Electrophilicity Parameters Research Articles

Electrophilicities oftrans-β-Nitrostyrenes

The kinetics of the reactions of the trans-β-nitrostyrenes 1a-f with the acceptor-substituted carbanions 2a-h have been determined in dimethyl sulfoxide solution at 20 °C. The resulting second-order rate constants were employed to determine the electrophile-specific reactivity parameters E of the trans-β-nitrostyrenes according to the correlation equation log k(2)(20 °C) = s(N)(N + E). The E parameters range from -12 to -15 on our empirical electrophilicity scale (www.cup.lmu.de/oc/mayr/DBintro.html). The second-order rate constants for the reactions of trans-β-nitrostyrenes with some enamines were measured and found to agree with those calculated from the electrophilicity parameters E determined in this work and the previously published N and s(N) parameters for enamines.

Electrophilicities of Acceptor‐Substituted Tritylium Ions

AbstractRates of hydride transfers from triphenylsilane to a series of substituted tritylium ions in dichloromethane solution at 20 °C have been determined spectrophotometrically. The obtained kinetic data have been used to evaluate electrophilicity parameters (E) for acceptor‐substituted tritylium ions according to the linear free energy relationship log k = sN(N + E), thus extending the previously established electrophilicity scale of differently substituted tritylium ions to more reactive systems. The rates of attack of water at meta‐fluoro‐substituted tritylium ions in aqueous acetonitrile solution have been determined by laser‐flash techniques. Hydroxide and methyl anion affinities of fluoro‐substituted tritylium ions have been calculated at the MP2(FC)/6‐31+ G(2d,p)//B3LYP/6‐31G(d,p) level of theory. Rate‐equilibrium relationships are discussed.

The N‐Alkylation of Substituted 4‐Tetrazolo[1,5‐a]pyridines: Easy Access to a New Series of Electrophiles

AbstractThe alkylation of 4‐substituted tetrazolo‐pyridines bearing electron‐withdrawing groups 7a–f to give the expected tetrazolo‐pyridinium salts 7a–f,Me or 7a–f,Et as a mixture of two N3/N2 isomers in good to quantitative yields in toluene, has been investigated. The nature of the alkyl group did not significantly affect the chemical shifts of the salts or the N3/N2 ratio, which was approximately 9:1, except for 7d,Me for which a 1:1 ratio was obtained. The alkylated tetrazolo‐pyridines were shown to react with cyclopentadiene and, in some cases, with 2,3‐dimethylbutadiene and isoprene, whereas the neutral tetrazolo‐pyridines remained unreactive towards dienes, indicating experimentally an increase in the electrophilicity of the heterocycles upon alkylation. TheDiels–Alder adducts were fully characterized through an extensive NMR and crystallographic study. It was found that the tetrazolo‐pyridinium salts either do not react or react very slowly with cyclohexadiene, showing the limitations of the scope of this activation. The theoretical scale of electrophilicity introduced by Domingo et al. on the basis of the global electrophilicity index, ω, defined by Parr, is also a very useful tool to discuss the relative reactivities of the various salts. The ω and ΔN indexes are shown to highlight the electrophilic activation of tetrazolo‐pyridines, 7a,Me and 7b,Me, which have indexes close to those of 4,6‐dinitrotetrazolo‐pyridine, which is one of the most electrophilic neutral heterocycles known to date. Using the known N and s parameters, which characterize the nucleophilicity of nucleophiles, the rate constants were found to fit the three‐parameter equation log k2 = s(N + E) introduced by Mayr to describe the feasibility of nucleophilic–electrophilic combinations. Based on this, the electrophilicity parameter E of 7a–b,Me was determined. With E values around –7, this corresponds to a positioning of the reactivity of the carbocyclic ring of the tetrazolo‐pyridinium salts in a domain of high electrophilicity previously defined for nitrobenzofuroxans.

Quantification of the Electrophilic Reactivities of Aldehydes, Imines, and Enones

The rates of the epoxidation reactions of aldehydes, of the aziridination reactions of aldimines, and of the cyclopropanation reactions of α,β-unsaturated ketones with aryl-stabilized dimethylsulfonium ylides have been determined photometrically in dimethyl sulfoxide (DMSO). All of these sulfur ylide-mediated cyclization reactions as well as the addition reactions of stabilized carbanions to N-tosyl-activated aldimines have been shown to follow a second-order rate law, where the rate constants reflect the (initial) CC bond formation between nucleophile and electrophile. The derived second-order rate constants (log k(2)) have been combined with the known nucleophilicity parameters (N, s(N)) of the aryl-stabilized sulfur ylides 4a,b and of the acceptor-substituted carbanions 4c-h to calculate the electrophilicity parameters E of aromatic and aliphatic aldehydes (1a-i), N-acceptor-substituted aromatic aldimines (2a-e), and α,β-unsaturated ketones (3a-f) according to the linear free-energy relationship log k(2) = s(N)(N + E) as defined in J. Am. Chem. Soc.2001, 123, 9500-9512. The data reported in this work provide the first quantitative comparison of the electrophilic reactivities of aldehydes, imines, and simple Michael acceptors in DMSO with carbocations and cationic metal-π complexes within our comprehensive electrophilicity scale.

Nucleophilicity parameters for strong nucleophiles in dimethyl sulfoxide. A direct alternative to the s(E + N) equation

AbstractA scale of nucleophilicity (N‴) for relatively strong nucleophiles (e.g. carbanions and amines), spanning over 5 orders of magnitude was constructed directly from experimental rate constants for reactions of 34 nucleophiles with a benzhydrylium cation, (lil)2CH+ (log k = N‴ in dimethyl sulfoxide at 20 °C). The equation log k = (E‴ + sEN‴ +c), where E‴ is an electrophilicity parameter, sE is a Swain‐Scott type of response parameter (to variation in nucleophilicity) for the electrophile, and c is a residuals term, is used to correlate second order rate constants for reactions of nucleophiles with other benzhydrylium cations, quinone methides (QM) and Michael‐acceptor electrophiles. Contrary to published claims (Mayr et al. Angew Chem. Int. Ed. 2002, 41, 92, and later work), sE increases as the reactivity of the QM decreases. The N‴ scale was extended a further 3 orders of magnitude by an extrapolation involving a QM electrophile. In contrast, published procedures involve over 40 reference electrophiles and over 100 adjustable parameters obtained from the equation log k = sN(E + N), where k is the rate constant, and sN is a nucleophile parameter. Values of N–N‴ in DMSO increase by 8 log units, as the reactivity of the nucleophile increases, because N is a floating scale whereas N‴ is a fixed scale. Copyright © 2010 John Wiley & Sons, Ltd.

ChemInform Abstract: Reactivity Parameters for Rationalizing Iminium‐Catalyzed Reactions

AbstractReview: 54 refs.

Counterion effects in iminium-activated electrophilic aromatic substitutions of pyrroles

Electrophilic substitution of pyrroles by α,β-unsaturated iminium ions is slow in acetonitrile when only weakly basic counterions are present. When the reactions are carried out in the presence of KCF(3)CO(2), fast deprotonation of the intermediate σ-adducts occurs, and the rate constant for the rate-determining CC bond-forming step can be predicted from the electrophilicity parameter E of the iminium ion and the N and s parameters of the pyrroles.

Characterization of the nucleophilic reactivities of thiocarboxylate, dithiocarbonate and dithiocarbamate anions

The kinetics of the reactions of thiocarboxylate and thiocarbonate anions with benzhydrylium ions have been determined in acetonitrile solution using laser-flash photolytic techniques. The second-order rate constants (k) correlate linearly with the electrophilicity parameters E of the benzhydrylium ions, as required by the correlation log k (20 °C) = s(N)(N + E) (J. Am. Chem. Soc., 2001, 123, 9500-9512), allowing us to calculate the nucleophile-specific parameters N and s(N) for these anions. With these parameters, a direct comparison of the reactivities of thiocarboxylate, dithiocarbonate and dithiocarbamate anions with other nucleophiles becomes possible.

Hydride Affinity Scale of Various Substituted Arylcarbeniums in Acetonitrile

Combined with the integral equation formalism polarized continuum model (IEFPCM), the hydride affinities of 96 various acylcarbenium ions in the gas phase and CH(3)CN were estimated by using the B3LYP/6-31+G(d)//B3LYP/6-31+G(d), B3LYP/6-311++G(2df,2p)//B3LYP/6-31+G(d), and BLYP/6-311++G(2df,2p)//B3LYP/6-31+G(d) methods for the first time. The results show that the combination of the BLYP/6-311++G(2df,2p)//B3LYP/6-31+G(d) method and IEFPCM could successfully predict the hydride affinities of arylcarbeniums in MeCN with a precision of about 3 kcal/mol. On the basis of the calculated results from the BLYP method, it can be found that the hydride affinity scale of the 96 arylcarbeniums in MeCN ranges from -130.76 kcal/mol for NO(2)-PhCH(+)-CN to -63.02 kcal/mol for p-(Me)(2)N-PhCH(+)-N(Me)(2), suggesting most of the arylcarbeniums are good hydride acceptors. Examination of the effect of the number of phenyl rings attached to the carbeniums on the hydride affinities shows that the increase of the hydride affinities takes place linearly with increasing number of benzene rings in the arylcarbeniums. Analyzing the effect of the substituents on the hydride affinities of arylcarbeniums indicates that electron-donating groups decrease the hydride affinities and electron-withdrawing groups show the opposite effect. The hydride affinities of arylcarbeniums are linearly dependent on the sum of the Hammett substituent parameters σ(p)(+). Inspection of the correlation of the solution-phase hydride affinities with gas-phase hydride affinities and aqueous-phase pK(R)(+) values reveals a remarkably good correspondence of ΔG(H(-)A)(R(+)) with both the gas-phase relative hydride affinities only if the α substituents X have no large electron-donating or -withdrawing properties and the pK(R)(+) values even though the media are dramatically different. The solution-phase hydride affinities also have a linear relationship with the electrophilicity parameter E, and this dependence can certainly serve as one of the most effective ways to estimate the new E values from ΔG(H(-)A)(R(+)) or vice versa. Combining the hydride affinities and the reduction potentials of the arylcarbeniums, we obtained the bond homolytic dissociation Gibbs free energy changes of the C-H bonds in the corresponding hydride adducts in acetonitrile, ΔG(HD)(RH), and found that the effects of the substituent on ΔG(HD)(RH) are very small. Simple thermodynamic analytic platforms for the three C-H cleavage modes were constructed. It is evident that the present work would be helpful in understanding the nature of the stabilities of the carbeniums and mechanisms of the hydride transfers between carbeniums and other hydride donors.

Scope and Limitations of Cyclopropanations with Sulfur Ylides

The rates of the reactions of the stabilized and semistabilized sulfur ylides 1a-g with benzhydrylium ions (2a-e) and Michael acceptors (2f-v) have been determined by UV-vis spectroscopy in DMSO at 20 °C. The second-order rate constants (log k(2)) of these reactions correlate linearly with the electrophilicity parameters E of the electrophiles 2 as required by the correlation log k(2) = s(N + E), which allowed us to calculate the nucleophile-specific parameters N and s for the sulfur ylides 1a-g. The rate constants for the cyclopropanation reactions of sulfur ylides with Michael acceptors lie on the same correlation line as the rate constants for the reactions of sulfur ylides with carbocations. This observation is in line with a stepwise mechanism for the cyclopropanation reactions in which the first step, nucleophilic attack of the sulfur ylides at the Michael acceptors, is rate determining. As the few known pK(aH) values for sulfur ylides correlate poorly with their nucleophilic reactivities, the data reported in this work provide the first quantitative approach to sulfur ylide reactivity.

Ambident Reactivities of Pyridone Anions

The kinetics of the reactions of the ambident 2- and 4-pyridone anions with benzhydrylium ions (diarylcarbenium ions) and structurally related Michael acceptors have been studied in DMSO, CH(3)CN, and water. No significant changes of the rate constants were found when the counterion was varied (Li(+), K(+), NBu(4)(+)) or the solvent was changed from DMSO to CH(3)CN, whereas a large decrease of nucleophilicity was observed in aqueous solution. The second-order rate constants (log k(2)) correlated linearly with the electrophilicity parameters E of the electrophiles according to the correlation log k(2) = s(N + E) (Angew. Chem., Int. Ed. Engl. 1994, 33, 938-957), allowing us to determine the nucleophilicity parameters N and s for the pyridone anions. The reactions of the 2- and 4-pyridone anions with stabilized amino-substituted benzhydrylium ions and Michael acceptors are reversible and yield the thermodynamically more stable N-substituted pyridones exclusively. In contrast, highly reactive benzhydrylium ions (4,4'-dimethylbenzhydrylium ion), which react with diffusion control, give mixtures arising from N- and O-attack with the 2-pyridone anion and only O-substituted products with the 4-pyridone anion. For some reactions, rate and equilibrium constants were determined in DMSO, which showed that the 2-pyridone anion is a 2-4 times stronger nucleophile, but a 100 times stronger Lewis base than the 4-pyridone anion. Quantum chemical calculations at MP2/6-311+G(2d,p) level of theory showed that N-attack is thermodynamically favored over O-attack, but the attack at oxygen is intrinsically favored. Marcus theory was employed to develop a consistent scheme which rationalizes the manifold of regioselectivities previously reported for the reactions of these anions with electrophiles. In particular, Kornblum's rationalization of the silver ion effect, one of the main pillars of the hard and soft acid/base concept of ambident reactivity, has been revised. Ag(+) does not reverse the regioselectivity of the attack at the 2-pyridone anion by increasing the positive charge of the electrophile but by blocking the nitrogen atom of the 2-pyridone anion.

Electrophilic Reactivities of 1,2‐Diaza‐1,3‐dienes

The kinetics of the reactions of 1,2-diaza-1,3-dienes 1 with acceptor-substituted carbanions 2 have been studied at 20 °C. The reactions follow a second-order rate law, and can be described by the linear free energy relationship log k(20 °C)=s(N+E) [Eq. (1)]. With Equation (1) and the known nucleophile-specific parameters N and s for the carbanions, the electrophilicity parameters E of the 1,2-diaza-1,3-dienes 1 were determined. With E parameters in the range of -13.3 to -15.4, the electrophilic reactivities of 1a-d are comparable to those of benzylidenemalononitriles, 2-benzylideneindan-1,3-diones, and benzylidenebarbituric acids. The experimental second-order rate constants for the reactions of 1a-d with amines 3 and triarylphosphines 4 agreed with those calculated from E, N, and s, indicating the applicability of the linear free energy relationship [Eq. (1)] for predicting potential nucleophilic reaction partners of 1,2-diaza-1,3-dienes 1. Enamines 5 react up to 10(2) to 10(3) times faster with compounds 1 than predicted by Equation (1), indicating a change of mechanism, which becomes obvious in the reactions of 1 with enol ethers.

Electrophilic Reactivities of Azodicarboxylates

The kinetics of the reactions of the azodicarboxylates 1 with the enamines 2 have been studied in CH(3)CN at 20 °C. The reactions follow a second-order rate law and can be described by the linear free energy relationship log k(2) (20 °C) = s(N+E) (E = electrophilicity parameter, N = nucleophilicity parameter, and s = nucleophile-specific slope parameter). With E parameters from -12.2 to -8.9, the electrophilic reactivities of 1 turned out to be comparable to those of α,β-unsaturated iminium ions, amino-substituted benzhydrylium ions, and ordinary Michael acceptors. While the E parameters of the azodicarboxylates 1 determined in this work also hold for their reactions with triarylphosphines, they cannot be used for estimating rate constants for their reactions with amines. Comparison of experimental and calculated rate constants for cycloadditions and ene reactions of azodicarboxylates provides information on the concertedness of these reactions.

Nucleophilicities and Nucleofugalities of Organic Carbonates

AbstractThe kinetics of the reactions of the methyl carbonate ion with benzhydrylium ions in acetonitrile have been studied by UV/Vis spectrophotometry. Substitution of the resulting second‐order rate constants and the electrophilicity parameters E of the benzhydrylium ions into the linear free energy relationship log k = s(N + E) yielded the nucleophilicity parameters N25 = 16.03 and s25 = 0.64 for methyl carbonate in acetonitrile. The kinetics of the reverse reactions, i.e., of the solvolyses of ring‐substituted benzhydryl alkyl carbonates in different aqueous solvents were followed by conductimetry. The obtained first‐order rate constants and the known electrofugality parameters Ef of benzhydrylium ions were used to determine the nucleofugality parameters Nf and sf of the ROCO2– groups by using the linear free energy relationship log k = sf(Nf + Ef). The leaving group abilities of carbonates decrease by a factor of about 300 from PhOCO2– over MeOCO2– and iBuOCO2– to tBuOCO2– in various alcoholic and aqueous solvents. tert‐Butyl carbonates (tBocO‐R) are, thus, considerably more stable with respect to heterolytic cleavage of the O–R bond than other organic carbonates.

Nucleophilic Reactivities of Imide and Amide Anions

The kinetics of the reactions of amide and imide anions 2a-o with benzhydrylium ions 1a-i and structurally related quinone methides 1j-q have been studied by UV-vis spectroscopy in DMSO and acetonitrile solution. The second-order rate constants (log k(2)) correlated linearly with the electrophilicity parameters E of 1a-q according to the correlation log k(2) = s(N + E) (Angew. Chem., Int. Ed. Engl. 1994, 33, 938-957), allowing us to determine the nucleophilicity parameters N and the nucleophile-specific parameters s for these nucleophiles. The reactivities of all sulfonamide and diacylimide anions are found in a relatively small range (15 < N < 22). Comparison with structurally related carbanions revealed that amide and imide anions are less reactive than carbanions of the same pK(aH). These effects can be attributed to the absence of resonance stabilization of one of the lone pairs in the amide or imide anions. As amide and imide anions are exclusively attacked at nitrogen by benzhydrylium ions, Kornblum's interpretation of the ambident reactivity of amide anions has to be revised.

Reactivity parameters for rationalizing iminium‐catalyzed reactions

AbstractThe correlation equation (1), lg k(20 °C) = s(E + N), where electrophiles are characterized by one (E) and nucleophiles are characterized by two parameters (N, s) was used to rationalize the scope of iminium‐catalyzed reactions. Kinetics of the reactions of iminium triflates, pregenerated from cinnamaldehyde and secondary amines, with cyclic ketene acetals were studied by UV–Vis spectroscopy. From the second‐order rate constants, electrophilicity parameters −10 &lt; E &lt; −7 have been derived for these iminium ions. Eqn (1) was found to correctly predict the rate constants for the reactions of the cinnamaldehyde‐derived iminium ions with pyrroles, indoles, and sulfur ylides. The zwitterion obtained from cinnamaldehyde and indoline‐2‐carboxylic acid reacts more than 105 times faster with a sulfur ylide than predicted by Eqn (1), which is explained by MacMillan's ‘electrostatic activation’. The failure of imidazolidinones to catalyze cyclopropanations of α,β‐unsaturated carbonyl compounds by sulfur ylides is not due to the low nucleophilic reactivity of sulfur ylides but due to their high Brønsted basicity which inhibits the formation of the iminium ions. Copyright © 2010 John Wiley &amp; Sons, Ltd.

Local Electrophilicity Predicts the Toxicity-Relevant Reactivity of Michael Acceptors

Electrophilic substances can form covalent bonds to proteins and DNA, resulting in reactive toxicity and according diseases such as dermal or respiratory sensitization and mutagenicity. Employing site-specific quantum chemical parameters for quantifying the energy change associated with the gain or loss of electronic charge, two new local electrophilicity parameters are derived. Application to a set of 31 α,β-unsaturated carbonyl compounds and their experimental rates of reaction toward glutathione as a model nucleophile yields r2 values up to 0.95, outperforming both the global electrophilicity and its earlier introduced local variant based on the condensed-to-atom Fukui function. A second data set demonstrates the suitability of the new reactivity parameters to also model Mayr’s electrophilicity parameter, again superior to existing approaches. The results indicate the suitability of the new parameters to screen, without experimental investigation, organic compounds for their electrophilic reactivity in...

A design to prevent floating within the N scale of nucleophilicity

AbstractTwo nucleophilicity scales (N′ and N″) including 96 nucleophiles, spanning 1017 in rate constant, have been constructed directly from experimental rate constants for reactions of nucleophiles with dianisyl (log k = N′) or dimethylaminobenzhydrylium (log k = N″) cations in dichloromethane at 20 °C. The two scales are linked/unified by the formula: N′ − N″ = 6.6. In contrast, published procedures (H. Mayr et al. J. Am. Chem. Soc. 2001, 123, 9500, and later work) involve 23 benzhydrylium cations and over 200 adjustable parameters obtained from the equation log k = s(E + N), where k is the rate constant, E is an electrophilicity parameter and s is a nucleophile‐specific sensitivity parameter. The definitions of N′ and N″ avoid a floating N scale, i.e. having less than the usual attachment to fixed reference points. New equations, log k = (E + sN′) or log k = (E + sN″), where s is now an electrophile‐specific parameter, are then used to correlate over 350 second‐order rate constants for reactions of other benzhydrylium cations with nucleophiles. For weaker, less polar, nucleophiles, s ∼ 1 and the new E and N′ parameters are in satisfactory agreement with published data for E and N. For more polar nucleophiles, s ≠ 1 and values of N − N″ vary by five log units. Copyright © 2010 John Wiley &amp; Sons, Ltd.

Electrophilic Reactivity of the α,α-Dimethylbenzyl (Cumyl) Cation

The cumyl cation was generated by laser flash photolysis of cumyl tris(4-chlorophenyl)phosphonium tetrafluoroborate in CH2Cl2 and identified by its UV spectrum. From the decay of its absorbance at λ = 335 nm in the presence of variable concentrations of several nucleophiles with CC double bonds, rate constants for the reactions of the cumyl cation with these π-nucleophiles were determined. The linear free energy relationship log k20°C = s(N + E) (eq 1) was used to calculate the electrophilicity parameter E = 5.74 of the cumyl cation from the rate constants determined in this work and the previously reported N and s parameters of the nucleophilic reaction partners. Substitution of E of the cumyl cation and of the previously reported N and s parameters of α-methylstyrene into eq 1 predicts the temperature-independent rate constant of the addition of the cumyl cation to α-methylstyrene (1.2 × 108 M−1 s−1), which is relevant for the cationic polymerization of α-methylstyrene.

SN2’ versus SN2 Reactivity: Control of Regioselectivity in Conversions of Baylis-Hillman Adducts

TiCl(4)-induced Baylis-Hillman reactions of alpha,beta-unsaturated carbonyl compounds with aldehydes yield the (Z)-2-(chloromethyl)vinyl carbonyl compounds 5, which react with 1,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine, and pyridines to give the allylammonium ions 6. Their combination with less than one equivalent of the potassium salts of stabilized carbanions (e.g. malonate) yields methylene derivatives 8 under kinetically controlled conditions (S(N)2' reactions). When more than one equivalent of the carbanions is used, a second S(N)2' reaction converts 8 into their thermodynamically more stable allyl isomers 9. The second-order rate constants for the reactions of 6 with carbanions have been determined photometrically in DMSO. With these rate constants and the previously reported nucleophile-specific parameters N and s for the stabilized carbanions, the correlation log k (20 degrees C)=s(N + E) allowed us to calculate the electrophilicity parameters E for the allylammonium ions 6 (-19 < E < -18). The kinetic data indicate the S(N)2' reactions to proceed via an addition-elimination mechanism with a rate-determining addition step.