Heteroatom Center Research Articles

Rapid (Deuterio)difluoromethylation of Heteroatoms using R‐22 Gas: A Demonstration of Flow Chemistry in Suppressing Intrinsic Reaction Pathways

The exploration and use of deuteriodifluoromethyl heteroatom groups (X‐CF2D) has been limited by persistent challenges, including the unavailability of CF2D precursor reagents, as well as safety, scalability, and environmental concerns associated with conventional batch‐mode syntheses. In this study, we report the use of atom‐efficient and cost‐effective R‐22 gas (ClCF2H) in continuous flow for the rapid installation of CF2H and CF2D groups on heteroatom centers. However, the intrinsic nucleophilic substitution between heteroatom anions and ClCF2H decreases the deuterium incorporation levels. Notably, a judiciously designed continuous flow system proves to suppress the previously unavoidable SN2 reaction and allows for the selective carbene coupling to generate X‐CF2D products with high deuterium incorporation levels up to 96%. Our continuous flow systems provide a broad scope of X‐CF2H and X‐CF2D products (X = S, O, N) within a short residence time of 5 minutes and scalability is also demonstrated.

Gold‐catalyzed C−H Functionalization of Phenothiazines with Aryldiazoacetates

AbstractPhenothiazine is an important structural motif in pharmaceuticals and advanced functional organic materials. However, the C−H functionalization reaction of N‐protected phenothiazine is rather unexplored and often shadowed by its chemical reactivity on the heteroatomic centers, which limits the diversity of its potential applications. This report demonstrates a straightforward approach towards the site‐selective C−H functionalization of phenothiazine at the para‐position of N atom via gold‐catalyzed carbene transfer reactions (37 examples, up to 83% yield). The mechanism behind the regionselectivity of the C−H functionalization reaction was also elucidated by a combination of computational and experimental studies.magnified image

A density functional theory perspective on 2,2,9,9‐tetrahalostannacyclonona‐3,5,7‐trienylidenes

AbstractCompared with cyclonona‐3,5,7‐trienylidene (1H), which turns out as a boat‐shaped singlet transition state for having a negative force constant, its heavier stanylenic analogues (2X), where X = H, F, Cl, Br, and I, emerge as boat‐shaped minima. This unsubstituted carbene has triplet ground state while exclusive of 2I, which initially take on a triplet multiplicity and eventually transforms to a less stable intramolecular ring opening product; other stanylenes (2H, 2F, 2Cl, and 2Br) have singlet ground state. Hence, stability anticipated by the singlet‐triplet splitting (ΔES‐T) decreases by going down in group 17 column: 2Br > 2Cl > 2F > 2H > 2I > 1H. Also, the HOMO‐LUMO energy separation (ΔEHOMO‐LUMO) increases as a result of substituting. The main stabilizing effect appears to be π– and σ–bond hyperconjugation among the iodine hetero atom and divalent center of triplet 2I. From a thermodynamic perspective, our scrutinized 2Br, 2Cl, and 2F are found 1.5 to 2 times more stable than that of the reported cyclopenta‐2,4‐dienstanylene and 2,5‐bis (halobora)‐cyclopentenstanylene analogues. From a kinetic perspective, these nine‐membered stanylenes are found 10 to 18 kcal/mol more stable than that of their corresponding five‐membered congeners. The NBO analysis on stable singlet 2Br‐S shows that there is a three‐type interaction including the first interaction between its bromine's lone pairs and tin's 5pπ orbital (mesomeric effect), second interaction between its bonding orbital (σCα‐Br) and tin's 5pπ orbital (positive hyperconjugation), and third interaction between its σ2Sn occupied orbital and antibonding orbitals of σ*Cα‐Br (negative hyperconjugation).

Controlled Triol-Derivative Bonding and Decoration Transformation on Cu-Centered Anderson-Evans Polyoxometalates.

To create new types of organic ligands covalently grafted onto polyoxometalates and identify the reaction mechanism, we selected Cu(II) as the central heteroatom for the synthesis of a series of disklike Anderson-Evans clusters bearing different triol derivatives on both their faces via one-pot and/or step-by-step routes. By using a [(n-C4H9)4N]4[Mo8O26] precursor cluster and copper acetate as the starting materials, several organically modified χ isomers with Cu(II) heteroatom centers were obtained. Starting from a [(n-C4H9)4N]2[Mo2O7] subcluster, however, a half-malposition coordination fashion of triol ligands with a δ isomer on one face and a χ isomer on the other face of the Anderson-Evans cluster was obtained. By changing the reaction solvent from acetonitrile to methanol, we realized a secondary organic modification of the triol-grafted clusters and obtained a triol ligand/methanol codecoration on the Anderson-Evans polyoxometalate. In addition, by changing the reaction environment, we succeeded in modulating the transformation of triol ligands from one site to another on the polyoxometalate cluster. Importantly, by control of the reaction condition, the methanol molecules were also taken off from the cluster.

Enhancement of CO2 Adsorption and Catalytic Properties by Fe-Doping of [Ga2(OH)2(L)] (H4L = Biphenyl-3,3',5,5'-tetracarboxylic Acid), MFM-300(Ga2).

Metal–organic frameworks (MOFs) are usually synthesized using a single type of metal ion, and MOFs containing mixtures of different metal ions are of great interest and represent a methodology to enhance and tune materials properties. We report the synthesis of [Ga2(OH)2(L)] (H4L = biphenyl-3,3′,5,5′-tetracarboxylic acid), designated as MFM-300(Ga2), (MFM = Manchester Framework Material replacing NOTT designation), by solvothermal reaction of Ga(NO3)3 and H4L in a mixture of DMF, THF, and water containing HCl for 3 days. MFM-300(Ga2) crystallizes in the tetragonal space group I4122, a = b = 15.0174(7) Å and c = 11.9111(11) Å and is isostructural with the Al(III) analogue MFM-300(Al2) with pores decorated with −OH groups bridging Ga(III) centers. The isostructural Fe-doped material [Ga1.87Fe0.13(OH)2(L)], MFM-300(Ga1.87Fe0.13), can be prepared under similar conditions to MFM-300(Ga2) via reaction of a homogeneous mixture of Fe(NO3)3 and Ga(NO3)3 with biphenyl-3,3′,5,5′-tetracarboxylic acid. An Fe(III)-based material [Fe3O1.5(OH)(HL)(L)0.5(H2O)3.5], MFM-310(Fe), was synthesized with Fe(NO3)3 and the same ligand via hydrothermal methods. [MFM-310(Fe)] crystallizes in the orthorhombic space group Pmn21 with a = 10.560(4) Å, b = 19.451(8) Å, and c = 11.773(5) Å and incorporates μ3-oxo-centered trinuclear iron cluster nodes connected by ligands to give a 3D nonporous framework that has a different structure to the MFM-300 series. Thus, Fe-doping can be used to monitor the effects of the heteroatom center within a parent Ga(III) framework without the requirement of synthesizing the isostructural Fe(III) analogue [Fe2(OH)2(L)], MFM-300(Fe2), which we have thus far been unable to prepare. Fe-doping of MFM-300(Ga2) affords positive effects on gas adsorption capacities, particularly for CO2 adsorption, whereby MFM-300(Ga1.87Fe0.13) shows a 49% enhancement of CO2 adsorption capacity in comparison to the homometallic parent material. We thus report herein the highest CO2 uptake (2.86 mmol g–1 at 273 K at 1 bar) for a Ga-based MOF. The single-crystal X-ray structures of MFM-300(Ga2)-solv, MFM-300(Ga2), MFM-300(Ga2)·2.35CO2, MFM-300(Ga1.87Fe0.13)-solv, MFM-300(Ga1.87Fe0.13), and MFM-300(Ga1.87Fe0.13)·2.0CO2 have been determined. Most notably, in situ single-crystal diffraction studies of gas-loaded materials have revealed that Fe-doping has a significant impact on the molecular details for CO2 binding in the pore, with the bridging M–OH hydroxyl groups being preferred binding sites for CO2 within these framework materials. In situ synchrotron IR spectroscopic measurements on CO2 binding with respect to the −OH groups in the pore are consistent with the above structural analyses. In addition, we found that, compared to MFM-300(Ga2), Fe-doped MFM-300(Ga1.87Fe0.13) shows improved catalytic properties for the ring-opening reaction of styrene oxide, but similar activity for the room-temperature acetylation of benzaldehyde by methanol. The role of Fe-doping in these systems is discussed as a mechanism for enhancing porosity and the structural integrity of the parent material.

Protected Amine Labels: A Versatile Molecular Scaffold for Multiplexed Nominal Mass and Sub-Da Isotopologue Quantitative Proteomic Reagents

We assemble a versatile molecular scaffold from simple building blocks to create binary and multiplexed stable isotope reagents for quantitative mass spectrometry. Termed Protected Amine Labels (PAL), these reagents offer multiple analytical figures of merit including, (1) robust targeting of peptide N-termini and lysyl side chains, (2) optimal mass spectrometry ionization efficiency through regeneration of primary amines on labeled peptides, (3) an amino acid-based mass tag that incorporates heavy isotopes of carbon, nitrogen, and oxygen to ensure matched physicochemical and MS/MS fragmentation behavior among labeled peptides, and (4) a molecularly efficient architecture, in which the majority of hetero-atom centers can be used to synthesize a variety of nominal mass and sub-Da isotopologue stable isotope reagents. We demonstrate the performance of these reagents in well-established strategies whereby up to four channels of peptide isotopomers, each separated by 4 Da, are quantified in MS-level scans with accuracies comparable to current commercial reagents. In addition, we utilize the PAL scaffold to create isotopologue reagents in which labeled peptide analogs differ in mass based on the binding energy in carbon and nitrogen nuclei, thereby allowing quantification based on MS or MS/MS spectra. We demonstrate accurate quantification for reagents that support 6-plex labeling and propose extension of this scheme to 9-channels based on a similar PAL scaffold. Finally, we provide exemplar data that extend the application of isotopologe-based quantification reagents to medium resolution, quadrupole time-of-flight mass spectrometers.

Role of the Somersault Rearrangement in the Oxidation Step for Flavin Monooxygenases (FMO). A Comparison between FMO and Conventional Xenobiotic Oxidation with Hydroperoxides

Model quantum mechanical calculations presented for C-4a-flavin hydroperoxide (FlHOOH) at the B3LYP/6-311+G(d,p) level suggest a new mechanism for flavoprotein monooxygenase (FMO) oxidation involving a concerted homolytic O-O bond cleavage in concert with hydroxyl radical transfer from the flavin hydroperoxide rather than an S(N)2-like displacement by the substrate on the C-4a-hydroperoxide OOH group. Homolytic O-O bond cleavage in a somersault-like rearrangement of hydroperoxide C-4a-flavinhydroperoxide (1) (FLHO-OH → FLHO···HO) produces an internally hydrogen-bonded HO(•) radical intermediate with a classical activation barrier of 27.0 kcal/mol. Model hydroperoxide 1 is used to describe the transition state for the key oxidation step in the paradigm aromatic hydroxylase, p-hydroxybenzoate hydroxylase (PHBH). A comparison of the electron distribution in the transition structures for the PHBH hydroxylation of p-hydroxybenzoic acid (ΔE(‡) = 23.0 kcal/mol) with that of oxidation of trimethylamine (ΔE(‡) = 22.3 kcal/mol) and dimethyl sulfide (ΔE‡ = 14.1 kcal/mol) also suggests a mechanism involving a somersault mechanism in concert with transfer of an HO(•) radical to the nucleophilic heteroatom center with a hydrogen transfer back to the FLH-O residue after the barrier is crossed to produce the final product, FLH-OH. In each case the hydroxylation barrier was less than that of the O-O rearrangement barrier in the absence of a substrate supporting an overall concerted process. All three transition structures bear a resemblance to the TS for the comparable hydroxylation of isobutane (ΔE(‡) = 29.2 kcal/mol) and for simple Fenton oxidation by aqueous iron(III) hydroperoxides. To our surprise the oxidation of N- and S-nucleophiles with conventional oxidants such as alkyl hydroperoxides and peracids also proceeds by HO(•) radical transfer in a manner quite similar to that for tricyclic hydroperoxide 1. Stabilization of the developing oxyradical produced by somersault rearrangement for concerted enzymatic oxidation with tricyclic hydroperoxide 1 results in a reduced overall activation barrier.

Selective 1D HCH experiment: a fast NMR tool that connect protons belonging to different spin systems

A selective 1D version of the HCH experiment (selHCH) is proposed for the efficient and fast correlation between protons belonging to different spin systems. The experiment consists of two consecutive, doubly selective heteronuclear J(CH) transfer steps that can individually be optimized. As any conventional proton-selective 1D experiment, the successful application of a frequency-selective 180° pulse on a well-isolated proton is the only practical requirement. The resulting clean selHCH spectrum probes to be an excellent complement to the conventional selTOCSY experiment to trace out proton-proton J connectivities through transparent non-protonated carbons or heteroatom centers. Several selHCH examples on small molecules are provided showing the improvements with respect to the selTOCSY experiment.

Expression and Characterization of Functional Dog Flavin-Containing Monooxygenase 3

Mammalian flavin-containing monooxygenase (FMO) enzymes catalyze oxidation at nucleophilic, heteroatom centers and are important for drug, xenobiotic, and endogenous substrate metabolism. In human liver, human FMO3 (hFMO3) is the most abundant FMO isoform and is known to contribute to the hepatic clearance of a variety of clinical drugs. The purpose of the current study was to express and compare the dog (beagle) FMO3 (dFMO3) to hFMO3. A full-length dFMO3 cDNA was obtained from liver by reverse transcription-polymerase chain reaction. Using a baculovirus expression system in Spodoptera frugiperda insect cells, dFMO3 was expressed to protein levels of 0.50 nmol/mg, as determined by liquid chromatography-fluorescence detection. Expressed dFMO3 displayed Michaelis-Menten kinetics, catalyzing NADPH-dependent N-oxidation of benzydamine, with K(m) and V(max) values of 18.6 microM and 0.63 nmol N-oxide formed/min/nmol of enzyme, respectively. Benzydamine N-oxidation catalyzed by hFMO3 showed values of 42.6 microM (K(m)) and 3.56 nmol/min/nmol of enzyme (V(max)). Human FMO3 was observed to catalyze the S-oxidation of sulindac sulfide, with respective K(m) and V(max) values of 69.3 microM and 35.4 nmol/min/nmol of enzyme. dFMO3 also catalyzed sulindac sulfide S-oxidation with 6.8 nmol/min/nmol of enzyme being the highest velocity observed. Finally, Western blot analysis indicated protein expression levels of dFMO3 in pooled dog liver and lung microsomes to be 27 and 9 pmol/mg, respectively. In summary, dFMO3 appears to be a functional enzyme expressed at appreciable levels in liver, but one with some kinetic properties that are substantially different from its human homolog hFMO3.

1π→1π* Ultraviolet Absorption Bands and Electronic Charge Transfers in Singlet Excited States of Sulfur Aromatic Heterocycles

Indoline‐2‐thione (BC), benzimidazole‐2‐thione (BN), benzoxazole‐2‐thione (BO), and benzothiazole‐2‐thione (BS) define an interesting series of aromatic compounds containing a NCS synthonic unit in a heterocyclic ring of five centers, substituted by atomic centers of the type C, N, O, or S, where the main electronic absorption bands are localized in the spectral range of ultraviolet A or B. The first two singlet electronic transitions of this series, 1S0→1S1(n,π*) and 1S0 → 1S2(π,π*), determine the main spectroscopic characteristic of these compounds in order to be used as potential photochemical actinometers of solar ultraviolet radiation. Furthermore, the second electronic transition, localized in the 270–360 nm ultraviolet spectral range, presents a hipsochromic spectral shift as function of the electronic nature of the heteroatomic centers in the heterocyclic ring. In order to determine a spectroscopic assignment of the main absorption bands in aqueous solution and analyze the effect of the substituent on the electronic charge distributions in the ground and the first two singlet excited electronic states, we have used a semiempirical molecular orbital calculation in the INDO/S‐CIS approach. On the other hand, we have carried out a molecular orbital calculation in the AM1 framework, in order to determine the energetic stability of the thiones with respect to the thiol compounds.

Organometallic Reactions in Aqueous Media: Indium‐Promoted Additions to 2‐Pyridyl and Glyoxylic Acid Oxime Ethers.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Recent Advances in the Synthesis of Optically Active Compounds Bearing a Chiral Heteroatom Center in the Group 13‐16 Elements

AbstractFor Abstract see ChemInform Abstract in Full Text.

Organometallic reactions in aqueous media: indium-promoted additions to 2-pyridyl and glyoxylic acid oxime ethers.

Oxime ethers derived from 2-pyridinecarboxaldehyde and glyoxylic acid can be effectively allylated in water with five differently functionalized allylic bromides promoted by indium. When the metal is positioned in close proximity of flanking heteroatomic centers, chelation by In is indeed operative and affects both reactivity and stereochemistry. Stereochemical assignments in the addition products were based on X-ray crystallographic measurements and spectral correlations.

Recent Advances in the Synthesis of Optically Active Compounds Bearing a Chiral Heteroatom Center in the Group 13-16 Elements

The design and construction of optically active molecules comprised of a chiral heteroatom center is a rapidly developing research field. This review focuses on the recent development in the synthesis of such molecules which possess a chiral heteroatom center of the group 13-16 metal elements, that is, boron, silicon, germanium, tin, arsenic, antimony, bismuth, selenium and tellurium. Keywords: Chiral Heteroatom, Elements, Bismuth, Antimony

ChemInform Abstract: Metal Ion Effects in Isotopic Hydrogen Exchange in Biologically Important Heterocycles

The binding of metal ions to heteroatomic centers of biomolecules has been utilized as a probe of metal ion effects in living systems. This article focuses on the effect of N-coordination by transition metals, especially Pt(II), Co(III), Cr(III), on isotopic C(2)−H or C(8)−H exchange of imidazoles, thiazoles, and purines. The usual reactivity trend, protonated ≫ metalated ≫ neutral substrate, is excepted for Cr(III)/1-methylimidazole, where Cr(III) activates stronger than H+. An interplay of factors is considered, including metal-to-ligand back-bonding, electronic structure of metal ions, and differences in crystal field stabilization energy.

Metal Ion Effects in Isotopic Hydrogen Exchange in Biologically Important Heterocycles

The binding of metal ions to heteroatomic centers of biomolecules has been utilized as a probe of metal ion effects in living systems. This article focuses on the effect of N-coordination by transition metals, especially Pt(II), Co(III), Cr(III), on isotopic C(2)-H or C(8)-H exchange of imidazoles, thiazoles, and purines. The usual reactivity trend, protonated >> metalated >> neutral substrate, is excepted for Cr(III)/1-methylimidazole, where Cr(III) activates stronger than H(+). An interplay of factors is considered, including metal-to-ligand back-bonding, electronic structure of metal ions, and differences in crystal field stabilization energy.

Sorption of Benzene on AlPO4-5 Containing Various Heteroatoms and Analytical Description of the System

Sorption of benzene on nonsubstituted AlPO4-5 occurs on adsorption centers originating from surface heterogeneity and created by structure defects. The metallic heteroatoms present in the framework of substituted AFI-type materials form additional centers able to bind the benzene molecules. This is equal to an increase of heterogeneity in comparison to nonsubstituted AlPO4-5. Sorption capacity of the MeAPO-5 materials depends on both the content of metal and its distribution throughout the crystals. The distribution parameter plays an important role and may even dominate the effect of the number of metallic heterocenters. Some of the equations based on the Polanyi−Dubinin potential theory can be accepted as suitable for characterizing the distribution of the adsorption potential and adsorption energy of the AFI-type molecular sieves. The dependence between the adsorption potential and the metal content may likely be disturbed by inhomogeneous distribution of the heteroatom centers.

Competitive Intramolecular/Intermolecular Chelation Options Operative during Indium-Promoted Additions to Pyridyl Aldehydes and to Glyoxylic Acid under Aqueous Conditions.

The stereochemical course of the 1,2-addition of six allylindium reagents to 2- and 3-pyridinecarboxaldehyde and to glyoxylic acid has been investigated in order to assess the level and direction of diastereoselectivity in these coupling reactions. When 2-PyCHO is involved, the results strongly suggest that the ring nitrogen becomes chelated to the indium atom in the aqueous environment. One striking observation is the crossover in stereoselectivity seen relative to the use of 3-PyCHO. A second revealing fact is the significantly faster rate of reaction of 2-PyCHO, as long as steric effects are not allowed to interfere. The varying product distributions observed in the latter experiments are attributed to other control elements such as intramolecular chelation within the indium reagent and nonbonded steric restrictions resident in either or both reaction partners. In the absence of extramolecular chelating events (e.g., when 3-PyCHO is involved), adherence to Felkin-Anh transition-state alignments is presumably exercised. The previous working assumption that indium(III) is capable of chelation to flanking heteroatomic centers in water is supported by the present investigation.

The Flavin-containing Monooxygenase 2 Gene (FMO2) of Humans, but Not of Other Primates, Encodes a Truncated, Nonfunctional Protein

Flavin-containing monooxygenases (FMOs) are NADPH-dependent flavoenzymes that catalyze the oxidation of heteroatom centers in numerous drugs and xenobiotics. FMO2, or "pulmonary" FMO, one of five forms of the enzyme identified in mammals, is expressed predominantly in lung and differs from other FMOs in that it can catalyze the N-oxidation of certain primary alkylamines. We describe here the isolation and characterization of cDNAs for human FMO2. Analysis of the sequence of the cDNAs and of a section of the corresponding gene revealed that the major FMO2 allele of humans encodes a polypeptide that, compared with the orthologous protein of other mammals, lacks 64 amino acid residues from its C terminus. Heterologous expression of the cDNA revealed that the truncated polypeptide was catalytically inactive. The nonsense mutation that gave rise to the truncated polypeptide, a C --> T transition in codon 472, is not present in the FMO2 gene of closely related primates, including gorilla and chimpanzee, and must therefore have arisen in the human lineage after the divergence of the Homo and Pan clades. Possible mechanisms for the fixation of the mutation in the human population and the potential significance of the loss of functional FMO2 in humans are discussed.

On the Influence of Heteroatoms in α‐ and β‐Functionalized Alkyl Transition‐Metal Compounds

AbstractThe first homoleptic trimethylsilylmethyl transition‐metal complexes were synthesized about 20 years ago in the research groups of Wilkinson and Lappert, resulting in a significant advance in the understanding of the thermodynamic and kinetic stability of transition‐metal‐carbon σ bonds. The relatively high thermal stability of these bonds provides a dramatic contrast to the Köbrich lithium carbenoids XCH2Li, known for about 30 years and famous for their extraordinarily high reactivity. Both compound classes illustrate that introduction of a heteroatom into an alkyl ligand can have a profound influence on the structure, stability, and reactivity of an alkylmetal compound, opening the possibility of entirely new reactions. Because of their simple and unambiguous structure, α‐ and β‐heteroatom‐substituted transitionmetal compounds containing the unit [MCH2Y] or [MCH2CH2–Y] (where Y is an element from the 4th–7th main groups or groups 14–17, not including C) are particularly suitable for studying effects of the nature of a heteroatom center (neutral/cationic, coordinatively saturated/Lewis basic) on structure, stability, and reactivity as a function of the type of complex, the nature of M, and the number of methylene groups separating M and Y. The diversity of stabilizing and destabilizing influences emanating from the heteroatom center generally produces a broad spectrum of reactivity and stability. This is reflected in an impressive way in homogeneous catalysis, where functionalized alkylmetal compounds arise as intermediates, as well as in the electronic influences of functionalized alkyl ligands, which are determined largely by the nature of the heteroelement present.