New approaches to the Cannizzaro and Tishchenko reactions

Article abstract of DOI:10.1080/00397910902916049

It is demonstrated that the titled reactions are best carried out at high concentrations, as indicated by mechanistic considerations: the observed high reaction orders and the possibility that the Cannizzaro reaction is driven by the hydrophobic effect, which effects proximity between the two molecules of the aldehyde reactant. The present studies have led to improved conditions, simplified workup, and excellent yields of products. The Tishchenko reaction converted benzaldehyde to benzyl benzoate with catalytic NaOMe/tetrahydrafuran in good yield, which is apparently unprecedented for this product of high commercial value.

Full text of DOI:10.1080/00397910902916049

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New Approaches to the
Cannizzaro and Tishchenko
Reactions
a
Sosale Chandrasekhar & Malempati Srimannarayana
a
a
Department of Organic Chemistry, Indian Institute
of Science, Bangalore, India
Version of record first published: 12 Nov 2009
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Approaches to the Cannizzaro and Tishchenko Reactions, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry,
39:24, 4473-4478
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1
Synthetic Communications , 39: 4473–4478, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902916049
New Approaches to the Cannizzaro
and Tishchenko Reactions
Sosale Chandrasekhar and Malempati Srimannarayana
Department of Organic Chemistry, Indian Institute of Science,
Bangalore, India
Abstract: It is demonstrated that the titled reactions are best carried out at high
concentrations, as indicated by mechanistic considerations: the observed high
reaction orders and the possibility that the Cannizzaro reaction is driven by the
hydrophobic effect, which effects proximity between the two molecules of the
aldehyde reactant. The present studies have led to improved conditions, simplified
workup, and excellent yields of products. The Tishchenko reaction converted
benzaldehyde to benzyl benzoate with catalytic NaOMe=tetrahydrafuran in good
yield, which is apparently unprecedented for this product of high commercial
value.
Keywords: Benzaldehyde, Cannizzaro, hydrophobic, oxidation, reduction,
Tishchenko
The Cannizzaro reaction is not only one of the oldest reactions in organic
chemistry but also remains of much synthetic and mechanistic impor-
[
1–3]
tance even today.
generally occurs in aqueous base and converts aromatic or nonenolisable
The reaction is an interesting redox process that
aldehydes (1, Scheme 1) to a mixture of the corresponding benzyl alcohol
(4) and benzoic acid (5).
The Cannizzaro reaction is generally believed to occur via the initial
addition of hydroxide ion to the aldehyde 1, with the resulting tetrahedral
intermediate 2 transferring a hydride ion to another molecule of 1 in a
Received December 18, 2008.
Address correspondence to Sosale Chandrasekhar, Department of Organic
Chemistry, Indian Institute of Science, CV Raman Avenue, Malleswaram,
Bangalore 560012, India. E-mail: sosale@orgchem.iisc.ernet.in
4
473

4474
S. Chandrasekhar and M. Srimannarayana
Scheme 1. Cannizzaro reaction of an aromatic aldehyde 1 forming the corre-
sponding benzyl alcohol (4) and benzoic acid (3) products via transition state I.
key in termolecular step. At strong base concentrations, dianion 3 is
formed and reacts analogously. The overall reaction is thus second order
in the aldehyde and either first or second order in hydroxide depending
on its concentration.
The Tishchenko reaction is an interesting variant of the Cannizzaro
reaction, in which an alkoxide ion nucleophile adds initially to a benzal-
dehyde (1), to produce finally the corresponding alkyl benzoate
[2,4,5]
(9, Scheme 2).
Scheme 2. Tishchenko reaction of benzaldehyde 1a catalyzed by sodium methox-
ide in THF, forming benzyl benzoate (11).

Cannizzaro and Tishchenko Reactions
4475
The objective of this study was the development of improved
procedures for these reactions, based on mechanistic considerations as
discussed. (The classical procedures generally require either long reaction
times or relatively high temperatures, and it would be desirable to
moderate these conditions.)
In the case of the Cannizzaro reaction, the high reaction orders men-
tioned previously, and the fact that the saturation concentration of the
aldehyde substrate in water would be constant at a given temperature,
indicate that a minimal quantity of water needs be employed. Also,
the need for an aqueous medium possibly indicates the hydrophobic
association of two molecules of the aldehyde.
We have found that the Cannizzaro reaction of several aromatic
aldehydes (1) may be conveniently effected with 4 molar equivalents of
potassium hydroxide, employed as a saturated aqueous solution, within
2
night reaction and a difficult workup because of the emulsification of
h at room temperature (Table 1). Previous procedures involved over-
[3]
the reaction mixture. Under our conditions, the reaction was particu-
larly rapid in the case of the activated nitro-substituted benzaldehydes.
(
this is a general problem with the Cannizzaro reaction.
In the case of electron-donating substituents, the yields were poor, but
[
1–3]
)
As a mechanistic aside, we have also attempted to evidence the
hydrophobic driving force for the Cannizzaro reaction. We observed that
the reaction with benzaldehyde is almost completely suppressed at high
ionic strengths of the aqueous medium. This is most likely the result of
the vastly decreased solubility of benzaldehyde in the aqueous medium,
from where it is ‘‘salted out’’ by the sodium chloride added to increase
the ionic strength. The reported ineffectiveness of phase-transfer catalysis
[6]
is understandable in this context, as the reaction occurs in the aqueous
phase. This is also supported by the report that the reaction is highly
[7]
inefficient in nonaqueous media.
Table 1. Percentage yields of the benzyl alcohol and benzoic acid products in the
Cannizzaro reaction of various benzaldehydes (cf. Scheme 1)
Yield (%) of
ArCH OH (4)
Yield (%) of
ArCO H (5)
Item
Reactant ArCHO (1)
2
2
1
2
3
4
5
6
Benzaldehyde (1a)
75 (4a)
92 (4b)
91 (4c)
85 (4d)
93 (4e)
85 (4f)
80 (5a)
93 (5b)
90 (5c)
90 (5d)
93 (5e)
91 (5f)
3-Nitrobenzaldehyde (1b)
4-Nitrobenzaldehyde (1c)
4-Methoxybenzaldehyde (1d)
4-Methylbenzaldehyde (1e)
2-Chlorobenzaldehyde (1f)

4476
S. Chandrasekhar and M. Srimannarayana
Table 2. Products formed in the Tishchenko reaction of aromatic aldehydes (1) in
ꢀ
THF at 25 C under various conditions (cf. Scheme 2)
Item
Reactant
Reagent Time (h)
Products
Yield (%)
1
2
3
4
5
Benzaldehyde (1a) NaOMe
Benzaldehyde (1a) PhCH ONa
NaOMe
16
16
18
14
10
Benzyl benzoate (11)
Benzyl benzoate (11)
Mixture
Mixture
None
70
18
<10
<10
—
2
a
1c
1d
a
NaOMe
NaOMe
a
1e
a
Compare with Table 1.
We have found that the Tishchenko reaction may be carried out with
benzaldehyde (1a) and sodium methoxide in catalytic amounts, again at
high concentrations in tetrahydrofuran (THF) solution. These conditions
led to the formation of benzyl benzoate (11) in excellent yields (Table 2),
presumably via the mechanism in Scheme 2. (This is analogous to
Scheme 1, with hydride transfer occurring from the tetrahedral intermedi-
ate 8 via transition state II.) The initially formed methyl benzoate (9) and
benzyl alcoholate (10) react further to form benzyl benzoate (11), thus
regenerating the methoxide ion.
The yield of benzyl benzoate is much less if benzyl alcoholate anion
10) is employed (Table 2, item 2), possibly a steric effect of the bulkier
(
benzyl alcoholate anion. The reaction also essentially failed with sub-
stituted benzaldehydes (Table 2, items 3–5). (The reaction was also
decelerated at high pressures, presumably because of a decrease in the dif-
fusion of the reactive species.)
In conclusion, improved experimental procedures for the Cannizzaro
reaction of aromatic aldehydes have been developed. These involve
shorter reaction times, minimal use of water, and a simplified workup.
The Tishchenko reaction of benzaldehyde has also been carried out under
considerably milder conditions than before.
EXPERIMENTAL
General Comments
The following instruments were used: Jasco Fourier-transform–infrared
(FT-IR) 410 and Jeol JNM-LA 300 FT NMR. IR spectra were recorded
on thin films, and H NMR spectra were measured at 300 MHz in CDCl
1
3
solution with tetramethylsilane (TMS) as internal standard. Evaporation
of solvent was performed in a rotary evaporator under reduced pressure.

Cannizzaro and Tishchenko Reactions
4477
General Procedures
Cannizzaro Reaction
The aromatic aldehyde (1.0 mmol) was added to a saturated solution of
potassium hydroxide (KOH, 4.0 mmol), and the mixture was stirred at
room temperature for 1–2 h. The thick slurry was treated with water
(
The extracts were washed with water and dried (MgSO ), and the solvent
10 ml), and the resulting mixture was extracted with CH Cl (20 ml).
2 2
4
was distilled off to obtain the crude benzyl alcohol product. The aqueous
part was acidified with 3 N HCl, extracted with CH Cl , and worked up
2
2
as before to obtain the benzoic acid product. The crude products were
purified by chromatography or recrystallization, and the products were
identified spectrally, typically as follows: 4-Methoxybenzyl alcohol 4d:
À1
nmax 3357 cm ; dH 3.80 (s, 3H), 4.61 (s, 2H), 6.88 (d, J 15 Hz, 2H),
7
1
.27 (d, J 15 Hz, 2H). 3-Nitrobenzoic acid 5b: n
706 cm ; dH 7.73 (m, 1H), 8.48 (m, 2H), 8.96 (s, 1H).
3444, 3095,
max
À1
Tishchenko Reaction
Benzaldehyde (1.0 mmol) was added to a solution of NaOMe (0.1 mmol)
ꢀ
in dry THF (3.0 ml), and the mixture was stirred at 25 C for 16 h. The
thick slurry was treated with water (1 ml), and the resulting mixture
was extracted with ethyl acetate (5 ml). The extracts were dried (Na SO ),
and the solvent was distilled off in vacuo to obtain the crude benzyl
2
4
benzoate product. This was purified by column chromatography (SiO )
2
À1
and identified spectrally. Benzyl benzoate (11): nmax 1718 cm ; dH 5.36
(
s, 2H), 7.40 (m, 6H), 7.56 (m, 2H), 8.08 (m, 2H).
ACKNOWLEDGMENT
We thank the Council of Scientific and Industrial Research (New Delhi)
for generous fellowship support to M. S.
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4478
S. Chandrasekhar and M. Srimannarayana
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