Why cyclohexane-1,4-dicarbaldehyde does not give aldol condensation?

Question

I was recently came to know as a fact that cyclohexane-1,4-dicarbaldehyde does not give the aldol condensation reaction in spite of possessing α-hydrogens. I was told that this is due to steric reasons, but I am trying to come up with a more specific reason, which does not require prior knowledge of this fact. Can anyone guide me towards a better explanation?

Edit 1: I am able to understand that there is absolutely no scope for an intramolecular aldol condensation. But what I am asking is whether even the aldol REACTION would take place, as basically the exact wording of the book is " cyclohexane-1,4-dicarbaldehyde gives zero aldol reaction products". So I am confused that what part is aldol reaction and/or condensation

Answer 1

Your claim is worded very poorly, and taken in the broadest sense, is not true. However, it's more complex than an outright yes or no.

If we're interested in fundamental reactivity, it suffices to look at cyclohexanecarbaldehyde, as there is no reason that the dialdehyde should be any different (apart from the likelihood that it gives very messy reactions in practice). The main issue is that "aldol reaction" is a very unspecific term, which is why you (and everybody else) is having trouble explaining it.

1. Firstly, it can refer either to condensations where you eliminate a molecule of water after the initial addition of an enolate, or to additions where the product is a β-hydroxyketone.

   Formally, any condensation involving cyclohexanecarbaldehyde as a nucleophilic component is not possible, because the α-carbon is tertiary. This includes the self-condensation, where it acts as both the nucleophile and electrophile. After forming a new bond, the α-carbon will become a quaternary centre, which cannot take part in elimination of water.

   

2. However, if CyCHO is the electrophilic component (i.e. a different enolate reacts with CyCHO), condensations are still possible. The crossed aldol condensation with acetone is well-documented in the literature:

   

3. If we go back to simple aldol additions, which still count as aldol reactions, there are many examples of CyCHO acting as the electrophilic component in an aldol addition. Here is a nice example (Tetrahedron: Asymmetry 2000, 11 (15), 3211–3220):

   

4. On the other hand, aldol additions with cyclohexanecarbaldehyde acting as the nucleophilic component are fairly rare. This reflects a general trend that aldol reactions generating quaternary centres (i.e. aldol reactions involving α,α-disubstituted enolates, such as the enolate of CyCHO) are traditionally very difficult to accomplish. This is mainly because of steric hindrance – the reacting centre of the enolate (the α-carbon) is bulky.

5. The above is a good rule of thumb, but there still are examples of CyCHO acting as the nucleophilic component in aldol reactions. Many of them involve secondary amine catalysis (example below taken from Org. Lett. 2003, 5 (23), 4369–4372), although there is one example of the lithium enolate of CyCHO attacking a carbonyl group.

   

   There are also plenty of examples where the silyl enol ether of CyCHO reacts with π-electrophiles. Silyl enol ethers are weaker nucleophiles than lithium enolates, so generally Lewis acid catalysis is required to form more powerful electrophiles. Still, these are considered to be aldol-type reactions (specifically Mukaiyama aldols).