Unveiling the synthesis and spectral characterizations of novel (E)-furan-2-yl acrylohydrazides: an exploration in molecular design

In this study, we present the synthesis of novel derivatives of 3-furan-2-yl acrylohydrazide using a meticulous three-step reaction sequence. The synthesis ends up in the condensation of (E)-3-(furan-2-yl) acrylohydrazide ( 3 ) with diverse benzaldehyde and acetophenone derivatives. Comprehensive characterization of the synthesized compounds was achieved through 1D nuclear magnetic resonance spectroscopic analyses ( 1 H and 13 C NMR), 2D nuclear magnetic resonance spectroscopy (HSQC, NOESY), and high-resolution mass spectrometry (HRMS). The investigation of 1 H NMR data at room temperature in deuterated dimethyl sulfoxide (DMSO-d 6 ) unveiled the existence of ( E )-3-(furan-2-yl) acrylohydrazide derivatives ( 4a – h ) in a conformational equilibrium, manifesting as a mixture of syn periplanar E (sp E ) and anti periplanar E (ap E ), Notably, compounds 4a and 4b predominantly adopted the sp E conformer ( E c=c sp E C=N ), while the remaining compounds ( 4c – h ), favored the antiperiplanar conformation ( E c=c ap E C=N ) even if for the 4g compound it was challenging to determine the E C=N conformer. These ﬁ ndings contribute valuable insights into the conformational dynamics of this class of compounds, holding signi ﬁ cance for applications in diverse scienti ﬁ c domains


Methods
Synthesis procedure for (E)-ethyl 3-(furan-2-yl) acrylate (2) In a 100 mL round-bottom flask (rbf) fitted with a magnetic stirrer, a reaction mixture comprising triphenylphosphine (PPh 3 , 1.5 eq., 36.46 mmol, 9,48 g), a saturated solution of sodium bicarbonate (NaHCO 3 ) (50 mL), ethyl 2-chloroacetate (1.8 eq, 43.40 mmol, 4.80 mL), and furan-2-carbaldehyde (1 eq, 24.10 mmol) was stirred at ambient temperature for a duration of 24 h.The reaction was monitored using thin-layer chromatography (TLC), and the completion of the reaction is indicated by TLC analysis.At the end of the reaction, the reaction mixture was extracted with dichloromethane (DCM), and the resulting organic layer was dried using magnesium sulfate (MgSO 4 ) before undergoing concentration under reduced pressure.Subsequently, diethyl ether (Et 2 O) was introduced to induce the precipitation of triphenylphosphine oxide (O=PPh 3 ), which was subsequently separated via filtration.The obtained crude product undergoes purification via column chromatography on silica gel, using cyclohexane or hexane as the eluent, resulting in the isolation of a brown oil with a purity of 77% (3.07 g).

Chemical synthesis
The N-acylhydrazone derivatives (4a-h) were obtained through a three-step synthetic pathway starting from furan-2-carbaldehyde (1).The initial step involved the addition of ethyl chloroacetate to aldehyde (1) in the presence of triphenylphosphine (PPh 3 ) under basic conditions, employing the Wittig reaction (El-Batta et al., 2007).Consequently, the ester (2) was obtained with a yield of 77%.Subsequently, the ester (2) reacted with hydrazine monohydrate (H 2 N-NH 2 .H 2 O) in ethanol at room temperature to yield the corresponding hydrazide (3) with a yield of 52%.Finally, a series of acrylohydrazide derivatives (4a-h) was synthesized with yields ranging from 23% to 96% (Table 1).This was achieved by condensing hydrazide (3) with various derivatives of benzaldehyde and acetophenone in ethanol at room temperature for 3 h, in the presence of a catalytic amount of concentrated hydrochloric acid (HCl) (Scheme 1).
The newly synthesized compounds (4a-h) were fully characterized using various analytical methods, notably NMR, which revealed the presence of a dynamic equilibrium between two isomers for each compound in the N-acrylohydrazone series (4a-h).The results of this stereochemical study will be discussed in the following section.

Spectral analysis
The examination of the 1 H NMR spectrum for compound (2) reveals the presence of two distinct E and Z isomers, with an approximate ratio of 88/12 (E/Z).Each isomer exhibits characteristic doublet signals.In the predominant E isomer, a doublet is observed at 6.27 ppm, corresponding to the alpha (a) proton adjacent to the carbonyl CO, while another doublet is detected at 7.38 ppm, indicative of the beta (β) proton.Conversely, in the minor Z isomer, the alpha (a) proton resonates at 5.69 ppm, while the beta (β) proton is discerned at 7.73 ppm.
The pronounced mesomeric attractive effect between the alkene and the carbonyl bonds results in notable deshielding of the beta (β) proton in the vicinity of the carbonyl.Furthermore, a quadruplet, integrating for two protons around 4.18 ppm, and a triplet, integrating for three protons at 1.26 ppm, are evident, corroborating the presence of the methyl group of the ester function.In the 13 C NMR spectrum, discernible peaks at 167 ppm (E isomer) and 165.96 ppm (Z isomer) confirm the presence of the carbonyl carbon in both forms.
The scrutiny of the 1 H NMR spectrum for compound (3) reveals the disappearance of signals attributed to the ethoxy group (OCH 2 CH 3 ) and the emergence of broad singlets at 4.05 and 7.19 ppm.These singlets correspond to the NH protons of the NH 2 and C(O)-NH groups, respectively.Even if compound (2) was initially utilized, consisting of a mixture of E and Z isomers in an 88/12 ratio, only the E isomer was successfully isolated for compound (3).
The 1 H NMR spectra of the ultimate compounds (4a-h), acquired in DMSO-d 6 , exhibit a marked duplication of signals pertaining to three neighboring atom groups within the amide fragment: NH, N=CH or N=C(CH 3 ), and CH=CH(CO) (Figs. 1-4).well as the azomethine (N=CH) and azoethylidine (N=C(CH 3 )) fragments.Additionally, a systematic duplication of signals is discernible in the 13 C NMR spectra for all compounds (4a-h).Comparison of the 1 H NMR spectra (Fig. 3) for compound (4h) recorded in deuterated chloroform (CDCl 3 ) and deuterated dimethyl sulfoxide (DMSO-d 6 ) reveals the presence of two conformers characterized by the splitting of the NH function signal, one at 11.70 ppm and the other at 11.53 ppm in the DMSO-d 6 spectrum.In contrast, the CDCl 3 spectrum indicates a singular conformer with the NH function signal appearing at 9.33 ppm.Notably, the chemical shift of NH is reduced in the CDCl 3 spectrum compared to the DMSO-d 6 spectrum.This observation aligns with the findings reported by Palla et al. (1986), suggesting that the marginal chemical shifts observed in the CDCl 3 spectra may be attributed to intramolecular hydrogen bonding.
Comparative analysis of the 1 H NMR spectra for compounds 4b and 4g, recorded in deuterated methanol (Methanol-d 4 ) and DMSO-d 6 (Figs. 2 and 4) indicates signal duplication for various protons.However, the NH signal is absent in the spectrum recorded in Methanol-d 4 , and the duplicated signals exhibit lower intensity compared to the 1 H NMR spectrum recorded in DMSO-d 6 .The duplicated NH signals manifest at 11.75 ppm and 11.93 ppm for compound (4g) and 10.63 ppm and 10.67 ppm for compound (4b).The absence of the NH signal in the spectra recorded in Methanol-d 4 may be ascribed to proton exchange with deuterium from the solvent.

Stereochemical analysis of Acrylohydrazide derivatives (4a-h)
The duplication of characteristic signals for NH and N=CH groups observed in both 1 H and 13 C NMR spectra (Tables 2 and 4) of the acrylohydrazides (compounds 4a-h) indicates the presence of two distinct isomers.Considering the structure of acrylohydrazide, this signal duplication could be attributed to the geometric stereoisomerism (Z or E) of the azomethine (N=CH) or azoethylidine (N=C(CH 3 )) fragment, or the ethylenic (CH=CH) group, or to a slow rotation around the N-N or N-C=O bond (Scheme 2).
Concerning the geometric stereoisomerism of the ethylenic fragment in acrylohydrazides, they all exhibit the E c=c configuration confirmed by the coupling   Due to the assembly of amide and imine functionalities, acrylohydrazides can exist as stereoisomers with a C=N double bond (geometric configurations Z or E) and as syn/ antiperiplanar conformers around the amide (C(O)-NH) bond (Scheme 2).In the 1 H NMR spectra, the maximum intensity difference for compounds (4a-h) confirms that both conformers were obtained with different ratios (Table 2).
Analysis of the various ratios among all possible conformers reveals that the synperiplanar (sp) conformer is predominant for compounds 4a-b, while the antiperiplanar (ap) conformer is favored for compounds 4c-d.For compounds 4e-h, the syn/anti-periplanar conformers are nearly in equal proportions.
Palla et al.'s (1986) previous work has demonstrated that the Z isomer of acrylohydrazides is characterized by a singlet around 14 ppm corresponding to the NH proton.The absence of a duplicated singlet around this chemical shift in the proton spectra (Fig. 1) suggests the absence of the Z(C=N) isomer.However, the correlation between the NH proton and the azomethine fragment in the NOESY spectrum of compounds 4h and 4f (Fig. 5) confirms the presence of the E(C=N) isomer, according to the findings of Palla et al. (1986).Regarding compounds 4a-f and 4h, the emergence of a weak correlation between the NH proton and azomethine (N=CH) and azoethylidine (N=C(CH 3 )) fragments in the NOESY spectrum (Fig. 2) confirms also the presence of the E(C=N) isomer.Table 3 summarizes the calculated ratios relative to the duplicated NH signal.These results indicate that the syn conformer is predominant for compounds 4a-b (thus, the stereochemistry Ec=c sp E C=N ), while for compounds 4c-h, the anti conformer is favored (Table 5).It is noteworthy that the proportion of the anti conformer decreases in favor of the syn conformer when transitioning from compounds 4c-d to 4g-h and from 4g-h to 4e-f.
Comparing the ratios of different conformers between compounds 4c-h and 4a-b reveals a reversal of the anti conformer in favor of the syn conformer when transitioning from compounds 4c-h to 4a-b.This inversion of conformers could be explained by the

CONCLUSION
This study successfully synthesized eight new derivatives of (E)3-furan-2-yl acrylohydrazide.The obtained compounds were comprehensively characterized through spectroscopic analyses, including 1D and 2D NMR, as well as high-resolution mass spectrometry.
The analysis of 1 H NMR data unveiled significant conformational diversity among the synthesized compounds.Compounds 4a-b demonstrated an Ec=c sp E C=N configuration, while all other compounds exhibited an Ec=c ap E C=N configuration.Notably, compounds 4g displayed an Ec=c ap configuration and likely E C=N , although confirmation of the latter was challenging.
Ultimately, this research contributes to the continum of prior investigations on Nacylhydrazones, emphasizing the stability of (E)-3-(furan-2-yl) acrylohydrazides.This understanding of their conformation properties opens promising avenues for future applications in diverse fields, such as the design of new materials.
In our research, we have developed N-acylhydrazones featuring diverse passivation groups.The incorporation of these groups has the potential to significantly influence their utility in solar energy applications, and also could exhibit promising bioactive properties.Our preliminary studies with our synthesis compounds have demonstrated their efficacy in inhibiting the growth of S. aureus, motivating further investigation into their potential as treatments for methicillin-resistant S. aureus infections.

Table 2
Chemical shift of protons in compounds 4a-h.

Table 3
Proportion of ratios relative to C(O)-NH in compounds 4a-h.

Table 4
Chemical shift of carbon in compounds 4a-h.