o-Nitrobenzyl Bromide

(R = Br)

[3958-60-9]  · C7H6BrNO2  · o-Nitrobenzyl Bromide  · (MW 216.04) (R = Cl)

[612-23-7]  · C7H6ClNO2  · o-Nitrobenzyl Chloride  · (MW 171.58)

(introduction of the 2-nitrobenzyl protecting group which can be cleaved selectively by photolysis1-4)

Alternate Name: 2-nitrobenzyl bromide.

Physical Data: (X = Br) mp 45-48 °C. (X = Cl) mp 46-48 °C, bp 127-133 °C/10 mmHg.

Solubility: sol most solvents; alkylations are frequently carried out in polar solvents such as DMF.

Form Supplied in: commercially available from many sources.

Handling, Storage, and Precautions: 2-nitrobenzyl halides are lachrymators and should be used in a well-ventilated fume hood.

The 2-Nitrobenzyl Group as a Protecting Group.

The 2-nitrobenzyl group is one of an increasing number of functions that have been employed as photolabile protecting groups in organic synthesis,1-4 and photolytic cleavage usefully adds to the range of deprotecting strategies in the armory of the organic chemist. One of the first examples of such a protecting group was in the use of 2-nitrobenzyl esters as protected carboxylic acids.5 UV irradiation of the esters yields the free acid and initially 2-nitrosobenzaldehyde (the mechanism of the rearrangement has been studied extensively1-4). The benzaldehyde is further converted to azobenzene-2,2-dicarboxylic acid which then acts as an internal light filter and so severely hampers the reaction. Benzylic substituents remove this problem and derivatives such as the a-phenyl-2-nitrobenzyl esters give much better yields (eq 1). The 2-nitrobenzyl unit has also been incorporated into a wide variety of photolabile polymer supports for solid phase peptide synthesis.6 Polystyrene supported 2-nitrobenzyl bromide has been used as a resin for anchoring the C-terminus amino acid residue to the solid phase as its 2-nitrobenzyl ester.7 Phosphate esters incorporating the photolabile 2-nitrobenzyl group have also been synthesized.8

2-Nitrobenzyl halides have been used extensively in the field of oligonucleotide synthesis9-15 as a protecting group (eqs 2 and 3) for the 2-OH of uridine,9 adenosine,10 cytidine,10 and guanosine.11 Treatment of the nucleoside with a strong base such as Bis(tri-n-butyltin) Oxide9 or Sodium Hydride10,11 followed by 2-nitrobenzyl bromide gives the expected ethers, though in very poor yields (ca. 25-30%). The benzylic protons of nitrobenzyl halides are quite acidic and so decomposition of the halides is significant under the strongly basic conditions. To bypass this problem some workers have used 2-nitrophenyldiazomethane instead of the substituted benzyl halide,16 but the increased yields are accompanied by poorer selectivity for the 2-OH over the 3-OH and introduce the problem of product separation. Another method, which has been used for making 4-nitrobenzyl ethers of simple alcohols, is to use p-nitrobenzyl trifluoromethanesulfonate derived from the corresponding alcohol.17

In the etherification of an alcohol using 2-nitrobenzyl bromide, Ireland18 used BaO/Barium Hydroxide instead of the stronger bases mentioned above (eq 4). The reaction is still capricious, and investigation of silver-assisted alkylations resulted in failure. Deprotection near the end of the synthesis though is effected smoothly and cleanly with UV irradiation (eq 5). For the protection of phenolic hydroxyl groups both Silver(II) Oxide in benzene19 and a Potassium Carbonate/Cesium Carbonate mixture20 (eq 6) have been used successfully.

The photolabile 2-nitrobenzyl group has been employed in carbohydrate chemistry21 for the protection of anomeric hydroxyl groups, and has also been used for other acetals.22 These derivatives, synthesized from 2-nitrobenzyl alcohol, are particularly useful as they impart greater crystallinity to the compounds and aid in purification.

The 2-nitrobenzyl group has been used to protect heteroatoms other than oxygen. The sulfur atom in the phosphorothioate group of some nucleotides has been protected as the S-(2-nitrobenzyl)phosphorothioate (eq 7), and with this protection the nucleotides can be successfully coupled and deprotected to give di- and trinucleotides.23

The N-1 atom in pyrazolidin-3-ones has been protected using 2-nitrobenzyl bromide in DMF (eq 8),24 as has the Nim-3 atom in histidine (eqs 9 and 10).25

In Williams' synthesis of (±)-aplysiatoxin, he used a N-(2-nitrobenzyl) protected glycine unit.26 The 2-nitrobenzyl group has been used to N-protect other biologically important compounds such as 5-fluorouracil, 2-deoxy-5-fluorouridine (eq 11),27 and purine bases.28 Glycine, an important inhibitory neurotransmitter, has been N-derivatized with the 2-nitrobenzyl group so that the biologically active compound can be released with UV photolysis as desired.29 This use of photolabile protecting groups for biologically active molecules has been reviewed recently.30

The 2-nitrobenzyl substituent has also found a use in the protection of amino groups (eq 12) as urethanes using 2-nitrobenzyloxycarbonyl chloride, giving a photolabile equivalent to the benzyloxycarbonyl (Z) group.31

Related Reagents.

o-Nitrobenzoyl Chloride; o-Nitrobenzyl Alcohol.

1. Amit, B.; Zehavi, U.; Patchornik, A. Isr. J. Chem. 1974, 12, 103.
2. Pillai, V. N. R. S 1980, 1.
3. Pillai, V. N. R. In Organic Photochemistry; Padwa, A., Ed.; Dekker: New York, 1987; Vol. 9, p 225.
4. Zehavi, U. Adv. Carbohydr. Chem. Biochem. 1988, 46, 179.
5. (a) Barltrop, J. A.; Plant, J. A.; Schofield, P. CC 1966, 822. (b) Patchornik, A.; Amit, B.; Woodward, R. B. JACS 1970, 92, 6333.
6. Ajayaghosh, A.; Pillai, V. N. R. JOC 1990, 55, 2826 and refs therein.
7. Ajayaghosh, A.; Pillai, V. N. R. T 1988, 44, 6661.
8. (a) Rubinstein, M.; Patchornik, A. T 1975, 31, 2107. (b) Givens, R. S.; Keuper, L. W. CRV 1993, 93, 55.
9. Ohtsuka, E.; Tanaka, S.; Ikehara, M. Nucleic Acids Res. 1974, 1, 1351.
10. Ohtsuka, E.; Tanaka, S.; Ikehara, M. CPB 1977, 25, 949.
11. Ohtsuka, E.; Tanaka, S.; Ikehara, M. S 1977, 453.
12. Tanaka, T.; Orita, M.; Uesugi, S.; Ikehara, M. T 1988, 44, 4331 and refs therein.
13. Cullis, P. M. CC 1984, 1510.
14. Hayes, J. A.; Brunden, M. J.; Gilham, P. T.; Gough, G. R. TL 1985, 26, 2407.
15. Gough, G. R.; Brunden, M. J.; Gilham, P. T. TL 1981, 22, 4177.
16. Bartholomew, D. G.; Broom, A. D. CC 1975, 38.
17. Fukase, K.; Tanaka, H.; Torii, S.; Kusumoto, S. TL 1990, 31, 389.
18. Ireland, R. E.; Thaisrivongs, S.; Dussault, P. H. JACS 1988, 110, 5768.
19. Krafft, G. A.; Sutton, W. R.; Cummings, R. T. JACS 1988, 110, 301.
20. Kees, K. L.; Musser, J. H.; Chang, J.; Skowronek, M.; Lewis, A. J. JMC 1986, 29, 2329.
21. (a) Zehavi, U.; Amit, B.; Patchornik, A. JOC 1972, 37, 2281. (b) Zehavi, U.; Patchornik, A. JOC 1972, 37, 2285.
22. Winnik, F. M.; Carver, J. P.; Krepinsky, J. J. JOC 1982, 47, 2701.
23. Lesnikowski, Z. J.; Jaworska, M. M. TL 1989, 30, 3821.
24. Perri, S. T.; Slater, S. C.; Toske, S. G.; White, J. D. JOC 1990, 55, 6037.
25. Kalbag, S. M.; Roeske, R. W. JACS 1975, 97, 440.
26. Miknis, G. F.; Williams, R. M. JACS 1993, 115, 536.
27. Lin, T.-S.; Wang, L.; Antonini, I.; Cosby, L. A.; Shiba, D. A.; Kirkpatrick, D. L.; Sartorelli, A. C. JMC 1986, 29, 84.
28. Kelley, J. L.; Linn, J. A.; Selway, J. W. T. JMC 1989, 32, 1757.
29. Billington, A. P.; Walstrom, K. M.; Ramesh, D.; Guzikowski, A. P.; Carpenter, B. K.; Hess, G. P. B 1992, 31, 5500.
30. McCray, J. A.; Trentham, D. R. Annu. Rev. Biophys. Chem. 1989, 18, 239.
31. (a) Amit, B.; Zehavi, U.; Patchornik, A. JOC 1974, 39, 192. (b) Cameron, J. F.; Frechet, J. M. J. JACS 1991, 113, 4303. (c) Cummings, R. T.; Krafft, G. A. TL 1988, 29, 65.

Andrew N. Boa & Paul R. Jenkins

Leicester University, UK

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