Duncan J. McLennan

The mechanism for nucleophilic substitution of α-carbonyl derivatives. Application of the valence-bond configuration mixing model

The valence-bond configuration mixing model (VBCM) is applied to the nucleophilic substitution reactions of α-carbonyl derivatives. The model appears to resolve satisfactorily a number of features of these reactions that current mechanisms have not dealt with. These include: (i) the dependence of the rate-enhancing efect of the carbonyl upon the nucleophilic strength of the entering group, (ii) the unusually large Hammett ρ value for the reaction of PhCOCH2Br with substituted pyridines, and (iii) the mechanism by which the rate-enhancing effect of the carbonyl group is transmitted to the reaction centre.

Hydrolysis and alkylating reactivity of aromatic nitrogen mustards

Rate constants for the hydrolysis of a series of aromatic nitrogen mustards Ar–X–C6H4-N(CH2CH2Cl)2(X = O, CH2, CONH, S, CO and SO2) in buffered aqueous acetone mixtures have been obtained using an HPLC technique which allows evaluation of the rate constants for hydrolytic displacement of both chlorines in consecutive reactions. Hydrolysis has a general-base-catalysed component and is accompanied by external chloride ion return. An aziridinium ion intermediate is implicated in at least one pathway. The mustards also alkylate the nucleophiles thiourea and 4-(4-nitrobenzyl)pyridine (NBP) and again the aziridinium ion intermediate is involved since the kinetic behaviour rules out a direct SN2 pathway.

An approach towards identification of product precursors in the solvolyses of diarylmethyl p-nitrobenzoates in ethanol–water solvents

The product ratios, ether: alcohol, for the solvolyses of the title compounds in ethanol–water solvent mixtures have been measured, and have been compared with ratios of the same products generated from the reactions of the corresponding diaryldiazomethanes in the same solvents. The ratios are similar although not always identical, and disparities are ascribed to solvation differences. The question of ‘selectivities’ of intermediates towards ethanol and water is addressed, and it is concluded that product ratios can be used as selectivity measures only when a single intermediate yields stable products. The present results thus throw little light on the reality or otherwise of stability–selectivity relationships in the present series. Internal return is suggested as an important component in the unassisted solvolysis of the esters.

Model calculations of hydrogen–deuterium isotope effects for E2 and E1cB dehydrochlorinations of 1,1-diaryl-2,2-dichlorethanes

A 14-atom transition-state model is employed as the basis for computations of primary β-deuterium and secondary α-deuterium isotope effects for the dehydrochlorination of the substrates Ar2CH·CHCl2 by alkoxide bases. The structure of the transition state is systematically altered by varying the bond orders of O ⋯ H, H ⋯ Cβ,CβCβ and Cα⋯ Cl, with a progressive change in the angular geometry about Cα and Cβ from tetrahedral to trigonal and proportional to the degree of CαCβ double bond character. These changes are translated into force constant changes by means of empirical relations involving bond orders, bond angles, and the associated force constants. The results of changing the way in which the imaginary reaction co-ordinate vibration is formulated are also investigated. Best agreement between experimental values of primary kH/kD isotope effects and computed isotope effects is obtained when proton transfer is allowed to dominate the reaction co-ordinate motion, with the reacting heavy atoms remaining relatively motionless.

Kinetics and mechanism of the cyclization of substituted N-phenyl-2-methyl-2(2-aminophenyl)propanamides and analogues

The cyclization of six N-aryl-2-(2-aminophenyl)alkylamides has been studied at various pH values. Compounds 1a, 2a and 3a had a similar leaving group (4-methoxyaniline) and varying degrees of steric bulk adjacent to the amide, while compounds 1a–1d had varying substituents on the leaving amine. The cyclization of all the compounds was found to be subject to general catalysis by acidic buffer components, with the buffer-independent pH profiles obeying the equation k0=kH3O+[H3O+]+kH2O. Bronsted analysis of the rate coefficients for buffer catalysis gave α values of ca. 0.4 for all compounds. The relative observed pseudo-first-order rate coefficients at pH 6.6 for compounds 3a, 2a and 1a were 1, 9 and 800, respectively, indicating the importance of ‘stereopopulation control’(Milstein and Cohen, J. Am. Chem. Soc., 1972, 94, 9158) on the rate of cyclization. However, cyclization rates were found to be independent of the electronic properties of the leaving amine. The mechanism of cyclization was considered to be rate-determining, concerted attack by the neutral amine, followed by proton transfer from a general acid to the amide oxygen.

Effect of reduction potential on the rate of reduction of nitroacridines by xanthine oxidase and by dihydro-flavin mononucleotide

The cytotoxicity of many nitroaromatic compounds is mediated by bioreduction. There is a correlation between the one-electron-reduction potentials and cytotoxic potencies of simple nitroheterocycles such as nitroimidazoles, but no such correlation is observed with DNA-binding nitroacridines related to the drug nitracrine. A study of the reduction of 1-nitroacridines by the enzyme xanthine oxidase and by reduced flavin mononucleotide, FMNH2(as a model of the enzymes active site) has been undertaken to explore the redox dependence in this series. The values of Vmax,/Km for reduction by xanthine oxidase, XOD, and the second-order rate constants of reduction by FMNH2, analysed using Marcus electron-transfer theory, indicate a correlation between reduction potential and the rate of reduction, but suggest that the potential-energy barrier for electron transfer is small relative to that imposed by requirements for association, orientation and desolvation of the reactants. The close similarity in Marcus parameters for reduction by FMNH2 and by XOD suggests that reduction occurs by a similar mechanism in each case. The free-energy change for electron transfer, ΔG‡o, is only 1–2 kJ mol–1. It appears that the rate of reduction is unlikely to be the only determinant of hypoxic cytotoxicity for the nitroacridines, although the applicability of findings with XOD to other nitroreductases is uncertain.

Comments on the putative ion pair mechanism for hydrolysis of methyl halides and methyl perchlorate

Calculations based on a linear free energy approach to the mechanism of hydrolysis of methyl halides and methyl perchlorate by Scott and Robertson suggest that rate-limiting attack of water (and other nucleophiles) on a preformed ion pair is involved. This result contrasts strongly with that of Abraham, who calculates, via a thermodynamic cycle, that the relevant ion pairs have free energies too high to allow their participation in the reactions, which are thus most likely concerted SN2 processes, and with experimental failure to detect ion pair intermediates in systems potentially more favourable for ion pair formation. The linear free energy approach of Scott is critically examined in the light of recent work by Ritchie, and is seen to rest on false premises. The quasi-thermodynamic treatment of Robertson, Annesa, and Scott is shown to be likewise unsound. The interpretation of the secondary kH/kD for methyl perchlorate hydrolysis in terms of an ion-pair intermediate is shown to be unnecessary in that a looser than usual SN2 transition state is also compatible with the results. The molecular basis of this looseness is discussed.

Solvolysis rates of diarylmethyl p-nitrobenzoates in aqueous ethanol. The question of solvent assistance and the validity of selectivity probes

Rate constants for solvolysis of diarylmethyl p-nitrobenzoates in ethanol–water and trifluoroethanol–water mixtures have been measured. Hammett ρ values and Winstein–Grunwald m parameters have been evaluated. The former are insensitive to solvent composition and the latter to ring substituent. Mechanistic speculation is regttired before these results can be assessed as contributors to debate on the reactivity–selectivity principle, and it is concluded, on the basis of the trifluoroethanol–water probe, that solvent assistance is absent.

Substituent effects on the hydrolysis of analogues of nitracrine {9-[3-(N,N-dimethylamino)propylamino]-1-nitroacridine}

Studies of the hydrolysis of the hypoxia-selective cytotoxic agent 9-[3-(N,N-dimethylamino)-propylamino]-1-nitroacridine (nitracrine) and several of its 4-substituted analogues and nitro-positional isomers have been carried out. Examination of the effects of pH and temperature on the hydrolysis of nitracrine itself shows that the reaction is subject to acid catalysis. The value of ΔH‡ increases from 46 to 63 kJ mol–1 as the pH falls from 6 to 3, while the value of ΔS‡ increases from –195 to –138 J K–1 mol–1. The rate constants for hydrolysis and the acid dissociation constants have been measured at pH 5 and 60 °C. Both the rate constants of hydrolysis, corrected for the substrate–protonation equilibrium, and the substrate–acid association constants are well fitted by the Ehrenson–Brownlee–Taft dual-substituent–parameter σR– relationship. The Swain–Unger–Rosenquist–Swain relationship shows weak correlation but the linear free-energy relationships of Hammett and Yukawa–Tsuno are not fitted. The results are discussed in terms of the resonance interactions of the possible intermediates in the hydrolysis pathways.

The carbanion mechanism of olefin-forming elimination. Part IV. Isotope effects in the dehydrochlorination of 1,1-diaryl-2,2,2-trichloroethanes by anionic bases in alcoholic solvents

Es wird z.B. die Dehydrochlorierung von 2,2,2-Trichlor-1,1-bis-(p-chlor-phenyl)-athan durch Thiophenolat, p-Nitro-phenolat und Methanolat untersucht.