Abstract
Eighteen new N-(E)-stilbenyloxyalkylcarbonyl-substituted hydrazones of ortho- (meta- and para-) chloro- (nitro-) benzaldehydes 1–18 and two analogous hydrazones of acetone 19-20 were prepared. The stereochemical behavior of 1–18 in dimethyl-d6 sulfoxide solution has been studied by NMR and NMR techniques, using spectral data of 19 and 20 as supporting material. The E-geometrical isomers and cis-/trans-amide conformers have been found for these hydrazones. Energy barriers of isomers are reported.
1. Introduction
The N-substituted hydrazones of aldehydes are of interest because of their biological and pharmacological activities [1–5], as well as considerable chelating power with transition metals [6–9]. They can be used in analytical chemistry to cover and analyze metals selectively as hydrazone complexes. Hydrazones of o-(m- and p-) chlorobenzaldehydes and o-(m- and p-) nitrobenzaldehydes have been reported in the literature [10–13].
Chloro- and nitrobenzaldehydes are widely used as reagents for organic synthesis, chiefly as reactants for manufacturing pharmaceuticals, plastic additives, pesticides, dyes and metal finishing agents. For example, 2-chlorobenzaldehyde is an intermediate for the optical brighteners production and finds its application as the brightening agent for zinc plating, whereas 2-nitrobenzaldehyde is a substrate for indigo synthesis in the Baeyer-Drewson method [14] and easy removable protection group for many functionalities [15].
However, despite the many synthetic applications of substituted benzaldehydes, to the best of our knowledge no work has been published in the literature about the synthesis and physicochemical properties of N-(E)-stilbenyloxyalkylcarbonyl substituted hydrazones of ortho- (meta- and para-) chloro- and (nitro-) benzaldehydes. These compounds, containing amide and hydrazone functions in their molecules, seemed to be suitable candidates for further chemical modifications and may be pharmacologically active and analytically useful. It ought to be pointed out that (E)-stilbenes hydroxylated at one to five positions as well as their ethereal derivatives are produced by woody plants and exhibit a broad spectrum of biological activity [16–20].
We have previously reported the synthesis, physicochemical properties, as well as mass spectrometric study of N-(E)-stilbenyloxyalkylcarbonyl substituted hydrazones of o-(m- and p-) hydroxybenzaldehydes and 2-(3- and 4-)pyridinecarboxyaldehydes [21–26]. Our studies have been recently extended to N-(E)-stilbenyloxymethylenecarbonyl substituted hydrazones of o-(m- and p-) chlorobenzaldehydes and o-(m- and p-) nitrobenzaldehydes 1–18. This paper deals with the synthesis and the investigation of the stereochemical behavior of these compounds in DMSO-d6 solution by means of 1H and 13C NMR spectroscopy.
2. Results and Discussion
Treatment of the corresponding o-(m- and p-) chlorobenzaldehydes and o-(m- and p-) nitrobenzaldehydes with the hydrazides of (E)-stilbenyl-4-oxyacetic acid [(E)-4′-chlorostilbenyl-4-oxyacetic acid, (E)-4′-nitrostilbenyl-4-oxyacetic acid] in boiling absolute ethanol (or boiling DMF) afforded 1–18 (Figure 1). N-(E)-4′-chlorostilbenyl-4-oxymethylenecarbonyl and N-(E)-4′-nitrostilbenyl-4-oxymethylenecarbonyl substituted hydrazones of acetone 19 and 20 (Figure 2) as the reference compounds have been obtained similarly. The structures of compounds 1–18 were determined by examining their UV/Vis, IR, 1H NMR and 13C NMR spectra as well as elemental analyses (Tables 1, 2, 3, 4, 5, 6, 7, and 8), the respective data for compounds 19 and 20 have been collected in Tables 10, 11, and 12.
The hydrazones 1–18 can exist as Z/E geometrical isomers about C=C bond of ethylene bridge in the stilbene part of the molecule, Z/E geometrical isomers about C=N bond of hydrazone moiety as well as cis/trans amide conformers (Figure 3).
Previously, we have demonstrated that N-(E)-stilbenyloxymethylenecarbonyl substituted hydrazones of o-(m- and p-) hydroxybenzaldehydes occurred as (E)-geometrical isomers about C=N bond in DMSO-d6 [24], as well as in the solid phase [23]. According to the literature hydrazones of o-(m- and p-) nitrobenzaldehydes are essentially planar with E configuration at the C=N double bond [10, 11], as well as N-acyl substituted hydrazones of pyridinecarboxaldehydes are present in dimethyl-d6 sulfoxide solution in the form of geometric (E)-isomers about C=N double bond [27]. (E)-configuration in the stilbene part of the molecules of 1–18 was determined on the basis of their UV/Vis and IR spectra. It has been pointed out that in the UV/Vis spectra of 1–18 are in the range 290.0–385.5 nm (Table 2). According to the literature [28–30] (E)-stilbenes exhibited the values of in the range 290–360 nm and for (Z)-stilbenes values of fall in the range 260–280 nm. The infrared spectra of 1–18 show a strong band in the range of 952–970 cm−1 which according to the literature [30, 31] can be attributed to the C–H out of the plane deformation vibration of the C–H bond of the (E)-ethylene bridge of the stilbene skeleton (Table 2).
The ratio of amide cis/trans conformers can be easily quantified by NMR techniques. In order to require information about the stereochemical behavior of 1–18 in polar dimethyl-d6 sulfoxide solution, we have investigated 1H NMR spectra of these compounds. We wish to establish whether it is possible to determine from this spectral analysis the ratio of cis/trans amide conformers of 1–18. According to our previous data [21] 1H NMR spectrum in DMSO-d6 solution of N-(E)-stilbenyl-4-oxymethylenecarbonyl substituted hydrazone of acetone is simpler [21] as it lacks the possibility of E/Z geometrical isomers about the C=N double bond. In this spectrum two sets of singlets of methylene and imine protons are seen, associated with the protons of the cis and trans amide conformers of this compound. The rate of cis/trans isomerization of this compound in DMSO-d6 has been followed by 1H NMR at several temperatures in order to evaluate the energy barrier of cis→trans conversion. The coalescence of methylene group signals of conformers of this hydrazone of acetone in DMSO-d6 solution occurred at about 100°C. The ΔG number values of 18.33 and 18.06 kcal/mol were found by dynamic NMR, using the coalescence temperature method [32]. The intensities of signals of methylene and imine protons have allowed us to make measurements of the ratio of cis/trans amide conformers. It ought to be pointed out that the ratio of the conformers at 25°C was the same as that measured at the same temperature at the end of the experiment dealing with the coalescence temperature. This is the proof that in DMSO-d6 solution of N-(E)-stilbenyloxymethylenecarbonyl substituted hydrazone of acetone the conversion of cis/trans amide conformers has been the only process of isomerization. These investigations have been extended to N-(E)-4′-chlorostilbenyl-4-oxymethylenecarbonyl and N-(E)-4′-nitrostilbenyl-4-oxymethylenecarbonyl substituted hydrazones of acetone. Reaction of acetone with hydrazide of (E)-4′-chlorostilbenyl-4-oxyacetic acid as well as (E)-4′-nitrostilbenyl-4-oxyacetic acid provided new N-substituted hydrazones of acetone 19 and 20, respectively (Figure 2). These compounds were included in this paper for comparative purposes. The structures of 19 and 20 were determined by examining their IR and 1H NMR spectra as well as elemental analyses (Tables 10–12). The spectral analysis revealed (E)-configuration of the geometric isomers 19 and 20 in the stilbene part of the molecules. The infrared spectra of 19 and 20 show a strong absorption band at 962 and 961 cm−1, respectively, which can be attributed to C–H out of plane deformation vibration of the ethylene bridge (Table 11).
In the 1H NMR spectra of 19 and 20 also two sets of protons of methylene and imine groups are seen. According to the literature [27] the upfield lines of methylene protons have been assigned to amide conformers cis and downfield lines of protons of the same groups to amide conformers trans. The intensities of 1H NMR signals of methylene protons have allowed us to make measurements of the ratio of cis/trans amide conformers. The chemical shifts and percentage of the conformers in dimethyl-d6 sulfoxide solution of 19 and 20 are summarized in Table 13. Having established the ratio of cis/trans amide conformers of 19 and 20 in DMSO-d6 solutions, we have applied the similar methodology in establishing the ratio of the respective conformers of 1–18 in the same solvent.
The rate of cis/trans isomerization of 10, 12 and 13 in dimethyl-d6 sulfoxide has been followed by 1H NMR measurements at several temperatures (20, 50, 60, 70, 80, 90, 100, 110, and 120°C) in order to evaluate the energy barrier of cis/trans conversion (Figure 3). The coalescence of methylene group signal of 10 conformers present in dimethyl-d6 sulfoxide solution occurred at about 85°C, whereas the coalescence of methylene group of 12 and 13 conformers at about 80°C and 100°C, respectively. The ΔG number values of 21.85 and 21.30 kcal/mol (10), 21.48 and 21.04 kcal/mol (12) as well as 22.70 and 22.31 kcal/mol (13) were found by dynamic NMR, using the well known coalescence-temperature method [32]. The intensities of the 1H signals of the protons of methylene groups of 1–18 have allowed us to make measurements of the ratio of cis/trans conformers. The chemical shifts and percentage of conformers of 1–18 in DMSO-d6 solution are summarized in Table 9. It ought to be pointed out that the ratio of the conformers at 20°C is the same at the beginning and at the end of the experiment dealing with the coalescence temperature. This can serve as a proof that in the DMSO-d6 solution of the investigated compounds 1–18 the conversion of cis/trans amide conformers is the only process of isomerization. We have also investigated the 13C NMR spectra of N-(E)-stilbenylo-4-oxymethylene carbonyl substituted hydrazones of acetone 19 and 20. The 13C NMR data of 19 and 20 are given in the Table 12. Assignments of 13C NMR resonances of these compounds were deduced on the basis of the literature data as well as the signal multiplicities, chemical shift theory and additivity rules. In the 13C NMR spectra of these compounds two sets of carbon signals are seen. According to the 13C assignments for N-acyl- and N-aroylhydrazones of methyl pyruvate [27] as well as the hydrazones of aromatic aldehydes [33], the upfield lines of carbonyl carbons and the downfield lines of methylene carbons have been assigned to amide conformer trans whereas the downfield lines of carbonyl carbons and the upfield lines of methylene carbons to the conformer cis. Having established the ratio of cis/trans amide conformers of 19 and 20 in DMSO-d6 solutions by 1H NMR technique, we have applied the similar methodology in establishing the ratio of conformers of N-substituted hydrazones of acetone on the basis of the height of the signals of the carbons of methylene groups in the 13C NMR spectra. The chemical shifts and the percentage of cis/trans amide conformers of 19 and 20 calculated from the heights of the signals of the protons in the 1H NMR spectra and the carbons in the 13C NMR spectra are given in the Table 13. It ought to be pointed out that in the cases of these compounds the differences between the values calculated from the data obtained from the 1H NMR spectra and 13C NMR spectra are at the level 1-2%. Having established on the basis of 13C NMR data the ratio of cis/trans amide conformers of N-substituted hydrazones of acetone 19 and 20, in DMSO-d6 solution, we have applied the similar methodology in establishing the ratio of conformers of compounds 1–18 in the same solution. In the 13C NMR spectra of 1–18 two sets of signals of carbon (Tables 4, 5, 7, and 8) are seen. Assignments of 13C NMR resonances of these compounds were deduced on the literature data, as well as signal multiplicities, chemical shift theory and additivity rules. It ought to be pointed out that upfield lines of carbonyl carbons and the downfield lines of methylene carbons have been assigned to amide conformer trans, whereas downfield lines of carbonyl carbons and the upfield lines of methylene carbons to amide conformer cis. The chemical shifts and the percentage of the cis/trans amide conformers of compounds 1–18 calculated from the heights of the signals of the protons in the 1H NMR spectra and the carbons in the 13C NMR spectra are given in the Table 10. It ought to be pointed out that in the cases of compounds 1, 4, 5, 11, 14, 15, 16, and 18 the differences between the values of the percents calculated from the data obtained form the 1H and 13C NMR spectra are at the level below 1%. In the cases of compounds 2, 3, 7, 9, 10 and 17 these differences are at the level of 1-2%, whereas in the cases of 8 and 12 at the level of 2-3%. Only in the cases of compounds 6 and 13 these differences have the values 5.16% and 4.21%, respectively.
3. Conclusions
It follows from the obtained results that the E-geometrical isomers of 1–18 as well as 19-20 undergo a rapid cis/trans amide equilibrium when dissolved in DMSO-d6 solution, with the cis amide conformer predominating. The ratio of amide cis/trans conformers of 1–18 and 19-20 can be determined on the basis of the analysis of both 1H and 13C NMR spectra. To the best of our knowledge no work has been published on the using of 13C NMR spectra in establishing the ratio of amide cis/trans conformers of N-substituted hydrazones.
4. Experimental
The NMR measurements were performed on a Varian Mercury Spectrometer operating at 300.07 MHz (proton) and 75.46 MHz (carbon). Data were obtained from DMSO-d6 solutions at concentrations between 0.25 and 0.40 M at ambient temperature. The chemical shifts were referenced to tetramethylsilane. 1H NMR spectra were recorded at a proton frequency of 300.07 MHz with a spectral width of 9000 Hz. The acquisition time was 2 s and a relaxation delay 1 s; 64 scans with 44.922 data points each were used. The 13C NMR spectra were obtained using a spectral width of 23,000 Hz and 1.5 s acquisition time; 2476 scans with 68992 data points each were used. UV/Vis spectra were recorded with a SPECORD UV/Vis spectrophotometer in CH3OH (1–3, 7–9, 13–15) and DMSO (4–6, 10–12, 16–18). IR spectra were recorded with a FTIR Bruker IFS-113 V spectrophotometer in KBr pellets. Elemental analyses were performed with a Vector Euro EA 3000 analyzer. values to silica gel F254 plates (Merck) were developed with chloroform-methanol 50 : 1 and observed under UV light ( = 254 and 366 nm).
Hydrazides of (E)-stilbenyloxyacetic acid, (E)-4′-chlorostilbenyl-4-oxyacetic acid [34] and (E)-4′-nitrostilbenyl-4-oxyacetic acid [35], as well as N-(E)-4-stilbenyloxymethylene- carbonyl substituted hydrazone of acetone [21] were obtained according to the literature.
The Synthesis of N-(E)-4′ -chloro-(nitro)stilbenyl-4-oxymethylenecarbonyl-Substituted Hydrazone of Acetone 19-20. General procedure. A solution of (E)-4′-chloro- (nitro-)-4-oxyacetic acid hydrazide (1 × 10−3 mol) in 60 mL of acetone was refluxed for 3 hours. Then half of the volume of acetone was evaporated on a rotatory evaporator and the residue was cooled in the refrigerator for 3 hours. The formed crystals were filtered, dried, and recrystallized form acetone (Table 10).
The Synthesis of N-(E)-stilbenyl-4-oxymethylenecarbonyl-Substituted Hydrazones of ortho-(meta- and para-) chloro- (nitro-)benzaldehydes 1–18. General Procedure. To a solution of 1 mmole of the corresponding hydrazide of (E)-stilbenyloxyacetic acid in 20 mL of DMF, 1.5 mmole of the corresponding o-(m- and p-) chloro- (nitro-) benzaldehyde was added. The reaction mixture was refluxed for 2 hours. Then the solvent was evaporates to dryness. The obtained solid was dissolved in 50 mL of boiling absolute ethanol, then boiled for 1 hour and concentrated to ca. volume on a rotatory evaporator. The residue was cooled, the precipitated solid was filtered off, dried, and recrystallized form corresponding solvent (Table 1).