- Quinuclidone
Quinuclidones are a class of
bicyclic organic compound s withchemical formula C7H11NO with twostructural isomer s for the base skeleton 3-quinuclidone and 2-quinuclidone.3-Quinuclidone (1-azabicyclo [2.2.2] octan-3-one) is an uneventful molecule that can be synthesized as the
hydrochloric acid salt in aDieckman condensation [Organic Syntheses , Coll. Vol. 5, p.989 (1973); Vol. 44, p.86 (1964) [http://www.orgsyn.org/orgsyn/prep.asp?prep=cv5p0989 Article] ] :Organic reduction of this compound gives the compoundquinuclidine , structurally related toDABCO which has one additional bridgehead nitrogen atom.The other isomer, 2-quinuclidone, appears equally uneventful but in fact it has defied synthesis until 2006. ["Synthesis and structural analysis of 2-quinuclidonium tetrafluoroborate" Kousuke Tani and Brian M. Stoltz Nature 441, 731-734 (8 June 2006) | doi|10.1038/nature04842] [Blogged on www.totallysynthetic.com [http://totallysynthetic.com/blog/?p=120 Link] June 11] [Bethany Halford "Amide With A Twist" Chemical and Engineering News June 12, 2006 Volume 84, Number 24 p. [http://pubs.acs.org/cen/news/84/i24/8424notw4.html Article] ] The reason is that this molecule is very unstable because its
amide group has theamine lone pair and thecarbonyl group not properly aligned as may be expected for an amide as a result ofsteric strain . This behaviour is predicted byBredt's Rule and formalamide group resembles in fact anamine as evidenced by the ease of salt formation.The
organic synthesis of thetetrafluoroborate salt of 2-quinuclidone is a six-step affair starting fromnorcamphor the final step being anazide -ketone Schmidt reaction (38% yield) [Reaction sequence: first step is aBaeyer-Villiger oxidation ofnorcamphor 1 withMeta-Chloroperoxybenzoic acid tobicyclic lactone 2, followed byorganic reduction withlithium aluminium hydride indiethyl ether todiol 3. The primaryalcohol group is replaced by atosylate group in 4 withtosyl chloride andtriethylamine and in turn displaced by anazide group in 5 by action ofsodium azide indimethylformamide . Oxidation of the alcohol to theketone 6 takes place withDess-Martin periodinane indichloromethane . The final step to 2-quinuclidonium tetrafluoroborate 8 is aSchmidt reaction through intermediate 7 withhydrogen tetrafluoroborate indiethyl ether . ] :This compound rapidly reacts with water to the corresponding
amino acid with achemical half-life of 15 seconds.X-ray diffraction showspyramidalization on the nitrogen atom (59° compared to 0 for referencedimethylformamide ) and torsion around thecarbon-nitrogen bond to an extent of 91°. Attempts to prepare the free base lead to uncontrolledpolymerization .It is nevertheless possible to estimate its basicity in an experiment in which amine pairs (the quinuclidonium salt and a reference amine such as
diethylamine orindoline ) are introduced into amass spectrometer . The relative basicity is then revealed by collision induced dissociation of the heterodimer. Further analysis via the extended kinetic method allows for the determination of the proton affinity and gas phase basicity of 2-quinuclidonium. This method has determined that quinuclidone ranks among secondary and tertiary amines in terms of proton affinity. ["Synthesis of 2-Quinuclidonium by Eliminating Water: Experimental Quantification of the High Basicity of Extremely Twisted Amides" Tony Ly, Michael Krout, Don K. Pham, Kousuke Tani, Brian M. Stoltz, and Ryan R. JulianJ. Am. Chem. Soc. ; 2007; 129(7) pp 1864 - 1865; (Communication) DOI|10.1021/ja067703m] This high basicity is hypothesized to be due to the loss of electron delocalization when the amide bond is twisted--this causes misalignment of the pi orbitals, resulting in loss of electron resonance.References
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