N-Hydroxyphthalimide

As described by Lassar Cohn in 1880, N-hydroxyphthalimide was produced from phthaloyl chloride and hydroxylamine hydrochloride in the presence of sodium carbonate.^[4]

The product forms as a red sodium salt under basic conditions, while white N-hydroxyphthalimide precipitates in 55% yield as the solution is acidified. N-hydroxyphthalimide is also produced by reacting hydroxylamine hydrochloride with diethyl phthalate in the presence of sodium acetate,^[5] or with phthalic anhydride in the presence of sodium carbonate with heating. In the last case, an overall yield of 76% is produced following purification by recrystallization.^[6]

Microwave irradiation of phthalic anhydride and hydroxylamine hydrochloride in pyridine produces N-hydroxyphthalimide in 81% yield.^[7] Even in the absence of a base, phthalic anhydride and hydroxylamine phosphate react to produce N-hydroxyphthalimide in 86% yield when heated to 130 °C.^[8]

N-Hydroxyphthalimide exists in two polymorphs, colorless and yellow, In the colorless white form, the NOH group is rotated about 1.19° from the plane of the molecule, while in the yellow form it is much closer to planarity (0.06° rotation).^[9]

The color of the synthesized N-hydroxyphthalimide is determined by the solvent used; the color transition from white to yellow is irreversible.^[10] N-Hydroxyphthalimide forms strongly colored, mostly yellow or red salts with alkali and heavy metals, ammonia and amines.^[11] Hydrolysis of N-hydroxyphthalimide by the addition of strong bases produces phthalic acid monohydroxamic acid by adding water across one of the carbon–nitrogen bonds.^[5] N-Hydroxyphthalimide ethers, on the other hand, are colorless and provide O-alkylhydroxylamines by alkaline hydrolysis or cleavage through hydrazine hydrate.

The "phthalylhydroxylamine" reported by Cohn was known to have a molecular formula of C
₈H
₅NO
₃, but the exact structure was not known.^[4] Three possibilities were discussed and are shown in the Figure below: a mono-oxime of phthalic anhydride ("phthaloxime", I), an expanded ring with two heteroatoms, (2,3-benzoxazine-1,4-dione, II), and N-hydroxyphthalimide (III).^[10][12] It was not until the 1950s that Cohn's product was definitely shown to be N-hydroxyphthalimide (III).^[13]

Nefkens and Tesser developed a technique for generating active esters from N-hydroxyphthalimide^[14] for use in peptide synthesis,^[15] an approach later extended to using N-hydroxysuccinimide.^[16] The ester linkage is formed between the N-hydroxyphthalimide and a carboxylic acid by elimination of water, the coupling achieved with N,N′-dicyclohexylcarbodiimide (DCC). For peptide synthesis, the N-terminus of the growing peptide is protected with tert-butyloxycarbonyl while its C-terminus (Z–NH–CH(R)–COOH) is coupled to N-hydroxyphthalimide. An ester of the next amino acid in the desired peptide sequence is shaken with activated ester, adding to the chain and displacing the N-hydroxyphthalimide. This reaction is quantitative and nearly instantaneous at 0 °C.^[15][17] The resulting ester needs to be hydrolysed before the cycle can be repeated.

The N-hydroxyphthalimide can be removed by shaking with sodium bicarbonate,^[15] but the N-hydroxysuccinimide approach shows greater reactivity and convenience, and is generally preferred.^[16][17]

Esters of N-hydroxyphthalimide and activated sulfonic acids such as trifluoromethanesulfonic anhydride or p-toluenesulfonyl chloride are used as so-called photoacids, which split off protons during UV irradiation.

The protons generated serve for the targeted local degradation of acid-sensitive photoresists.^[18]

N-Hydroxyphthalimide can be converted with vinyl acetate in the presence of palladium(II)acetate to the N-vinyloxyphthalimide, which is quantitatively hydrogenated to N-ethoxyphthalimide and subsequently O-ethylhydroxylamine.^[19]

A variety of functional groups can be oxidized with the aminoxyl radical (phthalimide-N-oxyl, PINO)^[20] formed by the abstraction of a hydrogen atom from N-hydroxyphthalimide under gentle conditions (similar to TEMPO):^[1]

Using molecular oxygen alkanes can be oxidized to form alcohols, secondary alcohols to ketones, acetals to esters and alkenes to epoxides.^[21][22][23] Amides can be converted into carbonyl compounds with N-hydroxyphthalimide and cobalt(II)salts under mild conditions.^[24]

Efficient oxidation reactions of precursors of important basic chemicals are of particular technical interest. For example, ε-caprolactam can be prepared using NHPI from the so-called KA oil ("ketone-alcohol" oil, a mixture of cyclohexanol and cyclohexanone) which is obtained during the oxidation of cyclohexane. The reaction proceeds via cyclohexanol hydroperoxide, which reacts with ammonia to give peroxydicyclohexylamine followed by a rearrangement in the presence of catalytic amounts of lithium chloride.^[22][25]

The use of N-hydroxyphthalimide as a catalyst in the oxidation of KA oil avoids the formation of the undesirable by-product ammonium sulfate which is produced by the conventional ε-caprolactam synthesis (Beckmann rearrangement of cyclohexanone oxime with sulfuric acid).

Alkanes are converted into nitroalkanes in the presence of nitrogen dioxide.^[26]

Cyclohexane is converted at 70 °C with nitrogen dioxide/air into a mixture of nitrocyclohexane (70%), cyclohexyl nitrate (7%) and cyclohexanol (5%).

N-hydroxyphthalimide serves as an oxidizing agent in photographic developers^[27] and as charge control agents in toners^[28] have been described in the patent literature.

The radical derived by removal of a hydrogen atom from N-hydroxyphthalimide is called N-phthalimido-N-oxyl, acronym being PINO. It is a powerful H-atom abstracting agent.^[1] The bond dissociation energy of NHPI (i.e., PINO–H) is 88–90 kcal/mol (370–380 kJ/mol), depending on the solvent.^[29]