Radical cyclization reactions produce mono- or polycyclic products through the action of radical intermediates. Since these are intramolecular transformations, they are often very rapid and selective. Selective generation of radicals can be achieved on carbons bonded to a variety of functional groups, and the reagents used to effect radical generation are numerous. The radical cyclization step usually involves the attack of a radical on a multiple bond. After this step occurs, the resulting cyclized radicals are quenched through the action of a radical scavenger, a fragmentation process, or an electron transfer reaction. Five- and six-membered rings are the most common products; the formation of increasingly smaller rings is rarely observed. For efficient radical cyclization to occur, three conditions must be met: A method must be available to generate a radical selectively on the substrate. radical cyclization must be faster than trapping the initially formed radical.[2]Say no to plagiarism. Get a tailor-made essay on "Why Violent Video Games Shouldn't Be Banned"? Get an original essay All steps must be faster than unwanted side reactions such as radical recombination or solvent reaction. Advantages: Because radical intermediates are not charged species, reaction conditions are often mild and functional group tolerance is high. Reactions can be carried out in almost any solvent, and the products are often synthetically useful compounds that can be carried forward using existing functionalities or groups introduced during radical trapping. Disadvantages: the relative rates of the various stages of radical cyclization reactions (and any side reactions) must be carefully controlled so that cyclization and trapping of the cyclized radical is favored. Side reactions are sometimes a problem, and cyclization is particularly slow for small and large rings (although macrocyclizations, which resemble intermolecular radical reactions, are often high yield). Mechanism and stereochemistry[edit]Prevailing mechanism[edit]Because there are many reagents for radical generation and trapping, it is not possible to establish a single prevailing mechanism. However, once a radical has been generated, it can react with multiple bonds intramolecularly to produce cyclized radical intermediates. The two ends of the multiple bond constitute two possible reaction sites. If the radical of the resulting intermediate ends up outside the ring, the attack is called “exo”; if it ends inside the newly formed ring the attack is called “endo”. In many cases, exocyclization is favored over endocyclization (macrocyclizations are the main exception to this rule). 5-Hexenyl radicals are the most synthetically useful intermediates for radical cyclizations, as the cyclization is extremely rapid and exoselective.[3] Although the exo radical is less thermodynamically stable than the endo radical, the faster exo cyclization is rationalized by better orbital overlap in the chair-like exo transition state (see below). (1) Substituents that affect the stability of these transition states can have a profound effect on the site selectivity of the reaction. Carbonyl substituents at the 2-position, for example, encourage 6-endo ring closure. Alkyl substituents at the 2-, 3-, 4-, or 6-position improve selectivity for the 5-exo closure. The cyclization of the 6-heptenyl radical homologue is still selective, but is much slower: consequently, the reactionsCompetitive collaterals are a major issue when these intermediates are involved. Furthermore, shifts of 1.5 can produce stabilized allylic radicals at comparable rates in these systems. In 6-hexenyl radical substrates, polarization of the reactive double bond with electron-attracting functional groups is often necessary to obtain high yields.[4] Stabilization of the initially formed radical with electron-withdrawing groups preferentially provides access to more stable 6-endo cyclization products.(2) Cyclization reactions of vinyl, aryl, and acyl radicals are also known. Under kinetic control conditions, 5-exo cyclization occurs preferentially. However, low concentrations of a radical scavenger establish thermodynamic control and provide access to the 6-endo products, not via 6-endo cyclization, but via 5-exo cyclization followed by 3-exo closure and subsequent fragmentation (Dowd rearrangement -Beckwith). While at high concentrations the exo product is rapidly trapped preventing subsequent rearrangement into the endo product[5], aryl radicals show similar reactivity. (3) Cyclization can involve multiple bonds containing heteroatoms such as nitriles, oximes, and carbonyls. An attack on the carbon atom of the multiple bond is almost always observed.[6] [7] [8] In the latter case the attack is reversible; however alkoxy radicals can be trapped using a stannane trapping agent. Stereoselectivity. The diastereoselectivity of radical cyclizations is often high. In most all-carbon cases, selectivity can be rationalized according to Beckwith's guidelines, which invoke the reagent-like exo transition state shown above.[9] Placement of substituents at pseudoequatorial positions in the transition state leads to cis products from simple secondary radicals. The introduction of polar substituents can favor trans products due to steric or electronic repulsion between the polar groups. In more complex systems, developing transition state models requires consideration of factors such as allylic strain and boat-like transition states[10](4). Chiral auxiliaries have been used in enantioselective radical cyclizations with limited success.[11] Small energetic differences between early transition states constitute a profound obstacle to success in this field. In the example shown, the diastereoselectivity (for both left stereocenter configurations) is low and the enantioselectivity is only moderate. (5) Substrates with stereocenters between the radical and multiple bonds are often highly stereoselective. Radical cyclizations to form polycyclic products often exploit this property.[12]Scope and limitations. Radical generation methods. The use of metal hydrides (hydrides of tin, silicon and mercury) is common in radical cyclization reactions; the main limitation of this method is the possibility of reduction of the initially formed radical by HM. Fragmentation methods avoid this problem by incorporating the chain transfer reagent into the substrate itself: the active chain-transporting radical is not released until cyclization has taken place. As a result, the products of fragmentation methods retain a double bond, and additional synthetic steps are usually required to incorporate the chain-carrying group. Atom transfer methods rely on the movement of an atom from the acyclic starting material to the cyclic radical to generate the product.[13][14] These methods use catalytic amounts of weak reagents, preventing problems associated with the presence of strong reducing agents (such as tin hydride). I am. 1, 1990, 1469.