Technology and Development of Organic Synthesis —— Selection of Solvents

Solvent type:

a.？ Proton solvents, or hydrogen bond donor solvents (Lewis acids), such as water, ethanol, acetic acid and ammonia;

b.？ Hydrogen bond acceptor solvents (Lewis bases), such as water, triethylamine, ethyl acetate, acetone and DMF；;

c.？ Polar aprotic solvents, or "non-hydroxyl solvents", such as DMSO, DMF and dimethylacetamide DMAc；; ;

d.？ Chloroalkane solvents such as dichloromethane, chloroform and carbon tetrachloride;

e.？ Fluorocarbon solvents, such as hexafluoroisopropanol;

f.？ Hydrocarbon solvents such as hexane, isooctane and toluene;

g.？ Ionic liquid;

h.？ Supercritical gases such as supercritical carbon dioxide.

The process of solute surrounded by solvent is called solvation, and the solvation of water is called hydration. Solvation value refers to the number of solvent molecules around ions. Generally speaking, the degree of solvation increases with the increase of charge number and the decrease of ion radius. The reactivity of a species increases with the decrease of solvation, because the solvated molecules shield the reactants and disperse the charge. Part of the molecule may be more easily dissolved by another solvent. For example, an aprotic solvent with uniform polarity, such as DMSO, solvates cations to make another part of anions react more easily. Crown ethers, which are usually used as phase transfer catalysts (PTC), also form complexes with cations, making anion sites more active. In a solvent mixture, two solvents can solvate different parts of molecules, so the solubility of the mixed solvent is better than any single solvent. There is an obvious example of how the decrease of the solvation degree of sodium hydroxide affects its reactivity: the alkalinity of solid sodium hydroxide (trimolecular hydrate) is 50000 times higher than that of 15% sodium hydroxide (1 1 molecular hydrate). (PTC is said to produce "naked anions", but a small amount of water is necessary, especially for solid-liquid phase transfer reactions. Water content is a key parameter in the development of phase transfer catalysis. ) Solvation is one of many important factors to consider when choosing solvents.

The importance of choosing solvents carefully;

A. Provide safe and harmless conditions for large-scale production for equipment and operators;

B. The physical and chemical properties of solvents, such as polarity, boiling point and water miscibility, affect the reaction rate, two-phase separation, crystallization effect and removal of volatile components by boiling or drying solids;

C other physical and chemical characteristics, such as the viscosity of the mixture, affect the quality and heat transfer, the formation of by-products and physical transportation;

D the difficulty of solvent recovery and reuse greatly affects the product cost (CoG).

The best solvent should be able to crystallize the reaction product directly.

The key principle of selecting solvents for rapid process scale-up is that homogeneous reaction is usually much faster than heterogeneous reaction and easy to scale up. If heterogeneous conditions are necessary, the solvent and reaction conditions must be selected so that the reaction mixture is liquid and easy to mix. For the traditional hydrogenation reaction, effective stirring is very important because it is a liquid-solid-gas dispersion system. In many cases, the separation of products can promote the reaction to continue. It is better to be able to crystallize rather than form precipitate or oil, in which case the raw materials will be involved.

For some reaction processes, heterogeneous conditions are favorable. Heterogeneous conditions can accelerate the reaction or reduce the degradation of products under the reaction conditions.

Phase transfer catalysts are usually used in two immiscible solvents, and the reaction takes place on the organic phase or interface. Sometimes bases, such as potassium carbonate, are also used in solid-liquid phase transfer catalytic reactions.

In some developed heterogeneous reactions, raw materials will dissolve as the reaction progresses. Some reactions are suspended from beginning to end. Choosing a solvent with certain solubility to the components can improve the reaction efficiency, such as adding ethanol or DMSO to the water phase for reaction. Some reactions, heterogeneous conditions may also increase side reactions.

Schotten-Baumann reaction is usually used for large-scale preparation of amides. Specifically, amine is condensed with acyl chloride or anhydride, and then the generated acid is neutralized with an alkali solution. If alkali is not added, the theoretical yield of the reaction between amine and acyl chloride with equal molar amount is only 50%. If no organic solvent is added, the product amide will precipitate and mix with the raw materials, so organic solvent is generally used. The use of water-immiscible organic solvents can reduce the degradation of hydrolyzable reagents and products.

The preparation of acyl chloride in dichloromethane requires more careful operation (Vilsmeier reagent can be dissolved in dichloromethane, but the reaction is exothermic and the product is easy to racemize). DMF is not suitable for the preparation of acyl chloride, DMF and chlorination reagent can form dimethylaminoformyl chloride (DMCC), which is carcinogenic to animals at μg/mg level.

Schotten-Baumann coupling reaction is carried out above pH 8, and acyl chloride is easy to hydrolyze, which shows the formation and racemization of azlactone. However, when pH