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.

2:1 Adducts Arising from Reactions between Benzynes and 1,3,4-Oxadiazoles.

2:1 adducts arise from the reaction of 2,5-diaryl-1,3,4-oxadiazoles and benzynes generated from the hexadehydro-Diels-Alder (HDDA) reaction. Density functional theory computations support a mechanistic manifold that includes a concerted SNAr process. Additionally, the benzyne trapping reaction of 2,5-dimethyl-1,3,4-oxadiazole affords an unusual acylimine-containing 2:1 adduct, which is the first case in which a dearomatized product has arisen from a HDDA reaction.

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.

Novel Conversions of a Multifunctional, Bio-sourced Lactone Carboxylic Acid.

The plant-derived compounds furfuryl alcohol and itaconic anhydride are known to undergo a Diels-Alder reaction at room temperature and in bulk to efficiently give an alkene-containing lactone carboxylic acid. Reported here is the conversion of this substance to a variety of derivatives via hydrogenation, epoxidation, or halolactonization reactions. Most notable is the formation of a set of three related acrylate or methacrylate esters (see graphical abstract) produced by direct acylative ring opening of ether bonds using Sc(OTf)3 and (meth)acrylic anhydride. These esters are viewed as promising candidates for use as biorenewable monomers in reversible addition-fragmentation chain transfer (RAFT) polymerization reactions.

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.

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.

Covalent Adduct Formation between ß-Lactoglobulin and Flavor Compounds under Thermal Treatments That Mimic Food Pasteurization or Sterilization.

Thermal processing (e.g., pasteurization and sterilization) is a critical step ensuring the microbial safety of our foods. Previous work from our laboratory has examined the covalent reactions occurring between proteins and a broad selection of flavor compounds under ambient storage temperatures (25-45 °C). However, similar research on reactions of flavor compounds with a protein under thermal processing conditions has not been investigated. In the current study, covalent adduct formation between ß-lactoglobulin (BLG) and 46 flavor compounds encompassing 13 different classes of functional groups was investigated under pasteurization and sterilization conditions by UPLC-ESI-QTOF-MS. BLG was chosen as a representative protein for this study because it is structurally well characterized, its molecular weight is well suited for ESI-MS analysis (18.2 kDa), and it is broadly used in the food industry. Schiff base, aza-Michael addition, and disulfide linkages were the main types of covalent interactions occurring across the reactive samples. Among them, isothiocyanates, aldehydes, and thiol-containing compounds were generally very reactive. Increasing the severity of the thermal treatment [high-temperature-short-time (HTST) pasteurization, in-container pasteurization (IC), and ultra-high-temperature (UHT) sterilization conditions] accelerated the reactions of BLG with flavor compounds, which revealed reactivity of three flavor compounds not previously observed to react at room temperature (eugenol, 4-vinyl phenol, and 3-nonen-2-one). Ketones [other than 2-hydroxy-3-methyl-2-cyclopenten-1-one (cyclotene), diketones, and unsaturated ketones], alcohols, acids, alkenes (terpenes), esters, lactones, 3-acetylpyridine, methyl anthranilate, vanillin, 2-methylthiophene, and dimethyl sulfone did not show measurable reactivity with BLG under the thermal processing conditions examined. An overall view of the data shows that the HTST heat treatment (72 °C for 15 s) had the least effect on the extent of reaction while in-container pasteurization conditions (63 °C for 30 min) produced a similar extent of reaction as the UHT (130 °C 30 s) heat treatment. These varying extents of adductation are in reasonable accord with what one might expect, given that the rates of most classes of chemical reactions occurring near ambient temperature increase by a factor of 2-4 for each increase of 10 K in temperature. Unfortunately, our methodology did not permit us to obtain meaningful data using the most aggressive standard sterilization thermal conditions (110 °C for 30 min) because extensive aggregation/coagulation removed essentially all of the BLG protein from the reaction mixtures prior to MS analysis.

The contrasting reactivity of trans- vs. cis-azobenzenes (ArN[double bond, length as m-dash]NAr) with benzynes.

We report here a study that has revealed two distinct modes of reactivity of azobenzene derivatives (ArN[double bond, length as m-dash]NAr) with benzynes, depending on whether the aryne reacts with a trans- or a cis-azobenzene geometric isomer. Under thermal conditions, trans-azobenzenes engage benzyne via an initial [2 + 2] trapping event, a process analogous to known reactions of benzynes with diarylimines (ArC[double bond, length as m-dash]NAr). This is followed by an electrocyclic ring opening/closing sequence to furnish dihydrophenazine derivatives, subjects of contemporary interest in other fields (e.g., electronic and photonic materials). In contrast, when the benzyne is attacked by a cis-azobenzene, formation of aminocarbazole derivatives occurs via an alternative, net (3 + 2) pathway. We have explored these complementary orthogonal processes both experimentally and computationally.

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.

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.

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.

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.

In Situ Allene Formation via Alkyne Tautomerization to Promote [4 + 2]-Cycloadditions with a Pendant Alkyne or Nitrile.

We have explored the net-[4 + 2]-cycloadditions of a variety of aryl (or alkenyl) alkynes. Tautomerization via base-catalyzed alkyne-to-allene isomerization produces a transient allene, which undergoes stepwise cyclization with not only a pendant alkyne but also a nitrile. The operative mechanisms for these reactions were studied by density functional theory and compared with the slower thermal cyclization of the precursor alkyne.

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.

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.

Trapping Reactions of Benzynes Initiated by Intramolecular Nucleophilic Addition of a Carbonyl Oxygen to the Electrophilic Aryne.

We describe here reactions in which a carbonyl oxygen atom initiates cascade reactions by nucleophilic attack on a covalently attached benzyne. The benzynes are produced by thermal cyclization of triynes via hexadehydro-Diels-Alder reaction. The initially produced oxocarbenium/aryl carbanionic zwitterion is protonated in situ by an external protic nucleophile (NuH) of appropriate acidity. The resulting ion pair (oxocarbenium+/Nu-) collapses through several different mechanistic manifolds, adding to the diversity of structural classes that can be generated.

Silicon as a powerful control element in HDDA chemistry: redirection of innate cyclization preferences, functionalizable tethers, and formal bimolecular HDDA reactions.

The 1,3-diyne and diynophile in hexadehydro-Diels-Alder (HDDA) reaction substrates are typically tethered by linker units that consist of C, O, N, and/or S atoms. We describe here a new class of polyynes based on silicon-containing tethers that can be disposed of and/or functionalized subsequent to the HDDA reaction. The cyclizations are efficient, and the resulting benzoxasiloles are amenable to protodesilylation, halogenation, oxygenation, and arylation reactions. The presence of the silicon atom can also override the innate mode of cyclization in some cases, an outcome attributable to a ß-silyl effect on the structure of intermediate diradicals. Overall, this strategy equates formally to an otherwise unknown, bimolecular HDDA reaction and expands the versatility of this body of aryne chemistry.

De novo Assembly of the Benzenoid Ring as a Core Strategy for Synthesis of the Isoindolinone Natural Products Isohericerin, Erinacerin A, and Sterenin A.

Here we describe the use of the hexadehydro-Diels-Alder (HDDA) reaction for the de novo construction of the isoindolinone scaffold and its application to the synthesis of the title natural products. The key isoindolinone-forming HDDA reaction involved an unprecedented substrate motif in which an amide carbonyl group was conjugated to the 4π 1,3-diyne component. In addition, a dimethylsilyl (-SiMe2H) substituent was exploited to trigger a Fleming-Tamao-Kumada oxidation for the installation of an essential phenolic hydroxyl group.

ß-Methyl-δ-valerolactone-containing Thermoplastic Poly(ester-amide)s: Synthesis, Mechanical Properties, and Degradation Behavior.

Poly(ester-amide)s (PEAs) have been prepared from (glucose-derived) ß-methyl-δ-valerolactone (MVL) by reaction of MVL-derived diamidodiols with diacid chlorides in solution to form poly(ester-amide)s having alternating diester-diamide subunits. The PEAs formed by this method exhibit plastic properties and are of sufficiently high molecular weight to be tough, ductile materials (stress at break: 41-53 MPa, strain at break: 530-640%). The length of the methylene linker unit (n = 1,2,3) between amide groups of the diamidodiols affects the Young's modulus; longer linkers reduce the stiffness of the materials. This allows tuning of the properties by judicious choice of precursors. MVL was also converted to a diacid chloride that was then used to prepare a PEA that is 76 wt% MVL-derived. The degradation rates of suspensions of these new PEAs in basic aqueous media were benchmarked and their instability in aqueous acid was also observed. NMR studies were used to detect the hydrolytic degradation products of both these PEAs as well as a structurally simpler analog.