Comparison of amine-induced cyclization of 6-chloro-1-hexynylphosphonate and isobutyl 7-chlorohept-2-ynoate

The reaction of 6-chloro-1-hexynylphosphonate with primary and secondary amines afforded exclusively 2-aminocyclohexenylphosphonates in 62-85% isolated yields. In contrast, reaction of various amines with isobutyl 7-chlorohept-2-ynoate in acetonitrile at 70 °C gave (E)-sec-butyl 2-(1-alkylpiperidin-2-ylidene)acetates in 65-78% isolated yields. Calculations offer an explanation for the difference in the behavior of the two compounds classes. It is shown that C-C cyclization in the alkyne-phosphonate group occurs via an initial formation of a zwitterionic intermediate, which is stabilized by both an inductive effect of the phosphonate group and a newly formed hydrogen bond. The alkyne-carboxylate group, on the other hand, proceeds via enamine formation as a result of the smaller inductive effect of the carboxylate combined with involvement of an allene-like resonance form. This resonance form both delocalizes the negative charge in the zwitterionic intermediate making it to be less available for attack, and affects the geometry thus preventing formation of the stabilizing hydrogen bond. Hence, the zwitterionic intermediate of the alkyne-carboxylates is less stable leading to formation of an enamine, which is followed by N-C cyclization to give the azaheterocycles.     

A mechanistic investigation into the zinc carbenoid-mediated homologation reaction by DFT methods: is a classical donor-acceptor cyclopropane intermediate involved?

An extensive density functional theory (DFT, M05-2X) investigation has been performed on the zinc carbenoid-mediated homologation reaction of β-keto esters. The mechanistic existence of a classical donor-acceptor cyclopropane intermediate was probed to test the traditional school of thought regarding these systems. Calculations of the carbenoid insertion step, following enolate formation, unmasked two possible pathways. Pathway B was shown to explain the proposed, but spectroscopically unobservable donor-acceptor cyclopropane intermediate, while the second (pathway A) reveals an alternative to the classical intermediate in that a cyclopropane transition state leads to product.     

Ethylene biosynthesis by 1-aminocyclopropane-1-carboxylic acid oxidase: a DFT study

The reaction catalyzed by the plant enzyme 1-aminocyclopropane-1-carboxylic acid oxidase (ACCO) was investigated by using hybrid density functional theory. ACCO belongs to the non-heme iron(II) enzyme superfamily and carries out the bicarbonate-dependent two-electron oxidation of its substrate ACC (1-aminocyclopropane-1-carboxylic acid) concomitant with the reduction of dioxygen and oxidation of a reducing agent probably ascorbate. The reaction gives ethylene, CO(2), cyanide and two water molecules. A model including the mononuclear iron complex with ACC in the first coordination sphere was used to study the details of O-O bond cleavage and cyclopropane ring opening. Calculations imply that this unusual and complex reaction is triggered by a hydrogen atom abstraction step generating a radical on the amino nitrogen of ACC. Subsequently, cyclopropane ring opening followed by O-O bond heterolysis leads to a very reactive iron(IV)-oxo intermediate, which decomposes to ethylene and cyanoformate with very low energy barriers. The reaction is assisted by bicarbonate located in the second coordination sphere of the metal.     

Rare beryllium icosahedra in the intermediate valence compound CeBe13

Single-crystal X-ray diffraction experiments show that the Be atoms in CeBe13 form a Be12 icosahedra, which is a very unusual structural feature due, in part, to the remarkably low valence electron count of Be. Magnetization studies show that CeBe13 displays intermediate valence behavior, in which valence fluctuations between the Ce 4f0 and 4f1 states give rise to enhanced electronic specific heat and magnetic susceptibility. Calculations using ab initio theory were used to determine the electronic structure and bonding and to give insight into the relationship between the crystal structure, the bonding, and the intermediate valence behavior of CeBe13. The hybridization between the localized f electrons and the conduction electrons is responsible for the large values of the electronic specific heat coefficient (gamma approximately 100 mJ/mol K2) and magnetic susceptibility (chi approximately 1 x 10-3 emu/mol), which is in marked contrast to those of ordinary metals that have gamma approximately 1 mJ/mol K2 and chi approximately 1 x 10-5 emu/mol values. The magnetic susceptibility, chi = M/H versus T, of a single crystal of CeBe13 exhibits a broad maximum at Tmax approximately 130 K and is typical of intermediate valence systems with an unusually large energy scale (Kondo), TK approximately 500 K.     

CDW and CDW-EIS investigations in an independent electron approximation for the resonant double electron capture by swift He2+ in helium

The CDW and CDW-EIS approximations are used to study the resonant double electron capture by He²⁺ in helium at intermediate and high impact velocities. Calculations of the total cross sections as a function of the impact energy are performed in an Independent Electron Approximation. A very good agreement with recent experimental data for capture into all states of the projectile is found although neither angular nor dynamical electron correlations are included in the calculations.     

Imine hydrosilylation using an iron complex catalyst: A computational study

The reaction mechanism for imine hydrosilylation in the presence of an iron methyl complex and hydrosilane was studied using density functional theory at the M06/6-311G(d,p) level of theory. Benzylidenemethylamine (PhCH = NMe) and trimethylhydrosilane (HSiMe₃) were employed as the model imine and hydrosilane, respectively. Hydrosilylation has been experimentally proposed to occur in two stages. In the first stage, the active catalyst (CpFe(CO)SiMe₃, 1 ) is formed from the reaction of pre-catalyst, CpFe(CO)₂Me, and hydrosilane through CO migratory insertion into the Fe Me bond and the reaction of the resulting acetyl complex intermediate with hydrosilane. In the second stage, 1 catalyzes the reaction of imine with hydrosilane. Calculations for the first stage showed that the most favorable pathway for CO insertion involved a spin state change, that is, two-state reactivity mechanism through a triplet state intermediate, and the acetyl complex reaction with HSiMe₃ follows a σ-bond metathesis pathway. The calculations also showed that, in the catalytic cycle, the imine coordinates to 1 to form an Fe C N three-membered ring intermediate accompanied by silyl group migration. This intermediate then reacts with HSiMe₃ to yield the hydrosilylated product through a σ-bond metathesis and regenerate 1 . The rate-determining step in the catalytic cycle was the coordination of HSiMe₃ to the three-membered ring intermediate, with an activation energy of 23.1 kcal/mol. Imine hydrosilylation in the absence of an iron complex through a [2 + 2] cycloaddition mechanism requires much higher activation energies. © 2018 Wiley Periodicals, Inc.     

The stepwise Diels-Alder reaction of 4-nitrobenzodifuroxan with Danishefsky's diene

The Diels–Alder reaction of 4‐nitrobenzodifuroxan (NBDF) with 1‐methoxy‐3‐trimethylsilyloxy‐1,3‐butadiene has been investigated experimentally and theoretically. Treatment of NBDF with excess diene in chloroform at room temperature was found to afford a single product that contained a carbonyl functionality. Based on an X‐ray structure and NMR spectroscopic data, the product appeared to be a result of the hydrolysis of the OSiMe₃ moiety of the thermodynamically more stable endo [2+4] cycloadduct, characterized by a cis arrangement of the MeO and NO₂ functionalities. In situ NMR investigations of the interaction were carried out at room temperature in CDCl₃ and at ?40 °C in deuterated acetonitrile. Calculations at the B3LYP/6‐31G* level in the gas phase and in acetonitrile were carried out under the assumption that the most stable cis conformation of the diene is also the most reactive in the interaction. The analysis revealed the NBDF/cis diene interaction involves the formation of a zwitterionic intermediate. Importantly, this intermediate is formed in two preferred conformations, which correspond to the endo and exo modes of approach of the reagents. Cyclization of these two identified conformations afforded the experimentally characterized endo and exo [2+4] cycloadducts. According to the calculations, the interconversion of the two conformers can either take place through a return to the pre‐reaction complexes or it can occur by rotation through an intermediate conformation of lesser stability. In view of the stepwise character of the interaction, the possibility that the intermediate zwitterion is the result of the interaction between NBDF and the trans diene could not be excluded. Calculations carried out with the most stable and more populated s‐trans conformer confirmed this idea and supported the role of the zwitterion in the overall interaction.     

CNDO/2 calculations and energy partitioning in the formation of acrylonitrile and propiolonitrile from acetylene and hydrocyanic acid

Calculations within the CNDO/2 approximation have been performed on HCN and HCCH oriented in a variety of ways with respect to each other. Total electronic energies and partitioned energies have been obtained which predict that an intermediate forms. Additional calculations on a variety of related configurations have also been carried out and a qualitative mechanism for the homogeneous, high temperature formation of both acrylonitrile and propiolonitrile from HCN and HCCH has been proposed.     

On the stability of the π-allyl intermediate in molybdenum-catalyzed asymmetric alkylations

Density functional theory calculations were performed on the apparent η³-π-allyl molybdenum intermediate that is observed during molybdenum-catalyzed asymmetric allylation [Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5379]. The relative stabilities of geometric isomers, diastereoisomers, and π-allyl rotamers of the π-allyl molybdenum intermediate were investigated. Calculations show that the observed intermediate is the most stable because of two factors: (1) the observed π-allyl molybdenum intermediate maximizes the bonding and back-bonding interactions between molybdenum and the π-allyl ligand; and (2) the observed π-allyl molybdenum intermediate minimizes the steric interactions between the chiral ligand and the π-allyl group.     

Mechanism of the tyrosine ammonia lyase reaction-tandem nucleophilic and electrophilic enhancement by a proton transfer

Quantum mechanics/molecular mechanics calculations in tyrosine ammonia lyase (TAL) ruled out the hypothetical Friedel-Crafts (FC) route for ammonia elimination from L-tyrosine due to the high energy of FC intermediates. The calculated pathway from the zwitterionic L-tyrosine-binding state (0.0?kcal mol(-1)) to the product-binding state ((E)-coumarate+H(2)N-MIO; -24.0?kcal mol(-1); MIO = 3,5-dihydro-5-methylidene-4H-imidazol-4-one) involves an intermediate (IS, -19.9?kcal mol(-1)), which has a covalent bond between the N atom of the substrate and MIO, as well as two transition states (TS1 and TS2). TS1 (14.4?kcal mol(-1)) corresponds to a proton transfer from the substrate to the N1 atom of MIO by Tyr300-OH. Thus, a tandem nucleophilic activation of the substrate and electrophilic activation of MIO happens. TS2 (5.2?kcal mol(-1)) indicates a concerted C-N bond breaking of the N-MIO intermediate and deprotonation of the pro-S β position by Tyr60. Calculations elucidate the role of enzymic bases (Tyr60 and Tyr300) and other catalytically relevant residues (Asn203, Arg303, and Asn333, Asn435), which are fully conserved in the amino acid sequences and in 3D structures of all known MIO-containing ammonia lyases and 2,3-aminomutases.     

Mechanism of the Tyrosine Ammonia Lyase Reaction—Tandem Nucleophilic and Electrophilic Enhancement by a Proton Transfer

Quantum mechanics/molecular mechanics calculations in tyrosine ammonia lyase (TAL) ruled out the hypothetical Friedel–Crafts (FC) route for ammonia elimination from L ‐tyrosine due to the high energy of FC intermediates. The calculated pathway from the zwitterionic L ‐tyrosine‐binding state (0.0 kcal mol^?1) to the product‐binding state ((E)‐coumarate+H₂N? MIO; ?24.0 kcal mol^?1; MIO=3,5‐dihydro‐5‐methylidene‐4H‐imidazol‐4‐one) involves an intermediate (IS, ?19.9 kcal mol^?1), which has a covalent bond between the N atom of the substrate and MIO, as well as two transition states (TS1 and TS2). TS1 (14.4 kcal mol^?1) corresponds to a proton transfer from the substrate to the N1 atom of MIO by Tyr300? OH. Thus, a tandem nucleophilic activation of the substrate and electrophilic activation of MIO happens. TS2 (5.2 kcal mol^?1) indicates a concerted C? N bond breaking of the N‐MIO intermediate and deprotonation of the pro‐S β position by Tyr60. Calculations elucidate the role of enzymic bases (Tyr60 and Tyr300) and other catalytically relevant residues (Asn203, Arg303, and Asn333, Asn435), which are fully conserved in the amino acid sequences and in 3D structures of all known MIO‐containing ammonia lyases and 2,3‐aminomutases.     

Density functional theory study on the mechanism of Rh-catalyzed decarboxylative conjugate addition: diffusion- and ligand-controlled selectivity toward hydrolysis or β-hydride elimination

The mechanism of Rh-catalyzed decarboxylative conjugate addition has been investigated with Density Functional Theory (DFT). Calculations indicate that the selectivity toward hydrolysis or β-hydride elimination of the investigated reaction is a compromise between diffusion control and kinetic control. Ligand control can be adjusted by modifying the intermolecular interaction between the Rh(I) enolate intermediate and water.     

Detection of ClSO with time-resolved Fourier-transform infrared absorption spectroscopy

ClSO was produced as an intermediate upon irradiating a flowing mixture of Cl2SO and Ar with a KrF excimer laser at 248 nm. A step-scan Fourier-transform infrared spectrometer coupled with a small multipass absorption cell was employed to detect time-resolved absorption spectrum of ClSO. A transient spectrum in the region 1120-1200 cm(-1), which diminished on prolonged reaction, is assigned to the S-O stretching (nu1) mode of ClSO. A spectrum with a resolution of 0.3 cm(-1) partially reveals rotational structure with the Q-branch at 1162.9 cm(-1). Calculations with density-functional theory (B3LYP/aug-cc-pVTZ) predict the geometry, vibrational, and rotational parameters of ClSO. An IR absorption spectrum of ClSO simulated based on predicted rotational parameters agrees satisfactorily with experimental results. ClSO produced from photolysis of Cl2SO at 248 nm is internally hot.     

Activation of leinamycin by thiols: a theoretical study

Reaction of thiols with the 1,2-dithiolan-3-one 1-oxide heterocycle found in leinamycin (1) results in the conversion of this antitumor antibiotic to a DNA-alkylating episulfonium ion (5). While the products formed in this reaction have been rationalized by a mechanism involving initial attack of thiol on the central sulfenyl sulfur (S2') of the 1,2-dithiolan-3-one 1-oxide ring, the carbonyl carbon (C3') and the sulfinyl sulfur (S1') of this heterocycle are also expected to be electrophilic. Therefore, it is important to consider whether nucleophilic attack of thiol at these sites might contribute either to destruction of the antibiotic or conversion to its episulfonium ion form. To address this question, we have used computational methods to examine the attack of methyl thiolate on each of the three electrophilic centers in a simple analogue of the 1,2-dithiolan-3-one 1-oxide heterocycle found in leinamycin. Calculations were performed at the MP2/6-311+G(3df,p)//B3LYP/6-31G level of theory with inclusion of solvent effects. The results indicate that the most reasonable mechanism for thiol-mediated activation of leinamycin involves initial attack of thiolate at the S2'-position of the antibiotic's 1,2-dithiolan-3-one 1-oxide heterocycle, followed by conversion to the 1,2-oxathiolan-5-one intermediate (3).     

Unraveling gold(I)-specific action towards peptidic disulfide cleavage: a DFT investigation

Ground-state disulfide dissociation is a target of prime importance in structural biochemistry. A main difficulty consists in avoiding competition with carbon–sulfur and backbone scission pathways. In tandem mass spectrometry, such selectivity is afforded using transition elements or coinage-metal ions as catalyst. Yet, the underlying gas-phase mechanistic details remain poorly understood. Gold(I)-assisted disulfide cleavage is investigated by means of DFT calculations, to elucidate the highly selective and specific catalytic action of this transition-metal cation, a most promising one in tandem mass spectrometry. The preferential cleavage of sulfur–sulfur versus carbon–sulfur linkages on dimethyldisulfide, taken as a prototypical aliphatic compound, is rationalized on the basis of molecular orbital arguments. Secondly, it is revealed that the disulfide dissociation profile is dramatically impacted by a peptidic environment. Calculations on L,L-cystine derivatives show two main factors: the topological frustration for an embedded -CH(2)-S-S-CH(2)- motif induces a 5 kcal mol(-1) penalty, whereas electrophilic assistance via complexation of nitrogen and oxygen atoms lowers activation barriers by a factor of 3. S-S weakening is both thermodynamically and kinetically driven by the versatile coordination mode of gold(I). The influence of amine-terminus group protonation is finally sketched: it gives rise to an intermediate reactivity. This study sheds lights on the key action of the peptidic environment in tuning the dissociation profile in the presence of this transition-metal monocation.     

Ketene-ketenimine rearrangements in the gas phase and in polar media. 1,3-Migration intermediates and sequential transition states

[reaction: see text] Calculations of the activation barrier for the 1,3-shifts of substituents X in alpha-imidoylketenes 1 (HN=C(X)-CH=C=O), which interconverts them with alpha-oxoketenimines 3 (HN=C=CH-C(X)=O) via a four-membered cyclic transition state TS2 have been performed at the B3LYP/6-311+G(3df,2p)//B3LYP/6-31G* level. Substituents with accessible lone pairs have the lowest activation barriers for the 1,3-shift (halogens, OR, NR2). The corresponding activation barriers for the alpha-oxoketene-alpha-oxoketene rearrangement of 4 via TS5 are generally lower by 1-30 kJ/mol. A polar medium (acetonitrile, epsilon = 36.64) was simulated using the polarizable continuum (PCM) solvation model. The effect of the solvent field is a reduction of the activation barrier by an average of 12 kJ/mol. In the cases of 1,3-shifts of amino and dimethylamino groups, the stabilization of the transition state TS2 in a solvent field is so large that it becomes an intermediate, Int2, flanked by transition states (TS2' and TS2') that are due primarily to internal rotation of the amine functions, and secondarily to the 1,3-bonding interaction. In the case of the alpha-oxoketene-alpha-oxoketene rearrangement of 4, there is a corresponding intermediate Int5 for the 1,3-amine shift already in the gas phase.     

Stopped-flow kinetics of tetrazine cycloadditions; experimental and computational studies toward sequential transition states

The Diels-Alder cycloadditions of tetrazines (1) with alkynes (2) are expected to give bicyclic adducts (3). Kinetic measurements of the cycloadditions of 1a and 1b with 2a give DeltaG(++) = 19.2 +/- 1.0 and 11.5 +/- 1.2 kcal/mol, respectively. Stopped-flow UV studies on the reaction of 1b with 2a show an isosbestic point at 428 nm; this places an upper limit of 11.6 +/- 2.6 kcal/mol on DeltaG(++) for loss of N(2) from the putative bicyclic intermediate 3b. Calculations (B3LYP/6-31G(d,p) + ZPVE) of transition structures for the reaction of tetrazinediacid 1d with propynylamine 2c are consistent with the experimental results for the reaction of 1b with 2a. This and several related model systems reveal two interesting features of the calculated energy surfaces. First, there may be no barrier for the loss of nitrogen from structures 3 and thus there may be two sequential transition states. This also extends Berson's correlation of activation energy with reaction energy in pericyclic reactions to significantly lower barriers. Second, for the cycloaddition of 4e and 2c, there is neither an intermediate nor a transition state between TS3e and the final product 6e. It appears that the energy surface "turns a corner" in the vicinity of a structure resembling 5e. This is not a mathematically well-defined point but has chemical consequences in that the overall exothermicity of the reaction from 4e to 6e is not felt in TS3e.     

Kinetics of chemical ionization in shock waves: III. Inert diluent gas effect on the chemical ionization rate

An experimental study of ionization in hydrogen azide decomposition and methane oxidation in shock waves is reported. In both cases, the kinetics of chemical ionization changes significantly upon the replacement of argon with helium as the inert diluent gas. The diluent effect is explained in terms of the hypothesis that the reactions responsible for chemical ionization proceed via the formation of an excited intermediate complex. Calculations using kinetic schemes of the ionization processes are carried out.     

Density functional study of a micro-1,1-carboxylate bridged Fe(III)-O-Fe(IV) model complex. 2. Comparison with ribonucleotide reductase intermediate X

Using broken-symmetry density functional theory, we have studied an experimentally proposed model for ribonucleotide reductase (RNR) intermediate X, which contains a single oxo bridge, one terminal H(2)O or OH(-) ligand, a bidentate carboxylate from Glu115, and a mono-oxygen bridge provided by Glu238. For the models proposed here, the terminal H(2)O/OH(-) ligand binds to site Fe1 which is closer to Tyr122. The diiron centers are assigned as high-spin Fe(III)Fe(IV) and antiferromagnetically coupled to give the S(total) = (1)/(2) ground state. Calculations show that the model with a terminal hydroxide in the antiferromagnetic [S(Fe1) = 2, S(Fe2) = (5)/(2)] state (Fe1 = Fe(IV), Fe2 = Fe(III)) is the lowest energy state, and the calculated isomer shift and quadrupole splitting values for this cluster are also the best among the four clusters studied here when compared with the experimental values. However, the DFT-calculated (1)H proton and (17)O hyperfine tensors for this state do not show good agreement with the experiments. The calculated Fe1-Fe2 distances for this and the other three clusters at >2.9 A are much longer than the 2.5 A which was predicted by the EXAFS measurements. The mono-oxygen bridge provided by Glu238 tends to be closer to one of the Fe sites in all clusters studied here, and it does not function as a bridge in helping to produce a short Fe-Fe distance. Overall, the models tested here are not likely to represent the core structure of RNR intermediate X. The model with the terminal OH(-) binding to the Fe1(III) center shows the best calculated (1)H proton and (17)O hyperfine tensors compared with the experimental values. This supports the earlier proposal based on analysis of ENDOR spectra (Willems et al.(16)) that the terminal oxygen group binds to the Fe(III) site in RNR-X.     

Ion pairing as a possible clue for discriminating between sodium and potassium in biological and other complex environments

For a series of biologically relevant anions, we present free energy changes upon replacing potassium with sodium in a contact ion pair. Calculations performed using a combination of molecular dynamics simulations and ab initio methods demonstrate the ordering of anions in a Hofmeister series. Small anionic groups such as carboxylates preferentially pair with sodium, while intermediate cases such as chloride or monovalent phosphate exhibit almost no specificity, and large anions (e.g., methylsulfonate) prefer potassium over sodium. These results can rationalize different behavior of Na+ versus K+ at the surface of hydrated proteins, DNA, and reversed micelles.