Solvent effect in the free-radical oxidation and electrophilic ipso and hydrogen displacement of p-methoxybenzyl alcohol and N-(p-methoxybenzyl)acetamide by Br2

Full text of DOI:10.1021/jo000211m

3880
J . Org. Chem. 2000, 65, 3880-3882
arrested with high selectivity to aldehydes (eqs 3 and 4).
Solven t Effect in th e F r ee-Ra d ica l
In contrast, aliphatic alcohols are much less reactive than
the corresponding aldehydes, and the esters are obtained
with high selectivity also at low conversion (eqs 5-7).
This behavior has been ascribed to polar and enthalpic
effects due to the different electronic configurations of
the alkyl (π-type) and acyl (σ-type) radicals.1-4
Similar results and a similar mechanism are also
involved in the bromine-catalyzed oxidation of N-benzy-
lacetamides by H2O2 in a two-phase system5 (eq 9).
Oxid a tion a n d Electr op h ilic Ip so a n d
Hyd r ogen Disp la cem en t of
p-Meth oxyben zyl Alcoh ol a n d
N-(p-Meth oxyben zyl)a ceta m id e by Br 2
Anna Bravo,*,† Francesca Fontana,‡ Barbara Dordi,† and
Francesco Minisci†
Dipartimento di Chimica, Politecnico di Milano, via
Mancinelli 7, I-20131 Milano, Italy, and Dipartimento di
Ingegneria, Universita` di Bergamo, viale Marconi 5,
I-24044 Dalmine BG, Italy
Received February 15, 2000
In tr od u ction
Reaction 9 is slower than reaction 1 as a result of the
faster reaction 3 compared to the analogous reaction with
N-benzylacetamides.5
Recently we have reported convenient, simple and
highly selective methods under mild conditions (room
temperature) for the oxidation of primary alcohols to
aldehydes or esters, depending on the benzylic or ali-
phatic nature of the alcohol.1,2 The reactions are based
on the oxidation of the alcohol by H2O2 catalyzed by
bromine or bromide ions in a two-phase system (eqs 1
and 2).
Since Br2 is the actual oxidant, the same results of eqs
1, 2, and 9 were obtained by using stoichiometric amounts
of Br2 in the absence of H2O2 in a two-phase system;1,2,5
the process is obviously much more expensive in this case.
Attempts to utilize the bromine-catalyzed oxidation of
p-methoxybenzyl alcohol or N-(p-methoxybenzyl)aceta-
mide by H2O2 for the synthesis of p-anisaldehyde, a useful
industrial intermediate, were unsuccessful; no substan-
tial reaction took place.
Recently a much more complex catalytic system was
-
reported,6 involving methyltrioxorenium with Br
as
cocatalyst, which gives results similar to those of eqs 1
and 2 in the oxidation of primary alcohols by H2O2. Also,
in this case p-methoxybenzyl alcohol was not oxidized,
but p-methoxybenzyl bromide was the only reaction
product. The mechanism of this catalysis was explained
through hydride abstraction by bromine, but we believe
that also this catalysis involves a hydrogen atom abstrac-
tion by Br• according to the free-radical chains of eqs 3-8.
In attempts to explain the behavior of p-methoxybenzyl
alcohol and acetamide, we have investigated the reaction
of these substrates by Br2 in a variety of solvents.
The reactions are promoted by ambient light, and the
actual oxidant is Br2, which operates by free-radical chain
processes1,2 in the organic phase (eqs 3-7); the formed
HBr is continuously extracted by the aqueous phase and
oxidized by H2O2 to Br2 (eq 8), shifting the equilibrium
of eq 3 to the right and making the process catalytic in
bromine.
Resu lts a n d Discu ssion
The reaction of p-methoxybenzyl alcohol with bromine
by the typical procedure1,2 to obtain aldehydes (H2O/
CH2Cl2 as solvent at room temperature) led to p-bro-
moanisole (1) as the main reaction product and to
anisaldehyde (2) in low yields, with 3-bromo-4-methoxy-
benzyl alcohol (3) as a minor product (eq 10).
Benzyl alcohols are much more reactive than the
corresponding aromatic aldehydes toward hydrogen
abstraction by Br• (eq 3), so that the oxidation can be
† Politecnico di Milano.
(3) Minisci, F. Top. Curr. Chem. 1976, 62, 38.
(4) Minisci, F.; Citterio, A. Adv. Free Rad. Chem. 1980, 6, 119.
(5) Manuscript in preparation.
(6) Espenson, J . H.; Zhu, Z.; Zauche, T. H. J . Org. Chem. 1999, 64,
1191.
‡ Universita` di Bergamo.
(1) Amati, A.; Dosualdo, G.; Zhao, L.; Bravo, A.; Fontana, F.; Minisci,
F.; Bjørsvik, H. R. Org. Process Res. Dev. 1998, 2, 261.
(2) Minisci, F.; Fontana, F. Chim. Ind. 1998, 80, 1309.
10.1021/jo000211m CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/18/2000

Notes
J . Org. Chem., Vol. 65, No. 12, 2000 3881
Sch em e 1
Ta ble 1. Rea ction of p-Meth oxyben zyl Alcoh ol (1 m m ol)
relevant because the two positions ortho to the methoxy
group are free, and the ipso substitution (formation of 1)
is always greatly or exclusively prevailing over the
normal ortho substitution (formation of 3), considering
that the bromination of anisole leads to the para isomer
in great prevalence7 (98.4%) but also to a minor amount
of the ortho isomer (1.6%). A possible interpretation
concerns the fact that the formation of the Wheland
intermediates (Scheme 1) could be reversible and +CH2-
OH is a better leaving group than proton under acid
conditions (HBr is formed in the reaction); this would
balance the unfavorable steric effect for the addition to
give ipso substitution.
The electrophilic ipso substitution of activated benzyl
alcohols is well-known,8-15 but in the reaction of p-
methoxybenzyl alcohol and Br2 the evaluation of the
normal ortho substitution was never reported, and
formation of anisaldehyde (2) was carefully sought but
not found.14
w ith Br 2
yieldsa (%)
solvent
n-hexane
n-hexane/H2O 1:1
CH2Cl2
CH2Cl2/H2O 1:1
AcOEt
AcOEt
Br2 (mmol)
1
2
3
0.8
0.8
0.8
0.8
0.8
1
16.3
48.2
38.1
59.9
24.4
28.6
70.7
42.5
36.9
75.5
93.8
21.3
tr
3.9
6.3
4.4
3.2
4.4
4.7
2.5
0.7
1.6
AcOEt/H2O 1:1
CH3CN
AcOH
1
0.8
0.8
1
1.8
1.2
4.8
CH3OH
CH3OHb
1
a
Yield based on reacted Br2. b Irradiation by incandescent lamp.
Under the same conditions but in a homogeneous
system (CH2Cl2 as solvent) the same products were
obtained, but the yields of 1 were significantly lower.
When the reaction was carried out in n-hexane, 2 was
the main reaction product, but 1 was still significant. By
using a different two-phase system (n-hexane/H2O) the
yields of 1 considerably increased, while 2 was obtained
only in traces. The results with a variety of solvents are
reported in Table 1. These results well explain why the
bromine-catalyzed oxidation of p-methoxybenzyl alcohol
by H2O2 is inhibited. The catalytic amount of Br2 is
consumed, and H2O2 cannot oxidize benzyl alcohol in the
absence of the catalyst. The inertness of p-methoxybenzyl
alcohol toward H2O2 in the absence of bromine has been
verified by a blank experiment.
At least three competitive processes are clearly in-
volved: the electrophilic ipso substitution of the -CH2-
OH group, the electrophilic ring bromination ortho to the
methoxy group, and the free-radical oxidation of -CH2-
OH to -CHO.
The solvents affect both the ratio between electrophilic
substitutions and free-radical oxidation [(1 + 3)/2] and
the ratio between ipso and hydrogen displacement (1/3).
Only in nonpolar solvents, such as n-hexane, the free-
radical oxidation (eqs 3 and 4) prevails slightly over the
electrophilic processes. This must be ascribed, in our
opinion, to the influence of solvent effect on the electro-
philic processes; on the other hand, the rate of the free-
radical oxidation should be substantially unaffected by
solvents. The solvent also influences the ratio between 1
and 3; in polar solvents 3 was not formed. The fact is
The reaction of N-(p-methoxybenzyl)acetamide with
Br2 led to similar results (eq 11). Moreover methyl
4-methoxybenzoate and methyl 3-bromo-4-methoxyben-
zoate were also formed when the reaction was carried
out in methanol solution, and the rate of the free-radical
processes was increased through irradiation by an in-
candescent light source. Clearly these last compounds
were formed by further oxidation of 2 and 4, according
to the mechanism of eqs 5-7. The results are reported
in Table 2. Also in this case three competitive processes
can be recognized: free-radical oxidation, electrophilic
(7) Stock, L. M.; Brown, H. C. J . Am. Chem. Soc. 1960, 82, 1942.
(8) Clarke, L.; Esselen, G. I. J . Am. Chem. Soc. 1911, 33, 1135.
(9) Clarke, L.; Patch, R. H. J . Am. Chem. Soc. 1912, 34, 912.
(10) Clarke, L.; Esselen, G. I. J . Am. Chem. Soc. 1914, 36, 308.
(11) Kohler, E. P.; Patch, R. H. J . Am. Chem. Soc. 1916, 38, 1205.
(12) Ziegler, E.; Snatzke, G. Monatsh. Chem. 1953, 84, 278.
(13) Stiles, M.; Sirti, A. J . J . Org. Chem. 1960, 25, 1691.
(14) Arnett, E. M.; Klingensmith, J . Am. Chem. Soc. 1965, 87, 1023.
(15) Arnett, E. M.; Klingensmith, J . Am. Chem. Soc. 1965, 87, 1032.

3882 J . Org. Chem., Vol. 65, No. 12, 2000
Notes
Ta ble 2. Rea ction of N-(p-Meth oxyben zyl)a ceta m id e (1
3) is faster than from N-benzylamides. This means that,
in this latter case, a higher concentration of Br• is
necessary; we verified this assumption by competitive
kinetics.5
m m ol) w ith Br 2
yieldsa (%)
solvent
n-hexane
Br2 (mmol)
1
2
4
5
The formation of 4 is also favored by the use of an
incandescent light source, but in some solvents (CH3OH,
AcOEt/H2O) ambient light is sufficient. In principle 4
could be formed either by electrophilic bromination of
anisaldehyde (2) or by free-radical oxidation of 5. The
latter explanation seems more likely on the basis of the
results obtained with an increasing amount of Br2 in
AcOEt/H2O medium; the amount of 4 increases with the
increased amount of Br2. The introduction of bromine
deactivates the aromatic ring of 5 toward further elec-
trophilic bromination, but it has a negligible effect on the
free-radical oxidation of the -CH2NHCOR group. More-
over, the electrophilic bromination of the aromatic ring
is certainly faster for N-(p-methoxybenzyl)acetamide
than for 2.
0.8
0.8
1
1
1
0.5
1
2
1
1
7.2
26.0
30.4
20.7
26.1
16.2
16.3
28.2
31.2
39.1
11.3
13.2
92.8
74.0
57.8
79.3
69.2
82.9
82.8
63.8
68.8
33.9
83.2
56.2
CH2Cl2
CH2Cl2/H2Ob 1:1
AcOEt
11.9
4.7
AcOEtb
AcOEt/H2O 1:1
AcOEt/H2O 1:1
AcOEt/H2Oc 1:1
CH3CN
0.9
0.7
0.7
0.4
6.5
CH3CNb
9.1
17.9
5.5
9.6
CH3OH
1
1
CH3OHb,d
12.3
a
Yield based on reacted Br2. b Irradiation by incandescent lamp.
c 2,4-Dibromoanisole, formed by further bromination, was evalu-
ated in 1. In addition, 6% of methyl 4-bromobenzoate and 2.1%
d
of methyl 3-bromo-4-methoxybenzoate were also formed.
ring bromination, and ipso substitution, which is signifi-
cant in all of the experiments of Table 2.
Exp er im en ta l Section
To the best of our knowledge it is the first time that
ipso substitution of the -CH2NHCOR group is observed
in electrophilic aromatic substitutions. This ipso substitu-
tion is somewhat less favorable than that of the -CH2-
OH group, and the ring bromination (formation of 5) is
generally prevailing. Two main factors are, in our opin-
ion, responsible for this behavior according to the mech-
anism of Scheme 1: +CH2OH is a better leaving group
than +CH2NHCOR, which presents a larger steric hin-
drance for the electrophilic attack.
Experiments entailed the use of 8 mL of organic solvent, in
which 1 mmol of p-methoxybenzyl alcohol or N(p-methoxyben-
zyl)acetamide were dissolved, and variable amounts of Br2, as
reported in Tables 1 and 2. In the case of the two-phase systems
reported in these Tables, 8 mL of H2O was also added. The
solutions or heterogeneous mixtures were stirred at room
temperature for 5 h. Where indicated the reaction medium was
irradiated by an incandescent light source (Osram Halolux UV-
stop 64479 230 V, 250 W). The reaction products dissolved in
the organic phase were identified by GC-MS by comparison with
authentic samples. The quantitative analysis was carried out
by GLC with internal standards. The results of typical experi-
ments with p-methoxybenzyl alcohol and N-(p-methoxybenzyl)-
acetamide are reported in Tables 1 and 2, respectively.
In this case, anisaldehyde (2) was formed in significant
amount only when the reaction mixture was irradiated
by an incandescent light source. This is due to the fact
that hydrogen abstraction by Br• from benzyl alcohols (eq
J O000211M