N-Heterocyclic Carbene-Catalyzed Synthesis of Ynones via C–H Alkynylation of Aldehydes with Alkynyliodonium Salts

2019 ◽  
Author(s):  
Adam A. Rajkiewicz ◽  
Natalia Wojciechowska ◽  
Marcin Kalek
Keyword(s):  
Density Functional ◽  
Bond Formation ◽  
Kinetic Studies ◽  
Density Functional Theory Calculations ◽  
Hypervalent Iodine ◽  
Functional Theory ◽  
Leaving Group ◽  
13C Labelling ◽  
Reaction Proceeds ◽  
Mechanism Of The Reaction

Alkynylation of aldehydes with alkynyl(aryl)iodonium salts catalyzed by an N-heterocyclic carbene (NHC) has been developed. The application of the organocatalyst and the hypervalent iodine group-transfer reagent allowed for metal-free C–H functionalization and C–C bond formation. The reaction proceeds under exceptionally mild conditions, at –40 ⁰C and in the presence of an amine base, providing access to an array of heteroaryl-propargyl ketones containing various substituents in good to excellent yields. The mechanism of the reaction was investigated by means of both experiments and density functional theory calculations. 13C-labelling and computations determined that the key alkynyl transfer step occurs via an unusual direct SN2 substitution of iodine-based leaving group by Breslow intermediate nucleophile at an acetylenic carbon. Moreover, kinetic studies revealed that the turnover-limiting step of the catalytic cycle is the generation of the Breslow intermediate, whereas the subsequent C–C bond-formation is a fast process. These results were fully reproduced and rationalized by the computed full free energy profile of the reaction, showing that the largest energy span is located between protonated NHC and the transition state for the carbene attack on the aldehyde substrate.<br>

scholarly journals N-Heterocyclic Carbene-Catalyzed Synthesis of Ynones via C–H Alkynylation of Aldehydes with Alkynyliodonium Salts

2019 ◽  
Author(s):  
Adam A. Rajkiewicz ◽  
Natalia Wojciechowska ◽  
Marcin Kalek
Keyword(s):  
Density Functional ◽  
Bond Formation ◽  
Kinetic Studies ◽  
Density Functional Theory Calculations ◽  
Hypervalent Iodine ◽  
Functional Theory ◽  
Leaving Group ◽  
13C Labelling ◽  
Reaction Proceeds ◽  
Mechanism Of The Reaction

Alkynylation of aldehydes with alkynyl(aryl)iodonium salts catalyzed by an N-heterocyclic carbene (NHC) has been developed. The application of the organocatalyst and the hypervalent iodine group-transfer reagent allowed for metal-free C–H functionalization and C–C bond formation. The reaction proceeds under exceptionally mild conditions, at –40 ⁰C and in the presence of an amine base, providing access to an array of heteroaryl-propargyl ketones containing various substituents in good to excellent yields. The mechanism of the reaction was investigated by means of both experiments and density functional theory calculations. 13C-labelling and computations determined that the key alkynyl transfer step occurs via an unusual direct SN2 substitution of iodine-based leaving group by Breslow intermediate nucleophile at an acetylenic carbon. Moreover, kinetic studies revealed that the turnover-limiting step of the catalytic cycle is the generation of the Breslow intermediate, whereas the subsequent C–C bond-formation is a fast process. These results were fully reproduced and rationalized by the computed full free energy profile of the reaction, showing that the largest energy span is located between protonated NHC and the transition state for the carbene attack on the aldehyde substrate.<br>

scholarly journals Demystifying the Soai Reaction

2019 ◽  
Author(s):  
Soumitra Athavale ◽  
Adam Simon ◽  
Kendall N. Houk ◽  
Scott Denmark
Keyword(s):  
Density Functional ◽  
Spectroscopic Analysis ◽  
Chiral Symmetry Breaking ◽  
Kinetic Studies ◽  
Density Functional Theory Calculations ◽  
Functional Theory ◽  
Group Transfer ◽  
Linear Behavior ◽  
Structural Mutations ◽  
Soai Reaction

The extraordinary Soai reaction has profoundly impacted chemists’ perspective of chiral symmetry breaking, absolute asymmetric synthesis and its role in the origin of biological homochirality. Herein, we describe the unprecedented observation of asymmetry amplifying autocatalysis in the alkylation of 5-(trimethylsilylethynyl)pyridine-3-carbaldehyde using diisopropylzinc. Kinetic studies with a “Trojan-horse” substrate and spectroscopic analysis of a series of zinc-alkoxides that incorporate specific structural mutations reveal a ‘pyridine-assisted cube escape’. The new cluster functions as a catalyst that activates the ‘floor-to-floor’ bound aldehyde and poises a coordinated diisopropylzinc moiety for alkyl group transfer. Transitionstate models leading to both the homochiral and heterochiral products were validated by density functional theory calculations. Moreover, experimental and computational analysis of the heterochiral complex provides a definitive explanation for the non-linear behavior of this system. Our deconstruction of the Soai system contributes substantially to understanding the mechanism of this transformation that has stood as a longstanding challenge in chemistry.<br>

scholarly journals Stereoretention in Styrene Heterodimerisation Promoted by One-Electron Oxidants

2020 ◽  
Author(s):  
Xinglong Zhang ◽  
Robert Paton
Keyword(s):  
Radical Cation ◽  
Density Functional ◽  
Bond Formation ◽  
Radical Cations ◽  
Reactive Intermediates ◽  
The Other ◽  
Reduced Form ◽  
Hypervalent Iodine ◽  
Functional Theory ◽  
Ambient Temperatures

<p>Radical cations generated from the oxidation of C=C p-bonds are synthetically useful reactive intermediates for C–C and C–X bond formation. Radical cation formation, induced by sub-stoichiometric amounts of external oxidant, are important intermediates in the Woodward-Hoffmann thermally disallowed [2+2] cycloaddition of electron-rich alkenes. Using density functional theory (DFT), we report the detailed mechanisms underlying the intermolecular heterodimerisation of anethole and β-methylstyrene to give unsymmetrical, tetra-substituted cyclobutanes. Reactions between <i>trans</i>-alkenes favour the <i>all-trans</i> adduct, resulting from a kinetic preference for <i>anti</i>-addition reinforced by reversibility at ambient temperatures since this is also the thermodynamic product; on the other hand, reactions between a <i>trans</i>-alkene and a <i>cis</i>-alkene favour <i>syn</i>-addition, while exocyclic rotation in the acyclic radical cation intermediate is also possible since C-C forming barriers are higher. Computations are consistent with the experimental observation that hexafluoroisopropanol (HFIP) is a better solvent than acetonitrile, in part due to its ability to stabilize the reduced form of the hypervalent iodine initiator by hydrogen bonding, but also through the stabilisation of radical cationic intermediates along the reaction coordinate.</p>

scholarly journals Hypervalent Iodine-Mediated Styrene Hetero- and Homodimerization Initiation Proceeds with Two-Electron Reductive Cleavage

2020 ◽  
Author(s):  
Aqeel A. Hussein ◽  
Yumiao Ma ◽  
Ahmed Al-Yasari
Keyword(s):  
Electron Transfer ◽  
Density Functional ◽  
Reductive Cleavage ◽  
Hypervalent Iodine ◽  
Functional Theory ◽  
Concerted Mechanism ◽  
Bonding Interaction ◽  
Reaction Proceeds ◽  
Dynamics Simulations ◽  
Insight Into

<p><a>A mechanistic insight into </a>the hetero- and homodimerizations (HETD and HOMD) of styrenes promoted by hypervalent iodine reagents (HVIRs; <b>DMP</b> and <b>PIDA</b>) and facilitated by HFIP to yield all <i>trans</i> cyclobutanes is reported using density functional theory (DFT) calculations. The initialization involving direct bimolecular one-electron transfer is found to be highly unfavored, especially for the <b>PIDA</b> system. At this point, we suggest that the reaction is initiated with an overall two-electron reductive cleavage of two I─O bond cleavages, affording I(III) (iodinane) and I(I) (iodobenzene) product with DMP and PIDA as oxidant, respectively. The resulting acetate groups are stabilized by the solvent HFIP through strong hydrogen bonding interaction, which promotes the electron transfer process. The nature of the electron transfer is studied in detail and found that the overall two-electron transfer occurs within tri-molecular complex organized by π-stacking interactions and as a stepwise and concerted mechanism for I(III) and I(V) oxidants, respectively. The reaction rate is determined by the initialization step: for I(III), the initiation is thermodynamically endergonic, whereas the endergonicity for I(V) is modest. Upon initialization, the reaction proceeds through a stepwise [2+2] pathway, involving a radical-cationic π-π stacked intermediate, either hetero- or homodimerized. DFT results supported by quasiclassical molecular dynamics simulations show that HOMD is dynamically competing pathway to HETD although the latter is relatively faster, in accordance with experimental observations. </p>

scholarly journals Hypervalent Iodine-Mediated Styrene Hetero- and Homodimerization Initiation Proceeds with Two-Electron Reductive Cleavage

2020 ◽  
Author(s):  
Aqeel A. Hussein ◽  
Yumiao Ma ◽  
Ahmed Al-Yasari
Keyword(s):  
Electron Transfer ◽  
Density Functional ◽  
Reductive Cleavage ◽  
Hypervalent Iodine ◽  
Functional Theory ◽  
Concerted Mechanism ◽  
Bonding Interaction ◽  
Reaction Proceeds ◽  
Dynamics Simulations ◽  
Insight Into

<p><a>A mechanistic insight into </a>the hetero- and homodimerizations (HETD and HOMD) of styrenes promoted by hypervalent iodine reagents (HVIRs; <b>DMP</b> and <b>PIDA</b>) and facilitated by HFIP to yield all <i>trans</i> cyclobutanes is reported using density functional theory (DFT) calculations. The initialization involving direct bimolecular one-electron transfer is found to be highly unfavored, especially for the <b>PIDA</b> system. At this point, we suggest that the reaction is initiated with an overall two-electron reductive cleavage of two I─O bond cleavages, affording I(III) (iodinane) and I(I) (iodobenzene) product with DMP and PIDA as oxidant, respectively. The resulting acetate groups are stabilized by the solvent HFIP through strong hydrogen bonding interaction, which promotes the electron transfer process. The nature of the electron transfer is studied in detail and found that the overall two-electron transfer occurs within tri-molecular complex organized by π-stacking interactions and as a stepwise and concerted mechanism for I(III) and I(V) oxidants, respectively. The reaction rate is determined by the initialization step: for I(III), the initiation is thermodynamically endergonic, whereas the endergonicity for I(V) is modest. Upon initialization, the reaction proceeds through a stepwise [2+2] pathway, involving a radical-cationic π-π stacked intermediate, either hetero- or homodimerized. DFT results supported by quasiclassical molecular dynamics simulations show that HOMD is dynamically competing pathway to HETD although the latter is relatively faster, in accordance with experimental observations. </p>

scholarly journals Demystifying the Soai Reaction

2019 ◽  
Author(s):  
Soumitra Athavale ◽  
Adam Simon ◽  
Kendall N. Houk ◽  
Scott Denmark
Keyword(s):  
Density Functional ◽  
Spectroscopic Analysis ◽  
Chiral Symmetry Breaking ◽  
Kinetic Studies ◽  
Density Functional Theory Calculations ◽  
Functional Theory ◽  
Group Transfer ◽  
Linear Behavior ◽  
Structural Mutations ◽  
Soai Reaction

The extraordinary Soai reaction has profoundly impacted chemists’ perspective of chiral symmetry breaking, absolute asymmetric synthesis and its role in the origin of biological homochirality. Herein, we describe the unprecedented observation of asymmetry amplifying autocatalysis in the alkylation of 5-(trimethylsilylethynyl)pyridine-3-carbaldehyde using diisopropylzinc. Kinetic studies with a “Trojan-horse” substrate and spectroscopic analysis of a series of zinc-alkoxides that incorporate specific structural mutations reveal a ‘pyridine-assisted cube escape’. The new cluster functions as a catalyst that activates the ‘floor-to-floor’ bound aldehyde and poises a coordinated diisopropylzinc moiety for alkyl group transfer. Transitionstate models leading to both the homochiral and heterochiral products were validated by density functional theory calculations. Moreover, experimental and computational analysis of the heterochiral complex provides a definitive explanation for the non-linear behavior of this system. Our deconstruction of the Soai system contributes substantially to understanding the mechanism of this transformation that has stood as a longstanding challenge in chemistry.<br>

scholarly journals Hypervalent Iodine-Mediated Styrene Hetero- and Homodimerization Initiation Proceeds with Two-Electron Reductive Cleavage

2020 ◽  
Author(s):  
Aqeel A. Hussein ◽  
Yumiao Ma ◽  
Ahmed Al-Yasari
Keyword(s):  
Electron Transfer ◽  
Density Functional ◽  
Reductive Cleavage ◽  
Hypervalent Iodine ◽  
Functional Theory ◽  
Concerted Mechanism ◽  
Bonding Interaction ◽  
Reaction Proceeds ◽  
Dynamics Simulations ◽  
Insight Into

<p><a>A mechanistic insight into </a>the hetero- and homodimerizations (HETD and HOMD) of styrenes promoted by hypervalent iodine reagents (HVIRs; <b>DMP</b> and <b>PIDA</b>) and facilitated by HFIP to yield all <i>trans</i> cyclobutanes is reported using density functional theory (DFT) calculations. The initialization involving direct bimolecular one-electron transfer is found to be highly unfavored, especially for the <b>PIDA</b> system. At this point, we suggest that the reaction is initiated with an overall two-electron reductive cleavage of two I─O bond cleavages, affording I(III) (iodinane) and I(I) (iodobenzene) product with DMP and PIDA as oxidant, respectively. The resulting acetate groups are stabilized by the solvent HFIP through strong hydrogen bonding interaction, which promotes the electron transfer process. The nature of the electron transfer is studied in detail and found that the overall two-electron transfer occurs within tri-molecular complex organized by π-stacking interactions and as a stepwise and concerted mechanism for I(III) and I(V) oxidants, respectively. The reaction rate is determined by the initialization step: for I(III), the initiation is thermodynamically endergonic, whereas the endergonicity for I(V) is modest. Upon initialization, the reaction proceeds through a stepwise [2+2] pathway, involving a radical-cationic π-π stacked intermediate, either hetero- or homodimerized. DFT results supported by quasiclassical molecular dynamics simulations show that HOMD is dynamically competing pathway to HETD although the latter is relatively faster, in accordance with experimental observations. </p>

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