Switching Chemoselectivity: Using Mechanochemistry to Alter Reaction Kinetics

Article abstract of DOI:10.1002/anie.201810141

A reaction manifold has been discovered in which the chemoselectivity can be altered by switching between neat milling and liquid assisted grinding (LAG) with polar additives. After investigation of the reaction mechanism, it has been established that this switching in reaction pathway is due to the neat mechanochemical conditions exhibiting different kinetics for a key step in the transformation. This proof of concept study demonstrates that mechanochemistry can be used to trap the kinetic product of a reaction. It is envisaged that, if this concept can be successfully applied to other transformations, novel synthetic processes could be discovered and known reaction pathways perturbed or diverted.

Full text of DOI:10.1002/anie.201810141

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Switching Chemoselectivity: Using Mechanochemistry to Alter
Reaction Kinetics
Authors: Joseph L. Howard, Michael C. Brand, and Duncan L. Browne
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201810141
Angew. Chem. 10.1002/ange.201810141
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10.1002/anie.201810141
Angewandte Chemie International Edition
COMMUNICATION
Switching Chemoselectivity: Using Mechanochemistry to Alter
Reaction Kinetics
Joseph L. Howard[a], Michael C. Brand[a] and Duncan L. Browne*[a]
Abstract: A reaction manifold has been discovered in which the
chemoselectivity can be altered by switching between neat milling and
liquid assisted grinding (LAG) with polar additives. After investigation
of the reaction mechanism, it has been established that this switching
in reaction pathway is due to the neat mechanochemical conditions
exhibiting different kinetics for a key step in the transformation. This
proof of concept study demonstrates that mechanochemistry can be
used to trap the kinetic product of a reaction. It is envisaged that, if
this concept can be successfully applied to other transformations,
novel synthetic processes could be discovered and known reaction
pathways perturbed or diverted.
under neat or non-polar LAG mechanochemical conditions
compared to solution or polar LAG conditions. Initially,
difluorinated diketone 1 was milled in the presence of cesium
carbonate and phenyl disulfide to afford tetrafluorohydroxyketone
2 in 72% isolated yield (Table 1, Entry 1). The unreacted disulfide
could also be isolated quantitatively from this reaction mixture.
This product/observation is in contrast to the result reported for
the same reagents in solution by Yi, Lu and co-workers, who
report the formation of the difluorothioether compounds 3a and
3b.7 Encouraged by the significantly different reactivity observed
under mechanochemical conditions, this reaction was
investigated further. It was found that under LAG conditions, using
DMSO, the reactivity could be switched completely to thioether
products 3a and 3b. This switch is dependent on the quantity of
Mechanochemistry is emerging as a technique for synthesis with
several synthetically important processes now reported in ball
milling devices and rapid growth in recent times.1,2 Furthermore,
it has been shown that, for certain examples, significant
advantages over solution chemistry can be obtained, such as a
decrease in reaction time or improvement in selectivity.1k There
are also examples where the use of mechanochemistry can alter
reactivity, resulting in different products when compared to
solution or liquid assisted grinding (LAG).1k,l For example,
previous work in our group has shown the use of LAG to control
the selectivity of mechanochemical fluorination (Scheme 1a).3 It
has also been shown that by using mechanochemical conditions,
the position of equilibrium can be altered, such as in disulfide
metathesis reactions for example (b, Scheme 1).4 This
demonstrates that it is possible to alter the thermodynamic
product of a reaction by conducting it in the solid-state under ball
milling and in the latter instance, crystal lattice energies help drive
the process. The majority of examples are limited to different
possible outcomes from the same reaction pathway. However,
work by Mack and co-workers demonstrated the possibility of
using LAG to change the reaction pathway (Scheme 1c).5 It was
found when performing a palladium catalysed alkyne-alkyne
(Glaser-Hay) coupling that on using a non-polar LAG additive, the
diyne product was obtained but with a polar LAG additive, the
enyne was produced. However, the origins of the different
reaction outcomes observed in this latter example remain elusive.
As it has already been shown that mechanochemical conditions
can alter both the thermodynamics4 and kinetics6 of covalent bond
forming reactions, we envisaged exploiting these possibilities to
alter the course of a reaction, leading to alternative products
(Scheme 1d). Indeed, we have serendipitously discovered a
reaction manifold that exhibits significantly different behavior
Scheme 1 Examples of using mechanochemistry to alter reactivity by
different methods
a) Using LAG to enhance selectivity - Previous work [3]
B
+
B
A
Selectfluor
milling
Selectfluor
milling
neat
C
polar LAG
O
O
O
O
O
O
Ph
Ph
Ph
Ph
Ph
Ph
F
F
F
b) Using mechanochemistry to perturb equilibria - Belenguer et al [4]
A
A
B
A
A
B
A
B
B
A
B
B
milling
solution
polar LAG
Cl
Cl
O2N
S
S
S
S
S
S
Cl
NO2
NO2
c) Using LAG to change reaction pathway - Mack & co-workers [5]
B
A
C
PS-PPh3-PdCl2
K2CO3
PS-PPh3-PdCl2
K2CO3
milling
milling
polar LAG
non-polar LAG
Ph
Ph
Ph
Ph
Ph
d) Using mechanochemistry to access alternative reaction - this work
[a]
J. L. Howard, M. C. Brand, Dr. D. L. Browne
School of Chemistry
D
+
B
C
A
Cardiff University
Main Building, Park Place, Cardiff CF10 3EQ
E-mail: dlbrowne@cardiff.ac.uk
Cs2CO3
milling
polar LAG
Cs2CO3
milling
neat
solution
or
Supporting information for this article is given via a link at the end of
the document. Information about the data underpinning the results
presented here, including how to access them, can be found in the
Cardiff University data catalogue at http://doi.org/10.1xxxxxxx.
O
O
O
O
HO Ph
F
S
Ph
S
Ph
Ph
Ph
Ph
S
Ph
Ph
F
F
F
F
F
F
F
This article is protected by copyright. All rights reserved.

10.1002/anie.201810141
Angewandte Chemie International Edition
COMMUNICATION
attack onto one of the ketones. This type of fragmentation has
been reported previously on similar structures, and may be
enhanced by the motif of three adjacent electropositive carbon
atoms.9 The product of this fragmentation, enolate 5, can now
react via different pathways, depending on the conditions. It can
either attack the electrophilic disulfide to enter into the thioether
reaction pathway, or can undergo a self-aldol reaction with the
protonated enolate 4 to yield the observed hydroxyketone product
(2). The reaction with the disulfide, observed under LAG
conditions with the more polar solvents, and also in solution,
yields difluorinated thoiether 3a. Under longer reaction times, or
at higher temperatures, this can fragment further to
difluoromethylthioether 3b.7 In order to probe the validity of the
proposed mechanism, we designed several control experiments
to test the various aspects.
Table 1 Effect of different liquid additives on reaction selectivity.
O
O
HO Ph
S
Ph
F
H
Ph
S
O
O
Ph
Ph
Ph
(1 equiv)
F
F
F
F
F
Ph
Ph
Cs2CO3 (3 equiv)
1 h
2
F
F
4
O
1
F
S
DMSO (x µL)
S
Ph
Ph
F
F
F
[mixer mill]
3a
3b
x (µL)
Entry
Yield 2a
Yield 3aa
Yield 3ba
1
2
3
4
5
0
25
50
100
150
88% (72%b)
0%
16%
0%
32%
0%
0%
0%
10%
12%
19%
22%
62% (56%b)
32%
21%
entries below this line explore the effect of varying LAG and associated dielec. const.
Liquid (50 µL) dielec. const. Yield 2a Yield 3aa Yield 3ba Yield 4a
Entry
Initially, the fragmentation of the difluorinated diketone 1
was investigated (Scheme 2, equations A-D). It was observed that
under the standard reaction conditions (as shown in Table 1, entry
1), benzoic acid could be isolated as a side product in 84% yield
along with the tetrafluoro alcohol (2) (Scheme 2, equation A). This
suggests that the identity of the nucleophile initiating the
fragmentation could be water or carbonate. However, no water
was deliberately added to the reaction, so the only water available
would be present in one of the other reagents. Control
experiments (Scheme 2, equations B-D) revealed that in the
absence of cesium carbonate, no reaction was observed, with
only starting material observed in the crude reaction mixtures. The
-
-
88%
86%
66%
76%
60%
60%
74%
26%
15%
23%
55%
31%
0%
0%
1%
1%
1%
1%
3%
1%
1%
25%
27%
4%
25%
62%
0%
0%
0%
0%
4%
0%
0%
1%
0%
0%
0%
1%
0%
12%
0%
10%
4%
6%
5%
7%
4%
3%
8%
5%
4%
4%
0%
5%
35%
6
7
8
9
10
11
12
13
14
15
16
17
hexane
toluene
EtOAc
THF
1.88
2.38
6.02
7.58
8.93
17.9
24.5
32.2
36.7
37.5
37.8
46.7
80.1
DCM
iPrOH
EtOH
NMP
DMF
MeCN
DMA
DMSO
H2O
18
19
28%
a Yield determined by 19F NMR compared to trifluorotoluene as an internal standard. b Isolated yield.
DMSO (Table 1, Entries 2-5). Beyond 50 μL, none of the
fluorinated alcohol 2 was observed, and the highest yield of 3a
was achieved by milling with 50 μL of DMSO. This is therefore an
example of a reaction where the pathway can be
completely altered by neat milling. Under neat milling conditions,
the disulfide is untouched, whereas use of LAG or solution phase
reaction conditions leads to the consumption of disulfide and
formation of the thioether products 3a and 3b.
2-
requirement for cesium carbonate supports the notion that CO3
acts as the initiating nucleophile, with subsequent
decarboxylation to benzoic acid (as depicted in the proposed
mechanism). The next part of the mechanism explored was the
presence and identity of the proposed intermediate difluoroketone
4 and its corresponding enolate 5 that is common to both reaction
pathways (Scheme 2, equations E & F). Indeed, preparation of
ketone 4 and subjection to both neat grinding and LAG conditions
yielded the expected products, demonstrating its competence in
both reaction pathways and supporting the notion that 4 is an
intermediate in both of these processes.10 Finally, in order to test
whether this process could be under thermodynamic control, the
reversibility of each step was examined (Scheme 2, equations G-
I). It was found that subjecting tetrafluoro alcohol 2 to stirring in
DMSO resulted in no transformation and full recovery of 2
(Scheme 2, equation G). Whereas, stirring alcohol 2 in DMSO
with cesium carbonate (no disulfide), led to the generation of
ketone 4 in 67% NMR yield (Scheme 2, equation H). Under
analogous conditions, but with inclusion of disulfide,
difluoromethylthioether 3b was observed in 84% yield (Scheme 2,
equation I). Reversibility was also observed in the mixer mill under
LAG conditions. On subjecting alcohol 2 to ball milling for one
hour in the presence of phenyl disulfide, cesium carbonate and
DMSO, thioethers 3a and 3b were observed (Scheme 2, equation
K). Whilst these experiments support the proposed mechanism,
they do not provide an explanation to the origin of the observed
chemoselectivity differences. In order to probe this phenomenon
further, different reaction times were investigated under both LAG
and neat conditions, the results are depicted in Scheme 3. Under
extended reaction times in the absence of a liquid additive,
thioether 3a was observed, in stark contrast to the observed
product after 1 hour. However, the formation of 3a appears to be
Having established that liquid assisted grinding has a
significant effect on the outcome of this reaction, it was
hypothesized that the nature of the solvent could lead to different
results. Indeed, it has been observed previously that solvents of
different polarities can be used for LAG to form different
polymorphs of cocrystals.8 We therefore tested a wide range of
solvents, with varying dielectric constants (Table 1, Entries 7-19).
It can be seen that the reactivity can again be switched,
depending on how polar the solvent is. The most polar solvents
tested (ε > 30, entries 14-19) seem to favour the reaction with
disulfide to form thioether 3a (with the exception of acetonitrile
and water). Indeed, in the case of water there appears to be very
little discrimination between the reaction products with the major
component of this reaction being the difluoroketone 4, thus
suggesting that water is not a critical factor in determining the
selectivity. However, the less polar solvents (entries 7-13) appear
to favour the formation of 2. These intriguing observations are, to
the best of our knowledge, unprecedented. While there are
previous examples where the selectivity, rate or products of a
reaction have been changed, switching to a different reaction
pathway using neat and LAG milling has not been previously
reported. It was therefore important to attempt to propose and
understand the mechanism of this process. Our proposed
mechanism is presented in Scheme 2, and commences with the
fragmentation of difluorodiketone 1, likely initiated by nucleophilic
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10.1002/anie.201810141
Angewandte Chemie International Edition
COMMUNICATION
Scheme 2 Proposed reaction mechanisms and control experiments. Yield determined by 19F NMR compared to trifluorotoluene as an internal standard.11
proposed mechanism
experiments on intermediate 4 -
(30 Hz, 1 h)
mill
O
Ph
S
F
S
O
F
S
H
Nu
S
Ph
S
Ph
O
Ph
S
DMSO (50 µL)
(PhS)2 (1 equiv)
Ph
+
S
O
Ph
+
F
Ph
Ph
F
Ph
Nu
F
[E] - 4 can be
converted
to 3a/b
+
Ph
F
F
F
Ph
Ph
3b
F
F
F
Cs2CO3 (3 equiv)
mill
3a
7
8
F
3b; 23%
3a; 29%
4
10; 36%
S
Ph
Cs2CO3 (3 equiv)
(PhS)2 (1 equiv)
Path A - solution or polar LAG
O
HO Ph
O
F
[F] - 4 can be
converted
to 2
F
+
start here
Ph
O
mill
F
F
O
O
O
O
O
F
Cs2CO3
F
4; 24% RSM
-CO2
2; 57%
F
4
Ph
+
Ph
F
Ph
O
O
Ph
O
Ph
F
F
5
1
Cs counterions assumed
6
experiments testing reversibility of 2 -
(r.t.)
solution
O
HO Ph
Path B - neat grinding
DMSO, 2 h
solution
[G] - 2 is
stable in solution
F
2; full recovery
H
Ph
F
F
F
2
O
O
HO Ph
O
O
Ph
F
5
H
F
F
F
O
Ph
Ph
Cs2CO3 (6 equiv)
DMSO, 2 h
Ph
[H] - 2 is unstable
in solution in
the presence of base
F
F
F
F
F
F
F
Ph
2
2
4
9
2
F
solution
4; 67%
experiments testing fragmentation of 1 -
(30 Hz, 1 h)
mill
O
O
O
Cs2CO3 (3 equiv)
(PhS)2 (1 equiv)
Cs2CO3 (6 equiv)
(PhS)2 (2 equiv)
Ph
[A] - benzoic acid
is a byproduct
F
S
[I] - 2 converts to
3a/b in solution
Ph
OH
Ph
Ph
F
F
mill
DMSO, 17 h
solution
F
[as Table 1 Entry 1]
1
1
10; 84%
3b; 84%
[B] - 1 is stable
to neat milling
1; full recovery
1; full recovery
mill
experiments testing reversibility of 2 -
(30 Hz, 1 h)
mill
DMSO (50 µL)
Cs2CO3 (6 equiv)
(PhS)2 (2 equiv)
DMSO (50 µL)
[C] - 1 is stable
to LAG milling
[J] - 2 converts
to 3a/b in the
presence of Ph
base, disulfide
& DMSO LAG
O
O
Ph
Ph
S
1
1
HO Ph
mill
F
S
F
Ph
+
DMSO (50 µL)
(PhS)2 (1 equiv)
F
F
F F
F
F
mill
[D] - 1 is stable
to LAG milling in
2
3a; 7%
3b; 24%
1; full recovery
the absence of base
mill
slow, with only 27% observed after 8 hours. It can be seen that
initially, self-aldol product 2 is formed, and is then subsequently
serving as a source for difluoro ketone 4.
reaction to generate 3a. However, polar solvents will be able to
break up this coating of enolate 5, allowing it to react with the
disulfide faster. This hypothesis was tested by subjecting the
reaction mixture to different quantities of DMSO under milling for
10 minutes (Scheme 6). It was found that on increasing the
quantity of DMSO, the major reaction product switched to 3a,
demonstrating that higher quantities of DMSO favour reaction
with the disulfide to form 3a.
However, upon extended milling durations ketone 4 then
slowly reacts with the disulfide to form 3a. This suggests that 3a
is the thermodynamic product of the system. Performing a similar
analysis under LAG conditions, demonstrates that at short
reaction times (10 minutes), 2 is indeed observable as a kinetic
product, also in stark contrast to the initial observations of the
system after one hour. Again, 2 is in equilibrium with 4, which
quickly reacts with the disulfide to form 3a. This demonstrates that
the addition of DMSO has a significant effect on the rate of
formation of 3a from 4, with this transformation being significantly
faster than under neat milling. The kinetic product of the system
is therefore 2, which is in equilibrium with 4 and can be trapped
using mechanochemical conditions without LAG. Under LAG with
DMSO, or in solution, the thermodynamic product 3a is instead
obtained. The physical reasons behind this decrease in reaction
rate under mechanochemical conditions is likely due to poor
mixing and the consequently non-homogeneous nature of the
reaction mixture. We hypothesise that after the Cs2CO3 mediated
fragmentation of 1, the surface of any particles of 1 will be coated
in enolate 5 (Scheme 4). Upon protonation to ketone 4, the local
concentration of 4 will be much greater than that of the disulfide,
so reaction between 4 and 5 to form 2 will be faster than the
In conclusion, a reaction manifold has been found in which
different products are obtained depending on whether it is
performed mechanochemically under neat grinding conditions, or
under LAG or solution conditions. Polar LAG additives were able
to switch the reaction pathway, whereas non-polar additives were
not. After investigating both the mechanism and the behavior at
different reaction times, it has been established that under neat
grinding, a kinetic product is being trapped that is not observed
under solution or polar LAG conditions. This is the first example
of using mechanochemistry to alter the chemoselectivity of a
reaction by altering the kinetics, this could lead to screening of
other reactions to search for new or overlooked reactivity
pathways.
Acknowledgements
This article is protected by copyright. All rights reserved.

10.1002/anie.201810141
Angewandte Chemie International Edition
COMMUNICATION
D.L.B is grateful to the EPSRC for a First Grant (D.L.B.
EP/P002951/1), CRD for a studentship award to J.L.H. and the
School of Chemistry at Cardiff University for generous support.
Keywords: ball milling
•
mechanochemistry
•
solventless
reactions • chemoselectivity • kinetics
neat milling
faster than reaction
with disulfide
under neat grinding 3a is observable after longer reaction times
Cs2CO3
H
S
Ph
Ph
S
O
Ph
S
A
O
O
O
HO Ph
(1 equiv)
F
Ph
Ph
Ph
Ph
Cs2CO3 (3 equiv)
1 h
mill for
O
O
O
O
O
F
3a
F
F
1
F
HO Ph
F
F
F
2
F
a further 7 h
F
F
Ph
Ph
Ph
Ph
Ph
F
F
2
F
F
F
F
F
Neat Grinding
1
5
4
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
LAG with polar solvent
Cs2CO3
(PhS)2
solvent
O
O
O
O
Yield 2
Yield3a
Yield 4
solvation of 5;
S
F
Ph
Ph
5 chaperoned from
surface of 1
Ph
Ph
Ph
F
F
F
F
F
1
3a
5
10 minutes - different quan::es DMSO
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
0
1
2
3
4
5
6
7
8
9
Time / hours
under LAG grinding 2 is observable at shorter reaction times
Ph
S
Ph
S
O
O
O
Ph
S
O
HO Ph
(1 equiv)
Yield 2
Yield 3a
Yield 4
F
Ph
Ph
Ph
Ph
mill 1 h
Cs2CO3 (3 equiv)
1 h
F
F
F
1
F
F
F
2
F
3a
DMSO (50 µL)
observable at
20 minutes
LAG
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
0
20
40
60
80
100
120
140
160
DMSO / μL
Scheme 4 Yields of products after milling for 10 minutes with different
quantities of DMSO. 11
Yield 2
Yield 3a
Yield 4
0
10
20
30
40
50
60
70
Time / min
2017, 5, 9599; g) S. L. James, C. J. Adams, C. Bolm, D. Braga, P. Collier,
T. Friščić,; F. Grepioni, K. D. M. Harris, G. Hyett, W. Jones, A. Krebs, J.
Mack, L. Maini, A. G. Orpen, I. P. Parkin, W. C. Shearouse, J. W. Steed,
D. C. Waddell, Chem. Soc. Rev. 2012, 41, 413; h) J.-L. Do and T. Friščić,
Synlett, 2017, 28, 2066–2092; i) T. K. Achar, A. Bose and P. Mal,
Beilstein J. Org. Chem., 2017, 13, 1907–1931; j) J. G. Hernández, Chem.
Eur. J., 2017, 23, 17157–17165; k) J. L. Howard, Q. Cao and D. L.
Browne, Chem. Sci., 2018, 9, 3080–3094. l) J. G. Hernández, C. Bolm,
J. Org. Chem. 2017, 82, 4007.
Scheme 3 Milling for different times under LAG and neat grinding
conditions.
[2]
For some recent examples of mechanochemical methodology see: a) C.
Bolm, R. Mocci, C. Schumacher, M. Turberg, F. Puccetti, J. G.
Hernández, Angew. Chem. 2018, 130, 2447–2450; Angew. Chem. Int.
Ed. 2018, 57, 2423–2426. b) K. J. Ardila-Fierro, D. E. Crawford, A.
Körner, S. L. James, C. Bolm, J. G. Hernández, Green Chem. 2018, 20,
1262–1269. c) H. Cheng, J. G. Hernández, C. Bolm, Adv. Synth.
Catal. 2018, 360, 1800–1804; d) Q. Cao, J. L. Howard, E. Wheatley, D.
L. Browne, Angew. Chem. 2018, 130, 11509-11513; Angew. Chem. Int.
Ed. 2018, 57, 11339-11343; e) Q. Cao, W. I. Nicholson, A. C. Jones, D.
L. Browne, Org. Biomol. Chem. 2018, accepted article; f) J. M. Andersen,
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10.1002/anie.201810141
Angewandte Chemie International Edition
COMMUNICATION
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[10] The relatively low yield of the desired products under LAG conditions is
thought to arise from the volatility of difluoromethylthioether 3b. However,
the side product of the fragmentation required to form 3b from 3a was
isolated as benzoic acid 10 in 36% yield, suggesting that the true yield of
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10.1002/anie.201810141
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
changing chemoselectivity using mechanochemistry
A reaction manifold has
J. L. Howard, M. C. Brand, D.
L. Browne*
milling
milling
been discovered in which
the chemoselectivity can
be altered by switching
between neat milling and
liquid assisted grinding
(LAG) with polar additives.
C
D
+
B
A
neat or
non-polar LAG
polar LAG
solution
Page No. – Page No.
[mixer mill]
[proposed mechanism]
[control experiments]
Changing Chemoselectivity
Using Mechanochemistry
to Alter Reaction Kinetics
[product switches with dielectric constant]
This article is protected by copyright. All rights reserved.