# Easier, Safer, and Greener: Unlocking the Power of Solid Reagents in Organic Reactions by Mechanochemistry

Adrien Gallego, Nicolas Pétry, Julien Pinaud, Olivia Giani, Frédéric Lamaty

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Adrien Gallego, Nicolas Pétry, Julien Pinaud, Olivia Giani, Frédéric Lamaty. Easier, Safer, and Greener: Unlocking the Power of Solid Reagents in Organic Reactions by Mechanochemistry. ChemistryEurope, 2025, pp.e202500232. 10.1002/ceur.202500232. hal-05389995

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# Easier, Safer, and Greener: Unlocking the Power of Solid Reagents in Organic Reactions by Mechanochemistry

Adrien Gallego, Nicolas Pétry, Julien Pinaud, Olivia Giani, and Frédéric Lamaty*

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Organic mechanochemistry is currently undergoing rapid advan-
ces, significantly contributing to sustainability and green chem-
istry by eliminating toxic organic solvents. This discipline can
further contribute to sustainability and safety by allowing the
use of well-chosen, safer, and easier-to-handle reactants, e.g.,
solid reagents. The solvent-free conditions inherent to mechano-
chemistry enhance, in many cases, the reactivity of these solid
reagents, which would otherwise be ineffective in solution, rep-
resenting a new paradigm for organic reactions. This Minireview

aims to emphasize the synergistic benefits of mechanochemistry and solid reagents in replacing hazardous substances typically used in organic synthesis. It will also highlight examples of well-known reactions that have experienced notable improvements in reactivity or selectivity using safer solid bases, acids, or gas surrogates. This represents an important transformative shift toward greener and safer methodologies in the field of organic chemistry.

**1. Introduction**

Since the beginning of modern organic chemistry in the late
1820s, the purpose of organic chemistry is to elaborate synthetic
pathways in order to prepare specific compounds by creating or
breaking molecular bonds. The conditions used in many named
reactions are often harsh and/or dangerous for the operators.
Due to environmental and health issues, the need to remove
hazardous substances from organic reactions is more than ever
required. Following this idea, solventless synthetic methodolo-
gies have emerged and are currently developing at a rapid pace.
Among them, mechanochemistry, including but not limited to
ball-milling, resonant acoustic mixing (RAM) or twin-screw
extrusion (TSE), is of main interest.[¹⁻³] According to the
International Union of Pure and Applied Chemistry (IUPAC), a
mechanochemical reaction is a chemical reaction induced by
the direct absorption of mechanical energy.[⁴] One of the key
advantages of mechanochemistry is its ability to perform reac-
tions in the solid state, eliminating the need for solvents, and
thus, contributing to greener and more sustainable chemistry.[⁵]
The mechanical energy supplied by the process leads to an
improved mixing and activation of the solid reactants, allowing
reactions to proceed efficiently. However, mechanochemistry is
not only limited to the use of solid chemicals, solid/liquid or
solid/gaseous system can also be envisioned. This technique
has been successfully applied to a wide range of organic reac-
tions, including C—C bond formation, oxidation, and reduction
processes.[⁶] The development of scale-up equipment makes it
suitable for both laboratory and industrial applications.
Although mechanochemistry aims to carry out solvent-free
reactions, the addition of a small amount of solvent is

sometimes required to enhance the reactivity: it is called
liquid-assisted grinding (LAG). [7,8] The amount of liquid to add
in a mechanochemical reaction is given by the η value,
expressed in µL mg⁻¹ and defined as the ratio of added liquid
volume to the total mass of reagents. In the case of ball-milling,
other parameters like type of ball-mill, milling time, frequency,
size, and number of balls can be optimized to achieve the
desired outcomes. As interest in the development of sustainable
synthetic methods continues to grow, mechanochemistry is
poised to play a crucial role in advancing the field of organic
chemistry.

This minireview will illustrate the synergistic contribution of
mechanochemistry and the use of solid reagents to replace haz-
ardous substances usually employed in organic synthesis,
highlighting recent advancements and case studies that demon-
strate the effectiveness of this approach. Mechanochemistry,
because of solvent-free conditions, enhances the reactivity of
these safer and easier-to-handle reagents, which would be inef-
fective in solution. By examining the underlying mechanisms and
optimizing process parameters, researchers can further expand
the scope and utility of this powerful technique in organic syn-
thesis, which represents a new paradigm in how to carry out
organic reactions.

As mentioned before, mechanochemistry is a very broad field
in which many advances have been made in these recent years. In
this minireview, we decided to focus mainly on one technology:
ball-milling, whose interest and implementation have been
extensively studied these past few years.[9] We herein describe
a few examples of replacement of toxic and/or volatile chemicals
such as butyl lithium (BuLi), pyridine, and nitric acid (HNO₃) by
safe inorganic solid salts. Some of them are commonly used in
the food industry, like baking soda (NaHCO₃), potassium
phospate (K₃PO₄, emulsifying agent), sodium hydrogen sulfate
NaHSO₄ (antibrowning agent), or sodium nitrite (NaNO₂, preser-
vative in the meat industry[10]). To facilitate the scientist's
methodology in replacing toxic/volatile compounds with safe
and solid alternatives, the examples drawn from the literature
have been classified according to the basic or acidic character
of the replacing agent. Finally, a part will be dedicated to the
substitution of gaseous substances (CO, NH₃, HF), again by using
inorganic compounds as gas surrogates (Mo(CO)₆, NH₄Cl, CaF₂).
Although zero-valent metals have been extensively investi-
gated,[11] their activation falls outside the scope of this minireview

A. Gallego, N. Pětry, F. Lamaty
IBMM, Univ Montpellier, CNRS, ENSCM
Montpellier, France
E-mail: frederic.lamaty@umontpellier.fr

A. Gallego, J. Pinaud, O. Giani
ICGM, Univ Montpellier, CNRS, ENSCM
Montpellier, France

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© 2025 The Author(s). ChemistryEurope published by Chemistry Europe and Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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since their use under mechanochemical conditions does
not aim to substitute hazardous substances to make the
reactions safer.

Currently, there is no universal schematic representation
of a mechanochemical reaction. All along this minireview, the
format proposed by Michalchuk et al., reported in **Figure 1A**,
will be used.[12] It consists of drawing a thumbnail below the
reaction arrow in which parameters such as the primary
mechanochemical action, the material of both jar and balls,
the milling time and frequency, the atmosphere, and the use
of additives are reported. As an example, Figure 1B describes
a reaction conducted in a 10 mL stainless steel jar, containing
a 10 mm diameter ball of the same material, subjected to milling
in a vibratory ball-mill at a frequency of 30 Hz for 20 min under a
nitrogen atmosphere, acetonitrile being added as a liquid addi-
tive. To avoid ambiguity, it is important to note that the unit of
frequency may vary depending on the milling device used. For
vibratory ball-mills, frequency is typically expressed in hertz
(Hz), whereas for planetary ball-mills, it is given in revolutions
per min (rpm). Furthermore, we tried to provide maximum
information from the reported examples, but unfortunately, in
certain cases, some details were sometimes missing in the origi-
nal papers.

## 2. Solid Bases

Many reactions in organic chemistry require the use of strong
and/or toxic bases such as *tert*-butyllithium (*t*-BuLi), lithium bis
(trimethylsilyl)amide (LiHMDS), lithium diisopropylamide (LDA),
sodium hydride (NaH), triethylamine (Et₃N)... The use of such
bases comes with several issues regarding their hazardous nature
and environmental impact. Most of them are pyrophoric and
can ignite spontaneously on exposure to air, requiring rigorous
inert atmosphere techniques and specialized equipment for safe
handling that complicate experimental setups and storage.
Moreover, many of them are sold as solutions whose concentra-
tion needs to be determined by titration prior to each use.
Additionally, the choice of a base to perform a reaction in solution
is related to its pKa value, measured in a chosen solvent. Since
mechanochemistry takes all the solvent out of the reaction, those
considerations become less relevant. While pKa tables in the gas-
eous phase can be found, to date, there is no reference in the
literature addressing this issue in the solid phase.[13,14] Greener,
safer and easier-to-handle inorganic bases such as carbonates
(K₂CO₃, Cs₂CO₃, NaHCO₃) or phosphates (NaH₂PO₄) can then be
envisioned to perform complex organic reactions under sol-
vent-free conditions.

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**Adrien Gallego** received a degree in chemistry and chemical engineering from CPE Lyon and a master degree in organic synthesis from the University Claude Bernard Lyon 1 in 2023 after a 6-months internship in T. Billard's group where he worked on the synthesis of acyl fluorides. He then joined IBMM and ICGM in Montpellier for his Ph.D. thesis, under the supervision of F. Lamaty, O. Giani, and J. Pinaud. He is currently working on the synthesis of monomers and polymers by mechanochemistry for biomedical applications.

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**Nicolas Pétry** received his Ph.D. in 2007 at ICSN (Gif-sur-Yvette) under the supervision of J.-M. Campagne, working on the total synthesis of dolastatin 14. In 2010, he joined the CNRS as an engineer in the Chemical Risk Prevention Unit (Gif-sur-Yvette). In 2012, he moved to Nancy in the group of Y. Fort and synthesized biomolecules for medical imaging applications (PET scan). In 2015, he joined F. Lamaty's group in Montpellier and is now specialized in mechano synthesis of biomolecules and polymers.

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**Julien Pinaud** is associate professor at the University of Montpellier. After obtaining his Ph.D. in polymer chemistry in 2010 at the University of Bordeaux, he joined the group of Michael F. Cunningham at Queen's University (ON, Canada) as postdoctoral fellow. In September 2022, he was appointed assistant professor at the University of Montpellier. Since then, his research activities at ICGM focus on polymer synthesis by ring-opening polymerization using environmentally friendly processes (photopolymerization, mechanochemistry...) for which he obtained the habilitation (HDR) in 2022.

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**Olivia Giani** graduated with a Ph.D. in 1991 from the University of Montpellier, and a habilitation (HDR) in 2010. She has been an assistant professor since 1995 and she is currently working as a polymer chemist at ICGM. Her research focuses on bio-based polymers, including the synthesis of cyclic synthons (NCAs, morpholine-diones...) from various amino acids and investigation of their ring-opening polymerization.

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**Frédéric Lamaty** graduated with a Ph.D. in chemistry from Purdue University (USA) under the guidance of Ei-chi Negishi. After completing a postdoctoral work with Marc Julia at the Ecole Normale Supérieure in Paris, he joined the National Center for Scientific Research (CNRS) in Montpellier, France. He holds currently a position of senior scientist and heads the Green Chemistry and Enabling Technologies team at IBMM. His research focuses on the development of sustainable methods for the synthesis of bio-active molecules, pioneering the development of mechanochemistry with applications in many areas of chemistry.
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<figure><img src="image_14.png" /><figcaption>**Figure 1.** Schematic representation of a mechanochemical reaction. A) Generic scheme with possible parameters B) Typical example.</figcaption></figure>

## 2.1. Carbonates

### 2.1.1. Wittig and Horner-Wadsworth-Emmons (HWE) Reactions

The first use of a carbonate in a ball mill to perform a reaction requiring a strong base was reported by Balema and Pecharsky in 2002.[15] They showed that the generation of phosphorus ylides and the subsequent Wittig reaction could be performed by milling a solid phosphonium salt with $K_2CO_3$ (Scheme 1), while usually LiHMDS or LDA are used. Stabilized phosphonium ylides could be isolated, while semistabilized or nonstabilized should be reacted directly with aromatic carbonyl compounds. Additionally, mechanochemistry offers a different and/or better selectivity. The products obtained after milling are in favor of the more thermodynamically stable E isomer, while, in solution, either the Z or a mixture of both E and Z is observed.

<figure><img src="image_15.png" /></figure>

<figure><img src="image_16.png" /><figcaption>**Scheme 1.** A) Mechanochemical generation of stabilized phosphorus ylides and B) one-pot Wittig reaction under ball milling.</figcaption></figure>

In 2010, our group applied a similar methodology for the preparation of unsaturated amino esters in a ball-mill through a HWE reaction (Scheme 2).[16] A real benefit of ball-milling was demonstrated in this study: full conversion could be reached, while only 45% conversion was observed when performed in a flask with a stir bar, even after heating at 50 °C. A very good selectivity, similar to the one obtained in solution, was also observed, with only the formation of the Z isomer in most of the cases. It is worth noting that two reactions involving a ketone instead of an aldehyde were unsuccessful.

In 2011, the group of Mack published the HWE reaction between benzaldehyde derivatives and triethyl phosphonoacetate to lead to $\alpha,\beta$-unsaturated esters (Scheme 3).[17] The authors were also able to show that both liquid aldehydes and

<figure><img src="image_17.png" /><figcaption>**Scheme 2.** Solvent-free synthesis of unsaturated amino esters in a ball mill.</figcaption></figure>

<figure><img src="image_18.png" /><figcaption>**Scheme 3.** Synthesis of $\alpha,\beta$-unsaturated esters under ball-milling conditions.</figcaption></figure>
compounds bearing electron-withdrawing groups (EWGs) improved the reaction rates. The former can be explained by a better mixing of reagents, since no solvent is used in the reaction. Finally, ketone trials also exhibited limited reactivity under these conditions.

The same group published in 2018 a comprehensive study about the LAG and ion pairing influence on the conversion and diastereoselectivity of a polymer-supported mechanochemical Wittig reaction.[18] First, to study the effect of the liquid additive, benzaldehyde, benzyl bromide, and polymer-supported triphenylphosphine were milled with K₂CO₃ in the presence of 1 mL of solvent (η = 1.1 µL mg⁻¹). The authors demonstrated that using polar solvents as liquid additives promotes the formation of the Z isomer and results in higher overall conversion. Conversely, less polar solvents or neat grinding favor E selectivity and lead to lower overall conversion. A thorough mechanistic study was undertaken showing that the reagent concentration and the dielectric constant of the solvent have an impact on the selectivity. By increasing the concentration of reactant, an E selectivity is favored. From a mechanistic point of view, ions behave in solution first as contact ion pair, which are then separated by solvent molecules to give separated ion pairs and finally free ion pairs. However, under solvent-free conditions, these steps are overcome, ensuring that all ions in the system remain as contact ion pairs. A six-membered ring intermediate, involving KBr formed after deprotonation by K₂CO₃, can be hypothesized to explain the E selectivity (Scheme 4). The authors also showed that the counterion from both the base and the halide could have a great impact on the conversion and the selectivity. Indeed, benzaldehyde, benzyl halide (bromide or chloride), and polymer-supported triphenylphosphine were subjected to ball-milling in presence of four different carbonate bases M₂CO₃ (M = Li, Na, K, Cs). According to hard and soft acids and bases (HSAB) classification, by pairing a hard acid (Li⁺ or Na⁺) with a moderately soft base (Br⁻), the conversion to stilbene is very limited. In this case,

when the ylide reacts with the aldehyde, the oxygen anion cannot bind to the phosphorous cation due to a mismatched counter ion pair, hindering the formation of the stilbene product. Having this in mind, the best conversion could be reached with a combination of a soft acid (Cs⁺ from cesium carbonate) with a borderline soft base (Br⁻ from benzylbromide), with an E:Z ratio of about 78:22. In summary, carbonates once again demonstrated their suitability for performing the Wittig reaction in a ball-mill. Careful selection of ion pairs in the presence of LAG enabled modulation of diastereoselectivity. Specifically, employing 1 mL (η = 1.1 µL mg⁻¹ when K₂CO₃ is used) of polar solvent such as ethanol in both steps of the reaction favored Z-selectivity, whereas its inclusion solely in the first step led to enhanced E-selectivity. These observations highlight the ability of mechanochemical conditions—characterized by high local concentrations of reactants—to promote selective transformations that may not be accessible via traditional solution-phase synthesis.

As an extension of the previous studies on the Wittig reaction in a ball mill, Friščić and coworkers reported the functionalization of carbonyl compounds using a hexameric halogen-bonded phosphonium salt cage.[19] The designed hexameric cage was formed through halogen bonding of phosphonium salts. The supramolecular entity was then able to encapsulate small carbonyl-containing molecules and react them to give the corresponding alkene through a Wittig reaction.

More recently, Castanheiro and coworkers described the ball-milling-assisted synthesis of monofluoroalkenes.[20] Aromatic and aliphatic aldehydes were milled with triethyl 2-fluoro-2-phosphonoacetate in the presence of Cs₂CO₃ to afford the corresponding alkene (Scheme 5). Under these conditions and using benzaldehyde as substrate, the Z isomer was obtained as a major product, although the selectivity remained low (E:Z ratio of 1:1.7). Noteworthy, the use of other kinds of carbonates such as K₂CO₃, Na₂CO₃, or Li₂CO₃ led preferentially to the formation of the E isomer, but with a considerable decrease in yield. The authors also

<figure><img src="image_19.png" /><figcaption>**Scheme 4.** Proposed mechanism of the solvent-free polymer-supported mechanochemical Wittig reaction.</figcaption></figure>
<figure><img src="image_20.png" /><figcaption>**Scheme 5.** Synthesis of monofluoroalkenes from aldehydes under ball milling.</figcaption></figure>

mentioned that the addition of water significantly increased the selectivity in favor of the Z isomer. As an example, replacing $Cs_2CO_3$ with an aqueous solution of CsOH led to the product formation in 18% yield with a E:Z ratio of 1:11.7.

Finally, the scopes of ketones and phosphonoacetates were studied (**Scheme 6**), with most substrates affording the desired product in good to excellent yields, except for aliphatic ketones, which showed reactivity but gave lower yields.

Finally, Templ and Schnürch reported a fast Wittig olefination under ambient and solvent-free conditions (**Scheme 7**).[21] They demonstrated that the use of solid base potassium tert-butoxide

(tBuOK) increased the reaction rates, allowing the formation of the product after milling only 30 s. Interestingly, the reaction was initially attempted using $K_2CO_3$ instead of tBuOK, but proved ineffective. When $M_2CO_3$ ($M = K$ or Cs) was used, the reaction proceeded much more slowly. The superior performance of tBuOK can be attributed to the in situ formation of tert-butanol upon its protonation, which acts as a liquid additive. Notably, conducting the reaction with 1.4 equiv. of tert-butanol and $Cs_2CO_3$—known to be quite soluble in this solvent—significantly reduced the time required to reach full conversion. In contrast, using $K_2CO_3$, which is poorly soluble in tert-butanol, resulted in no conversion. Moreover, Templ and Schnürch's protocol was adapted to ketone substrates to provide olefins in good yields. Nevertheless, the hygroscopicity of tBuOK makes it less easy to handle in comparison to carbonates.

## 2.2. Peptide Synthesis

Peptide synthesis in solution or in the solid-phase comes with several issues: the use of large volumes of hazardous organic solvents, coupling reagents, excess of starting protected amino acids, and hazardous organic bases such as triethylamine, diisopropylethylamine (DIEA), or piperidine for the deprotonation of ammonium salts or the removal of Fmoc protecting group.[22-24] Mechanochemical alternatives were extensively explored, including by our group, who reported the first solvent-free synthesis of peptides, by coupling a urethane-protected $\alpha$-amino acid N-carboxyanhydride (UNCA) derivative with $\alpha$-amino esters (**Scheme 8**) using safe and easy-to-handle $NaHCO_3$ as a base.[25] A range of peptides, including dipeptides and tripeptides, could be prepared with high yields and no epimerization. Moreover, the method was illustrated by the synthesis of aspartame, a well-known sweetener, which was obtained in its pure form within three steps.

In 2013, our group published an improved methodology to access di-, tri-, tetra-, and pentapeptides by addition of ethyl acetate (EtOAc) as a liquid additive (**Scheme 9**).[26] The robustness of

**Scope of ketones**

<figure><img src="image_21.png" /></figure>

**Scope of phosphonoacetates**

<figure><img src="image_22.png" /><figcaption>**Scheme 6.** Study of ketones reactivity and phosphonoacetates influence on the synthesis of monofluoroalkenes under solvent-free conditions.</figcaption></figure>

**Scope of different aldehydes and ketones**

<figure><img src="image_23.png" /></figure>

**Scope of different phosphonium halides**

<figure><img src="image_24.png" /><figcaption>**Scheme 7.** Wittig olefination under ambient and solvent-free conditions.</figcaption></figure>
<figure><img src="image_25.png" /></figure>

<figure><img src="image_26.png" /><figcaption>**Scheme 8.** Peptide synthesis by reaction of a UNCA with an α-amino ester.</figcaption></figure>

<figure><img src="image_27.png" /><figcaption>**Scheme 9.** Synthesis of di-, tri-, tetra-, and pentapeptides.</figcaption></figure>

this synthetic pathway could be illustrated with the preparation of Leu-enkephalin, an endogenous opioid peptide neurotransmitter.

## 2.3. Alkylation and Sulfonylation

Similar to its study on the Wittig reaction,[18] the group of Mack investigated the influence of ion pairing in alkylation reactions of phenols and benzyl alcohols (Scheme 10).[27] These reactions are generally carried out in solution using organic bases such as amines (e.g., Et<sub>3</sub>N), which can be harmful and volatile but carbonates or hydroxides are also sometimes employed. The authors identified that two crucial interactions drive the reaction under ball milling: the metal-oxygen interaction of the carbonate and the metal-halogen interaction, as it can be seen in the proposed Zimmerman-Traxler transition state. According to the authors and HSAB theory, both conversion and yield tend to increase as the alkali metal and halogen became larger and more polarizable, i.e., when M = Cs and X = Br. The alkylation of benzyl alcohols was investigated using both carbonates and hydroxides as bases. Among the alkali metal carbonates (M<sub>2</sub>CO<sub>3</sub>, M = Li, Na, K, Rb, Cs), cesium carbonate delivered the highest conversion and yield. Notably, increasing the base to 2 equiv. led to a marked improvement in both conversion and yield for all metal cations, except

lithium and sodium. The authors suggested that increasing the equivalents of base enhances the interaction between the alcohol and the halide, thereby promoting greater product formation. When hydroxides were employed, the desired product was obtained in appreciable yields. Once again, cesium stood out, with CsOH achieving quantitative conversion to the target compound.

A similar approach was reported for the alkylation of phenols useful in the synthesis of a 5-HT<sub>7</sub> receptor antagonist and extended its use for sulfonylation reactions, which usually requires the use of strong organic bases such as pyridine, in combination with 4-(Dimethylamino)pyridine (DMAP) (Scheme 11).[28–30]

## 2.4. Phosphates

Phosphates, known for their user-friendly nature and widespread use in the food industry, have demonstrated notable utility in mechanosynthesis. Complementary to what was previously reported with carbonates, peptide synthesis has also been studied by replacing organic bases (Et<sub>3</sub>N, pyridine...) by phosphates. Our group illustrated it with the direct coupling of N-protected α-amino acids with amino esters in the presence of a coupling agent, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

<figure><img src="image_28.png" /><figcaption>**Scheme 10.** Phenol and benzyl alcohol alkylation under mechanochemical conditions.</figcaption></figure>
<figure><img src="image_29.png" /></figure>

<figure><img src="image_30.png" /><figcaption>**Scheme 11.** Mechanochemical synthesis of a 5-HT<sub>7</sub> receptor antagonist.</figcaption></figure>

(EDC) (**Scheme 12**).[31] The addition of a liquid additive was found crucial for the outcome of this reaction. Indeed, neat grinding led to a very high standard deviation (38% in conversion), suggesting a lack of homogeneity in this system, possibly due to the use of a solid inorganic base. Thus, a liquid additive was added in the jar to improve the mixing, hence the homogeneity of the reaction mixture. Moreover, only polar and aprotic solvents provided a consistent improvement in the conversion. EtOAc or γ-valerolactone was thereby considered for LAG since dimethylformamide is a problematic solvent despite its efficiency.[32] It is worth mentioning that for some peptides, particularly when γ-valerolactone is used as a liquid additive, chromatography on silica gel was necessary to purify the product, thus increasing the environmental impact of the method. Then, the methodology was extended to the synthesis of tri- and tetrapeptides with satisfactory yields.

In 2022, the same approach was applied, with phosphate as a base, to conduct a gram-scale synthesis of a hexapeptide.[33] Two strategies were tested: Boc/Me (**Scheme 13A**) and Boc/Bn

(Scheme 13B). The first one led to the formation of the desired hexapeptide together with a nonapeptide impurity, probably related to the fragility of the methyl ester function under these conditions. The latter strategy provided enough stability to overcome this issue and allowed the formation of the product without impurity.

## 2.5. Alkoxides—Racemization

The necessity to avoid waste is part of the 12 principles of green chemistry. However, in many fields, such as total synthesis or pharmaceutical chemistry, the need to reach an enantiopure compound is of main interest, if not compulsory. Mechanochemistry has proven effective for the racemization of molecules, which can subsequently be subjected to kinetic resolution processes, providing only the desired enantiomer. In 2025, Brandel and Cartigny reported the racemization of a pharmaceutical compound, levetiracetam, under solvent-free conditions (Scheme 14).[34] Milling

<figure><img src="image_31.png" /><figcaption>**Scheme 12.** Direct coupling of α-amino acids with amino esters (DBS = dibenzenesulfonamide) and synthesis of tri- and tetrapeptides.</figcaption></figure>
<figure><img src="image_32.png" /><figcaption>**Scheme 13.** Two strategies to access hexapeptide via ball milling. A) Methyl ester strategy. B) Benzyl ester strategy.</figcaption></figure>

<figure><img src="image_33.png" /><figcaption>**Scheme 14.** Racemization of levetiracetam under ball-milling conditions.</figcaption></figure>

levetiracetam with sodium methoxide (MeONa), added as a solution in methanol, afforded an almost full racemization in 1 h. The authors then decided to look for a base, allowing neat-grinding racemization and showing less health hazards than MeONa. After studying different bases (carbonates, hydroxides, and 1, 8-diazabicyclo[5.4.0]undec-7-ene (DBU)), it appeared that NaOH was the most promising one. However, the neat-grinding experiments involving NaOH were not reproducible, probably due to the hygroscopic character of the base. A control experiment in which 10 µL of water was added to the jar showed that the reaction rate was drastically reduced. To address this issue, the addition of a solid additive, sodium chloride (NaCl), was envisioned. Finally, neat-grinding of levetiracetam with NaCl and NaOH was conducted and allowed the racemization in good proportions, but the standard deviation was still high because of the water trapped by NaCl. The authors suggested to set the reaction in a glovebox to control the humidity level. Under these last conditions, they were able to conduct the racemization of levetiracetam several times with a satisfactory standard deviation. From a mechanistic point of view, powder X-ray diffraction (PXRD) suggested that racemization did not occur in the crystalline phase and required a disordered phase, not detectable by X-ray.

### 3. Solid Acids

In classical organic chemistry, when an acid is required in a reaction, the choice often turns to strong mineral Brönsted acids such as HCl, H₂SO₄, and HNO₃. To the best of our knowledge, little is reported in the literature about the use of solid acids in ball milling. However, this kind of reagent would be a significant advantage to mechanochemists, either for safety considerations or because they would be easier to handle. We herein describe synthetic applications involving solid alternatives such as sodium hydrogen sulfate (NaHSO₄) and sulfamic acid (NH₂SO₃H). No corrosion-related issues with the milling jar materials were reported in the cited studies. Nevertheless, under conditions involving extended milling times or highly acidic environments, choosing ZrO₂ or polytetrafluoroethylene (PTFE) over stainless steel could be beneficial.

#### 3.1. Sodium Hydrogen Sulfate/Potassium Hydrogen Sulfate

Sodium or potassium hydrogen sulfate salt is obtained from sulfuric acid. Their relevance to organic mechanochemistry relies on their physical state: while H₂SO₄ is a liquid, NaHSO₄ and KHSO₄ are both solids. However, the latter is highly hygroscopic, reducing its use to nonwater-sensitive reactions. Although they are milder acids than H₂SO₄, their pKa seems to be low enough to protonate a lot of species in solvent-free conditions.

#### 3.2. Nitroso and Sydnones Synthesis

The development of a comprehensive database on the mutagenic potential of nitroso compounds, particularly active pharmaceutical ingredients (APIs)-like scaffolds, is hindered by limited available data.[35-37] Additionally, the availability of nitroso compounds is restricted due to their instability and toxicity, with few commercially accessible options. Thus, research depends on synthesizing these compounds from scratch, a process that often involves hazardous chemicals, toxic solvents, or harsh conditions.[38] Several methodologies were described in solution to access nitroso
<figure><img src="image_34.png" /></figure>

derivatives, by using toxic and/or corrosive nitrosating agents such as trichloromelamine, nitrogendioxide, or Bu₄NNO₂. Recently, the mechanochemical activation of NaHSO₄ and NaNO₂ found an application in the formation of nitroso derivatives (Scheme 15).[39,40] This methodology offers a safer and greener approach, avoiding the use of the previously mentioned nitrosating agents. Indeed, both NaNO₂ and NaHSO₄ are used in the food industry. The latter has also been described by the Food and Drug Administration (FDA) as a generally recognized as safe (GRAS) and has been listed on the Environmental Protection Agency (EPA) Safer Choice Safer Chemicals Ingredients List.[41] A range of N-nitrosamines, alkyl nitrites, 'NO' amides and ureas could be prepared in good to excellent yields by milling NaNO₂, NaHSO₄, and the corresponding amine, alcohol, amide, or urea.

In 2023, our group reported that milling an aminoacetonitrile compound and NaNO₂ with an excess of NaHSO₄ could lead to the formation of sydnone derivatives (Scheme 16),[40] heterocyclic compounds that find applications in pharmaceutical chemistry.[42-44] The iminosydnone preparation could be carried out through a simple one-pot two-step procedure, avoiding the isolation of the potentially toxic nitroso intermediate. Moreover, this methodology uses only solid reagents, avoiding the use of harmful and toxic Brönsted acids (HCl, HNO₃...) and organic solvents (dioxane, THF...).

### 3.3. Pyrazolynes and Flavones Synthesis

Similarly, the group of Su reported the formation of two other heterocycles by high-speed ball milling in the presence of MHSO₄ (M = Na or K) as acid catalyst (20 mol%): pyrazolines (Scheme 17A) and flavones derivatives (Scheme 17B).[45,46] After having developed a green synthetic route avoiding the use of hazardous reagents such as H₂SO₄, HCl, HBr, HI, or H₃PMo₁₂O₄₀·nH₂O/SiO₂, the reusability of the acidic catalyst was studied. In both cases, it was shown that MHSO₄ (M = Na or K) can be collected with the silica gel additive, dried at 120 °C for 4 h, and reused over four cycles with only a small decrease of the yield (about 5%).

### 3.4. Sulfamic Acid

Sulfamic acid (NH₂SO₃H) is a white crystalline and water-soluble solid that finds applications in many fields. It is used in industry as a precursor for sweet-tasting compounds or as a cleaning agent.[47-49] It is found, for instance, in household descalers for coffee makers. Sulfamic acid is often preferable to hydrochloric acid due to its safety (no acidic vapors and low toxicity).

<figure><img src="image_35.png" /><figcaption>Scheme 16. Sydnone synthesis through a nitroso compound intermediate.</figcaption></figure>

### 3.5. Multicomponent Reactions

From an organic chemistry point of view, the mechanochemical activation of sulfamic acid for the preparation of heterocycles has been reported by Banerjee and Lambat.[50,51] They detailed the formation of 4-oxo-tetrahydroindoles (Scheme 18) through a one-pot multicomponent reaction under ball milling conditions.[50] In the mechanism, dimedone initially undergoes alkylation with phenacyl bromide, forming a tricarbonyl intermediate. In the presence of sulfamic acid, the primary amine reacts with one of the keto groups of dimedone to yield an intermediate, which then undergoes dehydration to form an N-alkylenamine. The amino group subsequently attacks the carbonyl group of phenacyl bromide, leading to the formation of a last intermediate. Under acidic conditions, this compound cyclizes to furnish the final product after the elimination of a water molecule. It appeared that this methodology is very tolerant toward functional groups and, in the case of aromatic amines, the kinetics and the yields are increased with EWG on the aromatic ring. Moreover, the authors described the same reaction in refluxed ethanol. The use of sulfamic acid as catalyst allows the formation of the compound with better yields than with conventional reagents like trifluoroacetic acid (considered as a per- and polyfluoroalkyl substance, PFAS), benzoic acid, or *p*-toluene sulfonic acid, but with a lower yield than the mechanochemical one. Finally, similarly to NaHSO₄, the reusability of sulfamic acid has been studied. The catalyst was recovered and reused over five cycles without loss of catalytic activity, although a slight decrease in yield was observed.

### 3.6. Oxonium-Ene Reactions

Following the previous idea, Lambat and Banerjee published in 2021 a sulfamic acid-catalyzed oxonium-ene reaction under ball milling conditions.[51] Indeed, cyclic ethers and oxabicyclic compounds are widely studied due to their important biological activities.[52,53] The access to oxabicyclo derivatives often requires the use of Lewis acids (BF₃·Et₂O, InCl₃, In(OTf)₃) as nonreusable

<figure><img src="image_36.png" /><figcaption>Scheme 15. Mechanoactivation of NaHSO₄ and NaNO₂ for nitrosylation reactions.</figcaption></figure>
<figure><img src="image_37.png" /></figure>

<figure><img src="image_38.png" /><figcaption>Scheme 17. A) Pyrazoline and B) flavone synthesis using MHSO₄ (M = Na or K) under ball-milling conditions.</figcaption></figure>

<figure><img src="image_39.png" /><figcaption>Scheme 18. Multicomponent reaction in a ball mill using sulfamic acid as acidic catalyst.</figcaption></figure>

catalyst, toxic, and volatile organic solvents (dichloromethane, toluene) or long reaction times. In order to address the aforementioned drawbacks, Lambat and Banerjee studied the reaction of (-)-terpinen-4-ol and aldehydes or epoxides to form highly functionalized oxabicyclo [3.2.1]octenes under solvent-free mechanochemical conditions (Scheme 19). The authors reported that aliphatic aldehydes afforded higher yields of the products than the aromatic ones. In addition, aromatic derivatives bearing EWGs gave lower yields than substrates with electron-donating groups. Also, it must be noted that, in comparison to 2,2-disubstituted epoxides, monosubstituted epoxides did not react. The reusability of the acidic catalyst was again examined. It could be recovered and reused up to four times with little impact on the yield of the

reaction. Finally, the versatility of the method was tested on various terpineol derivatives (α-, β-, γ-terpineol), but none produced the desired product under the optimized conditions.

## 4. Solid Reagents as Gas Surrogates

Although mechanochemistry is usually considered to occur at the solid state, several reactions involving gaseous species have been developed. In 2019, Bolm and Hernández published a minireview summarizing their uses in ball-mills.[54] However, employing gases comes with safety issues related to the flammability/explosivity of H₂, the combustive aspect of O₂ or the toxicity of HCN, among
<figure><img src="image_40.png" /></figure>

<figure><img src="image_41.png" /><figcaption>**Scheme 19.** Sulfamic-catalyzed oxabicyclo[3.2.1]octenes synthesis under solvent-free mechanochemical conditions.</figcaption></figure>

others. To address these issues, some alternatives have been imagined by using solid reagents as gas surrogates in mechanochemical reactions, i.e., ammonium chloride (NH₄Cl), red prussiate (K₃[Fe(CN)₆]), calcium carbide (CaC₂), molybdenum hexacarbonyl (Mo(CO)₆), baking soda (NaHCO₃), and fluorspar (CaF₂). Exploring the following alternatives allowed for easier implementation of the reactions and improved their safety.

### 4.1. Ammonium Chloride (NH₄Cl)—Amination Reaction

In 2016, the group of Štrukil reported the in situ formation of gaseous ammonia by milling ammonium chloride (NH₄Cl) and sodium carbonate (Na₂CO₃) for the efficient amination of thiocarbamoyl benzotriazoles (Scheme 20).[55] Noteworthy, the presence of water in the reaction media seems to have a deleterious impact on the reaction outcome, reported as a "LAG inhibition" by the authors. Several experiments were conducted in order to verify

the aforementioned hypothesis, by milling the thiocarbamoyl benzotriazole intermediate with either NH₃aq, or using water as a liquid additive in combination with NH₄Cl/Na₂CO₃. In the first case, only 24% conversion was observed while 3% conversion was measured in the second one, where formation of gaseous ammonia was also detected. The authors proposed that the inhibitory effect of water in this type of reaction is tentatively attributed to strong hydrogen bonding between water and ammonia, leading to partial protonation and formation of solvated species (NH₄⁺(H₂O)ₙ). This reduces the nucleophilicity of ammonia, thereby limiting its reactivity toward the thiocarbamoyl benzotriazole intermediate.

### 4.2. Red Prussiate K₃[Fe(CN)₆]—Cyano Compounds and Amino Acid Derivatives Synthesis

Red Prussiate, K₃[Fe(CN)₆], is a nontoxic bright-red salt, which finds applications in many areas, such as photography as a light-sensitive component in cyanotype printing and as a bleaching agent in darkroom processes to control image contrast and tonality. In organic chemistry, it is mainly used as an oxidative agent or as a source of cyanide. However, the latter application generally requires high temperatures or preactivation steps. In 2018, Hernández and coworkers reported the mechanochemical activation of K₃[Fe(CN)₆] for the synthesis of amino acid derivatives (Scheme 21).[56]

During the optimization process, a slight pressure raise was observed in the milling jar, particularly when K₃[Fe(CN)₆] was milled with silica. In order to identify the responsible gaseous species, the experimental system described in Figure 2 was set up. A gas release was observed after only 15 min and a paper test (Cyantesmo) confirmed the formation of HCN during the reaction. Despite the fact that hazardous HCN is generated in situ to allow

<figure><img src="image_42.png" /><figcaption>**Scheme 20.** Solvent-free solid-state amination of thiocarbamoyl benzotriazoles.</figcaption></figure>
<figure><img src="image_43.png" /><figcaption>**Scheme 21.** Mechanochemical activation of red prussiate for the synthesis of amino acid derivatives.</figcaption></figure>

<figure><img src="image_44.png" /><figcaption>**Figure 2.** Experimental setup used to reveal the formation of HCN (Reproduced with permission.[56] Copyright 2018, John Wiley and sons).</figcaption></figure>

the reaction, the amounts are small and the procedure is still safer than working with a pressurized bottle of gas.

### 4.3. Calcium Carbide (CaC₂)—Alkyne Synthesis

Alkynes are very suitable frameworks in organic chemistry since they can undergo a plethora of reactions, such as click chemistry[57] or Sonogashira couplings.[58] The introduction of such a function usually results from the transfer of a triple bond either by deprotonation of terminal alkynes or by involving the haloalkynes in transition-metal catalyzed carbon-carbon and heteroatom-carbon couplings.[59] Acetylene can be considered as an alternative to introduce a triple bond.[60] However, it is a very hazardous and flammable gas, justifying the use of a safer and easier-to-handle alternative reagent: calcium carbide (CaC₂). Cortés-Lobo and Hernández published in 2024 a review about the use of CaC₂ as a C₂-synthon in mechanochemistry.[61] They explored different fields of chemistry, including organic chemistry, and we herein describe again a few examples. For instance, in 2018, Bolm and Hernández reported the one-pot synthesis of 1,4-diamino-2-butynes from aldehydes, amines, and calcium carbide.[62] They could thereby prove that the product formation resulted from the addition of nucleophilic [C₂]²⁻ to the electrophilic iminium carbons, without formation of hazardous acetylene (Scheme 22), making the procedure safer.

Subsequently, Hernández and coworkers illustrated the reactivity of CaC₂ as a [C₂]²⁻ nucleophile through the mechanosynthesis of odd-numbered tetraaryl[n]cumulenes.[63] A mixture of propargylic diols (cumulenes precursors) and propargyl alcohols was obtained after milling CaC₂ with ketones in the presence of KOH as an additive in a planetary ball-mill under nitrogen

atmosphere (Scheme 23). Despite a good tolerance toward functional groups, it should be noted that only moderate yields were reported for the synthesis of propargylic diols. Interestingly, scaling up the reaction fivefold resulted in increased yields across the tested substrates.

In 2020, Hosseini and Schreiner described the same reaction without KOH as an additive.[64] They identified that the atmosphere is a crucial point in this transformation. Actually, the nanoparticles resulting from the milling of CaC₂ are sensitive to the air and moisture, provoking a fast decomposition when exposed. Additionally, the authors suggested that a radical mechanism can be envisioned. When the mechanochemical activation of CaC₂ was extended to its reactivity with aryl halides, a competition between a radical and a dehydrohalogenation pathway could take place (Scheme 24). Although promising, the reaction between CaC₂ and aryl halides has only reached the proof-of-concept stage, as evidenced by the poor yield in the reported example.

Finally, Bolm and Hernández published in 2022 a Sonogashira-type mechanochemical synthesis of diarylethynes from aryl iodides and CaC₂ (Scheme 25).[65] Traces of diynes products could be observed, but their formation is drastically hindered by the use of ethanol as a liquid additive, which plays a crucial role in both yields and selectivities. This methodology has some drawbacks, like the requirement of palladium catalyst, bulky ligands, and addition of Cul.

Thus, calcium carbide seems like a good alternative to hazardous acetylene. However, commercially available CaC₂ has variable purities, ranging from 69 wt% to 99.9 wt%.[54] The presence of impurities such as CaO, Ca(OH)₂, CaS, Al₂O₃, and among others can influence the outcome of the reaction and/or contaminate the final product.

### 4.4. Molybdenum Hexacarbonyl Mo(CO)₆—Carbonylation Reactions

Reactions of carbonylation have been widely studied in solution, with the limitation of using flammable, toxic, and odorless carbon monoxide CO.[66,67] To address this issue, some metallic complexes have been explored, such as M(CO)₆ (M = Cr, W, Mo), due to their ability to release CO in situ. Hernández and Bolm studied the mechanochemical activation of solid metal carbonyl complexes to carry out carbonylation reaction in a ball-mill (Scheme 26).[68] After having tried the three metal complexes previously mentioned, it appeared that a competitive oxidative homocoupling reaction of the alcohol occurred with Cr(CO)₆ and W(CO)₆.
<figure><img src="image_45.png" /></figure>

Proposed mechanism

<figure><img src="image_46.png" /><figcaption>**Scheme 22.** Mechanochemical activation of calcium carbide for the synthesis of 1,4-diamino-2-butynes.</figcaption></figure>

<figure><img src="image_47.png" /><figcaption>**Scheme 23.** Synthesis of propargyl alcohols by milling CaC₂ with a ketone and formation of [3]cumulene.</figcaption></figure>

The desired compound was obtained with Mo(CO)₆ in 99% yield, without side product. Moreover, the use of K₃PO₄ as a base is responsible for the generation of CO. In order to elucidate the mechanism, the authors went deeper into the study by milling M(CO)₆ with K₃PO₄ and measuring the pressure inside the milling jar. Among the complexes studied, Cr(CO)₆ exhibited the greatest CO release. However, since the carbonylation reaction did not work well with this reagent, the authors concluded that gaseous CO was not the main active species involved in the carbonylation. Actually,

a fast CO transfer from Mo(CO)₆ to the active palladium catalyst took place.

The same methodology was applied to mechanochemical aminocarbonylation and sulfoximinocarbonylation reactions (**Scheme 27**).

Even if carbon monoxide is a side product of this methodology, the quantity produced is much less than the one required in carbonylation reactions with CO. The substitution of a gaseous species by solid Mo(CO)₆ makes the reaction safer and easier to
<figure><img src="image_48.png" /></figure>

<figure><img src="image_49.png" /><figcaption>**Scheme 24.** Proposed mechanism for the direct alkylation of aryl halides.</figcaption></figure>

<figure><img src="image_50.png" /><figcaption>**Scheme 25.** Synthesis of diarylethynes under solvent-free conditions.</figcaption></figure>

<figure><img src="image_51.png" /><figcaption>**Scheme 26.** Mo(CO)₆-mediated carbonylation reaction.</figcaption></figure>

perform. However, there are still drawbacks, like the use of metal catalysts and ligands, which raises the question of atom economy.

### 4.5. Sodium Hydrogen Carbonate NaHCO₃—Carboxylation Reactions

As it has been shown before, NaHCO₃ is a very useful base in organic mechanochemistry, but it can also be used as a renewable carbon source for the synthesis of relevant molecules. Recently, the group of Della Ca' reported the mechanoactivation of NaHCO₃ as CO₂ solid surrogate for carboxylation reactions.[69] Such transformations usually require high-pressure cylinders and handling gaseous carbon dioxide, making the implementation of the procedure hazardous. Consequently, easy-to-handle NaHCO₃ has been milled with either propargylic amines or epoxides to afford, respectively, oxazolidinones or carbonates (**Scheme 28**).

Labeled bioactive compounds could also be prepared in good to excellent yields by using NaH¹³CO₃. Mechanistic studies,

mainly carried out through PXRD, revealed that temperature plays a crucial role since NaHCO₃ needs to decompose to release CO₂. Therefore, attempts to use other carbonates, including KHCO₃, CsHCO₃, or Na₂CO₃, were unsuccessful, probably due to their much higher decomposition temperature. Moreover, the addition of guanidine seemed to favor the decomposition process, and CO₂ is then able to be incorporated in the oxazolidinone core under standard milling conditions. A similar study reported the conversion of an aziridine to an oxazolidinone using dry ice as a CO₂ source.[70]

In 2022, the group of Bolm reported the mechanochemical Grignard reaction with gaseous CO₂ and an alternative using sodium methyl carbonate (SMC).[71] Using SMC as a C1 source offered several advantages over the procedure involving gaseous CO₂: the synthetic route was one step shorter, milling times were reduced, and no argon atmosphere was required, simplifying the reaction by eliminating the need for specialized equipment. Despite these positive aspects, it is worth noting that the SMC method is less efficient in terms of product yield.
<figure><img src="image_52.png" /></figure>

<figure><img src="image_53.png" /><figcaption>**Scheme 27.** Mechanochemical aminocarbonylation and sulfoximinocarboxylation.</figcaption></figure>

<figure><img src="image_54.png" /><figcaption>**Scheme 28.** Synthesis of oxazolidinones and carbonates using NaHCO₃ as a CO₂ surrogate.</figcaption></figure>

### 4.6. Fluorspar CaF₂—Fluorination Reactions

Hydrogen fluoride is a cornerstone in fluorine chemistry since it is the precursor of all fluorinating reagents. However, the hazardous nature of this gas does not need to be proven anymore. It is very toxic, lethal, and highly corrosive. This is the reason why Gouverneur and Hayward investigated the mechanochemical activation of fluorspar (CaF₂) to bypass HF issues.[72] They showed that milling CaF₂ with K₂HPO₄ leads to reactive fluorinating species, called “Fluoromix” (Scheme 29).

This product could then be involved in fluorination reactions of sulfonyl chlorides, alkyl bromides, or aryl chlorides (Scheme 30). However, this second step was performed in solution; all the attempts in a ball mill did not give satisfactory results.

Mechanistic studies were conducted in order to determine why Fluoromix is such a good fluorinating reagent while CaF₂ remains strongly stable and inert under the same conditions. Since Fluoromix is stable, it can be subjected to ex situ analysis by PXRD or nuclear magnetic resonance (NMR) to determine the composition of the bulk crystalline phase. PXRD revealed

that during the preparation of Fluoromix, new crystalline phases appeared. The authors hypothesized the following metathesis:

$$CaF_2 + K_2HPO_4 \rightarrow CaHPO_4 + 2KF \quad (1)$$

Then, milling KF with K₂HPO₄ afforded the formation of new crystalline phase called X(K) and identified as K₃(HPO₄)F. Once X(K) is formed, it can react with CaHPO₄, leading to a second crystalline phase Y(KCa) with the proposed composition K₂ₓCa₃(PO₃F)₃(PO₄)₂. Thus, Fluoromix seems to be a mixture of X(K) and Y(KCa). In order to determine which crystalline phase is responsible for the fluorination reaction, both X(K) and Y(KCa) were prepared independently and involved in the synthesis of tosyl fluoride described above (Scheme 31). At the end, X(K) proved to be a highly effective fluorinating agent, affording the product with 90% NMR yield, in opposition to Y(KCa). This study reveals the power of solid reagents: by combining safe, easy to handle, and sometimes inert solid reagents with ball milling, new classes of chemicals can be accessed and their reactivity can be tuned as well.
<figure><img src="image_55.png" /></figure>

<figure><img src="image_56.png" /><figcaption>Scheme 29. Mechanochemical activation of fluorspar to give Fluoromix.</figcaption></figure>

<figure><img src="image_57.png" /><figcaption>Scheme 30. Fluoromix as a fluorinating reagent.</figcaption></figure>

## 5. Outlook

This minireview focused on the organic synthesis of small molecules, but the concepts presented herein could be easily applied to other fields of organic chemistry such as polymer chemistry. One can cite the example reported by the group of Moores, where solid NaOH is used for the solid-state mechanochemical ω-functionalization of poly(ethylene glycol) (Scheme 32).<sup>[73]</sup> Interestingly, intermolecular reactions leading to poly(ethylene glycol) monomethyl ether (mPEG) dimers were not observed by

the authors. This point illustrates the robustness of the method, as dilute conditions are generally required to perform such reactions in solution.

The combination of safe solid reagents and ball milling can also help to address societal issues. Very recently, the groups of Gouverneur and Paton described the phosphate-enabled mechanochemical PFAS destruction for fluoride reuse.<sup>[74]</sup> Conventional methods reported to repurpose fluoroplastics generally involve harsh conditions, opening a room for improvement.<sup>[75]</sup> The authors described the formation of two different PTFE mixtures depending on the phosphate used for the degradation of PTFE, showing again the power and tunability of combining solid reagents with mechanochemistry (Scheme 33). When PTFE was milled with $K_3PO_4$, “PTFE mixKF” was obtained whose fluorine composition was mainly F⁻ ions (84%) and $PO_3F^{2-}$ (15%). However, when $K_4P_2O_7$ was used as activator, a different mixture was formed: “PTFE mixPF”.<sup>[19F] NMR analysis revealed only traces of F⁻, the main species formed being $PO_3F^{2-}$. Noteworthy a significant quantity of $CO_2$ was released with $K_4P_2O_7$, which was not the case with $K_3PO_4$. Density functional theory (DFT) calculation indicated that the phosphate-mediated decomposition of PTFE is both enthalpically and entropically favorable. From a mechanistic point of view, it seems that water hinders the decomposition of PTFE since only 9% of fluoride anions could be recovered with $K_3PO_4\cdot H_2O$, while no reaction was observed with $K_3PO_4\cdot 3H_2O$ and full degradation was reached when anhydrous $K_3PO_4$ was employed.

This methodology was then successfully applied to a wide range of PFAS, both polymeric and nonpolymeric, including harmful perfluorooctanoic acid (PFOA). Finally, both PTFE mixKF and PTFE mixPF were treated in order to allow the formation of fluorinating reagents such as KF, tetramethylammonium fluoride (TMAF), or tetrabutylammoniumtetra(tert-butyl alcohol) fluoride (TBAF·(tBuOH)) (Scheme 34). All fluorinating reagents prepared from PTFE reacted as anticipated in the synthesis of various fluorochemicals, proving

<figure><img src="image_58.png" /><figcaption>Scheme 31. Preparation of both $X_{(K)}$ and $Y_{(KCa)}$ and reactivity studied in the fluorination reaction of tosyl chloride. A) Control experiments. B) Reactivity comparaison.</figcaption></figure>
<figure><img src="image_59.png" /><figcaption>Scheme 32. Functionalization of mPEG under ball-milling conditions.</figcaption></figure>

<figure><img src="image_60.png" /><figcaption>Scheme 33. Mechanochemical PTFE degradation.</figcaption></figure>

<figure><img src="image_61.png" /><figcaption>Scheme 34. Synthesis of fluorinating reagents from PFAS.</figcaption></figure>

the versatility of this method and opening new routes to address environmental and societal issues by taking advantage of mechanochemistry and all the solid reagents at our disposal.

The methodologies previously mentioned were all described in ball-mills. However, it is worth considering that they could be applied to other mechanochemical systems, such as RAM and
<figure><img src="image_62.png" /></figure>

<figure><img src="image_63.png" /><figcaption>**Scheme 35.** Knovenagel condensation through TSE.</figcaption></figure>

single or twin-screw extruders (TSE), particularly when scale-up is envisioned.[76] Crawford and James described the Knoevenagel condensation by TSE.[77,78] They were able to replace the hazardous piperidine or pyrrolidine usually used in solution by solid and harmless Na₂CO₃ (Scheme 35).

Another example to mention can be the synthesis of organic dyes described by James, such as perylene-3,4,9,10-tetracarboxylic acid diimides (PDIs),[79] which requires the use of large excess of

<figure><img src="image_64.png" /><figcaption>**Scheme 36.** Synthesis of PDIs by TSE.</figcaption></figure>

<figure><img src="image_65.png" /><figcaption>**Scheme 37.** Peptide synthesis and amide bond formation by TSE.</figcaption></figure>

<table><caption>**Table 1.** Table summarizing the specific features of the solid reagents highlighted in this minireview.</caption><thead><tr><th>Reagents</th><th>Application</th><th>Advantages</th><th>Drawbacks</th></tr></thead><tbody><tr><td>Carbonates</td><td>Wittig/HWE, Peptide synthesis, Alkylation, Sulfonylation, Carboxylation</td><td>Easier to handle, Modulation of diastereoselectivity in Wittig reactions by choosing the appropriate ion pairs</td><td>Homogeneity issues can sometimes appear in neat grinding</td></tr><tr><td>Phosphates</td><td>Peptide synthesis, Fluorination, PFAS degradation</td><td>Easier to handle, Safer</td><td>Hygroscopicity</td></tr><tr><td>Alkoxides</td><td>Wittig, Racemization</td><td>In situ formation of a liquid additive</td><td>Hygroscopicity, Health hazards</td></tr><tr><td>Hydroxides</td><td>Alkylation, Racemization, Polymers</td><td>Largely available, Inexpensive</td><td>Hygroscopicity</td></tr><tr><td>MHSO₄(M = Na or K)Sulfamic acid</td><td>Nitroso formation, Heterocycles</td><td>Safer, Easier to handle, Easy recovery when used as a catalyst</td><td>Hygroscopicity</td></tr><tr><td>CaC₂</td><td>Alkyne</td><td>Acetylene-free reactions</td><td>Purity, Air sensitive</td></tr><tr><td>CaF₂</td><td>Fluorination</td><td>Safer source of fluorine</td><td>Inert if used alone</td></tr><tr><td>NH₄Cl</td><td>Amination</td><td>Easier to handle, Largely available, Inexpensive</td><td>Hygroscopicity</td></tr><tr><td>Mo(CO)₆</td><td>Carbonylation</td><td>Nongaseous source of CO</td><td>Requires Palladium catalysts and ligands</td></tr><tr><td>K₃[Fe(CN)₆]</td><td>Cyanation</td><td>Safer than KCN or NaCN, In situ generation of HCNₗₐₗ</td><td>Light sensitive</td></tr></tbody></table>
<figure><img src="image_66.png" /></figure>

amine and high-boiling solvents in solution. In the case of demand-
ing amines, the addition of K₂CO₃ is mandatory as described in
**Scheme 36**.

Finally, amide bond formation and peptide synthesis by reactive extrusion have been extensively explored by our group (Scheme 37) and, by extension of the studies performed in a ball-mill, can be carried out in some cases in the presence of safe inorganic bases to replace hazardous DIEA, piperidine, or Et3N.[80-82] Considering this approach, 11 g of moclobemide, a well-known treatment for depression and social anxiety disorder, could be easily prepared with a good yield by coupling 4-chlorobenzoic acid and 4-aminoethylmorpholine in presence of NaHCO3 in a vertical extruder.

The wide range of advantages mentioned all along in this
minireview is consistently applicable to TSE. Furthermore, it
can be very beneficial to such a system to use solid reagents
since the barrel may open to air. TSE often involves elevated
temperatures, which can cause volatile reactants to evaporate
or decompose, resulting in the loss of valuable materials.
Using alternative solid reagents ensures consistent stoichiome-
try and maximized conversion improving reaction control,
product yield and purity.

6. Summary

Alongside this minireview, many reagents were highlighted as
alternatives in various applications. **Table 1** summarizes the advan-
tages and disadvantages of each reagent type, including their
fields of application.

**7. Conclusion**

This minireview summarizes research on the use of safe, sustain-
able, and easy-to-handle solid reagents in well-known organic reac-
tions carried out by mechanochemistry. On a small scale, vibratory
and planetary mills are commonly used, providing quick and effi-
cient access to the desired products while minimizing the con-
sumption of organic solvents. For the sake of clarity, the choice
of displaying only the use of solid bases, acids and gas surrogates
was made. The concept can thereby be applied to other reac-
tions, such as oxidation, reduction, or deprotection reactions,
with adapted solids.[83-87] Moreover, mechanochemical techniques
are not confined to laboratory-scale research. Scaling-up can be
achieved through RAM or reactive extrusion, which enables work-
ing with solids or concentrated mixtures and continuously produc-
ing the desired compounds. In the future, mechanochemistry could
become even more prominent in organic chemistry, making the
field greener and safer. Notably, industrial chemists are increasingly
interested in mechanochemistry.[88,89] Once widely adopted, this
approach will significantly reduce the use of organic solvents, and
combined with the use of less hazardous and toxic reagents will
dramatically contribute to the development of sustainable chemis-
try, positively impacting the environment.

**Acknowledgements**

The Université de Montpellier, the Centre National de la
Recherche Scientifique (CNRS) and the French National
Research Agency (contract ANR-22-CE19-0036) are gratefully
acknowledged for funding. We thank Marcelin Lamaty for his
contribution to the design of the graphical artwork.

**Conflict of Interest**

The authors declare no conflict of interest.

Keywords: ball-milling • inorganic reagents • mechanochemistry • organic synthesis • solid reagents

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Manuscript received: June 23, 2025

Revised manuscript received: September 10, 2025

Version of record online: