Rationalizing the Catalytic Activity of Copper in the Cycloaddition of Azide and Alkynes (CuAAC) with the Topology of∇²ρ(r) and∇∇²ρ(r)

Abstract

The distinct role of the Cu(I) in the Huisgen dipolar cycloaddition of azides to alkynes (denoted as CuAAC) is disclosed by following the evolution of the topology of the Laplacian of the electronic charge density, ∇(2)ρ(r), and its gradient vector field, ∇∇(2)ρ(r), along the reaction coordinate with several density functionals (wB97XD, LCwPBE, M06-2X, M06-L, B3LYP) and the 6-311++G(d,p) basis set. Remarkably, in view of the topology of ∇(2)ρ(r) and ∇∇(2)ρ(r), the mechanism appears to be diverse (asynchronous concerted or stepwise) depending on the reaction conditions. Overall, the catalyst orchestrates first the formation of the external N-C and subsequently the internal one by following alternatively a pericyclic-like or a pseudopericyclic-like mechanism. The role of the catalyst is envisaged as transforming the type of the mechanism from pericyclic to pseudopericyclic, and thence eventually facilitating the process. The mononuclear process (CuAAC) is concerted (with L = CH3CN) with all the functionals tested (i.e., wB97XD, LCwPBE, M06-2X, M06-L), except for the B3LYP who rendered a stepwise mechanism. Nevertheless, with L = H2O and CH3OH attached to the copper, the process becomes asynchronous concerted. Interestingly, upon introduction of the second Cu (Cu2AAC) at our best theory level (i.e., LCwPBE/6-311++G(d,p)), all the processes considered turned out to be concerted except for the 1,4-Cu2AAC which is predicted to be stepwise, with an extremely low enthalpy for the ring-contraction process (0.18 kcal/mol). This fact is explicated by the stability of the intermediate, which is in turn rationalized by the hole within the valence shell of the carbon attached to the Cu and the position of the (3, -3)LP, of the internal N, toward it. Furthermore, due to the tiny energy difference between the stepwise dinuclear and concerted mononuclear mechanisms (0.39 kcal/mol), we argue that the concurrence of both processes (CuAAC and Cu2AAC) is feasible.

Metal-catalyzed azide-alkyne “click” reactions: Mechanistic overview and recent trends

“…Following these pioneering computational works, several theoretical mechanistic investigations on the CuAAC reactions have been carried out, considering various copper systems, most of them multinuclear, and leading basically to similar qualitative conclusions [34,[58][59][60][61][62]. A recent investigation pointed out the possibility for a concerted vs. stepwise nature of the mechanism, however, depending on the ligand nature [63]. The most recent experimental mechanistic study by Fokin's group unambiguously demonstrated the participation of a dinuclear copper intermediate in the case of a CuAAC reaction in which a mixture of Cu(I)(aryl) complex and [Cu(I)(MeCN) 4 ] + were used ( Figure 2).…”

Unclicking the Click: Metal‐Assisted Mechanochemical Cycloreversion of Triazoles Is Possible

“…[3,4] Originally,the catalytic process has been proposed to proceed via amechanism that involves ametallacyclic intermediate, 7, with asingle Cu atom. [22,[25][26][27][28][29][30] It is thus conceivable that such Cu I -mediated mechanisms could bring Figure 1. [22,[25][26][27][28][29][30] It is thus conceivable that such Cu I -mediated mechanisms could bring Figure 1.…”

“…[24] Later, reaction mechanisms involving dinuclear Cu I complexes were detected experimentally and analyzed in terms of quantum chemical calculations to elucidate the details of the thermal reaction. [22,[25][26][27][28][29][30] It is thus conceivable that such Cu I -mediated mechanisms could bring Relative energies (with respect to the optimized species as indicated in the lower-left corners)a long the intrinsic reaction coordinates (IRC) of the rate-determining step in the thermal limit (F 0 = 0nN) and optimized at constant external forces (F 0 = 1, 2, 3, and 4nN) for the reaction mechanisms P1 to P6 as sketched in Figure 1.…”

Me3SiBr/InCl3 catalyzed allylation of alcohols: Identifying the combined Lewis structure and investigating the reaction mechanism

“…[22][23][24][25][26][27][28] All the geometries including reactants, intermediates, transition states, and products were obtained at ωB97XD/def2-SVP theory level. [29][30][31] ωB97XD is range-separated functional, which can obtain satisfactory accuracy for thermochemistry, kinetics, and noncovalent interactions and be used for reaction mechanism research [32][33][34][35][36] with def2-SVP basis set. [37][38][39] The calculation used solvent model SMD, [40][41][42] and hexane was taken as the solvent.…”