A New Approach Using Aromatic-Solvent-Induced Shifts in NMR Spectroscopy to Analyze β-Lactams with Various Substitution Patterns

Abstract

The chemical shifts of protons depend not only on the properties of the solute molecule but also on the medium in which the solute resides. A series of β-lactams with various substitution patterns were synthesized to study aromatic-solvent-induced shifts (ASISs) in chloroform and benzene by using ¹H NMR spectroscopy. The results agreed with those obtained by theoretical density functional theory calculations. The protons of the β-lactam ring are the most affected by the ASIS effect, and they tend to overlap due to the anisotropic effect of benzene.

Key words

lactams - NMR spectroscopy - solvent effect

• References and Notes

• 1 Williams DH, Wilson DA. J. Chem. Soc. B 1966; 144
• 2 Rummens FH. A, Krystynak R. J. Am. Chem. Soc. 1972; 94: 6914
• 3 Hatton JV, Richards RE. Mol. Phys. 1962; 5: 139
• 4 Bothner-By AA, Glick RE. J. Chem. Phys. 1957; 26: 1651
• 5 Laszlo P, Schleyer P. vonR. J. Am. Chem. Soc. 1964; 86: 1171
• 6 Schneider WG. J. Phys. Chem. 1962; 66: 2653
• 7 Schaefer T, Schneider WG. J. Chem. Phys. 1960; 32: 1218
• 8 Klinck RE, Stonthers JB. Can. J. Chem. 1962; 40: 1071
• 9 Barfield M, Grant DM, Ikenberry D. J. Am. Chem. Soc. 1975; 97: 6956
• 10 Hatton JV, Schneider WG. Can. J. Chem. 1962; 40: 1285
• 11 Laszio P, Engler EM. J. Am. Chem. Soc. 1971; 93: 1317
• 12 Kalyanam N. J. Chem. Educ. 1983; 60: 635
• 13 Yukihiko I, Taku M. Bull. Chem. Soc. Jpn. 1967; 40: 2030
• 14 Williams DH, Bhacca NS. Tetrahedron 1965; 2021
• 15 Hernández-Vázquez LG, Leyva MA, Metta-Magaña AJ, Escalante J. Helv. Chim. Acta 2012; 95: 2218
• 16 N-Alkylation of β-Lactams; General Procedure A 10 mL flask equipped with a magnetic stirrer was charged with the appropriate β-lactam (1 mmol) in anhyd THF (5 mL). The solution was cooled to –10 °C and treated with Bu₄NBr (0.1 equiv), the appropriate alkyl iodide or bromide (3 equiv), and freshly ground KOH pellets (1.6 equiv). After 2 h, the temperature was allowed to rise to –7 °C and the mixture was stirred overnight. The temperature was then increased to 0 °C and, when the reaction was nearly complete (TLC; 5 h), it was quenched with sat. aq NH₄Cl. The mixture was extracted with EtOAc and the extracts were purified by chromatography [silica gel, hexane–EtOAc (1:1)]. The spectral data for the lactams were consistent with those reported in the literature.^16,22,23 1-Methylazetidin-2-one (2) Yield: 23 mg (28%). FTIR (ATR): 1724.05 (C=O) cm^–1. ¹H NMR (400 MHz, CDCl₃): 3.23 (t, ³ J = 4 Hz, 2 H, CH₂N), 2.95 (t, ³ J = 4 Hz, 2 H, CH₂C=O), 2.83 (s, 3 H, CH₃). ¹³C NMR (100 MHz, CDCl₃): 170.4, 43.3, 39.9, 31.3.
• 17 Tsuzuki S, Honda K, Uchimaru T, Mikami M, Tanabe K. J. Am. Chem. Soc. 2000; 122: 3746
• 18 Nishio M. CrystEngComm 2004; 6: 130
• 19 3,3,4,4-Tetramethylazetidin-2-one (7) 2,3-Dimethylbut-2-ene (16.8 mmol, 2.0 mL, 1.5 equiv) in a 100 mL round-bottom flask was treated with chlorosulfonyl isocyanate (11.5 mmol, 1.0 mL) at 0–5 °C under N₂. The mixture became solid and was then dissolved in CHCl₃ (2.4 mL) and treated with 2 M aq NaSO₃ (17.38 mL, 34.5 mmol, 3 equiv). The reaction flask was then fitted with a reflux condenser and a stirrer bar and placed in a Discover CEM microwave oven. The microwave oven was programmed by the open-vessel method to heat at 80 °C at a microwave power of 50 W. The mixture was heated for 5 min and then allowed to cool to below 50 °C. After extraction with CH₂Cl₂ (4 × 3 mL), the two phases were separated and the organic phase was dried (Na₂SO₄) and concentrated under reduced pressure. The resulting crude product was purified by column chromatography [silica gel, hexane–EtOAc (8:2 to 4:6)] to give white crystals; yield: 1.23 g (84%); mp 98–99 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.22 (s, 6 H, CH₃–C–N), 1.11 (s, 6 H, CH₃–C–C=O). ¹³C NMR (100 MHz, CDCl₃): δ = 19.2, 24.5, 54.5, 58.21, 175.4. FAB-MS: m/z = 128 [M + H] ⁺ . HRMS (FAB): m/z [M + H] ⁺ calcd for C₇H₁₄NO: 128.1070; found: 128.1022.
• 20 CCDC 1487449 contains the supplementary crystallographic data for compound 7. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 21 Wolf SK, Grimwood DJ, McKinnon JJ, Turner MJ, Jayatilaka D, Spackman MA. Crystal Explorer, v. 3.1 2013
• 22 Hanai K, Maki Y, Kuwae A. Spectrochim. Acta, Part A 1986; 42: 861
• 23 McKinnon JJ, Jayatilaka D, Spackman MA. Chem. Commun. 2007; 3814