Synthesis of new Guanidium-Meldrum acid zwitterionic salts and dynamic NMR study of rotational energy barrier around C-NH bond of guanidine moiety

Intruduction

The Knoevenagel condensation of Meldrum acid with aromatic aldehydes with the aim of forming a carbon-carbon double bond is a well-documented reaction ¹ that carried out using various conditions. ² Arylidene Meldrum acids are useful reactive intermediates, being susceptible to 1, 4-addition, ³ in Diels-Alder reactions acting as activated dienophiles ⁴ and preparation of heterocyclic molecules such as coumarins, ⁵ indoles and benzofurans ⁶ and other useful compounds.^4,7Recently we prepared an unusual charge-separated Guanidium-meldrum acid zwitterionic salts using three component reaction. The zwitterions are often as an intermediate species in some reactions. ^8-10 we now describe the synthesis zwitterionic salts by means of a reaction of N, N, N’, N’-Tetramethyl-guanidine with conjugated electrophilic heterodienes. Dynamic NMR provides important kinetic data and affords good information in this matter on a dynamic process, when discussing the barrier separating two states that are observable by NMR spectroscopy. ¹¹ Thus, herein the free-energy of activation (ΔG^#) for restricted rotation around the C-NH bond of zwitterionic salt 4b is described.

Material and Methods

General

Compounds 1–3 were obtained from Fluka and Merck and were used without further purification. The following instruments were used: mp., Electrothermal-9100 apparatus, uncorrected; IR spectra, Shimadzu IR-460 spectrometer; ¹H and ¹³C NMR spectra, Bruker DRX-300 AVANC E instrument; in CDCl₃ at 300.1 MHz and 75.4 MHz, respectively, δ in ppm, J in Hz; EI-MS (70 eV): Finnigan-MAT-8430 mass spectrometer, in m/z. Elemental analyses (C, H, N) were performed with a Heraeus CHN-O-Rapid analyzer.

General procedure for preparation of Guanidium-meldrum acid zwitterionic salts (exemplified by 4b) To a magnetically stirred of 0.158 g of meldrum acid (1.1 mmol) and 0.120 g of 4-methylbenzaldehyde (1.0 mmol) in 10 cm³ of dry benzen (distilled from Na/benzophenone, 5.0 mL, 0.2 M) was added 200 µL of a 0.5 mM solution of pyrrolidinium acetate in benzene (prepared by dropwise addition of AcOH to piperidine in benzene, 0.1 mmol, 10 mol%) and stirred about 20 hour. Then the reaction mixture was washed with saturated NaHCO₃ solution (2 × 10 mL). Then 0.115 g of N, N, N’, N’-Tetramethyl guanidine (1.0 mmol) in 3 cm³ of benzen was added to organic layer over one minute at room temperature. After less four hours stirring at room temperature, the solvent was removed and the crude product washed by acetone (2 × 3 mL), and residue powder filtered.

5-{((bis (dimethylamino) methylene) ammonio) (phenyl) methyl}-2, 2-dimethyl-4, 6-dioxo-1, 3-dioxin-5-ide (4a)

White powder, mp 168-170 °C (decomp), 0.236 g, (68%). IR (KBr) (ν_max/cm⁻¹): 1612 (C=O), 1681 (C=N), 3254 (NH). ¹H NMR (300.1 MHz, CDCl₃): δ 1.56 (6H, s, CMe₂), 2.92 and 2.99 (12H, 2s, 2NMe₂), 5.67 (1H, d, ³J_HH = 8.6 Hz, HN-CH), 7.20 (1H, t, ³J_HH = 7.4 Hz, CH), 7.28 (2H, d, ³J_HH = 7.4 Hz, 2CH), 7.56 (2H, d, ³J_HH = 7.4 Hz, 2CH), 9.05 (1H, d, ³J_HH = 8.6 Hz, NH) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ 26.33 (CMe₂), 40.08, 40.79 (2NMe₂), 57.37 (HN-CH), 77.05 (HC-C-C) 102.32 (CMe₂), 126.1 (2CH), 127.4 (CH), 128.9 (2CH), 143.8 (C), 161.74 (N-C-NH), 166.66 (2C, s, 2C=O) ppm. MS, m/z (%): 347 (M⁺, < 1), 246 (34), 173 (100), 160 (41), 115 (79), 91 (21), 71 (52), 43 (37). Anal. Calcd for C₁₈H₂₅N₅O₃ (347.41): C, 62.23; H, 7.25; N, 12.10. Found: C, 62.18; H, 7.17; N, 12.20

5-{((bis (dimethylamino) methylene) ammonio) (p-tolyl) methyl}-2, 2-dimethyl-4, 6-dioxo-1, 3-dioxin-5-ide (4b)

White powder, mp 182-184 °C (decomp), 0.275 g, (76%). IR (KBr) (ν_max/cm⁻¹): 1608 (C=O), 1681 (C=N), 3236 (NH). ¹H NMR (300.1 MHz, CDCl₃): δ 1.55 (6H, s, CMe₂), 2.28 (3H, s, Me), 2.92 and 2.98 (12H, 2s, 2NMe₂), 5.67 (1H, d, ³J_HH = 8.5 Hz, HN-CH), 7.08 (2H, d,J = 7.8 Hz, 2 CH), , 7.38 (2H, d,J = 7.8 Hz, 2CH), 8.97 (1H, d, ³J_HH = 8.5 Hz, NH) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ 21.42 (Me), 26.34 (CMe₂), 40.07, 40.73 (2NMe₂), 57.22 (HN-CH), 77.05 (HC-C-C), 102.26, (CMe₂), 126.00 (2CH), 129.38 (2CH), 136.56 (C), 140.57 (C), 161.70 (N-C-NH), 166.65 (2C, s, 2C=O) ppm. MS, m/z (%): 361 (M⁺, < 1), 246 (91), 188 (84), 173 (97), 160 (30), 144 (22), 115 (100), 105 (16), 71 (45), 57 (18), 43 (34). Anal. Calcd for C₁₉H₂₇N₃O₄ (361.44): C, 63.14; H, 7.53; N, 11.63 Found: C, 63.27; H, 7.59; N, 11.58.

5-{((bis (dimethylamino) methylene) ammonio) (o-tolyl) methyl}-2, 2-dimethyl-4, 6-dioxo-1, 3-dioxin-5-ide (4c)

White powder, mp 187-189 °C (decomp), 0.300 g, (83 %). IR (KBr) (ν_max/cm⁻¹): 1635 (C=O), 1682 (C=N), 3229 (NH). ¹H NMR (300.1 MHz, CDCl₃): δ 1.53 (6H, s, CMe₂), 2.38 (3H, s, Me), 2.90 and 2.95 (12H, 2s, 2NMe₂), 5.85 (1H, d, ³J_HH = 8.6 Hz, HN-CH), 7.20 (1H, t, ³J_HH = 7.4 Hz, CH), 7.28 (2H, d, ³J_HH = 7.4 Hz, 2CH), 7.56 (2H, d, ³J_HH = 7.4 Hz, 2CH), 8.44. (1H, d, ³J_HH = 8.6 Hz, NH) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ 20.13 (Me), 26.23 (CMe₂), 39.97, 40.44 (2NMe₂), 55.29 (HN-CH), 76.47 (HC-C-C) 101.96 (CMe₂), 126.09 (CH), 126.45 (CH), 126.91 (CH), 130.62 (CH), 134.96 (C), 140.77 (C), 161.45 (N-C-NH), 166.57 (2C, s, 2C=O) ppm. MS, m/z (%): 361 (M⁺, < 1), 246 (73), 188 (87), 173 (94), 160 (37), 144 (19), 115 (100), 105 (9), 71 (37), 57 (23), 43 (49). Anal. Calcd for C₁₉H₂₇N₃O₄ (361.44): C, 63.14; H, 7.53; N, 11.63. Found: C, 63.24; H, 7.59; N, 11.56.

5-{((bis (dimethylamino) methylene) ammonio) (m-tolyl) methyl}-2, 2-dimethyl-4, 6-dioxo-1, 3-dioxin-5-ide (4d)

White powder, mp 180-183 °C (decomp), 0.286 g, (79 %). IR (KBr) (ν_max/cm⁻¹): 1612 (C=O), 1682 (C=N), 3262 (NH). ¹H NMR (300.1 MHz, CDCl₃): δ 1.56 (6H, s, CMe₂), 2.30 (3H, s, Me), 2.92 and 2.99 (12H, 2s, 2NMe₂), 5.67 (1H, d, ³J_HH = 8.6 Hz, HN-CH), 6.98-7.30 (4H, m,Ar), 9.00 (1H, d, ³J_HH = 8.6 Hz, NH) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ 21.93 (Me), 26.33 (CMe₂), 40.08, 40.79 (2NMe₂), 57.37 (HN-CH), 77.05 (HC-C-C) 102.32 (CMe₂), 123.13 (CH), 126.70 (CH), 127.85 (CH), 128.60 (CH), 138.20 (C), 143.41 (C), 161.74 (N-C-NH), 166.66 (2C, s, 2C=O) ppm. MS, m/z (%):361 (M⁺, < 1), 246 (68), 188 (73), 173 (100), 160 (29), 115 (96), 105 (22), 71 (40), 57 (16), 43 (31). Anal. Calcd for C₁₉H₂₇N₃O₄ (361.44): C, 63.14; H, 7.53; N, 11.63. Found: C, 63.09; H, 7.47; N, 11.68.

5-{((bis (dimethylamino) methylene) ammonio) (4-chlorophenyl) methyl}-2, 2-dimethyl-4, 6-dioxo-1, 3-dioxin-5-ide (4e)

White powder, mp 188-190 °C (decomp), 0.267 g, (70 %). IR (KBr) (ν_max/cm⁻¹): 1612 (C=O), 1682 (C=N), 3186 (NH). ¹H NMR (300.1 MHz, CDCl₃): δ 1.52 (6H, s, CMe₂), 2.87 and 2.93 (12H, 2s, 2NMe₂), 5.61 (1H, d, ³J_HH = 8.7 Hz, HN-CH), 7.19. (2H, d,J = 8.4 Hz, 2CH), 7.34 (2H, d,J = 8.4 Hz, 2CH), 8.83 (1H, d, ³J_HH = 8.7 Hz, NH) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ 26.33 (CMe₂), 40.02, 40.74 (2NMe₂), 56.82 (HN-CH), 77.11 (HC-C-C), 102.29 (CMe₂), 127.53 (2CH), 128.71 (2CH), 132.57 (C), 142.08 (C), 161.83 (N-C-NH), 166.46 (2C, s, 2C=O) ppm. MS, m/z (%): 383 (M⁺ + 2, 1), 382 (M⁺ + 1, 1), 381 (M⁺, 4), 368 (20), 245 (91), 208 (58), 196 (39), 180 (46), 173 (100), 164 (48), 136 (74), 115 (30), 101 (30), 71 (55), 57 (31), 43 (37). Anal. Calcd for C₁₈H₂₄ClN₃O₄ (381.84): C, 56.62; H, 6.34; N, 11.00. Found: C, 56.52; H, 6.44; N, 11.12.

5-{((bis (dimethylamino) methylene) ammonio) (2-chlorophenyl) methyl}-2, 2-dimethyl-4, 6-dioxo-1, 3-dioxin-5-ide (4f)

White powder, mp 181-183 °C (decomp), 0.275 g, (72 %). IR (KBr) (ν_max/cm⁻¹): 1608 (C=O), 1679 (C=N), 3236 (NH). ¹H NMR (300.1 MHz, CDCl₃): δ 1.57 (6H, s, CMe₂), 2.98 and 3.03 (12H, 2s, 2NMe₂), 5.68 (1H, d, ³J_HH = 8.7 Hz, HN-CH), 7.24-7.49 (4H, m,Ar), 9.00. (1H, d, ³J_HH = 8.7 Hz, NH) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ 26.37 (CMe₂), 40.12, 40.72 (2NMe₂), 56.76 (HN-CH), 77.09 (HC-C-C), 102.25, (CMe₂), 125.38 (CH), 125.86 (CH), 127.34 (CH), 129.56 (CH), 134.23 (C), 146.07 (C), 161.95 (N-C-NH), 165.56 (2C, s, 2C=O) ppm. MS, m/z (%): 383 (M⁺ + 2, < 1), 382 (M⁺ + 1, < 1), 381 (M⁺, 2), 245 (84), 208 (43), 196 (27), 180 (27), 173 (100), 164 (33), 136 (80), 115 (53), 71 (39), 57 (24), 43 (39). Anal. Calcd for C₁₈H₂₄ClN₃O₄ (381.84): C, 56.62; H, 6.34; N, 11.00. Found: C, 56.68; H, 6.465; N, 11.10.

5-{((bis (dimethylamino) methylene) ammonio) (4-fluorophenyl) methyl}-2, 2-dimethyl-4, 6-dioxo-1, 3-dioxin-5-ide (4g)

White powder, mp 173-175 °C (decomp), 0.267 g, (73 %). IR (KBr) (ν_max/cm⁻¹): 1597 (C=O), 1682 (C=N), 3171 (NH). ¹H NMR (300.1 MHz, CDCl₃): δ 1.56 (6H, s, CMe₂), 2.93 and 3.00 (12H, 2s, 2NMe₂), 5.68 (1H, d, ³J_HH = 8.6 Hz, HN-CH), 6.96 (2H, t,J = 8.7 Hz, 2CH), 7.49 (2H, dd,J = 8.7, 5.4 Hz, 2CH), 8.96 (1H, d, ³J_HH = 8.6 Hz, NH) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ 26.32 (CMe₂), 40.12, 40.80 (2NMe₂), 56.88 (HN-CH), 77.03 (HC-C-C), 102.37, (CMe₂), 115.44 (d, ³J_CF = 21 Hz, 2CH,), 127.69 (d, ²J_CF = 7.5 Hz, 2CH), 139.38 (d, ⁴J_CF = 3.1Hz, C), 161.79 (N-C-NH), 162.00 (d, ¹J_CF = 245 Hz, CF), 166.56 (2C, s, 2C=O) ppm. MS, m/z (%): 365 (M⁺, < 1), 245 (71), 192 (34), 173 (94), 160 (17), 148 (57), 115 (100), 71 (41), 57 (33), 43 (57). Anal. Calcd for C₁₈H₂₄FN₃O₄ (365.40): C, 59.17; H, 6.62; N, 11.50 Found: C, 59.04; H, 6.54; N, 11.58.

5-{((bis (dimethylamino) methylene) ammonio) (2-fluorophenyl) methyl}-2, 2-dimethyl-4, 6-dioxo-1, 3-dioxin-5-ide (4h)

White powder, mp 176-178 °C (decomp), 0.296 g, (81 %). IR (KBr) (ν_max/cm⁻¹): 1620 (C=O), 1678 (C=N), 3198 (NH). ¹H NMR (300.1 MHz, CDCl₃): δ 1.68 (6H, s, CMe₂), 2.89 and 3.06 (12H, 2s, 2NMe₂), 5.99 (1H, d, ³J_HH = 9.4 Hz, HN-CH), 6.92-7.64 (4H, m,Ar), 8.28. (1H, d, ³J_HH = 9.4 Hz, NH) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ 26.49 (CMe₂), 39.82, 40.45 (2NMe₂), 51.38 (HN-CH), 72.87 (HC-C-C) 102.41 (CMe₂), 115.37 (CH, d, ³ J_FC = 21.3 Hz,), 125.2 (d, ²J_FC = 9.4 Hz, CH), 129.6 (d, ³J_FC = 22.4 Hz, CH), 129.8 (d, ²J_FC = 9.9 Hz, C), 129.8 (CH, d, ⁴J_FC = 3.0 Hz,), 160.83 (d, ¹J_FC = 243.2 Hz, CF) 161.01 (N-C-NH), 167.02 (2C, s, 2C=O) ppm. MS, m/z (%): 365 (M⁺, < 1), 245 (71), 173 (94), 160 (17), 148 (57), 115 (100), 71 (41), 57 (53), 43 (57). Anal. Calcd for C₁₈H₂₄FN₃O₄ (365.40): C, 59.17; H, 6.62; N, 11.50. Found: C, 59.06; H, 6.54; N, 11.57.

5-{((bis (dimethylamino) methylene) ammonio) (4-nitrophenyl) methyl}-2, 2-dimethyl-4, 6-dioxo-1, 3-dioxin-5-ide (4i)

Yellow powder, mp 191-193 °C (decomp), 0.302 g, (77 %). IR (KBr) (ν_max/cm⁻¹): 1612 (C=O), 1682 (C=N), 3194 (NH). ¹H NMR (300.1 MHz, CDCl₃): δ 1.55 (6H, s, CMe₂), 2.92 and 3.01 (12H, 2s, 2NMe₂), 5.73 (1H, d, ³J_HH = 8.9 Hz, HN-CH), 7.71. (2H, d,J = 8.7 Hz, 2CH), 8.13 (2H, d,J = 8.7 Hz, 2CH), 8.92 (1H, d, ³J_HH = 8.9 Hz, NH) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ 26.34 (CMe₂), 40.28, 40.89 (2 NMe₂), 57.11 (HN-CH), 77.07 (HC-C-C), 102.61, (CMe₂), 124.03(2CH), 126.78 (2CH), 147.01 (C), 150.69 (C), 162.12 (N-C–NH), 166.41 (2C, s, 2C=O) ppm. MS, m/z (%): 392 (M⁺, < 1), 245 (100), 219 (24), 196 (92), 152 (52), 122 (5), 115 (4), 71 (22), 57 (20), 43(18). Anal. Calcd for C₁₈H₂₄N₄O₆ (392.41): C, 55.09; H, 6.16; N, 14.28. Found: C, 55.22; H, 6.19; N, 14.16.

5-{((bis (dimethylamino) methylene) ammonio) (4-methoxyphenyl) methyl}-2, 2-dimethyl-4, 6-dioxo-1, 3-dioxin-5-ide (4j).

White powder, mp 169-171 °C (decomp), 0.321 g, (85 %). IR (KBr) (ν_max/cm⁻¹): 1612 (C=O), 1682 (C=N), 3194 (NH). ¹H NMR (300.1 MHz, CDCl₃): δ 1.55 (6H, s, CMe₂), 2.90 and 2.96 (12H, 2s, 2NMe₂), 3.74 (3H, s, OMe), 5.63 (1H, d, ³J_HH = 8.4 Hz, HN-CH), 6.78 (2H, d,J = 8.7 Hz, 2CH), , 7.39 (2H, d,J = 8.7 Hz, 2CH), 8.94 (1H, d, ³J_HH = 8.4 Hz, NH) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ 26.34 (CMe₂), 40.05, 40.71 (2NMe₂), 55.62 (OMe), 56.93 (HN-CH), 77.08 (HC-C-C), 102.24, (CMe₂), 114.05 (2CH), 127.29 (2CH), 135.91 (C), 158.71 (C), 161.62 (N-C-NH), 166.62 (2C, s, 2C=O) ppm. MS, m/z (%): 377 (M⁺, 1), 246 (82), 204 (19), 189 (11), 173 (100), 160 (62), 121 (19), 115 (57), 71 (34), 57 (43), 43 (31). Anal. Calcd for C₁₉H₂₇N₃O₅ (377.43): C, 60.46; H, 7.21; N, 11.13. Found: C, 60.54; H, 7.27; N, 11.06.

5-{((bis (dimethylamino) methylene) ammonio) (4-(dimethylamino) phenyl) methyl}-2, 2-dimethyl-4, 6-dioxo-1, 3-dioxin-5-ide (4k)

White powder, mp 123-125 °C (decomp), 0.289 g, (74 %). IR (KBr) (ν_max/cm⁻¹): 1604 (C=O), 1682 (C=N), 3333 (NH). ¹H NMR (300.1 MHz, CDCl₃): δ 1.77 (6H, s, CMe₂), 2.96 and 2.99 (12H, 2s, 2NMe₂), 3.16 (Ar-NMe₂), 5.66 (1H, d, ³J_HH = 7.8 Hz, HN-CH), 6.68 (2H, d,J = 8.7 Hz, 2CH), 8.27 (2H, d,J = 8.7 Hz, 2CH), 8.93 (1H, d, ³J_HH = 7.8 Hz, NH) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ 26.34 (CMe₂), 39.81, 40.48 (2NMe₂), 41.05 (Ar-NMe₂) 56.90 (HN-CH), 77.01 (HC-C-C), 102.19, (CMe₂), 112.92 (2CH), 127.06 (2CH), 131.69 (C), 149.88 (C), 161.52 (N-C-NH), 166.78 (2C, s, 2C=O) ppm. MS, m/z (%): 390 (M⁺, < 1), 246 (89), 217 (21), 173 (94), 160 (31), 142 (16), 115 (100), 89 (27), 71 (42), 57 (24), 43 (42). Anal. Calcd for C₂₀H₃₀N₄O₄ (390.23): C, 61.52; H, 7.74; N, 14.35. Found: C, 61.60; H, 7.84; N, 14.39.

5-{((bis (dimethylamino) methylene) ammonio) (4-bromophenyl) methyl}-2, 2-dimethyl-4, 6-dioxo-1, 3-dioxin-5-ide (4l)

White powder, mp 204-206 °C (decomp), 0.324 g, (76 %). IR (KBr) (ν_max/cm⁻¹): 1613 (C=O), 1682 (C=N), 3193 (NH). ¹H NMR (300.1 MHz, CDCl₃): δ 1.574 (6H, s, CMe₂), 2.89 and 2.96 (12H, 2s, 2NMe₂), 5.62 (1H, d, ³J_HH = 8.7 Hz, HN-CH), 7.38 (4H, s, Ar) 8.87 (1H, d, ³J_HH = 8.7 Hz, NH) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ 26.35 (CMe₂), 40.05, 40.81 (2NMe₂), 56.91 (HN-CH), 77.07 (HC-C-C), 102.36, (CMe₂), 120.73 (C), 127.91 (2CH), 131.69 (2CH), 142.57 (C), 161.87 (N-C-NH), 166.50 (2C, s, 2C=O) ppm. MS, m/z (%): 427 (M⁺, < 1), 425 (M⁺, < 1), 325 (14), 246 (58), 253 (21), 173 (89), 209 (19), 160 (31), 115 (100), 71 (29), 57 (24), 43 (38). Anal. Calcd for C₁₈H₂₄BrN₃O₄ (426.30): C, 61.52; H, 7.74; N, 14.35. Found: C, 61.60; H, 7.81; N, 14.39.

Results and Discussion

The three component condensation reactions of Meldrum acid 1, benzaldehyde derivatives 2, and N, N, N’, N’-Tetramethyl-guanidine 3 proceeded with piperidinium acetate at room temperature in benzene and were complete within about a day. Analysis of the IR, ¹H and ¹³C NMR spectroscopy, and mass spectrometry spectra as well as elemental analysis confirm the formation and isolation of the desired zwitterion salts as shown in scheme 1. The IR spectrum of 4b exhibits a NH stretching band at 3236 cm^-1, signals for carbonyl groups at 1601 cm^-1 and for C=N at 1682 cm^-1. The ¹H NMR spectrum of 4b exhibited four single sharp lines readily recognized as CMe₂ (δ = 1.55 ppm), Ar-Me (δ = 2.28 ppm), two NMe₂ groups (δ = 2.92, 2.98 ppm), along with two characteristic doublets (δ = 5.67 and 8.97 ppm, ³J_HH = 8.5) for the H-C-NH moiety. All aromatic protons resonate at δ = 7.05-7.38 ppm.

 

Scheme1: Synthesis of Guanidium-Meldrum acid zwitterionic salts   Click here to View scheme

 

The ¹H-decoupled ¹³C NMR spectrum of 4b showed six distinct signals below 100 ppm, which were readily recognized as arising from Ar-Me (δ = 21.42 ppm), CMe₂ groups (δ = 26.34 ppm), two NMe₂ groups (δ = 40.06, 40.73 ppm), methine (δ = 57.22, 77.05 ppm) carbon atoms. The meldrum acid residue showed only one signal for the carbonyl (δ = 166.65) group, which is consistent with the presence of a local C_s symmetry, which exhibited characteristic signals with appropriate chemical shifts. The ¹H and ¹³C NMR spectra of the other compounds are similar to those of 4b except for the aryl groups, which exhibit characteristic signals with appropriate chemical shifts. The mass and elemental analyses data were in agreement with the proposed structures. The formation of zwitterionic salts 4 can be rationalized by initial formation of a conjugated electron-deficient heterodyne 5 through Knoevenagel condensation ⁽¹⁶⁾ of the 1 and benzaldehydes 2 using piperidinium acetate followed by a Michael-type ^{9, 11} addition reaction with N, N, N’, N’-Tetramethyl-guanidine 3 to afford compound 4 as shown in scheme 2. We didn’t show Cyclization of synthetic compounds at room temperature, ¹² refluxing for 5h and microwave irradiation.

 

Scheme2: Proposed mechanism for the formation of Guanidium-Meldrum acid zwitterionic salts  Click here to View scheme

 

The ¹H NMR spectrum of 4b in CDCl₃ at ambient temperature displayed two single resonances due to the NMe₂ (δ = 2.96, 3.02) protons. At about + 30 °C, the resonances arising from the NMe₂ protons were appreciably broadened when compared to the corresponding signals at room temperature, whereas other group’s resonances remained unchanged. The NMe₂ protons coalescences near + 35 °C and appeared as a fairly symmetrical line at + 40 °C. The variable temperature spectra allowed calculating the free-energy barrier for the C-NH bond two NMe₂ groups rotation in 4b (Scheme 3). Using the expression k = πΔυ/√2, first order rate constant (k = 39.96 s^-1) was calculated for the N-C bond rotation in 4b at 308 K as shown in Table. Application of the absolute rate theory with a transmission coefficient of 4b gave free-energy activation (ΔG^#) of 66 ± 2 k Jmol^-1, where all known sources of errors were estimated and included. ¹⁴ Only two 1:1 singlets are observed for the four diastereotopic methyl groups of the guanidino moiety in the ¹H and ¹³C NMR spectra of 4b at room temperature. Two rotational processes, i) C–NH bond rotation (A, B) and ii) C–NMe₂ bond rotation (C), can be envisaged in the guanidino moiety of 4. When both of these processes are fast on the NMR timescale, the four Me groups become equivalent and exhibit a single resonance, as for the spectra observed above 308 K. two observed signals for these groups’ shows one of the processes should be fast on the NMR timescale. We conceder the contribution of the valence-bond structures A and B to the resonance hybrid of 4 is in fact more important than that of C for the simple reason that they correspond to a more highly substituted carbon–nitrogen double bond. ¹⁴ Therefore the faster process can be the C–NH rotation (process i). In summary, we have reported the synthesis of guanidinium zwitterionic salts by an efficient and simple approach along with three component condensation in benzene in presence of piperidinium acetate at room temperature within one day. A dynamic NMR effect is observed in the ¹H NMR spectra of these compounds as a result of restricted rotation around C-NH bond for two NMe₂ groups.

 

Scheme3: Dynamic effect of synthesized zwitterionic salts  Click here to View scheme

 

Table: Selected 1H chemical shifts (300 MHz) and activation parameters of 4b in CDCl3  Click here to View table

 

Acknowledgment

Author gratefully acknowledges financial support from the Research Council of Khoy Branch Islamic Azad University.

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