DFT Investigation of the Diastereoselectivity of the MX2 and MX3

Feb 5, 2018 - Abstract | Full Text HTML | PDF w/ Links | Hi-Res PDF · Structural and Spectral Features of 4′-Substituted 2′-Hydroxychalcones in So...
3 downloads 9 Views 1MB Size
Subscriber access provided by UNIVERSITY OF TOLEDO LIBRARIES

Article 2

3

DFT Investigation of the Diastereoselectivity of MX and MX Lewis Acid Catalyzed Mukaiyama Aldol Reaction Between C,O,O-tris(trimethylsilyl)ketene Acetal and Aldehydes Slim Hadj Mohamed, Benoît Champagne, and Mahmoud Trabelsi

J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.7b11186 • Publication Date (Web): 05 Feb 2018 Downloaded from http://pubs.acs.org on February 7, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

The Journal of Physical Chemistry A is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Physical Chemistry

DFT Investigation of the Diastereoselectivity of MX2 and MX3 Lewis Acid Catalyzed Mukaiyama Aldol Reaction between C,O,Otris(trimethylsilyl)ketene Acetal and Aldehydes Slim Hadj Mohamed,a,b Benoît Champagne,b,* and Mahmoud Trabelsi,a a

Laboratory of Natural Substances, Faculty of Sciences, University of Sfax, 3038 Sfax, Tunisia.

b

Laboratory of Theoretical Chemistry, Theoretical and Structural Physical Chemistry Unit, Namur Institute of Structured Matter, University of Namur, rue de Bruxelles, 61, B-5000 Namur, Belgium.

ABSTRACT: The kinetics and diastereoselectivity of Mukaiyama aldol reaction between C,O,Otris(trimethylsilyl)ketene acetal and aldehydes bearing alkyl, vinyl, and aromatic substituents is influenced by the nature of Lewis acid catalysts. A density functional theory investigation using the M06-2X exchange-correlation functional and the PCM scheme to account for solvent effects has been carried out to characterize the structure and energetics of the transition state when the Lewis acid is ZnBr2 (MX2) or GaCl3 (MX3) in comparison to the uncatalyzed reaction. The main observations are i) the pro-syn transition states are always more stable than the pro-anti ones, ii) for MX2, the transition state presents a cyclic structure whereas it is open for MX3, owing to steric interactions, iii) the difference of activation free enthalpy between the pro-anti and pro-syn reactions decreases when the reaction is catalyzed, by either MX2 or MX3, demonstrating a reduction of the diastereoselectivity, iv) this decrease of diastereoselectivity is larger for MX3- than for MX2-catalyzed reaction, and v) the MX3-catalyzed reactions are kinetically favored by 1-2 kcal mol-1 with respect to the MX2-ones.

1 ACS Paragon Plus Environment

The Journal of Physical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 21

I. INTRODUCTION Mukaiyama aldol reaction1 is an efficient way to form carbon-carbon bonds and prepare in one step products with multiple stereocenters. The reaction between enolsilane derivative and carbonyl compounds provides a route for the stereoselective construction of b-hydroxycarbonyl units, which are important building blocks towards the synthesis of many natural products and pharmaceuticals. Since the discovery of the TiCl4-catalyzed reaction by Mukaiyama,1 a variety of Lewis acid (LA) catalysts (MX2 and MX3) with conventional metals such as Aluminum,2 Boron,3 Zinc4 Iron,4 Magnesium,4 and Mercury,4 have been used in organic solvents. With the development of organic chemistry in water, some researchers wanted to transpose the Mukaiyama reaction into an aqueous medium. So, Li et al.5 have studied the aqueous Mukaiyama reaction and found that the Lewis acids are not good catalysts because they favor the reaction with water rather than with the substrate (the carbonyl). Kobayashi et al. 6 , 7 reported that the use of the Lewis acid for the Mukaiyama aldol reaction in pure water proceeds with a low yield. This problem was solved when a small amount of surfactant was added in the reaction medium. Moreover, Loh and co-workers8,9 showed that InCl3 was an efficient hydro-compatible Lewis acid catalyst in aldol reactions of silyl enol ether with aldehydes. Both MX2 and MX3 Lewis acids are considered as good activating catalysts since they have been used to accelerate Mukaiyama aldol reaction.2-4, 10 In general, the MX2catalyzed Mukaiyama aldol reaction is less common than the reaction involving MX3 catalysts. Later on, Wong and Wong11 reported that MCl3 (M = B, Al, and Ga) metal chlorides are excellent Lewis acid catalysts for Mukaiyama reaction due to the high electronaffinity of the B, Al, and Ga metals. Theoretically, the stereoselectivity of LA-catalyzed Mukaiyama aldol reaction has been explained by using either closed cyclic transition state models10,12 (Zimmermann-Traxler transition state models13) or open transition state models3,14,15,16 (Figure 1). In 1994, Denmark et al. [12] have reported that the open transition state of MX2 (SnCl2)-catalyzed Mukaiyama reaction can be obtained only when the carbonyl of aldehyde is in antiperiplanar position with respect to the CC double bond of silyl enol ether whereas the cyclic transition state is possible when the carbonyl is in synclinal position.

2 ACS Paragon Plus Environment

Page 3 of 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Physical Chemistry

Figure 1. Open and cyclic transition states of Mukaiyama aldol reaction between silyl enol ether and aldehyde catalyzed by MXn (n = 2, 3) Lewis acids.

Open TS models of LA-catalyzed Mukaiyama aldol reactions were originally proposed by Heathcock3 when MXn, R1, R2, and R3 (Figure 1) are BF3, Ph, Me, and tBu, respectively. Then, complementary studies were published by Munoz-Muniz et al.,14 Lee et al.,15 and Hatanaka et al.,16 with other combinations of LA and R1-R3 substituents to analyze the transition state structures and to explain the diastereoselectivity. Munoz-Muniz et al.14 have studied the InCl3-catalyzed Mukaiyama aldol reaction between silyl enol ether Z and benzaldehyde by using several levels of approximation ranging from semi-empirical PM3 and ab initio HF/3-21G* to hybrid density functional theory (DFT), B3LYP/3-21G* and B3LYP/LANL2DZ. All methods support that the syn isomer is favored and that it is generated via a chelated closed, Zimmerman-Traxler-like, transition state. By contrast, the formation of the anti isomer is predicted to occur via an open transition structure, though its energy is significantly larger than for the syn isomer formation. By employing the M06/6-311G*//B3LYP/6-31G* level of theory and accounting for solvent effects with the polarizable continuum model (PCM), Lee et al.15 investigated and rationalized the steric effects and dipole-dipole interactions on the diastereoselectivity of BCl3-catalyzed Mukaiyama aldol reaction between (E) and (Z) isomers of silyl enol ethers bearing substituents of different size and aldehydes (acetaldehyde and benzaldehyde). They found that pro-anti pathways take place via antiperiplanar transition structures while the pro-syn pathways prefer synclinal transition structures. Their computational approach has also enabled to reproduce the pro-syn preference of the reaction between ethyl-substituted (Z)-silyl enol ether and ethyl trimethylsilyl t-butyl ketene acetal and benzaldehyde. Later on, in 2016, Lee et al. 17 investigated the stereoselectivity and compared the open and closed transition structures of the (acyloxy)borane-catalyzed Mukaiyama 3 ACS Paragon Plus Environment

The Journal of Physical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 21

reactions between silyl enol ether and acetaldehyde by using a combination of dispersion-corrected DFT calculations and transition state force fields (TSFF). They found that the closed transition structures are more stable than the open ones. Hatanaka et al.16 performed calculations with the dispersion-corrected B3LYP-D exchange-correlation (XC) functional together with the artificial force induced reaction (AFIR) method 18 , 19 , 20 to sample the large number of transition states of the Mukaiyama reaction between 1-(trimethylsiloxy)cyclohexene and benzaldehyde catalyzed by water-tolerant lanthanide LA [Eu(H2O)8]. They found that i) the pro-anti transition state favors a synclinal conformation whereas the pro-syn favors the antiperiplanar conformation and that ii) the latter is slightly favored over the former, ∆∆G≠ = ∆G≠(pro-anti) - ∆G≠(pro-syn) = 0.4 kcal/mol. The explanations of diastereoselectivity of vinylogous and homologous Mukaiyama aldol reactions have also been based on open transition state models. In 2005, Lopez et al.21 studied the BF3-catalyzed vinylogous Mukaiyama aldol reaction between 2-(trimethylsiloxy)furans and aldehydes at the B3LYP/6-311++G(2d,p)//B3LYP/6-31+G(d) level of theory. They found that i) this reaction is fairly sensitive to steric and electronic effects leading to very small differences in the activation barriers of stereodivergent pathways and that ii) the syn-g-hydroxyalkylbutenolides are formed preferentially following a g+ orientation of the two reactants with the aldehyde in the strans conformation. Recently, LeBlanc et al.22 used the M06/6-311G(d)//B3LYP/6-31G(d) method for modeling the transition state structures of BF3-catalyzed homologous Mukaiyama reaction of enols and [(trimethylsilyl)oxy]alkenes. The main results of that investigation are i) among the many transition state conformations, the lowest energy transition states are those with a synclinal geometry, in which the alkene is positioned over the cyclic oxyallyl cation, ii) the relative orientation of the alkene and oxyallyl cation is explained in terms of stabilizing intermolecular interactions, revealed by NBO analysis, between one or more fluorines of the complexed BF3 and hydrogens on the alkene moiety as well as between the oxygen on the alkene and the p-system of the oxyallyl cation, and iii) the energy differences between the transition states is not large. In general, the Mukaiyama aldol reaction between ketene silyl acetal is less common than the reaction involving silyl enol ether. Bellassoued and co-workers studied the Mukaiyama aldol reaction between C,O,O-tris(trimethylsilyl)ketene acetal 1 with a variety of aldehydes 2a-h (aliphatic, vinylic, and aromatic), catalyzed by MX2 and MX34,23,24 LA catalysts. In particular, when the 4 ACS Paragon Plus Environment

Page 5 of 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Physical Chemistry

HgI2 Lewis acid is used at room temperature and in toluene solutions, the aldol reaction produces syn

and

anti

β-trimethylsiloxy-α-trimethylsilyl

alkanoic

acid

silyl

esters

3

in

low

diastereoselectivity.24 Then, although a closed Zimmermann-Traxler transition state was proposed for the MX2-catalyzed mechanism of these reactions, the nature of the transition state was not discussed for MX3 catalysts. It should also be noted that i) in this reaction the silyl ketene acetal contains geminal OSiMe3 groups attached to carbon Ca (Figure 2) and that ii), owing to the complexity of this substrate and previous mechanisms discussed above, the respective structures of the transition states for the MX2- and MX3-catalyzed reactions remain to be unraveled. This led to the present DFT quantum chemistry investigation of the kinetics of this Mukaiyama aldol reaction between ketene silyl acetal 1 and these aldehydes (2a-h) (Figure 2), where both MX2 and MX3 Lewis acid catalysts are considered. In particular, the study focuses on the diastereoselectivity of the reaction using open and cyclic transition state models (Figure 1). This work complements our previous DFT investigation25 on the uncatalyzed form of the same Mukaiyama aldol reaction, which has been shown to present a high diastereoselectivity, in favor of the syn diastereoisomer.

Figure 2. Mukaiyama aldol reaction between the C,O,O-tris(trimethylsilyl)ketene acetal 1 and aldehydes 2a-2h.

II. THEORETICAL AND COMPUTATIONAL ASPECTS The calculations were carried out at the DFT level using the M06-2X exchange-correlation functional.26,27 The 6-31G(d) basis set was employed for all atoms with the exception of In, which was described using the LANL2DZ basis set.28 The transition states (TSs) were fully optimized by 5 ACS Paragon Plus Environment

The Journal of Physical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 21

using the Berny method. All TSs are characterized by a single imaginary vibrational frequency. To probe widely the potential energy surface and to locate the different TSs, several starting structures were considered in the geometry optimization. These transition structures were obtained by considering systematic rotations, by steps of 15°, around the Cβ-Cɣ bond [ØCα-Cβ-Cɣ-Oβ torsion angle]. The free enthalpies were evaluated at standard temperature (298.15 K) and pressure (1 atm). In all calculations (geometry optimizations and vibrational frequency calculations) solvent effects (toluene) were taken into account by using the Integral Equation Formalism (IEF) version of the Polarizable Continuum Model (IEF-PCM).29 All calculations were performed using the Gaussian 09 package.30

III. RESULTS AND DISCUSSION MX2 (ZnBr2) catalyzed Mukaiyama aldol reaction Table 1 lists the activation Gibbs enthalpies for the different (closed and open) transition states of the ZnBr2-catalyzed reaction between 1 and 2a-2h as well as their differences to highlight the preferred reaction path. In addition, representative geometrical parameters of these transition states are provided, i) two dihedral angles, ØCα-Cβ-Cɣ-Oβ (position of the CgOb carbonyl with respect to the CaCb double bond) and QSi-Cβ-Cɣ-Oβ (position of the CgOb carbonyl with respect to Cb-SiMe3), as well as ii) the d1(Cg…Cb), d2(Zn…Ob), d3(Zn…Oa/Oa’), and d4(Ob…Oa/Oa’) distances. For the reaction between 1 and 2a the corresponding quantities for the uncatalyzed reaction25 are also given. Structures of the transition states of Mukaiyama aldol reaction between C,O,Otris(trimethylsilyl)ketene acetal 1 and benzaldehyde 2a in the presence of ZnBr2 as a MX2 Lewis acid type show that the position of the Zn atom with respect to the oxygen atom of the trimethylsiloxy group of 1 is responsible for the conformation of the transition state (cyclic or open transition state). Moreover, the C,O,O-tris(trimethylsilyl)ketene acetal 1 possesses geminal OSiMe3 groups (Oa-SiMe3 and Oa’-SiMe3). These trimethylsiloxy groups have different chemical environments because the Oa’-SiMe3 group is on the same side as the SiMe3 group attached to Cb whereas the Oa-SiMe3 one is on the opposite side. In this case, when the Cg=Ob group is in gauche position with respect to Ca=Cb double bond, two positions for the CgOb-Zn carbonyl-metal group are possible: two oxygen atoms 6 ACS Paragon Plus Environment

Page 7 of 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Physical Chemistry

can complex the Zn atom, either that of the Oa-SiMe3 group (Tb’, Tc’) or of the Oa’-SiMe3 group (Ta’, Td’), leading both to the formation of a cyclic (closed) transition structures in chair conformation (Figure 3). On the other hand, when the Cg=Ob bond is in antiperiplanar position with respect to Ca=Cb double bond the Zn atom is only linked to the carbonyl oxygen of the aldehyde (Ob) because the distance between the Zn and Oa/Oa’ atoms of 1 are too large to allow coordination with Oa or Oa’ (the Zn-Oa distance amounts to 5.25 Å for pro-anti and 5.57 Å for pro-syn structures). The absence of this additional Zn-O complexation leads to open transition state structures, of which the energy is higher than these of the Ta’-Td’ cyclic transition states. Indeed, in comparison to the most stable closed TS structures, the relative free enthalpy of the TS1 (TS2) structures attains 21.5 kcal/mol (19.9 kcal/mol) (Table 1). The preference for the cyclic transition state over the open transition state has also been obtained in the case of the (acyloxy)borane-catalyzed Mukaiyama aldol reaction between silyl enol ether and acetaldehyde as studied by Lee et al.,17 who reported that the closed transition structure is 0.8 kcal/mol more stable than the open one due to the formation of a hydrogen bond between the hydrogen of silyl enol ether and the oxygen atom of the (acyloxy)borane Lewis acid. Still, in that work, the ∆G≠ difference is much smaller than for the reaction between 1 and 2a. Among the closed transition states, the Tb’ pro-anti structure is more stable than the Ta’. Similarly, the Tc’ pro-syn structure is more stable than the Td’. This leads to the conclusion that Tb’ is the favored pro-anti and Tc’ the favored pro-syn transition states. This result is in agreement with the energies of the Ta-Td cyclic transition states of the corresponding uncatalyzed reaction.25 However, in the latter case, the transition states where the carbonyl and Cb-SiMe3 group are on the same side are less stable those where the carbonyl and Cb-SiMe3 are on opposite sides. Then, Tc’ pro-syn presents a lower free enthalpy than Tb’ pro-anti so that the syn diastereomer is favored over its anti analog. By going from Tb’ to Tc’ the ØCα-Cβ-Cɣ-Oβ torsion angle decreases (from 47.5° to 35°) and accordingly the Ob…Oa distance (from 2.91 Å to 2.73 Å), leading to an increased interaction between the frontier orbitals where the donor and acceptor are in favorable position25,31 (see Figure S1 in Supporting information). This explains why the Tc’ structures are more stable than the Tb’ ones. Moreover, the transition state energy differences between Tb’ and Tc’ in the ZnBr2-catalyzed reaction are smaller (DDE¹ = 0.6 kcal/mol and DDG¹ = 0.9 kcal/mol) than in the uncatalyzed reaction 7 ACS Paragon Plus Environment

The Journal of Physical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 21

(The corresponding differences between the Tb and Tc structures are 1.8 kcal/mol for DDE¹ and 1.8 kcal/mol for DDG¹). So, the diastereoselectivity decreases strongly from the uncatalyzed to MX2Lewis acid catalyzed Mukaiyama aldol reaction. These values are in agreement with the experimental study of Bellassoued et al.,24,32 who reported that the diastereoselectivity decreases from the uncatalyzed32 to MX2-catalyzed Mukaiyama aldol reaction24 between silyl ketene acetal and aldehydes. The DG¹ variations as a function of the nature of R substituent are weak. Indeed, the DG¹ ranges from 7.5 kcal/mol (R = Hep) to 8.1 kcal/mol (R = 3-thienyl) for Tb’ and from 6.8 kcal/mol (R = -CH=C(Me)2) to 7.2 kcal/mol (R = 4-chlorophenyl) for Tc’. For all R substituents, d2 is smaller than d3, d1 decreases by going from Ta’ to Tb’ and the same occurs from Td’ to Tc’, with two exceptions, R = {3-(PhO)C6H4, Hep}, where d1 increases slightly.

Table 1. Activation free enthalpy (∆G≠, kcal/mol) and activation free enthalpy differences (∆∆G≠, kcal/mol) as evaluated with the IEFPCM/M06-2X/6-31G* method (T = 298.15 K; P = 1 bar, solvent = toluene) as well as representative geometrical parameters of the transition state structures, the ØCαCβ-Cɣ-Oβ and QSi-Cβ-Cɣ-Oβ dihedral angles (°) as well as the d1(Cβ…Cɣ), d2(Zn…Ob), d3(Zn…Oa/Oa’), and d4(Ob…Oa/Oa’) distances (Å).

1/2

TS

∆G≠

∆∆G≠a

Ø

Q

d1

d2

d3

d4

Tb

1/2a

pro-anti pro-anti pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti

31.0 32.8 29.3 35.0 8.0 8.7 29.5 7.1 8.9 27.1 7.8

0 (1.8) 2.2 0 5.8 0 (0.9) 0.6 21.5 0 1.8 19.9 0 (0.7)

56.3 17.7 29.2 71.5 47.5 321.4 175.2 35.0 301.3 185.3 45.7

180.0 251.9 155.9 309.3 174.0 86.7 305.9 161.7 65.9 308.6 170.8

1.96 2.21 2.15 2.14 3.02 3.15 2.14 2.88 3.15 2.24 2.98

2.06 2.04 1.93 2.01 2.05 1.95 2.07

2.10 2.09 5.25 2.19 2.10 5.57 2.12

2.57 2.47 2.43 2.60 2.91 2.87 2.73 3.13 3.11

Tb Ta Tc Td Tb’ T a’ TS1 Tc’ Td’ TS2 Tb’

1/2a…ZnBr2

1/2b…ZnBr2

8 ACS Paragon Plus Environment

Page 9 of 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Physical Chemistry

1/2c…ZnBr2

1/2d…ZnBr2

1/2e…ZnBr2

1/2f…ZnBr2

1/2g…ZnBr2

1/2h…ZnBr2

a

b

pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn

8.5 29.9 7.0 8.9 28.2 8.0 8.6 29.0 7.2 8.9 27.1 8.1 8.8 29.7 7.2 8.9 26.8 7.8 8.7 28.3 7.1 9.0 25.3 7.6 8.5 27.4 6.8 8.5 25.4 7.7 8.2 25.8 7.1 8.3 23.4 7.5 8.0 26.3 6.8 8.0 23.9

0.8 22.1 0 1.9 21.2 0 (0.8) 0.6 21.0 0 1.6 19.9 0 (0.9) 0.7 21.6 0 1.7 19.6 0 (0.7) 0.9 20.6 0 1.9 18.1 0 (0.8) 0.9 19.8 0 1.7 18.6 0 (0.6) 0.5 18.1 0 1.2 16.3 0 (0.7) 0.5 18.7 0 1.2 17.1

322.1 171.7 45.1 300.9 186.4 50.8 321.7 176.2 45.4 300.8 182.6 51.8 319.1 177.7 50.4 299.3 185.0 48.5 295.2 176.9 33.1 298.4 185.8 48.0 314.1 180.8 35.5 306.6 190.9 49.1 311.3 197.2 30.2 297.8 190.8 46.2 299.9 199.6 42.3 291.2 181.4

88.1 299.3 173.6 65.2 309.1 175.8 88.0 306.8 174.6 65.3 307.6 177.0 84.5 307.1 180.5 64.6 307.7 172.9 61.5 302.2 162.4 63.4 310.9 172.4 78.7 304.9 166.7 70.30 314.8 172.1 77.0 324.5 154.6 61.2 312.4 169.7 65.2 327.9 165.7 57.1 304.3

3.12 2.16 3.23 3.15 2.22 3.11 3.19 2.15 3.11 3.16 2.24 3.13 3.18 2.14 2.88 3.10 2.22 3.09 3.16 2.15 3.00 3.12 2.22 3.11 3.22 2.16 3.14 3.21 2.23 3.00 3.21 2.17 3.18 3.20 2.24 3.00 3.22 2.16 3.15 3.15 2.24

2.05 1.99 2.06 2.06 1.94 2.08 2.05 1.94 2.06 2.06 2.01 2.05 2.04 2.00 2.05 2.05 1.94 2.05 2.06 1.99 2.06 2.04 1.98 2.05 2.03 2.00 2.05 2.04 1.99 2.10 2.06 2.00 2.08 2.06 2.00 2.07 2.07 2.00 2.07 2.07 2.00

2.09 5.35 2.09 2.10 5.56 2.10 2.09 5.29 2.08 2.10 5.55 2.10 2.09 5.36 2.09 2.10 5.55 2.11 2.08 5.27 2.07 2.11 5.38 2.11 2.11 5.27 2.07 2.11 5.86 2.11 2.08 5.31 2.07 2.10 5.76 2.12 2.07 5.59 2.08 2.07 5.26

2.87 2.90 3.15 3.21 2.89 2.90 3.13 2.99 2.87 2.81 3.13 3.10 2.80 2.92 3.06 3.10 2.94 2.96 3.18 3.14 2.99 2.89 3.08 3.17 3.09 2.87 3.08 -

T a’ TS1 Tc’ Td’ TS2 Tb’ T a’ TS1 Tc’ Td’ TS2 Tb’ T a’ TS1 Tc’ Td’ TS2 Tb’ T a’ TS1 Tc’ Td’ TS2 Tb’ T a’ TS1 Tc’ Td’ TS2 Tb’ T a’ TS1 Tc’ Td’ TS2 Tb’ T a’ TS1 Tc’ Td’ TS2

Relative activation free enthalpy. In parentheses are given the free enthalpy differences between the most stable pro-anti and pro-syn transition states, ∆∆≠ = ∆≠(most stable pro-anti) – ∆≠(most stable pro-syn). Ta-Td are the transition states corresponding to the uncatalyzed reaction between 1 and 2a (Scheme 3 of Ref 21); Ta’-Td’ and TS1-TS2 are the transition states correspond to the ZnBr2 catalyzed reaction between 1 and 2 (Figure 3).

9 ACS Paragon Plus Environment

The Journal of Physical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 21

Figure 3. TS1-TS2 and Ta’-Td’ transition structures of MX2 catalyzed Mukaiyama aldol reaction between 1 and 2a.

MX3 (BCl3, AlCl3, GaCl3, and InCl3) catalyzed Mukaiyama aldol reaction First, we selected GaCl3 as Lewis acid catalyst to investigate the geometries of the transition state structures, the diastereoselectivity, and the kinetic of the Mukaiyama reactions between 1 and aldehydes 2 bearing alkyl, vinyl, or aromatic substituents. From modeling the transition states with MX3 Lewis acid we conclude that only the open transition states are possible owing to steric effects. Indeed, the formation of cyclic structures where the metal is complexed by both the oxygen of the carbonyl and the oxygen of one of the OSiMe3 groups leads to strong repulsive interactions between the chlorine atoms and the OSiMe3 groups. The d(Cβ…Cɣ) distance, ØCα-Cβ-Cɣ-Oβ torsion angle, activation energy difference (∆∆E≠), activation free energy (∆G≠), and free energy difference (∆∆G≠) 10 ACS Paragon Plus Environment

Page 11 of 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Physical Chemistry

between the pro-anti and pro-syn transition states of GaCl3-catalyzed Mukaiyama aldol reaction are listed in Table 2. The six pro-anti or pro-syn conformations of the TS structures (T1-T6) of GaCl3catalyzed reaction can usually be distinguished using the ØCα-Cβ-Cɣ-Oβ torsion angle. T1-T3 are proanti while T4-T6 are pro-syn (Table 2 and Figure 4). T1 and T4 adopt an antiperiplanar (ap) conformation while T2, T3, T5, and T6 are gauche conformations [synclinal (sc) and/or anticlinal (ac)]. Note that some synperiplanar (sp) transition states were also obtained but, since they are characterized by very small imaginary frequencies, they do not correspond to stable conformations due to the steric effects created by the chlorines and OSiMe3 groups. In T1 and T4 the ØCα-Cβ-Cɣ-Oβ angle ranges from 174.4 to 195.7° whereas T2, T3, T5, and T6 are characterized by ØCα-Cβ-Cɣ-Oβ angles belonging to the [37.8°,133.1°] interval in the synclinal or anticlinal domain. In the transition state structures, the Cβ…Cɣ bond lengths vary over a broad range, between 2.27 and 2.50 Å, in agreement with the results by Lee et al.15 (from 2.09 to 2.66 Å). For all substituents, in the case of the pro-anti TS, the ∆G≠ decreases slightly from the antiperiplanar T1 to the synclinal T2 whereas it is larger for the other synclinal structure (T3). Similarly, in the case of pro-syn the antiperiplanar T4 structure presents a slightly higher energy than T5 whereas for T6 the energy is further high. The large energy differences between T3 and T2 on one side and T6 and T5 on the other side were also observed between the Ta and Tb [Td and Tc] transition states of the uncatalyzed Mukaiyama aldol reaction.25 Indeed, in the (Ta, T3) and (Td, T6) transition states, the COβ is at the same side as the CβSiMe3 group while they are at opposite sides for (Tb, T2) and (Tc, T5), leading to less steric interactions. Therefore, for both pro-anti and pro-syn transition state structures, the variation of the carbonyl position with respect to the CαCβ double bond from +sc to -sc requires more energy than from sc/ac to ap position. The lower energy of the (Tb, Tb’, T2) and (Tc, Tc’, T5) transition state structures leads to conclude that for both uncatalyzed and (MX2, MX3)-catalyzed reactions, the transition states favor the situation where the carbonyl is on the opposite side to the SiMe3 substituent on the Cβ atom. For pro-anti, the most stable transition state is T2 whereas T5 is the most stable for the pro-syn reactions and it is also more stable than T2. In T5, the GaCl3 LA is further away from the rest of the structure, which creates therefore less steric effects than in T2 (Figure 3). The role of MX3-Lewis acid position on the stability of TSs was also highlighted by Heathcock et al.,3 who have reported that the pro-anti synclinal conformation 11 ACS Paragon Plus Environment

The Journal of Physical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 21

characterized by steric interactions between tBu (R3) and the BF3 Lewis acid (Figure 1) has been excluded.3 On the other hand, the R substituent is in interaction only with the Cβ-SiMe3 group for T2 whereas it is in interaction with both the Cβ-SiMe3 and OSiMe3 groups in T5 transition states. These two effects are antagonistic but the former is dominant so that the T5 energies are smaller than the T2 ones. Note that this favorable position of the R substituent is also found for the TC’ transition structure (Figure 3). It should be noted that in T1 the R substituent is also between the Cβ-SiMe3 and OSiMe3 groups but the COβ is on the same side as the Cβ-SiMe3 group, making their energies higher than those of T2 and T5. This leads to conclude that the carbonyl position has an important effect on the energy of transition states.

Figure 4. Conformation types (1-6) of the pro-anti and pro-syn transition states of MCl3-catalyzed Mukaiyama aldol reaction between 1 and 2a-2h.

12 ACS Paragon Plus Environment

Page 13 of 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Physical Chemistry

Table 2. Activation free enthalpy (∆G≠, kcal/mol) and activation free enthalpy differences (∆∆G≠, kcal/mol) as evaluated with the IEFPCM/M06-2X/6-31G* method (T = 298.15 K; P = 1 bar, solvent = toluene) as well as representative geometrical parameters of the transition structures, the Cβ…Cɣ distance (d, Å) and the ØCα-Cβ-Cɣ-Oβ torsion angle (Ø, deg). Only those TSs characterized by DDG≠ < 2.0 kcal/mol16 are listed.

1/2...GaCl3

TS

∆G≠

∆∆G≠a

d

Ø

Tb

1/2a…GaCl3

pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn

6.2 6.5 7.3 5.6 6.4 7.5 6.2 6.6 7.3 5.6 6.2 7.4 6.4 6.8 7.5 5.8 6.5 7.7 6.2 6.5 7.1 5.6 6.4 7.6 6.3 6.7 7.3 5.6 6.3 7.5 6.3 6.8 7.5 5.7 6.5 7.6

0 (0.5) 0.3 1.2 0 0.8 1.9 0 (0.6) 0.4 1.1 0 0.6 1.8 0 (0.6) 0.4 1.1 0 0.7 1.8 0 (0.5) 0.3 1.0 0 0.8 1.9 0 (0.6) 0.5 1.0 0 0.6 1.8 0 (0.6) 0.5 1.2 0 0.8 1.9

2.41 2.41 2.46 2.40 2.37 2.46 2.37 2.31 2.37 2.28 2.28 2.38 2.44 2.45 2.50 2.39 2.39 2.50 2.43 2.39 2.47 2.36 2.31 2.42 2.36 2.32 2.35 2.24 2.27 2.37 2.35 2.27 2.33 2.39 2.24 2.34

41.3 175.7 321.9 111.7 187.1 298.9 51.0 174.4 321.9 106.1 189.7 299.4 41.5 176.2 321.9 113.5 187.4 298.4 40.8 178.5 322.2 100.0 187.3 297.4 41.7 177.9 319.6 105.8 191.3 300.1 40.5 183.4 320.5 86.5 191.0 304.7

T2 T1 T3 T5 T4 T6 T2 T1 T3 T5 T4 T6 T2 T1 T3 T5 T4 T6 T2 T1 T3 T5 T4 T6 T2 T1 T3 T5 T4 T6 T2 T1 T3 T5 T4 T6

1/2b…GaCl3

1/2c…GaCl3

1/2d…GaCl3

1/2e…GaCl3

1/2f…GaCl3

13 ACS Paragon Plus Environment

The Journal of Physical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

1/2g…GaCl3

1/2h…GaCl3

a

b

pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn pro-anti pro-anti pro-anti pro-syn pro-syn pro-syn

6.5 7.0 7.7 6.0 7.0 7.9 6.1 6.6 7.4 5.7 6.7 7.3

0 (0.5) 0.5 1.2 0 1.0 1.9 0 (0.4) 0.5 1.2 0 1.0 1.7

Page 14 of 21

2.43 2.40 2.42 2.45 2.39 2.43 2.42 2.39 2.46 2.45 2.42 2.44

133.1 195.7 321.5 88.4 188.1 301.1 118.9 194.9 319.0 93.5 186.9 285.5

T2 T1 T3 T5 T4 T6 T2 T1 T3 T5 T4 T6

Relative activation free enthalpy. In parentheses are given the free enthalpy differences between the most stable pro-syn and pro-anti transition states, ∆∆≠ = ∆≠(most stable pro-anti) – ∆≠(most stable pro-syn). Types of transition structures, see Figure 4.

In order to study the influence of the volume of the Lewis acid on the diastereoselectivity and on the kinetic of this reaction, the geometries of the pro-anti and pro-syn transition states have been optimized for the reaction between 1 and 2a in the presence of B, Al, Ga, and In metal chlorides (MCl3) (Table 3). The transition energy differences between the most stable pro-anti and pro-syn transition states are small and vary hardly with the metal nature. Indeed, the ∆∆E≠ (∆∆G≠) values are equal to 0.6, 0.5, 0.5, and 0.5 (0.5, 0.6, 0.5, and 0.6) kcal/mol for BCl3, AlCl3, GaCl3, and InCl3, respectively. For the GaCl3-catalyzed reaction between 1 and 2a-2h, the amplitude of ∆∆G≠ ranges from 0.5 to 0.6 kcal/mol when R is an aromatic group, from 0.6 to 0.6 kcal/mol for vinylic groups, and from 0.4 to 0.5 kcal/mol if R is aliphatic. As a consequence, for B, Al, Ga, and In metal chlorides, the activation free enthalpies differences are all positive but small, leading to a weak diastereoselectivity. Note that this lack of metal effect on the diastereoselectivity contrasts with the experimental results due to Munoz-Muniz et al.,14 who observed an inversion of diastereoselectivity when going from InCl3 to CeCl3 LA-catalyzed Mukaiyama aldol reaction. Then, by going from the uncatalyzed to the MCl3 (M = B, Al, Ga, and In) catalyzed reactions, ∆∆G≠ decreases strongly, leading to conclude that the role of MCl3 Lewis acid catalyst in this aldol reaction is not limited to reduce the activation energies and accelerate the reactions because, at the same time, it decreases the diastereoselectivity in comparison to the uncatalyzed reaction.25

14 ACS Paragon Plus Environment

Page 15 of 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Physical Chemistry

Table 3. Activation free enthalpy (∆G≠, kcal/mol) and activation free enthalpy differences (∆∆G≠, kcal/mol) as evaluated with the IEFPCM/M06-2X/6-31G* method (T = 298.15 K; P = 1 bar, solvent = toluene) as well as d(Cβ…Cɣ) distances (d, Å), ØCα-Cβ-Cɣ-Oβ torsion angles (Ø, deg), and the types of the most stable pro-anti and pro-syn transition structures. 1/2a

TS

∆∆E≠a

∆G≠

∆∆G≠a

d

Ø

Tb

1/2a…BCl3

pro-anti pro-syn pro-anti pro-syn pro-anti pro-syn pro-anti pro-syn

0.6

6.6 6.1 6.4 5.9 6.2 5.6 6.7 6.1

0.5

2.55 2.43 2.50 2.48 2.41 2.40 2.39 2.36

38.8 112.1 38.7 115.0 41.3 111.7 54.2 112.4

T2 T5 T2 T5 T2 T5 T2 T5

1/2a…AlCl3 1/2a…GaCl3 1/2a…InCl3

0.5 0.5 0.5

0.6 0.5 0.6

a

The activation energy/free enthalpy differences between the most stable pro-anti and pro-syn transition states, ∆∆≠ = E(most stable pro-anti) – E(most stable pro-syn). b Types of transition structures, T2 and T5 are shown in Figure 4.

In the presence of ZnBr2 and MCl3 (M = B, Al, Ga, and In) metal chlorides, the pro-syn is located below the pro-anti transition states. So that globally, the syn product is the kinetic diastereomer. This kinetics is in agreement with i) the kinetics of the same reaction in the absence of catalyst,25 with ii) the kinetics of TiCl4-catalyzed Mukaiyama aldol reaction between ketene bis(trimethylsilyl) acetals and aldehydes as experimentally studied by Dubois et al., 33 and theoretically confirmed by Lee et al.,15 with iii) the kinetics of the BCl3-catalyzed Mukaiyama aldol reaction between E silyl enol ether and acetaldehyde as studied by Lee et al.,15 with iv) the kinetics of the lanthanide-catalyzed reaction between 1-(trimethylsiloxy)cyclohexene and benzaldehyde as studied by Hatanaka et al.,16 as well as with v) the kinetics of the InCl3-catalyzed reaction between silyl enol ether and benzaldehyde as studied by Munoz-Muniz et al.14 Figure 5 summarizes the relationship between the pro-anti versus pro-syn free enthalpy of activations for the LA-catalyzed Mukaiyama aldol reactions and those of the uncatalyzed reaction taken from Ref. 25. Besides a clear decrease of the pro-anti versus pro-syn DG≠ for the catalyzed reaction and a further reduction by going from ZnBr2 to GaCl3, there is no simple relationship between their amplitudes. Therefore, the diastereoselectivity of the reaction decreases when it is catalyzed by Lewis acid and it decreases when going from MX2 to MX3 Lewis acids.

15 ACS Paragon Plus Environment

Page 16 of 21

1.0

ZnBr 0.9

2

GaCl

3

0.8

0.7

0.6

0.5



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ΔΔG (anti-syn), LA-catalyzed, kcal/mol

The Journal of Physical Chemistry

2f

2e

2b 2c

2d 2a

2g

2h 0.4

0.8

1.0

1.2

1.4

1.6

1.8

2.0

2.2

2.4



ΔΔG (anti-syn), uncatalyzed, kcal/mol Figure 5. Relationship between the DDG≠(pro-anti-pro-syn) of the catalyzed and uncatalyzed Mukaiyama aldol reactions between 1 and 2a-2h.

IV. CONCLUSION Density functional theory with the M06-2X exchange-correlation functional and the PCM scheme to account for solvent effects has been used to study the geometries of the transition states and the diastereoselectivity of MX2 and MX3 Lewis acid-catalyzed Mukaiyama aldol reaction between C,O,O-tris(trimethylsilyl)ketene acetal and aldehydes bearing alkyl, vinyl, and aromatic substituents. These DFT calculations show that cyclic transition structures are the best models to describe the diastereoselectivity of the MX2-catalyzed reaction, where the metal is coordinated with both oxygen atoms (the oxygen of carbonyl atom and that of the siloxy group). These calculations confirm the mechanism proposed by Bellasoued et al.4 In this case, four types of cyclic transition states (Ta’-Td’) are obtained, with two pro-anti (Ta’, Tb’) and two pro-syn (Tc’, Td’) structures, Tb’ being the most stable pro-anti and Tc’ the most stable pro-syn structure. On the other hand, open transition structures are more suitable to rationalize the diastereoselectivity of the MX3-catalyzed reactions. In this case, six types of transition states (T1-T6) are possible, with three pro-anti (T1, T2, T3) and three pro-syn (T4, T5, T6). The T2 conformation is the most stable pro-anti and the T5 the 16 ACS Paragon Plus Environment

Page 17 of 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Physical Chemistry

most stable pro-syn. In all cases, the syn diastereoisomer is favored but the difference of activation free enthalpy between the pro-anti and pro-syn reactions decreases when the reaction is catalyzed and it is further reduced when going from MX2 to MX3 Lewis acids, demonstrating a reduction of the diastereoselectivity. Calculations have finally revealed that the free enthalpies of activation, DG≠, are systematically 1-2 kcal mol-1 smaller for the MX3-catalyzed reactions than with ZnBr2 as catalyst. To our knowledge, this effect has not yet been confirmed experimentally but could easily be verified owing to the common nature of the substrates and catalysts.

ASSOCIATED CONTENT The Supporting Information is available free of charge on the ACS Publications website at … HOMO of the Tb’ and Tc’ transition states, enthalpies and free enthalpies of reaction, atomic Cartesian coordinates (Å) and enthalpies for all transition states (PDF).

AUTHOR INFORMATION Corresponding Author *B. Champagne: E-mail: [email protected], Tel: +32 81 724554 ORCID Benoît CHAMPAGNE: 0000-0003-3678-8875 … Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS S.H.M. thanks the Fonds Spécial de Recherche of UNamur for his PhD grant. This work was supported by funds from the Belgian Government (IUAP No P7/5 “Functional Supramolecular 17 ACS Paragon Plus Environment

The Journal of Physical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 18 of 21

Systems”) and the Francqui Foundation. The calculations were performed on the computers of the Consortium des Équipements de Calcul Intensif, including those of the Technological Platform of High-Performance Computing, for which we gratefully acknowledge the financial support of the FNRS-FRFC (Conventions No. 2.4.617.07.F and 2.5020.11) and of the University of Namur.

REFERENCES (1)

Mukaiyama, T.; Narasaka, K.; Banno, K. New Aldol Type Reaction. Chem. Lett. 1973, 2, 10111014.

(2)

Mukaiyama, T. Metal Enolates in Organic Synthesis. Pure Appl. Chem. 1983, 11, 1749-1758

(3)

Heathcock, C. H.; Davidsen, S. K.; Hug, K. T.; Flippin, L. A. Acyclic Stereoselection. 36. Simple Diastereoselection in the Lewis Acid Mediated Reactions of Enol Silanes with Aldehydes. J. Org. Chem. 1986, 51, 3027-3037.

(4)

Bellassoued, M.; Lensen, N.; Bakasse, M.; Mouelhi, S. Two-Carbon Homologation of Aldehydes via Silyl Ketene Acetals: A New Stereoselective Approach to (E)-Alkenoic Acids. J. Org. Chem. 1998, 63, 8785-8789.

(5)

Li, C. J.; Chan, T. H. Organic Reactions in Aqueous Media; John Wiley & Sons: New-York; 1997; pp 115-160.

(6)

Kobayashi, S.; Nagayama, S.; Busujima, T. Lewis Acid Catalysts in Water. Correlation between Catalytic Activity in Water and Hydrolysis Constants and Exchange Rate Constants for Substitution of Inner-Sphere Water Ligands. J. Am. Chem. Soc. 1998, 120, 8287-8288.

(7)

Kobayashi, S.; Busujima, T.; Nagayama, S. On Indium (III) Chloride-Catalyzed Aldol Reactions of Silyl Enol Ethers with Aldehydes in Water. Tetrahedron Lett. 1998, 39, 1579-1582.

(8)

Loh, T.-P.; Pei, J.; Cao, G.-Q. Indium Trichloride Catalyzed Mukaiyama Aldol Reaction in Water. Chem. Commun. 1996, 1819-1820.

(9)

Loh, T.-P.; Chua, G.-L.; Vittal, J. J.; Wong, M.-W. Highly Stereoselective Indium TrichlorideCatalyzed Asymmetric Aldol Reaction of Formaldehyde and a Glucose-Derived Silyl Enol Ether in Water. Chem. Commun. 1998, 861-871.

(10)

Mahrwald, R. Diastereoselectivity in Lewis-Acid-Mediated Aldol Additions. Chem. Rev. 1999, 99, 1095-1120.

(11)

Wong, C. T.; Wong, M. W. Mechanism of Metal Chloride-Promoted Mukaiyama Aldol Reactions. J. Org. Chem. 2007, 72, 1425-1430.

(12)

Denmark, S. E.; Lee, W. Investigations on Transition-State Geometry in the Lewis Acid(Mukaiyama) and Fluoride-Promoted Aldol Reactions. J. Org. Chem. 1994, 59, 707-709.

18 ACS Paragon Plus Environment

Page 19 of 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Physical Chemistry

(13)

Zimmermann, H. E.; Traxler, M. D. The Stereochemistry of the Ivanov and Reformatsky Reactions. I. J. Am. Chem. Soc. 1957, 79, 1920-1923.

(14)

Munoz-Muniz, O.; Quintanar-Audelo, M.; Juaristi, E. Reexamination of CeCl3 and InCl3 as Activators in the Diastereoselective Mukaiyama Aldol Reaction in Aqueous Media. J. Org. Chem. 2003, 68, 1622-1625.

(15)

Lee, J. M.; Helquist, P.; Wiest, O. Diastereoselectivity in Lewis-Acid-Catalyzed Mukaiyama Aldol Reactions: A DFT Study. J. Am. Chem. Soc. 2012, 134, 14973-14981.

(16)

Hatanaka, M.; Maeda, S.; Morokuma, K. Sampling of Transition States for Predicting Diastereoselectivity Using Automated Search Method-Aqueous Lanthanide-Catalyzed Mukaiyama Aldol Reaction. J. Chem. Theory. Comput. 2013, 9, 2882-2886.

(17)

Lee, J. M.; Zhang, X.; Norrby, P.; Helquist, P.; Wiest, O. Stereoselectivity in (Acyloxy)boraneCatalyzed Mukaiyama Aldol Reactions. J. Org. Chem. 2016, 81, 5314-5321.

(18)

Maeda, S.; Morokuma, K. Communications: A Systematic Method for Locating Transition Structures of A + B ® X Type Reactions. J. Chem. Phys. 2010, 132, 241102-241106.

(19)

Maeda, S.; Morokuma, K. Finding Reaction Pathways of Type A + B ® X: Toward Systematic Prediction of Reaction Mechanisms. J. Chem. Theory Comput. 2011, 7, 2335-2345.

(20)

Maeda, S.; Ohno, K.; Morokuma, K. Systematic Exploration of the Mechanism of Chemical Reactions: the Global Reaction Route Mapping (GRRM) Strategy Using the ADDF and AFIR Methods. Phys. Chem. Chem. Phys. 2013, 15, 3683-3701.

(21)

Lopez, C. S.; Alvarez, R.; Vaz, B.; Faza, O. N.; de Lera, A. R. Simple Diastereoselectivity of the BF3.OEt2-Catalyzed Vinylogous Mukaiyama Aldol Reaction of 2-(Trimethylsiloxy)furans with Aldehydes. J. Org. Chem. 2005, 70, 3654-3659.

(22)

LeBlanc, L. M.; Boyd, R. J.; Jean Burnell, D. Density Functional Theory Study of BF3-Mediated Additions of Enols and [(Trimethylsilyl)oxy]alkenes to an Oxyallyl Cation : Homologous Mukaiyama Reactions. J. Phys. Chem A. 2015, 119, 6714-6722.

(23)

Bellassoued, M.; Mouelhi, S.; Fromentin, P.; Gonzalez, A. Two-Carbon Homologation of Ketones via Silyl Ketene Acetals: Synthesis of a,b-Unsaturated acids and a-trimethylsilyl dKetoacids. J. Organometal. Chem. 2005, 690, 2172-2179.

(24)

Bellassoued, M.; Mouelhi, S.; Lensen, N. Two-Carbon Homologation of Aldehydes via Silyl Ketene Acetals. Study of the Stereochemical Control in the Formation of (E)-Alkenoic Acids. J. Org. Chem. 2001, 66, 5054-5057.

(25)

Hadj Mohamed, S.; Trabelsi, M.; Champagne, B. Unraveling the Concerted Reaction Mechanism of the Noncatalyzed Mukaiyama Reaction between C,O,OTris(trimethylsilyl)ketene Acetal and Aldehydes Using Density Functional Theory. J. Phys. Chem. A 2016, 120, 5649-5657.

(26)

Zhao, Y.; Truhlar, D. G. Comparative DFT Study of van Der Waals Complexes: Rate-Gas Dimers, Alkaline-Earth Dimers, Zinc Dimer, and Zinc-Rate-Gas Dimers. J. Phys. Chem. A. 2006, 110, 5121-5129. 19 ACS Paragon Plus Environment

The Journal of Physical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 20 of 21

(27)

Zhao, Y.; Truhlar, D. G. The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics, Noncovalent Interactions, Excited States, and Transition Elements: Two New Functionals and Systematic Testing of Four M06-Class Functionals and 12 Other Functionals. Theor. Chem. Acc. 2008, 120, 215-241.

(28)

Wadt, W. R.; Hay, P. J. Ab Initio Effective Core Potentials For Molecular Calculations. Potentials For Main Group Elements Na to Bi. J. Chem. Phys. 1985, 82, 284-298.

(29)

Tomasi, J.; Mennucci, B.; Cammi, R. Quantum Mechanical Continuum Solvation Models Chem. Rev. 2005, 105, 2999-3094.

(30)

Frisch, M. J.; Trucks, G W.; Schlegel, H. B.; Scuseria, G.E.; Robb, M. A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; et al. Gaussian 09, revision A.01; Gaussian, Inc.: Wallingford, CT, 2010.

(31)

Seebach, D.; Knochel, P. 2’-Nitro-2’-Propen-1’-yl 2,2-Dimethylpropanoate (NPP), A Multiple Coupling Reagent. Helv. Chim. Acta. 1984, 67, 261-283.

(32)

Bellassoued, M.; Reboul, E.; Dumas, F. High Pressure Induced Mukaiyama Type Aldol Reaction of Bis Trimethylsilyl Ketene Acetals. Tetrahedron Letters. 1997, 38, 5631-5634.

(33)

Dubois, J. E.; Axiotis, G.; Bertounesque, E. Ketene bis(trimethylsilyl) Acetals. Cross-Aldol Condensation with Aldehydes. Stereochemistry of the Reaction. Tetrahedron Lett. 1984, 25, 4655-4658.

20 ACS Paragon Plus Environment

Page 21 of 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Physical Chemistry

Mukaiyama Aldol Reaction

syn anti Uncatalyzed

MX3-catalyzed MX2-catalyzed

TOC Graphic

21 ACS Paragon Plus Environment