Electron and Spin-Density
Analysis of Tirapazamine
Reduction Chemistry
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Abstract
Tirapazamine (TPZ, <b>1</b>, 3-amino-1,2,4-benzotriazine
1,4-<i>N</i>,<i>N</i>-dioxide), the radical anion <b>2</b> formed by one-electron reduction of <b>1</b>, and
neutral radicals <b>3</b> and <b>4</b> formed by protonation
of <b>2</b> at O(N4) or O(N1), respectively, and their N–OH
homolyses <b>3</b> → <b>5</b> + ·OH and <b>4</b> → <b>6</b> + ·OH have been studied with
configuration interaction theory, perturbation theory, and density
functional theory. A comprehensive comparative analysis is presented
of structures and electronic structures and with focus on the development
of an understanding of the spin-density distributions of the radical
species. The skeletons of radicals <b>3</b> and <b>4</b> are distinctly nonplanar, several stereoisomeric structures are
discussed, and there exists an intrinsic preference for <b>3</b> over <b>4</b>. The <i>N</i>-oxides <b>1</b>, <b>5</b>, and <b>6</b> have closed-shell singlet ground
states and low-lying, singlet biradical (<b>SP-1</b>, <b>SP-6</b>) or biradicaloid (<b>SP-5</b>) excited states.
The doublet radicals <b>2</b>, <b>3</b>, and <b>4</b> are heavily spin-polarized. Most of the spin density of the doublet
radicals <b>2</b>, <b>3</b>, and <b>4</b> is located
in one (N,O)-region, and in particular, <b>3</b> and <b>4</b> are not C3-centered radicals. Significant amounts of spin density
occur in both rings in the singlet biradical(oid) excited states of <b>1</b>, <b>5</b>, and <b>6</b>. The dipole moment of
the N2–C3(X) bond is large, and the nature of X provides a
powerful handle to modulate the N2–C3 bond polarity with opposite
effects on the two NO regions. Our studies show very low proton affinities
of radical anion <b>2</b> and suggest that the p<i>K</i><sub>a</sub> of radical [<b>2</b>+H] might be lower than 6.
Implications are discussed regarding the formation of hydroxyl from <b>3</b> and/or <b>4</b>, regarding the ability of <b>5</b> and <b>6</b> to react with carbon-centered radicals in a manner
that ultimately leads to oxygen transfer, and regarding the interpretation
of the EPR spectra of reduced TPZ species and of their spin-trap adducts
