Heterogeneous Metal-Catalyzed Exchange

By contrast with the radiation-induced procedures, isotope exchange reactions catalyzed by Group VIII transition metals are applicable to both deuterium and tritium labeling of heterocyclic compounds. Because of recent mechanistic developments in this field, it is possible to predict with some degree of certainty the reactivity of a molecule for deuteration and also for moderate levels of tritiation. If compensation for additional radiation-induced interactions is made, then the theory also satisfactorily explains high specific activity tritiations. 

Two types of metal-catalyzed procedures are now available for these reactions. Extensive studies have been made with heterogeneous systems which utilize a wide range of Group VIII transition metals. Recently, homogeneous metal-catalyzed systems have also been discovered.58 In this section, heterogeneous metal-catalyzed exchange only will be discussed and current homogeneous developments will be treated in the final section of this chapter. 

Heterogeneous metal catalysis is the most useful general method for the deuteration and/or tritiation of heterocyclic compounds.57 It involves exchange between the organic substrate and isotopic hydrogen (as water, usually, or gas) in the presence of a Group VIII transition metal catalyst at temperatures up to 180° [Eq. (18)]. 

The most efficient catalysts for these exchange reactions, particularly with isotopic water, are the oxides and chlorides of the metals previously mentioned. For simplicity, unsupported catalysts are 

Garnett, Proc. 2ndlnt. Conf. Methods Preparing Storing Label. Compounds, 1966, 709 (1968). 

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Compound classes labeled by heterogeneous metal-catalyzed tritium exchange from water include amino acids, peptides and proteins, sugars, polycyclic aromatic hydrocarbons, purines, pyrimidines and nucleosides, alkyl-substituted aromatics, alicyclic compounds and steroids, A-heterocycles and anilines and some O- and 5-heterocycles. The method is firmly fixed in the repertoire of methods of the commercial custom labeling industry. 

Scheme 3.20 Process flow scheme for the combined continuous flow reactors for transition-metal-catalyzed heterogeneous hydrogenation and ion-exchange-polymer-catalyzed epimerization and the subsequent batch biotransformations.

There are numerous reports and review articles on the use of tritiated water in acid, base and heterogeneous or homogeneous metal catalyzed tritium-hydrogen exchange reactions and their importance for the preparation of labeled physiologically active compounds in support of drug research and early development . Modern synthetic methods such as... 

It is well known that Rh(I) complexes can catalyze the carbonylation of methanol. A heterogenized catalyst was prepared by ion exchange of zeolite X or Y with Rh cations.126 The same catalytic cycle takes place in zeolites and in solution because the activation energy is nearly the same. The specific activity in zeolites, however, is less by an order of magnitude, suggesting that the Rh sites in the zeolite are not uniformly accessible. The oxidation of camphene was performed over zeolites exchanged with different metals (Mn, Co, Cu, Ni, and Zn).127 Cu-loaded zeolites have attracted considerable attention because of their unique properties applied in catalytic redox reactions.128-130 Four different Cu sites with defined coordinations have been found.131 It was found that the zeolitic media affects strongly the catalytic activity of the Cd2+ ion sites in Cd zeolites used to catalyze the hydration of acetylene.132... 

Diels-Alder reactions are thermal reactions requiring no catalysts (120). However, over the years both acid- and metal-based homogeneous or heterogeneous catalysts have been developed (121—127). Some catalysts used in Diels-Alder catalyzed reactions of butadiene are Fe(NO)2Cl—(CH3CH2)2A1C1, Pd[P(C H5)3]4, Cu(I) exchanged silica—alumina (128,129), large pore zeolites (130), and carbon molecular sieves. An electrochemical process has also been used to catalyze the self-condensation to vinylcyclohexene (131). When the asymmetric Ni catalyst (4) was used, specificity to the enantomeric (5)-4-vinylcyclohexene (132,133) was observed (26% enantiomeric excess). 

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