Chemical Physics Letters 477 (2009) 60–64

Contents lists available at ScienceDirect

Chemical Physics Letters

journal homepage: www.elsevier .com/locate /cplet t

Stereoselectivity of the aza-Diels–Alder reaction between cyclopentadiene andprotonated phenylethylimine derived from glyoxylates. A density functionaltheory study

Filipe Teixeira a, José E. Rodríguez-Borges b, André Melo a, M. Natália D.S. Cordeiro a,*

a REQUIMTE, Departamento de Química, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugalb CIQUP, Departamento de Química, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugal

a r t i c l e i n f o a b s t r a c t

Article history:Received 4 May 2009In final form 5 June 2009Available online 9 June 2009

0009-2614/$ - see front matter � 2009 Published bydoi:10.1016/j.cplett.2009.06.009

* Corresponding author.E-mail address: ncordeiro@fc.up.pt (M.N.D.S. Cord

The aza-Diels–Alder reaction of cyclopentadiene with protonated (S)-phenylethylimine of methyl carbox-ilate was studied using density functional theory (DFT) at the B3LYP/6-31G(d) level to elucidate thereported stereoselectivity of this reaction. Four independent reaction pathways were found, all of themproceeding through a concerted, asynchronous, mechanism. Inclusion of solvent effects revealed a highexo/endo stereoselectivity that decreases with increasing temperature, in good accordance with theexperimental reports.

� 2009 Published by Elsevier B.V.

1. Introduction

The Diels–Alder reaction is one of the most versatile tools in or-ganic synthesis [1]. A multitude of carbocyclic structures can beobtained by varying the nature of the diene and the dienophile.This class of reactions is also known for its remarkable stereo-and regioselectivity, allowing for the formation of up to four con-tiguous stereocenters at a time [2].

The addition of a dienophile to cyclopentadiene produces rigidbicyclic products. If the dienophile is a substituted ethylene, twoconfigurational isomers are possible: the endo and the exo isomers.Although exo isomers are usually the most stable ones, these reac-tions normally produce endo isomers in appreciable amounts,which might be explained by the relative stabilities of the transi-tion structures involved [3].

The aza-Diels–Alder reaction is possibly the most useful syn-thetic route for producing nitrogen-based heterocyclic ring sys-tems. Although these reactions may occur either with a nitrogencontaining diene or with a nitrogen containing dienophile, theuse of imine derivatives as dienophiles proved to be a particularlysuccessful synthetic strategy [2,4,5]. Due to its specific nature, theaza-Diels–Alder reaction has been proved to be a good syntheticroute for several drugs, natural products, biologically active pep-tides and chiral catalysts [6–8].

Despite their intrinsic interest and applications, the aza-Diels–Alder reaction remained relatively unexplored from a theoreticalpoint of view [9–14]. It has been shown that the electronic nature

Elsevier B.V.

eiro).

of the substituents at the diene/dienophile pair may strongly influ-ence the reaction pathways and determine either a concertedmechanism (synchronous or asynchronous) or a stepwise one withthe formation of an intermediate [14–19]. The presence of elec-tron-withdrawing groups in the dienophile and electron-releasinggroups in the diene, or vice-versa, will generally facilitate the pro-cess [19–21]. This decrease of the activation energy has been re-lated to the zwiterionic character of the transition state involvedin such process [22]. Experimentalists have always employed cat-alysts to improve the kinetics of this class of reactions. It is knownthat these processes are highly accelerated by the addition of Lewisacids, which promote the formation of an iminium cation complexthat rapidly undergoes cycloaddition with dienes, even at low tem-peratures, while giving good stereoselectivity yields [23–25].Therefore, a wide range of Lewis acids have been used to modifythe rate and exo/endo selectivities of these reactions [26,27].

2-[1-Phenylethyl]-2-aza-bicylo-[2.2.1]hept-5-ene-3-carboxi-lates have attracted considerable attention not only for the biolog-ical activity of some of its stereoisomers, but also for their potentialuse as a chiral catalyst [28–31]. A synthetic route to this class ofcompounds was established by Stella and co-workers in the early1990s and involves the aza-Diels–Alder reaction between a proton-ated phenylethylimine of methyl carboxilate (1) and cyclopentadi-ene (2), the result being the protonated cycloadducts 3–5 (Fig. 1)[23,24]. This reaction has been reported as being highly stereose-lective, with up to 98% exo/endo selectivity at 193 K and 87% at273 K [2,23]. However, these yields seem to be based on an incor-rect attribution of the absolute configuration of some carbonatoms, as stated by Hashimoto and co-workers [32]. Therefore, thismight lower the exo/endo selectivity of these reactions. Despite the

Fig. 1. The four possible cycloadducts formed by the aza-Diels–Alder reactionbetween cyclopentadiene and (S)-phenylethylimine of methyl carboxilate.

Fig. 2. Predicted structures for the reactants: cyclopentadiene (CP) and theprotonated (S)-1-phenylethylimine of methyl glyoxylate, optimized at the B3LYP/6-31G(d) level. Relevant bond lengths for IMIGLX: C1—C2 ¼ 1:519 Å;C2—N3 ¼ 1:501 Å; N3—C4 ¼ 1:279 Å; C4—C5 ¼ 1:513 Å. Bond lengths for CP aregiven in angstroms.

F. Teixeira et al. / Chemical Physics Letters 477 (2009) 60–64 61

works reported, there is no experimental data about whether theposition 3 of the cycloadducts would selectively assume (R) or(S) configuration.

The purpose of this work is to rationalize the present aza-Diels–Alder reaction, and its particular stereoselectivity. In order to real-istic model the reactions, density functional theory (DFT) calcula-tions were carried out and solvent effects also taken into accountusing continuous solvation methods.

2. Computational and theoretical methods

All calculations were carried out with the GAUSSIAN 03 package ofprograms [33]. In the DFT calculations, the Lee et al. [34] correla-

Fig. 3. Predicted structures for the molecular complexes for each possible approach

tion functional are used together with Becke’s three parameter ex-change functional (B3LYP) [35,36] along with the standard 6-31G(d) basis set.

The potential energy surface (PES) for this reaction was scannedsystematically for all possible intermediates and transition state

optimized at the B3LYP/6-31G(d) level. Bond lengths are given in angstroms.

62 F. Teixeira et al. / Chemical Physics Letters 477 (2009) 60–64

structures. The stationary points found on the PES were optimizedwithout any geometrical constrain using Benny’s algorithm [37].Harmonic frequencies were computed for the full-optimizedgeometries, allowing the assignment of stationary points as min-ima or transition states, as well as the zero-point energy (ZPE) cor-rections. Thermodynamic properties were evaluated at theexperimental temperatures T ¼ 193 K and T ¼ 273 K [23], using ascaling factor of 0.9613 as recommended [38].

In order to ensure that each saddle point connects two putativeminima, intrinsic reaction coordinate (IRC) calculations were per-formed in both forward and backward directions, using the Gonza-léz and Schlegel integration method [39,40].

The electronic structure of stationary points was analyzed usingthe natural bond orbital method [41]. Global electrophilicity in-dexes [22,42–45], defined in the context of the DFT, were also com-puted for the individual reactants.

Solvent effects have been considered by performing single-point energy calculations over the optimized structures, usingthe self-consistent reaction field method based on the polarizablecontinuum model of Tomasi and co-workers [46]. The selected sol-vent was dichloromethane, in order to match the solvent employedin the experimental work of Stella and co-workers [23].

3. Results and discussion

The aza-Diels–Alder reaction between (S)-phenylethylimine ofmethyl carboxilate 1 (IMIGLX) and cyclopentadiene 2 (CP) can take

Fig. 4. Predicted structures for the transition states and respective negative wave numbare given in angstroms.

place through four reaction channels, depending on the approachand orientation of CP towards IMIGLX (see Fig. 1).

Fig. 2 contains the most relevant geometrical features of thereactants, including the labeling of the atoms. Starting from thesegeometries, a careful scan of the PES allowed us to identify fourmolecular complexes (MCs) associated with very early stages ofthe reaction, and situated on a very flat region that controls the ac-cess to the different reaction channels. As can be seen in Fig. 3,these MCs correspond to van der Waals complexes characterizedby a large distance between the reactants. In addition, they werefound to be on average 6.42 kJ mol�1 lower in energy in relationto the isolated reactants (CP and IMIGLX).

By further analysis of the PES, we were able to characterize thetransition states (TSs) and the cycloadducts (PRODs) related to thefour reaction channels considered. Fig. 4 shows the optimizedgeometries for the four TS obtained, as well as their correspondingimaginary wavenumbers. In both MCs and TSs the C4—C7 distancesare shorter than the N3—C10 distance, suggesting an asynchronousmechanism.

All attempts to find on the PES intermediates that would pre-cede the formation of the products were unsuccessful. All IRC plotsshow three different regions: one slight increase in energy towardsthe TS, a slight decrease in energy until ‘halfway’ to the product,and a steeper descend in energy then follows until the product isformed. As an example, the IRC for the exo-3R channel is displayedin Fig. 5. This behaviour can be justified by a concerted, highlyasynchronous, mechanism.

ers for each possible approach optimized at the B3LYP/6-31G(d) level. Bond lengths

Fig. 5. B3LYP/6-31G(d) IRC plot for the exo-3R approach channel of the Diels–Alder reaction.

F. Teixeira et al. / Chemical Physics Letters 477 (2009) 60–64 63

The relative energies of the stationary points along the differentreaction pathways are listed in Table 1, together with the relativeGibbs energies at T ¼ 193 K and T ¼ 273 K . In the gas phase, theformation of the cycloadducts are thermodynamically favorableprocesses. As it can be seen, the transitions states that lead tothe exo isomers are more stable than ones leading to the endo prod-ucts, when comparing to the energy of the free reactants. More-over, when considering the relative Gibbs energy betweentransition states and reactants at T ¼ 193 K and T ¼ 273 K, onecan observe that the differences between activation barriers tendto fade with increasing temperature. The results suggest a highexo/endo selectivity that decreases with increasing temperature,as reported in the experimental studies [23,32].

The good accordance between gas phase calculations and theexperimental reports available lead us to further consider theimportance of solvent effects. Table 2 presents the relative energiesand Gibbs energies for these reactions in dichloromethane. Theseenergies were obtained by performing single-point energy calcula-tions on top of the gas phase stationary points, and modeling thesolvent using a solvation continuum method. Zero-point vibra-

Table 1Total energies, relative energies and Gibbs energya for the stationary pointscorresponding to the cycloaddition reactions of cyclopentadiene (CP) with theprotonated (S)-1-phenylethylimine of methyl glyoxylate (IMIGLX) in vacuum.

Energies Gibbs energy (kJ mol�1)

(Hartree) (kJ mol�1) 193 K 273 K

CP �194.011503IMIGLX �632.333602CP + IMGLX �826.345104 0.0 0.0 0.0endo-3RMC �826.673328 �26.92 �2.84 6.58TS �826.666964 �6.88 22.31 35.22PROD �826.701537 �81.91 �47.87 �31.76endo-3SMC �826.672486 �24.22 2.40 13.14TS �826.667999 �9.12 21.47 35.07PROD �826.702547 �84.82 �51.36 �35.53exo-3RMC �826.674651 �29.67 �4.99 4.94TS �826.669870 �14.13 16.44 30.01PROD �826.703525 �86.36 �52.05 �35.77exo-SMC �826.674099 �27.88 �0.34 10.90TS �826.669389 �12.37 18.74 32.62PROD �826.703998 �87.81 �53.72 �37.56

a Energies and Gibbs energies are relative to the free reactants and include thezero-point vibrational corrections. Gibbs energies also include the thermal trans-lational, rotational and vibrational contributions computed at T ¼ 193 K and 273 K.

tional corrections and thermal corrections to Gibbs energy werecalculated in the gas phase and added to the single-point energies.As it can be seen, the inclusion of the solvent destabilizes the TSswith respect to the reactants. Otherwise, the same patten emergesfrom these calculations: there is a significant stabilization of theexo transition states that becomes less noticeable at 273 K. Resultssuggest therefore that the inclusion of the solvent leads to thesame overall conclusions that were achieved using only gas phasecalculations.

The polar nature of these cycloadditions was evaluated by acharge transfer analysis at the corresponding TSs. Natural bondorbital analysis allowed us to study such transfers. In solution,the negative charge transferred from the donor (CP) to the acceptor(IMIGLX) in the TSs is 0.50e and 0.51e for the endo and exo pro-cesses, respectively. The large amount of charge transfer denotesthe high asynchronicity of the reaction pathways, and the higherpolar character of the exo processes explains why this process ismore favorable in solution. Alternatively, the cycloaddition reac-tion can be analysed in terms of the global electronic index – the

Table 2Total energies, relative energies and Gibbs energya for the stationary pointscorresponding to the cycloaddition reactions of cyclopentadiene (CP) with theprotonated (S)-1-phenylethylimine of methyl glyoxylate (IMIGLX) indichloromethane.

Energies Gibbs energy (kJ mol�1)

(Hartree) (kJ mol�1) 193 K 273 K

CP �194.011849IMIGLX �632.391133CP + IMIGLX �826.402982 0.0 0.0 0.0endo-3RMC �826.405075 �5.50 18.62 28.06TS �826.398406 12.02 41.26 54.19PROD �826.425648 �59.55 �25.46 �9.32endo-3SMC �826.403927 �2.48 24.18 34.94TS �826.399234 9.85 40.48 54.11PROD �826.427541 �64.52 �31.01 �15.15exo-3RMC �826.403785 �2.11 22.61 32.55TS �826.400758 5.84 36.47 50.06PROD �826.428054 �65.87 �31.51 �15.20exo-3SMC �826.403105 �0.32 27.26 38.52TS �826.400066 7.66 38.82 52.73PROD �826.428409 �66.80 �32.66 �16.48

a Energies and Gibbs energies are relative to the free reactants and include thezero-point vibrational corrections. Gibbs energies also include the thermal trans-lational, rotational and vibrational contributions computed at T ¼ 193 K and 273 K.

64 F. Teixeira et al. / Chemical Physics Letters 477 (2009) 60–64

electrophilicity power x – which can be defined within DFT. Thisstatic index roughly explains the global reactivity pattern observedin Diels–Alder reactions and is estimated using frontier molecularorbitals of the reactants [43]. IMGLX has a higher electrophilicitypower ðx ¼ 5:00 eVÞ than CP ðx ¼ 0:82 eVÞ, the former is thereforeconsidered as a strong electrophile, while the later is classified as agood nucleophile. The difference between the electrophilicities ofIMIGLX and CP ðDx ¼ 4:18 eVÞ confirms the polar character ofthe cycloaddition, which is quite higher than that of the non-polarcycloaddition between butadiene and ethylene ðDx ¼ 0:32 eVÞ[22,43–45].

Theoretical calculations at the B3LYP/6-31G(d) level allowed usto characterize four reaction pathways which lead to the four dias-teroisomeric products of the reaction concerned. The analysis ofthe reactants and transition state structures suggests a concertedasynchronous mechanism, similar to previous theoretical studiesof the same type [12,22,25,43–45]. The exo/endo selectivity waspredicted to decrease with increasing temperature in good accor-dance with the experimental observations.

Acknowledgements

Thanks are due to the Fundação para a Ciência e Tecnologia(FCT), Lisbon, Portugal, and to FEDER for financial support to CIQUPand to REQUIMTE. Moreover, this work was supported by FCT, Pro-ject PTDC/QUI/67407/2006.

References

[1] H.B. Kagan, O. Riant, Chem. Rev. 92 (1992) 1007.[2] G.B. Rowland, E.B. Rowland, Q. Zhang, J.C. Antilla, Curr. Org. Chem. 10 (2006)

981.[3] S. Pine, Organic Chemistry, fifth edn., McGraw-Hill, New York, 1987.[4] P.D. Bailey, G.R. Brown, P. Korber, A. Reed, R.D. Wilson, Tetrahedron: Asymmet.

2 (1992) 1263.[5] P.D. Bailey, P.A. Millwood, P.D. Smith, Chem. Commun. (1998) 633.[6] X. Gao, D.G. Hall, J. Am. Chem. Soc. 127 (2005) 1628.[7] H.M. Deutsch, D.M. Collard, L. Zhang, K.S. Burnham, A.K. Deshpande, S.G.

Holtzman, M.M. Schweri, J. Med. Chem. 42 (1999) 882.[8] R.A. Hughes, S.P. Thompson, L. Alcaraz, C.J. Moody, J. Am. Chem. Soc. 127

(2005) 15644.

[9] M.J.S. Dewar, S. Olivella, J.J.P. Stewart, J. Am. Chem. Soc. 108 (1986) 5771.[10] M.A. Mccarrick, Y.D. Wu, K.N. Houk, J. Am. Chem. Soc. 114 (4) (1992) 1499,

doi:10.1021/ja00030a066.[11] M.A. Mccarrick, Y.D. Wu, K.N. Houk, J. Org. Chem. 58 (12) (1993) 3330,

doi:10.1021/jo00064a020.[12] K.N. Houk, J. Gonzaléz, Y. Li, Acc. Chem. Res. 28 (1995) 81.[13] L.R. Domingo, M. Oliva, J. Andres, J. Org. Chem. 66 (18) (2001) 6151,

doi:10.1021/jo0015422.[14] L.R. Domingo, M. Arnó, R. Contreras, P. Pérez, J. Phys. Chem. A 106 (2002) 952.[15] R.J. Loncharich, F.K. Brown, K.N. Houk, J. Org. Chem. 54 (1989) 1129.[16] K.N. Houk, R.J. Loncharich, J.F. Blake, W.L. Jorgensen, J. Am. Chem. Soc. 111

(1989) 9172.[17] D.M. Birney, K.N. Houk, J. Am. Chem. Soc. 112 (1990) 4127.[18] W.L. Jorgensen, D. Lim, J.F. Blake, J. Am. Chem. Soc. 115 (1993) 2936.[19] R. Sustmann, S. Tappanchai, H. Bandmann, J. Am. Chem. Soc. 118 (1996) 12555.[20] L.R. Domingo, E. Chamorro, P. Pérez, J. Phys. Chem. A 112 (2008) 4046.[21] R. Sustmann, W. Sicking, J. Am. Chem. Soc. 118 (1996) 12562.[22] L.R. Domingo, M. Arnó, J. Andrés, J. Org. Chem. 64 (1999) 5867.[23] L. Stella, H. Abraham, J. Feneau-Dupont, B. Tinant, J.P. Declercq, Tetrahedron

Lett. 31 (18) (1990) 2603.[24] H. Abraham, L. Stella, Tetrahedron 48 (1992) 9707.[25] J.E. Rogríguez-Borges, X. García-Mera, F. Fernández, V.H.C. Lopes, A.L.

Magalhães, M.N.D.S. Cordeiro, Tetrahedron 61 (2005) 10951.[26] J.I. García, V. Martínez-Merino, J.A. Mayoral, L. Salvatella, J. Am. Chem. Soc. 120

(1998) 2415.[27] C.N. Alves, A.B.F. da Silva, S. Martí, V. Moliner, M. Oliva, J. Andrés, L.R. Domingo,

Tetrahedron 58 (2002) 2695.[28] J.M. Mellor, N.G.J. Richards, K.J. Sargood, D.W. Anderson, S.G. Chamberlin, D.E.

Davies, Tetrahedron Lett. 36 (1995) 6765.[29] D.C. Limburg et al., Bioorg. Med. Chem. Lett. 13 (2003) 3867.[30] P. Pinho, D. Guijarro, P.G. Andersson, Tetrahedron 54 (1998) 7897.[31] M.J. Södergren, P.G. Andersson, Tetrahedron Lett. 37 (1996) 7577.[32] N. Hashimoto, H. Yasuda, M. Hayashi, Y. Tanabe, Org. Process Res. Dev. 9

(2005) 105.[33] M.J. Frisch et al., GAUSSIAN 03, Gaussian, Inc., Wallingford, CT, 2004.[34] C. Lee, W. Yang, R.G. Parr, Phys. Rev. B 37 (1998) 785.[35] A.D. Becke, J. Chem. Phys. 98 (1993) 5648.[36] A.D. Becke, Phys. Rev. A 38 (1988) 3098.[37] H.B. Schlegel, J. Comput. Chem. 3 (1982) 214.[38] M.W. Wong, Chem. Phys. Lett. 256 (1996) 391.[39] C. Gonzalez, H.B. Schlegel, J. Chem. Phys. 95 (1991) 5853.[40] C. Gonzaléz, H.B. Schlegel, J. Phys. Chem. 94 (1990) 5523.[41] A.E. Reed, L.A. Curtiss, F. Weinhold, Chem. Rev. 88 (1988) 899.[42] R.G. Parr, L.v. Szentpály, S. Liu, J. Am. Chem. Soc. 121 (1999) 1924.[43] L.R. Domingo, M.J. Aurell, P. Pérez, R. Contreras, Tetrahedron 58 (2002)

4417.[44] L.R. Domingo, J. Andrés, C.N. Alves, Eur. J. Org. Chem. 2002 (2002) 2557.[45] L.R. Domingo, J. Org. Chem. 66 (9) (2001) 3211, doi:10.1021/jo001332p.[46] E. Cancès, B. Mennucci, J. Tomasi, J. Chem. Phys. 107 (1997) 3032.