Nucleophilic reactivities of the anions of nucleobases and their subunits

The kinetics of the reactions of different heterocyclic anions derived from imidazoles, purines, pyrimidines, and related compounds with benzhydrylium ions and structurally related quinone methides have been studied in DMSO and water. 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)(N+E) (H. Mayr, M. Patz, Angew. Chem. 1994, 106, 990-1010; Angew. Chem. Int. Ed. Engl. 1994, 33, 938-957) allowing us to determine the nucleophilicity parameters N and s(N) for these anions. In DMSO, the reactivities of these heterocyclic anions vary by more than six orders of magnitude and are comparable to carbanions, amide and imide anions, or amines. The azole anions are generally four to five orders of magnitude more reactive than their conjugate acids.     

Kinetics of the reactions of halide anions with carbocations: quantitative energy profiles for s(n)1 reactions

Rate constants for the reactions of Laser flash photolytically generated benzhydrylium ions (diarylcarbenium ions) with halide ions have been determined in various solvents, including neat and aqueous acetonitrile as well as some alcohols. Substitution of the rate constants into the correlation equation log k = s(N + E) yields the nucleophilicity parameters N for the halide ions in different solvents. Linear correlations with negative slopes are found between the nucleophilicity parameters N for Cl(-) and Br(-) in different solvents and the solvent ionizing powers Y of the corresponding solvents. Increasing halide solvation reduces the rates of carbocation/chloride combinations by approximately half as much as it increases the rates of ionizations of benzhydryl chlorides. Comparison of the solvent dependent nucleophilicity parameters N of halide anions and the nucleophilicity parameters N(1) for solvents yields a quantitative prediction of common ion rate depression, as demonstrated by the analysis of a variety of literature reported mass-law constants alpha. Combination of the rate constants for the reactions of benzhydrylium ions with halide ions (k(-)()(1)) reported in this work with the ionization constants of benzhydryl halides (k(1)) and the recently reported rate constants for the reactions of benzhydrylium ions with solvents (k(2)) yields complete quantitative free energy profiles for solvolysis reactions. The applicability of Hammond's postulate for interpreting solvolysis reactions can thus be examined quantitatively.     

Nucleophilicities of primary and secondary amines in water

The kinetics of the reactions of 26 primary and secondary amines with benzhydrylium ions in water were investigated photometrically. Because the parallel reactions of the benzhydrylium ions with hydroxide and water are much slower, the second-order rate constants for the reactions of amines with benzhydrylium ions could be determined reliably. Reactivities of anilines were also studied in acetonitrile solution. Plots of log k2,N for these reactions vs the electrophilicity parameters E of the benzhydrylium ions were linear, which allowed us to derive the nucleophilicity parameters N and s for amines as defined by the equation log k(20 degrees C)=s(E+N). Because the slope parameters for the different amines are closely similar; the relative nucleophilicities are almost independent of the electrophiles and can be expressed by the nucleophilicity parameters N. The correlation between nucleophilicity N and pKaH values is poor, and it is found that secondary alkyl amines and anilines are considerably more nucleophilic, while ammonia is much less nucleophilic than expected on the basis of their pKaH values.     

How constant are Ritchie's "constant selectivity relationships"? A general reactivity scale for n-, pi-, and sigma-nucleophiles

The kinetics of 82 reactions of benzhydrylium ions (Ar(2)CH(+)) with n-nucleophiles has been determined at 20 degrees C. Evaluation by the equation log k = s(N + E) delivered the reactivity parameters N and s for 15 n-nucleophiles (water, hydroxide, amines, etc.). All nucleophiles except water (s = 0.89) and (-)SCH(2)CO(2)(-) (s = 0.43) have closely similar slope parameters (0.52 < s < 0.71), indicating that the reactions of most n-nucleophiles approximately follow Ritchie's constant selectivity relationship (s = constant). The different slope parameter for water is recognized as the main reason for the deviations from the Ritchie relationship reported in 1986. Correlation analysis of the rate constants for the reactions of benzhydrylium ions with the n-nucleophiles (except H(2)O) on the basis of Ritchie's equation log k = N(+) + log k(0) yields a statistically validated set of N(+) parameters for Ritchie-type nucleophiles and log k(0) parameters for benzhydrylium ions. The N and s parameters of the n-nucleophiles derived from their reactions with benzhydrylium ions were combined with literature data for the reactions of these nucleophiles with other carbocations to yield electrophilicity parameters E for tritylium, tropylium, and xanthylium ions. While the E parameters for tropylium and xanthylium ions appear to be generally applicable, it is demonstrated that the E parameters of tritylium ions can be used to predict reactivities toward n-nucleophiles as well as hydride transfer rate constants but not rates for the reactions of tritylium ions with pi-nucleophiles. It is now possible to merge the large data sets determined by Ritchie and others with our kinetic data and present a nucleophilicity scale comprising n- (e.g., amines), pi- (e.g., alkenes and arenes), and sigma-nucleophiles (e.g., hydrides).     

Nucleofugality and nucleophilicity of fluoride in protic solvents

A series of p-substituted benzhydryl fluorides (diarylfluoromethanes) were prepared and subjected to solvolysis reactions, which were followed conductometrically. The observed first-order rate constants k(1)(25 °C) were found to follow the correlation equation log k(1)(25 °C) = s(f)(N(f) + E(f)), which allowed us to determine the nucleofuge-specific parameters N(f) and s(f) for fluoride in different aqueous and alcoholic solvents. The rates of the reverse reactions were measured by generating benzhydrylium ions (diarylcarbenium ions) laser flash photolytically in various alcoholic and aqueous solvents in the presence of fluoride ions and monitoring the rate of consumption of the benzhydrylium ions by UV-vis spectroscopy. The resulting second-order rate constants k(-1)(20 °C) were substituted into the correlation equation log k(-1) = s(N)(N + E) to derive the nucleophilicity parameters N and s(N) for fluoride in various protic solvents. Complete Gibbs energy profiles for the solvolysis reactions of benzhydryl fluorides are constructed.     

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.     

Free Energy Relationships for Reactions of Substituted Benzhydrylium Ions: From Enthalpy over Entropy to Diffusion Control

Second-order rate constants k(2) for the reactions of various donor- and acceptor-substituted benzhydrylium ions Ar(2)CH(+) with π-nucleophiles in CH(2)Cl(2) were determined by laser flash irradiation of benzhydryl triarylphosphonium salts Ar(2)CH-PAr(3)(+)X(-) in the presence of a large excess of the nucleophiles. This method allowed us to investigate fast reactions up to the diffusional limit including reactions of highly reactive benzhydrylium ions with m-fluoro and p-(trifluoromethyl) substituents. The rate constants determined in this work and relevant literature data were jointly subjected to a correlation analysis to derive the electrophilicity parameters E for acceptor-substituted benzhydrylium ions, as defined by the linear free energy relationship log?k(2)(20 °C) = s(N)(N + E). The new correlation analysis also leads to the N and s(N) parameters of 18 π-nucleophiles, which have only vaguely been characterized previously. The correlations of log?k(2) versus E are linear well beyond the range where the activation enthalpies ΔH(?) of the reactions are extrapolated to reach the value of ΔH(?) = 0, showing that the change from enthalpy control to entropy control does not cause a bend in the linear free energy relationship, a novel manifestation of the compensation effect. A flattening of the correlation lines only occurs for k(2) > 10(8) M(-1) s(-1) when the diffusion limit is approached.     

Solvent nucleophilicity

The rates of the reactions of benzhydrylium ions (diarylcarbenium ions) with solvent mixtures of variable composition (water/acetonitrile, methanol/acetonitrile, ethanol/acetonitrile, ethanol/water, and trifluoroethanol/water) have been determined photometrically by conventional UV-vis spectroscopy, stopped-flow methods, and laser flash techniques. It has been shown that the first-order rate constants follow the previously published relationship log k(20 degrees C) = s(N + E), where E is an empirical electrophilicity parameter, N is an empirical nucleophilicity parameter, and s is a nucleophile-specific slope parameter. From plots of log k versus E of the benzhydrylium ions are derived the solvent nucleophilicity parameters s and N, the latter of which are designated as N1 to emphasize that their use in the quoted correlation equation gives rise to first-order rate constants. A linear correlation between N1 and Kevill's solvent nucleophilicity NT based on S-methyldibenzothiophenium ions is reported, which allows one to interconvert the two sets of data. Because the N1 values are directly comparable to the previously reported nucleophilicity parameters N for pi-systems (www.cup.uni-muenchen.de/oc/mayr/), the systematic design of Friedel-Crafts reactions with solvolytically generated carbocations becomes possible.     

Rates and equilibria of the reactions of tertiary phosphanes and phosphites with benzhydrylium ions

The kinetics of the reactions of benzhydrylium ions and quinone methides with eight tertiary phosphanes and two phosphites were investigated photometrically. The nucleophilicity parameters N and slope parameters s of these nucleophiles were derived according to the equation log k(20 degrees C) = s(N + E). Correlations of the nucleophilicity parameters N with pK(Ha) and sigma(p) values as well as with the rate constants of reactions with other electrophiles are discussed. In some cases, equilibrium constants for the formation of phosphonium ions were measured, which allow one to determine the Marcus intrinsic barriers of DeltaG(0) (not equal) = 58 kJ mol(-1) for the reactions of triarylphosphanes with benzhydrylium ions. The N parameters [5.51 for P(OPh)3, 10.36 for P(OBu)3, 14.33 for PPh3, 15.49 for PBu3, 18.39 for P(4-Me2NC6H4)3] are compared with the reactivities of other classes of nucleophiles (see, www.cup. uni-muenchen.de/oc/mayr).     

Nucleophilicity parameters of enamides and their implications for organocatalytic transformations

The kinetics of the reactions of eleven substituted enamides with benzhydrylium ions (diarylcarbenium ions) were determined in acetonitrile solution. The second-order rate constants follow the correlation log k(2) (20 °C)=s(N)(E+N), which allowed us to derive reactivity parameters N and s(N). With 4.6相似文献   

Solvation Accounts for the Counterintuitive Nucleophilicity Ordering of Peroxide Anions

The nucleophilic reactivities (N , s _N) 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 (Ar₂CH⁺) 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 =s _N(N +E ) furnished nucleophilicity parameters (N , s _N) 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.     

Nucleophilic reactivities of carbanions in water: the unique behavior of the malodinitrile anion

The kinetics of the reactions of nine carbanions 1a-i, each stabilized by two acyl, ester, or cyano groups, with benzhydrylium ions in water were investigated photometrically at 20 degrees C. Because the competing reactions of the benzhydrylium ions with water and hydroxide ions are generally slower, the second-order rate constants of the reactions of the benzhydrylium ions with the carbanions can be determined with high precision. The rate constants thus obtained can be described by the Ritchie equation, log(k/k(0)) = N(+) (eq 1), which allows us to calculate Ritchie N(+) parameters for a series of stabilized carbanions, for example, malonate, acetoacetate, malodinitrile, etc., and compare them with those of other n-nucleophiles in water (hydroxide, amines, azide, thiolates, etc.). Because the Ritchie relationship (eq 1) is a special case of the more general relationship log k = s(N + E) (eq 4), the reactivity parameters N and s for the carbanions 1a-i can also be calculated and compared with the nucleophilic reactivities of a large variety of n-, pi-, and sigma-nucleophiles, including reactivities of carbanions in dimethyl sulfoxide. While the acyl and ester substituted carbanions are approximately 3 orders of magnitude less reactive in water than in dimethyl sulfoxide, the malodinitrile anion (1i) shows almost the same reactivity in both solvents. Correlations between the nucleophilic reactivities of carbanions with the pK(a) values of the corresponding CH acids reveal that the malodinitrile anion (1i) is considerably more nucleophilic than was expected on the basis of its pK(a) value. This deviation is assigned to the exceptionally low Marcus intrinsic barriers of the reactions of the malodinitrile anion (1i).     

Nucleophilicity parameters for amines, amino acids and peptides in water. Variations in selectivities for quinone methides

Second order rate constants for reactions of 4,4'-dimethylaminobenzhydrylium cations with amines and other nucleophiles in water define a scale of nucleophilicity (N(+)' = log k + 2.63). The N(+)' scale can be extended by linking directly to an established N(+) scale based on reactions of methyl vinyl pyridinium cations with amine nucleophiles. Logarithms of rate constants for other benzhydrylium ions and quinone methides (QMs) are correlated by the equation: log k = s(E)N(+)' + constant, having a nucleophilicity parameter (N(+)' defined as in the Ritchie N(+) equation with N(+)' = 4.75 for hydroxide ion), and an electrophile's response (selectivity) parameter (s(E), as in the Swain-Scott equation). Correlations for other benzhydrylium cations require only one slope and one intercept per cation, and fit data for up to 54 amines, amino acids and peptide nucleophiles; the slope s(E) increases as the reactivity of the cation decreases. Contrary to recent reports, s(E) is significantly less than unity for reactions of o- and p-benzoquinone methides. As the reactivities of QMs decrease, s(E) increases and the response of s(E) to changes in reactivity is larger for QMs than for cations.     

Nucleophilicities of nitroalkyl anions

The kinetics of the reactions of eight nitroalkyl anions (nitronate anions) with benzhydrylium ions and quinone methides in DMSO and water were investigated photometrically. The second-order rate constants were found to follow a Ritchie constant selectivity relationship with slightly smaller selectivities than those observed previously for other carbanions and O or N nucleophiles. Evaluation of the kinetic data by the correlation equation log k (20 degrees C) = s(N + E) yields the nucleophilicity parameters (N), which allow a comparison of the nucleophilicities of nitronates with those of other classes of compounds. Although the aliphatic nitronates 1a-c are more nucleophilic than the aromatic representatives 1d-h in DMSO, hydration reduces the nucleophilicities of aliphatic nitronates by a factor of 1 million, which is considerably greater than the reduction of the reactivities of the aromatic nitronates with the consequence that aromatic nitronates are more nucleophilic in water than aliphatic ones. The nucleophilic reactivities of nitronates are only slightly affected by substituent variation in DMSO and even less so in aqueous solution, which is considered to be the reason for the unusual rate equilibrium relationships, the so-called nitroalkane anomaly. Outer-sphere electron transfer does not occur in any of the reactions that were investigated.     

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.     

Reference scales for the characterization of cationic electrophiles and neutral nucleophiles

Twenty-three diarylcarbenium ions and 38 pi-systems (arenes, alkenes, allyl silanes and stannanes, silyl enol ethers, silyl ketene acetals, and enamines) have been defined as basis sets for establishing general reactivity scales for electrophiles and nucleophiles. The rate constants of 209 combinations of these benzhydrylium ions and pi-nucleophiles, 85 of which are first presented in this article, have been subjected to a correlation analysis to determine the electrophilicity parameters E and the nucleophilicity parameters N and s as defined by the equation log k(20 degrees C) = s(N + E) (Mayr, H.; Patz, M. Angew. Chem., Int. Ed. Engl. 1994, 33, 938-957). Though the reactivity scales thus obtained cover more than 16 orders of magnitude, the individual rate constants are reproduced with a standard deviation of a factor of 1.19 (Table 1). It is shown that the reactivity parameters thus derived from the reactions of diarylcarbenium ions with pi-nucleophiles (Figure 3) are also suitable for characterizing the nucleophilic reactivities of alkynes, metal-pi-complexes, and hydride donors (Table 2) and for characterizing the electrophilic reactivities of heterosubstituted and metal-coordinated carbenium ions (Table 3). The reactivity parameters in Figure 3 are, therefore, recommended for the characterization of any new electrophiles and nucleophiles in the reactivity range covered. The linear correlation between the electrophilicity parameters E of benzhydryl cations and the corresponding substituent constants sigma(+) provides Hammett sigma(+) constants for 10 substituents from -1.19 to -2.11, i.e., in a range with only very few previous entries.     

Reactions of carbocations with unsaturated hydrocarbons: electrophilic alkylation or hydride abstraction?

Benzhydryl cations were used as reference electrophiles to determine the hydride donor reactivities of unsaturated hydrocarbons. The kinetics of the reactions were followed by UV-vis spectroscopy and conductivity measurements, and it was found that the second-order rate constants for the hydride transfer processes were almost independent of the solvents or counterions employed. The rate constants correlate linearly with the previously published empirical electrophilicity parameters E of the benzhydrylium ions. Therefore, the linear free energy relationship log k(20 degrees C) = s(E + N) could be employed to characterize the hydride reactivities of the hydrocarbons by the nucleophilicity parameters N and s. The similarity of the slopes s for hydride donors and pi-nucleophiles allows a direct comparison of the reactivities of these different functional groups based on their nucleophilicity parameters N. Since nucleophilicity parameters of -5 < N < 0 have been found for a large variety of allylic and bisallylic hydride donors, a rule of thumb is derived that hydride transfer processes may compete with carbon-carbon bond-forming reactions when carbocations are combined with olefins of pi-nucleophilicity N < 0.     

Photogeneration of Benzhydryl Cations by Near-UV Laser Flash Photolysis of Pyridinium Salts

Laser flash irradiation of substituted N-benzhydryl pyridinium salts yields benzhydryl cations (diarylcarbenium ions) and/or benzhydryl radicals (diarylmethyl radicals). The use of 3,4,5-triamino-substituted pyridines as photoleaving groups allowed us to employ the third harmonic of a Nd/YAG laser (355 nm) for the photogeneration of benzhydryl cations. In this way, benzhydryl cations can also be photogenerated in the presence of aromatic compounds and in solvents which are opaque at the wavelength of the quadrupled Nd/YAG laser (266 nm). To demonstrate the scope and limitations of this method, the rate constants for the bimolecular reactions of benzhydryl cations with several substituted pyridines were determined in acetonitrile and with water in acetone. The obtained data agree with results obtained by stopped-flow UV-vis spectroscopic measurements. The rate constants for the reaction of the 4,4'-bis[methyl(2,2,2-trifluoroethyl)amino]benzhydrylium ion with 4-(dimethylamino)pyridine were also determined in dimethyl sulfoxide, N,N-dimethylformamide, and acetone. From the second-order rate constants, we derived the nucleophilicity parameters N and s(N) for the substituted pyridines, as defined by the linear free energy relationship, log k(2) = s(N)(N + E).     

Direct observation of the ionization step in solvolysis reactions: electrophilicity versus electrofugality of carbocations

Rates and equilibria of the reactions of highly stabilized amino-substituted benzhydrylium ions (Ar2CH+) with carboxylate ions have been determined photometrically in acetone and acetonitrile solutions. Treatment of covalent benzhydryl carboxylates (Ar2CH-O2CR) with aqueous acetone or acetonitrile leads to the regeneration of the colored amino-substituted benzhydrylium ions Ar2CH+, which do not undergo subsequent reactions with the solvent. One can, therefore, directly measure the first step of S(N)1 reactions. The electrofugality order, i.e., the relative ionization rates of benzhydryl esters Ar2CH-O2CR with the same anionic leaving group, does not correlate with the corresponding electrophilicity order, i.e., the relative reactivities of the corresponding benzhydrylium ions Ar2CH+ toward a common nucleophile. Thus, benzhydrylium ions which are produced with equal rates by ionization of the corresponding covalent esters may differ by more than 2 orders of magnitude in their reactivities toward nucleophiles, e.g., carboxylate ions. Variable intrinsic barriers account for the breakdown of the rate-equilibrium relationships. Complete free-energy profiles for the ionization of benzhydryl carboxylates Ar2CH-O2CR are constructed, which demonstrate that the transition states of these ionizations are not carbocation-like. As a consequence, variation of the solvent-ionizing power Y has only a small effect on the ionization rate constant (m = 0.35 to 0.55) indicating that small values of m in the Winstein-Grunwald equation do not necessarily imply an S(N)2 type mechanism.     

Electrophilicities of symmetrically substituted 1,3-diarylallyl cations

Kinetics of the reactions of nine symmetrically substituted 1,3-diarylallyl cations with different nucleophiles were studied photometrically in dichloromethane, acetonitrile, and DMSO solutions. The second-order rate constants k(2) were found to follow the correlation log k(2) = s(N)(N + E). The electrophilicity parameters E of the title cations were derived, using the known values of s(N) and N of the nucleophilic reaction partners, and compared with the electrophilicities of analogously substituted benzhydrylium ions. Good linear correlations were found between the electrophilicities E and the quantum chemically calculated gas-phase methyl anion affinities of the allyl cations and the σ(+) constants of the substituents X.