Selective oxidations of activated alcohols in water at room temperature

Article abstract of DOI:10.1039/c4cc05163g

Allylic and benzylic alcohols can be selectively oxidized to their corresponding aldehydes or ketones in water containing nanoreactors composed of the designer surfactant TPGS-750-M. The oxidation relies on catalytic amounts of CuBr, bpy, and TEMPO, with N-methyl-imidazole; air is the stoichiometric oxidant. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc05163g

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Selective oxidations of activated alcohols in water
at room temperature†
Cite this: Chem. Commun., 2014,
50, 11378
B. H. Lipshutz,* M. Hageman, J. C. Fennewald, R. Linstadt, E. Slack and
K. Voigtritter
Received 4th July 2014,
Accepted 30th July 2014
DOI: 10.1039/c4cc05163g
www.rsc.org/chemcomm
Allylic and benzylic alcohols can be selectively oxidized to their
corresponding aldehydes or ketones in water containing nanoreactors
composed of the designer surfactant TPGS-750-M. The oxidation
relies on catalytic amounts of CuBr, bpy, and TEMPO, with N-methyl-
imidazole; air is the stoichiometric oxidant.
Scheme 1 Oxidations of activated alcohols under green conditions: in
water at room temperature.
Mild and selective methods for the oxidation of alcohols to
aldehydes and ketones are among the most valuable processes
in organic chemistry. While many feature the use of catalytic
quantities of metal-based reagents, catalysis alone may not be as to where to localize, the concentration of oxygen within the
sufficient to anticipate widespread use, especially on an industrial hydrophobic inner core of a nanomicelle is expected to be much
scale. Indeed, today there is an increasing level of concern as to higher than in the surrounding water.5 When taken together
the environmental impact of such methodologies, most notably with the much higher concentrations of reactants and catalysts
from the standpoint of the stoichiometric oxidant, which ideally is typically found within these nanoreactors,6 the major para-
air. But even when a process is tailored to involve catalysis and a meters are well positioned to potentially arrive at a relatively
benign oxidizing agent, these together can be overshadowed by a environmentally benign oxidation.
single parameter that represents the main contributor to organic
We opted to focus on a base metal such as copper, rather than
waste: solvent.1 Hence, an oxidation that relies not only on the palladium or other transition metals7 that have also been used
virtues of a catalysis/air combination, but also that further for similar oxidations. There are several published procedures
adheres to the 12 Principles of Green Chemistry2 should enhance that utilize copper salts in the presence of catalytic amounts of
the appeal from the environmental perspective of such a process. TEMPO, as summarized in Table 1. Among those that can be
In this report, we describe an oxidation protocol for activated utilized at ambient temperature, we were led to investigate the
alcohols that uses catalytic amounts of a base metal (Principle 9), application of Stahl’s conditions: [Cu(MeCN)4]X where X = TfOꢀ,
involves air as the stoichiometric oxidant (Principle 7), relies on an BF4ꢀ, or PF6ꢀ, catalytic TEMPO (5 mol%), air, N-methylimidazole
innocuous and recyclable reaction medium (Principle 5), and (NMI), and 2,20-bipyridine (bpy) as ligand.8 Screening both copper
offers conditions leading to a very low E factor3 based on solvent salts [Cu(MeCN)4]OTf and [Cu(OTf)2]ꢁPhMe9 in water containing
usage (Principle 3) indicative of the level of greenness associated two weight percent TPGS-750-M did afford the desired product
with this new technology (Scheme 1).
aldehyde based on p-methoxybenzyl alcohol as educt, albeit in
The overarching concept behind the oxidation developed modest yields (Table 2). Far better results were achieved with
herein is the far greater dissolution properties of gases, such as CuBr, affording the targeted benzaldehyde in virtually quantitative
oxygen, in organic solvents rather than in water.4 Thus, when yield within four hours at room temperature. Other sources of
air is presented with the option in an aqueous micellar medium copper (e.g., CuCl, copper metal) gave lower levels of conversion,
although CuBr2 led to roughly comparable results.
The role of the surfactant was studied using several alternatives
Department of Chemistry & Biochemistry, University of California, Santa Barbara,
to TPGS-750-M (Table 3). As noted in previous work,19 particle size
CA 93106, USA. E-mail: lipshutz@chem.ucsb.edu
can play a significant role in determining the extent and quality
of a given reaction, and here again, the amphiphile engineered
to provide particles in the 50–60 nm range was the surfactant
† Electronic supplementary information (ESI) available: Experimental procedures
and details, copies of 1H and 13C NMR characterization data for all new
compounds. See DOI: 10.1039/c4cc05163g
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Table 1 Previous work on air/oxygen-based benzylic oxidations
Author
Year
Catalyst system
Ligand
Solvent
Atm
Temp. (1C)
Semmelhack10
Knochel11
Sheldon12
Falk13
1984
2002
2003
2005
2006
2007
2007
2009
2011
2013
2013
2014
CuCl
—
1
DMF
C8F17Br–PhCl
MeCN–H2O
MeCN–H2O
DMSO
H2O
PhMe
H2O
O2
O2
Air
O2
rt
90
rt
CuBrꢁSMe2
CuBr2/t-BuOK
Cu0/NaOH
bpy
bpy
TMDP
phen
—
rt
Ragauskas14
Repo15a
Cu(ClO4)2
O2
100
100
80
100
rt
rt
100
rt
CuSO4/NaOH
DABCO–CuCl/K2CO3
CuSO4/K2CO3
[Cu(MeCN)4]OTf/NMI
Cul/t-BuOK
O2 (10 atm)
O2
O2
Air
Air
Air
Air
Sekar16
Repo15b
2
Stahl8
bpy
L-Proline
3
MeCN
DMF
H2O
Ding17
Zhang18
This work
Cu(OAc)2ꢁH2O/Na2CO3
CuBr/NMI
bpy
TPGS-750-M, 2 wt% in H2O
Table 2 Screening of copper salts for the oxidation
Entry
Conditionsa
Conversionb (%)
1
2
3
4
5
6
7
8
[Cu(CH3CN)4]OTf
[Cu(OTf)]2ꢁPhMe
CuCl
64
58
63
Scheme 2 Comparison between an oxidation ‘on water’ vs. under micel-
lar conditions.
Cu0 powder
CuBr2
35
97
100(98)c
43
background reaction, which, as noted previously,22 oftentimes
does not lead to synthetically useful results (Scheme 2).
Several primary, benzylic alcohols could be smoothly oxidized to the
corresponding aldehydes in water at room temperature (Table 4). Most
reactions reached completion in 5 to 20 hours, and tend to be very
clean, with the associated isolated yields uniformly high. There appears
to be no obvious relationship between the nature of the substituents
on the aromatic ring and the time required for each oxidation.
Heteroatoms also seem to be well tolerated, including cases where a
sulfide and primary amine substituents are present (compounds 12
and 14, and 10, respectively). Since the pH of the reaction mixtures is 6,
these conditions do not interfere with a TMS-protected alkyne (11).
Secondary benzylic alcohols can also be oxidized under the
aqueous micellar conditions, although they are slower than the
corresponding primary cases and therefore required mild heating
to 40–45 1C. Three representative examples are shown in Scheme 3.
These observed differences in rate, as noted by Stahl,8 allow for the
selective oxidation of a primary over secondary benzylic alcohol, as
illustrated by the conversion of 22 into 23 (Scheme 4).
CuBr
CuBrd
CuBre
84
a
Alcohol (0.5 mmol), copper source (0.025 mmol), TEMPO (0.025 mmol),
bpy (0.025 mmol), NMI (0.05 mmol), TPGS-750-M (1.0 mL). b Determined by
GC analysis. Isolated yield. Reaction concentration 2.0 M. Reaction
run ‘‘on water’’.
c
d
e
Table 3 Impact of surfactant on a benzylic oxidation
Run
Surfactanta,b
Particle sizec (nm)
Conversiond (%)
1
2
3
4
5
Brij 30
110
53
9
17
10
58
100
83
46
34
TPGS-750-M
Cremophor EL
SDS
CTAB
a
b
Heteroaromatic primary alcohols could also be readily oxidized
under our standard room temperature conditions. The examples in
Table 5, including a formylated indole 24, a substituted furfural 25,
See ESI for structures of surfactants. Used as a 2 wt% solution in
c
d
water. Determined by dynamic light scattering. Determined by GC.
of choice.20 That the reactions are mainly happening within the an acetylenic thiophene 26, and a ferrocenyl derivative 27 suggest
nanomicellar core is evident from the competing ‘‘on water’’21 that functional group tolerance extends to this class of educts.
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Table 4 Representative examples of benzylic oxidations in water at rt
Table 5 Oxidations of heteroaromatic benzylic-like alcohols to their
corresponding aldehydes
Scheme 5 Selective oxidation of a benzylic over aliphatic alcohol.
Fig. 1 Representative examples of 11 allylic alcohol oxidations.
Reactions run with CuBr (5 mol%), TEMPO (5 mol%), bpy (5 mol%), NMI
(10 mol%), and 0.5 mL TPGS-750-M–H2O. All yields are isolated. a Run on
1 mmol scale, 0.75 M 2 wt% TPGS-750-M–H2O solution. b Average of two runs.
Scheme 6 Selective oxidation of 11 33 over 21 34 at rt.
Scheme 3 Representative examples of secondary benzylic/benzylic-like
oxidations.
(30–32) are illustrated in Fig. 1. Secondary allylic alcohols were
essentially unreactive under these conditions, thereby allowing
for selective oxidation of 33 over the secondary analog 34, with
both substrates in the pot (Scheme 6).
Scheme 4 Selective oxidation of a 11 over 21 benzylic alcohol (conditions
as in Scheme 3).
Primary, aliphatic alcohols undergo oxidation to the desired
aldehydes very slowly, even when mild heating (40–45 1C) is
applied. This allows for selective oxidations of activated over
unactivated polyols (e.g., Scheme 5).
In addition to benzylic and benzylic-like substrates, primary allylic
alcohols are also amenable to oxidation. Representative examples
Scheme 7 Potential for recycling of the aqueous reaction mixture, and
determination of E factors.
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7 Recent advances: (a) Y. Yan, X. Tong, K. Wang and X. Bai, Catal.
Commun., 2014, 43, 112; (b) M. M. Dell’Anna, M. Mali, P. Mastrorilli,
P. Cotugno and A. Monopoli, J. Mol. Catal. A: Chem., 2014, 386, 114.
8 J. M. Hoover and S. S. Stahl, J. Am. Chem. Soc., 2011, 133, 16901.
9 J. M. Hoover and S. S. Stahl, Org. Synth., 2013, 90, 240.
10 M. F. Semmelhack, C. R. Schmid, D. A. Cortes and C. C. Chou,
J. Am. Chem. Soc., 1984, 106, 3374.
11 G. Ragagnin, B. Betzemeier, S. Quici and P. Knochel, Tetrahedron,
2002, 58, 3985.
12 P. Gamez, I. W. C. E. Arends, J. Reedijk and R. A. Sheldon, Chem.
Commun., 2003, 2414.
13 D. Geiblmeir, W. G. Jary and H. Falk, Monatsh. Chem. Chem. Mon.,
2005, 136, 1591.
14 N. Jiang and A. J. Ragauskas, J. Org. Chem., 2006, 71, 7087.
15 (a) P. J. Figiel, M. Leskela and T. Repo, Adv. Synth. Catal., 2007,
349, 1173; (b) P. J. Figiel, A. Sibaouih, J. U. Ahmad, M. Nieger,
M. T. Raisanen, M. Leskela and T. Repo, Adv. Synth. Catal., 2009,
351, 2625.
Recycling of the aqueous reaction mixture could be smoothly
achieved using educt 4 as a model case (Scheme 7). With an ‘‘in-flask’’
workup, 5 was obtained with very low E factors,23 suggestive of an
overall environmentally attractive process, unlike literature methods
to date, although flow chemistry is becoming increasingly competitive
in this regard.24
In summary, methodology for selective oxidation of activated
alcohols to aldehydes and ketones has been developed that relies
on the greater solubility of gases, specifically oxygen, inside the
hydrophobic pockets associated with aqueous nanomicelles.
This allows for air to function as the stoichiometric oxidant,
rather than traditional oxidizing agents.
Financial support provided by the NSF (CHE 0948479) is
warmly acknowledged with thanks.
16 S. Mannam, S. K. Alamsetti and G. Sekar, Adv. Synth. Catal., 2007,
349, 2253.
17 G. Zhang, X. Han, Y. Luan, Y. Wang, X. Wen, L. Xu and C. Ding,
Chem. Commun., 2013, 49, 7908.
18 G. Zhang, X. Han, Y. Luan, Y. Wang, X. Wen, L. Xu, C. Ding and
J. Gao, RSC Adv., 2013, 3, 19255.
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