The frequent intervention of high spin and open-shell intermediates render mechanistic and kinetic investigations into iron catalysis tremendously difficult; the problems are potentiated by the oftentimes very limited stability of organo iron complexes in low or high oxidation states. It is safe to predict that this field will greatly benefit from a firm interface with bioinorganic chemistry with its long and successful holistic traditions.
To illustrate this aspect, reference is made to recent studies into the mechanism of iron-catalyzed cross coupling, which have been subject to considerable debate in the past. Mechanistic investigations, however, struggle with the characterization of pertinent organoiron intermediates which are exceptionally labile. At least for the case of MeMgX as the nucleophilic partner, however, a combined crystallographic, spectroscopic, and kinetic approach recently provided a consolidated picture. In contrast, Fe I complexes, which were prominently advocated elsewhere as causative agents, 95 , 96 basically proved incompetent.
While these results are deemed representative for the intricacies of mechanistic organoiron chemistry, the chosen integral approach to unravel the details is exemplary for future investigations into this unusually demanding field of research. However, the arsenal will have to adapt as renewable raw materials eventually become more important. Base metals are perhaps better apt to address the challenges posed by building blocks that are overfunctionalized primarily with O- and N-substituents, which living nature can deliver in quantity; iron catalysis at large will benefit from such a changing situation.
In a somewhat orthogonal sense, paradigm changes in the science of synthesis itself are also likely going to favor base metal catalysis on the longer run. Biosynthetic pathways for terpene synthesis, for instance, comprise distinct phases which largely separate the assembly and cyclization of the carbon backbone from its subsequent functionalization; to this end, nature has evolved oxidoreductases that allow functional groups to be stitched onto the rim of a given hydrocarbon skeleton with breathtaking regio- and stereoselectivity. Such practice was mandatory as long as no artificial catalysts able to mimic the function of oxidoreductases were available.
The past decade, however, has seen a number of designer catalysts that are able to effect C—H functionalizations with high precision at different sites of a hydrocarbon chain even in the absence of directing groups; many of them are iron-based and able to use commodity oxidants such as H 2 O 2. Overall, oxidation chemistry is arguably the single most important area to benefit from a stronger commitment to iron catalysis; the prominence of iron-dependent oxidizing enzymes in nature cannot be misleading and a now rapidly growing number of success stories using small-molecule designer catalysts augurs well for the future development of this particular field.
The directed functionalization of aromatic and heteroaromatic C—H groups is arguably no less relevant than the aliphatic C—H hydroxylation referred to above. Although aromatic C—H activation is currently reigned by metals such as Rh, Ir, Ru, and Pd, the number of promising examples using iron or its immediate neighbor elements is rising, even when it comes to C—C bond formation.
The propensity to engage in odd-numbered redox steps, which need to be suppressed when trying to confer nobility on iron, is the decisive asset in the catalytic C—H functionalization referred to above. It is, perhaps, a misconception or a lack of experience of the community at large that one-electron regimes are often considered less predictable and therefore a less desirable entry point for synthesis and catalysis research.
One could even argue that the opposite is true: since they usually lack precedence in the noble metal catalysis arena, iron-triggered radical processes may well serve as gateways to find and establish reactivity pattern that are elusive otherwise.
This notion finds correspondence in a growing body of work on iron-catalyzed cross coupling reactions of arylmagnesium halides with alkyl halides and, more recently, redox-active esters. The radical character surfaces in cascades in which a prototype radical 5- exo -cyclization precedes the actual coupling step. The same is true for nonradical processes, where iron cross coupling also becomes particularly valuable wherever it opens possibilities beyond the canon of palladium chemistry.
Such complementarity also speaks for the use of in situ generated iron hydrides as mediators of radical processes, notably for unorthodox functionalizations of alkenes. The carbon radicals primarily formed on reaction of an intermediate [Fe—H] species with an alkene partner can be engaged in reductive as well as oxidative follow-up chemistry that provides many opportunities for functionalization of sites that are usually difficult to address.
The promise of solving previously unmet selectivity issues opens new vistas for retrosynthesis beyond the conventional logic. The selected examples shown in Scheme 12 are representative. In the context of radical chemistry, brief reference has also to be made to the long-known ability of the earth abundant first row transition metals to effect auto-oxidation reactions by formation of high-energy oxygen radical intermediates.
A growing number of examples, however, suggest that even this assessment needs to be revisited, since iron-catalyzed Fenton-type reactions were tamed and used to form various C—C and C—X bonds by dehydrogenative coupling with appreciable selectivity and yield. These and many other examples suggest that the somehow pertinacious view that high-spin iron complexes favor unselective organic transformations is improper at best. Even less appreciated is the possibility that high spin iron complexes may actually provide distinct advantages and could be used as enabling vehicles in catalysis.
One possibility of benefiting from a high spin state might consist in the use of singly occupied orbitals to facilitate product dissociation.
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A priori, a single electron in the proper orbital suffices to foster decomplexation of a ligated product, which, in turn, will accelerate catalyst turnover, if this step is kinetically relevant. A perhaps more genuine use of high spin states relates to the stabilization of reactive intermediates that would be fleeting otherwise. A high spin iron complex with five or more d-electrons has no such empty orbital and therefore gains stability against this decomposition pathway Scheme It needs to be restated at this point, however, that orbital energy splitting and hence spin state is potentially geometry-dependent Scheme 1.
Whereas organometallic iron catalysis is still surprisingly short in examples that make deliberate use of such two-state reactivity, this concept is very well-established elsewhere. This makes it all the more remarkable that even Fe VI complexes have been firmly characterized, although their catalytic reactivity awaits detailed study. As mentioned above, the recent literature suggests that iron catalysis is potentially capable of covering almost the entire range of organic synthesis.
At the same time, however, it is fair to say that the current status does not necessarily live up to all the possibilities that this element provides; rather, competing methodologies—many of which rely on the use of noble metals—continue to define the state of the art in numerous areas. This gap between the tremendous scope and utilitarian advantages of iron catalysis on the one hand and the status quo on the other hand reflects the many challenges posed by the chemistry of this base metal. The growing awareness of the essential factors that need to be taken into consideration in concert with a steadily refined analytical, spectroscopic, and computational toolbox, however, will entail a rapid transition from mostly empirical knowledge to conceptually and mechanistically well-founded research.
In view of its many inherent advantages—not least the promise of a responsible paradigm for chemical synthesis—it is safe to state that research into homogeneous iron catalysis is only at the dawn of its development; intellectual incentives and utilitarian recompense are both ahead to reward the brave.
Enzyme Catalysis in Organic Synthesis: A Comprehensive Handbook 2nd
I sincerely thank all co-workers involved in our iron catalysis project for their excellent experimental work and intellectual contributions. National Center for Biotechnology Information , U. ACS Cent Sci. Published online Oct Author information Article notes Copyright and License information Disclaimer.
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Short abstract Homogeneous iron catalysis is currently a sparkling research area that has all it takes to become a beacon in the near future. Introduction Heterogeneous iron catalysis has arguably changed the world. Scheme 1. Scheme 2. Scheme 3. Scheme 4.
Scheme 5. Scheme 6. Scheme 7. Scheme 8. The Analytical Frontier The frequent intervention of high spin and open-shell intermediates render mechanistic and kinetic investigations into iron catalysis tremendously difficult; the problems are potentiated by the oftentimes very limited stability of organo iron complexes in low or high oxidation states. Scheme 9. Radical Approaches and Tasks beyond Reach of the Noble Cousins The propensity to engage in odd-numbered redox steps, which need to be suppressed when trying to confer nobility on iron, is the decisive asset in the catalytic C—H functionalization referred to above.
Scheme The Role of Spin State and Spin Change These and many other examples suggest that the somehow pertinacious view that high-spin iron complexes favor unselective organic transformations is improper at best. Acknowledgments I sincerely thank all co-workers involved in our iron catalysis project for their excellent experimental work and intellectual contributions. Notes The author declares no competing financial interest.
References Ertl G. Handbook of Heterogeneous Catalysis , 2nd ed. Iron Catalysis in Organic Synthesis. Iron-catalyzed Reactions in Organic Synthesis. Iron Catalysis. Fundamentals and Applications ; Springer: Heidelberg, ; Top. Catalysis without Precious Metals.
Wiley-VCH: Weinheim, Which Metals are Green for Catalysis?