Cyclization Reactions

Cyclization reactions are a special kind of carboxyl substitution or carbonyl addition reactions. While we are used to molecules reacting intermolecularly (i.e. with another molecule in solution) molecules can also react intramolecularly or with themselves. With this in mind, let’s look at how cyclization reactions work.

Same Reaction Same Result

First and foremost none of the reactions discussed today are new. Instead, they are a special subset of reactions we have already encountered. In light of this let’s recap the non-cyclizing reaction starting with carbonyl addition reactions.

Carbonyl Addition

In a carbonyl addition reaction, a nucleophile attacks the partially positive carbonyl carbon. Since carbon refuses to form 5-bonds one of the oxygen bonds breaks and picks up an H+ ion from solution to become an OH.

The end result is the addition of a nucleophile and a conversion of a carbonyl functional group to a hydroxyl. The same thing will occur in a cyclization reaction except here the nucleophile will come from within the molecule itself.

In this case the nucleophilic OH in blue wraps around and attacks the carbonyl carbon. This converts the carbonyl into a hydroxyl and the blue OH into an ether. Collectively this functional group is called a hemiketal.

The end result is identical to the -tal generating reactions except we are used to using a separate alcohol molecule. Since our molecule only had one alcohol that could react with the carbonyl it will stop at the hemi version. In the above example, we started with a ketone so we ended with a hemiketal if we had started with an aldehyde we would have ended with a hemiacetal.

That’s great but how did you know how large to make the ring and where to put any extra substituents. By counting! To determine the ring size begin by labeling the OH as number 1 then from there count until you hit the carbonyl carbon. This number tells you how big the ring is. In this case, we count 6 total atoms so this will be a six-membered ring (hexagon).

This numbering has nothing to do with nomenclature remember we only count the number of carbons present for our parent chain number when naming compounds.

Now draw a hexagon with oxygen as one of its members. Then number the atoms using the same numbering scheme as above. I often find it easiest to start with the hydroxyl (labeled1) since I know that one will be the O in the ring and the carbonyl carbon (labeled 6) since that will be on either side of the O in the ring. From there place the OH in the sixth position.

Now draw in any of the remaining substituents placing them at the same number in their linear and cyclic forms.

Now you have your new cyclic molecule. We will use this same numbering technique when looking at the carboxyl substitution cyclization reactions.

Carboxyl Substitution