Mechanisms of the Gewald Synthesis of 2-Aminothiophenes from Elemental Sulfur.

The Gewald reaction is a well-established one-pot method to access 2-aminothiophenes from carbonyl compounds, activated acetonitriles, and elemental sulfur. To elucidate the reaction's poorly understood mechanism, with regard to the decomposition of sulfur and polysulfide intermediates, we have performed a comprehensive computational study using density functional theory (DFT) calculations at the M06-2X (or ωB97X-D)/aug-cc-pV(T + d)Z/SMD(C2H5OH) level of theory. The results show that the reaction is initiated by a Knoevenagel-Cope condensation, followed by opening of the elemental sulfur, leading to polysulfide formation. The polysulfide intermediates can interconvert and decompose using various mechanisms including unimolecular cyclization, nucleophilic degradation, and scrambling. Protonation of the polysulfides changes their electrophilic behavior and provides a kinetically favorable pathway for their decomposition. This protonation-induced intermolecular degradation is feasible for polysulfides of all lengths, but unimolecular decomposition is kinetically favored for long polysulfides (≥6 sulfur atoms). None of the pathways provide any thermodynamic benefit due to the lack of resonance-stabilized leaving group, and a complex equilibrium of polysulfides of all lengths is expected in solution. Cyclization of the monosulfide with aromatization to the thiophene product is the only driving force behind the reaction, funneling all of the various intermediates into the observed product in a thermodynamically controlled process.

Transpersulfidation or H2S Release? Understanding the Landscape of Persulfide Chemical Biology.

Persulfides (RSSH) are biologically important reactive sulfur species that are endogenously produced, protect key cysteine residues from irreversible oxidation, and are important intermediates during different enzymatic processes. Although persulfides are stronger nucleophiles than their thiol counterparts, persulfides can also act as electrophiles in their neutral, protonated form in specific environments. Moreover, persulfides are electrophilic at both sulfur atoms, and the reaction with a thiolate can lead to either H2S release with disulfide formation or alternatively result in transpersulfidation. Despite the broad acceptance of these reaction pathways, the specific properties that control whether persulfides react through the H2S-releasing or transpersulfidation pathway remain elusive. Herein, we use a combined computational and experimental approach to directly investigate the reactivity between persulfides and thiols to answer these questions. Using density functional theory (DFT) calculations, we demonstrate that increasing steric bulk or electron withdrawal near the persulfide can shunt persulfide reactivity through the transpersulfidation pathway. Building from these insights, we use a synthetic persulfide donor and an N-iodoacetyl l-tyrosine methyl ester (TME-IAM) trapping agent to experimentally monitor and measure transpersulfidation from a bulky penicillamine-based persulfide to a cysteine-based thiol, which, to the best of our knowledge, is the first direct observation of transpersulfidation between low-molecular-weight species. Taken together, these combined approaches highlight how the properties of persulfides are directly impacted by local environments, which has significant impacts in understanding the complex chemical biology of these reactive species.

Substituent Effects on the Equilibria between Cyclopropylcarbinyl, Bicyclobutonium, Homoallyl, and Cyclobutyl Cations.

The cyclopropylcarbinyl (CPC) and bicyclobutonium (BCB) structures of the C4H7+ cation have been proposed as intermediates in various reactions forming cyclopropylcarbinyl, cyclobutyl, or homoallyl products. While these cations can react with nucleophiles stereospecifically, in each system there are usually multiple BCB/CPC cations in equilibrium with related cyclobutyl (CB) and homoallyl (HA) cations, from which stereospecificity is jeopardized. Using density functional theory (DFT) and DLPNO-CCSD(T) calculations, we studied the electronic and steric effects on the equilibria between mono- and polysubstituted C4H7+ cations. We find that the shapes of the potential energy surfaces (PESs) vary significantly, with structures that are minima for a given substituent becoming high-energy transition structures for another. Electron-donating groups at C1, C2, or C3/C4 positions favor CPC, BCB/CB, and HA structures, respectively. Electron-withdrawing groups yield shallower PESs where multiple related structures are energetically accessible. Strong Hammett correlations (σ+) are observed for the substituent effects, which appear to be additive. In addition, BCB cations with more substituents are energetically destabilized compared to CPC cations, except with donating substituents at the C2 position. This work allows predictions of the major structures expected in mixtures of CPC/BCB/CB/HA cations for given substituent patterns, and of the major products produced from such cations.

Synthetic and mechanistic study on the conjugate isothiocyanation of enones with trimethylsilyl isothiocyanate.

Alkyl isothiocyanates (R-NCS) have pharmacological applications and provide a synthetic handle to various functional groups including thioureas. There are however few methods to access alkyl isothiocyanates through the creation of the C-N bond. We have developed a simple approach for the conjugate isothiocyanation of enones by trimethylsilyl isothiocyanate (TMSNCS), which proceeds through the 1,4-addition of the weak isothiocyanate nucleophile to activated enones in the absence of external promoters. This method avoids the direct use of highly toxic acids and bases, produces ß-isothiocyanato carbonyl products in yields of 87-98% under mild conditions (less than 6 hours at 0 °C), and displays wide functional group tolerance. Density functional theory calculations highlighted competing cationic and anionic mechanisms, where the enone activation by the TMSNCS reagent is accelerated in protic solvents. The selective formation of the isothiocyanate vs. thiocyanate isomers is explained by the thermodynamically-controlled nature of the reaction in which only the conjugate isothiocyanation is exergonic.

Direct hydrogen selenide (H2Se) release from activatable selenocarbamates.

Hydrogen selenide (H2Se) is a possible bioregulator, potential gasotransmitter, and important precursor in biological organoselenium compound synthesis. Early tools for H2Se research have benefitted from available mechanistic understanding of analogous small molecules developed for detecting or delivering H2S. A now common approach for H2S delivery is the use of small molecule thiocarbamates that can be engineered to release COS, which is quickly converted to H2S by carbonic anhydrase. To expand our understanding of the chemical underpinnings that enable H2Se delivery, we investigated whether selenocarbamates undergo similar chemistry to release carbonyl selenide (COSe). Using both light- and hydrolysis-activated systems, we demonstrate that unlike their lighter thiocarbamate congeners, selenocarbamates release H2Se directly with concomitant isocyanate formation rather than by the intermediate release of COSe. This reaction mechanism for direct H2Se release is further supported by computational investigations that identify a ΔΔG‡ ∼ 25 kcal mol-1 between the H2Se and COSe release pathways in the absence of protic solvent. This work highlights fundamentally new approaches for H2Se release from small molecules and advances the understanding of reactivity differences between reactive sulfur and selenium species.

Cyclopropylcarbinyl-to-Homoallyl Carbocation Equilibria Influence the Stereospecificity in the Nucleophilic Substitution of Cyclopropylcarbinols.

The synthesis of quaternary homoallylic halides and trichloroacetates from cyclopropylcarbinols, as reported by Marek (J. Am. Chem. Soc. 2020, 142, 5543-5548), is one of the few reported examples of stereospecific nucleophilic substitution involving chiral bridged carbocations. However, for the phenyl-substituted substrates, poor specificity is observed and mixtures of diastereomers are obtained. To understand the nature of the intermediates involved and explain the loss of specificity for certain substrates, we have performed a computational investigation of the reaction mechanism using ωB97X-D optimizations and DLPNO-CCSD(T) energy refinements. Our results indicate that cyclopropylcarbinyl cations are stable intermediates in this reaction, while bicyclobutonium structures are high-energy transition structures that are not involved. Instead, multiple rearrangement pathways of cyclopropylcarbinyl cations were located, including ring openings to homoallylic cations. The activation barriers required to reach such structures are correlated to the nature of the substituents; while direct nucleophilic attack on the chiral cyclopropylcarbinyl cations is kinetically favored for most systems, the rearrangements become competitive with nucleophilic attack for the phenyl-substituted systems, leading to a loss of specificity through rearranged carbocation intermediates. As such, stereospecific reactions of chiral cyclopropylcarbinyl cations depend on the energies required to access their corresponding homoallylic structures, from which selectivity is not guaranteed.

Mechanisms of the Reaction of Elemental Sulfur and Polysulfides with Cyanide and Phosphines.

The reactions of elemental sulfur (S8 ) and polysulfides with nucleophiles are relevant to organic synthesis, materials science and biochemistry, but the mechanisms by which they operate are still unknown due to the inherent thermodynamic and kinetic instability of polysulfide intermediates. Using Density Functional Theory (DFT) calculations at the ωB97X-D/aug-cc-pV(T+d)Z/SMD(MeCN) // ωB97X-D/aug-cc-pVDZ/SMD(MeCN) level of theory, we studied the mechanisms behind the reaction of elemental sulfur and polysulfides with cyanide and phosphines, which quantitatively generate the monosulfide products thiocyanate and phosphine sulfides, respectively. All plausible pathways including nucleophilic decomposition, unimolecular decomposition, scrambling reactions, and attack on thiosulfoxides, have been considered to provide the first comprehensive mechanistic picture for this class of reactions. Overall, intramolecular cyclization is identified as the most favorable decomposition pathway for long polysulfides. For short polysulfides, a mixture of unimolecular decomposition, nucleophilic attack, and scrambling pathways can be expected.

Fast and Bioorthogonal Release of Isocyanates in Living Cells from Iminosydnones and Cycloalkynes.

Bioorthogonal click-and-release reactions are powerful tools for chemical biology, allowing, for example, the selective release of drugs in biological media, including inside animals. Here, we developed two new families of iminosydnone mesoionic reactants that allow a bioorthogonal release of electrophilic species under physiological conditions. Their synthesis and reactivities as dipoles in cycloaddition reactions with strained alkynes have been studied in detail. Whereas the impact of the pH on the reaction kinetics was demonstrated experimentally, theoretical calculations suggest that the newly designed dipoles display reduced resonance stabilization energies compared to previously described iminosydnones, explaining their higher reactivity. These mesoionic compounds react smoothly with cycloalkynes under physiological, copper-free reaction conditions to form a click pyrazole product together with a released alkyl- or aryl-isocyanate. With rate constants up to 1000 M-1 s-1, this click-and-release reaction is among the fastest described to date and represents the first bioorthogonal process allowing the release of isocyanate electrophiles inside living cells, offering interesting perspectives in chemical biology.

Benchmark of density functional theory methods for the study of organic polysulfides.

Elemental sulfur is often used in organic synthesis as its low cost and high abundance make it a highly desirable source of sulfur atoms. However, sulfur's unpredictable catenation behavior poses challenges to its widespread usage due to difficulties in designing new reactions that can account for its multifaceted reactivity. In order to accurately model sulfur's mechanisms using computational approaches, it is necessary to identify density functional theory (DFT) methods that are accurate on these systems. This study benchmarks 12 well-known DFT functionals that include local, non-local, and hybrid methods against DLPNO-CCSD(T)/aug-cc-pV(Q+d)Z//MP2/aug-cc-pV(T+d)Z/SMD(MeCN) for the accurate treatment of organic polysulfides, taking cyanide as a nucleophile. Our benchmarking results indicate that the M06-2X and B3LYP-D3(BJ) density functionals are the most accurate for calculating reaction energies, while local functionals performed the worst. For activation energies, MN15, MN15-L, M06-2X, and ωB97X-D are the most accurate. Our analysis of structural parameters shows that all functionals perform well for ground state optimizations except B97D3, while MN15-L and M06-2X performed best for transition structure optimizations. Overall, the four hybrid functionals MN15, M06-2X, ωB97X-D, and B3LYP-D3(BJ) appear adequate for studying the reaction mechanisms of polysulfides.

Selective chlorination of iminosydnones for fast release of amide, sulfonamide and urea-containing drugs.

Herein, we describe a methodology for iminosydnone chlorination and we demonstrate the high beneficial effect of this modification on the reactivity of these mesoionic dipoles in strain-promoted cycloaddition reactions. Exploiting their reaction with cyclooctynes, we used these new iminosydnones for bioorthogonal release of amide, urea and sulfonamide containing drugs. Notably, drugs containing a terminal amide function were released for the first time with good kinetic constants.

Photoinitiated anti-Hydropentafluorosulfanylation of Terminal Alkynes.

A photoinitiated anti-hydropentafluorosulfanylation of terminal alkynes using SF5 Cl and (TMS)3 SiH as the hydrogen atom donor is reported. This transformation generates selectively (Z)-(1-alken-1-yl)pentafluoro-λ6 -sulfanes (Z:E : >85:15), thus allowing the preparation of this previously unknown geometrical isomer. DFT calculations highlight that the selectivity is due to the intrinsic preference of SF5 -substituted vinylic radicals to adopt a cis geometry, and to increased steric contacts during the transition structures leading to the minor (E)-products.

Heterohelicenes through 1,3-Dipolar Cycloaddition of Sydnones with Arynes: Synthesis, Origins of Selectivity, and Application to pH-Triggered Chiroptical Switch with CPL Sign Reversal.

Regioselective access to heterohelicenes through the 1,3-dipolar cycloaddition of sydnones with arynes is described. Novel access to sydnones and poly(hetero)aromatic aryne precursors allowed the introduction of chemical diversity over multiple positions of the helical scaffolds. The origins of the unconventional regioselectivity during the cycloaddition steps was systematically investigated using density functional theory (DFT) calculations, unveiling the key features that control this reactivity, namely, face-to-face (π···π) or edge-to-face (C-H···π) interactions, primary orbital interactions and distortion from coplanarity in the transition structures (TSs) of the transformation. From the library of 24 derivatives synthesized, a pyridyl containing derivative displayed reversible, red-shifted, pH-triggered chiroptical switching properties, with CPL-sign reversal. It is found that protonation of the helicene causes a change of the angle between the electric and magnetic dipole moments related to the S1 → S0 transition, resulting in this rare case of reversible CPL sign inversion upon application of an external stimulus.

Recent advances in the stereoselective synthesis of acyclic all-carbon tetrasubstituted alkenes.

Alkenes bearing four carbon-based groups are ubiquitous motifs in chemical sciences due to their various applications from medicinal to materials chemistry, and as chemical platforms for the synthesis of complex, chiral molecules. As such, tremendous research efforts are currently ongoing in order to develop general procedures for the challenging stereoselective synthesis of all-carbon tetrasubstituted alkenes, especially for acyclic structures. Since classical approaches to carbon-carbon double bonds are not suitable for the high steric demand around tetrasubstituted alkenes, a variety of unique approaches to access these privileged functional groups have been developed in recent years. This review article highlights the most significant developments in the field from 2007 to 2020, with an emphasis on the mechanisms and remaining limitations of these contemporary methods. Specifically, recent advances in internal alkyne carbofunctionalizations, in multicomponent couplings or other cross-couplings from nucleophilic or electrophilic alkenyl partners, and in the development of miscellaneous methods, are discussed.

Experimental and Computational Study on the Anti-Markovnikov Hydrofunctionalization of Olefins Using Glycine-Extended AQ-Auxiliaries.

Two similar tridentate directing groups derived from glycine and 8-aminoquinoline were shown to enable the palladium-catalyzed anti-Markovnikov hydrofunctionalization of 4-pentenylamine with drastically different efficiencies. A computational investigation into the origin of the reactivity difference between these isomeric, carbonyl-transposed auxiliaries suggests that protonation state, thus charge of the substrate-metal complex prior to nucleopalladation is key. These investigations have culminated in a directing group design that can undergo Pd-catalyzed hydrofunctionalization under relatively mild conditions, as low as room temperature.

Identifying the true origins of selectivity in chiral phosphoric acid catalyzed N-acyl-azetidine desymmetrizations.

The first catalytic intermolecular desymmetrization of azetidines was reported by Sun and coworkers in 2015 using a BINOL-derived phosphoric acid catalyst (J. Am. Chem. Soc. 2015, 137, 5895-5898). To uncover the mechanism of the reaction and the origins of the high enantioselectivity, Density Functional Theory (DFT) calculations were performed at the B97D3/6-311+G(2d,2p)/SMD(toluene)//B97D3/6-31G(d,p)/CPCM(toluene) level of theory. Comparison of four possible activation modes confirms that this reaction proceeds through the bifunctional activation of the azetidine nitrogen and the thione tautomer of the 2-mercaptobenzothiazole nucleophile. Upon thorough conformational sampling of the enantiodetermining transition structures (TSs), a free energy difference of 2.0 kcal mol-1 is obtained, accurately reproducing the experimentally measured 88% e.e. at 80 °C. This energy difference is due to both decreased distortion and increased non-covalent interactions in the pro-(S) TS. To uncover the true origins of selectivity, the TSs optimized with the full catalyst were compared to those optimized with a model catalyst through steric maps. It is found that the arrangements displayed by the substrates are controlled by strict primary orbital interaction requirements at the transition complex, and their ability to fit into the catalyst pocket drives the selectivity. A general model of selectivity for phosphoric acid-catalyzed azetidine desymmetrizations is proposed, which is based on the preference of the nucleophile and benzoyl group to occupy empty quadrants of the chiral catalyst pocket.

Capture of Electrochemically Generated Fleeting Carbazole Radical Cations and Elucidation of Carbazole Dimerization Mechanism by Mass Spectrometry.

The capture of reactive intermediates is important for the elucidation of reaction mechanisms. We report the first observation of electrochemically generated, short-lived radical cations of carbazole (t1/2 ≈ 97 µs) and two N-substituted carbazole derivatives by mass spectrometry. In addition, online investigation of the reactivity of electrochemically generated carbazole radical cations supports that the carbazole dimerization mechanism involves the reaction of one radical cation with one neutral molecule rather than the previously proposed coupling of two radical cations.

Thiourea-Catalyzed C-F Bond Activation: Amination of Benzylic Fluorides.

We describe the first thiourea-catalyzed C-F bond activation. The use of a thiourea catalyst and Ti(OiPr)4 as a fluoride scavenger allows the amination of benzylic fluorides to proceed in moderate to excellent yields. Preliminary results with S- and O-based nucleophiles are also presented. DFT calculations reveal the importance of hydrogen bonds between the catalyst and the fluorine atom of the substrate to lower the activation energy during the transition state.

Rate and Computational Studies for Pd-NHC-Catalyzed Amination with Primary Alkylamines and Secondary Anilines: Rationalizing Selectivity for Monoarylation versus Diarylation with NHC Ligands.

The relative rates of arylation of primary alkylamines with different Pd-NHC catalysts have been measured, as have the relative rates of arylation of the secondary aniline product in an attempt to understand the key ligand design features necessary to have high selectivity for the monoarylated amine product. As the substituents on the N-aryl ring of the NHC increase in size, selectivity for monoarylation increases and this is further enhanced by chlorinating the back of the NHC ring. Computations have been performed on the catalytic cycle of this transformation in order to understand the selectivity obtained with the different catalysts.

One-Pot Sequential Kumada-Tamao-Corriu Couplings of (Hetero)Aryl Polyhalides in the Presence of Grignard-Sensitive Functional Groups Using Pd-PEPPSI-IPentCl.

We report a general and rapid chemoselective Kumada-Tamao-Corriu (KTC) cross-coupling of aryl bromides in the presence of chlorides or triflates with functionalized Grignard reagents at 0 °C in 15 min by using Pd-PEPPSI-IPentCl (C4). Nucleophiles and electrophiles (or both) can contain Grignard-sensitive functional groups (-CN, -COOR, etc.). Control experiments together with DFT calculations suggest that transmetallation is rate limiting for the selective cross-coupling of Br in the presence of Cl/OTf with functionalized Grignard reagents. One-pot sequential KTC/KTC cross-couplings with bromo-chloro arenes have been demonstrated for the first time. We also report the one-pot sequential KTC/Negishi cross-couplings using C4 showcasing the versatility of this methodology.

Sydnone-Based Approach to Heterohelicenes through 1,3-Dipolar-Cycloadditions.

The first approach to pyrazole-containing helicenes via sydnone-aryne [3 + 2]-cycloaddition is described. An unprecedented regioselectivity in the cycloaddition step toward the more sterically constrained product was observed in the presence of extended aromatic scaffolds. DFT calculations enabled understanding the origin of this unexpected selectivity.