Yesterday, while having a project discussion, we got into asking how strong a salt-bridge is, and realised that we are trying to answer one of the perpetually alive and kicking questions of chemistry. I then realised that this question belongs into the class of some other PAQs (Perpetually Alive Questions)
1. How strong is a hydrogen bond?
2. Do "low-barrier, strong" hydrogen bonds exist?
3. How do enzymes exactly stabilize transition states and bring about such enormous stabilization? What forces contribute to this?
4. How do you distinguish between a 'weak' hydrogen bon and a Van der Waals contact?
5. Why do molecules adopt one crystal structure and not another equienergetic one?
6. What is the origin of the rotation barrier in ethane?
Some of these questions (such as 4.) depend as much on convenience and arbitrary definition as on having definite answers. There are also ones where one can make good general guesses and yet lack predictive ability (such as 5.). The protein folding problem also falls into this category.
Many of these questions concern my favourite topics, especially those related to hydrogen bonds. While hyperconjugation has been advanced as the source of the rotation barrier in ethane, proton sponges have been postulated as model systems for demonstrating "strong" hydrogen bonds. According to Dunitz, crystal structure prediction really boils down to choosing between equienergetic possibilities rather than asking why one of them exists. As for enzymes, Kendall Houk seems to think that efficiencies above a certain extent may imply covalent rather than non-covalent binding.
All questions make for exciting discussion and much fun, and the great thing is that even partial answers make for great intellectual debate and even scientific advancement. Roll on! Chemistry remains alive because of such questions. But PhD.s may get prolonged, an emphatic disadvantage.
More such questions?