3.8.2.3. Category 3: Activation through Salt Formation

The rationale behind the activation upon protonation (salt formation) of an enediyne with a basic functionality near the enediyne moiety lies in the fact that the electron-withdrawing effect (−I or electron transfer) of the protonated species lowers the repulsion between the in-plane alkyne π orbitals (Koga−Morokuma hypothesis).

By electron withdrawal the protonated enediyne lowers the singlet−triplet gap and thus favors the triplet state. The triplet state is proven to be a better hydrogen abstractor than a singlet. Thus, the triplet state produces the cleavage of DNA. Computational analysis supports this which revealed that a singlet diradical abstract hydrogen much in a slower rate compared to the triplet diradical. The prediction has been confirmed for the singlet didehydroanthracenediradical, for which the hydrogen-abstraction rate from 2-propanol was found to be reduced by 2−3 orders of magnitude relative to phenyl or 9-anthryl radicals. For a singlet ground-state biradical to show radical-like chemistry, e.g., hydrogen abstraction, it must add extra energy to scale up the singlet−triplet gap. The singlet lies below the triplet because it is stabilized and, accordingly, one has to pay back the stabilization energy to reach a TS where the two electrons in the nonbonded molecular orbitals (NBMOs) are uncoupled to reach the triplet state.

It can also be summarized that an increase in the electron density in the intervening σ bonds can increase the through-bond coupling and hence increase the singlet−triplet splitting. Conversely, a decrease in electron density will decrease the coupling and hence decrease the singlet−triplet gap. Thus, the in-plane lone pair of the nitrogen atom in the 2,5-didehydropyridine diradical lies antiperiplanar to the σ bonds coupling the NBMOs and therefore could donate electron density. However, when the nitrogen is protonated, the effect is reversed. This has been confirmed by ab initio computed singlet−triplet gaps, where the didehydropyridine with its lone pair shows a much larger singlet−triplet gap in comparison to the protonated form. The protonated azaenediyne liesg mostly in the triplet state and hence should be a better hydrogen-atom abstractor.

The first strategy is reflected in the works from the research group of Alabugin et al., as well as from Basak's group. Alabugin et al. has reported that the rate of BC in benzannulatedenediynes can be tuned by varying the electronic nature of the ortho substituents. The most striking of them is the acceleratory effect on BC kinetics when an amino group at the ortho position is protonated B (Scheme 69) (The ortho effects on BC has been described in Module 1).

Scheme 69. Ortho effect on protonation on the rate of BC of benzannulated enediynes.

Such acceleration of the BC rate upon protonation has also been reported by Basak et al. in the case of 2,6-diamino pyridine-based enediynes E . The latter was prepared by double N-alkylation of the bis-sulfonamide B . Deprotection using PhSH under basic conditions (K₂CO₃) gave the free amine E. The reactivity of the enediyne E and its salts F(X), F(Y), F(Z) with acids of various pK _a values (X-Z) was studied by DSC, which indicated the lowering of the onset temperature for BC upon salt formation. Interestingly, the extent of lowering was shown to depend upon the degree of salt formation, which was monitored by ¹H nuclear magnetic resonance (NMR) studies. The greater the degree of salt formation, higher the lowering of the onset temperature for BC (Scheme 70).

Scheme 70. Reactivity of pyridine diamine based enediyne upon salt formation.

Another set of example of salt formation and enhancement of rate of BC is shown by the 10-membered azaenediyne shown in Scheme 71.

Scheme 71. Synthesis and reactivity of free amine from 10-membered azaenediyne.

The cyclization chemistry of C, N -dialkynyl imine azaenediyne A in which one of the ene carbons is replaced by nitrogen was first reported by Kerwin's group. They have reported that the ultimate product of BC, (G), could only be isolated if there was a small amount of picric acid. Computational studies have shown that the singlet diradical (F), which is stabilized by the pyridine N lone pair, is a poor hydrogen-atom abstractor as compared to the triplet diradical (C), which is mainly the species generated from the protonated form of azaenediyne E (Scheme 72).

Scheme 72. Reactivity of azaenediyne under acidic pH.