Bis(p-nitrophenyl) Sulfite

[35887-81-4]  · C12H8N2O7S  · Bis(p-nitrophenyl) Sulfite  · (MW 324.29)

(preparation of p-nitrophenyl esters for use in peptide synthesis)

Physical Data: mp 98-100 °C; bp 172-174 °C/11 mmHg.

Solubility: sol MeCN.

Preparative Method: by the reaction of p-Nitrophenol with Thionyl Chloride in the presence of Pyridine in benzene at 0 °C.7

Purification: recrystallization from chloroform/hexane. Several recrystallizations are required to obtain the reagent in a pure form.

Handling, Storage, and Precautions: may be stored as a solution in acetonitrile at -30 °C; under these conditions, decomposition occurs only slowly. Decomposition and reaction products are p-nitrophenol and sulfur dioxide. Handle with gloves and in a fume hood.

Bis(p-nitrophenyl) sulfite is used to prepare activated p-nitrophenol esters.1-5 These esters have found exclusive application as a method for carboxyl activation. The p-nitrophenol activated esters are stable and their major application is in the synthesis of peptide bonds. The activated ester is prepared by the reaction of a peptide or N-protected amino acid in pyridine with bis(p-nitrophenyl) sulfite (eq 1).

Some racemization has been observed where the amino acid is not a glycine or proline residue. An example of the use of this reagent is in the preparation of a cyclic peptide (eq 2).4

The p-nitrophenol esters are stable to acid (such as anhydrous TFA) but are moisture sensitive. Therefore, some hydrolysis of the ester occurs in the amine deprotection (eq 3). Following amine deprotection, further treatment with a base such as pyridine results in amide formation, to give the corresponding peptide (eq 4).

Carboxyl activation by other aryl esters based on halogen-substituted phenols has been investigated. Those derived from 2,4,5-trichlorophenol have found the widest application.6 Pentafluorophenyl esters have also been prepared and react preferentially in the presence of p-nitrophenol esters.8 Where the hydrogenolysis of benzyloxycarbonyl groups is required in the presence of acyl esters, the halogen-substituted acyl esters are preferred, as traces of unremoved p-nitrophenol can give rise to reactive p-aminophenol. It is also possible to prepare p-nitrophenol esters from p-nitrophenol and 1,3-Dicyclohexylcarbodiimide9 or tris-p-nitrophenyl phosphite.10

1. Iselin, B.; Rittel, W.; Sieber, P.; Schwyzer, R. HCA 1957, 40, 373.
2. Iselin, B.; Schwyzer, R. HCA 1960, 43, 1760.
3. Studer, R.; Lergier, W. HCA 1965, 48, 460.
4. Montonori, O.; Izumiya, N. BCJ 1965, 38, 1831.
5. Aoyagi, H.; Izumiya, N. BCJ 1966, 39, 1747.
6. Pless, J.; Boissonnas, R. HCA 1963, 46, 1609.
7. May, S.; Kaiser, E. JACS 1969, 91, 6491.
8. Kisfaludy, L.; Roberts, J.; Johnson, R.; Mayers, G.; Kovacs, J. JOC 1970, 35, 3563.
9. Rothe, M.; Kunitz, F. LA 1957, 609, 88.
10. Farrington, J.; Hextall, P.; Kenner, G.; Turner, J. JCS 1957, 1407.

Mark Prickett

University of Bristol, UK

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