andrea costen- frontier molecular orbital theory and the role of water in the endo/exo...
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Frontier Molecular Orbital Theory and the Role of Water in the Endo/Exo Diastereoselectivity and Regioselectivity
of Intermolecular Diels-Alder Reactions
002.469Specific Methods in Organic Synthesis
Andrea Costen
April 15, 2003
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Organic molecules often possess a high degree of hydrophobic character leading
to their preferential association with a non-aqueous environment. It may seem surprising,
therefore, to learn that Diels-Alder reactions undergo rate enhancement, as well as
increased diastereoselectivity and regioselectivity in an aqueous environment. The aim
of this paper is to provide a theory to explain waters role in this seemingly curious
phenomenon. After a brief introduction of the Diels-Alder reaction, a description of
hydrophobic packing and hydrogen bonding in relation to rate enhancement will be
presented. This will be followed by a brief discussion of frontier molecular orbital (FMO)
theory and its significance in Diels-Alder chemistry. With regard to hydrophobicity,
hydrogen bonding, and FMO theory, consideration will then be given to the role water
plays in enhancing both endo diasteroselectivity and regioselectivity in these reactions.
The Diels-Alder reaction is one of the most synthetically useful reactions for
forming six-membered rings through new carbon-carbon, carbon-heteroatom and
hetoeratom-heteroatom bonds. In a [4 e + 2 e] cycloaddition, a conjugated diene reacts
with a dienophile to form the new six-membered ring adduct. 1 The Diels-Alder reaction is
a bimolecular pericyclic reaction whose mechanism, in the majority of cases, is
described as a concerted process (Figure 1).
Figure 1: Schematic representation of a concerted pericyclic Diels-Alder reaction mechanism.
Although there are some cases in which the reaction occurs through a biradical intermediate, suchinstances will not be discussed in this paper.
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It is well established that both hydrophobic interactions and hydrogen bonding play
a significant role, especially with respect to rate acceleration, in Diels-Alder reactions in
aqueous media. 2-6 Hydrophobic interactions are defined as the association of nonpolar
groups, or compounds, with each other in aqueous systems, driven by the tendancy of
the surrounding water molecules to seek their most stable (disordered) state. 7 The
tendancy of water to form highly structured solvation shells around nonpolar solutes in a
process known as hydrophobic hydration 8 is entropically unfavorable. Bringing two or
more nonpolar molecules together, however, releases some of the solvent shell water
molecules back into free solution; this is more entropically favorable and also minimizes
the interactions between the nonpolar solute and polar solvent. 9
Blokzijl et al. 10 introduced the term enforced pairwise hydrophobic interaction to
describe the hydrophobic effect specific to the bimolecular process of the Diels-Alder
reaction. Since the bimolecular reaction requires both diene and dienophile to interact
with each other unseparated by aqueous solvent, the word enforced was introduced to
distinguish this particular association from those hydrophobic interactions that do not lead
to the activated complex. The high cohesive energy density of water reduces the surface
contact between the hydrophobic molecules and the water molecules, forcing the
reactants to occupy as little space as possible. This decrease in volume of the reactants
enhances the already negative volume of activation that is characteristic of Diels-Alder
chemistry and results in reaction rate acceleration. 5,9 In addition to the enforced
hydrophobic interactions, hydrogen bonding also enhances reaction rate.
The Diels-Alder reaction always proceeds best with an electron rich diene and
an electron poor dienophile. Substituting an electron-withdrawing group (EWG) at one or
both of the sp 2 hybridized centres of the dienophile creates a more electron-deficient
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alkene. 11 In aqueous media, the presence of EWGs are significant because nonbonding
pairs of electrons from electronegative atoms in the EWG(s) can create hydrogen bonds
with hydrogen from water molecules (Figure 2). It is believed that hydrogen bonding to
the activated complex accelerates the reaction in the same way as Lewis acid
catalysis, 4,5 i.e. by causing greater polarization of the dienophile. 1
Figure 2: Schematic representation of the activated complex hydrogen bonded to water molecules in aqueous media. The hydrogen bonds are represented by the heavydashed lines between the carbonyl oxygens and the water hydrogens. Red arrowsindicate direction of increased polarization through inductive effect.
Since both hydrophobic packing and hydrogen bonding are established as causing
rate acceleration of Diels-Alder reactions in aqueous media, these two phenomena must
also be present in any discussion of Diels-Alder diastereoselectivity and regioselectivity in
the presence of water. To fully understand how water might also enhance selectivity,
however, FMO theory must first be presented to explain the electronic interactions
between the diene and the dienophile.
Electronic interactions in cycloaddition reactions, including Diels-Alder, can be
represented by molecular orbitals (MO). Focusing on the bonds of the diene and
dienophile, the relative energies of the molecular orbitals can be represented as
outlined in Figure 3. The highest energy orbital containing electrons is called the highest
HO
HH
OH
HO H
O
O
O
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HOMO
LUMO
-9.03 eV
+1.0 eV
-10.52 eV
+1.5 eV
LUMO
HOMO
antibonding
bonding
occupied molecular orbital (HOMO), whereas the lowest energy orbital with no electrons
is the lowest unoccupied molecular orbital (LUMO); these two orbitals are the frontier
molecular orbitals. The HOMO of one molecule delivers electrons to the LUMO of
another molecule in an intermolecular cycloaddition; 12 the extent of this interaction is
inversely proportional to the energy separation between the HOMO and LUMO 13 and only
takes place when these orbitals have the same symmetry (Figure 4).
-0.42 -0.42
E = 10.53 eV
+0.41 -0.41
+0.57 - 0.57 E = 11.52 eV
Figure 3: Molecular orbitals for butadiene and ethene with HOMO and LUMO energies andorbital coefficients. 12 The HOMO of the diene and the LUMO of the dienophile are thereactive orbitals since their energy difference is smaller than the other possibleinteraction. Note that symmetrical molecules have symmetrical orbital coefficients.
(a) (b)
Figure 4: Bonding interactions between frontier molecule orbitals. Notice in (a) that both theHOMO of butadiene and the LUMO of ethene are antisymmetrical and can, therefore,bond at both ends of the molecules. In (b), however, the HOMO of the ethene issymmetrical whereas its LUMO is antisymmetrical. This combination is bonding at oneend of the molecules but antibonding at the other end, therefore no cycloadditionoccurs.
+0.56 +0.56
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The magnitude of each orbital, the orbital coefficient, also plays and important part
in Diels-Alder reactions. Figure 5 illustrates how the substitution of an EWG at the
system influences the magnitude of electron density in each orbital as well as theenergies of the HOMO and LUMO. When the system is substituted with an EWG,
electron density is pulled away from the nearest sp 2 centre. This diminishes the
corresponding orbital coefficient, making it smaller, while leaving the more distal sp 2
centre with the larger coefficient. This also has an energy lowering effect on the HOMO
and LUMO, with the LUMO being affected to a greater extent. 12 These effects will be
discussed further in relation to diastero- and regioselectivity.
Figure 5: Changes in orbital coefficients and HOMO/LUMO energies upon substitution at thealkene with an EWG. The dashed lines are provided as reference points.
When Diels-Alder reactions are done in aqueous solvent, not only is there an
increase in reaction rate, but also an increased preference for endo selectivity 2,14 (Table
1), as well as regioselectivity 4 (Table 2). These phenomena can be explained through
hydrophobicity, hydrogen bonding and FMO theory. In any reaction not subjected to
CO 2Me
CO 2Me
O
O
+0.69-0.47
+0.71 -0.71
+0.71 +0.71
+1.5 eV
-10.52 eV+0.43
+0.33
0 eV
-10.72 eV
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stereospecific control, a competition exists for diastereoselectivity and regioselectivity of
the product(s). Since it is well established that Diels-Alder reaction rate increase is due
to hydrophobicity and hydrogen bonding in water, one must ask what effect each of these
aspects might have on the outcome of competitive selectivity.
Table 1: The effect of aqueous solvent on the selectivity of Diels-Alder reactions betweencyclopentadiene and either acrylonitrile 14 or methyl vinyl ketone. 9
Dienophile Solvent endo/exo
Methanol (70%) 1.98Methanol (60%) 2.05Methanol (30%) 2.26
Water 2.34 Neat 3.85EtOH 8.50.15 M Cyclopentadiene in H 2O 21.40.007 M Cyclopentadiene in H 2O 22.5
Table 2: The effect of aqueous solvent on the regioselectivity of the Diels-Alders reactionbetween isoprene and acrylonitrile. 14
Solvent para/meta
1,4-dioxane (60%) 3.161,4-dioxane (50%) 3.381,4-dioxane (30%) 3.47Water 3.76
When the high cohesive energy density of water forces the diene and dienophile to
occupy as little volume as possible, the favored position of the hydrophobic molecules is
that which has the least contact with water. Since the activated complex that leads to
the endo product is significantly more compact than that which leads to the exo product
(Figure 6), this serves as part of the explanation for an increase in endo
O
CN
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OO
diastereoselectivity. 9,10,15 When the activated complex is in the compact state that leads
to the endo product, there is also an opportunity for favorable secondary orbital
interactions that is not available in the exo activated complex. 16
(a) (b)
Figure 6: Schematic representation of the (a) compact endo activated complex vs. the (b) muchless compact exo activated complex. The molecules are colored to help distinguish thediene and the dienophile.
In FMO theory, primary orbital interactions lead to the formation of new bonds
whereas secondary orbital interactions (SOI) are those that occur in regions of the
activated complex apart from the specific reaction site. 17 Favorable SOIs stabilize the
transition state, thus lowering the energy of the system. Since SOIs can only occur in the
compact endo transition state, the stability provided by these additional interactions
allows to the endo diastereomer to out-compete the exo diastereomer. The reactionbetween butadiene and cyclopropene will serve as a general example of this theory, as
many studies have provided data in support of SOI using this reaction. 16-19
In a comparison of the endo transition state with exo transition state of the Diels-
Alder reaction between butadiene and cyclopropene, evidence suggests that a SOI exists
between the methylene hydrogen of cycloproprene and the C 2 and C 3 orbitals of
butadiene (Figure 7). The C-H bond that points toward the butadiene moiety is reported
as being longer than the other C-H bond at the sp 3 centre, suggesting that an attractive
interaction is indeed taking place (a shortened bond length would be expected in a
repulsive interaction). 16 SOI has also been demonstrated between these two molecules
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through increased bond order and charge transfer, as well as by a lowering of the FMO
energies. 18 None of these trends are noted in the exo transition state.
(a) (b) (c)
Figure 7: Orbital interactions between butadiene and cyclopropene. Diagram (a) shows twodifferent schematic representations of SOIs in the endo transition state and (b) showsthat these SOIs are not possible in the exo transition state. 16,19 Diagram (c) 17 shows apair of interacting molecular orbitals.
The theory of SOI, together with the highly compact state of the endo activated
complex due to hydrophobicity, provides a plausible rational for the enhanced endo
diastereoselectivity of Diels-Alder reaction in aqueous media. It has already been
mentioned that the dienophile in a Diels-Alder reaction is often substituted with an EWG.
As the EWG pulls electron density away from the alkene decreasing the orbital coefficient
at the nearest sp 2 centre, it is increasing the electron density in its own adjacent orbital.
Since this orbital of the EWG is that which would participate in SOIs, increased overlap
provided by a larger orbital coefficient will lead to greater stability in the system.
Hydrogen bonding between the EWG and water in the aqueous solvent increases
polarization of the dienophile, therefore this interaction will further increase the magnitude
HH
HH
primary orbitalinteractions
SOI
primary orbitalinteractions
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of the EWG orbital coefficient, thus enhancing the stabilizing SOIs and lowering the
energy of the endo transition state even further 1 (Figure 8). This allows the endo/exo
competition to swing even further in favor of the endo adduct.
Figure 8: Schematic representation of the changes in orbital coefficients enhanced by hydrogenbonding at the EWG of the dienophile. The hydrogen bonds are represented by theheavy dashed lines between the carbonyl oxygens and the water hydrogens. Reddashed lines indicate the primary orbital interactions and the blue dashed linerepresents the SOI of the enlarged orbital coefficient with a secondary orbital of thediene.
As well as enhancing endo diastereoselectivity, aqueous media increases the
regioselective outcome of Diels-Alder reactions. Again, hydrophobicity will act to create a
compact transition state, but does not seem to have any other direct impact on
regioselectivity. Instead, FMO theory and hydrogen bonding provide a plausible
explanation for waters role in the competition over the regiochemistry of the adduct.
According to FMO theory, regioselectivity is controlled by the magnitude of the
orbital coefficients. The favored orientation of the product will be that which brings
together the largest and smallest coefficients of the diene with the largest and smallest
coefficients of the dienophile, respectively. 13 It has already been mentioned that EWG
substitution on the dienophile will decrease the magnitude of the orbital coefficient at the
nearest sp 2 hybridized centre. In addition, substituting the diene with an electron
O
H
O
H
H
HO
H
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Me
Me
MeO
MeO
donating group (EDG), a favorable condition for Diels-Alder reactions, increases the
magnitude of the orbital coefficient farthest from the site of substitution for a 1-substituted
diene and nearest to the site of substitution for a 2-substituted diene (Table 3). By
considering the magnitudes of each coefficient in the diene and dienophile, one can
predict the regiochemistry of the product. Combinations of EDG 1-substituted dienes and
EWG substituted dienophiles preferentially give the ortho regioisomer, while reactions
with EDG 2-substituted dienes preferentially give the para regioisomer.
Table 3: Orbital coefficients for EDG substituted dienes and EWG substituted dienophiles. 12
c1 c2 c3 c4 HOMO LUMO
Diene C 1 C 2 Dienophile C 3 C4
0.314 0.315 0.58 0.48
0.340 0.296 0.43 0.33
0.235 0.313 0.44 0.30
0.352 0.103 0.60 0.49
Water enhances regioselectivity in the same way it affects the orbital coefficients
in diastereoselectivity. Acting in a similar manner to Lewis acids, 14 when water hydrogen
bonds with an electronegative atom on the dienophile, it will decrease the magnitude of
the nearest sp 2 orbital coefficient by pulling electron density away from this centre. This
R
R
1
2
X
CO 2Me
COH
Cl
CN
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reduction in orbital size increases the preference for a bonding interaction to take place
between the larger coefficients, directing the regiochemistry of the adduct. Hydrogen
bonding in aqueous media, therefore, serves to augment the polarity of the dienophiles
primary orbital coefficients, thus increasing even further the likelihood of the para or ortho
product, depending on the substitution pattern of the diene, over the meta product (Figure
9).
(a)
(b)
Figure 9: Schematic representation of waters role in affecting the magnitude of orbitalcoefficients and increasing regioselectvity. Formation of (a) ortho and pararegioisomers is dictated by pairing of large and small coefficients. This selectivityincreases when (b) water hydrogen bonds to the EWG of the dienophile effectivelydecreasing the magnitude of the nearest orbital coefficient.
Aqueous media plays a very important role in the diastero- and regioselectivity of
intermolecular Diels-Alder reactions. Even though it seems water should hinder this
chemistry, empirical evidence shows that it does just the opposite. Using frontier
molecular orbital theory to provide a model for how hydrophobicity and hydrogen bonding
might influence the preference for the endo diastereomer and the para or ortho
regioisomers, the effect of water becomes seemingly less curious and far more apparent.
OMe
MeO
O
H
O
H
OMe MeOO
H
O
H
OH H
O
H
H
O
H
HOH H
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