Nucleophilic Functionalization Research Articles

A Bifunctional Reagent Designed for the Mild, Nucleophilic Functionalization of Pyridines.

Herein is reported the design and application of a reagent for the direct functionalization of pyridines. These reactions occur under mild conditions and exhibit broad functional group tolerance, enabling the late-stage functionalization of drug-like molecules. The reagent can be easily prepared on large scale from inexpensive reagents, and reacts in the title reaction with acetonitrile, sodium chloride, and sodium methanesulfonate as the sole byproducts. Although this Communication focuses primarily on reactions with cyanide as nucleophile, preliminary experiments with other nucleophiles foreshadow the broad reaching synthetic utility of this approach.

A DFT computational study on the molecular mechanism of reaction between pyridinium salts and π-deficient ethylenes: Why furan derivatives are formed instead of feasible cyclopropane derivatives and [3 + 2] cycloadducts?

The reaction between 1-(2-amino-2-oxoethyl)pyridinium ylide 4 (PY4) and 1-methylene-3,4-dihydronaphthalen-2(1H)-one 5 (MDN5) in the presence of acetonitrile (CH3CN) was theoretically studied at the M06-2X/6-31G(d,p) computational level. Calculated relative Gibbs free energies indicate that encounters between PY4 and MDN5 in the reaction mixture result in the formation of the highly zwitterionic betaine-like intermediate IM1ca in an entirely C1C5 regio- and a cisoid-anti stereoselective manner over the course of a Michael addition reaction through a very low barrier (4.2kcal/mol) and a highly exergonic (24.7kcal/mol) pathway. While C1C5 regioselectivity can be rationalized via the analysis of the computed nucleophilic and electrophilic Parr functions at the reactive sites of reagents, the cisoid-anti stereoselectivity predominance over the cisoid-syn one can nicely be portrayed within the non-covalent interactions (NCIs) analysis at the cisoid-anti transition state TS1ca and cisoid-syn transition state TS1cs involved in the Michael addition reaction. The electron-localization function (ELF) quantum topological analysis obviously demonstrates that the C1 carbon atom in PY4 exhibits a pseudoradical character indicating the high reactivity of PY4 toward C5 electrophilic attack of MDN5 which is characterized with a very low barrier associated with the C1C5 single bond formation along the Michael addition step. Upon formation of IM1ca, in excellent agreement with the experimental outcomes, an SNi-like reaction converts IM1ca into trans-furan derivative 8 together with pyridine via a high barrier (23.9kcal/mol) but a highly irreversible pathway making compound 8 as the only reachable product under “thermodynamically-controlled” conditions (refluxing over 8h). In other words, neither [3+2] cycloadduct 6 (as the kinetically most favourable but thermodynamically most unfavourable product) nor cyclopropane derivative 7 (as both kinetically and thermodynamically most undesirable product) can be obtained under the reaction conditions. From the molecular mechanism point of view, the ELF analyses indicate that while C1C5 single bond formation within the Michael addition reaction takes place via a C- to -C coupling of two pseudoradical C1 and C5 centers, formation of C1O8 single bond accompanied with the C1N15 single bond breaking at the generated IM1ca to afford compound 8 is a direct consequence of donation of some electron density of O8 oxygen lone electron pairs to the C1 carbon atom.

Toward understanding regioselectivity and molecular mechanism in the synthesis of CF2H-containing 2-pyrazolines: A molecular electron-density theory study

The domino process between a CF2H-containing diazoalkane, DAA 2, and an electron-deficient alkene, ANI 3, in the presence of chloroform was theoretically studied at the DFT-MPWB1 K/6-311G(d,p) computational level. The initializing step in this domino process is associated with the C1 nucleophilic attack of DAA 2 at the C4 carbon atom of ANI 3 over the course of a polar zw-type 32CA reaction in an entirely C1-C4 regioselective manner to furnish corresponding 1-pyrazoline derivative CA1n. While a stepwise 1,3-H shift reaction assisted by an acetate anion and/or a thermal N2 extrusion reaction can subsequently convert CA1n into corresponding 2- pyrazoline PYZ 4 or cyclopropane CP 5 derivatives, respectively, exploration of the relative Gibbs free energy profile evidently demonstrates that experimentally isolated PYZ 4 is the only reachable product of the studied domino reaction. Analysis of the calculated nucleophilic and electrophilic Parr functions at the reactive sites of DAA 2 and ANI 3, respectively, rationalizes the C1-C4 regioselectivity observed experimentally. An electron localization function (ELF) topological analysis of some selected points along the most favorable reactive channel involved in the initializing 32CA reaction allows establishing a non-concerted two-stage one-step molecular mechanism for the 32CA reaction of DAA 2 toward ANI 3.

Secondary Phosphine Oxides as Multitalented Preligands En Route to the Chemoselective Palladium‐Catalyzed Oxidation of Alcohols

AbstractSecondary phosphine oxides O=PHR2 (SPOs) were identified as multitalented preligands for the chemoselective Pd‐catalyzed oxidation of alcohols by a hydrogen‐abstracting methodology. SPOs were found to promote the hydrogen‐abstraction step as well as hydrogen transfer to a Michael acceptor by generating a putative active H−Pd species. The catalytic system operates under neutral conditions and was proven to be compatible with various electrophilic and nucleophilic functionalities within the substrates as well as water‐ and air‐sensitive functional groups.

Local chemical potential, local hardness, and dual descriptors in temperature dependent chemical reactivity theory.

In this work we establish a new temperature dependent procedure within the grand canonical ensemble, to avoid the Dirac delta function exhibited by some of the second order chemical reactivity descriptors based on density functional theory, at a temperature of 0 K. Through the definition of a local chemical potential designed to integrate to the global temperature dependent electronic chemical potential, the local chemical hardness is expressed in terms of the derivative of this local chemical potential with respect to the average number of electrons. For the three-ground-states ensemble model, this local hardness contains a term that is equal to the one intuitively proposed by Meneses, Tiznado, Contreras and Fuentealba, which integrates to the global hardness given by the difference in the first ionization potential, I, and the electron affinity, A, at any temperature. However, in the present approach one finds an additional temperature-dependent term that introduces changes at the local level and integrates to zero. Additionally, a τ-hard dual descriptor and a τ-soft dual descriptor given in terms of the product of the global hardness and the global softness multiplied by the dual descriptor, respectively, are derived. Since all these reactivity indices are given by expressions composed of terms that correspond to products of the global properties multiplied by the electrophilic or nucleophilic Fukui functions, they may be useful for studying and comparing equivalent sites in different chemical environments.

Phosphine-Promoted Migrative Cyclization of Sulfonylalkynol and Sulfonylalkynamide for the Synthesis of Oxa- and Azacycles

A catalytic amount of phosphine or DMAP promoted the migrative cyclization of propargyl sulfones bearing an internal nucleophilic functionality in a γ-umpolung manner.

Environmental Electrophiles: Protein Adducts, Modulation of Redox Signaling, and Interaction with Persulfides/Polysulfides.

Included among the many environmental electrophiles are aromatic hydrocarbon quinones formed during combustion of gasoline, crotonaldehyde in tobacco smoke, methylmercury accumulated in fish, cadmium contaminated in rice, and acrylamide in baked foods. These electrophiles can modify nucleophilic functions such as cysteine residues in proteins forming adducts and in the process activate cellular redox signal transduction pathways such as kinases and transcription factors. However, higher concentrations of electrophiles disrupt such signaling by nonselective covalent modification of cellular proteins. Persulfide/polysulfides produced by various enzymes appear to capture environmental electrophiles because of the formation of their sulfur adducts without electrophilicity. We therefore speculate that persulfide/polysulfides are candidates for the regulation of redox signal transduction pathways (e.g., cell survival, cell proliferation, and adaptive response) and toxicity during exposure to environmental electrophiles.

Cooperative Pd(0)/Rh(II) Dual Catalysis: Interceptive Capturing of π-Allyl Pd(II) Complexes with α-Imino Rh(II) Carbenoids

Extensive effort has been expended to utilize π-allyl palladium complexes as electrophilic allyl donor intermediates in cooperative dual catalysis, but their counteranions such as carboxylates and alkoxides are almost always discarded as waste. We have developed a cooperative Pd(0)/Rh(II) dual-catalysis system that utilizes both electrophilic allyl and nucleophilic counteranion functionalities inherent in the starting allylic substrates. In this cooperative catalysis, redox-compatible Pd(0) and Rh(II) catalysts selectively activate allylic substrates and N-sulfonyl-1,2,3-triazoles to generate π-allyl Pd(II) complexes and 1,3-ambivalent equivalent α-imino Rh(II) carbenoid intermediates, respectively. The counteranion of the π-allyl Pd(II) complex acts as a nucleophile transferring to the electrophilic carbenic carbon to form Pd/Rh-associated zwitterionic intermediates, in which the cationic palladium species may coordinate with both counteranion and imine nitrogen in the same plane, establishing the Z geom...

The efficient synthesis of diethyl carbonate via coupling reaction from propylene oxide, CO2 and ethanol over binary PVEImBr/MgO catalyst

Direct synthesis of diethyl carbonate (DEC) from propylene oxide, CO2 and ethanol via coupling reaction over a heterogeneous catalyst was demonstrated. In this work, a cross linked poly(ionic liquid) containing poly(1-vinyl-3-ethylimidazolium bromide)(PVEImBr) moiety was prepared via a free radical polymerization. Meanwhile, the MgO nanoplatelet with abundant basic sites was prepared, which was combined with PVEImBr to form a composite catalyst of PVEImBr/MgO. N2 physisorption, TG, XRD, SEM, CO2-TPD and FT-IR were conducted to thoroughly characterize the structure and texture of the catalysts. The as-prepared heterogeneous catalyst, which simultaneously possessed the dual function of nucleophilicity and basicity, was used in the coupling reaction of propylene oxide, CO2 and ethanol to synthesize diethyl carbonate and propylene glycol. The composite catalyst could promote the reaction with high efficiency, and a good catalytic performance of 54.4% diethyl carbonate yield and 59.8% propylene glycol yield could be achieved. The 1H NMR and DFT calculation disclosed that greatly faster reaction rate was ascribed to the synergistic effect between the BrƟ anion of PVEImBr and hydroxyl group of ethanol. Accordingly, a mechanism of the sequential reaction consisting of cycloaddition and transesterification steps was proposed.

ChemInform Abstract: Rhodium‐Catalyzed C—S and C—N Functionalization of Arenes: Combination of C—H Activation and Hypervalent Iodine Chemistry.

AbstractSulfonylation, thioetherification, thiocyanation, and other heterofunctionalization reactions of arenes bearing a pyridyl‐directing group are achieved via initial Rh(II)‐catalyzed C—H hyperiodination of the arenes followed by uncatalyzed nucleophilic functionalization.

Tandem Long Distance Chain-Walking/Cyclization via RuH2(CO)(PPh3)3/Brønsted Acid Catalysis: Entry to Aromatic Oxazaheterocycles.

A novel route to 1,3-oxazaheterocycles based on cooperative Ru-H/Brønsted acid catalysis is reported. The use of the commercially available RuH2(CO)(PPh3)3 complex allows for an efficient long distance chain-walking process while the Brønsted acid is responsible for generation of an electrophilic iminium ion which is trapped intramolecularly by an alcohol moiety. The alcohol, besides its nucleophilic function, also plays an important role in the stabilization of the Ru catalyst.

Rhodium-Catalyzed C-S and C-N Functionalization of Arenes: Combination of C-H Activation and Hypervalent Iodine Chemistry.

Rhodium-catalyzed sulfonylation, thioetherification, thiocyanation, and other heterofunctionalizations of arenes bearing a heterocyclic directing group have been realized. The reaction proceeds by initial Rh(III) -catalyzed C-H hyperiodination of arene at room temperature followed by uncatalyzed nucleophilic functionalization. A diaryliodonium salt is isolated as an intermediate, which represents umpolung of the arene substrate, in contrast to previous studies that suggested umpolung of the coupling partner.

Differential protein labeling based on electrochemically generated reactive intermediates.

A specific labeling method for cysteine moieties in proteins was developed. Electrochemical oxidation of phenolic compounds such as phenol or acetaminophen leads to the generation of the reactive intermediates benzoquinone and N-acetyl-p-benzoquinone imine, which can subsequently react with nucleophilic thiol functions in peptides or proteins. Differential labeling of cysteine residues was successfully demonstrated with native as well as heavy-isotope labeled forms of the corresponding labeling compounds. The specific mass differences on the peptide level were successfully analyzed by mass spectrometry for the tripeptide glutathione. Free cysteines in various proteins such as β-lactoglobulin A, human serum albumin, hemoglobin, and human carbonic anhydrase I were successfully labeled. Tryptic digestion of differentially labeled carbonic anhydrase I and hemoglobin allowed the identification of the binding site in the proteins. The obtained mass difference allowed an easy identification of the cysteine containing peptides. With these experiments, it was successfully demonstrated that the developed method can serve as a tool for counting cysteine moieties in proteins and, thus, be used as an additional technique in protein identification experiments.

Novel pathways for fuels and lubricants from biomass optimized using life-cycle greenhouse gas assessment

Decarbonizing the transportation sector is critical to achieving global climate change mitigation. Although biofuels will play an important role in conventional gasoline and diesel applications, bioderived solutions are particularly important in jet fuels and lubricants, for which no other viable renewable alternatives exist. Producing compounds for jet fuel and lubricant base oil applications often requires upgrading fermentation products, such as alcohols and ketones, to reach the appropriate molecular-weight range. Ketones possess both electrophilic and nucleophilic functionality, which allows them to be used as building blocks similar to alkenes and aromatics in a petroleum refining complex. Here, we develop a method for selectively upgrading biomass-derived alkyl methyl ketones with >95% yields into trimer condensates, which can then be hydrodeoxygenated in near-quantitative yields to give a new class of cycloalkane compounds. The basic chemistry developed here can be tailored for aviation fuels as well as lubricants by changing the production strategy. We also demonstrate that a sugarcane biorefinery could use natural synergies between various routes to produce a mixture of lubricant base oils and jet fuels that achieve net life-cycle greenhouse gas savings of up to 80%.

Regioselective Nucleophilic Functionalization of Antiaromatic Nickel(II) Norcorroles

AbstractTreatment of antiaromatic nickel(II) norcorrole with potassium cyanide provided nickel(II) 3‐cyanonorcorrole with perfect regioselectivity without the help of a catalyst. The reaction of the nickel(II) norcorrole with phenol or thiophenol in the presence of a base also yielded substitution products. The antiaromatic 16π conjugation system in the norcorrole core was preserved in the functionalized products. Introduction of phenylthio groups significantly decreased the HOMO–LUMO gap and enhanced the near IR absorption property.

Regioselective Nucleophilic Functionalization of Antiaromatic Nickel(II) Norcorroles.

Treatment of antiaromatic nickel(II) norcorrole with potassium cyanide provided nickel(II) 3-cyanonorcorrole with perfect regioselectivity without the help of a catalyst. The reaction of the nickel(II) norcorrole with phenol or thiophenol in the presence of a base also yielded substitution products. The antiaromatic 16π conjugation system in the norcorrole core was preserved in the functionalized products. Introduction of phenylthio groups significantly decreased the HOMO-LUMO gap and enhanced the near IR absorption property.

Density functional theory molecular modelling and experimental particle kinetics for CO2–char gasification

Experimental measurements and DFT atomistic modelling were conducted to elucidate the mechanisms for gasification chemistry of char with CO2 gas. The molecular models used were based on experimental representations of coal chars derived from the vitrinite- and inertinite-rich South African coals at 1000°C. The HRTEM and XRD techniques were used to construct parallelogram-shaped PAH stacks of highest frequency in the vitrinite-rich (7×7) and intertinite-rich (11×11) char structures. Computations were executed to get the nucleophilic Fukui functions, at DFT–DNP level, to elucidate the nature and proportions of carbon active sites and quantify their reactivity. The DFT–DNP-computed reaction pathways and transition states, to obtain the energy of reaction and activation energies for the gasification reactions of CO2 with active carbon sites were examined. These results were compared with TGA experimental results at 900–980°C. The mean nucleophilic Fukui function of the H-terminated char models and active sites located at similar edge positions decreased with increasing size of char molecules and followed the sequence: zigzag>armchair>tip active sites. The mean DFT–DNP values for the activation energy of 233kJmol−1 at the reactive carbon edge was in agreement with the experimental 191±25kJmol−1 and 210±8kJmol−1 for the respective chars.

Diaryliodoniums by Rhodium(III)‐Catalyzed CH Activation: Mild Synthesis and Diversified Functionalizations

AbstractDiaryliodonium salts play an increasingly important role as an aryl source. Reported is the first synthesis of diaryliodoniums by rhodium(III)‐catalyzed CH hyperiodination of electron‐poor arenes under chelation assistance. This CI coupling reaction occurred at room temperature with high regio‐selectivity and functional‐group compatibility. Subsequent diversified nucleophilic functionalization of a diaryliodonium allowed facile construction of CC, CN, CO, CS, CP and CBr bonds, and in all cases the initial functionalization occurred at the arene containing the chelating‐group.

Diaryliodoniums by Rhodium(III)-Catalyzed C-H Activation: Mild Synthesis and Diversified Functionalizations.

Diaryliodonium salts play an increasingly important role as an aryl source. Reported is the first synthesis of diaryliodoniums by rhodium(III)-catalyzed C-H hyperiodination of electron-poor arenes under chelation assistance. This C-I coupling reaction occurred at room temperature with high regio-selectivity and functional-group compatibility. Subsequent diversified nucleophilic functionalization of a diaryliodonium allowed facile construction of C-C, C-N, C-O, C-S, C-P and C-Br bonds, and in all cases the initial functionalization occurred at the arene containing the chelating-group.

Synthetic Amino Acids for Applications in Peptide Ligation–Desulfurization Chemistry

Native chemical ligation is a powerful tool for the convergent assembly of homogeneous peptide and protein targets from unprotected peptide fragments. The method involves the chemoselective coupling of a peptide thioester with a peptide bearing an N-terminal cysteine (Cys) residue and is mediated by the nucleophilic Cys thiol functionality. A widely adopted extension of the technique for the disconnection of protein targets at alanine (Ala) ligation junctions has been the application of post-ligation desulfurization protocols for the mild removal of the Cys thiol moiety. Recently, attention has turned to the construction of synthetic amino acid building blocks bearing suitably positioned β-, γ-, or δ-thiol ligation auxiliaries with a view to expanding the scope of the ligation–desulfurization manifold. To date, several thiol-derived amino acids have been prepared, greatly increasing the generality and flexibility of chemoselective ligation technologies for the chemical synthesis of diverse protein targets. This review will highlight the current synthetic approaches to these important amino acid building blocks.