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991.
The SER spectra of 4-, 3- and 2-cyanopyridines adsorbed on a silver electrode are presented. The results show that cyanopyridines may adsorb in two different orientations, end-on (with the N atom of the Py ring bound to the surface) and flat, and that for potentials more negative than −1.1 V (SCE), the cyanopyridine radical anions can also be detected. The SERS intensity vs. potential curves show more than one potential of maximum SERS intensity which are assigned to the existence of more than one species on the electrode surface. The analytical potentially of SERS on electrodes has also been investigated. It is shown that the relative SERS intensity (νCN of the 4-CNPy (2120 cm−)/breathing mode of Py (1008 cm−1)), at a fixed Py bulk concentration and at a fixed potential and exciting radiation, depends linearly on the 4-CNPy bulk concentration in the range 10−7-10−5M. The selectivity of the technique has also been investigated by studying the SER spectrum and the SERS intensity vs. potential curves for a mixture of 10−3M 4-CNPy, pyridine (Py) and 4-methylpyridine(4-MePy) in 0.1 M KCl aqueous solution. 相似文献
992.
Andre L. KilpatrickKalyan Nagulapalli Joel M. EskenGregory M. Ferrence John F. Hansen 《Tetrahedron letters》2003,44(19):3789-3791
Two equivalents of dimethyl acetylenedicarboxylate react with 3,5-diphenyl-4-methoximino-4H-pyrazole 1,2-dioxide in acetonitrile under reflux. The major product was shown by X-ray analysis to be a 5,8-epoxyisoxazolo[2,3-d]-[1,4]-diazepine derivative. 相似文献
993.
Joel F. Liebman 《Structural chemistry》1990,1(4):395-397
In what follows, I use the first person singular pronoun, I. This by no means precludes the option of my coauthoring articles, nor does it preclude consideration of unsolicited contributions by others for inclusion under the rubric of this column. 相似文献
994.
Joel Hfliger Keith Livingstone Constantin G. Daniliuc Ryan Gilmour 《Chemical science》2021,12(17):6148
Simple α-(bromomethyl)styrenes can be processed to a variety of 1,1-difluorinated electrophilic building blocks via I(I)/I(III) catalysis. This inexpensive main group catalysis strategy employs p-TolI as an effective organocatalyst when combined with Selectfluor® and simple amine·HF complexes. Modulating Brønsted acidity enables simultaneous geminal and vicinal difluorination to occur, thereby providing a platform to generate multiply fluorinated scaffolds for further downstream derivatization. The method facilitates access to a tetrafluorinated API candidate for the treatment of amyotrophic lateral sclerosis. Preliminary validation of an enantioselective process is disclosed to access α-phenyl-β-difluoro-γ-bromo/chloro esters.Simple α-(bromomethyl)styrenes can be processed to a variety of 1,1-difluorinated electrophilic building blocks via I(I)/I(III) catalysis.Structural editing with fluorine enables geometric and electronic variation to be explored in functional small molecules whilst mitigating steric drawbacks.1 This expansive approach to manipulate structure–function interplay continues to manifest itself in bio-organic and medicinal chemistry.2 Of the plenum of fluorinated motifs commonly employed, the geminal difluoromethylene group3 has a venerable history.4 This is grounded in the structural as well as electronic ramifications of CH2 → CF2 substitution, as is evident from a comparison of propane and 2,2-difluoropropane (Fig. 1, upper). Salient features include localized charge inversion (C–Hδ+ to C–Fδ−) and a widening of the internal angle from 112° to 115.4°.5 Consequently, geminal difluoromethylene groups feature prominently in the drug discovery repertoire6 to mitigate oxidation and modulate physicochemical parameters. Catalysis-based routes to generate electrophilic linchpins that contain the geminal difluoromethylene unit have thus been intensively pursued, particularly in the realm of main group catalysis.7–9 Motivated by the potential of this motif in contemporary medicinal chemistry, it was envisaged that an I(I)/I(III) catalysis platform could be leveraged to convert simple α-(bromomethyl)styrenes to gem-difluorinated linchpins: the primary C(sp3)–Br motif would facilitate downstream synthetic manipulations (Fig. 1, lower). To that end, p-TolI would function as a catalyst to generate p-TolIF2in situ in the presence of an external oxidant10 and an amine·HF complex. Alkene activation (I) with subsequent bromonium ion formation (II)11 would provide a pre-text for the first C–F bond forming process (III) with regeneration of the catalyst. A subsequent phenonium ion rearrangement12/fluorination sequence (III and IV) would furnish the geminal difluoromethylene group and liberate the desired electrophilic building block.Open in a separate windowFig. 1The geminal difluoromethylene group: bioisosterism, and catalysis-based access from α-(bromomethyl)styrenes via I(I)/I(III) catalysis.To validate this conceptual framework, a short process of reaction optimization (1a → 2a) was conducted to assess the influence of solvent, amine·HF ratio (Brønsted acidity)13 and catalyst loading (Table 1). Initial reactions were performed with p-TolI (20 mol%), Selectfluor® (1.5 equiv.) as an oxidant, and CHCl3 as the reaction medium. Variation of the amine : HF ratio was conducted to explore the influence of Brønsted acidity on catalysis efficiency (entries 1–4). An optimal ratio of 1 : 6 was observed enabling the product 2a to be generated in >95% NMR-yield. Although reducing the catalyst loading to 10 and 5 mol% (entries 5 and 6, respectively) led to high levels of efficiency (79% yield with 5 mol%), the remainder of the study was performed with 20 mol% p-TolI. Notably, catalytic vicinal difluorination was not observed at any point during this optimization, in contrast with previous studies from our laboratory.9d,i A solvent screen revealed the importance of chlorinated solvents (entries 7 and 8): in contrast, performing the reaction in ethyl trifluoroacetate (ETFA) and acetonitrile resulted in a reduction in yield (9 and 10). Finally, a control reaction in the absence of p-TolI confirmed that an I(I)/I(III) manifold was operational (entry 11). An expanded optimization table is provided in the ESI.†Reaction optimizationa
Open in a separate windowaStandard reaction conditions: 1a (0.2 mmol), Selectfluor® (1.5 equiv.), amine : HF source (0.5 mL), solvent (0.5 mL), p-TolI, 24 h, rt.bDetermined by 19F NMR using α,α,α-trifluorotoluene as internal standard.To explore the scope of this geminal difluorination, a series of α-(bromomethyl)styrenes were exposed to the standard reaction conditions (Fig. 2). Gratifyingly, product 2a could be isolated in 80% yield after column chromatography on silica gel. The parent α-(bromomethyl)styrene was smoothly converted to species 2b, as were the p-halogenated systems that furnished 2c and 2d (71 and 79%, respectively). The regioisomeric bromides 2e and 2f (70 and 62%, respectively) were also prepared for completeness to furnish a series of linchpins that can be functionalized at both termini by displacement and cross-coupling protocols (2a, 2e and 2f). Modifying the amine : HF ratio to 1 : 4.5 provided conditions to generate the tBu derivative 2g in 68% yield.14 Electron deficient aryl derivatives were well tolerated as is demonstrated by the formation of compounds 2h–2k (up to 91%). Disubstitution patterns (2l, 81%), sulfonamides (2m, 75%) and phthalimides (2n, 80%) were also compatible with the standard catalysis conditions. Gratifyingly, compound 2n was crystalline and it was possible to unequivocally establish the structure by X-ray crystallography (Fig. 2, lower).15 The C9–C8–C7 angle was measured to be 112.6° (cf. 115.4° for 2,2-difluoropropane).5 Intriguingly, the C(sp3)–Br bond eclipses the two C–F bonds rather than adopting a conformation in which dipole minimization is satisfied (F1–C8–C9–Br dihedral angle is 56.3°).Open in a separate windowFig. 2Exploring the scope of the geminal difluorinative rearrangement of α-(bromomethyl)styrenes via I(I)/I(III) catalysis. Isolated yields after column chromatography on silica gel are reported. X-ray crystal structure of compound 2n (CCDC 2055892†). Thermal ellipsoids shown at 50% probability.Cognizant of the influence of Brønsted acidity on the regioselectivity of I(I)/I(III) catalyzed alkene difluorination,9d the influence of the amine : HF ratio on the fluorination of electronically non-equivalent divinylbenzene derivatives was explored (Fig. 3, top). Initially, compound 3 bearing an α-(trifluoromethyl)styrene motif was exposed to the standard catalysis conditions with a 1 : 4.5 amine : HF ratio. Exclusive, chemoselective formation of 4 was observed in 79% yield. Simple alteration of the amine : HF ratio to 1 : 7.5 furnished the tetrafluorinated product 5 bearing both the geminal and vicinal difluoromethylene16 groups (55% yield. 20% of the geminal–geminal product was also isolated. See ESI†). Relocating the electron-withdrawing group (α-CF3 → β-CO2Me) and repeating the reaction with 1 : 4.5 amine : HF generated the geminal CF2 species 7 in analogy to compound 4. However, increasing the amine : HF ratio to 1 : 6.0 led exclusively to double geminal difluorination (8, 55%).Open in a separate windowFig. 3Exploring the synthetic versatility of this platform. (Top) Leveraging Brønsted acidity to achieve chemoselective fluorination. (Centre) Bidirectional functionalization. (Bottom) Preliminary validation of an enantioselective variant.Similarly, bidirectional geminal difluorination of the divinylbenzene derivatives 9 and 11 was efficient, enabling the synthesis of 10 (46%) and 12 (70%), respectively. This enables facile access to bis-electrophilic fluorinated linchpins for application in materials chemistry.Preliminary validation of an enantioselective variant8d was achieved using the trisubstituted alkene 13. To that end, a series of C2-symmetric resorcinol-based catalysts were explored (see Fig. 3, inset). This enabled the generation of product 15 in up to 18 : 82 e.r. and 71% isolated yield. It is interesting to note that this catalysis system was also compatible with the chlorinated substrate E-14. A comparison of geometric isomers revealed a matched-mismatched scenario: whilst E-14 was efficiently converted to 16 (75%, 14 : 86 e.r.), Z-14 was recalcitrant to rearrangement (<20%).To demonstrate the synthetic utility of the products, chemoselective functionalization of linchpin 2a was performed to generate 17 (57%) and 18 (87%), respectively (Fig. 4). Finally, this method was leveraged to generate an API for amyotrophic lateral sclerosis. Whereas the reported synthesis17 requires the exposure of α-bromoketone 19 to neat DAST over 7 days,18 compound 2h can be generated using this protocol over a more practical timeframe (24 h) on a 4 mmol scale. This key building block was then processed, via the amine hydrochloride salt 20, to API 21.Open in a separate windowFig. 4Selected modification of building blocks 2a and 2h. Conditions: (a) NaN3, DMF, 110 °C, 16 h. (b) Pd(OH)2/C (10 mol%), EtOH, 1 M HCl, rt, 24 h; (c) CDI, Et3N, THF, 60 °C, 16 h; (d) malonyl chloride, DCM, 0 °C, 2 h. 相似文献
Entry | Solvent | Amine/HF | Catalyst loading [mol%] | Yieldb [%] |
---|---|---|---|---|
1 | CHCl3 | 1 : 4.5 | 20 | 72 |
2 | CHCl 3 | 1 : 6.0 | 20 | >95 |
3 | CHCl3 | 1 : 7.5 | 20 | 94 |
4 | CHCl3 | 1 : 9.23 | 20 | 87 |
5 | CHCl3 | 1 : 6.0 | 10 | 87 |
6 | CHCl3 | 1 : 6.0 | 5 | 79 |
7 | DCM | 1 : 6.0 | 20 | >95 |
8 | DCE | 1 : 6.0 | 20 | 93 |
9 | ETFA | 1 : 6.0 | 20 | 84 |
10 | MeCN | 1 : 6.0 | 20 | 50 |
11 | CHCl3 | 1 : 6.0 | 0 | <5 |
995.
An SPE-LC-MS/MS method was developed, validated and applied to the determination of nicotine and five major metabolites in human urine: cotinine, trans-3'-hydroxycotinine, nicotine-N-glucuronide, cotinine-N-glucuronide and trans-3'-hydroxycotinine-O-glucuronide. A 500 microL urine sample was pH-adjusted with phosphate buffer (1.5 mL) containing nicotine-methyl-d3, cotinine-methyl-d3 and trans-3'-hydroxycotinine-methyl-d3 internal standards. For the unconjugated metabolites, an aliquot (800 microL) of the buffered solution was applied to a 30 mg Oasis HLB-SPE column, rinsed with 2% NH4OH/H2O (3.0 mL) and H2O (3.0 mL) and eluted with methanol (500 microL). The eluate was analyzed isocratically (100% methanol) by LC-MS/MS on a diol column (50 x 2.1 mm). For the total metabolites, a beta-glucuronidase/buffer preparation (100 microL) was added to the remaining buffered solution and incubated at 37 degrees C (20 h). An aliquot (800 microL) of the enzymatically treated buffered solution was extracted and analyzed in the same manner. The conjugated metabolites were determined indirectly by subtraction. The quantitation range of the method (ng/mL) was 14-10,320 for nicotine, 15-9800 for cotinine and 32-19,220 for trans-3'-hydroxycotinine. The validated method was used to observe diurnal variations from a smoker's spot urine samples, elimination half-lives from a smoker's 24 h urine samples and metabolite distribution profiles in the spot and 24 h urine samples. 相似文献
996.
William L. Kubasek Dennis Spann Joel W. Hockensmith 《Photochemistry and photobiology》1993,58(1):1-10
Pulsed laser cross-linking provides a means of introducing a covalent bond between proteins and the nucleic acids to which they are bound. This rapid cross-linking effectively traps the equilibrium that exists at the moment of irradiation and thus allows examination of the protein-nucleic acid interactions that existed. Laser irradiation may also induce photodestruction of protein and we have used the bacteriophage T4 gene 32 protein to investigate this phenomenon. Our results show that both nonspecific and specific photoproducts can occur, specifically at wavelengths where the peptide backbone of proteins is known to absorb. These results demonstrate that nonspecific photodegradation can be correlated with the formation of a specific photodegradation product. The formation of this product was monitored to show that product yield is nonlinearly dependent on laser power and wavelength. We have also investigated an unexpected photoproduct whose formation is dependent on the length of the polynucleotide to which the gene 32 protein binds and that further demonstrates the complexities of analyzing protein-nucleic acid interactions through the use of UV laser cross-linking. These data provide essential information for the establishment of appropriate conditions for future studies that use UV cross-linking of protein-nucleic acid complexes. 相似文献
997.
The preparation of substituted pyridines from cycloalkanones by elaboration of an aromatic ring is described. 相似文献
998.
Joel L. StevensThomas D. Welton Jay P. DevilleVictor Behar 《Tetrahedron letters》2003,44(49):8901-8903
Bromine substituents on naphthoquinones effectively activate and orient the [3+2] dipolar cycloaddition reaction with nitrile oxides to generate regiodefined type II polyketide building blocks. 相似文献
999.
1000.
Aina McEvoy Joel Creutzberg Raushan K. Singh Morten J. Bjerrum Erik D. Hedegrd 《Chemical science》2021,12(1):352
Catalytic breakdown of polysaccharides can be achieved more efficiently by means of the enzymes lytic polysaccharide monooxygenases (LPMOs). However, the LPMO mechanism has remained controversial, preventing full exploitation of their potential. One of the controversies has centered around an active site tyrosine, present in most LPMO classes. Recent investigations have for the first time obtained direct (spectroscopic) evidence for the possibility of chemical modification of this tyrosine. However, the spectroscopic features obtained in the different investigations are remarkably different, with absorption maximum at 420 and 490 nm, respectively. In this paper we use density functional theory (DFT) in a QM/MM formulation to reconcile these (apparently) conflicting results. By modeling the spectroscopy as well as the underlying reaction mechanism we can show how formation of two isomers (both involving deprotonation of tyrosine) explains the difference in the observed spectroscopic features. Both isomers have a [TyrO–Cu–OH]+ moiety with the OH in either the cis- or trans-position to a deprotonated tyrosine. Although the cis-[TyrO–Cu–OH]+ moiety is well positioned for oxidation of the substrate, preliminary calculations with the substrate reveal that the reactivity is at best moderate, making a protective role of tyrosine more likely.With QM/MM, we investigate the mechanism of tyrosine deprotonation in lytic polysaccharide monooxygenases. Our results support deprotonation and our calculated UV-vis spectra show that two isomers must be formed to match recent experiments. 相似文献