Page 262 - Advanced Organic Chemistry Part B - Reactions & Synthesis

234 3.2.7. Summary of Nucleophilic Substitution at Saturated Carbon
3
CHAPTER 3 Some of the nucleophilic substitution reactions at sp carbon that are most
Functional Group valuable for synthesis were outlined in the preceding sections, and they all fit into
Interconversion the general mechanistic patterns that were discussed in Chapter 4 of Part A. The
by Substitution,
Including Protection and order of reactivity of alkylating groups is benzyl ∼ allyl > methyl > primary >
Deprotection secondary. Tertiary halides and sulfonates are generally not satisfactory because of
the preference for elimination over S 2 substitution. Owing to their high reactivity
N
toward nucleophilic substitution, -haloesters, -haloketones, and -halonitriles are
usually favorable reactants for substitution reactions. The reactivity of leaving groups
is sulfonate ∼ iodide > bromide > chloride. Steric hindrance decreases the rate of
nucleophilic substitution. Thus projected synthetic steps involving nucleophilic substi-
tution must be evaluated for potential steric problems.
Scheme 3.2 gives some representative examples of nucleophilic substitution
processes drawn from Organic Syntheses and from other synthetic efforts. Entries 1 to
3 involve introduction of cyano groups via tosylates and were all conducted in polar
aprotic solvents. Entries 4 to 8 are examples of introduction of the azido functional
group by substitution. The reaction in Entry 4 was done under phase transfer condi-
tions. A concentrated aqueous solution of NaN was heated with the alkyl bromide
3
and 5 mol % methyltrioctylammonium chloride. Entries 5 to 7 involve introduction of
the azido group at secondary carbons with inversion of configuration in each case. The
reactions in Entries 7 and 8 involve formation of phosphoryl esters as intermediates.
These conditions were found preferable to the Mitsunobu conditions for the reaction
in Entry 7. The electron-rich benzylic reactant gave both racemization and elimination
via a carbocation intermediate under the Mitsunobu conditions. Entries 9 and 10 are
cases of controlled alkylation of amines. In the reaction in Entry 9, the pyrrolidine was
used in twofold excess. The ester EWGs have a rate-retarding effect that slows further
alkylation to the quaternary salt. In the reaction in Entry 10, the monohydrochloride
of piperazine is used as the reactant. The reaction was conducted in ethanol, and
the dihydrochloride salt of the product precipitates as reaction proceeds, which helps
minimize quaternization or N,N -dialkylation. The yield of the dihydrochloride is

97–99%, and that of the amine is 65–75% after neutralization of the salt and distillation.
The reaction in Entry 11 is the O-alkylation of an amide. The reaction was done in
refluxing benzene, and the product was obtained by distillation after the neutralization.
Sections D through H of Scheme 3.2 involve oxygen nucleophiles. The hydrolysis
reactions in Entries 12 and 13 both involve benzylic positions. The reaction site in
Entry 13 is further activated by the ERG substituents on the ring. Entries 14 to 17 are
examples of base-catalyzed ether formation. The selectivity of the reaction in Entry 17
for the meta-hydroxy group is an example of a fairly common observation in aromatic
systems. The ortho-hydroxy group is more acidic and probably also stabilized by
chelation, making it less reactive.
CH 3 O CH 3 O CH 3 O
H K K
O O O
K CO 3 CH I
3
2
HO – O CH O
3
Dialkylation occurs if a stronger base (NaOH) and dimethyl sulfate is used. Entry 18 is
a typical diazomethane methylation of a carboxylic acid. The toxicity of diazomethane