DOI: 10.1002/chem.201406478

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& Reaction Mechanisms

Theoretical Studies on the Asymmetric Baeyer–Villiger Oxidation Reaction of 4-Phenylcyclohexanone with m-Chloroperoxobenzoic Acid Catalyzed by Chiral Scandium(III)–N,N’-Dioxide Complexes Na Yang, Zhishan Su,* Xiaoming Feng, and Changwei Hu*[a] Abstract: The mechanism and enantioselectivity of the asymmetric Baeyer–Villiger oxidation reaction between 4phenylcyclohexanone and m-chloroperoxobenzoic acid (mCPBA) catalyzed by ScIII–N,N’-dioxide complexes were investigated theoretically. The calculations indicated that the first step, corresponding to the addition of m-CPBA to the carbonyl group of 4-phenylcyclohexanone, is the rate-determining step (RDS) for all the pathways studied. The activation barrier of the RDS for the uncatalyzed reaction was predicted to be 189.8 kJ mol¢1. The combination of an ScIII–N,N’-dioxide complex and the m-CBA molecule can construct a bi-

Introduction The Baeyer–Villiger (BV) oxidation[1, 2] is a convenient and widely used method for the preparation of esters or lactones. Optically active lactones are core structures of a number of biologically active compounds and have extensive applications in industry and biochemistry.[2] Since its discovery by Baeyer and Villiger in 1899,[1] some efficient catalysts, including biocatalysts (particularly enzymes),[3] organocatalysts,[4] and Lewis acidic transition-metal complexes,[5, 6] have been developed to obtain various optically active lactones. The generally accepted mechanism of BV oxidation described by Criegee involves two steps: the addition of the peroxy acid to the carbonyl group to form a tetrahedral intermediate (the so-called Criegee intermediate), followed by rearrangement of the Criegee intermediate in a concerted manner to yield ester or lactone product with the release of a carboxylic acid.[7] Despite many experimental and theoretical investigations of the mechanism, two questions are still under debate: 1) whether the first or second step of the reaction is the ratedetermining step (RDS) and 2) what are the key factors influencing the migration ability of alkyl groups of the ketone?[8–13] In the 1950s, a rate-limiting, acid-catalyzed migration mechanism was proposed by Hawthorne and Emmons[8] and then [a] Dr. N. Yang, Dr. Z. Su, Prof. Dr. X. Feng, Prof. Dr. C. Hu Key Laboratory of Green Chemistry & Technology Ministry of Education, College of Chemistry Sichuan University, Chengdu, 610064 (P. R. China) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201406478. Chem. Eur. J. 2015, 21, 7264 – 7277

functional catalyst in which the Lewis acidic ScIII center activates the carbonyl group of 4-phenylcyclohexanone while m-CBA transfers a proton, which lowers the activation barrier of the addition step (RDS) to 86.7 kJ mol¢1. The repulsion between the m-chlorophenyl group of m-CPBA and the 2,4,6-iPr3C6H2 group of the N,N’-dioxide ligand, as well as the steric hindrance between the phenyl group of 4-phenylcyclohexanone and the amino acid skeleton of the N,N’-dioxide ligand, play important roles in the control of the enantioselectivity.

proved by kinetic studies on a series of p-substituted acetophenones by Simamura and co-workers.[9] However, depending on the reaction conditions and the nature of reactants, a switch in mechanism from rate-determining migration to rate-determining addition could also be observed,[10] which is supported by computational studies by Reyes et al.[11a–c] and Grein et al.[12] In addition, the acid generated by decomposition of the peroxy acid or generated as byproduct during the reaction may also change the RDS.[11] Compared with extensive studies on uncatalyzed BV oxidation reactions and those catalyzed by small organic molecules, metal catalysis is slightly less fruitful. Some Pt-, Zr-, Re-, Se-, As-, Sn-, W-, and Mo-based homogeneous[14] and solid catalysts[15] have been shown to efficiently activate hydrogen peroxide for BV oxidation reactions. By means of a combination of kinetic and spectroscopic techniques, the possible reactive species have been experimentally proposed.[14c, 16] In PtII-catalyzed BV oxidation reactions of simple cyclic ketones with hydrogen peroxide, Strukul and coworkers thought that the ketone substrate coordinates to the vacant coordination site of [(dppe)Pt(CF3)(solv)] + (dppe = a series of tetraphenyldiphosphines) to form reactive species.[16] However, a different mechanism involving initial cleavage of the hydroxy bridge in [{(dppe)M(m-OH)}2]2 + (M = Pd, Pt) assisted by H2O2 and the formation of a (HOO)Pt(ketone) intermediate may be favorable when [{(dppe)M(m-OH)}2]2 + is employed.[14c] With regards to mechanistic aspects of the catalytic BV oxidation reaction, theoretical studies were also carried out to model possible catalytically active species and to explore the role of Lewis acidic metal catalysts.[17] For example, Sever and Root investigated several possible mechanisms for Sn- and Ti-catalyzed BV oxidations of acetone with hydrogen peroxide

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Full Paper using DFT methods.[17a,b] The calculations indicated that the between 1 a and m-CPBA includes two steps: 1) the peracid, catalyzed reactions proceed through a Criegee intermediate m-CPBA, attacks the carbonyl carbon atom of 1 a with formacontaining a five-membered chelate ring, which effectively action of the Criegee intermediate (addition step); 2) concerted tivates both reactants in the addition step and facilitates the migration of one of the adjacent carbon atoms to the perester departure of a hydroxyl group in the following rearrangement. oxygen atom, reforming the carbonyl group with the loss of In a bifunctional active-site model of an Sn–beta zeolite cataa proton and cleavage of the O¢O bond to produce an mlyst that was theoretically simulated by Corma and co-workers, chlorobenzoic acid (m-CBA) molecule (migration step). The dethe Sn atom acts as a Lewis acid to activate cyclohexanone, tailed mechanism for each elementary step is discussed below. and an adjacent basic oxygen atom of the SnOH group interacts with H2O2 by hydrogen bonding.[17c] Although these studies provide valuable insights into molecular pathways of the reactions, the mechanism involving strong chiral catalyst–substrate interactions, especially the key factors for enantiocontrol in asymmetric BV oxidation, remains theoretically unresolved. The C2-symmetric chiral N,N’-dioxide–metal complexes developed by us proved to be excellent catalysts for a many asymmetric transformations.[18] Recently, experimental results also proved that catalytic enantioselective BV oxidations of racemic and meso cyclic ketones could be achieved in the presence of Scheme 2. Mechanism of the uncatalyzed BV oxidation reaction between 1 a and mCPBA. chiral ScIII–N,N’-dioxide complex catalysts to afford

Scheme 1. Asymmetric BV oxidation reaction between 1 a and m-CPBA catalyzed by an ScIII–N,N’-dioxide complex.

optically active e-lactones with excellent yields and ee values (up to 99 % yield and 95 % ee, Scheme 1). Interestingly, the yields and enantioselectivities of the products are sensitive to structural changes of the chiral N,N’-dioxide ligands (e.g., substituent of the aniline moiety and amino acid skeleton) or substrates.[19] To understand the mechanism of the BV oxidation reaction, explore the geometries and energetics of the key species, and rationalize the reactivity/enantioselectivity of the catalysts, we carried out theoretical investigations of the BV oxidation reaction of 4-phenylcyclohexanone (1 a) with m-chloroperoxobenzoic acid (m-CPBA) catalyzed by ScIII–N,N’-dioxide complexes by ONIOM and DFT methods.

Results and Discussion Uncatalyzed BV reaction (path 1) On the basis of the commonly accepted BV mechanism for peroxycarboxylic acids, the uncatalyzed BV oxidation reaction Chem. Eur. J. 2015, 21, 7264 – 7277

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As shown in Scheme 2, the reaction starts with initial formation of molecular complex 1-IM1, in which the substrate 1 a is activated by the terminal H atom of m-CPBA with a H5···O1 distance of 1.770 æ. The C=O bond is weakened with a corresponding increase in the O1¢C2 bond length (from 1.212 æ in free 1 a to 1.223 æ) and a decrease in the Wiberg bond index (from 1.826 in free 1 a to 1.726). The increased positive charge on the C2 atom (0.625 e in free 1 a versus 0.669 e in 1-IM1) also indicates its enhanced electrophilicity, which facilities the subsequent addition process. The C2¢O6 bond is then formed concomitantly with hydrogen transfer from O6 to O1 atom via four-membered concerted transition state 1-TS1 to produce the Criegee intermediate 1-IM2. The activation barrier is predicted to be 189.8 kJ mol¢1 for this step. For 1-IM2, the dissociating O6¢O7 bond is antiperiplanarly situated to the migrating C2¢C3 bond with a dihedral angle gC3-C2-O6-O7 of 176.78.[30] Natural bond orbital (NBO) analysis showed that the negative charge accumulated on the C3 atom is ¢0.508 e. The Wiberg index of the C2¢C3 bond decreases from 0.989 in 1 a to 0.970 in 1-IM2, that is, the C2¢C3 bond becomes weaker. In the following step, the rearrangement of Criegee intermediate 1-IM2 occurs by migration of the C3 atom to the O6 atom. Simultaneously, proton H5 transfers from O1 to O7 concomitantly with the cleavage of the O6¢O7 bond, and one m-CBA molecule is released. The activation barrier of this migration step is predicted to be 91.7 kJ mol¢1. Herein, the addition step is predicted to be the RDS for the uncatalyzed reaction with an activation barrier of 189.8 kJ mol¢1, which is similar to those of theoretical investigations on the BV oxidation reaction between acetone and performic acid by Grein and co-workers at the (PCM)B3LYP/6-31 + + G(d,p) level of theory.[12] Such a high activation barrier indicates that it is difficult for a BV oxidation reaction to occur in the absence of catalyst.

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Full Paper Reaction catalyzed by m-CBA or m-CPBA (path 2)

tially formed. The catalytic m-CBA molecule interacts with both the substrate 1 a and the oxidant m-CPBA simultaneously through hydrogen bonding. For 2 a-IM1, the geometry seems loose with a longer distance between O1 and C2 (1.224 versus 1.212 æ in free 1 a). The O¢H bond length in the m-CPBA moiety is longer than that in free m-CPBA by 0.002 æ, and this indicates slight weakening of the O¢H bond. Then, m-CPBA attacks the carbonyl group of 1 a via concerted transition state 2 a-TS1 to produce the Criegee intermediate 2 a-IM2. The activation barrier for this addition step is predicted to be 129.1 kJ mol¢1, which is significantly lower than that of the uncatalyzed BV oxidation reaction, by 60.7 kJ mol¢1 (Figure 1). This positive role of acid is also supported by theoretical calculations of Cruz and co-workers on the BV oxidation reaction of

Recently, both theoretical and experimental investigations proved that BV oxidation reactions could be accelerated in the presence of acids. The acid molecule was assumed to act as both proton donor and acceptor, decreasing the activation barrier of the addition step.[13a,e,f,i,j] Meanwhile, our experiments also indicated that the BV oxidation reaction between 1 a and m-CPBA could occur even without the ScIII–N,N’-dioxide complex, affording racemic products in a yield of 19 %.[19] Considering that, under normal experimental conditions, a partner acid always accompanies the peracid,[8] it is reasonable to think that a small amount of m-CBA (at least 1 %) still exists in the reaction system, although the m-CPBA used experimentally was recrystallized in a purity of 99 %.[19] Therefore, it is mechanistically interesting to check whether both acidic m-CBA and an extra m-CPBA molecule could act as efficient organocatalysts for the BV oxidation reaction between 1 a and m-CPBA. Calculations indicated that the reaction mechanisms catalyzed by m-CBA (path 2 a) or an extra m-CPBA molecule (path 2 b) are very similar (Scheme 3), and the activation barrier of the addition step (the RDS) of the pathway catalyzed by m-CBA is 68.2 kJ mol¢1 lower than that of the m-CPBA-catalyzed pathway (Figure 1). Therefore, m-CBA was chosen as a representative case to explore the role of the acid. As shown in Scheme 3, threemolecule complex 2 a-IM1 is ini- Scheme 3. Mechanism of the BV oxidation reaction between 1 a and m-CPBA catalyzed by m-CBA or m-CPBA.

Figure 1. Energy profiles for the uncatalyzed BV oxidation reaction between 1 a and mCPBA and the reactions catalyzed by m-CBA and m-CPBA. Chem. Eur. J. 2015, 21, 7264 – 7277

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propanone with peracetic acid catalyzed by acetic acid at the (SCI-PCM)B3LYP/6-311G**//B3LYP/6-311 + + G** level of theory.[13e] Then, starting from 2 a-IM2, alkyl migration would occur along two different pathways (paths 2 aa and 2 ab) to form the final product 2 a. Competing transition states 2 aa-TS2 and 2 abTS2 were located and involve intramolecular alkyl migration with and without the aid of m-CBA, respectively. Calculations indicated that the final ring-expansion step could occur easily via eight-membered cyclic transition state 2 aa-TS2 with an activation barrier of 57.3 kJ mol¢1 when m-CBA is removed from 2 a-IM2 (the activation barrier along path 2 ab via 2 ab-TS2 is 82.5 kJ mol¢1). These results verify that mCBA can accelerate the BV oxidation reaction by decreasing the activation barrier of the addition step, which is in agreement with the theoretical studies by Alvarez-Idaboy and co-workers.[13e,f] Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper In the BV oxidation reaction, protonation of the Table 2. Selected structural parameters (bond lengths [æ] and angles [8]) and the corketone would increase the positive charge of the carresponding deformation energies [kJ mol¢1] for addition transition states catalyzed by bonyl carbon atom in the transition state of the addidifferent oxycarboxylic acids. tion step, enhance the electrophilicity of this atom, Fragment Parameter TFAA m-CBA BA FA AA m-CPBA and facilitate the addition process.[11b] Note that O¢H Dr(O10¢H9) 0.514 0.343 0.297 0.352 0.287 0.278 bond breaking or proton release from the acid is inacid 259.1 167.7 147.6 168.3 143.9 140.2 DEd volved in the presence of the acidic m-CBA or mDqO1-C2-C12 38.6 38.3 37.8 37.9 37.9 46.7 CPBA. Therefore, it would be interesting to explore 1a Dr(C2=O1) 0.075 0.065 0.063 0.065 0.062 0.094 the relationship between the acidity of the catalysts 47.9 41.9 40.9 40.6 40.5 78.9 DEd DgC13-O7-O6-H5 75.1 74.2 75.9 75.4 78.5 81.9 and their reactivity. Compared with m-CPBA, m-CBA m-CPBA Dr(O6¢H5) 0.113 0.162 0.189 0.158 0.192 0.226 is a stronger acid, which could be verified by the 45.1 64.0 76.6 62.7 79.5 96.3 DEd ¢1 smaller gas-phase proton affinity (1495.3 kJ mol for m-CPBA and 1421.3 kJ mol¢1 for m-CBA). When 1 a is protonated by m-CBA, the acid–base interaction between 1 a and m-CBA is stronger, and more pronounced elecin the C12-C2-O1 bond angle (46.78) and O1¢C2 distance trophilicity of the carbonyl group of the reactant complex re(0.094 æ) of 1 a (Table 2). In addition, the large changes in dihesults. This causes more effective catalytic performance of mdral angle gC13-O7-O6-H5 (81.98) and O6¢H5 distance (0.226 æ) for m-CPBA also correspond to its large distortion in m-CPBA-TS1. CBA over m-CPBA, which leads to a lower activation barrier. In As a result, the deformation energies of the m-CPBA addition, the activation barriers of the key carbonyl addition (96.3 kJ mol¢1) and 1 a fragments (78.9 kJ mol¢1) in m-CPBAsteps in the BV oxidation reaction between 1 a and m-CPBA in the presence of four other oxycarboxylic acids—formic acid TS1 are higher than those in transition states catalyzed by the (FA),[12, 13i] acetic acid (AA),[13e] trifluoroacetic acid (TFAA),[11b] and other five acids (40.5–47.9 kJ mol¢1 for 1 a and 45.1– benzoic acid (BA)—were also evaluated. As expected, the acti79.5 kJ mol¢1 for m-CPBA, respectively). Besides, these special vation barriers of the addition step of the C=O bond decrease orientations of the fragments in m-CPBA-TS1 reduce the orbias the corresponding PA values decrease, and a good linear tal overlap between the fragments and result in weaker intercorrelation was observed (R2 = 0.981) excluding m-CPBA (see action than in the other five acid-catalyzed transition states Figure S2a in the Supporting Information). These results indi(¢297.3 versus ¢399.7 to ¢306.0 kJ mol¢1). Consequently, the cate that an oxycarboxylic acid with higher acidity may be m-CPBA-catalyzed pathway has higher activation barrier more favorable for the BV oxidation reaction. (18.0 kJ mol¢1) than the other five acid-catalyzed ones (¢47.6 Decomposition of the activation barrier DrE– into a distortion to ¢42.0 kJ mol¢1). energy and an interaction energy yields valuable insight into For the other five oxycarboxylic-acid-catalyzed reactions, the the difference in the activation barriers of different pathways differences in the deformation energies are mainly caused by in acid-catalyzed BV oxidation reactions. The contributions to the distortions of the catalyst acids, whereas the structural disthe interaction energy and distortion energy of the three fragtortions and deformation energies of the 1 a and m-CPBA fragments (acid, m-CPBA, and 1 a) during the formation of the ments in the five transition states are comparable (Table 2). Intransition states in the addition step are listed in Table 1, in terestingly, we found that the acid with higher acidity has the which the deformation energy reflects the structural distortion greater O10¢H9 bond elongation, which results in a larger deof the fragment and the interaction energy represents the information energy term. However, the interactions between teraction between them.[29] fragments in the addition transition states are also affected by the acidity of the acids, since the interaction energies deCompared with the other five acids, the additional O atom crease linearly with the corresponding proton affinity (PA) of the peracid m-CPBA makes the fragments in m-CPBA-TS1 values (R2 = 0.982, Figure S2b in the Supporting Information). deform more heavily to achieve a suitable orientation for addiFor example, for TFAA-TS1, which has the highest acidity tion to the C=O bond. The structural distortion of the fragamong the five acids, although the interaction term is lower ments in m-CPBA-TS1 is reflected by relatively large changes than those of the others by approximately 81.0 kJ mol¢1, it has the largest deformation term Table 1. Energies of activation reactions and their components in the carbonyl addition step in the presence (352.1 kJ mol¢1). Such high deforof oxycarboxylic acid and PAs of the oxycarboxylic acids involved in the reaction. All energies are given in kJ mol¢1. mation energy overwhelms the more favorable interaction – PA Reaction DEint-1 DEint-2 DEint(reaction) DEd of fragments DEd DrE energy, and thus the activation acid m-CPBA 1 a barrier of the TFAA-catalyzed 1 a + m-CPBA + TFAA!TFAA-TS1 0.0 ¢399.7 ¢399.7 259.1 45.1 47.9 352.1 ¢47.6 1387.9 path is only 5.4 kJ mol¢1 lower 1 a + m-CPBA + m-CBA!m-CBA-TS1 0.0 ¢318.7 ¢318.7 167.7 64.0 41.9 273.5 ¢45.2 1421.3 than those of the other acid-cat1 a + m-CPBA + BA!BA-TS1 0.0 ¢309.9 ¢309.9 147.6 76.6 40.9 265.2 ¢44.7 1447.9 1 a + m-CPBA + FA!FA-TS1 0.0 ¢313.6 ¢313.6 168.3 62.7 40.6 271.6 ¢42.0 1472.6 alyzed paths. 1 a + m-CPBA + AA!AA-TS1 0.0 ¢306.0 ¢306.0 143.9 79.5 40.5 263.8 ¢42.2 1490.4 In summary, for the five oxy1 a + m-CPBA + m-CPBA!m-CPBA-TS1 0.0 ¢297.3 ¢297.3 140.2 96.3 78.9 315.3 18.0 1495.3 carboxylic-acid-catalyzed reacChem. Eur. J. 2015, 21, 7264 – 7277

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Full Paper tions, the favorable interaction energies between the Table 3. Linear correlations of deformation energies and the selected structural pafragments have positive effects on the activation barrameters for the addition transition states catalyzed by different oxycarboxylic acids. riers of the reactions (overwhelming the unfavorable Linear correlation Equation R2 deformation energies) and thus result in lower activation barriers (¢47.6 to ¢42.0 kJ mol¢1). On the contraa DEd of acid vs. Dr(O10¢H9) DEd(acid) = 506.460 Dr(O10¢H9)¢3.673 0.993 b DEd of 1 a vs. DqO1-C1-C12 DEd(1 a) = 4.275 DqO1-C1-C12¢120.550 0.987 ry, the high deformation energy caused by the addiDEd(1 a) = 1202.500 Dr(C2 < C- > O1)¢36.533 0.958 c DEd of 1 a vs. Dr(C2¢O1) tional O atom of the catalytic peracid m-CPBA exerts d DEd of m-CPBA vs. Dr(O6¢H5) DEd(m-CPBA) = 453.93 Dr(O6¢H5)¢7.985 0.993 more significant influence on the activation barrier than the interaction energy during the formation of transition state m-CPBA-TS1. Accordingly, the activation barrier from the reactants to m-CPBA-TS1 is as high as namely, twisting of the dihedral angle gC13-O7-O6-H5 and increase 18.0 kJ mol¢1. of the O6¢H5 bond length, of the m-CPBA fragment can be observed during the formation of TS1s (Figure 2 and Table 2). To assess the origin of the dramatic differences in deformaThe m-CPBA fragment of m-CPBA-TS1 exhibits the most dration energies for the six acids, the constituent fragments of matic change in dihedral angle gC13-O7-O6-H5(81.98) and the largTS1s were structurally analyzed and visualized (Figure 2). Furthermore, the correlations between the deformation energies est elongation of the O6¢H5 bond (0.226 æ), which may be reand changes in certain bond lengths and angles were studied lated to its highest deformation energy of 96.3 kJ mol¢1. (Table 3 and Figure S3 in the Supporting Information). The deTherefore, the oxycarboxylic acids could be used as efficient formations of the acid catalysts are mainly reflected by the organocatalysts to accelerate the BV oxidation reaction beelongation of the O10¢H9 bond. A good linear correlation was tween 4-phenylcyclohexanone (1 a) and m-chloroperoxobenzoobserved between deformation energies DEd(acid) and changes ic acid (m-CPBA) by participating in the proton-transfer process. The acidity of the acid catalyst may have a great effect in O10¢H9 bond length Dr(O10¢H9) with R2 = 0.993. TFAA-TS1 has the largest O10¢H9 bond elongation, which results in a sizon the activation barrier of the addition step of the C=O bond. able increase in deformation energy (259.1 kJ mol¢1), which is The deformation energies of the acid catalyst and the m-CPBA in agreement with its lowest PA value (1387.9 kJ mol¢1; fragment may greatly contribute to the activation barrier of Table 1). For the 1 a fragment, both elongation of the C2¢O1 the addition step of the C=O bond, whereas the interaction bond and decrease of the O1-C2-C12 angle q may be mainly energies have a positive effect on it. The deformation energy responsible for its deformation energy (Figure 2). The deformaterm exhibits a good linear correlation with the changes in tion energies of the 1 a fragment (40.5–47.9 kJ mol¢1) are comsome structural parameters in TS1s. parable for the five oxycarboxylic acids. Both the magnitude of Reaction catalyzed by ScIII–N,N’-dioxide complexes C2¢O1 bond elongation Dr(C2¢O1) and the change in bond angle DqO1-C2-C12 clearly depend on the deformation energy of (paths 3–5) 1 a (R2 = 0.987 and 0.958, respectively). Two main changes, Experimental studies have verified that ScIII–N,N’-dioxide complexes are effective catalysts for BV oxidation reactions affording the corresponding products in good yields (up to 91 %).[19] Importantly, the enantioselectivities of the products could be increased remarkably (up to 95 % ee) by using an ScIII–N,N’-dioxide complex as metal catalyst. To understand the mechanism of the BV oxidation reaction catalyzed by ScIII–N,N’-dioxide complexes and identify the factors that control the enantioselectivity, the BV oxidation reaction between 1 a and m-CPBA was further studied. Considering the key structural characters of 1 a and mCPBA substrates (carbonyl O atom for coordination) and posFigure 2. Structural deformation of three constituent fragments (acid, 1 a, and m-CPBA) in the formation of addisible electrostatic interaction betion transition states in the acid-catalyzed BV oxidation reaction (the situations in m-CBA-TS1 are shown as examtween one OTf counterion and ples). Chem. Eur. J. 2015, 21, 7264 – 7277

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Figure 3. Three kinds of hexacoordinate model ScIII complexes I–III.

the ScIII cation, three possible hexacoordinate ScIII model complexes are proposed (Figure 3). Accordingly, three possible reaction pathways (paths 3–5) starting from hexacoordinate ScIII model complexes I–III were investigated in detail.

of 1 a to the ScIII center to form 3-COM. In 3-COM, the C=O bond of 1 a is activated remarkably by the ScIII center, as is verified by the increase in bond length (from 1.212 æ in free 1 a to 1.244 æ) and the decrease in Wiberg bond index (from 1.826 in free 1 a to 1.518) of the C2¢O1 bond. Next, the oxidant mCPBA enters the reaction system and is fixed by one of the carbonyl O atoms of the N,N’-dioxide ligand by hydrogen bonding to form intermediate 3-IM1. Then, Criegee intermediate 3-IM2 is produced via 3-TS1, in which nucleophilic attack of C=O bond occurs with concomitant proton transfer from the m-CPBA moiety to the carbonyl O1 atom of 1 a. In Criegee intermediate 3-IM2, the dissociating O6¢O7 bond is arranged in an antiperiplanar orientation to the adjacent dissociating C2¢C3 bond with a g3-2-6-7 dihedral angle of ¢173.68.[30] In the following step, the alkyl group migrates from C2 to O6 to form a new C3¢O6 bond. Simultaneously, H5 attached to carbonyl O1 of 1 a transfers to carbonyl O8 of m-CPBA, producing the product complex 3-IM3. Calculations predict the addition step of the C=O bond to be the RDS with an activation barrier of 154.1 kJ mol¢1 (from 3-IM1 to 3-TS1), which is even higher than that of path 2 a (129.1 kJ mol¢1 from the reactants to 2 aTS1) in the absence of the Sc(OTf)3 N,N’-dioxide catalyst and suggests that this reaction is energetically unfavorable. Path 4: both 1 a and m-CPBA coordinate to the ScIII center

On path 4, 1 a and m-CPBA simultaneously coordinate to the ScIII center to form a hexacoordinate ScIII complex (Figure 5). Furthermore, a stepwise (not concerted) rearrangement proIn accordance with the experimental observations, a possible cess of the Criegee intermediate is involved, in which alkyl mireactive species in which an OTf anion is coordinated to the gration from C2 to O6 is followed by proton transfer to release ScIII center has been proposed for reactions catalyzed by an one m-CBA molecule. Sc(OTf)3–N,N’-dioxide catalyst.[31] Then, the remaining vacant The initial coordination of 1 a and m-CPBA to the ScIII center coordinate site of hexacoordinate ScIII complexes would offer takes place with the formation of 4-COM (ScIII-complex-II). The a possible coordination position for activation of the carbonyl C1¢O2 distance in 1 a is elongated by 0.027 æ (from 1.212 æ in substrate. As shown in Figure 4, path 3 starts with coordination free 1 a to 1.239 æ), which is less than that in 3-COM. According to NBO analysis, the net charges on 1 a and m-CPBA are 0.177 and 0.184 e, which indicate charge transfer from the substrates to the framework of the ScIII complex. The resulting significant enhancement of the electrophilicity of the carbonyl compound favors the following addition process of the C=O bond. Then, the C2¢O6 bond in 4-IM1 is formed via concerted four-membered cyclic transition state 4-TS1 with an activation barrier of 200.7 kJ mol¢1 for this step. Starting from Criegee intermediate 4-IM1, alkyl migration and release of mCBA occur through a two-step mechanism: formation of a new O6¢C3 bond followed by H5 transfer from O1 to O8. The activation barrier for the formation of seven-membered cyclic intermediate 4-IM2 via 4-TS2 is predicted to be 54.9 kJ mol¢1. Finally, the proton on the carbonyl O atom of 1 a transfers to m-CBA via 4TS3, generating the product complex 4-IM3 with a low activation barrier (28.2 kJ mol¢1) in this step. The addition step of the C=O bond was also found Figure 4. Energy profile for the BV oxidation reaction between 1 a and m-CPBA catalyzed to be the RDS with an activation barrier of by ScIII–N,N’-dioxide complex along path 3. Path 3: substrate 1 a coordinates to the ScIII center

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Full Paper fers to occur along path 5 rather than along path 2 a. In 5-COM, the C=O bond of 1 a is activated remarkably by the ScIII center, which is verified by the increase in bond length (from 1.212 æ in free 1 a to 1.253 æ) and the decrease of Wiberg bond index (from 1.826 in free 1 a to 1.423) of the C2¢O1 bond. Simultaneously, the O10¢H9 bond of mCPBA is also activated by the hydrogen bonding of m-CBA with the bond length increasing by 0.013 æ. As shown in Figure 6, the whole mechanism includes two steps: the addition step and migration step. The addition step occurs via eight-membered transition state 5-TS1 to form Figure 5. Energy profile for the BV oxidation reaction between 1 a and m-CPBA catalyzed by ScIII–N,N’-dioxide the intermediate 5-IM1. In 5complex along path 4. TS1, the H9 atom attached to the O10 atom of m-CBA transfers to carbonyl O1 of 1 a, while hydroxy H5 of m-CPBA transfers to carbonyl O11 of m-CBA 200.7 kJ mol¢1 (from 4-COM to 4-TS1), which is even higher with concerted formation of a C2¢O6 bond. As a result, the acthan those of the uncatalyzed reaction and path 3 and sugtivation barrier of this step is predicted to be 86.7 kJ mol¢1. In gests that path 4 is impossible. 5-IM1, O10¢H9 and O11¢H5 distances are 1.003 and 0.976 æ, respectively. The dissociating O6¢O7 bond lies nearly in the III Path 5: cooperative effect between the Sc –N,N’-dioxide comsame plane as the C2¢O1 bond of 1 a, with a dihedral angle plex and m-CBA gO1-C2-O6-O7 of 172.68. Isomerization of intermediate 5-IM1 occurs As discussed above, m-CBA can be used as an efficient organowith the formation of Criegee intermediate R-5-IM2, in which catalyst for the BV oxidation reaction between 1 a and mthe dissociating O6¢O7 bond is oriented antiperiplanar to the CPBA. Thus, we wondered whether a cooperative effect exists adjacent dissociating C2¢C3 bond with a gC3-C2-O6-O7 dihedral between ScIII–N,N’-dioxide complex and m-CBA to accelerate the BV oxidation reaction between 1 a and m-CPBA. Considering the possible coordinative interactions between m-CBA and the ScIII center, the mechanism starting from ScIII-complexIII was studied, in which the initial substrate complex is formed by 1 a and m-CBA (not m-CPBA) coordinating to the ScIII center simultaneously. Meanwhile, another substrate m-CPBA is activated by hydrogen bonding of the m-CBA moiety with the formation of 5-COM. The relative energy of 5-COM is 85.7 kJ mol¢1 lower than that of 2 a-IM1, which suggests that it is more possible for 5-COM to form than for 2 a-IM1 in the presence of Figure 6. Energy profile for BV oxidation reaction between 1 a and m-CPBA catalyzed by ScIII–N,N’-dioxide comSc(OTf)3. Thus, the reaction pre- plex along path 5. Chem. Eur. J. 2015, 21, 7264 – 7277

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Full Paper angle of ¢142.58. In the following step, O6 inserts into C2¢C3 bond, forming a seven-membered cyclic product, accompanied by H5 transfer from O1 to O8 and regeneration of the carbonyl C=O bond. The addition step was found to be the RDS with an activation barrier of 86.7 kJ mol¢1. Therefore, bifunctional-catalysis character can be realized by the combination of ScIII–N,N’dioxide complex and m-CBA to form a reactive species. As a result, the activation barrier to generate e-lactones could be significantly decreased. Comparison of the pathway catalyzed by the “bifunctional” catalyst (path 5) and the pathways with only ScIII–N,N’-dioxide complex (paths 3 and 4) or m-CBA (path 2 a) as catalyst

tronic rearrangement also leads to increased polarity of the C= O bond, which could be verified by more positive charges accumulated on the C2 atom (from 0.625 to 0.728–0.748 e). The largest degree of activation of the C=O bond is found in 5COM, which could be verified by the smallest Wiberg index of 1.423. Compared to 4-COM and 5-COM, the weaker activation of the C=O bond of the ketone moiety in 3-COM may be ascribed to the weaker Lewis acidity of its ScIII center, which is caused by coordination of the OTf anion. In addition, structural analysis also indicated that both 3-TS1 and 4-TS1 have a more strained four-membered ring. However, this unfavorable effect could be avoided in 5-TS1 with eight-membered ring, as is also observed in the above-mentioned m-CBA-catalyzed BV oxidation reaction. Therefore, the coordinating m-CBA can help to a construct a suitable hydrogen-bond network and participates in proton transfer by acting as an efficient proton acceptor and donor. Thus, path 5, starting from 5-COM, has the lowest activation barrier (86.7 kJ mol¢1). Energy decomposition analysis (EDA) also helped us to understand the difference in reactivity for the three kinds of hexacoordinate ScIII complexes by comparison of energy contributions of fragments (Table 5).[29] For the most energetically fa-

The energy profiles for BV oxidation reactions catalyzed by ScIII complexes and m-CBA are shown in Figures 4–6 and Figure 1, respectively. Calculations predict the addition step to be the RDS for all four pathways. From the view point of energy, path 5 is more favorable with the lowest activation barrier of 86.7 kJ mol¢1. Although the relative energy of transition state 3-TS1 with the highest potential energy (¢52.1 kJ mol¢1) along path 3 is lower than those of 4-TS1 along path 4 (79.5 kJ mol¢1) or 5-TS1 along path 5 (74.2 kJ mol¢1), the activaTable 5. Energies of activation reaction and their components in the addition step catalyzed by ScIII–N,N’-dioxtion barrier for the key C=O adide complex. All energies are given in kJ mol¢1. dition step from 3-IM1 to 3-IM2 via 3-TS1 is as high as DEint-2 DEint(reaction) DEd of fragments DEd DrE– Reaction DEint-1 154.1 kJ mol¢1 (200.7 kJ mol¢1 for 1a m-CPBA m-CBA Cat.[a] path 4 and 86.7 kJ mol¢1 for 3-IM1!3-TS1 ¢330.4 ¢402.7 ¢72.3 110.2 77.2 – 11.1 198.5 126.2 path 5). Such a high activation 4-COM!4-TS1 ¢529.7 ¢516.8 12.9 95.0 59.8 – ¢7.5 147.3 160.2 5-COM!5-TS1 ¢540.2 ¢635.9 ¢95.7 95.3 61.5 ¢10.4 ¢3.3 143.1 47.4 barrier makes it difficult for the 2 + 3 + BV oxidation reaction to occur [a] Cat. refers to ScL(OTf) or ScL for 3-IM1 or 4-COM and 5-COM, respectively. along path 3 or 4 under the experimental conditions (0 8C).[19] vored path 5, both DEint(reaction) (¢95.7 kJ mol¢1) and DEd To get insight into the differences in reactivity of the three III (143.1 kJ mol¢1) are the lowest among the three paths. During kinds of Sc complexes in BV oxidation reactions, NBO analysis III the formation of 5-TS1, the 1 a and m-CPBA fragments need of the three initial hexacoordinate Sc complexes were perless deformation (deformation energies are 95.3 and formed. The key geometric parameter (C=O bond length of 1 a 61.5 kJ mol¢1 for 1 a and m-CPBA, respectively) for changing substrate) and electronic properties are listed in Table 4. NBO from the geometries in 5-COM to their geometries in 5-TS1. analysis indicates that an orbital interaction exists between the Moreover, the m-CBA and catalyst fragments (Table 5) even lone electron pair of the O1 atom in the carbonyl moiety of 1 a have negative deformation energies. As a result, the addition and the unfilled valence nonbonding orbital of the ScIII cation process of path 5 has the lowest deformation energy DEd of (LPO1!LP*Sc: 88.9 kJ mol¢1 for 3-COM, 149.1 kJ mol¢1 for 4143.1 kJ mol¢1. Besides, the interactions between the m-CBA COM, and 134.7 kJ mol¢1 for 5-COM, respectively). As a result, and 1 a or m-CPBA fragments are enhanced, since the O10¢ 1 a becomes more reactive towards the attack of peracid with H9···O1 and O6¢H5···O11 hydrogen bonds in 5-COM change increasing C=O bond length by about 0.027–0.041 æ. The elecinto covalent interactions in 5-TS1. Simultaneously, a new covalent interaction appears between the C2 and O6 atoms. Table 4. NBO analysis of the three ScIII complexes and the substrate comThese interactions result in the strongest interaction energy of plex in path 2 a and the activation barriers of the addition steps. ¢95.7 kJ mol¢1.[29d] Accordingly, the addition process of path 5 occurs more easily with a gas-phase activation barrier of Species C=O bond Wiberg index Charge Charge Activation 47.4 kJ mol¢1. length [æ] of C=O bond on O1 [e] on C2 [e] barrier [kJ mol¢1] With respect to 3-IM1, the 1 a fragment achieves a relaxed free 1 a 1.212 1.826 ¢0.561 0.625 – geometry on coordinating to the ScIII center, while the m3-COM 1.244 1.518 ¢0.702 0.748 154.1 4-COM 1.239 1.542 ¢0.690 0.728 200.7 CPBA fragment keeps a geometry similar to that of the free m5-COM 1.253 1.423 ¢0.786 0.737 86.7 CPBA molecule. When the addition occurs, these two frag2 a-IM1 1.224 1.720 ¢0.615 0.669 129.1 ments should change their geometries significantly to apChem. Eur. J. 2015, 21, 7264 – 7277

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Full Paper proach each other to achieve the addition process. Accordingly, the deformation energies of 1 a and m-CPBA fragments on path 3 are 14.9 and 15.7 kJ mol¢1 higher than those on path 5. Besides, the enhanced steric hindrance between the OTf anion and m-CPBA fragment results in a positive deformation energy of the catalyst fragment (11.1 kcal mol¢1). As a result, the reaction from 3-IM1 to 3-TS1 has a high deformation energy DEd of 198.5 kJ mol¢1. For path 4, although the change from 4COM to 4-TS1 has a comparable deformation energy to that from 5-COM to 5-TS1, it involves a positive DEint(reaction) (12.9 kJ mol¢1). As a result, the gas-phase activation barrier is as high as 160.2 kJ mol¢1. Therefore, the strong interactions between the four fragments and their suitable orientation in 5COM, which is constructed in the presence of an m-CBA molecule, contribute to the lower activation barrier of the carbonyl addition step on path 5 compared to path 3 or path 4. Furthermore, the pathway catalyzed by the “bifunctional” catalyst (path 5) and the pathway with only m-CBA as catalyst (path 2 a) were compared. As discussed above, the reaction process of path 5 is analogous to that of path 2 a, with the difference being the coordination of 1 a and m-CBA to the ScIII center of the ScIII–N,N’-dioxide complex catalyst. As shown in Table 4, the carbonyl group of 1 a in 5-COM is more strongly activated by the Lewis acidic ScIII center than that in 2 a-IM1 by the m-CBA molecule through hydrogen bonding (the C=O bond lengths of 5-COM and 2 a-IM1 are 1.253 and 1.224 æ, respectively). Compared to path 2 a the O¢H bond length of the oxidant m-CPBA molecule in 5-COM is longer (1.002 in 5-COM versus 0.991 æ in 2 a-IM1), which also suggests stronger activation of m-CPBA. Accordingly, the activation barrier of the addition step (the RDS) of path 5 is 42.4 kJ mol¢1 lower than that of path 2 a. Besides, ESI mass spectroscopy was employed to survey possible reactive species in the BV oxidation reaction catalyzed by the ScIII–N,N’-dioxide complex (Figure 7 and Figures S4–S6 in the Supporting Information). These results indicate that, in the presence of substrate 1 a, one of the OTf anions dissociates +Sc3 + +2 ¢OTf] + (m/z = 1127.4475, calcd: from the complex [L+ +Sc3 + +¢OTf]2 + (m/z = 489.2254, 1127.4461) to give complex [L+ calcd: 489.2468). As expected, a new peak corresponding to +Sc3 + +m-CBA¢]2 + (m/z = 492.2610, calcd: the complex [L+ 492.2658) was detected when peracid m-CPBA was added to the reaction system.[32] Thus, m-CBA can coordinate to the Sc center by replacing one OTf anion to form a reactive ScIII complex intermediate. Therefore, ESI-MS experiments support our theoretical prediction of the reactive species (ScIII-complex-III in Figure 3). Path 5 is the most likely pathway for the BV oxidation reaction between 1 a and m-CPBA by a bifunctional catalysis mechanism catalyzed by the ScIII–N,N’-dioxide complex. In summary, the combination of ScIII–N,N’-dioxide-complex and m-CBA can form a reactive species that shows bifunctional catalytic character and can effectively catalyze the BV oxidation reaction between 1 a and m-CPBA with a reasonable activation barrier of 86.7 kJ mol¢1. The Lewis acidic ScIII center plays an important role in the activation of the carbonyl group of 1 a, and the m-CBA moiety transfers a proton by simultaneously constructing a suitable hydrogen-bonding network. Chem. Eur. J. 2015, 21, 7264 – 7277

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Figure 7. ESI mass spectra in positive-ion mode for a) the 1:1 [L/Sc(OTf)3]:1 a mixture and b) the reaction system. The reactions were performed with L/ metal (5 mol %) and 1 a (0.10 mmol) in EtOAc (0.5 mL) at 35 8C for 30 min followed by addition of m-CPBA (0.12 mmol) at 0 8C with a reaction time of +Sc3 + +2 ¢OTf] + (m/z = 1127.4475, calcd: 1127.4461); 6 h. HRMS: [L+ +Sc3 + +¢OTf+ +m[L + Sc3 + + ¢OTf]2 + (m/z = 489.2254, calcd: 489.2468); [L+ +Sc3 + +m-CBA¢]2 + (m/ CBA¢] + (m/z = 1133.4995, calcd: 1133.4840); [L+ z = 492.2610, calcd: 492.2658).

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transition state of R-5-TS2, which places the large substituent (m-chlorophenyl) attached to the C=O bond of the deprotonated m-CPBA moiety away from the bulky 2,4,6-iPr3C6H2 group of the N,N’-dioxide ligand, would produce the predominant R product. These results are qualitatively in agreement with the experimental observations.[19]

Alkyl migration is predicated to be the stereocontrolling step for the overall asymmetric BV oxidation reaction, and two optically active e-lactones with R or S configuration can be produced in the final ring-expansion step. Hence, the origin of enantioselectivity of the BV oxidation reaction catalyzed by ScIII–N,N’dioxide complexes along path 5 was further studied. Once intermediate 5-IM1 is formed, two possible Criegee intermediates, R-5-IM2 and S-5-IM2, can be generated by rotating the O6¢ O7 single bond about the O6¢ C2 axis. Accordingly, the deprotonated m-CPBA fragment is reoriented with a dihedral angle gC3-C2-O6-O7 of ¢142.58 for R-5-IM2 and 45.18 for S-5-IM2. Then, insertion of the O6 atom into the C2¢C3 or C2¢C4 bond affords elactones with R or S configuration via transition state R-5-TS2 (path 5 a) or S-5-TS2 (path 5 b), respectively (Figure 8). For R-5TS2, the O6 atom in the deprotonated m-CPBA moiety gets closer to the dissociating C2¢C3 bond of the protonated 1 a moiety, with O6···C2 and O6···C3 distances of 1.351 and 2.174 æ, respectively. The sterically demanding m-chlorophenyl group attached to the C13=O8 bond is placed away from the bulky 2,4,6-iPr3C6H2 group of the N,N’dioxide ligand to avoid steric interaction. Furthermore, the mchlorophenyl group of the mCBA moiety is forced to tilt below the pseudoplane of the octahedron to minimize steric hindrance. However, S-5-TS2 suf- Figure 8. Structures of the intermediates and transition states for the two competing migration processes. fers remarkable repulsion between the 2,4,6-substituted phenyl group of the amide in the N,N’-dioxide ligand and the An EDA analysis also provided more insight into the origin m-chlorophenyl group of the deprotonated m-CPBA moiety. of the energy differences between the two competing transiMoreover, the approaching O6 atom forces the phenyl ring in tion states (R-5-TS2 and S-5-TS2). As shown in Table 6, the inprotonated 1 a to be close to the bulky five-membered ring of teraction energies corresponding to migration of the two alkyl the amino acid skeleton of the N,N’-dioxide ligand by rotation groups are ¢392.1 and ¢393.1 kJ mol¢1, respectively, which about the O1¢C2 single-bond axis in protonated 1 a, which suggests that the interactions between the four fragments are may further reduce its stabilization. Consequently, the relative comparable when the transition states are formed. The differenergy of S-5-TS2 is 20.5 kJ mol¢1 higher than that of R-5-TS2. ences in the activation barriers DrE– mainly come from the deformation energy of the protonated 1 a fragment (334.6 versus Therefore, it is reasonable to consider that the more favorable Chem. Eur. J. 2015, 21, 7264 – 7277

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Full Paper tween L1-R-5-TS2 and L1-S-5TS2 (20.5 kJ mol¢1). This result is in agreement with the experiReaction DEint-1 DEint-2 DEint(reaction) DEd of fragments DEd DrE– mental observations that a slight protonated deprotonated m-CBA ScL3 + superiority of L1 (88 % ee for L11a m-CPBA Sc(OTf)3 system and 86 % ee for 5-IM1!R-5-TS2 ¢796.9 ¢1189.0 ¢392.1 334.6 94.6 ¢15.0 39.1 453.3 61.1 L2–Sc(OTf)3 system) is ach5-IM1!S-5-TS2 ¢796.9 ¢1190.0 ¢393.1 345.6 96.2 ¢15.2 49.1 475.7 82.6 ieved.[19] Next, the effects of different substituents (2,4,6-iPr3C6H2 and C6H5) on the amide moiety were compared (L2 versus L3). The difference in relative ener345.6 kJ mol¢1) and the catalyst fragment (39.1 versus gies between the two competing transition states 49.1 kJ mol¢1). The significant structural change of the latter is (39.1 kJ mol¢1 for L3-R-5-TS2 versus 35.2 kJ mol¢1 for L3-S-5reflected by the larger q19-20-21 angle (Scheme 4) of the N,N’-diTS2) is only ¢3.9 kJ mol¢1, which suggests that racemic prodoxide ligand in S-5-TS2 (126.28 in R-5-TS2 versus 130.08 in S-5TS2). Besides, the rotation of the O6¢O7 bond results in more ucts could be obtained. Structural analysis indicates a conjugadramatic structural change of the protonated 1 a fragment, estive character between one of the carbonyl groups and the pecially from 5-IM1 to S-5-TS2 (345.6 kJ mol¢1), which is also planar phenyl substituent on the amide moiety of the N,N’-dioxide ligand in both L3-R-5-TS2 and L3-S-5-TS2 when the substituents in the 2,4,6-positions of the phenyl group are removed. The dihedral angles gC14-C15-N16-C17 and gC15-N16-C17-C18 in L3-R-5-TS2 (Scheme 4) are ¢5.0 and ¢24.988, respectively. This particular orientation leaves enough space for the phenyl ring in the protonated 1 a moiety to move away from the amino acid skeleton, which decreases the steric hindrance between the phenyl ring in the protonated 1 a moiety and the amino acid skeleton of the N,N’-dioxide ligand. Besides, the orientation of the protonated 1 a moiety forces the deprotonated mCPBA moiety be close to the phenyl group of the N,N’-dioxide ligand, and this clearly results in a p–p interaction between the m-chlorophenyl group of the deprotonated m-CPBA Scheme 4. Transition state L1-R-5-TS2 and the N,N’-dioxide ligands considmoiety and the phenyl substituents of the N,N’-dioxide ligand ered. in L3-S-5-TS2. However, this p–p interaction is not observed in L3-R-5-TS2, because the deprotonated m-CPBA moiety in L3R-5-TS2 is far from the phenyl group of the N,N’-dioxide responsible for the higher activation barrier of the process ligand. As a result, the difference in activation barrier decreases from 5-IM1 to S-5-TS2. from 20.5 kJ mol¢1 in L1 to ¢3.9 kJ mol¢1, which is consistent To further evaluate the steric effect of the N,N’-dioxide ligand on the enantioselectivity of the asymmetric BV oxidation with the decrease in the experimental ee value (from 88 % for reaction, two more N,N’-dioxide ligands (L2 and L3) with differL1 to 0 % for L3). Thus, the substituents on the amide moiety ent amino acid skeletons (L1 versus L2) or different substituand the amino acid skeleton of the N,N’-dioxide ligand can ents on amide moiety (L2 versus L3) were considered help to construct a suitable chiral environment by adjusting (Scheme 4). The relative energies of the competing transition the orientation of the protonated 1 a moiety and deprotonated states in the alkyl migration step are listed in Table 7. Firstly, m-CPBA moiety through repulsion between the m-chlorophenthe effect of different amino acid skeletons (L1 derived from (S)-ramipril versus L2 derived from (S)-piTable 7. Relative energies [kJ mol¢1] of the competing transition states in the stereopecolic acid) was investigated. When the bulky fivecontrolling migration step and the ee values [%] obtained by experimental investigamembered ring of the amino acid skeleton in L1 is tion.[19] replaced by a single six-membered ring (L2), the relaAmino acid Substituent on Species DG– Product DDG–[a] Exptl ee tive energies of the competing transition states are skeleton amide moiety conf. 47.0 (L2-R-5-TS2) and 65.2 kJ mol¢1 (L2-S-5-TS2), and L1-R-5-TS2 58.4 R derived from hence the product with R configuration is predomi20.5 88 2,4,6-iPr3C6H2 L1-S-5-TS2 78.9 S (S)-ramipril nant. The steric hindrance between the phenyl group of the protonated 1 a moiety and the amino acid L2-R-5-TS2 47.0 R 18.2 86 2,4,6-iPr3C6H2 L2-S-5-TS2 65.2 S skeleton of the N,N’-dioxide ligand decreases when derived from N,N’-dioxide ligand L2 (with smaller amino acid skele(S)-pipecolic acid L3-R-5-TS2 39.1 R ¢3.9 0 C6 H 5 ton) is used, and this results in a smaller energy difL3-S-5-TS2 35.2 S ference between L2-R-5-TS2 and L2-S-5-TS2 of [a] The energies of the transition states generating R product were set to zero. 18.2 kJ mol¢1, which is slightly smaller than that beTable 6. Energies of activation reactions and their components in the migration step catalyzed by ScIII–N,N’-dioxide complex. All energies are given in kJ mol¢1.

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Full Paper yl group of deprotonated m-CPBA and the 2,4,6-iPr3C6H2 group of the N,N’-dioxide ligand, as well as steric hindrance between the phenyl group of protonated 1 a and the chiral amino acid skeleton of the N,N’-dioxide ligand, which plays an important role in the enantioselectivity of the BV oxidation reaction. In addition, the influence of the substituent at the 4-position of the cyclohexanone substrate on enantioselectivity was also explored by investigating the asymmetric BV oxidation reaction between 4-methyl-substituted cyclohexanones and m-CPBA catalyzed by L1-ScIII-complex. As expected, the difference in the relative energy between Me-R-5-TS2 (60.2 kJ mol¢1) and Me-S-5-TS2 (78.0 kJ mol¢1) is 17.8 kJ mol¢1, which is smaller than that between the corresponding transition states for 1 a (20.5 kJ mol¢1) with a bulkier phenyl group at the 4-position. This result is in agreement with the decrease in experimental ee value (from 88 % for 1 a to 84 %). Thus, the enantiocontrol of the reaction is sensitive to the steric hindrance between the substituent at the 4-position of the cyclohexanone and the amino acid skeleton of the N,N’-dioxide ligand, which is consistent with the experimental observation that the enantioselectivity increased gradually with increasing steric hindrance of the alkyl group in the 4-position.[19] In summary, the steric nature of the catalyst has a critical effect on the migratory aptitude. Both the substituents on the amide moiety (R) and the amino acid skeleton of the N,N’-dioxide ligand may play important roles in the construction of a suitable chiral environment for asymmetric catalysis. Importantly, the enantiocontrol of the reaction is sensitive to substituents at the aniline moiety. In addition, steric repulsion between the substituent in the 4-position of the cyclohexanone substrate and the amino acid skeleton also exerts a great effect on the enantioselectivity of the reaction.

2) The combination of ScIII–N,N’-dioxide complex and m-CBA can form a reactive species that can effectively catalyze the BV oxidation reaction between 1 a and m-CPBA with a reasonable activation barrier of 86.7 kJ mol¢1. The Lewis acidic ScIII center activates the carbonyl group of 1 a, while the mCBA moiety participates in the proton-transfer process by constructing a suitable hydrogen-bond net. The putative ScIII–N,N’-dioxide reactive intermediate with bifunctionalcatalysis character is also supported by the ESI-MS results. 3) The repulsion between the m-chlorophenyl group of mCPBA and the 2,4,6-iPr3C6H2 group of the N,N’-dioxide ligand and steric hindrance between the phenyl group of 1 a and the amino acid skeleton of the N,N’-dioxide ligand play important roles in the control of the enantioselectivity and lead to predominant formation of the R product. These results are in good agreement with experimental observations.

Computational Details All calculations were performed with Gaussian 09.[20] Considering the computational cost, the ONIOM[21] method was used in the geometrical optimization. The high and low layers of the ONIOM scheme are depicted in Scheme 5. The core region was treated with the M06[22] functional and 6-31G(d) basis set.[23] The low layer was optimized at the HF/STO-3G level. The bonds between atoms in the core and the outer layers were broken and saturated with hydrogen atoms (link atoms) for the higher level part of the ONIOM calculations on the core system. Frequency calculations at the same level of theory were performed to identify all the stationary points as minima (zero imaginary frequency) or transition

Conclusion DFT and ONIOM investigations of the mechanism and enantioselectivity of the asymmetric Baeyer–Villiger oxidation reaction between 4-phenylcyclohexanone (1 a) and m-chloroperoxobenzoic acid (m-CPBA) catalyzed by ScIII–N,N’-dioxide complexes revealed the followings: 1) The addition step, corresponding to the addition of mCPBA to the carbonyl group of 1 a, is predicted to be the RDS of the uncatalyzed BV oxidation reaction with an activation barrier of 189.8 kJ mol¢1. The m-CBA molecule could serve as an efficient organocatalyst by participating in proton transfer (as a proton acceptor and donor), lowering the activation barrier of the addition step (RDS) to 129.1 kJ mol¢1. The acidity of the acid catalyst may has a great effect on the activation barrier of the addition step of the C=O bond. The deformation of the acid fragment and the m-CPBA fragment contribute much to the activation barrier of the addition step of the C=O bond. The deformation energy term exhibits a good linear correlation with some structural parameters (changes in selected bond lengths and angles) in the addition process. Chem. Eur. J. 2015, 21, 7264 – 7277

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Scheme 5. Layering of the ScIII–N,N’-dioxide complex in ONIOM calculations.

states (one imaginary frequency). An intrinsic reaction coordinate (IRC)[24] calculation was performed to further confirm that the optimized transition states correctly connected the relevant reactants and intermediates (or products). The theoretical level used in the present work was found to reproduce the crystal structure well at an acceptable computational cost (see Supporting Information, Figure S1 and Table S1). The effect of solvent on the reaction was further considered by employing the self-consistent reaction field (SCRF) method based on the polarized continuum model (PCM)[25] and SMD solvation model.[26] The Gibbs free energies of all intermediates and transition states in ethyl ethanoate solvent (e = 5.99) were obtained by single-point energy calculations at the M06/6-31G(d,p) level of theory at 273 K (corrected by zero-point effect), based on gasphase optimized geometries (method I). To obtain more accurate relative energies in solvent, the key intermediates and transition states involved in the RDS and stereocontrolling step of the reaction were reoptimized in ethyl ethanoate solvent at the

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Full Paper ONIOM[M06/6-31G(d):HF/STO-3G] level. Furthermore, the corresponding Gibbs free energies were re-evaluated by single-point energy calculations at the M06/6-31G(d,p) level of theory for comparison (method II). Calculations indicated that, although the relative energies obtained by using method II are lower than those calculated by method I (Tables S2–S4 in the Supporting Information), the same tendency in energy profiles was found. Therefore, unless otherwise specified, the Gibbs free energies calculated by method I were used in the discussion. (NBO[27] analysis was performed at the M06/6-31G(d,p) level to obtain further insight into the electronic properties of the system. To gain insight into the influence of acidity of an acid on reaction mechanism and reactivity, the gas-phase PA[28] was calculated as the negative molar enthalpy of Equation (1) at 298.15 K [Eq. (2)]

quency calculations at the M06/6-31G(d,p) level of theory on the geometries optimized in gas phase.

Acknowledgements We thank the National Natural Science Foundation of China (Nos. 21290182, 21102096, and 21321061) and Program for New Century Excellent Talents in University of China (No. NCET-13-0390) for financial support. Keywords: density functional calculations · enantioselectivity · oxidation · reaction mechanisms · scandium

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RCOO¢ ðgÞ þ Hþ ðgÞ ! RCOOHðgÞ

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