Monobromination of 2-hydroxy-6-methoxyacetophenone and studies of the non-covalent interactions in the crystal structure of 3-bromo-2-hydroxy-6-methoxyacetophenone

Abstract

In principle both position C-3 and C-5 of 2-hydroxy-6-methoxyacetophenone (1) should be able to react with N-bromosuccinimide (NBS), being jointly activated by the meta directing effect of the carbonyl group and strongly so by the ortho-para directing resonance effects of the hydroxyl and methoxy group, respectively. However, this acetophenone derivative reacted with NBS in acetic acid to afford 3-bromo-2-hydroxy-6-methoxyacetophenone (2), exclusively. Intramolecular hydrogen (CO…HO) bonding interaction in ortho-hydroxycarbonyl compounds result in a thermodynamically stable six-membered ring with the resultant complex resembling naphthalene. C-3 becomes the α-position of this naphthaneloid scaffold and therefore the most activated/nucleophilic for electrophilic attack by NBS. The molecular electrostatic potential (MEP) map of substrate 1 shows that C-3 accommodates higher negative charge than that on C-5 making the former centre more susceptible to electrophilic attack. Moreover, density functional theory (DFT) method also predicted the 3-Br isomer to be more stable and favoured than the 5-Br form in acetic acid solution and also in the gas phase. Single crystals of the monobrominated acetophenone 2 were obtained and the structure of this compound was accurately established with the aid of X-ray diffraction technique complemented with spectroscopic (NMR, FT-IR, Uv-Vis and HR-MS) and DFT methods. The intermolecular interaction pattern was studied by Hirshfeld surface analysis along with 2D fingerprint diagrams. The DFT calculations were also performed in the gas phase to correlate the experimental results with the simulated data.