Time-Resolved Resonance Raman and Density Functional Theory Investigation of the Photochemistry of (S)-Ketoprofen

Abstract

Ketoprofen is known to induce photosensitivity due to its specific structure and electronic features, and this limits its use in medical applications. In this Article, the photochemistry of (S)-ketoprofen has been investigated by time-resolved resonance Raman spectroscopy to gain additional information so as to better elucidate the possible photochemical reaction mechanism of ketoprofen in different solvents. In nonaqueous solvents like neat acetonitrile and isopropyl alcohol, and 1:1 acetonitrile:water and 1:1 acetonitrile:acidic water aqueous solvents, (S)-ketoprofen exhibits benzophenone-like photochemistry to produce a triplet state, which in turn produces a ketyl radical-like species that then undergoes a cross-coupling reaction with either a dimethyl radical (which is generated by hydrogen abstraction of isopropyl alcohol) or a water molecule, respectively, at the para-position to form a transient species that has a lifetime up to the microsecond time scale. However, photolysis of (S)-ketoprofen in a 1:1 acetonitrile:alkaline water solution and 3:7 acetonitrile:phosphate buffered solution appears to undergo a prompt decarboxylation reaction. Only one species was observed in the nanosecond time-resolved resonance Raman experiments under these conditions, and this species was tentatively assigned to be a triplet protonated biradical carbanion.

Water‐ and Acid‐Mediated Excited‐State Intramolecular Proton Transfer and Decarboxylation Reactions of Ketoprofen in Water‐Rich and Acidic Aqueous Solutions

“…Comparison of the decarboxyation reactions studied here with previous results for the dissociated KP (KP À ) in basic solutions indicates that the dissociated KP (KP À ) undergoes a substantially faster decarboxylation reaction [16][17][18][19][20][21][22][23] than the undissociated KP (KP) examined in this investigation. This suggests that the undissociated and dissociated KP have noticeably different chemical reactivity toward decarboxylation and this may be an interesting issue to study further in the future.…”

“…For example, a ketyl radical species is generated after the decay of 3 [KP] in 2-propanol solvent or in water solutions. [22,23] Previous studies indicated that water may play an important role in the photochemistry of the excited state. Ultrafast pump-probe spectroscopic studies on the hydrated 7-azaindole monomer provided evidence that an excited-state proton transfer can occur by means of a water proton bridge.…”

“…[23][24][25] The kinetics of the decarboxylation reactions of KP has shown a large dependence on the polarity of the solvent. [21] That is to say, the polar protic solvent is proposed to be the donor of a proton or hydrogen to aid the formation of an intramolecular proton transfer as the initial step to induce the photodecarboxylation.…”

“…This behavior is significantly different from that previously observed for KP in basic aqueous solutions and in lower-water-concentration solutions. [22,23] The ns-TR 3 spectra ( Figure 8A) [KP] species may decay on the sub-nanosecond timescale, which is smaller than the time resolution of ns-TR 3 instrument used in our experiments. Although the amount of the acid is smaller than the pK a = 4.7 of the KP in the solution (pH 3), the ESIPT and decarboxylation reaction do not take place to an appreciable degree.…”

Water Concentration Dependent Photochemistry of Ketoprofen in Neutral Aqueous Solutions

“…However, the use of KP can lead to photosensitivity and phototoxicity because of its specific structure and electronic properties. The neutral form of ketoprofen that exists in the absence of a base displays typical benzophenone-like photochemistry 6 , while the deprotonated ketoprofen that exists in the presence of a base undergoes an efficient photodecarboxylation process 6,7 and therefore it appears that the photochemistry of KP is likely determined by the precursors, the neutral form of 3 [KP] or the deprotonated 3 [KP -1 ]. [2][3][4][5] These results revealed that the photochemistry of KP in aqueous solution is strongly affected by its acid-base chemistry.…”