Four-membered Transition State Research Articles

Intramolecular Pericyclic Re-hydroboration via Six-membered Transition State: Synthesis of Fused Borolo[3,2-b]siloles.

We experimentally demonstrate a new type of the intramolecular reaction between non-activated alkyne units and the dialkylboryl group (9-BBN), which was previously only hypothesized and studied on a calculational level. The reaction described here can formally be classified as a 1,2-hydroboration reaction, but, in contrast to the classical mechanism via a cyclic four-membered transition state, the reaction proceeds by a pericyclic mechanism involving a six-membered transition state. In practice, the reaction allows the synthesis of a new class of the borolenes fused with silole or dihydrosilole units. Thus, the heating (125°C) of 2,3-dihydrosiloles or 2,3-dihydrosilolo[2,3-b]silole bearing 9-BBN and propargyl or dimethylpropargyl groups in positions 4 and 5, respectively, affords, in high to moderate yields, di- and tricyclic compounds containing a borolo[3,2-b]silole unit. In all cases, the reactions are accompanied by an unprecedented dehydroboration of the 9-BBN fragment, leading, in the final products, to a cyclooct-4-enyl group on the boron atom. The effects of the substituents on the rate and the selectivity of the reaction are discussed. The structures of all the new compounds have been determined from HRMS together with multinuclear 1D and 2D NMR spectroscopy, the results of which are in excellent agreement with DFT calculated chemical shifts.

The Unimolecular Chemistry of Methyl Chloroformate Ions and Neutrals: A Story of Near-Threshold Decomposition.

The near-threshold dissociation of ionized and neutral methyl chloroformate (CH3COOCl, MCF) was explored with imaging photoelectron photoion coincidence spectroscopy. The threshold photoelectron spectrum (TPES) for MCF was acquired for the first time; the large geometry changes upon ionization of MCF result in a broad, poorly defined TPES. Franck-Condon simulations are consistent with an adiabatic ionization energy (IE) of 10.90 ± 0.05 eV. Ionized MCF dissociates by chlorine atom loss at a measured 0 K appearance energy (AE) of 11.30 ± 0.01 eV. Together with the above IE, this AE suggests a reaction barrier of 0.40 ± 0.05 eV, consistent with the SVECV-f12 computational result of 0.41 eV. At higher internal energies, the loss of CH3O• becomes competitive due to its lower entropy of activation. Pyrolysis of neutral MCF formed the anticipated major products CH3Cl + CO2 (R1) and the minor products HCl + CO + CH2O (R2). The thermal decomposition products were identified by their photoion mass-selected threshold photoelectron spectrum (ms-TPES). Possible reaction pathways were explored computationally to confirm the dominant ones: R1 proceeds by a concerted Cl atom migration via a four-membered transition state in agreement with the mechanism proposed in the literature. R2 is a two-step reaction first yielding 2-oxiranone by HCl loss, which then decomposes to CH2O and CO. Kinetic modeling of the neutral decomposition could simulate the observed reactions only if the vibrational temperature of the MCF was assumed not to cool in the expansion.

A DFT Study of Imine Exchange Reactions in Iron(II)-Coordinated Pincers.

The imine bond is among the most applied motifs in dynamic covalent chemistry. Although its uses are varied and often involve coordination to a transition metal for stability, mechanistic studies on imine exchange reactions so far have not included metal coordination. Herein, we investigated the condensation and transimination reactions of an Fe2+-coordinated diimine pyridine pincer, employing wB97XD/6-311G(2d,2p) DFT calculations in acetonitrile. We first experimentally confirmed that Fe2+ is strongly coordinated by these pincers, and is thus a justified model ion. When considering a four-membered ring-shaped transition state for proton transfers, the required activation energies for condensation and transimination reaction exceeded values expected for reactions known to be spontaneous at room temperature. The nature of the incoming and exiting amines and the substituents on the para-position of the pincer had no effect on this. Replacing Fe2+ with Zn2+ or removing it altogether did not reduce it either. However, addition of two ethylamine molecules lowered the energy barriers to be compatible with experiment (19.4 and 23.2 kcal/mol for condensation and transimination, respectively). Lastly, the energy barrier of condensation of a non-coordinated pincer was significantly higher than found for Fe2+-coordinating pincers, underlined the catalyzing effect of metal coordination on imine exchange reactions.

Regio- and enantioselective CuH-catalyzed 1,2- and 1,4-hydrosilylation of 1,3-enynes

We report a copper-catalyzed ligand-controlled selective 1,2- and 1,4-hydrosilylation of 1,3-enynes, which furnishes enantiomerically enriched propargyl- and 1,2-allenylsilane products in high yields with excellent enantioselectivities (up to 99% ee). This reaction proceeds under mild conditions, shows broad substrate scope for both 1,3-enynes and trihydrosilanes, and displays excellent regioselectivities. Mechanistic studies based on deuterium-labeling reactions and density functional theory (DFT) calculations suggest that allenylcopper is the dominant reactive intermediate under both 1,2- and 1,4-hydrosilylation conditions, and it undergoes metathesis with silanes via selective four-membered or six-membered transition state, depending on the nature of the ligand. The weak interactions between the ligands and the reacting partners are found to be the key controlling factor for the observed regioselectivity switch. The origin of high enantiocontrol in the 1,4-hydrosilylation is also revealed by high level DLPNO-CCSD(T) calculations.

Organocatalytic Activation of Donor-Acceptor Cyclopropanes: A Tandem (3 + 3)-Cycloaddition/Aryl Migration toward the Synthesis of Enantioenriched Tetrahydropyridazines.

An organocatalytic enantioselective (3 + 3)-cycloaddition reaction of racemic cyclopropane carbaldehydes and aryl hydrazones has been demonstrated for the first time. A wide range of enantioenriched tetrahydropyridazines with an exocyclic double bond were obtained with moderate to good yields and good to excellent enantiomeric excesses. Mechanistic investigations hinted toward a matched/mismatched kinetic resolution, and control experiments and DFT calculations unveiled that 1,3-aryl migration was concerted and intramolecular and proceeds via a four-membered transition state.

Regioselective Derivatization of Silylated [20]Silafulleranes

Silafulleranes with endohedral Cl- ions are a unique, scarcely explored class of structurally well-defined silicon clusters and host-guest complexes. Herein, we report regioselective derivatization reactions on the siladodecahedrane [nBu4N][Cl@Si20(SiCl3)12Cl8] ([nBu4N][1]), which has its cluster surface decorated with 12 SiCl3 and 8 Cl substituents in perfect Th symmetry. The room-temperature reaction of [nBu4N][1] with excess iBu2AlH in ortho-difluorobenzene (oDFB) furnishes perhydrogenated [nBu4N][Cl@Si20(SiH3)12H8] ([nBu4N][2]) in 50% yield; the non-pyrophoric [2]- is the largest structurally authenticated (by X-ray diffraction) hydridosilane known to date. A simple switch from pure oDFB to an oDFB/Et2O solvent mixture suppresses core hydrogenation and results in the formation of [nBu4N][Cl@Si20(SiH3)12Cl8] ([nBu4N][3]). In addition to the exhaustive Cl/H exchange at all 44 Si-Cl bonds of [1]- and the regioselective 36-fold silyl group hydrogenation, we achieved the simultaneous introduction of Me substituents at all 8 SiCl vertices along with the conversion of all 12 SiCl3 to SiH3 groups by treating [nBu4N][1] with Me2AlH/Me3Al in oDFB ([nBu4N][Cl@Si20(SiH3)12Me8], [nBu4N][4]; 73%). Quantum-chemical free-energy calculations find an SN2-Si-type hydrogenation of the exohedral SiCl3 moieties in [1]- (trigonal-bipyramidal intermediate) slightly preferred over metathesis-like SNi-Si substitutions (four-membered transition state). Cage hydrogenation likely occurs via SNi-Si processes. The experimentally demonstrated influence of an Et2O co-solvent, which drastically increases the respective reaction barriers, is attributed to the increased stability of the resulting iBu2AlH-OEt2 adduct and its higher steric bulk compared to free iBu2AlH.

Pyrolytic elimination of ethylene from ethoxyquinolines and ethoxyisoquinolines: a computational study

This work reports a thermo-kinetic study on unimolecular thermal decomposition of some ethoxyquinolines and ethoxyisoquinolines derivatives (1-ethoxyisoquinoline (1-EisoQ), 2-ethoxyquinoline (2-EQ), 3-ethoxyquinoline (3-EQ), 3-ethoxyisoquinoline (3-EisoQ), 4-ethoxyquinoline (4-EQ), 4-ethoxyisoquinoline (4-EisoQ), 5-ethoxyquinoline (5-EQ), 5-ethoxyisoquinoline (5-EisoQ), 8-ethoxyquinoline (8-EQ) and 8-ethoxyisoquinoline (8-EisoQ)) using density functional theory DFT (BMK, MPW1B95, M06-2X) and ab initio complete basis set-quadratic Becke3 (CBS-QB3) calculations. In the course of the decomposition of the investigated systems, ethylene is eliminated with the production of either keto or enol tautomer. The six-membered transition state structure encountered in the path of keto formation is much lower in energy than the four-membered transition state required to give enol form. Rate constants and activation energies for the decomposition of 1-EisoQ, 2-EQ, 3-EQ, 3-EisoQ, 4-EQ, 4-EisoQ, 5-EQ, 5-EisoQ, 8-EQ, and 8-EisoQ have been estimated at different temperatures and pressures using conventional transition state theory combined with Eckart tunneling and the unimolecular statistical Rice–Ramsperger–Kassel–Marcus theories. The tunneling correction is significant at temperatures up to 1000 K. Rate constants results reveal that ethylene elimination and keto production are favored kinetically and thermodynamically over the whole temperature range of 400–1200 K and the rates of the processes under study increase with the rising of pressure up to 1 atm.

Catalytic, Z-Selective, Semi-Hydrogenation of Alkynes with a Zinc–Anilide Complex

The reversible activation of dihydrogen with a molecular zinc anilide complex is reported. The mechanism of this reaction has been probed through stoichiometric experiments and density functional theory (DFT) calculations. The combined evidence suggests that H2 activation occurs by addition across the Zn-N bond via a four-membered transition state in which the Zn and N atoms play a dual role of Lewis acid and Lewis base. The zinc hydride complex that results from H2 addition has been shown to be remarkably effective for the hydrozincation of C═C bonds at modest temperatures. The scope of hydrozincation includes alkynes, alkenes, and a 1,3-butadiyne. For alkynes, the hydrozincation step is stereospecific leading exclusively to the syn-isomer. Competition experiments show that the hydrozincation of alkynes is faster than the equivalent alkene substrates. These new discoveries have been used to develop a catalytic system for the semi-hydrogenation of alkynes. The catalytic scope includes both aryl- and alkyl-substituted internal alkynes and proceeds with high alkene: alkane, Z:E ratios, and modest functional group tolerance. This work offers a first example of selective hydrogenation catalysis using zinc complexes.

How to Break the Law: trans‐Hydroboration and gem‐Hydroboration of Alkynes

AbstractClassical hydroboration is the textbook example of an organometallic reaction under rigorous frontier orbital control: a synergetic bonding mode between substrate and reagent evolves into a four‐membered transition state that enforces syn/suprafacial delivery of H−BR2 to the π‐system. This strict stereochemical “law” remained valid for decades, even after the advent of metal‐catalyzed hydroboration. During the last decade, however, numerous possibilities emerged that allow this paradigm to be challenged. Thus, direct trans‐hydroboration of terminal as well as internal alkynes was achieved through radical, ionic, organocatalytic, and metal‐catalyzed manifolds, which are summarized in this review. Among them, pathways involving either metal vinylidenes (Rh, Ir, Ru, Fe) derived from terminal alkynes or metallacyclopropenes (η2‐vinylmetal complexes) derived from an internal triple bond and a [CpXRu]‐based catalyst represent the currently most widely applicable solutions. The latter type of intermediates is also accountable for the equally perplexing gem‐hydroboration of alkynes: geminal delivery of a borane to a triple bond has no precedent in the classical canon. The only forerunner was gem‐hydrogenation, which represents an unconventional yet highly useful entry into discrete ruthenium carbene complexes. The close mechanistic ties between these transformations are outlined, and brief reference is also made to remotely related reactions such as trans‐diboration and trans‐carboboration.

Hemiacetal-based dynamic systems: a new mechanistic insight.

The formation of hemiacetals from pyrazine trifluoromethylketone as a model receptor and four simple alcohols was studied by using quantum chemical calculations and NMR spectroscopy. Free energy profiles for four types of mechanistic pathways were calculated and discussed with respect to kinetic and thermodynamic measurements. We show that hemiacetal formation is facilitated by an assisted proton transfer process via a pseudo eight-membered transition state which brings the theory and experiment into close agreement. Also, a newly proposed mechanistic pathway for hemiacetal formation via a five-membered transition state leading to zwitterionic intermediates is discussed. Direct proton transfer in a pseudo four-membered transition state can be ruled out due to the high energy of transition states with respect to other mechanistic pathways. We also show that in the case of hemiacetals, water and alcohol molecules cannot account sufficiently for the H-transfer process via six-membered transition states.

Biomolecule-Compatible Dehydrogenative Chan-Lam Coupling of Free Sulfilimines.

Inspired by the discovery of a S═N bond in the collagen IV network and its essential role in stabilizing basement membranes, sulfilimines have drawn much attention in the fields of chemistry and biology. However, their further uptake is hindered by the lack of mild, efficient, and environmentally benign protocols by which sulfilimines can be constructed under biomolecule-compatible conditions. Here, we report a terminal oxidant-free copper-catalyzed dehydrogenative Chan-Lam coupling of free diaryl sulfilimines with arylboronic acids with excellent chemoselectivity and broad substrate compatibility. The mild reaction conditions and biomolecule-compatible nature allow the employment of this protocol in the late-stage functionalization of complex peptides, and more importantly, as an effective bioconjugation method as showcased in a model protein. A combined experimental and computational mechanistic investigation reveals that an inner-sphere electron-transfer process circumvents the sacrificial oxidant employed in traditional Chan-Lam coupling reactions. An energetically viable concerted pathway was located wherein a copper hydride facilitates hydrogen-atom abstraction from the isopropanol solvent to produce dihydrogen via a four-membered transition state.

Insights into the thermal degradation mechanisms of polyethylene terephthalate dimer using DFT method

The thermal degradation mechanisms of polyethylene terephthalate (PET) dimer were studied by the B3P86 density functional theory (DFT) approach at 6–31++G (d, p) base set in this paper. Seven possible reaction paths were designed and analyzed, and the thermodynamic parameters for all reactions were computed. The calculated results indicate that the bond dissociation energy values (BDEs) of C–C bonds on the main-chain are the smallest, followed by those of C–O bonds. The kinetics analysis indicates that the concerted reactions are obviously liable to occur rather than radical reactions in the initial thermal decomposition process. In the processes of initial reactions, all concerted reactions occurred by six-membered cyclic transition states (TSs) are more prone to carry out than those happened by four-membered cyclic transition states. The research results show that the primary products of PET dimer pyrolysis are terephthalic acid, vinyl terephthalate, CH3CHO and divinyl terephthalate. CH3CHO is mainly formed by a concerted reaction in the initial degradation process, and CO2 is mainly produced by the decarboxylation via a concerted reaction and CO is mainly produced by the decarbonylation of a radical in secondary degradation.

Diaryliodonium Salt-Based Synthesis of N-Alkoxyindolines and Further Insights into the Ishikawa Indole Synthesis.

A diaryliodonium salt-based strategy enabled the first systematic synthesis of rarely accessible N-alkoxyindolines. Mechanistic analyses suggested that the reaction likely involves reductive elimination of iodobenzene from iodaoxazepine via a four-membered transition state, followed by Meisenheimer rearrangement. Substrates with N-carbamate protection afforded indole in a manner similar to that of the Ishikawa indole synthesis. Preinstallation of a stannyl group as an iodonium salt precursor greatly expanded the substrate scope, and further mechanistic insights are discussed.

"Thermometer" Ions Can Fragment Through an Unexpected Intramolecular Elimination: These Are Not the Fragments You Are Looking For.

Benzylpyridinium analogs are effective thermometer ions since monitoring the formation of the benzylium fragment produced from heterolytic cleavage of the C-N bond can be linked to the ion's internal energy. In this study, three para-substituted benzylpyridinium ions containing ethoxy (OEt), isopropoxy (OiPr) and tert-butoxy (OtBu) substitutents were synthesized and evaluated as chemical thermometers. Intriguingly, the product ion spectra of the three benzylpyridinium ions were dominated by m/z 107 instead of the anticipated benzylium species. Deuterium labeling suggested that the m/z 107 fragment resulted from an intramolecular elimination (Ei), which formed via a four-membered transition state (TS). The fragmentation pathway appears to be an anomaly within the mass spectrometry literature, as four-membered pericyclic TSs are usually accompanied by the formation of an exceptionally stable neutral molecule (e.g., CO2). Quantum-chemical calculations confirmed our hypothesis that stabilization of the strained TS is afforded by hyperconjugation (ΔG‡ tert-butoxy < isopropyoxy < ethoxy).

Peptide Hydrolysis by Metal (Oxa)cyclen Complexes: Revisiting the Mechanism and Assessing Ligand Effects.

The mechanism responsible for peptide bond hydrolysis by Co(III) and Cu(II) complexes with (oxa)cyclen ligands has been revisited by means of computational tools. We propose that the mechanism starts by substrate coordination and an outer-sphere attack on the amide C atom of a solvent water molecule assisted by the metal hydroxo moiety as a general base, which occurs through six-membered ring transition states. This new mechanism represents a more likely scenario than the previously proposed mechanisms that involved an inner-sphere nucleophilic attack through more strained four-membered rings transition states. The corresponding computed overall free-energy barrier of 25.2 kcal mol-1 for hydrolysis of the peptide bond in Phe-Ala by a cobalt(III) oxacyclen catalyst (1) is consistent with the experimental values obtained from rate constants. Also, we assessed the influence of the nature of the ligand throughout a systematic replacement of N by O atoms in the (oxa)cyclen ligand. Increasing the number of coordinating O atoms accelerates the reaction by increasing the Lewis acidity of the metal ion. On the other hand, the higher reactivity observed for the copper(II) oxacyclen catalyst with respect to the analogous Co(III) complex can be attributed to the larger Brönsted basicity of the copper(II) hydroxo ligand. Ultimately, the detailed understanding of the ligand and metal nature effects allowed us to identify the double role of the metal hydroxo complexes as Lewis acids and Brönsted bases and to rationalize the observed reactivity trends.

Catalytic and non-catalytic hydroboration of carbonyls: quantum-chemical studies.

The addition of hydroboranes across several unsaturated moieties is a universal synthetic tool for the reduction or functionalization of unsaturated moieties. Given the sustainable nature of this process, the development of more environmentally-benign approaches (main-group catalysis or uncatalysed approaches) for hydroboration has gained considerable recent momentum. The present paper examines both catalyst-free and KF-mediated hydroboration of carbonyl compounds with the use of quantum-chemical methods. The results of computations for several potential reaction pathways are juxtaposed with experiment-based calculations, which leads to stepwise mechanisms and energy profiles for the reactions of pinacolborane with benzaldehyde and acetophenone (in the presence of KF). For each step of these reactions, we provide an accurate description of the geometric and electronic structures of corresponding stationary points. Five different levels of theory are employed to select the most applicable theoretical approach and develop a computational protocol for further research. Upon selection of the best-performing methods, larger molecular systems are studied to explore possible more complex pathways at the M06-2X/6-311++G(2d,p) and ωB97XD/6-311++G(2d,p) levels of theory, which brings up multi-pathway, overlapping catalytic cycles. The mechanism of solvent-free, catalyst-free hydroboration of aldehydes is also revisited through the prism of the elaborated methodology, which leads to a whole new perspective on the pathways of this and similar reactions, with a multimolecular cascade of hydride transfers being more energetically favoured than a four-membered transition state.

Hydroboration of carbonyls and imines by an iminophosphonamido tin(II) precatalyst.

A novel three-coordinated tin(II) chloride [Ph2P(NtBu)2]SnCl (1) supported by an N,N'-di-tert-butyliminophosphonamide having two phenyl groups on the phosphorus atom was synthesized by the reaction of the starting lithium iminophosphonamide [Ph2P(NtBu)2]Li with SnCl2·(dioxane) in toluene. The molecular structure of 1 was established by X-ray diffraction analysis. Tin(II) chloride 1 can act as an efficient precatalyst for the hydroboration of a wide variety of aldehydes, ketones, and imines at -10 °C. DFT calculations propose that hydroboration involves hydride transfer from the corresponding tin(II) hydride intermediate [Ph2P(NtBu)2]SnH (10) to the carbonyl substrates via four-membered transition states (TS-12), affording three-coordinated tin(II) alkoxide intermediates [Ph2P(NtBu)2]SnOR (13), followed by the stepwise reaction of 13 with HBpin (pin = pinacolate) to release the boronate esters and regenerate the tin(II) hydride 10. The stoichiometric reaction of the in site-generated 10 with benzophenone 2a at -10 °C led to the formation of 13. Moreover, 13 also stoichiometrically reacted with HBpin at -10 °C, forming the corresponding boronate ester 3a and 10 based on the 1H NMR spectrum of the reaction mixture.

Halogenated salt assisted Cu-catalyzed asymmetric 1,4-borylstannation of 1,3-enynes: enantioselective synthesis of allenylstannes.

An enantioselective 1,4-borylstannation of 1,3-enynes employed a chiral sulfoxide phosphine (SOP)/Cu complex as a catalyst, and the desired products, chiral allenylstannes, were first synthesized by asymmetric catalysis with satisfactory yields and enantioselectivies. In this protocol, a catalytic amount of additive, a halogenated salt, plays a crucial role in the success. Control experiments and theoretical studies disclosed that the four-membered ring transmetallation transition states which were stabilized by a halide anion are the key to yields and stereochemical outcomes.

Deoxygenative Tri- and Difluoromethylthiolation of Carboxylic Acids with Benzothiazolium Reagents.

Deoxygenative syntheses of fluorinated thioesters directly from carboxylic acids have been developed employing benzothiazolium reagents. The process using BT-SCF3 represents an attractive approach toward these SCF3-containing compounds that avoids the use of metal -SCF3 salts or preactivated acyl electrophiles. Moreover, the in situ activation of BT-SCF2H allows for an unprecedented nucleophilic difluoromethylthiolation reaction. DFT calculations support a mechanistic scenario involving a four-membered transition state where acyl substitution occurs without the formation of an unstable free -SCF2H anion.

Hydrolysis versus aminolysis of a potential nerve agent tabun: a computational reaction mechanism study

The mechanism for the hydrolysis and aminolysis reactions of potential nerve agent tabun have been investigated both at DFT/M062X level and at ab initio MP2 level of theory. Effect of solvent water has also been incorporated using Minnesota SMD model. Based on leaving groups, there are three probable dissociation pathways of tabun: (1) elimination of HCN, (2) elimination of dimethyl amine and (3) elimination of ethanol. Each of the pathways follows a stepwise neutral route through two transition states. From the mechanism, it has been established that the HCN removal pathway is most favorable than the other two due to greater leaving tendency of the cyanide group. The reaction possesses two four-membered transition state in each path, i.e., for the addition of ammonia/water and for the release of leaving groups. As the four-membered cyclic TSs are not so favorable, the investigated reactions were found quite a bit high energetic. The first addition step of the H2O or NH3 is found as the rate-determining step. The reactivity of ammonia toward tabun has been found highly favorable (by ~ 7.6 kcal mol−1) than the water. This can be easily explained using the fact that the nucleophilicity of NH3 is higher than the H2O. Further, we have seen that water can be a very effective catalyst in the aminolysis reaction as it reduces the barrier of activation of the RDS by ~ 10 kcal mol−1. Self-catalyzed hydrolysis of water has also been performed, and it decreases the activation of ~ 11 kcal mol−1 than the uncatalyzed pathways. The significant reduction of energy of activation takes place due to the formation of six-membered transition states that makes much easier hydrogen transfer compared to the four-membered transition state formed in case of uncatalyzed aminolysis reactions.