o-Nitrobenzyl Alcohol

[612-25-9]  · C7H7NO3  · o-Nitrobenzyl Alcohol  · (MW 153.15)

(photoremovable protective group for ketones and aldehydes,1 carboxylic acids,2 anhydrides,3 acid chlorides,4 and amines;5a reaction with isocyanates to generate protected amines;5b,c,d protection of amino acids;2b,6 protection of the hydroxyl groups of ribonucleotides,7a,b,c dinucleotides,7d and furanoses;7e synthesis of a novel catalyst in the polymerization of epoxides;8 formation of leaving groups of enhanced ability;9 reaction with formyl Meldrum's acid to afford the formylacetate;10 oxidation to the corresponding aldehyde11 or carboxylic acid12)

Alternate Name: o-NBA.

Physical Data: mp 70-72 °C; bp 270 °C. The thermal stability of nitrobenzyl alcohols has been examined.17 Its conformation in solution has been studied using 17O NMR18a and 13C NMR18b analysis.

Form Supplied in: light tan powder.

Handling, Storage, and Precautions: light-sensitive. Harmful if swallowed or inhaled.

Mechanism of Action.

Under photolysis,19 acidic,20 and electron bombardment21 conditions, the transformation of o-nitrobenzyl alcohol or its derivatives involves an internal redox reaction sequence followed by liberation of the deprotected alcohol or amine (eq 1). Analogously, the photorearrangement of esters of o-NBA, obtained through its reaction with acid chlorides2a,4 or anhydrides,3 also induces an internal redox reaction (eq 2).

Protection of Ketones and Aldehydes.

o-NBA serves as a photoremovable protective group for aldehydes and ketones. Bis-acetals are prepared in a high-yield exchange reaction, except with hindered ketones for which it is necessary to employ the diol o-O2NC6H4CH(OH)CH2OH. The acetals are removed in excellent yield by irradiation at 350 nm in benzene (eq 3).1

Generation of Carboxylic Acids.

Photolabile phosphatidylcholine (PLPC) has been synthesized by reaction of o-NBA with dodecanedioyl dichloride followed by 1,3-Dicyclohexylcarbodiimide coupling. Subsequent photolysis of the resulting 2-nitrobenzyl esters results in the instantaneous disintegration of the PLPC liposomes, thus opening up the possibility of their use as drug carriers in vivo.4 Irradiation of copolymers with o-nitrobenzyl ester side groups, synthesized from methacrylyl chloride, generates free carboxylic acids, as illustrated in eq 4.2a The positive photosensitive polyiimide biphenyl precursor pictured in eq 5 has been made by treatment of biphenyltetracarboxylic acid dianhydride (BPDA) with o-NBA.3

Protection of Amines.

Reaction of o-NBA with Phosgene yields the stable compound o-nitrobenzyloxycarbonyl chloride (eq 6).5a Subsequent reaction with 2-amino-2-deoxy-D-glucose cleanly affords the protected amine. The yields of the free amines obtained upon irradiation (eq 7) are lowered by side reactions with the o-nitrobenzaldehyde generated under the reaction conditions.2a,5a,b Yields are increased by the addition of polymeric aldehydes or sulfuric acid to the reaction mixture during irradiation,5a or by utilizing the related 2,6-dinitrobenzyl alcohol in the first step.5b Functional group tolerance for this entire reaction sequence is impressively high.

Reaction with isocyanates also provides a route to carbamates, which serve as masked amines5b,c (eq 8) or as diamines5d for epoxy resin curing. Carbamates of o-NBA possess moderate antitumor activity.22

Protection of Amino Acids.

Photolabile N-protected amino acids and peptides have also been synthesized via their chloroformates.2b,6 Quantitative deprotection proceeds without racemization23,24 when an excess of Sulfuric Acid or Semicarbazide hydrochloride is added to the reaction mixture (eq 9). Conversely, treatment of serine with o-NBA in the presence of catalytic p-Toluenesulfonic Acid provides the o-nitrobenzyl ester of serine (eq 10).2b

Protection of Hydroxyl Groups.

Photolabile 2-O-(o-nitrobenzyl) derivatives of various ribonucleotides7a-c as well as dinucleotides7d have been synthesized, and their subsequent photodeprotections, which yield the corresponding alcohols, examined (eq 11). Protection of the anomeric hydroxyl functionality of 2-deoxy-D-ribofuranose has been accomplished using o-NBA (eq 12).7e This protective group is quite stable to acidic conditions, and has proven invaluable in the synthesis of abasic oligonucleotides. Similar conditions are employed in the synthesis of bis(o-nitrobenzyl) ethers.25

Miscellaneous Reactions.

o-Nitrobenzyl triphenylsilyl ether, a latent photogenerated source of triphenylsilanol, has been synthesized from o-NBA (eq 13). This new catalyst, upon irradiation at 365 nm, serves as a coinitiator in the polymerization of epoxides.8

Greatly enhanced leaving group ability has been realized by use of o-NBA. Steroidal sulfonates synthesized from the sulfonylating agent formed in eq 14 undergo bimolecular azide displacements more efficiently than traditional sulfonates.9

o-Nitrobenzyl formylacetate has been made by the reaction of formyl Meldrum's acid with o-NBA in dry toluene (eq 15).10 a-Hydroxyimino phosphonates can serve as precursors to alkyl metaphosphates when photolabile ester groups are incorporated (eq 16).26

Oxidations and Reductions.

Oxidation of o-nitrobenzyl alcohol to its aldehyde has been accomplished using bis(dihydrogentellurato)MIII where M = CuIII and AgIII,11a chromium trioxide and alumina,11b biphasic nitric acid,11c bromamine-B,11d ethyl chlorocarbamate,11e potassium bromate in aqueous HCl,11f pyridinium fluorochromate,11g N-bromoacetamide,11h thallium(III),11i ammonium molybdate tetrahydrate in 6 M HCl,11j 1-chlorobenzotriazole,11k pyridine oxodiperoxychromium(VI),11l cobalt(III) hydroxide,11m cerium(IV) perchlorate,11n or silver(II) oxide in acidic media.11o Oxidation to o-nitrobenzoic acid is possible using methyltrioctylammonium tetrakis(oxodiperoxotungsto)phosphate,12a electrogenerated superoxide,12b (NH4)VO3 and dilute HClO4,12c or benzyltrimethylammonium tribromide.12d Biological oxidation of o-nitrotoluene to o-NBA by Pseudomonas sp. strain JS150 and Pseudomonas putida F1 has also been reported.13

Reduction of esters of o-nitrobenzyl alcohol to yield o-NBA can be accomplished using sodium borohydride in aqueous media.14 Reductions of o-nitrobenzaldehyde to o-NBA using sodium borohydride under phase transfer conditions,15a dimethoxyborane-CoCl2,15b and trimethoxysilane-lithium methoxide15c have been reported. Reduction of the nitro group of o-NBA to the amine using catalytic hydrogenation with Pd0 and polybenzimidazole resin in DMF is likewise known.16

Related Reagents.

o-Nitrobenzyl Bromide.

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D. Todd Whitaker

Detroit Country Day School, Beverly Hills, MI, USA

K. Sinclair Whitaker

Wayne State University, Detroit, MI, USA

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