Synthesis mechanosynthesis

A concept named molecular manufacturing, which was originally proposed by K. Eric Drexler [99] in 1992, has attracted the attention of some investigators [100, 118-121]. Molecular manufacturing is defined as the production of complex structures via non-biological mechanosynthesis (and subsequent assembly operations) [99]. A chemical synthesis controlled by mechanical systems operating on the atomic scale and performing direct positional selection of reaction sites by atomic-precision manipulation systems is known as mechanosynthesis. 

Mechanosynthesis. Chemical synthesis controlled by mechanical systems operating on the atomic scale and performing direct positional selection of reaction sites by atomic-precision manipulation systems. 

Rozental O.M., Fotiev V.A., Avvakumov E.G., Fedanchin E.l. Mechanosynthesis of yttrium and barium cuprates. Proc. All-Union Scientific and Technological Conference Mechanochemical synthesis , Vladivostok, 1990 112-14. 

The first attempt to systematically investigate contamination from iron during organic mechanosynthesis was reported in 2015 by Metro et al. [36]. The effect of wear from grinding jars and balls on the metal contamination levels was investigated in the synthesis of A-benzylbenzamide, prepared by amide coupling... 

Facile mechanochemical synthesis of thioureas was developed by Strukil et al. (Scheme 3.46) [32], Formation of new thioamide C—N bond was achieved by reaction of aromatic isothiocyanates 166 with aromatic amines (Table 3.20). Addition of small amount of methanol (LAG) was beneficial and the high yields were obtained regardless on the reactant physical state. The whole synthesis was carried out without the use of bulk organic solvents, that is solvent-free mechanosynthesis was quantitative, which voids the use of solvent for purification. Mechanochemical reaction... 

Similarly to A-thiocarbamoylbenzotriazoles, their hw-variants represent masked aryl isothiocyanates useful in thiourea mechanosynthesis. They allow the synthesis of bisthioureas -A-thiocarbamoylbenzotriazole 199 with p-anisidine and Na2C03 gave bisthiourea 203 quantitatively after 3h (Scheme 3.52). Alternatively, the same... 

A rapid, solvent-free and general synthesis of short- and long-chain substi-tnted zwitterionic meta- and para-amino benzoquinones was reported by Cuccia, Friscic et al. (Scheme 3.96) [64], Yields obtained by ball milling were compared with solution procedure, melt reactions, and mechanosynthesis in a cell lysis mill (Table 3.52). Authors demonstrated that cell lysis mill could be successfully employed to mechanosynthesis of organic compounds, and it is also suitable for coordination-based reactions. In transamination synthesis of meta-aminobenzo-quinones 350, an excess of amine was used, whereas para-aminobenzoquinones 352 are synthesized by condensation of 1,4-benzoquinone and an alkylamine in a 3 2 ratio. After chromatographic workup, it was determined that the yields were comparable for all four methods employed, while the solution reactions are the slowest. 

Reproduced from Huskic I, Halasz I, FrlScl6 T, VanSk H. Mechanosynthesis of nitrosobenzenes a proof-of-principle study In combining solvent-free synthesis with solvent-free separations. 

Equally effective was the complexation of C70 by HSVM (lOmin, Cjq j-cyclodextrin 1 8), while the other functionalized C50 derivatives afforded water-soluble 1 1 complexes, since functional groups prevent the formation of the bicapped 1 2 complexes. By mechanochemical treatment, fullerene 50 also complexes with sulfocalix[8]arene (lOmin, equimolar amounts), and the obvious advantage of the solid-state complexation is illustrated by the complexation of sulfocalix [8]arene with fullerene dimer (also prepared by mechanosynthesis, see chapter Applications of Ball Milling in Nanocarbon Material Synthesis). Dimer is hardly soluble in most common organic solvents, but the mechanochemical treatment of an equimolar mixture of sulfocalix[8]arene and fullerene dimer for lOmin afforded bicapped complex, which is about twice more soluble in water than in commonly used ODCB. 

Besides synthesis of pharmaceutical co-crystals, mechanosynthesis has been successfully applied to the synthesis of pharmaceutical salts. Trask et al. have demonstrated mechanochemical screening for pharmaceutical salts by grinding the model API molecules trimethoprim and pyrimethamine with seven pharmaceutically acceptable carboxylic acids formic, acetic, maleic, fumaric, succinic, glutaric and salicylic. The results of screening experiments (Table 8.2) demonstrate that LAG is more versatile than neat grinding in screening for pharmaceutical salts. More importantly, the application of mechanochemical techniques not only led to the formation of already reported salt forms but also enabled the discovery of 14 new salt forms. 

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