Combined Computational and Experimental Study Reveals Complex Mechanistic Landscape of Brønsted Acid-Catalyzed Silane-Dependent P═O Reduction.

The reaction mechanism of Brønsted acid-catalyzed silane-dependent P═O reduction has been elucidated through combined computational and experimental methods. Due to its remarkable chemo- and stereoselective nature, the Brønsted acid/silane reduction system has been widely employed in organophosphine-catalyzed transformations involving P(V)/P(III) redox cycle. However, the full mechanistic profile of this type of P═O reduction has yet to be clearly established to date. Supported by both DFT and experimental studies, our research reveals that the reaction likely proceeds through mechanisms other than the widely accepted "dual activation mode by silyl ester" or "acid-mediated direct P═O activation" mechanism. We propose that although the reduction mechanisms may vary with the substitution patterns of silane species, Brønsted acid generally activates the silane rather than the P═O group in transition structures. The proposed activation mode differs significantly from that associated with traditional Brønsted acid-catalyzed C═O reduction. The uniqueness of P═O reduction originates from the dominant Si/O═P orbital interactions in transition structures rather than the P/H-Si interactions. The comprehensive mechanistic landscape provided by us will serve as a guidance for the rational design and development of more efficient P═O reduction systems as well as novel organophosphine-catalyzed reactions involving P(V)/P(III) redox cycle.

Cobalt-Catalyzed Deacylative Ipso-C-C Bond Functionalization: An Approach toward Indole-Acyloins and Its Photophysical Studies.

Selective functionalization of the indole-C3-C bond with aromatic/heteroaromatic 1,2-diketones has been uncovered for the first time. Cobalt catalyst was found to be an effective catalyst for this unusual transformation. This ipso-C-C bond functionalization occurred in the presence of easily available weakly coordinating groups such as ketone and ester. One of the salient features of this methodology is the in situ generation of water from hexafluoro-2-propanol which acts as a reactant for the removal of the pivaloyl/ester group in a deacylative manner. The plausible mechanism has been supported by DFT calculations. Moreover, photophysical studies show the potential utility of indole-C3-acyloin and indolo-fused carbazole, which could be used in photovoltaic and optoelectronic application.

Allyl-Allyl Coupling Promoted by Catalyst Systems with two Palladium Atoms - A Plethora of Potentially Pericyclic Processes.

Recently, Huang and co-workers reported a catalytic reaction that utilizes H2 as the sole reductant for a C-C coupling of allyl groups with yields up to 96 %. Here we use computational quantum chemistry to identify several key features of this reaction that provide clarity on how it proceeds. We propose the involvement of a Pd-Pd bound dimer precatalyst, demonstrate the importance of ligand π-π interactions and counterions, and identify a new, energetically viable, mechanism involving two dimerized, outer-sphere reductive elimination transition structures that determine both the rate and selectivity. Although we rule out the previously proposed transmetalation step on energetic grounds, we show it to have an unusual aromatic transition structure in which two Pd atoms support rearranging electrons. The prevalence of potential metal-supported pericyclic reactions in this system suggests that one should consider such processes regularly, but the results of our calculations also indicate that one should do so with caution.

Overcoming a Radical Polarity Mismatch in Strain-Release Pentafluorosulfanylation of [1.1.0]Bicyclobutanes: An Entryway to Sulfone- and Carbonyl-Containing SF5-Cyclobutanes.

The first assortment of achiral pentafluorosulfanylated cyclobutanes (SF5-CBs) are now synthetically accessible through strain-release functionalization of [1.1.0]bicyclobutanes (BCBs) using SF5Cl. Methods for both chloropentafluorosulfanylation and hydropentafluorosulfanylation of sulfone-based BCBs are detailed herein, as well as proof-of-concept that the logic extends to tetrafluoro(aryl)sulfanylation, tetrafluoro(trifluoromethyl)sulfanylation, and three-component pentafluorosulfanylation reactions. The methods presented enable isolation of both syn and anti isomers of SF5-CBs, but we also demonstrate that this innate selectivity can be overridden in chloropentafluorosulfanylation; that is, an anti-stereoselective variant of SF5Cl addition across sulfone-based BCBs can be achieved by using inexpensive copper salt additives. Considering the SF5 group and CBs have been employed individually as nonclassical bioisosteres, structural aspects of these unique SF5-CB "hybrid isosteres" were then contextualized using SC-XRD. From a mechanistic standpoint, chloropentafluorosulfanylation ostensibly proceeds through a curious polarity mismatch addition of electrophilic SF5 radicals to the electrophilic sites of the BCBs. Upon examining carbonyl-containing BCBs, we also observed rare instances whereby radical addition to the 1-position of a BCB occurs. The nature of the key C(sp3)-SF5 bond formation step - among other mechanistic features of the methods we disclose - was investigated experimentally and with DFT calculations. Lastly, we demonstrate compatibility of SF5-CBs with various downstream functionalizations.

Borane-Catalyzed C-F Bond Functionalization of gem-Difluorocyclopropenes Enables the Synthesis of Orphaned Cyclopropanes.

Herein, we disclose an approach to synthesize tert-alkyl cyclopropanes by leveraging C-F bond functionalization of gem-difluorocyclopropenes using tris(pentafluorophenyl)borane catalysis. The reaction proceeds through the intermediacy of a fluorocyclopropenium ion, which was confirmed by the isolation of [Ph2(C6D5)C3]+[(C6F5)3BF]-. We found that silylketene acetal nucleophiles were optimal reaction partners with fluorocyclopropenium ion intermediates yielding fully substituted cyclopropenes functionalized with two α-tert-alkyl centers (63-93% yield). The regioselectivity of the addition to cyclopropenium ions is controlled by their steric and electronic properties and enables access to 3,3-bis(difluoromethyl)cyclopropenes in short order. The resulting cyclopropene products are readily reduced to the corresponding orphaned cyclopropanes under hydrogenation conditions. Quantum chemical calculations reveal the nature of the C-F bond cleavage steps and provide evidence for catalysis by boron and not silylated oxonium ions, though Si-F bond formation is the enthalpic driving force for the reaction.

A Shapeshifting Roadmap for Polycyclic Skeletal Evolution.

Polycyclic ring systems are ubiquitous three-dimensional (3D) structural motifs central to the function of many biologically active small molecules and organic materials. Indeed, subtle changes to the overall molecular shape and connectivity of atoms in a polycyclic framework (i.e., isomerism) can drastically alter its function and properties. Unfortunately, direct evaluation of these structure-function relationships typically requires the development of distinct synthetic strategies toward a specific isomer. Dynamic, "shapeshifting" carbon cages present a promising approach for sampling isomeric chemical space but are often difficult to control and are largely limited to thermodynamic mixtures of positional isomers about a single core scaffold. Here, we describe the development of a new shapeshifting C9-chemotype and a chemical blueprint for its evolution into structurally and energetically diverse isomeric ring systems. By leveraging the unique molecular topology of π-orbitals interacting through-space (homoconjugation), a common skeletal ancestor evolved into a complex network of valence isomers. This unusual system represents an exceedingly rare small molecule capable of undergoing controllable and continuous isomerization processes through the iterative use of just two chemical steps (light and organic base). Computational and photophysical studies of the isomer network provide fundamental insight into the reactivity, mechanism, and role of homoconjugative interactions. Importantly, these insights may inform the rational design and synthesis of new dynamic, shapeshifting systems. We anticipate this process could be a powerful tool for the synthesis of structurally diverse, isomeric polycycles central to many bioactive small molecules and functional organic materials.

Regiocontrol via Electronics: Insights into a Ru-Catalyzed, Cu-Mediated Site-Selective Alkylation of Isoquinolones via a C-C Bond Activation of Cyclopropanols.

A site-selective C(3)/C(4)-alkylation of N-pyridylisoquinolones is achieved by employing C-C bond activation of cyclopropanols under Ru(II)-catalyzed/Cu(II)-mediated conditions. The regioisomeric ratios of the products follow directly from the electronic nature of the cyclopropanols and isoquinolones used, with electron-withdrawing groups yielding predominantly the C(3)-alkylated products, whereas the electron-donating groups primarily generate the C(4)-alkylated isomers. Density functional theory calculations and detailed mechanistic investigations suggest the simultaneous existence of the singlet and triplet pathways for the C(3)- and C(4)-product formation. Further transformations of the products evolve the utility of the methodology thereby yielding scaffolds of synthetic relevance.

Stereodivergent Zweifel Olefination and its Mechanistic Dichotomy.

Stereoselective Zweifel olefination using boronate complexes carrying two different reactive π-systems was achieved to synthesize vinyl heteroarenes and conjugated 1,3-dienes in good yield and up to 100 % stereoselectivity, which remains unexplored until now. Most importantly, we report the unprecedented formation of E vs. Z-vinyl heteroarenes for different heteroarenes under identical conditions. Density functional theory (DFT) investigations unveil the mechanistic dichotomy between olefin and heteroarene activation followed by 1,2-migration, leading to E or Z-vinyl heteroarenes respectively. We also report a previously unknown reversal of stereoselectivity by using 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as an electrophile. The Zweifel olefination using a boronate complex that carries two different olefins was previously unexplored due to significant challenges associated with the site-selective activation of olefins. We have solved this problem and reported the site-selective activation of olefins for the stereoselective synthesis of 1,3-dienes.

Evidence for C-F Bond Formation through Formal Reductive Elimination from Tellurium(VI).

The fundamental challenge of C-F bond formation by reductive elimination has been met by compounds of select transition metals and fewer main group elements. The work detailed herein expands the list of main group elements known to be capable of reductively eliminating a C-F bond to include tellurium. Surprising and novel modes of both sp2 and sp3 C-F bond formation were observed alongside formation of TeIV cations during two separate attempts to synthesize/characterize fluorinated organotellurium(VI) cations in superacidic media (SbF5 /SO2 ClF). Following detailed low-temperature NMR experiments, the mechanisms of the two unique reductive elimination reactions were probed and investigated using density functional theory (DFT) calculations. Ultimately, we found that an "indirect" reductive elimination pathway is likely operative whereby Sb plays a key role in fluoride abstraction and C-F bond formation, as opposed to unimolecular reductive elimination from a discrete TeVI cation.

Catalyst-Controlled Regiodivergence in Rearrangements of Indole-Based Onium Ylides.

We have developed catalyst-controlled regiodivergent rearrangements of onium-ylides derived from indole substrates. Oxonium ylides formed in situ from substituted indoles selectively undergo [2,3]- and [1,2]-rearrangements in the presence of a rhodium and a copper catalyst, respectively. The combined experimental and density functional theory (DFT) computational studies indicate divergent mechanistic pathways involving a metal-free ylide in the rhodium catalyzed reaction favoring [2,3]-rearrangement, and a metal-coordinated ion-pair in the copper catalyzed [1,2]-rearrangement that recombines in the solvent-cage. The application of our methodology was demonstrated in the first total synthesis of the indole alkaloid (±)-sorazolon B, which enabled the stereochemical reassignment of the natural product. Further functional group transformations of the rearrangement products to generate valuable synthetic intermediates were also demonstrated.

Synthesis and antibacterial studies of teixobactin analogues with non-isostere substitution of enduracididine.

Teixobactin is a structurally and mechanistically novel antimicrobial peptide with potent activities against Gram-positive pathogens. It contains l-allo-enduracididine (End) residue which is not readily accessible. In this report, we have used convergent Ser Ligation as the key step to prepare a series of teixobactin analogues with End being substituted with its non-isostere moieties. Among these analogues, compounds T16, T27 and T29 exhibited the best antimicrobial activities against different Gram-positive bacteria with MICs ranging from 0.25 to 1.0 µM. Structure-activity relationship is also established for further development of more promising teixobactin analogues.

Discovery of a Formal Dyotropic Rearrangement during Acid-Mediated Dioxabicyclo[4.2.1]nonanone Formation.

A new reaction mechanism for the construction of dioxabicyclo[4.2.1]nonanone skeletons via a cation cascade has been proposed and examined by DFT and ab initio computations. This mechanism features the following steps: (1) intramolecular Friedel-Crafts-type cyclization with a methyl oxocarbenium cation formed by carboxylate disconnection, (2) electron-rich aromatic ring assisted methoxide loss followed by lactone formation, and (3) stepwise dyotropic rearrangement resulting in skeletal isomerization from a dioxabicyclo[3.2.2]nonanone to the dioxabicyclo[4.2.1]nonanone product observed experimentally. The high regioselectivity and driving force for the overall rearrangement were rationalized, and Lewis and Brønsted acid mediated reactivities were compared.

Revisiting a classic carbocation - DFT, coupled-cluster, and ab initio molecular dynamics computations on barbaralyl cation formation and rearrangements.

Density functional theory computations were used to model the formation and rearrangement of the barbaralyl cation (C9H+ 9). Two highly delocalized minima were located for C9H+ 9, one of C s symmetry and the other of D 3h symmetry, with the former having lower energy. Quantum chemistry-based NMR predictions affirm that the lower energy structure is the best match with experimental spectra. Partial scrambling was found to proceed through a C 2 symmetric transition structure associated with a barrier of only 2.3 kcal mol-1. The full scrambling was found to involve a C 2v symmetric transition structure associated with a 5.0 kcal mol-1 barrier. Ab initio molecular dynamics simulations initiated from the D 3h C9H+ 9 structure revealed its connection to six minima, due to the six-fold symmetry of the potential energy surface. The effects of tunneling and boron substitution on this complex reaction network were also examined.

Analogies between photochemical reactions and ground-state post-transition-state bifurcations shed light on dynamical origins of selectivity.

Revealing the origins of kinetic selectivity is one of the premier tasks of applied theoretical organic chemistry, and for many reactions, doing so involves comparing competing transition states. For some reactions, however, a single transition state leads directly to multiple products, in which case non-statistical dynamic effects influence selectivity control. The selectivity of photochemical reactions-where crossing between excited-state and ground-state surfaces occurs near ground-state transition structures that interconvert competing products-also should be controlled by the momentum of the reacting molecules as they return to the ground state in addition to the shape of the potential energy surfaces involved. Now, using machine-learning-assisted non-adiabatic molecular dynamics and multiconfiguration pair-density functional theory, these factors are examined for a classic photochemical reaction-the deazetization of 2,3-diazabicyclo[2.2.2]oct-2-ene-for which we demonstrate that momentum dominates the selectivity for hexadiene versus [2.2.2] bicyclohexane products.

UV-Visible Absorption Spectra of Solvated Molecules by Quantum Chemical Machine Learning.

Predicting UV-visible absorption spectra is essential to understand photochemical processes and design energy materials. Quantum chemical methods can deliver accurate calculations of UV-visible absorption spectra, but they are computationally expensive, especially for large systems or when one computes line shapes from thermal averages. Here, we present an approach to predict UV-visible absorption spectra of solvated aromatic molecules by quantum chemistry (QC) and machine learning (ML). We show that a ML model, trained on the high-level QC calculation of the excitation energy of a set of aromatic molecules, can accurately predict the line shape of the lowest-energy UV-visible absorption band of several related molecules with less than 0.1 eV deviation with respect to reference experimental spectra. Applying linear decomposition analysis on the excitation energies, we unveil that our ML models probe vertical excitations of these aromatic molecules primarily by learning the atomic environment of their phenyl rings, which align with the physical origin of the π →π* electronic transition. Our study provides an effective workflow that combines ML with quantum chemical methods to accelerate the calculations of UV-visible absorption spectra for various molecular systems.