Page 272 - Advanced Organic Chemistry Part B - Reactions & Synthesis

244 Carboxylic acids can be converted to acyl chlorides and bromides by a combi-
nation of triphenylphosphine and a halogen source. Triphenylphosphine and carbon
CHAPTER 3 tetrachloride convert acids to the corresponding acyl chloride. 100 Similarly, carboxylic
Functional Group acids react with the triphenyl phosphine-bromine adduct to give acyl bromides. 101
Interconversion 102
by Substitution, Triphenylphosphine–N-bromosuccinimide also generates acyl bromide in situ. All
Including Protection and these reactions involve acyloxyphosphonium ions and are mechanistically analogous
Deprotection
to the alcohol-to-halide conversions that are discussed in Section 3.1.2.

O
+ +
H + Ph PBr RC O PPh + HBr
RCO 2 3 3
O O
+
Br – + RC O PPh 3 RCBr + Ph P O
3
Acyl chlorides are highly reactive acylating agents and react very rapidly with
alcohols and other nucleophiles. Preparative procedures often call for use of pyridine
as a catalyst. Pyridine catalysis involves initial formation of an acyl pyridinium ion,
which then reacts with the alcohol. Pyridine is a better nucleophile than the neutral
alcohol, but the acyl pyridinium ion reacts more rapidly with the alcohol than the acyl
chloride. 103
O O O
R′OH +
+
RCCl + N RC N RCOR′ + HN
Cl –

An even stronger catalytic effect is obtained when 4-dimethylaminopyridine (DMAP)
is used. 104 The dimethylamino group acts as an electron donor, increasing both the
nucleophilicity and basicity of the pyridine nitrogen.

CH 3 CH 3
.. CH 3 + CH 3
N N

..
N N –
..
..
The inclusion of DMAP to the extent of 5–20 mol % in acylations by acid anhydrides
and acyl chlorides increases acylation rates by up to four orders of magnitude and
permits successful acylation of tertiary and other hindered alcohols. The reagent
combination of an acid anhydride with MgBr 2 and a hindered tertiary amine,
e.g., i-Pr NC H or 1,2,2,6,6,-pentamethylpiperidine, gives an even more reactive
2
2
5
acylation system, which is useful for hindered and sensitive alcohols. 105
100
J. B. Lee, J. Am. Chem. Soc., 88, 3440 (1966).
101 H. J. Bestmann and L. Mott, Justus Liebigs Ann. Chem., 693, 132 (1966).
102
K. Sucheta, G. S. R. Reddy, D. Ravi, and N. Rama Rao, Tetrahedron Lett., 35, 4415 (1994).
103
A. R. Fersht and W. P. Jencks, J. Am. Chem. Soc., 92, 5432, 5442 (1970).
104 G. Hoefle, W. Steglich, and H. Vorbruggen, Angew. Chem. Int. Ed. Engl., 17, 569 (1978);
E. F. V. Scriven, Chem. Soc. Rev., 12, 129 (1983); R. Murugan and E. F. V. Scriven, Aldrichimica
Acta, 36, 21 (2003).
105
E. Vedejs and O. Daugulis, J. Org. Chem., 61, 5702 (1996).