Reductive N-methylation of amines using dimethyl carbonate and molecular hydrogen: Mechanistic insights through kinetic modelling

doi:10.1016/j.cej.2018.06.174

Chemical Engineering Journal

Volume 351, 1 November 2018, Pages 1129-1136

https://doi.org/10.1016/j.cej.2018.06.174 Get rights and content

Highlights

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Ruthenium-catalyzed reductive N-methylation of amines.
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Presence of induction period strongly influenced by temperature.
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Transformation between different type of catalytic species.
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Inactivation of some catalytic species during reaction.
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Kinetic modelling showing excellent correspondence with experiments.

Abstract

Kinetic analysis of ruthenium-catalyzed reductive N-methylation of amines using dimethyl carbonate as C1 source and molecular hydrogen as reductant has been performed. Kinetic equations have been derived and kinetic modelling has been performed for experimental data generated previously at a constant hydrogen pressure as well as for additional experiments performed at different hydrogen pressures. The study has revealed interesting kinetic features related to an induction period strongly influenced by temperature. A kinetic model has been proposed based on advanced reaction mechanism featuring transformation between different type of catalytic species and inactivation of them during the reaction. Kinetic modelling was done for all data sets together showing excellent correspondence between calculations and experiments.

Introduction

Kinetic analysis of complex non-catalytic and catalytic organic reactions has become a tool more and more utilized in academia and industry [1], [2], [3], [4], [5]. This kind of analysis has acquired relevance in chemical reaction engineering [6], [7], [8], [9], [10], where rather complex mechanisms are rigorously treated using numerical data fitting. In particular, for catalysis, a kinetic phenomenon, elucidation of kinetics is an essential part. Typically, experimental data are collected as a function of the parameters considered important for the reaction, i.e. concentrations, temperature, pressures, pH, catalyst loading, volume, etc. Thereafter, a reaction mechanism is proposed based on mechanistic, spectroscopic and kinetic data, estimating the rate constants by regression analysis. Finally, the adequacy of the model is judged based on criteria such as residual sums of squares and parameter significance.

Classical methods of organic chemistry typically provide only a snapshot of a particular reaction (conversion and selectivity after a certain reaction time). In fact, monitoring reaction kinetics of catalytic reactions with a synthetic interest is not a commonly used tool. However, the kinetic information, together with various spectroscopy and computational methods, could provide a substantial amount of mechanistic information useful in the improvement of synthetic methodologies.

The selective N-methylation of amines is a frequently used reaction in organic synthesis, affording valuable compounds used as drugs, agrochemicals or dyes [11], [12], [13]. From an industrial perspective, the preferred methylation agents are formaldehyde, using the Eschweiler–Clarke methodology [13] and methanol, employing zeolites as dehydration catalysts [14]. An interesting alternative to these methodologies would be the use of dimethyl carbonate (DMC) in the presence of a reducing agent, as DMC is a non-toxic, safe and biodegradable compound which is currently used in the industry. Moreover, among the currently used protocols for the synthesis of DMC, an emerging one is based on the reaction of carbon dioxide with methanol [15], [16], [17].

Traditionally, the employment of DMC as a methylating agent involved a B_AL2 mechanism, in which the methyl carbon of the methoxy group acts as the electrophile.[18], [19] This methodology presents drawbacks, such as using high reaction temperatures (>160 °C) to avoid carbamoylation processes and having a limited substrate scope. In contrast, selective N-methylation of amines with dialkyl carbonates and a reducing agent, where the C double bond O moiety is the one used for the methylation, has also been described. Former examples of this reaction employed as catalysts a photo-activated iron-complex [20] or a platinum based complex [21] in the presence of hydrosilanes. The generation of large amounts of waste due to the use of an excess of hydrosilanes, and the limited substrate scope (only secondary amines were reactive), were important limitations of these protocols.

Recently, the first N-methylation of amines using DMC and molecular hydrogen has been described employing the [Ru/Triphos/HNTf₂] system as catalyst (Scheme 1) [22], [23], [24] where Triphos stands for 1,1,1-tris(diphenylphosphinomethyl)ethane [11]. The presence of the acid HNTf₂ as co-catalyst (2.5 eq respect to the Ru loading) was key for the catalytic activity of the system. A mechanistic explanation for the role of the additive implies the formation of the [Ru(Triphos)]²⁺ cation species stabilized by the weakly coordinating ⁻[NTf₂] (bis(trifluoromethanesulfonyl)imide) [25]. This reductive N-methylation protocol, using dimethyl carbonate as C1 source and hydrogen as a reducing agent, was successfully applied for a wide range of primary and secondary aromatic and aliphatic amines. In addition, kinetic profiles for the formation of N-methylaniline 2 and N,N-dimethylaniline 3 under 60 bar of H₂ at several reaction temperatures (130, 140, 150 and 160 °C) were reported. A tentative reaction mechanism for the N-methylation of aromatic amines using this Ru-catalyzed methodology was proposed.

Interestingly, the experimental data reported in this work [11] clearly display a S-shape behaviour for the disappearance of aniline at low temperatures. In order to reveal mechanistic aspects of this reaction and to propose a rate equation capable to fit the experimental data, in the current work kinetic equations have been derived and kinetic modelling has been performed for the N-methylation of aniline 1 with DMC and molecular hydrogen. Moreover, additional experiments have been done at different hydrogen pressures to reveal the influence of the molecular hydrogen on the induction period as well as on the main reaction per se.

Section snippets

Kinetic study for N-methylation of aniline

A 100 mL glass inlet containing a stirring bar was sequentially charged with aniline 1 (279.6 μL, 3.0 mmol), n-hexadecane (250.0 mg) as an internal standard, Ru(acac)₃ (24.1 mg, 0.06 mmol, 2 mol%), Triphos (58.5 mg, 0.09 mmol, 3 mol%), THF (12 mL) as solvent, dimethyl carbonate (868.2 μL, 9.0 mmol, 3 eq.) and a freshly prepared 0.2 M THF solution of the acid co-catalyst HNTf₂ (750.0 μL, 0.15 mmol, 5 mol%). Afterwards, the reaction vial was then placed into a 100 mL autoclave. Once sealed, the

Kinetic data

Kinetic data for the N-methylation of aniline 1 with DMC at 60 bar of hydrogen and using different reaction temperatures, were already reported [11]. In addition, yield/time kinetic profiles were performed at 150 °C using several hydrogen pressures (Fig. 1). An analysis of these data shows that, at certain conditions, there is a clear induction period, where the reaction rate is rather low, since concentration of the starting substrate does not change. Thereafter, there is a rate acceleration,

Conclusions

Ruthenium-catalyzed reductive N-methylation of amines using dimethyl carbonate as C1 source was performed at 130–160 °C exploring the influence of hydrogen pressure. At certain conditions, an induction period was observed, associated with low reaction rates. Such induction periods followed by rate acceleration were seen to be dependent on hydrogen pressure and were more pronounced at low temperature. Mechanistically presence of the induction period was explained by in-situ generation of active

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Reductive N-methylation of amines using dimethyl carbonate and molecular hydrogen: Mechanistic insights through kinetic modelling

Highlights

Abstract

Introduction

Section snippets

Kinetic study for N-methylation of aniline

Kinetic data

Conclusions

Appl. Catal. A. Gen.

Catal. Today

Appl. Catal., A

J. Ind. Eng. Chem.

J. Phys. Org. Chem.

J. Mol. Catal. A. Chem.

Polyhedron

Mol. Catal.

Equilibrium of homochiral oligomerization of a mixture of enantiomers. Its relevance to nonlinear effects in asymmetric catalysis

J. Phys. Chem. B

Kinetic profiling of catalytic organic reactions as a mechanistic tool

J. Am. Chem. Soc.