Regioselective Partial Hydrogenation and Deuteration of Tetracyclic (Hetero)aromatic Systems Using a Simple Heterogeneous Catalyst.

The introduction of added '3-dimensionality' through late-stage functionalisation of extended (hetero)aromatic systems is a powerful synthetic approach. The abundance of starting materials and cross-coupling methodologies to access the precursors allows for highly diverse products. Subsequent selective partial reduction can alter the core structure in a manner of interest to medicinal chemists. Herein, we describe the precise, partial reduction of multicyclic heteroaromatic systems using a simple heterogeneous catalyst. The approach can be extended to introduce deuterium (again at late-stage). Excellent yields can be obtained using simple reaction conditions.

Nucleophilicities and Nucleofugalities of Thio- and Selenoethers.

Rate constants for the reactions of dialkyl chalcogenides with laser flash photolytically generated benzhydrylium ions have been measured photometrically to integrate them into the comprehensive benzhydrylium-based nucleophilicity scale. Combining these rate constants with the previously reported equilibrium constants for the same reactions provided the corresponding Marcus intrinsic barriers and made it possible to quantify the leaving group abilities (nucleofugalities) of dialkyl sulfides and dimethyl selenide. Due to the low intrinsic barriers, dialkyl chalcogenides are fairly strong nucleophiles (comparable to pyridine and N-methylimidazole) as well as good nucleofuges; this makes them useful group-transfer reagents.

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.

Ambident Reactivity of Acetyl- and Formyl-Stabilized Phosphonium Ylides.

The kinetics and mechanism of the reactions of formyl-stabilized ylide Ph3P═CHCHO (1) and acetyl-stabilized ylide Ph3P═CHCOMe (2) with benzhydrylium ions (Ar2CH(+), 3) were investigated by UV-vis and NMR spectroscopy. As ambident nucleophiles, ylides 1 and 2 can react at oxygen as well as at the α-carbon. For some reactions, it was possible to determine the second-order rate constant for O-attack as well as for C-attack and to derive the nucleophile-specific parameters N and sN according to the correlation lg k (20 °C) = sN(E + N) for both nucleophilic sites. Generally, O-attack of benzhydrylium ions is faster than C-attack. However, the initially formed benzhydryloxyvinylphosphonium ions can only be observed by NMR spectroscopy when benzhydryl cations with high Lewis acidity are employed. In other cases, rearrangement to the thermodynamically more stable products arising from C-attack occurs. The results derived from our investigations are employed to rationalize the behavior of ambident nucleophiles 1 and 2 in reactions with carbon-centered electrophiles in general. It is shown that the principle of hard and soft acids and bases (HSAB) and the related Klopman-Salem concept of charge and orbital control lead to incorrect predictions of regioselectivity. We also show that the rate of the Wittig reaction of ylide 2 with aldehyde 14 is significantly faster than the rate of either C- or O-attack calculated using lg k (20 °C) = sN(E + N), thus indicating that the oxaphosphetane is formed by a concerted [2 + 2] cycloaddition.

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.

The modern interpretation of the Wittig reaction mechanism.

The mechanism of the Wittig reaction has long been a contentious issue in organic chemistry. Even now, more than 50 years after its announcement, its presentation in many modern undergraduate textbooks is either overly simplified or entirely inaccurate. In this review, we gather together the huge body of evidence that has been amassed to show that the Li salt-free Wittig reactions of non-stabilised, semi-stabilised and stabilised ylides all occur under kinetic control by a common mechanism in which oxaphosphetane (OPA) is the first-formed and only intermediate. The numerous recent significant additions to the subject - including computational studies and experimental material pertinent to both steps of the reaction (OPA formation and its decomposition) are discussed in detail, and the currently accepted explanations for the source of the stereoselectivity in Wittig reactions are given. We also present the other mechanistic proposals that have been made during the history of the Wittig reaction, and show how they are unable to account for all of the experimental evidence that is now available. Details of certain experimental facts to do with Wittig reactions in the presence of Li cation are also included, although the precise mechanistic details of such reactions are yet to be established conclusively. We make the case that a clear distinction should henceforth be made between the unknown "Li-present" and the now well-established "Li salt-free" Wittig mechanisms.

Unequivocal experimental evidence for a unified lithium salt-free Wittig reaction mechanism for all phosphonium Ylide types: reactions with ß-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-ß-hydroxyphosphonium salt) in reactions involving aldehydes bearing heteroatom substituents in the ß-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.

A convenient and mild chromatography-free method for the purification of the products of Wittig and Appel reactions.

A mild method for the facile removal of phosphine oxide from the crude products of Wittig and Appel reactions is described. Work-up with oxalyl chloride to generate insoluble chlorophosphonium salt (CPS) yields phosphorus-free products for a wide variety of these reactions. The CPS product can be further converted into phosphine.

Competition between N and O: use of diazine N-oxides as a test case for the Marcus theory rationale for ambident reactivity.

The preferred site of alkylation of diazine N-oxides by representative hard and soft alkylating agents was established conclusively using the 1H-15N HMBC NMR technique in combination with other NMR spectroscopic methods. Alkylation of pyrazine N-oxides (1 and 2) occurs preferentially on nitrogen regardless of the alkylating agent employed, while O-methylation of pyrimidine N-oxide (3) is favoured in its reaction with MeOTf. As these outcomes cannot be explained in the context of the hard/soft acid/base (HSAB) principle, we have instead turned to Marcus theory to rationalise these results. Marcus intrinsic barriers (ΔG ‡ 0) and Δr G° values were calculated at the DLPNO-CCSD(T)/def2-TZVPPD/SMD//M06-2X-D3/6-311+G(d,p)/SMD level of theory for methylation reactions of 1 and 3 by MeI and MeOTf, and used to derive Gibbs energies of activation (ΔG ‡) for the processes of N- and O-methylation, respectively. These values, as well as those derived directly from the DFT calculations, closely reproduce the observed experimental N- vs. O-alkylation selectivities for methylation reactions of 1 and 3, indicating that Marcus theory can be used in a semi-quantitative manner to understand how the activation barriers for these reactions are constructed. It was found that N-alkylation of 1 is favoured due to the dominant contribution of Δr G° to the activation barrier in this case, while O-alkylation of 3 is favoured due to the dominant contribution of the intrinsic barrier (ΔG ‡ 0) for this process. These results are of profound significance in understanding the outcomes of reactions of ambident reactants in general.

First ever observation of the intermediate of phosphonium salt and ylide hydrolysis: P-hydroxytetraorganophosphorane.

P-Hydroxytetraorganophosphorane, the long-postulated intermediate in phosphonium salt and ylide hydrolysis, has been observed and characterised by low temperature NMR, finally definitively establishing its involvement in these reactions. The results require modification of the previously accepted mechanism for ylide hydrolysis: P-hydroxytetraorganophosphorane is generated directly by 4-centre reaction of ylide with water.