Visible-light TiO2-catalyzed synthesis of dihydrobenzofurans by oxidative [3 + 2] annulation of phenols with alkenyl phenols.

An oxidative strategy for the preparation of dihydrobenzofurans via heterogeneous photocatalysis is reported. This method leverages the surface interaction between the alkenyl phenol and the TiO2 solid surface, which enables direct activation by visible light without the need for pre-functionalization or surface modification. The resulting alkenyl phenoxyl radical is proposed to be selectively captured by a neutral phenol nucleophile, rendering ß-5' coupling with excellent chemo- and regio-selectivity. The reaction proceeds under benign conditions, using an inexpensive, nontoxic, and recyclable photocatalyst under visible light irradiation with air as the terminal oxidant at room temperature.

Isomer-resolved unimolecular dynamics of the hydroperoxyalkyl intermediate (•QOOH) in cyclohexane oxidation.

The oxidation of cycloalkanes is important in the combustion of transportation fuels and in atmospheric secondary organic aerosol formation. A transient carbon-centered radical intermediate (•QOOH) in the oxidation of cyclohexane is identified through its infrared fingerprint and time- and energy-resolved unimolecular dissociation dynamics to hydroxyl (OH) radical and bicyclic ether products. Although the cyclohexyl ring structure leads to three nearly degenerate •QOOH isomers (ß-, γ-, and δ-QOOH), their transition state (TS) barriers to OH products are predicted to differ considerably. Selective characterization of the ß-QOOH isomer is achieved at excitation energies associated with the lowest TS barrier, resulting in rapid unimolecular decay to OH products that are detected. A benchmarking approach is employed for the calculation of high-accuracy stationary point energies, in particular TS barriers, for cyclohexane oxidation (C6H11O2), building on higher-level reference calculations for the smaller ethane oxidation (C2H5O2) system. The isomer-specific characterization of ß-QOOH is validated by comparison of experimental OH product appearance rates with computed statistical microcanonical rates, including significant heavy-atom tunneling, at energies in the vicinity of the TS barrier. Master-equation modeling is utilized to extend the results to thermal unimolecular decay rate constants at temperatures and pressures relevant to cyclohexane combustion.

Vibrational spectroscopy and dissociation dynamics of cyclohexyl hydroperoxide.

Organic hydroperoxides (ROOH) are ubiquitous in the atmospheric oxidation of volatile organic compounds (VOCs) as well as in low-temperature oxidation of hydrocarbon fuels. The present work focuses on a prototypical cyclic hydroperoxide, cyclohexyl hydroperoxide (CHHP). The overtone OH stretch (2νOH) spectrum of jet-cooled CHHP is recorded by IR multiphoton excitation with UV laser-induced fluorescence detection of the resulting OH products. A distinctive IR feature is observed at 7012.5 cm-1. Two conformers of CHHP are predicted to have similar stabilities (within 0.2 kcal mol-1) and overtone OH stretch transitions (2νOH), yet are separated by a significant interconversion barrier. The IR power dependence indicates that absorption of three or more IR photons is required for dissociation of CHHP to cyclohexoxy (RO) and OH radical products. Accompanying high-level single- and multi-reference electronic structure calculations quantitatively support the experimental results. Calculations are extended to a range of organic hydroperoxides to examine trends in bond dissociation energies associated with RO + OH formation and compared with prior theoretical results.

Quantification of Hydrogen-Bond-Donating Ability of Biologically Relevant Compounds.

Hydrogen bonding is a key factor in the design of ligands for biological binding, including drug targets. Our group previously developed a method for experimentally assessing the hydrogen-bond-donating ability of an analyte using UV-vis titrations with a colorimetric sensor. Using this method, 79 new titrations were performed on weak hydrogen-bond donors, with a focus on heterocycles and pharmaceutically relevant motifs. The hydrogen-bond donating abilities of drug compounds and the substructures of drug compounds were also measured. These titrations will be used to build a database of hydrogen-bond donors.

Synthesis of Phenol-Pyridinium Salts Enabled by Tandem Electron Donor-Acceptor Complexation and Iridium Photocatalysis.

Herein, we describe a dual photocatalytic system to synthesize phenol-pyridinium salts using visible light. Utilizing both electron donor-acceptor (EDA) complex and iridium(III) photocatalytic cycles, the C-N cross-coupling of unprotected phenols and pyridines proceeds in the presence of oxygen to furnish pyridinium salts. Photocatalytic generation of phenoxyl radical cations also enabled a nucleophilic aromatic substitution (SNAr) of a fluorophenol with an electron-poor pyridine. Spectroscopic experiments were conducted to probe the mechanism and reaction selectivity. The unique reactivity of these phenol-pyridinium salts were displayed in several derivatization reactions, providing rapid access to a diverse chemical space.

Recent advances in oxidative phenol coupling for the total synthesis of natural products.

Covering: 2008 to 2023This review will describe oxidative phenol coupling as applied in the total synthesis of natural products. This review covers catalytic and electrochemical methods with a brief comparison to stoichiometric and enzymatic systems assessing their practicality, atom economy, and other measures. Natural products forged by C-C and C-O oxidative phenol couplings as well as from alkenyl phenol couplings will be addressed. Additionally, exploration into catalytic oxidative coupling of phenols and other related species (carbazoles, indoles, aryl ethers, etc.) will be surveyed. Future directions of this particular area of research will also be assessed.

Mechanistic Insights of Copper Catalyzed Trifluoromethyl Aziridine Opening: Regioselective and Stereospecific Aryl Grignard Addition.

The copper catalyzed regioselective and stereospecific opening of CF3-aziridines is reported. This method focuses on the synthesis of α-CF3-ß-arylethylamines, which can be potential key intermediates in the synthesis of synthetic analogues and biologically active molecules. Density functional theory calculations reveal the nature of the active copper species and the role of the LiClMgX2 (X = Cl or I) as a Lewis acid. Further, the computed mechanism accounts for the high regioselectivity of this transformation.

A five-carbon unsaturated Criegee intermediate: synthesis, spectroscopic identification, and theoretical study of 3-penten-2-one oxide.

Biogenic alkenes, such as isoprene and α-pinene, are the predominant source of volatile organic compounds (VOCs) emitted into the atmosphere. Atmospheric processing of alkenes via reaction with ozone leads to formation of zwitterionic reactive intermediates with a carbonyl oxide functional group, known as Criegee intermediates (CIs). CIs are known to exhibit a strong absorption (π* ← π) in the near ultraviolet and visible (UV-vis) region due to the carbonyl oxide moiety. This study focuses on the laboratory identification of a five-carbon CI with an unsaturated substituent, 3-penten-2-one oxide, which can be produced upon atmospheric ozonolysis of substituted isoprenes. 3-Penten-2-one oxide is generated in the laboratory by photolysis of a newly synthesized precursor, (Z)-2,4-diiodopent-2-ene, in the presence of oxygen. The electronic spectrum of 3-penten-2-one oxide was recorded by UV-vis induced depletion of the VUV photoionization signal on the parent m/z 100 mass channel using a time-of-flight mass spectrometer. The resultant electronic spectrum is broad and unstructured with peak absorption at ca. 375 nm. To complement the experimental findings, electronic structure calculations are performed at the CASPT2(12,10)/aug-cc-pVDZ level of theory. The experimental spectrum shows good agreement with the calculated electronic spectrum and vertical excitation energy obtained for the lowest energy conformer of 3-penten-2-one oxide. In addition, OH radical products resulting from unimolecular decay of energized 3-penten-2-oxide CIs are detected by UV laser-induced fluorescence. Finally, the experimental electronic spectrum is compared with that of a four-carbon, isoprene-derived CI, methyl vinyl ketone oxide, to understand the effects of an additional methyl group on the associated electronic properties.

Practical Synthesis of Terminal Vinyl Fluorides.

The synthesis of di- and trisubstituted vinyl fluorides with high isomeric purity remains a challenge for organic synthesis. While many methods exist to access these compounds, the separation of the desired isomer from the minor isomer and/or starting materials often is difficult. Herein, we report a practical method to access di- and trisubstituted vinyl fluorides via a selective Horner-Wadsworth-Emmons olefination/hydrolysis, which provides crystalline 2-fluoroacrylic acids in high (>98%) E-isomeric purity. A subsequent silver-catalyzed stereoretentive decarboxylation provides the title substances with high isomeric purity and without the need for tedious chromatography to remove the minor isomer. The process was amenable to a variety of aldehydes and ketones and provided a diverse array of di- and trisubstituted vinyl fluorides. The sequence was applied to the synthesis of antibacterial and anti-inflammatory compounds.

Net-1,2-Hydrogen Atom Transfer of Amidyl Radicals: Toward the Synthesis of 1,2-Diamine Derivatives.

Hydrogen atom transfer (HAT) processes are among the most useful approaches for the selective construction of C(sp3)-C(sp3) bonds. 1,5-HAT with heteroatom-centered radicals (O•, N•) have been well established and are favored relative to other 1,n-HAT processes. In comparison, net 1,2-HAT processes have been observed infrequently. Herein, the first amidyl radicalls are reported that preferentially undergo a net 1,2-HAT over 1,5-HAT. Beginning with single electron transfer from 2-azaallyl anions to N-alkyl N-aryloxy amides, the latter generate amidyl radicals. The amidyl radical undergoes a net-1,2-HAT to generate a C-centered radical that participates in an intermolecular radical-radical coupling with the 2-azaallyl radical to generate 1,2-diamine derivatives. Mechanistic and EPR experiments point to radical intermediates. Density functional theory calculations provide support for a base-assisted, stepwise-1,2-HAT process. It is proposed that the generation of amidyl radicals under basic conditions can be greatly expanded to access α-amino C-centered radicals that will serve as valuable synthetic intermediates.

Asymmetric Total Synthesis of Chaetoglobin A.

An asymmetric total synthesis of chaetoglobin A was achieved. Atroposelective oxidative coupling of a phenol incorporating all but one carbon of the final product was used as a key step to generate axial chirality. The stereochemical outcome of the catalytic oxidative phenolic with the highly substituted phenol used herein was found to be opposite that of the simpler congeners reported previously, providing a cautionary tale about extrapolating asymmetric processes from simple to more complex substrates. Optimization of the postphenolic coupling steps including formylation, oxidative dearomatization, and selective deprotection steps are outlined. The tertiary acetates of chaetoglobin A were exceptionally labile due to activation by the adjacent keto groups, which complicated each of these steps. In contrast, the final oxygen to nitrogen exchange proceeded readily and the spectroscopic data from the synthetic material matches that of the isolated natural product in all respects.

Protodemetalation of (Bipyridyl)Ni(II)-Aryl Complexes Shows Evidence for Five-, Six-, and Seven-Membered Cyclic Pathways.

Protonation of C-M bonds and its microscopic reverse, metalation of C-H bonds, are fundamental steps in a variety of metal-catalyzed processes. As such, studies on protonation of C-M bonds can shed light on C-H activation. We present here studies on the rate of protodemetalation (PDM) of a suite of arylnickel(II) complexes with various acids that provide evidence for a concerted, cyclic transition state for the PDM of C-Ni bonds and demonstrate that five-, six-, and seven-membered transition states are particularly favorable. Our data show that while the rate of protodemetalation of arylnickel(II) complexes scales with acidity for many acids, several are faster than predicted by pKa. For example, while acetic acid and acetohydroxamic acid are much less acidic than HCl, they both protodemetalate arylnickel(II) complexes significantly faster than HCl. Our data also show how in the case of acetohydroxamic acid, a seven-membered cyclic transition state (CH3C(O)NHOH) can be more favorable than a six-membered transition state (CH3C(O)NHOH). Similarly, five-membered transition states, such as for pyrazole, are highly favorable as well. Comparison of transition state polarization (from density functional theory) compares these new nickel transition states to better-studied precious-metal systems and demonstrates how the base can change the polarization of the transition state giving rise to opposing electronic preferences. Collectively, these studies suggest several new avenues for study in C-H activation as well as approaches to accelerate or slow protodemetalation in nickel catalysis.

Synthesis of Sulfilimines Enabled by Copper-Catalyzed S-Arylation of Sulfenamides.

Herein, an unprecedented synthetic route to sulfilimines via a copper-catalyzed Chan-Lam-type coupling of sulfenamides is presented. A key to success in this novel transformation is the chemoselective S-arylation of S(II) sulfenamides to form S(IV) sulfilimines, overriding the competitive, and more thermodynamically favored, C-N bond formation that does not require a change in the sulfur oxidation state. Computations reveal that the selectivity arises from a selective transmetallation event where bidentate sulfenamide coordination through the sulfur and oxygen atoms favors the S-arylation pathway. The mild and environmentally benign catalytic conditions enable broad functional group compatibility, allowing a variety of diaryl or alkyl aryl sulfilimines to be efficiently prepared. The Chan-Lam coupling procedure could also tolerate alkenylboronic acids as coupling partners to afford alkenyl aryl sulfilimines, a class of scaffolds that cannot be directly synthesized via conventional imination strategies. The benzoyl-protecting groups could be conveniently removed from the product, which, in turn, could be readily transformed into several S(IV) and S(VI) derivatives.

Hydrogen Bonding Parameters by Rapid Colorimetric Assessment: Evaluation of Structural Components Found in Biological Ligands and Organocatalysts.

Hydrogen bonding is a key molecular interaction in biological processes, drug delivery, and catalysis. This report describes a high throughput UV-Vis spectroscopic method to measure hydrogen bonding capacity using a pyrazinone sensor. This colormetric sensor reversibly binds to a hydrogen bond donor, resulting in a blue shift as additional equivalents of donor are added. Titration with excess equivalents of donor is used to determine the binding coefficient, ln(Keq ). Over 100 titrations were performed for a variety of biologically relevant compounds. This data enabled development a multiple linear regression model that is capable of predicting 95 % of ln(Keq ) values within 1 unit, allowing for the estimation of hydrogen bonding affinity from a single measurement. To show the effectiveness of the single point measurements, hydrogen bond strengths were obtained for a set of carboxylic acid bioisosteres. The values from the single point measurements were validated with full titrations.

Visible-Light-Induced Oxidative Coupling of Phenols and Alkenylphenols with a Recyclable, Solid Photocatalyst.

A photocatalytic method for phenol and alkenylphenol oxidative coupling is reported using an inexpensive heterogeneous titanium dioxide photocatalyst with air and visible light. During the coupling process, the Ti-substrate complex is activated under visible light through a ligand to metal charge transfer effect, and the diphenol adduct is proposed to form through a radical cation. The heterogeneous TiO2 catalyst remains stable throughout the reaction and can be easily removed and reused multiple times.

Organocatalyzed Visible Light-Mediated gem-Borosilylcyclopropanation.

The borosilylcyclopropanation of styrene derivatives using a (diiodo(trimethylsilyl)methyl)boronic ester carbene precursor is reported herein. The key reagent was synthesized in a 4-step sequence using inexpensive and commercially available starting materials. This method enabled the preparation of novel 1,1,2-tri- and 1,1,2,2-tetrasubstituted borosilylcyclopropanes up to excellent yields and diastereoselectivity. The reaction is organocatalyzed by eosin Y in the presence of visible light. A mechanism consistent with the experimental observations was postulated based on density functional theory calculations. The versatility of these entities was highlighted through post-functionalization reactions.

Electronic Spectroscopy and Dissociation Dynamics of Vinyl-Substituted Criegee Intermediates: 2-Butenal Oxide and Comparison with Methyl Vinyl Ketone Oxide and Methacrolein Oxide Isomers.

The 2-butenal oxide Criegee intermediate [(CH3CH═CH)CHOO], an isomer of the four-carbon unsaturated Criegee intermediates derived from isoprene ozonolysis, is characterized on its first π* ← π electronic transition and by the resultant dissociation dynamics to O (1D) + 2-butenal [(CH3CH═CH)CHO] products. The electronic spectrum of 2-butenal oxide under jet-cooled conditions is observed to be broad and unstructured with peak absorption at 373 nm, spanning to half maxima at 320 and 420 nm, and in good accord with the computed vertical excitation energies and absorption spectra obtained for its lowest energy conformers. The distribution of total kinetic energy released to products is ascertained through velocity map imaging of the O (1D) products. About half of the available energy, deduced from the theoretically computed asymptotic energy, is accommodated as internal excitation of the 2-butenal fragment. A reduced impulsive model is introduced to interpret the photodissociation dynamics, which accounts for the geometric changes between 2-butenal oxide and the 2-butenal fragment, and vibrational activation of associated modes in the 2-butenal product. Application of the reduced impulsive model to the photodissociation of isomeric methyl vinyl ketone oxide reveals greater internal activation of the methyl vinyl ketone product arising from methyl internal rotation and rock, which is distinctly different from the dissociation dynamics of 2-butenal oxide or methacrolein oxide.

Modifications to a Biphenolic Antibacterial Compound: Activity against ESKAPE Pathogens.

Forty-four analogs of honokiol, a compound with known antibacterial activity, especially with respect to oral bacteria, were synthesized to explore the structure-activity relationships against the ESKAPE pathogens. Compounds with high therapeutic indices (hemolysis20 /MIC) were identified. In particular, ester-linked compounds that would be less than environmentally durable than biaryl ether antibacterials such as the broadly used triclosan were found to be active. MRSA mutants could be generated against some, but not all, of the highly active compounds. Based on gene sequencing results, membrane permeability, intracellular sodium, and intracellular pH assays revealed overlapping mechanisms of action.