Introduction

In recent years, investigation on carbacylamidophosphates is an important part of phosphoramidates chemistry. These compounds with the C(O)NHP(O) skeleton have attracted attention because of their properties as prodrugs [1–3], ureas inhibitors [4], and efficient ligands in coordination chemistry either as O-donor or O,O′-donor ligand [5–7]. On the other hand, isonicotinamide (Scheme 1) that is a pyridine derivative with an amidic C(O)NH2 group in para position, possesses strong anti-tubecular, anti-pyretic, fibrinolytic, and anti-bacterial properties [8].

Scheme 1
scheme 1

Isonicotinamide structure

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Polymorphism is an important phenomenon in different area of science especially in pharmaceutical investigations (many drugs receive regulatory approval for only a single crystal form or polymorph). In fact, the bioavailability of two polymorphs can differ appreciably, they are likely to perform differently in development and formulations processes, and are often a major problem in the delivery of pharmaceutical products. A well-known example of the effect of polymorphism causing real pharmaceutical problems is the ritonavir (an important AIDS drug), the Abbott compound [9, 10]. Norman and co-workers. reported two polymorphs of diazaphosphole compound (Scheme 2) [11].

Scheme 2
scheme 2

Diazaphosphole structure

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In this work, we synthesized some new phosphoric triamides with general formula 3-NC5H4C(O)NHP(O)XY (X=Y=Cl (1), X=Y=NH–C(CH3)3 (2a, 2b), X=Y=N(C4H9)2 (3), X=Cl, Y=N(C2H5)2 (4) that are derived from isonicotinamide. Surprisingly, the two polymorphs of compound 2 (2a, 2b) were obtained and their crystal structures were determined by X-ray crystallography. The spectroscopic and structural parameters of the polymorphs 2a and 2b were compared. Furthermore, the effects of substituents on 31P chemical shifts and 2 J(PNHamide) coupling constants were discussed.

Experimental

Synthesis

N-isonicotinyl-phosphoramidicdichloride, 3-NC5H4C(O)NHP(O)Cl2 (1)

To a suspension of phosphorous pentachloride (10 mmol, 2.08 g) in dry CCl4, isonicotinamide (3-NC5H4C(O)NH2) (10 mmol, 1.22 g) was added and the mixture was refluxed for 20 h. After cooling the flask, formic acid (10 mmol, 0.46 g) was added drop-wise into the solution at 0˚c and the resulting flask contents were stirred at room temperature for 6 h. The powder product was filtered, washed with CCl4, and dried under vacuum.

Yield: 55%. Decomposed. Anal. Calc. for C6H5N2Cl2O2P (%): C 30.15, H 2.11, N 11.72. Found: C 30.14, H 2.11, N 11.73. 1H-NMR (500.13 MHz, d6-DMSO): δ = 7.95 (s, 2H), 8.81 (s, 2H), 9.88 (d, 2 J(PNH) = 6.7 Hz), 1H, Hamide). 13C-NMR (125.77 MHz, d6-DMSO): δ = 165.10 (s, C=O), 145.55 (s), 143.17 (s), 125.93 (s). 31P-NMR (202.46 MHz, d6-DMSO): δ = −4.24 (d, 2 J(PNH) = 6.7 Hz). IR (KBr, cm−1): νmax = 3600 (m, NH), 3419 (m, NH), 3068 (m, CH), 1669 (s, C=O), 1597 (s), 1520 (s), 1480 (s), 1305 (s), 1252 (s), 1225 (s, P=O), 1198 (m), 1171 (m), 1108 (s), 1053 (s), 988 (m), 940 (s), 921 (m), 885 (m), 839 (m), 799 (m), 765 (m), 749 (s), 684 (m), 671 (s), 558 (m), 542 (s), 503 (m), 482 (m), 468 (m).

General procedure for the synthesis of compounds 2–4

Compounds 2a and 3 were synthesized from the reaction of 10 mmol of 1 with 20 mmol of corresponding amines and 20 mmol triethylamine in dry chloroform at −5 °C. After 6 h of stirring, the mixture was filtered and the solvent was evaporated at room temprature. The precipitate was washed with H2O and dried. Compound 4 was prepared in the same way but 10 mmol of diethylamine plus 10 mmol of triethylamine were added to the mixture of 1. The products were recrystallized from a mixture of choroform/n-hexan.

2a: Yield: 65%. m.p. = 267 °C. Anal. Calc. for C14H25N4O2P (%): C 53.83, H 8.07, N 17.94. Found: C 53.81, H 8.08, N 17.92. 1H-NMR (500.13 MHz, d6-DMSO): δ = 1.21(s, 18 H, CH3), 4.06 (d, 2J(PNH) = 7.3 Hz, 2H, Hamine), 7.84 (m, 2 H), 8.70 (m, 2H), 9.79 (d, 2J(PNH) = 4.4 Hz, 1H, Hamide). 13C NMR (125.77 MHz, d6-DMSO): δ = 166.61 (s, C=O), 150.07 (s), 141.12 (d, 3J(P,C) = 8.2 Hz), 121.53 (s), 50.34 (s), 31.12 (d, 3J(P,C) = 4.9 Hz). 31P-NMR (202.46 MHz, d6-DMSO): δ = 2.18 (b). IR (KBr, cm−1): νmax = 3390 (w, NH), 3232 (m, CH), 2967 (m), 1673 (s, C=O), 1441 (s), 1387 (s), 1361 (m), 1282 (m), 1227 (m), 1197 (s, P=O), 1119 (m), 1048 (s), 1017 (s), 887 (s), 850 (m), 820 (m), 757 (s), 695 (s), 573 (m).

3: Yield: 75%. Decomposed. Anal. Calc. for C22H41N4O2P (%): C 62.24, H 9.73, N 13.20. Found: C, 62.22; H, 9.72; N, 13.21. 1H-NMR (500.13 MHz, d6-DMSO): δ = 0.83 (t, 3J(H,H) = 7.4 Hz, 12H), 1.21 (m, 8H), 1.45 (m, 8H), 2.96 (m, 8H), 7.77 (dd, 3J(H,H) = 4.5 Hz, 5J(P,H) = 1.6 Hz, 2H), 8.72 (dd, 3J(H,H) = 4.5 Hz, 6J(P,H) = 1.6 Hz, 2H), 9.48 (b, 1H, Hamide). 13C NMR (125.77 MHz, d6-DMSO): δ = 13.68 (s), 19.66 (s), 30.30 (s), 45.00 (d, 2J(P,C) = 3.9 Hz), 121.59 (s), 141.13 (d, 3J(P,C) = 8.7 Hz), 150.10 (s), 166.83 (s, C=O). 31P NMR (202.46 MHz, d6-DMSO): δ = 13.11 (m). IR (KBr, cm−1): νmax = 3072 (m, CH), 2960 (m, CH), 2864 (m), 2735 (w), 1943 (w), 1675 (s,C=O), 1556 (m), 1457 (s), 1375 (m), 1281 (m), 1191 (s, P=O), 1040 (s), 994 (m), 932 (m), 877 (m), 840 (m), 785 (m), 755 (m), 697 (m), 555 (m), 495 (m).

4: Yield: 60%. m.p = 179 °C. Anal. Calc. for C10H15N3ClO2P (%): C 43.57, H 5.48, N 15.24. Found: C 43.56, H 5.47, N 15.25. 1H-NMR (500.13 MHz, d6-DMSO): δ = 1.15 (t, 3J(H,H) = 7.2 Hz, 3H), 2.88 (q, 3J(H,H) = 7.3 Hz, 2H), 7.78 (d, 3J(H,H) = 7.6 Hz, 2H), 8.79 (d, 3J(H,H) = 5.1 Hz, 2H), 9.74 (s, 1H, Hamide). 13C-NMR (125.77 MHz, d6-DMSO): δ = 165.23 (s, C=O), 150.17 (s), 121.29 (s), 79.11 (s), 41.06 (s), 10.85 (s). 31P-NMR (202.46 MHz, d6-DMSO): δ = −16.39 (s). IR (KBr, cm−1): νmax = 3278 (w, NH), 3081 (w, CH), 2737 (w), 2496 (w), 1671 (s, C=O), 1655 (s), 1599 (m), 1558 (m), 1505 (s), 1455 (s), 1390 (w), 1333 (m), 1289 (m), 1239 (P=O), 1166 (w), 1105 (s), 1064 (s), 994 (m), 956 (s), 887 (m), 879 (m), 852 (m), 836 (s), 815 (s), 757 (s), 723 (m), 707 (m), 698 (m), 663 (w), 621 (w).

N-3-isonicotinyl-N′,N″-bis(tert-butyl) phosphoric triamide, 3-NC5H4C(O)NHP(O)[NH–C(CH3)3]2 (2b)

To a solution of 2a (3 mmol, 0.936 g) in absolute ethanol, LaCl3, 7H2O (1 mmol, 0.371 g) was added and the solution was refluxed for 4 h. The product was recrystallized from a solution of ethanol/acetonitrile.

m.p = 213 °C. Anal. Calc. for C14H25N4O2P (%): C 53.83, H 8.07, N 17.94. Found: C 53.84, H 8.06, N 17.93. 1H-NMR (500.13 MHz, d6-DMSO): δ = 1.21 (s, 18 H, CH3), 4.08 (d, 2 J(PNH) = 7.0 Hz, 2H, Hamine), 7.84 (m, 2H), 8.70 (m, 2H), 9.80 (d, 2 J(PNH) = 7.0 Hz, 1H, Hamide). 13C-NMR (125.77 MHz, d6-DMSO): δ = 166.68 (s, C=O), 150.13 (s), 141.18 (d, 3 J(P,C) = 7.8 Hz), 121.60 (s), 50.40 (s), 31.18 (d, 3 J(P,C) = 4.8 Hz). 31P-NMR (202.46 MHz, d6-DMSO): δ = 2.18 (b). IR (KBr, cm−1): νmax = 3379 (s, NH), 2970 (w, CH), 1663 (s, C=O), 1446 (m), 1387 (m), 1363 (m), 1289 (m), 1207 (s, P=O), 1120 (w), 1019 (s), 995 (m), 893 (m), 851 (m), 758 (m), 701 (m), 578 (s).

Spectroscopic measurements

1H-, 13C-, and 31P-spectra were recorded on a Bruker Avance DRS 500 spectrometer. 1H and 13C chemical shifts were determined relative to internal Me4Si, 31P chemical shifts relative to 85% H3PO4 as external standards, respectively. The field strong to acquisition of 1H-, 13C-, and 31P-NMR spectra were 500.13, 125.77, and 202.46 MHz, respectively. Infrared (IR) spectra were recorded on a Shimadzu model IR-60 spectrometer. Elemental analysis was performed using a Heraeus CHN-O-RAPID apparatus.

X-ray measurements

X-ray data of compound 2a were collected on a Bruker SMART 1000 CCD [12] and of 2b on a Bruker APEX II CCD area detector [13] single crystal diffractometer with graphite monochromated MoKα radiation (λ = 0.71073 Å). The structures were refined with SHELXL-97 [14] by full matrix least squares on F 2. The positions of hydrogen atoms were obtained from the difference Fourier map. Routine Lorentz and polarization corrections were applied and an absorption correction was performed using the SADABS program for these structures [15, 16].

Results and discussion

Spectroscopic study

In this work, new phosphoramidates were synthesized from the reaction of PCl5 and isonicotinamide followed by oxidation with HCOOH to yield N-isonicotinyl-phosphoramidicdichloride (1) as an intermediate. The reaction of 1 with corresponding amines in the presence of an HCl scavenger such as triethylamine gave desired phosphoramidates 2a–4.

Surprisingly, the structure of 2b, which is a polymorph of 2a, was obtained from a solution of 2a in presence of LaCl3·7H2O in 3:1 M ratio (Scheme 3). Several parameters affect the formation of a polymorph such as solvent, certain impurities or additives, concentration, temperature, the geometry of covalent bonds, and the stirring conditions [17–19]. It is noteworthy that with 2:1 M ratio of 2a:LaCl3·7H2O, this solution did not yield 2b and it only gave 2a. In this case, the presence of the metal salt in solution caused formation of this polymorph. It is probably due to the weak coordination of compound 2a from P=O bond to La(III) center and then dissociation of O–La(III) linkage to form a new polymorph (2b). A possible description for the formation of 2b with 3:1 M ratio of ligand:metal not with 2:1 ratio, maybe is the higher ligand concentration that provides more opportunities for the ligand to interact with metal ion.

Scheme 3
scheme 3

Preparation pathway for compounds 1–4

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It is noteable that the interaction of 2a with other metal ions such as CeCl3·7H2O, ZnCl2, and NiCl2 did not yield 2b or a complex compound and it just left starting material. Application of La(NO3)3.6H2O, Ce(NO3)3·7H2O, Sm(NO3)3·7H2O, Er(NO3)3·7H2O, HgCl2, and SnCl2(CH3)2 afforded their corresponding complexes. The metal effect on the formation of different polymorphs have been investigated [20–25]. For a related example to our work, the effect of lanthanum ions on the lipid polymorphism of phosphatidylethanolamines was reported [26].

It should be stated that this polymorphism is not owing to the effect of the water from the hydrated LaCl3, because the 2:1 M ratio of 2a:LaCl3·7H2O did not afford 2b. To check the effects of H2O solvent on the formation of polymorh 2b, the interaction of 10 mmol of 2a with 30 mmol of H2O was studied, but this mixture did not give 2b.

Since, the crystals of compound 2a were obtained from choroform/n-hexan mixture and those of compound 2b from ethanol/acetonitrile solution, thus the recrystallization of 2a was performed again from ethanol/acetonitrile and that of 2b from chloroform/hexane mixture, but they did not indicate any changes. Therefore, it could be concluded that these polymorphs are not formed because of solvent influence.

Some spectroscopic data of compounds 1–4 are presented in Table 1. It could be observed from the table that replacement of the two Cl atoms in 1 by electron donating amine groups in compounds 2a, 2b, and 3 shifts the δ(31P) to down field. Also, the more electron donating dibutylamine groups have a greater effect on shifting the δ(31P) to down field than tert-butylamine moieties. It is interesting that in 4 with one Cl atom and one amine goup the δ(31P) shifts significantly to upfield. It seems that the Cl atom acts a donor group via resonance effect in 4 while comparatively it acts strongly as an electron withdrawing group in 1. Interestingly, long-range 5,6 J(P,H) = 1.6 Hz coupling constants are observed in 3 for the splitting of aromatic protons by phosphorus atom. The υ(P=O) value decreases by replacement of chlorine atoms in 1 with amine groups in 2a and 3. The υ(C=O) indicated an opposite trend.

Table 1 Spectroscopic NMR and IR data of compounds 1–4
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Interestingly, different melting points equal to 267 °C and 213 °C are obtained for 2a and 2b, respectively, showing a more thermally stable structure for 2a. Although, the δ(31P) values are identical for both of them, there are several differences in the spectroscopic parameters of polymorphs 2a and 2b. For example, the 2 J(PNHamide) coupling constant in 2b (7.0 Hz) is very much greater than in 2a (4.4 Hz). This may be described by their different spatial orientations leading to various torsion angles. The O1–P1–H1N–N1 torsion angles obtained from X-ray crystal structures are −162.5° and −154.42° for 2a and 2b. In the molecules the 2 J(PNHamine) and 3 J(P,C) coupling constants are nearly the same. The ν(P=O) in 2a is weaker than in 2b while ν(C=O) is stronger in 2a. Since the P=O and C=O bond lengths in the structures of 2a and 2b are approximately identical (see “X-ray crystallography” section), the differences in their ν(P=O) and ν(C=O) may be interpreted by the strengths of P=O…H–N hydrogen bonds. The O1…H1N distance in 2a and 2b are 1.97° and 1.93°, respectively. The weaker hydrogen bonding in 2a perhaps leads to a weaker P=O bond.

X-ray crystallography

Single crystals of compound 2a were prepared from choroform/n-hexan mixture and those of compound 2b from a solution of ethanol/acetonitrile after slow evaporation at room temperature. The crystal data and the details of the X-ray analysis are given in Table 2, selected bond lengths and angles in Table 3, and selected torsion angles in Table 4.

Table 2 Crystal data and structure refinement for compounds 2a, 2b
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Table 3 Selected bond lengths (Å) and angles (°) for compounds 2a and 2b
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Table 4 Selected torsion angles (°) for compounds 2a and 2b
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The structures of the two polymorphs 2a and 2b (Figs. 1, 2, respectively) display some differences in the solid state. For example, 2a crystallizes in monoclinic system with P21/n space group while 2b in a triclinic system with P–1 space group. The P=O and all P–N bonds are longer in 2a than in 2b but the C=O bond length is smaller in 2a. The differences in the bond angles are not significant while the torsion angles differ in great extent even up to ≈20°.

Fig. 1
figure 1

Molecular structure and atom labeling scheme for compound 2a (50% probability ellipsoids)

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Fig. 2
figure 2

Molecular structure and atom labeling scheme for compound 2b (50% probability ellipsoids)

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In these two structures, the phosphoryl and the carbonyl groups indicate anti-configurations with O(1)–P(1)–C(1)–O(1) torsion angle of −162.07° and −155.57° for 2a and 2b, respectively. The phosphorus atoms have distorted tetrahedral configuration, so that the bond angles around P(1) atoms in the compounds are in the range from 101.72(6)° to 119.63(6)°. The P=O bond lengths in compounds 2a and 2b are 1.481(1) and 1.483(1) Å, respectively, that are larger than the normal P=O bond length (1.45 Å) [27].

The P–Namide bonds (about 1.69 Å) are longer than the P–Namine bonds (about 1.63 Å), because of the resonance interaction of the Namide with the C=O π system that cause a partial multiple bond character in C–Namide (the C–Namide bond lengths are shorter than the C–Namine bond lengths (Table 3). All of the P–N bonds are shorter than the typical P–N single bond (1.77 Å [27]). This is probably owing to the electrostatic effects of polar bonds that overlap with P–N sigma bond [28].

The environment of the nitrogen atoms is practically planar. In compound 2a the angles C(1)–N(1)–P(1), C(1)–N(1)–H(1N) and P(1)–N(1)–H(1N) are 125.64(9)°, 120.4°, and 113.1°, respectively, with average 119.71°. The sum of surrounding angles around N(2), N(3), and N(4) atoms are 359.96, 354.16°, and 359.37°, respectively. Similar results were obtained for the nitrogen atoms of structure 2b that confirm the sp 2 hybridization for the N atoms, although due to the repulsion and steric interactions, some angles are greater, and others are smaller than 120°. This observation suggests the existence of partial multiple bond character between phosphorus and nitrogen atoms that has always been confirmed by the crystallographic data of our previously reported similar compounds [29–34].

These structures contain one amidic hydrogen atom and form centrosymetric dimers through intermolecular –P=O…H–N– hydrogen bonds (Table 5). In 2a, there are also N(2)–H(2N)…N(4), N(3)–H(3N)…O(2) and weak C(3)–H(3A)…O(1) intermolecular H-bonds. Thus, pairs of dimers are linked into an extended three-dimensional network via these H-bonds (Fig. 3). In the network of 2b, there are N(2)–H(2N)…N(4) and weak C(3)–H(3A)…O(1), C(13)–H(13A)…O(2) intermolecular hydrogen bonds. Moreover, there are intramolecular electrostatic interactions between O(2) of C=O group and N(3) atoms with the O…N distance of 2.980 Å in 2b. All of the mentioned hydrogen bonds lead to a two dimensional polymeric chain (Fig. 4).

Table 5 Hydrogen bonds for compounds 2a and 2b (Å, °)
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Fig. 3
figure 3

A three-dimensional polymeric chain produced by strong- and weak hydrogen bonds in the crystalline lattice of compound 2a

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Fig. 4
figure 4

A two-dimensional polymeric chain produced by strong hydrogen bonds and electrostatic interactions in the crystalline lattice of compound 2b

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Supplementary data

Crystallographic data for the structures 2a and 2b have been deposited with Cambridge Crystallographic Data Center as supplementary publication nos. CCDC 740179 (C14H25N4O2P) and CCDC 740180 (C14H25N4O2P). Copies of the data may be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +441223336033; E-mail: deposit@ccdc.cam.ac.uk or www: http://www.ccdc.cam.ac.uk).