[21646-99-1] · C8H20O5P2 · Tetraethyl Pyrophosphate · (MW 258.22)
(peptide synthesis; phosphonylation of ketones, aldehydes, and perfluoroalkyl iodides)
Alternate Name: TEPP.
Physical Data: bp 79-81 °C/0.15 mmHg; d 1.057 g cm-3; nD 1.434.
Solubility: sol acetonitrile, 1,1,2-trichloro-1,2,2-trifluoroethane.
Form Supplied in: colorless liquid; commercially available.
Preparative Methods: the most convenient method involves the reaction of diethyl phosphite with diethyl phosphorochloridite. Diethyl phosphorochloridite (223 g) is added rapidly to a solution of diethyl phosphite (138 g) and triethylamine (101 g) in benzene (200 ml). The mixture is filtered and the benzene removed by distillation at reduced pressure. The product is isolated by further distillation at reduced pressure (79-81 °C/0.15 mmHg) in 41% yield.
Analysis of Reagent Purity: product purity is assessed by refractive index.
Handling, Storage, and Precautions: protect from moisture; irritant; handle in a fume hood.
Tetraethyl pyrophosphite will react with amino acids at either the free amine (eq 1) to give amidophosphites, or at the free carboxylic acid (eq 2) to give mixed anhydrides, and both are activated for peptide formation. Diethyl Phosphonite is a good solvent for amino acids and peptides and so the most convenient procedure for peptide formation involves heating an N-protected amino acid with an amino acid ester (eq 3) with an excess of TEPP in diethyl phosphite solution. If the amino acid ester is used as the HCl salt, addition of Triethylamine is advantageous. The product is precipitated by the addition of water or an organic solvent. No racemization has been observed in this procedure with dipeptide formation; however, variable amounts of racemization are observed in tripeptide formation where Cbz protecting groups are used. TEPP has been successfully used in the synthesis of important medium sized peptides, e.g. oxytocin.2
Tetraethyl pyrophosphite can function as both an electrophile and a nucleophile. The electrophilic behavior is exemplified by the formation of mixed anhydrides from carboxylic acids (eq 4).3 TEPP shows a nucleophilic character in reaction with carbonyl compounds. Addition of TEPP to aldehydes and ketones (eq 5)4-6 gives phosphonium alkoxide intermediates, which undergo an intramolecular transfer of phosphite yielding mixed phosphonate-phosphite adducts. A further equivalent of carbonyl reportedly results in further oxidation to phosphonate-phosphate adducts.
Reaction of perfluoroalkyl iodides with TEPP and 1,1-Di-t-butyl Peroxide in 1,1,2-trichloro-1,2,2-trifluoroethane gives diethyl phosphonites, which on oxidation with t-Butyl Hydroperoxide form diethyl perfluoroalkylphosphonates in good yield (eq 6).7,8 The standard Arbuzov reaction is not generally applicable to fluoroalkyl phosphonates.
Christopher D. Spilling
University of Missouri-St. Louis, MO, USA