Chemical transformations and chemical
separations are the two separate aspects of chemical 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:
1. thermodynamic bond energy calculations.
2. model studies using other substrates
3. kinetic data on the reaction type
4. a proposed or established mechanistic pathway
5. results of initial attempts
6. physical characteristics of the substrate, reagent and proposed
solvents
7. possible or known stoichiometry
8. reaction database results
Most reactions are analogs 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. This blog asks and
tries to answer the question, “Could we construct a protocol that would be consistently more efficient than hunches
for getting reactions, which at first fail, to succeed?” “Can we assemble a series of questions that
can guide us almost directly to simple ingenious adjustments that make these
reactions work?”
Let us use a standard problem analysis
approach. A failed reaction is an example of a deviation. 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 fructuous direction. Often we already
have useful information we just don’t know how to read the clues left by the
misbehaving molecules:
1. Did the mixture turn black and/or precipitate an additional phase?
2. Did the substrate signal disappear according to our analytical
method?
3. Was there a noticeable sign of reaction either physically or
according to the method of detection?
4. Does the reaction occur so rapidly that if a sample is inspected at half-addition time of the rate-controlling reactant, one can already see new materials present?
5. After complete addition is
there still no evidence of anything going on?
6. Does a reaction mixture that 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 that occur in the test reaction that
failed? We are trying to answer the
question, “Is the cause of failure some interaction that does not involve the
substrate, such as reagent degradation under the reaction conditions?”
7. Are the reagents and solvents purified or are they already
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 as
possible of the possible, but less likely, causes. First, simplify the problem by eliminating causes that can easily be avoided (impurities in starting materials);
then when the reaction is successful return and find out whether the ordinary grades of materials will work
equally well. The principle 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.
8. A common cause of total failure is the wrong reagent, wrong solvent,
or an improperly prepared reagent.
9. Is the reaction failing or is the analytical method that is
providing that result failing. Try a
different method to follow the reaction's course.
10. Is the substrate itself a mixture and that is what is responsible
for the reaction mixture?
11. Is there any reaction when the reactants are left for a much
extended period under the reactive conditions (ie. 3 days or 1 week)? Is it
just a very slow reaction?
12. Are the starting materials that enter the stoichiometric equation
still present or have some of them disappeared?
13. When the reaction components are used in stoichiometric ratio is
there some recovered starting material?
14. Is the reaction product completely the incorrect material or is
there a mixture of correct and incorrect products (competitive reactions)?
15. How many side products are there in fact? One, several, many?
16. 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)?
17. How much change is possible in the substrate? (only portions of the
molecule that are later removed, such as protecting groups can be
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?
18. Is(are) the functional group(s) in the substrate in an environment
that 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?
19. When trying different solvents, use the conditions of an example
done in the same solvent if possible. The solvent is the most significant variable after substrate and reagent. If
you are using a solvent different from that in any of the literature examples expect
trouble.
20. If prior art examples of the reaction are all run in solvents in
which your substrate is insoluble anticipate problems. Could you easily modify the substrate by changing
protecting groups, for example, to give solubility in one of the demonstrated
solvents?
21. Could 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 done in the presence of a non-reacting group as
in your substrate.
22. Does one of the reactants polymerize under the reaction
conditions? Is a high dilution head
required? Would one help?
23. Is an excess of either reactant disadvantageous? Would a motor-driven syringe addition, to keep
both reactants at low concentration, help?
24. If the reaction proceeds, but not far enough or not completely, can
the equilibrium be driven by the removal of a co-product or by starting with an excess of a
co-reactant?
25. Is the desired product being formed but then destroyed in a
subsequent reaction? Should a trapping
agent, derivatizing reagent, or a second immiscible solvent be added to remove
the product once formed? Could a different solvent
be used from which product would precipitate?
26. 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? ie. Pyrolysis
27. Could the equilibrium be tricked by only bringing the catalyst in
contact with the reactants and not the product? (for example: fractionating distillation column with only the volatile reactant condensing being returned to the still pot through a catalyst-filled tube reactor)
28. Could some of the reactants or intermediates be physically separated
from each other by immobilization on polymeric resins (Wolf & Lamb
reactions)?
29. Could the reaction rate of the desired reaction be deleteriously
affected by salt effects where the co-product is a salt?
30. 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?
31. Consider 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?
32. Have you adequately excluded oxygen and/or water? These are the most common interferences.
33. Have you investigated what catalysts for your transformation might
be reported in the literature? Making
the desired reaction go faster can help its competitiveness and reduce so by-products.
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