ABSTRACT
Amides are ubiquitous in biologically active natural products and commercial drugs. The most common strategy for introducing this functional group is the coupling of a carboxylic acid with an amine, which requires the use of a coupling reagent to facilitate elimination of water. However, the optimal reaction conditions often appear rather arbitrary to the specific reaction. Herein, we report the development of statistical models correlating measured rates to physical organic descriptors to enable the prediction of reaction rates for untested carboxylic acid/amine pairs. The key to the success of this endeavor was the development of an end-to-end data sciencebased workflow to select a set of coupling partners that are appropriately distributed in chemical space to facilitate statistical model development. By using a parameterization, dimensionality reduction, and clustering protocol, a training set was identified. Reaction rates for a range of carboxylic acid and primary alkyl amine couplings utilizing carbonyldiimidazole (CDI) as the coupling reagent were measured. The collected rates span five orders of magnitude, confirming that the designed training set encompasses a wide range of chemical space necessary for effective model development. Regressing these rates with high-level density functional theory (DFT) descriptors allowed for identification of a statistical model wherein the molecular features of the carboxylic acid are primarily responsible for the observed rates. Finally, out-of-sample amide couplings are used to determine the limitations and effectiveness of the model.
ABSTRACT
This study presents a Ni-photoredox method for indole N-arylation, broadening the range of substrates to include indoles with unprotected C3-positions and base-sensitive groups. Through detailed mechanistic inquiries, a Ni(I/III) mechanism was uncovered, distinct from those commonly proposed for Ni-catalyzed amine, thiol, and alcohol arylation, as well as from the Ni(0/II/III) cycle identified for amide arylation under almost identical conditions. The key finding is the formation of a Ni(I) intermediate bearing the indole nucleophile as a ligand prior to oxidative addition, which is rare for Ni-photoredox carbon-heteroatom coupling and has a profound impact on the reaction kinetics and scope. The pre-coordination of indole renders a more electron-rich Ni(I) intermediate, which broadens the scope by enabling fast reactivity even with challenging electron-rich aryl bromide substrates. Thus, this work highlights the often-overlooked influence of X-type ligands on Ni oxidative addition rates and illustrates yet another mechanistic divergence in Ni-photoredox C-heteroatom couplings.
ABSTRACT
This perspective details advances made in the field of Ni-catalyzed C-N bond formation. The use of this Earth abundant metal to decorate amines, amides, lactams, and heterocycles enables direct access to a variety of biologically active and industrially relevant compounds in a sustainable manner. Herein, different strategies that leverage the propensity of Ni to facilitate both one- and two-electron processes will be surveyed. The first part of this Perspective focuses on strategies that facilitate C-N couplings at room temperature by accessing oxidized Ni(III) intermediates. In this context, advances in photochemical, electrochemical, and chemically mediated processes will be analyzed. A special emphasis has been put on providing a comprehensive explanation of the different mechanistic avenues that have been proposed to facilitate these chemistries; either Ni(I/III) self-sustained cycles or Ni(0/II/III) photochemically mediated pathways. The second part of this Perspective details the ligand designs that also enable access to this reactivity via a two-electron Ni(0/II) mechanism. Finally, we discuss our thoughts on possible future directions of the field.
ABSTRACT
This work demonstrates the dominance of a Ni(0/II/III) cycle for Ni-photoredox amide arylation, which contrasts with other Ni-photoredox C-heteroatom couplings that operate via Ni(I/III) self-sustained cycles. The kinetic data gathered when using different Ni precatalysts supports an initial Ni(0)-mediated oxidative addition into the aryl bromide. Using NiCl2 as the precatalyst resulted in an observable induction period, which was found to arise from a photochemical activation event to generate Ni(0) and to be prolonged by unproductive comproportionation between the Ni(II) precatalyst and the in situ generated Ni(0) active species. Ligand exchange after oxidative addition yields a Ni(II) aryl amido complex, which was identified as the catalyst resting state for the reaction. Stoichiometric experiments showed that oxidation of this Ni(II) aryl amido intermediate was required to yield functionalized amide products. The kinetic data presented supports a rate-limiting photochemically-mediated Ni(II/III) oxidation to enable C-N reductive elimination. An alternative Ni(I/III) self-sustained manifold was discarded based on EPR and kinetic measurements. The mechanistic insights uncovered herein will inform the community on how subtle changes in Ni-photoredox reaction conditions may impact the reaction pathway, and have enabled us to include aryl chlorides as coupling partners and to reduce the Ni loading by 20-fold without any reactivity loss.
ABSTRACT
Herein, the development of a mild sustainable protocol to couple primary alkyl chlorides and bromides with amides is described. In contrast to current methodologies, our system does not require the use of strongly basic conditions, high temperatures, or the addition of an organometallic catalyst, thereby enabling access to a remarkably orthogonal scope. K3PO4 is used to facilitate the formation of secondary and tertiary amides, which are ubiquitous scaffolds in bioactive molecules and natural products. Alkylated amide products are obtained in good to excellent yields, with no substantial limitations observed based on the steric and electronic properties of either coupling partner.
Subject(s)
Amides , Biological Products , Alkylation , Bromides , CatalysisABSTRACT
The development of an intermolecular and enantioselective aza-Wacker reaction is described. Using indoles as the N-source and a selection of alkenols as the coupling partners selective ß-hydride elimination toward the alcohol was achieved. This strategy preserves the newly formed stereocenter by preventing the formation of traditionally observed enamine products. Allylic and homoallylic alcohols with a variety of functional groups are compatible with the reaction in high enantioselectivity. Isotopic-labeling experiments support a syn amino-palladation mechanism for this new class of aza-Wacker reactions.
Subject(s)
Indoles/chemistry , Alkylation , StereoisomerismABSTRACT
Herein we describe the development of a Pd-catalyzed enantioselective Markovnikov addition of carbamates to allylic alcohols for the construction of α-tertiary and α-secondary amines. The reaction affords a range of ß-amino alcohols, after reduction of the aldehyde in situ, which contain a variety of functional groups in moderate yields and moderate to good enantioselectivities. These products can be readily oxidized to ß-amino acids, valuable building blocks for the synthesis of biologically active compounds. Mechanistic studies indicate that the C-N bond formation occurs via a syn amino-palladation mechanism, an insight which may guide future reaction development given the limited number of enantioselective syntheses of α-tertiary amines.
Subject(s)
Alcohols/chemistry , Alkenes/chemistry , Amines/chemistry , Carbamates/chemistry , StereoisomerismABSTRACT
A combination of electrochemical, spectroscopic, computational, and kinetic studies has been used to elucidate the key mechanistic aspects of the previously reported enantioselective iminium ion trapping of photochemically generated carbon-centered radicals. The process, which provides a direct way to forge quaternary stereocenters with high fidelity, relies on the interplay of two distinct catalytic cycles: the aminocatalytic electron-relay system, which triggers the stereoselective radical trap upon iminium ion formation, and the photoredox cycle, which generates radicals under mild conditions. Critical to reaction development was the use of a chiral amine catalyst, bearing a redox-active carbazole unit, which could rapidly reduce the highly reactive and unstable intermediate generated upon radical interception. The carbazole unit, however, is also involved in another step of the electron-relay mechanism: the transiently generated carbazole radical cation acts as an oxidant to return the photocatalyst into the original state. By means of kinetic and spectroscopic studies, we have identified the last redox event as being the turnover-limiting step of the overall process. This mechanistic framework is corroborated by the linear correlation between the reaction rate and the reduction potential of the carbazole unit tethered to the aminocatalyst. The redox properties of the carbazole unit can thus be rationally tuned to improve catalytic activity. This knowledge may open a path for the mechanistically driven design of the next generation of electron-relay catalysts.
ABSTRACT
Herein we describe our efforts to elucidate the key mechanistic aspects of the previously reported enantioselective photochemical α-alkylation of aldehydes with electron-poor organic halides. The chemistry exploits the potential of chiral enamines, key organocatalytic intermediates in thermal asymmetric processes, to directly participate in the photoexcitation of substrates either by forming a photoactive electron donor-acceptor complex or by directly reaching an electronically excited state upon light absorption. These photochemical mechanisms generate radicals from closed-shell precursors under mild conditions. At the same time, the ground-state chiral enamines provide effective stereochemical control over the enantioselective radical-trapping process. We use a combination of conventional photophysical investigations, nuclear magnetic resonance spectroscopy, and kinetic studies to gain a better understanding of the factors governing these enantioselective photochemical catalytic processes. Measurements of the quantum yield reveal that a radical chain mechanism is operative, while reaction-profile analysis and rate-order assessment indicate the trapping of the carbon-centered radical by the enamine, to form the carbon-carbon bond, as rate-determining. Our kinetic studies unveil the existence of a delicate interplay between the light-triggered initiation step and the radical chain propagation manifold, both mediated by the chiral enamines.
ABSTRACT
A metal-free, photochemical strategy for the direct alkylation of indoles was developed. The reaction, which occurs at ambient temperature, is driven by the photochemical activity of electron donor-acceptor (EDA) complexes, generated upon association of substituted 1H-indoles with electron-accepting benzyl and phenacyl bromides. Significant mechanistic insights are provided by the X-ray single-crystal analysis of an EDA complex relevant to the photoalkylation and the determination of the quantum yield (Φ) of the process.
ABSTRACT
The oxidation of hexachlorocyclohexane isomers in the aqueous phase (Milli-Q and groundwater) was studied using persulfate activated by ferrioxalate and solar light at circumneutral pH. The experiments were conducted in a solar simulator reactor with local radiation fluxes qw= 1.12·10-7 E cm-2s-1 and in compound parabolic collectors with solar light (qw≈10-7 E cm-2s-1) for 390 min. The effect of activator dosage (18-125 µM ferrioxalate) and persulfate concentration (520-2600 µM) on hexachlorocyclohexane conversion and oxalate and oxidant consumption was analyzed. Conversion of about 95% of ß isomer was achieved at 390 min using 1300 µM of initial persulfate and 63 µM of Fe3+ concentration despite this ß isomer being the most recalcitrant to oxidation (XHexachlorocyclohexanes=0.98). Dechlorination above 80% was achieved under these conditions, analyzing the chlorides released into the water. The influence of chloride and bicarbonate on hexachlorocyclohexanes degradation was analyzed in milli-Q water and in groundwater. Hexachlorocyclohexane conversion at 390 min decreases from 98% to 83, 75 and 65% in the presence of chloride, bicarbonate or groundwater, respectively. Results obtained with compound parabolic collectors and solar light using 2600 µM Na2S2O8 and 63 µM Fe for removing hexachlorocyclohexanes agreed with those from the solar simulator reactor, supporting using solar light to activate persulfate for sustainable abatement of persistent organic pollutants in aqueous matrixes.
Subject(s)
Groundwater , Pesticides , Water Pollutants, Chemical , Hexachlorocyclohexane , Bicarbonates , Chlorides , Oxalates/chemistry , Groundwater/chemistry , Water , Oxidation-Reduction , Water Pollutants, Chemical/analysis , Sulfates/chemistryABSTRACT
This work reports the preliminary results of the development of composite self-assembling membranes obtained by the combination of reduced graphene oxide (rGO) with commercial Degussa P25 titanium dioxide (TiO2). The purpose is to demonstrate the possibility of combining, in the same self-standing material, the capability to treat wastewater containing both inorganic and organic pollutants by exploiting the established ability of rGO to capture metal ions together with that of TiO2 to degrade organic substances. Moreover, this study also investigates the potential photocatalytic properties of tionite (TIO), to demonstrate the feasibility of replacing commercial TiO2 with such waste-derived TiO2-containing material, fulfilling a circular economy approach. Thus, rGO-TiO2 and rGO-TIO composite membranes, 1:1 by weight, were prepared and characterized by SEM-EDX, XRD, thermogravimetry, as well as by Raman and UV-Vis spectroscopies to verify the effective and homogeneous integration of the two components. Then, they were tested towards 3-mg L-1 aqueous synthetic solutions of Fe3+ and Cu2+ ions to evaluate their metal adsorption ability, with values of the order of 0.1-0.2 mmol gmembrane-1, comparable or even slightly higher than those of pristine rGO. Finally, the ability of the composites to degrade a common organic pesticide, i.e., Imidacloprid®, was assessed in preliminary photocatalysis experiments, in which maximum degradation efficiencies of 25% (after 3 h) for rGO-TiO2 and of 21% (after 1 h) for rGO-TIO were found. The result of tionite-containing membranes is particularly promising and worthy of further investigation, given that the anatase content of tionite is roughly 1/6 of the one in commercial TiO2.
ABSTRACT
This paper describes a mild strategy to promote amide arylations. Photoinduced oxidation of a Ni(II) aryl amido intermediate is proposed to facilitate the challenging C-N reductive elimination step at moderate temperatures. Notably, the mildly basic conditions employed facilitate access to a broad scope including protected amino acids, heterocycles, phenols, and sterically hindered substituents. Hence, this work presents an attractive strategy to enable late-stage functionalization of pre-existing amide moieties in commercial drugs and natural products.
Subject(s)
Biological Products , Nickel , Amides , Amino Acids , Catalysis , Nickel/chemistry , Phenols , Photochemical ProcessesABSTRACT
The promising properties of anatase TiO(2) nanocrystals exposing specific surfaces have been investigated in depth both theoretically and experimentally. However, a clear assessment of the role of the crystal faces in photocatalytic processes is still under debate. In order to clarify this issue, we have comprehensively explored the properties of the photogenerated defects and in particular their dependence on the exposed crystal faces in shape-controlled anatase. Nanocrystals were synthesized by solvothermal reaction of titanium butoxide in the presence of oleic acid and oleylamine as morphology-directing agents, and their photocatalytic performances were evaluated in the phenol mineralization in aqueous media, using O(2) as the oxidizing agent. The charge-trapping centers, Ti(3+), O(-), and O(2)(-), formed by UV irradiation of the catalyst were detected by electron spin resonance, and their abundance and reactivity were related to the exposed crystal faces and to the photoefficiency of the nanocrystals. In vacuum conditions, the concentration of trapped holes (O(-) centers) increases with increasing {001} surface area and photoactivity, while the amount of Ti(3+) centers increases with the specific surface area of {101} facets, and the highest value occurs for the sample with the worst photooxidative efficacy. These results suggest that {001} surfaces can be considered essentially as oxidation sites with a key role in the photoxidation, while {101} surfaces provide reductive sites which do not directly assist the oxidative processes. Photoexcitation experiments in O(2) atmosphere led to the formation of Ti(4+)-O(2)(-) oxidant species mainly located on {101} faces, confirming the indirect contribution of these surfaces to the photooxidative processes. Although this work focuses on the properties of TiO(2), we expect that the presented quantitative investigation may provide a new methodological tool for a more effective evaluation of the role of metal oxide crystal faces in photocatalytic processes.
Subject(s)
Nanoparticles/chemistry , Titanium/chemistry , Catalysis , Oxidants/chemistry , Oxygen/chemistry , Particle Size , Photochemical Processes , Surface Properties , Ultraviolet RaysABSTRACT
Highly efficient photoactive antimicrobial coatings were obtained using zinc oxide-reduced graphene oxide nanocomposites (ZnO-rGO). Their remarkable antibacterial activity and high stability demonstrated their potential use for photoactive biocide surfaces. The ZnO-rGO nanocomposites were prepared by the sol-gel technique to create photocatalytic surfaces by spin-coating. The coatings were deeply characterised and several tests were performed to assess the antibacterial mechanisms. rGO was homogeneously distributed as thin sheets decorated with ZnO nanoparticles. The surface roughness and the hydrophobicity increased with the incorporation of graphene. The ZnO-rGO coatings exhibited high activity against the Gram-positive bacterium Staphylococcus aureus. The 1 wt% rGO coated surfaces showed the highest antibacterial effect in only a few minutes of illumination with up to 5-log reduction in colony forming units, which remained essentially free of bacterial colonization and biofilm formation. We demonstrated that these coatings impaired the bacterial cells due to cell membrane damage and intracellular oxidative stress produced by the photogenerated reactive-oxygen species (ROS). The enhancement of the ZnO photocatalytic performance upon rGO incorporation is due to the increased detected generation of hydroxyl radicals, attributed to the reduction of electron-hole pair recombination. This intimate contact between both components also conveyed stability against zinc leaching and improved the coating adhesion.
Subject(s)
Anti-Bacterial Agents/pharmacology , Graphite/pharmacology , Nanocomposites/chemistry , Zinc Oxide/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/radiation effects , Graphite/chemistry , Graphite/radiation effects , Light , Materials Testing , Microbial Sensitivity Tests , Nanocomposites/radiation effects , Staphylococcus aureus/drug effects , Zinc Oxide/chemistry , Zinc Oxide/radiation effectsABSTRACT
Photoactive coatings of sol-gel ZnO suspensions were electrosprayed on glass substrates to produce self-cleaning antimicrobial functionalized surfaces. ZnO-functionalized materials exhibited a uniform external surface consisting of a pattern of microspheres with diameters in the 100-300 nm range. Electrospray allowed surface densities up to 0.30 mg cm-2 that displayed considerable hydrophilicity. Water contact angle decreased with UV irradiation to values below 10°. Two different UV doses were tested by adjusting the irradiation time to simulate Summer-Spring and Winter-Fall conditions. The functionalized coatings showed excellent photocatalytic properties towards the photodegradation of Methylene blue. The electrosprayed surfaces also displayed antibacterial activity against Staphylococcus aureus, with >99.5% reduction in the number of culturable cells. The biocidal activity is attributed to the photogenerated reactive oxygen species on the surface of ZnO coatings and the bioavailable zinc ions produced from ZnO dissolution. The photoactive coatings kept surfaces free from bacterial colonization and biofilm formation.
Subject(s)
Anti-Infective Agents/pharmacology , Zinc Oxide/chemistry , Zinc Oxide/pharmacology , Biofilms/drug effects , Catalysis , Methylene Blue/chemistry , Nanoparticles , Photochemistry , Reactive Oxygen Species/chemistry , Reactive Oxygen Species/pharmacology , Seasons , Staphylococcus aureus/drug effects , Surface Properties , Ultraviolet Rays , Water/chemistryABSTRACT
A photocatalytic sol of TiO2 nanoparticles has been used for creating self-cleaning antimicrobial flat and porous glass surfaces. The substrates were irradiated to study their photocatalytic properties and behavior in the presence of biofilm-forming bacteria. Smooth glass surfaces and glass microfiber filters were covered with 1.98×10-3±1.5×10-4gcm-2 and 8.55×10-3±3.0×10-4gcm-2 densities, respectively. Self-cleaning properties were analyzed using the methylene blue 365nm UV-A photodegradation test. TiO2-coated filters achieved rapid and complete photodegradation of methylene blue because of the better TiO2 dispersion with respect to the glass slides. The effect of functionalized surfaces on the growth and viability of bacteria was studied using the strains Staphylococcus aureus and Pseudomonas putida. After irradiation (2h, 11.2Wm-2, 290-400nm), the initially hydrophobic surface turned hydrophilic. The antibacterial effect led to extensive membrane damage and significant production of intracellular reactive oxygen species in all TiO2-loaded irradiated specimens. The reduction of cell viability was over 99.9% (>3-log) for TiO2 on glass surfaces. However, the polymeric extracellular matrix formed before the irradiation treatment was not removed. This study highlights the importance of bacterial colonization during dark periods and the difficulty of removing the structure of biofilms.
Subject(s)
Anti-Bacterial Agents , Biofilms/drug effects , Nanoparticles , Pseudomonas putida/drug effects , Staphylococcus aureus/drug effects , Titanium , Ultraviolet Rays , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/radiation effects , Catalysis , Extracellular Matrix/drug effects , Methylene Blue/chemistry , Nanoparticles/chemistry , Nanoparticles/radiation effects , Photolysis , Pseudomonas putida/growth & development , Pseudomonas putida/physiology , Staphylococcus aureus/growth & development , Staphylococcus aureus/physiology , Surface Properties , Titanium/chemistry , Titanium/pharmacology , Titanium/radiation effectsABSTRACT
The objective of this work is double-firstly to explore the photocatalytic efficiency of five different commercial TiO2 catalysts in the photodegradation of a mixture of pesticides classified by the EU as priority pollutants and secondly to analyze the correlation between their physicochemical properties and the inhibition of the studied photocatalytic process when natural water was employed. Photocatalytic efficiencies when ultrapure water was used seem to point out that surface area was not a prerequisite for the photodegradation of the selected mixture of pesticides. On the other hand, significant differences in total organic carbon (TOC) conversions were obtained with the two studied water compositions. On one side, Evonik materials appear to be mostly inhibited when natural water was employed, whereas on the other, it should be remarked that anatase Sigma-Aldrich (SA) and, particularly, Hombikat UV100 (HBK) materials presented a very limited photo-efficiency inhibition or even a higher initial rate of TOC removal when a natural water matrix was used, probably due to their specific surface properties (PZC, S BET). Therefore, heterogeneous photocatalysis has proved to be a promising technology for the degradation of the selected mixture of pesticides where the final photo-efficiency of the five commercial titania catalysts studied here responds to a complex balance between its surface and structural properties.