 8a was enantiomerically resolved using preparative HPLC on a chiral stationary phase (Fig. inset and Supplementary Fig. ), and both of the thus obtained enantiomers of 8a were subsequently subjected to circular dichroism (CD) analysis in CH2Cl2. (+)-8a was isolated as the first fraction (tR = 12.4 min) and showed explicit positive and negative Cotton effects at 232 and 249 nm (Fig. ). The CD spectrum of the second fraction, which corresponds to (-)-8a, displayed perfect mirror symmetry, supporting the mirrorimage architecture of these enantiomers. As suggested by the calculated flipping barrier of model TEQ 9, the enantiomeric purity of homochiral (+)-8a did not diminish upon heating, not even after 20 h at 240 °C in diphenyl ether, confirming the potential utility of 8a as a chiral ligand, especially under harsh reaction conditions (Fig. ). Interestingly, C2-symmetric cyclic diamide 5, which could be resolved in a similar manner, was highly susceptible to racemization, even at 40 °C, with an empirically determined racemization barrier of 25.1 kcal×mol -1 (Supplementary Section 6), which is consistent with the calculated value of 26.1 kcal×mol -1 (Supplementary Fig. ). It is intriguing that the minute structural difference between 8a and diamide 5 endows TEQ 8a with such a significantly higher structural rigidity and consequently, practical stereochemical integrity as a chiral ligand. Owing to the diagonal substitution of p-anisyl groups on the periphery of TEQ 8a, boronic acid-assisted partial hydride reduction of the two non-substituted quinoline units proceeded in a highly regioselective and diastereoselective fashion, furnishing C2-symmetric octahydro-TEQ (TEQ-H8) 10 in 70% yield (Fig. ) . Each of the reduced tetrahydroquinoline units adopted equatorial connectivity at the 2 position relative to the neighbouring quinoline unit, whose structure was unequivocally determined by X-ray crystallography. Structural optimization using DFT calculations revealed that diastereomeric rac-TEQ-H8 10′, which is characterized by axial connectivity, displayed a highly strained structure and was by 14.7 kcal×mol -1 less stable than 10, accounting for the exclusive formation of 10 (Supplementary Fig. ). The structure of 10 is particularly important due to its close similarity to porphyrins and phthalocyanines in terms of the arrangement of the four nitrogen atoms and the -2 charge upon complexation with metal cations, and can thus be expected to serve as a chiral variant of these nitrogen-based tetradentate ligands. Given that the scope of alkynes in the final step to construct the TEQ architecture was unexpectedly narrow (Supplementary Section 2), we conducted a structural modification of the periphery of TEQ starting from 8a. While attempts to apply standard demethylation protocols using conventional Lewis acids (e.g., AlCl3 or BBr3) were unsuccessful, treatment of neat 8a with pyridine×HCl furnished phenol 8b. Conversion to triflate 8c with Tf2O and pyridine, followed by Sonogashira-Hagihara coupling with phenylacetylene afforded 8d . Installation of PEG chains on the phenolic moieties proceeded smoothly to give TEQ derivative 8e, which exhibits ambiphilic miscibility in polar and nonpolar media.