N-Hydroxyphthalimide
   HOME

TheInfoList



OR:

''N''-Hydroxyphthalimide is the ''N''-hydroxy derivative of
phthalimide Phthalimide is the organic compound with the formula C6H4(CO)2NH. It is the imide derivative of phthalic anhydride. It is a sublimable white solid that is slightly soluble in water but more so upon addition of base. It is used as a precursor ...
. The compound can be utilized as a
catalyst Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
for
oxidation reaction Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
s, in particular for the selective oxidation (e. g.
alkane In organic chemistry Organic chemistry is a subdiscipline within chemistry involving the science, scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms tha ...
s to
alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...
s) with
molecular oxygen There are several known allotropy, allotropes of oxygen. The most familiar is oxygen, molecular oxygen (O2), present at significant levels in Atmosphere of Earth, Earth's atmosphere and also known as dioxygen or triplet oxygen. Another is the hig ...
under mild conditions.


Occurrence and production

The synthesis of ''N''-hydroxyphthalimide from phthaloyl chloride and
hydroxylamine hydrochloride Hydroxylammonium chloride is the hydrochloric acid salt of hydroxylamine. Hydroxylamine is a biological intermediate in nitrification (biological oxidation of ammonia with oxygen into nitrite) and in anammox (biological oxidation of nitrite and a ...
in the presence of sodium carbonate in aqueous solution was first reported by Lassar Cohn in 1880 (referred to as "Phthalylhydroxylamin"). The product forms as a red sodium salt under basic conditions, while white ''N''-hydroxyphthalimide precipitates in 55% yield as the solution is
acidified In computer science, ACID ( atomicity, consistency, isolation, durability) is a set of properties of database transactions intended to guarantee data validity despite errors, power failures, and other mishaps. In the context of databases, a ...
. ''N''-hydroxyphthalimide is also produced by reacting hydroxylamine hydrochloride with
diethyl phthalate Diethyl phthalate (DEP) is a phthalate ester. It occurs as a colourless liquid without significant odour but has a bitter, disagreeable taste. It is more dense than water and insoluble in water; hence, it sinks in water. Synthesis and application ...
in the presence of
sodium acetate Sodium acetate, CH3COONa, also abbreviated Na O Ac, is the sodium salt of acetic acid. This colorless deliquescent salt has a wide range of uses. Applications Biotechnological Sodium acetate is used as the carbon source for culturing bacteria ...
, or with
phthalic anhydride Phthalic anhydride is the organic compound with the formula C6H4(CO)2O. It is the anhydride of phthalic acid. Phthalic anhydride is a principal commercial form of phthalic acid. It was the first anhydride of a dicarboxylic acid to be used comm ...
in the presence of sodium carbonate with heating. In the last case, an overall yield of 76% is produced following purification by recrystallization. Microwave irradiation of phthalic anhydride and hydroxylamine hydrochloride in
pyridine Pyridine is a basic (chemistry), basic heterocyclic compound, heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakl ...
produces ''N''-hydroxyphthalimide in 81% yield. Even in the absenceof a base, phthalic anhydride and hydroxylamine phosphate react to produce ''N''-hydroxyphthalimide in 86% yield when heated to 130 °C.


Properties

''N''-Hydroxyphthalimide is a colorless to yellow, odorless crystalline powder which is soluble in water and organic solvents such as
acetic acid Acetic acid , systematically named ethanoic acid , is an acidic, colourless liquid and organic compound with the chemical formula (also written as , , or ). Vinegar is at least 4% acetic acid by volume, making acetic acid the main componen ...
,
ethyl acetate Ethyl acetate ( systematically ethyl ethanoate, commonly abbreviated EtOAc, ETAC or EA) is the organic compound with the formula , simplified to . This colorless liquid has a characteristic sweet smell (similar to pear drops) and is used in glues ...
and acetonitrile. The compound exists in two different-colored monoclinic crystal forms. In case of 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). The color of the synthesized ''N''-hydroxyphthalimide depends on the type of solvent used; the color transition from white to yellow is irreversible. ''N''-Hydroxyphthalimide forms strongly colored, mostly yellow or red salts with
alkali In chemistry, an alkali (; from ar, القلوي, al-qaly, lit=ashes of the saltwort) is a basic, ionic salt of an alkali metal or an alkaline earth metal. An alkali can also be defined as a base that dissolves in water. A solution of ...
and
heavy metals upright=1.2, Crystals of lead.html" ;"title="osmium, a heavy metal nearly twice as dense as lead">osmium, a heavy metal nearly twice as dense as lead Heavy metals are generally defined as metals with relatively high density, densities, atomi ...
, ammonia and amines. Hydrolysis of ''N''-hydroxyphthalimide by the addition of strong bases produces phthalic acid mono
hydroxamic acid A hydroxamic acid is a class of organic compounds bearing the functional group RC(O)N(OH)R', with R and R' as organic residues and CO as a carbonyl group. They are amides (RC(O)NHR') wherein the NH center has an OH substitution. They are often us ...
by adding water across one of the carbon–nitrogen bonds. ''N''-Hydroxyphthalimide ethers, on the other hand, are colorless and provide ''O''-alkylhydroxylamines by alkaline hydrolysis or cleavage through
hydrazine hydrate Hydrazine is an inorganic compound with the chemical formula . It is a simple pnictogen hydride, and is a colourless flammable liquid with an ammonia-like odour. Hydrazine is highly toxic unless handled in solution as, for example, hydrazine ...
. The "phthalylhydroxylamine" reported by Cohn was known to have a
molecular formula In chemistry, a chemical formula is a way of presenting information about the chemical proportions of atoms that constitute a particular chemical compound or molecule, using chemical element symbols, numbers, and sometimes also other symbols, ...
of but the exact structure was not known. Three possibilities were discussed and are shown in the Figure below: a mono-
oxime In organic chemistry, an oxime is a organic compound belonging to the imines, with the general formula , where R is an organic side-chain and R’ may be hydrogen, forming an aldoxime, or another organic group, forming a ketoxime. O-substitu ...
of phthalic anhydride ("phthaloxime", I), an expanded ring with two heteroatoms, (2,3-benzoxazine-1,4-dione, II), and ''N''-hydroxyphthalimide (III). It was not until the 1950s that Cohn's product was definitely shown to be ''N''-hydroxyphthalimide (III).


Applications and reactions

Nefkens and Tesser developed a technique for generating
active ester In organic chemistry, an active ester is an ester functional group that is highly susceptible toward nucleophilic attack. Activation can be imparted by modifications of the acyl or the alkoxy components of a normal ester, say ethyl acetate. Typical ...
s from ''N''-hydroxyphthalimide for use in
peptide synthesis In organic chemistry, peptide synthesis is the production of peptides, compounds where multiple amino acids are linked via amide bonds, also known as peptide bonds. Peptides are chemically synthesized by the condensation reaction of the carboxy ...
, an approach later extended to using ''N''-hydroxysuccinimide. The ester linkage is formed between the ''N''-hydroxyphthalimide and a
carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxyl ...
by
elimination Elimination may refer to: Science and medicine * Elimination reaction, an organic reaction in which two functional groups split to form an organic product *Bodily waste elimination, discharging feces, urine, or foreign substances from the bo ...
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 In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ...
of the next
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
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. Esters of ''N''-hydroxyphthalimide and activated sulfonic acids such as
trifluoromethanesulfonic anhydride Trifluoromethanesulfonic anhydride, also known as triflic anhydride, is the chemical compound with the formula (CF3SO2)2O. It is the acid anhydride derived from triflic acid. This compound is a strong electrophile, useful for introducing the trif ...
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
photoresist A photoresist (also known simply as a resist) is a light-sensitive material used in several processes, such as photolithography and photoengraving, to form a patterned coating on a surface. This process is crucial in the electronic industry. ...
s. ''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 after purified by cleavage, yielding ''O''-ethylhydroxylamine. A variety of different functional groups can be oxidized with the
aminoxyl radical Aminoxyl denotes a radical functional group with general structure R2N–O•. It is commonly known as a nitroxyl radical or a nitroxide, however IUPAC discourages the use of these terms, as they erroneously suggest the presence of a nitro group. ...
(phthalimide-''N''-oxyl, PINO) formed by the abstraction of a hydrogen atom from ''N''-hydroxyphthalimide under gentle conditions (similar to
TEMPO In musical terminology, tempo ( Italian, 'time'; plural ''tempos'', or ''tempi'' from the Italian plural) is the speed or pace of a given piece. In classical music, tempo is typically indicated with an instruction at the start of a piece (ofte ...
): Using molecular oxygen alkanes can be oxidized to form alcohols, secondary alcohols to ketones, acetals to esters and alkenes to
epoxide In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale ...
s.
Amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...
s 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. 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 The Beckmann rearrangement, named after the German chemist Ernst Otto Beckmann (1853–1923), is a rearrangement of an oxime functional group to substituted amides. The rearrangement has also been successfully performed on haloimines and nitrones ...
of cyclohexanone oxime with sulfuric acid). Alkanes are converted into nitroalkanes in the presence of nitrogen dioxide.
Cyclohexane Cyclohexane is a cycloalkane with the molecular formula . Cyclohexane is non-polar. Cyclohexane is a colorless, flammable liquid with a distinctive detergent-like odor, reminiscent of cleaning products (in which it is sometimes used). Cyclohex ...
is converted at 70 °C with nitrogen dioxide/air into a mixture of nitrocyclohexane (70%), cyclohexyl nitrate (7%) and cyclohexanol (5%). Furthermore, applications of ''N''-hydroxyphthalimide as oxidizing agents in
photographic developer In the processing of photographic films, plates or papers, the photographic developer (or just developer) is one or more chemicals that convert the latent image to a visible image. Developing agents achieve this conversion by reducing the silve ...
s and as charge control agents in toners 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.


References

{{DEFAULTSORT:Hydroxyphthalimide, N- Phthalimides