I’ve been working with a guy (let’s call him Doug) who is a premed taking an organic chemistry course (Org 2) at a community college. The following question came up on one of his problem sets.
Doug gave the answer as B, when in fact the answer was A. So the question came up, why does this starting material form A and not B?
Well, once the first oxygen of the diol adds to the carbonyl carbon, the second hydroxyl group can do two things. It can add to the other carbonyl (to form the 7-membered ring D), or it can just sit around until the neighbouring hemiacetal is protonated, which will allow for ionization, 5-membered ring formation, formation of G and eventual formation of A after repeating the process (see below).
Let’s say you form the seven-membered ring to make hemiacetal D. Can D go on to form another cyclic ketal? No. In order for that to happen, you’d need to protonate the hemiacetal and have the oxygen lone pair displace H2O, forming oxonium ion E, which is disfavored (anti-Bredt) due to poor overlap of the oxygen p orbital with the p orbital on the bridgehead carbon. So since the reaction is reversible, you’re eventually going to funnel back to C, which will go on to form your final product A. The 7-membered ring is a cul-de-sac.
There’s also the key fact that product B is geometrically impossible, since the bridgehead oxygens are pointing 180 degrees away from each other and there’s no way that a 2-carbon chain is going to span that gap.
Let’s review the key concepts contained in that explanation.
- Reactions which are in conditions of equilibrium can form products which are “cul-de-sacs”, which can “funnel back” to starting materials and eventually go down the favored reaction pathway.
- Bridgehead double bonds don’t form due to the fact that the bridgehead p-orbital is positioned at right angles to the p orbital of the neighboring p-orbital, resulting in poor orbital overlap.
- Atomic geometry has huge implications for whether or not certain products can form. Just because you can imagine it, doesn’t mean you can make it.
I haven’t even mentioned the fact that 5-membered ring formation is faster than 7-membered ring formation, since that’s generally outside the realm of a sophomore organic chemistry course. Nor did I mention that 7-membered ring D is probably going to have a fair amount of ring strain due to the fact that there will be some unavoidable eclipsing interactions. Finally, although this doesn’t impact the answer, there’s also the issue that 1,3 diketones exist predominantly in their enol form, and the resonance would have important implications in slowing down the rate of this reaction should one ever attempt it in the lab.
So with all this in mind, I said:
“Well, Doug, if you have the choice between forming a 5 or 6 membered ring versus a 7-membered ring,it’s generally best not to form the 7-membered ring.”
That might seem like a pretty lame answer. Why not go into the full explanation? I admit it probably wasn’t the best answer in this situation (I’m always learning!) but some triage was required. Doug was still struggling with predicting the products of simple acetal formation. In other words, predicting the product from a simple ketone and a simple alcohol was a skill he was still trying to pick up. The full explanation for the problem would have taken 5-10 minutes and we had limited time available. On the Organic Chemistry Student’s Hierarchy of Needs, applying Bredt’s rule in acetal formation seemed like a luxury compared to just getting the basics down. Also, Doug was clearly having problems seeing molecules in 3-D. I thought it would be best to get him to focus on the basics. So we spent the next few minutes predicting the products from a series of different ketones/aldehydes with various alcohols.
It also got me wondering about the instructor’s choice of problems. What was the teaching value of that problem? Why present a problem dealing with an esoteric sub-case of acetal formation? How many other students in her class at this community college were like Doug, struggling with getting the basics down? Was the instructor evaluating her students on this type of knowledge? Why not focus on drills aimed at pounding home the key principles?
In organic chemistry, things can get very complex very quickly. A question with a simple ketone – say, cyclohexanone – would have been straightforward, but adding a second carbonyl in the β position suddenly ambushes the student with a complex set of questions about reaction rates, equilibria, bonding, and structure. In advanced level organic chemistry, we deal with these types of complexities all the time. In a sophomore course, however, the goal of many instructors and textbooks is to hide the complexity from students while they are still in the process of learning the basics. It’s a bit like M. Night Shayamalan’s The Village, where the adults have created an artificially simple 19th-century reality to hide their children from the complexities of the modern world.
What deceivingly simple-looking problems have you encountered?