Substituent effects on kinetics

Certain substituents are known to withdraw electron density from a reaction site, thus rendering a developing negative charge at that site less intense 

Where did the o values come from Hammett chose to define them from a particular reaction, the ionization of benzoic acid. In this case, and many others, the equilibrium constants rather than rate constants were measured. For equilibria, the Hammett equation is written in terms of equilibrium constants (Eq. 4.50). Since the ionization of a series of 

In the ionization of benzoic acid, a negative charge develops on the substituent-carrying molecule. Any other reaction in which a negative charge develops would be affected in the same direction by the substituents and it would be found to have a positive value for p. In reactions where a positive charge develops in the transition state or the product, the 

Estimates of the size of the charge in a transition state have been made by taking a ratio of p values for a rate and an equilibrium in very similar reactions [20], 

In some reactions, electron-donating substituents in the para position can have a greater effect than their a values would predict. These are cases where a direct resonance contribution can be made as in benzyUc carbo-cation formation (Eq. 4.51). 

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Later work examined substituent effects on kinetically controlled alkylations [68, 69] (Scheme 32). Substitution at the 5-position is well tolerated in these reactions. Reductive lithiation of a series of 4-phenylthio-l,3-dioxanes and quenching of the axial alkyllithium intermediate with dimethyl sulfate provided the flzzfz -l,3-diols in good yield, with essentially complete selectivity. 

The progress of the reaction at the transition state, a, is usually obtained from the coefficients of the extended Brpnsted equation (19) or of other rate-equilibrium relationships which compare substituent effects on kinetics and thermodynamics. Using (24) the p values can also express this position if Pk for rates and pe for equilibria of the same elementary step are available. 

A comparison of the kinetics of hydrolysis and isotopic exchange of amides A and B was carried out. Some of the data are given below. An interesting observation is that there is more C=0 exchange for A than for B. From this observation, and other data given, develop a stepwise mechanism for the hydrolysis of each amide and a qualitative comparison of the substituent effects on the various steps. 

Similarly, carboxylic acid and ester groups tend to direct chlorination to the / and v positions, because attack at the a position is electronically disfavored. The polar effect is attributed to the fact that the chlorine atom is an electrophilic species, and the relatively electron-poor carbon atom adjacent to an electron-withdrawing group is avoided. The effect of an electron-withdrawing substituent is to decrease the electron density at the potential radical site. Because the chlorine atom is highly reactive, the reaction would be expected to have a very early transition state, and this electrostatic effect predominates over the stabilizing substituent effect on the intermediate. The substituent effect dominates the kinetic selectivity of the reaction, and the relative stability of the radical intermediate has relatively little influence. 

Substituent effects on spin preference and kinetic stabilities... 

Substituent effects on the are remarkable. Electron-withdrawing groups at the 5 -position, e.g., 5 -nitro-substitution (indoline component), and donor substituent at the 8-position (benzothiopyran component) in 44 leads to a longer wavelength shift. As the polarity of the solvent increases, the max of the colored form of spiroindolinobenzothiopyran results in hypsochromic shift. This can be interpreted as the existence of a polar structural component of the colored form in the ground state. Kinetic study has suggested that the zwitterionic structure largely contributes to the colored form of 6-nitrospiroindolinobenzothiopyran, as well as spiropy-rans.97 Based on H-NMR and X-ray analysis,98 99 the existence of an... 

An extended form of (39) has been used to analyse kinetic substituent effects on bromination of alkenes GRaC=CR()R) , where G is a conjugatively electron-donating group and R is alkyl (Bienvenue-Goetz and Dubois, 1981). 

By using PHIP-NMR studies, various intermediates such as the previously elusive dihydrides of neutral and cationic hydrogenation catalysts, as well as hydrogenation product/catalyst complexes, have already been detected during the hydrogenation of styrene derivatives using cationic Rh catalysts. Information about the substituent effect on chemical shifts and kinetic constants has been obtained via time-resolved PASADENA NMR spectroscopy (DYPAS). 

Substituent effect on the kinetic stability (4(7 in kcal mol-1 at Tc) of RNH3C104 complexes of crown ethers [257] in CD2C12 ... 

Substituent effects on the -(aminoethyl)cyclohexenone photochemistry were carried out to study the relative kinetic acidities of the tertiary aminium radical47. The ease of the methylene hydrogen to be removed as H+ increased in the order of X = alkyl < Si(CH3)3 < C=CH (equation 13). 

A kinetic smdy has been reported of substituent effects on the reactions of 2-phenoxy- and 2-(4-nitrophenoxy)-3-nitro-5-X-thiophenes with benzylamine and with A-methylbenzylamine in benzene as solvent. The intramolecularly hydrogen-bonded intermediate (14) is postulated. Reactions of the 5-unsubstimted thiophenes (X = H) are not base-catalysed, indicating that nucleophilic attack is rate limiting, and the more basic secondary amine shows higher reactivity than the primary... 

Structures have been determined for [Fe(gmi)3](BF4)2 (gmi = MeN=CHCF[=NMe), the iron(II) tris-diazabutadiene-cage complex of (79) generated from cyclohexanedione rather than from biacetyl, and [Fe(apmi)3][Fe(CN)5(N0)] 4F[20, where apmi is the Schiff base from 2-acetylpyridine and methylamine. Rate constants for mer fac isomerization of [Fe(apmi)3] " were estimated indirectly from base hydrolysis kinetics, studied for this and other Schiff base complexes in methanol-water mixtures. The attenuation by the —CH2— spacer of substituent effects on rate constants for base hydrolysis of complexes [Fe(sb)3] has been assessed for pairs of Schiff base complexes derived from substituted benzylamines and their aniline analogues. It is generally believed that iron(II) Schiff base complexes are formed by a template mechanism on the Fe " ", but isolation of a precursor in which two molecules of Schiff base and one molecule of 2-acetylpyridine are coordinated to Fe + suggests that Schiff base formation in the presence of this ion probably occurs by attack of the amine at coordinated, and thereby activated, ketone rather than by a true template reaction. ... 

The kinetic and activation parameters for the decomposition of dimethylphenylsilyl hydrotrioxide involve large negative activation entropies, a significant substituent effect on the decomposition in ethyl acetate, dependence of the decomposition rate on the solvent polarity (acetone-rfe > methyl acetate > dimethyl ether) and no measurable effect of the radical inhibitor on the rate of decomposition. These features indicate the importance of polar decomposition pathways. Some of the mechanistic possibilities involving solvated dimeric 71 and/or polymeric hydrogen-bonded forms of the hydrotrioxide are shown in Scheme 18. 

Zhang, X., Gramlich, G., Wang, X. and Nau, W.M. (2002) A joint structural, kinetic, and thermodynamic investigation of substituent effects on host-guest complexation of bicyclic azoalkanes by -cyclodextrin./. Am. Chem. Soc., 124 (2), 254-263. 

By comparison with the extensive kinetic results available for the quatemization of six-membered rings, especially where substituent effects on reactivity are concerned, few quantitative studies have involved five-membered heterocyclic rings. These are considered next. 

In connection with the substituent effects, the kinetic stability of benzyne is suggested to be increased by electron withdrawal (-/) and decreased by electron release (+/).73 However, the inference cannot be extrapolated to selectivity of substituted arynes in general. For example, in additions involving competition between phenyllithium and lithium piperidide, the methyl substituents (+/) on benzyne increase its selectivity, whereas methoxy groups (-/) decrease it (Scheme 6). On the other hand, in reactions of car-banions derived from acetonitrile in alkylamine solvents both +/ and -/ benzyne substituents lower selectivity and cause predominant amination. Thus, the method was found unsuitable for preparation of many substituted benzyl nitriles.74 In symmetrically disubstituted arynes there is partial cancellation of polarization, and in fact acceptable yields of acetonitrile adducts could be obtained from 3,6-dimethoxy-benzyne.75 The selectivity of substituted arynes varies with the set of nucleophiles in the competition and no comprehensive theory or simple generalization is available on this point. 

Substituent effects on cyclizations of simple nucleophilic hexenyl radicals have been well studied, and much quantitative rate data is available.12 The trends that emerge from this data can often be translated to qualitative predictions in more complex settings. Once the large preference for S-exo cyclization is understood, other substituent effects can often be interpreted in the same terms as for addition reactions. For example, electronegative substituents activate the alkene towards attack, and alkyl substituents retard attack at the carbon that bears them. The simple hexenyl radical provides a useful dividing point = 2 x 10s s-1. More rapid cyclizations are easily conducted by many methods, but slower cyclizations may cause difficulties. Like the hexenyl radical, most substituted analogs undergo irreversible S-exo closure as the predominate path. However, important examples of kinetic 6-endo closure and reversible cyclization will be presented. 

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