Mechanochemistry: Fundamentals, applications and future

12-14 September 2022, Cambridge and Online Mechanochemistry: Fundamentals, applications and future

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Introduction

Mechanochemistry: Fundamentals, applications and future Faraday Discussion is organised by the Faraday Division of the Royal Society of Chemistry This book contains abstracts of the posters presented at Mechanochemistry: Fundamentals, applications and future Faraday Discussion . All abstracts are produced directly from typescripts supplied by authors. Copyright reserved. Oral presentations and discussions All delegates at the meeting, not just speakers, have the opportunity to make comments, ask questions, or present complementary or contradictory measurements and calculations during the discussion. If it is relevant to the topic, you may give a 5-minute presentation of your own work during the discussion. These remarks are published alongside the papers in the final volume and are fully citable. If you would like to present slides during the discussion, please let the session chair know and load them onto the computer in the break before the start of the session.

Faraday Discussion volume Copies of the discussion volume will be distributed approximately 6 months after the meeting. To expedite this, it is essential that summaries of contributions to the discussion are received no later than Wednesday 21 September 2022 for questions and comments and Wednesday 5 October 2022 for responses.

Posters Posters have been numbered consecutively: P02-P66 The poster session will take place on Monday 12 September at 18:00 BST.

The posters will be available to view throughout the discussion by clicking on the link in the virtual lobby. During the dedicated poster sessions, online authors will be available to use the networking functions in the virtual lobby. Use the inbox in the top light blue bar of the virtual lobby screen to send the poster presenter a message or request a video call with them by clicking on their name in the networking section at the bottom of the screen.

Poster prize The Faraday Discussions poster prize will be awarded to the best student poster as judged by the committee.

Networking sessions There will be regular breaks throughout the meeting for socialising, networking and continuing discussions started during the scientific sessions. During the networking sessions, all delegates will have access to join online networking rooms and can set theses up from the virtual lobby.

Scientific Committee

Invited Speakers

Stuart James (Chair) Queen’s University Belfast, UK Tomislav Friscic McGill University, Canada James Batteas Texas A&M University, USA Deborah Crawford University of Bradford, UK Hajime Ito Hokkaido University, Japan James Mack University of Cincinnati, USA Lucia Maini University of Bologna, Italy

Elena Boldyreva (Introductory lecture) Novosibirsk, Russia Stephen Craig (Closing remarks lecture) Duke University, USA

Carsten Bolm RWTH Aachen University, Germany

Robert Carpick University of Pennsylvania, USA

Franziska Emmerling Bundesanstalt für Materialforschung und -prüfung (BAM), Germany

Felipe Garcia The University of Oviedo, Spain

Jeung Gon Kim Jeonbuk National University, South Korea

Ashlie Martini University of California Merced, USA

Maria Elena Rivas Johnson Matthey, UK

Faraday Discussions Forum

www.rscweb.org/forums/fd/login.php

In order to record the discussion at the meeting, which forms part of the final published volume, your name and e-mail address will be stored in the Faraday Forum. This information is used for the collection of questions and responses communicated during each session. After each question or comment you will receive an e-mail which contains some keywords to remind you what you asked, and your password information for the forum. The e-mail is not a full record of your question. You need to complete your question in full on the forum . The deadline for completing questions and comments is Wednesday 21 September 2022 .

The question number in the e-mail keeps you a space on the forum. Use the forum to complete, review and expand on your question or comment. Figures and attachments can be uploaded to the forum. If you want to ask a question after the meeting, please e-mail faraday@rsc.org. Once we have received all questions and comments, responses will be invited by e-mail . These must also be completed on the forum . The deadline for completing responses is Wednesday 5 October 2022 . Please note that when using the Forum to submit a question or reply, your name and registered e-mail address will be visible to other delegates registered for this Faraday Discussions meeting. Key points: • The e-mail is not a full record of your comment/question. • All comments and responses must be completed in full on the forum Deadlines: Questions and comments Wednesday 21 September 2022 Responses Wednesday 5 October 2022

Poster presentations

P02

Self-assembly of organometallic squares through mechanochemical activation of Re-CO bonds Thomas Auvray McGill University, Canada The regioselective synthesis of nanographenes via photo- mechanochemistry Daniel Baier Ruhr-University Bochum, Germany Mechanochemically driven 3D heterostructuring of metal chalcogenides Viktor Balema ProChem Inc., USA The role of liquid amount in organic mechanochemical reactions investigated by resonant acoustic mixing (RAM) Linda Bechnak McGill university, Canada Temperature controlled, mechanochemical balling milling and twin- screw extrusion Robert Bolt University College London, UK Light-induced mechanical effects on crystals: from soft to catastrophic Tristan Borchers McGill University, Canada Exploring the polymorphism of sofosbuvir via mechanochemistry: effect of milling jar geometry and material Argyro Chatziadi University of Chemistry and Technology Prague, Czech Republic Rapid and solventless chlorination of pyrazoles by ball milling Jia-Xin Chen Tunghai University, Chinese Taipei

P03

P04

P05

P06

P07

P09

P10

P11

Sustainable polymer chemistry of high-performance materials by mechanochemistry Niamh Curran Queen’s University Belfast, UK From molecules in solution to molecules on surfaces – using supramolecular dyads to form functional self-assembled networks on graphene David Kreher CNRS, France Exploring neat grinding and liquid-assisted-grinding to obtain different polymorphs of curcumin and its Schiff base curcumin derivatives Aniele De Moura UNESP-São Paulo State University, Brazil Mechanochemistry: a green and efficient tool to obtain curcumin derivaties with a functionalized ω-poly(ethylene glycol) Aniele De Moura UNESP-São Paulo State University, Brazil Mechanochemical self-assembly of cavity-containing anionic salicylic acid-based metallostructures Jean-Louis Do Concordia University, McGill University, Canada Solid-state synthesis of BINOLs by copper-based catalysis Farshid Effaty Concordia University, McGill University, Canada

P12

P13

P14

P15

P16

P17

Substituent effects on tribochemical processes James Ewen Imperial College London, UK

P18

Direct insights into the liquid assisted grinding environment from molecular dynamics simulations Michael Ferguson McGill University, Canada Co-crystals of antibiotics with natural antimicrobials: product diversity resulting from different synthetic approaches Cecilia Fiore University of Bologna, Italy

P20

P22

Pressure dependence of a photon energy emitted from a material and an advanced density functional theory Kimichika Fukushima South Konandai Science Research, Theoretical Division, Japan The influence of external forces on the reaction pathways of cyclobutane systems: a computational study Anne Germann Heinrich Heine University, Germany Mineralising toxic ‘Forever Chemicals’ by high energy ball milling Kapish Gobindlal University of Auckland, New Zealand What maketh a pore? The formation of porosity in the solid-state Sven Grätz Ruhr-Universität Bochum, ACI, Germany Facile approach to synthesis of ionic polymers by mechanochemical solid-state conditions Lee Gue-Seon Jeonbuk National University, South Korea In situ Raman spectroscopy for monitoring ZIF-8 synthesis using twin- screw extrusion Nikita Gugin Bundesanstalt für Materialforschung und -prüfung, Germany Mechanochemical synthesis of 3,5-isoxazoles and its synthetic applications in the desymmetrization of unbiased poly(alkyne) systems Rafael Hernandez Concordia University, Canada Theoretical investigation of transition metal complexes with mechanochromic properties Maria Jaworska University of Silesia in Katowice, Poland Mechanical energy or heat? Thermal modulation of the kinetics of a mechanically activated solvent-free organic transformation Patrick Julien McGill University, Canada

P23

P24

P25

P26

P27

P28

P29

P30

P31

Mechanoenzymatic hydrolysis of cotton to cellulose nanocrystals Sandra Kaabel Aalto University, Finland Mechanochemical synthesis of the copper autunites – a new route to remediation of potentially toxic elements Caroline Kirk University of Edinburgh, UK A concept of template-assisted mechanosynthesis for solid-state production of bifunctional fe-n-c oxygen electrocatalyst Akmal Kosimov University of Tartu, Estonia Inspiring Mechanochemical interconversions of halogen-bonded cocrystals by periodic DFT calculations Lavanya Kumar University of Warsaw, Poland

P32

P33

P35

P36

Increasing the applicability of mechanophores Sourabh Kumar University of Bremen, Germany

P37

Liquids with high compressibility: experimental demonstration Beibei Lai Queen’s University Belfast, UK A greener route to blue: solid-state synthesis of phthalocyanines Daniel Langerreiter Aalto University, Finland Mechanochemical non-catalytic methanolysis of poly(bisphenol a carbonate) Hyo Won Lee Jeonbuk National University, South Korea

P38

P39

P40

Solvent-free, lipase-catalyzed lactam synthesis Cameron Lennox McGill University, Canada

P41

Elucidating the compression mechanism of compressible liquids Siyuan Liu Queen’s University Belfast, UK

P42

Mechanochemical synthesis of a Li-K heterobimetallic electride and its versatile reactivity Erli Lu Newcastle University, UK Design strategies of tunable visible-NIR mechanochromism in polymeric materials Xiaocun Lu Clarkson University, USA Halogen-bonded supramolecular capsule functionalizes its guest via mechanochemical Wittig olefination Joseph Marrett McGill University, Canada Solvent-free synthesis of pharmaceuticals by twin-screw extrusion Aaron McCalmont Queens University Belfast, UK

P43

P44

P45

P46

Be all ears to the bead’s tempo: development of a new operando technique to understand what is happening during ball-milling reactions

Sébastien Mittelette ICGM-CNRS, France

P47

Probing the role of energetics in the mechanosynthesis of multicomponent crystal forms Sharmarke Mohamed Khalifa University, United Arab Emirates Highly efficient mechanochemical synthesis of coumarinyl semicarbazides Maja Molnar Faculty of food technology Osijek, Croatia The Ehrenfest force in chemistry: a prospective model for mechanochemistry? Aldo de Jesús Mortera-Carbonell National Autonomous University of Mexico, Mexico

P48

P49

P51

Mechanochemistry in Warsaw Karolina Opała Polish Academy of Sciences, Poland

P53

Harnessing the catalytic activity of copper and vanadium ores by mechanochemistry Francesco Puccetti RWTH Aachen University, Germany Miniaturisation of mechanochemical reactions for parallel synthesis Sarah Raby Buck University College London, UK Mechanochemical pre-treatment leading to sustainable synthesis of microporous and layered titanosilicates Isabel Santos-Vieira University of Aveiro, Portugal From mechanochemistry to biocatalysis: first mechanosynthesis of a gox - iron(iii) trimesate metal organic framework Alessandra Scano Università di Cagliari, Italy Mechanochemical preparation of photothermal agent based on casein- capped CuS nanoparticles proposed by Taguchi design of experiments Martin Stahorský Slovak Academy of Sciences, Slovakia Understanding the mechanochemical effects of SpeedMixing through the lens of pharmaceutical cocrystals Yong Teoh Mcgill University, Canada Ball-milling for the green synthesis of metal-organic frameworks: a design-of-experiment approach Qian Yu University of Exeter, UK State-of-the-art mechano-synthesis of substituted 1,2-naphthoquinones Kenneth Trejos-Cuadra University of Costa Rica, Costa Rica Mechanical activation of zinc and manganese and their application in nickel-catalysed cross-electrophile coupling Matthew Williams Cardiff University, UK

P54

P55

P56

P58

P59

P60

P61

P62

P63

Solventless and template-free synthesis of SOD zeolite Haochen Wu Queen’s University Belfast, UK

P64

Mechenochemical synthesis of hexafluorosilicate(SIFSIX)-containing metal-organic framworks (MOFs) Yizhi Xu University of Warsaw, Poland Mechanochemical synthesis of highly crystalline boroxine-linked covalent organic frameworks (COFs) via trimethylboroxine Ehsan Hamzehpoor Mcgill University, Canada

P66

Self-assembly of organometallic squares through mechanochemical activation of Re-CO bonds

Thomas Auvray , José G. Hernández, Tomislav Friščić* Department of Chemistry, McGill University, Montreal (Canada)

As an efficient methodology for rapid and environmentally-friendly synthesis, mechanochemistry is growing explosively, with notable applications in organic and polymer chemistry, and in the preparation of advanced materials such as metal-organic frameworks and pharmaceutical co-crystals. 1 One area that has been largely neglected until recently is organometallic chemistry. There is only a handful of reports on the mechanochemical formation of species containing metal-carbon bonds, including our own report on the multi-step and multi- component one-pot synthesis of monovalent group VII metal carbonyl complexes. 2 We have indeed shown than one can prepare [M(CO) 3 XL] complexes (where M is Mn(I) or Re(I)), X a halide and L a bidentate ligand such as 1,10-phenanthroline) via multistep, one-pot ball-milling reactions starting from zero-valent metal carbonyl precursors. Following the successful synthesis of these simple mononuclear species, we now turn to the synthesis of more complex organometallic architectures based on these group VII metal carbonyl units, motivated by previous report showing that solvent-free mechanochemical conditions drastically accelerate the formation of the desired self-assembled structure. 3 Rhenium carbonyl supramolecular assemblies have received a lot of attention since the initial report of Slone et al. of a luminescent molecular square. 4 Taking advantage of the redox- and photo- reactivity of rhenium carbonyl species, several synthetic strategies have been developed for the preparation in solution of self-assembled architectures of various shape and nuclearity. Over the course of our study, we showed that during neat milling, mechanochemical activation of the Re-CO bonds takes place and leads to the formation of pre-assembled linear oligomers, previously never isolated, that reorganize rapidly into the targeted molecular squares in solution. References

1. T. Friščić, C. Mottillo, H.M. Titi, Angew. Chem. Int. Ed. , 2020 , 59, 1018–1029 2. J.G. Hernández, I.S. Butler, T. Friščić, Chem. Sci. , 2014 , 5, 3576–3582 3. A. Orita, L. Jiang, T. Nakano, N. Ma, J. Otera, Chem. Commun. , 2002 , 1362–1363 4. V.Slone, J.T. Hupp, C.L. Stern, T.E. Albrecht-Schmitt, Inorg. Chem. , 1996 , 35, 4096-4097

P02

The regioselective synthesis of nanographenes via photo- mechanochemistry Daniel Baier, Carolina Spula, Dr. Sven Grätz, Prof. Dr. Lars Borchardt Ruhr-Universität Bochum, Germany The use of mechanical force to initiate chemical reactions is as old as mankind itself. [1] Likewise, light-induced reactions have been taking place on earth since time immemorial. [2] Both mechanochemistry and photochemistry allow unique reactivities and the synthesis of otherwise inaccessible compounds. The combination of both is a promising approach for the synthesis of new or elusive compounds; for example, by overcoming solubility limitations in photochemical reactions. So far, there has been little work on the combination of irradiation and milling. [3] The main reasons for this are the lack of suitable equipment and the violent milling environment. In this contribution we present our work in the field of photo-mechanochemistry. [4] We present our custom-made photoreactor for performing solid-state reactions and show how nanographenes, a notorious poorly soluble compound class, can be synthesized using this method. Specifically, we use two examples - the Mallory reaction and the cyclodehydrochlorination (CDHC) - to show how photochemical reactions can be carried out with almost complete solvent avoidance. Building on these results, we show how the CDHC can be used for the regioselective synthesis of nanographenes using two larger polyphenylene compounds. This is the first work on the combination of milling and UV light and the first report on the regioselective assembly of nanographenes using mechanochemistry. References 1. L. Takacs, Chem. Soc. Rev. 2013, 42, 7649. 2. H. D. Roth, Angew. Chem. Int. Ed. Engl. 1989, 28, 1193.

3. T. Friščić, Angew. Chem. Int. Ed. 2020, 59, 1018. 4. D. Baier, Manuscript under preparation, 2022.

P03

Mechanochemically driven 3D heterostructuring of metal chalcogenides

Viktor P. Balema ProChem Inc., USA

The presentation discusses generation of 3D-heterostructures with incommensurate arrangements from well-defined building blocks using unconventional synthetic approach, comprising mechanochemically facilitated reshuffling of layered transition-metal dichalcogenides MX 2 [1,2], and non-layered rare-earth metal monochalcogenides REX to form MX 2 /M’X 2 or (REX) n MX 2, nano-assemblies, where M (M’) = W, Mo, Ta, Nb; RE = Sm, and X = S or Se [3]. The discovered solid-state transformations are directed by atomic-scale interaction between chemically and structurally similar or dissimilar solids toward ordering.In the case of the layered MoS 2 and HfS 2 [1], 3D-heterostructuring is energetically favorable over alloying in M'X 2 - MX 2 systems, where M,M' = W, Mo, Ta, Nb, and X = S, or Se [2]. Density-functional theory calculations validated experimental results. The obtained 3D-hetero assemblies demonstrate diverse electron transport behavior, varying from metallic conductivity to indirect band gap semiconductivity, and superconductivity in some misfit heterostructures [1,3,4]. Potential scale up of mechanochemical processes will be discussed as well. References 1. Z. Hlova et al. Nanoscale Adv. (2021),3, 4065 Z. Hlova et al. Chem. Commun. (2018),54,12574 Dolotko et al. Nat. Commun. (2020),11,3005 B. Sreedhara et al. Chem. Mater. (2022), 34, 1838

P04

The role of liquid amount in organic mechanochemical reactions investigated by resonant acoustic mixing (RAM) Linda Bechnak a , Robin S. Stein b , Hatem M. Titi a , Stefan Koenig c , Karthik Nagapudi c and Tomislav Friščić a a Department of Chemistry, McGill University, Canada, b MC2 Facility, NMR/EPR,McGill University, Canada, c Genentech, One Dna Way, South San Francisco, USA Although mechanochemistry has been established as a powerful tool for green and sustainable synthesis 1-3 , parameters that control the outcome of mechanochemical reactions are not yet well understood. One important parameter is the liquid additive, known to frequently strongly influence mechanochemical reaction pathways. Whereas a limited amount of work has been dedicated to the role of liquid amount, expressed as the parameter η , in context of cocrystallization, 4,5 there are little to no studies in the context of organic mechanochemical transformations. 6 This work investigates how the amount of liquid additive affects mechanochemical organic reactions, based on resonant acoustic mixing (RAM) technique 7,8 and Schiff base condensation as a model reaction. The reaction model chosen allowed us to study the effect of η on the stoichiometric outcome as well, providing a rare example of a systematic study capable of directly comparing neat reactions to those conducted at low η values (identical to those used in liquid-assisted grinding), as well as slurry and solution conditions. References 1. Do, J.-L.; Friščić, T. ACS Cent. Sci. 2017 , 3 , 13-19.

2. Andersen, J.; Mack, J. Green Chem . 2018 , 20 , 1435-1443 3. Moores, A. Curr. Opin. Green Sustain. Chem. 2018 , 12 , 33-37. 4. Friščić, T. et al . CrystEngComm. 2009, 11 , 418-426. 5. Hasa, D.; Miniussi, E.; Jones, W. Cryst. Growth Des. 2016 , 16 , 4582–4588. 6. Chen, L.; Regan, M.; Mack, J. ACS Catal. 2016 , 6 , 868–872. 7. Nagapudi, K.; Umanzor, E. Y.; Masui, C. Int. J. Pharm. 2017 , 521 , 337-345. 8. Titi, H. M.; Do, J.-L.; Howarth, A. J.; Nagapudi, K.; Friščić, T. Chem. Sci. 2020 , 11 , 7578-7584.

P05

Temperature controlled, mechanochemical balling milling and twin- screw extrusion Robert R. A. Bolt a , Sarah Raby Buck a , Jamie A. Leitch a , Duncan L. Browne a and Katharine Ingram b a UCL, United Kingdom, b Syngenta, United Kingdom Introduction Whilst primarily mechanochemical reactions are limited to room temperature reactions, their solution counterparts often utilise increased temperatures to improve reaction efficiency as well as reduce reaction times. The addition of heat to mechanochemical reactions has come under increasing interest within the field and has already been demonstrated to have significant positive effects upon the expansion of reaction scopes as well as unlocking new pathway. [1] Results and Discussion At the outset of this project, we aimed to transition away from the stark over-reliance on palladium complexes to more earth-abundant, inexpensive metal systems. This was achieved through the implementation of a controllable heating device to rapidly form new C-C bonds from aryl sulfamate and boronic acid precursors, wherein optimal temperature and heating regimes were determined. [2] Exploration of the scope led to the determination of the reaction’s dependency upon heat to enable C-C bond formation in our nickel-catalysed system. In addition, we have successfully scaled the reaction using twin screw extrusion technology which enabled us to increase product synthesis more than 100-fold to decagram scale. [3]

Conclusions and Outlook It has been demonstrated that the use of temperature-controlled device in conjunction with mechanochemistry can reduce reaction times as well as activate previously inert compounds. Furthermore, it has been shown that the application of this heat system can be readily scaled to a flow‑like system to synthesis on gram scale, and further explorations into this transition is underway. References 1. Seo, N. Toyoshima, K. Kubota and H. Ito, J. Am. Chem. Soc ., 2021 , 143 , 6165–6175 2. Bolt, R. R. A.; Raby‑Buck, S. E.; Ingram, K.; Leitch, J. A.; Browne, D. L. Manuscript in Preparation 3. Bolt, R. R. A.; Leitch, J. A.; Jones, A. C.; Nicholson, W. I.; Browne, D. L. Soc. Rev. , 2022 , 51, 4243-4260

P06

Light-induced mechanical effects on crystals: from soft to catastrophic Tristan H. Borchers , Christopher J. Barrett, and Tomislav Friščić McGill University, Canada The past decade has seen an increased interest in photo-responsive and optical materials, namely materials which engage with light to produce desired, predictable responses. Polymers and liquid crystalline optical materials have been well-studied over the past 30 years, revealing materials that exhibit significant photo- mechanical effect, i.e., mechanical bending upon irradiation by visible or ultraviolet (UV) light. Our interest lies in the study and design of crystalline materials exhibiting photo-mechanical behavior and this presentation will outline the light-responsive behavior of organic single- and multi-component crystals (co-crystals) involving azobenzene dyes. Specifically, we will outline how the use of trans - and cis - isomers of a fluorinated azobenzene capable of acting as a halogen bond donor can lead to a wide diversity of new photo-responsive materials, exhibiting behavior that can be mild, such as changes in colour, or more profound, such as mechanical bending, 1,2,3 or even leading to crystal disintegration that can be used to enable micrometer-precision machining. 4 In particular, we will present a novel cocrystal material that can exhibit all three types of photo-responsive behavior depending on the density of applied visible laser radiation. References 1. Bushuyev, O. S., Tomberg, A., Friščić, T. & Barrett, C. J. Shaping Crystals with Light: Crystal-to-Crystal Isomerization and Photomechanical Effect in Fluorinated Azobenzenes. Journal of the American Chemical Society 135 , 12556-12559, doi:10.1021/ja4063019 (2013). 2. Bushuyev, O. S., Singleton, T. A. & Barrett, C. J. Fast, Reversible, and General Photomechanical Motion in Single Crystals of Various Azo Compounds Using Visible Light. Advanced Materials 25 , 1796-1800, doi:10.1002/adma.201204831 (2013). 3. Bushuyev, O. S., Corkery, T. C., Barrett, C. J. & Friščić, T. Photo-mechanical azobenzene cocrystals and in situ X-ray diffraction monitoring of their optically-induced crystal-to-crystal isomerisation. Chem. Sci. 5 , 3158-3164, doi:10.1039/ c4sc00987h (2014). 4. Borchers, T. H. et al. Cold photo-carving of halogen-bonded co-crystals of a dye and a volatile co-former using visible light. Nature Chemistry 14 , 574-581, doi:10.1038/s41557-022-00909-0 (2022).

P07

Exploring the polymorphism of sofosbuvir via mechanochemistry: effect of milling jar geometry and material Argyro Chatziadi 1 , Eliška Skořepová 1,3 , Martin Kohout 1 , Luděk Ridvan 2 , Miroslav Šoóš 1 1 Department of Chemical Engineering,University of Chemistry and Technology Prague, Czech Republic, 2 Zentiva, k.s., U kabelovny 130, Czech Republic, 3 Institute of Physics of the Czech Academy of Sciences, Czech Republic Mechanochemistry has been used as a green and sustainable method to explore the polymorphism of several active pharmaceutical ingredients. 1 Until now, many experimental conditions have been investigated to understand how they affect polymorphic transformations, such as the nature and amount of liquid additive 2 and the type and number of milling balls 3 . However, the effect of the properties of the milling jar started to be explored only recently. 4 In this study we investigate and compare the polymorphic transformations of sofosbuvir in stainless steel and polypropylene jars. Interestingly, it is observed that in polypropylene jars, not only the rate of transformation is faster but also the conditions that are developed during these experiments favour the formation of a new form of sofosbuvir, not observed in stainless steel jar experiments. Analysis of the energetics of the system shows that these results are a consequence of the different geometry of the jars and of a significant rise in temperature due to the properties of the material. These findings are an important step toward understanding and even predicting how the choice of jar material affects the kinetics and polymorphic transformation of an active pharmaceutical ingredient during milling. References 1. D. Hasa and W. Jones, Advanced Drug Delivery Reviews , 2017, 117, 147–161. 2. A. Chatziadi, E. Skořepová, J. Rohlíček, M. Dušek, L. Ridvan and M. Šoóš, Crystal Growth and Design , 2020, 20 , 139–147. 3. F. Fischer, N. Fendel, S. Greiser, K. Rademann and F. Emmerling, Organic Process Research & Development , 2017, 21 , 655–659. 4. L. S. Germann, M. Arhangelskis, M. Etter, R. E. Dinnebier and T. Friščić, Chemical Science , 2020, 11 , 10092–10100.

P09

Rapid and solventless chlorination of pyrazoles by ball milling Jia-Xin CHEN , Chi-Min CHEN, Ching Tat TO* Department of Chemistry, Tunghai University, Taiwan Mechanochemical reaction via ball milling utilized the absorption of mechanical energy from friction between grinding ball and reactant in a grinding jar. There are increasing practices of mechanochemistry because of these advantages: (1) solventless (2) room temperature; and (3) enhanced reaction rate and product yield. 1 In this work, various substituted pyrazoles were chlorinated with only slight excess of trichloroisocyanuric acid (TCCA) in a mixer-type ball mill to afford the corresponding 4-chloropyrazoles in good yields. This reaction is aimed to employ no solvent and is carried out at room temperature. Simple filtration workup provided NMR spectroscopically pure products without column chromatography. Gram-scale synthesis is feasible. Mechanistic studies through competition experiments suggested an electrophilic aromatic substitution mechanism.

References 1. Howard, J. L.; Cao, Q.; Browne, D. L. Chem. Sci. 2018 , 9 , 3080-3094.

P10

Sustainable polymer chemistry of high-performance materials by mechanochemistry Niamh Curran and Stuart James Queen’s University Belfast, Northern Ireland Benzoxazines are an advanced type of phenolic resin with attractive properties for aerospace applications. They are characterised as possessing a relatively long shelf life and offer considerable molecular-design flexibility. The monomers are formed by melt-synthesis, which is typically solventless, followed by ring opening polymerisation to give the polybenzoxazines. 1 The batch reactor processes, currently used to produce benzoxazine monomer and formulations thereof are time and energy intensive and plagued by batch-to-batch variations. Extrusion methods enable scaling of mechanochemical and melt phase synthesis under continuous, solvent-free or low-solvent conditions. Some examples of organic reactions that have been successfully demonstrated using twin screw extrusion (TSE) include Knoevenagel condensation, imine formation, aldol reaction and the Michael addition. 2 TSE has been demonstrated as a suitable reactor technology to synthesize benzoxazines monomers and polymers, but greater understanding is required. Here we will discuss the use of TSE to form benzoxazine monomers. References 1. D. Allen and H. Ishida, Polymer , 2009, 50 , 613-626 2. D. E. Crawford, C. K. G. Miskimmin, A. B. Albadarin, G. Walker and S. L. James, Green Chem. , 2017, 19 , 1507-1518

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From molecules in solution to molecules on surfaces – using supramolecular dyads to form functional self-assembled networks on graphene Quentin Fernez a , Shiva Moradmand b , Michele Mattera a , William Djampa-Tapi c , Céline Fiorini-Debuisschert c , Fabrice Charra c , David Kreher d , Fabrice Mathevet ab , Imad Arfaoui b and Lydia Sosa Vargas a * a Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire (IPCM), France, b Sorbonne Université, CNRS, Laboratoire de la Molécule aux Nano-Objets : Réactivité, France, c Université Paris-Saclay, CEA-CNRS, France, d Université Versailles St-Quentin-en-Yvelines, France Using supramolecular chemistry to functionalise graphene for photonic applications is a challenging issue due to graphene’s capacity to quench any emission from molecules adsorbed on its surface. To overcome this problem, we propose the use of molecular dyads to form ordered self-assemblies on graphene-like substrates. These dyads are designed to reduce surface quenching by positioning the emissive component out-of-the plane of the substrate. We use a zinc porphyrin and a phthalocyanine as molecular pedestals to immobilise the dyads onto the graphene thanks to a nanoporous network; and a perylenetetracarboxylic diimide, as the emissive component. In order to obtain reproducible, functional, 2D self-assemblies on graphene from two different sets of molecules, we need to identify and characterise precisely the species present in the solution. So, we studied the formation of these dyads by absorbance, fluorescence and NMR spectroscopy in solution. We then analysed their self- assembling properties by scanning tunnelling microscopy; after drop-casting the dyad solutions on a nanoporous template. In solution, we demonstrate that these components can form two types of dyads, depending on the supramolecular interactions that dominate the equilibrium in the solution. A metal-ligand association was observed between the perylene and the porphyrin pedestal, whilst the phthalocyanine led to a dyad formed via π-π interactions. Finally, from STM observations, we conclude that the same dyads present in the solution are present on the surface. References 1. A. K. Geim and K. S. Novoselov, Nature Materials, 2007, 6, 183–191. 2. N. Petrone, C. R. Dean, I. Meric, A. M. van der Zande, P. Y. Huang, L. Wang, D. Muller, K. L. Shepard and J. Hone, NanoLett., 2012, 12, 2751–2756. 3. C. Anichini and P. Samorì, Small, 2021, 17, 2100514. 4. V. Georgakilas, M. Otyepka, A. B. Bourlinos, V. Chandra, N. Kim, K. C. Kemp, P. Hobza, R. Zboril and K. S. Kim, Chem. Rev., 2012, 112, 6156–6214. 5. S. Le Liepvre, P. Du, D. Kreher, F. Mathevet, A.-J. Attias, C. Fiorini-Debuisschert, L. Douillard and F. Charra, ACS Photonics, 2016, 3, 2291–2296. 6. L. Sosa-Vargas, E. Kim and A.-J. Attias, Mater. Horiz., DOI:10.1039/C7MH00127D 7. F. Würthner, C. R. Saha-Möller, B. Fimmel, S. Ogi, P. Leowanawat and D. Schmidt, Chem. Rev., 2016, 116, 962–1052. 8. C. Arrigoni, G. Schull, D. Bléger, L. Douillard, C. Fiorini-Debuisschert, F. Mathevet, D. Kreher, A.-J. Attias and F. Charra, J. Phys. Chem. Lett., 2010, 1, 190–194. 9. Q Fernez, S. Moradmand, M. Mattera, W. Djampa-Tapi, C. Fiorini-Debuisschert, F. Charra, D. Kreher, F. Mathevet, I. Arfaoui and L. Sosa Vargas, unpublished results, submitted recently to J. Mat. Chem. C, 2022.

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Exploring neat grinding and liquid-assisted-grinding to obtain different polymorphs of curcumin and its Schiff base curcumin derivatives Aniele De Moura a , Alexandre Cuin b , Flávio Junior Caires a a UNESP, School of Sciences, Chemistry Department, Brazil, b Chemistry Department, Federal University of Juiz de Fora, Brazil Curcumin is a turmeric that presents several biological applications, among them: antioxidant, anti-inflammatory, and antitumor activity, however, it presents low bioavailability, due to its low solubility in water. 1 To overcome this problem, several researchers work on the development of curcumin derivatives, such as Schiff bases, which can potentialize its properties. In this way, the eco-friendly mechanochemical method was applied to obtain a curcumin glycine Schiff base derivative (CGD). 2 The syntheses were carried out in a Restch mixer mill 400 MM, under 20 Hz of frequency, sing a stainless-steel jar (10 mL) and a stainless-steel ball (7 mm). The authors have also evaluated if CGD could be obtained by neat-grinding (NG) and Liquid-Assisted-Grinding (LAG). After the NG synthesis, it was observed a product with an orange coloration (NG CGD), while at the end of the LAG synthesis it was observed a yellow compound (LAG CGD). These compounds were evaluated by ¹H NMR, which confirmed the obtention of the Schiff bases. The liquid used in LAG syntheses can enable the generation of several polymorphs, therefore, NG CGD and LAG CGD were analyzed by XRD (powder), and the results suggested that it was obtained two polymorphs for each synthesis (Figure 1.a). Moreover, it is the knowledge 3 polymorphs of curcumin (CUR), which normally can be obtained by using organic solvents through different crystallization methods, then it was evaluated if curcumin (CUR) could generate different polymorphs under solid-state synthesis. 1 CUR was milled, using the same conditions applied for CGD, as a result, it was observed that it displays different colorations at the end of NG (orange product) and LAG (yellow product) syntheses. The XRD diffractograms confirmed the obtention of different polymorphs (Figure 2.a). Comparing the experimental and theoretical diffractogram of curcumin, it was observed that NG CUR presents a mixture of polymorphs in Form I and III, while the LAG presents a polymorphic structure related to the Form I. 2

Figure 1. XRD powder diffractograms of NG and LAG CGD (a), CUR, NG CUR and LAG CUR (c), and, CGD milled with different amounts of ethanol (c).

Furthermore, it has been already reported that the amount of liquid in LAG synthesis is a parameter that influences the obtention of polymorphs, 2 therefore, the authors evaluated how the amount of liquid can influence in CGD polymorphism. The diffractograms displayed in Figure 1.c show that the polymorphism interconversion occurs with an eta parameter (h) higher than 0.06 mL/mg. In summary, the authors concluded that the mechanochemical method can be applied to obtain different polymorphs of curcumin and its curcumin-glycine Schiff base, in addition, a liquid can be used to control the polymorphic form of these compounds, considering an h ≈ 0.07-0.16- μL/mg for each synthesis. References

1. New polymorphs of curcumin. Chem Comm . 2011. 2. Mechanochemistry for Synthesis. Angew Chem . 2020.

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Mechanochemistry: a green and efficient tool to obtain curcumin derivaties with a functionalized ω-poly(ethylene glycol) Aniele de Moura a , Caroline Gagilieri a , Luiz Octávio Terciotti a , Daniel Rinaldo b and Flávio Junior Caires a,b a School of Sciences, Chemistry Department, Brazil, b Institute of Chemistry,UNESP-São Paulo State University, Brazil Curcumin is a yellow polyphenolic compound, present in Curcuma longa L. (turmeric) rhizome.¹ This compound displays a broad spectrum of biological activity, among them: antioxidant, anti-inflammatory, antitumor, and antibacterial activity; however, it is soluble in water, resulting in low bioavailability.¹ In this way, several authors have synthesized curcumin derivatives aiming to improve their properties and/or solubility. An alternative is the functionalization of these compounds with poly (ethylene glycol), which can improve its solubility in water.² However, the syntheses of Schiff bases, functionalization of poly (ethylene glycol), and also Steglich esterification, are commonly proceeded in solution, requiring long time synthesis. 1,3 Based on these, this works deals with the mechanochemical syntheses of a curcumin Schiff Base (DCG), a ω-poly (ethylene glycol) functionalized (PEG_SA), and then by esterification of the synthesized curcumin Schiff base (DCG_MONO and DCG_DIES). All the syntheses were carried out on a Retsch Mixer Mill MM 400 (Retsch, Germany), in 10 mL stainless steel or zirconium oxide jars, using one stainless steel or zirconium oxide ball. The synthesis of DCG was proceeded by milling curcumin and Glycine. After the synthesis, the compound was purified by washing with water. The synthesis of PEG_SA was carried out by milling PEG 8000 and succinic anhydride in the presence of triethylamine. The product was purified by organic extraction (water: toluene), then the aqueous solution was evaporated and purified PEG_SA was obtained. Finally, the esters (DCG_MONO and DCG_DIES) were obtained by the Steglich esterification protocol (Figure 1). The esterification was proceeded by milling PEG_SA with 4-dimethylaminopyridine (DMAP-1 st step), then it was added N,N'-Dicyclohexylcarbodiimide (DCC) in the jar (2 nd step), the 3 rd step of the reaction is followed by the addition of DCG in the jar. To obtain DCG_ MONO it was used 1 mmol of DCG, while to obtain DCG_DIES it was used 2 mmol of DCG. The purification of

the products was proceeded using cold dichloromethane. Figure 1: Reaction synthesis scheme of DCG_MONO and DCG_DIES.

All the products were characterized by FTIR and ¹H NMR, which confirmed the obtention of the suggested structures. By these results, the authors conclude that the mechanochemical method was an efficient tool that makes possible the obtention of different compounds class by solid-state reactions. References 1. A review on biological activities of Schiff base, hydrazone, and oxime derivatives of curcumin. 2020. 2. Solid-state mechanochemical ω-functionalization of poly(ethylene glycol). 2017. 3. One-pot synthesis of Curcumin-NSAIDs prodrug, spectroscopic characterization, conformational analysis, chemical reactivity, intramolecular interactions and first order hyperpolarizability by DFT method. 2016.

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Mechanochemical self-assembly of cavity-containing anionic salicylic acid-based metallostructures Jean-Louis Do 1,2 , Farshid Effaty 1,2 , Thomas Auvray 2 , Hatem M. Titi 2 , Xavier Ottenwaelder 1 , Louis A. Cuccia 1 , and Tomislav Friščić 2 1 Department of Chemistry and Biochemistry, Concordia University, Canada, 2 Department of Chemistry, McGill University, Canada Supramolecular metallostructures have contributed significantly towards our understanding of self-assembly, molecular recognition, interactions with biologically relevant molecules, catalysis, and design of therapeutics. 1-3 Studies on these materials, however, have largely focused on the synthesis of cationic and neutral systems. The preparation of new and complex anionic structures as functional materials has been scarce and further hindered by the conventional limitations of solution-based chemistry, particularly reactant solubility and the need for varying levels of dilution to achieve high selectivity and obtain crystalline materials. We now describe the potential to exploit mechanochemistry as a mild, rapid, scalable, and environmentally friendly means to access a number of new anionic, salicylic acid-based helicates, pseudohelicates, and cages independent of specialized reaction conditions. 4-6 We demonstrate how these structures can be self-assembled via a ball milling strategy from tri- and tetravalent metal cations in the presence of methylene-bridged salicylic acids using liquid- and ion-and-liquid-assisted grinding (LAG and ILAG, respectively). We demonstrate the different nuances of their self-assembly in solution versus in the solid state, as well as in the presence of various inorganic and organic cations. We further discuss the implications of this mechanochemical methodology on the discovery of new anionic solids and functional materials. References

1. C. Piguet, G. Bernardinelli, and G. Hopfgartner, Chem. Rev. , 1997 , 97 , 2005-2062. 2. Y. Fang, W. Gong, L. Liu, Y. Liu, and Y. Cong, Inorg. Chem. , 2016 , 55, 10102-10105. 3. L. Wang et al. , Chem. Commun. , 2018 , 54 , 2212-2215. 4. J.-L. Do, H. M. Titi, L. A. Cuccia, and T. Friščić, Chem. Commun. , 2021 , 57 , 5143-5146.

5. P. Cucos, M. Pascu, R. Sessoli, N. Avarvari, F. Pointillart, and M. Andruh, Inorg. Chem. , 2006 , 45 , 7035-7037. 6. P. Cucos, L. Sorace, C. Maxim, S. Shova, D. Patroi, A. Caneschi, and M. Andruh, Inorg. Chem. , 2017 , 56 , 11668-11675.

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Solid-state synthesis of BINOLs by copper-based catalysis Farshid Effaty 1,2 , Patrick A. Julien 1 , Xavier Ottenwaelder* 2 , Tomislav Friščić* 1 1 Chemistry Department, McGill University, Canada, 2 Chemistry and Biochemistry Department, Concordia University, Canada Mechanochemical reactions, particularly those involving ball milling, are increasingly being investigated as a means of achieving greener, more efficient, and novel reactivity in the absence of bulk solvents. Catalytic milling reactions have received few reports, and their reactivity is poorly understood.[1] The mechanochemical synthesis of 1,1-bi-2-naphthol (BINOL) and derivatives, a versatile family of ligands used in a wide range of metal-based and organocatalytic systems, is presented here. The presentation will specifically describe a catalytic mechanochemical approach for the synthesis of BINOL via a copper-catalyzed C-H activation and compare it to previously reported solution reactivity. The results show that mechanochemical synthesis of BINOL can proceed faster and at lower temperatures than equivalent solution syntheses, while also providing an excellent model for fundamental studies of the behavior of catalytic milling reactions of crystalline solids, based on real-time monitoring using in situ techniques such as powder X-ray diffraction and hot-stage microscopy. References 1. M. Nakajima, S. Hashimoto, M. Noji, and K. Koga, “Aerobic Oxidative Coupling of 2-Naphthol Derivatives Catalyzed by a Copper-Amine Complex without Solvent,” Chem. Pharm. Bull. , 1998 , 46 . 1814-1815.

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Substituent effects on tribochemical processes James P. Ewen, Jie Zhang, Carlos Ayestarán Latorre, Daniele Dini and Hugh A. Spikes Department of Mechanical Engineering, Imperial College London, UK Tribometer experiments using high-friction and low-friction base oils have shown that the tribofilm formation by the lubricant additive zinc dialkyldithiophosphate (ZDDP) increases exponentially with shear stress [1]. The rate of this mechanochemical process can be described using the Bell model. Commercial ZDDPs containing mostly secondary alkyl groups form tribofilms much faster than those with primary alkyl groups, with the main difference being the pre-exponential factor (rather than the activation energy or activation volume) [2]. The same observation has recently been made from reactive nonequilibrium molecular dynamics (NEMD) simulations of trialkyl phosphates. Here, using carefully designed tribometer experiments under well-controlled conditions, we show how the mechanochemical reactivity of ZDDP can be altered by tailoring the additive's alkyl substituents. Specific examples include the observations that additives with long alkyl chains only form tribofilms at high temperature, while those containing bulky cycloaliphatic groups are particularly effective at high stress. We expect these findings to be useful for the rational design of high-performance lubricant additives for specific applications [4]. References 1. Zhang, J; Spikes, H.A. On the Mechanism of ZDDP Antiwear Film Formation. Tribol. Lett. 2016, 63, 24. https://doi. org/10.1007/s11249-016-0706-7 2. Zhang, J.; Ewen, J.P.; Ueda, M.; Wong, J.S.S.; Spikes, H.A. Mechanochemistry of Zinc Dialkyldithiophosphate on Steel Surfaces under Elastohydrodynamic Lubrication Conditions. ACS Appl. Mater. Interfaces 2020, 12, 6662–6676. https://doi. org/10.1021/acsami.9b20059 3. C. Ayestarán Latorre, J.E. Remias, J.D. Moore, H.A. Spikes, D. Dini, J.P. Ewen. Mechanochemistry of Phosphate Esters Confined between Sliding Iron Surfaces. Commun. Chem. 2021 4, 178.https://doi.org/10.1038/s42004-021-00615-x 4. Zhang, J.; Ewen, J.P.; Spikes, H.A. Substituent Control of Mechanochemical Tribofilm Formation. Mol. Syst. Des. Eng. 2022. https://doi.org/10.1039/D2ME00049K

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Direct insights into the liquid assisted grinding environment from molecular dynamics simulations Michael Ferguson 1 , Yonger Xie 1 , Audrey Moores 1,2,3 and Tomislav Friščić 1 1 Department of Chemistry, McGill University, Canada, 2 Centre in Green Chemistry and Catalysis, Department of Chemistry, McGill University,Canada, 3 Department of Materials Engineering, McGill University, Canada Mechanochemical strategies are continually proving to be of high importance in the development of more sustainable strategies for the synthesis of a wide range of molecular targets and functional materials. One of the most successful mechanochemical strategies is liquid assisted grinding (LAG), where small amounts of liquid are added to solid-state reaction systems. 1 The inclusion of liquid additives, where the liquid-to-solids ratio ( η )is usually below 2 μL per mg , has been shown to improve reaction yields, reduce reaction times, and provide access to previously unobtainable solid products. 1 However, we do not yet have a complete description of the LAG environment. In this work classical force field molecular dynamics are employed to study how varying amounts of a liquid additive affect the mobility of aryl N-thiocarbamoylbenzotriazole molecules in the solid-state, revealing a substantial disruption of the solid structure upon increasing η . Evaluating the molecular mobility and localized molecular distributions at different η values provides much-needed microscopic insights into the role of liquid additives in enhancing solid-state reactivity. References 1. T. Friščić, C. Mottillo and H. Titi, Angew.Chem.Int.Ed. , 2019, 59 , 1018-1029.

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Co-crystals of antibiotics with natural antimicrobials: product diversity resulting from different synthetic approaches Cecilia Fiore 1 , Oleksii Shemchuk 2 , Alessandra Baraghini 3 , Simone d’Agostino 1 , Vittorio Sambri 3,4 , Manuela Morotti 3 , Silvia Zannoli 3 , Fabrizia Grepioni 1 and Dario Braga 1 1 Dipartimento di Chimica “Giacomo Ciamician”, Università di Bologna, Italy, 2 Institute of Condensed Matter and Nanosciences, UCLouvain, Belgium, 3 U.O. Microbiologia - Laboratorio Unico Centro Servizi AUSL Romagna, Italy, 4 Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale Università di Bologna, Italy The phenomenon of antimicrobial resistance is one of the major medical challenges in most healthcare systems [1] in which common pathogenic strains are developing antibiotic-resistant genes. The quest for new antimicrobial agents obtained through conventional organic synthesis can nowadays be supplemented by supramolecular interactions designed with a crystal engineering approach[2]. Recently Desiraju et al. reported a multicomponent solid consisting of an antibacterial (norfloxacin) and an antimicrobial (sulfathiazole) showing enhancement of in vitro biological activity and improved physicochemical behavior [3]. Following this path, we apply co-crystallization strategies as a viable, eco-friendly, and inexpensive way to obtain new materials with modified properties [4,5]. In our latest work [6] we have prepared and structurally characterized co-crystals of three similar antibiotics of the cephalosporin (CFS) class, namely cephalexin, cefradine, and cefaclor, with thymol as the co-former. The reaction between cephalosporins and thymol was performed using three different methods: solution, slurry, and mechanochemical liquid-assisted grinding, with resulting product diversity and stability. In recent work [7], we have reported that co-crystallization of the antibiotic ciprofloxacin with thymol and carvacrol shows an increment in the antibacterial activity as compared to the starting materials and their physical mixtures. The project herein presents analogous experiments, involving the antibiotics of the CFS class, which unexpectedly show a significant increase in the minimal inhibitory concentration. References 1. Brown and Wright, Nature , 2016 , 529, 336. 2. Wouters, Quéré, Pharmaceutical salts and co-crystals , Royal Society of Chemistry, 2011 . 3. Gopi, Ganguly , Desiraju, Mol. Pharm. , 2016 , 13, 3590. 4. Shemchuk, Braga, Grepioni, Turner, RSC Adv. , 2020 , 10, 2146. 5. Fiore, Shemchuk, Grepioni, Turner, Braga, CrystEngComm , 2021 , 23, 4494.

6. Fiore, Baraghini, Shemchuk, Sambri, Morotti, Grepioni, Braga, Cryst. Growth Des . 2022 , 22, 1467. 7. Shemchuk, d’Agostino, Fiore, Sambri, Zannoli, Grepioni, Braga, Cryst. GrowthDes. , 2020 , 20, 6796.

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