Organic Chemistry 342-2016
LABNOTES-3
FEB 20-APR 5, 2016
Pharmaceutical Role-Playing Project part 3: Reaction Design and Execution
EXPERIMENTAL DESIGN: Practically everything about your reaction will hinge upon how
you answer this question: “How much should I use?” I cannot answer that for you, but I can offer
some useless guidelines-“enough but not too much”.
All kidding aside, you will want to seriously consider this question. In truth, you will want to use
enough material that your other ingredients can be accurately measured, will yield enough product
to carry on to the next reaction if it succeeds, but not so much that a failed reaction will consume
too much of your precious supply. While you will have balances available to you that are accurate
to the tenth-milligram (0.0001 g), it is difficult to accurately/reliably/reproducibly measure less
than one milligram or one microliter. Additionally, when your reaction is over and you have
isolated your product, you will want enough to characterize. Think about what “scale” or size of
reaction you have been accustomed to working with so far in lab.
Another thing to consider is what glassware you have available to use. You need to have
everything “fit” into the glassware during the reaction. If you are simply stirring a reaction at
room temperature, it is OK to fill the glassware up to 80% full, however if you are refluxing your
reaction, you should not exceed 65% full. Don’t forget to add up all of the volumes you will be
using. In particular, some reaction procedures have more than one addition during the course of
the reaction, so don’t forget to account for volumes that are added after the reaction is “over”. It is
unlikely that you will need glassware larger than in the macrokit (i.e. 250-mL flask).
One of the obvious considerations is to not use all of your materials in a single “all-of-nothing”
experiment. It is likely that you will have to conduct each reaction more than once, since “real”
research is not nearly as time and student-tested as the experiments that you have been doing in
lab. However, because of time constraints, it will be very unlikely that you will be doing each
reaction more than three or four times (unless the reaction procedure is very straightforward).
I like to completely plan a reaction from start to finish, including all of the calculations of masses
and volumes to use, all of the glassware I will need, and a timeline for the reaction before opening
a single reagent bottle. Careful planning will save you tremendous time, especially if your
reaction needs to be carried out using Schlenk techniques (i.e air or moisture sensitive, see below).
Time management is crucial for a successful experiment. You will not want to start a reaction at
6pm that requires you to add something eight hours later (for example).
Remember that to scale your reaction, you will want to preserve the molar equivalents (#eq) of the
reactants from the experiment that you are following, as well as the concentrations of reactants in
solution. Reaction times and temperatures are not scaled. This is the main reason for the #eq
column in your lab book, for it allows easy conversion from one reaction scale to another.
EXTENDEND REACTIONS: If your reaction time interval exceeds the laboratory timeframe,
for example “stirred for 60 h”, it will be very important that you plan your reaction carefully. You
will not want to have to deal with your reactions at odd or inconvenient times once you have them
started. If your experiment has a 6 hour reflux, but a very quick work-up, you might want to start
the experiment early in the morning and have it “finish” during your normal laboratory time so
that you can work it up during lab hours. If your experiment needs to go overnight, you do not
have to “babysit” it, rather special precautions will be taken to ensure the reaction does not go
awry during the middle of the night. An example is securing the water hoses of the condenser with
copper wire so that they do not pop off unexpectedly during the night and flood the computer
cluster on the second floor. You will want to watch your reaction until it establishes equilibrium
before leaving it unattended, since you will need to be confident it will not change during the
unobserved period. This is more critical for refluxed reactions than experiments stirred at room
temperature. Also if you need to maintain a heated reaction, an oil bath must be used to ensure
unattended, constant temperature conditions. You should equilibrate an oil bath to your desired
temperature at least one day prior to needing it.
AIR/WATER-SENSITIVE REACTIONS: If your reaction is air or water sensitive (one clue is
the use of dry or anhydrous solvents), it is even more critical that you meticulously plan your
experiment. All of the glassware that is potentially in physical contact (including vapor) with your
reaction needs to be either dried (heated) in the oven at 100oC overnight and assembled hot under
dry nitrogen (don’t forget the stirring vane/bar). The reason for this is that a fine layer of water
molecules are absorbed to all glass surfaces and the water molecules need to be heated off and not
allowed to reabsorb to the surface if the glassware cools in the ambient atmosphere. There is a
shortcut available as an alternative to overnight drying, but it is dangerous and shows poor
planning on your part. Since I will have to help you learn some special techniques for this type
of experiment, it will be critical that you make an appointment with me a day before you
wish to do your reaction so that I can explain this technique and you are able to prepare to
do it. I will also need to make sure that a Schlenk vacuum line is available to you. You might
want to consider doing any “easy” reactions first before tackling the more technically challenging
air-sensitive reaction.
SET-UP and WORK-UP: There are two main components to reaction design/implementation:
set-up and work-up. Once the reaction is completed, the procedure to isolate and purify your
desired compound from the complex mixture is called the “work-up”. It tends to be the most
difficult portion of synthetic chemistry if you do not have literature precedent for “fishing” your
compound out of the reaction mixture. Two common techniques that you have yet to use in a
work-up procedure are rotary evaporation, sometimes called solvent removal in vacuo or under
reduced pressure, and column chromatography. We have access to both, but hopefully your
product will be pure enough to avoid column chromatography.
TIME-MANAGEMENT: Since most reactions are dangerous, and students need to know
someone is available to help in an emergency situation, it is very important that you realize that I
need to be present in the department when you are conducting your reactions. That means that you
must plan your laboratory time with my schedule in mind. Please remember that I have
obligations outside of Concordia, and that spending time with my wife and daughter is important
to me. I will try to be accommodating when I can – and I will ask that you do the same. When
planning your lab time, please try to adhere to the following guidelines:
- I MUST be in the lab (or thereabouts) when you are physically in the lab (i.e. setting up
a reaction, working up a reaction), but I do not need to be around if you are taking
melting points, running the GC/MS, taking IR or NMR spectra, or if the reaction is
running overnight. It is my hope that you will be able to do everything during your
scheduled lab time, and this is why serious thought about choosing your reactions is so
important. You will need to check with me/give me advance notice if you plan to do
any work outside of lab times. My daily schedule is available online and on my office
door if you need to check my availability during normal working hours. I am willing to
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extend the lab hours if I am available, but I will need advance notice (24 hour or more)
to arrange it, and even then it may not be possible in some situations.
The scheduled lab times are fair game for any company regardless of whether it is
“your” lab time. However if things get too congested, crowded or dangerous and those
companies that are using “their” lab time are unable to work productively, I will have
to dismiss interlopers.
All reactions should be planned out so that they are started and completed during
reasonable hours (i.e. no reactions should be started before 8:30 a.m., and the lab
should be vacated no later than 6 p.m., unless other arrangements have been made with
me prior to the need). Julie and Eliana appreciate your consideration of my time…
Both organic chemists must be present during the setup and workup, but not necessarily
while the reaction is “cooking”
ANALYSIS: Once you have your product in hand and wish to analyze it, the analytical chemist
will need to take an 1H/13C-NMR of the sample first. The reason for this is that injecting water,
acids or “dirty” samples into the GC/MS will significantly damage the instruments. Once the
analytical chemist can verify to me that your sample is injectable (a NMR spectra) then I will
allow her to use the GC/MS to analyze your reactions products.