Dimethylcuprate-Catalyzed Decarboxylative Coupling of Allyl Acetate

Allylic alkylation of organocuprates represents an important class of C–C bond forming reactions. A drawback of these reactions is their stoichiometric nature. Although metal-catalyzed decarboxylative coupling reactions offer new opportunities for formation of C–C bonds, catalytic allylic alkylation reactions of organocuprates have not been previously reported. Here, multistage mass spectrometry experiments performed on ion trap mass spectrometers in conjunction with electronic structure calculations are used to demonstrate that the dimethylcuprate anion, [CH₃CuCH₃]⁻, can catalyze decarboxylative coupling of allyl acetate in the gas phase via a simple two-step catalytic cycle. In step 1, [CH₃CuCH₃]⁻ undergoes a cross-coupling reaction with allyl acetate to yield [CH₃CuO₂CCH₃]⁻ as the major product ion. Step 2 involves subjecting the product ion to collision-induced decarboxylation to re-form [CH₃CuCH₃]⁻, thereby closing the catalytic cycle. Since the details of step 2 have been previously described (Rijs, N.; Khairallah, G. N.; Waters, T.; O’Hair, R. A. J. J. Am. Chem. Soc. 2008, 130, 1069−1079), here the focus is on step 1. Comparison of the reactivity of dimethylcuprate toward allylic susbtrates reveals that while allyl acetate reacts around 70 times more slowly than allyl iodide, it is more selective for cross-coupling. This is rationalized by DFT calculations, which reveal that an increase in kinetic barrier is responsible for both reactivity trends. The lowest energy path was found to involve a stepwise π-oxidative addition proceeding via an η²-C₃H₅O₂CCH₃ intermediate and extrusion of a leaving group (LG) anion, followed by a reductive elimination where this LG is recomplexed to the copper center. Finally, DFT calculations were used to shed light on the role of leaving groups LG = CH₃CO₂^–, I^–, Br^–, Cl^– in the allylic alkylation. While selectivity is indeed achieved at the cost of reactivity, the LG effects were more complex than can be accounted for by a simple consideration of the anion proton affinity (APA) of the LG

Dimethylcuprate-Mediated Transformation of Acetate to Dithioacetate

Dithiocarboxylic acids, RCS₂H, and their esters, RCS₂R′, are useful reagents that can be synthesized by the reaction of carbon disulfide with organometallic reagents. Here the coinage-metal-mediated transformation of acetate to dithioacetate is explored in the gas phase using multistage mass spectrometry experiments in a linear ion trap mass spectrometer in conjunction with density functional theory (DFT) calculations. The ion–molecule reactions between coinage-metal dimethylmetalate anions [CH₃MCH₃]⁻ (M = Au, Ag, Cu), formed via double decarboxylation of the metal acetate anions, [CH₃CO₂MO₂CCH₃]⁻, and carbon disulfide, were examined. Only [CH₃CuCH₃]⁻ reacts with CS₂ with a reaction efficiency of 0.8% of the collision rate to yield the adduct [CH₃CuS₂CCH₃]⁻ (77.5%) as well as CH₃CS₂^– (22.5%). Collision-induced dissociation (CID) of the adduct [CH₃CuS₂CCH₃]⁻ gives CH₃CS₂^– as the major product, with a small amount of [CuS₂CCH₂]⁻ being formed via loss of methane. DFT calculations reveal the following. (i) [CH₃CuCH₃]⁻ reacts via oxidative addition to form a Cu­(III) intermediate, followed by reductive elimination of CH₃CS₂^–, which is captured by Cu to form [CH₃CuS₂CCH₃]⁻. This energetic adduct can fragment via loss of CH₃CS₂^– or can be collisionally cooled by the helium bath gas used in the experiments. (ii) Loss of CH₄ from [CH₃CuS₂CCH₃]⁻ also involves a Cu­(III) intermediate and results in formation of the metalladithiolactone [Cu­(CH₂CS₂)]⁻

Nontargeted Identification of Reactive Metabolite Protein Adducts

Metabolic bioactivation of many different chemicals results in the formation of highly reactive compounds (chemically reactive metabolites, CRMs) that can lead to toxicity via binding to macromolecular targets (e.g., proteins or DNA). There is a need to develop robust, rapid, and nontargeted analytical techniques to determine the identity of the protein targets of CRMs and their sites of modification. Here, we introduce a nontargeted methodology capable of determining both the identity of a CRM formed from an administered compound as well as the protein targets modified by the reactive metabolite in a single experiment without prior information. Acetaminophen (<i>N</i>-acetyl-<i>p</i>-aminophenol, APAP) and ¹³C₆-APAP were incubated with rat liver microsomes, which are known to bioactivate APAP to the reactive metabolite <i>N</i>-acetyl-<i>p</i>-benzoquinone imine (NAPQI). Global tryptic digestion followed by liquid chromatographic/mass spectrometric (LC/MS) analysis was used to locate “twin” ion peaks of peptides adducted by NAPQI and for shotgun proteomics via tandem mass spectrometry (MS/MS). By the development of blended data analytics software called Xenophile, the identity of the amino acid residue that was adducted can be established, which eliminates the need for specific parametrization of protein database search algorithms. This combination of experimental design and data analysis software allows the identity of a CRM, the protein target, and the amino acid residues that are modified to be rapidly established directly from experimental data. Xenophile is freely available from https://github.com/mgleeming/Xenophile

Mass Spectrometric and Computational Studies on the Reaction of Aromatic Peroxyl Radicals with Phenylacetylene Using the Distonic Radical Ion Approach

Product and mechanistic studies were performed for the reaction of aromatic distonic peroxyl radical cations 4-PyrOO^•+ and 3-PyrOO^•+ with phenylacetylene (<b>7</b>) in the gas phase using mass spectrometric and computational techniques. PyrOO^•+ was generated through reaction of the respective distonic aryl radical cation Pyr^•+ with O₂ in the ion source of the mass spectrometer. For the reaction involving the more electrophilic 4-PyrOO^•+, a rate coefficient of <i>k</i>₁ = (2.2 ± 0.6) × 10^–10 cm³ molecule^–1 s^–1 was determined at 298 K, while a value of <i>k</i>₂ = (8.2 ± 2.1) × 10^–11 cm³ molecule^–1 s^–1 was obtained for the reaction involving the less electrophilic 3-PyrOO^•+. This highlights the role of polar effects in these reactions, which are likely of high relevance for processes in combustions and atmospheric transformations. The mechanism was studied by computational methods, which showed that radical addition occurs exclusively at the less substituted alkyne site to give the distonic vinyl radical cation <b>8</b>. The latter undergoes a series of subsequent rearrangements/fragmentations that are similar for both isomeric PyrOO^•+. γ-Fragmentation in <b>8</b> leads to the distonic aryloxyl radical cation PyrO^•+ and a singlet carbene <b>10</b>. The product association complex [PyrO^•+ – <b>10</b>] is the starting point for two important subsequent reactions, e.g., (i) rapid hydrogen transfer to form ketenyl radical <b>11</b> and the closed-shell species PyrOH⁺, and (ii) oxygen transfer from PyrO^•+ to <b>10</b> that leads to α-keto aldehyde <b>13</b> and Pyr^•+, followed by hydrogen abstraction to give acyl radical <b>14</b> and PyrH⁺. Additional major products are the closed-shell aromatic carbonyl compounds <b>20</b> and <b>30</b> that result from multistep rearrangements in vinyl radical <b>8</b>, which are terminated by homolytic bond scission and release of neutral acyl radicals

Dimethylcuprate-Mediated Transformation of Acetate to Dithioacetate

Dithiocarboxylic acids, RCS₂H, and their esters, RCS₂R′, are useful reagents that can be synthesized by the reaction of carbon disulfide with organometallic reagents. Here the coinage-metal-mediated transformation of acetate to dithioacetate is explored in the gas phase using multistage mass spectrometry experiments in a linear ion trap mass spectrometer in conjunction with density functional theory (DFT) calculations. The ion–molecule reactions between coinage-metal dimethylmetalate anions [CH₃MCH₃]⁻ (M = Au, Ag, Cu), formed via double decarboxylation of the metal acetate anions, [CH₃CO₂MO₂CCH₃]⁻, and carbon disulfide, were examined. Only [CH₃CuCH₃]⁻ reacts with CS₂ with a reaction efficiency of 0.8% of the collision rate to yield the adduct [CH₃CuS₂CCH₃]⁻ (77.5%) as well as CH₃CS₂^– (22.5%). Collision-induced dissociation (CID) of the adduct [CH₃CuS₂CCH₃]⁻ gives CH₃CS₂^– as the major product, with a small amount of [CuS₂CCH₂]⁻ being formed via loss of methane. DFT calculations reveal the following. (i) [CH₃CuCH₃]⁻ reacts via oxidative addition to form a Cu­(III) intermediate, followed by reductive elimination of CH₃CS₂^–, which is captured by Cu to form [CH₃CuS₂CCH₃]⁻. This energetic adduct can fragment via loss of CH₃CS₂^– or can be collisionally cooled by the helium bath gas used in the experiments. (ii) Loss of CH₄ from [CH₃CuS₂CCH₃]⁻ also involves a Cu­(III) intermediate and results in formation of the metalladithiolactone [Cu­(CH₂CS₂)]⁻

Solution and Gas-Phase Investigations of Trimethylsilylpropyl-Substituted Pyridinium Ions. Manifestation of the Silicon δ Effect

Computational studies on the <i>N</i>-methyl-2-trimethyl-M-propylpyridinium ions <b>15a</b> (M = Si), <b>15b</b> (M = Ge), <b>15c</b> (M = Sn), and <b>15d</b> (M = Pb) and <i>N</i>-methyl-4-trimethyl-M-propylpyridinium ions <b>16a</b> (M = Si), <b>16b</b> (M = Ge), <b>16c</b> (M = Sn), and <b>16d</b> (M = Pb) provide evidence for a significant through-bond (double hyperconjugative) interaction between the M–CH₂ bond and the low-lying π* orbital of the pyridinium ion. The strength of this interaction increases in the order Si < Ge < Sn < Pb, in line with the σ-donor abilities of the C–M bond. The through-bond interaction for M = Si has been studied in solution using ¹³C and ²⁹Si NMR studies; however, the effect is small. The collision-induced dissociation fragmentation reactions of <b>15a</b> and <b>16a</b> are strongly influenced by the through-bond interaction, with the major fragmentation pathway proceeding via extrusion of ethylene to yield the trimethylsilylmethyl-substituted pyridinium ions <b>1a</b> and <b>2a</b>

Gas-Phase Unimolecular Reactions of Pallada- and Nickelalactone Anions

Electrospray ionization in combination with multistage mass spectrometry experiments in a linear ion trap mass spectrometer was used to generate and study the gas-phase ion chemistry of the metallalactones [(CH₃CO₂)­Ni­(CH₂CO₂)]⁻ (<i>m</i>/<i>z</i> 175, <b>5a</b>) and [(CH₃CO₂)­Pd­(CH₂CO₂)]⁻ (<i>m</i>/<i>z</i> 223, <b>5b</b>). Low-energy collision-induced dissociation (CID) resulted in decarboxylation to produce novel organometallic ions at <i>m</i>/<i>z</i> 131 (Ni) and <i>m</i>/<i>z</i> 179 (Pd). Isotope labeling experiments, bimolecular gas-phase reactions with allyl iodide, and DFT calculations reveal that decarboxylation primarily occurs from the acetato ligand to yield ions of the form [(CH₃)­M­(CH₂CO₂)]⁻ (M = Pd, Ni). Further CID experiments on [(CH₃)­M­(CH₂CO₂)]⁻ together with DFT calculations highlight the following. (1) Both palladium and nickel can facilitate C–C bond formation, with elimination of ethylene being observed. (2) The mechanism for formation of ethylene from [(CH₃)­M­(CH₂CO₂)]⁻ is inherently different for M = Pd versus M = Ni. Elimination of ethylene is competitive with further decarboxylation in the case of nickel, and nickel remains in the 2+ oxidation state throughout. In contrast, the palladium complex is reduced to palladium(0) upon C–C bond formation and undergoes a second decarboxylation before ethylene is released. Finally, the products of the ion–molecule reactions of [(CH₃)­Pd­(CH₂CO₂)]⁻ (<b>7b</b>) with allyl iodide provide evidence for the formation of the Pd­(IV) intermediate [(CH₃)­(I)­(CH₂CHCH₂)­Pd­(CH₂CO₂)]⁻, which decomposes via a range of processes, including losses of iodide, propionate, allyl, and methyl radicals and reductive elimination of butane and methyl iodide

Gas-Phase Reactivity of Group 11 Dimethylmetallates with Allyl Iodide

Copper-mediated allylic substitution reactions are widely used in organic synthesis, whereas the analogous reactions for silver and gold are essentially unknown. To unravel why this is the case, the gas-phase reactions of allyl iodide with the coinage metal dimethylmetallates, [CH₃MCH₃]⁻ (M = Cu, Ag and Au), were examined under the near thermal conditions of an ion trap mass spectrometer and via electronic structure calculations. [CH₃CuCH₃]⁻ reacted with allyl iodide with a reaction efficiency of 6.6% of the collision rate to yield: I^– (75%); the cross-coupling product, [CH₃CuI]⁻ (24%); and the homo-coupling product, [C₃H₅CuI]⁻ (1%). [CH₃AgCH₃]⁻ and [CH₃AuCH₃]⁻ reacted substantially slower (reaction efficiencies of 0.028% and 0.072%). [CH₃AgCH₃]⁻ forms I^– (19%) and [CH₃AgI]⁻ (81%), while only I^– is formed from [CH₃AuCH₃]⁻. Because the experiments do not detect the neutral product­(s) formed, which might otherwise help identify the mechanisms of reaction, and to rationalize the observed ionic products and reactivity order, calculations at the B3LYP/def2-QZVP//B3LYP/SDD6-31+G­(d) level were conducted on four different mechanisms: (i) S_N2; (ii) S_N2′; (iii) oxidative-addition/reductive elimination (OA/RE) via an M­(III) η³-allyl intermediate; and (iv) OA/RE via an M­(III) η¹-allyl intermediate. For copper, mechanisms (iii) and (iv) are predicted to be competitive. Only the Cu­(III) η³-allyl intermediate undergoes reductive elimination via two different transition states to yield either the cross-coupling or the homo-coupling products. Their relative barriers are consistent with homo-coupling being a minor pathway. For silver, the kinetically most probable pathway is the S_N2 reaction, consistent with no homo-coupling product, [C₃H₅AgI]⁻, being observed. For gold, no C–C coupling reaction is kinetically viable. Instead, I^– is predicted to be formed along with a stable Au­(III) η³-allyl complex. These results clearly highlight the superiority of organocuprates in allylic substitution reactions

Unraveling Organocuprate Complexity: Fundamental Insights into Intrinsic Group Transfer Selectivity in Alkylation Reactions

The near thermal conditions of an ion-trap mass spectrometer were used to examine the intrinsic gas-phase reactivity and selectivity of nucleophilic substitution reactions. The well-defined organocuprate anions [CH₃CuR]^<b>–</b> (R = CH₃CH₂, CH₃CH₂CH₂, (CH₃)₂CH, PhCH₂CH₂, PhCH₂, Ph, C₃H₅, and H) were reacted with CH₃I. The rates (reaction efficiencies, ϕ) and selectivities (the product ion branching ratios) were compared with those of [CH₃CuCH₃]^<b>–</b> reacting with CH₃I. Alkyl R groups yielded similar efficiencies, with selectivity for C–C bond formation at the coordinated R group. Inclusion of unsaturated R groups curbed the overall reactivity (ϕ = 1 to 2 orders of magnitude lower). With the exception of R = PhCH₂CH₂, these switched their selectivity to C–C bond formation at the CH₃ group. Replacing an organyl ligand with R = H significantly enhanced the reactivity (8-fold), resulting in the selective formation of methane. Unique decomposition and side-reactions observed include: (1) spontaneous β-hydride elimination from [RCuI]^<b>–</b> byproducts; and (2) homocoupling of the pre-existing organocuprate ligands in [CH₃CuC₃H₅]^<b>–</b>, as shown by deuterium labeling. DFT (B3LYP-D/Def2-QZVP//B3LYP/SDD:6-31+G­(d)) predicts that the alkylation mechanism for all species is via oxidative addition/reductive elimination (OA/RE). OA is the rate-limiting step, while RE determines selectivity: the effects of R on each were examined

Theoretical Approaches To Estimating Homolytic Bond Dissociation Energies of Organocopper and Organosilver Compounds

Although organocopper and organosilver compounds are known to decompose by homolytic pathways among others, surprisingly little is known about their bond dissociation energies (BDEs). In order to address this deficiency, the performance of the DFT functionals BLYP, B3LYP, BP86, TPSSTPSS, BHandHLYP, M06L, M06, M06-2X, B97D, and PBEPBE, along with the double hybrids, mPW2-PLYP, B2-PLYP, and the ab initio methods, MP2 and CCSD­(T), have been benchmarked against the thermochemistry for the M–C homolytic BDEs (<i>D</i>₀) of Cu–CH₃ and Ag–CH₃, derived from guided ion beam experiments and CBS limit calculations (<i>D</i>₀(Cu–CH₃) = 223 kJ·mol^–1; <i>D</i>₀(Ag–CH₃) = 169 kJ·mol^–1). Of the tested methods, in terms of chemical accuracy, error margin, and computational expense, M06 and BLYP were found to perform best for homolytic dissociation of methylcopper and methylsilver, compared with the CBS limit gold standard. Thus the M06 functional was used to evaluate the M–C homolytic bond dissociation energies of Cu–R and Ag–R, R = Et, Pr, <i>i</i>Pr, <i>t</i>Bu, allyl, CH₂Ph, and Ph. It was found that <i>D</i>₀(Ag–R) was always lower (∼50 kJ·mol^–1) than that of <i>D</i>₀(Cu–R). The trends in BDE when changing the R ligand reflected the H–R bond energy trends for the alkyl ligands, while for R = allyl, CH₂Ph, and Ph, some differences in bond energy trends arose. These trends in homolytic bond dissociation energy help rationalize the previously reported (Rijs, N. J.; O’Hair, R. A. J. <i>Organometallics</i> <b>2010</b>, <i>29</i>, 2282–2291) fragmentation pathways of the organometallate anions, [CH₃MR]⁻