Organic chemistry problems
- Solvolysis of the norbornyl cation: Why is the norbornyl cation so stable? Is it symmetrical? If so, why? This problem has been largely settled for the unsubstituted norbornyl cation, but not for the substituted cation. See Non-classical ion.
- On water reactions: Why are some organic reactions accelerated at the water-organic interface?
- What is the origin of the bond rotation barrier in ethane, steric hindrance or hyperconjugation?
- What is the origin of the alpha effect? Nucleophiles with an electronegative atom and one or more lone pairs adjacent to the nucleophilic center are particularly reactive.
- Better-than perfect enzymes: Why do some enzymes exhibit faster-than-diffusion kinetics? See Enzyme kinetics.
- What is the origin of homochirality in amino acids and sugars?
- 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? 
- What are the chemical origins of life? How did non-living chemical compounds generate self-replicating, complex life forms?
Physical chemistry problems
- What is the electronic structure of the high temperature superconductors at various points on the phase diagram? Can the transition temperature be brought up to room temperature? See Superconductivity.
- Feynmanium: What are the chemical consequences of having an element, with an atomic number above 137, whose 1s electrons must travel faster than the speed of light? Is “Feynmanium” the last chemical element that can physically exist? The problem may actually occur at approximately Element 173, given the finite extension of nuclear-charge distribution. See the article on Extension of the periodic table beyond the seventh period and section Relativistic effects of Atomic orbital.
- How can electromagnetic energy (photons) be efficiently converted to chemical energy? (E.g. splitting of water to hydrogen and oxygen using solar energy.)
- What is the nature of bonding in hypervalent molecules? See Hypervalent molecules.
- What is the structure of water? According to Science Magazine in 2005, one of the 100 outstanding unsolved problems in science revolves around the question of how water formshydrogen bonds with its neighbors in bulk water. See: water cluster
- How to count the messenger out (eurekalert.org)
- Chemistry (slideshare.net)
- ACS Relaunches Journal of Combinatorial Chemistry (pubs.acs.org)
- Chemists deserve more credit (2): The 150th anniversary of the first international science conference (metamodern.com)
- A Faster Way to Understand and Optimize your Chemistry (prweb.com)
- Artificial enzyme removes natural poison (eurekalert.org)