Photochemistry of 2,6‐D'ichlorodiphenylamine and 1‐Chlorocarbazole, the Photoactive Chromophores of Diclofenac, Meclofenamic Acid and Their Major Photoproducts

Abstract

Diclofenac and meclofenamic acid are two structurally related nonsteroidal anti‐inflammatory drugs with some photosensitizing potential. Their photochemistry involves cyclization to monohalogenated carbazoles. In principle, photocyclization could occur by photodehalogenation, followed by intramolecular radical addition, or by 6TT electrocyclization and subsequent dehydrohalogenation of the intermediate dihydrocarbazoles. Previously, it has been assumed that the reaction follows the first pathway and that the key species associated with phototoxicity are the resulting aryl radicals. In the present work, we have performed photophysical and photochemical studies on 2,6‐dichlorodiphenylamine (la). This is a suitable model compound because since it contains the active chromo‐phore present in diclofenac and meclofenamic acid, and its photoreactivity should be relevant to the understanding of the photobiological properties of both drugs. Our results clearly show that the first photochemical reaction is a very rapid 6iT‐electrocyclization, and hence no radicals are formed at this stage. Instead, cleavage of the carbon‐halogen bond occurs in the 1‐chlorocarbazole photoproduct 2a. The reduced lifetime of the 2a triplet (as compared with the unsubstituted carbazole) and the observed reaction quenching by oxygen are in agreement with the reaction occurring from the excited triplet state. Overall, the above results suggest that the potential phototoxicity of diclofenac and meclofenamic acid is due to a photobiologically active photoproduct that is able to generate radicals upon photolysis, rather than to the parent drug.

Triplet Excimers of Fluoroquinolones in Aqueous Media

“…The involvement of triplet excimers in some photodehalogenation processes has been suggested to justify the results. − However, there are also precedents for unreactive excimers in the photosubstitutions of halogenated aromatic compounds . The correlation between transient species observed, emission properties determined, and photodegradation studies has revealed that FQ triplet excited state is the intermediate responsible for photoproduct formation and that the triplet excimer generation is mainly a deactivation pathway.…”

Photodegradation mechanism of the common non-steroid anti-inflammatory drug diclofenac and its carbazole photoproduct

“…29 Further studies have shown that the first photochemical reaction is a very rapid 6p electrocyclization and that no radicals are formed during this step. 35 This implies that the phototoxicity of the parent compound is due to the formation of a biologically active photoproduct (CCA), which in turn is able to generate radicals upon photolysis. The photolysis rate of a tricyclic compound (such as CCA) is approximately four to fivefold faster than that for a dicyclic molecule (DF in this case).…”

“…Previous experimental studies have shown that DF undergoes photodegradation under natural sunlight, and that its photoproducts arise from the following main steps: (i) formation of an inter-ring carbon-carbon bond after loss of a chlorine atom, forming chlorocarbazole and hydrochloric acid, 30,32,34,35 (ii) subsequent loss of the second chlorine atom on further irradiation, 30 (iii) formation of photosubstituted hydroxylcarbazole or reduced product after the second photodechlorination, 30,32,35,36 and (iv) decarboxylation after the second dechlorination process. 36 The release of hydrochloric acid in the dechlorination process leads to an increase in acidity which may have an adverse effect if sufficient concentration is produced.…”

Computational insights into the photocyclization of diclofenac in solution: effects of halogen and hydrogen bonding

“…It is important to note that photosensitive drugs exhibit different responses upon exposure to light, such as photodecomposition and specific photochemical reactions such as photocyclization. [10][11][12] Among pharmaceutical entities that are highly photosensitive with potential consequent hazardous properties is diclofenac (DCF) (2-[2 0 ,6 0 -(dichlorophenyl)amino](phenyl)acetic acid). DCF is one of the most widely used non-steroidal anti-inflammatory drugs (NSAIDs) and is frequently prescribed for the treatment of pain and inflammation associated with various rheumatic and nonrheumatic diseases; its chemical structure is shown in Scheme 1.…”