N-Hydroxyphthalimide Explained

N-Hydroxyphthalimide is the organic compound with the formula . A white or yellow solid, it is a derivative of phthalimide. The compound is as a catalyst in the synthesis of other organic compounds.[1] [2] It is soluble in water and organic solvents such as acetic acid, ethyl acetate and acetonitrile.[3]

Occurrence and production

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]

Properties

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, but the exact structure was not known. 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]

Applications and reactions

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. The resulting ester needs to be hydrolysed before the cycle can be repeated.

The N-hydroxyphthalimide can be removed by shaking with sodium bicarbonate, but the N-hydroxysuccinimide approach shows greater reactivity and convenience, and is generally preferred.[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) 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.[20] Amides can be converted into carbonyl compounds with N-hydroxyphthalimide and cobalt(II)salts under mild conditions.

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.[20]

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.

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[21] and as charge control agents in toners[22] have been described in the patent literature.

Phthalimido-N-oxyl (PINO)

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. The bond dissociation energy of NHPI (i.e., PINO–H) is, depending on the solvent.[23]

Notes and References

  1. Francesco. Recupero. Carlo. Punta. Chem. Rev.. Free Radical Functionalization of Organic Compounds Catalyzed by N-Hydroxyphthalimide. 107. 9. 2007. 3800–3842. 10.1021/cr040170k. 17848093.
  2. Lucio. Melone. Carlo. Punta. Beilstein J. Org. Chem.. Metal-free aerobic oxidations mediated by N-hydroxyphthalimide. A concise review. 9. 2013. 1296–1310. 10.3762/bjoc.9.146 . 3701383. 23843925. free.
  3. Encyclopedia: Cristian. Gambarotti. Carlo. Punta. Francesco. Recupero. Maria. Zlotorzynska. Glenn. Sammis. Encyclopedia of Reagents for Organic Synthesis. N-Hydrophthalimide. N-Hydroxyphthalimide. 2013. 10.1002/047084289X.rn00598.pub2. 978-0471936237.
  4. Lassar. Cohn. Justus Liebigs Ann. Chem.. Phthalylhydroxylamin: Ueberführung der Phthalsäure in Salicylsäure. N-hydroxyphthalimide: Conversion of phthalic acid into salicylic acid. German. 205. 3. 1880. 295–314. 10.1002/jlac.18802050304.
  5. Ludwig. Bauer. Stanley V.. Miarka. J. Am. Chem. Soc.. The Chemistry of N-Hydroxyphthalimide. 79. 8. 1957. 1983–1985. 10.1021/ja01565a061.
  6. H.. Gross. I.. Keitel. J. Prakt. Chem.. Zur Darstellung von N-Hydroxyphthalimid und N-Hydroxysuccinimid. German. On the preparation of N-hydroxyphthalimide and N-hydroxysuccinimide. 311. 4. 1969. 692–693. 10.1002/prac.19693110424.
  7. Microwave‐assisted Synthesis of N‐Hydroxyphthalimide Derivatives. Kazuhiro. Sugamoto. Yoh‐ichi. Matsushita. Yu‐hei. Kameda. Masahiko. Suzuki. Takanao. Matsui. 67–70. 2005. 10.1081/SCC-200046498. Synth. Commun.. 35. 1. 96623891 .
  8. EP. 1085013. application. Verfahren zur Herstellung cyclischer N-Hydroxy-dicarboximide [Process for the preparation of cyclic ''N''-hydroxydicarboximides]. 2001-03-21. 2000-08-31. 1999-09-07. Elke Fritz-Langhals. Consortium für elektrochemische Industrie GmbH.
  9. Hendrik. Reichelt. Chester A.. Faunce. Henrich H.. Paradies. J. Phys. Chem. A. Elusive forms and structures of N-hydroxyphthalimide: The colorless and yellow crystal forms of N-hydroxyphthalimide. 111. 13. 2007. 2587–2601. 10.1021/jp068599y. 17388355. 2007JPCA..111.2587R .
  10. D. E.. Ames. T. F.. Grey. J. Chem. Soc.. N-Hydroxy-imides. Part II. Derivatives of homophthalic and phthalic acid. 1955. 3518–3521. 10.1039/JR9550003518.
  11. Book: Andrea. Porcheddu. Giampaolo. Giacomelli. Zvi. Rappaport. Joel F.. Lieberman. Synthesis of oximes and hydroxamic acids. The Chemistry of Hydroxylamines, Oximes, and Hydroxamic Acids, Part 1. Wiley. Chichester. 2009. 224–226. 978-0-470-51261-6.
  12. Oscar L.. Bradly. Leslie C.. Baker. Richard F.. Goldstein. Samuel. Harris. J. Chem. Soc.. LXVIII. - The isomerism of the oximes. Part XXXIII. The oximes of opianic acid and of phthalic anhydride. 1928. 529–539. 10.1039/JR9280000529.
  13. Charles D.. Hurd. Charles M.. Buess. Ludwig. Bauer. J. Org. Chem.. Succino- and phthalo-hydroxamic acids. 19. 7. 1954. 1140–1149. 10.1021/jo01372a021.
  14. Recl. Trav. Chim. Pays-Bas. 1962. 81. 8. 683–690. Synthesis and reactions of esters of N-hydroxyphthalimide and N-protected amino acids. G. H. L.. Nefkens. G. I.. Tesser. R. J. F.. Nivard. 10.1002/recl.19620810807.
  15. A Novel Activated Ester in Peptide Synthesis. G. H. L.. Nefkens. G. I.. Tesser. J. Am. Chem. Soc.. 1961. 83. 5. 1263. 10.1021/ja01466a068.
  16. The Use of Esters of N-Hydroxysuccinimide in Peptide Synthesis. George W.. Anderson. Joan E.. Zimmerman. Francis M.. Callahan. J. Am. Chem. Soc.. 1964. 86. 9. 1839–1842. 10.1021/ja01063a037.
  17. Book: Bodanszky, Miklos. Principles of Peptide Synthesis. 2nd. 9783642780561. https://books.google.com/books?id=nvHvCAAAQBAJ&pg=PA34. Activation and Coupling. 9–61. Springer-Verlag. 1993. 10.1007/978-3-642-78056-1_2.
  18. EP. 0919867 . Chemisch verstärkter Resist für die Elektronenstrahllithografie . 2003-05-21 . 1998-11-17 . K. Elian, E. Günther, R. Leuschner . Infineon Technologies AG.
  19. WO. 1995025090 . Cyclic N-alkenyloxyimides and a method for the preparation of cyclic N-alkenyloxyimides, the corresponding cyclic N-alkoxyimides and O-alkoxyamines . 1995-09-21 . 1995-03-14 . D.M.C. Callant, A.M.C.F. Castelijns, J.G. De Vries . DSM N.V..
  20. Web site: Discovery of a carbon radical producing catalyst and its application to organic synthesis. TCIMAIL, Number 116. Tokyo Chemical Industry Co. Ltd.. 2016-08-11. April 2003.
  21. ,Method of processing silver halide photographic lightsensitive material. EP. 0664479. application. 1994-07-26. 1994-12-06. 1993-12-06. W. Ishikawa. T. Sampei. Konica Corp..
  22. US. 5332637. Electrostatographic dry toner and developer compositions with hydroxyphthalimide. 1994-07-26. 1993-08-31. 1993-08-31. J.C. Wilson. S.M. Bonser. H.W. Osterhoudt. Eastman Kodak Co..
  23. 10.1080/01614940902743841. Phthalimide‐N‐oxyl (PINO) Radical, a Powerful Catalytic Agent: Its Generation and Versatility Towards Various Organic Substrates. 2009. Coseri. Sergiu. Catalysis Reviews. 51. 2. 218–292. 97018136 .