On the Brassard's rule of regioselectivity in Diels–Alder reactions between haloquinones and polar dienes

Mauricio Maldonado-Domínguez, Karen Ruiz-Pérez, Oscar González-Antonio, Margarita Romero-Ávila, José Méndez-Stivalet and Blas Flores-Pérez*
Facultad de Química, Departamento de Química Orgánica, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510, México, D.F., Mexico. E-mail: blasflop@hotmail.com

Received 31st May 2016 , Accepted 28th July 2016

First published on 29th July 2016


Abstract

The [4 + 2] polar Diels–Alder reaction between nucleophilic dienes and haloquinones proceeds with remarkably high regioselectivity. In the present work, we simulated diene–dienophile bimolecular encounters in a model stoichiometric reaction between haloquinones and Brassard's diene, using Monte Carlo sampling; the energetics of the stacking modes was then studied through DFT calculations. QTAIM analysis for the theoretical electron density was applied to describe contacts between π-systems, foreseeing chemically-productive paths for pre-cycloaddition assemblies associated with the experimental regioisomer. Upon thermally-triggered cycloaddition, Brassard's rule of selectivity manifests: only certain stacked microstates consolidate asynchronously into cycloadducts. The halogen atom tunes electron density at the reactive centers, as confirmed by NMR and calculations. Unidimensional energy landscapes were derived to capture energetic profiles of the studied reaction. The model systems were synthesized with high regioselectivity, delving further into the role of halogen substituents.


1. Introduction

The Diels–Alder [4 + 2] cycloaddition can be described as an orbital overlap between a diene–dienophile pair. Complementarity between the HOMO of a diene (a donor) and the LUMO of an acceptor (the dienophile) promotes electronic redistribution across a transient, delocalized system shared by both species in a concerted, pericyclic process. Brassard and coworkers observed, the preferred outcome of the reaction between vinylketene acetals and haloquinones, resembling a formal [4 + 2] cycloaddition (Fig. 1).1 From the possible isomeric adducts, a single product was consistently obtained, regardless of functionalization; the halogen atom in the quinone core is key for this outcome. In studies performed by Pérez and coworkers,2 a double cycloaddition of the Brassard type was performed on 2-bromo-1,4-benzoquinone. The brominated side reacted regioselectively, while the non-halogenated portion displayed both possible outcomes, but when they tested 2,6-dibromoquinone an exceptional regioselectivity was attained.
image file: c6ra14073d-f1.tif
Fig. 1 Formal [4 + 2] cycloaddition observed by Brassard and colleagues, between a vinylketene acetal and a bromojuglone.

This stark selectivity has been expediently grasped in strategic steps towards the synthesis of (±)-mevashuntin by Moody and that of (S)-bisoranjidiol by Kozlowski.3,4 Spinochromes and echinochromes, quinone dyes found in sea urchins and other equinoderms, are among the molecules which may be readily-accessed this way.5

Orbital coefficients in the diene–dienophile π-system have been part of effective theoretical approaches. Differences in absolute value were found, with the halogen-bearing C atom in quinones displaying small coefficients.6 In terms of electron density distribution, this translates to the hardness or softness of the reacting centers, as illustrated in Fig. 2. Highly reactive and asymmetric dienes and heterodienes, with important nucleophilic character, may react with electrophilic dienophiles; these features imprint the concerted-cycloaddition mechanism with a nucleophilic-addition component, desynchronizing bond-formation along the [4 + 2] pathway.


image file: c6ra14073d-f2.tif
Fig. 2 A contact between polarizable portions of the diene and dienophile may lead to bond formation. X is a halogen atom, usually Cl or Br.

Asynchronicity in the Diels–Alder reaction has been studied both theoretically and experimentally, through the analysis of kinetic isotope effects7 and the observation of zwitterionic intermediates, as the one shown in Fig. 3.8


image file: c6ra14073d-f3.tif
Fig. 3 Formal [4 + 2] cycloaddition, where a zwitterionic intermediate was spectroscopically detected. A polar medium was essential to render this species detectable.

Hetero Diels Alder (HDA) reactions are known to proceed asynchronously, given orbital-size mismatch and dipolar contributions.9 Recently, Linder and Brinck analyzed some examples, where regioselective cycloaddition is given by a dominant nucleophilic-addition coordinate.10

Evidence of the stepwise pathway followed by DA and HDA reactions has been provided in independent reports by Domingo and Jasiński, establishing theoretically and experimentally the polar mechanism; in these studies, the formation of pre-reaction complexes, leading to zwitterionic intermediates for some very polar reactions is approached theoretically and experimentally.11–15 These features are linked to the reactivity of nitroalkenes in DA reactions, and can also be accountable for the stereoselectivity observed in haloquinone-involving cycloadditions.

Intermediates derived from stepwise bond formation have already been remarkably isolated by Grunwell and coworkers (Fig. 4).16 Again, a single regioisomer was obtained, displaying the marked selectivity of this process.


image file: c6ra14073d-f4.tif
Fig. 4 Products from a Brassard-type cycloaddition, suggesting a zwitterionic intermediate when a high nucleophilic-addition character is present.

In their comprehensive review of DA cycloadditions to quinones in synthesis, Moody and Nawrat refer to this empirical observation of regioselectivity as the Brassard's rule.17 Interested in quinone reactivity, we explored in this work a polar [4 + 2] Diels–Alder reaction approach to the naphthoquinone core.

We applied Monte Carlo sampling (MC) to model mixing and aggregation of reactants. Density Functional Theory (DFT) was used for calculation of relative energies for the set of bimolecular diene–dienophile aggregates generated. The plausible reaction paths in these complexes, located via quantum theory of atoms in molecules (QTAIM),18 were explored in silico; finally, the regioisomeric reaction paths in competition were compared, to fully capture the associated energy landscapes. The model systems were then synthesized, confirming and giving further insight into the studied reaction.

2. Methods

2.1 Computational scheme

Bimolecular stacked states between quinones Q1–Q4 and Brassard's diene were sampled using the mixing task in the Blends program,19 bundled within Materials Studio 8 (MS8).20 This method produces random mixtures, which are ranked by total energy, using the COMPASS force field (FF). 10[thin space (1/6-em)]000[thin space (1/6-em)]000 energy samples were generated, with a reference temperature of 298 K. The top 100 configurations were optimized within the same scheme. The top 20 aggregates were further refined through DFT.

For DFT computations, the meta-GGA functional M06-2X21 with the 6-31+G(d) basis was selected, to account for noncovalent contacts. Implicit solvation in toluene was introduced using the polarizable continuum model (PCM).22 All stationary states were confirmed by frequency computations, with only real frequencies for minima and a single imaginary frequency for transition states. Single point energies were computed for these stationary states, using the 6-311++G(2d,p) basis, with PCM solvation. Natural Bonding Orbitals (NBO) were computed at this level for selected systems.23 NBO-resulting charges were used to determine the Global Electron Density Transfer (GEDT), assigning this way non-polar, polar or ionic character to TSs where the first new bond is formed.24 IRC calculations were performed to verify the connection between these transition states, reactants and intermediates (see ESI). All DFT calculations were carried out using Gaussian '09.25

For selected stacked complexes, electron densities derived from single point calculations with the abovementioned flexible basis were subject to topological analysis within the framework of the quantum theory of atoms in molecules (QTAIM). The AIMAll suite was employed with this purpose.26 Connectivity and integration was performed on all atoms. Critical points and delocalization indices were derived this way and served our analysis of π-stacking previous to polar Diels–Alder reaction.

2.2 Experimental methods

Model haloquinones Q1–Q3 were obtained by sequential oxidation of commercially available halovanillins. Dakin oxidation, followed by reaction with SiO2-supported cerium-ammonium nitrate,27 afforded the desired compounds with good yields.

Quinone Q4 was not accessible through this route, and was synthesized via nucleophilic displacement of bromine by iodide from Q3. Refluxing Q3 in acetic acid with excess NaI yielded and inseparable mixture of Q3 and Q4. Brassard's diene was synthesized following a reported methodology, starting from methyl acetoacetate.28

Cycloadditions were carried out using equimolar amounts of quinone and diene in refluxing toluene, followed by elution through a column of silica. All compounds were characterized through 1H- and 13C-NMR and mass spectrometry.

3. Results and discussion

Cycloaddition between dipolar dienes and haloquinones is mostly exploited to access substituted naphthoquinones, usually without isolation of the intermediate cycloadduct, which is subject to elimination and aromatization to afford the desired product. With this in mind, we selected model systems where regioselectivity reflected in the final, aromatized product. Our model haloquinones are expected to react with Brassard's diene to afford naphthoquinone N2 (shown in Fig. 5), ideally with no detectable amounts of regioisomeric N1, the dimethyl derivative of natural product flaviolin. Compound N1 was obtained by Brassard during his seminal investigation,29 yet the isomeric product N2 is not reported in the literature. Therefore, we studied Brassard's rule within this scheme.
image file: c6ra14073d-f5.tif
Fig. 5 Probable cycloaddition routes between the Brassard diene and 2-methoxy-6-haloquinones, used as dienophiles in the present study.

3.1 The reactive system

We selected Brassard's diene, a highly activated and nucleophilic reactant, to provide the HOMO for the studied transformation and 2-methoxy-6-haloquinones were used as dienophiles. All stable halogen atoms were tested (compounds Q1–Q4), probing the effect of halogen size and electronegativity on the studied reaction (Fig. 6). Atomic charges for systems Q1–Q4, derived from natural population analysis (NPA), are also illustrated. These values showed correlation with experimental 13C-NMR chemical shift for compounds Q1–Q4, synthesized from the corresponding halovanillins.
image file: c6ra14073d-f6.tif
Fig. 6 NPA-charges for Brassard's diene and quinones Q1–Q6, at the M06-2X/6-31+G(d) level, plotted against 13C-NMR in solution, using CDCl3 as solvent.

It can be seen that C2′ and C4′ atoms in the diene structure are electron-donating positions, while C1′ is electron-deficient, with a local positive charge.

Electronegativity values follows the trend F > OMe > Cl > Br > I. This reflects on a change from alpha-withdrawal to alpha-donation via induction on atom C2. Simultaneously, an inflection from beta-donation (OMe and F) towards beta-depletion (Cl, Br and I) on atom C3 in quinones can be detected, as halogen becomes heavier along the series. Fluorine strongly deshields C2, while C3 becomes shielded due to 1,3-donation. NPA-derived atomic charges correlate with this behaviour, revealing accumulation of negative charge in C3 atomic basin. In this respect, Q6 (X = OMe) features the strongest donor, with a maximum 30 ppm downfield shift, relative to Q5. As halogen becomes heavier, beta donation switches to beta depletion with a maximum shift of +10 ppm in Q4.

3.2 The π-stacked complexes

The polarizable reactants are predicted to spontaneously stack upon contact, displaying electron redistribution in a step previous to the cycloaddition event. These bimolecular aggregates will be called π complexes throughout this work.

Stacked states may display variable lifetimes, and be subject to association–dissociation–diffusion cycles, until a complex with the adequate geometry and sufficient kinetic energy overcomes an activation barrier. As an attempt to sample the space of stacked configurations, a set of 10[thin space (1/6-em)]000[thin space (1/6-em)]000 bimolecular mixtures was generated through random sampling for each diene–dienophile pair. The generated complexes were ranked by total energy, and the top 100 results were subject to geometry optimization with molecular mechanics, MM.

As Day and Thompson point out, a set of molecules interacting through van der Waals forces will arrange so intermolecular surface contact is maximized;30 parallel stacking of π-systems fulfills this condition, with orbital overlap between subsystems contributing to electron delocalization. The average energy found for stacked arrays is −9.4 ± 0.1 kcal mol−1 for Q1 −9.9 ± 0.1 kcal mol−1 for Q2, −10.0 ± 0.1 kcal mol−1 for Q3 and −9.8 ± 0.1 kcal mol−1 for Q4, relative to free reagents in vacuum, with a marked independence from functionalization.

The top 5 ranked structures for each quinone–diene pair were further optimized through DFT, to account for electronic effects in noncovalent contacts. The average energy found for stacked arrays at the M06-2X/6-311++G(2d,2p) level, with implicit solvation in toluene, is −12.7 ± 1.9 kcal mol−1 for Q1, −11.5 ± 0.9 kcal mol−1 for Q2, −12.6 ± 0.4 kcal mol−1 for Q3 and −12.7 ± 0.2 kcal mol−1 for Q4. Computed energies are nearly halogen-independent, consistent with MM, with average aggregation energy of −12.4 ± 0.5 kcal mol−1 for the whole set of stacked microstates.

Delocalization indices (DIs), derived from AIM analysis, are known to correlate with the chemical concept of bond orders.31 Given the transient and electronically diffuse nature of contacts in stacking, the sum of delocalization indices, Σ(DI), in the studied set of π-complexes is shown in Fig. 7, as a measure of the electron density being shared between diene and dienophiles. Endo complexes feature the largest values, consistent with kinetic endo selectivity.


image file: c6ra14073d-f7.tif
Fig. 7 Bimolecular stacked microstates between quinones Q1–Q4 and Brassard's diene. DFT energies at the M06-2X/6-311++G(2d,2p) level, and sum of delocalization indices associated to π-stacking are included for each system. Productive assemblies are enclosed.

Regarding the exothermic formation of these complexes, various π-contacts manifest, including not only carbon–carbon bond paths, but also oxygen–oxygen and halogen–oxygen interactions.32 Additionally, H-bond networks contribute cooperatively to bimolecular assembly (see ESI for full AIM networks).

Close inspection of these complexes does not predict contacts between the nucleophilic end of the diene and the C2 electrophilic position of the quinone. Thus, bond paths connecting starting materials with the unobserved regioisomer are not predicted. 1,2-Addition to carbonyl centers C1 and C4 is foreseen, yet DFT study of the corresponding adducts suggests these routes are highly disfavored (see ESI for DFT study on alternative addition routes).

The most relevant interactions are schematized in Fig. 8, where a mapping of the contact polarization for the endo stacked microstate leading to N2 is shown, together the network of intermolecular bond paths for the resulting complex, obtained through AIM analysis. In this supramolecular species, donor–acceptor pairs can be identified, giving a rough idea of the nature of each π-contact.


image file: c6ra14073d-f8.tif
Fig. 8 Intermolecular contact framework, illustrating donor (A) and acceptor (N) atoms in Brassard's diene and quinone Q2. Orange surfaces (isovalue = 0.035) indicate negative electrostatic potential.

In general, carbonyl centers are predicted to behave as positive anchor points. Intermolecular stacking is optimal in the N2-related complexes, where C1 atom in Brassard's diene is temporarily locked in close proximity to the soft, non-halogen-bearing carbon, with a predicted directional contact between carbon atoms. Evolution along this path triggers the cycloaddition sequence.

It was possible to identify some similarities between the most favorable stacked species. For example, for the chalcogen–chalcogen interactions, productive stacking would tend to range from 3.00 to 3.05 Å; chalcogen–halogen distances would lead to productive stacking when ranging from 3.00 to 3.60 Å, depending on what oxygenated portion interacts; hydrogen bonding induced by the halogen atom would elongate as the halogen grows heavier, with distances being shortest for Cl–H contacts and longest for I–H interactions; C2′–C1 favorable distances upon stacking lie in the vicinity of 2.99 Å. Finally, C4′–C3 contacts for the favorable stacked species averaged 3.16 Å.

3.3 The cycloaddition pathway

In the stacked complex leading to the exo-N1 route, a network of overlapping density contributes to stabilize the bimolecular contact. This complex, however, does not display chemically-productive bond paths, thus cycloaddition is not a foreseeable fate for this aggregate. From the topology of the corresponding π-complexes, no productive interactions manifest in the route to N1, suggesting this reaction pathway is virtually inaccessible. The four competing cycloaddition paths were studied by DFT, for every quinone–diene pair, comparing the endo and exo approaches to N1 and N2. The set of unidimensional energy landscapes for a selected example are shown in Fig. 9.
image file: c6ra14073d-f9.tif
Fig. 9 Unidimensional energy landscape, computed at the M06-2X/6-311++G(2d,2p) level for the two cycloaddition pathways to N2, in toluene. Energies (kcal mol−1) of the intermediates (Intendo, Intexo), transition states (TS1,2endo, TS1,2exo) and formal cycloadducts (DAendo, DAexo), relative to the reactants Q2 and Brassard diene, as well as key structures are shown.

As chemistry begins, electron density polarizes towards electronegative centers.

The DFT activation barriers to initiate this reaction are, in general, lower for the N2 route, compared to the isomeric N1 formation (Table 1), following Brassard's rule. In general, the endo approach is computed to be the lowest-energy pathway for cycloaddition to occur. This is consistent with kinetic endo selectivity, arising from orbital secondary interactions, as donor–acceptor pairs stack in a complementary fashion.

Table 1 Potential energies (kcal mol−1) for the N2 route, computed at the M06-2X/6-311++G(2d,2p) level in toluene. Values are relative to the energy of the isolated reactants
  πC TS1 ΔEAct1 Int TS2 ΔEAct2 DA
Endo F −12.3 0.6 12.9 −6.7 −0.6 6.1 −38.0
Cl −13.0 −2.1 10.9 −9.0 −7.9 1.1 −35.7
Br −13.0 −2.2 10.8 −8.8 −7.4 1.4 −35.8
I −13.1 −1.9 11.2 −8.5 −1.8 6.7 −36.0
Exo F −11.6 3.3 14.9 −5.9 −4.3 1.6 −32.4
Cl −12.4 0.6 13.0 −7.5 −6.0 1.5 −31.5
Br −12.4 0.7 13.1 −7.2 −5.2 2.0 −30.6
I −12.8 1.0 13.8 −6.7 −4.5 2.2 −35.5


Remarkably, in the route to N2, the computed activation energies to reach the transition state (TS1) are nearly halogen-independent. Linked to this is the predicted formation of a zwitterionic intermediate, connecting the first transition state (TS1, a late TS according to Hammond's postulate) with TS2, an early TS.

For all the TS1 calculated, Natural Population Analysis provided the corresponding atomic charges. These calculations allowed calculating the corresponding GEDT values to estimate the charge transferred at every transition state. GEDT values ranged from 0.40 e to 0.62 e, showing that all these transition states undergo a stepwise, ionic-DA reaction, following the classification proposed by Domingo (ESI contains the complete series of GEDT values).24

Asynchronous evolution is predicted along all the [4 + 2] cycloaddition pathways, although higher energy costs are expected for the N1 route to manifest, with an increase in activation energy as the halogen atom becomes heavier (Table 2). This trend is consistent with a steric component.

Table 2 Potential energies (kcal mol−1) for the N1 route, computed at the M06-2X/6-311++G(2d,2p) level in toluene. Values are relative to the energy of the isolated reactants
  πC TS1 ΔEAct DA
Endo F −11.3 7.1 18.4 −34.5
Cl −11.1 8.8 19.9 −31.9
Br −11.8 8.9 19.7 −32.5
I −11.9 8.8 20.7 −34.1
Exo F −11.4 2.7 14.1 −35.8
Cl −12.2 5.6 17.8 −35.1
Br −12.1 6.1 18.2 −34.9
I −13.3 6.5 19.8 −33.9


The Brassard formal [4 + 2] reaction route may be hence summarized as follows:

(1) Bimolecular assemblage of a dipolar diene with a quinone acceptor. If the geometry of this stacked complex is adequate, cycloaddition may take place. This is predicted only for the N2 route.

(2) As the nascent bond forms, a nucleophilic addition component polarizes electron density toward the α-haloenone acceptor subsystem.

(3) The zwitterionic intermediate couples electronic relaxation with a conformational change, which leads to consolidation of the second bond, completing the formal [4 + 2] cycloaddition.

3.4 Experimental tests

2-Methoxy-6-halobenzoquinones were accessed through a synthetic route involving a Dakin oxidation of substituted vanillin derivatives V1–V3, followed by oxidation with SiO2-supported CAN, as illustrated in Fig. 10. 5-Iodovanillin did not lead to the expected product Q4, yielding extensive decomposition products, probably linked to side-reactions involving oxidation on the heavy iodine atom. Q4 was accessed through an alternative route, featuring nucleophilic displacement of Br (from Q3) by iodide, in refluxing acetic acid, leading to an inseparable 2[thin space (1/6-em)]:[thin space (1/6-em)]1 mixture of Q4[thin space (1/6-em)]:[thin space (1/6-em)]Q3. The preparation of the Brassard's diene is described elsewhere. The final cycloaddition was performed in refluxing toluene, using stoichiometric amounts of diene and dienophile, followed by elution through a column of silica, with isolated yields of 51% (X = F), 60% (X = Cl), 71% (X = Br) and 74% (X = I).
image file: c6ra14073d-f10.tif
Fig. 10 Synthetic studies on the [4 + 2] cycloaddition between haloquinones Q1–Q4 and Brassard's diene.

Reactions proceeded smoothly with substrates Q1–Q4, leaving not only the methoxylated flank unreacted (proven to be donor, instead of acceptor, in the soft carbon), but also reacting exclusively with the expected selectivity on the halogenated subsystem, leading to N2 in all cases. This shows the π-donating character of MeO, captured in the natural population analysis and 13C-NMR, effectively switches the reactivity of the conjugated, potentially reactive, position to a donor, blocking nucleophilic attack. Halogens, on their side, range from moderately π-donating such as fluorine in Q1 (reflected in the abnormally high activation energies computed for fluorinated systems), to strongly depleting as iodine in Q4. Evidence shows this does not affect selectivity, leading to preferential addition on the soft position on the halogenated portion of quinones.

4. Conclusions

A description of the charge distribution in the reactants through natural population analysis and 13C-NMR experiments, was achieved, showing how halogens influence the electronic characteristics of the reactive center in haloquinones.

Through a tandem DFT-AIM computational approach, a mechanistic proposal was reached, describing the regioselective manner in which the [4 + 2] cycloaddition of polar dienes to haloquinones proceeds. Stochastic sampling of the chemical subspace of diene–dienophile aggregates confirmed unequivocally the kinetically favoured route, being the one observed by Brassard. It is noteworthy that this selectivity depends on the presence of a halogen atom within the quinone structure and not on its identity.

Orbital overlap, hydrogen bonding, chalcogen–chalcogen stacking and chalcogen–halogen interactions are the main contributors for stabilization of these zwitterionic aggregates, where the structural and electronic features of nucleophilic addition are already present in those complexes leading to the experimentally observed isomer. With the aid of QTAIM, it is possible to trace this outcome back to π-stacked states, where cycloaddition can be thermally triggered.

Acknowledgements

The authors would like to thank CONACyT for the scholarship granted to Karen Ruiz-Pérez (273441). Thanks to USAII: Rosa Isela del Villar for NMR, Georgina Duarte Lisci and Margarita Guzmán Villanueva for MS, Nayeli López Balbiaux and Victor Lemus Neri for EA and Marisela Gutiérrez Franco for IR analyses. Thanks to Adrián Vazquez Sánchez, Rafael Arcos Ramos and Marco A. Almaraz Girón for insightful discussions during elaboration of this manuscript.

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Footnotes

Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra14073d
In the reaction between quinone Q4 and Brassard's diene, the actual reaction mixture included Brassard's diene and the previously obtained, 2[thin space (1/6-em)]:[thin space (1/6-em)]1 inseparable mixture of Q3 and Q4.

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