Mechanochemical carbon-carbon bond formation that proceeds via a cocrystal intermediate

Article abstract of DOI:10.1039/c8cc07853j

We report the first cocrystal as an intermediate in a solid-state organic reaction wherein molecules of barbituric acid and vanillin assume a favorable orientation for the subsequent Knoevenagel condensation.

Full text of DOI:10.1039/c8cc07853j

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Mechanochemical carbon–carbon bond formation
that proceeds via a cocrystal intermediate†
Cite this: Chem. Commun., 2018,
54, 13216
a
a
a
a
bc
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Stipe Lukin,‡ Martina Tireli,‡ Ivor Loncaric, Dajana Barisic, Primoz Sket,
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Domagoj Vrsaljko,d Marco di Michiel,e Janez Plavec,bcf Krunoslav Uzarevic *a and
Received 1st October 2018,
Accepted 31st October 2018
´
a
Ivan Halasz
*
DOI: 10.1039/c8cc07853j
rsc.li/chemcomm
We report the first cocrystal as an intermediate in a solid-state organic
reaction wherein molecules of barbituric acid and vanillin assume a
favorable orientation for the subsequent Knoevenagel condensation.
The Knoevenagel condensation is an important carbon–carbon
bond forming reaction. More than a hundred years after the
original report by Knoevenagel,1 Suzuki2 and Kaupp3 demon-
strated an efficient and quantitative Knoevenagel condensation
Scheme 1 Solid-state Knoevenagel condensation of van and barb under
mechanochemical milling conditions. The new CQC bond is shown in red.
in the solid state achieved by milling. Other studies of solvent- first step of the Knoevenagel condensation. Furthermore, solid-state
free Knoevenagel condensation reactions soon followed.4–10 ab initio calculations offer a plausible reaction path for the CQC
The reaction of barbituric acid (barb) and vanillin (van) was bond to form within the cocrystal. Liquid-assisted grinding (LAG)
even used as a model mechanochemical organic reaction for with ethanol considerably accelerated the reaction in comparison to
assessing energetics of milling,11,12 to test twin-screw extrusion LAG with non-protic liquids or neat grinding. On the other hand,
for solid-state organic synthesis,13 and latest, to reveal a peculiar LAG with a strong non-nucleophilic base provided a reaction
deviation of solid-state reaction kinetics from the one observed in pathway that circumvented the cocrystal intermediate.
solution, stemming from changes in the rheology of the milled
As far as we are aware, the Knoevenagel condensation of barb
sample.14 However, studies of barb–van Knoevenagel condensa- and van studied here is the first mechanochemical organic reac-
tion were thus far limited to ex situ reaction monitoring by, tion where a cocrystal of reactants is formed in situ during milling
e.g., solution UV-Vis11 or NMR spectroscopies.14
before the targeted reaction and the formation of a new covalent
In this work, we employ real-time in situ Raman spectro- bond occurred. Nevertheless, cocrystals as multicomponent solids
scopy monitoring15,16 to reveal that the solid-state Knoevenagel have been recognised as a promising medium to conduct solid-
condensation (Scheme 1) of barb and van proceeds through a state reactions efficiently and selectively.17–19 As such, they have
cocrystal intermediate. In the cocrystal, packing of barb and been used at length in crystal engineering to design and construct
van is such that molecules of barb are suitably positioned for solids to enable specific and usually photochemical reactivity.20–23
the nucleophilic attack to the carbonyl C-atom of van, which is the Targeted use of cocrystals to achieve thermal solid-state reactions
has also been explored, albeit to a lesser extent.24–29
a
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Milling of 1 mmol of barb and 1 mmol of van was performed
using a vibratory IST500 ball mill operating at 30 Hz, and
equipped with 2 stainless steel balls of 7 mm (each weighing
1.4 g) in diameter as the milling media. In situ monitoring of
neat grinding revealed only mixing of reactants during the first
70 minutes of milling after which a new intermediate phase
started to emerge, and it was followed by a slow formation of the
product I over a period of several hours (Fig. 1). According to
solution NMR, I was the expected Knoevenagel condensation
product and was amorphous as evidenced by PXRD (Fig. S2,
ESI†). In a repeated experiment, we used in situ monitoring to
isolate the intermediate by stopping the reaction at an appropriate
ˇ
´
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Ruder Boskovic Institute, Bijenicka c. 54, 10000 Zagreb, Croatia.
E-mail: krunoslav.uzarevic@irb.hr, ivan.halasz@irb.hr
b National Institute of Chemistry, Slovenian NMR Center, Ljubljana, Slovenia
c EN-FIST Center of Excellence, Ljubljana, Slovenia
d Faculty of Chemical Engineering and Technology, University of Zagreb,
Zagreb, Croatia
e ESRF – the European Synchrotron, 71 Avenue des Martyrs, 38000 Grenoble, France
f Faculty of Chemistry and Chemical Technology, University of Ljubljana,
Ljubljana, Slovenia
† Electronic supplementary information (ESI) available: Experimental and com-
putational details, in situ Raman and PXRD data, thermal measurements, NMR
data and FTIR data. CCDC 1869002 and 1818969. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c8cc07853j
‡ These authors contributed equally to this work.
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Fig. 1 In situ Raman monitoring of neat grinding of barb and van. Raman
spectra of barb, van, the cocrystal, and I are given above the 2D plot.
Formation of the cocrystal can be monitored by the Raman band at
1735 cmÀ1 that corresponds to the CQO stretching of barb molecules in
the cocrystal. The Raman band of the newly formed CQC bond at 1542 cmÀ1
indicates the formation of I. Intensity colour code: blue – low, red – high.
time and solved its crystal structure from laboratory PXRD data
(Fig. 2a), revealing it to be a 1 : 1 cocrystal of barb and van.
The cocrystal exhibits ribbons of barb molecules while
molecules of van pack in stacks (Fig. 2b). Strong N–HÁ Á ÁO
hydrogen bonds connect molecules of barb within the ribbons,
leaving one carbonyl O atom to be an acceptor in a hydrogen
bond with the hydroxy group of van. Having both reacting
molecules within a crystal brings to mind the topochemical
principle which anticipates that the reacting centers should be
close.30 The topochemical principle may hardly be applicable here
since the average crystal structure needs not to reflect the changes
occurring at the molecular level.31 However, we do note that the
Fig. 2 (a) Rietveld plot for the 1 : 1 barb:van cocrystal structure determined
from powder diffraction data collected using CuKa X-rays. A high-angle
region is enlarged to reveal more details. Refinement parameters: Rp = 2.3%,
Rwp = 3.1%, RBragg = 1.0%, and gof = 1.91. (b) Ribbons of barb and stacks of van
molecules in the cocrystal. Orange circles highlight the closest distance
between the barb methylene group and the van carbonyl group. The 3.7 Å
is the distance between the corresponding carbon atoms. Dashed bonds
represent hydrogen bonds. (c) Two Knoevenagel condensation product
molecules and one water molecule in the asymmetric unit of II. Arrows point
to newly formed CQC bonds.
arrangement of molecules in the barb:van cocrystal is such that one water molecule simultaneously leaves, and the calculated
the barb methylene group and the aldehyde group of van are energy barrier is below 350 kJ molÀ1 (Fig. 3). This, however, is
separated by only ca. 3.7 Å and suitably orientated for the addition an overestimation of the energy barrier resulting from the for-
of the barb nucleophile to the carbonyl C atom of van (Fig. 2b).
mation of one product molecule out of the four pairs of barb and
We were thus inspired to examine the potential topochemical van in the cocrystal unit cell. Periodic repetition of the unit cell
reaction in the cocrystal by using solid-state ab initio calculations. prevents relaxation of the crystal geometry as it would be the case if
Indeed, we have been able to identify a plausible reaction path for only one molecule of the product would form in a bigger crystal.
the barb methylene group to attack the aldehyde C atom of van Calculations of a single pair of reactant molecules under vacuum
and to create a new CQC bond within the cocrystal. In the process, gave an energy barrier of around 130 kJ molÀ1 (Fig. S1, ESI†).
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Fig. 3 Minimum energy path for the reaction of one molecule of barb and
one molecule of van within the unit cell of the cocrystal. The dashed line is
cubic spline interpolation and is a guide to the eye.
Since the neat grinding reaction takes over 14 hours to complete,
we tried to accelerate the product formation with the use of liquid-
assisted grinding.18,32,33 Liquid additives are known to accelerate
and also selectively direct mechanochemical reactions,34,35 or even
may act as an acid–base catalyst.16 Here, we have explored LAG
with the addition of 20 mL of acetonitrile (MeCN), nitromethane
(MeNO2), ethanol (EtOH) and N,N-diisopropylethylamine (dipea).
LAG with MeCN or MeNO2 resulted in fast cocrystal formation
which started 3 min into milling (Fig. 4a and Fig. S4, S5, ESI†).
Surprisingly, the subsequent CQC bond formation was slowed down
revealing a prolonged life-span of the cocrystal under those reaction
conditions (Fig. 4). This can be explained by the stabilisation of the
cocrystal with the liquid additives, as was previously observed in
Fig. 4 (a) Formation kinetics and life-span of barb:van cocrystal in neat
grinding and LAG reactions, derived from the cocrystal Raman band at
1735 cmÀ1, and (b) kinetics of CQC bond formation derived from changes
in intensities of the band at 1542 cmÀ1. LAG with EtOH yielded III while
other liquids yielded I. The intensity of the CQC band is lower in III than
in I. Note the different scales in (a) and (b).
related systems.35,36 However, the amorphous product I remained have chosen this reaction for a monitoring experiment using in situ
stable after 50 hours of neat grinding (Fig. S3, ESI†), and prolonged synchrotron PXRD,37–39 in tandem with Raman spectroscopy.35,40
milling in LAG reactions resulted in transformation of I to new forms PXRD showed persistent but diminishing diffraction signals from
of the Knoevenagel condensation product, II and III, observed after reactants, and a weak signal coming from the cocrystal. The
ca. 15 and ca. 20 hours of continuous milling, respectively (Fig. S4 Knoevenagel product, however, for a limited period of 70 min
and S5, ESI†).
milling, remained X-ray amorphous, but Raman spectroscopy
The new forms II and III are crystalline, as opposed to the revealed its formation soon into milling, as evidenced by the
amorphous form I (Fig. S2, ESI†), and each has a distinct Raman emergence of the CQC Raman band at 1542 cmÀ1 (Fig. S31, ESI†).
spectrum (Fig. S24, ESI†). According to solution NMR, both II and
With dipea, a non-nucleophilic base, the reaction proceeded
III are the expected Knoevenagel condensation product (Fig. S2, directly from reactants to I (Fig. S7, ESI†) circumventing the
S12–S14 and S24, ESI†), and thermal analysis suggested that I and cocrystal. Bulky isopropyl and ethyl groups of dipea possibly could
II are hydrates while III is likely anhydrous (Fig. S25–S28, ESI†). not achieve interactions that would stabilise the cocrystal, as was the
Formation of a hydrate product was previously suggested3 and case with other liquids. As a base, it also likely facilitates proton
is not surprising since water is a byproduct of Knoevenagel con- abstraction from barb and thus the nucleophilic attack on the
densation. This is corroborated by the crystal structure of II, also carbonyl group of van, resulting in a faster reaction rate than in neat
confirming the molecular structure of the Knoevenagel condensa- grinding.
tion product (Fig. 2c). Possible tautomeric variations in II and III are
excluded based on 15N solid-state NMR spectra which exhibited the were also interested in thermal initiation of Knoevenagel condensa-
same chemical shifts for nitrogen atoms (Fig. S20, ESI†).
tion in the cocrystal.17,24 Heating the cocrystal to 150 1C resulted in
Being able to isolate the barb:van cocrystal as a pure phase, we
The reaction using EtOH as a protic liquid additive revealed fast complete conversion to the anhydrous product III (Fig. S2, ESI†).
cocrystal formation, but also a significantly increased rate of CQC Interestingly, our attempts to synthesise the cocrystal from solution
bond formation, which was complete within ca. 2 hours (Fig. 4 and failed (Fig. S30, ESI†), indicating that it may be accessible only by
Fig. S6, ESI†). Since other studied reactions were rather slow, we milling.34,41
13218 | Chem. Commun., 2018, 54, 13216--13219
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cocrystal as an intermediate in a mechanochemical organic
reaction. Remarkably, the cocrystal suitably positioned the reacting
centers for the subsequent carbon–carbon bond formation.
Coupled with crystal engineering, this observation reveals possibi-
lities for controlled use of cocrystals for targeted reactivity in
milling reactions. Moreover, with the choice of liquid additives,
we were able to affect cocrystal formation and its stability under
milling. We also highlight the value of in situ reaction monitoring
which enabled identification and isolation of this unique and
easily overlooked intermediate. Currently, we are undertaking a
detailed in situ kinetic study of this model organic reaction with
the intention to elucidate the influence of liquid additives.
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We are grateful to Mr Vitomir Stanisic, Mr Ivan Kulcsar and
-
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the team at the fine-mechanics workshop of the Ruder Boskovic
Institute for their continuous support. We thank Tomislav Stolar for
critically reading the manuscript. Croatian Science Foundation
(Grant No. UIP-2014-09-4744) is gratefully acknowledged. IH is
grateful to the Adris Foundation for financial support. SL is sup-
ˇ
ported by the Croatian Science Foundation. PS and JP acknowledge
support by the Slovenian Research Agency, grant number
P1-0242. IL was supported by the European Union through the
European Regional Development Fund – the Competitiveness and
Cohesion Operational Programme (KK.01.1.1.06) and the H2020
CSA Twinning project No. 692194, RBI-T-WINNING.
ˇˇ ´
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35 S. Lukin, T. Stolar, M. Tireli, M. V. Blanco, D. Babic, T. Friscic,
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36 A. M. Belenguer, G. I. Lampronti, A. J. Cruz-Cabeza, C. A. Hunter and
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37 I. Halasz, S. A. J. Kimber, P. J. Beldon, A. M. Belenguer, F. Adams,
Conflicts of interest
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V. Honkimaki, R. C. Nightingale, R. E. Dinnebier and T. Friscic, Nat.
Protoc., 2013, 8, 1718–1729.
There are no conflicts of interest to declare.
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38 T. Friscic, I. Halasz, P. A. Beldon, A. M. Belenguer, F. Adams, S. A. J.
¨
Kimber, V. Honkimaki and R. E. Dinnebier, Nat. Chem., 2013, 5, 66–73.
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39 K. Uˇzarevic,I.HalaszandT.Friscic,J. Phys. Chem. Lett., 2015, 6, 4129–4140.
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