Derivatives of the triaminoguanidinium ion, 6. Aminal-forming reactions with aldehydes and ketones

2.1 Reaction of the triaminoguanidinium ion with acetone

In an earlier paper, we have reported the synthesis of N,N′,N″-tris(propan-2-iminyl)guanidine 4 from 1 (X=Cl) and acetone [6]. A threefold condensation reaction probably gave rise to guanidinium salt 2, which, however, was not isolated as a pure product. Rather, the solid residue obtained after evaporation of the solvent was treated with aqueous NaOH to furnish the neutral guanidine 4 (Scheme 1). We report now, that under modified conditions two novel species could be isolated, which are likely intermediates in the conversion of triaminoguanidinium ion 1 into N,N′,N″-tris(propan-2-ylidenamino)guanidinium ion 2. To this end, an anion exchange 1-Cl→1-SO₄ was performed by passing an aqueous solution of the former over an ion-exchange resin loaded with sulfate ions. When the aqueous solution of 1-SO₄ was exposed to acetone vapor, a crystalline precipitate was formed which was identified as the double salt (5a, 5b) SO₄·2H₂O (30% yield after 3 days) by an X-ray crystal structure determination (Fig. 2). We assume that a network of hydrogen bonds between NH groups, sulfate ions and water molecules accounts for the low solubility in the water-acetone reaction medium.

Scheme 1:

Reaction of the N,N′,N″-triaminoguanidinium ion 1 with acetone. ^aAcetone as solvent, 4 days, r.t.; see ref. [6].

Fig. 1:

N,N′,N″-Triaminoguanidinium salts 1 and derivatives thereof.

Fig. 2:

Solid-state structure of the co-crystal of 5a (lower part of picture) and 5b with one SO₄²⁻ anion and two H₂O molecules in the asymmetric unit (Mercury). Hydrogen bonds are shown as blue-violet dashed bonds. N–H⋯O hydrogen bonds connect both cations with sulfate anions (one of the two SO₄²⁻ ions shown does not belong to the asymmetric unit), and O–H⋯O hydrogen bonds between sulfate anions and water molecules are also present. For the sake of clarity, not all short intermolecular contacts are shown. Selected bond lengths in 5a (Å): C1–N1 1.322, C1–N3 1.323, C1–N5 1.348, N1–N2 1.426, N3–N4 1.425, N5–N6 1.417, C2–N2 1.480, C2–N4 1.479. Selected bond lengths in 5b (Å): C5–N7 1.322, C5–N9 1.336, C5–N11 1.342, N11–N12 1.390, N7–N8 1.417, C6–N8 1.479, C6–N10 1.477, N10–N9 1.428(3); all estimated standard deviations are at ±0.003 Å.

Evidently, the two 2,3,4,5-tetrahydro-1,2,4,5-tetrazin-1-ium ions 5a and 5b result from a cyclic aminal (N,N-acetal) formation involving two branches of 1 and the carbonyl compound. This process is similar to the formation of five- or six-membered cyclic aminals from secondary 1,n-diamines (n=1, 2) and aldehydes [12], [13], [14] or ketones [13], [14] in aqueous reaction media. These preparations have been shown to be equilibrium reactions [13], [14]. Moreover, evidence for the reversibility of the aminal synthesis from imines and primary amines comes from transimination reactions in organic solvents [15]. By analogy it was not unexpected that further exposure of isolated (5a, 5b)SO₄·2H₂O followed by deprotonation with aqueous NaOH furnished the neutral guanidine derivative 4, which was identified by its ¹H and ¹³C NMR signals (see ref. [6]).

2.2 Reaction of the N,N′,N″-tris(benzylamino) guanidinium ion with aldehydes

The reaction of N,N′,N″-tris(benzylamino)guanidinium salt 3-Cl with paraformaldehyde under acidic conditions furnished the symmetrically tetrasubstituted 1,2,4,5-tetrazinane 6 in moderate yield (Scheme 2). The molecular structure was confirmed by an XRD analysis, which revealed a centrosymmetric chair conformation of the tetrazinane ring with axial benzyl substituents and trans-positioned vicinal triazole rings (Fig. 3); for a tetrazinane with analogous conformation, see ref. [16].

Scheme 2:

Reaction of tris(benzylamino)guanidinium salt 3-Cl with aldehydes.

Fig. 3:

Solid-state structure of 6 (Ortep). The molecule has a crystallographic inversion center. Torsion angle C11–N2–N1ⁱ–C2ⁱ 135.95°.

In contrast to formaldehyde, the reaction of benzaldehyde with 3-Cl required harsher conditions and only the 3-(2-benzylidenehydrazin-1-yl)-1H-1,2,4-triazole 7 was finally isolated in modest yield (Scheme 2). An XRD structure determination (Fig. 4) revealed the identity of 7 and also showed, that in the crystal structure centrosymmetric dimers are present, which are held together by two N–H⋯N hydrogen bridges. A hydrogen-bonded eight-membered ring motif is thus created (graph set R22(8) [17]). The 3-amino-1H-1,2,4-triazole moiety H–N_amino–C=N is isostructural to a COOH group, and analogous homo-dimers are often found in solid-state structures of carboxylic acids; furthermore, the same hydrogen bond pattern occurs in several 3-amino-1,2,4-triazolium carboxylate complexes [18]. In the crystal structure of the parent 3-amino-1H-1,2,4-triazole, on the other hand, all nitrogen atoms are involved in a network of hydrogen bonds, but centrosymmetrical eight-membered cyclic dimers as in 7 are not present [19].

Fig. 4:

Solid-state structure of 7 (Mercury). A centrosymmetric dimer is shown, which is maintained by two N–H⋯N hydrogen bonds [distances (Å): N2⋯N4 3.042(2), N4–H 0.89(2), N2⋯H(N4) 2.19(2); angle N2⋯H–N4 159.3(16)°].

A mechanistic proposal for the reaction of triaminoguanidinium salt 3-Cl with formaldehyde (generated in situ from paraformaldehyde) or benzaldehyde is presented in Scheme 3. It is based on the assumption that 4-hydrazinyl-1,2,4-triazoles 9 (R=H or Ph) are the key intermediates, which are formed by condensation of the aldehyde with one of the nucleophilic benzylamine nitrogen atoms, 1,5-cyclization to an N-protonated triazolidine, and deprotonation as well as β-elimination of benzylamine. In the presence of formaldehyde, the benzylhydrazine side-chain of 9 is transformed into an azomethine imine dipole 8 which can dimerize in a formal (3+3) cycloaddition to furnish 1,2,4,5-tetrazinane 6. The formation of symmetrically substituted 1,2,4,5-tetrazinanes from hydrazine [20] or substituted hydrazines [16], [21], [22] and aldehydes or ketones is known. Starting from N¹-alkyl-N²-acylhydrazines, the azomethine imine intermediate has been trapped in 1,3-dipolar cycloaddition reactions [21], [22]. In the presence of benzaldehyde, 3-Cl does not appear to react in the same manner; instead, a spontaneous benzylamine → benzylimine dehydrogenation could generate hydrazone 7.

Scheme 3:

Proposed mechanism of the reaction of 3-Cl with aldehydes.

2.3 Reaction of N,N′,N″-tris(benzylamino)guanidine with acetone

N,N′,N″-Tris(benzylamino)guanidine (10) is readily obtained by base-assisted deprotonation of guanidinium salt 3-Cl with aqueous NaOH (Scheme 4). We noticed, however, that the aqueous solution of 3-Cl instantanously developed a yellow color on contact with the base and turned orange on prolonged standing. Control experiments showed this phenomenon to occur only in the presence of air and also with amine bases instead of NaOH. NMR monitoring revealed that a stepwise dehydrogenation of the three PhCH₂–NH groups of 10 took place, which finally resulted in tris(benzylidenamino)guanidine 13. The latter can be obtained more conveniently by deprotonation of N,N′,N″-tris(benzylidenamino)guanidinium chloride 14 (which is in fact the direct synthetic precursor of 3-Cl [9]). A crystal structure determination confirmed the identity of 13 (Fig. 5).

Scheme 4:

Formation and stepwise dehydrogenation of N,N′,N″-tris(benzylamino)guanidine 10 in basic medium. a=exposure to air.

Fig. 5:

Solid-state molecular structure of 13 (Ortep). Bond distances (Å): C1–N1 1.356(3), C1–N2 1.329(3), C1–N3 1.343(3), N1–N4 1.371(2), N2–N5 1.406(3), N3–N6 1.388(3), N4–C2 1.277(3), N5–C3 1.260(3), N6–C4 1.299(3).

The progress of the dehydrogenation cascade was monitored by ¹NMR spectroscopy (Table 1). It can be seen, that under the given reaction conditions the first step (10→11) has an appromixate half-life time of 1 h, whereas the reaction mixture contains 11 and 12 in the ratio 14:86 after 72 h. The last step (12→13) appears to be rather slow, and only a small amount of 13 (9%) was observed after 90 h. The spontaneous dehydrogenation of the benzylamino groups in 10–12 is remarkable. In other cases, the conversion of a benzylhydrazine into a benzylhydrazone with oxygen was achieved in the presence of transition-metal catalysts (N-methyl-N-phenyl-N′-benzylhydrazine, air, Ru(bpyrz)²⁺, hν [23]; benzyl 2-benzylhydrazinecarboxylate, O₂, Cu(OAc)₂ [24]).

A remarkable feature in the molecular structure of guanidine 13 (Fig. 5) is worth being mentioned. The C–N bond lengths in the CN₃H₂ core are rather similar, the imine bond C–N2 bond (1.329 Å) being distinctly longer than a typical C=N double bond and the two C–NH single bonds (1.343 and 1.356 Å) being shorter than expected (for a comparison, see the bond distances in the guanidine moiety of 16, Fig. 6). This kind of bond length equalization may be due to extended π (cross-)conjugation, which includes the two n orbitals of the NH nitrogen atoms. A positional disorder, caused by 120° rotations around the axis perpendicular to the CN₃ plane, which would mimic a C₃-symmetric molecule, appears less likely, as no residual electron density in a reasonable geometry that would suggest the presence of a hydrogen atom bonded at N2 was found. On the other hand, NMR spectra of 13 in (CD₃)₂SO (DMSO-d₆) are temperature-dependent: spectra taken at T=298 K point to a static strucure with three magnetically different branches of the molecule, in contrast to a time-averaged C₃-symmetric structure at 353 K (see Section 4.5). As we have discussed for N,N′,N″-tris(propan-2-iminyl)guanidine [6], prototropic tautomerism in the CN₃H₂ core is likely to be the dominant dynamic process.

Fig. 6:

Molecules 15 (left) and 16 in the 1:1 cocrystal (Ortep). Bond distances (Å) in 15: C1–N1 1.287(2), C1–N3 1.372(2), C1–N5 1.389(2), N5–N6 1.374(2), N6–C19 1.283(2), N1–N2 1.434(2), N3–N4 1.425(2). Bond distances (Å) in 16: C28–N7 1.394(2), C28–N9 1.366(2), C28–N12 1.285(2), N7–N8 1.452(2), N9–N10 1.430(2), N11–N12 1.451(2). Intermolecular hydrogen bonds between 15/15 and 15/16 [d(N–H)/d(H⋯N)/d(N⋯N)/<(N–H⋯N)]: N3–H⋯N4 (−x, −y+1, −z) 0.86 Å/2.42 Å/3.216 Å/155°; N5–H⋯N11 0.99/2.21/3.202/175; N5–H⋯N12 0.99/2.69/3.544/145; N7–H⋯N12 (−x, −y+1, −z+1) 0.87/2.24/3.106/172; N10–H⋯N1) 0.92/2.18/3.059/159.

To explore the reactivity of tris(benzylamino)guanidine 10 and its dehydrogenated descendants toward acetone, the procedure indicated in Scheme 5 was applied. Deprotonation of guanidinium salt 3-Cl generated guanidine 10, which was exposed to air for 1 h, then dissolved in acetone. Addition of pentane by the vapor diffusion method provided crystals, which were identified as 1:1 cocrystals of 1,2,3,4-tetrahydro-1,2,4,5-tetrazine 15 and 2H,3H,4H,6H,7H,8H-[1,2,3]triazolo[4,3-b][1,2,4,5]tetrazine 16 (Fig. 6). (For a synthesis of the fully unsaturated parent system, see ref. [25]). The two compounds, which were obtained in 56% combined yield, could not be separated by liquid chromatography. Taking into account the aforementioned observations concerning the stepwise aerobic dehydrogenation of guanidine 10, we suggest that both guanidines 10 and 11 are involved in the reaction. Acetone could react with 10 to form an aminal 17, which after dehydrogenation of the PhCH₂–NH group would deliver tetrazinane 15. On the other hand, formation of a cyclic five-membered aminal 18 could be formed from 11 and acetone, and a subsequent intramolecular amine-to-imine aminal formation would provide the bicyclic tetrazine derivative 16. As the sequence of individual steps (dehydrogenation vs. aminal formation) may be interchanged, modified reaction pathways cannot be excluded (nor the possibility that both products come from the same precursor, guanidine 10 or 11).

Scheme 5:

Synthesis of tetrazinane derivatives 15 and 16 and a mechanistic proposal.

Figure 6 shows molecules of 15 and 16 in the cocrystal. As one would expect, the C=N double bond in the guanidine moieties of both molecules is distinctly shorter [C–N1 1.287(2), C28–N12 1.285(2) Å] than the C–N single bonds (1.366–1.394 Å). This excludes the presence of an NH tautomer with an exocyclic C=N bond, in contrast to the situation in guanidine 13. In the crystal structure, molecules of 15 and 16 are connected by several N–H···N hydrogen bonds; one of them is found between two molecules of 15, the other ones between molecules of 15 and 16.

4.1 General information

NMR spectra were recorded on Bruker Avance 400 (¹H: 400.13 MHz; ¹³C: 100.62 MHz) and Avance 500 spectrometers (¹H: 500.14 MHz, ¹³C: 125.76 MHz). The signal of the solvent was used as an internal standard: δ^H((CH₃)₂SO)=2.50 ppm, δ^C((CD₃)₂SO)=39.43 ppm. NMR spectra were measured at T=298±2 K, if not stated otherwise. IR spectra: Bruker Vector 22; wavenumbers (cm⁻¹) and intensities (vs=very strong, s=strong, m=medium, w=weak, br=broad) are given. Elemental analyses: elementar vario MICRO cube. Melting points were determined with a Büchi Melting Point B-540 apparatus; the heating rate was 3 K min⁻¹. The reactions were carried out under air atmosphere if not stated otherwise.

Guanidinium salts 1-Cl [29], 3 [9] and 14 [9] were prepared as reported.

4.2 (6-(Hydrazin-1-yl)-3,3-dimethyl-2,3,4, 5-tetrahydro-1,2,4,5-tetrazin-1-ium (5a) and 3,3-dimethyl-6-(2-propan-2-ylidene)hydrazin-1-yl)-2,3,4,5-tetrahydro-1,2,4,5-tetrazin-1-ium (5b) sulfate (1:1 cocrystal) (5a·5b·SO₄)

A chromatographic column (l=50 cm, diameter 5 cm) was charged with a strongly basic anion exchanger (type III, OH form, Merck Supelco, 4.0 g) dispersed in water (50 mL). An anion exchange was achieved by passing a saturated aqueous solution of sodium sulfate (40 mL) through the column, followed by an aqueous wash (10 mL) and elution with a solution of N,N′,N″-triaminoguanidinium chloride (1-Cl, 2.00 g, 14.22 mmol) in water (5 mL). Slow addition of acetone to the slightly orange-colored eluate by vapor diffusion led to a deeper coloration and colorless crystals of (5a, 5b)SO₄·2H₂O appeared, which were isolated by filtration. A suitable crystal was used for X-ray diffraction. Freeze-drying of this batch afforded 921 mg (2.16 mmol, 30%) of the anhydrous double salt (5a, 5b)SO₄ as a microcrystalline solid; m. p. 180°C (dec.). – ¹H NMR ((CD₃)₂SO, 500.14 MHz): δ=1.12 (s, 6 H, C(CH₃)₂), 1.14 (s, 6 H, C(CH₃)₂), 1.90 (s, 6 H, N=C(CH₃)₂), 3.60–6.1 (broad unstructured signals with maximum intensities at 4.45 and 5.32 ppm, 8 H, NH_tetrazine + NH₂), 7.70–10.50 (region of coalescing signals) ppm. – ¹³C NMR ((CD₃)₂SO, 125.76 MHz): δ=17.98 (N=C(CH₃)₂), 22.42 (C(CH₃)₂) 22.49 (C(CH₃)₂), 24.84 (N=C(CH₃)₂), 62.29 (C(CH₃)₂), 64.50 (C(CH₃)₂), 150.02 ((CN₃)⁺), 152.96 (N=C(CH₃)₂), 153.15 ((CN₃)⁺) ppm. – IR (KBr): ν=3700–2800 (very broad, strong maximum at 3211), 1676 (s), 1626 (vs), 1440 (m), 1378 (m), 1335 (m), 1266 (m), 1241 (m), 1115 (vs), 981 (m), 821 (m), 619 (s) cm⁻¹. – Anal. for (C₄H₁₃N₆)⁺×(C₇H₁₇N₆)⁺×SO₄²⁻ (C₁₁H₃₀N₁₂O₄S, 426.50 g mol⁻¹): calcd. C 30.98, H 7.09, N 39.41, S 7.52; found C 30.77, H 6.93, N 39.59, S 7.39.

4.3 1,4-Dibenzyl-2,5-bis(1-benzyl-1H-1,2,4-triazol-3-yl)-1,2,4,5-tetrazinane (6)

N,N′,N″-Tris(benzylamino)guanidinium chloride (3-Cl) (1.64 g, 4.00 mmol) was dissolved in chloroform (30 mL) and paraformaldehyde (360 mg, corresponding to 12.00 mmol formaldehyde) suspended in methanol (15 mL) as well as hydrochloric acid (2 m, 2 mL) were added. The stirred mixture was heated at reflux for 2 h, a clear solution being formed already after 10 min. The solution was allowed to assume room temperature and stirred for additional 16 h, then concentrated as far as it remained clear. On exposure to an ether atmosphere overnight, colorless crystals separated, which were isolated by filtration, washed with Et₂O, and re-dissolved in hot MeOH–acetone (3:1 v/v). The product was precipitated by addition of water, filtered off, and freeze-dried. Yield: 984 mg (1.60 mmol, 42%); m.p. 190.9–191.4°C. – ¹H NMR ((CD₃)₂SO, 500.14 MHz): δ=3.98 (s, 4 H, CH₂N–CH₂Ph), 4.69 (broad s, 4 H, NCH₂N), 5.30 (s, 4 H, N_triazole–CH₂Ph), 7.17–7.19 (m, 6 H, H_Ph), 7.30–7.40 (m, 14 H, H_Ph), 8.38 (s, 2 H, N=CH) ppm. – ¹³C NMR ((CD₃)₂SO, 125.76 MHz): δ=52.05 (N_triazole–CH₂Ph), 53.41 (CH₂N–CH₂Ph), 57.58 (NCH₂N); 126.87, 127.62, 127.74, 127.83, 128.53, 128.68 (all CH_Ph); 136.78 (i-C_Ph), 137.96 (i-C_Ph), 143.79 (N=CH), 165.12 (N=C) ppm. – IR (KBr): ν=3511 (m), 3029 (m), 2933 (m), 2858 (m), 1634 (s), 1550 (vs), 1494 (s), 1452 (s), 1370 (m), 1318 (m), 1209 (m), 1154 (m), 1069 (m), 1024 (s), 801 (m), 742 (s) cm⁻¹. – Anal. calcd. for C₃₄H₃₄N₁₀ (582.72 g mol⁻¹): C 70.08, H 5.88, N 24.04; found C 69.73, H 5.97, N 24.22.

4.4 1-Benzyl-3-(2-((E)-benzylidene)hydrazin-1-yl)-5-phenyl-1H-1,2,4-triazole (7)

A stirred solution of N,N′,N″-tris(benzylamino)guanidinium chloride (3-Cl) (2.05 g, 5.00 mmol) and benzaldehyde (1.1 mL, 10.88 mmol) in chloroform (50 mL) was heated at 50°C for 67 h. The solution turned green and benzylammonium chloride precipitated, which was filtered off and washed with CHCl₃. The combined filtrates were placed in a separatory funnel and washed with water (50 mL) and hydrochloric acid (1 m, 2 mL) to remove any benzylamine. The organic phase was separated, dried (MgSO₄), and the residue obtained after solvent evaporation was submitted to a flash chromatography over silica gel (eluent ethyl acetate, R_f=0.7–1.0). The obtained product was dried at 0.05 mbar to yield a beige-colored solid. Yield: 597 mg (1.69 mmol, 34%); m. p. 170.9–171.9°C. – ¹H NMR ((CD₃)₂SO, 400.13 MHz): δ=5.40 (s, 2 H, CH₂), 7.16 (d, J=7.1 Hz, 2 H, H_Ph), 7.28–7.38 (m, 6 H, H_Ph), 7.52–7.54 (m, 2 H, H_Ph), 7.59–7.61 (m, 3 H, H_Ph), 7.65–7.68 (m, 2 H, H_Ph), 8.02 (s, 1 H, N=CH), 10.83 (s, 1 H, NH) ppm. – ¹³C NMR ((CD₃)₂SO, 100.61 MHz): δ=51.91 (CH₂); 125.91, 126.67, 127.60, 127.79, 128.30, 128.36, 128.65, 128.74, 128.98, 130.11 (all CH_Ph); 135.42 (C_Ph), 136.80 (CH₂C_Ph), 139.31 (N=CHPh), 153.61 (C-5_triaz), 160.98 (C-3_triaz) ppm. – IR (KBr): ν=3197 (s), 3034 (s), 1737 (m), 1569 (s), 1532 (s), 1471 (s), 1450 (s), 1416 (m), 1363 (s), 1322 (s), 1300 (s), 1247 (m), 1222 (m), 1158 (m), 1123 (s), 1061 (m), 1029 (m), 1013 (m), 930 (m), 752 (s), 721 (s), 695 (s) cm⁻¹. – Anal. calcd. for C₂₂H₁₉N₅ (353.43 g mol⁻¹): C 74.77, H 5.42, N 19.82; found C 74.67, H 5.44, N 19.72.

4.5 N,N′,N″-Tris(benzylidenamino)guanidine (13)

To a solution of N,N′,N″-tris(benzylidenamino)guanidinium chloride (14, 1.76 g. 4.37 mmol) [9] in methanol (40 mL) was gradually added an aqueous solution of NaOH (5 m, 10 mL). After stirring during 1 h at ambient temperature, the precipitate was filtered off, washed with diethylether and water and dried at 130°C/0.05 mbar) to furnish 1.38 g (3.75 mmol, 86%) of a yellow solid. M. p. 199.0–200.0°C. – ¹H NMR ((CD₃)₂SO, 400.13 MHz): δ=7.41–7.48 (m, 9 H, H_Ph), 7.70 (d, J=7.2 Hz, 2 H, o-H_Ph), 7.86 (d, J=7.2 Hz, 2 H, o-H_Ph), 7.91 (d, J=6.8 Hz, 2 H, o-H_Ph), 8.34 (s, 1 H, N=CH), 8.40 (s, 1 H, N=CH), 8.47 (s, 1 H, N=CH), 10.22 (s, 1 H, NH), 10.59 (s, 1 H, NH) ppm. – ¹H NMR ((CD₃)₂SO, 500.16 MHz, T=353 K, fast exchange region): δ=7.38–7.45 (m, 9 H, H_Ph), 7.81 (d, J=7.1 Hz, 6 H, o-H_Ph), 8.41 (s, 3 H, N=CH), 10.21 (br. s, 2 H, NH) ppm. – ¹³C NMR ((CD₃)₂SO, 125.76 MHz, T=353 K): δ=126.67, 128.23, 128.80 (two C_Ph signals probably coincide at 128.23), 135.00 (N=CH), 151.50 (CN,N,N) ppm. – IR (KBr): ν=3320 (m), 3056 (w), 3022 (w), 1625 (s), 1580 (s), 1538 (s), 1487 (s), 1447 (s), 1429 (s), 1351 (m), 1286 (m), 1226 (m), 1136 (s), 1092 (s), 1069 (m), 940 (m), 758 (s), 694 (s) cm⁻¹. – Anal. calcd. for C₂₂H₂₀N₆ (368.44 g mol⁻¹): C 71.72, H 5.47, N 22.81; found C 71.95, H 5.47, N 22.74.

4.6 Synthesis and stepwise dehydrogenation of guanidine 10

An air stream was continuously passed through a magnetically stirred solution of N,N′,N″-tris(benzylamino)guanidinium chloride (3-Cl, 100 mg) in (CD₃)₂SO while aqueous NaOH (5 m, 0.15 mL) was gradually added from a syringe. The solution instantly developed a yellow color and turned deep orange after 10 min. The progress of the reaction was monitored by NMR spectroscopy, showing the formation of guanidines 10, 11, 12 and 13 (see Tables 1 and 2), which were not isolated. After 90 h, hydrochloric acid (2 m) was added, whereupon the NMR signals of guanidinium salt 14 appeared. In a parallel experiment, the air stream was replaced by argon. The color of the solution remained yellow and only guanidine 10 was observed, which was re-converted into 3-Cl by addition of hydrochloric acid.

Table 2:

¹H and ¹³C NMR data of guanidine derivatives 10–13.

Compound		NMR data (δ values, solvent (CD3)2SO)a
3-Cl		1H: 3.73 (s, 6H, 4-H), 5.65 (s, 3H, 3-H), 7.30 (m, 15 H, H), 8.79 (s, 3 H, 2-H) 13C: 54.42 (C-4), 127.36, 128.20, 129.09, 137.01 (ipso-CPh), 156.99 (C-1)
10		1H: 3.74 (s, 6H, 4-H), 4.45 (s, 3H, 3-H), 6.64 (s, 2H, 2-H), 7.20-7.40 (m, 15H, 5-H) 13C: 55.83 (C-4), 156.06 (C-1)
11		1H: 3.86 (s, 2H, 8-H), 3.99 (s, 2H, 7-H), 4.86 (s, 1H, 4-H), 5.02 (s, 1H, 5-H), 7.31 (s, 1H, 3-H), 7.65 (s, 1H, 2-H), 7.72 (m, 2H, 9-H), 8.20 (s, 1H, 6-H) 13C: 55.69 (C-7), 55.92 (C-8); 137.01, 138.32, 139.92 (3.i-CPh); 146.88 (C-6), 159.46 (C-1)
12		1H: 4.08 (d, J=4.0 Hz, 2H, 7-H), 4.89 (dd, J=4.0 and 3.2 Hz, 1H, 4-H), 7.77 (m, 2H, HPh), 7.91 (m, 2H, HPh), 8.08 (d, J=3.2 Hz, 1H, 3-H), 8.28 (s, 1H, 5-H), 8.31 (s, 1H, 6-H), 10.46 (s, 1H, 2-H) 13C: 55.30 (C-7), 142.30 (C-6), 148.70 (C-5), 155.60 (C-1)
13		See Section 4.4

1. ^a1H spectra measured at 400.13 MHz, T=298 K; ¹³C spectra measured at 100.61 MHz, T=298 K. Spectra of 26 recorded at T=353 K. Due to overlapping signal sets in the product mixtures, signals of phenyl rings are reported incompletely or not at all. Where necessary, signal assignments were taken from 2D correlation spectra.

4.7 2,4-Dibenzyl-3,3-dimethyl-6-(2-((E)-benzylidene)hydrazin-1-yl)-1,2,3,4-tetrahydro-1,2,4,5-tetrazine (15) and 2,7-dibenzyl-6,6-dimethyl-3-phenyl-2H,3H,4H,6H,7H,8H-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine (16)

N,N′,N″-Tris(benzylamino)guanidinium chloride (3-Cl) (350 mg, 0.85 mmol) was suspended in ethyl acetate (45 mL), aqueous NaOH (0.33 m, 45 mL) was added and the biphasic liquid mixture was exposed to ultrasonic irradiation for 5 min. A color change from colorless to yellow was observed. The mixture was transferred into a separatory funnel and the organic phase was extracted with more water, isolated, dried (Na₂SO₄), and set aside with air contact for 1 h. After solvent evaporation, a viscous yellow oil remained, which was dissolved in acetone (2 mL). Upon addition of pentane by the vapor diffusion method, tufts of columnar pale yellow crystals were formed overnight, which were identified as 1:1 cocrystals of 15 and 16 by XRD analysis. Yield: 199 mg (0.48 mmol, 56%); melting range of 40–140°C. – IR (KBr): ν=3500–2000 (continuous absorption with several maxima), 1626 (m), 1585 (m), 1559 (m), 1489 (m), 1449 (m), 1363 (m), 750 (m), 694 (m) cm⁻¹. – Anal. calcd. for C₂₅H₂₈N₆×C₂₅H₂₈N₆ (C₅₀H₅₆N₁₂, 825.07 g mol⁻¹): C 72.79, H 6.84, N 20.37; found C 72.81, H 6.73, N 20.29.

NMR data for 15: ¹H NMR ((CD₃)₂SO, 400.13 MHz): δ=1.30 (s, 6 H, CH₃), 3.82 (s, 2 H, CH₂), 3.92 (s, 2 H, CH₂), 7.10–7.50 (m, 15 H, H_Ph), 7.30 (s, 1 H, CH₂NNH), 7.67 (s, 1 H, N=CH), 9.88 (s, 1 H, N=C–NH) ppm. – ¹³C NMR ((CD₃)₂SO, 100.61 MHz): δ=20.73 (CH₃), 55.11 (CH₂), 56.27 (CH₂), 70.74 (C(CH₃)₂), 125.62, 126.08, 126.25, 126.37, 126.52, 127.65, 127.81, 127.94, 128.26, 128.44, 128.54, 128.61, 128.68, 128.77, 129.20 (CH_Ph, 15 and 16), 135.70, 138.19, 139.48, 139.57, 139.67, 141.37 (C_Ph, both compounds), 136.38 (N=CH), 141.37 (NH–C=N) ppm.

NMR data for 16: ¹H NMR ((CD₃)₂SO, 400.13 MHz): δ=1.22 (s, 3 H, CH₃), 1.30 (s, 3 H, CH₃), 3.18 and 3.60 (AB spin system, 2 H, ²J=13.2 Hz, CH_AH_B–NC(CH₃)₂), 3.44 (d, 1 H, J=11.6 Hz, CHPh), 3.70 and 4.01 (AB spin system, 2 H, ²J=12.8 Hz, CH_AH_B–NCH), 5.32 (d, 1 H, J=11.6 Hz, NHCH), 7.10–7.50 (m, 15 H, H_Ph), 7.49 (s, 1 H, NHC=N) ppm. – ¹³C NMR ((CD₃)₂SO, 100.61 MHz): δ=20.32 (CH₃), 20.73 (CH₃), 56.31 (CH₂NCH), 58.33 (CH₂N–C(CH₃)₂), 74.99 (CH_Ph), 83.67 (C(CH₃)₂), 149.50 (NHC=N) ppm.

4.8 Crystal structure determinations

Experimental details and crystal data are given in the Supporting Information available online (see below). Molecule plots were prepared using Ortep-3 for Windows [30] or Mercury [31].