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From reactants to products: How is each step in the free radical cyclization process precisely controlled?
In organic chemistry, free radical cyclization is an important transformation process that generates cyclic products via free radical intermediates. The process can generally be divided into three basic steps: selective free radical generation, free radical cyclization, and conversion of the cyclized free radicals into the final products. In these cyclization reactions, how to control the rate and selectivity of each step remains a research topic that has received widespread attention.
Introduction to Free Radical Cyclization Reaction
Free radical cyclization reactions usually produce monocyclic or polycyclic products. Because they are changes within the molecule, the rapidity and selectivity of the reaction are often very obvious. Selective free radical generation of these reactions can be achieved on carbon atoms to which a variety of functional groups are attached. A wide variety of reagents are used, and these reactions are generally carried out under mild conditions with high tolerance for functional groups.
The inherently uncharged nature of the free radical intermediates means that these reaction conditions tend to be mild and allow the use of a range of different solvents.
The free radical cyclization step generally involves the attack of free radicals on multiple bonds. After this step is completed, the generated cyclized free radicals will be consumed through the action of scavengers, fragmentation processes or electron transfer reactions. Five-membered and six-membered rings are the most common products of this type of reaction, while the formation of small and large rings is relatively rare. Effective free radical cyclization requires three conditions to be met: there must be a method to selectively generate free radicals, the cyclization rate must be faster than the capture of the initially generated free radicals, and all steps must be faster than undesirable side reactions, such as free radical Recombines or reacts with a solvent.
Mechanism and Stereochemistry
Mainstream Mechanism
Due to the existence of multiple free radical generating and capturing agents, it is not realistic to identify a single dominant mechanism. However, once the free radical is generated, it can react with multiple bonds in an intramolecular manner to form cyclized radical intermediates. These reactions can be divided into "outer loop" and "inner loop" attacks:
Exo-ring attack means that the free radical is outside the ring after the reaction, while endo-ring attack means that the free radical is inside the newly formed ring.
In many cases, exocyclic cyclization is favored over endocyclic cyclization. The presence of radicals can affect the stability of these transition states, which in turn can have a profound impact on the selectivity of the reaction site. Taking the 2-position carbon group as an example, it can promote the closure of the 6-endo ring, while the 1,2, 1,3 and 1,4-position carbon groups are more conducive to the closure of the 5-exo ring.
Stereoselectivity
The stereoselectivity of free radical cyclizations is often very high and depends mainly on the transition state during the reaction. To improve the stereoselectivity of the reaction, the substituent can be placed at the quasi-equilibrium position of the transition state to obtain cis or trans products. For substrates containing stereogenic centers, the stereoselectivity between free radicals and multiple bonds can also be quite obvious.
Scope and Limitations
Free Radical Generation Methods
The use of metal hydrides (such as tin, silicon, and mercury hydrides) to generate free radicals is a common method, but the main limitation of this method is that the initially generated free radicals may be reduced. The fragmentation algorithm avoids this problem by incorporating the interlocking reagent into the substrate. Meanwhile, the atom transfer method utilizes the process of transferring an atom from a tertiary starting material to a cyclic radical. These methods typically use small amounts of weak reagents, effectively preventing the problems caused by the use of strong reducing agents.
Ring size
Generally speaking, it is not easy to generate small rings via free radical cyclization. Nevertheless, the formation of small rings is possible if the cyclized radical can be trapped before re-opening. In addition, free radical cyclization can also generate polycyclic and macrocyclic rings, and the selectivity and yield of the rings in these processes can be controlled.
Comparison with other methods
Compared to cationic cyclization, which is usually Thermodynamic control. Free radical cyclizations are usually much faster than anionic cyclizations and avoid β-elimination side reactions. However, compared with these methods, the major limitation of free radical cyclization lies in its potential side reactions.
Experimental conditions and procedures
Typical conditionsFree radical reactions must be performed under an inert atmosphere because molecular oxygen is a triplet radical and will interfere with free radical intermediates. Since the relative rates of multiple processes have a significant impact on the reaction, concentrations need to be carefully adjusted to optimize reaction conditions. The reaction is usually carried out in a solvent with high bond dissociation energy, such as benzene, methanol or phenyl trifluoride. Even the reaction under aqueous conditions is acceptable because the O-H bond of water has a strong bond dissociation energy.
Example Program
A typical procedure is to reflux a mixture of the bromoformate, AIBN and trioctylstannous hydride in dry benzene for one hour and then isolate the desired product by chromatography. This reaction can synthesize the target compound with high yield.
The processes of free radical cyclization demonstrate exquisite control over chemical reactions, and it is fascinating to understand how they achieve such high selectivity and efficiency at the microscopic level.
