This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. Article Cite This: J. Phys. Chem. A 2018, 122, 451−459 pubs.acs.org/JPCA Reaction Mechanism of Organocatalytic Michael Addition of Nitromethane to Cinnamaldehyde: A Case Study on Catalyst Regeneration and Solvent Effects Published as part of The Journal of Physical Chemistry virtual special issue “Manuel Yań̃ez and Otilia Mó Festschrift”. ́ † ‡ ‡ ,‡ Katarzyna Swiderek, Alexander R. Nödling, Yu-Hsuan Tsai, Louis Y. P. Luk,* † § and Vicent Moliner*, , † Departament de Química Física i Analítica, Universitat Jaume I, 12071 Castellon,́ Spain ‡ School of Chemistry, Cardiff University, CF10 3AT Cardiff, United Kingdom § School of Chemistry, University of Bath, BA2 7AY Bath, United Kingdom *S Supporting Information ABSTRACT: The Michael addition of nitromethane to cinnamaldehyde has been computationally studied in the absence of a catalyst and the presence of a biotinylated secondary amine by a combined computational and experimental approach. The calculations were performed at the density functional theory (DFT) level with the M06-2X hybrid functional, and a polarizable continuum model has been employed to mimic the effect of two different solvents: dichloromethane (DCM) and water. Contrary to common assumption, the product-derived iminium intermediate was absent in both of the solvents tested. Instead, hydrating the C1−C2 double bond in the enamine intermediate directly yields the tetrahedral intermediate, which is key for forming the product and regenerating the catalyst. Enamine hydration is concerted and found to be rate-limiting in DCM but segregated into two non-rate-limiting steps when the solvent is replaced with water. However, further analysis revealed that the use of water as solvent also raises the energy barriers for other chemical steps, particularly the critical step of C−C bond formation between the iminium intermediate and nucleophile; this consequently lowers both the reaction yield and enantioselectivity of this LUMO-lowering reaction, as experimentally detected. These findings provide a logical explanation to why water often enhances organocatalysis when used as an additive but hampers the reaction progress when employed as a solvent. ■ INTRODUCTION elucidate the effectofsolventsonorganocatalysisby Secondary amine organocatalysts have been widely used in investigating the reaction mechanism. organic synthesis as they are known to be multifunctional and The tolerance of a secondary amine organocatalytic reaction − able to mediate a plethora of chemical transformations.1 3 toward the presence of water greatly varies. It has been reported that pure water or buffer can be used for certain Because they drive the progress of a reaction by inducing 11−14 covalent intermediate formation, performing acid/base reac- organocatalytic reactions, whereas for others a solvent mixture containing different ratios of miscible organic solvent tion, and controlling stereoselectivity via hydrogen bonding 3,15−17 ff and water can be tolerated. In fact, all chemical steps in a and steric e ects, secondary amine organocatalysts are often ff referred to as the minimalist versions of enzymes.3 However, secondary amine organocatalytic reaction cycle can be a ected unlike enzyme catalysis, many organocatalytic reactions cannot by the presence of water. When a carbonyl substrate reacts tolerate a reaction medium that contains a large degree of with a secondary amine organocatalyst, an initial reactive − aqueous solvent.1 3 This has consequently affected the iminium ion intermediate is formed. In the case where proline was used as the catalyst, the corresponding iminium development of many potential applications. Combining ff organocatalysts with enzymes in a one-pot multistep system, intermediate can lead to the formation of an o -target parasitic for example, has been considered as an efficient approach to produce chiral synthons with a minimal amount of solvent Received: November 30, 2017 waste, but finding a compatible solvent system can be an Revised: December 18, 2017 − extremely challenging task.3 10 To this end, it is essential to Published: December 19, 2017 © 2017 American Chemical Society 451 DOI: 10.1021/acs.jpca.7b11803 J. Phys. Chem. A 2018, 122, 451−459 The Journal of Physical Chemistry A Article species that can also be reversed by including water in the elucidate the molecular mechanism of this LUMO-lowering − reaction.18 20 On the other hand, water also disfavors the reaction and to analyze how a change of the reaction medium formation of the iminium intermediate, shifting the equilibrium affects the efficiency of organocatalysis. toward the free catalyst.3 It is also believed that the reaction cycle eventually leads to the formation of the second iminium ■ COMPUTATIONAL METHODS intermediate, which upon hydrolysis yields the product and 21,22 Pyrrolidine-derived organocatalysts often contain bulky or catalyst. To the best of our knowledge, no studies have hydrogen-bonding substituent groups at the carbons adjacent − been performed to investigate the mechanism of product to the reacting nitrogen.29 35 The physical properties of these release, though it appears that the step of hydrolysis is likely ff 21,22 substituents can a ect the step of product hydrolysis. In order favored by the presence of water. Indeed, this may explain to exclude these effects, we did not choose a popular system, − why previous kinetic investigations revealed that the step of i.e., Jørgensen−Hayashi or MacMillan catalysts,1 3 but a product release becomes rate-limiting when water is simple 3-aminoproline derivative coupled to biotin at the C- completely removed from the reaction. Moreover, water 3 position. This would allow better solubility in water in greatly increases the dielectric constant of the reaction comparative experimental studies. Hence, the present theoreti- medium, which is suggested to perturb the energies of 3 cal study has been performed with the molecular model of an transition states (TSs) and stereoselectivity of the reaction. organocatalytic LUMO-lowering reaction where a biotin Even though solvent screening is often done on a trail-and- moiety was added to the C-3 position of the pyrrolidine error basis when a new reaction is performed,3 a thorough ff catalyst via an amide linkage (Figure 1). The potential energy study that analyzes the e ect of water on organocatalysis has surfaces (PESs) for the Michael addition of nitromethane to not been achieved. cinnamaldehyde have been obtained at the DFT level with the Density functional theory (DFT) has been widely used in 36,37 22−25 M06-2X hybrid functional and the 6-31+G(d,p) basis set, the mechanistic investigations of organocatalysis. The following the suggestions of Truhlar and co-workers for studies substrate-derived iminium ion intermediate and the TSs of main-group thermochemistry and kinetics36 to get an localized in the gas phase have been analyzed to explain the appropriate accuracy in relative energies.38 Recent studies on stereoselectivity of chiral imidazolidinones and pyrroli- 22,23,26−28 ff reactivity carried out in our laboratories also support the dines. However, the solvent e ect on organocatalysis selection of this combination of functional and basis set for − has not been interrogated in this manner. Furthermore, to the reactions in enzymes39 42 and in solution.43 The effect of the best of our knowledge, the full reaction process including the solvent was introduced by means of a solute electron density mechanism of product release in any of the secondary amine model (SMD) developed by Truhlar and co-workers.44 Once organocatalyses has not been investigated. Here, the Michael fi α β the rst-order saddle points were located and characterized, addition of nitromethane to , -unsaturated aldehyde the intrinsic reaction coordinate (IRC) path was traced down catalyzed by a pyrrolidine-derived organocatalyst has been from the saddle points to the corresponding minima using the investigated at the DFT level with a polarizable continuum full gradient vector. The global rms residual gradient in the ff − − model to mimic the e ect of dichloromethane (DCM) and optimized structures was always less than 0.04 kcal mol 1 Å 1. aqueous solution (Scheme 1). The aim of this work is to It is important to note that no constraints were applied to any of the geometry optimizations. In order to avoid possible Scheme 1. Organocatalytic Michael Addition of artifacts, such as odd interaction complexes, defining a proper Nitromethane to Cinnamaldehyde orientation in the starting point structures is a crucial step. Also, keeping in mind that the reaction under study is a multistep process, the IRC calculations traced forward from a TS structure do not necessarily converge in the end of the backward path traced from the following IRC. Efforts have therefore been made to get a converged intermediate result from consecutive steps of the reaction path. Zero-point energies and thermal contributions to the enthalpy and to Figure 1. Schematic representation of the reactants complex (RC), products complex (PC), and intermediate states located along the catalyzed Michael addition of nitromethane to cinnamaldehyde in DCM. R = NH-biotin. The direct noncatalyzed reaction from RC to PC is indicated in the dashed rectangle. Labels of key atoms are shown in the RC panel. 452 DOI: 10.1021/acs.jpca.7b11803 J. Phys. Chem.