Periodic Reporting for period 5 - ECO-ZEN (Enabling Catalytic Cross Couplings with only Zinc Electrophiles, Nucleophiles and Boranes)
Reporting period: 2023-10-01 to 2024-04-30
Catalysis is a key process enabling the formation of important value added products from simpler starting materials and is ubiquitous in chemical processes. Catalysis is estimated to contribute > 35 % of global GDP and recent estimates indicate that 90% of industrial chemicals are synthesized in processes that require at least one catalytic step. However, many catalysts are based on rare and expensive elements, collectively called the platinum group metals (PGMs), that have significant supply chain risks thus are classed as critically endangered raw materials by the EU. Furthermore, these elements also have significant toxicity concerns, which imposes considerable purification costs particularly in the production of pharmaceuticals. Therefore the replacement of catalysts containing PGMs with alternatives that are based only on highly abundant, inexpensive, low-toxicity elements is a crucial endeavour.
One vital catalytic process, called cross coupling, is essential across many industries as it forms carbon-carbon bonds. This Nobel prize winning chemistry is an essential tool for constructing the carbon backbone in organic-materials, pharmaceuticals and agrochemicals. The Suzuki-Miyaura (S-M) cross coupling reaction is the most prevalent cross-coupling method as it is reliable, modular and utilises low toxicity, easy to handle starting materials based on boron, termed organoboranes. S-M couplings are ubiquitous in both academia and industry, for example they are one of the top five most utilised reactions in pharmaceutical research laboratories. Despite its undeniable power there are drawbacks and limitations associated with the S-M reaction. For example, S-M couplings are currently dependent on toxic catalysts based on a rare PGM Pd, and to a lesser extent Ni (which is also highly toxic). Furthermore, while S-M couplings are very powerful for making flat (two dimensional) molecules it does not work effectively to form more three dimensional structures, which are essential as nature is three dimensional! This has led to an over-representation of flat molecules that are less “drug-like” in pharmaceutical research programs and thus there needs to be new modular methods to make C-C bonds in three dimensional structures. Therefore the important challenges addressed by this proposal are:
Overarching Objective 1: Generating S-M cross coupling process for forming C-C bonds in 3D molecules that uses low toxicity earth abundant catalysts based on zinc and boron. This objective was ultimately expanded to include the development of zinc catalysed C-H borylation processes and catalytic C-Zn bond formation.
Overarching Objective 2: Synthesising new and useful organoboranes using only simple precursors and without using PGM catalysts.
One vital catalytic process, called cross coupling, is essential across many industries as it forms carbon-carbon bonds. This Nobel prize winning chemistry is an essential tool for constructing the carbon backbone in organic-materials, pharmaceuticals and agrochemicals. The Suzuki-Miyaura (S-M) cross coupling reaction is the most prevalent cross-coupling method as it is reliable, modular and utilises low toxicity, easy to handle starting materials based on boron, termed organoboranes. S-M couplings are ubiquitous in both academia and industry, for example they are one of the top five most utilised reactions in pharmaceutical research laboratories. Despite its undeniable power there are drawbacks and limitations associated with the S-M reaction. For example, S-M couplings are currently dependent on toxic catalysts based on a rare PGM Pd, and to a lesser extent Ni (which is also highly toxic). Furthermore, while S-M couplings are very powerful for making flat (two dimensional) molecules it does not work effectively to form more three dimensional structures, which are essential as nature is three dimensional! This has led to an over-representation of flat molecules that are less “drug-like” in pharmaceutical research programs and thus there needs to be new modular methods to make C-C bonds in three dimensional structures. Therefore the important challenges addressed by this proposal are:
Overarching Objective 1: Generating S-M cross coupling process for forming C-C bonds in 3D molecules that uses low toxicity earth abundant catalysts based on zinc and boron. This objective was ultimately expanded to include the development of zinc catalysed C-H borylation processes and catalytic C-Zn bond formation.
Overarching Objective 2: Synthesising new and useful organoboranes using only simple precursors and without using PGM catalysts.
This grant has led to 27 peer review publications all in high-quality chemistry journals. This has also enabled significant follow-on funding to be raised to further pursue several of the breakthroughs.
The key highlights are given below based on the two overarching topics focused on in this ERC grant.
(i) Zinc catalysed C-E bond formation, (E = B or Zn).
Significant success has been made in this area using zinc complexes as catalysts for C-B and C-Zn bond formation. This has included synthesising and then using low coordinate zinc-hydrides as catalysts for alkyne C-H borylation and hydroboration. The paper covering this work was published in 2019 and now has > 100 citations. It also led to a follow on study using tandem Zn/B compounds as catalysts for converting alkynes to 1,1,1-triborylalkanes. Subsequently, the learning from these two initial studies on alkyne borylation enabled us to develop zinc catalysts that catalyse C-H borylation using pinacol borane and catecholborane. This led to two publications on this topic. In addition to these highly successful breakthroughs, a number of other results were found that have been published using zinc compounds for catalytic applications. The final work in this area developed the initial results on an unprecedented catalytic in base C-H zincation (C-H to C-Zn bond formation) process, this was taken forward and recently published. This offers a completely new catalytic approach to make C-Zn bonds direct from C-H precursors without using precious metal catalysts or stoichiometric strong bases. In total, 8 publications came from this topic.
(ii) Synthesising new and useful organoboranes using only simple precursors and without using precious metal catalysts.
This section became the dominant part of the work researched through this ERC grant. Therefore, we have sub-divided this into two topics which correspond to WP3 and WP4 of the proposal.
(a) Directed C-H functionalisation (WP3)
Through this WP we have developed a range of novel directed C-H borylation processes. This includes using ubiquitous carbonyl derivatives as directing groups, using simple anilines in directed borylation and more recently developing the concepts of borylation direct borylation and borylation reduction borylation. The latter two are complex cascade multi-borylations that lead to complex products in one pot processes. These breakthroughs were only possible through the knowledge generated in this grant and the multiple person team assembled to tackle this topic. Overall, this led to 12 publications. The first paper published on directed borylation in 2019 has now been cited > 90 times.
(b) Haloboration (WP4).
Haloboration is the addition of a boron unit and a halogen across an unsaturated hydrocarbon, and in contrast to hydroboration this transformation is very under explored. Through this grant we have dramatically advanced this area in multiple ways, including: understanding the mechanism/product distribution from combining alkynes with simple BX3 species (X = Cl or Br). This enabled us to rationally develop cascade process where haloboration is coupled to subsequent steps to form boron containing organic materials. We have also developed a fundamentally new way of using organoboranes, specifically as fluoride phase transfer agents. Finally, we have used haloboration as a new way to access BO-containing heterocycles which represent useful precursors for accessing beta-lactamase inhibitors, which are crucial to tackle the issue of antibiotic resistance. Overall, this WP resulted in 7 publications.
The key highlights are given below based on the two overarching topics focused on in this ERC grant.
(i) Zinc catalysed C-E bond formation, (E = B or Zn).
Significant success has been made in this area using zinc complexes as catalysts for C-B and C-Zn bond formation. This has included synthesising and then using low coordinate zinc-hydrides as catalysts for alkyne C-H borylation and hydroboration. The paper covering this work was published in 2019 and now has > 100 citations. It also led to a follow on study using tandem Zn/B compounds as catalysts for converting alkynes to 1,1,1-triborylalkanes. Subsequently, the learning from these two initial studies on alkyne borylation enabled us to develop zinc catalysts that catalyse C-H borylation using pinacol borane and catecholborane. This led to two publications on this topic. In addition to these highly successful breakthroughs, a number of other results were found that have been published using zinc compounds for catalytic applications. The final work in this area developed the initial results on an unprecedented catalytic in base C-H zincation (C-H to C-Zn bond formation) process, this was taken forward and recently published. This offers a completely new catalytic approach to make C-Zn bonds direct from C-H precursors without using precious metal catalysts or stoichiometric strong bases. In total, 8 publications came from this topic.
(ii) Synthesising new and useful organoboranes using only simple precursors and without using precious metal catalysts.
This section became the dominant part of the work researched through this ERC grant. Therefore, we have sub-divided this into two topics which correspond to WP3 and WP4 of the proposal.
(a) Directed C-H functionalisation (WP3)
Through this WP we have developed a range of novel directed C-H borylation processes. This includes using ubiquitous carbonyl derivatives as directing groups, using simple anilines in directed borylation and more recently developing the concepts of borylation direct borylation and borylation reduction borylation. The latter two are complex cascade multi-borylations that lead to complex products in one pot processes. These breakthroughs were only possible through the knowledge generated in this grant and the multiple person team assembled to tackle this topic. Overall, this led to 12 publications. The first paper published on directed borylation in 2019 has now been cited > 90 times.
(b) Haloboration (WP4).
Haloboration is the addition of a boron unit and a halogen across an unsaturated hydrocarbon, and in contrast to hydroboration this transformation is very under explored. Through this grant we have dramatically advanced this area in multiple ways, including: understanding the mechanism/product distribution from combining alkynes with simple BX3 species (X = Cl or Br). This enabled us to rationally develop cascade process where haloboration is coupled to subsequent steps to form boron containing organic materials. We have also developed a fundamentally new way of using organoboranes, specifically as fluoride phase transfer agents. Finally, we have used haloboration as a new way to access BO-containing heterocycles which represent useful precursors for accessing beta-lactamase inhibitors, which are crucial to tackle the issue of antibiotic resistance. Overall, this WP resulted in 7 publications.
The project is completed, so please see the box above for overview of the results.