EXPERIMENTS ON THE SYNTHESIS OF THE TERPENEY. 21%CCXXI~I.-Expei.i~ne.nts O I L the Sy.lzthesis o f the Twpenes.Part XIV. synthesis of d- am! 1- A 5 - m - ~ e ~ ~ t h e n o l ( 8 ) ,cll-A4-nl-Ment~~eiLo1(8) and their Derivatives.By WILLIAM HENIUY PZRKIN, jun-OF the six possible menthenols of t.he meta-series,* the followingfour have, so far, been synthesised :CMe CHMe/\ /\y*2 yH p 2 p\/ \/CH2 CH,CH, CH*C Me2*OH CH2 C*Cble2*OH(A2. 1 Al-( Dihydrocarvestrenol)(Trans., 1907, 91, 498.) (Trans., 1905, 87, 1101.)CHMe CMe(A3) (Trans., 1905, 87, 1099 ;coinpare this vol., p. 1029.)A6-( Dihydroisocarvestren 01).(Trans., 1908, 93, 1887.)The present communication containsof the remaining two, namely:CHMe/\ p F"2CH CH*CMe,*OH andOf the former, the d- and Z- andan account of the synthesisCHMe/\QH2 7%CH CH*CMen*OH.\/ YCH(A4.)dl-modifications have beenprepared, whereas of the latter only the dl-modification wasobtained, and that in very small quantity.A short time since (Trans., 1909, 95, lSS9), Meldrum and Perkinshowed that 5-hydroxy-m-toluic acid is reduced by sodium andisoamyl alcohol to l-methylcycZohexan-5-ol-3-carboxylic acid + :C0,HCHMe<CH2*CH(Co2H)Me/,-> -+ CH2--CH(OH)>cH29OHCOnH* Menthenols of the type of terpineol are here referred to.t In the paper referred to, this acid was called " l-methyIcycZohexan-3-01-5-carboxylic acid," but the alternativd ntiiiibering is more suitable2130 PERKIN : EXPERTMENTS ON THEand, in the present communication, it is shown that this reductionmay also be effected in alcoholic solution, provided that the alcoholhas been completely dehydrated by distillation over calcium.When 1-methylcyclohexan-5-01-3-carboxylic acid is treated withhydrobromic acid, it is readily converted into 5-bromcll-methyl-c~~Zohexane-3-carhoxylic acid, and the ester of this acid, whendigested with diethylaniline, yields a mixture of the esters of theacids :1 -Met hyl-A5-cyclohexene- 3 -carboxylic acid.1 -Methyl - A4-cyclohexene - 3 -carboxylic acid.and these acids, of which the former is produced in by far thelarger quantity," were separated by the fractional crystallisationof their calcium salts.The constitution of the former of theseacids (A5) was demonstrated by the examination of the products ofthe oxidation of h~--m-menthenol(8) obtained from its ester by theaction of magnesium methyl iodide (p.2132). The constitution ofthe other acid (A*) was proved by the fact that, when boiled withconcentrated aqueous potassium hydroxide, it is converted into1-methyl-A3-cycZohexene-3-carboxylic acid :the fly-unsaturated acid becoming a/3- in the usual manner.Ethyl dl-1-methyl-AS-cyclohexene-3-carboxylate reacts readily withmagnesium methyl iodide with the formation of dld6-m-mert-thenoZ(8) (b. p. 115-117°/30 mm.), and this, when boiled withaqueous oxalic acid, yields &-A5 :8(9)-m-menthadiene (b. p.175-176') :CH,*CH(CMe2*OH )CHMe<CH (;cH>CH, andCHMe<CH2*CH(CMe:CH ) CH (-l&>CH2.Under similar conditions, ethyl dZ-1-methyl-A%ycZohexenecarb-oxylate yields A4-mmenthenol(8) (b. p.115-117°/30 mm.) andA4:8(g)-mmenthadiene (b. p. 175-177O) :* It has often been observed, in cases where two isomeric unsaturated acids areformed by the elimination of hydrogen bromide from a bronio-acid, that veryslight changes in the conditions of experiment often effect in a remarkable mannerthe proportions of the isomerides produced. Two experiments were made on theelimination of hydrogen bromide from ethyl 5-bromo-1-me thylcyclohexane-3-carboxylate by means of diethylaniline. In the one the yield of l-methyl-a4-cyclo-hexene-3-carboxylic acid obtained on hydrolysis was 5 per cent., in the other,apparently under tho same couditions, the yield was less than 1 per centSYNTHESIS OF THE TERPENES.PART X1V. 2131CH,*CH( C0,Et) cH>CH yieldsCHMe<CH2---Besolution of dl-l-MetTlyl-h~-cyclohexene-3-carbo~lic A cia? andPreparation of the d- and LModifications of A6-m-Mentheno1(8).As the amount of pure dZ-l-~ethyl-A5-cycZohexene-3-carboxylicacid which had accumulated during these experiments amountedto more than 160 grams, it was thought that it would be interestingto attempt its resolution, and then to convert the active acids intothe corresponding menthenols and menthadienes. This wasultimately accomplished with the aid of either Z-menthylamine orquinine, the salt produced in b0t.h cases being the salt of the dextro-acid.The 1-ment.hylamine salt, after repeated recrystallisation, had[a],, -1.7O, and from this salt the acid was regenerated and con-verted into its ester and the corresponding menthenol and terpeneby processes already described in the case of the dl-acid. Theobserved rotations of these substances may be conveniently tabulatedthus :rain.cl-l-Methyl-A5-cycZohexene-3-carboxylic acid .........-I- 33.1"Ethyl d-1-methylcycZohexenecarboxglate ............... + 30.5&A5 8(9)-m-Menthadiene ................................... + 29'6d-A5-m-Nenthenol(8) ...................................... + 36 7After the d-acid had been removed, as far as practicable, bytreatment with Z-menthylamine and quinine, the Z-l-methyl-A5-c~clohexene-3-carboxylic acid, contained in the mother liquor ofthese salts, was nearly pure, since its rotation was [a], -30*9O, ascompared with the rotation [a], + 33'1O of the correspondingd-acid.From this Z-acid the same derivatives were prepared as in thecase of the d-acid, and these and their rotations may again betabulated :ta3D.E-l-Methyl-A5-cyc~ohexene-3-carboxylic acid .........- 30.9"Ethyl E-l-methylcycclohexenecarboxylate ............... - 27 -4Z-As--?)a-Menthenol( 8) ...................................... - 32-6Z-A5:8(9).-m,-~enthadiene .................................... - 25.3The constitutions assigned to these active menthenola andmenthadienes, and indirectly therefore those of the correspondin21 32 PERKIN: EXPERIMENTS ON THEinactive substances and also that of l-methyl-A5-cyc2ohexene-3-carboxylic acid, were proved in the following manner.Pure d-A5-m-menthenol(8) was oxidised with permanganate andthen with dichromate under the conditions described on p.2143,and the resulting acid converted into the ethyl ester, which waspurified by fractional distillation under diminished pressure. Theester, C;2H2004, thus obtained distilled at 188-190°/20 mm., andhad [a]= -18*7*.When this ester was hydrolysed, it yielded a mixture of twoisomeric lactonic acids, CI0Hl6O4, which melt at 102O and 136Orespectively, and are obviously the cis- and trans-lactones ofa-methyl-y-hydroxyisoprop yladipic acid :C02H*CHMe*C?H2-CH(CMe2*OH)*CH,*C0,H.The formation of this acid by the oxidation of A5-m-menthenol(8)may be expressed in the following manner:CHMe CHMe/ \\ /CH2C0,H FH2/\\/CH,RH FH,CH CH*CMe,*OH ---+ CO,H CH*CMe,*OHand its easy conversion into the lactone:CHMe/ \C0,H FH2CHGMe,/ >oCH2--GOproves that the menthenol from which it is derived must have thedouble linking in the A5-position, since the dibasic acid which mightresult from the oxidation of the menthenol of the other alternativeconstitution (A4) :CHMe CHMewould hardly be expected to pass into a lactone.The oxidation of d-A5-m-menthenol(8) is very similar to thatof ordinary terpineol, which, with chromic acid, yields methoethyl-heptanonolide (I), and then, with hypobromite, homoterpenylic aciSYNTHESIS OF THE TERPENES. PART Xlv.2133(11) (Wallach, Ber., 1895, 28, 1773; Tiemann and Semmler, ibid.,2141) :CMe COMe C0,H>o $ H-CMe,CH,-CO\$!H*CMe 2>0 CH2-CO(1.1 (11.)A similar series of oxidations carried out with Z-A5-m-menthenol(S)gave again the ester, C12H2004, of the mixed lactonic acids.Thishad [aID +17*4O, and yielded, on hydrolysis, the cis- and trans-lactones of melting points 1 0 2 O and 1 3 6 O , which had been obtainedfrom the &modification. Moreover, it is curious that, whilst theester, C12H2004, was, in both cases, optically active, the lactonesobtained on hydrolysis, although they still contain two asymmetriccarbon atoms, should prove to be inactive.These oxidation experiments show conclusively not onlythat the two active series tabulated on p. 2131 represent d- andI-modifications of the same substances, but also that these sub-stances have t,he constitutions which have been assigned to them.In connexion with this series of researches on the synthesis ofthe terpenes, there is one point of importance which should be madequite clear.When a menthenol is synthesised from the ester ofthe corresponding acid by the action of magnesium methyl iodide,for example :CMe,*OH C0,Etthe menthenol which is obtained is quite pure and homogeneous.When, however, water is eliminated from such a, menthenol, theresulting menthadiene is probably, as a rule, not a homogeneoussubstance, but may consist of a mixture, in varying proportions,of the isomerides:CMe:CH, CMe,Me/-\ and\=/ \=/and possibly, owing to intramolecirlar change, the third isomerideof the type:may also be present.It is well known, especially from th2134 PERKIN : EXPERIMENTS ON THEresearches of Wallach, that ordinary terpineol, on treatment withdehydrating agents, yields not only dipentene, but also terpinoleneand a-terpinene :Terpineol. Dipentene.Terpinnlene. a -Te r pin en e ,The conversion of terpineol into terpinolene appears to takeplace most readily when dilute acids are used as the dehydratingagent. Thus, Baeyer (Bey., 1894, 27, 447) recommends 30 percent. oxalic acid as the best reagent for converting terpineol intoterpinolene.I n the present communication it is stated that the reagent whichwas found most suitable for the elimination of water from A*- andAbn-menthenol(8) was 6 per cent. oxalic acid, and it seems thereforevery probable that the products obtained in each case may bemixtures of a t least two menthadienes:A4-?a-Menthenol(8).A4:8(9)-m,. A4:3(8).1)72-,CMe,*OH CMe:CH, CMe,aIe/2\a5-m-Menthenol(8). A5: 8(9).pn.. A5 : 3(8)-m-.\=/Me/-\ \=/ Me/-\ \=/It would be difficult to separate and identify such isomericproducts of the elimination of water even if large quantities ofthe menthenols were available, and, in the present case, where thepreparation of even small quantities of material is very laborious,this problem cannot, in the meantime, be solved. It has thereforebeen decided to retain for the present t'he names A4:8(9)- andAS :g(Q)-m-menthadiene for the hydrocarbons, and the determinationaf the exact nature of these products of dehydration must be leftuntil a better method for their preparation has been discovered.When larger quantities of material are available, an effort willalso be made accurately to determine the physical constants of allthe substances mentioned in this paper.The probability that substances of the terpinolene type arefrequently produced during the elimination of water from thementhenols according to the process :>CH*CMe,*OH -+ >C:CMe,suggests an explanation for some of the remarkable results whicSYNTHESIS OF THE TERPENES.PART XIV. 2135have been obtained, more particularly during the course of theinvestigation of optically active menthenols and menthadienes. Inthe first place, it is important to note that the above process cannottake place when the >CMe,*OH group is attached t o a doublylinked carbon atom, as in :>C-CMe,*OH. Apart from fund*mental intramolecular change, which both chemical properties andphysical measurements show t o be most improbable, menthenolscontaining this grouping can only yield conjugated menthadienescontaining the grouping >C*CMe:CH,, and there can be littledoubt that the several synthetical menthadienes of this type whichhave already been described (compare this vol., p.2154) are pureindividuals.Some time since, Kay and Perkin (Trans., 1906, 89,840) resolveddl-1-methyl-A3-cycZohexene-4-carboxylic acid :into its active constituents, and prepared from the d- and 2-acids,05 and I-pmenthenol(8) and d- and LA3 :8(g)-pmenthadiene :in the usual manner.Taking the d-series as the example, theopticd activity of these substances may be conveniently tabulated :1.b.d-l-Methyl-Aa-cycZohexene-4-carboxylic acid ......... -I- 101 *loEthyl d-1-methylcycZohexenecarboxglate ............ -i- 86.5d-A3-p-Menthonol(8) ...................................... +67*0d-~~:~@)-p-Methadiene .................................... + 98.2It will be observed that, in this case, the menthadiene has a muchhigher rotation than the menthenol from which it is produced bythe elimination of water. Subsequently Fisher and Perkin (Trans.,1908, 93, 1872) resolved dZ-l-methyl-A1-cycZohexene-4-carboxylicacid :and prepared from the active acids, the menthenols (terpineols) andmenthadienes (limonenes) :in the same way.values were observed as the rotations of these substances :Taking, t19 the example, the &series, the following[.ID* Z-l-Methyl-~1-cycZohexene-4-carboxylic acid ..,...:..Ethyl I-methylcyclohexenecarboxylate .................. - 5 2I-A'-p-Menthenol(8) ...................................... - 46'6E-A1:8(D)-p-Menthadiene .................................... - 5'0- 582136 PERKIN : EXPERIMENTS ON THEIt is clear that the relationship between the values for thedifferent substances given in this table are very similar to thoseshown in the preceding table, with the exception of the strikingdifferences in the rotations of the menthadienes. It is well knownthat the active limonenes are somewhat easily racemised withformation of dipentene, and for this reason we were careful toconduct the elimination of water at the ordinary temperature withthe aid of magnesium methyl iodide, and we were surprised to findthat, instead of obtaining a hydrocarbon of higher rotation thanthe menthenol (terpineol) (Llimonene has [a], - 120°), the rotationhad decreased to -5O.No doubt this result was partly due toracemisation, because we were able to show that the substancecontained considerable quantities of dipentene." But it is veryprobable that the low rotation is also due to the hydrocarboncontaining considerable quantities of terpinolene :which is of necessity inactive.shown that, when &A5-m-menthenol(8) ([a]D + 36'7O) :I n the present communication it isis digested with 6 per cent.oxalic acid, the resulting d-A5:8(9)-rn-menthadiene ([a],, + 29.6O) :has a, lower rotation than the menthenol instead of a higher one,as might have been expected from the experiments of Kay andPerkin just referred to. This would seem t o indicate thatthis terpene may contain A5:3(8)-m-rnenthadiene :and the rather high numbers obtained for the refractive power as theresult of preliminary physical measurements seem to support thisview. I f this is the case, one of the asymmetrical carbon atoms ofthe menthenol will have disappeared during the formation of thissubstance by the elimination of water, and this may be theexplanation of the drop in the rotation.* As the presence of dipentene was only proved qualitatively, the statement (Zoc.cit., p.1873: that the hydrocarbon of [u],-5" consisted essentially of dipenteneahould not have been made, and is probably incorrectSYNTHESIS OF THE TERPENES. PART XIV. 2137EXPERIMENTAL.Preparation of I-Methyl-h5-cyclohexene-3-carboxylic A cid andl-Met 12. yl-b4-cycloh exene-Scar6 oxylic A cid.I n the first experiments (Trans., 1909, 95, 1897), the reductionof 5-hydroxy-m-toluic acid was carried out in isoamyl-alcoholicsolution with sodium, but it was subsequently found that the acidis also reduced, although with some difficulty, when its solution inabsolute alcohol* is treated with sodium. The pure acid, inquantities of 50 grams, dissolved in alcohol (1250 grams) wasreduced by the rapid addition of sodium (180 grams) substantiallyin the manner described in detail in the case of the reduction of4-hydroxy-o-toluic acid (Trans., 1909, 95, 1876).After extractingin the usual way, the acid was reduced it second time under thesame conditions, and in all about 1 kilogram of the hydroxy-acidwas worked up, and yielded about 840 grams of reduction product.This acid (which consists for the most part of trans-l-methylcyclo-hexan-5-ol-3-carboxylic acid, compare Zoc. cit., p. l89l), in quantitiesof 50 grams, was mixed with three volumes of fuming hydrobromicacid (sat%urated at Oo), and, after remaining for two days a t theordinary temperature, the liquid was heated on the water-bath fortwo hours, when it separated into two layers. The product wasmixed with water, extracted twice with ether, and, after drying andevaporating, the crude bromo-acid was digested with alcohol (200c.c.) and sulphuric acid (20 c.c.) for four hours on the water-bath,and then left for twenty-four hours.On adding water, the heavybromo-ester was precipitated, and was extracted with ether, theethereal solution was thoroughly washed with water and dilutesodium carbonate, carefully dried, evaporated, and the crudc esterheated to boiling with three volumes of diethylaniline for eighthours. Excess of dilute hydrochloric acid was then added, theunsaturated ester extracted with ether, the ethereal solution washedfirst with dilute hydrochloric acid, and then with sodium carbonate,and distilled in steam.tThe volatile ester was extracted with ether, dried, and distilled,when almost the whole quantity passed over a t 140-150°/100 mm.,and weighed 710 grams.I n order to avoid any possibility of intr%molecular change (compare,p. 2146), the hydrolysis of this ester was* Distillcd over calcium, see footnote, Trans., 1909, 95, 1876.t When all the unsaturated ester had passed over, a considerable amount of aviscid, brown rcsidue remained in the distilling flask. This was extracted withether, and yielded 011 treatment with hydrogen bromide, diethylaniline, etc., exactlyas described above, a further quantity of unsaturated ester, which was added to thatobtained as the result of the first operation.VOL. XCVII. 7 2138 PERKIN: EXPERIMENTS ON THEvery carefully carried out. The ester was gradually mixed withexactly the quantity of alcoholic potassium hydroxide required forhydrolysis, the addition extending over about a week, and afterremaining for ten days in all, at the ordinary temperature, waterwas added, and any non-hydrolysed ester extracted with ether.Theaqueous solution was nearly neutralised with hydrochloric acid,saturated with carbon dioxide, evaporated until quite free fromalcohol, acidified, and the unsaturated acids were extracted withether and distilled, when almost the whole quantity passed over at140-142°/20 mm. It has already been mentioned (p. 2130) thatthis acid is a mixture of l-methyl-A~-cycZohexene-3-carboxylic acidand 1-rnethyl-A4-cycZohexene-3-carboxylic acid, and, in order toseparate these, the oil was digested with much water and excessof freshly precipitated calcium carbonate on the water-bath forseveral hours.After filtering and concentrating considerably, thecalcium salt of the A5-acid separated as a voluminous mass of ballsof needles, and the mother liquor, on concentration, depositedfurther crops of this same salt.After a certain concentration had been reached, the brownmother liquors yielded a crop of calcium salt quite different inappearance from the calcium salt of the A5-acid. This salt wasdecomposed by hydrochloric acid, and the acid extracted, distilledunder diminished pressure, and again made into calcium salt, andby repeating the process of fractional crystallisation, the twocalcium salts were, as far as could be seen, completely separated.dl- 1 -Met h yZ-A5-cyclo h exen e-3-car b ox ylZc A cia?.I n preparing this acid, the pure calcium salt, obtained in theway described in the last section, was decomposed by dilute hydrochloric acid, the oily acid extracted wit.h ether, the ethereal solutionwashed, dried, and evaporated, and the acid distilled underdiminished pressure :0.1957 gave 0.4897 CO, and 0.1561 H,O.C8H1,02 requires C = 68.5 ; H = 8.6 per cent.dl-l-MethyZ-A5-cyclohexene-3-carbozyl~c acid is a rather viscidoil, which distils at 145O/20 mm.or 177-180°/100 mm., and,especially when warm, has a very unpleasant odour. The highlycharacteristic catcium salt appears to have the formula(C,H,lO,)&a,5 H2O :0.1908 of the air-dried salt lost 0.0411 at looo, and yieldedH20 = 21.54 ; Ca= 9.67.0.1332 lost 0.0287 at looo.0.1128 gave 0.0370 CaSO,.Ca=9.65.C=68.2; H=8-8.0.0627 CaSO,.HiO=21-64.(CBH,,02)2Ca,5H20 requires H20 = 22.06 ; C a r 9.8 per centSYNTHESIS OF THE TERPENES. PART XIV. 2139These analyses, for which I am indebted to Dr. A. N. Meldrum,were carried out with three different preparations of the salt,Ethyl dl-l-MethyZ-A5-cyclohexene-3-carboxyZate.-Thk ester wasprepared by warming the acid (15 grams) with alcohol (100 c.c.)and sulphuric acid (6 c.c.) for three hours on the water-bath.Water was then added, the ester extracted with ether, the etherealsolution washed with water and sodium carbonate, dried, evaporated,and the oil distilled under diminished pressure :0.1117 gave 0-2914 CO, and 0-0984 H20.This ester distils a t 141-143°/100 mm., and possesses aC=71.2; H=9-8.CloH,,O2 requires C= 71.4 ; H = 9.5 per cent.penetrating and most unpleasant odour.dl-A5-m-iZfent7~enoZ( 8) and dl-As : 8(9)-m-iWenthadierce.I n preparing dZ-A5-m-menthenol(8), ethyl dZ-l-methyl-A6-cycZo-hexene-3-carboxylate (10 grams) was added to an ethereal solutionof magnesium methyl iodide containing 4 grams of magnesium, allrise of temperature above 25O being checked by cooling with water.After twenty-four hours, the product was decomposed by theaddition of water and then dilute hydrochloric acid, the etherealsolution washed well, dried, and eva.porated, and the residue mixedwith a solution of 2 grams of potassium hydroxide in methyl alcohol,and left for two days in order that any trace of unchanged estermight be removed.The neutral oil was then precipitated by water,extracted, and distilled under diminished pressure :0.1515 gave 0.4319 CO, and 0.1604 H,O.CloHIBO requires C = 77.9 ; H = 11.7 per cent.dl-h5-m-NenthenoZ(8) distils at 115-117O/ 30 mm., and is a viscid,colourless oil, possessing a strong and pleasant odour of terpineoland peppermint. I n order to convert this tertiary alcohol intothe corresponding hydroca,rbon, it was boiled with 6 per cent.aqueous oxalic acid in a reflux apparatus for three hours, thendistilled in steam, and the distillate extracted with ether. Aftercarefully drying over potassium carbonate and removing the etherby evaporation, the residual oil distilled almost completely at172-180°, and two distillations over sodium yielded the pureterpene :C=77-7; H=11*8.0.1192 gave 0.3834 CO, and 0.1282 H,O.CloHl, requires C = 88.2 ; H = 11.8 per cent.dl-A5 :8(g)-ni-Menthndiene distils a t 175-176O/ 765 mm., and hasa pronounced odour of lemons, which, however, is quite distinctfrom that of limonene.C = 87.9 ; H = 11.92140 PERKIN : EXPERIMENTS ON THEResoldon of dl-l-MethyZ-b~-oyclohexene-3-carboxyt?~c Acid.The resolution of this acid into its active modifications may beaccomplished with the aid either of l-menthylamine or of quinine.I.Experiments with 1-Nenthy1amine.-The acid available for thispurpose weighed rather more than 160 grams, and wans dividedinto two parts. The oil (80 grams) was dissolved in 570 C.C.ofN / 10-sodium carbonate, heated to boiling, and mixed with a solutionof pure I-menthylamine hydrochloride (120 grams), when a viscidsyrup separated which soon began to crystallise. After remainingovernight, the aqueous liquid was decanted* from the semi-solidcake; the latter was then washed, and left in contact with porousporcelain until quite hard and dry; it then weighed 105 grams.The crude salt was rubbed with a little pure acetone in a mortar,quickly filtered, and the colourless residue crystallised from acetone,from which it separated in long, slender needles:0-9028, made up to 20 C.C. with alcohol, gave a, -0'48O in a2-dcm. tube at 16O, whence [a], -5'3O.After two more crystallisations, the salt had [a],, - 2 * 8 O , andafter two further crystallisations, [a], - 1*7O, and it thereforeconsists of the Z-menthylamine salt of d-l-methyl-A5-cycZohexene-3-carboxylic acid :0-1108 gave 5.1 C.C.N, at 18O and 760 mm. N=5.3.C,,H3,O2N requires N = 4.7 per cent.By extracting the porous plates which had been employed inpurifying the crude I-menthylamine salt as explained above, andcarefully working up all mother. liquors, about 120 grams of thepure I-menthylamine salt of rotation [a], - 1'7O were ultimatelyobtained, and this was decomposed by dilute sodium hydroxide, andafter the I-menthylamine had been extracted with ether, thealkaline solution was acidified, the active acid extracted with ether,and distilled under diminished pressure :0.1931 gav9 0.4819 CO, and 0.1532 H,O.d-1 -Me t hyZ-A~-cyclohexene-3-car b ox ylic acid boils at 14 5 O / 20 mm.,and has the following rotation :1-0088, made up to 20 C.C.with ethyl acetate, gave a, +3.34O ina 2-dcm. tube at 16O, whence [aJD +33*l0.Ethyl d-l-NethyLA~-cyclohexene-3-carboxyEate was prepared bymixing the acid (40 grams) with alcohol (200 grams) and sulphuricacid (15 c.c.), and, after remaining at the ordinary temperature for* These aqueous liquors yield, on acidifying and extracting with ether, nearlyC=68*1; H=8.8.C8HI2O2 requires C = 68.5 ; H =8*6 per cent.10 grams of acid, which was used in another experimentSYNTHESlS OF THE TERPENES. PART X1V. 2141a week, water was added, and the oily ester extracted with ether.The ethereal solution W;L~ well washed with sodium carbonate,dried, and evaporated.The ester distilled at 140-141°/100 mm.its a mobile liquid with it penetrating and very unpleasant odour:Cl0H1,O2 requires C = 71.4 ; H = 9.5 per cent.0.1856 gave 0.4849 CO, and 0.1626 H,O.0-9520, made up to 20 C.C. with ethyl acetate, gave a, +2*9l0 ina 2-dcm. tube at 16'5O, whence [ulD + 30.5O.11. Experiment with Q&nine.-This met'hod of resolution, whichappears to give good results, was carried out subsequent to theexperiments with Z-menthylamine, just described, and with a com-paratively smail quantity of the dZ-acid. The acid (45 grams) wasdigested in ethyl acetate solution with quinine (125 grams), andthe clear solution left in the ice-chest for eight days, when a con-siderable quantity of a crystalfine crust had separated.This wascollected, twice recrystallised from ethyl acetate, and then decom-posed in the usual manner, when it yielded an acid which distilledat 142O/20 mm., which had the following high rotation:1.0052, made up to 20 C.C. with ethyl acetate, gave a,, + 3'31O ina 2-dcm. tube at 16O, whence [uID + 32'9O.It would have been interesting again to have converted the activeacid into the quinine salt in order to determine whether a higherrotation would have resulted than the +33*Io obtained in the caseof the resolution with 2-menthylamine, but unfortunately the acidwas accidentally lost.C=71*2; H=9*8.d-h5-m-Nenthenol(8) and d-A5 :8(9)-m-Menthadiene.The conversion of ethyl d-1-methyl-A5-cyclohexene-3-carboxylateinto d-A5-m-menthenol(8) was brought about by adding the ester(15 grams) to an ethereal magnesium methyl iodide solution con-taining 6 grams of magnesium, the temperature being kept below2 5 O during mixing and subsequently. After twenty-four hours, theproduct was decomposed by water and hydrochloric acid in theusual manner, the ethereal solution washed well, dried, andevaporated.The residual oil distilled remarkably constantly at115O/30 mm.:0.1438 gave 0.4120 CO, and 0.1551 H,O.0.8810, made up to 20 C.C. with alcohol, gave a, +3.25O in a2-dcm. tube at 16O, whence [a]= +36-7O.d-A5-m-MenthenoZ(8) is a colourless, rather viscid oil, possessing astrong odour of terpineol and ment.hol; even when kept for severalmonths, it showed no signs of crystallising, and an attempt toprepare a crystalline phenylurethane was also unsuccessful.C=78.1; H=12.0.CloH180 requires C = 77.9 ; H = 11.7 per cant2142 PElZKIN : EXPERIMENTS ON THEWhen a drop of sulphuric acid is added to the so1uti.m of thismenthenol in acetic anhydride, a faint pink colour, like dilutepermanganate, is produced, and, on keeping, this gradually becomesmore violet and then fades.The menthenol (5 c.c.) was shakenwith dilute sulphuric acid (350 C.C. of 5 per cent.) for seven dayson the machine, the product distilled in a current of steam, andthe volatile oil extracted and distilled under the ordinary pressure,when almost the whole quantity passed over at about 203*, andevidently consisted of the unchanged menthenol, only traces atmost of the corresponding terpene having been produced.Tliesolution in the steam distillation flask yielded, after saturation withammonium sulphate and extraction with ether, about 0-5 gram ofa syrup, which gradually crystallised and evidently consisted of thecorresponding terpin, but the quantity was too small for purification.When the menthenol was mixed with three volumes of fuminghydrobromic acid (saturated a t Oo), it did not appear to dissolve,and, even after several weeks, no solid additive product had beenformed.d-A5 :*(g)-m-Menthadiene.-This terpene is formed when d-As-m-menthenol(8) (10 grams) is digested with aqueous oxalic acid(100 C.C. of 6 per cent.) in a reflux apparatus for six hours, andthe product distilled in a current of steam.The volatile oil was extracted with ether, the ethereal solutiondried very carefully, evaporated, and the residue distilled, whenalmost the whole passed over below 180°, and, after twice frac-tionating over sodium, the terpene distilled constantly at 175-176O :C,,H,, requires C = 88.2 ; H = 11.8 per cent.0-1142 gave 0.3706 CO, and 0.1248 H,O.0.9124, made up to 20 C.C.with ethyl acetate, gave a, +2*7l0 inC=88.5; H=12.1.a 2-dcm. tube at 17O, whence [aID +29*6O.l-l-Met hyZ-A5-cyclohexene-3-carbosylic A cid, l-A5-m-MenthenoZ(8),and l-A5 :g@)-m-Menthadiene.The mother liquors from the separation of the Z-menthylamineand quinine salts of d-l-methylcydohexene-3-carboxylic acid weredecomposed in the usual manner, and the acid (60 grams), whichdistilled at 142-146O and had [a], -21*4O, was systematicallytreated with Z-menthylamine and quinine, with the result that anacid was ultimately obtained which distilled at 142O/20 mm.andhad the following rotation :1'1009, made up to 20 C.C. in ethyl acetate, gave % -3-41O ina 2-dcm. tube at 15O, whence [a]! -30.9O.It follows therefore that this acid is nearly pure l-l-methyl-A5-cyclohexene-3-carboxylic acid, since the rotation of the correSYNTHESIS OF THE TERPENES. PART XIV. 2143sponding d-acid was found to be + 33*1°. Unfortunately no suitablecrystalline salt of the I-acid was discovered, although experimentswere made with d-bornylamine, d-isomenthylamine, and most ofthe usual alkaloids, and therefore complete separation could notbe carried out.Ethyl 1-1-2ClethyI-A5-cyclo~exene-3-carboxykate, prepared from theacid by means of alcoholic sulphuric acid in the usual manner,distilled at 140-14Z0/ 100 mm.:1.0090, made up to 20 C.C. with ethyl acetate, gave a, -2'78O ina 2-dcm. tube at 15O, whence [aID -27'4O.This ester (27 grams) was added to an ethereal solution ofma.gnesium methyl iodide containing 10 grams of magnesium, and,after remaining overnight, the product was decomposed by dilutehydrochloric acid in the usual manner, and yielded 22 grams ofl-A5-m-menthenoZ(8), which distilled at 104-105°/ 20 mm. :0.1429 gave 0.4083 CO, and 0.1521 H,O.0.9986, made up to 20 C.C. with ethyl acetate, gave a, -32'5O ina 2-dcm. tube at 17O, whence [a], -32'6O.The whole of this menthenol was boiled with dilute oxalic acid(6 per cent.) for three hours, the product distilled in a current ofsteam, and fractionated, first under ordinary conditions, and thentwice over sodium ; the l-A5:8(9)1m-mlenthcGdiene thus obtained dis-tilled at 175-176O, and had a strong odour of lemons :C =77.7 ; H = 11.8.C,,H,,O requires C = 77.9 ; H = 11.7 per cent.0.1056 gave 0.3414 CO, and 0.1135 H,Q.1.0021, made up to 20 C.C.with ethyl acetate, gave a, -2.58O inC=88.1; H=11-9.requires C = 88.2 ; H = 11.8 per cent.a, 2-dcm. tube at 16O, whence [a], -25'3O.Formation of the cis- and trans-lactones of a-Methyl-y-hydroxy-isopropyladipjc Acid by the Oxidation of d- and LA5-m-Men-thenol(8).In carrying out this oxidation, dA5-m-menthenol(8) (5 grams)was suspended in water and powdered ice (1 litre), and then a1 per cent.solution of permanganate (13 grams) added in severalportions, the whole being mechanically shaken after each addition.The slight excess of permanganate was removed by sodium sulphite,and, after heating on the water-bath and filtering, the filtrate andwashings of the manganese precipitate were evaporated to it smallbulk. The brown liquid was then rendered acid wit.h dilutesulphuric acid, and further oxidised on the water-bath withpotassium dichromate and sulphuric acid until action ceased. Theproduct was saturated with ammonium sulphate and repeatedl2144 PERMIN : EXPERIMENTS ON THEextracted with ether on the machine, the ethereal solution was driedand evaporated, and the syrupy residue esterified by boiling with10 per cent.alcoholic sulphuric acid for twelve hours.The ester was extracted with ether, the ethereal solutionthoroughly washed with sodium carbonate, dried and evaporated,and the residue fractionated, when about twethirds distilled at188-190°/20 mm. :0.1228 gave 0.2811 CO, and 0.0975 H,O.1.0021, made up to 20 C.C. with alcohol, gave aD -1-88O in a2-dcm. tube at 1 7 O , whence [a], -18.7O.This ester was digested with dilute hydrochloric acid (3 per cent.)for several hours, evaporated to a small bulk, and the filteredliquid left over solid potassium hydroxide in a vacuum desiccatorfor some weeks, when the gummy mass gradually became semi-solid.It was placed in contact wit>h porous porcelain until quitecolourless, and then several times crystallised from water, when aglistening mass of plates was obtained, which consisted of the Eactoneof trans-a-methyZ-y-hydroxyisopropgZadi+c acid * (compare p.2132) :0.0907 gave 0.1999 CO, and 0.0657 H20.CloH160, requires C = 60.0 ; H = 8.0 per cent.0.1888, dissolved in water and titrated with Y/lO-NaOH,neutralised 9.5 c.c., whereas this amount of a monobasic acid,C,,HI6O4, should neutralise 9-4 C.C. A further 20.5 C.C. of N/10-NaOH (making 30 C.C. in all) were then added, the solution heatedto boiling, and titrated back, when it was found that the totalneutralised was 19.2 C.C. The amount required for neutralisationon the assumption that the lactone-acid, C,,H,,04, had becomedibasic by hydrolysis is 18.8 C.C.The solution was concentrated, acidified, heated to boiling for afew seconds, and allowed to cool; it then rapidly deposited glisteningplates of’the tram-lactone.This lactone melts at 136O, and isreadily soluble in warm water, but rather sparingly so in the cold;the hot saturated solution clouds on cooling, but rapidly crystallisesif the sides of the vessel are rubbed with a gIass rod.It is remarkable that, although obtained from a strongly activeester simply by boiling with dilute hydrochloric acid, this lactune,as also the corresponding cis-lactone (see below), should be quiteinactive.The cis-lactone.-The porous plates, used in the purification ofthe crude mixed lactones, were extracted with ether, the ethereal* This snbstance has been provisionally named tram- in order to distinguish i tfrom the more readily soluble modification of lower melting point which has beencalled cis-.C=62.6; H=8*8.CI2H,,O, requires C = 63-2 ; H = 8.8 per cent.C=60*1; H=7.9SYNTHESIS OF THE TERPENES.PART XIV. 2 14sextract mixed with water and the aqueous mother liquors of thetrans-lactone, and digested with carefully purified animal charcoal.After filtering and evaporating to a small bulk, the solutionwas left over sulphuric acid, when it gradually deposited a massof crystals, which were drained on porous porcelain and fractionallycrystallised from water. I n this way, a separation of the trans-and .cis-lacton es was ultimately accomplished.The cis-Zactone melts at about 102O, is readily soluble in warmwater, and the concentrated solution clouds on cooling, as does thatof the tmns-lactone, and then deposits the lactone in glisteningplates.On one occasion an aqueous solution, which had graduallyconcentrated in the air, deposited the cis-lactone in the form of athick, glistening, prismatic crystal like a crystal of sugar. Theanalysis and titration of this lactone gave the following results :C=60*2; H=8.0. 0.1117 gave 0.2471 CO, and 0*0800 H,O.CIoH,,O4 requires C = 60.0 ; H = 8.0 per cent.0.2090, dissolved in water, neutralised 10.4 C.C. of N / 10-NaOH,whereas this amount of a monobasic acid, C1,,HI6O4, shouldneutralise 10.45 C.C.On boiling with an excess of sodium hydroxide and titratingback, it was found that 20.9 C.C.had been neutralised, which isexactly the amount the lactonic acid, after hydrolysis, shouldiieutralise. The solution was concentrated, acidified, and boiled,when, on cooling, the lactone of melting point 102O crystallised out.An exactly similar series of experiments were made on theoxidation of Z-A5-m-menthenol(8), and as they yielded a similar ester,C,,H,,04, of rotation [aID + 17'4O, which, on hydrolysis, was con-verted into the inactive cis- and trans-lactones of melting points102O and 1 3 6 O respectively, it is hardly necessary to give the detailsof these experiments.dl-l-2llethyZ-A4-cyclohexene-3-carboxyZ~c Acid, dl-A4-m-MenthenoZ(8),and dl-A4 :g@)-m-Menthadiene.The calcium salt of 1-rnethyl-A4-m-cycZohexenecarboxylic acid,obtained as explained on p.2138, was decomposed with dilute hydro-chloric acid, the oily acid extracted with ether, the ethereal solutiondried and evaporated, and the residual viscid oil distilled underdiminished pressure, when the whole quantity passed over at143--146O/20 mm. :0.1256 gave 0-3159 C 0 2 and 0.0991 H20.C8H,,02 requires C=68*6; H=8*6 per cent.The constitution of this acid was proved by its conversion into1-methyl-A3-cycZohexene-3-carboxylic acid when boiled with alkalis,C=68*5; H=8-72146 SYNTHESIS OF THE TERPENEB. PART XIV.an isomeric change which was brought asbout under the followingconditions. The acid (8 grams) w w digested with aqueous potassiumhydroxide (50 C.C.of 30 per cent.) for four hours in a Jena-glassreflux apparatus, the solution was acidified, the acid extracted,dried, and left in contact with 30 C.C. of 8 per cent. alcoholicsulphuric acid at the ordinary temperature for fifteen hours. Waterwas then added, the oil extracted with ether, the ethereal solutionwashed with water, and then shaken with sodium carbonate inorder to dissolve unesterified acid.* When the aqueous extract wasacidified, an oily acid was deposited, which gradually crystallised,and this was collected and left in contact with porous porcelainuntil quite free from oil. The ester which had been producedyielded, on boiling with 30 per cent. potassium hydroxide andsubsequent fractional esterification, a further quantity of the aamesolid (AS) acid, and, when the operation was repeated a third time,a small quantity of solid acid was again obtained.Apparently acondition of equilibrium is established between the A4- and A3-acidsduring this process.The solid acid was dissoIved in sodium carbonate, digested withanimal charcoal, again precipitated, and the colourless, crystallinemass, after remaining in contact with porous porcelain until quitedry, was analysed. Found, C=68.6; H=8.7. Calc., C=68*6;H=8*6 per 'cent.)That this acid is l-methyl-A3-cycZohexene-3-carboxylic acid wasproved by the melting point, 58-60°, and by the fact that, whenmixed with some of this acid, which had been prepared by Perkinand Tattersall (Trans., 1905, 87, 1094) by another process, themixture melted at the same temperature as the components.Theidentity was further proved by converting the acid into the di-bromide (m. p. 165O) and hydrobromide (m. p. 108-109°; comparethis vol., p. 2152).Ethyl l-MethyZ-A4-cycl ohexeme-3-curb oxytat e.-This ester wasprepared by digesting the acid (10 grams) with 6 per cent. alcoholicsulphuric acid (50 c.c.) for three hours, and, after the addition ofwater, extracting with ether in the usual way. It distilled at142-144°/100 mm., and had a most unpleasant and penetratingodour.This ester (10 grams) was added to an ethereal solution ofmagnesium methyl iodide, containing 4 grams of magnesium, and,after remaining for twenty-four hours, water was added and the* This method of separation depends on the fact that l-methyl-A3-cyclohexene-carboxylic acid is an a@-unsaturated acid, and is esterified with greater difficulty than1-methyl-~4-cyclohexenecarboxylic acid, which contains the ethylene linking in the&-position. The value of this process of separation will be discussed in detail ina subsequent communicationSYNTHESIS OF TEIE TERPENES. PART XV. 2147product distilled in a current of steam. The distillate wasextracted with ether, the ethereal solution dried and evaporated,and the A4-m-nzenthenoZ(8) didilled under diminished pressure,when it passed over at 115--117°/30 mm. as a viscid oil which hada strong odour of terpineol and menthol :0.1145 gave 0.3267 CO, and 0-1224 H,O.Cl,-,H,,O requires C = 77.9 ; H = 11.7 per cent.A4 :a(s)-rn-nlenthn~~ene was obtained from A4-m-menthenol(8) byboiling with 6 per cent. aqueous oxalic acid exactly as describedin the preparation of A5:8(9)-m-menthadiene (p. 2139). It waspurified by distillation in a current of steam and then twice oversodium, and boiled at 175--177"/757 mm.:0.1347 gave 0.3358 CO, and 0.1452 R,O.C,,H,, requires C=88.2; H=11.8 per cent.The amount of these substances available was very small, and anattempt will be made to find a more satisfactory method for thepreparation of l-methyl-A4-cycZohexene-3-carboxylic acid in order, ifpossible, to prepare the active menthenols and menthadienes derivedfrom it..C=77*8; H=11.3.C=88-2; H=11*9.The author is indebted to Dr. A. N. Meldrum and Mr. L. Bensonfor preparing the l-methylcycZohexan-5-ol--3-carboxylic acid requiredfor this investigation, and to Miss B. Dobson for carrying out mostof the analyses and determinations of refractive power.The author also wishes to state that much of the heavy expenseof this research was met by a grant from the Research Fund ofthe Royal Society.THE UNIVERSITY,M ANCHESTER