Crystallographic and oxygen-17 NMR studies of nitro group torsion angles in a series of 4-alkylaminonitroquinolines designed as hypoxia-selective cytotoxins

Abstract

Nitro group torsion angles have been determined by ¹⁷O NMR spectroscopy for a series of 4-(alkyl-amino)nitroquinolines and their ortho-methyl-substituted analogues. Crystal structures were determined for two pairs of compounds, to further evaluate the validity of Boykin's equation. The crystallographic torsion angles were used to calculate a modified version of the equation, relating ¹⁷O chemical shift values (δ) and nitro group torsion angles (θ), applicable to N-heterocyclic systems, as follows: θ= 1.18(±0.13)δ– 661. This equation was then used to compute nitro group torsion angles for the nitroquinolines. Unhindered nitro groups were close to coplanar with the aromatic ring as expected, while addition of one ortho methyl group increased the torsion angle to ca. 30°. The 5-nitro derivative had a nitro group torsion angle of ca. 80°, due to peri interactions with the 4-aminoalkyl sidechain. The 8-nitroquinoline derivative is the first example of a nitroaromatic with a peri aromatic nitrogen substituent, and the torsion angle of 70–78°(measured by both NMR spectroscopy and X-ray crystallography) indicates the substantial steric effect of the nitrogen lone pair. Addition of a 7-methyl group in the other nitro ortho position of this compound results in the nitro group being virtually at right angles to the ring (torsion angle 86°). A comparison was made between the measured torsion angles and those calculated using the AM1 and PM3 methods. The former underestimates the nitro torsion angles in these systems, while the PM3 method significantly overestimates them. Overall, no simple relationship exists in the nitroquinolines between nitro group torsion angles and the reduction potentials of the compounds.