Studies on oxidations with IBX: Oxidation of alcohols and aldehydes under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2004.05.044

A variety of allylic and benzylic alcohols are oxidized to their respective carbonyl compounds with IBX under solvent-free conditions at ca. 60-70°C. It has also been found that some of the aromatic aldehydes also undergo oxidation when heated with IBX at 90°C under solvent-free conditions; notably, this transformation does not occur under the otherwise identical but heterogeneous conditions.

Full text of DOI:10.1016/j.tetlet.2004.05.044

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5419–5424
Studies on oxidations with IBX: oxidation of alcohols
and aldehydes under solvent-free conditions
Jarugu Narasimha Moorthy,* Nidhi Singhal and P. Venkatakrishnan
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
Received 14 April 2004; revised 5 May 2004; accepted 11 May 2004
Abstract—A variety of allylic and benzylic alcohols are oxidized to their respective carbonyl compounds with IBX under solvent-
free conditions at ca. 60–70 ꢀC. It has also been found that some of the aromatic aldehydes also undergo oxidation when heated with
IBX at 90 ꢀC under solvent-free conditions; notably, this transformation does not occur under the otherwise identical but hetero-
geneous conditions.
ꢁ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
that permit better solubility and hence application in
more common organic solvents.7 Other efforts aimed at
exploiting the potential of IBX in organic oxidations
include its application in ionic liquids8 and in the pres-
ence of container molecules such as cyclodextrins,9
which modify the solubility. Quite remarkably, More
and Finney have very recently shown that the limited
solubility of IBX in most of the organic solvents at
elevated temperatures is substantial enough to achieve
oxidation of primary and secondary alcohols to alde-
hydes and ketones, respectively.10 We drew inspiration
from this report to accomplish the oxidation of highly
insoluble and difficultly oxidizable lactols, derived from
benzocyclobutenols, to lactones under modified condi-
tions.11 During these studies, we discovered that IBX
works wonderfully as an oxidizing agent under solvent-
free conditions. Herein, we wish to document this hith-
erto unknown facet of IBX to oxidize alcohols to the
corresponding carbonyl compounds without the use of
any solvent. Further, we also wish to unravel the distinct
reactivity of IBX in oxidizing selectively some aldehydes
to the corresponding acids, while the same transforma-
tion does not occur under the otherwise identical but
heterogeneous conditions.10
Oxidation of alcohols to carbonyl compounds consti-
tutes one of the fundamental transformations in organic
synthesis. Despite the availability of a variety of meth-
ods, there is a growing need for green methodologies
that obviate the use of copious amounts of heavy metal
oxidants and environmentally unfriendly halogenated
solvents.1 From this point of view, readily available
iodine (V) reagents are highly attractive.2 In particular,
o-iodoxybenzoic acid (referred to as IBX), a precursor
of the well-known DMP (Dess–Martin periodinane
reagent), has become a very popular and convenient
oxidizing agent due to its nontoxic nature and ease of
preparation.2 The major drawback, however, is its vir-
tual insolubility in common organic solvents. It is pre-
cisely this property, which precluded its applications in
organic oxidation reactions for almost a century.3 The
recent demonstration by Frigerio and co-workers4 of the
utility of IBX in DMSO for oxidation of alcohols has
sparked a revival of interest in IBX-mediated reactions
due to its cheapavailability and the ease with which the
oxidation reactions may be conducted.2 In recent years,
Nicolaou and co-workers,2;5 and others6 have uncov-
ered a variety of very useful transformations accom-
plished by IBX. Considerable effort has also been
focused toward the synthesis of modified IBX reagents
2. Oxidation of primary alcohols
The oxidation of primary allylic and benzylic alcohols
occurs in a facile manner on heating with IBX under
solvent-free conditions for the durations shown in Table
1 (CAUTION! IBX has been reported to explode on
Keywords: IBX; Oxidations; Solvent-free; Alcohols.
* Corresponding author. Tel.: +91-512-2597438; fax: +91-512-25974-
36; e-mail: moorthy@iitk.ac.in
0040-4039/$ - see front matter ꢁ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.044

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J.Narasimha Moorthy et al./ Tetrahedron Letters 45 (2004) 5419–5424
Table 1. Results of the oxidation of primary alcohols with IBXa
Entry
1
Alcohol
Equiv
Time (h)
Yieldb (%)
Product distributionc
Aldehyde
Acid
1.25
2.00
1.0
3.0d
>95
70
100
43
CH2OH
57
2
3
4
5
Br
CH2OH
1.25
1.25
1.25
1.25
1.0
1.5
1.0
3.0
89
88
95
84
100
100
100
100
O N
CH OH
2
2
H CO
3
CH OH
2
CH2OH
CH3
CH2OH
CH3
6
7
1.25
2.0e
84
60
40
H3C
H3C
OCH3
CH2OH
CH3
2.00
3.00
2.0
4.0d
90
91
100
100
H3C
H3C
CH3
8
9
1.25
0.75b
72
100
CH2OH
CH2OH
1.25
2.50
0.5
1.5
89
86
100
36
64
10
11
1.25
1.25
0.5
1.5
75f
100
O
CH2OH
CH2OH
90
71
100
100
S
12
13
HOH2C
CH2OH
2.50
2.0
2.0
Cetyl alcohol
3.0e;g
a Under solvent-free conditions, the temperature was 60 ꢀC unless otherwise mentioned, see text.
b Isolated yields. The conversion was P95% except for entry 8 (72%).
c Relative distribution normalized to 100%.
d Temperature ¼ 60–90 ꢀC.
e Temperature ¼ 70 ꢀC.
f The remaining material was unidentifiable.
g No oxidation was observed.
heating).12 All of the benzylic and allylic alcohols
including the heteroaromatic analogues yielded the
corresponding aldehydes in respectable isolated yields
(72–95%), when the oxidation was conducted with
1.25 equiv (entries 1–6, 8–11). Indeed, the benzylic diol
(entry 12) was oxidized to terephthalaldehyde in 71%
isolated yield with excess reagent. However, the ali-
phatic cetyl alcohol could not be oxidized even with
2.0 molar equiv of IBX (entry 13). In contrast, the ste-
rically-hindered benzylic alcohols (entries 6 and 7)
underwent clean oxidation in yields higher than 84%;
interestingly the formation of mesitoic acid was ob-
served in significant amounts even for 1.25 molar equiv
of IBX (entry 6). When IBX was used in excess, over-
oxidation to acids (entries 1, 6, and 9) was observed in
appreciable yields (vide infra). Importantly, the dura-
tions for the conversion of alcohols to aldehydes were
found to be comparable to those for oxidation in
DMSO (1/2–5 h)4 and under heterogeneous conditions
(ca. 1/2–3 h).10

J.Narasimha Moorthy et al./ Tetrahedron Letters 45 (2004) 5419–5424
5421
3. Oxidation of secondary alcohols
4. Oxidation of aromatic aldehydes
In a similar vein, the oxidation of secondary allylic and
benzylic alcohols also proceeded smoothly to the
respective ketones in good yields (Table 2, entries 1–6).12
The vicinal diol did not afford the glyoxal, but under-
went selective benzylic oxidation as revealed by 1H
NMR spectroscopy (entry 7); cleavage of the 1,2-diol
was not observed. The 1,3-diol, however, underwent
oxidation to the diketone when treated with excess IBX
(entry 8). It is noteworthy that monooxidation was not
observed regardless of whether more or less molar
equivalent of IBX were employed. Again, oxidation was
ineffective with aliphatic substrates such as cholesterol
and menthol (entries 9 and 10).
The formation of acids from some of the alcohols (Table
1) when IBX was used in excess amounts prompted us to
examine the oxidation of aldehydes. The prototypical
aromatic aldehyde, viz., benzaldehyde, was found to
undergo oxidation at 60 ꢀC, albeit in low yields. The
oxidation was found to be more facile at slightly higher
temperatures, ca. 90 ꢀC. Accordingly, we subjected
rather less-volatile aldehydes to oxidation at 90 ꢀC
(Table 3). Whereas p-bromobenzaldehyde underwent
oxidation to the acid in 63% isolated yield in 3 h (Table
3, entry 1), p-nitro, and p-methoxy aldehydes were
found to react sluggishly with the former undergoing no
oxidation at all (entries 2 and 3). Rather inexplicably,
Table 2. Results of the oxidation of the secondary alcohols to ketonesa
Entry
Alcohol
Equiv
Time (h)
Conv. (%)
Yieldb (%)
OH
83
81
1.25
2.00
3.0
2.0
100
100
1
CH3
OH
2
3
2.00
2.0
100
93
H3CO
CH3
OH
OH
1.25
2.00
3.0
2.0
100
100
92
87
4
5
2.00
3.0
100
94
OH
2.00
2.00
3.0
6.0
60
60
84
84
OH
6
7
1.50
2.50
1.0
2.0
95
70c
OH
d
CH2OH
OH
OH
8
2.50
4.0
89
62e
CH3
9
10
Cholesterol
())-Menthol
2.00
2.00
5.0f
3.0f
a Under solvent-free conditions, temperature ¼ 70 ꢀC, see text.
b Isolated yields based on conversion.
c The remaining material was unidentifiable.
d From 1H NMR analysis of the crude reaction mixture, only benzylic oxidation was found to occur with the formation of glyoxal being negligible,
yields were not determined.
e Oxidation of both of the groups was found to occur simultaneously regardless of the molar equivalent of IBX employed.
f No oxidation was observed.

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J.Narasimha Moorthy et al./ Tetrahedron Letters 45 (2004) 5419–5424
Table 3. Results of the oxidation of aldehydes to acidsa
Entry
1
Aldehyde
Equiv/temp
(ꢀC)/time (h)
Conv. Yieldb
(%)
(%)
Br
CHO
1.25/90/3
70
63
c
2
3
2.0/90/10
1.25/90/5
O2N
CHO
H3CO
CHO
14
14
50
50
CHO
4
2.0/90/10
CH3
CHO
5
6
1.25/90/4.5
1.25/90/4.0
75
73
80
86
Figure 1. 1H NMR (400 MHz, MeOH-d4) spectral monitoring of the
solid-state reaction of p-bromobenzyl alcohol with 2.5 molar equiv of
IBX: (a) alcohol and IBX mixture after grinding in a mortar and pestle
for 5–10 min; (b) after heating at 60 ꢀC for 1 h; (c) after 2 h,
temp ¼ 90 ꢀC; (d) after 3 h, temp ¼ 90 ꢀC.
H3C
CH3
CHO
a Mass balance in all the cases was >90%, except for entry 1 (63%).
b Isolated yields based on conversion.
c No acid was detected.
The oxidation of alcohols to aldehydes is known to occur
by the mechanism shown in Scheme 1.2a;c Removal of
the water formed at the reaction temperature (60–70 ꢀC)
(see Ref. 12 for the procedure) may facilitate the for-
ward process.13
mesitaldehyde underwent smooth oxidation, while
naphthalene-2-carboxaldehyde reacted only sluggishly
(entries 4 and 5). Cinnamaldehyde underwent facile
oxidation to the acid in an excellent isolated yield (entry
6). In contrast, the oxidation of p-bromobenzaldehyde
and mesitaldehyde with 3.0 equiv of IBX as a suspended
material in ethyl acetate at reflux for 3 h under hetero-
geneous conditions10 did not lead to the corresponding
acids. This signifies the unique reactivity that appears to
be especially associated with IBX under solvent-free
conditions.
The IBX-mediated oxidation of aldehydes to acids is
heretofore unknown and is a difficult procedure to
rationalize. We propose that the addition intermediate
of the type shown in Scheme 2 may form via initial
protonation of the aldehyde by IBX followed by attack
of its conjugate base; it should be noted that IBX has
been reported to be a mild acid.14 The reason as to why
only some aldehydes react to afford the acids (Table 3)
should be traceable to the subtle electronic factors
operative in steps 1 and 2 of the proposed mechanism.
5. Direct oxidation of alcohols to acids and
mechanistic rationalizations
Encouraged by the oxidation of aldehydes, we examined
the direct conversion of alcohols to acids. The progress
of the reaction of p-bromobenzyl alcohol, a represen-
Ar
H
H
O
O
OH
O
HO
1
tative case, was directly monitored by H NMR spec-
OH
I
I
∆
troscopy. Thus, the alcohol and IBX (2.5 equiv) were
ground together with a mortar and pestle, and the
reaction of the solid mixture on heating was analyzed by
1H NMR spectroscopy in MeOH-d4 at regular time
intervals. As can be seen from Figure 1, the formation of
aldehyde in small amounts was observed upon mere
grinding. On heating the mixture at 60 ꢀC for 1 h in a
Kugelrohr (Buchi glass oven),12 complete conversion to
the aldehyde occurred (spectrum b). Continued heating
at 90 ꢀC for 2 h led to the acid almost quantitatively, see
traces c and d. Although IBX and its reduction product
remained as suspended solid materials, the signals due to
some solubility in this solvent are clearly evident in the
region around ca. d 8.0 in all of the spectra. Clearly, the
oxidation of alcohols to acids proceeds via two steps.
O
Ar CH2OH
O
O
IBX
H2O
Ar
H
H
O
O
O
OH
I
I
∆
O
Ar CHO
O
O
IBA
Scheme 1. Mechanism of the IBX-mediated oxidation of alcohols to
aldehydes.

J.Narasimha Moorthy et al./ Tetrahedron Letters 45 (2004) 5419–5424
5423
derivatives with enhanced reactivity should constitute
very useful reagents for facile oxidation of alcohols and
aldehydes at room temperature under solvent-free con-
ditions, and we are continuing our investigations toward
this goal.
O
OH
O
O
O
I
Ar
∆
Ar
Ar
H
H
OH
O
O
O
O
IBX
IBA
Step 1
∆
I
OH
I
CAUTION! IBX has been reported to detonate upon
heavy impact and heating over 190 ꢀC.17
O
O
Step 2
OH
O
Acknowledgements
Scheme 2. Mechanism of the IBX-mediated oxidation of aldehydes to
acids.
We thank the Department of Science and Technology
(DST), India for financial support. N.S. and P.V. are
grateful to C.S.I.R. for junior research fellowships.
The direct conversion of alcohols to acids with a mild
oxidizing agent is an important transformation in or-
ganic synthesis. Based on a rational approach that in-
volves the initial conversion of an aldehyde to the
corresponding hemiacetal via nucleophilic attack with
an additive such as 2-hydroxypyridine/N-hydroxysuc-
cinimide followed by oxidation with IBX, Mazitschek
et al. have very recently demonstrated the oxidation of
alcohols-to-aldehydes-to-acids;15 the reaction times in
DMSO are as long as 16 h. In light of this, the oxidation
of aromatic aldehydes observed with IBX under solvent-
free conditions is noteworthy.
References and notes
1. (a) Noyori, R.; Aoki, M. Chem.Commun. 2003, 1977–
1986; (b) Brink, G.-J. T.; Arends, I. W. C. E.; Sheldon,
R. A. Science 2000, 287, 1636–1639.
2. (a) Nicolaou, K. C.; Baran, P. S. Angew.Chem.Int.Ed.
2002, 41, 2678–2720; (b) Zhdankin, V. V.; Stang, P. J.
Chem.Rev. 2002, 102, 2523–2584; (c) Wirth, T. Angew.
Chem.Int.Ed. 2001, 40, 2812–2814.
3. Hartmann, C.; Meyer, V. Chem.Ber. 1893, 26, 1727.
4. (a) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994,
43, 8019–8022; (b) Frigerio, M.; Santagostino, M.; Spu-
tore, S.; Palmisano, G. J.Org.Chem. 1995, 60, 7272–7276.
5. (a) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T.
Angew.Chem.Int.Ed. 2003, 42, 4077–4082; (b) Nicolaou,
K. C.; Mathison, C. J. N.; Montagnon, T. J.Am.Chem.
Soc. 2004, 126, 5192–5201.
6. (a) Shukla, V. G.; Salgaonkar, P. D.; Akamanchi, K. G.
J.Org.Chem. 2003, 68, 5422–5425; (b) Magdziak, D.;
Rodriguez, A. A.; Water, R. W. V. D.; Pettus, T. R. R.
Org.Lett. 2002, 4, 285–288; (c) Wu, Y.; Huang, J.-H.;
Shen, X.; Hu, Q.; Tang, C.-J.; Li, L. Org.Lett. 2002, 4,
2141–2144; (d) Surendra, K.; Krishnaveni, N. S.; Reddy,
M. A.; Nageswar, Y. V. D.; Rao, K. R. J.Org.Chem.
2003, 68, 9119–9121.
7. (a) Ozzane, A.; Pouysegu, L.; Depernet, D.; Francois, B.;
Quideau, S. Org.Lett. 2003, 5, 2903–2906; (b) Thottum-
kara, A. P.; Vinod, T. K. Tetrahedron Lett. 2002, 43, 569–
572; (c) Zhdankin, V. V.; Smart, J. T.; Zhao, P.; Kiprof, P.
Tetrahedron Lett. 2000, 41, 5299–5302; (d) Zhdankin, V.
V.; Koposov, A. Y.; Netzel, B. C.; Yashin, N. V.; Rempel,
B. P.; Freguson, M. J.; Tykwinski, R. R. Angew.Chem.Int.
Ed. 2003, 42, 2194–2196; (e) Mulbaier, M.; Giannis, A.
Angew.Chem.Int.Ed. 2001, 40, 4393–4394.
In summary, we note the following for the solvent-free
oxidation of alcohols and aldehydes with IBX:
• Both primary and secondary aliphatic alcohols do
not undergo oxidation with the exception of entry 8
in Table 2, whereas the allylic and benzylic alcohols
react readily (Tables 1 and 2) without any depen-
dence on the electronic factors. The results suggest
the necessity of some unsaturation in the molecules
to achieve appropriate orientation with respect to
IBX for reaction to ensue in the solvent-free state.
• The oxidation of alcohols to aldehydes occurs with a
small excess (1.25–1.50 equiv) of IBX and over-oxida-
tion to acids can be controlled with temperature.
• Intriguingly, the sterically-hindered mesityl alcohol
undergoes direct oxidation to the acid, while 2-meth-
oxy-4,6-dimethylbenzyl alcohol yields only the alde-
hyde (Table 1, entries 6 and 7).
• Some aromatic aldehydes are found to undergo oxi-
dation to the corresponding acids (Table 3), whilst
being unreactive under identical but heterogeneous
conditions, cf. More and Finney.10
8. Liu, Z.; Chen, Z.-C.; Zheng, Q.-G. Org.Lett. 2003, 5,
3321–3323.
9. Surendra, K.; Krishnaveni, N. S.; Reddy, M. A.; Nage-
swar, Y. V. D.; Rao, K. R. J.Org.Chem. 2003, 68, 2058–
2059.
10. More, J. D.; Finney, N. S. Org.Lett. 2002, 4, 3001–3003.
11. Moorthy, J. N.; Singhal, N.; Mal, P. Tetrahedron Lett.
2004, 45, 309–312.
12. The typical experimental procedure involved heating the
mixture of alcohol/aldehyde and finely powdered IBX in a
Kugelrohr (glass oven, Buchi) at 60–70 ꢀC (for alcohols) or
at 90 ꢀC (for aldehydes) for the appropriate durations
given in Tables 1–3. For liquid substrates, their ether
solutions were treated with finely powdered IBX, the
Although IBX has been reported to be sensitive to hard
impact and high temperatures, we have not had a single
instance of any explosion at the temperatures employed
at 1–2 mmol scale operations. We admit that the sol-
vent-free oxidation protocol described herein cannot be
applied to large-scale operations in view of the explosion
hazards. Given that the potential of IBX as an oxidizing
agent went unnoticed for well over a century due to its
insolubility in a variety of organic solvents, the observed
results are indeed a revelation. In view of the importance
associated with IBX in terms of eco-friendly advantages
and its ease of regeneration with oxone,16 modified IBX

5424
J.Narasimha Moorthy et al./ Tetrahedron Letters 45 (2004) 5419–5424
solvent removed and the solid admixture thus formed was
heterolysis. The former has been proposed in the case of
oxidation of electron-rich amines, see: Ref. 5b. A similar
SET process is unlikely in the case of alcohols.
14. Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J.Am.Chem.
Soc. 2000, 122, 7596–7597.
15. Mazitschek, R.; Mulbaier, M.; Giannis, A. Angew.Chem.
Int.Ed. 2002, 41, 4059–4061.
16. Frigerio, M.; Santagostino, M.; Sputore, S. J.Org.Chem.
1999, 64, 4537–4538.
heated. In the case of crystalline substrates, IBX and the
substrate were ground together with a mortar and pestle,
and the admixture was heated in a Kugelrohr oven.
Filtration of the reaction mixture over a short-pad of silica
gel afforded the aldehydes/acids. The IBX employed for
the reactions was prepared by the reported procedure, see:
Boeckman, R. K., Jr.; Shao, P.; Mullins, J. J. Org.Synth.
77, 141.
13. The exclusion of water may occur either by homolysis
involving a single electron transfer mechanism (SET) or by
17. Plumb, J. B.; Harper, D. J. Chem.Eng.News 1990, July
16, 3.