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The secret of free radical cyclization: How to quickly form a ring structure inside a molecule?
Free radical cyclization reaction is an important reaction type in organic chemical transformations, which can effectively generate compounds with cyclic structures. This process involves artificially generated free radical intermediates. This article will delve into the mechanism, stereoselectivity and associated advantages and disadvantages of these reactions, especially how to form cyclic structures quickly and accurately inside the molecule.
Basic steps of free radical cyclization reaction
This type of reaction is mainly divided into three basic steps: selective free radical generation, free radical cyclization, and conversion of the cyclized product. During cyclization reactions, most free radicals are generated on carbons connected to various functional groups; and the reagents that generate free radicals can be described as diverse.
"Because the free radical intermediate is not a charged species, the reaction conditions are usually mild and have a high tolerance for a variety of functional groups."
Mechanism and stereochemistry
Mainstream mechanism
Due to the numerous free radical generating and capturing reagents, no single dominant mechanism can be determined. However, once a radical is generated, it can react through internal multiple bonds to form a cyclized radical intermediate.
"In many cases, exo cyclization is preferred over endo cyclization, and there are exceptions to this rule for macrocyclization reactions."
Stereoselectivity
The dilock selectivity of free radical cyclization reactions is usually very high, and many all-carbon cases can be rationalized according to the Beckwith guideline. When substituents are placed at pseudo-equatorial positions in the transition state, cis products are often produced; while the introduction of polar substituents may promote the formation of trans products.
Scope and Limitations
Free radical generation method
In free radical cyclization reactions, the use of metal hydrides is very common. Although this method is effective, the main limitation is that it may cause the initially generated free radicals to be reduced by H-M. Other methods such as splitting and atom transfer are also favored.
Ring size
Generally speaking, radical cyclization to produce small rings presents difficulties; however, the process can proceed smoothly if the cyclizing radical can be captured before reopening. Usually, the market that can generate five-membered and six-membered rings is the most common.
"In comparison with other cyclization methods, free radical cyclization avoids the problems associated with Wagner-Meerwein rearrangements and does not require strong acidic conditions."
Experimental conditions and procedures
Free radical reactions must be carried out under an inert atmosphere because carbon dioxide interferes with free radical intermediates. The reaction is usually carried out in a solvent with high bond dissociation energy, such as benzene or methanol, which are suitable choices.
The following is a typical example procedure: a mixture containing 549 mg of bromoaldehyde, 30.3 mg of AIBN, and 0.65 ml of Bu3SnH is refluxed in dry benzene for 1 hour. Subsequent separation and purification steps are then performed.
With the deepening of research, free radical cyclization reactions have shown their importance in synthetic chemistry. They can not only generate a variety of cyclic compounds, but also extend more functional connections. With the advancement of science and technology, can this reaction open up new synthetic pathways and thereby promote the development of modern chemistry?
