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kilomentor | 02 February, 2007 06:20
Chemical transformations and chemical separations are the building blocks of process synthesis. It is chemical transformations that create the reaction intermediates that connect postulated starting materials to desired final product. What information might we have as pointers to decide how to achieve a conversion:
Most reactions are analogues of previous known reactions and 2, 6 and 7 are usually sufficient, with chromatography, to get the first small quantities of the desired material- it is when reactions inexplicably fail totally that the ordinary chemist scratches his head and makes random changes. “Could we construct a protocol which would be consistently more efficiently than hunch experimentation for causing reactions which at first fail, to succeed?” “Can we construct a series of questions that can guide us to simple ingenious adjustments that make these reactions work?”
Applying the Kepner-Tregoe problem-solving methodology, a failed reaction is an example of deviation in a problem analysis. What is the deviation? It is a deviation not from the normal but from what we want and expected. What is it not?
Some particular questions can set one off in a fruitful direction. Often we already have useful information we just don’t know how to read the signs left by the misbehaving molecules:
Did the mixture turn black and/or precipitate an additional phase?
Did the substrate signal disappear according to your analytical method?
Was there a noticeable sign of reaction either visually or according to the method of detection?
Does any reaction occur so rapidly that if a sample is inspected at half addition time of one reactant, one can already see new materials present?
Are all reactions slow compared to the time of mixing?
Does a reaction mixture which contains all the components except the substrate and which is subjected to the same regime of conditions, turn color or show any of the by-products which occur in the test reaction which failed? We are trying to answer the question is the cause something other than the reagent and conditions together?
Are the reagents and solvents purified or are they impure? When a reaction fails it is usually a wise step in subsequent investigation to use highly purified materials. The reason is that when you are looking for an unknown cause it is vitally important to remove as many potential but less likely causes as possible. First solve the problem of failed reaction; then return and find out whether the ordinary grades of materials will work equally well. The rule is to drive for a positive result taking every precaution, then knowing that a solution is available, find out how many of these precautions can be relaxed with the same good result.
A common cause of total failure is the wrong reagent, wrong solvent or an improperly prepared reagent. When a reaction unexpectedly fails in the laboratory- before making changes- confirm the failure while collecting more information.
Is the reaction failing or is the analytical method, which is providing the result failing. Try a different method of following the reaction.
Is one reactant itself a mixture, which is responsible for the reaction mixture?
Is there any reaction when the reactants are left for a much extended period under the reactive conditions (i.e. 3 days or 1 week). Is it just a very slow reaction? A slow reaction can be addressed simply by using severe conditions. Failure to react is not a problem. Just hit it harder.
re Are the starting components of the equation still present or do they disappear?
WWhen the reaction components are used in stoichiometric ratio is there some recovered starting material?
Is Is the reaction product completely the incorrect material or is there a mixture of correct and incorrect product (competitive reactions)?
How many side products can you detect? One, several, many?
1 How much change is possible in the actual reagent? How many choices do you have for doing the transformation? Ie. Chlorination (many), carbanion(fewer), oxidation (many)?
1 How much variation is possible in the substrate? (only portions of the molecule which are later removed, such as protecting groups can be normally changed). Does the Newman Rule of 6 or the inductive effect of changes at these variable sites suggest some influence at the desired reaction site?
1IIs(are) the functional group(s) in the substrate in an environment which is significantly different from any of the same functional groups in the literature precedents? Could it be that this difference accounts for the non-reactivity?
1 When trying different solvents use the conditions of an example done in that same solvent if possible. Solvent is the most significant variable after substrate and reagent.
2 If prior art examples of the reaction are all run in solvents in which your substrate is insoluble anticipate problems. Trying to modify the substrate by some modifiable substituents that will give solubility in the demonstrated solvent can solve the problem.
21Could the failure of the planned reaction be caused by the presence of another interfering functionality. Using reaction database searching try to find an example of the transformation you are trying in the presence of a non-reacting group the same as the one in your desired substrate.
2 Does one of the reactants polymerize under the reaction conditions? Polymerization is often detected as a smear in TLC or a broad signal in HPLC. Is a high dilution head required? Would it help?
IIs an excess of either reactant disadvantageous? Would motor-driven syringe addition to keep both reactants at low concentration help?
If the reaction proceeds but not far enough or not completely, can some changes make the equilibrium be driven by the removal of a co-product?
2 Is the desired product being formed but then destroyed in a subsequent reaction? Should a trapping agent or derivatizing reagent or a second immiscible solvent be added to remove the product once formed? Could a solvent be selected from which product could precipitate?
2 Is the desired reaction product destroyed thermally by the severity of the conditions under which it is formed? Would a continuous reactor of some form in which the reactants are physically moved through a reactive zone into a stable zone help? i.e. pyrolysis.
2 Could the equilibrium be tricked by only bringing the catalyst in contact with the reagents and not the product? (ie distilling column under total reflux with condensate being return to the reactor pot through a catalyst filled tube)
2 Could some of the reactants or intermediates be physically separated from each other by immobilization on polymeric resins (Wolf & Lamb reactions).
Where the co-product is a salt, could the desired reaction’s rate be prominently effected by salt effects?
What is the co-product of the reaction? Can it be changed in such a way as to drive the reaction forward? i.e. insoluble co-product, volatile co-product, gaseous co-product, trappable co-product?
31Consider whether a radical chain reaction is destroying some component of your desired transformation. Would a radical inhibitor stop the competing process or slow it down sufficiently?
3 Have you adequately excluded oxygen and/or water? These are the most common interferences.
Have you investigated what possible catalysts for your desired transformation there might be reported in the literature? Making the desired reaction go faster can help its competitiveness and reduce by-products.
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