Conformational Effects of Regioisomeric Substitution on the Catalytic Activity of Copper/Calix[8]arene C-S Coupling

Functionalization of the phenolic rim of p-tert-butylcalix[8]arene with phenanthroline to create a cavity leads to formation of two regioisomers. Substitution of positions 1 and 5 produces the known C-2v-symmetric regioisomer 1,5-(2,9-dimethyl-1,10-phenanthroyl)-p-tert-butylcalix[8]arene (L-1,L-5), while substitution of positions 1 and 4 produces the C-s-symmetric regioisomer 1,4-(2,9-dimethyl-1,10-phenanthroyl)-p-tert-butylcalix[8]arene (L-1,L-4) described herein. [Cu(L-1,L-4)I] was synthesized from L-1,L-4 and CuI in good yield and characterized spectroscopically. To evaluate the effect of its cavity on catalysis, Ullmann-type C-S coupling was chosen as proof-of-concept. Selected aryl halides were used, and the results compared with the previously reported Cu(I)/L-1,L-5 system. Only highly activated aryl halides generate the C-S coupling product in moderate yields with the Cu(I)/L-1,L-4 system. To shed light on these observations, detailed computational investigations were carried out, revealing the influence of the calix[8]arene macrocyclic morphology on the accessible conformations. The L-1,L-4 regioisomer undergoes a deformation that does not occur with L-1,L-5, resulting in an exposed catalytic center, presumably the cause of the low activity of the former system. The 1,4-connectivity was confirmed in the solid-state structure of the byproduct [Cu(L-1,L-4-H)(CH3CN)(2)] that features Cu(I) coordinated inside a cleft defined by the macrocyclic framework.

Automated summary

Functionalization of p-tert-butylcalix[8]arene with phenanthroline at the phenolic rim created two regioisomers, with substitution at positions 1 and 5 producing a known symmetric regioisomer and substitution at positions 1 and 4 producing a newly described symmetric regioisomer. The C-S coupling reaction using the newly synthesized regioisomer showed lower activity compared to the previously reported system, potentially due to a difference in the exposed catalytic center caused by a deformation in the regioisomer's structure. Detailed computational investigations confirmed the 1,4-connectivity and revealed the influence of the calix[8]arene macrocyclic morphology on accessible conformations.