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Short Note

2-(1H-Imidazol-2-yl)-2,3-dihydro-1H-perimidine

by
Zhanina Petkova
1,
Rusi Rusew
2,
Snezhana Bakalova
1,
Boris Shivachev
2,* and
Vanya Kurteva
1,*
1
Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Street, bl. 9, 1113 Sofia, Bulgaria
2
Institute of Mineralogy and Crystallography “Acad. Ivan Kostov”, Bulgarian Academy of Sciences, Acad. G. Bonchev Street, bl. 107, 1113 Sofia, Bulgaria
*
Authors to whom correspondence should be addressed.
Molbank 2023, 2023(1), M1587; https://doi.org/10.3390/M1587
Submission received: 31 January 2023 / Revised: 10 February 2023 / Accepted: 13 February 2023 / Published: 15 February 2023
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Abstract

:
The novel compound 2-(1H-imidazol-2-yl)-2,3-dihydro-1H-perimidine was obtained in very good yield via a known eco-friendly protocol. The product was isolated in pure form as a solvate by simple filtration from the crude mixture. Its structure was assigned by 1D and 2D NMR experiments and was confirmed by high resolution MS and single crystal XRD. The temperature of methanol release was determined by DSC and the energy of the process theoretically estimated.

1. Introduction

Perimidines are π-amphoteric tricyclic aromatic heterocycles [1] with a broad variety of applications [2,3,4,5,6]. The most synthetic protocols present a one-pot two-step procedure; formation of dihydroperimidines followed by dehydration [7,8]. The intermediate dihydroperimidines also exhibit a diverse range of properties; some examples are shown in Figure 1.
Numerous derivatives display variable bioactivities, such as antibacterial [9,10], anti-tumor [11], anti-neoplastic [12], PTP1B inhibitory [13], etc., and applications such as chemosensors for hypochlorite [14] and Cu2+ ions [15,16,17], carbene pincer ligands [18,19,20,21], antioxidants for lubricants [22], and many others. Among the protocols for the synthesis of 2,3-dihydroperimidines, the condensation between naphthalene-1,8-diamines and carbonyl compounds, mainly aldehydes, is relatively simple and so economically relevant that it practically has no alternative and has been intensively exploited. For that reason, the main attempts of scientific groups have been directed towards the synthesis of a broad variety of derivatives by development of efficient catalysts [23,24,25,26,27,28,29,30,31].
Recently, we reported on the synthesis and anticancer activity of a series of perimidines [32], including the new 2-imidazolyl derivative. As a continuation, we focused our attention on their precursors, the corresponding dihydro-analogues. Therefore, we present herein the synthesis and solution and solid-state characterization of a novel dihydroperimidine compound, 2-(1H-imidazol-2-yl)-2,3-dihydro-1H-perimidine.

2. Results and Discussion

2.1. Synthesis

The novel dihydroperimidine derivative 2-(1H-imidazol-2-yl)-2,3-dihydro-1H-perimidine is obtained via a simple eco-friendly protocol, shown in Scheme 1. The condensation between 1,8-diaminonaphthalene and imidazole-2-carbaldehyde is carried out at room temperature in various solvents, such as acetonitrile, THF, methanol, and even water according to a recently reported procedure [33]. The best results, 88% yield and easy work-up, are obtained in methanol for two main reasons. On the one hand, both reagents have good solubility in alcohols, while the limited solubility of bis-amine in acetonitrile and THF resulted in relatively low yields after significant reaction prolongation, and no conversion was detected in water where both compounds are completely insoluble. On the other hand, the target product possesses limited solubility in methanol at room temperature allowing its isolation in pure form by simple filtration of the crude reaction mixture.
The structure of the product was assigned by 1D and 2D NMR spectra (see Supporting Information). The 1H spectrum in DMSO-d6 shows characteristic signals for the aromatic perimidine protons; two doublets of doublets with 3J and 4J at 6.529 and 7.009 ppm for CH-4+9 and CH-6+7, respectively, and a doublet with two 3J for CH-5+8 at 7.160 ppm. The CH-2 connecting both fragments appears as a singlet at 5.470 ppm, while both NH protons give a singlet at 6.832 ppm. The imidazolyl unit shows two very broad singlets at 6.910 and 7.133 ppm for CH protons, most probably due to slow exchange, and a broad singlet at 12.277 ppm for NH. The assignment of the signals was based on the characteristic interactions in a NOESY experiment, namely NH/CH-4+9, NH/CH-2 and imidazolyl NH with both broad singlets for CH. 13C spectrum shows a signal for CH-2 at 62.03 ppm, three intensive signals for perimidine CH-4+9, CH-6+7, and CH-5+8 at 105.21, 116.09, and 127.29 ppm, respectively, two signals with very low intensities for imidazolyl CH at 117.68 and 127.45 ppm and four signals for quaternary carbons. The latter are assigned as Cq-3a1 at 113.03 ppm, Cq-6a at 134.75 ppm, Cq-3a+9a at 142.99 ppm, and Cq-2 of imidazolyl unit at 147.43 ppm by analysing the specific interactions in an HMBC experiment. The product’s structure was confirmed by high resolution mass-spectra, where molecular ions were detected in both positive and negative mode.
The NMR spectra also show signals for a hydrogen bonded molecule of methanol (1:1 ratio product/MeOH); doublet at 3.173 ppm for CH3 and quartet at 4.114 ppm for OH in the proton spectrum and a signal for methyl carbon at 49.06 ppm. This pattern is valid for both crude and recrystallised from methanol products. The methanol OH quartet and CH3 doublet gave negative correlations in a NOESY experiment with both imidazolyl CH protons and with OH, respectively, all possessing very low intensities as expected due to the broad imidazolyl signals detected in the proton spectrum. Based on these observations, it can be concluded that the product forms stable 1:1 solvate both during its preparation and recrystallization.
The DSC data (Figure 2a) disclose that the methanol molecules start to leave the crystal structure around 60 °C and the process is complete around 110 °C (the calculated H is 193 kJ/mol). According to the DSC data the solvent release is not accompanied by a phase transition and the next endothermic effect is the melting of the compound (H = 84 kJ/mol). The thermogravimetric data visualizing the mass losses observed during heating of the title compound are shown on Figure 2b. The registered weight loss up to 110 °C is ~13 wt% and correlates with the theoretical estimations for methanol release (12%). After 180 °C the TG registers the losses associated to the melting and evaporation of the title compound.

2.2. Crystallography

The title compound 2-(1H-imidazol-2-yl)-2,3-dihydro-1H-perimidine appears as pale beige-coloured prisms obtained by slow-evaporation from methanol. The crystal structure of the studied compound was solved in the monoclinic P21/c space group with cell parameters – a = 11.5777(9) Å, b = 9.2885(11) Å, c = 13.9591 Å and β = 113.472(3)° (Table S1). The compound crystallizes as a crystal solvate as one molecule methanol is entrapped in the crystal structure (four molecules per unit cell). A close inspection of the molecular features reveals that 2-(1H-imidazol-2-yl)-2,3-dihydro-1H-perimidine is built up of two main fragments: 2,3-dihydro-1H-perimidine (fragment 1) and 1H-imidazole (fragment 2) connected by a single –(H)C–C– covalent bond (namely C6–C5, see Figure 3). Furthermore, fragment 1 consists of a planar (r.m.s.d = 0.037Å) naphthalene ring system and a six membered hetero ring formed by the mutual C8–C18–C16 atoms of the naphthalene backbone and a N–C(H)–N group. The hetero ring is in an envelope conformation with the N–C–N group hinged with respect to the naphthalene ring at 49.86(16)°. The imidazole moiety is actually planar (r.m.s.d = 0.001 Å) and the mean plane between the two ring systems (1H-perimidine and imidazole) is 95.74(7)°.
The crystal structure of 2-(1H-imidazol-2-yl)-2,3-dihydro-1H-perimidine is stabilized by three types of hydrogen bonding interactions: O–H…N, N–H…O, and N–H…N. The first type is represented by the strongest hydrogen bonding interaction (D…A distance of 2.731 Å) between the N4 atom of fragment 2 and the methanol molecule. The second type (N-H…O) is represented by two distinct hydrogen bonding interactions involving the two N–H groups 1H-perimidine N17–H17…O19 and N7–H7…O19 – with D…A distances of 3.005 and 3.047 Å, respectively. The third type of hydrogen bonding interactions (N–H…N) involves the N1-H1…N7 atoms of imidazole and 1H-perimidine from adjacent molecules. This leads to the formation of dimmers through R(22)10 motifs and chains propagating along c (Figure 4). The comparison of the recovered powder diffraction pattern (Figure S1) and that calculated from single crystal data show that the title compound is monophasic with high purity.
The networks of hydrogen bonds assemble the 2-(1H-imidazol-2-yl)-2,3-dihydro-1H-perimidine and methanol into a quite stable chain architecture (Figure 4, Table 1). Indeed, the NMR data in solution also expose the presence of the MeOH…imidazole interaction. This fact suggested that the named interaction may be quite energetic, e.g., the formed hydrogen bond should be stronger than the three other ones detected. This hypothesis is supported by the comparison of D…A distances (2.733 to 3.047 Å) where the O19–H19…N4 is the shortest (2.733 Å). In an attempt to explain this observation, we generated intermolecular framework interactions for methanol… 2-(1H-imidazol-2-yl)-2,3-dihydro-1H-perimidine and calculated their corresponding interaction energies (Table 2). The calculated energies (Table 2) were compared with the experimentally obtained enthalpy of methanol release (193 J/g, Figure 2). The computed “hydrogen bonding” interaction values are shown in Table 2. Again, the strongest one (–34.6 kJ/mol) is between MeOH and the imidazole moiety. The 1H-perimidine…MeOH interaction energies with values of – 28.7 and –23.3 kJ//mol are slightly weaker but not significantly when compared to –34.6 kJ/mol. The last computed interaction energy (N1H1…N7, –83.2 kJ/mol) could be related to the melting effect of the compound.
The experimentally observed endothermic release of methanol is accompanied by the destruction of the hydrogen bond interactions plus the energy for the evaporation of methanol (35 kJ/mol). A comparison between the DSC enthalpy (experimental 51.7 kJ/mol) and computed interactions energies (SUM of energies, 63.9 kJ/mol) suggests that the computed interaction energies appear to be overestimated by ~10% but reproduce correctly the strength of the various interactions.
Finally, a brief comparison between the product and its dehydrogenated analogue, 2-(1H-imidazol-2-yl)-1H-perimidine [32]. Both compounds are methanol insoluble, but the latter does not form a similar solvate (Figure 5) despite the last purification step being trituration with methanol. This difference could be explained by a delocalization of the imidazolyl NH in the aromatic molecule, while in dihydroperimidine it is located on the imidazolyl unit due to the absence of conjugation.

3. Materials and Methods

3.1. General

All reagents were purchased from Aldrich, Merck and Fluka and were used without any further purification. The deuterated dimethylsulfoxide was purchased from Deutero GmbH. Fluka silica gel (TLC-cards 60778 with fluorescent indicator 254 nm) plates were used for TLC chromatography and Rf-value determination. The melting point was determined in a capillary tube on SRS MPA100 OptiMelt (Sunnyvale, CA, USA) automated melting point system with heating rate of 1 °C per min. The NMR spectra were recorded on a Bruker Avance NEO 400 spectrometer (Rheinstetten, Germany) in DMSO-d6; the chemical shifts are quoted in ppm in δ-values against the solvent peak at 2.5 ppm and the coupling constants were calculated in Hz. The assignment of the signals was confirmed by applying two-dimensional NOESY, HSQC, and HMBC techniques. The spectra were processed with the Topspin 3.6.3 program. For simplicity, the imidazole nuclei are depicted as “Im”. The IR spectrum was measured on a Shimadzu IR Spirit FT-IR spectrometer (Shimadzu Corporation, Kyoto, Japan, USA) using QATR-S as a single-reflection ATR measurement attachment. The mass spectra were recorded in both positive and negative mode on a Q Exactive Plus Hybrid Quadrupole-Orbitrap Mass Spectrometer Thermo Scientific (ESI HR-MS). The spectra were processed with Xcalibur Free Style program version 4.5 (Thermo Fisher Scientific Inc., Waltham, MA, USA). DSC analyses were performed on a Discovery DSC250 (TA Instruments, New Castle DE, USA). Samples weighing between 1 and 5 mg were heated in aluminum pans from 20 to 350 °C (10 °C·min−1) in nitrogen (flow rate 25 mL·min−1). The enthalpy values (9 J/g) of the endothermic effects (methanol release) and melting of the synthesized compound were determined from indium melting calibration. Thermogravimetric analyzes were performed using a Q50 analyzer (TA Instruments). Ten mg of sample was placed in a ceramic container and measurements were made in the temperature range of 20 to 200 °C with a heating rate of 10 °C·min−1 under a nitrogen flow rate of 25 mL·min−1.

3.2. Synthesis of 2-(1H-Imidazol-2-yl)-2,3-Dihydro-1H-Perimidine (1:1 MeOH Solvate)

A solution of 1,8-diaminonaphthalene (2 mmol) and imidazole-2-carbaldehyde (2 mmol) in MeOH (10 mL) was stirred at rt for 10 h. The solid phase formed was filtered off and washed with small portions of cold MeOH to give the pure product: 88% yield; Rf 0.17 (5% MeOH in DCM); pale beige solid; m. p. 186.1–186.3 °C; 1H NMR 3.173 (d, 3H, J 5.0, CH3 MeOH), 4.114 (q, 1H, J 5.0, OH MeOH), 5.470 (s, 1H, CH-2), 6.529 (dd, 2H, J 7.4, 0.6, CH-4+9), 6.832 (s, 2H, NH-1+3), 6.911 (s, 1H, CH Im), 7.009 (dd, 2H, J 8.2, 0.6, CH-6+7), 7.133 (s, 1H, CH Im), 7.160 (dd, 2H, J 8.0, 7.6, CH-5+8), 12.277 (s, 1H, NH Im); 13C NMR 49.06 (CH3 MeOH), 62.03 (CH-2), 105.21 (CH-4+9), 113.03 (Cq-3a1), 116.09 (CH-6+7), 117.68 (CH Im), 127.29 (CH-5+8), 127.45 (CH Im), 134.75 (Cq-6a), 142.99 (Cq-3a+9a), 147.43 (Cq Im); IR (ATR) 3206, 3111, 3052, 2804, 1600, 1518, 1459, 1406, 1376, 1265, 1164, 1121, 1108, 1087, 1070, 856, 819, 756, 723, 628, 441 cm−1; HRMS (ESI+) m/z calcd. for C14H13N4+ [M+H]+ 237.1135, found 237.1133, ∆ = −0.2 mDa; HRMS (ESI−) m/z calcd. for C14H11N4− [M-H]− 235.0978, found 235.0980, ∆ = 0.2 mDa.

3.3. Crystallography

Pale beige coloured crystal blocks from the titled compound were obtained by recrystallization from methanol. Suitable crystals with appropriate sizes (0.25 × 0.2 × 0.18 mm3) were mounted on a nylon loop using cryoprotective Paratone oil. Diffraction data were collected on a Bruker D8 Venture diffractometer equipped with IµS micro-focus sealed X-ray source (MoKα radiation, λ = 0.71073 Å) and a PHOTON II CPAD detector. Diffraction data were processed in the APEX4 software package [34]; peaks were integrated with the Bruker SAINT software [35] using a narrow-frame algorithm. Intensities were scaled and the data corrected for absorption effects using the Multi-Scan method (SADABS) [35]. The structure was solved with the intrinsic phasing method and refined by the full-matrix least-squares method on F2 (ShelxT and ShelxL program packages [36,37]) using OLEX—ver. 1.5 software [38]. All non-hydrogen atoms were located successfully from the Fourier map and were refined anisotropically. Hydrogen atoms were placed on calculated positions riding on the parent carbon atoms using the following scheme: Ueq = 1.2 for C–Haromatic = 0.93 Å, C–Hmethyl = 0.96 Å. ORTEP-3v2 software [39] was used to illustrate the molecules present in the asymmetric unit. Three-dimensional packing and visualization of the molecules of the title compound was made using CCDC Mercury [40]. The most important data collection and crystallographic refinement parameters for 3 are given in Table S1. Complete crystallographic data for the reported structure were deposited in the CIF format with the Cambridge Crystallographic Data Centre as 2215392. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html, deposited on 26 October 2022, (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +441223336033; E-mail: [email protected]).
The diffraction patterns of powdered samples and computed from SCXRD data were compared to establish the crystalline properties, purity, and eventual presence of additional phases. Powder XRD patterns were collected from the ground residue of the title compound (manually in an agate mortar). The ground (powder) sample of the synthesized compound was placed in a zero background holder and data were collected on an Empyrean Powder X-ray diffractometer (Malvern Panalytical, The Netherlands) in the 2–50° 2θ range using Cu radiation (λ = 1.5406 Å) and a PIXcel3D detector (Figure S1).

3.4. Computational Studies

Intermolecular frameworks for the title compound were generated from the crystal structure (CIF) with Crystalexplorer 21.5 [41] and the corresponding interaction energies calculated for all unique molecular pairs methanol… 2-(1H-imidazol-2-yl)-2,3-dihydro-1H-perimidine using experimental crystal geometries; energies were calculated at CE- B3LYP … B3LYP/6-31G(d,p) level [42] using Tonto [43].

4. Conclusions

2-(1H-Imidazol-2-yl)-2,3-dihydro-1H-perimidine was obtained in high yield by condensation between 1,8-diaminonaphthalene and imidazole-2-carbaldehyde. The product was isolated by simple filtration and characterized by 1D and 2D NMR, IR, and HRMS spectra. The single crystal XRD indicates that the compound crystallizes in the monoclinic P21/c space group. It was found that the product forms stable 1:1 solvate both in solution and solid state. DSC revealed that the methanol molecule leaves the crystal structure in the temperature interval 60–110 °C without phase transition and the energy of its release was theoretically estimated to be around 35 kJ/mol.

Supplementary Materials

The following supporting information can be downloaded online, Figure S1: Comparison of powder diffractogram (red) and calculated (blue) from single crystal data for 4ClB:Pro co-crystals; Figure S2: 1H NMR spectrum of 2-(1H-imidazol-2-yl)-2,3-dihydro-1H-perimidine in DMSO-d6; Figure S3: Partial 1H NMR spectrum of 2-(1H-imidazol-2-yl)-2,3-dihydro-1H-perimidine in DMSO-d6; Figure S4: NOESY spectrum of 2-(1H-imidazol-2-yl)-2,3-dihydro-1H-perimidine in DMSO-d6; Figure S5: Partial NOESY spectrum of 2-(1H-imidazol-2-yl)-2,3-dihydro-1H-perimidine in DMSO-d6; Figure S6: 13C NMR spectrum of 2-(1H-imidazol-2-yl)-2,3-dihydro-1H-perimidine in DMSO-d6; Figure S7: HSQC spectrum of 2-(1H-imidazol-2-yl)-2,3-dihydro-1H-perimidine in DMSO-d6; Figure S8: HMBC spectrum of 2-(1H-imidazol-2-yl)-2,3-dihydro-1H-perimidine in DMSO-d6; Figure S9: IR spectrum of 2-(1H-imidazol-2-yl)-2,3-dihydro-1H-perimidine; Figure S10: HRMS spectrum in positive mode (ESI+); Table S1: The most important data collection and crystallographic refinement parameters.

Author Contributions

The conceptualization belongs to S.B. and V.K. The synthetic experiments and NMR analyses were carried out by V.K. The ESI HR-MS spectra were conducted by Z.P. The DSC, TGA single crystal and powder XRD were performed by R.R. and B.S. The calculations were determined by B.S. All authors contributed to the discussion of the results and in the manuscript writing. All authors have read and agreed to the published version of the manuscript.

Funding

This research is funded by the Bulgarian National Science Fund, project DN 19/11.

Data Availability Statement

Not applicable.

Acknowledgments

The financial support by the Bulgarian National Science Fund, project DN 19/11 from 10 December 2017, is gratefully acknowledged.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are not available from the authors.

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Figure 1. Representatives of 2,3-dihydro-1H-perimidine derivatives showing various applications.
Figure 1. Representatives of 2,3-dihydro-1H-perimidine derivatives showing various applications.
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Scheme 1. Synthesis of 2-(1H-imidazol-2-yl)-2,3-dihydro-1H-perimidine.
Scheme 1. Synthesis of 2-(1H-imidazol-2-yl)-2,3-dihydro-1H-perimidine.
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Figure 2. Thermal analysis of the title compound. (a) DSC thermogram of the title compound disclosing two endothermic effects associated with the release of methanol (60–110 °C) and (b) TGA data reveling a weight loss of ~13% corresponding to methanol molecule.
Figure 2. Thermal analysis of the title compound. (a) DSC thermogram of the title compound disclosing two endothermic effects associated with the release of methanol (60–110 °C) and (b) TGA data reveling a weight loss of ~13% corresponding to methanol molecule.
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Figure 3. A representation of the molecules present in the asymmetric unit of the title compound along with the employed numbering scheme; atomic displacement parameters (ADP) are at 50% probability level, hydrogen atoms are shown as small spheres with arbitrary radii.
Figure 3. A representation of the molecules present in the asymmetric unit of the title compound along with the employed numbering scheme; atomic displacement parameters (ADP) are at 50% probability level, hydrogen atoms are shown as small spheres with arbitrary radii.
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Figure 4. Observed hydrogen bonding interactions stabilizing the crystal packing in the title compound.
Figure 4. Observed hydrogen bonding interactions stabilizing the crystal packing in the title compound.
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Figure 5. 1H NMR spectra of 2-(1H-imidazol-2-yl)-2,3-dihydro-1H-perimidine (down) and 2-(1H-imidazol-2-yl)-1H-perimidine (up) in DMSO-d6.
Figure 5. 1H NMR spectra of 2-(1H-imidazol-2-yl)-2,3-dihydro-1H-perimidine (down) and 2-(1H-imidazol-2-yl)-1H-perimidine (up) in DMSO-d6.
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Table
Table 1. Observed hydrogen bonding interactions in the title compound.
Table 1. Observed hydrogen bonding interactions in the title compound.
DHAd(D-H)/Åd(H-A)/Åd(D-A)/ÅD-H-A/°
O19H19N40.89(3)1.84(3)2.731(2)175(3)
N1H1N710.94(3)2.13(3)3.035(3)162(2)
N7H7O1920.81(2)2.19(2)3.005(2)177(2)
N17H17O1930.87(3)2.19(3)3.047(3)170(2)
11-x,2-y,1-z; 21-x,1/2+y,3/2-z;31-x,1-y,1-z
Table
Table 2. Interaction energies (kJ/mol) computed using single crystal geometries.
Table 2. Interaction energies (kJ/mol) computed using single crystal geometries.
RElectron DensityEeleEpolEdisErepEtot
O19H19…N44.99B3LYP/6-31G(d,p)−62.3−14.6−11.684.5−34.6
N17H17…O194.63B3LYP/6-31G(d,p)−21.4−5.3−15.126.5−23.3
N7H7…O194.60B3LYP/6-31G(d,p)−28.0−6.5−16.532.5−28.7
N1H1…N75.23B3LYP/6-31G(d,p)−70.1−16.8−60.690.7−83.2
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Petkova, Z.; Rusew, R.; Bakalova, S.; Shivachev, B.; Kurteva, V. 2-(1H-Imidazol-2-yl)-2,3-dihydro-1H-perimidine. Molbank 2023, 2023, M1587. https://doi.org/10.3390/M1587

AMA Style

Petkova Z, Rusew R, Bakalova S, Shivachev B, Kurteva V. 2-(1H-Imidazol-2-yl)-2,3-dihydro-1H-perimidine. Molbank. 2023; 2023(1):M1587. https://doi.org/10.3390/M1587

Chicago/Turabian Style

Petkova, Zhanina, Rusi Rusew, Snezhana Bakalova, Boris Shivachev, and Vanya Kurteva. 2023. "2-(1H-Imidazol-2-yl)-2,3-dihydro-1H-perimidine" Molbank 2023, no. 1: M1587. https://doi.org/10.3390/M1587

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