Inverse addition method

The lithium aluminium hydride reductions often proceed at room temperature or below and are usually rapid and free from side reactions. The compound to be reduced is added slowly to an excess of the reagent suspended or dissolved in ether (normal addition). Selective reduction of polar groups in the presence of other reducible functions can frequently be achieved by an inverse addition method the reagent is added slowly to the substance to be reduced, so that the reagent is never present in excess. Thus, by inverse addition cinnamaldehyde (6.44) is reduced to cinnamyl alcohol (6.3). Normal addition gives dihydrocinnamyl alcohol (6.4). 

Diphenylcyclopropenylium ion 1 was reduced with sodium borohydride to give 1,2-diphenyl-cyclopropene (2). However, unless the inverse addition method was applied, 2 was rapidly attacked by the unchanged cyclopropenylium ion, resulting in cleavage of the three-membered ring and recyclization to afford 1,2,4,5-tetraphenylbenzene (3) as the final product in quantitative yield. 

In addition to the efflux method, several experiments have been performed by means of an inverse GPC method to assess the capsule permeability. Such measurements are considered to be more accurate and representative for high molecular weight species since they are not sensitive to protein adsorption on the capsule surface. This method, however, cannot be used for a massive screening of capsule permeability due to its time requirements. 

The yield in the previously published method for the preparation of this sulfide is low, affording chiefly l,2-bis(phenylthio)ethane. The problem is overcome here by utilization of an inverse addition procedure. 

Order of Addition—Variation in the order of addition of substrate, alkylUthinm, and electrophile are possible. The method of choice will be dictated by the chemistry. Inverse addition of the substrate to a solution of -BuLi in the appropriate solvent may be a particularly useful approach, because it ensures that there is an excess of the alkyllithium at all times during the addition. Clearly, potential problems (HAZOP review) that may result from starting with a reactor charged with n-BuLi need to be considered. 

---