An Eco-Friendly Ultrasound-Assisted Synthesis of Novel Fluorinated Pyridinium Salts-Based Hydrazones and Antimicrobial and Antitumor Screening.

The present work reports an efficient synthesis of fluorinated pyridinium salts-based hydrazones under both conventional and eco-friendly ultrasound procedures. The synthetic approach first involves the preparation of halogenated pyridinium salts through the condensation of isonicotinic acid hydrazide (1) with p-fluorobenzaldehyde (2) followed by the nucleophilic alkylation of the resulting N-(4-fluorobenzylidene)isonicotinohydrazide (3) with a different alkyl iodide. The iodide counteranion of 5-10 was subjected to an anion exchange metathesis reaction in the presence of an excess of the appropriate metal salts to afford a new series of fluorinated pyridinium salts tethering a hydrazone linkage 11-40. Ultrasound irradiation led to higher yields in considerably less time than the conventional methods. The newly synthesized ILs were well-characterized with FT-IR, ¹H NMR, (13)C NMR, (11)B, (19)F, (31)P and mass spectral analyses. The ILs were also screened for their antimicrobial and antitumor activities. Within the series, the salts tethering fluorinated counter anions 11-13, 21-23, 31-33 and 36-38 were found to be more potent against all bacterial and fungal strains at MIC 4-8 µg/mL. The in vitro antiproliferative activity was also investigated against four tumor cell lines (human ductal breast epithelial tumor T47D, human breast adenocarcinoma MCF-7, human epithelial carcinoma HeLa and human epithelial colorectal adenocarcinoma Caco-2) using the MTT assay, which revealed that promising antitumor activity was exhibited by compounds 5, 12 and 14.

1. Introduction

In recent years, the development of clean, safe and efficient eco-friendly protocols has become a major challenge in green chemistry. Ultrasound (US) has been extensively adopted as a promising green pathway [1] in several organic transformations. US was reported to drastically increase reaction rates, improve yields and provide high purity of products with an easy work-up [2,3,4]. An enhanced selectivity and reduction of chemical hazards using this safe ultrasound method have been well documented [2,3,4].

Ionic liquids (ILs) have emerged as fascinating new green solvents as alternatives to volatile organic solvents due to their sought-after properties such as negligible vapor pressure, high thermal stability, high ionic conductivity and high ability to solvate both polar and non-polar compounds [2,5]. Their most attractive features are their very low volatility, nonflammability and stability, which make them suitable for applications in diverse fields, such as organic synthesis, catalysis and biocatalysis, analytical chemistry, nanotechnology, food science and as function fluids (e.g., lubricants, heat transfer fluids and corrosion inhibitors) [4,5]. Recently, some acidic task-specific ILs were used as solvents and catalysts for the hydrolysis/conversion of cellulose and lignocellulosic biomass [6].

ILs have also demonstrated promising applications for medicinal chemistry, including antimicrobial, antiseptic, anticancer and anti-inflammatory activities [7].

Because the synthesis of ionic liquids [5,8] is not easy, chemists have developed several green protocols for the clean and safe synthesis of IL liquids including microwave (MW), ultrasound (US) and solvent-free reactions.

Hydrazones are an important class of Schiff bases and are widely used as antimalarial [9], anticancer [10], antibacterial [11], antifungal [12], antitubercular [13], antimicrobial [14] and antiviral [15] agents. The azomethine linkage on the Schiff base structures are responsible for their bioactivity, enabling them to serve as models for biologically important scaffolds [16]. In addition, there are many commonly used drugs incorporating hydrazone groups in their structures.

In view of the emerging importance of ILs and hydrazones as antimicrobial and anticancer agents and our general interest in ultrasound-assisted organic synthesis, we focus on developing a straightforward, safe and ecofriendly method for the synthesis of fluorinated pyridinium ILs tethering a hydrazone linkage under ultrasound irradiation and conventional heating. To the best of our knowledge, the synthesis of ionic liquids carrying a hydrazone functionality has not been previously reported in the literature. However, the synthesized compounds were found to be salts rather than ILs and were screened for their antimicrobial and antitumor activities in order to evaluate the synergistic effect resulting from the clubbing of these salts with azomethine hydrazone functionality in a single molecular frame work.

2. Results and Discussion

2.1. Chemistry

In the present work, several attempts to find the optimum conditions for the synthesis of new classes of fluorinated pyridinium ionic liquid-based hydrazone have been investigated under both conventional and ultrasound methods. These attempts led to the finding that the alkylation of isonicotinic acid hydrazide with several alkyl iodides in different solvents such as acetonitrile, toluene and methanol afforded very poor yields (24%–28%) of compound 4, under either conventional heating or US. In addition, no reaction was observed under several attempts to condensate the resulting 4 with p-fluorobenzaldehyde (2) in the presence of a catalytic amount of HCl in boiling ethanol and/or under ultrasonic conditions (Scheme 1).

Scheme 1

Synthesis of halogenated pyridinium salts tagged with hydrazone 5–10 under conventional method (CM) and ultrasound irradiation (US).

Conversely, the successful strategy for synthesizing the target 5–10 was based on the alkylation of N-(4-fluorobenzylidene)isonicotinohydrazide (3) with the appropriate alkyl halides under both conventional and US conditions. Thus, the condensation of acid hydrazide 1 with p-fluorobenzaldehyde (2) afforded the corresponding hydrazone 3 in excellent yield (90%) in refluxing ethanol for 1 h; a comparable yield has been obtained within 30 min under ultrasound irradiation. The resulting hydrazone 3 has been alkylated with different alkyl iodides, furnishing the target halogenated pyridinium salts 5–10 in 83%–91% yields, as shown in Scheme 1.

When the alkylation was carried out under ultrasound irradiation, great reductions in reaction time (12–14 h) were observed with higher yields (90%–94%) compared to those obtained under the classical method (72 h) (Table 1).

Table 1

Conventional versus ultrasound times and yields of hydrazone 3 and pyridinium salts 5–10.

Compound No.	R	Conventional Method CM		Ultrasound Method US
		Time (h)	Yield (%)	Time (h)	Yield (%)
3	–	1	90	0.5	96
5	C2H5	72	85	12	94
6	C3H7	72	83	12	93
7	C4H9	72	85	14	90
8	C5H11	72	91	14	94
9	C6H13	72	86	14	92
10	C7H15	72	91	14	94

The structures of the hydrazones 5–10 have been established based on their mass and spectroscopic data (1H NMR, 13C NMR, 19F NMR). The NMR spectra of the synthesized compounds 5–10 measured in DMSO-d6 revealed the presence of a diastereomeric mixture (i.e., E/cis and E/trans) for each imino-amide moiety.

The N-hexyl derivative 9 was selected to discuss the NMR data used to confirm the success of the quaternization reaction. From its 1H NMR spectrum, the appearance of the diagnostic CH and NCH as a triplet at δH 0.88 ppm and a doublet of doublets at δH 4.70 ppm, respectively, are clear evidence for the success of the alkylation reaction. The remaining methylene groups were also observed.

The spectrum also revealed the presence of two singlets at δH 8.16 and 8.50 ppm, with a ratio of 1:3, which have a total integration of one proton characteristic of the imine proton (HC=N). In addition, the NH group split into two singlets at δH 12.47 and 12.52 ppm that have a total integration of one proton with the same ratio (Figure 1). Moreover, eight aromatic protons resonated in their appropriate chemical shifts with a similar isomeric pattern to that observed for the NH and H–C=N groups. To confirm the solvent effect for the isomerism of hydrazones, the 1H NMR spectrum of compound 9 was recorded in a less polar solvent (CDCl3). Consequently, one singlet signal was observed at δH 12.25 ppm for the NH proton and at δH 9.13 ppm for the HC=N proton, corresponding to the cis and trans conformers of the E isomer (Figure 2). These results agree with those previously reported in our work, where the hydrazone functionality was proven to exhibit E/cis and E/trans geometrical isomerism in polar solvents such as DMSO-d6, while only the E/cis or E/trans isomer was recorded in a less polar solvent (CDCl3) [17,18].

Figure 1

1H NMR spectrum of compound 9 in DMSO-d6.

Figure 2

1H NMR spectrum of compound 9 in CDCl3.

Further assignment of the diastereomer formation for compound 9 was supported by 13C NMR and dept-135 experiments. In the 13C NMR spectrum, each peak of compound 9 appeared as two sets of signals due to the presence of the diastereomeric mixture. In the aliphatic region, the methyl and NCH2 carbons resonated as two sets of signals at 61.43 and 61.51, respectively. The C=N and C=O groups of the E/cis and E/trans diastereomers also resonated as double peaks at δC 159.27–165.72 ppm.

The 19F NMR spectrum (Figure 3) also proved the formation of a diastereomeric mixture (E/cis and E/trans) through the appearance of two characteristic multiplets at δF −109.90 to −109.82 and −109.44 to −109.36 ppm, attributed to the aromatic fluorine atom.

Figure 3

19F NMR spectrum of compound 9 in DMSO-d6.

The structure of compound 9 was also confirmed by the electron impact mass spectrum, which showed a molecular ion peak at 459.38 [M+].

All the newly synthesized iodonated pyridinium salts 5–10 have been subjected to a metathesis reaction in which the iodide anion has been displaced by different anions. The anion exchange reactions were carried out by their refluxing with different metal salts such as NaBF4, KPF6, NaOCOCF3, NaSCN, or NaNO3, in acetonitrile as solvent for 16 h to give new specific-based hydrazones 11–40 in 80%–98% yields (Scheme 2).

Scheme 2

Synthesis of specific-based hydrazones 11–40.

When these reactions were assisted by ultrasound irradiation, 6 h were required to afford comparable yields of the same ILs (Table 2).

Table 2

Conventional versus ultrasound times and yields of compounds 11–40.

Compound No.	R	Y	Conventional Method CM		Ultrasound Method US
			Time (h)	Yield (%)	Time (h)	Yield (%)
11	C2H5	PF6	16	94	6	98
12	C2H5	BF4	16	85	6	92
13	C2H5	COOCF3	16	80	6	90
14	C2H5	NO3	16	89	5	98
15	C2H5	SCN	16	98	6	98
16	C3H7	PF6	16	93	6	96
17	C3H7	BF4	16	81	6	90
18	C3H7	COOCF3	16	85	6	94
19	C3H7	NO3	16	82	5	92
20	C3H7	SCN	16	85	5	96
21	C4H9	PF6	16	88	6	94
22	C4H9	BF4	16	83	6	90
23	C4H9	COOCF3	16	85	6	92
24	C4H9	NO3	16	83	5	90
25	C4H9	SCN	16	83	5	92
26	C5H11	PF6	16	86	6	94
27	C5H11	BF4	16	90	6	98
28	C5H11	COOCF3	16	80	6	92
29	C5H11	NO3	16	94	5	98
30	C5H11	SCN	16	96	5	98
31	C6H13	PF6	16	91	6	98
32	C6H13	BF4	16	98	6	98
33	C6H13	COOCF3	16	89	6	92
34	C6H13	NO3	16	87	5	94
35	C6H13	SCN	16	98	5	98
36	C7H15	PF6	16	98	6	98
37	C7H15	BF4	16	98	6	98
38	C7H15	COOCF3	16	80	6	88
39	C7H15	NO3	16	83	6	88
40	C7H15	SCN	16	80	6	86

The analysis of the NMR spectra of compounds 11–40 revealed that their 1H and 13C NMR are practically the same as those recorded for their precursors 5–10, with the isomeric splitting pattern. Accordingly, the 31P NMR, 19F NMR and mass spectra analyses have supported the success of the metathesis reaction. In the 31P NMR spectrum of compound 31, the appearance of a characteristic multiplet signal at δP −157.37 to −131.02 ppm confirms the presence of the PF6− anion. In addition, its 19F NMR spectrum displays two characteristic singlets at δF −71.10 and −69.22 ppm, confirming the presence of a fluorine atom in its PF6− form, while the aromatic fluorine atom was assigned as two multiplets at δF (−109.90 to −109.82) ppm and (−109.44 to −109.36) ppm. In addition, the presence of a molecular ion peak at 473.39 [M+] in its mass spectrum supports the structure of compound 31. The iodide anion exchange of 9 using NaBF4 as a metal salt led to the formation of compound 32, with its structure supported by its 11B NMR and 19F NMR spectra. The appearance of a characteristic doublet at δB −1.28 ppm in the 11B NMR spectrum confirmed the incorporation of the boron anion in its structure.

The 19F NMR spectrum displays two doublets at δF −148.30 and −145.25 ppm, attributed to the fluorine anion (BF4−), while the aromatic fluorine was recorded at δF −109.90 to −109.82 ppm and −109.45 to −109.37 ppm as two multiplets. The structure of IL 32 has also been established based on its electron impact mass spectrum, which shows a molecular ion peak at 415.22 [M+]. The anion exchange with trifluoroacetate has also been investigated and gave IL 33, as was also confirmed by its 19F NMR spectrum, which clearly shows a singlet at δF −73.50 ppm due to the CF3COO− anion. The aromatic fluorine atom resonated at the expected area. The mass spectral data reveals the presence of the molecular ion peak at 441.18 [M+] as evidence for the formation of compound 33.

Because 34 and 35 carrying NO3− and/or SCN− anion head-groups display similar 1H and 13C NMR spectra compared to their precursor 9, their formation becomes more evident based on their mass spectra. The mass spectra of compounds 34 and 35 display molecular ion peaks at 390.37 [M+] and 386.56 [M+], respectively.

2.2. Biological Assay

2.2.1. Antimicrobial Activity

Compounds 5–15, 21–25 and 31–40 were assessed in vitro for their efficacy as antimicrobial agents by the minimum inhibitory concentration (MIC) using the broth dilution method [19,20] against six standard bacterial strains (Streptococcus pneumonia, Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeuroginosa, Escherichia coli and Klebsiella pneumonia) and two fungi (Aspergillus fumigatus and Candida albicans). The MIC results are summarized in Table 3.

Table 3

Antimicrobial activity expressed as MIC (μg/mL).

Compound No.	Gram-Positive Organisms			Gram-Negative Organisms			Fungi
	Sp	Bs	Sa	Pa	Ec	Kp	Af	Ca
5	16	16	16	16	16	16	125	125
7	16	16	16	16	16	16	62.5	125
9	8	8	16	16	8	8	62.5	62.5
10	8	8	8	16	8	8	62.5	62.5
11	8	4	4	8	8	8	31.25	31.25
12	8	4	8	4	8	8	16	16
13	4	4	8	16	16	16	31.25	31.25
14	16	16	16	16	16	16	125	125
15	16	16	16	16	16	16	250	250
21	8	4	4	8	8	8	31.25	31.25
22	8	4	4	4	8	8	31.25	31.25
23	4	4	8	8	8	8	16	16
24	16	16	16	16	16	16	125	125
25	16	16	16	16	16	16	125	125
31	8	8	4	8	8	8	16	16
32	4	4	4	8	4	4	16	16
33	4	4	4	4	4	4	8	8
34	8	8	8	8	4	8	125	125
35	8	8	8	8	4	8	125	125
36	4	4	4	4	4	4	16	16
37	4	4	4	4	4	4	8	8
38	4	4	4	4	4	4	8	8
39	4	4	8	4	4	8	125	125
40	4	4	8	4	4	8	125	125
Ciprofloxacin	≤5	≤1	≤5	≤5	≤1	≤1	–	–
Fluconazole	–	–	–	–	–	–	≤1	≤1

The antibacterial activity screening for the halogenated pyridinium salts 5–10 against all of the bacterial strains demonstrated that all the compounds reveal promising antibacterial activities, with an MIC range of 8–16 µg/mL. In contrast, the opposite result was observed for the two fungal species, towards which the compounds showed no activity.

From the antibacterial activity results of compounds 11–40, it can be stated that those resulting from the metathetical anion exchange with fluorinated metal salts (PF6−, BF4− or CF3COO−) are more effective against all bacterial strains at an MIC of 4–8 µg/mL.

The antifungal bioassay results summarized in Table 3 reveal that, among the tested salts 11–40, compounds 21–23, 31–33 and 36–38 show good to excellent potency against all of the tested fungal strains, with an MIC range of 8–16 µg/mL. In fact, the highest antifungal activity, with an MIC of 8 µg/mL, was exhibited by compounds 33 and 38, possessing a CF3COO− counter anion and a C6 to C7 alkyl chain in the cation head group.

The antimicrobial activity and structure activity relationship reveal that the promising activity displayed by the halogenated 5–10 against all of the bacterial strains is presumably due to the chain length. The incorporation of a fluorine atom was found to dramatically increase the antimicrobial activity, as exhibited by the fluorinated 11–13, 21–23, 31–33 and 36–38 carrying PF6−, BF4− and/or CF3COO−. In addition, the metathetic exchange with these fluorinated metal salts resulted in higher antifungal activity.

In the antimicrobial screening, it was observed that compounds with long alkyl side chains possessing a fluorine atom in their anion head-group (PF6−, BF4− and CF3COO−) exhibit excellent activity compared to the corresponding halogenated precursors against all of the bacterial strains, indicating the influence of the presence of the fluorine atom in the structure of the ionic liquids.

2.2.2. Antiproliferative Activity

An in vitro evaluation of the antiproliferative activities of the newly synthesized compounds was investigated against four human tumor cell lines by using the protocol described in ISO 10993-5 [21]. The results are presented as IC50 ± SD values (Table 4). Each experiment was repeated three times. IC50 concentrations were obtained from the dose–response curves using Graph Pad Prism Software 5.

Table 4

LD50 values (ng/µL) of the examined compounds on four human cancer cell lines. Values are expressed as the mean ± SD of three experiments.

Compound No.	MCF-7	T47D	HeLa	Caco-2
5	286 ± 8	278 ± 10	292 ± 9	301 ± 11
11	Not active	Not active	Not active	Not active
12	512 ± 11	498 ± 6	503 ± 8	528 ± 10
13	Not active	Not active	Not active	Not active
14	465 ± 8	486 ± 13	471 ± 15	463 ± 9
15	Not active	Not active	Not active	Not active

Human ductal breast epithelial tumor T47D; Human breast adenocarcinoma MCF-7; Human epithelial carcinoma HeLa; Human epithelial colorectal adenocarcinoma Caco-2.

Only the compounds shown in Table 4 demonstrated a measurable IC50 against the tested cancer cell lines and thus can be used as model compounds for the construction of novel anticancer drugs. Interestingly, reducing the chain length of the compounds yielded more potent cytotoxic activities, suggesting a steric factor mediating either transport or molecular interaction with the cellular targets.

3. Experimental Section

3.1. General

Melting points were recorded on a Stuart Scientific SMP1 apparatus (Stuart, Red Hill, UK) and are uncorrected. The IR spectra were recorded using an SHIMADZU FTIR-8400S spectrometer (SHIMADZU, Boston, MA, USA). The NMR spectra were measured with a Bruker spectrometer (400 and 600 MHz, Brucker, Fällanden, Switzerland) using Tetramethylsilane (TMS) (0.00 ppm) as an internal standard. The ESI and EI mass spectra were measured by Finnigan LCQ and Finnigan MAT 95XL spectrometers (Finnigan, Darmstadt, Germany), respectively. Ultrasound-assisted reactions were performed in a Kunshan KQ-250B ultrasound cleaner (50 KHz, 240 W, Kunshan Ultrasonic Instrument, Kunshan, China).

3.2. Synthesis and Characterization of N-(4-Fluorobenzylidene) Isonicotinohydrazide (3)

3.2.1. Conventional Method

A mixture of isonicotinic acid hydrazide (1) (1 mmol) in ethanol (25 mL) and 4-fluorobenzaldehyde (2) (1.2 mmol) with three drops of hydrochloric acid was refluxed for 1 h. After cooling, the excess solvent was removed under reduced pressure. The product formed was collected and crystallized from ethyl acetate to furnish the desired compound 3 mp: 214–215 °C (Lit. mp: 216–220 °C) [22]. 1H NMR (600 MHz, DMSO-d6): δH = 7.27 (dd, 0.25H, J = 6 Hz, 12 Hz, Ar–H), 7.35 (dd, 1.75H, J = 6 Hz, 12 Hz, Ar–H), 7.59 (t, 0.25H, J = 6 Hz, Ar–H), 7.67 (d, 0.25H, J = 6 Hz, Ar–H), 7.82–7.84 (m, 3.5H, J = 6 Hz, Ar–H), 8.11 (s, 0.1H, H–C=N), 8.48 (s, 0.9H, H–C=N), 8.75 (d, 0.25H, J = 6 Hz, Ar–H), 8.81 (d, 1.75H, J = 6 Hz, Ar–H), 12.04 (s, 0.2H, CONH), 12.09 (s, 0.8H, CONH). 13C NMR (150 MHz, DMSO-d6): δC = 116.38, 116.53, 121.98, 123.53, 129.92, 129.98, 131.12, 140.89, 148.34, 150.02, 150.81 (Ar–C), 162.08, 162.94, 164.58 (C=N, C=O).

3.2.2. Ultrasound Method

A mixture of isonicotinic acid hydrazide (1) (1 mmol) in ethanol (25 mL) and 4-fluorobenzaldehyde (2) (1.2 mmol) with a few drops of hydrochloric acid was irradiated by ultrasound irradiation for 30 min at room temperature. The reaction proceeded as described above to furnish the same compound 3.

3.3. General Procedures for the Synthesis of Pyridinium Tagged Hydrazones 5–10

3.3.1. Conventional Method

A mixture of compound 3 (1 mmol) and the appropriate alkyl iodide with chain lengths ranging from C2 to C7 (1.5 mmol) in acetonitrile (30 mL) was refluxed for 72 h. After cooling, the solvent was removed under reduced pressure, and the solid formed was collected by filtration, washed with acetonitrile, and crystallized from dichloromethane to afford the desired pyridinium hydrazones 5–10.

3.3.2. Ultrasound Method

A mixture of compound 1 (1 mmol) and the appropriate alkyl iodide with chain lengths ranging from C2 to C7 (1.5 mmol) in acetonitrile (30 mL) was irradiated by ultrasound irradiation at room temperature. The reaction proceeded as described above to afford the desired pyridinium hydrazones 5–10.

1-Ethyl-4-(2-(4-fluorobenzylidene)hydrazinecarbonyl)pyridinium iodide (). It was obtained as yellow crystals; mp: 223–224 °C. FT-IR (KBr), cm−1: = 1613 (C=N), 1690 (C=O), 2893, 2960 (Al–H), 3075 (Ar–H). 1H NMR (600 MHz, DMSO-d6): δH = 1.58–1.63 (m, 3H, CH3), 4.70–4.75 (m, 2H, NCH2), 7.26 (dd, 0.5H, J = 6 Hz, 12 Hz, Ar–H), 7.37 (dd, 1.5H, J = 6 Hz, 12 Hz, Ar–H), 7.63 (dd, 0.5H, J = 6 Hz, 12 Hz, Ar–H), 7.89 (dd, 1.5H, J = 6 Hz, 12 Hz, Ar–H), 8.17 (s, 0.25H, H–C=N), 8.40 (d, 0.5H, J = 6 Hz, Ar–H), 8.51 (s, 0.75H, H–C=N), 8.53 (d, 1.5H, J = 6 Hz, Ar–H), 9.26 (d, 0.5H, J = 6 Hz, Ar–H), 9.35 (d, 1.5H, J = 6 Hz, Ar–H), 12.48 (s, 0.8H, CONH), 12.51 (s, 0.2H, CONH).13C NMR (150 MHz, DMSO-d6): δC = 16.59, 16.72 (CH3), 57.07, 57.16 (NCH2), 116.32, 116.46, 116.51, 116.65, 126.60, 127.62, 129.91, 129.97, 130.24, 130.30, 130.50, 130.70, 130.71, 145.36, 145.62, 146.01, 147.75, 149.84, 149.99 (Ar–C), 159.26, 162.86, 163.18, 164.83, 165.70 (C=N, C=O). 19F NMR (377 MHz, DMSO-d6): δF = (−109.89 to −109.81), (−109.43 to −109.35) (2m, 1F, Ar–F). MS (ES) m/z = 399.36 [M+].

4-(2-(4-Fluorobenzylidene)hydrazinecarbonyl)-1-propylpyridinium iodide (). It was obtained as yellow crystals; mp: 186–187 °C. FT-IR (KBr), cm−1: = 1615 (C=N), 1689 (C=O), 2890, 2955 (Al–H), 3065 (Ar–H). 1H NMR (400 MHz, DMSO-d6): δH = 0.90–0.95 (m, 3H, CH3), 1.95–2.04 (m, 2H, NCH2CH2), 4.68 (dd, 2H, J = 4 Hz, 8 Hz, NCH2), 7.27 (dd, 0.5H, J = 8 Hz, 12 Hz, Ar–H), 7.38 (dd, 1.5H, J = 8 Hz, 12 Hz, Ar–H), 7.62 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.89 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.16 (s, 0.25H, H–C=N), 8.41 (d, 0.5H, J = 4 Hz, Ar–H), 8.51 (s, 0.75H, H–C=N), 8.55 (d, 1.5H, J = 8 Hz, Ar–H), 9.25 (d, 0.5H, J = 4 Hz, Ar–H), 9.34 (d, 1.5H, J = 8 Hz, Ar–H), 12.49 (s, 0.75H, CONH), 12.53 (s, 0.25H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 9.27, 9.30 (CH3), 23.11, 23.19 (NCH2CH2), 61.30, 61.38 (NCH2), 114.86, 115.06, 115.27, 125.22, 126.18, 128.43, 128.52, 128.81, 128.90, 129.11, 129.26, 129.29, 144.14, 144.78, 146.41, 148.39, 148.72 (Ar–C), 157.85, 161.35, 163.82, 164.30 (C=N, C=O). 19F NMR (377 MHz, DMSO-d6): δF = (−109.89 to −109.83), (−109.41 to −109.33) (2m, 1F, Ar–F). MS (ES) m/z = 413.35 [M+].

1-Butyl-4-(2-(4-fluorobenzylidene)hydrazinecarbonyl)pyridinium iodide (). It was obtained as yellow crystals; mp: 184–185 °C. FT-IR (KBr), cm−1: = 1620 (C=N), 1687 (C=O), 2882, 2961 (Al–H), 3071 (Ar–H). 1H NMR (600 MHz, DMSO-d6): δH = 0.93–0.96 (m, 3H, CH3), 1.30–1.38 (m, 2H, CH2CH3), 1.93–2.00 (m, 2H, NCH2CH2), 4.71 (dd, 2H, J = 6 Hz, 12 Hz, NCH2), 7.26 (dd, 0.5H, J = 6 Hz, 12 Hz, Ar–H), 7.37 (dd, 1.5H, J = 6 Hz, 12 Hz, Ar–H), 7.62 (dd, 0.5H, J = 6 Hz, 12 Hz, Ar–H), 7.89 (dd, 1.5H, J = 6 Hz, 12 Hz, Ar–H), 8.16 (s, 0.25H, H–C=N), 8.40 (d, 0.5H, J = 6 Hz, Ar–H), 8.50 (s, 0.75H, H–C=N), 8.54 (d, 1.5H, J = 6 Hz, Ar–H), 9.25 (d, 0.5H, J = 6 Hz, Ar–H), 9.33 (d, 1.5H, J = 6 Hz, Ar–H), 12.48 (bs, 1H, CONH). 13C NMR (150 MHz, DMSO-d6): δC = 13.79, 13.81 (CH3), 19.23, 19.30 (CH2CH3), 32.99, 33.08 (NCH2CH2), 61.22, 61.29 (NCH2), 116.31, 116.46, 116.51, 116.65, 126.65, 127.62, 129.86, 129.92, 130.24, 130.30, 130.54, 130.72, 145.58, 146.19, 147.82, 149.82 (Ar–C), 159.26, 163.19, 164.84, 165.71 (C=N, C=O). 19F NMR (377 MHz, DMSO-d6): δF = (−109.88 to −109.84), (−109.41 to −109.33) (2m, 1F, Ar–F). MS (ES) m/z = 427.28 [M+].

4-(2-(4-Fluorobenzylidene)hydrazinecarbonyl)-1-pentylpyridinium iodide (). It was obtained as yellow crystals; mp: 216–217 °C. FT-IR (KBr), cm−1: = 1622 (C=N), 1682 (C=O), 2891, 2970 (Al–H), 3070 (Ar–H). 1H NMR (400 MHz, DMSO-d6): δH = 0.86–0.90 (m, 3H, CH3), 1.25–1.37 (m, 4H, 2×CH2), 1.93–2.02 (m, 2H, NCH2CH2), 4.68 (t, 2H, J = 8 Hz, NCH2), 7.23 (t, 0.5H, J = 8 Hz, Ar–H), 7.37 (dd, 1.5H, J = 8 Hz, 12 Hz, Ar–H), 7.62 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.89 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.15 (s, 0.25H, H–C=N), 8.40 (d, 0.5H, J = 8 Hz, Ar–H), 8.50 (s, 0.75H, H–C=N), 8.53 (d, 1.5H, J = 8 Hz, Ar–H), 9.25 (d, 0.5H, J = 8 Hz, Ar–H), 9.34 (d, 1.5H, J = 8 Hz, Ar–H), 12.47 (bs, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 13.70, 13.71 (CH3), 21.51, 27.47, 27.55 (2×H2), 30.20, 30.31 (NCH2CH2), 60.91, 60.99 (NCH2), 115.76, 115.97, 116.18, 126.15, 127.11, 129.35, 129.44, 129.73, 129.82, 130.20, 130.23, 145.08, 145.68, 147.33, 149.33, 149.63 (Ar–C), 158.76, 162.28, 164.75, 165.22 (C=N, C=O). 19F NMR (377 MHz, DMSO-d6): δF = (−109.89 to −109.81), (−109.41 to −109.34) (2m, 1F, Ar–F). MS (ES) m/z = 441.10 [M+].

4-(2-(4-Fluorobenzylidene)hydrazinecarbonyl)-1-hexylpyridinium iodide (). It was obtained as yellow crystals; mp: 227–228 °C. FT-IR (KBr), cm−1: = 1625 (C=N), 1695 (C=O), 2883, 2975 (Al–H), 3080 (Ar–H). 1H NMR (600 MHz, DMSO-d6): δH = 0.88 (t, 3H, J = 6 Hz, CH3), 1.29–1.33 (m, 6H, 3×CH2), 1.95–1.97 (m, 2H, NCH2CH2), 4.70 (dd, 2H, J = 6 Hz, 12 Hz, NCH2), 7.25 (dd, 0.5H, J = 6 Hz, 12 Hz, Ar–H), 7.37 (dd, 1.5H, J = 6 Hz, 12 Hz, Ar–H), 7.62 (dd, 0.5H, J = 6 Hz, 12 Hz, Ar–H), 7.89 (dd, 1.5H, J = 6 Hz, 12 Hz, Ar–H), 8.16 (s, 0.25H, H–C=N), 8.40 (d, 0.5H, J = 6 Hz, Ar–H), 8.50 (s, 0.75H, H–C=N), 8.53 (d, 1.5H, J = 6 Hz, Ar–H), 9.25 (d, 0.5H, J = 6 Hz, Ar–H), 9.33 (d, 1.5H, J = 6 Hz, Ar–H), 12.47 (s, 0.75H, CONH), 12.52 (s, 0.25H, CONH). 13C NMR (150 MHz, DMSO-d6): δC = 14.28, 14.30 (CH3), 22.32, 25.52, 25.55 (3×CH2), 31.01, 31.09 (NCH2CH2), 61.43, 61.51 (NCH2), 116.29, 116.44, 116.51, 116.65, 126.13, 126.65, 127.62, 129.86, 129.91, 130.24, 130.30, 130.70, 130.71, 145.56, 146.18, 147.82, 149.82 (Ar–C), 159.27, 163.19, 164.84, 165.72 (C=N, C=O). 19F NMR (377 MHz, DMSO-d6): δF = (−109.90 to −109.82), (−109.44 to −109.36) (2m, 1F, Ar–F). MS (ES) m/z = 455.38 [M+].

4-(2-(4-Fluorobenzylidene)hydrazinecarbonyl)-1-heptylpyridinium iodide (). It was obtained as yellow crystals; mp: 218–219 °C. FT-IR (KBr), cm−1: = 1628 (C=N), 1688 (C=O), 2894, 2962 (Al–H), 3075 (A–H). 1H NMR (400 MHz, DMSO-d6): δH = 0.84–0.88 (m, 3H, CH3), 1.23–1.31 (m, 8H, 4×CH2), 1.94–2.00 (m, 2H, NCH2CH2), 4.70 (dd, 2H, J = 4 Hz, 8 Hz, NCH2), 7.22 (t, 0.5H, J = 8 Hz, A–H), 7.34 (t, 1.5H, J = 8 Hz, A–H), 7.62 (dd, 0.5H, J = 8 Hz, 12 Hz, A–H), 7.88 (dd, 1.5H, J = 4 Hz, 8 Hz, A–H), 8.16 (s, 0.25H, H–C=N), 8.40 (d, 0.5H, J = 8 Hz, Ar–H), 8.50 (s, 0.75H, H–C=N), 8.53 (d, 1.5H, J = 8 Hz, Ar–H), 9.25 (d, 0.5H, J = 4 Hz, Ar–H), 9.34 (d, 1.5H, J = 8 Hz, Ar–H), 12.47 (bs, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 13.86 (CH3), 21.91, 25.31, 25.36, 27.99, 30.51, 30.63, 30.95, 30.98 (5×CH2), 60.94, 61.01 (NCH2), 115.75, 115.95, 116.17, 126.14, 127.11, 129.36, 129.45, 129.72, 129.81, 130.06, 130.21, 130.24, 145.09, 145.67, 147.34, 149.36, 149.63 (Ar–C), 158.76, 162.27, 164.75, 165.20 (C=N, C=O). 19F NMR (377 MHz, DMSO-d6): δF = (−109.93 to −109.85), (−109.43 to −109.35) (2m, 1F, Ar–F). MS (ESI) m/z = 469.42 [M+].

3.4. General Metathesis Procedure for the Synthesis of Specific 11–40

3.4.1. Conventional Method

A mixture of compounds 5–10 (1 mmol) in acetonitrile (8 mL) and potassium hexafluorophosphate, sodium tetrafluoroborate, sodium nitrate, sodium thiocyanate and/or sodium trifluoroacetate (1.2 mmol) was heated under reflux for 16 h. After cooling, the solid formed was filtered and washed with water and/or chloroform to give the desired compounds 11–40.

3.4.2. Ultrasound Method

A mixture of compounds 5–10 (1 mmol) in acetonitrile (8 mL) and potassium hexafluorophosphate, sodium tetrafluoroborate, sodium nitrate, sodium thiocyanate and/or sodium trifluoroacetate (1.2 mmol) was irradiated by ultrasound irradiation for 5–6 h at room temperature. The reaction proceeded as described above to afford the same compounds 11–40.

1-Ethyl-4-(2-(4-fluorobenzylidene)hydrazinecarbonyl)pyridinium hexafluorophosphate (). It was obtained as yellow crystals; mp: 175–176 °C. 1H NMR (400 MHz, DMSO-d6): δH = 1.57–1.63 (m, 3H, CH3), 4.69–4.74 (q, 2H, J = 4 Hz, 8 Hz, NCH2), 7.24 (t, 0.5H, J = 8 Hz, Ar–H), 7.35 (t, 1.5H, J = 8 Hz, Ar–H), 7.63 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.89 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.16 (s, 0.25H, H–C=N), 8.40 (d, 0.5H, J = 8 Hz, Ar–H), 8.50 (s, 0.75H, H–C=N), 8.53 (d, 1.5H, J = 8 Hz, Ar–H), 9.24 (d, 0.5H, J = 4 Hz, Ar–H), 9.33 (d, 1.5H, J = 8 Hz, Ar–H), 12.49 (bs, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 16.00, 16.12 (CH3), 56.51, 56.61 (NCH2), 115.71, 115.89, 116.11, 126.05, 127.08, 129.32, 129.41, 129.66, 129.74, 129.98, 130.16, 130.19, 144.79, 145.09, 145.43, 147.27, 149.32, 149.46 (Ar–C), 158.72, 161.91, 162.22, 164.69, 165.13 (C=N, C=O). 31P NMR (162 MHz, DMSO-d6): δP = −157.37 to −131.03 (m, 1P, PF6). 19F NMR (377 MHz, DMSO-d6): δF = −71.09, −69.20 (2s, 6F, PF), (−109.89 to −109.81), (−109.43 to −109.35) (2m, 1F, Ar–F). MS (ES) m/z = 417.95 [M+].

1-Ethyl-4-(2-(4-fluorobenzylidene)hydrazinecarbonyl)pyridinium tetrafluoroborate (). It was obtained as yellow crystals; mp: 205–206 °C. 1H NMR (400 MHz, DMSO-d6): δH = 1.57–1.63 (m, 3H, CH3), 4.69–4.74 (q, 2H, J = 4 Hz, 8 Hz, NCH2), 7.24 (t, 0.5H, J = 8 Hz, Ar–H), 7.35 (t, 1.5H, J = 8 Hz, Ar–H), 7.63 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.89 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.16 (s, 0.25H, H–C=N), 8.40 (d, 0.5H, J = 8 Hz, Ar–H), 8.50 (s, 0.75H, H–C=N), 8.53 (d, 1.5H, J = 8 Hz, Ar–H), 9.24 (d, 0.5H, J = 4 Hz, Ar–H), 9.33 (d, 1.5H, J = 8 Hz, Ar–H), 12.48 (s, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 16.06, 16.19 (CH3), 56.57, 56.67 (NCH2), 115.77, 115.96, 116.18, 126.11, 127.13, 129.39, 129.47, 129.72, 129.81, 130.04, 130.21, 130.24, 144.86, 145.14, 145.50, 147.30, 149.37, 149.51 (Ar–C), 158.77, 162.28, 164.76, 165.20 (C=N, C=O). 11B NMR (128 MHz, DMSO-d6): δB = −1.29 (d, 1B, BF4). 19F NMR (377 MHz, DMSO-d6): δF = (−109.85 to −109.82), (−109.42 to −109.34) (2m, 1F, Ar–F), −148.28, −148.29 (2d, 4F, BF4). MS (ES) m/z = 359.46 [M+].

1-Ethyl-4-(2-(4-fluorobenzylidene)hydrazinecarbonyl)pyridinium trifluoroacetate (). It was obtained as yellow crystals; mp: 211–212 °C. 1H NMR (400 MHz, DMSO-d6): δH = 1.57–1.63 (m, 3H, CH3), 4.69–4.75 (q, 2H, J = 8 Hz, 12 Hz, NCH2), 7.27 (dd, 0.5H, J = 8 Hz, 12 Hz, Ar–H), 7.35 (t, 1.5H, J = 8 Hz, Ar–H), 7.63 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.89 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.16 (s, 0.25H, H–C=N), 8.40 (d, 0.5H, J = 8 Hz, Ar–H), 8.51 (s, 0.75H, H–C=N), 8.53 (d, 1.5H, J = 4 Hz, Ar–H), 9.25 (d, 0.5H, J = 4 Hz, Ar–H), 9.34 (d, 1.5H, J = 8 Hz, Ar–H), 12.49 (bs, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 16.00, 16.13 (CH3), 56.50, 56.59 (NCH2), 115.71, 115.89, 116.11, 126.03, 127.06, 129.33, 129.41, 129.64, 129.73, 129.97, 130.16, 130.19, 144.80, 145.07, 145.42, 147.29, 149.30, 149.44 (Ar–C), 158.73, 161.89, 162.20, 164.67, 165.12 (C=N, C=O). 19F NMR (377 MHz, DMSO-d6): δF = −73.49 (s, 3F, CF), (−109.89 to −109.82), (−109.45 to −109.37) (2m, 1F, Ar–F). MS (ES) m/z = 385.22 [M+].

1-Ethyl-4-(2-(4-fluorobenzylidene)hydrazinecarbonyl)pyridinium nitrate (). It was obtained as yellow crystals; mp: 210–211 °C. 1H NMR (400 MHz, DMSO-d6): δH = 1.57–1.63 (m, 3H, CH3), 4.69–4.74 (q, 2H, J = 8 Hz, 12 Hz, NCH2), 7.24 (t, 0.5H, J = 8 Hz, Ar–H), 7.35 (t, 1.5H, J = 8 Hz, Ar–H), 7.63 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.89 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.16 (s, 0.25H, H–C=N), 8.40 (d, 0.5H, J = 8 Hz, Ar–H), 8.51 (s, 0.75H, H–C=N), 8.53 (d, 1.5H, J = 4 Hz, Ar–H), 9.25 (d, 0.5H, J = 4 Hz, Ar–H), 9.34 (d, 1.5H, J = 4 Hz, Ar–H), 12.49 (bs, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 16.00, 16.13 (CH3), 56.50, 56.59 (NCH2), 115.71, 115.89, 116.11, 126.03, 127.06, 129.33, 129.41, 126.65, 129.73, 129.97, 130.16, 130.19, 144.81, 145.08, 145.46, 147.24, 149.30, 149.44 (Ar–C), 158.72, 161.89, 162.21, 164.36, 164.68, 165.13 (C=N, C=O). 19F NMR (377 MHz, DMSO-d6): δF = (−109.89 to −109.81), (−109.43 to −109.35) (2m, 1F, Ar–F). MS (ES) m/z = 334.37 [M+].

1-Ethyl-4-(2-(4-fluorobenzylidene)hydrazinecarbonyl)pyridinium thiocyanate (). It was obtained as yellow crystals; mp: 203–205 °C. 1H NMR (400 MHz, DMSO-d6): δH = 1.58–1.63 (m, 3H, CH3), 4.69–4.75 (q, 2H, J = 8 Hz, 12 Hz, NCH2), 7.24 (t, 0.5H, J = 8 Hz, Ar–H), 7.35 (t, 1.5H, J = 8 Hz, Ar–H), 7.63 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.89 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.16 (s, 0.25H, H–C=N), 8.40 (d, 0.5H, J = 8 Hz, Ar–H), 8.50 (s, 0.75H, H–C=N), 8.53 (d, 1.5H, J = 8 Hz, Ar–H), 9.24 (d, 0.5H, J = 4 Hz, Ar–H), 9.33 (d, 1.5H, J = 8 Hz, Ar–H), 12.49 (bs, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 16.01, 16.12 (CH3), 56.52, 56.62 (NCH2), 115.70, 115.89, 116.11, 126.04, 127.07, 129.32, 129.40, 129.50, 129.65, 129.74, 129.95, 130.15, 130.18, 144.79, 145.09, 145.44, 147.24, 149.31, 149.45 (Ar–C), 158.72, 162.21, 164.69, 165.12 (C=N, C=O). 19F NMR (377 MHz, DMSO-d6) δF = (−109.89 to −109.81), (−109.43 to −109.35) (2m, 1F, Ar–F). MS (ES) m/z = 330.17 [M+].

4-(2-(4-Fluorobenzylidene)hydrazinecarbonyl)-1-propylpyridinium hexafluorophosphate (). It was obtained as yellow crystals; mp: 180–181 °C. 1H NMR (400 MHz, DMSO-d6): δH = 0.89–0.95 (m, 3H, CH3), 1.94–2.05 (m, 2H, NCH2CH2), 4.67 (dd, 2H, J = 4 Hz, 8 Hz, NCH2), 7.26 (dd, 0.5H, J = 8 Hz, 12 Hz, Ar–H), 7.37 (dd, 1.5H, J = 8 Hz, 12 Hz, Ar–H), 7.62 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.89 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.16 (s, 0.25H, H–C=N), 8.41 (d, 0.5H, J = 8 Hz, Ar–H), 8.50 (s, 0.75H, H–C=N), 8.54 (d, 1.5H, J = 8 Hz, Ar–H), 9.24 (d, 0.5H, J = 8 Hz, Ar–H), 9.33 (d, 1.5H, J = 8 Hz, Ar–H), 12.47 (bs, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 11.16, 11.19 (CH3), 25.00, 25.08 (NCH2H2), 63.22, 63.30 (NCH2), 116.75, 116.94, 117.16, 127.13, 128.09, 130.33, 130.41, 130.71, 130.79, 130.99, 131.18, 131.21, 146.06, 146.67, 148.34, 150.32, 150.64 (Ar–C), 159.75, 163.26, 165.73, 166.19 (C=N, C=O).31P NMR (162 MHz, DMSO-d6): δP = −152.98 to −135.42 (m, 1P, PF6). 19F NMR (377 MHz, DMSO-d6): δF = −71.08, −69.19, (2s, 6F, PF), (−109.89 to −109.83), (−109.41 to −109.33) (2m, 1F, Ar–F). MS (ES) m/z = 431.37 [M+].

4-(2-(4-Fluorobenzylidene)hydrazinecarbonyl)-1-propylpyridinium tetrafluoroborate (). It was obtained as yellow crystals; mp: 162–163 °C. 1H NMR (400 MHz, DMSO-d6): δH = 0.90–0.95 (m, 3H, CH3), 1.94–2.05 (m, 2H, NCH2CH2), 4.65 (t, 2H, J = 8 Hz, NCH2), 7.26 (dd, 0.5H, J = 8 Hz, 12 Hz, Ar–H), 7.35 (t, 1.5H, J = 8 Hz, Ar–H), 7.62 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.89 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.16 (s, 0.25H, H–C=N), 8.41 (d, 0.5H, J = 8 Hz, Ar–H), 8.50 (s, 0.75H, H–C=N), 8.54 (d, 1.5H, J = 8 Hz, Ar–H), 9.23 (d, 0.5H, J = 8 Hz, Ar–H), 9.31 (d, 1.5H, J = 4 Hz, Ar–H), 12.46 (s, 0.75H, CONH), 12.50 (s, 0.25H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 10.18 (CH3), 24.02, 24.10 (NCH2H2), 62.26, 62.35 (NCH2), 115.77, 115.96, 116.18, 126.15, 127.12, 129.34, 129.43, 129.73, 129.82, 130.05, 130.20, 130.23, 145.10, 145.69, 147.39, 149.36 (Ar–C), 158.78, 162.29, 164.76, 165.21 (C=N, C=O). 11B NMR (128 MHz, DMSO-d6): δB = −1.29 (d, 1B, BF4). 19F NMR (377 MHz, DMSO-d6): δF = (−109.89 to −109.80), (−109.41 to −109.33) (2m, 1F, Ar–F); −148.29, −148.24 (2d, 4F, BF4). MS (ESI) m/z = 373.49 [M+].

4-(2-(4-Fluorobenzylidene)hydrazinecarbonyl)-1-propylpyridinium trifluoroacetate (). It was obtained as yellow crystals; mp: 151–152 °C. 1H NMR (400 MHz, DMSO-d6): δH =0.89–0.95 (m, 3H, CH3), 1.94–2.03 (m, 2H, NCH2CH2), 4.65 (t, 2H, J = 8 Hz, NCH2), 7.24 (t, 0.5H, J = 8 Hz, Ar–H), 7.38 (dd, 1.5H, J = 8 Hz, 12 Hz, Ar–H), 7.62 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.89 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.16 (s, 0.25H, H–C=N), 8.41 (d, 0.5H, J = 8 Hz, Ar–H), 8.50 (s, 0.75H, H–C=N), 8.54 (d, 1.5H, J = 8 Hz, Ar–H), 9.24 (d, 0.5H, J = 8 Hz, Ar–H), 9.33 (d, 1.5H, J = 8 Hz, Ar–H), 12.50 (bs, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 10.12, 10.15 (CH3), 23.97, 24.06 (NCH2H2), 62.15, 62.24 (NCH2), 115.71, 115.90, 116.12, 126.08, 127.04, 129.27, 129.36, 129.66, 129.74, 129.97, 130.15, 144.99, 145.62, 147.29, 149.23 (Ar–C), 158.71, 162.21, 165.17 (C=N, C=O). 19F NMR (377 MHz, DMSO-d6): δF = −73.47 (s, 3F, CF), (−109.87 to −109.79), (−109.40 to −109.31) (2m, 1F, Ar–F). MS (ES) m/z = 399.00 [M+].

4-(2-(4-Fluorobenzylidene)hydrazinecarbonyl)-1-propylpyridinium nitrate (). It was obtained as yellow crystals; mp: 172–173 °C. 1H NMR (400 MHz, DMSO-d6): δH = 0.90–0.95 (m, 3H, CH3), 1.94–2.05 (m, 2H, NCH2CH2), 4.69 (dd, 2H, J = 4 Hz, 8 Hz, NCH2), 7.25 (dd, 0.5H, J = 8 Hz, 12 Hz, Ar–H), 7.36 (dd, 1.5H, J = 8 Hz, 12 Hz, Ar–H), 7.62 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.89 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.16 (s, 0.25H, H–C=N), 8.40 (d, 0.5H, J = 8 Hz, Ar–H), 8.52 (s, 0.75H, H–C=N), 8.54 (d, 1.5H, J = 8 Hz, Ar–H), 9.26 (d, 0.5H, J = 8 Hz, Ar–H), 9.35 (d, 1.5H, J = 4 Hz, Ar–H), 12.45 (ds, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 8.49 (CH3), 22.31, 22.41 (NCH2H2), 60.58, 60.64 (NCH2), 114.08, 114.26, 114.48, 124.45, 125.43, 127.69, 127.78, 128.04, 128.13, 128.35, 128.51, 128.54, 143.38, 143.43, 14.00, 145.65, 147.72, 147.96 (Ar–C), 157.06, 160.26, 160.59, 162.73, 163.06, 163.46 (C=N, C=O). 19F NMR (377 MHz, DMSO-d6): δF = (−109.89 to −109.80), (−109.41 to −109.33) (2m, 1F, Ar–F). MS (ES) m/z = 348.29 [M+].

4-(2-(4-Fluorobenzylidene)hydrazinecarbonyl)-1-propylpyridinium thiocyanate (). It was obtained as yellow crystals; mp: 160–161 °C. 1H NMR (400 MHz, DMSO-d6): δH = 0.91–0.96 (m, 3H, CH3), 1.96–2.05 (m, 2H, NCH2CH2), 4.68 (dd, 2H, J = 4 Hz, 8 Hz, NCH2), 7.24 (t, 0.5H, J = 8 Hz, Ar–H), 7.35 (t, 1.5H, J = 8 Hz, Ar–H), 7.63 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.89 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.16 (s, 0.25H, H–C=N), 8.42 (d, 0.5H, J = 8 Hz, Ar–H), 8.50 (s, 0.75H, H–C=N), 8.55 (d, 1.5H, J = 8 Hz, Ar–H), 9.24 (d, 0.5H, J = 4 Hz, Ar–H), 9.32 (d, 1.5H, J = 4 Hz, Ar–H), 12.50 (bs, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 10.20 (CH3), 25.04, 24.12 (NCH2H2), 62.28, 62.36 (NCH2), 115.76, 115.95, 116.16, 126.15, 127.13, 129.35, 129.44, 129.65, 129.72, 129.81, 130.02, 130.05, 130.22, 130.25, 145.10, 145.67, 147.40, 149.36, 149.66 (Ar–C), 158.79, 161.96, 162.27, 164.42, 164.74, 165.19 (C=N, C=O). 19F NMR (377 MHz, DMSO-d6): δF = (−109.89 to −109.83), (−109.41 to −109.33) (2m, 1F, Ar–F). MS (ES) m/z = 344.48 [M+].

1-Butyl-4-(2-(4-fluorobenzylidene)hydrazinecarbonyl)pyridinium hexafluorophosphate (). It was obtained as yellow crystals; mp: 145–146 °C. 1H NMR (400 MHz, DMSO-d6): δH = 0.91–0.96 (m, 3H, CH3), 1.28–1.39 (m, 2H, CH2CH3), 1.91–2.00 (m, 2H, NCH2CH2), 4.70 (dd, 2H, J = 4 Hz, 8 Hz, NCH2), 7.26 (t, 0.5H, J = 8 Hz, 12 Hz, Ar–H), 7.35 (t, 1.5H, J = 8 Hz, Ar–H), 7.62 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.89 (dd, 1.5H, J = 8 Hz, 12 Hz, Ar–H), 8.15 (s, 0.25H, H–C=N), 8.40 (d, 0.5H, J = 8 Hz, Ar–H), 8.50 (s, 0.75H, H–C=N), 8.53 (d, 1.5H, J = 8 Hz, Ar–H), 9.24 (d, 0.5H, J = 4 Hz, Ar–H), 9.33 (d, 1.5H, J = 8 Hz, Ar–H), 12.46 (s, 0.75H, CONH), 12.51 (s, 0.25H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 13.27, 13.30 (CH3), 18.73, 18.80 (CH2CH3), 32.48, 32.57 (NCH2H2), 60.79 (NCH2), 115.77, 115.96, 116.18, 126.16, 127.13, 129.35, 129.44, 129.73, 129.82, 130.05, 130.20, 130.23, 145.08, 145.69, 147.33, 149.34 (Ar–C), 158.76, 162.28, 164.76, 165.21 (C=N, C=O). 31P NMR (162 MHz, DMSO-d6): δP = −152.98 to −135.42 (m, 1P, PF6). 19F NMR (377 MHz, DMSO-d6): δF = −71.09, −69.19 (2s, 6F, PF), (−109.88 to −109.84), (−109.41 to −109.33) (2m, 1F, Ar–F). MS (ES) m/z = 445.02 [M+].

1-Butyl-4-(2-(4-fluorobenzylidene)hydrazinecarbonyl)pyridiniumtetrafluoroborate (). It was obtained as yellow crystals; mp: 172–173 °C. 1H NMR (400 MHz, DMSO-d6): δH = 0.92–0.97 (m, 3H, CH3), 1.28–1.39 (m, 2H, CH2CH3), 1.92–2.01 (m, 2H, NCH2CH2), 4.71 (t, 2H, J = 8 Hz, NCH2), 7.27 (dd, 0.5H, J = 8 Hz, 12 Hz, Ar–H), 7.38 (dd, 1.5H, J = 8 Hz, 12 Hz, Ar–H), 7.63 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.90 (dd, 1.5H, J = 8 Hz, 12 Hz, Ar–H), 8.16 (s, 0.25H, H–C=N), 8.41 (d, 0.5H, J = 4 Hz, Ar–H), 8.51 (s, 0.75H, H–C=N), 8.55 (d, 1.5H, J = 8 Hz, Ar–H), 9.27 (d, 0.5H, J = 4 Hz, Ar–H), 9.36 (d, 1.5H, J = 4 Hz, Ar–H), 12.49 (s, 0.75H, CONH), 12.53 (s, 0.25H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 11.76 (CH3), 17.20, 17.27 (CH2CH3), 30.96, 31.06 (NCH2CH2), 59.19, 59.24 (NCH2), 114.25, 114.44, 114.66, 124.62, 125.59, 127.84, 127.93, 128.20, 128.29, 128.50, 128.66, 128.69, 143.54, 144.17, 145.75, 147.79, 148.07 (Ar–C), 157.23, 160.41, 160.74, 163.21, 164.68 (C=N, C=O). 11B NMR (128 MHz, DMSO-d6): δB = −1.29 (d, 1B, BF4). 19F NMR (377 MHz, DMSO-d6): δF = (−109.89 to −109.81), (−109.40 to −109.33) (2m, 1F, Ar–F); −148.22, −148.16 (2d, 4F, BF4). MS (ES) m/z = 387.27 [M+].

1-Butyl-4-(2-(4-fluorobenzylidene)hydrazinecarbonyl)pyridinium trifluoroacetate (). It was obtained as yellow crystals; mp: 178–179 °C. 1H NMR (400 MHz, DMSO-d6): δH = 0.91–0.96 (m, 3H, CH3), 1.28–1.37 (m, 2H, CH2CH3), 1.92–2.01 (m, 2H, NCH2CH2), 4.71 (t, 2H, J = 8 Hz, NCH2), 7.25 (dd, 0.5H, J = 8 Hz, 12 Hz, Ar–H), 7.36 (dd, 1.5H, J = 8 Hz, 12 Hz, Ar–H), 7.62 (dd, 0.5H, J = 8 Hz, 12 Hz, Ar–H), 7.88 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.16 (s, 0.25H, H–C=N), 8.40 (d, 0.5H, J = 8 Hz, Ar–H), 8.51 (s, 0.75H, H–C=N), 8.54 (d, 1.5H, J = 8 Hz, Ar–H), 9.27 (d, 0.5H, J = 8 Hz, Ar–H), 9.36 (d, 1.5H, J = 8 Hz, Ar–H), 12.45 (bs, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 13.26, 13.28 (CH3), 18.71, 18.78 (CH2CH3), 32.45, 32.55 (NCH2CH2), 60.75, 60.79 (NCH2), 115.76, 115.94, 116.16, 126.14, 127.12, 129.38, 129.47, 129.72, 129.81, 130.01, 130.21, 130.24, 145.11, 145.70, 147.31, 149.40, 149.62 (Ar–C), 158.93, 161.95, 162.27, 164.42, 164.74, 165.14 (C=N, C=O). 19F NMR (377 MHz, DMSO-d6): δF = −73.47 (s, 3F, CF), (−109.87 to −109.81), (−109.40 to −109.32) (2m, 1F, Ar–F). MS (ESI) m/z = 414.00 [M+ + H].

1-Butyl-4-(2-(4-fluorobenzylidene)hydrazinecarbonyl)pyridinium nitrate . It was obtained as yellow crystals; mp: 170–171 °C. 1H NMR (400 MHz, DMSO-d6): δH = 0.92–0.97 (m, 3H, CH3), 1.29–1.38 (m, 2H, CH2CH3), 1.92–2.02 (m, 2H, NCH2CH2), 4.71 (t, 2H, J = 8 Hz, NCH2), 7.27 (dd, 0.5H, J = 8 Hz, 12 Hz, Ar–H), 7.38 (dd, 1.5H, J = 8 Hz, 12 Hz, Ar–H), 7.63 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.90 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.17 (s, 0.25H, H–C=N), 8.41 (d, 0.5H, J = 4 Hz, Ar–H), 8.52 (s, 0.75H, H–C=N), 8.55 (d, 1.5H, J = 8 Hz, Ar–H), 9.28 (d, 0.5H, J = 8 Hz, Ar–H), 9.36 (d, 1.5H, J = 4 Hz, Ar–H), 12.49 (s, 0.75H, CONH), 12.53 (s, 0.25H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 15.03, 15.06 (CH3), 20.47, 20.53 (CH2CH3), 34.22, 34.32 (NCH2CH2), 62.46, 62.51 (NCH2), 117.52, 117.71, 117.93, 127.89, 128.86, 131.12, 131.20, 131.47, 131.56, 131.77, 131.93, 131.96, 146.81, 147.44, 149.02, 151.06, 151.34 (Ar–C), 160.50, 163.68, 164.01, 166.15, 166.48, 166.94 (C=N, C=O).19F NMR (377 MHz, DMSO-d6): δF = (−109.89 to −109.81), (−109.40 to −109.33) (2m, 1F, Ar–F). MS (ESI) m/z = 362.27 [M+].

1-Butyl-4-(2-(4-fluorobenzylidene)hydrazinecarbonyl)pyridinium thiocyanate (). It was obtained as yellow crystals; mp: 172–173 °C. 1H NMR (400 MHz, DMSO-d6): δH = 0.92−0.96 (m, 3H, CH3), 1.28−1.37 (m, 2H, CH2CH3), 1.92−2.01 (m, 2H, NCH2CH2), 4.72 (dd, 2H, J = 4 Hz, 8 Hz, NCH2), 7.24 (t, 0.5H, J = 8 Hz, Ar–H), 7.38 (dd, 1.5H, J = 8 Hz, 12 Hz, Ar–H), 7.63 (dd, 0.5H, J = 8 Hz, 12 Hz, Ar–H), 7.89 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.16 (s, 0.25H, H–C=N), 8.41 (d, 0.5H, J = 8 Hz, Ar–H), 8.51 (s, 0.75H, H–C=N), 8.54 (d, 1.5H, J = 4 Hz, Ar–H), 9.27 (d, 0.5H, J = 8 Hz, Ar–H), 9.36 (d, 1.5H, J = 8 Hz, Ar–H), 12.49 (bs, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 13.46, 13.48 (CH3), 18.89, 18.96 (CH2CH3), 32.65, 32.74 (NCH2CH2), 60.88, 60.94 (NCH2), 115.94, 116.13, 116.35, 126.32, 127.29, 129.53, 129.62, 129.90, 129.99, 130.20, 130.36, 130.39, 145.24, 145.87, 147.46, 149.49, 149.77 (Ar–C), 158.93, 162.44, 164.91, 165.38 (C=N, C=O). 19F NMR (377 MHz, DMSO-d6): δF = (−109.88 to −109.84), (−109.41 to −109.33) (2m, 1F, Ar–F). MS (ES) m/z = 358.26 [M+].

4-(2-(4-Fluorobenzylidene)hydrazinecarbonyl)-1-pentylpyridinium hexafluorophosphate (). It was obtained as yellow crystals; mp: 195–196 °C. 1H NMR (400 MHz, DMSO-d6): δH = 0.86−0.91 (m, 3H, CH3), 1.23−1.37 (m, 4H, 2×CH2), 1.93–2.02 (m, 2H, NCH2CH2), 4.69 (dd, 2H, J = 4 Hz, 8 Hz, NCH2), 7.23 (t, 0.5H, J = 8 Hz, Ar–H), 7.37 (dd, 1.5H, J = 8 Hz, 12 Hz, Ar–H), 7.62 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.89 (dd, 1.5H, J = 8 Hz, 12 Hz, Ar–H), 8.15 (s, 0.25H, H–C=N), 8.40 (d, 0.5H, J = 8 Hz, Ar–H), 8.50 (s, 0.75H, H–C=N), 8.53 (d, 1.5H, J = 8 Hz, Ar–H), 9.24 (d, 0.5H, J = 4 Hz, Ar–H), 9.33 (d, 1.5H, J = 8 Hz, Ar–H), 12.46 (s, 0.75H, CONH), 12.51 (s, 0.25H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 13.69 (CH3), 21.50, 27.47, 27.55 (2×H2), 30.20, 30.31 (NCH2CH2), 60.92, 61.00 (NCH2), 115.76, 115.96, 116.18, 126.16, 127.12, 129.34, 129.43, 129.73, 129.81, 130.20, 130.23, 145.09, 145.69, 147.34, 149.34 (Ar–C), 158.76, 162.28, 164.76, 165.22 (C=N, C=O).31P NMR (162 MHz, DMSO-d6): δP = −152.98 to −135.42 (m, 1P, PF6). 19F NMR (377 MHz, DMSO-d6): δF = −69.21, −71.10 (2s, 6F, PF), (−109.89 to −109.81), (−109.41 to −109.34) (2m, 1F, Ar–F). MS (ES) m/z = 459.90 [M+].

4-(2-(4-Fluorobenzylidene)hydrazinecarbonyl)-1-pentylpyridinium tetrafluoroborate (). It was obtained as yellow crystals; mp: 205–206 °C. 1H NMR (400 MHz, DMSO-d6): δH = 0.86–0.90 (m, 3H, CH3), 1.23–1.37 (m, 4H, 2×CH2), 1.93–2.00 (m, 2H, NCH2CH2), 4.68 (t, 2H, J = 4 Hz, 8 Hz, NCH2), 7.23 (t, 0.5H, J = 8 Hz, Ar–H), 7.37 (dd, 1.5H, J = 8 Hz, 12 Hz, Ar–H), 7.62 (dd, 0.5H, J = 8 Hz, 12 Hz, Ar–H), 7.89 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.15 (s, 0.25H, H–C=N), 8.40 (d, 0.5H, J = 8 Hz, Ar–H), 8.50 (s, 0.75H, H–C=N), 8.53 (d, 1.5H, J = 8 Hz, Ar–H), 9.25 (d, 0.5H, J = 4 Hz, Ar–H), 9.34 (d, 1.5H, J = 8 Hz, Ar–H), 12.47 (bs, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 13.70 (CH3), 21.51, 27.47, 27.55 (2×CH2), 30.20, 30.31 (NCH2CH2), 60.99 (NCH2), 115.76, 115.96, 116.18, 126.15, 127.11, 129.35, 129.44, 129.73, 129.82, 130.20, 130.23, 145.08, 145.68, 147.32, 149.33, 149.63(Ar–C), 158.76, 162.28, 164.75, 165.22 (C=N, C=O).11B NMR (128 MHz, DMSO-d6): δB = −1.29 (d, 1B, BF4). 19F NMR (377 MHz, DMSO-d6): δF = (−109.89 to −109.81), (−109.42 to −109.34) (2m, 1F, Ar–F); −148.28, −148.23 (2d, 4F, BF4). MS (ES) m/z = 401.00 [M+].

4-(2-(4-Fluorobenzylidene)hydrazinecarbonyl)-1-pentylpyridinium trifluoroacetate (). It was obtained as yellow crystals; mp: 201–202 °C. 1H NMR (400 MHz, DMSO-d6): δH = 0.86–0.90 (m, 3H, CH3), 1.23–1.37 (m, 4H, 2×CH2), 1.93–2.00 (m, 2H, NCH2C2), 4.68 (t, 2H, J = 8 Hz, NCH2), 7.23 (t, 0.5H, J = 8 Hz, Ar–H), 7.37 (dd, 1.5H, J = 8 Hz, 12 Hz, Ar–H), 7.62 (dd, 0.5H, J = 8 Hz, 12 Hz, Ar–H), 7.89 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.15 (s, 0.25H, H–C=N), 8.40 (d, 0.5H, J = 8 Hz, Ar–H), 8.50 (s, 0.75H, H–C=N), 8.53 (d, 1.5H, J = 8 Hz, Ar–H), 9.25 (d, 0.5H, J = 8 Hz, Ar–H), 9.34 (d, 1.5H, J = 8 Hz, Ar–H), 12.48 (bs, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 13.70, 13.72 (CH3), 21.51, 27.47, 27.55 (2×CH2), 30.20, 30.31 (NCH2CH2), 60.92, 60.99 (NCH2), 115.76, 115.96, 116.18, 126.15, 127.11, 129.35, 129.44, 129.73, 129.81, 130.21, 130.24, 145.08, 145.69, 147.34, 149.33 (Ar–C), 158.77, 162.28, 164.75, 165.22 (C=N, C=O). 19F NMR (377 MHz, DMSO-d6): δF = −73.50 (s, 3F, CF), (−109.87 to −109.83), (−109.42 to −109.35) (2m, 1F, Ar–F). MS (ESI) m/z = 428.00 [M+ + H].

4-(2-(4-Fluorobenzylidene)hydrazinecarbonyl)-1-pentylpyridinium nitrate (). It was obtained as yellow crystals; mp: 200–201 °C. 1H NMR (400 MHz, DMSO-d6): δH = 0.86–0.90 (m, 3H, CH3), 1.23–1.37 (m, 4H, 2×CH2), 1.93–2.00 (m, 2H, NCH2CH2), 4.68 (t, 2H, J = 8 Hz, NCH2), 7.23 (t, 0.5H, J = 8 Hz, Ar–H), 7.37 (dd, 1.5H, J = 8 Hz, 12 Hz, Ar–H), 7.62 (dd, 0.5H, J = 8 Hz, 12 Hz, Ar–H), 7.89 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.15 (s, 0.25H, H–C=N), 8.40 (d, 0.5H, J = 8 Hz, Ar–H), 8.50 (s, 0.75H, H–C=N), 8.53 (d, 1.5H, J = 8 Hz, Ar–H), 9.25 (d, 0.5H, J = 8 Hz, Ar–H), 9.34 (d, 1.5H, J = 8 Hz, Ar–H), 12.47 (bs, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 13.70, 1371 (CH3), 21.51, 24.47, 27.55 (2×H2), 30.20, 30.31 (NCH2H2), 60.91, 60.99 (NCH2), 115.76, 115.97, 116.19, 126.15, 127.12, 129.35, 129.44, 129.73, 129.82, 130.20, 130.23, 145.08, 145.69, 147.33, 149.33 (Ar–C), 158.76, 162.28, 164.75, 165.22 (C=N, C=O). 19F NMR (377 MHz, DMSO-d6): δF = (−109.89 to −109.81), (−109.42 to −109.34) (2m, 1F, Ar–F). MS (ES) m/z = 376.70 [M+].

4-(2-(4-fluorobenzylidene)hydrazinecarbonyl)-1-pentylpyridinium thiocyanate (). It was obtained as yellow crystals; mp: 197–198 °C. 1H NMR (400 MHz, DMSO-d6): δH = 0.86–0.90 (m, 3H, CH3), 1.23–1.37 (m, 4H, 2×CH2), 1.93–2.00 (m, 2H, NCH2CH2), 4.68 (t, 2H, J = 8 Hz, NCH2), 7.23 (t, 0.5H, J = 8 Hz, Ar–H), 7.37 (dd, 1.5H, J = 8 Hz, 12 Hz, Ar–H), 7.62 (dd, 0.5H, J = 8 Hz, 12 Hz, Ar–H), 7.89 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.15 (s, 0.25H, H–C=N), 8.40 (d, 0.5H, J = 8 Hz, Ar–H), 8.50 (s, 0.75H, H–C=N), 8.53 (d, 1.5H, J = 8 Hz, Ar–H), 9.25 (d, 0.5H, J = 8 Hz, Ar–H), 9.34 (d, 1.5H, J = 8 Hz, Ar–H), 12.47 (s, 0.75H, CONH), 12.51 (s, 0.25H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 13.70, 1371 (CH3), 21.51, 27.47, 27.55 (2×CH2), 30.20, 30.31 (NCH2CH2), 60.92, 61.00 (NCH2), 115.76, 115.96, 116.18, 126.15, 127.12, 129.36, 129.44, 129.73, 129.82, 130..02, 130.20, 130.23, 145.08, 145.69, 147.32, 149.34, 149.63(Ar–C), 158.76, 162.28, 164.75, 165.21 (C=N, C=O).19F NMR (377 MHz, DMSO-d6): δF = (−109.89 to −109.81), (−109.42 to −109.34) (2m, 1F, Ar–F). MS (ES) m/z = 372.00 [M+].

4-(2-(4-Fluorobenzylidene)hydrazinecarbonyl)-1-hexylpyridinium hexafluorophosphate (). It was obtained as yellow crystals; mp: 143–144 °C. 1H NMR (400 MHz, DMSO-d6): δH = 0.86–0.93 (m, 3H, CH3), 1.28–1.34 (m, 6H, 3×CH2), 1.94–2.00 (m, 2H, NCH2C2), 4.69 (dd, 2H, J = 4 Hz, 8 Hz, NCH2), 7.25 (dd, 0.5H, J = 8 Hz, 12 Hz, Ar–H), 7.37 (dd, 1.5H, J = 8 Hz, 12 Hz, Ar–H), 7.62 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.89 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.16 (s, 0.25H, H–C=N), 8.40 (d, 0.5H, J = 4 Hz, Ar–H), 8.50 (s, 0.75H, H–C=N), 8.53 (d, 1.5H, J = 4 Hz, Ar–H), 9.24 (d, 0.5H, J = 8 Hz, Ar–H), 9.31 (d, 1.5H, J = 4 Hz, Ar–H), 12.49 (bs, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 13.74, 13.76 (CH3), 21.80, 25.01, 25.04, 30.50, 30.58 (4×CH2), 60.96, 61.04 (NCH2), 115.73, 115.94, 116.16, 126.15, 127.14, 129.33, 129.42, 129.72, 129.80, 130.06, 130.20, 130.25, 145.04, 145.12, 145.65, 147.40, 149.37, 149.65 (Ar–C), 158.77, 161.96, 162.28, 164.43, 164.76, 165.20 (C=N, C=O). 31P NMR (162 MHz, DMSO-d6) δP = −157.37 to −131.02 (m, 1P, PF6). 19F NMR (377 MHz, DMSO-d6): δF = −71.10, −69.22 (2s, 6F, PF), (−109.90 to −109.82), (−109.44 to −109.36) (2m, 1F, Ar–F). MS (ES) m/z = 473.39 [M+].

4-(2-(4-Fluorobenzylidene)hydrazinecarbonyl)-1-hexylpyridinium tetrafluoroborate (). It was obtained as yellow crystals; mp: 204–205 °C. 1H NMR (400 MHz, DMSO-d6): δH = 0.86–0.92 (m, 3H, CH3), 1.29–1.30 (m, 6H, 3×CH2), 1.94–2.00 (m, 2H, NCH2CH2), 4.68 (t, 2H, J = 8 Hz, NCH2), 7.23 (t, 0.5H, J = 8 Hz, Ar–H), 7.35 (t, 1.5H, J = 8 Hz, Ar–H), 7.62 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.89 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.16 (s, 0.25H, H–C=N), 8.40 (d, 0.5H, J = 4 Hz, Ar–H), 8.50 (s, 0.75H, H–C=N), 8.54 (d, 1.5H, J = 8 Hz, Ar–H), 9.25 (d, 0.5H, J = 8 Hz, Ar–H), 9.33 (d, 1.5H, J = 8 Hz, Ar–H), 12.48 (bs, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 13.70, 13.72 (CH3), 21.75, 24.95, 24.99, 30.40, 30.45, 30.53 (4×CH2), 60.89, 60.97 (NCH2), 115.69, 115.89, 116.11, 126.09, 127.07, 129.29, 129.38, 129.66, 129.75, 129.98, 130.17, 130.20, 145.01, 145.61, 147.34, 149.31, 149.59 (Ar–C), 158.72, 162.22, 164.70, 165.15 (C=N, C=O). 11B NMR (128 MHz, DMSO-d6): δB = −1.28 (d, 1B, BF4). 19F NMR (377 MHz, DMSO-d6): δF = (−109.90 to −109.82), (−109.45 to −109.37) (2m, 1F, Ar–F); −148.30, −145.25 (2d, 4F, BF4). MS (ES) m/z = 415.22 [M+].

4-(2-(4-fluorobenzylidene)hydrazinecarbonyl)-1-hexylpyridinium trifluoroacetate (). It was obtained as yellow crystals; mp: 214–215 °C. 1H NMR (400 MHz, DMSO-d6): δH = 0.86–0.92 (m, 3H, CH3), 1.28–1.30 (m, 6H, 3×CH2), 1.94–2.00 (m, 2H, NCH2CH2), 4.68 (t, 2H, J = 8 Hz, NCH2), 7.23 (t, 0.5H, J = 8 Hz, Ar–H), 7.35 (t, 1.5H, J = 8 Hz, Ar–H), 7.62 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.89 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.16 (s, 0.25H, H–C=N), 8.40 (d, 0.5H, J = 8 Hz, Ar–H), 8.50 (s, 0.75H, H–C=N), 8.54 (d, 1.5H, J = 8 Hz, Ar–H), 9.25 (d, 0.5H, J = 8 Hz, Ar–H), 9.33 (d, 1.5H, J = 8 Hz, Ar–H), 12.50 (bs, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 13.76, 13.79 (CH3), 21.81, 25.01, 25.04, 30.50, 30.59 (4×CH2), 60.93, 61.00 (NCH2), 115.75, 115.96, 116.17, 126.14, 127.12, 129.35, 129.43, 129.71, 129.80, 130.03, 130.24, 130.27, 145.09, 145.66, 147.43, 149.34, 149.64 (Ar–C), 158.80, 162.27, 164.42, 164.74, 165.22 (C=N, C=O). 19F NMR (377 MHz, DMSO-d6): δF = −73.50 (s, 3F, CF), (−109.90 to −109.82), (−109.46 to −109.38) (2m, 1F, Ar–F). MS (ES) m/z = 441.18 [M+].

4-(2-(4-Fluorobenzylidene)hydrazinecarbonyl)-1-hexylpyridinium nitrate (). It was obtained as yellow crystals; mp: 214–215 °C1H NMR (400 MHz, DMSO-d6): δH = 0.86–0.92 (m, 3H, CH3), 1.28–1.33 (m, 6H, 3×CH2), 1.94–2.00 (m, 2H, NCH2CH2), 4.70 (t, 2H, J = 8 Hz, NCH2), 7.26 (dd, 0.5H, J = 8 Hz, 12 Hz, Ar–H), 7.35 (t, 1.5H, J = 8 Hz, Ar–H), 7.63 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.89 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.17 (s, 0.25H, H–C=N), 8.41 (d, 0.5H, J = 8 Hz, Ar–H), 8.51 (s, 0.75H, H–C=N), 8.54 (d, 1.5H, J = 4 Hz, Ar–H), 9.27 (d, 0.5H, J = 8 Hz, Ar–H), 9.36 (d, 1.5H, J = 8 Hz, Ar–H), 12.50 (bs, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 13.76, 13.78 (CH3), 21.81, 25.01, 25.04, 30.46, 30.50, 30.59 (4×CH2), 60.93, 60.99 (NCH2), 115.75, 115.95, 116.17, 126.14, 127.12, 129.36, 129.45, 129.72, 129.80, 130.05, 130.23, 130.26, 145.08, 145.68, 147.37, 149.35, 149.62 (Ar–C), 158.78, 161.94, 162.26, 164.41, 164.73, 165.20 (C=N, C=O). 19F NMR (377 MHz, DMSO-d6): δF = (−109.90 to −109.82), (−109.45 to −109.37) (2m, 1F, Ar–F). MS (ESI) m/z = 390.37 [M+].

4-(2-(4-Fluorobenzylidene)hydrazinecarbonyl)-1-hexylpyridinium thiocyanate (). It was obtained as yellow crystals; mp: 189–190 °C. 1H NMR (400 MHz, DMSO-d6): δH = 0.86–0.92 (m, 3H, CH3), 1.28–1.33 (m, 6H, 3×CH2), 1.94–2.00 (m, 2H, NCH2CH2), 4.70 (dd, 2H, J = 4 Hz, 8 Hz, NCH2), 7.23 (t, 0.5H, J = 8 Hz, Ar–H), 7.35 (t, 1.5H, J = 8 Hz, Ar–H), 7.62 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.89 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.16 (s, 0.25H, H–C=N), 8.41 (d, 0.5H, J = 8 Hz, Ar–H), 8.50 (s, 0.75H, H–C=N), 8.54 (d, 1.5H, J = 8 Hz, Ar–H), 9.25 (d, 0.5H, J = 8 Hz, Ar–H), 9.33 (d, 1.5H, J = 8 Hz, Ar–H), 12.50 (bs, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 13.70, 13.72 (CH3), 21.75, 24.96, 24.99, 30.45, 30.54 (4×CH2), 60.89, 60.97 (NCH2), 115.69, 115.89, 116.11, 126.09, 127.07,129.29, 129.37, 129.52, 129.75, 130.00, 130.17, 130.20, 145.01, 145.61, 147.32, 149.29, 149.57 (Ar–C), 158.72,161.89, 162.21, 164.36, 164.69, 165.15 (C=N, C=O). 19F NMR (377 MHz, DMSO-d6): δF = (−109.90 to −109.82), (−109.45 to −109.37) (2m, 1F, Ar–F). MS (ES) m/z = 386.56 [M+].

4-(2-(4-Fluorobenzylidene)hydrazinecarbonyl)-1-heptylpyridinium hexafluorophosphate (). It was obtained as yellow crystals; mp: 209–210 °C. 1H NMR (400 MHz, DMSO-d6): δH = 0.85–0.88 (m, 3H, CH3), 1.25–1.31 (m, 8H, 4×CH2), 1.91–2.00 (m, 2H, NCH2CH2), 4.69 (t, 2H, J = 8 Hz, NCH2), 7.23 (t, 0.5H, J = 8 Hz, Ar–H), 7.35 (t, 1.5H, J = 8 Hz, Ar–H), 7.62 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.89 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.16 (s, 0.25H, H–C=N), 8.40 (d, 0.5H, J = 4 Hz, Ar–H), 8.51 (s, 0.75H, H–C=N), 8.54 (d, 1.5H, J = 8 Hz, Ar–H), 9.25 (d, 0.5H, J = 4 Hz, Ar–H), 9.34 (d, 1.5H, J = 8 Hz, Ar–H), 12.49 (bs, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 13.87 (CH3), 21.91, 25.31, 25.36, 28.00, 30.51, 30.64, 30.96, 30.98 (5×CH2), 60.94, 61.01 (NCH2), 115.75, 115.96, 116.18, 126.14, 127.11, 126.36, 129.44, 129.73, 129.81, 130.05, 130.21, 130.24, 145.07, 145.67, 147.33, 149.34, 149.63 (Ar–C), 158.77, 162.28, 164.75, 165.22 (C=N, C=O). 31P NMR (162 MHz, DMSO-d6): δP = −157.37 to −131.02 (m, 1P, PF6). 19F NMR (377 MHz, DMSO-d6) δF = −71.10, −69.21 (2s, 6F, PF), (−109.93 to −109.85), (−109.43 to −109.35) (2m, 1F, Ar–F). MS (ES) m/z = 487.37 [M+].

4-(2-(4-fluorobenzylidene)hydrazinecarbonyl)-1-heptylpyridinium tetrafluoroborate (). It was obtained as yellow crystals; mp: 203–204 °C. 1H NMR (400 MHz, DMSO-d6): δH = 0.85–0.89 (m, 3H, CH3), 1.25–1.31 (m, 8H, 4×CH2), 1.92–2.01 (m, 2H, NCH2CH2), 4.71 (dd, 2H, J = 4 Hz, 8 Hz, NCH2), 7.26 (dd, 0.5H, J = 8 Hz, 12 Hz, Ar–H), 7.38 (dd, 1.5H, J = 8 Hz, 12 Hz, Ar–H), 7.63 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.90 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.16 (s, 0.25H, H–C=N), 8.41 (d, 0.5H, J = 8 Hz, Ar–H), 8.51 (s, 0.75H, H–C=N), 8.54 (d, 1.5H, J = 4 Hz, Ar–H), 9.27 (d, 0.5H, J = 8 Hz, Ar–H), 9.35 (d, 1.5H, J = 4 Hz, Ar–H), 12.49 (s, 0.75H, CONH), 12.53 (s, 0.25H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 14.04 (CH3), 22.09, 25.47, 25.53, 28.17, 30.68, 30.81, 31.12, 31.15 (5×CH2), 61.09, 61.16 (NCH2), 115.92, 116.13, 116.35, 126.31, 127.27, 129.53, 129.62, 129.90, 129.99, 130.18, 130.35, 130.38, 145.23, 145.84, 147.43, 149.49, 149.77 (Ar–C), 158.93, 162.09, 162.43, 164.56, 164.91, 165.39 (C=N, C=O). 11B NMR (128 MHz, DMSO-d6): δB = −1.14 (d, 1B, BF4). 19F NMR (377 MHz, DMSO-d6): δF = (−109.76 to −109.69), (−109.25 to −109.17) (2m, 1F, Ar–F); −148.08, −148.03 (2d, 4F, BF4). MS (ES) m/z = 429.21 [M+].

4-(2-(4-Fluorobenzylidene)hydrazinecarbonyl)-1-heptylpyridinium trifluoroacetate (). It was obtained as yellow crystals; mp: 203–204 °C. 1H NMR (400 MHz, DMSO-d6): δH = 0.85–0.88 (m, 3H, CH3), 1.23–1.31 (m, 8H, 4×CH2), 1.94–2.02 (m, 2H, NCH2C2), 4.69 (dd, 2H, J = 4 Hz, 8 Hz, NCH2), 7.23 (t, 0.5H, J = 8 Hz, Ar–H), 7.38 (dd, 1.5H, J = 8 Hz, 12 Hz, Ar–H), 7.62 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.89 (dd, 1.5H, J = 4 Hz, 8 Hz, Ar–H), 8.16 (s, 0.25H, H–C=N), 8.40 (d, 0.5H, J = 8 Hz, Ar–H), 8.50 (s, 0.75H, H–C=N), 8.53 (d, 1.5H, J = 4 Hz, Ar–H), 9.25 (d, 0.5H, J = 8 Hz, Ar–H), 9.33 (d, 1.5H, J = 8 Hz, Ar–H), 12.50 (bs, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 12.67 (CH3), 20.71, 24.11, 24.16, 26.08, 29.31, 29.44, 29.75, 29.78 (5×CH2), 59.71, 59.78 (NCH2), 114.54, 114.76, 114.98, 124.94, 125.90, 128.22, 128.51, 128.59, 128.85, 129.01, 129.04, 143.85, 144.46, 146.19, 148.09 (Ar–C), 157.59, 161.06, 163.53, 164.04 (C=N, C=O). 19F NMR (377 MHz, DMSO-d6): δF = −73.48 (s, 3F, CF), (−109.91 to −109.83), (−109.43 to −109.35) (2m, 1F, Ar–F). MS (ES) m/z = 455.90 [M+].

4-(2-(4-Fluorobenzylidene)hydrazinecarbonyl)-1-heptylpyridinium nitrate (). It was obtained as yellow crystals; mp: 204–205 °C. 1H NMR (400 MHz, DMSO-d6): δH = 0.85–0.89 (m, 3H, CH3), 1.24–1.32 (m, 8H, 4×CH2), 1.94–2.01 (m, 2H, NCH2CH2), 4.70 (t, 2H, J = 8 Hz, NCH2), 7.26 (dd, 0.5H, J = 8 Hz, 12 Hz, Ar–H), 7.38 (dd, 1.5H, J = 8 Hz, 12 Hz, Ar–H), 7.63 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.90 (dd, 1.5H, J = 8 Hz, 12 Hz, Ar–H), 8.17 (s, 0.25H, H–C=N), 8.41 (d, 0.5H, J = 8 Hz, Ar–H), 8.52 (s, 0.75H, H–C=N), 8.55 (d, 1.5H, J = 8 Hz, Ar–H), 9.27 (d, 0.5H, J = 4 Hz, Ar–H), 9.36 (d, 1.5H, J = 4 Hz, Ar–H), 12.50 (bs, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 14.08 (CH3), 22.12, 25.51, 25.56, 28.20,30.72, 30.84, 31.16, 31.18 (5×CH2), 61.12, 61.18 (NCH2), 115.95, 116.16, 116.37, 126.34, 127.30, 129.57, 129.65, 129.93, 130.01, 130.21, 130.39, 130.42, 145.25, 145.88, 147.47, 149.51, 149.80 (Ar–C), 158.95, 162.12, 162.46, 164.93, 165.42 (C=N, C=O). 19F NMR (377 MHz, DMSO-d6): δF = (−109.93 to −109.85), (−109.43 to −109.35) (2m, 1F, Ar–F). MS (ES) m/z = 404.90 [M+].

4-(2-(4-Fluorobenzylidene)hydrazinecarbonyl)-1-heptylpyridinium thiocyanate (). It was obtained as yellow crystals; mp: 175–176 °C. 1H NMR (400 MHz, DMSO-d6): δH = 0.85–0.89 (m, 3H, CH3), 1.25–1.32 (m, 8H, 4×CH2), 1.94–2.01 (m, 2H, NCH2CH2), 4.70 (t, 2H, J = 8 Hz, NCH2), 7.26 (dd, 0.5H, J = 8 Hz, 12 H, Ar–H), 7.38 (dd, 1.5H, J = 8 Hz, 12 Hz, Ar–H), 7.63 (dd, 0.5H, J = 4 Hz, 8 Hz, Ar–H), 7.90 (dd, 1.5H, J = 8 Hz, 12 Hz, Ar–H), 8.17 (s, 0.25H, H–C=N), 8.40 (d, 0.5H, J = 4 Hz, Ar–H), 8.51 (s, 0.75H, H–C=N), 8.54 (d, 1.5H, J = 4 Hz, Ar–H), 9.27 (d, 0.5H, J = 8 Hz, Ar–H), 9.35 (d, 1.5H, J = 4 Hz, Ar–H), 12.51 (bs, 1H, CONH). 13C NMR (100 MHz, DMSO-d6): δC = 14.02 (CH3), 22.07, 25.47, 28.52, 28.16, 30.69, 30.81, 31.11, 31.14 (5×CH2), 61.09, 61.17 (NCH2), 115.89, 116.10, 116.32, 126.30, 127.27, 129.51, 129.60, 129.88, 129.97, 130.16, 130.19, 130.34, 130.37, 145.21, 145.82, 147.42, 149.48, 149.75 (Ar–C), 158.91, 162.08, 162.41, 164.55, 164.89, 165.36 (C=N, C=O). 19F NMR (377 MHz, DMSO-d6): δF = (−109.93 to −109.85), (−109.43 to −109.35) (2m, 1F, Ar–F). MS (ES) m/z = 400.00 [M+].

3.5. Biological Activity

3.5.1. Antimicrobial Activity

Antimicrobial Evaluation Using the MIC Assay

The in vitro minimum inhibitory concentrations (MICs) of the antimicrobial activities were measured by the broth microdilution method [19,20]. The tested pathogenic strains were provided by the Regional Center for Mycology and Biotechnology (RCMB).

Cell Lines

The synthesized compounds 5–40 were evaluated for their antimicrobial activity against Streptococcus pneumonia RCMB 010010, Bacillus subtilis RCMB 010067, Staphylococcus aureus RCMB 010025 (Gram-positive bacteria), Pseudomonas aeuroginosa RCMB 010043, Escherichia coli RCMB 010052, Klebsiella pneumonia RCMB 010058 (Gram-negative bacteria), Aspergillus fumigates RCMB 02568 and Candida albicans RCMB 05036 (Fungi). The tested compounds (10 mg) were dissolved in dimethylsulfoxide (DMSO, 1 mL) and then diluted in culture medium (Mueller-Hinton Broth for bacteria and Sabouraud Liquid Medium for fungi) with further progressive dilutions to obtain final concentrations of 1, 2, 4, 8, 16, 31.25, 62.5, 125, 250 and 500 mg·mL−1. The DMSO content never exceeded 1% v/v. The tubes were inoculated with 105 cfu·mL−1 (colony forming units/mL) and incubated at 37 °C for 24 h. Growth controls consisting of media and media with DMSO at the same dilutions as used in the experiments were employed.

3.5.2. Anticancer Activity

Human breast adenocarcinoma MCF-7, human ductal breast epithelial tumor T47D, human epithelial carcinoma Hela and human epithelial colorectal adenocarcinoma Caco-2 were cultivated in Dulbecco’s modified Eagle medium (DMEM, Biochrom, Berlin, Germany). All cell lines were cultured at 37 °C, and all media were supplemented with 1% 2 mM l-glutamine (Lonza), 10% fetal calf serum (Gibco, Paisley, UK), 50 IU/mL penicillin/streptomycin (Sigma, St. Louis, MO, USA) and amphotericin B (Sigma, St. Louis, MO, USA). For the cytotoxicity test, each examined compound was added to the culture medium and incubated for 48 h in an atmosphere of 5% CO2 and 95% relative humidity at 37 °C.

Cytotoxicity Evaluation Using the MTT Assay

The cytotoxic effects associated with the examined compounds were evaluated according to the protocol described in ISO 10993-5 [21]. Cells were seeded at a density of 8 × 103 cells per well in 96-well plates in the appropriate medium. In all assays, the drugs were dissolved in DMSO immediately before the addition to the cell cultures, and an equal amount of solvent was added to control the cells. At the end of the exposure period, the MTT (3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide) (Sigma-Aldrich, Dorset, UK) assay was carried out as previously described (ISO, 2009). The yellow tetrazolium dye of MTT was reduced by metabolically active cells into an intracellular purple formazan product. The absorbance values of each well were determined with a microplate enzyme-linked immuno-assay (ELISA) reader equipped with a 570-nm filter. The survival rates of the controls were set to represent 100% viability. Untreated cultures were used as the control groups.

4. Conclusions

The synthesis of fluorinated pyridinium-based hydrazones 5–10 was successfully achieved through the alkylation of N-(4-fluorobenzylidene)isonicotinohydrazide (3) with the appropriate alkyl iodides under both conventional and ultrasound conditions. The ultrasound-assisted metathetic synthesis has also been investigated and gave the desired 11–40. A comparison of the results from using US with that under the classical method revealed an improvement in the reaction yields and a reduction in the reaction time. Most of the synthesized compounds showed good to excellent antibacterial activity at MIC 4–16 µg/ml, whereas only 12, 23, 31–33 and 36–38 were found active against fungal strains at MIC 8–16 µg/ml. On the other hand, the tested 5, 12 and 14 showed significant antiproliferative activity against four different human cancerous cell lines at moderate doses.