José G. Hernández

Asymmetric Aldol Reaction Organocatalyzed by (S)-Proline-Containing Dipeptides: Improved Stereoinduction under Solvent-Free Conditions

The organocatalytic activity of the methyl ester of (S)-proline-(S)-phenylalanine, (S,S)-2, in the asymmetric aldol reaction between cyclohexanone and acetone with various aromatic aldehydes under solvent-free conditions in a ball mill has been evaluated. α,α-Dipeptide (S,S)-2 catalyzed the stereoselective formation of the expected aldol products, with higher diastereo- and enantioselectivity relative to similar reactions in solution, up to 91:9 anti:syn diastereomeric ratio and up to 95% enantiomeric excess.

Green Synthesis of α,β- and β,β-Dipeptides under Solvent-Free Conditions

The reactivity of N-tert-butyloxycarbonyl-N-carboxyanhydrides derived from β-alanine, (S)-β(3)-homophenylglycine, and (S)-β(3)-carboxyhomoglycine with different α- and β-amino ester hydrochlorides was examined under ball-milling activation. In particular, good to excellent yields of several relevant α,β- and β,β-dipeptides were obtained. An illustrative application of this methodology consisted in the high-yield synthesis of the mammalian α,β-dipeptide N-Boc-l-carnosine-OMe.

Altering Product Selectivity by Mechanochemistry

Mechanochemical activation achieved by grinding, shearing, pulling, or milling opens unique opportunities in synthetic organic chemistry. Common features are that mechanochemistry facilitates reactions with insoluble reactants, enables high-yielding solvent-free synthetic procedures, and shortens reaction times, among others. However, mechanochemical techniques can also alter chemical reactivity and selectivity compared to the analogous solution-based protocols. As a consequence, solvent-free milling can lead to different product compositions or equilibration mixtures than in solution. Reactions by milling have also allowed the trapping and characterization of elusive intermediates and materials. In this Perspective we highlight a few selected examples that illustrate the value of mechanochemistry in uncovering interesting chemical reactivity, which is often masked in typical liquid-phase synthesis.

Multi-step and multi-component organometallic synthesis in one pot using orthogonal mechanochemical reactions

We demonstrate that the mechanochemical strategies for oxidative addition and ligand substitution on organometallic centers can be mutually orthogonal, permitting the rational design of multi-component mechanochemical reaction procedures for assembling complex or solution-sensitive organometallic species from three, four or even five components in one pot. The herein established synthetic procedures represent a new level of complexity in mechanochemical reactions by milling and are the first to combine redox and ligand substitution reactions into mechanochemical strategies for either one-pot sequential (“telescoping”) or one-pot multi-component syntheses. This ability to combine mechanochemical transformations has enabled the solvent-free, room-temperature syntheses of relatively complex organometallics directly for simple zerovalent metal carbonyls as the simplest precursors. In particular, we demonstrate the efficiency of mechanochemical oxidative addition by targeting selected pentacarbonyl halides (fluoride, chloride, bromide, iodide) of rhenium(I) and manganese(I), and illustrate the potential of multi-step organometallic mechanochemistry in the syntheses of selected fac-tricarbonyl complexes of these metals.

A mechanochemical strategy for oxidative addition: remarkable yields and stereoselectivity in the halogenation of organometallic Re(I) complexes

A simple solvent-free mechanochemical procedure enables rapid and high-yielding oxidative halogenation of model organometallic Re(I) compounds with excellent and tunable stereoselectivity, demonstrating how mechanochemistry can advance and simplify fundamental organometallic transformations.

Mechanochemical Strecker Reaction: Access to α-Aminonitriles and Tetrahydroisoquinolines under Ball-Milling Conditions.

A mechanochemical version of the Strecker reaction for the synthesis of α-aminonitriles was developed. The milling of aldehydes, amines, and potassium cyanide in the presence of SiO2 gave the corresponding α-aminonitriles in good to high yields. The high efficiency of the mechanochemical Strecker-type multicomponent reaction allowed the one-pot synthesis of tetrahydroisoquinolines after a subsequent internal N-alkylation reaction.

Mechanoenzymatic peptide and amide bond formation

Mechanochemical chemoenzymatic peptide and amide bond formation catalysed by papain was studied by ball milling. Despite the high-energy mixing experienced inside the ball mill, the biocatalyst proved stable and highly efficient to catalyse the formation of α,α- and α,β-dipeptides. This strategy was further extended to the enzymatic acylation of amines by milling, and to the mechanosynthesis of a derivative of the valuable dipeptide L-alanyl-L-glutamine.

C‐H Bond Functionalization by Mechanochemistry

The advances made in the mechanosynthesis of inorganic and organometallic complexes and the excellent past developments with metal-catalyzed cross-coupling reactions by high-speed ball milling have sufficienly laid the ground work for the merging of C-H functionalization and mechanochemical techniques. In recent years, the fast development of mechanochemical C-H activation have given us examples of metal-catalyzed olefinations, amidations, halogenations, and oxidative couplings, among others. This concept article will describe some of the events that led to the development of mechanochemical C-H activation, the current state-of-the-art, the present challenges of this merge, and some unique scenarios in which mechanochemistry could complement the traditional solution-based approaches.

Mechanochemical Enzymatic Kinetic Resolution of Secondary Alcohols under Ball‐Milling Conditions

Mechanosynthesis is a valuable technique, offering attractive alternatives for the preparation of organic, inorganic, and organometallic products. Surprisingly, mechanochemical enzymatic transformations have only scarcely been studied until now. Here, we demonstrate the use of lipase B from Candida antarctica (CALB) in acylative kinetic resolutions of secondary alcohols in mixer and planetary mills. Despite the mechanical stress caused by the high‐speed ball milling, the biocatalyst proved highly effective, stable, and, in part, recyclable under the applied mechanochemical conditions.

Organocatalytic Chemoselective Primary Alcohol Oxidation and Subsequent Cleavage of Lignin Model Compounds and Lignin

A one-pot two-step degradation of lignin β-O-4 model compounds initiated by preferred oxidation of the primary over the secondary hydroxyl groups with a TEMPO/DAIB system has been developed [TEMPO=2,2,6,6-tetramethylpiperidine-N-oxyl, DAIB=(diacetoxy)iodobenzene]. The oxidised products are then cleaved by proline-catalysed retro-aldol reactions. This degradation methodology produces simple aromatics in good yields from lignin model compounds at room temperature with an extension to organosolv beech-wood lignin (L1) resulting in known cleavage products.