Published as part of the Special Section dedicated to Scott E. Denmark on the occasion
of his 65th birthday
Abstract
2,2-Bis(3-methylbut-2-enyl)-3-oxobutanenitrile [2,2-bis(prenyl)-3-oxobutyronitrile],
an unusual bifunctional nitrile odorant with a fruity rosy, green odor was found to
exhibit surprising differences in its detection thresholds (0.25 ng/L air for hyperosmics;
19 ng/L air for hyposmics) and perceived odor characters. To investigate this remarkable
phenomenon, 13 derivatives of 2,2-bis(3-methylbut-2-enyl)-3-oxobutanenitrile were
synthesized by either monoalkylation of 3-oxo-2-phenylbutanenitrile, or by dialkylation
of sodium 1-cyano-2-oxopropan-1-ide or methyl or ethyl cyanoacetate, or by direct
derivatization of 2,2-bis(3-methylbut-2-enyl)-3-oxobutanenitrile via its vinyl triflate
and Negishi cross coupling. These systematic permutations of the substitution pattern
allowed some insight to be gained into the underlying structure–odor relationships
and the construction of a simple olfactophore model, albeit no final conclusion could
be drawn as to whether the nitrile or carbonyl function acts as the prime osmophore
of the bifunctional compounds. Depending on slight genetic variations and the corresponding
differences in the receptor morphology both can engage in H-bond interactions with
the olfactory receptors, which might explain the observed largely diverging sensitivities.
Methyl 2-cyano-2,2-bis(3-methylbut-2-enyl)acetate with a uniform odor threshold of
0.38 ng/L air turned out to be the most interesting floral, rosy odorant of this study,
followed by 3-methyl-2,2-bis(3-methylbut-2-enyl)but-3-enenitrile with only a nitrile
function and varying odor thresholds (0.40 ng/L air vs. 125 ng/L air).
Key words
bifunctional compounds - cross coupling - dialkylation - fragrance materials - molecular
modeling - nitriles - rose odorants - structure–odor correlation
