Ï-Stacking Interactions and C - American Chemical

CRYSTAL GROWTH & DESIGN

π-Stacking Interactions and CsH‚‚‚X (X ) O, Aryl) Hydrogen Bonding as Directing Features of the Supramolecular Self-Association in 3-Carboxy and 3-Amido Coumarin Derivatives

2003 VOL. 3, NO. 1 35-45

Efreń V. Garcıá-Baéz,† Francisco J. Martıńez-Martıńez,† Herbert Ho¨pfl,‡ and Itzia I. Padilla-Martıńez*,† Departamento de Quı´mica, Unidad Profesional Interdisciplinaria de Biotecnologıá del IPN, Av. Acueducto s/n Barrio la Laguna Ticoma´ n, Me´ xico, D. F. 07340, Me´ xico, and Centro de Investigaciones Quı´micas, Universidad Auto´ noma del Estado de Morelos, Cuernavaca Morelos, Me´ xico Received September 10, 2002;

Revised Manuscript Received October 7, 2002

ABSTRACT: The crystallographic study of 3-carboxy coumarins 1-4 and 3-amido coumarins 5 and 6 is reported in the context of crystal engineering. The former compounds are described as two fused rings with opposed polarity, which are associated through parallel displaced π-stacking interactions. The benzenoid ring B and the lactone ring L of one molecule interact with the lactone ring L′ and benzenoid ring B′ of the partner molecule with mean interplanar and mean intercentroid distances ranging between 3.385(6) and 3.67(2) Å and 3.679(1) and 4.081(3) Å, respectively. Among the six possible arrangements between two pairwise overlapping coumarin molecules, the anti tail-to-tail orientation was the most frequently observed. Pairing through π-stacking interactions is less favored when changing the 3-carboxy for a 3-amido group or even annulled, as in 3-oxalamate 6, because of the increasing H-bonding capability of the 3-amido group. The fused polar rings of coumarins 1-6 can also associate through π-stacking interactions in the presence of weak interactions such as C-H‚‚‚X (X ) O or aromatic ring), as long as these associations do not slip the molecular planes too far so that subsequent π-stacking interactions are avoided. Introduction Coumarins constitute an important class of naturally occurring and synthetic compounds, which exhibit a wide variety of pharmacological activities such as anticoagulant, spasmolytic, diuretic, anthelmintic, and hypoglucemic properties.1 More recently, specific inhibitory activities have also been reported,2-6 especially for 2-oxo-2H-1-benzopyran-3-carboxy derivatives such as tautomerase,4 elastase,5 and R-chimotripsin inhibitors.6 Detailed 13C NMR studies in solution of 3-carboxy and 3-amido coumarin derivatives have been published elsewhere;7 however, to our knowledge so far, no systematic structural study in the solid state of these compounds has been undertaken. In the Cambridge Structural Database (CSD, version 5.23), only one 3-carboxyamido8 and two 3-amido coumarins9,10 are registered. Therefore, despite the considerable importance of this kind of compounds, little is known about their intermolecular interactions that could be an aid in the elucidation of the molecular recognition processes involved in their biological activity. Moreover, their structures show particular features that make them interesting in the context of crystal engineering, since only single rings, fused hydrocarbon aromatics, and heterocyclic fused rings in the context of DNA base pairing have been widely studied. Herein, the crystallographic study of ethyl-coumarin-3-carboxylate 1, 3-carboxyamido coumarin derivatives 2-4, and 3-amido coumarin derivatives 5 and 6 is reported (Chart 1). In * To whom correspondence should be addressed. Tel: (55)5729-6000 ext. 56324. Fax: (55)5729-6000 ext. 56325. E-mail: ipadilla@ acei.upibi.ipn.mx. † Unidad Profesional Interdisciplinaria de Biotecnologıá del IPN. ‡ Universidad Auto ´ noma del Estado de Morelos.

Chart 1.

Compounds Studied in This Paper

this paper, these fused heterocycles allowed the study of self-association through π-stacking interactions or hydrogen bonding depending upon the structural changes done at the 3-substituent. Experimental Section Compounds. Ethyl coumarin 3-carboxylate 1 and acetamido coumarin 5 were prepared as reported in the literature.11,12 N-[(2-Oxo-2H-1-benzopyran-3-yl)carboxyl]benzylamide 2, N-[1-(R,S)-((2H-1-benzopyran-2-oxo-3-yl)carboxyl)methyl]benzylamide 3, N-[(2H-1-benzopyran-2-oxo-3-yl)carboxyl]piperidylamide 4, and ethyl N-[(2H-1-benzopyran-2-oxo3-yl)amin]oxalamate 6 were synthesized following the synthetic procedure described below. 1H and 13C NMR assignments of compound 2 were achieved on the basis of COSY and HETCOR experiments. NMR data of 1 and 3-6 were reported elsewhere.7,13 All chemicals and solvents were of reagent grade and used as received (Aldrich). General Synthetic Procedure. A 4.59 mmol (1.00 g) amount of ethyl coumarin-3-carboxylate 1 and 1.1 mmol of the corresponding amine were dissolved in 20 mL of ethyl alcohol. The solution was heated for 24 h under reflux. After it was cooled to room temperature, the resulting solid was filtered and recrystallized from ethyl alcohol. N-[(2-Oxo-2H-1-benzopyran-3-yl)carboxyl]benzylamide 2. White solid, mp 152-153 °C. IR νKBr (cm-1): 3332

10.1021/cg0255826 CCC: $25.00 © 2003 American Chemical Society Published on Web 12/03/2002

36

Crystal Growth & Design, Vol. 3, No. 1, 2003

Garcıá-Baéz et al.

Table 1. Crystallographic Data for Compounds 1-6 compd CCDC no. emp. form form. wt cryst. size (mm3) cryst. system space group a (Å) b (Å) c (Å) R (°) β (°) γ (°) V (Å3) Z F(calcd) (Mg/m3) µ (mm-1) F(000) 2θ (°) R (int) no. parameters GOOF final R (4σ) final wR2 res. peak max (e/Å3)

1 191065 C12H10O4 218.20 0.2 × 0.3 × 0.4 monoclinic P2(1)/c 7.9350(3) 15.7742(6) 8.7577(4) 90 108.2180(1) 90 1041.24(7) 4 1.392 0.105 456 52.00 0.025 186 1.045 0.0474 0.1227 0.175

2 191066 C17H13NO3 279.29 0.3 × 0.2 × 0.1 triclinic P1 h 5.8253(6) 9.6992(10) 25.142(3) 95.038(2) 94.262(2) 101.515(2) 1380.4(2) 4 1.344 0.093 584 55.98 0.054 483 0.972 0.0467 0.0910 0.124

3 191067 C18H15NO3 293.31 0.3 × 0.3 × 0.4 triclinic P1 h 5.8914(6) 7.9956(9) 16.114(2) 98.317(2) 92.667(2) 102.673(2) 730.37(14) 2 1.334 0.091 308 55.06 0.065 200 1.036 0.0784 0.2148 0.315

(N-H), 1702 (CdO lactone), 1656 (CdO amide). 1H NMR (ppm): H(4) 8.88, H(5) 7.98, H(6) 7.44, H(7) 7.74, H(8) 7.50, NH 9.13, CH2 4.54, phenyl 7.22-7.37. 13C (ppm): C(2) 160.3, C(3) 119.0, C(4) 147.5, C(5) 130.2, C(6) 125.1, C(7) 134.1, C(8) 116.1, C(9) 153.9, C(10) 118.4, NCdO 161.2, CH2 42.7, Ci 138.9, Co 128.4, Cm 127.4, Cp 126.9. N-[1-(R,S)-((2H-1-Benzopyran-2-oxo-3-yl)carboxyl)methyl]benzylamide 3. White solid, mp 122-123 °C. IR νKBr (cm-1): 3329 (N-H), 1706 (CdO lactone), 1658 (CdO amide). Anal. calcd % (found %) for C18H15NO3: C, 73.70 (73.85); H, 5.15 (5.39). N-[(2H-1-Benzopyran-2-oxo-3-yl)carboxyl]piperidylamide 4. White solid, mp 179-180 °C. IR νKBr (cm-1): 1713 (CdO, lactone), 1609 (CdO, amide). Anal. calcd % (found %) for C15H15NO3: C, 70.38 (70.02); H, 5.93 (5.82). Ethyl N-[(2H-1-Benzopyran-2-oxo-3-yl)amin]oxalamate 6. White solid, mp 117-118 °C. IR νKBr (cm-1): 3349 (N-H), 1699 (CdO). Anal. calcd % (found %) for C13H11NO5: C, 59.77 (59.18); H, 4.24 (4.18). Instrumental Methods. Melting points were measured on a Electrothermal IA 9100 apparatus and were uncorrected. IR spectra were recorded in KBr disks using a Perkin-Elmer 16F PC IR spectrophotometer. Elemental analyses were performed on a Perkin-Elmer 2400 elemental analyzer. 1H and 13 C NMR spectra were recorded on a Varian Mercury 300 (1H, 300.08; 13C, 75.46 MHz) equipment in [2H6]DMSO (dimethyl sulfoxide) solution, measured with SiMe4 as internal reference following standard techniques. X-ray Crystallography of 1-6. Crystals suitable for an X-ray structural determination were obtained from slow evaporation of saturated toluene solutions. The data for 1-5 were measured on a Bruker Apex diffractometer with a CCD area detector using graphite-monochromated Mo KR radiation (0.71073 Å, T ) 293 K). A total of 2424 frames (complete sphere) were collected via ω-rotation (∆/ω ) 0.3°) at 10 s per frame (program Smart).14 The measured intensities were reduced to F2 and corrected for absorption with SADABS (program SAINT-NT).15 The cell parameters were determined by using reflections from all frames collected. The data for 6 were measured on an Enraf-Nonius CAD-4 diffractometer using graphite-monochromated Mo KR radiation (0.71073 Å, T ) 293 K), and the scan mode used was ω/2Θ. The molecular structure was resolved by direct methods (SHELXS-86).16 The WinGX (version 1.64.03a)17 software package was used for refinement and data output. In all cases, the refinement was based on full-matrix least-squares methods, with anisotropic displacement parameters for all non-H atoms. Every hydrogen atom was determined by Fourier difference maps, and their individual positions and isotropic displacement parameters

4 191068 C15H15NO3 257.28 0.2 × 0.3 × 0.5 monoclinic C2/c 16.509(4) 8.732(2) 18.498(4) 90 103.301(4) 90 2595.2(10) 8 1.317 0.092 1088 55.06 0.120 233 0.943 0.0743 0.1990 0.385

5 191069 C11H9NO3 203.19 0.4 × 0.4 × 0.5 monoclinic P2(1)/c 10.0907(13) 4.8785(6) 19.096(2) 90 99.591(2) 90 926.9(2) 4 1.456 0.108 424 55.16 0.045 172 1.031 0.0590 0.1188 0.246

6 191070 C13H11NO5 261.23 0.4 × 0.4 × 0.5 monoclinic P2(1)/n 5.7160(10) 18.239(4) 11.637(2) 90 99.85(3) 90 1195.3(4) 4 1.452 0.113 544 50.06 0.033 217 1.031 0.0370 0.0938 0.142

were refined. The analysis of short contacts was realized using the PLATON18 program. The most relevant crystallographic data are shown in Table 1.

Results and Discussion Molecular Structure of 3-Carboxy Coumarins 1-6. The molecular structures of compounds 1-6 are shown in Figures 1a-6a, and a summary of selected bond lengths and torsion angles is given in Table 2. Two independent molecules were found in the unit cell of coumarin 2, labeled as 2 and 2(A). The graph set notation Gad(n) (G ) S for intramolecular rings, R for rings, C for chains, and D for discrete patterns; a ) number of acceptors, d ) number of donors involved in H-bonding, and n ) number of atoms in the pattern) was used to describe the hydrogen-bonding patterns.19-21 Ethyl coumarin-3-carboxylate 1 presents a syn conformation between the 3-carboxy and the lactone carbonyl groups. This arrangement seems to be less frequent than the anti, since the former is only found in rigid systems. In contrast, 3-carboxyamido coumarins 2-4 have an anti conformation between the two carbonyl groups; however, the dihedral angle C(2)C(3)C(11)O(11) strongly depends on the substituent present in the carboxyamido function. In the structure of the already reported primary 3-carboxyamido coumarin8 and the secondary 3-carboxyamides 2 and 3, this angle is approximately 180° (-178.7, 174.9(3) (mean), and -170.6(3)°, respectively), whereas in the tertiary carboxyamide 4 the carboxyamido group strongly deviates from planarity (112.8(2)°). These results suggest that the anti conformation in 2 and 3 is stabilized by an intramolecular S(6) (six member ring)19-21 hydrogenbonding interaction between the amide hydrogen and the lactone carbonyl group N(12)-H‚‚‚O(2). Hydrogen bonding also defines the preferred conformer in amido coumarins 5 and 6. In both structures, the exocyclic amidocarbonyl moiety adopts a syn conformation in relation to the endocyclic C(3)-C(4) double bond with dihedral C(4)C(3)N(11)C(12) angles of -21.7(2) and 1.1(2)° for 5 and 6, respectively. In compound 6, the oxalamate carbonyls arrange in an anti conformation

π-Stacking and Hydrogen Bonding in Coumarins

Crystal Growth & Design, Vol. 3, No. 1, 2003 37

Figure 1. Crystal structure of coumarin 1. (a) Molecular structure; (b) molecular arrangement on the bc plane showing the C(5) motif. Overlapping pattern: (c) lateral view showing BL′, B′L, and LL′ intercentroid and C(13)H‚‚‚B′ distances (B for benzenoid and L for lactone rings), which define an R22(14) motif (H(13)BC(4)C(3)C(11)O(12)C(13) benzenoid ring B was counted as one point); (d) top view. Oxygen atoms are in red, and carbon and hydrogen atoms are in gray.

as it has been found in other systems.22,23 In 3acetamido coumarin 5, two intramolecular hydrogen bonds N(11)H‚‚‚O(2) and C(4)H‚‚‚O(12) define an S22(9)[S(6)S(5)] pattern (Figure 5a), whereas in oxalamate 6 an S32(10)[S(6)S(5)S(5)] hydrogen-bonding pattern is defined by the additional N(11)-H‚‚‚O(13) interaction (Figure 6a). The intramolecular threecentered hydrogen bond formed (O(2)‚‚‚H(11)‚‚‚O(13) angle of 139.6(9)°, Σ∠H ) 360(3)°) imposes to the structure an almost completely planar arrangement23 (C(2)C(3)N(11)C(12) dihedral angle of 179.5(2)°). Characteristic intramolecular H-bonding distances, angles, and descriptors for 2, 3, 5, and 6 are summarized in Table 3. Among the 3-carboxyamido coumarins 2-4, the C(3)C(4) and C(11)-N(12) bond lengths depend on the dihedral angle between the C(2)O and the C(11)O carbonyl groups, showing the shortest values for compound 4, in which the carboxyamido group is tilted out of coumarin mean plane (C(4)C(3)C(11)O(11) ) -59.9°). These results suggest the loss of electronic delocalization between the amide carbonyl moiety and the endocyclic double bond in compound 4, and as a consequence, the

electron-withdrawing effect of the 3-carboxyamido group is reduced so that the amount of electron density within the amide functional group is enhanced. Some important structural differences can be observed between 3-carboxy coumarins 1-4 and 3-amido coumarins 5 and 6. The former show a lengthening of the O(1)-C(2) bond and a shortening of the HN-CO bond relative to 3-amido coumarins 5 and 6 (compare N(12)-C(11) for 1-4 and N(11)-C(12) for 5 and 6, Table 1). The C(11)O and C(12)O bond lengths are very similar for both series since the amide carbonyl bond length is not sensitive to resonance effects.24,25 These data reflect the electronwithdrawing and electron-donating capabilities of the carboxyamide and amide groups, respectively. Although the differences between the bond distances are small, the results are in agreement with those obtained by NMR in solution.7 The 3-carboxy group in 1-4 strongly deshields C(4) (147-149 ppm) and shields C(3) (118119 ppm) whereas the 3-amido group generates a meaningless chemical shift difference between the two carbon atoms (123-125 ppm). The data as a whole suggest that the lactone ring is strongly electron deficient in 3-carboxy coumarins 1-4 (Scheme 1a), whereas

38



Table 2. Representative Bond Lengths (Å) and Torsion Angles (°) for Compounds 1-6 Bond Lengths O(1)-C(2) O(1)-C(9) O(2)-C(2) C(2)-C(3) C(3)-C(4) C(4)-C(10) C(3)-C(11) C(11)-O(11) N(12)-C(11) N(11)-C(12) C(3)-N(11) C(12)-O(12)

1

2

2(A)

3

4

5

6

1.379(2) 1.377(2) 1.197(2) 1.467(2) 1.349(2) 1.429(2) 1.490(2) 1.197(2)

1.364(2) 1.383(2) 1.221(2) 1.454(3) 1.343(3) 1.425(3) 1.490(3) 1.229(3) 1.336(3)

1.368(2) 1.378(2) 1.222(2) 1.453(3) 1.341(3) 1.426(3) 1.488(3) 1.221(2) 1.333(3)

1.375(3) 1.382(3) 1.216(3) 1.452(4) 1.342(3) 1.425(3) 1.507(11) 1.216(3) 1.336(3)

1.371(3) 1.373(4) 1.210(3) 1.458(5) 1.327(4) 1.434(4) 1.507(3) 1.228(3) 1.325(4)

1.354(3) 1.380(3) 1.207(3) 1.457(3) 1.338(3) 1.435(3)

1.353(3) 1.381(2) 1.211(3) 1.456(3) 1.341(3) 1.445(3)

1.360(3) 1.396(3) 1.215(3)

1.350(3) 1.400(3) 1.208(2)

C(2)C(3)C(11)O(11) C(4)C(3)C(11)O(12) C(4)C(3)C(11)N(12) C(4)C(3)C(11)O(11) C(2)C(3)C(11)N(12) C(2)C(3)N(11)C(12) C(4)C(3)N(11)C(12) N(11)C(12)C(13)O(14)

11.7(2) 9.4(2)

174.6(3) 170.9(3) -7.7(3) -6.9(3)

Torsion Angles 175.3(3) -170.6(3)

interaction

2

N(12)-H‚‚‚O(2) N(12A)-H‚‚‚O(2A) N(12)-H‚‚‚O(2) N(11)-H‚‚‚O(2) C(4)-H‚‚‚O(12) N(11)-H‚‚‚O(2) C(4)-H‚‚‚O(12) N(11)-H‚‚‚O(13)

3 5 6

120.0(2) -59.9(2) -67.4(2) 157.3(2) -21.7(2)

Table 3. Intramolecular H-Bonding Interactions Observed for 3-Carboxyamido Coumarins 2 and 3 and 3-Amido Coumarins 5 and 6

compd

-171.3(3) 9.3(3)

176.0(3) -4.7(3) -4.0(2)

112.8(2)

D‚‚‚A H‚‚‚A distance distance C-H‚‚‚A (Å) (Å) angle (°) motifa 2.713(3) 2.704(3) 2.728(3) 2.692(3) 2.842(3) 2.653(2) 2.969(2) 2.65(2)

1.89(3) 1.87(3) 2.07(3) 2.28(2) 2.32(2) 2.26(2) 2.24(2) 2.23(2)

139(2) 136(3) 134(3) 108(2) 115(2) 110(2) 118(1) 139(1)

S(6) S(6) S(6) S(5) S(6) S(5) S(6) S(5)

a Graph set notation Ga (n) (G ) S for intramolecular rings, R d for rings, C for chains, and D for discrete patterns; a ) number of acceptors, d ) number of donors involved in H-bonding, and n ) number of atoms in the pattern) was used to describe the hydrogen-bonding patterns.19-21

Scheme 1. (a) Resonance Structures for 3-Carboxy Coumarins 1-4 and (b) 3-Amido Coumarins 5 and 6

in 3-amido coumarins 5 and 6 the 3-amido group can partially revert the lactone ring polarity (Scheme 1b). In this context, 3-carboxy coumarins 1-4 can be considered to consist of two fused rings with opposed polarity: the electron rich benzenoid ring (B) and the electron deficient lactone ring (L) (Scheme 1). Crystal Packing of 3-Carboxyamido Coumarins 1-4. The above-mentioned differences in polarity between the fused benzenoid and the lactone rings in 1-4 are reflected in their crystalline packing. Therefore, the 3-carboxy coumarins 1-4 are self-associated through

179.5(2) 1.1(2) 176.5(2)

Table 4. Summary of the Mean Intercentroid and Interplanar Distances as Well as Angles r and γ for the Benzenoid Ring B and the Lactone Ring L of 3-Carboxy Coumarins 1-4 compd 1d 2e 2(A)f 3g 4h

rings BL′ and B′L BB′ LL′ BL′ and B′L BB′ LL′ BL′ and B′L BB′ LL′ BL′ and B′L BB′ LL′ BL′ and B′L BB′ LL′

intercentroid interplanar Rb distance (Å) distancea (Å) (deg) 3.8298(8) 4.8907(9) 4.1323(8) 4.756(2) 5.536(2) 5.116(1) 3.679(1) 4.026(2) 4.739(1) 4.000(2) 5.028(2) 4.288(2) 4.081(3) 3.775(3) 5.539(3)

3.47(3)i 3.480(2) 3.408(2) 3.34(2)i 3.418(3) 3.375(3) 3.385(6)i 3.404(3) 3.402(3) 3.67(2)i 3.706(3) 3.671(3) 3.54(8)i 3.555(3) 3.471(3)

3.3(2) 0.0(2) 0.0(2) 2.8(3) 0.0(3) 0.0(3) 1.1(3) 0.0(3) 0.0(3) 1.3(3) 0.0(3) 0.0(3) 2.7(3) 0.0(3) 0.0(3)

γc (deg) 25(1)i,e 44.6(2) 34.5(2) 45.5(7)i,e 51.9(3) 48.7(3) 23.1(5)i 32.3(3) 44.1(3) 25.3(9)i 42.5(3) 31.1(3) 29(2)i 19.6(3) 51.2(3)

a Perpendicular distance between the centroid of the first ring and the centroid of the second ring mean plane of the partner molecule. b Dihedral angle between the first ring mean plane and the second ring mean plane of the partner molecule. c Angle between the centroid of the first ring and the normal to the second ring mean plane of the partner molecule. Symmetry operators: d -x, -y, 1 - z. e 1 - x, 1 - y, -z. f 1 - x, 1 - y, 1 - z. g 2 - x, 2 y, 1 - z. h 1 - x, -y, -z. i Mean value of BL′ and LB′ interactions.

π-stacking interactions forming homodimers. Two molecules are interacting through parallel displaced π-interactions. The benzenoid ring B and the lactone ring L interact with the lactone ring L′ and benzenoid ring B′ of the partner molecule, respectively (prime for the partner molecule). Both molecules are related to each other through an inversion center of symmetry with the pendant 3-lateral chain pointing toward the partner molecule, thus allowing, in the case of 1-3, a maximum number of C-H‚‚‚π interactions to occur at the expense of reduced π-stacking interactions. Interplanar and intercentroid distances and angles are shown in Table 4, and crystal packing structures are shown in Figures 1b-4b. The mean interplanar distances lie in the range between 3.34 and 3.71 Å and are therefore in agreement with π-π-stacking interactions. They are shorter than



Figure 2. Crystal structure of coumarin 2 with two independent molecules in the asymmetric unit labeled as 2 (left) and 2(A) (right). (a) Molecular structure of 2 and 2(A), intramolecular NH‚‚‚O contacts are shown (S(6) ring); (b) molecular arrangement on the bc plane showing intermolecular C-H‚‚‚X contacts (X ) O, aryl) for 2 and 2(A) (entries a-i of Table 5), bifacial a‚‚‚b and d‚‚‚e bridges can be appreciated. Overlapping pattern for 2 and 2(A): (c) lateral view, intercentroid BL′, B′L, and C(6)H‚‚‚Ph distances for 2 as well as BL′, B′L, and BB′ distances for 2(A) are shown (H(6)PhC(13)N(12)C(11)C(3)C(4)C(10)C(5)C(6) form an R22(20) motif, Ph counted as one point); (d) top view. Oxygen atoms are in red, nitrogen is in blue, and carbon and hydrogen are in gray.

the value of 3.77 Å measured in the benzene-fluorobenzene cocrystal.26 The intercentroid distances, the dihedral angle R between the first ring mean plane and the second ring mean plane of the partner molecule, and the angle γ between the centroid of the first ring and the normal to the second ring mean plane of the partner molecule are in agreement with parallel displaced or offset face-to-face π-stacking interactions (Table 4, Figures 1c-4c). Herein, a parallel displaced arrange-

ment is considered to occur, if both the intercentroid and the interplanar distances between two parallel rings are enclosed between a lower limit of 3.4 Å and an upper limit of 4.6 Å. The former value corresponds to the sum of the van der Waals radii of two carbon atoms between two benzene molecules.27,28 The higher limit value of 4.6 Å was taken from the X-ray measurements of the intercentroid distances in the double phenyl embrace between Ph4P+ cations.29

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Table 5. Weak Aromatic C-H‚‚‚X (X ) O or π-Ring) Interactions Observed in the Crystalline Packing of Coumarin 2a

entry

interaction

C‚‚‚Xb distance (Å)

a b c d e f g h i

C(6)-H‚‚‚Phe C(6A)-H‚‚‚Phf C(17A)-H‚‚‚Be C(16)-H‚‚‚Ph(A)g C(19)-H‚‚‚Ph(A)h C(5)-H‚‚‚O(11)i C(8)-H‚‚‚O(2)j C(4A)-H‚‚‚O(11A)k C(5A)-H‚‚‚O(11A)k

3.795(3) 4.050(3) 3.636(3) 3.853(4) 3.864(4) 3.279(3) 3.430(3) 3.343(3) 3.320(3)

H‚‚‚Xb distance (Å)

C-H‚‚‚Xb angle (°)

motifc

2.84(2) 3.16(2) 2.71(2) 3.05(4) 3.04(3) 2.33(2) 2.53(2) 2.52(2) 2.49(2)

159(2) 152(2) 156(2) 153(3) 147(2) 155(2) 166(2) 149(2) 149(2)

R22(20)d Db Dc Dd De R22(14) R22(12) R22(10) R22(14)

graph set notationc

R22(34)[R22(20)DbDc] C12(7)[DdDe] C22(11)[R22(14)R22(12)] R12(6)[R22(10)R22(14)]

a The letter A is used for one of the two molecules found in the asymmetric unit of coumarin 2. b X ) O or the centroid of the corresponding aromatic ring, Ph for the pendant phenyl ring, and B for the benzenoid ring. c Graph set notation Gad(n) (G ) S for intramolecular rings, R for rings, C for chains, and D for discrete patterns; a ) number of acceptors, d ) number of donors involved in H-bonding, and n ) number of atoms in the pattern) was used to describe hydrogen-bonding patterns.19-21 d The aryl ring was taken as one point for counting purposes. Symmetry codes: e 1 - x, 1 - y, -z. f 2 - x, 1 - y, 1 - z. g 1 + x, y, z. h x, -1 + y, z. i 2 - x, 1 - y, -z. j -x, -y, -z. k 2 - x, 2 - y, 1 - z.

Applying the above criteria, at least two π-stacking interactions BL′ and B′L are found as common features in the homodimers of 1, 2(A), 3, and 4; however, there are no π-stacking interactions between the other independent molecules of compound 2. In addition, the following π-stacking interactions are found, one LL′ interaction for the homodimers of 1 and 3 and one BB′ interaction for the homodimers of 2(A) and 4. In general, the intercentroid distance depends on the sort of interacting rings and increases in the following direction: BL′ and B′L < LL′ < BB′, in agreement with the expected attractive interaction between two rings of opposed polarity (high electron-low electron density rings), followed by the less repulsive interaction between two rings with low electron density and finally the most repulsive interaction between two rings with high electron density.30 An exception is found for the homodimer of 4, which shows the shortest value for the BB′ interaction, probably due to the steric demand exerted by the piperidine ring and the reduced electronwithdrawing effect of the 3-carboxyamido group, which is tilted out of coumarin mean plane (vide supra). Among the six possible assemblies formed by pairwise overlapping of two coumarin molecules 1-4 (syn headto-head, syn head-to-tail, syn tail-to-tail, anti head-tohead, anti head-to-tail, and anti tail-to-tail), the most frequently observed is the anti tail-to-tail orientation (compounds 1, 3, and 4; Figures 1d, 3d, and 4d, respectively), whereby the endocyclic C(3)C(4) double bond lies near above the middle of the benzenoid ring of the partner molecule. Furthermore, the anti headto-head orientation is found as a complementary assembly for 2(A) (Figure 2d) in which case the C(3)C(4) double bond lies out of the overlapping region. In both assemblies, the endocyclic C(3)C(4) double bonds of two neighboring molecules are far away from each other in contrast to the preferred pattern found in other coumarins, which exhibited a close proximity.31 The abovementioned stacking arrangement seems to be the result of a balance between van der Waals repulsive, favorable dispersion, and electrostatic interactions between two rings of opposed polarity: the benzenoid ring (high electron density) and the lactone ring (low electron density).32 Subtle differences among the crystal structures for 1-4 were observed, which arise from differences in the

steric requirements of the 3-carboxy moiety. Of particular interest in the context of this paper is the supramolecular structure of coumarin 2. Additionally to the already discussed π-stacking interactions, one series of the two independent molecules found in the unit cell 2(A) is associated through complementary aryl C-H‚‚‚O hydrogen bonding,33 forming the six member ring R12(6)[R22(10)R22(14)] at the binary level of graph set notation. The other molecule series (labeled as 2) is associated only through aryl C-H‚‚‚O34 and aryl C-H‚‚‚π hydrogen bonding.35 In this case, the intercentroid BL′ distance is beyond the higher limit for a parallel displaced π-stacking interaction (see Table 4). The C-H‚‚‚O network formed by the last series is described by the eleven member chain C22(11)[R22(14) R22(12)]. Nevertheless, both molecule series (2 and 2(A)) form staircase columns interlinked by aryl C-H‚‚‚π interactions involving the benzenoid coumarin ring and the aryl ring of the pendant benzylamido group. Thereby, each aryl ring acts both as C-H donor and as π-acceptor allowing the formation of intra- and interdimer interactions (Figure 2b). This bifacial bridging mode is rather uncommon but highly relevant to crystal engineering since it is directional.36 Because π-π-parallel displaced and C-H‚‚‚π (T-shaped) interactions are isoenergetic,37,38 the overall crystal packing arrangement observed for coumarin 2 seems to be the result of the formation of a maximum number of intermolecular interactions at the expense of reduced π-stacking interactions. A summary of all C-H‚‚‚X (X ) O or aryl ring) distances, related angles, descriptors, and binary graph set notations of the network is given in Table 5. It should be noted that the C-H‚‚‚π interactions are longer than the C-H‚‚‚O hydrogen bonds and are near the higher limit of other C-H‚‚‚π contacts found in the Cambridge Structural Database.39 Additional weak hydrogen-bonding interactions are rather common within the dimers of 1-4. In coumarin 1, the pendant 3-ethyl carboxylate group is tilted out of the molecular plane toward the benzenoid ring of the partner molecule, generating the interdimer C-H‚‚‚π motif R22(14) (the benzenoid ring was taken as one point for counting purposes) that in conjunction with the intermolecular C(5) motif (C(13)H(B)‚‚‚O(11)) de-



Table 6. Intermolecular H-Bonding Interactions Observed for 3-Carboxyamido Coumarins 1, 3, and 4 and 3-Amido Coumarins 5 and 6

compd

interaction

D‚‚‚Xa distance (Å)

1

C(13)-H(B)‚‚‚O(11)d C(13)-H(A)‚‚‚Be C(7)-H‚‚‚Phf C(4)-H‚‚‚O(11)g C(6)-H‚‚‚O(2)h N(11)-H‚‚‚O(2)i C(13)-H‚‚‚O(12)j C(5)-H‚‚‚O(14)k C(5)-H‚‚‚O(12)k C(4)-H‚‚‚O(12)k C(15)-H‚‚‚O(1)l

3.344(2) 3.900(2) 3.755(3) 3.212(5) 3.400(7) 3.070(3) 3.468(4) 3.319(2) 3.551(7) 3.524(2) 3.202(2)

3 4 5 6

H‚‚‚Xa distance (Å)

D-H‚‚‚Xa angle (°)

motifb

2.599(2) 3.01(3) 2.95(3) 2.27(3) 2.67(7) 2.21(2) 2.56(5) 2.52(2) 2.70(2) 2.65(2) 2.60(2)

135(1) 150(1) 143(2) 158(3) 154(1) 164(2) 159(3) 145(1) 152(1) 148(1) 118(1)

C(5) R22(14)c R22(22)c R22(10) C(8) R22(10) C(4) R22(18) R22(16) R22(12) C(9)

graph set notationb C22(7)[C(5)R22(14)]

C32(11)[R22(10)C(8)] C12(9)[R22(10)C(4)]

C33(10)[R22(18)R22(16)R22(12)C(9)]

a D ) C or N, X ) O or the centroid of the corresponding aromatic ring, Ph for the pendant phenyl ring, and B for the benzenoid ring. Graph set notation Gad(n) (G ) S for intramolecular rings, R for rings, C for chains, and D for discrete patterns; a ) number of acceptors, d ) number of donors involved in H-bonding, and n ) number of atoms in the pattern) was used to describe hydrogen-bonding patterns.19-21 c The aryl ring was taken as one point for counting purposes. Symmetry codes: d x, 1/2 - y, 1/2 + z. e 1 - x, 1 - y, 1 - z. f 2 - x, 2 - y, 1 - z. g 1 - x, y, 1/2 - z. h 1/2 + x, -1/2 + y, z. i -x, -y, -z. j x, -1 + y, z. k -x, -y, 1 - z. l -3/2 + x, 1/2 - y, -1/2 + z. b

Figure 3. Crystal structure of coumarin 3. (a) Molecular structure of 3, intramolecular NH‚‚‚O contact S(6) is shown; (b) molecular arrangement on the bc plane showing intradimer C-H‚‚‚π contacts, which define an R22(22) motif (H(7)PhC(13)N(12)C(11)C(3)C(2)O(1)C(9)C(8)C(7) Ph ring was counted as one point). Overlapping pattern: (c) lateral view, intradimer (BL′ and LL′) and interdimer (BL′ and BB′) intercentroid distances are shown; (d) top view. Oxygen atoms are in red, nitrogen is in blue, and carbon and hydrogen are in gray.

42



Figure 4. Crystal structure of coumarin 4. (a) Molecular structure of 4; (b) molecular arrangement on the ac plane showing intermolecular C-H‚‚‚O contacts, the R22(10) and C(8) motifs can be appreciated. Overlapping pattern: (c) lateral view, BL′, B′L, and BB′ intercentroid distances are shown; (d) top view. Oxygen atoms are in red, nitrogen is in blue, and carbon and hydrogen are in gray.

fines the seven member chain C22(7)[C(5)R22(14)] (Figure 1b,c and Table 6). The sterically hindered 3-carboxy coumarins 3 and 4 associate through parallel displaced π-stacking interactions (vide supra) forming, in the case of 3, an intradimer aryl C-H‚‚‚π interaction between C(7)-H of the coumarin ring and the centroid of the pendant aryl ring of the partner molecule defining an R22(22) ring (the aryl ring was taken as one point for counting purposes) (Figure 3b, Table 6). In contrast, in the absence of π-acceptors as in coumarin 4, intramolecular C(6)H‚‚‚O(2) and C(4)H‚‚‚O(11) interactions are formed, defining the C(8) chain and the R22(10) ring motifs shown in Figure 4b (Table 6). In compound 3, the short mean interplanar (3.62(2) Å) and intercentroid distances (BB′ ) 3.933(2) Å and LB′ ) 4.028(2) Å) found between neighboring dimers suggest that π-stacking interactions can also occur between pairs of dimers, resulting in the formation of columns of infinite size (Figure 3c). A summary of all C-H‚‚‚X (X ) O or π ring) distances, related angles, descriptors, and binary graph set notations of the network for compounds 1 and 3 and 4 is given in Table 6. Crystal Packing of 3-Amido Coumarins 5 and 6. The 3-amido moiety is a moderate electron donor group that does not completely revert the polarity of the lactone ring in 3-amido coumarins 5 and 6. The electron

density on the O(1) atom is delocalized to the C(2)O carbonyl moiety making it a better acceptor for hydrogen bonding than in 3-carboxy coumarins 1-4 (Scheme 1b). Strong amide carbonyl hydrogen-bonding interactions NH‚‚‚O between adjacent columns direct the crystal packing of 3-acetamido coumarin 5, giving rise to the formation of R22(10) hydrogen-bonded rings. Because of the residual partial positive charge that must remain on the O(1) atom of the lactone ring (Scheme 1), the hydrogen-bonded dimers of coumarin 5 further stack in the syn head-to-tail orientation forming a continuous twin column, in which only one BL′ π-stacking interaction per molecule is found (interplanar and intercentroid distances of 3.48(2) Å and 3.659(2) Å, angles R and γ of 2.2(3) and 17.6(3)°, respectively). This association is complemented by the weak intrastack C(13)H‚‚‚O(12) hydrogen bonding defining a C(4) motif (Figure 5b, Table 6). Hydrogen bonding is also the main directing force that rules the solid state assembly of compound 6. In addition to the intramolecular hydrogenbonding interactions previously described, intermolecular H-bonds associate molecules in pairs through the combined action of the three center H-bond O(12)‚‚‚ H(5)‚‚‚O(14) and the bifurcated H-bond H(4)‚‚‚O(12)‚‚‚ H(5).40 Pairs of 6 are interlinked through a weak intermolecular C(15)H(15B)‚‚‚O(1) interaction defining



Figure 5. Crystal structure of coumarin 5. (a) Molecular structure of 5, showing the S(5)S(6) intramolecular hydrogen-bonding interactions; (b) molecular arrangement showing the stacking of hydrogen-bonded dimers, where the R22(10) and C(4) motifs can be appreciated. Overlapping pattern: (c) lateral view, intercentroid BL′ distance is shown; (d) top view. Oxygen atoms are in red, nitrogen is in blue, and carbon and hydrogen are in gray.

a C(9) motif (Figure 6b). The binary graph set C33(10)[R22(18)R22(16)R22(12)C(9)] describes the entire network (Table 6). A summary of all D-H‚‚‚X (D ) C, N and X ) O or π-ring) distances, related angles, descriptors, and binary graph set notations of the network for compounds 5 and 6 is given in Table 6. In oxalamate 6, the molecular planes are slipped beyond the higher limit for π-stacking interactions and are therefore not considered as such (5.1907(2) Å intercentroid distance). However, a partial overlapping is observed between the carbonyl group C(12)O and the aromatic cloud of the benzenoid ring with a mean interplanar distance of 3.36(2) Å (-x, -y, 1 - z) (Figures 6c,d). The interplanar separation between layers (2.99(2) Å, -1 + x, y, z) is significantly smaller than the expected for aromatic rings and very close to the value found in strongly polar crystals (3.07 Å for 2-amino-5-nitropyridine).41 This relatively close layer packing could be the result of maximizing attractive dispersion interactions. Conclusions The supramolecular structures exhibited by 3-carboxy and 3-amido coumarins 1-6 are directed by a balance between parallel displaced π-stacking, weak aryl C-H‚‚‚π and strong N-H‚‚‚O hydrogen-bonding interactions. 3-Carboxy coumarins 1-4 self-associate in

homodimers through parallel displaced π-stacking interactions between complementary rings of opposed polarity, in which the benzenoid ring B of the coumarin molecule represents the high electron density ring and the lactone ring L the low electron density ring. For BL′ and B′L interactions, the mean interplanar and mean intercentroid distances range between 3.385(6) and 3.67(2) Å and 3.679(1) and 4.081(3) Å, respectively. From the six possibilities of overlapping between two paired coumarin molecules, the anti tail-to-tail orientation was the most frequently observed, while the anti head-to-head orientation was found as a complementary orientation in the crystal packing of molecule series 2(A). The probability of pairing through π-stacking interactions is less favored when the 3-carboxy group is changed for a 3-amido group or even annulled as in 3-oxalamate 6, due to the increased H-bonding capability of the 3-amido group. Besides the above-described interactions between the complementary polar rings in 3-carboxy coumarins, intermolecular association in the solid state can be accompanied by further weak interactions such as C-H‚‚‚X bonding (X ) O or aromatic ring). This is only possible as long as H-bonding associations do not slip the molecular planes too far away from each other that subsequent π-stacking interactions are avoided. In less polar fused rings such as 5 and 6, hydrogen bonding can prevent complementary ring

44



Figure 6. Crystal structure of coumarin 6. (a) Molecular structure of 6, simple S(6) and S(5)S(5) three center intramolecular hydrogen-bonding interactions are shown; (b) molecular arrangement on the bc plane, intermolecular contacts O(14)‚‚‚H(5)‚‚‚ O(12)‚‚‚H(4) and C(15)H‚‚‚O(1) labeled as a-d, respectively, are shown (see Table 6). Overlapping pattern: (c) lateral view, showing the interlayer distance; (d) top view. Oxygen atoms are in red, nitrogen is in blue, and carbon and hydrogen are in gray.

association through π-stacking interactions and, as in the case of coumarin 6, can pack the aromatic rings relatively close in order to maximize attractive dispersion interactions. Concerning H-bonding, some general conclusions can be obtained. Apparently, amide NH groups (compounds 2, 3, 5, and 6) are always engaged in an intramolecular H-bonding, forming S(n) motifs (n ) 5, 6). Among the rest of H-bonding donors in 1-6, C(4)H is the one most frequently involved in intermolecular H-bonding, followed by C(5)H, whereas the oxygen atoms O(11) and O(12) act as the most frequent acceptors forming R22(n) motifs (n ) 10, 12 for C(4)H and n ) 14, 16 for C(5)H). However, in the presence of steric crowding, syn arrangement between the lactone and the 3-carboxy or 3-amido carbonyls or an intermolecularly engaged amide NH group (coumarins 3, 1, and 5, respectively), such interactions are avoided. This conclusion is also supported by the already reported structures of 3-carboxyamido coumarin8 (N(12)H‚‚‚ C(11)O intermolecular interaction, C(4)H and C(5)H do not act as donors) and coumarin 3-carboxylic acid42 (anti conformation between lactone and acid carbonyls, R22(10) motif for C(4)H‚‚‚O(11) and R22(14) motif for C(5)H‚‚‚O(11)).

Acknowledgment. We thank Professor M. RosalesHoz for access to the Enraf-Nonius CAD-4 diffractometer at CINVESTAV-IPN, Me´xico. This work was supported by CGPI-IPN (Grant 5201) and CONACYTMe´xico (Grant 33438-E). Supporting Information Available: X-ray crystallographic information files (CIF) and tables with X-ray structural information for 1-6. This material is available free of charge via the Internet at http://pubs.acs.org.

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