156 CAIN AND SIMONSEN: NITRO-ACIDS DERIVED FROMXXI. -Nityo-acids Dertved from 2 3- Dimethoxy-benxoic Acid and 4-Methoxyphthulic Acid.By JOHN CANNELL CAIN and JOHN LIONEL SIMONSEN.DURING the course of an investigation of the products obtainedby the oxidation of nitrosantalin dimethyl ether with potassiumpermanganate (T., 1912, 101, 1073) we isolated certain acids whichappeared to us to be nitro-derivatives of 2 : 3-dimethoxybenzoicacid and 4-methoxyphthalic acid. Since our knowledge of theseisomeric acids is somewhat scanty, we were unable t o identify theacids isolated, and we have therefore attempted the synthesis ofthe three isomeric nitro-2 : 3-dimethoxybenzoic acids and also of themononitro-derivatives of 4-methoxyphthalic acid. Although wehave not succeedFd in preparing all six acids, we have devisedmethods for the preparation of four of them.Of the three isomeric nitro-2 : 3-dimethoxybenzoic acids, only6-nitro-2 : 3-dimethoxybenzoic acid (I) has so far been described,0 Me OMe OMe/'\Oh2e (\OM(? NO,/\OM~\)CO,H NO,,,!CO,H \>cc), H(111.)having been prepaxed by Wegscheider and Klemenc (Monatsh.,1910, 31, 709) by the nitration of hemipink acid, during whichprocess one of the carboxyl groups was eliminated.They alsoNO2(1.1 w.2 : 3-DIMETHOXYBENZOIC ACID, ETC. 157brought forward evidence which left no doubt as to the constitutionof the acid they obtained.When 2 : 3-dimethoxybenzoic acid is nitrated under the con-ditions described in the experimental part of this paper (p.159),the main product of the reaction is an acid which melts at174-175O. This acid must be 5-nitro-2 : S-dimethozyben.zol.‘c acid(11), since it yields 4-nitroveratrole when heated with aniline.We have carried out a large number of experiments with theview of devising a method for the synthesis of the remainingisomeride, namely, 4-nitro-2 : 3-diinethoxybenzoic acid (111), especi-ally owing to the fact that the acid isolated by us from theoxidation of nitrosantalin dimethyl ether is apparently this acid.Unfortunately our efforts have so far not met with success.When 3-hydroxy-o-tolyl methyl ether (IV) is nitrated (seep. 160), it yields a dinitro-derivative, which is probably best repre-sented by the formula (V). This compound, on methylation andOM^ NO2,’\o~~e-, KO~(\OM~ XO,/\OM~ 1 \/ \OH --+- K02(/OH NH,j/OMe--f \/ I IOR/IC-~Me T\l0 Me Me(VI.) (VII.)CO,,H Me(1.) (VIII.)reduction, yields 2-nitro-5 : 6-dimethoxy-m-toluidine (VI), which, onelimination of the amino-group, gives 6-nitro-2 : 3-di~methoxytoluene(VII).The constitution of this substance is definitely proved bythe fact that it gave on oxidation 6-nitro-2 : 3-dimethoxybenzoicacid (I), identical in all respects with the acid described byWegscheider and Klemenc (loc. cit.). From this it follows thatthe dinitro-derivative mentioned above must be represented byeither formula, V or V a . An attempt was made t o decide betweenthese two formuh by the preparation of the diamine, since thisshould, were it an ortho-diamine, yield a phenazine derivative.The results obtained in these experiments were, unfortunately,inconclusive. We are, however, of the opinion that this substanceis 5 : 6-dinitrq-3-hydroxy-o-tolyl methyl ether (V), since, onmethylation and reduction, it yields only one nitroamine, whereasif it were represented by formula V a , one would expect to obtaina mixture of the two isomeric nitroamines.It has been pointe158 CAIN AKD SIMONSEK NITRO-ACIDS DERIVED FROMout recently by Hewitt, Johnson, and Pope (T., 1913, 103, 1628)that phenols possessing a nitro-group in the ortho-position withrespect to the hydroxy-group are esterified only with great diffi-culty. Although the nitro-group in 5 : 6-dinitro-3-hydroxy-o-tolylmethyl ether is in the meta-position with respect t o the hydroxy-group, we have in this case, too, found great difficulty in obtainingthe methyl ether.It is possible that this may be due in part tothe sparing solubility of the potassium salt.We next investigated the nitration of 2 : 3-dimethoxytoEuene,and we have found that in this case a mononitro-derivative (VIII)is formed, the nitro-group entering position 5 in the nucleus, sinceon oxidation 5-nitro-2 : 3-dimethoxybenzoic acid, identical with theacid formed by the nitration of 2 : 3-dimethoxybenzoic acid, wasobtained.So far as we are aware, the three isomeric nitro-4-methoxy-phthalic acids have not so far been prepared. The preparation oftwo of these acids did not offer any great difficulty, and is readilyfollowed from the scheme given below :Me(/\/' + MeO/\CO,H R'IeO&!O,H + MeO/\Me BO,J [MeNO2 NO2\/ 'CO,H KO2] lCO,H\/I I\/\/(XI.) (XIII.)M eO/\Cc ),H(XII.)When 4-methoxyphthalic acid (XII) is nitrated, a mixture ofacids is obtained, which can be readily separated by means of thedifference in the ease with which they undergo esterification (seep.162). The acid, which was completely esterified under theconditions of the experiment, gave a methyl ester melting a t 115O,and was evidently 5-nitro-4-niethozyphtha~~c acid (X), the aciditself melting at 2 0 1 O . That this view is correct was confirmed bythe fact that when 5-nitro-4-7nethozy-o-xylene (XIII) was oxidised,\ i . O 2 l lit yielded the same acid.The other product of the nitration was an acid which melted a t215-217O. This acid must obviously be either 3-7aitro-4-methoxy-phthalic acid ( I X ) or the isomeric 6-nitro-acid.That it is theformer is proved by the fact that it was prepared by the oxidationof 1-nitro-2-naphthyl methyl ether (XI)2 : 3-DIMETHOXYBENZOIC ACID, ETC.EXPERIMENTAL.1595-Nitro-2 : 3-dimethoxybenzoic Acid (11).As has been mentioned in the introduction (pp. 157, 158), wehave devised two methods for the preparation of this acid.(1) Nitratiou of 2 : 3-Bimethoxybenaoic Acid.--2 : 3-Dimethoxy-benzoic acid (1 gram) was mixed with nitric acid (D 1-25; 20 c.c.),and allowed to remain 'in the cold for ten minutes with constantstirring. The solid gradually passes into solution, and in a shorttime the liquid becomes pasty owing t o the separation of the nitro-acid.This was collected and purified by crystallisation from hotwater. Yield, 0.65 gram:0.1084 gave 0.19 CO, and 0.043 H,O.C,HSO,N requires C=47*6; H=3.9 per cent.5-Nitro-2 : 3-dinzethozybei~zoic ucid separates from hot water, inwhich it is only sparingly soluble, in prismatic needles, melting a t(2) Nitration of 2 : 3-Dimethoxytolue1ze.*-2 : 3-Dimethoxytoluene(6 grams) was dissolved in acetic acid (6 grams), and after coolingin a freezing mixture was gradually treated with a mixture ofnitric acid (D 1.4; 9 grams) and acetic acid (9 grams). In ashort time, crystals of 5-nitro-2 : 3-dimethoxytoluene (VIII)separated. These were collected, well washed with water, anddrained on porous porcelain (yield, 3 grams).For analysis, thenitro-compound was recrystallised from dilute alcohol, from whichi t separated in fine, colourless needles, melting at 175-176O:C=54*5; H=5*4.C=47.8; H=4*4.174-1 75'.0,1168 gave 0.2333 CO, and 0.0565 H,O.The mother liquors from the nitration gave a further quantityof the same substance on dilution with water.Oxidation of 5-Nitro-2 : 3-dimethozytolue1~e. - 5-Nitro-2 : 3-di-methoxytoluene (3 grams) was suspended in dilute sodium carbonatesolution, and heated to boiling for several hours with a 5 per cent.solution of potassium permanganate (350 c.c.). A@er removingthe manganese dioxide, the solution was concentrated and acidified,when the nitro-acid separated as a flocculent precipitate.The acidwas collected, and, after crystallisation from hot water, it melted a t174-175O and, was identical in every way with the acid obtained* 2 : 3-Dirnet?ioxyto2uei~e, C,H,,O,, does not seem, so fa1 as we are aware, to havebeen lweviously prepared. It was readily obtained by methylating 3-hydroxy-o- tolylmethyl ether by means of methyl sulphtite and potassium hydroxide, when itSeparated as a pleasant smelling liquid boiling at about 202-203".C,H,,O,N requires C = 54.8 ; H = 5.6 per cent160 CBIN AND SIRIONYEN 1 NITBO-ACIDS DERIVED E'ROXby the nitration of 2 : 3-dimethoxybenzoic acid (Found, C = 47.8 ;H=4.1. C,H906N requires C=47.6, H =3*9 per cent.).Ethyl 5-nitro-2 : 3-dimethoxybenzoate, which was prepared fromthe silver salt by means of ethyl iodide in the usual manner,crystallises from alcohol in fine, felted needles, melting a t 79O:C=51*8; H=5*0.0.1222 gave 0.2323 CO, and 0.0540 H,Q.CllHI3O6N requires C = 51.8 ; 13. = 5.1 per cent.I n order t o prove the constitution of the acid prepared by themethods described above, it was converted into 4-nitroveratrole inthe following manner. The acid (2 grams) was mixed with aniline(5 c.c.) and heated on the sand-bath f o r one hour. The darkbrown product was cooled, poured into dilute sulphuric acid andextracted with ether, when, on evaporation of the solvent, a semi-solid mass was obtained. This was drained on porous porcelain,and the so,lid remaining was found to consist of a phenolic acid,and not further examined.The plate which contained the main product of the reaction wasextracted in the usual manner, and the oil thus isolated wasmethylated with methyl sulphate.I n bhis way a yellow solid wasobtained which crystanised from alcohol in needles, melting at95-96O. When mixed with 4-nitroveratrole obtained from anothersource the melting point was unaltered.Nitration of 3-Hydroxy-o-tolyl itlethyl Ether (IV).5 : 6-Dinitro-3-hydroxy-o-tolyl Meth$ Ether (V).-For the p r eparation of this substance the phenol (5 grams) was dissolved inacetic acid (5 grams), and after cooling in a freezing mixture asolution of nitric acid (D 1.4; 8 grams) in acetic acid (8 grams)was slowly added. The deep brown solution was allowed to remainfor fifteen minutes in the cold, and then poured on ice, when abrown oil separated.This was dissolved in ether, the etherevaporated, and the viscid oil thus isolated was mixed with excessof a concentrated solution of potassium hydroxide, when a sparinglysoluble potassium salt (2.5 grams) was deposited. This wascollected and decomposed with dilute hydrochloric acid, when thephenol was obtained as a pale yellow oil, which rapidly solidified.On crystallisation from dilute alcohol, 5 : 6-diiiitro-3-hydroxy-o-tolyl methyl ether separated in sulphur-yellow needles, meltinga t 6 1 O :0.1307 gave 0-2035 CO, and 0.0445 H,O.C8H,0,N2 requires C = 42.1 ; H = 3.5 per cent.The phenol gives no colour with ferric chloride, and the potassiumsalt crystallises from water, in which it is only sparingly soluble,C=42.5; H=3-82 : &DIMETHOXY*BENZOIC ACID, ETC 161in yellow needles, which, when heated, explode with considerableviolence.5 : 6-Dimityo-2 : 3-dimethoxytoZuene.-Great difficulty was expe-rienced in preparing this substance, but ultimately the followingmethod was found to give satisfactory results.The dry and finelypowdered potassium salt of the phenol (7 grams) was mixed withmethyl sulphate (5 grams) and heated in a sealed tube for threehours a t 140-150°. The product, which was slightly charred, wasextracted with ether, the solution washed with potassium hydroxidesolution to remove any unchanged phenol, and evaporated, when5 : 6-di&r0-2 : 3-dinzethoxytoEuelte was obtained. On crystallisationfrom alcohol, it separated in colourless plates, melting a t 76-77O:0.146 gave 0.2372 CO, and 0.0582 H,O.C,H,,O,N, requires C = 44.5 ; H = 4-1 per cent.WlieJi this dinitro-compound was reduced with tin aiid hydro-chloric acid in the usual manner, the diamine was isolated as acolourless solid, which darkened with extreme rapidity on exposuret o the air.Attempts to prepare a plienazine derivative by meansof phenantliraquinone were unsuccessful, but for the reasons statedin the introduction we are inclined to the view that the amino-groups occupy the 5 : 6-positions.2-Xi tro-5 : 6-dim e t hoxy-m-t oluidiit e (VI) .-This substance wasobtained in an excellent yield when 5 : 6-dinitro-2 : 3-dimethoxy-toluene was reduced by ammonium hydrogen sulphide. The amineseparates from alcohol in orange-coloured, prismatic needles, meltinga t 9 5 O :C = 4 4 .3 ; H = 4 * 4 .0.1328 gave 0.2463 CO, and 0.0703 H,O.CgH1204Nz requires C = 50.9 ; H = 5-7 per cent.6-Nitro-2 : 3-dimethoxytolue?te (VII). -The nitroamine justdescribed (0.7 gram) was dissolved in alcohol (10 c.c.), and, afterthe addition of sulphuric acid (0.7 gram), amyl nitrite (1 grani)was slowly added to the well-cooled mixture. After fifteen minutesthe solution was heated on the water-bath until the evolutionof nitrogen had ceased. On the addition of water an oil separatedand rapidly solidified. It was collected and purified by repeatedcrystallisation from dilute alcohol, when i t separated iu fine needles,melting a t 47-48O :C=50*4; H=5*9.0.1067 gave 0.2055 UO, aiid 0.051 H,O.CgHl,04N,~H,0 requires C = 52.4 ; H = 5.8 per cent,.0 LC idn t io IZ of 6-Yi TO-2 : 3-di m e t ho zy t oZu e ne .-The ni tro-con1 y ouiitl(1 gram) was suspended in dilute sodium carbonate solution aiidtreated with a 5 per cent.solution of potassium permanganate until* Aiialysis of a different specimen gave C = 52 '4, H = 5-2.C!-512.5; H-5*3.%*VOL. cv. 162 CAIN AND SIMONSEN : NITRO-ACIDS DERIVED FROMa permanent pink colour was obtained. After removing themanganese dioxide the solution was concentrated, and on acidifi-cation 6-nitro-2 : 3-dimethosybenzoic acid separated as a flocculent,white precipitate. This was collected and purified by crystallisationfrom hot water, when it was obtained in needles melting a t 185O.Wegscheider and Klemenc (Zoc.cit.) give 189-1 90° (Found,C = 47.3 ; H = 4.3. CgHgO,N requires C =47*6 ; H = 3.9 per cent.).The identity of this acid with that obtained by the above mentionedauthors was confirmed by the preparation of the methyl ester,which melted, as stated by them, a t 76-77O.3- ciibd 5-ATitro-4-methoxyph thalic A cids.4-Methoxyplithalic acid (4 grams) was mixed with nitric acid(D 1-4; 12 c.c.), and heated on the water-bath for fifteen minutes.The acid gradually dissolved, and, on cooling, a small amount ofsolid separated. In order to separate the mixture of acids, thesolution was diluted with water, extracted with ether, the etherealsolution dried and evaporated, when a somewhat viscid, crystallinemass was obtained (4.6 grams).This was mixed with methylalcohol (30 c.c.), the solution saturated with hydrogen chloridea t Oo, and allowed t o remain overnight in the cold. On pouringinto water, an oil separated which was dissolved in ether, theethereal solution washed with sodium carbonate solution (whichwas reserved for further examination, see below), dried andevaporated. The viscid oil thus obtained slowly solidified in fineneedles, which were drained on porous porcelain -x (yield, 0.27 gram),Methyl 5-,?Vitro-4-methoxyphthalate was crystallised from methylalcohol, from which it separates in fine, silky needles, melting a t115O :0.1036 gave 0.1866 CO, and 0.0405 H,O.C,,H,,07N requires C = 49.1 ; H = 4.1 per cent,5-Nitro-4-methoxyphthaZic acid (X), obtained by the hydrolysisof this ester, crystallises from water in prisms which melt anddecompose a t 201O:C =$gel; H =4*3.0.1175 gave 0.1938 CO, and 0.0364 H,O.C9H707N requires C = 44.8 ; H = 2.9 per cent.This acid was also syntliesised as follows.5-Nitro-o-4-xyIenol(Diepolder, Her., 1909, 42, 2916; Crossley, T., 1913, 101, 1299)* This plate was extracted with ethyl acetate, a i d the cil thus obtained wasdistilled under diniinished pressure, wlieii it was found to boil a t 18'i-188"/13 iim.,and was unchanged methyl 4-methoxyphthalate. A small residue reiiiainerl in thedistilling flask, which solidified on cooling and, after crystallisation from methylalcohol, melted a t 115", and consisted of the nitro-ester.C = 45.0; H = 3-42 : 3-DIMETHOXYBENZOIC ACID, ETC.163was methylated by means of methyl sulphate to 5-nitro-4-nzetkoxy-o-xyZeTLe (XIII), which separates from alcohol in very pale yellowcrystals, melting a t 79O:0'1685 gave 11.6 C.C. N, a t 20° and 763.8 mm.C,H,,O,N requires N=7*7 per cent.On oxidation with dilute nitric acid (see Crossley and Renouf,T., 1909, 95, 207), a small amount of a ~~itromet~~~oxy-o-toZ~u~c acid,C,H,O,N,(Me : C0,H : NO, : Me0 = 1 : 2 : 4 : 5 or 1 : 2 : 5 : 4 ) , crys-tallising from water in white needles, melting a t 2 3 5 O , was collected,and the filtrate, on evaporation, yielded 5-nitro-4-methoxyphthalicacid, melting a t 2 0 1 O . The methyl ester of this acid was provedto be identical with that described above.The sodium carbonate washings from the ester mentioned abovewere acidified, when a solid separated; this was dissolved in ether,the ether removed, and the resulting solid boiled with alcoholicpotassium hydroxide, when the potassium salt separated in fineneedles.These were collected and decomposed with hydrochloricacid, and the solution extracted with ethyl acetate. On removingthe solvent, the acid was obtained in slender needles, which, oncrystallisation from moist ether, melted and decomposed a t215-217O :N=8.0.0.1029 gave 0.1688 CO, and 0.032 H,O.C,H,O,N requires C = 44.8 ; H = 2.9 per cent.3-Nitro-4-methoxyphthalic acid (IX) is only very sparinglysoluble in berume, chloroform, or dry ether, more readily so inmoist ether. It is somewhat readily soluble in water, ethyl acetate,or alcohol.The barium salt separates from a neutral solution ofthe ammonium salt on treatment with barium chloride in longneedles radiating from a centre, and is only very sparingly solublein water.The silver salt, preqared in the usual manner, was obtained asa caseous, white precipitate:0.1797 gave 0.0855 Ag. Ag=47*6.C,H,O7NAg, requires Ag = 47.6 per cent.The anhydride, prepared in the usual manner by means of acetylchloride, crystallises from benzene in glistening, prismatic needles,melting a t 137-138O :C=44*7; H=3*4.Found, C = 48.6 ; H = 2.7.The ethyl ester, prepared from the silver salt, crystallises fro~n0.1187 gave 0.2293 CO, and 0-0513 H,O. C-552.2; H=4*8.C,H50,N requires C = 48.4 ; H = 2.2 per ceut.alcohol in hair-like needles, melting a t 93-940 :C18H1S07N requires C = 52.5 .; H = 5.0 per cent.M 164 CIAIN AND SIMONSEN : NITRO-ACIDS, ETC'.OxidataojL of l-iVZ'tr0-2-i~apltt h$ M e t kyl Ether (XI).1-Nitro-2-naphthyl methyl ether (1 2 grains) was suspended indilute sodium carbonate solution and heated on the water-bathwith excess of potassium permanganate solution until the oxidation,which proceeds only very slowly, was complete.After separatingthe inangane2e dioxide, the solution was concentrated, acidified,and extracted several times with ethyl acetate. On removing thesolvent, an oil (3 grams) was obtained, wliicli rapidly solidified.After draining on porous porcelain, it was crystallised from a smallamount of water, when a sparingly soluble acid separated in needles(-1 ).The filtrate was evaporated t o dryness, the residue (2.8 grams)dissolved i n iuetliyl alcohol, and tlie solution saturated wit11hydrogen chloride and allowed to remain overniglit. T t was thenpoured into water, extracted wit11 ether, the ethereal solutionwaslietl with sodium carbonate solution, dried and evaporated.Tlie ester obtaiiiecl in this way was reserved for later investigation(see B below).The sodium carbonate washings from the above-mentioned esterwere acidified, and the solid which separated was dissolved inether. Tlie crystalline acid thus obthined evidently contained tracesof an ester, and was therefox mixed with alcoholic potassiumhydroxide, when the potassium salt separated in fine needles. Thefree acid obtained from the potassium salt was crystallised frommoist ether, when it was found to melt and decompose a t 215--217O,and was identical with the acid obtained by the nitration of4-methoxyphthalic acid.The identity was confirmed by deter-mination of the mixed melting points of the anhydride and of theethyl ester. There is therefore no doubt that the acid obtainedby tlie nitration of 4-metlioxyphtl~alic acid is 3-iiitro-4-methoxy-plithalic acid.It was mentioned above that a sparingly soluble acid (a) wasisolated on crystallising the crude oxidation product from water.For the purpose of purification this acid was converted by meansof its silver salt into the ethyl ester, which separates from alcoholin small prisms, melting a t 113O :0.1135 gave 0.2218 CO, and 0.053 H,O.This is apparently ethyl 2-nitro-3-methoxybenaoate, which doesnot seem to have been previously prepared. With the object ofseeing if this were tlie case, the remainder of the ester was hydro-lysed, and the acid, after isolation in the usual inaniier, crystallisedfrom hot water, when it separated in needles.The determinationC=53-3; H=5-3.C,,H,,O,N requires C = 53.3 ; H = 4.9 per centof the melting point was found to give considerable difficulty, sinceit was not a t all definite, and depended on the rate of heating.If the bath is previously heated to 135*, and the capillary tubethen introduced, the acid becomes slightly yellow a t 145O, andmelts with very vigorous decomposition a t 205-207O.2-Nitro-3-methoxybenzoic acid has been previously prepared byRieche (Ber., 1889, 22, 2352), and is stated to decompose a t 2 5 1 O .It is possible that the difference observed is due to water ofcrystallisation, since our acid, after drying in a vacuum oversulphuric acid, evidently contained water of crystallisation :0.1112 gave 0.1734 CO, and 0.0352 H,O.C!,H,O5N,1 +H,O requires C = 42.9 ; H = 4.4 per cent.Uiifortunately we had not sufficient of this acid for furtherinvestigation, but there seems little doubt from the method of itspreparation that it has the constitution assigned to it.The methyl ester mentioned above (B) consisted of methylphthalate, since on hydrolysis it gave phtha1ic acid, which wasidentified by the usual tests.C =42*5 ; H = 3.6.In conclusion we desire to express our thanks to Dr. C. Weizmannfor kindly supplying us with the 4-methoxyphthalic acid used inthis work, and to the Research Fund Committee of the ChemicalSociety for a grant which partly defrayed the cost of the investi-gation.24, AYLESTONE AVENUE,BRDNDESBURY PARK, N.W