1. food and drink
2. desserts and baking

Supplemental Material - Greener Solutions for the Organic Chemistry Teaching Lab
Student Handout:
Diels-Alder Reaction + Intramolecular Nucleophilic Acyl Substitution :
A Huge Increase in Molecular Complexity in One Reaction Flask
OH
OH
O
O
+
no heat
O
O
no solvent
O
H
+
O
O
_
O
O
O
O
O
(and enantiomer)
CO2H
Thomas E. Goodwin and Courtney Rogers, Department of Chemistry,
Hendrix College, Conway, Arkansas 72032 USA
Background Reading
You will need to read in your textbook and/or supplemental material supplied by the
instructor about the Diels-Alder reaction, nucleophilic acyl substitution, enantiotopic and
diastereotopic hydrogens in 1H NMR spectroscopy, and the type of two dimensional (2D)
NMR spectroscopy known as COSY (1H-1H COrrelation SpectroscopY).
Introduction
The original procedure (see the McDaniel & Weekly reference) called for boiling the two
reactants in the petrochemical solvent toluene (b.p. 110 oC). That is a classical way to
run Diels-Alder reactions, since most of them require quite a bit of heat in order to react.
We did not want to use toluene in the lab, so we sought a greener solvent; unfortunately,
we found none in which the reaction worked. Therefore, we tried simply heating the two
reactants to 90 oC for 15 minutes with no solvent and the reaction worked well. We also
found that it worked by heating the two reactants with no solvent in a microwave oven at
50% power for 30 seconds. Finally, we were surprised and delighted to find that it
worked well at room temperature with no solvent by merely stirring the two reactants
together with a spatula for 10-15 minutes.
This experiment illustrates a highly stereoselective reaction sequence that invites not only
a discussion of Diels-Alder reaction characteristics, but also a review of nucleophilic acyl
Experiment 2 – Solventless Diels-Alder Reaction/Nucleophilic Acyl Substitution Page 4
Supplemental Material - Greener Solutions for the Organic Chemistry Teaching Lab
substitution. Wender and Miller stated: “The ideal synthesis may be defined as one in
which the target molecule is prepared from readily available starting materials in one,
simple, safe, environmentally-acceptable, and resource-effective operation that proceeds
quickly and in quantitative yield” (Wender, P. A.; Miller, B. L. Toward the Ideal
Synthesis: Connectivity Analysis and Multibond-Forming Processes. In Organic
Synthesis: Theory and Applications; Hudlicky, T., Ed.; Jai Press: Greenwich, 1993; pp
27-66). This experiment approaches that ideal. The facile intramolecular nucleophilic
acyl substitution illustrates the relative nucleophilicity of an alcohol versus a carboxylic
acid. It also exemplifies a principle enunciated by the late R. B. Woodward: “We all
know that enforced propinquity often leads on to greater intimacy” (Woodward, R. B., as
quoted in Sharpless, K. B. Chem. Brit. 1986, 22, 38-44). That is, the higher probabilities
of collision and favorable entropy change for intramolecular processes lead to more
favorable reactions. Note that while the reactants are achiral, the product is chiral and
has four chirality centers. Although 16 stereoisomers of the product are possible, due to
the geometry requirements of the concerted Diels-Alder reaction, only two are produced:
the one shown above, and its enantiomer.
Green Aspects
The procedure is run on a very small scale (small amounts of reagents), and requires no
solvent at all. The only energy required is from you, and since your energy ultimately
comes from the sun, you will be using a renewable energy source for this green reaction.
As in all Diels-Alder reactions, the atom economy is 100%.
Safety Considerations
CAUTION: (E,E)-2,4-hexadien-1-ol (the diene) and maleic anhydride (the dienophile)
are skin irritants, corrosive, and irritating to the mucus membranes. The procedure can
easily be carried out safely, but we should take proper precautions anyway. Wear eye
protection; wear nitrile gloves; avoid breathing the compounds or skin contact; don’t
scratch your skin or eyes with your gloves; carry out the reaction and isolation in the
hood; dispose of unused product in the designated containers; as usual, wash your hands
immediately after lab.
Experimental Procedure
1. Preparation: Using an automatic pipet, carefully put 50 L (43.6 mg; 0.444 mmol) of
(E,E)-2,4-hexadien-1-ol (density 0.871 g/mL) into the bottom of a clean, dry, tared 10
mL beaker. [Note: The diene has a melting point around 32 oC. If you should find it
solidified, contact a lab assistant and we can melt it with gentle heating from a “heat gun”
(this is like a hair dryer). The diene may be a bit viscous—give it time to enter and exit
the automatic pipet tip. Be sure to check that the diene has not solidified and plugged up
the pipet tip.] Weigh the beaker. If you have 43.6 mg of diene, then add 44 mg (0.449
mmol) of finely powdered, solid maleic anyhydride to the same beaker. [Note: In order to
get a good yield of pure product, it is important that equimolar amounts of diene and
dienophile be used. Therefore, it is important to add the correct amounts of each reactant.
Experiment 2 – Solventless Diels-Alder Reaction/Nucleophilic Acyl Substitution Page 5
Supplemental Material - Greener Solutions for the Organic Chemistry Teaching Lab
After adding the diene to the beaker and determining the exact amount that you added (it
may be slightly different from 43.6 mg), you may calculate the number of mg of diene to
add so that you have an equimolar mixture.]
Use the small end of a clean, dry metal spatula to vigorously, continuously, and
thoroughly mix and stir the mixture until complete liquefaction and resolidification occur.
(Try to avoid getting the mixture any higher up on the sides of the beaker than
necessary.) Watch closely at the changes in texture and appearance that the mixture
undergoes, and write good observations in your notebook. At this point you will have a
white solid. This will take about 10-15 minutes. After solidification is complete, use a
second spatula if necessary to scrape the solid off the first spatula into the beaker. Weigh
the beaker so that you can get the mass of the product.
It is best to complete as many of the following activities as you have time to do; if
necessary, some may be done during the next lab period or outside of lab time: (1) carry
out the simple carboxylic acid tests described below; (2) obtain an infrared spectrum on
your product; (3) obtain a 1D 1H NMR spectrum and a 2D COSY spectrum using
acetone-d6 as the solvent, and tetramethylsilane (TMS) as the reference; (4) perform
molecular modeling using SPARTAN (see instructions below), and (5) take a melting
point on the Diels-Alder product (reported to be 159-161 oC). Whenever you finish for
the day, write your name on the beaker with a Sharpie, and give it to the lab assistant.
Intrepret the 2D COSY spectrum and assign the chemical shifts and coupling constants
for all of the hydrogens in the product. This may be done outside of the lab time, or in a
subsequent lab session. Detailed instructions for this COSY exercise are given below.
2. Simple Wet Chemical Test for a Carboxylic Acid:
Most carboxylic acids (pKa approx. 5) can be converted into a water-soluble sodium salt
(their conjugate base) when treated with an aqueous solution of a base like NaHCO3
(sodium hydrogen carbonate, also known as sodium bicarbonate, or ordinary baking
soda). This reaction also produces carbonic acid (the conjugate acid of the hydrogen
carbonate anion), which is in equilibrium with carbon dioxide and water. The carbon
dioxide gas bubbles away, producing effervescence. Alka-Seltzer® tablets contain a dry
mixture of acetylsalicylic acid (aspirin), citric acid, and sodium hydrogen carbonate. No
Bronsted-Lowry acid/base reactions occur as long as these components are dry, but when
water is added they dissolve and react, liberating CO2 gas as shown in equations 1-3
below. Therefore, Alka-Seltzer® in water contains principally the antacid sodium citrate
and the analgesic sodium acetylsalicylate. You will now carry out a similar reaction
using a small portion of your Diels-Alder reaction product, thus illustrating that it is a
carboxylic acid (see equation 4 below).
Use a metal spatula to transfer a small portion (about the size of a flea) of your product to
a small watchglass. Add an equal-sized portion of solid NaHCO3. Use a plastic pipet to
add a drop or two of water to the mixture and observe what happens. When the reaction
is over, discard the mixture in the waste jar that is provided. Rinse and dry the
watchglass and repeat the experiment with aspirin.
Experiment 2 – Solventless Diels-Alder Reaction/Nucleophilic Acyl Substitution Page 6
Supplemental Material - Greener Solutions for the Organic Chemistry Teaching Lab
O
O
O
O
O
OH
(1)
+
OH
(2)
O
O
O
OH
O
OH
+
O
OH
O
O
O
Na
O
H2O
OH
OH
HO
O
OH
O
OH
+
O
O
HO
OH
O
Na
O
HO
HO
carbonic acid
citric acid
(3)
+
Na
sodium hydrogen
carbonate
acetylsalicylic acid
(aspirin)
HO
Na
O
H2O
CO2 (gas)
+
H2O (liquid)
OH
carbonic acid
O
O
(4)
H2O
O
O
+
O
Na
O
OH
sodium hydrogen
carbonate
OH
3. Molecular Modeling:
O
O
+
O
HO
OH
carbonic acid
O
Na
We will not do this - Spring 2015
a. Build the structure below using SPARTAN. Be sure to get all appendages on the sixmembered ring CIS to one another.
O
7a
O
3a
5
OH
4
O
b. Start with an sp2 carbon (select it on the side, then click on the middle screen). Then
click on the end of the first double bond to create a C-C double bond. Now select an sp3
carbon, and click to add it to one end of the C-C double bond. Keep clicking to add sp3
carbons until you have six carbons on the screen (you will have created 1-hexene). It is
best if you click so as to end up with the six carbons approximating a hexagon ring.
Experiment 2 – Solventless Diels-Alder Reaction/Nucleophilic Acyl Substitution Page 7
Supplemental Material - Greener Solutions for the Organic Chemistry Teaching Lab
c. In order to close the 1-hexene into cyclohexene, do the following. From the top menu
bar, select BUILD, then MAKE BOND. Click on a hydrogen on one terminal carbon of
the chain, and a hydrogen on the other terminal carbon. SPARTAN will automatically
convert this to a C-C bond, thus you will have a distorted version of cyclohexene.
d. Now minimize the structure by selecting the E(arrow) from the top menu bar. This
converts the structure into the lowest energy conformation by minimizing steric strain,
torsional strain, angle strain, and creating proper bond lengths.
e. Now build on the five-membered ring. Be sure to select the sp2 or sp3 atom as
appropriate. (Remember, if you mess up, just select EDIT from the top menu bar, then
CLEAR.) Be sure to make the cis stereochemistry. Now, minimize the energy.
f. Now add the methyl and carboxyl groups (be sure to make them CIS), then minimize
again. Record the energy (see bottom right of screen). Rotate structure to notice its
concave and convex surfaces. Print a copy of the minimized structure and bring it to
your next lab session.
g. Measure and record the dihedral angles listed below (select GEOMETRY from the
top menu bar, then MEASURE DIHEDRAL, then click on four contiguous atoms and
read the angle in the lower right of the screen).
Angles: i. between hydrogens at 7a and 3a (see structure at top); ii. between 3a and 4;
iii. between 4 and 5.
h. Turn in with your final lab write-up the printed structure with energy and angles
written on the signed sheet.
4. Specific Instructions for Interpretation of the COSY NMR Spectrum
(Note: You may work in pairs or small groups on this exercise.)
a. Predict multiplicities (s, d, t, dd, etc.) for the hydrogens on the structure of the product;
label the diastereotopic hydrogens.
b. Look at the “normal” 1H NMR spectrum (not the COSY spectrum) and label the peaks
(H1a, H2, etc.) by looking at the chemical shifts written on the structure in your handout
(see also the McDaniel & Weekly article in the Journal of Chemical Education).
c. Look at the expanded portions of the normal 1H NMR spectrum to see if your
predicted peak multiplicities can be discerned (that is, if you predicted a doublet of
doublets, does one actually show up). Note that two of the peak patterns may not be well
resolved; if so we just have to label them “multiplets”.
d. Now look at the COSY NMR spectrum. Compare the spectrum on one axis to the
“normal” 1H NMR spectrum that you labeled in part 1 above, and label the COSY axis
analogously.
Experiment 2 – Solventless Diels-Alder Reaction/Nucleophilic Acyl Substitution Page 8
Supplemental Material - Greener Solutions for the Organic Chemistry Teaching Lab
e. Use the COSY spectrum to try and determine what is coupled to what. Be aware that
there is a small, long-range coupling through the pi bond between H-6 and H-7a, and
between H-7 and H-5; sometimes it is difficult for the COSY spectrum to pick this up.
The problem is that in running COSY spectra, one tries not to get the measurements too
sensitive (otherwise “ghost” peaks appear), or too insensitive (otherwise some small
couplings will be missed). It’s a tradeoff.
f. Compare your predictions from part 1 to your observations from the COSY analysis to
see if they are congruent; that is, do the assignments and couplings “make sense”.
g. Draw tree diagrams for all hydrogens (except the carboxylic acid one) directly on the
expanded versions of the proton NMR spectrum to account for all couplings. Be aware
that the absorbance pattern for two of the protons is often too complex to interpret fully
due to couplings to many protons. You may not be able to get coupling constants for
these; they are usually classified as “multiplets”.
h. For all the tree diagrams above, calculate all coupling constants (J) in Hz.
i. Make a table in which column 1 has chemical shifts in ppm (d) listed in descending
order; column 2 has the corresponding proton number (H6, H7, etc.); column 3 lists the
corresponding peak multiplicities (e.g., dd = doublet of doublets; t = triplet); column 4
lists all J’s for that particular proton (e.g. for a doublet of doublets: J4,5 = 12, J4,6 = 6 Hz).
j. Turn in the entire handout, plus any extra worksheets.
References
This experiment was modeled after one by K. F. McDaniel and R. M. Weekly (J. Chem.
Educ. 1997, 74, 1465-1467). Their experiment was adapted from Brettle, R.; Cummings,
D. P. J. Chem. Soc., Perkin Trans. 1 1977, 2835-2892.
Experiment 2 – Solventless Diels-Alder Reaction/Nucleophilic Acyl Substitution Page 9