GUTS Summary – 2011 Academic Year
“NEW ORGANIC CHEMISTRY LABS FOR CH 204”
John K. Snyder
The GUTS award for the 2011/2012 academic year focused on the
development of new laboratory procedures for CH 204, Organic Chemistry. The
experiments in this course have lagged behind recent advances in modern organic
chemistry, and there was a near desperate need for new procedures reflecting
modern synthetic organic chemistry. Further complicating the situation is the
reality that most organic laboratory manuals are themselves out of date and
expensive. We have established a database of modern organic experiments using
BU’s DCOMMON resource that is open to the public, so other educational institutions
may make use of the new, experimental procedures. The goal of the GUTS project
was to adapt new procedures taken directly from the recent organic literature for
use in the sophomore organic laboratory (CH 204) as well as in the two other
sophomore organic classes (CH 211/212 and CH 214). The award was used to
support a talented junior undergraduate, Howard Szeto, to troubleshoot and writeup up the procedures, and deposit them in the DCOMMON database. Given the lack
of other resources for developing new experiments, the GUTS proposal was
submitted.
Two new procedures were successfully completed, both of which we
incorporated into the CH 211/212 course as a pilot for use in CH 204. One of these
experiments (Acetal Formation) proved to be too challenging for the sophomore
undergraduate level, even with the advanced students in CH 211, so this procedure
will not be used in CH 204. The second experiment (Click Chemistry) was very
successful and will be used in all our sophomore level organic labs. The procedures
for both experiments are included on the following pages. The procedure for the
click chemistry has also been uploaded onto the DCOMMON website
(http://dcommon.bu.edu/xmlui/handle/2144/1415).
Intensive Organic Chemistry I, CH211 – Fall 2011
Experiment 5 – Acetal Formation
Introduction:
A common problem that organic chemists encounter is that functional groups
often react with a variety of reagents. For example, carbonyls react with alcohols, water,
cyanide, Grignard reagents, and organolithiums, to name a few. Likewise, many reagents
are unselective themselves and will react with a variety of functional groups. For
example, lithium aluminum hydride reacts with both ketones/aldehydes and
esters/amides. So, controlling which functional groups react and when they react is
important for any multistep synthesis, yet it poses a significant synthetic challenge.
One way to control reactivity is to reduce the nucleophilicity/electrophilicity or
acidity/basicity of functional groups, making them inert to a particular reagent. The best
way to do this is to use a protection group, which renders reactive functional groups
temporarily inert so that other, sometimes problematic transformations can proceed
smoothly. Let’s take the following Grignard reaction as an example. Suppose we were to
treat the alkyl bromide below with magnesium metal and then react it with the aldehyde
shown. If you thought you would generate the Grignard reagent, you would be mistaken.
The presence of the two alcohol units would simply protonate any Grignard reagent in
situ, resulting in the debrominated diol product upon workup.
One way to get around this is to reduce the reactivity of the alcohol groups
(essentially removing their acidic protons) by forming an acetal. Then, the Grignard
reagent can be prepared and reacted with a carbonyl to give an alcohol upon workup. The
protecting group can then subsequently be removed to give you the product you wanted
from the first reaction.
So, what makes a good protecting group? There are several factors to consider
when choosing a protecting group, with the relative importance of each dependent upon
the particular transformation. Protecting groups must be:
 Cheap or readily available
 Easy to add AND easy to remove
 Facile characterization (signals easy to see in NMR)
 Stable to a wide range of reaction conditions
 Stable to a wide range of purification conditions
In the example above, the protecting group can be added using acetone and sulfuric acid,
and removed with aqueous acid, so the reagents are cheap, readily available, and the
acetal is easy to form and also easy to hydrolyze. The characterization of the sample is
simple – a signal in the 13C NMR around 100 ppm and two extra methyl signals in the 1H
NMR. The acetal is stable to the Grignard reaction conditions and is also stable to column
chromatography. The only problem is that acetals are sensitive to acid. Hence, you would
want to avoid contact of the product with anything acidic.
Protecting groups can be applied to a variety of functional groups. Some of the
most common protecting groups are used for alcohols, amines, ketones/aldehydes, and
carboxylic acids, since these functional groups provide us with important reactivity
handles in synthesis. However, protecting groups are not always attractive, especially on
an industrial scale. Using a protecting group means that two steps are added to any
synthesis (one for addition, one for removal of protecting group). This increases the
overall cost of a synthesis and the length of time it takes to make the desired product. In
addition, the yield of a synthesis will often be lower and the use of reagents and solvents
makes the use of protecting groups environmentally unfriendly and atom ineconomical.
Despite these shortcomings, you will find protecting groups being used extensively in the
literature since organic chemists still are not as good as Nature at making molecules.
Acetal Formation
In this week’s experiment, you will be performing the first part of a multistep
sequence that involves acetal formation, oxidation, and olefination. You will each use a
sample of glycerol, which contains three alcohol functional groups (2 primary alcohols
and 1 secondary alcohol). Oxidation of glycerol directly will be unselective for these
hydroxyl groups. However, protection of two of the alcohols as an acetal will leave the
third alcohol available to participate in the oxidation reaction.
What is the mechanism for this reaction? Well, you know that in the presence of
acid and water, an acetal will hydrolyze to a ketone and two alcohol units. However, if
we use a diol instead of using water as our nucleophile, we call the transformation a
transacetalization. Transacetalizations are often performed for practical purposes – all of
the reagents are soluble in organic solvents. The driving force for the reaction is the
formation of the cyclic acetal, which is at an energy minimum and does not suffer from
the entropic cost of bringing two alcohol units together.
In this experiment, you will also be introduced to multistep synthesis. Since you
will be using the product you generate later in the semester, it is important that you
maximize your yield so that you have enough material to prepare the final compound.
Thus, learning how to work efficiently on a large scale is an important skill to learn. At
the end of the reaction, you will perform another liquid-liquid extraction that will allow
you to separate organic-soluble compounds from aqueous material, but also to wash away
excess DMF solvent. We will also review how to properly dry an organic solution so that
it is free of residual water. Analysis by 1H NMR, IR, and LC/MS will be used for
characterization.
References:
1. Kocienski, P. J. Protecting Groups, 3rd Ed.; Thieme, 1994, 679 p.
2. Darcy, R. J. Chem. Ed. 1994, 71 (12), 1090-1091.
3. Renoll, R. L.; Newman, M. S. Org. Syn. 1955, 3, 502; Renoll, R. L.; Newman, M.
S. Org. Syn. 1948, 28, 73.
Acetal Formation
Equipment:
Microscale glassware kit
25 and 50 mL beakers
10 mL graduated cylinder
1 mL syringes and needles
2.5 or 5 mL syringes
Pasteur pipets
Capillary tubes
TLC plates (thin)
Cotton
Rubber septa
Scintillation vials and caps
NMR tubes
HPLC vials
Thermowells
Stir bars
Chemicals:
Glycerol
Para-toluene sulfonic acid
Tetrahydrofuran
2,2-dimethoxypropane
Methylene chloride (2 x 500 mL)
5% Sodium bicarbonate solution (2 x 500 mL)
Sodium chloride solution (saturated aqueous brine, 2 x 500 mL)
KMnO4 TLC stain
Anhydrous sodium sulfate
Anhydrous magnesium sulfate
Methanol (2 x 200 mL)
Ethyl Acetate (2 x 500 mL)
Deionized water
CDCl3
Procedure: adapted from Darcy, R. J. Chem. Ed. 1994, 71 (12), 1090-1091.
Transacetalization: Using a Pasteur pipet, transfer 1 g (1.0 equiv.) of glycerol into a 10
mL round bottomed flask (glycerol is a syrupy liquid and will clog syringe needles).
Dissolve your sample in 1 mL tetrahydrofuran and stir at room temperature with a stir
bar. Add 3.0 equiv. of 2,2-dimethoxypropane (0.85 g/mL) via syringe and then add 0.02
equiv. para-toluenesulfonic acid and 0.5 equiv. anhydrous magnesium sulfate. Need to
do filter to remove MgSO4 Place a cap over the round bottomed flask and heat the
reaction mixture for 60 minutes at 70 °C using a Thermowell. While your reaction is
heating, prepare a small sample of glycerol in THF to use as a TLC reference. Obtain a
TLC of your reaction mixture after 30 minutes to determine whether it is complete. If it is
not, keep heating for a total of 60 minutes. For proper elution of your TLC, dilute both
your reaction mixture and your TLC standard with methylene chloride in a test tube,
otherwise THF will disrupt the separation on the TLC plate. Use 10% methanol/90%
ethyl acetate as your developing solvent. Visualize your spots both by UV and by
staining your sample with KMnO4 to visualize your spots.
Workup: Pour the reaction mixture into a 50 mL Falcon tube and wash the flask with
methylene chloride. Add a total volume of 20 mL methylene chloride to the Falcon tube,
followed by 10 mL 5% sodium bicarbonate (NaHCO3) solution. Cap the tube and shake
gently, periodically venting your sample. Separate the two layers and then remove the
organic phase. Extract with another 10 mL methylene chloride. To the combined organic
layers, add enough anhydrous sodium sulfate to dry the solution. Filter about 5 mL of the
solution into a tared scintillation vial through a Hirsch funnel containing a small piece of
cotton (to trap any solid Na2SO4). Evaporate the first portion on a hot plate before
filtering a second portion and evaporating again. Repeat this until you have filtered all of
your solution and have rinsed the Falcon tube with 5 mL methylene chloride. Place your
sample in an oven to dry for 5 minutes. Note: you may need to run a column to get rid of
excess 2,2-dimethoxypropane.
Analysis: Obtain a yield of your acetal, measure the IR spectrum of it, and submit a 1H
and 13C NMR (in ~0.7 mL CDCl3) and a GC/MS (<1 mg in 1.5 mL MeOH). Submit your
sample in a scintillation vial labeled with your name and structure to your TF, who will
save the acetal for use in the next stage of the multistep synthesis.
Pre-Lab Exercise:
These questions do not need to be explicitly answered in writing, but you should be able
to answer them prior to your arrival in lab. They will help you understand what is
happening during the experiment. Some of these questions will form the basis for your
JACS article, which will be due at the end of the semester. You should also have some
information already uploaded into Ensemble (reaction scheme, reagent table, etc.).
1. Draw a full mechanism for this transformation.
2. Why is glycerol the limiting reagent in this reaction instead of the 2,2dimethoxypropane (hint: think in terms of purification)?
3. What is the purpose of a protecting group and why do you need to perform this
step during this multistep scheme?
4. This reaction is run under acidic conditions. Can it be performed under basic
conditions?
Post-Lab Assignment: One JACS article will be written for the entire Multi-Step
Synthesis scheme (protection, oxidation, olefination), of which this experiment is the first
step. Therefore, you do not have a written assignment due next week. However, it is in
your best interest to write the experimental part of this reaction and analyze your spectral
data to save you time later in the semester. Your JACS article will be due the last week of
classes, the same week you have Exam 3, so plan ahead! More information on how to
write the JACS article will be provided soon.
Intensive Organic Chemistry II, CH212 – Spring 2012
Experiment 7 – Click Chemistry
Introduction:
Much like the cycloaddition reactions that occur with alkenes (ie.
dihydroxylation, bromination, ozonolysis, etc.), alkynes also have nucleophilic  bonds
that react with a variety of electrophiles in a concerted fashion. The best example of this
type of chemistry is the azide-alkyne [3+2] cycloaddition to form 1,2,3-triazoles under
thermal conditions. The transition state in this reaction involves the simultaneous flow of
6  electrons to form two new  bonds. Since this can occur in two different orientations,
both syn and anti products are observed.
While this chemistry has been known for some time, only recently has received
renewed attention. K. Barry Sharpless showed that the transformation can occur under
much more mild conditions, in high yields, and with little side products when copper(I) is
used as a catalyst. He termed this type of transformation “click chemistry” for its ease of
synthesis and for its potential use in a wide variety of applications.
The mechanism for this transformation is shown below. A copper(I) species will
react with an alkyne to form a copper(I)-acetylide, which then coordinates an azido
species. Since the reactants are in close proximity, the [3+2] cycloaddition occurs to
generate a copper(I)-triazole species. Protonation of the C-Cu bond generates the triazole
and completes the catalytic cycle.
Cu-catalyzed azide-alkyne cycloaddition
In this experiment, you will be performing an azide-alkyne cycloaddition reaction
with a copper catalyst. However, the reacting species will be generated in situ. First, since
Cu(I) salts are typically unstable, you will generate the active Cu(I) catalyst by reducing
CuSO4 with sodium ascorbate. Second, you will generate the azide in situ by reacting
sodium azide with a benzyl bromide by a simple SN2 mechanism. This will allow us to
use a variety of azides that may not normally be commercially available. You will
confirm product formation using all of the standard analytical techniques.
References:
4. Sharpless, W. D.; Wu, P.; Hansen, T. V.; Lindberg, J. G. J. Chem. Ed. 2005, 82
(12), 1833-1836.
Cu-catalyzed azide-alkyne cycloaddition
Equipment:
Microscale glassware kit
25 and 50 mL beakers
10 mL graduated cylinder
1 mL syringes and needles
50 mL centrifuge tubes
Pasteur pipets
Capillary tubes
TLC plates (thin)
Cotton
Scintillation vials and caps
NMR tubes
HPLC vials
Stir bars
Thermowells
Chemicals:
Benzyl bromide
4-nitrobenzyl bromide
Sodium azide
Phenyl acetylene
Diphenylacetylene
Copper(II) sulfate pentahydrate
Sodium ascorbate
Ethyl acetate (2 x 500 mL)
Hexanes (2 x 500 mL)
Methylene chloride (2 x 500 mL)
Methanol (2 x 500 mL)
Ammonium hydroxide solution (aqueous)
Sodium chloride solution (saturated, 500 mL)
Deionized water
CDCl3
Procedure: adapted from Sharpless, W. D.; Wu, P.; Hansen, T. V.; Lindberg, J. G. J.
Chem. Ed. 2005, 82 (12), 1833-1836.
Cycloaddition Reaction: Preheat a Thermowell to 100 ºC. In a 10 mL round bottom flask,
dissolve your benzyl bromide (3 mmol) and assigned acetylene (1.1 equiv.) in 4 mL of
1:1 tBuOH:H2O at room temperature. Then, add sodium azide (1.1 equiv.) to the reaction
mixture, followed by CuSO4*5H2O (5 mol %) and sodium ascorbate (10 mol %). Affix a
reflux condenser to your flask and heat the reaction to 100 ºC. While your reaction
mixture is stirring, obtain a TLC of your starting material (acetylene diluted in a few
drops of an organic solvent of your choice) so that you obtain an Rf of ~0.4. After 1 hour,
take a TLC of your reaction mixture to confirm presence of product.
Workup: Cool the reaction to room temperature and then extract with 10 mL of
methylene chloride. Separate the two layers and then wash the organic layer with 10 mL
deionized water and a few drops of ammonium hydroxide solution. An additional wash
with saturated sodium chloride solution (brine) may be necessary to destroy any
emulsions. Transfer the organic layer to a separate flask and dry over anhydrous sodium
sulfate. Filter this solution into a tared vial and concentrate on a rotovap (do not fill
higher than 1/3). If you are waiting for a rotovap or have too much solvent, you may boil
some solvent off on a hot plate with a stream of air, but do not overheat!
Analysis: Calculate a percent yield of your triazole, then obtain a 1H NMR (~ 50 mg of
product), IR, and LC/MS (<1 mg in 1.5 mL MeOH).
Pre-Lab Exercise:
These questions do not need to be explicitly answered in writing, but you should be able
to answer them prior to your arrival in lab. They will help you understand what is
happening during the experiment. You should also have some information already
uploaded into Ensemble (reaction scheme, reagent table, etc.).
5. Look up the dangers of working with azides. What precautions should you take
when working with these substances?
6. What is the role of aqueous ammonium hydroxide in the workup?
7. What is the role of sodium ascorbate in this reaction?
8. What regioselectivity do you expect to observe in this reaction?
Post-Lab Assignment: A worksheet will be completed for this experiment. It will be due
one week after you complete the experiment.