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Hydrogen bonding in crystalline mestranol methanolate
Journal of
MOLECULAR STRUCTURE ELSEVIER
Journal of Molecular Structure 447 (1998) 43-48
Hydrogen bonding in crystalline mestranol methanolate Thomas Steiner a'*, Nora Veldman b, Antoine M.M. Schreurs b, Jan Kanters b, Jan Kroon b ~lnstitut fiir Kristallographie, Freie Universiti~t Berlin, Takustrafle 6, D-14195 Berlin, Germany bBijvoet Center for Biomolecular Research, Department of Crystal and Structural Chemistry, Utrecht University, Padualaan 8, 3584 Utrecht, Netherlands
Received 20 November 1997; accepted 23 December 1997
Abstract
The crystal structure of the synthetic sex steroid mestranol is determined for a crystal grown from methanol. One methanol molecule per steroid molecule is incorporated in the crystal lattice and facilitates formation of a favourable cooperative hydrogen bond network. Close contacts are formed between methanol molecules, in which the hydroxyl O-atoms approach the methyl carbon atoms to 3.15 .~ in the so-called umbrella configuration. In the latter, the intermolecular interaction energy is close to zero. © 1998 Elsevier Science B.V. All rights reserved Keywords: Crystal structure; Hydrogen bonding; Sex steroids; Alkynes; C-H donors
I. Introduction
Synthetic 17a-ethynyl sex steroids are important model compounds for studying weak hydrogen bonding effects. In particular, the ethynyl residue C - C - H at position 17 is frequently found donating C - H . . . O [1] and C-H...Tr [2] hydrogen bonds. Occasionally, the 17ct-ethynyl group also acts as acceptor of O H...Tr hydrogen bonds directed at the carbon-carbon triple bond [3,4]. Weak hydrogen bonds of these types are of interest in themselves and are currently the subject of intense investigation [5,6]. Mestranol is the 3-O-methyl derivative of 17etethynylestradiol, and is of clinical importance because of its oral oestrogenic activity. Solvent-free crystals of mestranol can be grown from solutions in ethanol, propan-1-ol and propan-2-ol [4]. The crystal structure * Corresponding author.
of solvent-free mestranol exhibits a complex network of interwoven O - H . . . O , C - H . . . O and O-H...Tr hydrogen bonds, which has been characterised previously [4]. If mestranol is crystallized from methanol or from acetone, solvent molecules are incorporated in the crystal lattice. This leads to different crystal packing modes and to different hydrogen bonding schemes. The macroscopic properties of solvated and solvent-free crystals of mestranol are completely different; the solvent-free crystals are stable at ambient conditions, whereas crystals of the methanol solvate decay within a few days due to loss of solvent, and those of the acetonate decay within minutes. To shed light on these phenomena, the crystal structure of mestranol methanolate, l, has been determined and is described below. Attempts to characterize the acetone solvate from X-ray diffraction failed because of the extreme crystal instability.
0022-2860/98/$19.00 © 1998 Elsevier Science B.V. All rights reserved PII S0022-2860(98)00299-3
44
T. Steiner et al./Journal of Molecular Structure 447 (1998) 43-48
2. Experimental Mestranol, 17c~-ethynyl-3-methoxy-estra- 1,3,5[ 10]trien-17fl-ol, C21H2602, is commercially available (Sigma). The crystalline methanolate, 1, was prepared by slow evaporation of a methanolic solution. Crystals are unstable under ambient conditions due to loss of solvent: if left at atmosphere, the colourless transparent plates turn white and loose their X-ray diffraction pattern within a few days. Fortunately, crystal stability has been sufficient for X-ray data collection at room temperature using an area detector. Mestranol acetonate, 2, was crystallized by slow evaporation of solutions in acetone. Initially, the optical quality of the transparent plate-shaped crystals is excellent, but if in contact with the atmosphere, crystals decay within minutes. The crystals are so sensitive that all attempts to mount specimens in glass capillaries together with mother liquor, or to coat crystals with oil to prevent desolvation, failed. Therefore, only unit cell dimensions could be determined, Table 1 (Enraf-Nonius Turbo-CAD4 diffractometer with Cu Kc~ radiation). X-ray diffraction data for 1 were collected at room temperature on an Enraf-Nonius FAST area detector
(Mo K a radiation with X = 0.71073 A). The diffraction power of the crystal was only moderate. The structure was solved and refined with standard methods [7,8] (anisotropic refinement for non-H atoms, H-atoms treated in the riding model, no absorption correction). Refinement converged with R = 0.068 (for observed reflections). Relevant crystallographic data are given in Table 1; fractional atomic coordinates of the structure model are given in Table 2.
3. Results The molecular structure of mestranol as observed in the crystal structure of its methanol solvate, 1, is shown in Fig. 1. The conformation is very similar to the solvent-free crystal structure, and to that of the parent molecule 17c~-ethynylestradiol in the hemihydrate crystal structure [9], and need not be discussed here any further. The crystal packing of 1 is shown in Fig. 2 in a projection along the monoclinic axis y. The steroid molecules are oriented roughly parallel to the xzplane, thus forming a layer-type packing. The methanol solvent molecules are incorporated in such a way
Table 1 Crystallographic data for mestranol in different crystal structures
Reference Formula MW Habit Crystal system Space group a/A cA
/3/deg z z'
VZ 11~3 Dc/g cm-3
#/mm-~ Crystal size/mm Measured reflections Unique reflections Unique with 1 > 20(/) R (for I > 20(/)) R~ (for all data)
Methanolate
Acetonate
Solvent-free
this work C21H2602.CH40 342.5 thin plates monoclinic C2 (No. 5) 12.42(3) 6.85(3) 22.55(4) 96.1(2) 1908(10) 4 1 477(2) 1.192 0.077 0.68 x 0.25 × 0.05 8052 2986 1216 0.068 0.178
this work
[4]
thick plates monoclinic
prisms or plates monoclinic P21 (No. 4) 6.8622(8) 39.71(3) 6.997(5) 117.6(2) 1690(2) 4 2 422.5(5) 1.22
12.640(11) 6.826(2) 25.34(5) 102.20(14) 2137(5) 4 534(1 )
T. Steiner et al./Journal of Molecular Structure 447 (1998) 43-48
OH
0M~___ I Me
~
017
Fig. 1. Formula of mestranol and molecular structure as observed in the methanolate crystal structure. Displacement ellipsoids are drawn at th 30% probability level. O-atoms are drawn shaded.
that they form hydrogen bond bridges between pairs of steroid molecules, which are related by the crystallographic twofold axis. There are no direct contacts between thesesteroid molecules, so that the crystal cohesion in the region z= ½ is entirely due to solvent-mediated hydrogen bonds. A view of Fig. 2 immediately explains the desolvation of the crystals
45
at atmosphere, and the associated decay of the X-ray diffraction pattern. The methanol molecules are not trapped in interstitial voids, but are free to leave in the y-direction; if they leave then the entire packing arrangement must collapse. Of interest is a detailed view of the hydrogen bonding scheme. The methanol molecules and the steroid hydroxyl groups form cooperative cycles built by four O - H . . . O hydrogen bonds (Fig. 2). Because the cycle runs around the crystallographic twofold axis, only two of the four hydrogen bonds are symmetry independent. In the y-direction, these cycles are joined by pairs of C - H . . . O hydrogen bonds donated by the alkyne groups (Fig. 3; numerical data are given in Table 3). At their other ends, the steroid molecules are joined by a cyclic arrangement formed by mutual hydrogen bonds C(2)-H...O(3) (Fig. 4). Note that in this interaction, the H-..O separation is only 2.33 A. An interesting motif of intermolecular interactions is formed by the methanol molecules in their solvent channels. These molecules are arranged in zigzag chains, as shown in Fig. 5. The methyl groups form very short contacts with the hydroxyl O-atoms of the
Fig. 2. Crystal packing, shown in a projection along the monoclinic axis b. O - H . . . O hydrogen bonds are indicated by dashed lines.
46
T. Steiner et al./Journal of Molecular Structure 447 (1998) 43-48
Table 2 Fractional atomic coordinates of mestranol methanolate
03 O17 HI7 CI HI C2 H2 C3 C4 H4 C5 C6 H6A H6B C7 H7A H7B C8 H8 C9 H9 C10 Cll HIlA HI1B C12 H12A H12B C13 C14 H14 C15 HI5A HI5B CI6 H16A H16B C17 C18 HI8A H18B HI8C C20 C21 H21 C3' H3'A H3'B H3'C O(M) HI(M) C(M)
X
y
Z
Ue q (~2)
0.8599(2) 0.4779(3) 0.5466(12) 0.8156(3) 0.8653(3) 0.8653(3) 0.9534(3) 0.8032(3) 0.6912(3) 0.6422(3) 0.6407(3) 0.5194(3) 0.4913(3) 0.4890(3) 0.4717(3) 0.3856(3) 0.4809(3) 0.5304(3) 0.5298(3) 0.6488(3) 0.6477(3) 0.7022(3) 0.7102(3) 0.7924(3) 0.7156(3) 0.6566(4) 0.7005(4) 0.6606(4) 0.5380(4) 0.4808(3) 0.4896(3) 0.3594(4) 0.3377(4) 0.3074(4) 0.3488(4) 0.2953(4) 0.3165(4) 0.4647(4) 0.5334(4) 0.5753(4) 0.4492(4) 0.5724(4) 0.4849(5) 0.5003(6) 0.5146(6) 0.7989(3) 0.8539(3) 0.7491(3) 0.7470(3) 0.6487(5) 0.614(6) 0.7217(8)
0.3725(5) 0.0467(5) 0.049(6) 0.3659(7) 0.3642(7) 0.3721 (6) 0.3765(6) 0.3727(6) 0.3751(6) 0.3807(6) 0.3706(6) 0.3748(8) 0.4885(8) 0.2356(8) 0.4124(7) 0.3776(7) 0.5660(7) 0.2855(6) 0.1351 (6) 0.3537(6) 0.5022(6) 0.3617(6) 0.2275(7) 0.2835(7) 0.0788(7) 0.2233(8) 0.1229(8) 0.3683(8) 0.1589(6) 0.2898(7) 0.4389(7) 0.2351 (8) 0.1123(8) 0.3587(8) 0.1801 (9) 0.2817(9) 0.0329(9) 0.1925(7) 0.0601 (6) 0.1464(6) 0.1068(6) 0.0809(6) 0.3855(9) 0.5405(11) 0.6851 ( 11) 0.3692(8) 0.3694(8) 0.2380(8) 0.4978(8) 0.0531 (I 2) 0.047(I 1) 0.199(2)
1.03498(I 2) 0.58656(14) 0.5774(2) 0.8740(2) 0.8370(2) 0.9317(2) 0.9397(2) 0.9797(2) 0.9689(2) 1.0062(2) 0.9104(2) 0.9022(2) 0.9307(2) 0.9168(2) 0.8379(2) 0.8329(2) 0.8269(2) 0.7959(2) 0.8117(2) 0.7985(2) 0.7810(2) 0.8619(2) 0.7571(2) 0.7573(2) 0.7744(2) 0.6929(2) 0.6667(2) 0.6733(2) 0.6903(2) 0.7318(2) 0.7162(2) 0.7168(2) 0.7438(2) 0.7245(2) 0.6503(2) 0.6243(2) 0.6437(2) 0.6321 (2) 0.7073(2) 0.6763(2) 0.7051 (2) 0.7525(2) 0.6058(2) 0.5867(3) 0.5690(3) 1.0849(2) 1.1260(2) 1.0833(2) 1.0839(2) 0.5215(2) 0.4845(13) 0.5244(4)
0.0523(8) 0.0711(10) 0.082(20) 0.0429(9) 0.051 0.0444(10) 0.053 0.0384(9) 0.0386(9) 0.046 0.0387(9) 0.0484(10) 0.058 0.058 0.0504(12) 0.060 0.060 0.04 10(10) 0.049 0.0410(10) 0.049 0.0349(9) 0.0492(11) 0.059 0.059 0.0548(12) 0.066 0.066 0.0478(11) 0.0486(1 I) 0.058 0.0622(13) 0.075 0.075 0.0703(15) 0.084 0.084 0.0618(14) 0.0592(14) 0.089 0.089 0.089 0.075(2) 0.111(3) 0.133 0.0502(10) 0.075 0.075 0.075 0.150(2) 0.225 0.171(4)
-
T. Steiner et al./Journal of Molecular Structure 447 (1998) 43-48
47
Table 2 (continued) x H2(M) H3(M) H4(M)
y
0.6794(8) 0.772(3) 0.772(3)
0.339(2) 0.185(5) 0.193(6)
next molecule in the chain, with C...O separations of only 3.145(15),~. In these contacts, the mutual approach is not along a C - H vector of the methyl group, but rather in the direction of the O - C bond (angle O - C . . - O = 157.3(6)°). In this way, despite the short C.-.O approach, the contact distances of O to all methyl H-atoms are rather long, and the CMH...O anogles are strongly bent (H...O distances 2.73 ,~, 2.84 A and 3.38 A; C - H . . . O angles 102 °, 96 ° and 68 ° respectively). Furthermore, the shortest of the CM-H--.O contacts is associated with an even shorter C - H . . . H - C contact (H...H = 2.46 ,~). According to published quantum chemical calculations, methyl to oxygen contacts of this geometry ('umbrella configuration') have close to zero interaction energies [10], in contrast to linear contacts which can reasonably be regarded as weak hydrogen bonds. The umbrella configuration allows for a very short intermolecular approach and, therefore, optimization of closepacking requirements, practically without attractive or repulsive force.
~\
z
Ueq (,~2)
0.521 (3) 0.488(2) 0.5668(13)
0.26 0.26 0.26
On the whole, the hydrogen bond interactions in 1 appear to be favourable. The donor and the acceptor potentials of the hydroxyl groups are nicely satisfied, and a number of additional C - H . . . O hydrogen bonds are formed. This contrasts with the crystal structure of solvent-free mestranol [4], where hydrogen bond interactions are less favourable: no array of interconnected conventional hydrogen bonds can be formed, and the relevant functional groups resort to a weaker (but still cooperative) network of O - H . . . O , C - H . . . and O-H...Tr hydrogen bonds. Obviously, incorporation of a methanol molecule in 1 achieves the formation of a strong cooperative network of O - H . . . O hydrogen bonds, which could otherwise not be formed. It would also be of interest to study the crystal structure of the acetone solvate. Close similarity of the unit cell constants suggests a related crystal packing type to that in 1 (Table 1). Because the acetone molecule is a pure hydrogen bond acceptor, the mode
Fig. 4. Lateral contact of the steroid molecules involving a pair of weak hydrogen bonds C(2)-H...O(3).
MeOH
TY t
Fig. 3. The hydrogen bond arrangement involving the hydroxyl and ethynyl groups of mestranol, and the methanol solvent molecule• Oatoms are drawn shaded.
Y Fig. 5. The chain of methanol molecules extending along the crystallographic y-axis.
48
T. Steiner et al./Journal of Molecular Structure 447 (1998) 43-48
Table 3 Geometry of X - H . . . O hydrogen bonds in mestranol methanolate (for X - H bond lengths of 0.98 ,~ for O - H and 1.08 ,~ for C-H) Symmetry operation a OI7-H'"OM OM-H'" 'O17 C2-H"'O3 C21-H'"O17
H...O (,~.)
(i) (ii) (iii) (iv)
1.81 1.79 2.33 2.56
X.. "O (A) 2.704(10) 2.757(9) 3.415(10) 3.48(2)
X - H . . . O (deg) 150 171 175 142
a (i) x, y, z; (ii) x, 1 +y, z; (iii) 2-x, y, 2-z; (iv) I-x, y, 1-Z.
of intermolecular interactions must be different. If the crystal packing is actually isostructural to 1, the acetone molecules would be in places analogous to methanol in 1 and form a solvent layer parallel to the xy-plane, and act as acceptors of one O H.-.O=C hydrogen bond each. The hydroxyl acceptor potential would be unsatisfied. Unfortunately, these crystals are so unstable that only the unit cell dimensions could be determined, but not the crystal structure itself. It is noted, however, that the plateshaped crystals of mestranol acetonate can be easily grown to dimensions of several millimetres across, suggesting that the crystal packing as such is a favourable one.
Acknowledgements T.S. thanks Professor Wolfram Saenger for giving him the opportunity to carry out part of this work (compound 2) in his laboratory, and the research network 'Molecular Recognition Phenomena' of the
European Union for supporting a stay at the Utrecht University.
References [1] B. Lutz, J. van der Maas, J.A. Kanters, J. Mol. Struct. 325 (1994) 203-214. [2] B. Lutz, J.A. Kanters, J. van der Maas, J. Kroon, T. Steiner, J. Mol. Struct., 440 (1998) 81. [3] M.A. Viswamitra, R. Radhakrishnan, J. Bandekar, G.R. Desiraju, J. Am. Chem. Soc. 115 (1993) 4868-4869. I4] T. Steiner, B. Lutz, J. van der Maas, N. Veldman, A.M.M. Schreurs, J. Kroon, J.A. Kanters, Chem. Commum., (1997) 191-192. [5l R. Desiraju, Acc. Chem. Res. 29 (1996) 441-449. [6] T. Steiner, Chem. Commun., (1997) 727-734. [7] G.M. Sheldrick, SHELXS86, Program for the solution of crystal structures, University of G6ttingen, Germany, 1986. [8] G.M. Sheldrick, SHELXL93, Program for the refinement of crystal structures, University of GSttingen, Germany, 1993. [9] V.J. van'Geerestein, Acta Crystallogr. Sect. C: 43 (1987) 1206-1208. [10] T. van Mourik, F.B. van Duijneveldt, J. Mol. Struct. (Theochem) 341 (1995) 63.
MOLECULAR STRUCTURE ELSEVIER
Journal of Molecular Structure 447 (1998) 43-48
Hydrogen bonding in crystalline mestranol methanolate Thomas Steiner a'*, Nora Veldman b, Antoine M.M. Schreurs b, Jan Kanters b, Jan Kroon b ~lnstitut fiir Kristallographie, Freie Universiti~t Berlin, Takustrafle 6, D-14195 Berlin, Germany bBijvoet Center for Biomolecular Research, Department of Crystal and Structural Chemistry, Utrecht University, Padualaan 8, 3584 Utrecht, Netherlands
Received 20 November 1997; accepted 23 December 1997
Abstract
The crystal structure of the synthetic sex steroid mestranol is determined for a crystal grown from methanol. One methanol molecule per steroid molecule is incorporated in the crystal lattice and facilitates formation of a favourable cooperative hydrogen bond network. Close contacts are formed between methanol molecules, in which the hydroxyl O-atoms approach the methyl carbon atoms to 3.15 .~ in the so-called umbrella configuration. In the latter, the intermolecular interaction energy is close to zero. © 1998 Elsevier Science B.V. All rights reserved Keywords: Crystal structure; Hydrogen bonding; Sex steroids; Alkynes; C-H donors
I. Introduction
Synthetic 17a-ethynyl sex steroids are important model compounds for studying weak hydrogen bonding effects. In particular, the ethynyl residue C - C - H at position 17 is frequently found donating C - H . . . O [1] and C-H...Tr [2] hydrogen bonds. Occasionally, the 17ct-ethynyl group also acts as acceptor of O H...Tr hydrogen bonds directed at the carbon-carbon triple bond [3,4]. Weak hydrogen bonds of these types are of interest in themselves and are currently the subject of intense investigation [5,6]. Mestranol is the 3-O-methyl derivative of 17etethynylestradiol, and is of clinical importance because of its oral oestrogenic activity. Solvent-free crystals of mestranol can be grown from solutions in ethanol, propan-1-ol and propan-2-ol [4]. The crystal structure * Corresponding author.
of solvent-free mestranol exhibits a complex network of interwoven O - H . . . O , C - H . . . O and O-H...Tr hydrogen bonds, which has been characterised previously [4]. If mestranol is crystallized from methanol or from acetone, solvent molecules are incorporated in the crystal lattice. This leads to different crystal packing modes and to different hydrogen bonding schemes. The macroscopic properties of solvated and solvent-free crystals of mestranol are completely different; the solvent-free crystals are stable at ambient conditions, whereas crystals of the methanol solvate decay within a few days due to loss of solvent, and those of the acetonate decay within minutes. To shed light on these phenomena, the crystal structure of mestranol methanolate, l, has been determined and is described below. Attempts to characterize the acetone solvate from X-ray diffraction failed because of the extreme crystal instability.
0022-2860/98/$19.00 © 1998 Elsevier Science B.V. All rights reserved PII S0022-2860(98)00299-3
44
T. Steiner et al./Journal of Molecular Structure 447 (1998) 43-48
2. Experimental Mestranol, 17c~-ethynyl-3-methoxy-estra- 1,3,5[ 10]trien-17fl-ol, C21H2602, is commercially available (Sigma). The crystalline methanolate, 1, was prepared by slow evaporation of a methanolic solution. Crystals are unstable under ambient conditions due to loss of solvent: if left at atmosphere, the colourless transparent plates turn white and loose their X-ray diffraction pattern within a few days. Fortunately, crystal stability has been sufficient for X-ray data collection at room temperature using an area detector. Mestranol acetonate, 2, was crystallized by slow evaporation of solutions in acetone. Initially, the optical quality of the transparent plate-shaped crystals is excellent, but if in contact with the atmosphere, crystals decay within minutes. The crystals are so sensitive that all attempts to mount specimens in glass capillaries together with mother liquor, or to coat crystals with oil to prevent desolvation, failed. Therefore, only unit cell dimensions could be determined, Table 1 (Enraf-Nonius Turbo-CAD4 diffractometer with Cu Kc~ radiation). X-ray diffraction data for 1 were collected at room temperature on an Enraf-Nonius FAST area detector
(Mo K a radiation with X = 0.71073 A). The diffraction power of the crystal was only moderate. The structure was solved and refined with standard methods [7,8] (anisotropic refinement for non-H atoms, H-atoms treated in the riding model, no absorption correction). Refinement converged with R = 0.068 (for observed reflections). Relevant crystallographic data are given in Table 1; fractional atomic coordinates of the structure model are given in Table 2.
3. Results The molecular structure of mestranol as observed in the crystal structure of its methanol solvate, 1, is shown in Fig. 1. The conformation is very similar to the solvent-free crystal structure, and to that of the parent molecule 17c~-ethynylestradiol in the hemihydrate crystal structure [9], and need not be discussed here any further. The crystal packing of 1 is shown in Fig. 2 in a projection along the monoclinic axis y. The steroid molecules are oriented roughly parallel to the xzplane, thus forming a layer-type packing. The methanol solvent molecules are incorporated in such a way
Table 1 Crystallographic data for mestranol in different crystal structures
Reference Formula MW Habit Crystal system Space group a/A cA
/3/deg z z'
VZ 11~3 Dc/g cm-3
#/mm-~ Crystal size/mm Measured reflections Unique reflections Unique with 1 > 20(/) R (for I > 20(/)) R~ (for all data)
Methanolate
Acetonate
Solvent-free
this work C21H2602.CH40 342.5 thin plates monoclinic C2 (No. 5) 12.42(3) 6.85(3) 22.55(4) 96.1(2) 1908(10) 4 1 477(2) 1.192 0.077 0.68 x 0.25 × 0.05 8052 2986 1216 0.068 0.178
this work
[4]
thick plates monoclinic
prisms or plates monoclinic P21 (No. 4) 6.8622(8) 39.71(3) 6.997(5) 117.6(2) 1690(2) 4 2 422.5(5) 1.22
12.640(11) 6.826(2) 25.34(5) 102.20(14) 2137(5) 4 534(1 )
T. Steiner et al./Journal of Molecular Structure 447 (1998) 43-48
OH
0M~___ I Me
~
017
Fig. 1. Formula of mestranol and molecular structure as observed in the methanolate crystal structure. Displacement ellipsoids are drawn at th 30% probability level. O-atoms are drawn shaded.
that they form hydrogen bond bridges between pairs of steroid molecules, which are related by the crystallographic twofold axis. There are no direct contacts between thesesteroid molecules, so that the crystal cohesion in the region z= ½ is entirely due to solvent-mediated hydrogen bonds. A view of Fig. 2 immediately explains the desolvation of the crystals
45
at atmosphere, and the associated decay of the X-ray diffraction pattern. The methanol molecules are not trapped in interstitial voids, but are free to leave in the y-direction; if they leave then the entire packing arrangement must collapse. Of interest is a detailed view of the hydrogen bonding scheme. The methanol molecules and the steroid hydroxyl groups form cooperative cycles built by four O - H . . . O hydrogen bonds (Fig. 2). Because the cycle runs around the crystallographic twofold axis, only two of the four hydrogen bonds are symmetry independent. In the y-direction, these cycles are joined by pairs of C - H . . . O hydrogen bonds donated by the alkyne groups (Fig. 3; numerical data are given in Table 3). At their other ends, the steroid molecules are joined by a cyclic arrangement formed by mutual hydrogen bonds C(2)-H...O(3) (Fig. 4). Note that in this interaction, the H-..O separation is only 2.33 A. An interesting motif of intermolecular interactions is formed by the methanol molecules in their solvent channels. These molecules are arranged in zigzag chains, as shown in Fig. 5. The methyl groups form very short contacts with the hydroxyl O-atoms of the
Fig. 2. Crystal packing, shown in a projection along the monoclinic axis b. O - H . . . O hydrogen bonds are indicated by dashed lines.
46
T. Steiner et al./Journal of Molecular Structure 447 (1998) 43-48
Table 2 Fractional atomic coordinates of mestranol methanolate
03 O17 HI7 CI HI C2 H2 C3 C4 H4 C5 C6 H6A H6B C7 H7A H7B C8 H8 C9 H9 C10 Cll HIlA HI1B C12 H12A H12B C13 C14 H14 C15 HI5A HI5B CI6 H16A H16B C17 C18 HI8A H18B HI8C C20 C21 H21 C3' H3'A H3'B H3'C O(M) HI(M) C(M)
X
y
Z
Ue q (~2)
0.8599(2) 0.4779(3) 0.5466(12) 0.8156(3) 0.8653(3) 0.8653(3) 0.9534(3) 0.8032(3) 0.6912(3) 0.6422(3) 0.6407(3) 0.5194(3) 0.4913(3) 0.4890(3) 0.4717(3) 0.3856(3) 0.4809(3) 0.5304(3) 0.5298(3) 0.6488(3) 0.6477(3) 0.7022(3) 0.7102(3) 0.7924(3) 0.7156(3) 0.6566(4) 0.7005(4) 0.6606(4) 0.5380(4) 0.4808(3) 0.4896(3) 0.3594(4) 0.3377(4) 0.3074(4) 0.3488(4) 0.2953(4) 0.3165(4) 0.4647(4) 0.5334(4) 0.5753(4) 0.4492(4) 0.5724(4) 0.4849(5) 0.5003(6) 0.5146(6) 0.7989(3) 0.8539(3) 0.7491(3) 0.7470(3) 0.6487(5) 0.614(6) 0.7217(8)
0.3725(5) 0.0467(5) 0.049(6) 0.3659(7) 0.3642(7) 0.3721 (6) 0.3765(6) 0.3727(6) 0.3751(6) 0.3807(6) 0.3706(6) 0.3748(8) 0.4885(8) 0.2356(8) 0.4124(7) 0.3776(7) 0.5660(7) 0.2855(6) 0.1351 (6) 0.3537(6) 0.5022(6) 0.3617(6) 0.2275(7) 0.2835(7) 0.0788(7) 0.2233(8) 0.1229(8) 0.3683(8) 0.1589(6) 0.2898(7) 0.4389(7) 0.2351 (8) 0.1123(8) 0.3587(8) 0.1801 (9) 0.2817(9) 0.0329(9) 0.1925(7) 0.0601 (6) 0.1464(6) 0.1068(6) 0.0809(6) 0.3855(9) 0.5405(11) 0.6851 ( 11) 0.3692(8) 0.3694(8) 0.2380(8) 0.4978(8) 0.0531 (I 2) 0.047(I 1) 0.199(2)
1.03498(I 2) 0.58656(14) 0.5774(2) 0.8740(2) 0.8370(2) 0.9317(2) 0.9397(2) 0.9797(2) 0.9689(2) 1.0062(2) 0.9104(2) 0.9022(2) 0.9307(2) 0.9168(2) 0.8379(2) 0.8329(2) 0.8269(2) 0.7959(2) 0.8117(2) 0.7985(2) 0.7810(2) 0.8619(2) 0.7571(2) 0.7573(2) 0.7744(2) 0.6929(2) 0.6667(2) 0.6733(2) 0.6903(2) 0.7318(2) 0.7162(2) 0.7168(2) 0.7438(2) 0.7245(2) 0.6503(2) 0.6243(2) 0.6437(2) 0.6321 (2) 0.7073(2) 0.6763(2) 0.7051 (2) 0.7525(2) 0.6058(2) 0.5867(3) 0.5690(3) 1.0849(2) 1.1260(2) 1.0833(2) 1.0839(2) 0.5215(2) 0.4845(13) 0.5244(4)
0.0523(8) 0.0711(10) 0.082(20) 0.0429(9) 0.051 0.0444(10) 0.053 0.0384(9) 0.0386(9) 0.046 0.0387(9) 0.0484(10) 0.058 0.058 0.0504(12) 0.060 0.060 0.04 10(10) 0.049 0.0410(10) 0.049 0.0349(9) 0.0492(11) 0.059 0.059 0.0548(12) 0.066 0.066 0.0478(11) 0.0486(1 I) 0.058 0.0622(13) 0.075 0.075 0.0703(15) 0.084 0.084 0.0618(14) 0.0592(14) 0.089 0.089 0.089 0.075(2) 0.111(3) 0.133 0.0502(10) 0.075 0.075 0.075 0.150(2) 0.225 0.171(4)
-
T. Steiner et al./Journal of Molecular Structure 447 (1998) 43-48
47
Table 2 (continued) x H2(M) H3(M) H4(M)
y
0.6794(8) 0.772(3) 0.772(3)
0.339(2) 0.185(5) 0.193(6)
next molecule in the chain, with C...O separations of only 3.145(15),~. In these contacts, the mutual approach is not along a C - H vector of the methyl group, but rather in the direction of the O - C bond (angle O - C . . - O = 157.3(6)°). In this way, despite the short C.-.O approach, the contact distances of O to all methyl H-atoms are rather long, and the CMH...O anogles are strongly bent (H...O distances 2.73 ,~, 2.84 A and 3.38 A; C - H . . . O angles 102 °, 96 ° and 68 ° respectively). Furthermore, the shortest of the CM-H--.O contacts is associated with an even shorter C - H . . . H - C contact (H...H = 2.46 ,~). According to published quantum chemical calculations, methyl to oxygen contacts of this geometry ('umbrella configuration') have close to zero interaction energies [10], in contrast to linear contacts which can reasonably be regarded as weak hydrogen bonds. The umbrella configuration allows for a very short intermolecular approach and, therefore, optimization of closepacking requirements, practically without attractive or repulsive force.
~\
z
Ueq (,~2)
0.521 (3) 0.488(2) 0.5668(13)
0.26 0.26 0.26
On the whole, the hydrogen bond interactions in 1 appear to be favourable. The donor and the acceptor potentials of the hydroxyl groups are nicely satisfied, and a number of additional C - H . . . O hydrogen bonds are formed. This contrasts with the crystal structure of solvent-free mestranol [4], where hydrogen bond interactions are less favourable: no array of interconnected conventional hydrogen bonds can be formed, and the relevant functional groups resort to a weaker (but still cooperative) network of O - H . . . O , C - H . . . and O-H...Tr hydrogen bonds. Obviously, incorporation of a methanol molecule in 1 achieves the formation of a strong cooperative network of O - H . . . O hydrogen bonds, which could otherwise not be formed. It would also be of interest to study the crystal structure of the acetone solvate. Close similarity of the unit cell constants suggests a related crystal packing type to that in 1 (Table 1). Because the acetone molecule is a pure hydrogen bond acceptor, the mode
Fig. 4. Lateral contact of the steroid molecules involving a pair of weak hydrogen bonds C(2)-H...O(3).
MeOH
TY t
Fig. 3. The hydrogen bond arrangement involving the hydroxyl and ethynyl groups of mestranol, and the methanol solvent molecule• Oatoms are drawn shaded.
Y Fig. 5. The chain of methanol molecules extending along the crystallographic y-axis.
48
T. Steiner et al./Journal of Molecular Structure 447 (1998) 43-48
Table 3 Geometry of X - H . . . O hydrogen bonds in mestranol methanolate (for X - H bond lengths of 0.98 ,~ for O - H and 1.08 ,~ for C-H) Symmetry operation a OI7-H'"OM OM-H'" 'O17 C2-H"'O3 C21-H'"O17
H...O (,~.)
(i) (ii) (iii) (iv)
1.81 1.79 2.33 2.56
X.. "O (A) 2.704(10) 2.757(9) 3.415(10) 3.48(2)
X - H . . . O (deg) 150 171 175 142
a (i) x, y, z; (ii) x, 1 +y, z; (iii) 2-x, y, 2-z; (iv) I-x, y, 1-Z.
of intermolecular interactions must be different. If the crystal packing is actually isostructural to 1, the acetone molecules would be in places analogous to methanol in 1 and form a solvent layer parallel to the xy-plane, and act as acceptors of one O H.-.O=C hydrogen bond each. The hydroxyl acceptor potential would be unsatisfied. Unfortunately, these crystals are so unstable that only the unit cell dimensions could be determined, but not the crystal structure itself. It is noted, however, that the plateshaped crystals of mestranol acetonate can be easily grown to dimensions of several millimetres across, suggesting that the crystal packing as such is a favourable one.
Acknowledgements T.S. thanks Professor Wolfram Saenger for giving him the opportunity to carry out part of this work (compound 2) in his laboratory, and the research network 'Molecular Recognition Phenomena' of the
European Union for supporting a stay at the Utrecht University.
References [1] B. Lutz, J. van der Maas, J.A. Kanters, J. Mol. Struct. 325 (1994) 203-214. [2] B. Lutz, J.A. Kanters, J. van der Maas, J. Kroon, T. Steiner, J. Mol. Struct., 440 (1998) 81. [3] M.A. Viswamitra, R. Radhakrishnan, J. Bandekar, G.R. Desiraju, J. Am. Chem. Soc. 115 (1993) 4868-4869. I4] T. Steiner, B. Lutz, J. van der Maas, N. Veldman, A.M.M. Schreurs, J. Kroon, J.A. Kanters, Chem. Commum., (1997) 191-192. [5l R. Desiraju, Acc. Chem. Res. 29 (1996) 441-449. [6] T. Steiner, Chem. Commun., (1997) 727-734. [7] G.M. Sheldrick, SHELXS86, Program for the solution of crystal structures, University of G6ttingen, Germany, 1986. [8] G.M. Sheldrick, SHELXL93, Program for the refinement of crystal structures, University of GSttingen, Germany, 1993. [9] V.J. van'Geerestein, Acta Crystallogr. Sect. C: 43 (1987) 1206-1208. [10] T. van Mourik, F.B. van Duijneveldt, J. Mol. Struct. (Theochem) 341 (1995) 63.