Page 252 - Advanced Organic Chemistry Part B - Reactions & Synthesis

224 the role of S 2 reactions in the preparation of several classes of compounds. First,
N
however, it is desirable to review the important role that solvent plays in S 2
N
CHAPTER 3
reactions. The knowledgeable manipulation of solvent and related medium effects has
Functional Group led to significant improvement of many synthetic procedures that proceed by the S 2
Interconversion N
by Substitution, mechanism.
Including Protection and
Deprotection
3.2.1. General Solvent Effects

The objective in selecting the reaction conditions for a preparative nucleophilic
substitution is to enhance the mutual reactivity of the leaving group and nucleophile so
that the desired substitution occurs at a convenient rate and with minimal competition
from other possible reactions. The generalized order of leaving-group reactivity
−
−
−
RSO ∼I > Br > Cl pertains for most S 2 processes. (See Section 4.2.3 of Part A
−
N
3
for more complete data.) Mesylates, tosylates, iodides, and bromides are all widely
used in synthesis. Chlorides usually react rather slowly, except in especially reactive
systems, such as allyl and benzyl.
The overall synthetic objective normally governs the choice of the nucle-
ophile. Optimization of reactivity therefore must be achieved by selection of the
reaction conditions, particularly the solvent. Several generalizations about solvents
can be made. Hydrocarbons, halogenated hydrocarbons, and ethers are usually
unsuitable solvents for reactions involving ionic metal salts. Acetone and acetoni-
trile are somewhat more polar, but the solubility of most ionic compounds in these
solvents is low. Solubility can be considerably improved by use of salts of cations
having substantial hydrophobic character, such as those containing tetraalkylam-
monium ions. Alcohols are reasonably good solvents for salts, but the nucleophilicity
of hard anions is relatively low in alcohols because of extensive solvation. The
polar aprotic solvents, particularly dimethylformamide (DMF) and dimethylsulfoxide
(DMSO), are good solvents for salts and, by virtue of selective cation solvation,
anions usually show enhanced nucleophilicity in these solvents. Hexamethylphos-
phoric triamide (HMPA), N N-dimethylacetamide, and N-methylpyrrolidinone are
29
other examples of polar aprotic solvents. The high water solubility of these solvents
and their high boiling points can sometimes cause problems in product separation
and purification. Furthermore, HMPA is toxic. In addition to enhancing reactivity,
polar aprotic solvents also affect the order of reactivity of nucleophilic anions. In
DMF the halides are all of comparable nucleophilicity, 30 whereas in hydroxylic
−
−
solvents the order is I > Br > Cl − and the differences in reactivity are much
greater. 31
There are two other approaches to enhancing reactivity in nucleophilic substitu-
tions by exploiting solvation effects on reactivity: the use of crown ethers as catalysts
and the utilization of phase transfer conditions. The crown ethers are a family of cyclic
polyethers, three examples of which are shown below.

29
A. F. Sowinski and G. M. Whitesides, J. Org. Chem., 44, 2369 (1979).
30 W. M. Weaver and J. D. Hutchinson, J. Am. Chem. Soc., 86, 261 (1964).
31
R. G. Pearson and J. Songstad, J. Org. Chem., 32, 2899 (1967).