March 20, 1957
COMMUNICATIONS TO THE EDITOR
the chlorine or bromine is to the left (I, X’ = C1 or Br) the effect will be n e g a t k 8
I 0
1507
hibits a positive Cotton effect (peak6 a t 295 mp, [ a ] +498’) as does the halogen-free 1l-ketone,l3 while the axial llp-isomer shows a strong negative Cotton effect (trough6a t 337.5 mp, [a] - 1020”). (13) C. Djerassi and W . Closson, THISJOURNAL, 78,3761 (1956).
DEPARTMENT OF CHEMISTRY WAYNESTATE UNIVERSITY DETROIT, MICHIGAN X’
I
CARLDJERASSI
POSTGRADUATE MEDICAL SCHOOL
LONDON W. 12, ENGLAND RECEIVED FEBRUARY 14, 1957
W. KLYNE
Since the axially-oriented bromine or chlorine substituent in a-halocyclohexanones is often the more stable the presently described method MULTILAYER MEMBRANE ELECTRODES’ for the determination of absolute configuratiom of such ketones should be rather widely applicable. Sir: The steps to be taken are simple and particularly We have prepared a new membrane which is if the first one can be omitted, the entire sequence permeable almost exclusively to certain ions in the can be carried out on a micro-scale without using presence of other ions of the same charge. These up any material: (a) if both a and a’ positions membranes are multilayers, where transport of can be substituted and the exact location of the the potential-determining ion is transverse to the halogen atom does not follow from its mode of axis of orientation. preparation (e.g., epoxide opening followed by oxiMembranes were constructed by cracking a dation), then this must be established chemicallystandard slide in half, so as to insure a nearly perusually by dehydrohalogenation ; (b) the axial fect fit, because the effective membrane pore orientationlo of the a-halocyclohexanone must be width was 2.5 x cm. Each glass half-slide confirmed by ultraviolet7 and infraredg,l1 measure- was coated with 50 Y-type monolayers of barium ments; (c) the rotatory dispersion curve must be stearate, the two halves fitted together and cemeasured. It is then possible t o determine in the mented in place between slides having holes in their manner illustrated above (cf. I) which one of the centers, arms were attached for solutions and the two absolute configurations leads to the observed potential measured between saturated calomel (positive or negative) Cotton effect. electrodes. Attention should be called to two further apThe resistance of this membrane was 5.8 X lo7 plications of rotatory dispersion measurements ohms. Accordingly, a highly sensitive Keithley among a-halocyclohesanones. If the absolute Model 200 B vacuum-tube voltmeter accurate to configuration of the parent ketone is known but =t 1% was used with proper shielding. A conthe location ( a or a’)of the axial halogen atom is stant asymmetry potential of 1-3 mv. for identical not, then the rotatory dispersion curve will provide barium chloride solutions was read; constant and the answer. Conversely, if information concerning stable potential readings were obtained rapidly. the absolute configuration of the ketone and the Preliminary results obtained with this Multilocation of the halogen substituent is available, layer Membrane Electrode are given. Experibut spectroscopic determination of the orientation mentally determined potentials were corrected of the halogen atom is obscured by additional for asymmetry. Calculated e.m.f. values were obcarbonyl groups, a decision may be reached by tained using the tabulated data of ConWaf; a t means of the rotatory dispersion curve. An in- higher concentrations, mean activity coefficients teresting example is provided by the two epimeric were used. For dilute (< 0.02 M ) solution pairs methyl 3a-acetoxy-ll-bromo-12-ketocholanates1z whose concentration ratio was less than 2:1, calwhich possess virtually identical rotations ( [ y ] ~culated e.1n.f. values were reasonably accurate. +44’ and $-4o”) a t the conventional sodium D Multilayer Membrane Electrodes are shown to line. However, the rotatory dispersion curves* be reversible to barium ions, even in the presence disclose that once rotation measurements are con- of high concentrations of sodium ions, .A. real tinued in the ultraviolet range, a marked change is measure of this specificity cannot be obtained frorn noted. I n agreement with the postulates made in potential measurements, but is being deterniincd this paper, the equatorial 11a-bromo isomer ex- using transport, exchange, and other methods. ( 8 ) This effect may be so pronounced that it may carry over into the The ability of Multilayer Membrane Electrodes visible range of the spectrum. Consequently, a t times even comparito concentrate a specific ionic species without coniSOUS of molecular rotation differences (based only on [ P ] D values) with pletely immobilizing that species is responsible for steroid reference compounds may be used as has been done in the its specific function. The glass electrode is an exfriedelin series (E. J. Corey and J. J. Ursprung, THISJOURNAL, 78, 5041 (1956)). ample. This ideal or nearly ideal degree of speci(9) E. 5. Corey and H. J. Burke, i b i d . , 77, 5418 (1955), and earlier ficity results from its highly oriented or semi-crystalpapers. See, however, W. D. Kumler and A. C . Huitric, ibid., 78, line state. Pores, in the usual sense, are not pres3369 (1956). ent. Transport probably takes place by ex(10) I t appears (ref. 4) that even if the equatorial orientation is the more stable one it might still be possible to use this method if the correchange between adjacent barium ions. Nultisponding gem-dihalo ketone is available since one of the halogen layer Membrane Electrodes specific for other catatoms must now be axial. (11) R. N . Jones, D. A. Ramsay, F. Herling and K. Dobriner, THIS 2828 (1952). (12) Kindly provided by Dr. T. F. Gallagher, Sloan-Kettering Institute for Cancer Research. JOURNAL, 74,
(1) We wish t o thank tbe Office of Naval Research and the U. S. Public Health Service for the support given this work. (2) B. E. Conway, “Electrochemical Data,” Elsevler Publishing Co., N e w York, N. Y.,1952, p. 102.
COMMUNICATIONS ro THE EDITOR
1508
TABLEI BARIUMSTEARATE fif L-LTILAYER &lEMBRAXE ELECTRODES Chain S.C.E. llSolution 1 /Membrane /Solution 2ilS.C.E. Temperature, 25’
PO1.ENTIALS
OF
Solution 1 M
0.002 BaCl? 0.02 R ~ C L 0 . 0 1 BaC12 1 . 0 BaC12 0 . 0 2 BaC12 0 . 0 2 BaCll
1 .O
BaC12
Solution 2
M
0.001 BaCL 0.01 BaCL 0,001BaCl? 0 . 5 BaC12 0 . 0 1 BaClz 0.005 KaCl 0 . 0 1 BaC12 0.02 s a c 1 0 . 5 BaCL 2 . 0 XaC1
Experimental e.m.f. ( c o x , ) , mv.
7.65 6.65 25.15 ,j. 28
Calcd. e.m.f.,
mv .
C,.S;,
7.88 6.55 24.21 4.96 7.01
8.10
8.22
3.27
Vol. 79
in 1554 yield a t 573’ in a mineral otl suspensio~i.~ Alethylation of I yielded the %methyl ether, m.p. 1-23-144°; [ a ] ~ 122’ (chloroform); (L4?zul. Calcd. for C21H2801:C, 76.79; H, 8 59. Found: C, 76.94; H, 8.74). Acetylation gave the oily 11,21-diacetate6 which when ozonized furnished
+
I , R = 11; IC’ = B - O H ;
X 11, R
..
ions or anions could in principle be prepared from insoluble or non-ionized salts which formed multilayers; further work in this direction is in progress. The specific resistance of the multilayer transz’erse to the axis of orientation was 1.9 X l o 4 ohm cm. -4 hfultilayer Membrane 50 A. thick (10 molecule multilayer row) would have a resistance of 0.01 ohm cm.2, a value which approximates that of ion-specific natural membranes. Multilayer Membrane Electrodes can be used to measure activities of ions in mixed electrolytes. Problems of biochemical interest similarly can be attacked, such as the determination of calcium ion activities, the so-called “unbound” calcium concentration, in blood and other biological fluids.
=
x
=
1.1,R
=
>C=CH-CII20H CH,; R’ = P-OXC;
>c=o
111, R
=
s
=
P-OI~; OII
\ /
c---H
i
€10 0
O I I ; IC--H VIII, R = 01%;R’= a - O H ; OH X
=
\ /
c--€I
/
the lI@-acetoxy-3-methoxy-1,3,5 (10)-estratrien-1TI ~ E P A R T X EOF N TCHEMISTRY OF BROOKLYX HARRYP. GRECOR one ( I I ) , m.p. 236-238’; POLYTECHXIC INSTITUTE [a]D 117’ (chloroSCHONHORN BROOKLYN, NEWYORK HAROLD form); (-44nal. Calcd. for C20H26O4: C, 73.66; H, RECEIVEDFEBRUARY 6, 1957 ‘7.65.Found: C, 73.4G; H, 7.60). The structure
+
of I1 and therefore also that of I was established by the conversion of 11, using a lithium aluminum hydride reduction followed by a Birch type reducSir: tion, to llP-hydroxy-19-nortestosterone(111).6 Although aromatic A ring steroids are well This is the first described synthesis of an ll-oxyknown, their 11-oxygenated analogs have not been genated 19-norsteroid wherein the 11-hydroxyl described. W;e have prepared several members group was present during the chemical modification of this novel class of steroids and also have con- of Ring A. verted them to 11-oxygenated 19-norsteroids hithA novel reaction was encountered when I1 was erto only available through the 11-hydroxylation reduced with lithium in ammonia in the presence of the corresponding 1l-desoxy-l9-norsteroid~.~~~ of alcohol. The expected product I11 was not The key intermediate for these chemical trans- detected, but a compound was isolated to which formations is 19-nor-1,3,5(10),17(20)-pregnatetra- the following structure is assigned : 1-(a-hydroxyciie-3,llp,21-triol (I), n1.p. 200-202”; [ a ] D ethyl)-ll~,li~-dihydroxy-4-pregnen-3-one, 1n.p. 1 I O o (acetone); 281 nip, ab1 2,000; ( A d . 221-222’. ! : :A “17 m p , 3x1 = 15,000; (:Id. Culcd. for C20H2a03: C, 78.40; H, 8.35. Found: Calcd. for Cz~I-I,o@4: C, 71.83; 13, 9.04. Found: C , 76.62; H, 8.66). The surprising stability of C, 72.04; H, 8.90; C-l,lethyl 2j. Oxidation o f the 1 16-hydroxyl group under pyrolytic conditions this compound gave an oily tetraone which showed was demonstrated by the conversion of llp,21- a maximum in the ultraviolet a t 340 mmp, thus dihydroxy-1,4,17(20)-[cis]-pregnatrien-3-one3 to I ruling out a hydrosyethyl substituent a t 2 or 4. (1) 11-Ketoequilenin. which has both aromatic A a n d B rings was We postulate that this unique conipound niay be deicrilied by K. E. Slarker and E . Rohrman, THISJOURNAL, 61, 3314 formed by an internal Claisen type transfer of the (19:3!1). SYNTHESIS OF THE NOVEL 11-OXYGENATED 1,3,5( 10)-ESTRATRIENES
+
1 2 ) T h e 11or-hydroxyl group was introduced into a 19-norsteroid by a rnicrohiologicnl procedure, 12. I,, Pederson, J. A. Campbell, J. C. Iiabcock, S. H. Eppstein, 11. C. hlurray, A . Weintraub, R. C. hleeks, 1’. I). hreister, I-. M. Reineke and D. IT. Peterson,ibid., 78, 1512 ( 1 O . X ) . T h e llp-hydroxyl group was introduced by a n adrenal perfusion technique, F. R. Colton and J. W. Ralls, U. S. Patent 2,694,080 (19.54). ( 3 ) J . A . I I o x g , I;. 11. T.itic~~ln, A. 11. Piathan, A. R. Hanze. B. J. Llaperlcin, n7. 1’. Schneider, 1’. 1; Deal and J . Korman. T H I S J O U R N A L , 77, 4136 (195,j).
(4) E. D . Hershlxrg, 37. R u b i n and E. Schwenk, J . 01,~.CheiU., 15, 0‘32 (1050). ( 5 ) T h e 110-hydroxyl group is acylaterl with acetic anhydridcpyridine a t room temperature in t h e 19.nnr series. See also ref. 8 . footnote 7. (6) W e are indebted to J. A . Campbell and J. C. Babcock, of t h e Upjohn CompanI-, for a known sample of 1Ip-hydroxy-19-nortestosterone. whose preparation was described by J. C. Babcock a t the 129th Meeting of the American Chemical Society. Dallas, Texas, April 8-13, 1956. See p. 20hl of the Abstracts.
