Borane-pyridine acts as an efficient (5 mol%) liquid catalyst, providing improved solubility for the direct amidation of a wide range of aromatic and aliphatic carboxylic acids and amines to form secondary and tertiary carboxamides. Tolerance of potentially incompatible halo, nitro, and alkene functionalities has been demonstrated.

The catalytic activity of different classes of boron catalysts was studied in amidation reactions with 4-phenylbutylamine/benzoic acid, and with 2-aminopyridine/phenylacetic acid. Whilst a simple boronic acid catalyst showed high catalytic activity with the former substrates, it was completely inactive in the latter reaction. In contrast, a borate ester catalyst was able to mediate the amidation of both substrate pairs with moderate activity. By screening a range of borate esters we were able to identify a novel borate catalyst that shows high reactivity with a range of challenging carboxylic acids/amine pairs, enabling catalystic amidation reactions to be achieved effectively with these industrially relevant compounds. The reactions can be performed on multigram scale with high levels of efficiency, and in situ catalyst generation from commercially available reagents renders the process readily accessible for everyday laboratory use. Further experiments showed that the deactivating effect of 2-aminopyridine on boronic acid catalysts was due to its ability to stabilise catalytically inactive boroxines. Whilst a simple boronic acid catalyst showed high catalytic activity with the former substrates, it was completely inactive in the latter reaction. In contrast, a borate ester catalyst was able to mediate the amidation of both substrate pairs with moderate activity. By screening a range of borate esters we were able to identify a novel borate catalyst that shows high reactivity with a range of challenging carboxylic acids/amine pairs, enabling catalystic amidation reactions to be achieved effectively with these industrially relevant compounds. The reactions can be performed on multigram scale with high levels of efficiency, and in situ catalyst generation from commercially available reagents renders the process readily accessible for everyday laboratory use. Further experiments showed that the deactivating effect of 2-aminopyridine on boronic acid catalysts was due to its ability to stabilise catalytically inactive boroxines. A new borate ester amidation catalyst was developed, that shows higher reactivity with challenging carboxylic acids and amines. Reactions could be performed on multigram scale with the catalyst generated in situ from commercial reagents. Amide formation is typically a highly inefficient process which leads to the generation of significant quantities of waste, and there is considerable interest in rendering the process more efficient. 4 The most common readily available precursors to the amide unit, carboxylic acids and amines, must undergo a formal dehydration during the amide coupling reaction, and this is typically achieved either via pre-activation of the carboxylic acid or via the use of a stoichiometric dehydrating agent which provides activation in situ . In both cases the byproducts obtained are typically of high molecular weight, while the reagents used are often hazardous or toxic. Catalytic methods for amide formation from carboxylic acids and amines are gaining prominence, 5 and in such reactions the only stoichiometric byproduct is water. However, these reactions are still not widely employed in synthetic chemistry laboratories for a variety of reasons, notably a relatively narrow substrate scope and a lack of accessibility ( e.g. , slow reaction rates; catalysts that are not commercially available or are too expensive). In many cases the reaction scope is quite limited to the preparation of largely unfunctionalized amides. The application of most catalytic reactions to polar substrates and/or those containing coordinating functional groups is often low yielding or unreported. 5 However, these classes of amides are typically the ones most widely in demand for the many applications outlined above. Similarly, catalytic amidation reactions often fail with poorly nucleophilic amines (electron-deficient anilines, heterocyclic amines), and lower yields are frequently obtained from less-reactive carboxylic acids (benzoic acids, heterocyclic carboxylic acids, fluorinated carboxylic acids). 39 Scheme 1 Time course experiments of boron catalysts in the reaction of 4-phenylbutylamine and benzoic acid. We have previously observed that 2-aminopyridine is a particularly challenging amine for amidation reactions, 40 perhaps because it is poorly nucleophilic and also contains the adjacent coordinating pyridine nitrogen which is potentially able to chelate to Lewis acids and hence inhibit their ability to mediate amidation. We therefore examined the reactivity of the same boron catalysts on the more challenging substrate combination of phenylacetic acid and 2-aminopyridine to give amide 2 ( Scheme 2 ). Although B(OCH 2 CF 3 ) 3 has previously worked well for catalytic amidation of a range of challenging substrates, this is Other catalysts containing boronic acids such as 2,4-bis(trifluoromethyl)phenyl boronic acid E, where deleterious co-ordination of amines is reported to be hindered by the ortho substituent, 38 and the BNO heterocyclic catalyst F (DATB2) 29 were also low-yielding (entries 7–8). 3,4,5-Trifluorophenyl borate B [B(OAr F ) 3 , entry 9] was demonstrably the most reactive catalyst for this amidation, giving much higher conversions than other aryl borates (entries 10–12). A moderate isolated yield of the amide 4 (57%) could be obtained using B as a catalyst, if the reaction time was extended to 66 h. Notably, boronic acid catalyst A was also fairly effective for the amidation of non-coordinating electron-deficient anilines ( e.g. 20). With the borate catalyst B, moderately hindered acids/amines could be used ( e.g. 25, 27), but 1-adamantylamine showed low reactivity (26), perhaps unsurprisingly as it is poorly soluble in the reaction mixture. Proline amides (28–29) could be prepared, although when using a poorly reactive amine the yield was low (29). The catalyst could also be used to directly form an amide from the hindered amine acid l -valine (30).

Mechanochemical methodologies are reshaping synthetic organic chemistry by enhancing practicality and reducing environmental impact. This review presents a comprehensive account of mechanochemical methods for amide bond formation, arguably the most developed and industrially relevant area within mechanochemical organic synthesis. Covering literature from early contributions to the present (September 2025), the review organization follows key substrate classes and methodological strategies: amide bond formation via coupling of carboxylic acids or their activated derivatives with amines (Section 2), followed by unconventional approaches (Section 3) employing carboxylic acid and amine surrogates, redox chemistry, rearrangements, and transition metal-mediated reactions leading to amide products through alternative bond-forming pathways. Mechanoenzymatic transformations are treated separately (Section 4), with stereochemistry-related issues, such as the preservation of enantiomeric purity, discussed in Section 5. Section 6 highlights the use of amide bond formation as a model system for probing mechanochemical driving forces. Special attention is given to scalability and successful scale-up examples, alignment with green chemistry principles, limitations, unexplored areas, and challenges requiring further development. This review is intended as an accessible and thorough resource for synthetic chemists in both academia and industry, including those newly exploring the field of mechanochemistry, and it provides practical guidance for process optimization and scale-up. Synthesis of Amides by Condensation of Carboxylic Acids and Amines Condensation of readily available carboxylic acids with primary or secondary amines is the most direct and widely adopted strategy for amide bond formation. This section focuses on how these transformations have been adapted to mechanochemistry, providing the foundation for mechanochemical amide synthesis and reflecting similar processes developed in solution-phase chemistry. Direct Amide Coupling of Inactivated Carboxylic Acids The direct condensation of carboxylic acids and amines is considered the most favorable approach from a green chemistry perspective, as it avoids the use of amide coupling reagents and produces only water as a byproduct. − However, it requires high temperatures (typically above 150 °C), likely due to the formation of unreactive ammonium carboxylate salts. These conditions demand specialized equipment for heating and temperature control, which is not commonly available in standard mechanochemical setups. As a result, investigation of this strategy began only recently. In 2023, Stolar et al. Solvent-free synthesis of eight amides was achieved by leveraging the heating and mixing capabilities of a vertical corotating TSE ( Scheme ). Aromatic and aliphatic carboxylic acids, along with anilines and primary aliphatic amines, afforded the corresponding amide products in high yields of 83–97%. Primary and secondary benzylamines gave amides 5 and 6 upon reaction with palmitic acid in high 95% and 97% yields, although the latter required a longer reaction time. It generates benign byproducts, such as carbon dioxide and imidazole, which can be easily separated from the resulting amide product. The first CDI-mediated solvent-free For example, the synthesis of liquid amide 50 ( Scheme , B) was scaled up to a 25 mmol scale, and the product was purified by distillation, yielding 3.6 g (62%). In 2023, Zhu et al. demonstrated the scalability of the method up to 25 mmol scale using a planetary ball mill ( Scheme , C). A variety of amides was synthesized in 14–93% yields by coupling of nicotinic ( 54 , 55 ), picolinic ( 56 ), thiophene-2-carboxylic ( 57 ), benzoic ( 58 ), cyclopropane carboxylic ( 59 ) and sorbic acids ( 60 ) with benzylic, aliphatic amines and anilines. It was noting that benzotriazole-based coupling reagents such as TBTU may be potentially explosive and pose health hazards. , 2.3. Use of Amide Coupling Reagents for In Situ Activation The preceding section detailed mechanochemical strategies utilizing activated carboxylic acid derivatives that are either preformed or sequentially generated prior to reaction with amines. An alternative and attractive approach is the direct, in situ activation of carboxylic acids in the presence of amines by using stoichiometric amide (peptide) coupling reagents. Next, redox-based strategies are presented, including transition-metal-catalyzed C–H activation and other transformations involving organometallic intermediates ( Section ). Section subsequently covers reductive C–N coupling, C–F bond activation, and the Leuckart reaction. Finally, Section covers rearrangements and multicomponent reactions. 3.1. Use of Amine and Carboxylic Acid Surrogates Recent advances in mechanochemical amide bond formation have demonstrated the utility of various surrogates as alternatives to traditional carboxylic acids and amines. Metal-Mediated Transformations A number of studies have demonstrated the mechanochemical preparation of amides by employing stoichiometric organometallic reagents or transition metal catalysis, primarily via C–H activation reactions. These strategies rely on fundamentally different bond disconnections compared to the traditional amide synthesis route involving coupling of amines with carboxylic acids or their derivatives, enabling alternative routes to amide products. These reactions enable the efficient construction of complex amide-containing molecules in a single step, aligning well with the principles of green and sustainable synthesis. Polindara-García and Juaristi were the first to adapt the classical Ugi four-component reaction (involving an aldehyde, amine, carboxylic acid, and isocyanide) to high-speed ball-milling conditions (45 min, 25 Hz, agate vessel). Optimal results were obtained using methanol as a LAG additive and indium­(III) chloride (2 mol %) as a catalyst ( Scheme , A).

Cottons containing carboxylic acid groups display good wrinkle recovery properties after the simultaneous application of heat and vacuum. This wrinkle recovery can be removed by soaking the fabric in dilute base which converts the acid to the carboxylate salt. To reintroduce the cross link, as shown by electron microscopy, it is first necessary to convert the salt to the free acid and then subject the fabric to the heat and vacuum treatment. Wrinkle recovery values can be further improved by first treating the cotton to introduce either primary or tertiary amine groups and then treating with chloroacetic acid to introduce the carboxyl groups. Wrinkle recovery imparted by heat and vacuum is stable to acid and neutral washes. The procedure can also be used to impart and remove creases in fabrics. Because of the prolonged heating, the fabric tends to discolor, but this discoloration can be removed by mild chlorine bleaching without affecting the wrinkle recovery.

In vitro bioactivity of a synthesized prostaglandin E1-heparin conjugate. A covalently bound conjugate of commercial grade heparin and prostaglandin E1 (PGE1) was synthesized to provide the dual pharmacological role of decreasing the extent of platelet aggregation and inhibiting fibrin formation during thrombogenesis. The compound was synthesized using a modified mixed carbonic anhydride method of amide bond formation between the carboxylic acid moiety of PGE1 and a primary amine group on heparin. Quantitation of coupling was measured spectrophotometrically by monitoring a degradation product of the prostaglandin E1-heparin conjugate (prostaglandin B1-heparin conjugate). Bioactivity tests on the conjugates (activated partial thromboplastin time and platelet aggregation) confirmed that both the anticoagulant activity of heparin and the inhibitory effect of PGE1 on platelet aggregation were maintained. Published in Journal of pharmaceutical sciences (1986)

hexanediamine and a sub- stance X. This substance X is most probably \. an amine. B) a carboxylic acid. C. … formed from an amine and a carboxyl group or its acyl derivatives. In this question, an amine is already … there is a methyl group and a hydrogen, and on the other side, an ethyl group and a hydrogen. In this configura-

reactivity with amines (c. 3–5% conversion of the intermediate to the final amide). It is apparent that conventional chemical treatment of carboxylic groups on Graphene () is a variety of the element carbon which occurs naturally in small amounts. In graphene, the carbon forms a sheet of interlocked atoms as hexagons one carbon atom thick. The result resembles the face of a honeycomb. When many hundreds of graphene layers build up, they are called graphite. In technical terms, graphene is a carbon allotrope consisting of a single layer of atoms arranged Hydrazine reflux is commonly used for reducing SLGO to SLG(R), but titrations show that only around 20–30% of the carboxylic groups are lost, leaving a significant number available for chemical attachment. Analysis of SLG(R) generated by this route reveals that the system is unstable and using a room temperature stirring with hydrochloric acid (< 1.0 M) leads to around 60% loss of COOH functionality. Room temperature treatment of SLGO with carbodiimides leads to the collapse of the individual sheets into star-like clusters that exhibited poor subsequent reactivity with amines (c. 3–5% conversion of the intermediate to the final amide). It is apparent that conventional chemical treatment of carboxylic groups on SLGO generates morphological changes of individual sheets that leads to a reduction in chemical reactivity, which may potentially limit their use in composite synthesis. Therefore, chemical reaction types have been explored. SLGO has also been grafted with polyallylamine, cross-linked through epoxy groups. When filtered into graphene oxide paper, these composites exhibit increased stiffness and strength relative to unmodified graphene oxide paper. Full hydrogenation from both sides of the graphene sheet results in Graphane, but partial hydrogenation leads to hydrogenated graphene. Similarly, both-side fluorination of graphene (or chemical and mechanical exfoliation of graphite fluoride) leads to fluorographene (graphene fluoride), while partial fluorination (generally halogenation) provides fluorinated (halogenated) graphene.