Double Spin with a Twist: Synthesis and Characterization of a Neutral Mixed-Valence Organic Stable Diradical.

A convenient design strategy opens access to neutral open-shell mixed-valence species via the redox transformation of charged stable precursors, i.e., the spiro-fused borate anions. We have implemented this strategy for the synthesis of the first neutral mixed-valence diradical: two neutral mixed-valence radical fragments were assembled via a twisted biphenyl bridge. The diradical is a crystalline solid obtained in almost quantitative yield by using a facile synthetic procedure. It is stable at room temperature in the triplet ground state with a very small singlet/triplet gap. This metal-free diradical can reversibly form five redox states. The diradical exhibits an intense IVCT band in the NIR region and can be assigned as a Class 2 Robin-Day MV (mixed valence) system with weakly interacting redox centers. Computations suggest that this diradical finds itself in a unique tug-of-war between two electron delocalization patterns, Kekulé and non-Kekulé, which gives rise to two geometric isomers that are close in energy but drastically different in spin distribution and polarity. Such bistable spin-systems should be intrinsically switchable and promising for the design of functional spin devices. The scope and limitations of the new redox-strategy for the neutral MV radicals were also tested on other types of spiro-fused borates, revealing structural factors responsible for the evolution from transient to persistent and then to stable radicals.

Converting Strain Release into Aromaticity Loss for Activation of Donor-Acceptor Cyclopropanes: Generation of Quinone Methide Traps for C-Nucleophiles.

Here, we present a new approach for the activation of donor-acceptor cyclopropanes in ring-opening reactions, which does not require the use of a Lewis or Brønsted acid as a catalyst. Donor-acceptor cyclopropanes containing a phenolic group as the donor undergo deprotonation and isomerization to form the corresponding quinone methides. This innovative strategy was applied to achieve (4 + 1)-annulation of cyclopropanes with sulfur ylides, affording functionalized dihydrobenzofurans. Additionally, the generated ortho- and para-(aza)quinone methides can be trapped by various CH-acids.

Unusual Cascade Reactions of 8-Acetoxy-6-hydroxymethyllimonene with Salicylic Aldehydes: Diverse Oxygen Heterocycles from Common Precursors.

Chiral oxygen-containing heterocyclic compounds are of great interest for the development of pharmaceuticals. Monoterpenes and their derivatives are naturally abundant precursors of novel synthetic chiral oxygen-containing heterocyclic compounds. In this study, acid catalyzed reactions of salicylic aldehydes with (-)-8-acetoxy-6-hydroxymethyllimonene, readily accessible from α-pinene, leads to the formation of chiral polycyclic products of various structural types. Three of the six isolated chiral heterocyclic products obtained from salicylic aldehyde contain previously unknown polycyclic ring types. Having carried out the reaction in the presence of Brønsted or Lewis acids (Amberlyst 15, trifluoromethanesulfonic acid, trifluoroacetic acid and boron trifluoride etherate) or aluminosilicates (montmorillonite K10, halloysite nanotubes), we found that the nature of products depends on the catalyst as well as the reaction conditions (reaction time, reactant ratio, presence or absence of solvent). Detailed mechanistic insight on the complex cascade reactions for product formation is provided with extensive experimental and quantum mechanical computational studies.

Superelectrophilic Activation of Phosphacoumarins towards Weak Nucleophiles via Brønsted Acid Assisted Brønsted Acid Catalysis.

The electrophilic activation of various substrates via double or even triple protonation in superacidic media enables reactions with extremely weak nucleophiles. Despite the significant progress in this area, the utility of organophosphorus compounds as superelectrophiles still remains limited. Additionally, the most common superacids require a special care due to their high toxicity, exceptional corrosiveness and moisture sensitivity. Herein, we report the first successful application of the "Brønsted acid assisted Brønsted acid" concept for the superelectrophilic activation of 2-hydroxybenzo[e][1,2]oxaphosphinine 2-oxides (phosphacoumarins). The pivotal role is attributed to the tendency of the phosphoryl moiety to form hydrogen-bonded complexes, which enables the formation of dicationic species and increases the electrophilicity of the phosphacoumarin. This unmasks the reactivity of phosphacoumarins towards non-activated aromatics, while requiring only relatively non-benign trifluoroacetic acid as the reaction medium.

Facile synthesis of diiodoheteroindenes and understanding their Sonogashira cross-coupling selectivity for the construction of unsymmetrical enediynes.

Electrophile-promoted cyclizations of functionalized alkynes offer a useful tool for constructing halogen-substituted heterocycles primed for further derivatization. Preinstallation of an iodo-substituent at the alkyne prior to iodo-cyclization opens access to ortho di-iodinated heterocyclic precursors for the preparation of unsymmetrical heterocycle-fused enediynes. This general approach was used to prepare 2,3-diiodobenzothiophene, 2,3-diiodoindole, and 2,3-diiodobenzofuran, a useful family of substrates for systematic studies of the role of heteroatoms on the regioselectivity of cross-coupling reactions. Diiodobenzothiophene showed much higher regioselectivity for Sonogashira cross-coupling at C2 than diiodoindole and diiodobenzofuran. As a result, benzothiophene can be conveniently involved in a one-pot sequential coupling with two different alkynes, yielding unsymmetrical benzothiophene-fused enediynes. On the other hand, the Sonogashira reaction of diiodoindole and diiodobenzofuran formed considerable amounts of di-substituted enediynes in addition to the monoalkyne product by coupling at C2. Interestingly, no C3-monocoupling products were observed for all of the diiodides, suggesting that the incorporation of the 1st alkyne at C2 activates the C3 position for the 2nd coupling. Additional factors affecting regioselectivity were detected, discussed and connected, through computational analysis, to transmetalation being the rate-determining step for the Sonogashira reaction. Several enediynes synthesized showed cytotoxic activity, which is not associated with DNA strand breaks typical of natural enediyne antibiotics.

Interrupted Dance of Five Heteroatoms: Reinventing Ozonolysis to Make Geminal Alkoxyhydroperoxides from C═N Bonds.

Four heteroatoms dance in the cascade of four pericyclic reactions initiated by ozonolysis of C═N bonds. Switching from imines to semicarbazones introduces the fifth heteroatom that slows this dance, delays reaching the thermodynamically favorable escape path, and allows efficient interception of carbonyl oxides (Criegee intermediates, CIs) by an external nucleophile. The new three-component reaction of alcohols, ozone, and oximes/semicarbazones greatly facilitates synthetic access to monoperoxyacetals (alkoxyhydroperoxides).

Tethering Three Radical Cascades for Controlled Termination of Radical Alkyne peri-Annulations: Making Phenalenyl Ketones without Oxidants.

Although Bu3Sn-mediated radical alkyne peri-annulations allow access to phenalenyl ring systems, the oxidative termination of these cascades provides only a limited selection of the possible isomeric phenalenone products with product selectivity controlled by the intrinsic properties of the new cyclic systems. In this work, we report an oxidant-free termination strategy that can overcome this limitation and enable selective access to the full set of isomerically functionalized phenalenones. The key to preferential termination is the preinstallation of a "weak link" that undergoes C-O fragmentation in the final cascade step. Breaking a C-O bond is assisted by entropy, gain of conjugation in the product, and release of stabilized radical fragments. This strategy is expanded to radical exo-dig cyclization cascades of oligoalkynes, which provide access to isomeric π-extended phenalenones. Conveniently, these cascades introduce functionalities (i.e., Bu3Sn and iodide moieties) amenable to further cross-coupling reactions. Consequently, a variety of polyaromatic diones, which could serve as phenalenyl-based open-shell precursors, can be synthesized.

An Unusual Rearrangement of Pyrazole Nitrene and Coarctate Ring-Opening/Recyclization Cascade: Formal CH-Acetoxylation and Azide/Amine Conversion without External Oxidants and Reductants.

We report an unusual transformation where the transient formation of a nitrene moiety initiates a sequence of steps leading to remote oxidative C-H functionalization (R-CH3 to R-CH2OC(O)R') and the concomitant reduction of the nitrene into an amino group. No external oxidants or reductants are needed for this formal molecular comproportionation. Detected and isolated intermediates and computational analysis suggest that the process occurs with pyrazole ring opening and recyclization.

Two-Component versus Three-Component Condensations in the Race between Hydrazide, Triketone, and Hydrogen Peroxide-How do All Six Reactive Centers Cooperate to Incorporate the Most Diverse Set of Heteroatomic Bridges in a Tricyclic Frame?

Relief of stereoelectronic frustration drives the acid-catalyzed three-component condensation of ß,δ'-triketones with hydrazides and H2O2 to the direction where both nucleophiles and all three electrophilic carbons are involved in the formation of a tricyclic sp3-rich ring system that includes four heteroatoms. The otherwise inaccessible tricyclic N-substituted aminoperoxides are prepared rapidly and selectively from relatively simple substrates in good to high yields.

Hole Catalysis of Cycloaddition Reactions: How to Activate and Control Oxidant Upconversion in Radical-Cationic Diels-Alder Reactions.

In order to use holes as catalysts, the oxidized product should be able to transfer the hole to a fresh reactant. For that, the hole-catalyzed reaction must increase the oxidation potential along the reaction path, i.e., lead to "hole upconversion." If this thermodynamic requirement is satisfied, a hole injected via one-electron oxidation can persist through multiple propagation cycles and serve as a true catalyst. This work provides guidelines for the rational design of hole-catalyzed Diels-Alder (DA) reactions, the prototypical cycloaddition. After revealing the crucial role of hyperconjugation in the absence of hole upconversion in the parent DA reaction, we show how upconversion can be reactivated by proper substitution. For this purpose, we computationally evaluate the contrasting effects of substituents at the three possible positions in the two reactants. The occurrence and magnitude of hole upconversion depend strongly on the placement and nature of substituents. For example, donors at C1 in 1,3-butadiene shift the reaction to the hole-upconverted regime with an increased oxidation potential of up to 1.0 V. In contrast, hole upconversion in C2-substituted 1,3-butadienes is activated by acceptors with the oxidation potential increase up to 0.54 V. Dienophile substitution results in complex trends because the radical cation can be formed at either the dienophile or the diene. Hole upconversion is always present in the former scenario (up to 0.65 V). Finally, we report interesting stereoelectronic effects that can activate or deactivate upconversion via a conformational change.

"Stereoelectronic Deprotection of Nitrogen": Recovering Nucleophilicity with a Conformational Change.

Ureas are often thought of as "double amides" due to the obvious structural similarity of these functional groups. The main structural feature of an amide is its planarity, which is responsible for the conjugation between the nitrogen atom and carbonyl moiety and the decrease of amide nucleophilicity. Consequently, since amides are poor nucleophiles, ureas are often thought of as poor nucleophiles as well. Herein, we demonstrate that ureas can be distinctly different from amides. These differences can be amplified by rotation around one of the ureas' C-N bonds, which switches off the amide resonance and recovers the nucleophilicity of one of the nitrogen atoms. This conformational change can be further facilitated by the judicious introduction of steric bulk to disfavor the planar conformation. This change in reactivity is an example of "stereoelectronic deprotection," a concept when the desired reactivity of a functional group is produced by a conformational change rather than a chemical modification. This concept may be used complementarily to the traditional protecting groups. We also demonstrate both the viability and the utility of this concept by the synthesis of unusual 2-oxoimidazolium salts possessing quaternary nitrogen atoms at the urea moiety.

Design principles of the use of alkynes in radical cascades.

One of the simplest organic functional groups, the alkyne, offers a broad canvas for the design of cascade transformations in which up to three new bonds can be added to each of the two sterically unencumbered, energy-rich carbon atoms. However, kinetic protection provided by strong π-orbital overlap makes the design of new alkyne transformations a stereoelectronic puzzle, especially on multifunctional substrates. This Review describes the electronic properties contributing to the unique utility of alkynes in radical cascades. We describe how to control the selectivity of alkyne activation by various methods, from dynamic covalent chemistry with kinetic self-sorting to disappearing directing groups. Additionally, we demonstrate how the selection of reactive intermediates directly influences the propagation and termination of the cascade. Diverging from a common departure point, a carefully planned reaction route can allow access to a variety of products.

AIBN as an Electrophilic Reagent for Cyano Group Transfer.

AIBN is a convenient electrophilic cyanation reagent for transforming ArLi into ArCN under mild conditions. The addition/fragmentation cascade is controlled by Li···N chelation in which AIBN nitrogens assist in the nearly barrierless fragmentation into the desired ArCN product. Acidic C-H bonds in the fragmented byproduct partially consume ArLi by protonation. Density functional theory calculations and isotopic labeling probe the mechanism and explain the switch to substituted hydrazones in reactions with BuLi.

Design and Synthesis of Kekulè and Non-Kekulè Diradicaloids via the Radical Periannulation Strategy: The Power of Seven Clar's Sextets.

This work introduces an approach to uncoupling electrons via maximum utilization of localized aromatic units, i.e., the Clar's π-sextets. To illustrate the utility of this concept to the design of Kekulé diradicaloids, we have synthesized a tridecacyclic polyaromatic system where a gain of five Clar's sextets in the open-shell form overcomes electron pairing and leads to the emergence of a high degree of diradical character. According to unrestricted symmetry-broken UCAM-B3LYP calculations, the singlet diradical character in this core system is characterized by the y0 value of 0.98 (y0 = 0 for a closed-shell molecule, y0 = 1 for pure diradical). The efficiency of the new design strategy was evaluated by comparing the Kekulé system with an isomeric non-Kekulé diradical of identical size, i.e., a system where the radical centers cannot couple via resonance. The calculated singlet-triplet gap, i.e., the ΔEST values, in both of these systems approaches zero: -0.3 kcal/mol for the Kekulé and +0.2 kcal/mol for the non-Kekulé diradicaloids. The target isomeric Kekulé and non-Kekulé systems were assembled using a sequence of radical periannulations, cross-coupling, and C-H activation. The diradicals are kinetically stabilized by six tert-butyl substituents and (triisopropylsilyl)acetylene groups. Both molecules are NMR-inactive but electron paramagnetic resonance (EPR)-active at room temperature. Cyclic voltammetry revealed quasi-reversible oxidation and reduction processes, consistent with the presence of two nearly degenerate partially occupied molecular orbitals. The experimentally measured ΔEST value of -0.14 kcal/mol confirms that K is, indeed, a nearly perfect singlet diradical.

α-Methylstilbene Isomers: Relationship of Structure to Photophysics and Photochemistry.

Significant differences in the photochemical and photophysical behavior of trans-α-methylstilbene and trans-stilbene have been attributed to structural changes caused by the steric requirements of the methyl group. We present here the X-ray structures of cis- and trans-α-methylstilbene (c- and t-MeSt). This is the first X-ray structure of a cis-stilbene. Despite the pronounced departure from phenyl group coplanarity, the solid-state packing of t-MeSt resembles that of trans-stilbene in that both exhibit disorder with a bicycle pedal structural relationship, dynamic in t-St but static in t-MeSt. We compare the X-ray structures with calculated structures. We also compare our steady state and transient photochemical and spectroscopic results with predictions in a recent theoretical paper that anticipated some of our experiments. Deviations from planarity imposed by the methyl substitution account for the shorter lifetimes of the trans excited states. The rapid torsional relaxation of 1t-MeSt* to the twisted intermediate 1p*, ktp = 2.9 × 1012 s-1, observed using fs transient absorption spectroscopy, explains the sharp decrease in the fluorescence quantum yield of t-MeSt. We correct misconceptions that have appeared in the literature concerning the shape of the stilbene potential energy surface in S1. The nonplanarity due to methyl substitution leads to chirality issues that are relevant in biological molecules such as the protonated Schiff bases of retinal in the opsins.

Activation of O-Electrophiles via Structural and Solvent Effects: SN2@O Reaction of Cyclic Diacyl Peroxides with Enol Acetates.

The reactions of O-electrophiles, such as organic peroxides, with carbon nucleophiles are an umpolung alternative to the common approaches to C-O bond formation. Nucleophilic substitution at the oxygen atom of cyclic diacyl peroxides by enol acetates with the following deacylation leads to α-acyloxyketones with an appended carboxylic acid in 28-87% yields. The effect of fluorinated alcohols on the oxidative functionalization of enol acetates by cyclic diacyl peroxides was studied experimentally and computationally. Computational analysis reveals that the key step proceeds as a direct substitution nucleophilic bimolecular (SN2) reaction at oxygen (SN2@O). CF3CH2OH has a dual role in assisting in both steps of the reaction cascade: it lowers the energy of the SN2@O activation step by hydrogen bonding to a remote carbonyl and promotes the deacylation of the cationic intermediate.

Cascade Assembly of Bridged N-Substituted Azaozonides: The Counterintuitive Role of Nitrogen Source Nucleophilicity.

Counterintuitively, the low basicity of the NH2 group in hydrazides makes them preferred nucleophiles for the synthesis of the N-substituted azaozonides in acid-catalyzed three-component condensation with 1,5-diketones and H2O2. In the case of more basic N sources, e.g., hydrazine and primary amines, such condensation does not occur under these reaction conditions. The method can be applied to a wide range of hydrazides and affords the target bicyclic azaozonides in 27-86% yields.

Two Paths to Oxidative C-H Amination Under Basic Conditions: A Theoretical Case Study Reveals Hidden Opportunities Provided by Electron Upconversion.

Traditionally, cross-dehydrogenative coupling (CDC) leads to C-N bond formation under basic and oxidative conditions and is proposed to proceed via a two-electron bond formation mediated by carbenium ions. However, the formation of such high-energy intermediates is only possible in the presence of strong oxidants, which may lead to undesired side reactions and poor functional group tolerance. In this work we explore if oxidation under basic conditions allows the formation of three-electron bonds (resulting in "upconverted" highly-reducing radical-anions). The benefit of this "upconversion" process is in the ability to use milder oxidants (e. g., O2 ) and to avoid high-energy intermediates. Comparison of the two- and three-electron pathways using quantum mechanical calculations reveals that not only does the absence of a strong oxidant shut down two-electron pathways in favor of a three-electron path but, paradoxically, weaker oxidants react faster with the upconverted reductants by avoiding the inverted Marcus region for electron transfer.

Localized Antiaromaticity Hotspot Drives Reductive Dehydrogenative Cyclizations in Bis- and Mono-Helicenes.

We describe reductive dehydrogenative cyclizations that form hepta-, nona-, and decacyclic anionic graphene subunits from mono- and bis-helicenes with an embedded five-membered ring. The reaction of bis-helicenes can either proceed to the full double annulation or be interrupted by addition of molecular oxygen at an intermediate stage. The regioselectivity of the interrupted cyclization cascade for bis-helicenes confirms that relief of antiaromaticity is a dominant force for these facile ring closures. Computational analysis reveals the unique role of the preexisting negatively charged cyclopentadienyl moiety in directing the second negative charge at a specific remote location and, thus, creating a localized antiaromatic region. This region is the hotspot that promotes the initial cyclization. Computational studies, including MO analysis, molecular electrostatic potential maps, and NICS(1.7)ZZ calculations, evaluate the interplay of the various effects including charge delocalization, helicene strain release, and antiaromaticity. The role of antiaromaticity relief is further supported by efficient reductive closure of the less strained monohelicenes where the relief of antiaromaticity promotes the cyclization even when the strain is substantially reduced. The latter finding significantly expands the scope of this reductive alternative to the Scholl ring closure.

Carboxylate as a Non-innocent L-Ligand: Computational and Experimental Search for Metal-Bound Carboxylate Radicals.

We show that the carboxylate radical acts as an L-ligand with certain high-spin transition metal centers. Such coordination preserves the O-radical character needed for C-H activation via hydrogen atom transfer. Capture of the new C-radical by the metal and subsequent reductive elimination leads to formal C-H acyloxylation. Decarboxylation of the RCO2 radical is minimized through hybridization effects introduced by spiro-cyclopropyl moiety.