CRYSTAL STRUCTURES OF %HYDROXYTESTOSTERONES
Journal of Medicinal Chemistry, 1971, Vol. 14, No. 4 295
Crystalline Molecular Structures of Two Derivatives of ZP-Hydroxytestosterone Having an Unusual A-Ring Conformation W. L. DUAX,*CHAIMEGER,S. POKRYWIECKI, AND YOSHIOOSAWA' Medical Foundation of Buffalo Research Laboratories, Buffalo, New York i4BO.S Received September 1, 1970 I n the crystal structures of 2~-acetoxy-17p-chloroacetoxy-4-androsten-3-on~~eOH complex (1: 1 ) and 28,178diacetoxy-4-androsten-3-on1+p-bromophenol complex (1 : I), the A-rings of the steroids have been determined to be in an inverted half-chair conformation. This conformation is in sharp contrast to the normal half-chair conformation observed in the crystal structures of 14 other A'-3-one steroids including one with a 2pC1 substituent. Steric interaction between the 19-Me substituent and the acetate group in the 26 position may be the cause of this surprising conformational difference. I n the inverted half-chair arrangement, the conjugation of the cu,punsaturated ketone system in the A-ring is disrupted, atoms 0(2), C(2), C(3), and O(3) achieve a nearly coplanar arrangement, and atoms C(3), C(4), C(5), C(lO), and C(1) also reside in nearly coplanar positions. This combination of the two coplanar arrangements of atoms may be an energetically favorable conformation and suggests that the inverted half-chair may also constitute a stable form of these molecules in solution.
From the interpretation of ORD, CD, and nmr measurements, the A-rings of some derivatives of testosterone having 20 substituents were predicted to be in a half-boat or "nonsteroidal" half-chair or twist conf ~ r m a t i o n . ' ~ -Because ~ steroid A-rings containing the 4-en-3-one system were found to be in the normal half-chair conformation in 14 molecular structures determined by X-ray crystallography? and because the boat form is energetically less favorable, we have undertaken the structural investigation of some of the steroids in which the A-ring is predicted to be in the halfboat conformation. The first such structure investigated, 2,2,6~-trichlorotestosterone acetate,*,$ was
found to have the conventional half-chair conformation of the A-ring in conflict with the previous interpretation of ORD, CD, and nmr ~ p e c t r a . ~ , ~ ' The conformation of the A-ring in 2P-hydroxytestosterone is of particular interest as this steroid is a natural metabolite of testosterone and a possible intermediate in the biosynthesis of 2-oxygenated estrogens. Since crystals of 2P-hydroxytestosterone suitable for X-ray analysis could not be obtained, and since the ORD and CD spectra of the acetateIb and chloroacetateI8 of 2P-hydroxytestosterone indicated that the Bring conformation of this steroid would be the same as that of the free compound, the crystal structures of 2P-hydroxytestosterone 2-acetate 17-chloroacetate (I) t 17p-Trimethylsiloxy-4-androsten-3-one,~ 17~-bromoacetoxy-ia-methyl(Figure 1)-methanol complex and 20-hydroxytestoste4-ebtren-3-onep 4-chloro-17,21-dihydroxy-4-pregnene-3,11,2O-trione,~ 178rone diacetate (11)-p-bromophenol complex were bromoacetoxy-9i3,10u-androst-4-en-3-one,~2,2,6~-trichloro-17,9-acetoxy-4determined in order to obtain definitive information androsten-3-one,s . 1ia~-p-bromobenzenesulfonyloxy-l7a-methyl-D-homo98,10~-ebtr-4-en-3-one,S 17~-hydroxy-4-androsten-3-one-p-bromophenol concerning the A-ring conformation in this group of complex (1: 1),fa 17p-(p-bromobenzoyloxy)-4-androsten-3-one,~~ lip-bromosteroids. acetoxy-8p-methyl-4-androsten-3-one,~~ 6&bromo-4-pregnene-3,2O-dione.l2 17p-hydroxy-4-androsten-3-one-mercuric chloride complex (2: 1), I 3 12aA-Ring Conformation.-In both crystalline modifibromo-llp-hydroxy-4-pregnene-3,2O-dione,14 22,23-dibromo-9p-ergost-4-encations the A-ring of 20-hydroxytestosterone diester 3-one," 9~-bromo-17p-hydroxy-l7a-methyl-4-androst~ne-3,ll-dione.~~ is in a conformation which is best described as an in$ Abbreviations used are: 28-hydroxytestosterone 2-acetate 17-chloroacet a t e , 28-acetoxy-l7,9-chloroacetoxy-4-androsten-3-one;28-hydroxytestosverted half-chair or a 6-membered envelope with atom terone diacetate, 28,178-diacetoxy-4-androsten-3-one; 2,2,6-trichlorotestosC(2) being the tip on the 01 side of the general plane of terone acetate, 2,2,6~-trichloro-17-acetoxy-4-androsten-3-one; Zp-hydroxyring A. Projections of A-rings in various conforma19-nortestosterone, 2,4,17p-dihydroxy-4-estren-3-one; testosterone, 178-hydroxy-4-androsten-3-one. tions viewed parallel to the C(5)-C(10) bond are (1) (a) Faculty Research Awardee, PRA-72, of the American Cancer presented in Figure 2. The inverted half-chair conSociety; (b) S. L. Patashnik, H. L. Kimball, a n d 5 . Burstein, Steroids, 2, 19 (1963); K . Kuriyama, E. Kondo, and K. Tori, Tetrahedron, 22, 1485 (1963). formation of the ring observed in the esters (a) is (2) Y. Yamato a n d H. Kaneko, ibid, 21, 2601 (1965). contrasted with the more commonly occurring half-chair (3) Y. Kondo, K . Kondo, T . Tahemoto, K . Yasuda, a n d G. Snatzke, ibid., conformations found in the structures of testosterone21, 1191 (1965). (4) C. M. Weeks, H. Hauptman, and D . A. Norton, submitted for publip-bromophenol complex (b),l0 2,2,6p-trichlorotestoscation. terone acetate (c), and 9a-bromo-17~-hydroxy-l701(5) W. L. Duax, A . Cooper, a n d D . A. Norton, unpublished. methy1-4-androstene-3,ll-dione(d),l 6 and a hypotheti(6) W. L. Duax, .4. Cooper, and D. A. Norton, Acta Crystallogr., Sect. B , 26, in press (1970). cal half-boat conformation of a cyclohexenone A-ring (7) W. E. Oberhansli a n d G. M . Robertson, Helu. C h i m . Acta, 6 0 , 53 (e). (1967). (8) W. L. Duax, Y. Osawa, A. Cooper, a n d D . A. Norton, Tetrahedron, in Atoms C(1), Q(3),C(4), C(5), and C(10) in I and 11 press. are within 0.09 A of a least-squares plane. The devia(9) R . T. Puckett, G . A. Sim, A. D. Cross, a n d J. B. Siddall, J . Chem. tions of individual atoms in the A-ring from this plane Soc. B , 783 (1967). (10) A . Cooper, G. K a r t h a , E. M. Gopalakrishna, a n d D . A. Norton, (Table I) are compared with the average deviations Acta Crystallogr., Sect. B , 26, 2409 (1969). from planarity of these atoms in the A4-3-one containing (11) H. Kayama, M. Shiro, T. Sato, Y. Tsukuda, H . Itazaki, a n d W. Nagata, Chem. Commun., 812 (1967). (12) E. M . Gopalakrishna, A. Cooper, a n d D . A . Norton, Acta Crystalloor., Sect. B , 26, 639 (1969). (13) A . Cooper, E. M . Gopalakrishna, a n d D . A. Norton, ibid., Sect. B , 24, 935 (1968). (14) A. Cooper a n d D . A. Norton, ibid., Sect. B , 24, 811 (1968). (15) B . Hesper, H. V. Geise, a n d C. Romers, R e d . Trau. C h i n . Pays-Bas, 88, 871 (1969). (16) A. Cooper, C. T. Lu, and D. A. Norton, J . Chem. Sac. B , 1228 (1968).
(17) Y. Kondo, T. Takemoto, and I(.Yasuda, Chem. P h a r m . Bull. (Tokyo), 12, 976 (1964). (18) Compound I , mp 190-19lo, Ag!Y' 244 ma ( e 15,300), mas prepared from testosterone cbloroacetate b y bromination followed by acetolysis. T h e details of the synthesis and the hydrolysis products are t o be published b y Y. Osawa a n d J. 0. Gardner.
296 Journal of Nedicinal Chemistry, 1971, Vol. 14, KO.4
(C) Figure 1.-Atomic numbering and ring nomenclature for 2phydroxytestosterone 2-acetate 17-chloroacetate.
, C(19)
/
TABLE I DEVIATIOXS O F INDIVIDVAL ATOMS FROM LEAST-SQUARES P L A N E S THROUGH ATOMSC(l), C(3), C(4), C(5), A N D C(10) OF STEROIDS HAVING CYCLOHEXENONE A-RINGS Atoms included least-squares plane
In R
Atoms for hich distance calculated
O(3)
--Distances
I
from plane,'
I1
A-
0.093 -0.14 CU) 0.078 0.12 -0.066 -0.081 C(3) 0.062 -0.09 C(4) 0.043 0.033 -0.05 C(5) 0.036 0.16 C(l0) -0.093 -0,107 0.48 C(2) -0.615 -0 562 0,007 -0.15 -0,030 C(6) 0 228 0.11 O(3) 0.243 The tabulated distances are (I)2phydroxytestosterone 2-acetate 17-chloroacetate1 (11)2p-hydroxytestosterone diacetate, and (111)average values for 14 steroids in which the A-rings show only minor deviations from the normal half-chair conformation.
steroids having the normal half-chair conformation of the A-ring. Of the atoms in the A4-ring,C(2) is seen to have the largest deviation from this plane, residing on the p side of the plane in the steroids having the normal halfchair A-ring conformation and on the a side of the plane when the h-ring is in the inverted half-chair conformation. Atoms O@), C(2), C ( 3 ) , and O ( 3 ) are planar to within 0.09 h in both csters arid the O(2)O ( 3 ) interatomic distance of 2.72 A is of H-bonding order. An intramolecular H bond between O(2) and O(3) has been considered as a possible stabilizing feature of "twist" and half-boat conformations of the A-ring of 2p-hgdroxg-A4-3-keto steroids.' l 9 However, w e n n hen atoms O(2) C ( 2 ) ,C ( 3 ) ,and 0(3) are in a planar conformation, as is the case in the inverted half-chair conformation, the required C(2)-0(2)-H(02) bond angle of approximately 109" nould prevent any effective overlap of the van der Waals radii of atoms H(02) and O ( 3 ) . The 0(2)-H(02) ...O ( 3 ) angle of approximately 90" nould be far short of the 133" minimum generally accepted a\ necessary for H bonding.1° The inverted half-chair conformation disrupts the A4-3-one conjugated system. When the A-ring is in the normal half-chair conformation the +unsaturated ketone system can achieve complete conjugation, as n as observed in the structure of 2,2,6fl-trichlorotestostcrone acetate in nhich the seven atoms [C(2), C ( 3 ) , C(4), C ( 3 ) . C(6), C(lO), and 0(3)] involved in the (19) 11 J 13rodie and \ Pillai Program of 51st Meeting of the Endocline Societi 1969, p 79 ( 2 0 ) J Donoliue in Structural Chemistrl and hlolecular Biologg ' 1 Rlch and S D a i i d s o n Ed , \IH Freeman San Francisco, C a l i f , 1968 p p
232-234
a
I
C(191
'Ex
I11
C(21
C(1)J C(3)J C(4), C(5), C(10)
,I'
cd)
tb)
( Q) Figure 2.--Steroid A-ring> containing the 4-en-3-one system projected parallel to the C(5)-C(10) bond in 2P-hydroxytestosterone 2-acetate 17-chloroacetate (a), testosterone-pbromophenol (b), 2,2,6P-trichlorotestosterone acetate (c), Sa-bromo17a-methyl-11-oxotestosterone (d), and a hypothetical halfboat conformation (e).
conjugated system nere planar to within +0.04 .I! The atoms immediately involved in the double bond conjugation, 0 ( 3 ) , C ( 3 ) , C($), and C(5), are almost alnays planar to within 0.03 A. Of the structures n i t h the half-chair A-ring conformation, only two exhibit any pronounced breakdown of the conjugation of the double bond demonstrated by a loss of planarity of these 4 atoms. I n 22,23-dibromo-9p-ergost-4-en-3one'j the strain associated n i t h the twist-boat conformations of the B- and C-rings is transmitted to the A-ring, and in 9 cr-bromo-17~-hydroxy-17~~-methyl-4andro~tene-3,ll-dione'~the flattening of the B- and C-rings caused by the Sa-halogen results in the pronounced arching of the h-ring toward the CY side of the steroid. The deviations of individual atoms from :L least-squares plane through atoms 0(3), C(3), C(4), and C(5) in structures I and I1 as \vel1 as other crystnllographically determined itructures are given iri Table 11. The 12 structureq in which these atoms are essentially planar are combined in column 111. Columns IV and V are the &I-ringhalf-chair structures which do riot exhibit total corijugatiori of the a$unsaturated ketone system. The 0(3)-C(3)-C(2)-R(2P) torsion angles for 4chlorocortisone 2,2,6~-trichlorotestosterone, and 2phydroxytestosterone 2,17-diacetate are illustrated iri Figure 3 . Compounds I and I1 have torsion angles of 16.2" and 16.0" indicating that the 2p substituent is in an eyuitorial position. If the 2p-hydrogen position in 4-chlorocortisone is representative of the normal position of a 2p substituent on the 4-en-3-one steroid in the half-chair conformation, the 74" torsion angle in 2,2,6~-trichlorotestosteroneacetate molecule indicates some strain in the A-ring of that structure. The strain introduced between the 2p-AcO and 19-3Ie groups, coupled ~ ' ith r the energetic favorability of :i planar confornmtion of atom. O(2), C(2), C O ) , and ~
J o u m l of Medicinal Chemistry, 1971, Val. 14, No. $,
CRYSTAL STRUCTURES OF ZHYDROXYTESTOSTERONES
291
TABLE I1 DEVIATIONS OF INDIVIDUAL ATOMSFROM LEAST-SQUARES PLANES THROUQH ATOMS C(3), C(4), C(5), AND O(3) OF STEROIDS HAVINGCYCLOHEXENONE A-RINGS Atoms for which distance calculated
Atoms included in least-squares plane
Distances from plane,"
I
I€
I11
A V
IV
-0.08 0.09 -0.07 -0.03 to f 0 . 0 4 -0.09 C(3), C(4), C(5), O(3) (33) -0.07 0.08 -0.07 -0.03 t o f 0 . 0 4 -0.08 C(4) 0.07 -0.08 -0.04 to f 0 . 0 3 0.07 0.08 C(5) 0.08 -0.09 0.08 -0.04 to $0.03 0.09 O(3) -0.23 0.39 -0.19 -0.04 to +0.36 -0.35 C(2) 0.01 0.19 -0.12 -0.07 to f 0 . 3 3 -0.11 C(6) -0.36 0.15 0.31 -0.21 to f0.16 0.25 C(10) The tabulated distances are ( I ) 2~-hydroxytestosterone2-acetate 17-chloroacetate, (11) 28-hydroxytestosterone diacetate, (111) average values for 12 steroids in which the A-rings show only minor deviations from the half-chair conformation, (IV) 22,23-dibromo11-dione. 9p-ergost-4-en-3-one, and (V) 9a-brorno-li~-hydroxy-l7a-methyl-4-androstene-3,
\
26-ce
28-0
0 3- C ( 3 ) , C ( 2 )
Figure 3 .-The 0(3)-C (3)-C (2)-R (2p) torsional angles in 4-chlorocortisone (a), 2,2,6p-trichlorotestosteroneacetate (b), and 20-hydroxytestosterone diacetate (c).
O(3) may provide enough energy to disrupt the conjugated double bond system and successfully adopt the inverted half-chair conformation. Elucidation of the structure of the 2P-OH derivatives of testosterone and 19-nortestosterone should provide additional information concerning the stability of the inverted half-chair A-ring conformation. Steroid Conformation.-All important intramolecular bonds and angles for the two structure determinations are compared in Figure 4. The averEge standard deviations in bond! and angles are hO.01 A and *0.So for I and h0.02 A and h1.2" for 11. None of the values for bonds and angles in the steroid nucleus are significantly different from those observed in similar molecules. All bonds and angles of the p-bromophenol complex, except for the terminal C-C bond in the acetate group bonded to C(2), are within 3 standard deviations of the corresponding values in the more accurate 2P-hydroxytestosterone 2-acetate 17-chloroacetate structure. The increase in the C(20)-C(21) bond length may be correlated with a close contact of the Br of an adjacgnt p-bromophenol molecyle to the C=O. This 3.27 A Br-0 distance is 0.08 A less than
4 110
124
Figure 4.-Interatomic distances and angles in the two molecules. I n each cme the top value is for 2p-hydroxytestosterone 2-acetate 17-chloroacetate and the standard deviations are epproximately 0.01 A for distances and 0.8' for angles. The bottom value is for 2j3-hydroxytestosterone diacetate and the standard deviations are 0.02 A for distances and 1.2' for angles.
the sum of the van der Waals radii. Approximately 15% of the p-bromophenol molecules in the crystal lattice are disordered (see Molecular Packing). The nature of the disorder is a minor translational shift which resultsoin an increase in this Br-0 contact length to 3.43 A. The B- and C-rings are in conventional chair conformations and the D-ring has a conformation intermediate between a @-envelopeand a half-chair. This conformation can be described by the parameters A = 23.6 and +m = 4S.2.21 I n Table 111, torsion angles of the rings are compared for the two crystalline derivatives of 2P-hydroxytestosterone and contrasted with those of testosterone found in the structure of testosterone-p-bromophenol (1: 1) complex. lo From inspection of the torsion angles, it is apparent that the crystal environment in these structures has almost no effect upon the conformation of the steroid nucleus and that the conformational change in the A-ring has little effect on the steroid beyond the A/B ring junction. The reversal of signs on the torsion angles of the A-ring is another characteristic of the half-chair inversion. (21) C. Altona, J. J. Geise, and C. Romers, Tetrahedron, 24, 13 (1968).
298 Journal of Medicinal Chemistry, 1971, Vol. 14, No. 4
DUAX,et al.
TABLE I11 TORSIONAL ANGLESIN THE RINGS=
1 0 1
-
-2
-
.i Ink-=-
-vm-l i
\
-2
C)
8 8 - METHYL -TESTOSTERONE BROMOAC ETATE
111, des
58.3 -42.4 12.1 4.7 9.7 -40.9
-56.1 34.8 -4.0 -5.8 -16.5 46.1
-58.4 51.9 -53.3 55.2 -55.2 60.0
-61.0 55.0 -56.0 56.8 -56.8 62.4
-52.3 53.6 -62.9 67.1 -60.1 54.0
-52.3 53.2 -54.0 55.8 -59.9 57.2
-53.4 54.5 -57.1 58.4 -62.1 59.3
-52.0 49.3 -55.4 59.6 -60.8 56.4
C(6)-C(7) C (7)-C (8) C@)-C(g) C(9)-C( 10) C( 10)-C (5)
- BROMOPHENOL
2
11, deg
60.0 -45.7 18.1 -1.1 11.8 -41.9
Ring B
3 2 8 - HYDROXYTESTOSTERONE DIACETATE p
I , deg
C ( 5 1-c(6)
-2
b)
Ring A
C (11-C (2) C (2)-C ( 31 C(3)-C(4) c (4)-C(5 1 C (5)-C (10) c (lO)-C( 1)
Ring C
C(8)-C(9) c (9)-C( 11) C (11)-C( 12) C(12)-C(13) C ( 13)-C( 14) C (14)-C (8) Ring D
d)
2.2.6 B - TRICHLORTESTOSTERONE
Figure 5.-Projection parallel to the least-squares plane through atoms C(5)-C(17) of 2p-hydroxytestosterone 2-acetate 17-chloroacetate (a), 20-hydroxytestosterone diacetate (b), 88methyltestosterone bromoacetate (e), and 2,2,6p-trichlorotestosterone (d).
While the steroid nuclei of the two crystalline modifications under investigation were unaltered by variation of environment. the orientation of the side chain bonded to C(17) was quite perceptibly altered. This is illustrated in Figure 5 which is a projection of the molecules parallel to the least-squares planes through atoms C(3) to C(17). The orientations of the acetate side chains in the structures of SP-methyltestosterone bromoacetate" and 2,2,6P-trichlorotestosterone acetate are :dso shonn in Figure 5 in order to illustrate that the variation of the acetate orientation is not necessarily correlated with the heavy-atom substitution on the side chain. The variation in the magnitude of the dihedral angles (Table IS'a) between the least-squares planes through the atoms of the 17 side chain and the atoms of the planar portion of the D-ring for these four molecules is a quantitative expression of the flexibility of the orientation of the 17-acetate side chain. The equivalence of the dihedral angles between the acetate group at C(2) and the planar configuration of 0(2), C(2), C ( 3 ) . and O ( 3 ) (Table IVb) indicates that the effect of the crystal environment upon the orientation of this side chain is minimal. This excellent conformational agreement is especially interesting in view of the disorder of the p-bromophenol in this region of complex 11. Molecular Packing and Hydrogen Bonding.-The dramatic contrast in the packing arrangement of the molecules in the tx$o derivatives is illustrated in Figure 8. In the structure of 2P-hydroxytestosterone diacetate, the p-bromophenol molecules and the B-, C-, and
45.7 45.4 48.3 C(13)-C(14) -33.8 -34.8 C(14)-C (15) -33.4 5.1 10.5 C(15)-C(16) 7.7 19.1 21.7 25.5 C(16)-C(17) C(17)-C(13) -44.9 -39.2 -40.8 a The tabulated torsion angles are those in ( I ) 20-hydroxytestosterone 2-acetate 17-chloroacetate, (11) 2/3-hydroxytestosterone diacetate, and (111)testosterone as found in a testosterone p-bromophenol complex.10
TABLE IV DIHEDR.4L ANGLES
I N V O L V I N G ACET.4TE
Structure
SIDE CH.4INS Dihedral angle, deg
a. Dihedral Angles between the Least-Squares Planes through Atoms 0(17), C(22), 0(22), and C(23) and the Least-Squares Planes through Atoms C(14), C(l5), C ( l 6 ) , and C(17) 8p-Methyltestosterone bromoacetate 44 2p-Hydroxytestosterone diacetate 52 2,2,6p-Trichlorotestosteroneacetate 90 2p-Hydroxytestosterone 2-acetate 17-chloroacetate 96 b. Dihedral Angles between the Least-Squares Planes through Atoms 0 ( 2 ) , C(20), 0(20), and C(21) and the Least-Squares Planes through Atoms 0 ( 2 ) , C(2), C(3), and O(3) 28-Hydroxytestosterone diacetate 21.6 2p-Hydroxytestosterone 2-acetate 17-chloroacetate 20.9
D-rings of the steroid lie in0 planes which are parallel to one another. The 2.73 h H k o n d s linking phenols to steroid molecules, the 3.27 A Br-0 conJacts, and other intermolecular contacts less than 3.7 A are indicated in Figure 6a, which is a projection down the a crystallographic axis. The disordered p-bromophenol molecules (not shown in Figure 6) are nearly superimposable upon the ordered p-brcmophenol in this projection and are translated 0.5 h parall$ to the a axis, increasing the H bond leongth to 3.00 A and the Br-0 contact distance to 3.43 A in 15% of the crystal lattice. The 2P-hydroxytestosterone %acetate 17-chloroacetate structure has been projected parallel to the C(7)-C(ll) vector in FiguJe 6b. Although the H bond is slightly qhorter (2.69 A) and similarly oriented with regard to
Journal of Medicinal Chemistrv, 1971, Vol. 14, No. 4 299
CRYSTAL STRUCTURES OF %HYDROXYTESTOSTERONES
\ I .
4.
b.
t
f
Figure 7.-Perspective views of a molecule of 28-hydroxytestosterone 2-acetate 17-ch1oroacetate-methano1, showing 50Y0 probability thermal vibration ellipsoids.
TABLE V CRYSTAL DATAFOR (I) 2P-HYDROXYTESTOSTERONE %ACETATE 17-CHLOROACETATE-METHANOL
J
J
Figure 6.--Immediate crystalline environment of 2p-hydroxytestosterone diacetate (a) and 28-hydroxytestosterone 2-acetate 17-chloroacetate (b).
the steroid molecule in both crystal lattices, the rest of the molecular environment is vastly different as is indicated by the nature of the closest contacts. I? the p-bromophenol complex all contacts less than 3.7 A are with the p face of the steroid, while in the methanol complex most close contacts are to the sides of the molecule.
Experimental Section Pertinent crystal data are presented in Table V. Crystals of both complexes were enclosed in capillaries to prevent decomposition during data collection. The unit cell constants were determined from least-squares refinements of three-dimensional vector (eight per parameter) having 28 > 60". The density was measured by flotation of the crystals in an aqueous potassium iodide solution. Intensities were measured by the stationarycrystalstationary-counter methodz2(Cu Ka = 1.5418 A). Since the background intensity was a uniform function of 28 above 40°, balanced nickel and cobalt filter measurements of 10% of the data were used to construct a background correction curve. Lorentz and polarization corrections were applied. The elongated b axes of the crystals were mounted parallel to the 4 axis of the diffractometer. The shape anisotropy measurements a t x = 90" were found to be less than +370 in I and *87,, in I1 over the 4 range covered in intensity collection. No absorption correction was deemed necessary becauie the primary motivation for this investigation was to determine molecular conformation and geometry of the steroid which was well established in the more accurate determination ( I ) and corroborated in the other (11). The structures were solved by straightforward application of the heavy-atom Atomic scattering factors were taken (22) T. C. Furnas, "Single Crystal Orienter Manual," General Electric Co., Milwaukee, Wis., 1957.
AND
(11)28-HYDROXYTESTOSTERONE DIACETATE- BROMOPHENOL I
Molecular formula Molecular weight Crystal system Space group
z
Cell dimensions, A
Cell volume, Aa Measured density, g/cm3 Calculated density, g/cm' Linear absorption coefficient cm-1 F(000) Crystal size, mm Solvent Final R Total reflections measured, 7, Reflections above background, 70
C23H31C105.CHaOH 422.9.132.0 Orthorhombic p212121 4 a = 13.458 i 0.002 b = 16.632=tO0.O03 c = 10.768 3z 0.002 2410.1 1.27
I1
Cz3Ha2059 BrCBHaOH 388.5.173.0 Monoclinic p21 2 a = 10.862 f 0.003 b = 16.844i0.004 c = 7.574 =I= 0.002 8 = 9 2 . 1 0 f 0.005' 1384.88
1.25
1.34
17.0
25.6
976 588 0.20 X 0.25 X 0.20 0.25 X 0.33 X 0 . 2 0 Methanol Hexane 9 . 8 (2398)
10.4 (2781)
8.0 (1870)
8 . 3 (2030)
from International Tables for X-Ray Crystallography.24 The positional parameters and anisotropic thermal parameters of all nonhydrogen atoms were refined by least squares, using a block diagonal approximation to the leasesquares normal equations. Structure1 refinedreadily t o a n R (definedm 2llF.I - [Fell/ZIFo\) of 9.8%. Structure I1 refined to an R of 117' before a threedimensional, electron-density difference map revealed the presence of the disordered p-bromophenol molecules. Introducing atoms having 15% occupancy a t the secondary p-bromophenol
(23) H . Lipson and W. Cochran, "The Determination of Crystal Structures, The Crystalline State," Vol. 111, Bell, London, 1953. (24) International Tables for X-Ray Crystallography, Vol. I , The Kynoch Press, Birmingham, England, 1962.
300 Journal of Xedicinal Chemistry, 1971, VoL 14, -Vo. 4
I)lTiX,
el
(11,
I 0.6798 0.7285 0.6468 0.5688 0.5510 0.4740 0.5299 0.5956 0.6676 0.6119 0.7394 0.7962 0.7222 0.6563 0.6033 0.6802 0.7686 0.6634 0.5423 0.8684 0.9204 0.8946 0.9291 0.7535 0.7877 0.6514 0.8187 0.8929 0.9255 0.7174 1.0384
c 1 c 2 c 3 c 4 c 5 C 6 c 7 C 8 c 9 c10 Cll c12 C13 C14 C15 C 16 C17 C18 C 19 c20 c21 c22 C23 C24 0 2 0 3 017 020 022 024
CL
z/c
Y/0
X/A
(
61 51 6)
(
51
I
5) 51
( (
( ( ( ( (
( ( ( ( ( (
5) 51 4) 51 6) 5) 51
5) 61 7) 6)
I 6 ) 6) I 6)
( (
8)
(
61
I
8)
1171 ( 41 ( 5 ) ( 41 ( 5 ) ( 6 ) (131 (
1)
0.8262 0.7821 0.7449 0.8009 0.8683 0.9284 1.0072 1.0364 0.9728 0.8949 1.0057 1.0816 1.1459 1.1109 1.1856 1.2519 1.2136 1.1789 0.9131 0.6905 0.6287 1.3136 1.3717 0.4881 0.7170 0.6770 1.2717 0.7215 1.3032 0.5171 1.4241
41 4) 41 4) 51 ( 5 ) I 51 ( 4 ) ( 4) ( 4 ) ( 5 ) ( 4 ) ( 41 ( 4 ) I 5) ( 4) ( 4 ) I 5) I 51 ( 51 ( 7 ) 1 5 ) ( 51 115) ( 3) I 4) I 3 ) ( 5 ) ( 51 I 7) ( 1)
0.6642 0.7672 0.8520 0.8820 0.8155 0.8621 0.6964 0.7916 0.7441 0.7040 0.6456 0.6872 0.7309 0.6341 0.8894 0.8782 0.8063 0.6219 0.5928 0.7758 0.7099 0.7694 0.6750 0.9413 0.7141 0.8881 0.7237 0.8752 0.8718 0.8301 0.7198
(
I ( ( ( ( (
7) 7) 71 71 71
8)
7) I 7) I 6) ( 7 ) ( 71 I 7) L 61 ( 7 ) 8 ) 81 71 7)
81 81 10)
8)
IO) 19) 5 ) 6) 5) 6) 71 15)
21
c 1 c 2
c 3 c c C c e
L 9 c10 c11 c12 C13 C 14 C15 Cl6 C 17 C1Q C 19 c20 c21 c22 C23 0 2 0 3 017 020 022 c I* c 24 c 3* c 4* c 5* C 6*
0* BR
position allowed the refinement t o proceed to nn R o f 9 . 4 7 ; . In electron-density difference map> 33 of the 37 1%ntoni.: of the p bromophenol comples aiid all €I i r i itluctiire I escept those 011 the C atom of the methanol niolecule were located. Holding I1 atom positional aiid therniill parameters constant two cycles of refinement 011 all data, using n weighting x h e m e of the form [(IF,/ - 15),’1.512]xhich made the average weighted 1 ’{ 1 qiiare:: of (lF,J - I F c ] )a t differelit raiiges of IF,,! 1ie:uiy eqiial, resulted iii fiiinl If f:tetora of 8.0 :ind 8.:jc-; for ob-erved data in I :irid 11, respectively. Povitiorial parameter.: for all iioii-li :iturn. :ire listed in Table VI. i2nisotrupic thermal parameters for 11o11-1%aturn-. and 11 tom poiitioiial parameters and lists ~f observed and cttlciilateti atrricture factors nre available from the authors iipo11 recjiiest. Figure i presents two peripective v i e w of niolecrile I i i i whicli ellipsoid. describe the anisotropic thermal riiotioii of the atoms :is observed in the cr>-stnl structure. Cornpnrisoii o f the::e diagrams vith those of 1 2 - a - b r o m o - l l ~ - h y d r o s ~ ~ i r o g e ~ t e r ofor iie
+
4 5 6 7 8
-0.0998 -0.1202 -0.1774 -0.1208 -0.0470 0.0193 0.1601 0.2011 0.1249 -0.0164 0.1710 0.3092 0.3863 0.3363 0.4366 0.5520 0.5156 0.3765 -0.0462 -0.1934 -0.2891 0.6261 0.7024 -0.2038 -0.2621 0.6018 -0.1167 0.5834 0.7635 0.6416 0.5520 0.5767 0.6909 0.7910 0.4613 0.1121
L /C
Y/b
X/A
9 9 10 10 9 9 ) 9 )
91 8 )
8 ) 10 I 8 )
8 ) 8 )
9) 9) 9 ) 111 10 1
11)
(
( (
16) 91 131 7) 8 )
6)
(10)
9) 113) ( 15) (13) (13) (13) (14) 110) I 2) (
0.5695 0.6562 0.6650 0.6115 0.5524 0.5082 0.5240 0.5012 0.5445 0.5267 0.5280 0.5472 0.4989 0.5224 0.4912 0.5023 0.5249 0.4071 0.4364 0.7639 0.7883 0.5097 0.4507 0,6862 0.7064 0.4808 0.8063 0.5732 0.2441 0.2237 0.2214 0.2410 0.2599 0.2628 0.2381 0.7500
(
I ( ( ( ( ( ( ( (
61 7) 8 )
8) 7) 8 ) 7) 61 61 61
I
8)
(
I
7) 6) 61
(
8 )
(
I 8 ) ( 7) ( 7 )
L
7)
I
7) (101 ( 7) (11) ( 5 ) ( 5 ) I 51 I 6) ( 6 ) (10) I 9) (
8)
I 91 1111 1111 ( (
8 ) 21
0.6643 0.6188 0.4318 0.3059 0.3465 0.2060 0.2431 0.4322 0.5691 0.5358 0.7606 0.7888 0.6576 0.4691 0.3507 0.4541 0.6446 0.6849 0.5575 0.7861 0.9182 0.9263 1.0340 0.7454 0.3984 0.7671 0.7248 0.9729 0.8358 0.8Pll 0.7506 0.5746 0.5349 0.6547 0.4511 0.9640
(12) (14)
(15) (141
(13) (121 (12) (12) (111 (121 I l l ) 111) (11) 10)
12I 12) 12) 16) 16 1 14 1 19) 13) 181 10) 13) 9) 14) 9) 19 1 22 1 19) (18) (20) (261 (13) ( 31
