Mechanisms of the Aerobic Oxidation of Alcohols to Aldehydes and Ketones, Catalysed under Mild Conditions by Persistent and Non-Persistent Nitroxyl Radicals and Transition Metal Salts - Polar, Enthalpic, and Captodative Effects

Article abstract of DOI:10.1002/ejoc.200300332

The oxidation of alcohols to aldehydes and ketones by air or oxygen under mild conditions (room temperature and atmospheric pressure), catalysed by persistent and non-persistent nitroxyl radicals in combination with transition metal salts, appears to be the most convenient of the numerous processes developed for these purposes. The thermochemistry, the kinetics, and the Hammett correlations have allowed us to establish, on a quantitative basis, the fundamental difference between the oxidation catalysed by persistent and non-persistent nitroxyl catalysts. In the latter case, an interesting significant captodative effect is displayed for the first time for the oxidation of substituted benzyl alcohols; the importance of enthalpic and polar effects is emphasised.

Full text of DOI:10.1002/ejoc.200300332

FULL PAPER
Mechanisms of the Aerobic Oxidation of Alcohols to Aldehydes and Ketones,
Catalysed under Mild Conditions by Persistent and Non-Persistent
Nitroxyl Radicals and Transition Metal Salts ؊ Polar, Enthalpic,
and Captodative Effects
[
a]
[a]
[a]
[a]
Francesco Minisci,* Francesco Recupero, Andrea Cecchetto, Cristian Gambarotti,
[a]
[a]
[a]
[b]
Carlo Punta, Roberta Faletti, Roberto Paganelli, and Gian Franco Pedulli
Keywords: Alcohols / Aldehydes / Radicals / Redox chemistry / Transition metals
The oxidation of alcohols to aldehydes and ketones by air or
oxygen under mild conditions (room temperature and atmo- sistent nitroxyl catalysts. In the latter case, an interesting sig-
spheric pressure), catalysed by persistent and non-persistent nificant captodative effect is displayed for the first time for
nitroxyl radicals in combination with transition metal salts, the oxidation of substituted benzyl alcohols; the importance
between the oxidation catalysed by persistent and non-per-
appears to be the most convenient of the numerous processes
developed for these purposes. The thermochemistry, the kin-
etics, and the Hammett correlations have allowed us to es-
tablish, on a quantitative basis, the fundamental difference
of enthalpic and polar effects is emphasised.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
persistent phthalimide-N-oxyl (PINO) radical (2), generated
in situ from N-hydroxyphthalimide (NHPI), associated with
II
[2]
In recent preliminary reports, we have described new a Co salt.
highly selective catalysts for the aerobic oxidation of pri-
mary and secondary alcohols to the corresponding alde-
[1]
hydes and ketones based on persistent and non-persist-
ent[ nitroxyl radicals in combination with transition metal
salts [Equation (1)].
2]
(
1)
TEMPO has been utilised widely as a catalyst for the
oxidations of alcohols with a variety of oxidants.
The aerobic oxidation, catalysed by TEMPO in combi-
These processes appear to be particularly convenient,
among the numerous processes developed for these pur-
poses, not only with regard to general synthetic involve-
[
3]
ments, but also for industrial applications, because of the nation with other transition metal salt complexes, has also
high selectivity, the possibility of recovering and recycling been utilised: TEMPO/CuCl catalyses the aerobic oxi-
2
the catalysts, the simple and mild reaction conditions and dation of benzyl alcohols to aromatic aldehydes, but it is
the cheap oxidant (air or oxygen at room temperature and ineffective with less-reactive aliphatic and alicyclic al-
[
4]
atmospheric pressure).
Two catalytic systems are particularly useful: the persist- lyst at 100 °C and 10 bar of pressure; a system of
ent tetramethylpiperidine-N-oxyl (TEMPO) radical (1) in TEMPO/CuBr·Me S, perfluorinated bipyridine and bi-
combination with Mn and Co nitrates and the non- phasic perfluoroctane/chlorobenzene has been utilised at 90
cohols; TEMPO/[RuCl (PPh ) ] affords an efficient cata-
2 3 3
[
5]
2
II
II
[1]
[
6]
°
C; TEMPO/PhenS/Pd(OAc) at 100 °C and 30 bar is an
Dipartimento di Chimica, Materiali e Ingegneria Chimica effective system for the oxidation of a variety of alcohols.
2
[
a]
[7]
‘
‘Giulio Natta’’ Ϫ Politecnico di Milano,
Our catalytic system, TEMPO in combination with small
amounts of Mn(NO and Co(NO , appears, to the best
of our knowledge, to be the cheapest and most effective
the oxidation of alcohols occurs with high selectivity and
complete conversion with air at room temperature and at-
Via Mancinelli 7, 20131 Milano (MI), Italy
Fax: (internat.) ϩ39-02-23993080
)
)
3 2
3
2
E-mail: francesco.minisci@polimi.it
Dipartimento di Chimica Organica ‘ ‘A . Mangini’’ Ϫ Universit a`
di Bologna
[
b]
(
Via S. Donato 15, 4, 40127 Bologna (BO), Italy
Eur. J. Org. Chem. 2004, 109Ϫ119
DOI: 10.1002/ejoc.200300332
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109

F. Minisci et al.
FULL PAPER
mospheric pressure).[1] In a recent review, Sheldon et al.[5a] oxidations by anchoring TEMPO to solid supports, such as
[
11]
[12]
reported that our aerobic oxidation procedure of alcohols silica and the mesoporous silica, MCM-41, entrapping
[
13]
is catalysed by copper salts, which cause the reoxidation TEMPO in a sol-gel,
of TEMPO to the oxoammonium cation; this statement is of a commercially available antioxidant, CHIMASSORB
erroneous because the most-active metal salt in our process 944, which is an oligomeric, sterically hindered amine (MW
or utilising the nitroxyl derivative

[
1]
[14]
is Mn(NO ) , whose catalytic activity is exalted in combi- ca. 3000).
In all these cases, however, the catalysts are
active when using NaOCl as the oxidant, but they appear
been associated with Cu(NO ) , which, by itself, is much much less active for aerobic oxidations, particularly with
3
2
nation with Co(NO ) ; only in a few cases has Mn(NO )
3
2
3 2
3
2
II
less active than the Mn salt. Moreover, the metal salt does aliphatic alcohols.
not reoxidise TEMPO to the oxoammonium cation, but in-
Thus, the radical 3 appears to be, as far as we know,
stead the oxidation of N-hydroxypiperidine to TEMPO, the most useful nitroxyl radical for the aerobic oxidation of
while the oxoammonium cation is formed by disproportin- benzylic and aliphatic primary and secondary alcohols to
[1]
ation of TEMPO catalysed by the acidic medium.
the corresponding aldehydes and ketones under very mild
The aerobic oxidation of primary alcohols to carboxylic conditions, as well as for the ease of recycling of the cata-
acid catalysed by NHPI has been reported by the Ishii lyst.
[
8]
group, who did not realise, however, the different behav-
iour of benzylic and aliphatic alcohols during this catalysis.
[
2]
We have shown that the oxidation of primary benzylic
alcohols, catalysed by NHPI, leads to aromatic aldehydes
in high selectivity and only after the complete conversion
of the benzylic alcohols does the further oxidation of the
aromatic aldehydes to carboxylic acids occur; in contrast,
the oxidation of primary aliphatic alcohols leads to car-
boxylic acids without significant formation of aldehydes,
even at low conversion.
These selectivities clearly indicate that, with PINO cataly-
sis, the primary benzyl alcohols are much more reactive
than the corresponding aromatic aldehydes, while for non-
benzylic alcohols the corresponding aldehydes are, in con-
trast, much more reactive than the starting alcohols. With
TEMPO catalysis, the alcohols are much more reactive in
all cases than the corresponding aldehydes.
We have suggested in preliminary reports[1,2] that the dif-
ferent selectivities of the two N-oxyl radicals, TEMPO and
PINO, as catalysts for the oxidation of alcohols, should be
related to the thermochemical aspects concerning the OϪH
bonds of the corresponding hydroxylamines, TEMPO-H
and PINO-H(NHPI), and to polar effects. To understand
the factors that affect these different selectivities, we have
determined the Bond Dissociation Enthalpies (BDE) of the
OϪH bonds in the hydroxylamine derivatives, the effects of
substituents in the oxidation of alcohols catalysed by the
nitroxyl radicals TEMPO and 3, and the absolute rate con-
stants for the hydrogen atom abstraction from benzylic
CϪH bonds of substituted benzyl alcohols by the PINO
radical, pointing out in this paper, on a quantitative basis,
the relative importance of the enthalpic and polar effects
and displaying, for the first time, an interesting kinetic
captodative effect in a free radical autoxidation.
For practical applications in the synthesis of aldehydes,
the catalysis by TEMPO has the advantage of a general
character with respect to the oxidation of benzylic and non-
benzylic alcohols and higher stability relative to the PINO
radical, which undergoes a much faster decomposition by
a unimolecular process.[9] The aerobic oxidation by PINO
radical catalysis is limited to the synthesis of aromatic alde-
hydes, but it has the advantage that the radical is generated
in situ from the cheap NHPI, which is readily prepared
from phthalic anhydride and hydroxylamine; moreover
NHPI can be more easily recovered and recycled, relative
to TEMPO, because of its low solubility in several solvents.
More recently, to eliminate the disadvantages (high cost
and difficulties in recovering and recycling the catalyst) in
using TEMPO catalysis, we[ developed, in collaboration
with CIBA Speciality Chemicals, a new TEMPO-analogous
catalyst, characterised by a macrocyclic polypiperidine-N-
oxyl radical structure 3, that is even more active than
TEMPO for the aerobic oxidation of benzylic and non-
benzylic alcohols to the corresponding aldehydes and ke-
tones, but above all the presence of amino groups presents
10]
Results and Discussion
Catalysis by TEMPO and CIBA CBX
A remarkable aspect of the catalysis by the persistent ni-
the great advantages of easy recovery and recycling of the troxyl radical TEMPO or 3 and non-persistent PINO rad-
catalyst as its ammonium salt, considering that the catalysis icals is the fact, reported in our preliminary reports,[ that
1,2]
is effective only in acidic medium as we discuss below.
in the aerobic oxidation of primary alcohols the two differ-
Several groups have addressed the problem of recycling ent kinds of catalyst, even though they are formally quite
the rather expensive nitroxyl radicals utilised in catalytic similar (N-oxyl radicals), give different results.
110
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Aerobic Oxidation of Alcohols to Aldehydes and Ketones
FULL PAPER
The uncatalysed oxidation of organic compounds by mo-
lecular oxygen under mild conditions is generally character-
ised by free radical chain processes (autoxidation).
A thermochemical investigation of the values of the BDE
of the OϪH bonds in hydroxylamine derivatives (TEMPO-
H, 4, N-benzoylmethyl hydroxylamine, 5, and NHPI, 6) al-
lowed us to obtain useful quantitative information concern-
ing the mechanism of the aerobic oxidation of alcohols cat-
alysed by hydroxylamines.
(3)
The results listed in Table 1 clearly indicate that the quite
general reaction of hydrogen atom abstraction from a CϪH
bond by an oxygen-centered radical [Equation (4)] is largely
endothermic with TEMPO [Equation (5)] (∆H ഠ 12Ϫ25
kcal/mol), while it is slightly exothermic (∆H ഠ Ϫ6 to Ϫ3
kcal/mol) for benzyl alcohols and endothermic (∆H ഠ
7
Ϫ8kcal/mol) for aliphatic alcohols in the reactions with
PINO [Equation (6)].
We used the EPR radical equilibration technique[15] to
measure the values of BDE of the OϪH bonds; Table 1
presents the results.[
(
(
5)
6)
9]
Table 1. Values of the BDE for the OϪH bonds in the hydroxylam-
ines 4, 5, and 6
Hydroxylamine
BDE (kcal/mol)
4
5
6
69.6
79.2
88.1
The hydrogen atom abstraction by TEMPO [Equa-
tion (5)] is too endothermic, especially for non-benzylic al-
cohols, to occur under mild conditions. The non-radical
character of the aerobic oxidation of the alcohols catalysed
by TEMPO and Mn(NO ) /Co(NO ) is, in any case,
clearly demonstrated by the fact that under the same con-
ditions, but in the absence of TEMPO, the aldehydes and
ketones are readily oxidised to carboxylic acids by free-rad-
These data indicate that the carbonyl groups directly
bonded to the nitrogen atom (N-acylhydroxylamines)
strongly increase the values of the BDE of the OϪH bonds
relative to alkylhydroxylamines.
Qualitatively, the phenomenon is similar to that observed
for the values of BDE of the OϪH bonds in alcohols
3
2
3 2
ical chains, while the corresponding alcohols are quite in-
(ROϪH, 104 kcal/mol) and hydroperoxides (ROOϪH, 88
[17,18]
ert.
Thus, TEMPO has two basic functions during the
catalysis: it catalyses the oxidation of the alcohols, but it
also inhibits further aerobic oxidation of aldehydes and ke-
kcal/mol) relative to carboxylic acids (RCOOϪH, 110 kcal/
mol) and peracids [R(CO)OOϪH, 93 kcal/mol). Even in
these cases, an acyl group increases the strength of the
OϪH bonds and this effect can be ascribed to the energy
difference between the oxygen-centred radicals and the cor-
responding hydroxyl derivatives. The effect is much more
marked for acyl hydroxylamines, because of the fact that in
tones, which occurs readily under the same conditions in
[17,18]
the absence of TEMPO,
that determines its very high
selectivity. The inhibition of the aerobic oxidation of alde-
hydes and ketones is related to the fact that TEMPO is a
persistent radical that reacts rapidly with a variety of differ-
ent radicals [Equation (7)] and breaks free-radical chains.
dialkyl nitroxides the structures 7 and 8 contribute to the
resonance to approximately the same extent[
16]
[Equa-
tion (2)]; such a stabilisation is not possible for alkoxyl,
·
RϪO , radicals and it has a lower contribution for peroxyl,
·
ROO , radicals [Equation (3)]. The presence of carbonyl
groups reduces the importance of the mesomeric structures
(
7)
8
and 10, because of its electron-accepting character, but
the effect is larger for structure 8.
In addition, the catalysed oxidation of alcohols by O2
and TEMPO in combination with Mn(NO3)2 and
Co(NO ) must be, therefore, related to the reaction of the
oxoammonium salt, generated from TEMPO, and the al-
cohols [Equation (8)], as suggested by a variety of different
3
2
(
2)
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F. Minisci et al.
FULL PAPER
oxidants,[3] in contrast to the other aerobic oxidations cata- Table 2. Relative rates, for the aerobic oxidation of substituted
lysed by TEMPO associated with Ru or Pd complexes for benzyl alcohols catalysed by TEMPO, 3, and 3/p-toluenesulfonic
II
II
which the suggested[5] role of the nitroxyl radical involves
acid (PTS) in conjunction with Mn /Co
the oxidation of the metal complex to a higher oxidation
state, which is the actual oxidant of the alcohol.
X
TEMPO
/k
3
k
3 ϩ PTS
/k
k
X
H
X
/k
H
k
X
H
p-OMe
m-OMe
p-Me
m-Me
p-Cl
m-Cl
p-CN
m-CN
2.88
0.93
2.23
1.10
0.30
0.24
0.13
0.13
0.14
0.12
2.47
1.02
Ϫ
1.04
1.05
0.78
0.81
0.43
0.49
Ϫ
3.74
0.74
Ϫ
1.02
0.94
0.64
0.43
0.42
0.54
Ϫ
(
8)
p-NO
m-NO
2
2
The function of O in combination with Mn(NO ) and
2
3 2
Co(NO ) is to regenerate TEMPO from the N-hydroxypip-
3
2
eridine [Equation (9)].
(
9)
The catalysis is effective only in an acidic medium (the
oxidation takes place in acetic acid solution, but not in
acetonitrile under the same conditions, that allows the use
of the catalyst 3 as its ammonium salt with p-toluene-
sulfonic acid), which indicates that the oxoammonium salt
is generated by the disproportionation equilibrium of
TEMPO [Equation (10)].
Figure 1. Substituent effects in the aerobic oxidation of substituted
benzyl alcohols under TEMPO catalysis
(
10)
Previous results for the oxidation by the oxoammonium
salt have shown that the hydrogen isotopic effect is higher
This equilibrium [Equation (10)] is affected by the acidity
of the reaction medium, but even when it is unfavourable
the fast reaction between the oxoammonium salt and the
alcohol [Equation (8)] shifts the equilibrium to the right.
[
20]
under acidic conditions (k /k ഠ 3.1)
than under alka-
H
D
[
21]
[21]
line (k /k ഠ 1.8) conditions. These results suggested
H
D
that under acidic conditions the rate-determining step
should be the α-proton abstraction from the adduct 11
The mechanism of Equation (8) is still not completely [Equation (11)], which justifies the higher kinetic isotopic
clear and we have investigated the effects that the substitu- effect, while under alkaline conditions the equilibrium for-
ents on the aromatic ring have on the aerobic oxidation of mation of the complex 12 [Equation (12)] might occur at a
benzyl alcohols using competitive kinetics. The results with rate similar to that of the proton transfer, and both contrib-
TEMPO and 3 in acetic acid and in the presence of p-tolu- ute to the rate-determining step. The effect of the substitu-
enesulfonic acid are reported in Table 2 and the Hammett ents on the oxidation of substituted benzyl alcohols would
correlations from these results are presented in Figures 1, 2, be opposite, when considering that the α-proton abstraction
and 3.
is favoured by electron-withdrawing groups and the forma-
112
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Aerobic Oxidation of Alcohols to Aldehydes and Ketones
FULL PAPER
Figure 3. Substituent effects in the aerobic oxidation of substituted
benzyl alcohols using 3 as a catalyst in the presence of p-toluene-
sulfonic acid
Figure 2. Substituent effects in the aerobic oxidation of substituted
benzyl alcohols using 3 as catalyst
tion of the complexes 11 and 12 is favoured by electron- ing that under acidic conditions the formation of the adduct
donating substituents.
11, which is favoured by electron-releasing substituents in
The Hammett correlations (Figures 1Ϫ3) from the results the benzyl alcohols, occurs almost simultaneously with the
presented in Table 2, however, indicate that also under acid α-proton abstraction favoured, in contrast, by electron-
conditions the rate of formation of the adduct 11 prevails withdrawing substituents; both steps contribute with op-
over the deprotonation, with electron-donating groups acti- posite polar effects to the rate determining step, which bal-
vating and electron-withdrawing substituents deactivating ances the overall polar effect, but the nucleophilic character
the oxidation according to the nucleophilic character of the of the substituted benzyl alcohols, which affects the ad-
benzyl alcohols. The opposite behaviour is expected if the dition rate to the oxoammonium salt, always pre-
deprotonation is the rate-determining step. The polar effect vails. This interpretation also explains the somewhat less
of the substituents, however, is not high (the ρ parameters satisfactory
Hammett
correlations
presented
in
are relatively small); we explain this behaviour by suggest- Figures 1Ϫ3 for the strongly electron-withdrawing substitu-
Eur. J. Org. Chem. 2004, 109Ϫ119
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113

F. Minisci et al.
FULL PAPER
ents (p-NO and p-CN), which further increase the rate of to C-deprotonation should be a function not only of the
2
[
19]
the α-proton abstraction in Equation (11) and contribute medium’s acidity, as shown by the isotope effect, but also
[
22]
more to balance the less-marked nucleophilic character of of the substituent.
p-nitro- and p-cyano-benzyl alcohols. could be more complex, however, considering that the same
The same interpretation explains, in our opinion, the system catalyses the aerobic oxidation of benzyl ethers to
higher polar effect (larger value of ρ) observed with esters, while our catalyst, which is more active in the oxi-
TEMPO relative to the radical 3, which has a similar nitro- dation of alcohols relative to the laccase system, is com-
xide group structure; the protonation of the amino groups pletely inert towards the oxidation of benzyl ethers.
The catalysis by TEMPO/laccase
[
22]
in 3 increases the electrophilic character of the oxoammon-
The latter compounds, in contrast, are oxidised readily
ium salt and the rate of addition of the benzyl alcohol, to esters by O and NHPI catalysis in combination with a
2
II
which increases the contribution of proton abstraction in Co salt, which is a free-radical chain process as is dis-
Equation (11) to the rate-determining step.
cussed below.
Our catalytic system of aerobic oxidation is active only
in an acidic medium because of the fundamental role of the Catalysis by N-Hydroxyphthalimide (NHPI)
disproportionation equilibrium of Equation (10), so that
the effect of the substituents cannot be evaluated under al-
kaline conditions.
The report by Ishii and co-workers[8] on the aerobic oxi-
dation of primary alcohols to carboxylic acids under NHPI
catalysis did not consider the different behaviour of
benzylic and non-benzylic alcohols, as we demonstrated in
[
22]
More recently, TEMPO has been utilised as a catalyst
for the aerobic oxidation of benzyl alcohols to aromatic al-
dehydes in combination with a much more expensive metal
complex, the enzyme laccase (a family of ‘‘blue copper’’ oxi-
dase proteins), with the results obtained being similar to
those from our catalyst system, which, however, is more ac-
tive. The effect of the substituents was quite peculiar in that
all the substituents, either electron-withdrawing or electron-
donating, activated the oxidation, as presented in the
Table 3 where the results are compared with those obtained
using our catalytic system.
[2]
a preliminary report. The different selectivity is remark-
able since a free-radical mechanism appears to be involved
in this catalysis and aldehydes are generally more reactive
than the corresponding alcohols in the uncatalysed free-
radical autoxidation, simply because, for enthalpic and po-
[23]
·
lar reasons,
the acylperoxyl radicals, RCOOO , arising
from aldehydes are more reactive than the α-hydroxyper-
·
oxyl radicals, RCH(OH)OO , arising from alcohols. Next,
we indicate that the thermochemistry, kinetics, and the sub-
stituent effects explain this behaviour well.
The value of the BDE of the OϪH bond in NHPI (88.1
kcal/mol; Table 1) suggests that the hydrogen atom abstrac-
tion from benzyl alcohols by the PINO radical is slightly
exothermic and Equation (6) must be considered an equilib-
rium, which, however, is shifted to the right by the fast reac-
Table 3. Relative rates for the aerobic oxidation of p-X-C
CH OH catalysed by TEMPO and laccase or TEMPO and Mn
and Co nitrates
6
H
4
-
II
2
II
II
II
X
TEMPO/laccase k
X
/k
H
TEMPO/Mn /Co
tion of the benzyl radical with O [Equation (13)], followed
2
OMe
Cl
2.5
1.8
1.3
1.2
2.80
0.30
0.14
2.23
by the hydrogen atom abstraction from NHPI [Equa-
tion (14)] and the generation of a catalytic cycle [Equa-
tions (6), (13), and (14)].
NO
Me
2
The results of laccase catalysis have been explained[22] by
a change in the rate-determining step of the oxidation as a
function of the substituent and a V-shaped Hammett plot
(
13)
has been obtained with the σ constants. Thus, the change
I
of the rate-determining step from the nucleophilic O-attack
(
15)
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Aerobic Oxidation of Alcohols to Aldehydes and Ketones
We have determined that the absolute rate constant for
FULL PAPER
Nitroxyl radicals are generally electrophilic in nature, but
the hydrogen atom abstraction by the tert-butylperoxyl rad- this polar character is considerably enhanced by the pres-
ical from the OϪH bond of NHPI[ [Equation (15)] sup- ence of the two carbonyl groups in PINO [Equation (18)].
ports Equation (14). In addition, Equations (14) and (15)
9]
can be considered equilibrium processes because the values
of BDE of the OϪH bonds in NHPI and ROOϪH are al-
most identical (88 kcal/mol); the rate constant k15 [Equa-
(
18)
tion (15)] is, however, much higher than that for the hydro-
gen atom abstraction by the peroxyl radical from benzyl
alcohol [Equation (16)].
The effects are similar to those observed with acyl per-
·
·
oxyl, RC(ϭO)OO , and acyloxyl, RC(ϭO)O , radicals when
(
16)
·
·
compared to alkyl peroxyl, ROO , and alkoxyl, RO , rad-
icals; the former are more electrophilic than the latter.[
The phenomenon is more marked with PINO than with
23]
Thus, Equation (14) prevails highly over Equation (16), acylperoxyl and acyloxyl radicals because the nitrogen atom
which justifies the catalytic cycle based on Equations (6), can stabilise a positive charge, as in Equation (18), better
(13), and (14).
than carbon or oxygen atoms.
By EPR spectroscopy, we have verified the occurrence of
To evaluate the polar effect, we investigated the influence
hydrogen atom abstraction by the PINO radical from the of the substituents on the aromatic ring toward the aerobic
CϪH bonds of benzyl alcohol and other substrates, which oxidation of benzyl alcohols catalysed by NHPI and deter-
strongly supports the radical character of these oxidations; mined the absolute rate constants by competitive kinetics.
moreover, we have evaluated the absolute rate constants of The results are reported in Table 5.
these hydrogen atom abstractions, which we compare with
Table 5. Absolute rate constants for the hydrogen atom abstraction
the corresponding hydrogen atom abstraction by the tert-
6 4
from p-X-C H -CHOH-H by PINO radical at 25 °C
butylperoxyl radical.[
9,15]
In spite of the fact that the values of the BDE of the
OϪH bonds in NHPI and tBuOOϪH are identical (88
kcal/mol), the PINO radical is considerably more reactive
in the abstraction of the hydrogen atom from a CϪH bond
k (Ϫ1 sϪ1
X
)
X H
k /k
H
28.3
65.9
48.1
150.0
43.3
35.1
25.7
30.6
15.2
27.5
13.5
1.00
2.33
1.70
5.3
1.53
1.24
0.91
1.08
0.54
0.97
0.48
p-Me
m-Me
p-OMe
m-OMe
(Table 4) than is the peroxyl radical. This different reactivity
cannot, therefore, be ascribed to the enthalpic effect, but
instead to the polar effect in relation to a more-pronounced p-Cl
m-Cl
electrophilic character of the PINO radical relative to the
p-CN
peroxyl radical, and also by considering that the phenom-
m-CN
enon is particularly marked for benzyl alcohol [Equa-
p-NO
m-NO2
2
tion (17)].
Table 4. Absolute rate constants at 25 °C for the hydrogen atom
abstraction by PINO and tert-butylperoxyl radical[
9]
Figure 4 displays a Hammett correlation between the re-
H (PINO)/k(tBuOO·) sults presented in Table 5 and values of σ ; a satisfactory
Ϫ1 Ϫ1
Ϫ1 Ϫ1
(tBuOO·) 
ϩ
RH
k
H (PINO)

s
k
s
k
correlation is observed with the exception of the data from
PhCH
PhCH
PhCHMe
PhCH
cyclohexane 0.047
3
2
0.38
2.24
3.25
0.036
0.20
0.22
0.13
0.0034
10.5
11.2
14.8
218
the reactions of p-nitro- and p-cyanobenzyl alcohols, in
which the strongly electron-withdrawing substituents have
a negligible effect on the reactivity, while the m-nitro- and
m-cyanobenzyl alcohols are significantly deactivated. We
CH
2
3
2
OH 28.3
13.8
(
17)
Eur. J. Org. Chem. 2004, 109Ϫ119
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115

F. Minisci et al.
FULL PAPER
todative effect is still relevant for the hydrogen atom ab-
straction from benzylic CϪH bonds; that result is also sup-
ported by the proton hyperfine splitting constant of the p-
[
26]
cyanobenzyl methyl ether radical.
Thus, the captod-
ative effect appears to determine the significant decrease of
the values of the BDE of the benzylic CϪH bonds in p-
cyano- and p-nitrobenzyl alcohols; that phenomenon is re-
flected in a favourable enthalpic effect, which balances the
unfavourable polar effect, resulting from the development
of positive charge on the benzylic carbon atom in the tran-
sition state of the hydrogen atom abstraction [Equa-
tion (17)].
For all the other substituents reported in Table 5, the ef-
fects on the values of the BDE of their benzylic CϪH bonds
[
27]
is rather poor
and the polar effect largely prevails over
the enthalpic effect, which leads to a good Hammett corre-
lation.
The equilibrium of Equation (14) is shifted to the right
by the redox decomposition of the hydroperoxide [Equa-
tion (20)]; a catalytic amount of m-chlorobenzoic acid avo-
II
ids the precipitation of the cobalt salt; the presence of Co
is necessary for the oxidation to occur.
Figure 4. Substituent effects in the aerobic oxidation of substituted
nder NHPI catalysis
(
20)
explain this behaviour by a captodative effect, which, quali-
[
24]
The alkoxyl radical reacts very fast with NHPI, which
leads to the formation of the aldehyde and regeneration of
the PINO radical [Equation (21)].
tatively,
suggests that pairs of substituents having op-
posite polarities act in synergy on the stabilisation of a rad-
ical according to the resonance structures of Equation (19).
We have not evaluated the rate constant of Equation (21),
but the alkoxyl radicals are much more reactive in hydrogen
atom abstractions than are the peroxyl radicals for obvious
enthalpic reasons (the values of the BDE for ROϪH and
ROOϪH are 104 and 88 kcal/mol, respectively): the alkoxyl
radicals abstract hydrogen atoms from CϪH bonds [Equa-
(
19)
5
7
tion (22)] with rate constants 10 Ϫ10 times larger than do
the peroxyl radicals [Equation (23)].
We have determined the absolute rate constant for the
hydrogen atom abstraction from the OϪH group of NHPI
by the peroxyl radical (k15 ϭ 7.2·103
 s ) [Equa-
Ϫ1 Ϫ1
From a quantitative point of view, relationships have been
observed between the α- and β-proton EPR spectroscopic
hyperfine splitting constants and the radical stabilisation
enthalpy (RSE) and with the BDE values of the corre-
sponding CϪH bond;[ the overall effects exceed the sum
of the individual substituent effects, which emphasises the
synergetic captodative stabilisation.[
Although the phenylogy [Equation (19)] attenuates the
substituent effect, relative to a captodative effect in which
the two substituents are directly bonded to the radical cen-
tre, the results of Table 5 and Figure 4 indicate that the cap-
tion (15)]; if the rate of hydrogen atom abstraction by the
alkoxyl radical occurs to the analogous extent of Equa-
tions (22) and (23), relative to the peroxyl radical, we
should expect a diffusion-controlled rate for Equation (24).
25]
25]
(
22)
(23)
116
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Eur. J. Org. Chem. 2004, 109Ϫ119

Aerobic Oxidation of Alcohols to Aldehydes and Ketones
FULL PAPER
More recently,[28] NHPI also has been utilised as a cata-
lyst for the aerobic oxidation of benzyl alcohols to alde-
hydes in combination with the enzyme laccase, with results
similar to those obtained using our catalytic system, which,
however, is always more active and much cheaper; the re-
sults suggest that both reactions have effectively the same
mechanism. The function of laccase would be similar to
that of the Co salt, i.e., in the regeneration of the PINO
radical in a catalytic cycle according to reactions similar to
those of Equations (14), (15), (18), (21), and (22). The ef-
fect, however, of the substituents and the Hammett corre-
lation observed with laccase are rather different to those
(
24)
The CoIII salt can be reduced to CoII either by NHPI
Equation (25)] or by the hydroperoxide [Equation (26)] to
[
generate a redox chain.
reported in this paper. No significant captodative effect was
25) observed when using the NHPI/laccase catalyst, but a satis-
(
(
ϩ
factory Hammett correlation with respect to the σ con-
stants, having a value of ρ of Ϫ0.89, was reported, including
the data for p-nitrobenzyl alcohol. Since both the values of
the BDE and the rates of hydrogen atom abstraction of the
26)
benzylic CϪH bonds are not generally affected by solvents
(
in contrast to the behaviour of phenolic OϪH bonds for
The results in Table 5 explain well the high selectivity ob-
served in the oxidation of primary benzyl alcohols to aro-
matic aldehydes; these latter species can be oxidised further
to carboxylic acids only after the complete oxidation of the
starting benzyl alcohols, which clearly shows that the al-
cohols are much more reactive than are the corresponding
aldehydes. The different reactivity must be ascribed to a
more-marked polar effect in the hydrogen atom abstraction
from the alcohols [Equation (17)] than that from the alde-
hydes, and also to a more-favourable enthalpic effect [Equa-
tion (6)].
With non-benzylic alcohols, in contrast, the enthalpic ef-
fect is dominant [the values of the BDE for RCH(OH)ϪH
are 8Ϫ10 kcal/mol larger than those of RC(O)ϪH] and that
phenomenon makes these aldehydes much more reactive
than their corresponding alcohols, which are selectively oxi-
dised to carboxylic acids, even at low conversions.
The different electronic configurations of the benzyl and
benzoyl radicals explain the fact that the values of the BDE
for both aromatic and aliphatic RC(O)ϪH bonds are effec-
tively identical (ca. 87 kcal/mol). The values of the BDE of
the benzylic ArCH(OH)ϪH bonds are lower than those of
aliphatic RCH(OH)ϪH bonds because the benzyl radicals
are π-type radicals and they are stabilised by resonance with
the aromatic ring [Equation (27)] and, obviously, that is not
possible with aliphatic ketyl radicals. the benzoyl radicals
are σ-type radicals and they cannot be stabilised by a simi-
lar resonance effect [Equation (28)].
which both the values of the BDE and the rates of hydrogen
atom abstraction are influenced by the solvents ), it is un-
likely that the different solvents used with the NHPI/laccase
and NHPI/Co(OAc) catalyst systems can be the cause of
the different results. It is likely that the mechanism of the
oxidation is somewhat more complex in the reaction of the
much more complex laccase/NHPI catalyst that it is for
[29]
2
II
Co /NHPI.
Very recently, thermochemical data for the OϪH bond in
NHPI and kinetic data for the hydrogen atom abstraction
from CϪH bonds by the PINO radical have been re-
ported.
NHPI agrees very well with the results previously reported
by us, but the kinetic data are rather different and that
phenomenon cannot be ascribed to a solvent effect, which
is negligible for the hydrogen atom abstraction from CϪH
bonds. In particular the higher rate constant reported by
Espenson et al.
benzaldehyde relative to benzyl alcohol is in clean contrast
with our result that benzyl alcohol is quantitatively oxi-
dised to benzaldehyde without formation of significant
amounts of benzoic acid in the aerobic oxidation catalysed
by NHPI. This result suggests that benzyl alcohol is much
more reactive than benzaldehyde; moreover, all the re-
sults
CϪH bonds by PINO is the rate-determining step in these
aerobic oxidations catalysed by NHPI. On the other hand,
both polar and enthalpic effects suggest that benzyl al-
cohols must be more reactive than the corresponding alde-
hydes towards hydrogen atom abstraction by electrophilic
radicals, and PINO is certainly an electrophilic radical on
the basis of its structure and the results presented in Fig-
ure 4 and Table 5. The opposite behaviour demonstrated by
aliphatic primary alcohols further supports the finding that
the hydrogen atom abstraction by PINO is rate-determin-
ing; in this case, the enthalpic effect dominates and it makes
the aldehydes much more reactive than the alcohols.
[30]
The value of the BDE for the OϪH bond in
[9]
[27]
[30]
for the hydrogen atom abstraction from
[2]
[2,8,17]
indicate that the hydrogen atom abstraction from
(
27)
(
28)
Eur. J. Org. Chem. 2004, 109Ϫ119
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
117

F. Minisci et al.
FULL PAPER
Experimental Section
E) Oxidation of Benzyl Alcohols Catalysed by 3 on a Preparative
Scale: A solution of the alcohol (90 mmol), the nitroxyl radical
catalyst
Mn(NO
3
(2.2 mmol), p-toluenesulfonic acid (4.5 mmol),
(1.8 mmol), and Co(NO (1.8 mmol) was stirred in
Materials: The catalysts, with the exception of CIBA CBX (3), the
benzyl alcohols and the aromatic aldehydes are commercially avail-
able and were used without further purification. The catalyst 3,
prepared according to a recent patent, was provided by CIBA
3
)
2
3 2
)
acetic acid (100 mL) at room temperature for 3 h under air at at-
mospheric pressure. The acetic acid was evaporated and benzal-
dehyde was extracted with methyl tert-butyl ether (98% yield). The
nitroxyl catalyst is insoluble and can be recovered as the am-
monium salt of p-toluenesulfonic acid and recycled without loss
of activity.
Speciality Chemical Inc.[
31]
General Procedures for Determining the Relative and Absolute Rate
Constants of the Aerobic Oxidations of Substituted Benzyl Alcohols:
Competitive kinetics were utilised to determine the relative rate
constants of the aerobic oxidations of benzyl alcohols to aromatic
aldehydes.
[
[
[
1]
2]
3]
A. Cecchetto, F. Fontana, F. Minisci, F. Recupero, Tetrahedron
Lett. 2001, 42, 6653.
F. Minisci, C. Punta, F. Recupero, F. Fontana, G. Pedulli,
Chem. Commun. 2002, 688.
For a review, see: A. E. S. de Nooy, A. C. Besemer, H. van
Bekkum, Synthesis 1996, 1153.
Since we have evaluated[9] by EPR the absolute rate constant for
the hydrogen atom abstraction from benzyl alcohol by the PINO
Ϫ1 Ϫ1
radical (28.3 
s
at 25 °C), which is the rate-determining step
of the oxidation, the absolute rate constants for the substituted
benzyl alcohols, reported in Table 5, have been obtained from their
relative rates.
[4]
M. F. Semmelhack, C. R. Schmid, D. A. Cortes, S. Chou, J.
Am. Chem. Soc. 1984, 106, 3374.
5] [5a]
[
For a review, see: R. A. Sheldon, I. W. C. E. Arends, G. J.
[
5b]
Brink, A. Dijksman, Acc. Chem. Res. 2002, 35, 774.
A.
Competitive experiments were run between benzyl alcohol,
PhCH OH, and substituted benzyl alcohols, XC H CH OH, and
2 6 4 2
Dijksman, I. W. C. E Arends, R. A. Sheldon, Chem. Commun.
1999, 1591; A. Dijksman, I. W. C. E Arends, R. A. Sheldon
Platinum Metals Rev. 2001, 45, 15; A. Dijksman, A. Marino-
Gonzalez, A. Mairata i Payeras, I. W. C. E. Arends, R. A.
Sheldon, J. Am. Chem. Soc. 2001, 123, 6826.
B. Betzemeier, M. Cavazzini, S. Quici, P. Knochel, Tetrahedron
Lett. 2000, 41, 4343.
G. J. Brink, I. W. C. E. Arends, R. A. Sheldon, Science 2000,
suitable reaction times were utilised to have low conversions of the
benzyl alcohols to the aromatic aldehydes. The abundances of the
latter compounds were determined by GC using internal standards
and the response factors obtained from authentic samples. The
relative rate constants were evaluated using Equation (29).
[
[
[
[
6]
7]
8]
9]
2
87, 1636.
For a review, see: Y. Ishii, S. Sakaguchi, T. Iwahama, Adv.
Synth. Catal. 2001, 343, 393.
R. Amorati, M. Lucarini, V. Mugnaini, G. F. Pedulli, F. Mini-
sci, F. Fontana, F. Recupero, P. Astolfi, L. Greci, J. Org. Chem.
(
29)
2
003, 68, 1747.
[
[
10]
11]
F. Minisci, F. Recupero, M. Rodin o` , M. Sala, A. Schneider,
Org. Process Res. Dev. 2003, 7, 794Ϫ798.
A) Aerobic Oxidation of Benzyl Alcohols Catalysed by TEMPO,
Mn(NO , and Co(NO : A solution of benzyl alcohol (3 mmol),
substituted benzyl alcohol (3 mmol), TEMPO (0.15 mmol),
Mn(NO (0.06 mmol), and Co(NO (0.06 mmol) in acetic acid
10 mL) was stirred under an O atmosphere for 1.5 h.
T. Fey, H. Fischer, S. Bachmann, K. Albert, C. Bolm, J. Org.
Chem. 2001, 66, 8154; C. Bolm, T. Fey, Chem. Commun.
3
)
2
3 2
)
1
999, 1795.
[
12]
M. J. Verhoef, J. A. Peters, H. van Bekkum, Stud. Surf. Sci.
Catal. 1999, 125, 465.
3
)
2
3 2
)
(
2
[13]
R. Ciriminna, J. Blum, D. Avnir, M. Pagliaro, Chem. Commun.
2000, 1441.
The yields of benzaldehyde and substituted benzaldehydes were de-
termined by GC analysis using p-chlorobenzaldehyde and m-tolual-
dehyde as internal standards. The relative rates, evaluated by Equa-
tion (29), are reported in Table 2.
[
14]
A. Dijksman, I. W. C. E. Arends, R. A. Sheldon, Chem. Com-
mun. 2000, 271.
[15]
M. Lucarini, G. F. Pedulli, M. Cipollone, J. Org. Chem. 1994,
59, 5063; M. Lucarini, G. F. Pedulli, P. Pedrielli, S. Cabiddu,
C. Fattuoni, J. Org. Chem. 1996, 61, 9259; M. Lucarini, G. F.
B) Aerobic Oxidation of Benzyl Alcohols Catalysed by 3,
Pedulli, L. Valgimigli, R. Amorati, F. Minisci, J. Org. Chem.
Mn(NO
scribed in A) with the only difference that the catalyst 3
0.04 mmol) was used instead of TEMPO. The results are reported
3 2 3 2
) , and Co(NO ) : The procedure is identical to that de-
2
001, 66, 5456; G. Brigati, M. Lucarini, V. Mugnaini, G. F.
Pedulli, J. Org. Chem. 2002, 67, 4828.
[
16]
(
H. G. Aurich, in: The Chemistry of Amino, Nitroso, Nitro Com-
pounds and their Derivatives (Ed.: S. Patai), Wiley, Chichester,
in Table 2.
1
982, chapter 14.
[
[
[
[
[
17]
18]
19]
20]
21]
C) Aerobic Oxidation of Benzyl Alcohols Catalysed by 3,
Mn(NO ) , Co(NO ) , and p-Toluenesulfonic Acid: The procedure
3 2 3 2
is identical to that described in B), except for the presence of p-
toluenesulfonic acid (0.3 mmol). The results are reported in
Table 2.
F. Minisci, F. Recupero, G. F. Pedulli, M. Lucarini, J. Mol.
Catal. A 2003, 204Ϫ205, 63.
F. Minisci, F. Recupero, F. Fontana, H. R. Bjørsvik, L. Liguori,
Synlett 2002, 610.
W. Schiff, L. Stefaniak, J. Skolimowski, G. A. Webb, J. Mol.
Struct. 1997, 407, 1.
V. A. Golubev, V. N. Borislavskii, A. L. Aleksandrov, Izv. Akad.
Nauk SSSR, Ser. Khim. 1977, 2025.
D) Aerobic Oxidation of Benzyl Alcohols Catalysed by NHPI and
Co(OAc)
benzyl alcohol (3 mmol), NHPI (0.3 mmol), Co(OAc)
0.015 mmol), and m-chlorobenzoic acid (0.15 mmol) was stirred
2
: A solution of benzyl alcohol (3 mmol), substituted
M. F. Semmelhack, C. R. Schmid, D. A. Cortes, Tetrahedron
Lett. 1986, 27, 1119.
[22]
2
(
F. D’Acunzo, P. Baiocco, M. Fabbrini, C. Galli, P. Gentili, Eur.
J. Org. Chem. 2002, 4195.
23]
in acetonitrile (5 mL) for 30 min. The quantitative analysis of the
aldehydes was performed as in A) and the results are reported in
Table 5.
[
A. Bravo, H. R. Bjørsvik, F. Fontana, F. Minisci, A. Serri, J.
Org. Chem. 1996, 61, 9409.
118
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Eur. J. Org. Chem. 2004, 109Ϫ119

Aerobic Oxidation of Alcohols to Aldehydes and Ketones
FULL PAPER
P. Baiocco, A. M. Barreca, M. Fabbrini, C. Galli, P. Gentili,
Org. Biomol. Chem. 2003, 1, 191.
P. Pedrielli, G. F. Pedulli, Gazz. Chim. Ital. 1997, 127, 509; M.
I. De Heer, H. G. Karth, P. Mulder, J. Org. Chem. 1999, 64,
6969.
[
[
24]
25]
[28]
[29]
H. G. Viehe, Z. Janausek, R. Mereny, L. Stella, Acc. Chem.
Res. 1985, 18, 148.
F. M. Welle, H. D. Beckhaus, C. Rüchardt, J. Org. Chem. 1997,
62, 552; J. J. Brocks, H. D. Beckhans, A. L. J. Beckwith, C.
Ruchardt, J. Org. Chem. 1998, 63, 1935.
[
[
26]
27]
[30]
[31]
L. Sylvander, L. Stella, H. G. Korth, R. Sustmann, Tetrahedron
Lett. 1985, 26, 749.
N. Koshino, V. Cai, J. H. Espenson, J. Phys. Chem. A 2003,
107, 4262.
D. A. Pratt, J. S. Wright, K. U. Ingold, J. Am. Chem. Soc. 1999,
A. Zedda, M. Sala, A. Schneider, WO 02/058844 A1, Ciba Spe-
cialty Chemicals, 2002.
121, 4877; D. A. Pratt, G. A. Di Lobic, G. F. Pedulli, K. H.
Ingold, J. Am. Chem. Soc. 2002, 124, 11085.
Received May 30, 2003
Eur. J. Org. Chem. 2004, 109Ϫ119
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
119