List of unsolved problems in chemistry

Last updated June 20, 2025

This is a list of unsolved problems in chemistry . Problems in chemistry are considered unsolved when an expert in the field considers it unsolved or when several experts in the field disagree about a solution to a problem.

Physical chemistry problems

Can the transition temperature of high-temperature superconductors be brought up to room temperature?
How do the spin–orbit coupling, other relativistic corrections, and inter-electron effects modify the chemistry of the trans-actinides?^[1]^[2]
Is it possible to create a practically-useful lithium–air battery?^[3]

Organic chemistry problems

What is the origin of homochirality in biomolecules?^[4]
Why are accelerated kinetics observed for some organic reactions at the water-organic interface?^[5]^{[ non-primary source needed ]}
Do replacement reactions of aryl diazonium salts (dediazotizations) predominantly undergo S_N1 or a radical mechanism?^[6]
Can an electrochemical cell reliably perform organic redox reactions?^[7]
Which "classic organic chemistry" reactions admit chiral catalysts?
- Is it possible to construct a quaternary carbon atom with arbitrary (distinguishable) substituents and stereochemistry?
Can artificial enzymes replace the need for protecting groups when modifying sensitive compounds?^[8]

Inorganic chemistry problems

Are there any molecules that certainly contain a phi bond?
Is there a less labor- or energy-intensive technique for titanium refinement than the Kroll process?^[9]
Does nitrogen admit metastable allotropes under standard conditions?^[10]
Can new solvents or other techniques make direct carbon capture economical?^[11]
- Can artificial photosynthesis make any common fuels?^[12]
What is a reliable synthesis and stabilization method for catenary allotropes of sulfur and carbon?

Biochemistry problems

Enzyme kinetics : Why do some enzymes exhibit faster-than-diffusion kinetics?^[13]
Protein folding problem: Is it possible to predict the secondary, tertiary and quaternary structure of a polypeptide sequence based solely on the sequence and environmental information? Inverse protein-folding problem: Is it possible to design a polypeptide sequence which will adopt a given structure under certain environmental conditions?^[4]^[14] This has been achieved for several small globular proteins in recent years.^[15] In 2020, it was announced that Google's AlphaFold, a neural network based on DeepMind artificial intelligence, is capable of predicting a protein's final shape based solely on its amino-acid chain with an accuracy of around 90% on a test sample of proteins used by the team.^[16]
RNA folding problem: Is it possible to accurately predict the secondary, tertiary and quaternary structure of a polyribonucleic acid sequence based on its sequence and environment?
Protein design: Is it possible to design highly active enzymes de novo for any desired reaction?^[17]
Biosynthesis: Can desired molecules, natural products or otherwise, be produced in high yield through biosynthetic pathway manipulation?^[18]

References

↑ Philip Ball (November 2010). "Would element 137 really spell the end of the periodic table? Philip Ball examines the evidence". Chemistry World . Royal Society of Chemistry.
↑ Morss, Lester R.; Edelstein, Norman M.; Fuger, Jean, eds. (2006). The Chemistry of the Actinide and Transactinide Elements (3rd ed.). Dordrecht, The Netherlands: Springer. ISBN 978-1-4020-3555-5.
↑ Christensen, J.; Albertus, P.; Sanchez-Carrera, R. S.; Lohmann, T.; Kozinsky, B.; Liedtke, R.; Ahmed, J.; Kojic, A. (2012). "A Critical Review of Li–Air Batteries". Journal of the Electrochemical Society. 159 (2): R1. doi: 10.1149/2.086202jes .
1 2 "So much more to know". Science. 309 (5731): 78–102. July 2005. doi: 10.1126/science.309.5731.78b . PMID 15994524.
↑ Narayan, Sridhar; Muldoon, John; Finn, M. G.; Fokin, Valery V.; Kolb, Hartmuth C.; Sharpless, K. Barry (2005). ""On Water": Unique Reactivity of Organic Compounds in Aqueous Suspension". Angewandte Chemie International Edition. 44 (21): 3275–3279. doi: 10.1002/anie.200462883 . PMID 15844112.
↑ Ussing R, Singleton A (February 2005). "Isotope effects, dynamics, and the mechanism of solvolysis of aryldiazonium cations in water". Journal of the American Chemical Society. 127 (9): 2888–2889. Bibcode:2005JAChS.127.2888U. doi: 10.1021/ja043918p . PMID 15740124.
↑ Lowe, Derek (24 Aug 2017). "Electrochemistry For All". In the Pipeline. American Association for the Advancement of Science . Retrieved 23 August 2023.
↑ Miles, Ned Carter (2023-08-05). "'Endless possibilities': the chemists changing molecules atom by atom". The Observer. ISSN 0029-7712 . Retrieved 2023-08-24.
↑ Potter, Brian. "The Story of Titanium". Construction Physics. Retrieved 2023-08-24. In the 1950s, it was hoped/assumed that a better process for producing titanium sponge would come along to replace the Kroll process, which is a laborious and energy-intensive batch process that must be done in an inert atmosphere. But such a process has never materialized...likewise, turning titanium sponge into metal is an energy and capital-intensive process [that] has also changed little since the 1950s.
↑ Lewars, Errol G. (2008). Modeling Marvels: Computational Anticipation of Novel molecules. Springer Science+Business Media. pp. 141–63. doi:10.1007/978-1-4020-6973-4. ISBN 978-1-4020-6972-7.
↑ Sanz-Pérez, Eloy S.; Murdock, Christopher R.; Didas, Stephanie A.; Jones, Christopher W. (12 October 2016). "Direct Capture of carbon dioxide from Ambient Air". Chemical Reviews. 116 (19): 11840–11876. doi: 10.1021/acs.chemrev.6b00173 . PMID 27560307.
↑ Styring, Stenbjörn (21 December 2011). "Artificial photosynthesis for solar fuels". Faraday Discussions. 155 (Advance Article): 357–376. Bibcode:2012FaDi..155..357S. doi:10.1039/C1FD00113B. PMID 22470985.
↑ Hsieh M, Brenowitz M (August 1997). "Comparison of the DNA association kinetics of the Lac repressor tetramer, its dimeric mutant LacIadi, and the native dimeric Gal repressor". J. Biol. Chem. 272 (35): 22092–6. doi: 10.1074/jbc.272.35.22092 . PMID 9268351.
↑ King, Jonathan (2007). "MIT OpenCourseWare - 7.88J / 5.48J / 7.24J / 10.543J Protein Folding Problem, Fall 2007 Lecture Notes - 1". MIT OpenCourseWare . Archived from the original on September 28, 2013. Retrieved June 22, 2013.
↑ Dill KA; et al. (June 2008). "The Protein Folding Problem". Annu Rev Biophys. 37: 289–316. doi:10.1146/annurev.biophys.37.092707.153558. PMC 2443096 . PMID 18573083.
↑ Callaway, Ewen (2020-11-30). "'It will change everything': DeepMind's AI makes gigantic leap in solving protein structures" . Nature. 588 (7837): 203–204. Bibcode:2020Natur.588..203C. doi:10.1038/d41586-020-03348-4. PMID 33257889. S2CID 227243204.
↑ "Principles for designing ideal protein structures. | the Baker Laboratory". Archived from the original on 2013-04-01. Retrieved 2012-12-19.
↑ Peralta-Yahya, Pamela P.; Zhang, Fuzhong; Del Cardayre, Stephen B.; Keasling, Jay D. (2012). "Microbial engineering for the production of advanced biofuels". Nature. 488 (7411): 320–328. Bibcode:2012Natur.488..320P. doi:10.1038/nature11478. PMID 22895337. S2CID 4423203.

External links

"First 25 of 125 big questions that face scientific inquiry over the next quarter-century". Science. 309 (125th Anniversary). 1 July 2005.
Unsolved Problems in Nanotechnology: Chemical Processing by Self-Assembly - Matthew Tirrell - Departments of Chemical Engineering and Materials, Materials Research Laboratory, California NanoSystems Institute, University of California, Santa Barbara [No doc at link, 20 Aug 2016]

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[1] Philip Ball (November 2010). "Would element 137 really spell the end of the periodic table? Philip Ball examines the evidence". Chemistry World . Royal Society of Chemistry.

[transactinides-2] Morss, Lester R.; Edelstein, Norman M.; Fuger, Jean, eds. (2006). The Chemistry of the Actinide and Transactinide Elements (3rd ed.). Dordrecht, The Netherlands: Springer. ISBN 978-1-4020-3555-5.

[Christensen2012-3] Christensen, J.; Albertus, P.; Sanchez-Carrera, R. S.; Lohmann, T.; Kozinsky, B.; Liedtke, R.; Ahmed, J.; Kojic, A. (2012). "A Critical Review of Li–Air Batteries". Journal of the Electrochemical Society. 159 (2): R1. doi: 10.1149/2.086202jes .

[Science-4] 1 2 "So much more to know". Science. 309 (5731): 78–102. July 2005. doi: 10.1126/science.309.5731.78b . PMID 15994524.

[5] Narayan, Sridhar; Muldoon, John; Finn, M. G.; Fokin, Valery V.; Kolb, Hartmuth C.; Sharpless, K. Barry (2005). ""On Water": Unique Reactivity of Organic Compounds in Aqueous Suspension". Angewandte Chemie International Edition. 44 (21): 3275–3279. doi: 10.1002/anie.200462883 . PMID 15844112.

[6] Ussing R, Singleton A (February 2005). "Isotope effects, dynamics, and the mechanism of solvolysis of aryldiazonium cations in water". Journal of the American Chemical Society. 127 (9): 2888–2889. Bibcode:2005JAChS.127.2888U. doi: 10.1021/ja043918p . PMID 15740124.

[7] Lowe, Derek (24 Aug 2017). "Electrochemistry For All". In the Pipeline. American Association for the Advancement of Science . Retrieved 23 August 2023.

[8] Miles, Ned Carter (2023-08-05). "'Endless possibilities': the chemists changing molecules atom by atom". The Observer. ISSN 0029-7712 . Retrieved 2023-08-24.

[9] Potter, Brian. "The Story of Titanium". Construction Physics. Retrieved 2023-08-24. In the 1950s, it was hoped/assumed that a better process for producing titanium sponge would come along to replace the Kroll process, which is a laborious and energy-intensive batch process that must be done in an inert atmosphere. But such a process has never materialized...likewise, turning titanium sponge into metal is an energy and capital-intensive process [that] has also changed little since the 1950s.

[Lewars-10] Lewars, Errol G. (2008). Modeling Marvels: Computational Anticipation of Novel molecules. Springer Science+Business Media. pp. 141–63. doi:10.1007/978-1-4020-6973-4. ISBN 978-1-4020-6972-7.

[ReviewDAC2016-11] Sanz-Pérez, Eloy S.; Murdock, Christopher R.; Didas, Stephanie A.; Jones, Christopher W. (12 October 2016). "Direct Capture of carbon dioxide from Ambient Air". Chemical Reviews. 116 (19): 11840–11876. doi: 10.1021/acs.chemrev.6b00173 . PMID 27560307.

[Styring-12] Styring, Stenbjörn (21 December 2011). "Artificial photosynthesis for solar fuels". Faraday Discussions. 155 (Advance Article): 357–376. Bibcode:2012FaDi..155..357S. doi:10.1039/C1FD00113B. PMID 22470985.

[13] Hsieh M, Brenowitz M (August 1997). "Comparison of the DNA association kinetics of the Lac repressor tetramer, its dimeric mutant LacIadi, and the native dimeric Gal repressor". J. Biol. Chem. 272 (35): 22092–6. doi: 10.1074/jbc.272.35.22092 . PMID 9268351.

[14] King, Jonathan (2007). "MIT OpenCourseWare - 7.88J / 5.48J / 7.24J / 10.543J Protein Folding Problem, Fall 2007 Lecture Notes - 1". MIT OpenCourseWare . Archived from the original on September 28, 2013. Retrieved June 22, 2013.

[15] Dill KA; et al. (June 2008). "The Protein Folding Problem". Annu Rev Biophys. 37: 289–316. doi:10.1146/annurev.biophys.37.092707.153558. PMC 2443096 . PMID 18573083.

[16] Callaway, Ewen (2020-11-30). "'It will change everything': DeepMind's AI makes gigantic leap in solving protein structures" . Nature. 588 (7837): 203–204. Bibcode:2020Natur.588..203C. doi:10.1038/d41586-020-03348-4. PMID 33257889. S2CID 227243204.

[17] "Principles for designing ideal protein structures. | the Baker Laboratory". Archived from the original on 2013-04-01. Retrieved 2012-12-19.

[18] Peralta-Yahya, Pamela P.; Zhang, Fuzhong; Del Cardayre, Stephen B.; Keasling, Jay D. (2012). "Microbial engineering for the production of advanced biofuels". Nature. 488 (7411): 320–328. Bibcode:2012Natur.488..320P. doi:10.1038/nature11478. PMID 22895337. S2CID 4423203.

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