# Synthesis and structural characterization of β-phosphonated thiosemicarbazones: Investigation of their Z/E interconversion by NMR and DFT computing

Sirine Salhi, Dorra Kanzari-Mnallah, Isabelle Jourdain, Michael Knorr, Jan-Lukas Kirchhoff, Carsten Strohmann, Youssef Arfaoui, Mohamed Lotfi Efrit, Hedi M'rabet, Azaiez Ben Akacha

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Sirine Salhi, Dorra Kanzari-Mnallah, Isabelle Jourdain, Michael Knorr, Jan-Lukas Kirchhoff, et al. Synthesis and structural characterization of β-phosphonated thiosemicarbazones: Investigation of their Z/E interconversion by NMR and DFT computing. Journal of Molecular Structure, 2026, 1353, pp.144576. 10.1016/j.molstruc.2025.144576. hal-05363667

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# Synthesis and structural characterization of β-phosphonated thiosemicarbazones: Investigation of their Z/E interconversion by NMR and DFT computing

Sirine Salhi<sup>a,b</sup>, Dorra Kanzari-Mnallah<sup>a,*</sup>, Isabelle Jourdain<sup>b,D</sup>, Michael Knorr<sup>b,*</sup>, Jan-Lukas Kirchhoff<sup>c,D</sup>, Carsten Strohmann<sup>c</sup>, Youssef Arfaoui<sup>d,D</sup>, Mohamed Lotfi Efrit<sup>a</sup>, Hedi M'rabet<sup>a,D</sup>, Azaiez Ben Akacha<sup>a,*</sup>

## ARTICLE INFO

### Keywords:

Phosphonated thiosemicarbazone

Hydrazone

UV-vis

Z/E interconversion

Conformations

NMR

X-ray diffraction

DFT computing

## ABSTRACT

This work aims to present the synthesis of thiosemicarbazones (TSCs) bearing a Ph₂P(=O)CH₂- moiety, a yet unknown subclass of TSCs, along with their crystal structures and the Z/E interconversion occurring in solution. For this purpose, eight new phosphonated thiosemicarbazones Ph₂P(=O)CH₂{C=N-NH(C=S)-NH-R}CH₃ (4a R = Ph; 4b R = p-FC₆H₄; 4c R = p-ClC₆H₄; 4d R = 3,5-Me₂C₆H₃; 4e R = 2,5-(MeO)₂C₆H₃; 4f R = CH₂C₆H₅; 4g R = C₆H₁₁; 4h R = CH₂-CH=CH₂) were prepared by nucleophilic addition of β-phosphonated hydrazone Ph₂P(=O)CH₂(C=N-H₂)CH₃ 2 across various aromatic and aliphatic isothiocyanates R-N=C=S. The synthesis of 4 is accompanied by competing formation of the phosphonated azine Ph₂P(=O)CH₂{C(Me)=N-N=C(Me)}CH₂P(=O)Ph₂ 3 and of bis(N-arylthioureas) or bis(N-alkylhexylthioureas) 5, lowering the overall yield of 4. All products were characterized by multinuclear NMR, FT-IR spectroscopy and UV-vis spectroscopy. NMR spectroscopy of 4 at variable temperature indicates the coexistence of E and Z-isomers in solution with respect to the relative position of the substituents around the hydrazonic -C=N-NH- array. Several crystal structure determinations by single crystal X-ray diffraction (SC-XRD) reveal that in the solid state exclusively the E isomer is present, except for 4e which adopts a Z configuration due to an intramolecular C-O···H-N and P=O···H-N hydrogen bonding. For all derivatives, also an intramolecular N-H···N bonding is evidenced. The individual molecules of 4a, 4b, 4d, 4f, 4g and 4h are associated by strong intermolecular P=O···H-N hydrogen bonding in form of supramolecular macrocyclic dimers or 1D chains. These secondary interactions were further examined by a Hirshfeld surface analysis of 4f. For a comparison of the experimental SC-XRD parameters with the theoretical calculated ones and the preferred configuration, DFT calculations at the B3LYP/6-311<sup>g</sup> G (d, p) level were performed both in solution and in the gas phase. A computing of the Intrinsic Reaction Coordinates (IRC) revealed that the E-isomer of 4a is energetically more stable than the Z-isomer, since there is less steric crowding.

## 1. Introduction

Organophosphorus compounds represent an important category of chemical entities. They are characterized by the presence of organic constituents bonded directly to phosphorus or attached through a het- eroatom. They constitute a prevalent class of chemicals ubiquitously found in the human environment [1]. In consideration of their

extraordinary attributes and potent biological activities, they are widely utilized in medicine, agriculture and industrial processes [2–7]. Among the plethora of organophosphorus compounds featuring a biological activity are also those bearing a diphenylphosphine oxide Ph₂P=O or phosphonate (RO)₂P(=O) entity (Fig. 1) [8–14]. Therefore, several strategies have been developed to attach these motifs on an organic scaffold. For example, oxidation of the Ph₂PCH₂-entity of norflaxin with

<footnote><sup>a</sup> Laboratory of Selective Organic and Heterocyclic Synthesis-Biological Activity Evaluation, SOHES, (LR17ES01), Faculty of Science of Tunis, University Tunis El Manar, Tunis 2092, Tunisia</footnote>

<footnote><sup>b</sup> Institut UTINAM - UMR CNRS 6213, Université Marie et Louis Pasteur, 16, route de Gray, Besançon 25030, France</footnote>

<footnote><sup>c</sup> Anorganische Chemie, Technische Universität Dortmund, Otto-Hahn-Str. 6, Dortmund 44227, Germany</footnote>

<footnote><sup>d</sup> Laboratory of Applications, Characterizations, and Modeling of Materials (LR18ES08), Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis 2092, Tunisia</footnote>

<footnote>* Corresponding authors.</footnote>

<footnote>E-mail addresses: dorrakenzari@gmail.com (D. Kanzari-Mnallah), michael.knorr@univ-fcomte.fr (M. Knorr), azaiez.benakacha@fst.utm.tn (A.B. Akacha).</footnote>
$H_2O_2$ yields Norfloxacin phosphine oxide (compound A) shown in Fig. 1 [8]. The aziridine phosphine oxide B was obtained from (S)-2-phenyl-aziridine and $ClPPh_2(=O)$ in the presence of sec-BuLi [9]. Salin and Islamov have demonstrated that addition of $H-P(=O)$ compounds to $\alpha$-methylene-$\gamma$-butyrolactones such as tulipalin A and arglabin under $n$-Bu$_3$P catalysis allows an efficient access to $Ph_2P(=O)$ or $(RO)_2P(=O)$-functionalized $\gamma$-butyrolactones [12]. Another methodology involves a radical cascade reaction of phosphine oxides with 2-aryloxy phenylacetylenes leading to diphosphonyl xanthenes such as E [13]. Other representative examples including the sparfloxacin derivate D or (3-(N-hydroxyformamido)propyl)phosphonic acid C bearing the $Ph_2P(=O)$ or $(RO)_2P(=O)$ motif in their structure and exhibiting antibacterial and anticancer activities are illustrated in Fig. 1 [10,11].

On the other hand, thiosemicarbazones (TSCs), organosulfur compounds with the formula $R_2NC(=S)NH-N=CR_2$, have been thoroughly examined owing to their pharmacological and medical attributes, as well as their remarkable structural diversity [15–20]. The initial reports regarding their medicinal potential against leprosy and tuberculosis emerged in 1950 [21,22]. Subsequently, their notable characteristics, including antiviral [23,24], antibacterial [25,26], anti-fungal [27], antidiabetic [28], anti-malarial [29], antioxidant [30,31] and anti-tumor activity [32–34] have attracted considerable attention.

In general, thiosemicarbazones are obtained from the condensation reaction between a N-substituted thiosemicarbazide $R(H)NC(=S)NHNH_2$ and an aldehyde or a ketone [35–38]. This route was for example applied for the preparation of biological active isatin-$\beta$-thiosemicarbazones by combining equimolar quantities of isatin (1H-Indole-2,3-dione) and various thiosemicarbazides [38]. Alternatively, they are accessible by treatment of an isothiocyanate $R-N=C=S$ with a hydrazone [39,40], as exemplified by addition of an isatin-derived hydrazone to p-tolyl isothiocyanate producing 2-(5-(morpholinosulfonyl)-2-oxoindolin-3-ylidene)-N-(4-methylphenyl) hydrazine-1-carbothioamide [40].

One activity of our research groups is focused on the synthesis of new potentially bioactive organophosphorus compounds [41–47] as well as the coordination chemistry of thion- and urea-derived organic molecules bearing a C=S function (thiocarbamates $ROC=S)N(H)R$ and phosphonothioamidates $(RO)_2P(=O)C(=S)N(H)R$) [42,45]. Therefore, our

principal objectives for this manuscript are the preparation of new phosphonated thiosemicarbazones which are expected to preserve the pharmacological proprieties of both organophosphorus compounds and thiosemicarbazones. Herein, we present a modified method initially developed by us for thiosemicarbazones bearing a six-membered dioxaphosphorinane residue [48], allowing to synthesize $Ph_2P(=O)CH_2$-functionalized TSCs 4 employing $\beta$-phosphonated hydrazone 2 as starting material (Schemes 1 and 2). Note that we are not aware of any other TSC prepared by other laboratories bearing organophosphorus substituents. The variation of R on the substitution pattern of thiosemicarbazones 4 was done with the aim to (i) investigate the general applicability of this synthetic route in function of the R group, (ii) to elucidate the impact of steric and electronic parameters on the conformational Z/E ratio (see below), (iii) to study the influence of R on the biological activity and finally (iv) to dispose of a wide panel of thiosemicarbazones as potential S,N chelating ligands for future studies in the domain of coordination chemistry [49]. Additionally, the presence of a harder (according to Pearson's HSAB principle) P=O donor site could enrich the coordination abilities of these phosphonated TSCs [50, 51].

The molecular structures of the products were confirmed by multi-nuclear NMR techniques, FT-IR and UV-vis spectroscopic analysis, X-ray crystallography and DFT computing. Variable temperature $^{31}$P{$^1$H} NMR affirmed a Z/E isomerization equilibrium operating around the hydrazonic C=N bond. Additionally, a discussion about the factors governing the relative stability of both isomeric forms in solution is presented.

## 2. Results and discussion

### 2.1. Synthesis of $\beta$-phosphonated hydrazone 2 and crystallographic characterization of phosphonated azine 3

The synthesis of phosphorus allenes of type 1 involves the reaction of a precursor possessing $P(III)-Cl$ bond with propargylic alcohol [52]. To prepare the $\beta$-phosphonated hydrazones 2, hydrazine monohydrate was added dropwise to a solution of diphenyl(propa-1,2-dien-1-yl)phosphine oxide 1 [53]. Hydrazone 2 was obtained as a mixture of Z (syn)

<figure><img src="image_3.png" /><figcaption>**Fig. 1.** Examples of P=O-functionalized organophosphorus compounds featuring biological activities.</figcaption></figure>
<figure><img src="image_4.png" /><figcaption>**Scheme 1.** Synthesis strategy for the phosphonated hydrazone 2 and azine 3, formed as secondary product.</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>**Scheme 2.** Synthesis strategy affording the phosphonated thiosemicarbazones 4a-h along with bis(N-arylthioureas) and bis(N-alkylthioureas) as minor secondary products.</figcaption></figure>

and E (anti) isomers (Scheme 1) with respect to the relative arrangement of the substituents around the R₁R₂C≡N-NH-bond, as confirmed by the observation of two signals in ³¹P{¹H} NMR (see Fig. S5). This is in agreement with our previous study [54,55] concerning β-phosphonated hydrazones bearing 1,3,2-dioxaphosphorinane rings. In the same sense, other papers on the synthesis of functionalized hydrazones had evidenced the product formation as pairs of Z and E isomers [56].

When attempting to grow single crystals of hydrazone 2 for its characterization by X-ray crystallography, we isolated by serendipity some crystals of a second minor compound with a RR'C=N-N=CRR' scaffold, namely the phosphonated azine ((2E,2'E)-hydrazine-1,2-diylidenebis(propan-1-yl-2-ylidene))bis(diphenylphosphine oxide) 3. The unexpected formation of this compound may be explained, as described in a previous article for a related phosphonated azine [54], by the nucleophilic addition between the allenylphosphonate 1 with in situ prepared hydrazone 2, as outlined in Scheme 1. However, the signals of the azine were identified from the oily phase formed in hydrazone synthesis reaction. The proton-decoupled ³¹P{¹H} NMR spectrum of 3 in CDCl₃ exhibits a broadened signal at δ 25.9 ppm, in line with the

chemical shift reported by Shaw *et al.* for Z,Z-P(=O)Ph₂CH₂C(Bu')=N-N=C(Bu')CH₂P(=O)Ph₂ (δ 25.1 in CDCl₃) [57]. The ¹H NMR spectrum in CDCl₃ shows a duplication of the PCH₂ and N=C-CH₃ resonances in an almost 50:50 ratio. The first set appears as two doublets centered at δ 3.46 and 3.35 with ²Jₚ₉ couplings of 12.0 Hz. The methyl signals at δ 1.87 and 1.58 are split into doublets due to ⁴Jₚ₉ couplings of about 4.0 Hz. In line with the broad ³¹P resonance, which even broadens upon heating to 50° C; we therefore suppose that azine 3 exists in solution like hydrazone 2 in form of two conformational isomers such as 3 E,E and 3 E,Z (Scheme 1).

The crystal structure contains two independent azine or phosphonated α-diimine molecules 3-M1 and 3-M2, crystallizing in the monoclinic space group P2₁/c. The centrosymmetric molecular structure of 3-M2 is shown in Fig. 2. Overall, the structure is quite reminiscent to its analogue 2,2'-(2E,2'E)-hydrazine-1,2-diylidenebis(3-phenylpropan-1-yl-2-ylidene))bis(5-methyl-5-propyl-1,3,2-dioxaphosphinane 2-oxide) (CSD refcode VOXPAD), bearing a six-membered dioxaphosphorinane ring instead of Ph₂P=O [54]. The mid-point of the azine-type N-N bond forms an inversion center. This bond length is identical with respect to
<figure><img src="image_6.png" /><figcaption>**Fig. 2.** Molecular structure of azine **3** at 100 K. Selected bond lengths (Å) and angles (°) for **M2**: P3–O3 1.496(4), P3–C31 1.506(8), C32–C33 1.496(9), N3–N3¹ 1.411(9), N3–C32 1.294(8); O3–P3–C34 111.7(3), O3–P3–C40 111.6(3), O3–P3–C31 115.1(3), P3–C31–C32 116.5(4), C31–C32–N3 115.3(6), C32–N3–N3¹ 112.7 (7), C33–C32–N3 127.7(6). Symmetry operation to generate equivalent atoms: ¹₁-x, 1-y, 1-z.</figcaption></figure>

that of the latter (1.411(9) vs. 1.412(5) Å) and matches that of other symmetric azines such as 2'-hydroxyacetophenone azine (1.415(3) Å) or (E,E)-2,5-bis(5-chloro-2-methoxyphenyl)-3,4-diazahexa-2,4-diene (1.1415(5) Å). For (E,E)-4,4'-dimethyl-2,2'-((1,1'-dibenzylazino)diphenol bearing a benzyl substituent at the C=N carbon, a somewhat shorter N–N bond length of 1.399(3) Å) is reported [58–60]. Another phosphonated azine quite comparable with **3** is the above mentioned compound Z,Z-P(=O)Ph₂CH₂C(Bu')=N-N=C(Bu)CH₂P(=O)Ph₂ [57], in which the methyl substituent on the iminic carbon atom is replaced by a bulky *t*-butyl group. The crystal structure of the latter azine (CSD refcode SUMBEH) reveals a Z,Z conformation around the -C(Bu')=N-N array, whereas **3** adopts an *E*,*E* conformation. So, it seems that the steric requirement of R (Bu' vs. Me) plays a crucial role on the conformation. Note that **M1** is somewhat less symmetric than **M2** and contains two crystallographically different Ph₂P(=O)CH₂C(Me)=N moieties. The molecular structure of **M1** and the packing of **M1** and **M2** in the crystal are illustrated in the Supporting Material as Figs. S34 and S35. As in the latter four examples, there is a *transoid* (or *E*,*E*) conformation around the central C=N-N=C motif forming a torsion angle of -180° for **M1** and of -174.74° for **M2**. There is no intramolecular contact worth mentioning, some weaker secondary intermolecular hydrogen bonding occurs between C6–H6B···O2¹ (2.49 Å), C1–H1A···O3³ (2.49 Å), C28–H28···O2² (2.41 Å), C18–H18···O3³ (2.47 Å), C20–H20···O2¹ (2.47 Å), and C43–H43···O1⁵ (2.45 Å).

## 2.2. Synthesis of Z/E phosphonated thiosemicarbazones 4

The thiosemicarbazones **4a–h** were synthesized in ethanol by nucleophilic addition of phosphonated hydrazone **2** with isothiocyanates R-N=C=S bearing a large panel of aromatic and aliphatic R substituents (Scheme 2). Like hydrazone **2**, which exist as a mixture of *E* and *Z* isomers (described in Section 2.1), all the corresponding TSCs form equilibrating mixtures of *Z* and *E* isomers in solution, but are isomerically pure in the crystalline state.

Compounds **4** were isolated as microcrystalline white powders, which were subsequently collected through filtration. Each resulting product underwent purification by washing with cooled ethanol, followed by recrystallization from EtOH. Notably, all derivatives exhibit high solubility in dimethyl sulfoxide (DMSO), but are sparingly soluble in less polar solvents such as toluene. Structural confirmation was accomplished through multinuclear NMR techniques including ³¹P{¹H},

¹H, ¹³C{¹H}, ¹⁹F, FT-IR and UV-vis spectroscopy, corroborated by X-ray crystallographic analysis at 100 K.

The overall yields did not exceed 65 %, since smaller amounts of bis (N-arylthioureas) or bis(N-alkylhexylthioureas) were present in the crude reaction mixture as evidenced by NMR [61–66]. During purification of the crude product **4a** obtained by treatment of **2** with phenyl isothiocyanate from hot ethanol, some colorless crystals were isolated. The crystallographic characterization revealed the occurrence of the literature-known bis(N-phenylthiourea) **5a**, adopting a twisted *cisoid* or *s*-*cis* conformation around the central N–N bond with a C1–N1–N1¹–C1¹ torsion angle of -121.95° [65]. An illustration of the molecular structure and of the packing, revealing strong intermolecular N–H···S interactions, is shown as Fig. S36 in the Supporting Material. Similarly, bis (*N*-p-fluorophenylthiourea) **5b** was isolated. The crystal structure, conformational analysis and spectroscopic characterization of this product were recently communicated by us [61]. We have not investigated the decomposition mechanism involving a cleavage of the Ph₂P(=O) moiety **5b** but demonstrated that bis(*N*-p-fluorophenylthiourea) **5b** can be readily synthesized by direct treatment of *p*-FC₆H₄N=C=S with hydrazine in a 2:1 ratio [61]. Note that bis(*N*-cyclohexylthiourea) **5g**, which has in the crystalline state like **5a**, *b* a *cisoid* conformation with respect to the central N–N bond, is already literature-known [67]. For further characterizing of azine **3** and the TSCs, these compounds were also analyzed by GC/MS using electron ionization. Unfortunately, in any case the molecular peak could be detected due to fragmentation processes. However, the peaks of the fragments, which are detailed in the experimental section, correspond well to the respective molecular structure. The absence of the molecular peak may be due to the limited thermal stability and the strong association of the compounds through extensive hydrogen bonding (see below). The mass spectral fragmentation mechanism of thiosemicarbazones synthesized from acetophenones under GC/MS conditions has been discussed in detail elsewhere [68].

## 2.3. Spectroscopic and structural studies of the phosphonated thiosemicarbazones 4

### 2.3.1. NMR characterization

All NMR spectra exhibit a duplication of the signals. Based on previous research of other research groups on the *E/Z* isomer distribution of thiosemicarbazones [69,70] this observation can be explained by *Z/E*
isomerization equilibrium. To verify this hypothesis for 4, the ³¹P{¹H} NMR spectra of 4 g and 4h were recorded at different temperatures (Fig. 3). Exploiting the spectral evolution shown in Fig. 3, we note that increasing the temperature causes (i) a shift of the signals of both isomers to lower field, and (ii) to change their relative intensities, supporting the occurrence of an isomerization process in solution [30].

No further evolution of the *E/Z* isomer ratio was noticed when heating the sample of 4h for 2 h. When recording again the ³¹P NMR spectrum of 4h after 24 h at ambient temperature, the chemical shifts and *E/Z* isomer ratio corresponded approximatively to those observed initially, confirming the reversibility of the interconversion process. We have also recorded the evolution of the ³¹P NMR spectra of the *N*-aryl derivatives 4a and 4c at variable temperature (Fig. S17). As for 4g and 4h, a low-field shift of the resonances occurs when rising the temperature. However, the *E/Z* isomer ratio is less affected in function of temperature. Noteworthy, an extensive decomposition occurred rapidly when raising the temperature above 110 °C, whereas the spectrum of the *N*-allyl derivative 4h revealed no degradation even after heating at 130 °C for 2 h. These observations indicate that the *N*-aliphatic derivatives are in solution thermally more stable than the *N*-aromatic ones.

The coexistence of derivatives 4a-h as a mixture of *Z/E* isomers in solution was also confirmed by other multinuclear NMR studies. In the ¹H NMR spectra of compounds 4f-h, the methylenic P-CH₂ groups resonating at about δ 3.55 ppm with minimal variance (Δδ ±0.36 ppm) are split into doublets due to a ²J<sub>HP</sub> coupling of 15.3 Hz with minimal variance (±0.5 Hz) for the *Z* isomer and a ²J<sub>HP</sub> of 13.5 Hz with minimal variance (±0.3 Hz) for the *E* isomer. Also, the CH₃ groups at about δ 1.75 ppm with minimal variance (Δδ ±0.25 ppm) appear as doublets due to a weak long-range ⁴J<sub>PH</sub> coupling of 2.2 Hz with minimal variance (±0.2 Hz) for the *Z* isomer and a ²J<sub>PH</sub> of 1.8 Hz with minimal variance (±0.4 Hz) for the *E* isomer. The signals corresponding to the =C-NH-R group is found at δ 8.5 ppm with minimal variance (Δδ ±1 ppm). However, in the *N*-aryl compounds 4a-c, there is a notable difference, as this proton signals appears at approximately δ 11.00 ppm, with minimal variance (Δδ ±0.5 ppm). This deviation is likely a consequence of the inclusion of a phenyl group, which can exert an electron-withdrawing inductive effect, causing an upfield shift of the labelled peak compared to other compounds in the same class. The chemical shifts for the remaining substituents in 4d-h (CH₃, CH₃O benzyl, allyl, and cyclohexyl) were observed below δ 5.00 ppm. The spectroscopic details are presented in

the experimental section.

In the ¹³C{¹H} NMR spectra, the signal corresponding to the carbon of the C=S group appears as a singlet within the range between 176.21–179.64 ppm. The chemical shifts corresponding to the carbon of C=N group are observed in the 144.19–147.94 ppm region, with an approximately ²J<sub>CP</sub> coupling constant of 9.5 Hz with minimal variance (±0.5 Hz). The aromatic carbons of the aryl groups are detected between 124.51–139.61 ppm. In the ¹³C NMR spectrum of derivative 4b, both C-P and C-F couplings can be observed due to the presence of a fluorine atom at the para-position of the aryl group. As illustrated in Fig. 4 and summarized in Table 1, the chemical shifts and coupling constants of the aromatic carbons were carefully analyzed. The two doublets observed at δ 159.91 and 159.83 ppm, corresponding to the C1 carbon atoms of the p-F-C<sub>arom</sub> of the *Z* and *E* isomers. This observation highlights a significant coupling constant of ¹J<sub>CF</sub> = 241.5 Hz and corroborates the coexistence of *E/Z* isomers. Also the two *ortho*-carbon atoms C2 at around δ 115 ppm give rise to two distinct doublets due to a ²J<sub>CF</sub> coupling of 22.4 Hz (Fig. 4).

Accordingly, also the ¹⁹F NMR spectrum of 4b shown in Fig. S15 displays two close resonances for the *E* and *Z* isomers at δ −117.33 and −117.41 ppm in a 64:36 integration ratio.

### 2.3.2. X-Ray crystallographic investigation of thiosemicarbazones 4

To elucidate the preferred configuration in the solid state, the crystal structures of several *N*-aryl and *N*-alkyl derivatives were determined by SCXRD at 100 K. Suitable crystals were grown from hot ethanol. To ascertain the isomeric purity of the crystalline samples, the data of several crystals of 4a were checked and compared by running fast-scans.

The molecular structure of Ph₂P(=O)CH₂{C=N-NH(C=S)-N(H)Ph}CH₃ 4a (E-2-(1-(diphenylphosphoryl)propan-2-ylidene)-N-phenyl-hydrazine-1-carbothioamide) crystallizing in the triclinic space group *P*1, shown in Fig. 5, reveals that the asymmetric unit contains two independent molecules 4a-M1 and 4a-M2 with slightly different bond lengths and angles. Both *M1* and *M2* adopt a *E*-configuration (or *transoid* configuration) around their respective hydrazonic CH₂-C(Me)=N-NH motifs. The torsion angles C1-N2-N3-C8 for 4a-M1 amounts to 176.5 (7)° and that of 4a-M2 defined by C23-N5-N6-C30 is −176.2(7)°. For *M1*, the P=O bond is orthogonally arranged with respect to the plane formed by the C10-C8-N3-N2-C1-S array. The C8-N3 bond lengths of 1.288(9) Å indicates a hydrazonic C=N double bond and compares well

<figure><img src="image_7.png" /><figcaption>**Fig. 3.** ³¹P{¹H} NMR spectra of 4 g and 4h recorded at different temperatures in DMSO-d₆: for *E* (red circles) and *Z* (yellow circles) isomers.</figcaption></figure>
<figure><img src="image_8.png" /><figcaption>Fig. 4. Part of the ¹³C{¹H} NMR spectrum of 4b in the 114–116 and 125–137 ppm ranges (25 °C, 100.62 MHz, DMSO-d₆). The inset shows that the doublet of C1 caused by a ¹J<sub>CF</sub> coupling is doubled due to a coexistence of E/Z isomers. Signals marked with an asterisk* correspond to bis(N-p-fluorophenylthiourea) 5b [61].</figcaption></figure>

<table><caption>**Table 1**

¹³C{¹H} chemical shifts and coupling constant of the Z/E isomers of 4b.</caption><thead><tr><th></th><th></th><th>C1</th><th>C2</th><th>C3</th><th>C4</th><th>C9</th><th>C10</th><th>C11</th><th>C12</th></tr></thead><tbody><tr><td rowspan="2">δ (ppm)</td><td><i>E</i></td><td>159.83</td><td>115.37</td><td>127.84</td><td>135.58</td><td>133.54</td><td>131.00</td><td>129.10</td><td>132.22</td></tr><tr><td><i>Z</i></td><td>159.91</td><td>115.10</td><td>126.89</td><td>135.86</td><td>132.74</td><td>131.09</td><td>129.29</td><td>132.80</td></tr><tr><td rowspan="2">J (Hz)</td><td><i>E</i></td><td><sup>1</sup>J<sub>CF</sub> = 241.9</td><td><sup>2</sup>J<sub>CF</sub> = 22.4</td><td><sup>3</sup>J<sub>CF</sub> = 8.2</td><td><sup>4</sup>J<sub>CF</sub> = 2.7</td><td><sup>1</sup>J<sub>CP</sub> = 98.6</td><td><sup>2</sup>J<sub>CP</sub> = 9.2</td><td><sup>3</sup>J<sub>CP</sub> = 11.5</td><td><sup>4</sup>J<sub>CP</sub> = 2.0</td></tr><tr><td><i>Z</i></td><td><sup>1</sup>J<sub>CF</sub> = 241.8</td><td><sup>2</sup>J<sub>CF</sub> = 22.4</td><td><sup>3</sup>J<sub>CF</sub> = 8.3</td><td><sup>4</sup>J<sub>CF</sub> = 2.7</td><td><sup>1</sup>J<sub>CP</sub> = 99.3</td><td><sup>2</sup>J<sub>CP</sub> = 9.5</td><td><sup>3</sup>J<sub>CP</sub> = 11.8</td><td><sup>4</sup>J<sub>CP</sub> = 2.5</td></tr></tbody></table>

with those reported for (E)-N-methyl-2-[1-(2-oxo-2H-chromen-3-yl) ethylidene]hydrazinecarbothioamide (1.282(3) Å), salicyl-aldehyde-N (4)-morpholino-thiosemicarbazone (1.275(3) Å) and E-1-cyclopentano-4-phenyl-3-thiosemicarbazone (1.275(3) Å). Also the C=S bond length of 1.677(7) Å fits with those reported for the latter three thiosemicarbazones [1.674(2), 1.680(2) and 1.673(3) Å] [71–73]. The mean N–N bond length of M1 and M2 is 1.385(8) Å, laying in the same range reported for the compounds cited above [1.366(2), 1.371(3) and 1.387 (4) Å] and matches also with that of 4-formylpyridine thiosemicarbazone (1.365(6) Å) [74], where the shortening of the N–N bond with respect to a simple sp³ N–N bond like such in hydrazine (1.46 Å) [75] is explained by resonance. Since the earliest crystallographic reports on thiosemicarbazones, is it known that this class of thione compounds has a strong propensity to form supramolecular interactions with neighboring molecules. For example, in the crystal of formylpyridine and E-1-cyclopentano-4-phenyl-3-thiosemicarbazone, the individual molecules are linked by weak intermolecular N-H···S hydrogen bonds into dimer-like units which are held together by strong N-H···N hydrogen bonds [73]. In the case of 4a, no N-H···S contacts are present. Instead, both for 4a-M1 and 4a-M2 an intramolecular N-H···N bonding of 2.24 Å forces the resulting five-membered cycles to be quite planar (angle N-H···N 106°). For comparison, 2.17 Å are reported for E-1-cyclopentano-4-phenyl-3-thiosemicarbazone with an angle N-H···N of 104°.

Additionally, there are two close intermolecular P=O···H–N contact with 4a-M2 of 1.98(9) and 2.00(8) Å, indicating a strong P=O···H–N hydrogen bonding (Fig. 5 bottom), generating a dimeric motif and forming 14-membered supramolecular macrocycle. The respective N2–H2···O2 and N5–H5···O1 angles are 158(7)° and 163(8)°. These two

types of secondary bonding are in line with the broadened ν(N-H) vibration observed in the IR spectrum (see below).

To see whether the *p*-fluoro aryl derivate **4b** adopts the same *E* configuration as encountered for **4a**, crystals of 2-(1-(diphenylphosphoryl)propan-2-ylidene)-N-(4-fluorophenyl)hydrazine-1-carbothioamide crystallizing in the monoclinic space group *P*2₁ were grown from hot EtOH. Since C-F bonds may also contribute to additional secondary interactions as encountered for the dithiourea compound **5b** [61], the structural characterization appeared to be particularly interesting. The intramolecular interactions of the molecular structure of **4b** are quite similar to those of **4a** (Fig. 6; Table S1). However, there is a striking difference compared with the formally OD supramolecular cyclic structures of **4a**. In the case of **4b**, the individual molecules are associated through strong intermolecular hydrogen bonding of 2.098 Å (d(N2···O) 2.879 Å) occurring between P=O···H2–N2. Unfortunately, the quality of the crystallographic data is quite mediocre, so that a concise discussion is not appropriate. But based on a comparison with the crystallographic data of Ph₂P(=O)CH₂{C=N-NH(C=S)-N(H)Cy}CH₃ **4g** (see below), we suggest that **4b** forms like the latter compound an infinite supramolecular 1D ribbon in the crystalline state (Fig. S37). In addition to the intermolecular N–H···O bonding, there are also weak C–F···H1B–C1 contacts of 2.283 Å with the CH₂-P methylene group of an adjacent molecule, extending the supramolecular network to 2D.

To check whether the electronic effect of the aryl substituent (-M vs. +M) we also prepared (E)-N-(3,5-dimethylphenyl)-2-(1-(diphenylphosphoryl)propan-2-ylidene)hydrazine-1-carbothioamide **4d** bearing two electron-donating methyl groups by reaction of 3,5-dimethylphenyl isothiocyanate with hydrazone **2**. The overall structure and
<figure><img src="image_9.png" /><figcaption>**Fig. 5.** (Top) Molecular structure of the N-phenyl thiosemicarbazone **4a**. Apart from the N-bound H atoms, all other H atoms are omitted. Selected bond lengths (Å) and angles (°) for **4a-M1**: P1–O1 1.492(5), P1–C10 1.813(7), C10–C8 1.503(10), N3–C8 1.288(9), N3–N2 1.384(8), N2–C1 1.369(9), C1–N1 1.350(9), C1–S1 1.677 (7), N1–C2 1.428(9); N1–C1–S1 125.5(6), C2–N1–C1 126.9(7), S1–C1–N2 119.6(5), N1–C1–N2 114.9(7), C1–N2–N3 117.0(6), N2–N3–C8 117.8(6), N3–C8–C10 116.0(6), N3–C8–C9 125.5(6), C8–C10–P1 115.8(5), O1–P1–C10 114.1(3). (Bottom) Supramolecular dimeric association of **4a** through intermolecular N-H···O bonding.</figcaption></figure>

conformational features remain quite similar with those of **4a** and **4b**, the torsions angles around the N–N bond (C1–N2–N3–C10 176.5(3)°) and the hydrazonic CH₂–C(Me)=N–NH array (N2–N3–C10–C12 –178.8 (2)°), indicating an *E*-configuration. There are again intramolecular N1–H1···N3 secondary interactions, with 2.098 Å even closer than those encountered for **4a** (angle N1–H1···N3 112(7)°). Like in **4a**, two molecules form a supramolecular dimer through mutual N2–H2···O1² hydrogen bonding. However, the intermolecular contact in this 14-

membered macrocycle is somewhat loser (2.20 vs. 2.00 Å), furthermore the cycle is constructed by association between two **4d-M1** molecules and not between **M1** and **M2** as in **4a** (see Fig. 7). Such a dimeric association occurs also between **4d-M2** and **4d-M2'**.

As second N-aryl derivative featuring electron-donating substituents we synthesized also Ph₂P(=O)CH₂{C=N–NH(C=S)–NH–C₆H₃(OMe)₂}CH₃ **4e** bearing two methoxy groups at the *o*- and *m*-position through reaction of **2** with 2,5-dimethoxyphenyl isothiocyanate. The molecular
<figure><img src="image_10.png" /><figcaption>**Fig. 6.** Molecular structure of the N-4-fluorophenyl thiosemicarbazone 4b Apart from the N-bound H atoms, all other H atoms are omitted. Selected bond lengths (Å) and angles (deg): C4–S 1.66(2), P–O 1.49(2), P–C1 1.92(2), N1–C2 1.27(2), C3–C2 1.45(3), N1–N2 1.38(2), N2–C4 1.40(2), N3–C4 1.33(2), S–C4 1.66(2); N3–C4–S 125.8(13), C4–N3–C5 125.4(16), N2–C4–S 119.9(14), N2–C4–N3 114.3(17), N2–N1–C2 118.3(15), N1–N2–C4 117.0(15), N1–C2–C3 128.9(19), P–C1–C2 111.0(15), O–P–C1 120.3(11).</figcaption></figure>

<figure><img src="image_11.png" /><figcaption>**Fig. 7.** Molecular structure of thiosemicarbazone 4d, showing the intramolecular N1–H1···N3 bonding and the dimeric association through intermolecular N2–H2···O bonding. Apart from the N-bound H atoms, all other H atoms are omitted. Selected bond lengths (Å) and angles (deg) for M1: P1–O1 1.494(2), P1–C12 1.816(3), C12–C10 1.504(4), N3–C10 1.281(4), N3–N2 1.387(3), N2–C1 1.367(4), N1–C2 1.428(4), S1–C1 1.680(3), N1–C1 1.343(4); N1–C1–S1 127.5(2), C1–N1–C2 129.8(3), S1–C1–N2 118.5(2), N1–C1–N2 114.1(3), C1–N2–N3 117.9(2), N2–N3–C10 117.4(2), N3–C10–C12 116.8(3), N3–C10–C11 125.8(3), C10–C12–P1 117.9(2), O1–P1–C12 111.80(13). Symmetry operation to generate equivalent atoms: $^{1}$-x, -y, 1-z; $^{2}$-1-x, 1-y, -z; $^{3}$-1+x, +y, +z; $^{4}$1+x, +y, +z.</figcaption></figure>

structure of this colorless solid crystallizing in the monoclinic space group P2₁/c is shown in Fig. 8 and reveals that 4e differs conformationally from the rest of series 4. This derivative exhibits no significant intermolecular hydrogen bonding but features two strong intramolecular secondary interactions. The first one occurs through a P=O···H2–N2 of 2.09(2) Å forming a seven-membered cycle with a

P=O···H2–N2 angle of 150.0(19)°. The second one is generated by a N1–H1···O2 contact of 2.12 Å with the MeO-substituent at the *ortho*-position of the N-aryl cycle forming a five-membered cycle, the N-H···O angle being 113° Such a N-H···O contact of 2.12 Å with a N-H···O angle of 113° is also found in 2-(1-(4-bromophenyl)ethylidene)-N-(2,4-dimethoxyphenyl)hydrazinecarbothioamide [76] (CSD refcode QUZKAY). As
<figure><img src="image_12.png" /><figcaption>**Fig. 8.** Molecular structure of the *N*-2,5-dimethoxyphenyl thiosemicarbazone **4e**. Apart from the *N*-bound H atoms, all other H atoms are omitted. Selected bond lengths (Å) and angles (deg): P–O1 1.4989(14), P–C4 1.8089(17), C4–C2 1.507(2), N3–C2 1.286(2), N3–N2 1.399(2), N2–C1 1.371(2), N1–C17 1.412(2), S1–C1 1.676(2), N1–C1 1.347(2), O2–C23 1.426(2), O3–C24 1.415(2); N1–C1–S 128.62(13), N2–C1–S 118.26(13), N1–C1–N2 113.08(15), C1–N2–N3 119.34(14), N2–N3–C2 116.22(14), N3–C2–C4 125.08(15), N3–C2–C3 117.49(15), C4–P–C5 105.47(8), C4–P–C11 107.00(8), O1–P–C4 111.73(8), C18–O2–C23 116.68(14), C21–O3–C24 117.92(14). Symmetry operation to generate equivalent atoms: ¹¹+x, +y, +z.</figcaption></figure>

in the latter dimethoxy-thiosemicarbazone, the H1 atom is also involved
in second bifurcated interaction of 2.11 Å of with the N3 atom of the
hydrazone moiety. In addition, a weaker C22–H22···S contact of 2.58 Å
forming a six-membered cycle with a C–H···S angle of 128° completes
the intramolecular interactions. This compares well with 2-(1-(4-bro-
mophenyl)ethylidene)-N-(2,4-dimethoxyphenyl)hydrazinecarbothioa-
mide, where a C–H···S contact of 2.58 (C–H···S angle of 129°) with an
*ortho*-H atom of the aryl cycle bearing the two methoxy groups is noticed
[76]. Note that according to a recent review article, intramolecular
C–H···S contacts in this range are considered as moderate-to-strong ones
[77]. This C–H···S contact is unique in the series of *N*-aryl thio-
semicarbazones 4, since in the other derivatives such as 4a the *N*-aryl
group is tilted moving away the *ortho*-H atom and the thione function [d
(C–H···S 3.284) Å], whereas in 4e the aryl cycle is coplanar with the
N1–C1–S motif. So, the molecule prefers a *Z*-configuration around the
hydrazonoic C=N bond (torsion angle C4–C2=N3–N2 = –4.8(2)°),
which is stabilized by three intramolecular interactions.

After having structurally characterized a series of *N*-aryl TSCs, we
turned our attention to the preparation of several phosphonated *N*-alkyl
thiosemicarbazones to investigate the impact of an alkyl residue on the
structural features (see below). The following three derivatives **4f**, **4g**
and **4h** were prepared by reaction of hydrazone **2** with benzyl-, cyclo-
hexyl- and allyl isothiocyanate, respectively (Scheme 2). The *N*-benzyl
derivative Ph₂P(=O)CH₂{C=N–NH(C=S)–N(H)CH₂Ph}CH₃ **4f** crystal-
lizes in the triclinic space group *P*-1 (Table S2) and the asymmetric unit
contains like in the case of **4a** two independent molecules **4f-M1** and **4f-
M2**, featuring slightly different bond lengths and angles. Again, both
molecules adopt the *E*-configuration, the torsion angle C16–N2–N1–C14
of **4f-M1** being –171.23(9)°. The mean C=N bond length of 1.2848(12)
Å matches with those of other benzylic thiosemicarbazones such as *N*-
benzyl-1-[(cyclohexylidene)amino]thiourea [1.2814(18) Å] and (E/Z)-
4-benzyl-1-(1-ferrocenylethyl)thiosemicarbazone 1.284(2) Å] [78,79].
Also, the mean C=S bond length of 1.6892(10) Å fits with those reported
for latter two examples [1.6898(13) and 1.6912(17) Å]. As discussed for

(E/Z)-4-benzyl-1-(1-ferrocenylethyl) thiosemicarbazone, the central core involving the *N*-iminothiourea moiety is nearly planar, the benzylic CH₂ group being also present in the same plane. This planarity is ascribed to a significant delocalization of nitrogen lone pair towards the thione group and hence to a partial double bond character of N-C bonds of the thiourea moiety [N3–C16 1.3413(13) Å]. The same planarity and partial double bond character is also observed for the N-C bond of the thiourea moiety of *N*-benzyl-1-[(cyclohexylidene)amino]thiourea [1.3323(17) Å]. As reported for 3-benzyl-1-[(1,2,3,4-tetrahydronaphthalen-1-ylidene)amino]thiourea (CSD refcode DABPOO), there is an intramolecular N1–H1···N3 bonding (2.20 vs. 2.17 Å), with an identical N–H···N angle of 108° [78]. Similar to the case of **4a**, there are also two close intermolecular P=O···H–N contacts with **4f-M2** of 1.99 and 1.98 Å, indicating a strong P=O···H–N hydrogen bonding, generating a dimeric motif and forming 14-membered supramolecular macrocycle. The respective N2–H2···O2 and N5–H5···O1 angles are 154.4° and 153.3°. Again, these multiple secondary interactions are in line with the broadened ν(N–H) vibration observed in the IR spectrum (see below). Furthermore, a weaker C11–H11···O1² of 2.39 Å contact occurs between one *meta*-H atom of a P–C₆H₅ group and the O1 atom of an adjacent **4f-M1** molecule (see Fig. 9).

For the supramolecular analysis of TSC **4f**, also a Hirshfeld surface
analysis was conducted. Details are presented in the Supporting Material
(Fig. S38). Additionally, fingerprint plots were generated to provide a
detailed view of the intermolecular interactions (Fig. S39).

To evaluate the impact of more sterically crowded cyclohexyl group
vs. planar aryl groups, the derivative (*E*)-*N*-cyclohexyl-2-(1-(*diphenyl-
phosphoryl*)propan-2-ylidene)hydrazine-1-carbothioamide **4g** was pre-
pared by reaction of cyclohexyl isothiocyanate with hydrazone **2**. The
colorless compound crystallizes upon recrystallisation from hot EtOH in
the orthorhombic space group *P*2₁*2*1*2*₁ (Table S2). The molecular
structure is shown in Fig. 10 (top) and reveals that the molecule adopts
the *E*-isomeric form both around the *N*–*N* bond (torsion angle
C7–N2–N3–C8 –178.77(12)°) and the hydrazonic CH₂*C=N(Me)*–*NH
<figure><img src="image_13.png" /><figcaption>**Fig. 9.** View of the asymmetric unit of the N-benzylic thiosemicarbazone 4f, containing two independent molecules M1 and M2 associated by intermolecular N-H···O bonding. The aromatic H atoms are omitted for clarity. Selected bond lengths (Å) and angles (deg) for 4f-M1: C16–S1 1.6869(10), C39–S2 1.6915(10), P1–O1 1.4934 (8), N2–C16 1.3615(12), N1–C14 1.2850(12), N1–N2 1.3833(11), N3–C16 1.3413(13), N3–C17 1.4522(13); N2–C16–S1 119.13(8), N3–C16–S1 125.19(8), N1–N2–C16 117.37(8), N2–N1–C14 118.19 (8), 117.84 (8), O1–P1–C7 110.97(5). Symmetry codes to generate equivalent atoms: ¹1+x, +y, +z; ²1+x, +y, +z.</figcaption></figure>

array (torsion angle N2–N3–C8–C10 179.37(10)°), as encountered for **4a**, **4b**, **4d**, and **4f**. The separation of 3.728 Å between the P=O function and H1–N1 is too remote for forming an intramolecular hydrogen bonding. Instead, there is short intramolecular N1–H1···N3 bonding of 2.135 Å forming a five-membered cycle, whereas in N-phenyl derivative **4a** this contact is weaker (2.238 Å). For comparison, an intramolecular N-H···N contact of 2.28(2) Å is reported for 2-hydroxyacetophenone N (4)-cyclohexyl thiosemicarbazone (CSD refcode LEPFIW) [80].

However, as in **4b**, a strong intermolecular N2–H2···O² hydrogen bonding of 2.07(2) Å occurs between two neighboring molecules, thus generating a 1D supramolecular ribbon (Fig. 10, bottom). The angle N2–H2···O² of 169.4(18)° is close to linear.

A survey of the literature reveals also the existence of several crystallographically characterized thiosemicarbazones bearing a N-allyl group as thiourea moiety. Selected examples are N-allyl-2-cyclopentylidenehydrazinecarbothioamide (CSD refcode HUQQAN), butane-2,3-dione 2-(N-allylthiosemicarbazone) (CSD refcode JEXXIU), or 2-(2-oxoacenaphthylen-1(2H)-ylidene)-N-(prop-2-en-1-yl)hydrazine-1-carbothioamide (CSD refcode KECGUY), or 2-acetylpyridine 4-allylthiosemicarbazone (CSD refcode FUWCIK), which features also an antitumor activity [81–84].

The molecular structure of (E)-N-allyl-2-(1-(diphenylphosphoryl) propan-2-ylidene)hydrazine-1-carbothioamide **4h**, obtained by reaction of allyl isothiocyanate with hydrazone **3**, is depicted in Fig. 11. The molecule adopts like **4f** the *E* configuration around the C2=N1 bond and as in **4g**, relatively short intramolecular N3–H3···N1 bonding of 2.149 Å gives rise to a five-membered cycle and contributes to the planarity of the N3–C4–N2–N1–C5 array. For N-allyl-2-cyclopentylidenehydrazinecarbothioamide and 2-acetylpyridine 4-allylthiosemicarbazone, such N–H···N contacts (2.25 and 2.18 Å) are

considered as bonding [81,84]. The shortest contact between the S atom and the H5 atom of the allyl group amounts to 2.25 Å. As encountered for **4d**, there are two close intermolecular P=O···H-N contact with **4h-M1'** of 1.983(14) Å. This strong P=O···H-N hydrogen bonding gives rise to a centrosymmetric 14-membered supramolecular macrocycle, the respective N2–H2···O angle is with 167.1(13)° close to linear.

For comparison, the most pertinent bond lengths, angles and torsions occurring within the Cᵢ=Nₐ–N₉H–CⱼS–NₐCₖ array of **4** are listed in Tables 2 and 3. Note that for **4e** existing as the *Z*-isomer, the torsion angle Cᵢ–Nₐ–N₉–Cⱼ of 164.77(15)° deviates from the mean value of about 175° determined for the *E*-isomers.

Table 4 resumes the hydrogen bond interactions present in the phosphonated TSCs **4**. All compounds display an intramolecular N···H-N bonding involving the thioamide and the imine groups giving rise to a five membered ring and the hydrazonic NH is always involved in a hydrogen bond with the oxygen of the Ph₂P=O moiety. Surprisingly, it is an intramolecular interaction in **4e**, while it is an intermolecular one for all other TSCs. In **4a**, **4d**, **4f** and **4h**, two intermolecular hydrogen bonds NH···O are engaged between two molecules leading to dimeric units. In **4b** and **4g**, intermolecular NH···O interactions result in the formation a 1D ribbon. In contrast to bis(N-phenylthiourea) **5a** (see Fig. S36) and other literature-known TSCs such as N-(2-methoxyphenyl)-2-(propan-2-ylidene)hydrazine carbothioamide [85], where S···H bonding occurs, this kind of interaction is almost absent for series **4**.

A comparison of hydrogen bonds of the type N–H···N reveals that their strength is significantly lower than that of the structurally similar N–H···O interactions due to their considerably smaller and less linear angles. These moderately strong N–H···O contacts, which can also be confirmed by analyzing the bond lengths, are likely the dominant interactions in the solid state. As a result, they play a crucial role in the
<figure><img src="image_14.png" /><figcaption>**Fig. 10.** (Top) Molecular structure of N-cyclohexyl thiosemicarbazone 4g Apart from the N-bound H atoms, all other H atoms are omitted. Selected bond lengths (Å) and angles (°): C7–S 1.6858 (12), P–O 1.4963(10), N1–C7 1.3374(15), N1–C8 1.2850 (14), N2–N3 1.3830(13), N2–C7 1.3725 (14), N3–C8 1.2850 (14); N1–C7–S 125.22 (9), N2–C7–S 119.33(9), N3–N2–C7 116.81(9), N2–N3–C8 119.76(10), O–P–C10 112.90(6). (Bottom) Supramolecular 1D ribbon formed through intra-molecular N2–H2···O² bonding. Symmetry codes to generate equivalent atoms: ¹−1+x, +y, +z; ²−1/2+x, 1/2-y, 1-z; ³1/2+x, 1/2-y, 1-z.</figcaption></figure>

crystal packing, leading to an arrangement of the molecules that maximizes strong N–H···O interactions within the crystal lattice. In contrast, the strength of N–H···N interactions is inherently limited by the structurally imposed angle present in all TSC compounds, classifying them as weak interactions.

### 2.3.3. UV–Visible studies

In this work we were also interested in the UV-visible absorption properties of these phosphonated thiosemicarbazones. The UV–Vis spectra of TSCs 4 recorded in the protic solvent MeOH are illustrated in Fig. 12a. We can note a slight bathochromic effect of the low energy band going from the N-aryl derivatives 4b (R = p-FC₆H₄) and 4d (R = 3,5-xylyl-C₆H₃) with respect to 4a (R = Ph) (Table 5 and Fig. 12b) due to the variation of the conjugation. In the literature, these low energy bands between 250 and 350 nm are attributed to n → π* transitions and the high energy bands between 200 and 250 nm to π → π* transitions [86,87]. Since in contrast to n → π* transitions, π → π* transitions are insensitive to the solvent proticity, the UV–vis spectra of 4a, 4b and 4d were also recorded in the polar aprotic solvent MeCN. Fig 12c shows that the overall shape of the absorption spectra is not much affected by the nature of the solvent, but the superposition of the absorption spectra

measured in methanol and acetonitrile shows that the position and intensity of all the bands is sensitive to the proticity of the solvent. This suggests that the observed bands are a mixture of n → π* and π → π* transitions with a significant contribution from the latter.

### 2.3.4. Computational analyses

#### 2.3.4.1. Theoretical DFT conformational study and NMR assignments for Z/E isomers of 4.
A theoretical DFT study using the B3LYP/6–311+G (d, p) basis set was conducted to determine the more stable configuration for the N-phenyl substituted derivative 2-(1-(diphenylphosphoryl) propan-2-ylidene)-N-phenylhydrazine-1-carbothioamide (4a), which serves as a representative example of diastereomeric conformational isomers. The Intrinsic Reaction Coordinates (IRC) [88] for the two isomers are shown in Fig. 13. Both reactions were found to be exothermic, with energy values of −11.24 and −10.22 kcal/mol for the E and Z isomers, respectively, using the explicit solvation model (in ethanol). In the gas phase, the corresponding energies are −21.73 and −10.39 kcal/mol, respectively. Based on the activation energy calculations, the E isomer follows a kinetically favored path (6.26 kcal/mol in the explicit model and 13.84 kcal/mol in the gas phase) compared to the Z isomer
<figure><img src="image_15.png" /><figcaption>**Fig. 11.** Molecular structure of the N-allylic thiosemicarbazone 4h, showing the intramolecular N3-H3···N1 bonding and the dimeric association through inter-molecular N2-H2···O bonding. Apart from the N-bound H atoms, all other H atoms are omitted. Selected bond lengths (Å) and angles (°): C4–S 1.6901(7), P–O 1.4942 (6), N2–C4 1.3361(10), N1–C2 1.2831(9), N1–N2 1.3863(8), N3–C4 1.3361(10), N1–C2 1.2831(9) C5–C6A 1.495(3), C7A–C6A 1.310(3); N2–C4–S1 119.53(5), N3–C4–S1 124.71(6), N1–N2–C4 116.02 (6), N2–N1–C2 119.32 (6), O–P–C8 111.35 (3). Symmetry operation to generate equivalent atoms: $^11+x, +y, +z$; $^21-x, 1-y, 1-z$.</figcaption></figure>

<table><caption>**Table 2**
Selected bond lengths (Å) in the $C_i=N_a-N_bH-C_jS-N_cC_k$ core of 4.</caption><thead><tr><th></th><th>C<sub>4</sub>=N<sub>a</sub></th><th>N<sub>a</sub>=N<sub>b</sub></th><th>N<sub>b</sub>=C<sub>j</sub></th><th>C<sub>j</sub>=S</th><th>C<sub>j</sub>=N<sub>c</sub></th><th>N<sub>c</sub>=C<sub>k</sub></th><th>Torsion angle (°)<br>C<sub>i</sub>=N<sub>a</sub>-N<sub>b</sub>-C<sub>j</sub></th></tr></thead><tbody><tr><td>4a-M1</td><td>1.288(9)</td><td>1.384(8)</td><td>1.369(9)</td><td>1.677(7)</td><td>1.350(9)</td><td>1.428(9)</td><td>176.5(7)</td></tr><tr><td>4a-M2</td><td>1.286(9)</td><td>1.386(8)</td><td>1.358(9)</td><td>1.681(7)</td><td>1.356(9)</td><td>1.417(9)</td><td>-176.2(7)</td></tr><tr><td>4b</td><td>1.27(2)</td><td>1.38(2)</td><td>1.40(2)</td><td>1.66(2)</td><td>1.33(2)</td><td>1.41(3)</td><td>-179(2)</td></tr><tr><td>4d-M1</td><td>1.281(4)</td><td>1.387(3)</td><td>1.367(4)</td><td>1.680(3)</td><td>1.343(4)</td><td>1.428(4)</td><td>176.5(3)</td></tr><tr><td>4d-M2</td><td>1.284(4)</td><td>1.386(3)</td><td>1.370(4)</td><td>1.677(3)</td><td>1.350(4)</td><td>1.420(4)</td><td>-176.3(3)</td></tr><tr><td>4e</td><td>1.286(2)</td><td>1.399(2)</td><td>1.371(2)</td><td>1.676(2)</td><td>1.347(2)</td><td>1.412(2)</td><td>164.77(15)</td></tr><tr><td>4f-M1</td><td>1.2850(12)</td><td>1.3833(11)</td><td>1.3615(12)</td><td>1.6869(10)</td><td>1.3413(13)</td><td>1.4522(13)</td><td>-171.23(9)</td></tr><tr><td>4f-M2</td><td>1.2846(12)</td><td>1.3837(11)</td><td>1.3590(12)</td><td>1.6915(10)</td><td>1.3390(12)</td><td>1.4509(12)</td><td>170.03(9)</td></tr><tr><td>4g</td><td>1.2850(14)</td><td>1.3830(13)</td><td>1.3725(14)</td><td>1.6858(12)</td><td>1.3374(15)</td><td>1.4629(15)</td><td>-178.77(12)</td></tr><tr><td>4h</td><td>1.2831(9)</td><td>1.3863(8)</td><td>1.3656(9)</td><td>1.6901(7)</td><td>1.3361(10)</td><td>1.4573(11)</td><td>174.13(6)</td></tr></tbody></table>

<table><caption>**Table 3**
Selected bond angles (°) in the $C_i=N_a-N_bH-C_jS-N_cC_k$ core of 4.</caption><thead><tr><th></th><th>C<sub>Mc</sub>C<sub>i</sub>N<sub>a</sub></th><th>C<sub>p</sub>C<sub>i</sub>N<sub>a</sub></th><th>C<sub>i</sub>N<sub>a</sub>N<sub>b</sub></th><th>N<sub>a</sub>N<sub>b</sub>C<sub>j</sub></th><th>N<sub>b</sub>C<sub>j</sub>S</th><th>SC<sub>j</sub>N<sub>c</sub></th><th>N<sub>b</sub>C<sub>j</sub>N<sub>c</sub></th><th>C<sub>j</sub>N<sub>c</sub>C<sub>k</sub></th></tr></thead><tbody><tr><td>4a-M1</td><td>125.7(6)</td><td>116.0(6)</td><td>117.8(6)</td><td>117.0(6)</td><td>119.6(5)</td><td>125.5(6)</td><td>114.9(7)</td><td>126.9(7)</td></tr><tr><td>4a-M2</td><td>124.7(7)</td><td>117.0(6)</td><td>118.0(6)</td><td>117.8(6)</td><td>120.4(5)</td><td>124.4(5)</td><td>115.2(6)</td><td>126.2(6)</td></tr><tr><td>4b</td><td>128.9(19)</td><td>114.7(15)</td><td>118.3(15)</td><td>117.0(15)</td><td>119.9(14)</td><td>125.8(13)</td><td>114.3(17)</td><td>125.4(16)</td></tr><tr><td>4d-M1</td><td>125.8(3)</td><td>116.8(3)</td><td>117.4(2)</td><td>117.9(2)</td><td>118.5(2)</td><td>127.5(2)</td><td>114.1(3)</td><td>129.8(3)</td></tr><tr><td>4d-M2</td><td>125.9(3)</td><td>116.4(3)</td><td>117.1(2)</td><td>118.0(2)</td><td>118.3(2)</td><td>127.9(2)</td><td>113.9(3)</td><td>129.8(3)</td></tr><tr><td>4e</td><td>117.49(15)</td><td>125.08(15)</td><td>116.22(14)</td><td>119.34(14)</td><td>118.26(13)</td><td>128.62(13)</td><td>113.08(15)</td><td>132.33(16)</td></tr><tr><td>4f-M1</td><td>126.31(9)</td><td>116.24(8)</td><td>118.19(8)</td><td>117.37(8)</td><td>119.13(8)</td><td>125.19(8)</td><td>115.67(9)</td><td>124.86(9)</td></tr><tr><td>4f-M2</td><td>125.72(9)</td><td>116.77(8)</td><td>117.84(8)</td><td>117.19(8)</td><td>119.29(7)</td><td>124.73(7)</td><td>115.97(8)</td><td>124.74(9)</td></tr><tr><td>4g</td><td>126.40(10)</td><td>115.84(10)</td><td>119.76(10)</td><td>116.81(9)</td><td>119.33(9)</td><td>125.22(9)</td><td>115.44(10)</td><td>126.76(10)</td></tr><tr><td>4h</td><td>126.38(6)</td><td>115.66(6)</td><td>119.32(6)</td><td>116.02(6)</td><td>119.53(5)</td><td>124.71(6)</td><td>115.74(6)</td><td>124.85(7)</td></tr></tbody></table>

(7.76 kcal/mol in the explicit model and 18.20 kcal/mol in the gas phase). These results align with the X-ray diffraction analysis, which shows that, except for 4e, all other TSCs (4a, 4b, 4d, 4f, 4g, 4h), adopt

an *E* configuration in the crystalline state (see Section 2.3.2). For further investigation, theoretical DFT calculations for compound 4e were performed, showing that the *E* configuration is more stable than the *Z*
<table><caption>**Table 4**
Intermolecular and intramolecular hydrogen bond lengths (Å) and angles (°).</caption><thead><tr><th rowspan="2"></th><th colspan="2">Intramolecular hydrogen bond</th><th colspan="3">Intermolecular hydrogen bond</th><th rowspan="2">Association type</th></tr><tr><th>N···H (Å)</th><th>N···H···N (°)</th><th>O···H···N (Å)</th><th>O···H (Å)</th><th>O···H···N (°)</th></tr></thead><tbody><tr><td>4a</td><td>2.238<br>2.244</td><td>105.71<br>112.49</td><td>2.769<br>2.816</td><td>2.00<br>1.98</td><td>158<br>163</td><td>M1M2 dimer</td></tr><tr><td>4b</td><td>2.14<br>2.098</td><td>109.9<br>112.23</td><td>2.879<br>2.869</td><td>2.098<br>2.20</td><td>146<br>132.8</td><td>chain</td></tr><tr><td>4d</td><td>2.102<br>2.104</td><td>112.19<br>114.31</td><td>2.835<br>-</td><td>2.18<br>-</td><td>131.1<br>-</td><td>M1M1' dimer<br>M2M2 dimer</td></tr><tr><td>4e<sup>a</sup></td><td>2.167<br>2.168</td><td>108.10<br>107.95</td><td>2.811<br>2.790</td><td>1.99<br>1.98</td><td>154.4<br>153.3</td><td>M1M2 dimer</td></tr><tr><td>4f</td><td>2.135<br>2.149</td><td>112.28<br>109.92</td><td>2.936<br>2.837</td><td>2.07<br>1.983</td><td>169.4<br>167.1</td><td>chain<br>M1M1' dimer</td></tr></tbody></table>

configuration by 1.46 kcal/mol. The observed Z configuration in the crystal structure of 4e is likely attributed to the influence of secondary interactions and packing forces within the crystal, which drive the molecules to adopt the Z configuration.

These findings contrast from earlier studies on β-cycloalkoxyphosphonated hydrazones [54,55], where both DFT calculations and X-ray diffraction confirmed that the Z isomer predominates due to the presence of intramolecular N-H···O=P hydrogen bonding in the Z structure. Similarly, our previous work on thiosemicarbazones containing a dioxaphosphorinane ring also suggested that the Z isomer is the favored one because of the same N-H···O=P hydrogen bonding interaction [48]. However, in our current investigation on TSCs with a diphenylphosphite group, despite the potential for hydrogen bonding between the NH and O=P groups in the Z isomer, steric repulsion between the methyl and phenyl groups appears to be the dominant factor. This steric hindrance leads to a more stable E isomer, as illustrated in Fig. 14.

This allows us to attribute confidentially the predominant signals in the NMR spectra to the E isomer and the second less intense signal set to

<figure><img src="image_16.png" /><figcaption>**Fig. 12.** (a) Normalized absorption spectra recorded for compounds 4a-d and 4f-h in MeOH. (b) Superposition of the absorption spectra of N-aryl compounds 4a, 4b and 4d in CH<sub>3</sub>OH. (c) Superposition of the absorption spectra of N-aryl compounds 4a, 4b and 4d in CH<sub>3</sub>CN.</figcaption></figure>

<table><caption>**Table 5**
Absorption data of compounds 4a-d and 4f-h in methanol at 298 K.</caption><thead><tr><th>Compound</th><th>4a</th><th>4b</th><th>4c</th><th>4d</th><th>4f</th><th>4g</th><th>4h</th></tr></thead><tbody><tr><td>λ<sub>abs</sub> nm<br>(ε x 10<sup>-3</sup>M<sup>-1</sup>cm<sup>-1</sup>)</td><td>274 (25.6)</td><td>277 (26.2), 220 (29.2)</td><td>281 (28.6), 252 (22.6)</td><td>283 (24.8), 221 (24.3)</td><td>276 (26.6)</td><td>274 (30.8)</td><td>275 (22.1), 221 (27.7)</td></tr></tbody></table>

<footnote><sup>a</sup> Other intramolecular interactions: O···H···N 2.09 Å, 150.0° (PO); 2.12 Å, 113° (MeO); S···H···C 2.58 Å, 129°.</footnote>
<figure><img src="image_17.png" /><figcaption>Fig. 13. The Intrinsic reaction coordinate of thiosemicarbazone 4a in the gas phase (a) and in ethanol (explicit) (b).</figcaption></figure>

<figure><img src="image_18.png" /><figcaption>Fig. 14. Optimized structures of the 4a E and 4a Z isomers.</figcaption></figure>

the Z isomer. The ³¹P NMR spectroscopic findings for the Z/E isomer ratios are summarized in Table 6.

### 2.3.4.2. Comparison of the theoretical and experimental geometric properties of 4a E.
For a comparative evaluation of the experimental results by DFT computing, the 4a E structure was optimized using the B3LYP functional, 6-311+G (d, p) basis set. Table 7 summarizes selected structural parameters (bond lengths, angles) of 4a E generated from SC-XRD and DFT calculation. The results reveal good agreement between theoretical and experimental values with correlation coefficients of R² = 0.998, R² = 0.999 for bond length (DFT (gas)/ SCXRD), (DFT (EtOH)/ SCXRD), respectively and R² = 0.980 and R² = 0.984 for the angles (DFT (gas)/ SCXRD) and (DFT (EtOH) / SCXRD) (Fig. 15). The small difference between the experimental and calculated parameters is constantly anticipated given that SC-XRD results are obtained from the solid state.

Similar calculated bond lengths were found for P21=028: 1.511 Å in the gas phase and 1.516 Å in ethanol, consistent with a double bond character, corresponding to 1.492(5) Å in SC-XRD. This is in agreement with previous work using SC-XRD to study structures bearing a Ph₂P(=O) moiety [89]. In fact, Swamy et al. showed that the P=O bond length is equal to 1.490 Å in 3-(diethylamino)-4-(diphenylphosphoryl)-1-naphthol. The calculated C2-S1 bond length in the gas phase (1.697 Å in EtOH) is close to the experimental one (1.682 vs.1.67(7) Å). These values match again with those reported in the literature [90,91]. For example, Basri et al. studied the structure of (Z)-N-cyclohexyl-2-(2-((2-oxo-2H-chromen-3-yl)-methoxy)benzylidene)hydrazine-carbothioamide by means of SC-XRD and DFT calculation and found for the crystallographic C-S bond length 1.687 Å and 1.681 Å using DFT B3LYP/6-311+G (d, p) [90]. Likewise, quite similar experimental and calculated bond angles were found. As a representative example, a value

<table><caption>**Table 6**

³¹P-{¹H} NMR chemical shifts and relative proportions of the Z/E isomers of 4a-h at 298 K.</caption><thead><tr><th></th><th></th><th>4a</th><th>4b</th><th>4c</th><th>4d</th><th>4e</th><th>4f</th><th>4g</th><th>4h</th></tr></thead><tbody><tr><td rowspan="2">δ <sup>31</sup>P (ppm)</td><td><i>E</i></td><td>26.88</td><td>27.16</td><td>28.68</td><td>28.55</td><td>29.81</td><td>26.97</td><td>26.67</td><td>27.04</td></tr><tr><td><i>Z</i></td><td>28.79</td><td>29.04</td><td>29.77</td><td>29.67</td><td>28.74</td><td>28.94</td><td>28.85</td><td>28.96</td></tr><tr><td>Z/E</td><td><i>E</i></td><td>73.56</td><td>68.98</td><td>72.93</td><td>71.42</td><td>36.12</td><td>66.29</td><td>72.08</td><td>67.14</td></tr><tr><td>%</td><td><i>Z</i></td><td>26.44</td><td>31.02</td><td>27.07</td><td>28.58</td><td>63.85</td><td>33.71</td><td>27.92</td><td>32.86</td></tr></tbody></table>
<table><caption>**Table 7**
Selected bond lengths (Å) and angles (°) from X-ray diffraction and DFT optimization for the **4a E** isomer.</caption><thead><tr><th>Bond lengths (Å)</th><th>Exp<br>SCXRD</th><th>Calc.<br>in gas<br>phase</th><th>Calc.<br>in EtOH</th><th>Angles (°)</th><th>Exp<br>SCXRD</th><th>Calc.<br>in gas<br>phase</th><th>Calc.<br>in EtOH</th></tr></thead><tbody><tr><td>P21=O28</td><td>1.492(5)</td><td>1.511</td><td>1.516</td><td>N3-C2-S1</td><td>125.5(6)</td><td>126.0</td><td>125.3</td></tr><tr><td>C2-S1</td><td>1.677(7)</td><td>1.682</td><td>1.697</td><td>C5-N3-C2</td><td>126.9(7)</td><td>128.5</td><td>127.4</td></tr><tr><td>N7-N4</td><td>1.384(8)</td><td>1.373</td><td>1.383</td><td>S1-C2-N4</td><td>119.6(5)</td><td>119.8</td><td>119.7</td></tr><tr><td>C11=N7</td><td>1.288(9)</td><td>1.283</td><td>1.282</td><td>N3-C2-N4</td><td>114.9(7)</td><td>114.2</td><td>114.9</td></tr><tr><td>C2-N3</td><td>1.350(9)</td><td>1.357</td><td>1.350</td><td>C2-N4-N7</td><td>117.0(6)</td><td>119.1</td><td>118.4</td></tr><tr><td>C2-N4</td><td>1.369(9)</td><td>1.376</td><td>1.367</td><td>N4-N7-C11</td><td>117.8(6)</td><td>119.2</td><td>118.2</td></tr><tr><td>P21-C16</td><td>1.813(7)</td><td>1.844</td><td>1.842</td><td>N7=C11-C16</td><td>116.0(6)</td><td>117.3</td><td>117.6</td></tr><tr><td>N3-C5</td><td>1.428(9)</td><td>1.420</td><td>1.424</td><td>C11-C16-P21</td><td>115.8(5)</td><td>116.6</td><td>117.9</td></tr><tr><td>P21-C29</td><td>1.815 (7)</td><td>1.830</td><td>1.827</td><td>N7=C11-C17</td><td>125.5(6)</td><td>125.0</td><td>125.4</td></tr><tr><td>C11-C16</td><td>1.503(10)</td><td>1.513</td><td>1.510</td><td>O28-P21-C16</td><td>114.1(3)</td><td>113.4</td><td>113.6</td></tr></tbody></table>

<figure><img src="image_19.png" /><figcaption>**Fig. 15.** DFT/SC-XRD graphical correlation for bond lengths (a) and angles (b) of **4a E**.</figcaption></figure>

of 114.2° is found for N3-C2-N4 in the gas phase and 114.9° in ethanol as solvent. These results are in line with the experimental value of 114.9 (7)° and also with the previous work of Basri *et al.* [90] where the authors reported a value of 116.7° and 115.0° for SC-XRD and DFT B3LYP/6-311+G (d, p), respectively.

Of course, the question arises why TSCs **4** like other TSCs described in the literature occur as equilibrating *E/Z* isomeric mixtures in solution. The driving force and mechanism of this interconversion has been the topic of several articles, both experimentally or by DFT computing [56, 69, 70, 92–96]. This may be due to a simple temperature-dependent inversion at the nitrogen atom of the C=N bond, also well studied for dissymmetric imines $R_1R_2C=N$ [97–100]. Alternatively, this reversible isomerization may occur through rotation (direct isomerization), or alternatively a tautomerization process involving N-H-shifts providing a thiol (C=S → C-SH) intermediate. Taherpour *et al.* summarize based on DFT computing, that the solvents have a strong impact on the *E/Z* isomerization of TSCs in which the inversion mechanism is the most likely mechanism in aprotic (and less polar) solvents, whereas a catalytic tautomerization mechanism prevails in protic (and polar) solutions [93]. Since we have employed the protic solvent EtOH as reaction medium for the synthesis of **4**, tautomerization may account for the *E/Z* interconversion. Since mechanistic investigation are not the topic of our contribution, we have not explored this aspect in-depth.

### 2.3.4.3. Theoretical/experimental infrared investigation of thiosemicarbazone **4**
Valuable information about the structure of **4** is also provided by the infrared spectra. In order to analyze the characteristic vibrations of each segment of TSCs **4**, we refer to prior studies involving similar systems [69,90,101] and also employed computational

chemistry techniques applied to **4a**. In fact, the calculated IR spectrum (obtained from calculated wavenumbers at B3LYP/6-311+G (d, p) exhibits a commendable agreement with the experimental one (Fig. 16), facilitating the characterization of the spectral features associated with distinct chemical groups. The IR spectra of the series **4** display characteristic absorption bands within the functional group region. Prominent bands within the wavenumber range of 3288–3320 and 3104–2939 cm⁻¹ are attributed to the stretching vibrations of the NH, CHarom and CHaliph groups, respectively. The splitting and broadening of the ν(NH) band in the experimental IR spectrum are caused by the N-H···N and N-H···O hydrogen bonding discussed in the crystallographic section (which are not taken in account for the computed spectrum. The distinct band at 1639 cm⁻¹ is associated to C=N group. The absorption bands of C=S group appear at 1386 and 748 cm⁻¹, the strong ν(P=O) vibration is found at 1159 cm⁻¹.

## 3. Experimental section

### 3.1. Apparatus

For NMR analysis, ³¹P{¹H}, ¹H, ¹³C{¹H} and ¹⁹F NMR spectra were acquired using a Bruker AVANCE 400 HD instrument. Chemical shifts were reported in ppm relative to the residual solvent peak (7.27 ppm for CHCl₃) for ¹H spectra, (77.00 ppm for CDCl₃) for ¹³C spectra and referenced to H₃PO₄ for the ³¹P spectra. The ¹⁹F spectrum is referenced to CFCl₃. The coupling constants *J* are expressed in Hz. The multiplicity of signals was indicated by the abbreviations *s* (singlet), *d* (doublet), *t* (triplet), and *m* (multiplet). The infrared spectra were recorded using a Bruker Vertex FT-IR spectrometer. A Platinum Attenuated Total
<figure><img src="image_20.png" /><figcaption>Fig. 16. Calculated (red) and experimental (black) ATR-IR spectra of 4a.</figcaption></figure>

Reflectance (ATR) accessory with a diamond crystal was employed. UV-vis spectra were obtained on a VARIAN-Cary 300 array spectro-photometer. Melting points were determined using an Electrothermal melting point apparatus with a precision of ± 2 °C. GC-MS analyses were performed on a SHIMADZU, GCMS-QP2010 SE system. For the CHNS elemental analysis and melting points, recrystallized samples also used for X-ray crystallography have been used.

### 3.2. Preparation of 1-(diphenylphosphine oxide) prop-1,2-diene 1

Allene 1 was synthesized as previously described [102,103] M.W. = 240.24 g/mol; yield 70 %); white solid; m.p. (80 °C ± 2) ; ³¹P{¹H} NMR (CDCl₃): 23.48. ¹H NMR (CDCl₃): δ ¹H = 3.80 (dd, ³J<sub>HP</sub> = 11.17 Hz, ¹J<sub>HH</sub> = 6.82 Hz, 2H, =CH₂), 5.75-5.79 (m, 1H, -CH=), 7.36-7.70 (m, 10H, H<sub>arom</sub>). ¹³C{¹H} NMR (CDCl₃): δ ¹³C = 76.53 (d, ³J<sub>CP</sub> = 12.75 Hz, =CH₂), 84.62 (d, ¹J<sub>CP</sub> = 104.43 Hz, =CH), 127.98-132.93 (m, C<sub>arom</sub>), 214.14 (s, =C=).

### 3.3. Preparation of (2-hydrazineylidenepropyl)diphenylphosphine oxide 2

Hydrazone 2 was synthesized as previously described [53,104]. M. W. = 272.29 g/mol; yield 80 %); white solid; m.p. : 100 °C; Z-isomer: ³¹P {¹H} NMR (CDCl₃): δ ³¹P = 30.37. NMR (CDCl₃): δ ¹H = 1.42 (d, ⁴J<sub>HP</sub> = 2.73 Hz, 3H, CH₃), 3.35 (d, ²J<sub>HP</sub> = 14.55 Hz, 2H, CH₂), 5.90 (s, 2H, NH₂), 7.31-7.72 (m, H<sub>arom</sub>). ¹³C{¹H} NMR (CDCl₃): δ ¹³C = 25.19 (d, ³J<sub>CP</sub> = 1.81 Hz, CH₃), 34.28 (d, ¹J<sub>CP</sub> = 65.23 Hz, CH₂), 128.6-133.5 (m, C<sub>arom</sub>), 143.08 (d, ²J<sub>CP</sub> = 10.23 Hz, C=N). E-isomer: ³¹P{¹H} NMR (CDCl₃): δ ³¹P = 28.99. ¹H NMR (CDCl₃): δ ¹H = 1.74 (d, ⁴J<sub>HP</sub> = 2.62 Hz, 3H, CH₃), 3.24 (d, ²J<sub>HP</sub> = 13.97 Hz, 2H, CH₂); 4.90 (s, 2H, NH₂), 7.31-7.72 (m, H<sub>arom</sub>). ¹³C{¹H} NMR (CDCl₃): δ ¹³C = 15.22 (d, ³J<sub>CP</sub> = 1.01 Hz, CH₃), 41.35 (d, ¹J<sub>CP</sub> = 66.97 Hz, CH₂), 128.4-132.6 (m, C<sub>arom</sub>), 143.17 (d, ²J<sub>CP</sub> = 8.87, C=N). GC-MS (Azine 3): *m/z* = 357 [P(O)-CH-C(CH₃)=N-N=C(CH₃)-CH₂-P(O)-C(CH₅)₂], 341 [P(O)-C-C=N-N=C(CH₃)-CH₂-P(O)-C(CH₅)₂], 295 [CH-C=N-N=C(CH₃)-CH₂-P(O)-C(CH₅)₂], 77 [C₆H₅].

### 3.4. General procedure for the preparation of thiosemicarbazones 4

Isothiocyanate derivatives (20 mmol) were added dropwise to a solution of β-phosphonate hydrazone (20 mmol, 5.44 g) dissolved in absolute ethanol (50 mL). The reaction mixture is stirred at room temperature until the onset of formation of white precipitate. The

reaction mixture is then cooled in an ice bath to complete the precipitation of the product. The resulting solid product was recovered by vacuum filtration and washed with absolute ethanol. 4b was synthesized according to our previous published procedure [61]. To remove the side products 3 and 5, samples were recrystallized from EtOH to isolate the analytical pure products.

### 3.4.1. N-phenyl-2-(1-(diphenylphosphoryl)propan-2-ylidene)hydrazine-1-carbothioamide 4a

M.W. = 407.47 g/mol; yield = 5.29 g, 65 %; white solid; m.p. 178 °C; Z-isomer: ³¹P{¹H} NMR (DMSO-d₆): δ ³¹P = 29.04. ¹H NMR (DMSO-d₆): δ ¹H = 1.81 (d, ⁴J<sub>HP</sub> = 2.23 Hz, 3H, CH₃), 4.00 (d, ²J<sub>HP</sub> = 15.55 Hz, 2H, CH₂-P), 7.14-7.94 (m, H<sub>arom</sub>), 9.82 (s, 1H, N-NH), 11.14 (s, 1H, NH-Ph). ¹³C{¹H} NMR (DMSO-d₆): δ ¹³C = 25.83 (d, ³J<sub>CP</sub> = 1.58 Hz, CH₃), 124.51-139.61 (m, C<sub>arom</sub>), 146.49 (d, ²J<sub>CP</sub> = 9.10 Hz, C=N), 177.19 (s, C=S). E-isomer: ³¹P{¹H} NMR (DMSO-d₆): δ ³¹P = 27.16. ¹H NMR (DMSO-d₆): δ ¹H = 2.01 (d, ⁴J<sub>HP</sub> = 1.31 Hz, 3H, CH₃), 3.74 (d, ²J<sub>HP</sub> = 13.42 Hz, 2H, CH₂-P), 7.14-7.94 (m, H<sub>arom</sub>), 9.65 (s, 1H, N-NH), 10.67 (s, 1H, NH-Ph). ¹³C{¹H} NMR (DMSO-d₆): δ ¹³C = 19.06 (d, ³J<sub>CP</sub> = 2.59 Hz, CH₃), 35.12 (d, ¹J<sub>CP</sub> = 61.6 Hz, CH₂-P), 124.51-139.61 (m, C<sub>arom</sub>), 147.78 (d, ²J<sub>CP</sub> = 8.96 Hz, C=N), 176.47 (s, C=S). IR-ATR (cm⁻¹): 748 ν(C-S); 1159 ν(P=O); 1386 ν(C-S); 1639 ν(C=N); 3201-3288 ν(NH). Anal. Calc. for C₂₂H₂₂N₃OPS: C, 64.85; H, 5.44; N, 10.31; S, 7.87 %. Found: C, 65.18; H, 5.35; N, 9.84; S, 7.42 %. GC-MS: *m/z* = 215 [(Ph₂)-P(O)-CH₂], 201 [(Ph₂)P=O], 152 [H₂N-C(S)-NH-Ph], 91 [H₂N-C(S)-NH-NH₂], 77 [C₆H₅], 63 [H₂N-CH₂-SH].

### 3.4.2. N-(4-fluorophenyl)-2-(1-(diphenylphosphoryl)propan-2-ylidene)hydrazine-1-carbothioamide 4b

M.W. = 425.46 g/mol; yield = 5.53 g, 65 %); white solid; m.p.198 °C; Z-isomer: ³¹P{¹H} NMR (DMSO-d₆): δ ³¹P = 28.94. ¹⁹F NMR (DMSO-d₆): δ ¹⁹F = -117.41. ¹H NMR (DMSO-d₆): δ ¹H = 1.81 (d, ⁴J<sub>HP</sub> = 2.20 Hz, 3H, CH₃), 4.01 (d, ²J<sub>HP</sub> = 15.55 Hz, 2H, CH₂-P), 7.14-7.94 (m, H<sub>arom</sub>), 9.84 (s, 1H, N-NH), 11.16 (s, 1H, NH-p-F-Ph). ¹³C{¹H} NMR (DMSO-d₆) at 298 K: δ ¹³C = 25.82 (d, ³J<sub>CP</sub> = 2.51 Hz, CH₃), 126.85-136.00 (m, C<sub>arom</sub>), 146.54 (d, ²J<sub>CP</sub> = 9.08 Hz, C=N), 159.91 (d, ¹J<sub>CF</sub> = 241.8 Hz, C-F), 177.59 (s, C=S). E-isomer: ³¹P{¹H} NMR (DMSO-d₆): δ ³¹P = 26.97. ¹⁹F NMR (DMSO-d₆): δ ¹⁹F = -117.33. ¹H NMR (DMSO-d₆): δ ¹H = 2.01 (d, ⁴J<sub>HP</sub> = 1.35 Hz 3H, CH₃), 3.73 (d, ²J<sub>HP</sub> = 13.44 Hz, 2H, CH₂-P), 7.14-7.94 (m, H<sub>arom</sub>), 9.63 (s, 1H, N-NH), 10.72 (s, 1H, NH-p-F-Ph). ¹³C{¹H} NMR (DMSO-d₆): δ ¹³C = 19.01 (d, ³J<sub>CP</sub> = 2.51 Hz, CH₃), 34.61 (d, ¹J<sub>CP</sub> = 61.69 Hz, CH₂-P), 126.85-136.00 (m,
C<sub>arom</sub>), 147.89 (d, <sup>2</sup>J<sub>CP</sub> = 8.88 Hz, C=N), 159.83 (d, <sup>1</sup>J<sub>CF</sub> = 241.94 Hz, C-F), 176.89 (s, C=S). IR-ATR (cm<sup>-1</sup>): 738 ν(C-S); 1152 ν(P=O); 1384 ν(C-S); 1601 ν(C=N); 3199 –3287 ν(NH).

### 3.4.3. N-(4-chlorophenyl)-2-(1-(diphenylphosphoryl)propan-2-ylidene)hydrazine-1-carbothioamide 4c

M.W. = 441.08 g/mol; yield = 5.65 g, 64%; white solid; m.p. 190 °C; Z-isomer: <sup>31</sup>P{<sup>1</sup>H} NMR (DMSO-d<sub>6</sub>): δ <sup>31</sup>P = 28.96. <sup>1</sup>H NMR (DMSO-d<sub>6</sub>): δ<sup>1</sup>H = 1.82 (d, <sup>4</sup>J<sub>HP</sub> = 2.14 Hz, 3H, CH<sub>3</sub>), 4.01 (d, <sup>2</sup>J<sub>HP</sub> = 15.55 Hz, 2H, CH<sub>2</sub>-P), 7.37–7.94 (m, H<sub>arom</sub>), 9.90 (s, 1H, N-NH), 11.23 (s, 1H, NH-Ph). <sup>13</sup>C{<sup>1</sup>H} NMR (DMSO-d<sub>6</sub>): δ<sup>13</sup>C = 25.83 (d, <sup>3</sup>J<sub>CP</sub> = 1.52 Hz, CH<sub>3</sub>), 125.97–138.50 (m, C<sub>arom</sub>), 146.83 (d, <sup>2</sup>J<sub>CP</sub> = 9.06 Hz, C=N), 177.20 (s, C=S). E-isomer: <sup>31</sup>P{<sup>1</sup>H} NMR (DMSO-d<sub>6</sub>): δ <sup>31</sup>P = 27.04. <sup>1</sup>H NMR (DMSO-d<sub>6</sub>): δ<sup>1</sup>H = 2.02 (d, <sup>4</sup>J<sub>HP</sub> = 0.92 Hz, 3H, CH<sub>3</sub>), 3.74 (d, <sup>2</sup>J<sub>HP</sub> = 13.36 Hz, 2H, CH<sub>2</sub>-P), 7.37–7.94 (m, H<sub>arom</sub>), 9.75 (s, 1H, N-NH), 10.80 (s, 1H, NH-Ph). <sup>13</sup>C{<sup>1</sup>H} NMR (DMSO-d<sub>6</sub>): δ<sup>13</sup>C = 19.07 (d, <sup>3</sup>J<sub>CP</sub> = 2.57 Hz, CH<sub>3</sub>), 35.16 (d, <sup>1</sup>J<sub>CP</sub> = 61.58 Hz, CH<sub>2</sub>-P), 125.97–138.50 (m, C<sub>arom</sub>), 148.20 (d, <sup>2</sup>J<sub>CP</sub> = 8.84 Hz, C=N), 176.46 (s, C=S). IR-ATR (cm<sup>-1</sup>): 735 ν(C-S); 1156 ν(P=O); 1434 ν(C-S); 1589 ν(C=N); 3196 –3271 ν(NH). GC-MS: *m/z* = 169 [H<sub>5</sub>C<sub>6</sub>(Cl)-N-C-S], 127 [H<sub>5</sub>C<sub>6</sub>(Cl)-NH<sub>2</sub>], 111 [H<sub>5</sub>C<sub>6</sub>-Cl], 75 [HN-NH-CH=S], 50 (H<sub>3</sub>P=O).

### 3.4.4. N-(3,5-dimethylphenyl)-2-(1-(diphenylphosphoryl)propan-2-ylidene)hydrazine-1-carbothioamide 4d

M.W. = 435.53 g/mol; yield = 5.22 g, 60%; white solid; m.p. 178 °C; Z-isomer: <sup>31</sup>P{<sup>1</sup>H} NMR (CDCl<sub>3</sub>): δ <sup>31</sup>P = 29.67. <sup>1</sup>H NMR (CDCl<sub>3</sub>): δ<sup>1</sup>H = 1.77 (d, <sup>4</sup>J<sub>HP</sub> = 2.33 Hz, 3H, CH<sub>3</sub>), 2.33 (s, 6H, Me<sub>2</sub>), 3.50 (d, <sup>2</sup>J<sub>HP</sub> = 14.73 Hz, 2H, CH<sub>2</sub>-P), 6.87–7.86 (m, H<sub>arom</sub>), 9.10 (s, 1H, NH-Ph), 11.14 (s, 1H, N-NH). <sup>13</sup>C{<sup>1</sup>H} NMR (CDCl<sub>3</sub>): δ<sup>13</sup>C = 17.72 (d, <sup>3</sup>J<sub>CP</sub> = 2.07 Hz, CH<sub>3</sub>), 21.26 (s, Me), 36.67 (d, <sup>1</sup>J<sub>CP</sub> = 61.64 Hz, CH<sub>2</sub>), 121.74–138.30 (m, C<sub>arom</sub>), 144.85 (d, <sup>2</sup>J<sub>CP</sub> = 9.85 Hz, C=N), 177.52 (s, C=S). E-isomer: <sup>31</sup>P{<sup>1</sup>H} NMR (CDCl<sub>3</sub>): δ <sup>31</sup>P = 28.55. <sup>1</sup>H NMR (CDCl<sub>3</sub>): δ<sup>1</sup>H = 2.06 (d, <sup>4</sup>J<sub>HP</sub> = 2.02 Hz, 3H, CH<sub>3</sub>), 2.35 (s, 6H, Me<sub>2</sub>), 3.44 (d, <sup>2</sup>J<sub>HP</sub> = 13.62 Hz, 2H, CH<sub>2</sub>-P), 6.87–7.86 (m, H<sub>arom</sub>), 8.64 (s, 1H, N-NH), 8.50 (s, 1H, NH-Ph). <sup>13</sup>C{<sup>1</sup>H} NMR (CDCl<sub>3</sub>): δ<sup>13</sup>C = 26.01 (d, <sup>3</sup>J<sub>CP</sub> = 2.04 Hz, CH<sub>3</sub>), 21.34 (s, Me), 40.96 (d, <sup>1</sup>J<sub>CP</sub> = 64.78 Hz, CH<sub>2</sub>), 121.74–138.30 (m, C<sub>arom</sub>), 144.23 (d, <sup>2</sup>J<sub>CP</sub> = 9.19 Hz, C=N), 175.95 (s, C=S). IR-ATR (cm<sup>-1</sup>): 734 ν(C-S); 1159 ν(P=O); 1388 ν(C-S); 1616 ν(C=N); 3012–3319 ν(NH). Anal. Calc. for C<sub>24</sub>H<sub>26</sub>N<sub>3</sub>OPS: C, 66.19; H, 6.02; N, 9.65; S, 7.36%. Found: C, 65.98; H, 5.85; N, 9.84; S, 7.42%. GC-MS: *m/z* = 163 [H<sub>4</sub>C<sub>6</sub>(Me)<sub>2</sub>-N-C=S], 148 [H<sub>4</sub>C<sub>6</sub>(Me)-N-C=S], 121 [H<sub>4</sub>C<sub>6</sub>(Me)<sub>2</sub>-NH<sub>2</sub>], 105 [H<sub>4</sub>C<sub>6</sub>(Me)-NH], 91 [H<sub>2</sub>N-C(S)-NH-NH<sub>2</sub>], 77 [C<sub>6</sub>H<sub>5</sub>], 63 [H<sub>2</sub>N-CH<sub>2</sub>-SH].

### 3.4.5. N-(2,5-dimethoxyphenyl)-2-(1-(diphenylphosphoryl)propan-2-ylidene)hydrazine-1-carbothioamide 4e

M.W. = 467.52 g/mol; yield = 5.79 g, 62%; white solid; m.p. 178 °C; Z-isomer: <sup>31</sup>P{<sup>1</sup>H} NMR (CDCl<sub>3</sub>): δ <sup>31</sup>P = 29.81. <sup>1</sup>H NMR (CDCl<sub>3</sub>): δ<sup>1</sup>H = 1.69 (d, <sup>4</sup>J<sub>HP</sub> = 2.36 Hz, 3H, CH<sub>3</sub>), 3.42 (d, <sup>2</sup>J<sub>HP</sub> = 14.69 Hz, 2H, CH<sub>2</sub>-P), 3.72 (s, 3H, OMe), 3.74 (s, 3H, OMe), 6.80–8.70 (m, H<sub>arom</sub>), 9.77 (s, 1H, NH-Ph), 11.09 (s, 1H, N-NH). <sup>13</sup>C{<sup>1</sup>H} NMR (CDCl<sub>3</sub>): δ<sup>13</sup>C = 26.19 (d, <sup>3</sup>J<sub>CP</sub> = 2.17 Hz, CH<sub>3</sub>), 36.64 (d, <sup>1</sup>J<sub>CP</sub> = 61.86 Hz, CH<sub>2</sub>), 56.57 (s, OMe), 56.61 (s, OMe), 107.57–132.80 (m, C<sub>arom</sub>), 144.55 (d, <sup>2</sup>J<sub>CP</sub> = 9.87 Hz, C=N), 153.30 (s, C-OMe), 174.96 (s, C=S). E-isomer: <sup>31</sup>P{<sup>1</sup>H} NMR (CDCl<sub>3</sub>): δ <sup>31</sup>P = 28.74. <sup>1</sup>H NMR (CDCl<sub>3</sub>): δ<sup>1</sup>H = 1.97 (d, <sup>4</sup>J<sub>HP</sub> = 2.49 Hz, 3H, CH<sub>3</sub>), 3.38 (d, <sup>2</sup>J<sub>HP</sub> = 14.13 Hz, 2H, CH<sub>2</sub>-P), 3.73 (s, 3H, OMe), 3.79 (s, 3H, OMe), 6.80–8.70 (m, H<sub>arom</sub>), 9.49 (s, 1H, N-NH), 8.34 (s, 1H, NH-Ph). <sup>13</sup>C{<sup>1</sup>H} NMR (CDCl<sub>3</sub>): δ<sup>13</sup>C = 17.32 (d, <sup>3</sup>J<sub>CP</sub> = 0.93 Hz, CH<sub>3</sub>), 41.64 (d, <sup>1</sup>J<sub>CP</sub> = 64.03 Hz, CH<sub>2</sub>), 55.86 (s, OMe), 56.57 (s, OMe), 107.57–132.80 (m, C<sub>arom</sub>), 144.38 (d, <sup>2</sup>J<sub>CP</sub> = 8.77 Hz, C=N), 153.33 (s, C-OMe), 175.96 (s, C=S). IR-ATR (cm<sup>-1</sup>): 741 ν(C-S); 1164 ν(P=O); 1357 ν(C-S); 1601 ν(C=N); 3159–3392 ν(NH). Anal. Calc. for C<sub>24</sub>H<sub>26</sub>N<sub>3</sub>OPS: C, 61.66; H, 5.61; N, 8.99; S, 6.86%. Found: C, 61.88; H, 5.85; N, 9.14; S, 7.02%.

### 3.4.6. N-benzyl-2-(1-(diphenylphosphoryl)propan-2-ylidene)hydrazine-1-carbothioamide 4f

M.W. = 421.50 g/mol; yield = 5.05 g, 60%; white solid; m.p. 238 °C; Z-isomer: <sup>31</sup>P{<sup>1</sup>H} NMR (CDCl<sub>3</sub>): δ <sup>31</sup>P = 29.77. <sup>1</sup>H NMR (CDCl<sub>3</sub>): δ<sup>1</sup>H = 1.58 (d, <sup>4</sup>J<sub>HP</sub> = 2.32 Hz, 3H, CH<sub>3</sub>), 3.37 (d, <sup>2</sup>J<sub>HP</sub> = 14.78 Hz, 2H, CH<sub>2</sub>-P), 4.83 (d, <sup>3</sup>J<sub>HH</sub> = 5.64 Hz, CH<sub>2</sub>-Ph), 7.13–7.74 (m, H<sub>arom</sub>), 10.95 (s, 1H, -N=NH). <sup>13</sup>C{<sup>1</sup>H} NMR (CDCl<sub>3</sub>): δ<sup>13</sup>C = 25.87 (d, <sup>3</sup>J<sub>CP</sub> = 2.12 Hz, CH<sub>3</sub>), 36.54 (d, <sup>1</sup>J<sub>CP</sub> = 61.82 Hz, CH<sub>2</sub>-P), 48.55 (s, CH<sub>2</sub>-Bn), 127.56–144.88 (m, C<sub>arom</sub>), 144.94 (d, <sup>2</sup>J<sub>CP</sub> = 9.73 Hz, C=N), 179.64 (s, C=S). E-isomer: <sup>31</sup>P{<sup>1</sup>H} NMR (CDCl<sub>3</sub>): δ <sup>31</sup>P = 28.68. <sup>1</sup>H NMR (CDCl<sub>3</sub>): δ<sup>1</sup>H = 1.92 (d, <sup>4</sup>J<sub>HP</sub> = 2.08 Hz, 3H, CH<sub>3</sub>), 3.26 (d, <sup>2</sup>J<sub>HP</sub> = 13.74 Hz, 2H, CH<sub>2</sub>-P), 4.70 (d, <sup>3</sup>J<sub>HH</sub> = 5.78 Hz, CH<sub>2</sub>-Ph), 7.14 (t, <sup>3</sup>J<sub>HH</sub> = 5.40 Hz, 1H, NH-Bn), 7.13–7.74 (m, H<sub>arom</sub>), 8.73 (s, 1H, NH-Bn), 10.95 (s, 1H, -N=NH). <sup>13</sup>C{<sup>1</sup>H} NMR (CDCl<sub>3</sub>): δ<sup>13</sup>C = 17.57 (d, <sup>3</sup>J<sub>CP</sub> = 1.84 Hz, CH<sub>3</sub>), 40.86 (d, <sup>1</sup>J<sub>CP</sub> = 64.75 Hz, CH<sub>2</sub>), 48.27 (s, CH<sub>2</sub>-Bn), 127.56–144.88 (m, C<sub>arom</sub>), 144.23 (d, <sup>2</sup>J<sub>CP</sub> = 9.17 Hz, C=N), 177.92 (s, C=S). IR-ATR (cm<sup>-1</sup>): 731 ν(C-S); 1160 ν(P=O); 1385 ν(C-S); 1586 ν(C=N); 3323 ν(NH). Anal. Calc. for C<sub>23</sub>H<sub>24</sub>N<sub>3</sub>OPS: C, 65.54; H, 5.74; N, 9.97; S, 7.61%. Found: C, 65.98; H, 5.85; N, 9.74; S, 7.90%. GC-MS: *m/z* = 215 [(Ph<sub>2</sub>-P)(O)-CH<sub>2</sub>], 201 [(Ph<sub>2</sub>P=O)], 152 [H<sub>2</sub>N-C(S)-NH-Ph], 91 [H<sub>2</sub>N-C(S)-NH-NH<sub>2</sub>], 77 [C<sub>6</sub>H<sub>5</sub>], 63 [H<sub>2</sub>N-CH<sub>2</sub>-SH].

### 3.4.7. N-cyclohexyl-2-(1-(diphenylphosphoryl)propan-2-ylidene)hydrazine-1-carbothioamide 4g

M.W. = 413.52 g/mol; yield = 4.13 g, 50%; White solid; m. p. 203 °C; Z-isomer: <sup>31</sup>P{<sup>1</sup>H} NMR (DMSO-d<sub>6</sub>): δ <sup>31</sup>P = 28.85. <sup>1</sup>H NMR (DMSO-d<sub>6</sub>): δ<sup>1</sup>H = 1.53–1.81 (m, H<sub>Cy</sub>), 1.73 (d, <sup>4</sup>J<sub>HP</sub> = 2.32 Hz, 3H, CH<sub>3</sub>), 3.91 (d, <sup>2</sup>J<sub>HP</sub> = 15.53 Hz, 2H, CH<sub>2</sub>-P), 7.35–7.92 (m, H<sub>arom</sub>), 10.84 (s, 1H, N-NH). <sup>13</sup>C{<sup>1</sup>H} NMR (DMSO-d<sub>6</sub>): δ<sup>13</sup>C = 25.33–25.79 (m, CH<sub>2</sub>Cy), 53.08 (s, 1H, CH<sub>Cy</sub>), 128.98–135.11 (m, CH<sub>arom</sub>), 145.57 (d, <sup>2</sup>J<sub>CP</sub> = 8.58 Hz, C=N), 177.21 (s, C=S). E-isomer: <sup>31</sup>P{<sup>1</sup>H} NMR (DMSO-d<sub>6</sub>): δ <sup>31</sup>P = 26.67. <sup>1</sup>H NMR (DMSO-d<sub>6</sub>): δ<sup>1</sup>H = 1.06–1.29 (m, H<sub>Cy</sub>), 1.96 (d, <sup>4</sup>J<sub>HP</sub> = 1.65 Hz, 3H, CH<sub>3</sub>), 3.64 (d, <sup>2</sup>J<sub>HP</sub> = 13.43 Hz, 2H, CH<sub>2</sub>-P), 7.35–7.92 (m, H<sub>arom</sub>), 10.30 (s, 1H, N-NH). <sup>13</sup>C{<sup>1</sup>H} NMR (DMSO-d<sub>6</sub>): δ<sup>13</sup>C = 19.03 (d, <sup>3</sup>J<sub>CP</sub> = 2.79 Hz, CH<sub>3</sub>), 25.04–32.47 (m, CH<sub>2</sub>Cy), 52.24 (s, 1H, CH<sub>Cy</sub>), 128.98–135.11 (m, CH<sub>arom</sub>), 146.85 (d, <sup>2</sup>J<sub>CP</sub> = 9.12 Hz, C=N), 176.73 (s, C=S). IR-ATR (cm<sup>-1</sup>): 740 ν(C-S); 1154 ν(P=O); 1387 ν(C-S); 1561 ν(C=N); 3243–3314 ν(NH). Anal. Calc. for C<sub>24</sub>H<sub>26</sub>N<sub>3</sub>OPS: C, 63.90; H, 6.83; N, 10.16; S, 7.75%. Found: C, 64.18; H, 5.85; N, 9.81; S, 7.40%. GC-MS: *m/z* = 279 [Ph-P(O)-CH<sub>2</sub>-C(CH<sub>3</sub>)=N-NH-C(S)-NH-CH<sub>2</sub>-C], 207 [Ph-P(O)-CH<sub>2</sub>-C(CH<sub>3</sub>)=N-NH-CH], 149 [Ph-P(O)-CH-C], 113 [N-C(S)-NH-N=CH-C<sub>2</sub>], 57 [HN-NH-C-NH].

### 3.4.8. N-allyl-2-(1-(diphenylphosphoryl)propan-2-ylidene)hydrazine-1-carbothioamide 4h

M.W. = 371.44 g/mol; yield = 3.49 g, 47%; white solid; m.p. 202 °C; Z-isomer: <sup>31</sup>P{<sup>1</sup>H} NMR (DMSO-d<sub>6</sub>): δ <sup>31</sup>P = 26.88. <sup>1</sup>H NMR (DMSO-d<sub>6</sub>): δ<sup>1</sup>H = 1.75 (d, <sup>4</sup>J<sub>HP</sub> = 2.23 Hz, 3H, CH<sub>3</sub>), 3.92 (d, <sup>2</sup>J<sub>HP</sub> = 15.52 Hz, 2H, CH<sub>2</sub>-P), 4.15 (t, <sup>3</sup>J<sub>HH</sub> = 5.67 Hz, 2H, CH<sub>2</sub>-CH), 5.03–5.06 (m, 1H, CH<sub>2</sub>-CH=CH), 5.09–5.11 (m, 1H, CH<sub>2</sub>-CH=CH), 5.84–5.91 (m, 1H, CH=CH<sub>2</sub>), 7.49–7.92 (m, H<sub>arom</sub>), 8.28 (t, <sup>3</sup>J<sub>HH</sub> = 5.92 Hz, 1H, NH-allyl), 10.84 (s, 1H, N-NH). <sup>13</sup>C{<sup>1</sup>H} NMR (DMSO-d<sub>6</sub>): δ<sup>13</sup>C = 25.76 (d, <sup>3</sup>J<sub>CP</sub> = 1.63 Hz, CH<sub>3</sub>), 46.23 (s, CH<sub>2</sub>-CH), 116.10 (s, CH=CH<sub>2</sub>), 129.03–134.51 (m, C<sub>arom</sub>), 135.37 (s, CH=CH<sub>2</sub>), 147.04 (d, <sup>2</sup>J<sub>CP</sub> = 9.11 Hz, C=N), 178.68 (s, C=S). E-isomer: <sup>31</sup>P{<sup>1</sup>H} NMR (DMSO-d<sub>6</sub>): δ <sup>31</sup>P = 26.88. <sup>1</sup>H NMR (DMSO-d<sub>6</sub>): δ<sup>1</sup>H = 1.96 (d, <sup>4</sup>J<sub>HP</sub> = 1.65 Hz, 3H, CH<sub>3</sub>), 3.64 (d, <sup>2</sup>J<sub>HP</sub> = 13.68 Hz, 2H, CH<sub>2</sub>-P), 4.10 (t, <sup>3</sup>J<sub>HH</sub> = 5.61 Hz, 2H, CH<sub>2</sub>-CH), 5.07–5.09 (m, 1H, CH<sub>2</sub>-CH=CH), 5.12–5.13 (m, 1H, CH<sub>2</sub>-CH=CH), 5.75–5.83 (m, 1H, CH=CH<sub>2</sub>), 7.49–7.92 (m, H<sub>arom</sub>), 7.69 (t, <sup>3</sup>J<sub>HH</sub> = 5.94 Hz, 1H, NH-allyl), 10.30 (s, 1H, N-NH). <sup>13</sup>C{<sup>1</sup>H} NMR (DMSO-d<sub>6</sub>): δ<sup>13</sup>C = 18.99 (d, <sup>3</sup>J<sub>CP</sub> = 2.22 Hz, CH<sub>3</sub>), 34.92 (d, <sup>1</sup>J<sub>CP</sub> = 61.83 Hz, CH<sub>2</sub>-P), 45.92 (s, CH=CH<sub>2</sub>), 116.22 (s, CH=CH<sub>2</sub>), 129.03–134.51 (m, C<sub>arom</sub>), 134.98 (s, CH=CH<sub>2</sub>), 147.04 (d, <sup>2</sup>J<sub>CP</sub> = 9.07 Hz, C=N), 178.35 (s, C=S). IR-ATR (cm<sup>-1</sup>): 739 ν(C-S); 1118 ν(P=O); 1390 ν(C-S); 1643 ν(C=N); 3075–3324 ν(NH). Anal. Calc. for C<sub>19</sub>H<sub>22</sub>N<sub>3</sub>OPS: C, 61.44; H, 5.97; N, 11.31; S, 8.63%. Found: C, 61.98; H, 6.13; N, 11.54; S, 8.95%.
### 3.5. General X-ray crystal structure analysis and refinement

Data collection for 3, 4a, 4b, 4d, 4e, 4f, 4g and 4h and 5a was performed on Bruker D8 Venture four-circle diffractometers from Bruker AXS GmbH (Karlsruhe, Germany). CPAD detectors used were Photon II (MoKα and CuKα) from Bruker AXS GmbH; X-ray sources: Microfocus source IμS Mo and Cu from Incoatec GmbH with mirror optics HELIOS and a single hole collimator from Bruker AXS GmbH. Programs used for data collection were APEX5 Suite [105] (v2023.9–2) and integrated programs SAINT (V8.40A; integration) as well as SADABS (2018/7; absorption correction) from Bruker AXS GmbH [106]. The SHELX programs were used for further processing [107]. The solution of the crystal structures was done with the help of the program SHELXT [108], the structure refinement with SHELXL [109]. The processing and finalization of the crystal structure data was done with program OLEX2 v1.5 [110]. All non-hydrogen atoms were refined anisotropically. For the hydrogen atoms, the standard values of the SHELXL program were used with $U_{iso}(H) = -1.2 U_{eq}(C)$ for CH₂ and CH and with $U_{iso}(H) = -1.5 U_{eq}(C)$ for CH₃. Some H atoms were refined freely using independent values for each $U_{iso}(H)$. The crystallographic and refinement data are presented in Tables S2 and S3 (see supporting information).

Data have been deposited at the Cambridge Crystallographic Data Centre as CCDC 2323106 (4 g), CCDC 2323105 (4a), CCDC 2323108 (4h), CCDC 2323109 (4f), CCDC 2422267 (5a), CCDC 2422268 (3), CCDC 2422269 (4b), CCDC 2422270 (4d) and CCDC 2422275 (4e). The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/getstructures. The structure was solved by direct methods and refined by full-matrix least-squares on $F^2$.

### 3.6. Theoretical calculations

All calculations were carried out using the Gaussian 16 program suite of programs (version C.01) [111], the B3LYP [112,113] functionals in combination with the 6–311+G (d, p) basis set. It is noteworthy that all structures exhibited a true energy minimum on their potential energy surfaces, as evidenced by the absence of imaginary frequency values.

## 4. Conclusion

We succeeded in synthesizing the novel phosphonated thiosemicarbazones 4a-h from the β-phosphonated hydrazone 2, which in turn was prepared from the corresponding phosphonated allene 1. Furthermore, as secondary product the azine 3 and some bis(thioureas) 5 were isolated or spectroscopically observed. Several hypotheses are proposed to explain the formation of these by-products. Hydrazone 2, as well as TSCs 4a-h, were shown to exist, in solution, as Z/E stereoisomeric mixtures due to inversion processes occurring at the hydrazonic C=N bond. Variable-temperature ³¹P NMR analysis of 4g and 4h revealed an equilibrium between Z and E isomers. These NMR studies at elevated temperature also revealed that the N-aryl TSCs undergo progressively decomposition above 110 °C, whereas the N-aliphatic derivatives are thermally more stable in solution. In addition, theoretical IRC calculations for compound 4a indicated that the E isomer is more stable than the Z isomer due to steric repulsion between the methyl and phenyl groups. Therefore, the predominant signals in the NMR spectra were attributed to the E isomer. This result was confirmed by the SC-XRD analysis revealing that in the solid state the E configuration is stabilized by intra- and intermolecular hydrogen bonding. These hydrogen-bonding is dominated by strong N-H···O=P interactions giving rise to supramolecular dimeric macrocycles or 1D ribbons. The only exception is the N-2,5-dimethoxyphenyl derivative 4e which adopts a Z configuration due to an intramolecular C-O···H-N bonding between a methoxy group and the NH group of thiourea moiety and a second one forming a seven-membered N-H···O=P cycle. More in-depth studies on the biological activity, such as the antioxidant and anticancer activities of our

phosphonated TSCs accompanied by molecular docking studies will be the topic of a forthcoming manuscript. Furthermore, the ability of these phosphonated TSCs as act as ligands towards both *d*-block and *p*-block metals is currently under investigation.

### CRediT authorship contribution statement

**Sirine Salhi:** Writing – original draft, Investigation, Formal analysis.
**Dorra Kanzari-Mnallah:** Writing – original draft, Software, Project administration, Investigation, Formal analysis.
**Isabelle Jourdain:** Methodology, Formal analysis, Conceptualization.
**Michael Knorr:** Writing – review & editing, Writing – original draft, Validation, Project administration, Conceptualization.
**Jan-Lukas Kirchhoff:** Visualization, Investigation, Data curation.
**Carsten Strohmann:** Resources, Data curation.
**Youssef Arfaoui:** Visualization, Software, Data curation.
**Mohamed Lotfi Efrit:** Resources, Funding acquisition.
**Hedi M'rabet:** Supervision.
**Azaiez Ben Akacha:** Supervision.

### Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

### Acknowledgements

This work was supported financially by the general directorate of scientific research, Tunisian ministry of scientific research. This work has been achieved in the frame of the EIPHI Graduate School (contract "ANR-17-EURE-0002"). We thank Abderrahim Khatyr for recording and interpreting the UV–vis spectra and Stephanie Beffy from the Plateforme Chimie UTINAM for the recording of the NMR spectra and S. Adache from SynBioN (Université de Lorraine-CNRS–http://synbion.univlorraine.fr/accueil/) for the elemental analyses.

### Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.molstruc.2025.144576.

### Data availability

Data will be made available on request.

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