The palladium­(II)-mediated chemical uncaging reaction of propargylic substrates is a recent addition to the field of chemical biology and medicinal chemistry in the activation of bio and prodrug molecules. Most of the strategies used involve C–O bond breaking in molecules bearing protected amino and hydroxyl groups. Although this reaction has been known for many decades, its catalytic cycle in aqueous milieu remains unclear. Our mechanistic investigation results unveil that full propargylic substrate conversion occurs through biphasic kinetics of different rates, where the fastest reaction phase involves a Pd­(II) anti-Markovnikov hydration of the propargyl moiety, followed by the C–O bond breaking through a β-O elimination and lasts only for two turnovers due to product inhibition. The second slower reaction phase involves the hydrolysis of the substrate promoted by Pd(0) species formed during the first phase of the reaction. These findings are crucial for the potential development of bioorthogonal Pd catalysts for the uncaging of propargylic protected bioactive and drugs molecules.

Cu I /TEMPO (TEMPO = 2,2,6,6-tetramethylpiperidinyloxyl) catalyst systems are versatile catalysts for aerobic alcohol oxidation reactions to selectively yield aldehydes. However,several aspects of the mechanism are yet unresolved, mainly because of the lack of identification of any reactive intermediates.H erein, we report the synthesis and characterization of adinuclear [L1 2 Cu 2 ] 2+ complex 1,whichinpresence of TEMPO can couple the catalytic 4H + /4 e À reduction of O 2 to water to the oxidation of benzylic and aliphatic alcohols.The mechanisms of the O 2 -reduction and alcohol oxidation reactions have been clarified by the spectroscopic detection of the reactive intermediates in the gas and condensed phases,aswell as by kinetic studies on each step in the catalytic cycles.Bis(moxo)dicopper(III) (2)and bis(m-hydroxo)dicopper(II) species 3 are shown as viable reactants in oxidation catalysis.T he present study provides deep mechanistic insight into the aerobic oxidation of alcohols that should serve as av aluable foundation for ongoing efforts dedicated towards the understanding of transition-metal catalysts involving redox-active organic cocatalysts.

Cervical cancer is the fourth most common neoplasia in women and the infection with human papilloma virus (HPV) is its necessary cause. Screening methods, currently based on cytology and HPV DNA tests, display low specificity/sensitivity, reducing the efficacy of cervical cancer screening programs. Herein, molecular signatures of cervical cytologic specimens revealed by liquid chromatography-mass spectrometry (LC-MS), were tested in their ability to provide a metabolomic screening for cervical cancer. These molecules were tested whether they could clinically differentiate insignificant HPV infections from precancerous lesions. For that, high-grade squamous intraepithelial lesions (HSIL)-related metabolites were compared to those of no cervical lesions in women with and without HPV infection. Samples were collected from women diagnosed with normal cervix (N = 40) and from those detected with HSIL from cytology and colposcopy (N = 40). Liquid-based cytology diagnosis, DNA HPV-detection test, and LC-MS analysis were carried out for all the samples. The same sample, in a customized collection medium, could be used for all the diagnostic techniques employed here. The metabolomic profile of cervical cancer provided by LC-MS was found to indicate unique molecular signatures for HSIL, being two ceramides and a sphingosine metabolite. These molecules occurred independently of women’s HPV status and could be related to the pre-neoplastic phenotype. Statistical models based on such findings could correctly discriminate and classify HSIL and no cervical lesion women. The results showcase the potential of LC-MS as an emerging technology for clinical use in cervical cancer screening, although further validation with a larger sample set is still necessary.

Reactivities of non-heme iron(IV)-oxo complexes are mostly controlled by the ligands.C omplexes with tetradentate ligands such as [(TPA)FeO] 2+ (TPA = tris(2-pyridylmethyl)amine) belong to the most reactive ones.Here,weshow af ine-tuning of the reactivity of [(TPA)FeO] 2+ by an additional ligand X(X= CH 3 CN,CF 3 SO 3 À ,ArI, and ArIO;ArI = 2-(t BuSO 2)C 6 H 4 I) attached in solution and reveal at hus far unknown role of the ArIO oxidant. The HATr eactivity of [(TPA)FeO(X)] +/2+ decreases in the order of X: ArIO > MeCN > ArI % TfO À .Hence,ArIO is not just amere oxidant of the iron(II) complex, but it can also increase the reactivity of the iron(IV)-oxo complex as alabile ligand. The detected HAT reactivities of the [(TPA)FeO(X)] +/2+ complexes correlate with the Fe = Oand FeO À Hstretching vibrations of the reactants and the respective products as determined by infrared photodissociation spectroscopy. Hence,t he most reactive [(TPA)FeO-(ArIO)] 2+ adduct in the series has the weakest Fe=Obond and forms the strongest FeOÀHb ond in the HATreaction. Scheme 1. Iron(IV)-oxo complexes formed by oxidation of [(TPA)Fe II-(TfO) 2 ]w ith ArIO (ArI = 2-(t BuSO 2)C 6 H 4 I).

Aldehyde deformylation reactions by metal dioxygen adducts have been proposed to involve peroxyhemiacetal species as key intermediates. However, direct evidence of such intermediates has not been obtained to date. We report the spectroscopic characterization of a mononuclear cobalt(III)-peroxyhemiacetal complex, [Co(Me 3 -TPADP)(O 2 CH(O)CH(CH 3 )C 6 H 5 )] + ( 2 ), in the reaction of a cobalt(III)-peroxo complex ( 1 ) with 2-phenylpropionaldehyde (2-PPA). The formation of 2 is also investigated by isotope labeling experiments and kinetic studies. The conclusion that the peroxyhemiacetalcobalt(III) intermediate is responsible for the aldehyde deformylation is supported by the product analyses. Furthermore, isotopic labeling suggests that the reactivity of the cobalt(III)-peroxo complex depends on the second reactant. The aldehyde inserts between the oxygen atoms of 1 , whereas the reaction with acyl chlorides proceeds by a nucleophilic attack. The observation of the peroxyhemiacetal intermediate provides significant insight into the initial step of aldehyde deformylation by metalloenzymes.

Reaction monitoring by electrospray ionization mass spectrometry (ESI-MS) is a popular method for investigation of reaction mechanisms. Here, we present a new approach based on a coupling between a modular capillary flow reactor and ESI-MS. The flow reactor allows a sequential adding of the reactants. We demonstrate the approach for oxidation of Ph 2 S by ArIO catalyzed by [(TPA)Fe(TfO) 2 ] (ArIO = 2-( t BuSO 2 )C 6 H 4 IO, TPA = tris (2-pyridylmethyl)amine, TfO À = triflate). In steps, we could follow the formation of the reactive iron(IV)oxo complexes, then the oxygen transfer reaction from the iron(IV)oxo to the sulfide, and finally the reoxidation of the iron complexes. The flow reactor also allows kinetic experiments by changing relative concentrations of the reactants. We could analyze in detail the formation of various [(TPA)Fe IV O(X)] 2 + / + complexes (X = MeCN, ArI, ArIO, TfO À ) and compare their relative reactivity with Ph 2 S. The [(TPA)Fe IV O(MeCN)] 2 + complex is the most reactive complex for the oxygen atom transfer reaction whilst [(TPA)Fe IV O(ArIO)] 2 + prevails in solution under catalytic conditions.

Efficient electrocatalytic CO 2 reduction requires developing catalysts with high selectivities and high activities, which is simultaneously difficult to achieve. Here, we present a new approach to tune the CO 2 reduction activity based on host-guest chemistry enabled by an iron porphyrin cage catalyst. The cage design allows the hosting of alkali metals in the side walls causing a change in the electrostatic potential inside the cage cavity. Density functional theory calculations show that the guest potassium ions assist the reduction of CO 2 by inverting the two-electron transfer from iron(0) to CO 2 from endothermic to exothermic. Accordingly, electrochemical experiments with the cage catalyst show that in the presence of the potassium ions, the overpotential for the CO 2 reduction decreases, and the catalytic activity increases while the high selectivity of the cage is retained. A novel coupling between the electrochemical cell and a mass spectrometer allowed the trapping of the key intermediates. Cryogenic ion spectroscopy characterization of the intermediates showed the details of the potassium ions hosting in the reduced cage and of the stabilization of the Fe-COOH intermediates by the interaction with the potassium ions at the single-molecule level.

Reactivities of non‐heme iron(IV)‐oxo complexes are mostly controlled by the ligands. Complexes with tetradentate ligands such as [(TPA)FeO]2+ (TPA=tris(2‐pyridylmethyl)amine) belong to the most reactive ones. Here, we show a fine‐tuning of the reactivity of [(TPA)FeO]2+ by an additional ligand X (X=CH3CN, CF3SO3−, ArI, and ArIO; ArI=2‐(tBuSO2)C6H4I) attached in solution and reveal a thus far unknown role of the ArIO oxidant. The HAT reactivity of [(TPA)FeO(X)]+/2+ decreases in the order of X: ArIO > MeCN > ArI ≈ TfO−. Hence, ArIO is not just a mere oxidant of the iron(II) complex, but it can also increase the reactivity of the iron(IV)‐oxo complex as a labile ligand. The detected HAT reactivities of the [(TPA)FeO(X)]+/2+ complexes correlate with the Fe=O and FeO−H stretching vibrations of the reactants and the respective products as determined by infrared photodissociation spectroscopy. Hence, the most reactive [(TPA)FeO(ArIO)]2+ adduct in the series has the weakest Fe=O bond and forms the strongest FeO−H bond in the HAT reaction.