Page 255 - Advanced Organic Chemistry Part B - Reactions & Synthesis

CO 227
K 2 3
NC CH Cl NC CH 2 OH
2
H O,100°C SECTION 3.2
2
2.5h 85% Ref. 39
Introduction of
Functional Groups by
Ether formation from alkoxides and alkylating reagents is a reaction of wide
Nucleophilic Substitution
synthetic importance. The conversion of phenols to methoxyaromatics, for example, at Saturated Carbon
is a very common reaction. Methyl iodide, methyl tosylate, or dimethyl sulfate can
be used as the alkylating agents. The reaction proceeds in the presence of a weak
base, such as Na CO or K CO , which deprotonates the phenol. The conjugate bases
3
3
2
2
of alcohols are considerably more basic than phenoxides, so -elimination can be a
problem. Phase transfer conditions can be used in troublesome cases. 40 Fortunately,
the most useful and commonly encountered ethers are methyl and benzyl ethers, where
elimination is not a problem and the corresponding halides are especially reactive
toward substitution.
Two methods for converting carboxylic acids to esters fall into the mecha-
nistic group under discussion: the reaction of carboxylic acids with diazo compounds,
especially diazomethane and alkylation of carboxylate anions by halides or sulfonates.
The esterification of carboxylic acids with diazomethane is a very fast and clean
41
reaction. The alkylating agent is the extremely reactive methyldiazonium ion, which
is generated by proton transfer from the carboxylic acid to diazomethane. The collapse
of the resulting ion pair with loss of nitrogen is extremely rapid.
+
–
RCO H + CH N [RCO + CH N ] RCO CH + N 2
2
2 2
3
3 2
2
2
The main drawback to this reaction is the toxicity of diazomethane and some
of its precursors. Diazomethane is also potentially explosive. Trimethylsilyldia-
zomethane is an alternative reagent, 42 which is safer and frequently used in prepa-
ration of methyl esters from carboxylic acids. 43 Trimethylsilyldiazomethane also
44
O-methylates alcohols. The latter reactions occur in the presence of fluoroboric acid
in dichloromethane.
Especially for large-scale work, esters may be more safely and efficiently prepared
by reaction of carboxylate salts with alkyl halides or tosylates. Carboxylate anions
are not very reactive nucleophiles so the best results are obtained in polar aprotic
solvents 45 or with crown ether catalysts. 46 The reactivity order for carboxylate salts is
+
+
+
Na < K < Rb < Cs . Cesium carboxylates are especially useful in polar aprotic
+
solvents. The enhanced reactivity of the cesium salts is due to both high solubility
and minimal ion pairing with the anion. 47 Acetone is a good solvent for reaction of
carboxylate anions with alkyl iodides. 48 Cesium fluoride in DMF is another useful
39 J. N. Ashley, H. J. Barber, A. J. Ewins, G. Newbery, and A. D. Self, J. Chem. Soc., 103 (1942).
40
F. Lopez-Calahorra, B. Ballart, F. Hombrados, and J. Marti, Synth. Commun., 28, 795 (1998).
41 T. H. Black, Aldrichimia Acta, 16, 3 (1983).
42 N. Hashimoto, T. Aoyama, and T. Shiori, Chem. Pharm. Bull., 29, 1475 (1981).
43
T. Shioiri and T. Aoyama, Adv. Use Synthons Org. Chem., 1, 51 (1993); A. Presser and A. Huefner,
Monatsh. Chem., 135, 1015 (2004).
44 T. Aoyama and T. Shiori, Tetrahedron Lett., 31, 5507 (1990).
45
P. E. Pfeffer, T. A. Foglia, P. A. Barr, I. Schmeltz, and L. S. Silbert, Tetrahedron Lett., 4063 (1972);
J. E. Shaw, D. C. Kunerth, and J. J. Sherry, Tetrahedron Lett., 689 (1973); J. Grundy, B. G. James, and
G . Pattenden, Tetrahedron Lett., 757 (1972).
46
C. L. Liotta, H. P. Harris, M. McDermott, T. Gonzalez, and K. Smith, Tetrahedron Lett., 2417 (1974).
47 G. Dijkstra, W. H. Kruizinga, and R. M. Kellog, J. Org. Chem., 52, 4230 (1987).
48
G. G. Moore, T. A. Foglia, and T. J. McGahan, J. Org. Chem., 44, 2425 (1979).