55 research outputs found
A Focus Honoring Helmut Schwarz's Election to the National Academy of Sciences
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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, [CH<sub>3</sub>CuCH<sub>3</sub>]<sup>−</sup>, can catalyze
decarboxylative coupling of allyl acetate in the gas phase via a simple
two-step catalytic cycle. In step 1, [CH<sub>3</sub>CuCH<sub>3</sub>]<sup>−</sup> undergoes a cross-coupling reaction with allyl
acetate to yield [CH<sub>3</sub>CuO<sub>2</sub>CCH<sub>3</sub>]<sup>−</sup> as the major product ion. Step 2 involves subjecting
the product ion to collision-induced decarboxylation to re-form [CH<sub>3</sub>CuCH<sub>3</sub>]<sup>−</sup>, 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 η<sup>2</sup>-C<sub>3</sub>H<sub>5</sub>O<sub>2</sub>CCH<sub>3</sub> 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 = CH<sub>3</sub>CO<sub>2</sub><sup>–</sup>, I<sup>–</sup>, Br<sup>–</sup>,
Cl<sup>–</sup> 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
Mechanism of Deoxygenation and Cracking of Fatty Acids by Gas-Phase Cationic Complexes of Ni, Pd, and Pt
Deoxygenation and subsequent cracking of fatty acids are key steps in production of biodiesel fuels from renewable plant sources. Despite the fact that multiple catalysts, including those containing group 10 metals (Ni, Pd, and Pt), are employed for these purposes, little is known about the mechanisms by which they operate. In this work, we utilized tandem mass spectrometry experiments (MSn) to show that multiple types of fatty acids (saturated, mono-, and poly-unsaturated) can be catalytically deoxygenated and converted to smaller hydrocarbons using the ternary metal complexes [(phen)M(O2CR)]+], where phen = 1,10-phenanthroline and M = Ni, Pd, and Pt. The mechanistic description of deoxygenation/cracking processes builds on our recent works describing simple model systems for deoxygenation and cracking, where the latter comes from the ability of group 10 metal ions to undergo chain-walking with very low activation barriers. This article extends our previous work to a number of fatty acids commonly found in renewable plant sources. We found that in many unsaturated acids cracking can occur prior to deoxygenation and show that mechanisms involving group 10 metals differ from long-known charge-remote fragmentation reactions
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 <sup>13</sup>C<sub>6</sub>-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
Dimethylcuprate-Mediated Transformation of Acetate to Dithioacetate
Dithiocarboxylic
acids, RCS<sub>2</sub>H, and their esters, RCS<sub>2</sub>R′,
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 [CH<sub>3</sub>MCH<sub>3</sub>]<sup>−</sup> (M = Au, Ag, Cu), formed via double decarboxylation
of the metal acetate anions, [CH<sub>3</sub>CO<sub>2</sub>MO<sub>2</sub>CCH<sub>3</sub>]<sup>−</sup>, and carbon disulfide, were examined.
Only [CH<sub>3</sub>CuCH<sub>3</sub>]<sup>−</sup> reacts with
CS<sub>2</sub> with a reaction efficiency of 0.8% of the collision
rate to yield the adduct [CH<sub>3</sub>CuS<sub>2</sub>CCH<sub>3</sub>]<sup>−</sup> (77.5%) as well as CH<sub>3</sub>CS<sub>2</sub><sup>–</sup> (22.5%). Collision-induced dissociation (CID)
of the adduct [CH<sub>3</sub>CuS<sub>2</sub>CCH<sub>3</sub>]<sup>−</sup> gives CH<sub>3</sub>CS<sub>2</sub><sup>–</sup> as the major
product, with a small amount of [CuS<sub>2</sub>CCH<sub>2</sub>]<sup>−</sup> being formed via loss of methane. DFT calculations
reveal the following. (i) [CH<sub>3</sub>CuCH<sub>3</sub>]<sup>−</sup> reacts via oxidative addition to form a Cu(III) intermediate, followed
by reductive elimination of CH<sub>3</sub>CS<sub>2</sub><sup>–</sup>, which is captured by Cu to form [CH<sub>3</sub>CuS<sub>2</sub>CCH<sub>3</sub>]<sup>−</sup>. This energetic adduct can fragment via
loss of CH<sub>3</sub>CS<sub>2</sub><sup>–</sup> or can be
collisionally cooled by the helium bath gas used in the experiments.
(ii) Loss of CH<sub>4</sub> from [CH<sub>3</sub>CuS<sub>2</sub>CCH<sub>3</sub>]<sup>−</sup> also involves a Cu(III) intermediate
and results in formation of the metalladithiolactone [Cu(CH<sub>2</sub>CS<sub>2</sub>)]<sup>−</sup>
Dimethylcuprate-Mediated Transformation of Acetate to Dithioacetate
Dithiocarboxylic
acids, RCS<sub>2</sub>H, and their esters, RCS<sub>2</sub>R′,
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 [CH<sub>3</sub>MCH<sub>3</sub>]<sup>−</sup> (M = Au, Ag, Cu), formed via double decarboxylation
of the metal acetate anions, [CH<sub>3</sub>CO<sub>2</sub>MO<sub>2</sub>CCH<sub>3</sub>]<sup>−</sup>, and carbon disulfide, were examined.
Only [CH<sub>3</sub>CuCH<sub>3</sub>]<sup>−</sup> reacts with
CS<sub>2</sub> with a reaction efficiency of 0.8% of the collision
rate to yield the adduct [CH<sub>3</sub>CuS<sub>2</sub>CCH<sub>3</sub>]<sup>−</sup> (77.5%) as well as CH<sub>3</sub>CS<sub>2</sub><sup>–</sup> (22.5%). Collision-induced dissociation (CID)
of the adduct [CH<sub>3</sub>CuS<sub>2</sub>CCH<sub>3</sub>]<sup>−</sup> gives CH<sub>3</sub>CS<sub>2</sub><sup>–</sup> as the major
product, with a small amount of [CuS<sub>2</sub>CCH<sub>2</sub>]<sup>−</sup> being formed via loss of methane. DFT calculations
reveal the following. (i) [CH<sub>3</sub>CuCH<sub>3</sub>]<sup>−</sup> reacts via oxidative addition to form a Cu(III) intermediate, followed
by reductive elimination of CH<sub>3</sub>CS<sub>2</sub><sup>–</sup>, which is captured by Cu to form [CH<sub>3</sub>CuS<sub>2</sub>CCH<sub>3</sub>]<sup>−</sup>. This energetic adduct can fragment via
loss of CH<sub>3</sub>CS<sub>2</sub><sup>–</sup> or can be
collisionally cooled by the helium bath gas used in the experiments.
(ii) Loss of CH<sub>4</sub> from [CH<sub>3</sub>CuS<sub>2</sub>CCH<sub>3</sub>]<sup>−</sup> also involves a Cu(III) intermediate
and results in formation of the metalladithiolactone [Cu(CH<sub>2</sub>CS<sub>2</sub>)]<sup>−</sup>
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<sup>•+</sup> and 3-PyrOO<sup>•+</sup> with phenylacetylene (<b>7</b>) in the gas phase using mass spectrometric and computational techniques.
PyrOO<sup>•+</sup> was generated through reaction of the respective
distonic aryl radical cation Pyr<sup>•+</sup> with O<sub>2</sub> in the ion source of the mass spectrometer. For the reaction involving
the more electrophilic 4-PyrOO<sup>•+</sup>, a rate coefficient
of <i>k</i><sub>1</sub> = (2.2 ± 0.6) × 10<sup>–10</sup> cm<sup>3</sup> molecule<sup>–1</sup> s<sup>–1</sup> was determined at 298 K, while a value of <i>k</i><sub>2</sub> = (8.2 ± 2.1) × 10<sup>–11</sup> cm<sup>3</sup> molecule<sup>–1</sup> s<sup>–1</sup> was obtained for the reaction involving the less electrophilic 3-PyrOO<sup>•+</sup>. 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<sup>•+</sup>. γ-Fragmentation in <b>8</b> leads to
the distonic aryloxyl radical cation PyrO<sup>•+</sup> and
a singlet carbene <b>10</b>. The product association complex
[PyrO<sup>•+</sup> – <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<sup>+</sup>, and (ii) oxygen transfer from PyrO<sup>•+</sup> to <b>10</b> that leads to α-keto aldehyde <b>13</b> and Pyr<sup>•+</sup>, followed by hydrogen abstraction
to give acyl radical <b>14</b> and PyrH<sup>+</sup>. 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
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–CH<sub>2</sub> 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 <sup>13</sup>C and <sup>29</sup>Si 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 [(CH<sub>3</sub>CO<sub>2</sub>)Ni(CH<sub>2</sub>CO<sub>2</sub>)]<sup>−</sup> (<i>m</i>/<i>z</i> 175, <b>5a</b>) and [(CH<sub>3</sub>CO<sub>2</sub>)Pd(CH<sub>2</sub>CO<sub>2</sub>)]<sup>−</sup> (<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 [(CH<sub>3</sub>)M(CH<sub>2</sub>CO<sub>2</sub>)]<sup>−</sup> (M = Pd, Ni). Further CID experiments
on [(CH<sub>3</sub>)M(CH<sub>2</sub>CO<sub>2</sub>)]<sup>−</sup> 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 [(CH<sub>3</sub>)M(CH<sub>2</sub>CO<sub>2</sub>)]<sup>−</sup> 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 [(CH<sub>3</sub>)Pd(CH<sub>2</sub>CO<sub>2</sub>)]<sup>−</sup> (<b>7b</b>) with allyl iodide provide evidence
for the formation of the Pd(IV) intermediate [(CH<sub>3</sub>)(I)(CH<sub>2</sub>CHCH<sub>2</sub>)Pd(CH<sub>2</sub>CO<sub>2</sub>)]<sup>−</sup>, which decomposes via a range of processes, including losses of
iodide, propionate, allyl, and methyl radicals and reductive elimination
of butane and methyl iodide
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 [CH<sub>3</sub>CuR]<sup><b>–</b></sup> (R = CH<sub>3</sub>CH<sub>2</sub>, CH<sub>3</sub>CH<sub>2</sub>CH<sub>2</sub>, (CH<sub>3</sub>)<sub>2</sub>CH, PhCH<sub>2</sub>CH<sub>2</sub>,
PhCH<sub>2</sub>, Ph, C<sub>3</sub>H<sub>5</sub>, and H) were reacted
with CH<sub>3</sub>I. The rates (reaction efficiencies, ϕ) and
selectivities (the product ion branching ratios) were compared with
those of [CH<sub>3</sub>CuCH<sub>3</sub>]<sup><b>–</b></sup> reacting with CH<sub>3</sub>I. 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 = PhCH<sub>2</sub>CH<sub>2</sub>, these switched
their selectivity to C–C bond formation at the CH<sub>3</sub> 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]<sup><b>–</b></sup> byproducts; and (2) homocoupling of the pre-existing organocuprate
ligands in [CH<sub>3</sub>CuC<sub>3</sub>H<sub>5</sub>]<sup><b>–</b></sup>, 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
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