A Combined Experimental and Computational Investigation on the Unusual Molecular Mechanism of the Lossen Rearrangement Reaction Activated by Carcinogenic Halogenated Quinones

Abstract

The classic Lossen rearrangement is a well-known reaction describing the transformation of an O-activated hydroxamic acid into the corresponding isocyanate. In this study, we found that chlorinated benzoquinones (CnBQ) serve as a new class of agents for the activation of benzohydroxamic acid (BHA), leading to Lossen rearrangement. Compared to the classic one, this new kind of CnBQ-activated Lossen rearrangement has the following unique characteristics: (1) The stability of CnBQ-activated BHA intermediates was found to depend not only on the degree but also on the position of Cl-substitution on CnBQs, which can be divided into two subgroups. (2) It is the relative energy of the anionic CnBQ–BHA intermediates that determine the rate of this CnBQ-activated rearrangement, which is the rate-limiting step, and the Cl or H ortho to the reaction site at CnBQ is crucial for the stability of the anionic intermediates. (3) A pKa–activation energy correlation was observed, which can explain why the correlation exists between the rate of the rearrangement and the acidity of the conjugate acid of the anionic leaving group, the hydroxlated quinones. These findings may have broad implications for future research on halogenated quinoid carcinogens and hydroxamate biomedical agents.

An Exceptionally Facile Two-Step Structural Isomerization and Detoxication via a Water-Assisted Double Lossen Rearrangement

“…Based on the findings of the current study, earlier research on Lossen rearrangement17212223, the fact that N -hydroxy phthalimide anion is a particularly effective nucleophile, and the involvement of water, we proposed a unique TCBQ-activated and water-assisted Lossen rearrangement mechanism for the isomerization of NHPI to IA (Fig. 6).…”

“…Indeed, we recently found that benzohydroxamic acid can be activated by halogenated quinones (XBQs) to produce phenyl isocyanate, which requires the formation of an anionic N intermediate1723. However, in the present study, the anionic N intermediate cannot be formed by losing a proton because the N atom is linked to two carbonyl groups.…”

“…Due to the strong acidity of TrCBQ-OH (pK a : 1.10) and DDBQ (pK a1 : 0.58; pK a2 : 2.72)18303132, the conjugate acids of the anionic leaving groups in the present study, it is expected that the rate of rearrangement of the postulated reaction intermediate (IN1) should be very fast. However, when TCBQ was substituted with 2,6-DCBQ, the acidity of the conjugate acid of the anionic leaving group, 2-chloro-6-hydroxy-benzoquinone, was much weaker (pK a = 3.65)23. We would then expect that the 1:1 substitution adduct of NHPI/2,6-DCBQ should be stable enough for isolation and identification by HPLC-MS. We found that this was indeed the case (Fig.…”

“…Based on our previous work1723, we expected that o -carboxy benzohydroxamic acid could be readily activated by TCBQ to generate o -carboxy phenyl isocyanate via Lossen rearrangement. If the mechanism proposed above for the formation of IA via the o -carboxy phenyl isocyanate intermediate were correct, then IA should also be produced from o -carboxy benzohydroxamic acid activated by TCBQ.…”

Insights into the one-electron reduction behavior of tetrachloro-o-benzoquinone: a DFT and molecular dynamics study

“…6,7 Recently, more and more studies have shown that chlorinated benzoquinones, such as p-TCBQ and DCBQ, can react with the organic hydroperoxides or benzohydroxamic acids to produce the hydroxyl radical, organic alkoxyl radicals, and quinone ketoxy radicals experimentally, [8][9][10][11][12][13][14][15][16][17] which can be used to partially elucidate the potential carcinogenicity of the polyhalogenated aromatic environmental pollutants since these active radicals can cause oxidative damage to the DNA, protein, and lipids. 13 Despite the extensive studies on the structure and chemical reactivity of p-TCBQ experimentally and theoretically, [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] however, its isomer, namely o-TCBQ, has been paid less attentions although o-TCBQ has been involved in the toxicity of the bleached kra chlorination effluent many years ago. [27][28][29][30][31][32] Moreover, considering the fact that p-TCBQ behaves as a good electron acceptor generally and its chemical reactivity is governed by its intrinsic property, so some questions remain unclear for o-TCBQ.…”