Salient Achievements in Synthetic Organic Chemistry Enabled by Mechanochemical Activation

Abstract Although known for millennia, it is only recently that mechanochemistry has received serious attention by chemists. Indeed, during the past 15 years an extraordinary number of reports concerning solid-state chemical transformations through grinding and milling techniques have been recorded. This short review discusses the circumstances that led this renaissance, highlighting the present intense interest in so-called green chemistry, the enabling capacity of mechanochemistry to handle insoluble substrates, and the identification of the profound influence that additives can have on mechanochemically activated reactions. The core of this account focuses on salient developments in synthetic organic chemistry, especially in amino acid and peptide­ mechanosynthesis, the successful employment of mechanochemical activation in combination with asymmetric organocatalysis, the promising combination of mechanochemical activation with enzymatic and whole cell biocatalysis, the remarkable achievement of multicomponent selective reactions via complex, multistep reaction pathways, and the mechanosynthesis of representative heterocycles. The final section comments on some pending tasks in the area, such as scaling-up of milling processes to be of practical use in the chemical industry, the requirement of easier and more efficient control of reaction parameters and monitoring devices, and consequently the careful analysis of additional procedures for a proper understanding of mechanochemical phenomena. 1 Introduction 2 Brief History of Mechanochemistry 3 Milling Equipment and Reaction Parameters 4 Attributes of Mechanochemistry That Propelled Its Present Renaissance 4.1 Enormous Attention Being Presently Paid to Sustainable Chemistry 4.2 Reduced Energy Consumption 4.3 Additive-Based Mechanochemistry 4.4 Handling of Insoluble Reactants 4.5 ‘Impossible’ Reactions That Are Successful by Milling 4.6 Successful Handling of Air- and Water-Sensitive Reagents by Ball Milling 5 Salient Developments in the Mechanochemical Activation of Synthetic Organic Chemistry 5.1 Amino Acid and Peptide Mechanosynthesis 5.2 Asymmetric Organic Synthesis and Asymmetric Organocatalysis under Ball-Milling Conditions 5.3 Mechanoenzymology 5.4 Multicomponent Reactions Activated by Mechanochemistry 5.5 Mechanosynthesis of Heterocycles and Modification of Heterocycles 6 Future Directions 6.1 Scaling-Up Mechanochemical Protocols 6.2 Temperature-Controlled Mechanochemistry 6.3 Understanding Mechanochemical Transformations 6.4 Emerging Mechanochemical Techniques 7 Conclusions