A problem that presents itself on-scale, but which is not any difficulty in the laboratory is the exothermicity of many chemical reactions. It is much easier to control the temperature of an exothermic reaction to a narrow range of reaction temperatures than to do so in the plant. The reason, of course, is the much lower ratio of total volume to surface area in the laboratory.
Upon scale-up, exothermic reactions that do not suffer from this difficulty are those in which the reaction temperature is the reflux temperature of the reaction solvent.
An idea that might be useful in scaling down reactions so that they become more transferable to the plant would be to use a binary solvent mixture for exothermic reactions comprising in major part that solvent which is selected on the basis of the facilitation it provides for the particular reaction mechanism, for example, a dipolar-aprotic solvent for an SN2 nucleophilic substitution such as DMSO, and a minor solvent component that is chosen to have a boiling point at the desired reaction temperature. The minor solvent, of course, must be inert to the reaction conditions and must not at a level that inhibits the required reaction. For example, acetone might be combined with DMSO to maintain an upper reaction temperature of 56∞C. Acetone would not likely interfere with the substitution since it is also a dipolar aprotic solvent.
If a laboratory process was developed with such a mixture of solvents, there would not be any difficulty controlling the temperature of the reaction on scale up. At the end of the reaction, if the isolation can more easily be conducted upon a mixture in 100% DMSO, the acetone can be distilled away.
Another possibility for the minor component of the solvent mixture could be a solvent that forms an azeotrope with water so that the solvent combination could be dried in situ.
Another strategy for choosing a solvent for a reaction is to select the solvent from which the intermediate in the step is going to be finally crystallized. Although the substrate and reagents may not be substantially soluble in this solvent, this may not matter. The reaction may proceed even though a homogeneous solution is not immediately achieved. Indeed, based upon the work done with ‘on water’ reactions, almost complete insolubility can be a significant advantage. The advantage of homogeneous solution is most important for the ease of doing an in-process check for reaction completion rather than difficulties in getting a satisfactory reaction rate. The situation does not have the difficulty of a reaction without solvent at all where the absence of a material that can boil prevents the reactor contents from disposing of thermal energy and can lead to a runaway exotherm.
The phenomenon of reactions ‘on water’ often works because the water importance is not as a solvent for the reaction but it acts as a heat sink to modulate the exothermicity and increase the ‘minimum stirrable volume’.
In another situation, the substantial ‘on water’ phase is a buffer to remove an acid or base co-product that is formed but could interfere with further reaction. In brominations ‘on water’ the aqueous phase removes the HBr co-product.
Another solvent idea is dependent upon the fact that a 1:1 v/v mixture of DMF and cyclohexane is thermomorphic. At 60 C it is a homogeneous single phase but at 25 C it forms two separable phases. Chinese Chemical Letters Vol. 16, No. 8, pp 1017-1020, 2005 http://www.imm.ac.cn/journal/ccl.html
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