The oxidation of alcohols to aldehydes and ketones with N-bromosuccinimide in polyethylene glycol: An experimental and theoretical study

Article abstract of DOI:10.1002/poc.1404

Oxidation of aliphatic and aromatic alcohols has been studied by using N-bromosuccinimide (NBS) as oxidant and polyethylene glycol (PEG) as reaction medium under mild reaction conditions. Temperature and solvent effect are studied. Theoretical study is also done with the Gaussian 98 suite of program and the calculation results are in good accordance with the experimental outcome. This system offers a very clean, convenient, environmentally benign method for the oxidation of alcohols. Copyright

Full text of DOI:10.1002/poc.1404

Research Article
Received: 15 January 2008,
Revised: 21 March 2008,
Accepted: 7 May 2008,
Published online in Wiley InterScience: 2 June 2008
(www.interscience.wiley.com) DOI 10.1002/poc.1404
The oxidation of alcohols to aldehydes and
ketones with N-bromosuccinimide in
polyethylene glycol: an experimental and
theoretical study
a
a
a
a
a
*
Ji-Cai Fan , Zhi-Cai Shang , Jun Liang , Xiu-Hong Liu and Yang Liu
Oxidation of aliphatic and aromatic alcohols has been studied by using N-bromosuccinimide (NBS) as oxidant and
polyethylene glycol (PEG) as reaction medium under mild reaction conditions. Temperature and solvent effect are
studied. Theoretical study is also done with the Gaussian 98 suite of program and the calculation results are in good
accordance with the experimental outcome. This system offers a very clean, convenient, environmentally benign
method for the oxidation of alcohols. Copyright ß 2008 John Wiley & Sons, Ltd.
Supplementary electronic material for this paper is available in Wiley InterScience at http://www.mrw.interscience.wiley.com/
suppmat/0894-3230/suppmat/
Keywords: N-bromosuccinimide; polyethylene glycol; temperature effect; solvent effect; Gaussian 98
however, even the most commonly used catalytic oxidations
INTRODUCTION
have some limitations such as pH of the medium, hazardous
reagents, and solvents, formation of side products, etc.[43–47]
Furthermore, most of these methods are carried out at very low
concentration levels, which may involve challenging product and
catalyst separation steps. Therefore, oxidation of alcohols with
common oxidant is now considered most desirable especially in
large-scale synthesis.
N-bromosuccinimide (NBS), a cheap and convenient reagent,
has recently received considerable attention as catalyst not only
for bromination, but also for various other organic transform-
ations.[48–59] NBS reacts differently with many organic com-
pounds, depending upon the nature of the reactant and reaction
conditions in solution. Recently, it is used in a variety of oxidation
reactions under various conditions, including the oxidation of
alcohols.[60–64] However, these alcohol oxidation reactions are
usually carried out using either anhydrous solvents or in acidic/
basic media at varied temperatures.[60–62] Moreover, the
selectivities observed were also not encouraging in some
cases.[65–69] Thus there is still demand for clean, safe, and
efficient procedures for the oxidation of various alcohols.
Green chemistry is becoming a central issue in both academic
and industrial research in the 21st century.[70–74] The recent
increased awareness of the detrimental effects of organic
solvents in the environment has led to rapid growth in the
Carbonyl compounds constitute an important group in organic
chemistry, because carbonyl groups are present as an essential
constituent of pharmaceutical, dyes, fragrances, industrially
important chemicals, and natural products.[1,2] Oxidation of
alcohols to carbonyl compounds is among the most important
functional group transformations available to the synthetic che-
mists.[3–7] Although, numerous methods have been developed,
there are still some limitations. Amongst them, stoichiometric
oxidants such as manganese dioxide,[8,9] chromium(VI)-based
oxidants,[10–13] hypervalent Iodine,[14–19] activated dimethyl
sulfoxides,[20–25] etc. in the organic solvents (DMSO, CH2Cl2,
and acetone) were the most commonly used. Though these
methods are being used in various types of organic syntheses,
there are also some drawbacks. As for the heavy metal oxidants,
apart from being expensive, form toxic wastes, whereas
hypervalent iodine, oxidants such as o-iodoxybenzoic acid
(IBX) are explosive on impact or on heating to more than
200 8C. The activated dimethyl sulfoxide gives rise to awfully
smelling dimethyl sulfide. Another most conventional industrial
oxidant,[26] nitric acid, though cheap, unavoidably forms various
nitrogen oxides. There are also aerobic oxidation methods
that use copper,[27–30] palladium,[31,32] and ruthenium com-
pounds.[33–36] Some of these methods are limited to benzylic
alcohols and also require two equivalents of the catalyst per
[27–29]
research on alternative reaction media. Media considered
[75]
equivalent of the alcohol
or the presence of a base and
include: (a) the use of supercritical fluids
that have the
additives like di-(t-butyl azodihydrazine).[30] Additionally, other
heterogeneous catalyst systems reported include Ru/CeO2,[37]
[RuCl2(p-cymene)]2 on activated carbon,[38] tetrapropyl
ammonium perruthenate (TPAP)/MCM-41,[39] Ru-hydroxyapatite,[40]
Ru-hydrotalcite,[41] Pd-hydrotalcite.[42] Nevertheless, most of
these systems are effective for only activated and benzylic
alcohols. There are a variety of method reported in literature,
*
Correspondence to: Z.-C. Shang, Department of Chemistry, Zhejiang Univer-
sity, Hangzhou 310027, China.
E-mail: shangzc@zju.edu.cn
a
J.-C. Fan, Z.-C. Shang, J. Liang, X.-H. Liu, Y. Liu
Department of Chemistry, Zhejiang University, Hangzhou 310027, China
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J.-C. FAN ET AL.
[100,101]
[102]
advantage of facile solvent removal and easy recyclability but
require high pressure; (b) fluorous based systems [76–79] that have
the advantage of being highly hydrophobic but expensive and
for which the solvents are probably innocuous but have the
disadvantage of being volatile; (c) more recently, environmentally
benign solvents such as ionic liquids,[80–83] water,[84–86] and
polyethylene glycol (PEG).[87–91] Ionic liquids have a particularly
useful set of properties, being nonvolatile and virtually insoluble
in water and alkanes but readily dissolving many transition metal
catalysts, at the same time, they are very expensive. While the use
of water as solvent is probably a desirable approach, this is often
not possible due to the hydrophobic nature of the reactants and
the sensitivity of many catalysts to aqueous conditions. PEG and
its monomethyl ethers are inexpensive, thermally stable,
recoverable, and nontoxic media for phase transfer catalysts.[92,93]
PEG is also a biologically acceptable polymer, which has been
used extensively in drug delivery and in bioconjugates as tool for
diagnostics. Important as it is, PEG has hitherto not been widely
used as a solvent medium but has been used as a support for
various transformations.[94–98] We herein report PEG 400 as the
reaction medium for the oxidation of alcohols to the correspond-
ing carbonyl compounds using NBS as oxidant. The methodology
is clean, convenient, environmentally benign and the yield is
excellent.
using Becke’s three-parameter (B3)
along with the Lee–Yang–Parr (LYP)
exchange functional
nonlocal correlation
functional (B3LYP).[103–105] The standard split-valence double-j
*
basis set with polarization functions on heavy atoms, 6-31G , was
adopted. Solvation energies of the reactants and products as well
as the free energies of all the reactions were considered using the
polarizable continuum model (PCM) with the permittivities of
36.64, 8.93, 4.90, and 2.38 for CH3CN, CH2Cl2, CHCl3, and C7H8,
respectively. This approach has proven to provide a reasonably
good description of polarization effect of the solvent.
RESULTS AND DISCUSSION
The oxidation of a variety of activated and non-activated alcohols
was carried out by heating the reaction mixture of substrate
(1 mmol) and NBS (1 mmol) in PEG 400 (2 g) at 60 8C. Under these
conditions, most alcohols studied were smoothly converted to
the corresponding carbonyl compounds in excellent yields and
these results are presented in Table 1. Benzylic primary alcohols
(Table 1, entries 1–4) gave excellent yields of the corresponding
aldehydes in short reaction times without any noticeable
overoxidation to the carboxylic acids. Meanwhile, presence of
benzene ring adjacent to the —OH group in the alcohol appears
to enhance the conversion. For example, benzyl alcohols (Table 1,
entries 1–4), a-methyl benzyl alcohol (Table 1, entry 5), and
benzhydrol (Table 1, entry 6) were found to be very reactive and
required shorter reaction time for the oxidation. Furthermore,
aromatic substituted alcohols (Table 1, entries 1–6) were found to
be more reactive than alicyclic alcohols (Table 1, entries 8–9). The
EXPERIMENTAL SECTION
Materials
All the oxidants and substrates used were commercially available
and analytical grade. The substrates were used directly without
further purification.
*
calculation at the B3LYP/6-31g level by means of DFT method
shows that the C—H (the hydrogen on the carbon atom bearing
the —OH group) bond energy of cyclohexanol was 27.87 and
33.32 kcal/mol larger than that of benzyl alcohol and a-methyl
benzyl alcohol, respectively. This strongly indicates that the
substitute of hydrogen (on the carbon atom bearing the —OH
group) by bromine is more easily for benzyl alcohol and a-methyl
benzyl alcohol compared with cyclohexanol. Therefore, the
calculation result is a good answer to the question: why aromatic
substituted alcohols are more reactive than alicyclic alcohols. In
addition, it is noteworthy to mention that neither oxidation nor
addition was observed in the carbon–carbon double bond of
cinnamyl alcohol (Table 1, entry 7), keeping intact the functional
group.
Competitive reactions were also done with a series of
para-substituted benzyl alcohol derivatives in order to evaluate
the influence of electronic factors on the reaction. From the
results (Table 1, entries 1–3) we can see: electron-releasing
substituents on benzyl alcohol enhance the reaction rate.
Theoretical study of the substituent effect was also carried out
by DFT method to compare with the experimental outcomes, and
the calculation results (Table 5, entries 1–3) show that the free
energies for the oxidation of benzyl alcohols with electron-
releasing substituents is smaller than those with electron-
withdrawing substituents. This indicates that electron-releasing
substituents on benzyl alcohol could enhance the reaction rate.
The experiments and the calculations are compatible with each
other very well.
General experimental procedure
for the oxidation of alcohols
NBS (0.178 g, 1 mmol) was added to a stirred solution of alcohol in
PEG 400 (2 g) and the mixture was heated to the reaction
temperature (60 8C) with continuous stirring. At the end of the
reaction, the reaction mixture was diluted with water, extracted
with ethyl ether, and then the organic layer was dried over
anhydrous Na2SO4. The solvent was evaporated to dryness in
vacuo to give the crude product. The identity of the products was
confirmed by 1H NMR and by comparison with authentic samples
Scheme 1.
CALCULATION METHODS
All the electronic structure calculations were performed by
means of the Gaussian 98 program packages.[99] All structures
were optimized by density functional theory (DFT) methods,
To check the efficiency and at the same time evaluate the
scope of this procedure, the oxidation of primary aliphatic
alcohols was also examined. It was surprising to find that for
Scheme 1. Oxidation of alcohols under optimized conditions
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OXIDATION OF ALCOHOLS TO ALDEHYDES AND KETONES
Table 1. Oxidation of alcohols to carbonyl compounds
Entry
1
Substrate
Product
Time (h)
1.0
Yield (%)a
94
2
3
1.0
2.0
98
92
4
5
2.0
2.0
99
95
6
7
2.0
4.0
98
57
8
9
6.0
8.0
83
87
a Yield was determined by GC.
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J.-C. FAN ET AL.
Scheme 2. Oxidation of primary aliphatic alcohols
2-phenylethanol (1), besides phenylacetaldehyde (1a, 1%), and
unreacted 2-phenylethanol (1, 78%), the substitution products
2-bromoethyl benzene (1b, 9%), and 4-bromo-benzeneethanol
(1c, 12%) were also obtained; however, for n-octanol (2), affording
the overoxidated product octanoic acid (2a, 2%) and substituted
product 1-bromo-octane (2b, 15%), instead of the expected
octanal (Scheme 2). It is known that NBS oxidation of organic
compound is complicated by parallel bromine oxidation,
accordingly, these results indicate that this methodology fails
in the case of primary aliphatic alcohols, but it is very efficient for
primary and secondary aromatic alcohols as well as alicyclic
alcohols. Previous study also shows that both primary and
secondary aromatic alcohols having the —OH group on the
carbon adjacent to the aromatic nucleus are oxidized by
N-bromoacetamide (NBA) or NBS to aldehydes and ketones in
good yields, however, aliphatic primary alcohols as well as
aromatic alcohols in which the hydroxyl group is not so located,
for example, 2-phenylethanol, 3-phenyl-1-propanol, cinnamyl
alcohol, benzylisopropylcarbinol C6H5CH2CHOHCH(CH3)2, and
(C6H5CH2)2CHOH, dibenzylcarbinol, give the corresponding
carbonyl compounds in yields below 1%.[106]
Figure 1. The free energies (kcal/mol) of the oxidation of benzyl alcohol
at different temperature
Theoretical work was also done in order to test the effect of
temperature on the reaction. The free energies for the oxidation
of benzyl alcohol to benzaldehyde were calculated at different
temperature (25, 40, 60, 80, and 100 8C, respectively) at the
B3LYP/6-31g level, and the results are collected in Fig. 1. From
the results we can conclude: with the increase in the temperature,
Optimizing the reaction conditions
With a view to evaluate the molar ratio of substrate to NBS, the
oxidation of benzyl alcohol to benzaldehyde was examined. In
the absence of NBS, no reaction was found, and with the increase
of the amount of NBS, the reactivity of the reaction increase, but
when NBS was increased to more than 1.0 equivalent, there’s no
increase in the yield of benzaldehyde. That is to say, 1.0
equivalent of NBS is enough for the oxidation and there is no
need to increase the amount of NBS.
*
Table 2. Effect of the temperaturea
Temperature
(8C)
Time
(h)
Yield
(%)b
Entry
Substrate
Experimental and theoretical study
of the temperature effect
1
2
3
4
5
Benzyl alcohol
Benzyl alcohol
Benzyl alcohol
Benzyl alcohol
Benzyl alcohol
r. t.
40
60
80
2.0
1.0
1.0
1.0
1.0
69
64
94
89
75
In order to evaluate the efficiency of the reaction, the oxidation of
benzyl alcohol at different temperature was carried out and the
results were collected in Table 2. From the results we can
conclude that with the increase in the temperature, the yield of
the reaction increased, but it began to decrease when the
temperature was increased to higher, 60 8C was selected as the
reaction temperature in the following reaction.
100
a Reaction conditions: substrate (1 mmol), NBS (1 mmol), PEG
400 2 g.
b Yield was determined by GC.
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OXIDATION OF ALCOHOLS TO ALDEHYDES AND KETONES
Table 3. Effect of the various solventsa
Table 4. (Continued)
CH3CN CH2Cl2 CHCl3 C7H8
Entry
Substrate
Solvent
Time (h)
Yield (%)b
À10.73
À8.84 À7.16 À4.25
1
2
3
4
5
Benzyl alcohol
Benzyl alcohol
Benzyl alcohol
Benzyl alcohol
Benzyl alcohol
PEG 400
CH3CN
CH2Cl2
CHCl3
1.0
1.0
1.0
1.0
1.0
94c
80
77d
65
À6.43
À6.43
À5.32 À4.32 À2.58
À5.31 À4.31 À2.58
C7H8
37
a Reaction conditions: substrate (1 mmol), NBS (1 mmol), sol-
vent (3 ml) at 60 8C.
b Yield was determined by GC.
c PEG 400 2 g.
d Reaction at refluxing temperature.
À7.51
À8.53
À6.24 À5.10 À3.07
À7.09 À5.78 À3.48
À8.84 À7.29 À4.41
À7.45 À6.12 À3.72
the free energies of the reaction decrease, that is to say, the
reaction occurs more easily at higher temperature, however, our
experimental results show that the yield of the reaction decreases
when the temperature is increased to higher than 60 8C. The
Table 4. Solvation energies (kcal/mol) of reactants and pro-
ducts in different solvents
À10.54
À8.90
CH3CN CH2Cl2 CHCl3 C7H8
À9.03
À7.46 À6.05 À3.60
À6.74
À9.17
À5.59 À4.55 À2.73
À7.58 À6.15 À3.66
À8.30 À6.77 À4.07
À9.96
À8.20 À6.63 À3.93
À13.24 À11.12 À9.14 À5.58
À10.57
À8.62
À8.78 À7.16 À4.31
À7.05 À5.67 À3.34
À10.00
À5.45
À5.37
À4.58 À3.78 À2.32
À4.52 À3.73 À2.30
À10.90
À8.98 À7.26 À4.34
(Continues)
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J.-C. FAN ET AL.
Table 5. The free energies (kcal/mol) of all the reactions in different solvents
Entry
1
Substrate
CH3CN
CH2Cl2
CHCl3
C7H8
À45.49
À44.67
À43.94
À42.50
2
3
À59.71
À41.79
À46.33
À41.03
À45.54
À40.36
À44.23
À39.00
4
5
À46.66
À46.60
À45.96
À46.12
À45.27
À45.61
À43.80
À43.98
6
7
À48.08
À46.57
À47.59
À44.33
À46.86
À43.84
À45.17
À43.81
8
9
À44.04
À46.15
À43.18
À45.37
À42.38
À45.06
À40.60
À44.01
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OXIDATION OF ALCOHOLS TO ALDEHYDES AND KETONES
solvent polarity, the free energies of all the reactions decrease,
which indicates that the reaction occurs more easily in polar
solvent than in apolar one from thermodynamic point of view.
This is very well in accordance with the solvation energy results in
Table 4. Consequently, in the reaction, polar solvent (PEG) is
preferred.
Table 6. The dipole moment of NBS in different solvents
Solvent
m(D)
CH3CN
3.65
CH2Cl2
3.54
CHCl3
3.43
C7H8
3.22
It is assumed that the remarkable enhanced reaction rates
could possibly be explained by the enhancement of the reactivity
of NBS as a result of increased polarization of the N—Br bond in
the more polar PEG medium.[107,108] To support this idea,
Srinivasan et al.[108] recorded the 13C NMR spectrum of NBS in IL
([bbim]BF4), DMF, CH3CN, and CCl4, respectively. The increased
polarization of the carbonyl group of NBS from the non-polar CCl4
to the polar solvent IL ([bbim]BF4) supports the above hypothesis.
Meanwhile, the dipole moment of NBS in the four selected
solvents (CH3CN, CH2Cl2, CHCl3, and C7H8) was also calculated
with the DFT method and the results were collected in Table 6,
the results indicate that the dipole moment of NBS in solvent
increases with the increase in solvent polarity, which means an
enhanced polarization of N—Br bond in polar solvent. PEG is a
more polar solvent than CH3CN, hence it may increase the
polarization of N—Br bond even more and therefore the
reactivity of NBS for the alcohol oxidation under our optimized
conditions.
The mechanism of the oxidation has not been clearly
established, although two interpretations have been
advanced.[109] One involves the formation of hypobromite
species 1 and the other proceeds through bromine substitution
of an hydrogen on the carbon atom bearing the —OH group, as
shown in Scheme 3:
It has been suggested that the primary or secondary alcohol
forms a hypobromite species 1 [110] which readily loses hydrogen
bromide to form the carbonyl product. Meanwhile, there are
also several lines of evidence in support of the B. For example,
the oxidative cleavage of ethyl benzyl ether, which cannot
form a hypobromite, is effected readily by NBS to form
benzaldehyde.[111] Moreover, the rupture of the C—H bond and
the formation of a C—C1 bond are illustrated by the conversion of
benzaldehyde to benzoyl chloride using N-chloro succinimide.[112]
Which mechanism is more possible in the reaction? With this in
mind, we calculated the free energy of the reaction for the
formation of both 1 and 2 (Scheme 3). The oxidation of benzyl
alcohol was selected as model and the results show that the free
energy of path A and B in Scheme 3 is 1.18 and À30.80 kcal/mol,
exact reason for the divarication between experimental results
and theoretical outcomes is not clear at this moment, but we
think it maybe for the reason that the properties of PEG are
related to temperature, for example, PEG is stable at normal
temperature but when the temperature is increased to 120 8C or
higher, oxidation reaction with air could occur. Therefore, higher
temperature than 60 8C is not suitable for the reaction.
Experimental and theoretical study of the solvent effect
Solvent is an important factor in organic reaction, it has some
effects on the chemical equilibrium, rate as well as the
mechanism of the chemical reaction. To evaluate the efficiency
of this method, we also carried out the oxidation of benzyl
alcohol to benzaldehyde in other different organic solvents
besides PEG 400, and these results are shown in Table 3. Although
among the various common solvents studied, acetonitrile was
found to be more suitable, but in general, PEG 400 was the best
one and required shortest reaction time.
Theoretical study of the solvent effect of four different organic
solvents on both reactants and products are carried out using the
*
PCM also at the B3LYP/6-31g level, and the results are collected
in Tables 4 and 5. For PEG is a polymer, it is difficult to calculate its
interaction with chemical compounds by the Gaussian 98 suite of
program with the PCM. Therefore, the theoretical explanation for
PEG’s effect on the reactions can only be done based on the
tendency obtained from the calculated results of the selected
solvents other than directly with calculations.
The calculated results (Table 4) indicate that with the increase
in solvent polarity, the interactions between solvent and
reactants as well as solvent and products increase, which means
that increasing the polarity of solvent could stabilize the reactants
as well as products. As for PEG 400, its polarity is the highest
among all the solvents selected, thus inducing from the results in
Table 4, it could stabilize the reactants and products even more.
As can be seen from the calculated free energies of all the
reactions in four different solvents (Table 5): with the increase in
Scheme 3. Two possible reaction mechanisms
J. Phys. Org. Chem. 2008, 21 945–953
Copyright ß 2008 John Wiley & Sons, Ltd.
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J.-C. FAN ET AL.
respectively. This means that path B is a more reliable mechanism
in the reaction. Furthermore, succinimide 3 is also detected in the
reaction mixture by GC-MS analysis.
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CONCLUSIONS
PEG offers a convenient, efficient, inexpentsive, non-ionic liquid,
and eco-friendly reaction medium for the oxidation of a variety of
activated and non-activated alcohols with NBS as oxidant. The use
of NBS as oxidant makes this protocol more advantageous than
previously reported methods. Meanwhile, using PEG as solvent
makes it environmental friendly than organic solvents commonly
used. Furthermore, the simplicity of the system, selective
oxidation of alcohol in the presence of C–C double bond, simple
reaction conditions and excellent yields of the products make it a
facile, ideal, and attractive synthetic tool for the oxidation of
alcohols to the corresponding carbonyl compounds. Moreover,
the experimental results of the reaction were proved by DFT
calculations with the Gaussian 98 suite of program.
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