We report a photochemically induced, hydroxy-directed fluorination that addresses the prevailing challenge of high diastereoselectivity in this burgeoning field. Numerous simple and complex motifs showcase a spectrum of regio- and stereochemical outcomes based on the configuration of the hydroxy group. Notable examples include a long-sought switch in the selectivity of the refractory sclareolide core, an override of benzylic fluorination, and a rare case of 3,3′-difluorination. Furthermore, calculations illuminate a low barrier transition state for fluorination, supporting our notion that alcohols are engaged in coordinated reagent direction. A hydrogen bonding interaction between the innate hydroxy directing group and fluorine is also highlighted for several substrates with 19F–1H HOESY experiments, calculations, and more. We report a photochemical, hydroxy-directed fluorination that addresses the prevailing challenge of high diastereoselectivity. Numerous motifs showcase a range of regio- and stereochemical outcomes based on the configuration of the hydroxy group.The hydroxy (OH) group is treasured and versatile in chemistry and biology.1 Its ubiquity in nature and broad spectrum of chemical properties make it an attractive source as a potential directing group.2 The exploitation of the mild Lewis basicity exhibited by alcohols has afforded several elegant pathways for selective functionalization (e.g., Sharpless epoxidation,3 homogeneous hydrogenation,4 cross-coupling reactions,5 among others6). Recently, we reported a photochemically promoted carbonyl-directed aliphatic fluorination, and most notably, established the key role that C–H⋯O hydrogen bonds play in the success of the reaction.7 Our detailed mechanistic investigations prompt us to postulate that other Lewis basic functional groups (such as –OH) can direct fluorination in highly complementary ways.8 In this communication, we report a hydroxy-directed aliphatic fluorination method that exhibits unique directing properties and greatly expands the domain of radical fluorination into the less established realm governing high diastereoselectivity.9Our first inclination that functional groups other than carbonyls may influence fluorination regiochemical outcomes was obtained while screening substrates for our published ketone-directed radical-based method (Scheme 1).8a In this example, we surmised that oxidation of the tertiary hydroxy group on substrate 1 cannot occur and would demonstrate functional group tolerance (directing to C11, compound 2). Surprisingly, the two major regioisomers (products 3 and 4) are derivatized by Selectfluor (SF) on C12 and C16 – indicative of the freely rotating hydroxyl directing fluorination. Without an obvious explanation of how these groups could be involved in dictating regiochemistry, we continued the mechanistic study of carbonyl-directed fluorination (Scheme 2A). We established that the regioselective coordinated hydrogen atom abstraction occurs by hydrogen bonding between a strategically placed carbonyl and Selectfluor radical dication (SRD).7 However, we noted that the subsequent radical fluorination is not diastereoselective due to the locally planar nature of carbonyl groups. Thus, we posed the question: are there other directing groups that can provide both regio- and diastereoselectivity? Such a group would optimally be attached to a sp3 hybridized carbon; thus the “three dimensional” hydroxy carbon logically comes to mind as an attractive choice, and Scheme 1 illustrates the first positive hint.Open in a separate windowScheme 1Observed products for the fluorination of compound 1.Open in a separate windowScheme 2(A) Proposed mechanism, (B) β-caryophyllene alcohol hypochlorite derivative synthetic probe, (C) isodesmic relation of transition states showing the general importance of the hydroxy group to reactivity (ωB97xd/6-31+G*), and (D) 1H NMR experiment with Selectfluor and various additives at different concentrations.We began our detailed study with a simple substrate that contains a tertiary hydroxyl group. Alcohol 5 was synthesized stereoselectively by the reaction of 3-methylcyclohexanone, FeCl3, and 4-chlorophenylmagnesium bromide;10 the 4-chlorophenyl substituent allows for an uncomplicated product identification and isolation (aromatic chromophore). We sought to determine optimal reaction conditions by examination of numerous photosensitizers, bases, solvents, and light sources (7 Although we utilize cool blue LEDs (sharp cutoff ca. 400 nm), CFLs (small amount of UVB (280–315 nm) and UVA (315–400 nm)) are useable as well.11 A mild base additive was also found to neutralize adventitious HF and improve yields in the substrates indicated (
Open in a separate windowaUnless stated otherwise: substrate (0.25 mmol, 1.0 equiv.), Selectfluor (0.50 mmol, 2.0 equiv.), NaHCO3 (0.25 mmol, 1.0 equiv.), and sensitizer (0.025 mmol, 10 mol%) were dissolved in MeCN (4.0 mL) and irradiated with cool white LEDs for 14 h.Substrate scopea
Open in a separate windowaUnless otherwise specified, the substrate (0.25 mmol, 1.0 equiv.), Selectfluor (0.50 mmol, 2.0 equiv.), NaHCO3 (0.25 mmol, 1.0 equiv. or 0.0 equiv.), and benzil (0.025 mmol 10 mol%) were stirred in MeCN (4.0 mL) and irradiated with cool white LEDs for 14 h. Yields were determined by integration of 19F NMR signals relative to an internal standard and confirmed by isolation of products through column chromatography on silica gel. Yields based on recovered starting material in parentheses. Major diastereomer (with respect to C–F bond) depicted where known.b1.2 equiv. of Selectfluor used.c1.0 equiv. of NaHCO3.d0.0 equiv. of NaHCO3.e3.0 equiv. of Selectfluor used.fIncluding the monofluoride (approx. 11%) with starting material.The screening concurrently buttresses our claim that hydroxy-directed fluorination is proceeding through a mechanism involving a network of C–H⋯OH hydrogen bonds.12 Other N–F reagents (for example, N-fluorobenzenesulfonimide and N-fluoropyridinium tetrafluoroborate) do not provide the desired fluorinated product 6. The 1,3-diaxial relationship shown in Fig. 1 presents an intramolecular competition: tertiary vs. secondary C–H abstraction (O⋯H–C calculated distances: 2.62 and 2.70 Å at B3LYP 6-311++G**, respectively). The tertiary fluoride is the major product in this case.Open in a separate windowFig. 1Example of an intramolecular competition (secondary vs. tertiary C–H abstraction/fluorination) and calculated C–H⋯O distances of compound 5 (B3LYP/6-311++G**).With optimized conditions established, we assessed the site-selectivity of the method with a molecule derived from the acid catalyzed cyclization of α-caryophyllene, β-caryophyllene alcohol (commonly used as a fragrance ingredient in cosmetics, soaps, and detergents).13 When subjected to fluorination conditions, it targets the strained cyclobutane ring (substrate 7) in 52% yield (14 The hydroxy group stereochemistry is poised to direct fluorination to either the C8 or C10 positions (compound 9) due to the plane of symmetry (Fig. 3A). Moreover, we synthesized a complementary derivative through PCC oxidation followed by a Grignard reaction, thereby switching directionality of the hydroxy group (Fig. 3A) to target the C3 or C5 positions instead (compound 8). We found the resultant fluorinated products to be what one expects if engaged in coordinated hydrogen atom transfer (HAT) (55% and 40% for molecules 9 and 8) – a change in regiochemistry based on the stereochemistry of the alcohol. Additionally, only a single stereoisomer is produced for both (d.r. 99 : 1) and reinforce this study as a salient example of diastereoselective radical fluorination.Open in a separate windowFig. 3Examples of hydroxy group stereochemical switches.In the midst of characterizing compound 9, we uncovered a noteworthy hydrogen bonding interaction. Firstly, our plan was to identify the –OH peak within the 1H NMR spectrum and determine if there is a through-space interaction with fluorine in the 19F–1H HOESY NMR spectrum (ultimately aiding in assigning the stereochemistry of the fluorine).15 At first glance, no peaks were immediately discernible as the –OH; however, when a stoichiometric amount of H2O is added, it becomes apparent that the –OH group and geminal proton to the hydroxy peaks broaden by rapid proton exchange (Fig. 2A). Upon closer examination of the dry 1H NMR spectrum, the –OH peak appears to be a sharp doublet of doublets: one bond coupling to the geminal C–H proton of 9 Hz and one of the largest reported through-space couplings to fluorine of 20 Hz. The 19F–1H HOESY spectrum also supports our regio- and stereochemical assignment – a strong interaction between fluorine and Ha, Hb, and Hd, as well as no apparent interaction with Hc and He (Fig. 2B). Consequently, we postulate that intramolecular hydrogen bonding is responsible for the considerable coupling constant. This conclusion is also supported by calculations at B3LYP/6-311++G** (Fig. 2C): the O–H–F angle is given as 140° and F⋯H–O bond distance is 1.97 Å.Open in a separate windowFig. 2(A) Top spectrum (pink) has broadened peaks due to adventitious H2O in solution. (B) Strong interaction observed between the installed fluorine and designated hydroxy proton in the 19F–1H HOESY NMR spectrum. (C) Calculated structure for compound 9 at B3LYP/6-311++G* revealing the hydroxy proton aiming toward the fluorine.Appreciating the complexity and biological significance of steroids,16 we derivatized dehydroepiandrosterone to afford fluorinated substrate 10 (42%; d.r. 99 : 1). Computational modeling assisted in verifying that the β-hydroxy group targets the C12 position (B3LYP/6-311++G**); furthermore, the β-fluoro isomer is the major product (validated by NOESY, 1H, and 19F NMR). Additionally, we subjected 17α-hydroxyprogesterone (endogenous progestogen steroid hormone17) to fluorination conditions and found the α-fluoro product (11) as the major diastereomer in 55% yield (99 : 1 d.r.). To investigate further the notion of coordinated fluorination and explanation of the observed stereoisomers (e.g., β-hydroxy/β-fluoro and α-hydroxy/α-fluoro), we calculated a simplified system comparing the fluorination of 1-propyl radical and γ-propanol radical (Scheme 2C). The reaction can be distilled into two key steps: a site-selective HAT, followed by a diastereoselective fluorination reaction. The following isodesmic relation (ωB97xd/6-31+G*, −7.63 kcal mol−1) illustrates the stabilizing energetic role that the hydroxy group plays in commanding diastereoselectivity. The transition states represent low barrier processes; a solvent dielectric was necessary to find saddle points.Additionally, a simple Protein Data Bank (PDB) survey showed numerous intermolecular close contacts between hydroxy groups and H–C–+NR3 moieties.18 What is more, solutions of Selectfluor with various alcohols at different concentrations reveal characteristic H–C–+NR3 downfield chemical shifts in the 1H NMR spectra (Scheme 2D).19 Both of these observations buttress the claim of a putative hydrogen bonding interaction between Selectfluor and the hydroxy group.We theorize that the regioselective HAT step proceeds similarly to the reported carbonyl-directed pathway (Scheme 2A) involving Selectfluor radical cation coordination (considering the likenesses in conditions and aforementioned Lewis basicity logic). Alternatively, one can imagine the reaction proceeding through a Barton20 or Hofmann–Löffler–Freytag21 style mechanism. To probe this possibility, we employed a β-caryophyllene alcohol hypochlorite derivative to form the alkoxy radical directly, and found that under standard conditions there is complex fragmentation and nonselective fluorination (Scheme 2B). Lastly, we compared the hydroxy versus carbonyl group SF coordination computationally. The carbonyl group is preferred to bind to SF through nonclassical C–H⋯O hydrogen bonds preferentially over the hydroxy group, as the following isodesmic relation shows (acetone and t-BuOH as models; ωB97xd/6-31+G*, −3.81 kcal mol−1), but, once again, rigidity and propinquity are ultimately more important factors in determining directing effects (Scheme 3).Open in a separate windowScheme 3Isodesmic equation comparing carbonyl versus hydroxy group Selectfluor coordination.The tetrahedral nature of hydroxy groups provides unique access to previously unobtainable sites. For example, we compared menthol and an alkylated congener to form products 12 and 13 (Fig. 3B). The hydroxy group in the precursor to 12 is in the equatorial position, mandating the exocyclic isopropyl group as the reactive site (40% yield).22 In the precursor to 13, the methyl and isopropyl substituent lock the hydroxy group into the axial position, targeting its endocyclic tertiary site through a 1,3-diaxial relationship to afford fluorinated product in 57% yield (d.r. 99 : 1). In all, the comparison showcases the versatility in directing ability, offering a choice of regio- and stereoselectivity based on the stereochemistry of the hydroxy group. The directing system only necessitates two features based on our results: (1) the hydroxy group must be either secondary or tertiary (primary tends to favor oxidation) and (2) the oxygen atom must be within the range of 2.4–3.2 Å of the targeted secondary or tertiary hydrogen.Among the several biologically active compounds we screened, caratol derivatives 14 and 15 were found to be attractive candidates that reveal directed fluorination to an exocyclic isopropyl group (23).24 After extraction, isolation, and derivatization, molecules 14 and 15 are afforded in 65% and 83% yield (25 Groves,9f Britton,26 and others.27 The derived alcohol finally overrode this natural tendency and directed to the predicted position in 56% (d.r. 99 : 1) (product 16). Smaller amounts of competitive polar effect fluorination were observed at the C2 and C3 positions, highlighting how challenging a problem the functionalization of the sclareolide core presents.28,29An altered dihydroactinidiolide was found to participate in the fluorination through a 1,3-diaxial guided HAT and fluorination in 55% yield (product 17, d.r. 99 : 1). We next modeled several more substrates that participated in similar 1,3 relationships; however, each exhibited a variation from one another (e.g., ring size or fused aromatic ring). Products 19 and 18 displayed the reaction''s capability to direct to the desired positions with an expanded (65%; d.r. 99 : 1) and reduced (45%; d.r. 99 : 1) ring system when compared to the previous 6-membered ring examples. Additionally, we examined a methylated α-tetralone derivative. The desired 3-fluoro product 20 forms in 43% yield (d.r. 99 : 1), overriding benzylic fluorination (Scheme 4).30 Under identical conditions α-tetralone provides 4-fluorotetralone in 48% yield. In similar motif, 1-phenylindanol, we intentionally targeted the benzylic position in a 90% and 10 : 1 d.r. (product 21). Unlike the methylated α-tetralone derivative, the geometry of the starting material calculated at B3LYP/6-311++G** shows the hydroxy group is not truly axial and is 4.30 Å from the targeted C–H bond, explaining the dip in diastereoselectivity.Open in a separate windowScheme 4Comparing fluorination outcomes for different functional groups.Next, we examined an isomer of borneol that is widely used in perfumery, fenchol.31 The secondary alcohol displays a diastereoselective fluorination in 38% (d.r. 99 : 1) (product 22). Our last designed motif was ideally constructed to have a doubly-directing effect. Our observations show that a well-positioned hydroxy group not only provides sequential regioselective hydrogen atom abstraction but also displays a powerful demonstration of Selectfluor guidance to afford the cis-difluoro product (23) in 33% yield (85% brsm, d.r. 99 : 1). Spectroscopically (1H, 13C, and 19F NMR), the product possesses apparent Cs symmetry and showcases close interactions (e.g., diagnostic couplings and chemical shifts). cis-Polyfluorocycloalkanes are of intense current interest in materials chemistry, wherein faces of differing polarity can complement one another.32All in all, this photochemical hydroxy-directed fluorination report represents one of the first steps in commanding diastereoselectivity within the field of radical fluorination. An ability to dictate regio- and stereoselectivity is demonstrated in a variety of substrates by simply switching the stereochemistry of the hydroxy group. Computations support the key role of Selectfluor coordination to the key hydroxy group in the fluorination step. Future studies will seek to uncover other compatible Lewis basic functional groups, expanding further the versatility of radical fluorination. 相似文献
With the advancement of technology worldwide, security is essential for online information and data. This research work proposes a novel image encryption method based on combined chaotic maps, Halton sequence, five-dimension (5D) Hyper-Chaotic System and Deoxyribonucleic Acid (DNA) encoding. Halton sequence is a known low-discrepancy sequence having uniform distribution in space for application in numerical methods. In the proposed work, we derived a new chaotic map (HaLT map) by combining chaotic maps and Halton sequence to scramble images for cryptography applications. First level scrambling was done by using the HaLT map along with a modified quantization unit. In addition, the scrambled image underwent inter- and intra-bit scrambling for enhanced security. Hash values of the original and scrambled image were used for initial conditions to generate a 5D hyper-chaotic map. Since a 5D chaotic map has complex dynamic behavior, it could be used to generate random sequences for image diffusion. Further, DNA level permutation and pixel diffusion was applied. Seven DNA operators, i.e., ADD, SUB, MUL, XOR, XNOR, Right-Shift and Left-Shift, were used for pixel diffusion. The simulation results showed that the proposed image encryption method was fast and provided better encryption compared to ‘state of the art’ techniques. Furthermore, it resisted various attacks. 相似文献
Cathode thickness plays a major role in establishing an active area for an oxygen reduction reaction in energy converter devices, such as solid oxide fuel cells. In this work, we prepared SrFe0.9Ti0.1O3−δ–Ce0.8Sm0.2O1.9 composite cathodes with different layers (1×, 3×, 5×, 7×, and 9× layer). The microstructural and electrochemical performance of each cell was then explored through scanning electron microscopy and electrochemical impedance spectroscopy (EIS). EIS analysis showed that the area-specific resistance (ASR) decreased from 0.65 Ωcm2 to 0.12 Ωcm2 with the increase in the number of layers from a 1× to a 7×. However, the ASR started to slightly increase at the 9× layer to 2.95 Ωcm2 due to a higher loss of electrode polarization resulting from insufficient gas diffusion and transport. Therefore, increasing the number of cathode layers could increase the performance of the cathode by enlarging the active area for the reaction up to the threshold point. 相似文献
Thin and transparant single crystalline plates of calcium tungstate have been grown by using the method of isothermal flux evaporation at 840°C. The floating plates exhibited spiral depression on their top as-grown surfaces as revealed by high resolution (20 A°) electron-optical plant. It is believed that the spiral pattern results from thermal etching at the sites of helical dislocations. 相似文献
Textural studies have been carried out in AlSb films deposited by coevaporation method under high vacuum at different substrate temperatures between 450° to 625 °C. The films have been examined by X-ray and electron diffraction techniques. It was observed that the films deposited around 550 °C were found to exhibit [110] and [111] textures and the films deposited at higher substrate temperatures (above 600 °C) were found to exhibit only [111] textures. 相似文献
Non-steroidal anti-inflammatory drugs (NSAIDs) are generally utilized for numerous inflammatory ailments. The long-term utilization of NSAIDs prompts adverse reactions such as gastrointestinal ulceration, renal dysfunction and hepatotoxicity; however, selective COX-2 inhibitors prevent these adverse events. Various scientific approaches have been employed to identify safer COX-2 inhibitors, as in any case, a large portion of particular COX-2 inhibitors have been retracted from the market because of severe cardiovascular events. This study aimed to develop and synthesize a novel series of indomethacin analogues with potential anti-inflammatory properties and fewer side effects, wherein carboxylic acid moiety was substituted using DCC/DMAP coupling. This study incorporates the docking of various indomethacin analogues to detect the binding interactions with COX-2 protein (PDB ID: 3NT1). MD simulation was performed to measure the stability and flexibility of ligand–protein interactions at the atomic level, for which the top-scoring ligand–protein complex was selected. These compounds were evaluated in vitro for COX enzymes inhibition. Likewise, selected compounds were screened in vivo for anti-inflammatory potential using the carrageenan-induced rat paw oedema method and their ulcerogenic potential. The acute toxicity of compounds was also predicted using in silico tools. Most of the compounds exhibited the potent inhibition of both COX enzymes; however, 3e and 3c showed the most potent COX-2 inhibition having IC50 0.34 µM and 1.39 µM, respectively. These compounds also demonstrated potent anti-inflammatory potential without ulcerogenic liability. The biological evaluation revealed that the compound substituted with 4-nitrophenyl was most active. 相似文献
Etching of {111} cleavage faces of CaF2 crystals in aqueous solution of 50% HCl is carried out in citric acid set silica gel, and the kinetics of growth of etch pits at the sites of dislocations is investigated as a function of temperature, time of etching and height of gel column above the crystal surface. It is observed that the transient period required to initiate etch pit at the sites of a dislocation decreases (1) at particular temperature, with a decrease in gel height, and (2) for a particular gel height, with an increase in the temperature of etching. It is also observed that the morphology of dislocation etch pits remains triangular irrespective of the gel height and the temperature of etching. The results are compared with those of solution etching and discussed. 相似文献
