Benzhydrylium Ions Research Articles

2‐Methylene‐1,2‐dihydropyridines (2‐pyNHOs): Highly Nucleophilic Enamines

AbstractThe high reactivity of 2‐methylene‐1,2‐dihydropyridines also known as 2‐methylpyridinium derived N‐heterocyclic olefins (2‐pyNHOs) has been recognized in organic synthesis, yet a quantification of their nucleophilicity is lacking. Herein we used stopped‐flow photometry to determine the nucleophilicity of a series of 2‐pyNHOs from the kinetics of their reactions with quinone methides and benzhydrylium ions as reference electrophiles in four organic solvents at 20 °C. The kinetic data was evaluated by using the Mayr‐Patz equation, lg k(20 °C)=sN(N+E), which gave nucleophilicity parameters N (and sN). With N in the range of 19.4–21.2 (in DMSO), 2‐pyNHOs exceed the reactivity of classical enamines, such as pyrrolidino‐cyclopent‐1‐ene. The addition of 2‐pyNHOs to quinone methides resulted in the formation of zwitterionic adducts with pyridinium and phenolate moieties. Subsequent tautomerization yielded entirely neutral pyridine‐2(1H)‐ylidene‐phenol species in several cases. Formation of the zwitterionic adducts from 2‐pyNHOs and neutral electrophiles was almost equally fast in the polar solvents acetonitrile and DMSO, but proceeded one to two orders of magnitude slower in the less polar solvents dichloromethane or THF.

Quantitative Structure-Reactivity Relationships for Synthesis Planning: The Benzhydrylium Case.

Selective and feasible reactions are among the top targets in synthesis planning. Mayr's approach to quantifying chemical reactivity has greatly facilitated the planning process, but reactivity parameters for new compounds require time-consuming experiments. In the past decade, data-driven modeling has been gaining momentum in the field, as it shows promise in terms of efficient reactivity prediction. However, state-of-the-art models use quantum chemical data as input, which prevent access to real-time planning in organic synthesis. Here, we present a novel data-driven workflow for predicting reactivity parameters of molecules that takes only structural information as input, enabling de facto real-time reactivity predictions. We use the well-understood chemical space of benzhydrylium ions as an example to demonstrate the functionality of our approach and the performance of the resulting quantitative structure-reactivity relationships (QSRRs). Our results suggest that it is straightforward to build low-cost QSRR models that are accurate, interpretable, and transferable to unexplored systems within a given scope of application. Moreover, our QSRR approach suggests that Hammett σ parameters are only approximately additive.

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.

Nucleophilicities of Cyclic α‐Diazo Carbonyl Compounds

AbstractThe one‐bond nucleophilic reactivities of seven cyclic α‐diazo carbonyl compounds in dichloromethane were determined by analyzing the kinetics of their reactions with benzhydrylium ions (one‐bond reference electrophiles) at 20 °C according to the Mayr‐Patz equation. Though not calibrated for pericyclic reactions, the identified nucleophilicities also reflect relative reactivities of the α‐diazo carbonyl compounds in 1,3‐dipolar cycloadditions with dimethyl acetylenedicarboxylate. These (3+2)‐cycloadditions primarily gave spirocyclic 3H‐pyrazoles, which underwent thermal [1,5]‐sigmatropic (van Alphen‐Hüttel) rearrangements to furnish 1H‐pyrazole‐fused tricyclic products.

Uncertainty Quantification of Reactivity Scales.

According to Mayr, polar organic synthesis can be rationalized by a simple empirical relationship linking bimolecular rate constants to as few as three reactivity parameters. Here, we propose an extension to Mayr's reactivity method that is rooted in uncertainty quantification and transforms the reactivity parameters into probability distributions. Through uncertainty propagation, these distributions can be transformed into uncertainty estimates for bimolecular rate constants. Chemists can exploit these virtual error bars to enhance synthesis planning and to decrease the ambiguity of conclusions drawn from experimental data. We demonstrate the above at the example of the reference data set released by Mayr and co‐workers [J. Am. Chem. Soc. 2001, 123, 9500; J. Am. Chem. Soc. 2012, 134, 13902]. As by‐product of the new approach, we obtain revised reactivity parameters for 36 π‐nucleophiles and 32 benzhydrylium ions.

Elucidation of the Nucleophilic Potential of Diazocyclopentadiene

AbstractDiazocyclopentadiene reacts with benzhydrylium ions (Ar2CH+) to give 2,5-dibenzhydryl-substituted diazocyclopentadienes. The kinetics have been determined photometrically in dichloromethane under pseudo-first-order conditions using diazocyclopentadiene in excess. Plots of the second-order rate constants (log k 2) versus the electrophilicity parameters E of the benzhydrylium ions gave the nucleo­philicity parameter N = 4.84 and susceptibility s N = 1.06 for diazo­cyclopentadiene according to the correlation log k(20 °C) = s N(E + N). Diazocyclopentadiene thus has a similar nucleophilic reactivity as pyrrole. Previously reported electrophilic substitutions of diazocyclopentadiene are rationalized by these parameters and new reaction possibilities are predicted.

Quantification of the Lewis Basicities and Nucleophilicities of 1,3,5‐Tris(dialkylamino)benzenes

AbstractEquilibrium constants for the formation of Wheland complexes from 1,3,5‐tris(dialkylamino)benzenes and benzhydrylium ions (Ar2CH+) have been determined photometrically in dichloromethane solution at 20 °C. The Lewis basicity of the ring carbons increases in the series trimorpholinobenzene<tripiperidinobenzene<tripyrrolidinobenzene. Wheland complexes, which are formed with equilibrium constants 102<K/M−1<106 in the reactions of triaminobenzenes with carbenium ions, show temperature‐dependent dynamic 1H NMR spectra, due to rapid reverse reactions and recombination at different positions of the triaminobenzenes. Since the rates of the formation of the Wheland complexes are too high to be measured directly, they were calculated as the product of photometrically determined equilibrium constants and the rate constants for the reverse reactions, which were derived from the dynamic 1H NMR spectra. The experimentally determined equilibrium and rate constants were in good agreement with the results of DFT calculations using the SMD solvent model. The calculations show that in all cases the Wheland complexes are thermodynamically more stable than the ammonium ions formed by attack of the benzhydrylium ions at the amino group of the title compounds, which explains the exclusive formation of Wheland complexes in thermodynamically controlled reactions. With nucleophilicity parameters in the range 10<N<15 the triaminobenzenes have comparable nucleophilic reactivities as enamines, silyl ketene acetals as well as stabilized phosphonium and sulfonium ylides.

Unimolecular Fragmentation Properties of Thermometer Ions from Chemical Dynamics Simulations.

Thermometer ions are widely used to calibrate the internal energy of the ions produced by electrospray ionization in mass spectrometry. Typically, benzylpyridinium ions with different substituents are used. More recently, benzhydrylpyridinium ions were proposed for their lower bond dissociation energies. Direct dynamics simulations using M06-2X/6-31G(d), DFTB, and PM6-D3 are performed to characterize the activation energies of two representative systems: para-methylbenzylpyridinium ion (p-Me-BnPy+) and methyl,methylbenzhydrylpyridinium ion (Me,Me-BhPy+). Simulation results are used to calculate rate constants for the two systems. These rate constants and their uncertainties are used to find the Arrhenius activation energies and RRK fitted threshold energies which give reasonable agreement with calculated bond dissociation energies at the same level of theory. There is only one fragmentation mechanism observed for both systems, which involves C-N bond dissociation via a loose transition state, to generate either benzylium or benzhydrylium ion and a neutral pyridine molecule. For p-Me-BnPy+ using DFTB and PM6-D3 the formation of tropylium ion, from rearrangement of benzylium ion, was observed but only at higher excitation energies and for longer simulation times. These observations suggest that there is no competition between reaction pathways that could affect the reliability of internal energy calibrations. Finally, we suggest using DFTB with a modified-Arrhenius model in future studies.

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.

Metal Enolates – Enamines – Enol Ethers: How Do Enolate Equivalents Differ in Nucleophilic Reactivity?

The kinetics of the reactions of trimethylsilyl enol ethers and enamines (derived from deoxybenzoin, indane-1-one, and α-tetralone) with reference electrophiles (p-quinone methides, benzhydrylium and indolylbenzylium ions) were measured by conventional and stopped-flow photometry in acetonitrile at 20 °C. The resulting second-order rate constants were subjected to a least-squares minimization based on the correlation equation lg k = s N(N + E) for determining the reactivity descriptors N and s N of the silyl enol ethers and enamines. The relative reactivities of structurally analogous silyl enol ethers, enamines, and enolate anions towards carbon-centered electrophiles are determined as 1, 107, and 1014, respectively. A survey of synthetic applications of enolate ions and their synthetic equivalents shows that their behavior can be properly described by their nucleophilicity parameters, which therefore can be used for designing novel synthetic transformations.

Nucleophilicity and Electrophilicity Parameters for Predicting Absolute Rate Constants of Highly Asynchronous 1,3-Dipolar Cycloadditions of Aryldiazomethanes.

Kinetics of the reactions of aryldiazomethanes (ArCHN2) with benzhydrylium ions (Ar2CH+) have been measured photometrically in dichloromethane. The resulting second-order rate constants correlate linearly with the electrophilicities E of the benzhydrylium ions which allowed us to use the correlation lg k = sN( N + E) (eq 1) for determining the nucleophile-specific parameters N and sN of the diazo compounds. UV-vis spectroscopy was analogously employed to measure the rates of the 1,3-dipolar cycloadditions of these aryldiazomethanes with acceptor-substituted ethylenes of known electrophilicities E. The measured rate constants for the reactions of the diazoalkanes with highly electrophilic Michael acceptors ( E > -11, for example 2-benzylidene Meldrum's acid or 1,1-bis(phenylsulfonyl)ethylene) agreed with those calculated by eq 1 from the one-bond nucleophilicities N and sN of the diazo compounds and the one-bond electrophilicities of the dipolarophiles, indicating that the incremental approach of eq 1 may also be applied to predict the rates of highly asynchronous cycloadditions. Weaker electrophiles, e.g., methyl acrylate, react faster than calculated from E, N, and sN, and the ratio of experimental to calculated rate constants was suggested to be a measure for the energy of concert Δ G‡concert = RT ln( k2exptl/ k2calcd). Quantum chemical calculations indicated that all products isolated from the reactions of the aryldiazomethanes with acceptor substituted ethylenes (Δ2-pyrazolines, cyclopropanes, and substituted ethylenes) arise from intermediate Δ1-pyrazolines, which are formed through concerted 1,3-dipolar cycloadditions with transition states, in which the C-N bond formation lags behind the C-C bond formation. The Gibbs activation energies for these cycloadditions calculated at the PCM(UA0,CH2Cl2)/(U)B3LYP-D3/6-31+G(d,p) level of theory agree within 5 kJ mol-1 with the experimental numbers showing the suitability of the applied polarizable continuum model (PCM) for considering solvation.

Intramolecular Hydrogen‐Bonding Modulates the Nucleophilic Reactivity of Ammonium‐Peroxycarboxylates

The ammonium‐peroxycarboxylic acid mesylates derived from γ‐aminobutyric acid, β‐alanine, and β‐piperidinopropionic acid were synthesized and characterized by spectroscopic methods and X‐ray crystallography. To study the nucleophilic reactivities of the corresponding ammonium‐ and amino‐peroxycarboxylates, the kinetics of their reactions with a series of benzhydrylium ions (Ar2CH+) were investigated in alkaline, aqueous solutions at 20 °C. Using sequential‐mixing stopped‐flow UV/Vis photometry, the rates of the reactions of the short‐lived nucleophiles with Ar2CH+ were determined and analyzed by the linear free energy relationship lg k = sN(N + E) furnishing nucleophilicity parameters (N, sN) of the peroxycarboxylates. Quantum chemical calculations indicate that the reactivity of the zwitterionic ammonium‐peroxycarboxylates is attenuated by intramolecular N–H···O hydrogen bonding.

Synthesis, Structure, and Properties of Amino‐Substituted Benzhydrylium Ions – A Link between Ordinary Carbocations and Neutral Electrophiles

Optimized synthetic procedures for the straightforward access to eleven amino‐substituted diarylmethylium tetrafluoroborates are described. These benzhydrylium ions cover a range of seven orders of magnitude in electrophilicity and provide a link between ordinary carbocations and neutral electrophiles. Five of these highly stabilized benzhydrylium tetrafluoroborates were characterized by single‐crystal X‐ray crystallography. While the experimentally determined bond lengths and angles in the solid state perfectly agree with those calculated by DFT methods for the gas phase and aqueous solution, crystal packing accounts for large differences in the twist angles of the aryl groups found in the solid state as compared to calculated structures.

Nucleophilic Reactivities of Bleach Reagents.

The nucleophilicities of the oxidants hydroperoxide, hypochlorite, hypobromite, bromite, and peroxymonosulfate were determined by following the kinetics of their reactions with a series of benzhydrylium ions of known electrophilicity ( E) in alkaline, aqueous solutions at 20 °C. The reactivities of the oxidants correlate only weakly with their basicities. Analyzing the rate constants by using the relationship log k2 = sN( N + E) gave the parameters N (and sN), which were applied to predict the rates of Weitz-Scheffer epoxidations.

Which Factors Control the Nucleophilic Reactivities of Enamines?

Changes in rate constants, equivalent to changes in Gibbs energies of activation ΔG≠ , are commonly referred to as kinetic effects and differentiated from thermodynamic effects (Δr G°). Often, little attention is paid to the fact that structural effects on ΔG≠ are composed of a thermodynamic (Δr G°) and a truly kinetic (intrinsic) component (ΔG0≠ ), as expressed by the Marcus equation. Rate and equilibrium constants have been determined for a number of reactions of enamines with benzhydrylium ions (Aryl2 CH+ ), which has allowed the determination of Marcus intrinsic barriers and a differentiated analysis of structure-reactivity relationships. To our knowledge, this is the first report in which the Lewis basicity of a πCC bond towards carbon-centered Lewis acids (for example, carbenium ions) has quantitatively been determined. The synthesis, structures, and properties of deoxybenzoin-derived enamines ArCH=C(Ph)NR2 , which have been designed as reference nucleophiles for the future quantification of electrophilic reactivities, are explicitly described.

Nucleophilicities of Alcohols and Water in Acetonitrile Based on Reactivities of Benzhydrylium Ions

Abstract The decay rate constants of benzhydrylium ions generated by laser irradiation in acetonitrile have been determined photometrically. The decay of the stable carbocation with an electron-releasing substituent was decelerated with addition of LiClO4, being attributed to the decrease of the recombination of the cations with the counter anions. On the contrary, the decay of the highly reactive carbocation was accelerated, indicating the occurrence of the reaction with perchlorate anion. The second-order rate constants (k2) for the reactions of benzhydrylium ions with methanol, ethanol, i-propanol, t-butanol, and water were determined in acetonitrile in the presence of 3 mM LiClO4 for benzhydrylium ions less electrophilic than 3,5-dimethyl-4′-chlorobenzhydrylium ion and in the absence of LiClO4 for the remaining reactive benzhydrylium ions. Their logarithms were linearly correlated with the electrophilicity parameters (E) in Mayr’s equation, log k2 = sN(E + N). Based on the correlations the nucleophilicity parameters (N) were evaluated for these nucleophiles in acetonitrile, MeOH, 6.86; EtOH, 7.13; i-PrOH, 6.82; t-BuOH, 5.35; H2O, 5.79. The low nucleophilicity of t-butanol regardless of its high gas-phase basicity representing the inherent nature in molecular structure suggests the importance of steric environment at the transition state of the combination of benzhydrylium ions with nucleophiles.

Solvation Accounts for the Counterintuitive Nucleophilicity Ordering of Peroxide Anions.

The nucleophilic reactivities (N, sN ) of peroxide anions (generated from aromatic and aliphatic peroxy acids or alkyl hydroperoxides) were investigated by following the kinetics of their reactions with a series of benzhydrylium ions (Ar2 CH+ ) in alkaline aqueous solutions at 20 °C. The second-order rate constants revealed that deprotonated peroxy acids (RCO3- ), although they are the considerably weaker Brønsted bases, react much faster than anions of aliphatic hydroperoxides (ROO- ). Substitution of the rate constants of their reactions with benzhydrylium ions into the linear free energy relationship lg k=sN (N+E) furnished nucleophilicity parameters (N, sN ) of peroxide anions, which were successfully applied to predict the rates of Weitz-Scheffer epoxidations. DFT calculations with inclusion of solvent effects by means of the Integral Equation Formalism version of the Polarizable Continuum Model were performed to rationalize the observed reactivities.

Reactivity-Tuning in Frustrated Lewis Pairs: Nucleophilicity and Lewis Basicity of Sterically Hindered Phosphines.

The nucleophilicity and Lewis basicity of sterically hindered phosphines, widely used in catalysis and in frustrated Lewis pair (FLP) chemistry, have been quantified by determining the rates and equilibrium constants of their associations with reference systems (benzhydrylium and tritylium ions) of calibrated electrophilicities and Lewis acidities. These structure-reactivity investigations allow a rationalization of the Lewis acid-base interactions all along the way from covalent Lewis adducts to FLPs. Comparisons of the association of phosphines of increasing sizes (Ph3 P, (o-tolyl)3 P, and tBu3 P) with the triarylborane B(C6 F5 )3 and with the isoelectronic tritylium ions Ar3 C+ provide detailed insights for the future fine-tuning of the reactivities of FLPs. As a proof of concept, tritylium-ion-derived FLPs were shown to react with alkynes, as reported for the FLPs derived from the benchmark triarylborane B(C6 F5 )3 .

Philicity, fugality, and equilibrium constants: when do rate-equilibrium relationships break down?

AbstractLinear free energy relationships, in particular relationships between rate and equilibrium constants, are the basis for our rationalization of organic reactivity. Whereas relationships between the kinetic terms nucleophilicity and nucleofugality and the thermodynamic term basicity have been in the focus of interest for many decades, much less attention has been paid to the relationships between electrophilicity, electrofugality, and Lewis acidity. By usingp- andm-substituted benzhydrylium ions (Aryl2CH+) as reference electrophiles, reference electrofuges, and reference Lewis acids of widely varying electron demand and constant steric surroundings of the reaction center, we have developed comprehensive reactivity scales which can be employed for classifying polar organic reactivity and for rationally designing synthetic transformations. It is a general rule that structural variations in electron-surplus species, which increase basicities, also increase nucleophilicities and decrease nucleofugalities, and that structural variations in electron-deficient species, which increase Lewis acidities also increase electrophilicities and decrease electrofugalities. Deviations from this behavior are analyzed, and it is shown that variations in intrinsic barriers are responsible for the counterintuitive observations that structural variation in one of the reactants alters the rates of forward and backward reactions in the same direction. A spectacular example of this phenomenon is found in vinyl cation chemistry: Vinyl cations are not only generated several orders of magnitude more slowly in SN1 reactions than benzhydrylium ions of the same Lewis acidity, but also react much more slowly with nucleophiles.

Nucleophilic Reactivities of Bis‐Acceptor‐Substituted Benzyl Anions

The kinetics of the reactions of bis‐acceptor‐substituted benzyl anions (PhCXY–, X,Y = CN, CO2Et, COPh, SO2Ph) with benzhydrylium ions and quinone methides (reference electrophiles) have been determined in dimethyl sulfoxide solution at 20 °C. The reactions follow second‐order kinetics, first order with respect to the electrophile and first order with respect to the carbanion. The addition of 18‐crown‐6 ether, which efficiently coordinates to the anions' counter ions K+, did not affect the kinetics, which indicates that the measured rate constants refer to the reactivities of the nonpaired carbanions. Comparison with the reactivities of the structurally analogous secondary carbanions HCXY– shows that replacement of H at the carbanionic center by Ph reduces the nucleophilic reactivities towards a reference benzhydrylium ion by factors in the range of only 1.2 (X,Y = SO2Ph) to 6 (X,Y = CO2Et). The plots of lg k2 versus the electrophilicity parameters E of the reference electrophiles are linear, thereby indicating that the correlation lg k2(20 °C) = sN(E + N), which characterizes nucleophiles by the two solvent‐dependent parameters sN and N and electrophiles by the parameter E, is applicable. In this way, it becomes possible to integrate these carbanions into our comprehensive nucleophilicity scale, which provides a direct comparison of the nucleophilic reactivities of different families of compounds.