Radical Polarity.

The polarity of a radical intermediate profoundly impacts its reactivity and selectivity. To quantify this influence and predict its effects, the electrophilicity/nucleophilicity of >500 radicals has been calculated. This database of open-shell species entails frequently encountered synthetic intermediates, including radicals centered at sp3, sp2, and sp hybridized carbon atoms or various heteroatoms (O, N, S, P, B, Si, X). Importantly, these computationally determined polarities have been experimentally validated for electronically diverse sets of >50 C-centered radicals, as well as N- and O- centered radicals. High correlations are measured between calculated polarity and quantified reactivity, as well as within parallel sets of competition experiments (across different radical types and reaction classes). These multipronged analyses show a strong relationship between the computed electrophilicity, ω, of a radical and its relative reactivity (krel vs Δω slopes up to 40; showing mere Δω of 0.1 eV affords up to 4-fold rate enhancement). We expect this experimentally validated database will enable reactivity and selectivity prediction (by harnessing polarity-matched rate enhancement) and assist with troubleshooting in synthetic reaction development.

Cyclopropanation with Non-Stabilized Carbenes via Ketyl Radicals.

A radical mechanism enables simple and robust access to nonstabilized, alkyl iron carbenes for novel (2 + 1) cycloadditions. This Fe-catalyzed strategy employs simple, aliphatic aldehydes as carbene precursors in a practical, efficient, and stereoselective cyclopropanation. This air- and water-tolerant method permits convenient generation of iron carbenes and coupling to an exceptionally wide range of sterically and electronically diverse alkenes (nucleophilic, electrophilic, and neutral). A transient ketyl radical intermediate is key to accessing and harnessing this rare, alkyl iron carbene reactivity. Mechanistic experiments confirm the (a) intermediacy of ketyl radicals, (b) iron carbene formation by radical capture, and (c) nonconcerted nature of the (2 + 1) cycloaddition.

γ C-H Functionalization of Amines via Triple H-Atom Transfer of a Vinyl Sulfonyl Radical Chaperone.

A selective, remote desaturation has been developed to rapidly access homoallyl amines from their aliphatic precursors. The strategy employs a triple H-atom transfer (HAT) cascade, entailing (i) cobalt-catalyzed metal-HAT (MHAT), (ii) carbon-to-carbon 1,6-HAT, and (iii) Co-H regeneration via MHAT. A new class of sulfonyl radical chaperone (to rapidly access and direct remote, radical reactivity) enables remote desaturation of diverse amines, amino acids, and peptides with excellent site-, chemo-, and regioselectivity. The key, enabling C-to-C HAT step in this cascade was computationally designed to satisfy both thermodynamic (bond strength) and kinetic (polarity) requirements, and it has been probed via regioselectivity, isomerization, and competition experiments. We have also interrupted this radical transfer dehydrogenation to achieve γ-selective C-Cl, C-CN, and C-N bond formations.

Cross-Selective Aza-Pinacol Coupling via Atom Transfer Catalysis.

A cross-selective aza-pinacol coupling of aldehydes and imines has been developed to afford valuable ß-amino alcohols. This strategy enables chemoselective conversion of aliphatic aldehydes to ketyl radicals, in the presence of more easily reduced imines and other functional groups. Upon carbonyl-specific activation by AcI, a photoinitiated Mn catalyst selectively reduces the resulting α-oxy iodide by an atom transfer mechanism. The ensuing ketyl radical selectively couples to imines, precluding homodimerization by a classical reductive approach. In this first example of reductive, ketyl coupling by atom transfer catalysis, Zn serves as a terminal reductant to facilitate Mn catalyst turnover. This new strategy also enables ketyl radical couplings to alkenes, alkynes, aldehydes, propellanes, and chiral imines.

Vicinal, Double C-H Functionalization of Alcohols via an Imidate Radical-Polar Crossover Cascade.

A double functionalization of vicinal sp3 C-H bonds has been developed, wherein a ß amine and γ iodide are incorporated onto an aliphatic alcohol in a single operation. This approach is enabled by an imidate radical chaperone, which selectively affords a transient ß alkene that is amino-iodinated in situ. Overall, the radical-polar-crossover cascade entails the following key steps: (i) ß C-H iodination via 1,5-hydrogen atom transfer (HAT), (ii) desaturation via I2 complexation, and (iii) vicinal amino-iodination of an in situ generated allyl imidate. The synthetic utility of this double C-H functionalization is illustrated by conversion of aliphatic alcohols to a diverse collection of α,ß,γ substituted products bearing heteroatoms on three adjacent carbons. The radical-polar crossover mechanism is supported by various experimental probes, including isotopic labeling, intermediate validation, and kinetic studies.

Development of an Imine Chaperone for Selective C-H Functionalization of Alcohols via Radical Relay.

The design of a radical relay chaperone to promote selective C-H functionalizations is described. A saccharin-based imine was found to be uniquely suited to effect C-H amination of alcohols via an in situ generated hemiaminal. This radical chaperone facilitates the mild generation of an N-centered radical while also directing its regioselective H atom transfer (HAT) to the ß carbon of an alcohol. Upon ß C-H halogenation, aminocyclization, and reductive cleavage, an NH2 is formally added vicinal to an alcohol. The development, synthetic utility, and chemo-, regio-, and stereoselectivity of this imine chaperone-mediated C-H amination is presented herein.

Catalytic Alkene Difunctionalization via Imidate Radicals.

The first catalytic strategy to harness imidate radicals has been developed. This approach enables alkene difunctionalization of allyl alcohols by photocatalytic reduction of their oxime imidates. The ensuing imidate radicals undergo consecutive intra- and intermolecular reactions to afford (i) hydroamination, (ii) aminoalkylation, or (iii) aminoarylation, via three distinct radical mechanisms. The broad scope and utility of this catalytic method for imidate radical reactivity is presented, along with comparisons to other N-centered radicals and complementary, closed-shell imidate pathways.

Directed ß C-H Amination of Alcohols via Radical Relay Chaperones.

A radical-mediated strategy for ß C-H amination of alcohols has been developed. This approach employs a radical relay chaperone, which serves as a traceless director that facilitates selective C-H functionalization via 1,5-hydrogen atom transfer (HAT) and enables net incorporation of ammonia at the ß carbon of alcohols. The chaperones presented herein enable direct access to imidate radicals, allowing their first use for H atom abstraction. A streamlined protocol enables rapid conversion of alcohols to their ß-amino analogs (via in situ conversion of alcohols to imidates, directed C-H amination, and hydrolysis to NH2). Mechanistic experiments indicate HAT is rate-limiting, whereas intramolecular amination is product- and stereo-determining.

Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis.

Modern drug discovery relies on the continual development of synthetic methodology to address the many challenges associated with the design of new pharmaceutical agents. One such challenge arises from the enzymatic metabolism of drugs in vivo by cytochrome P450 oxidases, which use single-electron oxidative mechanisms to rapidly modify small molecules to facilitate their excretion. A commonly used synthetic strategy to protect against in vivo metabolism involves the incorporation of electron-withdrawing functionality, such as the trifluoromethyl (CF(3)) group, into drug candidates. The CF(3) group enjoys a privileged role in the realm of medicinal chemistry because its incorporation into small molecules often enhances efficacy by promoting electrostatic interactions with targets, improving cellular membrane permeability, and increasing robustness towards oxidative metabolism of the drug. Although common pharmacophores often bear CF(3) motifs in an aromatic system, access to such analogues typically requires the incorporation of the CF(3) group, or a surrogate moiety, at the start of a multi-step synthetic sequence. Here we report a mild, operationally simple strategy for the direct trifluoromethylation of unactivated arenes and heteroarenes through a radical-mediated mechanism using commercial photocatalysts and a household light bulb. We demonstrate the broad utility of this transformation through addition of CF(3) to a number of heteroaromatic and aromatic systems. The benefit to medicinal chemistry and applicability to late-stage drug development is also shown through examples of the direct trifluoromethylation of widely prescribed pharmaceutical agents.

Catalytic Desymmetrization by C-H Functionalization as a Solution to the Chiral Methyl Problem.

Breaking the mirror (plane): A palladium-catalyzed desymmetrization strategy via ß C-H activation provides an alternate approach for solving the age-old challenge of introducing an α-methyl stereocenter to a molecule.

Seven Post-synthetic Covalent Reactions in Tandem Leading to Enzyme-like Complexity within Metal-Organic Framework Crystals.

The design of enzyme-like complexity within metal-organic frameworks (MOFs) requires multiple reactions to be performed on a MOF crystal without losing access to its interior. Here, we show that seven post-synthetic reactions can be successfully achieved within the pores of a multivariate MOF, MTV-IRMOF-74-III, to covalently incorporate tripeptides that resemble the active sites of enzymes in their spatial arrangement and compositional heterogeneity. These reactions build up H2N-Pro-Gly-Ala-CONHL and H2N-Cys-His-Asp-CONHL (where L = organic struts) amino acid sequences by covalently attaching them to the organic struts in the MOFs, without losing porosity or crystallinity. An enabling feature of this chemistry is that the primary amine functionality (-CH2NHBoc) of the original MOF is more reactive than the commonly examined aromatic amines (-NH2), and this allowed for the multi-step reactions to be carried out in tandem within the MOF. Preliminary findings indicate that the complexity thus achieved can affect reactions that were previously accomplished only in the presence of enzymes.

Triiodide-Mediated δ-Amination of Secondary C-H Bonds.

The Cδ -H amination of unactivated, secondary C-H bonds to form a broad range of functionalized pyrrolidines has been developed by a triiodide (I3 (-) )-mediated strategy. By in situ 1) oxidation of sodium iodide and 2) sequestration of the transiently generated iodine (I2 ) as I3 (-) , this approach precludes undesired I2 -mediated decomposition which can otherwise limit synthetic utility to only weak C(sp(3) )-H bonds. The mechanism of this triiodide-mediated cyclization of unbiased, secondary C(sp(3) )-H bonds, by either thermal or photolytic initiation, is supported by NMR and UV/Vis data, as well as intercepted intermediates.

Carbonyl cross-metathesis via deoxygenative gem-di-metal catalysis.

Carbonyls and alkenes are versatile functional groups, whose reactivities are cornerstones of organic synthesis. The selective combination of two carbonyls to form an alkene-a carbonyl cross-metathesis-would be a valuable tool for their exchange. Yet, this important synthetic challenge remains unsolved. Although alkene/alkene and alkene/carbonyl cross-metathesis reactions are known, there is a lack of analogous methods for deoxygenative cross-coupling of two carbonyl compounds. Here we report a pair of strategies for the cross-metathesis of unbiased carbonyls, allowing an aldehyde to be chemo- and stereoselectively combined with another aldehyde or ketone. These mild, catalytic methods are promoted by earth-abundant metal salts and enable rapid access to an unprecedentedly broad range of either Z- or E-alkenes by two distinct mechanisms-entailing transiently generated (1) carbenes and ylides (via Fe catalysis) or (2) doubly nucleophilic gem-di-metallics (via Cr catalysis).

Cyclopropanation of unactivated alkenes with non-stabilized iron carbenes.

Cyclopropanes are ubiquitous in medicines, yet robust synthetic access to a wide range of sterically and electronically diverse analogs remains a challenge. To address the synthetic limitations of the most direct strategy, (2+1) cycloaddition, we sought to develop a variant that employs non-stabilized carbenes. We present herein an FeCl2-catalyzed cyclopropanation that uniquely employs aliphatic (enolizable) aldehydes as carbene precursors. A remarkably broad range of alkenes may be coupled with these non-stabilized, alkyl carbenes. This extensive scope enables the synthesis of novel classes of cyclopropanes bearing alkyl, benzyl, allyl, halide, and heteroatom substituents, as well as spirocyclic and fused bicycles. Over 40 examples illustrate the broad generality, efficiency, selectivity, functional group tolerance, and practical utility of this approach. Mechanistic insights, gathered from stereochemical probes and competition experiments, are included to reveal the applicability of this non-stabilized carbene route for novel cyclopropane synthesis.

Aza-Heterocycles via Copper-Catalyzed, Remote C-H Desaturation of Amines.

The majority of medicines contain a nitrogen atom within a five- or six- membered ring. To rapidly access both such aza-heterocycles, we sought to develop a remote C-H desaturation of amines. Inspired by the Hofmann-Löffler-Freytag synthesis of five-membered pyrrolidines, we tackled the century-old challenge of synthesizing six-membered piperidines by H-atom transfer. We present herein a double, vicinal C-H oxidation by dual catalysis, entailing Ir photocatalytic initiation of 1,5-HAT by an N-centered radical and Cu-catalyzed interception of the C-centered radical to facilitate desaturation. By this mechanism, two C-H bonds (δ and ε to N) are regioselectively removed from unbiased, remote positions of an alkyl chain. Over 50 examples illustrate efficiency, selectivity, functional group tolerance, and medicinal utility of this synthesis of both internal and terminal δ vinylic amines and aza-heterocycles. Mechanistic experiments probe the alkylcopper intermediate, as well as kinetics and regioselectivity of the HAT and elimination steps.

Radical Aza-Heck Cyclization of Imidates via Energy Transfer, Electron Transfer, and Cobalt Catalysis.

A radical aza-Heck cyclization has been developed to afford functionally rich products with four contiguous C-heteroatom bonds. This multi-catalytic strategy provides rapid syntheses of dense, medicinally relevant motifs by enabling the conversion of alcohol-derived imidates to heteroatom-rich fragments containing vinyl oxazolines/oxazoles, allyl amines, ß-amino alcohols/halides, and combinations thereof. Mechanistic insights of this process show how three distinct photocatalytic cycles cooperate to enable: (1) imidate radical generation by energy transfer, (2) dehydrogenation by Co catalysis, and (3) catalyst turnover by electron transfer.

Carbene reactivity from alkyl and aryl aldehydes.

Carbenes are highly enabling reactive intermediates that facilitate a diverse range of otherwise inaccessible chemistry, including small-ring formation and insertion into strong σ bonds. To access such valuable reactivity, reagents with high entropic or enthalpic driving forces are often used, including explosive (diazo) or unstable (gem-dihalo) compounds. Here, we report that common aldehydes are readily converted (via stable α-acyloxy halide intermediates) to electronically diverse (donor or neutral) carbenes to facilitate >10 reaction classes. This strategy enables safe reactivity of nonstabilized carbenes from alkyl, aryl, and formyl aldehydes via zinc carbenoids. Earth-abundant metal salts [iron(II) chloride (FeCl2), cobalt(II) chloride (CoCl2), copper(I) chloride (CuCl)] are effective catalysts for these chemoselective carbene additions to σ and π bonds.

Regioselective Radical Amino-Functionalizations of Allyl Alcohols via Dual Catalytic Cross-Coupling.

The regioselective amination and cross-coupling of a range of nucleophiles with allyl alcohols has been enabled by a dual catalytic strategy. This approach entails the combined action of an Ir photocatalyst that enables mild access to N-radicals via an energy transfer mechanism, as well as a Cu complex that intercepts the ensuing alkyl radical upon cyclization. Merger of this Cu-catalyzed cross-coupling enables a broad range of nucleophiles (e.g. CN, SCN, N3, vinyl, allyl) to engage in radical amino-functionalizations of olefins. Notably, stereo, regio, and kinetic probes provide insights into the nature of this Cu-based radical interception.

Thermal and Barrier Characterizations of Cellulose Esters with Variable Side-Chain Lengths and Their Effect on PHBV and PLA Bioplastic Film Properties.

Cellulose esters (CEs) are promising biodegradable substitutes for traditional petroleum-based plastic materials. Research on structure-property relationships of CEs is necessary to evaluate their suitability for industrial applications such as food packaging. Cellulose esters with different side-chain lengths were synthesized and studied. Their thermal and moisture barrier properties were characterized. Cellulose triheptanoate (CTH) was proved to have an optimal moisture barrier (WVTR = 0.31 g·mil/day/in.2) and was used to blend with poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) and polylactic acid (PLA) bioplastics. CTH addition improved the PLA thermal stability, enhanced the ductility, and increased the moisture barrier by 32%, while it decreased the PHBV thermal stability, weakened the ductility, and reduced the moisture barrier by 90%. We demonstrated that by proper choice of the combination of CE and bioplastic, bioplastic blends with unique and useful synergistic properties can be obtained. These blends can potentially be used for commercial applications, such as biodegradable flexible packaging.