The Half- Addition In-Process Check (IPC)

 Smart laboratory practice can save process development time and make a chemist more valuable to his or her employer. What kind of synthetic organic chemist would be taking a thin-layer chromatography sample when only 1/2 of the reagent has been added into a reaction? As KiloMentor will explain below: a smart one.

The gradual addition of one of the reactants into a reacting system is typical. The purpose is to avoid an exothermic runaway reaction. 

If the analysis of a quenched reaction mixture at the half-addition point shows both significant product along with either a substantial temperature increase inside the reactor or the need for cooling to prevent such an exotherm, then the need for the precaution is proven.

When this is observed, it signals that the processing is likely sensitive to the rate of addition of the reactant being added because a lot of the reacting is occurring under conditions where the reactant being added is depleted in the reactor compared to its stoichiometry as represented in a balanced equation. If the actual average ratio of reactants is different from that specified by the balanced equation for the desired transformation then in some instances a different chemical outcome can arise from a different mode of reacting. This is convoluted to put in words but simple to illustrate.

Suppose one is attempting to execute the transformation

 1.0 A + 1.0 B reacts to form 1.0 A-B 

where the integers identify the number of moles of A, B, and the adduct A-B.  The transformation issuing conducted by adding gradually, drop by drop A into the entire mole of B. The reaction is exothermic and external cooling must be applied to keep the mixture at a safe temperature. As small portions of A mix together with all of B, A—B is quickly formed, in fact so quickly that essentially no A remains in the mixture between aliquots of addition. All that is in the mixture one could conclude is the formed A—B and the remaining B.

The actual average ratio A: B at any point is far from 1:1!

Now suppose that another reaction in solving A—B is possible. Suppose A—B can react with a second molecule of B:

A—B reacts with B to give B—A—B. Then this overall transformation can be represented as

1.0 A reacts with 2.0 B giving 1.0 B—A—B

This is more consistent with what the actual stoichiometry is and is likely promoted by this need for the gradual addition of A.

What we can conclude is that the gradual addition of one reactant to the other may favor side reactions with other stoichiometries more consistent with the actual average ratio of reactant that occurs in the reactor. Substantial formation of product at the 1/2 addition point is a warning that this may be occurring.  

If the gradual addition is to control the heat of mixing or some other preliminary reaction equilibration then it is OK to see no product at this half-addition stage.

If this misfortune is occurring what can be done? In the example we have looked at the gradual addition of B to A is likely to minimize the formation of B—A—B. In other instances, the gradual simultaneous addition of both A and B at the same rate may be examined. This way the actual ratio of A to B is held more closely constant near 1:1 through the reaction time.

But these solutions are made pertinent only after the 1/2 addition IPC has warned the researcher that they may be particularly needed.