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.

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.

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.

Infrared Fingerprint and Unimolecular Decay Dynamics of the Hydroperoxyalkyl Intermediate (•QOOH) in Cyclopentane Oxidation.

A transient carbon-centered hydroperoxyalkyl intermediate (•QOOH) in the oxidation of cyclopentane is identified by IR action spectroscopy with time-resolved unimolecular decay to hydroxyl (OH) radical products that are detected by UV laser-induced fluorescence. Two nearly degenerate •QOOH isomers, ß- and γ-QOOH, are generated by H atom abstraction of the cyclopentyl hydroperoxide precursor. Fundamental and first overtone OH stretch transitions and combination bands of •QOOH are observed and compared with anharmonic frequencies computed by second-order vibrational perturbation theory. An OH stretch transition is also observed for a conformer arising from torsion about a low-energy CCOO barrier. Definitive identification of the ß-QOOH isomer relies on its significantly lower transition state (TS) barrier to OH products, which results in rapid unimolecular decay and near unity branching to OH products. A benchmarking approach is utilized to compute high-accuracy stationary point energies, most importantly TS barriers, for cyclopentane oxidation (C5H9O2), building on higher level reference calculations for ethane oxidation (C2H5O2). The experimental OH product appearance rates are compared with computed statistical microcanonical rates using RRKM theory, including heavy-atom tunneling, thereby validating the computed TS barrier. The results are extended to thermal unimolecular decay rate constants at temperatures and pressures relevant to cyclopentane combustion via master-equation modeling. The various torsional and ring puckering states of the wells and transition states are explicitly considered in these calculations.

Infrared signature of the hydroperoxyalkyl intermediate (·QOOH) in cyclohexane oxidation: An isomer-resolved spectroscopic study.

Infrared (IR) action spectroscopy is utilized to characterize carbon-centered hydroperoxy-cyclohexyl radicals (·QOOH) transiently formed in cyclohexane oxidation. The oxidation pathway leads to three nearly degenerate ·QOOH isomers, ß-, γ-, and δ-QOOH, which are generated in the laboratory by H-atom abstraction from the corresponding ring sites of the cyclohexyl hydroperoxide (CHHP) precursor. The IR spectral features of jet-cooled and stabilized ·QOOH radicals are observed from 3590 to 7010 cm-1 (∼10-20 kcal mol-1) at energies in the vicinity of the transition state (TS) barrier leading to OH radicals that are detected by ultraviolet laser-induced fluorescence. The experimental approach affords selective detection of ß-QOOH, arising from its significantly lower TS barrier to OH products compared to γ and δ isomers, which results in rapid unimolecular decay and near unity branching to OH products. The observed IR spectrum of ß-QOOH includes fundamental and overtone OH stretch transitions, overtone CH stretch transitions, and combination bands involving OH or CH stretch with lower frequency modes. The assignment of ß-QOOH spectral features is guided by anharmonic frequencies and intensities computed using second-order vibrational perturbation theory. The overtone OH stretch (2νOH) of ß-QOOH is shifted only a few wavenumbers from that observed for the CHHP precursor, yet they are readily distinguished by their prompt vs slow dissociation rates to OH products.

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.

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.

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.

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.

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.

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.

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.

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.

Ir and NHC Dual Chiral Synergetic Catalysis: Mechanism and Stereoselectivity in γ-Butyrolactone Formation.

Cooperative dual catalysis is a powerful strategy for achieving unique reactivity by combining catalysts with orthogonal modes of action. This approach allows for independent control of the absolute and relative stereochemistry of the product. Despite its potential utility, the combination of N-heterocyclic carbene (NHC) organocatalysis and transition metal catalysis has remained a formidable challenge as NHCs readily coordinate metal centers. This characteristic also makes it difficult to rationalize or predict the stereochemical outcomes of these reactions. Herein, we use quantum mechanical calculations to investigate formation of γ-butyrolactones from aldehydes and allyl cyclic carbonates by means of an NHC organocatalyst and an iridium catalyst. Stereoconvergent activation of the racemic allyl cyclic carbonate forms an Ir-π-allyl intermediate and activation of an unsaturated aldehyde forms an NHC enolate, the latter of which is rate-limiting. Union of the two fragments leads to stereodetermining C-C bond formation and ultimately ring closure to generate the product lactone. Notably, CO2 loss occurs after formation of the C-C bond and Et3NH+ plays a key role in stabilizing carboxylate intermediates and in facilitating proton transfer to form the NHC enolate. The computed pathways agree with the experimental findings in terms of the absolute configuration, the enantiomer excess, and the different diastereomers seen with the (R)- and (S)-spiro-phosphoramidite combined with the NHC catalyst. Calculations reveal the lowest energy pathway includes both an NHC ligand and a phosphoramidite ligand on the iridium center. However, the stereochemical features of this Ir-bound NHC were found to not contribute to the selectivity of the process.

Biomolecule-Compatible Dehydrogenative Chan-Lam Coupling of Free Sulfilimines.

Inspired by the discovery of a S═N bond in the collagen IV network and its essential role in stabilizing basement membranes, sulfilimines have drawn much attention in the fields of chemistry and biology. However, their further uptake is hindered by the lack of mild, efficient, and environmentally benign protocols by which sulfilimines can be constructed under biomolecule-compatible conditions. Here, we report a terminal oxidant-free copper-catalyzed dehydrogenative Chan-Lam coupling of free diaryl sulfilimines with arylboronic acids with excellent chemoselectivity and broad substrate compatibility. The mild reaction conditions and biomolecule-compatible nature allow the employment of this protocol in the late-stage functionalization of complex peptides, and more importantly, as an effective bioconjugation method as showcased in a model protein. A combined experimental and computational mechanistic investigation reveals that an inner-sphere electron-transfer process circumvents the sacrificial oxidant employed in traditional Chan-Lam coupling reactions. An energetically viable concerted pathway was located wherein a copper hydride facilitates hydrogen-atom abstraction from the isopropanol solvent to produce dihydrogen via a four-membered transition state.

Rapid Allylic 1,6 H-Atom Transfer in an Unsaturated Criegee Intermediate.

A novel allylic 1,6 hydrogen-atom-transfer mechanism is established through infrared activation of the 2-butenal oxide Criegee intermediate, resulting in very rapid unimolecular decay to hydroxyl (OH) radical products. A new precursor, Z/E-1,3-diiodobut-1-ene, is synthesized and photolyzed in the presence of oxygen to generate a new four-carbon Criegee intermediate with extended conjugation across the vinyl and carbonyl oxide groups that facilitates rapid allylic 1,6 H-atom transfer. A low-energy reaction pathway involving isomerization of 2-butenal oxide from a lower-energy (tZZ) conformer to a higher-energy (cZZ) conformer followed by 1,6 hydrogen transfer via a seven-membered ring transition state is predicted theoretically and shown experimentally to yield OH products. The low-lying (tZZ) conformer of 2-butenal oxide is identified based on computed anharmonic frequencies and intensities of its conformers. Experimental IR action spectra recorded in the fundamental CH stretch region with OH product detection by UV laser-induced fluorescence reveal a distinctive IR transition of the low-lying (tZZ) conformer at 2996 cm-1 that results in rapid unimolecular decay to OH products. Statistical RRKM calculations involving a combination of conformational isomerization and unimolecular decay via 1,6 H-transfer yield an effective decay rate keff(E) on the order of 108 s-1 at ca. 3000 cm-1 in good accord with the experiment. Unimolecular decay proceeds with significant enhancement due to quantum mechanical tunneling. A rapid thermal decay rate of ca. 106 s-1 is predicted by master-equation modeling of 2-butenal oxide at 298 K, 1 bar. This novel unimolecular decay pathway is expected to increase the nonphotolytic production of OH radicals upon alkene ozonolysis in the troposphere.

Oxidative dehydrogenative couplings of alkenyl phenols.

Alkenyl phenols are utilized by nature in the construction of one of the most important biopolymers, lignin. Using similar building blocks, an array of distinct structures can be formed by selective dimerization of the starting phenols to form lignans, neolignans, oxyneolignans, and norlignans. Given the multitude of possible outcomes, many methods have been reported to affect the desired bond formations and access these biologically relevant scaffolds. The most biomimetic of these methods, discussed here, involve the unprotected phenols undergoing oxidative bond formation that proceeds via dehydrogenative coupling. This review aims to place the known literature in context, highlight the progress made toward the synthesis of these important molecules, and recognize the gaps and limitations that still exist.

Accounting for Strong Ligand Sensitivity in Pd-Catalyzed α-Arylation of Enolates from Ketones, Esters, and Nitroalkanes.

The mechanism of the Pd-catalyzed α-arylation of three model enolates is studied focusing on an analysis of their very different reactivities. In particular, the low reactivity of nitronates under standard arylation conditions and their high sensitivity to the nature of catalytic systems are addressed. The three canonical steps for each of the reaction systems are examined, and key trends surrounding the stability of intermediates and transition states are delineated. A framework based on molecular orbital analyses and the hard-soft acid-base (HSAB) theory is advanced to explain the observed reactivity trends. The local softness of the enolates was found to be a key parameter controlling the energy of the enolate-catalyst complexes. The low reactivity of the nitroalkane enolates is attributed to slow reductive elimination, a consequence of the hard nature of the nitronate. Analysis of reactivity of nitromethane in α-arylation with Pd catalysts containing Buchwald ligands reveals destabilization of the L2Pd species as a major non-enolate-specific acceleration mechanism as well as less electron-rich ligands accelerating reductive elimination as a nitronate-specific mechanism. The corresponding energetics and feasibility that favor C-arylation versus O-arylation are outlined.

Total Synthesis of Pyrolaside B: Phenol Trimerization through Sequenced Oxidative C-C and C-O Coupling.

A facile method to oxidatively trimerize phenols using a catalytic aerobic copper system is described. The mechanism of this transformation was probed, yielding insight that enabled cross-coupling trimerizations. With this method, the natural product pyrolaside B was synthesized for the first time. The key strategy used for this novel synthesis is the facile one-step construction of a spiroketal trimer intermediate, which can be selectively reduced to give the natural product framework without recourse to stepwise Ullmann- and Suzuki-type couplings. As a result, pyrolaside B can be obtained expeditiously in five steps and 16 % overall yield. Three other analogues were synthesized, thus highlighting the utility of the method, which provides new accessibility to this area of chemical space. A novel xanthene was also synthesized through controlled Lewis acid promoted rearrangement of a spiroketal trimer.