Electrocyclic Ring-opening Reaction Research Articles

Noncovalent Modulation of Chemoselectivity in the Gas Phase Leads to a Switchover in Reaction Type from Heterolytic to Homolytic to Electrocyclic Cleavage.

Inthe gas phase, thermal activation of supramolecular assemblies such as host-guest complexes leads commonly to noncovalent dissociation into the individual components. Chemical reactions, for example of encapsulated guest molecules, are only found in exceptional cases. As observed by mass spectrometry, when 1-amino-methyl-2,3-diazabicyclo[2.2.2]oct-2-ene (DBOA) is complexed by the macrocycleb-cyclodextrin, its protonated complex undergoes collision-induced dissociation into its components, the conventional reaction pathway. Inside the macrocyclic cavity of cucurbit[7]uril (CB7), a competitive chemical reaction of monoprotonated DBOA takes place upon thermal activation, namely a stepwise homolytic covalent bond cleavage with the elimination of N2, while the doubly protonated CB7•DBOA complex undergoes an inner-phase elimination of ethylene, a concerted, electrocyclic ring-opening reaction. These chemical reaction pathways stand in contrast to the gas-phase chemistry of uncomplexed monoprotonated DBOA, for which an elimination of NH3predominates upon collision-induced activation, as a heterolytic bond cleavage reaction. The combined results, which can be rationalized in terms of organic-chemical reaction mechanisms and density-function theoretical calculations, demonstrate that chemical reactions in the gas phase can be steered chemoselectively through noncovalent interactions.

Rehybridization dynamics into the pericyclic minimum of an electrocyclic reaction imaged in real-time

Electrocyclic reactions are characterized by the concerted formation and cleavage of both σ and π bonds through a cyclic structure. This structure is known as a pericyclic transition state for thermal reactions and a pericyclic minimum in the excited state for photochemical reactions. However, the structure of the pericyclic geometry has yet to be observed experimentally. We use a combination of ultrafast electron diffraction and excited state wavepacket simulations to image structural dynamics through the pericyclic minimum of a photochemical electrocyclic ring-opening reaction in the molecule α-terpinene. The structural motion into the pericyclic minimum is dominated by rehybridization of two carbon atoms, which is required for the transformation from two to three conjugated π bonds. The σ bond dissociation largely happens after internal conversion from the pericyclic minimum to the electronic ground state. These findings may be transferrable to electrocyclic reactions in general.

Evaluating the predictive character of the method of constrained geometries simulate external force with density functional theory

Mechanochemistry is a fast-developing field of interdisciplinary research with a growing number of applications. Therefore, many theoretical methods have been developed to quickly predict the outcome of mechanically induced reactions. Constrained geometries simulate External Force (CoGEF) is one of the earlier methods in this field. It is easily implemented and can be conducted with most DFT codes. However, recently, we observed totally different predictions for model systems of epoxy resins in different conformations and with different density functionals. To better understand the conformational and functional dependence in typical CoGEF calculations we present a systematic evaluation of the CoGEF method for different model systems covering homolytic and heterolytic bond cleavage reactions, electrocyclic ring opening reactions and scission of non-covalent interactions in hydrogen-bond complexes. From our calculations we observe that many mechanochemical descriptors strongly depend on the functional used, however, a systematic trend exists for the relative maximum Force. In general, we observe that the CoGEF procedure is forcing the system to high energetic regions on the molecular potential energy profiles, which can lead to unexpected and uncorrelated predictions of mechanochemical reactions. This is questioning the true predictive character of the method.

A Look Inside the Black Box of Machine Learning Photodynamics Simulations.

Photochemical reactions are of great importance in chemistry, biology, and materials science because they take advantage of a renewable energy source, mild reaction conditions, and high atom economy. Light absorption can excite molecules to a higher energy electronic state of the same spin multiplicity. The following nonadiabatic processes induce molecular transformations that afford exotic molecular architectures and high-energy-isomers that are inaccessible by thermal means. Computational simulations now complement time-resolved instrumentation to reveal ultrafast excited-state mechanistic information for photochemical reactions that is essential in disentangling elusive spectroscopic features, excited-state lifetimes, and excited-state mechanistic critical points. Nonadiabatic molecular dynamics (NAMD), powered by surface hopping techniques, is among the most widely applied techniques to model the photochemical reactions of medium-sized molecules. However, the computational efficiency is limited because of the requisite thousands of multiconfigurational quantum-chemical calculations multiplied by hundreds of trajectories. Machine learning (ML) has emerged as a revolutionary force in computational chemistry to predict the outcome of the resource-intensive multiconfigurational calculations on the fly. An ML potential trained with a substantial set of quantum-chemical calculations can predict the energies and forces with errors under chemical accuracy at a negligible cost. The integration of ML potentials in NAMD dramatically extends the maximum simulation time scale by ∼10 000-fold to the nanosecond regime.In this Account, we present a comprehensive demonstration of ML photodynamics simulations and summarize our most recent applications in resolving complex photochemical reactions. First, we address three fundamental components of ML techniques for photodynamics simulations: the quantum-chemical data set, the ML potential, and NAMD. Second, we describe best practices in building training data and our procedure toward training the ML photodynamics model with our recent literature contributions. We introduce a convenient training data generation scheme combining Wigner sampling and geometrical interpolation. It trains reliable and effective ML potentials suitable for subsequent active learning to detect undersampled data. We demonstrate how active learning automatically discovers new mechanistic pathways and reproduces experimental results. We point out that atomic permutation is an essential data augmentation approach to improve the learnability of distance-based molecular descriptors for highly symmetric molecules. Third, we demonstrate the utility of ML-photodynamics by showing the results of ML photodynamics simulations of (1) photo-torquoselective 4π disrotatory electrocyclic ring closing of norbornyl cyclohexadiene, which reveals a thermal conversion from experimentally unobserved intermediates to the reactant in 1 ns; (2) [2 + 2] photocycloaddition of substituted [3]-syn-ladderdienes in competition with 4π and 6π electrocyclic ring-opening reactions, uncovering substituent effects to explain the reported increased quantum yield of substituted cubane precursors; and (3) photochemical 4π disrotatory electrocyclic reactions of fluorobenzenes in nanoseconds with XMS-CASPT2-level training data. We expect this Account to broaden understanding of ML photodynamics and inspire future developments and applications to increasingly large molecules within complex environments on long time scales.

Ultrafast Ring-Opening Reaction of 1,3-Cyclohexadiene: Identification of Nonadiabatic Pathway via Doubly Excited State.

The photoinduced ring-opening reaction of 1,3-cyclohexadiene (CHD) to produce 1,3,5-hexatriene (HT) plays an essential role in the photobiological synthesis of vitamin D3 in the skin. This reaction follows the Woodward-Hoffmann rule, and C5-C6 bond rupture via an electronically excited state occurs with conrotatory motion of the end CH2 groups. However, it is noted that the photoexcited S1(π,π*) state of CHD is not electronically correlated with the ground state of HT, and the reaction must proceed via nonadiabatic transitions. In the present study, we have clearly observed the nonadiabatic reaction pathway via the doubly excited state of CHD using ultrafast extreme UV photoelectron spectroscopy. The results indicate that the reaction occurs in only 68 fs and creates product vibrational coherence. Extensive computational simulations support the interpretation of experimental results and provide further insights into the electronic dynamics in this paradigmatic electrocyclic ring-opening reaction.

Design and synthesis of 1,8-naphthalimide functionalized benzothiadiazoles

Push-pull derivatives BTD2–BTD5 were designed and synthesized via Pd-catalyzed Sonogashira cross-coupling reaction followed by [2+2] cycloaddition–electrocyclic ring-opening reaction.

Multiconfigurational Calculations and Nonadiabatic Molecular Dynamics Explain Tricyclooctadiene Photochemical Chemoselectivity

Sunlight is a renewable energy source that can be stored in chemical bonds using photochemical reactions. The synthesis of exotic and strained molecules is especially attractive with photochemical techniques because of the associated efficient and mild reaction conditions. We have understood the photophysics and subsequent photochemistry of a possible cubane precursor, tricyclo[4,2,0,02,5]octa-3,7-diene with complete active space self-consistent field (CASSCF) calculations with an (8,7) active space and the ANO-S-VDZP basis set to. The CASSCF energies were corrected with a second-order perturbative correction CASPT2(8,7)/ANO-S-VDZP. The S0 → S1 vertical excitation energy of 1 is 6.25 eV, which is a π → π* excitation. The minimum energy path from the S1 Franck-Condon point leads to a 4π-disrotatory electrocyclic ring-opening reaction to afford bicyclo[4,2,0]octa-2,4,7-triene. The 2D potential energy surface scan located a rhomboidal S1/S0 minimum energy crossing point connecting 1 and cubane, suggesting that a cycloaddition is theoretically possible. We used the fewest switches surface hopping to study the photodynamics of this cycloaddition: 85% of 1722 trajectories relaxed to eight products; the major products are bicyclo[4,2,0]octa-2,4,7-triene (30%) and cycloocta-1,3,5,7-tetraene (32%). Only 0.4% of trajectories undergo a [2 + 2] cycloaddition to form cubane.

Synthesis of Dibenzoxazonines by Domino [2+2] Cycloaddition—4π Electrocyclic Ring Opening Reaction of Cyclic Imines with Ynamides

Synthesis of Dibenzoxazonines by Domino [2+2] Cycloaddition—4π Electrocyclic Ring Opening Reaction of Cyclic Imines with Ynamides

The Dewar Isomer of 1,2-Dihydro-1,2-azaborinines: Isolation, Fragmentation, and Energy Storage.

The photochemistry of 1,2-dihydro-1,2-azaborinine derivatives was studied under matrix isolation conditions and in solution. Photoisomerization occurs exclusively to the Dewar valence isomers upon irradiation with UV light (>280 nm) with high quantum yield (46 %). Further photolysis with UV light (254 nm) results in the formation of cyclobutadiene and an iminoborane derivative. The thermal electrocyclic ring-opening reaction of the Dewar valence isomer back to the 1,2-dihydro-1-tert-butyldimethylsilyl-2-mesityl-1,2-azaborinine has an activation barrier of (27.0±1.2) kcal mol-1 . In the presence of the Wilkinson catalyst, the ring opening occurs rapidly and exothermically (ΔH=(-48±1) kcal mol-1 ) at room temperature.

Orbital Phase Theory and the Diastereoselectivity of Some Organic Reactions

The orbital phase refers to the relationship between orbitals that originates from their wave character. We show here that the orbital phase essentially determines the diastereoselectivity of the following three organic reactions. 1) Torquoselectivity of the electrocyclicring-opening reaction of 3-substituted cyclobutenes; 2) Contradictory torquoselectivity of the retro-Nazarov reaction; 3) Diastereoselectivity in electrophilic addition to substituted ethylenes.

Accurate Isomerization Enthalpy and Investigation of the Errors in Density Functional Theory for Dihydroazulene/Vinylheptafulvene Photochromism Using Diffusion Monte Carlo

We investigate the isomerization enthalpy of the dihydroazulene/vinylheptafulvene (DHA/VHF) molecular photoswitch system derivatives using electronic structure calculation methods including density functional theory (DFT), quantum Monte Carlo (QMC), and coupled cluster (CCSD(T)). Recent efforts have focused on tuning the isomerization enthalpy of the photoswitch for solar thermal energy storage applications using substitutional functional groups on its five- and seven-membered carbon rings, predominantly using DFT for the energy predictions. However, using the higher accuracy QMC and CCSD(T) methods, we show that in many cases DFT incorrectly predicts the isomerization enthalpy, and the errors depend on the functional groups substituted and the choice of the DFT functional. Isomerization of the DHA to VHF molecule is an electrocyclic ring-opening reaction on the five-membered ring of the DHA isomer. We find that the DFT errors are correlated to the electrocyclic ring-opening reactions of cyclobutene and c...

Asymmetric Total Syntheses of Colchicine, β-Lumicolchicine, and Allocolchicinoid N-Acetylcolchinol-O-methyl Ether (NCME).

A concise and highly enantioselective synthesis of colchicine (>99% ee) in eight steps and 9.3% overall yield, without the need for protecting groups, was developed. A unique Wacker oxidation was used for enabling regioselective construction of the highly oxidized and synthetic challenging tropolone C-ring. Furthermore, asymmetric syntheses of β-lumicolchicine and N-acetylcolchinol-O-methyl ether (NCME) were achieved. Notably, NCME was synthesized from β-lumicolchicine by an unusual decarbonylation and electrocyclic ring-opening cascade reaction.

Synthesis of multi-substituted cyclobutenes: Cyclic strategy for [2 + 2] cycloaddition of ketene silyl acetals with propiolates

Cyclic ketene silyl acetals were utilized for [2 + 2] cycloaddition with propiolates to prevent an undesired electrocyclic ring opening reaction. Trimethylaluminum catalyzed this cycloaddition to afford the cyclobutene derivatives in high yields. The advantage of this reaction was highlighted by the successful application of β-substituted propiolates to afford the multi-substituted cyclobutenes. Furthermore, we applied this methodology to the late stage functionalization of natural product artemisinin.

Femtosecond x-ray spectroscopy of an electrocyclic ring-opening reaction.

The ultrafast light-activated electrocyclic ring-opening reaction of 1,3-cyclohexadiene is a fundamental prototype of photochemical pericyclic reactions. Generally, these reactions are thought to proceed through an intermediate excited-state minimum (the so-called pericyclic minimum), which leads to isomerization via nonadiabatic relaxation to the ground state of the photoproduct. Here, we used femtosecond (fs) soft x-ray spectroscopy near the carbon K-edge (~284 electron volts) on a tabletop apparatus to directly reveal the valence electronic structure of this transient intermediate state. The core-to-valence spectroscopic signature of the pericyclic minimum observed in the experiment was characterized, in combination with time-dependent density functional theory calculations, to reveal overlap and mixing of the frontier valence orbital energy levels. We show that this transient valence electronic structure arises within 60 ± 20 fs after ultraviolet photoexcitation and decays with a time constant of 110 ± 60 fs.

The trimerization of acetylenes involves a cascade of biradical and pericyclic processes.

Thorough computational studies were performed on mechanisms and energies for the thermal trimerizations of neutral or electron-rich acetylenes used as cross-linkers in organic hard-masks for lithography applications. These studies indicate that the operative mechanism proceeds through initial cyclobutadiene formation via a biradical mechanism. Cyclobutadienes form Dewar benzenes via Diels-Alder cycloadditions, or biradical processes, or both, before producing benzenes by electrocyclic ring-opening reactions. These pathways are preferred to alternatives involving concerted trimerizations or mechanisms involving carbene intermediates.

Cyclobutenes: At a Crossroad between Diastereoselective Syntheses of Dienes and Unique Palladium-Catalyzed Asymmetric Allylic Substitutions.

The rich chemistry of cyclobutanes is underpinned by a large body of synthetic literature devoted to their synthesis and decoration. This is motivated by the widespread representation of cyclobutane moieties in biologically active natural products and man-made molecules. Surprisingly, this vast array of knowledge finds no parallel in the chemistry of cyclobutenes, their unsaturated analogues. In particular, a dearth of methods to synthesize enantioenriched cyclobutenes is apparent upon cursory investigation of the literature. As a leading example, the photocycloaddition of maleic anhydride to acetylene or dichloroethylene, probably a benchmark of cyclobutene synthesis, delivers a meso cyclic anhydride which can be further converted to a cyclobutene product by enantioselective desymmetrization by ring opening. Nonetheless, such an approach delivers products with a rather inflexible substitution pattern around the four-membered ring. The lack of general approaches has motivated our group and others to develop novel routes to cyclobutene scaffolds, leading to the development of a strategy that combines photochemistry and catalysis. Indeed, we have coupled the simple and efficient photochemical isomerization of 2-pyrone into a strained bicyclo[2.2.0] lactone with palladium-catalyzed allylic alkylation as a simple and versatile access to functionalized cyclobutenes. Several nucleophiles can be added to the activated, strained intermediate, including malonate anions and azlactones. The products are mono- and bicyclic building blocks richly decorated with functional groups. Importantly, they are formed with high levels of diastereoselectivity as expected by the tenets of palladium-catalyzed allylic alkylation, which posit that the oxidative addition and nucleophilic capture steps proceed with inversion of configuration, resulting in overall retention (inversion + inversion). However, the transposition of the methodology to an asymmetric version subsequently led to the surprising discovery of a family of highly enantioselective, diastereodivergent catalytic processes. Indeed, we observed a ligand-dependent stereochemical outcome for a range of palladium-catalyzed allylic alkylations affording either overall retention or overall inversion of configuration, and that with very high levels of enantio- and diastereoselectivity. The new family of diastereodivergent reactions enables the conversion of the aforementioned racemic bicyclo[2.2.0] lactone into each of 4 stereoisomeric products, at will. Although the mechanistic details at the origin of this unusual stereodivergence are not yet fully elucidated, it became clear through our studies that unique Pd-allyl complexes, residing preferentially as their σ-(monohapto)-bound isomers, are at the heart of the process. The cyclobutenes prepared can also engage in electrocyclic ring-opening reactions (often spontaneous depending on the substitution pattern) that link this chemistry with that of diene and polyene frameworks. Using the strategies laid out above, our group was then able to harness the high stereospecificity of electrocyclic reactions and design modular syntheses of several natural products and natural product fragments. We believe that the methods presented herein shall soon pave the way for the streamlined synthesis of more complex polyenic natural products.

Photochemical locking and unlocking of an acyl nitroso dienophile in the Diels–Alder reaction

Photochromic Diels–Alder cycloadducts consisting of acyl nitroso dienophiles, which are known nitroxyl (HNO) donors, and dithienyldienes are presented. The dithienylethene-type photochromic cycloadducts were found to exhibit reversible electrocyclic ring closing and ring opening reactions to ‘lock’ or ‘unlock’ the retro Diels–Alder reaction, respectively. The release of an acyl nitroso dienophile via a retro Diels–Alder reaction at 92°C was shown to occur only from the open or ‘unlocked’ form of a photochromic dithienylcyclopentene and not from the closed or ‘locked’ isomer.

Biphenalenylidene: Isolation and Characterization of the Reactive Intermediate on the Decomposition Pathway of Phenalenyl Radical.

First isolation and characterization of biphenalenylidenes, which have long been unidentified reactive intermediates on the decomposition pathway of phenalenyl radical, were accomplished. Photoinduced electrocyclic ring-opening reaction of anti-dihydroperopyrene resulted in a successful conversion to E-biphenalenylidene, which enabled a detailed investigation of the electronic structure of E-biphenalenylidene by means of spectroscopic techniques. A stereoisomer, Z-biphenalenylidene, was also observed by suppressing a facile E-Z isomerization to E-biphenalenylidene in a rigid matrix. Furthermore, Z-biphenalenylidene demonstrated a thermal ring-closure in conrotatory process, which is not conforming to the Woodward-Hoffmann rule. These unusual reactivities of biphenalenylidene are ascribed to the ground states destabilized by its singlet biradical character, which was fully supported by theoretical calculations. The presence of E-biphenalenylidene on the decomposition pathway of phenalenyl was confirmed experimentally, leading to the full understanding of the decomposition mechanism of phenalenyl.

Enhanced Mechanophore Activation within Micelles

We describe the enhanced mechanophore activation within nanosized core–shell micelles, which also present temperature and ultraviolet (UV) light-responsive properties. The model micelle was fabricated by the self-assembly of an amphiphilic block copolymer of poly(tert-butyl acrylate-b-N-isopropylacrylamide) with one spiropyran (SP) moiety at the midpoint of chain [SP-(t-BA88-b-NIPAM62)2, P2]. Micellization of P2 in tetrahydrofuran (THF)/water mixed solvent enhanced the reactivity of the electrocyclic ring-opening reaction of SP to merocyanine (MC) isomer under sonication because micellization caused SP-centered PtBA block entangled and partially swelled in the micellar core and the increase of the dielectric constant of the medium around the SP, which could facilitate the conversion of SP to MC. This new enhanced mechanophore activation model demonstrated here is valuable as a probe to detect stress activation within nanosized particles and to design multiple-responsive materials.

Mono-, Di-, and Trifluoroalkyl Substituent Effects on the Torquoselectivities of Cyclobutene and Oxetene Electrocyclic Ring Openings.

The reactivities and torquoselectivities of electrocyclic ring opening reactions of fluoromethyl-substituted cyclobutenes and oxetenes were studied with M06-2X density functional theory. The torquoselectivities of a series of mono-, di-, and trifluoromethylcyclobutenes and oxetenes result from the interplay of favorable orbital interactions and closed-shell repulsions. When the substituent rotates inward, there can be a favorable interaction between the breaking σ(CO) bond and the σ(CF)* orbital (σ(CO) → σ(CF)*) of the fluoromethyl group in fluoromethyloxetenes. The preference for rotation of a fluoromethyl group is decreased in trifluoromethyloxetenes because closed-shell repulsions between the breaking σ(CO) bond and trifluoromethyl substituent orbitals compete with the σ(CO) → σ(CF)* interaction.