Formation of carbon-deuterium bonds

The labeling of organic compounds with stable or radioactive isotopes now constitutes an extremely important area of preparative chemistry. The number of publications in that field has grown to such an extent that it is almost impossible to find them all. This alone indicates the ever growing importance of labeled compounds in diverse branches of science moreover, the work reactivates the experimental demands on preparative chemists because an extraordinarily large number of compounds of different isotopic composition are open to synthesis. For instance, even such a relatively simple molecule as propane can afford no less than twenty-nine different deuterium-labeled compounds with eight different molecular formulae. 

Most of the reactions involved in this work, and particularly those with radioactive isotopes, require special laboratory installations and are now, and are likely to remain, the domain of specialists. It should be noted also that they rarely lead to truly homogeneous substances, but rather to mixtures of molecules containing the label at different places and in different proportions, either necessarily—because the pure isotope is not available as starting material or the labeling reaction is not wholly controllable—or intentionally, because economic factors, inconveniently high specific activities and the resulting difficulties of protection against radiation and autoradiolysis, or other considerations leave no other course open. 

Considerations of this kind do not apply to labeling with deuterium, which is available cheaply as the almost pure isotope and is not dangerous. Deuterium-labeled compounds are, for instance, used in analysis, in studies of reaction mechanism, for investigation of isotope effects, and for research on the metabolism of biochemically important substances. They are of particular value for the determination of the structure of chemical substances both by means of chemical reactions and by means of mass spectroscopy or IR or NMR spectroscopy. Moreover, the perdeuterated compounds are important solvents for use in these physical measurements. 

Deuterium-labeled compounds1 are prepared almost exclusively by chemical methods. There is no physical method for deuterium-labeling similar to that 

Preparative methods in which previously labeled, simple organic compounds are used in conventional syntheses. 

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The addition of water or hydrogen halide to carbon-carbon double bonds is normally almost valueless as a method for formation of new C-H bonds. However, for formation of carbon-deuterium bonds it is purposeful, as deuterium is a stable component of a molecule only when bonded to carbon whereas the deuterium of an OD group is labile and thus removable. 

The fourth edition has been expanded by a chapter on the Formation of Carbon-Phosphorus Bonds and by another on the Formation of Carbon-Deuterium Bonds . The chapter on Alteration of Nitrogen Groups in Carbon-Nitrogen Compounds has been substantially expanded, but the remaining parts of the book have merely been completed by inclusion of preparative processes discovered in recent years. 

Following the biosynthetic mechanism, initial ionization of GDP to the cation followed by the subsequent addition of the IDP unit forms the FDP cation in a reaction that is catalyzed by FPPS prenyltransferase (Scheme 7.1) [2]. The mechanism is based on the findings that the enzyme, which normally catalyzes the addition of GDP to IDP, is also able to catalyze the hydrolysis of GDP [3]. Deuterium experiments of this hydrolysis process either with D O or with (1S)-[1- H] GDP indicated that C—O bond was broken and the chirality of the C-1 carbon of GDP was inverted in this process. In addition, when trifluoromethyl group was present at the C-3 position or fluoro atom at the C-2 position of the allylic substrate, destabilization of the cation has been witnessed as observed on the retard of enzyme reaction [4]. In the elimination step (Scheme 7.1) hydrogen is removed from C-2 of IDP part with simultaneous formation of a double bond. The formation of a trans or cis double bond during the FPPS reaction depends on the spatial orientation of IDP relative to the elongating FDP. In the tranx-prenyltransferases, the GDP... 

Support for such an interaction of the H—C bonds with the carbon atom carrying the positive charge is provided by substituting H by D in the original halide, the rate of formation of the ion pair is then found to be slowed down by 10% per deuterium atom incorporated a result compatible only with the H—C bonds being involved in the ionisation. This is known as a secondary kinetic isotope effect, secondary... 

The mechanism described in Scheme 2 was rejected on the grounds that the steric requirement for the abstraction of a hydrogen atom from -CHD-of species (IV) could not be met. Assuming an atomically flat surface, and sp3 hybridization of the carbon atom bonded to the surface, the plane of the Ce-ring in (IV) is in such a configuration that the hydrogen atom of -CHD- is directed away from the surface, and the deuterium atom toward the surface. Thus, unless the species is adsorbed near a step in the metal lattice, the loss of this hydrogen and the formation of a second carbon-metal bond would require a very considerable distortion of adsorbed species. 

The important observation is that all of the isotope effects are large and inverse. Therefore, the transition states in these reactions must be very crowded, i.e. the Ca—H(D) out-of-plane bending vibrations in the transition state must be high energy (Poirier et al., 1994). As a result, these workers concluded that nitrogen-a-carbon bond formation is more advanced than a-carbon-iodine bond rupture in the transition state. It is interesting, however, that in spite of the small secondary a-deuterium KIEs, these authors concluded that the N—C bond formation is only approximately 30% complete in the transition state. 

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