Frontier Molecular Orbital Theory and the Role of Water in the Endo/Exo Diastereoselectivity and Regioselectivity of Intermolecular Diels-Alder

Reactions

002.469 Specific Methods in Organic Synthesis

Andrea Costen

April 15, 2003

1 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 [4e + 2e] 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, such instances will not be discussed in this paper.

2 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 hydration8 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 sp2 hybridized centres of the dienophile creates a more electron-deficient

3 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
H O

H O O O H

O H

Figure 2: Schematic representation of the activated complex hydrogen bonded to water molecules in aqueous media. The hydrogen bonds are represented by the heavy dashed lines between the carbonyl oxygens and the water hydrogens. Red arrows indicate 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

4 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 LUMO13 and only takes place when these orbitals have the same symmetry (Figure 4).

LUMO +1.0 eV
-0.42 +0.56 -0.42 +0.56

+1.5 eV

LUMO

E = 10.53 eV

+0.41 +0.57

-0.41

HOMO -9.03 eV
- 0.57

E = 11.52 eV

HOMO -10.52 eV

Figure 3: Molecular orbitals for butadiene and ethene with HOMO and LUMO energies and orbital coefficients.12 The HOMO of the diene and the LUMO of the dienophile are the reactive orbitals since their energy difference is smaller than the other possible interaction. Note that symmetrical molecules have symmetrical orbital coefficients.

antibonding bonding

(a)

(b)

Figure 4: Bonding interactions between frontier molecule orbitals. Notice in (a) that both the HOMO 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 is symmetrical whereas its LUMO is antisymmetrical. This combination is bonding at one end of the molecules but antibonding at the other end, therefore no cycloaddition occurs.

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 the energies of the HOMO and LUMO. When the system is substituted with an EWG, electron density is pulled away from the nearest sp2 centre. This diminishes the corresponding orbital coefficient, making it smaller, while leaving the more distal sp2 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.

O O
+0.71 -0.71 +0.69

+1.5 eV

-0.47

CO2Me

0 eV

+0.71 +0.71

+0.43

-10.52 eV

+0.33

CO2Me -10.72 eV

Figure 5: Changes in orbital coefficients and HOMO/LUMO energies upon substitution at the alkene 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 selectivity2,14 (Table 1), as well as regioselectivity4 (Table 2). These phenomena can be explained through hydrophobicity, hydrogen bonding and FMO theory. In any reaction not subjected to

6 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 between cyclopentadiene and either acrylonitrile14 or methyl vinyl ketone.9 Dienophile
CN

Solvent Methanol (70%) Methanol (60%) Methanol (30%) Water Neat EtOH 0.15 M Cyclopentadiene in H2O 0.007 M Cyclopentadiene in H2O

endo/exo 1.98 2.05 2.26 2.34 3.85 8.5 21.4 22.5

Table 2: The effect of aqueous solvent on the regioselectivity of the Diels-Alders reaction between isoprene and acrylonitrile.14 Solvent 1,4-dioxane (60%) 1,4-dioxane (50%) 1,4-dioxane (30%) Water para/meta 3.16 3.38 3.47 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

7 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

O
(a) (b)

Figure 6: Schematic representation of the (a) compact endo activated complex vs. the (b) much less compact exo activated complex. The molecules are colored to help distinguish the diene 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 reaction between 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 DielsAlder reaction between butadiene and cyclopropene, evidence suggests that a SOI exists between the methylene hydrogen of cycloproprene and the C2 and C3 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 sp3 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

8 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.
H H

H
SOI primary orbital interactions

primary orbital interactions

(a)

(b)

(c)

Figure 7: Orbital interactions between butadiene and cyclopropene. Diagram (a) shows two different schematic representations of SOIs in the endo transition state and (b) shows that these SOIs are not possible in the exo transition state.16,19 Diagram (c)17 shows a pair 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 sp2 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

9 of the EWG orbital coefficient, thus enhancing the stabilizing SOIs and lowering the energy of the endo transition state even further1 (Figure 8). This allows the endo/exo competition to swing even further in favor of the endo adduct.

H O H

H O
Figure 8: Schematic representation of the changes in orbital coefficients enhanced by hydrogen bonding at the EWG of the dienophile. The hydrogen bonds are represented by the heavy dashed lines between the carbonyl oxygens and the water hydrogens. Red dashed lines indicate the primary orbital interactions and the blue dashed line represents the SOI of the enlarged orbital coefficient with a secondary orbital of the diene.

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 sp2 hybridized centre. In addition, substituting the diene with an electron

10 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
R2 R
1

c1 c2 HOMO C1 C2 0.315 Dienophile

c3 c4 X LUMO C3 0.58 C4 0.48

Diene
Me Me

0.314

COH

0.340

0.296

0.43

0.33

CO2Me
MeO MeO

0.235

0.313

Cl

0.44

0.30

0.352

0.103

CN

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 sp2 orbital coefficient by pulling electron density away from this centre. This

11 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).
OMe O H MeO H O O H OMe O H H H O O H H H O H MeO H O

(a)

(b)

Figure 9: Schematic representation of waters role in affecting the magnitude of orbital coefficients and increasing regioselectvity. Formation of (a) ortho and para regioisomers is dictated by pairing of large and small coefficients. This selectivity increases when (b) water hydrogen bonds to the EWG of the dienophile effectively decreasing 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.

12 References
1 2 3 4

5 6

7 8 9 10

11 12 13 14

15 16

17

18

19

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