THE FOUR OPTICALLY ISOMERIC L-MENTHYLAMINES. 65 IX. - The Four Optically Isomeric I-Menthylamines and their Xults. By FRANK TUTIN and FREDERIC STANLEY KIPPINQ. IN the course of the investigation of the isomeric salts derived from hydrindamine (Kipping, Trans., 1903, 83, 873) and methylhydrind- amine (Tattersall and Kipping, Trans,, 1903,83, 918), it seemed par- ticularly important to try and obtain corresponding isomerides from some optically active base of a totally different type, and among such bases which are moderately accessible, menthylamine seemed to be the most suitable. Two compounds, distinguished as I- and d-menthylamines, have been known for some time: E-menthylamine was obtained by reducing nitromenthene with zinc and sulphuric acid (Xoriya, Trans., 1881, 39, 77), and also by reducing the osime of I-menthone with sodium and alcohol (Andres and Andreef, Ber., 1S98, 25, 609) ; d-menthylamine mas prepared from the oxime of d-menthone (Andres and Andresf, Zoc.cit.), and was also obtdined, together with the I-base, by heating I-men. thone with ammonium formate (Witllach and Kuthe, Annulen, 1893, 276, 306); in the latter case, the two bases mere separated by fractionally crystalliaing their formyl derivatives, which are the original products of the reaction. These I- and d-bases, which are liquids, have been characterised by preparing from them a number of simple derivatives, and the specific rotations of many of the latter have been determined by Binz (Zeit. physikal. Chem., 1893, 12, 727). Our investigations shorn that the base produced by the reduction of the oxime of '' I-menthone " is a mixture of four optically isomeric menthylamines, in which, however, three of the bases are present in relatively very small quantities.The base obtained by the action of ammonium formate on I-menthone is likewise a mixture of these four optical isomerides, but apparently in proportions different from those in which they occur in the reduction product of the Z-oxirne. The explanation of these facts is t o be found in the origin and in the methods of formation of the basic mixtures. Leaving out of con- sideration the reduction of nitromenthene, the other methods for the preparation of the base start from menthone, a ketone which contains two asymmetric groups and which, in its turn, is produced by the oxidation of menthol with sulphuric acid and dichromate, The menthone obtained by carrying out this oxidation with dilute sulphuric acid and dichromate at 30" has a specific rotation [a], - 26" to - 28' and is called Gmenthone ; when, however, oxidation is accom- VOL.LXXXV. F66 TUTIN AND KIPPING: THE FOUR OPTICALLY plished with the aid of concentrated acid at 30°, the product has a specific rotation [a], + 2 6 O t o +2S0 and is called d-menthone, the ‘‘ inversion ” being due to the action of the concentrated acid (Beck- mann, AnnaZen, 1889, 250, 322). The application of the terms ZGWO- and dextro- to these two products and the observation that they have approximately equal but opposite specific rotations seem to have caused some confusion as to the relationship between these two ketones (compare Richter, Organ.Chern., 1898, p. 340; Vorlander, Ber., 1903, 36, 268), That they are not enantiomorphously related is indicated by the differences in physical properties and more especially by the values of the specific rotations of their oximes, both of which compounds are hvorotatory, having specific roiations of [ ~ ~ ] ~ - 4 0 * 7 ~ to -42.5O and -4.85’ to - 6.67’ respectively. That the conversion of “I-menthone ” into ‘r d-menthone ” by the action oE acids or of alcoholic solutions of alkalis is not an optical “ inversion ” but a partial racemisation is also rendered highly pro- bable, even if not proved, by the fact that the product, ‘‘ d-menthone,” is optically active. A consideration of the constitution of menthone leads t o the same conclusion : assuming that the oxidation of menthol with dilute acid and dichromate gives one product only, then of the two asymmetric groups in this ketone which may be represented by - -, one only would probably undergo change under the influence of acids or alkalis, namely, that which is capable of keto-enolic tautomerism ; the result would be a mixture, probablyof unequal quantities,of the - - and - + isomerides, the formation of which may be indicated as follows :- Prp Prp Prg PrP I I C CH( 4- ) I I /Y-) / \ /\ CH( - ) / \ \./ FH2 FH*OH $!HZ 70 -+ $!H2 ?*OH -+ YH, 70 CH2 CH, CH, CH, f- CH, CH, +- CH, CK, \ / CHMe(-) I-Menthol. I-Meathone. Enolic form. (d-Menthone or) I-isoMeuthone. The values of the specific rotations of the partially racemised ketonic mixture would depend, therefore, on those of its two components and on the proportions in which they are present, and since it is quite possible that partial racemisation occurs to some extent even in the oxidation with dilute sulphuric acid and dichromate, ordinary I-menthone ” itself may be a mixture of the two optical isomeridea.Whether ‘’ I-menthone ” is one definite compound or not, the oxime repared from it in the usual way in alkaline solution is doubtless a \ / CHMe( - ) \ / CHMe( - ) CHMo( - )TSOMERIC L-MENTHP LAlfINES AN.D THBlR SALTS. 67 mixture of the oximes derived respectively from the - - and - + ketones, and consequently, on reduction, since a third asymmetric group is produced, four optically isomeric menthylamines will be formed, as experiment shows, however, in very unequal quantities : these four isomerides would be the forms - - - and - + - derived from the - - ketone, and - - + and - + + derived from the - + ketone.Similar arguments hold good in the case of the formation of the base by heating menthone with ammonium formate ; although there is here no freealkali, the high temperature would, no doubt, tend to give in the first place a mixture of two menthones, from each of which two menthylamines would then be produced ; these four compounds would be identical respectively with those obtained from the oxime, provided that in both cases the asymmetric group containing the methyl radicle undergoes no change ; were this group also to undergo inversion, then obviously four additional isomerides ( + - - , + + - , + - + , + + + ) would be formed, and an optically inactive mixture of four externally compensated bases would be the final result.As we show later that all the four bases obtained in these reactions are optically active, it is prove6 that throughout all the changes involved in the production of menthylamine from menthol one of the asymmetric groups escapes racemisat ion. Nomenclature.-If we assign to I-menthone the configuration - - , then d-menthone would have the + + configuration, and the ketone obtained from I-menthone by the action of acids or of alkalis would have the - + configuration, and might be named I-isomenthone. The two menthylamines derived from I-menthone may then be distinguished as I-menthylamine ( - - - ) and Eneomenthylamine ( - + -)! respec- tively (compare Forster, Trans., 1898, 63, 391 ; Tattersall and Hipping, ibid., 1903, 83, 919), those derived from the isoketone being named I-isomenthylamine and I-isoneomenthylamine respec- tively.The four isomerides derived from the true d-menthone (+ +) and from d-isomenthone (+ - ) could then be distinguished in a similar manner. We have adopted this system in dealing with the four bases described in this paper, and as the choice of the configuration origin- ally assigned t o any one isomeride is, of course, purely arbitrary, we retain the name I-menthylamine for the base produced in the largest quantity by the reduction of the oxime of ‘‘ I-menthone ” and assign t o it the configuration - - -. One of the other three compounds undergoes partial racemisation, giving a base which is not I-menthylamine, and as the latter and the other two isomerides are stable; we infer t h a t this partial racemisation takes place in the group >CH*NH,, which is known to change very F 268 TUTIN AND KIPPING: THE FOUR OPTICALLY readily in some cases ; if this is so, the base which undergoes change and that into which it is partially transformed would have the con- figurations - - + and - + +, since the - -+ - compound would give Z-menthylamine. The two isomerides in question are therefore named the Eiso-bases, the unstable one being distinguished as Z-isoneo- menthylamine ; the remaining compound is called Z-neomenthylamine, Isomeric l-Benthylaminne d-13romocampizol.szlphoncctes.--Havin,a ob- tained an optically pure kmenthylamine in sufficient quantity and having satisfied ourselves that the base did not undergo partial racemisa- tion under the conditions of our experiments, we were able to study the question of the existence of isomeric salts ; it was thus proved that Z-menthy lamine gives with the bromo-acid, isomeric salts cor- responding with those obtained from hydrindamine and methyl- hydrindamine, but, as in some earlier cases, i t seemed impossible to obtain the compound of lower molecular rotation in a pure condition, that is t o say, free from its iaomeride.The separation of the four isomeric menthylamines already men- tioned was accomplished by fractionally crystallising the hydro- chlorides, d-bromocarnphorsulphonates, deamphorsulphonates, formyl and benzoyl derivatives in the manner indicated in the experimental part of this paper.Z-Menthylamine is isolated from the reduction product of menthone- oxime without much difficulty by either of the first two processes, but in order to separate the remaining mixture of isomerides none of the first four methods is sufficient, and it is necessary to convert the bases into their benzoyl derivatives, which are then submitted t o a prolonged and troublesome process of fractional crystallisation. The bases are regenerated by hydrolysing their benzoyl derivatives with dilute sulphuric acid, but, unfortunately, in this process one of the isomerides (Z-isoneomenthylamine) undergoes partial racemieation, giving the Z-iso-base, so that we have been unable to obtain it, except in the form of its benzoyl derivative.The following table shows the principal cornpunds which have been prepared : I- isoneo- &Base. Z-neo-Base. Z-iso-Case. Base. 31. p. [a],. M.p. [aln. M.p. [ a ] , . 111.1). [a]D. d-Bromocamphorsulphonate 226" 4- 43 -2" 70--75"('!) - 166" + 65" - _ d-Camphorsulphonate ...... 158 - 5.3 188 f11'8" 177 +21'7" - Benzoyl derivative ... ...... ... 156 - 61.9 128 - 17.4 121 ~r22.7 104" - 3.8" The specific rotations of the salts were determined in aqueous solu- tions, those of the benzopl derivatives in chloroform.ISOMERIC L-MENTHYLAMINES AND THEIR SALTS. 69 EXPERIMENTAL. Isokctio2z of 1-Menthylamine Hgclrochlode. The base obtained by the reduction of the oxime of '( I-menthone " with sodium and alcohol was distilled in steam, neutralised with hydrochloric acid, and the salt systematically cry stallised from water ; the most sparingly soluble portion consisted of coarse needles of I-menthylamine hydrochloride, the more readily soluble fractions, which were apparently mixtures, separated in more slender needles.The specific rotation of the pure salt and those of the two most readily soluble fractions were determined with the following result : * I-Menthylamine hydrochloride. Mixture of hydrochlorides. [a],. r a],. Solvent, chloroform - 45.4" 7 9 9 , - 45.6 1 i::: } different samples. ,, water ...... - 36.6 - 28.0 L 31 ID. [ 11 ID. 9 9 ,, ...... - 70.1 - 53.5 The value obtained in aqueous solution for the pure salt is rather higher than that obtained by Binz (Zoc.cit.), whose sample possibly Contained an isomeride, the existence of which in the original reduction product is indicated by the lower specific rotations of the more readily soluble fractions, 1-Me~ethylamirie d - B r o r } i o c a t i L ~ ? L o ~ s ~ Z ~ ~ ~ o ~ ~ t e , C,,H,,*NH,,C,,H,,O Br*SO, H. The base from the most sparingly soluble hydrochloride (see above) gives, with d-bromocamphorsulphonic acid, a salt which crystallises readily in well-defined prisms melting at about 225'. When crystal- lised two or three times, this substance appears to be homogeneous and its meltiDg point hardly changes appreciably, but, as will be shown later, i t really consists of a mixture OF salts, both, however, derived from pure Z-menthylamine. Z-Menthg lamine d-bromocamphorsulphonate is very sparingly soluble i n ethyl acetate, sparingly so in water ; it dissolves readily in alcohol or chloroform, but is practically insoluble in light petroleum. The specific rotation of H sample which had been crystallised fifteen times from dilute alcohol was determined: in chloroform, [.ID + 4 8 5 O ; in water, [a], +43*25", [M!= being 201.5'.* I n these and in all futiire o p t i d determinations, unless otherwise stated, 20 C.C. of solution contained 0.5 gram of the substance.70 TUTIN AND KIPPING: THE FOUR OPPICALLY Taking the molecular rotation of the brornocamphorsulphonic acid as [MID + 270, that of the base would be [M,I, - 685, a result which agrees closely with that deduced from the specific rotation of the hydrochloride. This compound, when prepared from the base contained in the pure d-bromocamphorsulphonate, crystallised in large needles melting at 158"; it was moderately soluble in water, readily so in alcohol, and very soluble in chloroform ; when deposited from aqueous solution, it contained water of crystal lisat ion.The specific rotation was determined with a sample of the dried salt : in chloroform, [a], +9*5" ; in water, [.ID - 5*3", [MI,, in the latter case being - 20.5". Taking the molecular rotation of the acid as [MI, +51", that of the basic ion would be [MI, - 71-5", which is somewhat higher than the values previously obtained. Benxoyl-l-MenthyZcLmine, C,oH1,NH*CO*C,H,. The benzoy 1 derivative, prepared from the pure bromocamphor- sulphonate by the Schotten-Baumann method, crystallised from alcohol in large needles melting a t 156" ; in chloroform, [a],, = 61.9'.The Existence of Isomeric Merzth&mi~t,es iw the Reduction Product o j ( L 1-MentAoneoxime." Fractional crystallisation oE the hydrochloride of the crude base, obtained by reducing I-menthoneoxirne, gave, as already stated, products diff9ring in specific rotation ; the d-bromocamphorsulphonate, prepared from all the more readily soluble fractions of the hydrochloride, or from the original basic reduction product', proved t o be a mixture, from which, by repeated crystallisation from dilute alcohol, we isolated ( a ) a salt melting at 225', identical with pure Z-menthylamine d-bromo- camphorsulphonate ; (6) a salt melting very indefinitely a t 170-1'763, which was obviously a mixture, and the further treatment of which is described later.The salt melting at 225' formed by far the greater proportion of the whole product, even when the d-bromocamphorsulphonate was prepared from the more readily soluble portions of the fractionated hydro- chloride.ISOMERIC L-MENTHYLAMINES AND THEIR SALTS. 71 The For mat ion of Isomeric 1- Memt h ylarnine d -B?.onaoca~nZphors2Clpho1aCGte0. A considerable quantity of 1-menthylamine d-bromocamphorsulphon- ate was prepared partly by the fractional crystallisation from dilute alcohol of the salt obtained from the pure hydrochloride, and partly in a similar manner from the crude d-bromocamphorsulphonate ; when, judging by the melting point and crystallino form, it seemed that we had obtained a definite compound, the whole of the pnre material was separated into six fractions, and the first and last were examined polarimetrically in chloroform solution ; the first fraction gave [a]= + 48*5*, whilst the last fraction had [a]TJ +48.0°.As these two extreme fractions had practically the same specific rotation and melted simultaneously at 224--225+5O, it seemed that the salt was homogeneous ; nevertheless, we rejected the last fraction and its mother liquors. The remaining salt was then decomposed with barium hydroxide, regenerated from its component acid and base in the usual way (compare Trans., 1903, 83, 906), and the product systematically crystallised from dilute alcohol ; after thus obtaining nine fractions, each of which had been crystallised several times, and all OF which seemed identical, the melting points and optical properties of tho first and last fractions were determined. In water./-J-, In chloroform, M. p. r a I". [ M I D . [ a In, First. , . . . , 2 26' + 43.75O 203.8' 48-75' Last ...... 221 + 38% 180-8 42-8 These experiments afforded almost conclusive evidence of the exis- tencq of isomeric salts, but in order to establish this fact beyond all question the first fraction only was decomposed and regenerated from its components ; the salt thus obtained, when repeatedly crystallised from aqueous alcohol, gave extreme fractions having the same melting points as before (226' and 221'), and the specific rotation [.ID of the last fraction was found to be + 39.5O in water and + 43.1' in chloro- form, these results agreeing closely with those previously obtained.The last fractions (m. p. 221°) from the two preparations were added together and the mixture crystallised six times from dilute alcohol ; the first fraction then melted moderately sharply a t 222O, and its specific rotation in chloroform was [a], + 44.4'. In these results we have a complete analogy between the case of 2-menthylamine and that of d-hydrindamine (Zoc. cit.) or I-methyl - hydrindamine (Zoc. cit.) ; in spite of its apparent purity, the salt melting at about 221' is undoubtedly a mixture and contains a considerable quantity of the isomeride melting a t 226O, although it does not seem72 TUTIN AND KIPPING: THE FOUR OPTICALLY probable that a complete separation of the two components could be accomplished even by further crystallisation of very large quantities of material.Attempts to Isolate other Isomeric MenthgZamines. The salt melting indefinitely a t 170-176", which is obtained on crystallising from dilute alcohol the d-bromocamphorsulphonate of the base prepared by the reduction of '' I-menthoneoxime," forms tufts of short, slender needles and has a specific rotation of [.ID + 50" (ap- proximately) corresponding with a molecular rotation of [MID + 233' in aqueous solution. This substance had the characteristics of a mixture, and all attempts to isolate a pure compound by crystallisation from dilute alcohol were unavailing. As the salt of Z-menthylamine with Reychler's d-camphorsulphonic acid was found to crystallise very readily from water, a separation of the bases in this crude d-bromocamphorsulphonate was attempted with the aid of this .acid.We therefore liberated the basic mixture and prepared the d-camphorsulphonate, which crystnllised from water in needles ; after several crystallisations, the most sparingly soluble frac- tion, when dried in the air, melted a t 144-147", but when dried at looo for several hours it melted a t 164-165", this difference indicat- ing water of crystallisation. As this fraction of the salt appeared to be pure, its specific rotation in water was determined with the follow- ing result : [.ID + 5*8', [ MI, + 22-4". The molecular rotation of the base in this salt would therefore be [MID - 2 9 O , that of the acid being As we expected that the base would be "d-menthylamine," it appeared probable that this salt, in spite of its having been repeatedly crystallised, was redly a mixture containing a considerable proportion of the salt of the I-base ; it was therefore converted again into the d-bromocamphorsulphonate. On crystallising this salt from ethyl acetate containing a little chloroform, a further quantity of I-mecthyl- amine d-bromocamphorsulphonate, melting a t 225', was separated.The residue then crystallised from aqueous alcohol in very slender, bulky needles melting a t 164--167O, but after many further crystal- lisations it melted sharply and constantly at 170°, and appeared to be homogeneous. A sample thus prepared, when examined polarimetric- ally, gave [ a ] D + 63.5' in aqueous solution, whence [MI, + 295.9' ; this value indicating the presence of a dextrorotatory base having the molecular rotation [MID + 26O, whereas the value for '' d-mentbyl- amine," calculated from that of the hydrochloride examined by Binz, Not feeling satisfied that this salt was derived from pure " d-menthyl- arnine," and the qiiantity being too small for further crystallisation, we [MID +51*O0.is [MID 4-33'.ISOMERIC L-MERTHYLAMINES AND TEEIR SALTS. 7 3 prepared some base by heating Lmenthone with ammonium formate, and hydrolysed the crude mixture of formjl derivatives directly with hydrochloric acid. The base thus obt,ained was converted into the d-bromocamphor- sulphonate, and this salt, although showing a great tendency to separate as an oil from its solution in dilute alcohol, was finally obtained in tufts of fine needles, which, after recrystallisation, melted a t 168*, the melting point not being raised by further crystal- lisation.The specific rotation of this salt was determined with the following result : in chloroform, [.ID t-54.5'; in water, [a]= -t63.9', [MID being 297.7'. As the specific rotation of the salt melting a t 170' obtained from the products of the reduction of the oxime wits [ a ] D + 63.5' in aqueous solution, it seemed as if this substance was a pure salt of a d-base, but when a sample was converted into the hydyochloride, which crystal- lised from water in needles melting a t 230-232", and a fraction of this product was examined in aqueous 8olutior1, it was found to be optically inactive, whilst another fraction gave [ a]D + 6.8' in aqueous solution, and a third was laxorotatory.A solution of the base in dilute alcohol prepared from a portion of the inactive hydrochloride was also examined and found to be inactive. Isohtion of Pour Benxo?llmenthyEarrzines. The base in the d-bromocamphorsulphonate melting a t 170" is there- fore a mixture, even after the exhaustive purification which it has undergone; this was proved in the following manner: the benzoyl derivative was prepared by the Schotten-Baumann method from both the samples of d-bromocamphorsulphonates melting a t 1 68-170" and having specific rotations of 63.5" and 63.9' respectively. When crystallised from alcohol, both preparations were found to be mixtures, and as the result of a prolonged and very troublesome process of frac- tional crystallibation four benzoyl derivatives were ultimately isolated in a pure condition.(I) The most sparingly-soluble fraction, which cryetallised i u long needles, melted a t 156O, had- [a], - 61.9" in chloroform solution, and was identical with the benzoyl derivative of Lmenthylamine. (2) A compound which crystallised in long, glistening leaf-like plates, melted at 128', and had [&Ir, - 17.4' in chloroform solution. (3) A compound which crystallised in thick tufts of short, fine needles, mdted a t 104O, and had [ a ] D - 3.8' in chloroform solution. As this derivative was the most fusible isomeride and might there- fore have been a mixture, it was recrystallised three times from74 TUTIN AND KTPPING: THE FOUR OPTICALLY alcohol, and the specific rotation again determined in chloroform solution, was [a], - 3-9O, indicating that the substance is pure.(4) The most readily soluble fractions gave a benzoyl derivative which crystallised in very long, slender needles, melted at 121’, and had [ ulD + 22.7’ in chloroform solution. During the fractional crystallisation of the benzoyl derivatives, it was observed that when the original solutions were allowed to evaporate spontaneously, short, thick prisms mere obtained, together with needles ; when, however, these apparently homogeneous prisms were recrystal- lised, they gave needles and the glistening plates of the benzoyl derivative melting at 128’. The proportions of these four benzoyl derivatives actually isolated from the crude mixture were approxi- mately equal, but the compound melting a t 104’ was perhaps obtained in rather the largest quantity.The various mother liquors contained a very considerable fraction of the total material. At tempts to sepamte the Isorne r ic For rny Zm en ti& y lamin es. Having proved that the basic product of tbe reduction of “I-men- thoneoxime,” as well as that obtained by heating “I-menthone ” with ammonium formate, is a mixture of a t least four menthylamines, not easily separated through the agency of their benzoyl derivatives, and, moreover, having found that these benzoyl derivatives are hydrolysed only with great difficulty, i t seemed desirable to try and isolate the four arnines in the form of their formyl derivatives, especially as the latter were known to undergo hydrolysis with moderate ease, and could there- fore serve for the preparation of the bases themselves with less chance of partial racemisation. A considerable quantity of formylmenthylnmine was therefore prepared, and, instead of hydrolysing directly, the crude product was crystallised first from ether and then from ethyl acetate, from which it finally separated in well-defined, four-sided prisms melting at 112-113’.The melting point of this, the principal cryst,alline product, was constant, but the mother liquors deposited a small quantity of crystals melting at 117”; when these two prepara- tions were mixed together, the mixture melted at 115’. The two specimens were, therefore, not different substances, but the more sparingly soluble fractions (a. p. 112-113”) probably contained a small quantity of another formyl derivative not easily removed by cry st allisatio n.1 -isoLWenthyZamine. The solid formyl derivative (m. p. 112-113O) WHS then hydrolysed with strong hydrochloric acid ; the hydrochloride thus obtained, after crystallisation from water, melted at 186-187’. The base in this saltISOMERIC L-MENTHYLAMINES AND THEIR SALTS. 75 was then combined with d-bromocamphorsulphonic acid, and the com- pound thus obtained cry stallised from dilute alcohol in well-defined needles melting a t 1 6 6 O . The specific rotation of this salt was deter- mined in aqueous solution and found to be [a],+65", whence [MID + 303' ; this gives a molecular rotation of the base [MI, + 33", a value which is identical with that calculated from the molecular rotation of the '' d-menthylamine " hydrochloride described by Binz The base from this most sparingly soluble fraction of the d-bromo- camphorsulphonate gave a pure benzoyl derivative melting at 1 21°, but the most soluble portions of the d-bromocamphorsulphonate seemed impure, and when the base contained in them was cmverted into the benzoyl derivative, the latter on fractional cry stallisation gave, in addition t o the compound melting a t 12l0, a small quantity of the benzoyl derivative melting at 128'.The formyl derivative melting a t 112-113" is, therefore, impure in spite of repeated frac- tional crystallisation, and apparently the best way of obtaining a pure base is t o hydrolyse the formyl derivative and crystallise R salt pre- pared from the basic mixture.The salt of this base, I-isomenthyl- amine, with Reychler's d-camphorsulphonic acid, was prepared for the purpose of comparison with the d-camphorsulphonate of the base obtained on hydrolysing the benzoyl derivative melting at 1 2 8 O (p. 77). It was moderately soluble in water, cry stallising in needles which, when dried at loo", melted at 177". The specific rotation of this salt in aqueous solution was determined'and found to be [a], + 21*7', whence [MI, +83.9", so that the calculated value for the base is (ZOC. cit.). [MIL, + 33'. Furthe?' Examination of Formyl Derivatives. The ethereal mother liquors from the crystitllisation of the formyl derivative were evaporated, and the brown, syrupy residue distilled under 12 mm. pressure. After some unchanged menthone had passed over, about two-thirds of the remaining liquid distilled 2 t 208--215', giving an almost colourless, highly refractive, viscous liquid, to which a small quantity of ethyl acetate was added, when a larger quantity of the formyl derivative, melting at 112-113", was obtained than that which crystallised from the ethereal solution of the original substance. This product, when separated from a n uncrystallisable residue, was hydrolysed with strong hydrochloric acid and the base converted into the d-bromocamphorsulphonate. This salt, which appeared highly impure, and only crystallised partially when kept for some time in a vacuum, was therefore converted into the benzoyl derivative, the latter being fractionally crystallised from alcohol,76 TUTIN AND KIPPING: THE FOUR OPTICALLY Probably about 75 per cent.of this product consisted of the deriva- tive melting a t 12S0, this being identical with that obtained in small quantity from the formyl derivative melting a t 112-113°, but some of the benzoyl derivative melting a t 121O was also isolated, together with a small quantity of the isomeride melting a t 156". The distillation was stopped when the temperature reached 238' ; the residue in the flask was hydrolysed and converted into the benzoyl derivative, which, on fractional crystallisation from alcohol, was found to consist chiefly of the derivative melting a t 1 5 6 O , and a smaller amount of the derivative melting at 104O, although the proportion of the latter was not nearly so large as that obtained before in the fractional crystallisation of the benzoyl derivatives from the crude mixture of formyl derivatives ; this fact, and further evidence obtained later, seemed to show that the formyl derivative corresponding with this benzop 1 derivative had partially racemised on distillation.I n all the experiments in which the bases obtained from the formgl derivatives were separated by means of their benzoyl compounds, the proportion of the benzoyl derivative melting a t 156' was always less than that of the isomerides melting at 128' and 1 2 1 O . Hydrolysis of the Benxoyl Derivatives. The preceding experiments show that it is practically impossible, or at least very difficult, to separate the four formyl derivatives present in the original mixture ; the compound melting a t 112--113O, which is the only crystalline substance obtained in any quantity, serves for the preparation of one base only, namely, I-isomenthy lamine. We were therefore obliged to make use of the benzoyl derivatives for the preparation of the two remaining bases, and as i t was necessary t o prove that the bases did not racemise during hydroly,' ris, we recon- verted them either into the benzoyl derivative or into some salt which had bean previously shown to be homogeneous.The benzoylmenthylamines do not hydrolyse appreciably when boiled for many hours with strong hydrochloric acid, and when dilute sulphuric acid (1 : 1) is used, the only basic product obtained is a small quantity of ammonia. A sample of the benzoyl derivative of I-menthylamine was heated for 6-8 hours in a sealed tube at 149-160O with strong hydro- chloric acid and a small quantity of glacial acetic acid; at the end of this time, the benzoyl derivative was completely decomposed into benzoic acid and a quantity of tarry matter mixed with menthene and menthylamine.The base was combined with d-bromocamphor- sulphonic acid, and as the salt thus obtained melted a t 824' after recrystalliPation, the base seemed not to have racemised.ISOMEHIC L-MENTHYLAMINES AND THEIR SALTS. 77 Some of the pure benzoyl-derivative of Lisomenthylamine (m. p. 1'21') was hydrolysed in a similar manner, and the base again converted into the benzoyl derivative, which still melted a t 12l0, thus indicating that racemisation had not taken place to any appreciable extent.1- Neomenthylcbmine. As the benzoyl derivative melting at 128' appeared to be derived from a base which had not hitherto been isolated, it was analysed to prove that it really was a menthylamine derivative. Found, C = 78.80 ; H = 9.67. C17H,,0N requires C = 78.76 ; H = 9.65 per cent. This benzoyl derivative was then hydrolysed in the manner already described, but the base, which was isolated by distillation in steam, was obtained in very poor yield. The d-bromocamphor- sulphonate prepared from the distillate was dissolved in dilute alcohol and the solvent allowed to evaporate, but the salt separated as an oil, although, when slowly evaporated in a vacuum desiccator, the solution deposited nodular masses, which, when dried a t the ordinary temperature, melted a t 70-75'.Since this salt could not be ob- tained in well-defined crystals from the ordinary solvents, it was decomposed with caustic potash, and the base, when distilled in steam and combined with Reychler's d-camphorsulphonic acid, yielded a salt crystallising from the concentrated aqueous solution in Well-defined needles, which, after recrystallisation, melted constantly at 188' This salt had the appearance of a pure substance, and as it was less fusible than the d-camphorsulphonates of either of the other two bases we concluded that racemisation had not taken place to any appreciable extent. I-Neomenthylamine d-camphorsulphonate is moderately soluble in water, alcohol, or ethyl acetate, and dissolves very readily in chloro- form; it crystallises from water in a hydrated state. The specific rotation of this salt in aqueous solution was determined and found to be [a]. + 11*8', whence [MI, + 45.7'. This gives [MI, - 6" (approx- imately) for the molecular rot-ttion of the base, the constant for the acid being [MID + 5 1 -0". I-isoKeomenthylamine. The benzoyl derivative of I-isoneomenthylamine, melting a t 104", was hydrolysed in a similar manner, and the d-bromocamphor- sulphonate of the base dissolved in dilute alcohol ; the salt crystallised in fine needles, but had the characteristics of a mixture, arid after three recrystallisations melted a t about 169" ; from the mother liquors,78 HAGA : PEROXYLAMINESULPHONATES AND tufts of needles were obtained, which, after recry stallisation, appeared less impure than the more sparingly soluble fraction and melted at about 157'O. The base contained in this apparently impure d-bromocamphm- sulphonate was again benzoylated ; the product, after fractiona crystallisation from alcohol, consisted principally of the original benzoyl derivative melting at 1 0 4 O , but a certain amount of benzoyl Eisomenthylamine (m. p. 121') was contained in the more readily soluble fractions. It therefore appeared highly probable that Lisoneo- menthylamine had undergone change to a certain extent, and this evidence confirms that obtained previously in examining the distilla tion products of the formyl derivatives, but with the quantity of material at our disposal we were unable to obtain salts of the base free from its closely related isomeride. The authors desire to record their thanks to the Government Grant Committee of the Royal Society for financial assistance in carrying out this work. UNIVERSITY COLLEGE, NOTTINGE AM.