Search

A kinetic study of the aminolysis of substituted (methylthio)benzylidene Meldrum's acids, 2-SMe-Z with the aliphatic primary amines, n-butylamine, glycinamide, methoxyethylamine, and aminoacetonitrile, in aqueous DMSO at 20 °C is reported. With all amines the reaction is strictly second-order, that is, first-order in 2-SMe-Z and first-order in the amine. A three steps mechanism has been proposed. The first step is a rate-limiting attachment of the amine to form the tetrahedral intermediate (T), and the subsequent steps are a fast acid–base equilibrium followed by a fast R‴CH2NH or H2O catalyzed expulsion of the leaving group. The Bronsted plot for k1 for the reaction of 2-SMe-H with four primary amines showed a good correlation between log k1 and pK with βnuc = 0.32 ± 0.02, a slightly lower value than that for the reactions of secondary amines (βnuc = 0.41 ± 0.01). The Hammett plot for n-butylamine yields ρ(k1) = 0.40 ± 0.05 which is smaller than that for the reaction of piperidine with the same substrates (ρ(k1) = 0.72 ± 0.07) and also for the reactions of HOCH2CH2S− (ρ(k1) = 1.18), CF3CH2O− (ρ(k1) = 1.14) and OH− (ρ(k1) = 1.11) addition to 2-H-H (ρ(k1) = 1.11). All these observations are consistent with the suggested mechanism. Copyright © 2006 John Wiley & Sons, Ltd.

Although maternal meiotic errors predominate in most studies of nonmosaic trisomy, studies of trisomy ascertained through confined placental mosaicism (CPM) have shown a high rate of somatic errors. However, origin of trisomy of many of the chromosomes involved in CPM has not been evaluated previously in cases ascertained through spontaneous abortions (SAs). Therefore, it was impossible to determine if the relative lack of meiotic errors in trisomy-CPM cases was a characteristic of the specific chromosome involved or due simply to ascertainment through a mosaic state. In the present study, parental and meiotic/somatic stages of origin of trisomy were determined in 89 SAs involving trisomy of chromosomes 2, 4 to 10, 12, 15, 17, and 20. Comparisons were then made to origin of trisomy in cases of confined and generalized trisomy mosaicism. Although somatic errors are generally more common in mosaic cases, this depends on the specific chromosome involved. The results suggest that there are chromosome-specific differences in the relative frequency of somatic chromosome gain or loss and/or the ability of an early somatic loss of one chromosome from a trisomic conceptus to "rescue" the pregnancy. As mean maternal age was less in the somatic than meiotic origin cases (P < 0.01), the age distribution of the study population should also influence the probability of detecting a somatic error. No phenotypic differences were apparent when cases were subdivided based on either parent or stage of origin of the trisomy.

Publisher Summary This chapter describes the developments regarding the principle of nonperfect synchronization (PNS). The foundations of the PNS rest mainly on a relation between two fundamental concepts of physical organic chemistry: the concept of intrinsic barriers and the concept of transition state imbalances. The benefit of determining intrinsic barriers or intrinsic rate constants as the measures of chemical reactivity is that they can be used to describe the reactivity of an entire reaction family, irrespective of the thermodynamic driving force of a particular member of that family, and to make comparisons between different families. Because the observed trends in the intrinsic barriers can plausibly be explained by assuming that charge delocalization lags behind proton transfer, this may be taken as evidence for the existence of imbalance. The higher intrinsic rate constant for 1,1-dinitroethane compared to that for CH3NO2 is open to two interpretations, but both are related to the steric hindrance of the coplanarity of the two nitro groups in the anion. Even though the intrinsic barriers of the gas-phase reactions depend on the same factors as solution-phase proton transfers—such as resonance, polar, and polarizability effects—the electrostatic effects involving the proton-in-flight constitute an important additional factor.

Reactions of anions with acrylonitrile, acrolein, methyl vinyl ketone, and methyl acrylate at room temperature under SIFT conditions are described. Stabilized carbanions such as benzyl anion, cyanomethyl anion, cyclohexadienide, acetone enolate, and nitromethyl anion add to activated carbon-carbon double bonds in a process that is competitive with other modes of reaction. With acrylonitrile and methyl acrylate, addition is in a 1,4 or Michael fashion, while with acrolein and methyl vinyl ketone, 1,2 addition completes with 1,4 addition. Hydroxide, methoxide, fluoride, and cyanide do not add to activated olefins by either mode. A mechanism is proposed for hydride transfer from cyclohexadienide to activated olefins

Fischer carbene complexes have over the last 25 years become a major focus of many synthetic groups. On the other hand, until recently there have been only a few kinetic and/or thermodynamic studies of even the simplest reactions of these complexes. A number of such studies have now been carried out in my laboratory. This review summarizes the results obtained thus far and focuses on three areas: (1) thermodynamic and kinetic acidities of carbene complexes that contain an ionizable proton on the carbon adjacent to the carbene carbon; (2) mechanism and structure-reactivity relationships in the reactions of carbene complexes with nucleophiles; (3) mechanism of hydrolysis of carbene complexes with and without ionizable protons.

A kinetic study of the reaction of benzylidene Meldrum's acid, PhCHC(COO)2C(CH3)2 (5-H), with a series of thiolate and alkoxide ions in 50% DMSO−50% water (v/v) at 20 °C is reported. The reactions ...

Nucleophilic vinylic substitution (SNV), in which a leaving group such as halogen is replaced by a carbon, oxygen, nitrogen, sulfur, or other nucleophile, is an important synthetic tool. It generat...

Rate constants (kB1 and kBH−1) for the reversible deprotonation of triphenyl(2-Z-9-fluorenyl)phosphonium ions (Z = H, Br, NO2) by piperidine, morpholine, n-butylamine, 2-methoxyethylamine, glycine ethyl ester, cyanomethylamine, OH− and water were determined in 50% Me2SO–50% (v/v) water at 20°C. Bronsted αCH (variation of carbon acid) and β values (variation of amine), and intrinsic rate constants [log k0 = log kB1/q when pKBHa - pKCHa + log(p/q) = 0] were obtained. αCH decreases with increasing basicity of the amine whereas βB decreases with increasing acidity of the carbon acid. These trends, which imply changes in the transition-state structure with reactivity, can be described by the interaction coefficient pxy = ∂βB/∂pKCHa = ∂αCH/ - ∂pKBHa = 0.03 (primary amines) and 0.01 (piperidine/morpholine). αCH is smaller than βB, indicating an imbalance due to a lag in the delocalization of the negative charge into the fluorenyl moiety at the transition state. The influence of the Ph3P+ group on the intrinsic rate constant is analyzed in terms of possible contributions by inductive/field (I), resonance (R), polarizability (P) and steric (S) effects. Using 9-carbomethoxyfluorene as a reference, it is shown that the stronger electron-withdrawing I effect of the Ph3P+ group relative to the COOMe group enhances log k0 substantially; the fact that the R effect of Ph3P+ is weaker than that of COOMe also contributes to an increase in k0, and so does the P effect of the phosphorus. All these increases are virtually completely offset by the rate-retarding S effect of the bulky Ph3P+ group. A similar analysis for the Me2S+ derivative studied by Murray and Jencks [J. Am. Chem. Soc. 112, 1880 (1990)] leads to similar conclusions except that the still smaller R effect is probably one of the main reasons why k0 for the Me2S+ derivative is more than ten times higher than for the Ph3P+ derivative; another potential reason is a difference in the steric effect.

The question as to what extent aromaticity in a reactant or product is expressed in the transition state of a reaction has only recently received serious attention. Inasmuch as aro- maticity is related to resonance, one might expect that, in a reaction that leads to aromatic products, its development at the transition state should lag behind bond changes as is invari- ably the case for the development of resonance in reactions that lead to delocalized products. However, recent experimental and computational studies on proton transfers from carbon acids suggest the opposite behavior, i.e., the development of aromaticity at the transition state is more advanced than the proton transfer. The evidence for this claim is based on the deter- mination of intrinsic barriers that show a decrease with increasing aromaticity. According to the Principle of Nonperfect Synchronization (PNS), this decrease in the intrinsic barrier im- plies a disproportionately large amount of aromatic stabilization of the transition state. Additional evidence for the high degree of transition state aromaticity comes from the cal- culation of aromaticity indices such as HOMA, NICS, and the Bird Index. Possible reasons why the degree to which aromaticity and resonance are expressed at the transition state is dif- ferent are discussed.

Publisher Summary This chapter deals with the chemistry of the Fischer-type complexes. The key to the rich chemistry of the Fischer carbene complexes is that they can undergo reactions at several sites; they include modification of the carbene fragment, reaction on the side chain or the metal, and insertion of unsaturated organic molecules into the metal–carbon bond. After such elaborations of the carbene complex, removal of the metal to complete the synthesis of the target organic molecule is usually a simple task. The most prominent systems studied so far are the Fischer carbene complexes of the Group 6 metals. The chapter discusses nucleophilic substitution process, for example, the replacement of the MeO group by a group with a different heteroatom, such as an amino or thioalkyl group. This reaction proceeds via a tetrahedral intermediate and is similar to nucleophilic substitutions on carboxylic esters. Another common reaction based on the acidity of the α-carbon proton—that is, the carbon attached to the carbene carbon—has also been discussed in detail. The carbanion that results from the deprotonation of the α-carbon can act as a nucleophile and react with a variety of electrophiles, especially in the presence of Lewis acid catalysis, to form many different products.

Gas-phase acidities of acrolein and methyl acrylate were measured by bracketing in a flowing afterglow/SIFT apparatus. For acrolein ΔG°acid = 369 ± 4 kcal mol−1 and for methyl acrylate ΔG°acid = 373 ± 4 kcal mol−1. These acidities are substantially lower than those of the saturated analogs propionaldehyde and methyl acetate, respectively, even though hydrogens attached to sp2-hybridized carbon are intrinsically more acidic than those attached to sp3-hybridized carbon. Resonance stabilization of the neutral form by conjugation of the CC double bond with the carbonyl group and allenic destabilization of the anionic form of the two acids can account for the relatively low acidities.

Rate constants for the reversible deprotonation of acetylacetone were measured in carboxylate and amine buffers in water and in 50%, 90% and 95% Me2SO at 20°C. The Bronsted plot for the carboxylate ions is curved in the Me2SO—water mixtures, but straight in water. The curvature is in the direction predicted by the Reactivity—Selectivity Principle (RSP). However, the Bronsted plot for the reaction with primary amines is straight in all solvents. This suggests that the curvature observerd with the carboxylate ions is caused by loss of solvation of the base; this loss of solvation is ahead of bond formation in the transition state rather than being a manifestation of the RSP. (Note that all Bronsted plots are based on pKa values measured in the respective solvents.) The intrinsic rate constant (k0) for proton transfer increases with the addition of Me2SO, and more so with the carboxylate buffers than with the amines. This increase in k0 is attributed to delayed solvation of the developing enolate ion in the transition state; with the carboxylate buffers, an additional factor is the early loss of solvation of the base. The various solvation effects observed in this study can all be understood in the context of the Principle of Imperfect Synchronization (PIS).

N-Methyl-N-β-hydroxyethyl picramide (PH) forms a 1:1 (PHS2−) and a 1:2 (PHS) anionic σ-complex with sulfite ion. In alkaline solution PH is present mainly in the form of its spiro Meisenheimer complex (M−) which also adds sulfite ion to form a complex MS3−. Rate and equilibrium constants for the various reactions which interrelate the five species PH, PHS2−, PHS, M−, and MS3− (scheme I) were determined. PHS and MS3− can, in principle, exist in the form of two geometric isomers. Despite a careful search by nuclear magnetic resonance and kinetic techniques, no experimental manifestation of this isomerism could be found. Various limiting situations are discussed under which the absence of experimental evidence does or does not exclude the presence of two isomers. Our preferred but unproven interpretation is that in the case of PHS one isomer (trans?) is thermodynamically strongly favored over the other, whereas in the case of MS3− both isomers are of similar thermodynamic stability and have also similar rates. This latter feature would make the isomerism kinetically undetectable. Several other features of scheme I make it an instructive example in complex chemical kinetics.

(1) The rates of reaction of 2, 4-dinitrofluorobenzene with morpholine have been measured in benzene solution, with and without the addition of pyridine or 1, 4-diaza-bicyclo[2.2.2]octane (DABCO) as catalysts. (2) The reaction is catalyzed by morpholine, pyridine and DABCO; the rate laws as functions of these bases are expressed by equations (2)–(4). (3) The reaction is considerably more sensitive to pyridine and DABCO catalysis than that of 2, 4-dinitrofluorobenzene with the sterically identical, but more basic piperidine. These findings confirm a previously found trend of greater sensitivity to base catalysis with decreasing base strength of the reacting amine.

(1) Acidity constants of 2,3,4,5,6-d5-, 2,4,6-d3- and 3,5-d2-anilinium ion, of 2,6-d2−4-toluidinium and 4-d-2,6-xylidiniumion have been measured in aqueous solution.

(1) The rates of the reactions of 2.4-dinitrofluorobenzene and 2.4-dinitrochlorobenzene with p-anisidine have been measured in benzene solution, with and without the addition of pyridine and 1.4-diaza-[2.2.2]-bicyclooctane (DABCO) as catalysts.

(1) The rates of the reactions of 2,4-dinitrofluoro- and 2,4-dinitrochlorobenzene with piperidine as influenced by the addition of dimethylsulfoxide and p-dioxane have been measured in benzene solution.

The first and second proton addition equilibrium constants of 1,1-bis-(4′, 4″-dimethylaminophenyl)-ethylene (1) have been measured by the spectrophotometric method in methanol and in dimethylsulfoxide. Defined as acid dissociation constants of the mono- and diprotonated adduct they are: K1 (CH3OH) = 8.3 (± 0.9) · 10−6M, K2 (CH3OH) = 1.22 (± 0.06) · 10−4M, K1 (DMSO) = 2.3 (± 0.9) · 10−3M, K2 (DMSO) ≥ 1M. The evaluation of the electronic and the NMR. spectra demonstrates that the equilibrium of the two monoprotonated tautomers 2 (methyl-carbenium ion) and 3 (ammonium ion) is, in methanol to about 96% on the side of the ammonium ion (tautomeric equilibrium constant K23 = [3]/[2] ≅ 23). The tautomer 2 cannot be detected in dimethylsulfoxide. The possible causes of these solvent effects are discussed.

(1) The rates of reaction of 2,4-dinitrofluorobenzene with benzylamine and with N-methylbenzylamine have been measured in benzene solution, with and without the addition of pyridine or 1, 4-diaza-bicyclo[2.2.2]octane (DABCO) as catalyst. (2) Both reactions are catalyzed by the reacting amine, by pyridine and by 1, 4-diaza-bicyclo[2.2.2]octane. (3) Whereas the dependence on base concentration is linear in the case of N-methyl-benzylamine, the rate constants are curvilinearly related to base concentration in the reaction with benzylamine. Steric effects are shown to be responsible for this different behaviour, which is easily understood in terms of the two-step intermediate mechanism (eq.1) for nucleophilic aromatic substitutions. (4) Part of the pyridine catalysis has to be attributed to a medium effect, as can be shown directly in the reaction involving benzylamine. (5) The sensitivity of both reactions to base catalysis is much greater than that of the reaction of piperidine with 2, 4-dinitrofluorobenzene, but is found to be considerably smaller than in the reaction of p-anisidine with the same substrate, thus suggesting a correlation between the basicity of the reacting amine and the sensitivity of the reaction to base catalysis.

The Disparity reaction proposed in a recent application of Marcus-Grunwald theory to nitroalkane ionization is shown to put the reaction's transition state in an energy-diagram region where electronic rearrangement leads proton transfer, contrary to experimental evidence; it is suggested that addition of solvent reorganization to electronic rearrangement as the second reaction progress variable would remedy this situation.