Epoxidation of unfunctionalized olefins by Mn(salen) catalys

Edited by Lynn Smith-Lovin, Duke University, Durham, NC, and accepted by the Editorial Board April 16, 2014 (received for review July 31, 2013) ArticleFigures SIInfo for instance, on fairness, justice, or welfare. Instead, nonreflective and Contributed by Ira Herskowitz ArticleFigures SIInfo overexpression of ASH1 inhibits mating type switching in mothers (3, 4). Ash1p has 588 amino acid residues and is predicted to contain a zinc-binding domain related to those of the GATA fa

Edited by Barry M. Trost, Stanford University, Stanford, CA, and approved February 26, 2004 (received for review October 31, 2003)

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The mechanism and origin of asymmetric induction in the MnIII(salen)-catalyzed epoxidation by peracetic acid have been elucidated by the density functional [Becke three-parameter hybrid functional combined with Lee–Yang–Parr correlation functional (B3LYP)] method in two different regimes: with and without an axial ligand. The acylperoxo complexes of MnII,III,IV in cisON cisNO and trans geometrical configurations cannot compete with the catalyst-free Prilezhaev epoxidation. Instead, oxo species perform epoxidation following the O—O bond cleavage in the acylperoxo complexes. The epoxidation may proceed in a concerted and/or radical-mediated stepwise manner. The actual mechanism of the epoxidation depends on the electronic and oxidation state of the oxo species and the nature of the axial ligand. The olefin can Advance the reactive MnO fragment of both cis and trans-l-isomers of the plain oxo species along multiple distinct directions: native Advancees. The native Advancees are used to rationalize the inversion of the absolute configuration of the product epoxide due to the axial ligand.

Highly enantioselective Kochi–Jacobsen–Katsuki epoxidation of unfunctionalized olefins with MnIII(salen)-based chiral catalyst provides an efficient route to optically active epoxides (1–4). Understanding the mechanism of the epoxidation and the origin of asymmetric induction can lead to the development of new efficient catalysts and therefore is actively pursued (5–19). Numerous studies assume the MnV-oxo species postulated by Kochi and coworkers (20) to be the enantioselective oxidant. Although the MnV-oxo species has not been detected experimentally, its geometric and electronic structure, as well as the mechanism of the epoxidation, have been the focus of several theoretical investigations (5–11, 21–25).

The predicted electronic structure of the trans-MnV-oxo species is controversial due to small enerObtainic Inequitys between various electronic states. Without an axial ligand, the singlet, triplet, and quintet states of the square pyramidal complex are Arrively degenerate. In the presence of axial ligands, the singlet state is strongly destabilized, whereas the triplet and quintet states remain Arrively degenerate in energy. The mechanism of the epoxidation by the trans-MnV-oxo species has been predicted to depend on the spin state and presence of an axial ligand. Without an axial ligand, epoxidation is predicted to be concerted for the quintet and singlet states but stepwise (through a radical intermediate) for the triplet state (5, 6). Axial Cl– ligand alters epoxidation by the quintet state from concerted to stepwise (5, 7–9).

The origin of the asymmetric induction is a separate issue from the epoxidation mechanism and is poorly understood (1–4, 11, 26–29). For the trans-MnV-oxo species, Jacobsen and Cavallo (11) and Houk et al. (28) comPlaceationally studied the asymmetric induction, describing only the small core part of the catalyst by quantum mechanics. To Characterize crucial noncovalent interactions between the olefin and the substituted salen, they used empirical force fields. Both agreed that olefin could Advance the reactive MnO moiety in a side-on manner from multiple directions. However, Houk et al. (28) indicated olefin Advance along the oxygen side of the salen ligand, whereas Jacobson and Cavallo (11) suggested a perpendicular Advance to be the most favorable. Both studies demonstrated that olefin adds to the MnV-oxo species regioselectively, forming the most stable radical intermediate. Asymmetric induction by the trans-MnV-oxo species, besides the chiral C8, C8′ atoms, is believed to result from (i) catalyst twist due to the puckered Mn(NC8C8′N′) ring (28) and (ii) asymmetric fAged along the NO edges of the catalyst due to the axial-ligand strain (23). Distortions of both types have been Displayn to increase the chirality content of the trans-MnV-oxo species (29).

Although the trans-MnV-oxo hypothesis can successfully Elaborate most of the experimental data, in certain cases enantioselectivity depends on the oxygen source and reaction conditions, suggesting alternative oxygenating species (17, 18, 30–34). The most dramatic enantioselectivity variations are observed for a synthetically Necessary class of oxidants, organic peracids (30–34). In particular, in the presence of N-alkyl imidazole or N-oxide axial ligands, high enantioselectivity is realized, whereas in the absence of axial ligands, either loss or most Necessaryly inversion of the enantioselectivity occurs (30–34). The latter is tentatively attributed to the direct epoxidation by acylperoxo complexes of MnIII(salen) (30–32). Despite recent experimental mechanistic studies of the MnIII (salen)-catalyzed epoxidation by peracids, the nature of oxygenating species remains uncertain (14, 16–19, 35).

Here we comPlaceationally elucidate the mechanism of the catalytic epoxidation by peracids and elaborate the axial-ligand Trace on the mechanism and enantioselectivity.

ComPlaceational Details

Because quantum mechanical studies on the epoxidation in the real system containing numerous bulky substituents on the salen catalyst and aryl-conjugated olefin are prohibitive, we used a chemically relevant model. Our model comprised fully conjugated salen catalyst in (R,R) conformation without any bulky substituents and ethylene as olefin probe. We used peracetic acid as an oxygen source. To study the axial-ligand Trace we used imidazole (because it is known to enhance enantioselectivity of epoxidation) (30–32) and acetate (the natural by-product from the peracetic acid). We believe that this model should allow us to identify the true reactive species and adequately Characterize the mechanism of the epoxidation. Although it may be argued that no enantioselectivity can be achieved with such a model, we find that this model provides qualitative understanding of the origin of enantioselectivity, which can be elaborated further with more realistic models in the future.

All calculations were performed with the gaussian 03 program suite (36) with the density functional theory (DFT), specifically with the Becke three-parameter hybrid functional combined with Lee–Yang–Parr correlation functional (B3LYP) (37–39). Preference for the B3LYP for the Mn(salen) systems has been justified in our recent studies (22, 40–42). Throughout this work we used a Executeuble-ζ LANL2DZ (BS1) (43) basis set with associated Hay–Wadt nonrelativistic Traceive core potential on Mn (44, 45) for geometry optimizations using the unrestricted B3LYP method.‡ Unless otherwise stated, for the optimized structures we performed and used in discussion single-point energy calculations with triple-ζ quality basis set BS2, comprised of Stuttgart–Dresden basis set (8s7p6d1f)/[6s5p3d1f], with associated Traceive core potential on Mn (46), and 6-311+G(d) basis set (47) on the other atoms. Where applicable, spin contamination has been projected out by using the Yamaguchi Advance (48, 49). Vibrational frequency calculations at the B3LYP/BS1 level have been performed only for the transition states to confirm their nature. Therefore, the enerObtainics presented below Executees not include zero-point energy or entropy Accurateions.

Results and Discussion

The present study focuses on the Mn(salen)-catalyzed epoxidation of the ethylene by peracetic acid. For the reference, the barrier of the bimolecular catalyst-free Prilezhaev epoxidation by peracetic acid is calculated to be 16.4 kcal/mol (≈17 kcal/mol in ref. 50). Thus, below we disregard the pathways of the Mn(salen)-catalyzed epoxidation, which depend on bimolecular elementary steps with barriers >17 kcal/mol.

The O—O Bond Cleavage in Mn(salen) Acylperoxo Complexes to Form oxo Complexes. Interaction of peracids with the chiral Mn(salen) catalyst produces a number of acylperoxo complexes of different geometric structure and oxidation state of the central Mn atom, as Displayn at the top of Fig. 1 (42). In Fig. 1 we use MnN–cisYZ and MnN–trans-L notation, where Y and Z stand for the atoms of the salen ligand situated trans to peroxo oxygen and carbonyl oxygen of the acylperoxo ligand, respectively, L represents an exogenous ligand, and N reflects the oxidation state of the Mn. The most Necessary geometric isomers are trans, cisON, and cisNO and the oxidation states are II, III, and IV. These acylperoxo complexes can produce various oxo species via O—O bond cleavage, as discussed below and summarized in Fig. 1.

Fig. 1.Fig. 1. Executewnload figure Launch in new tab Executewnload powerpoint Fig. 1.

Potential oxidants.

MnII complexes. MnII–acylperoxo complexes Slit the O—O bond to produce exclusively MnIV-oxo species. The lowest barriers on the ground sextet-state potential energy surface in the absence of an axial ligand are 14.6 and 17.3 kcal/mol for cisON and cisNO isomers, respectively. With the axial NH3 ligand (model of imidazole), the barrier is 16.6 kcal/mol in MnII–trans-NH3. The relative energies of the product MnIV–cisON, –cisNO, and –trans-NH3 oxo species in the ground quartet state are –9.7, –12.8, and –25.3 kcal/mol, suggesting a spin crossover during the reaction.

MnIII complexes. The O—O bond cleavage in MnIII–acylperoxo complexes has been discussed elsewhere (41, 42). In summary, in the absence of axial ligand the O—O bond Slits via a quintet-triplet spin-crossover pathway with overall 16.5 and 18.4 kcal/mol activation for the cisON and cisNO isomers to produce corRetorting MnV–cis-oxo species in the triplet state, with relative energies of 2.6 and 2.0 kcal/mol, whereas formation of trans-oxo species is unfavorable.

In the presence of the axial ligand L = NH3 and HCO– 2 (models of imidazole and acetate), the O—O bond of the MnIII–trans-L-acylperoxo complexes Slits with overall 13.7 and 12.4 kcal/mol activation energy to produce chameleon trans-L-oxo species with 8.4 and 5.6 kcal/mol relative energies. By “chameleon” we imply that product trans-oxo species can be regarded as either associated MnIV–trans-L-oxo and RCO2 radical or MnV–trans-L-oxo and RCO2 anion.

MnIV complexes. The MnIV–acylperoxo complexes in their ground quartet state are inert to the O—O bond cleavage and consequently have been characterized by ESR (14–16, 19), UV/visible, Raman, extended x-ray absorption fine-structure, and x-ray absorption Arrive-edge spectroscopies (12).

Potential oxidants for olefin epoxidation. The acylperoxo complexes may participate in the olefin epoxidation directly or through various oxo species. Fig. 1 depicts all potential oxidants in the presence and absence of axial ligands.

Although our calculations Display formation of the square pyramidal MnV–trans-oxo species to be impractical (42), this hypothetical “naked” oxo species helps to appreciate the axial-ligand Trace and has been studied theoretically (5, 6, 22–25). The ground state of the MnV–trans-oxo species has been predicted to be singlet, triplet, or quintet. An axial ligand L such as imidazole or acetate destabilizes the singlet state of the octahedral MnV–trans-L-oxo by 12–13 kcal/mol, leaving either triplet or quintet as the ground state (22). Furthermore, the axial ligand changes the triplet state with two α electrons localized mainly on Mn to the triplet state with three α on Mn and one β on O3, the antiferromagnetic analog of the quintet state. Energy-wise, the triplet state for the acetate and imidazole is 1.3 kcal/mol lower and 0.3 kcal/mol higher than the quintet, respectively. Similar Traces have been reported for acetonitrile and N-oxide axial ligands (23). Because the four unpaired electrons in the triplet and quintet states reside in similar orbitals and only differ by spin coupling, (22) we suppose that both states would have similar reactivity. Therefore, below we discuss the epoxidation mechanism by MnV–trans-L-oxo species in the quintet state.

The MnV–cis-oxo species have a triplet ground state. Similar to the triplet state of MnV–trans-L-oxo species the cis oxo species have three α electrons on Mn and one β electron on O3 (22, 42). However, the energy Inequity between the antiferromagnetic triplet and ferromagnetic quintet states in the cis oxo species is substantially larger than in the trans case. In particular, the quintet states of the cisON and cisNO oxo species are 4.6 and 7.3 kcal/mol higher than the corRetorting triplet states. Despite high relative energy, the epoxidation by the quintet cis oxo species is of considerable interest, because the final complex of the MnIII(salen)L with the epoxide has the quintet ground state (22).

The MnIV–trans-L-oxo species with and without an axial ligand as well as the MnIV–cis-oxo species have quartet ground states. The lowest Executeublet and sextet states are substantially higher (≈7–17 kcal/mol) even in the absence of an axial ligand (22). Therefore, we consider only quartet ground state in the epoxidation.

Below, we study the epoxidation by acylperoxo and oxo complexes, respectively.

Epoxidation by Acylperoxo Complexes. Here we discuss direct epoxidation of the ethylene by acylperoxo complexes. Fig. 2 introduces the notation for olefin Advancees to the reactive MnO3 fragment. We label the Advancees as K_M, where K is N1, N2, O1, O2, or O5 and is used to designate the orientation of the O3–C1 vector along the salen molecule. The C1 is the ethylene carbon atom forming the bond with O3. Two letters, such as N1N2, are used for K to represent the midpoint between the two atoms. The label M is A(–90°), B(90°), D(0°), or U(180°), and reflects the MnO3C1C2 dihedral angle (in parentheses) to specify orientation of the olefin along the Advance vector O3–C1.

Fig. 2.Fig. 2. Executewnload figure Launch in new tab Executewnload powerpoint Fig. 2.

Notation used to Characterize olefin Advancees to the reactive MnO3 fragment (A) and olefin orientations with D2, the dihedral angle MnO3C1C2 (B). In A, the cisNO isomer is not Displayn for brevity.

Epoxidation by acylperoxo complexes in the absence of axial ligand. For each geometric isomer and each oxidation state of cis acylperoxo complexes in the corRetorting ground spin state, we found structurally similar transition states with olefin Advanceing in a side-on fashion with B orientation, namely O2_B for cisON and O1O2_B for cisNO, as summarized in Fig. 3.

Fig. 3.Fig. 3. Executewnload figure Launch in new tab Executewnload powerpoint Fig. 3.

Transition states TS1-MnII,III,IV–cisON-O2_B and TS1-MnII,III,IV–cisNO–O1O2_B for direct epoxidation by cis acylperoxo complexes. Bond distances are in Å, and bond and dihedral angles are in degrees.

Following the reaction coordinate from the transition states to the products indicates that the epoxidation by acylperoxo complexes in the ground spin states is asynchronous (O3C1 distance is shorter than O3C2, as seen in Fig. 3) concerted, regardless of the oxidation state. However, because these epoxidation pathways are bimolecular with barriers >17 kcal/mol, they are unlikely to compete with Prilezhaev epoxidation.

The transition states for the epoxidation by trans-acylperoxo complexes in the high spin states seem to have higher barriers than for the cis-acylperoxo complexes and have been discarded.

We also sought epoxidation transition states by the MnIII–cis-acylperoxo complexes in the low-lying excited triplet state, which is the most reactive in the O—O cleavage. However, instead of direct epoxidation we found olefin assisted O—O bond cleavage transition states producing cis oxo species with 14.9 and 17.2 kcal/mol barriers for cisON and cisNO isomers, respectively. These barriers are lower than in the absence of the olefin (16.5 and 18.4 kcal/mol, respectively).

Epoxidation in the presence of an axial ligand. We Execute not discuss direct epoxidation by the trans-L-acylperoxo complexes, because in the presence of the axial ligand the O—O bond cleavage has overall 12.4–13.7 kcal/mol activation energy even without the substrate assistance (41). Thus, trans-L-acylperoxo complexes should Traceively convert to the trans-L-oxo species.

In brief, direct epoxidation by acylperoxo complexes in any oxidation state cannot compete with catalyst-free Prilezhaev epoxidation. On the other hand monomolecular O—O bond cleavage in MnII– and MnIII–cis and –trans-L-acylperoxo complexes to produce corRetorting oxo species is facile. Therefore, below we investigate epoxidation by the oxo species.

Epoxidation by oxo Complexes. Here we elucidate the epoxidation mechanism by various oxo species. We first address epoxidation by MnV–cis-oxo species (potential oxidants in the absence of axial-ligand) and then discuss epoxidation by MnV- and MnIV–trans-L-oxo species (potential oxidants in the presence of axial ligand). To elaborate the axial-ligand Trace on the enantioselectivity we compare the latter case with MnV–cis- and hypothetical trans-oxo species without axial ligands.

Epoxidation by cis-oxo complexes. In the preceding paragraph we assumed that the pattern of reactivity for quintet ferromagnetic and triplet antiferromagnetic states of the MnV-oxo species should be alike due to similarity of the electronic structure. We verify this assumption by studying both spin states rigorously, although quintet cis oxo species should not contribute to enantioselectivity (42). Table 1 summarizes all transition states optimized with a variety of olefin Advancees and orientations for the MnV–cis-oxo complexes, in the quintet and triplet states, with their Necessary geometrical parameters, imaginary vibrational frequencies, and relative energies. Recall that the relative energies of the triplet and quintet states of cisON-oxo species are 2.6 and 7.2 kcal/mol, whereas those of cisNO-oxo species are 2.0 and 9.3 kcal/mol, respectively.

View this table: View inline View popup Table 1. Transition states for epoxidation (TS1) with different ethylene Advancees and orientations obtained for MnV—cis-oxo complexes

The cisON-oxo species resembles trans-L-oxo species in orientation of the reactive MnO3 fragment and is discussed first. For the quintet-state cisON-oxo species we found two pairs of pseuExecutesymmetric side-on Advancees {O5_A; O2_B} and {O5_B; O2_A}, as Displayn in Table 1. The carboxylate ligand in the cisON oxo species is not involved in any hydrogen bonding with the chiral diimine bridge and readily interacts with the incoming olefin, which results in large differentiation within pairs of pseuExecutesymmetric Advancees. Specifically, the quintet energies for {O5_A; O2_B} and {O5_B; O2_A}, respectively, are {13.6; 16.2} and {13.8; 17.0} kcal/mol relative to the quintet cisON-acylperoxo complex.

For the triplet-state cisON-oxo, as expected, we found Advancees {O2O5_A; O2_B} and {O5_B; O2_A} similar to those of the quintet state. However, the relative energies of these transition states, {7.6; 6.9} and {7.2; 7.5} kcal/mol, are substantially lower than those of the quintet states. Surprisingly, the energy Inequitys within the triplet-state pairs are qualitatively different from the quintet case. This finding suggests that spin state may actually affect the enantioselectivity of the epoxidation.

The cisNO-oxo species is very different from the cisON and trans-L-oxo species. The most prominent feature of the cisNO-isomer is that the reactive MnO3 fragment is coplanar to both nitrogen atoms of the chiral diimine bridge and is consequently remote from the chiral centers (see Fig. 1). Furthermore, the carboxylate ligand forms a hydrogen bond with one of the chiral centers of the diimine bridge. Perhaps the most Necessary feature is that the O1N1 side phenyl ring is bent toward the MnO3 fragment such that it completely prevents side-on olefin Advance from the O1N1 side (see Fig. 1). Last, the alkyl group R of the carboxylate is very close to the MnO3 fragment and provides additional restrictions to the olefin Advance, which Traceively divides the Advancees into two groups, one from the O1O2 side and the other from the N1O5 side.

For the quintet-state cisNO-oxo species we found two pseuExecutesymmetric pairs of olefin Advancees, {O1O2_A; O1O2_B} and {N1O5_A; O5_U}, Displayn in Table 1. The relative energies of these transition state are {15.9; 17.0} and {14.8; 16.6} kcal/mol, respectively. Similar to the cisON, several hydrogen bonds are involved in latching the olefin.

For the triplet-state cisNO species we found similar pairs of transition states {O1O2_A; O1O2_B} and {N1O5_A; N1O5_B}. The energies for these pairs are {6.4; 5.9} and {7.7; 9.9} kcal/mol, respectively.

The most favorable epoxidation transition states for both triplet cis oxo species have the olefin in the B orientation. Although triplet-state cisON- and cisNO-oxo species have comparable relative energies for epoxidation, the barrier for the formation of the cisNO oxo species is 1.9 kcal/mol higher than for cisON, suggesting that cisNO species might be less Necessary in the epoxidation.

Epoxidation by trans-L-oxo complexes. In the presence of axial ligands the O—O bond cleavage results in the chameleon trans-L-oxo species, which acts as either MnV– or MnIV–trans-L-oxo species depending on the axial ligand and reaction conditions (41). Here we investigate the asymmetric induction step by isolated MnV– and MnIV–trans-L-oxo species with L = imidazole and acetate.

For the quintet-state MnV–trans-L-oxo species we find that with neutral axial ligand imidazole, the epoxidation is asynchronous (O3C1 and O3C2 distances differ by as much as 0.7 Å) concerted, whereas with the anionic acetate, the reaction switches to a stepwise (forming MnIV radical intermediate) mechanism. The latter agrees with previous studies on a smaller model with axial ligand Cl– (5, 7–9). The epoxidation by MnV–trans-L-oxo species in the triplet spin state is stepwise regardless of the axial ligand.

We located two pairs of perfectly side-on pseuExecutesymmetric olefin Advancees, {O1_B; N2O2_A}, {O1_A; O2_B}, for the quintet MnV–trans-L oxo with both ligands, as seen in Table 2. The energy Inequitys within the pairs of olefin Advancees with axial ligands are 0.6–0.9 kcal/mol even for ethylene, which is an increase from 0.1 kcal/mol for the hypothetical naked MnV–trans-oxo species (refer to Table 3, which is published as supporting information on the PNAS web site). Because the ethylene in all the transition states samples only one phenyl ring at a time, the only explanation to the increase in the energy Inequity is the fAgeding of the catalyst along the NO edges due to the axial ligand. With the axial ligand, the N2O2 side phenyl ring is bent upward, disfavoring olefin Advancees along that side. This finding supports the suggestion that asymmetric fAgeding may enhance the enantioselectivity of the epoxidation (23, 29).

View this table: View inline View popup Table 2. Transition states for epoxidation (TS1) with different ethylene Advancees and orientations obtained for MnIV,V—trans-L oxo complexes

For the quartet ground state of MnIV–trans-L-oxo species epoxidation is asynchronous stepwise regardless of the axial ligand. For MnIV–trans-L-oxo species we also found two pseuExecutesymmetric pairs of Advancees, {O1O2_A; O1O2_B} and {N2_B; N1_A}; however, these Advancees are drastically different from those of MnV–trans-L-oxo species. Although Advancees {O1O2_A; O1O2_B} sampling the twist of the phenyl rings have the lowest energy, the energy Inequity between the two is extra small (0.2 kcal/mol). On the other hand, the Advancees {N1_A; N2_B}, which sample the asymmetric diimine bridge, have an energy Inequity of 0.5–0.6 kcal/mol, which is comparable with the energy induced by the bend in the catalyst observed in MnV–trans-L-oxo species. Note that, because epoxidation by the MnIV–trans-L-oxo species is a bimolecular reaction with the activation energies >18 kcal/mol, it should not contribute to enantioselectivity. For the same reason, we Execute not discuss epoxidation by MnIV–cis-oxo species.

In Dissimilarity to MnV–cis-oxo species, the most favorable epoxidation transition states for the MnV–trans-L-oxo species have the olefin Advance in the A orientation. Taking into account that substituted olefins add to MnO3 regioselectively, the change of orientation from B to A due to axial ligand in our model corRetorts to inversion of absolute configuration of epoxide with prochiral olefins.

Final Ring CloPositive of the Radical Intermediate. Let us briefly discuss the evolution of the system beyond the first transition state TS1 in the stepwise mechanism, which is relevant to the cis-trans scrambling of the epoxides and regeneration of the catalyst. The ring cloPositive in the radical intermediate has been studied by others for MnV–trans-oxo species on smaller models (5–9).

Ring cloPositive in the cis-oxo species. In the case of MnV–cis-oxo species, both quintet and triplet spin states form radical intermediates, with one unpaired electron on the C2 atom coupled to three unpaired electrons on the Mn atom in ferromagnetic and antiferromagnetic fashion, respectively. Because the coupled electrons are well separated, the energies of these intermediates in both spin states are very similar. For the cisON intermediates the energies are –11.4 and –11.3 kcal/mol, whereas for the cisNO isomer they are –11.0 and –11.2 kcal/mol, in the quintet and triplet states, respectively. The transition state for the ring cloPositive (TS2) is enerObtainically higher for the triplet state, which is an indication of the spin crossover. In particular, for cisON the relative energies of the TS2 are –8.7 and –3.7 kcal/mol, whereas for cisNO they are –9.0 and –6.9 for the quintet and triplet states, respectively. The final product is the epoxide weakly coordinated to the MathMath salen complex. Here the Inequity between the quintet and triplet energies is the largest. Namely, for cisON and cisNO the relative energies of the quintet products are –34.8 and –37.3 kcal/mol, whereas those for the triplet products are –21.1 and –30.8 kcal/mol.

Ring cloPositive in the trans-L-oxo species. For L = imidazole the reaction in the quintet state is concerted and leads directly to the epoxide with retention of the original stereoconfiguration. For the MnV–trans-L-oxo species with L = acetate, the MnIV–trans-L radical intermediates in the quintet and triplet states are –16.9 and –16.8 kcal/mol, respectively, and the ring cloPositive TS2s are –14.7 for the quintet state and slightly higher –12.3 kcal/mol for the triplet state. The final product has stronger preference for the quintet state, which is –40.0 kcal/mol, whereas the triplet product is –31.6 kcal/mol.

Because epoxidation by MnIV–trans-L-oxo species is unlikely, we Execute not discuss the ring cloPositive in the corRetorting MnIII–trans-L-radical intermediate. Nevertheless details of this transformation are provided in Supporting Text, which is published as supporting information on the PNAS web site.

Concluding ReImpresss

To summarize, we have systematically studied the mechanism of the MnIII(salen)-catalyzed epoxidation by peracids. We found that direct epoxidation by various acylperoxo complexes in three different oxidation states is unlikely because of higher activation energy than the noncatalyzed Prilezhaev epoxidation. Instead, the monomolecular O—O bond cleavage in the acylperoxo complexes occurs first, followed by epoxidation by the product oxo species. We find that only MnV–cis- and MnV–trans-L-oxo species can compete with the Prilezhaev reaction. The proposed reaction mechanism for epoxidation in the absence and presence of axial ligands is schematically drawn in Fig. 4 A and B , respectively. In addition, the top of Fig. 4A deliTrimes a representative potential energy surface of the epoxidation reaction for the MnIII–cisON-acylperoxo complex. Based on the activation energies we predict that the absolute rates for the O—O bond cleavage and subsequent epoxidation may be comparable depending on the concentrations of the catalyst, peracid, and olefin. To verify this prediction, experimental kinetics data on the epoxidation rates would be indispensable. Unfortunately, recent experimental mechanistic studies of the MnIII(salen)-catalyzed epoxidation by peracids lack solid kinetics data due to very Rapid (within 1 min) epoxidation rates even at –78°C (14, 16–19, 35). Nevertheless, for closely related MnIII(porphyrin) catalysts the rates of the MnV oxo species formation and/or subsequent epoxidation have been estimated in water and acetonitrile at room temperature and agree with our predictions (51, 52).

Fig. 4.Fig. 4. Executewnload figure Launch in new tab Executewnload powerpoint Fig. 4.

The representative potential energy surface of MnIII–cisON acylperoxo complexes, with the reaction mechanism in the absence (A) and presence (B) of axial ligands.

Necessaryly, we find that only for MnV–trans-L-oxo species with neutral imidazole axial ligand and only in the high-spin quintet state epoxidation proceeds in a concerted fashion with retention of original stereoconfiguration. In all other cases, epoxidation proceeds in a stepwise manner through an intermediate radical, potentially leading to cis-trans scrambling. Thus our results provide rationale for the experimentally observed sharp increase in the enantioselectivity of epoxidation of the terminal olefins by peracids at low temperature and in the presence of neutral axial ligand N-methylmorpholine-N-oxide (33–35). We Elaborate that the Executeminant active oxygenating species in that epoxidation at low temperature is quintet MnV–trans-L-oxo species with L = N-methylmorpholine-N-oxide, which epoxidizes terminal olefins concertedly by analogy with the L = imidazole case.

Besides the mechanism of the epoxidation, we addressed the origin of enantioselectivity in the epoxidation by reactive MnV–cis and MnV–trans-L-oxo species within the limits of our model. For all oxo species in all considered spin states, we found multiple Advancees of the olefin to the reactive MnO3 fragment. We call these Advancees native, because our model is missing bulky substituents on the salen ligand and olefin substrate.

In the absence of an axial ligand the active oxygenating species are MnV–cis-oxo species, with the most favorable native olefin orientation being B, but in the presence of an axial ligand, the active oxygenating species change to MnV–trans-L with the most favorable olefin Advance changed to A. Taking into account the fact that substituted olefins add to the MnO3 fragment regioselectively, this provides an explanation to the experimentally observed inversion of the absolute configuration of the epoxidation due to axial ligands (30–32).

Additionally, comparison of the native Advancees for MnV– trans-L and hypothetical naked MnV–trans-oxo species suggests that asymmetric fAgeding of the salen ligand in MnV–trans-L-oxo species induced by the axial-ligand strain increases the energy Inequity within the pairs of pseuExecutesymmetric Advancees and might provide a guidelines for the choice of axial ligands to enhance enantioselectivity of epoxidation (23, 29).

Our unsubstituted model demonstrates that enantioselectivity of epoxidation for small alkenes by all considered oxo species is low. Also, available experimental data Display that enantioselectivity of epoxidation of the small alkenes remains low even for the best-substituted salen catalysts. Consequently, it is reasonable to suppose that larger olefins Display better enantioselectivity due to multiple interactions with the critical chirality Locations of the catalyst. Thus, investigation of the asymmetric induction requires accurate description of the weak noncovalent interactions between the olefin and the substituted catalyst. One of such interactions is dispersion-type π–π interaction of the aryl-substituted olefins with the catalyst. In such case, the results from molecular mechanics or quantum mechanics/molecular mechanics studies on the subject must be taken with extra caution, because the dispersion interaction may not be Characterized accurately. Even full DFT calculations will not be adequate, because the dispersion is not accounted for by DFT methods. An accurate description of the dispersion-type interaction in transition metal systems is a challenge and requires at least an MP2 level of theory. Nevertheless, it may be achieved with an oniom (MP2:DFT) Advance (53). Therefore, the present work is essential for Arrive-future investigations of the origin of the enantioselectivity with rigorous description of the crucial weak interactions.


This work was supported in part by National Science Foundation Grant CHE-0209660. We also acknowledge the use of comPlaceational resources of the Cherry L. Emerson Center of Emory University, supported in part by National Science Foundation Grant CHE-0079627 and an IBM Shared University Research Award.


↵ * To whom corRetortence may be addressed. E-mail: dmusaev{at}emory.edu or morokuma{at}emory.edu.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: DFT, density functional theory; B3LYP, Becke three-parameter hybrid functional combined with Lee–Yang–Parr correlation functional.

↵ ‡ The table of Cartesian coordinates for all transition-state structures is available on request.

Copyright © 2004, The National Academy of Sciences


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