Radical cyclization reactions produce mono- or polycyclic products through the action of radical intermediates. Because these are intramolecular transformations, they are often very rapid and selective. Selective radical generation can be achieved at carbons bonded to a variety of functional groups, and the reagents used to effect radical generation are numerous. The radical cyclization step generally involves the attack of a radical on a multiple bond. Once this step is complete, the resulting cyclized radicals are deactivated by 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 smaller and larger rings is rarely observed. Three conditions must be met for efficient radical cyclization to take place: A method must be available to generate a radical selectively on the substrate. The radical cyclization must be faster than the trapping of the radical initially formed. .[2]Say no to plagiarism. Get a tailor-made essay on “Why Violent Video Games Should Not Be Banned”? Get an original essay All steps must be faster than unwanted side reactions such as free radical recombination or reaction with a solvent. Advantages: Because radical intermediates are not charged species, the reaction conditions are often mild and the tolerance of functional groups is high. Reactions can be carried out in almost any solvent, and the products are often synthetically useful compounds that can be made using existing functionalities or groups introduced during radical scavenging. Disadvantages: the relative rates of the different stages of radical cyclization reactions (and possible side reactions). ) must be carefully controlled so that cyclization and trapping of the cyclized radical are 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]Dominant mechanism[ edit]Because many reagents exist for radical generation and scavenging, it is not possible to establish a single dominant mechanism. However, once a radical is 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 in the resulting intermediate ends up outside the ring, the attack is called "exo"; If it ends up inside the newly formed ring, the attack is called "endo." In many cases, exocyclization is favored over endocyclization (macrocyclizations are the major exception to this rule). 5-Hexenyl radicals are the most synthetically useful intermediates for radical cyclizations, because the cyclization is extremely rapid and exo-selective.[3] Although the exo radical is less thermodynamically stable than the endo radical, the faster exocyclization is rationalized by better orbital overlap in the chair-shaped 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, promote closure of the 6-endo ring. The alkyl substituents inpositions 2, 3, 4 or 6 improve selectivity for 5-exo closure. The cyclization of the homologous 6-heptenyl radical is still selective, but it is much slower. As a result, competitive side reactions are a significant problem when these radical intermediates are involved. Additionally, changes 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-withdrawing functional groups is often necessary to achieve high yields.[4] Stabilization of the radical initially formed with electron-withdrawing groups allows preferential access to more stable 6-endo cyclization products. (2) Cyclization reactions of vinyl, aryl and acyl radicals are also known. Under kinetically controlled conditions, 5-exo cyclization takes place preferentially. However, low concentrations of a radical scavenger establish thermodynamic control and provide access to 6-endo products, not via 6-endo cyclization, but by 5-exo cyclization followed by 3-exo closure and d a later fragmentation (Dowd-Beckwith rearrangement). Whereas at high concentrations, the exo product is rapidly trapped, preventing further rearrangement to the endo product. [5] Aryl radicals exhibit similar reactivity. (3) Cyclization can involve multiple bonds containing heteroatoms such as nitriles, oximes, and carbonyls. Attack at 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 scavenger. 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 reactive-like exo transition state presented above.[9] Placing substituents in pseudoequatorial positions in the transition state leads to cis products from single secondary radicals. The introduction of polar substituents can favor trans products due to steric or electronic repulsion between polar groups. In more complex systems, developing transition state models requires consideration of factors such as allylic strain and boat-shaped transition states[10][4]. Chiral auxiliaries have been used in enantioselective radical cyclizations with limited success.[11] A major obstacle to success in this area is the small energy differences between the first transition states. In the example shown, the diastereoselectivity (for both left stereocenter configurations) is low and the enantioselectivity is only moderate.(5) Substrates with stereocenters between radical and multiple bonding are often highly stereoselective. Radical cyclizations to form polycyclic products often take advantage of this property.[12]Scope and limitations. Radical generation methods. The use of metal hydrides (tin, silicon, and mercury hydrides) is common in radical cyclization reactions; the main limitation of this method is the possibility of reduction of the radical initially formed by HM. Fragmentation methods avoid this problem by incorporating the chain transfer reagent into the substrate itself: the active chain-carrying radical is released only after cyclization. The products of fragmentation methods thus retain a double bond and additional synthesis steps are usually. 1, 1990, 1469.