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The mechanism and enantioselectivity of the organocatalytic Diels-Alder reaction were computationally investigated by density functional theory at the B3LYP/6-31G(d) level of theory. The uncatalyzed Diels-Alder reaction was also studied to explore the effect of the organocatalyst on this reaction in terms of energetics, selectivity, and mechanism. The catalyzed reaction showed improved endo/exo selectivity and the free energy of activation was significantly lowered in the presence of the catalyst. Both uncatalyzed and catalyzed reactions exhibited concerted asynchronous reaction mechanism with the degree of asynchronicity being more evident in the presence of the catalyst. The Corey's experimentally derived predictive selection rules for the outcome of the organocatalytic Diels-Alder reaction were also theoretically analyzed and excellent agreement was found between experiment and theory.
Key words: DFT; secondary kinetic isotope effects; chiral organocatalyst; asynchronous concerted mechanism; Diels-Alder reaction
Enantioselective Organocatalytic Diels-Alder Reactions: A Density Functional Theory and Kinetic Isotope Effects Study
Nasr Y.M. Omar, Noorsaadah A. Rahman, Sharifuddin Md Zain
Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia
The mechanism and enantioselectivity of the Diels-Alder reaction catalyzed by the oxazaborolidinium cation organocatalyst are computationally investigated by density functional theory at the B3LYP/6-31G(d) level of theory. The Corey's experimentally derived predictive selection rules for the outcome of the organocatalytic Diels-Alder reaction are also theoretically analyzed and excellent agreement is found between experiment and theory.
The Diels-Alder cycloaddition reaction is one of the most powerful reactions for the construction of six-membered rings with several stereogenic centers in a regio- and stereo-controlled way. In addition, this reaction is seen as the key step in the synthesis of many important compounds such as reserpine, cortisone and myrocin C.
The development of enantioselective Diels-Alder reactions involving the use of chiral organocatalysts has been the subject of numerous studies.1-11 For example, the chiral oxazaborolidinium cation 3 has been shown to be a very useful and versatile catalyst for the synthesis of many biologically complex molecules such as estrone, the oral contraceptive desogestrel, and the antiflu drug oseltamivir.3
In the Diels-Alder reaction, a molecule with a conjugated system of four ° electrons (the diene) reacts with another molecule with two ° electrons (the dienophile) to produce a molecule with a six-membered ring by the formation of two new ï³ bonds. The nature of the formation of these new ï³ bonds has been the subject of long debate.12-16 Two mechanisms are possible; a concerted mechanism involving a partial formation of the two new ï³ bonds in a single transition structure, and a stepwise mechanism having a biradical or zwitterionic intermediate with one of the ï³ bonds formed. In the concerted mechanism, if the two ï³ bonds are formed to the same extent, then the reaction is synchronous. Otherwise, it is asynchronous. Although an agreement has been reached in favor of the concerted mechanism, the presence of external influences such as a catalyst may change the mechanism from concerted to stepwise.17-19 Furthermore, the existence of both concerted and stepwise trajectories has been suggested by femtosecond dynamics investigations of the Diels-Alder reaction.20,21
With the use of electronic structure calculations it is possible to gain insights into the details of chemical reactions and molecular structures and properties that are difficult to achieve experimentally. In addition, electronic structure calculations help elucidate experimental results and make predictions that can then be tested experimentally. In such calculations, appropriate stationary points on the potential energy surface corresponding to equilibrium and transition structures are often located and characterized, and a reaction mechanism(s) is then proposed.
Density functional methods often yield energies within the desired chemical accuracy (errors less than 2 kcal/mol) despite their inability to systematically improve such accuracy.22 The inclusion of electron correlation in DFT as well as DFT's high computational efficiency have allowed the computation of many chemically interesting systems without imposing serious constraints on the system size. Numerous examples of the application of DFT to the Diels-Alder reaction are found in the chemical literature. The B3LYP/6-31G(d) has been the method of choice for such application and has proven to produce energies and thermochemical quantities comparable with experiment in addition to high quality equilibrium and transition structures.19,23-26
Recently, Pi and Li19 investigated by means of DFT the molecular mechanism of the Diels-Alder reaction between 2-methyl acrolein and cyclopentadiene catalyzed by a simplified model of catalyst 3. They concluded that the uncatalyzed Diels-Alder reaction proceeds via an asynchronous concerted mechanism while in the presence of the catalyst the mechanism changes from concerted to stepwise with a zwitterionic intermediate. In addition to the Pi and Li study, Paddon-Row et al.26 reported the results of a DFT analysis of the mechanism of the Diels-Alder reactions between 1,3-butadiene and different dienophiles catalyzed by 3. In contrast to the results found by Pi and Li, the mechanism of these catalyzed Diels-Alder reactions is found to be concerted but highly asynchronous.
The work described in this study explores the application of density functional theory for better understanding of the Diels-Alder reactions involving chiral oxazaborolidinium cation as an organocatalyst. The rules affecting the site selectivity and enantioselectivity are computationally investigated, and the mechanistic aspects of the Diels-Alder reactions in the presence of the oxazaborolidinium cation are described. The understanding of the role of the catalyst is of importance in order to improve the catalyst itself or to help design other enantioselective syntheses.
Single-point energy calculations, geometry optimizations, and vibrational frequencies of the reactants, transition structures and products were carried out in vacuo using density functional theory with the B3LYP functional and the 6-31G(d) basis set as implemented in the Gaussian 03 program.27 Geometry optimizations to local minima and transition structures were accomplished with the Berny algorithm28 in redundant internal coordinates29 without any symmetry restriction. Vibrational frequency calculations were performed at the optimized geometries to verify whether the obtained structures are minima or transition structures as well as to determine zero-point vibrational energies and thermochemical quantities (enthalpies, entropies, and Gibbs free energies). The vibration associated with the imaginary frequency was ensured to correspond to a displacement in the direction of the reaction coordinate. This was achieved with the graphical user interface for Gaussian program (GaussView). The zero-point vibrational energies and thermochemical quantities were calculated using frequencies scaled by 0.9804. Thermochemical quantities were calculated at both 298 K and 178 K and at 1.0 atm pressure.
The intrinsic reaction coordinate (IRC) as implemented in Gaussian 03 was computed using the same calculation level. A total of 40 points were examined along the reaction path (both the forward and the backward directions) with a default step size of 0.1 amu1/2 Bohr.
The ISOEFF07 program30 was used for kinetic isotope effects calculations at 298 K.
Results and Discussion
(1) Description of the studied reactions and stereochemical nomenclature
The Diels-Alder reaction of quinones is highly useful in the synthesis of many complex natural products. An example of an enantioselective reaction utilizing the chiral oxazaborolidinium cation catalyst 3 in a Diels-Alder reaction has been shown by Corey in a reaction between 2-methyl-1,3-butadiene (isoprene) 1 and 2,3-dimethyl-1,4-benzoquinone 23,6 and is illustrated in Figure 1.
The structure and stereochemical configuration of the major product from this reaction can be predicted using the experimentally derived Corey's predictive selection rules and mechanistic model.2,3,8 These can be summarized as follows:
At the transition state, the bonding of the diene to carbon ï¢ to the carbonyl group that coordinates with the catalyst is stronger than bonding to carbon α (i.e. a concerted asynchronous reaction pathway).
The double bond of the benzoquinone bearing two hydrogens is more reactive than that bearing substituents (site selectivity).
The predominant product will result from coordination of the catalyst to the oxygen lone pair from the a side (i.e. syn to the HCâ•CH subunit that undergoes the [4 + 2]-cycloaddition) rather than the b side (i.e. anti to the HCâ•CH subunit that undergoes the [4 + 2]-cycloaddition) since a is sterically more accessible than b (Figure 1). The primary interaction in this coordination complex is between the carbonyl oxygen and the boron of the catalyst. The secondary interaction is between the Cα-H hydrogen and the catalyst oxygen (i.e. a nonconventional hydrogen bond).31,32
The preferred catalyst coordination is at the more basic of the two benzoquinone oxygens. In addition, the coordination of the catalyst to the carbonyl persists not only in the transition state but even in the Diels-Alder cycloadduct.
The preferred addition of the diene is to the front face of the α,ï¢ double bond (i.e. away from the phenyl groups of the catalyst). The other route of addition is to the rear face of the α,ï¢ double bond.
The favored 3-dimensional transition state corresponds to the endo arrangement of the diene and the catalyst-coordinated benzoquinone (i.e. the reactants lie directly on top of one another so that the two hydrogens attached to the α and ï¢ carbon atoms end up syn to the two-carbon unsaturated bond in the product). If the two hydrogens end up anti to the two-carbon unsaturated bond in the product, then the transition state corresponds to the exo arrangement.
In the Diels-Alder Reaction A (Figure 1), there is a pair of possible enantiomers of the catalyst 3, either the S or the R stereoisomer. In addition, there are two rotamers for each configuration resulting from the rotation about the B-o-tolyl bond. Besides, there are two possible sites (double bonds) on the benzoquinone that the diene can attack approaching from either the front or the rear face. Moreover, the catalyst coordination to the benzoquinone can be syn or anti to the HCâ•CH subunit that undergoes the [4 + 2]-cycloaddition. Since there are two stereogenic carbons in the products, there will be up to four diastereomeric transition states ((S,R), (R,S), (R,R), and (S,S)). Fortunately, in this reaction, there is no issue of regioselectivity since 2,3-dimethyl-1,4-benzoquinone is C2 symmetric. Also, since the two benzoquinone oxygens are equally available for catalyst coordination, Corey's predictive rule number 4 does not apply here. Thus, there would be numerous possible pathways for this reaction to proceed.
To simplify matters, the model catalyst 4 is used throughout this investigation. This catalyst eliminates the need for the rotamers mentioned above to be considered and reduces the computational cost as it requires smaller number of basis functions compared to the catalyst 3. The (S)-enantiomer of the catalyst 4 is used since it is the more commonly used enantiomer in experimental studies.4-11,33
As for the possible diastereomeric products, only the enantiomeric pair (S,R) and (R,S) is considered in the current work since the (S,R)-enantiomer is the major product observed experimentally (Figure 1).3,6
To investigate the site selectivity, only the uncatalyzed reaction pathways are considered. These are depicted in Figures 2 and 3. In Figure 2, the diene attack is on the less substituted double bond of the benzoquinone while in Figure 3 the diene attack is on the methyl substituted double bond of the benzoquinone. In each case, the approach of the diene to the dienophile can be either endo or exo. Hence, there are four different reaction pathways for the uncatalyzed reaction to proceed.
Based on the results of the site selectivity investigation (see below), only the addition of the diene to the less substituted double bond of the benzoquinone in the presence of catalyst 4 as illustrated in Figures 4 and 5 is studied here. In Figure 4, the coordination of catalyst 4 to the oxygen of the dienophile is syn to the HCâ•CH subunit that undergoes the [4 + 2]-cycloaddition whereas in Figure 5 the coordination is anti to the HCâ•CH subunit that undergoes the [4 + 2]-cycloaddition. In each case, the approach of the diene to the dienophile can be either endo or exo and can be from either the front face or the rear face of the α,ï¢ double bond. Thus, there are eight possible reaction pathways for the catalyzed reaction to proceed. Four of these pathways lead to the major product observed experimentally (i.e. the endo enantiomer) and the other four lead to the exo enantiomer. This enables us to study the mechanism and the enantioselectivity of the catalyzed reaction.
(2) Geometries and energetics of stationary points
The B3LYP/6-31G(d) optimized structures of the reactants are shown in Figure 6. The syn R4 and anti R5 coordination complexes between benzoquinone R2 and catalyst R3 are also shown in Figure 6. A stronger coordination is observed for the syn complex having a B-O bond length shorter by 0.06 Å than that of the anti complex. Besides, the syn complex exhibits a nonconventional hydrogen bond between the Cα-H hydrogen and the catalyst oxygen with 2.27 Å bond length. The stronger coordination in addition to the presence of hydrogen bonding in the syn complex led to a 7.0 kcal/mol stabilization for the syn complex as compared to the anti complex. This corresponds to almost a 100% of the Boltzmann population being represented by the syn complex. Furthermore, the Gibbs free energies for the syn and anti coordination complexes are lower than those of the separated reactants (R2 + R3) by 9.8 and 2.8 kcal/mol at 178 K, respectively. At 298 K, however, the anti coordination is unfavored since the complex free energy is 2.7 kcal/mol higher than the separated reactants. The syn coordination is still favored but with a stabilization of only 4.4 kcal/mol.
The optimized transition structures at the B3LYP/6-31G(d) level of theory for the uncatalyzed Reactions B and C are given in Figures 7 and 8, respectively. As is shown in the figures, the transition structures involving the attack of the diene at the less substituted double bond of the benzoquinone are more stable by > 7 kcal/mol at 178 K. This is in agreement with Corey's predictive rule number 2 discussed earlier.
For the uncatalyzed Reaction B, at 178 K, the conversion rate to the endo product is 12 times faster than the rate at which the exo product is formed. However, this rate is reduced by 4 times at 298 K. The endo/exo selectivity is calculated to be 84.7% and 52.1% at 178 K and 298 K, respectively.
The average degree of asynchronicity for the transition structures is found to be 0.07 Å (Figure 7) and these two transition structures, therefore, correspond to concerted asynchronous reaction pathways. This asynchronicity can be rationalized by the frontier molecular orbital (FMO) theory.34 For example, in TS1, the slight asynchronicity of 0.09 Å is due to the LUMO having slightly larger coefficient on the ï¢ carbon of the benzoquinone rendering it more electrophilic than the α carbon (the ï¢ carbon contributes 4.7% of the LUMO while the α carbon contributes 4.2% of the LUMO). As a result, a slightly larger overlap between the ï¢ carbon and the diene HOMO leads to a slightly stronger and shorter bond at the transition structure.
Table 1 lists the B3LYP/6-31G(d) computed transition structures for the catalyzed Reactions D and E. The syn transition structures are more stable than their anti counterparts by about 3.3 to 9.9 kcal/mol (Table 1). For both syn and anti transition structures, the B-O bond length is shorter (on average) than that of the reactant by 0.07 Å and 0.11 Å, respectively indicating stronger complexation at the transition state. A relatively stronger coordination is observed for the syn transition structures with B-O bond lengths shorter by about 0.01 to 0.04 Å than those of the anti transition structures. As in the case of the reactants, the syn transition structures possess a nonconventional hydrogen bond between the Cα-H hydrogen and the catalyst oxygen with bond lengths in the range of 2.40 - 2.53 Å. On these grounds, Corey's predictive rule number 3 holds valid for the studied reactions.
For the endo transition states at 178 K, the lowest energy transition state is TS5 representing ~ 97.55% of the Boltzmann population of the endo transition states. This transition state involves the diene addition to the front face of the α,ï¢ double bond of the benzoquinone and the catalyst is coordinated syn to this bond. This result supports Corey's predictive rules 3 and 5 mentioned earlier. The next lowest transition state TS7 has ~ 2.45% of the Boltzmann population of the endo transition states. It is similar to TS5 but the diene addition is to the rear face of the α,ï¢ double bond of the benzoquinone. At 298 K, TS5 and TS7 contribute ~ 90.02% and ~ 9.94% of the Boltzmann population, respectively. The remaining 0.04% is due to TS11, which is similar to TS7 but with the catalyst coordinated anti to the α,ï¢ double bond that undergoes the cycloaddition.
As for the exo transition states at 178 K, TS8 represents the most stable transition state with ~ 99.98% of the Boltzmann population of the exo transition states. It is similar to TS7 except that the arrangement is exo. The remaining 0.02% is for TS6, which is similar to TS8 but with the diene addition to the front face of the α,ï¢ double bond of the benzoquinone. The percentages at 298 K are ~ 99.18% and 0.82% for TS8 and TS6, respectively.
At 178 K, the endo pathway is 116 times faster than the exo route but it is reduced by ~ 12 times at 298 K. In addition, as compared to the uncatalyzed reaction, the reaction rate is markedly enhanced in the presence of the catalyst through lowering the activation free energy barriers by more than 13 kcal/mol (Figure 9). The catalyst also leads to an enhanced enantioselectivity and the percent enantiomeric excess (%ee) is calculated to be 98.3% and 80.5% at 178 K and 298 K, respectively. This is in agreement with Corey's predictive rule number 6 that the preferred transition state has an endo arrangement. The enantiomeric excess of the product observed experimentally is 90% (Figure 1). This discrepancy between the experimental and calculated enantioselectivities can be attributed to computational errors such as simplification of the catalyst, and approximations and inaccuracies associated with the DFT/B3LYP method. In addition, reaction conditions are presumably more complex and different from those of computation.
The average degree of asynchronicity for the transition structures is calculated to be 0.93 Å (cf. Table 1). Thus, these transition structures point to concerted but highly asynchronous reaction pathways where the bond between the diene and carbon ï¢ of the dienophile is being formed in a larger extent than the bond between the diene and carbon α of the dienophile. This result reinforces Corey's predictive rule number 1 discussed earlier. Similar to the uncatalyzed case, the asynchronicity can be explained by the frontier molecular orbital (FMO) theory.34 For instance, the high degree of asynchronicity (0.99 Å) found in the transition structure TS5 is due to the LUMO having much larger coefficient on the ï¢ carbon of the benzoquinone causing it to be much more electrophilic than the α carbon (the ï¢ carbon possesses 12.9% of the LUMO while the α carbon has only 2.0% of the LUMO). This results in a much larger overlap between the ï¢ carbon and the diene HOMO leading to a much stronger and shorter bond at the transition structure.
Table 2 illustrates typical IRC paths computed starting from transition structures TS5 and TS8. As is evident from the table, the bond between the diene and carbon ï¢ of the dienophile is being formed in a larger extent than the bond between the diene and carbon α of the dienophile pointing to concerted highly asynchronous reaction pathways.
(3) Kinetic isotope effects
Equilibrium isotope effects (EIEs) are the result of bonding and non-bonding interactions at minimum stationary points. On the other hand, kinetic isotope effects (KIEs) yield information about transition structures and result from isotopic substitution that has an effect on the rate of the reaction.35,36 Comparison of experimental KIEs with theoretically calculated ones is useful in elucidating organic reaction mechanisms. KIEs can also provide information on the transition structures such as the extent of bond formation.14-16,37-39
Isotopic substitution does not alter the electronic energy and structure but changes the vibration associated with the isotopically substituted bond which in turn influences the zero-point vibrational energy (ZPVE). Often, isotopic substitution involves replacing hydrogen by deuterium (or tritium) since hydrogen isotopes have the largest relative mass differences.35,36
Primary kinetic isotope effects result from isotopic substitution of a hydrogen atom directly involved in the reaction while secondary kinetic isotope effects (2°-KIEs) result from isotopic substitution of a hydrogen atom not directly involved in the reaction.40 2°-KIEs can be normal () or inverse (), where kH and kD are the reaction rate constants for hydrogen and deuterium, respectively. In Diels-Alder reactions, the hybridized state of termini carbons of the diene and dienophile change from sp2 to sp3 resulting in an increase of the corresponding C-H out-of-plane bending frequency.36,41 Hence, an inverse 2°-KIE is expected for the Diels-Alder reaction. In addition, KIEs for the stepwise mechanism are all normal whereas for the concerted mechanism are all inverse.41
In the ISOEFF07 program, the requirements for the theoretical calculation of KIEs are the isotopic frequencies for the reactant and the transition state. Based on the transition state theory, the KIE can be computed from the frequencies of the normal modes of vibration by30
where L and H represent the light and heavy isotopes, respectively, R and ‡ denote the reactant and transition state, respectively, and ï® is the isotopic frequency. where h and kB are Planck's and Boltzmann constants and T is the temperature.
The KIEs can be calculated accurately as long as the vibrational frequencies are computed accurately. In this work, the frequencies calculated by the Gaussian program at the B3LYP/6-31G(d) level of theory were used as the input for the ISOEFF07 KIEs calculations. To account for the anharmonicity of molecular vibrations, the frequencies were scaled by 0.9613 during the ISOEFF07 KIEs calculations.
Table 3 shows the experimental values for the KIEs for analogous uncatalyzed and catalyzed Diels-Alder reactions reported in the literature as well as the theoretically calculated KIEs obtained in this study for TS1, TS2, TS5 and TS8. From the table, there is a good agreement between the calculated and experimental KIEs. The different 2H 2°-KIEs at C-1 over C-4 point to asynchronicity in bond formation to C-1 versus C-4 at the transition structure37 with the asynchronicity being more pronounced for the catalyzed reaction. In addition, for TS1 and TS2, the small difference of 13C KIEs at C-1 and C-4 suggest a slightly asynchronous mechanism. For TS5 and TS8, the large 13C KIE at C-1 and small 13C KIEs at the other carbons could indicate both stepwise mechanism and highly asynchronous concerted mechanism.39 The 2H 2°-KIEs, however, clearly show a concerted mechanism. The large inverse 2H 2°-KIEs at C-4 are indicative of bond formation to C-4 at the transition structure.39 Such inverse 2H 2°-KIEs are not characteristic of a stepwise mechanism.39 Hence, the studied catalyzed reaction is presumed to proceed through a concerted but highly asynchronous mechanism.
(4) Preliminary data and further investigations
The Danishefsky's diene (trans-1-methoxy-3-trimethylsilyloxy-1,3-butadiene) is a useful diene in the Diels-Alder reaction and has been employed in the synthesis of many compounds.42,43 It is an electron-rich diene and thus shows a high reactivity towards dienophiles. The presence of the methoxy group renders the Diels-Alder reaction regiospecific by connecting the electrophilic carbon attached to the methoxy group with the most nucleophilic atom of the dienophile.
As mentioned above, understanding the role of the catalyst can help in the design of other enantioselective syntheses. Hence, in this part of the work, the application of the model catalyst 4 to a Diels-Alder reaction involving Danishefsky diene is explored. The studied reaction pathways are depicted in Figures 10 and 11. The following simplifications are made in the studied reaction: (1) the model (S)-catalyst 4 is used, (2) the same dienophile as in Corey's reaction (Figure 1) is used considering only the diene addition to the less substituted double bond of the dienophile, (3) a simpler structure for the Danishefsky diene is used by replacing the trimethylsilyloxy group by a methoxy group, (4) the use of the Danishefsky diene introduces one more stereogenic center into the product and hence there are 8 possible diastereomeric products of which only 4 are considered, and (5) since there is no experimental data, the reaction is studied at only 298 K.
Only four transition structures could be located on the potential energy surface for this reaction (Table 4). These transition structures lead to the two diastereomers endo-R and exo-R. The exo transition state TS14 represents the most stable transition state with an almost 100% of the Boltzmann population of the exo transition states. It involves the Danishefsky diene addition to the front face of the α,ï¢ double bond of the dienophile and the catalyst is coordinated syn to this bond. The carbon atom connected to the methoxy group possesses the R configuration. The next lowest exo transition state is TS16. It is similar to TS14 except that the diene addition is to the rear face of the α,ï¢ double bond of the benzoquinone. The lowest energy endo transition state is TS13 representing ~ 81.28% of the Boltzmann population of the endo transition states. It is similar to TS14 but the transition state arrangement is endo. The next lowest endo transition state is TS15 having ~ 18.72% of the Boltzmann population of the endo transition states. It is similar to TS13 but with the diene addition to the rear face of the α,ï¢ double bond of the dienophile.
In contrast to Reaction D, the exo pathway for Reaction F is found to be 12 times faster than the endo channel. However, the endo-R product is 4.3 kcal/mol more stable than the exo-R product. Thus, Reaction F can be controlled both kinetically and thermodynamically with the exo product being the kinetically favored product and the endo product being the thermodynamically favored product (Figure 9). In addition, in the presence of the Danishefsky diene, the stereoselectivity of the reaction is fairly enhanced. The percent diastereomeric excess (%de) is calculated to be 88.2%. Therefore, based on these preliminary data, the use of catalyst 4 is recommended for reactions such as Reaction F.
The average degree of asynchronicity for the transition structures is found to be 1.49 Å (cf. Table 4). Thus, the Diels-Alder reaction involving the Danishefsky diene is more asynchronous than that involving isoprene (1.49 Å vs. 0.93 Å). To further elucidate the mechanism, KIEs are calculated for Reaction F and are given in Table 3. At the transition states, the average distance between C-1 of the Danishefsky diene and carbon α of the benzoquinone is calculated to be 3.85 Å (Table 4). This distance is larger than the van der Waals contact distance (3.40 Å) of the two carbons and hence there is no hint of bonding between the two carbons at these transition states. Despite this fact, the theoretically calculated KIEs (Table 3) indicate a concerted but highly asynchronous reaction mechanism instead of a stepwise mechanism.
It should be pointed out that the complete description of a chemical reaction mechanism requires more than just locating stationary points along a reaction path. The time-evolution of the chemical process (i.e. molecular dynamics) is of importance for distinguishing between concerted and stepwise mechanisms. As stated above, femtosecond dynamics studies have suggested the presence of both concerted and stepwise trajectories for the Diels-Alder reaction.20,21 Ab initio molecular dynamics (AIMD) calculations employing the atom-centered density matrix propagation (ADMP) method44-46 have been used to study important chemical reactions such as the Staudinger reaction.47-49 Compared to other AIMD methods, the ADMP method has the fundamental advantage of linear scaling of computational time with system size.44-46 The study of organocatalytic Diels-Alder reaction using the ADMP method for gaining further insights into the mechanism of this vital reaction is thus recommended.
The enantioselectivity and mechanism of the Diels-Alder reaction between isoprene 1 and 2,3-dimethyl-1,4-benzoquinone 2 in the presence of the model chiral cationic oxazaborolidinium catalyst 4 have been studied by density functional theory using the B3LYP functional together with the 6-31G(d) basis set. Both uncatalyzed and catalyzed reactions were investigated to explore the effect of the catalyst on this reaction in terms of energetics, selectivity, and mechanism. The free energy of activation was significantly lowered (> 13 kcal/mol) in the presence of the catalyst. In addition, the catalyzed reaction showed an improved endo/exo selectivity of greater than 13 percentage points. Moreover, both uncatalyzed and catalyzed reactions showed concerted asynchronous reaction mechanism with the degree of asynchronicity being more evident in the presence of the catalyst.
Two different types of dienes were considered in the current work, namely, isoprene and Danishefsky diene. In the presence of the catalyst, both dienes showed comparable stereoselectivity. The Diels-Alder reaction in the presence of isoprene is most likely to go through the endo channel while in the presence of Danishefsky diene, the exo route is favored. In both cases, the preferred catalyst coordination is syn to the HCâ•CH double bond of the dienophile that undergoes the [4 + 2]-cycloaddition and the diene addition is to the front face of this double bond. Based on the optimized transition structures and theoretical kinetic isotope effects calculations, the Diels-Alder reactions involving both dienes are predicted to proceed through concerted but highly asynchronous mechanism. The degree of asynchronicity is more pronounced in the presence of Danishefsky diene. The theoretical outcome of the current study is in excellent agreement with Corey's experimentally derived predictive selection rules.8
This study was financially supported by the Malaysian Academy of Science via SAGA Grant No. 66-02-03-0037. The authors are grateful to the Centre for Information Technology (University of Malaya) and MIMOS Berhad for providing computer facilities.