Please cite this article in press as: J. Mielby, et al., Mechanistic investigation of the one-pot formation of amides by oxidative coupling of alcohols with amines in methanol, Catal. Today (2012), http://dx.doi.org/10.1016/j.cattod.2012.04.026 ARTICLE IN PRESS G Model CATTOD-7994; No. of Pages 6 Catalysis Today xxx (2012) xxx–xxx Contents lists available at SciVerse ScienceDirect Catalysis Today jou rn al h om epage: www.elsevier.com/locate/cattod Mechanistic investigation of the one-pot formation of amides by oxidative coupling of alcohols with amines in methanol Jerrik Mielby a,b , Anders Riisager a,b , Peter Fristrup b,∗ , Søren Kegnæs a,b,∗∗ a Centre for Catalysis and Sustainable Chemistry b Department of Chemistry, Technical University of Denmark, Building 207, DK-2800 Kgs. Lyngby, Denmark a r t i c l e i n f o Article history: Received 20 November 2011 Received in revised form 17 April 2012 Accepted 23 April 2012 Available online xxx Keywords: Gold catalysis Oxidative coupling Amide formation Mechanism Hammett study a b s t r a c t The one-pot formation of amides by oxidative coupling of alcohols and amines via intermediate formation of methyl ester using supported gold and base as catalysts was studied using the Hammett methodology. Determining the relative reactivity of four different para-substituted benzyl alcohol derivatives showed that the first step of the reaction generates a partial positive charge in the benzylic position (i.e. by hydride abstraction), while the second step of the reaction builds up negative charge in the rate determining step. The aminolysis of the methyl ester intermediate was further investigated by means of DFT/B3LYP. The transition state structures and energies were determined for both a concerted and a neutral two-step reaction mechanism. As expected, the base-promoted two-step mechanism was found to be the most energetically favourable and this reaction mechanism was used to construct a theoretical Hammett plot that was in good agreement with the one obtained experimentally. © 2012 Elsevier B.V. All rights reserved. 1. Introduction Formation of amides is a fundamental reaction in chemical synthesis and is used in the production of a broad range of bulk commodities, high-value fine chemicals, agrochemicals, and pharmaceuticals [1]. Amides are usually prepared by coupling of carboxylic acids and amines using a coupling reagent or by acti- vation of the carboxylic acid. Alternative procedures include the Staudinger ligation [2], aminocarbonylation of aryl halides [3], and oxidative amidation of aldehydes [4]. Unfortunately, all these methods require the use of stoichiometric amounts of reagents, making them generally expensive and wasteful reactions [5]. In the search for a more sustainable chemical production, great efforts have been put into replacing the stoichiometric reagents with catalytic processes. This approach is not only cheaper and more environmentally friendly but also facilitates the possibility of start- ing from substrates other than carboxylic acids, thus paving the way for previously unavailable synthetic routes to amides [5]. In 2007 Milstein and co-workers [6] reported the first direct acy- lation of amines by alcohols under liberation of molecular hydrogen using a homogeneous ruthenium catalyst. Although this simple and highly atom-efficient reaction have inspired several other research ∗ Corresponding author. Tel.: +45 45 25 21 23; fax: +45 45 88 31 36. ∗∗ Corresponding author at: Centre for Catalysis and Sustainable Chemistry. Tel.: +45 45 25 24 02; fax: +45 45 88 31 36. E-mail addresses: pf@kemi.dtu.dk (P. Fristrup), skk@kemi.dtu.dk (S. Kegnæs). groups to further develop this reaction [7,8], the special handling of expensive metal complexes and ligands remains a limitation that may prevent general application. In contrast, the handling of a heterogeneous catalyst is usually more straightforward [9]. Since the first fundamental studies by Bond et al. [10], Hutch- ings [11], Haruta et al. [12], and Prati and Rossi [13], supported gold nanoparticles have been recognised as surprisingly active and selective heterogeneous catalysts for a number of aerobic oxida- tions using molecular oxygen (or even air) as the terminal oxidant [14,15]. From the standpoint of green and sustainable chemistry these oxidations are attractive, because oxygen is a cheap and abun- dant oxidant that produces water as the only by-product. Recently, we reported that the combination of supported gold nanoparticles and base forms an efficient and highly selective catalytic system for the one-pot synthesis of amides by aero- bic oxidative coupling of alcohols or aldehydes with amines in methanol [16] (see Scheme 1). In the first step of this reaction, a methyl ester is obtained by the gold-catalysed aerobic oxidation of the alcohol or aldehyde in methanol [17,18]. It is notable that in this step the methanol serves as both solvent and reactant. In the second step of the reaction, addition of amine affords the amide by base-catalysed aminolysis of the methyl ester. As the same base promotes both steps of the reaction, the oxidative coupling can be performed in a convenient one-pot procedure under mild reaction conditions (25–65 ◦ C, atmo- spheric pressure). It is important to mention that this approach is conceptually different from the gold-catalysed reactions previ- ously reported by Wang et al. [19] and Soulé et al. [20], which are 0920-5861/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.cattod.2012.04.026