Preparation of Large Perphenylbiaryls: Can Intermolecular Coupling Compete with Intramolecular Cyclization of Precursors?

The highly substituted naphthalenes 1,2,3,4,5,6,7-heptaphenylnaphthalene (13), 2,3,4,5,6,7,8-heptaphenyl-1-naphthol (12), 1-bromo-2,3,4,5,6,7,8-heptaphenylnaphthalene (4), and 1-(phenylethynyl)-2,3,4,5,6,7,8-heptaphenylnaphthalene (5) were prepared by a variety of methods, and all but 5 were crystallographically characterized.  The attempted Ullmann coupling of 4 to give tetradecaphenyl-1,1'-binaphthyl (3), at both 270 °C and 350 °C, yielded instead 1,2,3,4,5,6-hexaphenylfluoranthene (17) via an intramolecular cyclization reaction.  When the alkyne 5 was heated with tetracyclone (6) at 350 °C, 1-(pentaphenylphenyl)-2,3,4,5,6,7,8-heptaphenylnaphthalene (7) was formed in 3% yield.  However, greater amounts of 5,6,7,8,9,14-hexaphenyldibenzo[a,e]pyrene (20, 11%) and 1,2,3,4,5,6,7-heptaphenylfluoranthene (21, 11%) were produced, the former by intramolecular cyclization and dehydrogenation of 5 and the latter by an intramolecular Diels-Alder reaction of 5 followed by extrusion of acetylene.  The X-ray structure of 7 shows it to be an exceptionally crowded biaryl, and the X-ray structure of 20 shows it to be a saddle shaped polycyclic aromatic hydrocarbon.

Exo-Selective Diels-Alder Reactions.

The Diels-Alder reaction stands as one of the most pivotal transformations in organic chemistry. Its efficiency, marked by the formation of two carbon-carbon bonds and up to four new stereocenters in a single step, underscores its versatility and indispensability in synthesizing natural products and pharmaceuticals. The most significant stereoselectivity feature is the "endo rule". While this rule underpins the predictability of the stereochemical outcomes, it also underscores the challenges in achieving the opposite diastereoselectivity, making the exo-Diels-Alder reactions often considered outliers. This review delves into recent examples of exo-Diels-Alder reactions, shedding light on the factors inverting the intrinsic tendency. We explore the roles of steric, electrostatic, and orbital interactions, as well as thermodynamic equilibriums in influencing exo/endo selectivity. Furthermore, we illustrate strategies to manipulate these factors, employing approaches such as bulky substituents, s-cis conformations, transient structural constraints, and innovative control physics. Through these analyses, our aim is to provide a comprehensive understanding of how to predict and design exo-Diels-Alder reactions, paving the way for new diastereoselective catalyst systems and expanding the chemical scope of Diels-Alder reactions.

Structure-Antitumor Activity Relationships of Aza- and Diaza-Anthracene-2,9,10-Triones and Their Partially Saturated Derivatives.

The 1,8-Diazaanthracene-2,9,10-triones, their 5,8-dihydro derivatives, and 1,8-diazaanthracene-2,7,9,10-tetraones, structurally related to the diazaquinomycin family of natural products, were synthesized in a regioselective fashion employing Diels-Alder strategies. These libraries were studied for their cytotoxicity in a variety of human cancer cell lines in order to establish structure-activity relationships. From the results obtained, we conclude that some representatives of the 1,8-diazaanthracene-2,9,10-trione framework show potent and selective cytotoxicity against solid tumors. Similar findings were made for the related 1-azaanthracene-2,9,10-trione derivatives, structurally similar to the marcanine natural products, which showed improved activity over their natural counterparts. An enantioselective protocol based on the use of a SAMP-related chiral auxiliary derived was developed for the case of chiral 5-substituted 1,8-diazaanthracene-2,9,10-triones, and showed that their cytotoxicity was not enantiospecific.

Solid-State Generation of Diarylisonaphthofuran and Its Mechanochemical Diels-Alder Reaction with Epoxynaphthalene.

A solid-state method was developed for generating diarylisonaphthofurans from 1,3-diaryl-1,3-dihydronaphthofuranols. The generated reactive molecules were stable in the solid state and could be stored without any extra precautions. X-ray diffraction analysis revealed a typical quinoidal structure. Furthermore, the mechanochemical Diels-Alder reaction of 1,3-diarylisonaphthofurans with epoxynaphthalenes afforded synthetically attractive diepoxypentacenes.

Design and Synthesis of a Ferrocene-Based Diol Library and Application in the Hetero-Diels-Alder Reaction.

Diol scaffolds have been utilized as highly effective catalysts and ligands in a wide range of catalytic asymmetric transformations. For scaffolds to be successful as broadly used motifs, they should be prepared cheaply through facile routes and be easily handled. Herein, the synthesis of a family of planar chiral diols based on a modular and robust three-step route is described, which yields catalytically active diols in >99 % de and >99 % ee, with up to seven different chiral elements. These diols have been characterized by X-ray crystallographic analysis, which provides clear evidence for the likely transition state when applied in the asymmetric hetero-Diels-Alder reaction. Without altering the stereochemistry of the catalyst backbone, it is possible to access both enantiomers of the product by varying the substitution of the catalyst at the α-position.

How Bases Catalyze Diels-Alder Reactions.

We have quantum chemically studied the base-catalyzed Diels-Alder (DA) reaction between 3-hydroxy-2-pyrone and N-methylmaleimide using dispersion-corrected density functional theory. The uncatalyzed reaction is slow and is preceded by the extrusion of CO2 via a retro-DA reaction. Base catalysis, for example, by triethylamine, lowers the reaction barrier up to 10 kcal mol-1 , causing the reaction to proceed smoothly at low temperature, which quenches the expulsion of CO2 , yielding efficient access to polyoxygenated natural compounds. Our activation strain analyses reveal that the base accelerates the DA reaction via two distinct electronic mechanisms: i) by the HOMO-raising effect, which enhances the normal electron demand orbital interaction; and ii) by donating charge into 3-hydroxy-2-pyrone which accumulates in its reactive region and promotes strongly stabilizing secondary electrostatic interactions with N-methylmaleimide.

Modulating Energy Transfer and Light-Emitting Colors by Chiral Dye Exchange and Achiral-to-Chiral Dye Conversion.

New chiral and achiral dyes were synthesized by using clean, highly efficient Diels-Alder 'click' reactions. We prepared pure endo- and exo- stereoisomers and blue-light-emitting single crystal of an exo-isomer. 1 H NMR spectroscopy and single-crystal X-ray diffraction reveal the precise spatial configurations of endo- and exo-dye stereoisomers. Single-crystal X-ray diffraction results reveal the dynamic nature of Diels-Alder covalent bonds. By reversible formation and cleavage of dynamic covalent bonds, an achiral dye was converted to a chiral dye, where achiral dansyl dye moiety was replaced by chiral moiety. Before achiral-to-chiral dye conversion, the dye system displayed dansyl acceptor green light-emitting color due to intramolecular fluorescence resonance energy transfer, where the blue emission of pyrene donor fluorophore was not observed. After achiral-to-chiral dye conversion, light-emitting colors of dye system change from green to blue, where the pyrene-to-dansyl fluorophore energy transfer was suppressed, and pyrene fluorophore blue emission was restored. Chiral transfer occurs in a chiral dye solid from non-chromophore alky chirality to pyrene chromophore. Thus, the chiral dye solid displayed chiral optical behaviors, i. e., circular dichroism and circularly polarized luminescence.

Two-Way Catalysis in a Diels-Alder Reaction Limits Inhibition Induced by an External Electric Field.

Oriented external electric fields (EEFs) act as catalysts that can induce selectivity in chemical reactions. The responses of the Diels-Alder (DA) reaction between butadiene and ethylene (BDE-DA) as well as cyclopentadiene and ethylene (CPDE-DA) towards EEF stimuli are investigated here using density functional theory (B3LYP) calculations. EEF is a vector that catalyzes the reaction in one direction while inhibiting it in the opposite direction. Here we report that the inhibitive direction becomes rate-enhancing after some increase in the EEF. The EEF value that brings about the maximum possible inhibition for the reaction is defined as the electrostatic resistance point (ERP). The possibility of both normal and inverse electron-demand DA reactions causes catalytic activity in both directions of the EEF starting at a unique ERP value. The C5 substituents of cyclopentadiene control the ERP values depending upon the resistance power that the functional group provides against the EEF. The endo and exo diastereomeric transition states of the DA reaction have distinct ERP values and the difference (ΔERP) provides the through-space electrostatic contribution to the stereoselectivity on a relative scale. Thus, the ERP values can be used as a gauge for the electrostatic interactions between substituent groups and external stimuli.

Anion-π catalysis on carbon allotropes.

Anion-π catalysis, introduced in 2013, stands for the stabilization of anionic transition states on π-acidic aromatic surfaces. Anion-π catalysis on carbon allotropes is particularly attractive because high polarizability promises access to really strong anion-π interactions. With these expectations, anion-π catalysis on fullerenes has been introduced in 2017, followed by carbon nanotubes in 2019. Consistent with expectations from theory, anion-π catalysis on carbon allotropes generally increases with polarizability. Realized examples reach from enolate addition chemistry to asymmetric Diels-Alder reactions and autocatalytic ether cyclizations. Currently, anion-π catalysis on carbon allotropes gains momentum because the combination with electric-field-assisted catalysis promises transformative impact on organic synthesis.

The Pursuit of Perphenylterphenyls.

Tetradecaphenyl-p-terphenyl (2) was synthesized from 2,3,5,6-tetraphenyl-1,4-diiodobenzene (11) by two methods. Ullmann coupling of 11 with pentaphenyliodobenzene (9) gave compound 2 in 1.7 % yield, and Sonogashira coupling of 11 with phenylacetylene, followed by a double Diels-Alder reaction of the product diyne 12 with tetracyclone (6), gave 2 in 1.5 % overall yield. The latter reaction also gave the monoaddition product 4-(phenylethynyl)-2,2',3,3',4',5,5',6,6'-nonaphenylbiphenyl (13) in 4 % overall yield. The X-ray structures of compounds 2 and 13 show them to possess core aromatic rings distorted into shallow boat conformations. Density functional calculations indicate that these unusual structures are not the lowest energy conformations in the gas phase and may be the result of packing forces in the crystal. In addition, while uncorrected DFT calculations indicate that the strain energy in compound 2 is approximately 50 kcal/mol, dispersion-corrected DFT calculations suggest that it is essentially unstrained, due to compensating, favorable, intramolecular interactions of its many phenyl rings. An attempted synthesis of tetradecaphenyl-o-terphenyl (4) by reaction of diphenylhexatriyne (14) with three equivalents of tetracyclone at 350 °C gave only the diadduct 2-(phenylethynyl)-2',3,3',4,4',5,5',6,6'-nonaphenylbiphenyl (15) in 17 % yield. Even higher temperatures failed to produce 4 and lowered the yield of 15, perhaps due to rapid decomposition of the starting materials. Ullmann coupling of 3,4,5,6-tetraphenyl-1,2-diiodobenzene (16) and compound 9 also failed to give compound 4.

On the Notation of Catastrophes in the Framework of Bonding Evolution Theory: Case of Normal and Inverse Electron Demand Diels-Alder Reactions.

This paper generalizes very recent and unexpected findings [J. Phys. Chem. A, 2021, 125, 5152-5165] regarding the known "direct- and inverse-electron demand" Diels-Alder mechanisms. Application of bonding evolution theory indicates that the key electron rearrangement associated with significant chemical events (e. g., the breaking/forming processes of bonds) can be characterized via the simplest fold polynomial. For the CC bond formation, neither substituent position nor the type of electronic demand induces a measurable cusp-type signature. As opposed to the case of [4+2] cycloaddition between 1,3-butadiene and ethylene, where the two new CC single bonds occur beyond the transition state (TS) in the activated cases, the first CC bond occurs in the domain of structural stability featuring the TS, whereas the second one remains located in the deactivation path connecting the TS with the cycloadduct.

Bioinspired Total Synthesis of Erectones A and B, and the Revised Structure of Hyperelodione D.

The field of biomimetic synthesis seeks to apply biosynthetic hypotheses to the efficient construction of complex natural products. This approach can also guide the revision of incorrectly assigned structures. Herein, we describe the evolution of a concise total synthesis and structural reassignment of hyperelodione D, a tetracyclic meroterpenoid derived from a Hypericum plant, alongside some biogenetically related natural products, erectones A and B. The key step in the synthesis of hyperelodione D forms six stereocentres and three rings in a bioinspired cascade reaction that features an intermolecular Diels-Alder reaction, an intramolecular Prins reaction and a terminating cycloetherification.

Energetics of Formation of Cyclacenes from 2,3-Didehydroacenes and Implications for Astrochemistry.

The carriers of the diffuse interstellar bands (DIBs) are still largely unknown although polycyclic aromatic hydrocarbons, carbon chains, and fullerenes are likely candidates. A recent analysis of the properties of n-acenes of general formula C4n+2 H2n+4 suggested that these could be potential carriers of some DIBs. Dehydrogenation reactions of n-acenes after absorption of an interstellar UV photon may result in dehydroacenes. Here the reaction energies and barriers for formation of n-cyclacenes from 2,3-didehydroacenes (n-DDA) by intramolecular Diels-Alder reaction to dihydro-etheno-cyclacenes (n-DEC) followed by ejection of ethyne by retro-Diels-Alder reactions are analyzed using thermally assisted occupation density functional theory (TAO-DFT) for n=10-20. It is found that the barriers for each of the steps depend on the ring strain of the underlying n-cyclacene, and that the ring strain of n-DEC is about 75 % of that of the corresponding n-cyclacene. In each case, ethyne extrusion is the step with the highest energy barrier, but these barriers are smaller than CH bond dissociation energies, suggesting that formation of cyclacenes is an energetically conceivable fate of n-acenes after multiple absorption of UV photons.

On the Mechanism of Au-Catalyzed Enynamide-yne Dehydro-Diels-Alder Reactions: An Experimental and Computational Study.

Gold-catalyzed dehydro-Diels-Alder reactions of ynamide derivatives allow efficient access to a variety of N-containing aromatic heterocycles. A dual gold catalysis mechanism was postulated for transformations involving the formation of C-C bonds by reaction between a terminal alkyne and an enynamide fragment. In this article, complete experimental and computational investigations into the mechanism of such a transformation are reported. Support for a dual gold catalysis was found and it was shown that the concerted or stepwise nature of the cyclization event depends on the substitution of the ynamide moiety. The reaction was found to proceed in three stages: 1) formation of a σ,π-digold complex from the terminal alkyne, 2) cyclization to produce a gem-diaurated aryl complex, and 3) catalyst transfer to free the product and regenerate the σ,π-digold complex.

Non-conventional Behavior of a 2,1-Benzazaphosphole: Heterodiene or Hidden Phosphinidene?

The titled 2,1-benzazaphosphole (1) (i. e. ArP, where Ar=2-(DippN=CH)C6 H4 , Dipp=2,6-iPr2 C6 H3 ) showed a spectacular reactivity behaving both as a reactive heterodiene in hetero-Diels-Alder (DA) reactions or as a hidden phosphinidene in the coordination toward selected transition metals (TMs). Thus, 1 reacts with electron-deficient alkynes RC≡CR (R=CO2 Me, C5 F4 N) giving 1-phospha-1,4-dihydro-iminonaphthalenes 2 and 3, that undergo hydrogen migration producing 1-phosphanaphthalenes 4 and 5. Compound 1 is also able to activate the C=C double bond in selected N-alkyl/aryl-maleimides RN(C(O)CH)2 (R=Me, tBu, Ph) resulting in the addition products 7-9 with bridged bicyclic [2.2.1] structures. The binding of the maleimides to 1 is semi-reversible upon heating. By contrast, when 1 was treated with selected TM complexes, it serves as a 4e donor bridging two TMs thus producing complexes [µ-ArP(AuCl)2 ] (10), [(µ-ArP)4 Ag4 ][X]4 (X=BF4 (11), OTf (12)) and [µ-ArP(Co2 (CO)6 )] (13). The structure and electron distribution of the starting material 1 as well as of other compounds were also studied from the theoretical point of view.

A Concise Total Synthesis of Dehydroantofine and Its Antimalarial Activity against Chloroquine-Resistant Plasmodium falciparum.

The total synthesis of dehydroantofine was achieved by employing a novel, regioselective, azahetero Diels-Alder reaction of easily accessible 3,5-dichloro-2H-1,4-oxazin-2-one with 14 a as a key step. Furthermore, it is demonstrated that dehydroantofine is a promising candidate as a new antimalarial agent in a biological assay with chloroquine-resistant Plasmodium falciparum.

How Oriented External Electric Fields Modulate Reactivity.

A judiciously oriented external electric field (OEEF) can catalyze a wide range of reactions and can even induce endo/exo stereoselectivity of cycloaddition reactions. The Diels-Alder reaction between cyclopentadiene and maleic anhydride is studied by using quantitative activation strain and Kohn-Sham molecular orbital theory to pinpoint the origin of these catalytic and stereoselective effects. Our quantitative model reveals that an OEEF along the reaction axis induces an enhanced electrostatic and orbital interaction between the reactants, which in turn lowers the reaction barrier. The stronger electrostatic interaction originates from an increased electron density difference between the reactants at the reactive center, and the enhanced orbital interaction arises from the promoted normal electron demand donor-acceptor interaction driven by the OEEF. An OEEF perpendicular to the plane of the reaction axis solely stabilizes the exo pathway of this reaction, whereas the endo pathway remains unaltered and efficiently steers the endo/exo stereoselectivity. The influence of the OEEF on the inverse electron demand Diels-Alder reaction is also investigated; unexpectedly, it inhibits the reaction, as the electric field now suppresses the critical inverse electron demand donor-acceptor interaction.

Reversible Diels-Alder Reactions with a Fluorescent Dye on the Surface of Magnetite Nanoparticles.

Diels-Alder reactions on the surface of nanoparticles allow a thermoreversible functionalization of the nanosized building blocks. We report the synthesis of well-defined magnetite nanoparticles by thermal decomposition reaction and their functionalization with maleimide groups. Attachment of these dienophiles was realized by the synthesis of organophosphonate coupling agents and a partial ligand exchange of the original carboxylic acid groups. The functionalized iron oxide particles allow a covalent surface attachment of a furfuryl-functionalized rhodamine B dye by a Diels-Alder reaction at 60 °C. The resulting particles showed the typical fluorescence of rhodamine B. The dye can be cleaved off the particle surface by a retro-Diels-Alder reaction. The study showed that organic functions can be thermoreversibly attached onto inorganic nanoparticles.

Unveiling the Ionic Diels-Alder Reactions within the Molecular Electron Density Theory.

The ionic Diels-Alder (I-DA) reactions of a series of six iminium cations with cyclopentadiene have been studied within the Molecular Electron Density Theory (MEDT). The superelectrophilic character of iminium cations, ω > 8.20 eV, accounts for the high reactivity of these species participating in I-DA reactions. The activation energies are found to be between 13 and 20 kcal·mol-1 lower in energy than those associated with the corresponding Diels-Alder (DA) reactions of neutral imines. These reactions are low endo selective as a consequence of the cationic character of the TSs, but highly regioselective. Solvents have poor effects on the relative energies, and an unappreciable effect on the geometries. In acetonitrile, the activation energies increase slightly as a consequence of the better solvation of the iminium cations than the cationic TSs. Electron localization function (ELF) topological analysis of the bonding changes along the I-DA reactions shows that they are very similar to those in polar DA reactions. The present MEDT study establishes that the global electron density transfer (GEDT) taking place at the TSs of I-DA reactions, and not steric (Pauli) repulsions such as have been recently proposed, are responsible for the features of these types of DA reactions.

Hetero-Diels-Alder Reactions of In Situ-Generated Azoalkenes with Thioketones; Experimental and Theoretical Studies.

The hetero-Diels-Alder reactions of in situ-generated azoalkenes with thioketones were shown to offer a straightforward method for an efficient and regioselective synthesis of scarcely known N-substituted 1,3,4-thiadiazine derivatives. The scope of the method was fairly broad, allowing the use of a series of aryl-, ferrocenyl-, and alkyl-substituted thioketones. However, in the case of N-tosyl-substituted cycloadducts derived from 1-thioxo-2,2,4,4-tetramethylcyclobutan-3-one and the structurally analogous 1,3-dithione, a more complicated pathway was observed. By elimination of toluene sulfinic acid, the initially formed cycloadducts afforded 2H-1,3,4-thiadiazines as final products. Advanced DFT calculations revealed that the observed high regioselectivity was due to kinetic reaction control and that the (4 + 2)-cycloadditions of sterically less unhindered thiones occurred via highly unsymmetric transition states with shorter C..S-distances (2.27-2.58 Å) and longer N..C-distances (3.02-3.57 Å). In the extreme case of the sterically very hindered 2,2,4,4-tetramethylcyclobutan-1,3-dione-derived thioketones, a zwitterionic intermediate with a fully formed C‒S bond was detected, which underwent ring closure to the 1,3,4-thiadiazine derivative in a second step. For the hypothetical formation of the regioisomeric 1,2,3-thiadiazine derivatives, the DFT calculations proposed more symmetric transition states with considerably higher energies.