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The 1H and 13C NMR spectra of the antimalarial drug arte-ether (a derivative of qinghaosu) have been obtained and stereospecific assignments made using standard one- and two-dimensional techniques. Proton homonuclear spin-coupling constants were quantified from J-resolved and E.COSY experiments and confirmed that the solution conformation of arte-ether is similar to that of the reported crystal structure of artmether. A conformational model was generated using AM1 semi-empirical energy calculations, and was consistent with both the measured spin-coupling constants and experimental NOE data.

One factor responsible for the enhanced thermal stability of S-nitroso-N-acetylpenicillamine (SNAP), compared with S-nitroso-N-acetylcysteine (SNAC), has been shown, by ab initio calculations on model compounds, to be steric interactions in the dimerisation reaction leading to disulfide formation. Studies using DSC and TGA indicate that the two gem methyl groups in SNAP do not have a substantial effect on the strength of the –S–NO bond.

Decomposition of S-nitrosothiols (RSNO) in aqueous solution at pH 7.4 is brought about by copper ions, either present as an impurity or specifically added. The primary products are nitric oxide and the disulfide. In the presence of the specific Cu+ chelator, neocuproine, reaction is progressively inhibited as the [neocuproine] is increased, the reaction eventually stopping completely. The characteristic UV–VIS spectrum of the Cu+ adduct can be obtained from the reaction solutions. This shows clearly that Cu+ and not Cu2+ is the effective catalyst. Two limiting kinetic conditions can be identified for a range of S-nitrosothiols at specific copper ion concentrations (a) a first-order dependence and (b) a zero-order dependence upon [RSNO]. Normally both situations also have a short induction period. This induction period can be removed by the addition of the corresponding thiol RSH. A mechanism is proposed in which Cu+ is formed by reduction of Cu2+ by thiolate anion via an intermediate, possibly RSCu+. Loss of nitric oxide from RSNO is then brought about by Cu+, probably via another intermediate in which Cu+ is bound to the nitrogen atom of the NO group and another electron-rich atom (such as nitrogen from an amino group, or oxygen from a carboxylate group) involving a six-membered ring. As well as NO this produces both RS– and Cu2+ which then are part of the cycle regenerating Cu+. Thiolate ion is oxidised to RS˙ which dimerizes to give the disulfide. Depending on the structure (and hence reactivity) of RSNO either Cu+ formation or its reaction with RSNO can be rate-limiting. Computer modelling of the reaction scheme allows the generation of absorbance time plots of the same forms as those generated experimentally, i.e. first- or zero-order, both with or without induction periods. We suggest that the thiolate ion necessary to bring about Cu2+ reduction is either present as a thiol impurity or is generated in small quantities by partial hydrolysis of the nitrosothiol, which results in an induction period. Addition of small quantities of thiol removes the induction period and leads to catalysis but larger quantities bring about a rate reduction by, it is suggested, complexation of the Cu2+. For two very unreactive substrates, S-nitrosoglutathione and S-nitroso-N-acetylcysteine very large induction periods were observed, typically three hours. This results, we suggest, from competitive re-oxidation of Cu+ to Cu2+ by the dissolved oxygen. Experiments carried out anaerobically confirm this, since there is then no induction period. Addition of hydrogen peroxide extends the induction period ever further. The results are discussed in terms of the biological properties of S-nitrosothiols which are related to nitric oxide release.

Under acid conditions 5-aminolevulinic acid reacts with acetylacetone to give 3-acetyl-4-(2-carboxyethyl)-2-methylpyrrole (1). There is also formation of a small amount of the Fischer–Fink product (2). Use of 13C and 15N NMR spectroscopy showed that the first condensation product to accumulate is the enaminoketone (5). The trifluoro analogue of 5 can be isolated and its cyclisation to 8 was monitored. There is a substantial spontaneous reaction and the acid-catalysed process occurs by specific acid catalysis.

Benzil 2 reacts readily with 1,2-phenylenediamine 1 to give 2,3-diphenylquinoxaline 3. By the use of 13C NMR spectroscopy with a labelled substrate the course of the reaction has been determined. A parallel study of the reaction between benzil and 6-methoxy-2,4,5-triaminopyrimidine gave only an indication of the pathway because of the large number of possible intermediates.

The stereochemistries of the reactions between cyanate and aspartic acid and 3-methylaspartic acid have been examined. The product of the first reaction, N-carbamoylaspartic acid 3. can cyclise to give either dihydroorotic acid 5 or 5-carboxymethylhydantoin 4. Acid catalysed cyclisation gives the latter while catalysis by the enzyme dihydroorotase gives the former. Introduction of a double bond into 3 changes the course of non-enzymatic cyclisation and a six-membered ring compound orotic acid 1 is the product. It is proposed that the double bond prevents intramolecular hydrogen bonding.

Reaction of thiourea with 1-phenylpropane-1,2-dione in the presence of acid results in formation of 4,4′-methylenebis(5-phenyl-4-imidazoline-2-thione)11c. A mechanism of reaction is proposed, based on intermediates isolated from this and related reactions and on the detection of intermediates by 13C NMR spectroscopy using labelled reactants. With 1,3-dimethylthiourea the reaction ceases on formation of 1-(1,3-dimethyl-5-phenyl-2-thio-4-imidazolinyl)methyl-1,3-dimethylthiourea 4a and the analogue of this derived from thiourea is proposed as an intermediate in the formation of 11c. The two isomeric N-methyl analogues (11a and 11b) of 11c are obtained on reaction of 1-phenylpropane-1,2-dione with 1-methylthiourea. 1-Phenylbutane-1,2-dione and 1,3-diphenylpropane-1,2-dione react similarly, but 3-methyl-1-phenylbutane-1,2-dione does not react at all.

Benzil reacts with 1,3-dimethylthiourea, 1-methylthiourea, and thiourea in acid solution to give 4,5-diphenyl-4-imidazolines (3) which, in the cases of 1-methylthiourea and thiourea, readily form disulphides 11. Another product of reaction is a bicyclic compound 4 in which it appears that in one thiourea moiety sulphur has been replaced by oxygen. A mechanistic pathway for the formation of 3 and 4 is proposed involving thiourea acting as a sulphur nucleophile, urea as a leaving group, and the thermal decomposition of thiiranes.

Benzil reacts under alkaline conditions with 1,3-dimethylthiourea to form 4,5-dihydroxy-1,3-dimethyl-4,5-diphenyltetrahydroimidazole-2-thione (1); with 1-methylthiourea to form 3-methyl-5,5-diphenyl-2-thiohydantoin (9); and with thiourea to form both the corresponding hydantoin and 3a,7a-diphenyltetrahydroimidazo[4,5-d]imidazole-2,5-dithione (19). The use of high field n.m.r. spectroscopy and benzil labelled with carbon-13 in the carbonyl group has permitted delineation of the reaction mechanisms and detection of a number of transient intermediates.

The chymotrypsin-catalysed hydrolyses of a number of substituted aryl acetates have been studied. For all the esters with poorer leaving groups the reactions obey simple first-order kinetics. Esters with a 4-nitro-group show ‘burst’ kinetics but this is not the case for esters with equally good leaving groups but no 4-nitro-group. This distinction does not occur when pyridine is the catalyst.

The carbanions of malononitrile, ethylmalononitrile, and dimethyl malonate react with pentacyanonitrosylferrate (nitroprusside) to form highly coloured adducts. A kinetic study has shown that, in the second and third cases, there is rate-determining reaction between carbanion and nitroprusside but, in the first, the product is that formed by a second ionisation to give [Fe(CN)5N(O)C(CN)2]4–.

No evidence was obtained from 15N n.m.r. spectroscopy for the scrambling of the nitrogens of benzenediazonium ions in solution or during coupling. The 15N chemical shifts in acetonitrile solution are modified on complexation with a crown ether. The scope of crowns as phase-transfer catalysts for azocoupling reactions has been examined.

Reaction of urea with 1,2-diaminoethane results in formation of imidazolidin-2-one (1). Isotopic labelling and a study of the reactions of N-alkylated 1,2-diaminoethane indicate that the reaction mechanism involves an isocyanate intermediate. 1,3-Diaminopropane gives a similar product.

In acid solution 1-phenylpropane-1,2-dione reacts with urea to give a bicyclic compound (2), with 1,3-dimethyl-and 1,3-diethyl-urea to give the spiro-compounds (4) and (10), and with 1-methylurea to give a bicyclic compound of possible structure (11), (12), or (13). Mechanisms for formation of the first three compounds are suggested and the tendency of the diol intermediates to eliminate water is discussed. The methyl group of the dione is one site of reaction.

The isomerisation of benzylpenicillin to benzylpenicillenic acid is catalysed by imidazole, N-methylimidazole, and 2-methylimidazole. For each catalyst there is a different rate equation. The dominant reaction path is general acid assisted reaction of benzylpenicillin with imidazole. A mechanism is proposed in which, after reaction with the imidazole at the carbonyl group of the β-lactam ring, there is protonation of the β-lactam nitrogen and ring-opening. The mechanism proposed parallels that suggested by Morris and Page for the aminolysis of penicillins.

The mechanism of aromatic iodination proposed previously has been confirmed by a study of the reactions of substituted thiophens. For 2-phenylthiophen the kinetic hydrogen isotope effect depends upon the substrate concentration, which is consistent with the reaction scheme.

The effect of methyl groups on the rate of protodetritiation of 2- and 3-tritiothiophen in perchloric acid has been examined and activation parameters for the reactions have been calculated. The activating effect of a second methyl is non-additive. Reaction at the 3-position is less susceptible to substituent effects than that at the 2-position. With 2-methyl-, 2,4-dimethyl-, and 2,5-dimethyl-thiophen, as well as ring hydrogen exchange, there is slower exchange on certain methyl groups.

The carbanion of ethyl cyanoacetate reacts with pentacyanonitrosylferrate (2–)(nitroprusside) to form a coloured adduct, which decomposes to an oxime and aquapentacyanoferrate (3–). Although the pKa of ethyl cyanoacetate is similar to that of malononitrile, no second ionisation could be detected in the kinetic data. Reasons for this are discussed.

A study of kinetic isotope effects and activation parameters indicates that, in the hydrolysis of phenyl chloroformate, acetate ion and pyridine act as nucleophilic catalysts. Both the spontaneous and pyridine catalysed hydrolyses of substituted phenyl chloroformates fit a Hammett plot. The effect of solvent polarity and added salt indicates that there is little charge separation in the transition state for hydrolysis. The mechanism of reaction is discussed.

In acid solution benzil reacts with urea and with 1-methylurea to give the bicyclic products (2) and (3b) and with 1,3-dimethylurea to give 1,3-dimethyl-5,5-diphenylhydantoin (5). The initial step in the reaction is attack by urea on protonated benzil to give the diol (6). Further reaction of (6) is governed by its tendency to eliminate water.

Intense, transient colours are produced during the nitrosation of a number of aromatic compounds. The spectrum of that obtained from 4-iodoanisole has been determined by stopped-flow spectrophotometry. The kinetics of the formation of the coloured species from 2-(4-iodophenoxy)ethanesulphonic acid in aqueous solution have been examined. It is concluded that the coloured species are σ-complexes.

Urea and 1-methylurea react with both aromatic and aliphatic acyloins to form 4-imidazolin-2-ones but, under the same reaction conditions, 1,3-dimethylurea does not react. However, 1,3-dimethylurea does react with diacetyl to form 4,4′-methylenebis-(1,3,5-trimethyl-4-imidazolin-2-one)(4a). The carbon atom lost in the formation of (4a) is eliminated as formaldehyde. We propose a reaction mechanism which involves formation of an oxetan ring. With 1-methylurea and urea the main products of reaction with diacetyl are the bicyclic compounds (6a–c). However, it is possible that reactions analogous to that leading to the formation of (4a) also occur and that the carbonium ion (5c) is the coloured species formed in the well known colorimetric procedure for the determination of urea concentrations in biological liquids.

Both the kinetics and the products for the hydrolysis of 2,3,3-triethyloxaziridine in aqueous acid at 25 °C are reported. The reaction is subject to general acid or base catalysis in acetic acid buffers, but in aqueous perchloric acid, the acid catalysis is slight with the rate reaching an unusually sharp maximum in ca. 0.9M HClO4 and then decreasing at higher acidities. Comparison with 2-[αα′-2H2]ethyl-3,3-diethyloxaziridine reveals a substantial primary deuterium isotope effect at low acidities (k0H/k0Dca. 2.7) which steadily decreases to become negligible in 6.68M HClO4. The variation in kinetic parameters relates to a change in the reaction products. In ca. 1M HClO4 the major products are diethyl ketone and acetaldehyde, but N-ethylhydroxylamine is formed at the expense of acetaldehyde as the acidity increases.The results are analysed and shown to be consistent with a mechanism requiring concurrent protonation of both O and N atoms of the oxaziridine ring. The O-conjugate acid intermediate undergoes relatively rapid decomposition to diethyl ketone and acetaldehyde by an E-2 process where cleavage of the O–N bond is synchronous with H+-abstraction from the N-ethyl group. The N-conjugate acid is much more stable. N-Ethylhydroxylamine is formed either by thermal decomposition or by a slow breakdown of the N-conjugate acid. Calculations suggest that O and N basicities are very similar and this unusual result is attributed to steric hindrance to solvation of the N-conjugate acid.

The kinetics of the reactions of five substituted benzenediazonium ions with up to eleven different pyrroles have been examined in detail by stopped-flow spectrophotometry. All the evidence favours attack of the unprotonated pyrrole in an SE2 mechanism, with a steady-state intermediate. A consideration of two linear free-energy relationships shows that little can be deduced about the nature of any transition state in these reactions. However, protonated pyrrole is a good model for the steady-state intermediate. The activating effects of a methyl group towards electrophilic attack at various positions on the ring have been calculated. The special reactions of 3,4-dimethyl- and 2,3,4,5-tetra-methyl-pyrrole are discussed.

Nitration of 3-iodoanisole in the presence of nitrous acid was found to give 3-nitroanisole, 3-iodo-4-nitroanisole, and 3,6-di-iodo-4-nitroanisole. Nitration of 2,6-dimethyl-4-iodoanisole was found to result in the displacement of iodine. The rate of reaction was studied as a function of nitrous acid concentration and acidity. The results confirm the mechanism for nitrodeiodination proposed previously.

Whereas the neutral form of pyrrole reacts with 4-nitrobenzenediazonium ions, the parallel reaction of imidazole involves the anion. The involvement of the imidazole anion is based on kinetic evidence, pressure studies, and MNDO calculations. N-Methylation affects not only the kinetics of reaction but also the products. With the neutral form of imidazole it is suggested that the predominant reaction with an aryldiazonium ion is reversible attack on a ring nitrogen.

The kinetics of the reaction between various pyrroles and 4-dimethylaminobenzaldehyde (DMAB) in acid solution has been examined by stopped-flow spectrophotometry. The mechanism is rate-determining attack by O-protonated DMAB on free pyrrole followed by elimination of water. The activating effect of a methyl group on various positions in the pyrrole ring has been determined.

Pyridine bases catalyse the hydrolysis of aryl acetates and activation parameters for several of these reactions have been determined. The size of the kinetic isotope effect indicates nucleophilic catalysis. Substitution at the 2-position in pyridine prevents nucleophilic catalysis, but a much slower general base catalysed pathway was detected and it is argued that this occurs even when nucleophilic catalysis appears to be the mechanism. Anion desolvation may be important in the reaction with hydroxide ion with aryl esters.

Hydrolysis rates in aqueous acid up to 7M and at 25 °C are reported for six oxaziridines bearing various N-alkyl- and either aryl- or alkyl-C-substituents. The major reaction products are also identified. With earlier data, these results show that the extent of acid-catalysis is overwhelmingly determined by the structure of the N-alky substituent (tertiary > secondary > primary) irrespective of the hydrolysis pathway, which is influenced by both N-and C-substituents. The kinetic acidity dependences confirm that some oxaziridines may undergo concurrent protonation at both O and N atoms, with N-conjugate acid formation being more extensive for compounds with primary than for those with secondary or tertiary alkyl-N-substituents. Generally, the products arise from hydrolysis of the O-conjugate acid, but for compounds bearing C-aryl substituents hydrolysis of the N-conjugate acid is also important. The influence of N-alkyl substituents on conjugate acid formation is not related to the usual electronic interactions, but can be rationalised by steric inhibition to solvation of the N-conjugate acid. Calculations suggest that the basicities of oxaziridine O and N atoms are closely similar.

The kinetics of the cyclisation of o-cyanobenzamide to give 3-iminoisoindolin-1-one in aqueous solution have been studied, and the mechanism of alkaline hydrolysis of this compound has been compared with that of phthalimide and N-methylphthalimide.

Hydrogen exchange at the unsubstituted positions in 1,2,5-trimethyl- and 1,3,4-trimethyl-pyrrole in aqueous buffer has been examined. The two positions were found to be of similar reactivities. General acid catalysis was detected. No hydrogen exchange on the methyl groups of 2,3,4,5-tetramethylpyrrole, even in strong acid, was detected. The 13C n.m.r. spectrum of the tetramethylpyrrole was examined.

MNDO calculations do not predict correctly the tautomer of creatinine (1) present in aqueous solution as deduced from n.m.r. evidence. The reason is substantial hydrogen bonding to the solvent. However, calculations do illuminate the form of protonated creatinine and lead to a semi-quantitative explanation of the higher basicity of glycocyamidines with exocyclic CN, e.g. methylcreatinine (2). Both calculations and spectroscopy show the ring-opening reaction of creatinine in alkaline solution to give creatine (5). The significance of this to the clinical assay of creatinine (the Jaffe reaction) is discussed. In acid solution creatinine undergoes slow ring closure.

Reaction between 2-nitroethanol and sodium hypobromite gives bromopicrin (CBr3NO2) in high yield. A kinetic study indicates that 2,2-dibromo-2-nitroethanol is an intermediate and that the rate-determining step is proton removal from 2-nitroethanol.

The conversion of 4-iodoanisole into 2-iodo-4-nitroanisole by nitric acid has been shown to occur by rapid nitrodeiodination and iodination to give 2,4-di-iodoanisole and 4-nitroanisole, gradual nitrodeiodination of the former compound at the 4-position with the production of free iodine, and then very slow iodination of the latter compound at the 2-position. Nitrous acid acts as a catalyst and the preliminary step is thought to be nitrosodeiodination. The ortho:para ratio for the methoxy-group in nitrosodeiodination is very low. The ipso factors of Perrin and Skinner are discussed in detail in the light of this and other work.