Understanding the fragmentation mechanisms of methoxy-, mesyl-, and tosyl-lapachol derivatives by computational chemistry and mass spectrometry analysis

- Fragmentation mechanisms are proposed to lapachol derivatives.
- Protonation sites and energetic profile were obtained using computational chemistry.
- Combined results help understand the reactivity of derivatives in the gas-phase.

Quinone derivatives are promising anticancer, antimalarial, and antileishmanial drug candidates. Lapachol is the main natural quinonoid compound studied to date. The synthesis of lapachol (2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone) derivatives can help characterization of these compounds in biological matrixes or extracts, particularly by electrospray ionization tandem mass spectrometry (ESI-MS/MS). The synthesized 2-methoxy-, 2-tosyl- and 2-mesyl- derivatives were protonated and fragmented by collisional-induced dissociation (CID); their fragmentation mechanisms were proposed based on CID results and DFT calculations. Quantum Theory of Atoms-in-Molecules, QTAIM, was performed and the bond weakening/reinforcement from bond critical point analysis of electronic densities was used to suggest the fragmentation pathways.Results herein were compared to data previously reported for lapachol (2-hydroxy-1,4-naphthoquinone). The tosyl derivative underwent an interesting fragmentation mechanism, which was comparable to the mechanism undergone by protonated lapachol. Therefore, identifying these compounds by the product-ions produced during ESI-MS/MS spectrometry is feasible.

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