Entropy dominates equilibrium constants in the difference between inter- and intramolecular reactions. In Chapter 6 we explained that hemiacetal formation is unfavourable because the C=O double bond is more stable than two C–O single bonds. This is clearly an enthalpy factor depending simply on bond strength. That entropy also plays a part can be clearly seen in favourable intramolecular hemiacetal formation of hydroxyaldehydes. The total number of carbon atoms in the two systems is the same, the bond strengths are the same and yet the equilibria favour the reagents (MeCHO + EtOH) in the inter- and the product (the cyclic hemiacetal) in the intramolecular case.
The difference is one of entropy. In the first case two molecules would give one with an increase in order as, in general, lots of things all mixed up have more entropy than a few large things (when you drop a bottle of milk, the entropy increases dramatically). In the second case one molecule gives one molecule with little gain or loss of order. Both reactions have negative ?S° but it is more negative in the first case.
