GB2180234A - Producing arylnitrones in high yield - Google Patents

Abstract

Arylnitrones are prepared in high yield by reaction of an arylhydroxylamine and an arylaldehyde in the presence of an acid catalyst, an organic solvent for the reactants and an arylnitrone antisolvent.

Description

SPECIFICATION Method for producing arylnitrones in high yield This invention is related to the production of arylnitronesthrough the reaction of arylhydroxylamines and arylaldehydes. More particularly, it is directed to a method for producing arylnitrones in higheryields from the reactants described above.

Certain diarylnitrones have been found to be useful in contrast enhancement photolithography. A more particular description ofsuch diarylnitrones, methodsfortheir production andtheiruse is found in copending applications U.S. Serial Nos. 735,016, 675,915 and EP 851 15858.4.

Arylnitrones aretypically obtained by reaction of arylhydroxylamine with an aldehyde, preferably an arylaldehyde in accordance with the following equation.

wherein Ar and Ar' are aromatic moieties of from 6 to 30 carbon atoms. This condensation reaction istypically one of equilibrium. In many cases, such as when reacting phenylhydroxylamine,the equilibrium favors the nitrone. In such an instance, yields as high as 98% may be isolated by simply evaporating the solvent and recrystallizing the crude product. In other instances, such as where arylhydroxylamines with electron withdrawing substituents are utilized, the equilibrium lies furtherto the left.The solution to this problem has been to shiftthe equilibrium to the production of nitrone by the removal ofthewatercoproduct. This istypically accomplished by refluxing the solution of reactants through a watertrapto azeotropically removewateras it is formed. Shifting the equilibrium to nitrone in such a manner is undesirable in that side reactions involving the arylhydroxylamine can result, particularly when the starting materials are not absolutely pure.

Alternatively, it is possible to utilize drying agents such as molecular sieves to remove the water of condensation. It has been observed, however, that decomposition ofthe arylhydroxylamines can be accelerated by the drying agents (zeolites) used to trap water. Therefore, a reaction scheme which favors the production of arylnitrones withoutcausing a side reaction with aryhydroxylamine is desired.

Surprisingly, it has been found that the addition of large quantities of an antisolvent, such as water, to the reaction represented by equation I shifts the equilibrium toward the production of the arylnitrone, which is contrary to the methods described above. The antisolvent serves two precipitate the arylnitrone during the reaction. Although water has been utilized to precipitate nonpolararylnitronesfrom solution bySplitterand Calvin, J. Org. Chem. Vol.20(1955), pp. 1111-11 15, the reaction between the arylhydroxylamine and arylal- dehyde is 98% complete atthattime and the water serves only to isolate the nitrone which has alreadyformed.

This invention provides a method for producing arylnitrones which comprises (a) reacting arylhydroxylamine with arylaldehyde to produce arylnitrone in the presence of an acid catalyst, an antisolventforarylnitrone and an organic solvent forthe aryihydroxylamine and arylaldehyde,thequantity of organic solvent being sufficiently large to solubilize both thearylhydroxylamine and arylaldehyde and the quantity of antisolvent being sufficiently large to precipitate the arylnitrone formed.

The primary object of the present invention is to provide a method for producing high yields ofarylnitrone.

Another object of the present invention is to provide a method for producing high yields of arylnitronewith little or no side reaction ofthe arylhydroxylamine utilized.

Afurther object of the present invention is to enhance the rate of production of arylnitrones from reactions of arylhydroxylamine and arylaldehyde without significantly affecting the yield. Other objects will be obvious from the discussions herein.

The present invention is based on the discoveries that (1) the equilibrium for the reaction of equation I can be driven to the production of arylnitrone by the addition of an antisolvent, such as water, and (2) reactions involving arylhydroxylamines and arylaldehydes of low reactivity can be accelerated by introducing an acid catalyst to minimize the deleterious effects of large volumes of antisolvent.

The arylnitroneswhich can be produced by the process ofthis invention include those represented by formula I below

wherein Zis(R3)a-Q-R4- orR5-; Q is a monovalent, divalent ortrivalent substituent or linking group; each of R, R1, R2 and R3 is independently hydrogen, an alkyl orsubstituted alkyl radical containing 1 to8 carbon atoms oran aromatic radical containing 6to 13 carbon atoms; R4is an aromatic radical containing 6to 13 carbon atoms; R5is an aromatic heterocyclic radical containing 6 to 20 carbon atoms in which the hetero atoms are at least one of oxygen, nitrogen and sulfur;; R6 is an aromatic hydrocarbon radical containing 6 to 20 carbon atoms; Xis halogen, cyano groups, aliphatic acyl radicals offrom 1 to 8 carbon atoms, alkyl or substituted alkyl radicals of 1 to 8 carbon atoms, aryl or substituted aryl radicals of to 13 carbon atoms oralkoxy carbonyl radicals offrom 2 to 8 carbon atoms; aisfrom0to2,bisfrom0to3,and n isfrom 0to4.

As is apparent from formula I, the nitrones may either beoc-aryl-N-aryinitrones or conjugated analogs thereof in which the conjugation is between the aryl group and the carbon atom. The oi acryl group is frequently substituted, most often with a dialkylamino group in which the alkyl groups contain 1 to 4carbon atoms. The R2 radical is typically hydrogen and R6 is usually phenyl.

The identityofthe Qvalue is not critical and suitablevalueswill beapparentto those skilled in the art. Qwill be monovalent, divalent, ortrivalentasthe value of a is 0,1 or2. Examples of monovalentvaluesfor Qare fluorine, chlorine, bromine, iodine, alkyl radicals offrom 1 to 6 carbon atoms and aryl radicals offrom 6to 13 carbon atoms. Examples ofthe divalentvaluesfor Q are oxygen, sulfur, carbonyl, alkylene and arylene.An example of a trivalent value for 0 is nitrogen. Preferably, Q is fluorine, chlorine, bromine, iodine, oxygen, sulfur or nitrogen.

The following nitrones are illustrative of those which may be prepared by the process ofthisinvention- ol-(4-diethylaminophenyl)-N-phenylnitron ot-(4-diethylaminophenyl)-N-(4-chlorophenyl)-nitrone a-(4-diethylaminophenyl)-N-(3,4-dichlorophenyl)-nitrone o-(4,diethylaminophenyl)-N-(4-carbethoxyphenyl)-nitrone a-(4-diethylaminophenyl)-N-(4-acetylphenyl)-nitrone a-(4-dimethylaminophenyl)-N-(4-cyanophenyl)-nitrnne a-(4-methoxyphenyl)-N-(4-cyanophenyl)nitrone a-(9-julolidinyl)-N-phenylnitrone a-(9-julolidinyl)-N-(4-chlornphenyl)nitrnne a-[2-(1,1-diphenylethenyl)]-N-phenylnitrone a-[2-(1-phenylpropenyl)]-N-phenylnitrone An especially preferred arylnitrone is o'-(4-diethylaminophenyl)N-phenylnitrnne.

The arylhydroxylamines which are reacted in the process ofthis invention are oftheformula: HO-NH-R6Xb 11 wherein R6, X and bare as defined above. These arylhydroxylamines are typically obtained by the reduction of nitroaromatic compounds with zinc powder our by catalytic hydrogenation. The reduction reaction with hydrogen typicallytakes place in the presence of a noble metal hydrogenation catalyst, such as platinum, rhenium, rhodium, palladium and nickel. Moderated reduction reactions are disclosed by Rylander et al. in U.S. Patent 3,694,509 and in copending application Serial No. 762, 358, which are incorporated herein by reference. Copending application Serial No. 762,358 is assigned to the same assignee as the present invention.

This invention provides particular utility in producing arylnitrones from arylhydroxylamines with electron withdrawing groups. The electron withdrawing groups of these arylhydroxylamines are positioned on the aromatic nucleus, i.e. they are those arylhydroxylamines of formula It where b is not zero and Xis as previously defined. Reaction with polar arylhydroxylaminestypically provides less than a 90% yield of nitrone and often below a 75% yield when in equilibrium. It is most desirable to drive the equilibrium toward the production arylnitroneforsuch arylhydroxylamines.

The aldehydes utilized in the present invention are oftheformula

wherein Z, R, R1 and n are as defined above and R2 is hydrogen. These arylaldehydes may be produced by any ofthe methods well known to those skilled in the art. A common method for producing arylaldehydes is the addition offormaldehydeto an aromatic compound having olefinic radicals. Such an aromatic compound is typically reacted with carbon monoxide and hydrogen under heat and pressure in the presence of an appropriate catalyst. This procedure and others are described in greater detail in Encyclopedia of Chemical Technology, 3rd Ed., Vol. 1, 794-796(1978), which is incorporated by reference herein.

Other methods for producing arylaldehyde include the reaction of carbon monoxide with aromatic hydrocarbons or aryl halides and the reduction of aromatic carboxylic acids, described in Encyclopedia ofChemical Technology, 3rd Ed., Vol.4, p.781 and Vol. 11, p.238 (1978), and incorporated herein by reference. It should be obvious that other methods for producing the arylhydroxylamines and arylaldehydes utilized in this invention are suitable.

The arylhydroxylamine and arylaldehyde are reacted in the presence of an acid catalyst within a reaction medium of an arylnitrone antisolvent and an organic solvent. The arylnitrone antisolvent serves to precipitate the arylnitrone. Typical antisolvents include water, aliphatic hydrocarbons of from 3to 8 carbon atoms and aromatic and substituted aromatic hydrocarbons from 6 to 10 carbon atoms. Particular organic antisolvents include hexane, heptane, butane, propane, benzene, toluene, octane and xylene. The preferred antisolvent is water.

The organic solvent solubilizes a substantial portion ofthe arylhydroxylamine and the arylaldehyde.

Suitable solvents include loweraliphatic alcohols, ethers and ketones. Non-oxygenated, polarsolvents are also suitable. Suitable lower aliphatic alcohols include methanol, ethanol, isopropanol, propanol, n-butanol and t-butanol. Suitable non-oxygenated solvents include acetonitrile pyridine and the like. The preferred solvents are ethanol, methanol, diethylether, acetic acid, dimethoxyethane, dioxane, diglyme, acetone and acetonitrile, with alcohol solvents being most preferred. The organic solvent utilized to solubilize the arylhydroxylamine and arylaldehyde may also serve as the antisolventforthe arylnitrone. For example, ethers of 2to8 carbon atoms will solubilize the reactants in this process and precipitate the arylnitrone.

The quantity of organic solvent utilized must be sufficiently large to solubilize the arylhydroxylamine and the arylaldehyde. Typically 0.25 to 2.0 liters or organic solvent per mole of arylhydroxylamine and arylaldehyde are suitable, depending on their solubility within the organic solvent. The quantity of solvent utilized typically comprises about lOto 75% by weight ofthe reaction medium.

The quantity of antisolvent utilized should be sufficiently large to precipitate the arylnitrone formed within the reaction medium. This quantity will vary with the antisolvent utilized and the arylnitrone formed. Typically 0.25 to 2 liters per mole ofarylnitrone issuitableto cause precipitation ofthe arylnitrone. Valueswithinthe lower range are preferred where suitable. The volume ratio ofantisolventto organicsolventwithinthe reaction medium typically falls within the range offrom about 0.25to 2 when such quantities are used.

Essentially any protonic acid will provide catalysis forthe reaction of arylhydroxylamine and the arylaldehy- de. The term "crotonic acid" as used herein is intended to describe compounds which dissociate in water and provide afree proton to form H30+. These include both mineral acids and organic acids. It may be found that certain acids are undesirable in that they cause side reactions with the starting materials. Suitable acids arethe strong mineral acids, such as hydrogen halides and the oxo-acids ofsulfur, phosphorous and nitrogen.

Hydrogen halides such as hydrogen chloride, hydrogen bromide and hydrogen fluoride all will enhance the rate of reaction. Suitable phosphorous oxide acids include phosphorous acid, phosphoric acid and the like.

Suitablesulfuroxide acids include sulfurous (H2SO3), sulfuric (H2SO4), and the like. Other suitable mineral acids are nitric acid HNO3) and perchloric.

Also suitable are the strong carboxylic acids and sulfonic acids. The term "strong carboxylic acid", as used herein, is intended to include carboxylic acids having dissociation constant values which approach or exceed that of acetic acid. Particular examples of suitable carboxylic acids include, acetic acid, formic acid, propanoic acid, butanoic acid, 2-methylpropanoic acid, pentanoic acid, hexanoic acid, heptanoic acid, chioroacetic acid, trichloroacetic acid, trifluoroacetic acid, phenylacetic acid, 2-chlorobutanoic acid, 3-chlorobutanoic acid, dichloroacetic acid, 4-chlorobutanoic acid, 5-chlorobutanoic acid, and the like. The sulfonic acids are preferred and include methanesu Ifonic acid, ethylsulfonic acid, phenyl sulfonic acid, butylsulfonic acid and the like.

Also included within the suitable acids arethe acid functionalized polymer resins such asthatunderthe tradename Amberlyst XN-1 005 produced by Rohm and Haas Co. These acids are convenient in that they remain a solid and can be easily removed from a reaction mixture. These resins aretypicallyfunctionalized with carboxylic acid or sulfonic acid groups.

The quantity of acid utilized need only be sufficiently large to provide catalysis ofthe reaction of arylhydroxylamine and arylaldehyde. Quantities within the range of about 0.1 to 1 Oweight percent of the total reaction medium, including organic solvent and the nitrone antisolvent are suitable. Larger quantities are also suitable, particularly where an organic acid is used as the organic solvent. Such catalysis overcomes the deleterious effects caused by the presence of large volumes of arylnitrone antisolvent. The reaction can proceed at temperatures ranging from about 00C to about 1 500C and preferably from 15 to 300C.

In many cases, the reaction mixture is cooled upon the production of arylnitrone so as to cause precipitation of the arylnitrone. The reaction mixture may be cooled after equilibrium has been reached or as the reaction approaches equilibrium. Thetemperature atwhich the precipitation of arylnitrone occurs depends on the arylnitrone,the quantity of arylnitrone antisolvent in the reaction medium and the quantity of organic solvent present in said medium. Precipitation may occur priorto cooling of the reaction mixture in cases wherethe nitrone is sufficiently insoluble in the reaction mixture. To completely precipitate the arylnitrone within solution, cooling to temperatures within the range of about O"to 1 O"C is preferred.Highertemperatures may be preferred where the arylnitrone is precipitated continuously as it is formed.

In an embodiment of this invention, the reaction medium is cooled priorto reaction of arylhydroxylamine and arylaldehyde. This occurs where the reaction of arylhydroxylamine and arylaldehyde is permitted to proceed to equilibrium in the absence ofarylnitrone antisolvent. Arylnitrone antisolvent is added to the reaction medium so as to precipitate the arylnitrone previously formed. The arylhydroxylamine and arylaldehyde remaining within the equilibrated mixture is then reacted in the presence ofantisolvent and acid catalyst in accordance with the process of this invention to produce additional arylnitrone. This additional arylnitronetypically precipitates immediately upon formation.In such an embodiment, the initial reaction of arylhydroxylamine need not take place in the presence of an acid catalyst. The acid catalyst may be added to the reaction medium with the quantity of antisolvent.

In another embodiment of this invention, the aryhydroxylamine is produced in situ bythe reduction of a nitroaromaticcompound. This reduction can be performed with hydrogen in accordance with the procedures disclosed by Rylander et al. in U.S. Patent 3,694,509 and in copending application S.N. 762,358 filed August 5, 1985. The reduction reaction typically takes place in the presence of a noble metal catalyst, preferably platinum on carbon, at a temperature offrom 0 C to 1 OO"C.

A reaction moderator may also be used to prevent overreduction to arylamines. Reaction moderators are described more particularly by Rylander et al. and in copending application S.N. 762,358, referred to above.

Examples of suitable moderators include dimethylsulfide, triphenylphosphine, triethylphosphine and the like.

Typical nitroaromatic compounds include nitrobenzene, p-ethoxy nitrobenzene, p-nitroethylbenzoate, p-nitroacetophenone, etc.

The reaction with arylhydroxylamine and arylaldehyde can be accomplished in conventional equipment either batchwise or continuously. In a typical reaction scheme, the arylhydroxylamine and arylaldehyde are introduced to the reaction with the organic solvent. The acid catalyst is subsequently added with gradual addition ofthe desired quantity of antisolvent. Upon precipitation ofthe arylnitrone, it may be recovered by conventional techniques such as by centrifuge orfiltration.

The following examples are provided to illustrate the invention. It is not intended to limit the scope ofthis invention to the embodiments described therein.

Example I Into a 50 milliliter vessel were added 1.81 grams (10 millimoles) of p-(ethoxycarbonyl) phenylhydroxylamine and 1.77 grams (10 millimoles) of p-diethylaminobenzaldehyde and 20 milliliters of 50% aqueous ethanol.

Methanesulfonicacid (30 milligrams) was then added and the nitrone product began to appearimmediatelyas a precipitate. The reaction mixture was cooled to about 0 C and stirred for two hours to precipitate substantially all ofthe nitrone formed. The product was filtered and washed with 50% aqueous ethanol and dried at 55"C undervacuum over night. The arylnitrone produced, a-(4-diethylaminophenyl)-N-(4-carbethoxyphenyl)- nitrone (3.01 grams, 89% yield), was 98% pure.

Example11 Into an atmospheric hydrogenatorwere placed 1.23 grams (10 millimoles) of nitrobenzene, 1.77 grams (10 millimoles) of p-diethylaminobenzaldehyde, 20 milligrams oftriphenylphosphine, 60 microliters (1 millimole) of acetic acid, 10 milliliters of absolute ethanol and 50 milligrams of 5% platinum on carbon catalyst. The system was charged with hydrogen and stirred at room temperature until 20 millimoles of hydrogen had been reacted. The reaction mixture was filtered and the platinum on carbon catalyst was washed with 5 milliliters of ethanol. The motherliquorwas cooled to 0 C and then treated with 20 milliliters of water while stirring.The nitrone precipitated and was filtered.In total, three crops of crystals were obtained yielding 2.44 grams (91%) of 94% pure o-(4-diethylaminophenyl)-N-phenyl nitrone.

Example 111 Asolution of 500 grams (2.6 moles) of ethyl-p-nitrobenzoate in 1.5 liters of ethanol was hydrogenated to the hydroxylamine using 12 grams of 5% platinum on charcoal catalystand 106 milliliters ofdimethylsulfoxideas a moderator. Once the nitrocompound was completely consumed, the reaction was filtered and the filtrate combined with 386 grams (2.2 moles, 0.85 equivalents) of p-diethylaminobenzaldehyde and 69 milliliters of acetic acid. After three hours of stirring at room temperature, NMR analysis revealed the reaction had reached an equilibrium statewith 73% conversion of aldehydeto the a-(4-diethylaminophenyl)-N-phenyl nitrone.The solution was cooled to about 4"C and treated gradually with 1.25 liters ofwaterwhile stirring vigorously. The nitrone precipitated out as a yellow powder, which after one hourwas collected by filtration. The crude product was redissolved in 1.2 kilograms of methanol, cooled and precipitated with 550 milliliters of water. The precipitated nitrone was collected and dried in a vacuum oven at 55 C to give 613 grams (1.8 moles, 82% yield) ofthe a-(4-diethylaminophenyl)-N-(4-carbethyoxyphenyl)-nitrnne, which was determined to be 95% pure by high pressure liquid chromatography. This illustrates the improved yield obtained by the addition ofwater.

Example Into a 1 0cc single neck flask were added 0.88 grams (5 millimoles) of4-diethylaminobenzaldehyde, 0.90 grams (5 millimoles) of p-(ethoxycarbonyl)-phenylhydroxylamine, 2.0 grams of tetrahydrofuran and 10 microliters of methanesulfonic acid. After stirring for 1 hour, the equilibrium value of 45% nitronewas reached and 4.0 grams ofcyclohexane was then added. After stirring for 72 hours, the nitrone precipitate formed was filtered to give 0.76 grams of product. The reaction mixture was cooled to provide a second crop of crystals which weighed 0.20 grams. The product was washed with 50% aqueous ethanol and dried to provide a total yield of about 0.96 grams (57%) of 98% pure a-(4-diethylaminophenyl)-N-(4-carbethoxyphenyl)-nitrnne.

The examples above illustrate particular embodiments of this invention. Variations of these embodiments will be obvious to those skilled in the art and are considered within the scope of this invention.

Claims (24)

1. A method for producing arylnitrones which comprises reacting arylhydroxylamine with arylaldehydeto produce arylnitrone in the presence of an acid catalyst, an antisolventfor arylnitrone and an organic solventfor the arylhydroxylamine and arylaldehyde, the quantity of organic solvent being sufficiently large to solubilize both the arylhydroxylamine and arylaldehyde, the quantity of antisolvent being sufficiently large to precipitate a substantial portion ofthe arylnitroneformed.

2. A method as in claim 1 wherein the antisolventforarylnitrone iswater.

3. A method as in claim 1 wherein the antisolventforarylnitrone is selected from the group consisting of aliphatic hydrocarbons of from 3to 8 carbon atoms plus aromatic and alkylaromatic hydrocarbons offrom 6to 10 carbon atoms.

4. A method as in claim 3wherein the antisolvent is selected from the group consisting of benzene, toluene, heptane, cyclohexane, octane and xylene.

5. A method as in claim 1 comprising the additional step of cooling the reaction mixture to atemperature sufficiently low to precipitate additional arylnitrone.

6. A method as in claim 5wherein the reaction mixture is cooled to a temperature within the range offrom aboutO Cto 10 C.

7. A method as in claim 1 wherein the diarylnitrone produced isoftheformula

wherein Z is (R3)a - Q - R4- or R5-; Q is a monovalent, divalent ortrivalent substituent or linking group; each of R, R1, R2 and R3 is independently selected from the group consisting of hydrogen, both alkyl and substituted alkyl radicals of 1-8 carbon atoms and aromatic radicals containing 6-13 carbon atoms; R4 is an aromatic radical containing 6-13 carbon atoms; R5 is an aromatic heterocyclic radical containing 6-20 carbon atoms in which the hetero atoms are selected from the group consisting of oxygen, nitrogen and sulfur; R6is an aromatic hydrocarbon radical containing 6-20 carbon atoms;; Xis selected from the group consisting of halogen, cyano groups, aliphatic acyl radicals offrom 1 to 8carbon atoms, alkyl and substituted alkyl radicals of 1-8 carbon atoms, aryl and substituted aryl radicals 6-13carbon atoms, and alkoxycarbonyl radicals offrom 2to 8 carbon atoms, a is from 0 to 2; b is from O to 3; and n is from 0 to 4.

8. A method as in claim 7 wherein the arylhydroxylamine is oftheformula

wherein R5 is phenyl, Xis as defined in claim 2 and b is from 1 to 2.

9. A method as in claim 7wherein the arylaldehyde is of the formula

wherein R2 is hydrogen, n isO and Z is as defined in claim 7.

10. A method as in claim 1 wherein the arylaldehyde is selected from the group consisting of 4-diethylaminobenzaldehyde, 4-dimethylaminobenzaldehyde, 4-methoxy-benzaldehyde, 9-julolidinyl-aldehyde, 2-aldehyde(1 ,1 -diphenyl)ethylene and 2-aldehyde(1-phenyl)propylene andthearylhydroxylamine is selected from the group consisting of phenylhydroxylamine, 4-chlorophenylhydroxylamine, 3,4-dichlorophenylhydroxylamine, 4-ethoxycarbonylphenylhydroxylamine, 4-acetylphenylhydroxylamine and 4-cyanophenylhydroxylamine.

11. A method as in claim 1 wherein the acid catalyst is selected from the class consisting of strong carboxylic acids, sulfonic acids, hydrogen halides and the oxoacids of phosphorus, nitrogen and sulphur.

12. A method as in claim 11 wherein the acid is selected from the group consisting of hydrogen chloride, hydrogen bromide, hydrogen fluoride, perchloric, acetic, formic, propanoic, butanoic, pentanoic, hexanoic, heptanoic, 2-methylpropanoic, chloroacetic, trichloroacetic, trifluoroacetic, phenylacetic, phosphoric, phosphorus, sulfurous, sulfuric and nitric acid.

13. A method as in claim 12 wherein the quantity of acid catalyst utilized falls within the range of about 0.1 to 10% by weight ofthe orga nic so lvent a nd water within the reaction mixture.

14. A method as in claim 1 wherein the arylnitrone produced is selected from the group consisting of a-(4-diethylaminophenyl)-N-phenylnitrnne a-(4-diethylaminophenyl)-N-(4-chlorophenyl)-nitrone a-(4-diethylaminophenyl)-N-(3,4-dichlorophenyl)-nitrone o-(4-diethylaminophenyl )-N-(4-carbethoxyphenyl )-nitrone a-(4-diethylaminophenyl)-N-(4-carbutoxyphenyl)-nitrone a-(4-diethylaminophenyl)-N-(4-acetylphenyl)-nitrone a-(4-diethylaminophenyl)-N-(4-cyanophenyl)-nitrone a-(4-methoxyphenyl)-N-(4-cyanophenyl)nitrone a-(9-julolidinyl)-N-phenylnitrone a-(9julolidinyl)-N-(4-chlorophenyl)nitrone o-[2-(1 1 -diphenylethenyl) ]-N-phenylnitrone a-[2-(1 -phenylpropenyl ) ]-N-phenylnitrone.

15. A method as in claim 1 wherein the organic solvent is selected from the class consisting of lower aliphatic alcohols offrom 1 to 6 carbon atoms, aliphatic nitriles of from 1 to 8 carbon atoms, lower alkyl esters offrom 1 to 6 carbon atoms and loweralkyl ketones offrom 1 to 6 carbon atoms which are liquid at an ambient temperature.

16. A method as in claim 15 wherein the solvent is selected from the group consisting of methanol, ethanol, isopropanol, propanol, n-butanol, t-butanol, xylene, diethylether, acetic acid, dimethoxyethane, dioxane, diglyme, acetone and acetonitrile.

17. A method as in claim 1 wherein the quantity of arylnitrone antisolvent utilized falls within the rangeof about 0.25 to 2 liters per mole of arylnitrone produced.

18. A method as in claim 1 wherein the volume ratio of arylnitrone antisolventto organic solventfalls within the range of 0.25 to 2.0.

19. A method as in claim 1 wherein the arylnitrone antisolvent and organic solvent are one and the same.

20. A method as in claim 19 wherein the organic solvent and arylnitrone antisolvent is an ether of from 2to 8 carbon atoms.

21. A method as in claim 1 2wherein the quantity of organic solvent utilized fallswithinthe rangeofabout 0.5to 2 liters per mole of arylhydroxylamine and arylaldehyde.

22. A method for making aryl nitrone which comprises: (a) reacting arylhydroxylamine and arylaldehyde in the presence of organic solvent and acid catalystto produce an equilibrated mixture ofarylnitrone, arylaldehyde and arylhydroxylamine, the quantity of acid being sufficientlylargeto catalyze the reaction; (b) adding with agitation, an arylnitrone antisolvent in a quantity sufficiently large to precipitate the arylnitrone and (c) reacting the arylhydroxylamine and arylaldehyde within said equilibrated mixture to produce arylnitrone.

23. A method as in claim 22 wherein the antisolvent is water.

24. An arylnitrone when produced by a method as claimed in any one ofthe preceding claims.

24. A method as in claim 22 wherein the equilibrated mixture is cooled to a temperature sufficiently lowto precipitate a substantial portion of arylnitrone in solution.

25. A method as in claim 22 wherein the acid catalyst is selected from the group consisting of acetic acid, methanesulfonic, formic acid, propanoic acid, butanoic acid, pentanoic acid, hexanoic acid, heptanoic acid, 2-methylpropanoic acid, chloroacetic acid, trichloroacetic acid, trifluoroacetic acid, phenylacetic acid, phosphoric acid, phosphorus acid, sulfurous acid, sulfuric acid, and nitric acid.

23. A method for producing arylnitrones as claimed in claim 1, substantially as hereinbefore described in any one ofthe examples.