A Molecular Electron Density Theory Study of the Reactivity and

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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 J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03093 • Publication Date (Web): 19 Jan 2018 Downloaded from http://pubs.acs.org on January 19, 2018

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The Journal of Organic Chemistry

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,*a Mar Ríos-Gutiérrez,a and Patricia Pérezb a

Department of Organic Chemistry, University of Valencia, Dr. Moliner 50, E-46100 Burjassot, Valencia, Spain. b Universidad Andres Bello, Facultad de Ciencias Exactas, Departamento de Ciencias Químicas, Av. República 498, 8370146, Santiago, Chile. e-mail: [email protected] web: www.luisrdomingo.com

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/6-311G(d,p) computational level. Both, reactivity and selectivities are rationalised 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 regio- and 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.

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2 1. Introduction Since the first examples gathered by Irvin in 1938,1 demonstrating that nitrones 1 are capable of undergoing 1,3-additions, the [3+2]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 acids5 and the high efficiency of this transformation6 combine to make this reaction a powerful method for heterocyclic synthesis.7 O

S

R1N R1 N R2HC

R2

S +

5-isoxazolidines 3

O

Nitrones 1

O R1N

ethylenes 2

S R2

4-isoxazolidines 4

Scheme 1. 32CA reaction of nitrones 1 with ethylenes 2. 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 characterise 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 categorised, in 1969, pericyclic reactions, in which “all first 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 behaviour 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 “concerted on a closed curve”, thus ruling out the pericyclic mechanism.12 Recent MEDT studies devoted to


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

H

H

H C

N CH2

Azomethine ylide 6

H2C

N

C

NH

Azomethine imine 7

Nitrile ylide 8

H H

N H2C

O Nitrone 9

Structure pseudodiradical

pseudoradical

pdr-type

pmr-type

carbenoid

zwitterionic

cb-type

zw-type

Reactivity

Scheme 2. Electronic structure of TACs and reactivity types in 32CA reactions with ethylene 5.13 Recent MEDT studies of 32CA reactions of nitrones have emphasised that these reactions take place via a non-concerted 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 non-bonding electron density of the nitrone oxygen to the βconjugated carbon of electrophilic ethylenes.12a These studies also emphasised that



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4 Conceptual Density Functional Theory (CDFT) reactivity indices16 are a powerful and easily accessible tool to predict the non-polar or polar character of zw-type 32CA reactions, which plays a crucial role in activation energies.14 In the last 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. Regio- and 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 two regioisomeric pathways were performed to characterise the molecular mechanism, the O−C and C−C single bond formation was not properly characterised.18 CO2Et N O n

N

N

13

n H 14

CO2Et

O CO2Et

+

+ n

11 n = 1 12 n = 2

O

H 15

Scheme 3. 32CA reaction of cyclic nitrones 11 and 12 with ethyl acrylate 13.

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, was used (see Scheme 4).

Scheme 4. 32CA reaction of cyclic nitrone 12 with the series of ethylene derivatives 13 and 16.19


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5

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 non-polar solvent, was used in the slower ones. This change of the solvent polarity agrees with the expected polar or non-polar 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 favours 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; and 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 Table 1. Experimental conditions, i.e. reaction temperature (in ºC), 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 CHO CN CO2Et Ph Me

Temp 25 25 0 110 110

Time Solvent 0.2 DCM 0.5 DCM 0.2 DCM 5 Toluene 4 Toluene

17 68

18 24

19

20

20 15 22 0

61 69 78 100

Yield 96 92 96 92 53

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)



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6 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,Ndimethyl nitrone 21 with ethylene 5 and with the ethylene derivative series 16 were also analysed in order to understand the participation of nucleophilic C,N-dialkyl nitrones in zwtype 32CA reactions (see Scheme 5). This comprehensive study complements our 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 zw-type 32CA reactions.

O N

12

H3C

H3C

O

R

N

21

5 R=H 16a R = CHO 16b R = CN 16c R = Ph 16d R = Me 16e R = NO2 16f R = NO 16g R = CO2Me

Scheme 5. Nitrones 12 and 21, ethylene 5 and the series of ethylene derivatives 16 involved in the 32CA reactions studied herein. 2. Computational methods A recent analysis about the applicability of the B3LYP,20 MPWB1K21 and M06-2X22 functionals in the study of non-polar 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 ussing 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 Supplementary Material).25 Optimisations were carried out using the Berny analytical gradient optimisation method.26 The stationary points were characterised by frequency computations in order to verify that TSs have one and only one imaginary frequency. The


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7 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 GonzálezSchlegel integration method.28 Solvent effects of DCM or toluene were taken into account by full optimisation of the gas phase structures at the MPWB1K/6-311G(d,p) computational level using the polarisable 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 (qi), obtained by a natural population analysis (NPA),31 of the atoms belonging to each framework (f) at the TSs; i.e. GEDT (f) =

; 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 reference 16b. All computations were carried out with the Gaussian 09 suite of programs.33 Topological analysis of the electron localisation function (ELF)34 was performed with the TopMod35 package using the corresponding MPWB1K/6-311G(d,p) monodeterminantal wavefunctions 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 visualised using the GaussView program,37 while the representation of the ELF basin isosurfaces was done by using the UCSF Chimera program.38 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,N-dimethyl 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 analysed 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 analysed 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 analysed; (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



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8 analysed in order to understand the behaviour of nucleophilic C,N-dialkyl nitrones in zwtype 32CA reactions; (vi) later, a BET study of the 32CA reaction of nitrone 21 with acrolein 16a along the most favourable meta/endo reaction path, and with propene 16d along the most favourable 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 the meta/ortho regioselectivity in the zw-type 32CA reactions is discussed; and finally, (viii) the unexpected ortho regioselectivity experimentally found in the 32CA reactions involving weak electrophilic ethylenes such as ethyl acrylate 13 and acrylonitrile 16b is also analysed. 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 characterise 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 localisation 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 localisation 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


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9 bottom side. Negative charges are coloured 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 to the O1 oxygen and that of the disynaptic basins associated to 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, labelled V(A), are associated with nonbonding regions, i.e. lone pairs or pseudoradical centers, while disynaptic basins, labelled 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 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 localisation 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 analysed 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



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10 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 delocalisation 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 characterising 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, electrophilicity, ω, and nucleophilicity, N, at the GS of nitrones 12 and 21 and ethylene derivatives 16 are given in Table 2.


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11

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

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

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

N 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 towards 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 non-polar 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,N-dimethyl 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.



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12 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, 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 non-symmetric electrophilic/nucleophilic pairs along a polar process, the most favourable 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 and electrophilic P k + 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 characterise the most electrophilic and nucleophilic centers of the species involved in these 32CA reactions, the nucleophilic P k − Parr functions of nitrones 12 and 21, as well as the electrophilic P k + 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 analysed (see Figure 2).


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13

Figure 2. Three-dimensional (3D) representations of the B3LYP/6-31G(d) Mulliken atomic spin densities of radical cations 12·+ and 21·+, and radical anions 16a·- and 16g·-, together with the nucleophilic P k − Parr functions of nitrones 12 and 21, and the electrophilic P k + Parr functions of acrolein 16a and methyl acrylate 16g. Analysis of the nucleophilic P k − Parr functions at the reactive sites of nitrones 12 and 21 indicates that the O1 oxygen, with a P k − 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 P k + Parr functions at the reactive sites of acrolein 16a indicates that the C4 carbon is the most electrophilic center of this species, having a value of P k + = 0.54. Therefore, it is predictable that the most favourable 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 P k + 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 behaviour 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



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14 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 non-symmetry 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 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 to 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, TS1i-mn, TS1i-mx, TS1i-on and TS1i-ox, and the corresponding 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 reaction of nitrone 12 with ethylenes 16a and 16d are given in Table 3. Total energies are given in Table S4 Supplementary Material.

Scheme 6. 32CA reaction of cyclic nitrone 12 with ethylenes 16a,d.

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)


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15 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 behaviour 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 to 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, TS1dox being 3.2 kcal·mol-1 lower in energy than TS1d-mx, and moderately exo selective, 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 non-polar zw-type 32CA reaction involving propene 16d is ortho/exo selective; and 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). 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. gas phase 16a (R=CHO) TS1a-mn TS1a-mx TS1a-on TS1a-ox 17a 18a 19a 20a a

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

DCM 4.0 5.5 8.3 9.0 -28.4 -30.0 -29.2 -29.6

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

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

Solvent effects increase the activation energies and decrease reaction energies very insignificantly, by between 2 – 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.



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16 Based on the incorrect representation of TACs as 1,2-zwitterionic 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 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 optimised at the MPWB1K/6-311++G(d,p) computational level. Total and relative gas phase energies are given in Table S5 in Supplementary Material, 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 stabilisation 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 stabilisation 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 non-use 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 Supplementary Material. 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 unfavourable entropies associated to these bimolecular processes. The endo stereoselectivity found in the reaction involving acrolein 16a is slightly decreased due to the most unfavourable activation entropy associated to TS1a-mn. Finally, the exergonic


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17 character of the formation of isoxazolidines 17a,d to 20a,d, by between 9.1 – 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 favourable meta TSs are geometrically more asynchronous than the ortho ones; (ii) at the meta TSs, the shorter C−O distance corresponds to the more favourable 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 favourable meta TSs; (vi) solvent effects of toluene cause unappreciable changes in the TSs associated with the non-polar 32CA reaction between cyclic nitrone 12 and propene 16d; and 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.



Page 18 of 41

18

Figure 3. MPWB1K/6-311G(d,p) gas phase optimised 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/6311++G(d,p) gas phase ones are given in brackets.

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


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19 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 favourable TS, the faster the reaction. Cycloadditions with GEDT values near 0.0e correspond to non-polar 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 favourable 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 non-polar 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 non-covalent interactions, namely, electrostatic interactions, hydrogen bonds, van der Waals interactions, etc. While favourable 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 non-polar 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 favourable the relative orientation of both polarised frameworks at the TSs, the stronger the electrostatic interactions. In order to characterise such electrostatic interactions, the molecular electrostatic potential (MEP) of the more favourable meta regioisomeric TSs was analysed (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 5), these electrostatic interactions are not as effective in exo TS1a-mx (see Figure 5). Consequently, the more favourable electrostatic interactions taking place in TS1a-mn with respect to



Page 20 of 41

20 TS1a-mx appear to be responsible for the experimental endo stereoselectivity of the polar 32CA reaction with acrolein 16a.

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 TS1amx. On the other hand, the exo stereoselectivity in non-polar reactions is expected to be mainly the result of repulsive van der Waals interactions developed along the endo reaction paths. Thus, in order to characterise the origin of the exo stereoselectivity in the non-polar 32CA reaction of cyclic nitrone 12 with propene 16d, the topology of the NCI46 taking place at the more favourable ortho regioisomeric TSs was analysed. 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 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 non-polar 32CA reaction with propene 16d.

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


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21 3.5. The role of the electrophilic character of ethylenes in zw-type 32CA reactions of C,Ndialkyl 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 to these 32CA reactions indicate that they take place through one-step mechanisms. The gas phase activation energies and GEDT associated to 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 Supplementary Material.

H3C N H3C

O

TS2i-mn

TS2i-on

endo

1 O

H3 C 2N 3

meta H3 C

N H3 C

N

O R

H 22i R

H3 C

H3 C

21

O TS2i-mx

H 23i R

endo H3C R 5 ortho

H 24i

+ 4 exo 5 R=H H3 C 16e R = NO2 16f R = NO 16a R = CHO TS2i-ox H3 C 16b R = CN 16g R = CO2Me 16c R = Ph 16d R = Me

N

O R

H 25i

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 to 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



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22 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 behaviour is a consequence of the more favourable 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 rationalisation given in section 3.4; (vi) similarly to the reaction involving nitrone 12, there is a change of the regio- and stereoselectivity for the non-polar 32CA reaction with propene 16d. Now, the ortho/exo TS2d-ox is the most favourable one; and 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 regioand stereoisomeric TSs involved in the 32CA reactions of C,N-dimethyl nitrone 21 with ethylenes 16. The computed GEDT at the most favourable TS of each 32CA reaction is given in e. Ethylene R= TS2i-mn TS2i-mx TS2i-on TS2i-ox GEDT a

16e

16f

16a

16b

16g

NO2

NO

CHO

CN

CO2Me

Ph

Me

-3.9 -0.9 3.3 6.3 0.25

2.4 3.0 7.1 7.6 0.16

1.8 4.3 6.4 7.2 0.16

2.8 3.5 6.6 6.0 0.12

11.0 9.0 10.4 9.5 0.06

13.7 12.9 11.5 9.6 0.00

-4.1 -0.5 2.6 2.6 0.24

Relative to nitrone 21 and the corresponding ethylene 16


16c

16d

5 H 10.0

0.02

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23 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.

Figure 7. Plot of the MPWB1K/6-311G(d,p) computed activation energies, in kcal·mol-1, associated with the most favourable 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 favourable TS (R2 = 0.97); and (b) the electrophilicity ω index, in eV, of the ethylene derivatives 16 (R2 = 0.95). PREGUNTAR 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 favourable 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 Supplementary Material. 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/6311G(d,p) ones, by between -34.2 and -37.7 kcal·mol-1. Consequently, these very similar



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24 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)/cc-pVTZ method is used. The gas phase geometries of the most favourable 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 favourable 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 non-polar 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 non-polar reactions involving electron-releasing groups, the bulky substituents are arranged in an exo mode. Thus, while favourable electrostatic interactions appearing along the endo approach between the two polarised fragments are responsible for the endo stereoselectivity in polar reactions, the unfavourable steric hindrance appearing along the endo approach make the exo reaction paths the most favourable 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


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25

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

3.6. BET study of non-polar 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 BET36 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,



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26 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 analysed in order to understand the origin of the activation and reaction energies associated to 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 favourable ortho/exo and meta/endo reaction paths, respectively, are given in Supplementary Material. In this section, the bonding changes arising from these BET studies and their associated energies along the two zw-type 32CA reactions are summarised and described in a chemical fashion. 3.6.1. Study of the non-polar 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 favourable ortho/exo reaction path associated with of the non-polar zw-type 32CA reaction between C,N-dimethyl nitrone 21 and propene 16d are summarised 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 characterised by ten differentiated phases which, in turn, can be reorganised in three Groups A – C associated to 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. 8.6 kcal·mol−1, is mainly associated to the formation of the two C3 (first) and C4 (second) pseudoradical centers at the interacting carbons, which are involved in the subsequent C3−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 to 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 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 in a more extent; (iii) formation of the first C3−C4 single


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27 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 non-bonding 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 Supplementary Material): 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 behaviour contrast with the low geometrical asynchronicity found at TS2d-ox, ∆d = 0.04 (see Figure 8), emphasising 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 and 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 non-polar 32CA reaction between the simplest nitrone 9 and ethylene 5 (see Supplementary Material) allows establishing a great similitude. The two non-polar 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.



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28

Table 5. Groups A – C in which the sequential bonding changes along the most favourable ortho/exo reaction path associated with the non-polar zw-type 32CA reaction between C,Ndimethyl nitrone 21 and propene 16d can be chemically reorganised. Distances are given in angstroms, Å, the MPWB1K/6-311G(d,p) relativea energies involved in each group, ∆E, 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 characterising the corresponding topological phases is also included.

Group

A

a

Phases

I – IV TS2d-ox

d1(O1−C5) d2(C3−C4)

∆E

GEDT

3.20 ≥ d1 > 2.12 3.69 ≥ d2 > 2.16

13.6

0.00

Topological characterisation Depopulation of the V(N2,C3) and V(C4,C5) disynaptic basins and creation of a V(N2) monosynaptic basin

B

V, VI

2.12 ≥ d1 > 1.96 2.16 ≥ d2 > 1.94

-5.1

-0.10

Formation of V(C3) and V(C4) monosynaptic basins

C

VII – X

1.96 ≥ d1 ≥ 1.43 1.94 ≥ d2 ≥ 1.53

-44.0

-0.28

Formation of V(O1,C5) and V(C3,C4) disynaptic basins

Relative to the first point of the reaction path, P0-I.


Chemical process Rupture of the N2-C3 and C4C5 double bonds and formation of the N2 lone pair Formation of C3 and C4 pseudoradical centers Formation of the O1−C5 and C3−C4 single bonds

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29

Figure 9. Phases in which the MPWB1K/6-311G(d,p) IRC associated with the non-polar 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 coloured areas represent the different groups in which the reaction is topologically divided. Relative energies (∆E, in kcal·mol-1) are given with respect to the separated reagents, the nitrone 21 and propene 16d.

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 favourable meta/endo reaction path associated with the polar zw-type 32CA reaction between C,Ndimethyl nitrone 21 and acrolein 16a are summarised 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 characterised by ten differentiated phases which, in turn, can be reorganised in five Groups A – E associated to 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 characterised 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



Page 30 of 41

30 VIII and releases a low MRE of ca. 0.7 kcal·mol-1, is associated to 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 to 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 to 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 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 non-bonding electron density of the nitrone O1 oxygen to the β-conjugated C4 carbon the acrolein framework, a behaviour 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; and 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 non-polar 32CA reaction involving propene 16d is more asynchronous than the polar 32CA reaction involving acrolein 16a.


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31

Table 6. Groups A – E in which the sequential bonding changes along the most favourable meta/endo reaction path associated with the polar zw-type 32CA reaction between nitrone 21 and acrolein 16a can be chemically reorganised. Distances are given in angstroms, Å, the MPWB1K/6-311G(d,p) relativea energies involved in each group, ∆E, 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 characterising the corresponding topological phases is also included.

Group

a

Phases

d1(O1−C4) d2(C3−C5)

∆E

GEDT

Topological characterisation

Chemical process Rupture of the acrolein C4−C5 and nitrone N2−C3 double bonds and formation of the N2 lone pair

A

I–V (TS2a-mn)

2.69 ≥ d1 > 1.79 3.12 ≥ d2 > 2.32

7.7

0.14

Depopulation of the V(N2,C3) and V(C4,C5) disynaptic basins and creation of a V(N2) monosynaptic basin

B

VI, VII

1.79 ≥ d1 > 1.70 2.32 ≥ d2 > 2.24

-1.9

0.11

Formation of the V(C5) monosynaptic basin

Formation of the acrolein C5 pseudoradical center

C

VIII

1.70 ≥ d1 > 1.68 2.24 ≥ d2 > 2.22

-0.7

0.10

Formation of the V(O1,C4) disynaptic basin

Formation of the first O1−C4 single bond

D

IX

1.68 ≥ d1 > 1.57 2.22 ≥ d2 > 2.07

-6.7

0.01

Formation of the V(C3) monosynaptic basin

Formation of the nitrone C3 pseudoradical center

E

X

1.57 ≥ d1 ≥ 1.42 2.07 ≥ d2 ≥ 1.56

-27.0

-0.20

Formation of the V(C3,C5) disynaptic basin

Formation of the second C3−C5 single bond

Relative to the first point of the IRC, P0-II.



Page 32 of 41

32

Figure 10. Phases in which the MPWB1K/6-311G(d,p) IRC associated with the polar zwtype 32CA reaction between C,N-dimethyl 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 coloured areas represent the different groups in which the reaction is topologically divided. Relative energies (∆E, in kcal·mol-1) are given with respect to the separated reagents, nitrone 21 and 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 non-symmetric reagents, the most favourable 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 behaviour 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 non-polar 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 Supplementary Material). A similar bonding pattern is found along the most favourable ortho/exo reaction path associated with the non-polar zw-type 32CA reaction of cyclic nitrone 12 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


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33 in non-polar 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.

Regioselectivity in zw-type 32CA reactions of C,N-dialkyl nitrones R

R

R

N

3

O

C

R N

1 1

C 3

O

R

R 4

4

EWG

EDG

non-polar reaction

polar reaction

ortho reaction path

meta reaction path

Scheme 8. A schematic representation of the electron density reorganisation associated with the initial formation of the C-C or C-O single bonds along the ortho and meta reaction path associated with the non-polar and polar zw-type 32CA reactions of C,N-dialkyl nitrones with nucleophilic or electrophilic ethylenes. 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 (ii) the 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/6-311G(d,p) computational level (see the 32CA reaction of methyl acrylate 16g in Table 4). Consequently, these DFT



Page 34 of 41

34 functionals are not also able to account the unexpected ortho regioselectivity experimentally observed. In the non-substituted 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 behaviour is found in the case of nucleophilic ethylenes such as propene 16d. Conversely, the presence of an efficient electron-withdrawing group such as –CHO, –NO2 or –NO enables an easy polarisation of the C−C double bond of the ethylene, favouring 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 –CO2R could be not efficient enough, and consequently, the depopulation of the β-conjugated C4 carbon could be more unfavourable than the formation of the corresponding pseudoradical center, thus favouring 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 unfavourable than the homolytic rupture of the C−C double bond, thus favouring the initial formation of the C−C single bond over the C−O one, and accordingly, an ortho regioselectivity, a behaviour not reproduced through DFT calculations.

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 analysed 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 characterising the strong nucleophilic character of these nitrones, thus explaining the acceleration experimentally observed towards electrophilic ethylenes. These 32CA reactions take place through a non-concerted one-step mechanism. The 32CA reaction involving electrophilic acrolein 16a is 6.3 kcal·mol-1 lower in energy than


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35 that involving propene 16d. The use of this strong electrophilic ethylene also produces important changes in both the regio- and stereoselectivity; thus, while the non-polar 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 non-covalent interactions taking place at the TSs. While the endo stereoselectivity found in polar reactions can be associated to the more favourable electrostatic interactions taking place at the polar endo TSs, the exo stereoselectivity found in non-polar reactions may be a consequence of the more unfavourable 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 zwtype 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 understanding of the unexpected ortho regioselectivity, which cannot be modelled by standard computational methods. Finally, a BET study of the most favourable 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 behaviours of zw-type 32CA reactions of nucleophilic C,N-dialkyl nitrones. While non-polar 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 non-bonding electron density of the nitrone oxygen, the most nucleophilic center of the nitrone, to the β-conjugated carbon 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



Page 36 of 41

36 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 does not only decrease 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 rationalisation 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.

Supplementary Material. 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/6-311++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/6-311G(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.

Acknowledgements: 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. M. R.-G. also thanks MINECO for a pre-doctoral contract co-financed by the European Social Fund (BES-2014-068258).


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37

References. (1)

Irvin, L. Chem. Rev. 1938, 23, 193-285.

(2)

Confalone, P. N.; Huie, E. M. Org. React. 2004, 36, 1-174.

(3)

Martin, J. N.; Jones, R. C. F. Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products; Wiley: Chichester,, 2002; Vol. 59.

(4)

(a) Merino, P. Stuttgart,, 2004.(b) Merino, P. Stuttgart, 2011; Vol. 2010/4.

(5)

(a)Kanemasa, S. Synlett 2002, 1371-1387. (b) Kanemasa, S.; Padwa, A., Pearson, W. H., Eds.; Wiley: Chichester, United Kingdom., 2002; Vol. 59, p 755-815. (c) Evans, D. A.; Kleinbeck, F.; Rüping, M.; Christmann, M., Bräse, S., Eds.; Wiley-VHC: 2006, p 72-77.

(6)

Rück-Braun, K.; Freysoldt, T. H. E.; Wierschem, F. Chem. Soc. Rev. 2005, 34, 507516.

(7)

(a) Brandi, A.; Cardona, F.; Cicchi, S.; Cordero, F. M.; Goti, A. Chemistry-a European Journal 2009, 15, 7808-7821. (b) Frederickson, M. Tetrahedron 1997, 53, 403-425. (c) Gothelf, K. V. In Cycloaddition Reactions in Organic Synthesis; S., K., Jorgensen, K. A., Eds.; Wiley-VCH, Inc: New York, 2002, p 211-247. (d) Revuelta, J.; Cicchi, S.; Goti, A.; Brandi, A. Synthesis-Stuttgart 2007, 485-504.

(8)

Andrés, J.; Gracia, L.; González-Navarrete, P.; Safont, V. S. Comput. Theor. Chem. 2015, 1053, 17-30.

(9)

Domingo, L. R. Molecules 2016, 21, 1319.

(10) Woodward, R. B.; Hoffmann, R. Angew. Chem. Int. Ed. Engl. 1969, 8, 781-853. (11) (a) Houk, K. N. Acc. Chem. Res. 1975, 8, 361-369; (b) Houk, K. N.; Gonzalez, J.; Li, Y. Acc. Chem. Res. 1995, 28, 81-90; (c) Arrieta, M. C. Torre, A. Cózar, M. A. Sierra, F. P. Cossío, Synlett 2013; 24, 535-549. (12) (a) Ríos-Gutiérrez, M.; Pérez, P.; Domingo, L. R. RSC Adv. 2015, 58464-58477. (b) Ríos-Gutiérrez, M.; Darù, A.; Tejero, T.; Domingo, L. R.; Merino, P. Org. Biomol. Chem. 2017, 15, 1618-1627. (c) Domingo, L. R.; Ríos-Gutiérrez, M.; Pérez, P. RSC Adv. 2017, 7, 26879 - 26887. (13) Domingo, L. R.; Ríos-Gutiérrez Molecules 2017, 750. (14) Domingo, L. R.; Aurell, M. J.; Pérez, P. Tetrahedron 2014, 70, 4519-4525. (15) Domingo, L. R. RSC Adv. 2014, 4, 32415-32428.



Page 38 of 41

38 (16) (a) Geerlings, P.; De Proft, F.; Langenaeker, W. Chem. Rev. 2003, 103, 1793-1873 (b) Domingo, L. R.; Ríos-Gutiérrez, M.; Pérez, P. Molecules 2016, 21, 748. (17) (a) Merino, P.; Greco, G.; Tejero, T.; Hurtado-Guerrero, R.; Matute, R.; Chiacchio, U.; Corsaro, A.; Pistara, V.; Romeo, R. Tetrahedron 2013, 69, 9381- 9390; (b) Painter, P. P.; Pemberton, R. P.; Wong, B. M.; Ho, K. C.; Tantillo, D. J. J. Org. Chem. 2014, 79, 432-435; (c) Jasinski, R. Tetrahedron Lett. 2015, 56, 532-535; (d) RocaLopez, D.; Polo, V.; Tejero, T.; Merino, P. J. Org. Chem. 2015, 80, 4076-4083; (d) Barber, J. S.; Styduhar, E. D.; Pham, H. V.; McMahon, T. C.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2016, 138, 2512- 2515; (e) Daru, A.; Roca-Lopez, D.; Tejero, T.; Merino, P. J. Org. Chem. 2016, 81, 673- 680; (f) Roca-Lopez, D.; Daru, A.; Tejero, T.; Merino, P. RSC Adv. 2016, 6, 22161- 22173;(g) Sexton, T. M.; Freindorf, M.; Kraka, E.; Cremer, D. J. Phys. Chem. A 2016, 120, 8400−8418. (18) Adjieufack, A. I.; Ndassa, I. M.; Patouossa, I.; Mbadcam, J. K.; Safont, V. S.; Oliva, M.; Andrés, J. Phys. Chem. Chem. Phys. 2017, 19, 18288-18302. (19) Ali, S. A.; Wazeer, M. I. M. J. Chem. Soc. Perkin Trans. I 1988, 597-605. (20) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652. (b) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785-789. (21) Zhao, Y.; Truhlar, G. D. J. Phys. Chem. A 2004, 108, 6908-6918. (22) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215-241. (23) Domingo, L. R.; Ríos-Gutiérrez, M.; Pérez, P. Tetrahedron 2017, 73, 1718-1724. (24) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab initio Molecular Orbital Theory; Wiley: New York, 1986. (25) Bartlett, R. J.; Musiał M. Rev. Mod. Phys. 79, 291 -352. (26) (a) Schlegel, H. B. J. Comput. Chem. 1982, 3, 214-218. (b) Schlegel, H. B. In Modern Electronic Structure Theory; Yarkony, D. R., Ed.; World Scientific Publishing: Singapore, 1994. (27) Fukui, K. J. Phys. Chem. 1970, 74, 4161-4163. (28) (a) González, C.; Schlegel, H. B. J. Phys. Chem. 1990, 94, 5523-5527. (b) González, C.; Schlegel, H. B. J. Chem. Phys. 1991, 95, 5853-5860. (29) (a)Tomasi, J.; Persico, M. Chemical Review 1994, 94, 2017-2094. (b) Simkin, B. Y.; Sheikhet, I. I. Quantum chemical and statistical theory of solutions : a computational approach; Ellis Horwood: London, 1995.


Page 39 of 41 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


39 (30) (a) Cances, E.; Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 107, 3032-3041. (b) Cossi, M.; Barone, V.; Cammi, R.; Tomasi, J. Chem. Phys. Lett. 1996, 255, 327-335. (c) Barone, V.; Cossi, M.; Tomasi, J. J. Comput. Chem. 1998, 19, 404-417. (31) (a) Reed, A. E.; Weinstock, R. B.; Weinhold, F. J. Chem. Phys. 1985, 83, 735-746. (b) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. Rev. 1988, 88, 899-926. (32) Domingo, L. R.; Pérez, P.; Sáez, J. A. RSC Adv. 2013, 3, 1486-1494. (33) 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.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussain 09, Revision D.01; Gaussian, Inc., Wallingford CT, 2013. (34) Becke, A. D.; Edgecombe, K. E. J. Chem. Phys. 1990, 92, 5397-5403. (35) Noury, S.; Krokidis, X.; Fuster, F.; Silvi, B. Comput. Chem. 1999, 23, 597-604. (36) Krokidis, X.; Noury, S.; Silvi, B. J. Phys. Chem. A 1997, 101, 7277-7282. (37) Dennington, R.; Keth, T.; Millam, J. GaussView, version 3. Shawnee Mission, Kansas, 2009. (38) Pettersen, E. F.; Goddard, T. D.; Huang, C. C.; Couch, G. S.; Greenblatt, D. M.; Meng, E. C.; Ferrin, T. E. Journal of Computational Chemistry 2004, 25, 1605-1612. (39) Silvi, B. J. Mol. Struct. 2002, 614, 3-10. (40) Pauling, L. The Nature of the Chemical Bond An Introduction to Modern Structural Chemistry; Cornell University Press: New York, 1960. (41) Huisgen, R. Proc. Chem. Soc. 1961, 357-397. (42) Domingo, L. R.; Sáez, J. A.; Pérez, P. Chem. Phys. Lett. 2007, 438, 341-345.



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40 (43) (a) Parr, R. G.; Pearson, R. G. J. Am. Chem. Soc. 1983, 105, 7512-7516. (b) Parr, R. G.; Yang, W. Density Functional Theory of Atoms and Molecules; Oxford University Press: New York, 1989. (44) Parr, R. G.; von Szentpaly, L.; Liu, S. J. Am. Chem. Soc. 1999, 121, 1922-1924. (45) Domingo, L. R.; Chamorro, E.; Pérez, P. J. Org. Chem. 2008, 73, 4615 - 4624. (46) Johnson, E. R.; Keinan, S.; Mori-Sanchez, P.; Contreras-Garcia, J.; Cohen, A. J.; Yang, W. T. Journal of the American Chemical Society 2010, 132, 6498-6506. (47) (a) Jasiński, R. Tetrahedron 2013, 69, 927-932. (b) Jasiński, R.; Ziółkowska, M.; Demchuk, O.; Maziarka, A. Open Chemistry 2014, 12, 586-593. (c) Jasiński, R. Chem. Heterocycl. Compd. 2009, 45, 748-749. (d) Jasiński, R.; Mróz, K.; Kącka, A. J. Heterocyclic Chem. 2016, 53, 1424-1429.


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41

Graphical Abstract

endo meta O N

O

N

1st

nd

H2

G = CHO G

CHO

+ G = CH3 ortho

2nd

CH3

exo H


O

N 1st

A Molecular Electron Density Theory Study of the Reactivity and

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