Cyclization reactions (ring formation)

Written by J.A Dobado | Last Updated on April 22, 2024

What are cyclization reactions or ring formation reactions?

The most common cyclization reactions are those in which a nucleophilic atom interacts with an electrophile. Therefore, the predominant reaction types are as follows:

  • The nucleophilic shift in a saturated carbon atom.
  • Nucleophilic addition on an unsaturated carbon.
  • Nucleophilic addition-removal.

An example of the ring formation reaction is the Paal-Knorr synthesis of pyrroles from 1,4-dicarbonyl compounds and primary amines.


The cyclization step involves nucleophilic attack on a carbonyl group by the nitrogen of the intermediate. The 1,4-dicetone acts as an electrophile in both steps. In addition, different variants of interactions are possible.


Types of building blocks

  • Double electrophilic reagents.


  • Double nucleophilic reagents.


  • Reagents with electrophilic and nucleophilic centers.


Compounds containing the carbonyl group (>C=O) are frequently used as electrophiles and can be aldehydes, ketones, acid chlorides, esters and other acid derivatives.

On the other hand, the synthesis of benzofused heterocycles involves the formation of a heterocyclic ring on a benzene ring.

To summarize, there are two general approaches:

  • Based on ortho-substituted benzenes: For example, to synthesize quinoline from 2-aminobenzaldehyde and a reagent with two carbons with electrophilic and nucleophilic centers.


  • From a monosubstituted benzene in which an orthofree position acts as a nucleophilic center (susceptible to electrophilic attack). For example, aniline and a doubly electrophilic three-carbon reagent such as an α,β-unsaturated ketone.


In the more complex derivatives, if the two ortho-positions are free, and are not equivalent, there is the possibility of obtaining isomers.


Nomenclature of cyclizations

There is a nomenclature system to describe the possible types of cyclisation. This system is based on the hybridisation state of the atom attacked by the nucleophile. This is named together with the type of electron displacement away from that atom in the cyclisation reaction. If it takes place inside the forming ring it is called endo and if it takes place outside it is called exo.


Intramolecular displacement on a saturated carbon atom is an exo-tet process, whereas nucleophilic addition and addition-elimination reactions in carbonyl compounds are exo-trig processes.

Feasibility of the cycling process

In order to decide whether a specific type of ring system can be efficiently prepared through these cyclization processes, two aspects must be taken into account:

  • The size of the ring to be formed.
  • The nature of the transition state leading to its formation.

The activation free energy (ΔG) of the cyclization process is constituted by an activation enthalpy term (ΔH) and an activation entropy term (ΔS).

ΔG  =  ΔH  –  T·ΔS

The activation entropy (ΔS) of the intramolecular process is related to the probability that the two ends of the chain approach each other. This probability decreases as the chain length increases. The value of ΔS becomes larger with chain size, but since it presents a negative sign in the equation, the effect is to decrease ΔS.

The activation enthalpy (ΔH) reflects the stress present in the transition state leading to the product and is generally lower when forming 5- and 6-membered rings, and slightly higher in 3- and 4-membered rings that are more highly stressed.

The ΔH values are also higher for the formation of medium-sized rings (from 8 to 11 members). This is due to the non-bonding interactions they exhibit.

Likewise, the ΔG values of rings of these dimensions are high, making it difficult to form them by cyclization processes.

Another factor in determining the greater or lesser ease of a specific cyclization process is the approach geometry of the nucleophile to the electrophile in the transition state.

For example, in bimolecular nucleophilic displacement on a saturated carbon requires a transition state in which the nucleophile attacks on the side opposite to that occupied by the leaving group.


However, the attack of the nucleophile on the carbonyl (>C=O), preferably takes place above or below the plane of the molecule. Moreover, it takes place at an angle of about 100° with respect to the carbonyl group close to the tetrahedral angle (109.5°). Likewise, for other bonds -C≡N or -C≡C- they are about 120º.


Naturally, certain reasonable deviations from these geometries can be allowed, but the restrictions may make it difficult for some types of reactions, of those seen above, for the formation of rings of 5 members or less.

Baldwin’s Rules

Balwin, in 1976 for the first time and later in 1977 established a set of rules for ring closure, based on the preferred trajectories of the approaches.

For example, it was suggested that the endo-trig process would be difficult to achieve for rings smaller than 6 members. Certainly, these reactions are not very common but there are certain examples such as the 5-endo-trig cyclization of N-(hydroxyethyl)imines to form dihydro oxazoles.


Some, but not all, anomalies of this type have been eliminated by performing a detailed investigation of the mechanism.

The 5-endo-trig process is at first sight even more difficult, but there are several examples of such reactions.

It could be explained by the fact that the triple bond has a π bond above and below the molecular plane.


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