Peter A. Byrne

Unequivocal Experimental Evidence for a Unified Lithium Salt-Free Wittig Reaction Mechanism for All Phosphonium Ylide Types: Reactions with β-Heteroatom-Substituted Aldehydes Are Consistently Selective for cis-Oxaphosphetane-Derived Products

The true course of the lithium salt-free Wittig reaction has long been a contentious issue in organic chemistry. Herein we report an experimental effect that is common to the Wittig reactions of all of the three major phosphonium ylide classes (non-stabilized, semi-stabilized, and stabilized): there is consistently increased selectivity for cis-oxaphosphetane and its derived products (Z-alkene and erythro-β-hydroxyphosphonium salt) in reactions involving aldehydes bearing heteroatom substituents in the β-position. The effect operates with both benzaldehydes and aliphatic aldehydes and is shown not to operate in the absence of the heteroatom substituent on the aldehyde. The discovery of an effect that is common to reactions of all ylide types strongly argues for the operation of a common mechanism in all Li salt-free Wittig reactions. In addition, the results are shown to be most easily explained by the [2+2] cycloaddition mechanism proposed by Vedejs and co-workers as supplemented by Aggarwal, Harvey, and co-workers, thus providing strong confirmatory evidence in support of that mechanism. Notably, a cooperative effect of ortho-substituents in the case of semi-stabilized ylides is confirmed and is accommodated by the cycloaddition mechanism. The effect is also shown to operate in reactions of triphenylphosphine-derived ylides and has previously been observed for reactions under aqueous conditions, thus for the first time providing evidence that kinetic control is in operation in both of these cases.

Why Are Vinyl Cations Sluggish Electrophiles

The kinetics of the reactions of the vinyl cations 2 [Ph2C═C+-(4-MeO-C6H4)] and 3 [Me2C═C+-(4-MeO-C6H4)] (generated by laser flash photolysis) with diverse nucleophiles (e.g., pyrroles, halide ions, and solvents containing variable amounts of water or alcohol) have been determined photometrically. It was found that the reactivity order of the nucleophiles toward these vinyl cations is the same as that toward diarylcarbenium ions (benzhydrylium ions). However, the reaction rates of vinyl cations are affected only half as much by variation of the nucleophiles as those of the benzhydrylium ions. For that reason, the relative reactivities of vinyl cations and benzhydrylium ions depend strongly on the nature of the nucleophiles. It is shown that vinyl cations 2 and 3 react, respectively, 227 and 14 times more slowly with trifluoroethanol than the parent benzhydrylium ion (Ph)2CH+, even though in solvolysis reactions (80% aqueous ethanol at 25 °C) the vinyl bromides leading to 2 and 3 ionize much more slowly (half-lives 1.15 yrs and 33 days) than (Ph)2CH-Br (half-life 23 s). The origin of this counterintuitive phenomenon was investigated by high-level MO calculations. We report that vinyl cations are not exceptionally high energy intermediates, and that high intrinsic barriers for the sp2 ⇌ sp rehybridizations account for the general phenomenon that vinyl cations are formed slowly by solvolytic cleavage of vinyl derivatives, and are also consumed slowly by reactions with nucleophiles.

The Mechanism of Phosphonium Ylide Alcoholysis and Hydrolysis: Concerted Addition of the O−H Bond Across the P=C Bond

The previous work on the hydrolysis and alcoholysis reactions of phosphonium ylides is summarized and reviewed in the context of their currently accepted mechanisms. Several experimental facts relating to ylide hydrolysis and to salt and ylide alcoholysis are shown to conflict with those mechanisms. In particular, we demonstrate that the pKa values of water and alcohols are too high in organic media to bring about protonation of ylide. Therefore, we propose concerted addition of the water or alcohol O-H bond across the ylide P=C bond. In support of this, we provide NMR spectroscopic evidence for equilibrium between ylide and aclohol that does not require the involvement of phosphonium hydroxide. We report the first P-alkoxyphosphorane to be characterised by NMR spectroscopy that does not undergo exchange on an NMR timescale. Two-dimensional NMR spectroscopic techniques have been applied to the characterisation to P-alkoxyphosphoranes for the first time.

Introduction to the Wittig Reaction and Discussion of the Mechanism

The Wittig reaction [1] is perhaps the most commonly used method for the synthesis of alkenes. Several excellent reviews on the topic have previously been written [2–5]. The reaction (see Scheme 1.1) occurs between a carbonyl compound (aldehyde or ketone in general, 2) and a phosphonium ylide (1). The latter species is a carbanion stabilised by an adjacent phosphorus substituted with three carbons, giving alkene (3) and phosphine oxide (4) as the by-product. The ylide can be represented by resonance structures 1a (fully ionic ylide form) and 1b (ylene form), which show between them the ionic character of the P–C bond and the contribution to the stabilisation of the carbanion by phosphorus.

A Convenient Chromatography-Free Method for the Purification of Alkenes Produced in the Wittig Reaction

Phosphines and reagents derived from them are ubiquitous in organic chemistry. Commonly used applications range from the synthesis of alkenes by the Wittig reaction, the synthesis of alkyl halides from alcohols by Appel or Mitsunobu reactions, and the synthesis of amines by the Staudinger reaction. Phosphine ligands are also widely used as ligands in the metal complexes used to catalyse reactions such as the Heck, Suzuki, and Sonagashira reactions among others.

Wittig Reactions of Aldehydes Bearing a β-Heteroatom Substituent

In this work, the kinetic selectivity of the OPA forming step in Wittig reactions of semi-stabilised and stabilised ylides is inferred from the observed Z/E ratio of the alkene product. It is thus very important to be sure that the alkene Z/E ratio is truly reflective of the kinetic OPA cis/trans ratio, and to be aware of possible means by which there may arise a non-correspondence between the two ratios. Changes may occur to the Z/E ratio both during and after the Wittig reaction. The latter problem is prosaic but pernicious. It is not sufficiently recognised that Z-1,2-disubstituted alkenes are quite easily converted, under a variety of conditions, to a Z/E mixture and sometimes completely to the E-isomer.