Y. Chiang

Reactive intermediates. Some chemistry of quinone methides

Quinone methides were produced in aqueous solution by photochemical dehydration of o-hydroxybenzyl alcohols (o-HOC6H4CHROH; R = H, C6H5, 4-CH3OC6H4), and flash photolytic techniques were used to examine their rehydration back to starting substrate as well as their interaction with bromide and thiocyanate ions. These reactions are acid-catalyzed and show inverse isotope effects (kH+/kD+ < 1), indicating that they occur through preequilibrium protonation of the quinone methide on its carbonyl carbon atom followed by rate-determining capture of the benzyl carbocations so formed by H2O, Br-, or SCN-. With some quinone methides (R = C6H5 and 4-CH3OC6H4) this acid catalysis could be saturated, and analysis of the data obtained in the region of saturation for the example with R = 4-CH3OC6H4 produced both the equilibrium constant for the substrate protonation step and the rate constant for the rate-determining step. Energy relationships comparing the quinone methides with their benzyl alcohol precursors are derived.

Alkylation of guanosine and 2′-deoxyguanosine by o-quinone α-(p-anisyl)methide in aqueous solution

Rates of alkylation of guanosine and 2′-deoxyguanosine with o-quinone α-(p-anisyl)methide were measured by flash photolysis in a series of aqueous sodium hydroxide solutions and bicarbonate ion, t-butylhydrogenphosphonate ion, and biphosphate ion buffers. The data so obtained provide rate profiles for these nucleoside plus quinone methide reactions over the range pH = 7–14, which furnish guanosine and deoxyguanosine acidity constants consistent with literature information. These profiles also provide rate constants that show the reaction of o-quinone α-(p-anisyl)methide with guanosine and deoxyguanosine to be fairly fast processes, considerably faster than the biologically wasteful reaction of the quinone methide with water, which is the ubiquitous medium in biological systems; that makes the quinone methide a potent guonosine and deoxyguanosine alkylator.

Conjugate addition of water to α‐carbonylcarbenes

α-Carbonylcarbenes (2a–c) generated by UV photolysis of 2-diazophenylacetic acid (1a), its methyl ester (1b) and 4-diazo-3-isochromanone (1c) in aqueous solution undergo conjugate addition of water across the entire carbonylcarbene moiety to give enols (3a–c) of the corresponding α-hydroxycarbonyl compounds. These carbenes are long-lived, with microsecond lifetimes in aqueous solution.

Generation of o-quinone α-carbomethoxymethide by photolysis of methyl 2-hydroxyphenyldiazoacetate in aqueous solutionDedicated to Professor Dr Z. R. Grabowski and Professor Dr J. Wirz on the occasions of their 75th and 60th birthdays.Electronic supplementary information (ESI) available. Tables S1–S4 of rate data. See http://www.rsc.org/suppdata/cp/b2/b211444p/

Flash photolysis of methyl 2-hydroxyphenyldiazoacetate (8) in dilute aqueous perchloric acid solution and acetic acid and biphosphate ion buffers produced a transient species that was identified as o-quinone α-carbomethoxymethide (9). This structural assignment is based upon solvent isotope effects, the form of buffer catalysis, UV absorption maxima, and the identity of decay rate constants with those determined for the transient obtained by flash photolysis of other, more conventional, quinone methide precursors, namely the benzyl alcohol methyl 2-hydroxy mandelate (10) and its acetate, 2′-acetoxy-2-hydroxyphenylacetate (11).

Flash photolytic generation and study of 5-methoxy-o-quinone α-phenylethide in aqueous solution: comparison of cis and trans isomer reactivity

Cis and trans isomeric 5-methoxy-o-quinone alpha-phenylethides were generated by flash photolysis of o-hydroxybenzyl alcohol and o-hydroxystyrene precursors and their rates of decay were measured in aqueous solutions of perchloric acid, sodium hydroxide, and biphosphate (dihydrogen phosphate) ion and carbonate ion buffers. The data so obtained gave two parallel rate profiles displaced from one another by about an order of magnitude, the faster of which could be assigned to the cis isomer and the slower to the trans isomer. Both rate profiles showed acid catalyzed, uncatalyzed, and hydroxide ion catalyzed portions, with acid catalysis becoming saturated at the high acidity end of the range investigated. This saturation implies a pre-equilibrium mechanism involving quinone ethide protonation on carbonyl oxygen for the acid catalyzed process, and analysis of the data shows the trans isomer to be a slightly stronger base than the cis isomer. The fact that two separate rate profiles are observed implies that the cationic intermediates formed by substrate protonation in these acid catalyzed processes do not interconvert on the time scale of the quinone ethide decay reactions, and that in turn indicates that the former ethide bonds of the cationic intermediates have substantial double-bond character; a lower limit of 10 kcal mol(-1) may be estimated for the barrier to rotation about this bond.

Phenylacetaldehyde and its cis- and trans-enols and enolate ions. Determination of the cis : trans ratio under equilibrium and kinetic control

A method of determining individual keto–enol equilibrium and acid dissociation constants for systems in which unstable enols can exist in cis and trans isomeric forms is developed and is applied to phenylacetaldehyde in aqueous solution; the results give equilibrium cis : trans ratios of 35 : 65 in acidic and neutral solutions and 20 : 80 in a basic solution (where the enols are converted to enolate ions), but show considerably by less cis : trans differentiation for enols formed under kinetic control.

Fractionation factors for the aqueous hydroxide ion and solvent isotope effects on the ionisation of 1,8-bis(dimethyamino)naphthalene (proton sponge)

Isotopic fractionation factors ϕa and ϕb for the hydroxy hydrogen and hydrogen-bonded water hydrogens of the solvated hydroxide ion are important in controlling solvent isotope effects upon reactions involving the hydroxide ion, and were required for a vibrational analysis of the solvated ion. The product ϕaϕb3= 0.434 is accurately available from e.m.f. measurements corrected for free energies of ion transfer between H2O and D2O, but separation of ϕa and ϕb, which requires measurements in H2O–D2O mixtures, is known to be subject to considerable uncertainty. Thus careful measurements with 1,8-bis(dimethylamino)naphthalene gave KD2O/KH2O= 0.420 ± 0.006 for the ratio of basic ionisation constants in H2O and D2O and ϕP= 0.901 ± 0.014 for the fractionation factor of the protonated base, but measurements in 1 : 1 H2O–D2O gave an ionisation constant too small to be consistent with any reasonable fractionation factor model for the hydroxide ion. Alternative methods of dissecting ϕa and ϕb, from measurements of isotope separation factors between hydroxide solutions and water vapour and autoprotolysis constants of H2O–D2O mixtures, are critically reviewed and optimum values are assessed. The results are shown to be sensitive to experimental error and to medium effects but not to departures from the Rule of the Geometric Mean.

The relationship between HR and H0 in moderately concentrated aqueous perchloric and hydrochloric acids

HR is a non-linear function of H0 in 0·1–1·5 M aqueous perchloric and hydrochloric acids; this complicates data extrapolation through these regions but is of use in connection with mechanistic details of acid catalysis.

The hydrolytic reactivity of homoprostacyclin: implications for the physiological control of bleeding

Rates of hydrolysis of the vinyl ether group of homoprostacyclin (2), which differs from prostacyclin only in that it has four instead of three carbon atoms in the chain joining this group to a carboxy function, were measured in H2O solution over the pH range 1–9 and in D2O solution in D2PO4––DPO42– buffers. The rate profile so obtained shows that homoprostacyclin is eight times more reactive in its carboxylate than in its carboxylic acid form, and an isotope effect on the accelerated reaction indicates that this rate increase is the result of intramolecular catalysis by the carboxylic acid group. This eight-fold acceleration is significantly less than the 100-fold increase produced by intramolecular catalysis in the case of prostacyclin itself, and that suggests that natural evolution has given prostacyclin the correct lifetime it needs to be effective in the physiological mechanism for the control of bleeding by adjusting the length of the carbon chain joining its vinyl ether and carboxy groups.

(Z)-6,9-epoxynon-5-enoic acid: a simple model which mimics the unusual hydrolytic lability of prostacyclin

Evidence supporting the hypothesis that hydrolysis of the vinyl ether group of prostacyclin, accelerated by its carboxylic acid function operating in the carboxylate form, is responsible for the unusual hydrolytic lability of this substance is provided by the remarkably similar behaviour of (Z)-6,9-epoxynon-5-enoic acid; the latter is a simple model of prostacyclin which contains all of the structural features needed for this destabilization mechanism to function.