Studies on the Radziszewski Reaction—Synthesis and Characterization of New Imidazole Derivatives

Abstract

Two new long-chain N-alkyl imidazole derivatives, 2-(1-octadecyl-imidazol-2-yl)pyridine and 2-(furan-2-yl)-1-(octadecane-1-yl)-1H-imidazole, were synthesized via the Radziszewski reaction followed by N-alkylation. This is the first report of furan-imidazole obtained by this route using furfuraldehyde as a renewable biomass-derived precursor. FTIR, 1D/2D solution NMR, and HRMS confirmed the structural elucidation, while XRD and solid-state ¹³C CPMAS NMR corroborated the crystal structures of the precursors. Notably, previously misassigned ¹H and ¹³C chemical shifts reported in the literature for pyridine and furan-imidazole precursors were corrected. Furthermore, ¹³C CPMAS NMR spectra of those precursors are reported here for the first time. These findings expand the scope of the Radziszewski reaction and provide new insights into the structural characterization of imidazole-based systems.

1. Introduction

Imidazoles are heterocyclic compounds with applications in several fields, including natural product chemistry, pharmacology, biochemistry, and medicinal chemistry. Heinrich Debus reported the first synthesis of imidazole in 1858 [1]. Later, in 1882, the Polish chemist Bronisław Leonard Radziszewski, in his search for the synthesis of 2,4,5-triphenylimidazole, a synthetic compound with fluorescent and chemiluminescent properties known as lophine, also prepared imidazole through a new route, now known as the Radziszewski reaction [2]. Radziszewski studies laid the groundwork for synthesizing imidazole from a wide variety of aldehydes. The Radziszewski reaction (Figure 1) is based on a multi-component process with a fascinating atomic economy, as all atoms from three or more precursors are incorporated into a single product. This efficiency makes the method attractive for sustainable synthesis, as it prevents chemical waste. The reaction requires an aldehyde, a nitrogen source, and a 1,2-dicarbonyl compound.

Although Radziszewski’s strategy was successful, the reactions involved harsh conditions, making compounds preparation difficult. Therefore, the development of new methods for synthesizing substituted imidazoles remains of strategic importance, especially considering their broad biological and technological relevance and applications. Zhang et al. [3] reviewed their diverse medicinal applications of imidazoles, including antifungal, antibacterial, anticancer, and antihypertensive activities. Notable examples are ketoconazole, miconazole, clotrimazole, dacarbazine, and losartan, which highlight the versatility of the imidazole scaffold in modern drug discovery [4,5,6]. Beyond the pharmaceutical field, imidazoles are also employed in agrochemicals. They are being explored in emerging research for dyes for solar cells and other optical applications, as well as in functional materials and catalysis [7,8]. Due to their wide-ranging applications, efficient and sustainable methods for the synthesis of imidazoles are highly relevant and necessary.

There has been limited recent research on the synthesis of imidazoles via methods that only form one of the heterocycle’s bonds. Fang et al. [9] reported a novel protocol for the cyclization of amido-nitriles to form disubstituted imidazoles. The reaction conditions were mild enough for the inclusion of a variety of functional groups, including aryl halides, as well as aromatic and saturated heterocycles. That reaction is reported to proceed via nickel-catalyzed addition to the nitrile, which is followed by protodemetalation, tautomerization, and dehydrative cyclization, affording the desired 2,4-disubstituted NH-imidazoles in yields ranging from poor to excellent, depending on the coupling partners.

Another strategy that has been explored recently is to combine a C2–N3 fragment with an N1–C4–C5 unit. For example, Shi et al. [10] employed this disconnection to form trisubstituted NH-imidazoles via the reaction of benzimidates with 2H-azirines in the presence of zinc (II) chloride. A related method was reported by Man et al. [11] and Tikhomolova et al. [12] for the synthesis of 2-aminoimidazoles under various conditions. Their protocol involves the in situ conversion of vinylazides into 2H-azirines, which subsequently reacted with cyanamide to form the desired 2-aminoimidazoles in moderate to excellent yield. Both of these methods afford NH-imidazoles with control of substitution at the 2, 4, and 5 positions. Furthermore, an ester moiety could be incorporated regioselectively at either the C-4 or C-5 positions, depending on the chosen protocol.

One of the most widely used approaches for imidazoles synthesis is the simultaneous formation of four bonds of the heterocycle’s core with both metal-catalyzed and metal-free processes being reported recently. For example, Sundar and Rengan [13] synthesized imidazoles from the three-component reaction between benzylic alcohol, 1,2-diketone, and excess ammonium acetate. This borrowing hydrogen process was catalyzed by a diruthenium(II) catalyst under aerobic conditions. The method enables the synthesis of NH-imidazoles with regioselective substitution at the C-2, C-4, and C-5 positions, and is tolerant of aryl and heteroaryl functional groups.

Mechanochemistry has also been explored for the synthesis of imidazole derivatives. Mlostoń et al. [14] reported the synthesis and transformations of 2-unsubstituted imidazole N-oxides using a solvent-free ball-milling strategy, which provided a greener alternative to traditional routes, avoiding the need for hazardous solvents. Nanocatalysts were tested by Mohammed et al. [15] for the preparation of benzoimidazole derivatives. However, such routes do not always achieve high-yield product purity. There are many approaches to synthesizing the imidazole ring; however, many synthetic routes involve drastic conditions and complex preparations of the starting materials in addition to the synthesis steps. Moreover, many of these steps do not always yield products with good purity; additionally, using special catalysts during the synthesis process increases the total cost of the synthetic route. Muñoz et al. [16] reviewed the Radziszewski reaction up to 2014, and more recently, Yu et al. [17] published a review in 2023 on the use of ultrasound irradiation for synthesizing imidazole derivatives, utilizing catalysts and various nitrogen sources.

Several groups have investigated imidazole-based ligands. Holmes et al. [18] studied the synthesis of ligands containing imidazole complex-forming agents, such as 2,2′-bipyridyl. These authors reported the first preparation of 2-(1H-imidazol-2-yl)pyridine (compound 1, Figure 2) from the 2-acetylpyridine oxime, through the toluene-p-sulphonate intermediate with potassium in dry ethanol. Gerber et al. [19] synthesized the same compound using pyridine 2-aldehyde and aqueous glyoxal, dissolved in ethyl alcohol, and added 20% ammonia at 0 °C.

The N-alkylation of imidazole could be performed by employing the N-imidazole anion [20]. A wide variety of methods have been developed for generating imidazole anions and for direct alkylation with alkyl halides. The synthesis of N-substituted heterocycles was reported by Harring [21], who used NaOH to abstract the H-N from the imidazole ring in the synthesis of N-methyl and N-butyl imidazole, yielding 69% of the product. Gerber et al. [19] reported a method for synthesizing the alkyl derivative (insertion of methyl) from metallic sodium and ethyl alcohol, followed by the addition of iodomethane, yielding 64% of the product. Wang et al. [22] synthesized methyl, propyl, and butyl derivatives from imidazole by using aqueous NaOH and DMF as the solvent. Okewole et al. [23] synthesized heptyl, octyl, and decyl pyridyl imidazole derivatives by modifying the Haring method, using KOH instead of NaOH, while Karim et al. [24] synthesized N-exadecyl imidazole derivative with NaH and THF, in the presence of phase transfer catalysts.

The synthesis of 2-(furan-2-yl)-1H-imidazole (compound 3, Figure 3) via Radziszewski reaction had not been reported previously. The synthesis of compound 3 was reported by Ledesma et al. [25], but through the dehydrogenation of 2-(furan-2-yl)-4,5-1H-dihydroimidazole in the presence of Pd as a catalyst to obtain the imidazole ring.

However, no studies on the synthesis of alkyl-furan-imidazole derivatives through the reaction studied here were found. The use of furan-2-carbaldehyde, a biomass byproduct [26], as a reagent in the Radziszewski reaction provides a renewable route with a high added value.

This work reported the synthesis of new imidazole derivatives containing a C₁₈-alkyl and pyridine ring and a C₁₈-alkyl and furan ring (compounds 2 and 4), through the Radziszewski reaction, followed by alkylation with 1-bromooctadecane. Spectroscopic characterization, including Fourier transform infrared and solution ¹H and ¹³C NMR, confirmed the structures of the precursors and the alkylated products. Based on detailed 1D and 2D solution NMR data, some previously misassigned chemical shifts of pyridine and furan ring precursors were investigated for correction. Additionally, ¹³C solid-state NMR, widely applied in fields such as catalysis, biomaterials, and pharmaceuticals [27,28,29,30,31], was employed here to characterize these compounds. To the best of our knowledge, this is the first report of ¹³C cross-polarization magic angle spinning (CP MAS NMR) spectra for compounds 1 and 3.

2. Materials and Methods

2.1. Materials

Pyridine-2-aldehyde (99%, Sigma-Aldrich, Darmstadt, Germany), glyoxal (40% in water, Sigma-Aldrich), ammonium hydroxide (Analytical grade, Vetec, Rio de Janeiro, Brazil), ethanol (99%, Sigma-Aldrich), anhydrous diethyl ether (99%, Tedia, Rio de Janeiro, Brazil), ethyl acetate (98%, Sigma-Aldrich) and 1-bromooctadecane (99%, Sigma-Aldrich) were reagent grade chemicals used as received. Furfuraldehyde (Sigma-Aldrich) was purified by distillation (B.P. 161 °C) and maintained in the dark under an inert atmosphere to prevent oxidation. Melting points were determined using an analog melting point apparatus, model 431 (Fisatom Equipamentos Científicos Ltd. São Paulo, Brazil), operating at 115–230 V, 50–60 Hz, with a temperature range of 50–300 °C. Thin-layer chromatography (TLC) was performed with aluminum plates of silica gel 60 F₂₅₄ as the stationary phase (Macherey-Nagel GmbH & Co. KG, Düren, Germany), and portable UV lamp Spectroline^®, model ENF-260C (Spectronics Corporation, Westbury, NY, USA), operating at 115 V, 60 Hz, with UV-C (254 nm) emission.

2.2. Synthesis of 2-(1H-imidazol-2-yl)pyridine (Compound 1)

A cold solution of 2-pyridinecarboxaldehyde (187 mmol) in ethanol was added to 20 mL of a 40% aqueous glyoxal solution in ethanol (20 mL), followed by ammonium hydroxide (64 mL), as described by Wang et al. [22]. A brownish-yellow solution was obtained and stored at 0 °C under stirring for 1 h, then stirred for 2–24 h at room temperature. Most of the ethanol was removed under reduced pressure, and the remaining solution was extracted several times with ethyl ether. The combined solution was evaporated under reduced pressure to afford a red, oily product, which was purified by chromatography on silica gel using ethyl acetate as eluent.

2.3. Synthesis of 2-(1-OctadecyliImidazol-2-yl)pyridine (Compound 2)

The alkylation of the imidazole ring was achieved by adding 0.06 mol of potassium hydroxide to a solution of 0.06 mol of 2-pyridyl imidazole in 50 mL of acetone, followed by dropwise addition of 0.06 mol of 1-alkyl bromide, as described by Okewole et al. [23]. The mixture was stirred for 30 min and then refluxed at 40 °C for 72 h. It was then cooled and filtered to remove the KBr salt. The resulting solution was concentrated by rotary evaporation and purified using a silica gel chromatographic column with ethyl acetate as the mobile phase.

2.4. Synthesis of 2-(Furan-2-yl)-1H-imidazole (Compound 3)

The synthesis was adapted from Wang et al. [22], which employed pyridyl carbaldehyde as the reagent. A cold solution of previously distilled furan-2-carbaldehyde (36.2 mmol, 3.0 mL) in ethanol (4 mL) was added to an ice-cold solution of 40% aqueous glyoxal (5.4 mL) in ethanol (4 mL). Then, ice-cold concentrated aqueous NH₃ (12.8 mL) was added immediately. The yellow-brown solution was kept at 0 °C for one hour and stirred for four hours at room temperature. The ethanol was removed under reduced pressure, and the resulting solution was extracted several times with ethyl ether. The combined solutions were evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using a mixture of acetone and hexane (1:3) as the mobile phase to give a yellow solid. The reactions were monitored by UV-visible spectroscopy: from the reaction medium of the synthesis of 2-(furan-2-yl)-1H-imidazole, a follow-up was made in triplicate with UV-visible analysis through the UV band at λ_max 271 nm, of the furan-2-carbaldehyde (Figure S1, Supplementary Material). A 20 μL aliquot was removed and diluted in 10 mL of ethanol every hour. A 150 μL aliquot was taken for each aliquot and diluted in 10 mL of ethanol before analysis.

2.5. Synthesis of 2-(Furan-2-yl)-1-(octadecan-1-yl)-1H-imidazole (Compound 4)

The 2-(furan-2-yl)-1H-imidazole (3.52 mmol, 472 mg) was dissolved in acetone (10 mL), followed by the addition of KOH (3.52 mmol, 197 mg). 1-Bromooctadecane (3.52 mmol, 1178 mg) was added slowly to the mixture, which was stirred for 2 h at room temperature, followed by an additional 50 h at 55 °C. The mixture was filtered to remove KBr, and the resulting solution was dried over sodium sulfate (Na₂SO₄). A dark brown oil was obtained after the filtration and solvent evaporation under reduced pressure. The sample was purified on a chromatographic column using hexane and acetone (3:1) as the mobile phase.

2.6. Characterization Techniques

FT-IR spectra were recorded in the range of 4000–400 cm⁻¹ on a Bruker Alpha II spectrometer using the KBr pellet technique. Approximately 2 mg of the sample was mixed with spectroscopic-grade potassium bromide and pressed into a pellet. The measurements were performed with a resolution of 4 cm⁻¹, collecting 16 scans for both sample and background. Spectra were processed without baseline correction or smoothing.

X-ray diffraction analyses were performed on a Rigaku Ultima IV, type I X-ray diffractometer with a high-frequency X-ray generator. The diffractograms were collected using CuKα radiation (1.54 Å), with a 2θ scan range of 5–50° and a tube voltage of 40 kV and a current of 20 mA.

UV-Vis spectrophotometric measurements were carried out using a Shimadzu UV-2600 spectrophotometer (Shimadzu Corporation, Kyoto, Japan), operating in the 185–900 nm range with a 1.0 nm spectral bandwidth, in double-beam mode. Analyses were performed using 1 cm quartz cuvettes, and data acquisition was managed using UV Probe software (version 2.43, Shimadzu, Kyoto, Japan). Solvent blanks were used for baseline correction.

High-resolution mass spectra were acquired on a Q Exactive Plus Orbitrap mass spectrometer (Thermo Scientific, Bremen, Germany) equipped with an electrospray ionization (ESI) source operating in positive ion mode. The acquisition was performed in full MS mode, with a scan range of m/z 50–900, resolution of 140,000 FWHM at m/z 200, AGC target of 1.0 × 10⁶, and maximum injection time of 50 ms. The spray voltage was set at 3.5 kV, with a capillary temperature of 320 °C, sheath gas flow of 50 a.u., auxiliary gas flow of 10 a.u., and sweep gas flow of 2 a.u.

Solution NMR data were recorded on a Bruker Avance III 500 Spectrometer equipped with a BBO S2 5.0 mm probe. All NMR experiments were performed at 20 °C: ¹H, proton-decoupled ¹³C, ¹H-¹H COSY, ¹H–¹³C HSQC, and ¹H–¹³C HMBC data sets were collected. A sample of 20 mg was dissolved in 600 μL of CDCl₃ or DMSO-d₆ and transferred to a 5 mm NMR tube. Chemical shifts were referenced to an internal TMS (tetramethylsilane) standard at 0.0 ppm.

Solid-state ¹³C CPMAS NMR spectra were recorded on a Bruker Avance III 400 WB NMR spectrometer (9.4 T), operating at a Larmor frequency of 100.64 MHz (¹³C), equipped with a Bruker double-resonance 4 mm probe head rotating at 10 kHz, at ambient temperature. Samples were packed into 4 mm ZrO₂ rotors and stopped with Kel-F caps. ¹H-¹³C cross-polarization spectra were obtained using a ramped-amplitude pulse sequence (with amplitudes ranging from 70% to 100% on the ¹H channel), employing a contact time of 50 to 10,000 μs and a recycled delay of 5 s, with scans between 2048 and 8192. ¹³C chemical shifts were externally referred to the C=O of glycine (δ 176.03 ppm).

3. Results

3.1. 2-(1H-imidazol-2-yl)pyridine (Compound 1)

Compound 1 was synthesized using modifications of the Radziszewski method. Reaction conditions were adapted to improve yield. In particular, the reaction time was optimized to 2 h, as confirmed by the disappearance of the aldehyde in TLC analysis. Pale yellow needle crystals are formed, and the yield after purification was 37%, with a melting point of 136.0 °C.

Powder X-ray diffraction data obtained for compound 1 are shown in Figure 4. It was possible to observe sharp diffraction peaks in the 2θ degrees range of 10–40 °, confirming the crystalline nature of that compound, in agreement with the CCDC (No. 807749, Figure S2, Supplementary Material). The values of 2θ degrees and relative intensities are listed in Table S1 (Supplementary Material).

The infrared spectrum of 2-(1H-imidazol-2-yl)pyridine provided evidence of the presence of functional groups in the synthesized compound (Figure S3, Supplementary Material). The 3112 cm⁻¹ band highlights the presence of the ν_N-H associated with secondary amines, while an absorption band at 1694 cm⁻¹, corresponds to ν_C=N. The 1594 cm⁻¹ band, attributed to δ_N-H (often obscured by the ν_C=C aromatic absorptions), indicates the presence of secondary amine. The 3047 cm⁻¹ absorption highlights the ν_C=C of aromatics in the structure of compound 1. Additionally, the 1459 cm⁻¹ band corresponding to the ν_C=C aromatic group is observable.

The ¹H NMR spectrum of compound 1 is shown in Figure S4 (Supplementary Material). The assignments of the pyridine and imidazole rings could be established through comparison with literature data, and simulation using ACD Program v.6.0. Table S2 (Supplementary material) lists the chemical shifts and coupling constants measured from the spectrum. The 2D H, H COSY spectrum (Figure S5, Supplementary material) confirmed the proton assignments.

Figure 5 depicts the ¹³C NMR spectra obtained in solution and solid-state. Regarding solution NMR, ¹³C{H} and ¹³C DEPT-135 (Figure S6, Supplementary Material), as well as heteronuclear 2D HSQC and HMBC (Figures S7 and S8, Supplementary Material), confirmed the carbon assignments (Table S3, Supplementary Material). On the other hand, a split signal was observed for carbon C8 in the ¹³C CPMAS spectrum, alongside an unresolved pattern for most of the carbons.

3.2. 2-(1-Octadecyl-imidazol-2-yl)pyridine (Compound 2)

The synthesis of compound 2 followed the procedure reported by Okewole et al. [23], using acetone as solvent. The product was obtained as a brown oil after solvent removal, with a pyridyl imidazole conversion of 100%, as confirmed by TLC. After purification, the yield varied from 35% to 41%.

High-resolution mass spectrometry (HRMS) analysis (Figure S9, Supplementary Material) confirmed the molecular mass of 2-(1-octadecyl-imidazol-2-yl)pyridine, with a [M+H]⁺ at m/z = 398.35232 (theor.: 397.63972 g/mol), consistent with the molecular formula C₂₆H₄₃N₃.

The infrared spectrum of compound 2 is shown in Figure 6, which displays the infrared spectra of 2-(1H-imidazol-2-yl)pyridine and its alkylated product, 2-(1-octadecyl-imidazol-2-yl)pyridine, for comparison. It was observed that when the N-H hydrogen atom is replaced by a C18 alkyl chain, the infrared spectrum of the resulting 2-(1-octadecyl-imidazol-2-yl)pyridine is characterized by the appearance of intense absorptions at 2856 and 2933 cm⁻¹.

Figure 7 shows the ¹H and ¹³C NMR spectra of compound 2 in a CDCl₃ solution. By comparing the signals observed for the precursor 2-(1H-imidazol-2-yl)pyridine, it would be possible to confirm the octadecyl chain linked to the N, through the triplet at 4.54 ppm (³J_9,10 = 7.40 Hz) and the singlet at 48.40 ppm, respectively. Table S4 (Supplementary Material) lists the NMR chemical shifts observed for 2-(1-octadecyl-imidazol-2-yl)pyridine, a new imidazole derivative not previously reported in the literature.

3.3. 2-(Furan-2-yl)−1H-imidazole (Compound 3)

The reaction of furan-2-carbaldehyde with glyoxal in the presence of NH₄OH as a nitrogen source (Radziszewski route) was monitored by UV-visible spectroscopy through the variation in absorbance intensity at 271 nm, corresponding to furan-2-carbaldehyde (Figure S10, Supplementary Material). During the 10 h reaction follow-up by UV spectroscopy (Figure 8), the minimum absorbance value of furan-2-carbaldehyde was observed after five hours.

In parallel with the formation of the 2-(furan-2-yl)-1H-imidazole, bands at 274 nm and 295 nm were also seen, confirming the product’s presence by UV analysis (Figure S11, Supplementary Material). The product was obtained as a yellow solid in 7% yield, with a melting point of 169–170 °C.

Figure 7. ¹H (top) and ¹³C (bottom) NMR spectra (CDCl₃, 500 MHz) of 2-(1-octadecyl-imidazol-2-yl)pyridine. The numbers indicated in the figure refer to the protons and carbons assignments in the chemical structure.

Figure 7. ¹H (top) and ¹³C (bottom) NMR spectra (CDCl₃, 500 MHz) of 2-(1-octadecyl-imidazol-2-yl)pyridine. The numbers indicated in the figure refer to the protons and carbons assignments in the chemical structure.

Figure 8. Ultraviolet monitoring of 2-(furan-2-yl)-1H-imidazole synthesis reaction at λ_max 271 nm. Green dots are experimental data (replicate = 3).

Figure 8. Ultraviolet monitoring of 2-(furan-2-yl)-1H-imidazole synthesis reaction at λ_max 271 nm. Green dots are experimental data (replicate = 3).

XRD diffraction (Figure 9) evidences the crystallinity of the material obtained through the Radziszewski route. Diffraction peaks positions and relative intensities were listed in Table S5 (Supplementary Material). The values were comparable to those reported in the CCDC (No. 665861, Figure S12, Supplementary Material).

In the infrared spectrum of the compound 3, a band at 3454 cm⁻¹ can be assigned to the N-H stretching vibration. The bands at 3151, 3112, 3099, 3016, and 3000 cm⁻¹ correspond to C-H stretching modes. The bands at 1627 and 1505 cm⁻¹ are attributed to C=C stretching in furanic compounds. In addition, the bands at 1593 and 1547 cm⁻¹ are generally associated with imidazole C=C stretching, and the bands at 1456 and 1438 cm⁻¹ were assigned to C=N stretching. Finally, the carbonyl band, which disappears in the product spectrum, is visible in the furan-2-carbaldehyde FTIR spectrum at 1673 cm⁻¹ (Figure S13, Supplementary Material).

The compound 3 was characterized by ¹H solution NMR (Figure S14, Supplementary Material), with the chemical shifts and coupling constants listed in

Table 1. ¹H NMR chemical shifts of 2-(furan-2-yl)-1H-imidazole.

Hydrogen Number	1H This Work a		1H Simulated (ppm) b	1H Literature (ppm) c	1H Literature (ppm) d
	δ (ppm)/Multiplicity	Coupling Constant (Hz)
8	12.53/s	-	10.56	-	-
1	7.73/dd	J1,3 = 0.5; J1,2 = 1.8	7.87	6.82	7.31
6	7.09/s	-	6.79	7.71	7.04
7	7.09/s	-	6.79	7.10	6.70
3	6.79/dd	J1,3 = 0.5; J2,3 = 3.4	6.81	6.57	5.05
2	6.59/dd	J1,2 = 1.8; J2,3 = 3.4	6.54	6.82	6.32

^a solution spectrum (DMSO-d₆, 500 MHz), dd-doublet of doublets, s-singlet; ^b spectrum generated using ACD/Labs NMR Predictor; ^c solution spectrum (DMSO-d₆) ref. [25]; ^d calculated, average values from GIAO and CSGT, ref. [25].

. The 2D H, H-COSY NMR spectrum (Figure S15, Supplementary Material) confirmed the proposed assignments. In particular, 2D COSY spectrum confirmed that H1 at 7.73 ppm is coupled with H2 (at 6.59 ppm), with a coupling constant of 1.8 Hz.

¹³C solution NMR and ¹³C solid-state CPMAS NMR spectra were also obtained (Figure 10), and the corresponding chemical shifts are listed in

Table 2. ¹³C NMR chemical shifts of 2-(furan-2-yl)-1H-imidazole.

Carbon Number	13C, ppm This Work a	13C Solid State, ppm This Work b	13C, ppm Simulated c	13C, ppm Literature d	13C Calculated, ppm Literature e
4	146.36	146.1	144.82	146.26	151.02
1	142.53	142.6	141.90	122.50	141.17
5	138.55	139.4	140.07	138.06	138.80
6	128.60	127.9; 127.0	120.39	142.52	142.99
7	116.99	118.0; 117.0	116.43	122.50	113.52
2	111.68	110.0	113.59	111.67	105.86
3	106.31	106.4	105.13	106.42	112.56

^a solution spectrum (DMSO-d₆, 500 MHz); ^b CPMAS spectrum (100 MHz); ^c from ACD/Labs NMR Predictor; ^d solution spectrum (DMSO-d₆), ref. [24]; ^e calculated, average values from GIAO and CSGT, ref. [24].

. Figure S16 (Supplementary Material) shows the DEPT-135 spectrum, thus confirming the ¹³C solution assignments. In addition, 2D ¹H,¹³C correlations (HSQC and HMBC experiments, shown in Figures S17 and S18, Supplementary Material) supported the proposed assignments.

In the ¹³C solid-state NMR spectrum of compound 3, the carbons C6 and C7 are split, suggesting the presence of at least two distinct crystalline structures. The assignment of protonated carbons was confirmed through the spectrum obtained with a contact time of 50 microseconds (Figure S19, Supplementary Material).

3.4. 2-(Furan-2-yl)-1-(octadecan-1-yl)-1H-imidazole (Compound 4)

A slightly brown oil product (1.20 g, 88% yield) was obtained following the procedure reported in the literature for the short-chain alkylation of the H-N imidazole ring. The molecular mass of compound 4 was determined by high-resolution mass spectrometry (HRMS) analysis (Figure S20, Supplementary Material), which confirmed the molecular mass of 2-(furan-2-yl)-1-(octadecane-1-yl)-1H-imidazole, with a [M+H]⁺ at m/z = 387.33608 (theor.: 386.61378 g/mol), consistent with the molecular formula C₂₅H₄₂ON₂.

The infrared spectrum of compound 4 is shown in Figure 11, alongside those of compound 3 and 1-octadecyl bromide for comparison. Bands at 3112, 2924, and 2853 cm⁻¹ confirmed the presence of the alkyl moiety, and the absence of the N-H stretching at 3454 cm⁻¹ confirmed the product.

The 1D ¹H and ¹³C solution NMR spectra (Figure 12) evidenced that, besides the alkylated product, an absorption due to CH₂-O is also present, at 3.40 ppm (triplet, J = 6.9 Hz) and 60.4 ppm, respectively. That finding is coherent with the formation of octadecyl alcohol, resulting from a nucleophilic attack of the KOH on the alkyl bromide. Complementary analyses by solution NMR are shown in the Supplementary Material (Figure S21). The assignment of the NMR signals observed for 2-(furan-2-yl)-1-(octadecan-1-yl)-1H-imidazole is shown in Table S6 (Supplementary Material) and confirms the structure of the new biomass-derived product.

4. Discussion

In the synthesis of 2-(1H-imidazol-2-yl)pyridine, compound 1, Wang et al. [22] reported a yield of 42% after 5 h of reaction, while Gerber et al. [19] distilled the product as an oil under high vacuum, achieving 75% yield. In our work, a purified yield of 37% was obtained after 2 h of reaction. To improve the yield, an attempt was made to recrystallize the product in ethyl acetate; however, the amount of pure product was very low. Further studies will be conducted using ultrasound to enhance the reaction yield, as suggested by Yu et al. [17]. Compared with XRD available in the literature, the 2θ values of the more intense diffraction peaks agree in part with the crystalline structure already published. Tinant et al. [32] reported the crystal structure of 2-(1H-imidazol-2-yl)pyridine and noted that the crystals diffracted only to 2θ = 46.5°, in line with our XRD results. The infrared spectrum aligns with that obtained by Okewole et al. [23], who observed the bands due to ν_NH and ν_C=C of the imidazole ring. The ¹H and ¹³C solution NMR chemical shifts matched literature values, except for the ¹³C assignments published by Voss et al. [33], in which the positions of C6 and C5 were inverted. The low intensity of carbons C6 and C7 of the imidazole ring, at 130.3 ppm and 117.82 ppm, respectively, is noteworthy and would be due to tautomerism in the imidazole moiety [34]. In the ¹³C CP MAS solid-state NMR spectrum, besides the low resolution of the absorptions compared to the solution spectrum, some split signals can be seen, suggesting that more than one crystalline phase is present or that the contribution of various molecules within the unitary cell is significant. Tinant et al. [32] established the crystal structure of compound 1. Those authors reported that the asymmetric part of the unit cell contains eight organic molecules, corroborating the broad shape and splitting of the signals observed in the ¹³C CP MAS spectrum of the present work. To the best of our knowledge, this is the first report of the ¹³C CP MAS spectrum of compound 1.

Figure 12. ¹H (top) and ¹³C (bottom) NMR spectra (CDCl₃, 500 MHz, top) of 2-(furan-2-yl)-1-(octadecan-1-yl)-1H-imidazole. Signals assigned as ‘a’ refer to octadecyl alcohol as a subproduct and ‘s’ as a solvent. The numbers indicated in the figure refer to the hydrogens and carbons assignments in the chemical structure.

Figure 12. ¹H (top) and ¹³C (bottom) NMR spectra (CDCl₃, 500 MHz, top) of 2-(furan-2-yl)-1-(octadecan-1-yl)-1H-imidazole. Signals assigned as ‘a’ refer to octadecyl alcohol as a subproduct and ‘s’ as a solvent. The numbers indicated in the figure refer to the hydrogens and carbons assignments in the chemical structure.

In the synthesis of compound 2, the 2-(1-octadecyl-imidazol-2-yl)pyridine, the conversion of the reagent imidazolyl was quantitative, although the yield of the pure product ranged from 35–41%. Okewole et al. [23] obtained alkylated products with heptyl, octyl, and decyl groups in yields ranging from 41–53%. Karim et al. [24] synthesized the 16-carbon alkylated compound, using THF as a solvent, sodium hydride to generate the N:^- ânion, and TBAB as a phase transfer catalyst, although no yields were reported. While the authors pointed out that the presence of phase transfer catalysts is fundamental for a successful reaction, we successfully obtained the C18-alkylated pyridyl imidazole derivative without a catalyst, simply by using vigorous magnetic bar stirring. Additionally, it is crucial to emphasize that the dropwise addition of the alkyl halide to the reaction medium is a vital step for the total conversion of the reactants. Further studies are underway to increase the yield of the pure product. The infrared spectrum of the 2-(1-octadecyl-imidazol-2-yl)pyridine is characterized by the appearance of intense absorptions at 2856 and 2933 cm⁻¹. These bands result from the stretching of the aliphatic C-H bond of the long alkyl chain. Karim et al. [24] synthesized a product with 16 carbons and reported the appearance of peaks at 2850 and 2920 cm⁻¹, which is consistent with our observations. Solution ¹H and ¹³C agree with the expected values from simulations.

The synthesis of compound 3, 2-(furan-2-yl)-1H-imidazole, was successfully monitored by UV spectroscopy. As reported by Sharma et al. [35], such reactions can last up to 24 h without a catalyst; however, we obtained 44% yield after 4 h of reaction. The intermediate of Radziszewski reactions is believed to be a diimine that results from the reaction of one equivalent of glyoxal with two equivalents of an N-source, as proposed by Asressu et al. [36]. After 1 h of stirring at 0 °C, the ¹³C NMR spectrum evidenced the presence of the amine alcohol (intermediate I, shown in Figure 13) as the first intermediate, as indicated by the ¹³C signal at 84 ppm and ¹H absorption at 5.8 ppm (Figure S22 and Table S7, Supplementary Material). Tuguldurova et al. published a theoretical analysis of the intermediates in the reactions of glyoxal with ammonia [37] and glyoxal with acetaldehyde and ammonia [38], conducted in aqueous solution, which included a rigorous thermodynamic analysis. They proposed a similar structure, as indicated for intermediate I, along with other structures, as a function of pH and the amount of reagents.

The final product, a yellow solid, must be stored in an inert atmosphere and at room temperature to prevent darkening. That observation is supported by recent results published by Almeida et al. [39], which refer to the oxidation of the imidazole ring by air. The FTIR absorptions of compound 3 agreed with data reported by Ledesma et al. [25], who published a structural and vibrational study of 2-(2′-furyl)-1H-imidazole, including ¹H and ¹³C data from the experimental spectra and DFT calculations. The ¹H NMR results from the present work indicate that the chemical shifts of H6 and H7 of the imidazole ring are identical, reflecting the strong delocalization due tautomerism: the proton moves from one nitrogen to the other [28]. The assignment of H1 and H2 of the furan ring, indicated in the published work as being at the same chemical shift of 6.2 ppm, has distinct electronic shieldings due to the proximity of H1 to the oxygen of the furan ring. The ¹³C NMR data were also compared with those published by Ledesma et al. [25], and similar inconsistencies were noted. Ledesma et al. [25] assigned identical shifts to C2 and C7, whereas our data indicated distinct environments. The C2, belonging to the furan ring, is positioned near oxygen, a highly electronegative heteroatom, which reduces the electron density around the nucleus of C2, resulting in less shielding. Differently, the C7, located in the imidazole ring, is adjacent to nitrogen, which also exerts an electronegative influence, albeit with a more pronounced resonance effect. This nitrogen stabilizes charges and redistributes electrons, resulting in a relative increase in the electronic shielding of C7 [40], which generates the chemical shifts observed in this work. DFT calculations reported by Ledesma et al. [25] predicted the existence of two molecular conformations, and that in the solid phase and solution, the two conformations are in equal populations for 2-(furan-2-yl)-1H-imidazole (CCDC N^o 665861, Figure S12, Supplementary Material). Based on the literature, the observed split in the solid-state ¹³C CPMAS spectrum of compound 3 could be attributed to the distinct crystalline structures of the two conformers.

Regarding compound 4, 2-(furan-2-yl)-1-(octadecane-1-yl)-1H-imidazole, a slightly brown oil with 88% yield was obtained. There was no data available in the literature about this new imidazole derivative. The published yields obtained through alkylation using imidazole derivatives vary according to the alkyl radical, with yields of 82% for the methyl radical, 75% for the propyl radical, and 89% for the butyl radical [22].

5. Conclusions

In this work, two new long-chain N-alkylated imidazole derivatives were synthesized and characterized: 2-(1-octadecyl-imidazol-2-yl)pyridine and 2-(furan-2-yl)-1-(octadecane-1-yl)-1H-imidazole. The latter represents the first report of an alkyl-furan-imidazole derivative obtained via the Radziszewski reaction, using furfuraldehyde, a renewable biomass precursor, as a starting material. FTIR, 1D/2D NMR, and HRMS confirmed structural elucidation in solution. At the same time, solid-state ¹³C CPMAS spectra, presented for the first time for the pyridine and furan precursors, were consistent with the crystallographic structures deposited at the CCDC. Furthermore, the study allowed the correction of previously published incorrect assignments of ¹H and ¹³C chemical shifts for the precursors, providing more accurate and reliable spectroscopic data. Another relevant aspect was the demonstration that N-alkylation with the C18 chain can be performed without the use of phase transfer catalysts, only with vigorous stirring, expanding the applicability of the reaction. Thus, this work presents new, previously unpublished derivatives, new solid-state spectroscopic characterizations, and corrected NMR assignment data, thereby expanding the scope of the Radziszewski reaction and opening up prospects for the synthesis of imidazole derivatives with potential in areas of pharmacological and advanced materials interest.