A co-operative bimetallic approach for the transformation of lithiation

Project: Research

Description

"Lithiation is one of best tools for building molecules big and small. Its application transcends chemistry and crosses over to other disciplines such as biochemistry and materials science. It offers an efficient direct way of breaking inert C-H bonds (ubiquitous in organic compounds) and transforming them into reactive C-Li bonds which in turn can be used to make a myriad of molecules, that mankind needs to sustain the quality of our daily lives. Organolithium tools find employment in academic laboratories worldwide and in the manufacture of many fine chemicals, in particular pharmaceuticals (it has been estimated that 95% of manufactured pharmaceuticals involve an organolithium tool in their preparation). The best known organolithium tool, butyllithium is near ubiquitous in synthetic chemistry, and its importance continues to escalate as evidenced by the fact that the chemical company FMC recently opened new butyllithium plants in Hyderabad (India) and Zhangjiagang (China) to service the rapidly expanding pharmaceutical business in the emerging BRIC (Brazil-Russia-India-China) economies. Because butyllithium can break numerous carbon-hydrogen bonds as well as performing other bond-breaking, bond-making tasks, it is widely used in drug development. Organolithium tools are also used to prepare other specialty chemicals such as agrochemicals, biochemicals, catalysts, dyes and perfumes.

How to perfect C-H bond activation is one of the World's most pressing scientific grand challenges as new innovative ways must be found for converting cheap and abundant raw materials such as alkanes into precious functionalised organic compounds given the rapid depleting of fossil fuels. Despite its vast utility, lithiation, a direct form of C-H bond activation, suffers from severe limitations. A major limitation which puts a question mark against its long term sustainability is that it is exclusively a stoichiometric process. For example one mole of the organolithium tool is needed to make one mole of the target product. Moreover, lithiation often requires energy wasteful cryogenic conditions as well as ethereal solvents which are expensive and hazardous on a large scale. It also has many intrinsic chemical limitations including a poor tolerance of functional groups, a failure to react with weakly acidic C-H bonds, and incompatibility with subsequent transition metal catalysed bond-forming reactions.

To transform lithiation into a substoichiometric process, ultimately developing it to a catalytic process is the ambitious goal of this project. For example, to use as little as 0.1 mole or less of the organolithium tool to make one mole of the target product. To reach this goal, the project will develop a new concept in bimetallic chemistry, synergistic stepwise metal - metal' co-operativity (basically two metals working one after the other in separate molecules) building on the successful, but wholly distinct foundation of synergic synchronised metal - metal' co-operativity (basically two metals working side-by-side in the same molecule) that the PI has recently pioneered. Initially a lithium-zinc co-operativity will be screened. Developing catalytic lithiation will be groundbreaking with direct chemical and economic benefits as well as indirect societal benefits given the long list of applications mentioned above. A library of interesting, useful new chemistry not currently possible in lithiation will emerge on the journey to achieving catalytic lithiation, including improved methods for direct C-H bond activation, new combined lithiation - Negishi coupling and other combined lithiation - transition metal bond forming strategies, reactions with high functional group tolerance, and "greener" processes using more environmentally friendly solvents and milder reaction conditions. Bonds impossible to break with existing organolithium tools will also be broken using new potassium based tools."

Key findings

The challenge behind this project was to upgrade lithiation (Li-H exchange reactions) and metallation (metal-hydrogen exchange reactions) in general. Though metallation has served the synthetic community for several decades as a key vehicle towards the synthesis and manufacture of agrochemicals, biosynthetic chemicals, functional materials, pharmaceuticals and many other commodity fine chemicals, it is severely limited by low functional group tolerance, the instability of metallated intermediates, the need for subambient temperatures and the lack of any catalytic regime. The last challenge represents the grandest of them all.

Towards finding a catalytic regime we developed a cycle in which a lithium amide (e.g., lithium 2,2,6,6-tetramethylpiperidide, LiTMP) would deprotonate an organic substrate, for example a substituted aromatic compound, then intercept this with a zinc amide or aluminum amide of the same amide anion (e.g., TMP) so that a new, more stable, C-Zn or C-Al bond would form and at the same time regenerate the original lithium amide to close the cycle. Though the initial lithiations were successful, and the subsequent transmetallation produced the target Zn-C or Al-C bonds, the interception reaction produced bimetallic (e.g., Li-Zn or Li-Al) ates that stopped the recycling of the lithium reagent. We traced this stoppage to the coordinatively saturated nature of the ate, that is, they would not eliminate LiTMP.

Subsequently, we exploited this seemingly problematic ate coordinative saturation in an exciting new concept of “trans-metal-trapping”. Thus, carrying out lithiations of challenging weakly acidic substrates such as anisoles via LiTMP that produced poor yields of the desired lithiated products but introducing an aluminium trapping agent, for example a bisalkyl-amide, we not only stabilised sensitive metallated intermediates but remarkably could shift reaction equilibria such that desired products could be obtained in quantitative yield. Published in the high impact journal Chemical Science (2014, 5, 3031), this breakthrough suggests that refinement of trans-metal-trapping could potentially transform any failed lithiation reaction into a successful lithiation reaction, thus achieving one of the main goals of the project. We demonstrated this in our next study. Conventional lithiation of benzotriazole, an important heterocycle in numerous material and biochemical applications, via monometallic LiTMP produced an unclean reaction in which ring opening and N2 extrusion of the heterocycle took place. However, attempting the same reaction with the bimetallic trans-metal-trapping approach led to much cleaner reactions and high yields of the desired aluminated benzotriazoles.

Another part of the project established that donor-activated alkali metal dipyridylamides could activate zinc alkyl reagents towards alkylation of aromatic ketones. In the best cases, the nucleophilic addition occurred at the para position of the aromatic ring, in a highly unusual regioselective process. On their own, the zinc alkyls are inert, thus showing that a bimetallic synergic reactivity is operating in these reactions. The fact that the alkali metal component of the synergic partnership could function under substoichiometric conditions, suggests that it should be possible with further work to make these reactions catalytic.

Overall the project has contributed significantly to the development of synergistic reactivity in polar organometallic chemistry.




StatusFinished
Effective start/end date1/03/1329/02/16

Funding

  • EPSRC (Engineering and Physical Sciences Research Council): £313,249.00

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Metals
Amides
Lithium
Zinc
Functional groups
Alkali Metals
Agrochemicals
Metal working
Molecules
Pharmaceutical Preparations
Chemical activation
Aluminum
Organic compounds
Anisoles
Transition metals
Thymidine Monophosphate
Fragrances
Biochemistry
Alkanes
Functional materials