Five-membered Transition State Research Articles

Geminal Aminocyanation Enabled by Ylide Mediated Rearrangement.

Herein, we describe experimental and computational studies to understand the features of oxycyanopyridinium ylides generated in situ from oxy-cyanopyridines and rhodium carbene. This chemistry has enabled the concomitant formation of both C-N and C-C bonds, providing a complementary approach for cyanation reactions. Density functional theory calculations indicate the sequential metal-bound ylide formation, rhodium-associated five-membered transition state, and 1,4-cyano group relocation. Moreover, the enantioselective rearrangement has been realized by using chiral dirhodium complexes as the catalysts.

Oxy-pyridinium Ylides Mediated 1,4-Pyridyl/Aryl Translocation.

Molecular rearrangement via carbene transfer is a powerful tool to access molecular diversity. Herein, we describe an efficient approach to selective pyridyl/aryl relocation via a rhodium-catalyzed aminoarylation of diazo compounds, providing a promising strategy to access ortho-pyridyl N-alkylated pyridone scaffolds in a single operation. This reaction features the novel reactivity of oxy-pyridinium ylide, rhodium-associated five-membered transition state, and 1,4-pyridyl/aryl relocation. A computational study discloses the initial oxy-pyridinium ylide formation, keto-enol tautomerization, and 1,4-pyridyl migration to complete the whole rearrangement.

Protodemetalation of (Bipyridyl)Ni(II)-Aryl Complexes Shows Evidence for Five-, Six-, and Seven-Membered Cyclic Pathways.

Protonation of C-M bonds and its microscopic reverse, metalation of C-H bonds, are fundamental steps in a variety of metal-catalyzed processes. As such, studies on protonation of C-M bonds can shed light on C-H activation. We present here studies on the rate of protodemetalation (PDM) of a suite of arylnickel(II) complexes with various acids that provide evidence for a concerted, cyclic transition state for the PDM of C-Ni bonds and demonstrate that five-, six-, and seven-membered transition states are particularly favorable. Our data show that while the rate of protodemetalation of arylnickel(II) complexes scales with acidity for many acids, several are faster than predicted by pKa. For example, while acetic acid and acetohydroxamic acid are much less acidic than HCl, they both protodemetalate arylnickel(II) complexes significantly faster than HCl. Our data also show how in the case of acetohydroxamic acid, a seven-membered cyclic transition state (CH3C(O)NHOH) can be more favorable than a six-membered transition state (CH3C(O)NHOH). Similarly, five-membered transition states, such as for pyrazole, are highly favorable as well. Comparison of transition state polarization (from density functional theory) compares these new nickel transition states to better-studied precious-metal systems and demonstrates how the base can change the polarization of the transition state giving rise to opposing electronic preferences. Collectively, these studies suggest several new avenues for study in C-H activation as well as approaches to accelerate or slow protodemetalation in nickel catalysis.

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.

Iron-Catalyzed Enantioselective Radical Carboazidation and Diazidation of α,β-Unsaturated Carbonyl Compounds.

Azidation of alkenes is an efficient protocol to synthesize organic azides which are important structural motifs in organic synthesis. Enantioselective radical azidation, as a useful strategy to install a C-N3 bond, remains challenging due to the inherently instability and unique structure of radicals. Here, we disclose an efficient enantioselective radical carboazidation and diazidation of α,β-unsaturated ketones and amides catalyzed by chiral N,N'-dioxide/Fe(OTf)2 complexes. An array of substituted alkenes was transformed to the corresponding α-azido carbonyl derivatives in good to excellent enantioselectivities, benefiting the preparation of chiral α-amino ketones, vicinal amino alcohols, and vicinal diamines. Control experiments and mechanistic studies proved the radical pathway in the reaction process. The DFT calculations showed that the azido transferred to the radical intermediate via an intramolecular five-membered transition state with the internal nitrogen of the Fe-N3 species.

Circumambulatory Rearrangements of 5-Halo-1,2,3,4,5-pentaphenylcyclopentadienes

DFT quantum chemical calculations at the CAM-B3LYP/Def2TZVP level of theory showed that intramolecular migrations of halogens in 5-halo-1,2,3,4,5-pentaphenylcyclopentadienes (C5Ph5Hlg, Hlg = F, Cl, Br, I) involve chiral conformation of their molecules with a propeller arrangement of phenyl groups via 1,5-sigmatropic shifts around the five-membered ring through asymmetric transition states with energy barriers ΔE≠ZPE of 42.5 (F), 26.2 (Cl), 20.2 (Br), and 15.2 kcal/mol (I). The results were consistent with the data of dynamic NMR spectroscopy. The P and M enantiomers are readily interconvertible (ΔE≠ZPE = 1.7–3.7 kcal/mol) by way of synchronous flips of the phenyl groups. The calculated barriers to alternative 1,3-halogen shifts in C5Ph5Hlg are considerably higher than those for 1,5-shifts: ΔE≠ZPE = 60.7 (F), 38.6 (Cl), 32.0 (Br), and 27.9 kcal/mol (I).

Facile difluoromethylation of aliphatic alcohols with an S-(difluoro-methyl)sulfonium salt: reaction, scope and mechanistic study.

A facile and practical approach for the difluoromethylation of aliphatic alcohols with an S-(difluoromethyl)sulfonium salt was developed. A wide variety of alcohols with broad functional groups are compatible to furnish the corresponding alkyl difluoromethyl ethers in good to excellent yields under mild reaction conditions. Control experiments and DFT computational studies suggest that the difluoromethylation of alcohols mainly proceeds via a difluorocarbene pathway involving a five-membered transition state with the participation of water, whose crucial role in this reaction was also elucidated by control experiments.

Enantioselective 1,2-Anionotropic Rearrangement of Acylsilane through a Bisguanidinium Silicate Ion Pair.

Highly enantioselective bisguanidinium-catalyzed tandem rearrangements of acylsilanes are reported. The acylsilanes were activated via an addition of fluoride on the silicon to form a penta-coordinate anionic silicate intermediate. The silicate then underwent alkyl or aryl group migration from the silicon atom to the neighboring carbonyl carbon atom (1,2-anionotropic rearrangement), followed by [1,2]-Brook rearrangement to provide the secondary alcohols in high yields with excellent enantioselectivities (up to 95% ee). The isolation of an α-silylcarbinol intermediate as well as DFT calculations revealed that the 1,2-anionotropic rearrangement occurred via a bisguanidinium silicate ion pair, which is the stereodetermining step. The chiral center formed is then retained without inversion through the subsequent [1,2]-Brook rearrangement. Crotyl acylsilanes were smoothly transformed into homoallylic linear crotyl alcohols with retention of E/Z geometry, and no branched alcohols were detected. This clearly suggested that the 1,2-anionotropic rearrangement occurred through a three-membered instead of a five-membered transition state.

Oxidative Asymmetric [2 + 3] Annulation of Aldehydes with Azomethine Imines Enabled by N-Heterocyclic Carbene Catalysis.

An efficient asymmetric [2 + 3] annulation of simple aldehydes with N,N'-cyclic azomethine imines via oxidative N-heterocyclic carbene (NHC) catalysis is disclosed, affording bicyclic pyrazolidinones bearing two vicinal tertiary stereogenic centers with moderate to good yields (56-84% for 19 examples), good to excellent diastereoselectivities (>20:1 for 17 examples), and good to excellent enantioselectivities (66-98% for 19 examples). This direct α-carbon functionalization reaction of aldehyde can be readily performed on gram scale under mild conditions, and a five-membered transition state is proposed to rationalize the stereochemical outcome.

Mechanisms of reactions of sulfur hydride hydroxide: tautomerism, condensations, and C-sulfenylation and O-sulfenylation of 2,4-pentanedione.

The conformations, equilibrium structures, hydrogen bonds, and non-covalent interactions involved in the mechanisms of tautomerization, condensations, and C-sulfenylation and O-sulfenylation of 2,4-pentanedione by sulfur hydride hydroxide (hydrogen thioperoxide, oxadisulfane, H-SOH) have been studied using BD(T), CCSD(T), and QCISD(T) with the cc-pVTZ basis set and using B3LYP, B3PW91, CAM-B3LYP, PBE1PBE, PBEh1PBE, LC-ωPBE, M06-2X, and ωB97XD with the 6-311+G(d,p) basis set. All levels of theory predict the sulfenyl (H-SOH) tautomer of hydrogen thioperoxide to be lower in energy than the sulfinyl (H2S═O) tautomer. Four reasonable mechanisms were considered for the tautomerization of the sulfenyl tautomer of hydrogen thioperoxide to the sulfinyl tautomer: a cyclic three-membered water-free transition state (TS, CCSD(T) activation energy barrier E(⧧) = 65.1 kcal/mol), a cyclic five-membered transition state with one water molecule (TSH2O, E(⧧) = 31.1 kcal/mol), a cyclic seven-membered transition state with two water molecules (TS2H2O, E(⧧) = 14.5 kcal/mol), and a cyclic nine-membered transition state with three water molecules (TS3H2O, E(⧧) = 5.6 kcal/mol). The mechanisms involve hydrogen-bonded reactant complexes and hydrogen-bonded product complexes. The CCSD(T)-predicted energy barriers for the condensation of hydrogen thioperoxide to form thiosulfinic acid through transition states with zero, one, and two waters are E(⧧) = 42.0, 18.3, and 0 kcal/mol, respectively. Mixed condensation reactions are predicted to afford organosulfur products and compounds containing sulfur-selenium bonds. Hydrogen thioperoxide is predicted to add to 2,4-pentanedione to form C-sulfenylated (sulfide, thioether) and O-sulfenylated (sulfenate ester) products. Similar mechanistic trends and reaction pathways are observed in the tautomerism, condensations, and C-sulfenylation and O-sulfenylation reactions of hydrogen thioperoxide. The water molecules set up proton relay networks (bridges) that reduce ring strain, generate favorable conformations for reactivity, lower energy barriers, and increase the numbers of stabilizing hydrogen bonds and nonbonding interactions.

Theoretical study on the reaction mechanism of carbon dioxide reduction to methanol using a homogeneous ruthenium(II) phosphine catalyst

Quantum-chemical calculations using the density functional TPSS were carried out for the catalytic reduction of carbon dioxide to methanol using a ruthenium catalyst and hydrogen gas. Preparation of the active species as well as the catalytic cycle were modeled on the quantum-chemical level with solvent effects included by means of a continuum solvation model. Outer as well as inner sphere mechanisms were considered to gain insight into the details of carbon dioxide reduction using a ruthenium(II) catalyst. The overall Gibbs free reaction energy for CO2+3 H2→MeOH+H2O is computed to be −13.0kJ/mol. The highest reaction barrier (112.4kJ/mol) is found for the outer sphere hydrogen transfer from the active ruthenium species to carbon dioxide via a five-membered transition state structure.

Kinetic control in the formation of meso-dithia[3.3]-paracyclophane S,S′-dioxide

meso-(R,S)-Dithia[3.3]-paracyclophane S,S′-dioxide is formed with complete stereoselection by the thermolysis of 3,3′-[1,4-phenylene-bis(methylenesulfinyl)]-dipropanoate—that generates in situ two transient sulfenic acid functions—in the presence of p-diethynylbenzene. By employing an improved procedure that we have recently optimized, the title compound has been prepared in a 70% yield as a single diastereoisomer. A density functional B3LYP/6-311+G(d,p) study demonstrates that the final syn-addition cyclization step takes place under kinetic control, through a five-membered transition state that defines the stereochemistry of the resulting cyclophane.

Computational insight of the mechanism of Algar–Flynn–Oyamada (AFO) reaction

The present DFT investigation supports a previous conclusion of Dean et al. that hydroxylation occurs without epoxide intermediate at room temperature due to a strong electrostatic interaction of peroxide ions with π electrons of CC bonds of chalcone, and 3-hydroxyflavone has been found to be the major product. The calculated activation energy difference (ΔG#) of initial enolization followed by hydroxylation or simultaneous cyclization and hydroxylation has been found to be negligible (∼4 kcal mol−1). On the other hand, epoxide formation requires significant activation energy, which is supposed to occur at high temperatures. In addition, if epoxide is formed, the ring opens by an attack of phenolic oxygen, occurring preferentially at α position via a five-member transition state due to a low activation barrier height (19.82 kcal mol−1 in the gas phase and 19.55 kcal mol−1 in ethanol) compared to that of a six-member transition state (44.41 kcal mol−1 at B3LYP in the gas phase and 38.55 kcal mol−1 in ethanol). It is also observed that the solvation study does not affect the main conclusion of the paper. These findings also support the previous observation of Dean et al. Predicted ΔG# in different DFT functionals are consistent, although the total energy is significantly different.

The positive role of cadmium in TS-1 catalyst for butadiene epoxidation

A series of Cd modified titanium silicalite 1 catalysts with different Cd content (xCd-TS-1, x=1–15) were successfully prepared by ultrasound impregnation. Epoxidation of butadiene over these catalysts were investigated using hydrogen peroxide as oxidant, which indicated that Cd greatly improve the catalytic performance of TS-1 and the selectivity of epoxide. Various characterization methods including quantum chemical calculation were employed to explore the specific roles of Cd in promoting TS-1 catalytic activity. Theoretical calculation consistently suggested TiO bond were weakened owing to the introduction of Cd, which resulted in the structure of Cd-TS-1 becoming more relaxant. As a consequence, it is favorable to methanol solvent and H2O2 interacting with the Ti active site to form five-member transition state during reaction. It was observed that catalysts modified with 1–5wt% Cd presented both high catalytic activity and good reusability. The highest yield of 0.63mol/L of vinyloxirane (VO) was obtained, while turnover number (TON, determined as the molar VO obtained per molar Ti atom) could reach to 1466.

Reactions of aminyl radicals during radiolysis and photolysis of aqueous solutions of amino alcohols and their derivatives

It has been found that the radiolysis of the aqueous solutions of α,β-amino alcohols leads to the formation of degradation products of the parent substances. The experimental data suggest that the degradation process includes the stage of the formation of aminyl radicals, which undergo decomposition with the simultaneous cleavage of -C-C- and -O-H bonds through a five-membered transition state. The radiation-induced degradation of amino alcohols is enhanced in an alkaline medium, in which the amino group is deprotonated, and is blocked via the etherification of the hydroxyl group in the parent substances or the introduction of reducing agents.

DFT studies on the mechanism of the conversion of thiols into disulfides and dihydrogen catalyzed by CpMn(CO)3 complex

A mechanism for conversion of thiols into disulfides and dihydrogen catalyzed by CpMn(CO)3 was studied in detail with the aid of density functional theory computations. Four major steps are involved in both of the two possible pathways (path1 and path2): (1) a ligand substitution process (dissociation of one carbonyl ligand and subsequent addition of RSH to the metal center); (2) intermolecular hydride migration; (3) addition of RSH and release of dihydrogen; (4) production of S2R2 and regeneration of the catalyst. Migration of the hydrogen from RSH to Cp ring can not be completed in one step, but need to form the key intermediate CpMnH(CO)2SR first. Ligand substitution process is the rate-determined reaction step. Path1 is the dominant pathway compared with path2, which mainly results from difficult formation of the five-member transition state in path2.

A novel hydrogen migration of dialkylphosphonic acid esters using electrospray ionization tandem mass spectrometry

In this paper, attention is focused on analysis of the fragmentation of α-hydroxy-β-amino phosphonate esters designed as inhibitors of protein kinase A. An interesting proton migration mechanism in the cleavage of the P-C bond is investigated by electrospray ionization tandem mass spectrometry. A possible rearrangement mechanism is proposed and verified by high-resolution mass spectra using isotope deuterium/hydrogen-exchange technology and additionally checked by detailed DFT calculation based on Gaussian software. The result clearly indicates that this mechanism proceeds by a five-membered ring concerted transition state with activation energy 11.3 kcal mol(-1) for the compound 3f. The overall reaction is endothermic with an energy 13.2 kcal mol(-1). The effect of different substituents and different metal ions for rearrangement of these esters is studied by experiment and theory. It is concluded that this rearrangement process is energetically unfavorable and hence only occurs in the mass spectrometer.

Pyrolysis of tert-Butyl tert-Butanethiosulfinate, t-BuS(O)St-Bu: A Computational Perspective of the Decomposition Pathways

A systematic theoretical study has been performed on the low pressure thermal decomposition pathways of t-BuS(O)St-Bu using the CCSD(T)/cc-pV(D+d)Z//B3LYP/6-311++G(2d,2p), CCSD(T)/cc-pV(D+d)Z//PBEPBE/6-311++G(2d,2p), and G3B3 level of theories. Rate constants for the unimolecular decomposition pathways are calculated using Rice−Ramsperger−Kassel−Marcus (RRKM) theory. On the basis of the experimental observation and theoretical predictions, the pyrolysis channels are considered as primary and secondary pyrolysis reactions. The primary decomposition via a five-membered transition state leads to the formation of tert-butanethiosulfoxylic acid (t-BuSSOH) and 2-methylpropene (C4H8) almost exclusively having low-pressure limit rate constant k(1)(0) = 4.67 × 10(−6)T(−4.67) exp(−11.64 kcal mol(−1)/RT) cm3 mol(−1) s(−1) (T = 500−800 K). The primary decomposition via a six-membered transition state is also identified, and that leads to the tert-butanethiosulfinic acid t-BuS(OH)S, which is the branched chain isomer of t-BuSSOH. The formation of t-BuSSOH is thermodynamically as well as kinetically favorable over t-BuS(OH)S formation, and therefore the second product could not be found experimentally. Furthermore, calculation on secondary pyrolysis pathways involving the decomposition of t-BuSSOH leads to the formation of 1-oxatrisulfane (trans-HSSOH and cis-HSSOH) and their branched isomer S(SH)OH. These three secondary product formation rates are competitive, but thermodynamics do not favor the formation of the branched isomer. Among the secondary pyrolysis products, trans-HSSOH is the most stable one, and its formation rate constant at low pressure is calculated to be k(3)(0) = 5.49 × 10(28)T(−10.70) exp(−36.22 kcal mol(−1)/RT) cm3 mol(−1) s(−1) (T = 800−1500 K). Finally, the secondary pyrolysis pathway from less stable product t-BuS(OH)S is also predicted, and that leads to trans-HSSOH and cis-HSSOH products with almost equal rates. A bond-order analysis using Wiberg bond indexes obtained by natural bond orbital (NBO) calculation predicts that the primary and secondary pyrolysis of t-BuS(O)St-Bu occur via E1-like mechanism.

New insight into the formation mechanism of imidazolium-based halide salts

By performing density functional theory calculations, the Menshutkin reaction between the N-methyl imidazole with chloroethane is reexamined to rationalize the experimental discovery. The calculated results show that the reaction proceeds via a S(N)2 mechanism with a barrier of 119.1 kJ mol(-1) which is much lower than that reported in previous literature according to a five-membered transition state mechanism. Moreover, it is found that the barrier is further reduced to 98.1 kJ mol(-1) in toluene solution. The present result validates the experimental finding that the Menshutkin reaction for synthesizing N-alkyl imidazolium halide salts proceed smoothly at lower heating temperature.

Diastereo‐ and Enantioselective Hydrogenation of α‐Amino‐β‐Keto Ester Hydrochlorides Catalyzed by an Iridium Complex with MeO‐BIPHEP and NaBArF: Catalytic Cycle and Five‐Membered Chelation Mechanism of Asymmetric Hydrogenation

The development of Ir-catalyzed asymmetric hydrogenation of α-amino-β-keto ester hydrochlorides is described. This reaction proceeds through a dynamic kinetic resolution to produce anti-β-hydroxy-α-amino acid esters in a high diastereo- and enantioselective manner. Mechanistic studies have revealed that this unique asymmetric hydrogenation proceeds through reduction of the ketone moiety via the five-membered transition state involving the chelation between the oxygen of the ketone and the nitrogen of the amine function. The relationship studies between the hydrogen pressure and the stereoselectivity have disclosed two mechanisms dependent on hydrogen pressure. Under low hydrogen pressure (<15 atm), the reaction rate proportionally increased with the hydrogen pressure. However, under the high hydrogen conditions, the reaction rate exponentially accelerated along with the increasing hydrogen pressure, which suggests the participation of two or more of hydrogen atoms.