Chem 324
2005
Diels Alder Stereochemistry Worksheet
This is not an assignment
Diels-Alder stereochemistry is defined by the so-called endo rule (or cis endo rule).
Unfortunately, “endo” and “exo” are unfamiliar terms so we spent some time in class
talking about their meaning. This worksheet provides some examples of Diels-Alder
reactions and leads you through the use of the endo rule. You do not need to turn
anything in. The worksheet is simply for your own benefit. Come see me if you have
problems getting the right answer.
What are endo and exo?
I am most familiar with endo and exo as stereochemical labels for bicyclic rings. The
Diels-Alder reaction normally makes a cyclohexene product, but it makes a bicyclic ring
structure if the diene is part of a cyclic system. An example is provided by the reaction of
cyclopentadiene and maleic anhydride:
H
H
fast
O
O
O
O
O
O
ENDO product
ENDO approach
O
O
O
O
slow
O
H
H
EXO approach
O
EXO product
Two different products are possible, and both contain a new bicyclic structure:
norbornene (aka bicyclo[2.2.1]heptene). The endo and exo labels describe the orientation
of a substituent (in this case OC-O-CO) on the saturated two-carbon bridge. An endo
substituent points back towards the alkene bridge (see ENDO product). An exo
substituent points away from the bridge.
Chem 324
2005
The endo rule
The endo rule for predicting Diels-Alder stereochemistry applies to reactions involving a
dienophile with one or more unsaturated substituents. The rule states that the kinetic
product is obtained from a transition state in which the dienophile substituent is “endo”
with respect to the diene.
In the case of a cyclic diene, like the one shown above, the meaning of “endo” is
straightforward and so is application of the endo rule. You can just draw products with
endo unsaturated substituents (that is, endo with respect to the alkene bridge).
The interpretation of “endo” is far less obvious for acyclic dienes. In such cases, one
needs to compare the two approaches and notice the orientation of the substituent relative
to the diene. The endo approach places the substituent over (or cis to) the diene.
B
B
A
unsat
A
unsat
unsat
unsat
B A
ENDO approach
B A
EXO approach
A method to this madness?
The best way to use the endo rule is to be as methodical as possible. Here is one approach
that will help you make accurate predictions:
1. Identify the unsaturated substituent in your dienophile
2. Draw an ENDO approach (or build a model). Make sure you line up the carbons
that form the new sigma bonds (dashed lines, see above), and place the
unsaturated substituent over the pi system of the diene.
3. Draw (or build) a BOAT-SHAPED ENDO product. This should be a new
drawing (or model). It should use the geometry from step 2, but the bond pattern
should be that of the cyclohexene product. The combination of geometry and
bond pattern should give you a boat cyclohexene.
4. Re-draw (or adjust your model) so that the ring is flat (half-chair). What is the
configuration of each chiral center? What is the relative stereochemistry of ring
substituents?
Consider the reaction between trans-1-methoxy-1,3-butadiene and acrylonitrile:
Chem 324
2005
OMe
OMe
C N
CN
Step #1 identifies the unsaturated substituent as CN. Steps #2-4 are represented by the
three images shown below (starting on the left, there is an ENDO approach, a BOATSHAPED ENDO product, and a flattened version of the same product):
Æ
Æ
It is a little hard to see 3-D relationships in these images, so you should work through the
problem on your own and refer to these drawings as guideposts to keep you on track.
By the way, I am not advocating Spartan as the best tool for solving these problems. It
was simply a convenient way for me to generate models and pictures for this worksheet.
If you want to give Spartan a try, here are some tips:
9 ENDO approach. I built this model in two stages. First, I build the diene. To add
a separate dienophile, I clicked alkene, the Insert button, and then I clicked
inside the building area. Normal mouse operations rotate/translate the entire
model. To maneuver one piece of the model, click on a piece to make it active,
and press CTRL while you move the mouse.
9 BOAT-SHAPED ENDO product. There is no simple way to add bonds between
the two pieces in the model. I got around this problem by searching Spartan’s
library of transition states (when Spartan finds a match, it replaces the two pieces
with a single model containing partial bonds). To search the library, I added
curved arrows (transition button) to the ENDO approach model, and then
clicked the double curved arrow button in the lower right. This gave me a
transition state model with partial single and double bonds. I changed these partial
bonds to the “product” bonds by clicking on Expert, selecting the desired bond
type, and double-clicking the desired partial bond.
9 Flattened product. This was easy. I just clicked the minimize button.
The in-class discussion identified two principal stumbling blocks: 1) visualizing the endo
approach, and 2) seeing stereochemical relationships in the product. My method will help
you with both, but you need to practice it and you need to be methodical. Avoid shortcuts.
Chem 324
2005
Examples
1. Oakes et al., Chem. Commun., 1999, 1459. They studied Diels-Alder reactions
between cyclopentadiene and acrylate esters, CH2=CHCO2R, in different media. They
discovered that, using supercritical CO2 (scCO2) as the reaction medium, they could vary
endo:exo from 3:1 to 4:1 by varying the external pressure. (Note, scCO2 is a
“supercritical fluid” with liquid and gas-like properties; the latter includes
compressibility.) They also investigated the effect of Lewis acid catalysts on endo:exo
ratios. They found that a Sc+3 salt raised endo:exo to 10:1 (in toluene), 11:1 (in
chloroform), and 24:1 (in scCO2). Æ Draw the endo and exo products.
2. MacMillan et al., J. Amer. Chem. Soc., 2002. They investigated cycloadditions
between ethyl vinyl ketone, EtCOCH=CH2, and several simple dienes. As a rule, endo
selectivity was not very high. They reasoned that making the dienophile more electronpoor should improve selectivity (and reaction rate, and yield) and this might be achieved
by converting the carbonyl group, C=O, into an iminium ion, C=NR2+. They also
reasoned that it should be possible to produce the iminium ion catalytically by combining
the ketone with a small amount of acid and a small amount of a chiral amine, HNRR’.
Their best chiral amine turned out to be:
O
N
N
H
O
Two “typical” experiments are described below (both gave endo:exo >200:1, %ee > 90).
Æ Draw the missing products (assume “ortho/para” rule and “endo” rule both operate).
O
OMe
.2 eq cat
Et
O
>200:1, 96%ee
.2 eq HClO4
EtOH, -30oC
.2 eq cat
Et
.2 eq HClO4
EtOH, -30oC
>200:1, 90%ee
3. Stoodley et al., Chem. Commun., 1997, 1371. They studied the reaction shown below.
Endo selectivity was relatively modest (and certain ring substituents could even reverse
the selectivity), but ortho/para regioselectivity was very high. Æ Which reactions give
ortho products? Para products? Which product is endo and which is exo?
Chem 324
2005
CO2Me
MeO2C
X
Y
MeO2C
Y
+
O2N
Y
X = OMe
X = OSiMe3
X = OAc
X = OMe
O2N
Y=H
Y=H
Y=H
Y = OSiMe3
O2N
X
X
67
68
> 95
35
33
32
5
65
4. Cho et al., Tet. Lett., 2001, 42, 8193. These chemists investigated inverse electron
demand Diels-Alder reactions involving 3,5-dibromo-2-pyrone (“diene”) and various
cyclic silyl enol ethers. The dienophiles differed only in their ring size, which ranged
from 4-8 atoms. All of the reactions occurred slowly (1-3 days) and in good yields
(>73%). Most dienophiles gave mainly the endo product (>90:1), but the cyclooctene
gave mainly the exo product (2:1). I have drawn the endo product obtained from the
cyclopentenyl silyl enol ether. Æ What is the diene’s structure? Does this reaction obey
the ortho/para rule? The authors say the reaction obeys the endo rule (except for the
cyclooctene reactant); how do you think they define endo?
Br
OSiMe3
Br
OSiMe3
O
+ diene
O
5. Gorman et al., Chem. Commun., 1998, 25. Another inverse electron demand reaction.
4:5 ratios were 99:1 for various R = Et, i-Bu, n-Bu in the presence of the iron catalyst (96
h at 23 oC, or 18 h at 60 oC), but no reaction occurred without the catalyst. Æ Do these
reactions obey the ortho/para rule? The endo rule?
O
CO2Et
OR
Fe(O2CR')3
O
O
OR
+
OR
+
CO2Et
CO2Et
4
5
Answers
You can view answers to these problems by downloading the answer sheet from the 324
Molecular Models Download page.
http://academic.reed.edu/chemistry/alan/324/models.html