Enantioselective Organocatalytic Diels Alder Reactions Biology Essay

The mechanism and enantioselectivity of the organocatalytic Diels-Alder reaction were computationally investigated by denseness functional theory at the B3LYP/6-31G ( vitamin D ) degree of theory. The uncatalyzed Diels-Alder reaction was besides studied to research the consequence of the organocatalyst on this reaction in footings 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 accelerator. Both uncatalyzed and catalyzed reactions exhibited conjunct asynchronous reaction mechanism with the grade of asynchronicity being more apparent in the presence of the accelerator. The Corey ‘s by experimentation derived prognostic choice regulations for the result of the organocatalytic Diels-Alder reaction were besides theoretically analyzed and first-class understanding was found between experiment and theory.

Cardinal words: DFT ; secondary kinetic isotope effects ; chiral organocatalyst ; asynchronous concerted mechanism ; Diels-Alder reaction

Graphical abstract

Enantioselective Organocatalytic Diels-Alder Reactions: A Density Functional Theory and Kinetic Isotope Effects Study

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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 denseness functional theory at the B3LYP/6-31G ( vitamin D ) degree of theory. The Corey ‘s by experimentation derived prognostic choice regulations for the result of the organocatalytic Diels-Alder reaction are besides theoretically analyzed and first-class understanding is found between experiment and theory.

Introduction

The Diels-Alder cycloaddition reaction is one of the most powerful reactions for the building of 6-membered rings with several stereogenic centres in a regio- and stereo-controlled manner. In add-on, this reaction is seen as the cardinal measure in the synthesis of many of import compounds such as Raudixin, Cortone Acetate and myrocin C.

The development of enantioselective Diels-Alder reactions affecting the usage of chiral organocatalysts has been the topic of legion studies.1-11 For illustration, the chiral oxazaborolidinium cation 3 has been shown to be a really utile and various accelerator for the synthesis of many biologically complex molecules such as theelin, the unwritten preventive desogestrel, and the antiflu drug oseltamivir.3

In the Diels-Alder reaction, a molecule with a conjugated system of four & A ; deg ; negatrons ( the diene ) reacts with another molecule with two & As ; deg ; negatrons ( the dienophile ) to bring forth a molecule with a 6-membered ring by the formation of two new i?? bonds. The nature of the formation of these new i?? bonds has been the topic of long debate.12-16 Two mechanisms are possible ; a conjunct mechanism affecting a partial formation of the two new i?? bonds in a individual passage construction, and a stepwise mechanism holding a biradical or zwitterionic intermediate with one of the i?? bonds formed. In the conjunct mechanism, if the two i?? bonds are formed to the same extent, so the reaction is synchronal. Otherwise, it is asynchronous. Although an understanding has been reached in favour of the conjunct mechanism, the presence of external influences such as a accelerator may alter the mechanism from concerted to stepwise.17-19 Furthermore, the being of both concerted and bit-by-bit flights has been suggested by femtosecond kineticss probes of the Diels-Alder reaction.20,21

With the usage of electronic construction computations it is possible to derive penetrations into the inside informations of chemical reactions and molecular constructions and belongingss that are hard to accomplish by experimentation. In add-on, electronic construction computations help clarify experimental consequences and do anticipations that can so be tested by experimentation. In such computations, appropriate stationary points on the possible energy surface matching to equilibrium and passage constructions are frequently located and characterized, and a reaction mechanism ( s ) is so proposed.

Density functional methods frequently yield energies within the coveted chemical truth ( mistakes less than 2 kcal/mol ) despite their inability to consistently better such accuracy.22 The inclusion of electron correlativity in DFT every bit good as DFT ‘s high computational efficiency have allowed the calculation of many chemically interesting systems without enforcing serious restraints on the system size. Numerous illustrations of the application of DFT to the Diels-Alder reaction are found in the chemical literature. The B3LYP/6-31G ( vitamin D ) has been the method of pick for such application and has proven to bring forth energies and thermochemical measures comparable with experiment in add-on to high quality equilibrium and passage structures.19,23-26

Recently, Pi and Li19 investigated by agencies of DFT the molecular mechanism of the Diels-Alder reaction between 2-methyl propenal and cyclopentadiene catalyzed by a simplified theoretical account of accelerator 3. They concluded that the uncatalyzed Diels-Alder reaction returns via an asynchronous concerted mechanism while in the presence of the accelerator the mechanism alterations from concerted to stepwise with a zwitterionic intermediate. In add-on to the Pi and Li survey, Paddon-Row et al.26 reported the consequences 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 consequences found by Pi and Li, the mechanism of these catalyzed Diels-Alder reactions is found to be concerted but extremely asynchronous.

The work described in this survey explores the application of denseness functional theory for better apprehension of the Diels-Alder reactions affecting chiral oxazaborolidinium cation as an organocatalyst. The regulations impacting the site selectivity and enantioselectivity are computationally investigated, and the mechanistic facets of the Diels-Alder reactions in the presence of the oxazaborolidinium cation are described. The apprehension of the function of the accelerator is of importance in order to better the accelerator itself or to assist plan other enantioselective syntheses.

Computational Detailss

Single-point energy computations, geometry optimisations, and vibrational frequences of the reactants, passage constructions and merchandises were carried out in vacuo utilizing density functional theory with the B3LYP functional and the 6-31G ( vitamin D ) footing set as implemented in the Gaussian 03 program.27 Geometry optimisations to local lower limit and passage constructions were accomplished with the Berny algorithm28 in excess internal coordinates29 without any symmetricalness limitation. Vibrational frequence computations were performed at the optimized geometries to verify whether the obtained constructions are minima or passage constructions every bit good as to find zero-point vibrational energies and thermochemical measures ( heat contents, informations, and Gibbs free energies ) . The quiver associated with the fanciful frequence was ensured to match to a supplanting in the way of the reaction co-ordinate. This was achieved with the graphical user interface for Gaussian plan ( GaussView ) . The zero-point vibrational energies and thermochemical measures were calculated utilizing frequences scaled by 0.9804. Thermochemical measures were calculated at both 298 K and 178 K and at 1.0 atm force per unit area.

The intrinsic reaction co-ordinate ( IRC ) as implemented in Gaussian 03 was computed utilizing the same computation degree. A sum of 40 points were examined along the reaction way ( both the forward and the backward waies ) with a default measure size of 0.1 amu1/2 Bohr.

The ISOEFF07 program30 was used for kinetic isotope effects computations at 298 K.

Consequences and Discussion

( 1 ) Description of the studied reactions and stereochemical terminology

The Diels-Alder reaction of quinones is extremely utile in the synthesis of many complex natural merchandises. An illustration of an enantioselective reaction using the chiral oxazaborolidinium cation accelerator 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 construction and stereochemical constellation of the major merchandise from this reaction can be predicted utilizing the by experimentation derived Corey ‘s prognostic choice regulations and mechanistic model.2,3,8 These can be summarized as follows:

At the passage province, the bonding of the diene to carbon i?? to the carbonyl group that coordinates with the accelerator is stronger than adhering to carbon ? ( i.e. a conjunct asynchronous reaction tract ) .

The dual bond of the benzoquinone bearing two Hs is more reactive than that bearing substituents ( site selectivity ) .

The prevailing merchandise will ensue from coordination of the accelerator to the O lone brace from the a side ( i.e. syn to the HCa•?CH fractional monetary unit that undergoes the [ 4 + 2 ] -cycloaddition ) instead than the b side ( i.e. anti to the HCa•?CH fractional monetary unit that undergoes the [ 4 + 2 ] -cycloaddition ) since a is sterically more accessible than B ( Figure 1 ) . The primary interaction in this coordination composite is between the carbonyl O and the B of the accelerator. The secondary interaction is between the C?-H H and the accelerator O ( i.e. a nonconventional H bond ) .31,32

The preferable accelerator coordination is at the more basic of the two benzoquinone Os. In add-on, the coordination of the accelerator to the carbonyl persists non merely in the passage province but even in the Diels-Alder cycloadduct.

The preferable add-on of the diene is to the front face of the ? , i?? dual bond ( i.e. off from the phenyl groups of the accelerator ) . The other path of add-on is to the rear face of the ? , i?? dual bond.

The favorite three-dimensional passage province corresponds to the endo agreement of the diene and the catalyst-coordinated benzoquinone ( i.e. the reactants lie straight on top of one another so that the two Hs attached to the ? and i?? C atoms end up syn to the two-carbon unsaturated bond in the merchandise ) . If the two Hs end up anti to the two-carbon unsaturated bond in the merchandise, so the passage province corresponds to the exo agreement.

In the Diels-Alder Reaction A ( Figure 1 ) , there is a brace of possible enantiomorphs of the accelerator 3, either the S or the R stereoisomer. In add-on, there are two rotamers for each constellation ensuing from the rotary motion about the B-o-tolyl bond. Besides, there are two possible sites ( dual bonds ) on the benzoquinone that the diene can assail nearing from either the forepart or the rear face. Furthermore, the accelerator coordination to the benzoquinone can be syn or anti to the HCa•?CH fractional monetary unit that undergoes the [ 4 + 2 ] -cycloaddition. Since there are two stereogenic Cs in the merchandises, there will be up to four diastereomeric passage provinces ( ( 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. Besides, since the two benzoquinone Os are every bit available for accelerator coordination, Corey ‘s prognostic regulation figure 4 does non use here. Therefore, there would be legion possible tracts for this reaction to continue.

To simplify affairs, the theoretical account accelerator 4 is used throughout this probe. This accelerator eliminates the demand for the rotamers mentioned above to be considered and reduces the computational cost as it requires smaller figure of footing maps compared to the accelerator 3. The ( S ) -enantiomer of the accelerator 4 is used since it is the more normally used enantiomorph in experimental studies.4-11,33

As for the possible diastereomeric merchandises, merely the enantiomeric brace ( S, R ) and ( R, S ) is considered in the current work since the ( S, R ) -enantiomer is the major merchandise observed by experimentation ( Figure 1 ) .3,6

To look into the site selectivity, merely the uncatalyzed reaction tracts are considered. These are depicted in Figures 2 and 3. In Figure 2, the diene onslaught is on the less substituted dual bond of the benzoquinone while in Figure 3 the diene onslaught is on the methyl substituted dual bond of the benzoquinone. In each instance, the attack of the diene to the dienophile can be either endo or exo. Hence, there are four different reaction tracts for the uncatalyzed reaction to continue.

Based on the consequences of the site selectivity probe ( see below ) , merely the add-on of the diene to the less substituted dual bond of the benzoquinone in the presence of accelerator 4 as illustrated in Figures 4 and 5 is studied here. In Figure 4, the coordination of accelerator 4 to the O of the dienophile is syn to the HCa•?CH fractional monetary unit that undergoes the [ 4 + 2 ] -cycloaddition whereas in Figure 5 the coordination is anti to the HCa•?CH fractional monetary unit that undergoes the [ 4 + 2 ] -cycloaddition. In each instance, the attack 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 ? , i?? dual bond. Therefore, there are eight possible reaction tracts for the catalyzed reaction to continue. Four of these tracts lead to the major merchandise observed by experimentation ( i.e. the endo enantiomorph ) and the other four lead to the exo enantiomorph. This enables us to analyze the mechanism and the enantioselectivity of the catalyzed reaction.

( 2 ) Geometries and energetics of stationary points

The B3LYP/6-31G ( vitamin D ) optimized constructions of the reactants are shown in Figure 6. The syn R4 and anti R5 coordination composites between benzoquinone R2 and accelerator R3 are besides shown in Figure 6. A stronger coordination is observed for the syn complex holding a B-O bond length shorter by 0.06 & A ; Aring ; than that of the anti composite. Besides, the syn complex exhibits a nonconventional H bond between the C?-H H and the accelerator O with 2.27 & A ; Aring ; bond length. The stronger coordination in add-on to the presence of H bonding in the syn composite led to a 7.0 kcal/mol stabilisation for the syn composite as compared to the anti composite. This corresponds to about a 100 % of the Boltzmann population being represented by the syn composite. Furthermore, the Gibbs free energies for the syn and anti coordination composites are lower than those of the detached reactants ( R2 + R3 ) by 9.8 and 2.8 kcal/mol at 178 K, severally. At 298 K, nevertheless, the anti coordination is unfavored since the complex free energy is 2.7 kcal/mol higher than the detached reactants. The syn coordination is still favored but with a stabilisation of merely 4.4 kcal/mol.

The optimized passage constructions at the B3LYP/6-31G ( vitamin D ) degree of theory for the uncatalyzed Reactions B and C are given in Figures 7 and 8, severally. As is shown in the figures, the passage structures affecting the onslaught of the diene at the less substituted dual bond of the benzoquinone are more stable by & A ; gt ; 7 kcal/mol at 178 K. This is in understanding with Corey ‘s prognostic regulation figure 2 discussed earlier.

For the uncatalyzed Reaction B, at 178 K, the transition rate to the endo merchandise is 12 times faster than the rate at which the exo merchandise 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, severally.

The mean grade of asynchronicity for the passage structures is found to be 0.07 & A ; Aring ; ( Figure 7 ) and these two passage constructions, hence, correspond to concerted asynchronous reaction tracts. This asynchronicity can be rationalized by the frontier molecular orbital ( FMO ) theory.34 For illustration, in TS1, the little asynchronicity of 0.09 & A ; Aring ; is due to the LUMO holding somewhat larger coefficient on the i?? C of the benzoquinone rendering it more electrophilic than the ? C ( the i?? C contributes 4.7 % of the LUMO while the ? C contributes 4.2 % of the LUMO ) . As a consequence, a somewhat larger convergence between the i?? C and the diene HOMO leads to a somewhat stronger and shorter bond at the passage construction.

Table 1 lists the B3LYP/6-31G ( vitamin D ) computed passage constructions for the catalyzed Reactions D and E. The syn passage constructions are more stable than their anti opposite numbers by approximately 3.3 to 9.9 kcal/mol ( Table 1 ) . For both syn and anti passage constructions, the B-O bond length is shorter ( on norm ) than that of the reactant by 0.07 & A ; Aring ; and 0.11 & A ; Aring ; , severally bespeaking stronger complexation at the passage province. A comparatively stronger coordination is observed for the syn passage constructions with B-O bond lengths shorter by approximately 0.01 to 0.04 & A ; Aring ; than those of the anti passage constructions. As in the instance of the reactants, the syn passage structures possess a nonconventional H bond between the C?-H H and the accelerator O with bond lengths in the scope of 2.40 – 2.53 & A ; Aring ; . On these evidences, Corey ‘s prognostic regulation figure 3 holds valid for the studied reactions.

For the endo passage provinces at 178 K, the lowest energy passage province is TS5 stand foring ~ 97.55 % of the Boltzmann population of the endo passage provinces. This passage province involves the diene add-on to the front face of the ? , i?? dual bond of the benzoquinone and the accelerator is coordinated syn to this bond. This consequence supports Corey ‘s prognostic regulations 3 and 5 mentioned earlier. The following lowest passage province TS7 has ~ 2.45 % of the Boltzmann population of the endo passage provinces. It is similar to TS5 but the diene add-on is to the rear face of the ? , i?? dual bond of the benzoquinone. At 298 K, TS5 and TS7 contribute ~ 90.02 % and ~ 9.94 % of the Boltzmann population, severally. The staying 0.04 % is due to TS11, which is similar to TS7 but with the accelerator coordinated anti to the ? , i?? dual bond that undergoes the cycloaddition.

As for the exo passage provinces at 178 K, TS8 represents the most stable passage province with ~ 99.98 % of the Boltzmann population of the exo passage provinces. It is similar to TS7 except that the agreement is exo. The staying 0.02 % is for TS6, which is similar to TS8 but with the diene add-on to the front face of the ? , i?? dual bond of the benzoquinone. The per centums at 298 K are ~ 99.18 % and 0.82 % for TS8 and TS6, severally.

At 178 K, the endo tract is 116 times faster than the exo path but it is reduced by ~ 12 times at 298 K. In add-on, as compared to the uncatalyzed reaction, the reaction rate is markedly enhanced in the presence of the accelerator through take downing the activation free energy barriers by more than 13 kcal/mol ( Figure 9 ) . The accelerator besides leads to an enhanced enantioselectivity and the per centum enantiomeric surplus ( % EE ) is calculated to be 98.3 % and 80.5 % at 178 K and 298 K, severally. This is in understanding with Corey ‘s prognostic regulation figure 6 that the preferable passage province has an endo agreement. The enantiomeric surplus of the merchandise observed by experimentation is 90 % ( Figure 1 ) . This disagreement between the experimental and deliberate enantioselectivities can be attributed to computational mistakes such as simplification of the accelerator, and estimates and inaccuracies associated with the DFT/B3LYP method. In add-on, reaction conditions are presumptively more complex and different from those of calculation.

The mean grade of asynchronicity for the passage structures is calculated to be 0.93 & A ; Aring ; ( californium. Table 1 ) . Therefore, these passage constructions point to concerted but extremely asynchronous reaction tracts where the bond between the diene and C i?? of the dienophile is being formed in a larger extent than the bond between the diene and C ? of the dienophile. This consequence reinforces Corey ‘s prognostic regulation figure 1 discussed earlier. Similar to the uncatalyzed instance, the asynchronicity can be explained by the frontier molecular orbital ( FMO ) theory.34 For case, the high grade of asynchronicity ( 0.99 & A ; Aring ; ) found in the passage construction TS5 is due to the LUMO holding much larger coefficient on the i?? C of the benzoquinone doing it to be much more electrophilic than the ? C ( the i?? C possesses 12.9 % of the LUMO while the ? C has merely 2.0 % of the LUMO ) . This consequences in a much larger convergence between the i?? C and the diene HOMO taking to a much stronger and shorter bond at the passage construction.

Table 2 illustrates typical IRC waies computed get downing from passage constructions TS5 and TS8. As is apparent from the tabular array, the bond between the diene and C i?? of the dienophile is being formed in a larger extent than the bond between the diene and C ? of the dienophile indicating to concerted extremely asynchronous reaction tracts.

( 3 ) Kinetic isotope effects

Equilibrium isotope effects ( EIEs ) are the consequence of bonding and non-bonding interactions at minimal stationary points. On the other manus, kinetic isotope effects ( KIEs ) output information about passage constructions and consequence from isotopic permutation that has an consequence on the rate of the reaction.35,36 Comparison of experimental KIEs with theoretically calculated 1s is utile in clarifying organic reaction mechanisms. KIEs can besides supply information on the passage constructions such as the extent of bond formation.14-16,37-39

Isotopic permutation does non change the electronic energy and construction but changes the quiver associated with the isotopically substituted bond which in bend influences the zero-point vibrational energy ( ZPVE ) . Often, isotopic permutation involves replacing H by heavy hydrogen ( or tritium ) since H isotopes have the largest comparative mass differences.35,36

Primary kinetic isotope effects result from isotopic permutation of a H atom straight involved in the reaction while secondary kinetic isotope effects ( 2 & A ; deg ; -KIEs ) consequence from isotopic permutation of a H atom non straight involved in the reaction.40 2 & A ; deg ; -KIEs can be normal ( ) or reverse ( ) , where kH and kD are the reaction rate invariables for H and heavy hydrogen, severally. In Diels-Alder reactions, the hybridized province of termini Cs of the diene and dienophile alteration from sp2 to sp3 ensuing in an addition of the corresponding C-H out-of-plane bending frequency.36,41 Hence, an opposite 2 & A ; deg ; -KIE is expected for the Diels-Alder reaction. In add-on, KIEs for the stepwise mechanism are all normal whereas for the conjunct mechanism are all inverse.41

In the ISOEFF07 plan, the demands for the theoretical computation of KIEs are the isotopic frequences for the reactant and the passage province. Based on the passage province theory, the KIE can be computed from the frequences of the normal manners of quiver by30

( 1 )

where L and H represent the visible radiation and heavy isotopes, severally, R and ‡ denote the reactant and passage province, severally, and i?® is the isotopic frequence. where H and kilobit are Planck ‘s and Boltzmann invariables and T is the temperature.

The KIEs can be calculated accurately every bit long as the vibrational frequences are computed accurately. In this work, the frequences calculated by the Gaussian plan at the B3LYP/6-31G ( vitamin D ) degree of theory were used as the input for the ISOEFF07 KIEs computations. To account for the anharmonicity of molecular quivers, the frequences were scaled by 0.9613 during the ISOEFF07 KIEs computations.

Table 3 shows the experimental values for the KIEs for correspondent uncatalyzed and catalyzed Diels-Alder reactions reported in the literature every bit good as the theoretically deliberate KIEs obtained in this survey for TS1, TS2, TS5 and TS8. From the tabular array, there is a good understanding between the deliberate and experimental KIEs. The different 2H 2 & A ; deg ; -KIEs at C-1 over C-4 point to asynchronicity in bond formation to C-1 versus C-4 at the passage structure37 with the asynchronicity being more pronounced for the catalyzed reaction. In add-on, for TS1 and TS2, the little difference of 13C KIEs at C-1 and C-4 suggest a somewhat asynchronous mechanism. For TS5 and TS8, the big 13C KIE at C-1 and little 13C KIEs at the other Cs could bespeak both stepwise mechanism and extremely asynchronous concerted mechanism.39 The 2H 2 & A ; deg ; -KIEs, nevertheless, clearly show a conjunct mechanism. The big opposite 2H 2 & A ; deg ; -KIEs at C-4 are declarative of bond formation to C-4 at the passage structure.39 Such reverse 2H 2 & A ; deg ; -KIEs are non characteristic of a stepwise mechanism.39 Hence, the studied catalyzed reaction is presumed to continue through a conjunct but extremely asynchronous mechanism.

( 4 ) Preliminary information and farther probes

The Danishefsky ‘s diene ( trans-1-methoxy-3-trimethylsilyloxy-1,3-butadiene ) is a utile 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 therefore shows a high responsiveness towards dienophiles. The presence of the methoxy group renders the Diels-Alder reaction regiospecific by linking the electrophilic C attached to the methoxy group with the most nucleophilic atom of the dienophile.

As mentioned above, understanding the function of the accelerator can assist in the design of other enantioselective syntheses. Hence, in this portion of the work, the application of the theoretical account accelerator 4 to a Diels-Alder reaction affecting Danishefsky diene is explored. The studied reaction tracts are depicted in Figures 10 and 11. The undermentioned simplifications are made in the studied reaction: ( 1 ) the theoretical account ( S ) -catalyst 4 is used, ( 2 ) the same dienophile as in Corey ‘s reaction ( Figure 1 ) is used sing merely the diene add-on to the less substituted dual bond of the dienophile, ( 3 ) a simpler construction for the Danishefsky diene is used by replacing the trimethylsilyloxy group by a methoxy group, ( 4 ) the usage of the Danishefsky diene introduces one more stereogenic centre into the merchandise and hence there are 8 possible diastereomeric merchandises of which merely 4 are considered, and ( 5 ) since there is no experimental informations, the reaction is studied at merely 298 K.

Merely four passage constructions could be located on the possible energy surface for this reaction ( Table 4 ) . These passage structures lead to the two diastereomers endo-R and exo-R. The exo passage province TS14 represents the most stable passage province with an about 100 % of the Boltzmann population of the exo passage provinces. It involves the Danishefsky diene add-on to the front face of the ? , i?? dual bond of the dienophile and the accelerator is coordinated syn to this bond. The C atom connected to the methoxy group possesses the R constellation. The following lowest exo passage province is TS16. It is similar to TS14 except that the diene add-on is to the rear face of the ? , i?? dual bond of the benzoquinone. The lowest energy endo passage province is TS13 stand foring ~ 81.28 % of the Boltzmann population of the endo passage provinces. It is similar to TS14 but the passage province agreement is endo. The following lowest endo passage province is TS15 holding ~ 18.72 % of the Boltzmann population of the endo passage provinces. It is similar to TS13 but with the diene add-on to the rear face of the ? , i?? dual bond of the dienophile.

In contrast to Reaction D, the exo tract for Reaction F is found to be 12 times faster than the endo channel. However, the endo-R merchandise is 4.3 kcal/mol more stable than the exo-R merchandise. Therefore, Reaction F can be controlled both kinetically and thermodynamically with the exo merchandise being the kinetically favorite merchandise and the endo merchandise being the thermodynamically favorite merchandise ( Figure 9 ) . In add-on, in the presence of the Danishefsky diene, the stereoselectivity of the reaction is reasonably enhanced. The per centum diastereomeric surplus ( % de ) is calculated to be 88.2 % . Therefore, based on these preliminary informations, the usage of accelerator 4 is recommended for reactions such as Reaction F.

The mean grade of asynchronicity for the passage structures is found to be 1.49 & A ; Aring ; ( californium. Table 4 ) . Therefore, the Diels-Alder reaction affecting the Danishefsky diene is more asynchronous than that affecting isoprene ( 1.49 & A ; Aring ; vs. 0.93 & A ; Aring ; ) . To farther clarify the mechanism, KIEs are calculated for Reaction F and are given in Table 3. At the passage provinces, the mean distance between C-1 of the Danishefsky diene and C ? of the benzoquinone is calculated to be 3.85 & A ; Aring ; ( Table 4 ) . This distance is larger than the new wave der Waals contact distance ( 3.40 & A ; Aring ; ) of the two Cs and hence there is no intimation of adhering between the two Cs at these passage provinces. Despite this fact, the theoretically deliberate KIEs ( Table 3 ) indicate a conjunct but extremely asynchronous reaction mechanism alternatively of a stepwise mechanism.

It should be pointed out that the complete description of a chemical reaction mechanism requires more than merely turn uping stationary points along a reaction way. The time-evolution of the chemical procedure ( i.e. molecular kineticss ) is of importance for separating between concerted and bit-by-bit mechanisms. As stated above, femtosecond kineticss surveies have suggested the presence of both concerted and bit-by-bit flights for the Diels-Alder reaction.20,21 Ab initio molecular kineticss ( AIMD ) computations using the atom-centered denseness matrix extension ( ADMP ) method44-46 have been used to analyze of import chemical reactions such as the Staudinger reaction.47-49 Compared to other AIMD methods, the ADMP method has the cardinal advantage of additive grading of computational clip with system size.44-46 The survey of organocatalytic Diels-Alder reaction utilizing the ADMP method for deriving farther penetrations into the mechanism of this critical reaction is therefore recommended.

Decision

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 theoretical account chiral cationic oxazaborolidinium accelerator 4 have been studied by denseness functional theory utilizing the B3LYP functional together with the 6-31G ( vitamin D ) footing set. Both uncatalyzed and catalyzed reactions were investigated to research the consequence of the accelerator on this reaction in footings of energetics, selectivity, and mechanism. The free energy of activation was significantly lowered ( & A ; gt ; 13 kcal/mol ) in the presence of the accelerator. In add-on, the catalyzed reaction showed an improved endo/exo selectivity of greater than 13 per centum points. Furthermore, both uncatalyzed and catalyzed reactions showed concerted asynchronous reaction mechanism with the grade of asynchronicity being more apparent in the presence of the accelerator.

Two different types of dienes were considered in the current work, viz. , isoprene and Danishefsky diene. In the presence of the accelerator, both dienes showed comparable stereoselectivity. The Diels-Alder reaction in the presence of isoprene is most likely to travel through the endo channel while in the presence of Danishefsky diene, the exo path is favored. In both instances, the preferable accelerator coordination is syn to the HCa•?CH dual bond of the dienophile that undergoes the [ 4 + 2 ] -cycloaddition and the diene add-on is to the front face of this dual bond. Based on the optimized passage constructions and theoretical kinetic isotope effects computations, the Diels-Alder reactions affecting both dienes are predicted to continue through concerted but extremely asynchronous mechanism. The grade of asynchronicity is more marked in the presence of Danishefsky diene. The theoretical result of the current survey is in first-class understanding with Corey ‘s by experimentation derived prognostic choice rules.8

Recognitions

This survey was financially supported by the Malayan Academy of Science via SAGA Grant No. 66-02-03-0037. The writers are thankful to the Centre for Information Technology ( University of Malaya ) and MIMOS Berhad for supplying computing machine installations.