Leaving Group Effects on the Selectivity of the Silylation of Alcohols: The Reactivity–Selectivity Principle Revisited

TBS protection of primary alcohol naphthalen-1-ylmethanol (<b>4a</b>) and secondary alcohol 1-(naphthalen-1-yl)­ethanol (<b>4b</b>) has been studied under various reaction conditions. The primary/secondary selectivity is largest in the comparatively slow Lewis base catalyzed silylation in apolar solvents and systematically lower in DMF. Lowest selectivities (and fastest reaction rates) are found for TBS triflate <b>1b</b>, where only minor effects of solvent polarity or Lewis base catalysis can be observed

Mechanisms of Hydride Abstractions by Quinones

The kinetics of the hydride abstractions by 2,3-dichloro-5,6-dicyano-<i>p</i>-benzoquinone (DDQ) from 13 C–H hydride donors (acyclic 1,4-dienes, cyclohexa-1,4-dienes, dihydropyridines), tributylstannane, triphenylstannane, and five borane complexes (amine–boranes, carbene–boranes) have been studied photometrically in dichloromethane solution at 20 °C. Analysis of the resulting second-order rate constants by the correlation log <i>k</i>₂(20 °C) = <i>s</i>_N(<i>E</i> + <i>N</i>) (J. Am. Chem. Soc. 2001, 123, 9500) showed that the hydride abstractions from the C–H donors on one side and the Sn–H and B–H hydride donors on the other follow separate correlations, indicating different mechanisms for the two reaction series. The interpretation that the C–H donors transfer hydrogen to the carbonyl oxygen of DDQ while Sn–H and B–H hydride donors transfer hydride to a cyano-substituted carbon of DDQ is supported by quantum-chemical intrinsic reaction coordinate calculations and isotope labeling experiments of the reactions of D₈-cyclohexa-1,4-diene, Bu₃SnD, and pyridine·BD₃ with 2,5-dichloro-<i>p</i>-benzoquinone. The second-order rate constants of the reactions of tributylstannane with different quinones correlate linearly with the electrophilicity parameters <i>E</i> of the quinones, which have previously been derived from the reactions of quinones with π-nucleophiles. The fact that the reactions of Bu₃SnH with quinones and benzhydrylium ions are on the same log <i>k</i>₂ vs <i>E</i> (electrophilicity) correlation shows that both reaction series proceed by the same mechanism and illustrates the general significance of the reactivity parameters <i>E</i>, <i>N</i>, and <i>s</i>_N for predicting rates of polar organic reactions

The Lewis Base-Catalyzed Silylation of AlcoholsA Mechanistic Analysis

Reaction rates for the base-catalyzed silylation of primary, secondary, and tertiary alcohols depend strongly on the choice of solvent and catalyst. The reactions are significantly faster in Lewis basic solvents such as dimethylformamide (DMF) compared with those in chloroform or dichloromethane (DCM). In DMF as the solvent, the reaction half-lives for the conversion of structurally similar primary, secondary, and tertiary alcohols vary in the ratio 404345:20232:1. The effects of added Lewis base catalysts such as 4-<i>N</i>,<i>N</i>-dimethylaminopyridine (DMAP) or 4-pyrrolidinopyridine (PPY) are much larger in apolar solvents than in DMF. The presence of an auxiliary base such as triethylamine is required in order to drive the reaction to full conversion

Sequential Oxidative α‑Cyanation/Anti-Markovnikov Hydroalkoxylation of Allylamines

Iron-catalyzed oxidative α-cyanations at tertiary allylamines in the allylic position are followed by anti-Markovnikov additions of alcohols across the vinylic CC double bonds of the initially generated α-amino nitriles. These consecutive reactions generate 2-amino-4-alkoxybutanenitriles from three reactants (allylamines, trimethylsilyl cyanide, and alcohols) in one reaction vessel at ambient temperature

Theoretical Prediction of Selectivity in Kinetic Resolution of Secondary Alcohols Catalyzed by Chiral DMAP Derivatives

The mechanism of esterification of the secondary alcohol 1-(1-naphthyl)­ethanol <b>9</b> by isobutyric anhydride catalyzed by 4-pyrrolidinopyridine (PPY, <b>11</b>) and a series of single enantiomer atropisomeric 4-dialkylaminopyridines <b>8a</b>–<b>g</b> has been studied computationally at the B3LYP/6-311+G­(d,p)//B3LYP/6-31G­(d) level. Comparison of the levels of enantioselectivity predicted computationally with the results obtained experimentally allowed the method to be validated. The value of the approach is demonstrated by the successful prediction that a structural modification of an aryl group within the catalyst from phenyl to 3,5-dimethylphenyl would lead to improved levels of selectivity in this type of kinetic resolution (KR) reaction, as was subsequently verified following synthesis and evaluation of this catalyst (<b>8d</b>). Experimentally, the selectivity of this type of KR is found to exhibit a significant deuterium isotope effect (for <b>9</b> vs <b><i>d</i>₁</b>-<b>9</b>)

Transfer Hydrogenation as a Redox Process in Nucleotides

Using a combined theoretical and experimental strategy, the heats of hydrogenation of the nucleotide bases uracil, thymine, cytosine, adenine, and guanine have been determined. The most easily hydrogenated base is uracil, followed by thymine and cytosine. Comparison of these hydrogenation enthalpies with those of ketones and aldehydes derived from sugar models indicates the possibility of near-thermoneutral hydrogen transfer between uracil and the sugar phosphate backbone in oligonucleotides

Kinetics and Mechanism of Oxirane Formation by Darzens Condensation of Ketones: Quantification of the Electrophilicities of Ketones

The kinetics of epoxide formation by Darzens condensation of aliphatic ketones <b>1</b> with arylsulfonyl-substituted chloromethyl anions <b>2</b> (ArSO₂CHCl^–) have been determined photometrically in DMSO solution at 20 °C. The reactions proceed via nucleophilic attack of the carbanions at the carbonyl group to give intermediate halohydrin anions <b>4</b>, which subsequently cyclize with formation of the oxiranes <b>3</b>. Protonation of the reaction mixture obtained in THF solution at low temperature allowed the intermediates to be trapped and the corresponding halohydrins <b>4</b>-H to be isolated. Crossover experiments, i.e., deprotonation of the halohydrins <b>4</b>-H in the presence of a trapping reagent for the regenerated arylsulfonyl-substituted chloromethyl anions <b>2</b>, provided the relative rates of backward (<i>k</i>_–CC) and ring closure (<i>k</i>_rc) reactions of the intermediates. Combination of the kinetic data (<i>k</i>₂^exptl) with the splitting ratio (<i>k</i>_–CC/<i>k</i>_rc) gave the second-order rate constants <i>k</i>_CC for the attack of the carbanions <b>2</b> at the ketones <b>1</b>. These <i>k</i>_CC values and the previously reported reactivity parameters <i>N</i> and <i>s</i>_N for the arylsulfonyl-substituted chloromethyl anions <b>2</b> allowed us to use the linear free energy relationship log <i>k</i>₂(20 °C) = <i>s</i>_N(<i>N</i> + <i>E</i>) for deriving the electrophilicity parameters <i>E</i> of the ketones <b>1</b> and thus predict potential nucleophilic reaction partners. Density functional theory calculations of the intrinsic reaction pathways showed that the reactions of the ketones <b>1</b> with the chloromethyl anions <b>2</b> yield two rotational isomers of the intermediate halohydrin anions <b>4</b>, only one of which can cyclize while the other undergoes retroaddition because the barrier for rotation is higher than that for reversal to the reactants <b>1</b> and <b>2</b>. The electrophilicity parameters <i>E</i> correlate moderately with the lowest unoccupied molecular orbital energies of the carbonyl groups, very poorly with Parr’s electrophilicity indices, and best with the methyl anion affinities calculated for DMSO solution

Kinetics and Mechanism of Oxirane Formation by Darzens Condensation of Ketones: Quantification of the Electrophilicities of Ketones

The kinetics of epoxide formation by Darzens condensation of aliphatic ketones <b>1</b> with arylsulfonyl-substituted chloromethyl anions <b>2</b> (ArSO₂CHCl^–) have been determined photometrically in DMSO solution at 20 °C. The reactions proceed via nucleophilic attack of the carbanions at the carbonyl group to give intermediate halohydrin anions <b>4</b>, which subsequently cyclize with formation of the oxiranes <b>3</b>. Protonation of the reaction mixture obtained in THF solution at low temperature allowed the intermediates to be trapped and the corresponding halohydrins <b>4</b>-H to be isolated. Crossover experiments, i.e., deprotonation of the halohydrins <b>4</b>-H in the presence of a trapping reagent for the regenerated arylsulfonyl-substituted chloromethyl anions <b>2</b>, provided the relative rates of backward (<i>k</i>_–CC) and ring closure (<i>k</i>_rc) reactions of the intermediates. Combination of the kinetic data (<i>k</i>₂^exptl) with the splitting ratio (<i>k</i>_–CC/<i>k</i>_rc) gave the second-order rate constants <i>k</i>_CC for the attack of the carbanions <b>2</b> at the ketones <b>1</b>. These <i>k</i>_CC values and the previously reported reactivity parameters <i>N</i> and <i>s</i>_N for the arylsulfonyl-substituted chloromethyl anions <b>2</b> allowed us to use the linear free energy relationship log <i>k</i>₂(20 °C) = <i>s</i>_N(<i>N</i> + <i>E</i>) for deriving the electrophilicity parameters <i>E</i> of the ketones <b>1</b> and thus predict potential nucleophilic reaction partners. Density functional theory calculations of the intrinsic reaction pathways showed that the reactions of the ketones <b>1</b> with the chloromethyl anions <b>2</b> yield two rotational isomers of the intermediate halohydrin anions <b>4</b>, only one of which can cyclize while the other undergoes retroaddition because the barrier for rotation is higher than that for reversal to the reactants <b>1</b> and <b>2</b>. The electrophilicity parameters <i>E</i> correlate moderately with the lowest unoccupied molecular orbital energies of the carbonyl groups, very poorly with Parr’s electrophilicity indices, and best with the methyl anion affinities calculated for DMSO solution

Quantification and Theoretical Analysis of the Electrophilicities of Michael Acceptors

In order to quantify the electrophilic reactivities of common Michael acceptors, we measured the kinetics of the reactions of monoacceptor-substituted ethylenes (H₂CCH-Acc, <b>1</b>) and styrenes (PhCHCH-Acc, <b>2</b>) with pyridinium ylides <b>3</b>, sulfonium ylide <b>4</b>, and sulfonyl-substituted chloro­methyl anion <b>5</b>. Substitution of the 57 measured second-order rate constants (log <i>k</i>) and the previously reported nucleophile-specific parameters <i>N</i> and <i>s</i>_N for <b>3</b>–<b>5</b> into the correlation log <i>k</i> = <i>s</i>_N(<i>E</i> + <i>N</i>) allowed us to calculate 15 new empirical electrophilicity parameters <i>E</i> for Michael acceptors <b>1</b> and <b>2</b>. The use of the same parameters <i>s</i>_N, <i>N</i>, and <i>E</i> for these different types of reactions shows that all reactions proceed via a common rate-determining step, the nucleophilic attack of <b>3</b>–<b>5</b> at the Michael acceptors with formation of acyclic intermediates, which subsequently cyclize to give tetrahydroindolizines (stepwise 1,3-dipolar cycloadditions with <b>3</b>) and cyclopropanes (with <b>4</b> and <b>5</b>), respectively. The electrophilicity parameters <i>E</i> thus determined can be used to calculate the rates of the reactions of Michael acceptors <b>1</b> and <b>2</b> with any nucleophile of known <i>N</i> and <i>s</i>_N. DFT calculations were performed to confirm the suggested reaction mechanisms and to elucidate the origin of the electrophilic reactivities. While electrophilicities <i>E</i> correlate poorly with the LUMO energies and with Parr’s electrophilicity index ω, good correlations were found between the experimentally observed electrophilic reactivities of 44 Michael acceptors and their calculated methyl anion affinities, particularly when solvation by dimethyl sulfoxide was taken into account by applying the SMD continuum solvation model. Because of the large structural variety of Michael acceptors considered for these correlations, which cover a reactivity range of 17 orders of magnitude, we consider the calculation of methyl anion affinities to be the method of choice for a rapid estimate of electrophilic reactivities

Preparation of Tri- and Tetrasubstituted Allenes via Regioselective Lateral Metalation of Benzylic (Trimethylsilyl)alkynes Using TMPZnCl·LiCl

The zincation of various 1-(trimethylsilyl)-3-aryl-1-propynes with TMPZnCl·LiCl followed by a Pd-catalyzed coupling with aryl halides provides arylated allenes in 52–92% yield. Subsequent metalation with TMPZnCl·LiCl and cross-coupling with a second different aryl halide provides regioselectively tetrasubstituted allenes in 42–70% yield. This sequence can be performed in a one-pot procedure. DFT calculations and NMR studies support the formation of allenylzinc and propargyllithium intermediates starting from 1-(trimethylsilyl)-3-phenyl-1-propyne