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Mechanochemical Synthesis of Organic Compounds
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Mechanochemical Synthesis of Organic Compounds

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Organic Chemistry".

Deadline for manuscript submissions: closed (15 December 2022) | Viewed by 31671

Special Issue Editor

Prof. Dr. Michel Baron

E-Mail Website
Guest Editor
Université de Toulouse, IMT Mines Albi, CNRS UMR 5302, Centre RAPSODEE, Campus Jarlard, CEDEX 09, 81013 Albi, France
Interests: green chemistry; medicinal chemistry; mechanochemistry; sustainable processes; scaling-up; theoretical chemistry

Special Issue Information

Dear Colleagues,

The aim of this Special Issue is to provide an updated overview of mechanochemical synthesis of organic compounds.

In recent years, organic mechanochemistry has developed rapidly due to its many advantages in terms of green processes: it needs less or no solvent and can be considered an economical and eco-responsible process.

Usually, mechanochemical organic reactions are carried out in ball mills, and recently also using twin-screw extrusion allowing continuous processes. The reactions are often conducted on mixtures of solids, sometimes in the presence of small amounts of water or solvent.

One difficulty is the characterization of the mixture during the process if compared to a classical solvent process. However, some techniques have been adapted and developed to potentially control organic mechanochemical processes, reactions, and kinetics in real time: NIR, Raman, NMR spectroscopy, X-Ray spectrometry, etc.

One important challenge is to understand what occurs during a mechanochemical process: depending on the reagents and operating conditions, various events can take place: hot spots, partial solubility, local melting, eutectics, etc. How mechanical stress is transmitted to powders, then from powders to orbitals is a matter of importance. Recent studies have shown that an external force can decrease the activation energy of an organic reaction and allow specific transformations.

The future is still to be explored to gain access to specific molecules that are difficult to synthesize, to develop green processes, and to scale them up, to control reactions and avoid mass effects at industrial scale.

Finally, one goal and future challenge would be to progress in the understanding and explanation of the transfer of energy at different scales (macroscopic and microscopic), from external forces to powders, crystals, molecules, and orbitals during mechanochemical syntheses, and toward the possible formalization of specific mechanochemical rules still to be developed.

This open-access Special Issue opens the door to original advanced exploration of all these theoretical, experimental, and industrial aspects. Full research articles and reviews covering these topics are welcome.

Prof. Dr. Michel Baron
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • mechanochemistry
  • green synthesis
  • organic synthesis
  • ball-milling
  • characterization
  • mechanisms
  • orbitals
  • scaling-up

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Published Papers (9 papers)

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Research

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21 pages, 960 KiB  
Article
Reshuffle Bonds by Ball Milling: A Mechanochemical Protocol for Charge-Accelerated Aza-Claisen Rearrangements
by Christian Schumacher, Lieselotte Fritz, Lena M. Hanek, Vitali Sidorin, Daniel Brüx and Carsten Bolm
Molecules 2023, 28(2), 807; https://doi.org/10.3390/molecules28020807 - 13 Jan 2023
Cited by 3 | Viewed by 3032
Abstract
This study presents the development of a mechanochemical protocol for a charge-accelerated aza-Claisen rearrangement. The protocol waives the use of commonly applied transition metals, ligands, or pyrophoric Lewis acids, e.g., AlMe3. Based on (heterocyclic) tertiary allylamines and acyl chlorides, the desired [...] Read more.
This study presents the development of a mechanochemical protocol for a charge-accelerated aza-Claisen rearrangement. The protocol waives the use of commonly applied transition metals, ligands, or pyrophoric Lewis acids, e.g., AlMe3. Based on (heterocyclic) tertiary allylamines and acyl chlorides, the desired tertiary amides were prepared in yields ranging from 17% to 84%. Moreover, the same protocol was applied for a Belluš–Claisen-type rearrangement resulting in the synthesis of a 9-membered lactam without further optimization. Full article
(This article belongs to the Special Issue Mechanochemical Synthesis of Organic Compounds)
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Scheme 1

11 pages, 1792 KiB  
Article
N-Formylsaccharin: A Sweet(able) Formylating Agent in Mechanochemistry
by Federico Cuccu, Francesco Basoccu, Claudia Fattuoni and Andrea Porcheddu
Molecules 2022, 27(17), 5450; https://doi.org/10.3390/molecules27175450 - 25 Aug 2022
Cited by 5 | Viewed by 2795
Abstract
The acylation of amines has always attracted a deep interest as a synthetic route due to its high versatility in organic chemistry and biochemical processes. The purpose of this article is to present a mechanochemical acylation procedure based on the use of acyl-saccharin [...] Read more.
The acylation of amines has always attracted a deep interest as a synthetic route due to its high versatility in organic chemistry and biochemical processes. The purpose of this article is to present a mechanochemical acylation procedure based on the use of acyl-saccharin derivatives, namely N-formylsaccharin, N-acetylsaccharin, and N-propionylsaccharin. This protocol furnishes a valuable solvent-free alternative to the existing processes and aims to be highly beneficial in multi-step procedures due to its rapid and user-friendly workup. Full article
(This article belongs to the Special Issue Mechanochemical Synthesis of Organic Compounds)
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Graphical abstract

23 pages, 3227 KiB  
Article
Synthesis of Mixed Dinucleotides by Mechanochemistry
by Faisal Hayat, Mikhail V. Makarov, Luxene Belfleur and Marie E. Migaud
Molecules 2022, 27(10), 3229; https://doi.org/10.3390/molecules27103229 - 18 May 2022
Cited by 4 | Viewed by 2816
Abstract
We report the synthesis of vitamin B1, B2, and B3 derived nucleotides and dinucleotides generated either through mechanochemical or solution phase chemistry. Under the explored conditions, adenosine and thiamine proved to be particularly amenable to milling conditions. Following optimization of the chemistry related [...] Read more.
We report the synthesis of vitamin B1, B2, and B3 derived nucleotides and dinucleotides generated either through mechanochemical or solution phase chemistry. Under the explored conditions, adenosine and thiamine proved to be particularly amenable to milling conditions. Following optimization of the chemistry related to the formation pyrophosphate bonds, mixed dinucleotides of adenine and thiamine (vitamin B1), riboflavin (vitamin B2), nicotinamide riboside and 3-carboxamide 4-pyridone riboside (both vitamin B3 derivatives) were generated in good yields. Furthermore, we report an efficient synthesis of the MW+4 isotopologue of NAD+ for which deuterium incorporation is present on either side of the dinucleotidic linkage, poised for isotopic tracing experiments by mass spectrometry. Many of these mixed species are novel and present unexplored possibilities to simultaneously enhance or modulate cofactor transporters and enzymes of independent biosynthetic pathways. Full article
(This article belongs to the Special Issue Mechanochemical Synthesis of Organic Compounds)
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14 pages, 1484 KiB  
Article
Mechanochemical Dimerization of Aldoximes to Furoxans
by Run-Kai Fang, Kuan Chen, Chuang Niu and Guan-Wu Wang
Molecules 2022, 27(8), 2604; https://doi.org/10.3390/molecules27082604 - 18 Apr 2022
Cited by 2 | Viewed by 2659
Abstract
Solvent-free mechanical milling is a new, environmentally friendly and cost-effective technology that is now widely used in the field of organic synthesis. The mechanochemical solvent-free synthesis of furoxans from aldoximes was achieved through dimerization of the in situ generated nitrile oxides in the [...] Read more.
Solvent-free mechanical milling is a new, environmentally friendly and cost-effective technology that is now widely used in the field of organic synthesis. The mechanochemical solvent-free synthesis of furoxans from aldoximes was achieved through dimerization of the in situ generated nitrile oxides in the presence of sodium chloride, Oxone and a base. A variety of furoxans was obtained with up to a 92% yield. The present protocol has the advantages of high reaction efficiency and mild reaction conditions. Full article
(This article belongs to the Special Issue Mechanochemical Synthesis of Organic Compounds)
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Graphical abstract

16 pages, 1835 KiB  
Article
Manipulating Reaction Energy Coordinate Landscape of Mechanochemical Diaza-Cope Rearrangement
by Tingting Cheng, Wenxian Ma, Hao Luo, Yangzhi Ye and KaKing Yan
Molecules 2022, 27(8), 2570; https://doi.org/10.3390/molecules27082570 - 15 Apr 2022
Cited by 2 | Viewed by 2835
Abstract
Chiral vicinal diamines, a unique class of optically-active building blocks, play a crucial role in material design, pharmaceutical, and catalysis. Traditionally, their syntheses are all solvent-based approaches, which make organic solvent an indispensable part of their production. As part of our program aiming [...] Read more.
Chiral vicinal diamines, a unique class of optically-active building blocks, play a crucial role in material design, pharmaceutical, and catalysis. Traditionally, their syntheses are all solvent-based approaches, which make organic solvent an indispensable part of their production. As part of our program aiming to develop chemical processes with reduced carbon footprints, we recently reported a highly practical and environmentally-friendly synthetic route to chiral vicinal diamines by solvent-free mechanochemical diaza-Cope rearrangement. We herein showed that a new protocol by co-milling with common laboratory solid additives, such as silica gel, can significantly enhance the efficiency of the reaction, compared to reactions in the absence of additives. One possible explanation is the Lewis acidic nature of additives that accelerates a key Schiff base formation step. Reaction monitoring experiments tracing all the reaction species, including reactants, intermediates, and product, suggested that the reaction profile is distinctly different from ball-milling reactions without additives. Collectively, this work demonstrated that additive effect is a powerful tool to manipulate a reaction pathway in mechanochemical diazo-Cope rearrangement pathway, and this is expected to find broad interest in organic synthesis using mechanical force as an energy input. Full article
(This article belongs to the Special Issue Mechanochemical Synthesis of Organic Compounds)
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Scheme 1

18 pages, 5520 KiB  
Article
Mechanochemical Applications of Reactive Extrusion from Organic Synthesis to Catalytic and Active Materials
by Emanuela Calcio Gaudino, Giorgio Grillo, Maela Manzoli, Silvia Tabasso, Simone Maccagnan and Giancarlo Cravotto
Molecules 2022, 27(2), 449; https://doi.org/10.3390/molecules27020449 - 10 Jan 2022
Cited by 22 | Viewed by 4765
Abstract
In the past, the use of mechanochemical methods in organic synthesis was reported as somewhat of a curiosity. However, perceptions have changed over the last two decades, and this technology is now being appreciated as a greener and more efficient synthetic method. The [...] Read more.
In the past, the use of mechanochemical methods in organic synthesis was reported as somewhat of a curiosity. However, perceptions have changed over the last two decades, and this technology is now being appreciated as a greener and more efficient synthetic method. The qualified “offer” of ball mills that make use of different set-ups, materials, and dimensions has allowed this technology to mature. Nevertheless, the intrinsic batch nature of mechanochemical methods hinders industrial scale-ups. New studies have found, in reactive extrusion, a powerful technique with which to activate chemical reactions with mechanical forces in a continuous flow. This new environmentally friendly mechanochemical synthetic method may be able to miniaturize production plants with outstanding process intensifications by removing organic solvents and working in a flow mode. Compared to conventional processes, reactive extrusions display high simplicity, safety, and cleanliness, which can be exploited in a variety of applications. This paper presents perspective examples in the better-known areas of reactive extrusions, including oxidation reactions, polymer processing, and biomass conversion. This work should stimulate further developments, as it highlights the versatility of reactive extrusion and the huge potential of solid-phase flow chemistry. Full article
(This article belongs to the Special Issue Mechanochemical Synthesis of Organic Compounds)
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10 pages, 9964 KiB  
Article
Ionic Liquid-Assisted Grinding: An Electrophilic Fluorination Benchmark
by Pavel A. Zaikin, Ok Ton Dyan, Innokenty R. Elanov and Gennady I. Borodkin
Molecules 2021, 26(19), 5756; https://doi.org/10.3390/molecules26195756 - 23 Sep 2021
Cited by 16 | Viewed by 2556
Abstract
We demonstrated the influence of liquid additives on the rate and selectivity of mechanochemical fluorination of aromatic and 1,3-dicarbonyl compounds with F-TEDA-BF4. Substoichiometric catalytic quantities of ionic liquids speed up the reaction. We proposed an improved protocol for ionic liquids-assisted fluorination [...] Read more.
We demonstrated the influence of liquid additives on the rate and selectivity of mechanochemical fluorination of aromatic and 1,3-dicarbonyl compounds with F-TEDA-BF4. Substoichiometric catalytic quantities of ionic liquids speed up the reaction. We proposed an improved protocol for ionic liquids-assisted fluorination that allows easy and efficient isolation of fluorinated products by vacuum sublimation. A careful choice of additive results in high yields of fluorinated products and low E-factor for the overall process. Here, we report a benchmarking study of various ionic liquids in comparison with representative molecular solvents. A lower viscosity of ionic liquid additive is typically associated with higher yields and a higher degree of difluorination. Ionic liquids with fluorous anions (triflate and triflimide) are shown to be the most efficient catalysts for ionic liquid-assisted grinding. Full article
(This article belongs to the Special Issue Mechanochemical Synthesis of Organic Compounds)
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14 pages, 2190 KiB  
Article
Solvent-Free Mechanochemical Synthesis of High Transition Biphenyltetracarboxydiimide Liquid Crystals
by Jehan Y. Al-Humaidi, Siham A. Alissa, Kanubhai D. Katariya, Khulood A. Abu Al-Ola, Mohamed Hagar and Khaled D. Khalil
Molecules 2021, 26(10), 3035; https://doi.org/10.3390/molecules26103035 - 19 May 2021
Cited by 9 | Viewed by 2151
Abstract
A series of high temperature alkyl and alkoxy biphenyltetracarboxydiimide liquid crystals have been prepared under ball mill method using solvent-free mechanochemical approach. The thermal properties of the prepared compounds were investigated by deferential scanning calorimetry (DSC) measurements and the textures were identified by [...] Read more.
A series of high temperature alkyl and alkoxy biphenyltetracarboxydiimide liquid crystals have been prepared under ball mill method using solvent-free mechanochemical approach. The thermal properties of the prepared compounds were investigated by deferential scanning calorimetry (DSC) measurements and the textures were identified by polarized optical microscope (POM). The compounds showed smectic mesomorphic behaviour. The results showed the increasing nature of transition temperature Cr-SmC with chain length with increments of the SmC mesophase range. However, the mesophase range of the SmA was decreased with the terminal chain length either for the alkyl or alkoxy terminal groups. Moreover, the DFT theoretical calculations have been conducted give a detailed projection of the structure of the prepared compounds. A conformational investigation of the biphenyl part has been studied. A deep illustration of the experimental mesomorphic behaviour has been discussed in terms of the calculated aspect ratio. A projection of the frontier molecular orbitals as well as molecular electrostatic potential has been studied to show the effect of the polarity of the terminal chains on the level and the gab of the FMOs and the distribution of electrostatic charges on the prepared molecules. Full article
(This article belongs to the Special Issue Mechanochemical Synthesis of Organic Compounds)
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Review

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27 pages, 8964 KiB  
Review
Synthesis of Biologically Relevant 1,2,3- and 1,3,4-Triazoles: From Classical Pathway to Green Chemistry
by Lori Gonnet, Michel Baron and Michel Baltas
Molecules 2021, 26(18), 5667; https://doi.org/10.3390/molecules26185667 - 18 Sep 2021
Cited by 26 | Viewed by 5195
Abstract
Green Chemistry has become in the last two decades an increasing part of research interest. Nonconventional «green» sources for chemical reactions include micro-wave, mechanical mixing, visible light and ultrasound. 1,2,3-triazoles have important applications in pharmaceutical chemistry while their 1,2,4 counterparts are developed to [...] Read more.
Green Chemistry has become in the last two decades an increasing part of research interest. Nonconventional «green» sources for chemical reactions include micro-wave, mechanical mixing, visible light and ultrasound. 1,2,3-triazoles have important applications in pharmaceutical chemistry while their 1,2,4 counterparts are developed to a lesser extent. In the review presented here we will focus on synthesis of 1,2,3 and 1,2,4-triazole systems by means of classical and « green chemistry » conditions involving ultrasound chemistry and mechanochemistry. The focus will be on compounds/scaffolds that possess biological/pharmacophoric properties. Finally, we will also present the formal cycloreversion of 1,2,3-triazole compounds under mechanical forces and its potential use in biological systems. Full article
(This article belongs to the Special Issue Mechanochemical Synthesis of Organic Compounds)
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