A Cascade of Strain-Driven Events Converting Benzynes to Alkynylbenzocyclobutenes to 1,3-Dien-5-ynes to Cyclic Allenes to Benzocyclohexadienones.

Here, we report a strain-promoted cascade reaction that proceeds via multiple strained intermediates, ultimately driven by the high potential energy inherent in alkyne triple bonds (C≡C). More specifically, four alkynes (three from an HDDA benzyne precursor and the fourth from a conjugated enyne reaction partner) are transformed into eight of the skeletal carbons in the benzocyclohexadienone products. The reaction pathway proceeds sequentially via strained benzyne, benzocyclobutene, and cyclic allene intermediates. DFT computations suggest that the slowest step following benzyne generation is the 4π-electrocyclic ring-opening of the alkynylbenzocyclobutene to a 1,3-dien-5-yne (an alkynylxylylene) intermediate. The activation energy for the subsequent 6π-electrocyclic ring-closure is lower than that for related acyclic dienynes because of the aromaticity that is being regained in the transition structure. Finally, the isolation of the benzocyclohexadienone products rather than their phenolic tautomers is notable.

Defining the Macromolecules of Tomorrow through Synergistic Sustainable Polymer Research.

Transforming how plastics are made, unmade, and remade through innovative research and diverse partnerships that together foster environmental stewardship is critically important to a sustainable future. Designing, preparing, and implementing polymers derived from renewable resources for a wide range of advanced applications that promote future economic development, energy efficiency, and environmental sustainability are all central to these efforts. In this Chemical Reviews contribution, we take a comprehensive, integrated approach to summarize important and impactful contributions to this broad research arena. The Review highlights signature accomplishments across a broad research portfolio and is organized into four wide-ranging research themes that address the topic in a comprehensive manner: Feedstocks, Polymerization Processes and Techniques, Intended Use, and End of Use. We emphasize those successes that benefitted from collaborative engagements across disciplinary lines.

Deciphering molecular structures: NMR spectroscopy and quantum mechanical insights of halogenated 4H-Chromenediones.

Sesquiterpene lactones (SL) represent a class of secondary metabolites found in the Asteraceae family, notable for their unique structures. The SL α-santonin (1) and its derivatives are worthy of mention due to their diverse biological properties. Additionally, 4H-chromenes and 4H-chromones are appealing frameworks holding the capability to be used as structural motifs for new drugs. Furthermore, unambiguous structural elucidation is crucial for developing novel compounds for diverse applications. In this context, it is common to find in the literature molecules erroneously assigned. Therefore, the use of quantum mechanical calculations to simulate NMR chemical shifts has emerged as a valuable strategy. In this work, we conceived the synthesis of two halogenated 4H-chromenediones derived from photosantonic acid (2), a photoproduct arising from irradiation of α-santonin (1) in the ultraviolet region. The structure of the chlorinated and brominated products was determined by NMR analysis, with the aid of quantum mechanical calculations at the B3LYP/6-311 + G(2d,p)//M062x/6-31 + G(d,p) level of theory. All analyses were in agreement and led to the assignment of the brominated 4H-chromene-2,7-dione as (3S,3aS,5aR,9bS)-5a-(2-bromopropan-2-yl)-3-methyl-3,3a,5,5a,8,9b-hexahydro-4H-furo[2,3-f]chromene-2,7-dione (11b) and of the chlorinated 4H-chromene-2,7-dione as (3S,3aS,5aR,9bS)-5a-(2-chloropropan-2-yl)-3-methyl-3,3a,5,5a,8,9b-hexahydro-4H-furo[2,3-f]chromene-2,7-dione (12b). The diastereoselectivities of the reactions were explained based on products and intermediates formation energy calculated using B3LYP/6-31 + G(d,p) as the level of theory. Structures 11b and 12b were identified as the thermodynamic and kinetic products of the reaction among all candidates. Consequently, the strategy utilized in this study is robust and successfully illustrates the use of quantum mechanical calculations in the structural elucidation of new compounds with potential applications as novel drugs or products.

Phosphorane-Promoted C-C Coupling during Aryne Annulations.

Arynes are fleeting, high-energy intermediates that undergo myriad trapping reactions by nucleophiles. Their unusual reactivity compared to other electrophiles can spur unexpected mechanistic pathways enroute to the formation of benzenoid products. Herein we explore a particularly unique case of thermally generated arynes reacting with phosphoranes to form helical dibenzothiophenes and -selenophenes. Multiple new helical polycyclic aromatic products are reported. DP4+ and X-ray crystallographic analysis were used in tandem to confirm the structural topologies of selected products and to demonstrate the utility of DP4+ for distinguishing between isomeric polycyclic aromatic compounds. Lastly, we discuss a plausible mechanism consistent with DFT computations that accounts for the product formation; namely, ligand coupling (i.e., reductive elimination) within a hypervalent, pentacarbon-ligated σ-phosphorane furnishes the dibenzothio- or dibenzoselenophene.

A Distinct Mode of Strain-Driven Cyclic Allene Reactivity: Group Migration to the Central Allene Carbon Atom.

Strained cyclic allenes are reactive species that can be trapped in a variety of complementary fashions that capitalize on their inherent high potential energy. 1,2,4-Cyclohexatrienes represent a subclass of allenes that, notably, can be conveniently generated by a net [4 + 2] cycloaddition within a 1,3-enyne bearing a tethered alkyne via a tetradehydro-Diels-Alder reaction. A limitation to the use of this type of thermally generated cyclic allene as a construct for the introduction of molecular complexity is their propensity to isomerize to benzenoids via a simple net 1,5-hydrogen atom migration. We have discovered that when the enyne component of the substrate is modified as an enol silyl ether (or an enol ester), migration of the silyl (or acyl) group can become the predominant event. Specifically, an appropriately electrophilic group can migrate from the O atom to the central allene carbon adjacent to the 1-siloxy(acyloxy) substituent. This process leads to highly substituted phenolic products (e.g., o-silyl phenols) following tautomerization of the intermediate cyclohexa-2,4-dienone. Experimental studies show that this novel mode of reactivity is general; DFT studies reveal the unimolecular nature of the group migration.

Intramolecular Cyclization of Alkynylheteroaromatic Substrates Bearing a Tethered Cyano Group: A Strategy for Accessing Fused Pyridoheterocycles.

Heterocyclic substrates containing a conjugated alkyne and a pendant nitrile were shown to cyclize in an overall tetradehydro-Diels-Alder reaction to give products in which the initial heterocycle bears a newly fused pyridine ring. Base-promoted tautomerization of the alkyne to its isomeric allene allows this process to occur at ambient temperature. DFT studies support many of the mechanistic interpretations of the overall results.

Neighboring Group Effects on the Rates of Cleavage of Si-O-Si-Containing Compounds.

The presence of a nearby tethered functional group (G, G = tertiary amide or amine) can significantly impact the rate of cleavage of an Si-O bond. We report here an in situ 1H NMR spectroscopic investigation of the relative rates of cleavage of model substrates containing two different Si-O substructures, namely alkoxydisiloxanes [GRO-Si(Me2)-O-SiMe3] and carbodisiloxanes [GR-Si(Me2)-O-SiMe3]. The trends in the relative rates (which slowed with increasing chain length, with a notable exception) of alkoxydisiloxane hydrolyses were probed via computation. The results correlated well with the experimental data. In contrast to the hydrolysis of the alkoxydisiloxanes, the carbodisiloxanes were not fully hydrolyzed, but rather formed an equilibrium mixture of starting asymmetric disiloxane, two silanols, and a new symmetrical disiloxane. We also uncovered a facile siloxy-metathesis reaction of an incoming silanol with the carbodisiloxane substrate [e.g., Me2NR-Si(Me2)-O-SiMe3 + HOSiEt3 ⇋ Me2NR-Si(Me2)-O-SiEt3 + HOSiMe3] facilitated by the pendant dimethylamino group, a process that was also probed by computation.

Hexadehydro-Diels-Alder Reaction: Benzyne Generation via Cycloisomerization of Tethered Triynes.

The hexadehydro-Diels-Alder (HDDA) reaction is the thermal cyclization of an alkyne and a 1,3-diyne to generate a benzyne intermediate. This is then rapidly trapped, in situ, by a variety of species to yield highly functionalized benzenoid products. In contrast to nearly all other methods of aryne generation, no other reagents are required to produce an HDDA benzyne. The versatile and customizable nature of the process has attracted much attention due not only to its synthetic potential but also because of the fundamental mechanistic insights the studies often afford. The authors have attempted to provide here a comprehensive compilation of publications appearing by mid-2020 that describe experimental results of HDDA reactions.

Quaternary Ammonium Ion-Tethered (Ambient-Temperature) HDDA Reactions.

The hexadehydro-Diels-Alder (HDDA) reaction converts a 1,3-diyne bearing a tethered alkyne (the diynophile) into bicyclic benzyne intermediates upon thermal activation. With only a few exceptions, this unimolecular cycloisomerization requires, depending on the nature of the atoms connecting the diyne and diynophile, reaction temperatures of ca. 80-130 °C to achieve a convenient half-life (e.g., 1-10 h) for the reaction. In this report, we divulge a new variant of the HDDA process in which the tether contains a central, quaternized nitrogen atom. This construct significantly lowers the activation barrier for the HDDA cycloisomerization to the benzyne. Moreover, many of the ammonium ion-based, alkyne-containing substrates can be spontaneously assembled, cyclized to benzyne, and trapped in a single-vessel, ambient-temperature operation. DFT calculations provide insights into the origin of the enhanced rate of benzyne formation.

Examples Showing the Utility of Doping Experiments in 1H NMR Analysis of Mixtures.

Here we provide examples that demonstrate the value of using properly designed and easily performed doping experiments to give insights about the nature of the analyte(s) present in a 1H NMR sample. Two mixtures, the first quite complex and the second far less so, have been chosen: (i) the crude pyrolysate from reaction of butyric acid in (supercritical) water at 600 °C and (ii) a mixture of two basic amines. In the former, 13 distinct carbonyl-containing compounds, ranging in relative concentration of nearly 2 orders of magnitude, were positively identified. The latter highlights the advantage of using a doping experiment as opposed to merely comparing the spectra from two separate samples containing the same analyte.

TMS is Superior to Residual CHCl3 for Use as the Internal Reference for Routine 1H NMR Spectra Recorded in CDCl3.

Tetramethylsilane was recommended for use as an internal reference compound in proton NMR spectroscopy over 60 years ago. However, it is a common practice that researchers reference the analyte chemical shifts to the residual proton resonance in the deuterated solvent in which the spectrum is recorded. Because CDCl3 is the most commonly used NMR solvent for routine analysis of organic compounds, the effect of various functional groups on the CHCl3 resonance is important. Described here are results that show why referencing spectra to TMS rather than CHCl3 in CDCl3 results in more accurate chemical shifts and should be the recommended practice. Simultaneous measurement of separate compartments of unperturbed CDCl3/TMS vis-à-vis CDCl3/TMS/solute solutions using a concentric tube arrangement was key. This study is reported in this venue because the audience/readership is quite appropriate and is, hopefully, both receptive to and appreciative of the guidance provided.

The pentadehydro-Diels-Alder reaction.

In the classic Diels-Alder [4 + 2] cycloaddition reaction, the overall degree of unsaturation (or oxidation state) of the 4π (diene) and 2π (dienophile) pairs of reactants dictates the oxidation state of the newly formed six-membered carbocycle. For example, in the classic Diels-Alder reaction, butadiene and ethylene combine to produce cyclohexene. More recent developments include variants in which the number of hydrogen atoms in the reactant pair and in the resulting product is reduced by, for example, four in the tetradehydro-Diels-Alder (TDDA) and by six in the hexadehydro-Diels-Alder (HDDA) reactions. Any oxidation state higher than tetradehydro (that is, lacking more than four hydrogens) leads to the production of a reactive intermediate that is more highly oxidized than benzene. This increases the power of the overall process substantially, because trapping of the reactive intermediate can be used to increase the structural complexity of the final product in a controllable and versatile manner. Here we report an unprecedented overall 4π + 2π cycloaddition reaction that generates a different, highly reactive intermediate known as an α,3-dehydrotoluene. This species is in the same oxidation state as a benzyne. Like benzynes, α,3-dehydrotoluenes can be captured by various trapping agents to produce structurally diverse products that are complementary to those arising from the HDDA process. We call this new cycloisomerization process a pentadehydro-Diels-Alder (PDDA) reaction-a nomenclature chosen for chemical taxonomic reasons rather than mechanistic ones. In addition to alkynes, nitriles (RC≡N), although non-participants in aza-HDDA reactions, readily function as the 2π component in PDDA cyclizations to produce, via trapping of the α,3-(5-aza)dehydrotoluene intermediates, pyridine-containing products.

Electronic Character of α,3-Dehydrotoluene Intermediates Generated from Isolable Allenyne-Containing Substrates.

We report here the generation of α,3-dehydrotoluenes, a relatively rare subset of reactive intermediates of the dehydroaromatic family, from isolable allenynes. The substructure motif in the allenyne substrates is distinct from, and complementary to, those found in Myers-Saito/Schmittel-type cycloisomerizations. The reactions reported here give rise to product profiles that provide insight about the electronic nature (i.e., diradical vs. zwitterion vs. cyclic allene) of the particular isomeric DHT(s) that is(are) produced under different reaction conditions differing most significantly in the polarity of the reaction solvent. One example also revealed previously unobserved carbene-like reactivity of the DHT.

Sulfurane [S(IV)]-Mediated Fusion of Benzynes Leads to Helical Dibenzofurans.

Here we disclose a sulfurane-mediated method for the formation of dimeric dibenzofuran helicenes via the reaction between diaryl sulfoxides and hexadehydro-Diels-Alder (HDDA) derived benzynes. A variety of S-shaped and U-shaped helicenes were formed under thermal conditions. Both experimental and DFT studies support a sulfur(IV)-based coupling (aka ligand coupling) mechanism involving tetracarbo-ligated S(IV) intermediates undergoing reductive elimination to afford the helicene products. This process involves the de novo generation of five new rings in a single operation and constitutes a new method for the construction of topologically interesting, polycyclic aromatic compounds.

Fatty-acid derivative acts as a sea lamprey migratory pheromone.

Olfactory cues provide critical information for spatial orientation of fish, especially in the context of anadromous migrations. Born in freshwater, juveniles of anadromous fish descend to the ocean where they grow into adults before migrating back into freshwater to spawn. The reproductive migrants, therefore, are under selective pressures to locate streams optimal for offspring survival. Many anadromous fish use olfactory cues to orient toward suitable streams. However, no behaviorally active compounds have been identified as migratory cues. Extensive studies have shown that the migratory adult sea lampreys (Petromyzon marinus), a jawless fish, track a pheromone emitted by their stream-dwelling larvae, and, consequently, enter streams with abundant larvae. We fractionated extracts of larval sea lamprey washings with guidance from a bioassay that measures in-stream migratory behaviors of adults and identified four dihydroxylated tetrahydrofuran fatty acids, of which (+)-(2S,3S,5R)-tetrahydro-3-hydroxy-5-[(1R)-1-hydroxyhexyl]-2-furanoctanoic acid was shown as a migratory pheromone. The chemical structure was elucidated by spectroscopies and confirmed by chemical synthesis and X-ray crystallography. The four fatty acids were isomer-specific and enantiomer-specific in their olfactory and behavioral activities. A synthetic copy of the identified pheromone was a potent stimulant of the adult olfactory epithelium, and, at 5 × 10-13 M, replicated the extracts of larval washings in biasing adults into a tributary stream. Our results reveal a pheromone that bridges two distinct life stages and guides orientation over a large space that spans two different habitats. The identified molecule may be useful for control of the sea lamprey.

Characterization of stereoisomeric 5-(2-nitro-1-phenylethyl)furan-2(5H)-ones by computation of 1 H and 13 C NMR chemical shifts and electronic circular dichroism spectra.

In the present work, we describe the preparation of two diastereomers from the enantioselective Michael addition of furan-2(5H)-one to (E)-(2-nitrovinyl)benzene catalyzed by a dinuclear Zn-complex. The relative configurations of the diastereomeric products were assigned by comparing nuclear magnetic resonance (NMR) experimental chemical shift data with those computed by density functional theory (DFT) methods. Corrected mean absolute error (CMAE) and CP3 analyses were used to compare the data sets. The absolute configuration of each diastereomer was initially assigned by analysis of electronic circular dichroism (ECD) data, which was consistent with that of the known X-ray crystallographic structure of the product of a related reaction, namely, (R)-5-((R)-1-(4-chlorophenyl)-2-nitroethyl)furan-2(5H)-one.

Reactions of HDDA Benzynes with C,N-Diarylimines (ArCH=NAr').

o-Benzynes can be utilized to construct heterocyclic motifs using various nucleophilic and cycloaddition trapping reactions. Acridines have been synthesized by capture of C,N-diarylimines with benzynes generated by classical methods (i.e., from ortho-elimination of precursor arene compounds), although in poor yields. We report here that these imines can be trapped by benzynes generated by the hexadehydro-Diels-Alder (HDDA) reaction in an efficient manner to produce 1,4-dihydroacridine products. These dihydroacridines were subsequently aromatized using MnO2 to provide structurally complex acridines.

One-Pot, Three-Aryne Cascade Strategy for Naphthalene Formation from 1,3-Diynes and 1,2-Benzdiyne Equivalents.

Here we disclose a cascade strategy for naphthyne formation that capitalizes on the traditional benzyne generation (i.e., from an ortho-silyl aryl triflate) and the thermal hexadehydro-Diels-Alder (HDDA) reaction. In this transformation, three distinct aryne species work in tandem, two of which can be formally considered as a 1,2-benzidyne, and each undergoes a different type of trapping event. Many examples were explored by varying the naphthyne capture chemistry as well as the 1,2-benzdiyne equivalent. This strategy enables rapid construction of various naphthalene products and has potential for the synthesis of extended polycyclic arenes.

The Aza-hexadehydro-Diels-Alder Reaction.

The generation of pyridynes from diyne nitriles is reported. These cyano-containing precursors are analogues of the triyne substrates typically used for the hexadehydro-Diels-Alder (HDDA) cycloisomerization reactions that produce ring-fused benzynes. Hence, the new processes described represent aza-HDDA reactions. Depending on the location of the nitrile, either 3,4-pyridynes (from 1,3-diynes containing a tethered cyano group) or 2,3-pyridynes (from 1-cyanoethyne derivatives containing a tethered alkyne) are produced. In situ trapping of these reactive intermediates leads to highly substituted and functionalized pyridine derivatives. In several instances, unprecedented pyridyne trapping reactions are seen. Differences in reaction energetics between the aza-HDDA substrates and that of their analogous HDDA (triyne) substrates are discussed.

Alkane desaturation by concerted double hydrogen atom transfer to benzyne.

The removal of two vicinal hydrogen atoms from an alkane to produce an alkene is a challenge for synthetic chemists. In nature, desaturases and acetylenases are adept at achieving this essential oxidative functionalization reaction, for example during the biosynthesis of unsaturated fatty acids, eicosanoids, gibberellins and carotenoids. Alkane-to-alkene conversion almost always involves one or more chemical intermediates in a multistep reaction pathway; these may be either isolable species (such as alcohols or alkyl halides) or reactive intermediates (such as carbocations, alkyl radicals, or σ-alkyl-metal species). Here we report a desaturation reaction of simple, unactivated alkanes that is mechanistically unique. We show that benzynes are capable of the concerted removal of two vicinal hydrogen atoms from a hydrocarbon. The discovery of this exothermic, net redox process was enabled by the simple thermal generation of reactive benzyne intermediates through the hexadehydro-Diels-Alder cycloisomerization reaction of triyne substrates. We are not aware of any single-step, bimolecular reaction in which two hydrogen atoms are simultaneously transferred from a saturated alkane. Computational studies indicate a preferred geometry with eclipsed vicinal C-H bonds in the alkane donor.