Chapter 10: Regioselectivity

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Chapter 10 is in a portable document file (pdf) and can be viewed by clicking the blue Chapter 10 button. The drawing below the button illustrates the importance of ring size to the regioselectivity of radical cyclization. Beside and below this drawing is a summary of Chapter 10.

This image shows the regioselectivity in cyclization of a carbohydrate radical.
Summary of Chapter 10

Regioselectivity is a term that describes reactions in which one structural isomer is generated in preference to other possible structural isomers. It refers to reactions that involve a single functional group (e.g., a multiple bond in an unsaturated compound) and to those in which abstraction of a particular atom or group takes place in compounds that contain at least one other atom or group of the same type.

Most addition reactions are regioselective because a radical adds to the less-substituted carbon atom in a carbon–carbon multiple bond. Steric effects are the primary factor controlling most such reactions, but in those where steric effects are minimal, polar effects often become the determining factor.

Internal addition of a radical to a multiple bond often has the choice of generating either a five- or a six-membered ring or either a six- or seven-membered ring. Regioselectivity in most of these reactions favors formation of the smaller ring even though cyclization to give the larger ring often produces the thermodynamically more stable radical.

The reverse of radical addition to a double bond is β-fragmentation. Where carbohydrates are concerned, oxygen-centered radicals generally undergo a β-fragmentation that involves ring opening. Carbon-centered radicals also undergo β-fragmentation that can cause ring opening, and can lead to unsaturated compounds by radical expulsion.

Regioselectivity in hydrogen-atom abstraction depends on the abstracting agent and can vary considerably. The extremely reactive hydroxyl radical can abstract a hydrogen atom from any of the six carbon–hydrogen bonds in α-D-glucopyranose. This type of reaction is exothermic and exhibits little, if any, site selectivity. Hydrogen-atom abstraction by a bromine atom, on the other hand, is an endothermic process that is highly regioselective.

Intramolecular hydrogen-atom abstraction often involves reaction of an oxygen-centered radical. Since the most stable transition state for internal hydrogen-atom transfer nearly always has a six-membered ring, the 1,5-hydrogen-atom migration (1,5-radical translocation) that occurs is a highly regioselective reaction. Only the most reactive carbon-centered radicals (e.g., vinylic and primary) consistently are able to abstract hydrogen atoms from carbon–hydrogen bonds. Such abstraction usually is an intramolecular reaction.

Site selectivity occurs in reactions of compounds with groups and atoms other than hydro­gen, but such reactions are rare because few carbohydrates contain two or more of the same reactive groups (or atoms). Compounds with two of the same O-thiocarbonyl groups or two isocyano groups are known to react selectively with the tri-n-butyltin radical. In such reactions significant selectivity exists if there is a choice between forming a primary or a secondary radical.