R. XORMAN JONES
5242
AND
BEATRICE S. GALLAGHER
3-Cycloethylene Ketal of Cortisone B.M.D.(XVIII).Ethylene glycol (40 cc.) was added t o a solution of cortisone B.M.D. (XVII) (3.0 g.) in benzene (400 cc.) containing p toluenesulfonic acid monohydrate (200 mg.) and heated under reflux with a water separator for 8 hours. Sodium bicarbonate solution (20 cc., 5%) and water (250 cc.) were added and the product isolated with benzene. Removal of the solvent and crystallization of the product from benzenehexane afforded the 3-cycloethylene ketal of cortisone A.M.D. ( X V I I I ) (1.75 g.), m.p. 188-192', raised by several D crystallizations from benzene-hexane to 200-202', [a] -88'; XVIII exhibited no selective absorption in the ultraviolet. A n d . Calcd. for C2jH3107:C , 67.24; H, 7.67; 0,25.09. Found: C,66.79; H , 7 . 7 3 ; 0,25.26. Permonophthalic Acid Oxidation of the 3-Cycloethylene Ketal of Cortisone B .M .D. (XVIII).-Permonophthalic acid ( 3 . 8 g . ) in ether (50 cc.) was added dropwise over 15 minutes to a solution of t h e cycloethylene ketal of cortisone B.M.D. (XI'III) (4.75 g.) in chloroform (50 cc.) at -10". After keeping at 0' for 16 hours the solution was washed n i t h cold 5yb sodium bicarbonate solution until i t was acid free and then with water t o neutrality. Removal of the wlvent after dr5 ing over sodium sulfate afforded a product which was adsorbed from benzene onto alumina (200 g.). Elution with benzeneether (80:20, 1.5 1.) afforded the 3cycloethylene ketal of cortisone B.M .D.-Sa,Ga-epoxide ( X I X a ) (2.55 g.), m.p. 293-297'. The analytical sample from ethyl acetate-hexane had m.p. >300°, [ a ] D -90". A n a l . Calcd. for C?&408: C , 64.92; H , 7.41; 0 , 2 7 6 7 . Found: C,64.76; H,7.63; 0 , 2 7 3 8 . Potassium Cyanide Cleavage of the 3-Cycloethylene Ketal of Cortisone B.M.D.-Sa,6a-epoxide (XIXa).-Potassium cyanide ( 2 . 5 9.) was added to a solution of the epoxide XIXa (1.23 g.) in ethylene glycol (50 cc.) and heated under reflux for 45 minutes. Addition of water and isolation with ethyl acetate afforded a product which wis adsorbed from benzene onto alumina (50 g.). Elution with benzene (750 cc.) afforded the A6-6-cya;o-3-cycloethj lene ketal ( X X a ) (250 mg.), m.p. 262-264 , raised by several crystallizations 224 from benzene-hexane to 267-269", ID -138", ":,A: mp, E 10,073. .4nal. Calcd. for C&&x: C, 66.22; H , 7.05; N, 2.97. Found: C, 66.59; H , 7.15; N, 3.34. Further elution with benzeneether (90: 10, 750 cc.) afforded t y the 6-cyano enol ether XXIa (420 mg.), m.p. 192-197 , raised by several crystallizations from ben-
[CONTRIBVTION FROM
THE
lrol. 81
zene-hexane to 209-21lo, [,ID -13no, k",t,"," 284-286 m p , e 18,200. Anal. Calcd. for C26H3307N: C, 66.22; H , 7.05; X , 2.97. Found: C,66.iG; H , 7.02; N,3.14. Potassium Cyanide Cleavage of Cortisone Bis-ketal-5a,6aepoxide (XIXb).-Potassium cyanide (4.0 g.) was added to a solution of cortisone bis-ketal-joc,6a-epoxide~3 ( X I X b ) (2.0 9.) in ethylene glycol (80 cc.) and heated under reflux for 1 hour. Addition of water to the cooled solution and extraction with ethyl acetate gave a product which was adsorbed from methylene dichloride-benzene ( 1 :30, 500 cc.) onto alumina (80 g.). Elution with ether-acetone (90: 10, 1 1.) afforded after one crystallization from acetone-hexane 6-cyano-A6-pregnene-17a,21-diol-1 1-one - 3,2O - bis - cycloethylene ketal acetate (XXb) (440 mg.), m.p. 273-275", raised by several crystallizations from acetone-hexane to 277-279", [ a ] ~ -56'; " : :A 22-1 mp, E 11,000; ::A: 3450, 2200 and 1705 cm.-'. Anal. Calcd. for C26H3507K: C, 65.94; H , 7.45; N, 2.96. Found: C,65.64; H , 7 . 6 6 ; S , 3 . 0 7 . Further elution with ether-acetone (70:30, 800 cc.) afforded 6-cyano-3-(2 '-hydroxyethyl)-A3~5-pregnadiene-I7a,21diol-11-one-20-cycloethylene ketal ( X X I b ) (370 mg.), m.p. 2~l7-2-19"~raised by several crystallizations from ethyl ace~ X",t."," 284-286 mp, tate-hexane to 248-250°, [ a ] -59'; e 17,800; ;:A: 3450,2200, 1690 and 1625 cm.-'. Anal. Calcd. for C2&607x: C , 65.94; H , 7.45; K, S , 2 . 9 6 . Found: C,65.64; H,7.66; S , 3 . 0 6 . 6~Cyanocortisone(XXII).-Perchloric acid (3.7 cc., 35%) was added to a solution of 6-cyano-3-(2'-hydrox\-ethyl)A3pS-pregnadiene-170,2 1-diol - 11,20- dione -20 - cycloethylene ketal ( X X I b ) (220 mg.) in tetrahydrofuran ( 7 . 4 cc.). After 3 hours at room temperature water was added and the product extracted with ethyl acetate. The combined extracts were washed with sodium bicarbonate solution ( j o b ) , mater and then dried over sodium sulfate. Removal of the solvent afforded 6a-cyanocortisone ( X X I I ) as an amorphous solid, 1n.p. 152-162', which resisted crystallization; [ a ]D -22' 220-222 and 286-288 mp, E 4,300 and (dioxane); " : :A 3500, 2200, 1720(sh), 1700, 10,800, respectively; ::A: 1670 and 1625 cm.-l. The analysis for XXII was unsattsfactory. Anal. Calcd. for C Q ~ H ~ ~ O C,~ 68.55; K: H, 7.06; N , 3.63. Found: C,67.56; H , 7 . 3 1 ; N,2.95.
POSTAL 2679, MEXICO,D . F. APARTADO
DIVISION OF PURECHEMISTRYOF THE NATIONALRESEARCHCOUKCILOF CANADAAND SLOAN-KETTERING INSTITUTE FOR CAXCERRESEARCH']
THE
The Infrared Spectra of Steroid Lactones BY R. NORMAN JONES
AND
BEATRICES . GALLAGHER
RECEIVEDFEBRUARY 20, 1959 Characteristic features of the infrared spectra of twenty-six types of steroid lactones are summarized and discussed. For saturated -1- and &lactones it is observed that, in the absence of direct perturbing influences such as the inductive effects of vicinal substituents, the C=O stretching frequency in solution is negligibly influenced by the location of the lactone group with respect to the steroid ring system. The ranges previously assigned to the positions of the C=O stretching bands of saturated y- and &lactone systems are confirmed, and other absorption specific to different types of steroid lactones is noted between 1450 and 1350 cm. -1. The unsaturated lactone systems of A20[z2)-cardenolides and A20~22-bufadienolides exhibit two bands in the C=O stretching region of the spectrum; the relative intensities of the two bands show large solvent effects, b u t they are not significantly influenced b y the formal extension of the conjugated system into ring D.
Numerous publications during the past few years have served to focus attention on the prevalence of lactone groups in naturally occurring compounds; typical examples are the bitter principles, such as pictrotoxin and limonin, the santonins, nepetalactone, and gibberellic acid. Lactones are also encountered in steroids; unsaturated y - and 6(1) Published a s Contribution KO.5303 from the Laboratories of the National Research Council of Canada, and No, XXXII in the series "Studies in Steroid hletabolism."
lactone ring systems characterize the cardiac, squill and bufalin aglycones m-hile various types of saturated steroid lactones have been obtained in the course of synthetic and degradative studies. Infrared spectrometrv has been used extensively to distinguish betm-een y- and &lactone ring systems in natural products; a range of 1780-l7GO cm.-' is commonly reported for the C=O stretching frequency in saturated y-lactones and 1750-1'735 cm.-'
Oct. 5J 1059
5243
INFRARED SPECTRA OF STEROID LACTONES
for saturated &lactones.* Nevertheless, the spectroscopic distinction between y- and &-lactoneshas not always been reliable. I n columbin, a dilactone, Barton and Elad3 observed carbonyl bands a t 1750 and 1725 cm.-l in chloroform solution; they assigned the band a t 1725 cm.-’ unequivocally to a saturated &lactone group, but they could not differentiate spectroscopically between a y- and &lactone ring for the second carbonyl band. Subsequent chemical investigations established i t to be a /3, y-unsaturated-a-hydroxy-&lactone. The positions of lactone carbonyl bands have been recorded along with other analytical data in several papers dealing with the structure of individual natural products, and some lactone carbonyl frequencies have been reported for steroids. However, the characterizing features of such lactone spectra have not hitherto been considered collectively. The object of this paper is to amplify and coordinate such scattered observations on the infrared spectra of steroid lactones and, in particular, to draw attention to the anomalous absorption associated with the cardenolide and A20,22-bufadienolidestructures. A subsequent paperg will report in greater detail certain features of lactone spectra that are exhibited to better advantage in simpler model compounds. Experimental T h e spectra measured in our laboratories were determined on Perkin-Elmer model 112 and model 21 spectrometers. Calcium fluoride prisms were used above 1300 cm.? and sodium chloride prisms below. The estimated precision of the reported band positions is *2 cm.-l. T h e steroids were acceptable “analytical” samples and none exhibited any spectrographically recognizable impurity. T h e sources of the individual compounds are acknowledged in the footnote t o Table I . T h e complete spectra, together with the spectra of related model compounds will be published separately.1°
Results and Discussion In Table I the characteristic group frequencies are listed for the individual steroid lactones. The complete data including values taken from other publications are summarized in Table 11. Many of the compounds also contained other carbonyl groups but, in general, there was no difficulty in recognizing the lactone carbonyl absorption. Saturated y-Lactones.-Lactones of types I-IV have been examined in our laboratories and the infrared spectra of several additional types of ylactones have been reported in the literature, these VII,’? VIIII3 and include structures V7,11 1x.13
(2) L. J. Bellamy, “The Infrared Spectra of Complex Molecules,” Methuen & Co., London, second ed., 1958, p. 179. (3) D. H . R. Barton and D . Elad, J . Chem. Soc., 2085, 2090 (1956). (4) R . N.Jones, P. Humphries and K . Dobriner, THISJOURNAL, la, 956 (1950). (5) R . N. Jones and F. Herling, J. O y g . Chem., 19, 1252 (1954). ( 6 ) G. Roberts, B. S. Gallagher and R . N. Jones. “The Infrared Absorption Spectra of Steroids-An Atlas, Volume 11,” Interscience Publishers, Inc., New York, N. Y . , 1958, pp. 22-26. (7) V. J. Schmidlin, G. Anner, J.-R. Billiter and A . Wettstein, Experientia, 11, 365 (1955). ( 8 ) C. Gual, R . I . Dorfman and H . Rosenkrantz, Speclrochim. Acta, 13, 248 (1958). (9) R. N.Jones, T . Ito, C. L. Angell and R . J. D . Smith, Can. J. Chem., in press, (10) R . S . Jones, T.Ito, C. L. Angell and R . J. D . Smith, National Research Council of Canada Bulletin No. 7. (11) S.A. Simpson, J. F. Tait, A. Wettstein, R . Neher, J yon Euw, 0.Schindler and T . Reichstein, Helw. Chim. Acta, 57, 1200 il:’54)
CH,
1 ,o-c=o
b-C c, I H r CI H *
I
,CH,C=O
~HC\CH20 -I
x
,CH,C=O
I
I11
I1
’
’ -1v
VI
o=c, IX
VI1
Structures I-VI1 exhibit sharp intense carbonyl bands between 1789 and 1777 cm.-’ in carbon tetrachloride solution, and between 1782 and 1772 cm.-’ in chloroform solution. This agrees with values commonly reported for monocyclic compounds. Neighboring carbonyl groups, such as those occurring in 11,17-diketones and 21acetoxy-20-ketones, are known to induce characteristic displacements of C=O stretching frequencies, but no comparable effects are apparent in the oxygenated lactone structures X-XIV described by Wettstein and collaborator^,^ all of which show the lactone carbonyl band between 1779 and 1770 ern.-' in methylene chloride solution. For the lactol XV a C=O stretching band a t 1764 ern.-' has been reported14; here the lowering might be attributed to the vicinal hydroxyl group but the extent of the displacement cannot be fully assessed since the solvent is not stated. The lactones of types VI11 and IX, derived from steroidal sapogenins, are also reported to absorb a t a significantly lower frequency (1773 ern.-' in carbon disulfide and 1764 cm.-’ in methylene dichloride).I3
X
a YH3
XI,R=-H XII, R = -0 -CO-CHj XIII, R = -OH CsHi;
0-c c=o
P
?@
o=c,
OH XV
In IV the carbonyl band of the A4-3-ketonegroup occurs a t 1686 cm.-l in carbon tetrachloride solu(12) T . L. Jacobs and N. Takahashi, THISJOURNAL,80, 4865 (1958). (13) J. W.Corcoran and H . Hirschmann, ibid., ‘78, 2325 (1956). (14) F.L.Weisenborn, D. C. Remy and T. L. Jacobs, ibid., 1 8 , 552 (1954). The stereochemistry of X V at C(5) is not specifically defined but the hydroxyl group is presumably a.
5244
R.NORMAN
JONES AND BErlTRICE
s. G A L L s G I I E R
Vol. 81
TABLE I CIIARACTERISI I C .'BSORPTION
Structure
BAXDS I N THE INFRARED SPECTRA O F STEROID L A C T O X E S Sol---Characteristic bands, cm.- -- I Carbonylc Otherd Sourceb vent
Compounda
A. I
I1
111 IV
Saturated y-lactones
XVIII
XVIII
x1x
1425; 1392,' 12028,h 1424,c 1392,' 1202,gsh 1424,e 1390,' 12008sh 1424,e 1 1768,h
3
CHCli
1775,1716,1680
11700
3
CHCIi
1777,1711,1678
11748
cs1
1744
1420,6
1078.0 10500
Ccli
1747
1417;
1078,U1047"
CS!
1742
CSZ
1745
CClr
1740
CClr
173gk
CSz
1767,1742
CHCla
1718
CClr
1737k
CSa
1742'
i
CHCla
1718
i
11140
CSz CCIr CHCla CClr CMCls
174Zk 1743 1722 1742 1723
i i i
ll0P
CClr
1744
1418,8 1401,i 1180,Urh10378*"
CCI,
1742'
1419;
[email protected],g*h1042°9h
8 - H y d r o x y - 3 , 2 0 - d i k e t o - ~ ~ - l 7 ~ - p r e g n e n - l 9acid - o i clactone
3
B.
XVll
1777,1733 1778,1718 1778,1679 1786,1736 1775,1727 1789,1736 1776,1728 1781,1710,1686 1772,1705,1677 178?,1709,1686 1772,1704,1675
3
8,21-Dihydroxy-3,20-diketo-A~-pregnen-lQ-oic acid 8: 19. lactone 8,21-Dihydroxy-3,20-diketo-A'-l7a-pregnen-l9-oic acid 8: 19-lactone
XVI
CClr CClr CC14 CCI4 CHCls CClr CHClr CClr CHCls CCId CHCls
3,9-Acetoxy-20-hydroxy-A5-cholenic acid lactone 38-Benzoxy-20-hpdroxy- As-cholenic acid lactone 20-Hydroxy-3-keto-~4-cholenicacid lactone 3 S - A c e t o x y - l ~ - h y d r o x y ~ c a r d a n o l i d(dihydroxy-digitoxie genin acetate) 38-Acetoxy-14-hydroxy-lia-cardanolide (17-iso-dihydroxydigitoxigenin acetate) 8 - H y d r o x y - 3 . ? ~ l - d i k e t ~ - ~ ~ - p r e g n e n - acid l ~ - o lactone ic
1 1
1 2
2
142?,e IIGSRah ,.
ll63Q.h 116.58 1170Uzh
Saturated &lactones
5-Hydroxy-3 :5-seco-4-norcholestan-3-oic acid lactone 1 5,178-Dihydroxy-3 : 5-seco-4-norandrostan-3-oic acid 3 15. lactone 1 5,178-Dihydroxy-3: 5-seco-4-nor-17-methylandrostan-3-oic acid 3: &lactone 1 5,20-Dihydroxy-3.5-seco-4-norallopregnan-3-oic acid 3: 5lactone 1 acid 3B,lG-Dihydroxy-16 : 17-seco-A~-androsten-l7-oic 16: 17-lactone 4 38. Acetoxy-16-hydroxy-16 : 17-seco-A~-androsten-17-oicacid 4 lactone 3-Acetoxy-13-hydroxy-13 : 17-s~~o-A'~3~~('O)-estratrien-l7oic acid lactone (estrololactone acetate) 5,6 3a,l3-Dihydroxy-13 : 17-seco-androstan-17-oic acid 13 :17lactone (andrololactone) 7 acid 3a-Acetoxy- 13-hydroxy- 13 : 17-seco-androstan-17-oic lactone (andrololactone acetate) 7 3~-Acetoxy-13-hydroxy-13 : 17-seco-androstan-17-0ic acid lactone (isoandrololactone acetate)' 5,s acid 13 : 173~,13-Dihydroxy-13: 17-seco-etiocholan-17-oic 7 lactone (3a-etiocholanololactone) 3~-Acetoxy-13-hydroxy-13 : 17-reco-etiocholan-17-oic acid lactone (3~-etiocholanololactone acetate) 8 7 13-Hydroxy-3-keto-13:17-seco- Al :'-androstadien-17-oic acid lactone 13-Hydroxy-3-keto-13: I7-seco-4~-antlrosten-17-oicacid 9 lactone 38-17-Dihydroxy-16: 17-seco-4~-androsten-l~-oic acid 4 16: 17-lactone 3~-Acetoxy-17-hydroxy-lG : l7-seco- AS-androsten- 16-oic 4 acid lactone
'
i
i
%
11180 1422: I l 1 6 u ~ h i
i
142OE 1102e
C. Unsaturated ?-lactones XXVII XXVIII XXlX
xxx XXXI XXXIl XXXIII
3B-14-Dihydroxy-A~o~z*)-cardenolide (digitoxigenin) 2 CHCIa 3~-Acetoxy-l4-hydroxy-A~~l22)-cardenolide (digitoxigenin 2 CSz acetate) CHCls 3~.5,14-Trihydroxy-19-0~0423(2Z)-cardenolide (strophanthidin) 2 CHClr 3~,16-Diacetoxy-A.I~11S)'20cl2)-cardadienolide (14-anhydrogi2 CS? CHClr toxigsnin diacetate) 3~.14-Dihydroxy-4l~(l7),~~*~)-cardadienolide (16-anhydrogi2 CHCla toxigenin) 38-Acetoxy-14-hydroxy- A.la(i7)~zo:z2)-cardadienolide 2 CSn CHCla (16-anhydrogitoxigenin acetate) 3 ~ - A c e t o x y - A ~ ~ ( ~ ~ ) ~ l ~ ~ ~ ~ ~ ~ ~ o (14,16( ~ ~ ) - c a r d a t r i e 2n ~ l i CS? de dianhydrogitoxigenin acetate) CHCla
1787,m1747" 17R3,m1756," 1738 178+.m17?d,"1730 lfi20' 1790,m1748," 1718P 1624O 1 7 ~ 3 417%,"173Q ,~ 1787," 17S2,n 1730 1628' 1790." 1748" 1624" 178A,m175Ln 1737 178S,m17-18."' (2732) 1622' 1780," 1750," 1735 1786,m 1 7 3 8 ' ~ ~ 1612,' 1.568'
D. Unsaturated &lactones XXXVII XXXVIII XXXIX XL X1,l
3,3,14-Dihydroxy-A2o*22-bufadienolide (bufalin) 3~,5,14-Trihydroxy-l9-oxo-A~~~~~.bufadienolide (hellebrigenin) 3pAcetoxy-5, 14-dihydroxy-19-oxo-A~~~~-bufadienolide (hellebrigenin acetate) 38,16-Diacetouy-~1~(l5)~zo~ZZ-bufatrienolide (14-anhydrobiifotalin diacetate) 3~-Acetoxy-A~~il~),ls"l.z".z1-bufatetraenolide (l4,lG dian liydro-ilesacetyl-bllfotalin acetate)
2
CRCh
(1740). 1718
1636'
2
CHCIs
(1740), 171SP
1R3S0
2
CHClr
csz
1740 1718p 1781, 17ROP (1748), 172OP 174@ 1723k
163Go
2
CHCls 2
C& CHCla
1(i78
1632," 1600'
The nomenclature used here has been modified from that of our previous publications to conform more closely with (1).B. J. the recommendations of the I.U.P.A.C. as reported in Chemistry 6 Industry, pp. SN1-SN11 (June 23rd, 1951). Brent, Organon, Inc., Orange, N. J . ; (2) T. Reichstein, University of Basel, Basel, Switz.; ( 3 ) M. Ehrenstein, University ?f Pennsylvania Medical School, Philadelphia, Pa.; (4)G. Papineau-Couture and G. A. Grant, Ayerst, McKenna and H a m a
INFRARED SPECTRA OF STEROID LACTONES
Oct. 5, 1959
5245
son Ltd., Montreal, Can.; ( 5 ) R. F. Jacobsen, Worcester Foundation for Experimental Biology, Worcester, Mass., (6) W. W. Westerfeld, Syracuse University, N. Y .; (7) compound synthesized a t the Sloan-Kettering Institute, New York, N. Y. ; Bands not (8) D. -4. Prins, Cleveland Clinic, Cleveland, 0.; (9) J. Fried, Squibb Laboratories, New Brunswick, N. J. See text. * Band assigned to associated with the lactone carbonyl are'italicized; inflections are given in parentheses. Band assigned to C-0 stretching vibration of lactone -CHrCO-O- group. Band assigned to C(18) methyl group. group. Measured in carbon disulfide solution. Region not measured. i Band tentatively assigned to CO-0-CHr, The carbonyl bands of these compounds were regroup in a six-membered ring. Overlapped by acetate absorption. ported previously in ref. 4 where they were assigned erroneously to structure XVII; see also ref. 21. The C=O frequencies re"Norported here are based on new and more precise measurements than those reported in ref. 4. m "Abnormal band." mal" band. C=C stretching band. p Overlapped by C(19) aldehyde absorption. Q
TABLE I1 SUMMARY TABLE OF STEROID LACTONE BANDPOSITIONS SolStructure
vent
C=O stretching band,c cm.-1
Other bands, cm. - 1
A. Saturated y-lactones I I1
20-Hydroxy-cholanic acid lactone Cardanolide
I11
17-a-Cardanolide
1v
8-Hydroxy-19-oic acid lactone
V
llj3-Hydroxy-18-oid acid lactonea
VI
VI11
1l8,l8-Epoxy-18-hydroxy-20-oic acid lactone" 5-Hydroxy-2 : 5-seco-3,4-bisnor-2-oic acid lactone' 16B-Hydroxy-bisnorallocholanicacid lactone
IX
16~-Hydroxy-20-isobisnorallocholanic acid lactone
XV
6,5-Dihydroxy-2 :5-scco-3,4-bisnor-2-oicacid lactoneb
V II
B.
CCt CClr CHCla CCh CHCli CCIr CHCI, CHClr CHzClx CHCla CClr CSt CHzClt CSt CHzCI2
..
1778-1777 1786 1775 1789 1776 1782-1781 1777-1772 1782 1779-1770 1779 1785 1773 1764 1773 1764 1764
1425-1424.6 1392-1390'. 1424.6 1 1 7 6 8 ~ ~
1202-1200°1h
117P1165h
1175,' 10170 1184,g 1017' 1184,P 1016' 1171,'lOlG'
Saturated &lactones
XVI
5-Hydroxy-3 :5-scco-4-nor-3-oic acid lactone
XVII
16-Hydroxy-16: 17-seco-17-oic acid lactone
XVIII
l3E-Hydroxy-13 : 17-scco-l7-oic acid lactone
XIX
17-Hydroxy-16: l7-scco-16-oic acid lactone
XX
5-Chloro-5-hydroxy-3 :6-scco-4-nor-3-oic acid lactoned
CS; CCIr CClr
1744-1742 1747 1740-1739
CSt CCt CHClr CCh
1742 1743-1737 1723-1718 1744-1741
..
1078,' 1050,' 1420-1417,' 1078,Q10470 1401,j 1155-1154.0~~ ll10-l108Q*h 104&10450~A 1116' 1422-1420' 1118-11020 1419-1418,' 1401-1400,j 1192-1190'*h 1042-1037'J*h
1770
C. Saturated elactones XXIV
xxv
13E-Hydroxy-12: 13-seco-5a,22a-spirosta~-l2-oic acid lactone acid 11-Keto-13E-hydroxy-13 :~7a-scco-~-homo-17a-oic lactone
D. XXVIIXXIX
xxx
168-Acetoxy- AI'(
XXXIXXXII XXXIII
Al6clil,rcl2)-Cardadienolide
XXXVI XXXVIIXXXIX XL
5-Hydroxy-2 : 5-seco 3: 4-bisnor-As-2-oic acid lactone
XLI
A ~ ~ UI6(171,a~2r-Bufatetraenolide QI
XLII
5-Hydroxy-As-4-nor-3-oic acid lactonebBd
N),"["Lcardadienolide
16(171,2o[tl)-Cardatrienolide
A2orZ2-Bufadienolide 16j3-Acetoxy-A''' '5)'*0*2*-bufatrienolide
1727 1705
CHClr
See text, p. 13
Unsaturated y-lactones
Aa~~~))-Cardenolide
A14(LJ )r
CSz CHCla
C b CHClt CSz CHCla CSI CHCla CSI CHCla cch
1783,'" 1756" 1790-1784," 1748-1745" 1784," 1758" 1787,'" 1752" 1783,'" 1755" 1790-1788,m 1748" 1780,m 1750" 1786,% 1738'3'' 1806
CHCla CSi CHCli CSz CHClt CClr
(1740), 1718 1751,1736 (1748), 172Qk 1740k 1723k 1757-1756
1624-1619' 1628' 1624-1622O 1612,O 1568" 1705' 1636' 1638" 1632,' l6OO0 16G7"0
See ref. 7, 11. See ref. 14. C Points of inflection indicated by parentheses. See ref. 28. eJ~&jAm~n#o See footnote to Table I. This value is reported for a series of compounds in ref. 31; 1682 em.-* has been reported subsequently for one compound in ref. 12. See ref. 12.
tion. This is higher than the normal position a t 1681-1677 In chloroform solution I V absorbs a t 1680-1675 crn.-l, while the normal range is 1668-1660 cm.-'. The A4 C=C stretching vibration is also displaced in these compounds from 1619-1613 to 1635 ern.-' (CHCla soln.). It would appear therefore that the bridging of ring B by the lactone group increases the rigidity of the A/B ring system and so induces steric strains in
the conjugated ketone structure. Dipole-dipole interactions between the two carbonyl groups could also raise the ketone and C=C stretching frequencies, but if this were so, the lactone carbonyl frequency would also be affected. Saturated y-lactones exhibit characteristic features in the region between 1500 and 1300 cm.-' associated primarily with deformation vibrations of C-H bonds. Representative examples are
R.
5246
1 c C015 Y
hpI
cell
3 m W tell
5 0 1 S:.n
s. GALLAGHER
NORMAN JONES AND BEATRICE
1 Sal
E
F
Soir
I Pn c e l l '
CHI :0
AcO
VOI. 81
with stretching vibrations of the C-0 linkages. Lactones of structures 11-IV exhibit such a band near 11'70 cm.-'.whereas for structure I the analogous band occurs a t 1200 cm. (Table I). Saturated &Lactones.-The saturated steroid &lactones we have examined are of types XVIXIX. Three of these contain the lactone group in an enlarged ring D ; these compounds, obtained initially by oxidation of 17-keto~teroids'~~~" and 17-cu-hydroxy-20-ketosteroids,?' have been a subject of study- by several investigatorsIY-15 arid the earlier literature has been summarized in the paper by Murray, Johnson, Pederson and Ott.?j
A mm 1 1400
1300
1400
1300
1400
1300
Fig. I.-C-H deformation vibrations of saturated -/-lactoiles in CCh solution: A, structure I, comparison with D demonstrates characteristic bands e and f . Band e is assigned to the a-methylene group of the lactone ring and band f to the C(18)methyl group displaced to higher frequency in the lactone spectrum. B, structure 11, cornparison witli E demonstrates characteristic band d assigncri t o the N methylene group of the lactone ring. C, structure I\.,coinparison with F demonstrates no new absorption in the lactone spectrum, b u t band f , assigned to the C(19Lmethq-1 group, is lost.
shown in Fig. 1, where the spectra of the lactones are compared with the spectra of closely related steroids lacking the lactone group. In the spectra of ketones and acyl esters containing a methylene group in the a-position to carbonyl, a small band is observed near 1420 cm.-'. This has been shown by selective deuteration to involve the a-methylene hydrogen atoms and has been assigned to the scissoring vibration of the C-H bonds.l5.l6 The lactones 1-111, which likewise contain an a-methylene group, exhibit a small band near 1425 an.--' (Fig. lA, band e ; Fig. l B , band d); this band is lacking from the spectra of the comparison compounds in Figs. 1D and 1E and can be assigned to the a-methylene scissoring vibration. In the spectrum shown in Fig. lC, band d a t 1420 cm.-' is associated with the scissoring vibration of the C(2) methylene and is not derived from the lactone group. A band of comparable intensity is present in the curve in Fig. 1 F ; similar bands have been noted in the spectra of other A4-3ketones and they disappear on substitution a t C(2).17 From Figs. 1C and 1 F it is also seen that band f is not present in the spectrum of the lactone. This is undoubtedly the C(19) methyl symmetrical bending vibration; between 1400 and 1300 cm. -I, the curve in Fig. 1C closely resembles the spectrum of 19-norprogesteronel*which also lacks this band. Lactones, like esters, exhibit strong absorption in the region 1200-1100 cm.-l probably associated (15) R . N. Jones, A. R . H. Cole a n d B. Kolin, THISJOURNAL, 74, 5602 (1952). (16) M. E. Isabelle a n d L. C. Leitch, Con. J , Chem., 36, 440 (1958). (17) R. N. Jones and A. R. H Cole, THISJOURNAL, 74, 5648 (1952). (18) See Chart 417 of ref. 6.
XVII
XYI
W A V E N U M B E R (cm-0.
$lr
c=o o=c.
@=o@ I
' H XVIII
H XIX
c1
XX
XI1 four types of 8-lactones exhibit the typical C=O stretching band between 1747 and 1737 ern.-' in carbon disulfide and carbon tetrachloride solution. These observations are consistent with data in the literature for simpler monocyclic saturated 8-lactones and acyl ester carbonyl groups in strainless systems.26 In his recent monograph,? Bellamy discusses the possibility that the 8-lactone carbonyl frequency may be enhanced where the lactone forms part of a strained polycyclic ring system. This may well be true, but the example cited by Bellamy unfortunately mas based on a typographical error in one of our earlier publicationsj which was later ~orrected.~'For the chlorolactone X X Turnerz8 has reported the C-0 band at 17'70 ern.-' (solvent not stated). The absorption of representatire 6-lactones in the region 1500-1300 cm.-l is shown in Figs. 2 and 3. The structures shown in Figs. 2A, 3-4 and 3B exhibit the small band a t 1322-1418 cm.-' assigned to the methylene group vicinal to the lactone carbonyl ; these spectra should be compared with Figs. 2C, 3C and 3D and also with the lactone in Fig. 2B which have no a-methylene group. (19) U'. W. Westerfeld, J . B i d C h e w . , 143, 177 (1942). ( 2 0 ) R. P. Jacobsen, ibid., 171, 61 (1947). (21) PIT. S. Leeds, D. K. Fukushima and T. F.Gallagher, THISJ O U R N A L , 76, 2265 (1954). ( 2 2 ) C. v. Seemann and G. R. G r a n t , t b i r f . . 72,1073 (19501. (23) J . Jacques, A. Horeau and R Courrier, Compl. r e n d . , 229, 321 (1949). (24) N. I,. Wendler, D Tau], and H. I.. Slate-, THISJ O V R X A L , 7 7 , 3559 (1956). (25) 31. F . Murray, n. A . Johnqon, R 1,. Perlcrson and A . C . O t t , ibid., 7 8 , 981 (1956). (26) According to Gual, Dorfman and KosenkrantzP estrololactone, a steroid of structure XVIII, exhibits a n anomalously low carbonyl frequency u,hen measured in a potassium bromide disk. T h e acetate of this compound absorbs normally in solution (Table I ) and t h e band displacement of t h e free alcohol in t h e solid state must result from intermolecular hydrogen bonding i n t h e crystal lattice. T h i s provides a n excellent example of t h e hazards associated with structural assignments based on spectra measured in t h e solid phase. (27) Page 22 of ref. 6. (28) R. B. Turner, THIS JOURNAL 7a, 579 (1950)
Oct. 5 , 1959
5247
INFRARED SPECTRA OF STEROID LACTONES
80 - 6
i
40 -
BO
60
60
40
40
20
AcO
a
0
2
Conc.
-
I mrn. c e l l
&
' : 0 8 0 z w
Conc.
a
C8H17
C
w
0
t
60
K
w
60 I
AcO."
60-
Imm. c e l l
80 . D
z
H
-
AcO
ti
60 h i
40
20
20
20
I
1
8
1400
I
,
!
,
1400
1300
20
I
!
Conc.O.01 l
Compounds of structure XVII and XVIII show a prominent narrow band near 1400 cm.-' (Fig. 2B, band e; Fig. 3B, band f ) which must also be associated with the lactone group. Comparison of the structures of the four types of &lactones suggests this band may require the presence of the group -COOCHz- in a six-membered ring. A similar band is observed in XXI, but not in X X I I or X X I I I , and a strong band at 1402 cm.-l is reported in the spectrum of 6-valerolactone. 29 No analogous band is seen in open chain esters of the type R-CO-0-CH2-R', nor in I1 or I11 where the s.ame grouping occurs in a five-membered ring, and the association of this band with the -COOCH2- group is speculative.
p o&o
R
XXI
XXII, R=-H XXIII. R=-CH3
(29) R . S. Rssrnussen and
(1919).
R.R. Brattain, TXISJOURNAL, 71, 1073
1300
1400
,
Imrn.cell !
1300
WAVE NUMBER (ern:'). Fig. 3.-C-H deformation vibrations of saturated &lactones in CClr solution: A, structure XYIII, comparison with C demonstrates characteristic bands e and f . Band e is assigned to the a-methylene group of the lactone ring and band f is unassigned. B, structure XIX, comparison with D demonstrates characteristic bands e and f . Band e is assigned to the amethylene group of the lactone ring, and band f to the -CO-0-CHz- system in a six-membered ring.
groups are also present in the molecule these bands are difficult to recognize, and their use for structural diagnosis is limited unless similar steroids lacking the lactone group are available for comparison. Saturated e-Lactones.-Meager information is available concerning steroids possessing e-lactone groups ; compounds containing the structures XX1s'"O and X X V 4 have been described. The
eo
I:;t" XXIV
AcO
H xxVI
0
@
Q C b 0
&Lactones show prominent bands in the lower frequency region between 1230 and 1000 cm.-l as noted in the right hand column of Table I. The position of these bands is variable in the different types of &lactones. JVhere other functional
M I
l
1400
1300
WAVE NUMBER (ern?). Fig. 2.-C-H deformation vibrations of saturated &lactones in CCla solution: A, structure XYIa. comparison with C demonstrates characteristic bands c and d. Band c is assigned to the a-methylene group of the lactone ring and band d to the C( 19 )-methyl group displaced t o higher frequency in the lactone spectrum. B, structure XVII, comparison with D demonstrates characteristic band e tentatively assigned to t h e -CO-O-CH2-system in a six-membered ring
,
AcO
H
xxv
lactone carbonyl group of XXIV is reported to absorb a t 1727 cm.-I (CS2) and 1705 cm.-' (CHCla), and these band positions are significantly lower than those reported for &lactones (cf. Table 11). (30) E . S. Rothman, M. E , Wall and C. R . Eddy, ibid., 76, 527 (1954).
,5248
R. NORMAN JONES
AND
A
1
:ii 8
1800
I800
1700
WAVE
1800
1700
NUMBER
1700
(cm7l).
Fig. 4.-Infrared spectrum in C=O stretching region: A, digitoxigenin acetate ( X X V I I I ) i n CS2 soln. (satd. s o h , 1-mm. cell); B, digitoxigenin acetate ( X X V I I I ) in CHC13 s o h . (0.006 AI, 1-mm. cell); C, strophanthidin ( X X I X ) in CHClj soln. (satd. s o h , 1-mm. cell).
For XXV bands are reported a t 1724 and 1709 ern.-' in chloroform. The homolog with a 6lactone structure (XXVI) absorbs a t 1730 and 1706 crn.-l in the same solvent. In view of the several carbonyl functions present, the lactone frequency cannot be assigned with certainty, though it would appear that in this case the band 0 //
J0
4 4 OH
R
H
xxvrr,R = -OH
ivij OH OH XXIX
HO
XXVIII, R = - O A ~ 0
//
AcO~
.4cO
R
X
X
I
I
I
H XXXI,R=-OH XXXII,R= - 0 A c
position is not significantly affected by the ring enlargement. However the relative intensities of the two carbonyl bands are not reported, and if the lo.ir.er frequency band were significantly more intense in XXV than in XXVI the e-lactone group might be contributing to the 1709 ern.-' band of
BEATRICES. GALLAGHER
VOl. 81
XXV and the &-lactonegroup to the 1730 cm.-’ group of XXVI. This would be consistent rtith the observations on XXIV in indicating a fall ill the carbonyl frequency with ring enlargement. Unsaturated y-Lactones.-The a,@-unsaturated side y-lactone group of the A20(22)-cardenolide chain is unusual in exhibiting two prominent bands in the region commonly associated with the C=O stretching 1 ibration. Observations on a series of model compounds containing this ring system9 have established that the phenomenon is specific to the lactone ring and does not involve intra- or intermolecular association with hydroxyl or other functional groups on the steroid ring system. The relative intensities of the two peaks are little influenced by concentration, but they are sensitive to changes in solvent polarity and to temperature. The spectroscopic and structural significance of the two bands will be considered in connection with the model compounds in another publication9 and here we shall deal only with the bands as observed in steroid spectra. The spectrum of digitoxigenin acetate (XXVIII) in carbon disulfide solution exhibits three bands between 1800 and 1700 crn.-l (Fig. 4A). The band a t lowest frequency (1738 cm.-l) can be assigned to the C(3) acetate group and the doublet a t 1783 and 1756 cm.-l to the lactone ring. The 1756 cm.-l band can be considered “normal” since conjugation would be expected to lower the C=O frequency by 20-30 ern.-' from the position a t 1786 crn.-l in the dihydro compound 11. The band a t 1783 ern.-' is the “abnormal” one. I n more polar solvents the intensity of this abnormal band diminishes greatly while that of the normal band increases, as is shown for the same compound in chloroform solution in Fig. 4B. While change of solvent polarity produces a large effect on the relative intensities of the two bands, the frequency shifts are small. The spectrum of strophanthidin (XXIX) in chloroform solution (Fig. 4C) illustrates the cardenolide lactone doublet uncomplicated by overlapping acetate absorption, as the C(19) aldehyde carbonyl absorption is well separated at its normal position31(1719 cm.-l). The spectra of several cardiac aglycone derivatives unsaturated in ring D also have been examined. The spectrum of 14-anhydrogitoxigenin diacetate (XXX) shows the a,&unsaturated ylactone carbonyl doublet with the additional absorption of the superimposed acetate bands a t their normal positions (Fig. 5). I n 16-anhydrogitoxigenin acetate (XXXII) formal conjugation exists between the A20(22)-doublebond of the cardenolide ring and the A16-bondof ring D; nevertheless the C=O stretching absorption is closely similar to that of digitoxigenin acetate (Fig. 6). The same holds true for 14,16-dianhydrogitoxigenin acetate (XXXIIl), the spectrum of which is shown in Fig. 7. The insensitivity of the lactone carbonyl frequency to extended conjugation in ring D suggested initially that steric resistance might be preventing the lactone ring from taking up a configuration coplanar with ring D. Experiments with atom (31) W. J. Xomaczynski, P R Steyermark, E. Koiw, J Genest and R. i S Jones, C a n . J BLochem Physrol , 34, 1023 (1956)
INFRARED SPECTRA OF STEROID LACTONES
Oct. 5, 1959
In
6
cs2
CHCL3
c a
a
0 v)
m
a
5249
was pointed out several years ago by Cromwell and collaborator^^^ that the extension of conjugation from an a,P-unsaturated ketone to an a,p;y,6di-unsaturated ketone induced only a small additional lowering of the carbonyl stretching frequency : extended conjugation influences the electronically excited states much more than the ground state of the molecule and consequently the ultraviolet spectrum is affected much more than the infrared spectrum.
F
A
z
W 0
2 80 0
w
a
I-
Q
a 60
I
0
I
v)
1800 WAVE
1700
1700
1800
NUMBER
(cm-1).
Fig. 5.-Infrared spectrum C-0 stretching region: A, 14-anhydrogitoxigenin diacetate ( X X X ) in Cs2 soln. (satd. s o h , 1-mm. cell) ; B, 14-anhydrogitoxigenin diacetate ( X X X ) in CHCl, soh. (0.005 M , 1-mm. cell).
I CHCL,
1 0
b a
40
z W 0
20 CL
1 I
I
WAVE
v)
m
a
I-:
z
W 0
a w a
WAVE
F
I
1700
I
1
I
1800
1700
NUMBER
(crnFI).
Fig. 7.-Infrared spectrum in C=O stretching region: A, 14,16-dianhydrogitoxigenin acetate ( X X X I I I ) in CS2 s o h (0.007 M,1-mm. cell); B, 14,lG-dianhydrogitoxigenin acetate ( X X X I I I ) in CHC13 soln. (0.007 M , 1-mm. cell).
0
1700
a
1800
8oi
1800
m
1800
I700
NUMBER ( c m 7 l ) .
spectrum C-0 stretching region: A, 16-anhydrogitoxigenin acetate ( X X X I I ) in Cs2 s o h . (satd. B, 16-anhydrogitoxigenin acetate soln., 1-mm. cell); ( X X X I I ) in CHCla soln. (0.005 M , 1-mm. cell). Fig. 6.-Infrared
models demonstrated, however, that, if present a t all, such an effect must be small. Furthermore the lactone carbonyl frequencies of XXXIV and XXXV are also quite similarg and here there can be no question of a steric barrier to coplanarity. It
axxxv
In chloroform solution the C=C stretching bands of these structures are also observed, and in all cases except X X X I I I the A20(22)C=C vibration is noted as a weak band between 1620 and 1630 cm.-l (Tables I and 11). Compound X X X I I I shows two very strong C=C stretching bands a t 1612 and 1578 cm.-l; these are probably vibrations of the ring D diene system, and the weaker cardenolide C=C band may be submerged beneath them. Another type of unsaturated y-lactone (XXXVI) has been observed by Jacobs and Takaliashi12
to give strong bands a t 1806 and 1705 em.-' in a carbon tetrachloride solution. These bands can be assigned respectively to the C=O and C=C stretching modes, and their high frequencies are consistent with similar vibrations of acyl enol esters. Unsaturated I-Lactones.-The di-unsaturated 6-lactone system characteristic of the bufadienolide side chain exhibits a doublet carbonyl spectrum (32) N. H. Cromwell, F. A. Miller, A. R.Johnson, R. L. Frank and D.J. Wallace, THISJOURNAL, 71, 3337 (1949).
R. NORMAN JONES
5250
AND
BEATRICES. GALLAGHER
similar to that of the A*0(22)-cardenolides, but with both bands displaced to lower frequency, consistent with extended conjugation and the increase in the ring size. Because of the poor solubility of the steroid bufadienolides in carbon disulfide or carbon tetrachloride, the sensitivity of the relative band intensities to the solvent polarity is observed more effectively with model compounds, such as 5-methylcu-pyroneg (XXIII), but the discussion here will be restricted to the steroid aglycone spectra.
1
P o
rfo
XXXVII
XXXI-III,R =-OH X X X I S , K = --OhC
The spectra of buialin (XXXYII) and hellebrigenin (XXXVIII) in chloroform solution exhibit the low frequency band a t 1T18 crn.-l and the high frequency band as an inflection a t 17-40 cm.-l (Fig. 8). I n the case of hellebrigenin the C(19) aldehyde also contributes to the absorption a t 1711; cm.-].
VOl. 81
separated from that of the C(3)-acetate group, it is evident that here, as with the y-lactones, there can be little if any coupling between the unsaturated systems of the lactone ring and ring D in the electronic ground state.
i
0 I-
n
CK 0 v)
m
a
F
z W
0
U
I A
CHCL,
W
a
n
80 -
60
B
CHCL,
-
t--1-
I
1750
1650
x 1750
1650
NUMBER (ern-'). spectrum in C-C) stretching regiuri' A, bufalin (XXXT-11) in CHC1; sjlii. (satd so111, 1-rnm cell), B, hellebrigenin (XXXX-IIII in CHC17 ~ o l n ( i n t d s o h , 1-mm. cell 1 WAVE
Pig. 8.-Infrared
The spectrum of 14anhydrobufatalin diacetate (XL) both in carbon disulfide and in chloroform is shown in Fig. 9. Here the intensification of the high frequency band in the less polar solvent is clearly demonstrated. I n the C=C stretching region chloroform solutions of the bufadienolides all absorb weakly near 1636 cm.-I. Structure XLI exhibits a broad carbonyl band with maximum a t l f 2 3 cm.-l in chloroform solution. Although the lactone absorption cannot be
1750
WAVE
1650
1750
NUMBER
1650
(ern,').
Fig. 9. -Infrared spectrum in C=O stretching region: A, l-l--aiihydrobufatalindiacetate (XL) in CS9 solti. (satd. soln., I-tnni. cell); €3, l-l-anh?-drobufatalirl diacetate ( S L 1 in CHCla solii. ((1.005I[, 1-min. cell).
Unsaturated &lactones of the enol ester type have been esainiried by Iiosenkrantz and (;ut33 and by Jacobs and Takahashi.l? A s would he anticipated, t h t C-0 frequency is raised ( 1737 cni.-' in C S L s o h . ) and the C=C frequency is also increased (Table IIj. The spectra of fully cyclic enol lactones of structures XXXT-111 h a w not been studied in the steroid series, hut for nepetalactone34 (XLIT-) C-0 and C==C hands have been reportctl a t 1 i ( i 4 and 1 ( XLIIj
CH?(,) .
I
Summarizing Remarks.. - T h e C:--(.) strctvliillg bands in the spectra of steroid lactones nieasurcti in solution can be used effectively for differentiatini: ( 3 3 ) I3 Roienkraritz . a i r 1 R I ( > , i t , Jrt.1;' ( ! * i : v . . l r t t ~ . 3 6 , IO00 i3). ,.'
