Theoretical Study on Copper(I)-Catalyzed Cross-Coupling between Aryl Halides and Amides

Abstract

The density functional theory method augmented with the CPCM solvation model was used to study the mechanism of Cu(I)-catalyzed aryl amidation. On the basis of the comparison of multiple reaction pathways, it was determined that diamine-ligated copper(I) amidate was the most reactive intermediate in the reaction mixture for the oxidative addition to aryl halide. Cationic diamine-ligated Cu(I) was calculated to have a lower free energy barrier for oxidative addition, but its concentration in the reaction mixture was too low to represent a useful catalyst. On the other hand, multiple ligation of the amide to Cu(I) at low diamine concentration led to the least reactive intermediate and, thereby, retarded the oxidative addition. Further calculations showed that oxidative addition was the rate-limiting step in Cu-catalyzed aryl amidation. Unlike the transformation from Pd(0) to Pd(II), the Cu(I) → Cu(III) oxidative addition product was pentacoordinated and, thereby, more sensitive to the steric hindrance. A major portion of the overall energy barrier in the oxidative addition to Cu(I) was contributed by the highly unfavorable formation of a 2η complex between copper(I) amidate and aryl halide. Reductive elimination occurred through a square pyramidal structure from the pentacoordinated Cu(III) intermediate. Reductive elimination was a very facile step as compared to oxidative addition. Furthermore, our calculation indicated that trans-N,N‘-dimethylcyclohexane-1,2-diamine was an excellent ligand for Cu-catalyzed aryl amidation, whereas TMEDA was almost completely inactive. These theoretical results were in good agreement with experimental observations, suggesting the possibility of using a combined theoretical and experimental approach to rationally improve Cu(I)-catalyzed cross-coupling reactions.

Understanding the Heteroatom Effect on the Ullmann Copper-Catalyzed Cross-Coupling of X-Arylation (X = NH, O, S) Mechanism

“…The energy barriers in toluene shown in Table 2 can be compared with those reported in the literature. Our values are in general lower than those informed before, to mention, the N-arylation of amide (+28.7 kcal/mol) [57], the O-arylation (+34.2 kcal/mol) [59], and the S-arylation (+39.3 kcal/mol) [60] reactions. Indeed, a direct comparison can be done with the last value shown which corresponds to the reaction between PhI and PhSH.…”

“…As it was reported elsewhere [57,60,64], there are many copper species that can be formed depending on the reaction conditions. The disproportionation process usually leads to inactive species.…”

“…Conversely, Buchwald and Houk by experimental and computational methods claimed that the SET and HAT mechanisms are energetically more favorable for Ullmann N-and O-arylation of alkyl amines and alcohols with aryl iodides [51]. Further support to these one-electron mechanisms was given by a number of detailed theoretical studies on the N-, O-, and S-arylation reported by Zhang and co-workers [57][58][59][60][61]. They confirmed that [(L)Cu I (Nu)] species is indeed the most reactive towards aryl halide among all the other possible copper species.…”

Chemoselectivity and the Curious Reactivity Preferences of Functional Groups

“…Alternatively, an equilibrium may exist that allows the formation of small amounts of 153, but activation of the aryl halide proceeds faster from the CuÀN intermediate than from the CuÀC intermediate (k 1 @ k 2 ; the nature of the aryl halide activation step is not well understood). [131] The transformation of ambident bis-nucleophilic species can also be controlled by using main-group elements. If a molecule contains more than one acidic functional group, the ambident nature of the conjugate base can be especially difficult to control since either one of the reactive centers can participate in a reaction with an added electrophile.…”

Antagonistic Effect of Acetates in C–N Bond Formation with In Situ Generated Diazonium Salts: A Combined Theoretical and Experimental Study

“…[61] This type of theoretical level has proven its accuracy in the mechanistic investigations of copper-catalyzed C-N bond-forming reactions. [8,[62][63][64][65] The heats of formation of complexes with various numbers of ligands and various conformations were theoretically evaluated (see Table 2). We assumed to start that a neutral Cu I complex is formed (complexes I-V).…”