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. 2025 Sep 19;10(38):43719–43734. doi: 10.1021/acsomega.5c03898

Improved Syntheses, Crystal Structures Analysis, DFT Calculation, Anticancer and Antibacterial Properties of Some 4‑(Benzylamino)benzoic Acid Derivatives

Ahmed K Hijazi †,‡,*, Qusai M Sarayrah ‡, Abdelrahman W Malkawi ‡, Hassan Abul-Futouh §, Ziyad A Taha ‡, Deeb Taher ∥, Osama H Abusara ⊥, Ahmad Q Daraosheh †, Ahmad A L Ahmad #,, Waleed M Al-Momani ∇
PMCID: PMC12489855  PMID: 41048799

Abstract

A series of 4-(benzylamino)­benzoic acid derivatives ArCH2NH-4-C6H4CO2H (1–19) (Ar = C6H5 (1); 4–Cl–C6H4 (2); 4-NMe-C6H4 (3); 4–Br–C6H4 (4); 3-NO2–C6H4 (5); 4-NO2–C6H4 (6); 2-OMe-C6H4 (7); 3-OMe-C6H4 (8); 4-OMe-C6H4 (9); 2,3-OMe-C6H3 (10); 3,4-OMe-C6H3 (11); 2-OH, 3-OMe-C6H3 (12); 3-OMe, 4-OH-C6H3 (13); 3,5-OMe, 4-OH-C6H4 (14); 2-OH-5–Br–C6H3 (15), 3-OH-C6H4 (16); 4-SMe-C6H4 (17); 2,3-OH-C6H3 (18); 3-CF3–C6H4 (19)) were synthesized via reductive amination of p-aminobenzoic acid with substituted benzaldehydes and sodium borohydride. The structures were confirmed by MS, FT-IR, NMR, and E.A., with single-crystal X-ray diffraction elucidating key intermolecular interactions in compounds 2, 4, 7–9 and 11. Hirshfeld surface analysis and 2D fingerprint plots highlighted noncovalent interactions contributing to crystal packing. DFT calculations (PBE0/def2-TZVP/CPCM) provided optimized geometries, HOMO–LUMO gaps, and electrostatic surface potentials. TD-DFT simulations supported experimental UV–vis spectra. Several derivatives (2, 3, 5, 7, 8, 10, 11, 13–16) showed moderate antibacterial activity (MIC = 64–128 μg/mL) against different strains of bacteria, while compound 18 exhibited promising anticancer activity with IC50 values of 90.69 μM against Non-Small Cell Lung Cancer cell line (A549) and 32.22 μM against Small Cell Lung Cancer cell line (H69).

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1. Introduction

One of the main objectives of contemporary science is to promote the quality of life for all creatures. This primarily entails the creation of novel drugs and improving the methods for synthesizing already-existing pharmaceuticals in a medicinal context. Due to the presence of the amino group in many natural and agricultural products, − amine compounds are significantly important in pharmaceutical, chemical, and biological production. − Many different ways to produce amines include: (I) reduction of imine, nitriles, amides, nitro groups. (II) nucleophilic substitution reactions: Gabriel Synthesis, Hofmann rearrangement, Curtius Rearrangement.

Reductive aminations (RA) constitute a significant class of reactions widely applied in research laboratories and industries for the synthesis of amines as well as pharmaceuticals, agrochemicals, and biomolecules. − According to researchers 25% of the formation of a bond between carbon and nitrogen in drug industry takes place via reductive amination between carbonyls (aldehyde/ketones) with amines, which represent a highly efficient and facile pathway to amine synthesis, because it is a suitable synthetic procedure, selective production of unsymmetrically substituted secondary, tertiary amines, and broad substance scope.

Para-aminobenzoic acid (PABA) belongs to the vitamins B group (vitamin B10). Furthermore, PABA well-known in biochemistry, as it synthesized by yeasts, plants, and some bacteria. As known, it is necessary for the synthesis of folic acid. In mammals and humans, PABA is not synthesized but formed by some bacteria, such as (Escherichia coli) in the human intestinal tract. Moreover, in medicinal chemistry, PABA was one of the main biologically active constituents to be utilized in sunscreen, as Patented in 1943. The initial in vivo experiment on mice demonstrated that PABA lessened UV damage and, in addition, ensured against skin cancer in rodents. ,

This report presents an optimized procedure, based on literature methods, for the synthesis and spectroscopic characterization of 4-(benzylamino)­benzoic acid derivatives. − Additionally, the crystal structures of six of these compounds are presented. DFT calculations were employed to predict the geometrical structures, and computational studies were conducted to explore the bonding interactions including anagostic interactions within the compounds. The structures of these compounds are illustrated in Scheme . The biological activities of these compounds were explored against different strains of bacteria, A549 (Non-Small Cell Lung Cancer cell line) and H69 (Small Cell Lung Cancer cell line).

1. Synthesis of 1–19; (i) 4-Aminobenzoic Acid (1 equiv), Substituted Benzaldehyde (1 equiv), Methanol, About 5–10 min; (ii) 1–19 (1 equiv), NaBH4 (1.5 equiv), Methanol, Ambient Temperature About 5 min.

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2. Experimental Section

2.1. General

All solvents and commercial reagents (p-amino benzoic acid, benzaldehyde, p-chlorobenzaldehyde, p-bromobenzaldehyde, p-dimethylaminobenzaldehyde, m-nitrobenzaldehyde, p-nitrobenzaldehyde, 5-bromo-2-hydroxybenzaldehyde, and m-hydroxybenzaldehyde, o-methoxy-benzaldehyde, m-methoxy-benzaldehyde, p-methoxy-benzaldehyde, 2,3-dimethoxy-benzaldehyde, 3,4-dimethoxy-benzaldehyde, 4-hydroxy-3-methoxybenzaldehyde, 2-hydroxy-3-methoxy-benzaldehyde, 4-hydroxy-3,5-dimethoxy-benzaldehyde, 4-methylthio-benzaldehyde, 2,3-dihydroxy-benzaldehyde, and 3-trifloromethyl-benzaldehyde) were purchased from Sigma-Aldrich and used as received without purification.

2.2. Instruments

TLC was performed on Merck silica gel 60 F254. NMR spectra were recorded on a Bruker-Avance 400 MHz spectrometer. The residual solvent protons (1H) or the solvent carbon (13C) were used as internal standards. 1H NMR data are presented as follows: chemical shift in ppm (δ). The following abbreviations are used in reporting NMR data: s, singlet; d, doublet; t, triplet; dd, doublet of doublets; m, multiplet. ATR-FTIR spectra of the resulting compounds were recorded on a Bruker Vertex 70-FT-IR spectrometer at room temperature coupled with a Vertex Pt-ATR accessory, in the range of 4000–400 cm–1 at room temperature with 4 cm–1 resolutions. A UV-1800 UV–visible spectrophotometer (Shimadzu Corporation) was used to obtain UV–visible spectra at 25 °C in DMSO solution with a concentration of 5 × 10–5 M. High-Resolution Mass Spectra were recorded on SHIMADZU LC MSMS 8050With UHPLC 2060C.

2.3. Single-Crystal X-ray Diffraction Measurements (SC-XRD)

SC-XRD data for compounds 2, 4, 7–9, and 11 were collected using a Bruker D8 QUEST ECO diffractometer equipped with a sealed tube source (Mo Kα, λ = 0.71073 Å) operating at 50 mV/20 mA and a Photon 50 detector. Suitable crystals were mounted using a dual-thickness MiTeGen Micro Loop. The crystals were maintained at 296 K during data collection. Cell parameters were determined and refined using all observed reflections. Structures were then solved by direct methods with the APEX 3 software suite, followed by further refinement using the Olex2 (V1.2.10) program, in conjunction with the SHELXL refinement package.

2.4. Hirshfeld Surfaces

Hirshfeld surfaces of 2, 4, 7–9, and 11 and their associated 2D fingerprint plots were generated using CrystalExplorer17.5 program and were analyzed to identify the most relevant intermolecular interactions. The Hirshfeld surfaces were mapped over the normalized contact distance (d norm). The Hirshfeld surface colors are used to visualize the interatomic contacts as longer than vdW contacts (blue), equal to vdW (white), and shorter than vdW (red). The colors of the points on the 2-D fingerprint plots correspond to the frequency of the d e and d i combinations on the Hirshfeld surface.

2.5. Computational

All calculations and geometry optimizations of 1–19 were performed using a variety of softwares: ORCA code version 4.2.0., the hybrid GGA functional called PBE0 and the Ahlrichs triple-ζ def3-TZVP basis set. The effect of DMSO was considered using the conductor-like polarizable continuum model (CPCM). The vertical electronic excitations based were computed using the Time-Dependent Density Functional Theory (TD-DFT) formalism in DMSO applying the CPCM solvation model using the hybrid Coulomb-Attenuating Method B3LYP (CAM-B3LYP) functional and the def2-TZVP basis set. Gabedit program was used to compute the isosurface densities of the orbitals.

2.6. Cell Subculture and Growth Conditions

Dulbecco’s Modified Eagle Medium (DMEM), Roswell Park Memorial Institute (RPMI)-1640 Medium (RPMI), and Dulbecco’s Phosphate Buffered Saline (PBS) were purchased from Euroclone. Heat inactivated Fetal Bovine Serum (FBS) was purchased from Capricorn Scientific. Three different types of cell lines were purchased from ATCC. HGF cells were grown in 10% FBS/DMEM, while A549 and H69 cells were grown in 10% FBS/R. Cells were incubated at 310 K in humidified air atmosphere of 5% CO2. HGF and A549 cells washed with PBS and supplemented with fresh complete media to maintain their growth. H69 cells are suspended cells and complete media was continuously changed during splitting.

2.7. Cell Viability Assays Using Resazurin Dye Method

Resazurin sodium salt was purchased from Sigma-Aldrich. Compounds 1–19 were synthesized by our group. The cell viability assays were conducted as described in literature. ,

2.8. Antibacterial Activity

The antibacterial activities were tested by evaluating the antibacterial behavior of the synthesized 4-(benzyl)­amino)­benzoic acid derivatives against six different pathogenic bacteria, which were obtained from the Ministry of Health-Jordan, using two different methods: the agar diffusion method and the microbroth dilution method to determine the Minimum Inhibitory Concentration (MIC, μg/mL) as reported previously. ,

2.9. General Procedure for Reductive Amination Reaction between 4-Aminobenzoic Acid and Benzaldehyde Derivatives to Produce 4-(Benzylamino)­Benzoic Acid Derivatives

The 4-(benzylamino) benzoic acid derivatives were synthesized by the reductive amination reaction as shown in Scheme . P-Aminobenzoic acid (1 g, 7.29 mmol) was reacted with benzaldehyde, (0.77 g, 7.29 mmol) in 5–10 mL solution of methanol. After about 5–10 min, the imine precipitated as a colored powder. Thereafter, sodium borohydride (0.41 g, 10.9 mmol) was added in small portions, the precipitate dissolved, and the color faded after about 5 min. After that, a solution of 10% HCl (ca. 20 mL) was added until 4-(benzylamino)­benzoic acid precipitated as powder. The product was filtered off, washed several times with distilled water and cold ethanol, and dried in the lab atmosphere. All other derivatives were prepared in the same manner.

2.9.1. Synthesis of 4-(Benzylamino)­benzoic Acid (1)

White Solid. Yield: 0.98 g (4.31 mmol, 98%). FT–IR (ATR, ν, cm–1): 2536–3100 (COOH), 3422 (NH), 1655 (CO). 1H NMR: (DMSO-d 6, 400 MHz): δ 11.98 (s, 1H, COOH), 7.64 (d, J = 8.51 Hz, 2H, Ar–H), 7.34 (m, 4H, Ar–H), 7.24 (m, 1H, Ar–H), 7.03 (t, J = 5.98 Hz, 1H, NHCH2), 6.60 (m, 2H, Ar–H), 4.33 (d, J = 5.99 Hz, 2H, HNCH 2). 13C NMR: (DMSO-d 6,101 MHz): δ 167.42 (1C, COOH), 152.39 (1C, Ar–C), 139.43 (1C, Ar–C), 131.04 (2C, Ar–CH), 128.34 (2C, Ar–CH), 127.14 (2C, Ar–CH), 126.78 (1C, Ar–CH), 117.21 (1C, Ar–C), 111.15 (2C, Ar–CH), 45.89 (1C, CH 2NH). Anal. Calcd for C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C, 73.84; H, 5.84; N, 6.20. λmax: 305 nm, εmax: 21325. MS m/z: calcd for C14H14NO2 [M + H]+, 227.10; found, 228.00.

2.9.2. Synthesis of 4-((4-Chlorobenzyl)­amino)­benzoic Acid (2)

White Solid. Yield: 0.95 g (3.63 mmol, 95%). FT–IR (ATR, ν, cm–1): 2514–3000 (COOH), 3416 (NH), 1651 (CO). 1H NMR: (DMSO-d 6, 400 MHz): δ 11.82 (s, 1H, COOH), 7.64 (d, J = 8.55 Hz, 2H, Ar–H), 7.36 (m, 4H, Ar–H), 7.04 (t, J = 5.80 Hz, 1H, NHCH2), 6.57 (d, J = 8.60 Hz, 2H, Ar–H), 4.32 (d, J = 5.90 Hz, 2H, HNCH 2). 13C NMR: (DMSO-d 6, 101 MHz): δ 167.47­(1C, COOH), 152.21 (1C, Ar–C), 138.61 (1C, Ar–C), 131.34 (1C, Ar–C–Cl), 131.12 (2C, Ar–CH), 128.99 (2C, Ar–CH), 128.34 (2C, Ar–CH), 117.47 (1C, Ar–C), 111.27 (2C, Ar–CH), 45.19 (1C, CH 2NH). Anal. Calcd for C14H12ClNO2: C, 64.25; H, 4.62; N, 5.35. Found: C, 64.46; H, 4.83; N, 5.36. λmax: 304 nm, εmax: 22200. MS m/z: calcd for C14H13ClNO2 [M + H]+, 261.06; found, 262.00.

2.9.3. Synthesis of 4-((4-(Dimethylamino)­benzyl)­amino)­benzoic Acid (3)

White Solid. Yield: 0.88 g (3.25 mmol, 88%). FT–IR (ATR, ν, cm–1): 2479–3111 (COOH), 3400 (NH), 1693 (CO). 1H NMR: (DMSO-d 6, 400 MHz): δ 11.99 (s, 1H, COOH), 7.63 (d, J = 7.62 Hz, 2H, Ar–H), 7.27 (d, J = 7.26 Hz, 2H, Ar–H), 6.95 (t, J = 6.93 Hz, 1H, NHCH2), 6.90 (d, J = 6.89 Hz, 2H, Ar–H), 6.59 (d, J = 6.58 Hz, 2H, Ar–H), 4.25 (d, J = 4.24 Hz, 2H, HNCH 2), 2.86 (s, 6H, N­(CH3) 2). 13C NMR: (DMSO-d 6, 101 MHz): δ 167.81­(1C, COOH), 152.32 (1C, Ar–C), 149.60 (1C, Ar–C), 130.95 (2C, Ar–CH), 128.14 (2C, Ar–CH), 127.47 (1C, Ar–C), 126.64 (1C, Ar–C), 112.47 (2C, Ar–CH), 111.08 (2C, Ar–CH), 45.57 (1C, CH 2NH), 40.28 (2C, N(CH3) 2). Anal. Calcd for C16H18N2O2: C, 71.09; H, 6.71; N, 10.36. Found: C, 69.9; H, 6.66; N, 10.30. λmax: 307 nm, εmax: 10200. MS m/z: calcd for C16H19N2O2 [M + H]+, 270.14; found, 271.25.

2.9.4. Synthesis of 4-((4-Bromobenzyl)­amino)­benzoic Acid (4)

White Solid. Yield: 0.91 g (2.97 mmol, 91%). FT–IR (ATR, ν, cm–1): 2515–3100 (COOH), 3422 (NH), 1653 (CO). 1H NMR: (DMSO-d 6, 400 MHz): δ 12.01 (s, 1H, COOH), 7.63 (d, J = 8.72 Hz, 2H, Ar–H), 7.50 (d, J = 8.35 Hz, 2H, Ar–H), 7.28 (d, J = 8.33 Hz, 2H, Ar–H), 7.05 (t, J = 6.05 Hz, 1H, NHCH2), 6.56 (d, J = 8.76 Hz, 2H, Ar–H), 4.30 (d, J = 5.86 Hz, 2H, HNCH 2). 13C NMR: (101 MHz, DMSO-d 6): δ 167.37 (1C, COOH), 152.15 (1C, Ar–C), 139.00­(1C, Ar–C), 131.19 (2C, Ar–CH), 131.05 (2C, Ar–CH), 129.31 (2C, Ar–CH), 119.72 (1C, Ar–C–Br), 117.40 (1C, Ar–C), 111.20 (2C, Ar–CH), 45.18 (1C, CH 2NH). Anal. Calcd for C14H12BrNO2: C, 54.92; H, 3.95; N, 4.58. Found: C, 54.75; H, 4.02; N, 4.65. λmax: 304 nm, εmax: 10700. MS m/z: calcd for C14H13BrNO2 [M + H]+, 305.01; found, 306.20.

2.9.5. Synthesis of 4-((3-Nitrobenzyl)­amino)­benzoic Acid (5)

Yellow Solid. Yield: 0.96 g (3.53 mmol, 96%). FT–IR (ATR, ν, cm–1): 2600–3150 (COOH), 3330 (NH), 1605 (CO). 1H NMR: (DMSO-d 6, 400 MHz): δ 12.11 (s, 1H, COOH), 8.19 (s, 1H, Ar–H), 8.09 (dd, J = 8.13 Hz, 1H, Ar–H), 7.80 (dd, J = 7.69 Hz, 1H, Ar–H), 7.64 (m, 3H, Ar–H), 7.18 (t, J = 6.20 Hz, 1H, NHCH2), 6.60 (d, J = 8.71 Hz, 2H, Ar–H), 4.49 (d, J = 6.17 Hz, 2H, HNCH 2). 13C NMR: (DMSO-d 6,, 101 MHz): δ 167.38 (1C, COOH), 151.96 (1C, Ar–C), 147.94 (1C, Ar–C–NO2), 142.31 (1C, Ar–C), 133.85 (1C, Ar–CH), 131.14 (2C, Ar–CH), 129.92 (1C, Ar–CH), 121.85 (1C, Ar–CH), 121.59 (1C, Ar–CH), 117.72 (1C, Ar–C), 111.32 (2C, Ar–CH), 45.01 (1C, CH 2NH). Anal. Calcd C14H12N2O4 for: C, 61.67; H, 4.44; N, 10.29. Found: C, 61.76; H, 4.41; N, 10.35. λmax: 300 nm, εmax: 20825. MS m/z: calcd for C14H13N2O4 [M + H]+, 272.08; found, 273.00.

2.9.6. Synthesis of 4-((4-Nitrobenzyl)­amino)­benzoic Acid (6)

Yellow Solid. Yield: 0.91 g (3.34 mmol, 91%). FT–IR (ATR, ν, cm–1): 2500–3310 (COOH), 3410 (NH), 1604 (CO). 1H NMR: (DMSO-d 6, 400 MHz): δ 12.06 (s, 1H, COOH), 8.20 (d, J = 8.31 Hz, 2H, Ar–H), 7.66 (d, J = 8.37 Hz, 2H, Ar–H), 7.60 (d, J = 8.42 Hz, 2H, Ar–H), 7.20 (t, J = 6.10 Hz, 1H, NHCH2), 6.59 (d, J = 8.48 Hz, 2H, Ar–H), 4.51 (d, J = 5.93 Hz, 2H, HNCH 2). 13C NMR: (101 MHz, DMSO-d 6): δ 167.33 (1C, COOH), 151.95 (1C, Ar–C), 148.02 (1C, Ar–C), 146.49 (1C, Ar–C–NO2), 131.09 (2C, Ar–CH), 128.03 (2C, Ar–CH), 123.52 (2C, Ar–CH), 117.72 (1C, Ar–C), 111.27 (2C, Ar–CH), 45.30 (1C, CH 2NH). Anal. Calcd for C14H12N2O4: C, 61.67; H, 4.44; N, 10.29. Found: C, 61.70; H, 4.40; N, 10.31. λmax: 302 nm, εmax: 30700. MS m/z: calcd for C14H13N2O4 [M + H]+, 272.08; found, 273.10.

2.9.7. Synthesis of 4-((2-Methoxybenzyl)­amino)­benzoic Acid (7)

White Solid. Yield: 0.96 g (3.73 mmol, 96%). FT–IR (ν, cm–1): 2515–3100 (COOH), 3422 (NH), 1653 (CO). 1H NMR: (DMSO-d 6, 400 MHz): δ 11.97 (s, 1H,, COOH), 7.67 (d, J = 8.54 Hz, 2H, Ar–H), 7.27 (m, 2H, Ar–H), 7.02 (d, J = 8.11 Hz, 1H, Ar–H), 6.92 (t, J = 7.39 Hz, 1H, NHCH2), 6.88 (dd, J = 6.86 Hz, 1H, Ar–H), 6.59 (d, J = 8.59 Hz, 2H, Ar–H), 4.30 (d, J = 5.56 Hz, 2H, HNCH 2), 3.85 (s, 3H, OCH 3). 13C NMR: (DMSO-d 6,101 MHz): δ 167.40 (1C, COOH), 156.87 (1C, Ar–C–OCH3), 152.48 (1C, Ar–C), 131.04 (2C, Ar–CH), 128.03 (1C, Ar–CH), 127.74 (1C, Ar–C), 126.49 (1C, Ar–CH), 120.11 (1C, Ar–CH), 116.99 (1C, Ar–C), 110.92 (2C, Ar–CH), 110.58 (2C, Ar–CH), 55.29 (1C, OCH 3), 40.79 (1C, CH 2NH). Anal. Calcd for C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found: C, 70.05; H, 5.91; N, 5.50. λmax: 305 nm, εmax: 19725. MS m/z: calcd for C15H16NO3 [M + H]+, 257.11; found, 258.10.

2.9.8. Synthesis of 4-((3-Methoxybenzyl)­amino)­benzoic Acid (8)

White Solid. Yield: 0.96 g (3.73 mmol, 96%). FT–IR (ν, cm–1): 2479–3111 (COOH), 3400 (NH), 1693 (CO).1HNMR: (DMSO-d 6, 400 MHz): δ 12.00 (s, 1H, COOH), 7.65 (d, J = 8.74 Hz, 2H, Ar–H), 7.24 (t, J = 8.09 Hz, 1H, NHCH2), 7.02 (dd, J = 5.99 Hz, 1H, Ar–H), 6.92 (m, 3H, Ar–H), 6.59 (d, J = 8.77 Hz, Ar–H), 4.30 (d, J = 5.90 Hz, 2H, HNCH 2), 3.72 (s, 3H, OCH 3). 13C NMR: (DMSO-d 6, 101 MHz): δ 167.39 (1C, COOH), 159.37 (1C, Ar–C–OCH3), 152.37 (1C, Ar–C), 141.12 (1C, Ar–C), 131.01 (2C, Ar–CH), 129.39 (1C, Ar–CH), 119.27 (1C, Ar–CH), 117.21 (1C, Ar–C), 112.84 (2C, Ar–CH), 112.04 (1C, Ar–CH), 111.16 (1C, Ar–CH), 54.92 (1C, OCH 3), 45.82 (1C, CH 2NH). Anal. Calcd for C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found: C, 69.99; H, 5.90; N, 5.47. λmax: 305 nm, εmax: 17475. MS m/z: calcd for C15H16NO3 [M + H]+, 257.11; found, 258.10.

2.9.9. Synthesis of 4-((4-Methoxybenzyl)­amino)­benzoic Acid (9)

White Solid. Yield: 0.86 g (3.34 mmol, 86%). FT–IR (ν, cm–1): 2500–3310 (COOH), 3410 (NH), 1604 (CO). 1H NMR: (DMSO-d 6, 400 MHz): δ 11.99 (s, 1H, COOH), 7.64 (d, J = 8.70 Hz, 2H, Ar–H), 7.26 (d, J = 8.58 Hz, 2H, Ar–H), 6.95 (t, J = 5.86 1H, NHCH2), 6.89 (d, J = 8.67 Hz, 2H, Ar–H), 6.58 (d, J = 8.77 Hz, 2H, Ar–H), 4.25 (d, J = 5.76 Hz, 2H, HNCH 2), 3.72 (s, 3H, OCH 3). 13C NMR: (DMSO-d 6, 101 MHz): δ 167.43 (1C, COOH), 158.21 (1C, Ar–C–OCH3), 152.37 (1C, Ar–C), 131.15 (1C, Ar–C), 130.99 (2C, Ar–CH), 128.41 (2C, Ar–CH), 117.10 (1C, Ar–C), 113.76 (2C, Ar–CH), 111.13 (2C, Ar–CH), 55.00 (1C, OCH 3), 45.34 (1C, CH 2NH). Anal. Calcd for C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found: C, 70.07; H, 5.83; N, 5.50. λmax: 305 nm, εmax: 18375. MS m/z: calcd for C15H16NO3 [M + H]+, 257.11; found, 258.10.

2.9.10. Synthesis of 4-((2,3-Dimethoxybenzyl)­amino)­benzoic Acid (10)

White Solid. Yield: 0.96 g (3.34 mmol, 96%). FT–IR (ν, cm–1): 2536–3100 (COOH), 3422 (NH), 1655 (CO). 1H NMR: (DMSO-d 6, 400 MHz): δ 11.98 (s, 1H, COOH), 7.65 (d, J = 8.76 Hz 2H, Ar–H), 7.02 (m, 2H, Ar–H), 6.89 (m, 2H, Ar–H, and NHCH2), 6.59 (d, J = 8.80 Hz, 2H, Ar–H), 4.31 (d, J = 5.86 Hz, 2H, HNCH 2), 3.80 (s, 3H, OCH 3), 3.77 (s, 3H, OCH 3). 13C NMR: (101 MHz, DMSO-d 6): δ 167.41 (1C, COOH), 152.39 (1C, Ar–C–OCH3), 152.31 (1C, Ar–C–OCH3), 146.46 (1C, Ar–C), 132.42 (1C, Ar–C), 131.05 (2C, Ar–CH), 123.76 (1C, Ar–CH), 120.00 (1C, Ar–CH), 117.08 (1C, Ar–C), 111.75 (1C, Ar–CH), 110.96 (2C, Ar–CH), 60.13 (1C, OCH 3), 55.63 (1C, OCH 3), 40.74 (1C, CH 2NH). Anal. Calcd for C16H17NO4: C, 66.89; H, 5.96; N, 4.88. Found: C, 66.87; H, 5.97; N, 4.91. λmax: 305 nm, εmax: 31250. MS m/z: calcd for C16H18NO4 [M + H]+, 287.12; found, 288.20.

2.9.11. Synthesis of 4-((3,4-dimethoxybenzyl)­amino)­benzoic Acid (11)

White Solid. Yield: 0.91 g (3.17 mmol, 91%). FT–IR (ν, cm–1): 2600–3150 (COOH), 3330 (NH), 1605 (CO). 1H NMR: (DMSO-d 6, 400 MHz): δ 11.98 (s, 1H, COOH), 7.64 (d, J = 8.62 Hz, 2H, Ar–H), 6.96 (m, 4H, Ar–H), 6.60 (d, J = 8.64 Hz, 2H, Ar–H, and NHCH2), 4.24 (d, J = 5.74 Hz, 2H, HNCH 2), 3.73 (s, 3H, OCH 3), 3.71 (s, 3H, OCH 3). 13C NMR: (DMSO-d 6,, 101 MHz): δ 167.49 (1C, COOH), 152.46 (1C, Ar–C–OCH3), 148.77 (1C, Ar–C–OCH3), 147.77 (1C, Ar–C), 131.68 (1C, Ar–C), 131.03 (2C, Ar–CH) 119.26 (1C, Ar–CH), 117.11 (1C, Ar–CH), 111.77 (1C, Ar–CH), 111.26 (2C, Ar–CH), 111.21 (1C, Ar–CH), 55.53 (1C, OCH 3), 55.43 (1C, OCH 3), 45.78 (1C, CH 2NH). Anal. Calcd C16H17NO4: C, 66.89; H, 5.96; N, 4.88. Found: C, 66.91; H, 5.92; N, 4.90. λmax: 305 nm, εmax: 18675. MS m/z: calcd for C16H18NO4 [M + H]+, 287.12; found, 288.20.

2.9.12. Synthesis of 4-((2-Hydroxy-3-methoxybenzyl)­amino)­benzoic Acid (12)

White Solid. Yield: 0.89 g (3.26 mmol, 89%). FT–IR (ν, cm–1): 2600–3200 (COOH), 3386 (NH), 3322 (OH), 1670 (CO). 1H NMR: (DMSO-d 6, 400 MHz): δ 11.95 (s, 1H, COOH), 8.75 (s, 1H, Ar–C–OH), 7.63 (d, J = 8.68 Hz, 2H, Ar–H), 6.85 (m, 4H, Ar–H), 6.57 (d, J = 8.71 Hz, 2H, Ar–H, and NHCH2), 4.25 (d, J = 5.84 Hz, 2H, HNCH 2), 3.73 (s, 3H, OCH 3), 3.71 (s, 3H, OCH 3). 13C NMR: (101 MHz, DMSO-d 6): δ 167.50 (1C, COOH), 152.60 (1C, Ar–C–OCH3), 147.32 (1C, Ar–C–OH), 143.87 (1C, Ar–C), 131.07 (2C, Ar–CH), 125.53­(1C, Ar–C), 120.08 (1C, Ar–C), 118.63 (1C, Ar–C), 116.87 (1C, Ar–CH), 110.95 (1C, Ar–CH), 110.42 (2C, Ar–CH), 55.81 (1C, OCH 3), 40.73 (1C, CH 2NH). Anal. Calcd for C15H15NO4: C, 65.92; H, 5.53; N, 5.13. Found: C, 65.86; H, 5.58; N, 5.09. λmax: 305 nm, εmax: 11600. MS m/z: calcd for C15H16NO4 [M + H]+, 273.10; found, 274.00.

2.9.13. Synthesis of 4-((4-Hydroxy-3-methoxybenzyl)­amino)­benzoic Acid (13)

White Solid. Yield: 0.95 g (3.48 mmol, 95%). FT–IR (ν, cm–1): 2600–3200 (COOH), 3386 (NH), 3322 (OH), 1670 (CO). 1H NMR: (DMSO-d 6, 400 MHz): δ 11.96 (s, 1H, COOH), 8.75 (s, 1H, Ar–C–OH), 7.64 (d, J = 8.68 Hz, 2H, Ar–H), 6.86 (m, 3H, Ar–H), 6.77 (t, J = 6.73 Hz, 1H, HNCH2), 6.57 (d, J = 8.71 Hz, 2H, Ar–H), 4.26 (d, J = 5.84 Hz, 2H, HNCH 2), 3.80 (s, 3H, OCH 3). 13C NMR: (DMSO-d 6, 101 MHz): δ 167.95 (1C, COOH), 153.05 (1C, Ar–C–OCH3), 147.78 (1C, Ar–C), 144.32 (1C, Ar–C–OH), 131.52 (2C, Ar–CH), 125.98 (1C, Ar–C), 120.54 (1C, Ar–CH), 119.08 (1C, Ar–CH), 117.33 (1C, Ar–C), 111.40 (2C, Ar–CH), 110.88 (1C, Ar–CH), 56.87 (1C, OCH 3), 40.73 (1C, CH 2NH). Anal. Calcd for C15H15NO4: C, 65.92; H, 5.53; N, 5.13. Found: C, 65.88; H, 5.49; N, 5.13. λmax: 305 nm, εmax: 14825. MS m/z: calcd for C15H16NO4 [M + H]+, 273.10; found, 274.00.

2.9.14. Synthesis of 4-((4-Hydroxy-3,5-dimethoxybenzyl)­amino)­benzoic Acid (14)

White Solid. Yield: 0.82 g (2.70 mmol, 82%). FT–IR (ν, cm–1): 2516–3016 (COOH), 3353 (NH), 3152 (OH), 1679 (CO). 1H NMR: (DMSO-d 6, 400 MHz): δ 12.03 (s, 1H, COOH), 8.20 (s, 1H, Ar–C–OH), 7.65 (d, J = 8.66 Hz, 2H, Ar–H), 6.86 (t, J = 5.66 Hz, 1H, HNCH), 6.63 (d, J = 6.61 Hz, 4H, Ar–H), 4.19 (d, J = 5.63 Hz, 2H, HNCH 2), 3.72 (s, 6H, OCH 3). 13C NMR: (DMSO-d 6, 101 MHz): δ 167.50 (1C, COOH), 152.52 (1C, Ar–C), 147.99 (2C, Ar–C–OCH3), 134.45 (1C, Ar–C–OH), 131.03 (2C, Ar–CH), 129.17 (1C, Ar–C), 117.10 (1C, Ar–C), 111.21 (2C, Ar–CH), 104.97 (2C, Ar–CH), 55.97 (2C, OCH 3), 46.32 (1C, CH 2NH). Anal. Calcd for C16H17NO5: C, 63.36; H, 5.65; N, 4.62. Found: C, 63.40; H, 5.62; N, 4.64. λmax: 306 nm, εmax: 14600. MS m/z: calcd for C16H18NO5 [M + H]+, 303.11; found, 304.10.

2.9.15. Synthesis of 4-((5-Bromo-2-hydroxybenzyl)­amino)­benzoic Acid (15)

White Solid. Yield: 0.85 g (2.64 mmol, 85%). FT–IR (ATR, ν, cm–1): 2600–3200 (COOH), 3386 (NH), 3322 (OH), 1670 (CO). 1H NMR: (DMSO-d 6, 400 MHz): δ 10.02 (s, 1H, OH), 7.66 (d, J = 8.73 Hz, 2H, Ar–H), 7.21 (m, 3H, Ar–H and NH), 6.81 (d, J = 8.46 Hz, 1H, Ar–H), 6.57 (d, J = 8.73 Hz, 2H, Ar–H), 4.23 (d, 2H, HNCH 2). 13C NMR: (DMSO-d 6, 101 MHz): δ 167.52 (1C, COOH), 154.47 (1C, Ar–C–OH), 152.28 (1C, Ar–C), 131.24 (2C, Ar–CH), 130.30 (1C, Ar–C), 130.28 (1C, Ar–CH), 128.02 (1C, Ar–CH), 117.40 (1C, Ar–CH), 117.17 (1C, Ar–CH), 111.15 (2C, Ar–CH), 110.12 (1C, Ar–C–Br), 40.48 (1C, CH 2NH). Anal. Calcd for C14H12BrNO3: C, 69.75; H, 5.85; N, 4.40. Found: C, 69.68; H, 5.80; N, 4.37. λmax: 305 nm, εmax: 12500. MS m/z: calcd for C14H13BrNO3 [M + H]+, 321.00; found, 322.00.

2.9.16. Synthesis of 4-((3-Hydroxybenzyl)­amino)­benzoic Acid (16)

White Solid. Yield: 0.80 g (3.29 mmol, 80%). FT–IR (ATR, ν, cm–1): 2516–3016 (COOH), 3353 (NH), 3152 (OH), 1679 (CO). 1H NMR: (DMSO-d 6, 400 MHz): δ 11.98 (s, 1H, COOH), 9.33 (s, 1H, OH), 7.64 (d, J = 8.65 Hz, 2H, Ar–H), 7.11 (dd, J = 7.75 Hz, 1H, Ar–H), 7.00 (t, J = 5.89 Hz, 1H, NHCH2), 6.57 (m, 5H, Ar–H), 4.25 (d, J = 5.98 Hz, 2H, HNCH 2). 13C NMR: (DMSO-d 6, 101 MHz): δ 167.49 (1C, COOH), 157.49 (1C, Ar–C–OH), 152.49 (1C, Ar–C), 140.99 (1C, Ar–C), 131.07 (2C, Ar–CH), 129.36 (1C, Ar–CH), 117.68 (1C, Ar–C), 117.08 (1C, Ar–CH), 113.79 (2C, Ar–CH), 113.76 (1C, Ar–CH), 111.13 (1C, Ar–CH), 46.83 (1C, CH 2NH). Anal. Calcd for C14H13NO3: C, 69.12; H, 5.39; N, 5.76. Found: C, 69.22 1; H, 5.41; N, 5.74. λmax: 305 nm, εmax: 14975. MS m/z: calcd for C14H14NO3 [M + H]+, 243.09; found, 244.10.

2.9.17. Synthesis of 4-((4-(Methylthio)­benzyl)­amino) Benzoic Acid (17)

White Solid. Yield: 0.80 g (2.93 mmol, 80%). FT–IR (ATR, ν, cm–1): 2516–3016 (COOH), 3333 (NH), 1665 (CO). 1H NMR: (DMSO-d 6, 400 MHz): δ 12.06 (s, 1H, COOH), 7.64 (d, J = 8.47 Hz, 2H, Ar–H), 7.27 (d, J = 8.00 Hz, 2H, Ar–H), 7.20 (d, J = 8.00 Hz, 2H, Ar–H) 6.97 (t, J = 5.86 1H, NHCH2), 6.57 (d, J = 8.49 Hz, 2H, Ar–H), 4.27 (d, J = 5.04 Hz, HNCH 2), 2.42 (s, 3H, SCH 3). 13C NMR: (DMSO-d 6, 101 MHz): δ 167.79 (1C, COOH), 152.26 (1C, Ar–C–SCH3), 136.37 (1C, Ar–C), 136.33 (1C, Ar–C), 131.14 (2C, Ar–CH), 127.94 (2C, Ar–CH), 126.25 (2C, Ar–CH), 117.84 (1C, Ar–C), 111.29 (2C, Ar–CH), 48.71 (1C, SCH 3), 45.52 (1C, CH 2NH). Anal. Calcd for C15H15NO2S: C, 65.91; H, 5.53; N, 5.12. Found: C, 65.88; H, 5.50; N, 5.09. λmax: 307 nm, εmax: 11200. MS m/z: calcd for C15H16NO2S [M + H]+, 273.09; found, 274.08.

2.9.18. Synthesis of 4-((2,3-Dihydroxybenzyl)­amino) Benzoic Acid (18)

White Solid. Yield: 0.72 g (2.78 mmol, 72%). FT–IR (ATR, ν, cm–1): 2516–3020 (COOH), 3402 (NH), 3157 (OH), 1675 (CO). 1H NMR: (DMSO-d 6, 400 MHz): δ 11.96 (s, 1H, COOH), 9.31 (s, 1H, Ar–C–OH), 8.44 (s, 1H, Ar–C–OH), 7.63 (d, J = 8.52 Hz, 2H, Ar–H), 6.65 (m, 4H, Ar–H, and NHCH2), 6.54 (d, J = 8.00 Hz, 2H, Ar–H), 4.29 (d, J = 4.00 Hz, 2H, HNCH 2). 13C NMR: (101 MHz, DMSO-d 6): δ 167.61 (1C, COOH), 152.73 (1C, Ar–C–OH), 145.02 (1C, Ar–C–OH), 143.10 (1C, Ar–C), 131.14 (2C, Ar–CH), 125.92 (1C, Ar–C), 118.78 (1C, Ar–C), 118.71 (1C, Ar–C), 116.88 (1C, Ar–CH), 114.04 (1C, Ar–CH), 111.05 (2C, Ar–CH), 41.01 (1C, CH 2NH). Anal. Calcd for C14H13NO4: C, 64.86; H, 5.05; N, 5.40. Found: C, 64.82; H, 5.08; N, 5.43. λmax: 305 nm, εmax: 30600. MS m/z: calcd for C14H14NO4 [M + H]+, 259.09; found, 260.09.

2.9.19. Synthesis of 4-((3-(Trifluoromethyl)­benzyl)­amino)­benzoic Acid (19)

White Solid. Yield: 0.95 g (3.22 mmol, 95%). FT–IR (ATR, ν, cm–1): 2500–3011 (COOH), 3424 (NH), 1671 (CO). 1HNMR: (DMSO-d 6, 400 MHz): δ 12.06 (s, 1H, COOH), 7.63 (m, 6H, Ar–H, and, Ar–H), 7.13 (t, J = 8.09 Hz, 1H, NHCH2), 6.61 (d, J = 8.00 Hz, 2H, Ar–H), 4.48 (d, J = 4.00 Hz, 2H, HNCH 2). 13C NMR: (DMSO-d 6, 101 MHz): δ 167.47 (1C, COOH), 152.17 (1C, Ar–C-CF3), 141.24 (1C, Ar–C), 131.29 (1C, Ar–C), 131.17 (2C, Ar–CH), 129.45 (1C, Ar–CH), 129.02 (1C, CF3), 125.67 (1C, Ar–C), 123.63 (1C, Ar–CH), 123.59 (1C, Ar–CH), 117.63 (1C, Ar–CH), 111.30 (2C, Ar–CH) 45.34 (1C, CH 2NH). Anal. Calcd for C15H12NO2F3: C, 61.02; H, 4.10; N, 4.74. Found: C, 61.05; H, 4.07; N, 4.77. λmax: 304 nm, εmax: 16200. MS m/z: calcd for C15H13NO2F3 [M + H]+, 295.08; found, 296.08.

3. Result and Discussion

3.1. Synthesis

Compounds 1, 2, 4, 8, 9, 12, 14, 17, 19 have been prepared previously by different research groups under different conditions (high temperatures, long reaction times and presence of a catalyst) with low yields. ,,,− The 4-(benzylamino) benzoic acid derivatives (1–19) ArCH2NH-4-C6H4CO2H (1–19) (Ar = C6H5 (1); 4–Cl–C6H4 (2); 4-NMe-C6H4 (3); 4–Br–C6H4 (4); 3-NO2–C6H4 (5); 4-NO2–C6H4 (6); 2-OMe-C6H4 (7); 3-OMe-C6H4 (8); 4-OMe-C6H4 (9); 2,3-OMe-C6H3 (10); 3,4-OMe-C6H3 (11); 2-OH, 3-OMe-C6H3 (12); 3-OMe, 4-OH-C6H3 (13); 3,5-OMe, 4-OH-C6H4 (14); 2-OH-5–Br–C6H3 (15), 3-OH-C6H4 (16); 4-SMe-C6H4 (17); 2,3-OH-C6H3 (18); 3-CF3–C6H4 (19)) were synthesized in a one pot reaction with yields ranging from 72% to 96% by reacting 4-aminobenzoic acid (1 equiv) and various benzaldehyde derivatives (1 equiv) in methanol to produce imine which was reduced in situ by addition of excess sodium borohydride, in about 5–10 min (Scheme ). The 4-(benzylamino) benzoic acid derivatives were characterized using FT–IR spectroscopy, 1H NMR, 13C­{1H}-NMR, MS and EA. The structures of 2, 4, 7–9, and 11 were determined via SC-XRD analysis. The UV–vis characteristics of 1–19 were examined experimentally and via DFT calculations.

The formation of the 4-(benzylamino) benzoic acid derivatives (1–19) was determined through FT–IR spectroscopy, showing bands of their characteristic functional groups (Figure ). FT–IR analysis of the 4-(benzylamino) benzoic acid derivatives (1–19) revealed three major bands in the range of 2500–3150 cm–1, 1604–1693 cm–1 and 3330–3422 cm–1 which are assigned for OH, CO in COOH, and NH functional groups, respectively. − The appearance of the NH stretching as a sharp peak confirms the occurrence of the reduction step in the reductive amination reaction. − Furthermore, stretching phenolic hydroxyl bands appear in the range of 3322–3152 cm–1, for compounds 12–16 and 18.

1.

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Representative FTIR spectra of some prepared compounds.

The formation of the 4-(benzylamino) benzoic acid derivatives 1–19 was further confirmed by 1H NMR and 13C­{1H}-NMR spectroscopy (Figures S19–S36). The 1H NMR spectra of the 4-(benzylamino) benzoic acid derivatives 1–19 showed triplet peaks for the amine N–H in the range of δ 6.59–7.26 ppm while the carboxylic acid protons appeared as a sharp singlet peak between 11.82 and 12.11 ppm. The methine proton ArCH2NH-4-C6H4CO2H signals observed in the range of 4.20–4.51 ppm as doublet. Aromatic protons appeared with various kinds of coupling, with chemical shifts range between 6.54 and 8.20 ppm. , The 13C­{1H}-NMR spectra indicated that the aryl moiety was present within the range of 110.97–159.37 ppm. , The methine carbon signals were observed between 40.28–46.83 ppm. Additionally, the carbonyl carbon atoms in the 4-(benzylamino) benzoic acid 1–19 resonated in the ranges of 167.33–167.81 ppm. ,

The ESI-MS spectra of 4-(benzylamino) benzoic acid derivatives 1–19 are present in the Supporting Information (Figures S1–S18). They confirmed the structures of the compounds. 4-(Benzylamino)­benzoic acid derivatives 1–19 m/z signals corresponding to [M + H]+ matched the calculated values.

3.2. Molecular Structures

Colorless single crystals of the 4-(benzylamino)­benzoic acid derivatives 2, 4, and 7–9, as well as 11, were successfully obtained by evaporation of their THF solutions at ambient temperature. Their molecular structures were determined by SC-XRD analysis (Figure ). Crystallographic data, including collection and refinement parameters for compounds 2, 4, 7–9, and 11, are presented in Table S1. Selected bond lengths (Å) and bond angles (°) are provided in Tables S2 and S3, respectively.

2.

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Molecular structures (50% probability) of compounds 2, 4, 7–9, and 11.

Crystallographic analysis revealed that complexes 2, 4 and 8 crystallizes in the triclinic space group P1̅, while complex 7, 8, and 11 crystallize in the monoclinic space group P21/c. In compounds 2, 4, 7–9, and 11, two substituted aromatic rings at either end of the −CH2–NH– linkage (Caryl–CH2–NH–Ccarbox torsion angle: −72.6 (3) ° for 2, −73.7 (4) ° for 4, −76.9 (3)° for 7, −167.1 (3) ° for 8, 174.2 (2) for 9, 73.9 (5)° for 11). The secondary amine N atom has a practically planar trigonal configuration deviating from the mean plane of the adjacent atoms by 0.089 Å for 2, 0.121 Å for 4, 0.048 Å for 7, 0.075 Å for 8, 0.051 Å for 9 and 0.068 Å for 11. The C4–N1 bond length (1.355–1.370 Å) is shorter than the C8–N1 bond length (1.436–1.444 Å), suggesting delocalization of the of the N atom lone pair with the adjacent benzoic acid ring benzoate unit through n–π conjugation with, which is consistent with previous reported distances in crystal structure of the 4-[(2-hydroxy-3-methoxy-benzyl)­amino]-benzoic acid. The C–O, C–Cl, C–Br bond lengths are in the expected ranges consistent with previous findings compounds. Additionally, the C4–N1–C8 angles range from 123.22° to 124.48°. The dihedral angles between the two phenyl ring are 83.42° for 2, 84.58° for 4, 75.14° for 7, 85.68° for 8, 84.75° for 9 and 80.97° for 11.

Compound 2 crystallizes with one molecule in the asymmetric unit. There is a pairwise O···H interaction (C2–H2···H2:1.642 Å, ∠ 175.52°) between the carboxylic oxygen from one molecule and the proton of the carboxylic acid from an adjacent molecule (Figure S37 and Table S4). This characteristic is consistently observed across all compounds and appears to serve as the primary structure-directing interaction within the crystal lattice. A short contacts N–H···π (N1–H1A···C13:2.818 Å, ∠134.44°; N1–H1A···C14:2.760 Å, ∠158.09°) are also observed wherein one of the amine proton interacts with the aromatic carbons (Figure S37).

The study of noncovalent interactions plays a crucial role in crystal engineering, as these interactions govern the packing and organization of molecular units in the solid state. To facilitate visualization of these interactions, Hirshfeld surfaces mapped over dnorm , shape index, curvedness, and fragment patch are presented for the compounds in Figures S47–S51. Hirshfeld surface analyses and the corresponding two-dimensional fingerprint plots for compounds 2, 4, 7–9, and 11 were generated using the CrystalExplorer17.5 software (Figures S52–S57). ,− The percentage contributions of Hirshfeld surface contacts for the 4-(benzylamino)­benzoic acid derivatives are summarized in Table S5. Figure illustrates the primary intermolecular interactions identified through Hirshfeld surface analysis across all the studied crystal structures.

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(a) Hirshfeld surface contacts in 2 (O–H···O and N–H···π). (b) Hirshfeld surface contacts in b (O–H···O and N–H···π). (c) Hirshfeld surface contacts in 7 (O–H···O and C–H···π). (d) Hirshfeld surface contacts in 8 (O–H···O, N–H···π and N–H···O). (e) Hirshfeld surface contacts in 9 (O–H···O, N–H···O and C–H···O). (f) Hirshfeld surface contacts in 11 (O–H···O, N–H···O, C–H···O, C–H···π and N–H···C).

Hirshfeld surface analysis of compound 2 reveals that H···H interactions constitute 39.4% of the total surface area (Figure S52b), including a notable short contact (2.381 Å, ∠ = 129.98°) between aromatic hydrogen atoms of adjacent molecules (Figure S38). The combined O···H/H···O interactions, visualized as characteristic spikes in the fingerprint plot (Figure S51c)a feature consistently observed across all studied compounds account for 16.6% of the surface (Figure S52c).

Compound 4 crystallizes with one molecule present in the symmetric unit. Again, the pairwise O···H interaction [1.792 Å] is evident (Figure S39). Notably, the substitution of different halogen atoms at the para position leads to an elongation of the pairwise O···H interaction distance, increasing from 1.642 Å in compound 2 to 1.792 Å in compound 4. This trend correlates with the incorporation of larger halogen substituents, which impart slight structural flexibility, resulting in less efficient molecular packing and consequently longer O···H contacts. Additionally, short N–H···π interactions are observed between amine protons and aromatic carbon atoms oriented toward the amine group, similar to those found in compound 2. These interactions are consistent with their comparable packing motifs (N1–H1A···C10:2.785 Å, ∠ = 135.44°; N1–H1A···C11:2.696 Å, ∠ = 161.05°; Figure S39). Figure S40 illustrates the molecular packing of the structure along the ab plane, revealing a pairwise C–H···O interaction (C10–H10···O2, d = 2.684 Å, ∠ = 141.84°; highlighted in pink) and a short H···H contact (2.334 Å), both of which contribute to the stabilization of the crystal lattice. , Hirshfeld surface analysis of compound 4 reveals the lowest contribution of H···H interactions among the studied structures, accounting for only 39.1% of the surface area (Figure S53b). The O···H/H···O interactions contribute 16.0% to the surface (Figure S53c), and, due to the structural similarities, exhibit characteristics closely resembling those observed in compound 2.

Compound 7 crystallizes with a single molecule in the asymmetric unit. A pairwise O–H···O hydrogen bond is observed, analogous to that seen in compounds 2 and 4 (O2–H2···O2:1.521 Å, ∠172.79°) (Figure S41). ,, Unlike compounds 2 and 4, where the amine group engages in intermolecular hydrogen bonding, the amine group in compound 7 remains nonparticipatory in intermolecular interactions. This absence likely contributes to the observed shortening of the O–H···O hydrogen bond distance in 7 (1.521 Å), compared to the longer distances in compounds 2 (1.642 Å) and 4 (1.792 Å). The variation in this interaction is likely governed by both the electronic and steric effects associated with the methoxy substituent. Additionally, the methyl group facilitates a network of C–H···π interactions involving the phenyl rings (C15–H15A···C10:2.896 Å, ∠146.72°; N1–H1A···C11:2.888 Å, ∠120.46°) (Figure S41). These interactions give rise to a two-dimensional supramolecular chain extending along the b-axis. ,,− The Hirshfeld surface analysis of compound 7 reveals an increased contribution from O···H/H···O and C···H/H···C interactions, comprising 20.6% (Figure S54c) and 25.9% (Figure S54b) of the surface, respectively, relative to compounds 2 and 4. This enhancement is consistent with the substitution of the halogen atom by a methoxy group, which introduces additional hydrogen-bond donor and acceptor sites. Additionally, H···H contacts dominate the surface of compound 7, accounting for 49.1% (Figure S54a), which is notably higher than in compounds 2 and 4. This trend is attributed to the absence of halogen atoms and the presence of the methoxy group in compound 7, which results in a proportionally higher number of hydrogen atoms, thereby increasing the likelihood of H···H contacts.

Compound 8 crystallizes with two molecules in the asymmetric unit. The solid-state structure of compound 8 is stabilized by a range of noncovalent interactions, with O–H···O, C–H···O, and N–H···O intermolecular hydrogen bonds being the most prominent. − These interactions involve the five crystallographically independent molecules present in the asymmetric unit (Figure S42). Notably, the C15–H15A···O1 hydrogen bond exhibits a distance of 2.672 Å and an almost linear angle of 164.67°, while the C10–H10···O4 interaction measures 2.675 Å with an angle of 149.01°, indicating the relative strength and directionality of these hydrogen bonds. These interactions extend forming an extended supramolecular network. In addition to the C–H···O interactions, compound 8 also forms strong N–H···O hydrogen bonds. Interactions , For instance, the N2–H2B···O1 interaction with a carbonyl oxygen has a bond length of 2.415 Å and an angle of 139.73°, while N1–H1···O3 involves the methoxy oxygen of an adjacent molecule (2.163 Å, ∠177.22°), signifying a strong and nearly linear hydrogen bond. Furthermore, an N–H···π interaction is observed between N1–H1 and the adjacent phenyl ring (N1–H1···C13:2.869 Å, ∠150.28°) (Figure S43). ,,, Additionally, C–H···π interactions contribute to the crystal packing of compound 8, with observed interactions such as C29–H29···C17 (2.783 Å, ∠128.45°). The crystal structure of compound 8 reveals the presence of weak C–H···CH 2 intermolecular interactions. One such interaction involves the hydrogen atom of aromatic C–H donor and a carbon atom of an adjacent molecule C2–H2A···C8 (2.890 Å, ∠172.26°), which may contribute to the stabilization of the packing framework. ,,− The presence of closed-shell H···H contacts (2.395 Å) further stabilizes the three-dimensional framework (Figure S44). Hirshfeld surface analysis of compound 8 indicates the highest contribution of O···H/H···O interactions among all examined structures, accounting for 24.4% of the total surface area (Figure S55c). In contrast, compound 8 exhibits the lowest proportion of H···H contacts among the methoxy-substituted compounds studied, accounting for only 45.9% of the surface (Figure S55b). Furthermore, The electrostatic potential surface displayed in Figure d further establishes the N–H···O interaction where the atoms involved in strong hydrogen bonds, unlike the pairwise interactions observed in 2, 4 and 7.

The solid-state structure of compound 9 is stabilized by multiple noncovalent interactions, with N–H···O intermolecular hydrogen bonds being the most prominent. Interactions , Notably, the N1–H1···O4 interaction exhibits a bond length of 2.278 Å and a bond angle of 148.25°, while the N2–H2B···O1 interaction displays a bond length of 2.228 Å and an angle of 157.94°, both indicative of strong hydrogen bonding (Figure S45). In addition, compound 9 features weaker C–H···C interactions (C11–H11···C8:2.823 Å, ∠167.52°; C28–H28···C23:2.830 Å, ∠167.78°) (Figure S45). One notable close contact is a pairwise interaction observed in compounds 4, 8, and 9, where a carbonyl oxygen engages in a hydrogen bond interaction with an aromatic proton (Figures S40, S42, and S46). Among the latter, the C18–H18···O3 interaction, with a bond length of 2.644 Å and an angle of 158.77°, reflects moderate hydrogen bonding strength (Figure S46). − Furthermore, C···O contacts (3.152 Å) are observed between adjacent carboxylic acid groups, contributing additional van der Waals stabilization to the crystal packing (Figure S46). This interaction represents the other principal structure-directing feature in the crystal structure and accounts for the markedly different packing observed in compound 9 compared to all other studied structures. The Hirshfeld surface analysis of compound 9 reveals the lowest proportion of O···H/H···O interactions among the methoxy-substituted structures examined, contributing 18.8% to the total surface area (Figure S56c). In contrast, H···H contacts account for 50.0%, representing a relatively higher contribution compared to compound 8 (Figure S56b). Furthermore, C···O interactions constitute 1.9% of the surface; notably, these interactions differ in nature from those observed in the other compounds studied, suggesting a distinct mode of molecular packing in compound 9 (Figure S56f).

The crystal structure of compound 11 is likewise reinforced by a network of C–H···O and N–H···O intermolecular hydrogen bonds (Figure S47). The C–H···O interactions involve methyl hydrogen atoms and oxygen atoms from carboxylic acid groups (C15–H15C···O5:2.679 Å, ∠112.17°; C31–H31C···O1:2.690 Å, ∠121.65°), as well as methoxide groups (C8–H8B···O7:2.680 Å, ∠129.76°). In addition, N–H···O hydrogen bonding is observed between the amine protons and methoxide oxygen atoms (N1–H1···O7:2.574 Å, ∠133.06°; N1–H1···O8:2.383 Å, ∠142.19°; N2–H2B···O3:2.275 Å, ∠142.31°; N2–H2B···O4:2.627 Å, ∠137.44°) (Figure S47). Interactions , Moreover, compound 11 exhibits C–H···π interactions (C2–H2A···C25:2.896 Å, ∠143.42°; C30–H30···C11:2.831 Å, ∠176.94°), which further contribute to the stabilization of the three-dimensional supramolecular framework. Hirshfeld surface analysis of compound 11 shows the highest contribution of H···H interactions among all investigated structures, comprising 51.3% of the total surface area (Figure S57b). In contrast, O···H/H···O interactions account for 20.0%, which is notably greater than that observed in compound 9 (Figure S57c). Additionally, C···H/H···C interactions represent 24.9% of the surface (Figure S57d), consistent with the incorporation of a second methoxy substituent. However, the presence of this additional methoxy group does not lead to an enhancement in C–H···C or O···H/H···O interactions within the crystal structure.

3.3. DFT Calculations and Electronic Structures

The geometries of compounds 2, 4, and 7–9, as well as 11, were optimized using the PBE0/def2-TZVP level of theory with the CPCM solvation model (DMSO) and compared to their experimentally determined X-ray crystal structures. The optimized structural parameters are summarized in Tables S2 and S3. Notably, the calculated bond lengths and angles exhibit good agreement with the experimental data, confirming the reliability of the computational model. ,−

To explore the electronic properties of the 4-(benzylamino)­benzoic acid derivatives 1–19, vertical excitation energies were computed using time-dependent density functional theory (TD-DFT). The calculated absolute energies of the Frontier molecular orbitals (HOMO and LUMO) are summarized in Table S6, offering insights into the HOMO–LUMO energy gaps across the series. Additionally, Table S7 presents the key electronic transitions, providing a comprehensive overview of the excitation characteristics of these compounds.

Figure illustrates the calculated relative Frontier orbital energies for compounds 1–19, revealing a distinct trend. The LUMO orbitals exhibit a slight decrease in energy levels, except for compounds 5 and 6. The nitro (NO2) substituent significantly influences the LUMO energy, while the dimethylamine (Me2N) group notably affects the HOMO energy. This effect can be attributed to the extended π-delocalization facilitated by the nitro and dimethylamine groups. Analysis of the calculated HOMO–LUMO energy gaps, as illustrated in Figure and detailed in Table S6, indicates that the incorporation of different functional groups leads to relatively consistent gap values across compounds 1–19, with the exception of compounds 3, 5, and 6, which exhibit notable deviations. The HOMO–LUMO energy gap decreases by approximately 0.7 eV for compound 3 (Me2N) compared to its corresponding unsubstituted compound (1). In contrast, for compounds 5 (3-NO2) and 6 (4-NO2), the HOMO–LUMO energy gaps decrease by 1.40 and 1.35 eV, respectively, compared to their corresponding unsubstituted compound (1).

4.

4

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Calculated HOMO and LUMO energies of 1–19.

For compounds 1, 2, 4 and 7–19, the HOMO – 1 and HOMO orbitals are primarily localized on the substituted benzyl group and the benzoic acid moiety, respectively (Figures S58–Figure S76). In contrast, for compounds 3, 5, and 6, this localization is reversed, with the HOMO – 1 orbitals situated on the benzoic acid and the HOMO orbitals on the substituted benzyl group. The LUMO orbitals predominantly reside on the benzoic acid moiety for compounds 1–4 and 7–19. However, for compounds 5 and 6, the LUMO orbitals are consistently localized on the substituted benzyl group. Regarding the LUMO + 1 orbitals, they are consistently localized on the substituted benzyl group for compounds 1, 2, 4, 7, 8, 15, 17 and 19, whereas they are localized on the benzoic acid moiety for compounds 3, 5, 6, 9–14 and 18.

The UV–vis absorption profiles of the 4-(benzylamino)­benzoic acid derivatives 1–19, recorded in DMSO solutions (Table S7), prominently display intense bands in the UV region, primarily attributed to π–π* transitions. ,, These derivatives exhibit distinct absorption peaks around 275 nm, with extinction coefficients ranging from 1.02–3.13 × 104 M–1 cm–1. ,,, To further analyze these bands, TD-DFT calculations were performed on the optimized geometries of the derivatives. The calculated spectra closely match the experimental absorption maxima (λmax) for compounds 1–19 (Table S7). For derivatives 1, 2, 4 and 7–19, the observed transitions originate from the HOMO to LUMO states. In compound 3 (Me2N), the transitions arise from the HOMO–1 to LUMO states, while for compounds 5 and 6, the transitions occur from the HOMO to LUMO + 1 states (Table S7). ,

To further elucidate noncovalent interactions, the overall interaction energy and its individual components surrounding a selected molecule within a 3.8 Å radius were calculated using Crystal Explorer for compounds 2, 4, 7, 8, 9, and 10. The electrostatic (E ele), polarization (E pol), dispersion (E dis), and exchange-repulsion (E rep) contributions were estimated based on wave functions computed at the HF/3-21G level for compounds 2, 4, 7, 8, 9 and 10. In the intermolecular topology network, molecules sharing the same color represent interacting pairs (Figure S76), with colors corresponding to specific symmetry operations (Sym op); R denotes the centroid-to-centroid distance between molecules (Table ). Each interacting molecule is associated with a vector property influencing the topology of intermolecular interactions within the crystal lattice. The energy frameworks depicting pairwise interactions within the topology network are presented in Figures , S77, and S78, constructed by linking interacting atoms. Analysis of these frameworks indicates that dispersion energy (E dis) is the predominant contributor to the total interaction energy, playing a key role in stabilizing the crystal structures. The highest dispersion energies were observed for compound 10 (−57.9 kJ·mol–1), followed by 8 (−52.2), 7 (−49.6), 2 (−44.9), 9 (−44.9), and 4 (−44.4). Nonetheless, these large dispersion contributions are offset by significant exchange-repulsion energies (E rep), yielding an overall interaction energy ranking of 9 > 7 ≈ 4 > 10 > 8 > 2. The data set reveals several strongly interacting dimers across compounds 2, 4, 7, 8, 9, and 11, with notable total interaction energies (E tot) such as −30.5 kcal/mol in compound 2, −31.6 kcal/mol in compound 4, −33.5 kcal/mol in compound 7, and an exceptionally strong interaction of −176.4 kcal/mol in compound 9. While these highly stabilizing contacts represent dominant contributors to lattice cohesion, a comprehensive analysis that also includes all unique dimers with moderate interaction energies (−10 to −30 kcal/mol) is essential to capture the full complexity of the crystal packing. Limiting the focus to only the most stabilizing dimers risks overlooking the cumulative effects of weaker, yet structurally significant interactions such as N–H···C, C–H···C, C···O stacking, and long-range dispersion forces. These interactions, though individually less stabilizing, often form repetitive motifs as observed in compounds 4 and 7 that help propagate structural order and influence overall packing preferences. The observed diversity in symmetry operations and centroid distances, ranging from close contacts under 6 Å to extended interactions beyond 13 Å, suggests a hierarchical and cooperative packing network that cannot be adequately described through isolated pairwise interactions alone. Notably, dimers with longer centroid separations can still exhibit substantial dispersion contributions, such as the −36.0 kcal/mol interaction at 5.95 Å in compound 2. In general, strong dimeric interactions (E tot < – 30 kJ/mol) are primarily dispersion-driven, especially in compounds 2, 4, and 9, with additional contributions from electrostatics and polarization in highly stabilizing contacts (e.g., −89.3 kJ/mol in compound 4 and −176.4 kJ/mol in compound 9), likely arising from directional hydrogen bonding (H···O) or N–H···O. In contrast, compound 10 exhibits a more diffuse network composed of moderately stabilizing dimers (−20 to −40 kJ/mol), indicating a packing arrangement less reliant on any single dominant interaction. Instances of unphysical or anomalous values, such as undefined energies (nan) or abnormally high repulsion (E rep), were observed for certain dimers in compounds 8 and 10, likely due to numerical instabilities or geometric overlaps, and are flagged accordingly in Table .

1. Interaction Topology Energy Table for 2, 4, 7, 8, 9 and 11 at the HF/3-21G Level of Theory.

3.3.

3.3.

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a

Color codes indicate the molecule with the crystal structures, as shown in Figure S76.

b

N represents the number of molecules.

c

Symop is the relational symmetry operation to the ventral molecule.

d

R is the distance between the molecular centroids.

5.

5

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Total intermolecular interaction topology energy framework between neighboring molecules within each molecular crystal structure.

3.4. Anticancer Properties

Cell viability assays were conducted using resazurin dye colorimetric method by treating HGF, A549, and H69 cell lines for 72 h with compounds 1–19. Compounds were initially tested on HGF cell line to identify their toxicity on normal cell line and later tested on cancer cell lines. The results are summarized in Table .

2. Cytotoxicity (IC50) of 1–19 on HGF, A549, and H69 Cell Lines after Treatment for 72 h; n = 3 .

  IC50 (±SEM) μM; n = 3
compound HGF A549 H69
1 >100 >100 >100
2 >100 >100 >100
3 >100 >100 >100
4 >100 >100 >100
5 >100 >100 >100
6 >100 >100 >100
7 >100 >100 >100
8 >100 >100 >100
9 >100 >100 >100
10 >100 >100 >100
11 >100 >100 >100
12 >100 >100 >100
13 >100 >100 >100
14 >100 >100 >100
15 >100 >100 >100
16 >100 >100 >100
17 >100 >100 >100
18 >100 90.69 ± 10.23 32.22 ± 7.08
19 >100 >100 >100
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a

∼50% cell viability at 100 μM.

The results showed that all compounds were noncytotoxic on the normal HGF cell line. Hence, their investigation on cancer cell lines would be worth investigating. NSCLC (A549) and SCLC (H69) cell lines were used. However, only compound 18 showed a cytotoxic effect on A549 and H69 cell lines with IC50 values of 90.69 μM and 32.22 μM, respectively. The dose–response curves for compound 18 are presented in Figures and . In addition, the selectivity index , for compound 18 on H69 cell line is greater than 3 and this presents a selective toxic agent on SCLC cell line. Although compound 18 did not show a marked cytotoxicity on A549 cell line, compound 18 may be further evaluated against other cancer cell lines as well as being optimized to increase its toxicity, especially on H69 cell line. In addition, all these compounds may be further investigated on other cancer cell lines and they may show a cytotoxic effect.

6.

6

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Dose–response curve for compound 18 on A549 cell line, generated by GraphPad Prism version 9.0, n = 3.

7.

7

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Dose–response curve for compound 18 on H69 cell line, generated by GraphPad Prism version 9.0, n = 3.

3.5. Antibacterial Properties

The antibacterial activity of compounds (1–19) was tested in vitro by determining MIC values via the micro broth dilution method against several pathogenic bacteria (En, Sa, MRSA, Ec, Kp, and Se). The MIC was defined as the minimal inhibitor concentration that has an optical density less than that of amoxicillin (positive control). As a negative control, DMSO solvent does not affect the antibacterial activity of tested bacteria.

Table shows that compounds 1, 4, 6, 9, and 12 were inactive against neither Gram-negative nor Gram-positive bacteria strains. All other compounds showed differentiated MIC values against all tested bacterial strains. The MIC values showed that compounds 3, 5, 11, 13, 14, 16–19 were entirely inactive toward all types of Gram-positive bacteria and against Gram-negative Ec. Besides, compounds 3, 5, 11, 13, 14 and 16 showed moderate activity against Gram-negative Kp and Se (MIC = 64 μg/mL). All other compounds showed low activities toward different strains of bacteria, (MIC = 128–256 μg/mL).

3. Antibacterial Activity Data of Compounds 1–19 .

  (MIC, μg/mL)
  Gram-positive
 Gram-negative
compound En Sa MRSA Ec Kp Se
1 --- --- --- --- --- ---
2 128 --- --- --- 64 64
3 --- --- --- --- 64 64
4 --- --- --- --- --- ---
5 --- --- --- --- 64 64
6 --- --- --- --- --- ---
7 128 --- --- --- 64 64
8 256 --- --- --- 64 64
9 --- --- --- --- --- ---
10 256 --- --- --- 64 64
11 --- --- --- --- 64 64
12 --- --- --- --- --- ---
13 --- --- --- --- 64 64
14 --- --- --- --- 64 64
15 64 --- --- --- 64 128
16 --- --- --- --- 64 64
17 --- --- --- --- 256 ---
18 --- --- --- --- 256 ---
19 --- --- --- --- 256 ---
DMSO (−ve control) --- --- --- --- --- ---
amoxicillin (+ve control) 16 16 16 32 16 16
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The effect of lipopolysaccharide (LPS) is considered to be the cause of the higher activity observed against Gram-negative bacteria, a major component of the surface of such organisms.

LPS is a major entity in determining the virulence and pathogenicity of Gram-negative bacteria and the effectiveness of the outer membrane barrier function. The compounds can penetrate the cell membrane by coordinating the metal ion through donor atoms to LPS, causing damage to the outer cell membrane, and inhibiting the nucleic acid synthesis and protein synthesis and therefore inhibiting bacterial growth.

4. Conclusion

A simple synthetic method for preparing 4-(benzylamino)­benzoic acid derivatives with the general formula ArCH2NH-4-C6H4CO2H (1–19) is described. This involves treating 4-amino benzoic acid with benzaldehyde derivatives followed by reduction with sodium borohydride. The molecular structures of compounds 2, 4, 7–9, and 11 were elucidated by single-crystal X-ray diffraction. The structures of 2, 4, 7–9, and 11 revealed the formation of O–H···O, N–H···O, N···O, C–H···O, N–H···π, and C–H···π, intermolecular interactions. The noncovalent interactions are thoroughly analyzed structurally, and their assessment using Hirshfeld surface analysis is also given. Moreover, structural features were confirmed through PBE0/def2-TZVP/CPCM­(DMSO) calculations, which included geometry optimization and vibrational frequency analysis. Furthermore, TD-DFT calculations were conducted to interpret the experimental electronic spectra of both the ligand and the corresponding compounds. DFT results for the 4-(benzylamino)­benzoic acid derivatives 1, 2, 4 and 7–19 indicated that the lowest and highest energy absorption bands are characterized by π–π* transition (HOMO to LUMO). In compound 3 (Me2N), the transitions arise from the HOMO–1 to LUMO states, while for compounds 5 and 6, the transitions occur from the HOMO to LUMO + 1 states. The anticancer activities of the newly synthesized 4-(benzylamino)­benzoic acid derivatives (1–19) were explored against H69 and A549 cell lines. Compound 18 displayed the most potent cytotoxic effect with IC50 of 90.69 μM against A549 and IC50 32.22 μM against H69. Several of these compounds (2, 3, 5, 7, 8, 10, 11, 13–16) showed moderate antibacterial activities toward different strains of bacteria, Gram-negative and Gram-positive.

Supplementary Material

ao5c03898_si_001.pdf (8MB, pdf)

Acknowledgments

A.A. acknowledges Prof. Alice E. Bruce and Prof. Mitchell R. M. Bruce in the Department of Chemistry at the University of Maine for use of the Bruker D8 QUEST ECO diffractometer for single-crystal X-ray diffraction measurements. The authors acknowledge Omar. Y. Assaifi from Taawon for Laboratory & Scientific Supplies for the mass measurements.

Crystallographic data (excluding structure factors) have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication CCDC 2379919 for 2, CCDC 2379920 for 4, CCDC 2379921 for 7, CCDC 2379922 for 8, CCDC 2379923 for 9 and CCDC 2379924 for 11. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [E- mail: deposit@ccdc.cam.ac.uk].

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.5c03898.

  • Experimental part, MS data (Figures S1–S18), 1H, 13C NMR spectra (Figures S19–S36), Experimental and calculated structures parameters (Tables S1–S7), Intermolecular interactions and isosurface densities (Figures S37–S74) (PDF)

Conceptualization, Ahmed Hijazi; Data curation, Ziyad Taha and Osama Abusara; Formal analysis, Qusai Sarayrah, Abdelrahman Malkawi, Hassan Abul Futouh, Ziyad Taha, Osama Abusara, Ahmad Ahmad, Ahmad Daraosheh and Waleed Al-Momani; Funding acquisition, Ahmed Hijazi; Investigation, Ahmed Hijazi, Qusai Sarayrah and Abdelrahman Malkawi; Methodology, Ahmed Hijazi, Qusai Sarayrah, Osama Abusara and Waleed M. Al-Momani; Project administration, Ahmed Hijazi; Resources, Ahmed Hijazi, Deeb Taher, Ahmad Daraosheh and Waleed Al-Momani; Software, Hassan Abul Futouh, Deeb Taher and Ahmad Ahmad; Supervision, Ahmed Hijazi, Hassan Abul Futouh and Ziyad Taha; Writingoriginal draft, Ahmed Hijazi; Writingreview and editing, Hassan Abul Futouh, Ziyad Taha, Deeb Taher and Osama Abusara.

This work was supported by Deanship of Scientific Research, Jordan University of Science and Technology (Grant # 20220400).

The authors declare no competing financial interest.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ao5c03898_si_001.pdf (8MB, pdf)

Data Availability Statement

Crystallographic data (excluding structure factors) have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication CCDC 2379919 for 2, CCDC 2379920 for 4, CCDC 2379921 for 7, CCDC 2379922 for 8, CCDC 2379923 for 9 and CCDC 2379924 for 11. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [E- mail: deposit@ccdc.cam.ac.uk].

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