Intramolecular Diels Alder reactions in highly organized imidazolium salt-based ionic liquid crystals

Abstract

This paper describes the development of a new family of ionic liquid crystals based on imidazolium salts and their applications as media for intramolecular Diels Alder reactions. The use of highly organized smectic T phases was shown to be an efficient method to obtain the intramolecular Diels Alder product in high yields, without using high dilution conditions. The ionic liquid crystal media can be recycled in an easy procedure and reused up to at least five times, without loss of reactivity and selectivity.

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Introduction

The growing awareness of the use of environmentally benign solvents has led to the increasing importance of ionic liquids as alternative solvents for various organic reactions.¹ Ionic liquids (ILs) represent an interesting class of solvents, as they are liquid at low temperatures, thermally and chemically stable and non-volatile.² Ionic liquids have shown significant advantages when used as solvents for organic transformations, in terms of giving similar to higher yields compared to those obtained in traditional organic solvents, as well as a high recyclability.^2–5 Ionic liquids, by providing an ionic environment, may have a positive effect on reactions possessing polar transition states. The solvent effect is thus more pronounced in ionic liquids and some condensation reactions, as the Diels Alder,⁴ Mannich⁵ or Friedlander⁶ reactions have been conducted successfully in ionic liquids. Imidazolium-based ionic liquids have been shown to enhance the reaction rate and the stereoselectivity of the Diels Alder reaction⁴ by hydrogen bonding of the most acidic hydrogen of the imidazolium cation and the carbonyl group of the substrate. However, the slow diffusion rate in ionic liquids and hence the acceleration of the intermolecular reactions result in competitive intermolecular products when ionic liquids are used as solvents for the Diels Alder reaction.⁷ A common way to solve this problem is the use of high dilution conditions, preventing the reactant molecules to meet each other and to form intermolecular product. However, this approach requires an important amount of ionic liquids. Therefore, a successful strategy to obtain the intramolecular Diels Alder (IMDA) product in high yields might be to create a certain isolation of the reactant molecules in the reaction mixture by using an organized media.

Liquid crystals (LC) are a class of compounds that can show both unorganized and organized structures depending on the temperature (thermotropic liquid crystals), or the composition of the mixture (lyotropic liquid crystals).⁸ The highly organized structure of LC has been showed to affect the outcome of organic reactions performed in LC as reaction media, by interacting with the transition state of the reaction. Leigh et al.⁹ showed that rod-like organized LC favour the product resulting from a rod-like transition state over the product resulting from a globular transition state. This effect was even more pronounced when the liquid crystal was more organized, by reducing the diffusion rate and the rotation of the substrate molecules.¹⁰ It is reasonable to state that a LC state can isolate molecules dispersed into them and that any isolation effect in obtained the isotropic phases. This means that the isolation of the substrate molecules can be controlled by the temperature.

Imidazolium-based thermotropic and lyotropic ionic liquid crystals (ILCs) combine the self-organization properties of liquid crystals (LC) with the unique solvent properties and ion-conducting properties of imidazolium-based ILs. The properties of ILCs are significantly different from those of conventional liquid crystals¹¹ and change depending on the molecular architecture of the salts and nature of the counterion used. Herein, we report the synthesis, characterization of new ILCs and their use as solvent for the intramolecular Diels Alder reaction. We demonstrate that the organized structure of the liquid crystalline phase favours the formation of the intramolecular Diels–Alder product and the coordinating properties of the ILC accelerate the reaction rate, compared to a classical LC.

Results and discussion

Naphthalene core was previously reported to lower the transition temperature of various LC.¹² Recently, our group demonstrated that dicationic ILCs based on imidazolium salts form a smectic T phase.¹³ The transition temperatures being too high to be used as organized solvents for an organic transformation, we decided to replace phenyl core with a naphthalene moiety in order to reduce the anisotropy of the mesogen and to lower the transition temperature of the ILC (Scheme 1).

Scheme 1 Dialkyl(1,5-naphthalene)diimidazolium salts.

The synthesis of the dialkyl(1,5-naphthalene)diimidazolium salts from the 1,5-diimidazolenaphtalene is outlined in Scheme 2. All the compounds can be synthesized in grams scale in a four-step procedure from the commercially available 1,5-diaminonaphthalene, by a first diazotization reaction¹³ followed by a copper-catalyzed Ullmann reaction following the procedure developed by Taillefer.¹⁴ The alkylation of the diimidazole intermediate by either 1-bromododecane or 1-bromohexadodecane resulted in the desired bromide salts and then different imidazolium salts were obtained by anion metathesis. We decided to use fluorinated anions as NTf₂, OTf, PF₆ and BF₄ which generally result in non-hygroscopic and more acidic ionic liquids.^1,15

Scheme 2 Synthesis of dialkyl(1,5-naphthalene)diimidazolium salts.

Thermophysical properties

The imidazolium salts were first characterized by thermogravimetric analysis in order to study the effect of the counterion and the length of the alkyl chain on the thermal stability of these salts. Results presented in Fig. 1 show that the nature of the counterion has a higher influence on the thermal stability of the imidazolium salts than the length of the alkyl chains (NTf₂⁻ ≅ BF₄⁻ > TfO⁻ > Br⁻ > PF₆⁻). All the salts were stable up to 200 °C, but the NTf₂ salts were the most stable ones, up to 250 °C.

Fig. 1 Decomposition temperatures (based on 1% weight loss) of dialkyl(1,5-naphthalene)diimidazolium salts.

Liquid crystal properties

For all the compounds, their mesomorphic properties and phase transition temperatures were investigated by differential scanning calorimetry (DSC), polarizing optical microscopy (POM), and powder X-ray diffractometry (PXRD). To avoid hydration of the imidazolium salts, all the compounds were dried under vacuum before the PXRD and DSC analyses. Only the NTf₂ salts showed a liquid – isotropic transition (Fig. 2), also confirmed by polarized optical microscope (POM).

Fig. 2 DSC traces of 1e and 2e (second heating/cooling cycle).

The phase transition temperatures and the corresponding enthalpy changes derived for compounds 1e and 2e in both heating and cooling cycles are shown in Table 1. Both compounds 1e and 2e showed lancet-like texture (Fig. 3). The lancet-like texture was already reported in highly ordered liquid crystalline phase, for example smectic E or smectic T phases.¹⁶ In the PXRD patterns of both NTf₂ salts, equidistant peaks were observed, showing the lamellar structure of an ordered phase. In the wide angles region, the broad hallow band was not observed, but sharp Bragg reflections appeared, indicative of an ordered arrangement within a smectic T phase for both compounds 1e and 2e. The unit cell parameter a of the square lattice was 10.6 Å for both compounds 1e and 2e compounds, but the thickness of the layer was 27.7 Å for 1e and 31.9 Å for 2e respectively, supporting the hypothesis of a tetragonal structure of a smectic T phase. The value of 10.6 Å for parameter a is in agreement with the size of NTf₂ anion (6.6 Å). However, the thickness of the layer is smaller than the estimated molecular length (8.4 Å). This observation suggests a certain degree of interdigitation between two adjacent molecules.

Table 1 Phase transition temperatures and corresponding enthalpies ΔH determined from 1^st cooling and 2^nd heating DSC thermograms^a

	T/°C (Cr1 → Cr2) (ΔH/J g^−1)	T/°C (Cr2 → LC) (ΔH/J g^−1)	T/°C (LC → I) (ΔH/J g^−1)
a Abbreviations: Cr1, Cr2 for the solid crystalline phases (S in the DSC traces), LC for liquid crystal phase, and I for isotropic phases.
Compounds on heating
1e	87 (33.4)	93 (11.6)	123 (7.5)
2e	—	94 (58.3)	166 (8.2)
Compounds on cooling
1e	55	57 (57.8)	117 (8.1)
2e	—	65 (80.0)	162 (7.9)

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Fig. 3 PXRD pattern and POM image of 1e and 2e at 90 °C.

ILCs as solvents for the intramolecular Diels Alder reaction

IMDA reaction is a very important reaction in organic synthesis, as many C–C bonds can be formed at the same time and it can be used as a tool to synthesize cyclic compounds.¹⁷ Moreover, substrates belonging to the ester-tethered 1,3,9-decatriene system have low reactivity in the IMDA reaction, because their cis conformation is not favored due to trans-annular and non-bonding electron pair interactions (Scheme 3).⁹

Scheme 3 Intermolecular and intramolecular Diels Alder products for the ester-tethered 1,3,9-decatriene substrate.

As an alternative to the previously described high dilution conditions in ILs for the IMDA reaction,⁷ we decided to use ILCs 1e and 2e as solvent, hypothesising that the ILCs in the LC phase will be able to disperse the substrate molecules and will favor the intramolecular reaction (Fig. 4).

Fig. 4 Schematic representation of the dispersion of the substrate in the LC phase.

We decided to perform the IMDA of various substrates at various concentrations in both traditional bis(trifluoromethane sulfonyl)imide 1-butyl-3-methylimidazolium [Bmim][NTf₂] ionic liquid and 1e, as it possess a lower transition temperature than 2e. The same procedure was applied when the traditional ionic liquid was used as solvent.

As shown in Table 2, considerably less intermolecular product was obtained in the ILC 1e, compared to the traditional IL, even in high concentration conditions, for all the tested substrates. The best results in terms of selectivity were obtained for the non-substituted substrates, where no intermolecular product was observed at 1 : 8, 1 : 16 and 1 : 32 substrate : ILC ratios. For substrates presenting a substituent on the diene moiety, the intramolecular product is the major product obtained and the intermolecular product was obtained also at less than 5%. However, all the substrates possessing a substituent to the dienophile moiety showed no reactivity in both IL and ILC, where no conversion was obtained even after 36 hours. The presence of a substituent on the dienophile moiety may cause steric hindrance in the transition state, preventing the reaction to take place.

Table 2 Diels Alder reactions in various dilution conditions

Ratio substrate : solvent	Substrate	IL [Bmim][NTf2] isolated yield (%)		ILC (1e) isolated yield (%)
		Inter	Intra^a	Inter	Intra^a
a Only the endo diastereoisomer of the intramolecular product was observed.
1 : 4		14	22	10	58
1 : 8		16	41	1	70
1 : 16		9	63	—	75
1 : 32		7	69	—	73
1 : 4		15	54	5	72
1 : 8		12	48	3	75
1 : 16		13	53	2	71
1 : 32		8	68	2	73
1 : 4		8	52	6	71
1 : 8		8	57	5	72
1 : 16		7	54	5	71
1 : 32		6	63	5	73

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The influence of the LC phase, compared to the solid phase was studied by performing the same reaction at different temperatures, under the same concentration (Table 3). It is not surprising that performing the reaction in the solid state (at 50 °C) gave lower results in terms of selectivity and reactivity, compared to those obtained in the LC phase.

Table 3 Influence of the solvent organization on the selectivity of the Diels Alder reaction performed at 1 : 8 substrate : 1e ratio

Substrate	Isolated yields (%)
	Reaction at 50 °C		Reaction at 90 °C
	Inter	Intra	Inter	Intra
	20	31	1	70

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The favoured intramolecular reaction in high concentration conditions may be the result of the presence of the highly organized structure of the smectic T phase around the substrate, preventing two substrate molecules to react and give the intermolecular product.

Table 4 and Fig. 5 present data obtained for fully optimized B3LYP/6-31G(d) geometries of cis and trans-1,3,9-decatriene conformers in the presence of 2 equivalents of IL and ILCs. First, the calculations correctly predict the endo selectivity for the IMDA reaction in the presence of both IL and ILCs. The second conclusion that can be drawn when looking at the energy difference between the cis and trans conformers, is that the cis conformation is favored in the presence of the ILCs. The π–π between the diene unit and the naphthalene core, as well as the additional hydrogen bond observed in this case may be responsible for the higher specificity of the IMDA reactive conformer.

Table 4 B3LYP/6-31G(d) energy difference between conformers cis and trans and length of hydrogen bonds of the cis conformer with IL and ILC

ΔE (cis-trans) (kcal mol^−1)		Hydrogen bond 1 (Å)		Hydrogen bond 2 (Å)
IL	ILC	IL	ILC	IL	ILC
2.38	5.01	1.85	1.35	None	1.61

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Fig. 5 Optimized geometries of the 1,3,9-decatriene substrate with 2 equivalents of (a) IL or (b) ILCs (the NTf₂ anions are not shown for clarity).

The Diels Alder reactions performed in ILCs gave higher conversions compared to the ones performed in traditional ionic liquids. This increased reactivity is probably due to the more acidic H-2 of the imidazolium cation in ILCs, due to its conjugation with the naphthalene ring (Table 4). By hydrogen bonding the carbonyl group of the substrate, the imidazolium cation of the ILC may also lower the energy of the transition state.

Recyclability of the ILC

After the reaction was completed, the reaction mixture was extracted with diethyl ether and the ILC was directly reused for further reactions. As shown in Table 5, the ILC can be reused up to at least 5 catalytic runs, without loss of reactivity and selectivity.

Table 5 Recycling of 1e after each Diels Alder reaction performed at 1 : 8 substrate : 1e ratio (reaction performed at 90 °C for 18 h)

Substrate	Catalytic run	Isolated yields (%)
		Inter	Intra
	1	1	72
	2	2	70
	3	1	74
	4	1	74
	5	1	71

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Conclusions

In conclusion, we synthesized and characterized new family of imidazolium salts-based ionic liquid crystals which exhibited highly ordered smectic T phase, with transition temperatures below 100 °C. The use of these ILCs as reaction media in the Diels Alder reaction allowed the formation of the intramolecular products in high concentration conditions. Recycling studies showed that the ionic liquid crystals were still active after at least five catalytic runs without loss of reactivity or selectivity. These new ILCs may be useful as reaction media for different macrocyclization reactions, which may broaden the scope of this methodology to other organic reactions.

Acknowledgements

We thank the Natural Sciences and Engineering Research Council of Canada (NSERC), the Fonds Québécois pour la Recherche, la Nature et les Technologies (FQRNT), the Centre in Green Chemistry and Catalysis and the Université de Montréal for financial support. We thank S. Essiembre and P. Ménard-Tremblay for assistance in PXRD and POM studies.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: General and analytical methods, synthesis and characterization of the compounds, TGA curves and molecular modelling details. See DOI: 10.1039/c4ra11693c

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