Computational and Theoretical Chemistry 1030 (2014) 25–32

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Computational and Theoretical Chemistry

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A DFT study of the domino reactions between imidazole NHC,ketenimines and DMAD or MP acetylene derivatives yieldingspiro-pyrroles

2210-271X/$ - see front matter � 2014 Elsevier B.V. All rights reserved.http://dx.doi.org/10.1016/j.comptc.2013.12.022

⇑ Corresponding author.E-mail addresses: esseffar@uca.ma, esseffar@gmail.com (M. Esseffar).

M’hamed Esseffar a,⇑, Rachid Jalal b, M. José Aurell c, Luis R. Domingo c,⇑a Université Cadi Ayyad, Faculté des Sciences-Semlalia, Département de Chimie, BP 2390 Marrakesh, Moroccob Université Cadi Ayyad, Faculté des Sciences et Techniques, Département des Sciences Chimique, BP 549 Marrakesh, Moroccoc Departamento de Química Orgánica, Universidad de Valencia, Dr. Moliner 50, E-46100 Burjassot, Valencia, Spain

a r t i c l e i n f o

Article history:Received 20 November 2013Received in revised form 19 December 2013Accepted 19 December 2013Available online 28 December 2013

Keywords:Imidazole carbenesKeteniminesAcetylene carboxylates[3+2] cycloadditionsDomino reactionsDFT calculations

a b s t r a c t

The domino reactions of imidazole carbene 9, ketenimine 10 and DMAD 5 or MP 7 to yield the formal[3+2] cycloadducts 12 or 14 have been investigated using DFT methods at the B3LYP/6-31G� level. Thesedomino reactions are initialized by the nucleophilic attack of imidazole 9 on ketenimine 10 to yield thezwitterionic intermediate 11. The second reaction is a formal [3+2] cycloaddition (32CA) reactionbetween the zwitterionic intermediate 11 and acetylene carboxylates DMAD 5 or MP 7 yielding spiro-pyrroles 12 and 14. These formal 32CA reactions are initialized by the nucleophilic attack of the N3 nitro-gen of intermediate 11 on the most electrophilic centres of these acetylene derivatives yielding zwitter-ionic intermediates, which by a fast ring-closure afford spiro-pyrroles 12 and 14. The first step of theseformal 32CA reactions is completely chemoselective, while the reaction with MP 7 is completely regio-selective. Analysis of DFT reactivity indices allows one to explain the behaviour of these domino reac-tions. The nucleophilic addition of imidazole 9 to ketenimine 10 generates a strong nucleophilicintermediate 11 able to attack electrophilic acetylenes DMAD 5 or MP 7 in the subsequent reaction.

� 2014 Elsevier B.V. All rights reserved.

1. Introduction

In the two last decades, N-heterocyclic carbenes (NHCs) havereceived enormous attention. Among the reactions of nucleophilicNHCs, those with various heterocumulenes have been continu-ously explored and have gained important applications. For exam-ple, several NHCs undergo [4+1] cycloadditions with vinylisocyanates to afford hydroindolones in good yields [1], while witharyl isocyanates, the nucleophilic NHCs can either afford 1+1 ad-ducts, indole-2-ones [2], or 1+2 adducts, imidazoline-2,4-dionederivatives [3], depending on the structure of either reactant.

In addition to the cycloaddition to heterocumulenes to affordcyclic products, NHCs are also known to form stable zwitterionsin the nucleophilic addition to cumulenes and heterocumulenes,such as allenoates [4], isothiocyanates [5], isoselenocyanates [6],carbon dioxide [7] and carbon disulphide [8].

In recent years, the ambident bis-dipoles derived from the addi-tion of NHCs to aryl isothiocyanates have been developed intoversatile synthons for the construction of novel spiro- and fusedthiophene or pyrrole derivatives [9]. Recently, Cheng et al. [10] re-ported that thiazole a and benzothiazole (b) NHCs underwent

cycloaddition with two equivalents of ketenimines c to producethiazole- d and benzothiazole-spiro-pyrrole (e) derivatives in goodyields (see Scheme 1).

These reactions proceeded via a domino nucleophilic additionof NHC to the C@N bond of ketenimine followed by a formal[3+2] cycloaddition (32CA) of the zwitterionic intermediate withthe C@C bond of ketenimine. However, zwitterionic intermediatescould not be isolated. They considered that the sulphur atom of thi-azoles was not a strong enough electron–donor to stabilise the cat-ion centres of these intermediates in the reaction.

Regarding the importance of these reactions, pyrrolidine hasfound in many natural products with great pharmaceutical anindustrial interest. As a consequence, the synthesis of the pyrroli-dine skeleton has received much interest in organic synthesis,being utilised in important fields such as materials science, medic-inal chemistry, and pharmacology. The present reactions provide apowerful protocol for the construction of novel polyfunctional thi-azole-spiro-pyrrole compounds that are not readily accessible byother methods.

To find new types of formal C+ACAN� dipoles that could beused as versatile synthons in the construction of novel pyrrolederivatives, they undertook the study of the reactions of benzimid-azole and triazole NHCs with ketenimines, and thus explored theirsynthetic applications [11]. Thus, the reaction of benzimidazolium

Scheme 1.

26 M. Esseffar et al. / Computational and Theoretical Chemistry 1030 (2014) 25–32

1 with ketenimine 2 in the presence of t-BuOK proceeded rapidlyand efficiently at �20 �C to afford salt 3 in 58–92% yields, whichwas elucidated spectroscopically and by microanalysis [11] (seeScheme 2).

Further treatment of salt 3 with a base yielded a zwitterionicintermediate 4 which could be regarded as a feasible electron-rich1,3-dipole participating in a formal 32CA reaction with electrondeficient ethylenes and acetylenes. Thus, the further treatment ofsalt 3 with t-BuOK and subsequently with dimethyl acetylenedi-carboxylate (DMAD) 5 or methyl propiolate (MP) 7 afforded thecorresponding formal [3+2] cycloadducts 6 and 8 as the only struc-tural isomer, respectively (see Scheme 3) [11].

Structural isomeric cycloadducts 6 and 8 appear to be obtainedfrom an initial nucleophilic attack of the nitrogen atom of thezwitterionic intermediate 4 on the acetylenic carbon atoms ofthese electron-deficient acetylenes. Consequently, these results

N

NBn

Bn

CArN

1Cl

Base 2

Scheme

N

N

NHAr

CO2Me

MeBn

BnCl 3

Base

N

NBn

Bn4

Scheme

indicated the non-participation of the allylic carbon atom in thenucleophilic attack, the reaction being entirely chemoselective.On the other hand, the use of the asymmetric substituted MP 7yielded the formation of only one regioisomeric cycloadduct, thus,this reaction being also completely regioselective. Finally, thequestion if these formal 32CA reactions take place via a one-stepmechanism or via a two-step mechanism remains unresolved.

Consequently, we decided to perform a DFT study for the forma-tion of zwitterionic intermediates such as 4, and the further formal32CA reactions with the electron-deficient substituted acetylenesDMAD 5 and MP 7. For this propose, the reaction of imidazoleNHC 9 with ketenimine 10, and the further treatment of the zwit-terionic intermediate 11 with 5 or 7 to yield the formal [3+2] cyc-loadducts 12 or 14, as reactions model of those studied by Chenget al. [11] were investigated using DFT methods at the B3LYP/6-31G� level (see Scheme 4).

N

N

NHAr

CO2Me

MeBn

Bn

Me

CO2Me

Cl 3

2.

NAr

CO2Me

Me

N

NBn

Bn

N

MeO2CCO2Me

Ar

MeO2CMe

CO2Me

CO2Me

CO2Me

N

NBn

Bn

N

MeO2C

Ar

MeO2CMe

5 6

7

8

3.

N

N

NPh

MeO2C

MeMe

Me

R

CO2Me

N

NMe

Me

N

MeO2CR

Ph

MeO2CMe

5 R = CO2Me7 R = H

N

NMe

Me N

Me CO2Me

Ph

+

9 10 11

12 R = CO2Me14 R = H

Scheme 4.

M. Esseffar et al. / Computational and Theoretical Chemistry 1030 (2014) 25–32 27

2. Computational methods

DFT computations were carried out using the B3LYP [12] hybridmeta functional, together with the standard 6-31G� basis set [13].The optimizations were carried out using the Berny analytical gra-dient optimization method [14]. The stationary points were char-acterised by frequency computations in order to verify that TSshave one and only one imaginary frequency. The IRC paths [15]were traced in order to check the energy profiles connecting eachTS to the two associated minima of the proposed mechanism usingthe second order González-Schlegel integration method [16]. Sol-vent effects of toluene were taken into account through singlepoint energy calculations using the polarisable continuum model(PCM) as developed by Tomasi’s group [17] in the framework ofthe self-consistent reaction field (SCRF) [18]. The electronic struc-tures of stationary points were analysed by the natural bond orbi-tal (NBO) method [19]. All computations were carried out with theGaussian 09 suite of programs [20].

The global electrophilicity index, x, is given by the followingexpression [21], x ¼ ðl2=2gÞ, in terms of the electronic chemicalpotential l and the chemical hardness g. Both quantities may beapproached in terms of the one-electron energies of the frontiermolecular orbitals HOMO and LUMO, eH and eL, as l � ðeH þ eLÞ=2and g � ðeL � eHÞ, respectively [22]. Recently, we introduced anempirical (relative) nucleophilicity index [23], N, based on theHOMO energies obtained within the Kohn-Sham scheme [24],and defined as N = EHOMO(Nu) � EHOMO(TCE). Nucleophilicity is re-ferred to tetracyanoethylene (TCE), because it presents the lowestHOMO energy in a long series of molecules already investigated inthe context of polar cycloadditions. This choice allows us to conve-niently handle a nucleophilicity scale of positive values. The localelectrophilicity indices [25], and the local nucleophilicity indices[26], Nk, were evaluated using the following expressions [27]:xk ¼ xPþk and Nk ¼ NP�k , where Pþk and P�k are the electrophilicand nucleophilic Parr functions [27], respectively, obtainedthrough the analysis of the Mulliken atomic spin density of theradical anion and the radical cation of the studied molecules.

3. Results and discussions

The reactions between imidazole NHC 9, ketenimine 10 andacetylene derivative 5 or 7 to yield spiro-pyrroles 12 or 14 aredomino reactions that comprise two consecutive reactions (seeScheme 5): (i) the nucleophilic attack of imidazole NHC 9 on thecentral C2 carbon of ketenimine 10 to yield the zwitterionic inter-mediate 11; and (ii) the formal 32CA reaction between the zwitter-ionic intermediate 11 and DMAD 5 or MP 7 to yield the formal[3+2] cycloadducts 12 or 14. The total and relative energies of allstationary points involved in these domino reactions are given inTable 1.

3.1. Study of the formation of the zwitterionic intermediate 11

The first reaction of these domino processes is the nucleophilicattack of the C1 carbon of imidazole NHC 9 on the central C2 car-bon of ketenimine 10. The activation energy in toluene associatedwith the nucleophilic attack of the imidazole NHC 9 on ketenimine10 is of 8.3 kcal/mol, the addition reaction being exothermic by�27.6 kcal/mol. These kinetic and thermodynamic parametersmake the addition process very favourable, formation of the zwit-terionic intermediate 11 being irreversible.

The geometries of TS1 and zwitterionic intermediate 11 are gi-ven in Fig. 1. At TS1 the distance between the C1 and C2 carbonatoms is 2.487 Å, whereas the length of C1AC2 single bond at thezwitterionic intermediate 11 is 1.498 Å. The large distance be-tween the C1 and C2 atoms at TS1 indicates the earlier nature ofthis TS.

Ketenimine 10 has an N3@C2@C4 heteroallenic structure withtwo orthogonal double bonds sharing the sp hybridised C2 car-bon atom. Consequently, the nucleophilic attack on the C2 carboncan be related with the participation of the C2AN3 or C2AC4double bonds. Interestingly the C1AC2AN3AC(Ph) andC1AC2AC4AC(CO2Me) dihedral angles at TS1, 84.4 and 2.7 de-grees, indicated the participation of the N3@C2 double bondalong nucleophilic attack.

The natural population analysis (NPA) of TS1 and of the zwitter-ionic intermediate 11 provides insight into the chemical features ofthe first reaction of these domino processes. The global chargetransfer (GCT) along the nucleophilic attack of imidazole NHC 9on ketenimine 10 was estimated by sharing the natural atomiccharge of TS1 and 11 between imidazole and ketenimine frame-works. The GCT at TS1 and intermediate 11, 0.15e and 0.82e,respectively, points to the high polar nature of the additionprocess.

The bond order [28] (BO) values of the C1AC2, C2AN3 andC2AC4 bonds at intermediate 11 are 0.99, 1.45 and 1.38, respec-tively, while the natural charges at the C1, C2, N3 and C4 atomsare 0.52e, 0.15e, �0.56e and �0.29e, respectively. The C1AC2BO value, ca 1.0, indicates that there is no conjugation betweenthe positively charged imidazole residue and the negativelycharged ketenimine one in intermediate 11. This behaviourtogether with the high charge separation found between imidaz-ole and ketenimine frameworks indicate that intermediate 11 hasa high zwitterionic character. On the other hand, the C2AN3 andC2AC4 BO values together with the natural charges at the N3 andC4 atom indicate that the negative charge of the zwitterionicintermediate 11 is delocalized within the N3AC2AC4 allylicframework. The NPA of the electronic structure of intermediate11 indicates that the C1AC2AN3 and C1AC2AC4 frameworkshave not a dipole structure participating in 1,3-dipolarcycloadditions.

N

NMe

MeMeO2C

CO2Me

N

N

N

NPh

MeO2C

MeMe

Me

CO2Me

CO2Me

N

NMe

Me

N

MeO2CCO2Me

Ph

MeO2CMe

Ph

Me

CO2Me

TS1

TS22 TS32IN2 13

12

5

5

3

4

N

NMe

Me N

Me CO2Me

Ph

+

9 10

N

NMe

MeMeO2C

N

CO2Me

N

NMe

Me

N

MeO2C

Ph

MeO2CMe

Ph

Me

CO2Me

TS23

TS24 TS34IN4 15

14

7

11

[TS31]IN1

TS21

1 21

3

4

6

5

6

Scheme 5.

Table 1Total (E, in au) and relative (DE, in kcal/mol) energies, in gas phase and toluene, of allstationary points involved in the domino reactions between imidazole NHC 9,ketenimine 10 and acetylene derivative DMAD 5 or MP 7.

Gas phase Toluene

E DE E DE

9 �304.792467 �304.796152010 �630.966019 �630.96958975 �533.0754121 �533.07963807 �305.2009304 �305.2040821TS1 �935.7481038 6.5 �935.7525815 8.311 �935.7992320 �25.6 �935.8097729 �27.6TS21 �1468.8610515 8.5 �1468.871758 11.1IN1 �1468.8818977 �4.6 �1468.896056 �4.212 �1468.9250877 �31.7 �1468.932528 �27.1TS22 �1468.8486722 16.3 �1468.859714 18.6IN2 �1468.8810781 �4.0 �1468.892776 �2.1TS32 �1468.8806696 �3.8 �1468.892275 �1.813 �1468.9246889 �31.4 �1468.932725 �27.2TS23 �1240.9821303 11.3 �1240.993033 13.114 �1241.0608997 �38.1 �1241.067113 �33.4TS24 �1240.9697717 19.1 �1240.980654 20.8IN4 �1240.9901233 6.3 �1241.003910 6.2TS34 �1240.9886487 7.2 �1241.000111 8.615 �1241.0542277 �33.9 �1241.061406 �29.8

Fig. 1. B3LYP/6-31G� geometries of TS1 and zwitterionic intermediate 11. Lengthsare given in Angstroms.

28 M. Esseffar et al. / Computational and Theoretical Chemistry 1030 (2014) 25–32

3.2. Study of the formal 32CA reaction between the zwitterionicintermediate 11 and DMAD 5

Formation of the spiro-pyrrole 12 is a stepwise process initiatedby the nucleophilic attack of the N3 nitrogen of the zwitterionicintermediate 11 on the conjugated C5 carbon atom of DMAD 5 toyield a new zwitterionic intermediate IN21, which through a ringclosure process affords the formal [3+2] cycloadduct 12. Due tothe heteroallylic structure of the anionic N3-C2AC4 framework of

zwitterionic intermediate 11, a competitive channel initiated bythe nucleophilic attack of the allylic C4 carbon is also feasible(see Scheme 5). This chemoselective channel enables the formationof the spiro-pyrrole 13, which is not observed experimentally.

The activation energies associated with the nucleophilic attacksof the N3 nitrogen or C4 carbon atoms of zwitterionic intermediate11 on the conjugated C5 carbon atom of DMAD 5, via TS21 or TS22,are 11.1 and 18.6 kcal/mol respectively, formation of the corre-sponding intermediates IN1 and IN2 being exothermic by �4.2and �2.1 kcal/mol. TS22 is 7.5 kcal/mol higher in energy thanTS21; consequently, the nucleophilic attack of the N3 nitrogen ofintermediate 11 on DMAD 5 is completely chemoselective.

The subsequent ring closure at IN2 to yield spiro-pyrrole 13, viaTS32, has unappreciable activation barrier; 0.3 kcal/mol, due to thefavourable electronic interactions between the positively charged

M. Esseffar et al. / Computational and Theoretical Chemistry 1030 (2014) 25–32 29

C1 carbon of the imidazole framework and the negatively chargedC6 carbon of the acetylenic one. All attempts to locate the TS asso-ciated with the ring closure at the intermediate IN1 were unsuc-cessful. After a slight rotation of the C1AC2 single bond, IN1drops towards spiro-pyrrol 12 without any appreciable barrier. Fi-nally, formation of spiro-pyrroles 12 and 13 is exothermic by ca27 kcal/mol; these formal 32CA reactions being irreversible.

The geometries of TS21, TS22 and TS23 are given in Fig. 2. At theTSs associated to the nucleophilic attacks of the N3 or C4 atoms ofthe zwitterionic intermediate 11 on the conjugated C5 position ofDMAD 5 the distance between the N3 and C5 atoms in TS21 andbetween the C4 and C5 atoms in TS22 are 1.983 and 2.320 Å,respectively. The most favourable TS21 is more advanced thanTS22. At intermediates IN1 and IN2, the lengths of the N3AC5and C4AC5 single bonds are 1.479 and 1.566 Å, respectively, whilethe distances between the C1 and C6 carbons are 3.270 and3.166 Å. Finally, at TS32 the distance between the C1 and C6 car-bons is 2.943 Å.

At the TSs associated with the nucleophilic attacks of the N3 orC4 atoms of the zwitterionic intermediate 11 on the conjugated C5position of DMAD 5, The GCT that flows from the nucleophilicintermediate 11 to electrophilic DMAD 5 is 0.36e at TS21 and0.35e at TS22. These high values point to high polar processes.

3.3. Study of the formal 32CA reaction between the zwitterionicintermediate 11 and MP 7

Due to the presence of two nucleophilic centres in intermediate11, the N3 and C4 atoms, and the asymmetric substitution on thetwo acetylenic carbons of MP 7, four isomeric channels are feasible.They are related with the nucleophilic attacks of the N3 and C4atoms of the zwitterionic intermediate 11 on the C5 and C6 atomsof acetylene. Since the regioisomeric nucleophilic attacks on thenon-conjugated C6 carbon of MP 7 are very unfavourable (seebelow), only the two competitive chemoisomeric channels associ-ated with the nucleophilic attacks of the N3 or C4 atoms of the

Fig. 2. B3LYP/6-31G� geometries of the TSs involves in the formation of spiro-pyrroles 12 and 13. Lengths are given in Angstroms.

zwitterionic intermediate 11 on the conjugated C5 carbon of MP7, yielding spiro-pyrroles 14 and 15 were studied (see Scheme 5).Interestingly, while the formation of spiro-pyrrole 14 takes placethrough a two-stage one-step mechanism, the formation of spiro-pyrrole 15 takes place through a two-step mechanism.

The activation energies associated with the nucleophilic attacksof the N3 nitrogen or C4 carbon atoms of zwitterionic intermediate11 on the conjugated C5 carbon atom of MP 7, via TS23 or TS24, are13.1 and 20.8 kcal/mol, respectively, formation of intermediate IN4along the stepwise mechanism being endothermic by 6.2 kcal/mol.The activation energies associated with the nucleophilic attacks ofintermediate 11 on MP 7 are slightly higher than those associatedwith the nucleophilic attacks of 11 on DMAD 5 as a consequence ofthe lower electrophilic character of the former (see below). TS24 is7.9 kcal/mol higher in energy than TS23; consequently, the nucle-ophilic attack of 11 on MP 7 is also completely chemoselective.Intermediate IN4 with very low activation energy, 2.4 kcal/mol, isconverted into the spiro-pyrrol 15. Formation of spiro-pyrroles14 and 15 is strongly exothermic by 33.4 and 29.8 kcal/mol,respectively; these formal 32CA reactions being also irreversible.

The geometries of TS23, TS24 and TS34 are given in Fig. 3. At theTSs associated with the nucleophilic attacks of the N3 or C4 atomsof the zwitterionic intermediate 11 on the conjugated C5 positionof MP 7 the distance between the N3 and C5 atoms in TS23 and be-tween the C4 and C5 atoms in TS24 are 1.965 and 2.327 Å, respec-tively. The most favourable TS23 is more advanced than TS24.These lengths are similar to those in TS21 and TS22.

At TS23 associated with the one-step mechanism, the distancebetween the C4 and C6 carbons is 2.958 Å. The N3AC5 andC4AC6 distances at TS23 points to a high asynchronous TS, inwhich only the N3AC5 single bond is being formed. Analysis ofthe N3AC5 and C4AC6 bond length evolution along the IRC fromTS23 to spiro-pyrrol 14 affirms the two-stage nature of this one-step mechanism. At the highly asynchronous TS23, theC2AN3AC5AC6 dihedral angle of 6.5 degrees prevents the forma-tion of a zwitterionic intermediate. The main difference between

Fig. 3. B3LYP/6-31G� geometries of the TSs involved in the formation of spiropyrrols 14 and 15. Lengths are given in Angstroms.

30 M. Esseffar et al. / Computational and Theoretical Chemistry 1030 (2014) 25–32

TS23, associated with the two-stage one-step mechanism, andTS21, associated with the two-step mechanism, is the hindrancebetween the second carboxylate group present in DMAD 5 andthe phenyl group present in ketenimine 10, that prevents thefavourable approach mode present in TS23. Note that at TS21 theC2AN3AC5AC6 dihedral angle is 106.4 degrees, while the C1AC6distance is 3.532 Å.

At intermediate IN4, the length of the C4AC5 single bond is1.541 Å, while the distance between the C1 and C6 carbons is3.148 Å. Finally, at TS24 the distance between the C1 and C6 car-bons is 2.811 Å.

At the TSs associated with the nucleophilic attacks of the N3 orC4 atoms of the zwitterionic intermediate 11 on the conjugated C5position of MP 7, the GCT that fluxes from the nucleophilic inter-mediate 11 to electrophilic MP 7 is 0.33e at TS23 and 0.33e atTS24. These high values point to a highly polar processes. TheseGCT values are slightly lower than those found at TS21 and TS22,a consequence of the lower electrophilic character of MP 7 thanDMAD 5.

3.4. Analysis of these domino reactions based on the DFT reactivityindices

Finally, these domino reactions were analysed using the reactiv-ity indices defined within the conceptual DFT [29]. The globaldescriptors, named electronic chemical potential l, chemical hard-ness g, global electrophilicity x, and global nucleophilicity N indi-ces for the series of reagents shown in Scheme 5 are given inTable 2.

The electronic chemical potential l of ketenimine 10, �3.76 eV,is lower than that of imidazole NHC 9, �2.08 eV. Consequently,along a polar process the GCT will take place from imidazoleNHC 9 to ketenimine 10, in clear agreement with the flux of elec-tron density found at TS1. On the other hand, DMAD 5 and MP 7have lower electronic chemical potentials l, �4.68 and �4.42 eV,than the zwitterionic intermediate 11, �2.52 eV. Consequently,along a polar process the GCT will take place from intermediate11 to these acetylene derivatives, in clear agreement with the fluxof electron density found at the corresponding TSs.

Imidazole NHC 9 has a very low electrophilicity x index,0.33 eV, but it has a very high nucleophilicity N index, 3.78 eV, thusbeing classified as a strong nucleophile [30]. On the other hand,ketenimine 10 has an electrophilicity x index of 1.44 eV and anucleophilicity N index of 2.90 eV. Thus, it can participate as eitherelectrophile or nucleophile in polar reactions. Considering thereactivity indices of both reagents, the most favourable electronicinteraction will be that between imidazole NHC 9 acting as nucle-ophile and ketenimine 10 acting as electrophile, in clear agreementwith the analysis made for the GCT.

Intermediate 11 has a very low electrophilicity x index [31],0.98 eV, but presents a very high nucleophilicity N index, 4.97 eV,being a strong nucleophile. Two interesting conclusions can bedrawn from those values: (i) while the electrophilicity x index ofintermediate 11 is lower than that of ketenimine 10, Dx(10-11) =�0.46 eV, the nucleophilicity N index of intermediate 11 has been

Table 2Electronic chemical potential l, chemical hardness g, global electrophilicity x, andglobal nucleophilicity indices N, in eV, for the series of reagents shown in Scheme 5.

l g x N

DMAD 5 �4.68 6.37 1.72 1.25MP 7 �4.42 6.43 1.52 1.49ketenimine 10 �3.76 4.92 1.44 2.90intermediate 11 �2.52 3.25 0.98 4.97imidazole NHC 9 �2.08 6.52 0.33 3.78

noticeably increased, DN(10-11) = +2.07 eV. This behaviour accountsfor the enhanced reactivity experienced by ketenimine 10. Notethat once intermediate 11 is formed, it becomes more nucleophilicthan imidazole NHC 9.

Finally, the electrophilicity x of DMAD 5 and MP 7 is 1.72 and1.52 eV, being classified as strong and moderate electrophiles[31], respectively. On the other hand, they have very low nucleo-philicity N values, 1.25 and 1.49 eV, being classified as marginalnucleophiles. Consequently, along these formal 32CA reactions itis expected that while intermediate 11 behaves as a strong nucle-ophile, the acetylene derivatives DMAD 5 and MP 7 behaves asstrong and moderate electrophiles, respectively. The larger electro-philicity of DMAD 5 when compared to MP 7 is in agreement withthe lower activation energy found along the nucleophilic attack ofintermediate 11, and with the larger GCT found at the correspond-ing TSs.

Along a polar reaction involving asymmetric reagents, the mostfavourable reactive channel is that involving the initial two-centreinteraction between the most electrophilic and nucleophilic cen-tres of both reagents [32]. Recently, we have proposed the electro-philic Pþk and nucleophilic P�k Parr functions derived from theexcess of spin electron density reached via a GCT process fromthe nucleophile to the electrophile [27]. Analysis of these Parrfunctions accounts for the most favourable CAC bond formationvia a C-to-C pseudodiradical coupling of the most electrophilicand nucleophilic centres of reagents in neutral species.[27] Themaps of the ASD and nucleophilic P�k Parr functions of the radicalcation of imidazole NHC 9 and intermediate 11, together withmaps of the ASD, and electrophilic Pþk Parr functions of the radicalanions of ketenimine 10 and acetylene derivatives DMAD 7 and MP5 are given in Fig. 4.

Along the first reaction of these domino processes, analysis ofthe nucleophilic P�k Parr functions of imidazole NHC 9 indicatesthat the C1 carbon atom is the most nucleophilic one of this

Fig. 4. Maps of the ASD and nucleophilic P�k Parr functions of the radical cation ofimidazole 9 and intermediate 11, together with maps of the ASD, and electrophilicPþk Parr functions of the radical anions of ketenimine 10 and acetylene derivativesDMAD 7 and MP 5.

M. Esseffar et al. / Computational and Theoretical Chemistry 1030 (2014) 25–32 31

species, P�1 ¼ 1:03. On the other hand, analysis of the electrophilicPþk Parr functions of ketenimine 10 indicated that the central C2carbon is the most electrophilic centre of this molecule,Pþ2 ¼ 0:44. Consequently, the most favourable nucleophilic/electro-philic interaction will be that between the C1 carbon of imidazole 9and the C2 carbon of ketenimine 10.

Along the second reaction of these domino processes, analysisof the electrophilic Pþk Parr functions of acetylene derivatives indi-cates that while DMAD 7 presents a symmetric electrophilic acti-vation at the two acetylene carbon atoms, the asymmetricallysubstituted MP 5 generates an asymmetric electrophilic activationat the two acetylenic carbons, Pþ5 ¼ 0:45 and Pþ6 ¼ �0:02. Notethat the non-conjugated position presents a slight deactivation.In both acetylene derivatives, the acetylene carbons are moreelectrophilically activated than the carbonyl carbons. The valuesof the electrophilic Pþk Parr functions at the acetylenic carbonsof MP 5 account for the complete regioselectivity experimentallyobserved.

An unexpected result is found at the nucleophilic intermediate11, to nucleophilic P�k Parr functions that the C4 carbon, P�4 ¼ 0:52,is more nucleophilically activated than the N3 nitrogen P�4 ¼ 0:37.Consequently, the most favourable nucleophilic/electrophilic inter-actions will be between the C4 of intermediate 11 and the C5 car-bon of these acetylene derivatives, a behaviour that disagrees withthe complete N chemoselectivity experimentally observed.

In order to explain these unexpected results the geometries ofthe TSs involved in the nucleophilic attacks of intermediate 11 toDMAD 5 and MP 7 must be revisited. At TS22 and TS24, DMAD 5and MP 7 approach intermediate 11 along the perpendicular planeof the heteroallylic N3AC2AC4 framework, while at TS21 andTS23, electrophiles approach intermediate 11 along the same planeof the heteroallylic N3AC2AC4 framework, in the direction of theN3 lone pair (see TS23 in Fig. 5), i.e, in these formal 32CA reactionsthe formation of the first NAC single bond does not take place atthe centres with excess of electron density resulting of the GCT,the C4 carbon, but the centre with most electron density, the N3nitrogen. Note that the Mulliken changes at the heteroallylic frag-ment of the radical cation of intermediate 11 are �0.50e at N3 and0.07e at C4. Consequently, it appears that the chemoselectivity ofintermediate 11 is controlled by charges and not by the excess ofelectron density such as is observed in Diels–Alder and 32CAreactions.

Fig. 5. Nucleophilic attack of intermediate 11 on the conjugated position of MP 7involving the N3 lone pair.

4. Conclusions

The reaction of imidazole NHC 9 with ketenimine 10, and thefurther treatment with DMAD 5 or MP 7 to yield spiro-pyrroles12 or 14 has been investigated using DFT methods at the B3LYP/6-31G� level, as reaction models of those reactions experimentallystudied by Cheng et al.[11] These reactions are domino processeswhich are initialized by the nucleophilic attack of imidazole NHC9 on ketenimine 10 to yield zwitterionic intermediate 11. The firstreaction of these domino processes is kinetically, Ea = 8.3 kcal/mol,and thermodynamically, Er = �27.6 kcal/mol, favourable. The sec-ond reaction is a formal 32CA reaction between zwitterionic inter-mediate 11 and the electrophilic acetylenes DMAD 5 or MP 7yielding spiro-pyrroles 12 and 14. These formal 32CA reactionsare initialised by the nucleophilic attack of the N3 nitrogen or C4carbon atoms the of zwitterionic intermediate 11 on the most elec-trophilic centres of these acetylene derivatives yielding zwitter-ionic intermediates, which by a fast ring-closure process affordspiro-pyrroles 12 and 14. The first step of these formal 32CA reac-tions is completely chemoselective; the nucleophilic attack of theN3 nitrogen being ca 7.5 kcal/mol lower in energy than the attackof the C4 carbon. Formation of spiro-pyrroles 12 and 14 is stronglyexothermic: �27.2 and �33.4.

The activation energy associated with the nucleophilic attack ofzwitterionic intermediate 11 on DMAD 5, 11.1 kcal/mol, is lowerthan that associated with the attack on MP 7, 13.1 kcal/mol, as aconsequence of the higher electrophilic character of DAMD 5 thanMP 7. On the other hand, the unappreciable barrier for the ring clo-sure along the nucleophilic attack of zwitterionic intermediate 11on MP 7 causes this 32CA reaction to take place via a two-stageone-step mechanism.

Analysis of the DFT reactivity indices explains the behaviour ofthese domino reactions. The nucleophilic addition of imidazoleNHC 9 to ketenimine 10 generates a strong nucleophilic intermedi-ate 11 able to attack electrophilic acetylenes DMAD 5 or MP 7 in asubsequent reaction. Analysis of the electrophilic Pþk Parr functionsat the two acetylenic carbons of MP 5 accounts for the completeregioselectivity experimentally observed.

Interestingly, nucleophilic P�k Parr functions suggest that the C4carbon belonging to the N3AC2AC4 allylic framework is the mostnucleophilic centre of intermediate 11. However, kinetically themost favourable channel corresponds to the attack of the N3 nitro-gen atom. An analysis of the geometry of TS23 indicates that theseformal 32CA reactions begin with the nucleophilic attack of the N3lone pair instead of the conjugated C4 carbon of the N3AC2AC4heteroallylic framework.

Acknowledgement

This work was supported by research funds provided by theUniversity of Valencia (Project UV-INV-AE13-139082).

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