2790 HARDING : SUBSTITUTION INpounds. PLwt 11. Acetyl-nit vo-sdstitut ion.By VICTOR JOHN HARDING.BY the term acetyl-nitro-substitution is meant the displacement ofan acetyl group by a nitro-group. This displacement can be effectedby the action of nitric acid on certain methoxyacetophenones, andi t is believed to be direct, without the formation of any inter-mediate hydrogen-substituted compound. So far as i t has beenstudied, it is dependent on the, presence of methoxy-groups in thebenzene nucldns and on the position of the acetyl group. It is notthought, however, that acetyl-nitro-substitution differs fundament-ally from the substituticn of a hydrogen atom by the nitro-group(hydrogen-nitro-substitution), methoxy-groups merely enabling thenucleus to be more readily nitrated and thus giving an opportunityfor the less mobile acetyl group to bo substituted more easily thanwould otherwise have been the case.The only instance in the literature of acetyl-nitro-substitution isthe observation of Harding and Weizmann (T., 1910, 97, 1131),who found that 4 : 5-dimethoxy-o-tolyl methyl ketone very readilygave 4-nitrohomocatechol dimethyl ether when treated with nitricacid :OM0 0 MeThe displacement of the aldehyde group by the nitro-group(formyl-nitro-substitution) in aromatic methoxy-aldehydes, however,had been studied by Sslway (!I!., 1909, 95, 1155), who drew theconclusion t'hat the displacement was direct.The analogous case oE the displacement of a carboxyl group by anitro-group (carboxyl-nitro-substitat-ion) was discussed in the first ofthis series of communications (T., 1911, 99, 1585).From a numberof examples and the author's own experimental work, it wasdeduced that:(a) The substitution was direct, without the intermediate forma-tion of the parent phenol ether.( b ) The substitution took place only when the carboxyl groupoccupied a position which in the parent phenol ether was activetowards nitric acid.The present communicatiori, which deals with acetyl-nitro-substiAROMATIC IIYDROXY-COMPOUNDS, PART 11. 2791tution, is a study of the action of nitric acid on a series of metlioxyacetophenones.(a) p-Me th oxyace tophenone, OMw C,H,*COMe.The action of nitric acid on this ketone was first studied byGatterinann, Ehrhardt, and Maisch (Ber., 1890, 23, 1202).Theuse of a mixture of concentrated sulphuric acid and nitric acidresulted in the formation of di-4-methoxybenzoylf uroxan (dianisoyl-glyoxime peroxide) :OMe*C6H4* GO* 7~~OMe*C,H,*CO'C 2'On the other hand, Pope (P., 1912, 28, 331) obtained the normalnitration product, 3-nitro4-methoxyacetophenone.The latter result the author has confirmed, but by using nitricacid alone has obtained on two occasions the furoxan and a t othertimes the nitro-ketone.Acetyl-nitro-substitution does not take place in pmethoxyaceto-phenone, and Salway (Zoc. cit.) failed to find any formyl-nitro-substitution during the nitration of anisaldehyde. The nitration ofanisic acid, however, by a mixture of warm concentrated sulphuricand nitric acids results in carboxyl-nitro-substitution, a mixture of2 : 6-dinitroanisic acid and 2 : 4-dinitroanisole being obtained :OMe Ohlo OMe(compare Cahours, A nizalen, 1849, 69, 236).(b) 3 : 4-Di?nethoxyacetophenone.The action of nitric acid 011 this ketone does not appear to havebeen studied previously. I n the cold o r in warm glacial acetic acidsolution, acetyl-nitro-substitution takes place very readily with theformation of 4 : 5-dinitroveratrole :OMe(c) 3 : 4 : 5-Tri?,i~tl~osyncetoI,heno?i~.This ketone has previously been prepared by Maubhrier ( J .p.Chem., 1910, [ii], 82, 275) by tvhe action of diazomethane on gall-aldehyde trirnetliyl ether, arid by the acid hydrolysis of ethy27 92 HABDIXG : SUBSTITUTION IN3 : 4 : 5-trimethoxybenzoylacetate. The melting point, as stated byMauthner, is 7 2 O .Bogert and Isham (J. Amer. Ghem. Soc., 1914,36, 514) repeated the preparation from ethyl 3 : 4 : 5-trimethoxy-bmzoylacetate, and gave t'he melting point as 78O. The author hasprepared this ketone, however, by the following series of reactions:OMe OMe 031e0Mf)OMe z' OMr()Ol\la\/'CO-NH,\/COCl\/CO,HOMe OMe-+ PClB OMe/)OMe\/CNhleMg1--3 OMe().OJleA C\/The preparation of gallamide trimethyl ether has been describedin a previous paper (Harding, T., 1911, 99, 1593), and its con-version into the nitrile is easily effected by the use of phosphoruspentachloride in hot benzene solution. Up t'o this point the yieldsare excellent, butj the conversion of gallonitrilel trimethyl ether into3 : 4 : 5-trimetEioxyacetophenoiie does not proceed as smoothly andin as good a yield as might be expected from analogous reactions.Large amounts of a nitrogenous substance are produced, whichpossesses the empirical constitution C,,H,,O,N,, is soluble in sodiumcarbonate solution, and gives rise t o an insoluble potassium saltwhen treated with 50 per cent.aqueous potassium hydroxide. Theketone is formed only in small amount&, and is separated from theunchanged nitrile by taking advantage of the insolubility of thelatter in cold dry ether. 3 : 4 : 5-Trimethoxyacetophenone crystal-lises from light petroleum in needle@, melting a t 77-79O, and givesa piperonylidene derivative melting at 130-131O.The action of nitric acid on this ketone was as expected fromits analogy t o gallic acid trimethyl ether and myristicinaldehyde.Acetyl-nitro-substitution takes place very readily, and 5-nitropyro-gallol trimethyl ether is produced.Moreover, the substitution is adirect, one, f o r had there been the1 formation of intermediateproducts in any recognisable amount, such as gallic acid trimethylether from the oxidation of the ketone or pyrogallol trimethylether from its hydrolysis, tho occurrence of these compounds wouldhave become evident by the finding in the nitration product ofnitrogallic acid trimethyl ether or 2 : 6-dimethoxybenzoquinone(Part I).Neither of these two compounds was found, although both areeasily identified, and thus it is believed that the acetyl-nitro-substi-tution is directAEOMATIC HYDROXY-COMPOUNDS.PART IT. 2793(d) 2 : 3 : 4-Ts.imethoxya.cetophetio~~e.This well-known ketone has always been prepared by tlie methyla-tion of 2-hydroxy-3 : 4-dimetl-toxyacetoplienone (Perkin and Wilson,T., 1903, 83, 129; David and Kostanecki, Ber., 1903, 36, 2191;Bulow and Schmid, Ber., 190G, 39, 214). Unsuccessful attemptswere made to prepare i t directly from the condensation of acetylchloride and pyrogallol trimethyl ether through the agency ofaluminium chloride. Even although the reaction was only allowedto proceed a couple of hours and the temperature kept a t Oo, theproduct of the reaction was always the hydroxy-ketone, the methylgroup in position 3 being hydrolysed.Using ferric chloride, how-ever, as a condensing agent, partial success was attained.2 : 3 : 4-Trimethoxyacetophenone was produced, although only insmall amount, and its identity established by means of itspiperonylidene derivative.The action of cold concentrated nitric acid on 2 : 3 : 4-trimethoxy-acetophenone gives rise to 6-nitro-2 : 3 : 4-trimethoxyacetophenone :0 5.38 OMeThe positJon 6, and not 5, is assigned t o the nitro-group from theanalogous reactions of nit'ric acid on pyrogallolcarboxylic acid tri-methyl ether (Harding, T., 1911, 99, 1585) and on its methyl ester(Pollak and Goldstein, Animlen, 1907, 351, 161).The nitro-ketone, however, was isolated only as its piperonylidenederivative, and even that proved extremely difficult, and it iseasily conceived that in the oily nitration mixture which wasobtained, 4-nitropyrogallol trimethyl ether might have existed andits presence remained undetected.I n this way evidence of acetyl-nitro-substitution might have been overlooked. I n order to throwfurther light on this point, 2 : 3 : 4-trimethoxyacetophenone wassubmitted to the vigorous action of warm nitric acid. I f any4-nitropyrogallol trimethyl ether had been produced in the lessvigorous nitration i t would certainly have shown itself in the moreextended action as 4 : 5-dinitropyrogallol trimethyl ether (compareThoms and Siebeling, Ber., 1911, 44, 2115). No 4 : 5-dinitropyro-gallol trimethyl ether was found, and the only product isolatedfrom the vigorous nitration of 2 : 3 : 4-trimethoxyacetophenme wasa compound which from its elementary analysis corresponded withdi-6-nitro-2 : 3 : 4-trimethoxybenzoylfuroxan 2794 HARDING : SUBSTITUTION INThus i t will bo seen that the evidence is quite against the occur-rence of 4-nitropyrogallol trimethyl ether iii the oily nitrationproduct of 2 : 3 : 4-trimethoxyacetophenone.Acetyl-nitro-substitn-tion does not take place when the acetyl group occupie8 position 4in pyrogallol trimethyl ether. I n this way acetyl-nitro-substitutionis quite analogous t o carboxyl-nitro-substitution. I n neither casedoes the substitution take place except when the acetyl or carboxylgroup occupies a position which is active towards nitric acid inthe parent phenol ether. The distribution of forces set up by themethoxy-groups determines the position entered by the nitro-groupwhether the group previously attacked be hydrogen, acetyl, orcarboxyI.The corresponding case for the aldehyde group has n o tyet been experimentally determined, although the author has nodoubt that it will be found t o follow the same rule.l n the next communication, which will follow shortly, an accountwill he given of a series of experiments on the' action of nitric acidon a number of polymethoxy-derivatives of benzene in the presenceof carbamide and of hydrogen peroxide.EXPERIMENTAL.Action of Nitric dcid 078 ~ - i ~ ~ e t l ~ o x ? / a c e t o p ~ e r z o ~ z e .Five grams of pinethoxyacetophenone were dissolved in 20 C.C.of concentrated nitric acid and allowed t o remain overnight.Onpouring into water an oily solid separated, which soon hardened,and on being submitted t o a process of fractional crystallisationfrom alcohol proved t o be entirely 3-nitro-4-methoxyacetophenone.No mono- or di-nitroanisole was found (Pope, P., 1912, 28, 331).In another experiment in which the time of reaction was onlyfifteen minutes much unchanged ketone was recovered, and a smallamount of di-pmethoxybenzoylf uroxaii was isolated. The lattercompound was identified by its melting point and analysis. Theformation of any nitro-ketone was not observed, although the wholeof the recovered p-methoxyac&ophenone was converted into itspiperonylideiie derivative and fractionally crystallised.3-Nitro-km ethoxyphenyl 3 : 4-Me thgle nedioxystyryl He tone,CH,<~>C,H,- CH : c H.co C,H,(NOJ OM^.This unsaturated ketone is readily obhined by condensing3-nitro-4-methoxyacetophenone snd piperonal in alcoholic solutionby a trace of potassium hydroxide. The ketone separates instantlyfrom the alcoholic solution, and is pnrified by crystallisation fromglacial acetic acid, from which it separates in needles melting a XROMATIC HTDROXT-CON POUNDS. PART 11. 2795194O. Its solution in concentrated sulphuric acid is reddish-purple :0.1301 gave 0.2979 CO, and 0.0501 H,O. C = 62.4; H =4*2.Ci7Hl,0,N requires C = 62.4 ; H = 4.0 per cent.d ctiolb of iVitric Acid o n 3 : 4-Dinzetl~oxyncetophenone. Formationof 4 : 5-Dinitroveratrole.One grain of 3 : 4-diniethoxyacetoplienone was dissolved in 10 C.C.of concentrated nitric acid, and the reaction kept under control by2 stream of running water.A t the end of ten minutes the productwas poured into water, 2nd the yellow solid which separated wascollected and purified by crystallisation from alcohol. It crystal-lised in bright yellow needles, melting a t 131--132O, and wasfound to be identical with 4 : 5-dinitroveratrole.One gram of 3 :4-dimetlioxyacetophenone was dissolved in 10 C.C.of glacial acetic acid, 2 C.C. of concentrated nitric acid were added,and the solution was warmed. A vigorous reaction occurred, andwhen this had subsided the product was cooled and poure'd intowater, when 4 : 5-dinitroveratrole separated and was easily identified.0MeThis nitrile has previously been described by Heffter and Capell-mann (Ber., 1905, 38, 3634), who obtained i t by heating togethera mixture of gallic acid trimethyl ether and lead thiocyanate.It has also been described by Semmler (Ber., 1908, 41, 1918),who prepared it by boiling oxiiiiinogallaldehyde trimethyl ether forhalf-an-hour with acetic anhydride.The melting point' is given as9 5 O by Heffter and Capellmann and 93O by Semmler. Gallonitriletrimethyl ether is very readily and conveniently prepared fromgallamide trimethyl ether (Harding, T., 1911, 99, 1593) by theaction of phosphorus pentachloride. The two substances weremixed in equimolecular amounts in the presence of a little benzene,and heated together for a couple of hours in boiling water.Thebenzene and phosphoryl chloride were then removed by distillationunder diminished pressure. Any attempt, however, t o distil thenitrile a t this stage resulted in decomposition, and therefore theproduct was partly purified by crystallisation from aqueous alcohol.The nitzile was then distilled under diminished pressure, andfinally purified by crystallisat ion from methyl alcohol. The mdtingpoint was found t o be 9 3 O , and the yield 70 per cent. (Found,N = 7.2. CIOHliOSN requires N = 7.2 per cent.)2796 SIARDING : SITRSTITUTION 1N3 : 4 : 5-Trimetlzoxyacetophe?~o1ze, o~s(\ONle.\/AcThree grams of magnesium and 15 grams of methyl iodide' wereconverted into magnesium methyl iodide in ethereal solution. Thegreater part of the ether was removed by distillation, and an equalamount of benzene added.A solution of gallonitrile trimethylether (20 grams) in benzene was then added, and the reactionallowed to continue for eighteen hours on a gently-heated water-bath. The yellow, insoluble product was decomposed by ice anddilute hydrochloric acid. More ether was added, and the aqueoussolution extracted with a further quantity of ether. The combinedethereal extracts were washed with water, dilute sodium carbonatesolution, and dilute aqueous pot'assium hydroxide in turn. Thesodium carbonate washings were reserved (p. 2799). The etherealextract was finally washed with dilute hydrochloric acid, dried,evaporated, and the residual oil fractionated under diminishedpressure. The fractions of higher boiling point which becamepartly solid were then triturated two o r three times with pure dryether. This dissolved the ketone and a small amount of oil, leavingthe nitrile, which is almost insoluble in pure dry ether.Theethereal solution was filtered and evaporated, when the residual oilcrystallised on keeping. The ketone crystallised from light petrol-eum in needles melting a t 77-79O (Found, C=62*6; H=6*8.Calc., C=62*8; I3=6.6 per cent.).3 : 4 : 5-(rrimethoxyphetzyl 3 : 4-Methylenedioxystyryl Ketone,This derivative is prepared in an exactly similar manner to theisomeric 2 : 3 : 4-trimethoxyphenyl 3 : 4-methylenedioxystyryl ketone(p. 2797). It crystallises from alcohol in bright yellow needles,melting a t 130-131°, and dissolves in concentrated sulphuric acidwith a reddish-violet coloration :0.1179 gavel 0.2907 CO, and 0.0583 H,O.C=67*3; H=5*5.C,,H,,O, requires C = 66.6 ; H = 5.5 per cent.An oily phenylhydrazone, C,,H,O,N,, was obtained by the con-densation of 3 : 4 : 5-trimetlioxyacetophenone and phenylhydrazinein acetic acid solutionAROMATIC HE'DROST-C'OMPOUNDS. PART 11. 2797Action of Nitric A cid on 3 : 4 : 5-T9.i,iietlhozyacct~~~~~en~~nti :Formataoih of 5-NitmpgrognlloE Trimet hyE E' t her.Half a gram of the ketone was dissolved in 2 C.C. of warmglacial acetic acid, and 0.5 C.C. of concentrated nitric acid added.There was an instantaneous reaction, and the product was heatedon the water-bath until the copious evolution of nitrous fumes hadceased.On cooling and pouring into water, 5-nitropyrogalloltrimethyl ether was precipitated, and was readily identified byits crystalline form (from :tlcohol) and its melting point. Whenmixed with a specimen of 5-nitropyrogallol trimethyl ether preparedfrom pyrogallol trimethyl ether the melting point remainedunaltcred.OMt!Fifteen grams of pyrogallol trimethyl ether and 9 grams ofacetyl chloride were dissolved in carbon disulphide, 15 grams ofanhydrous ferric chloride added, and the reaction was allowed tocontinue overnight. The black product was decomposed by ice anddilute hydrochloric acid, the carbon disulphide removed by distilla-tion in a current of steam, and the residual, dark-coloured, oilysolid ext'racted by means of ether. The ethereal extract was washedwith diluto potassium hydroxide, which removed much 2-hydroxy-3 : 4-dimethoxyacetophenone, dried, and distilled, when an oil boil-ing a t 295-297O passed over.This was identified by analysis(Found, C = 62.7 ; H = 6.6 ; C,,H,,O, requires C = 62.8 ; H = 6.6 percent.) and by its piperonylidene derivative as 2 : 3 : 4-trimethoxy-acet op henone.2 : 3 : 4-Trimethoxyphenyl 3 : 4 - 1 N e t ~ y l e n e d i o x y ~ t ~ r y ~ Ketone,This derivative was prepared by mixing equimolecular amountsof piperonal and 2 : 3 : 4-trimethoxyacetophenone in alcoholic solu-tion, and condensing them by means of a few drops of 50 per cent.aqueous potassium hydroxide and boiling. Thel product was cooled,a little water added, and the piperonylidene compound separat'edout as an oily solid, which rapidly hazdened. It crystallises froinalcohol in stout needles, melting a t 101-102°, and dissolves inconcentrated sulphuric acid with a deep red colour:0.1188 gave 0.2953 CO, and 0.0594 H,O.C=66*9; H=5*5.VOT,. CV. 8lJC,,H,,O, requires C = 66.6 ; H = 5.5 per cent2798 HARDING : SUBSTITUTION INThe same piperonylidene derivative is obtained by the condensa-tion of piperonal wilh 2 : 3 : 4-trimethoxyacetophenone preparedeither by the direct condensation of acetyl chloride and pyrogalloltrimethyl ether through the agency of ferric chloride (see above)or by the methylation of 2-hydroxy-3 : 4-dimethoxyacetophenone(compare Perkin and Wilson, T., 1903, 83, 129).Action of Nitric Acid o n 2 : 3 : 4-Trimethoxyacetophettotie.(a) Formation o f 6( !)-Nitro-2 : 3 : 4-trimethoxyucetopherio?te,OMeTwo grams of 2 : 3 : 4-trimethoxyacetophenone were dissolved inconcentrated nitric acid, and the solution was kept cold for fifteenminutes by immersion in running water.There was no violentreaction, and a t the end of that time the solution was diluted withmuch water, when a heavy oil separated, which did not solidify onkeeping. I n order to determine whether this oil consisted chieflyof unchanged 2 : 3 : 4-trimethoxyacetophenone or a nitro-ketone, i twas converted into its piperonylidene derivative. The oil wasextracted by means of ether, the ethereal solution washed withdilute) sodium carbonate solution, dried, and evaporated. Theresidual oil was dissolved in boiling alcohol, a considerable excessof piperonal added, and a few drops of aqueous potassium hydr-oxide.Condensation took place' readily, the piperonylidene com-pound separating as a red oil, which could not be obtained in asolid condition. The1 alcoholic solution was diluted with water, andthe whole of the red oil which separated was extracted by meansof ether. The ethereal solution was then washed several timeswith a concentrated solution of sodium hydrogen sulphite t o removethe excess of piperonal, dried, and evaporated. This residual oilwas almost insoluble in cold alcohol, but dissolved readily in theboiling solvent, which, on cooling, deposited the piperonylidenecompound as an oil. By exposure t o a temperature of about -15Ofor more than a week, however, the oil solidified, and a pale yellowsolid was obtained, which crystallised from alcohol and melted at96-97O to a deep yellow liquid.The almost colourless crystals,however, always contained some of a deep yellow colour, but afterseveral crystallisations the whole changed into a deep yellow modi-fication. This melted a t 11 1-1 1 2 O , dissolved in concentratedsulphuric acid with a reddish-yellow colour, and evidently conAROMATIC HYDROXY-COMPOUNDS. PART 11. 2799sided of 6-nitxo-2 : 3 : 4-tririiertlioxypliellyl 3 : 4-metl~ylenecliosystyrylketone :0.1188 gave 0.2541 CO, and 0.0432 H20. C = 58.4 ; H = 4.0.0.1749 ,, 7-2 C.C. N, (moist) a t 25O and 758 mm. N=4*5.C,,HI7O,N requires C = 58.9 ; H = 4.3 ; N = 3.6 per cent.(b) Formotion of Di-6-nitro-2 : 3 : 4-trimethoxybenzoyIficroxan,NO,*C',H(OMe),*CO CN O,*C,H( ORle),-CO*C ' >N,O,.This action of hot concentrated nitric acid on 2 : 3 : 4-trimethoxy-acetophenone was investigated in the hope that acetyl substitutionwould occur, and as a result that 4: 5-dinitropyrogallol trimethylether would he isolated.One gram of 2 : 3 : 4-trimethoxyaceto-phenone was dissolved in concentrated nitric acid and the solutionboiled until the vigorous reaction, which had set in, ceased. Theproduct was dilut'ed with water, when a slightly oily solid wasprecipitated. The water was decanted, and on adding alcohol theproduct became completely solid. It was collected and purified bycrystallisation from benzene, from which it separated in small,faintly yellow needles :0.1217 gave 0.2098 CO, and 0.0413 H20. C=47*0; H2-3.7.C22H,,01,N, requires C = 46.9 ; H = 3.5 per cent.Bi-6-dro-2 : 3 : 4-trimethoxyb enzoylfwoxnn is insoluble in water,alcohol, or dilute sodium carbonate, but dissolves in hot aceticacid.No 4 : 5-dinitropyrogallol trimethyl ether was isolated fromthe mother liquors.Isolutioi~ of u Compound, CslHn07N2, from the Actioii ofMagnesium Methyl Iodide o n Gallonitrile T'nirnethgl E'ther (p. 2795).The sodium carbonate washings from the Grignard reaction(p. 2796) were evaporated on the water-bath for a short time toremove ths ether, cooled, and 50 per cent. aqueous potassiumhydroxide was added until no more precipitate appeared. The pre-cipitated potassium salt was collected, suspended in warm water,and decomposed by dilute hydrochloric acid, when an oil wasprecipitated which solidified on cooling. The solid was collectedand purified by crystallisation from benzene, from which i tseparated in sniall prisms melting a t 125-126O:0.1236 gave0.2773 CO, and 0.0564 H20. C?=61.1; H=5.1.0.2280 required 11.6 C.C. il'/lO-H,SO,.C21H2,07N2 requires C = 60.9 ; H = 5.3 ; N = 6.7 per cent.C2,H,,@7N, ,, C=61.1; H=4*9; N=6.8 ,, ,,* Other analyses gave C=61'2 ; H=5*2 ; N=6*5.N = 6*6.*8 u 2800 LE SUEUR AND WITHERS: THE MECHANISMIt, was found that, a cleterininntion of tthe hasicity of the8 acid hytitration witli normal alkali gave untrustworthy results, the end-point with phenolplithalein being extremely indefinite.I n conclusim, I desire to thank the Research Fund Committeeof the Chemical Societ\y for the grant which has defrayed part oft h e cost of this investigation.MCGILL ~ ~ N l V l C l X 3 l * ~ Y ,~fOXrREA1,