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

Abstract

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-1,10phenanthroyl)-p-tert-butylcalix[8]arene (L 1,5 ), 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 1,4 ) described herein. [Cu(L 1,4 )I] was synthesized from L 1,4 and CuI in good yield and characterized spectroscopically. To evaluate the effect of its cavity on catalysis, Ullmann-type CÀ S coupling was chosen as proof-of-concept. Selected aryl halides were used, and the results compared with the previously reported Cu(I)/L 1,5 system. Only highly activated aryl halides generate the CÀ S coupling product in moderate yields with the Cu(I)/L 1,4 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 1,4 regioisomer undergoes a deformation that does not occur with L 1,5 , 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 1,4 À H)(CH 3 CN) 2 ] that features Cu(I) coordinated inside a cleft defined by the macrocyclic framework.

PyConSolv: A Python Package for Conformer Generation of (Metal-Containing) Systems in Explicit Solvent

“…The collapsed structure is in stark contrast to those generated in explicit solvent via PyConSolv (see Figure , bottom left). As it is known from experiments that an intact cavity is vital for any catalysis to take place, , PyConSolv yields structures that are a better representation of the solution phase conformations.…”

“…This inherent flexibility needs to be taken into account, in order to obtain an accurate energy profile for the reaction 15 or to explain the difference in activity between various regioisomers. 14 Using PyConSolv, with PBE0/def2-SVP/D3+CPCM-(Chloroform), 31,72,79,80 the system shown in Figure 2 was parametrized and solvated in chloroform. The trajectory was aligned on the copper and phenanthroline moieties.…”

“…Cu­(I)-phenanthroyl encapsulated by calix[8]­arene is a catalyst that has proven to be very complex to model, with the macrocyclic cage being particularly mobile. This inherent flexibility needs to be taken into account, in order to obtain an accurate energy profile for the reaction or to explain the difference in activity between various regioisomers …”

“…While the importance of conformers is well-known and a key feature in drug design pipelines, , it has gathered some attention in the field of homogeneous catalysis as early as the 1990s. − However, conformer searches are by no means widespread in standard mechanistic studies today. A systematic exploration of the conformational space, by generating rotamers, can be employed for simple systems, with few degrees of freedom, but quickly becomes unfeasible for larger molecules.…”

“…We would like to stress here that the force-field parameters are generated in such a way that the QM optimized structure is retained. While the use of a bonded model, as implemented in MCPB, provides accurate results for many different (transition-)­metal-containing complexes, ,,,− the generation of parameters is a tedious and error prone process, due to the amount of user intervention that is required.…”