Bredt's rule
Empirical observation in organic chemistry
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Through Organic chemistry, Strain (chemistry) and Pi bond
An anti-Bredt molecule is a moecule which does not follow Bredt's rule. For example, two of the following norbornene isomers violate Bredt's rule and are too unstable to prepare:
Causes and consequences
Bredt's rule results from geometric strain: a double bond at a bridgehead atom necessarily must be trans in at least one ring. For small rings (fewer than eight atoms), a trans alkene cannot be achieved without substantial angle and ring and angle strain (the p orbitals are improperly aligned for a π bond through twisting and pyramidalization). Bredt's rule also applies to carbocations and, to a lesser degree, free radicals, because these intermediates also prefer a planar geometry with 120° angles and sp2 hybridization. It generally does not apply to hypervalent heteroatoms, although they are commonly written with a formal double bond.
Bredt's rule can predict the viability of competing elimination reactions in a bridged system. For example, the metal alkyl complexes usually decompose quickly via beta elimination, but Bredt strain prevents tetranorbornyl complexes from doing so. Bicyclo[5.3.1]undecane-11-one-1-carboxylic acid undergoes decarboxylation on heating to 132 °C, but the similar compound bicyclo[2.2.1]heptan-7-one-1-carboxylic acid remains stable beyond 500 °C, because the decarboxylation proceeds through an anti-Bredt enol.
Bredt's rule may also prevent a molecule from resonating with certain valence bond isomers. 2-Quinuclidonium does not exhibit the usual reactivity of an amide, because the iminoether tautomer would violate the rule.
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Anti-Bredt molecules
There has been active research to seek anti-Bredt molecules, with success quantified in S, the non-bridgehead atom count. The above norbornene system has S = 5, and Fawcett originally postulated that stability required S ≥ 9 in bicyclic systems and S ≥ 11 in tricyclic systems. For bicyclic systems examples now indicate a limit of S ≥ 7, with several such compounds having been prepared. Bridgehead double bonds can be found in some natural products.
Anti-Bredt molecules were historically difficult to synthesize and even harder to isolate, but advances in chemical synthesis have overcome the rule. Early breakthroughs came from Wiseman, Keese, Wiberg, and others, validating anti-Bredt olefin intermediates. Other support for the possible intermediacy of anti-Bredt olefins came more recently. In 2024, a solution to synthesizing and using anti-Bredt olefins in cycloadditions was reported, and was followed by computational studies and the discovery of a palladium-catalyzed annulation.