Solvent Anions Enable Photoinduced Borylation and Phosphonation of Aryl Halides via EDA Complexes.

We report the synthesis of aryl boronic esters and aryl phosphonate esters promoted by visible-light in the absence of transition-metals or photoredox catalysts. The transformation proceeds at room temperature using sodium hydride, as a non-nucleophilic base, and exhibits functional group tolerance for anilines, amides, and esters. UV-vis spectroscopy, radical trapping experiments, and computational (TD-DFT) calculations suggest an electron-donor-acceptor (EDA) complex between solvent anions and aryl halides as the species responsible for this reactivity.

Photoinduced C(sp3)-H Chalcogenation of Amide Derivatives and Ethers via Ligand-to-Metal Charge-Transfer.

A photoinduced, iron(III) chloride-catalyzed C-H activation of N-methyl amides and ethers leads to the formation of C-S and C-Se bonds via a ligand-to-metal charge transfer (LMCT) process. This methodology converts secondary and tertiary amides, sulfonamides, and carbamates into the corresponding amido-N,S-acetal derivatives in good yields. Mechanistic work revealed that this transformation proceeds through a hydrogen atom transfer (HAT) involving chlorine radical intermediates.

Photoredox Polyfluoroarylation of Alkyl Halides via Halogen Atom Transfer.

Polyfluoroarene moieties are of interest in medicinal chemistry, agrochemicals, and material sciences. Herein, we present the first polyfluoroarylation of unactivated alkyl halides via a halogen atom transfer process. This method converts primary, secondary, and tertiary alkyl halides into the respective polyfluoroaryl compounds in good yields in the presence of amide, carbamate, ester, aromatic, and sulfonamide moieties, including derivatives of complex bioactive molecules. Mechanistic work revealed that this transformation proceeds through an alkyl radical generated after the halogen atom transfer.

Dimsyl Anion Enables Visible-Light-Promoted Charge Transfer in Cross-Coupling Reactions of Aryl Halides.

A methodology is reported for visible-light-promoted synthesis of unsymmetrical chalcogenides enabled by dimsyl anion in the absence of transition-metals or photoredox catalysts. The cross-coupling reaction between aryl halides and diaryl dichalcogenides proceeds with electron-rich, electron-poor, and heteroaromatic moieties. Mechanistic investigations using UV-Vis spectroscopy, time-dependent density functional theory (TD-DFT) calculations, and control reactions suggest that dimsyl anion forms an electron-donor-acceptor (EDA) complex capable of absorbing blue light, leading to a charge transfer responsible for generation of aryl radicals from aryl halides. This previously unreported mechanistic pathway may be applied to other light-induced transformations performed in DMSO in the presence of bases and aryl halides.

Transition-Metal-Free Photoredox Phosphonation of Aryl C-N and C-X Bonds in Aqueous Solvent Mixtures.

Herein, we present an efficient and mild methodology for the synthesis of aromatic phosphonate esters in good to excellent yields using 10H-phenothiazine, an inexpensive commodity chemical, as a photoredox catalyst. The reaction exhibits wide functional group compatibility enabling the transformation in the presence of ketone, amide, ester, amine, and alcohol moieties. Importantly, the reaction proceeds using a green solvent mixture primarily composed of water, thus lowering the environmental footprint of this transformation compared to current methods. The transformation also proceeds under atmospheric conditions, which further differentiates it from current methods that require inert atmosphere. Mechanistic work using fluorescence quenching experiments and radical trapping approaches support the proposed mechanism.

Photochemical Regioselective C(sp3)-H Amination of Amides Using N-Haloimides.

A metal-free regioselective C(sp3)-H amination of amides using N-haloimides in the presence of lithium tert-butoxide and visible light is presented herein. This photoexcited approach is straightforward, and it aminates a wide variety of amides under mild conditions without the use of photocatalysts, external radical initiators, or oxidants. A halogen-bonded intermediate between the tert-butoxide base and the N-haloimide is proposed to be responsible for the increased photoreactivity. Calculations show that the formation of this electron donor-acceptor complex presents an exergonic energy profile.

Metal-free visible-light-promoted C(sp3)-H functionalization of aliphatic cyclic ethers using trace O2.

Presented is a light-promoted C-C bond forming reaction yielding sulfone and phosphate derivatives at room temperature in the absence of metals or photoredox catalyst. This transformation proceeds in neat conditions through an auto-oxidation mechanism which is maintained through the leaching of trace amounts of O2 as sole green oxidant.

Synthesis of Imide and Amine Derivatives via Deoxyamination of Alcohols Using N-Haloimides and Triphenylphosphine.

A deoxyamination methodology of activated and unactivated alcohols is presented. The reaction is mediated by phosphonium intermediates generated in situ from N-haloimides and triphenylphosphine. The protocol allows for the synthesis of phthalimide and amine derivatives in moderate to good yields at room temperature. A series of NMR experiments have provided insight into the reactive intermediates involved and the mechanism of this deoxyamination reaction.

Amide Synthesis through the In Situ Generation of Chloro- and Imido-Phosphonium Salts.

We describe a methodology for the amidation of carboxylic acids by generating phosphonium salts in situ from N-chlorophthalimide and triphenylphosphine. Aliphatic, benzylic, and aromatic carboxylic acids can be transformed into their amide counter parts using primary and secondary amines. This functional group interconversion is achieved at room temperature in good to excellent yields. Mechanistic work shows the in situ formation of chloro- and imido-phosphonium salts that react as activating agents for carboxylic acids and generate an acyloxy-phosphonium species.

Regioselective α-Amination of Ethers Using Stable N-Chloroimides and Lithium tert-Butoxide.

Herein we describe a metal-free regioselective α-amination of ethers mediated by N-chloroimides in ethereal solvents in the presence of lithium tert-butoxide. This reactivity of N-chloroimides leads to the synthesis of hemiaminal ethers in good to excellent yields at room temperature. This C-H functionalization is achieved without the use of a light, heat source, or external radical initiators. Initial mechanistic work indicates that the reaction proceeds through a radical pathway.

Gold(I)-Catalyzed Intramolecular Hydroamination of Unactivated Terminal and Internal Alkenes with 2-Pyridones.

The cationic gold phosphine complex [(P1)Au(NCMe)]+SbF6- [P1 = P(t-Bu)2o-biphenyl; 2] catalyzes the intramolecular hydroamination of 6-alkenyl-2-pyridones to form 1,6-carboannulated 2-pyridones in high yield. The hydroamination of 6-(γ-alkenyl)-2-pyridones was effective for monosubstituted and 1,1- and 1,2-disubstituted aliphatic alkenes, and the method was likewise effective for the hydroamination of 6-(δ-alkenyl)-2-pyridones. Spectroscopic analysis of mixtures of 6-(3-butenyl)-2-pyridone, (P1)AuCl, and AgSbF6 established the N-bound 2-hydroxypyridine complex [(P1)Au(NC6H3-2-OH-6-CH2CH2CH═CH2)]+ SbF6- as the catalyst resting state.

Exhaustive Suzuki-Miyaura reactions of polyhalogenated heteroarenes with alkyl boronic pinacol esters.

A novel Suzuki-Miyaura protocol is described that enables the exhaustive alkylation of polychlorinated pyridines. This method facilitates a formal synthesis of normuscopyridine and the rapid assembly of a dumbbell shaped portion of a [2]rotaxane.

Selective and Serial Suzuki-Miyaura Reactions of Polychlorinated Aromatics with Alkyl Pinacol Boronic Esters.

Among cross-coupling reactions, the Suzuki-Miyaura transformation stands out because of its practical advantages, including the commercial availability and low toxicity of the required reagents, mild reaction conditions, and functional group compatibility. Nevertheless, few conditions can be used to cross-couple alkyl boronic acids or esters with aryl halides, especially 2-pyridyl halides. Herein, we describe two novel Suzuki-Miyaura protocols that enable selective conversion of polychlorinated aromatics, with a focus on reactions to convert 2,6-dichloropyridines to 2-chloro-6-alkylpyridines or 2-aryl-6-alkylpyridines.

Chemoselective detection and discrimination of carbonyl-containing compounds in metabolite mixtures by 1H-detected 15N nuclear magnetic resonance.

NMR spectra of mixtures of metabolites extracted from cells or tissues are extremely complex, reflecting the large number of compounds that are present over a wide range of concentrations. Although multidimensional NMR can greatly improve resolution as well as improve reliability of compound assignments, lower abundance metabolites often remain hidden. We have developed a carbonyl-selective aminooxy probe that specifically reacts with free keto and aldehyde functions, but not carboxylates. By incorporating (15)N in the aminooxy functional group, (15)N-edited NMR was used to select exclusively those metabolites that contain a free carbonyl function while all other metabolites are rejected. Here, we demonstrate that the chemical shifts of the aminooxy adducts of ketones and aldehydes are very different, which can be used to discriminate between aldoses and ketoses, for example. Utilizing the 2-bond or 3-bond (15)N-(1)H couplings, the (15)N-edited NMR analysis was optimized first with authentic standards and then applied to an extract of the lung adenocarcinoma cell line A549. More than 30 carbonyl-containing compounds at NMR-detectable levels, six of which we have assigned by reference to our database. As the aminooxy probe contains a permanently charged quaternary ammonium group, the adducts are also optimized for detection by mass spectrometry. Thus, this sample preparation technique provides a better link between the two structural determination tools, thereby paving the way to faster and more reliable identification of both known and unknown metabolites directly in crude biological extracts.

Electron Ionization-Induced Release of Coded Isotopic Reporter Ions in an m/z Zone of Minimal Interference for Quantifiable, Multiplexed GC-MS Analyses.

We describe an isotope coding strategy that enables simultaneous GC-MS analysis of multiple samples for substrate identification and quantification. The method relies on direct measurement of isotopic ethyl carbenium ions serving as mass spectral tags in a zone of minimal interference (ZMI) at m/z 31-37. Sample aldehyde and ketone mixtures were reacted with isotopic 2-aminooxyethyl propionates to illustrate the method, which determined the relative abundance of the mixed compounds with an average 95% accuracy. ZMI reporter ion detection also enables chemoselective substrate profiling and absolute quantification, as demonstrated using a biologically derived sample.

A chemoselective, one-pot transformation of aldehydes to nitriles.

This paper describes a procedure for direct conversion of aldehydes to nitriles using O-(diphenylphosphinyl)hydroxylamine (DPPH). Aldehydes are smoothly transformed to their corresponding nitriles by heating with DPPH in toluene. The reaction can be accomplished in the presence of alcohol, ketone, ester, or amine functionality.

Fragmentation of oxime and silyl oxime ether odd-electron positive ions by the McLafferty rearrangement: new insights on structural factors that promote α,ß fragmentation.

The McLafferty rearrangement is an extensively studied fragmentation reaction for the odd-electron positive ions from a diverse range of functional groups and molecules. Here, we present experimental and theoretical results of 12 model compounds that were synthesized and investigated by GC-TOF MS and density functional theory calculations. These compounds consisted of three main groups: carbonyls, oximes and silyl oxime ethers. In all electron ionization mass spectra, the fragment ions that could be attributed to the occurrence of a McLafferty rearrangement were observed. For t-butyldimethylsilyl oxime ethers with oxygen in a ß-position, the McLafferty rearrangement was accompanied by loss of the t-butyl radical. The various mass spectra showed that the McLafferty rearrangement is relatively enhanced compared with other primary fragmentation reactions by the following factors: oxime versus carbonyl, oxygen versus methylene at the ß-position and ketone versus aldehyde. Calculations predict that the stepwise mechanism is favored over the concerted mechanism for all but one compound. For carbonyl compounds, C-C bond breaking was the rate-determining step. However, for both the oximes and t-butyldimethylsilyl oxime ethers with oxygen at the ß-position, the hydrogen transfer step was rate limiting, whereas with a CH(2) group at the ß-position, the C-C bond breaking was again rate determining. n-Propoxy-acetaldehyde, bearing an oxygen atom at the ß-position, is the only case that was predicted to proceed through a concerted mechanism. The synthesized oximes exist as both the (E)- and (Z)-isomers, and these were separable by GC. In the mass spectra of the two isomers, fragment ions that were generated by the McLafferty rearrangement were observed. Finally, fragment ions corresponding to the McLafferty reverse charge rearrangement were observed for all compounds at varying relative ion intensities compared with the conventional McLafferty rearrangement.

Fluorophore-gold nanoparticle complex for sensitive optical biosensing and imaging.

Fluorophores have been extensively used as the signal mediator in biosensing and bioimaging for a long time. Enhancement of fluorescence can amplify the signal, thus improving the sensitivity, enabling earlier and accurate disease detection and diagnosis. Some metal nanoparticles, such as gold and silver, can generate a strong electromagnetic field on their surface (surface plasmon field) upon receiving photonic energy. When a fluorophore is placed in the field, the field can affect the fluorophore electrons participating in fluorescence emission and change the fluorescence output. The change can be from complete quenching to significant enhancement, depending on the metal type, particle size and shape, excitation/emission wavelengths and quantum yield of the fluorophore, and the distance between the fluorophore and the particle surface. In this study, the effects of these parameters on the fluorescence enhancement of commonly used fluorophores by gold nanoparticles (GNPs) are theoretically analyzed. Experimentally, an NIR contrast agent with enhanced fluorescence was developed by carefully tailoring the distance between Cypate (ICG based fluorophore) and a GNP, via biocompatible spacer constructs. The effect of the GNP size (3.7-16.4 nm) and spacer length (3.2-4.6 nm) on fluorescence enhancement was studied, and the spacer length that provided the significant enhancement was determined. The spacer of 3.9 nm with 16.4 nm GNP provided the fluorescence of 360% of the control. The experimental data qualitatively agreed with the theoretical results and, thus, the theoretical analysis can be used as a guide for significantly improving the sensitivity of existing fluorescent contrast agents by properly utilizing GNPs and spacers.