Carbon Dioxide Activation & Utilisation

In collaboration with Dr. Gerard McGlacken in UCC.

Carbon dioxide utilisation continues to capture the attention of chemists due to the ever-increasing global levels of CO₂ gas and the negative effects of global warming. [1,2] The major cause of this is the burning of fossil fuels, deforestation, and our modern industrialised lifestyle. [3] However, CO₂ is a valuable and environmentally friendly C1 building block for the synthesis of various value-added chemicals. Many medicinally important compounds contain the elements of CO₂ within their structure, including α,β-unsaturated carboxylic acids and enoates. CO₂ has an inherently low reactivity and therefore must be activated before it can be converted into another product. [4] In this project, a novel strategy has been developed for utilisation of CO₂ as a chemical feedstock, enabling synthesis of valuable products that are not accessible through existing CO₂ utilisation methodologies. PhD and post-doctoral positions to work on development of both stoichiometric and catalytic variants of this methodology are presently available.

References

1. NASA website

2. IPCC, 2014: Climate Change 2014: Synthesis Report. Contribution of Working Groups I, II and III to the Fifth Assessment Report of the Intergovernmental Panel on Climate Change [Core Writing Team, R.K. Pachauri and L.A. Meyer (eds.)]. IPCC, Geneva, Switzerland, 151 pp.

3. Yu, B.; Diao, Z.-F.; Guo, C.-X.; He, L.-N. J. CO₂ Util. 2013, 1, 60.

4. Lang, X.-D.; He, X.; Li, Z.-M.; He, L.-N. Curr. Opin. Green Sustain. Chem. 2017, 7, 31.

Development of Environmentally Benign Replacements for Hazardous Standard Organic Reagents

Many of the reagents and solvents used in organic chemistry are harmful to the environment and may be toxic and/or carcinogenic. [5]  This project aims to develop methods for activating environmentally benign, stable organic chemicals (e.g. alcohols, aldehydes) to achieve the same outcomes as with standard hazardous reagents (alkyl halides and other alkylating agents, acyl halides). Strategies to achieve the ultimate goal of rendering these transformations catalytic are under development in our lab.

Development of Novel Means of Understanding Activation Barriers and Selectivities in Reactions of Ambident Nucleophiles

Reactions of ambident nucleophiles and electrophiles are extremely prevalent at all levels of organic synthesis. [6] However, the factors that control selectivity between the reactive sites of an ambident reactant (i.e. which of the sites undergoes a given reaction more favourably) evade simple classification. By far the most popular method for rationalising the selectivities in reactions of ambident reactants makes use of the principle of hard and soft acids and bases (the “HSAB principle”). [7] Although this rationale is pervasive in any discussion on ambident reactivity,[8] there exists a major problem with its application:  the HSAB principle has been shown to predict the wrong product in almost 50% of all known reactions of ambident nucleophiles! [9]

Therefore, the HSAB principle cannot be providing the true explanation for the observed selectivities in reactions of ambident nucleophiles in which the expected outcome (based on HSAB theory) does match the experimental outcome. [9] In order that this incorrect rationale ceases to be employed in research publications and taught in undergraduate chemistry courses, it is imperative that the true reasons underlying the selectivities observed in reactions of ambident reactants are uncovered. In this project, a novel means of rationalising the outcomes of reactions of ambident nucleophiles and electrophiles is under development. [10] This rationale will enable development of new insights on the nature of activation barriers for chemical reactions in general, and will facilitate the development of new linear free energy relationships.

References

5. Selected recent examples: (a) Biswas, A.; Neudörfl, J.-M.; Schlörer, N. E.; Berkessel, A. & co-workers; Angew. Chem. Int. Ed. 2021, 60, 4507; (b) McLaughlin, C.; Slawin, A. M. Z.; Smith, A. D. Angew. Chem. Int. Ed. 2019, 58, 15111.

6. e.g. Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd edition; Oxford University Press:  New York; 2012, p. 355–357.

7. Selected recent example: Maiti, S.; Mal, P. J. Org. Chem. 2018, 83, 1340.

8. Mayr, H.; Breugst, M.; Ofial, A. R. Angew. Chem. Int. Ed. 2011, 29, 6470.

9. The new rationale will develop upon the following:  Sheehy, K. J.; Bateman, L. M.; Flosbach, N. T.; Breugst, M.; Byrne, P. A. Chem. Sci. 2020, 11, 9630.

Catalytic Asymmetric Synthetic Methodology

The majority of pharmaceutical compounds are chiral (in particular new drug candidates), and are required by law to be administered as single enantiomers (i.e. enantiopure form).¹⁰ As a consequence, asymmetric synthetic methods that enable enantioselective synthesis of chiral compounds are of great importance.¹¹ This project is focused on the development of catalytic methodology for highly enantioselective production of existing pharmaceutical compounds and new drug candidates of high therapeutic potential.  Particular focus is placed on developing methods that are environmentally friendly and sustainable, e.g. through use of organocatalysts rather than transition metal catalysts. The long term goal of this project is to substantially reduce the environmental impact of the pharmaceutical industry.

References

10. (a) Leek, H. et al; Drug. Discov. Today 2017, 22, 133; (b) Federsel, H.-J. Chirality 2003, 15, S128.

11. 2001 Nobel Prize winners’ addresses – Knowles, Noyori and Sharpless, for their contributions to asymmetric synthesis:  (a) Knowles, W. S. Angew. Chem., Int. Ed. 2002, 41, 1998; (b) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008; (c) Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2024.

Streamlining of Carbohydrate Synthesis

The use of the protecting group methodology is widespread in organic chemistry, and particularly so in carbohydrate chemistry. To achieve one net chemical transformation, numerous chemical steps and separate purification steps are required, and significant protecting group waste is generated in the process. This barrier to synthetic access to carbohydrates prevents their enormous potential as therapeutic agents¹² from being exploited to anything like the extent that is possible. In contrast, the level of use of protein and nucleotide-based drugs has exploded in recent years,¹³ facilitated by the advent of methods that allow access to these biomolecules in pure form and large quantities.¹⁴ This project aims to find means of circumventing the need for the protecting group methodology in carbohydrate synthesis, hence making synthetic access to carbohydrates as therapeutic targets a viable general strategy.

References

12. Hudak, J. E.; Bertozzi, C. R. Chem. Biol. 2014, 21, 16.

13. (a) Fosgerau, K.; Hoffmann, T. Drug Discov. Today 2015, 20, 122; (b) Bray, B. L. Nat. Rev. Drug Discov. 2003, 2, 587;  (c) Steinl, C. A.; Castanotto1, D. Mol. Ther. 2017, 25, 1; (d) Khvorova, A.; Watts, J. K. Nat. Biotechnol. 2017, 35, 238.

14. (a) Merrifield, R. B. Angew. Chem. Int. Ed. 1985, 24, 799; (b) Caruthers, M. H. Science 1985, 230, 281; (c) Saiki, R. K.; Gelfand, D. H.; Stoffel, S.; Scharf, S. J.; Higuchi, R.; Horn, G. T.; Mullis, K. B.; Erlich, H. A. Science 1988, 4839, 487; (d) Makrides, S. C. Microbiol. Rev. 1996, 60, 512; (e) Rosano, G. L.; Ceccarelli, E. A. Front. Microbiol. 2014, 5, 172.

Other Interests

Byrne Chemistry Research Group also maintain interests in the following areas:

• Predicting and modelling rates of chemical reactions
• Development of quantitative Lewis basicity scales
• Applications of ¹⁵N NMR spectroscopy
• Spectroscopic observation of reactive intermediates
• The Wittig reaction
• The theory of chemical bonding