A mechanistic study of the participation of azomethine ylides and carbonyl ylides in [3+2] cycloaddition reactions

Tetrahedron 71 (2015) 1050e1057

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A mechanistic study of the participation of azomethine ylides and carbonyl ylides in [3þ2] cycloaddition reactions rez b Luis R. Domingo a, *, Maria J. Aurell a, Patricia Pe nica, Dr. Moliner 50, E-46100 Burjassot, Valencia, Spain Universidad de Valencia, Departamento de Química Orga rica, Av. Repu  blica 230, Universidad Andres Bello, Facultad de Ciencias Exactas, Departamento de Ciencias Químicas, Laboratorio de Química Teo 8370146 Santiago, Chile a

b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 4 November 2014 Received in revised form 22 December 2014 Accepted 29 December 2014 Available online 3 January 2015

The participation of azomethine ylides (AYs) and carbonyl ylides (CYs) in [3þ2] cycloaddition (32CA) reactions has been analysed at the DFT B3LYP/6-31G(d) level. The asymmetric substitution breaks the pseudodiradical character of the simplest three-atom-components (TACs), modifying their electrophilic and nucleophilic behaviours. These TACs react quickly towards electrophilic nitroethylene. However, while the reaction with AY takes place via a zw-type mechanism, the reaction with CY appears to take place via a pr-type mechanism. A different behaviour is found in the reactivity towards the nucleophilic methyl vinyl ether. While AY presents a high activation energy, CY presents a high reactivity via a pr-type mechanism. These reactions are completely regioselective, displaying exo stereoselectivity. The present study makes it possible to establish that the substitution provokes a different reactivity pattern in these TACs; while in CYs does not substantially modify their pr-type reactivity, AYs only participate in zw-type 32CA reactions towards electrophilic ethylenes. Ó 2015 Elsevier Ltd. All rights reserved.

Keywords: [3þ2] Cycloaddition reactions Azomethine ylides Carbonyl ylides Molecular mechanisms DFT calculations

1. Introduction Cycloaddition reactions are among of the most useful reactions of the huge repertoire of synthetic organic chemistry due to their ability to build regio- and/or stereoselectively cyclic motifs with organic molecules.1 Unlike DielseAlder (DA) reactions, which can be classified as non-polar DA (N-DA) reactions with high activation energies, and polar DA (P-DA) reactions with low activation energies,2 [3þ2] cycloaddition (32CA) reactions lack a clear systematisation of their reactivity based on the nucleophilic/electrophilic behaviour of the reagents. Based on the distortion/interaction energy model, Ess and Houk analysed the 32CA reactions of nine different three-atomcomponents (TACs) 1e3 with ethylene 5 and acetylene 6 (see Scheme 1),3 finding that the computed B3LYP/6-31G(d) activation enthalpies correlated very nicely with the distortion energies. They concluded that the distortion energy of the TAC and ethylene 5, or acetylene 6, towards the TS is the major factor controlling the reactivity differences of TACs.3b However, no structure/reactivity relationship for these TACs able to predict their reactivity could be established.

* Corresponding author. E-mail address: [email protected] (L.R. Domingo). URL: http://www.luisrdomingo.com http://dx.doi.org/10.1016/j.tet.2014.12.094 0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

HC

Z

H2C

CH 6

X

N

N

CH2 5

Z

N

1a X = N, Z= O 1b X = N, Z = NH 1c X = N, Z = CH2 2a X = CH, Z= O 2b X = CH, Z = NH 2c X = CH, Z = CH2

X

HC

Z Y

X

H2C

CH 6

CH2 5

Y H2C

Z

Z

Z Y

3a Y = NH, Z= O 3b Y = NH, Z = NH 3c Y = NH, Z = CH2 4a Y = S, Z= O 4b Y = S, Z = NH 4c Y = S, Z = CH2 Scheme 1.

The nine 32CA reactions of Ess and Houk’s series 1e3 and three sulfur-centred TACs 4 towards ethylene 5 and acetylene 6 were recently studied in order to find a structure/reactivity relationship (see Scheme 1).4 A good correlation between the pseudodiradical character, the hardness h, and the nucleophilicity N index of the TAC with the feasibility of these non-polar reactions was established.

L.R. Domingo et al. / Tetrahedron 71 (2015) 1050e1057

This study allowed establishing a useful classification of 32CA reactions into pseudodiradical-type (pr-type) reactions involving TACs with a high pseudodiradical character, which take place easily through an earlier TS with non-polar character, and zwitterionictype (zw-type) reactions involving TACs with a high zwitterionic character, characterised by favourable nucleophilic/electrophilic interactions, taking place through polar TSs.4 In order to prove this hypothesis, a series of the most common TACs used in organic synthesis5 showing low reactivity in 32CA reactions towards ethylene were recently explored to determine if the electronic activation of both TACs and ethylene derivatives might favour the 32CA reactions via a polar zw-type mechanism.6 To this end, a series of seven non-substituted TACs having a zwitterionic structure, nitrile ylide 7, nitrile imine 8, nitrile oxide 9, diazoalkane 10, azide 11, nitrone 12, and methyl nitronate 13, were studied analysing their electrophilic/nucleophilic behaviour (see Scheme 2). Note that these TACs, being among the most frequently used in the synthesis of heterocyclic compounds, display a 1,2-zwitterionic structure.6

HC

N

CH2

HC

Nitrile ylide 7

N

HC

NH

Nitrile imine 8

H2C

N

N

HN

O

N

N

Azide 11

Diazoalkane 10

OMe

H H2C

O

CO2Me Ph

The general characteristic of these TACs 7e13 is their high nucleophilic and low electrophilic behaviour. Computed activation energies indicate that non-substituted TACs react quickly towards 1,1-dicyanoethylene 14 showing their ability to react with electrophilic ethylenes. However, when these TACs are electrophilically activated by an appropriate substitution there seems to be insufficient activation to react with nucleophilic ethylenes. The electrophilic activation of the TAC moiety for nucleophilic attacks was determined by the coordination with a Lewis acid only. All 32CA reactions studied in this work presented a high regioselectivity.6 The simplest azomethine ylide (AY) 3c and carbonyl ylide (CY) 16, which have a high pseudodiradical character,7 participate in prtype 32CA reactions towards ethylene 5 with very low activation energies, below 2.5 kcal/mol (see Scheme 3). However, in spite of the great significance of these TACs in the synthesis of the heterocyclic pyrrolidine 15 and tetrahydrofuran 17, these simple 32CA reactions have no synthetic interest.

+ 5

3c

N H 15

+

Note the necessity of the presence of two groups of a different electronic nature, one electron-releasing group (ERG) and one electron-withdrawing group (EWG), in order to favour the thermal heterolytic CeC cleavage of aziridines and epoxides. This opposite substitution causes an asymmetric electronic reorganization in AYs and CYs favouring zwitterionic structures such as 22 and 23 in Scheme 5 towards the pseudodiradical structures as 3c and 16 in Scheme 3. Consequently, the reactivity of these substituted TACs may change from a pr-type mechanism shown in the 32CA reactions of the simplest AY 3c and CY 16 to a zw-type mechanism for asymmetrically disubstituted AYs and CYs.

O

Scheme 2.

O

Scheme 4.

CO2Me

Methyl nitronate 13

Nitrone 12

N H

Experimentally, the AYs and CYs used in 32CA reactions are intermediate species generated in situ in the reaction medium, which can be obtained via a thermal ring opening of adequately substitutes aziridines and epoxides8 such as 18 and 20 (see Scheme 4).

N

N H2C

N

Nitrile oxide 9

1051

5

O

16

17 Scheme 3.

N

CO2Me

Ph

H 22

O

CO2Me

23 Scheme 5.

Due to the relevance of the substituted AYs and CYs such as 22 and 23 in the synthesis of pyrrol and furan skeletons, the reactivity of these substituted TACs towards a series of ethylene derivatives of different electronic nature in 32CA reactions is analysed herein in order to establish a general reactivity model for these relevant TACs. 2. Computational methods DFT computations were carried out using the B3LYP9 functional, together with the standard 6-31G(d) basis set.10 The optimisations were carried out using the Berny analytical gradient optimisation method.11 The stationary points were characterised by frequency computations in order to verify that TSs have one and only one imaginary frequency. The electronic structures of the TSs were analysed by the natural bond orbital (NBO) method.12 All computations were carried out with the Gaussian 09 suite of programs.13 The global electrophilicity index, u, is given by the following expression,14 u¼(m2/2h), in terms of the electronic chemical potential m and the chemical hardness h. Both quantities may be approached in terms of the one-electron energies of the frontier molecular orbitals HOMO and LUMO, 3 H and 3 L, as mz(3 Hþ3 L)/2 and hz(3 L3H), respectively.15 Recently, we introduced an empirical (relative) nucleophilicity index,16N, based on the HOMO energies obtained within the KohneSham scheme,17 and defined as N¼EHOMO(Nu)EHOMO(TCE). Nucleophilicity is referred to tetracyanoethylene (TCE), because it presents the lowest HOMO energy in a large series of molecules already investigated in the context of polar cycloadditions. This choice allows the convenient handling of

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L.R. Domingo et al. / Tetrahedron 71 (2015) 1050e1057

a nucleophilicity scale of positive values. Electrophilic Pkþ and nucleophilic Pk Parr functions18 were obtained through the analysis of the Mulliken atomic spin density (ASD) of the radical anion and the radical cation of AYs 22 and CY 23.

density reached via the global electron density transfer (GEDT) process from the nucleophile to the electrophile, which are powerful tools in the study of the local reactivity in polar processes.18 Accordingly, the electrophilic Pkþ and nucleophilic Pk Parr functions for AY 22 and CY 23 are analysed (see Fig. 1).

3. Results and discussion The present study has been divided into three parts: (i) in the first part, an analysis of the DFT reactivity indices at the ground state of the reagents is carried out; (ii) in the second part, the 32CA reactions of AY 22 with ethylene 5, with the electrophilic nitroethylene 24, and with the nucleophilic methyl vinyl ether (MVE) 25, respectively, are studied; (iii) finally, the 32CA reactions of CY 23 with ethylene 5, and the substituted ethylenes 24, and 25, respectively, are analysed. 3.1. Analysis of the DFT reactivity indices of AYs, CYs, and the ethylene derivatives Studies devoted to DA and 32CA reactions have shown that the analysis of the reactivity indices defined within the context of the conceptual DFT19 is a powerful tool to understand the reactivity in polar cycloadditions. DFT reactivity indices, namely, electronic chemical potential, m, hardness, h, electrophilicity, u, and nucleophilicity, N, indices of AYs 3c, 22 and 27, CY 16 and 23, ethylene 5, nitroethylene 24 and MVE 25 are given in Table 1. Table 1 B3LYP/6-31G(d) electronic chemical potential, m, hardness, h, electrophilicity, u, and nucleophilicity, N, indices, in eV, of AYs 3c, 22 and 27, CY 16 and 23, ethylene 5, nitroethylene 24 and MVE 25

23 Disubstituted CY 24 Nitroethylene 27 Disubstituted N-Ph AY 22 Disubstituted AY 16 Simplest CY 5 Ethylene 25 MVE 3c Simplest AY

m

h

u

N

4.07 5.33 3.74 3.66 2.68 3.37 2.43 1.82

2.82 5.44 2.76 3.28 3.82 7.77 6.98 4.47

2.93 2.61 2.53 2.05 0.94 0.73 0.42 0.37

3.64 1.07 4.00 3.82 4.53 1.86 3.20 5.07

The simplest AY 3c and CY 16 present low electrophilicity u indices, 0.37 (3c) and 0.94 (16) eV, being classified as marginal and moderate electrophiles, respectively. However, they have very high nucleophilic N indices, 5.07 (3c) and 4.53 (19) eV, being classified as strong nucleophiles. Inclusion of two EW eCO2Me groups in the C1 carbon, and the ER ePh substituent in the C3 carbon of AY 3c and CY 16 notably increases the electrophilicity u indices of these TACs: 2.05 (22) and 2.93 (23) eV, being classified as strong electrophiles. This substitution decreases the corresponding nucleophilicity N indices: 3.82 (22) and 3.64 (23) eV. In spite of this fact, they remain classified as strong nucleophiles. Consequently, it is expected that these TACs can participate in zw-type 32CA reactions towards nucleophilic and electrophilic ethylenes.6 The inclusion of one phenyl substituent in the N2 nitrogen atom of AY 22 increases the electrophilicity u index, 2.53 eV, and the nucleophilicity N index, 4.00 eV, of AY 27. Consequently, it is expected that AY 27 will be more reactive than AY 22 in zw-type 32CA reactions. Along a polar reaction involving the participation of asymmetric reagents, the most favourable reactive channel is that involving the initial two-centre interaction between the most electrophilic centre of the electrophile and the most nucleophilic centre of the nucleophile.20 Recently, we proposed the electrophilic Pkþ and nucleophilic Pk Parr functions derived from the excess of spin electron

Ph

0.75 0.16 CO2Me 0.28 0.06 C1 -0.43 N 0.61 CO2Me C3 0.03 H -0.13 22

0.75 CO2Me

0.07 0.42 0.28 Ph

C3

C1

O 0.67 CO2Me -0.36 0.13 0.04 23

Fig. 1. B3LYP/6-31G(d) nucleophilic Pk Parr functions, in blue, and electrophilic Pk Parr functions, in red, and the natural atomic charges, in grey, in AYs 22 and CY 23.

As can be seen, these TACs present ambiphilic behaviours. Consequently, the electrophilic Pkþ and nucleophilic Pk Parr functions were analysed (see Fig. 1). The C1 carbon atom of both TACs is the most nucleophilic centre of these molecules. The corresponding nucleophilic Pk Parr functions are 0.61 (22) and 0.67 (23). Note that the C3 carbons present low nucleophilic activation, 0.16 (22) and 0.07 (23). On the other hand, the C3 carbon atom of both TACs is the most electrophilic centre of these molecules. The corresponding electrophilic Pkþ Parr functions are 0.28 (22) and 0.42 (23). The lower value found for AY 22 is a consequence of an electrophilic activation of the N2 nitrogen atom, 0.22 (not shown in Fig. 1). The C3 carbon atoms are more electrophilically activated than the C1 ones. Note that the C1 carbons present low electrophilic activation, 0.03 (22) and 0.13 (23). This analysis is in complete agreement with the regioselectivity observed in the 32CA reactions of these TACs (see later). Fig. 1 also shows the natural atomic charges (see numbers in grey) in the three atoms of TACs 22 and 23. First, it can be seen that the charge distribution in these atoms does not correspond to the zwitterionic structure given in Scheme 5. Note, that while the C3 carbon of AY 22 has a negligible positive charge, 0.06e, the C1 carbon of CY 23 has a negligible positive charge, 0.04e. It is interesting to remark that the most nucleophilically activated centre in these TACs is the C1 carbon atom with a low negative charge, 0.13e, in AY 22, and with a very light positive charge, 0.04e, in CY 23. On the other hand, the most electrophilically activated centre in these TACs is located at the C3 carbon, which presents a positive charge, 0.06e at CY 22 and 0.28e at CY 23. However, note that the most positive charged atom in these TACs correspond to the two carboxylate carbon atoms, ca. 0.75e. This results support the proposal that the electrophilic and the nucleophilic local activation in a molecule is not charge controlled.21

3.2. Study of the 32CA reactions of AY 22 with ethylene 5, nitroethylene 24, and MVE 25 In order to analyse the reactivity of AY 22 and CY 23 in 32CA reactions, three ethylenes displaying different reactivities were selected: ethylene 5, which does not participate in polar reactions, nitroethylene 24 and MVE 25, which participate as a strong electrophile and as a strong nucleophile, respectively, in polar reactions (see Scheme 6). NO2 5

24 Scheme 6.

OMe 25

L.R. Domingo et al. / Tetrahedron 71 (2015) 1050e1057

The 32CA reaction of the simplest AY 3c with ethylene 5, displayed in Scheme 3, has been commented above.7a This 32CA takes place through a one-step mechanism, via a very early TS. The activation energy associated to this 32CA reaction is very low, 1.2 kcal/ mol, the reaction being strongly exothermic, 68.6 kcal/mol. This 32CA reaction represents the model of the pr-type reaction.6 The pseudoradical structure of the simplest AY 3c makes it possible to explain these energy results.7a While in the non-polar DA reaction between cyclopentadiene and ethylene three CeC double bonds must be broken to reach the pseudodiradical species involved in the subsequent CeC bond formation,22 the simplest AY 3c already presents the pseudodiradical structure before reacting with ethylene 5. In order to investigate how the high reactivity of the simplest AY 3c via a pr-type mechanism is affected by the substitution on AYs, the 32CA reaction between the asymmetrically substituted AY 22 with ethylene 5 was analysed first (see Scheme 7). Due to the symmetry of ethylene 5, only one reactive channel is feasible for this cycloaddition. The 32CA reaction between AY 22 and ethylene 5 takes place through a one-step mechanism. Consequently, one TS, TS-A and one CA were located and characterised. Energy results are given in Table 2. The 32CA reaction between AY 22 and ethylene 5, via TS-A, presents a high activation energy, 14.4 kcal/mol, being an exothermic reaction by 32.3. Consequently, the substitution on AY 22 makes the 32CA reaction towards ethylene 5 kinetically and thermodynamically very unfavourable when compared to the 32CA reaction of the simplest AY 3c with 5.

Scheme 7.

Table 2 B3LYP/6-31G(d) relative energies, in kcal/mol, of the TSs and CAs involved in the 32CA reactions of AY 22 with ethylene 5, nitroethylene 24 and MVE 25, and in the 32CA reaction of AY 27 with nitroethylene 24 AY

Ethylene

22 22

5 24

22

25

27

24

ortho

endo exo endo exo endo exo

meta

DEact

DEreact

DEact

DEreact

14.4 8.9 10.4 14.2 12.3 9.3 8.2

32.3 28.7 26.4 27.8 24.5 42.2 42.1

6.4 5.1 19.4 18.8 6.4 2.0

31.6 32.0 27.4 28.7 44.8 44.8

The opposite EW and ER character of the substituent present in the C1 (two eCO2Me groups) and in the C3 (one ePh group) carbons in AY 22 causes the rupture of the symmetrical electronic structure presents in the pseudodiradical AY 3c. This characteristic could produce a change of reactivity of AYs from a pr-type mechanism for the simplest AY 3c to a zw-type mechanism for the substituted AY 22. Consequently, it is expected that substituted AYs present a poor reactivity towards ethylene 5 via a zw-type mechanism, in clear agreement with these energy results. The lengths of the two CeC forming bonds at the TS of the 32CA reaction of AY 22 with ethylene 5 are given in Table 3. At TS-A, the lengths of the C1eC5 and C3eC4 forming bonds are 2.372  A and 2.168  A, respectively. These lengths suggest an asynchronous bond formation process, in which the CeC bond formation at the C3 carbon of AY 22 is more advanced than that at the C1 carbon.

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Table 3 Lengths, d(CxeCy) in Angstroms, of the two single forming bonds, and GEDT, in e, at the TSs of the 32CA reactions of AY 22 with ethylene 5, nitroethylene 24 and MVE 25, and in 32CA reaction of AY 27 with nitroethylene 24 AY

Ethylene

22 22

5 24

22

25

27

24

ortho

endo exo endo exo endo exo

meta

C1eC5

C3eC4

GEDT

C1eC4

C3eC5

GEDT

2.372 2.531 2.634 2.575 2.663 2.545 2.642

2.168 2.099 2.064 2.052 2.056 2.220 2.109

0.00 0.20 0.17 0.14 0.14 0.16 0.14

2.098 2.091 2.301 2.304 2.251 2.108

2.599 2.639 2.185 2.168 2.682 2.756

0.28 0.29 0.03 0.01 0.25 0.30

Finally, the polar character of this 32CA reaction was evaluated computing the GEDT at TS-A. The natural atomic charges at the TS, obtained through a natural population analysis (NPA), were shared between the AY and the ethylene frameworks. The GEDT at the TS is given in Table 3. At TS-A the GEDT is 0.00e, indicating the non-polar character of this 32CA reaction. Most of the TACs participating in 32CA reactions present a high nucleophilic character.6 In addition, it is expected that the presence of the two EW eCO2Me groups in AY 22 increases its electrophilicity. Consequently, in order to analyse the response of AY 22 towards electrophilic and nucleophilic ethylenes via a zw-type mechanism, the 32CA reactions of AY 22 with nitroethylene 24, as an electrophilic ethylene, and with MVE 25, as a nucleophilic ethylene, were studied. Due to the asymmetry of both AY 22 and CY 23, and the substituted ethylenes 24 and 25, four reaction channels are feasible for each one of these 32CA reactions (see Scheme 8). They are related to the two stereoisomeric approach modes of the substituent present in the ethylenes relative to the N2 nitrogen or O2 oxygen of these TACs, named endo and exo, and the two regioisomeric approach modes of the non-substituted C4 carbon of these ethylenes towards the C1 or C3 carbons of these TACs; depending on the position of the Z group relative to the two eCO2Me groups, the two regioisomeric possibilities are named ortho and meta. The four reactive channels were studied in order to analyse the stereo- and regioselectivity in these 32CA reactions. All these reactions take place through a one-step mechanism; consequently, one TS and the corresponding CA were found and characterised along each of the four competitive channels of the 32CA reactions studied. Relative energies are given in Table 2.

Scheme 8.

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L.R. Domingo et al. / Tetrahedron 71 (2015) 1050e1057

Along the 32CA reaction of AY 22 with nitroethylene 24, the activation energies associated to the four competitive channels are 8.9 (TS-B-on), 10.4 (TS-B-ox), 6.4 (TS-B-mn) and 5.1 (TS-Bmx) kcal/mol; these 32CA reactions are exothermic between 26.4 and 32.0 kcal/mol. Some interesting conclusions can be drawn from these energy results: (i) the TS associated with the most favourable channel, TS-B-mx, is 9.3 kcal/mol lower in energy than the TS of the 32CA reaction between AY 22 and ethylene 5; (ii) when comparing the reaction energies, it turns out that they are hardly influenced by the substitution; (iii) this 32CA reaction is completely regioselective as the most favourable meta TS-B-mx is 3.8 kcal/mol below that of the ortho TS-B-on; (iv) this 32CA reaction presents a low exo stereoselectivity as the exo TS-B-mx is only 1.3 kcal/mol below that of the endo TS-B-mn. The lengths of the two CeC single bonds at the TSs of the 32CA reaction of AY 22 with nitroethylene 24 are given in Table 3. The geometry of the most favourable TS-B-mx is given in Fig. 2. At the ortho TSs, the lengths of the C1eC5 and C3eC4 forming bonds are 2.531 and 2.099  A at TS-B-on and 2.634 and 2.064  A at TS-B-ox, respectively, while at the meta TSs the lengths of the C1eC4 and C3eC5 forming bonds are 2.098 and 2.599  A at TS-B-mn and 2.091 and 2.639  A at TS-B-mx, respectively. Some appealing conclusions can be drawn from these geometrical parameters: (i) these lengths indicate that these TSs correspond to asynchronous CeC bond formation processes; and (ii) the asynchronicity in the CeC bond formation is determined by the electrophilic nitroethylene 24;23 in all cases, the CeC bond formation at the non-substituted C4 carbon of nitroethylene 24, the b-conjugated position of the ethylene, is more advanced than that at the C5 one.

Fig. 2. Most favourable TSs involved in the 32CA reactions of AY 22 with nitroethylene 24, TS-B-mx, and with MVE 25, TS-C-ox, and in the 32CA reaction of AY 27 with 24, TSD-mx. The distances are given in Angstroms.

Finally, the polar character of this 32CA reaction was evaluated computing the GEDT at the corresponding TSs. The values of the GEDT, which fluxes from the AY to the nitroethylene framework, fluctuate from 0.17e at TS-B-ox to 0.29e at TS-B-mx. The high GEDT value found at the most favourable TS-B-mx indicates that this 32CA reaction has a high polar character, as a consequence of the high nucleophilic character of AY 22, N¼3.82 eV, and the high electrophilic nitroethylene 24, u¼2.61 eV. Consequently, the large acceleration found in the 32CA reaction of AY 22 with nitroethylene 24, when compared to the 32CA reaction of AY 22 and ethylene 5, is an effect of the increase of the polar character of the reaction, in clear agreement with a zw-type mechanism.4

Similar to the 32CA reaction of AY 22 with nitroethylene 24, the 32CA reaction of AY 22 with MVE 25 can take place along four competitive channels (see Scheme 8). The relative energies associated with the four reactive channels are also given in Table 2. Along the 32CA reaction of AY 22 with MVE 25, the activation energies associated with the four competitive channels are 14.2 (TS-Con), 12.3 (TS-C-ox), 19.4 (TS-C-mn) and 18.8 (TS-C-mx) kcal/mol; the 32CA reactions are exothermic between 24.5 and 28.7 kcal/ mol. Some appealing conclusions can be drawn from these energy results: (i) the TS associated with the most favourable channel, TSC-ox, is only 2.1 kcal/mol lower in energy than the TS of the 32CA reaction between AY 22 and ethylene 5. Consequently, AYs do not tend to react towards nucleophilic ethylenes;6 (ii) this 32CA reaction is completely regioselective as the ortho TS-C-ox is 6.5 kcal/ mol below that of the meta TS-C-mx. Consequently, a change of the ortho/meta regioselectivity is observed with the electronic nature of the ethylene; (iii) This 32CA reaction also presents a low exo stereoselectivity as the exo TS-C-ox is 1.9 kcal/mol below that of the endo TS-C-on. The lengths of the two CeC single bonds at the TSs of the 32CA reactions of AY 22 with MVE 25 are given in Table 3. The geometry of the most favourable TS-C-ox is given in Fig. 2. At the ortho TSs, the lengths of the C1eC5 and C3eC4 forming bonds are 2.575 and 2.052  A at TS-C-on and 2.663 and 2.056  A at TS-C-ox, respectively, while at the meta TSs, the lengths of the C1eC4 and C3eC5 forming bonds are 2.301 and 2.185  A at TS-C-mn and 2.304 and 2.168  A at TS-C-mx, respectively. Some appealing conclusions can be drawn from these geometrical parameters: (i) while along the more favourable ortho channels these lengths indicate that these 32CA reactions are associated with high asynchronous CeC bond formation processes, along the more unfavourable meta channels these lengths indicate that the TSs are associated with slightly asynchronous CeC processes; and (ii) along the two regioisomeric channels the reactions are characterised by the attack of the C4 or the C5 carbon of MVE 25 on the C3 carbon of AY 22. Consequently, the C3 electrophilic centre AY 22 controls the asynchronicity in the CeC single bond formation. At the TSs associated with the 32CA reaction between AY 22 and MVE 25, the GEDT values fluctuate from 0.01e at TS-C-mx to 0.14e at TS-C-ox. The low values found at the more favourable ortho TSs, 0.14e, suggest that this 32CA reaction has a low polar character. Note that the GEDT at the most unfavourable meta TSs is negligible. Unlike P-DA reactions, which are endo selective, these 32CA reactions show some exo selectivity. Favourable electronic interactions at the zwitterionic TSs involved in P-DA reactions are responsible for the endo selectivity.24 However, unfavourable steric interactions along the endo approach mode can overcome weak electronic interactions making cycloadditions completely exo selective. In order to verify this behaviour in 32CA reactions, the reaction between the N-phenyl AY 27 and nitroethylene 24 was studied (see Scheme 8). Along the 32CA reaction of AY 27 with nitroethylene 24, the activation energies associated to the four competitive channels are 9.3 (TS-D-on), 8.2 (TS-D-ox), 6.4 (TS-D-mn) and 2.0 (TS-Dmx) kcal/mol, whereas the formation of the corresponding CAs is exothermic between 42.1 and 44.8 kcal/mol. Some appealing conclusions can be drawn from these energy results: (i) the TS associated with the most favourable channel, TS-D-mx, is 3.1 kcal/ mol lower in energy than the TS of the 32CA reaction between AY 22 and nitroethylene 24, in clear agreement with more nucleophilic character of AY 27 than AY 22 (see Table 1). Consequently, the presence of the phenyl substituent at the N2 nitrogen atom accelerates the 32CA reaction; (ii) the presence of the phenyl substituent makes the 32CA reaction more exothermic; (iii) this 32CA reaction remains completely regioselective as the most favourable meta TSD-mx is 6.2 kcal/mol below that of the ortho TS-D-ox; (iv) this 32CA

L.R. Domingo et al. / Tetrahedron 71 (2015) 1050e1057

reaction presents a complete exo stereoselectivity as the exo TS-Dmx is 4.4 kcal/mol below that of the endo TS-D-mn. The lengths of the two CeC single bonds at the TSs of the 32CA reaction of AY 27 with nitroethylene 24 are given in Table 3. The geometry of the most favourable TS-D-mx is given in Fig. 2. At the ortho TSs, the lengths of the C1eC5 and C3eC4 forming bonds are 2.545 and 2.220  A at TS-D-on and 2.642 and 2.109  A at TS-D-ox, respectively, while at the meta TSs the lengths of the C1eC4 and C3eC5 forming bonds are 2.251 and 2.682  A at TS-B-mn and 2.108 and 2.756  A at TS-B-mx, respectively. Some interesting conclusions can be drawn from these geometrical parameters: (i) these lengths indicate that these TSs correspond to asynchronous CeC bond formation processes; and (ii) the asynchronicity in the CeC bond formation is determined by the electrophilic nitroethylene 24; in all cases, the CeC bond formation at the non-substituted C4 carbon of nitroethylene 24, the b-conjugated position of the ethylene, is more advanced than that at the C5 one; (iii) an analysis of the geometries of AY 27 and the TSs involved in the 32CA reaction of AY 27 with nitroethylene 24 shows that the aromatic ring of the N-phenyl substituent presents a perpendicular rearrangement relative to the plain of AY as a consequence of the hindrance provoked by the substituents present in C1 and C2 (see Fig. 2). This behaviour prevents the endo approach of substituted ethylenes such as nitroethylene 24, making the 32CA reaction completely exo selective. The GEDT values, which flux from the AY to the nitroethylene framework, fluctuates from 0.14e at TS-D-ox to 0.30e at TS-D-mx (see Table 3). The high GEDT value found at the most favourable TSD-mx, which is slightly higher than that at TS-C-mx, indicates that this 32CA reaction has a high polar character, in clear agreement with a zw-type mechanism.4 Consequently, the presence of the phenyl substituent in the N2 nitrogen in AY 27 accelerates the 32CA reaction and increases the exo selectivity. This acceleration is a consequence of the higher nucleophilic character of AY 27, N¼4.00 eV, when compared to AY 22, N¼3.82 eV (see Table 1).

3.3. Study of the 32CA reactions of CY 23 with ethylene 5, nitroethylene 24 and MVE 25 CYs and AYs are isoelectronic TACs with a similar structure. Consequently, it is expected that they present a similar reactivity. First, the 32CA reaction of CY 23 with ethylene 5 was analysed (see Scheme 9). The relative energies are given in Table 4.

Scheme 9.

Table 4 B3LYP/6-31G(d) relative energies, in kcal/mol, of the TSs and CAs involved in the 32CA reactions of CY 23 with ethylene 5, nitroethylene 24 and MVE 25 Ethylene

Z

5 24

H NO2

25

OCH3

ortho

endo exo endo exo

meta

DEact

DEreact

DEact

DEreact

3.1 3.2 2.2 2.1 0.2

60.8 54.6 54.6 54.5 54.5

0.0 2.2 7.3 5.4

57.6 58.6 54.5 53.5

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Interestingly, the substituted CY 23 shows a high reactivity towards ethylene 5. This 32CA reaction has an activation energy of only 3.1 kcal/mol, the reaction being strongly exothermic, 60.8 kcal/mol (see Table 4). These energy results differ with those found in the 32CA reaction of AY 22 with ethylene 5, in which the substitution produces a strong deactivation of AY 22 towards ethylene. Consequently, it can be expected that CY 23 presents a different reactivity than AY 22. The lengths of the two CeC forming bonds at TS-G are given in Table 5. The lengths of the C1eC5 and C3eC4 forming bonds are 2.492 and 2.373  A, respectively. These lengths suggest a synchronous bond formation process in which the CeC single bond formation at the C3 carbon of CY 23 is slightly more advanced than that at the C1 carbon. Note that TS-G is earlier and more synchronous than TS-A associated with the 32CA reactions of AY 22 with ethylene 5. Table 5 Lengths, d(CxeCy) in Angstroms, of the two single forming bonds, and GEDT, in e, at the regioisomeric TSs of the 32CA reactions of CY 23 with ethylene 5, nitroethylene 24 and MVE 25 Ethylene

Z

5 24

H NO2

25

OCH3

ortho

endo exo endo exo

meta

C1eC5

C3eC4

GEDT

C1eC4

C3eC5

GEDT

2.492 2.512 2.622 2.703 2.756

2.373 2.350 2.311 2.263 2.292

0.03 0.10 0.09 0.16 0.15

2.357 2.415 2.388 2.354

2.686 2.648 2.383 2.293

0.15 0.14 0.08 0.08

The polar character of this 32CA reaction was evaluated computing the GEDT at TS-G. The GEDT is given in Table 5. The GEDT at TS-G, 0.03e, indicates that this 32CA reaction has a non-polar character. Consequently, the high reactivity of CY 23 towards ethylene 5 along a non-polar 32CA reaction supports a pr-type mechanism. Note that ethylene 5 does not participate in zw-type reactions. Then, the 32CA reactions of CY 23 with nitroethylene 24, and with MVE 25 were studied. Due to the asymmetry of both reagents, four competitive reactive channels are feasible (see Scheme 8). The four reactive channels were studied in order to analyse the stereoand regioselectivity in these 32CA reactions. All these reactions also take place through a one-step mechanism; consequently, one TS and the corresponding CA were found and characterised along each one of the four competitive channels. The relative energies are given in Table 4. Along the 32CA reaction of CY 23 with nitroethylene 24, the activation energies associated to the four competitive channels are 3.2 (TS-E-on), 2.2 (TS-E-ox), 0.0 (TS-E-mn) and 2.2 (TS-E-mx) kcal/mol; these 32CA reactions are exothermic between 54.6 and 58.6 kcal/mol. Some appealing conclusions can be drawn from these energy results: (i) the TS associated with the most favourable channel, TS-E-mx, is located 2.2 kcal/mol below the reagents. This energy result points at the high reactivity of CY 23; (ii) this 32CA reaction is completely regioselective as the most favourable meta TS-E-mx is 4.4 kcal/mol below that of the ortho TS-E-ox; (iv) this 32CA reaction presents an exo stereoselectivity as the exo TS-E-mx is 2.2 kcal/mol below that of the endo TS-E-mn. The lengths of the two CeC single bonds at the TSs of the 32CA reaction of CY 23 with nitroethylene 24 are given in Table 5. The geometry of the most favourable TS-E-mx is given in Fig. 3. At the ortho TSs, the lengths of the C1eC5 and C3eC4 forming bonds are 2.512 and 2.350  A at TS-E-on and 2.622 and 2.311  A at TS-E-on, respectively, while at the meta TSs, the lengths of the C1eC4 and C3eC5 forming bonds are 2.357 and 2.686  A at TS-E-mn and 2.415

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and 2.648  A at TS-E-mx, respectively. Some attractive conclusions can be drawn from these geometrical parameters: (i) these lengths indicate that these TSs correspond to asynchronous CeC bond formation processes; (ii) the asynchronicity is determined by the electrophilic nitroethylene 24; in all cases the CeC bond formation at the non-substituted C4 carbon of nitroethylene 24 is more advanced than that at the C5 one; (iii) the more favourable TS-D-mx is less asynchronous as a consequence of its earlier character. Note that at this TS the C1eC4 length is 2.415  A.

The GEDT values at the TSs of the four competitive channels range from 0.08e at TS-F-mn to 0.16e at TS-F-on. The GEDT at the more favourable TS-F-ox, 0.15e, indicates that this 32CA reaction has a low polar character. A comparison of the reactions of AY 22 and CY 23 towards the nucleophilic MVE 25 evidences a different reactivity pattern. While the reaction of AY 22 presents high activation energy via a low polar TS, a behaviour that does not favour a zw-type mechanism, the reaction of CY 23 presents a high reactivity via a low polar TS, in complete agreement with a pr-type mechanism.2

4. Conclusion

Fig. 3. Most favourable TSs involved in the 32CA reactions of CY 23 with nitroethylene 24, TS-E-mx, and with MVE 25, TS-F-ox. The distances are given in Angstroms.

The polar character of this 32CA reaction was evaluated computing the GEDT at the TSs. The GEDT values at the TSs are given in Table 5. The GEDT values at the TSs of the four competitive channels range from 0.09e at TS-E-ox to 0.15e at TS-E-mn. The TSs associated with the more favourable meta channels present low GEDT values, indicating that this reaction will have a low polar character. Consequently, the high reactivity of CY 23, and low polar character of the 32CA reaction of this TACs with nitroethylene 24 indicate that this reaction takes place through a pr-type mechanism.2 Finally, the 32CA reaction of CY 23 with the nucleophilic MVE 25 was studied. Along the 32CA reaction of CY 23 with MVE 25, the activation energies associated to the four competitive channels are 2.1 (TS-F-on), 0.2 (TS-F-ox), 7.3 (TS-F-mn) and 5.4 (TS-F-mx) kcal/mol; these 32CA reactions are strongly exothermic between 53.5 and 54.5 kcal/mol. Some appealing conclusions can be drawn from these energy results: (i) the TS associated with the most favourable ortho/exo channel, TS-F-ox, is located 0.2 kcal/ mol below the reagents. This energy result emphasises the high reactivity of CY 23 towards nucleophilic ethylenes. Note that the activation energy associated with the 32CA reaction of AY 22 with MVE 25 is 12.3 kcal/mol; (ii) this reaction presents a complete ortho regioselectivity as the ortho TS-F-ox is 5.6 kcal/mol below that of the meta TS-F-mx. Consequently, a change of the ortho/ meta regioselectivity is observed with the electronic nature of the ethylene: (iii) this reaction presents an exo selectivity as the exo TS-F-ox is 2.3 kcal/mol below that of the endo TS-F-on; and (iv) these energy results clearly indicate that CY 23 is more reactive than AY 22. The lengths of the two CeC single bonds at the TSs of the 32CA reaction of CY 23 with MVE 25 are given in Table 5. The geometry of the most favourable TS-F-ox is given in Fig. 3. At the ortho TSs, the lengths of the C1eC5 and C3eC4 forming bonds are 2.703 and 2.263  A at TS-F-on and 2.756 and 2.292  A at TS-E-ox, respectively, while at the meta TSs, the lengths of the C1eC4 and C3eC5 forming bonds are 2.388 and 2.383  A at TS-F-mn and 2.354 and 2.293  A at TS-F-mx, respectively. Some interesting conclusions can be drawn from these geometrical parameters: (i) while along the more favourable ortho channels these lengths indicate that these 32CA reactions are associated to high asynchronous CeC bond formation processes, along the meta channels these lengths indicate that the TSs are associated to synchronous CeC bond formation processes; and (ii) along the ortho channels the reaction is characterised by the attack of the nucleophilic C4 carbon of MVE 25 on the C3 carbon of CY 23.

The participation of substituted AYs and CYs in 32CA reactions has been analysed using DFT reactivity indices and the transition state theory at the B3LYP/6-31G(d) level of theory. It was shown that the simplest AY and CY quickly participate in pr-type 32CA via non-polar TSs towards non-activated ethylenes due to the pseudodiradical character of these TACs.7 However, these simplest TACs are not standard in organic synthesis; most AYs and CYs present ER and EW groups in each of two terminal carbon atoms, respectively. This asymmetric substitution breaks the symmetric electronic structure of the simplest AY and CY, modifying the electrophilic and nucleophilic behaviours of the TACs. The changes on the electronic structure of these substituted TACs can modify the pr-type reactivity to a zwtype one. In order to investigate the changes in reactivity with the substitution pattern, the 32CA reactions of AY 22 and CY 23, towards ethylene 5, which does not participate in polar reactions, the electrophilic nitroethylene 24, and the nucleophilic MVE 25 have been analysed. Interestingly, while the substituted AY 22 presents high activation energy towards ethylene 5, 14.4 kcal/mol, the substituted CY 23 remains highly reactive. This dissimilar reactivity indicates different behaviours for these disubstituted TACs. An analysis of the DFT reactivity indices at the ground state of the reagents indicates that the presence of ERG and EWG in AY 22 and CY 23 increases the electrophilicity and slightly decreases the nucleophilicity of the simplest AY 3c and CY 16. In spite of this decrease of nucleophilicity, AY 22 and CY 23 remain as strong nucleophiles. This behaviour is analysed by comparing the activation energies involved in the 32CA reactions of these TACs towards the electrophilic nitroethylene 24 and the nucleophilic MVE 25. As expected, these TACs react quickly towards nitroethylene 24. However, while the reaction AY 22 takes place via a polar TS, in agreement with a zw-type mechanism, CY 23 appears to react via a pr-type mechanism characterised by a very low activation energy via early and low polar TS. Inclusion of a phenyl substituent in the N2 nitrogen atom of AY 22 decreases the activation energy and increase the polarity of the TS as a consequence of an increase of the nucleophilic character of AY 27. A different behaviour is also found in the reactivity of these TACs towards the nucleophilic MVE 25. While AY 22 presents a high activation energy via a low polar TS, in spite of its electrophilic character, CY 23 presents a high reactivity via a low polar TS, in agreement with a pr-type mechanism. Due to the polarisation of the electronic structure of both reagents with the substitution, these reactions are completely regioselective, but display a moderate exo stereoselectivity. The present comparative study makes it possible to establish that the substitution provokes a dissimilar reactivity in AYs and CYs. While the substitution in CYs does not modify their pr-type reactivity, reacting quickly with all type of ethylenes along non-

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polar processes, AYs only participate in zw-type 32CA reactions towards electrophilic ethylenes. Acknowledgements This work has been supported by the Ministerio de Ciencia e  n of the Spanish Government, project CTQ2013-45646-P, Innovacio FONDECYT grant No. 1140341, and Millennium Nucleus of Chemical Processes and Catalysis (CPC), project No. 120082. Prof. L.R.D. also n thanks FONDECYT for continuous support through Cooperacio Internacional. References and notes 1. (a) Carruthers, W. Some Modern Methods of Organic Synthesis, 2nd ed.; Cambridge University Press: Cambridge, UK, 1978; (b) Carruthers, W. Cycloaddition Reactions in Organic Synthesis; Pergamon: Oxford, UK, 1990. 2. Domingo, L. R.; S aez, J. A. Org. Biomol. Chem. 2009, 7, 3576e3583. 3. (a) Ess, D. H.; Houk, K. N. J. Am. Chem. Soc. 2007, 129, 10646e10647; (b) Ess, D. H.; Houk, K. N. J. Am. Chem. Soc. 2008, 130, 10187e10198. 4. Domingo, L. R.; Emamian, S. R. Tetrahedron 2014, 70, 1267e1273. 5. Padwa, A. Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry toward Heterocycles and Natural Products; John Wiley & Sons: New York, 2002, Vol. 59. rez, P. Tetrahedron 2014, 70, 4519e4525. 6. Domingo, L. R.; Aurell, M. J.; Pe rez, P. Lett. Org. Chem. 2010, 7, 432e439; (b) 7. (a) Domingo, L. R.; Chamorro, E.; Pe ez, J. A. J. Org. Chem. 2011, 76, 373e379. Domingo, L. R.; Sa rez, P.; Chamorro, 8. (a) Bentabed-Ababsa, G.; Derdour, A.; Roisnel, T.; S aez, J. A.; Pe E.; Domingo, L. R.; Mongin, F. J. Org. Chem. 2009, 74, 2120e2133; (b) Bentabedez, J. A.; Roisnel, T.; Ababsa, G.; Hamza-Reguig, S.; Derdour, A.; Domingo, L. R.; Sa Dorcet, V.; Nassar, E.; Mongin, F. Org. Biomol. Chem. 2012, 10, 8434e8444. 9. (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785e789; (b) Becke, A. D. J. Chem. Phys. 1993, 98, 5648e5652.

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