Bis(p-nitrophenyl) Phenylphosphonate

[38873-91-5]  · C18H13N2O7P  · Bis(p-nitrophenyl) Phenylphosphonate  · (MW 400.28)

(efficient peptide coupling agent causing little racemization1,2)

Physical Data: mp 99-101 °C.3

Form Supplied in: off-white to tan granules.3

Preparative Method: heat phenylphosphonic dichloride (PhP(O)Cl2) with 2 equiv of 4-nitrophenol at 160 °C for 4 h.4

Purification: recrystallize from CCl4 (mp 94-96 °C).4

Handling, Storage, and Precautions: hygroscopic; store in a cool dry place. Incompatible with strong oxidizing agents, acids, and bases.3

Peptide Synthesis.

Bis(p-nitrophenyl) phenylphosphonate (see also Bis(o-nitrophenyl) Phenylphosphonate) has been used as a coupling reagent in the condensation of the tetrabutylammonium salt of N-benzoyl-L-leucine with glycine ethyl ester. These are the reactants used in the Young's test,5 which is known as the most severe racemization test. The most favorable solvent used in the coupling was DMF and the reaction proceeded to the corresponding dipeptide in 93% yield, at below 0 °C with little racemization (95-97% L-isomer) (eq 1).

The advantage of using the tetrabutylammonium salt in the coupling reaction was that it increased both solubility6 and nucleophilicity of the carboxylic component, enabling the reaction to take place without using tertiary amines, which play a major role in causing racemization. The quarternary ammonium salts were prepared by the reaction of alkaline n-Bn4N+HSO4- or Bu4N+ OH- on the carboxylic acid.1

This method has also been efficiently applied to the synthesis of opioid agonist leucine-enkephalin2 (L-Tyr-Gly-Gly-L-Ppe-L-Leu) without protection of the phenolic hydroxy group in the tyrosine residue.2

1. Mukaiyama, T.; Morito, N.; Watanabe, Y. CL 1979, 11, 1305.
2. Watanabe, T.; Morito, N.; Kamekawa, K.; Mukaiyama, T. CL 1981, 1, 65.
3. The Sigma-Aldrich Library of Chemical Safety Data, 2nd ed.; Vol 1, p 443.
4. Loran, J. S.; Naylor, R. A.; Williams, A. JCS(P2) 1977, 418.
5. Williams, M. W.; Young, G. T. JCS 1963, 881.
6. Luisi, P. L.; Bonner, F. J.; Pellegrini, A.; Wiget, P.; Wolf, R. HCA 1979, 62, 740.

Harjinder S. Bansal

Zeneca Agrochemicals, Bracknell, UK

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