Next Article in Journal
Fine-Tuning of the Optical and Electrochemical Properties of Ruthenium(II) Complexes with 2-Arylbenzimidazoles and 4,4′-Dimethoxycarbonyl-2,2′-bipyridine
Previous Article in Journal
CCSD(T) Rotational Constants for Highly Challenging C5H2 Isomers—A Comparison between Theory and Experiment
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 28
Issue 18
10.3390/molecules28186540
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Polydentate N,O-Ligands Possessing Unsymmetrical Urea Fragments Attached to a p-Cresol Scaffold

by
Stanislava E. Todorova
1,
Rusi I. Rusew
2,
Boris L. Shivachev
2,* and
Vanya B. Kurteva
1,*
1
Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 9, 1113 Sofia, Bulgaria
2
Institute of Mineralogy and Crystallography “Acad. Ivan Kostov”, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 107, 1113 Sofia, Bulgaria
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(18), 6540; https://doi.org/10.3390/molecules28186540
Submission received: 14 August 2023 / Revised: 5 September 2023 / Accepted: 7 September 2023 / Published: 9 September 2023
(This article belongs to the Section Organic Chemistry)
Browse Figures
Versions Notes

Abstract

:
In this study, three series of polydentate N,O-ligands possessing unsymmetrical urea fragments attached to a p-cresol scaffold are obtained, namely mono- and bi-substituted open-chain aromatics, synthesised using a common experiment, as well as fused aryloxazinones. Separate protocols for the preparation of each series are developed. It is found that in the case of open-chain compounds, the reaction output is strongly dependent on both bis-amine and carbamoyl chloride substituents, while oxazinones can be effectively obtained via a common protocol. The products are characterized via 1D and 2D NMR spectra in solution and using single-crystal XRD. A preliminary study on the coordination abilities of the products performed via ITC shows that there are no substantial interactions in the pH range of 5.0–8.5 in general.

1. Introduction

Solvent extraction is among the most powerful techniques applied in separation science and technology [1,2,3,4,5,6,7,8] at both the laboratory and industrial scale. In particular, synergistic extraction is an active field of research and development in modern coordination chemistry, having a great impact on metal separation and treatment and the recycling of industrial wastes [9,10,11,12,13,14,15]. The proper selection of a combination of extractants and synergists results in a multiple increase in the extraction efficiency and the better separation of metals. Therefore, the discovery of new extraction systems is a topical and rapidly evolving trend in modern chemistry.
Polydentate molecules are of growing interest as they are widely applied as scaffolds in the combinatorial synthesis of artificial receptors for ions with medical and environmental potential [16,17,18,19]. Among the broad variety of synthetic compounds, polyoxaaza ligands have received special attention due to their outstanding coordination abilities [20,21,22,23,24,25,26,27,28,29,30,31,32]. Compounds with urea moieties in particular have shown a wide range of applications in various fields such as polymers, agrochemicals and pharmaceuticals, as well as good biological activity profiles [33,34,35,36,37,38,39,40]. However, the direct synthesis of asymmetric urea possesses a serious drawback, namely the formation of unwanted symmetric urea. Therefore, synthesis efforts nowadays are directed towards developing efficient indirect protocols.
Recently, we reported on the efficiency of two novel polydentate ligands, shown in Figure 1, as synergists in the isolation and separation of metal ions [41]. These ligands possess unsymmetrical urea fragments attached to a p-cresol scaffold and can be generally divided into open-chain substituted aromatics (S1) and fused aryloxazinones (S2). The concept was to design polydentate ligands with variable coordination abilities, controlled according to differences in the substitution pattern and geometry of the molecules [42]. The compounds were obtained in a common experiment and were isolated from the complex mixture with a low overall yield [43].
Herein, we report on the optimization of separate synthetic protocols for each ligand series, solution and solid-state characterization, and report a preliminary study on the coordination properties of the products.

2. Results and Discussion

Our efforts were initially directed towards open-chained ligands due to the observed diverse extraction efficiency of S1 towards various metal ions [41]. Starting bis-amines were obtained by grinding commercially available 2-hydroxy-5-methyl-1,3-benzenedicarboxaldehyde and primary amine in solventless conditions, followed by sodium borohydride reduction. As reported [43], the compounds S1 and S2 were isolated from a very complex mixture obtained via the direct reaction of the corresponding p-cresol-based secondary bis-amine (1b), phosgene as toluene solution and aniline in the presence of pyridine as a base. In an attempt to override the formation of oxazinone-ring-containing compounds, the reaction among bis-amine 1, phosgene and primary amine was performed as a two-step protocol; the initial formation of carbamic chloride and the subsequent reaction with bis-amine (Scheme 1).
Three types of N-substituents were chosen, namely phenyl, benzyl and phenethyl, i.e., aryl, benzyl and alkyl, in order to tune the nitrogen basicity and steric flexibility. The conditions were varied and it was found that the optimal conditions for the predominant formation of product 2 or 3 are different for each example, and that the reaction out-put is strongly dependent on the base, reagents’ proportions and solvent; meanwhile, prolongation and dilution have no significant impact. Selected results are summarized in Table 1.
The transformation performed between aniline-derived bis-amine (1a) and phenylcarbamic chloride in the presence of pyridine as a base led to the formation of two main products, isolated in a moderate overall yield (up to 57%); mono- and bis-acylated ligands 2aa and 3aa (Scheme 1, Table 1), i.e., only N-acylated products. On the contrary, the oxygen was also attacked when using N,N-diisopropylethylamine (DIPEA), leading to the formation of compounds 4 (Figure 2 and Figure S1) and 5 (Figure 3), together with 2aa in a 51% overall yield (entry 1). For this reason, all further experiments were performed in the presence of pyridine as a base.
As seen in Table 1, increasing the carbamic chloride portion leads to an increase in the percentage of product 3 in general, while the solvent effect is dependent on the N-substituents. The best conversion is achieved in toluene, except in ligands 2ac/3ac, where the overall yield is higher in dichloroethane (entries 9 vs. 10), 2ba/3ba (entries 12 vs. 13) and 2cc/3cc (entries 26 vs. 28), and where the results in toluene and benzene are commensurable. However, the best conditions for the preparation of a particular ligand, 2 or 3, are more sensitive to the solvent used. All carbamic chlorides operate the most effectively in toluene, except for a few examples. Phenylcarbamic chloride is the most effective in benzene only for the ligand 2ba (entry 12). Similar conversions with benzylcarbamic chloride are achieved for 2cb in toluene and dichloroethane (entries 22 vs. 25). When using phenylethylcarbamic chloride, benzene is the right solvent for 2bc (entry 16) and 2cc (entry 26), dichloroethane is the right solvent for 3ac (entry 10), while the yields of 3cc are identical in toluene and dichloroethane (entries 28 vs. 29). The best results for all bis-amines are also obtained in toluene, with few exceptions. Starting from 1a, dichloroethane is the preferable solvent only for ligand 3ac (entry 10). The best yields from 1b are obtained in benzene for ligands 2ba (entry 12) and 2bc (entry 16). When starting from 1c, benzene is the right solvent for 2cc (entry 26), whereas the results in toluene and dichloroethane are comparable for ligands 2cb (entries 22 vs. 25) and 3cc (entries 28 vs. 29).
The structures of the products are assigned using 1D and 2D NMR spectra and confirmed via single-crystal XRD of selected samples. The NMR spectra show characteristics for each series pattern (Table 2). Separate signals are observed for each group in compounds 2, while all groups of both p-cresol scaffold and substituents show common signals in symmetrical molecules 3, the effect being the most discernible for CH protons of p-cresol scaffold (CH-3 and CH-5) and methylene groups, which are in an area free of other signals. The latter is demonstrated in the example of the 1b-derived ligands 2ba and 3ba, as shown in Figure 4.
At the same time, the chemical shifts in some signals are strongly dependent on the substitution pattern (Table 2). The proton resonances for CH-3 and CH-5 of the p-cresol scaffold are shifted upfield and downfield, respectively, in mono-substituted ligands obtained from 1a (R1 = Ph, 2aa, 2ab, 2ac); meanwhile, in bi-substituted analogues, the signals are in between. For the rest of the ligands (R1 = Bn, phenethyl), the chemical shifts in the two signals in the spectra of ligand 2 and the signal in the spectra of 3 possess very close values. The signals for both bridged methylene groups (CH2-Cq-2 and CH2-Cq-6) are shifted upfield in the spectra of all ligands of 2 with respect to the corresponding signal in 3. The carbon resonances for CH-3 and CH-5 are slightly shifted downfield in 3 with respect to 2 in all couples, except in ligands 2ab/3ab and 2ac/3ac, in which the signal of compound 3 is in between those of the corresponding ligand 2; meanwhile, that for the methylene group of 3 is in between both signals in the spectra of 2 in all examples.
Several phases appropriate for single-crystal XRD were grown and analysed. The ORTEP views are shown in Figure 5. A comparison between the two types of ligand shows that the fragments bearing unsymmetrical urea moiety possess conserved molecular geometry, while the remaining part(s) of the molecules seems to be more flexible and lead to variations in the molecular geometry and distance between the coordination centres. The latter is illustrated in the example of ligands 2ba and 3ba in Figure 5f.
Compound 2ab crystallizes in the monoclinic Cc space group with two molecules in the ASU. The overlay of the two molecules provides an RMSD of 1.0635 Å (Figure S2a), and shows that the molecular geometry differs due to the flexibility of the side chains and the observed rotation of the terminal benzyl moieties around the N–C bond, e.g., rotamers or conformational isomerism is plausible. For both molecules, an intramolecular O–H…O hydrogen bond stabilizes the molecular geometry. A classical N–H…O interaction between adjacent molecules produces C22(8) chains, propagating along the c axis. Although several weak interactions, namely C–H…O, N–H…π (Table S6, Figure 6a,b), are detected, the three-dimensional packing molecules of the molecules of 2ab produce pseudo-layers stacked along a (Figure S2b).
Compound 2ac crystallizes in the orthorhombic Pca21 space group with one molecule in the ASU. The hydrogen bonding interactions are similar to those observed in compound 2ab: one intramolecular O5-H5…O9 and intermolecular N2-H2…O9 (Figure 6c and Table S7). The intermolecular hydrogen bond again produces a chain motif C11(4) propagating along a. Again, the presence of an aromatic ring in the molecule of 2ac is responsible for several weak interactions (Figure 6). The combination of hydrogen bonds and a weak interaction produces pseudo-layers stacked along c (Figure S3). The hydrogen bonding patter in 2ba, 2bc and 3ba is analogous to 2ab and 2ac. The basic difference is the presence of two intramolecular hydrogen bonds instead of one. The intermolecular interaction again produces chains with graphsets C11(10) for 2ba, 2bc and C11(12) 3ba (Figure 7 and Tables S8–S10). The three-dimensional arrangement of the molecules again produces pseudo-layers, as shown in Figure S4.
A two-step sequence was chosen for the preparation of fused aryloxazinone ligands with an unsymmetrical urea fragment (7). Bis-amines 1 were submitted to a reaction with phosgene solution (Scheme 2). The proportions, base, and reaction duration were varied and it was found that two equivalents of phosgene, pyridine as a base, and a 2 h reaction time at room temperature are the optimal conditions. The intermediate products 6 were easily isolated via chromatography in 40–50% yields. Further prolongation did not result in better conversion, while the use of equimolar amounts of the reagents significantly decreased the yields.
It has to be noted that a side-product was isolated in a low yield (2%) from the reaction of 1a in parallel with chloride 6a, whose structure was determined to be, via NMR and XRD, amino oxazinone 8a (Figure 8), the precursor of 6a. Based on this observation, it can be suggested that phenol oxygen is initially attacked by phosgene, followed by cyclization and N-acylation.
The second step was performed in different proportions and with different bases, solvents, temperatures, and reaction durations. Finally, the conditions were optimized and the products were isolated via chromatography in a 87% yield after 19 h of stirring at 50 °C in dichloroethane with 2.5 equivalents of primary amine, in the absence of another base. The results are summarized in Table 3.
The structures of the products were assigned using 1D and 2D NMR spectra. The chemical shifts in the bridge methylene (CH2-Cq-2 and CH2-Cq-6) and skeleton methyne (CH-3 and CH-5) groups are dependent on the substitution pattern within the series, the effect being more significant on methylene group resonances (Table 4). The influence of the chloride 6 substituent (R1) is inessential in general, while that of primary amine (R2) causes substantial shifts in particular signals. The latter is illustrated for the ligands obtained with 6a–c and aniline in Figure 9.
The structures of the products were confirmed via the single-crystal XRD of selected samples, as shown in Figure 10. The overlay of the molecules present in the ASU of the crystal structures revealed that the geometry of the benzoxazinone unit is highly conserved (Figure 11). In 6a, only an acceptor (C=O) is available and the molecular geometry minimizes its surficial area/interactions by closing on itself in order to promote halogen bonding and π…π/CH3 interactions (Figure 12). In 7aa, 7ab, and 7bb, a donor and acceptor are present and the crystal structure stabilization is “dominated” by a hydrogen-bonding NH…O interaction. In 7aa and 7ab, neighbouring molecules produce a zig-zag chain with a C11(10) graphset (Figure 13a,b, Tables S11 and S12), while in 7bb, the formation of a dimmer is preferred (R22(20), Figure 13c, Table S13).
A comparison between the geometry of the three types of ligands, namely 2, 3 and 7, shows that the open-chain substituted compounds are oriented towards the optimal intramolecular H-bonding of the urea’s heteroatoms, while the preferred geometry of oxazinones is driven by intermolecular bonding, as illustrated in Figure 14. At the same time, two types of H-bonding are observed in the open-chain compounds. In some products, like 2ab and 2ac, H-bonding involves hydroxyl proton and carbonyl oxygen (Figure 14b), while hydroxyl proton and nitrogen are bonded in others (Figure 14c).
Finally, a preliminary study on the coordination abilities of the products was performed by using isothermal titration calorimetry (ITC). This test is a sensitive and effective method that can provide information about complexation reactions and hence the strength of metal–ligand coordination. In this work, ITC is employed to detect the interactions of calcium (II), lead (II) and potassium (I) ions with the synthesized polydentate N,O-ligands (Table S6) at an approximately neutral pH range (5.0–8.5). The latter is chosen in an attempt to keep the conditions as green as possible. Typical representations of the ITC data showing interaction and a lack of interaction are shown in Figure 15a,b, respectively.
The remaining data are given in Table S14 (Supplementary Material). The fitted association constants of the interaction of compounds 2ba, 2bc, 2cb, 3bb, and 3cc with metals are provided in Table 5 and illustrated in Figures S5–S10.
The ITC data reveal that most of the compounds do not interact with the particular metal ions tested. Only a few unveil interactions with a sensible Ka strength, mostly in slightly acidic conditions. The latter shows that the ligands likely need more acidic or more basic media to bind metal ions. This suggestion outlines a possible direction for further study regarding the interaction of compounds in a more broad pH range with an enlarged panel of metal ions.

3. Materials and Methods

3.1. General

All reagents were purchased from Aldrich, Merck and Fluka, and were used without any further purification. The deuterated solvents were purchased from Deutero GmbH. Fluka silica gel (TLC-cards 60778 with fluorescent indicator 254 nm) was used for TLC chromatography and Rf-value determination. Merck Silica gel 60 (0.040–0.063 mm) was used for the flash chromatography purification of the products. The melting points were determined in capillary tubes using the SRS MPA100 OptiMelt (Sunnyvale, CA, USA) automated melting point system with a heating rate of 1 °C per min. The NMR spectra were recorded on the Bruker Avance II+ 600 spectrometer (Rheinstetten, Germany) in CDCl3; the chemical shifts were quoted in ppm in δ-values against tetramethylsilane (TMS) as an internal standard, and the coupling constants were calculated in Hz. The assignment of the signals was confirmed by applying two-dimensional COSY, NOESY, HSQC and HMBC techniques. The spectra were processed using the Topspin 2.1 program. The turbo spray mass spectra of compounds 2aa, 3ba, 6a, 4, 7aa, 7ab, and 7bb were obtained using API 150EX (AB/MAS Sciex), and the ESI spectra of compounds 3aa, 2ab, 3ab, 2ac, 3ac, 2bb, 3bb, 2bc, 3bc, 2ca, 3ca, 2cb, 3cb, 2cc, 3cc, 5, 6c, 7ac, 7bc, 7ca, 7cb, and 7cc were obtained using the Single Quadrupole Liquid Chromatograph Mass Spectrometer Shimadzu LCMS-2020. The spectra were processed using Xcalibur Free Style program version 4.5 (Thermo Fisher Scientific Inc., Waltham, MA, USA).
The characterization of compounds 2ba and 7ba is given in ref. [43]. Compound 6b was an object of individual further study and its characterization will be published in due course.

3.2. General Procedure for the Preparation of Bis-Amines 1

Step 1: A mixture of 2,6-diformyl-4-methylphenol (657 mg; 4 mmol) and its corresponding amine (8.1 mmol) was ground in a mortar. In the case of solid bis-imines, the solid phase formed was triturated with hexane.
  • 2,6-bis((phenylimino)methyl)-4-methylphenol: 92% yield; reddish solid; m. p. 118.1–118.3 °C (lit. 99–100 °C [44], red crystals 134–135.5 °C and yellow crystals 117–119 °C [45]).
  • 2,6-bis((benzylimino)methyl)-4-methylphenol: 99% yield; orange solid; m. p. 69.6–69.7 °C (lit. 68–72°C [46]).
  • 2,6-bis((phenylethylimino)methyl)-4-methylphenol: 68% yield; orange oil; 1H NMR 2.28 (s, 3H, CH3), 3.01 (t, 4H, J 7.4, CH2-Ph), 3.85 (t, 4H, J 7.4, CH2-N), 7.19–7.24 (m, 6H, CH-2+6 and CH-4 Ph), 7.29 (t, 4H, J 7.5, CH-3+5 Ph), 7.45 (bs, 2H, CH-3 and CH-5), 8.438 (bs, 2H, CH=N), 13.92 (bs, 1H, OH).
Step 2: To a solution of 2,6-bis-iminomethyl-4-methylphenol (4 mmol) in CH3OH (10–15 mL), NaBH4 (341 mg; 9 mmol) was added portion-wise and the mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the products were partitioned between CH2Cl2 and water. The organic phase was washed with water, dried over Na2SO4 and evaporated to dryness to obtain pure oily products, which were subjected to a further reaction without purification, except 1c, which was purified via flash chromatography on silica gel.
  • 1a: 99% yield; reddish oil; 1H NMR 2.32 (s, 3H, CH3), 4.39 (s, 4H, CH2), 6.82 (dd, 4H, J 7.6, 1.1, CH-2+H-6 Ph), 6.88 (tt, 2H, J 7.3, 1.1, CH-4 Ph), 7.03 (s, 2H, CH-3 and CH-5), 7.27 (td, 4H, J 7.4, 1.1, CH-3+5 Ph); 13C NMR 20.6 (CH3), 46.4 (CH2), 114.7 (CH-2+6 Ph), 119.3 (CH-4 Ph), 124.4 (Cq-2 and Cq-6), 128.8 (CH-3 and CH-5), 128.9 (Cq-4), 129.3 (CH-3+5 Ph), 147.9 (Cq-1 Ph), 152.8 (Cq-1).
  • 1b: 98% yield; yellowish oil; NMR identical with the literature data [47].
  • 1c: 88% yield; colourless oil; 1H NMR 2.20 (s, 3H, CH3), 2.86 (t, 4H, J 6.9, CH2-Ph), 2.92 (td, 4H, J 6.9, 1.3, CH2-N), 3.87 (s, 4H, CH2-bridge), 4.89 (bs, 2H, NH), 6.80 (s, 2H, CH-3 and CH-5), 7.19-7.22 (m, 6H, CH-2+6 and CH-4 Ph), 7.29 (td, 4H, J 7.4, 1.7, CH-3+5 Ph); 13C NMR 20.40 (CH3), 35.8 (CH2-Ph), 49.9 (CH2-N), 50.6 (CH2-bridge), 123.5 (Cq-2 and Cq-6), 126.3 (CH-4 Ph), 127.7 (Cq-4), 128.6 (CH-2+6 Ph), 128.7 (CH-3+5 Ph), 128.8 (CH-3 and CH-5), 139.4 (Cq-1 Ph), 154.1 (Cq-1).

3.3. General Procedure for the Preparation of Ligands 2 and 3

Step 1: To a commercial 15% solution of phosgene in toluene (2 mmol), an amine (1 mmol) was added in an argon atmosphere and the mixture was stirred at room temperature for 40 min. The mixture was bubbled with argon to eliminate the excess phosgene and the crude carbamic chloride (CC) was further used without purification.
Step 2: To a solution of bis-amine (1) and pyridine in toluene, carbamic chloride was added portion-wise in an argon atmosphere and the mixture was stirred at room temperature for 24 h. The products were partitioned between toluene and brine. The organic layer was washed with 10 % aq. HCl and then with brine, dried over MgSO4, and evaporated to dryness. The product was purified via flash chromatography on silica gel by using a mobile phase with a gradient of polarity from DCM to 2% MeOH/DCM. The reagents’ proportions and the corresponding yields are summarized in Table 1. Molecules 28 06540 i001
Structure and numeration scheme of ligands 2; ligands 3 are symmetrical.
  • Ligand 2aa: Rf 0.65 (0.5% MeOH/DCM); colourless solid; m. p. 111.6–112.8 °C; 1H NMR 2.09 (s, 3H, CH3), 4.36 (s, 2H, CH2-Cq-6), 4.77 (s, 2H, CH2-Cq-2), 6.13 (s, 1H, NH-CO), 6.37 (d, 1H, J 2.0, CH-3), 6.70 (tt, 1H, J 7.3, 0.9, CH-4 Ph-N(6) of R1), 6.72 (dd, 2H, J 8.6, 0.9, CH-2+6 Ph-N(6) of R1), 7.03 (m, 1H, CH-4 Ph of R2), 7.04 (d, 1H, J 2.1, CH-5), 7.16 (ddt, 2H, J 8.5, 7.3, 1.9, CH-3+5 Ph-N(6) of R1), 7.19 (dd, 2H, J 8.5, 1.5, CH-2+6 Ph-N(2) of R1), 7.25 (m, 4H, CH-2+6 and CH-3+5 Ph of R2), 7.46 (tt, 1H, J 7.1, 1.3, CH-4 Ph-N(2) of R1), 7.48 (ddt, 2H, J 8.6, 7.0, 1.3, CH-3+5 Ph-N(2) of R1), 9.94 (bs, 1H, OH); 13C NMR 20.36 (CH3), 44.5 (CH2-Cq-6), 50.5 (CH2-Cq-2), 113.6 (CH-2+6 Ph-N(6) of R1), 117.6 (CH-4 Ph-N(6) of R1), 119.8 (CH-2+6 Ph of R2), 122.6 (Cq-2), 123.7 (CH-4 Ph of R2), 126.8 (Cq-6), 127.9 (Cq-4), 128.9 (CH-3+5 Ph of R2), 129.0 (CH-4 Ph-N(2) of R1), 129.1 (CH-2+6 Ph-N(2) of R1), 129.2 (CH-3+5 Ph-N(6) of R1), 130.1 (CH-5), 130.5 (CH-3+5 Ph-N(2) of R1), 130.9 (CH-3), 137.8 (Cq-1 Ph of R2), 140.2 (Cq-1 Ph-N(2) of R1), 148.3 (Cq-1 Ph-N(6) of R1), 152.0 (Cq-1), 156.1 (C=O); ESI MS m/z 226 [M-NPhCONHPh]+ (100), 371 [M − Cl]+ (36), 407 [M+1]+ (58), 429 [M + Na]+ (18).
  • Ligand 3aa: Rf 0.35 (0.5% MeOH/DCM); pale brown solid; m. p. 91.1–91.3 °C; 1H NMR 2.07 (s, 3H, CH3), 4.88 (s, 4H, CH2-Cq-2 and CH2-Cq-6), 6.59 (s, 2H, NH-CO), 6.677 (s, 2H, CH-3 and CH-5), 7.00 (tt, 2H, J 7.4, 1.0, CH-4 Ph of R2), 7.22 (m, 8H, CH-2+6 Ph of R1 and CH-3+5 Ph of R2), 7.31 (dd, 4H, J 8.6, 1.0, CH-2+6 Ph of R2), 7.33 (tt, 2H, J 7.4, 1.1, CH-4 Ph of R1), 7.42 (t, 4H, J 7.6, CH-3+5 Ph of R1), 10.06 (bs, 1H, OH); 13C NMR ; 20.4 (CH3), 49.4 (CH2-Cq-2 and CH2-Cq-6), 119.6 (CH-2+6 Ph of R2), 123.2 (CH-4 Ph of R2), 124.0 (Cq-2 and Cq-6), 128.16 (Cq-4), 128.24 (CH-4 Ph of R1), 128.6 (CH-2+6 Ph of R1), 128.8 (CH-3+5 Ph of R2), 130.1 (CH-3+5 Ph of R1), 131.0 (CH-3 and CH-5), 138.5 (Cq-1 Ph of R2), 141.1 (Cq-1 Ph of R1), 151.2 (Cq-1), 155.5 (C=O); ESI MS m/z 557 [M + 1]+ (16), 579 [M + Na]+ (54), 595 [M + K]+ (7), 1135 [2M + Na]+ (100).
  • Ligand 2ab: Rf 0.70 (1% MeOH/DCM); colourless solid; m. p. 137.2–137.3 °C; 1H NMR 2.09 (s, 3H, CH3), 4.37 (s, 2H, CH2-Cq-6), 4.40 (d, 2H, J 5.8, CH2 of R2), 4.58 (t, 1H, J 5.8, NH-CO), 4.72 (s, 2H, CH2-Cq-2), 6.34 (d, 1H, J 2.0, CH-3), 6.69 (tt, 1H, J 7.3, 1.0, CH-4 Ph-N(6) of R1), 6.72 (dd, 2H, J 8.4, 0.7, CH-2+6 Ph-N(6) of R1), 7.04 (d, 1H, J 1.8, CH-5), 7.11 (dd, 2H, J 8.6, 1.4, CH-2+6 Ph-N(2) of R1), 7.17 (m, 4H, CH-3+5 Ph-N(6) of R1 and CH-2+6 Ph of R2), 7.23 (tt, 1H, J 7.4, 1.9, CH-4 Ph of R2), 7.29 (td, 2H, J 7.6, 1.6, CH-3+5 Ph of R2), 7.36 (tt, 1H, J 7.3, 1.2, CH-4 Ph-N(2) of R1), 7.41 (ddt, 2H, J 8.5, 7.1, 1.1, CH-3+5 Ph-N(2) of R1), 10.24 (bs, 1H, OH); 13C NMR 20.38 (CH3), 44.4 (CH2-Cq-6), 44.9 (CH2 of R2), 50.8 (CH2-Cq-2), 113.5 (CH-2+6 Ph-N(6) of R1), 117.4 (CH-4 Ph-N(6) of R1), 123.0 (Cq-2), 126.9 (Cq-6), 127.3 (CH-2+6 Ph of R2), 127.4 (CH-4 Ph of R2), 127.7 (Cq-4), 128.63 (CH-4 Ph-N(2) of R1), 128.65 (CH-3+5 Ph of R2), 128.9 (CH-2+6 Ph-N(2) of R1), 129.1 (CH-3+5 Ph-N(6) of R1), 130.1 (CH-5), 130.4 (CH-3+5 Ph-N(2) of R1), 130.9 (CH-3), 138.8 (Cq-1 Ph of R2), 140.6 (Cq-1 Ph-N(2) of R1), 148.6 (Cq-1 Ph-N(6) of R1), 152.2 (Cq-1), 158.7 (C=O); ESI MS m/z 359 [M-PhCH2 + 1]+ (100), 452 [M + 1]+ (47), 474 [M + Na]+ (16), 490 [M + K]+ (2), 926 [2M + Na]+ (20).
  • Ligand 3ab: Rf 0.27 (1% MeOH/DCM); colourless solid; m. p. 142.7–142.9 °C; 1H NMR 2.09 (s, 3H, CH3), 4.40 (d, 4H, J 5.8, CH2 of R2), 4.49 (t, 2H, J 5.8, NH-CO), 4.83 (s, 4H, CH2-Cq-2 and CH2-Cq-6), 6.68 (s, 2H, CH-3 and CH-5), 7.16 (dd, 4H, J 8.1, 1.4, CH-2+6 Ph of R1), 7.17 (m, 6H, CH-2+6 and CH-4 Ph of R2), 7.28 (m, 6H, CH-4 Ph of R1 and CH-3+5 Ph of R2), 7.35 (ddt, 4H, J 7.9, 7.4, 1.7, CH-3+5 Ph of R1), 10.02 (bs, 1H, OH); 13C NMR 20.5 (CH3), 44.4 (CH2-Cq-6), 44.8 (CH2 of R2), 49.6 (CH2-Cq-2 and CH2-Cq-6), 124.4 (Cq-2 and Cq-6), 127.2 (CH-4 Ph of R2), 127.3 (CH-2+6 Ph of R2), 127.67 (Cq-6), 127.69 (Cq-4), 128.5 (CH-2+6 Ph of R1), 128.6 (CH-3+5 Ph of R2), 129.9 (CH-3+5 Ph of R1), 130.2 (CH-3 and CH-5), 139.3 (Cq-1 Ph of R2), 141.6 (Cq-1 Ph of R1), 151.5 (Cq-1), 158.0 (C=O); ESI MS m/z 585 [M + 1]+ (43), 607 [M + Na]+ (89), 623 [M + K]+ (15), 1191 [2M + Na]+ (100).
  • Ligand 2ac: Rf 0.55 (1% MeOH/DCM); colourless solid; m. p. 134.5–134.6 °C; 1H NMR 2.08 (s, 3H, CH3), 2.73 (t, 2H, J 6.8, CH2-Ph of R2), 3.42 (td, 2H, J 6.8, 5.9, CH2-N of R2), 4.22 (t, 1H, J 5.7, NH-CO), 4.37 (s, 2H, CH2-Cq-6), 4.67 (s, 2H, CH2-Cq-2), 6.33 (d, 1H, J 2.0, CH-3), 6.69 (tt, 1H, J 7.3, 1.0, CH-4 Ph-N(6) of R1), 6.72 (dd, 2H, J 8.6, 1.0, CH-2+6 Ph-N(6) of R1), 6.96 (m, 2H, CH-2+6 Ph-N(2) of R1), 7.02 (dd, 2H, J 8.4, 1.2, CH-2+6 Ph of R2), 7.04 (d, 1H, J 1.8, CH-5), 7.15-7.20 (m, 5H, CH-3+5 Ph-N(6) of R1 and CH-3+5 and CH-4 Ph of R2), 7.34 (m, 3H, CH-3+5 and CH-4 Ph-N(2) of R1), 10.28 (bs, 1H, OH); 13C NMR 20.3 (CH3), 36.0 (CH2-Ph of R2), 42.1 (CH2-N of R2), 44.4 (CH2-Cq-6), 50.5 (CH2-Cq-2), 113.4 (CH-2+6 Ph-N(6) of R1), 117.3 (CH-4 Ph-N(6) of R1), 123.0 (Cq-2), 126.4 (CH-4 Ph of R2), 126.9 (Cq-6), 127.6 (Cq-4), 128.4 (CH-4 Ph-N(2) of R1), 128.5 (CH-2+6 Ph of R2), 128.7 (CH-2+6 Ph-N(2) of R1), 128.8 (CH-3+5 Ph of R2), 129.1 (CH-3+5 Ph-N(6) of R1), 130.0 (CH-5), 130.1 (CH-3+5 Ph-N(2) of R1), 130.8 (CH-3), 138.7 (Cq-1 Ph of R2), 140.5 (Cq-1 Ph-N(2) of R1), 148.6 (Cq-1 Ph-N(6) of R1), 152.1 (Cq-1), 158.6 (C=O); ESI MS m/z 373 [M-PhCH2 + 1]+ (100), 466 [M + 1]+ (55), 489 [M + Na]+ (5), 504 [M + K]+ (1), 954 [2M + Na]+ (15).
  • Ligand 3ac: Rf 0.21 (1% MeOH/DCM); colourless solid; m. p. 132.8–132.9 °C; 1H NMR 2.09 (s, 3H, CH3), 2.74 (t, 4H, J 6.9, CH2-Ph of R2), 3.42 (td, 4H, J 6.9, 6.0, CH2-N of R2), 4.42 (t, 2H, J 5.7, NH-CO), 4.37 (s, 4H, CH2-Cq-2 and CH2-Cq-6), 6.65 (d, 2H, J 2.0, CH-3 and CH-5), 7.02 (dd, 4H, J 8.8, 1.4, CH-2+6 Ph of R1), 7.06 (dd, 4H, J 8.5, 1.4, CH-2+6 Ph of R2), 7.16 (tt, 2H, J 7.3, 1.2, CH-4 Ph of R2), 7.20 (ddt 4H, J 8.3, 7.0, 1.2, CH-3+5 Ph of R2), 7.25 (tt, 2H, J 7.3, 1.3, CH-4 Ph of R1), 7.29 (ddt, 4H, J 8.4, 7.1, 1.3, CH-3+5 Ph of R1), 10.02 (bs, 1H, OH); 13C NMR 20.5 (CH3), 36.1 (CH2-Ph of R2), 42.1 (CH2-N of R2), 49.3 (CH2-Cq-2 and CH2-Cq-6), 124.4 (Cq-2 and Cq-6), 126.2 (CH-4 Ph of R2), 127.5 (Cq-4), 127.6 (CH-4 Ph of R1), 128.46 (CH-3+5 Ph of R2), 128.48 (CH-2+6 Ph of R1), 128.7 (CH-2+6 Ph of R2), 129.7 (CH-3+5 Ph of R1), 130.1 (CH-3 and CH-5), 139.1 (Cq-1 Ph of R2), 141.5 (Cq-1 Ph of R1), 151.4 (Cq-1), 157.9 (C=O); ESI MS m/z 613 [M + 1]+ (34), 635 [M + Na]+ (100), 652 [M + K]+ (10).
  • Ligand 3ba: Rf 0.47 (1% MeOH/DCM); colourless solid; m. p. 181.5–181.6 °C; 1H NMR 2.24 (s, 3H, CH3), 4.50 (bs, 4H, CH2-Cq-2 and CH2-Cq-6), 4.62 (s, 4H, CH2 of R1), 6.90 (s, 2H, CH-3 and CH-5), 6.99 (bt, 2H, J 7.3, CH-4 Ph of R2), 7.19 (bt 4H, J 7.9, CH-3+5 Ph of R2), 7.30-7.37 (bm, 10H, CH Ph), 7.41 (bt 4H, J 7.7, CH-3+5 Ph of R1), 11.23 (bs, 1H, OH); 13C NMR 20.4 (CH3), 49.7 (CH2-Cq-2 and CH2-Cq-6), 49.8 (CH2- of R1), 119.9 (CH-2+6 Ph of R2), 123.1 (Cq-2 and Cq-6), 123.7 (CH-4 Ph of R2), 127.2 (CH-4 Ph of R1), 128.7 (Cq-4), 128.8 (CH-3+5 Ph of R2), 128.9 (CH-2+6 Ph of R1), 129.2 (CH-3+5 Ph of R1), 132.2 (CH-3 and CH-5), 138.6 (Cq-1 Ph of R1), 138.9 (Cq-1 Ph of R2), 151.6 (Cq-1), 157.2 (C=O); ESI MS m/z 226 [PhNHCONHCH2Ph]+ (28), 360 [M-PhCH2NHCONHPh+1]+ (95), 585 [M + 1]+ (100), 1170 [2M + 1]+ (59).
  • Ligand 2bb: Rf 0.26 (3% MeOH/DCM); yellow solid; m. p. 121.0–121.2 °C; 1H NMR 2.21 (s, 3H, CH3), 3.72 (s, 2H, CH2-N(6) of R1), 3.87 (s, 2H, CH2-Cq-6), 4.34 (s, 2H, CH2-Cq-2), 4.45 (d, 2H, J 5.6, CH2-NH of R2), 4.66 (s, 2H, CH2-N(2) of R1), 6.01 (bs, 1H, NH-CO), 6.74 (d, 1H, J 1.3, CH-5), 6.82 (d, 1H, J 1.3, CH-3), 7.17 (dd, 2H, J 7.7, 1.1, CH-2+6 Ph of R2), 7.19-7.24 (m, 5H, CH Ph), 7.28 (m, 2H, 2 CH-4 Ph), 7.33 (m, 6H, CH Ph), 11.34 (bs, 1H, OH); 13C NMR 20.5 (CH3), 44.8 (CH2-Cq-2), 44.9 (CH2 of R2), 50.2 (CH2-N(2) of R1), 51.5 (CH2-Cq-6), 52.6 (CH2-N(6) of R1), 122.4 (Cq-6), 123.7 (Cq-2), 126.8 (CH Ph), 127.2 (CH-2+6 Ph of R2), 127.4 (2 CH Ph), 127.4 (Cq-4), 127.6 (CH Ph), 127.8 (CH Ph), 128.29 (2 CH Ph), 128.33 (2 CH Ph), 128.6 (2 CH Ph), 128.69 (2 CH Ph), 128.72 (CH-5), 129.5 (CH-3), 138.2 (Cq-1 Ph of N(6)-R1), 138.6 (Cq-1 Ph of N(2)-R1), 139.9 (Cq-1 Ph of R2), 153.2 (Cq-1), 158.8 (C=O); ESI MS m/z 480 [M + 1]+ (100), 502 [M + Na]+ (7), 982 [2M + Na]+ (20).
  • Ligand 3bb: Rf 0.36 (1% MeOH/DCM); colourless solid; m. p. 152.6–152.7 °C; 1H NMR 2.20 (s, 3H, CH3), 4.39 (d, 4H, J 5.5, CH2-NH of R2), 4.42 (s, 4H, CH2-Cq-2 and CH2-Cq-6), 4.52 (d, 4H, J 5.5, CH2 of R1), 5.35 (bs, 1H, NH-CO), 6.83 (s, 2H, CH-3 and CH-5), 7.14 (d 4H, J 7.4, CH-2+6 Ph of R1), 7.20 (t, 2H, J 7.4, CH-4 Ph of R1), 7.26 (m, 8H, CH-3+5 Ph of R1 and CH-2+6 Ph of R2). 7.29 (t, 2H, J 7.3, CH-4 Ph of R2), 7.35 (dd 4H, J 7.6, 7.3, CH-3+5 Ph of R2), 10.71 (bs, 1H, OH); 13C NMR 20.4 (CH3), 45.0 (CH2 of R2), 46.9 (CH2-Cq-2 and CH2-Cq-6), 50.2 (CH2 of R1), 123.9 (Cq-2 and Cq-6), 127.0 (CH-2+6 Ph of R2), 127.1 (CH-4 Ph of R1), 127.3 (CH-2+6 Ph of R1), 127.6 (CH-4 Ph of R2), 128.2 (Cq-4), 128.5 (CH-3+5 Ph of R1), 128.9 (CH-3+5 Ph of R2), 130.9 (CH-3 and CH-5), 137.1 (Cq-1 Ph of R1), 139.2 (Cq-1 Ph of R2), 151.9 (Cq-1), 159.3 (C=O); ESI MS m/z 613 [M + 1]+ (26), 635 [M + Na]+ (100), 651 [M + K]+ (15).
  • Ligand 2bc: Rf 0.22 (3% MeOH/DCM); yellow solid; m. p. 140.9–141.1 °C; 1H NMR 2.21 (s, 3H, CH3), 2.78 (t, 2H, J 7.0, CH2-Ph of R2), 3.49 (td, 2H, J 7.0, 5.7, CH2-N of R2), 3.78 (s, 2H, CH2-N(6) of R1), 3.92 (s, 2H, CH2-Cq-6), 4.30 (s, 2H, CH2-Cq-2), 4.55 (s, 2H, CH2-N(2) of R1), 5.45 (bs, 1H, NH-CO), 6.77 (bs, 1H, CH-5), 6.80 (bs, 1H, CH-3), 7.09 (dd, 2H, J 7.5, 1.1, CH-2+6 Ph of R2), 7.15 (tt, 1H, J 7.3, 1.0, CH-4 Ph of R2), 7.20 (ddt, 2H, J 7.5, 7.2, 1.0, CH-3+5 Ph of R2), 7.27 (m, 4H, CH Ph), 7.29 (dd, 2H, J 7.6, 1.2, CH-2+6 Ph), 7.33 (m, 4H, CH Ph), 11.13 (bs, 1H, OH); 13C NMR 20.6 (CH3), 36.4 (CH2-Ph of R2), 42.3 (CH2-N of R2), 45.2 (CH2-Cq-2), 50.0 (CH2-N(2) of R1), 51.4 (CH2-Cq-6), 52.6 (CH2-N(6) of R1), 122.5 (Cq-6), 123.6 (Cq-2), 126.1 (CH-4 Ph of R2), 127.2 (CH Ph), 127.55 (CH-2+6 Ph), 127.65 (CH Ph), 128.0 (Cq-4), 128.2 (CH Ph), 128.36 (2 CH Ph), 128.39 (CH-3+5 Ph of R2), 128.6 (2 CH Ph), 128.7 (2 CH Ph), 128.8 (CH-2+6 Ph of R2), 128.9 (CH-5), 129.4 (CH-3), 138.2 (Cq-1 Ph of N(2) R2), 138.3 (Cq-1 Ph of N(6) R2), 139.6 (Cq-1 Ph of R2), 153.2 (Cq-1), 159.0 (C=O); ESI MS m/z 387 [M-PhCH2 + 1]+ (8), 494 [M + 1]+ (100), 516 [M + Na]+ (4), 987 [2M + 1]+ (14), 1010 [2M + Na + 1]+ (8).
  • Ligand 3bc: Rf 0.34 (1% MeOH/DCM); colourless solid; m. p. 131.6–131.7 °C; 1H NMR 2.24 (s, 3H, CH3), 2.88 (t, 4H, J 7.1, CH2-Ph of R2), 3.49 (bt, 4H, J 7.1, CH2-N of R2), 4.24 (d, 4H, J 4.9, CH2 of R1), 4.34 (s, 4H, CH2-Cq-2 and CH2-Cq-6), 4.89 (bs, 2H, NH-CO), 6.88 (s, 2H, CH-3 and CH-5), 7.12 (d, 4H, J 7.3, CH-2+6 Ph of R1), 7.17 (m, 6H, CH Ph), 7.22-7.28 (m, 10H, CH Ph), 10.79 (bs, 1H, OH); 13C NMR 20.5 (CH3), 36.4 (CH2-Ph of R2), 45.0 (CH2 of R1), 46.6 (CH2-Cq-2 and CH2-Cq-6), 49.2 (CH2-N of R2), 123.8 (Cq-2 and Cq-6), 126.7 (CH Ph), 127.1 (CH Ph), 127.5 (CH-2+6 Ph of R1), 128.1 (Cq-4), 128.5 (2 CH Ph), 128.8 (4 CH Ph), 130.6 (CH-3 and CH-5), 139.09 (Cq-1 Ph), 139.11 (Cq-1 Ph), 151.8 (Cq-1), 159.1 (C=O); ESI MS m/z 641 [M + 1]+ (39), 663 [M + Na]+ (100), 679 [M + K]+ (15).
  • Ligand 2ca: Rf 0.24 (1% MeOH/DCM); colourless oil; 1H NMR 2.23 (s, 3H, CH3), 2.82 (t, 2H, J 6.9, CH2-Ph of N(6) R1), 2.93 (m, 4H, CH2-Ph of N(2) R1 and CH2-N of N(6) R1), 3.63 (t, 2H, J 7.5, CH2-N of N(2) R1), 3.95 (s, 2H, CH2-Cq-6), 4.35 (s, 2H, CH2-Cq-2), 6.77 (d, 1H, J 1.6, CH-5), 6.94 (d, 1H, J 1.7, CH-3), 6.97 (tt, 1H, J 7.3, 1.1, CH-4 Ph of R1), 7.14 (dd, 2H, J 8.2, 1.2, CH-2+6 Ph of R2), 7.21 (m, 2H, CH-4 Ph of R1 and CH-4 Ph of R2), 7.24–7.32 (m, 8H, CH-3+5 Ph and CH-2+6 Ph of R1), 7.36 (bd, 2H, J 7.6, CH-2+6 Ph of R1); 13C NMR 20.5 (CH3), 34.4 (CH2-Ph of N(2) R1), 35.4 (CH2-Ph of N(6) R1), 46.4 (CH2-Cq-2), 49.3 (CH2-N of N(6) R1), 49.6 (CH2-N of N(2) R1), 52.0 (CH2-Cq-6), 119.3 (CH-2+6 Ph of R1), 122.1 (CH-4 Ph of R1), 122.3 (Cq-6), 123.8 (Cq-2), 126.6 (CH-4 Ph of R2), 128.5 (Cq-4), 128.5 (CH-4 Ph of R1), 128.58 (2 CH Ph), 128.62 (2 CH Ph), 128.68 (2 CH Ph), 128.73 (2 CH Ph), 129.0 (2 CH Ph), 129.1 (CH-5), 130.1 (CH-3), 138.6 (Cq-1 Ph of N(6) R1), 139. 7 (Cq-1 Ph of N(2) R1), 140.1 (Cq-1 Ph of R2), 153.2 (Cq-1), 156.0 (C=O); ESI MS m/z 494 [M + 1]+ (100), 496 [M + Na]+ (8), 532 [M + K]+ (1), 987 [2M + 1]+ (17), 1010 [2M + Na + 1]+ (17).
  • Ligand 3ca: Rf 0.35 (1% MeOH/DCM); yellow solid; m. p. 118.5–118.8°C; 1H NMR 2.30 (s, 3H, CH3), 2.97 (t, 4H, J 6.9, CH2-Ph of R1), 3.60 (t, 4H, J 6.9, CH2-N of R1), 4.45 (bs, 4H, CH2-Cq-2 and CH2-Cq-6), 6.95 (m, 3H, CH Ph), 6.99 (s, 2H, CH-3 and CH-5), 7.15 (m, 6H, CH Ph), 7.28 (m, 7H, CH Ph), 7.36 (m, 4H, CH Ph), 11.35 (bs, 1H, OH); 13C NMR 20.5 (CH3), 34.1 (CH2-Ph of R1), 46.7 (CH2-Cq-2 and CH2-Cq-6), 49.2 (CH2-N of R1), 119.8 (Cq-2 and Cq-6), 123.1 (2 CH-4 Ph), 128.6 (Cq-4), 128.8 (8 CH Ph), 128.96 (2 CH-4 Ph), 129.03 (8 CH Ph), 131.9 (CH-3 and CH-5), 138.8 (Cq-1 Ph of R2), 139.3 (Cq-1 Ph of R1), 153.6 (Cq-1), 158.2 (C=O); ESI MS m/z 494 [M-PhNHCO + 1]+ (23), 613[M + 1]+ (32), 635 [M + Na]+ (100), 651 [M + K]+ (13).
  • Ligand 2cb: Rf 0.14 (2% MeOH/DCM); colourless solid; m. p. 90.3–90.5 °C; 1H NMR 2.20 (s, 3H, CH3), 2.77 (t, 2H, J 6.9, CH2-Ph of N(6) R1), 2.86 (t, 2H, J 6.9, CH2-N of N(6) R1), 2.91 (dd, 2H, J 7.8, 7.4, CH2-Ph of N(2) R1), 3.61 (dd, 2H, J 7.7, 7.5, CH2-N of N(2) R1), 3.86 (s, 2H, CH2-Cq-6), 4.30 (s, 2H, CH2-Cq-2), 4.38 (d, 2H, J 5.5, CH2 of R2), 5.66 (bs, 1H, NH-CO), 6.73 (d, 1H, J 1.7, CH-5), 6.89 (d, 1H, J 1.7, CH-3), 7.14 (dd, 2H, J 8.1, 1.2, CH-2+6 Ph), 7.17-7.30 (m, 13H, CH Ph); 13C NMR 20.5 (CH3), 34.8 (CH2-Ph of N(2) R1), 35.5 (CH2-Ph of N(6) R1), 44.8 (CH2 of R2), 45.880 (CH2-Cq-2), 49.5 (CH2-N of N(6) R1), 49.9 (CH2-N of N(2) R1), 52.0 (CH2-Cq-6), 122.2 (Cq-6), 124.0 (Cq-2), 126.3 (CH Ph), 126.6 (CH Ph), 126.9 (CH Ph), 127.4 (2 CH Ph), 128.3 (Cq-4), 128.4 (2 CH Ph), 128.6 (2 CH Ph), 128.69 (2 CH Ph), 128.71 (CH-5), 128.73 (2 CH Ph), 129.0 (2 CH Ph), 129.1 (CH-3), 138.9 (Cq-1 Ph of N(6) R1), 139.6 (Cq-1 Ph of N(2) R1), 139.9 (Cq-1 Ph of R2), 153.2 (Cq-1), 158.5 (C=O); ESI MS m/z 508 [M + 1]+ (100), 530 [M + Na]+ (9), 1037 [2M + Na]+ (100).
  • Ligand 3cb: Rf 0.41 (2% MeOH/DCM); colourless solid; m. p. 151.6–152.0 °C; 1H NMR 2.24 (s, 3H, CH3), 2.88 (t, 4H, J 7.1, CH2-Ph of R1), 3.49 (bt, 4H, J 7.0, CH2-N of R1), 4.24 (d, 4H, J 4.4, CH2 of R2), 4.34 (s, 4H, CH2-Cq-2 and CH2-Cq-6), 4.89 (bs, 2H, NH-CO), 6.88 (s, 2H, CH-3 and CH-5), 7.12 (d, 4H, J 7.3, CH-2+6 Ph), 7.17 (m, 6H, CH Ph), 7.25 (m, 10H, CH Ph), 10.79 (bs, 1H, OH); 13C NMR 20.5 (CH3), 34.4 (CH2-Ph of R1), 45.0 (CH2 of R2), 46.6 (CH2-Cq-2 and CH2-Cq-6), 49.2 (CH2-N of R1), 123.8 (Cq-2 and Cq-6), 126.7 (2 CH-4 Ph), 127.1 (2 CH-4 Ph), 127.5 (4 CH Ph), 128.1 (Cq-4), 128.5 (4 CH Ph), 128.8 (8 CH Ph), 130.6 (CH-3 and CH-5), 138.7 (Cq-1 Ph of R1), 139.1 (Cq-1 Ph of R2), 151.8 (Cq-1), 159.1 (C=O); ESI MS m/z 641 [M + 1]+ (18), 663 [M + Na]+ (100), 679 [M + K]+ (14).
  • Ligand 2cc: Rf 0.11 (2% MeOH/DCM); colourless oil; 1H NMR 2.204 (s, 3H, CH3), 2.73 (t, 2H, J 7.1, CH2-Ph of R2), 2.84 (t, 2H, J 7.4, CH2-Ph of N(2) R1), 2.87 (dd, 2H, J 7.0, 6.7, CH2-Ph of N(6) R1), 2.96 (dd, 2H, J 7.0, 6.6, CH2-N of N(6) R1), 2.73 (td, 2H, J 7.0, 5.8, CH2-N of R2), 3.61 (bt, 2H, J 7.4, CH2-N of N(2) R1), 3.92 (s, 2H, CH2-Cq-6), 4.24 (s, 2H, CH2-Cq-2), 4.95 (bs, 1H, NH-CO), 6.77 (bs, 1H, CH-5), 6.84 (d, 1H, J 1.6, CH-3), 7.14-7.19 (m, 7H, CH Ph), 7.21-7.24 (m, 4H, CH Ph), 7.2707.31 (m, 4H, CH Ph); 13C NMR 20.5 (CH3), 34.5 (CH2-Ph of N(2) R1), 35.2 (CH2-Ph of N(6) R1), 36.4 (CH2-Ph of R2), 42.1 (CH2-N of R2), 45.9 (CH2-Cq-2), 49.35 (CH2-N of N(6) R1), 49.44 (CH2-N of N(2) R1), 51.6 (CH2-Cq-6), 122.0 (Cq-6), 123.8 (Cq-2), 126.2 (CH-4 Ph), 126.4 (CH-4 Ph), 126.6 (CH-4 Ph), 128.2 (Cq-4), 128.4 (2 CH Ph), 128.6 (2 CH Ph), 128.68 (2 CH Ph), 128.73 (2 CH Ph), 128.80 (2 CH Ph), 128.85 (2 CH Ph), 129.0 (CH-5), 129.4 (CH-3), 138.6 (Cq-1 Ph), 139.4 (Cq-1 Ph), 139.5 (Cq-1 Ph), 153.1 (Cq-1), 158.6 (C=O); ESI MS m/z 522 [M + 1]+ (100), 544 [M + Na]+ (4), 1043 [2M + 1]+ (8), 1066 [2M + Na + 1]+ (2).
  • Ligand 3cc: Rf 0.29 (1% MeOH/DCM); colourless solid; m. p. 107.2–107.3 °C; 1H NMR 2.22 (s, 3H, CH3), 2.73 (t, 4H, J 7.1, CH2-Ph of R2), 2.80 (t, 4H, J 7.2, CH2-Ph of R1), 3.35 (td, 4H, J 6.8, 6.1, CH2-N of R2), 3.40 (bd, 4H, J 7.1, CH2-N of R1), 4.28 (s, 4H, CH2-Cq-2 and CH2-Cq-6), 4.67 (bs, 1H, NH-CO), 6.84 (s, 2H, CH-3 and CH-5), 7.12 (m, 8H, CH-2+6 Ph), 7.18 (m, 2H, CH-4 Ph), 7.21-7.28 (m, 10H, CH Ph), 10.77 (bs, 1H, OH); 13C NMR 20.5 (CH3), 34.3 (CH2-Ph of R1), 36.2 (CH2-Ph of R2), 42.1 (CH2-N of R2), 46.6 (CH2-Cq-2 and CH2-Cq-6), 49.1 (CH2-N of R1), 124.0 (Cq-2 and Cq-6), 126.3 (CH Ph), 126.6 (CH Ph), 128.0 (Cq-4), 128.3 (CH Ph), big common signals for CH Ph at 128.5, 128.7, 128.7 and 128.8, 130.5 (CH-3 and CH-5), 139.0 (Cq-1 Ph), 139.2 (Cq-1 Ph), 151.7 (Cq-1), 158.9 (C=O); ESI MS m/z 669 [M + 1]+ (58), 691 [M + Na]+ (100), 707 [M + K]+ (11).
Molecules 28 06540 i002
Structure and numeration scheme of ligands 4 and 5.
  • Ligand 4: Rf 0.30 (DCM); pale red solid; m. p. 149.8–150.0 °C; 1H NMR 2.28 (s, 3H, CH3), 3.80 (bs, 2H, NH), 4.27 (s, 4H, CH2), 6.63 (d, 4H, J 7.9, CH-2+6 Ph of R1), 6.71 (t, 2H, J 7.3, CH-4 Ph of R1), 7.08 (bt, 1H, J 6.7, CH-4 Ph of R2), 7.14 (dd, 4H, J 8.5, 7.4, CH-3+5 Ph of R1), 7.17 (s, 2H, CH-3 and CH-5), 7.28 (m, 4H, CH-2+6 and CH-3+5 Ph of R2); 13C NMR 20.2 (CH3), 43.8 (CH2), 113.1 (CH-2+6 Ph of R1), 117.9 (CH-4 Ph of R1), 118.9 (CH-2+6 Ph of R2), 124.1 (CH-4 Ph of R2), 129.0 (CH-3+5 Ph of R2), 129.2 (CH-3+5 Ph of R1), 129.3 (CH-3 and CH-5), 131.9 (Cq-2 and Cq-6), 136.5 (Cq-4), 137.0 (Cq-1 Ph of R2), 144.6 (Cq-1), 147.7 (Cq-1 Ph of R1), 151.6 (C=O); ESI MS m/z 226 [M-CONHPh-NPh]+ (100), 319 [M-CONPh + 1]+ (14), 438 [M + 1]+ (41), 876 [2M + 1]+ (3).
  • Ligand 5: Rf 0.38 (0.5% MeOH/DCM); colourless solid; m. p. 112.6–112.7 °C; 1H NMR 2.16 (s, 3H, CH3), 4.17 (bs, 1H, NH), 4.27 (s, 2H, CH2-Cq-6), 4.96 (s, 2H, CH2-Cq-2), 6.14 (s, 1H, NH-CON), 6.61 (dd, 2H, J 8.4, 0.9, CH-2+6 Ph-N(6) of R1), 6.68 (tt, 1H, J 7.3, 1.0, CH-4 Ph-N(6) of R1), 6.74 (bs, 1H, CH-3), 6.95 (tt, 1H, J 6.8, 1.8, CH-4 Ph), 6.99 (tt, 1H, J 7.4, 1.0, CH-4 Ph of O R2), 7.15, m, 11H, CH-5 and 10 CH Ph), 7.28 (dd, 2H, J 8.4, 0.9, CH-2+6 Ph of O R2), 7.32 (tt, 1H, J 7.4, 1.3, CH-4 Ph), 7.36 (ddd, 2H, J 8.4, 7.0, 1.4, CH-3+5 Ph), 7.64 (bs, 1H, NH-COO); 13C NMR 20.9 (CH3), 43.4 (CH2-Cq-6), 48.5 (CH2-Cq-2), 112.9 (CH-2+6 Ph-N(6) of R1), 117.5 (CH-4 Ph-N(6) of R1), 118.9 (CH-2+6 Ph of O R2), 119.6 (CH-2+6 Ph of N R2), 123.0 (CH-4 Ph), 123.5 (CH-4 Ph of O R2), 128.4 (CH-4 Ph), 128.7 (2 CH Ph), 128.8 (2 CH Ph), 129.0 (2 CH Ph), 129.2 (2 CH Ph), 129.4 (CH-5), 130.1 (CH-3+5 Ph), 130.3 (Cq-2), 130.7 (CH-3), 132.7 (Cq-6), 135.7 (Cq-4), 137.5 (Cq-1 Ph), 138.5 (Cq-1 Ph of N R2), 140.5 (Cq-1 Ph), 145.1 (Cq-1), 148.2 (Cq-1 Ph of N R2), 151.7 (C=O-O), 154.2 (C=O-N); ESI MS m/z 557 [M + 1]+ (98), 579 [M + Na]+ (100), 595 [M + K]+ (14), 1135 [2M + Na]+ (47).

3.4. General Procedure for the Preparation of Ligands 7

General procedure for the preparation of chlorides 6: To a solution of bis-amine 1 (1 mmol) and pyridine (2 mmol), toluene phosgene (2 mmol, as 15% commercial solution in toluene) was added and the mixture was stirred at room temperature in an argon atmosphere for 2 h. The products were partitioned between toluene and brine. The organic layer was washed with 10 % aq. HCl and then with brine, dried over MgSO4, and evaporated to dryness. The product was purified via flash chromatography on silica gel by using a mobile phase with a gradient of polarity from DCM to 0.4% MeOH/DCM. Molecules 28 06540 i003
Structure and numeration scheme of intermediates 6, ligands 7, and their precursors 8. This numeration scheme was chosen in an attempt to facilitate a comparison with ligands 2 and 3.
  • Ligand 6a: 49% yield; Rf 0.65 (1% MeOH/DCM); red solid; m. p. 178.3–178.6 °C; 1H NMR 2.37 (s, 3H, CH3), 4.71 (s, 2H, CH2-Cq-2), 5.08 (s, 2H, CH2-Cq-6), 6.86 (bs, 1H, CH-3), 7.17 (bdd, 2H, J 7.3, 1.0, CH-2+6 Ph-N(2)), 7.28 (bs, 1H, CH-5), 7.30 (bm, 3H, CH-2+6 and CH-4 Ph-N(6)), 7.37 (bm, 3H, CH-3+5 and CH-4 Ph-N(2)), 7.42 (bdd, 2H, J 8.0, 7.5, (bm, 3H, CH-3+5 Ph-N(6)); 13C NMR 20.9 (CH3), 50.0 (CH2-Cq-6), 50.3 (CH2-Cq-2), 118.0 (Cq-2), 122.9 (Cq-6), 125.0 (CH-2+6 Ph-N(6)), 125.5 (CH-3), 127.2 (CH-4 Ph-N(6)), 128.3 (CH-2+6 Ph-N(2)), 128.7 (CH-4 Ph-N(2)), 129.38 (CH-3+5 Ph-N(2)), 129.41 (CH-3+5 Ph-N(6)), 129.6 (CH-5), 134.3 (Cq-4), 141.5 (Cq-1 Ph-N(2)), 144.6 (Cq-1 Ph-N(6)), 145.6 (Cq-1), 149.8 (O=C-O), 150.0 (O=C-Cl); ESI MS m/z 252 [M-NPhCOCl]+ (73), 345 [M-NHPh]+ (100), 438 [M + 1]+ (49), 876 [2M + 1]+ (14).
  • Ligand 6c: 39% yield; Rf 0.51 (1% MeOH/DCM); colourless oil; Some NMR signals are duplicated due to hindered rotation; depicted as “A” and “B”; A:B = 1.3:1; 1H NMR 2.26 (s, 3H, CH3, A), 2.28 (s, 3H, CH3, B), 2.96 (m, 4H, CH2-Ph of N(6) R1, A+B), 3.00 (t, 4H, J 7.4, CH2-Ph of N(2) R1, A+B), 3.60 (t, 2H, J 7.8, CH2-N of N(6) R1, B), 3.69 (t, 4H, J 7.6, CH2-N of N(2) R1, A+B), 3.72 (t, 2H, J 7.8, CH2-N of N(6) R1, A), 4.25 (s, 2H, CH2-Cq-2, A), 4.26 (s, 2H, CH2-Cq-2, B), 4.57 (s, 2H, CH2-Cq-6, A), 4.71 (s, 2H, CH2-Cq-6, B), 6.73 (s, 2H, CH-3, A+B), 6.93 (s, 1H, CH-5, B), 7.05 (s, 1H, CH-5, A), 7.20-7.24 (m, 12H, CH Ph, A+B), 7.27-7.33 (m, 8H, CH Ph, A+B); 13C NMR 20.8 (CH3, A), 20.9 (CH3, B), 33.3 (CH2-Ph of N(2) R1, A+B), 33.5 (CH2-Ph of N(6) R1, B), 34.8 (CH2-Ph of N(6) R1, A), 46.6 (CH2-Cq-6, A), 48.26 (CH2-Cq-2, B), 48.30 (CH2-Cq-2, A), 48.7 (CH2-Cq-6, B), 51.4 (CH2-N of N(2) R1, A+B), 51.7 (CH2-N of N(6) R1, B), 52.8 (CH2-N of N(6) R1, A), 117.3 (Cq-2, A), 117.4 (Cq-2, B), 122.9 (Cq-6, B), 123.0 (Cq-6, A), 125.2 (CH-3, B), 125.5 (CH-3, A), 126.7 (CH Ph), 126.8 (CH Ph), 127.5 (CH-5, B), 128.68 (CH Ph), 128.73 (CH Ph), 128.8 (CH Ph), 128.9 (CH Ph), 129.0 (CH Ph), 129.9 (CH-5, A), 134.0 (Cq-4, A+B), 137.6 (Cq-1 Ph-N(6), A), 137.8 (Cq-1 Ph-N(6), B), 138.4 (Cq-1 Ph-N(2), A+B), 145.2 (Cq-1, A), 145.7 (Cq-1, B), 150.1 (O=C-Cl, A+B), 150.1 (O=C-O, A+B); ESI MS m/z 401 [M-COCl + 1]+ (100), 463 [M + 1]+ (1.5), 925 [2M + 1]+ (2).
  • Ligand 8a: 2% yield; Rf 0.54 (1% MeOH/DCM); deep red solid; m. p. 135.8–135.9 °C; 1H NMR 2.27 (s, 3H, CH3), 4.46 (s, 2H, CH2-Cq-6), 4.76 (s, 2H, CH2-Cq-2), 6.67 (dd, 2H, J 8.6, 1.0, CH-2+6 Ph-N(6)), 6.71 (tt, 1H, J 7.3, 1.0, CH-4 Ph-N(6)), 6.80 (bs, 1H, CH-3), 7.16 (m, 3H, CH-5 and CH-3+5 Ph-N(6)), 7.31 (tt, 1H, J 7.3, 1.2, CH-4 Ph-N(2)), 7.38 (dd, 2H, J 8.4, 1.2, CH-2+6 Ph-N(2)), 7.44 (dd, 2H, J 8.4, 7.4, CH-3+5 Ph-N(2)); 13C NMR 20.8 (CH3), 42.4 (CH2-Cq-6), 50.6 (CH2-Cq-2), 113.2 (CH-2+6 Ph-N(6)), 117.66 (Cq-2), 117.70 (CH-4 Ph-N(6)), 124.4 (CH-3), 125.3 (CH-2+6 Ph-N(2)), 126.7 (Cq-6), 127.3 (CH-4 Ph-N(2)), 128.9 (CH-5), 129.2 (CH-3+5 Ph-N(6)), 129.4 (CH-3+5 Ph-N(2)), 133.9 (Cq-4), 141.7 (Cq-1 Ph-N(2)), 145.6 (Cq-1), 147.6 (Cq-1 Ph-N(6)), 150.4 (C=O).
General procedure for the preparation of ligands 7: A mixture of chloride 6 (1 mmol) and primary amine (2.5 mmol) in dichloroethane was stirred at 50 °C for 19 h. The products were partitioned between dichloroethane and brine. The organic layer was washed with 10 % aq. HCl and then with brine, dried over MgSO4, and evaporated to dryness. The product was purified via flash chromatography on silica gel by using a mobile phase with a gradient of polarity from DCM to 1% MeOH/DCM. The yields are given in Table 3.
  • Ligand 7aa: Rf 0.62 (3% MeOH/DCM); colourless solid; m. p. 235.2–235.3 °C; 1H NMR 2.34 (s, 3H, CH3), 4.71 (s, 2H, CH2-Cq-2), 5.12 (s, 2H, CH2-Cq-6), 6.36 (s, 1H, NH), 6.80 (bs, 1H, CH-3), 7.01 (tt, 1H, J 7.4, 1.1, CH-4 Ph of R2), 7.26 (m, 3H, CH Ph), 7.29–7.37 (m, 9H, 8 CH Ph and CH-5 at 7.326), 7.43 (m, 4H, CH Ph); 13C NMR 21.0 (CH3), 46.9 (CH2-Cq-6), 50.4 (CH2-Cq-2), 117.6 (Cq-2), 119.3 (CH-2+6 Ph of R2), 123.0 (CH-4 Ph of R2), 124.6 (CH-3), 125.1 (2 CH Ph), 125.6 (Cq-6), 127.1 (CH-4 Ph), 128.2 (CH-4 Ph), 128.3 (2 CH Ph), 128.8 (2 CH Ph), 129.3 (CH-5), 129.3 (2 CH Ph), 130.2 (2 CH Ph), 134.1 (Cq-4), 138.7 (Cq-1 Ph of R2), 141.3 (Cq-1 Ph of R1), 141.7 (Cq-1 Ph of R1), 145.4 (Cq-1), 150.2 (O=C-O), 154.5 (O=C-N); ESI MS m/z 226 [PhNHCONHPhCH3]+ (52), 345 [M-CONHPh + 1]+ (73), 464 [M + 1]+ (100), 486 [M + Na]+ (5), 928 [2M + 1]+ (3).
  • Ligand 7ab: Rf 0.42 (3% MeOH/DCM); colourless solid; m. p. 130.9–131.0 °C; 1H NMR 2.34 (s, 3H, CH3), 4.46 (d, 2H, J 4.7, CH2 of R2), 4.72 (s, 2H, CH2-Cq-2), 4.78 (bs, 1H, NH), 5.08 (s, 2H, CH2-Cq-6), 6.79 (bs, 1H, CH-3), 7.25 (m, 5H, CH Ph), 7.27-7.33 (m, 7H, 6 CH Ph and CH-5 at 7.298), 7.36 (bt, 2H, J 7.6, CH-3+5 Ph), 7.47 (bt, 2H, J 7.7, CH-3+5 Ph); 13C NMR 21.0 (CH3), 44.8 (CH2 of R2), 47.0 (CH2-Cq-6), 50.5 (CH2-Cq-2), 117.6 (Cq-2), 124.4 (CH-3), 125.1 (2 CH Ph), 126.0 (Cq-6), 127.1 (CH-4 Ph), 127.2 (2 CH Ph), 127.3 (2 CH Ph), 127.8 (CH-4 Ph), 128.2 (CH-4 Ph), 128.6 (2 CH Ph), 129.2 (CH-5), 129.3 (CH-3+5 Ph), 130.0 (CH-3+5 Ph), 134.0 (Cq-4), 139.5 (Cq-1 Ph of R2), 141.69 (Cq-1 Ph of R1), 141.73 (Cq-1 Ph of R1), 145.4 (Cq-1), 150.3 (O=C-O), 157.3 (O=C-N); ESI MS m/z 226 [PhNHCONHCH2Ph]+ (90), 345 [M-CONHCH2Ph+1]+ (71), 359 [M-CONPh]+ (68), 478 [M + 1]+ (100), 500 [M + Na]+ (7), 956 [2M + 1]+ (8).
  • Ligand 7ac: Rf 0.41 (3% MeOH/DCM); colourless oil; 1H NMR 2.35 (s, 3H, CH3), 2.79 (t, 2H, J 6.8, CH2-Ph of R2), 3.48 (td, 2H, J 6.8, 5.8, CH2-N of R2), 4.40 (t, 1H, J 5.5, NH), 4.70 (s, 2H, CH2-Cq-2), 5.04 (s, 2H, CH2-Cq-6), 6.78 (bs, 1H, CH-3), 7.10 (m, 4H, 2 CH-2+6 Ph), 7.19 (tt, 1H, J 7.4, 1.2, CH-4 Ph), 7.24 (tt, 2H, J 7.4, 1.2, CH-3+5 Ph of R2), 7.26(d, 1H, J 1.1, CH-5), 7.27-7.32 (m, 6H, CH Ph), 7.41 (ddt, 2H, J 8.4, 7.4, 1.9, CH-3+5 Ph); 13C NMR 21.0 (CH3), 36.1 (CH2-Ph of R2), 42.0 (CH2-N of R2), 46.7 (CH2-Cq-6), 50.4 (CH2-Cq-2), 117.6 (Cq-2), 124.3 (CH-3), 125.1 (2 CH Ph), 126.1 (Cq-6), 126.3 (CH-4 Ph), 127.1 (CH-4 Ph), 127.6 (CH-4 Ph), 128.2 (2 CH Ph), 128.5 (2 CH Ph), 128.8 (2 CH Ph), 129.1 (CH-5), 129.3 (CH-3+5 Ph of R1), 129.8 (2 CH Ph), 133.9 (Cq-4), 139.2 (Cq-1 Ph of R2), 141.6 (Cq-1 Ph of R1), 141.7 (Cq-1 Ph of R1), 145.3 (Cq-1), 150.3 (O=C-O), 157.2 (O=C-N); ESI MS m/z 492 [M + 1]+ (10), 514 [M + Na]+ (35), 1006 [2M + Na]+ (47).
  • Ligand 7bb: Rf 0.43 (2% MeOH/DCM); colourless solid; m. p. 109.8–110.4 °C; 1H NMR 2.24 (s, 3H, CH3), 4.24 (s, 2H, CH2-Cq-2), 4.45 (s, 2H, CH2 of R2), 4.54 (s, 2H, CH2-Cq-6), 4.62 (s, 2H, CH2-N(6) of R1), 4.64 (s, 2H, CH2-N(2) of R1), 4.97 (bs, 1H, NH), 6.71 (bs, 1H, CH-3), 6.98 (bs, 1H, CH-5), 7.17 (dd, 2H, J 7.8, 1.2, CH-2+6 Ph), 7.21 (tt, 1H, J 7.4, 1.2, CH-4 Ph), 7.25 (tt, 2H, J 7.5, 1.2, CH-3+5 Ph of R2), 7.27 (m, 3H, CH Ph), 7.31–7.36 (m, 7H, CH Ph); 13C NMR 20.8 (CH3), 44.88 (CH2 of R2), 44.92 (CH2-Cq-6), 46.5 (CH2-Cq-2), 50.9 (s, 2H, CH2-N(6) of R1), 52.5 (s, 2H, CH2-N(2) of R1), 116.9 (Cq-2), 124.4 (Cq-6), 124.9 (CH-3), 127.0 (CH-4 Ph), 127.4 (2 CH Ph), 127.4 (CH-4 Ph), 127.4 (CH-4 Ph), 128.1 (CH-5), 128.2 (2 CH Ph), 128.3 (2 CH Ph), 128.4 (2 CH Ph), 128.7 (2 CH Ph), 128.9 (2 CH Ph), 134.0 (Cq-4), 135.2 (Cq-1 Ph of N(2) R1), 137.7 (Cq-1 Ph of N(6) R1), 139.5 (Cq-1 Ph of R2), 145.2 (Cq-1), 150.5 (O=C-O), 158.3 (O=C-N); ESI MS m/z 373 [M-CONCH2Ph]+ (93), 506 [M + 1]+ (100), 528 [M + Na]+ (9), 1012 [2M + 1]+ (38).
  • Ligand 7bc: Rf 0.39 (2% MeOH/DCM); colourless oil; 1H NMR 2.247 (s, 3H, CH3), 2.77 (t, 2H, J 6.9, CH2-Ph of R2), 3.50 (bt, 2H, J 6.8, CH2-N of R2), 4.26 (s, 2H, CH2-Cq-2), 4.46 (s, 2H, CH2-Cq-6), 4.54 (s, 2H, CH2-N(6) of R1), 4.63 (bs, 1H, NH), 4.66 (s, 2H, CH2-N(2) of R1), 6.71 (bs, 1H, CH-3), 6.94 (bs, 1H, CH-5), 7.06 (dd, 2H, J 7.7, 1.2, CH-2+6 Ph), 7.12 (tt, 1H, J 7.3, 1.3, CH-4 Ph), 7.19 (m, 4H, CH-3+5 Ph of R2 and 2 CH Ph), 7.25 (tt, 1H, J 7.3, 1.1, CH-4 Ph), 7.29–7.37 (m, 7H, CH Ph); 13C NMR 20.8 (CH3), 36.3 (CH2-Ph of R2), 42.2 (CH2-N of R2), 44.9 (CH2-Cq-6), 46.6 (CH2-Cq-2), 50.7 (CH2-N(6) of R1), 52.5 (s, 2H, CH2-N(2) of R1), 116.8 (Cq-2), 124.5 (Cq-6), 124.8 (CH-3), 126.1 (CH-4 Ph), 127.3 (2 CH Ph), 127.4 (CH-4 Ph), 128.1 (CH-5), 128.2 (CH-4 Ph), 128.3 (2 CH Ph), 128.49 (2 CH Ph), 128.70 (2 CH Ph), 128.71 (2 CH Ph), 128.9 (2 CH Ph), 133.9 (Cq-4), 135.3 (Cq-1 Ph of N(2) R1), 137.6 (Cq-1 Ph of N(6) R1), 139.3 (Cq-1 Ph of R2), 145.2 (Cq-1), 150.6 (O=C-O), 158.3 (O=C-N); ESI MS m/z 520 [M + 1]+ (14), 542 [M + Na]+ (48), 558 [M + K]+ (2), 1062 [2M + Na]+ (100).
  • Ligand 7ca: Rf 0.60 (3% MeOH/DCM); colourless solid; m. p. 133.1-133.2 °C; 1H NMR 2.27 (s, 3H, CH3), 2.92 (t, 2H, J 7.2, CH2-Ph of N(6) R1), 3.00 (t, 2H, J 7.4, CH2-Ph of N(2) R1), 3.61 (t, 2H, J 7.2, CH2-N of N(6) R1), 3.68 (t, 2H, J 7.4, CH2-N of N(2) R1), 4.25 (s, 2H, CH2-Cq-2), 4.56 (s, 2H, CH2-Cq-6), 6.53 (bs, 1H, NH), 6.72 (bs, 1H, CH-3), 6.98 (bt, 1H, J 7.1, CH-4 Ph), 7.02 (bs, 1H, CH-5), 7.24 (m, 8H, CH Ph), 7.30 (m, 6H, CH Ph); 13C NMR 20.82 (CH3), 33.2 (CH2-Ph of N(2) R1), 34.6 (CH2-Ph of N(6) R1), 45.4 (CH2-Cq-6), 48.3 (CH2-Cq-2), 49.8 (CH2-N of N(6) R1), 51.3 (CH2-N of N(2) R1), 117.2 (Cq-2), 128.4 (CH-2+6 Ph of R2), 122.6 (CH-4 Ph of R2), 124.4 (Cq-6), 125.1 (CH-3), 126.6 (CH-4 Ph), 126.7 (CH-4 Ph), 128.70 (2 CH Ph), 128.71 (2 CH Ph), 128.78 (2 CH Ph), 128.79 (2 CH Ph), 128.97 (2 CH Ph), 129.03 (CH-5), 134.0 (Cq-4), 138.3 (Cq-1 Ph of N(2) R1), 139.3 (Cq-1 Ph of N(6) R1 and Cq-1 Ph of R2), 145.5 (Cq-1), 150.1 (O=C-O), 155.8 (O=C-N); ESI MS m/z 520 [M + 1]+ (11), 542 [M + Na]+ (54), 558 [M + K]+ (4), 1062 [2M + Na]+ (100).
  • Ligand 7cb: Rf 0.39 (3% MeOH/DCM); colourless oil; 1H NMR 2.236 (s, 3H, CH3), 2.90 (dd, 2H, J 7.6, 7.4, CH2-Ph of N(6) R1), 2.98 (dd, 2H, J 7.6, 7.4, CH2-Ph of N(2) R1), 3.57 (dd, 2H, J 7.6, 7.4, CH2-N of N(6) R1), 3.66 (dd, 2H, J 7.6, 7.4, CH2-N of N(2) R1), 4.23 (s, 2H, CH2-Cq-2), 4.36 (s, 2H, CH2 of R2), 4.49 (s, 2H, CH2-Cq-6), 4.71 (bs, 1H, NH), 6.68 (bs, 1H, CH-3), 6.95 (bs, 1H, CH-5), 7.19 (m, 5H, CH Ph), 7.24 (m, 5H, CH Ph), 7.28 (m, 5H, CH Ph); 13C NMR 20.8 (CH3), 33.2 (CH2-Ph of N(2) R1), 34.8 (CH2-Ph of N(6) R1), 44.8 (CH2 of R2), 46.0 (CH2-Cq-6), 48.2 (CH2-Cq-2), 49.9 (CH2-N of N(6) R1), 51.3 (CH2-N of N(2) R1), 117.1 (Cq-2), 124.6 (Cq-6), 124.7 (CH-3), 126.4 (CH-4 Ph), 126.7 (CH-4 Ph), 127.0 (CH-4 Ph), 127.5 (2 CH Ph), 128.1 (CH-5), 128.4 (2 CH Ph), 128.6 (2 CH Ph), 128.7 (2 CH Ph), 128.8 (2 CH Ph), 128.9 (2 CH Ph), 133.9 (Cq-4), 138.4 (Cq-1 Ph of R2), 139.1 (Cq-1 Ph of N(2) R1), 139.6 (Cq-1 Ph of N(6) R1), 145.3 (Cq-1), 150.1 (O=C-O), 158.0 (O=C-N); ESI MS m/z 534 [M+1]+ (14), 556 [M + Na]+ (83), 572 [M + K]+ (5), 1090 [2M + Na]+ (100).
  • Ligand 7cc: Rf 0.40 (3% MeOH/DCM); colourless oil; 1H NMR 2.237 (s, 3H, CH3), 2.74 (t, 2H, J 7.0, CH2-Ph of R2), 2.82 (dd, 2H, J 7.7, 7.4, CH2-Ph of N(6) R1), 3.00 (dd, 2H, J 7.7, 7.3, CH2-Ph of N(2) R1), 3.44 (dd, 2H, J 7.0, 6.8, CH2-N of R2), 3.46 (dd, 2H, J 7.8, 7.5, CH2-N of N(6) R1), 3.68 (dd, 2H, J 7.7, 7.2, CH2-N of N(2) R1), 4.24 (s, 2H, CH2-Cq-2), 4.40 (bs, 1H, NH), 4.42 (s, 2H, CH2-Cq-6), 6.68 (bs, 1H, CH-3), 6.91 (bs, 1H, CH-5), 7.14 (m, 4H, CH Ph), 7.19 (m, 2H, 2 CH-4 Ph), 7.24 (m, 5H, CH Ph), 7.29 (m, 4H, CH Ph); 13C NMR 20.8 (CH3), 33.3 (CH2-Ph of N(2) R1), 34.7 (CH2-Ph of N(6) R1), 36.2 (CH2-Ph of R2), 42.0 (CH2-N of R2), 44.8 (CH2-Cq-6), 48.3 (CH2-Cq-2), 49.7 (CH2-N of N(6) R1), 51.3 (CH2-N of N(2) R1), 117.0 (Cq-2), 124.6 (CH-3), 124.8 (Cq-6), 126.2 (CH-4 Ph), 126.4 (CH-4 Ph), 126.7 (CH-4 Ph), 128.2 (CH-5), 128.5 (2 CH Ph), 128.6 (2 CH Ph), 128.7 (2 CH Ph), 128.77 (2 CH Ph), 128.80 (2 CH Ph), 128.85 (2 CH Ph), 133.8 (Cq-4), 138.4 (Cq-1 Ph of N(2) R1), 139.0 (Cq-1 Ph of N(6) R1), 139.4 (Cq-1 Ph of R2), 145.3 (Cq-1), 150.16 (O=C-O), 158.0 (O=C-N); ESI MS m/z 548 [M + 1]+ (18), 570 [M + Na]+ (100), 586 [M + K]+ (7), 1118 [2M + Na]+ (99).

3.5. Crystallography

Colorless (compounds 2ab, 2ac, 2bc, 3ba, 4-solvate, 5, 6a, 7aa, 7ab, 7bb and 8a), yellow (compound 2ba) or reddish (compound 4) crystal blocks (compounds 2ab, 4-solvate, 7ab, 7bb and 8a), plates (compounds 2ba, 3ba, 4, 5 and 6a) or prisms (compounds 2ac, 2bc and 7aa) were obtained via recrystallization from suitable solvents. Single crystals with an appropriate size ((0.2 − 0.3) × (0.15 − 0.3) × (0.05 − 0.12) mm3) and diffraction quality were carefully selected and mounted on a nylon loop or glass capillary using cryoprotectant oil (Paratone) or epoxy glue. Diffraction data were collected on a SupernovaDual diffractometer equipped with an Atlas CCD detector using micro-focus MoKα radiation (λ = 0.71073 Å). The data were processed using CryAlisPro software 41.117a-64bit [48]. The structures were solved with direct or intrinsic phasing methods and refined using the full-matrix least-squares method on F2 (ShelxS, ShelxT and ShelxL program packages [49,50] integrated in OLEX v.1.5 software [51]). All non-hydrogen atoms were located successfully from the Fourier map and were refined anisotropically. All hydrogen atoms riding on a parent carbon atom were placed on calculated positions using the following scheme: Ueq = 1.2 for C-Haromatic = 0.93 Å, C-Hmethyl = 0.96 Å and C-Hmethylenic = 0.97 Å. The hydrogen atoms bonded to a heteroatom (e.g., nitrogen or oxygen) were located using the electron density maps. ORTEP-3v2 software [52] was used to illustrate the molecules in the asymmetric unit (ASU). The three-dimensional packing visualization of the molecules was performed using CCDC Mercury [53]. The most important data collection and crystallographic refinement parameters are given in Tables S1–S5. The complete crystallographic data for the reported structures have been deposited in the CIF format with the CCDC as 2287291 to 2287303. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures (accessed on 7 August 2023).

3.6. Isothermal Titration Calorimetry (ITC)

All ITC experiments were performed at 298.15 K (25 °C) using an Affinity ITC isothermal titration calorimeter (TA Instruments, Northampton, MA, USA). The calibration of the Affinity ITC calorimeter was carried out electrically by using electrically generated heat pulses. The active cell volume of the calorimeter was 0.19 mL, with a syringe volume up to 0.2 mL. The reference cell was filled with the nanopure water, with a conductivity not exceeding 0.18 µS cm−1 (Adrona, Riga, Latvia). The data, specifically those regarding the heat normalized per mole of injectant, were processed with nanoAnalylze (TA Instruments). A CaCl2–EDTA titration (test kit TA Instruments) was performed in order to check the apparatus and processing of the results (n—stoichiometry, Kd, ΔH). The typical experiment for assessing polydentate N,O-ligands includes 30 injections of 2.0 µL into the reaction cell. The reaction cell contains the polydentate ligand at a concentration of 0.15–0.4 mM, whereas the syringe contains 1.0–1.5 mM of buffered solution of chloride or nitrate Ca2+, Pb2+, K+ salts. The first (initial) 2 µL injection was discarded from each data set to remove the effect of titrant diffusion and enable the equilibration process. All reagents, e.g., compounds 2aa to 7cc (Table S6), were dissolved directly into the 0.1 M buffer solution with pH 5.0, 7.0 or 8.5. The buffer pH was adjusted with HCl or NaOH, and all solutions were degassed prior to titration. A background titration, consisting of an identical titrant solution but with the buffer solution in the reaction cell only, was removed from each experimental titration to account for the heat of dilution. The titrant was injected at 200–300 s intervals to ensure that the titration peak returned to the baseline before the next injection. For homogeneous mixing in the cell, the stirrer speed was kept constant at 125 rpm.

4. Conclusions

In this study, three series of polydentate N,O-ligands possessing unsymmetrical urea fragments attached to a p-cresol scaffold are obtained; mono- and bi-substituted open chain aromatics and fused aryloxazinones. The open-chain compounds 2 and 3 are obtained together via a two-step protocol and separated using column chromatography. The conditions are optimized and individual procedures are developed for each product due to the observed strong dependence of the reaction output on both the bis-amine and carbamoyl chloride substituents. On the contrary, oxazinones 7 are effectively obtained via a common protocol. The products are characterized via 1D and 2D NMR spectra in solution and via single-crystal XRD in solid state. It is shown that the open-chain substituted compounds 2 and 3 are oriented towards the optimal intramolecular H-bonding of the urea’s heteroatoms, while the preferred geometry of oxazinones 7 is driven by intermolecular bonding. A preliminary study on the coordination properties of the products at an approximately neutral pH range is performed using ICT. The results show that most of the compounds do not interact with the particular metal ions tested and it is suggested that the ligands need more acidic or more basic media to bind metal ions.
The protocols offer unlimited possibilities for the preparation of libraries of targets by varying the amines used and via further N-substitution as well.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28186540/s1, Crystallographic data (Tables S1–S13 and Figures S1–S4), ITC study (Table S14 and Figures S5–S10) and Original NMR spectra (Figures S11–S180).

Author Contributions

The synthetic experiments and NMR analysis were accomplished by S.E.T. and V.B.K. The single-crystal XRD and ICT analyses were performed by R.I.R. and B.L.S. All authors contributed to the discussion of the results and to the writing of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data of the current study are available from the corresponding authors upon reasonable request.

Acknowledgments

The financial support by The Bulgarian Science Fund, project DCOST-01-23, by the Research and Development and Innovation Consortium Sofia Tech Park, and by the European Regional Development Fund within the Operational Programme Science and Education for Smart Growth 2014-2020 under the Project Centre of Excellence “National centre of mechatronics and clean technologies”, project BG05M2OP001-1.001-0008, is gratefully acknowledged.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are not available from the authors.

References

  1. Cox, M. Solvent Extraction Principles and Practice, 2nd ed.; Rydberg, J., Cox, M., Musikas, C., Choppin, G.R., Eds.; Marcel Dekker Inc.: New York, NY, USA, 2004; Chapter 11; pp. 455–505. [Google Scholar]
  2. Kislik, V.S. Solvent Extraction. Classical and Novel Approaches; Elsevier B.V.: Amsterdam, The Netherlands, 2012. [Google Scholar]
  3. Regel-Rosocka, M.; Alguacil, F.J. Recent trends in metals extraction. Rev. Metal. 2013, 49, 292–316. [Google Scholar] [CrossRef]
  4. Wilson, A.M.; Bailey, P.J.; Tasker, P.A.; Turkington, J.R.; Grant, R.A.; Love, J.B. Solvent extraction: The coordination chemistry behind extractive metallurgy. Chem. Soc. Rev. 2014, 43, 123–134. [Google Scholar] [CrossRef] [PubMed]
  5. El-Nadi, Y.A. Solvent extraction and its applications on ore processing and recovery of metals: Classical approach. Sep. Pur. Rev. 2017, 46, 195–215. [Google Scholar] [CrossRef]
  6. Moyer, B.A. (Ed.) Ion Exchange and Solvent Extraction: Vol. 23, Changing the Landscape in Solvent Extraction; CRC Press, Taylor & Francis Group: Boca Raton, FL, USA, 2020. [Google Scholar]
  7. Narayanan, R.P.; Palantavida, S. Selective extraction and solid state complexation of iron(III) with bis(β-diketone) ligand. Mater. Today Proc. 2021, 41, 638–643. [Google Scholar] [CrossRef]
  8. Zhang, J.; Wenzel, M.; Steup, J.; Schaper, G.; Hennersdorf, F.; Du, H.; Zheng, S.; Lindoy, L.F.; Weigand, J.J. 4-Phosphoryl pyrazolones for highly selective lithium separation from alkali metal ions. Chem. Eur. J. 2022, 28, e202103640. [Google Scholar] [CrossRef]
  9. Fu, F.; Wang, Q. Removal of heavy metal ions from wastewaters: A review. J. Environ. Manag. 2011, 92, 407–418. [Google Scholar] [CrossRef] [PubMed]
  10. Liu, H.-w.; Yang, T.; Chen, Q.-d.; Shen, X.-h. Extraction behaviors of ionic liquid systems and application perspectives in reprocessing of spent nuclear fuel. J. Nucl. Radiochem. 2015, 37, 286–309. [Google Scholar]
  11. Alyapyshev, M.Y.; Babain, V.A.; Ustynyuk, Y.A. Recovery of minor actinides from high-level wastes: Modern trends. Russ. Chem. Rev. 2016, 85, 943–961. [Google Scholar] [CrossRef]
  12. Mohapatra, P.K. Actinide ion extraction using room temperature ionic liquids: Opportunities and challenges for nuclear fuel cycle applications. Dalton Trans. 2017, 46, 1730–1747. [Google Scholar] [CrossRef]
  13. Leoncini, A.; Huskens, J.; Verboom, W. Ligands for f-element extraction used in the nuclear fuel cycle. Chem. Soc. Rev. 2017, 46, 7229–7273. [Google Scholar] [CrossRef]
  14. Fan, Y.; Li, Y.; Shu, X.; Wu, R.; Chen, S.; Jin, Y.; Xu, C.; Chen, J.; Huang, C.; Xia, C. Complexation and separation of trivalent actinides and lanthanides by a novel DGA derived from macrocyclic crown ether: Synthesis, extraction, and spectroscopic and density functional theory studies. ACS Omega 2021, 6, 2156–2166. [Google Scholar] [CrossRef]
  15. Nyamato, G.S. Perspectives and prospects of chelation extraction of heavy metals from wastewater: A review. Water Sci. Technol. 2023, 88, 47–61. [Google Scholar] [CrossRef]
  16. Lehn, J.M. Supramolecular Chemistry: Concepts and Perspectives; Wiley: Hoboken, NJ, USA, 1995. [Google Scholar]
  17. Atmani, C.; El Hajj, F.; Benmansour, S.; Marchivie, M.; Triki, S.; Conan, F.; Patinec, V.; Handel, H.; Dupouy, G.; Gómez-García, C.J. Guidelines to design new spin crossover materials. Coord. Chem. Rev. 2010, 254, 1559–1569. [Google Scholar] [CrossRef]
  18. Easmon, J. Copper and iron complexes with antitumour activity. Expert Opin. Therap. Patents 2002, 12, 789–818. [Google Scholar] [CrossRef]
  19. Kundu, S.; Egboluche, T.K.; Hossain, M.A. Urea- and thiourea-based receptors for anion binding. Acc. Chem. Res. 2023, 56, 1320–1329. [Google Scholar] [CrossRef] [PubMed]
  20. Bond, A.H.; Dietz, M.L.; Chiarizia, R. Incorporating size selectivity into synergistic solvent extraction:  A review of crown ether-containing systems. Ind. Eng. Chem. Res. 2000, 39, 3442–3464. [Google Scholar] [CrossRef]
  21. Wainwright, K.P. Applications for polyaza macrocycles with nitrogen-attached pendant arms. Adv. Inorg. Chem. 2001, 52, 293–334. [Google Scholar]
  22. Chaudhary, A.; Singh, R.V. Review: Metal complexes of polyaza and polyoxaaza macrocyclic ligands: A look into the past and present work. Rev. Inorg. Chem. 2008, 28, 35–76. [Google Scholar] [CrossRef]
  23. Marchetti, F.; Pettinari, R.; Pettinari, C. Recent advances in acylpyrazolone metal complexes and their potential applications. Coord. Chem. Rev. 2015, 303, 1–31. [Google Scholar] [CrossRef]
  24. Doidge, E.D.; Roebuck, J.W.; Healy, M.R.; Tasker, P.A. Phenolic pyrazoles: Versatile polynucleating ligands. Coord. Chem. Rev. 2015, 288, 98–117. [Google Scholar] [CrossRef]
  25. Pestov, A.V.; Slepukhin, P.A.; Charushin, V.N. Copper and nickel chelate complexes with polydentate N,O-ligands: Structure and magnetic properties of polynuclear complexes. Russ. Chem. Rev. 2015, 84, 310–333. [Google Scholar] [CrossRef]
  26. Atanassova, M.; Kurteva, V. Synergism as a phenomenon in solvent extraction of 4f-elements with calixarenes. RSC Adv. 2016, 6, 11303–11324. [Google Scholar] [CrossRef]
  27. Liang, Y.; Wang, X.; Zhao, S.; He, P.; Luo, T.; Jiang, J.; Liang, W.; Cai, J.; Xu, H. A new photoresponsive bis (crown ether) for extraction of metal ions. ChemistrySelect 2019, 4, 10316–10319. [Google Scholar] [CrossRef]
  28. Florés, O.; Velic, D.; Mabrouk, N.; Bettaïeb, A.; Tomasoni, C.; Robert, J.-M.; Paul, C.; Goze, C.; Roussakis, C.; Bodio, E. Rapid synthesis and antiproliferative properties of polyazamacrocycle-based bi- and tetra-gold(i) phosphine dithiocarbamate complexes. ChemBioChem 2019, 20, 2255–2261. [Google Scholar] [CrossRef] [PubMed]
  29. Götzke, L.; Schaper, G.; März, J.; Kaden, P.; Huittinen, N.; Stumpf, T.; Kammerlander, K.K.K.; Brunner, E.; Hahn, P.; Mehnert, A.; et al. Coordination chemistry of f-block metal ions with ligands bearing bio-relevant functional groups. Coord. Chem. Rev. 2019, 386, 267–309. [Google Scholar] [CrossRef]
  30. Pedersen, K.S.; Baun, C.; Nielsen, K.M.; Thisgaard, H.; Jensen, A.I.; Zhuravlev, F. Design, synthesis, computational, and preclinical evaluation of natTi/45Ti-labeled urea-based glutamate PSMA ligand. Molecules 2020, 25, 1104. [Google Scholar] [CrossRef] [PubMed]
  31. Martinelli, J.; Callegari, E.; Baranyai, Z.; Fraccarollo, A.; Cossi, M.; Tei, L. Semi-rigid (aminomethyl) piperidine-based pentadentate ligands for Mn(II) complexation. Molecules 2021, 26, 5993. [Google Scholar] [CrossRef]
  32. Wang, J.-Y.; Mei, L.; Huang, Z.-W.; Chi, X.-W.; Geng, J.-S.; Hu, K.-Q.; Yu, J.-P.; Jiao, C.-S.; Zhang, M.; Chai, Z.-F.; et al. Coordination-Adaptive Polydentate Pseudorotaxane Ligand for Capturing Multiple Uranyl Species. Inorg. Chem. 2022, 61, 3058–3071. [Google Scholar] [CrossRef]
  33. Katritzky, A.R.; Oliferenko, A.; Lomaka, A.; Karelson, M. Six-membered cyclic ureas as HIV-1 protease inhibitors: A QSAR study based on CODESSA PRO approach. Bioorg. Med. Chem. Lett. 2002, 12, 3453–3457. [Google Scholar] [CrossRef]
  34. Kane, J.L., Jr.; Hirth, B.H.; Liang, B.; Gourlie, B.B.; Nahill, S.; Barsomian, G. Ureas of 5-aminopyrazole and 2-aminothiazole inhibit growth of gram-positive bacteria. Bioorg. Med. Chem. Lett. 2003, 13, 4463–4466. [Google Scholar] [CrossRef]
  35. Brugel, T.A.; Maier, J.A.; Clark, M.P.; Sabat, M.; Golebiowski, A.; Bookland, R.G.; Laufersweiler, M.J.; Laughlin, S.K.; VanRens, J.C.; De, B.; et al. Development of N-2,4-pyrimidine-N-phenyl-N′-phenyl ureas as inhibitors of tumor necrosis factor alpha (TNF-α) synthesis. Part 1. Bioorg. Med. Chem. Lett. 2006, 16, 3510–3513. [Google Scholar] [CrossRef]
  36. Kuhl, O. N-phosphino carboxylic acid amides, lactams and ureas: Synthesis, properties and applications. Coord. Chem. Rev. 2006, 250, 2867–2915. [Google Scholar] [CrossRef]
  37. Zhou, C.-H.; Zhang, H.-Z.; Cui, S.-F.; Lv, J.-S.; Yan, C.-Y.; Wan, K.; Zhang, Y.-Y.; Zhang, S.-L.; Cai, G.-X.; Geng, R.-X.; et al. Recent developments in organometallic supramolecular complexes as anticancer drugs. In Advances in Anticancer Agents in Medicinal Chemistry; Prudhomme, M., Ed.; Bentham Books: Potomac, MD, USA, 2013; Volume 2, Chapter 2; pp. 46–129. [Google Scholar]
  38. Elkamhawy, A.; Viswanath, A.N.I.; Pae, A.N.; Kim, H.Y.; Heo, J.C.; Park, W.K.; Lee, C.O.; Yang, H.; Kim, K.H.; Nam, D.H.; et al. Discovery of potent and selective cytotoxic activity of new quinazoline-ureas against TMZ-resistant glioblastoma multiforme (GBM). Eur. J. Med. Chem. 2015, 103, 210–222. [Google Scholar] [CrossRef] [PubMed]
  39. Maurer, D.; Breit, B. Urea-substituted tetramethylcyclopentadienyl ligands for supramolecularly accelerated RhIII-catalyzed ortho-C−H olefination of benzoic acid derivatives. Chem. Eur. J. 2021, 27, 2643–2648. [Google Scholar] [CrossRef]
  40. AlNajjar, Y.T.; Gabr, M.; ElHady, A.K.; Salah, M.; Wilms, G.; Abadi, A.H.; Becker, W.; Abdel-Halim, M.; Engel, M. Discovery of novel 6-hydroxybenzothiazole urea derivatives as dual Dyrk1A/α-synuclein aggregation inhibitors with neuroprotective effects. Eur. J. Med. Chem. 2022, 227, 113911. [Google Scholar] [CrossRef]
  41. Atanassova, M.P.; Todorova, S.E.; Kurteva, V.B.; Todorova, N.I. Insights into the synergistic selectivity of 4f-ions implementing 4-acyl-5-pyrazolone and two new unsymmetrical NH-urea containing ring molecules in an ionic liquid. Sep. Purif. Technol. 2018, 204, 328–335. [Google Scholar] [CrossRef]
  42. Todorova, S.; Kurteva, V.; Shivachev, B.; Nikolova, R.P. Crystal structures of novel polydentate N,O-ligands. Acta Cryst. 2016, A72, s403. [Google Scholar] [CrossRef]
  43. Todorova, S.; Atanassova, M.; Kurteva, V. Data on the synthesis and characterization of two novel polydentate ligands possessing unsymmetrical NH-urea fragment. Data Brief 2018, 20, 933–939. [Google Scholar] [CrossRef]
  44. Ameerunisha, S.; Srinivas, B.; Zacharias, P.S. Specific transport of copper(II) ions across liquid membrane by Schiff base ligands. Bull. Chem. Soc. Jpn. 1994, 67, 263–266. [Google Scholar] [CrossRef]
  45. Rozwadowski, Z.; Dziembowska, T.; Schroeder, G.; Brzezinski, B. Studies of intramolecular hydrogen bonds in di-Schiff bases of 2-hydroxy-5-methyl isophthaldehyde. J. Mol. Struct. 1998, 444, 221–225. [Google Scholar] [CrossRef]
  46. Grzybowski, J.J.; Urbach, F.L. Binuclear metal complexes. 2. A unique mononuclear copper(I) complex with a potentially binucleating Schiff base ligand. Inorg. Chem. 1980, 19, 2604–2608. [Google Scholar]
  47. Beer, P.D.; Fox, O.D. Redox-Active Self Assembled Metallomacrocycles. British. UK Patent Application, GB 2364305 A, 23 January 2002. [Google Scholar]
  48. Rigaku, O.D. Crysalis Pro; Rigaku Oxford Diffraction Ltd.: Yarnton, UK, 2015. [Google Scholar]
  49. Sheldrick, G.M. SHELXT–Integrated space-group and crystal-structure determination. Acta Crystallogr. Sect. A 2015, 71, 3–8. [Google Scholar] [CrossRef] [PubMed]
  50. Sheldrick, G.M. Crystal structure refinement with SHELXL. Acta Crystallogr. Sect. C 2015, 71, 3–8. [Google Scholar] [CrossRef]
  51. Dolomanov, O.V.; Bourhis, L.J.; Gildea, R.J.; Howard, J.A.; Puschmann, H. OLEX2: A complete structure solution, refinement and analysis program. J. Appl. Crystallogr. 2009, 42, 339–341. [Google Scholar] [CrossRef]
  52. Farrugia, L.J. WinGX and ORTEP for Windows: An update. J. Appl. Crystallogr. 2012, 45, 849–854. [Google Scholar] [CrossRef]
  53. Macrae, C.F.; Sovago, I.; Cottrell, S.J.; Galek, P.T.; McCabe, P.; Pidcock, E.; Platings, M.; Shields, G.P.; Stevens, J.S.; Towler, M.; et al. Mercury 4.0: From visualization to analysis, design and prediction. J. Appl. Crystallogr. 2020, 53, 226–235. [Google Scholar] [CrossRef] [PubMed]
Molecules 28 06540 g001
Figure 1. Structures of the ligands S1 and S2.
Figure 1. Structures of the ligands S1 and S2.
Molecules 28 06540 g001
Molecules 28 06540 sch001
Scheme 1. Synthesis of ligands 2 and 3.
Scheme 1. Synthesis of ligands 2 and 3.
Molecules 28 06540 sch001
Molecules 28 06540 g002
Figure 2. Structure and ORTEP view of the O-acylated product 4.
Figure 2. Structure and ORTEP view of the O-acylated product 4.
Molecules 28 06540 g002
Molecules 28 06540 g003
Figure 3. Structure and ORTEP view of the O,N-diacylated product 5.
Figure 3. Structure and ORTEP view of the O,N-diacylated product 5.
Molecules 28 06540 g003
Molecules 28 06540 g004
Figure 4. 1H NMR spectra of products 2ba and 3ba.
Figure 4. 1H NMR spectra of products 2ba and 3ba.
Molecules 28 06540 g004
Molecules 28 06540 g005
Figure 5. ORTEP view of the products: (a) 2ab, (b) 2ac, (c) 2ba, (d) 2bc, (e) 3ba; and (f) overlay of the two independent molecules in the asymmetric unit of 2ba (green) and 3ba (red).
Figure 5. ORTEP view of the products: (a) 2ab, (b) 2ac, (c) 2ba, (d) 2bc, (e) 3ba; and (f) overlay of the two independent molecules in the asymmetric unit of 2ba (green) and 3ba (red).
Molecules 28 06540 g005
Molecules 28 06540 g006
Figure 6. Visualization of the hydrogen bonds (a,c) and weak interactions (b,d) in 2ab and 2ac, respectively.
Figure 6. Visualization of the hydrogen bonds (a,c) and weak interactions (b,d) in 2ab and 2ac, respectively.
Molecules 28 06540 g006
Molecules 28 06540 g007
Figure 7. Observed hydrogen bonds in (a) 2ba, (b) 2bc and (c) 3ba.
Figure 7. Observed hydrogen bonds in (a) 2ba, (b) 2bc and (c) 3ba.
Molecules 28 06540 g007
Molecules 28 06540 sch002
Scheme 2. Synthesis of ligands 7.
Scheme 2. Synthesis of ligands 7.
Molecules 28 06540 sch002
Molecules 28 06540 g008
Figure 8. The structure and ORTEP drawing of compound 8a; symmetry operation (i) x, 2–y, 1–z.
Figure 8. The structure and ORTEP drawing of compound 8a; symmetry operation (i) x, 2–y, 1–z.
Molecules 28 06540 g008
Molecules 28 06540 g009
Figure 9. Methylene groups’ area of the 1H (a) and 13C (b) NMR spectra of products 7aa, 7ba and 7ca.
Figure 9. Methylene groups’ area of the 1H (a) and 13C (b) NMR spectra of products 7aa, 7ba and 7ca.
Molecules 28 06540 g009
Molecules 28 06540 g010
Figure 10. ORTEP view of the products 6a (a), 7aa (b), 7ab (c), and 7bb (d).
Figure 10. ORTEP view of the products 6a (a), 7aa (b), 7ab (c), and 7bb (d).
Molecules 28 06540 g010
Molecules 28 06540 g011
Figure 11. Overlay of the two independent molecules in the asymmetric unit of 6a (grey) and 7aa (blue).
Figure 11. Overlay of the two independent molecules in the asymmetric unit of 6a (grey) and 7aa (blue).
Molecules 28 06540 g011
Molecules 28 06540 g012
Figure 12. Visualization of the weak interactions in the structure of 6a.
Figure 12. Visualization of the weak interactions in the structure of 6a.
Molecules 28 06540 g012
Molecules 28 06540 g013
Figure 13. Visualization of the molecular interactions in (a) 7aa, (b) 7ab, and (c) 7bb.
Figure 13. Visualization of the molecular interactions in (a) 7aa, (b) 7ab, and (c) 7bb.
Molecules 28 06540 g013
Molecules 28 06540 g014
Figure 14. Interactions in selected samples of the products: (a) oxazinones, 7aa, 7ab and 7bb; (b) open-chain compounds, 2ab and 2ac; (c) open-chain compounds, 2ba, 2bc and 3ba.
Figure 14. Interactions in selected samples of the products: (a) oxazinones, 7aa, 7ab and 7bb; (b) open-chain compounds, 2ab and 2ac; (c) open-chain compounds, 2ba, 2bc and 3ba.
Molecules 28 06540 g014
Molecules 28 06540 g015
Figure 15. Typical calorimetric titration isotherms of (a) the binding interaction between 2ba and Pb2+, along with the fitted association constant; (b) titration isotherm showing no interaction between 7ab and Ca2+; (c) successful model fit for 2ba and; (d) unsuccessful attempt to model the interaction for 7ab.
Figure 15. Typical calorimetric titration isotherms of (a) the binding interaction between 2ba and Pb2+, along with the fitted association constant; (b) titration isotherm showing no interaction between 7ab and Ca2+; (c) successful model fit for 2ba and; (d) unsuccessful attempt to model the interaction for 7ab.
Molecules 28 06540 g015
Table 1. Synthesis of ligands 2 and 3.
Table 1. Synthesis of ligands 2 and 3.
EntryConditions aProducts
2Yield, %3Yield, %Total, %
1DIPEA, 1a:CC 1:1.5, toluene, 24 h2aa153aa-51 b
21a:CC 1:1, benzene, 2 h19traces19
31a:CC 1:2, toluene, 24 h391352
41a:CC 1:3, toluene, 24 h352257
51a:CC 1:1, toluene, 2 h2ab303abtraces30
61a:CC 1:2, toluene, 24 h322355
71a:CC 1:1, benzene, 2 h2actraces3ac--
81a:CC 1:2, benzene, 2 h17traces17
91a:CC 1:2, toluene, 2 h39847
101a:CC 1:2, DCE, 2 h303262
111b:CC 1:2, toluene, 24 h2bac213ba-21
121b:CC 1:2, benzene, 24 h37744
131b:CC 1:4, toluene, 24 h191736
141b:CC 1:1, toluene, 2 h2bb343bbtraces34
151b:CC 1:2, toluene, 24 h-4646
161b:CC 1:1, benzene, 2 h2bc263bc-26
171b:CC 1:2, benzene, 2 h16-16
181b:CC 1:2, toluene, 24 h172845
191b:CC 1:2, DCE, 2 h82735
201c:CC 1:1.5, toluene, 24 h2ca443ca1761
211c:CC 1:2, toluene, 24 h204363
221c:CC 1:2, toluene, 24 h2cb153cb4358
231c:CC 1:3, toluene, 4 h-4343
241c:CC 1:1, DCE, 2 h7traces7
251c:CC 1:2, DCE, 2 h181634
261c:CC 1:1, benzene, 2 h2cc423cc2163
271c:CC 1:2, benzene, 2 h-1919
281c:CC 1:2, toluene, 24 h203959
291c:CC 1:2, DCE, 2 h-3838
a Common conditions: pyridine (unless anything else noted), solvent, rt; CC means carbamic chloride; b Other isolated products: 25% 4, 11% 5; c Equal to S1 on Figure 1.
Table 2. Selected 1H and 13C NMR resonances (ppm) of ligands 2 and 3.
Table 2. Selected 1H and 13C NMR resonances (ppm) of ligands 2 and 3.
Lig.CH-3
CH-3		CH-5
CH-5		CH2-Cq-2
CH2-Cq-2		CH2-Cq-6
CH2-Cq-6
2aa6.372
130.90		7.042
130.14		4.773
50.47		4.363
44.54
3aa6.667/131.034.876/49.40
2ab6.344
130.90		7.042
130.08		4.723
50.81		4.372
44.43
3ab6.678/130.234.828/49.63
2ac6.327
130.83		7.038
129.99		4.667
50.51		4.374
44.36
3ac6.647/130.074.778/49.29
2ba *6.843
130.79		6.800
129.16		4.362
45.21		4.015
51.62
3ba6.900/132.164.501 (br)/49.72
2bb6.822
129.46		6.741
128.72		4.336
44.76		3.869
51.46
3bb6.833/130.944.416/46.94
2bc6.802
129.43		6.770
128.93		4.295
45.21		3.922
51.44
3bc6.879/130.644.893/46.64
2ca6.939
130.11		6.771
129.08		4.349
46.39		3.952
52.00
3ca6.989/131.934.446/46.66
2cb6.886
129.06		6.726
128.71		4.297
45.80		3.861
52.00
3cb6.879/130.644.335/46.64
2cc6.840
129.36		6.769
129.04		4.244
45.87		3.925
51.62
3cc6.844/130.464.284/46.57
* Published in ref. [43], S1 in Figure 1.
Table 3. Synthesis of ligands 7.
Table 3. Synthesis of ligands 7.
Starting ChlorideProducts
Compd.Yield, %Compd.Yield, %Compd.Yield, %
6a7aa737ab847ac84
6b7ba a877bb797bc71
6c7ca727cb717cc68
a Equal to S2 on Figure 1.
Table 4. Selected 1H and 13C NMR resonances (ppm) for the ligands 7.
Table 4. Selected 1H and 13C NMR resonances (ppm) for the ligands 7.
Lig.CH-3
CH-3		CH-5
CH-5		CH2-Cq-2
CH2-Cq-2		CH2-Cq-6
CH2-Cq-6
7aa6.798
124.56		7.326
129.30		4.710
50.43		5.120
46.86
7ab6.791
124.35		7.298
129.15		4.715
50.49		5.084
47.05
7ac6.777
124.26		7.260
129.09		4.704
50.45		5.037
46.74
7ba *6.749
125.33		7.015
129.30		4.279
46.56		4.595
45.33
7bb6.709
124.87		6.978
128.11		4.240
46.54		4.537
44.92
7bc6.707
124.80		6.938
128.13		4.260
46.57		4.464
44.87
7ca6.720
125.10		7.020
129.03		4.251
48.26		4.556
45.38
7cb6.685
124.69		6.948
128.09		4.229
48.24		4.490
44.95
7cc6.681
124.62		6.907
128.16		4.244
48.26		4.425
44.80
* Published in ref. [43], S2 on Figure 1.
Table 5. Summary of the ITC results for the titration of either Ca(II) chloride, Pb(II) chloride or KCl with 2ba, 2bc, 2cb, 3bb, 3cc derivatives; all interactions are for pH 5.0 and are conducted at 25 °C with 125 rpm continuous stirring; Ka is the association constant; n represents the stoichiometry, e.g., the number of molecules that associate to a metal ion.
Table 5. Summary of the ITC results for the titration of either Ca(II) chloride, Pb(II) chloride or KCl with 2ba, 2bc, 2cb, 3bb, 3cc derivatives; all interactions are for pH 5.0 and are conducted at 25 °C with 125 rpm continuous stirring; Ka is the association constant; n represents the stoichiometry, e.g., the number of molecules that associate to a metal ion.
Cell Contents [mM]Syringe Contents [mM] ΔH [kJ·mol−1] Ka.106 [M−1]n
EDTA 0.15CaCl2 0.95−16.54 ± 0.361.30 ± 4.910.886
2ba 0.20PbCl2 1.2062.95 ± 9.850.31 ± 0.250.869
2ba 0.20CaCl2 1.20−100.00 ± 7.720.024 ± .0591.856
2bc 0.20PbCl2 1.10−16.62 ± 0.440.14 ± 0.330.545
2cb 0.30PbCl2 1.50−37.27 ± 20.160.17 ± 0.600.201 *
3bb 0.25KCl 1.10−13.48 ± 0.451.00 ± 0.580.444
3cc 0.20KCl 1.20−16.06 ± 1.480.54 ± 0.710.424
* Independent model used, but the formation of the complex is likely a combination of models.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Todorova, S.E.; Rusew, R.I.; Shivachev, B.L.; Kurteva, V.B. Polydentate N,O-Ligands Possessing Unsymmetrical Urea Fragments Attached to a p-Cresol Scaffold. Molecules 2023, 28, 6540. https://doi.org/10.3390/molecules28186540

AMA Style

Todorova SE, Rusew RI, Shivachev BL, Kurteva VB. Polydentate N,O-Ligands Possessing Unsymmetrical Urea Fragments Attached to a p-Cresol Scaffold. Molecules. 2023; 28(18):6540. https://doi.org/10.3390/molecules28186540

Chicago/Turabian Style

Todorova, Stanislava E., Rusi I. Rusew, Boris L. Shivachev, and Vanya B. Kurteva. 2023. "Polydentate N,O-Ligands Possessing Unsymmetrical Urea Fragments Attached to a p-Cresol Scaffold" Molecules 28, no. 18: 6540. https://doi.org/10.3390/molecules28186540

Article Metrics

Back to TopTop