Abstract
Nitration of four 1-adamantyl bearing aromatic ketones with mixed acid, acetyl nitrate, silver nitrate and guanidine nitrate was studied under various conditions. The ketones with conjugated carbonyl group or with a benzyl group were examined and a considerably high amount of ortho isomer was observed in all cases. The proportion of ortho nitration showed the same trends for both examined groups of ketones. Unprecedently, the ortho isomer was formed quantitatively upon the reaction of 1-(1-adamantyl)-3-phenylpropan-2-one with acetyl nitrate in acetic anhydride. Influence of electronic, steric and complexation effect of carbonyl group on regioselectivity is discussed. An alternative reaction pathway including complexation of nitrating agent and a pre-equilibrium of protonated and nitronium coordinated carbonyl in particular is suggested to play crucial and general role in nitrations of aromatic carbonyl compounds.
Highlights
The discovery of antiviral activity of 1-adamantylamine[1] in 1964 hand in hand with the development of commercially applicable procedure for synthesis of adamantane, based on the Schleyer method[2] published in 1957, induced the expansion of the application of adamantane moiety in various branches of chemistry, especially in chemistry of biologically active compounds
Mixture of sulfuric and nitric acids, nitric acid in acetic anhydride, silver nitrate with acetyl chloride in acetonitrile and guanidine nitrate in sulfuric acid were employed for nitration of four adamantane bearing ketones and acetophenone as a reference compound. 1Adamantyl phenyl ketone (1) was nitrated quantitatively with all the tested nitrating systems except silver nitrate (Table 1; entries 1–7)
They describe the decrease of ortho/meta ratio from 0.37 in 80% sulfuric acid to 0.25 in 96% H2SO4, they suppose acetophenone to be nitrated as the free base up to acidities at least as high as that represented by 90% sulfuric acid.28a Earlier paper by Baker and Moffitt ascribed similar observation to an increasing contribution of protonated form of ketone.28b We performed nitration with mixed acid at 30 °C and at –15 °C (Table 1; entries 1, 2) with the ortho/meta/para regioisomers distribution 29/37/34 and 14/56/30 respectively
Summary
The discovery of antiviral activity of 1-adamantylamine[1] in 1964 hand in hand with the development of commercially applicable procedure for synthesis of adamantane, based on the Schleyer method[2] published in 1957, induced the expansion of the application of adamantane moiety in various branches of chemistry, especially in chemistry of biologically active compounds. Adamantane bearing molecules were introduced as apoptosis inducers,[3] potential anticancer drugs,[4] substances for diabetes treatment,[5] canabinoid receptor ligands,[6] quinolines with anti-tuberculosis activity,[7] compounds with antiviral properties,[8] neuroprotective agents[9] or drugs against Gaucher disease.[10]. This interest originates from the unique properties of the adamantane moiety, which can be introduced into potential or known biologically active compounds and in this way improve its properties. The most frequent method for anilines preparation is aromatic nitration followed by reduction
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