[@ONTRIBUTION FROM THE D E P a R T M E S T
CHEMISTRY, V I L L A N O V A COLLEGE]
P-PHENYL-l-CHLOR0-2-&lETHYLAR!IINOPROPANE. I. REACTION WITH METALS AND WITH HYDROGEN
SOME REACTPOKS
ALEXANDER GERO Received July lY
1961
1-Phenyl-1-chloro-2-methylaminopropane
PhCHClCHCHB was first pre-
KHCH, pared by Emde (1) n a stu dy of of ephedrin e phedrinee derivatives, derivat ives, continuing conti nuing earlie earlierr studies studi es by Schmidt Schmidt (2) who ha d prepared th e corresponding corresponding 1-phenyl-11-phenyl-1-bromobromo-2-met 2-methylhylaminopropane and reduced it to desoxyephedrine, PhCHZCHCH3 with zincSHCH3 copper and hydrochloric acid. His yield, as reported later by his student Emde, wa 10%. Emde hydrogenated both and Schmidt's bromine compound catalytically desoxyephedrine in yields of 80-90%. Both authors obtained a hydrocarbon as by-product, which Schmidt identified fied as propylbenzene, while Emde s of of propenylbenzene PhCH=CHCH3 without giving any proof of iden tity other th an the th e smell smell f the hydrocarbon. Emde also found a high-molecular base in his hydrogenation mixture. Because the th e analysis an d mo! mo!ec ecul ular ar weight of of this base corresponded approximately approxi mately to dimer of of desoxyephedrine, Emd e named it didesoxyephedrine. He considered I1 an as possible structures for didesoxyephedrine and was able to reject but not to prove IP PhCHz CKCH3
PhCH-CHCR3
NCH8
"CR,
PhCHCHCH3
The Th e introduct introd uction ion of of desoxyephedrine as a drug some years yea rs ago has rekindled interest in The present paper is report on attempts to throw some light on the reasons why Schmidt's and Emde's hydrogenation methods led to such di1-ergent 1-ergent yields, yields, and on the ide ntity nti ty of of didesoxyephedrine. preliminary, it mas mas ascertained th at the t he same yield yield of 10% desoxyephedrine is obtained with when hydrogenated with zinc-copper and hydrochloric acid as Schmidt obtained with the bromine compound. In subsequent experiments only was used. The zinc-copper couple was then replaced by zinc alone in one experiment, by alkali-activated aluminum in an other. Zinc Zinc afforded afforded about the same yield yield as zinc-copper, while aluminum did not react. On the other hand, calcium hydride, while without effect in itself, gave yields 1731
1732
ALEXANDER G E E 0
desoxyephedrine ine comparable to t o those Emde Th en use in conjunction with of desoxyephedr palladium, in acidic solution. Since a metal hydride in acidic solution is source molecular hydrogen ( 3 ) :
E-
H30+
NzO
the calcium hydride experiment amounts to a duplkathn of Emde’s catalytic hydrogenation, From these results it is plain th at two difierent difierent mechanism mechanismss must be work, depending on whether hydrogen froni zinc and acid or catalytically-excited molecular hydrogen is used as a hydrogenating agent. In the first case replacement chlorine chlorine by hydrogen is minor reaction, reaction, in th e latte r the principal principal one. Next, the several metal-and-acid reductions mere repeated in the presence of palladium catalyst in order to decide whether the faster rate the reaction TABLE
REDUCTIOS l-?HESrL-l-CHLoRO-2-METHYLA~IIn”B ’~IELD~ REDUCING AGENT
Desoxyephedrine (%
Hydrocarbon (71) 77
HCl.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Zn-Cu-Pd AI-Pd IpG1.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hn-Pd C H a C O O H b . .. . . . . . . . . . . . . . . . . . . . . . . . . . . CaH2-Pd HC1.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
74 42 26
44 80-90 88
Yields do not add up to 100% because some is inevitab!y inevitab!y hydrol yzed of ephedrine and pseudoephedrine. Yield Yield reported b y Emde (1). Fo all other results see experimental part paper.
46
36
trace trace mixture the presen
the reaction R--@I 2H so, then in the presence of the catalyst which reverses the HCI. reaction 2H the same high yields should be obtained as with molecular hydrogen and palladium catalyst. Furthermore, the by-product hydrocarbon was isolate isolated d in every case and it s qua nti ty determined. The results of the above above experiments are summarized in Table I. It is immediately apparent that the most important competitive reaction in the hydrogenation with metal and acid is no the conversion atomic to molecular hydrogen but the conversion of hydrocarbon, which cannot be suppressed even by increasing th e concentration f atomic hydrogen by th catalyst. The identity of the hydrocarbon was not established at this point. As will be reported below, propenylbenzene was identified as the primary product f th e reaction reaction,, in conformity conformity with with Emde’s report; repo rt; whether, whether, and t o what e xtent, xten t, it is further furt her hydrogenated t o propylbenzene propylbenzene as reported reported by Schmidt, is irrelevant I. to the reacti reactions ons
2H
is responsible for the bad yields
PHEXYL-~-CHLORO-~-METHYLAMIIITOPROPANE
The results results summarized summarized in Tab le
1733
may be expressed by the scheme PhCHzCWCH3 "CH3
PhCH
/'
PhCH=CHGRa path being the main reaction with hydrogen and palladium as the hydrogenating agent, and path with metal and acid. Obviously the presence a metal has something do with the predominance of path 2. In order to obtain further information on its mode action, was reacted with zinc alone, without solrent and without acid. reaction is almost instantaneous, strongly exothermic, and results in good yield propenylbenzene, without any an y identifiable identifiable side reactions. reactions. This confirms the r61e the metal, and we may interpret the findings reported above by t he assumption t ha t the th e zinc zinc donates t 0 electrons electrons to t he polar C-Cl C-Cl d N bond bo nd of allowing th e ions C - an d CK3NH- o break brea k away, aw ay, and leaving the biradical PhCHCHCH3 behind which is propenylbensene when the orbitals orbitals of th e two odd electrons overlap overlap form a electron pair. Hydrogen, on th e other hand , is not metallic enough o break th e slightly slightly polar C N bond bu it can break bre ak e 1 bond which in a subs su bsti titu tute ted d benzyl chloride-i chloride-i very highly polar. Consequently a monoradical PhCH
CH "CH3
is formed, which quickly combines either with a hydrogen atom to form desoxyephedrine, or, to a lesser extent, with another radical IV to form To test this hypothesis, was reacted with copper, an element even less metallic than hydrogen. It might be reasonably expected yield the monoradical which, in the absence atomic hydrogen, can only dimerize. The expectation was confirmed and the product obtained showed the properties Emde reports for didesoxyephedrine. This may be considered as evidence for structure I1 for desoxyephedrine which Emde had suggested without being able to prove prove it Furt Fu rthe herr studies, concerning concerning the behaviour o as nitrogen mustard, will be reported later. EXPERIMENTAL
(V wa prepared fro= ephedrine hydrochloride ( M e r c l r ) and thionyl chloride, following the directions given by Emde (1). -Phenyl-I-chloro-2-methyl -Phenyl-I-chloro-2-methylaminopropane aminopropane ydrochloride
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ALEXANDER GERO
H y d r o g e n a t i o n w i t h z i n c a n d h y d ro ro c h lo lo r i c a ci ci d . 22 g., was dissolved in 101) ml. of conc'd hydrochloric acid. To this solution 65 g. zinc dust, moistened with water, was added. When the reaction subsided, it was kept going by adding more hydrochloric acid. When all th e zin was dissolved, dissolved, the solution was was distilled w ith s tea m as long as propenylbenze propenylbenzene ne came over, and was made alkaline and the steam distillation continued as long as he distillate wa alkaline. alkaline. The distillate was extracted extracted with ether, the ether dried with sodium sulfate and saturated with HCl gas. The precipitated desoxyephedrine hydrochloride was washed with ethe r and drie d; yield yield 2.3 g. (12%), m.p. 171", [a]: 18" 5, wat er) . These data are in agreement with the physical constants reported by Emde (4). H y d r o g e n a t i o n w i t h z i n c in the presence of p a l l a d i u m a n d h y d ro ro c h lo lo r ic i c a c i d was performed in t he same manner except except th at th e zinc zinc was previously previously immersed immersed in solution of 0.65 g. palladous chloride in ml. conc'd hydrochloric acid and 80 l. of hot water, after of palladous few minutes filtered, and washed washed with x-ater. zinc-copper hydrogenation was carried out likewise but the was first immersed in a solution solution of 50 g. of cupric sulfate in 120C ml of water u ntil t he blue color color disappeared, filtered, and washet washetii with w ater Fo th e reaction o z i n c - c o p p e r the presence of p a l l a d i u m , th e copper-pla ted zinc zinc was palladized palladized a s described described above. H y d r o g e n a t i o n w i t h p a ll ll a d iz iz e d a l u m i n u r n an h y d r o c h l o r i c a c i d . Aluminum powder (Reynolds g.) was washed successively with benzene, methanol, water, then immersed in 30 ml. of 0.1% NaOW solution. After minutes, 100 ml of water added and the aluminum filtered and r es he d with water. (Activation by this method was chose chosen n instead of th e convent convention iona! a! amalgamation in order avoid subsequent poisonin poisonin of the palladium.) palladium.) solution 0.2 g. of of pa lla dous chl orid e in 0 nil. nil. of of hot ho t wat er was th en p oure on aluminum and left overnight. The palladized aluminum was filtered and washed with water and added to a solution of 22 mixture of 200 ml conc'd hydrochloric aci d an d 2 0 ml. of water. The reaction slow slow to sta rt but became became gradually quite vigorous and had to be moderated b y outside coolin cooling. g. When When the reaction st oppe d, th e unreacted aluminum as dissolved conc'd conc'd hydrochloric acid, the mixture distilled with stea m, and treated a8 before.
ro c h lo lo r ic ic a c i d the presence palladium. h7ydrogeruation w i t h c a l c i u m h y d r i d e a n d h y d ro of methanol. To th is solution was was added a solution of as dissolved in 100 ml. of 11 0.25 g. of of palla dium chloride in ml of hot conc'd hydrochloric acid (Solution Calcium
hydride 11 g., generously generously supplied supplied by Metal Hydrides, Inc .) was covere covered d w ith 10 ml. of methanol an d solutio was 8,d 8,dde ded d t such a rate t ha t t he tem pera ture of of t he reaction mixture stayed stayed a 35-49", with o utside cooling f nec essary. When When th e initially-vigorous hydrogen development subsided, enough conc'd hydrochloric acid was added to bring the about and the mixture stirred during hour. The clear solution was filtered from the palladium black and washed with 20 ml . of of wate w ate r. Th en 250 250 ml. distilled remove the methanol and whatever propenylbenzene might have been formed (no more tha n a trace was ever foand ), the residue residue made made alkaline, and treate d as in previous previous experiments. The results obtained in t he foregoing experiments experiments ar e assembled assembled in Tabl P r o p e n y l b e n z e n e fr0.n a n d z i n c . were 11 g.) and 6 g. f anhy drous sodium car bon ate were suspended in 20 ml. ethe r. 30 30 ml. of of water was added, and a gita ted. The aqueous layer was washed with ether, the united ether solutions dried quickly with magnesium sulfate and filtered. filtered. The filtrate was was kept kept under under vacuum until the ether had evaporat ed. Then zinc zinc dust was was adde d. The mixture mixture heated u p spontaneously spontaneously to ebullition, ebullition, and t he g. reaction was moderated by cooling. The resulting liquid had a pure hydrocarbon smell and boiled at 173" uncorr.; (b.p. of propenylbenzene 176') of propylbenxene 159.5"). Th unsatura tion test was was positive, positive, and 1 te st ne gative ; yield 4.8 g. (81.6%). D i d e so s o x y ep e p h e d r in in e f r o m and copper. preliminary experiment gave no results when th e technique of th e reaction w ith zinc was was follow followed. ed. Apparently the copper does not react vigorously enough establish good contac t with t he liquid. Therefore the follow following ing method was used: g. of anhydr ous sodium ace tat e was was dissolved in 80 ml. of of w ater , an
l-PHE3’YL-l-CHLORO-2-METHYLA41IR’OPROPAKE
1735
14.4 of was dissolved dissolved in th e aceta te solution. (These are the act ual conditions of Emde’s hydrogenation which yielded both desoxyephedrine and didesoxyephndrine.),Then didesoxyephndrine.),Then g. of copper powder was added and the mixture mechanically stirred during 12 hours. Excess alkali wa3 added and the mixture distilled with steam to hydrolyze unreacted and to reinove all possibl possiblee volati le products (ephedri ne, pseudoephedrine etc.) The residue was extracted with eth er, the ether extract dried with magne magnesium sium sulfate. sulfate. yellow oil remained (32%), m.p. 71” (Emde reports 7 0 ” ) ; 9.31% which crystallized slom~ly, ield .1 (calc’d 9,4497c), insoluble insoluble precipitate with mercuric chloride chloride in HCl solution (Emde reports t he same). The low yield was apparently due to incomplete reaction, since large amounts of copper also were were found unreac ted. SUMNARY
1. In the reduction of 1-phenyl-1-chloro-2-methylaminopropane
cornpetitive reactions are demonstrated, one being hydrogenation to desoxyephedrine, the other the formation propenylbenaene by agents more metallic than hydrogen. Th e mechanisms mechanisms of of both bo th reactions are ar e discus discussed sed and interprete by means intermediate mono- and biradieals. 3. The simultaneous formation of didesoxj-ephedrine (2 5-bis-methylamino3,4-diphenylhexane) is interpreted as dimerization of the th e monoradic monoradical, al, a nd evidence for its structur stru cturee is offered offered rrILL.4XOVA,
PEKSSYLVANIA
REFERES’CES
EMDE,elu. EMDE,elu. Chim. A c t a , 12 36 (1929) (1929).. See particularly , p. 387 (2) SCHMIDT,r c h . Pharm., 262, 120 (1914). (3) HUGHES,SGOLD, S GOLD, Chem. Xoc., 493 (1934). .U-D WILSON,
(4) Ref.
1, p.
374.
