Isotope Labeling Reveals Fast Atomic and Molecular Exchange in Mechanochemical Milling Reactions

Article abstract of DOI:10.1021/jacs.8b12149

Using tandem in situ monitoring and isotope-labeled solids, we reveal that mechanochemical ball-milling overcomes inherently slow solid-state diffusion through continuous comminution and growth of milled particles. This process occurs with or without a ne

Full text of DOI:10.1021/jacs.8b12149

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Communication
Isotope Labeling Reveals Fast Atomic and Molecular
Exchange in Mechanochemical Milling Reactions
Stipe Lukin, Martina Tireli, Tomislav Stolar, Dajana Bariši#, Maria
Valeria Blanco, Marco Di Michiel, Krunoslav Užarevi#, and Ivan Halasz
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b12149 • Publication Date (Web): 04 Jan 2019
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Isotope Labeling Reveals Fast Atomic and Molecular Exchange in
Mechanochemical Milling Reactions
Stipe Lukin,† Martina Tireli,† Tomislav Stolar,† Dajana Barišić,† Maria Valeria Blanco,‡
Marco di Michiel,‡ Krunoslav Užarević,† and Ivan Halasz∗,†
†Division of Physical Chemistry, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia
‡ESRF - the European Synchrotron, 71 Avenue des Martyrs, 38000 Grenoble, France
Received December 30, 2018; E-mail: ivan.halasz@irb.hr
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Scheme 1. Cocrystal formation between ba and pyo. Exchangeable
hydrogen atoms of ba, pyo, and bapyo are denoted as H/D.
Abstract: Using tandem in situ monitoring and isotope-labeled
solids, we reveal that mechanochemical ball-milling overcomes
inherently slow solid-state diffusion through continuous com-
minution and growth of milled particles. This process occurs
with or without a net chemical reaction and also occurs be-
tween solids and liquid additives which can be practically used
for highly efficient deuterium labeling of solids. The presented
findings reveal a fundamental aspect of milling reactions and
also delineate a methodology that should be considered in the
study of mechanochemical reaction mechanisms.
where both ba and pyo were deuterated. In all, cocrystal for-
mation proceeds directly from reactants (Figs. S1-S5) and
without amorphization (Figs. S6 and S7).27 In experiments
Ball milling exerts mechanical energy through compres-
ba + pyo and ba-d + pyo-d no isotope exchange could be de-
sion, shearing, and friction to a solid reaction mixture, thus
tected since all exchangeable hydrogen atoms are of the same
coercing materials and molecules to react.1 Early theories
isotope. On the other hand, in experiments where either ba
of such mechanochemical reactions assumed short and local-
or pyo were deuterated, H/D exchange is possible. That
ized, but extreme conditions of highly-elevated temperature
is, ba-d could potentially transfer its deuteron to pyo and
and pressure achieved at the spots of milling ball impacts,
vice versa, pyo-d could transfer its deuteron to ba. These
providing conditions to overcome the high energy barrier of
two experiments resulted with essentially the same Raman
a solid-state reaction.2–5 However, with extension of milling
spectra after 25 min milling (Figs. 1, S8, S9), indicating the
to soft materials,6–8 a different view on mechanochemical
same isotope distribution between ba and pyo molecules in
reactivity is emerging9–12 where mechanochemical reactions
the product cocrystal.
are recognized to exhibit solution-like kinetics,13 intermedi-
Figure 1 depicts the most characteristic bands to assess
ates,14,15 remarkable selectivity16–18 strong temperature de-
H/D exchange in time-resolved Raman spectra. Vibration
pendence,10,19 and can be quite fast.20,21 These features in-
band of carboxylate group bending is found at 793 cm−1 for
dicate that extremely slow diffusion in crystalline solids22–24
ba and at 765 cm−1 for ba-d (S31). For bapyo-hh, the same
may be overcome by milling.
vibration of benzoic acid is now at 800 cm−1, while it is at
We thus hypothesized that molecular or atomic migra-
774 cm−1 in bapyo-dd. Since this is dominantly a vibration
tions among crystallites should be possible through surface
of the benzoic acid moiety, also in the cocrystal, we use it
contacts between milled solid particles, even without a net
to assess its deuteration state. In the ba-d + pyo experi-
chemical reaction. In this work, to address this fundamental
ment the band at 765 cm−1 diminishes, while the band at
aspect of mechanochemical milling, we have applied tandem
774 cm−1 increases in intensity as ba-d becomes incorpo-
in situ monitoring25,26 to milling of isotope-labeled solids
rated in the cocrystal. Importantly, the band at 774 cm−1
and show that milling results in fast exchange of atoms and
reaches ca. half the intensity as in the fully deuterated
molecules between crystallites, thus creating a reaction en-
bapyo-dd indicating that ca. half of deuterons were trans-
vironment that is not restrained by slow solid-state diffu-
ferred from ba-d to pyo in the bapyo-dh cocrystal. Switching
sion. Molecular and atomic exchange occurs both when new
the deuteron label in the ba + pyo-d experiment, the band
phases are formed during milling, but also between milled
at 774 cm−1 also increases in intensity, which can only be
solids which are non-reactive, and extends to milling of solids
due to deuteron transfer from pyo-d to ba, and reaches the
with liquid additives.
same intensity as in the previous ba-d + pyo experiment.
First, we study milling of benzoic acid (ba) and 2-pyridone
Potential deuteron transfer from pyo-d to ba, but without
(pyo) wherein a 1:1 cocrystal (bapyo) is formed (Scheme 1).
cocrystal formation should have been indicated by the emer-
Both ba and pyo bear one exchangeable hydrogen atom: the
gence of the pure ba-d band at 765 cm−1, which we do not
hydrogen of the carboxylate group of ba and the pyridinium
observe.
hydrogen of pyo. Cocrystal formation requires no net trans-
fer of hydrogen atoms as would be the case for example, with
salt formation, but any H/D exchange will influence energies
of molecular vibrations. We have performed experiments
where neither ba nor pyo were deuterated, where either ba
or pyo were deuterated (ba-d and pyo-d, respectively), and
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Scheme 2. Milling of ba and prc produces no net chemical change.
Exchangeable hydrogen atoms of ba and prc are denoted.
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mental evidence for the formation of the cocrystal between
these two compounds agrees with first principle calculations
where the most stable predicted cocrystal was found to
be thermodynamically unfavorable relative to reactants.28
Here, H/D exchange in the bulk could be enabled only
through fast formation of new contact surfaces between crys-
tallites of ba and prc, as a consequence of mixing and contin-
uous particle comminution and growth.29,30 While particle
comminution results from milling ball impacts, growth of
crystalline nanoparticles is here evident from a stable aver-
age particle size of both ba and prc (Fig. 2, S16)
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Figure 2. (a) Average particle size of ba and prc and b) weight
fractions of ba and prc during milling derived from in situ PXRD
data.
In situ Raman monitoring of milling where either ba or
prc were deuterated revealed changes in intensities of bands
corresponding to vibrations that are affected by H/D ex-
change. Milling ba + prc-d2 decreases intensity of the ba
band at 793 cm−1 and increases intensity of the band at
765 cm−1, as a result of deuteron transfer from prc-d2 to ba
and partial formation of ba-d (Fig 3). Alternatively, milling
of ba-d + prc increases the band at 793 cm−1 of ba and si-
multaneously decreases the band at 765 cm−1 of ba-d. Band
of prc at 796 cm−1 is shifted to 782 cm−1 upon deuteration,
without a change in intensity (Fig 3).
For comparison, milling of ba + prc and ba-d + prc-d2
exhibited no changes in both PXRD and Raman in situ
monitoring (Figs. S12 and S13). Thus, H/D exchange in
milling reactions cannot be merely a consequence of a paral-
lel chemical reaction, but is inherent to the milling process
itself indicating also that a thermodynamic equilibrium be-
tween solids is readily achieved during milling, in accordance
with previously described equilibration of solids,31 as well
polymorph selectivity through particle size reduction29 or
solvation of nanoparticles.32,33 To exclude the possibility of
H/D exchange being facilitated by moisture due to samples
being prepared in air,34 we have milled ba-d + prc where
the sample was prepared in a glovebox in an argon atmo-
sphere. The same H/D exchange was observed here as in
experiments where samples were prepared in air (Fig S17).
Figure 1. (a) Raman spectra of natural and deuterated reac-
tants and final Raman spectra of variously deuterated cocrystals
obtained after 25 min milling. Labeling: bapyo-xx, (x = h or d)
corresponds to deuteration of starting reactants, e.g. bapyo-hd
designates the product of the reaction ba + pyo-d. (b) Time-
resolved characteristic section of Raman spectra during milling
at room temperature.
NH rocking vibration band is at 1365 cm−1 for pyo and at
1309 cm−1 for pyo-d. This band in the bapyo-hh cocrystal is
found at 1376−1 and at 1314 cm−1 for bapyo-dd. Products
in ba + pyo-d and ba-d + pyo experiments exhibit bands
at 1320 and 1376 cm−1 of similar intensities, again as a
consequence of H/D exchange and indicate equal deuteron
distribution between ba and pyo moieties in the cocrystal.
To further explore the fast exchange of hydrogen atoms
during milling, we have milled the 1:1 mixture of ba and
paracetamol (prc, also known as acetaminophen), which re-
mains a physical mixture (Figs. S12-S15). Lack of experi-
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tion was faster at 50 ◦C, it was incomplete at low tempera-
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ture. Overall, we have observed the same H/D exchange as
for milling in ambient conditions (Fig. S21). H/D exchange
in the ba + prc system resulted in a slower H/D exchange at
low temperature, but was comparable for milling at 50 ◦C
and milling started from room temperature.
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We extend H/D exchange to liquid-assisted grinding
(LAG)41–43 where we have milled ba with D2O in the 1:1
stoichiometric ratio. Deuteration of ba, which is poorly solu-
ble in water at room temperature, could be readily observed
with an increase in intensity of the ba-d band at 765 cm−1
as deuteron is transfered from D2O to ba and a correspond-
ing decrease in intensity of the 793 cm−1 band belonging to
ba. (Fig. 4). On the 2 mmol scale, H/D exchange reached
equilbrium after about 30 min milling with the spectrum
consistent with a distribution of 2/3 of deuterium atoms
on ba. This confirms that D2O interacted chemically with
milled ba and indicates that poor solid’s solubility in the
added liquid is not an obstacle for such an interaction, in
accordance with previous observations of the role of water
in grinding.43
Efficient deuteration of ba inspired us to use LAG for
preparatory deuterium labeling, similar to a milling ap-
proach that has recently been applied to enrich samples with
17O.44 Here, we have been able to deuterate 2 mmol of ba
at room temperature by three-times milling with 4 mmol of
D2O and drying of the solid in between. In total we have
used only 216 µL of D2O to achieve almost full deuteration
of 244 mg of ba, which amounts to at least 60-fold solvent re-
duction as compared to solution deuteration (see Supporting
Information) and no loss of the deuterated solid.
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Figure 3. (a) Raman spectra of natural and deuterated ba and
prc and first and final Raman spectra for experiments ba + prc-
d2 and ba-d + prc. Color code: black - first spectrum, red - last
spectrum after 45 min milling. Since prc bears two exchangeable
protons and ba bears one, H/D ratio of exchangeable hydrogens
is 1:2 for the ba + prc-d2 experiment and 2:1 for milling ba-d +
prc, resulting in different final spectra in these two experiments.
(b) Time-resolved characteristic section of Raman spectra during
milling.
Despite recent advances,10,35,36 temperature control in
milling is currently not widely established,37,38 which may
be troublesome since milling is generally self-heating.39,40 In
our milling setup the temperature has gradually risen from
the starting room temperature to ca. 35 ◦C (Fig. S26).
Since H/D exchange involves breaking of chemical bonds,
which must be associated with an energy barrier, its rate
should depend on temperature.10 We have thus explored
H/D exchange at low temperature around nitrogen liquefac-
tion and at 50 ◦C (Figs. S27-S30). While cocrystal forma-
Figure 4. a) scheme shows exchangeable atoms for LAG reaction
with D2O. b) stacked time-resolved Raman spectra for milling of
ba with D2O as a liquid additive in the 1:1 stoichiometric ratio.
Spectra of pure ba and ba-d are given in Fig. 1
Finally, we show whole-molecule exchange by milling ba
and 13C-labeled ba (ba*, Fig. 5). PXRD monitoring showed
no phase transformations while Raman monitoring revealed
fast changes consistent with the formation of the baba*
heterodimer. Figure 5 represents Raman and FTIR-ATR
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Bučar for critically reading the manuscript, to Nikola Bil-
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iškov and Igor Milanović for their help with the use of a
glovebox, the team at the fine-mechanics workshop of the
Ruđer Bošković Institute and Nikola Cindro, Edi Topić and
Mirta Rubčić for their help with collecting a DSC thermo-
gram. We are also grateful to the Reviewers whose com-
ments and careful reading improved this manuscript. Com-
putations were done on the Isabella cluster at SRCE, Za-
greb. Financial support from the Croatian Science Foun-
dation (Grant No. 4744) and the Adris foundation is grate-
fully acknowledged. SL is supported by the Croatian Science
Foundation.
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Supporting Information Avail-
able
Experimental, tandem in situ Raman and PXRD plots,
Rietveld-extracted reaction profiles, temperature profiles,
computational details.
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