John A. Elvidge

Base-Catalyzed Hydrogen Exchange

Publisher Summary This chapter focuses on the base-catalyzed hydrogen exchange in heterocyclic compounds. Isotopic hydrogen exchange is becoming a widely employed method for preparing labeled compounds, being unsatisfactory only when the specificity of the process is uncertain and when the label can be replaced is high. A better understanding of the various factors involved in the preparation of labeled compounds as well as the stability of the label under widely different conditions is emphasized in the chapter. The conditions necessary to induce exchange vary widely and may be dictated by structural features. Proton-transfer reactions from heterocyclic compounds provide a favorable situation for the operation of a mechanism of exchange. Heterogeneous methods of exchange often involving expensive catalysts were widely used for incorporating tritium and deuterium into heterocyclic compounds. The isotopic exchange procedure is useful as a diagnostic tool for detection of minute traces of labeled compounds that can be seen in the recently developed method for assay of guanine residues in DNA. Many applications have resulted from studies of base-catalyzed isotope exchange reactions of heterocyclic compounds. Primary kinetic hydrogen isotope effects in the base catalyzed exchange of various heterocyclic compounds are tabulated in the chapter.

Tritium nuclear magnetic resonance spectroscopy. Part VI. Tritiated steroid hormones

The regio- and stereo-specificity of the labelling in a series of tritiated steroid hormones has been examined by 3H n.m.r., which also yields quantitative information on the distribution of the tritium between the labelled sites. Complete analysis is thus readily achieved non-destructively. Hydrogen chemical shifts for various skeletal sites are provided for the first time. The specificity of the methods of labelling steroids with tritium by catalytic reduction, catalysed exchange, and tritiodehalogenation are discussed.

Preparation of some highly polarised ethenes by the addition of amines to suitable carbonitriles

Substituted diaminomethylene derivatives of malononitrile (2) and of cyanoacetamides, cyanoacetates, and cyanothiolacetates (4)–(6) have been prepared from amine salts of tricyanomethane (1) and of related anions (3) having one ester or amide function in place of a cyano group.

Application of tritium nuclear magnetic resonance spectroscopy to the determination of isotopic fractionation factors in methanol–methoxide solutions

Tritium n.m.r. measurements of hydroxy chemical shifts in methanolic solutions of sodium methoxide have been used to determine an isotopic fractionation factor for the inner solvation shell of the methoxide ion and contributions from inner and outer solvation shells to the methoxide ion chemical shift. The identity of protium and tritium chemical shifts and the relationship between tritium and deuterium fractionation factors φT=φ1.442 mean that measurements in MeOH and MeOD double the information available from 1H n.m.r. measurements alone. The necessary assumption previously made to derive φ from 1H measurements, that secondary solvation does not contribute to the methoxide ion chemical shift, is shown to be incorrect, but the revised value of φ(0.7) differs only slightly from earlier values, although treatment of the secondary solvation shift as a variable leads to some loss of precision in the definition of φ. At high methoxide concentrations plots of chemical shift against concentration are distinctly curved. Contributions to the curvature from breakdown of the assumption that isotopic atom fractions in the solution as a whole and in the bulk solvent are identical are evaluated.

Use of tritium nuclear magnetic resonance for the direct location of 3H in biosynthetically-labelled penicillic acid

In a first application of 3H n.m.r. spectroscopy to a biosynthetic investigation, namely the incorporation of [3H]acetate by Penicillium cyclopium into penicillic acid (I), the stereospecificity of labelling of the vinyl methylene group is directly demonstrated and a biosynthetic pathway thereby proposed.

Catalytic tritiation of drugs and analysis of the tritium distribution by 3H n.m.r. spectroscopy.

Propranolol, phenobartitone, diphenylhydantoin, amphetamine, imipramine and propoxyphene have been tritiated using tritiated water and platinum catalyst (from the dioxide and sodium borohydride), and the pattern of labelling has been ascertained by 3H n.m.r. spectroscopy. The results show that this exchange procedure can lead to satisfactory incorporation of tritium at ‘stable’ aromatic positions. For imipramine where incorporation of tritium was low, an alternative acid‐catalysed procedure was satisfactory.

Heterocyclic imines and amines. Part 19. Isoquinoline and other products from α,o-dicyanostilbene and basic reagents

α,o-Dicyanostilbene (1) was cleaved by hydrazine or hydroxylamine under mildly acid conditions to o-cyanobenzyl cyanide (2) and benzaldehyde, isolated as derivatives. Sodamide with compound (1) gave 1-amino-4-cyano-3-phenylisoquinoline: alkoxides similarly gave the 1-alkoxy compounds, the presumed intermediate 3,4-dihydroisoquinoline from the methoxide reaction being isolated and separately dehydrogenated. Acid hydrolysis of the 1-ethoxy compound gave the known 4-cyano-3-phenylisoquinolin-1(2H)-one. With the anion of o-cyanobenzyl cyanide, compound (1) gave a 1-amino-4-cyano-3-(2-substituted phenyl)isoquinoline, which was oxidised to 1-amino-4-cyano-3-(2-carboxyphenyl)isoquinoline. The latter lost water at 210 °C to give yellow 12-cyano-5-iminoisoindolo[2,1-b]isoquinolin-7(5H)-one, closely related to known compounds.

Polyene acids. Part 11. Preparation of α-tritiated (or deuteriated) conjugated enoic and dienoic acids and their examination by triton magnetic resonance spectroscopy

Decarboxylation in boiling pyridine of conjugated ene[OO′-3H]dioic acids (from aryl or alkyl aldehydes and malonic acid, followed by exchange tritiation with labelled water) efficiently provided α-tritiated trans-αβ-unsaturated acids. Extended to croton- and cinnam-aldehydes, the method yielded conjugated dienoic acids labelled at both α- and γ-positions as shown by 3H n.m.r. Labelling at only the α-position was achieved by thermal monodecarboxylation of the intermediate from cinnamaldehyde. Mechanisms are discussed. Similar reactions can be used for the preparation of deuteriated αβ-unsaturated acids.

Tritium nuclear magnetic resonance spectroscopy. Part II. Chemical shifts, referencing, and an application

With the aid of compounds partially monotritiated by base-catalysed exchange with labelled water, corresponding triton and proton chemical shifts measured from internal tritiated water under the same conditions are shown to be the same. Applying this result and using the accurate resonance frequencies of the two nuclei measured at constant field on many of the compounds in organic solvents, a mean value, 1·06663975 (±3 × 10–8), has been obtained for the ratio of the Larmor frequencies, ωT/ωH. This value enables an accurate ghost reference for any 3H n.m.r. spectrum to be derived from the observed 1H n.m.r. frequency of the normal internal reference. The convenience of 3H n.m.r. spectroscopy for solving mechanistic problems is illustrated in respect of the Reimer–Tiemann reaction.

Heterocyclic imines and amines. Part 18. Conversion of o-cyanobenzyl cyanide into isoquinoline, benzylisoquinoline, and azachrysene products

With sodamide in formamide, o-cyanobenzyl cyanide dimerises in the two ways possible: it also adds formamide to yield 1-amino-3-formamidoisoquinoline (2). Each dimer undergoes cycloisomerisation: thus 1-amino-3-o-cyanobenzyl-4-cyanoisoquinoline (5a) and 6,11-diamino-12-cyanobenzo[c]phenanthridine (9) were isolated. o-Cyanobenzyl cyanide with sodium methoxide afforded (5a) very slowly in methanol but much more rapidly in dimethyl sulphoxide–methanol.