Cyclic voltammetry and controlled‐potential (bulk) electrolysis have been used to explore the electrochemical reduction of o‐nitrobenzaldehyde (o‐NBA) and 8 other aldehydes and ketones at glassy ...carbon cathodes in dimethylformamide containing various tetraalkylammonium tetrafluoroborate salts along with a proton donor (4‐chlorophenol). Cyclic voltammograms for reduction of o‐NBA exhibit three cathodic peaks attributable in succession to (a) one‐electron generation of the nitro radical‐anion, (b) three‐electron formation of the hydroxylamine, and (c) two‐electron production of benzisoxazole (anthranil). These findings have been employed to develop efficient controlled‐potential (bulk) electrosyntheses of the following compounds: benzisoxazole, methylbenzocisoxazole, 1,3dioxolo4′,5′,4,5benzo1,2‐cisoxazole, naphtho2,3‐cisoxazole, 6‐chlorobenzocisoxazole, 6‐methoxybenzocisoxazole, 3‐methyl‐benzocisoxazole, 3‐isopropylbenzocisoxazole, and 3‐phenylbenzocisoxazole. In addition, we have examined the use of a variety of proton donors to optimize the production of the desired product, and we have been able to recover the proton donor at the conclusion of the electrosynthesis. In each case, the synthesized product was separated by means of normal phase chromatography and identified with the aid of NMR spectros‐copy, gas chromatography (GC), and gas chromatography‐mass spectrometry (GC‐MS). Isolated yields of the desired products range from 63 to 92 %. Moreover, our electrosyntheses are catalyst‐free, environmentally green, and rapid (∼30 min).
Selective electrosynthesis: constant‐potential electrolysis (CPE) is employed to electrosynthesize anthranil and some of its congeners. Electrosynthesis is carried out at reticulated vitreous carbon cathodes in DMF containing 0.050 M TBABF4 and 4‐chlorophenol (as a proton donor), featuring high yield and short reaction time. The process is catalyst‐free and environmentally green, and the proton donor can be recovered entirely at the end of the process.
Electrochemical reduction of coumarin (1), 6-methylcoumarin (2), 7-methylcoumarin (3), 7-methoxycoumarin (4), and 5,7-dimethoxycoumarin (5) at carbon cathodes in dimethylformamide containing 0.10 M ...tetra-n-butylammonium tetrafluoroborate has been investigated by means of cyclic voltammetry and controlled-potential (bulk) electrolysis. Cyclic voltammograms for reduction of 1-5 exhibit two irreversible cathodic peaks: (a) the first peak arises from one-electron reduction of the coumarin to form a radical-anion intermediate, which is protonated by the medium to give a neutral radical; (b) although most of this radical undergoes self-coupling to yield a hydrodimer, reduction of the remaining radical (ultimately to produce a dihydrocoumarin) causes the second cathodic peak. At a potential corresponding to the first voltammetric peak, bulk electrolysis of 1-5 affords the corresponding hydrodimer as a mixture of meso and dl diastereomers. Although the meso form dominates, the dl-to-meso ratio varies, due to steric effects arising from substituents on the aromatic ring. Electroreduction of an equimolar mixture of 1 and 4 gives, along with the anticipated symmetrical hydrodimers, an unsymmetrical product derived from the two coumarins. A mechanistic scheme involving both radical-anion and radical intermediates is proposed to account for the formation of the various products.
Cyclic voltammetry and controlled-potential (bulk) electrolysis have been used, along with gas chromatography (GC) and gas chromatography–mass spectrometry (GC–MS), to investigate the electrochemical ...reductions of 2-bromo-5-chlorothiophene (1), 3-bromo-2-chlorothiophene (2), and 2,5-dibromothiophene (3) at silver cathodes in dimethylformamide (DMF) containing 0.050M tetramethylammonium perchlorate (TMAP) as the supporting electrolyte. Cyclic voltammograms for each compound exhibit two irreversible cathodic peaks that correspond to successive cleavage of the relevant carbon–halogen bonds. Controlled-potential electrolyses of 2-bromo-5-chlorothiophene revealed a two-electron cleavage of the carbon–bromine bond to afford 2-chlorothiophene as the major product along with traces of 3-bromo-2-chlorothiophene and 4-bromo-2-chlorothiophene, each arising from occurrence of a halogen dance. Bulk electrolysis of 3-bromo-2-chlorothiophene produces only 2-chlorothiophene in a two-electron process. Controlled-potential electrolysis of 2,5-dibromothiophene yields only 2-bromothiophene, via a process that involves a carbanion intermediate. A mechanistic scheme for the two-electron reduction of 2-bromo-5-chlorothiophene (1) is proposed that accounts for the formation of 2-chlorothiophene as well as two minor products that arise via a halogen dance.
Electrochemical reduction of 1,2-dibromohexane (1) and 1,6-dibromohexane (2) at silver cathodes in dimethylformamide (DMF) containing tetramethylammonium perchlorate (TMAP) has been investigated with ...the aid of cyclic voltammetry and controlled-potential electrolysis. Cyclic voltammograms for reduction of 1 and 2 both exhibit a single irreversible cathodic peak associated with reduction of carbon–bromine bonds; however, the cathodic peak potential (−0.33V) for 1 is significantly less negative than that (−1.00V) for 2, and the peak current for 1 is approximately half of that for 2. Cyclic voltammograms for 0.5–20.0mM solutions of 1 and 2, separately, show that the parameter Ipc/C* increases as the concentration (C*) decreases; this trend is likely due to a combination of adsorption phenomena and a potential-dependent transfer coefficient (α). Coulometric n values and product distributions arising from bulk electrolyses of 5.0mM solutions of 1 and 2 depend on the positions of the bromine atoms: (a) for 1, n was 2.13 and 1-hexene was the only product; (b) for 2, n was 2.12 and a mixture of products was obtained 1-hexene (21%), n-hexane (37%), 1,5-hexadiene (22%), 5-hexen-1-ol (9%), and a trace of n-dodecane. When 2 was electrolyzed in the presence of a proton or deuteron donor (2,2,2-trifluoroethanol or D2O), the n value and the amount of n-hexane increased, whereas 1-hexene and 1,5-hexadiene decreased in yield. We conclude that reduction of 1 follows a concerted mechanism, but that reduction of 2 proceeds via carbanionic intermediates.
•Catalytic reduction of DDT affords predominantly 4,4′-(ethane-1,1-diyl)bis(chlorobenzene) (DDNU).•Catalytic reduction of DDD and DDE yields mainly 1-chloro-4-(1-phenylvinyl)benzene.•Nickel(I) ...salen-catalyzed reduction of DDT involves the formation of radical intermediates.•Chemical modification of nickel(II) salen occurs during the catalytic reduction of DDT.
Cyclic voltammetry, controlled-potential (bulk) electrolysis, gas chromatography, gas chromatography–mass spectrometry, and high-performance liquid chromatography–electrospray ionization–mass spectrometry have been utilized to investigate the catalytic reduction of 4,4′-(2,2,2-trichloroethane-1,1-diyl)bis(chlorobenzene) (DDT) by nickel(I) salen electrogenerated at a carbon cathode in dimethylformamide (DMF) containing 0.050M tetramethylammonium tetrafluoroborate (TMABF4). Cyclic voltammograms for reduction of nickel(II) salen in the presence of DDT provide evidence for catalytic reduction such as enhanced cathodic current for the nickel(II) salen–nickel(I) salen redox couple and a decrease in the anodic current associated with oxidation of nickel(I) salen. Bulk electrolysis of nickel(II) salen–DDT solutions at reticulated vitreous carbon cathodes leads to a mixture of products that includes 1,1-diphenylethene, 1-chloro-4-(1-phenylvinyl)benzene, 4,4′-(ethene-1,1-diyl)bis(chlorobenzene) (DDNU), 4,4′-(2-chloroethene-1,1-diyl)bis(chlorobenzene) (DDMU), 4,4′-(2-chloroethane-1,1-diyl)bis(chlorobenzene) (DDMS), 4,4′-(2,2-dichloroethane-1,1-diyl)bis(chlorobenzene) (DDD), and 4,4′-(2,2-dichloroethene-1,1-diyl)bis(chlorobenzene) (DDE). In addition, we have detected adducts formed from a fragment of DMF and radical intermediates arising from reduction of DDT, along with nickel salen species for which the imino (CN) bond of the ligand is modified with different intermediates derived from catalytic reduction of DDT. A mechanistic scheme is proposed to account for the formation of products.
Humic acid (HA) is thought to promote NO
conversion to nitrous acid (HONO) on soil surfaces during the day. However, it has proven difficult to identify the reactive sites in natural HA substrates. ...The mechanism of NO
reduction on soil surrogates composed of HA and clay minerals was studied by use of a coated-wall flow reactor and cavity-enhanced spectroscopy. Conversion of NO
to HONO in the dark was found to be significant and correlated to the abundance of C-O moieties in HA determined from the X-ray photoelectron spectra of the C 1s region. Twice as much HONO was formed when NO
reacted with HA that was photoreduced by irradiation with UV-visible light compared to the dark reaction; photochemical reactivity was correlated to the abundance of C═O moieties rather than C-O groups. Bulk electrolysis was used to generate HA in a defined reduction state. Electrochemically reduced HA enhanced NO
-to-HONO conversion by a factor of 2 relative to non-reduced HA. Our findings suggest that hydroquinones and benzoquinones, which are interchangeable via redox equilibria, contribute to both thermal and photochemical HONO formation. This conclusion is supported by experiments that studied NO
reactivity on mineral surfaces coated with the model quinone, juglone. Results provide further evidence that redox-active sites on soil surfaces drive ground-level NO
-to-nitrite conversion in the atmospheric boundary layer throughout the day, while amphoteric mineral surfaces promote the release of nitrite formed as gaseous HONO.
Cyclic voltammetry and controlled-potential (bulk) electrolysis have been used to characterize the behavior of a structurally modified nickel(I) salen species, that can be electrogenerated at carbon ...cathodes in dimethylformamide (DMF) containing 0.10 M tetra‑n‑butylammonium tetrafluoroborate (TBABF4) to catalyze the reductions of 1‑bromodecane (1) and 1‑iododecane (2). This nickel(I) complex possesses a methyl protecting group on each imino (CN) bond, as well as a N‑methyl‑N‑phenylaminomethyl moiety on each aryl group. In its active form, the nickel(I) species can reduce 1 or 2 at a more positive potential than is needed to reduce either substrate directly at a carbon cathode. Bulk electrolysis of the parent nickel(II) complex in the presence of 1 and 2 results in a mixture of n‑eicosane, n‑decane, 1‑decene, and N,N‑dimethylundecanamide, that were identified and quantitated with the aid of gas chromatography–mass spectrometry (GC–MS) and gas chromatography (GC). A mechanistic scheme is proposed to account for the formation of the various products. Robustness of the new nickel(I) catalyst was also investigated and was compared to that encountered with unmodified nickel(I) salen.
•1‑Bromo‑ and 1‑iododecane undergo a one-step direct reduction at glassy carbon.•A modified nickel(II) salen procatalyst has been electrochemically investigated.•Cyclic voltammetry has been used to study catalytic reduction of 1‑halodecanes.•Radical intermediates arise from catalytic reduction of 1‑halodecanes.
•Reduction of phthalide gives a radical-anion that undergoes ring-opening in 3.5s.•Phthalide reduction gives 2-methylbenzoate esters with electrolyte-derived moieties.•Electrolysis of phthalide ...affords products that depend on the method of analysis.•Upon reduction, phthalide undergoes deuteration in the presence of deuterium oxide.
Cyclic voltammetry and controlled-potential (bulk) electrolysis have been used to investigate the direct reduction of phthalide at carbon electrodes in dimethylformamide (DMF) containing 0.10M tetramethylammonium perchlorate (TMAP) or tetra-n-butylammonium perchlorate (TBAP). Cyclic voltammograms recorded with a glassy carbon electrode exhibit a single cathodic peak and a corresponding anodic peak that arise, respectively, from one-electron reduction of phthalide to generate a radical-anion intermediate and from reoxidation of the intermediate. At a scan rate of 100mVs−1, quasi-reversible behavior is observed (due to ring-opening of the radical-anion), whereas fully reversible behavior is seen at 5Vs−1 or higher. Digital simulation of cyclic voltammograms indicates that the lifetime of the radical-anion is 3.5s. Bulk electrolysis of phthalide at a reticulated vitreous carbon cathode affords products that depend on the procedure used to analyze the catholyte. Direct injection of catholyte into a gas chromatograph shows phthalide and a 2-methylbenzoate ester bearing an alkyl moiety from the supporting-electrolyte cation. However, if the catholyte is partitioned between diethyl ether and aqueous hydrochloric acid before gas chromatographic analysis, phthalide and 2-methylbenzoic acid are observed. Thermally induced reactions that occur in the injector port of the gas chromatograph are responsible for the formation of the 2-methylbenzoate ester as well as for the phthalide found in all electrolyzed solutions.
This study aimed to determine protein expression levels of fibroblast growth factor receptors (FGFR) 1, 2 and 3 in early stage non‐small cell lung cancer (NSCLC). Additionally, a screen to define the ...frequency of FGFR3‐TACC3 translocation and FGFR3 amplification was performed. Archived tissues from 653 NSCLC samples (adenocarcinoma (AC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC)) were analysed with immunohistochemistry (IHC) for expression of FGFR1, 2 and 3. Expression levels of FGFR1, 2 and 3 were correlated with clinicopathological features. The presence of FGFR3‐TACC3 translocation was detected by RT‐PCR and FGFR3 amplification was detected by fluorescence in situ hybridization. FGFR1, 2 and 3 proteins were highly expressed in 64 (10.6%), 76 (12.9%) and 20 (3.3%) NSCLC tumour samples, respectively. Protein expression of FGFR1 was significantly related to worse overall survival in NSCLC. Furthermore, FGFR1 protein expression was associated with light smoking and histological subtype (AC), FGFR2 protein expression with female gender, younger age, histological subtype (AC) and lower tumour stage, and FGFR3 protein was significantly overexpressed in tumours of older patients and SCC histology. The FGFR3‐TACC3 fusion was detected in 3.0% (6/200) of NSCLC samples and the FGFR3 gene was amplified in 4.7% of IHC positive NSCLC samples (2/43). FGFR1, 2 and 3 proteins are expressed in a high number of early stage NSCLC and FGFR1 protein expression may serve as a prognostic biomarker. Recurrent translocations and amplifications in FGFR3 can be found in NSCLC. This study shows that FGFR family members are frequently aberrant in NSCLC and could be interesting therapeutic targets for the treatment of NSCLC.
Candidate immune biomarkers have been proposed for predicting response to immunotherapy in urothelial cancer (UC). Yet, these biomarkers are imperfect and lack predictive power. A comprehensive ...overview of the tumor immune contexture, including Tertiary Lymphoid structures (TLS), is needed to better understand the immunotherapy response in UC. We analyzed tumor sections by quantitative multiplex immunofluorescence to characterize immune cell subsets in various tumor compartments in tumors without pretreatment and tumors exposed to preoperative anti-PD1/CTLA-4 checkpoint inhibitors (NABUCCO trial). Pronounced immune cell presence was found in UC invasive margins compared to tumor and stroma regions. CD8
PD1
T-cells were present in UC, particularly following immunotherapy. The cellular composition of TLS was assessed by multiplex immunofluorescence (CD3, CD8, FoxP3, CD68, CD20, PanCK, DAPI) to explore specific TLS clusters based on varying immune subset densities. Using a k-means clustering algorithm, we found five distinct cellular composition clusters. Tumors unresponsive to anti-PD-1/CTLA-4 immunotherapy showed enrichment of a FoxP3
T-cell-low TLS cluster after treatment. Additionally, cluster 5 (macrophage low) TLS were significantly higher after pre-operative immunotherapy, compared to untreated tumors. We also compared the immune cell composition and maturation stages between superficial (submucosal) and deeper TLS, revealing that superficial TLS had more pronounced T-helper cells and enrichment of early TLS than TLS located in deeper tissue. Furthermore, superficial TLS displayed a lower fraction of secondary follicle like TLS than deeper TLS. Taken together, our results provide a detailed quantitative overview of the tumor immune landscape in UC, which can provide a basis for further studies.
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