Article pubs.acs.org/crystal
Design, Synthesis, X‑ray Structures of the New Coumarin Derivatives and Perspectives of Binding Them to Albumin and Vitamin K Epoxide Reductase Complex Subunit 1 Kinga Kasperkiewicz,† Magdalena Małecka,‡ Michal B. Ponczek,§ Pawel Nowak,§ and Elzbieta Budzisz*,† †
Department of Cosmetic Raw Materials Chemistry, Faculty of Pharmacy, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland ‡ Department of Theoretical and Structural Chemistry, Faculty of Chemistry, University of Lodz, Pomorska 163/165, 90-236 Lodz, Poland § Department of General Biochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland S Supporting Information *
ABSTRACT: A series of new coumarin derivatives with a di- or trimethoxybenzylamine moiety in the C-3 position were synthesized. The structures of all obtained compounds were characterized by IR, 1H NMR, MS, and elemental analysis. Two structures of coumarin were determined by X-ray crystallography. Hirshfeld surface analysis was employed in order to study intermolecular hydrogen bonds and other interactions. The structures of the other derivatives were modeled and optimized computationally. The binding of the new synthesized compounds into albumin structure and vitamin K epoxide reductase complex subunit 1 model is shown using molecular docking methods.
1. INTRODUCTION For a long time our scientific research has been focused on systematic synthetic and structural studies as well as biological activity of chromone, flavone, and coumarin derivatives as the ligands for metal ions complexes.1−3 Chromone, flavone, and coumarin derivatives exhibit many biological activities: antibacterial, antifungal, antiviral, and antitumor.4,5 One of the known activities of coumarins are anticoagulant properties.6 The most used anticoagulant in medicine are warfarin and acenocoumarol. Warfarin (see Figure 1) and other coumarin derivatives are called vitamin K antagonists, because of the inhibition of the vitamin K dependent gamma-carboxylation of clotting factors. Warfarin binds with blood plasma proteins in 99% primarily to albumin, and only 1% free fraction is biologically active, resulting in minor volume of distribution and low clearance. Petitpas et al. showed that for example warfarin combines in human serum albumin (HSA) domain II with triiodobenzoic acid complexation in domain II (Site-I).7 HSA is the most abundant transport protein of extracellular blood components, which is synthesized in the liver. Albumin binds different groups of ligands and transports various organic compounds including lipids, hormones, various metabolites and drugs.8,9 Taking into account that many crystal structures of albumin, including those structures with bound warfarin enantiomers, are available in Protein Data Bank (PBP) we decided to compare structures of newly synthesized coumarin © 2015 American Chemical Society
derivatives with warfarin with respect to the binding sites in albumin. What is more important warfarin inhibits vitamin K 2,3epoxide reductase, resulting in a decrease of the reduced form of vitamin K, which prevents the gamma-carboxylation and later activity of the vitamin K-dependent coagulation factors II, VII, IX, X, anticoagulant proteins C and S. The main aim of this study is to determine how modifications in the structures of warfarin influence the binding to the albumin. Our study is based on three goals. First, we synthesize the new coumarin derivatives with trimethoxy- and dimethoxy-substituent in the benzylamine moiety (Figure 1) and analyze their structures using spectroscopic methods. We would like to know how the substituents in benzyl group influence the physicochemical properties. Second, we have focused on the X-ray crystal structures analysis with respect to noncovalent interactions (i.e., C−H···O, C−H···π, π···π) in the crystal lattice, which play a crucial role in the supramolecular arrangement and crystal engineering.10−14 That analysis is completed by the Hirshfeld surface approach with the breakdown of the corresponding fingerprint plots. This allows meaningful differences to be revealed between intermolecular interaction in the presented compounds. Received: October 12, 2015 Revised: November 19, 2015 Published: November 30, 2015 456
DOI: 10.1021/acs.cgd.5b01456 Cryst. Growth Des. 2016, 16, 456−466
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Figure 1. Structures of warfarin and newly synthesized compounds.
And finally, employing the molecular docking methods, we would like to know how the new synthesized coumarins bind to the albumin and vitamin K epoxide reductase complex subunit 1 (VKORC1) in comparison to the warfarin. In contrast to many known albumin structures, together with such that include the associated R-warfarin and S-warfarin, experimental structures of the whole 2,3-epoxide reductase enzymatic complex has not been solved yet, and spatial structures are absent in PDB databases; thus we decided to model its catalytic part VKORC1, based on the known amino acid sequence to calculate affinities and binding sites of warfarin and new coumarin derivatives. This part potentially allows an assessment of the impact of the new derivatives on albumin and target enzyme. The first may play a role in the potential transport and bioavailability of the drug, and the second will help to judge potential alterations in the activity of the enzyme needed for proper vitamin-K regeneration, and thereby the normal gamma-carboxylation of coagulation factors.
2.2.2. Synthesis of 3-[1-(3,4,5-Trimethoxybenzylamino)benzylidene]-2H-chromene-2,4(3H)-dione(2a): 17 MS m/z (%): 468(100, M + Na), 446.1(15, M + 1H), 181. 2.2.3. Synthesis of 3-[1-(3,4,5-Trimethoxybezylamino)methylidene)-2H-chromene-2,4(3H)-dione (3a). 604 mg, 98%; mp = 205.4−206.0 °C. IR(KBr) ν(cm−1): 3433, 3410 (NH/OH), 1701 (CO), 1597, 1566, 1465 (aromat.), 1510 (NC), 1132(C−O−C). 1 H NMR (DMSO-d6): δ = 3.86 (s, 9H, O−CH3), 4.60 (s, 1H, = CH), 6.49−7.98(m, 6H, arom.), 12.09 (s, 1H, OH). MS m/z (%): 392 (100, M + Na), 370(50, M + 1H), 181. C20H19NO6 (369.30) Calculated C 65.04, H 5.19, N 3.79. Found C 64.90, H 5.03, N 3.82%. 2.2.4. Synthesis of 3-[1-(3,4-Dimethoxybezylamino)ethylidene)2H-chromene-2,4(3H)-dione (1b). 693 mg, 98%; mp = 150.4−151.5 °C. IR(KBr) ν(cm−1): 3421, 3446 (NH/OH), 1701 (CO), 1612, 1574, 1466 (aromat.), 1521 (NC), 1146(C−O−C). 1H NMR (DMSO-d6): δ = 3.77 (s, 6H, O−CH3), 4.79 (s, 2H, −CH2), 6.96−7.94 (m, 7H, arom.), 13.87 (s, 1H, OH). MS m/z (%): 352 (100, M − 1H), 337(10), 250(40). C20H19NO5 (353.31) Calculated C 67.98, H 5.42, N 3.96. Found C 68.29, H 5.36, N 3.95%. 2.2.5. Synthesis of 3-[1-(3,4-dimethoxybezylamino)benzylidene)2H-chromene-2,4(3H)-dione (2b). 374 mg, 47%; mp =125.0− 125.5 °C. IR(KBr) ν(cm−1): 3442, 3416 (NH/OH), 1708 (CO), 1608, 1584, 1467 (aromat.), 1514 (NC), 1156(C−O−C). 1H NMR (DMSO-d6): δ = 3.73 (s, 6H, O−CH3), 4.34 (s, 2H, −CH2), 6.81−7.96 (m, 7H, arom.), 13.84 (s, 1H, OH). MS m/z (%): 438(75, M + Na), 416 (100, M + 1H),151. C25H21NO5 (415.38) Calculated C 72.28, H 5.10, N 3.37. Found C 72.08, H 4.70, N 3.54%. 2.2.6. Synthesis of 3-[1-(3,4-dimethoxybezylamino)methylidene)2H-chromene-2,4(3H)-dione (3b). 604 mg, 89%; mp =183.1− 183.5 °C. IR(KBr) ν(cm−1): 3446, 3416 (NH/OH), 1699 (CO), 1646, 1608, 1481 (aromat.), 1518 (NC), 1160(C−O−C). 1H NMR (DMSO-d6): δ = 3.76 (s, 6H, O−CH3), 4.74 (s, 2H, −CH2), 6.98−7.87 (m, 7H, arom.), 8.58 (s, 1H, OH). MS m/z (%): 362 (75, M + Na), 340(100, M + 1H), 316(25). C19H17NO5 (339.28) Calculated C 67.26, H 5.05, N 4.13. Found C 67.20, H 4.91, N 4.27%. 2.2.7. Synthesis of 3-[1-(2,4-dimethoxybezylamino)ethylidene)2H-chromene-2,4(3H)-dione (1c). 523 mg, 74%; mp =129.8−130.4 °C. IR(KBr) ν(cm−1): 3420, 3424 (NH/OH), 1703 (CO), 1611, 1562, 1466 (aromat.), 1506 (NC), 1159(C−O−C). 1H NMR (DMSO-d6): δ = 3.80 (s, 6H, O−CH3), 4.71 (s, 2H, −CH2), 6.57−7.91 (m, 7H, arom.), 13.82 (s, 1H, OH). MS m/z (%): 376 (100, M + Na), 352 (M − 1H), 280 (10). C20H19NO5 (353.31) Calculated C 67.98, H 5.42, N 3.96. Found C 67.89, H 5.13, N 4.11%. 2.2.8. Synthesis of 3-[1-(2,4-Dimethoxybezylamino)benzylidene)2H-chromene-2,4(3H)-dione (2c). 397 mg, 50%; mp =121.1−123.0 °C. IR(KBr) ν(cm−1): 3443, 3416 (NH/OH), 1711 (CO), 1608, 1584, 1479 (aromat.), 1506 (NC), 1130(C−O−C). 1H NMR (DMSO-d6): δ = 3.82 (s, 6H, O−CH3), 4.23 (s, 2H, −CH2), 6.50−7.93 (m, 7H, arom.), 13.82 (s, 1H, OH) MS m/z (%): 438(100, M + Na), 416 (40, M + 1H), 400(5). C25H21NO5 (415.38) Calculated C 72.28, H 5.10, N 3.37. Found C 72.53, H 4.98, N 3.23%.
2. EXPERIMENTAL SECTION 2.1. Materials and Methods. Solvents used in the syntheses were of reagent grade or better quality and were dried according to standard methods. The melting points were determined using an Buchi B-540 apparatus, and they are reported as uncorrected values. The IR spectra were recorded on a Pey-Unicam 200G spectrophotometer in KBr. The 1H NMR spectra were recorded using a Bruker Avance III 600 MHz spectrometer. The ESI-MS spectroscopy was measured on 80 a Varian 500-MS LC Ion Trap mass spectrometer. For the new compounds satisfactory elemental analyses (±0.4% of the calculated values) were obtained in the Microanalytical Laboratory of the Department of Bioorganic Chemistry (Medical University, Lodz) using a PerkinElmer PE 2400 CHNS analyzer. Methyl 2-methyl-4-oxo-4H-chromene-3carboxylate (1), ethyl 2-phenyl-4-oxo-4H-chromene-3-carboxylate (2),15 methyl 4-oxo-4H-chromene-3-carboxylate (3),16 3-[1-(3,4,5trimethoxybenzylamino)ethyl]-2H-chromene-2,4(3H)-dione (1a), and 3-[1-(3,4,5-trimethoxybenzylamino)benzylidene]-2H-chromene2,4(3H)-dione (2a) were prepared according to literature procedures.15,17 2.2. General Procedure for Compounds 1a−c−3a−c. A solution of 3,4,5-trimethoxy-, 3,4-dimethoxy-, or 2,4-dimethoxybenzylamine (2 mmol) in methanol (1.0 mL) was added at room temperature to a solution of chromone derivatives 1−3 (2 mmol) in methanol (5 mL). The solid crude product, which precipitated after several minutes, was left at room temperature for 24 h and next filtered off, dried, and recrystallized from methanol or other solvents. Compounds 1a-c−3a-c were obtained as white solids. 2.2.1. Synthesis of 3-[1-(3,4,5-Trimethoxybenzylamino)ethylidene]-2H-chromene-2,4(3H)-dione(1a): 17 MS m/z (%): 406 (100, M + Na), 384(10, M + 1H), 265. 457
DOI: 10.1021/acs.cgd.5b01456 Cryst. Growth Des. 2016, 16, 456−466
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2.2.9. Synthesis of 3-[1-(2,4-Dimethoxybezylamino)methylidene)2H-chromene-2,4(3H)-dione (3c). 258 mg, 38%; mp =140.1−141.5 °C. IR(KBr) ν(cm−1): 3417, 3310 (NH/OH), 1697 (CO), 1645, 1608, 1482 (aromat.), 1508 (NC), 1157(C−O−C). 1H NMR (DMSO-d6): δ = 3.79 (s, 6H, O−CH3), 4.70 (s, 2H, −CH2), 6.55−8.63 (m, 7H, arom.), 11.91 (s, 1H, OH). MS m/z (%): 338 (100, M − 1H), 308(25), 286(40). C19H17NO5 (339.28) Calculated C 67.26, H 5.05, N 4.13. Found C 67.47, H 5.13, N 4.25%. 2.3. Crystallographic Analysis of Obtained Compounds. 2.3.1. X-ray Crystallography. X-ray crystal data for compounds 1b and 1c were measured from single colorless crystals using Xcalibur CCD diffractometer with Saphire detector (compound 1c) or SuperNova Dual diffractometer with Atlas S2 CCD detector (compound 1b) at 100 K with MoKα radiation (λ = 0.71073 Å). Data reduction in all cases were done using CrysAlis software18 with multiscan absorption correction.19 The structures were solved by direct methods and refined by full-matrix least-squares procedure using SHELXL-201320 program. All non-hydrogen atoms were refined anisotropically. The positions of hydrogen atoms (except H1 atom connected to N1) were calculated from known geometry (C−H bond lengths at 0.93, 0.97, and 0.96 Å for aromatic, methylene and methyl atoms, respectively) and treated as riding, where the isotropic thermal parameters of these hydrogen atoms were fixed as the multiple of the equivalent isotropic thermal parameters of the parent atoms. A summary of relevant crystallographic data is given in Table 1. 2.3.2. Hirshfeld Surface Analysis. The Hirshfeld surfaces21 were constructed using CrystalExplorer 3.121−23 based on the results of X-ray studies. In CrystalExplorer program the internal consistency is important when comparing structures; therefore, bond lengths of hydrogen atoms were normalized to neutron values (d(C−H) = 1.083 Å, d(O−H) = 0.983 Å, d(N−H) = 1.009 Å).24 For comparison of intermolecular scheme in crystal structures, the normalized contact distances, dnorm25 (eq 1) based on van der Waals radii, were mapped into the Hirshfeld surfaces. The values of dnorm is negative (red color) or positive (blue color) when intermolecular contacts are shorter or longer than van der Waals separations, respectively. The two-dimensional (2D) fingerprint plots were generated using di (distance from the surface to the nearest atom in the molecule itself) and de (distance from the surface to the nearest atom in the another molecule) as a pair of coordinates, in intervals of 0.01 Å, for each individual surface spot resulting in twodimensional histograms. dnorm =
di − rivdW rivdW
+
Table 1. Crystal Data, Data Collection, and Refinement of 1b and 1c 1b C20H19NO5 353.36 triclinic P1̅
C20H19NO5 353.36 monoclinic P21/c
8.5210(2), 9.7540(2), 10.3627(2) 88.716(1), 80.752(2), 88.282(2) 849.57(3) 2 1.381 100 0.71073 0.100 plate, colorless 0.15 × 0.09 × 0.03
12.8567(2), 13.1158(2), 9.9221(2) 90.0, 98.684(2), 90.0
α, β, γ (deg) V (Å3) Z Dx (Mg m−3) temperature (K) radiation type (Å) μ (mm−1) crystal form, color crystal size (mm) Data collection diffractometer data collection method no. of measured and unique reflections observed data with I > 2σ(I) Rint θmax (deg) overall completeness [%] Refinement refinement on all data R, wR [I > 2σ(I)] R, wR (all data) goodness of fit no. of parameters Δρmax, Δρmin (e·Å−3)
de − revdW revdW
compound Crystal data chemical formula Mr cell setting, space group a, b, c (Å)
(1)
SuperNova, Dual, Atlas CCD detector
1c
1653.94(5) 4 1.419 100 0.71073 0.103 block, colorless 0.26 × 0.26 × 0.14
ω scans 18008, 4920
Xcalibur diffractometer,Sapphire3 CCD detector ω scans 15435, 4801
4346
3889
0.0170 29.997 99.3
0.0290 29.99 99.9
F2 4920 0.0391, 0.1087 0.0444, 0.1116 1.077 242 0.438, −0.279
F2 4801 0.0401, 0.1015 0.0528, 0.1069 1.032 242 0.407, −0.231
subdomain IIA) according to structures 1H9Z and 1HA2, respectively with center x, y, z coordinates 34, 14, 9 and dimensions of all sides established as 20. Respectively for VKORC1 model following parameters were set: center 57.38, 70.893, 60.252 and size 20, 20, 26 to cover the volume which contained amino acids important for the function of the enzyme. Only 1 mode was generated for each dockings of the coumarin derivatives with RMSD l.b. and RMSD u.b. equal 0. Warfarin enantiomers bound in 1H9Z and 1HA2 structures were compared to 10-fold docking results with two generated modes. UCSF Chimera 1.10 (http://www.cgl.ucsf.edu/chimera/)33 was used for visualizing of docking results. This program was also employed to count RMSD of docked warfarin and other crystal molecules as well as to find hydrogen bonds and measure their distances.
26
2.4. Computational Details. Autodock Vina 1.1.2 (http://vina. scripps.edu/) an open-source program was used to compute binding places, poses as affinity energy for warfarin enantiomers and our coumarin derivatives in both tautomeric forms as ligands with albumin structures 1E7I, 1H9Z and 1HA2 as receptors. The albumin structures were downloaded from RCSB Protein Data Bank (http://www.rcsb. org/). The protein structures were deprived of all HETATM atoms, mostly lipids bound to albumin, R-warfarin and S-warfarin in structures 1H9Z and 1HA2, respectively. The albumins, R-warfarin and S-warfarin extracted from mentioned structures, crystallographic coordinates of 1b and 1c and computationally prepared structures of remaining synthesized derivatives (Scheme 1) were prepared properly for docking in ADT software (http://autodock.scripps.edu/resources/adt).27 Geometries of the structures without crystallographic coordinates were optimized in Avogadro (http://avogadro.cc)28 using MMFF94 force field.29 The amino acid sequence of VKORC1 - subunit C1 of 2,3epoxide reductase was downloaded from UniProt database (http:// www.uniprot.org/,30,31 UniProt ID: Q9BQB6) and an optimal structural model was generated using I-TASSER (Iterative Refinement Assembly Threading, http://zhanglab.ccmb.med.umich.edu/I-TASSER/).32 The model was processed in ADT as albumins. 10-fold dockings to HSA structures and VKORC1, and thereafter parsing of affinity energy for all compounds were automated by scripts written in Python. Autodock Vina search volume covered a cube with center set on the place of binding of R-(+)- and S-(−)-warfarin enantiomers (drug site I in
3. RESULTS AND DISCUSSION 3.1. Chemistry. We have synthesized the series of coumarin derivatives based on similar structure to warfarin (shown in green color in Figure 1) according to our previous published methods, using the reaction of 2-methyl/phenyl-4-oxo-4H-chromene-3carboxylic acid methyl/ethyl esters (1−3) with benzylamine derivatives (Scheme 1). The compounds were obtained in methanol as solvent with excellent yields (70−95%) for compounds of series a and b but slightly lower for the compounds of the series c. The structures of all seven new synthesized compounds (Scheme 1) 458
DOI: 10.1021/acs.cgd.5b01456 Cryst. Growth Des. 2016, 16, 456−466
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Scheme 1. Synthesis of the Obtained Compounds and Their Tautomeric Forms
Figure 2. View of molecular structure with atom numbering scheme of compounds 1b and 1c. Displacement ellipsoids at 30% level.
A common structural feature of studied compounds is an intramolecular N−H···O hydrogen bond (Table 3) which close an extra six-membered ring with S(6) graph set motif.35,36 Taking into account our previous studies17,37−39 and the bond distances within the OC−CC−N−H conjugated bond ring systems (Table 2), we can conclude that these interactions can Table 2. Bond Distances (Å) within the Intramolecular Hydrogen Bonding Ring for Resonance Assisted Hydrogen Bonds
were confirmed by elemental and spectral (IR, 1H NMR, MS) analysis (see Experimental Section). As we know from the literature,34 the obtained compounds may exist in three tautomeric forms A−C. However, as we observed in our previous papers the predominant forms are A and B. 3.1.1. IR Spectra. The most important IR spectral data for synthesized complexes are listed in the Experimental Section. The IR spectra of all compounds show characteristic stretching vibrations at ∼3400−3200 cm−1 corresponding to the ν(NH/ OH). The ν(CO) bands observed for each compounds occur at 1706−1700 cm−1. The ν(C−O−C) bands are observed at 1130−1160 cm−1. 3.1.2. 1H NMR. 1H NMR spectra data of complexes were recorded in DMSO-d6 and are presented in the Experimental Section. Position and intensity of the signals correspond to reagents used in synthesis. The hydroxyl group protons give signals at a range of 8.58−13.87 ppm. In coumarin derivatives (1a−3c) signals from protons of the methoxy group were found at 3.73−3.82 ppm as a singlet. The signals from methylene protons of the compounds (1a−3c) were observed at 4.23− 4.79 ppm as singlets. The aromatic protons are presented as multiplets around 6.49−8.63 ppm. 3.1.3. ESI-MS. ESI-MS spectrometry was carried out for all synthesized compounds. Scanning was performed from m/z = 100 to 1000. The experiments were performed in positive and negative ion-mode. Parent peaks have been found at (m/z) 406 for compound 1a, at (m/z) 468 for compound 2a, at (m/z) 392 for compound 3a, at (m/z) 352 for compound 1b, at (m/z) 438 for compound 2b and 2c, at (m/z) 362 for compound 3b, at (m/z) 376 for compound 1c, at (m/z) 338 for compound 3c. 3.2. Crystal Structure Description. The presented structures consist of a coumarin ring with (3,4-dimethoxybenzylamino)-ethyl or (2,4-dimethoxybenzylamino)-ethyl groups substituted at position 3 (Figure 2). The coumarin backbone is planar and forms the following dihedral angles with substituents rings: 73.06(4) and 82.33(4)0, respectively for compound 1b and 1c.
compound 1b compound 1c
C4O4
C4−C3
C3C31
C31−N1
1.256(2) 1.257(2)
1.441(2) 1.441(2)
1.434(2) 1.438(2)
1.321(2) 1.313(2)
be classified as resonance assisted hydrogen bonds (RAHBs), proposed by Gilli.40,41 In the solid state of structure 1b molecules are involved in C−H···O type hydrogen bonds and therefore self-assembled into double 2D sheets through C6−H6···O4i, (symmetry code (i): 1 − x, 1 − y, 1 − z) which form a motif described as R22(10).35,36 Additionally, together with C9−H9···O35iii (symmetry code (iii): −1 + x, y, −1 + z) hydrogen bond molecules create ring R44(36).35,36 Rings are located alternately forming 2D sheets perpendicular in direction (Figure 3). This arrangement could be also described as chains C(13) which are built by C9−H9···O35iii hydrogen bonds and linked into 2D sheets by C6−H6···O4i hydrogen interaction. The adjacent 2D sheets are connected to each other through C34−H34···O1ii interaction (symmetry code (ii): 1 − x, 2 − y, 1 − z), where R22(18) ring motif is produced (Figure S1). Similarly to the crystal structure of 1c (see below), there is no π···π interactions in the crystal packing of structure 1b. However, molecules are arranged close to each other with significant C···C contacts between: C32···C38 3.356(2) Å, C33···C33 3.386(2) Å, and C2···C2 3.900(2) Å (Figure 4). In the crystal packing of 1b further C32−H32A···π, C32−H32···π, and C37-H37···π interactions are also observed, where π electron rings are two methoxybenzene (C33−C38 at 1 − x, 2 − y, 2 − z), pyrane (O1−C10 at 1 − x, 2 − y, 1 − z) and benzene (C5−C10 at x, y, 1 + z), respectively. The crystal packing of 1c is dominated by C−H···O hydrogen bonds (Table 3) and C−H···π interaction (Table 4). The interactions C9−H9···O4iv and C6−H6···O1v (symmetry code (iv): −x, −1/2 + y, −1/2 − z, (v): −x, −1/2 + y, −1/2 − z) link molecules to chain which is additionally connected by 459
DOI: 10.1021/acs.cgd.5b01456 Cryst. Growth Des. 2016, 16, 456−466
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Figure 3. Crystal structure of compound 1b (a, b) and 1c (c, d) showing hydrogen bonds and motifs which are formed by hydrogen interactions. Hydrogen atoms not involved in hydrogen bonds are omitted for clarity. Symmetry codes: (i): 1 − x, 1 − y, 1 − z (ii): 1 − x, 2 − y, 1 − z, (iii): −1 + x, y, −1 + z, (iv): −x, −1/2 + y, −1/2 − z, (v): −x, −1/2 + y, −1/2 − z, (vi): x, 1 + y, z.
Table 3. Geometrical Parameters (in Å, 0) for Intra- and Intermolecular Hydrogen Bondsa compound 1b N1−H1···O4 C6−H6···O4i C34−H34···O1ii C9−H9···O35iii compound 1c N1−H1···O4 C9−H9···O4iv C6−H6···O1v C361−H36A···O2vi C361−H36B···O2vi
d(D−H)
d(H···A)
d(D···A)
