Mechanism of the Organocatalyzed Decarboxylative Knoevenagel−Doebner Reaction. A Theoretical Study

Abstract

We have investigated important intermediates and key transition states of the organocatalyzed Knoevenagel condensation using density functional theory and two different basis sets (6-31 G(d,p) and 6-311++G(2df,2pd)), both in gas phase and simulating the bulk solvent (pyridine) using the PCM method. Calculated structures for reactants, intermediates, and key transition states suggest that the secondary amine catalyst is essential, both for activating the aldehyde for nucleophilic attack, and in the possible decarboxylation pathways. The calculated results are shown to agree with available experimental information. On the basis of the results obtained, the studied mechanism may be important in the understanding of vinylphenol production during malting and brewing of wheat and barley grains.

Microwave-Assisted Knoevenagel-Doebner Reaction: An Efficient Method for Naturally Occurring Phenolic Acids Synthesis

“…Lowering the reaction temperature (90°C) and applying a longer reaction time (30 min) solved this issue and provided the same conversion rate of ferulic acid (72%, Table 2 –Entry 3) but with almost no formation of the corresponding 2-methoxy-4-vinylphenol (2%). In accordance with the results from the DoE and the work of Bermúdez et al ( 2010 ), this set of experiments confirms that the decarboxylation of ferulic acid into 2-methoxy-4-vinylphenol is promoted when the reaction is performed at high temperature (120°C) and with an excess of piperidine 1 .…”

“…(Sinha et al, 2007 ; Zago et al, 2015 ) Indeed, these works have shown that, depending on the reaction conditions, the Knoevenagel-Doebner condensation on p -hydroxycinnamaldehydes can result in a mixture of the corresponding PAs but also their vinylphenols. Many mechanisms have been proposed to account for this outcome and a theoretical thermodynamical study performed by Bermúdez et al ( 2010 ) has demonstrated that the most relevant one involves piperidine as a leaving group that can promote either the formation of the PAs or that of the vinylphenols. Not only this mechanism shows that an excess of piperidine is needed to access vinylphenols (blue route in Scheme 1 ), but also the calculations proved that the reaction must be heated at relatively high temperatures to overcome the unfavorable thermodynamic and kinetic factors of the formation of PAs and their corresponding vinylphenols.…”

Proline-Mediated Knoevenagel–Doebner Condensation in Ethanol: A Sustainable Access to p-Hydroxycinnamic Acids

“…Knoevenagel reactions are known to be really sensitive to reaction conditions and it has been shown that each reaction parameter impacts significantly p-hydroxycinnamic acid production as well as that of side-products (di-acid and vinyl phenol) (Scheme 1). Indeed high temperature is an essential factor that promotes decarboxylation of phydroxycinnamic di-acids into p-hydroxycinnamic acids (Scheme 1) 14 . Moreover, high temperatures also induce malonic acid degradation and acetic acid generation 15 .…”

Organocatalyzed Decarboxylation of Naturally Occurring Cinnamic Acids: Potential Role in Flavoring Chemicals Production

“…It has been argued that the formation of the trans-cinnamic acid is effectively non-reversible [12]. However, highlevel theoretical calculations showed that under employed conditions, Route 1 is essentially reversible [20].…”

“…Recently, a detailed computational study of the mechanism of the Knoevenagel-Doebner reaction was reported [20], answering questions regarding the mechanism of the reaction and opening the door to new ones. Hydroxycinnamic acids are ubiquitous in plants, and it has been proposed that enzymatic decarboxylation may be responsible for vinylphenol production [21].…”