EXCHANGE BOBl'lZWMVd 37 1922 UNIVERSITY OF PENNSYLVANIA THE METHYLATION OF PARA-AMINOPHENOL BY MEANS OF FORMALDEHYDE BY ERNEST CARL WAGNER A THESIS PRESENTED TO THE FACULTY OF THE GRADUATE SCHOOL IN PARTIAL FULFILLMENT OF THE REQUIRE- MENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY 1921 UNIVERSITY OF PENNSYLVANIA THE METHYLATION OF PARA-AMINOPHENOL BY MEANS OF FORMALDEHYDE BY ERNEST CARL WAGNER A THESIS PRESENTED TO THE FACULTY OF THE GRADUATE SCHOOL IN PARTIAL FULFILLMENT OF THE REQUIRE- MENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY 1921 ACKNOWLEDGMENT The subject of this study was suggested by Dr. W. T. Taggart, under whose super- vision and with whose encouragement the work described was undertaken. Much practical help and many useful sug- gestions were given by Dr. H. S. Lukens. To these gentlemen the writer takes this opportunity to express his appreciation. The Methylation of p-Aminophenol by Means of Formaldehyde A Study of Certain Methods for the Conversion of the Condensation-products of Formaldehyde and p-Aminophenol into N-Methyl-p-aminophenol This paper it divided as follows: /- The Condensations of Formaldehyde and Aromatic Amines A. Condensations in Neutral or Alkaline Media B. Condensations in Acid Media C. Summary of Important Condensations and Secondary Reactions //- Methylation of Aromatic Amines by Means of Formaldehyde III- Experimental Results on the Methylation of p-Aminophenol by Means of Formaldehyde IV- Summary I. The Condensations of Formaldehyde and Aromatic Amines In the condensations of formaldehyde with the amines, the fundamental change consists in the splitting out of the elements of water, with the result that a methylene-group is introduced. Typically the necessary hydrogen atoms are displaced from an amino-group, or from two imino-groups. It is characteristic of certain condensations, however, that only nuclear hydrogen atoms are involved. The course of the condensation depends upon (a) the nature of the medium in which condensation oc- curs, i.e., whether neutral, alkaline, or acid, (b) the relative pro- portions of amine and aldehyde, (c) the presence of substances with which further reaction may occur, and (d) the influence of substituent groups present in the amine molecule. METHYI N R > NH $&**& ______ i (tnethylene-di-phenamine base) 1 Annal., 302, 349. 'Alexander, Ber., 25, 2408 (1892). MKTHYLATION OF PARA-AMINOPHENOI, Compounds of these types are more or less generally referred to as "SchifFs Bases," which include also the condensation- products of other aldehydes. The earliest known and simplest formaldehyde condensation of type (a) among aromatic amines was studied by Pratesi and Tollens 3 in the case of aniline. Anhydroformaldehydeaniline, or anhydroformaniline, is thus obtained in the trimeric form (C 6 H 5 N.CH 2 ) 3 . 4 Polymerization occurs also with other amines, such as the toluidines 5 and p-aminophenol. 6 The existence of two forms of such compounds, having different melting points and solubilities, has been observed in several cases. This was attributed at first to different degrees of polymerization. It was shown by Bischoff, however, that (CH 3 .C 6 H 4 .N.CH,) n exists in two forms, both of which have the same molecular weight, corresponding to the formula (CH 3 .C 6 H 4 .N.CH 2 ) 3 . He concluded that the two forms must be geometrical isomers of the cis and trans types with respect to the CH 3 .C 6 H 4 -groups attached to the [ N.CH 2 -] 3 ring. Anhydroformaniline likewise probably exists in two forms. Dimeric forms of these anhydro-bases, such as (CH 3 .C 6 H 4 .N.CH 2 ) 2 , or structurally, CH 3 .C 6 H 4 .N<^ 2 >N.CH 4 .CH S , have been reported. 7 The general reaction of which the formaldehyde-aniline con- densation serves as a type was soon applied to the toluidines, etc., by Wellington and Tollens, 8 and has since that time been extended, where applicable, to apparently all amines of importance, both aliphatic and aromatic, as well as to many heterocyclic compounds. 3 Pratesi, Gazz. chint. ital., 14, 351 (1884); Tollens, Ber., 17, 653 (1884); 18,3309(1885). * Miller and PlochU, Ber. y 25, 2020, (1892); Bischoff, Ber., 3!, 3248 (1899). 6 Bischoff. /. c. D. R. P., 68707. 7 Ber. y 31, 2037, 3248; AnnaL, 256, 288. 8 Bcr., 18,3298(1885). F PARA-AMINOPHENOI, Condensation of two equivalents of amine and one of formalde- hyde is of type (b), and yields methylene-di-imine compounds of the type-formula Ar.NH.CH 2 .NH.Ar. Thus two molecules of aniline and one of formaldehyde form methylenediphenyldi-imine, or dianilinomethane : 8 C 6 H 5 .NH.CH 2 .NH.C 6 H 5 . By boiling this compound in alcohol, it is transformed into anhydroformaniline. 10 Exactly analogous condensations occur with other amines. 11 The most interesting reaction of the di-imine bases occurs when they are heated with amine-salts. Diamino-diphenylmethane derivatives are thus formed, by a rearrangement which recalls the transformation of hydrazobenzene to benzidine : 12 Ar.NH.CH 2 NH.Ar. *-> Ar.NH.CH 2 .Ar.NH 2 H* NH 2 .Ar.CH 2 .Ar.NH 2 . As these compounds are formed directly when condensation is conducted in presence of free acid, and with base in excess of formaldehyde, the secondary reaction just given belongs more properly to Section B, where its probable mechanism will be indicated. Condensations of types (a) and (b) may occur simultaneously, one or the other predominating; excess of aldehyde favors the first, while excess of amine favors the second. 13 Condensations of type (c) are characteristic of secondary amines, and are in no essential manner different from the pre- ceding. The methyltoluidines, for example, condense with formaldehyde to form (C 7 H 7 .N.CH 3 ) 2 CH 2 . 14 When heated with amine-salts, these compounds, like those obtained from primary amines, are rearranged to form dialkylamino-diphenylmethane derivatives. Compounds intermediate between the methylene-di-imine bases (Ar.NH.CH 2 NH.Ar.), and the diamino-diphenylmethanes 9 Pratesi, Bischoff, /. c. 10 Eberhardt and Welter, Ber., 27, 1804 (1894). 11 Eibner, Annal., 302, 349 (1898): Bischoff, /. c.\ Bischoff and Reinfeld, Ber., 36, 41 (1903); D. R. P. 138393, etc. 12 D. R. P. 63081, 107718. 13 Eibner; Eberhardt and Welter, /. c. 14 Braun, Ber., 41, 2145 ( I 98). METHYIyATlON OF PARA-AMINOPHENOI, (NH 2 .Ar.CH 2 .Ar.NH 2 ), viz., the aminobenzylanilines (NH 2 .Ar.- CH 2 .NH.Ar.), are formed when an anhydro formaldehyde-base is heated with an amine-salt : 15 C 6 H 5 .N:CH 2 + H.C 6 H 4 .NH a (HCl)~- C 6 H 5 .NH.CH 3 .C 6 H 4 .NH,(HC1). Condensations of nuclear-substituted amines proceed often in the normal manner; o-nitraniline, for example, yields Similar condensations occur with halogenated amines, aminoben- zoic acids, aminosulphonic acids, benzidine, tolidine, phenetidine, etc. It is of great practical importance that the methylene-group of the diphenylmethane compounds can be condensed with a third amine-molecule by oxidation, forming triphenylmethane deriva- tives, among which fuchsine and the homologous pararosanilines are included. 17 Primary condensation-products of the type Ar.N :CH 2 , although probably cyclic polymers devoid of double bonds, are able to unite, by addition, with several substances, the most important of which are (i) hydrogen, (2) sulphurous acid or bisulphites, and (3) hydrocyanic acid. These additions occur according to the follow- ing equations : 18 (1) Ar.N:CH 2 -f 2H .= Ar.NH.CH 3 (2) Ar.N:CH 2 + NaHSO 3 = Ar.NH.CH 2 SO 3 Na (3) Ar.N:CH 2 + HCN = Ar.NH.CH 2 .CN The bisulphite compound contains a replaceable SO 3 H or -SO 3 Na group : 19 by interaction with cyanide a phenylglycineni- trile results: Ar.NH.CH 2 .SO,Na + NaCN = Ar.NH.CH 2 .CN + Na 2 SO 3 . The synthesis of phenylglycine and its homologues is thus possible D. R. P. 87934- 16 Pulvermacher, Ber,, 25, 2764526, 955. 17 D. R. P. 53937, 55565, 61146, 67013, 73092. 18 Miller and Plochl, Ber., 25, 2020 (1892); Eibner, AnnaL, 3x6, 89 (1901); Lcpetit, Atti. accad. Lincei, 26, I, 126 (1917); Gazz. chitn. ital., 47, I, 197 (1917); C. A., 1918, 366. 19 Knoevenagel, Ber., 37, 4073 (1904). PARA-AMINOPHENOI, by a convenient method, as the products may be obtained directly by proper treatment of amine, cyanide, formaldehyde, and alkali. 20 Preparation of phenylglycine-o-carbonic acid is accomplished by a similar process, starting with anthranilic acid. 21 Condensations of formaldehyde with anthranilic acid or its esters have been rather carefully studied. 22 Union of the anhydro-base Ar.N :CH 2 with hydrocyanic acid or bisulphite may take place either after isolation of the base, or in a mixture of amine, formaldehyde, and cyanide or bisulphite. In the latter case it is to be supposed that the cyanhydrin or aldehyde- bisulphite is primarily formed, and reacts with the amine : iOH + HiN.H.Ar CH 2 + HCN -* CH 3 < Ar. NH.CH 2 . CN -f- H 2 O CH,0 + NaHS0 3 -~ CH a Ar.NH.CH 2 .Ar.NH 2 -w NH 2 .Ar.CH 2 .Ar.NH 2 . This transformation has been studied for o-nitraniline by Meyer and Rohmer, 37 and for several secondary amines by Braun. 38 It appears that the exochlor-compound is first formed, with splitting-off of a molecule of amine. The former may then pass into the anhydroaminobenzylalcohol, reaction of which with the amine first liberated yields the diphenylmethane compound which constitutes the end-product. For the simplest case the trans- formation may be indicated by the scheme : C 6 H 5 NH CHCD C 6 H 5 .NH.CH 2 .C1 C 6 H 4 C 6 H 5 NH >C1 * C 6 H 5 .NH,.HC1 --- ' CH, This general process is susceptible of many modifications. It is most simply carried out in a single operation, by interaction of formaldehyde and excess of amine in presence of acid. When mixed products are desired, the di-imine is first produced, and is further condensed with the salt of another amine. w D. R. P. 96762. n Ber. t 33, 250 (1901). 88 Ber., 4x, 2145 (1908.) M3THYLATION OF PARA-AMINOPHNOI< The same products may be obtained in still another way, from the p-aminobenzylaniline derivatives, NH 2 .Ar.CH 2 .NH.Ar, 39 which are formed by interaction of amine-salts with bases of the type Ar.N :CH 2 (pages 4 and 5). The p-amino-benzylaniline thus obtained, when heated with amine and hydrochloric acid, yields a diphenylmethane derivative, with elimination of a molecule of amine : NH 2 .C 6 H 4 .CH 2 .NH.C 6 H 5 + H.C 6 H 4 .NH 2 (HC1) * NH 2 .C 6 H 4 .CH 2 .C 6 H 4 .NH 2 (HC1) + C 6 H 5 .NH 2 . The anhydroaminobenzyl (or homologous) alcohols show a characteristic reaction with /?-arylhydroxylamines, by which result the p-amino-benzaldehydes : NH C 6 H 5 .NHOH + I >C 6 H,~ C 6 H 5 .N:CH.C 6 H 4 .NH a CH 2 (H20) ^ C 6 H 5 .NH 2 + OHC.C 6 H 4 .NH 2 . The same products are obtained by suitable reduction of nitro- compounds in neutral solution and in presence of formaldehyde. While the secondary amines condense with formaldehyde in the normal manner, by virtue of the presence of amino-hydrogen, the tertiary amines show a different behavior. Dimethylaniline, con- densed with formaldehyde in acetic acid solution, yields tetra- methyldiaminodiphenylmethane, (CH 3 ) 2 N.C 6 H 4 .CH 2 .C 6 H 4 .N(CH 3 ) 2 . 40 The m-aminophenols, and the corresponding cresols, react in the same way. 41 By dehydration and oxidation, the products of such condensations yield the pyronines. 42 The m-diamines condense similarly to form diphenylmethane derivatives, from which acridine compounds are obtainable by loss of ammonia and by oxidation. 43 The o-diamines yield imidazole compounds. 44 39 D. R. P. 87934, 104230, 105797, 108064, 109498. 40 Mohlau and Heinze, Ber., 35, 359 (1902); cf. Pinnoff, Ber., 27, 3166 (1894). 41 D. R. P. Anm., 5528; D. R. P. 58955, 75373; Ber., 27, 1894 (1894); /. pr. Ch,, 54, 217 (1896). 42 D. R. P. 59003, 63081, 75138, 84988, 99613- "Orloff, "Formaldehyde," Leipzig, 1909, pp. 97, 115-123, gives a general account, together with some of the numerous patents. 44 O. Fischer, Per., 25, 2711; 32, 245. 10 METHYIvATlON OF PARA-AMINOPHENOI, Amines of the naphthalene series condense with formaldehyde in acid solution with elimination of ammonia and water. Double junction between two naphthalene nuclei at their a and ft positions is effected through a -CH 2 - and an -NH- group. When. however, the /^-position is occupied, as by -SO 3 H, the amino- group is not involved, but the two nuclei are united through -CH 2 - attached at the 4-positions. 45 It will not be profitable to extend further the list of condensa- tions, though it is not even approximately complete. A brief and fairly comprehensive survey of the subject (up to about 1908) is given by Orloff. 46 Later work is recorded in the academic and patent literature. C Summary of Important Condensations of Formaldehyde and Aromatic Amines*' (i) Primary Condensations (a) In absence of acids, one molecule of formaldehyde and one molecule of primary amine react to form readily polymerized N-methylene-amines (anhydro- formaldehydeamines) : Ar.N:H 2 " o!CH 2 - Ar.N :CH 2 + H 2 O (b) In absence of acids, one molecule of formaldehyde and two molecules of primary or secondary amine react to form methylene-di-imino bases (methylene- diphenamines, dianilinomethanes") : Ar.NHiH Ar.NH Ar.NHiH U ; LH * ~~* Ar.NH >Li1 ' Ar R >N;H ^>NJH Ar R> N \ O CH, ^CU, + H,O Ar (c) Tertiary amines condense to form diphenylmethane derivatives : "Morgan, Proc., 16, 131; i95, 132 (1897); /. C. 5., 77, 814; 73, 536; Reed, /. pr. Ch., 35, 298; Bucherer and Seide, Ber. t 40, 859; Senier and Austin,/. C. S., QI, 1233; D. R. P. 84379. 46 /. c. pp. 81-123. * 7 Cf. Friedlander, V. p. 5. II METHYLATION OF PARA-AMINOPH^NOI, R,N.Ar.iH , R 2 N.Ar.JH ;; (d) In presence of acids, one molecule of amine and one of formaldehyde unite to form (in the case of HC1) the exochlormethylamino-compounds, which are converted by loss of hydrochloric acid into the reactive anhydroaminobenzyl alcohols. These are para-compounds, unless the para-position is initially occupied, in which case analogous compounds result with the -CH 2 - group otherwise disposed : Ar.NH:ILH : Cl + : O!CH 2 -HCI NH Ar.NH.CH a Cl Ar< I CH 2 (2) Secondary Condensations (a) The anhydro formaldehyde-amines unite with amine- salts in the cold to form p-aminobenzylaniline derivatives : Ar.N:CH 2 -f H.Ar.NH 2 (HCl) *-+ Ar.NH.CH 2 .Ar.NH 2 (HCl). (b) The p-aminobenzylanilines unite with amine-salts in acid medium, and at higher temperatures, forming diphenylmethane derivatives, with elimination of a molecule of amine: Ar.NH.CH 2 .Ar.NH 2 m ^ Ar.NH, NH 2 .Ar.H. NH 2 .Ar.CH 2 .Ar.NH 2 (c) The methylenedi-imine bases, when heated with amine-salts, pass into corresponding diphenyl- methane derivatives by rearrangement : Ar.NH.CH 2 .NH.Ar. **-* NH 2 .Ar.CH 2 .NH.Ar *H NH 2 .Ar.CH 2 .Ar.NH 2 . (d) The anhydroaminobenzylalcohols react with amine salts to form diphenylmethane derivatives: -f H.A CH, NH 12 OF PARA-AMINOPHENOI, II. Methylation of Aromatic Amines by Means of Formaldehyde Among the aromatic amines, the time-honored method of alkylation employs the alkyl halides. Much more convenient than this method, however, is that in which an alkyl sulphate, and especially methyl sulphate, is the active agent. 48 This method is coming into increasingly wide use, because of the activity of methyl sulphate, and because of the relative simplicity of the oper- ations. The methylation of p-aminophenol to N-methyl-p-amino- phenol may be accomplished by this means, which is probably that by which the process is now conducted commercially. Methylation may be effected similarly by the use of the methyl ester of p-toluene-sulphonic acid. 49 Other methods for conversion of primary to secondary amines include the following : (1) Action of methyl alcohol in presence of concentrated sulphuric acid. 50 (2) Hydrogenation of Schiff's bases catalytically, in presence of nickel 51 or metallic oxides. 62 (3) Alkylation of primary to secondary amines through action of alkyl iodides upon SchifFs bases. 83 This method involves intermediate formation of unstable quaternary compounds by addition of alkyl iodides to bases of the type R.N:CHR'. The quaternary salts, by hydrolysis, yield secondary amine and aldehyde : R.N:CHR' + R"I H S O R>NH -f CHO.R' + HI ^Ullman, Annal., 327, 164 (1903); Meldola and Hallely, /. C. S., I9I2T, 912; Werner,/. C.S., 105, 2762 (1914); Havasand Guyot, Chem. Ztg., 37, 812; Shepard, /. A. C. S., 38, 2507 (1916); Klemenc and Edhoffcr, Monats., 38, 553 (1918.) 49 Ullmann and Wenner, Annal., 327, 120 (1903); Weyl, "Method**," //, 1269 (1911.) 50 D. R. P. 288825. 61 Maihle, Bull. Soc. chim., 25, 321 (1919). M E. P. 124219. M Decker and Becker, Annal., 395, 362. 13 METHYI,ATION OF PARA-AMINOPHENOI, Among the secondary amines prepared by this method are methyl- and ethyl-aniline from benzylidine-aniline, and methyl-p-toluidine from benzylidine-p-toluidine. (4) Condensation of primary amine and phenol. 54 N-methyl- p-aminophenol may be prepared in this way from hydro- quinone and methylamine : HO.C 6 H 4 .iOH"TNH;H.CH 3 ^ " HO.C 6 H 4 .NH.CH S + H 2 O A somewhat similar method involves the interaction of p-chlor-phenol and methylamine: 55 HO.C 6 H 4 .;CTT~HT NH.CH 3 HO.C 6 H 4 .NH.CH 3 + HC1 These methods are more properly described as arylations of aliphatic amines than as alkylations of aromatic amines, though this distinction has no significance so far as concerns the products. Consideration of the several primary condensation-products of formaldehyde and the aromatic amines suggests four ways in which the introduced methylene-group might be changed to a methyl-group : 1 I ) Hydrogenation of the anhydro formaldehyde-amines : Ar.N :CH 2 + 2H **-> Ar.NH.CH 3 (2) Reduction of the exochlormethyl-amines obtained by condensation in acid solution: Ar.NH.CH 2 Cl + 2H *> Ar.NH.CH 3 + HC1 (3) Reduction of the bisulphite addition-products of the an- hydro formaldehyde-amines : Ar.NH.CH 2 .SO 3 Na + 2H - Ar.NH.CH 3 + NaHSO 3 (4) Hydrolysis of the hydrocyanic acid addition-products of the anhydroformaldehyde-amines, and elimination of carbon dioxide by heat : Ar.NH.CH 2 .CN M> Ar.NH.CH 2 .COOH *-* Ar.NH.CH 3 + CO 2 . 64 D. R. P. 260234- Harger,/. A. C. S., 41, 270 (1919). 66 D. R. P. 205415. METHYXATION OF PARA-AMINOPH3NOI, A brief discussion of methods hitherto applied for reactions such as the foregoing will be given first, and will be followed by a description of experiments on the methylation of p-aminophe- nol by these methods. This reaction was chosen because it ap- pears that the indicated methylation has not been effected by the above methods (except the last), and because the product, N-methyl-p-aminophenol, is a compound of considerable interest, its sulphate being the photographic developer known as "Metol." (i) Hydrogenation of the Anhydroformaldehyde-bases, i. e., of the Group -N: CH- The methods by which this reduction has been accomplished include the following : (a) Reduction by Sodium-amalgam, or by Sodium, and Ab- solute Alcohol These two methods constitute classic means for effecting this hydrogenation. 56 Fischer, avoiding the use of acids because of their decomposing effect upon the -N:CH- group, used the above agents for reductions such as that of benzylidene-aniline to benzylaniline. As is well known, the intensity of the reduction may be modified by use of different alcohols. 57 Attempts to re- duce the compound HO.C 6 H 4 .N :CH 2 by these means met with no success. (b) Reduction by Means of Zinc-dust and Alkali This method is the subject of several patents, dealing with the production of secondary from primary amines. 58 The alkylation or arylation is best carried out by interaction of amine and alde- hyde in presence of excess of reducing agent; the medium for the reaction is water, alcohol (or acetic acid, but not strong acids.) 59 These methods do not seem to have come into general use, and are probably not highly efficient: several attempted methylations of aniline gave only small yields of methylaniline. The reduction of benzylidine-p-aminophenol by means of zinc- 56 O. Fischer, Ber., 19, 748 (1886); Annal., 241, 328 (1887); 245, 279 (1888); Miller and Plochl, Ber., 25, 2020 (1892). 57 See, e. g., Miller and Plochl, /. c. M D. R. P. 75854, 105345; Prudhomme, Bull. soc. chim., 23, 69 (1905), 59 E. P. 102834, A. P. 1221077; /. C. S., 115, 198. 15 ME)THYI,ATION OF PARA-AMINOPHENOI, dust and sodium hydroxide, on the other hand, takes place without difficulty, 60 giving good yields of benzyl-p-aminophenol. In view of this fact, it is interesting to record that methylene-p- aminophenol resisted all efforts at reduction by the same process. (c) Reduction by Zinc in Acid Medium Miller and Plochl 61 showed that anhydro formaldehyde-aniline can be reduced to methylaniline by hydrochloric acid and zinc- dust. Goldschmidt 62 carried out the same reduction with tin and hydrochloric acid. No yields are stated for these reductions. By reduction of methyl ene-p- aminophenol with zinc-dust and acid, a partial conversion to N-methyl-p-aminophenol was ob- tained, as will appear in the experimental part (section III). (d) Reduction Electrolytically in Alkaline Medium By this method Brand and Honig 63 obtained benzylmethylamine and benzyl-p-aminophenol by the normal course of the reduction, and o-aminophenol and toluene from benzal-o-aminophenol. The writer was able to reduce benzylidine-p-aminophenol in this way, but methylene-p-aminophenol was not hydrogenated. (e) Reduction Electrolytically in Acid Solution Reduction under these conditions suffers the disadvantage that the operation of necessity extends over a considerable period of time, during which certain changes incident to the contact of the condensation-product and acid are in progress. It is therefore thought necessary to maintain a low temperature so long as acid and condensation-product are in contact. According to a recom- mended procedure, 64 the condensation-product is dissolved in 50 per cent sulphuric acid at -12, and electrolysis is conducted at or below o, using a cathode of lead, copper, nickel, or mercury. In this way both aliphatic and aromatic amines may be alkylated or arylated. Numerous reductions of methylene-p-aminophenol by a simi- lar process were carried out, using generally 40 per cent sul- 60 D. R. p. 211869, 61 /. c. 62 Chem. Ztg., 28, 1229 (1904). 63 Zeit. electroch., 18, 745. 64 D. R. P. 143197. 16 METHYLATION OF PARA-AMINOPHENOI, phuric acid and a cathode of lead. Certain of the trials were partially successful, while others, intended to be identical, were attended, so far as could be observed, and for reasons which were not discovered, by no absorption of hydrogen, and by the forma- tion of no detectable secondary amine. The process showed no uniform improvement when conducted at low temperature. (f) Electrolytic Reduction of Nitro-compounds in Presence of Formaldehyde Lob 65 and Goecke 86 carried out reductions of nitrotoluene in hydrochloric acid-alcohol solution, with a lead cathode, and in presence of an excess of formaldehyde. From p-nitrotoluene there were obtained dimethyl-p-totuidine (about 40 per cent), and another compound, called by Lob dimethylditoluidine, and by Goecke trimethylenetritoluidine (but which, it would appear, was probably an anhydroaminobenzyl alcohol). This process was applied to p-nitrophenol, both in presence of one equivalent of formaldehyde, and of an excess. In neither case could any mono-methyl-derivative be isolated, though some dimethyl-p-aminophenol was obtained; under the first-mentioned conditions some p-aminophenol resulted by simple reduction of p-nitrophenol. Similar reduction of p-nitrosophenol in presence of formaldehyde likewise failed to produce secondary amine. (g) Reduction by Sodium Hydrosulphite The applicability of sodium hydrosulphite for reduction of methylene-amines might appear a priori improbable in view of the readiness with which these compounds unite by addition with sulphurous acid or bisulphites; as commercial sodium hydrosul- phite always reeks with sulphur dioxide, the immediate forma- tion of the addition-product Ar.NH.CH 2 .SO 3 H seems probable. Reduction of such compounds to Ar.NH.CH 3 by hydrosulphite could hardly be expected. Attempted reductions of methyl ene-p-aminophenol by means of sodium hydrosulphite yielded no secondary amine, but a readily soluble yellow-white crystalline substance which evolved sulphur dioxide when warmed with acids. 65 Zeit. eleciroch., 4, 428 (1897/8). Ib., 9,470 (1903)- 17 METHYIvATlON OF PARA-AMINOPHENOI, (2) Reduction of the Exochlormethylanilines, formed by Acid Condensation Only a single intance has been found in which such a reduction is reported. Goldschmidt 67 reduced N-methyleneaniline (an- hydroformaniline) with tin and hydrochloric acid, condensed the resulting methylaniline with formaldehyde, and then reduced the resulting C 6 H 5 .N<;;J?* . with tin and hydrochloric acid, v~xl,L,l obtaining dimethylaniline. A prolonged attempt to duplicate the second reduction, using tin and hydrochloric acid at ioo, was without effect upon the exochlor-compound. Similar experiments were carried out with p-amino-phenol, which was condensed with formaldehyde in presence of hydrochloric or sulphuric acid in varying amounts. The product was subjected to reduction by various means, but in no case could the presence of secondary amine be detected. (5) Reduction of the Bisulphite Addition-products of the Anhydro formaldehyde-bases As a means for testing the possibility of effecting the change Ar.NH.CH 2 .SO 3 H - Ar.NH.CH 3 + HSO 3 Na, the bisulphite addition-product of methyleneaniline was prepared from formal- dehyde-bisulphite and aniline, 68 and was reduced by tin or zinc and hydrochloric acid. In both cases free sulphur was separated, but steam-distillation of the alkalized liquid yielded no volatile product. The possibility of splitting off the -SO 3 H group hydro- lytically was also studied, but positive results were not obtained. (4) Hydrolysis of the Hydrocyanic Acid Addition-pro- ducts of the Anhydr of ormaldehy de-Bases, and Elimina- tion of Carbon Dioxide by Heat The decarboxylation of p-hydroxy-phenyglycine was suggested by Paul 69 as a method for preparation of methyl-p-aminophenol. Trial of this method by Harger 70 gave poor results, and led him to a further study of the method of Merck and Co., using hydro- 87 Chent. Ztg., 28, 1229 (1904). 68 Orloff, /. ., p. 37. * Zeit. angcw. Ch. 10, 17 (1897). 70 /. A. 4 * s g 1 s **i ^'8 fc a N s 01 Benzal- comp. from filt. o ^ oo M fh tj- ^ 2 M^JLJ 5? R 8 s g S S S S s 5 J: R j: tfii o ^o q c< o8& t^ 10 t^. tO vb VO ro b b h ^ 3 1*1 2 fc "S 3 c a 2 K ^5 "3 a 1 1 ^^3 . a, ^ ft * ** * " 8 j| >o 10 10 m H * 1 8 g _o |.Sl s B ^1 = 38 & 8 5 i a 1 3 "? m "? 10 ir> D , "? IT. 10 lO IO u-> ID " 1 M H S~B s*i .& "i o 5 o N 4; M v q vO vd a ip 3 o Ifi -0 fO *' j & o 2 O o o 2 i METHYtATlON OF PARA-AMINOPHENOI, The data just given seem to justify the following conclusions : (1) The extent of the condensation is relatively independent of experimental conditions, provided that there are present at least one equivalent of formaldehyde, and two equivalents of sodium hydroxide, for each equivalent of p-aminophenol hydrochloride (or one equivalent of sodium hydroxide if free p-aminophenol is used). Excess of formaldehyde or of sodium hydroxide is without apparent effect. (2) Low temperature favors slightly increased condensation, as shown by the sixth, seventh, and ninth experiments, in com- parison with other trials, which were conducted at 15 20. (3) Condensation is not increased by prolongation of the time beyond two hours. As shown by experiments not listed above, over-night condensations tend to yield a denser and darker product, with no advantage in the matter of yield or of ease of reduction. (4) The volume in which condensation occurs is almost with- out effect. The only definite exception to this statement is pre- sented by the thirteenth experiment, in which the volume was relatively large, the result being that normal condensation was not quite complete at the end of two hours. (5) The last four experiments indicate that practically all the p-aminophenol hydrochloride taken initially is accounted for, either as methylene-p-aminophenol or as the uncondensed base. (6) Condensation of formaldehyde and p-aminophenol occurs to the extent of about 75 to 85 per cent. The experiments recorded above, together with many inciden- tal observations made during the course of the work, led to the adoption of the following Procedure for Condensation of Formaldehyde and p-Amino- phenol (a) Condensation Dissolve 10 parts of p-aminophenol hydro- chloride in about 60 parts of water, and filter the solution. Transfer the nitrate to a flask, and chill well under the tap, or better in ice. Add at one time one-half of a solution which con- tains 7.5 parts (somewhat more than two equivalents) of sodium MET HYI^ATION OF PARA-AMINOPH^NOI, hydroxide, and cool until the heat of neutralization is absorbed. Now add the remaining sodium hydroxide, which will dissolve the precipitated p-aminophenol. To the cold alkaline solution add 6 parts of 38 per cent formaldehyde (somewhat more than one equivalent) gradually, with rotation of the flask. Insert a stopper, and keep the flask in a cool place for two or three hours. (b) Isolation Pour the liquid into a large beaker or jar con- taining cold water, and provided with an efficient mechanical stirrer, and, appropriately supported above the precipitating vessel, a separatory funnel containing 30 per cent acetic acid. The volume at the time of precipitation should be rather large, or the liquid will become so filled with the precipitated product as to interfere with effective stirring. A volume somewhat greater than 500 cc. is convenient for precipitation of the condensation- product from 10-15 grams of p-aminophenol hydrochloride. With the stirrer in motion, allow 30 per cent acetic acid to drop into the liquid, until the reaction is distinctly acid to litmus. The condensation-product will be precipitated in a finely granular form which settles promptly and is easily filtered and washed. Filter off the product on a Biichner funnel, wash with cold water, press down well with a spatula, and dry the material as far as possible by suction. Transfer it to a watch-glass or plate, and keep in a slightly warm place for several hours, with occasional reduction of lumps as drying progresses. Dry finally at 8o-9O. The product is thus obtained as a loose, soft, grayish powder, which assumes a brown color after long exposure to the air. If the drying is done too rapidly, the condensation-product may become resinous. Precipitation by carbon dioxide gives equally good results, but is less rapid and less convenient; the use of sodium bicarbonate solution for the precipitation occasionally caused the separation of a coherent product. When reduction of the methyl ene-p-aminophenol is intended, it should be used shortly after precipitation, and without drying, as the completely dried product is reduced with difficulty. As will appear below, isolation of the condensation-product is not essential, and is quite properly omitted. 26 METHYLATION OF PARA-AMINOPH^NOIy Before the reduction of methylene-p-aminophenol is discussed, it is necessary to describe the methods of forming and handling the nitrosamine of N-methyl-p-aminophenol, since it is in this form that the reduction-product can be most readily and completely isolated, and the effectiveness of the reduction determined. p-Hydroxy-methylphenylnitrosamine, This compound is obtained by the usual procedure for nitro- samine formation: addition of sodium nitrite solution to the chilled acidified solution of the secondary amine. It separates from solution in crystalline form, the color of the crystals de- pending upon the presence of impurities in the solution. The pure secondary base yields nearly white, or gray, minute needles, having a low solubility in cold water. When precipitation is effected from solution containing p-aminophenol, formation of the nitrosamine is noticeably delayed, due no doubt to the superior reactivity of the primary base. In such cases, also, tar- formation is almost invariable, and the nitrosamine separates as brown granular crystals. Under unfavorable conditions the separation of tar has been considerable, rendering purification of the nitro- samine, without considerable loss, impossible. The nitrosamine is a somewhat unstable compound, and suf- fers serious decomposition, with darkening, if an attempt is made to dry it while moist with any trace of the acid mother- liquor, or to crystallize it from strong alcohol ; less extensive de- composition occurs if dilute alcohol is used. Rather oddly, the compound seems to be most satisfactorily crystallized from hot water, in which it is moderately soluble. For this purpose, the nitrosamine is suspended in water (about 50 cc. for each 3 grams), the mixture heated nearly to boiling, and about 5 cc. of alcohol added. Solution is completed without unnecessary heat- ing, and the liquid is cooled in ice. The nitrosamine crystallizes out rapidly, and with nearly quantitative completeness. For purposes of comparison, 2.0 grams of Metol (Hauff) were dissolved in 200 cc. of water, 10 cc. of strong hydrochloric acid added, and the solution cooled in an ice-bath. It was then treated dropwise with a 20 per cent solution of sodium nitrite, 27 METHYLATION OF PARA-AMINOPHENOL until a drop of the liquid, applied to potassium iodide paper, showed presence of nitrous acid in excess. The nitrosamine separated, during the addition of nitrite, as minute almost white needles, which were filtered off, and washed sparingly with cold water. After several recrystallizations from dilute alcohol, the nitrosamine was obtained as fairly large flat needles, slightly straw-tinged, and melting at 134.3 (corr.), with decomposition above the melting temperature. In regard to the melting-point of the nitrosamine, it should be added that Clarke 81 gives 136, a value never obtained by the writer. An interesting behavior was observed when an excess of nitrous acid was allowed to act upon the precipitated nitrosamine. There was obtained a bright yellow insoluble powder, which melted with decomposition at I26-I27, with previous softening. The bottle in which this material was kept was gradually colored a bright red on its entire inner surface. The reaction recalls the simultaneous nitrosation and nitration of methylaniline by means of nitrogen dioxide, as described by Stoermer. 82 Finally, it is of interest to consider the formation of the nitro- samine as an identification test for N-methyl-p-aminophenol. Attention may be called to the mercuric acetate test described by Harger 83 which is said to disclose the presence of metol in a con- centration of i :iooooo by the gradual development of a grape- juice color. The nitrosamine test is by no means so delicate as this, but is more characteristic. It appears that the mercuric acetate test is not entirely specific, since a by-product was obtained, by ether extraction of the alkalized solution after reduction of methylene-p-aminophenol, which was obviously not methyl-p-aminophenol (its sulphate was excessively soluble in water), but which responded to the mercuric acetate test more strongly than "metol" itself. The color developed was nearly blue, but in cases of doubt would certainly cause confusion. To test a material for presence of a salt of methyl-p-amino- phenol, a little of the substance is dissolved in a small volume of 81 /. Ind. Eng. Chem., 10, 891 (1918). 82 Arr., 31,2523 (1898). /. A. C. 5., 41, 270 (1919). 28 METHYLATION OF PARA-AMINOPHENOI, water, the solution acidified with a drop or two of hydrochloric acid, chilled, and sodium nitrite solution added in slight excess. A precipitate of minute needles, which usually appears suddenly, and which seems to fill the liquid, constitutes a positive test. If this material is recrystallized from a little water containing* alcohol, and its melting-point determined, the identification of methyl-p-aminophenol may be regarded as certain. Identification by means of the sulphate or the dibenzoyl-compound is less con- venient, as these derivatives are less characteristic in appearance, and have higher melting-points. (2) Reduction of N-Methylene-p-aminophenol to N-Methyl- p-aminophenol- Reference to page 15 shows the investigated methods of reduction to be the following: (a) Reduction by Sodium Amalgam, or Metallic Sodium, and Alcohol. (b) Reduction by Zinc-dust and Alkali. (c) Reduction by Zinc-dust and Acid. (d) Reduction Electrolytically in Alkaline Solution. (e) Reduction Electrolytically in Acid Solution. (f) Reduction Electrolytically of p-Nitrol-phenol or p- Nitroso-phenol in presence of Formaldehyde. (g) Reduction by Hydrosulphite. In all cases the success of the reduction was tested by means of the nitrosamine reaction. Of the above methods, only method (c) yielded positive results which were uniformly reproducible. Method (e) was attended with some success, and would possibly repay closer study. The other methods were apparently quite unsuccessful, and may be disposed of rather briefly. (a) Reduction by Sodium Amalgam, or by Sodium, and Absolute Alcohol Both aqueous (acid or alkaline) solutions of the condensation-product, and alcoholic solutions, were subjected to action of sodium amalgam. Reduction by metallic sodium was applied to the solution of methlyene-p- aminophenol in anhydrous ethyl alcohol. In neither case could 29 METHYLATION OF PARA-AMINOPHENOI, presence of secondary amine be detected in the liquids, after suitable preparation for precipitation of nitrosamine. (b) Reduction by Zinc-dust and Sodium Hydroxide This method was applied to the reduction of benzylidene- p- aminophenol and of methylene-p-aminophenol, obtained from p-aminophenol by condensation with, respectively, benzaldehyde and formaldehyde. It was expected that these compounds would behave similarly upon reduction; their chemical similarity is shown by the formulas HO.C 6 H 4 .N :CH.C 6 H 5 and HO.C 6 H 4 .N:CH 2 . Reduction of benzylidine-p-aminophenol 84 was quite success- ful : 17 grams of this compound gave 18 grams of benzyl-p- aminophenol hydrochloride, a yield of 89 per cent. The base was found to melt at 87-88 ; the nitrosamine, crystallized from dilute alcohol, melted at 142.5 (corr.). A picrate was prepared, as large bright yellow irregular prisms, very sparingly soluble in water, and melted at i66-i67 (corr.). It should be noted that the melting-point of the nitrosamine is given 85 as 148. The same procedure, as well as that of A. P. 1221077, w ^h varying temperatures, concentrations of alkali, and proportions of base and formaldehyde, when applied to the reduction of methylene-p-aminophenol, failed to produce any methyl-p-amino- phenol which could be separated as nitrosamine. (c) Reduction by Zinc-dust and Acid This method will be discussed in some detail below. (d) Reduction Electrolytically in Alkaline Medium As a test of the method, the benzylidine-p-aminophenol obtained from 22 grams of p-aminophenol hydrochloride and 16 grams of benzaldehyde was dissolved in 12 per cent sodium hydroxide solution, and subjected to reduction using iron electrodes. Absorption of hydrogen was very imperfect. A current of about 5 amperes (cathode area about 220 cm. 2 was continued for 3.5 hours, with continuous evolution of unabsorbed hydrogen. The liquid was finally acidified with sulphuric acid, filtered, and 84 D. R. P. 211869. 85 Zeit.electroch., 18, 745. 30 METHYLATION OF PARA-AMINOPHENOI, chilled, when 2 grams of the difficulty soluble benzyl-p-amino- phenol sulphate separated. The nitrosamine of this product melted at 142 (see page 30). The same procedure was applied for the reduction of methy- lene-p-aminophenol dissolved in 15 per cent sodium hydroxide solution. There was no apparent absorption of hydrogen, and no methylated product was detected in the liquid after reduction. (e) Reduction Electrolytically in Acid Solution The electrolytic cells used in all reductions recorded in this paper were identical in design with the cell devised by Dr. H. S. Lukens, whose description of it is now awaiting publication. Cells of three sizes were used, having capacities of 500 cc., 250 cc., and 100 cc. The last mentioned was used for reductions cit lower temperatures. The porous cup of this cell was closed by a large rubber stopper 86 which served as a support for the lead electrode, the liquid seal of the stirrer, the vent-tube, and an in- TABLE II. Electrolytic Reductions Nitros- P. A. P. gms. Method of preparation for electrolysis Amp. Volt Temp. Time hrs. Gas amine gms. f Yield 12.5 Condensed overnight. Poured into equal 10 4 - 6 None at first I.O 8 vol. 40 H 2 SO 4 25 Condensed 36 hours. 5-5- 4 3 H- + Added to equal vol. 7 after 80 $ H 2 SO 4 i hr. 12.5 Condensed 2 hours. 2 3-5 3-5 O.2 1.6 Ppted, byCH 3 COOH; dissolved in 45 gms. + from 25

; dis- 2 4 5- 9 5 + 2-4 18 solved in 90 cc. 40 # after H 2 SO 4 at 5. ihr. Small cell 12.5 Condensed 2 hours; ppted. by CH 3 COOH; dissolved in 200 cc. IO-II 6-7 not cooled 4 little for i hr I.O 8 20 alcoholic H 2 SO 4 then + 86 Tafel, Ber. t 33, 2209 (1900.) METHYIvATlON OF PARA-AMINOPHENOL serted thermometer. The electrodes of these cells were made of commercial lead. Results of some of the electrolytic reductions are tabulated above. The temperature, during addition of acid to condensa- tion-product (either isolated or in solution) was kept low 87 so as to avoid hydrolysis of the condensation-product. A number of experiments not listed above were entirely with- out positive result. The effect of amalgamating the cathode, or of using very pure lead, was not investigated. In the last ex- periment, an aliquot portion was examined, after reduction, for unchanged p-aminophenol : 37.5 per cent of that initially taken was recovered. (f) Electrolytic Reduction of p-Nitrophenol or of p-Nitroso- phenol in Presence of Formaldehyde Reference may be made to the statements which appear under the same heading on page 17. The reduction of 15 grams of p-nitrophenol in alcohol-hydro- chloric acid solution, in presence of 10 grams of 38 per cent for- maldehyde (about one equivalent), absorbed the hydrogen from a current of 10 amperes for over an hour. Electrolysis was con- tinued for nearly five hours, when evolution of unabsorbed gas was rapid. The clear red liquid was distilled free from alcohol, made alkaline with sodium carbonate, filtered, and extracted with ether. During distillation of the ether, a quantity of small crystalline plates separated. These were removed (1.4 gram), and were identified as p-aminophenol [m. p., i83-i85; m. p. of benzylidine-derivative, 185]. The solid material precipitated by sodium carbonate was dissolved in dilute hydrochloric acid, boiled with charcoal, filtered, and the solution precipitated by sodium acetate. A white amorphous material, weighing 2.2 grams, was obtained. This product seems to correspond to the by-product obtained by Lob and by Goecke during the electro- lytic reduction of p-nitrotoluene in presence of formaldehyde, and is possibly an anhydroamino-oxy-benzyl alcohol. The oil left after evaporation of the ether was subjected to vacuum distillation. At 18 mm., distillation began at 162, and 87 D. R. P. 143197- 32 METHYI^TION OF PARA-AMINOPHENOI, was continued up to 175 (25 mm.). The product was a dark brown, viscous oil, which could not be solidified ; its amount was too small to warrant purification. The data from the distilla- tion furnish some basis for the belief that dimethyl-p-amino- phenol (b. p. 30 = 162) was present. A number of similar reductions of p-nitro-phenol and of p-nitrosophenol were carried out in presence of formaldehyde, but in no case could any secondary base be isolated after re- duction. This method seems to serve only for the formation of dimethylanilines from the corresponding nitro- or nitroso-com- pounds ; mono-methylation apparently does not occur. (g) Reduction by Sodium Hydro sulphite- No addition need be made to the remark on page 17. (c) Reduction of N-Methylene-p-aminophenol to N-Methyl-p- aminophenol by Zinc-dust and Acid- After a number of preliminary trials, evidence of methylation, by zinc-dust and dilute hydrochloric acid, was first obtained by isolation of a benzoyl-compound melting at 172- 177 (m. p. dibenzoyl-methyl-p-aminophenol = 174)- By a similar pro- cedure, using sulphuric acid, a nitrosamine melting at I33-I34 was obtained, identical with that from metol. It was found that reduction by zinc and acid could be effected either with or with- out isolation of the condensation- product HO.C 6 H 4 .N :CH 2 . The yields were always small, however, a fact at first attributed to the decomposition of the methylene-p-aminophenol by hydrolysis. Data to be given later will show that this hydrolysis is by no means so considerable as was thought. The conditions by variation of which the reduction might be expected to be influenced are rather numerous; experiment has shown, however, that the process is actually rather unresponsive to modifications in conditions. The opinion is held at present that the small extent of the methylation is due in large part to a side-reaction of the same kind as that which diminished to about 40 per cent the yields in Lob's and in Goecke's electrolytic reduc- tions referred to previously. There seems to be reason to be- 33 METHYI,ATION OF PARA-AMINOPHEJNOL lieve that this side-reaction is only the normal action of acid upon the formaldehyde condensation-product, as shown on page 8. Results of a number of experiments will now be tabulated, showing the influence of various conditions upon the reduction. It is to be emphasized that the yields set down in Tables III, IV, and V, neglect the recoverable p-aminophenol present after re- duction, and are calculated on the basis of total p-aminophenol taken initially and that finally obtained in the methylated form (as nitrosamine). These yields are therefore given too low by about 10 per cent. TABLE III. Experiments to determine (a) Relative values of several methods for precipitating condensation-product. (b) Necessity for isolation of condensation-product. P. A. P. gms. Preparation for reduction Temp, of reduc- tion. Nitros- amine gms. Yield Remarks "5 Condensed over-night. Ppted. by CO 2 ; dissolved in 40 ft H 2 SO 4 at 5. in ice 3-5 27 Precip- itation by CO, 10 Condensed 2 hrs. Pptd. by CO 2 ; dissolved in 40 $ H 2 SO4 at i. 5-8 2.a 21 10 Pptd. by CO 2 ; diss. 4056 H 2 SO 4 at-2. -2 to +8 2.2 21 12-5 Pptd. CH 3 COOH; diss. 50 H 2 SO 4 (ice) in ice 2.9 22 Pptation. CH 3 COOH IO Pptd. CH 3 COOH; diss. 40 H 2 SO 4 ,-2. -2 to +8 2.1 20 20 Pptd. NaHCO 3 (large lump); diss. in 40$ H 2 SO 4 at o. c-6 4-0 19 NaHC0 3 10 Not isolated; sol. added to equal vol. (190 cc.) 4o$H 3 SO 4 at 15. J5- 33 2.2 21 Not isolated; not cooled. IO Not isolated; sol. added to equal vol. (130 cc.) 40