Direct alkylation of N,N-dialkyl benzamides with methyl sulfides under transition metal-free conditions

Amides are a fundamental and widespread functional group, and are usually considered as poor electrophiles owing to resonance stabilization of the amide bond. Various approaches have been developed to address challenges in amide transformations. Nonetheless, most methods use activated amides, organometallic reagents or transition metal catalysts. Here, we report the direct alkylation of N,N-dialkyl benzamides with methyl sulfides promoted by the readily available base LDA (lithium diisopropylamide). This approach successfully achieves an efficient and selective synthesis of α-sulfenylated ketones without using transition-metal catalysts or organometallic reagents. Preliminary mechanism studies reveal that the deprotonative aroylation of methyl sulfides is promoted by the directed ortho-lithiation of the tertiary benzamide with LDA.

Rate Dependence on Inductive and Resonance Effects for the Organocatalyzed Enantioselective Conjugate Addition of Alkenyl and Alkynyl Boronic Acids to β-Indolyl Enones and β-Pyrrolyl Enones

Two key factors bear on reaction rates for the conjugate addition of alkenyl boronic acids to heteroaryl-appended enones: the proximity of inductively electron-withdrawing heteroatoms to the site of bond formation and the resonance contribution of available heteroatom lone pairs to stabilize the developing positive charge at the enone β-position. For the former, the closer the heteroatom is to the enone β-carbon, the faster the reaction. For the latter, greater resonance stabilization of the benzylic cationic charge accelerates the reaction. Thus, reaction rates are increased by the closer proximity of inductive electron-withdrawing elements, but if resonance effects are involved, then increased rates are observed with electron-donating ability. Evidence for these trends in isomeric substrates is presented, and the application of these insights has allowed for reaction conditions that provide improved reactivity with previously problematic substrates.

Electron-Induced Decomposition of Uracil-5-yl O-(N,N-dimethylsulfamate): Role of Methylation in Molecular Stability

The incorporation of modified uracil derivatives into DNA leads to the formation of radical species that induce DNA damage. Molecules of this class have been suggested as radiosensitizers and are still under investigation. In this study, we present the results of dissociative electron attachment to uracil-5-yl O-(N,N-dimethylsulfamate) in the gas phase. We observed the formation of 10 fragment anions in the studied range of electron energies from 0–12 eV. Most of the anions were predominantly formed at the electron energy of about 0 eV. The fragmentation paths were analogous to those observed in uracil-5-yl O-sulfamate, i.e., the methylation did not affect certain bond cleavages (O-C, S-O and S-N), although relative intensities differed. The experimental results are supported by quantum chemical calculations performed at the M06-2X/aug-cc-pVTZ level of theory. Furthermore, a resonance stabilization method was used to theoretically predict the resonance positions of the fragment anions O− and CH3−.

Infrared characterization of formation and resonance stabilization of the Criegee intermediate methyl vinyl ketone oxide

Methyl vinyl ketone oxide (MVKO) is an important Criegee intermediate in the ozonolysis of isoprene. MVKO is resonance stabilized by its allyl moiety, but no spectral characterization of this stabilization was reported to date. In this study, we photolyzed a mixture of 1,3-diiodo-but-2-ene and O2 to produce MVKO and characterized the syn-trans-MVKO, and tentatively syn-cis-MVKO, with transient infrared spectra recorded using a step-scan Fourier-transform spectrometer. The O‒O stretching band at 948 cm−1 of syn-trans-MVKO is much greater than the corresponding bands of syn-CH3CHOO and (CH3)2COO Criegee intermediates at 871 and 887 cm−1, respectively, confirming a stronger O‒O bond due to resonance stabilization. We observed also iodoalkenyl radical C2H3C(CH3)I upon photolysis of the precursor to confirm the fission of the terminal allylic C‒I bond rather than the central vinylic C‒I bond of the precursor upon photolysis. At high pressure, the adduct C2H3C(CH3)IOO was also observed. The reaction mechanism is characterized.

Mechanism Dictates Mechanics: A Molecular Substituent Effect in the Macroscopic Fracture of a Covalent Polymer Network

<div><p>Here, we report covalent polymer gels in which the macroscopic fracture “reaction” is controlled by mechanophores embedded within mechanically active network strands. We synthesized poly(ethylene glycol) (PEG) gels through the end-linking of azide-terminated tetra-arm PEG (M_n= 5 kDa) with bis-alkyne linkers. Networks were formed under identical conditions, except that the bis-alkyne was varied to include either a <i>cis</i>-diaryl (<b>1</b>) or <i>cis</i>-dialkyl (<b>2</b>) linked cyclobutane mechanophore that acts as a mechanochemical “weak link” through a force-coupled cycloreversion. A control network featuring a bis-alkyne without cyclobutane (<b>3</b>) was also synthesized. The networks show the same linear elasticity (G' = 23~24 kPa, 0.1 – 100 Hz) and equilibrium mass swelling ratios (Q = 10~11 in tetrahydrofuran), but they exhibit tearing energies that span a factor of 8 (3.4 J∙m^-2, 10.5 J∙m^-2, and 27.1 J∙m^-2 for networks with <b>1</b>, <b>2</b>, and <b>3</b>, respectively). The difference in fracture energy is well aligned with the force-coupled scission kinetics of the mechanophores observed in single-molecule force spectroscopy experiments, implicating local resonance stabilization of a diradical transition state in the cycloreversion of <b>1 </b>as a key determinant of the relative ease with which its network is torn. The connection between macroscopic fracture and small molecule reaction mechanism suggests opportunities for molecular understanding and optimization of polymer network behavior. </p></div>

Mechanism Dictates Mechanics: A Molecular Substituent Effect in the Macroscopic Fracture of a Covalent Polymer Network

<div><p>Here, we report covalent polymer gels in which the macroscopic fracture “reaction” is controlled by mechanophores embedded within mechanically active network strands. We synthesized poly(ethylene glycol) (PEG) gels through the end-linking of azide-terminated tetra-arm PEG (M_n= 5 kDa) with bis-alkyne linkers. Networks were formed under identical conditions, except that the bis-alkyne was varied to include either a <i>cis</i>-diaryl (<b>1</b>) or <i>cis</i>-dialkyl (<b>2</b>) linked cyclobutane mechanophore that acts as a mechanochemical “weak link” through a force-coupled cycloreversion. A control network featuring a bis-alkyne without cyclobutane (<b>3</b>) was also synthesized. The networks show the same linear elasticity (G' = 23~24 kPa, 0.1 – 100 Hz) and equilibrium mass swelling ratios (Q = 10~11 in tetrahydrofuran), but they exhibit tearing energies that span a factor of 8 (3.4 J∙m^-2, 10.5 J∙m^-2, and 27.1 J∙m^-2 for networks with <b>1</b>, <b>2</b>, and <b>3</b>, respectively). The difference in fracture energy is well aligned with the force-coupled scission kinetics of the mechanophores observed in single-molecule force spectroscopy experiments, implicating local resonance stabilization of a diradical transition state in the cycloreversion of <b>1 </b>as a key determinant of the relative ease with which its network is torn. The connection between macroscopic fracture and small molecule reaction mechanism suggests opportunities for molecular understanding and optimization of polymer network behavior. </p></div>

Computational Study of Selected Amine and Lactam N-Oxides Including Comparisons of N-O Bond Dissociation Enthalpies with Those of Pyridine N-Oxides

A computational study of the structures and energetics of amine N-oxides, including pyridine N-oxides, trimethylamine N-oxide, bridgehead bicyclic amine N-oxides, and lactam N-oxides, allowed comparisons with published experimental data. Most of the computations employed the B3LYP/6-31G* and M06/6-311G+(d,p) models and comparisons were also made between the results of the HF 6-31G*, B3LYP/6-31G**, B3PW91/6-31G*, B3PW91/6-31G**, and the B3PW91/6-311G+(d,p) models. The range of calculated N-O bond dissociation energies (BDE) (actually enthalpies) was about 40 kcal/mol. Of particular interest was the BDE difference between pyridine N-oxide (PNO) and trimethylamine N-oxide (TMAO). Published thermochemical and computational (HF 6-31G*) data suggest that the BDE of PNO was only about 2 kcal/mol greater than that of TMAO. The higher IR frequency for N-O stretch in PNO and its shorter N-O bond length suggest a greater difference in BDE values, predicted at 10–14 kcal/mol in the present work. Determination of the enthalpy of sublimation of TMAO, or at least the enthalpy of fusion and estimation of the enthalpy of vaporization might solve this dichotomy. The “extra” resonance stabilization in pyridine N-oxide relative to pyridine was consistent with the 10–14 kcal/mol increase in BDE, relative to TMAO, and was about half the “extra” stabilization in phenoxide, relative to phenol or benzene. Comparison of pyridine N-oxide with its acyclic model nitrone (“Dewar-Breslow model”) indicated aromaticity slightly less than that of pyridine.

Rotational barrier and electron-withdrawing substituent effects: Theoretical study of -conjugation in para-substituted anilines

The rotational barrier RB around C–NH2 bond between the minimum and maximum states of 84 electron-withdrawing groups at para-position in aniline were studied at the density functional wB97X-D/6-31G** level. The rotational barrier was found to correlate strongly with shortening of the C–NH2 bond, increase of flattening of NH2 group, decrease in negative natural charge on amino nitrogen, increase in minimum ionization potential around lone pair of amino nitrogen, increase in maximum (positive) electrostatic potential on amino hydrogens, increase in NH2 stretching frequencies, and increase in stabilization energy. The rotational barrier was also found to correlate well with empirical pKa and Hammett σp constants. The rotational barrier is shown to be a reliable quantum mechanical approach to measure p-conjugation in para-substituted anilines. Based on RB a quantitative scale is constructed for the ability of electron-withdrawing substituents to resonate with aniline. A quinone-like structure has been proposed for stronger electron-withdrawing substituents where an extension of resonance stabilization requires the simultaneous presence of electron donor (NH2) and electron-withdrawing groups.

Exploring Student Thinking About Addition Reactions

While student reasoning about many of the reaction types covered in the organic chemistry curriculum have been studied previously, there is minimal research focused specifically on how students think about the mechanisms of addition reactions. This study addresses that gap by probing organic chemistry students’ thinking using think-aloud interviews as they worked through two different addition reactions. Students worked through the mechanisms using either paper and pencil or an app that dynamically represents the molecules. Overall, students were able to identify the steps of the two addition reactions but did not always successfully apply chemical thinking during the mechanistic steps. Specifically, both groups of students struggled with the concepts related to carbocation stability, frequently misapplying stabilization via substitution and demonstrating difficulty in identifying the potential for resonance stabilization. Our results suggest that instructors should emphasize the conceptual grounding directing mechanistic steps, in particular when determining carbocation stability.

Exploring Student Thinking About Addition Reactions

While student reasoning about many of the reaction types covered in the organic chemistry curriculum have been studied previously, there is minimal research focused specifically on how students think about the mechanisms of addition reactions. This study addresses that gap by probing organic chemistry students’ thinking using think-aloud interviews as they worked through two different addition reactions. Students worked through the mechanisms using either paper and pencil or an app that dynamically represents the molecules. Overall, students were able to identify the steps of the two addition reactions but did not always successfully apply chemical thinking during the mechanistic steps. Specifically, both groups of students struggled with the concepts related to carbocation stability, frequently misapplying stabilization via substitution and demonstrating difficulty in identifying the potential for resonance stabilization. Our results suggest that instructors should emphasize the conceptual grounding directing mechanistic steps, in particular when determining carbocation stability.