Acceptorless Dehydrogenation and Related Transformations |ChemFam #...

Greetings to everyone! In this post, I would like to talk about one of the emerging topics in chemical science that I am myself involved in studying and exploring. Although the exploration has not yet been completed nor it ever will, still I have made up my mind to write about this topic. Well in organic chemistry, the dehydrogenation reactions are quite a bit of major interests. These dehydrogenation reactions could be easily progressed by using a suitable base to abstract a proton, thereby facilitating the dehydrogenation process. But how about not using such type of bases? Here comes the significance of Acceptorless Dehydrogenations. Let’s not wait any further and dive into the topic.

Generally removal of hydrogen is a dehydrogenation reaction. Acceptorless dehydrogenation (AD) reactions can result not only in simple removal of hydrogen gas from various substances but also in surprisingly efficient and environmentally benign (green) synthetic methodologies when intermediates resulting from the initial dehydrogenation process undergo further reactions.

Simplified Dehydrogenation Strategies in Organic Synthesis

Here in (A), the catalyst liberates H₂ from both starting material and intermediate which can be exemplified by dehydrogenative coupling of primary alcohols with amines to form amides. This runs the successive acceptorless dehydrogenation with release of hydrogen gas.

In (B), it is seen a dehydrogenated intermediate couples with nucleophiles that can be exemplified by dehydrogenative coupling of alcohols with amines whereby liberating water to form imines that can be isolated or carried on to products such as pyrazines. This is interestingly releases water as well as hydrogen gas.

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In (C) the catalyst dehydrogenates the substrate and formally transfers the H atoms to an unsaturated intermediate which is exemplified by coupling of ammonia or amines with alcohols to form new amines liberating water but not H₂. This is some kind of borrowing of H₂.

In (D) dehydrogenation generates an electrophile and a nucleophile that reacts to form C-C bonds. Here, neither H₂ nor water is liberated. This is basically involves coupling of redox pairs.

General Process Overview

Conventional oxidations of organic compounds formally transfer hydrogen atoms from the substrate to an acceptor molecule such as oxygen, a metal oxide or a sacrificial olefin. In acceptorless dehydrogenation reactions, catalytic cleavage of C-H, N-H and/or O-H bonds liberates hydrogen gas with no need for a stoichiometric oxidant, thereby providing efficient activation of substrates. The hydrogen gas is itself valuable as a high energy, clean fuel source.

Acceptorless dehydrogenation reactions in which hydrogen is liberated and new bonds prospectively generated by further reactions of the dehydrogenated products are emerging as a powerful approach circumventing the need for stoichiometric oxidants or prefunctionalization of substrates.

Removal of hydrogen atoms from adjacent atomic centers of a hydrogen rich organic molecule is in most cases a thermodynamically unfavourable process. Thus, dehydrogenation of organic compounds often requires stoichiometric or excess molar amounts of oxidants such as oxygen, peroxides, iodates and metal oxides or sacrificial hydrogen acceptors leading to wasteful by-product generation. In the more atom-economical AD reaction, molecular hydrogen must be effectively removed from the reaction mixture to drive the equilibrium toward the products. Alternatively the liberated hydrogen can also be used in situ to hydrogenate unsaturated intermediates generated from a condensation reaction.

There has been development of a class of AD reactions in which the catalyst dehydrogenates both the starting compound and an intermediate compound, leading to the net-oxidized product with liberation of two equivalents of hydrogen.^A*

Reactions have also been developed in which both liberation of water take place.^B*

In a related class of reactions termed the ‘’borrowing hydrogen’’ approach, the catalyst hydrogenates an intermediate using the hydrogen removed from the starting compound. This method is also called ‘’hydrogen autotransfer’’. It does not involve net hydrogen evolution and the overall process is redox neutral.^C*

Dehydrogenation reaction can also couple a redox pair such as an alcohol C-H functionalization; upon alcohol dehydrogenation i.e., in presence of catalytic base, the generated metal hydride intermediate adds to the alkene to give a nucleophilic metal alkyl, followed by reaction of the latter with the intermediate keto compound to form a C-C bond.^D*

Precursors to Modern AD

In organic synthesis, the oxidation/dehydrogenation is carried out using conventional methods which use stoichiometric amounts or excess of inorganic oxidants such as chromium(IV) reagents, pressurised oxygen or peroxides. In addition to employing various additives, cocatalysts and catalytic systems combined with metal complexes and TEMPO (2,2,6,6-tetramethylpiperidinyl-1-oxy) results in stoichiometric waste generation which is undesirable environmentally and economically. Moreover, pressurised oxygen and peroxides pose explosion hazards. To circumvent these problems, dehydrogenation methods without use of conventional oxidants were developed.

Early investigations of AD emanated from heterogeneous catalysis. Dehydrogenation of linear primary alcohols resulted in β-branched primary alcohols as a result of condensation of the intermediate aldehydes followed by dehydration and hydrogenation. They were investigated much before the simple hydrogen transfer reactions were reported. The simple hydrogen transfer reactions has its origin in the Oppenauer oxidation of secondary alcohols to ketones in the presence of acetone, mediated by aluminim tert-butoxide and later catalysed by transition metal complexes.

Hydrogen transfer using alkanes as the hydrogen source is much more difficult due to generally unreactive C-H bonds. In 1979, Crabtree achieved stoichiometric dehydrogenation of alkanes using a cationic iridium(III)metal complex in the presence of a hydrogen acceptor.

Recent Advances in the AD

Pioneering examples of catalytic alkane hydrogen-transfer reactions by soluble complexes were independently reported by Felkin and colleagues and Crabtree and colleagues.

The acceptorles dehydrogenations reactions are being broadly studied and new emerging research projects have also contributing to the previously reported database. Some notable advances in the said subject has been reported in alkane dehydrogenation, alcohol dehydrogenation, dehydrogenative coupling of alcohols to form esters, dehydrogenative coupling of alcohols with amines to form amides.

Very recently, primary alcohols were oxidised by a scholar groups to the corresponding carboxylic acid salts using water as the terminal oxidant with liberation of hydrogen. The precatalyst was used for the in situ generation of catalyst which catalyses this transformation under acceptorless conditions. Interestingly water plays the role of both oxygen donor and reaction medium.

Outlook

AD is a rapidly growing area, propelled by the profound influence of fundamental organometallic chemistry, in part based on metal-ligand cooperation. This has led to reactions such as the dehydrogenative coupling of amines with alcohols to form amides, peptides and polyamides under neutral conditions with liberation of hydrogen gas and no waste generation.

The related dehydrogenation reactions that do not evolve hydrogen gas—namely the borrowing-hydrogen methodology and the coupling of redox pairs via intermediate generation of nucleophiles and electrophiles—allow construction of both C−N and C−C bonds from alcohols and provide efficient, atom-economical access to an assortment of
useful products.

As AD is increasingly applied in transformations of complex and bio-renewable molecules, it is not a matter of fact that many additional useful applications are bound to unfold. With that said, I am wrapping up my blog and will see you again with another chemophilic post.

B I B L I O G R A P H Y

AD & tranformations by C. Gunanathan and D. Milstein

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