Introduction

The benzofuran derivatives, isolated from natural sources as well as synthetic, show cytostatic and/or antitumor activity (e.g., [1–9]). Therein, neolignans isolated from the Persea species are cytotoxic in vitro to the human cancer cell lines: mouth epidermoid carcinoma, lung adenocarcinoma, and colon adenocarcinoma [7]. Recently, it was proved that derivatives of the 2- and 3-benzo[b]furancarboxylic acids showed also selective cytotoxicity against the human cancer cell lines [8, 9]. Moreover, the compounds containing the benzo[b]furan system show antiprotozoal and/or antifungal activity [10–13], e.g., amiodarone, a drug used as an antiarrhythmic agent, possess significant antifungal potential [14–19]. The derivatives of 2- and 3-benzo[b]furan-carboxylic acids, especially those containing halogen atom (Br or Cl) in their structure, are active against the Candida strains C. albicans and C. parapsilosis [20, 21], Mycobacterium tuberculosis [22] and are selective Pim kinase inhibitors [23].

Due to the wide spectrum of biological activity of such aromatic monocarboxylic acids, it is important to describe their molecular structure and patterns of intermolecular contacts. However, the papers on the molecular structure of relatively simple benzo[b]furan derivatives are very scarce and there is no report on the structure of any benzo[b]furan-monocarboxylic acid (see Supplementary Material). In this study, we present the conformational analysis of 7-acetyl-6-methoxy-3-methylbenzo[b]furan-2-carboxylic acid (1), 7-acetyl-5-bromo-6-hydroxy-3-methylbenzo[b]furan-2-carboxylic acid (2), 6-acetyl-5-hydroxy-2-methylbenzo[b]furan-3-carboxylic acid (3), and methyl ester of 6-acetyl-5-hydroxy-2-methylbenzo[b]furan-3-carboxylic acid (4) (Fig. 1). Moreover, the sodium complex (5) of the acid 1 has been synthesized. This compound is the first metal complex of benzo[b]furan-monocarboxylic acid for which the stereochemistry is determined. So far, the ammonium salts and transition metal complexes of benzo[b]furan-2,3-dicarboxylic acid have been analyzed by Goldberg et al. [24–27].

Fig. 1
figure 1

Chemical structure of the investigated compounds 1–4

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The main goal of this study is to describe the stereochemistry of the O-donor groups of investigated compounds. To achieve this goal, an X-ray crystallography was used and the theoretical calculations were performed to find all stable conformers of the derivatives of 2- and 3-benzo[b]furancarboxylic acids.

Experimental

Synthesis of ligands (1–4)

The chemicals were obtained from Sigma-Aldrich. The compounds 1–4 were synthesized according to the previously published papers [28–30]. Single crystals suitable for the X-ray diffraction were prepared by a slow evaporation of the solvent from the ethanolic solutions at room temperature; however, the crystals of 2 were of poor quality.

The IR spectra were performed between 4,000 and 400 cm−1 on a Perkin Elmer 1725× FT-IR spectrometer using the KBr pellets. The characteristic bands (cm−1) observed for compounds 1–4 are

  • 1: 3424 (ν O–H), 1694 (ν C=O), 1677 (ν C=O), 1449 (δ COH), 1383 (δs CH3), 1363 (δs CH3), 1281 (ν C–O)

  • 2: 2924 (ν O–H), 1685 (ν C=O), 1634 (ν C=O), 1448 (δ COH), 1371 (δs CH3), 1213 (ν C–O), 1153 (ν C–O)

  • 3: 3084 (ν O–H), 1685 (ν C=O), 1623 (ν C=O), 1420 (δ COH), 1368 (δs CH3), 1197 (ν C–O), 1186 (ν C–O)

  • 4: 3402 (ν O–H), 1717 (ν C=O), 1641 (ν C=O), 1372 (δs CH3), 1199 (ν O–C(=O)), 1152 (ν C–OH), 1091 (ν C(=O)–O)

Synthesis of complex (5)

The chemicals were obtained from Sigma-Aldrich. The sodium hydride was used as a deprotonation agent and as a source of Na cations [31, 32]. The ligand 1 (0.4 mmol) and sodium hydride (0.4 mmol) in 10 mL of ethanol solution were refluxed for 3 h in 30 °C. After several days, colorless crystals of sodium complex (5) were obtained.

X-ray crystallography

The diffraction data for the crystals of 1–5 were collected on Oxford Diffraction KM4 or Xcalibur diffractometers. The structures were solved by direct methods using the SHELXS-97 program and refined by the full-matrix least-squares method on F 2 using the SHELXL-97 program [33]. The non-hydrogen atoms were refined with anisotropic displacement parameters. The C-bonded H-atoms were positioned geometrically and allowed to ride on the attached atom. The primary positions of the O-bonded H-atoms were taken from the difference electron-density maps and they were riding during the refinement with the fixed O–H distance. The isotropic displacement parameters of the H-atoms were U iso(H) = 1.3 U eq(C) for the methyl groups and U iso(H) = 1.2 U eq(C/O) for the rest of atoms. The structural data for the poor-quality crystal of 2 were also included to the discussion. The crystallographic data, details of the data collection and refinement are given in Table 1.

Table 1 Crystal data and experimental parameters
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Computational details

The calculations were performed using the Gaussian03 program package [34] and the procedure tested previously for benzo[b]furans [35]. The geometry of molecules 1–4 in the gas phase was optimized with the B3LYP [36, 37] exchange–correlation potential, using a standard 6-31G(d) basis set [38]. The atomic coordinates found in the solid state were used as the initial guess. The PES scan study has been performed for the molecules 1–4. The scans started from the zero value of the torsion angle up to ±180°, with a step size of 10°. The geometry of conformers corresponding to the minima on the PES was optimized with the B3LYP method using 6-31++G(d,p) basis set. The vibrational frequency calculations were performed for the found conformers and all frequencies were real.

Results and discussion

Structural analysis of ligands (1–4)

Molecular structure in solid

The rigid aromatic benzo[b]furan system is substituted by several groups containing O-atoms, viz. OH, OCH3, C(=O)CH3, and COOH/COOCH3. In the crystal structures of 2 and 3, there are two molecules in the asymmetric part, labeled as A and B, thus, six molecular structures are compared. The bond lengths and angles of the molecules are within the expected ranges and are equal within the experimental error. The atom numbering and the conformations of 1–4 adopted in the crystal are shown in Fig. 2.

Fig. 2
figure 2

Molecular structures of 1–4 with thermal ellipsoid plot and atom-numbering scheme. View perpendicular and parallel to benzo[b]furan system

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The molecules of the studied compounds contain the acetyl group connected to the atom C7 in the molecules 1, 2 or C6 in 3, 4. The ortho-position of the acetyl and methoxy groups in acid 1 causes out-of-the-plane deviation of the acetyl fragment; the interplanar angle of the aromatic ring and this group is 45.7(9)° (Table 2). The methoxy group, present in 1, is coplanar with the aromatic ring (Table 2). The coplanarity of the methoxy group to the benzo[b]furan system and the rotation of the acetyl substituent is also observed in the molecular structures of two khellinone dimers [39, 40].

Table 2 Selected torsion angles (°) for molecules 1–4 observed in solid
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The ortho-position of the acetyl and hydroxyl groups present in two other acids (2, 3) and ester (4) promotes the formation of the O–Hhydroxyl···Oacetyl intramolecular hydrogen bond in the S 11 (6) motif [41] (Fig. 3; Table 3), which causes the coplanarity of the acetyl and benzo[b]furan moieties (Table 2). These are consistent with the stereochemistry of the analogous compounds [42, 43].

Fig. 3
figure 3

Intra- and intermolecular O–H···O hydrogen bonds observed in crystals 1–4

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Table 3 Geometric parameters of O–H···O hydrogen bonds in crystals 1–4
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The coplanarity of the carboxylic/ester group with the aromatic ring is observed for all investigated compounds (1–4) (Table 2). The dihedral angle CAr–C(=O)–O/Ar, where CAr is an aromatic C atom and Ar is an average plane passing through the aromatic system, equals 1.8(4)°, 4.1(5)°, 1.3(4)°, 2.4(4)°, 2.4(3)°, 4.8(1)°, for the molecules 1, 2A, 2B, 3A, 3B, and 4, respectively.

The carbonyl C=O bond of the CAr–C(=O)–OH fragment is in the trans (1, 2) or cis (3, 4) orientations with respect to the neighboring C–CH3 bond (Fig. 2). This orientation is consistent with other structural data [44, 45].

Crystal structure

The intramolecular O–H···O hydrogen bond, formed in the molecules 2–4, is accompanied by the intermolecular O–H···O bonds in the crystal structure of the carboxylic acids (1–3) (Fig. 3; Table 3). The carboxyl group, acting as a donor and acceptor in this contacts, creates dimers in the R 22 (8) motif [38, 39], typical for the carboxylic acids. In the crystal 1, the centrosymmetric dimers are formed (1·1), whereas in the crystals 2 and 3 the structural units are pairs of symmetry independent molecules (2A·2B and 3A·3B). The molecular dimers (1–3) or monomers (4) are linked by the C–H···O, C–H···π, and C–H···Br contacts (Table 4) and the molecular stacks in the crystals of 1–4 are observed (Fig. 4).

Table 4 Geometric parameters of C–H···O, C–H···Br, and C–H···π (C g ) contacts in crystals 1–4
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Fig. 4
figure 4

Comparison of crystal packing of 1–4. For 2 and 3, columns of symmetry-independent molecules are marked

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Conformational analysis in gas phase

Since the benzo[b]furan system is rigid, the potential energy surface (PES) for the internal rotation about the C Ar–C(=O) single bonds in the molecules 1–4 has been explored using quantum-chemical methods.

The search for stable conformers was focused on the rotation of COOH/COOCH3 group for all molecules and the C(=O)CH3 substituent for 1. The changes of the orientation of the acetyl group for other molecules were not considered, because in the molecules 2–4 this substituent is involved in a strong O–H···O intramolecular hydrogen bond and it is unlikely to obtain a different orientation of the acetyl group than that observed in the crystals [34].

To find stable conformers of the acid 1, the PES for the O5–C8–C7–C7A torsion angle has been scanned within the isolated molecule (Fig. 5). The restricted rotation about the C7–C8(=O)CH3 single bond yields two stable conformations: 1.1 and 1.2 (Fig. 6). The molecule 1.1 has the carbonyl group of the C8(=O)CH3 substituent in the trans orientation with respect to the C7A–O1 bond. The second conformer 1.2, energetically less favorable (ΔE = 0.17 kcal/mol), is characterized by the cis conformation of those fragments. The molecular structure of the most stable conformation in the gas phase (1.1) is in agreement with the stereochemistry of molecules adopted in the solid (Tables 2, 5).

Fig. 5
figure 5

PES calculated for rotation of carboxyl/ester groups of 1–4 (top) and acetyl group of 1 (bottom)

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Fig. 6
figure 6

Selected conformers of acid 1 and all conformers of molecules 2, 3, and 4. Values in brackets indicate calculated energy in hartree and relative energy in kcal/mol. *Solid-state conformer in respective crystals 1–4. **Solid-state conformer in crystal 5

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Table 5 Selected torsion angles (°) of conformers in the gas phase for molecules 1–4
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For all calculated conformers, the carboxyl or ester group is coplanar with the aromatic ring (Table 5). There are two possible relative orientations of the C=O bond (of the COOH/COOCH3 substituent) and the C2/C3–CH3 single bond: trans (1.1, 1.2, 2.1, 3.2, 4.2) and cis (1.3, 1.4, 2.2, 3.1, 4.1) (Fig. 6). The calculated electron energies for all conformers indicate that the cis orientation of C11=O2 and C2/C3–CH3 bonds is energetically more favorable.

Additional conformers, less populated, were found by changing the orientation of hydroxyl group for the acid molecules 1–3. By the rotation around the C11–O3(H) single bond, two conformations of COOH group can be distinguished for 2, 3 (Fig. 6), and for 1 (Fig. 7). The –OH group adopts either a synplanar or antiplanar conformation of the O=C–O–H moiety, where the synplanar structure is the most stable form. According to the literature, in the crystalline state, the antiplanar O=C–O–H form occurs when the O–H bond participates in an intramolecular O–H···O bond. This is observed for the 1,2-substituted dicarboxylic acids [46], e.g., 1-benzofuran-2,3-dicarboxylic acid and its ammonium salts [23–25]. Taking into account, the combinations of orientation of the COOH/COOCH3 group, four conformers of the acids 2 and 3, and two conformers of the ester 4 are predicted (Fig. 6).

Fig. 7
figure 7

All conformers of acid 1

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For the acid 1, three orientations of the methoxy group are possible (Fig. 7). If all rotations for the molecule 1 are considered, viz. around the C Ar–C(=O)CH3, C Ar–COOH and C Ar–OCH3 single bonds, 16 conformers will be found (Fig. 7).

Structural analysis of sodium complex (5)

Molecular structure

The asymmetric part consists of the Na+ cation and three organic units: 1A—the anion of compound 1, coordinating to Na+, 1B—the molecule of acid 1 coordinating to Na+ cation, and 1C—the molecule of compound 1 cocrystallizing outside of the Na+ coordination sphere: [Na +·1A −·1B]·1C (Fig. 8). The units 1A and 1B are tridentate ligands chelating through the O-atoms, i.e., O1 from the furan ring, O5 of the acetyl group and O2 of the carboxylate (1A) or the carboxyl group (1B), respectively. Thus, the Na+ exhibits sixfold coordination and a strongly deformed tetragonal bipyramid is formed (Fig. 9; Table 6). The Na–O bond distances are in the range 2.358(7)–2.461(6) Å (Table 6).

Fig. 8
figure 8

Molecular structure of 5 with thermal ellipsoid plot and atom-numbering scheme of organic components

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Fig. 9
figure 9

Coordination polyhedron of Na in complex 5 (a) and packing of complex units in crystal (b)

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Table 6 Selected bond distances and valence angles for Na+ coordination sphere in 5
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Stereochemistry of ligands

There are no significant differences between the respective bond distances and valence angles for the three organic units 1A, 1B, and 1C. However, the values of torsion angles describing the orientations of the O-donor groups vary (Table 7). For the anion 1A and acid 1B, which chelate to Na+, the C8=O5 acetyl and furan O1–C7A bonds are the cis oriented, thus the O5 carbonyl atom is included into the coordination sphere of Na+ (Fig. 9a). For the non-coordinating acid molecule 1C, the trans orientation of the respective bonds is observed. The C(=O)CH3 substituent of all conformers 1A, 1B, and 1C is tilted out-of-the-average mean plane determined by the aromatic atoms (Table 7). Furthermore, the acid molecules, 1B and 1C, have different conformations of the carboxyl group; the C11=O2 and C3–C10H3 bonds have the trans orientation for the chelating molecule 1B, and cis for 1C (Fig. 8). The methoxy group is coplanar with the benzo[b]furan system for all conformers (Table 7).

Table 7 Selected torsion angles (°) for ligands 1A and 1B, and cocrystalizing molecule 1C in crystal 5
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The comparison of stereochemistry of the acid molecules observed in the complex 5 with results of the theoretical analysis indicates that the molecule 1B corresponds to the conformer 1.2 from quantum-chemical calculations, while 1C has the same geometry as the conformer 1.3 (Figs. 6, 8).

Crystal structure

Two intermolecular O–H···O hydrogen bonds, present in the crystal structure of 5, link together the carboxyl and carboxylate groups in the following pattern: (COOH)B···(COO−)A···(COOH)C, in which the anion 1A acts as a double acceptor. It joins the acid molecules 1B and 1C through the O3C–H3C···O3A and O3B–H3B···O4A (x + 1/2, 1/2 − y, z + 1/2) hydrogen bonds. Thus, the monomeric neutral complexes form folded chains along the [101] direction (Fig. 10). In addition, the crystal structure of 5 is stabilized by the C–H···O contacts. These interactions arrange the complex units into the layers crossing along the c axis at an angle of about 70°, shown in Fig. 9.

Fig. 10
figure 10

Hydrogen-bonding pattern in crystal 5. Donor (D)···acceptor (A) distances are O3B···O4A 2.476(7) Å and O3C···O3A 2.675(7) Å. The D–H···A angles are O3B–H3B···O4A 160° and O3C–H3C···O3A 145°

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Conclusion

The central part of the analyzed molecules, the heterocyclic benzo[b]furan system, is rigid and the CAr–C and CAr–O bonds connecting the aromatic nucleus and substituted small functional groups are coplanar. Thus, the structural changes may occur only by a rotation of these substituents, i.e., the acetyl, carboxyl, hydroxyl, and/or methoxy groups. The series of conformers for the derivatives of 2- and 3-benzo[b]furancarboxylic acids in the crystalline and gas phase has been described. In both phases, the ortho-position of hydroxyl and acetyl groups forces the presence of the O–H···O intramolecular hydrogen bond, closing the six-membered ring.

The COOH/COOCH3 fragment is always coplanar with the aromatic system. In the gas phase, two substituents of the furan ring—the carboxyl and methyl groups—adopt the cis and trans orientations, while in the solid phase only one form is present. The C=O and C–CH3 bonds are trans for the derivatives of 2-benzo[b]furancarboxylic acid (1, 2), and cis for the derivatives of 3-benzo[b]furancarboxylic acid (3, 4). The trans conformation, energetically less favorable, observed in the crystals of 1 and 2, is probably induced by intermolecular forces. In the solid phase, the OH group of COOH substituent adopts the synplanar form of O=C–O–H bonds, whereas for the gas phase, two conformations are observed: antiplanar and energetically more favorable—synplanar.

The structural analysis of the sodium complex of acid 1 confirmed the existence of the ligand conformers identified by the quantum chemistry methods. Within the neutral complex unit, of the stoichiometry [Na + ·1A − ·1B]·1C, the organic moieties (1A–C) differ in the orientation of both the acetyl and carboxyl groups. The ligands 1A and 1B are tridentate chelating to the metal cation, whereas the molecule 1C cocrystallizes outside of the Na+ coordination sphere.