Ball Milling Towards Green Synthesis: Applications, Projects, Challenges

by Achim Stolle (Editor), Brindaban Ranu (Editor)

Overview

Ball milling has emerged as a powerful tool over the past few years for effecting chemical reactions by mechanical energy. Allowing a variety of reactions to occur at ambient temperatures and in solvent-free conditions, ball milling presents a greener route for many chemical processes.
Compared to the use of microwave and ultrasound as energy sources for chemical reactions, ball milling is not as familiar to chemists and yet it holds great potential. This book will introduce practicing chemists to the technique and will highlight its importance for green transformations. Current applications of ball milling will be covered in detail as well as its origin, recent developments and future scope, challenges and prospects.
Chemical transformations covered include carbon-carbon and carbon-heteroatom bond formation, oxidation by solid oxidants, asymmetric organo-catalytic reactions, dehydrogenative coupling, peptide syntheses and polymeric material syntheses. The book will provide a valuable guide for organic, inorganic and organometallic chemists, material scientists, polymer scientists, reaction engineers and postgraduate students in chemistry.

Product Details

ISBN-13:	9781849739450
Publisher:	RSC
Publication date:	12/05/2014
Series:	Green Chemistry Series , #31
Pages:	319
Product dimensions:	6.15(w) x 9.20(h) x (d)

About the Author

Professor Ranu has been actively pursuing research in the area of green synthesis for more than two decades. His work is centred primarily on the development of useful synthetic procedures under solvent-free reactions on inorganic solid support such as alumina and silica gel; use of ionic liquids, metal nanoparticles and supported metals as catalysts; reactions under microwave, ultrasound irradiation and ball milling among others. He is a Ph.D. and elected fellow of the Indian Academy of Sciences and Indian National Science Academy.

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Ball Milling Towards Green Synthesis

Applications, Projects, Challenges

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By Brindaban Ranu, Achim Stolle

The Royal Society of Chemistry

Copyright © 2015 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-1-84973-945-0

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CHAPTER 1

Carbon–Heteroatom Bond Forming Reactions and Heterocycle Synthesis under Ball Milling

BRINDABAN C. RANU, TANMAY CHATTERJEE AND NIRMALYA MUKHERJEE

1.1 Introduction

Chemical transformations involving mechanochemical (grinding) reactions using a mortar and pestle were initiated long ago during the early stage of evolution of chemistry. But due to variable and relatively low grinding strength and speed, limited chemical reactions were successfully carried out by grinding. To overcome this limitation, a mixer/shaker mill or a planetary mill has been developed and these devices provide much higher energy and are more reliable than hand grinding. Mixing in such a mill is generally referred to as "milling". Mechanical grinding in these mills is aided by the milling balls and hence it is called ball milling. Mechanochemistry using ball milling has received intense attention in organic synthesis in recent decades and is now a fast growing branch. Mechanochemical reactions in a ball mill depend on several parameters like milling frequency, milling time, size and number of milling balls, and the material of milling balls and beakers. The first two have been found to be the most important parameters. Basically two types of ball mills have been frequently used to perform organic transformations, i.e. mixer mill (MM) and planetary mill (PM) (for further details the reader is referred to Chapter 10).

The present chapter covers reactions involving carbon–heteroatom (C–N, C–O, C–S, C–Cl, C–Br, etc.) bond formation and synthesis of heterocycles under ball milling.

1.2 Carbon–Heteroatom Bond Forming Reactions under Ball Milling

1.2.1 C–N Bond Forming Reactions

Kaupp and co-workers have reported the quantitative formation of imines by ball milling a stoichiometric mixture of aldehyde and amine in less than 30 min (Scheme 1.1).

All the reactions were carried out below 0 °C except for the condensations of 4-nitroaniline with 4-hydroxybenzaldehyde and 4-nitrobenzaldehyde, which were performed at 60 and 80 °C, respectively.

The same group also investigated the solid-state reactions of hydrazine –hydroquinone (1 : 1 complex) and of hydrazine hydrochloride with solid aldehyde, ketone, carboxylic acid, thiohydantoin and 4-nitrophenyl isothiocyanate and found that only the hydrazine hydroquinone complex provides quantitative addition, condensation, ring opening and ring closure (Schemes 1.2 and 1.3).

Naimi-Jamal, Kaupp and co-workers employed "kneading ball-milling" for the stoichiometric quantitative preparation of synthetically versatile 2,4-dinitrophenylhydrazones from low-melting aldehydes and ketones. Owing to the potential explosive nature of dry 2,4-dinitrophenylhydrazine, 50 wt% deionized water was added to wet the crystals. Water was used as an auxiliary to minimize the risk of explosive destruction. The stoichiometric reaction of 2,4-dinitrophenylhydrazine with aldehydes or ketones occurred rapidly in the kneading ball mill at 25–70 °C for 10–20 min, giving the desired hydrazones in 58–100% yields (Scheme 1.4). When these reactions are performed in solution, strong acid catalysts are required. However, they occur much faster in the kneading ball mill in the absence of catalyst.

Similarly, aldehydes and ketones were stoichiometrically ball-milled with hydroxylamine hydrochloride at 25–140 1C for 10–120 min to provide the hydrated oxime salts in sticky form, which were then treated with a base to obtain the oximes in 75–100% yields (Scheme 1.5). NaCl in water and CO2 from carbonate were found to be the only wastes produced. Aldehydes were found to be more reactive than ketones towards hydroxylamine. The difference in reactivity of aldehydes and ketones can be utilized as a versatile method for selective protection of an aldehyde by oximation in the presence of a ketone.

Benzoylhydrazones were also obtained, by ball-milling benzhydrazide and solid aldehydes in a molar ratio of 1 : 1 for 1 h at 25–30 °C. However, the reaction of benzhydrazide with isatin required 3 h of ball milling for completion (Scheme 1.6).

Liquid assisted grinding (LAG) has been applied for the synthesis of imine from 5-aminosalicylic acid and vanillin or 2-hydroxy-1- naphthaldehyde in a ball mill for 5–30 min in the presence of a small amount of EtOH or EtOH-NEt3 (Scheme 1.7).

Wang and Gao have reported direct oxidative amidation of aldehydes with anilines under ball milling (Scheme 1.8). Oxone was used as an effective oxidant for the transformation of aldehydes into amides. Other oxidants like K2S2O8 and I2 failed to initiate the oxidative amidation.

MgSO4 was found to be the best dehydrating agent for removing the water formed in the reaction. In addition, when the oxidative amidation reaction was performed in organic solvents such as acetonitrile or toluene, under identical reaction conditions, the yield of the corresponding product was comparatively lower than the reaction under solvent-free condition in a ball mill. Anilines bearing electron-donating and electron-withdrawing groups underwent facile reaction with aldehydes bearing electron-withdrawing groups only. Reactions with aldehydes containing electron-donating groups were unsuccessful, indicating the importance of the electronic character of aldehydes. Aliphatic anilines were also inert under the reaction conditions. The replacement of an aldehyde by the corresponding carboxylic acid did not afford the amides, thereby discarding the possibility of oxidation of aldehyde to carboxylic acid by Oxone followed by reaction with aniline to give amide.

A tentative mechanism for the amidation reaction of aldehydes with anilines based on the above results was proposed (Scheme 1.9). This direct oxidative amidation reaction may proceed via two pathways. In pathway A, the interaction of an aldehyde and aniline produces imine readily, which is then oxidized by Oxone to generate oxaziridine 1 as the key intermediate. Rearrangement of oxaziridine to amide is known for both photochemical and thermal reactions. Initial cleavage of the N–O bond followed by migration of the substituent (hydrogen) trans to the nitrogen lone pair results in the formation of amide 2. In pathway B, nucleophilic addition of aniline to aldehyde produces carbinolamine intermediate 3, which is then oxidized by Oxone to form the amide. Even though control experiments showed that imine could be employed to perform the amidation directly, the exact mechanism of this reaction remains obscure and both pathways could be operational.

A new methodology has been developed for the desymmetrization of aromatic diamines to non-symmetrical thiourea derivatives by click-mechanochemistry in a ball mill. Phenylenediamines (o-, p-) were desymmetrized through a one-pot mechanochemical click reaction sequence to furnish mono- and bis(thio)ureas or mixed thiourea–ureas (Scheme 1.10).

o-Phenylenediamine reacted selectively with either one or two equivalents of phenyl isothiocyanate to yield the non-symmetrical amino-thiourea or the symmetrical bis-thiourea in 95% and 499% yields respectively. The excellent control of the stoichiometric composition of the product in mechanochemical click-thiourea coupling demonstrates that it provides a facile and clean one-pot route to desymmetrization of aromatic diamines, and to the synthesis of symmetrical and non-symmetrical bis-(thio)ureas that are obtained in poor yields in solution.

A chemoselective C–N bond formation has been achieved by the acylation of primary aliphatic amines using a vibrational ball mill in 10 min (120 min for aromatic amines). Azobenzene functionalized esters were employed to react with various amines (primary and secondary) in presence of a base, N,N-dimethyl-4-aminopyridine (DMAP), under vibrational ball-milling to synthesize the corresponding amides (Scheme 1.11).

Jin et al. have reported an efficient solvent and catalyst-free aza-Michael addition of chalcone to amine under the high-speed vibration ball-milling in a short reaction time (Scheme 1.12). In general, excellent yields were obtained, eliminating the usual side reactions. It was also observed that the yields of the corresponding products obtained using anilines were lower compared to those using benzyl amine or piperidine.

Kaupp's group has reported quantitative synthesis of enamino ketones by the reaction of cyclic 1,3-dicarbonyl compounds such as 1,3-cyclohexanedione, dimedone and dehydroacetic acid with aniline derivatives without any catalyst under ball milling within 1 h, followed by drying at 0.01 bar at 80 °C (Scheme 1.13).

Li and co-workers have reported the mechanochemical reaction of aliphatic primary amines with acyclic 1,3-dicarbonyl compounds such as 1,3-pentadione and ethyl acetoacetate in the absence of catalyst and solvent (Scheme 1.14). A series of enamino ketones and esters were obtained in 61–97% yields by ball milling the mixtures of amines and 1,3-dicarbonyl compounds in a ratio of 1 : 1 in a mixer mill at 30 Hz for 0.5–2 h.

Stolle et al. have developed a solvent-free methodology for the synthesis of enamines by the addition of amines to dialkyl acetylene dicarboxylates or alkyl propiolates using a planetary ball mill at 800 rpm (13.3 Hz) (Scheme 1.15). Fused quartz sand (SiO2) was used as inert grinding auxiliary to facilitate the energy entry in the presence of liquid substrates by adsorbing them on the surface. Significantly, reactions with several anilines and secondary alkyl amines were complete within five minutes with excellent yield of products. Besides the (E-/Z)-isomers, no other product was formed. Interestingly, addition of aniline or p-toluidine to dialkyl acetylene dicarboxylate produced the (E)-enamine as the major product whereas addition of the same amine to alkyl propiolate produces the (Z)-enamine as the major product.

Lamaty and co-workers reported the condensation of aldehydes with equimolar amounts of N-substituted hydroxylamines in a ball mill at a frequency of 30 Hz for 0.5–2 h to obtain various C-aryl and C-alkyl nitrones in 71–100% yields (Scheme 1.16). Significantly, reactions were performed in the presence of air and moisture and the products were obtained pure.

Though urea is very unreactive toward alkylation, the reaction of urea with 4-bromobenzyl bromide under mechanical milling in the presence of NaOH produced di(4-bromobenzyl)urea with 41% conversion for a total milling time of 34 h (Scheme 1.17).

1.2.2 C-O Bond Forming Reactions

Mechanochemical reaction of pyrazolone derivatives and phenacyl bromide under ball milling afforded the corresponding pyrazolyl ether derivative quantitatively within 1 h involving the C–O bond formation. The products were obtained after washing the crude with sodium carbonate solution followed by drying at 0.01 bar at 80 °C under vacuum (Scheme 1.18).

Mack and co-workers have reported the mechanochemical synthesis of dialkyl carbonates of various metal carbonates with the assistance of metal complexing reagents (Scheme 1.19). The reaction of various metal carbonates including Li2CO3, Na2CO3, K2CO3 and Cs2CO3 with 4-bromobenzyl bromide gave poor results (0–18% yields). However, the addition of 2 equivalents of 18-crown-6 improved the yield from 2% to 74%. The same product was obtained as the major one in the reaction of cyclohexanone with p-bromobenzyl bromide using K2CO3 as the base in the presence of 18-crown-6. Under the optimal conditions, other aliphatic halides such as benzyl bromide, (2-bromoethyl)benzene and benzyl chloride provided dialkyl carbonates in 58–67% yields.

Recently, Ranu et al. have developed an efficient procedure for transesterification in a ball mill in the absence of any solvent, acid/base or metal catalyst (Scheme 1.20). The reactions were carried out on the surface of basic alumina, which plays a dual role of a grinding auxiliary and a base. A wide variety of esters such as methyl, ethyl and allyl esters were transesterified with various alcohols including benzyl, cinnamyl, alkyl (primary, secondary) etc. Heteroaryl (pyridine, thiophene and furan) substituted difficulty.

1.2.3 C–X (X1 = F, Cl, I, SCN, OAc etc.) Bond Forming Reaction

Mack et al. have reported the heterogeneous nucleophilic additions of alkali salts of thiocyanate, azide, acetate and halides to 4-bromobenzyl bromide with or without 18-crown-6 by ball milling (Scheme 1.21). It was found that thiocyanate and azide provided excellent yields of the nucleophilic addition products, whereas the potassium and sodium salts of fluoride, chloride, acetate and cyanide provided relatively low yields of the corresponding addition products. On the other hand, 18-crown-6 can complex with K+ cation to increase the basicity and nucleophilicity of the employed nucleophiles, and thus the addition of 18-crown-6 led to a better conversion and increase in yield for all of the potassium salt nucleophiles including fluoride, acetate and cyanide, which were previously unsuccessful.

1.2.4 C–X (X = S, Se and Te) Bond Forming Reactions

Kaupp and co-workers have reported the quantitative formation of thiouronium salt from solid 2-mercaptobenzimidazole and phenacyl bromide under ball milling for 1 h (Scheme 1.22).

Recently, Ranu et al. have developed a convenient and efficient procedure for the transition metal-, ligand- and solvent-free synthesis of aryl chalcogenides by employing a C-X (X = S, Se, Te) bond forming reaction between aryl diazonium tetrafluoroborates and diaryl dichalcogenides in the presence of KOH and neutral alumina as grinding auxiliary under ball milling (Schemes 1.23–1.25). A wide variety of diaryl chalcogenides were synthesized within short reaction time (15–30 min) providing moderate to good yields (62–90%) of products.

1.3 Synthesis of Heterocycles

1.3.1 Nitrogen-containing Heterocycles

1,2,3-Triazoles, five-membered nitrogen-containing heterocycles, have received considerable interest because of their useful applications as agrochemicals, dyes, corrosion inhibitors, photostabilizer, materials and in pharmaceutical industries. Stolle and co-workers have reported the first ligand- and solvent-free mechanochemical synthesis of triazole from azides and alkynes using a planetary ball mill (Scheme 1.26).

The applicability of this protocol to a broad variety of substrates enables easy access to a wide range of complex triazoles. Click polymerization in a ball mill without destroying the polymer backbone is also successful (Scheme 1.27).

Ranu et al. introduced a different protocol where 1,4-disubstituted-1,2,3-triazoles were synthesized by a simple one-pot three-component reaction of alkyl halide/aryl boronic acid, sodium azide and terminal alkynes on the surface of Cu/Al2O3 catalyst by ball-milling under solvent-free conditions (Scheme 1.28). Usually no chromatographic separation/purification was required and no toxic organic solvent is used in the entire process. This protocol avoids handling of hazardous organo-azide and provides easy access to aryl-alkyl and aryl-aryl substituted 1,2,3-triazoles. From the X-band EPR spectrum and XPS study it was found that the copper was present in the +2 oxidation state throughout the reaction cycle. SEM and AFM analysis exhibited the uniform spherical morphology of the catalyst.

Another nitrogen-containing five-membered heterocycle, pyrazoline, can be effectively synthesized from chalcones and phenyl-hydrazines in the presence of NaHSO4 • H2O using high speed ball milling (HSBM) (Scheme 1.29).

It was found that better yield of pyrazolines was obtained when the substrates contained electron–donating groups. The easy catalyst recovery and its reusability make this procedure more attractive. When other α, β-unsaturated ketones were treated with thiosemicarbazide/phenyl hydrazine in the presence of this catalyst the corresponding 2-pyrazoline derivatives were obtained in good yields (Scheme 1.30), which demonstrates the general applicability of this protocol.

In 1999, Kaupp and co-workers reported a one-pot synthesis of highly substituted pyrroles (Scheme 1.31), which gives moderate yields in solution, but quantitative yields in solid–solid variant at much lower temparatures. Mechanochemical reaction of primary or secondary enamine esters 4a–d or the enamine ketone 7 with trans-1,2-dibenzoylethene (5) under ball milling afforded pyrroles 6 or indole 9 quantitatively within 3 h despite the multistep course of the reaction.

A plausible reaction pathway is depicted in Scheme 1.32. In the first step, Michael addition followed by the hydrogen transfer produces 11, which undergoes an imine/enamine rearrangement to give 12. The generated amino group then interacts with the carbonyl function leading to the formation of a five-membered ring 13, which provides pyrrole 14 by the elimination of water. An analogous mechanism was postulated for indole starting from 7. Furthermore, the quantitative formation of thioorotic acid amide 17 from a cascade reaction between the thiohydantoin 15 and methyl amine shows the versatility of this method (Scheme 1.33).

(Continues...)

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Table of Contents

Carbon-carbon bond forming /coupling reactions by ball milling;
Carbon – heteroatom bond forming reactions under ball milling;
Oxidation by solid oxidants using ball milling;
Asymmetric organocatalytic reactions under ball milling;
Metal catalysed ball milling chemistry;
Peptide synthesis by ball milling;
Technical implications of organic syntheses in ball mills;
Cross dehydrogenative coupling reactions by ball milling;
Ball milling induced cracking of functional resins for chromatography-free purification;
Ball milling promoted chemical bonding between cellulose and plastics;
Ball milling in the synthesis of useful polymeric composites