Deuterium substituents

No o-isomer is ever obtained, and (94) and (95) are found not to be interconvertible under the conditions of the reaction. This, coupled with the fact that eNH2 is known to be able to remove protons (deuterons) from a benzene ring [it removes proton (deuteron) 106 times faster from fluorobenzene with an o-deuterium substituent than from deuteriobenzene itself],... 

The discussion thus far has emphasized sensitivity of the frequency of C02 s v3 mode to local stress, sensitivity of its absorption intensity to IR polarization, and sensitivity of both properties to resonant coupling of dimers. For the type of crystals under consideration, which consist mostly of simple hydrocarbon groups, these factors probably dominate in determining the IR spectral characteristics. Other factors can be involved, however, and although they can make simple interpretation of the spectra more problematic, they can also provide additional information about the environment of the C02 probe molecule. The following examples illustrate how one can track the motion of C02 over distances of 1-15 A by observing its proximity to free radical centers or to halogen or deuterium substituents in the crystal lattice. This information complements the previously discussed structural studies, which related to structure within the dimer rather than to the location of the C02 in the crystal matrix. 

Under suitable conditions, even dideuterated derivatives can be used for kinetic studies as long as the deuterium substituents do not occupy adjacent sites. Ericsson et al. (6) showed that estimating the reactivities of positions 4 and 6 in general is feasible from a single kinetic run on 4, 6-dideuteroguaiacol (G4,6). The dedeuteration process proceeds as follows ... 

To determine the stereoselectivity of diastereotopic proton abstraction from the Pro-R methylene group of ACPC (9) in the fragmentation (occurring between Pro-S p-C and a-C), 2-ethyl-[3-Di]-ACPC (8a) was prepared with the ethyl side chain and deuterium substituent in cis relationship. Incubation of this compound followed by in situ reductive enzymatic trapping with (25)-lactate dehydrogenase yielded 2-hydroxy-[3-D]-hexanoate where the R,5-placement of D was analyzed by NMR and the D-content by mass spectrometry. These results had defined the stereoselectivity for )5-H-abstraction from the Pro-R methylene of 2-ethyl-ACPC (8) as the proton removal in the overall fragmentation process and by analogy the same in ACPC (9). These results place stereochemical constraints on the ACPC deaminase process and were accommodated in Scheme 10. 

A special type of substituent effect which has proved veiy valuable in the study of reaction mechanisms is the replacement of an atom by one of its isotopes. Isotopic substitution most often involves replacing protium by deuterium (or tritium) but is applicable to nuclei other than hydrogen. The quantitative differences are largest, however, for hydrogen, because its isotopes have the largest relative mass differences. Isotopic substitution usually has no effect on the qualitative chemical reactivity of the substrate, but often has an easily measured effect on the rate at which reaction occurs. Let us consider how this modification of the rate arises. Initially, the discussion will concern primary kinetic isotope effects, those in which a bond to the isotopically substituted atom is broken in the rate-determining step. We will use C—H bonds as the specific topic of discussion, but the same concepts apply for other elements. 

The efficiency of reduction of benzophenone derivatives is greatly diminished when an ortho alkyl substituent is present because a new photoreaction, intramolecular hydrogen-atom abstraction, then becomes the dominant process. The abstraction takes place from the benzylic position on the adjacent alkyl chain, giving an unstable enol that can revert to the original benzophenone without photoreduction. This process is known as photoenolization Photoenolization can be detected, even though no net transformation of the reactant occurs, by photolysis in deuterated hydroxylic solvents. The proton of the enolic hydroxyl is rapidly exchanged with solvent, so deuterium is introduced at the benzylic position. Deuterium is also introduced if the enol is protonated at the benzylic carbon by solvent ... 

The di-7r-methane rearrangement has been studied in a sufficient number of cases to develop some of the patterns regarding substituent effects. When the central sf carbon is unsubstituted, the di-7i-methane mechanism becomes less favorable. The case of 1,1,5,5-tetraphenyl-l,4-pentadiene is illustrative. Although one of the products has the expected structure for a product of the di-7t-methane rearrangement, labeling with deuterium proves that an alternative mechanism operates ... 

Even isotopes qualify as different substituents at a chirality center. The stereochemistry of biological oxidation of a derivative of ethane that is chrial because of deuterium (D = H) and tritium (T = H) atoms at carbon, has been studied and shown to... 

Aliphatic sulfonyl chlorides that have a-hydrogen substituents, react with simple tertiary amines, such as trimethylamine, to generate sulfenes or perhaps their amine adducts 446). These species are suggested by the incorporation of one (but not more) deuterium atoms on reaction of sulfonyl chlorides with deuterated alcohols and triethylamine (447-450). A 2 1 adduct of sulfene and trimethylamine with proposed sulfonyl-sulfene structure could be isolated (451). 

Charton has recently examined substituent effects in the ortho position in benzene derivatives and in the a-position in pyridines, quinolines, and isoquinolines. He concludes that, in benzene derivatives, the effects in the ortho position are proportional to the effects in the para position op). However, he finds that effects of a-sub-stituents on reactions involving the sp lone pair of the nitrogen atoms in pyridine, quinoline, and isoquinoline are approximately proportional to CT -values, or possibly to inductive effects (Taft s a ). He also notes that the effects of substituents on proton-deuterium exchange in the ortho position of substituted benzenes are comparable to the effects of the same substituents in the a-position of the heterocycles. 

The Diels-Alder reaction of a diene with a substituted olefinic dienophile, e.g. 2, 4, 8, or 12, can go through two geometrically different transition states. With a diene that bears a substituent as a stereochemical marker (any substituent other than hydrogen deuterium will suffice ) at C-1 (e.g. 11a) or substituents at C-1 and C-4 (e.g. 5, 6, 7), the two different transition states lead to diastereomeric products, which differ in the relative configuration at the stereogenic centers connected by the newly formed cr-bonds. The respective transition state as well as the resulting product is termed with the prefix endo or exo. For example, when cyclopentadiene 5 is treated with acrylic acid 15, the cw fo-product 16 and the exo-product 17 can be formed. Formation of the cw fo-product 16 is kinetically favored by secondary orbital interactions (endo rule or Alder rule) Under kinetically controlled conditions it is the major product, and the thermodynamically more stable cxo-product 17 is formed in minor amounts only. 

Problem 10.10 How might you replace a halogen substituent by a deuterium atom if you wanted to prepare a deuterated compound ... 

We wanted to know whether it was possible to effect the exchange of protons not only with deuterium but also with alkyl groups provided by alkyl halides. In other terms, we wished to extend the various functionalizations performed on a single methyl substituent to the six methyl groups of [FeCp(C6Me6)] +. ... 

The log rate versus acid strength curve for the latter compound is of the exact form expected for reactions of the free base, whilst that of the former compound is intermediate between this form and that obtained for the nitration of aniline and phenyltrimethylammonium ion, i.e. compounds which react as positive species. That these compounds react mainly or entirely via the free base is also indicated by the comparison of the rate coefficients in Table 8 with those in Table 5, from which it can be seen that the nitro substituent here only deactivates weakly, whilst the chloro substitutent appears to activate. In addition, both compounds show a solvent isotope effect (Table 9), the rate coefficients being lower for the deuterium-containing media, as expected since the free base concentration will be lower in these. 

---