Effect of Cyclodextrins on Electrophilic Aromatic Bromination in Aqueous Solutions
1109
Table 2. NMR signals used for determining product ratios
Spectroscopic dataA
7.22 (2 H, m, H3, H5), 6.91–6.80 (3 H, m, H2, H4, H6), 3.77 (3 H, s, OCH3)
Compound Solvent
Reference
B
B
(3a)
(3b)
CDCl3
[D6]DMSO 7.54 (2 H, d, J 7.5, H2, H6), 7.26 (2 H, t, J 7.5, H3, H5), 7.00 (1 H, t, J 7.5, H4), 2.02 (3 H, s,
NHCOCH3)
B
B
(3c)
(4a)
CDCl3
CDCl3
7.38 (2 H, m, H3, H5), 7.24 (1 H, m, H4), 7.09 (2 H, m, H2, H6), 2.28 (3 H, s, COCH3)
7.54 (1 H, dd, J 8.0 and 1.5, H6), 7.27 (1 H, ddd, J 8.0, 7.5 and 1.5, H5), 6.90 (1 H, dd, J 8.5 and
1.5, H3), 6.84 (1 H, ddd, J 8.5, 7.5 and 1.5, H4), 3.89 (3 H, s, OCH3)
(4b)
(4c)
[D6]DMSO 7.61 (1 H, d, J 7.5 and 1.5, H6), 7.33 (1 H, td, J 7.5 and 1.5, H5), 7.10 (1 H, td, J 7.5 and 1.5, H4),
2.06 (3 H, s, NHCOCH3)
[19]
[20]
CDCl3
7.60 (1 H, dd, J 8.5 and 1.5, H6), 7.32 (1 H, ddd, J 8.0, 7.5 and 1.5, H5), 7.13 (1 H, m, H3), 7.12
(1 H, m, H4), 2.34 (3 H, s, COCH3)
B
B
(5a)
(5b)
(5c)
(6a)
(6b)
(7a)
CDCl3
6.70 (2 H, d, J 9.0, H2, H6), 7.29 (2 H, d, J 9.0, H3, H5), 3.79 (3 H, s, OCH3)
[D6]DMSO 7.53 (2 H, d, J 9.0, H3, H5), 7.43 (2 H, d, J 9.0, H2, H6), 2.02 (3 H, s, NHCOCH3)
CDCl3
CDCl3
7.46 (2 H, d, J 9.0, H3, H5), 6.96 (2 H, d, J 9.0, H2, H6), 2.27 (3 H, s, COCH3)
7.65 (1 H, d, J 2.5, H3), 3.87 (3 H, s, OCH3)
[21]
[22]
[D6]DMSO 7.72 (1 H, d, J 2.1, H3), 2.11 (3 H, s, NHCOCH3)
[23]
B
CD3OD
7.11 (1 H, t, J 8.0, H5), 6.71 (2 H, m, H4, H6), 6.66 (1 H, m, H2), 3.73 (3 H, s, OCH3),
2.28 (3 H, s, ArCH3)
B
(7b)
(9a)
CD3OD
CD3OD
7.35 (1 H, br s, H2), 6.90 (1 H, br d, J 8.0, H4), 7.15 (1 H, t, J 8.0, H5), 7.30 (1 H, br d, J 8.0, H6)
7.35 (1 H, d, J 8.5, H5), 6.83 (1 H, d, J 3.0, H2), 6.63 (1 H, dd, J 8.5 and 3.0, H6), 3.74 (3 H, s, OCH3), [24]
2.32 (3 H, s, ArCH3)
(9b)
CD3OD
CD3OD
CD3OD
CD3OD
CD3OD
CD3OD
CD3OD
CD3OD
7.47 (1 H, d, J 2.5, H2), 7.41 (1 H, d, J 8.5, H5), 7.28 (1 H, dd, J 8.5 and 2.5, H6)
7.49 (1 H, d, J 9.0, H5), 6.80 (1 H, d, J 9.0, H6)
7.53 (1 H, d, J 8.5, H5)
7.60 (1 H, s, H6), 6.69 (1 H, s, H3)
7.60 (1 H, br s, H6), 7.76 (1 H, s, H3)
7.79 (1 H, s, H5)
[25]
B
(11a)
(11b)
(13a)
(13b)
(14a)
(14b)
(X)
[26]
B
[26]
B
7.87 (1 H, s, H5)
7.12 (1 H, ddq, J 8.5, 3.0 and 0.5), 7.68 (1 H, d, J 8.5)
[26]
—
A Discrete signals were not observed for all resonances; those which could not be unambiguously assigned are not shown.
B Spectrum of an authentic sample.
cyclodextrins on chlorination reported previously.[9–12] In the
case of anisole (3a), the cyclodextrins also limit the extent of
formationofthedibromide(6a), andagainitisα-cyclodextrin
that has the greatest effect. It seems likely that this is mainly
due to the cyclodextrins retarding further bromination of
the monobromide (5a) by blocking the 2-position. The net
result of these effects is an increase in the yields of the
monobromides (5a) and (5b), from 73 to 94, and 55 to 98%,
respectively, and a substantial decrease in the quantity of the
corresponding by-products, from 27 to 6, and 45 to 2%. The
cyclodextrins do not alter the regioselectivity of bromination
of phenyl acetate (3c), although β-cyclodextrin decreases the
extent of reaction (Table 1, entries 7–9). In the reactions of the
methylanisole (7a) and methylacetanilide (7b), the cyclodex-
trins increase the yields of the monobromides (9a) and (9b),
probably by limiting the subsequent reactions of (9a) and (9b)
to give the dibromides (11a), (11b), (13a), and (13b) and tri-
bromides (14a) and (14b), as well as by decreasing the extent
of reaction by way of the monobromides (8a), (8b), (10a),
(10b), (12a), and (12b), to give (11a), (11b), (13a), (13b),
(14a), and (14b). Again the effect of the cyclodextrins is to
prevent bromination adjacent to the methoxy and acetamido
groups, in a similar manner to that seen with anisole (3a) and
acetanilide (3b), but in the methylated systems β-cyclodextrin
has the greatest effect. When 1.1 mol equiv. of the bromi-
nating agent was used with β-cyclodextrin, the yields of the
monobromides (9a) and (9b) increased from 37 to 86, and 39
to 72%, respectively, and there was a substantial decrease in
R
(3)
a–c
a–c
R
R
Br
(4)
Br
a,b
a,b
(5)
R
Br
a R = OMe
b R = NHAc
c R = OAc
Br
(6)
Scheme 1.
In the reactions of anisole (3a) and acetanilide (3b), both
α- and β-cyclodextrin change the ratios of formation of the
monobrominated products (4a), (4b), (5a), and (5b) in favour
of the para-substituted isomers (5a) and (5b) (Table 1, entries
1–6). The effect is greatest with α-cyclodextrin. It is thus
apparent that the cyclodextrins limit ortho bromination of the
substrates (3a) and (3b), presumably through the formation of
inclusion complexes which restrict access of the brominating
agent, in a manner that is directly analogous to the effect of