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Identical Molecular Strings Woven Differently by. Intermolecular Interactions in Dimorphs of myo-Inositol. 1,3,5-Orthobenzoate. Gaurav Bhosekar,† Ch...
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Identical Molecular Strings Woven Differently by Intermolecular Interactions in Dimorphs of myo-Inositol 1,3,5-Orthobenzoate Gaurav Bhosekar,† Chebrolu Murali,‡ Rajesh G. Gonnade,† Mysore S. Shashidhar,*,‡ and Mohan M. Bhadbhade*,†

CRYSTAL GROWTH & DESIGN 2005 VOL. 5, NO. 5 1977-1982

Center for Materials Characterization and the Division of Organic Synthesis, National Chemical Laboratory, Pune 411008, India Received June 16, 2005

ABSTRACT: myo-Inositol 1,3,5-orthobenzoate exhibits polymorphic behavior depending upon the solvent and time allowed for crystallization. Long plates (form I, monoclinic P21/n) are produced on crystallization from methanol, while crystallization from ethyl acetate mostly yielded squarish plates (form II, monoclinic P21/c). The latter could also be obtained by achieving rapid nucleation from a supersaturated solution of methanol. Remarkably, the overall conformation of the individual molecules is very similar in both polymorphs, although free rotations were possible for the phenyl ring and for the three O-H groups. O-H‚‚‚O linked one-dimensional isostructural molecular strings in the two forms weave differently by weak intermolecular interactions to produce the dimorphs. Striking difference is seen in the “zipping” of molecular layers via phenyl‚‚‚phenyl contacts; thermodynamic crystals of form I utilize a well-recognized “edge-to-face” herringbone pattern, making C-H‚‚‚π interactions, whereas the kinetic crystals of form II show rather uncommon “edge-to-edge” organization, which makes short Ph-H‚‚‚H-Ph contacts. Introduction Polymorphism is an intensely researched topic of current interest having tremendous basic and commercial importance.1 The impact is evident by an outburst of publications, patents, conferences, and special issues of journals on this enigmatic phenomenon.2 One of the main objectives in the study of polymorphism is to understand the effect of various parameters of crystallization experiment in controlling the nucleation to obtain a desired polymorph. The effect of solvent, an important parameter influencing nucleation, continues to be the subject of investigations.3 Encouraged by the frequently encountered polymorphic behavior of many myo-inositol derivatives,4 myo-inositol 1,3,5-orthobenzoate (1) was screened for the same property. In this article, we report structures of two polymorphs of 1,5 one thermodynamic (form I) and the other kinetic (form II). The two structures show interesting differences in the weaving of identical molecular strings by (weak) intermolecular interactions. Remarkable differences are seen in the “zipping” of molecular layers via phenyl‚‚‚phenyl contacts. Form I utilizes a well recognized “edge-to-face” herringbone pattern making C-H‚‚‚π interactions, whereas form II shows rather uncommon “edge-to-edge” organization, which makes short Ph-H‚‚‚H-Ph contacts (H‚‚‚H ) 2.35 Å). Experimental Section Preparation of myo-Inositol 1,3,5-Orthobenzoate (1). myo-Inositol (9.072 g, 50.40 mmol), trimethyl orthobenzoate (19.04 mL, 110.87 mmol), and p-toluenesulfonic acid (2.5 g, 14.51 mmol) in dry DMF (80 mL) were heated at 145-150 °C * To whom correspondence should be addressed. Tel.: (91) (20) 25902252. Fax: (91) (20) 25883067. E-mail: [email protected] (M.M.B.); [email protected] (M.S.S.). † Center for Materials Characterization. ‡ Division of Organic Synthesis.

for 3.5 h. The clear solution obtained was cooled to room temperature and triethylamine (2.02 mL) was added. The reaction mixture was concentrated under reduced pressure. The gum obtained was purified by flash column chromatography (silica gel; eluent 60% ethyl acetate-40% petroleum ether): yield 12.45 g (93%); mp 210-211 °C; IR (Nujol) ν 34503200 cm-1; 1H NMR (200 MHz, (CD3)2SO) δ 7.80-7.50 (m, 2H), 7.45-7.20 (m, 3H), 5.71-5.47 (d, 2H, D2O exchangeable, J ) 5.5 Hz), 5.46-5.24 (d, 1H, D2O exchangeable, J ) 6.3 Hz), 4.55-4.37 (m, 2H), 4.30-4.08 (m, 4H); 13C NMR (75 MHz, (CD3)2SO) δ 137.9, 129.0, 127.5, 125.5, 106.5, 75.9, 70.1, 67.3, 58.0. Anal. Calcd for C13H14O6: C, 58.64; H, 5.30. Found: C, 58.27; H, 5.33. myo-Inositol orthobenzoate has been mentioned earlier in the literature.5 However, neither a procedure for its preparation nor any data for its characterization have been reported. Crystallization of 1 was attempted from 12 solvents, out of which 9 solvents (methanol, ethanol, water, 2-propanol, dichloromethane, acetone, tetrahydrofuran, nitromethane, triethylamine) produced long platelike crystals (form I, Figure 1A) and 3 solvents (ethyl acetate, dioxane, acetonitrile) yielded more square platelike crystals (form II, Figure 1B). Although, melting points (209-211 °C) were quite similar, DTA/TGA curves showed small but significant differences in the endotherms before the melting of the crystals began. The crystals of form II could also be obtained by cooling a saturated hot methanol solution of 1 to room temperature (∼2 h, Figure 1C). X-ray Data Collection, Structure Determination, and Refinement. The single-crystal diffraction data were collected on a Bruker AXS Smart Apex CCD diffractometer at 293(2) K. The X-ray generator was operated at 50 kV and 30 mA using Mo KR radiation. Data were collected with a ω scan width of 0.3° and with three different settings of φ (0°, 90°, 180°), keeping the sample-to-detector distance fixed at 6.145 cm and the detector position (2θ) fixed at -28°. The data were reduced using SAINTPLUS,6 and an empirical absorption correction was applied using the package SADABS.6 XPREP6 was used to determine the space group. The crystal structure was solved by direct methods using SHELXS977 and refined by full-matrix least-squares methods using SHELXL97.7 Molecular and packing diagrams were generated using ORTEP32.8 Geometrical calculations were done using PLATON.9 All the hydrogen atoms were located from a difference Fourier

10.1021/cg050272j CCC: $30.25 © 2005 American Chemical Society Published on Web 08/11/2005

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Figure 1. Structural formula of 1: (A) long plates of form I from methanol; (B) square plates of form II from ethyl acetate; (C) form II crystals from methanol by rapid crystallization. Table 1. Crystal Data for the Polymorphs of 1 chem formula Mr temp/K morphology cryst size cryst syst space group a (Å) b (Å) c (Å) R (deg) β (deg) γ (deg) V (Å3) Z Dcalcd (g cm-3) µ (mm-1) θmax (deg) h, k, l (min, max) no. of rflns collected no. of unique rflns no. of obsd rflns no. of params GOF R1 (all) R1 (obsd) wR2 (all)

form I

form II

C13H14O6 266.24 293(2) long plate 0.51 × 0.28 × 0.21 monoclinic P21/n 6.2323(9) 33.014(5) 6.4077(9) 90 115.897(2) 90 1186.0(3) 4 1.491 0.12 25.5 (-7, 7), (-38, 39), (-6, 7) 8778 2203 2078 228 1.15 0.046 0.044 0.105

C13H14O6 266.24 293(2) needle 0.92 × 0.23 × 0.11 monoclinic P21/c 17.080(4) 6.3196(14) 11.361(3) 90 108.087(4) 90 1165.7(4) 4 1.517 0.12 25.0 (-20, 18), (-7, 7), (-13, 11) 5607 2055 1776 228 1.05 0.040 0.034 0.096

map, and their positional coordinates and isotropic thermal parameters were refined. Details of data collection and refinement are given in Table 1.

Results and Discussion The fact that form II crystals could be obtained by rapid crystallization from methanol solution shows that these are kinetic crystals, while form I crystals are thermodynamic.4c Single-crystal X-ray data (Table 1) reveal that unit cell parameters of form II bear a curious multiple relationship with those of form I. Initially it appeared that the unit cells could be transformed into each other, but the crystal structures revealed differences in the molecular packing that explained the relationship between the unit cell parameters. Crystal structures of forms I and II showed very similar conformations of individual molecules, although free rotations were possible for the phenyl ring and for the three O-H groups (Figure 2). The similarity in O-H group orientation could be because of two intramolecular O-H‚‚‚O hydrogen bonds, O6-H6A‚‚‚O4 and O2H2A‚‚‚O3; the former is somewhat stronger than the latter (Table 2). Another common significant feature in both of the structures is linking of the molecules via the strongest

Figure 2. ORTEP view of (A) form I, with possible free rotations (blue arrows) shown, and (B) form II. Dotted lines (‚‚‚) indicate O6-H6A‚‚‚O4 and O2-H2A‚‚‚O3 intramolecular hydrogen bonds. Table 2. Geometrical Parameters of the O-H‚‚‚O Hydrogen Bonds D-H‚‚‚Aa

D-H (Å)

H‚‚‚A (Å)

Form I 1.88(3) 2.03(2) 1.97(3) 2.41(2)

O(4)-H(4A)‚‚‚O(2)a O(2)-H(2A)‚‚‚O(6)b O(6)-H(6A)‚‚‚O(4)c O(2)-H(2A)‚‚‚O(3)c

0.84(3) 0.84(2) 0.82(3) 0.84(2)

O(4)-H(4A)‚‚‚O(2)d O(2)-H(2A)‚‚‚O(6)e O(6)-H(6A)‚‚‚O(4)c O(2)-H(2A)‚‚‚O(3)c O(6)-H(6A)‚‚‚O(2)f

Form II 0.86(2) 1.93(2) 0.849(19) 2.006(19) 0.85(2) 2.03(2) 0.849(19) 2.539(19) 0.85(2) 2.62(2)

D‚‚‚A (Å)

D-H‚‚‚A (deg)

2.712(2) 2.755(2) 2.691(2) 2.851(2)

172(2) 144(2) 146(2) 113.0(18)

2.779(2) 2.802(1) 2.762(1) 2.940(1) 3.098(2)

166.8(18) 155.7(18) 143.9(18) 110.0(15) 116.5(16)

a Symmetry code: (a) x, y, z + 1; (b) x - 1, y, z - 1; (c) x, y, z; (d) x, y - 1, z; (e) x, -y + 3/2, z + 1/2; (f) -x, y - 1/2, -z + 1/2.

intermolecular hydrogen bond, O4-H4A‚‚‚O2, resulting in a one-dimensional H-bonded polymer. This molecular string aligns along the c axis in form I and along the b axis in form II, explaining the near-equality of these axes in forms I and II (Figure 3). From this isostructurality in one dimension, intermolecular interactions weave the common strings differently, leading to two different paths of nucleation.4c Although the nucleation process cannot be visualized, we propose a possible sequence of events in the form of a drawing (Figure 4) inferred from the final observed structures that emerge out of a dynamic equilibrium between various strong and weak interactions in solution. The sequence of crystallization events is proposed to start from the formation of a one-dimensional strongly

Polymorphs of myo-Inositol 1,3,5-Orthobenzoate

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Figure 3. Identical intermolecular O4-H4A‚‚‚O2 hydrogen bonded molecular string shown (A) along the c axis in the unit cell in form I and (B) along the b axis in the unit cell in form II, with (C) a close-up view of the string in form I. Table 3. Geometrical Parameters of the C-H‚‚‚O Hydrogen Bonds in Crystals of 1 H‚‚‚A (Å)

D‚‚‚A (Å)

D-H‚‚‚A (deg)

C(1)-H(1)‚‚‚O(3)a C(2)-H(2)‚‚‚O(4)b C(3)-H(3)‚‚‚O(2)c C(4)-H(4)‚‚‚O(6)d

Form I 0.967(19) 2.814(18) 0.966(16) 2.682(17) 0.975(17) 2.500(17) 0.972(18) 2.561(18)

3.592(2) 3.644(2) 3.392(2) 3.329(2)

137.9(13) 174.1(13) 152.0(13) 136.0(13)

C(1)-H(1)‚‚‚O(3)e C(1)-H(1)‚‚‚O(4)f C(2)-H(2)‚‚‚O(4)g C(3)-H(3)‚‚‚O(2)h C(4)-H(4)‚‚‚O(1)i C(4)-H(4)‚‚‚O(6)j

Form II 0.940(15) 2.792(15) 0.940(15) 2.719(16) 0.971(13) 2.524(13) 0.985(15) 2.873(15) 0.983(16) 2.812(16) 0.983(16) 2.597(15)

3.452(2) 3.397(2) 3.352(2) 3.712(2) 3.485(2) 3.372(2)

128.1(11) 129.7(11) 143.0(11) 143.6(11) 126.3(11) 135.8(12)

D-H‚‚‚Aa

D-H (Å)

a Symmetry code: (a) x + 1, y, z; (b) -x + 1, -y, -z + 2; (c) -x, -y, -z + 1; (d) x - 1, y, z; (e) x, -y + 3/2, z - 1/2; (f) x, y + 1, z; (g) -x, y + 1/2, -z + 1/2; (h) -x, -y + 1, -z + 1; (i) x, y - 1, z; (j) x, -y + 1/2, z + 1/2.

Table 4. Geometrical Parameters of the C-H‚‚‚π Hydrogen Bonds in Crystals of 1 X-H‚‚‚Cga

Figure 4. Drawing giving the proposed pathways of dimorph formation.

H-bonded string (step 1), their different C-H‚‚‚O adhesions to form bilayers (step 2), formation of two different 2D layers from these bilayers via O-H‚‚‚O as well as C-H‚‚‚O and C-H‚‚‚π interactions (step 3), and finally the cohesion between these layers via different phenyl‚‚‚ phenyl zipping (step 4) that extends the growth of the crystals in the third dimension. This drawing (Figure 4) is elaborated below with details of intermolecular interactions in the crystal. As stated earlier, the branching point (step 2 in Figure 4) is networking of identical molecular strings via different interactions. The dimeric C-H‚‚‚O interactions (C2-H2‚‚‚O4) between these rows (Figure 5A) create a center of inversion in form I, whereas the catameric C2H2‚‚‚O4 and O6-H6A‚‚‚O2 contacts (Tables 2 and 3) between the two rows create a 21-screw relationship in form II (Figure 5B). These different dumbbell-shaped bimolecular rows in crystal forms I and II assemble to

H‚‚‚Cg (Å)

H-Perp (Å)

X‚‚‚Cg (Å)

X-H‚‚‚Cg (deg)

C5-H5‚‚‚Cg(5)a C11-H11‚‚‚Cg(5)b

3.20(2) 2.81(3)

Form I 3.015 2.783

3.887(2) 3.746(3)

129.3(14) 178(3)

C6-H6‚‚‚Cg(5)c C10-H10‚‚‚Cg(5)d

Form II 2.918(17) 2.707 3.18(2) 3.039

3.849(2) 3.860(3)

168.7(11) 131.3(19)

a Cg(5) ) geometric centers of phenyl ring C8-C13. Symmetry code: (a) x + 1, y, z + 1; (b) x - 1/2, -y + 1/2, z - 1/2; (c) x, -y + 3/ , z - 1/ ; (d) -x + 1, y + 1/ , -z + 3/ . 2 2 2 2

form two-dimensional molecular layers (step 3, Figure 4) via O2-H2A‚‚‚O6 hydrogen bonds, with the adjacent rows having different symmetry relations. The O-H‚‚‚O linking in form I is with a purely translated adjacent row (Figure 6A), whereas in form II the linking is with the next c-glide-related row (Figure 6B). This justifies an approximate doubling of the c axis in form II as compared to the a axis in form I. The relationships between the successive molecules along the O2H2A‚‚‚O6 (Figure 6) hydrogen-bonded row are quite different in the two forms; there are no significant interactions between the adjacent molecules in form I, whereas an emergence of C-H‚‚‚π contacts is seen in form II (Figure 7, Table 4).10 The inositol ring H atom (H6) approaches closer to the c-glide-related edge atoms C8, C9, and C13 of the

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Figure 5. Different associations of common molecular rows to form (A) centrosymmetric dimers via C4-H2‚‚‚O4 interactions (form I) and (B) 21-screw related catamers via C2-H2‚‚‚O4 and O6-H6A‚‚‚O2 interactions.

Figure 6. 2D-layer formation from common molecular rows, with a O2-H2A‚‚‚O6 H bond being formed (A) between translated molecular rows in form I and (B) between glide-related rows in form II.

Figure 7. Bilayer formation of O2-H2A‚‚‚O6 linked molecular rows: (A) C3-H3‚‚‚O2 interaction in form I; (B) C6-H6‚‚‚π interaction in form II.

phenyl ring rather than pointing toward the center of the π cloud (Figure 7B). Bilayer formations along this row also show differences; form I makes centrosymmetric C3-H3‚‚‚O2 interactions linking four molecules, whereas form II shows a somewhat compromised O2H2A‚‚‚O6 interaction (O6‚‚‚O2 ) 3.098(2) Å, O6-H6A ) 0.85(2) Å, H6A‚‚‚O2 ) 2.62(2) Å, ∠O6-H6A‚‚‚O2 ) 116.5(16)°) with a 21 related row that also links four

molecules. Finally, the crystal growth in the third dimension would have to take place when these twodimensional layers of orthobenzoate molecules stack along the b axis in form I (Figure 8A) and along the a axis in form II (Figure 8C). A striking difference between phenyl‚‚‚phenyl contacts is seen at this stage; a well recognized edge-to-face organization is seen in form I (Figure 8B), whereas a rather uncommon edge-

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Figure 8. Packing of molecules with an enlarged view of Ph‚‚‚Ph interactions: (A, B) edge-to-face organization in form I with C11-H11‚‚‚π interactions; (C, D) edge-to-edge organization of aromatic rings in form II with C12-H12‚‚‚H12-C12 short contacts.

to-edge approach is seen in form II (Figure 8D). Phenyl rings from the two layers related by an n-glide are zipped via C-H‚‚‚π interactions forming a herringbone pattern11 in form I; the atom H11 does not point to the center of the ring but makes closer contacts with the three edge atoms C10, C11, and C12 (Figure 8B) and the angle between the two phenyl rings is 85.11(8)°. In sharp contrast, parallel phenyl rings across the center of symmetry are zipped by short C-H‚‚‚H-C contacts (H‚‚‚H ) 2.35 Å) in form II (Figure 8D). Surprisingly, there are no significant π‚‚‚π or C-H‚‚‚π interactions between the phenyl rings from different layers (the distances between neighboring phenyl rings are >6 Å, and the angle along the row is 42.61(6)°). Therefore, the cohesion of 2D layers along the a axis in form II seems to be only via short H‚‚‚H contacts. The short H‚‚‚H contacts investigated in metal hydrides and also in some organic molecules have been seen as a new type of attractive interaction.12 The H‚‚‚H contact in the present structure is just at the boundary of the sum of the van der Waals radii (2.35 Å), and any conclusion based on this alone could be fortuitous. However, the packing mode of aromatic rings observed in form II could imply a weak adhesive interaction and deserves some attention. Conclusions Polymorphs of 1 obtained under kinetic and thermodynamic conditions show different ways with which identical molecular strings are glued by weak intermolecular interactions. The isostructurality is restricted only to one dimension, due to the strongest H-bonded molecular tape formation in these dimorphs.13 We have

proposed how nucleation paths may diverge due to various options of intermolecular interactions14 resulting in different symmetry relationships. Different paths from nucleation leading to successful crystal growth are, to a large extent, still a mystery.15 However, the observations as presented here should prove valuable in sharpening our tools for polymorph prediction.16 The Ph‚‚‚Ph contacts in form II are expected to be of interest from experimental and theoretical points of view,17 since interactions between aromatic rings are important due to their role in the stability of biological macromolecules such as DNA18 and proteins19 and also in drug-receptor interactions.11b Acknowledgment. We thank the Department of Science and Technology, New Delhi, India, for funding this work. C.M. thanks the CSIR of India for a Senior Research Fellowship. We gratefully acknowledge Dr. S. D. Pradhan for TG/DTA analysis. Supporting Information Available: A figure tiging TG/ DTA data and CIF files giving single-crystal X-ray crystallographic data for the two polymorphs of 1. This material is available free of charge via the Internet at http://pbcs.acs.org.

References (1) Selected books and reviews: (a) Polymorphism in Pharmaceutical Solids, Drugs and the Pharmaceutical Sciences; Brittain, H. G., Ed.; Marcel Dekker: New York, 1999; Vol. 95. (b) Bernstein, J. Polymorphism in Molecular Crystals; Oxford University Press: Oxford, Great Britain, 2002. (c) Sarma, J. A. R. P.; Desiraju, G. R. In Crystal Engineering: Polymorphism and Pseudopolymorphism in Organic Crystals: A Cambridge Structural Database Study; Seddon, S. R., Zaworotko, M., Eds.; Kluwer: Norwell, MA, 1999; p 325. (d) Threlfall, T. L. Analyst 1995, 120, 2435. (e) Desiraju, G. R. Science 1996, 278, 404.

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(2) Some special issues: (a) Polymorphism and Crystallization. In Org. Process Res. Dev. 2000, 4, 371. (b) Polymorphism in Crystals: Fundamentals, Prediction and Industrial Practice. In Cryst. Growth Des. 2003, 3, 867. International Conferences: (c) Polymorphism in Crystals: Fundamentals, Prediction and Industrial Practice, Saddlebrook Resort, Tampa, FL, Feb 2003. (d) Diversity Amidst Similarity: a Multidisciplinary Approach to Polymorphs, Solvates and Phase Relationships, 35th Course: International School of Crystallography, June 9-20, Erice, Sicily, Italy, 2004. (3) (a) Threlfall, T. Org. Process Res. Dev. 2000, 4, 384. (b) Jetti, R. K. R.; Boese, R.; Sarma, J. A. R. P.; Reddy, L. S.; Vishweshwar, P.; Desiraju, G. R. Angew. Chem., Int. Ed. 2003, 42, 1963. (4) (a) Steiner, T.; Hinrichs, W.; Saenger, W.; Gigg, R. Acta Crystallogr. 1993, B49, 708. (b) Sureshan, K. M.; Gonnade, R. G.; Puranik, V. G.; Shashidhar, M. S.; Bhadbhade, M. M. Chem. Commun. 2001, 881. (c) Gonnade, R. G.; Shashidhar, M. S.; Bhadbhade, M. M. Chem. Commun. 2004, 2530. (d) Manoj, K.; Sureshan, K. M.; Gonnade, R. G.; Bhadbhade, M. M.; Shashidhar, M. S. Cryst. Growth Des. 2005, 5, 833. (5) Yeh, S.-M.; Lee, G. H.; Wang, Y.; Luh, T.-Y. J. Org. Chem. 1997, 62, 8315. (6) SMART (V 5.628), SAINT (V 6.45a), XPREP, SHELXTL; Bruker AXS Inc., Madison, WI, 2004. (7) Sheldrick, G. M. SHELXL97, Program for Crystal Structure Refinement; University of Go¨ttingen, Go¨ttingen, Germany, 1997. (8) Johnson, C. K. ORTEP III, Report ORNL-5138; Oak Ridge National Laboratory, Oak Ridge, TN, 1976.

Bhosekar et al. (9) Spek, A. L. Acta Crystallogr. 1990, A46, C34. (10) (a) Nishio, M.; Hirota, M.; Umezawa, Y. The CH/π Interaction: Evidence, Nature and Consequences; Wiley-VCH: Weinheim, Germany, 1998. (b) Yamakawa, M.; Yamada, I.; Noyori, R. Angew. Chem., Int. Ed. 2001, 40, 2818. (c) Boese, R.; Clark, T.; Gavezzotti, A. Helv. Chim. Acta 2003, 86, 1085. (d) Nishio, M. CrystEngComm 2004, 6, 138. (11) (a) Cox, E. G.; Cruickshank, D. W. J.; Smith, J. A. S. Proc. R. Soc., London 1958, 247, 1. (b) Jennings, W. B.; Farrell, B. M.; Malone, J. F. Acc. Chem. Res. 2001, 34, 885. (c) Mayer, E. A.; Castellano, R. K.; Diederich, F. Angew. Chem., Int. Ed. 2003, 42, 1210. (12) (a) Crabtree, R. H.; Siegbahn, P. E. M.; Eisenstein, O.; Rheingold, A. L.; Koetzle, T. F. Acc. Chem. Res. 1996, 29, 348. (b) Crabtree, R. H. Science 1998, 282, 2001. (c) Custelcean, R.; Jackson, J. E. Chem. Rev. 2001, 101, 1963. (d) Robertson, K. N.; Knop, O.; Cameron, T. S. Can. J. Chem. 2003, 81, 727. (e) Wang, C.-C.; Tang, T.-H.; Wu, L.-C.; Wang, Y. Acta Crystallogr. 2004, A60, 488. (13) Fa´bia´n, L.; Ka´lma´n, A. Acta Crystallogr. 2004, B60, 547. (14) Steed, J. W. CrystEngComm 2003, 5, 169. (15) Gavezzotti, A.; Filippini, G. Chem. Commun. 1998, 287. (16) Dunitz, J. D. Chem. Commun. 2003, 545. (17) Koch, U.; Egert, E. J. Comput. Chem. 1995, 16, 937. (18) Saenger, W. Principles of Nucleic Acid Structures; SpringerVerlag: New York, 1984. (19) Burley, S. K.; Petsko, G. A. Adv. Protein Chem. 1988, 39, 125.

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