A Molecular Electron Density Theory Study of the Reactivity and

Article Cite This: J. Org. Chem. 2018, 83, 2182−2197

pubs.acs.org/joc

A Molecular Electron Density Theory Study of the Reactivity and Selectivities in [3 + 2] Cycloaddition Reactions of C,N‑Dialkyl Nitrones with Ethylene Derivatives Luis R. Domingo,*,† Mar Ríos-Gutiérrez,† and Patricia Pérez‡ †

Department of Organic Chemistry, University of Valencia, Dr. Moliner 50, E-46100 Burjassot, Valencia, Spain Universidad Andres Bello, Facultad de Ciencias Exactas, Departamento de Ciencias Químicas, Av. República 498, 8370146, Santiago, Chile

‡

S Supporting Information *

ABSTRACT: The zw-type [3 + 2] cycloaddition (32CA) reactions of C,N-dialkyl nitrones with a series of ethylenes of increased electrophilic character have been studied within the Molecular Electron Density Theory (MEDT) at the MPWB1K/6311G(d,p) computational level. Both, reactivity and selectivities are rationalized depending on the polar character of the reaction. Due to the strong nucleophilic character of C,N-dialkyl nitrones, the corresponding zw-type 32CA reactions are accelerated with the increased electrophilic character of the ethylene, which also plays a crucial role in the reaction mechanism, thus determining the regioand stereoselectivities experimentally observed. While, in the 32CA reactions with nucleophilic ethylenes, the reaction begins with the formation of the C−C single bond, determining the ortho regioselectivity, in the 32CA reactions with strong electrophilic ethylenes, the reaction begins with the formation of the C− O single bond involving the β-conjugated carbon of the ethylene, determining the meta regioselectivity. The present MEDT study also provides an explanation for the unexpected ortho regioselectivity experimentally found in the 32CA reactions involving weak electrophilic ethylenes such as ethyl acrylate and acrylonitrile.

1. INTRODUCTION

Since the beginning of the present century, there has been a growing interest in explaining the chemical reactivity arising from the analysis of the changes of the electron density along the reaction path. The advantage of this choice is based on the fact that electron density is a local function defined within the exact many body theory, and it is also an experimentally accessible scalar field, allowing a sound description of bonding changes to characterize a reaction mechanism.8 In this context, in 2016, Domingo proposed the Molecular Electron Density Theory (MEDT),9 which establishes that the feasibility for the changes in the electron density along a reaction path is responsible for the reactivity in organic chemistry. After Woodward and Hoffmann categorized, in 1969, pericyclic reactions, in which “all f irst order changes in bonding relationships take place in concert on a closed curve”,10 one-step 32CA reactions were classified as pericyclic reactions assuming a similar electronic behavior to Diels−Alder reactions, i.e., the participation of [4 + 2] π electrons.11 However, many recent MEDT studies of 32CA reactions have shown that the bonding changes along one-step reaction paths take place sequentially, instead of “concerted on a closed curve”, thus ruling out the pericyclic mechanism.12 Recent MEDT studies devoted to the

Since the first examples gathered by Irvin in 1938, demonstrating that nitrones 1 are capable of undergoing 1,3additions, the [3 + 2] cycloaddition (32CA) reaction of nitrones 1 with ethylenes 2 to yield regioisomeric isoxazolidines 3 and/or 4 (see Scheme 1)2 has been widely used as a key step for the synthesis of heterocycles and natural products.3 The availability and facile use of nitrones 1,4 the tuneability of the reaction by using chiral Lewis acids,5 and the high efficiency of this transformation6 combine to make this reaction a powerful method for heterocyclic synthesis.7 1

Scheme 1. 32CA Reaction of Nitrones 1 with Ethylenes 2

Received: December 7, 2017 Published: January 19, 2018 © 2018 American Chemical Society

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DOI: 10.1021/acs.joc.7b03093 J. Org. Chem. 2018, 83, 2182−2197

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The Journal of Organic Chemistry understanding of the reactivity of three-atom-components (TACs) participating in 32CA reactions with ethylene 5 have allowed establishing a useful classification of these nonpolar cycloaddition reactions into pseudodiradical-type (pdr-type), pseudoradical-type (pmr-type), carbenoid-type (cb-type), and zwitterionic-type (zw-type) reactions, depending on the electronic structure of the TAC (see Scheme 2).13 The

Scheme 3. 32CA Reaction of Cyclic Nitrones 11 and 12 with Ethyl Acrylate 13

Scheme 2. Electronic Structure of TACs and Reactivity Types in 32CA Reactions with Ethylene 513

two regioisomeric pathways were performed to characterize the molecular mechanism, the O−C and C−C single bond formation was not properly characterized.18 In 1988, Ali et al. reported an experimental study concerning the regio- and stereochemistry of the 32CA reactions of cyclic nitrones.19 Interestingly, for cyclic nitrone 12, a wide range of ethylene derivatives of different electronic nature, i.e., electrophilic or nucleophilic character, were used (see Scheme 4). Scheme 4. 32CA Reaction of Cyclic Nitrone 12 with the Series of Ethylene Derivatives 13 and 1619

activation energy of these 32CA reactions increases in the following order: pdr-type < pmr-type ≤ cb-type < zw-type, zwitterionic TACs being the least reactive.13 Both, the simplest nitrone (H2CNHO) 9, an allylic-type TAC, and the simplest nitrile oxide (HCNO) 10, a propargylic-type TAC, are zwitterionic TACs participating in zw-type 32CA reactions, which demand the nucleophilic activation of the TAC and the electrophilic activation of the ethylene, or vice versa, so that the reaction can take place easily.14 Recent MEDT studies of 32CA reactions of nitrones have emphasized that these reactions take place via a nonconcerted one-step mechanism in which the two new single bonds are formed in a more or less asynchronous manner.12 These studies allowed establishing the nature of the bonding changes along the zw-type 32CA reactions of nitrones; each one of the two regioisomeric pathways begins by the formation of the C−C or the O−C single bond. As the formation of the C−C and O−C single bonds has a different pattern, these regioisomeric paths have different molecular mechanisms. While the C−C single bond formation begins at a distance of ca. 2.0 Å by the C-to-C coupling of two pseudoradical centers,15 formation of the O−C single bond begins at the short distance of ca. 1.7 Å through the donation of part of the nonbonding electron density of the nitrone oxygen to the β-conjugated carbon of electrophilic ethylenes.12a These studies also emphasized that Conceptual Density Functional Theory (CDFT) reactivity indices16 are a powerful and easily accessible tool to predict the nonpolar or polar character of zw-type 32CA reactions, which plays a crucial role in activation energies.14 In the past years, many DFT studies have been devoted to the understanding of 32CA reactions of nitrones with ethylenes derivatives.17 Very recently, Andrés et al. studied the 32CA reactions of cyclic nitrones 11 and 12 with ethyl acrylate 13 (see Scheme 3).18 After testing some ab initio and DFT methods, the B3LYP/6-31G(d) and M06-2X/6-311++G(d,p) DFT levels were selected as the most appropriate ones. Regioand stereoselectivities were found dependent on the computational method, but no experimental data were considered in order to validate the selected computational levels. For the 32CA reaction of cyclic nitrone 12, the M06-2X/6-311+ +G(d,p) calculations predicted a meta/endo selectivity. Although Bonding Evolution Theory (BET) studies along the

From the experimental results reported by Ali et al.,19 some appealing conclusions can be drawn (see Table 1): (i) In general, the temperature and the time used in these 32CA reactions increased from 16a (R = CHO), an electrophilic ethylene, to 16d (R = Me), a nucleophilic ethylene. (ii) Dichloromethane (DCM, ε = 10.1), a polar solvent, was used in the faster reactions, while toluene (ε = 2.4), a nonpolar solvent, was used in the slower ones. This change of the solvent polarity agrees with the expected polar or nonpolar character of these 32CA reactions. (iii) While the 32CA reaction involving acrolein 16a (R = CHO) is meta/endo selective, that involving propene 16d (R = Me) is ortho/exo selective. (iv) The increase of reactivity in this series of zw-type 32CA reactions on going from 16d (R = Me) to 16a (R = CHO) is in complete agreement with the increase of the electrophilicity ω index computed for this series of ethylene derivatives.16b Due to the nucleophilic character of C,N-dialkyl nitrones, it is expected that the increase of the electrophilic character of the ethylene favors these zw-type 32CA reactions through the increase of the polar character of the reaction.14 (v) Although ethylenes 13, 16a, and 16b demand similar reaction conditions, i.e., low temperatures, low reaction times, and a polar solvent, in agreement with their electrophilic character, the observed selectivities are different. While the 32CA reaction with acrolein 16a is mainly meta/endo selective, those involving acrylonitrile 16b and ethyl acrylate 13 are mainly ortho/exo selective. Finally, (vi) the ortho/exo selectivity experimentally observed in the 32CA reaction of cyclic nitrone 12 with ethyl acrylate 13 is opposite to the meta/endo one reported by Andrés et al. at the M06-2X/6-311++G(d,p) calculation level.18 2183


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Table 1. Experimental Conditions, i.e., Reaction Temperature (in °C), Time (in Hours), Solvent, Mixture Composition, and Yields (in %), for the Series of 32CA Reactions of Cyclic Nitrone 12 with Ethylene Derivatives 13 and 16 Reported by Ali et al.19 16a 16b 13 16c 16d

R

temp

time

solvent

17

18

CHO CN CO2Et Ph Me

25 25 0 110 110

0.2 0.5 0.2 5 4

DCM DCM DCM toluene toluene

68

24

19

20

yield

20 15 22 0

61 69 78 100

96 92 96 92 53

González−Schlegel integration method.28 Solvent effects of DCM or toluene were taken into account by full optimization of the gas phase structures at the MPWB1K/6-311G(d,p) computational level using the polarizable continuum model (PCM) developed by Tomasi’s group29 in the framework of the self-consistent reaction field (SCRF).30 The global electron density transfer (GEDT)15 was computed by the sum of the natural atomic charges (q), obtained by a natural population analysis (NPA),31 of the atoms belonging to each framework ( f) at the TSs; i.e., GEDT ( f) = ∑q∈f q; f = nucleophile, electrophile. The sign indicates the direction of the electron density flux in such a manner that positive values mean a flux from the considered framework to the other one. CDFT global reactivity indices16 and Parr functions32 were computed using the equations given in ref 16b. All computations were carried out with the Gaussian 09 suite of programs.33 Topological analysis of the electron localization function (ELF)34 was performed with the TopMod35 package using the corresponding MPWB1K/6-311G(d,p) monodeterminantal wave functions and considering a cubical grid of step size of 0.1 Bohr. For the BET studies,36 the corresponding reaction paths were followed by performing the topological analysis of the ELF for 280 and 652 nuclear configurations along the meta/endo (16a) and ortho/exo (16d) IRC paths, respectively. The molecular geometries and ELF basin attractor positions were visualized using the GaussView program,37 while the representation of the ELF basin isosurfaces was done by using the UCSF Chimera program.38

The experimental data reported by Ali et al.19 for the 32CA reactions of cyclic nitrone 12 with this wide range of ethylene derivatives of increased electrophilicity16b prompted us to carry out an MEDT study of these zw-type 32CA reactions at the MPWB1K/6-311G(d,p) computational level in order to establish the general trend of reactivity of C,N-dialkyl nitrones, as well as the regio- and stereoselectivities, in this important class of 32CA reactions. To this end, the 32CA reactions of cyclic nitrone 12 with acrolein 16a, as an electrophilic ethylene, and with propene 16d, as a nucleophilic ethylene, experimentally performed by Ali et al.,19 were studied. In addition, the 32CA reactions of model C,N-dimethyl nitrone 21 with ethylene 5 and with the ethylene derivative series 16 were also analyzed in order to understand the participation of nucleophilic C,N-dialkyl nitrones in zw-type 32CA reactions (see Scheme 5). This comprehensive study complements our Scheme 5. Nitrones 12 and 21, Ethylene 5, and the Series of Ethylene Derivatives 16 Involved in the 32CA Reactions Studied Herein

3. RESULTS AND DISCUSSION The present MEDT study has been divided into eight sections: (i) First, the electronic structures of cyclic nitrone 12 and C,Ndimethyl nitrone 21, as a reduced model of the former, are studied. (ii) Then, the CDFT reactivity indices of nitrones 12 and 21 and ethylene derivatives 16 are analyzed in order to establish the participation of these species in zw-type 32CA reactions. (iii) In the third part, the general reactivity of nucleophilic C,N-dialkyl nitrones and selectivities in zw-type 32CA reactions are analyzed studying the reactions of cyclic nitrone 12 with acrolein 16a, as an electrophilic ethylene, and propene 16d, as a nucleophilic ethylene. (iv) Next, the origin of the endo/exo stereoselectivity in these 32CA reactions is analyzed. (v) In the fifth section, the activation energies associated with the 32CA reactions of C,N-dimethyl nitrone 21 with the series ethylene derivatives 16 are analyzed in order to understand the behavior of nucleophilic C,N-dialkyl nitrones in zw-type 32CA reactions. (vi) Later, a BET study of the 32CA reaction of nitrone 21 with acrolein 16a along the most favorable meta/endo reaction path, and with propene 16d along the most favorable ortho/exo reaction path, is performed in order to understand the molecular mechanism of zw-type 32CA reactions involving nucleophilic C,N-dialkyl nitrones. (vii) In the seventh section, the origin of the meta/ortho regioselectivity in the zw-type 32CA reactions is discussed; and finally. (viii) The unexpected ortho regioselectivity experimentally found in

previous studies of zw-type 32CA reactions involving a specific ethylene derivative and, particularly, offers a more far-reaching understanding of the reactivity of nucleophilic nitrones in zwtype 32CA reactions.

2. COMPUTATIONAL METHODS A recent analysis about the applicability of the B3LYP,20 MPWB1K,21 and M06-2X22 functionals in the study of nonpolar and polar cycloaddition reactions allowed selecting the MPWB1K functional as the most adequate one for the study of this type of organic reactions.23 Consequently, DFT calculations were performed by using the MPWB1K functional together with the 6-311G(d,p) basis set.24 The suitability of this DFT computational level for the study of the aforementioned zw-type 32CA reactions was asserted by performing CCSD(T)/cc-pVTZ single point energy calculations at the stationary points involved in the 32CA reaction between nitrone 21 and acrolein 16a (see Table S9 in the Supporting Information).25 Optimizations were carried out using the Berny analytical gradient optimization method.26 The stationary points were characterized by frequency computations in order to verify that TSs have one and only one imaginary frequency. The IRC paths27 were traced in order to check and obtain the energy profiles connecting each TS to the two associated minima of the proposed mechanism using the second-order 2184


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representation of the molecular system. Note that Lewis’s bonding model is built based on electron populations instead on the number of basins. Therefore, within Lewis’s bonding model,40 the V(O1) and V′(O1) monosynaptic basins can be related to O1 oxygen lone pairs, the V(O1,N2) disynaptic basin to a somewhat depopulated O1−N2 single bond and the V(N2,C3) and V′(N2,C3) disynaptic basins to an N2−C3 double bond, in agreement with the bonding pattern generally represented for nitrones (see the proposed ELF-based Lewis structure in Figure 1). Although there are some slight differences in the electron populations of the ELF basins as well as in the ELF topology, i.e., number of basins and/or shape of the ELF localization domains, between the simplest nitrone 9 and C,N-dialkyl nitrones 12 and 21, the three molecules present a very similar bonding pattern (see Figure 1). Consequently, the presence of neither pseudoradical nor carbenoid centers at nitrones 9, 12, and 21, presenting, instead, an N2−C3 double bond, indicates that these TACs possess a zwitterionic electronic structure that enables their participation in zw-type 32CA reactions only.13 Once the bonding pattern of these TACs was established, the charge distribution was analyzed through NPA. Natural atomic charges of the most relevant centers are shown together with the proposed ELF-based Lewis structures given in Figure 1. NPA of the three TACs reveals that, while the O1 oxygen center is negatively charged by ca. 0.55e, the N2 and C3 centers present negligible charges. While the N2 nitrogen presents no charge and the C3 carbon a negative charge of −0.21e at the simplest nitrone 9, the alkyl substitution causes their depopulation by 0.11e (N2) and by ca. 0.20e (C3) at nitrones 12 and 21. These values, as well as the computed dipolar moments, 3.71 D (9), 4.35 D (21), and 4.66 D (12), indicate that these TACs present a charge separation that makes them dipolar species, but contrast with the expected charges arising from Lewis’s bonding model (see Figure 1). Note that the molecular charge distribution is the consequence of the asymmetric electron density delocalization within a molecule resulting from the presence of different nuclei in the molecule, rather than the consequence of the resonance Lewis structures. It is worth mentioning, therefore, that the term “zwitterionic” used in our classification does not refer to a dipolar electronic structure of the TAC, but to the specific bonding pattern (considering no charges) of the principal octet resonance Lewis structure represented by Huisgen for “1,3-dipoles”.41 3.2. Analysis of the CDFT Reactivity Indices at the Ground State (GS) of the Reagents. Numerous studies devoted to DA and 32CA reactions have shown that the analysis of the reactivity indices defined within CDFT16 is a powerful tool to predict and understand the reactivity in cycloaddition reactions. The feasibility of zw-type 32CA reactions depends on their polar nature, i.e., the nucleophilic character of the TAC and the electrophilic character of the ethylene derivative, or vice versa.14 Consequently, the analysis of the CDFT reactivity indices at the GS of the reagents allows characterizing their reactivity in zw-type 32CA reactions. A very good linear correlation between the CDFT reactivity indices obtained by using different DFT functionals and basis sets can be established.42 As the first electrophilicity ω and nucleophilicity N scales were given at the DFT B3LYP/6-31G(d) computational level, the present CDFT analysis was performed at this level.16b The B3LYP/6-31G(d) global indices, namely, the electronic chemical potential, μ, chemical hardness, η,

the 32CA reactions involving weak electrophilic ethylenes such as ethyl acrylate 13 and acrylonitrile 16b is also analyzed. 3.1. ELF Topological Analysis and NPA of Nitrones 12 and 21. One appealing procedure that provides a straightforward connection between the electron density distribution and the chemical structure is the quantum chemical analysis of Becke and Edgecombe’s ELF.34 Therefore, in order to characterize the electronic structure of nitrones 12 and 21 and, thus, to predict their reactivity in 32CA reactions,13 a topological analysis of the ELF of these TACs and the simplest counterpart 9, as the reference (see Scheme 2), was first performed. ELF localization domains, ELF basin attractor positions together with the most representative valence basin populations, as well as the proposed ELF-based Lewis structures together with the natural atomic charges are shown in Figure 1.

Figure 1. MPWB1K/6-311G(d,p) ELF localization domains of nitrones 9, 21, and 12, represented at an isosurface value of ELF = 0.75, at the top side. ELF basin attractor positions, together with the most representative valence basin populations, at the center, and the proposed ELF-based Lewis structures, together with the natural atomic charges, at the bottom side. Negative charges are colored in red, positive charges in blue, and negligible charges in green. ELF valence basin populations and natural atomic charges are given in average number of electrons, e.

ELF topological analysis of nitrones 9, 21, and 12 shows the presence of two V(O1) and V′(O1) monosynaptic basins, integrating total populations of 5.85e (9), 5.90e (21), and 5.93e (12), one single V(O1,N2) disynaptic basin integrating 1.57e (9), 1.54e (21), and 1.52e (12), and one or two disynaptic basins between the N2 and C3 centers, V(N2,C3), integrating total populations of 3.62e (9), 3.83e (21), and 3.84e (12). The increase of the alkyl substitution in the following order 9 < 21 < 12 produces an increase of the population of the monosynaptic basins associated with the O1 oxygen and that of the disynaptic basins associated with the N2−C3 double bond. These changes account for the increase of the nucleophilicity of these TACs in the same order (see section 3.2). Within the ELF context, monosynaptic basins, labeled V(A), are associated with nonbonding regions, i.e., lone pairs or pseudoradical centers, while disynaptic basins, labeled V(A,B), connect the core of two nuclei A and B and, thus, correspond to a bonding region between A and B.39 This description, together with the ELF valence basin populations, recovers Lewis’s bonding model, providing a very suggestive graphical 2185


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The Journal of Organic Chemistry electrophilicity, ω, and nucleophilicity, N, at the GS of nitrones 12 and 21 and ethylene derivatives 16 are given in Table 2.

propene 16d, N = 2.32 eV, is a moderate nucleophile and ethylene 5, N = 1.86 eV, a marginal nucleophile. zw-type 32CA reactions demand the participation of strong nucleophiles and strong electrophiles to take place easily. Since nitrones 12 and 21 are classified as strong nucleophiles, N > 3.57 eV, and marginal electrophiles, ω < 0.85 eV, it is expected that they will participate in polar 32CA reactions with strong electrophilic ethylenes. Since the electrophilicity of the series of electrophilic ethylenes 16a,b,e−g increases in the order methyl acrylate 16g < acrylonitrile 16b < acrolein 16a < nitroethylene 16e < nitrosoethylene 16f, it is expected that the reaction rate will increase in this order. By approaching nonsymmetric electrophilic/nucleophilic pairs along a polar process, the most favorable reactive pathway is that associated with the initial two-center interaction between the most electrophilic center of the electrophile and the most nucleophilic center of the nucleophile. Recently, Domingo proposed the nucleophilic Pk− and electrophilic Pk+ Parr functions,32 derived from the changes of spin electron density reached via the GEDT process from the nucleophile to the electrophile, as a powerful tool to study the local reactivity in polar and ionic processes. Accordingly, in order to characterize the most electrophilic and nucleophilic centers of the species involved in these 32CA reactions, the nucleophilic Pk− Parr functions of nitrones 12 and 21, as well as the electrophilic Pk+ Parr functions of acrolein 16a, taken as the model of the series of experimental electrophilic ethylenes reported by Ali et al.,19 and methyl acrylate 16g were analyzed (see Figure 2).

Table 2. B3LYP/6-31G(d) Electronic Chemical Potential (μ), Chemical Hardness (η), Global Electrophilicity (ω), and Global Nucleophilicity (N), in eV, of Ethylene 5, Nitrones 12 and 21, and Ethylene Derivatives 16 16f (R = NO) 16e (R = NO2) 16a (R = CHO) 16b (R = CN) 16g (R = CO2Me) 15 16c (R = Ph) 9 21 5 12 16d (R = Me)

μ

η

ω

N

−4.45 −5.33 −4.38 −4.70 −4.31 −4.25 −3.43 −3.43 −2.97 −3.37 −2.83 −3.01

3.34 5.45 5.23 6.34 6.22 6.19 5.20 5.54 5.17 7.77 5.29 7.57

2.96 2.60 1.84 1.74 1.49 1.46 1.13 1.06 0.85 0.73 0.76 0.60

3.00 1.07 2.12 1.25 1.70 1.77 3.09 2.92 3.57 1.86 3.65 2.32

The electronic chemical potentials43 μ of the C,N-dialkyl nitrones, μ = −2.83 (12) and −2.97 (21) eV, are higher than those of electrophilic ethylenes 16a,b,e−g, between −4.31 (16g, R = CO2Me) and −5.33 (16e, R = NO2) eV. These values suggest that, along a polar reaction, the GEDT15 will flux from the nitrones toward the electrophilic ethylenes. On the other hand, ethylene 5, styrene 16c, and propene 16d have an electronic chemical potential μ similar to that of these nitrones. Consequently, the corresponding 32CA reactions will have a nonpolar character. The electrophilicity ω indices44 of the C,N-dialkyl nitrones are 0.76 (12) and 0.85 (21) eV, being classified on the borderline between marginal and moderate electrophiles within the electrophilicity scale. 16b On the other hand, the nucleophilicity N indices45 of the these nitrones are 3.65 (12) and 3.57 (21) eV, being classified as strong nucleophiles within the nucleophilicity scale.16b The presence of the two alkyl substituents in C,N-dialkyl nitrones 12 and 21 notably increases the nucleophilicity of these species with respect to that of the simplest nitrone 9, N = 2.92 eV. In addition, the similar nucleophilicity of nitrones 12 and 21 supports C,Ndimethyl nitrone 21 as a suitable reduced electronic model of experimental cyclic nitrone 12. The strong nucleophilic character of experimental cyclic nitrone 12 makes its participation in polar 32CA reactions with electrophilic ethylenes possible. Both, the electrophilicity ω and the nucleophilicity N indices of ethylenes 16 vary in a wide range depending on the nature of the substituents. For ethylenes 16a,b,e−g, the electrophilicity ω index ranges from 1.49 eV in methyl acrylate 16g to 2.96 eV in nitrosoethylene 16f, being classified as strong electrophiles. Note, however, that, within this classification of strong electrophiles, there are weaker and stronger electrophiles. The nucleophilicity N index of these species varies inversely, all of them being classified as marginal nucleophiles except nitrosoethylene 16f, which is a moderate nucleophile, N = 3.00 eV. On the other hand, the electrophilicity ω indices of styrene 16c, ethylene 5, and propene 16d are 1.13, 0.73, and 0.60 eV, respectively, thus being marginal electrophiles. Finally, while styrene 16c, N = 3.09 eV, is classified as a strong nucleophile,

Figure 2. Three-dimensional (3D) representations of the B3LYP/631G(d) Mulliken atomic spin densities of radical cations 12•+ and 21•+, and radical anions 16a•− and 16g•−, together with the nucleophilic Pk− Parr functions of nitrones 12 and 21, and the electrophilic Pk+ Parr functions of acrolein 16a and methyl acrylate 16g.

Analysis of the nucleophilic Pk− Parr functions at the reactive sites of nitrones 12 and 21 indicates that the O1 oxygen, with a Pk− value of ca. 0.76, is the most nucleophilic center of these species. Note that the C3 carbon is only half as nucleophilically activated as the O1 oxygen. On the other hand, analysis of the electrophilic Pk+ Parr functions at the reactive sites of acrolein 16a indicates that the 2186


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isoxazolidine for each one of them. Consequently, these 32CA reactions take place through a one-step mechanism (see Scheme 6). Relative energies in gas phase and in solvent of the stationary points involved in the 32CA reactions of nitrone 12 with ethylenes 16a and 16d are given in Table 3. Total energies are given in Table S4 in the Supporting Information. The activation energies associated with the 32CA reaction of nitrone 12 with acrolein 16a range from 1.4 to 7.8 kcal·mol−1, while those associated with the 32CA reaction of nitrone 12 with propene 16d range from 7.7 to 12.4 kcal·mol−1. On the other hand, formation of the corresponding isoxazolidines is exothermic by −32.9 to −34.3 kcal·mol−1 (17a−20a) and −34.9 to −40.6 kcal·mol−1 (17d−20d). Some appealing conclusions can be drawn from these energy results: (i) The 32CA reaction involving electrophilic acrolein 16a has a very low activation energy, 1.4 kcal·mol−1; this behavior is a consequence of the strong nucleophilic and electrophilic character of nitrone 12 and acrolein 16a, respectively, which enables a polar zw-type 32CA reaction. (ii) This 32CA reaction is completely meta regioselective, TS1a-mn being 5.9 kcal· mol−1 lower in energy than TS1a-on, and slightly endo stereoselective, TS1a-mn being 1.4 kcal·mol−1 lower in energy than TS1a-mx. (iii) The activation energy associated with the 32CA reaction involving nucleophilic propene 16d is 7.7 kcal· mol−1. This activation energy is 6.3 kcal·mol−1 higher in energy than that involving acrolein 16a. (iv) For propene 16d, the 32CA reaction is highly ortho regioselective, TS1d-ox being 3.2 kcal·mol−1 lower in energy than TS1d-mx, and moderately exo stereoselective, TS1d-ox being 2.2 kcal·mol−1 lower in energy than TS1d-on. (v) These relative energies are in reasonable agreement with the experimental results reported by Ali et al.;19 while the polar zw-type 32CA reaction involving acrolein 16a is meta/endo selective, the nonpolar zw-type 32CA reaction involving propene 16d is ortho/exo selective. Finally, (vi) formation of isoxazolidines 17a−d to 20a−d is strongly exothermic, by between 33 and 41 kcal·mol−1. Consequently, these 32CA reactions should be considered irreversible (see later). Solvent effects increase the activation energies and decrease reaction energies very insignificantly, by between 2 and 4 kcal· mol−1, due to a slightly better solvation of reagents than TSs and cycloadducts (see Table 3), but practically do not modify the regio- and stereoselectivities found in gas phase. On the basis of the incorrect representation of TACs as 1,2zwitterionic Lewis structures in which a negative charge and a positive charge are entirely located, many authors have suggested the use of diffuse functions.18 However, NPA

C4 carbon is the most electrophilic center of this species, having a value of Pk+ = 0.54. Therefore, it is predictable that the most favorable nucleophilic/electrophilic interaction along the attack of nitrones 12 and 21 onto the electrophilic ethylenes in a polar process will take place between the O1 oxygen center, the most nucleophilic center of these nitrones, and the C4 carbon, the most electrophilic center of the ethylenes. Interestingly, analysis of the electrophilic Pk+ Parr functions at the reactive sites of methyl acrylate 16g indicates that the C4 carbon is even more electrophilically activated than that in acrolein 16a, a behavior that contrasts with the regioselectivity experimentally observed for ethyl acrylate 13 (see Table 1).19 3.3. Study of the 32CA Reactions of Cyclic Nitrone 12 with Acrolein 16a and Propene 16d. The experimental 32CA reactions of cyclic nitrone 12 with acrolein 16a and propene 16d were selected as the most representative reaction models for the 32CA reactions of cyclic nitrone 12 with the electrophilic and nucleophilic ethylenes experimentally studied by Ali et al. (see Scheme 4).19 Due to the nonsymmetry of the two reagents, i.e., nitrone 12 and ethylenes 16a,d, these 32CA reactions can take place along four isomeric reaction paths (see Scheme 6): one pair of stereoisomeric reaction paths and one Scheme 6. 32CA Reaction of Cyclic Nitrone 12 with Ethylenes 16a,d

pair of regioisomeric ones. The regioisomeric pathways are related to the initial formation of the C3−C4 (ortho) or O1− C4 (meta) single bonds, while the endo and exo stereoisomeric reaction paths are associated with the relative approach of the substituent of the ethylene with respect to the bent nitrone N2 nitrogen, in such a manner that, along the endo pathway, the substituent approaches it. A search of the stationary points associated with the four competitive reaction paths allowed finding only one TS, TS1imn, TS1i-mx, TS1i-on, and TS1i-ox, and the corresponding

Table 3. MPWB1K/6-311G(d,p) Relativea Electronic Energies (in kcal·mol−1), in Gas Phase and in Solvent, for the Species Involved in the 32CA Reactions of Nitrone 12 with Ethylenes 16a,d 16a (R = CHO) TS1a-mn TS1a-mx TS1a-on TS1a-ox 17a 18a 19a 20a a

gas phase

DCM

1.4 2.8 7.3 7.8 −32.9 −34.3 −33.6 −34.1

4.0 5.5 8.3 9.0 −28.4 −30.0 −29.2 −29.6

16d (R = Me) TS1d-mn TS1d-mx TS1d-on TS1d-ox 17d 18d 19d 20d

gas phase

toluene

12.4 10.9 9.9 7.7 −34.9 −37.8 −39.4 −40.6

14.1 12.5 11.6 9.4 −32.8 −35.8 −37.4 −38.5

Relative to 12 and ethylenes 16a or 16d. 2187


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The Journal of Organic Chemistry analysis of nitrones shows that the O1 oxygen atom has a negative charge less than 0.60e, and the N2 nitrogen a positive charge less than 0.11e, thus being the use of diffuse functions unnecessary. In order to test this hypothesis, the stationary points involved in the polar 32CA reaction between cyclic nitrone 12 and acrolein 16a were optimized at the MPWB1K/ 6-311++G(d,p) computational level. Total and relative gas phase energies are given in Table S5 in the Supporting Information, while the geometries of the TSs are shown in Figure 3. The inclusion of diffuse functions increases the activation energies by ca. 1.7 kcal·mol−1 and decreases the exothermic character of the reaction by 2.2 kcal·mol−1, as a consequence of a slightly higher stabilization of cyclic nitrone 12 than the other stationary points. In addition, the TS geometries are not substantially modified (see later) and, due to a similar stabilization of all the TSs, the selectivities remain unchanged. Note that the unappreciable changes observed with the inclusion of diffuse functions are already taken into account with the inclusion of solvent effects. These energy and geometrical comparative analyses justify the nonuse of diffuse functions in the study of cycloaddition reactions. In order to investigate how thermal corrections and entropies can modify the relative electronic energies and selectivities, thermodynamic calculations in the experimental reaction conditions for the 32CA reactions of cyclic nitrone 12 with ethylenes 16a and 16d were performed. Enthalpies, entropies, and Gibbs free energies are given in Tables S6 and S7 in the Supporting Information. Inclusion of thermal corrections to the electronic energies does not significantly modify the relative enthalpies; while relative activation enthalpies have slightly increased by 0.8−1.1 kcal·mol−1 for the reaction involving acrolein 16a, and by 1.5−1.7 kcal·mol−1 for the reaction involving propene 16d, relative reaction enthalpies have slightly decreased by 3.1−4.5 kcal·mol−1. Although the activation enthalpies have slightly increased with respect to the activation

energies in solvent, the selectivities remain practically unchanged. The inclusion of entropies to enthalpies strongly increases relative Gibbs free energies by between 14.4−18.8 kcal·mol−1 for the reaction involving acrolein 16a, and by 17.7− 23.7 kcal·mol−1 for the reaction involving propene 16d, as a consequence of the unfavorable entropies associated with these bimolecular processes. The endo stereoselectivity found in the reaction involving acrolein 16a is slightly decreased due to the most unfavorable activation entropy associated with TS1a-mn. Finally, the exergonic character of the formation of isoxazolidines 17a,d to 20a,d, by between 9.1 and 16.2 kcal· mol−1, makes these 32CA reactions thermodynamically irreversible. The geometries of the TSs involved in the 32CA reactions of cyclic nitrone 12 with ethylenes 16a,d, including the distances between the carbon and oxygen nuclei involved in formation of the new O(C)−C single bonds in gas phase and in solvent, are displayed in Figures 3 and 4. Some appealing conclusions can be drawn from these geometrical data: (i) In the polar 32CA reaction between nitrone 12 and acrolein 16a, the most favorable meta TSs are geometrically more asynchronous than the ortho ones. (ii) At the meta TSs, the shorter C−O distance corresponds to the more favorable two-center interaction between the most nucleophilic center of nitrone 12, the O1 oxygen, and the most electrophilic center of acrolein 16a, the C4 carbon, in complete agreement with the analysis of the Parr functions at the GS of the reagents. (iii) The ortho TSs present an inverse geometrical asynchronicity, the C−C distance being shorter than the C−O one. However, the shorter distance corresponds to that involving the C4 carbon of the ethylene. (iv) The two pairs of stereoisomeric TSs present similar C−C and C−O distances. (v) Solvent effects of DCM make the TSs associated with the polar 32CA reaction between the cyclic nitrone 12 and acrolein 16a slightly more advanced and more asynchronous with respect to the gas phase geometries. This effect is more marked at the most favorable meta TSs. (vi)

Figure 3. MPWB1K/6-311G(d,p) gas phase optimized geometries of the TSs involved in the polar 32CA reaction between cyclic nitrone 12 and acrolein 16a. Distances are given in angstroms, Å. Distances in DCM are given in parentheses, while the MPWB1K/6-311++G(d,p) gas phase ones are given in brackets.

Figure 4. MPWB1K/6-311G(d,p) gas phase optimized geometries of the TSs involved in the nonpolar 32CA reaction between cyclic nitrone 12 and propene 16d. Distances are given in angstroms, Å. Distances in toluene are given in parentheses. 2188


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5), these electrostatic interactions are not as effective in exo TS1a-mx (see Figure 5). Consequently, the more favorable electrostatic interactions taking place in TS1a-mn with respect to TS1a-mx appear to be responsible for the experimental endo stereoselectivity of the polar 32CA reaction with acrolein 16a. On the other hand, the exo stereoselectivity in nonpolar reactions is expected to be mainly the result of repulsive van der Waals interactions developed along the endo reaction paths. Thus, in order to characterize the origin of the exo stereoselectivity in the nonpolar 32CA reaction of cyclic nitrone 12 with propene 16d, the topology of the NCI46 taking place at the more favorable ortho regioisomeric TSs was analyzed. NCI topological analysis of TS1d-on and TS1d-ox indicates that the van der Waals interactions (green surfaces) taking place in these TSs are mainly repulsive. Interestingly, the repulsive green surface present in TS1d-on is slightly more extended than that present in TS1d-ox (see Figure 6), clearly

Solvent effects of toluene cause unappreciable changes in the TSs associated with the nonpolar 32CA reaction between cyclic nitrone 12 and propene 16d. Finally, (vii) inclusion of diffuse functions at the MPWB1K/6-311++G(d,p) level does not significantly modify the MPWB1K/6-311G(d,p) geometries. Thorough studies have made it possible to establish good correlations between the polar character of the reactions and their feasibility; the more polar the reaction, i.e., the higher the GEDT at the most favorable TS, the faster the reaction. Cycloadditions with GEDT values near 0.0e correspond to nonpolar processes, whereas values higher than 0.2e correspond to polar processes. The GEDT computed at the gas phase TSs associated with the 32CA reaction of cyclic nitrone 12 with acrolein 16a is 0.17e at TS1a-mn, 0.15e at TS1a-mx, 0.11 at TS1a-on, and 0.09e at TS1a-on, the most favorable meta/endo TS being the most polar one. These values reveal the polar character of this 32CA reaction. On the other hand, the TSs associated with the 32CA reaction of cyclic nitrone 12 with propene 16d present a negligible GEDT, between 0.01e and 0.00e, being indicative of the nonpolar character of this 32CA reaction. 3.4. Origin of the Endo/Exo Stereoselectivity in the 32CA Reactions of Cyclic Nitrone 12 with Acrolein 16a and Propene 16d. Endo/exo stereoselectivity in cycloaddition reactions may be the result of a series of weak noncovalent interactions, namely, electrostatic interactions, hydrogen bonds, van der Waals interactions, etc. While favorable electrostatic interactions could play an important role in the endo stereoselectivity in polar cycloaddition reactions, repulsive steric interactions developed along the endo approach mode could be responsible for the exo stereoselectivity in nonpolar cycloaddition reactions. The polar character of the 32CA reaction of cyclic nitrone 12 with acrolein 16a causes the corresponding TSs to have a zwitterionic character due to the charge separation resulting from the GEDT, 0.17e. While the nucleophilic nitrone framework becomes somewhat positively charged, the electrophilic acrolein one becomes somewhat negatively charged. Thus, the more favorable the relative orientation of both polarized frameworks at the TSs, the stronger the electrostatic interactions. In order to characterize such electrostatic interactions, the molecular electrostatic potential (MEP) of the more favorable meta regioisomeric TSs was analyzed (see Figure 5). Analysis of the MEP of both TSs shows that, while the bluest (most positively charged) regions of the nitrone framework, i.e., the methylene hydrogens, precisely face the reddest region (most negatively charged) of the acrolein moiety, i.e., the carbonyl oxygen, in endo TS1a-mn (see Figure

Figure 6. MPWB1K/6-311G(d,p) repulsive NCI gradient isosurfaces, represented at an isovalue of 0.5 au, of the ortho regioisomeric TSs involved in the nonpolar 32CA reaction between cyclic nitrone 12 and propene 16d.

confirming that the additional steric hindrance between the methyl hydrogens of the propene framework and methylene hydrogens of the nitrone one in endo TS1d-on could be responsible for the exo stereoselectivity in the nonpolar 32CA reaction with propene 16d. 3.5. Role of the Electrophilic Character of Ethylenes in zw-type 32CA Reactions of C,N-Dialkyl Nitrones. Finally, the activation energies of the 32CA reactions of C,N-dimethyl nitrone 21, as a reduced model of cyclic nitrogen 12, with the series of ethylene derivatives 16 of increased electrophilic character were studied in order to understand the role of the electrophilic character of the ethylene in zw-type 32CA reactions of nucleophilic C,N-dialkyl nitrones. Besides the electrophilic ethylenes 13 and 16a,b,g studied by Ali et al.,19 nitroethylene 16e and nitrosoethylene 16f were also used as models of strong electrophilic ethylenes. Note that Jasiński studied the 32CA reactions of nitrones with nitroethylenes both experimentally and theoretically in depth.47 Similar to the 32CA reactions of cyclic nitrone 12, these 32CA reactions can take place along four competitive reaction pathways (see Scheme 7). Analysis of the stationary points involved in the four competitive reaction paths associated with these 32CA reactions indicate that they take place through onestep mechanisms. The gas phase activation energies and GEDT associated with the four regio- and stereoisomeric TSs are given in Table 4, while the total gas phase energies of the stationary points involved in these 32CA reactions are given in Table S8 in the Supporting Information.

Figure 5. MPWB1K/6-311G(d,p) MEPs, represented at an isovalue of 0.004, of the meta regioisomeric TSs involved in the polar 32CA reaction of nitrone 12 with acrolein 16a. MEP scales range by between ±8.803 Bohr−1 for TS1a-mn and ±8.721 Bohr−1 for TS1a-mx. 2189


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Interestingly, following conclusion (ii), when the activation energies for this series of 32CA reactions are plotted versus the computed GEDT at the TSs, a very good linear correlation (R2 = 0.97) is observed (see Figure 7a). These results assert our assumption that the feasibility of zw-type 32CA reactions depends on their polar character.13 Similarly, when the activation energies are plotted versus the computed electrophilicity ω index of the ethylene derivative, a good linear correlation is also obtained (R2 = 0.95; see Figure 7b). These linear correlations, also observed in polar Diels−Alder reactions,16b assert the relevance of the analysis of the CDFT indices at the GS of the reagents in the study of the reactivity in polar reactions. Finally, the suitability of the MPWB1K functional to study these zw-type 32CA reactions was tested by performing CCSD(T)/cc-pVTZ single point energy calculations at the stationary points involved in the most favorable 32CA reactions of C,N-dimethyl nitrone 21 with acrolein 16a. The CCSD(T)/ cc-pVTZ total and relative energies are given in Table S9 in the Supporting Information. The CCSD(T)/cc-pVTZ activation energies, by between 3.7−6.4 kcal·mol−1, are found very close to the MPWB1K/6-311G(d,p) ones, 2.7−7.6 kcal·mol−1. On the other hand, CCSD(T)/cc-pVTZ reaction energies, by between −29.5 and −33.2 kcal·mol−1, are found ca. 5 kcal· mol−1 less exothermic than the MPWB1K/6-311G(d,p) ones, by between −34.2 and −37.7 kcal·mol−1. Consequently, these very similar energy results allowed asserting the use of the selected MPWB1K/6-311G(d,p) computational level to study these zw-type 32CA reactions, though it is worth noting that the experimentally found selectivity is lost when the CCSD(T)/ccpVTZ method is used. The gas phase geometries of the most favorable TSs associated with the 32CA reactions between C,N-dimethyl nitrone 21 and ethylenes 16 are displayed in Figure 8. Analysis of the distances between the carbon and oxygen nuclei involved in formation of the new O(C)−C single bonds in gas phase allowed drawing some appealing conclusions: (i) From a geometrical point of view, the four most favorable meta/endo TSs correspond to very advanced and very asynchronous processes. (ii) This trend increases with the electrophilic character of the ethylene 16. (iii) In the meta regioisomeric TSs involving electrophilic ethylenes 16a,b,e−g, the shorter C−O distance corresponds to the two-center interaction between the most nucleophilic center of nitrone 21, the O1 oxygen, and the most electrophilic center of these ethylenes, the β-conjugated C4 carbon. (iv) The C−O and C−C distances in the ortho regioisomeric TS2d-ox and in TS3 associated with the nonpolar 32CA reaction involving ethylene 5 are very similar. (v) In the polar reactions involving electron-withdrawing groups, an endo approach mode is achieved, while, in nonpolar reactions involving electron-releasing groups, the bulky

Scheme 7. 32CA Reactions between C,N-Dimethyl Nitrone 21 and the Series of Ethylene Derivatives 16a−g

Analysis of the activation energies given in Table 4 allows drawing the following appealing conclusions: (i) The activation energies associated with the 32CA reactions of C,N-dimethyl nitrone 21 with acrolein 16a, 2.4 kcal·mol−1 (TS2a-mn), and with propene 16d, 9.6 kcal·mol−1 (TS2d-ox), are similar to those associated with the 32CA reactions involving cyclic nitrone 12 (see Table 3), thus supporting nitrone 21 as a reduced model for the experimental cyclic nitrone 12. (ii) There is a clear trend in the decrease of the activation energy with the increase of the electrophilic character of the ethylene derivative, i.e., the polar character of the reaction measured by the GEDT (see Table 4). (iii) In the series of polar 32CA reactions (16a,b,e−g), the computed MPWB1K/6-311G(d,p) meta regioselectivity increases with the polar character of the reaction. This behavior is a consequence of the more favorable two-center interaction taking place in polar reactions between the most nucleophilic center of the nitrone, the O1 oxygen, and the most electrophilic center of the ethylene, the C4 carbon. (iv) The meta regioselectivity found for the 32CA reaction involving nitroethylene 16e is in complete agreement with that experimentally found by Jasiński in the 32CA reactions of nitrones with nitroethylene derivatives.47 (v) Similarly, for the series of strong electrophilic ethylenes 16e (R = NO2), 16f (R = NO), and 16a (R = CHO), the computed endo stereoselectivity also increases with the polar character of the reaction, in agreement with the rationalization given in section 3.4. (vi) Similarly to the reaction involving nitrone 12, there is a change of the regio- and stereoselectivity for the nonpolar 32CA reaction with propene 16d. Now, the ortho/exo TS2d-ox is the most favorable one. Finally, (vii) the computed meta/endo selectivity found in the 32CA reactions involving the two electrophilic ethylenes 16b (R = CN) and 16g (R = CO2Me) is opposite to the ortho/exo selectivity experimentally found by Ali et al. (see Table 1).19 Note that these ethylenes are the least electrophilic species among the electrophilic series 16a,b,e−g.

Table 4. MPWB1K/6-311G(d,p) Gas Phase Activation Energiesa (in kcal·mol−1) of the Regio- and Stereoisomeric TSs Involved in the 32CA Reactions of C,N-Dimethyl Nitrone 21 with Ethylenes 16b

a

ethylene

16e

16f

16a

16b

16g

16c

16d

5

R= TS2i-mn TS2i-mx TS2i-on TS2i-ox GEDT

NO2 −4.1 −0.5 2.6 2.6 0.24

NO −3.9 −0.9 3.3 6.3 0.25

CHO 2.4 3.0 7.1 7.6 0.16

CN 1.8 4.3 6.4 7.2 0.16

CO2Me 2.8 3.5 6.6 6.0 0.12

Ph 11.0 9.0 10.4 9.5 0.06

Me 13.7 12.9 11.5 9.6 0.00

H 10.0

0.02

Relative to nitrone 21 and the corresponding ethylene 16. bThe computed GEDT at the most favorable TS of each 32CA reaction is given in e. 2190


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Figure 7. Plot of the MPWB1K/6-311G(d,p) computed activation energies, in kcal·mol−1, associated with the most favorable TSs involved in the 32CA reactions of C,N-dimethyl nitrone 21 with ethylenes 16 versus (a) the polarity of the reactions measured by the GEDT, in e, computed at the most favorable TS (R2 = 0.97), and (b) the electrophilicity ω index, in eV, of the ethylene derivatives 16 (R2 = 0.95).

hindrance appearing along the endo approach make the exo reaction paths the most favorable ones (see section 3.4). This theoretical analysis of the stereoselectivity is in complete agreement with the experimental results reported by Ali et al.19 3.6. BET Study of Nonpolar and Polar zw-type 32CA Reactions of C,N-Dialkyl Nitrones. When trying to achieve a better understanding of the mechanism of an organic reaction, the so-called BET 36 has proven to be a very useful methodological tool. This quantum-chemical methodology makes it possible to understand the bonding changes along a reaction path and, thus, to establish the nature of the electronic rearrangement associated with a given molecular mechanism.8 Within MEDT, the bonding changes are topologically and energetically analyzed in order to understand the origin of the activation and reaction energies associated with an organic reaction. The complete BET studies for the 32CA reactions of C,N-dimethyl nitrone 21 with propene 16d and acrolein 16a, along the most favorable ortho/exo and meta/endo reaction paths, respectively, are given in the Supporting Information. In this section, the bonding changes arising from these BET studies and their associated energies along the two zw-type 32CA reactions are summarized and described in a chemical fashion. 3.6.1. Study of the Nonpolar zw-type 32CA Reaction between C,N-Dimethyl Nitrone 21 and Propene 16d. The sequential bonding changes resulting from the BET study along the most favorable ortho/exo reaction path associated with the nonpolar zw-type 32CA reaction between C,N-dimethyl nitrone 21 and propene 16d are summarized in Table 5, while the phases and groups in which the corresponding IRC is topologically divided are represented in Figure 9. Some appealing conclusions can be drawn from this BET study: (i) The molecular mechanism of this reaction is topologically characterized by 10 differentiated phases which, in turn, can be reorganized in three Groups A−C associated with significant chemical events (see Table 5 and Figure 9): (a) Group A, which comprises Phases I−IV and demands an energy cost (EC) of ca. 13.6 kcal·mol−1, is associated with the rupture of the N2−C3 and C4−C5 double bonds of the reagents, leading to the formation of the N2 nitrogen lone pair at the nitrone framework; (b) Group B, which comprises Phases V and VI and releases a molecular relaxation energy (MRE) of ca. 5.1 kcal·mol−1, is mainly associated with the formation of the two C3 (first) and C4 (second) pseudoradical centers at the interacting carbons, which are involved in the subsequent C3−

Figure 8. MPWB1K/6-311G(d,p) gas phase optimized geometries of the most favorable TSs associated with the zw-type 32CA reactions between C,N-dimethyl nitrone 21 and ethylenes 16. Distances are given in angstroms, Å.

substituents are arranged in an exo mode. Thus, while favorable electrostatic interactions appearing along the endo approach between the two polarized fragments are responsible for the endo stereoselectivity in polar reactions, the unfavorable steric 2191


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Table 5. Groups A−C in Which the Sequential Bonding Changes along the Most Favorable Ortho/Exo Reaction Path Associated with the Nonpolar zw-type 32CA Reaction between C,N-Dimethyl Nitrone 21 and Propene 16d Can Be Chemically Reorganizeda

Distances are given in angstroms, Å, the MPWB1K/6-311G(d,p) relative energies (relative to the first point of the reaction path, P0-I) involved in each group, ΔE, are given in kcal·mol−1, and GEDT values are given in average number of electrons, e. A simplified representation of the molecular mechanism by Lewis’s structures arising from the topological analysis of the ELF of the points Pi-I characterizing the corresponding topological phases is also included.

a

high EC demanded to reach this TS, 13.6 kcal·mol−1, can mainly be related to the rupture of the nitrone N2−C3 and propene C4−C5 double bonds, the former to a more extent. (iii) Formation of the first C3−C4 single bond begins at a C−C distance of ca. 1.97 Å through the C-to-C coupling of the two C3 and C4 pseudoradical centers. (iv) Formation of the second O1−C5 single bond begins at an O−C distance of ca. 1.77 Å through the donation of nonbonding electron density of the nitrone O1 oxygen to the C5 carbon of the propene framework. (v) ELF topology of point P9-I shows a high asynchronicity in the C−C and C−O single bond formation (see the Supporting Information): i.e., formation of the second O1−C5 single bond begins at the last Phase X with an initial population of 0.71e, when the C3−C4 single bond, whose formation begins in Phase VII, has already reached ca. 87% of its final population in 25d. This behavior contrasts with the low geometrical asynchronicity found at TS2d-ox, Δd = 0.04 (see Figure 8), emphasizing that the analysis of the geometrical asynchronicity is not valid when the nature of the single bonds that are going to be formed, i.e., C−C and C−O, is different.12a Finally, (vi) a comparative analysis of the BET study of the ortho/exo reaction path associated with the 32CA reaction between C,N-dimethyl nitrone 21 and propene 16d and that of the nonpolar 32CA reaction between the simplest nitrone 9 and ethylene 5 (see the Supporting Information) allows establishing a great similitude. The two nonpolar processes begin with the formation of the C−C single bond through the C-to-C coupling of two pseudoradical centers, while formation of the C−O single bond takes place at the last phase of the reaction path.

Figure 9. Phases in which the MPWB1K/6-311G(d,p) IRC associated with the nonpolar zw-type 32CA reaction between C,N-dimethyl nitrone 21 and propene 16d is topologically divided. The red point indicates the position of TS2d-ox, black dashed lines separate the phases defined by points Pi-I along the IRC, while colored areas represent the different groups in which the reaction is topologically divided. Relative energies (ΔE, in kcal·mol−1) are given with respect to the separated reagents, the nitrone 21 and propene 16d.

C4 single bond formation; and finally, (c) Group C, which comprises Phases VII−X and releases a high MRE of 44.0 kcal· mol−1, is mainly associated with the formation of the two new C3−C4 (first) and O1−C5 (second) single bonds and to the molecular electronic relaxation associated with the formation of isoxazolidine 25d. (ii) As TS2d-ox is found in Phase IV, the 2192


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Table 6. Groups A−E in Which the Sequential Bonding Changes along the Most Favorable Meta/Endo Reaction Path Associated with the Polar zw-type 32CA Reaction between C,N-Dimethyl Nitrone 21 and Acrolein 16a Can Be Chemically Reorganizeda

Distances are given in angstroms, Å, the MPWB1K/6-311G(d,p) relative (relative to the first point of the IRC, P0-II) energies involved in each group, ΔE, are given in kcal·mol−1, and GEDT values are given in average number of electrons, e. A simplified representation of the molecular mechanism by Lewis’s structures arising from the topological analysis of the ELF of the points Pi-II characterizing the corresponding topological phases is also included. a

3.6.2. Study of the 32CA Reaction between C,N-Dimethyl Nitrone 21 with Acrolein 16a. The sequential bonding changes resulting from the BET study along the most favorable meta/endo reaction path associated with the polar zw-type 32CA reaction between C,N-dimethyl nitrone 21 and acrolein 16a are summarized in Table 6, while the phases and groups in which the corresponding IRC is topologically divided are represented in Figure 10. Some appealing conclusions can be drawn from this BET study: (i) The molecular mechanism of this polar 32CA reaction is topologically characterized by 10 differentiated phases which, in turn, can be reorganized in five Groups A−E associated with significant chemical events (see Table 6 and Figure 10): (a) Group A, which comprises Phases I−V and demands an EC of ca. 7.7 kcal·mol−1, is characterized by the rupture of the C4−C5 double bond of acrolein 16a and the rupture of the N2−C3 double bond of nitrone 21, leading to

the formation of the N2 nitrogen lone pair at the nitrone framework; (b) Group B, which comprises Phases VI and VII and releases an MRE of ca. 1.9 kcal·mol−1, is associated with the formation of the first C5 pseudoradical center at the acrolein framework demanded for the formation of the second C3−C5 single bond; (c) Group C, which comprises only Phase VIII and releases a low MRE of ca. 0.7 kcal·mol−1, is associated with the formation of the first O1−C4 single bond; (d) Group D, which comprises only Phase IX and releases an MRE of ca. 6.7 kcal· mol−1, is associated with the formation of the second C3 pseudoradical center at the nitrone framework demanded for the subsequent C3−C5 single bond formation; and finally, (e) Group D, which comprises only the last Phase X and releases a high MRE of 27.0 kcal·mol−1, is associated with the formation of the second C3−C5 single bond and to the molecular electronic relaxation associated with the formation of isoxazolidine 22a. (ii) As TS2a-mn is found in Phase IV, the 2193


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with the nonpolar zw-type 32CA reaction of C,N-dimethyl nitrone 21 with propene 16d. Consequently, the meta/ortho regioselectivity in zw-type 32CA reactions involving C,N-dialkyl nitrones appears to be controlled by the polar nature of the reaction. Thus, while, in nonpolar 32CA reactions, the reaction begins with the formation of the C−C single bond involving the nitrone C3 carbon and the β-conjugated C4 carbon of the ethylene derivative, in polar 32CA reactions, the reaction begins with the formation of the C−O single bond involving the nitrone O1 oxygen, which is the most nucleophilic center of the nitrone, and the β-conjugated C4 carbon of the ethylene derivative, which is the most electrophilic center of this molecule (see Scheme 8). Note that, in both cases, the reaction begins at the nonsubstituted C4 carbon of the ethylene.

Figure 10. Phases in which the MPWB1K/6-311G(d,p) IRC associated with the polar zw-type 32CA reaction between C,Ndimethyl nitrone 21 and acrolein 16a is topologically divided. The red point indicates the position of TS2a-mn, black dashed lines separate the phases defined by points Pi-II along the IRC, while colored areas represent the different groups in which the reaction is topologically divided. Relative energies (ΔE, in kcal·mol−1) are given with respect to the separated reagents, nitrone 21 and acrolein 16a.

Scheme 8. Schematic Representation of the Electron Density Reorganization Associated with the Initial Formation of the C−C or C−O Single Bonds along the Ortho and Meta Reaction Path Associated with the Nonpolar and Polar zwtype 32CA Reactions of C,N-Dialkyl Nitrones with Nucleophilic or Electrophilic Ethylenes

moderate EC demanded to reach this TS, 8.0 kcal·mol−1, can mainly be related to the rupture of the double bonds of the reagents. (iii) Formation of the first O1−C4 single bond begins in Phase VI at an O−C distance of ca. 1.70 Å through the donation of nonbonding electron density of the nitrone O1 oxygen to the β-conjugated C4 carbon of the acrolein framework, a behavior anticipated through the analysis of the Parr functions at the GS of the reagents (see section 3.2). (iv) Formation of the second C3−C5 single bond begins in Phase IX at a C−C distance of 2.07 Å through the C-to-C coupling of the two C3 and C5 pseudoradical centers. Finally, (v) formation of the second C3−C5 single bond begins at the last Phase X with an initial population of 1.06e, when the O1−C4 single bond, whose formation begins in Phase VIII, has already reached ca. 75% of its final population in 22a. This result suggests that the single bond formation in the nonpolar 32CA reaction involving propene 16d is more asynchronous than the polar 32CA reaction involving acrolein 16a. 3.7. Origin of the Meta/Ortho Regioselectivity in the zw-type 32CA Reactions of C,N-Dialkyl Nitrones with Ethylene Derivatives. zw-type 32CA reactions demand the nucleophilic activation of the TAC and the electrophilic activation of the ethylene, or vice versa, in order to take place easily through a polar process.14 In polar reactions involving two nonsymmetric reagents, the most favorable regioisomeric reaction path is that involving the two-center interaction between the most electrophilic center of the TAC, i.e., the O1 oxygen in the case of nitrones, and the most electrophilic center of the ethylene derivative,12a i.e., the β-substituted carbon, a behavior that can be anticipated by the analysis of the Parr functions at the GS of the reagents.32 On the other hand, BET analysis of the nonpolar zw-type 32CA reaction of the simplest nitrone 9 with ethylene 5 indicates that this reaction takes place through an asynchronous one-step mechanism in which the formation of the C−C single bond is more advanced than the formation of the C−O one, which takes place at the end of the reaction path (see the Supporting Information). A similar bonding pattern is found along the most favorable ortho/exo reaction path associated

3.8. Origin of the Inverse Ortho Regioselectivity Experimentally Found for the 32CA Reactions Involving Ethyl Acrylate 13 and Acrylonitrile 16b. Analysis of the participation of ethyl acrylate 13 and acrylonitrile 16b in the 32CA reactions with cyclic nitrone 12, experimentally studied by Ali et al.,19 allows obtaining two appealing conclusions (see Table 1): (i) The reaction conditions, i.e., temperature, reaction time, and solvent, are similar to those used in the 32CA reaction involving electrophilic acrolein 16a. And observed ortho regioselectivity is opposite to the meta one found in the 32CA reaction involving acrolein 16a. B3LYP/6-31G(d) and M06-2X/6-311++G(d,p) thermodynamic calculations carried out for the 32CA reaction between cyclic nitrone 12 and ethyl acrylate 1318 showed a similar meta/ endo selectivity to that found herein at the MPWB1K/6311G(d,p) computational level (see the 32CA reaction of methyl acrylate 16g in Table 4). Consequently, these DFT functionals are not also able to account for the unexpected ortho regioselectivity experimentally observed.19 In the nonsubstituted ethylene 5, the rupture of the C−C double bond demanded for the initial C−C single bond formation takes place via a homolytic process. A similar behavior is found in the case of nucleophilic ethylenes such as propene 16d. Conversely, the presence of an efficient electronwithdrawing group such as −CHO, −NO2, or −NO enables an easy polarization of the C−C double bond of the ethylene, favoring the depopulation of the β-conjugated C4 carbon in order to achieve the C−O bond formation. However, the presence of less electron-withdrawing groups such as −CN or 2194


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The Journal of Organic Chemistry −CO2R could be not efficient enough, and consequently, the depopulation of the β-conjugated C4 carbon could be more unfavorable than the formation of the corresponding pseudoradical center, thus favoring the initial formation of the C−C single bond. In summary, the B3LYP, MPWB1K, and M06-2X functionals predict in all cases a meta regioselectivity for the 32CA reactions involving strong electrophilic ethylenes, in agreement with the experimental reaction conditions. However, in the 32CA reactions involving weak electron-withdrawing groups such as −CN or −CO2R, it appears that the depopulation of the β-conjugated C4 carbon of the C−C double bond of the ethylene could be more unfavorable than the homolytic rupture of the C−C double bond, thus favoring the initial formation of the C−C single bond over the C−O one and, accordingly, an ortho regioselectivity, a behavior not reproduced through DFT calculations.

standing of the unexpected ortho regioselectivity, which cannot be modeled by standard computational methods. Finally, a BET study of the most favorable reaction paths associated with the 32CA reactions of C,N-dimethyl nitrone 21 with propene 16d and with acrolein 16a allows establishing the general mechanistic behaviors of zw-type 32CA reactions of nucleophilic C,N-dialkyl nitrones. While nonpolar zw-type 32CA reactions involving weak electrophilic ethylenes begin with the formation of the C−C single bond through the C-to-C coupling of two carbon pseudoradical centers, polar zw-type 32CA reactions involving strong electrophilic ethylenes begin with the formation of the O−C single bond through the donation of nonbonding electron density of the nitrone oxygen, the most nucleophilic center of the nitrone, to the β-conjugated carbon of the electrophilic ethylene, the most electrophilic center of the ethylene. Interestingly, this mechanism demands the initial depopulation of the β-conjugated carbon of the substituted ethylene, a feature only possible when strong electron-withdrawing groups such as the −CHO or the −NO2 are present at the α-position. An MEDT comparative analysis of the 32CA reactions of the C,N-dialkyl nitrones 12 and 21 with ethylene derivatives allows establishing that the electrophilic activation of the ethylene not only decreases the activation energy of these zw-type 32CA reactions but also changes the molecular mechanism, and consequently the experimentally observed regioselectivity. The present MEDT study provides an insightful rationalization of the general reactivity of nucleophilic C,N-dialkyl nitrones with ethylene derivatives in zw-type 32CA reactions, making a huge contribution to the theoretical, as well as experimental, understanding of the zw-type chemistry.

4. CONCLUSIONS The zw-type 32CA reactions of C,N-dialkyl nitrones with ethylenes of increased electrophilic character have been studied within MEDT at the MPWB1K/6-311G(d,p) DFT computational level. Both, reactivity and selectivities have been analyzed depending on the polar character of the reaction, i.e., the electrophilic character of the ethylene. Topological analysis of the ELF of C,N-dialkyl nitrones 12 and 21 allows establishing their zwitterionic structure, which enables their participation in zw-type 32CA reactions, while analysis of the CDFT indices allows characterizing the strong nucleophilic character of these nitrones, thus explaining the acceleration experimentally observed toward electrophilic ethylenes. These 32CA reactions take place through a nonconcerted one-step mechanism. The 32CA reaction involving electrophilic acrolein 16a is 6.3 kcal·mol−1 lower in energy than that involving propene 16d. The use of this strong electrophilic ethylene also produces important changes in both the regioand stereoselectivity; thus, while the nonpolar 32CA reaction involving propene 16d is ortho/exo selective, the polar 32CA reaction involving acrolein 16a is meta/endo selective, in clear agreement with the experimental outcomes. The endo/exo stereoselectivity experimentally observed is explained in terms of weak noncovalent interactions taking place at the TSs. While the endo stereoselectivity found in polar reactions can be associated with the more favorable electrostatic interactions taking place at the polar endo TSs, the exo stereoselectivity found in nonpolar reactions may be a consequence of the more unfavorable van der Waals interactions related to the steric hindrance developed along the endo approach mode. Analysis of the activation energies of the 32CA reactions of nucleophilic C,N-dimethyl nitrone 21 with a wide series of ethylene derivatives 16 of increased electrophilic character allows establishing a very good correlation between the electrophilic character of the ethylene and the feasibility of the reactions, in complete agreement with the proposed zw-type reactivity. The observed meta/endo selectivity is well correlated with the polar character of the reaction. However, the predicted regioselectivity fails when ethylenes with weak electrophilic character such as methyl acrylate 16g are considered; i.e., DFT calculations using different functionals predict a meta/endo selectivity, while the reaction was experimentally found to be ortho/exo selective. Our MEDT study provides an under-

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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.7b03093. BET studies of the zw-type 32CA reactions of the simplest nitrone 9 with ethylene 5 and of C,N-dimethyl nitrone 21 with acrolein 16a and propene 16d. Tables with MPWB1K/6-311G(d,p) total electronic energies, in gas phase and in solvent, as well as thermodynamic data, for the stationary points involved in the 32CA reactions of cyclic nitrone 12 with ethylenes 16a,d; MPWB1K/6311++G(d,p) total and relative gas phase electronic energies for the stationary points involved in the 32CA reaction of cyclic nitrone 12 with acrolein 16a; MPWB1K/6-311G(d,p) total and relative gas phase electronic energies for the stationary points involved in the 32CA reactions of C,N-dimethyl nitrone 21 with ethylenes 5 and 16; CCSD(T)/cc-pVTZ//MPWB1K/6311G(d,p) total and relative gas phase electronic energies for the stationary points involved in the 32CA reaction of C,N-dimethyl nitrone 21 with acrolein 16a. MPWB1K/ 6-311G(d,p) gas phase total energies, unique imaginary frequency, and Cartesian coordinates of the stationary points involved in the 32CA reactions of cyclic nitrone 12 with ethylenes 16a,d (PDF)

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*E-mail: [email protected]. Web: www.luisrdomingo.com. 2195


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Luis R. Domingo: 0000-0002-2023-0108 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by the Ministry of Economy and Competitiveness (MINECO) of the Spanish Government, project CTQ2016-78669-P (AEI/FEDER, UE), and Fondecyt (Chile) grant 1140341. Prof L. R. D. thanks Fondecyt for continuous support through Cooperación Internacional. M.R.G. also thanks MINECO for a predoctoral contract cofinanced by the European Social Fund (BES-2014-068258).

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