Mechanochemically Assisted Synthesis of Hexaazatriphenylenehexacarbonitrile

Article abstract of DOI:10.1021/acs.joc.1c00253

1,4,5,8,9,11-hexaazatriphenylenehexacarbonitrile (HAT CN) was synthesized mechanochemically at room temperature. The coupling of hexaketocyclohexane and diaminomaleonitrile was conducted in 10 min by vibratory ball milling. The effects of milling parameters, acids, dehydrating agents, and liquid-assisted grinding were rationalized. With 67%, the yield of this mechanochemical approach exceeds that of state-of-the-art wet-chemical syntheses while being superior with respect to time-, resource-, and energy-efficiency as quantified via green metrics.

Full text of DOI:10.1021/acs.joc.1c00253

pubs.acs.org/joc
Article
Mechanochemically Assisted Synthesis of
Hexaazatriphenylenehexacarbonitrile
Wilm Pickhardt, Maximilian Wohlgemuth, Sven Grätz, and Lars Borchardt*
Cite This: https://doi.org/10.1021/acs.joc.1c00253
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: 1,4,5,8,9,11-hexaazatriphenylenehexacarbonitrile (HAT CN) was synthesized
mechanochemically at room temperature. The coupling of hexaketocyclohexane and
diaminomaleonitrile was conducted in 10 min by vibratory ball milling. The effects of milling
parameters, acids, dehydrating agents, and liquid-assisted grinding were rationalized. With
67%, the yield of this mechanochemical approach exceeds that of state-of-the-art wet-chemical
syntheses while being superior with respect to time-, resource-, and energy-efficiency as
quantified via green metrics.
coupled in refluxing acetic acid (118 °C). The obtained raw
product consists only of 50% HAT-CN and requires
purification. Oschatz et al. refined the synthetic procedure by
purification using hot nitric acid as well as refluxing acetonitrile
to obtain pure HAT-CN (for more details, see Supporting
Information, chapter 2.4).15 This two-step reaction requires 2
days of work, of which 7 h are taken up by pure heating time.
Additionally, high amounts of hazardous solvents are required
to obtain around 50% yield.11,18 All of these factors render the
synthesis neither sustainable, scalable, or economically viable.
Within this contribution, we present a facile, cheap, time-
resource-, and energy-efficient alternative based on mecha-
nochemistry.19−28 Compared to the traditional wet-chemical
approach, the reaction mixture requires no external heating.
The activation energy is provided by the colliding milling balls
inside ball mills, and the reactions run in the absence of
solvents within minutes.29−33
INTRODUCTION
■
1,4,5,8,9,11-Hexaazatriphenylenehexacarbonitrile (HAT-CN)
is a hydrogen-free trigonal planar conjugated aromatic
compound, with a composition close to the C2N stoichiom-
etry. It is promising in OLED (organic light-emitting diode)
architectures, where it can be used either as a protective layer,1
as a doping material in hole injection layers,1−4 or even as a
standalone interlayer.5,6 It also finds applications in organic
solar cells,7−10 for the directed growth of graphene5,11−14 and
the synthesis of porous carbon materials with high N-
content.15 HAT-CN is commonly synthesized by a two-step
reaction of hexaketocyclohexane and diaminomaleonitrile
(Figure 1).16 We would like to note that, although it is
RESULTS AND DISCUSSION
■
With this contribution, we present a fast mechanochemically
assisted synthesis of HAT-CN in as little as 10 min of milling,
followed by a second step utilizing hot HNO3. The yields after
those two steps are even higher than in traditional syntheses.
We were able to completely omit the use of acetic acid and
Figure 1. Synthetic pathway to obtain HAT-CN. Hexaketocyclohex-
ane and diaminomaleonitrile are coupled in a condensation reaction
with subsequent oxidation steps.
commonly referred to as hexaketocyclohexane octahydrate,
this is not representative of the structure of the molecule.
Crystallographic studies of Weigand and co-workers have
shown that the molecule is, in fact, dodecahydroxycyclohexane
dihydrate.17 However, since the community knows it as
hexaketocyclohexane, we have decided to stick to the
terminology for consistency. In the literature synthesis, first
published by Czarnik et al.,16 both starting materials are
Special Issue: Enabling Techniques for Organic Syn-
thesis
Received: February 1, 2021
© XXXX The Authors. Published by
American Chemical Society
https://doi.org/10.1021/acs.joc.1c00253
J. Org. Chem. XXXX, XXX, XXX−XXX
A

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
acetonitrile applying a mechanochemical approach, thus vastly
improving the synthesis. Adapting the liquid phase protocol,
we first investigated the reaction under strongly acidic
conditions. However, the use of p-toluenesulfonic acid only
leads to a low yield of 29% (Table 1, entry 2). The use of
a
Table 1. Screening of Solid Acids and Reaction Conditions
entry
additive
pKa
yield [%]
b
1
2
4
5
6
7
8
9
sulfuric acid
−3.00
−2.80
1.23
1.92
2.75
11
29
41
35
25
0
para-toluene sulfonic acid monohydrate
oxalic acid
KHSO4
salicylic acid
benzoic acid
ascorbic acid
P2O5
4.20
5.25
0
0
10
11
12
FeCl3 anhydride
MgSO4
0
17
48
49
none
none
c
13
a
All approaches were milled for 10 min at 35 Hz in a 10 mL ZrO2 vial
containing 0.40 g of hexaketocyclohexane, 1.10 g of diaminomaeoni-
trile, and a Ø = 10 mm ZrO2 milling ball. Acids sorted by pKa.
b
Sulfuric acid is a liquid, and MgSO4 was added as a bulk material.
c
Milled for 60 min
sulfuric acid gave even lower yields of 11% (Table 1, entry 1).
These disheartening results lead to a change of mind, as we
understood that the acid strength is not the decisive factor in
this reaction. Following this realization, other acids were
tested, which are solid but, in some cases, very weak regarding
their pKa. Some of the weaker organic solvents did not show
any yield (Table 1, entries 7 and 8), but the use of oxalic acid
leads to a significant improvement. It was the most efficient
conversion, yielding 41% HAT-CN after mere 10 min of
mixing (Table 1, entry 5). As the results were inconsistent
regarding the used acids pKa (see Table 1, entries 1−8), we
hypothesized that the milling additive might play a crucial role
and tested additives from a rheological perspective. Magnesium
sulfate, phosphorus pentoxide, and other additives were used
to shift the equilibrium of the condensation reaction due to
their dehydrating properties.33,34 This screening gave yields of
only a maximum of 17% (Table 1, entries 9−11). Following
this result, we conducted the condensation reaction under neat
conditions (i.e., acid-free and additive-free, however, please
note that hexaketocyclohexane contains crystal water), mixing
only the starting materials in the ball mill. This resulted in a
yield of 48%. This simplified the reaction greatly but requested
a further investigation, as the reaction appeared to run entirely
different from what was known from the liquid phase (Table 1,
entry 12). Longer milling periods of up to 60 min did not show
a significantly enhanced conversion (Table 1, entry 13). To
test the scalability, the approach was performed in bigger vials
with higher quantities, leading to the same conversion as the
smaller scale batches (Table S1, entry 12). During this
screening, we observed that the reaction mixture in the neat
approach appeared to be mud-like. We concluded that the
water formed during the condensation leads to this
appearance. As water might act physically or chemically as a
self-accelerating side product, liquid-assisted grinding using
water was tested (Figure 2).
Figure 2. Spectroscopic analysis of HAT-CN. (A) 13C{1H} NMR
(300 MHz, CO(CD3)2) spectrum of pure HAT-CN. (B) IR spectrum
of HAT-CN. (C) Stacked Raman spectra of HAT-CN and the
starting materials used in the synthesis of HAT-CN. (1) Raman
spectrum of HAT-CN. (2) Raman spectrum of hexaketocyclohexane.
(3) Raman spectrum of diaminomaleonitril.
We have investigated the influence of small quantities of
various liquids (liquid-assisted grinding (LAG) with η between
0.1 and 0.5).35,36 For a first try, a η of 0.2 was used. This led to
no product formation (Table 2, entry 2). The raw mixture
appeared not to be a dark brown paste but a slurry, leading to
the conclusion that a η of 0.2 was too high. Smaller amounts of
water enhanced the yield significantly up to 67% (Table 2,
entries 3 and 4). Please note that, even under neat conditions,
i.e., η of 0, there is still crystal water from the
hexaketocyclohexane present. As LAG with a η of 0.1 seemed
to be the optimum, further investigations of LAG showed that
small amounts of protic solvents like methanol and ethanol
enhance the reaction rate by a small margin but not as efficient
B
https://doi.org/10.1021/acs.joc.1c00253
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
This observation shows strong parallels with the accelerated
Table 2. Screening of Liquid-Assisted Grinding and One-
Pot Two-Step Process
37
a
̌
̌
́
aging, described by Friscic et al. For comparison, the
conventional liquid-phase synthesis already shows HAT-CN
formed after the coupling in refluxing acetic acid (cf.
Supporting Information, section 2.4). This points toward a
different mechanistic pathway of the mechanochemical and the
liquid-phase synthesis.
entry
LAG additive
LAG amount [η]
yield [%]
1
2
3
4
5
6
7
8
9
48
0
H2O
H2O
H2O
methanol
ethanol
toluol
DCM
DMF
H2O
0.2
0.1
0.05
0.1
0.1
0.1
0.1
0.1
0.1
67
62
45
50
29
36
19
47
0
Overall, we were able to significantly improve the synthesis
of HAT-CN by performing the condensation reaction in as
little as 10 min inside a ball mill. Thus, making it significantly
more sustainable by completely avoiding acetic acid and
acetonitrile. The use of water as a liquid-assisted grinding
additive led to a yield of up to 67%, significantly outperforming
the state of the art. To further enhance the environmental
compatibility, we conducted the reaction without any excess
diaminomaleonitrile, leading to less product but overall better
green metrics. The product mass intensity is lower by a factor
of up to 795. With our synthetic pathway, 78% CO2
equivalents can be saved. Our synthetic approach does not
rely on high excesses of one starting material, solvents, or high
temperatures and, therefore, is more cost- and time-efficient
than the traditional way, while giving improved yields.
b
10
11
c
a
All approaches were milled for 10 min at 35 Hz in a 10 mL ZrO2 vial
containing 0.40 g of hexaketocyclohexane, 1.10 g of diaminomaleoni-
b
trile, and 1 Ø = 10 mm ZrO2 milling ball. 0.42 g of
c
diaminomaleonitrile (stoichiometric amount) was used After the
first step, the solution workup was replaced by adding 1 mL of 30%
HNO3 (9.36 mmol) to the milling vessel and milling the mixture for
another 10 min at 30 Hz.
as water (Table 2, entries 5 and 6). Water appears to be a
critical additive, which may function as a stabilizing agent.
Switching to common, aprotic organic solvents like DCM and
toluene (Table 2, entries 7 and 8), the yields are lowered
drastically, supporting the suspicion that the water is involved
in the reaction not as a solvent, as the solubility of both starting
materials in water is poor compared to the other used LAG
additives. Using DMF as an additive led to a drastic decrease in
conversion, which might be because of side reactions.
Therefore, we could conclude that polar protic solvents are
beneficial for this condensation reaction.
EXPERIMENTAL SECTION
■
General Information. All reagents were obtained from
commercial suppliers and were used without purification. Acids and
solvents for the LAG were used in the anhydrous form if not
mentioned otherwise. Water used in LAG was taken from a tap for the
deionized form. The mechanochemical step was carried out in a
Retsch MM400 and Retsch MM500 nano/vario ball mill. Commercial
milling vessels out of zirconium dioxide were used. Zirconium dioxide
(Type ZY-S) milling balls with a diameter of 10 mm were purchased
from Sigmund Lindner GmbH. The average weight of one milling ball
is 3.19
0.05 g. Nuclear magnetic resonance spectroscopy was
recorded on a Bruker BRUKER Avance III HD 300 MHz NMR
spectrometer. As a solvent and internal standard, acetone-d6 was used.
Fourier transform infrared spectroscopy (FT-IR) was carried out on a
SHIMADZU IR Spirit with a QATR-S ATR unit. Each sample was
measured with 15 scans with a resolution of 4 in the range from 400
to 4000 cm−1. Elemental analysis was carried out on a vario Micro
cube from Elementar Analysensysteme GmbH at 1200 °C. Raman
spectra were obtained using a RENISHAW inVia Qontor Raman
microscope with 50× object (NA = 0.50, 8.2 mm free working
distance). The wavelength for the measurement was 785 nm with
0.001−10% laser power dependent on the sample. The exposure time
varied between 20s and 2 accumulations and 1s and 20
accumulations, of which the latter resulted in the best spectra.
Synthesis of 1,4,5,8,9,11-Hexaazatriphenylenehexacarbo-
nitrile. In a typical synthesis, the reactants were placed in a 10 mL
ZrO2 milling vial together with a Ø = 10 mm ZrO2 milling ball. Then,
0.400 g (1.30 mmol, 1 equiv) of hexaketocyclohexane-octahydrate,
1.10 g (10.20 mmol, 7,84 equiv) of diaminomaleonitrile and the
respective additives were added (for detailed information, see section
1 of the Supporting Information). The mixture was milled for 10 min
at 35 Hz in a Retsch MM500 mixer ball mill (MBM). After the
milling, the raw mixture was transferred into a flask and stirred in 30%
HNO3 in a 110 °C oil bath for an hour. After cooling, the orange-solid
HAT-CN was filtered, washed with water, and dried. An evenly bright
yellow solid was isolated (0.3319 g, 0.864 mmol) in 67% yield.
13C{1H} NMR (300 MHz, CO(CD3)2): δ 143.4, 136.6, 114.4 ppm.
To verify the merit of our approach in terms of
sustainability, we calculated the green metrics (cf. Supporting
Information, section 3). The stoichiometric approach has a
795-times better mass productivity and process mass intensity
compared to the solution-based protocol. In addition, the
reaction time is strongly reduced, and thus, the global warming
potential of the process can be reduced by 78%. Overall, the
sustainability of the reaction has been vastly increased by the
use of mechanochemistry.
Analogously to the conventional route, the presented
synthesis also involves a workup with HNO3. As reported for
the conventional route, this serves as a purification step to
dissolve unreacted or incompletely reacted (1- or 2-fold
condensation, excess diaminomaleonitrile) reaction products.
We attempted to substitute this liquid phase workup with a
second treatment inside the ball mill. Oxidizing agents like
potassium peroxymonosulfate, sodium perchlorate, sodium
percarbonate, or liquid HNO3 (Table 2, entry 11 and Table
S2) were employed in a one-pot two-step process, but no
product could be isolated for any of them. In the
mechanochemical approach, however, this treatment is crucial
for another reason. As our analysis shows that no HAT-CN but
an intermediate is formed during the milling process. This
intermediate must be an adduct of the two starting materials in
a precoordinated fashion, as the starting materials themselves
are not stable under 30% HNO3 conditions (for a detailed
discussion, see Supporting Information, section 2.4). If the
intermediate is exposed to the same conditions, however, it is
transferred into HAT-CN and precipitating from the solution.
FT-IR: ν 2240, 1340, 1226, 1146 cm−1. Raman: ν 2253, 1400, 1480,
1540, 700 cm−1. HRMS (MALDI-TOF, TCNQ): M+ 384.7 m/z.
Elemental analysis: 54.6%, C; 43.1%, N; 0.4%, H; 0%, S. The melting
point is reported to be >500 °C and was not further explored for
analysis.
Upscaling the Synthesis of 1,4,5,8,9,11-Hexaazatriphenyle-
nehexacarbo-nitrile in the MM-500. To check the scalability of
C
https://doi.org/10.1021/acs.joc.1c00253
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
this reaction, a bigger batch of the reactants was placed in a 45 mL
ZrO2 milling vial together with 22 Ø = 10 mm ZrO2 milling balls.
Then, 2.50 g (8.01 mmol, 1 equiv) of hexaketocyclohexane-
octahydrate and 6.84 g (63.27 mmol, 7.90 equiv) of diaminomaleoni-
trile were placed in the milling vessel. The mixture was milled for 10
min at 35 Hz in a Retsch MM500 mixer ball mill (MBM). After the
milling, the raw mixture was transferred into a flask and stirred in 30%
HNO3 in a 110 °C oil bath for an hour. After cooling, the orange-solid
HAT-CN was filtered, washed with water, and dried. An evenly bright
yellow solid was isolated (1.7625 g, 4.5870 mmol) in 57% yield.
13C{1H} NMR (300 MHz, CO(CD3)2): δ 143.4, 136.6, 114.4 ppm.
REFERENCES
■
(1) Lee, J.-H.; Lee, S.; Kim, J.-B.; Jang, J.; Kim, J.-J. A high
performance transparent inverted organic light emitting diode with
1,4,5,8,9,11-hexaazatriphenylenehexacarbonitrile as an organic buffer
layer. J. Mater. Chem. 2012, 22, 15262.
(2) Dai, Y.; Zhang, H.; Zhang, Z.; Liu, Y.; Chen, J.; Ma, D. Highly
efficient and stable tandem organic light-emitting devices based on
HAT-CN/HAT-CN:TAPC/TAPC as a charge generation layer. J.
Mater. Chem. C 2015, 3, 6809−6814.
(3) Lim, J.-W.; Jun Kang, S.; Lee, S.; Kim, J.-J.; Kim, H.-K.
Transparent Ti-In-Sn-O multicomponent anodes for highly efficient
phosphorescent organic light emitting diodes. J. Appl. Phys. 2012, 112,
023513.
FT-IR: ν 2240, 1340, 1226, 1146 cm−1. Raman: ν 2253, 1400, 1480,
1540, 700 cm−1.
Synthesis of 1,4,5,8,9,11-Hexaazatriphenylenehexacarbo-
nitrile in a One-Pot Two-Step Approach. The reactants were
placed in a 10 mL ZrO2 milling vial together with a Ø = 10 mm ZrO2
milling ball. Then, 0.400 g (1.30 mmol, 1 equiv) of hexaketocyclohex-
ane-octahydrate and 1.10 g (10.20 mmol, 7.84 equiv) of
diaminomaleonitrile were placed in the milling vessel. The mixture
was milled for 10 min at 35 Hz in a Retsch MM500 mixer ball mill
(MBM). After the milling, various oxidative agents were added
(according to Table S2) to the milling vial, and the milling was
continued. The volume of HNO3 required to oxidize the raw mixture
leads to slurry grinding. After the milling, the raw mixture was washed
with water and dried. A dark brown paste was obtained, which did not
show any traces of HAT-CN. Other oxidants such as Kaliummono-
peroxosulfat, sodium perchlorate, or sodium percarbonate show
similar results.
(4) Albrecht, K.; Matsuoka, K.; Fujita, K.; Yamamoto, K. Carbazole
dendrimers as solution-processable thermally activated delayed-
fluorescence materials. Angew. Chem., Int. Ed. 2015, 54, 5677−5682.
(5) Liao, L. S.; Slusarek, W. K.; Hatwar, T. K.; Ricks, M. L.;
Comfort, D. L. Tandem Organic Light-Emitting Diode using
Hexaazatriphenylene Hexacarbonitrile in the Intermediate Connector.
Adv. Mater. 2008, 20, 324−329.
(6) Wang, Y.; Liang, Q.; Huang, J.; Ma, D.; Jiao, Y. Investigation of
the hole transport characterization and mechanisms in co-evaporated
organic semiconductor mixtures. RSC Adv. 2017, 7, 28494−28498.
(7) Sun, Y.; Welch, G. C.; Leong, W. L.; Takacs, C. J.; Bazan, G. C.;
Heeger, A. J. Solution-processed small-molecule solar cells with 6.7%
efficiency. Nat. Mater. 2012, 11, 44−48.
(8) Cnops, K.; Rand, B. P.; Cheyns, D.; Verreet, B.; Empl, M. A.;
Heremans, P. 8.4% efficient fullerene-free organic solar cells exploiting
long-range exciton energy transfer. Nat. Commun. 2014, 5, 3406.
(9) Dou, L.; You, J.; Hong, Z.; Xu, Z.; Li, G.; Street, R. A.; Yang, Y.
25th anniversary article: a decade of organic/polymeric photovoltaic
research. Adv. Mater. 2013, 25, 6642−6671.
(10) Heeger, A. J. 25th anniversary article: Bulk heterojunction solar
cells: understanding the mechanism of operation. Adv. Mater. 2014,
26, 10−27.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00253.
Screening experiments with different additives; 1H NMR
spectra; MALDI-MS spectra and EA comparison;
mechanistic consideration, green metrics calculation
(PDF)
(11) Segura, J. L.; Juárez, R.; Ramos, M.; Seoane, C. Hexaaza-
triphenylene (HAT) derivatives: from synthesis to molecular design,
self-organization and device applications. Chem. Soc. Rev. 2015, 44,
6850−6885.
(12) Kaplan, A.; Yuan, Z.; Benck, J. D.; Govind Rajan, A.; Chu, X. S.;
Wang, Q. H.; Strano, M. S. Current and future directions in electron
transfer chemistry of graphene. Chem. Soc. Rev. 2017, 46, 4530−4571.
(13) Rogers, J. A. Electronic materials: making graphene for
macroelectronics. Nat. Nanotechnol. 2008, 3, 254−255.
(14) Feng, L.; Liu, Z. Graphene in biomedicine: opportunities and
challenges. Nanomedicine (London, U. K.) 2011, 6, 317−324.
(15) Walczak, R.; Savateev, A.; Heske, J.; Tarakina, N. V.; Sahoo, S.;
AUTHOR INFORMATION
■
Corresponding Author
Lars Borchardt − Inorganic Chemistry I, Ruhr-Universität
Bochum, 44801 Bochum, Germany; orcid.org/0000-
0002-8778-7816; Email: lars.borchardt@rub.de
Epping, J. D.; Kuhne, T. D.; Kurpil, B.; Antonietti, M.; Oschatz, M.
̈
Authors
Controlling the strength of interaction between carbon dioxide and
nitrogen-rich carbon materials by molecular design. Sustainable Energy
Fuels 2019, 3, 2819−2827.
Wilm Pickhardt − Inorganic Chemistry I, Ruhr-Universität
Bochum, 44801 Bochum, Germany
(16) Kanakarajan, K.; Czarnik, A. W. Synthesis and some reactions
of hexaazatriphenylenehexanitrile, a hydrogen-free polyfunctional
heterocycle with D3h symmetry. J. Org. Chem. 1986, 51, 5241−5243.
(17) Klapötke, T. M.; Polborn, K.; Weigand, J. J. Dodecahydrox-
ycyclohexane dihydrate. Acta Crystallogr., Sect. E: Struct. Rep. Online
2005, 61, 1393−1395.
Maximilian Wohlgemuth − Inorganic Chemistry I, Ruhr-
Universität Bochum, 44801 Bochum, Germany
Sven Grätz − Inorganic Chemistry I, Ruhr-Universität
Bochum, 44801 Bochum, Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00253
(18) Kanakarajan, K.; Czarnik, A.W. Synthesis and some reactions of
hexaazatriphenylenehexanitrile, a hydrogen-free polyfunctional het-
erocycle with D3h symmetry.
Notes
(19) Rightmire, N. R.; Hanusa, T. P. Advances in organometallic
synthesis with mechanochemical methods. Dalton Trans. 2016, 45,
2352−2362.
The authors declare no competing financial interest.
̌
̇
(20) Geciauskaite, A. A.; García, F. Main group mechanochemistry.
Beilstein J. Org. Chem. 2017, 13, 2068−2077.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the funding from the European
Research Council (ERC) under the European Union’s
Horizon 2020 research and innovation program (“Mechano-
cat”, grant agreement no. 948521).
(21) Achar, T. K.; Bose, A.; Mal, P. Mechanochemical synthesis of
small organic molecules. Beilstein J. Org. Chem. 2017, 13, 1907−1931.
(22) Do, J.-L.; Friscic, T. Mechanochemistry: A Force of Synthesis.
̌
̌
́
ACS Cent. Sci. 2017, 3, 13−19.
D
https://doi.org/10.1021/acs.joc.1c00253
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(23) Hernández, J. G.; Bolm, C. Altering Product Selectivity by
Mechanochemistry. J. Org. Chem. 2017, 82, 4007−4019.
(24) Tan, D.; García, F. Main group mechanochemistry: from
curiosity to established protocols. Chem. Soc. Rev. 2019, 48, 2274−
2292.
(25) Bolm, C.; Hernández, J. G. Mechanochemistry of Gaseous
Reactants. Angew. Chem., Int. Ed. 2019, 58, 3285−3299.
̌
̌
́
(26) Friscic, T.; Mottillo, C.; Titi, H. M. Mechanochemistry for
Synthesis. Angew. Chem., Int. Ed. 2020, 59, 1018−1029.
(27) Kubota, K.; Ito, H. Mechanochemical Cross-Coupling
Reactions. Trends Chem. 2020, 2, 1066−1081.
(28) Mocci, R.; Colacino, E.; Luca, L. de; Fattuoni, C.; Porcheddu,
A.; Delogu, F. The Mechanochemical Beckmann Rearrangement: An
Eco-efficient “Cut-and-Paste” Strategy to Design the “Good Old
Amide Bond. ACS Sustainable Chem. Eng. 2021, 9, 2100−2114.
(29) Grätz, S.; Oltermann, M.; Vogt, C. G.; Borchardt, L.
Mechanochemical Cyclodehydrogenation with Elemental Copper:
An Alternative Pathway toward Nanographenes. ACS Sustainable
Chem. Eng. 2020, 8, 7569−7573.
̌
́
̌
̌
́
(30) Strukil, V.; Igrc, M. D.; Eckert-Maksic, M.; Friscic, T. Click
mechanochemistry: quantitative synthesis of ″ready to use″ chiral
organocatalysts by efficient two-fold thiourea coupling to vicinal
diamines. Chem. - Eur. J. 2012, 18, 8464−8473.
(31) Haferkamp, S.; Fischer, F.; Kraus, W.; Emmerling, F.
Mechanochemical Knoevenagel condensation investigated in situ.
Beilstein J. Org. Chem. 2017, 13, 2010−2014.
(32) Stolle, A.; Szuppa, T.; Leonhardt, S. E. S.; Ondruschka, B. Ball
milling in organic synthesis: solutions and challenges. Chem. Soc. Rev.
2011, 40, 2317−2329.
(33) Hasaninejad, A.; Zare, A.; Balooty, L.; Mehregan, H.;
Shekouhy, M. Solvent-Free, Cross-Aldol Condensation Reaction
Using Silica-Supported, Phosphorus-Containing Reagents Leading
to α,α′-Bis(arylidene)cycloalkanones. Synth. Commun. 2010, 40,
3488−3495.
(34) Guo, Y.-L.; Li, Y.-H.; Chang, H.-H.; Kuo, T.-S.; Han, J.-L.
Molecular sieve mediated sequential Knoevenagel condensation/
decarboxylative Michael addition reaction: efficient and mild
conditions for the synthesis of 3,3-disubstituted oxindoles with an
all carbon quaternary center. RSC Adv. 2016, 6, 74683−74690.
(35) Krusenbaum, A.; Grätz, S.; Bimmermann, S.; Hutsch, S.;
Borchardt, L. The mechanochemical Scholl reaction as a versatile
synthesis tool for the solvent-free generation of microporous
polymers. RSC Adv. 2020, 10, 25509−25516.
(36) Howard, J. L.; Sagatov, Y.; Repusseau, L.; Schotten, C.;
Browne, D. L. Controlling reactivity through liquid-assisted grinding:
the curious case of mechanochemical fluorination. Green Chem. 2017,
19, 2798−2802.
̌
̌
̌
́
(37) Cliffe, M. J.; Mottillo, C.; Stein, R. S.; Bucar, D.-K.; Friscic, T.
Accelerated aging: a low energy, solvent-free alternative to
solvothermal and mechanochemical synthesis of metal−organic
materials. Chem. Sci. 2012, 3, 2495.
E
https://doi.org/10.1021/acs.joc.1c00253
J. Org. Chem. XXXX, XXX, XXX−XXX