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Bredt's rule

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In organic chemistry, an anti-Bredt molecule is a bridged molecule with a double bond at the bridgehead. Bredt's rule is the empirical observation that such molecules only form in large ring systems. For example, two of the following norbornene isomers violate Bredt's rule, and are too unstable to prepare:

Bridgehead atoms violating Bredt's rule in red

The rule is named after Julius Bredt, who first discussed it in 1902[1] and codified it in 1924.[2] In 2024, Neil Garg and his team showed that formation of anti-Bredt molecules is possible, even if only as short-lived intermediates.[3]

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 ring and angle strain (the p orbitals are improperly aligned for a π bond). 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.[4]

There has been an active research program to seek anti-Bredt molecules,[5][6] 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[7] and S ≥ 11 in tricyclic systems.[8] For bicyclic systems examples now indicate a limit of S ≥ 7,[4] with several such compounds having been prepared.[9] Bridgehead double bonds can be found in some natural products.[10]

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.[11] 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.[4]

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.[12]

Although exceptions to the rule have long been known, in 2024 chemists from University of California, Los Angeles demonstrated a general method to access Anti-Bredt olefins with S ≤ 7.[6][13]

See also

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References

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  1. ^ Bredt, J.; Houben, Jos.; Levy, Paul (1902). "Ueber isomere Dehydrocamphersäuren, Lauronolsäuren und Bihydrolauro-Lactone". Ber. Dtsch. Chem. Ges. (in German). 35 (2): 1286–1292. doi:10.1002/cber.19020350215.
  2. ^ Bredt, J. (1924). "Über sterische Hinderung in Brückenringen (Bredtsche Regel) und über die meso-trans-Stellung in kondensierten Ringsystemen des Hexamethylens". Justus Liebigs Ann. Chem. (in German). 437 (1): 1–13. doi:10.1002/jlac.19244370102.
  3. ^ Conroy, Gemma (2024-11-01). "Chemists make 'impossible' molecules that break 100-year-old bonding rule". Nature. doi:10.1038/d41586-024-03538-4.
  4. ^ a b c Bansal, Raj K. (1998). "Bredt's Rule". Organic Reaction Mechanisms (3rd ed.). McGraw-Hill Education. pp. 14–16. ISBN 9780074620830.
  5. ^ Köbrich, Gert (1973). "Bredt Compounds and the Bredt Rule". Angew. Chem. Int. Ed. 12 (6): 464–473. doi:10.1002/anie.197304641.
  6. ^ a b McDermott, Luca; Walters, Zach G.; French, Sarah A.; Clark, Allison M.; Ding, Jiaming; Kelleghan, Andrew V.; Houk, K. N.; Garg, Neil K. (1 November 2024). "A solution to the anti-Bredt olefin synthesis problem". Science. 386 (6721). doi:10.1126/science.adq3519.
  7. ^ Fawcett, Frank S. (1950). "Bredt's Rule of Double Bonds in Atomic-Bridged-Ring Structures". Chem. Rev. 47 (2): 219–274. doi:10.1021/cr60147a003. PMID 24538877.
  8. ^ "Bredt's Rule". Comprehensive Organic Name Reactions and Reagents. 116: 525–528. 2010. doi:10.1002/9780470638859.conrr116. ISBN 9780470638859.
  9. ^ Hall, H. K.; El-Shekeil, Ali (1980). "Anti-Bredt molecules. 3. 3-Oxa-1-azabicyclo[3.3.1]nonan-2-one and 6-oxa-1-azabicyclo[3.2.1]octan-7-one, two atom-bridged bicyclic urethanes possessing bridgehead nitrogen". J. Org. Chem. 45 (26): 5325–5328. doi:10.1021/jo01314a022.
  10. ^ Mak, Jeffrey Y. W.; Pouwer, Rebecca H.; Williams, Craig M. (2014). "Natural Products with Anti-Bredt and Bridgehead Double Bonds" (PDF). Angew. Chem. Int. Ed. 53 (50): 13664–13688. doi:10.1002/anie.201400932. PMID 25399486.
  11. ^ Li Huidong; Hu Yucheng; Wan Di; Zhang Ze; Fan Qunchao; King, R. Bruce; Schaefer, Henry F. "Dispersion Effects in Stabilizing Organometallic Compounds". Journal of Physical Chemistry A. doi:10.1021/acs.jpca.9b06769. Supporting Information.
  12. ^ Tani, Kousuke; Stoltz, Brian M. (2006). "Synthesis and structural analysis of 2-quinuclidonium tetrafluoroborate" (PDF). Nature. 441 (7094): 731–734. Bibcode:2006Natur.441..731T. doi:10.1038/nature04842. PMID 16760973. S2CID 4332059.
  13. ^ Conroy, Gemma (1 November 2024). "Chemists make 'impossible' molecules that break 100-year-old bonding rule". nature.com. Retrieved 3 November 2024.
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