Symmetrical Intermediates Research Articles

Theoretical Study of Bond-Switching in 1,6-Dihydro-6a-thia-1,6-diazapentalene (10-S-3) Systems Compared with Corresponding Oxygen Analogues

Abstract Theoretical study of the mechanism of bond-switching of 5-(1-aminoethylimino)-3-methyl-1,2,4-thiadiazole and 5-(2-aminovinyl)isothiazole was carried out by using simplified models of 1,6-dihydro-6a-thia-1,6-diazapentalene (10-S-3) systems and corresponding oxygen analogs. Geometries and energetics were examined along unimolecular and bimolecular reaction paths by hybrid density functional theory (DFT) calculations with triple-zeta class basis sets by taking into account solvent effects which is estimated by the polarizable continuum model. It was clarified that the unimolecular reactions cannot proceed due to the high energy barriers around 70 kcal mol−1. On the other hand, the bimolecular processes in neutral and acidic conditions can be accomplished for the sulfur compounds, not for the oxygen ones. The differences of the reactivities between the sulfur and oxygen compounds were found to be due to the difference of the stability of the symmetric intermediates with the hypervalent three-center four-electron bonds.

Racemization of Isobornyl Chloride via Carbocations: A Nonclassical Look at a Classic Mechanism

Our understanding of carbonium ions as intermediates in chemical reaction mechanisms derives from the early work of Julius Stieglitz and the more famous Hans Meerwein, the latter studying the racemization of isobornyl chloride when treated with Lewis acids. This review analyzes how key mechanistic concepts for this reaction evolved and gives the pedagogy a modern slant based on results obtained from accurate quantum mechanical calculations. Thus, originally thought of as involving ionization of the C−Cl bond to form a carbocation that then undergoes a transannular hydride shift, an analysis of modern calculations (using AIM- and ELF-based quantum electronic topology) reveals that a more appropriate description of the bonding at the transition state for this transfer is a nonclassical 3-center-2-electron interaction. We see how other concepts important to organic chemistry such as symmetric intermediates and stereoelectronic control emerge along the way.

Evidence for reverse flux through pyruvate kinase in skeletal muscle

Conversion of lactate to glucose was examined in myotubes, minced muscle tissue, and rats exposed to 2H2O or 13C-enriched substrates. Myotubes or minced skeletal muscle incubated with [U-(13)C3]lactate released small amounts of [1,2,3-(13)C3]- or [4,5,6-(13)C3]glucose. This labeling pattern is consistent with direct transfer from lactate to glucose without randomization in the tricarboxylic acid (TCA) cycle. After exposure of incubated muscle to 2H2O, [U-(13)C3]lactate, glucose, and glutamine, there was minimal release of synthesized glucose to the medium based on a low level of 2H enrichment in medium glucose but 50- to 100-fold greater 2H enrichment in glucosyl units from glycogen. The 13C enrichment pattern in glycogen from incubated skeletal muscle was consistent only with direct transfer of lactate to glucose without exchange in TCA cycle intermediates. 13C nuclear magnetic resonance (NMR) spectra of glutamate from the same tissue showed flux from lactate through pyruvate dehydrogenase but not flux through pyruvate carboxylase into the TCA cycle. Carbon from an alternative substrate for glucose production that requires metabolism through the TCA cycle, propionate, did not enter glycogen, suggesting that TCA cycle intermediates do not exchange with phosphoenolpyruvate. In vivo, the 13C labeling patterns in hepatic glycogen and plasma glucose after administration of [U-(13)C3]lactate did not differ significantly. However, skeletal muscle glycogen was substantially enriched in [1,2,3-(13)C3]- and [4,5,6-(13)C3]glucose units that could only occur through skeletal muscle glyconeogenesis rather than glycogenesis. Lactate serves as a substrate for glyconeogenesis in vivo without exchange into symmetric intermediates of the TCA cycle.

Structural and Configurational Properties of Ethene, Silaethene, Germaethene, and Stannaethene: A Density Functional Theory Study and Natural Bond Orbital Analysis

B3LYP/6-31G*-B3LYP/3-21G,* and B3LYP/LANL2DZ**-based density functional theory (DFT) methods were used to investigate the ground-state structural and configurational properties of ethene (1), silaethene (2), germaethene (3), and stannaethene (4). All three methods showed that the ground-state structure of compounds 1–4 is planar. The results confirmed that the π bond energies (rotational barriers) are decreased from compound 1 to 4. The double-bond rotation energy profiles show the existence of plane symmetrical intermediates, due to the pyramidalization at the silicon, germanium, and tin center in compounds 2–4 , respectively. Based on the B3LYP/6-31G*, B3LYP/3-21G* and B3LYP/LANL2DZ** optimized ground state geometries, the Natural Bond Orbital (NBO) analysis of donor-acceptor (bond-antibond) interactions revealed that the stabilization energies associated with the electronic delocalization from σ M−H bonding orbitals to π * C = M antibonding orbitals increase from compounds 1 to 4. Also, the donor-acceptor interactions, as obtained from NBO analysis, could fairly explain the decrease of occupancies of σ M − H bonding orbital and the increase of occupancies of π * C = M antibonding orbitals from compounds 1 to 4. Also, the NBO results showed that by increase of π C = M → σ * M − H resonance energy in compounds 1–4, the π C = M bonding orbital occupancies decrease, while the σ * M − H antibonding orbital occupancies increase. The results confirmed that by increase of σ M − H → π * C = M and also π C = M → σ * M − H resonance energies, the π bond energies (rotational barriers) decrease from compounds 1 to 4. It has to be noted that the energy gap between π C = M bonding and π * C = M antibonding orbitals decreased from compounds 1 to 4.

Ab inito study and NBO analysis of the enantiomerization energy profile of tetra- peri-substituted overcrowded naphthalenes

Ab initio molecular orbital (MO) and density functional theory methods were used to investigate the structural and conformational properties of 1,4,5,8-tetra- tert-butyl naphthalene ( 1), 1,4,5,8-tetrakis(trimethylsilyl)naphthalene ( 2), 1,4,5,8-tetrakis(trimethylgermyl)naphthalene ( 3) and 1,4,5,8-tetrakis(trimethylstannyl)naphthalene ( 4). HF/3-21G*//HF/3-21G*, MP2/3-21G*//HF/3-21G*, B3LYP/3-21G*//HF/3-21G*, HF/LANL2DZ*//HF/LANL2DZ*, MP2/LANL2DZ*//HF/LANL2DZ* and B3LYP/LANL2DZ*//HF/LANL2DZ* results revealed that the most stable form of these compounds has D 2 symmetry, and, therefore, they should present optical activity. The enantiomerization processes for compounds 1– 4 could take place via plane symmetrical intermediates (with C 2 h symmetry). MP2/3-21G*//HF/3-21G* results show that the plane-symmetrical ( C 2 h symmetry) geometries of compounds 1– 4 are less stable (about 8.40, 5.18, 8.01, and 6.37 kcal mol −1, respectively) than the axial-symmetrical geometries ( D 2 symmetry). Also, in compounds 1– 4, the plane symmetrical intermediate ( C 2 h symmetry) is less stable than the axial-symmetrical ( D 2 symmetry) geometry, about 10.07, 6.80, 9.49 and 7.33 kcal mol −1, respectively, as calculated by B3LYP/3-21G*//HF/3-21G* level of theory. The barrier heights for interconversion of the D 2 to C 2 h geometries for compounds 1– 4 are 29.32, 14.89, 12.28 and 9.24 kcal mol −1, as calculated by MP2/3-21G*//HF/3-21G* level of theory. Also, B3LYP/3-21G*//HF/3-21G* results show that the required energy for ring flipping ( D 2 to D 2 ′ ) for these compounds is 28.41, 13.48, 11.52, 8.33 kcal mol −1. In both axial and plane symmetrical ( D 2 and C 2 h ) geometries of compounds 1– 4, the naphthalene rings are puckered and their aromatic characters are relatively perturbed. For compounds 1– 3, the calculations were also performed at B3LYP/6-311+G**//HF/6-31G*, MP2/6-31G*//HF/6-31G* and HF/6-31G*//HF/6-31G* levels of theory. However, the comparison showed that the results at HF/3-21G*//HF/3-21G*, B3LYP/3-21G*//HF/3-21G* and MP2/3-21G*//HF/3-21G* methods correlated well with those obtained at HF/6-31G*//HF/6-31G*, B3LYP/6-311+G**//HF/6-31G* and MP2/6-31G*//HF/6-31G* levels of theory. Further, NBO analysis, based on the HF/3-21G* optimized ground state geometries, revealed that in compounds 1– 4, the resonance energy associated with σ C aryl – M to σ C 9 – C 10 * delocalization is 1.43, 3.53, 3.96 and 4.62 kcal mol −1, respectively. These resonance energy values could explain the easiness of ring flipping processes from compound 4 to 1. The NBO results are in good agreement with the calculated energy barriers for ring flipping in compounds 1– 4, as calculated by MP2, B3LYP and HF methods, using all electron (3-21G*) and pseudopotential (LANL2DZ*) basis sets.

An ab initio Molecular Orbital Study of the Conformational Properties of all-(Z)-Cyclododeca-1,4,7,10-tetraene

Ab initio HF/6-31G* and MP2/6-31G*//HF/6-31G* methods were used to calculate the structure optimization and conformational interconversion pathways for all-(Z )-cyclododeca-1,4,7,10-tetraene. This compound adopts the symmetrical crown (C4v) conformation. Ring inversion takes place via symmetrical intermediates, such as boat-chair (BC, Cs) and twist (C2h) conformers and requires about 22.3 kJ · mol−1. The calculated strain energies for BC and twist conformers are 5.9 and 13.5 kJ · mol−1. The results of semiempirical AM1 calculations for structural parameters and relative energies of the important geometries of the title compound are in good agreement with the results of ab initio methods.

Biosynthesis of Erythrina alkaloids in Erythrina crista-galli.

A precursor application system was developed to allow the study of Erythrina alkaloid formation in Erythrina crista-galli. Fruit wall tissue of this species was recognized as the major site of alkaloid biosynthesis. The application of radioactively and 13C-labelled potential precursors showed that the hitherto assumed precursor (S)-norprotosinomenine was not incorporated into the Erythrina alkaloids. In contrast, (S)-coclaurine as well as (S)-norreticuline were metabolized to erythraline and erythrinine, respectively, suggesting that a coclaurine-norreticuline pathway is operative in Erythrina alkaloid formation. Feeding of [1-13C]-labelled (S)-norreticuline with subsequent NMR spectroscopy demonstrated that the resulting erythraline was exclusively labelled at position C-10. Therefore, the participation of a symmetrical intermediate of the diphenoquinone type in Erythrina alkaloid biosynthesis can be excluded.

Biosynthesis of bitter acids in hops. A (13)C-NMR and (2)H-NMR study on the building blocks of humulone.

The biosynthesis of humulone, an antibacterial bitter acid from hops, was studied by isotope-incorporation experiments using (13)C-labelled glucose or (2)H(2)O. (13)C enrichments, (2)H enrichments and (13)C(13)C coupling patterns identify isovaleryl-CoA, malonyl-CoA and dimethylallyl pyrophosphate as precursors for humulone. Dimethylallyl pyrophosphate, which serves as a building block for the bitter acid, is generated via the deoxyxylulose pathway of terpenoid biosynthesis. The data confirm that a symmetrical intermediate is involved in humulone formation.

Unusual rearrangements of 2-aroylimidoyl-2-phenylethylidene to 2,5-disubstituted oxazoles

Flash vacuum pyrolysis of 2-aroyl-3-phenylisoxazol-5(2H)-ones leads to good yields of 2-aryl-4-phenyloxazoles, and smaller quantities of 2-aryl-5-phenyloxazoles and 5-aryl-2-phenyloxazoles. The mechanism of formation of the 2,5-disubstituted products has been investigated by 13C and substituent labelling, and a non-statistical breakdown of a symmetrical intermediate is invoked to rationalise the product formation.

Theoretical study of degenerate Boulton–Katritzky rearrangements. Semiempirical and ab initio procedures

A theoretical study of degenerate Boulton–Katritzky rearrangements concerning the anions of the 3-formylamino-1,2,4-oxadiazole, 3-formylmethyl-isoxazole and 3-hydroxy-iminomethyl-1,2,5-oxadiazole has been carried out by using semiempirical MNDO and ab initio Hartree–Fock procedures. Different transition structures and reactive pathways were obtained in the two cases. Semiempirical treatment shows asymmetrical transition states and non-concerted processes via symmetrical intermediates. By contrast, ab initio procedures describe concerted and synchronous processes involving symmetrically-located transition states. Some comments and criticisms on the theoretical treatment of these typical rearrangements of five-membered heterocycles are reported.

An Unusual Determinant of Chirality. Unique Solution Chemistry and Novel NMR Spectroscopic Changes in Fluxional Re(V)O Complexes with Rearranging meso N2S2 Ligands

The nature of metal species in aqueous solution is often ambiguous since the two processes, OH- coordination and ligand deprotonation, have the same pH profile. This problem plagues the assessment of the form of some radiopharmaceuticals present at physiological pH. Representative M(V)O(N2S2) (M = 99mTc, Re) radiopharmaceuticals include ReO(ECH3) complexes (ECH3 = thrice deprotonated ethylene di(cysteine), ECH6). We found that syn-ReO(dl-ECH3) (1) (meso-ECH3, formed from dl-cysteine) and the tetramethyl analog, syn-ReO(dl-TMECH3) (2, TMECH6 = ethylene di(penicillamine)), have uniquely informative spectral properties. Two equivalents of OH- convert 1 and 2 to the dianionic form. This form of 2 has only one set of three penicillamine (pen) 1H NMR signals near pH 6. However, these signals underwent major changes from pH 6 to 10 as follows: they broadened and collapsed; two equal sets of three signals emerged; these then broadened and collapsed; and the original set of three signals reemerged. Combined with the Raman data given below, these results require that one form is present from pH 6 to 10 and that this form be chiral and both conformationally and configurationally fluxional; one N is protonated and the other N bears a lone pair (Lp). The determinant of chirality of this NH/NLp form is the site of the NH group. The magnetic equivalence leading to one set of pen signals observed at the low and high ends of the pH range demonstrates the occurrence of fast exchange of the NH site between the two N's. This exchange leads to rapid inversion of complex chirality through symmetric intermediates, an NH/NH monoanion and an NLp/NLp trianion, in the acid- and base-catalyzed processes, respectively. At neutral pH, the H+ and OH- concentrations are low; as a result, the inversion of chirality is slow compared to the NMR time scale, and the two halves of the ligand are magnetically inequivalent. The two ReO bands found in a fixed ratio in the resonance Raman spectra of 2 between pH 6 and 10 indicate that two major NH/NLp conformers are present throughout the range, including physiological pH. Two conformers of a form axially ligated by OH- cannot explain the two equal sets of pen NMR signals. However, two NH/NLp conformers differing only in NLp orientation and in rapid interchange via NLp inversion explain all the spectral results. Thus, the use of fast and slow time scale spectroscopies eliminates the ligation/deprotonation ambiguity in this case.

1,3-Bisalkylcarbonyl- and 3-Alkylcarbonyl-5-fluorouracil Prodrugs: Syntheses, Thermal, and Hydrolytic Stability

Four homologous 1,3-bisalkylcarbonyl and the corresponding 3-alkylcarbonyl derivatives of 5-fluorouracil (1, 5-FU) have been synthesized and characterized by 1H nuclear magnetic resonance, and infrared and ultraviolet spectroscopy. The 1,3-bisacetyl derivative hydrolyzed rapidly in pH 7.1 buffer at 32°C (t1/2 =0.8 min) to give the 3-acetyl derivative. The hydrolyses of 3-acetyl-, 6, and 3-propionyl-5-FU, 7, were much slower (t1/2 = 200 and 300 min, respectively) and they were biexponential. Both the 1,3- and the 3-derivatives hydrolyzed in the presence of formaldehyde to give significant, and approximately equal amounts of 1- and 3-alkylcarbonyloxymethyl-5-FU derivatives, in addition to 5-FU, which suggested that for both types of derivatives the hydrolyses of the 3-alkylcarbonyl group went through a symmetrical O2-alkylcarbonyl intermediate. The 1,3-derivatives were thermally unstable above about 110°C, giving up to about 20% of the corresponding 1-alkylcarbonyl derivatives at 140°C. On the other hand, the 3-derivatives were thermally unstable even at 95°C, where complete decomposition to 1- and 1,3-derivatives as well as 5-FU was observed.

Selective manipulation of only one of two similar sites within a molecule ‘odin reactions’: Strategic advantage for synthesis and tactics available

AbstractApproaches used to effect selective reaction at one of two or more similar sites in a molecule are reviewed. The nature of the problem is defined and the strategic advantage to be gained through the use of symmetrical intermediates is outlined early and re‐emphasised throughout the discussion with specific examples of multistage syntheses of important products. The various tactics used to effect site selectivity in a late synthetic step are described in a logical sequence and presented in a form aimed to help in the design of syntheses of unsymmetric products from symmetric intermediates.

Metabolic studies on Saccharomyces cerevisiae containing fused citrate synthase/malate dehydrogenase

We have constructed two different fusion proteins consisting of the C-terminal end of CS1 fused in-frame to the N-terminal end of MDH1 and HSA, respectively. The fusion proteins were expressed in mutants of Saccharomyces cerevisiae in which CS1 and MDH1 had been deleted and the phenotypes of the transformants characterized. The results show that the fusion proteins are transported into the mitochondria and that they restore the ability for the yeast mutants CS1-, MDH1-, and CS1-/MDH1- to grow on acetate. Determination of CS1 activity in isolated mitochondria showed a 10-fold increase for the strain that expressed native CS1, relative to the parental. In the transformant with CS1/MDH1 fusion protein, parental levels of CS1 were observed, while one-fifth this amount was observed for the strain expressing the CS1/HSA conjugate. Oxygen consumption studies on isolated mitochondria did not show any significant differences between parental-type yeast and the strains expressing the different fusion proteins or native CS1. [3(-13)C]Propionate was used to study the Krebs TCA cycle metabolism of yeast cells containing CS1/MDH1 fusion constructs. The 13C NMR study was performed in respiratory-competent parental yeast cells and using the genetically engineered yeast cells consisting of CS1- mutants expressing native CS1 and the fusion proteins CS1/MDH1 and CS1/HSA, respectively. [3(-13)C]Propionate is believed to be metabolized to [2(-13)C]succinyl-CoA before it enters the TCA cycle in the mitochondria. This metabolite is then oxidized through two symmetrical intermediates, succinate and fumarate, followed by conversion to malate, oxalacetate, and other metabolites such as alanine.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for orientation-conserved transfer in the TCA cycle in Saccharomyces cerevisiae: 13C NMR studies.

When [4-13C]glutamate is incubated with yeast cells, the [13C]aspartate formed shows a [2-13C]/[3-13C] ratio that is greater than 1. If the conversion occurs through the Krebs TCA cycle with the symmetrical intermediates succinate and fumarate, the ratio is expected to be 1. The addition of fluoroacetate to the incubation increases the ratio further. When the mutants Aco1- or CS1- are used, little or no aspartate is formed. When [2-13C]acetate is incubated with yeast, the C2-/C3-aspartate ratio is 1.5 at 2 min and decrease to 1.0 after 10 min of incubation. These results indicate that orientation-conserved transfer occurs at the succinate thiokinase and succinate dehydrogenase steps of the Krebs TCA cycle.

Channeling of TCA cycle intermediates in cultured Saccharomyces cerevisiae

Oxidation of [3-13C]propionate was studied in cultured yeast cells, and the distribution of label in the 2- and 3-positions of alanine was detected by 13C NMR. [3-13C]Propionate forms [2-13C]succinyl-CoA in the mitochondria which then enters the citric acid cycle and forms malate through two symmetrical intermediates, succinate and fumarate. If these symmetrical intermediates randomly diffuse from one enzyme to the next in mitochondria as is normally assumed, then 13C labeling in malate C2 and C3 must be equal. However, any direct transfer of metabolites from site to site between succinate thiokinase, succinate dehydrogenase, and fumarase would result in an uneven distribution of 13C in malate C2 and C3 and any molecules derived from malate. Since pyruvate may be derived from malate via the malic enzyme and subsequently converted into alanine by transamination, any 13C asymmetry in alanine C2 and C3 must directly reflect the 13C distribution in the malate pool. During oxidation of [3-13C]propionate, we detect a significant quantity of labeled alanine, where 13C enrichment in C3 is significantly higher than that in C2. Inhibition of succinate dehydrogenase with malonate or creating conditions that increase the chances of a back-reaction (from malate to fumarate) result in a significant decrease in the asymmetric labeling of alanine. Ubiquinone-deficient yeast cells (having only 10% of the oxidative capacity of wild-type cells) could slowly oxidize propionate, but in this case the 13C labeling was equal in the C2 and C3 of alanine, showing that isotope randomization had occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

The mechanism of succinate or fumarate transfer in the tricarboxylic acid cycle allows molecular rotation of the intermediate

Mitochondria were incubated with l[5- 13C]glutamic acid and the distribution of the label between the two carboxyl carbon atoms of the l-aspartic acid formed was determined by 13C NMR. The reaction sequence leading from l-glutamic acid to l-aspartic acid spans the tricarboxylic acid cycle reactions involving the two symmetrical intermediates succinate and fumarate. The C2 symmetry of these intermediates in principle permits a discrimination of the mechanism of their transfer between their enzyme sites of production and utilization. A direct transfer of metabolite from site to site by translation alone predicts an unequal distribution of 13C between the C1 and C4 of aspartate, whereas molecular rotation during transfer allows for a scrambling of the original C5 label. Under several conditions of different glutamate concentrations and solvent osmotic pressures, equal labeling in the C1 and C4 carbons of aspartate is observed. This observation is inconsistent with a transfer mechanism restricting molecular rotation for both intermediates but is compatible with both a random diffusion and a direct transfer mechanism provided the latter allows molecular rotation.

Synthesis of substituted dibenzophospholes. Part 6. Preparation of symmetrical and non-symmetrical quaterphenyl intermediates

Further examples are given of the synthetic approach to 4,6-diaryldibenzophospholes by arylation of 1,3-dinitrobenzene and coupling of the resulting biphenyls to symmetrically substituted quaterphenyls. Satisfactory procedures are described for the monoarylation of 2,2′,4,4′-tetranitrobiphenyl and for arylation of the products to provide non-symmetrically substituted tetranitroquaterphenyls. Some procedures for the regioselective alkoxydenitration of tetranitroquaterphenyls are described.

Diastereoselective ene reaction in the photooxygenation of the silyl cyanohydrins of .alpha.,.beta.-unsaturated aldehydes: necessity for a common symmetrical intermediate of the perepoxide type

Diastereoselective ene reaction in the photooxygenation of the silyl cyanohydrins of .alpha.,.beta.-unsaturated aldehydes: necessity for a common symmetrical intermediate of the perepoxide type

Übergangsmetall-carbin-komplexe: LXXIX. Darstellung und dynamisches verhalten von cis- cyanodiethylaminocarbin-komplexen des wolframs mit den zweizähnigen liganden 2,2′-bipyridyl und 1,10- phenanthrolin

trans-Br(CO) 2L 2WCNEt 2 complexes [L 2 = 2,2′-bipyridyl (2,2′-bipy), 1,10- phenanthroline (ophen)] react with KCN undergoing substitution of the halogen ligand by cyanide to yield the neutral NC(CO) 2L 2WCNEt 2 complexes. Spectroscopic investigations indicate that in this reaction the halogen ligand in the trans position to the carbyne ligand has been replaced by the chelate ligand while the CN group occupies a cis coordination site relative to the carbyne ligand. The new complexes show fluxional behavior which is demonstrated by the temperature dependance of their NMR spectra. A symmetrical intermediate is assumed in the dynamic process, which is based upon the fluctuation of the chelate ligand between two cis / trans positions to the carbyne ligand.