A very modern reducing agent
The Institute of Inorganic Chemistry AS CR, in the Czech Republic, reviews the benefits of using the reducing agent Synhydrid in place of lithium hydrido aluminate in modern industrial organic synthesis
The Institute of Inorganic Chemistry AS CR, in the Czech Republic, reviews the benefits of using the reducing agent Synhydrid in place of lithium hydrido aluminate in modern industrial organic synthesis
Synhydrid or Sodium Dihydrido-bis (2-methoxyethoxo) aluminate (SDMA) has the chemical formulae NaAlH2(OCH2CH2OCH3)2 and is a complex hydride, soluble in aprotic organic solvents including aromatic hydrocarbons. It was first prepared in 1965 by the Institute of Inorganic Chemistry of the Academy of Science in the Czech Republic.
During the past 40 years, Synhydrid has increasingly been introduced as a replacement for the widely used lithium aluminium hydrides (LiAlH4 and LAH), mainly because it has a very similar reaction force and can reduce a similar variety of compounds, but is a safer chemical agent to handle and more suitable in many technological processes.
Synhydrid, when supplied as a 70% toluene solution, is not self-igniting, but reacts vigorously with water and protic solvents, although not explosively so, therefore allowing continuous and easily-controlled dosing into the reaction mixture. Technology based on Synhydride can lead to the replacement of flammable agents, such as ethyl ether, or other unpleasant agents such as tetrahydrofuran, with a variety of other solvents, particularly aromatic hydrocarbons. Solvent alterations from non-polar hydrocarbons up to high polar glyms can lead in many cases to quite different products.
The thermal stability of Synhydrid up to 170oC enables reduction reactions to be carried out at relatively high temperatures at which LiAlH4 would decompose. A specific example of a reaction using Synhydride is the methylation of hydrocarbons and the reduction products formed from other compounds.
The following article provides a summary of the differences between the reduction properties of Synhydrid and those of LiAlH4, although it is not exhaustive and does not mention cases where both compounds behave similarly or the differences are insignificant.
This summary of reductions and analogous reactions is designed to provide inspiration and point out the type of reactions where the use of Synhydrid could offer new applications or simplified technology.
Geminal diphenyl olefins are, at 80oC, already reduced by Synhydrid in toluene to the corresponding saturated hydrocarbon.
Reaction shceme 1
Saturated aromatic hydrocarbons at 160-175oC dimerize, or can be methylated.
Reaction scheme 2
Dehalogenation: The compound LiAlH4 is more ef-ficient in the parallel dehalogenation of bromine or iodine with the much less reactive chlorine. However, Synhydrid is a better dehalogenation agent than LiAlH4 for some aromatic compounds.
Reduction of carbonyl compounds: Both hydrides will reduce aldehyde and ketone carbonyl groups very easily. During the reaction of aromatic aldehydes and ketones, a partial hydrogenolysis up to the corresponding hydrocarbon takes place even when performing the reduction in ether or tetrahydrofuran. This side reaction, which in most cases is undesirable, does not appear until above 100oC when using Synhydrid. The hydrogenolysis is promoted by the presence of 1st class substituents on the aromatic ring.
Reaction scheme 3
Reduction of carboxylic acids and their derivatives: Alifatic carboxylic acids are reduced equally well by both LiAlH4 and Synhydrid. As a rule, the double bond remains intact in the resulting products. Synhydride can also reduce insoluble salts of carboxylic acids effectively. In terms of the reduction of esters, chlorides and amides of aliphatic acids (R-CO2R", R-COCl, R-CONH2,) at room or elevated temperatures there is no substantial difference between both agents.
Aromatic carboxylic acids reduced by LiAlH4 produce a better yield than is produced using Synhydrid. In adition, when reducing with Synhydrid in xylene under reflux (140oC), the reduction of the carboxylic group proceeds up to methyl.
Reduction of esters to aldehydes: At laboratory temperatures or at the boiling point of the solvent both agents behave in a similar way when reducing esters to aldehydes. However, when using Synhydrid at low temperatures, the aldehyde stage can be recognised which it cannot be with LiAlH4.
Reaction scheme 4
Reduction of amides to aldehydes: When reducing acid amides using LiAlH4, the aldehyde stage can be caught only in exceptional cases. In contrast a sophisticated method via N-acylsaccharin derivatives has been developed for the preparation of aldehydes from the respective acids, or their readily obtainable acid chlorides (R-CO-Cl) by reducing with Synhydrid.
Reaction scheme 5
The resulting yield of aldehyde reaches 65-80%, even when reducing unsaturated acids (e.g. cinnamic acid).
Reduction of nitriles: Aromatic nitriles are reduced with good yields to the corresponding primary amines by both LiAlH4 and Synhydrid. Unlike LiAlH4, however, Synhydrid does not reduce aliphatic nitriles with hydrogen on and (alpha- symbol) carbon atom.
For use in connection with the synthesis of aldehydes extended with the hydroxy methylene group, a method has been developed using Synhydrid for the partial reduction of cyanohydrins with hydroxyl protected by R2= CH(CH3)OC2H5.
Reaction scheme 6
Drying organic aprotic solvents: The main advantages of Synhydride compared with LiAlH4 are its solubility in a variety of organic solvents ranging from aromatic hydrocarbons to polar glycol ethers and its safer and simpler handling. Synhydride removes not only water but also other impurities containing organic active hydrogen (alcohols, amines, amides, organic acids etc.) or reducible compounds (primarily all dangerous peroxides but also aldehydes and ketones).