Synthesis, characterization and theoretical study of a new asymmetrical tripodal amine containing morpholine moiety

2.1 Chemical and starting materials

N-(3-aminopropyl)morpholine was commercial product from Fluka and was used without further purification. Solvents were of reagent grade purified by the usual methods. Tosylaziridine was prepared according to the literature method (Hata et al., 1980)

2.2 Physical measurements

FAB mass spectra were recorded using a Kratos-MS-50T spectrometer connected to a DS90 data system using 3-nitrobenzyl alcohol as the matrix. Elemental analyses were carried out using a Perkin–Elmer, CHNS/O elemental analyzer model 2400. ¹H and ¹³C NMR spectra were obtained using a Bruker Avance 500 MHz spectrometer.

2.3 X-ray crystal structure determination

Vapor diffusion of diethyl ether into a solution of [H₃L²]Br₃ in mixture of acetonitrile and methanol, afforded crystal suitable for study by X-ray crystallography. The details of the X-ray crystal data, and of the structure resolution and refinement, are given in Table 1. Measurements were made on a Bruker SMART CCD area diffractometer. All data were corrected for Lorentz and polarization effects. Empirical absorption corrections were also applied for all the crystal structures obtained (Sheldrick, 1996). Complex scattering factors were taken from the program package SHELXTL (Shelextl, 1997). The structure was solved by direct methods which revealed the position of all non-hydrogen atoms. The structure was refined on F² by a full-matrix least-squares procedure using anisotropic displacement parameters for all non-hydrogen atoms. The hydrogen atoms were located in their calculated positions and refined using a riding model. Molecular graphics were generated using ORTEP-3 (Farrugia and Appl, 1997).

2.4 Synthesis of L¹

Tosylaziridine (9.91 g, 50 mmol) was dissolved in dry benzene (10 ml). A mixture of N-(3-aminopropyl)morpholine (3.60 g, 25 mmol) and dry benzene (10 ml) was added dropwise at a rate of about 10 ml/40 min. The system was fitted with a drying tube to prevent the absorption of water. It was also placed in a cool water bath to prevent the temperature from going above 25 °C. When the addition was finished, the mixture was stirred between 20 and 25 °C for about 12 h. Then it was heated to about 30 °C for 48 h and allowed to cool. Then the resulting precipitate was collected, washed with a small amount of dry benzene and ethanol and dried in vacuo. Yield: 10.60 g (90%). Anal. Calc. For C₂₅H₃₈N₄O₅S₂ (MW: 538.72): C, 55.74; H, 7.11; N, 10.40. Found: C, 56.02; H, 7.20; N, 10.56%. FAB-MS (m/z): 539.22 [M+1]⁺.

¹H NMR(CDCl₃, ppm): δ_H 7.72 (d, 4H, H-8), 7.22 (4H, d, H-9), 5.45 (b s, 2H, NH), 3.61 (t, 4H, H-6), 2.95 (t, 4H, H-5), 2.49 (t, 4H, H-1), 2.42 (s, 6H, H-11), 2.36 (b, 4H, H-2), 2.29 (t, 4H, H-3 and H-3′), 1.52 (m, 2H, H-4). ¹³C NMR (CDCl₃, ppm): δ_C 143.04 (C-8), 137.17 (C-11), 129.46 (C-9 or C-10), 126.88 (C-10 or C-9), 66.39 (C-1), 55.24 (C-3 and C-5),53.37 (C-2), 52.88 (C-6), 40.367 (C-7), 29.47 (C-4), 21.30 (C-12) (Fig. 2).

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Figure 2

Schematic structures of the L¹ and [H₃L²]Br₃ showing the lettering scheme for NMR assignments.

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2.5 Synthesis of [H₃L²]Br₃

L¹ (13.46 g, 25 mmol) was dissolved in a mixture of 48% HBr (64 ml) and acetic acid (36 ml) in a 250 ml round-bottomed flask. The flask was fitted with a reflux condenser and heated to reflux. As it was warmed up, the reaction mixture became more and more reddish until it changed to a deep red color. Dark oil formed after 24 h. Heating was continued for another 24 h to ensure that the reaction was completed. The reaction mixture was cooled to room temperature and then placed in an ice bath. The precipitate was filtered and washed with hot ethanol. A mixture of ether and absolute ethanol (1/1) was added slowly to the cooled filtrate. The mixture was stirred in the ice bath about 1 h. The resulting precipitate was collected and washed with ether/absolute ethanol mixture and dried in vacuo. Yield: 8.27 g (70%). Anal. Calc. For C₁₁H₂₉Br₃N₄O (MW: 473.09): C, 27.93; H, 6.18; N, 11.84. Found: C, 28.00; H, 6.09; N, 12.20%. FAB-MS (m/z): 231 [M+1]⁺.

¹H NMR(D₂O, ppm): δ_H 3.98 (d, ³J = 13.32 Hz, 2H, H-1α or H-1β), 3.69 (t, ³J = 12.82 Hz, 2H, H-2α or H-2β), 3.45 (d, ³J = 13.3 Hz, 2H, H-2α or H-2β), 3.30 (s, 8H, H-6, H-7), 3.16 (t, ³J = 9.3 Hz, 2H, H-3 or H-5), 3.105 (t, ³J = 8.1 Hz, 4H, H-2 β or H-2α, H-5 or H-3). ¹³C NMR(D₂O, ppm): δ_C 66.80 (C-1), 56.84 (C-3), 55.00 (C-2), 53.19 (C-5), 52.80 (C-3), 37.64 (C-6), 21.80 (C-4) (Fig. 2).

2.6 Computational methods

The structure of amine L² and its tri- and four protonated forms were calculated using Gaussian 03 set of programs (Frisch et al., 2003) The geometries of all species were fully optimized at B3LYP/6-31G^∗∗ level. Vibrational frequency analyses calculated at the same level of theory indicated that the optimized structures are at the stationary points corresponding to local minima without any imaginary frequency. A starting molecular-mechanics structure for the ab initio calculations was obtained using the HyperChem 5.02 program (Hyper Chem, 1997). The calculation of ¹³C NMR chemical shielding of (H₃L²)³⁺ was performed using GIAO/DFT (Ditchfield, 1974; Wolinski et al., 1990) and CSGT/DFT (Keith and Bader, 1992, 1993) methods at B3LYP/6-311++G^∗∗ level of theory.

3.1 Synthesis and structure determination

The FAB mass spectra confirm the presence of the desired final products as they show peaks at m/z 539.22 and 231 a. m. u. corresponding to L¹ and L², respectively.

The ¹H and ¹³C NMR spectra of L¹ and [H₃L²]Br₃ indicate that these compounds have been synthesized.

The ¹H and ¹³C NMR data for L¹ and [H₃L²]Br₃ are shown in Section 2, which uses the lettering scheme shown in Fig. 2. The ¹H and ¹³C signals were assigned using one- and two-dimensional ¹H–¹H COSY, ¹H–¹³C HMQC and DEPT spectra.

The ¹H and ¹³C NMR spectra of the ligands indicate that these compounds have been synthesized. In the ¹H NMR spectrum of L¹, the hydrogen of aromatic region appears in 7.72 and 7.22 corresponding to H-9 and H-10, respectively. These peaks are doublet. The hydrogens of NH appear in 5.45 ppm as a broad peak. The hydrogens of (C-1) which are close to the oxygen atom of the morpholine unit appear at 2.49 ppm as a triplet peak due to coupling with H-2. The hydrogens of methyl groups appeared in 2.42 ppm as a singlet peak. In ¹³C NMR of L¹, the aromatic region has four signals in 143.05, 126.89, 129.46 and 137.18 ppm. The signals of carbons of morpholine unit are appeared at 53.37 and 66.39 ppm corresponding to C-2 and C-1, respectively. The signals of methyl groups appear at 21.31 ppm.

In ¹H and ¹³C NMR spectra of [H₃L²]Br₃, in contrast to L¹, all peaks for the aromatic ring are completely removed. The hydrogens of C-6 and C-7 appear at 3.30 ppm as a single peak. The peaks for H-3 and H-5 appeared as triplets at 3.16 ppm, respectively. The four protons of methylene groups of the morpholine ring seem to be diastrotopic and appeared in four regions as two doublets and two triplets. The geminal couplings in each methylene group as well as coupling with the adjacent methylene groups were confirmed by the ¹H–¹H COSY spectrum. Thus, the NMR data confirm that the morpholine moiety has chair conformation similar to solid state and gas phase (see next section).

A single crystal of [H₃L²]Br₃ was prepared, and X-ray crystallography clearly showed that asymmetrical amine has been synthesized. An ORTEP representation of the crystal structure is shown in Fig. 3 together with the numbering scheme adopted.

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Figure 3

The molecular structure of the protonated amine (L²) in its crystal structure.

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3.2 Theoretical studies

As it was discussed in the previous section the tripodal ligand L² was crystallized in the acetonitrile-methanol solution as its trihydrobromide salt. The X-ray crystal structure analysis of the above salt proposed that three protons are bound to two nitrogen atoms of primary amine groups and nitrogen atom of the morpholine moiety. However, we note that in the ligand L² there are five basic groups. As can be seen in Fig. 4, for triprotonated form of the ligand, without considering intramolecular hydrogen bonding there are seven different structures that differ in the location of protons/charges.

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Figure 4

Schematic illustration of all possible microspecies for [H₃L²]³⁺.

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For any protonated species such different structures usually define as its microspecies. We were interested to study the structure of all above possible microspecies and their relative stability. We have also studied some conformers for a number of above microspecies with considering intramolecular hydrogen bonding. The optimized structures for microspecies I–VII with or without considering intramolecular hydrogen bonding are shown in Fig. 5. It should be note that for microspecies VI, both the optimized conformers have intramolecular hydrogen bonding in their structure.

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Figure 5

The optimized structures for all studied microspecies of [H₃L²]³⁺.

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The total energies of all above microspecies and their relative stabilities are compared in Table 2. As it can be seen, in the absence of intramolecular hydrogen bonding the microspecies I is between 12.30 and 59.22 kcal/mol more stable than other microspecies. The intramolecular hydrogen bonding makes some microspecies more stable, but still microspecies I has the most stable structure among all microspecies. On the other hand, due to interaction of solvent molecules with protonated amines and possible formation of intermolecular hydrogen bonding, we can probably ignore the formation of intramolecular hydrogen bonding in the solution (Salehzadeh et al., 2009a,b). We note that the microspecies I is characterized by X-ray crystal structure analysis in the solid state (see Fig. 3). Thus it is probable that this microspecies has been dominant in the solution and upon crystallization is separated. Obviously, if microspecies I is the dominant microspecies in the solution then we must see good agreement between the experimental NMR data for [H₃L²]Br₃ in solution and corresponding calculated data for I. Table 3 shows a comparison between the ¹³C NMR data of [H₃L²]Br₃ and corresponding calculated data for microspecies I and VII which are the most and the less stable microspecies, respectively. As it can be seen, there is a good agreement between the experimental and calculated data for microspecies I. On the other hand, calculated data for less stable microspecies are considerably far from the corresponding experimental data. Thus all above calculations show that microspecies I is probably a dominant microspecies for the triprotonated form of the ligand L².

In addition to above studies we were interested to compare the protonation ability of ligand L² with a number of known tripodal amines. It has shown that while tris(3-aminopropyl)amine, tpt, catches four protons in solution, tris(2-aminoethyl)amine, tren, catches only three protons. Now let us to compare the change of energy in following reaction:

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Figure 6

The optimized structures for all studied microspecies of [H₄L²]⁴⁺.

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