EXPLOITING SYNTHETIC AND STRUCTURAL SYNERGISM IN ALKALI-METAL-MEDIATED ORGANOTRANSITIONMETALLATION (AMMO)

The metallation reaction, where hydrogen is exchanged for a metal, is one of the most fundamental and important chemical transformations, being practised everyday in academic and industrial laboratories across the world. It is particularly useful in the manufacture of fine chemicals, pharmaceuticals, and polymers. Usually the metal employed in these reactions is lithium because of its high polarity and high reactivity. To attach a transition metal to carbon (aromatic) frameworks one would normally have to prepare the lithium derivative beforehand, then carry out a metal exchange reaction using a transition metal salt. This is necessary because transition metals are not generally reactive enough to be directly attached to an aromatic framework. However, there are limits to the usefulness of such exchange reactions due to solubility problems of the ionic salt in covalent organic solvents and to temperature sensitivities. This project will revolutionise this area as it will enable the development of the new concept of alkali-metal-mediated organotransitionmetallation (AMMO). Designing reagents containing an alkali metal and a transition metal within the same molecule, can lead to unique compounds that exhibit special synergic (mixed-metal) reactivities which cannot be replicated by alkali metal compounds or by transition metal compounds on their own (i.e. the single metal systems). Consequently using these two-metal based reagents, it is now possible to directly attach transition metal centres to aromatic frameworks. We have built prototype reagents based on lithium-manganese and sodium-manganese systems which can directly attach manganese to the carbon framework of the metallocene ferrocene, thus proving the concept. The innovative programme proposed will develop the synergic alkali metal chemistry of manganese with a range of other aromatic organic compounds and pioneer the same for other important transition metals including chromium, iron, cobalt and nickel. Incorporating transition metals with access to a large portfolio of properties (for example in redox chemistry, magnetochemistry and catalysis) within aromatic frameworks, will open up a treasure chest of new chemical opportunities outside the scope of conventional lithium-based aromatic compounds. The first transition metal host inverse crown macrocycles (special cyclic compounds with cationic host rings and anionic guest cores) will be prepared using AMMO. It is envisaged that, depending on the transition metal, some inverse crowns will exhibit interesting magnetic and material properties radically different to those of known inverse crowns which are based on magnesium and are therefore non-magnetic and non-redox active.

This project was designed to develop new reactions in chemistry that operate by two distinct metals working together synergistically. It is relevant to the synthesis of aromatic compounds of academic and industrial interest in areas such as fine chemical, agrochemical and pharmaceutical manufacture.

This highly productive project produced many high impact papers including several communications in Angewandte Chemie, Chemical Science and the Journal of the American Chemical Society. The theme running through the work was new synergistic chemistry created by having two distinct metals in bimetallic systems. Diffusion ordered spectroscopy (DOSY) was introduced for the first time in this area to establish that reagents considered to be lithium amidozincate species were in fact separate mixtures of lithium amides and zinc amides, in which the reaction synergies were executed in a stepwise manner, with deprotonation of an aromatic substrate by the lithium amide and then insertion into the new lithium-carbon bond by the transition metal species. This revised earlier thinking that such deprotonations occurred through a synchronized synergy in which both metals functioned simultaneously. This new concept of stepwise synergy was also found to be operative in lithium amidocadmate analogues. These findings helped to take this chemistry out of its black box and thus enable it to be tailored beyond trial and error.

Subjecting the biologically important heterocyclic compound thiophene to a sodium alkyl-amidozincate reagent remarkably produced a new type of cage compound that contained a novel [16]crown-4 zincocyclic core. This finding illustrated how an unwanted complication to a synthetic chemist, dimetallation of the substrate where only monometallation was wanted, can turn out to be an unearthed treasure to a supramolecular chemist. Interestingly, if the common practice of using metallated intermediates in situ in tandem bond-forming applications was used here, then this new concept in transition metal ring chemistry would have been missed. The ring system was elucidated by growing crystals of an active metallo intermediate from the reaction solution. Characterisation was carried out by a combination of X-ray crystallography and NMR spectroscopic studies.

Switching from zinc to aluminium also produced unprecedented breakthroughs. The most surprising was that the strong amide base, 2,2,6,6-tetramethylpiperidide, TMP, could be transformed into a strong acid by the synergic reactivity of a potassium-aluminate partnership. The acidity, which was a consequence of intramolecular steric effects within a K-C-Al-N template ring system, was manifested in deprotonation of a methyl sidearm that converted the TMP anion to a dianion. A lithium aluminium protocol was also found to be useful for deprotonating highly sensitive ethers and thioethers, such as tetrahydrofuran and its sulfur tetrahydrothiphene, and sedating the emerging cyclic anions. With conventional non-synergic organometallic bases, such sensitive anions decompose rapidly through ring-opening mechanisms.

Main group multiple C-H/N-H bond activation was achieved in a diamine by the synergistic combination of an alkali metal with zinc. Such activations, which included a dehydrogenation, are normally the domain of redox active transition metals, whereas here they were accomplished via a fixed oxidation state bimetallic pairing. Both experimental and DFT evidence were gathered to elucidate the mechanism involved in this novel diamine to diazaethene transformation.

Finally, relevant to catalysis, using N-heterocyclic carbene (NHC) ligands it was found possible to convert sterically bulky dialkylmagnesium and dialkylmanganese polymers to rare monomeric modifications.