Ab initio static and metadynamics investigations of the Wittig reaction

Abstract

To date, the Wittig reaction remains the most commonly used method in organic chemistry. The synthesis approach yields to a possible functionalization of the olefin product through the transformation of the carbonyl function (ketones or aldehydes) with a phosphoniumylide. In the present work, the two approaches are used to describe the mechanism of the Wittig reaction. Static quantum calculations at the DFT level of theory with a B3LYP functional and 6-31 g(d, p) basis set are carried out and correlated to metadynamics calculations, exploring the free energy landscape of the reaction. The free energy barriers are calculated along the trajectory path, and the mechanism is discussed with the main features observed in the MTD calculations when compared to static quantum investigations. The latter do not allow for the identification of all points that may occur along the reaction path. Static quantum calculation converges to limited geometry states, while the metadynamics converges to several metastable and stable geometries and configurations. Moreover, the strong dependence of the reaction dynamics upon the functional and pseudopotential used highlights the importance of the dispersion forces along the reaction path. A complete description of the reaction mechanism from both the free energy standpoint and the structural configurations of the molecular species is discussed in detail. The differences in the free energy profile are discussed in terms of the limited account of the dispersion interactions within the DFT approach and the standard local XC functionals, confirming the strong non-covalent interactions and molecular rearrangement of charged species that take place all along the reaction path.

A Close Look to the Oxaphosphetane Formation along the Wittig Reaction: A [2+2] Cycloaddition?

“…After decades of controversial debate, − it has become clear that the current interpretation of the lithium salt-free Wittig reaction mechanism between an ylide ( 1 ) and an aldehyde ( 2 ) implies essentially two kinetic steps: (i) the formation an oxaphosphetane (OPA, 3 ) as the only intermediate via a [2+2] cycloaddition (22CA) reaction followed by pseudorotation to other OPA form, and (ii) the subsequent stereospecific intermediate decomposition via [2+2] cycloreversion processes to form phosphine oxide ( 4 ) and the alkene ( 5 ) . No zwitterionic betaine intermediates are implied in this broadly useful reaction for the synthesis of alkenes, although the controversy regarding the nature of a possible intermediate seems to be far from over. − It is important to emphasize that the first step in the Wittig reaction plays a key role determining ( Z )/( E )-alkenes through cis/trans-1,2-oxaphosphetanes as intermediates by equilibrium between nonstabilized phosphonium ylide-benzaldehyde and 1,2-oxaphosphetane, i.e., the process of a “stereochemical drift” in the Wittig reaction of nonstabilized phosphonium ylide with benzaldehyde under salt-free condition. On such a context, Maryanoff et al first reported the system of triphenylphosphonium ethylide with benzaldehyde, and the NMR monitoring experiment in the reaction of n -Bu3PCHPr with t -BuCHO .…”

Exploring Free Energy Profiles of Enantioselective Organocatalytic Aldol Reactions under Full Solvent Influence

“…Reactions already studied in literature include the Wittig reaction [ 35 ], organocatalytic addition to , -unsaturated ketones [ 36 ], chiral catalyzed ketimine-ene reactions [ 37 ], weak acid dissociation [ 38 ], organocatalytic S 2 reactions [ 39 , 40 ], the catalytic vinylogous Henry reaction [ 41 ], base-catalyzed Knoevenagel condensations [ 42 , 43 ], the Meyer–Schuster rearrangement [ 44 ], enantiomerization of axially chiral biphenyls [ 45 ], and also proline-catalyzed reactions [ 46 , 47 , 48 ]. While some of these studies obtained their results by using static quantum chemical calculations and frequently described solvent influence via continuum solvation models [ 37 , 39 , 40 , 42 , 43 , 44 , 49 , 50 , 51 ], others were based on molecular dynamics simulations and often used tools such as metadynamics [ 35 , 38 , 43 , 46 , 52 , 53 , 54 ] and umbrella sampling [ 45 ] to investigate the potential energy surfaces of the reactions. The metadynamics approach, originally proposed by Parrinello et al [ 55 ], reveals the free energy surface of one or more reaction coordinates by applying an adaptive bias potential.…”

Dissection of the Mechanism of the Wittig Reaction

“…Regarding the betaine intermediates, the authors wrote "The unstable character of the betaine makes the intermediate forms untraceable in the early stage of the Wittig reaction". Whatever the case may be, since the transition state for oxaphosphetane formation (or cycloreversion, depending on the level of the theory in the work by Adda 32 ) is still the rate-determining step, the general mechanism in Scheme 1, which is backed by strong experimental evidence, will provide all the information needed to understand the chemical transformation.…”

“…The mechanism of the salt-free Wittig reaction has been widely studied using both experimental − and theoretical − approaches and has been quite controversial. In early mechanistic interpretations of the Wittig reaction, a conflict involving the formation of betaine or oxaphosphetane intermediates during the first step was the subject of abundant literature.…”

“…The dispute seems to have been settled because (i) at low temperatures, using 31 P NMR spectroscopy, oxaphosphetanes have been experimentally detected for the reactions of two families of ylides and (ii) because of the lack of experimental evidence for the betaines as reaction intermediates. ,− The mechanism described in Scheme is not a closed matter, indeed, as new experimental and theoretical evidence emerges, either, some details are clarified or alternative paths may be suggested. For example, very recently, Adda and co-workers treated the Wittig reaction of a single nonstabilized ylide with benzaldehyde under ab initio molecular dynamics and found a couple of betaine intermediates separated by low energy barriers preceding the transition state for oxaphosphetane formation. Regarding the betaine intermediates, the authors wrote “The unstable character of the betaine makes the intermediate forms untraceable in the early stage of the Wittig reaction”.…”