Characteristics of the Two Frontier Orbital Interactions in the Diels-Alder Cycloaddition

Article abstract of DOI:10.1021/jo0353740

Two electron-deficient dienes were reacted with a series of twelve electron-poor and electron-rich dienophiles to give, in some cases, the corresponding Diels-Alder adducts. Clear differences in the roles played by the two frontier orbital interactions em

Full text of DOI:10.1021/jo0353740

Ch a r a cter istics of th e Tw o F r on tier Or bita l In ter a ction s in th e
Diels-Ald er Cycloa d d ition
Claude Spino,* Hadi Rezaei, and Yves L. Dory
Universit e´ de Sherbrooke, D e´ partement de Chimie, 2500 Boulevard Universit e´ ,
Sherbrooke, QC, Canada J 1K 2R1
claude.spino@usherbrooke.ca
Received September 19, 2003
Two electron-deficient dienes were reacted with a series of twelve electron-poor and electron-rich
dienophiles to give, in some cases, the corresponding Diels-Alder adducts. Clear differences in the
roles played by the two frontier orbital interactions emerged. It was demonstrated that in the case
of normal Diels-Alder cycloadditions, the FMO theory could predict the relative reactivities between
dienophiles, while in the case of inverse-electron demand Diels-Alder reactions, it could not. It
was shown that the dissymmetry in electron-rich dienophiles increases their reactivities.
The Diels-Alder cycloaddition is arguably one of the
most powerful reactions in the arsenal of the synthetic
1
organic chemist. Synthetic plans that incorporate this
reaction depend on our ability to effectively predict the
relative reactivities of dienes and dienophiles. Studies
that can refine or modify the predictive power of existing
tools are still very useful. The frontier molecular orbital
2
(
FMO) theory as first expressed by Fukui continues to
be utilized extensively by synthetic organic chemists to
help them predict the reactivity and selectivity of many
3
organic reactions. As pertains to the Diels-Alder reac-
tion, predictions of reactivity and selectivity are normally
based on the strength of a single FMO interaction
between the diene and dienophile, the so-called “domi-
nant” interaction. The dominant interaction is usually
taken to be the one involving the two frontier orbitals
F IGURE 1. Frontier orbitals in the normal and inverse
electron-demand Diels-Alder cycloadditions.
While many reactions appear to disobey the FMO rule
5
of reactivity, IEDDA cycloadditions have an inordinate
2
having the smallest energy gap between them. As shown
amount of cases in that category. For example, why does
the dimerization of acrolein compete effectively with its
cycloadditions with electron-rich dienophiles despite typi-
in Figure 1, when the HOMOdiene-LUMOdienophile (Hde
-
L
do) energy gap is least, the reaction is called a normal
1
b
Diels-Alder cycloaddition (NDAC), while when the HO-
MOdienophile-LUMOdiene (Hdo-Lde) energy gap is smallest,
the reaction is dubbed “inverse-electron-demand Diels-
Alder cycloaddition” (IEDDAC). This definition presumes
that either of these two frontier orbital interactions confer
identical stabilization to the transition state for a given
energy gap, a presumption that has no solid foundation.2
cal energy gaps that give the latter 1.5-2.0 eVadvantage?
Why do a series of 2-azadienes react with a host of
electron-deficient dienophiles including methyl acrylate
but none react with ethyl vinyl ether despite FMO energy
gaps that favored the latter by 1.5 eV?6 Why does
2-carbomethoxy-1,3-butadiene 1 dimerize much faster
than it reacts with dihydropyran and other electron-rich
c,4
7
dienophiles? Inverse electron-demand Diels-Alder cy-
*
Address correspondence to this author. Phone: (819)-821-7087.
Fax: (819)-821-8017.
1) (a) Carruthers, W. In Cycloaddition Reactions in Organic
(
(4) (a) Bach, R. D.; McDouall, J . J . W.; Schlegel, H. B.; Wolber, G.
J . J . Org. Chem. 1989, 54, 2931-2935. (b) Coddens, B. A. A Quantita-
tive Description of the Three Molecular Orbital Four-Electron Interac-
tion, Ph.D. Thesis, Wayne State University, 1988.
(5) (a) Anh N. T.; Maurel F. New J . Chem. 1997, 21, 861-871. (b)
Kiselev, V. D.; Konovalov, A. I. Russ. Chem. Rev. 1988, 58, 230-249
and references therein.
(6) (a) Phino e Melo, T. M. V. D.; Fausto, R.; Rocha Gonsalves, A.
M. d’A.; Gilchrist, T. L. J . Org. Chem. 1998, 63, 5350-5355. See also:
(b) Sisti, N. J .; Motorina, I. A.; Tran Huu Dau, M.-E.; Riche C.; Fowler,
F. W.; Grierson, D. S. J . Org. Chem. 1996, 61, 3715-3728.
(7) (a) Spino, C.; Crawford, J .; Gugelchuk, M.; Cui, Y. J . Chem. Soc.,
Perkin Trans. 2 1998, 1499-1506. (b) Spino, C.; Crawford, J . Can. J .
Chem. 1993, 71, 1094-1097. (c) McIntosh, J . M.; Sieler, R. A. J . Org.
Chem. 1978, 43, 4431-4433.
Synthesis; Baldwin, J . E., Ed.; Pergamon Press: Exeter, UK 1990. (b)
Boger, D. L.; Weinreb, S. M. In Hetero Diels-Alder Methodology in
Organic Synthesis; Wasserman, H., Ed., Academic Press: San Diego,
CA, 1987. (c) Fringuelli, F.; Taticchi, A. In Dienes in the Diels-Alder
Reaction; J ohn Wiley & Sons: New York, 1990.
(
2) (a) Fukui, K. Acc. Chem. Res. 1981, 14, 363-368. (b) Fukui, K.
Acc. Chem. Res. 1971, 4, 57-64. (c) Fukui, K. Molecular Orbitals in
Chemistry, Physics, and Biology; Academic Press: New York, 1964; p
5
25.
3) (a) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
(
J ohn Wiley & Sons: Chichester, UK, 1976. (b) Anh, T. N. Orbitales
fronti e` res, manuel pratique; InterEditions & CNRS Editions: Paris,
France, 1995. (c) Rauk, A. Orbital Interaction Theory of Organic
Chemistry; Wiley-Interscience: New York, 1994.
1
0.1021/jo0353740 CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/08/2004
J . Org. Chem. 2004, 69, 757-764
757

Spino et al.
F IGURE 3. Electron-poor dienes 1-9.
dienophiles with high ω values should react faster with
dienes possessing low values of ω. For example, 1,3-
butadiene (ω ) 1.05) is expected to react faster with
methyl vinyl ketone (MVK, ω ) 1.65) than with ethylene
(ω ) 0.73). In addition, partners with large ∆ω are
expected to react through a very polar mechanism, which
may even be considered as an electrophile-nucleophile
reaction rather than a true cycloaddition.1 While the
difference in ω index is very useful for predicting the
relative reactivities of dienes and dienophiles, it is based
on FMOs and therefore it has many of the shortcomings
of the theory. For example, why does MVK undergo a
F IGURE 2. The NDAD is always favored over the IEEDAC
in cross-Diels-Alder cycloadditions.
cloaddition generally progress under much harsher con-
ditions than normal Diels-Alder cycloadditions,1b for
comparable Hde-Ldo and Hdo-Lde energy gaps.
We have shown some time ago that the Hde-Ldo
interaction exerts a larger influence on the energetics of
the Diels-Alder reaction than does the Hdo-Lde interac-
0b
8
tion. The most convincing experimental support for this
hypothesis comes from our observation that NDACs are
always favored over IEDDACs in the cross-Diels-Alder
cycloaddition between an electron-poor and an electron-
1
2
NDAC with 1,3-butadiene (140 °C, sealed reactor)
8
(∆ω ) 0.60) but MVK will not undergo an IEDDAC with
ethylene even though the ∆ω is larger (∆ω ) 0.85)? MVK
undergoes an IEDDAC with methylvinyl ether (∆ω )
rich diene (Figure 2). The fact that the same frontier
orbitals are involved in either the NDAC or the IEDDAC
removes any possible bias and alleviates the need for
calculating orbital energies. This domination of the
NDAC over the IEDDAC has nearly no exception, and
1
.23) under conditions (180 °C, sealed reactor) similar
to that needed for the MVK/1,3-butadiene reaction
despite a much larger ∆ω.13 Here too, IEDDACs pose a
problem in the interpretation of the relative reactivities
of dienes and dienophiles.
8
even strong steric effects did not overcome it. That is to
say, the system energetically profits more from a nar-
rower Hde-Ldo than from a narrower Hdo-Lde. This is an
important observation that emphasizes the preponder-
ance of the Hde-Ldo in influencing the transition structure
and thus the reaction rate. Domingo has discussed the
Electron-poor dienes such as 1-7 (Figure 3) have been
known for a long while to react with both electron-
deficient and electron-rich dienophiles.7 The ability of
these dienes to react with both types of dienophiles offers
an opportunity to probe further the role of the two
frontier orbital interactions in a single system. To the
best of our knowledge, no one has measured which of the
electron-deficient or electron-rich dienophiles reacted
faster with such dienes. In addition, no one has verified
if the FMO theory adequately predicted reactivity trends
for each category of dienophiles. Answers to these ques-
tions may establish with more precision and detail what
influence each of the frontier interactions (Hde-Ldoand
,14
[
4+2]-cycloaddition of furans with 4-carbomethoxy-6,6-
9
dimethoxy-o-quinone. These reactions represent rare
examples of a cross-Diels-Alder cycloaddition between
two dienes where the IEEDAC is favored over the NDAC.
However, the NDAC reaction of furans (i.e. furans acting
as the diene) is known to be often reversible.1c The
reaction was described as proceeding through a stepwise
mechanism with the furan acting as a nucleophile,
although a NDAC reaction followed by a Cope rearrange-
ment was not ruled out.
H
do-Lde) exerts on the rate of Diels-Alder reactions and
Domingo and co-workers have made several contribu-
tions on the subject of the mechanism of polar DA
reactions.10 In their analysis, dienes and dienophiles
(
12) J ohnson, W. K. J . Org. Chem. 1959, 24, 864-865.
10a
(13) Alonso, M. E.; Garc ´ı a, M. d. C. J . Org. Chem. 1985, 50, 988-
are ranked according to their calculated global electro-
992.
philicity index ω, as described by Parr.11 It is argued that
(14) (a) Baraldi, P. G.; Barco, A.; Benetti, S.; Manfredini, S.; Pollini,
G. P.; Simoni, D.; Zanirato, V. Tetrahedron 1988, 44, 6451-6454. (b)
Tarnchompoo, B.; Thebtaranonth, C.; Thebtaranonth, Y. Tetrahedron
Lett. 1987, 28, 6671-6674. (c) Honek, J . F.; Mancini, M. L.; Belleau,
B. Synth. Commun. 1984, 14, 483-491. (d) Duttman, H.; Weyerstahl,
P. Chem. Ber. 1979, 112, 3480-3485. (e) J ung, M. E.; Zimmerman, C.
N. J . Am. Chem. Soc. 1991, 113, 7813-7814. (f) Chou, T.-s.; Hung,
S.-C. J . Org. Chem. 1988, 53, 3020-3027. (g) Chou, T.-s.; Chang, C.-
Y.; Wu, M.-C.; Hung, S.-H.; Liu, H.-M.; Yeh, W.-Y. J . Chem. Soc., Chem.
Commun. 1992, 1643-1644. (h) Mandai, T.; Yokoyama, H.; Miki, T.;
Fukuda, H.; Kobata, H.; Kawada, M.; Otera, J . Chem. Lett. 1980,
1057-1060. (i) Martina, D.; Brion, F. Tetrahedron Lett. 1982, 23, 865-
868. (j) Poly, W.; Schomburg, D.; Hoffman, H. M. R. J . Org. Chem.
1988, 53, 3701-3710. (k) Bodwell, G.; Pi, Z. Tetrahedron Lett. 1997,
38, 309-312.
(
8) Spino, C.; Pesant, M.; Dory, Y. Angew. Chem., Int. Ed. 1998, 37,
3
262-3265.
(
(
9) Domingo L. R.; Aurell, M. J . J . Org. Chem. 2002, 67, 959-965.
10) (a) Domingo, L. R.; Aurell, M. J .; P e´ rez, P.; Contreras, R.
Tetrahedron 2002, 58, 4417-4423. (b) Domingo, L. R.; Aurell, M. J .;
P e´ rez, P.; Contreras, R. J . Org. Chem. 2003, 68, 3884-3890. (c)
Domingo, L. R.; Arn o´ , M.; Andr e´ s, J . J . Org. Chem. 1999, 64, 5867-
5
1
3
875. (d) Domingo, L. R.; Picher, M. T.; Aurell, J . J . Phys. Chem. A
999, 103, 11425-11430. (e) Domingo, L. R. J . Org. Chem. 2001, 66,
211-3214.
(
11) Parr, R. G.; von Szentpaly, L.; Liu, S. J . Am. Chem. Soc. 1999,
1
21, 1922-1924.
7
58 J . Org. Chem., Vol. 69, No. 3, 2004

Frontier Orbital Interactions in Diels-Alder Cycloaddition
TABLE 1. Kin etic Resu lts of th e [4+2]-Cycloa d d ition of
Dien e 7 w ith Dien op h iles 10-21
time to
completion (h)
yield
(%)
dienophilea
adduct
b
entry
c
1
2
3
4
5
6
7
10
11
12
13
14
15
16
22
23
24
25
6
4
5.5
14
100
100
100
100
c
c
c
F IGURE 4. Orbital energies (eV) and geometries of dienes 7
and 8.
(4 equiv) -
1
6
26
(neat) 0.5d
89e
8
9
0
17
18
19
e
1
27
28
(4 equiv) 1.5
91
89
100
e
(2 equiv) 2.5
c
1
1
1
2
20
21
6
a
equiv of dienophile. b Monitored by NMR. c Percent conver-
4
d
sion by NMR; product decomposes upon chromatography. Mi-
crowave oven, EVE as solvent. e Isolated yield.
TABLE 2. Kin etic Resu lts of th e [4+2]-cycloa d d ition of
Dien e 8 w ith Dien op h iles 10-21
time to
kr
yield
entry dienophilea adduct completionb (h) (mL/mol‚s) (%)
c
1
2
3
4
5
6
7
8
9
0
1
2
10
11
12
13
14
15
16
17
18
19
20
21
30
31
32
33
8
9
8
48
0.31
0.26
0.30
100d
83
90
30
e
F IGURE 5. Orbital energies (eV) and coefficients of dieno-
philes 10-21. Trimethoxyethene was used in lieu of diene 20
for the calculations.
1
1
1
35
36
4
9
0.77
0.24
83
57
a
equiv of dienophile. b Monitored by NMR. c Isolated yield.
2
thus lead to better predictions of diene and dienophile
reactivities. We therefore set out to measure the rates of
Diels-Alder cycloadditions of dienes 715 and 8 with
several electron-poor and electron-rich dienophiles. We
herein report our results, which led to an unexpected
observation about the role orbital coefficients may play
in the reactivity of dienes and dienophiles. We offer an
interesting and novel interpretation of this role.
d
Percent conversion by NMR; product decomposes upon chroma-
tography. e Gave 30% 33 and 32% 37.
16
With respect to both dienes, maleic anhydride (MA;
1
0), 1,1-carbethoxyethene (CEE; 11),19 and dimethyl
fumarate (DMFu; 12) were of similar reactivities (Tables
and 2, entries 1, 2, and 3). Maleic anhydride benefits
from a diminished steric encumbrance and a lower
LUMO (Figure 5). Methyl acrylate (MAc; 13) was much
less reactive and took 14 h to react with diene 7 (Table
1
Resu lts
1
, entry 4). With diene 8, it gave approximately a 50-50
The minimized geometries and orbital energies for the
two dienes are shown in Figure 4.17 We chose 12 dieno-
philes, all of which are shown in Figure 5 along with the
energies of their frontier orbitals. Tables 1 and 2 list the
time of reaction for each dienophile with diene 7 and 8,
respectively.18 Figures 6 and 7 display their Diels-Alder
adducts (in the absence of dienophile, dienes 7 and 8
dimerize to 29 and 37,1 respectively, via a Diels-Alder
cycloaddition).
mixture of adduct 33 and dimer 37 (Table 2, entry 4). As
we moved to more electron-rich dienophiles (e.g. 14-18),
the reactivity dropped completely (Tables 1 and 2).
Vinylene carbonate (14) (entry 5), dihydropyran (15)
(entry 6), ethyl vinyl ether (EVE; 16) (entry 7), 2,3-
2
0
dihydro-1,4-benzodioxane (17) (entry 8), and 2,3-dehy-
dro-1,4-dioxane (18) (entry 9),21 were unreactive with
dienes 7 and 8 and only the dimer 29 or 37, respectively,
was observed in these reactions. Diene 8 formed dimer
4b
3
7 even when heated to 150 °C in a sealed tube in neat
(
15) (a) Pesant, M. Master of Science Thesis, Universit e´ de Sher-
brooke, 1996. (b) Bodwell, G.; Pi, Z. Tetrahedron Lett. 1997, 38, 309-
12.
16) (a) Keah, H. H.; Rae I. D. Aust. J . Chem. 1993, 46, 1919-1928.
b) Hamon, D. P. G.; Spurr, P. R. Synthesis 1981, 873-874.
17) Calculations were done at the RHF/6-31G* level of theory with
Gaussian. See Supporting Information for details.
18) The dimerization of 7 is slightly faster than that of 8 and a
EVE. However, diene 7 was able to react in neat EVE
with microwave heating (Table 1, entry 7) but it was
unable to do so with dehydrodioxane 18. The reactivity
3
(
(
(
(19) Allinger, N. L.; Graham, J . C.; Dewhurst, B. B. J . Org. Chem.
1974, 39, 9, 2615-2617.
(20) Kashima, C.; Tomotake, A.; Omote, Y. J . Org. Chem. 1987, 52,
2, 5616-5621.
(
small quantity of dimer 29 often accompanied the desired cycloadducts.
This is why we chose to use 4 equiv of dienophiles for this case and we
felt that measured reaction rates would be less precise.
(21) Moss, R. D.; Paige, J . J . Chem. Eng. Data 1967, 12, 452-454.
J . Org. Chem, Vol. 69, No. 3, 2004 759

Spino et al.
TABLE 3. Ca lcu la ted HOMOs a n d LUMOs of Dien e 8
a n d Dien op h iles 10-14, 16, a n d 18-21
diene/
entry dienophile HOMO LUMO Ldo-H8 L8-Hdo
krel
1
2
3
4
5
6
7
8
9
0
1
8
-9.351 2.266
-12.130 1.026
-10.957 2.432
11.62
10.38
11.78
11.29
12.51
13.80
14.88
15.47
15.63
15.17
15.36
11.62
14.40
13.22
13.22
12.91
12.46 ,0.26
11.29
10.71 ,0.26
10.95
11.03
10
11
12
13
14
16
18
19
20
21
0.31
0.26
0.30
-10.95
1.937
-10.644 3.156
-10.190 4.451
-9.028 5.526
-8.448 6.116
-8.682 6.280
-8.767 5.823
-8.565 6.010
<0.26
<0.26
0.77
0.29
1
1
10.83 ,0.26
slightly more reactive than MA (10) and DMFu (12)
entries 1, 2, and 3). In contrast, 11 was slightly less
(
reactive than 10 or 12 with diene 8. EVE (16) was able
to react efficiently with diene 7 if a large excess was used
with microwave heating (Table 1, entry 7). This was not
the case with diene 8. Finally, 19 was more reactive with
7
2
than with diene 8 (compare entries 10 in Tables 1 and
).
F IGURE 6. Products from the Diels-Alder reaction of diene
with dienophiles 10-13, 16, 19, and 20.
7
Discu ssion
Table 3 lists the calculated energies of the frontier
orbitals for diene 8 and all dienophiles except 15 and 17.
L
8
-Hdo represents the calculated energy gap (eV) be-
tween each dienophile with respect to the LUMO of diene
represents the calculated energy gap (eV)
between the dienophile’s LUMO with respect to the
HOMO of diene 8. The H -L energy gap is relevant to
8
. Ldo-H
8
8
8
its dimerization. Note that the energy gaps between the
FMOs of the dienophiles and those of diene 7 would be
nearly identical since dienes 7 and 8 have nearly identical
calculated HOMO and LUMO energies (cf. Figure 4).
They were not included in Table 3 for clarity.
One observation is immediately striking: although the
H
do-Lde energy gaps of dienophiles 16 and 18-21 are
F IGURE 7. Products from the Diels-Alder reaction of diene
with dienophiles 10-13, 16, 19, and 20.
very close in value, their reactivities are vastly different.
This strongly supports our earlier suggestion that the
8
H
do-Lde energy gap is not a reliable tool for predicting
returned with dienophiles 19 and 20 but not 21. For
instance, 1,1-diethoxyethene (DEE; 19)22 was more reac-
tive than MA (10) or CEE (11) (compare entries 10 with
entries 1 and 2 in each table). The trialkoxysubstituted
ethene 2023 was less reactive than 19 but more reactive
than MAc (13) (entry 11 vs entries 10 and 4 in each
table). Tetramethoxyethylene (21)24 was unreactive (en-
tries 12) and only dimer 29 or 37 was isolated in this
case. Dienophiles 11 and 19 are of similar steric hin-
drance and both are more sterically hindered than the
unreactive EVE 16. We can thus conclude that the
electronics is the controlling element in the reactivity of
these dienophiles and not steric effects. Steric effects
may, however, lower the reactivity of 20 with respect to
DEE (19).
the relative reactivities of different dienes or dienophiles
in IEDDACs. By contrast, the Hde-Ldo energy gap for
dienophiles 10-14 reasonably predicts their relative
reactivities.
8
We can dismiss any significant steric effects to explain
the large differences in reactivity among dienophiles 15-
2
1 only by looking at the reactivity difference between
dienophiles 18 and 20. Clearly, 20 with its bulky tert-
butyldimethylsilyl group would be expected to be unre-
active if steric effects were dominant. Yet, it is more
reactive than 18 and also 21, which both possess a
smaller Hdo-Lde energy gap!
Another striking observation is that the Hdo-Lde
energy gaps of the unreactive electron-rich dienophiles
1
6-18 and 21 are smaller than the Hde-Ldo energy gaps
There are a few differences between the cycloaddition
results of dienes 7 and 8. In the case of 7, CEE (11) was
of the reactive electron-deficient dienophiles 11, 12, and
13 as well as the energy gap between the diene’s FMO
(i.e. its dimerization). Again, this unambiguously con-
(
22) Venneri, P. C.; Warkentin, J . Can. J . Chem. 2000, 78, 1194-
firms that these two frontier interactions affect the
reaction rate differently. We would otherwise wrongly
predict that dienophiles 16-18 and 21 should react more
rapidly than dienophiles 11-13 with dienes 7 and 8.
1
203.
(
(
23) Wissner, A. J . Org. Chem. 1979, 44, 4617-4622.
24) El-Saidi, M.; Kassam, K.; Pole, D. L.; Tadey, T.; Warkentin, J .
J . Am. Chem. Soc. 1992, 114, 8751-8752.
7
60 J . Org. Chem., Vol. 69, No. 3, 2004

Frontier Orbital Interactions in Diels-Alder Cycloaddition
F IGURE 8. Symmetry leads to coefficient cancellation at
transition state in the Hdo-Lde-(H-1)de interaction.
F IGURE 10. Vinyl ethers are better described as analogues
of enolate anions than substituted ethylenes.
which may be indicative of their generally lower
reactivities.1
b,26
What, then, would make polarized dienophiles reactive
in IEDDACs? The orbitals of a polarized electron-rich
dienophile are perhaps better described by considering
such dienophile as an analogue of an enolate anion rather
than a substituted ethylene (Figure 10).3 A cycloaddition
between an electron-poor diene and an electron-rich
dienophile, taken to its extreme, could be considered as
a Michael-type addition. In a full-fledged Michael addi-
tion, the most important (i.e. highly dominant) FMO
interaction should be the HOMO of the nucleophile (the
enolate anion) and the LUMO of the Michael acceptor
a
F IGURE 9. Energy diagram showing the fate of each frontier
orbital in a perfectly synchronous Diels-Alder reaction (eth-
ylene + butadiene).
However, and importantly, dienophiles 19 and 20 are
reactive and 19 slightly more so than maleic anhydride
(the electron-poor diene). Both FMOs are highly dissym-
(10) (entry 1, Tables 1 and 2). What makes these two
metric in terms of the relative size of their coefficients
at each end-carbon of the diene and each carbon of the
enolate anion (Figure 10). This highly dissymmetric
dienophiles more reactive than their electron-rich homo-
logues 15-18 and 21 with similar HOMO energies? The
answer, we believe, lies in their pronounced polarization
interaction leads to the formation of a single σ-bond in
(dissymmetry): In synchronous or nearly synchronous
the product.3
a,b
Therefore, in a highly asynchronous
Diels-Alder cycloadditions, the Hdo-Lde interaction suf-
fers orbital coefficient cancellation at the transition state
Diels-Alder transition state involving highly polarized
IEDDAC partners, it is plausible that the Hdo-Lde
level (Figure 8) with the net result being that the Hdo
-
interaction will be more like that of the HOMOenolate
-
L
de affects mainly the formation of the π-bond in the
4
,7,8,25
LUMOelectrophile interaction of a Michael addition. The fate
of the Hdo-Lde interaction in such highly asynchronous
cycloadditions can no longer be purely that of becoming
the product’s π-bond but must involve some σ-bond
formation and it will thus have more impact on the
overall energy of the transition state. In other words, in
IEDDAC, asynchronicity gives rise to a transition state
reduced in energy compared to a synchronous one. To the
best of our knowledge, no one has described the Hdo-Lde
interaction in that manner before.
cycloadduct (Figure 9).
Therefore, any change in the
H
do-Lde energy gap should result in a less pronounced
effect on the reaction rate than a corresponding change
in the Hde-Ldo energy gap, which is involved in the
formation of a σ-bond of the final cyclohexene (Figure 9).
This phenomenon could explain why variations in the
energy of the Hdo of symmetrically substituted dieno-
philes 14, 17, 18, and 21 do not have much effect on their
reactivities (cf. Table 3 and entries 5, 8, 9, and 12 in
Tables 1 and 2). Moreover, examples of IEDDA reactions
of symmetrical dienophiles are sparse in the literature,
Good experimental evidence from our own work and
that of others supports our hypothesis; symmetric dieno-
philes 17, 18, and 21 are unreactive despite a HOMO
energy that should favor them over more reactive dieno-
(
25) This arises from a compulsory mixing of Hdo with H-1de and
L
de in an antibonding and bonding way, respectively. For a clear
explanation of this phenomenon see: Woodward, R. B.; Hoffmann, R.
In The conservation of orbital symmetry; Verlag Chemie: Weinheim,
Germany, 1970; pp 21-30.
(26) Field, N. D. J . Am. Chem. Soc. 1961, 83, 3504-3507.
J . Org. Chem, Vol. 69, No. 3, 2004 761

Spino et al.
reaction rate to its more polarized homologue 11 with
both 7 and 8 (cf. entries 2 and 3 in Tables 1 and 2).
However, Domingo and co-workers have shown that the
highest acceleration in reaction rates comes from a
nonsymmetrical substitution of ethylene. For example,
1
4
,1-dicyanoethylene reacts with cyclopentadiene roughly
5 000 times more rapidely than acrylonitrile but tetra-
F IGURE 11. Dienes and dienophiles used in two separate
reaction rates studies.
cyanoethylene is only 1 000 times more reactive than 1,1-
diacyanoethylene. Their calculation agreed well with
experimental results, which were interpreted in terms
philes such as 16, 19, and 20; the latter, dissymmetric,
electron-rich dienophiles react faster with the dissym-
metric diene 7 than with symmetric diene 8 (compare
entries 7, 10, and 11 of each table); other observations
extracted from the literature lend further support to our
hypothesis: 1,2,4,5-tetrazine (38) reacts 18 times faster
with 15 than with 18 and 6 times faster with 39 than
with 40 (Figure 11);27 pyrones 42 are reactive toward 19
but unreactive toward 2,2-dimethyl-1,3-dioxole (41) (Fig-
ure 11) despite HOMO energies close in value (-8.89 vs
of the local electrophilicity index ω
κ
on each carbon of
10b
the substituted ethylenes.
Whether the reaction of
tetracyanoethylene is a true cycloaddition was, however,
questioned.
Yet other NDAC reactions could proceed faster when
highly polarized partners are involved. For example,
Danishefsky-type dienes react with aldehydes to give
dihydropyrans. It would be interesting to look at how
dissymmetry on the diene affects the reaction rate in
these cases.
-
8.69 eV, respectively);28 EVE, 2,3-dihydrofuran, and
other polarized electron-rich dienophiles were evidently
more reactive than 41 as well as a host of other 1,2-
alkoxyethenes (RO-CHdCH-OR) as dienophiles in the
Lewis acid-catalyzed cycloaddition with R,â-unsaturated
carbonyls.29
We offer that highly dissymmetric partners are inher-
ently more reactive than symmetric ones in IEDDAC if
the orbitals involved are of comparable energies and if
steric effects are not impeding. In other words, 1,1-
dialkoxyethenes (e.g. 19) are inherently better dieno-
philes than 1,2-dialkoxyethenes (e.g. 18). To the best of
our knowledge, no report comparing the reactivities of
dienophiles such as 19 and 18 has appeared in the
literature.
Con clu sion s
The above experiments demonstrate the following: (a)
The two frontier interactions in Diels-Alder cycloaddi-
tions are not equivalent. The Hdo-Lde should be used with
caution when predicting the relative reactivities of dienes
and dienophiles in IEDDA cycloadditions and the asyn-
chronicity of the transition state should be taken into
consideration. (b) In IEDDAC, polarized dienophiles are
more reactive than nonpolarized ones and thus (c) orbital
coefficients can be used to understand the relative
reactivity and not only the regiochemistry of Diels-Alder
cycloadditions. These demonstrations complement and
support our previously reported hypothesis regarding the
role that each frontier orbital plays in affecting the rates
of Diels-Alder reactions.8 Similar studies with other
dienes and heterodienes are ongoing and will be reported
in due course.
Nonetheless, there are examples in the literature of
IEDDACs where the reactivity trend can be explained
based on the Hdo-Lde energy gap.1b This is not contrary
to our present analysis since it suggests that within a
series of highly polarized electron-rich dienophiles, the
H
do-Lde energy gap should be a reliable prediction tool.30
Exp er im en ta l Section
The same could be true when comparing the relative
reactivities of a series of symmetrical dienophiles. We are
convinced that as more examples of IEDDAC are scru-
tinized in the present and future literature, the impor-
tance and value of dienophile polarization will be in-
creasingly recognized.
Typ ica l P r oced u r e for Diels-Ald er Rea ction s. To a
solution of diene 7 or 8 (0.5 mmol) in dry toluene (3 mL in the
case of 7 and 2 mL for 8) under argon was added a dienophile
(4 equiv for 7 and 2 equiv for 8, except where indicated). The
solution was then refluxed for the required time (see Tables 1
and 2). At the end of the reaction the solvent was evaporated
and the crude purified by flash chromatography on silica. In
one case, diene 7 was dissolved in ethyl vinyl ether (3 mL)
and heated with a microwave oven at 150 W for 30 min (130
Should coefficient size (i.e. polarization) also affect the
reactivity of normal Diels-Alder cycloadditions? Much
less so. The Hde-Ldo does not lead to coefficient cancel-
°
C, 70 psi).
lation in the product’s occupied σ-orbital,4
,8,22
and this
Where krel values are reported, aliquots of the reaction
interaction already results in the formation of a σ-bond.
mixture were collected at 15- or 30-min intervals and the
concentration of the starting diene or the cycloadduct was
measured against an internal standard (chlorobenzene). Charts
of 1/(a - b) ln((b(a - x)/a(b - x)) over time were used to extract
the rate constants. Each reaction was done three times.
Dissymmetry will neither impede nor help this situa-
tion.31 For example, CEE (11) is slightly less reactive than
maleic anhydride with diene 8 but slightly more reactive
than maleic anhydride with diene 7 (cf. entries 1 and 2
in Tables 1 and 2). Dimethyl fumarate (12) has a similar
(31) Singleton and co-workers have calculated that unpolarized
electron-poor dienophiles (acetylene dicarboxylate, dialkyl maleate, and
triazolinediones) have a highly asynchronous transition state with
nearly symmetrical dienes (isoprene or 2-tert-butyl-1,3-butadiene).
Calculated asynchronous transition states were lower in energy than
synchronous ones. They noted that reaction rates and kinetic isotope
effects agreed with these results though experimental support for the
calculated structures was notably ambiguous. Singleton, D. A.; Schul-
meier, B. E.; Hang, C.; Thomas, A. A.; Leung, S.-W.; Merrigan, S. R.
Tetrahedron 2001, 57, 5149-5160.
(
27) Sauer, J .; Heldmann, D. K.; Hetzenegger, J .; Krauthan, J .;
Sichert, H.; Schuster, J . Eur. J . Org. Chem. 1947, 12, 2885-2896.
28) Balazs, L.; Kadas, I.; Toke, L. Tetrahedron Lett. 2000, 41, 7583-
587.
(
7
(
29) The former went at -78 °C while the other required 25 °C and
higher catalyst loadings. See: Audrain, H.; Thorhauge, J .; Hazell, R.
G.; J orgensen, K. A. J . Org. Chem. 2000, 65, 4487-4497.
(
30) See some examples in refs 1b and 27.
7
62 J . Org. Chem., Vol. 69, No. 3, 2004

Frontier Orbital Interactions in Diels-Alder Cycloaddition
Ad d u ct 22. The reaction was performed according to the
general procedure starting with 196 mg of maleic anhydride.
After evaporation, 240 mg of crude 22 (100%) was isolated.
Ad d u ct 30. The reaction was performed according to the
general procedure starting with 98 mg of maleic anhydride.
After evaporation, 180 mg of crude 30 (100%) was isolated.
1
The product decomposed upon chromatography on silica gel.
H NMR (CDCl ) δ 2.62-2.68 (m, 2H), 2.98 (dd, 2H, J ) 18.7,
3
1
13
H NMR (CDCl
.43-2.58 (m, 3H), 2.87 (d, 1H, J ) 13 Hz), 3.58 (m, 1H), 3.84
3
) δ 1.59-1.85 (m, 2H), 2.06-2.26 (m, 2H),
3 3
2.2 Hz), 3.50 (m, 2H), 3.79 (s, 6H); C NMR (CD COCD ) δ
27 (t), 41.1 (d), 53.4 (q), 137.2 (s), 168.0 (s), 175.3 (s); IR (THF,
cm ) 1783, 1732, 1275; LRMS (m/z) 237, 236, 163, 105; HRMS
2
1
3
-1
(
s, 3H), 4.48 (d, 1H, J ) 8.8 Hz), 7.73 (s, 1H); C NMR (CDCl
δ 25.6 (t), 27.4 (t), 39.4 (t), 40.9 (d), 42.1 (d), 43.9 (d), 47.3 (d),
2.5 (q), 125.2 (s), 139.0 (d), 164.9 (s), 168.0 (s), 170.4 (s), 204.7
3
)
+
calcd for C11
H
9
O
6
(M - OCH
3
) 237.0399, found 237.0393.
5
Ad d u ct 31. The reaction was performed according to the
general procedure starting with 172 mg of 1,1-dicarbethoxy-
-
1
(
1
s); IR (neat, cm ) 1781, 1733, 1275; LRMS (m/z) 278, 180,
21, 83; HRMS calcd for C14 278.0790, found 278.0794.
Ad d u ct 23. The reaction was performed according to the
H
14
O
6
ethene. After purification by chromatography on silica gel
1
(hexanes:ether 70:30), 142 mg of 31 (83%) was isolated.
NMR (CDCl
Hz), 2.43 (m, 2H), 2.87 (m, 2H), 3.74 (s, 3H), 3.77 (s, 3H), 4.19
(q, 4H, J ) 6.6 Hz); 13C NMR (CDCl
) δ 14.0 (q), 23.9 (t), 26.3
(t), 31.1 (t), 52.2 (q, 2 Me), 61.8 (t), 70.4 (s), 132.19 (s), 134.6
H
general procedure starting with 345 mg of 1,1-dicarbethoxy-
ethene. After evaporation of the solvents under reduced
pressure, 180 mg of 23 (100%) was isolated. The product
decomposed upon chromatography on silica gel. 1H NMR
3
) δ 1.24 (t, 6H, J ) 6.6 Hz), 2.17 (t, 2H, J ) 6.6
3
-
1
(
CDCl
3
) δ 1.22 (m, 6H), 1.52-2.66 (m, 8H), 3.01-3.24 (m, 1H),
(s), 167.6 (s), 168.2 (s), 170.3 (s); IR (neat, cm ) 1734, 1658;
LRMS (m/z) 310, 237, 209, 163, 137; HRMS calcd for C15
(M - CH OH) 310.1052, found 310.1058.
3
1
2
.68, 3.73 (2s, 3H), 3.73 (m, 1H), 4.18 (m, 4H), 6.66, 6.70 (2m,
H); IR (neat, cm ) 1725, 1623; LRMS (m/z) 352, 320, 292,
47, 219, 205, 191, 173; HRMS calcd for C18 352.1522,
18 7
H O
-
1
3
H
24
O
7
Ad d u ct 32. The reaction was performed according to the
general procedure starting with 144 mg of dimethyl fumarate.
found 352.1529.
Ad d u ct 24. The reaction was performed according to the
general procedure starting with 288 mg of dimethyl fumarate.
Conversion was 100% by NMR but the product decomposed
Purification on silica gel with dichloromethane/ether (95/5)
1
gave 142 mg of 32 (90%). Mp 108 °C; H NMR (CDCl
3
) δ 2.4-
1
3
2.5 (m, 2H), 2.89-2.95 (m, 4H), 3.72 (s, 6H), 3.77 (s, 6H);
NMR (CDCl ) δ 28.5 (t), 40.1 (d), 52.4 (q, broad), 133.2 (s), 167.5
(s), 173.7 (s); IR (neat, cm ) 1731, 1662; LRMS (m/z) 283 (M
- OCH ), 250, 207, 163, 151; HRMS calcd for C13
283.0818, found 283.0808.
C
1
upon chromatography on silica gel. H NMR (CDCl
3
) δ 1.3-
3
-
1
+
1
2
2
3
.5 (m, 1H), 1.6-1.87 (m, 1H), 1.9-2.1 (m, 2H), 2.2-2.4 (m,
H), 2.5-2.7 (m, 2H), 3.05 (dd, 1H, J ) 11.4 and 6.11 Hz),
.89 (dd, 1H, J ) 11.4 and 10.2 Hz), 3.65 (s, 3H), 3.69 (s, 3H),
3
15 7
H O
-
1
.80 (s, 3H), 6.72 (m, 1H); IR (neat, cm ) 1730, 1658; LRMS
Ad d u ct 33. The reaction was performed according to the
general procedure starting with 86 mg of methyl acrylate. After
purification by chromatography on silica gel (hexanes:ether
50:50), 39 mg of 33 (30%) was isolated along with 55 mg (32%)
+
(
m/z) 324 (M ), 308, 292, 264, 232, 221, 205, 173; HRMS calcd
for C16 324.1209, found 324.1212.
20 7
H O
Ad d u ct 26. The reaction was performed with a microwave
oven (150 W for 30 min; 130 °C, 70 psi) in ethyl vinyl ether as
solvent. After purification by chromatography on silica gel
of dimer 37. Compound 33: 1H NMR (CDCl
) δ 1.66-1.74 (m,
1H), 2.06-2.13 (m, 1H), 2.30-2.46 (m, 1H), 2.48-2.51 (m, 4H),
3.70 (s, 3H), 3.76 (s, 6H); 13C NMR (CDCl
δ) 23.8 (t), 25.8 (t),
28.0 (t), 37.9 (d), 51.9 (q), 52.2 (q), 133.0 (s), 135.4 (s), 167.9
3
(
dichloromethane:ether 95:5), 112 mg of 26 (89%) was isolated
3
1
as a mixture of exo and endo isomers: H NMR (CDCl
3
) δ 1.17
-1
(
t, 6H, J ) 6.6 Hz), 1.30-1.85 (m, 6H), 2.00 (m, 6H), 2.21-
(s), 168.5 (s), 174.5 (s); IR (neat, cm ) 1717, 1652; LRMS (C.I.
NH , m/z) 272, 257, 225, 165, 137; HRMS calcd for C12
2
3
1
3
4
7
.62 (m, 8H), 3.27 (m, 1H), 3.4-3.55 (m, 2H), 3.6-3.7 (m, 2H),
3
17 6
H O
+
.70 (s, 3H), 3.75 (s, 3H), 3.89 (m, 1 H), 6.43 (m, 1H), 6.48 (m,
(MH ) 257.1025, found 257.1030.
1
3
H); C NMR (CDCl
3
) δ 15.3 (q), 15.4 (q), 22.5 (t), 22.8 (t),
Ad d u ct 35. The reaction was performed according to the
general procedure starting with 116 mg of 1,1-diethoxyethene.
After purification by chromatography on silica gel (dichlo-
1.1 (t), 31.3 (t), 32.0 (t), 34.9 (t), 37.3 (t), 38.0 (t), 40.2 (d),
0.5 (d), 45.9 (d), 50.8 (d), 52.0 (q), 52.3 (q), 64.3 (t), 64.6 (t),
4.5 (d), 74.5 (d), 128.3 (s), 130.4 (s), 140.4 (d), 142.4 (d), 170.9
1
romethane:ether 95:5), 119 mg of 35 (83%) was isolated. H
-
1
(
1
s), 172.0 (s), 199.4 (s), 200.8 (s); IR (neat, cm ) 1740, 1694,
NMR (CDCl ) δ 1.17 (t, 6H, J ) 7.7 Hz), 1.87 (t, 2H, J ) 6.6
3
+
618; LRMS (m/z) 252 (M ), 206, 180, 162, 147, 124, 121;
Hz), 2.43 (m, 2H), 2.59 (br s, 2H), 3.50 (q, 4H, J ) 7.7 Hz),
3.75 (s, 3H), 3.77 (s, 3H); 13C NMR (CDCl ) δ 15.3 (q), 25.3 (t),
HRMS calcd for C14 252.1361, found 252.1367.
20 4
H O
3
Ad d u ct 27. The reaction was performed according to the
general procedure starting with 232 mg of 1,1-diethoxyethene.
After purification by chromatography on silica gel (dichloro-
28.3 (t), 35.6 (t), 52.2 (q), 55.5 (t), 98.0 (s), 131.4 (s), 135.8 (s),
-
1
167.8 (s), 168.7 (s); IR (PhMe, cm ) 2995, 1728, 1726, 1653;
LRMS (m/z) 286, 255, 209, 181, 139, 116; HRMS calcd for
methane:ether 95:5), 134 mg of 27 (91%) was isolated as a
C
14
H
22
O
6
286.1416, found 286.1418.
1
single regioisomer. H NMR (CDCl
3
) δ 1.06-1.25 (m, 1H),
Ad d u ct 36. The reaction was performed according to the
general procedure starting with 218 mg of dienophile 20. After
purification by chromatography on silica gel (hexanes:ether
1
(
2
(
4
1
(
.08-1.12 (t, 6H, J ) 6.7 Hz), 1.45-1.51 (m, 1H), 1.66-1.84
m, 1H), 1.85-2.1(m, 4H), 2.24-2.37 (m, 1H), 2.42-2.60 (m,
H), 3.41-3.53 (m, 4H), 3.66 (s, 3H), 6.36 (m, 1H); 13C NMR
CDCl ) δ 15.1 (q), 22.7 (t), 30.6 (t), 33.8 (t), 36.3 (d), 40.4 (d),
9.8 (t), 52.2 (q), 55.5 (t), 56.0 (t), 99.3 (s), 128.2 (s), 141.6 (d),
1
60:40), 111 mg of 36 (57%) was isolated. H NMR (C
6
D
6
) δ 0.18
3
(s, 3H), 0.21 (s, 3H), 1.03 (s, 9H), 2.68-2.75 (m, 2H), 2.95 (m,
2H), 3.05 (s, 3H), 3.15 (s, 3H), 3.23 (t, 1H, J ) 3.5 Hz), 3.42 (s,
-
1
13
70.4 (s), 200.3 (s); IR (neat, cm ) 1736, 1691, 1628; LRMS
3
3H), 3.48 (s, 3H); C NMR (CDCl ) δ -3.0 (q), 18.4 (s), 25.8
+
m/z) 296 (M ), 251, 191, 163, 149, 134, 116; HRMS calcd for
296.1624, found 296.1619.
Ad d u ct 28. The reaction was performed according to the
(q), 29.8 (t), 33.4 (t), 48.5 (q), 52.2 (q), 57.2 (q), 77.7 (d), 98.3
-
1
C
16
H
24
O
5
(s), 132.1 (s), 132.6 (s), 167.8 (s), 168.4 (s); IR (neat, cm ) 1731,
1721, 1261; LRMS (m/z) 388, 343, 299, 267, 218, 197, 193;
HRMS calcd for C18H O Si 388.1917, found 388.1909.
32 7 1
general procedure starting with 436 mg of dienophile 20. After
purification by chromatography on silica gel (hexanes:ether
Dim er 37. The reaction was performed according to the
7
0:30), 70 mg of 28 (35%) was isolated as a single regio- and
general procedure with no dienophile starting with 85 mg of
1
stereoisomer. Mp 115 °C; H NMR (CDCl
3
) δ 0.14 (s, 3H), 0.18
8. After purification by chromatography on silica gel (hexanes:
1
(
2
3
s, 3H), 0.85 (s, 9H), 1.36-1.49 (m, 1H), 1.67-1.76 (m, 1H),
ether 95:5), 61 mg of 37 (72%) was isolated. H NMR (CDCl
3
)
.03-2.11 (m, 1H), 2.23-2.63 (m, 4H), 3.31 (s, 3H), 3.58 (s,
δ 2.12-2.19 (m, 3H), 2.37-2.45 (m, 1H), 2.58 (d, 1H, J ) 18.7
Hz), 2.87 (dd, 1H, 18.7, J ) 3.0 Hz), 3.67 (s, 3H), 3.73 (s, 3H),
3.74 (s, 3H), 3.78 (s, 3H), 5.74 (s, 1H), 6.42 (s, 1H); IR (neat,
1
3
3
H), 3.70 (m, 2H), 3.71 (s, 3H), 6.35 (m, 1H); C NMR (CDCl )
δ -4.1 (q), -1.8 (q), 18.9 (s), 22.7 (t), 26.1 (q), 27.2 (t), 40.3 (t),
-
1
4
1
1
2.8 (d), 48.9 (d), 52.4 (q), 53.7 (q), 61.6 (q), 83.2 (d), 100.0 (s),
27.5 (s), 139.8 (d), 170.4 (s), 200.0 (s); IR (neat, cm-1) 1739,
695, 1629; LRMS (m/z) 398, 353, 341, 309, 277, 235, 207, 189;
cm ) 3000, 2958, 2847, 1726, 1657, 1627, 1435, 1259, 1075;
13
C NMR (CDCl
52.3 (q), 52.5 (q), 65.8 (s), 126.3 (d), 128.5 (s), 133.5 (s), 139.9
(s), 166.2 (s), 167.8 (s), 168.2 (s), 174.4 (s); LRMS (C.I. NH
3
3
) δ 23.4 (t), 26.8 (t), 34.2 (t), 46.9 (q), 52.2 (q),
HRMS calcd for C20
H
34
O
6
Si
1
398.2124, found 398.2129.
J . Org. Chem, Vol. 69, No. 3, 2004 763

Spino et al.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13
m/z) 358 (MNH +
calcd for C15
), 341 (MH ), 309, 294, 249, 221, 189; HRMS
(M - CH OH) 308.0896, found 308.0905.
+
C
4
H
16
O
7
3
NMR spectra of compounds 8, 22, 26-28, 30-33, and 35-37
1
in addition to H NMR of 7, 23, and 24; calculation details
Ack n ow led gm en t. Our sincere thanks goes to our
colleague J ean Lessard for fruitful discussions. We
thank the Natural Sciences and Engineering Council
of Canada and the Universit e´ de Sherbrooke for finan-
cial support.
are included. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O0353740
7
64 J . Org. Chem., Vol. 69, No. 3, 2004