Page 253 - Advanced Organic Chemistry Part B - Reactions & Synthesis

O O 225
O O O O O O
SECTION 3.2
O O O O O O Introduction of
O Functional Groups by
O O Nucleophilic Substitution
at Saturated Carbon
15-crown-5 18-crown-6 dicyclohexano-18-crown-6

The first number designates the ring size and the second the number of oxygen atoms
in the ring. By complexing the cation in the cavity of the crown ether, these compounds
can solubilize salts in nonpolar solvents. In solution, the anions are more reactive as
nucleophiles because they are weakly solvated. Tight ion pairing is also precluded by
the complexation of the cation by the nonpolar crown ether. As a result, nucleophilicity
approaches or exceeds that observed in aprotic polar solvents, 32 but the crown ethers
do present some hazards. They are toxic and also have the potential to transport toxic
anions, such as cyanide, through the skin.
Another method of accelerating nucleophilic substitution is to use phase transfer
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catalysts, which are ionic substances, usually quaternary ammonium or phosphonium
salts, in which the hydrocarbon groups in the cation are large enough to convey
good solubility in nonpolar solvents. In other words, the cations are highly lipophilic.
Phase transfer catalysis usually is done in a two-phase system. The reagent is
dissolved in a water-insoluble solvent such as a hydrocarbon or halogenated hydro-
carbon. The salt of the nucleophile is dissolved in water. Even with vigorous
mixing, such systems show little tendency to react, because the nucleophile and
reactant remain separated in the water and organic phases, respectively. When a
phase transfer catalyst is added, the lipophilic cations are transferred to the nonpolar
phase and anions are attracted from the water to the organic phase to maintain
electrical neutrality. The anions are weakly solvated in the organic phase and therefore
exhibit enhanced nucleophilicity. As a result, the substitution reactions proceed
under relatively mild conditions. The salts of the nucleophile are often used in
high concentration in the aqueous solution and in some procedures the solid salts
are used.

3.2.2. Nitriles

The replacement of a halide or sulfonate by cyanide ion, extending the carbon
chain by one atom and providing an entry to carboxylic acid derivatives, has been
a reaction of synthetic importance since the early days of organic chemistry. The
classical conditions for preparing nitriles involve heating a halide with a cyanide salt
in aqueous alcohol solution.

32 M. Hiraoka, Crown Compounds: Their Characteristics and Application, Elsevier, Amsterdam, 1982.
33
E. V. Dehmlow and S. S. Dehmlow, Phase Transfer Catalysis, 3rd Edition, Verlag Chemie, Weinheim
1992; W. P. Weber and G. W. Gokel, Phase Transfer Catalysis in Organic Synthesis, Springer Verlag,
New York, 1977; C. M. Stark, C. Liotta, and M. Halpern, Phase Transfer Catalysis: Fundamentals,
Applications and Industrial Perspective, Chapman and Hall, New York, 1994.