1. Literature  

Whenever possible, the available literature should be consulted in order to make the reaction more efficient. There is no reason to invent a new reaction if plenty of work has been done in the field already. For most parts consulting the reader about the experimental procedure should be the first step because these procedures have already been optimized for the students in terms of resources and safety aspects. On some occasions, the procedure will not be provided in the reader i.e., the esterification in Chem 30BL or the proposal in Chem 30CL, which means that the student has to come up with his own procedure based on the literature.

Chemists use search engines and internet sources that make the search easier. Albeit, in some cases it takes some time to learn how these sources can be used efficiently. Most of these sources are web-based i.e., Scifinder, Reaxys, Orgsyn.org, Google Scholar. However, one has to keep in mind that not everything can be found in these sources, but they can usually provide meaningful information if the experimenter has a clear idea what he is looking for (Hint: this is where the chemical knowledge and intuition comes in). Most of the time, these sources provide references to research articles which contain procedures, physical properties and/or spectroscopic data. If this is not the case, the experimenter has to design his own experiment, which requires some more thorough planning.

The library assignment in Chem 30BL introduces the students to Reaxys. The students have to locate several research papers and extract information from these papers. The initial library  training in Chem 30Cl and the upper division labs adds Scifinder to the tool box. These tools are needed to write a formal report and/or a proposal.


2. Planning

Before carrying out a reaction, several issues have to be considered in its planning and scaling. The most important part is obviously to have a clear expectation about the chemistry involved in the reaction. Based on that the following issues have to be considered:

a. If reaction undergoes a ‘true equilibrium’ (K_eq<<100) i.e., esterification, the product yield can often be increased by using an excess of one of the reactants. Which reactant is used in excess often depends on the cost and the availability of the individual compounds. However, one has to keep the isolation of the product from the excess starting material later on in mind as well. In some reactions, the yield can be increased by removing one of the products i.e., as a gas, an insoluble precipitate (i.e., aldol reaction) or by distilling the main product or a byproduct out of the mixture (i.e., elimination reaction). In those cases, the Le Châtelier Principle is used (see also appropriate Equilibrium chapter for more details).

b. If the number of molecules increases during the reaction, the reaction is usually entropy driven. This is especially true for reactions that afford gases as byproducts i.e., the Diels-Alder reaction where N₂, CO and CO₂ gas is formed. In those cases, a higher reaction temperature can potentially promote the reaction (ΔG=ΔH-TΔS, if ΔS>0, ΔG becomes more negative for higher temperatures). Hence, a solvent with a higher boiling point i.e., 1,2-dimethoxyethane instead of diethyl ether can be very beneficial here considering that the rate of reaction for many reactions doubles if the temperature is increased by 10 ^oC! However, an elevated temperature is not always advantageous because the selectivity often decreases then as well.

c. If a reaction is very exothermic, it is necessary to cool the mixture initially to slow down the reaction. This prevents the reaction to get out of control, and often limits side reactions as well i.e., the reagent with the solvent, rearrangement, polynitration, etc.

d. In cases where a gas is formed as byproduct, the reaction has to be carefully controlled in order to prevent excessive foaming or an explosion. The glassware has to be larger than normal as well to have a buffer (calculate the quantity of gas formed to get an idea about the magnitude!). Boiling solutions that release gases tend to foam very heavily!

e. If a precipitate was formed, the reaction should be well stirred to prevent the precipitate from settling. A precipitate traps reactants and/or leads to overheating and violent bumping during reflux.

f. Reactive intermediates are usually only generated in-situ. Often times, they are not stable enough to be isolated, or the isolation is too tedious and does not justify the effort. There are several examples, where reactive species are obtained in the solution and immediately reacted i.e., thiamine (Benzoin condensation), enolate (Aldol condensation), benzyne (Diels-Alder reaction), nitronium ion (nitration), acylium ion (acylation), Grignard reagent, etc.

g. Which solvent is the best solvent for the reaction? Ideally, the reactants should dissolve very well, while the product or byproducts should be poorly soluble. This way the equilibrium is pushed in direction of the products. A large temperature range between the freezing point and the boiling point is also beneficial in many cases. However, a very high of a boiling point is not good either because the solvent is difficult to remove later on.

h. How fast is the reaction? If the reaction is slow, an increase of the reaction temperature can speed it up. From this point of view a solvent with a higher boiling point will be advantageous, because the temperature in the mixture is higher during reflux.


3. Scaling

The reactions that that are carried out in the laboratory are set up in a scale that enough material obtained to carry out its characterization if a decent yield is obtained. If a reaction were scaled up or scaled down, several things have to be kept in mind:

1. If a reaction is scaled up, larger equipment should to be used as well (if available). Often times, the reaction is more violent and more difficult to control, but does not necessarily afford much more of the product. A scaled up reaction often also requires much more time to complete during to mixing problems.

2. If a reaction is scaled down, one of the biggest problems is to prevent the loss of a significant amount of the product during the transfers. A common mistake is the use of a (big) Büchner funnel while processing a minute amount of precipitate. Surely, it goes faster to filter the solution, but it will also be very difficult to collect the product from the filter paper without contaminating it with many fibers or a significant loss of material.

3. If the scale of a reaction has to be adjusted, it is most important to maintain the appropriate ratio(s) of the reactants that are directly involved in the reaction. For instance, a procedure asks to react 5 g of compound A with 3 g of compound B and 1 g of compound C (which is the catalyst) in 50 mL of solvent. If only 2 g of compound A were available, 1.2 g of compound B and 0.4 g of compound C should be used to keep the ratio constant. The amount of solvent should be approximately 20 mL, but does not have to be measured to 20.00 mL accuracy! Note that the reaction time should remain the same because the rate of the reaction would not change much if similar concentrations were used in the reaction.

In summary, whenever a reaction is carried out, the following questions should be asked:

a. How much of the product is expected assuming 100 % yield (For most of the reactions carried out in this lab, a yield of 80+ % is more reasonable!)? How much product will be needed after characterization to continue the project if this is necessary?

b. For which chemicals in the reaction is it important to be accurate in the measurement? Where is an approximate amount good enough i.e., solvents, compounds used in a large excess already, catalyst, etc.?

c. If a compound has to be used in excess, which one should be used in excess?

d. What are the byproducts of the reaction? Can the formation of these byproducts be used as a driving force for the reaction? Is there an evolution of gases that requires a more controlled reaction and bigger size glassware?

e. Is it worth isolating an intermediate or is it better to proceed with the reaction and do the purification at the end of the reaction sequence?

f. How can the reaction progress be monitored using TLC? The information from the literature should provide an approximate idea about conditions but they are nothing absolute because there are many factors that influence the R_f-value i.e., the solvent used in the reaction. Are there any other methods to monitor the progress i.e., color change, precipitation, etc.?

g. How can the target compound be isolated? Which purity is required for the final product?

h. How can the student verify that the reaction afforded the desired product? Which characterization techniques are available i.e., melting point, spectroscopy, etc.?