Deuterium labelling reactions

A further piece of evidence to elucidate the catalytic pathway of silylformylation was provided by a pair of deuterium-labeled reactions. The results revealed that the scrambling of hydrogen atoms between a hydrosilane and a terminal acetylene is minimal during the reaction and that the hydrogen atom of the formyl group and the vinylic hydrogen are derived from the hydrosilane and the acetylenic proton, respectively (Eq. 8) [15 bj. 

C-C bond cleavage reactions of titanacyclopentanes and titanacyclohexane were independently studied by Grubbs [10] and Whitesides [11]. In the case of titanacyclopentane, ethylene was eliminated via a titanocene-bis(ethylene) complex as shown in Eq. 8. According to the deuterium labeling reaction, the real mechanism is more complicated, since scrambling of D was observed (Eq.9)[10]. 

Radiolabeled folate provides a powerful tool for folate bioavaHabiUty studies in animals and for diagnostic procedures in humans. Deuteration at the 3- and 5-positions of the central benzene ring of foHc acid (31) was accompHshed by catalytic debromination (47,48) or acid-cataly2ed exchange reaction (49). Alternatively, deuterium-labeled fohc acid (32) was prepared by condensing pteroic acid with commercially available labeled glutamic acid (50). 

On heating at 225°C, 5-aUykyclohexa-l,3-diene, A, undergoes intramolecular cycloaddition to give the tricyclic nonene B. The mechanism of formation of B was probed using the deuterium-labeled sample of A which is shown. Indicate the position of deuterium labels in product B if the reaction proceeds by (a) a [2 - - 2] cycloaddition or (b) a [4 -t- 2] cycloaddition. 

Deuterioboration of 5a-cholest-2-ene (171), followed by oxidation of the alkylborane intermediate with hydrogen peroxide in the presence of sodium hydroxide, illustrates the application of this method for the preparation of c/5-deuterium labeled alcohols.(For the preparation of tra 5 -deuterium labeled alcohols see section VII-A.) The predominant reaction product is 2a-di-5a-cholestan-3a-ol (172, 1.03 D/mole) which is accompanied by 3a-di-5a-cholestan-2a-ol (173) and other minor products." ... 

Only one of these methods, namely the reaction of halides with lithium aluminum deuteride, is a true displacement reaction, following the same course as the previously discussed displacement of sulfonate esters (section Vl-A). Thus, lithium aluminum deuteride treatment of 7a- and 7jS-bromo-3 -benzoyloxy-5a-cholestanes (195) and (196) gives the corresponding deuterium labeled cholestanols (197) and (198) respectively." ... 

Treatment of oc-cyclopropyl ketones with lithium in a mixture of N,N-d2 propylamine and hexamethylphosphortriamide is a recently reported method for deuterium labeling via reductive ring opening. This reaction provides y-labeled ketones in good yield (70-100%) and isotopic purity (85-93%). 

Deuterium labeling of certain positions in the steroid nucleus can be a serious problem if suitably functionalized starting materials are not available or if a particular part of the molecule to be labeled is unsuitable for the various reactions described previously in this chapter. In these cases, the only practical solution to this problem is to incorporate the appropriately labeled carbon fragment by synthesis of the desired skeleton. 

As another example, studies with deuterium-labeled substrates have shown that the reaction of ethanol with the coenzyme NAD+ catalyzed by yeast alcohol dehydrogenase occurs with exclusive removal of the pro-R hydrogen from ethanol and with addition only to the Re face of NAD+. 

A similar reaction the with rran.v-isomer 3b gave c -3,5-dimethylcyclohexene (4) with very high diastereoselectivity. Accordingly, the stereochemistry of this substitution is anti. Deuterium labeling experiments using the 1-deuterio or 3-deuterio derivative of 3 a showed that the ratio of SN2 /SN2 with lithium dimethylcuprate was about 50 50, while the ratio with lithium cyano(methyl)cupratc was >96 4. 

Terminally deuterium-labeled phenylacetylene was also used to elucidate the possible mechanism of this reaction. In view of all these results, a rationalization for the loss of the trimethylsilyl and the migration of the ethoxy group from its original position in the complex 96 has been put forward. Due to the contribution of the conjugated diarylcyclopentadiene moiety in 98 and 99, these molecules showed intense fluorescence with a relatively high quantum yield of 46%. 

The reaction of aldehydes with Wilkinson s catalyst goes through complexes of the form 26 and 27, which have been trapped. The reaction has been shown to give retention of configuration at a chiral and deuterium labeling demonstrates that the reaction is intramolecular RCOD give RD. 

The obvious way to distinguish between this mechanism and the ordinary E2 mechanism is by the use of deuterium labeling. For example, if the reaction is carried out on a quaternary hydroxide deuterated on the P carbon (R2CDCH2NMe OH ), the fate of the deuterium indicates the mechanism. If the E2 mechanism is in operation, the trimethylamine produced would contain no deuterium (which would be found only in the water). But if the mechanism is Ei, the amine would contain deuterium. In the case of the highly hindered compound (Me3C)2CDCH2NMe OH , the deuterium did appear in the amine, demonstrating an Ei mechanism for this ca.se. With simpler compounds, the mechanism is E2, since here the amine was deuterium-free. 

A catalytic mechanism, which is supported by deuterium-labeling experiments in the corresponding Ru-catalyzed procedure [146], is shown in Scheme 47. Accordingly, the reactive Fe-hydride species is formed in situ by the reaction of the iron precatalyst with hydrosilane. Hydrosilylation of the carboxyl group affords the 0-silyl-A,0-acetal a, which is converted into the iminium intermediate b. Reduction of b by a second Fe-hydride species finally generates the corresponding amine and disiloxane. 

Scheme 10 Deuterium-labeling experiment providing evidence for a metallacyclic reaction mechanism [17]...

The experiments with deuterium-labeled nitrosamines illustrate two important points. One is that oxidation of nitrosamines takes place at more than one position in the molecule, and the outcome of the balance of such competing reactions probably is the determinant of carcinogenic potency. The second is that the reason for the failure of carcinogenesis to be mirrored in many cases by the microsomally activated bacterial mutagenicity is that there can be several metabolic steps leading to formation of the proximate carcinogenic agent and not all of these need necessarily involve microsomal enzymes. ... 

---