endo- and exo-Stereochemistry in the Diels-Alder Reaction:
Kinetic versus Thermodynamic Control
Objectives:
To synthesize fused-ring compounds utilizing the Diels-Alder reaction(C)
To obtain 1H NMR spectra of endo and exo-7-Oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxy-N-phenylimide(T)
To assign the stereochemistry by characterization of the splitting patterns in the 1H NMR spectra(T)
To provide an explanation of the observed changes in the ratios of reactants and products (T)
The 7-oxabicyclo[2.2.l]heptene ring system is conformationally rigid. The difference in splitting patterns observed
between the exo and endo adducts (2 and 3) results from the
very different dihedral angles between the exo and endo
protons (on C-5/C-6) and the bridgehead protons (on C-l/C-4).
Examination of models of 2 and 3 indicates a dihedral angle
(H-C5-C4-H) of almost 90o for the exo isomer 2 and a small
dihedral angle for the endo isomer 3. These dihedral angles
are calculated to be 83o and 33.8o respectively using AM17 as
implemented in the HyperChem software package8. Using the
Karplus equation9, J = 8.5cos2θ -0.5cosθ -0.028 where θ = the
dihedral angle, the coupling constants for the exo isomer (2)
and the endo isomer (3) are calculated to be 0.04 and 5.4 Hz,
respectively.
Introduction:
The Nobel Prize was awarded to Otto Diels and Kurt
Alder in 1950 for their discovery and work on the reaction
that bears their names (Diels-Alder cycloaddition reaction)1.
This reaction involves the 1,4 addition of a dienophile2 to a
diene to produce a six-member cyclohexene. The Diels-Alder
reaction is extremely useful because, in a single step, it
produces two new carbon-carbon bonds and up to four
stereocenters. It is an example of a [4+2] cycloadditon
reaction (4 π electrons + 2π electrons) between a conjugated
1,3-diene and an alkene. The reaction works best if the
dienophile bears electron-withdrawing groups and if the diene
bears electron-donating groups. The reaction is highly
stereospecific and the orientation of the groups on the
dienophile are retained in the product.
The Diels-Alder reaction has been used extensively in the
synthesis of complex natural products because of the
regioselectivity of the reaction and the ability to exploit the
formation of a number of chiral centers in one reaction.
The majority of general organic chemistry texts present the
Diels-Alder reaction as yielding endo products. In most cases
the exo product is the thermodynamically more stable, but the
endo adduct forms much more rapidly, and kinetic control is
observed3. The exceptional exo stereochemistry of the furanmaleic anhydride adduct was first demonstrated by Woodward
and Baer4 using classical methods and later confirmed by Xray crystallography5. Lee and Herndon6 demonstrated that the
endo isomer forms more rapidly in a reversible reaction,
resulting in the ultimate dominance of the thermodynamic
(exo) product.
In the norbornene (bicycle[2.2.l]heptene) system, 1 (which
results from Diels-Alder additions to cyclopentadiene), endo
and exo stereochemistry can be
7 Hb
deduced
experimentally
from
differences in the coupling constants
Hx
3 4 5
of the bridgehead protons on C-1
Hx
and C-4 (Hb) to the exo (Hx) or
2 1 6
endo (Hn) protons on C-5 and C-6
Hn
(see below) (5). The geometry of the Hb
Hn
7-oxabicyclo[2.2.l]heptene system is
very similar to that of the
1
norbornenes, consequently, the
corresponding coupling constants are very similar.
O
O +
NPh
NPh
H
O
O
O
O
H
HO
+
O
NPh
H
2
O
3
Procedure:
Dissolve N-Phenylmaleimide (0.35 mmol) in 0.5 mL of
furan. Allow the mixture to stand for at least 20 h. Recover
the white, solid product by filtration and washed with 2 mL of
ether. Obtain a TLC of the product using 1:1 EtOAc-hexane.
Dissolve 50mg of the product in 1 mL of hot EtOAc and
chromatograph using silica gel on a 15-mL chromatographic
column and 1:1 EtOAc-hexane. Collect an initial 3-mL
fraction, followed by 1-mL fractions until a total of 22 mL of
eluant has been collected. Monitor the eluant by TLC.
Combine the fractions of the pure endo isomer and of the pure
exo isomer. Evaporate the solvent and obtain 1H NMR spectra
(CDCl3) of each.
The IR spectra are, endo: 1713, 1696 cm-1 ; exo: 1712
-1
cm . For 13C-NMR, (CDCl3) endo: δ 173.9, 134.6, 131.4,
129.2, 128.8, 126.3, 79.8, 45.9; exo: δ 175.3, 136.7, 131.5,
129.1, 128.8, 126.5, 81.4, 47.5.
NMR Experiment:
Prepare a mixture of 30 mg of N-phenylmaleimide, 20 mg of
furan, and 1 mL of CDCl3 in an NMR tube. Determine the
1
spectrum immediately after mixing. Store the reaction tube
either at room temperature (~23oC) or at 0oC. Obtain spectra at
1 week intervals for a period of four weeks.
Cleaning Up: Place the elution solvent mixture in the organic
solvents container. Place the used silica gel in the solid waste
container.
You are responsible for completing the accompanying
pre-lab exercise prior to the start of the 2nd laboratory
period.
1
Diels, O., Alder, K. Liebigs Ann. Chem., 460, 98 (1928)
2
to have an affinity for dienes, from the Greek philos, meaning
loving.
Computational Chemistry:
From the 1H NMR spectra of the isolated products,
molecular models and the Karplus equation9, deduce the
structures and assign the stereochemistry to each isomer.
3
Woodward, R. B., Hoffmann, R. The Conservation of Orbital
Symmetry, Chemie, Weinheim, Germany, 1970.
4
Woodward, R. B., Baer, R., J. Am. Chem. Soc. 70, 1161-1166
(1948).
Product Analysis:
From the 1H NMR spectra of the reaction mixture, follow
the reaction by obtaining the integrals of unreacted Nphenylmaleimide and of the endo and exo products.
When preparing your report you should use your own data
to present an analysis of the observed changes in the ratios of
reactants and products. You should also consider your results
relative to the average results of all people conducting the
measurements at the same reaction temperature. Finally, you
should comment on your results compared to the average
results obtained at the other reaction temperature. Use your
data and the group data to present an explanation of the
observed changes in the ratios of reactants and products.
Use the appended Excel spread sheet to record your data
and send it as an attachment to the lead instructor for the
experiment.
5
Baggio. S., Barriola, A., de Perazzo, P. K., J Chem. Soc.
Perkin Trans 2, 934 (1972).
6
Lee, M. W., Herndon, W. C., J Org. Chem.,43, 518 (1978).
7
Stewart, J. J. P., J Comp. Aided Mol. Design 4, 1 (1990)
8
HyperChem for Windows, Hypercube (1994)
9
Silverstein, R. M., Bassler, G. C., Morrill, T., Spectrometric
Identification of Organic Compounds, 5th edition, Wiley, New
York, p. 197 (1991)
2
SECTION________________
NAME_______________________
PRE-LAB EXERCISE (due beginning of 2nd lab period)
1. Provide complete answers to the following questions in the spaces provided.
i) Considering the Karplus equation and the dihedral angles, what patterns (not
necessary multiplicities) would you expect for the protons on C5/C6 and on C1/C4 in a
1
H NMR spectrum of the exo and endo isomers of the Diels-Alder product?
ii) Based on your expectations (above), assign the peaks observed in the region of the 1H
NMR spectrum of the Diels-Alder product (below) to H(exo), H(endo) and H(bridge,exo),
H(bridge,endo). NOTE: exo/endo refers to the isomers and NOT the protons.
5.6
5.4
5.2
5.0
4.8
4.6
4.4
4.2
4.0
3.8
3.6
3.4
3.2
3.0
2.8
2.6