Differing selectivities in mechanochemical versus conventional solution oxidation using Oxone

Article abstract of DOI:10.1016/j.tetlet.2013.02.056

A mechanochemical oxidation of methoxylated aromatic chemicals is described, providing an example of a very different selectivity as compared to solution-based chemistry. Oxone was shown to react with 1,2,3-trimethoxybenzene to yield predominantly 2,6-dimethoxybenzoquinone in the solid state or 2,3,4-trimethoxyphenol in solution. The difference in effective acidity of the reaction conditions was not apparently responsible for the observed selectivity. The mechanochemical method described is simple, reproducible, and gave higher yield at higher conversion of substrate compared to solution conditions.

Full text of DOI:10.1016/j.tetlet.2013.02.056

Tetrahedron Letters 54 (2013) 2344–2347
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Differing selectivities in mechanochemical versus conventional solution
oxidation using Oxone
S. L. Collom a, P. T. Anastas a, , E. S. Beach a, R. H. Crabtree b, , N. Hazari b, , T. J. Sommer a
⇑
⇑
⇑
a Center for Green Chemistry and Green Engineering, Yale University, 225 Prospect Street, New Haven, CT 06511, USA
b The Department of Chemistry, Yale University, PO Box 208107, New Haven, CT 06520, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A mechanochemical oxidation of methoxylated aromatic chemicals is described, providing an example of
a very different selectivity as compared to solution-based chemistry. Oxone was shown to react with
1,2,3-trimethoxybenzene to yield predominantly 2,6-dimethoxybenzoquinone in the solid state or
2,3,4-trimethoxyphenol in solution. The difference in effective acidity of the reaction conditions was
not apparently responsible for the observed selectivity. The mechanochemical method described is sim-
ple, reproducible, and gave higher yield at higher conversion of substrate compared to solution
conditions.
Received 19 December 2012
Revised 18 February 2013
Accepted 19 February 2013
Available online 26 February 2013
Keywords:
Mechanochemistry
Oxidation
Ó 2013 Elsevier Ltd. All rights reserved.
Oxone
Regioselectivity
Trimethoxybenzene
Mechanical activation of solid reactants is an alternative to
thermal, electrochemical, or photochemical means of promoting
chemical reactivity.1 Mechanochemistry has attracted consider-
able recent interest, especially in the area of green chemistry, ow-
ing to its inherent minimization of solvent usage2 and applicability
to a growing range of organic reactions.1,3–5 The avoidance of sol-
vent can potentially simplify product isolation and avoid the costs,
incompatibilities, and hazards6 associated with common solvents.
Also in some cases mechanochemistry outperforms conventional
procedures in terms of yield and selectivity.7–10 This has been re-
ported for common organic transformations such as the aldol
and Bayless–Hillman reactions. Although the physicochemical ori-
gin of mechanochemical activation is still a matter for debate, most
authors agree that the exposure of fresh reactants by grinding and
the localized heating effects of friction are important3,5 and it is be-
lieved that these features allow mechanochemical reactions to fol-
low pathways that are not always accessible under conventional
solution conditions.1
water-insoluble reactants. However, oxidation reactions have been
rarely attempted using mechanical activation due to the shock-
sensitive nature of many oxidants.9,11–15 OxoneÒ (potassium per-
oxymonosulfate, KHSO5 KHSO4 K2SO4),16,17 a common oxidant in
organic transformations, is a good candidate for mechanochemis-
try. It is shock-stable,17 commercially available, relatively non-
toxic, and easy to handle.18,19 In the triple salt, the inert
components act as diluents and may improve the stability of the
active oxidant in mechanical processing. Here we report the use
of Oxone to oxidize lignin-like methoxylated aromatic substrates,
showing that different selectivity is seen in mechanochemical
versus conventional solution chemistry.
The oxidation of 1,2,3-trimethoxybenzene (1) in aqueous solu-
tion was screened using varying amounts of Oxone (Table 1 and
SI-1). Compound 1 was not soluble in purely aqueous solutions
and a small amount (10% v/v) of a co-solvent, such as acetonitrile
(ACN), methanol, or acetone was required (entries 3, 5, 6). The
principal oxidized product was 2,3,4-trimethoxyphenol (4), which
could be obtained with a selectivity of up to 77% at 17% conversion,
with 0.5 equiv of Oxone (entry 1). However, if the conversion was
raised by increasing the reaction time, there was a significant drop
in selectivity. Similarly, when the number of equivalents of Oxone
was increased, the conversion increased but the selectivity for 4
was considerably lower.16 The yields of the 2,3- and 2,6-dim-
ethoxybenzoquinone by-products, 6 and 7, were relatively un-
changed as the number of equivalents of Oxone increased.
Especially at high conversions the overall mass balance for the
reaction was poor and a large quantity of unknown products was
formed. When 4 was tested as a substrate (entry 9) significant
Mechanochemistry can also facilitate reactions with reactants
of differing solubility preferences, for example in oxidation reac-
tions where water-soluble but organic-insoluble oxidants such as
hydrogen peroxide are needed to oxidize organic-soluble but
⇑
Corresponding authors. Tel.: +1 203 432 6165; fax: +1 203 436 8754 (P.T.A.);
tel.: +1 203 432 3295; fax: +1 203 432 6144 (R.H.C.); tel.: +1 203 432 0885; fax: +1
203 432 6144 (N.H.).
E-mail addresses: paul.anastas@yale.edu (P.T. Anastas), robert.crabtree@yale.edu
(R.H. Crabtree), nilay.hazari@yale.edu (N. Hazari).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.056

S. L. Collom et al. / Tetrahedron Letters 54 (2013) 2344–2347
2345
Table 1
Solution-based oxidation of substrates 1–5 using Oxonea
OMe
OMe
OMe
OMe
MeO
MeO
OMe MeO
OMe
OMe
OH
1
2
3
4
O
O
MeO
OMe MeO
OMe
OMe
OMe
O
OH
O
5
6
7
Entry
Substrate
Oxone Eq
Co-solvent
Conversionb
4c
6
7
1
1
1
1
1
1
1
2
3
4
5
0.5
1
2
4
2
2
2
2
2
d3-ACN
d3-ACN
d3-ACN
d3-ACN
d4-MeOH
d6-Acetone
d3-ACN
d3-ACN
d3-ACN
d3-ACN
17
26
55 (53)
81
67
55
4
<1
71
77
69
49 (54)
24
34
31
—
—
—
—
8
8
<1
4
6 (6)
6
2
2
—
—
12
—
2
3d
4
9 (10)
9
3
2
—
—
—
67
5
6
7
8
9
10e
2
89
a
b
c
20,22–24
Reaction conditions: 50
Conversion as percentage of starting material consumed.
l
mol substrate, 1 mL of 10% (v/v) co-solvent in D2O (9 mL), rt, 5 h. The reactions were monitored by 1H NMR spectroscopy
(SI-1).
Selectivities are given as percentages. They are the average of at least two replicates and were determined using an internal standard (tBuOH) or external standard
(sodium trimethylsilylpropionate-d4). No oxidation of tBuOH was observed under standard reaction conditions.
d
Numbers in parenthesis were obtained when the reaction was degassed and run under inert (N2) atmosphere (SI-2).
Isolated yield after 15 min from a large scale reaction (see SI-5).
e
conversion to unknown products was seen, indicating that 4 is not
stable under the reaction conditions and that low conversion is
therefore required for high selectivity. There was no change in
the reaction product distribution when the oxidation was carried
out under air or N2 (entry 3 and SI-2), so O2 does not actively
participate.
The solution oxidation was repeated on a larger scale (100 mg)
using 2 equiv of Oxone (SI-4). After 5 h the organic products were
extracted with chloroform and subsequently purified on a silica
column. The recovered material consisted of 1 (41%), 4 (30%), and
6 (4%) based on the moles of starting material, demonstrating that
the reaction is scalable. The formation of 4 as the primary product
stands in contrast to reports of the solution oxidation of 1 using
oxidants such as nitric acid or hypervalent iodine reagents, which
typically form 2,6-dimethoxybenzoquinone 7.21,25–27 There is one
previous report of the formation of 4 from the oxidation of 1 using
m-chloroperoxybenzoic acid but the yield and selectivity were sig-
nificantly lower than reported in this work.21
To further investigate the reaction pathway and the scope of the
solution oxidation a number of substrates similar to 1 were tested
(entries 7–10, SI-1, and SI-5). Essentially no reaction was seen with
the less activated aromatics 1,2-dimethoxybenzene (2) or anisole
(3), even at elevated temperatures, indicating that a highly acti-
vated system is required. Reaction with 3,4,5-trimethoxyphenol
(5) was extremely rapid and after 15 min 6 was isolated from the
reaction mixture in a selectivity of 67%. If the reaction was left
for longer times no tractable products were observed. In contrast,
4 is relatively stable for 15 min under the same conditions. The sta-
bility of 4 as compared to 5 may account for the observed selectiv-
ity of the reaction for 4.
Mechanochemical oxidation was performed by manually grind-
ing 1 with 3 equiv of Oxone in a small mortar and pestle (SI-10).
The reaction was ground periodically for a total of 1 h per day for
14 days. After this time the organic solids were extracted with
CDCl3. 1H NMR spectroscopy indicated that the starting material
was selectively converted into 2,6-dimethoxybenzoquinone (6)
which was isolated in 73% yield, with no evidence of any other or-
ganic products. This result is in sharp contrast with the solution-
based reaction which gave 4 as major product, with high selectivity
only at low conversion.
The reaction was further screened using less labor-intensive
methods for mechanical activation. Using an automated mortar-
and-pestle mixer28 to grind the solids, after 7 h the only product
observed by NMR spectroscopy was again 6, however the overall
isolated yield (13–21%) was low (SI-10). A series of control exper-
iments (see SI-11) indicated that the organic components of the
reaction mixture, including both starting material 1 and product
6, partially volatilized during the reaction, reducing the yield. Vol-
atilization of the organics may be due to the intense localized heat-
ing associated with grinding.
To limit mass loss, a ball-mill with a closed capsule was used
(see SI-10). Full conversion of 1 was observed after 2 h, most likely
because the higher localized energy associated with ball-milling
compared to mortar grinding promotes faster reaction.1,29,30
Although the sealed vessels reduced the mass loss, the yields of 6
and 7 were only 19% and 8%, respectively, based on moles of start-
ing material. We believe that the low yields are due to the intense
heat generated in the ball mill (which could not be cooled) and the
best results were achieved by limiting the milling time to 15 min,
allowing the capsule to cool to room temperature before resuming
milling (see SI-10).
The shortcomings of the previously attempted mechanochemi-
cal procedures, that is, loss of mass by volatilization, and low selec-
tivity of high energy milling, were avoided by using a commercially
available rotary rock tumbler/polisher.31 We adapted this equip-
ment for a new mechanochemical procedure with the goal of
improving reproducibility and maximizing product recovery. Reac-
tion mixtures were enclosed in vials containing stainless steel mill-
ing balls (Fig. 1). The vials were then arranged in the drum of the
tumbler using foam spacers to secure the vials for the duration
of the reactions and mixed for 7 days (SI-7). This approach gave a
mass balance of >95% and the reaction was selective for 6 (Table 2).

2346
S. L. Collom et al. / Tetrahedron Letters 54 (2013) 2344–2347
Figure 1. (a) Exterior view of the rock tumbler/polisher used to collect the data in Table 2. (b) View down the barrel (shown in a) showing the arrangement of the reaction
vials. Up to 10 vials were arranged with foam spacers to maintain stability and balanced rotation.
Table 2
Mechanochemical oxidation of substrate 1 using Oxonea
Entry
Oxone Eq
Organic recoveryb
Recovered 1c
Yield 6c
Mass balanced
1
2
3
0
1
2
4
6
>95
>95
>95
>95
95
69
62
<1
0
15
15
81
95
84
77
81
4
5e
>95 (>95)
<1 (<1)
82 (79)
82 (79)
a
Reactions were performed in four dram glass vials with two stainless steel milling balls (ꢀ3.5 g ea) along with Oxone and 1. Reactions were arranged in the drum of the
rock tumbler and allowed to spin for 7 days at rt (SI-7).
b
Organic recovery is percentage of products extracted from the reaction mixture using CDCl3 compared to organic starting material.
Isolated yield of 1 or 6 from column chromatography at the end of reaction.
Percentage of organic materials accounted for by isolated yields of 1 or 6 relative to organic starting material.
Numbers in parenthesis were obtained when the reaction was run under inert (N2) atmosphere (SI-8).
c
d
e
Table 3
3 h reaction. The results show that the pH of the solution had no
Solution based oxidation of lignin models 1 using Oxone as the oxidant in the
significant effect on the selectivity of the reaction. The ratio of 4
to 6 was approximately constant as a function of pH, suggesting
that the difference in effective acidity between the solution and so-
lid state reactions is not responsible for the change in selectivity. At
higher pH, Oxone decomposes faster,19 lowering the effective con-
centration of the active oxidant in solution. This could explain the
lower conversions and higher selectivity observed when K2CO3
was added. When the reaction was performed at pH 5, an 84%
selectivity of 4 at 33% conversion was observed, which is signifi-
cantly better than our results in the absence of an additive.
Our report thus provides a remarkable example of a complete
change of selectivity in mechanochemical activation versus con-
ventional solution. We have also described a simple, and reproduc-
ible procedure for carrying out the mechanically activated
reactions.
presence of acid or basea
Entry
H2SO4 (mM)
K2CO3 (mM)
pH
Conversionb
4c
6
7
1
2
3
4
5
6
7
1000
300
150
—
—
—
—
—
—
—
40
50
100
0
0.5
1
1.5
3
5
64
43
42
40
45
33
32
31
56
57
60
55
84
76
7
<1
4
6
11
11
7
6
9
—
—
—
15
6
—
7
a
Reaction conditions: 50 lmol 1, 100 lmol (2 equiv) Oxone, 1 mL of a 10% (v/v)
solution of d3-ACN in D2O. The pH was adjusted using H2SO4 and K2CO3, rt 3 h. The
reactions were monitored by 1H NMR spectroscopy (SI-3)
b
Conversion is percentage of starting material consumed by 1H NMR
spectroscopy.
c
Selectivities are given as and were determined using an internal standard
(tBuOH). They are the average of at least two runs.
Supplementary data
Isolated yields of 6 were as high as 82%. As in solution, the yield de-
pended on the amount of Oxone present with the best results ob-
tained using 4 or 6 equiv. In the mechanochemical reactions the
presence of excess Oxone does not over-oxidize the product and
in the best case the reaction could be run to full conversion with-
out affecting yield of 6. The reaction outcomes were identical un-
der air or N2.
The greater effective acidity of solid reagents was considered as
a possible reason for the distinct change in selectivity between the
solution and solid state reactions.32 The pH of the solution reac-
tions was varied to test for effects on product distribution (Table 3
and SI-3). A 100 mM solution of Oxone in 10% v/v ACN in water had
a measured pH of 1.5 and H2SO4 and K2CO3 were used as additives
to adjust the pH in the range of 0–7. Comparisons were made after
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
02.056.
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