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Article Cite This: J. Org. Chem. 2018, 83, 7825−7835

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Dinuclear Tricyclic Transition State Model for Carbonyl Addition of Organotitanium Reagents: DFT Study on the Activity and Enantioselectivity of BINOLate Titanium Catalysts Toshiro Harada* Faculty of Molecular Chemistry and Engineering, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan

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S Supporting Information *

ABSTRACT: In the presence of a catalytic amount of chiral BINOL derivatives (or BINOLs), a mixture of various organometallic compounds with Ti(OiPr)4 undergoes enantioselective addition to aldehydes and ketones. Although the catalyst and reacting nucleophile of the reaction have been elucidated to be (BINOLate)Ti2(OiPr)6 and RTi(OiPr)3, respectively, little is known about the properties of short-lived intermediates and transition structures. In this work, the mechanism of this reaction is investigated with the aid of DFT (M06) calculations. The study provides support for the following mechanistic understandings: (i) The direct racemic reaction proceeds through a pathway involving initial aggregation of RTi(OiPr)3 with Ti(OiPr)4 followed by carbonyl addition of the resulting dinuclear aggregate. (ii) The enantioselective reaction takes place through a pathway involving initial ligand exchange of RTi(OiPr)3 with (BINOLate)Ti2(OiPr)6 followed by the addition of the resulting chiral dinuclear titanium species via a chiral BINOLate-chelated, tricyclic transition structure. (iii) The enantioselective pathway is favorable not because BINOLate ligands accelerate the carbonyl addition but because the ligands stabilize the chiral dinuclear species against deaggregation through a chelating bridge. (iv) The chiral transition structure serves as a model accounting for the re-face addition generally observed in the reaction of aldehydes with (R)-BINOLs.

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INTRODUCTION Catalytic enantioselective carbonyl addition of organometallic reagents has attracted great interest for its synthetic utility as a fundamental method for constructing chiral molecular frameworks.1−9 Of various approaches developed so far, chiral titanium catalysis derived from BINOL and H8−BINOL derivatives (BINOLs),10,11 such as 1a−c and 2a−c, have contributed significantly in expanding the scope of the reaction with respect to carbonyl substrates and organometallic reagents (Scheme 1). Not only aldehydes but also ketones undergo enantioselective addition with the BINOL-derived titanium catalyst system as illustrated in representative reactions in Table 1. With the BINOL catalyst system, enantioselective alkylation, arylation (including heteroarylation), and vinylation have been realized through the use of a variety of readily available organometallic reagents, such as organozinc,12−17 -boron,18−20 -aluminum,21−27 -magnesium,28−33 and -titanium reagents.34−39 Despite such diversity, several common features are found in these reactions. First, enantiofacial selectivity is governed solely by the absolute configuration of the axially chiral ligands irrespective of organometallic nucleophiles employed. Aldehydes always undergo selective re- and si-face addition with (R)and (S)-BINOLs, respectively.40 Interestingly, the opposite selectivity is observed for ketones. Ketones undergo si- and reface addition with the (R)- and (S)-ligands, respectively. Second, reactions are generally carried out with more than a © 2018 American Chemical Society

stoichiometric amount of a titanium alkoxide, specifically Ti(OiPr)4, except those with organotitanium reagents (Table 1). It has been revealed that Ti(OiPr)4 plays a dual role in generation of a dinuclear titanium complex 3, as a chiral catalyst, through ligand exchange (eq 1)41−46 and in formation

of organotitanium reagent RTi(OiPr)3 (4), as a reacting species, through transmetalation (eq 2).[47,42,22] Third, the reactions exhibit high enantioselectivity (typically >90% ee), although the organotitanium reagent 4 is known to undergo facile addition to aldehydes without the aid of catalysis.48,49,38 It should be Received: March 21, 2018 Published: May 25, 2018 7825

DOI: 10.1021/acs.joc.8b00712 J. Org. Chem. 2018, 83, 7825−7835

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The Journal of Organic Chemistry

enhanced by the use of BINOL 1b,c and 2b,c, bearing a sterically demanding aryl group at the 3-position of parent BINOL (1a) and H8−BINOL (2a), respectively.54 The enhanced activity of the resulting catalysts enabled us to expand the scope of organometallic nucleophiles (entries 5, 6, 9, 10, and 12 in Table 1) and reduce the amount the chiral ligands to a practical level (0.25−2 mol %) keeping high enantioselectivity and short reaction time (typically 2−3 h) (entries 4, 10, 12, 15, and 19). Although catalysts derived from parent ligands 1a and 2a exhibit high enantioselective at higher catalyst loadings (10−20 mol %), reduction in the amount of the catalysts significantly degrades the enantioselectivity owing to the concurrent direct addition of the nucleophiles leading to racemic products. The 3-substituted BINOL-derived catalysts, on the other hand, is of high turnover frequency, overwhelming the direct racemic reaction,55 thus exhibiting high activity at the low catalyst loadings. Because of the synthetic versatility and high activity, studies have been carried out toward the elucidation of the mechanism of the enantioselective carbonyl addition catalyzed by BINOLderived chiral titanium complexes.36,41−44 Although the previous studies have provided valuable information on the solution structures and fluxional equilibrium of catalytically relevant species (vide inf ra), little is known about the properties of experimentally inaccessible short-lived intermediates and transition structures.56 In this work, we have performed density functional theory (DFT) calculations to shed light on the nature of catalysis by BINOL-derived chiral titanium complexes, from which we expected to answer (1) what the detailed mechanism of the direct racemic reaction is, (2) what the detailed mechanism of the catalytic enantioselective reaction is, (3) why the catalytic pathway is favorable relative to the direct pathway, and (4) what the transition structure model rationalizing observed

Scheme 1. Enantioselective Carbonyl Addition of Organometallic Reagents Catalyzed by Chiral Titanium Complexes Derived from BINOLs

noted that such a feature is uncommon in other catalytic enantioselective carbonyl addition reactions, in which non- or less-reactive organometallic reagents are employed as the nucleophiles50−52 with the aid of ligand accelerated catalysis.53 Recent reports from this laboratory revealed that the catalytic activity of the chiral titanium complexes is remarkably

Table 1. Representative Examples of Enantioselective Carbonyl Addition Catalyzed by BINOL-Derived Chiral Titanium Complexes entry addition to aldehydes (Scheme 1a) 1 2 3 4 5b 6 7 8 9 10 11b 12 13 14 15 addition to ketones (Scheme 1b) 16 17 18 19

RM Et2Zn

RZnBr (R = alkyl) RBR’2, (R = alkyl, vinyl) Et3Al Ar3Al RAlMe2 (R = vinyl) RMgX (R = alkyl) ArMgBr RTi(OiPr)3 (R = alkyl) ArTi(OiPr)3

Ar3Al RAliBu2 (R = vinyl) ArTi(OiPr)3

(equiv)

Ti(OiPr)4 (equiv)

BINOLs

mol %

selectivitya

3.0 3.0 3.0 3.0 2.7 1.5 3.0 1.2 3.0 2.2 2.0 1.2 1.2−2.0 1.2 1.5

1.4 1.4 1.4 1.4 7.2 3.0 1.2 1.3 3.0 5.8 0.9−1.4 3.0 0−2.0 0 0−0.2

1a 2a 1b 2b 2b 2b 2a 2a 2b 1b 1a 2b 1a 2a 2c

20 20 0.5 2 5 5 20 10 5 2 15−20 2 10 3−10 0.25

re re re re re re re re re re re re re re re

12 14 15 16 18 19 21 22 26 28 30 29 35 34 38

2.5 1.6 1.5 1.5

5.0 3.0 0.3 0

1a 1a 1a 1c

10 10 10 2

si si si si

23 25 36 39

a

Enantiofacial selectivity of the carbonyl compounds when (R)-BINOLs are used. dimethylamino)ethyl]ether was used as an additive. 7826

b

MgBr2 was used as an additive.

ref

b

and 13

and 20

and and and and

27 31 32 32

Bis[2-(N,N′-


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The Journal of Organic Chemistry enantioselectivity of the BINOL-derived catalysts is. The study have revealed a novel dinuclear tricyclic transition structure, which provides a critical basis in considering the above questions (Scheme 2).

were performed by the NBO program69 using the wave function obtained from the M06/BS1 level in CH2Cl2 with the SMD model. The 3D structures were prepared using CYLview.70

Scheme 2. Dinuclear Transition Structures for Carbonyl Addition of Organometallic Nucleophiles

RESULTS AND DISCUSSION Model Reaction of Formaldehyde with MeTi(OMe)3 (5a) and MeTi2(OMe)7 (6a). In our computational modeling, methylation of formaldehyde with mononuclear MeTi(OMe)3 (5a) was examined first. The calculations show that the reaction starts with initial coordination of the carbonyl oxygen atom to the titanium center of 5a to form association complex AC-5a with a pseudotrigonal-bipyramidal titanium center, followed by methyl addition to give product alkoxide P-5a via fourmembered transition structure TS-5a (Figure 1). The Gibbs free energy change (ΔG) of the association step is +4.6 kcal/ mol, in accord with lower Lewis acidity of titanium alkoxides.49d A free energy barrier for this pathway is +16.7 kcal/mol and overall reaction is significantly exergonic (−38.0 kcal/mol). The participation of dimeric species in the carbonyl addition of Grignard reagents and organolithium reagents has been demonstrated experimentally.71,72 Recent theoretical computational studies have revealed that these reactions, as well as the reaction of bimetallic organozincates (R3ZnLi), proceeds via a ladderlike transition state (Scheme 2).73−75 Considering the tendency of titanium alkoxides to form aggregate complexes,76−80 the reaction of formaldehyde with dinuclear MeTi2(OMe)7 (6a) was also chosen as a model reaction. Dinuclear aggregate complex 6a is calculated to be thermodynamically stable, requiring +11.8 kcal/mol free energy for deaggregation to give mononuclear 5a and Ti(OMe)4 (Figure 1). The two titanium centers of 6a are both pentacoordinated pseudotrigonal-bipyramidal, in which each μ-oxo bridge takes an apical and an equatorial position of one and the other titanium atom, respectively (Figure 2). This structure is generally found in the X-ray structural analysis of relevant dinuclear titanium alkoxide complexes.35,42,79−84 The reaction

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COMPUTATIONAL DETAILS The quantum chemical calculations were carried out with the Gaussian 0957 program package. Geometry optimizations and frequency calculations were performed at the M0658,59/BS1 level in CH2Cl2 using the SMD solvation model.60 BS1 designates a mixed basis set of LANL2DZ61,62 for the titanium atom and 6-31G(d)63 for other atoms. The results of frequency calculations were examined to confirm that each structure is a local minimum (no imaginary frequency) or a transition state (only one imaginary frequency). Thermodynamic corrections at 273.15 K (0 °C, the temperature frequently employed in the catalytic enantioselective addition) and 1 atm in CH2Cl2 were obtained at the M06/BS1 level. Considering from the size of molecules (up to 99 atoms), Grimme’s quasi-harmonic approximations (QHAs)64−66 were applied with the frequency cutoff value of 100 cm−1 to correct the effect of small frequency vibrational modes. The translational entropy in dichloromethane was evaluated by applying the Whitesides method,67 where the volume of a dichloromethane molecule and the density of dichloromethane solvent were taken as 56.6 Å3 and 1.3266 g/ cm3, respectively.68 Natural bond order (NBO) calculations

Figure 1. Calculated energy profile for the addition of MeTi(OMe)3 (5a) and MeTi2(OMe)7 (6a) to formaldehyde. The relative Gibbs and zeropoint corrected potential energy (in parentheses) obtained from the M06/BS1 calculations in CH2Cl2 (SMD) are given in kcal/mol. 7827


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Figure 2. Calculated structures of titanium complexes and key intermediates in the methylation of formaldehydes with 5a and 6a with distance in angstrom and NBO charges in parentheses.

of formaldehyde with 6a first forms association complex AC-6a with the free energy change of +2.1 kcal/mol. The value is smaller than that of AC-5a (+4.6 kcal/mol), suggesting higher Lewis acidity of 6a. Ti2 of AC-6a is hexa-coordinated pseudooctahedral, coordinated to the oxygen lone pair of the aldehyde in the carbonyl plane. The C−C bond formation occurs as the carbonyl carbon attached to Ti2 approaches the methyl group on Ti1 through a characteristic transition structure TS-6a, in which the carbonyl oxygen interacts simultaneously with Ti2 and Ti1 in the direction coplanar and perpendicular to the carbonyl plane, respectively.85 As Ti1 and Ti2 are also bridged by the two μ-oxo oxygen atoms, O3 and O4, TS-6a has a tricyclic structure. Both Ti1 and Ti2 centers are hexacoordinated pseudo-octahedral, where Ti1−O3−O4 plane and Ti2−O3−O4 plane are not coplanar, bending about 38°. All attempts to locate a ladderlike transition state in which carbonyl oxygen atom interacts with a single titanium center resulted in a change of the geometry to generate TS-6a with a simultaneous interaction with the two titanium centers. TS-6a is located +9.0 kcal/mol in free energy above the reactants (6a and formaldehyde). The value is significantly smaller than that of monocyclic transition structure TS-5a, indicating that the reaction pathway involving dinuclear aggregate 6a is preferable at least for the model reaction of the methoxy derivatives. The pathway via TS-6a leads to the formation of dinuclear product complex P-6a with high free energy gain (−37.8 kcal/mol). In the transition structure TS-5a and TS-6a, the CH3−Ti bond length is elongated 6.0% and 5.3%, respectively, as compared with the corresponding association complexes (Figure 2). The extent of bond elongation is considerably smaller than a value (21%) reported for the addition of Me3ZnLi to formaldehyde via a ladderlike transition state.75 In addition, the forming C−C bond lengths are relatively long in the transition structures (2.355 and 2.377 Å for TS-5a and TS6a, respectively).86 Furthermore, the natural bond orbital (NBO) charge change of the methyl carbon atom is very small from AC-5a to TS-5a (−1.035 → −1.017) and almost zero from AC-6a to TS-6a (−0.993 → −0.994), showing that the additional charge separation is not required in the transition states for the C−C bond formation. All these results, together with high exergonicity of the reactions, indicate that TS-5a and

TS-6a lay early on the C−C bond forming step. The positive charge on the carbonyl carbon is decreased from the associate complexes to the transition structures. In accord with the lower free energy barrier, the charge change of the process for 6a (+0.321 → + 0.250) is smaller than that for 5a (+0.317 → +0.219), implying that TS-6a is even earlier than TS-5a. Model Reaction of Formaldehyde with MeTi(OiPr)3 (5b), MeTi2(OiPr)7 (6b), and Me((R)-BINOLate)Ti2(OiPr)5 (7b). Previous studies on the structure of titanium alkoxides Ti(OR)4 have shown the formation of polynuclear aggregates [Ti(OR)4]n in solution, where n, or an association number, depends on the size of the alkoxy group.76−78 The titanium alkoxide aggregates undergo rapid ligand exchange to form fluxional mixture of several species.87,88 The mean value of the association number n of the mixture in benzene is about 3 for Ti(OR)4 (R = Et, Pr, Bu) and that for sterically demanding Ti(OiPr)4 is close to 1.89 On the other hand, a dinuclear aggregate structure is highly favorable for titanium complexes derived from BINOLs and Ti(OiPr)4.36,38,41−46,79 Thus, BINOLs react with two equivalent of Ti(OiPr)4 to form dinuclear complex 3 (eq 1), and the reaction of BINOLs and Ti(OiPr)4 in a 1:1 molar ratio results in the formation of dimeric aggregate complex 8 (eq 3). In solution, complex 3 is in

equilibrium with complex 8 and Ti(OiPr)4.41−44 Under the reaction conditions of the catalytic enantioselective carbonyl additions, where Ti(OiPr)4 is employed in large excess with respect to the ligands, the equilibrium of eq 3 is considerably shifted to the right-hand side and dimeric complex 8 is negligible.38 The DFT-calculation of the model reaction showed that the pathway involving MeTi2(OMe)7 (6a), via tricyclic transition structure TS-6a, is energetically more favorable than that involving MeTi(OMe)3 (5a), via four-membered transition structure TS-5a (Figure 1). However, the lower aggregation 7828


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The Journal of Organic Chemistry tendency of sterically demanding Ti(OiPr)4 suggests that the formation of isopropoxy derivative MeTi2(OiPr)7 (6b) from MeTi(OiPr)3 (5b) and Ti(OiPr)4 is unfavorable at equilibrium (eq 4). Accordingly, in considering the real reaction, a lower

amount, could well overwhelm the direct pathway involving 6b, a minor component of the aggregation equilibrium. To test the above hypothesis, the model reaction of formaldehyde with isopropoxy derivative 5b, 6b, and 7b was examined. As there are many conformers (3n; n = 3, 7, and 5 for 5b, 6b, and 7b, respectively) with respect to the isopropyl groups, we did not take a comprehensive approach in calculations but focused on a representative conformer. Although being less quantitative, the approach provided a basis for examining the above hypothesis. Mononuclear reagent 5b reacts with formaldehyde via association complex AC-5b and four-membered transition structure TS-5b with a free energy profile almost similar to that of methoxy derivative 5a (Figures 3, 4, and S-1). The pathway has a free energy barrier of +18.7 kcal/mol. On the other hand, a free energy barrier for the addition of dinuclear reagent 6b via AC-6b and tricyclic transition structure TS-6b is increased by +3.7 kcal/mol in comparison with that of the methoxy derivative 6a, presumably owing to the steric congestion around the isopropyl groups in the transition structure of the two hexa-coordinated pseudo-octahedral titanium centers. However, the free energy barrier of 12.7 kcal/mol is sufficiently lower than that of 5b.90 The addition of dinuclear BINOLate species 7b94 proceeds with initial formation of association complex AC-7b with a free energy loss of +4.7 kcal/mol, followed by tricyclic transition structure TS-7b(a), which is the most probable structure of several other isomeric transition structures rationalizing the experimentally observed enantioselectivity as will be discussed in the next section. The free energy barrier of this pathway (+12.2 kcal/mol) is almost same as that involving 6b, implying that the ligand acceleration is not prominent. Previously, the association number n of MeTi(OiPr)3 (5b) was determined by cryoscopy as 1.12 in benzene (0.026 M).89

concentration of 6b at the equilibrium should be also taken into account. On the other hand, dinuclear BINOLate complex Me((R)-BINOLate)Ti2(OiPr)5 (7b) might be stabilized by virtue of the chelating bridge of the bidentate ligand and not prone to deaggregation (eq 5). Indeed, Ph((S)-BINOLate)Ti2(OiPr)5, a phenyl derivative of 7b, has been prepared by Gau and co-workers by treatment of [((S)-BINOLate)Ti(OiPr)2]2 with PhTi(OiPr)3, and its structure has been determined by Xray crystallography.36 It has been proposed that the chiral dinuclear complex undergoes enantioselective carbonyl addition under the catalytic conditions. The dinuclear BINOLate complex 7b, as a chiral methylation reagent, would undergo enantioselective carbonyl addition via a tricyclic transition structure. Because of the anticipated stability of 7b against deaggregation, a pathway involving 7b, even with a catalytic

Figure 3. Calculated energy profile for the addition of MeTi(OiPr)3 (5b), MeTi2(OiPr)7 (6b), and Me((R)-BINOLate)Ti2(OiPr)5 (7b) to formaldehyde. The relative Gibbs and zero-point corrected potential energy (in parentheses) obtained from the M06/BS1 calculations in CH2Cl2 (SMD) are given in kcal/mol. 7829


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Figure 4. Calculated structures of titanium complexes and key intermediates in the methylation of formaldehydes with 7b.

From this value, it is evaluated that the molar fraction of dimer [MeTi(OiPr)3]2 is 12% and ΔG for the deaggregation is +1.0 kcal/mol at 0 °C. To check the validity of the current DFT method, ΔG for the deaggregation of [MeTi(OiPr)3]2 to give 5b in dichloromethane was calculated using M06/BS1. A free energy change of +2.3 kcal/mol is obtained for this process. Accordingly, the calculated energy is in agreement with the experimentally estimated value while being with some overestimation. A free energy change of +2.7 kcal/mol is obtained for deaggregation of MeTi2(OiPr)7 (6b) to give MeTi(OiPr)3 (5b) and Ti(OiPr)4 (Figure 3). As noted before, the dinuclear aggregate structures are highly stabilized against deaggregation by the μ-oxo bridge of BINOLates (eq 5). Indeed, the calculations showed that deaggregation of Me((R)-BINOLate)Ti2(OiPr)5 (7b) to give mononuclear ((R)-BINOLate)Ti(OiPr)2 (9b) and 5b is highly unfavorable with a free energy of +13.4 kcal/mol. The thermodynamic stability of dinuclear aggregate 7b against deaggregation as well as the free energy profile of the more realistic model reaction of isopropoxy derivatives 5b, 6b, and 7b provides strong support for the hypothesis that rationalizes the preferential catalytic enantioselective reaction overriding the direct racemic reaction. Although the present results indicate that direct racemic reaction proceeds with dinuclear aggregate 6b via TS-6b (Figure 3), kinetic study that supports alternative pathway involving mononuclear transition structure TS-5b has been reported by Reetz and Maus.48 The reaction of heptanal with MeTi(OiPr)3 (5b) in CH2Cl2 exhibited second-order kinetics, first-order in the aldehyde and first-order in 5b. The result led them to conclude that reacting species is not dinuclear aggregate [MeTi(OiPr)3]2 but mononuclear 5b itself. However, the product alkoxide of the reaction, [C6H13(Me)CHO]Ti(OiPr)3, closely resembles Ti(OiPr)4 and hence would undergo aggregation with 5b to form [MeTi(OiPr)3][{C6H13(Me)CHO}Ti(OiPr)3] (6b’). Therefore, the reported kinetics would be also in accord with a pathway involving dinuclear [MeTi(OiPr)3]2 and 6b’ as reacting species, provided that these species have similar reactivity and aggregation tendency. Enantioselectivity. The high enantioselectivity of chiral titanium complexes derived from BINOLs has attracted the elucidation of its origin. There is a common trend in enantioselectivity, that is R ligands preferentially gives the product derived from re-face attack of the aldehydes. The trend implies that there exists a common structure in the transition states.56 To clarify the structure, DFT calculations were carried out for possible isomeric transition structures for a model reaction of formaldehyde with Me((R)-BINOLate)Ti2(OMe)5 (7a). The core skeleton of the tricyclic transition structure (TS-6) is chiral (Scheme 3). Generally, enantioselectivities are higher

Scheme 3. Enantiomeric Core Skeletons of Tricyclic Transition Structure

for aromatic aldehydes (ArCHO) in comparison with sterically less demanding nonbranched aliphatic aldehydes (CH3(CH2)nCHO). When this transition-structure core is applied to the reaction of aldehydes, the carbonyl group, coordinating to Ti2 in a sterically favorable anti-manner, undergoes re-face addition. On the other hand, si-face addition takes place through enantiomeric transition-structure core entTS-6. There are each 11 distinguished cis coordination cites (i.e., a−b, a−c, a−e, a−f, b−c, b−d, b−f, b−g, c−d, c−e, and a− d) in TS-6 and in ent-TS-6 for bidentate ligands. The introduction of axially chiral (R)-BINOLate to TS-6 and entTS-6 at the same cis cites results in the formation a pair of diastereomeric transition structures. Of total 22 candidates of (R)-BINOLate-derived transition structures for the addition of 7a to formaldehyde, six are sterically infeasible. Transition state search for the others gave 16 transition structures TS-7a(a)− TS-7a(p) (Figures 5 and S-2) in increasing order of zero-point corrected potential energy (Table 2). The potential energy differences (ΔE) of these transition structures are within 11.7 kcal/mol (Table 2). There are five relatively low energy structures within an energy window of 3.0 kcal/mol. The most stable transition structure TS-7a(a) is lower in energy than the second stable TS-7a(b) and TS-7a(c) by 0.9 kcal/mol. In TS-7a(a), (R)-BINOLate occupies coordination cite a−e of TS-6. One oxygen atom of the ligand bridges between Ti1 and Ti2 at cite a and another is coordinated to Ti2 at cite e. In the second stable TS-7a(b), (R)-BINOLate takes coordination cite c−e of ent-TS-6, chelating only Ti2 without participating in μ-oxo bridge. Also in TS-7a(c), TS-7a(d) (ΔE = 1.1 kcal/mol), and TS-7a(e) (ΔE = 3.0 kcal/mol), Ti2 is chelated by the ligand at cite d−e of TS-6, at cite d−e of ent-TS-6, and at cite c−e of TS-6, respectively.95 When applied as the transition structure model for the reaction of aldehydes, TS-7a(a), TS-7a(c), and TS7a(e) induce experimentally observed re-face addition. On the other hand TS-7a(b) and TS-7a(d) leads to opposite si-face addition products. In considering the real reaction, the participation of the sterically demanding isopropoxy group in μ-oxo bridge might induce energy increase in transition states. Therefore, the 7830


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Figure 5. Calculated geometries of stable transitions structures in the addition of Me((R)-BINOLate)Ti2(OMe)5 (7a) to formaldehyde. The relative zero-point corrected potential energy (in parentheses) obtained from the M06/BS1 calculations in CH2Cl2 (SMD) is given in kcal/mol.

states. The absolute steric course of the reaction is governed by a match and mismatch between the ligand and the chiral transition-structure core (TS-6 and ent-TS-6). As shown in Scheme 4, TS-6 well matches with (R)-BINOLate to accommodate the ligand at cite a−e without steric constraint. On the other hand, it is sterically infeasible to place (R)BINOLate in ent-TS-6 at the same cite and the pair is mismatched. A matched pair of TS-6 and (R)-BINOLate results in TS-7a(a), through which re face addition of aldehydes might take place.

potential energy of the isopropoxy derivatives are estimated to be increased for TS-7a(b), TS-7a(c), TS-7a(d), and TS-7a(e), with two μ-OMe groups at coordination cites a and e, in comparison to TS-7a(a) with one μ-OMe group. Indeed, potential energy of TS-7b(b) and TS-7b(c) (the isopropoxide derivative of TS-7a(b) and TS-7a(c), respectively) was calculated to be +8.4 and +3.4 kcal/mol relative to TS-7b(a) (the isopropoxide derivative of TS-7a(a)), respectively (Figure 6). Accordingly, TS-7a(a) serves as the most likely transition structure model for the catalytic enantioselective re-face addition to aldehydes. At the present stage, it is difficult to propose a transition structure model for the addition to ketones that exhibit opposite si-facial selectivity. For ketones (RCOR’), TS-7a(a) is incompatible because smaller substituent R′ (e.g., methyl group) on the carbonyl group, syn to the coordinating Ti2, would cause unfavorable interaction with the naphthalene ring of the ligand, while the other four structures are sterically feasible (Figure 5). TS-7a(b) and TS-7a(d) are candidates of the transition structure model for ketones compatible with the observed selectivity. The present study showed that the enantioselectivity is not directly controlled by the unfavorable (or favorable) interaction between the chiral ligand (BINOLs) and substrates in transition

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CONCLUSION The mechanisms for the enantioselective carbonyl addition of organotitanium reagents RTi(OiPr)3 catalyzed by BINOLate titanium complex 3 have been investigated with the aid of DFT (M06) calculations. The study reveals the low-energy, dinuclear tricyclic transition structure for the addition of the organotitanium reagents in aggregate form and provides support for the following mechanistic understanding of the reaction (Scheme 5): (1) The direct racemic reaction of RTi(OiPr)3 proceeds through a pathway involving initial aggregation with Ti(OiPr)4 followed by carbonyl addition of the resulting dinuclear aggregate 10 via tricyclic transition structure TS-11. 7831


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The Journal of Organic Chemistry Table 2. Relative Potential Energy of Transition Structures for the Addition of Me((R)-BINOLate)Ti2(OMe)5 (7a) to Formaldehyde structure

chelating cite

enantiofacial selectivity

ΔEa (kcal/mol)

TS-7a(a) TS-7a(b) TS-7a(c) TS-7a(d) TS-7a(e) TS-7a(f) TS-7a(g) TS-7a(h) TS-7a(i) TS-7a(j) TS-7a(k) TS-7a(l) TS-7a(m) TS-7a(n) TS-7a(o) TS-7a(p)

TS-6; a−e ent-TS-6; c−e TS-6; d−e ent-TS-6; d−e TS-6; c−e ent-TS-6; b−f TS-6; c−d ent-TS-6; b−d TS-6; a−f TS-6; b−g ent-TS-6; c−d ent-TS-6; a−c TS-6; b−c ent-TS-6; f−g TS-6; f−g TS-6; b−d

re si re si re si re si re re si si re si re re

0.0 0.9 0.9 1.1 3.0 3.2 3.2 3.2 3.3 3.7 3.8 4.7 4.8 5.8 8.5 11.7

Scheme 5. Plausible Mechanism for the Enantioselective Carbonyl Addition of Organotitanium Reagents Catalyzed by BINOLate Titanium Complexes

a

The relative zero-point corrected potential energy obtained from the M06/BS1 calculations in CH2Cl2 (SMD).

Figure 6. Calculated geometries of transitions structure TS-7b(b) and TS-7b(c) in the addition of Me((R)-BINOLate)Ti2(OiPr)5 (7b) to formaldehyde. The zero-point corrected potential energy (in parentheses) relative to that of TS-7b(a) obtained from the M06/ BS1 calculations in CH2Cl2 (SMD) is given in kcal/mol.

Scheme 4. Match and Mismatch in Chiral Ligand and Transition Structure Core of 10. (4) Chiral transition structure TS-13 serves as a model accounting for the re-face addition commonly observed in the reaction of aldehydes with (R)-BINOLs.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00712. Calculated structures of titanium complexes and key intermediates in the methylation of formaldehydes with 5b and 6b (Figure S-1); calculated geometries of transition structures in the addition of 7a to formaldehyde (Figure S-2); Tables listing energies (Tables S1 and S-3) and relative electronic and free energies of TS-5b and TS-6b calculated using M06-D3/B1 (Table S2); and the optimized Cartesian coordinates and the imaginary frequencies of TSs (PDF)

(2) On the other hand, the enantioselective reaction takes place through a pathway involving initial ligand exchange of RTi(OiPr)3 with BINOLate titanium complex 3 followed by the addition of the resulting chiral dinuclear titanium species 12 via the corresponding chiral tricyclic transition structure TS-13. (3) The enantioselective pathway is favorable relative to the racemic pathway not because BINOLate ligands accelerate the carbonyl addition but because the ligands substantially stabilize chiral dinuclear species 12 against deaggregation through the chelating bridge, thus keeping its concentration higher than that

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Corresponding Author

*E-mail: [email protected]. 7832


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The Journal of Organic Chemistry ORCID

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Toshiro Harada: 0000-0002-9818-5386 Notes

The author declares no competing financial interest.

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ACKNOWLEDGMENTS We thank Prof. Hisayoshi Kobayashi of Kyoto Institute of Technology for helpful discussion. Thanks are also due to Professor Robert S. Paton (Colorado State University) for supporting with the QHA script. This work was supported by KAKENHI (no. 15K05500) from Ministry of Education, Culture, Sports, Science, and Technology (MEXT), Japan.

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(88) Holloway, C. E. Carbon-13 Nuclear Magnetic Resonance Study of Some Alkoxides of Titanium. J. Chem. Soc., Dalton Trans. 1976, 1050−1054. (89) 0.91 (0.018M) and 0.94 (0.052M) in C6H6 are reported. Kuehlein, K.; Clauss, K. Growth-Reaction of Ethylene to Methyltitanium Compounds. Makromol. Chem. 1972, 155, 145−68 1.01 (0.003−0.0016M) in C6H6 is also reported (reference 87).. (90) A reviewer suggested the inclusion of empirical dispersion correction (refs 91−93) to the calculations, considering the size of the molecules. We performed the reoptimization of TS-5b, TS-6b, 5b, 6b, and HCHO with the dispersion corrected M06 functional (M06-D3). While the activation free energy for four-membered transition structure transition structure TS-5b (M06-D3) changes only a little (−0.2 kcal/mol), that for tricyclic transition structure TS-6b is decreased by 1.3 kcal/mol (Table S-2). The result implies that dispersion interactions between relatively remote isopropyl groups operate in stabilizing the tricyclic transition structure. (91) Grimme, S.; Schreiner, P. R. Steric Crowding Can Stabilize a Labile Molecule: Solving the Hexaphenylethane Riddle. Angew. Chem., Int. Ed. 2011, 50, 12639−12642. (92) Grimme, S.; Hansen, A.; Brandenburg, J. G.; Bannwarth, C. Dispersion-Corrected Mean-Field Electronic Structure Methods. Chem. Rev. 2016, 116, 5105−5154. (93) Rösel, S.; Quanz, H.; Logemann, C.; Becker, J.; Mossou, E.; Cañadillas-Delgado, L.; Caldeweyher, E.; Grimme, S.; Schreiner, P. R. London Dispersion Enables the Shortest Intermolecular Hydrocarbon H···H Contact. J. Am. Chem. Soc. 2017, 139, 7428−7431. (94) The initial structure for the calculation were obtained from the X-ray crystallographic coordinates of Ph(BINOLate)Ti2(OiPr)5 (ref 36). (95) On the other hand, transition structures TS-7a(f), TS-7a(i),TS7a(j), TS-7a(n), and TS-7a(o), in which Ti1 bearing the methyl group is chelated by (R)-BINOLate are of higher energy (ΔE > 3.1 kcal/ mol), possibly owing to the electron-withdrawing nature of the ligand.

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