Hydroxyaldehydes hemiacetal formation

Entropy dominates equilibrium constants in the difference between inter- and intramolecular reactions. In Chapter 6 we explained that hcmiacetal formation is unfavourable because the C=0 double bond is more stable than two C-0 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 much lower thermodynamic stability of hemiorthoesters compared to hemiacetals is illustrated by comparing the equilibrium constant for the formation of [121] from the corresponding hydroxyester, 5 x 10-7 to 1 x 10" 6 (Table 17) with that for the formation of hemiacetal [123] from the corresponding hydroxyaldehyde [122] which is 8.1 in 75 25 dioxan-water... 

Very often, when the treatment of a 1,4- or a 1,5-diol with PDC leads to the initial formation of a hydroxyaldehyde that can equilibrate with a cyclic hemiacetal, the latter is further oxidized to a lactone.168... 

Lactols are easily transformed into lactones in TEMPO-mediated oxidations.49 When the oxidation of a diol leads to a hydroxyaldehyde that is able to equilibrate with a hemiacetal, the latter is further oxidized to a lactone.50 Interestingly, as TEMPO-mediated oxidations can be very selective in favouring oxidations of less hindered alcohols, lactone formation from diols can be very regioselective.500... 

Six-membered rings are relatively strain free, and the equihbrium favors formation of the cychc hemiacetal. This type of reaction is characteristic of bifunctional compounds containing both a hydroxyl group and a carbonyl group (an aldehyde or ketone moiety). When drawing the hemiacetal of a hydroxyaldehyde or hydroxyketone, it is crucial to keep track of ah carbon atoms. It is a common mistake to draw the hemiacetal with either too many or too few carbon atoms. The following exercises are designed to help you avoid those mistakes. 

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