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Catalytic Processes of Oxidation by Hydrogen Peroxide in the Presence of Br2 or HBr. Mechanism and Synthetic ApplicationsAlessandro Amati,† Gabriele Dosualdo,† Lihua Zhao,† Anna Bravo,† Francesca Fontana,† Francesco Minisci,*,† and
Hans-Rene´ Bjørsvik‡
Dipartimento di Chimica del Politecnico, Via Mancinelli 7, I-20131 Milano, Italy, and Borregaard Synthesis,
P.O. Box 162, N-1701 Sarpsborg, Norway
Abstract:
Abstract:
The mechanism and the synthetic applications for the oxidation
of alcohols, ethers, and aldehydes by H2O2 catalyzed by Br2 or
Br- in a liquid two-phase system (aqueous and organic) are
reported. Aliphatic and benzylic primary alcohols and ethers
show an opposite behavior, which has been rationalized on the
ground of the different electronic configurations of the intermediate
alkyl (ð-type) and acyl (ó-type) radicals and their
influence on enthalpic and polar effects. A two-phase system
is particularly useful also for an efficient benzylic bromination
by Br2 or Br-; the substitution of the benzyl bromide by OH,
OR, and OCOR regenerates Br-, which can be recycled. The
evaluation of the relative reactivities of the involved substrates
and intermediates has allowed to develop a variety of simple,
facile, convenient, and selective syntheses of alcohols, aldehydes,
ketones, esters, and benzyl bromides, which fulfill the conditions
for practical applications.
Hydrogen peroxide is a valuable oxidant for several
reasons: (i) low cost; (ii) low molar mass; (iii) high oxidation
potential (E° ) 1.77 V); (iv) formation of water as reduction
product, thus avoiding the environmental problems which
are frequently involved with other oxidants. However, a
significant disadvantage is represented by the high activation
energy required by many oxidations of organic compounds
by H2O2. For this reason, catalysis is often necessary to
activate H2O2 in these cases. The importance of bromine
catalysis in the autoxidation for a variety of industrial
processes is well-known.1 In the past, we2 have utilized
catalysis by halogens or halogen halides to achieve selective
oxidation of phenols to quinones, which do not occur in the
absence of catalyst. Hydroquinone or catechol derivatives
are not oxidized by H2O2 in the absence of catalyst, but the
oxidation smoothly and selectively takes place in the presence
of catalytic amount of I2 or of HI; the actual oxidant is I2
(eq 1).
The equilibrium of eq 1 is shifted at left because of the
low redox potential (E° ) 0.54 V) of I2, but the presence of
H2O2 determines the fast oxidation of HI (eq 2), shifting the
equilibrium of eq 1 at right.
Similarly, the oxidation of phenols substituted in the 2
and 6 positions does not occur by H2O2 in the absence of
catalyst, while it takes place with high selectivity in the
presence of Br2 or HBr; we1 have interpreted the reaction
according to eqs 3-5.
I2 and Br2 are much less oxidizing than H2O2, but they
are often more reactive and selective. Following a similar
general criterion, other research groups3-14 and, above all,
the Interox Chemicals Ltd. researchers have developed a
series of oxidation processes, which for their simplicity,
selectivity, and cheapness appear to be useful for practical
applications. Several of the reports from this group are
patents9-14 and, obviously, the reaction mechanisms were
not discussed. In this paper, we attempt to rationalize the
† Dipartimento di Chimica del Politecnico.
‡ Borregaard Synthesis.
(1) Walling, C. In ActiVe Oxygen in Chemistry; Foote, C. S., Valentine, J. S.,
Greenberg, A., Liebman, J. L., Eds.; Blackie Academic & Professional:
London, 1995; p 24.
(2) Minisci, F.; Citterio, A.; Vismara, E.; De Bernardinis, S.; Correale, M.;
Neri, C. (ENICHEM) Ital. Pat. 20754A/86 18/5/86. Minisci, F.; Citterio,
A.; Vismara, E.; Fontana, F.; De Bernardinis, S. J. Org. Chem. 1989, 54,
728.
(3) Dakka, J.; Sasson, J. Bull. Soc. Chim. Fr. 1988, 4, 756.
(4) Turner, P. J.; Routledge, V. I., Jeff, M. (Interox Chemicals Ltd.) EP 260054
1986. Xiao, L.; Longeray, R. Information Chim. 1990, 178.
(5) Johnson, R.; Reeve, K. M. Speciality Chemicals 1992, 12, 292.
(6) Wilson, S. Perform. Chemicals 1993, 39.
(7) Dakka, J.; Sasson, J. J. Chem. Soc. Chem. Commun. 1987, 1421.
(
Jones, C. W. Speciality Chemicals 1996, 16, 24.
(9) Dear, K. M.; Turner, P. J. (Interox Chemicals Ltd.) EP 334511, 1988.
(10) Turner, P. J.; Jeff, M. (Interox Chemicals Ltd.) EP 336567, 1988.
(11) Turner, P. J.; Jeff, M.; Reeve, K. M. (Interox Chemicals Ltd.) EP 336568,
1988.
(12) Dear, K. M.; Reeve, K. M.; Turner, P. J. (Interox Chemicals Ltd.) PCT Int.
Appl. WO 9002731, 1988.
(13) Longeray, R.; Lanteri, P.; Lu, X.; Huet, C. (Air Liquide) EP 424242, 1989.
(14) Jones, R. G. (Solvay Interox Ltd.) PCT Int. Appl. WO 9400407.
OH
OH
2HI + H2O2 f I2 + 2H2O (2)
OH
4HBr + 2H2O2 f 2Br2 + 4H2O (5)
Organic Process Research & Development 1998, 2, 261-269
S1083-6160(98)00028-0 CCC: $15.00 © 1998 American Chemical Society and Royal Society of Chemistry Vol. 2, No. 4, 1998 / Organic Process Research & Development ¥ 261
Published on Web 06/24/1998
involved overall reactivity and to show how the understanding
of the structure-reactivity relationship can lead to further
useful synthetic developments.
Oxidation of Alcohols and Aldehydes
Primary aliphatic alcohols, RCH2OH, react with H2O2
under mild conditions in a liquid two-phase system (water
and an organic solvent) in the presence of a catalytic amount
of Br2 or HBr to yield selectively the corresponding esters
(eq 6).
In the absence of Br2 or HBr, no reaction occurs under
the same conditions. The results obtained with a variety of
primary alcohols are reported in Table 1. We explain the
mechanism of the reaction by a free-radical chain process
leading to the acyl bromide (eq 7-10) and the simultaneous
alcoholysis of the acyl bromide (eq 11) and oxidation of HBr
by H2O2.
To the best of our knowledge, the possibility to obtain
esters from primary aliphatic alcohols by bromine-catalyzed
H2O2 oxidation was mentioned by only one line of a report,3
without any indication concerning the structure of the
alcohols, the yields, the experimental conditions, the selectivity,
or the mechanism.
The oxidation of the alcohol takes place in the organic
phase (eqs 8-11), so that the competition of the hydrolysis
of the acyl bromide to the corresponding carboxylic acid is
minimized, whereas the oxidation of HBr by H2O2 (eq 12)
occurs in the aqueous phase. In principle, the reaction could
be carried out in three steps: (i) preparation of the acyl
bromide by a stoichiometric amount of Br2; (ii) alcoholysis
of the acyl bromide; (iii) oxidation of HBr by H2O2.
However, apart the complexity of the stoichiometric oxidation
by Br2, the large amount of HBr developed during the
reaction leads to the bromination of the alcohol (eq 13), thus
reducing the overall selectivity of the oxidation.
In the catalytic process the fast eq 12 keeps the stationary
concentration of HBr very low and the reaction in eq 13 is
practically absent.
The reaction can be carried out by Br2 in the absence of
H2O2 in a two-phase system; also in this case, the stationary
concentration of HBr is very low in the organic phase,
because of the much higher solubility of HBr in the aqueous
phase. After Br2 has reacted, the addition of H2O2 in the
aqueous phase regenerates Br2 by oxidation of HBr, thus
making the overall process catalytic; in this way, the process
is faster compared to the use of a catalytic amount of Br2.
The reaction rate is directly related to the amount of Br2
or HBr. It is convenient, from a practical standpoint, to use
a relatively large amount of Br2 or HBr, to obtain a fast
reaction; after the separation of the organic phase, the
aqueous phase can be recycled without loss of the catalytic
activity.
The mechanism of eqs 7-10 assumes that the intermediate
aldehyde, R-CHO, is more reactive toward bromine than
the starting alcohol, R-CH2OH. We have verified this
assumption either by working at low conversion (by using a
large excess of alcohol with respect to H2O2 no substantial
amount of aldehyde was formed, but the ester is always the
reaction product) or by oxidizing a mixture of aldehyde
R-CHO and alcohol R¢-CH2OH; also in this latter case,
the ester RCOOCH2R¢ was obtained with good selectivity
(eq 14), which confirms that the aldehyde is much more
reactive than the alcohol.
The higher reactivity of the aldehyde compared to the
alcohol towards the free-radical bromination is justified by
the enthalpic effect. The energy of the RCHOH-H bond is
significantly larger (6-7 kcal/mol) than that of the RCO-H
bond; this makes eq 9 almost thermoneutral, whereas eq 7
is an endothermic process. The polar effects are favorable
Table 1. Oxidation of primary aliphatic alcohols to esters
by H2O2, catalyzed by HBr (eq 6)
alcohol solvent
time
(h)
convn
(%)
yield
(%)a
1-propanol CH2Cl2/H2O (1:1) 2 56 99
1-propanol CH2Cl2/H2O (1:1) 4 69 98
1-propanol CH2Cl2/H2O (1:1) 6 100 98
1-butanol CH2Cl2/H2O (1:1) 2 58 99
1-butanol CH2Cl2/H2O (1:1) 4 71 98
1-butanol CH2Cl2/H2O (1:1) 6 100 98
1-pentanol CH2Cl2/H2O (1:1) 6 100 97
1-hexanol CH2Cl2/H2O (1:1) 6 100 98
2-methyl-1-pentanol CH2Cl2/H2O (1:1) 6 100 95
1-heptanol CH2Cl2/H2O (1:1) 6 100 98
1-heptanol hexane/H2O (1:1) 6 61 97
1-heptanolb hexane/H2O (4:1) 6 58 95
1-heptanolc hexane/H2O (4:1) 24 91 91
1-heptanol AcOEt/H2O (1:1) 4 20 57
1-decanol CH2Cl2/H2O (1:1) 6 100 97
a Based on the converted alcohol. b 5% of heptanal is formed. c 9% of heptanal
is formed.
2HBr + H2O2 f Br2 + 2H2O (12)
R-CH2OH + HBr f R-CH2Br + H2O (13)
R-CHO + R¢-CH2OH + H2O2 f R-COO-CH2R¢ + 2H2O
(14)
R-CH2OH + Br¥ f [R-Cä+HOHâââHâââBrä-]‡ f
R-Cú HOH + HBr (15)
R-CO-H + Br¥ f [R-Cä+OâââHâââBrä-]‡ f
R-Cú O + HBr (16)
2RCH2OH + 2H2O298
Br2
or HBr
R-COO-CH2R + 4H2O (6)
R-CH2OH + Br¥ f R-C4 HOH + HBr (7)
R-C4 HOH + Br2 f R-CHO + Br¥ + HBr (
R-CHO + Br¥ f R-C4 O + HBr (9)
R-C4 O + Br2 f R-COBr + Br¥ (10)
R-COBr + R-CH2OH f R-COO-CH2R + HBr (11)
262 ¥ Vol. 2, No. 4, 1998 / Organic Process Research & Development
(eqs 15 and 16) for both eqs 7 and 9, but they can be
considered more pronounced with alcohols than with aldehydes,
as will be discussed later. However, the more
favorable polar effect with alcohols cannot balance the more
favorable enthalpic effect with aldehydes.
By the same simple and convenient two-phase procedure
secondary alcohols are selectively oxidized to the corresponding
ketones (eq 17). The results are summarized in
Table 2. Similar results were previously reported under more
drastic conditions and under irradiation.3,4
The new reaction (eq 14), based on the different reactivity
of aldehydes and alcohols, makes the potential range for the
synthesis of esters much larger, considering the great variety
of available aldehydes and alcohols. Even an alcohol such
as methanol, which is extremely soluble in water, can be
successfully utilized for the preparation of methyl esters. Less
water-soluble alcohols are even more effective, since the
esterification takes place in the organic phase. A variety of
esters obtained from aldehydes and alcohols are reported in
Table 3. As far as we know, this is the first time that the
synthesis of esters from aldehydes and alcohols is reported.
Benzylic alcohols behave quite differently from the
aliphatic ones; secondary benzylic alcohols are much more
reactive than are secondary aliphatic alcohols. The oxidation
of mixtures of secondary benzylic and aliphatic alcohols leads
to the selective oxidation of the benzylic derivatives to the
corresponding ketones, indicating that the reactivity of the
benzylic alcohol is >20 times higher than that of aliphatic
alcohols. Also this behavior is simply explained on the basis
of the enthalpic effect: the energy of the benzylic C-H bond
(ArC(R)(OH)-H) is 7-8 kcal/mol lower than that of the
corresponding alkyl C-H bond (R2COH-H), and this is
reflected on the rate of hydrogen abstraction by Br¥ (eq 18),
which determines the chemoselectivity of the reaction.
The esters, ArCOOCH2Ar, cannot be obtained from the
corresponding primary benzyl alcohols, ArCH2OH, according
to eq 6, because the reactivity is opposite compared to
primary aliphatic alcohols. Actually, benzyl alcohols are
much more reactive than the corresponding aromatic aldehydes,
so that the latter are not oxidized as long as the
alcohols are present, whereas in the aliphatic series the
aldehydes are much more reactive than the corresponding
alcohols and it is not possible to stop the oxidation of
alcohols to aldehydes. This inversion of reactivity could,
in principle, be explained by three behaviors: (i) the primary
benzyl alcohols are more reactive than the primary aliphatic
alcohols; (ii) the aliphatic aldehydes are more reactive than
the aromatic aldehydes; (iii) both behaviors are simultaneously
operating.
By competitive kinetics, we have verified that the condition
iii is fulfilled. The competitive reaction of benzyl
alcohol and 1-heptanol selectively leads to the oxidation of
benzyl alcohol, while a mixture of benzaldehyde and
1-heptanal leads with large prevalence to the oxidation of
1-heptanal.
We explain this opposite behavior between aryl and alkyl
derivatives by enthalpic and polar effects, as consequence
of the electronic configurations of R-hydroxyalkyl and acyl
radicals. Benzyl and alkyl radicals are ð-type radicals, in
which the unpaired electrons occupy p orbitals, while acyl
radicals are ó-type radicals, with the unpaired electron located
in hybrid orbitals of the carbon atom.2 This is clearly shown
by the hyperfine coupling of the ESR spectrum for the benzyl
and benzoyl radicals (Table 4): the major proton hyperfine
splitting is due to the meta hydrogen atoms in the benzoyl
radical.3 This is in contrast with the familiar para > ortho
> meta trend observed with the benzyl ð radical,4 due to
the resonance structures of eq 19, and it supports the lack of
stabilization of the benzoyl radical, due to the absence of
conjugation with the phenyl group (eq 20).
These electronic configurations are reflected in the bond
strengths (Table 5); there is no influence on the strengths of
the RCO-H bonds due to the substitution of a hydrogen
atom on alkyl, vinyl, or aryl groups,5 contrary to the behavior
of alkyl radicals.6
Since the strengths of the Ar-CHOH-H and ArCO-H
bonds are quite close, we explain the much higher reactivity
Table 2. Oxidation of secondary alcohols to ketones by
H2O2, catalyzed by Br2
alcohol convn (%) yield (%)a
2-hexanol 100 96
2-heptanol 98 99
2-decanol 99 98
cyclohexanol 94 87
cyclopentanol 96 91
2-adamantanol 100 96
Ph-CHOH-CH3 100 95
Ph-CHOH-Ph 98 88
a Based on the converted alcohol.
Table 3. Oxidation of aliphatic aldehydes to esters in the
presence of primary and tertiary alcohols
aldehyde alcohol convn (%)a yield (%)b
1-heptanal n-BuOH 96 92
1-heptanal 1-AdOH 89 87
1-heptanal t-BuOH 92 84
1-pentanal n-PrOH 87 91
1-pentanal n-BuOH 91 89
1-pentanal t-BuOH 83 87
a Converted aldehyde. b Based on the converted aldehyde.
R-CHOH-R¢ + H2O298
Br2
or HBr
R-CO-R¢ + 2H2O (17)
Table 4. Hyperfine coupling constants (a) of benzyl and
benzoyl radicals
a Ph-CH2
¥ Ph-CO¥
Ro-H 5.17 0.1
Rm-H 1.77 1.16
Rp-H 6.19 0.1
•
Vol. 2, No. 4, 1998 / Organic Process Research & Development ¥ 263
of the benzyl alcohols, compared to that of the corresponding
aldehydes, by the polar effect.2,7 The s-electrons are, on the
average, closer to the nucleus than are p-electrons; they
therefore experience a greater interaction with nucleus, that
is, s-orbitals have a higher electronegativity than p-orbitals.
It is therefore easier to remove an electron from a p-orbital
than from a s-orbital of the same quantum number in similar
structures. The larger the contribution of s-character to a
hybrid orbital, the greater the electronegativity of that hybrid
orbital and the higher the energy required to remove an
electron.
Thus, the contribution of polar forms to the transition state
will be larger in hydrogen abstraction from ArCHOH-H
(eq 15) than from ArCO-H (eq 16), that is, the polar effect
is more marked in eq 15 than in eq 16. This larger charge
separation is reflected in a lower activation energy and in a
higher reactivity for hydrogen abstraction from benzylic
alcohols than from aromatic aldehydes, even if the enthalpic
effects are substantially equal. In conclusion, the polar effect
determines the higher reactivity of primary benzylic alcohols
compared to the corresponding aldehydes. On the other
hand, primary benzylic alcohols are much more reactive than
primary aliphatic alcohols exclusively for enthalpic reasons
(different strength of the involved C-H bonds).
The higher reactivity of aliphatic aldehydes compared to
aromatic aldehydes is exclusively due to the polar effect
because the enthalpic effects are substantially equal (Table
5): alkyls are electron-releasing groups and so increase the
contribution of polar forms to the transition states, while aryl
groups are electron-withdrawing and decrease the charge
separation in the transition state (eq 16).
To a complete programming of the synthetic potentiality
of these oxidations, it was also important to know the relative
reactivities of aromatic aldehydes and aliphatic alcohols. We
have verified, always by competitive kinetics, that aromatic
aldehydes are much more reactive than methanol; clearly
the enthalpic effect is responsible for this selectivity. The
primary aliphatic alcohols are still somewhat less reactive
than aromatic aldehydes, but the difference of reactivity is
relatively small and the competitive oxidation of the two
substrates takes place with partial selectivity; in this case,
the higher polar effect for hydrogen abstraction from alcohols
is balanced by the more faVorable enthalpic effect for
hydrogen abstraction from aldehydes.
The evaluation of the relative rates and their rationalization
have allowed to develop the following three selective
syntheses:
(i) A general method to oxidize primary benzyl alcohols
to the corresponding aromatic aldehydes by always using
the same two-phase system above-described under mild
conditions and arresting the reaction when the benzyl alcohol
has reacted. The mechanism is illustrated by eqs 7 and 8;
the further oxidation does not occur owing to the lower
reactivity of ArCHO compared to ArCH2OH. The same
synthesis is not possible with primary aliphatic alcohols.
Several examples are reported in Table 6. The conversion
can be increased by increasing the amount of H2O2. A few
examples of oxidation by a similar procedure have been
previously reported3,4 without any mechanistic interpretation.
(ii) A general method to oxidize primary benzyl alcohols
to the corresponding methyl benzoates in the presence of
methanol, by using an excess of H2O2. The overall stoichiometry
is shown by eq 21. Some examples are reported in
Table 7.
(iii) A general method to oxidize primary benzyl alcohols
to benzoates of aliphatic alcohols (eq 22). Since the
difference of reactivity between ArCHO and RCH2OH is
Table 5. Strengths (kcal/mol) of C-H bonds
CH3-H 105 HCO-H 87.0
CH3-CH2-H 101 CH3CO-H 87.0
Ph-CH2-H 89 PhCO-H 86.9
CH2dCH-CH2-H 87 CH2dCH-CO-H 87.1
Table 6. Synthesis of aldehydes X-C6H4-CHO from
X-C6H4-CH2OH by bromine-catalyzed H2O2 oxidation
X ratio (alcohol:Br2:H2O2) convn (%)a yields (%)b
H 1:0.05:2 92 98
H 1:0.15:1.5 100 93
o-Me 1:0.15:2 97 91
m-Me 1:0.15:2 94 96
p-Me 1:0.15:2 98 90
o-Cl 1:0.15:2 98 93
p-Cl 1:0.05:2 99 97
p-Cl 1:0.15:1 94 93
p-Br 1:0.05:2 98 98
p-COOEt 1:0.15:2 93 94
p-CN 1:0.2:2 94 92
o-NO2 1:0.2:2 94 96
p-NO2 1:0.15:2 81 95
p-Ph 1:0.15:2 98 94
a Conversion of the benzyl alcohol. b Yields based on the converted alcohol.
Table 7. Oxidation of benzyl alcohols X-C6H4-CH2OH to
the corresponding methyl benzoates
X convn (%) yields (%)a
H 100 87
o-Me 100 83
p-Me 100 88
o-Cl 93 83
p-Cl 92 86
a Based on the converted benzyl alcohol.
ArCH2OH + CH3OH + 2H2O2 f Ar-COOCH3 + 4H2O
(21)
264 ¥ Vol. 2, No. 4, 1998 / Organic Process Research & Development
not large enough, a good selectivity is obtained by the slow
addition of the alcohol RCH2OH to the oxidizing two-phase
system, to keep the stationary concentration of RCH2OH
relatively low during the reaction. The results are summarized
in Table 8.
(iv) The synthesis of the same esters described by methods
ii and iii can be achieved by starting from the corresponding
aromatic aldehydes, which are intermediates in the reaction
in eq 22. The results are reported in Table 9.
The latter three processes have never been previously
reported, as far as we know; they are a direct consequence
of our mechanistic interpretation.
An interesting aspect of all the syntheses above-reported
is the fact that no chemical or photochemical initiation is
necessary to start the radical chains of eqs 7-10. We explain
this behavior by the formation of traces of Br2O during the
oxidation process; daylight is sufficient for the homolysis
of the weak Br-O bond (eq 23).
Oxidation of Ethers
Ethers are smoothly oxidized by H2O2 in a liquid twophase
system in the presence of catalytic amounts of Br2 or
HBr. The reaction products depend on the structure of the
ether and the reaction conditions. Thus, methyl benzyl ether
gives methyl benzoate according to eq 24.
This appears to be a simple oxidation of a benzylic CH2
group to carbonyl. However, the analysis of the reaction
products during the reaction course (Table 10) revealed that
benzaldehyde and methanol are initially formed and that only
after all of the ether has reacted, benzaldehyde is further
oxidized to methyl benzoate by procedure iv in the previous
section. Thus, methyl benzyl ether can be oxidized in this
way either to methyl benzoate (eq 24) or to benzaldehyde
(eq 25).
Also in this case, the reaction can be carried out by Br2
in a two-phase system, in the absence of H2O2; the aqueous
HBr is then oxidized by H2O2.
No reaction occurs under the same conditions in the
absence of Br2 or HBr, which indicates that the mechanism
for the oxidation of ethers (eqs 26-29) is quite similar to
the one discussed for alcohols (eqs 7-8). HBr is then
oxidized to H2O2 according to eq 12. The selectivity of the
process is determined, also in this case, by combined
favorable enthalpic (low energy of the benzylic bond) and
polar (eq 29) effects. With secondary benzyl ethers, the
corresponding ketones are obtained (eq 30).
The reaction represents a new general method for obtaining
aromatic aldehydes, ketones or esters from benzyl ethers.
Table 8. Oxidation of benzyl alcohols X-C6H4-CH2OH to
alkyl benzoates X-C6H4-COOR
X R-OH convn (%)a yields (%)b
H EtOH 93 84
H n-BuOH 86 82
H t-BuOH 91 93
o-Cl n-BuOH 97 83
p-Cl n-BuOH 92 88
o-Me n-BuOH 98 81
o-Me t-BuOH 78 94
p-Me t-BuOH 81 96
a Conversion of benzyl alcohol. b Yields based on the converted benzyl
alcohol.
Table 9. Oxidation of aromatic aldehydes, X-C6H4-CHO,
to alkyl benzoates X-C6H4-COOR
X R-OH convn (%)a yields (%)b
H MeOH 92 96
H EtOH 94 84
H n-BuOH 87 83
H t-BuOH 72 94
o-Cl MeOH 93 97
p-Cl MeOH 91 89
o-Me MeOH 92 87
p-Me MeOH 89 91
p-Me n-BuOH 91 78
p-Me t-BuOH 81 96
a Conversion of aldehyde. b Yields based on the converted aldehyde.
Table 10. Oxidation of benzyl methyl ether to benzaldehyde
(I), methyl benzoate (II), and mixed anhydride between
benzoic and formic acids (III)
yieldsb
T (°C) reaction time (h) convna (%) I II III
18 0. 5 18 87
18 1.3 32 91 2.1
18 2 48 89 5.3
18 3 70 87 9.1
18 5.5 99.5 81 18.3
18 26.5 100 20 60
42 2 100 33 40 25
42 4 100 61 32
a Conversion of benzyl ether. b Yields based on the converted benzyl ether.
Ph–CH2–OCH3 + Br
Ph–CH–OCH3 + Br2
• (26)
Ph–CH–OCH3 + Br •
Ph–CH–OCH3 + HBr
(27)
Br
Ph–CH–OCH3 + H2O
Br
Ph–CHO + CH3OH + HBr (28)
Ph–CH–H + Br •
OCH3
Ph–CH• • •H• • •Br
OCH3
d + d –
Ph–CH• + HBr
OCH3
(29)
Ph–C–H + H2O2 Ph–CO–R + CH3OH + H2O
R
OCH3
(30)
ArCH2OH + RCH2OH + 2H2O2 f Ar-COOCH2R + 4H2O
(22)
Br-O-Br f Br¥ + ¥O-Br (23)
PhCH2OCH3 + 2H2O2 f Ph-COOCH3 + 3H2O (24)
PhCH2OCH3 + H2O2 f Ph-CHO + CH3OH + 3H2O (25)
Vol. 2, No. 4, 1998 / Organic Process Research & Development ¥ 265
Some results are summarized in Tables 10 and 11. As for
the corresponding alcohols, discussed in the previous section,
also the oxidation of alkyl ethers is slower than that of benzyl
ethers: both hydrogen abstraction (eq 26) and hydrolysis of
the bromoethers (eq 28) are slower. Primary symmetrical
alkyl ethers give the corresponding esters (eq 31).
The reaction takes place by a mechanism identical to the
one depicted in eqs 26-28, but the aliphatic aldehyde is
much more reactive than both the alcohol R-CH2OH and
the starting ether, so that it is further oxidized to the ester
by a reaction similar to eq 14. Some results are reported in
Table 12.
Primary asymmetrical alkyl ethers, obviously, give two
esters (eq 32). Secondary alkyl ethers lead to the corresponding
ketones; the symmetric derivatives lead to only one
ketone, while the asymmetric ethers give two different
ketones (eq 33). Methyl alkyl ethers are oxidized to the
corresponding methyl esters (eq 34), while methyl-sec-alkyl
ethers give the ketone and methanol (eq 35).
In all of these cases the selectivity is determined by the
enthalpic effect, being the polar effect of the oxygen atom
substantially identical; the high sensitivity of hydrogen
abstraction by bromine atom to the bond strengths determines
the selectivity among primary, secondary, and tertiary C-H
bonds next to the oxygen atom. Cyclic ethers are oxidized
to the corresponding lactones (eq 36). The results with a
variety of ethers are reported in Table 13.
To the best of our knowledge, the oxidation of ethers by
H2O2, catalyzed by bromine has not been reported previously.
Benzylic Bromination in the Presence of H2O2
Free-radical bromination is one of the synthetic methodologies
more widely utilized for the functionalization of alkyl
aromatics because the easy nucleophilic substitution of the
benzylic bromine atom allows for the synthesis of a large
variety of derivatives, including alcohols, aldehydes, and
esters. For practical applications, the high molar mass and
cost of bromine are the main disadvantages. Molecular
bromine can be utilized by a classical free-radical chain
process (eqs 37 and 38).
Reaction 37 is almost thermoneutral (H-Br and benzylic
C-H bonds have very close strengths) and reversible; thus,
complete conversions are sometimes obtained with difficulty,
particularly with the less reactive electron-deficient alkyl
aromatics. To overcome this difficulty, the more expensive
N-bromosuccinimmide, NBS, is often utilized, also for
practical purposes. In this case, the stationary concentration
of H-Br is always kept very low by its fast reaction with
NBS (eq 39), minimizing in this way the reversibility (eq
40).
Table 11. Oxidation of secondary benzyl ethers,
X-C6H4-CH(R)-OMe, to the corresponding ketones,
X-C6H4-CO-R
X R convna (%) yieldsb (%)
H Me 98 94
H Et 96 97
o-Cl Me 97 92
p-Cl Et 99 89
o-Me Me 96 91
p-Me Me 92 94
p-Me Et 96 98
a Conversion of benzyl ether. b Yields based on the converted benzyl ether.
Table 12. Oxidation of dialkyl ethers, R-CH2-O-CH2-R,
to the corresponding esters, R-COOCH2R (IV)
yieldsa (%)
R convn (%) IV R-CH2OH R-COOH
n-Pr 94 65 10 8
n-Bu 92 73 7 6
n-hexyl 91 71 8 7
2-Me-pentyl 87 70 6 9
n-heptyl 89 71 9 8
a Yields based on the converted ether.
R-CH2-O-CH2-R + 2H2O2 f R-COO-CH2R + 3H2O
(31)
R-CH2-O-CH2-R¢ + 2H2O2 f
R-COO-CH2R¢
50%
+ RCH2-OCOR¢
50%
+ 3H2O (32)
R2CH-O-CHR¢2 + 2H2O2 f
R-CO-R + R¢-CO-R¢ + 3H2O (33)
Table 13. Oxidation of THF and other ethers
ether product
time
(h)
convn
(%)a
yield
(%)b
THF ç-butyrolactone 1 34.2 98
THF ç-butyrolactone 2 64.6 87
THF ç-butyrolactone 4 92.4 81
methyl cyclooctyl ether cyclooctanone 4 87 92
methyl cyclooctyl etherc cyclooctanone 4 96 97
dicyclohexyl ether cyclohexanone 4 98 93
methyl cyclohexyl ether cyclohexanone 4 91 96
a Conversions based on the oxidant. b Yields based on the conversion. c The
procedure is the same, with the difference that a stoichiometric amount of Br2
was used in a two-phase system in the absence of H2O2.
R-CH2-O-CH3 + 2H2O2 f R-COOCH3 + 3H2O
(34)
R2CH-O-CH3 + H2O2 f R-CO-R + CH3OH + H2O
(35)
Ar-CH3 + Br¥ a Ar-CH2
¥ + HBr (37)
Ar-CH2
¥ + Br2 f Ar-CH2-Br + Br¥ (38)
266 ¥ Vol. 2, No. 4, 1998 / Organic Process Research & Development
Similar results have been obtained by more simple and
convenient procedures carried out with Br2 or Br- in the
presence of H2O2
5,6,8-15 (eqs 41 and 42).
These procedures offer seven advantages over the use of
NBS or of Br2 in a homogeneous system: (1) the molar mass
and cost of H2O2 are much lower than those of NBS; (2)
bromination in the presence of H2O2 allows complete
utilization of bromine (eq 43) avoiding waste of one-half of
the employed bromine atoms (eq 42); (3) the stationary
concentration of HBr is always very low, due to the fast
oxidation by H2O2 and the reversibility of eq 37 is minimized;
(4) the experimental conditions and the separation
of the reaction products are very simple. At the end of the
reaction, the organic layer is separated and distillation of
the solvent provides the benzyl bromides.
(5) No chemical or photochemical initiation is necessary,
contrary to the bromination by NBS, because, as previously
discussed, daylight is sufficient for the initiation (eq 23);
(6) the two-phase system in the presence of H2O2 allows for
the use not only of Br2, but also of HBr or alkali bromide
(eq 42) (this aspect is of particular interest in the synthesis
of benzylic alcohols, ethers, and esters, since the latter can
be easily obtained by nucleophilic substitution of benzyl
bromides, which regenerates HBr, and can be recycled in
aqueous acidic (H2SO4) medium, thus making the overall
process catalytic in Br- (eq 43)); (7) since benzyl alcohols
and ethers can be further oxidized by H2O2 to aldehydes and
esters under bromine catalysis, as discussed in previous
sections, we can transform, e.g., a methyl aromatic into a
methyl benzyl ether and further into aromatic aldehydes and
esters, depending on the reaction conditions and the amount
of H2O2 (eq 44).
The benzylic bromination in a two-phase system is a
selective process, the only byprocess being the dibromination
at complete conversion of the alkylaromatic. For the
synthesis of aldehydes and esters, it is not necessary to
separate mono- and dibromides, as the latter directly provide
the aldehyde and HBr by hydrolysis (eq 45); HBr is then
recycled by H2O2 oxidation (eq 12).
The benzylic bromination is particularly difficult with
deactivated alkylbenzenes: in competitive bromination of
equimolar amounts of o-nitrotoluene and toluene, we have
observed that only the latter is substantially brominated.
Thus, we have carefully investigated the bromination of
o-nitrotoluene in different conditions, to recognize the factors
which affect the reactivity and also because of the practical
interest of the synthesis of o-nitrobenzaldehyde. The results,
reported in Table 14, reveal three new important factors
influencing the reaction: (1) the presence of water has a
dramatic influence on the reaction; no substantial bromination
takes place in the absence of water, whereas high conversions
and yields are obtained under the same conditions in the
presence of water; (2) an excess of H2O2 inhibits the
bromination; (3) by using n-hexane as solvent in the presence
of water, no bromination of o-nitrotoluene occurs, but 2- and
3-bromohexane are the only reaction products.
We have obtained similar results with 4-cyanotoluene.
Our interpretation is based on the reversibility of eq 37,
which is more marked in the presence of electron-withdrawing
groups (-NO2, -CN); since HBr is much more soluble
in water than in organic solvents, the aqueous phase extracts
HBr from the organic phase, in which bromination takes
place, thus minimizing the reversibility.
The inhibition, due to excess H2O2, must be related always
to the reduced reactivity of o-nitrotoluene towards the
bromine atom; this latter can abstract hydrogen atoms from
H2O2, leading to its decomposition according to eq 46.
With deactivated alkyl aromatics it is more convenient
to carry out the reaction by slowly adding the aqueous
solution of H2O2 to the reacting mixture, to avoid the
presence of excess H2O2, minimizing in this way eq 46.
The fact that in hexane solution the solvent is brominated
in place of o-nitrotoluene indicates that the polar effect, as
illustrated in eqs 15 and 16, is more important than the
(15) Jones, C. W.; Carter, N. G.; Oakes, S. C.; Wilson, S. L.; Johnstone, A. J.
J. Chem. Technol. Biotechnol. 1998, 71, 111.
(16) Minisci, F. Top. Curr. Chem. 1976, 62, 38.
(17) Krusic, P.; Rettig, T. A. J. Am. Chem. Soc. 1970, 92, 722.
(18) Dixon, W. T.; Norman, R. O. C. J. Chem. Soc. 1964, 4857.
(19) Sally, R. K.; Benson, S. W. J. Am. Chem. Soc. 1971, 93, 1592. Alfossi, G.
B.; Golden, D. M. J. Am. Chem. Soc. 1973, 95, 319.
(20) Benson, S. W. J. Chem. Educ. 1965, 42, 502.
(21) Minisci, F.; Citterio, A. AdV. Free Rad. Chem. 1980, 6, 119.
Table 14. Bromination of 2-nitrotoluene (Ar-CH3)
brominating
agent ArCH3:Br:H2O2 solvent
convn
(%)
yields
(%) of
ArCH2Bra
Br2 1:1:0 CH2Cl2 traces traces
Br2 1:0.5:0 CH2Cl2/H2O 1:1 20 99
Br2 1:1.2:0 CH2Cl2/H2O 1:2 91 89
Br2/H2O2
b 1:0.7:0 CH2Cl2 93 94
Br2/H2O2 1:0.5:0.5 CH2Cl2/H2O 1:1 34 98
Br2/H2O2 1:0.7:10 CH2Cl2/H2O 1:1 8 100
Br2/H2O2
c 1:0.7:1 hexane/H2O 1:1
HBr/H2O2 1:2:2 CH2Cl2/H2O 1:2 87 93
a Based on the converted 2-nitrotoluene. b 36% aqueous H2O2. c 2- and
3-Bromohexanes are formed.
Ar-CHBr2 + H2O f Ar-CHO + 2HBr (45)
Br¥ + H2O2 f HBr + HOO¥ f O2 (46)
Ar-CH2
¥ + Br2 f Ar-CH2Br + Br¥ (40)
2Ar-CH3 + Br2 + H2O2 f 2Ar-CH2Br + 2H2O (41)
Ar-CH3 + Br- + H+ + H2O2 f Ar-CH2Br + 2H2O (42)
Ar–CH3 Ar–CH2–Br
Br–,H2O2 –Br–,RO– Ar–CH2–OR (43)
Ar–CH3 Ar–CH2–OMe
Br–,H2O2
H2O2
2H2O2
Ar–CHO
Ar–COOMe
(44)
Vol. 2, No. 4, 1998 / Organic Process Research & Development ¥ 267
enthalpic effect (the benzylic C-H bond is 8-10 kcal/mol
weaker than the C-H bond in n-hexane). The results with
a variety of alkyl aromatics are reported in Table 15; with
deactivated substrates, the aqueous solution of H2O2 was
slowly added to the reaction mixture.
Tertiary C-H bonds are not suitable for the bromination
by this procedure, because HBr elimination takes place under
the reaction conditions, leading mainly to R-methylstyrene
and to cis- and trans-R-methyl-â-bromostyrenes (eq 47).
Experimental Section
General Procedures. Mass spectra were performed on
a GLC-MS Finnigan TSQ 70 instrument, using a Varian 3700
gas-chromatograph equipped with SBP-1 fused silica column
(30 m 0.2 mm i.d., 0.2 ím film thickness) and helium as
carrier gas.
GC analyses were performed on a capillary gas-chromatograph
equipped with SBP-5 fused silica column (25 m
0.25 mm i.d., 1 ím film thickness) at a hydrogen flow
rate of 8 cm3 min-1, PTV injector, and flame ionization
detector.
Starting materials and reagents were purchased commercially
and used without further purification.
All reaction products were known and were analyzed by
GC and GC-MS and by comparison with authentic samples.
General Oxidation Procedures. Oxidation of Primary
Aliphatic Alcohols to Esters. Five millimoles of the alcohol,
dissolved in 7.5 mL of CH2Cl2, was stirred for 2 h at room
temperature with 3 mmol of Br2 and 7.5 mL of water; 6
mmol of H2O2 (30% aqueous solution) was added within 2
h. The organic phase was separated, washed with aqueous
NaHCO3 solution, and analyzed by GC (ethyl heptanoate as
internal standard). The reaction products were identified by
GC-MS analysis and by comparison with authentic samples.
The results are reported in Table 1. The aqueous solution,
containing HBr, has been utilized for a further oxidation of
5 mmol of alcohol in 7.5 mL of CH2Cl2 by the addition of
7.5 mmol of H2O2 over 4 h: the results are quite similar.
Oxidation of Secondary Alcohols to Ketones. Procedure
A was utilized by employing half of the oxidant. The results
are reported in Table 2.
Oxidation of Aliphatic Aldehydes in the Presence of
Alcohols. Five millimoles of the aldehyde, 15 mmol of the
alcohol, and 2.5 mmol of Br2 dissolved in a mixture of 7.5
mL of CH2Cl2 and 7.5 mL of water were refluxed for 1 h;
2.5 mmol of H2O2 was added, and the mixture was refluxed
for an additional hour. The organic phase was separated
and analyzed by GC and GC-MS; authentic samples were
utilized for the identification and analysis of the reaction
products. The results are reported in Table 3.
Oxidation of Benzyl Alcohols to Aldehydes. Two millimoles
of the alcohol, dissolved in 10 mL of ACOEt and 2
mL of water, together with Br2 and H2O2 in the ratios
reported in Table 6, was refluxed for 4 h. The organic phase
was separated, washed with aqueous NaHCO3 solution, and
analyzed by GC (p-chlorobenzaldehyde as internal standard;
with p-chlorobenzyl alcohol, o-chlorobenzaldehyde was
utilized as internal standard). The reaction products were
identified by GC-MS analysis and by comparison with
authentic samples. The results are reported in Table 6.
Oxidation of Benzyl Alcohols to Methyl Benzoate. Five
millimoles of benzyl alcohol, 20 mmol of CH3OH, and 5
mmol of Br2 in 10 mL of CH2Cl2 and 10 mL of water were
refluxed for 2 h; 6 mmol of H2O2 were then added under
reflux over a 2 h period. The organic phase was separated
Table 15. Bromination of alkylbenzenes
substrate (S) brominating agent S:Br:H2O2 solvent convn (%) yields (%)a
toluene Br2/H2O2 1:0.7:1 CH2Cl2/H2O 1:1 93 94
tolueneb Br2/H2O2 1:1:1 CH2Cl2/H2O 1:1 100 70
toluene NaBr/H2O2 1:2:2 CH2Cl2/H2O 1:1 96 92
H2SO4 (1)
ethylbenzene Br2/H2O2 1:0.7:0.5 CH2Cl2/H2O 1:1 87 92
ethylbenzene NaBr/H2O2 1:2:2 CH2Cl2/H2O 1:1 91 94
H2SO4 (1)
ethylbenzene Br2/H2O2 1:2:1.5 CH2Cl2/H2O 1:1 93 89
cumenec Br2/H2O2 1:0.7:0.5 CH2Cl2/H2O 1:1 60 5
p-CN-toluene Br2 1:1:0 CH2Cl2 traces traces
p-CN-toluene Br2/H2O2 1:1:1 CH2Cl2/H2O 5:1 100 95
o-CN-toluene Br2/H2O2 1:1:1 CH2Cl2/H2O 5:1 97 98
o-Cl-toluene Br2/H2O2 1:1:1 CH2Cl2/H2O 1:1 100 94
p-Cl-toluene Br2/H2O2 1:1:1 CH2Cl2/H2O 1:1 100 93
p-Me-benzoic acid Br2/H2O2 1:1:1 CH2Cl2/H2O 1:1 100 87
Et-p-Me-benzoate Br2/H2O2 1:1:1 CH2Cl2/H2O 1:1 100 91
p-NO2-toluene Br2 1:1:0 CH2Cl2 21 100
p-NO2-toluened Br2/H2O2 1:1:1 CH2Cl2 100 88
p-NO2-ethylbenzened Br2/H2O2 1:1:1 CH2Cl2 98 86
2-NO2-4-MeO-toluene Br2/H2O2 1:1:1 CH2Cl2/H2O 1:2 85 98
a Based on the converted alkylbenzene. b 28% of PhCHBr2 is formed. c R-Methylstyrene and R-methyl-â-bromostyrenes are the main reaction products. d 36%
aqueous H2O2 has been utilised.
Ph–C–Br
Me
Me
–HBr
Ph–C CH2
Me
Br2 Ph–C–CH2Br
Br
Me
–HBr
Ph–C CHBr
Me
(47)
268 ¥ Vol. 2, No. 4, 1998 / Organic Process Research & Development
and analyzed by GC (ethyl benzoate as internal standard)
by using authentic samples and GC-MS analysis for the
identification of the reaction products. The results are
reported in Table 7.
Oxidation of Benzyl Alcohols to Alkyl Benzoates. Procedure
E has been utilized with benzyl alcohols and tertiary
aliphatic alcohols. With primary aliphatic alcohols, the
procedure has been modified as follows: 5 mmol of benzyl
alcohol, 1 mmol of aliphatic alcohol, and 5 mmol of Br2 in
10 mL of CH2Cl2 and 10 mL of water were refluxed. Over
4 h, 6 mmol of H2O2 and 4 mmol of aliphatic alcohol were
added. The organic phase was separated and analyzed by
GC and GC-MS. The results are reported in Table 8.
Oxidation of Aromatic Aldehydes to Alkyl Benzoates.
Procedures E and F were utilized by using half of the oxidant.
The results are reported in Table 9.
CompetitiVe Oxidations. One millimole of benzyl alcohol
and 2 mmol of 1-heptanol in 7 mL of CH2Cl2 were stirred
for 24 h at room temperature with 0.2 mmol of Br2 and 2
mmol of H2O2 (30% aqueous solution). The GC and GCMS
analyses of the organic solution revealed the presence
of 1-heptanol (36%), benzaldehyde (40%), benzyl alcohol
(1.5%), 1-heptyl benzoate (9%), and 1-heptyl heptanoate
(4%). The results indicate that benzyl alcohol is more than
20 times more reactive than 1-heptanol.
Two millimoles of benzaldehyde, 2 mmol of 1-heptanal,
and 6 mmol of methanol in 7 mL of CH2Cl2 were stirred for
24 h at room temperature with 0.2 mmol of Br2 and 2 mmol
of H2O2 (30% aqueous solution). The analysis of the organic
solution revealed the presence of benzaldehyde (40%),
1-heptanal (3.5%), methyl heptanoate (29%), and methyl
benzoate (11%).
Two millimoles of benzaldehyde and 2 mmol of 1-heptanol
in 7 mL of CH2Cl2 were stirred for 24 h at room
temperature with 0.2 mmol of Br2 and 2 mmol of H2O2. The
analysis showed the presence of 1-heptanol (35%), benzaldehyde
(24%), 1-heptyl benzoate (25%), and 1-heptyl
heptanoate (8%).
Oxidation of Ethers. Alkylbenzyl Ethers. Two millimoles
of methyl benzyl ether in 7.5 mL of CH2Cl2 were stirred for
24 h at room temperature with 0.2 mmol of Br2 and 4 mmol
of H2O2 (30% aqueous solution). The mixture was analyzed
during the reaction course after 0.5, 1.3, 2, 3, 5.5, and 26.5
h, and the results are reported in Table 10.
Di-n-alkyl Ethers. Two millimoles of di-n-alkyl ether,
0.2 mmol of Br2, and 4 mmol of H2O2 (30% aqueous
solution) were stirred for 4 h at room temperature in 7.5 mL
of CH2Cl2. The organic phase was separated and analyzed.
The results are reported in Table 12.
Oxidation of Tetrahydrofuran (THF) to ç-Butyrolactone.
Ten millimoles of THF and 4 mmol of Br2 were refluxed
for 1 h in a mixture of 5 mL of CH2Cl2 and 5 mL of water.
Four millimoles of H2O2 was added, and the mixture was
refluxed for 1 h; an additional 4 mmol of H2O2 was added,
and the mixture was refluxed for 2 h. The mixture was
analyzed after 1, 2, and 4 h, and the results are reported in
Table 13.
The same procedure was utilized with other ethers, and
the results are summarized in Table 13.
Bromination of Alkylbenzenes. Five millimoles of alkylbenzene,
dissolved in 15 mL of a CH2Cl2/H2O mixture
containing the other reagents in the ratios reported in Tables
14 and 15, were refluxed for 4 h. The CH2Cl2 solution was
separated from the aqueous phase and directly analyzed by
GC and GC-MS, by using p-chlorobenzyl bromide as internal
standard (with p-chlorotoluene the internal standard was
o-chlorobenzyl bromide) and authentic samples of the benzyl
bromides for the characterization. With substrates deactivated
by the presence of -NO2, -CN, and -COOR groups,
H2O2 was slowly added to the reacting mixture.
In competitive bromination of equimolar amounts of
o-nitrotoluene and toluene, only the latter is substantially
brominated. With cumene, only 5% of cumyl bromide was
formed; the main reaction products were R-methylstyrene
(72%) and a 1:1 mixture of cis- and trans-R-methyl-â-
bromostyrenes (21%). The products were characterized by
comparison (GC-MS) with authentic samples.
Received for review March 19, 1998.
OP980028J
Vol. 2, No. 4, 1998 / Organic Process Research & Development ¥ 269
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