Abstract
Over the last two decades many different auxiliary ligand systems have been utilized in the copper-catalyzed Ullmann amination reaction. However, there has been little consensus on the relative merits of the varied ligands and the exact role they might play in the catalytic process. Accordingly, in this work some of the most commonly employed auxiliary ligands have been evaluated for C–N coupling using reaction progress kinetic analysis (RPKA) methodology. The results reveal not only the relative kinetic competencies of the different auxiliary ligands but also their markedly different influences on catalyst degradation rates. For the model Ullmann reaction between piperidine and iodobenzene using the soluble organic base bis(tetra-n-butylphosphonium) malonate (TBPM) at room temperature, N-methylglycine was shown to give the best performance in terms of high catalytic rate of reaction and comparatively low catalyst deactivation rates. Further experimental and rate data indicate a common catalytic cycle for...
Highlights
The Ullmann C−N cross-coupling reaction dates back to the early 1900s, where the use of stoichiometric amounts of copper and high reaction temperatures allowed for the coupling of aryl halides and amines
The low cost and toxicity of copper coupled with the use of cheap and readily available auxiliary ligands based on N and O atoms makes it an attractive alternative to the otherwise successful palladium-catalyzed Buchwald−Hartwig reaction.18−21 Historically, the mechanism of the Ullmann reaction has been the subject of much debate, with often contradictory interpretations of experimental and computational data in the literature.22−25 This lack of understanding has hindered the development of more robust catalytic systems and the improvement of existing systems
Recent studies have all pointed toward the copper catalyst playing an important role in the activation of the aryl halide substrate,22,23 with spectroscopic evidence for an oxidative addition/reductive elimination pathway via a copper(III) intermediate.26−28 Despite these advances the role of the auxiliary ligand in the catalytic cycle remains relatively unexplored, with ligand optimization studies predominately based solely upon empirical final-yield figures, rather than any deeper kinetic or mechanistic insights
Summary
The Ullmann C−N cross-coupling reaction dates back to the early 1900s, where the use of stoichiometric amounts of copper and high reaction temperatures allowed for the coupling of aryl halides and amines. there were several drawbacks to this classical Ullmann reaction, where strong bases, long reaction times, and electron-deficient aryl substrates were required for the reaction to proceed. Studies on the TBPM-promoted ligand-free Ullmann reaction using the RPKA methodology carried out previously in our group have allowed us to recently propose a modified catalytic cycle (Scheme 2) and simplified steady-state rate law (eq 1 in Scheme 2) for this reaction and to explore in more depth possible catalyst deactivation pathways. We extend our studies on the mechanism of the catalytic Ullmann reaction by kinetically profiling a wide range of commonly used auxiliary ligands in the cross-coupling of piperidine and iodobenzene using TBPM as the base These results allow us to move beyond just looking at product yields and compare for the first time the influence of the auxiliary ligand on the rate of reaction, rate dependence in substrates, and catalyst deactivation/inhibition pathways
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