[13498-14-1] · Cl4O3P2 · Pyrophosphoryl Chloride · (MW 251.74)
Alternate Names: diphosphoryl chloride; pyrophosphoryl tetrachloride.
Physical Data: bp 60-65 °C/0.1 mmHg, 90 °C/12 mmHg.
Solubility: sol most organic solvents but reacts with alcohols.
Form Supplied in: liquid; available commercially.
Purification: redistil under reduced pressure.
Preparative Methods: prepared in 30% yield by heating Phosphorus(V) Oxide and Phosphorus Oxychloride in a sealed tube and separating the resulting mixture by fractional distillation.1 Alternatively, can be prepared by reaction of phosphoryl chloride with a controlled amount of water.2 Until recently, the most convenient method involved the reaction of phosphoric anhydride with Phosphorus(III) Chloride and Chlorine.3 A recent procedure involves the reaction at reflux of phosphoryl chloride with 0.2 equiv of methanol for 21 days followed by removal of the excess phosphoryl chloride and distillation of the residue to give the reagent (1) in 49% yield (eq 1).4
Handling, Storage, and Precautions: corrosive; reacts violently with water; irritating to eyes, respiratory system, and skin. Use in a fume hood.
Pyrophosphoryl chloride (1) has been used in the phosphorylation of a variety of primary alcohols. It reacts with primary alcohols according to the scheme in eq 2. Thus reaction at low temperature between (1) and a primary alcohol in the absence of solvent gives a dichlorophosphoric acid derivative (2), which on treatment with water gives a monophosphate (3).
This is a particularly effective sequence for the synthesis of nucleoside monophosphates. For example, treatment of 2´,3´-isopropylideneadenosine (4) with (1) below rt followed by treatment with water and subsequent removal of the isopropylidene group gave adenosine 5´-phosphate in 65-85% yield (eq 3).5 2´,3´-Isopropylideneguanosine reacted similarly. This method avoids the need for base catalysis and removal of organic residues.
This has been applied to systems other than nucleotides. For example, a range of C-21-hydroxylated steroids have been phosphorylated in high yield by reaction with (1) at 0 °C followed by quenching in ice water.6 The reaction fails with cortisone and produces considerable quantities of dehydration product with C-11-hydroxy steroids. These authors also report that little or no phosphorylation was observed when (1) was used in organic solvents.
In addition to the synthesis of monophosphates, pyrophosphoryl chloride has also been used to prepare pyrophosphate esters. Reaction of (1) with 2´,3´-isopropylideneadenosine (4) in the presence of Triethylamine gave the pyrophosphate ester (5), which on hydrolysis with aqueous Formic Acid gave a 22% yield of adenosine diphosphate (ADP) (6) (eq 4).7
This approach to pyrophosphate esters has been extended to mixed esters such as coenzyme A, although the yield was very low (<1%).7
In the classical Vilsmeier reaction, N,N-Dimethylformamide and phosphoryl chloride are used and the reaction is usually assumed to involve the N,N-dimethylchloromethyleneiminium ion as the electrophile (see also Dimethylchloromethyleneammonium Chloride). Recently, pyrophosphoryl chloride (1) has been investigated as the activating agent.4 Reaction of (1) with an excess of DMF or N-methylformanilide at 0 °C in the presence of an electron-rich aromatic compound followed by heating (for unreactive aromatics) or simply standing (for reactive substrates) followed by treatment with Sodium Hydroxide gave aromatic aldehydes in good yields (eq 5). The reaction gave 4-methoxybenzaldehyde from the usually unreactive anisole in 72% yield.
This reaction has been extended to a greater range of heterocycles, including furan and thiophene derivatives, and it has been shown that the bulky nature of the electrophilic species biases the reaction to give attack at the least hindered position.8 In addition, glyoxylation of dioxygenated benzenes, N-alkylpyrroles, and N-alkylindoles has been achieved in good yield using (1) and methyl oxamates derived from methyl oxalyl chloride and either pyrrolidine or morpholine (eq 6).8
King's College London, UK