Robin A. Cox

A Greatly Under-Appreciated Fundamental Principle of Physical Organic Chemistry

If a species does not have a finite lifetime in the reaction medium, it cannot be a mechanistic intermediate. This principle was first enunciated by Jencks, as the concept of an enforced mechanism. For instance, neither primary nor secondary carbocations have long enough lifetimes to exist in an aqueous medium, so SN1 reactions involving these substrates are not possible, and an SN2 mechanism is enforced. Only tertiary carbocations and those stabilized by resonance (benzyl cations, acylium ions) are stable enough to be reaction intermediates. More importantly, it is now known that neither H3O+ nor HO− exist as such in dilute aqueous solution. Several recent high-level calculations on large proton clusters are unable to localize the positive charge; it is found to be simply “on the cluster” as a whole. The lifetime of any ionized water species is exceedingly short, a few molecular vibrations at most; the best experimental study, using modern IR instrumentation, has the most probable hydrated proton structure as H13O6+, but only an estimated quarter of the protons are present even in this form at any given instant. Thanks to the Grotthuss mechanism of chain transfer along hydrogen bonds, in reality a proton or a hydroxide ion is simply instantly available anywhere it is needed for reaction. Important mechanistic consequences result. Any charged oxygen species (e.g., a tetrahedral intermediate) is also not going to exist long enough to be a reaction intermediate, unless the charge is stabilized in some way, usually by resonance. General acid catalysis is the rule in reactions in concentrated aqueous acids. The Grotthuss mechanism also means that reactions involving neutral water are favored; the solvent is already highly structured, so the entropy involved in bringing several solvent molecules to the reaction center is unimportant. Examples are given.

Rearrangement mechanisms for azoxypyridines and azoxypyridine N-oxides in the 100% H2SO4 region - The Wallach rearrangement story comes full circle

Kinetic studies of the Wallach rearrangements of four azoxypyridines, four azoxypyridine N-oxides, and one azoxypyridine N-methiodide have been carried out in the 100% H2SO4 acidity region. For all...

Revised Mechanisms for Simple Organic Reactions

Abstract The Jencks principle, that postulated mechanistic intermediates have to have a finite lifetime in the reaction medium, has in general not been applied to the mechanisms of organic reactions. In particular, oxygen-protonated species in which the positive charge cannot be delocalized, such as H3O+, R2HO+ and tetrahedral intermediates, and even some of those where it can, such as acylium ions and protonated esters, do not exist in aqueous media that are more dilute than concentrated acid. Nor do primary and secondary carbocations. This has considerable consequences; many accepted organic reaction mechanisms have to be modified. Examples of this are provided, particularly for reactions that take place in acidic solutions. For instance, ether hydrolysis is a general-acid-catalyzed process in which an oxygen-protonated species is not formed, and nor is a carbocation unless it is stable in the medium. Amide hydrolysis involves a second proton transfer in stronger acid media. Ester hydrolysis involves tetrahedral intermediates which are neutral, not charged, whether the medium is acidic, neutral or basic. Many other reactions are discussed.

The mechanisms of the hydrolyses of N-nitrobenzenesulfonamides,N-nitrobenzamides and some other N-nitro amides inaqueous sulfuric acid1

The mechanisms of the hydrolysis reactions of some N-nitrobenzenesulfonamides (YC6H4SO2NHNO2), N-nitrobenzamides (YC6H4CONHNO2) and N-methyl-N-nitrobenzamides (YC6H4CON(CH3)NO2) have been determined in aqueous sulfuric acid using the excess acidity method. Also studied were N-methyl-N-nitroacetamide and nitrourea, with N,N-dinitromethylamine for comparison. N-Nitrobenzenesulfonamides give either YC6H4SO2+ and NH2NO2 (electron-donating Y) or YC6H4SO2NH2 and NO2+ (electron-withdrawing Y) in A1 processes; the change in product is reflected in the different ρ+ values found for the two modes of cleavage. N-Nitrobenzamides behave similarly in strong acid, with an A1 reaction following presumed O-protonation, but in more moderate acid they exhibit a neutral water-catalysed hydrolysis mechanism, and in dilute acid the parent N-nitrobenzamides actually show hydroxide catalysis. N-Methyl-N-nitroacetamide shows only the neutral water-catalysed process. Nitrourea has an A1 acid-catalysed hydrolysis reaction in acid, analogous to the known B1 mechanism in base (also visible in dilute sulfuric acid), but has no water reaction; the pH-rate profile for the hydrolysis of this substance is here extended into the non-ideal acid region. N,N-Dinitromethylamine loses NO2+ in an A1 process following initial nitro-group protonation, giving N-nitromethylamine which is identifiable by its known hydrolysis rate. Activation parameters, m*m‡ slopes and ρ+ values given by the excess acidity analysis are shown to be compatible with the postulated mechanisms.

Acidity functions of aqueous fluorinated acid solutions by differential pulse polarography

Abstract The acidity functions of aqueous trifluoroacetic and trifluoromethanesulphonic acid mixtures, and aqueous hexafluoropropane-2, 2-diol solutions, have been determined by differential pulse polarography. The apparent shift of the half-wave potential for the ferrocene—ferricinium couple, as the solvent composition is changed, is used to indicate the change in potential of a glass electrode; acidity is measured as the H GF acidity function. The densities of two of these solvent systems as a function of composition are also reported. Trifluoromethanesulphonic acid—water mixtures represent the strongest aqueous acid solvent system so far studied.

Acid-catalysed aryl hydroxylation of phenylazopyridines: reaction intermediates, kinetics and mechanism1

A kinetic and product analysis study of the reactions of the three isomeric phenylazopyridines (PAPys) in aqueous sulfuric acid media (30–97 wt% H2SO4) is reported. The final products obtained from the reaction of 4-(phenylazo)pyridine (4-PAPy) are the hydroxylated product 4-(4-hydroxyphenylazo)pyridine, the reduction products 4-aminophenol and 4-aminopyridine, and a small amount of a dimerized product. 3-(Phenylazo)pyridine is unreactive, but 2-(phenylazo)pyridine gives the equivalent 2-(4-hydroxyphenylazo)pyridine, 4-aminophenol and 2-aminopyridine products. This product pattern, an oxidized azo-compound and two reduced amines, is similar to that found in the disproportionation of di-p-substituted hydrazinobenzenes observed in benzidine rearrangement studies. Consequently it has been proposed that the corresponding [N′-(4-hydroxyphenylhydrazino)]pyridines were formed as reaction intermediates in the present system; this is confirmed by showing that [N′-4-(4-hydroxyphenylhydrazino)pyridine synthesized independently gave the same products as 4-PAPy under the same conditions. The kinetic study shows that the 4-isomer reacted faster than the 2-isomer at all the acid concentrations investigated (the 3-isomer being inert). Rate maxima are observed, at ≈72 wt% H2SO4 for 4-PAPy and ≈86 wt% H2SO4 for 2-PAPy. To facilitate the kinetic analysis, values of pKBH22+ for the protonation of the substrates and the possible hydroxy products at the azo-group were determined, using the excess acidity method; the first protonation occurs on the pyridine nitrogen in the pH region. An excess acidity analysis of the observed pseudo-first-order rate constants as a function of acidity indicate an A2 mechanism, with the diprotonated substrate and either one HSO4– ion or one H2O molecule in the activated complex. The proposed mechanism thus involves nucleophilic attack of HSO4– or H2O at an aryl carbon of the diprotonated substrate in the slow step, resulting in an intermediate hydrazo species which gives the observed products in a subsequent fast step (cf. benzidine rearrangement).

The DO acidity function for perchloric acid

The DO acidity function, densities, and excess acidities for 0–56% w/w (0–9M) DClO4–D2O mixtures are reported. Differences between the HO and DO functions for perchloric acid arise from density differences, so that these functions are essentially identical when compared at the same molarity.

The Wallach rearrangement. Part XIV. Rearrangements of azoxynaphthalenes in sulphuric acid. Kinetics and mechanisms

The rates of rearrangement of the 1-naphthyl-, 2-naphthyl-, and phenyl-substituted azoxy-compounds (1)–(6) in moderately concentrated sulphuric acid solutions have been investigated. A mechanism involving quinonoid type intermediates is used to explain the acidity dependence of the observed rate constants for compounds (1), (2), and (4)–(6) at H2SO4 concentrations below ca. 83% w/w. Equilibrium protonation of the substrates (KSH+) is followed by nucleophilic attack (HSO4–) on aromatic carbon yielding the uncharged quinonoid intermediates (S′). Another equilibrium protonation of S′(KSH+) on the N–OH function is followed by rate-determining abstraction of an aryl-bound hydrogen with simultaneous loss of H2O. In contrast, compound (3) exhibits a linear log (rate) correlation with log aH2SO4 at all acidities, indicative of general acid catalysed formation of a dicationic intermediate; the other compounds also appear to react by this mechanism above 83% H2SO4. Thus in the low acid region the isomeric reactants (2) and (3) follow different reaction pathways while yielding a common product.

Effect of sulpholan upon dissociation of phenols in alkaline solution

The degrees of ionisation of 3,4,5-trimethylphenol and 2,4-di-t-butylphenol have been measured in water–sulpholan mixtures containing hydroxide ion. The solubilities of 3,4,5-trimethylphenol and 2,4,6-trinitroaniline in dilute aqueous sulpholan solutions have also been determined and activity coefficients derived for the neutral compounds. It is shown that the decrease in the degree of ionisation of phenols that accompanies addition of sulpholan to water applies to both ordinary phenols and those containing bulky ortho-substituents. The cause of this decrease can be traced to the large decrease in activity of the neutral compound that accompanies addition of small amounts of sulpholan to water. The differing ionisation behaviour of phenols and aromatic amines is discussed in terms of activity coefficient changes.