The formation of mixHC [8] and cycHC [8] proved to be sensitive to the monomer ratio and acid loading (Figure ). Variations of the monomer ratios within the range from 1:5 to 1:15 did not significantly affect the yield of chimeric mixHC [8] (Figure , Table ), however, using an excess of CU clearly resulted in the enhanced generation of cycHC [8] (Figure , Table ). The quantity of HClO 4 appeared as the vital parameter affecting the formation of mixHC [8]. The highest yields of mixHC [8] were attained within the specific range of HClO 4 loadings of 1.2-3.0 eq. (Figure ), while cycHC [8] was less dependent on the quantity of acid catalyst. This observation highlights the difference in formation of mixHC [8] and cycHC [8] in response to varied reaction conditions. The impacts of milling time and aging temperature appeared to be less significant, and the optimal temperature for ripening mixHC [8] was found to range from 40 to 65°C. RSM helped to reach a 20% yield of mixHC [8] under standard conditions -3 eq. of template, 1 h ball-milling followed by 24 h aging at 60 °C -selected for further optimization studies. ) as a template did not seem practical, since HSbF 6 mainly exists as the HF/SbF 5 superacid system. Hexafluorophosphate (PF 6 ˉ), on the other hand, serves as an efficient template for the synthesis of homomeric cycHC [8] in solution. Due to its advantageous templating potential, HPF 6 was chosen as an alternative reagent to mediate the solid-state synthesis of mixHC [8]. In addition, it is safer to handle compared to perchlorates that are known for their undesirable oxidative, flammable and explosive hazards. Interestingly, the use of HPF 6 resulted in decreased formation of homomeric cycHC [8], contrary to an improved yield (28%) of mixHC [8] (Figure , Table ). Since the self-assembly of mixHC [8] was highly sensitive to the quantity of acid (Figure ), we tested three hexafluorophosphate salts (AgPF 6 , [Cu(CH 3 CN) 4 ]PF 6 , KPF 6 ) as additives to partially substitute the acid while keeping the amount of template anion constant (Figure , Table ). Additionally, we anticipated that the Ag + and Cu + cations could serve as potential promoters for the generation of mixHC [8] due to their affinity for biotin. As depicted in Figure , the Ag + and Cu + salts had a negligible effect on formation of mixHC [8], while improving the yield of homomeric cycHC [8] compared to the reaction with HPF 6 . The latter points at the effective decrease in the concentration of antagonistic CU-rich mixed oligomers, which reassembled and provided CU to cyclize into cycHC [8]. The best result was achieved with KPF 6 , which afforded the highest yield of mixHC [8] (37%), with accompanying formation of cycHC [8] (38%) (Figure ). Further variation of HPF 6 /KPF 6 equivalence by RSM, however, did not improve the formation of mixHC [8] (see SI, Tables S8-S12, Figure ).