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

Imidazolidine-4-thiones (ITOs) are cyclic, secondary amines that were considered as potential prebiotic organocatalysts for light-driven 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.

Lactone Enolates of Isochroman-3-ones and 2-Coumaranones: Quantification of Their Nucleophilicity in DMSO and Conjugate Additions to Chalcones.

Owing to stereoelectronic effects, lactones often deviate in reactivity from their open-chain ester analogues as demonstrated by the CH acidity (in DMSO) of 3-isochromanone (pKa = 18.8) and 2-coumaranone (pKa = 13.5), which is higher than that of ethyl phenylacetate (pKa = 22.6). We have now characterized the reactivity of the lactone enolates derived from 3-isochromanone and 2-coumaranone by following the kinetics of their Michael reactions with p-quinone methides and arylidenemalonates (reference electrophiles) in DMSO at 20 °C. Evaluation of the experimentally determined second-order rate constants k2 by the Mayr-Patz equation, lg k2 = sN(N + E), furnished the nucleophilicity parameters N (and sN) of the lactone enolates. By localizing their position on the Mayr nucleophilicity scale, the scope of their electrophilic reaction partners becomes predictable, and we demonstrate a novel catalytic methodology for a series of carbon-carbon bond-forming reactions of lactone enolates with chalcones under phase transfer conditions in toluene.

Pyridinium-Derived Mesoionic N-Heterocyclic Olefins (py-mNHOs).

Mesoionic polarization allows access to electron-rich olefins that have found application as organocatalysts, ligands, or nucleophiles. Herein, we report the synthesis and characterization of a series of 3-methylpyridinium-derived mesoionic olefins (py-mNHOs). We used a DFT-supported design concept, which showed that the introduction of aryl groups in the 1-, 2-, 4-, and 6-positions of the heterocyclic core allowed the kinetic stabilization of the novel mesoionic compounds. Tolman electronic parameters indicate that py-mNHOs are remarkably strong σ-donor ligands toward transition metals and main group Lewis acids. Additionally, they are among the strongest nucleophiles on the Mayr reactivity scale. In reactions of py-mNHOs with electron-poor π-systems, a gradual transition from the formation of zwitterionic adducts via stepwise to concerted 1,3-dipolar cycloadditions was observed experimentally and analyzed by quantum-chemical calculations.

One-Bond-Nucleophilicity and -Electrophilicity Parameters: An Efficient Ordering System for 1,3-Dipolar Cycloadditions.

Diazoalkanes are ambiphilic 1,3-dipoles that undergo fast Huisgen cycloadditions with both electron-rich and electron-poor dipolarophiles but react slowly with alkenes of low polarity. Frontier molecular orbital (FMO) theory considering the 3-center-4-electron π-system of the propargyl fragment of diazoalkanes is commonly applied to rationalize these reactivity trends. However, we recently found that a change in the mechanism from cycloadditions to azo couplings takes place due to the existence of a previously overlooked lower-lying unoccupied molecular orbital. We now propose an alternative approach to analyze 1,3-dipolar cycloaddition reactions, which relies on the linear free energy relationship lg k2(20 °C) = sN(N + E) (eq 1) with two solvent-dependent parameters (N, sN) to characterize nucleophiles and one parameter (E) for electrophiles. Rate constants for the cycloadditions of diazoalkanes with dipolarophiles were measured and compared with those calculated for the formation of zwitterions by eq 1. The difference between experimental and predicted Gibbs energies of activation is interpreted as the energy of concert, i.e., the stabilization of the transition states by the concerted formation of two new bonds. By linking the plot of lg k2 vs N for nucleophilic dipolarophiles with that of lg k2 vs E for electrophilic dipolarophiles, one obtains V-shaped plots which provide absolute rate constants for the stepwise reactions on the borderlines. These plots furthermore predict relative reactivities of dipolarophiles in concerted, highly asynchronous cycloadditions more precisely than the classical correlations of rate constants with FMO energies or ionization potentials. DFT calculations using the SMD solvent model confirm these interpretations.

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 k 2 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.

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(CO2 Et)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

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 k2 (20 °C)=sN (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 sN of the sulfonium ylides and enamines. The resulting electrophilicity parameters (-21

Epigenetic Anti-Cancer Treatment With a Stabilized Carbocyclic Decitabine Analogue.

5-Aza-2'-deoxycytidine (Decitabine, AzadC) is a nucleoside analogue, which is in clinical use to treat patients with myelodysplastic syndrome or acute myeloid leukemia. Its mode of action is unusual because the compound is one of the few drugs that act at the epigenetic level of the genetic code. AzadC is incorporated as an antimetabolite into the genome and creates covalent, inhibitory links to DNA methyltransferases (DNMTs) that methylate 2'-deoxycytidine (dC) to 5-methyl-dC (mdC). Consequently, AzadC treatment leads to a global loss of mdC, which presumably results in a reactivation of silenced genes, among them tumor suppressor and DNA damage response genes. Because AzadC suffers from severe instability, which limits its use in the clinic, a more sophisticated AzadC derivative would be highly valuable. Here, we report that a recently developed carbocyclic AzadC analogue (cAzadC) blocks DNMT1 in the AML cell line MOLM-13 as efficient as AzadC. Moreover, cAzadC has a surprisingly strong anti-proliferative effect and leads to a significantly higher number of double strand breaks compared to AzadC, while showing less off-target toxicity. These results show that cAzadC triggers more deleterious repair and apoptotic pathways in cancer cells than AzadC, which makes cAzadC a promising next generation epigenetic drug.

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 π-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(π*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.

Lewis Acidic Boranes, Lewis Bases, and Equilibrium Constants: A Reliable Scaffold for a Quantitative Lewis Acidity/Basicity Scale.

A quantitative Lewis acidity/basicity scale toward boron-centered Lewis acids has been developed based on a set of 90 experimental equilibrium constants for the reactions of triarylboranes with various O-, N-, S-, and P-centered Lewis bases in dichloromethane at 20 °C. Analysis with the linear free energy relationship log KB =LAB +LBB allows equilibrium constants, KB , to be calculated for any type of borane/Lewis base combination through the sum of two descriptors, one for Lewis acidity (LAB ) and one for Lewis basicity (LBB ). The resulting Lewis acidity/basicity scale is independent of fixed reference acids/bases and valid for various types of trivalent boron-centered Lewis acids. It is demonstrated that the newly developed Lewis acidity/basicity scale is easily extendable through linear relationships with quantum-chemically calculated or common physical-organic descriptors and known thermodynamic data (ΔH BF 3 ). Furthermore, this experimental platform can be utilized for the rational development of borane-catalyzed reactions.

Inherent Reactivity of Spiro-Activated Electrophilic Cyclopropanes.

The kinetics of the ring-opening reactions of thiophenolates with geminal bis(acceptor)-substituted cyclopropanes in DMSO at 20 °C was monitored by photometric methods. The determined second-order rate constants of the SN 2 reactions followed linear relationships with Mayr nucleophilicity parameters (N/sN ) and Brønsted basicities (pKaH ) of the thiophenolates as well as with Hammett substituent parameters (σ) for groups attached to the thiophenolates. Phenyl-substituted cyclopropanes reacted by up to a factor of 15 faster than their unsubstituted analogues, in accord with the known activating effect of adjacent π-systems in SN 2 reactions. Variation of the electronic properties of substituents at the phenyl groups of the cyclopropanes gave rise to parabolic Hammett relationships. Thus, the inherent SN 2 reactivity of electrophilic cyclopropanes is activated by electron-rich π-systems because of the more advanced C1-C2 bond polarization in the transition state. On the other hand, electron-poor π-systems also lower the energetic barriers for the attack of anionic nucleophiles owing to attractive electrostatic interactions.

Nucleophilicities and Nucleofugalities of Thio- and Selenoethers.

Rate constants for the reactions of dialkyl chalcogenides with laser flash photolytically generated benzhydrylium ions have been measured photometrically to integrate them into the comprehensive benzhydrylium-based nucleophilicity scale. Combining these rate constants with the previously reported equilibrium constants for the same reactions provided the corresponding Marcus intrinsic barriers and made it possible to quantify the leaving group abilities (nucleofugalities) of dialkyl sulfides and dimethyl selenide. Due to the low intrinsic barriers, dialkyl chalcogenides are fairly strong nucleophiles (comparable to pyridine and N-methylimidazole) as well as good nucleofuges; this makes them useful group-transfer reagents.

Nucleophilic Reactivities of Thiophenolates.

The nucleophilic reactivities of substituted thiophenolates were determined by following the kinetics of their reactions with a series of quinone methides (reference electrophiles) in DMSO at 20 °C. The experimentally determined second-order rate constants were analyzed according to the Mayr-Patz equation log k = sN(N + E) to derive the nucleophile-specific reactivity parameters N and sN for ten thiophenolate ions.

Base-Promoted Cascade Reactions for the Synthesis of 3,3-Dialkylated Isoindolin-1-ones and 3-Methyleneisoindolin-1-ones.

Cascade reactions of ortho-carbonyl-substituted benzonitriles with ((chloromethyl)sulfonyl)benzenes as pronucleophiles led to new isoindolin-1-ones with a tetrasubstituted C-3 position or to (Z)-3-(sulfonyl-methylene)isoindolin-1-ones. The reactions start from readily available materials, are carried out under mild conditions, and do not require metal catalysis. Promoted only by the cheap and environmentally benign K2CO3 as the base, up to six elemental steps can be combined in a single pot. Hence, a sequential one-pot cascade/ß-elimination/alkylation furnished useful intermediates for the synthesis of aristolactam natural products. The observed selectivity and the mechanism were investigated by DFT studies.

From Carbodiimides to Carbon Dioxide: Quantification of the Electrophilic Reactivities of Heteroallenes.

Kinetics of the reactions of isocyanates, isothiocyanates, carbodiimides, carbon disulfide, and carbon dioxide with carbanions or enamines (reference nucleophiles) have been measured photometrically in acetonitrile or DMSO solution at 20 °C. The resulting second-order rate constants and the previously published reactivity parameters N and sN of the reference nucleophiles were substituted into the correlation log k2(20 °C) = sN(N + E) to determine the electrophilicity parameters of the heteroallenes: TsNCO (E = -7.69) ≫ PhNCO (E = -15.38) > CS2 (E = -17.70) ≈ PhNCS (E = -18.15) > PhNCNPh (E = -20.14) ≫ CyNCNCy (E ≈ -30). An approximate value could be derived for CO2 (-16 < E < - 11). Quantum chemical calculations were performed at the IEFPCM(DMSO)/B3LYP-D3/6-311+G(d,p) level of theory and compared with experimental Gibbs activation energies. The distortion-interaction model was used to rationalize the different reactivities of O- and S-substituted heteroallenes. Eventually it is demonstrated that the electrophilicity parameters determined in this work can be used as ordering principle for literature-known reactions of heteroallenes.

Lewis Acidity Scale of Diaryliodonium Ions toward Oxygen, Nitrogen, and Halogen Lewis Bases.

Equilibrium constants for the associations of 17 diaryliodonium salts Ar2I+X- with 11 different Lewis bases (halide ions, carboxylates, p-nitrophenolate, amines, and tris(p-anisyl)phosphine) have been investigated by titrations followed by photometric or conductometric methods as well as by isothermal titration calorimetry (ITC) in acetonitrile at 20 °C. The resulting set of equilibrium constants KI covers 6 orders of magnitude and can be expressed by the linear free-energy relationship lg KI = sI LAI + LBI, which characterizes iodonium ions by the Lewis acidity parameter LAI, as well as the iodonium-specific affinities of Lewis bases by the Lewis basicity parameter LBI and the susceptibility sI. Least squares minimization with the definition LAI = 0 for Ph2I+ and sI = 1.00 for the benzoate ion provides Lewis acidities LAI for 17 iodonium ions and Lewis basicities LBI and sI for 10 Lewis bases. The lack of a general correlation between the Lewis basicities LBI (with respect to Ar2I+) and LB (with respect to Ar2CH+) indicates that different factors control the thermodynamics of Lewis adduct formation for iodonium ions and carbenium ions. Analysis of temperature-dependent equilibrium measurements as well as ITC experiments reveal a large entropic contribution to the observed Gibbs reaction energies for the Lewis adduct formations from iodonium ions and Lewis bases originating from solvation effects. The kinetics of the benzoate transfer from the bis(4-dimethylamino)-substituted benzhydryl benzoate Ar2CH-OBz to the phenyl(perfluorophenyl)iodonium ion was found to follow a first-order rate law. The first-order rate constant kobs was not affected by the concentration of Ph(C6F5)I+ indicating that the benzoate release from Ar2CH-OBz proceeds via an unassisted SN1-type mechanism followed by interception of the released benzoate ions by Ph(C6F5)I+ ions.

Basicities and Nucleophilicities of Pyrrolidines and Imidazolidinones Used as Organocatalysts.

The Brønsted basicities pKaH (i.e., pKa of the conjugate acids) of 32 pyrrolidines and imidazolidinones, commonly used in organocatalytic reactions, have been determined photometrically in acetonitrile solution using CH acids as indicators. Most investigated pyrrolidines have basicities in the range 16 < pKaH < 20, while imidazolidinones are significantly less basic (10 < pKaH < 12). 2-(Trifluoromethyl)pyrrolidine (A14, pKaH 12.6) and the 2-imidazoliummethyl-substituted pyrrolidine A21 (pKaH 11.1) are outside the typical range for pyrrolidines with basicities comparable to those of imidazolidinones. Kinetics of the reactions of these 32 organocatalysts with benzhydrylium ions (Ar2CH+) and structurally related quinone methides, common reference electrophiles for quantifying nucleophilic reactivities, have been measured photometrically. Most reactions followed second-order kinetics, first order in amine and first order in electrophile. More complex kinetics were observed for the reactions of imidazolidinones and several pyrrolidines carrying bulky 2-substituents, due to reversibility of the initial attack of the amines at the electrophiles followed by rate-determining deprotonation of the intermediate ammonium ions. In the presence of 2,4,6-collidine or 2,6-di-tert-butyl-4-methyl-pyridine, the deprotonation of the initial adducts became faster, which allowed the rate of the attack of the amines at the electrophiles to be determined. The resulting second-order rate constants k2 followed the correlation log k2(20 °C) = sN(N + E), where electrophiles are characterized by one parameter (E) and nucleophiles are characterized by the two solvent-dependent parameters N and sN. In this way, the organocatalysts A1-A32 were integrated in our comprehensive nucleophilicity scale, which compares n-, π-, and σ-nucleophiles. The nucleophilic reactivities of the title compounds correlate only poorly with their Brønsted basicities.

CF3-Containing para-Quinone Methides for Organic Synthesis.

A new family of CF3-containing para-quinone methides (CF3-QMs) was systematically investigated for its suitability in organic synthesis. Addition of different nucleophiles gives access to target molecules with a benzylic CF3-containing stereogenic center straightforwardly. The electrophilicity parameter E of the prototypical CF3-QM 2,6-di-tert-butyl-4-(2,2,2-trifluoroethylidene)cyclohexa-2,5-dien-1-one was determined to be -11.68 according to the Mayr scale, making it one of the most reactive quinone methides known so far.

Predicting Absolute Rate Constants for Huisgen Reactions of Unsaturated Iminium Ions with Diazoalkanes.

The kinetics and stereochemistry of the reactions of iminium ions derived from cinnamaldehydes and MacMillan's imidazolidinones with diphenyldiazomethane and aryldiazomethanes were investigated experimentally and with DFT calculations. The reactions of diphenyldiazomethane with iminium ions derived from MacMillan's second-generation catalysts gave 3-aryl-2,2-diphenylcyclopropanecarbaldehydes with yields >90 % and enantiomeric ratios of ≥90:10. Predominantly 2:1 products were obtained from the corresponding reactions with monoaryldiazomethanes. The measured rate constants are in good agreement with the rate constants derived from the one-center nucleophilicity parameters N and sN of diazomethanes and the one-center electrophilicity parameters E of iminium ions as well as with quantum chemically calculated activation energies.

Ambident Reactivity of Phenolate Anions Revisited: A Quantitative Approach to Phenolate Reactivities.

Prompted by the observation that the regioselectivities of phenolate reactions (C versus O attack) are opposite to the predictions by the principle of hard and soft acids and bases, we performed a comprehensive experimental and computational investigation of phenolate reactivities. Rate and equilibrium constants for the reactions of various phenolate ions with benzhydrylium ions (Aryl2CH+) and structurally related quinone methides have been determined photometrically in polar aprotic solvents. Quantum chemical calculations at the SMD(MeCN)/M06-2X/6-31+G(d,p) level confirmed that O attack is generally favored under kinetically controlled conditions, whereas C attack is favored under thermodynamically controlled conditions. Exceptions are diffusion-limited reactions with strong electrophiles, which give mixtures of products arising from O and C attack, as well as reactions with metal alkoxides in nonpolar solvents, where oxygen attack is blocked by strong ion pairing. The Lewis basicity (LB) and nucleophilicity (N, sN) parameters of phenolates determined in this work can be used to predict whether their reactions with electrophiles are kinetically or thermodynamically controlled and whether the rates are activation- or diffusion-limited. Comparison of the measured rate constants for the reactions of phenolates with carbocations with the Gibbs energies for single-electron transfer manifests that these reactions proceed via polar mechanisms.