Selective oxoammonium salt oxidations of alcohols to aldehydes and aldehydes to carboxylic acids

Article abstract of DOI:10.1021/ol203096f

The oxidation of alcohols to aldehydes using stoichiometric 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (1) in CH₂Cl₂ at room temperature is a highly selective process favoring reaction at the carbinol center best able to accommodate a positive charge. The oxidation of aldehydes to carboxylic acids by 1 in wet acetonitrile is also selective; the rate of the process correlates with the concentration of aldehyde hydrate. A convenient and high yield method for oxidation of alcohols directly to carboxylic acids has been developed.

Full text of DOI:10.1021/ol203096f

ORGANIC
LETTERS
2
012
Vol. 14, No. 1
50–353
Selective Oxoammonium Salt Oxidations
of Alcohols to Aldehydes and Aldehydes
to Carboxylic Acids
3
Joseph C. Qiu, Priya P. Pradhan, Nyle B. Blanck, James M. Bobbitt,* and
William F. Bailey*
Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269-3060,
United States
William.Bailey@uconn.edu; James.Bobbitt@uconn.edu
Received November 18, 2011
ABSTRACT
The oxidation of alcohols to aldehydes using stoichiometric 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (1) in
CH Cl at room temperature is a highly selective process favoring reaction at the carbinol center best able to accommodate a positive charge. The
2
2
oxidation of aldehydes to carboxylic acids by 1 in wet acetonitrile is also selective; the rate of the process correlates with the concentration of
aldehyde hydrate. A convenient and high yield method for oxidation of alcohols directly to carboxylic acids has been developed.
1
The use of oxoammonium salts for oxidation of alco-
hols to aldehydes, ketones, or carboxylic acids provides a
nitroxide using a stoichiometric quantity of a primary
3
4
oxidant such as NaOCl. These rapid catalytic oxidations
are typically conducted in a basic reaction medium, and
under these conditions, it is generally observed that pri-
mary alcohols are oxidized more quickly than are second-
2
convenient and environmentally benign alternative to
3
metal-based reagents. Most commonly, such oxidations
are performed by in situ generation of the oxoammonium
cation by oxidation of a catalytic quantity of a stable
3
ary alcohols. The slower oxidation of secondary alcohols
in basic solution has been attributed to steric hinderance to
the formation of a preoxidation complex generated via
alkoxide attack on the electrophilic nitrogen atom of the
(
1) Oxoammonium refers to salts containing the NdO cation derived
from stable nitroxides, such as 2,2,6,6-tetramethylpiperidine-1-oxyl
TEMPO), by one-electron oxidation. It might be noted that, in the
5
(
oxoammonium cation.
past, the oxoammonium cation has been termed nitrosonium, immo-
nium oxide, oxopiperidinium, iminoxyl, and oxoamminium.
The oxidation of an alcohol to an aldehyde or a ketone
may also be accomplished under essentially neutral condi-
tions using a stoichiometric quantity of a preformed oxo-
(
2) Sheldon, R. A.; Arends, I. W. C. E.; Ten Brink, G.; Dijksman, A.
Acc. Chem. Res. 2002, 35, 774.
3) For a review, see: Bobbitt, J. M.; Br u€ ckner, C.; Merbouh, N. Org.
React. (NY) 2010, 74, 103.
4) (a) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem.
987, 52, 2559. (b) Anelli, P. L.; Montanari, F.; Quici, S. Organic
(
3
,6,7
ammonium salt.
Indeed, considerable benefit derives
(
1
Syntheses; Wiley: New York, 1993; Collect. Vol. 8, p 367 and references
therein.
(5) Bailey, W. F.; Bobbitt, J. M.; Wiberg, K. B. J. Org. Chem. 2007,
72, 4504.
1
0.1021/ol203096f r 2011 American Chemical Society
Published on Web 12/08/2011

from the use of a stoichiometric quantity of the stable, cry-
stalline oxoammonium salt, 4-acetamido2,2,6,6-tetramethyl-
piperidine-1-oxoammonium tetrafluoroborate (1). This
salt is commercially available, or may be easily prepared
7
from inexpensivematerials, and asillustrated inScheme 1,
Table 1. Relative Rates of Oxidation of Primary Alcohols to the
Corresponding Aldehydes by 1 in CH Cl (Scheme 1)
2 2
8
oxidations proceed at room temperature in methylene
chloride. Additionally, the oxidant acts as an indicator of
the extent of oxidation: the yellow slurry of 1 in CH Cl
2
2
becomes white as the oxidant is reduced to the insoluble
hydroxylamine salt (2). Products are isolated by simple
filtration and concentration of the filtrate.
Scheme 1
Some time ago, we reported that oxidation of allylic and
benzylic alcoholsinCH Cl using a molarequivalentof1 is
considerably more rapid than is the oxidation of aliphatic
2
2
9
primary alcohols. Moreover, in contrast to the relative
rates of oxidation in basic solutions, secondary alcohols
are more rapidly oxidized than are primary alcohols under
6
these conditions. Given the results of more recent studies
of the mechanism of oxoammonium oxidation of alcohols
a
Virtually identical relative rates have been reported in ref 6 for
oxidations using the perchlorate analog of 1.
5
in neutral media, we have reinvestigated the relative rates
of oxidation of primary alcohols to aldehydes using 1 in
CH Cl . As detailed below, the oxidation of primary
alcohols to the corresponding aldehydes displays synthe-
tically significant selectivity for oxidation ofsubstratesbest
able to accommodate a positive charge at the carbinol
carbon.
The relative rates of oxidation of representative primary
aliphatic, benzylic, allylic, and propargylic alcohols were
investigated in a series of competition experiments using
equimolar quantities of two alcohols and 1 molar equiv of
more slowly than benzyl alcohol, allyl alcohol, or cinnamyl
alcohol. Not surprisingly, more sterically hindered primary
alcohols (Table 1, entries 9 and 10) are oxidized somewhat
more slowly than 1-octanol (Table 1, entry 8). More sig-
nificantly, the rate of oxidation of a benzylic alcohol is
noticeably affected by the nature of a para-substituent
(Table 1, cf. entry 1 and entries 2À4). In the aggregate,
the results of these studies are fully in accord with a
mechanism, suggested in a computational investigation
2
2
5
of the oxidation and depicted in Scheme 2 that involves
formal hydride transfer from the R-carbon of the alcohol
to the oxygen atom of 1.
1
as a slurry in CH Cl . Multiple reaction mixtures invol-
2
2
ving various combinations of alcohols were run to comple-
tion, as indicated by a negative starch-KI test for the
1
presence of 1, and analyzed using H NMR by integration
ofthecarbinol CH resonance inthealcoholsand the CHO
2
Scheme 2
resonance in the aldehyde products. In all cases, the
relative rates for oxidation of the alcohols and the appear-
ance of the aldehydes were identical within the propagated
experimental error of the measurements (viz., 5%). The
results of these experiments are summarized in Table 1.
Cursory inspection of the data presented in Table 1
demonstrates that aliphatic primary alcohols are oxidized
(
(
6) Bobbitt, J. M. J. Org. Chem. 1998, 63, 9367 and references therein.
7) Bobbitt, J. M.; Merbouh, N. Organic Syntheses; Wiley: New York,
2009; Collect. Vol. 11, p 93.
(
8) TCI America; catalog number A2065.
9) This study (ref 6) used the perchlorate analog of 1: the oxidative
(
properties of the two salts are identical (ref 7).
Org. Lett., Vol. 14, No. 1, 2012
351

Catalytic quantities of the oxoammonium cation, when
used in conjunction with a primary oxidant, have been ob-
served to oxidize primary alcohols to carboxylic acids
Table 2. Oxidation of Primary Alcohols to Carboxylic Acids
(Scheme 3)
3
when the reaction is conducted in an aqueous medium.
We have found that such oxidations are easily accom-
plished using stoichiometric amounts of 1, as illustrated in
Scheme 3, by allowing a solution of a primary alcohol and
2
molar equiv of 1 in CH CNÀwater (90:10 by vol) to sit at
3
room temperature (typically overnight for unhindered ali-
phatic alcohols) until the reaction is complete as evidenced
by a color change from orange-brown to clear yellow-
orange and a negative test with starchÀKI paper. A simple
extractive workup affords essentially pure aliphatic car-
boxylic acids in good to excellent yields as evidenced by
the results presented in Table 2. It should be noted that the
hydroxylamine salt coproduct (2) is readily recycled via the
7
nitroxide to 1.
Scheme 3
It is of considerable significance that the oxidation of
benzyl alcohol to benzoic acid is a remarkably sluggish
process; after 20 d of reaction time, benzaldehyde con-
stituted ∼30% of the product mixture (Table 2, entry 11).
Clearly, whereas aliphatic alcohols are oxidized in CH Cl
2
2
solution to aldehydes less rapidly than benzylic alcohols
Table 1), the converse seems to be the case for oxidations
(
in aqueous media that lead to carboxylic acids (Table 2).
The relatively low yield of benzoic acid from the oxidation
of benzyl alcohol was not unexpected: we had noted in a
study of the oxidative cleavage of benzylic ethers by 1 in
aqueous acetonitrile that benzaldehyde is quite resistant to
a
Isolated yield of pure product after 8À12 h of reaction time unless
b
otherwise indicated. Reaction time of 20 d. Prepared from the diol
c
d
using 4 molar equiv of 1. The oxidation was terminated after 20 d; the
remainder of the product mixture was benzaldehyde.
1
0
oxidation by the oxoammonium cation.
As a practical matter, treatment of a primary aliphatic
alcohol and a benzylic alcohol with 1 in an aqueous
medium allows for selective oxidation of the aliphatic
alcohol to the corresponding carboxylic acid while oxida-
tion of the benzylic alcohol stops at the aldehyde stage.
Two examples of such selective oxidations are illustrated in
Scheme 4; isolated yields of pure products are shown.
In an effort to elucidate the origin of the sluggish oxi-
dation of benzaldehydes, the relative rates of oxidation of a
Scheme 4
representative assortment of aldehydes by 1 in CH CNÀ
3
D O (90:10 by vol) were investigated in a series of competi-
2
tion experiments. Reaction mixtures containing equimolar
quantities of two aldehydes and 1 molar equiv of 1 were
allowed to stand for 24 h at room temperature; the relative
extent of oxidation was assayed by integration of the CHO
1
H NMR signals of the residual aldehydes. The results of
these studies are summarized in Table 3.
(10) Pradhan, P. P.; Bobbitt, J. M.; Bailey, W. F. J. Org. Chem. 2009,
4, 9524.
7
3
52
Org. Lett., Vol. 14, No. 1, 2012

Table 3. Relative Rates of Oxidation of Aldehydes to
Carboxylic Acids by 1 in CH O (90:10 by vol)
CNÀD
Scheme 5
3
2
correlate with the concentration of aldehyde hydrate in the
reaction medium. The fact that p-nitrobenzaldehyde is oxi-
dized by 1 approximately five times faster than p-methoxy-
benzaldehyde (Table 3; cf. entries 2 and 3) is consistent
1
3
with this rationale.
The results presented above demonstrate that oxidations
of both alcohols and aldehydes using stoichiometric quan-
tities of 1, displaying significant selectivity that may be of
considerable synthetic utility. The consecutive oxidations
depicted in Scheme 5 illustrate the ability to control the site
of oxidation in a substrate containing similar functionalities.
The conversion of an aldehyde to the corresponding
carboxylic acid almost certainly involves as the rate-limit-
1
1
Acknowledgment. This work was supported by a grant
from the Office of Undergraduate Research at the Uni-
versity of Connecticut. We are grateful toTCI-Americafor
a gift of 4-amino-2,2,6,6-tetramethylpiperidine and Evo-
nik-Degussa for a gift of 4-acetamido-2,2,6,6-tetramethyl-
piperidin-1-oxyl.
ing step oxidation of the hydrate via hydride abstraction
by 1 (Scheme 2). However, the rate of such oxidations is a
function of both the rate constant and the concentration of
the hydrate. Given that the aldehydeÀhydrate equilibrium
is significantly less favorable for aromatic aldehydes
1
2
than for aliphatic aldehydes, the slow oxidation of
benzaldehydes vis- ꢀa -vis aliphatic aldehydes appears to
Supporting Information Available. Detailed experimen-
tal procedures and NMR spectra of products. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
(
11) (a) Wiberg, K. B. Oxidation in Organic Chemistry, Part A;
Academic Press: New York, 1965; pp 69À178. (b) Schmidt, A-K. C.;
Stark, C. B. W. Org. Lett. 2011, 13, 4164 and references therein.
(
12) (a) G oꢁ mez-Bombarelli, R.; Gonz ꢁa lez-P ꢁe rez, M.; P ꢁe rez-Prior,
M. T.; Casado, J. J. Phys. Chem. A 2009, 113, 11423. (b) Hine, J.
Structural Effects on Equilibria in Organic Chemistry; Wiley: New Your,
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J. Org. Chem. 1973, 38, 3164.
1975; pp 257À265. (c) Bell, A. P. Adv. Phys. Org. Chem. 1966, 4, 1.
Org. Lett., Vol. 14, No. 1, 2012
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