Reactivity of electrophilic cyclopropanes

Cyclopropanes that carry an electron-accepting group react as electrophiles in polar, ring-opening reactions. Analogous reactions at cyclopropanes with additional C2 substituents allow one to access difunctionalized products. Consequently, functionalized cyclopropanes are frequently used building blocks in organic synthesis. The polarization of the C1–C2 bond in 1-acceptor-2-donor-substituted cyclopropanes not only favorably enhances reactivity toward nucleophiles but also directs the nucleophilic attack toward the already substituted C2 position. Monitoring the kinetics of non-catalytic ring-opening reactions with a series of thiophenolates and other strong nucleophiles, such as azide ions, in DMSO provided the inherent SN2 reactivity of electrophilic cyclopropanes. The experimentally determined second-order rate constants k2 for cyclopropane ring-opening reactions were then compared to those of related Michael additions. Interestingly, cyclopropanes with aryl substituents at the C2 position reacted faster than their unsubstituted analogues. Variation of the electronic properties of the aryl groups at C2 gave rise to parabolic Hammett relationships

Nucleophilicity of Glutathione: A Link to Michael Acceptor Reactivities

Deprotonated glutathione is among the most potent biological nucleophiles and plays an important physiological role in cellular detoxification by forming covalent conjugates with Michael acceptors. The electrophilicity E of various Michael acceptors was characterized recently according to the Patz–Mayr relation lg k2=sN(N+E). We now determined the nucleophilic reactivity (N, sN) of glutathione (GSH) in aqueous solution at 20 °C to connect published GSH reactivities (kGSH) with Mayr's electrophilicity scale (E). In this way, electrophilicities E of more than 70 Michael acceptors could be estimated, which can now be used to systematically predict novel reactions with the multitude of nucleophiles whose nucleophilicity parameters N/sN are known

Cyclobutane Formation by the Reaction of Ethenesulfonyl Fluoride with Dimethyl Diazomalonate

Attempts to synthesize fluorosulfonyl-substituted pyrazolines by Huisgen reactions (1,3-dipolar cycloadditions) of dimethyl diazomalonate with ethenesulfonyl fluoride led to the formation of dimethyl (2R*,3S*,4R*)-2-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-3-(fluorosulfonyl)-4-((fluorosulfonyl)methyl)cyclobutane-1,1-dicarboxylate, a highly substituted cyclobutane derivative, which was characterized by NMR spectroscopy and single crystal X-ray crystallography. The mechanism of its formation was elucidated by carrying out the reaction at different temperatures and workup conditions. It is shown that an initial 1,3-dipolar cycloaddition yields a pyrazoline which extrudes nitrogen with formation of 1-fluorosulfonyl-2,2-bis(methoxycarbonyl)cyclopropane and dimethyl 2-(2-(fluorosulfonyl)ethylidene)malonate, the latter of which dimerized during chromatography on silica gel with formation of the isolated cyclobutane

Nucleophilicity of 4-(Alkylthio)-3-imidazoline Derived Enamines

Imidazolidine-4-thiones (ITOs) are cyclic, secondary amines that were considered as potential prebiotic organocatalysts for lightdriven α-alkylations of aldehydes by bromoacetonitrile (BAN). Recent studies showed that the initially supplied ITOs represent the pre-catalyst because they undergo S-alkylation with BAN to give 4-(alkylthio)-3-imidazolines (TIMs). Given that the same reagent mix that undergoes light-driven α-alkylations is also effective in the dark, we synthesized ten ITO- or TIM-derived enamines of aldehydes and characterized their nucleophilic reactivities by kinetic studies in acetonitrile. The experimental second-order rate constants k2 for reactions of enamines with benzhydrylium ions (reference electrophiles) were evaluated by the Mayr-Patz equation, lg k2(20 °C)=sN(N+E). The determined nucleophilicities N (and sN) reveal the reactivity profiles of these enamines under prebiotically relevant conditions as well as their potential for use in organocatalytic synthesis

4-[4-(Dimethyl­amino)benzyl­idene]-2,6-dimethyl­cyclo­hexa-2,5-dienone

The title compound, C17H19NO, crystallized with two mol­ecules per asymmetric unit. C—H⋯O hydrogen bonds lead to infinite chains along [100]. According to graph-set theory, the descriptor C 1 1(13)C 1 1(13) can be assigned

Reactivities of allenic and olefinic Michael acceptors towards phosphines

The kinetics of the reactions of tributylphosphine with allenic and olefinic Michael acceptors in dichloromethane at 20 °C was followed by photometric and NMR spectroscopic methods. Combination with DFT-calculated methyl anion affinities revealed the relevance of retroaddition barriers in phosphine-catalysed reactions when mixtures of allenic and olefinic substrates are used

trans-1-Phenyl­pyrrolidine-2,5-dicarbo­nitrile

In the title compound, C12H11N3, the plane of the phenyl ring and the least-squares plane of the pyrrolidine ring enclose an angle of 14.30 (6)°. The intra­cyclic N atom features a nearly trigonal-planar coordination geometry due to π-inter­actions with the aromatic system. The pyrrolidine ring is present in a twist conformation for which the closest pucker descriptor is C9 T C8. Weak inter­molecular C—H⋯N and C—H⋯π contacts occu

An Overlooked Pathway in 1,3-Dipolar Cycloadditions of Diazoalkanes with Enamines

Methyl diazoacetate reacts with 1-(N-pyrrolidino)cycloalkenes to give products of 1,3-dipolar cycloadditions and azo couplings. The kinetics and mechanisms of these reactions were investigated by NMR spectroscopy and DFT calculations. Orthogonal pi-systems in the 1,3-dipoles of the propargyl-allenyl type allow for two separate reaction pathways for the (3+2)-cycloadditions. The commonly considered concerted pathway is rationalized by the interaction of the enamine HOMO with LUMO+1, the lowest unoccupied orbital of the heteropropargyl anion fragment of methyl diazoacetate. We show that HOMO/LUMO(pi*(N=N)) interactions between enamines and methyl diazoacetate open a previously unrecognized reaction path for stepwise cycloadditions through zwitterionic intermediates with barriers approximately 40 kJ mol(-1) lower in energy in CHCl3 (DFT calculations) than for the concerted path

Pushing the Upper Limit of Nucleophilicity Scales by Mesoionic N-Heterocyclic Olefins

A series of mesoionic, 1,2,3-triazole-derived N-heterocyclic olefins (mNHOs), which have an extraordinarily electron-rich exocyclic CC-double bond, was synthesized and spectroscopically characterized, in selected cases by X-ray crystallography. The kinetics of their reactions with arylidene malonates, ArCH=C(CO2Et)2, which gave zwitterionic adducts, were investigated photometrically in THF at 20 °C. The resulting second-order rate constants k2(20 °C) correlate linearly with the reported electrophilicity parameters E of the arylidene malonates (reference electrophiles), thus providing the nucleophile-specific N and sN parameters of the mNHOs according to the correlation lg k2(20 °C)=sN(N+E). With 21<N<32, the mNHOs are much stronger nucleophiles than conventional NHOs. Some mNHOs even excel the reactivity of mono- and diacceptor-substituted carbanions. It is exemplarily shown that the reactivity parameters thus obtained allow to calculate the rate constants for mNHO reactions with further Michael acceptors and predict the scope of reactions with other electrophilic reaction partners including carbon dioxide, which gives zwitterionic mNHO-carboxylates. The nucleophilicity parameters N correlate linearly with a linear combination of the quantum-chemically calculated methyl cation affinities and buried volumes of mNHOs, which offers a valuable tool to tailor the reactivities of strong carbon nucleophiles

Quantification of the Electrophilicities of Diazoalkanes: Kinetics and Mechanism of Azo Couplings with Enamines and Sulfonium Ylides

Kinetics and mechanism of the reactions of methyl diazoacetate, dimethyl diazomalonate, 4-nitrophenyldiazomethane, and diphenyldiazomethane with sulfonium ylides and enamines were investigated by UV-Vis and NMR spectroscopy. Ordinary alkenes undergo 1,3-dipolar cycloadditions with these diazo compounds. In contrast, sulfonium ylides and enamines attack at the terminal nitrogen of the diazo alkanes to give zwitterions, which undergo various subsequent reactions. As only one new bond is formed in the rate-determining step of these reactions, the correlation lg k(2)(20 degrees C)=s(N)(N+E) could be used to determine the one-bond electrophilicities E of the diazo compounds from the measured second-order rate constants and the known reactivity indices N and s(N) of the sulfonium ylides and enamines. The resulting electrophilicity parameters (-21<E<-18), which are 11-14 orders of magnitude smaller than that of the benzenediazonium ion, are used to define the scope of one-bond nucleophiles which may react with these diazoalkanes