Phosphinooxazolines (often abbreviated PHOX) are a class of chiral ligands used in

asymmetric catalysis Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as "a chemical reaction (or reaction sequence) in which one or more new elements of chirality are formed in a substrate molecul ...

. Their complexes are particularly effective at generating single enatiomers in reactions involving highly symmetric

transition state In chemistry, the transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest potential energy along this reaction coordinate. It is often marked ...

s, such as allylic substitutions, which are typically difficult to perform stereoselectively. The ligands are bidentate and have been shown to be hemilabile with the softer P‑donor being more firmly bound than the harder N‑donor.

Synthesis

The synthesis of phosphinooxazolines is modular and it is not normally necessary to introduce the

phosphine Phosphine (IUPAC name: phosphane) is a colorless, flammable, highly toxic compound with the chemical formula , classed as a pnictogen hydride. Pure phosphine is odorless, but technical grade samples have a highly unpleasant odor like rotting ...

and

oxazoline Oxazoline is a five-membered heterocyclic organic compound with the formula . It is the parent of a family of compounds called oxazolines (emphasis on plural), which contain non-hydrogenic substituents on carbon and/or nitrogen. Oxazolines are the ...

moieties in any particular order. However while examples exist of the phosphine being introduced first, it is more common to see the synthesis of a phenyloxazoline which is subsequently combined with a source of diphenylphosphine. Methods for doing this depend on the nature of the substituent in the X position: PHOX ligand synthesis 2

* When X = fluorine coupling involves anionic displacement with a diphenylphosphine anion * When X = bromine this can be converted into a Grignard reagent and reacted with

chlorodiphenylphosphine Chlorodiphenylphosphine is an organophosphorus compound with the formula (C6H5)2PCl, abbreviated Ph2PCl. It is a colourless oily liquid with a pungent odor that is often described as being garlic-like and detectable even in the ppb range. It is u ...

, or coupled with

diphenylphosphine Diphenylphosphine, also known as diphenylphosphane, is an organophosphorus compound with the formula (C6H5)2PH. This foul-smelling, colorless liquid is easily oxidized in air. It is a precursor to organophosphorus ligands for use as catalysts. Syn ...

via a copper iodide catalysed reaction. * When X = hydrogen this undergoes directed ortho lithiation (facilitated by intramolecular coordination with the oxazoline) followed by reaction with

Of these methods the copper iodide catalysed reaction method is by far the simplest to carry out, as it does not require the synthesis of discrete anionic or organometallic species and is able to couple a wide range of materials in good to excellent yields.

In catalysis

Phosphinooxazolines are able to influence both the enantioselectivity and

regioselectivity In chemistry, regioselectivity is the preference of chemical bonding or breaking in one direction over all other possible directions. It can often apply to which of many possible positions a reagent will affect, such as which proton a strong base ...

of a range of metal catalysed reactions. In reactions involving symmetric transition states these properties work in concert to induce asymmetry and thus promote the formation of a single product. Enantioselectivity is controlled by the chirality of the ligand which is normally located on the oxazoline ring, however the P-centre may also be

stereogenic In stereochemistry, a stereocenter of a molecule is an atom (center), axis or plane that is the focus of stereoisomerism; that is, when having at least three different groups bound to the stereocenter, interchanging any two different groups cr ...

. Regioselectivity is controlled by variety of steric and electronic factors the most important of which being a form of

trans effect In inorganic chemistry, the trans effect is the increased lability of ligands that are trans to certain other ligands, which can thus be regarded as trans-directing ligands. It is attributed to electronic effects and it is most notable in square pla ...

, in which atoms complexed trans to the P‑atom become more electrophilic than ones located trans to the N‑atom. This is caused by the P‑atom engaging in

back bonding In chemistry, π backbonding, also called π backdonation, is when electrons move from an atomic orbital on one atom to an appropriate symmetry antibonding orbital on a ''π-acceptor ligand''. It is especially common in the organometallic chemi ...

, as it is a π‑electron acceptor.

Allylic substitutions

Phosphinooxazolines are used as ligands in allylic substitution reactions as both enantio- and regioselectivity is required to give an enantiomerically pure product due to the transition state being highly symmetric. In the example below all additions are enantioselective however the symmetric complex has no regiocontrol, resulting in a

racemic In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...

product. The asymmetric complex is both regioselective and enantioselective, resulting in a single enantiomer. Symmetric vs asymmetric

The primary application of PHOX ligands is in

palladium Palladium is a chemical element with the symbol Pd and atomic number 46. It is a rare and lustrous silvery-white metal discovered in 1803 by the English chemist William Hyde Wollaston. He named it after the asteroid Pallas, which was itself na ...

catalysts used for enantioselective allylic substitutions. They are able to effect a wide range of substitutions including allylic alkylations ( Tsuji-Trost reaction), aminations and sulfonylations.

Heck Reaction

Palladium complexes containing chiral phosphinooxazolines have been shown to be efficient catalysts for the

Heck reaction The Heck reaction (also called the Mizoroki–Heck reaction) is the chemical reaction of an unsaturated halide (or triflate) with an alkene in the presence of a base and a palladium catalyst (or palladium nanomaterial-based catalyst) to form a sub ...

. High yields and good to excellent enantioselectivities have been obtained, with the formation of by-products via C=C bond migration being greatly reduced. Pd-PHOX catalysts have also been used for intramolecular Heck reactions and examples exist where they have been shown to be superior to more common ligands such as

BINAP BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) is an organophosphorus compound. This chiral diphosphine ligand is widely used in asymmetric synthesis. It consists of a pair of 2-diphenylphosphinonaphthyl groups linked at the 1 and ...

Asymmetric Hydrogenation

The high enantio- and regiocontrol afforded by phosphinooxazoline ligands has fuelled research into their use for

asymmetric hydrogenation Asymmetric hydrogenation is a chemical reaction that adds two atoms of hydrogen to a target (substrate) molecule with three-dimensional spatial selectivity. Critically, this selectivity does not come from the target molecule itself, but from othe ...

Iridium Iridium is a chemical element with the symbol Ir and atomic number 77. A very hard, brittle, silvery-white transition metal of the platinum group, it is considered the second-densest naturally occurring metal (after osmium) with a density of ...

complexes incorporating phosphinooxazoline ligands have been shown to be effective for 'classic'

hydrogenation Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a catalyst such as nickel, palladium or platinum. The process is commonly employed to reduce or saturate organ ...

using H₂, with

ruthenium Ruthenium is a chemical element with the symbol Ru and atomic number 44. It is a rare transition metal belonging to the platinum group of the periodic table. Like the other metals of the platinum group, ruthenium is inert to most other chemical ...

and

catalysts having also been investigated for

transfer hydrogenation In chemistry, transfer hydrogenation is a chemical reaction involving the addition of hydrogen to a compound from a source other than molecular . It is applied in laboratory and industrial organic synthesis to saturate organic compounds and redu ...

. In addition to theoretical studies, the structural and kinetic properties of Ir-PHOX complexes have been investigated to better understand their behaviour as hydrogenation catalysts.

References