IDENTITY OF THE SUPPOSED @-2 : 5-DIMETHYLPIPERAZINE. 219XXVI.-I'he Identity of the Supposc?d p-2 : 5-Dimethyl-papra xzn.e.By WILLIAM JACKSON POPE and JOHN READ.IN a recent paper (T., 1912, 101, 2325) we have called at+ntionto the interesting character of the stereoisomerism which shouldbe exhibited by substances of the constitution :and have pointed out that the isomeride of the &-configurationshould Kiossess an axis of two-fold symmetry, but should be ofenanti0:rnorphous molecular configuration. Such a substance wouldthereforre be expected to exhibit optical activity in the amorphousstate. ,For the purpose of experimeiitally illustrating the importantsbreoc- ,hemica1 relationships which should hold between isomerideso f f h e constitution depicted, we endeavoured to resolve both of thedescrik led 2 : 5-dimethylpiperazines 220 POPE AND READ: THE IDENTITY OF THEinto enantiomorphously related components ; the substance of thetrans-configuration should, in accordance with the van't Hoff-LeBelconception, not be so resolvable, whilst the cis-compound ought t oexist in enantiomorphous, and therefore optically active, modifica-tions.Although the methods which we employed were of exhaus-tive applicability, neither substance could be resolved ; we weretherefore forced to the conclusion that both the a- and 8-2:5-di-methylpiperazines are potentially inactive, a conclusion which is indisaccord with t'he theoretical interpretation of the configurations.We have now subjected a- and &2:5-dimethylpiperazine to afurther experimental examination, arid have arrived a t the conclu-sion (1) that the substance described as B-2 : 5-dimethylpiperazinehas not the constitution hitherto assigned to it, and must be thecis-2 : 6-dimethylpiperazine,NH<CH(CI-I,)*CH,>NH.CH( C H 3)*C H,the conclusion (2) is also drawn that the non-resolution of thea-2 : 5-dimethylpiperazine indicates that this substance is t~ans-2 : 5-dimeth ylpiperazine.Conclusion (1) is based on the following experimental evidence :The so-called p-2 : 5-dimethylpiperazine cannot be resolved intooptically active components by means of its salts with opticallyactive acids or by means of its condensation products with d-oxy-methylenecamphor ; as it is scarcely credible that these methodsshould fail to reveal potential optical activity, it would seemimprobable that the substance is the cis-isomeride of the 2:5-di-methyl derivative. I n the present paper we increase the evidenceagainst the potential optical activity of this 8-isomeride by failingto resolve its N-dimethyl derivative, which, if it had the cis-con-figuration of the constitutionCH N( CH,)*C H Z>C<F3, b>C<cH, .N (C H ,)should, together with the parent secondary base, be resclvable.It is, however, conceivable that in spite of E.Fischar's demon-stration of a parallel case amongst the alanyl anhydri&es (Ber-,1906, 39, 467; 1906, 40, 3981), some discrepancy exists betweentheory and experiment, and that the cis-2 : 5-dimethylpi$~%Zineand its M-dimethyl derivative are both potentially inactive, ihecausethe configuration of both contains an axis of two-fold syp fimetrYalthough it is enantiomorphous. We have, however, prepar ed themonomethiodide of the tertiary base, and have been une bIe f~resolve this substance into optically active isomerides; thic: C c m -pound should have the constitutioSUPPOSED p-Z : 5-DIMETHY LPIPERAZINE.221and the configuration contains two dissimilar asymmetric carbonatoms, and possesses neither axes nor a centre of symmetry. Themolecular configuration is theref ore enantiomorphous in a differentdegree from those of the parent secondary or tertiary base, andshould consequently again be resolvable, whether it possesses thecis- or the trans-configuration.These facts led us to suspect strongly that the so-called 8-2 : 5-di-methylpiperazine has not the constitution which this nameindicates.I f we mume that the failure to resolve the quaternary ammon-ium salt named proves the absence of asymmetric carbon atoms inthe configuration of the compound, and that the preparation of the@secondary base by reduction- of a pyrazine derivative proves thatthe two methyl groups are attached to two different carbon atomsin the c l o d ring, the 8-base can only be the cis-2:6-dimethyl-piperazine of the constitutionThis constitution, which is suggested by the failure to resolve theseveral compounds named above into optically active components,is capable of verification in a quite different manner.The twosecondary nitrogen atoms in ths above molecular constitution aredifferent in kind, and each moneacidic derivative of the baseshould therefore exist in two isomeric forms; we accordinglyattempted to prepare isomerides of this kind, and were completelysuccessful. The supposed /3-2 : 5-dimethylpiperazine yields twomonobenzoyl derivatives, melting at 1 1 7 O and 109O respectively,and consequently the subsiance in question must have the constitu-tion of the 2 : 6-dimethylpiperazine given above.The preparation of a monobenzoyl derivative of a di-secondarybase, in which the two tervalent nitrogen atoms exhibit the sameorder of basicity, is known to be difficult; with the &base inquestion all modifications of the Schotten-Baumann reactionyielded the dibenzoyl derivative. The monobenzoyl derivative wasultimately obtained by treating the base in acetone solution withone molecular proportion of benzoyl chloride; as the latter reagentis added, the hydrochloride of the monobenzoyl derivative separatesfrom solution, and is thus conserved from the further action ofthe acid chloride.I n the present paper it is assumed, for purposesof description only and without other adequate ground, that thisbenzoyl group which first enters the molecule attaches itself to the4-nitrogen atom.The preparation of the 1-monobenzoyl derivative is less simple.In our previous paper we have shown that dimethylpiperazined222 POPE AND REAU: THE IDENTITY OF THEmethylenecamphar results from treating the base with d-oxy-methylenecamphor i n alcoholic acetic acid solution ; we now findthat on heating d-chloromethylenecamphor and the di-secondarybase, the monomethylenecamphor derivative,separates as its hydrochloride.The resulting methylenecamphorderivative can be benzoylated by the Schotten-Baumann reaction ;the methylenecamphor radicle can then be eliminated by treatmentwith bromine in the manner previously described (T., 1912, 101,2337), and the 1-monobenzoyl derivative of the secondary base isobtained.The two monobenzoyl derivatives thus obtained are, as alreadynoted, different substances, and neither is resolvable into opticallyactive components ; in connexion with their preparation we havebeen able t o prepare the isomeric 1-benzoyl-2 : 6-dimethylpiperazino-4-d-methylenecamphor and 4 - benzoyl - 2 : 6 - dimethylpiperazino-l-d-methylenecamphor, the different identity of which is made parti-cularly evident by the different rotation constants which theyexhibit.These and other corresponding derivatives described inthe present paper, in accordance with the conclusion that they arederived from the cis-2 : 6-dimethylpiperazine, have proved non-resolvable into optically active components.The mono-acidic derivatives of the dimethylpiperazine, in whichone acidic radicle, 9, has been introduced in the 4-position by thenew method, am capable of undergoing the Schotten-Baumannreaction; a second acidic radicle, B, can thus be introduced in the1-position. We have thus been able to prepare pairs of isomericdiacidic derivatives of the parent base, of the constitutions4-A .l-B and 4-B.1-8; this is again in accordance with theconstitution now proposed for the base.Lastly, we have been able to introduce a d-methylenecamphorresidue into the molecule of the base in the 4-position and aI-methylenecamphor radicle into the 1-position ; the product isoptically active, proving conclusively that the 1- and 4-positions arenot identically similar.The experimental evidence, briefly summarised above and statedin detail in the following pages, which indicates that the so-calledp-2 : 5-dimethylpiperazine is really the cis-2 : 6-dirnethylpiperazine,appears to be convincing. It is, however, difficult t o show in whatmanner the latter compound has resulted from the method ofpreparation used.Stoehr has described ( J .pr. C'hem., 1893, [ii], 47, 494; 1897, 55,49) several methods for the preparation of the 2 : 5-dimethylSUPPOSED p-2 : 5-DIMETHYLPIPERAZINE. 223pyrazine, which, by reduction, yielded him a-2 : 5-dimethylpiperazinemixed with a very small proportion of the j3-isomeride; he statesthat the parent tertiary base is conveniently obtained by thereduction of isonitrosoacetone, and that he was only able to isolatethe B-reduction product in quantity from the residues obtained onworking on an industrial scale. It may be suggested that in thetechnical procese the 2 : 5-dirnethylpyrazine used is not highlypurified before reduction to the piperazine derivative, and that i tcontains a small proportion of the isomeric 2 : 6-dimethylpyrazine ;we are not able to settle this point.It should, however, be notedthat Stoehr and Brandes ( J . p. Chem., 1896, [ii], 54,492) separateda crystalline base, which they presumed to be 2 : 6-dimethylpyrazine,from the product of the action of ammonia on dextrose; the reduc-tion of this substance may be expected to yield the B-base nowunder discussion.The a-2 : 5-dimethylpiperazine described by Stoehr, which we havepreviously investigated, is, in the present paper, shown to differin behaviour from the 8-isomeride; on applying the methods whichproved successful in the case of the latter substance it was notfound possible to prepare derivatives containing but one acidic ormethylenecamphor radicle in the molecule.There is therefore noreason to doubt that the constitution of the a-isomeride wascorrectly stated by Stoehr, and, since this substance has not beenfound capable of resolution into optically active antipodes, it appearssafe to conclude that it is actually trans-2 : 5dimethylpiperazine.It is remarkable that the a- and Bdimethylpiperazines, which wenow show to be the trans-2 : 5- and cis-2 : 6-dimethylpiperazinesrespectively, resemble each other extremely closely in physicalproperties ; the melting points, boiling points, and solubility rela-tionships are very similar, and, as has been indicated by Btoehr,the only certain rapid way t o distinguish between them is by meansof their dibenzoyl derivatives.The dibenzoyl derivative of thea-base melts at 225O, and that of the &base contains a molecule ofwater of crystallisation and melts at 147-148O; it is very note-worthy that almost identical crystalline forms are assigned to thetwo by Fock ( J . I;r. Chem., 1893, [ii], 47, 505; 1897, 55, 61); theyare monosymmetric, with the following axial ratios :a-Dibsnzoyl, a : 7) : c = 2.6233 : 1 : 1.6623.B-Dibenzoyl, a : b : c = 2.6833 : 1 : 1.6013.B = 71Q52J.~3 = 7201 7'.It is llot easy to see how two isomeric substances, one anhydrousand the other containing a molecular proportion of water of crystal-lisation, can resemble each other so closely in crystalline form224 POPE AND READ: THE IDENTITY OF THEEXPERIMENTAL.cis-1 : 2,: 4 : 6 - T e t ~ u m e t J t y l ~ ~ ~ ~ r u z i ? c e ,The P-base, separated from technical residues, very kindlysupplied by the Farbenfabriken vorm.I?. Bayer & Co., in themanner previously described, is finally purified by crystallisationfrom petroleum (b. p. 90-looo) and acetone; the colourless, trans-parent plates obtained in this way melt at l l O - l l l o , and are onlymoderately soluble in hot acetone, which is therefore the mostconvenient solvent to use in the final purification. The diberizoylderivative prepared from it by the Schotten-Baumann reactionafter drying a t looo, melts sharply a t 153O; there is therefore nodoubt that the P-base we have used in the present work is identicalwith that of Stoehr.The base is methylated in aqueous solution with methyl sulphate(three molecular proportions) ; the latter is added gradually togetherwith dilute sodium hydroxide in such a manner that the solution isalways kept cool and slightly alkaline.After warming to completethe reaction, solid sodium hydroxide is added when the liquid baseand solid sodium methyl sulphate separate; the former is causedto rise to the surface of the liquid by slight warming, and, afterremoval from the aqueous layer, is dried with potassium hydroxideand distilled. The base is obtained as a colourless liquid boilinga t 163--164O, which possesses a characteristic ammoniacal odour,and is practically non-volatile in steam; i t is miscible with waterand most organic solvents, including light petroleum, in all propor-tions.The pZu t iizic hZo&Ze, C8H,,N2,H2P tC1,,3H20, crys t allises from hotwater in lustrous, orange needles, which blacken a t about 270° anddecompose profoundly a t 275O; it is moderately soluble in hotwater, and practically insoluble in alcohol and other organicsolvents :0.5816 lost 0-0350 a t looo.C8HI8N,,H,PtC1,,2H@ requires H,O = 6.12 per cent.0.3960, dried a t looo, gave 0.1393 Pt.C8H,,N2,H2PtC1, requires Pt = 35.35 per cent.The picrate forms small, yellow crystals, and is practicallyinsoluble in water, alcohol, and acetone, but dissolves in excess ofbase or in dilute ammonia ; it decomposes suddenly a t about 280° :CsHI8N2,2C6Ha0,N3 requires C= 40.00; H= 4.03 per cent,H,0=6'02.Pt=35*17.0'1257 gave 0.1864 C02 and 0.0524 H20.@=40*44; H=4*66SUPPOSED 6-2 : 5-DIMETEYLPIPERAZINE. 225The above base, practically non-volatile in steam, is the soleproduct of methylation with methyl sulphate under the conditionsstated above. On treating the parent secondary base with alcoholicpotassium hydroxide and methyl iodide (two molecular proportions)two tertiary bases appear to be produced; one of these is identicalwith that just above described, whilst the other volatilisea readilyin steam. The latter yields a platinichloride, which, like that of theprevious base, contains two molecular proportions of water ofcrystallisation. The apparent difference between these two productahas not yet been further studied aa it does not affect the mainquestion under investigation.Attempts to Resolve cis-1 : 2 : 4 : 6-Xetramethylpiperaaine.The base combines with two molecular proportions of d-camphor-&sulphonic acid to yield a single crystalline salt, which melts a t223O, and forms minute, glistening needles or prisms when crystal-lised from a mixture of alcohol and acetone:0'1096 gave 0.2221 CO, and 0.0819 q0. C=55*27; H=8.36.CsHlsN2,2Cl,Hl,0*S03H requires C= 55.44 ; q=8-25 per cent.An aqwuus solution of 0.1949 gram, made up to 30 C.C.withwater at 20°, gave ~ + 0 * 5 6 ~ for the mercury-green line,whence [a] + 21'6O and [MI12 + 6503~.As no appreciable change in the rotatory power of the saltoccurred on recrystallisation, and as the value obtained is practi-cally identical with that for the acidic ion in aqueous solution, itis clear that the base cannot be resolved'by means of this salt.cis-1 : 2 : 4 : 6-Tetrameth~ylpiierazine d-a-Bromocampho&sdphonate, CsH18N2,2C,oHl,0Br~S0,H.This salt, prepared by evaporating t o dryness an aqueous solutionof the component base and acid, is very soluble in water or alcohol,and readily so in warm acetone.It separates from the lattersolvent in minute, glistening crystals, melting at 175O; the crystalsretain about 1.5 per cent. of water, which is driven off at looo,and the data given below refer to the salt which has been thusrendered anhydrous :0.0984 gave 0.1570 cy), and 0'0547 H20. C=43*47; H=6*21.CsH,,N,,C20H,0,Br2S2 requires C = 43-97 ; H = 6.33 per cent.The rotation constants are not altered by fractional crystallisa-tion : 0.1980 gram, made up to 30 C.C.with water, gave aHg green +2'57O in a 4-dcm. tube a t ZOO, whence [a] + 97.4O and [MI12 + 372O.These results show that the base has not been resolved into opticallyactive components by the aid of this salt.VOL. cv. 226 POPE AND READ: THE IDENTITY OF TEEcis-1 : 2 : 4 : 6-Tetrarnethglpipera~ke d-a-Bromocamphor-n-sdphonu t e, C8H,,N,,2 Cl,Hl,OBr* SO&This salt crystallises readily from acetone, in which it is sparinglysoluble, containing a little alcohol, in fine, colourless needlm, meltingat 249O:0.0787 gave 0.1267 C02 and 0*0468 H,O. C=43.91; H=6*65.C8H18N2,CmH,08Br,S, requires c= 43.97 ; H = 6-33 per cent.An aqueous solution containing 0.2010 gram of the salt in 30 C.C.gave aHggreen+ 2 3 6 O a t 20°, whence [a] + 88.1O and [MI12 + 336.5O.The final separation obtained on fractional crystallisation gave,with 0.2089 gram in 30 c.c., a +2*46O for the same wavelength,whence [a] +88.3O and [M]/2 +337O.The molecular rotatorypowers of the fractionated and unfractionated salt are nearly thesame, and are practically identical with the value determined forthe acidic ion; it is therefore concluded that no resolution hasbeen effected.The normal d-tartrate of the baae dissolves readily in water, andis moderately soluble in alcohol, from which solvent it crystallisesin white, opaque nodules containing about 10 per cent. of waterof crystallisstion, and melting below looo. The salt, both beforeand after fractional crystallisation, gives the specific rotatorypower of about + 20° in aqueous solution; as it was clearthat no resolution was effected by means of the tartrate the saltwas not further examined.The picrate prepared from the fractionated d-tartrate provedinactive in ammonia solution.cis-l : 2 : 4 : 6-Tetramethylp'perazine Monomethiodide,ct3H1sN2,cH31*On mixing acetone solutions of the tertiary base and excess ofmethyl iodide heat is evolved, and, provided the solution is notallowed to become too hot, long, lustrous, colourless needles of themethiodide slowly separate; the substance is readily soluble inwater or alcohol, and moderately so in acetone.It crystalliw froma mixture of alcohol and ether in small needles melting a t 227O,and deliquesces in the air; the solutions are neutral in reaction,and the salt does not combine with a second eqwivalent of anacid :0.2025 precipitated 7.2 C.C. N / 10-AgNO,.1=45*1.C,H,,N,,CH,I requires I = 44.7 per centSUPPOSEDr@-2 : 5-DIMETHYLPIPERAZINE. 227cis-l : 2 ; 4 : 4 ; 6-Pentarnethylpiperasonium d-a-Bromocamphor-.rr-sulphonut e, CS,H2,N,*~0,*C1,H1,OBr,l*5 H20.This salt is obtained by double decomposition between the abovemethiodide and the silver salt of the optically active acid inaqueous solution; it is extremely soluble in water or alcohol, and,when crystallised from a mixture of alcohol and acetone, is oblainedin glistening plates melting at 214O:0.1017 * gave 0.1823 GO, and 0.0665 H20.C9~1N2*S03*C,,Hl,0Brequires C=48*79 ; H = 7-55 per cent.0.8133 lost 0.0453 a t looo.H20=5'57.. C9H21N,*S03*C10H,40Br,l~5~0 requires H,O = 5-47 per cent.The rotatory power of the salt was not appreciably changed byfractional crystallisation ; 0'2020 gram of the anhydrous substance,made up to 30 C.C. with water, gave a t 20° uHggreen + 2*00° in a4-dcm. tube, whence [a] +74*3O and [MI +347O. No resolution isthyefore effected with the aid of this compound.C = 48-89 ; H = 7-32.cis-l : 2 : 4 : 4 : 6-€'entametiiybpiperazoni&n d-a-Bromocamphor-&sutphona.t e, C9~1N2~S03*CloH,,0Br.This salt, obtained by double decomposition in the same manneras the previous om, is very soluble in water or alcohol, and crystal-lises from a mixture of alcohol and acetone in colourless, lustrousprisms, melting a t 226--227O; it does not retain water of crystal-lisation :0*1388 gave 0'24'70 CO, and 0.0918 H20.C=48.53; H=7*40.C9~,N2*S03*CloH,,0Br requires C=48*79 ; H = 7-55 per cent.The salt as first prepared (a) and the final product of its frac-tional crystallisation ( b ) gave the following values for the rotationconstants with solutions containing 0-2000 gram in 30 C.C. ofaqueous solution a t ZOO for the mercury-green ray, 4-dcm. tubesbeing used:( a ) a + 2 * 1 6 O . [a] +51*Oo. [MI + 3 7 8 O .(b) u +2.18O. [a] +81.S0. [MI + 3 8 2 O .The fact that the molecular rotatory power is not appreciablyaltered by fractionation and is practically identical with that of theacid ion, indicates again that resolution has not been effected.cis-1 : 2 : 4 : 4 : 6-Pe~ztamef.hylpiperazonium d-Camphor-&wlphonate,C,~1N2'S03°C,0H,,0,H20.The salt prepared by the interaction of aqueous solutions of themethiodide and the silver salt of the optically active acid is very* Dried at 100".Q 228 POPE AND READ: THE IDENTITY OF THEsoluble in water or alcohol, and crystallises from hot acetone, inwhich it is moderately soluble, in small, colourless needles, melting,at 254O:0.1214 * gave 0.2609 CO, and 0.1014 H,O.C=58.61; H=9-35.0.5160 lost 0.0205 a t looo. H,O=3*97.The rotatory power of the salt was unchanged by fractionation,0.2014 gram, dried at looo, made up to 30 C.C. with water a t20°, gave a +0*46O for mercury-green light in a 4-dcm. tube,whence [a] -t-17*lo and [MI +66.5O.The corresponding d-tartrates, containing one and two equiva-lents of the acid to one of the base, were also prepared; they arevery soluble in water, but practically insoluble in alcohol or acetone,and are also very hygroscopic and difficult to obtain crystalline.In view of their unpromising character, they were not furtherinvestigated.C?91i&lN2*S03*Cl,H,,0 requires 0=58*71; H = 9-34 per cent.C9~lN2*S0,*Cl,Hl,0,H20 requires H20 = 4.43 per cent.and is practically identical with that of the acid ion:cis-1 : 2 : 4 : 6-Tetramethylpiperazin,e Dimethiodide,The pure cis-1 : 2 :4 : 6-tetramethylpiperazine boiling a t 163-164Ois heated at 150° in a sealed tube with a little methyl alcohol andrather more than two molecular proportions of methyl iodide forthree hours; the dark-coloured residue, after evaporation to dryness,is dissolved in alcohol and caused to crystallise.On repeated crystal-lisation from hot alcohol the dimethiodide is obtained in long,colourless needles, which are moderately soluble in the solvent andmelt at 241-242O. The substance is deliquescent, and practicallyinsoluble in acetone or chloroform :0*2000 precipitated 9.3 C.C. N / 10-AgNO,. I = 59.30.C8H18N2,2CH,I requires I = 59-63 per cent.cis-1 : 1 : 2 : 4 : 4 : 6-Eexamethylpiperazom~wm d-a-Bromocamphor-1-sulphonate, CloH&N2(S03*~oH140Br)2,H20.The dimethiodide reacts readily in aqueous solution with thesilver salt of the optically active acid; the new salt is extremelysoluble in water or alcohol, and insoluble in acetone.It crystallisesfrom a mixture of alcohol and acetone in lustrous, colourlessneedles, melting a t 287O:* Dried a t 100"SUPPOSED b-2 : 5-DIMETHYLPIPERAZINE. 2290.5317 lost 0.0112 a t looo.C,,€i&N,( S0,*Cl,H,,0Br),,H20 requires H20 = 2-22 per cent.0.1344 * gave 0'2252 CO, and 0.0769 H,O. C =45.70 ; H = 6.40.C,,H,N2(S03*C,,H,,0Br), requires C- 45.43 ; H= 6-62 per cent.On fractional crystallisation it was found that all the fractionsexhibit the same rotatory power; the weigh& of the first (a) andlast fractions (b) noted below, dried at looo, w0re made up to30 C.C. with water at 20°, and the rotatory powers determined formercury-green light in 4-dcm. tubes :(a) 0.2001 gram: a ;2.32O. [a] +87.0°. [M]i2 +344O.( b ) 0.1987 ,, a + 2.29O.[a] + 86'4O. [M]/2 + 342O.The constancy of the molecular rotation and the fact that itapproximates closely to that for the acidic ion indicates that thesalt is a uniform substance.H20=2.11.cis-1 : 1 ; 2 : 4 ; 4 6-€lexamethylp~peruzonium d-a-Bromocamphor-fl-sulphonat e, Clo&Nz( S03Cl,H,,0Br)2.This salt, prepared in the same manner it8 the preceding one,separates from a mixture of alcohol and acetone in soft, colourlessneedles, melting at 262O; on heating a t looo it loses less than1 per cent. in weight. The following data refer to material driedat looo, and the rotation constants for the first (a) and last (b)fractions are stated in the same terms as before:0.1107 gave 0.1848 CO, and 0.0676 H,O. C=45.53; H=6.83.C,,H,N,(S03~C?l,H,,0Br), requires C=45*43 ; H = 6-62 per cent.(a) 0.2070 gram: a +2*55O.[a] +92*5O. [M]/2 +366O.( 6 ) 0.2041 ,, a + 2'54O. [a] + 93'3O. [M]/2 + 370O.No indication of resolution is thus obtained, and the observedmolecular rotatory power is practically identical with that of theacidic ion.cis-1 ; 1 ; 2 ; 4 : 4 : 6-Hemmethylp~perazonium d-Camphor-fl-sulphonat e, C10&N2( S0,-Cl,H,,0)2,H20.This salt waa prepared by the interaction of the dimethiodideand the silver salt of the acid, and is very soluble in water oralcohol; it separates in glistening, colourless leaflets or needles onadding acetone to its warm alcoholic solution, and melts a t 306O :0'3566 lost 0.0110 at looo.C,,H,N,( S03*CloH,,0)2,H20 requires H20 = 2.76 per cent.0.1153" gave 0.2287 CO, and 0-0878 H,O.C=56-46; H=8*62#C,oH~N,(S0,*CloH,,0)2 requires C= 56-73 ; H= 8.58 per cent.* Dried at 100".%0=3.09230 POPE AND READ: THE IDENTITY OF THE0.2001 gram of the salt, dried a t looo, made up to 30 C.C. withwater at 20°, gave a +0*56O for mercury-green light in a4-dcm. ’tube, whence [a] +21*O0 and [M]/2 +66*5O.The several fractions had the same rotatory power, so that noevidence of resolution is afforded.The experimental results described in the previous pages indicatethat the Ndimethyl derivative of Stoehr’s fldimethylpiperazine ”and the corresponding mono- and di-methiodides, like the originalsecondary base, ars‘irresolvable into optically active components,Mono-acidic D er iva t i u es of fl-Dim e th ylpiperazine.”cis-4-Benzoyl-2 : 6-dimethylpipera&e,We spent some time in finding a method for the prepakationof these substances, in view of their importance, and are able todescribe the following method, which is of general application.An acetone solution of benzoyl chloride (1 mol.) is slowly runinto an acetone solution of the base (1 mol.) with constant stirring;the solution becomes hot, and a white, crystalline solid separates.After remaining for an hour the deposit is collected and well washedwith acetone; analysis shows it to be the pure hydrochloride of themonobenzoyl derivative :0.2515 precipitated 10.2 C.C.iV/lO-AgNO,. C1= 14.36.C13H,,0N2,HCl requires C1 =.l3*95 per cent.The hydrochloride is obtained in theoretical yield, and is readilysoluble in water or alcohol; it separates in minute, colourless crystalson slowly adding acetone to its alcoholic solution.The salt is dissolved in water, rendered alkaline with sodiumhydroxide, and the solution distilled in steam t o drive off ahyunchanged &base ; the residual liquor is then extracted withbenzene, and the monobenzoyldimethylpiperazine obtained by dis-tilling off the benzene.The free base is soluble in water, but isdeposited from the solution on addition of much sodium hydroxide ;it is very soluble in the ordinary organic solvents, with the excep-tion of light petroleum. It separates slowly from the cooledsolutions in hot light petroleum in arborescent growths of colourless,fine needles, melting at 117O; the crystals retain about one-half amolecular proportion of water of crystallisation, which is driven offa t looo:0.1000 * gave 0.2629 CO, and 0.0778 H20.C=71*70; H=8*71.CI3Hl8ON2 requira C= 71-51 ; H = 8-32 per cent.* Dried at 100”SUPPOSED a-2 : 5-DIMETHYLPIPERAZINE. 231The base is readily hydrolysed by boiling dilute hydrochloric acid,and benzoic acid crystallises out on cooling; it is noteworthy thatthe corresponding dibenzoyl derivative is stable even towardsboiling concentrated hydrochloric acid.The platinichloride separates from hot water in small, glistening,yellow crystals, melting and decomposing a t 256O; it is practicallyinsoluble in alcohol :0.4007 gave 0.0921 Pt. Pt=23*02.(C13H,,0N2),,~PtC16 requires Pt = 23.05 per cent.cis-4-Benzoyl-2 : 6-a?imethylp*perazine d-Camphor-&sulphona te,C6H13~20@OoC6H5,C10H150~ S;03H.On evaporating an aqueous solution of equivalent quantities ofthe acid and base to dryness a gummy residue is obtained, whichslowly becomes crystalline; after well washing with acetone thecrystalline salt is fractionally crystallised from hot acetone, inwhich it is sparingly soluble. The salt is obtained in fine, colourlessneedles, melting a t 197--199O, and is very soluble in water:0.1007 gave 0.2260 CO, and 0.0661 H,O.Cl,H,,0N,,CloH,,04s requires c= 61.29 ; H'= 7.61 per cent.The various fractions of the salts proved to be identical; thefirst (a) and last ( 6 ) fractions gave the following rotatory powersunder the conditions previously stated :( a ) .0.2074 gram : a + 0.41O. [MI + 66'7O.( 6 ) 0.2004 ,, a +0.40°. [a] + 15*0°. [MI + 67.4O.C=61*21; H=7*35.[a] + 14'8O.The molecular rotatory power is practically that of the acidic ion,and consequently no resolution has occurred.cis-4-Ben zo yl-2 : 6-dimet h ylpi prazine Hydrogen d-Tartrat e,C6Hl3N,* CO*C,H,,C,€&O,.ThO base and d-tartaric acid in molecular proportions ar0 evapor-ated to dryness in aqueous solution with repeated addition ofalcohol; the gummy residue is disaolved in a little alcohol andprecipitated as a gum by addition of excess of acetone. On boilingthe solution the gummy mass becomes crystalline, and is collected;after several crystallisations from boiling alcohol the salt is obtainedin minute, colourless, glistening crystals, melting a t 227-228O :0.1462 gave 0.2978 CO, and 0.0846 H,O.C =55.55 ; H= 6.48.C&~0N,,c$&@6 requires C = 55-40 ; H = 6-57 per cent.The salt has a specific rotatory power in aqueous solution formercury-green light of about [a] + 12O, and the rotation ia notchanged by fractional crystallisation. The base separated from thefrequently crystallised salt was optically inactive in alcoholi232 POPE AND READ: THE IDENTITY O F THEsolution, as was also the base recovered from the gummy residuesof the salt.The normal tartrate could not be obtained crystalline, and thetwo d-bromocamphorsulphonates, although crystalline, were sosoluble as to be unsuitable for fractional crystallisation.On treating the monobenzoyl derivative with benzoyl chlorideand sodium hydroxide solution it undergoes the Schotten-Baumannreaction, and the ordinary dibenzoyl derivative of the &base isformed.cis-p-Nitro-4-benzoyl-2 : 6-dimet~ylyipernziiae,The 8-dimethylpiperazine reacts with pnitrobenzoyl chloride inacetone solution in the manner just above described, and the hydrechloride of the mono-acidic derivative separates as a crystallinepowder; the salt is dissolved in warm water, the solution filteredand allowed to crystallise, when the hydrochloride is obtained insmall, opaque, white crystals.It is sparingly soluble in cold waterand less so in alcohol:0.3010 precipitated 10.0 C.C. N / 10-AgNO,. Cl= 11.80.C,,H,,O,N,,HCI requires C1= 11.85 per cent.The free base is obtained by adding sodium hydroxide solutionto the hydrochloride and extracting with benzene; it dissolvesreadily in hot water, benzene, alcohol, or acetone, and crystallisesfrom a mixture of acetone and light petroleum in small, glistening,yellow crystals, which melt a t 135-136O:0.1211 gave 0.2647 CO, and 0.0686 H,O.The salts of this base do not crystallise well, and no crystallinesalts with optically active acids could be obtained.When the crude hydrochloride is dissolved in water during itspurification a slight residue remains undissolved ; this consists ofthe corresponding diacidic derivative.The di-p-nitrob enzoyl deriv-ative is a very sparingly soluble substance, which crystallises fromboiling nitrobenzene in minute, yellow needles, melting a t 3150; itis not produced by aid of the Schotten-Baumann reaction on thecorresponding mono-substituted acidic derivative.C=59.61; H=6.34.Cl3R1,O3N3 requires C= 59-28 ; H = 6.51 per cent.cis-p-Bromo-4-b enzoyl-2 : 6-dimethyZpiperazine,C6Hl,N,- CO*c&f&Br.The base and the acid chloride interact in acetone solution in theusual way, and the hydrochloride is obtained in a 90 per cent,yield as a heavy, white precipitate; on treatment with aodiuSUPPOSED p-2 : 5-DIMETHYLPIPERAZINE. 233hydroxide the mono-substituted base results.This substance ispractically insoluble in water, but dissolves readily in alcohol orwarm acetone, from which it separates in aggregates of large,lustrous, opaque crystals, melting a t 126O :0-0997 * gave 0.1931 CO, and 0.0557 H20.C=52*82; H=6*25.The salts with optically active acids proved so soluble that theycould not be subjected to fractional crystallisation.The di-p-bromobenzoyl derivative is not formed during the abovemethod of preparation, but is obtained by the Schotten-Baumannreaction as a colourless compound, which crystallises from hotalcohol in glistening leaflets melting a t 215-216O.cis-4-Anisoyl-2 : 6-dimet hylpiperazine is obtained aa its hydrechloride in good yield with the aid of anisoyl chloride in acetonesolution; the base forms a viscid gum, which crystallises very slowly.The d-camphor-8-sulphonate crystallises in small, glistening needles,and its molecular rotatory power, [MIHggeen +62*5O in aqueoussolution, is not changed by fractional crystallisation.Thed-a-bromocamphor-wsdphomte could not be caused to crystallise.CI3H,,0N2Br requirw C = 52.51 ; H= 5-77 per cent.cis4-Nuph t ha1 ene-a-sulphon yL2 : 6dim e th y lpip erazine,C~H,3N2*SO2~C~oH,.Since the experimental results described above indicate that thesalts of the carboxylic derivatives of 8-dimethylpiperazine " withoptically active acids do not, as a class, crystallise readily, and i twas deeirable to obtain further evidence as to the non-resolvabilityof the mono-substitution derivatives, an attempt was made toprepare corresponding derivatives of the aromatic sulphonic acids.a-Naphthalenesulphonyl chloride reacts with the 8-base in acetonesolution, and the precipitation of the raulting hydrochloride iscompleted by warming on the water-bath.The salt formed is completely soluble in water, and is cleansed bywashing with acetone; after filtration, it is treated in aqueoussolution with sodium hydroxide, when the base separates as a gum,which rapidly crystallises.On crystallisation from aqueous alcoholit is obtained in glistening, colourless prisms, melting at about loooin its water of crystallisation; after drying a t looo the base meltsa t 122-123O. It is readily soluble in the ordinary organic solvents,but practically insoluble in water :0*1099 gave 0'2486 COz and 0.0646 H,O. C=61*69; H=6*58.0-3474 lost 0,0084 at looo. H,O= 2-42.C,,H,02N2S,+H20 requires C = 61.29 ; H = 6-76 ;H20 = 2-88 per cent.* Dried a t 100"234 POPE AND READ: THE IDENTITY OF THEThe hydrochloride separates in minute, glistening crystals whenan acetone solution of the base is treated with concentrated hydro-chloric acid in the requisite quantity; it dissolves readily in water :c1= 10.50.C,,H200~2S,HC1 requires C1= 10.41 per cent.0.3006 precipitated 8.9 C.C.NIlO-AgNO,.cis4-Naphthalene-a-sulphoql-2 : 6-dimethylpiperazine d-Camphor-/3-sdphonnte, C,6H200,dN2S,CloH160*S0,H.Equivalent quantities of the base and acid are mixed with water,and sufficient alcohol added to effect solution at the boiling tempera-ture; the salt separates on cooling in glistening, colourless needles,melting a t 256-257O :0.1055 gave 0'2240 CO, and 0.0644 H,O. C=57*91; H=6*83.C,,H,,O,N,S,C,,H,,O,S requires c= 58.16 ; H = 6.76 per cent.The salt wits found to be homogeneous on fractional crystallisa-tion from aqueous alcohol, and all the fractions exhibited the samerotatory power; 0.2023 gram, made up to 30 C.C.with water, gaveaHgmeen +0*33O in a 4-dcm. tube a t 20°, whence [a] +12*2O and[MI + 65-6O. The rotatory power is not sensibly different from thatattributable to the acidic ion. The base liberated from the severalfractions of the salt proved to be optically inactive in alcoholicsolut.ion.cis-4-Naphthale/ne-a-szcll)lTonyl-2 : 6-&met hylpiperazine d-a-Bromo-camphor-B-sulphonate, C16Hzo0,~,S,C,,H,,0~r*S0,H.This salt is prepared in the same manner as the preceding one,and is practically insoluble in water, although freely soluble inalcohol or acetone; it crystallises from aqueous alcohol in large,glistening, colourless prisms, melting a t 240-241O :0.1066 gave 0.1976 CO, and 0-0572 H,O.C = 50.55 ; H= 6.00.~ l , ~ 2 , ~ 2 ~ , ~ , ~ , o ~ , 6 ~ , ~ r ~ requires c= 50'70 ; H= 5-73 per cent.The rotatory power of the salt is unaffected by repeated crystal-lisation from aqueous alcohol; 0.1022 gram, made up to 30 C.C.with water, gave aHggreen +0.83O in a 4-dcm. tube a t 20°, whence[a] +60*9O and [MJ +375O. Alcoholic solutions of the base liber-ated from thO various fractions of the salt were found to beopticalIy inactive.cis-4-Naph t hal en e-a-sul ph onyL2 : &dime thy 1p.p e ~ a zin e d-a-Br om 0-camphor-r-sulphorte, C,,H2,0,N2S,Cl,H,,0Br*S0,H,H,0.On evaporating an aqueous alcoholic solution of correspondingweights of the acid and base t o drynew, a gummy residue isobtained, which slowly cryatalfises ; after washing the solid witSUPPOSED p-2 : 5-DIMETHYLPIPERAZINE.235cold water i t is recrystallised from warm aqueous alcohol. The saltis thus obtained in fine, soft, colourless needles, which char a t 150°and begin to melt at about 185O. A slight loss of weight occurs at100°, but the whole of the water of crystallisation can only beaccounted for in the combustion; the salt readily dissolves inalcohol or acetone, but is very sparingly soluble in water:0'1112 gave 0.2012 CO, and 0.0585 H,O. C=49*35; H=5*89.C16H2002N2S,C,0H,604BrS,H20 requires C = 49.26 ;H = 5-89 per cent.Ths rotatory power is not appreciably altered by fractionalcrystallisation; 0.1008 gram, made up to 30 C.C.with water, gaveaBggree,, +0*72O in a 4-dcm. tube a t 20°, whence [a] +53*6O and[MI +339O. The base separated from the several fractions provedt o be optically inactive in alcoholic solution.cis-4-d-Camph~or-~-s~phonyL2 : 6-dimethylpipe~azine,The exhaustive attempts described above indicate that the4-benzoyl and 4-naphthalene-a-sulphonyl derivatives of the parentbass cannot be resolved into optically active isomerides, and anothermethod of effecting the resolution was therefore applied. A 4-acidicderivative of the base wm prepared, in which the acidic group itselfwas optically active ; the possession of an enantiomorphous molecularconfiguration by the original base should then reveal itself by theproduction of two isomerides, conta.ining the d and Lforms of thebase respectively associated with the &form of the acid radicle(compare Kipping and Salway, T., 1904, 85, 438).On mixing acetone solutions of equivalent amounts of the baseand d-camphop-j3-sulphonyl chloride, reaction occurs, and is com-pleted by boiling for a short time; the hydrochloride of the abovesecondary monamine separates as a white, crystalline powder, whichis completely soluble in water, and is purified by washing withacetone.The base is separated from the salt by addition of sodiumhydroxide to the aqueous solution and extraction with benzene; itcrystallises from hot aqueous alcohol in large, lustrous, colourlessneedles, melting a t 166-167O :0-1516 gave 0.3260 CO, and 0.1164 H,O.U=58*65; H=8%9.C,,H,O,N,S requires C = 58.48 ; H= 8-60 per cent.The base is readily soluble in alcohol or benzene, but dissolvessparingly ih water ; the rotation constants were determined in alco-holic solution with the appended results. In this and the followingsets of rotatory-power determinations given in the present paper236 POPE AND READ: THE IDENTITY OF THEthe weight of substance was made up to 30 C.C. with the solvent,and the measuremenb made in 4-dcm. tubes a t 20°:0.1535 gram in alcohol.Hg, 5461. Hg, 5780. Na, 5893.a ............ -t O'i3" + 0.63" + 0-58"[a] ............ + 35 *7 + 30-8 + 28'3[MI ............ +117'0 -t 101.0 f 9 2 . 8Hg, 5461/Na, 5893 = 1.259. Hg, 5780/Na, 5893 = 1.086.The hydrochloride separates in a pure state on adding concen-trated hydrochloric acid to the acetone solution of the base, andforms minute, white crystals, very soluble in water :0.4142 precipitated 11.4 C.C.AT/ 10-AgNO,. C1= 9-76,C16H2,0,N28,HC1 requires c1= 9.74 per cent.0.3106 gram in water.tfg, 5461. Hg, 5780. Na, 5893.a ............ 4- 0.90" + 0.75" +0.70"[a] ............ + 21 *7 + 18'1 + 16'9[MI ........... +79.2 + 66-0 + 61.6Hg, 5461/Na, 5893 = 1'286. Hg, 5780/Na, 5893=1*071.The platinichzoride separates from water, in which it is sparinglysoluble, in small, granular, yellow crystals, melting at 264O; it isinsoluble in alcohol :0*5000 gave 0.0911 Pt. Pt=18*22.(C,6H280,N2S),,H~Ptc16 requires Pt = 18.29 per cent.Although this optically active compound gave every indication ofbeing homogeneous, i t appeared desirable to ascertain whether itis resolvable by crystallisation with the d- and Z-a-bromocamphor-a-sulphonic acids; the following salts were therefore examined :cis-4-d-Camphor-~-sulphonyl-2 : 6-dimetkylpiperazined-a-Bromocam phor-a-sdphonat e.The salt was prepared by crystallisation from equivalent amountsof the base and acid in hot dilute alcoholic solution; it is sparinglysoluble in boiling water, from which it separates in fine, long,glistening needles, melting at 277-279O :0.1302 gave 0.2324 CO, and 0.0748 H20.C=48.68; H=6*43.C,6H2s0,N2S,@,,Hl,0,BrS requiree C = 48-79 ; H = 6.78 per centSUPPOSED b-2 : 5-DIMETHYLPIPERAZINE. 2370.2071 gram in water.Hg, 5461.Hg, 5780. Na, 5893.u ............ + 1 -82" + 1 -55" + 1 -46"[MI.. .......... -+ 421 -0 + 359 *o + 338.0[u] ........... + 65 *9 + 56.1 + 52'9Hg, 5461/Na, 5893 = 1'247. Hg, 5780/Na, 5893 = 1-062.During the fractional crystallisation of this salt a very emallproportion was separated from the final mother liquors, which wasvery soluble in water and acetone, and melts a t 260-264O; analysisshowed this salt to be isomeric with the main product (C=48.98;H=6.78 per cent.), but the substance exhibite a molecular rotatorypower in aqueous solution of only [MI:,, gree,, + 372O. The quantityof this saIt obtained was so small that it affords no evidence thatthe base has been resolved; its production indicates rather thatd-camphor-j3-sulphonyl chloride is not a uniform substance.cis-4-d-Camphor-&sdphonyl-2 : 6-dimethylpiperazinel-a-Brom o camphor-r-sdphonu t e.This substance is prepared in the same way as its isomeride, andis somewhat more readily soluble in boiling water than is thatcompound ; it crystallises in short, glistening prism, melting a t284-285' :0.1395 gave 0.2484 CO, and 0.0842 H,O.c!=48*56; H=6*75,C,,~,803N,S,C,,H,,048rS requires C = 48-79 ; H = 6.78 per cent.0.2011 gram in water.a ............ - I .09" - 0 '92" - 0.88"[a] .......... - 40.7 - 34.3 - 32.8[&I] ........... - 260 .O '- 219'0 - 210-0Hg, 5461. Hg, 5780. Na, 5893.Hg, 5461/Na, 5893 = 1.139. Hg, 5780/Na, 5893 = 1.045.On endeavouring t o trace the quantitative correspondence whichshould exist between the molecular rotatory powers of these twosalts ( D d A and dBZA), the hydrochloride of the base (dB,HCl)and the ammonium salt of the acid (NH,,dA; Pope and Read, T.,1910, 97, 2201), no very close agreement is observed.The calcula-tion is summarised in the appended table :[MI in water. Hg, 5461. Hg, 5780. Na, 5893.dBdA (observed) ............ + 421 -2 -t 358 *7 + 337.8dBZA ,, ............ - 259'7 - 219.2 - 209 '6dl5 ion (calculated) ......... + 80.7 + 69.7 + 64.1dB,HCl (observed) ......... + 79.2 + 66% +61'6dA ion (calculated) ......... -k 340'4 + 288.9 + 273.7dA,NH, (obseived) ......... + 346'6 -k 295-2 + 2i8.238 POPE AND READ: THE IDENTITY OF THEFrom the final mother liquors obtained during the fractionalcrystallisation of the above salt a small fraction was again separ-ated, which differed from the main bulk of the salt; this substancemelted a t 271-274O, had the same composition as the latter(C=49.17; H=6*50 per cent.), and gave the molecular rotatorypower for the mercury-green of [MI -240° in aqueous solution.Isomeric jT)iacidic-cis-2 : 6-dimethylpiperazi~~es.The application of the method given above for introducing oneacidic group into position 4 of the cis-2 : 6-dimethylpiperazinemolecule, together with the Schotten-Baumann reaction, by meansof which two acidic groups may be simultaneously introduced intothe 4- and 1-positions in the.molecule, renders it possible to preparediacidic derivatives in which the two acidic radicles introduced aredifferent in constitution or composition.We can also introduce thetwo acidic radicles in the two alternative orders so as to produceisomeric diacidic derivatives of the constitutions 1A4B and 1B4A ;the characterisation of isomerides thus related naturally supportsour conclusion that the 1- and 4-positions in the molecule of theparent base are constitutionally different in environment. Onapplying benzoyl chloride to the cis-4-benzoyl-2 : 6-dimethylpiper-azine dmcribed above in accordance with the Schotten-Baumannreaction, the " dibenzoyl-/3-2 : 5-dimethylpiperazine " of Stoehr isobtained.cis-4-Bertzoyl-p-nitro-1-6 enzoyl-2 ; 6-dimethylpiperazine,On treating cis-4-benzoyl-2 : 6-dimethylpiperazine with p-nitro-benzoyl chloride according to the Schotten-Baumann method, bothsubstances being dissolved in acetone before addition of the aqueoussodium hydroxide solution, reaction occurs readily in the cold ;after addition of excess of alkali and dilution with much water theprecipitated diacidic derivative is collected.The product crystal-lises from hot alcohol, in which it is freely soluble, in clusters offaintly yellow, lustrous needles, melting a t 198O; the isomericcompound described below is not formed at the same time, and if atrace of the latter is mixed with the substance melting a t 198O themixture melts very indefinitely from 190° upwards:0.1193 gave 0.2860 (10, and 0.0596 H20. C=65*38; H=5*59.C,,H210,N, requires C'= 65-36 ; H = 5.77 per centSUPPOSED 8-2 : 5-DIMETHYLPIPERAZINE.239cis-1-Be~zoyl-p-nitro-4-benzoyl-2 : 6dimet Aylpiperazine,This substance is obtained by treating cis-pnitro-4-benzoyl-2 : 6-dimethylpiperazine with benzoyl chloride and sodium hydroxidesolution; it is somewhat less soluble in hot alcohol than itsisoxeride, and separates as the solution cools in small, yellow,crystalline granules, melting a t 206-207O. On melting the com-pound with a trace of its isomeride the mixture begins to softena t 192O, but does not melt completely until 202O; the non-identityof the two substances is thus proved by the test devised by Kippingand Pope (T., 1893, 63, 557):0.1145 gave 0.2'762 CO, and 0.0602 q0. C=65.79; H=5.88.C?BH,,O,N, requires C = 65-36 ; H = 5.77 per cent.cis-4-BenzoyLp-bromo-1-benzoyl-2 : 6-ctimethlylpipera.zine,C,H,*CO*N<CH2'C CB ,*CH(CR,) H(CHs)>N =CO*C,H,Br.The compound is obtained by the Schotten-Baumann reactionwith p-bromobenzoyl chloride on the 4-monobenzoyl derivative ofthe parent base already described; it separates from its hot alco-holic solution in long, transparent, colourless prisms, melting a t185-186O.Addition of a small quantity of the iaomeride describedbelow depresses the melting point to about 182O:0.1073 gave 0.2375 CO, and 0.0507 H,O. C=60*37; H=5-29.C2,H,,O2N,Br requires @= 59.85 ; E= 5-28 per cent.The isomeride of the preceding substance is produced by theSchotten-Baumann reaction with benzoyl chloride and cis-p-bromo-4-benzoyl-2 : 6-dimethylpiperazine ; it is more sparingly soluble inhot alcohol than the above compound, and crystallises in opaqueaggregates of colourless leaflets melting at 192-1 93O.Additionof a trace of the isomeride depresses the melting point to about182O :0.1027 gave 0.2267 CO, and 0.0479 S O . C= 60.20; H =5-22.C2,H,02N2Br requires C = 59.85 ; H = 5.28 per cent240 POPE AND READ: THE IDENTITY OF THEcis-4-Benzoyl-1-anisoyL2 : 6-dimet hylpiperazine,Anisoyl chloride reacts with the 4-monobenzoyl derivative in thepresence of aqueous sodium hydroxide to yield the above com-pound; the latter is readily soluble in most organic solvents, andcrystallises from aqueous alcohol in fine, glistening needles, meltinga t 140-141O:0.1202 gave 0.3162 CO, and 0.0752 H,O. C=71.83; H=7*01.C,,H2,0,N2 requires C= 71.55 ; H = 6-87 per cent.This compound is prepared by the action of benzoyl chloride oncis-4-anisoyl-2 : 6-dimethylpiperazine and sodium hydroxide ; it ismore easily soluble than its isomeride, and separates as a soft,opaque crust of crystals from its aqueous alcoholic solution.Itmelts not quite sharply at 87-91O:0.1002 gave 0,2636 CO, and 0.0623 -0. C= 71.75 ; H = 6.96.C&,H,O,N, requires C = 71.55 ; IT= 6.87 per cent.The preparation of the above three pairs of isomeric diacidicderivatives of " #I-dimethylpiperazine " proves the dissimilarity ofthe 1- and 4-positions in the molecule.cis-4-BemzoyLl-d-meth ylenecmphor-2 : 6-dime thytpiperazine,Since we have been able to prepare cis-4-benzoyl-2 : 6-dimethyl-piperazine it should be possible to obtain from it a monomethylene-camphor derivative by the same process which we have applied inmaking the dimethylenecamphor derivative of the parent diamine(T., 1912, 101, 2334).cis4-Benzoyl-2 : 6-dimethylpiperazine, dis-solved in 30 per cent. acetic acid, is treated in the manner previ-ously described with one molecular proportion of d-oxymethylene-camphor dissolved in ethyl alcohol; after warming for a short timethe solution is diluted with water and extracted with benzene.After extracting the benzene solution once with dilute hydrochloricacid and several times with dilute sodium hydroxide solution it isevapora-ted, and the solid residue crystallised from a mixture ofacetone and light petroleum. The new compound is then obtainedin small, glistening leaflets, melting a t 165-166O SUPPOSED p-2 : 5-DIMETHY LPIPERAZINE.2410.1164 gave 0.3260 CO, and 0.0950 H20. C= 76.38 ; H = 9.13.C2,H3,O2N2 requires C= 75.73 ; H = 8.48 per cent.0-1020 gram in alcohol.Hg, 5461. Hg, 5780. Na, 5893.u ......... ".. + 5-64" + 4'79" + 4'54"[u] ............ + 415.0 + 352.0 + 334.0[MI.. .......... + 1576.0 + 1338.0 + 1268'0Hg, 5461/Na, 5893 = 1.242. Hg, 57FO/Na, 5893 = 1.055.The constants are unaltered by fractional crystallisation, so thatthe compound is evidently homogeneous. The substance is readilyhydrolysed by hot concentrated hydrochloric acid in the usualmanner, and on treatment with bromine in alcoholic solution yieldsthe hydrobromide of the parent 4-benzoyl derivative; the baserecovered from the hydrobromide melts as before a t 117O, and isoptically inactive in alcoholic solution.cis-4-d-Me thy1 enecamphor-2 : 6-dim e t htylpiperazine,It appeared desirable to attempt the preparation of this corn-pound by a method similar in kind to that used in making thecorresponding 4-acidic derivatives ; the methylenecamphor derivativeshould yield a monobenzoyl derivative isomeric with the compoundjust described, and, since both must be optically active, a furtherconfirmation of the difference between the 1- and thO $-position inthe parent diamine should be furnished by observation of differ-ences between the optical properties of the two isomerides.On warming together equimolecular proportions of d-chloro-methylenecamphor (Bishop, Claisen, and Sinclair, A n d e n , 1894,281, 361), 8-dimethylpiperazine, and a small quantity of acetoneon the water-bath, the mixture soon becomes crystalline; when theproduct is dissolved in boiling alcohol, and acetone added afterconcentrating the solution, the hydrochloride of the new secondarybase quickly separates in small, colourless crystals.After separat-ing the salt it is dissolved in water and sodium hydroxide added;the base is extracted with benzene, and the benzene solution evapor-ated after washing with water to remove any unchanged diamine.The compound is very soluble in most organic solvents, butpractically insoluble in water ; it crystallises from light petroleumin very lustrous, glistening, colourlelss plates, melting at 71°, whichcontain water of crystallisation.After drying a t looo the anhydroussubstance melts a t 65-66O:VOL. cv. 242 POPE AND READ: THE IDENTlTY OF THE0.2551 lost 0.0198 a t looo. H20=7*76.0.1071 gave 0.2726 CO, and 0.1004 H20. C= 69.42 ; H = 10'49.C,7H,,0N,,H20 requires C = 69.33 ; H = 10.28 ; H20 = 6-12 per cent.0.1576 gram in alcohol.Hg, 5461. Hg, 5780. Na, 5893.a ............ + 10'86" + 9'18" + 8 -68"[u] ............ + 517.0 + 437'0 + 413-0[RI] .......... + 1519-0 + 1234.0 + 1215.0Hg, 5461/Na, 5893 = 1 *251. Hg, 5780/Xa, 5893 = 1,058.The hydrochloride, C,7H,,0N2,HCl, separates in fine, colourlessneedles when acetone solutions of hydrogen chloride and the baseare mixed in equivalent quantities; it is very soluble in water,and is hydrolyaed by addition of excess of hydrochloric acid, thecis-2 : 6-dimethylpiperazine hydrochloride produced being opticallyinactive :0.4038 precipitated 13.0 C.C.N / 10-AgNO,. C1= 11-42,C,7H,80N2,HCl requires C1= 11.34 per cent.0.2029 gram in water.a ............ +11*75" + 9.9')" + 9 *30"[u] ............ + 434.0 4- 366'0 + 344'0[MI ............ + 1357.0 + 1144-0 + 1074.0Hg, 6461. Hg, 5780. Na, 5893.HgJ 5561/NaJ 5803= 1'263. Hg, 5780/Na, 5893-1 065.The solution in water exhibits slight mutarotation, and thevalues give above were obtained one hour after the solution hadbeen made up; the value of aM61 + 11'75O fell t o + 1 1 ' 2 5 O in forty-two hours, and after three days rose to a constant value of + 11-33O.The sensitiveness of the base towards acid made i t impossible toprepare the platinichloride ; when an aqueous solution of the purehydrochloride is boiled, d-oxymethylenecamphor separates.Themonomethylenecamphor derivative is theref ore much more readilyhydrolysed than are the corresponding dimethylcnecamphor deriv-atives (T., 1912, 101, 2336).cis-l-Bems yl-4-d-me t h y le 11 e camphor-2 : 6-dime t hylpiperaa ine,The hydrochloride of the previously described secondary basereacts readily with benzoyl chloride in accordance with theSchotten-Baumann reaction; care must be taken to keep the solutionalkaline, as otherwise hydrolysis occurs, and d-methylenecamphorbenzoate and cicdibenzoyl-2 : 6-dimethylpiperazine are producedSUPPOSED p-2 : 5-DIMETHYLPIPERAZINE.243When about 50 per cent. excms of benzoyl chloride is added inportions to the alkaline mixture, excellent yields are obtained. Thenew derivative which separates is readily soluble in alcohol, andcrystallises from dilute alcohol in colourless, glistening platesmelting at %02-203° :0.1183 gave 0-3293 CO, and 0.0881 H,O. C=75.92; H=8*33.C24.H,0zNz requires C = 75.73 ; H = 8.48 per cent.0-1066 gram in alcohol.Hg, 5461. ~ g , 5780. Na, 5893.a ........... + 5 52" + 4.67" + 4'45"LMJ ............ + 1476'0 + 1254'0 + 1190'0[a] ............ + 388.0 + 327 *O + 313-0Hg, 6461/Na, 5893 = 1.240. Hg, 5780/Na, 5893 = 1.049.On boiling with dilute hydrochloric acid the substance readilyhydrolyses, yielding the l-monobenzoyl derivative described belowand d-oxymethylenecamphor.cis-1-23 en zo yl-2 : 6-dim e t h y Jpipe raz iiz e,On titrating the warm alcoholic solution of the previouslydescribed substance with bromine, evaporating, and shaking theresidue with benzene and water, the hydrobromide of the newsecondary base is found in the aqueous solution; after renderingthe latter alkaline and extracting with benzene, the base is obtainedin theoretical yield itg a crystalline mass on evaporating off thesolvent.The base is conveniently crystallised from hot lightpetroleum, in which it is readily soluble, and is obtained in hard,colourless, glistening prisms, melting at 109-1 loo. The substanceretains about 2.3 per cent. of wa-ter of crystallisation, which isdriven off a t looo, after crystallisation from petroleum; the analysiswas made with the anhydrous material:0.1100 gave 0.2877 CO, and 0.0812 H,O.q= 71-33 ; H = 8.26.C,,H,,ON, requires @= 71-51 ; H= 8.32 per cent.It will bO seen that this substance is quite different in propertiesfrom the isomeric 4-benzoyl derivative; it has a lower meltingpoint, and is much more soluble than the latter compound. Furtherconfirmation is thus obtained of the difference between the 1- and$-positions in the molecule of the parent base.It seemed desirable to attempt the resolution into optically activecomponents of the l-benzoyl derivative in the same manner ae wasdone with the isomeride244 POPE AND READ: THE IDENTITY OF THEcis-1-Benzo yl-2 : 6-dime t h ylp'perazine d-Cu m phor-B-su Zphon,at e,On evaporating an aqueous solution of the component base andacid a gummy residue is obtained, which crystallises on keeping ;the salt is extremely soluble in water or alcohol, but dissolves lessreadily in dry acetone.By fractional crystallisation from acetonea number of identical fractions are obtained, consisting of small,glistening crystals, melting a t 165O; the several fractions gave themolecular rotatory power [MI HZ gree,, + 67.4O in aqueous solution :C,$H1sON27C10HIij0 *SO,H.0*1026 gave 0.2293 CO, and 0.0693 H,O. C=60.95; H=7*56.CISHl,ON,,C,,H,,O,S requires C = 61.29; H= 7.61 per cent.cis-1-Benaoyl-2 ; 6-dim etA yllpiperuzin e d-a-Bromocnmphor-B-sulphomte, C,,H180N2,C,,H,,0Br*S0,H.This salt crystallises readily on evaporation of the aqueoussolution of the component acid and base; it separates from amixture of acetone and alcohol in soft, minute needles, melting at209O, and is shown t o be homogeneous by fractional crystallisationfrom the mixed solvent.All the fractions exhibit approximatelythe same molecular rotatory power of [MI Hp gree,l + 382O in diluteaqueous solution :0.1031 gave 0.1979 CO, and 0.0595 H20. C=52.35; H=6-46.C,,H,80N2,C,oH1,04BrS requires C= 52.15 ; H = 6-28 per cent.It is thus not possible to resolve the base by crystallisation withthe two optically active sulphonic acids.cis-4-d-l-l-.Dimethyler~ecamphor-2 : 6-dimethylp'perazine,The cis-4-d-methylenecamphor - 2 : 6 - dimethylpiperazine hydro-chloride described above is dissolved in water, and the equivalentquantity of sodium hydroxide solution added ; after acidifying withdilute acetic acid one molecular proportion of Z-oxymethylene-camphor is added in alcoholic solution.After warming on thewater-bath the mixture is diluted with water and extracted withbenzene; the benzene solution is extracted once with dilute hydro-chloric acid and several times with dilute sodium hydroxide solu-tion, and then evaporated to dryness. The crystalline residue isreadily soluble in most organic solvents, and separates from aqueousalcohol in fine, glistening scales, melting a t 259-260O ; fractionalcrystallisation showed it t o be a homogeneous substance SUPPOSED /3-2 : 5-DIMETHYLPIPERAZINE. 2450.1068 gave 0.2990 CO, and 0.0904 H,O. C=76.35; H=9*47.CBH,,Oa, requires C= 76.64 ; H = 9.66 per cent.0.2020 gram in alcohol.Hg, 5461.~ g , m o . Na, 5893.a ........... t 2.18" + 1 '84" + 1 '74"[u] ........... -t 81 -0 t 6 8 . 3 + 64.6[-\I] ............ -t355*O f299.0 + 283.0Hg, 5461/N~,, 5893= 1 *253. Hg, 57SO/Ka, 5593=l 057.The fact that this substance, although containing d- andE-camphor residues in equal amount, is strongly optically active,furnishes a strong proof that the 1- and 4-positions in the moleculeof the parent base are not identically similar. It is interesting tonote that the d-camphor residue, which is apparently present inthe lighter end of the molecule, exercises a much greater opticaleffect than does the Z-camphor residue, the di-derivative being verystrongly dextrorotatory.We have previously described the isomericcompound, in which two d-camphor residues are present (T., 1912,101, 2335).cis-1 : 4-Dinaph thalene-a-sulphonyl-2 : 6-dime thylpiperasine,C6H12N2(S02*CIOH7)2.This substance was prepared by the Schott'en-Baumann reactionfor comparison with the isomeride formed from the trans-2 : 5-di-methylpiperazine as described below. It crystallises from aqueousalcohol in minute, colourless needles, melting at about 97O in theirwater of crystallisation; after drying at looo the substance meltsa t 117-118°:0.4112 lost 0.0224 a t looo. H,O=5*45.0.1165 gave 0.2556 CO, and 0.0720 H,O. C= 59-84; H = 6.94.C,H260,N,S,,1.5H,0 requires C=59*85 ; H= 5-61 ;H,O = 5.18 per cent.Yrepara t i o n of d-Chlorom e t h ylenecamphor.d-Chloromethylenecamphor was first prepared by Bishop, Claisen,and Sinclair (A~znalen, 1894, 281, 361) by treating d-oxymethylene-camphor with phosphorus trichloride ; as these authors remarked,the yield is small because of the production of considerable quanti-ties of a phosphorus ester of methylenecamphor. We find that thisdisadvantage may be avoided by preparing the substance with theaid of phosphorus pentachloride. d-Oxymethylenecamphor isground in a mortar with an equal weight of phosphorus penta-chloride ; when the evolution of hydrogen chloride has ceased an246 IDENTITY OF THE SUPPOSED s-2 : 5-DIMETHYLPIPERAZINE.the whole mass has become liquid, the product is poured intocrushed ice. The chloro-derivative is then extracted with ether,and its subsequent purification effected in the manner describedby Claiser and his pupils; the yield is very satisfactory.trans-2 : 5-Dim e t h ylpiperasin e.For the reasons detailed in the early pagm of this paper wenow regard the a-2 : 5-dimethylpiperszine of Stoehr as the tram-2 : 5-dimethylpiperazine ; in the molecule the two nitrogen atomsoccupying t'he 1- and 4-positions are constitutionally similar inenvironment. It was consequently of interest to attempt thepreparation of the monoacidic derivatives of the trans-2 : 5-base inthe same manner as we have effected that of the correspondingderivatives of the cis-3 : 6-isomeride ; the methods applicable t othe latter case, however, fail completely in the former one.On treating trans-3 : 5-dimethylpiperazine, melting at 115-1 16O,with Eenzoyl chloride in acetone solution under the conditionsdescribed above, a copious precipitate results ; part of this dissolvesin water aiid is the hydrochloride of the dismine, whilst theremainder proves t o be the dibenzoyl derivative melting at 226O.Several lnodified methods of applying the reagent were adopted,but always with the same results as just mentioned.On applying a-naphthalenesnlphonyl chloride to the trans-2 : 5-base under similar conditions a mixture of the hydrochloride ofthe original base with trans-1 : 4-dinaphthalene-a-sulphonyl-2 : 5-dimethylpiperazine is obtained ; the new derivative is sparinglysoluble in the ordinary organic solvents, and separates from chloro-form in minute, colourless needles, melting at 269-270° :0.1083 gave 0.2512 CO, and 0.0591 H,O.C26H260,N,S, requires C = 63.11 ; H= 5.30 per cent.Similarly, on treating the tram-2 : 5-base with d-chloromethylene-camphor in the manner which, with the cis-2 : 6-isomeride, yields themonomethylenecamphor derivative, only the hydrochloride ofunchanged base can be isolated, together with the dimethylene-camphor derivative previously described.It is thus clear that the methods by aid of which the 4-mono-substituted acidic derivatives of cis-2 : 6-dimethylpiperazine can beprepared fail when applied to the trans-2 : 5-base; it is suggestedthat this is due t o the similarity of the 1- and 4-positions in theconstitutional formula of the latter substance.C=63*27; H=6*11.THE CHEMICAL LABORATORY,TIT E UNIVERSITY, CAM R ti I DGE