Chemistry - What does the intramolecular aldol condensation of 6-oxoheptanal form?

Solution 1:

Intramolecular-Aldol reactions involves heat, as you have mentioned, and the base used (NaOH) isn't much affected by steric factors. Therefore, the preferred product should be thermodynamically controlled product. Moreover, as you commented about the formed carbanion being less stable in case of 2° carbon, actually the carbanion is converted to an enolate then the reaction proceeds further. So, the 5-membered cyclic ring should be the major product.

Solution 2:

B.Anshuman has given a short answer, but I felt more explanation is needed to understand this situation. This reaction can be done in kineticlly controlled conditions (e.g., using $\ce{LDA/THF}$ as a base at $\pu{-78 ^\circ C}$) or in thermodynamically controlled conditions as in this case. Each case may give totally different major products. For example, alkylation of 2-methylcyclohexanone gives 6-alkyl-2-methylcyclohexanone as the predominanet product under kinetic conditions (1. $\ce{LDA/THF}/\pu{-78 ^\circ C}$; 2. $\ce{R-Cl/THF}/\pu{-78 ^\circ C}$, alkyl chloride is $1^\circ$ or $2^\circ$). However the same starting material would gives 2-alkyl-2-methylcyclohexanone as the amjor product under thermodynamic condition such as $\ce{NaOEt/EtOH}/\gt \pu{25 ^\circ C}$.

In above example shows that the thermodynamic conditions allow equilibration of the two possible enolates (which are derived from $2^\circ$ and $3^\circ$ carbanions); the one enolate with greater alkyl substitution on $\ce{C=C}$ would form in greater concentration (Zaitsev-like). The question in hand can also be treated like the same because the situation is similar ($1^\circ$ vs $2^\circ$ carbanions).

The literature has shown that the evidence for carbanion formation might not be the rate determining step (Ref.1). The abstract if the reference is given below for your benefit for reasoning:

Rate and equilibrium constants have been determined for both the aldol addition and the elimination steps in the intramolecular condensation reactions of 2,5-hexanedione, 2,6-heptanedione, 1-phenyl-1,5-hexanedione, and 5-oxohexanal. The overall thermodynamics are similar for cyclization of 2,5-hexanedione and 2,6-heptanedione; conversion of 2,5-hexanedione to the corresponding enone is actually more favorable, but the cyclization of 2,5-hexanedione is 2400 times slower than that of 2,6-heptanedione. As expected on the basis of intermolecular analogs, the addition step is less favorable and slower for 1-phenyl-1,5-hexanedione, and the addition step for 5-oxohexanal is more favorable though similar in rate to that for heptanedione. Detailed analysis of the kinetics and equilibrium for all of these compounds, as well as 2-(2-oxopropyl)benzaldehyde, in terms of Marcus theory, leads to the same intrinsic barriers for the intramolecular reactions as were seen previously for the intermolecular reactions. This means that rate constants for intramolecular aldol reactions should be predictable from the energetics of the reactions and that the effective molarity can be calculated. Methods for estimating thermodynamic quantities for reactants and products of these reactions have been examined.

Thus, my conclusion is formation of 5-membered ring is predominated here to give 1-acetylcyclohexene as the major product among three theoretically possible products.


  1. J. Peter Guthrie, Junan Guo, "Intramolecular Aldol Condensations:  Rate and Equilibrium Constants," J. Am. Chem. Soc. 1996, 118(46), 11472-11487 (