Supramolecular Interactions Based on Ionic Liquids for Tuning of the

Subscriber access provided by Northern Illinois University

Article

Supramolecular interactions based on ionic liquids for tuning of the catalytic efficiency of (L)-proline Raul Porcar, M. Isabel Burguete, Pedro Lozano, Eduardo Garcia-Verdugo, and Santiago V. Luis ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.6b01394 • Publication Date (Web): 01 Sep 2016 Downloaded from http://pubs.acs.org on September 3, 2016

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

ACS Sustainable Chemistry & Engineering is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 36

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Sustainable Chemistry & Engineering

Supramolecular interactions based on ionic liquids for tuning of the catalytic efficiency of (L)-proline Raul Porcar,a M. Isabel Burguete a Pedro Lozano, b Eduardo Garcia-Verdugo, a* Santiago V. Luis a* a

Departamento de Química Inorgánica y Orgánica, Universidad Jaume I, Av. Sos Baynat s/n,

12071 Castellón, Spain. E-mail: [email protected], [email protected] b

Departamento de Bioquímica y Biología Molecular B e Inmunología, Facultad de Química,

Universidad de Murcia, Campus de Excelencia Internacional Regional “Campus Mare Nostrum”, E-30100 Murcia, Spain KEYWORDS: Ionic liquid, Supramolecular, Catalysis, Aldol reaction, Asymmetric induction.

ABSTRACT: Non-covalent intermolecular interactions between (L)-proline and ionic liquids (ILs) are key to explain the different catalytic efficiencies observed for this organocatalyst in the aldol reaction carried out in ILs or in the presence of ILs as cosolvents. The catalytic behavior of (L)-proline has been studied in reaction media containing non-chiral (e.g. [Bmim][Cl]) and chiral (e.g.

[(R,R)-trans-Cy6-OAc-Im-Bu][Cl])

ILs

using

the

synthesis

of

4-hydroxy-4-(4-

nitrophenyl)butan-2-one via the aldol reaction between p-nitrobenzaldehyde and acetone as a model reaction. The high degree of supramolecular organization induced by the presence of the

ACS Paragon Plus Environment

1


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 36

ILs or chiral ILs (CILs) can contribute not only to enhance the activity, but also, in some cases, to tune the asymmetric induction.

INTRODUCTION Ionic liquids (ILs) are exceptional non-aqueous solvents for carrying out green catalytic processes and with a great potential for the development of new sustainable industrial technologies.1,2 They are defined as liquids at temperatures lower than 100ºC and are composed entirely by ions. Their use has led to a green chemical revolution because of the unique array of their physico-chemical properties (e.g. low vapor pressure, low flammability, high ionic conductivity, good dissolution power towards many substrates, high thermal and chemical stability, etc.). The physico-chemical characteristics of ILs depend not only of the coulombic forces established between the cation and the anion, but also on the formation of extended networks of additional interactions (H-bonds, π−π or C-H···π interactions among others) having strong implications on their three-dimensional (3D) organisation and therefore on their final properties. Although in the liquid-phase this network of interactions is weaker than in the solidphase, the local order in the liquid-phase resembles those found in solid phases. Indeed, ILs may be described as “polymeric supramolecular fluids” and, consequently, as systems that are highly structured in the liquid state.3,4,5 These networks can be reinforced by the introduction in the ILs of additional functional groups. Thus, for instance, the presence of groups like alcohol, nitrile or urea has a big impact in the intermolecular interactions and therefore in the supramolecular organization of the IL.6 Moreover, there is now much evidence indicating that some of the supramolecular organization can be maintained when they are mixed with other solvents.7 These interactions, which define the ILs molecular structure and properties, are highly dependent on the substitution pattern of the salt (e.g. the length of the alkyl chain(s)) as well as on the nature of the


2

Page 3 of 36

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


counterion. The sponge-like character of some ionic liquids (SLILs) is a recent example of the importance of such a highly organized network of interactions. ILs with long alkyl side-chains behave as temperature switchable ionic liquid/solid phases, which are able to dissolve hydrophobic molecular compounds (e.g. methyl oleate) as liquid phases and then provide a solid IL-phase net holding the dissolved compounds by freezing. These SLILs allow a simple release/separation of the liquid compounds dissolved from the solid IL-phase net by application of straightforward physical techniques (e.g. centrifugation).8 Organocatalytic reactions in water or in the presence of water can experiment significant changes, when compared with those carried out in organic solvents, as a consequence of the increase in H-bond interactions between the organocatalyst and water.9,10 Hence, in principle, and using a similar approach, the structural order of the ILs and their capacity to establish a variety of intermolecular (supramolecular) interactions may be used to tune the catalytic efficiency of an organocatalyst without the need to perform additional modifications in the structure of the catalyst.11 Besides, the use of ILs as solvents has some additional advantages:11,12 i) the catalytic process takes place under homogeneous conditions, being the organocatalyst soluble in the ILs; ii) the phase containing the IL with the catalyst can be recovered by a simple extraction process, allowing the reuse of the catalytic system for several cycles; iii) it is possible to develop chiral ionic liquids (CILs)12 and to exploit them as media either for chiral induction13 or for enantio-differentiation of chiral compounds.14,15,16 CILs derived from imidazole are relatively simple and easy to manufacture, since the introduction of chirality can be done either in the anion or in the cation, or even in both. The introduction of chirality as a design vector is highly interesting as chirality may define the selforganization of the chiral salts in a privileged three-dimensional chiral lattice.17 Although the


3


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 36

first attempts to use chiral solvents for chiral induction were introduced in 1975 by Seebach,18 the use of CILs reopens the possibility of developing new chiral solvents for application in asymmetric synthesis, in chiral chromatography or in stereoselective polymerizations. In the same way, CILs also allow developing new organocatalytic systems for use in asymmetric catalysis. Thus, in the last few years, different families of CILs have been synthesized and evaluated as a new type of non-innocent solvent for chiral induction,19 due to their specific properties and high degree of organization. In this regard, the immobilization in ILs of a variety of proline-based organocatalysts tagged with imidazolium or related IL-like fragments has represented a field of intense research in order to implement this approach.20,21,22,23 Thus, although a lot of effort has been carried out to develop efficient chemical reactions in ILs or using ILs as additives, additional efforts are still required to properly understand the processes taking place at a molecular and supramolecular level as essential element for the design of new processes. Accordingly, the main aim of this work has been to advance in the understanding of the key role of ILs, as nanostructured reaction media, in the tuning of the catalytic efficiency of organocatalytic systems. For this purpose, a well-known process involving the use of (L)-proline as organocatalyst for aldol reactions was selected as the benchmark reaction. Commercially available [BMIM][Cl) and eight different CILs, based on the butylimidazolium cation and containing enantiopure 1,2-disubtituted cyclohexyl or cyclopentyl units, were used either as reaction media (or major component of the reaction media), or as functional additives in the reaction media for improving the catalytic behavior of (L)-proline. The high degree of supramolecular organization induced by the ILs contributes to tune the resulting catalytic efficiency, not only enhancing the activity, but also the asymmetric induction, with the IL component being a non-innocent partner.24


4

Page 5 of 36

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


RESULTS AND DISCUSSION The aldol reaction is one of the most useful processes for C-C bond formation, being able to provide access to the synthesis of chiral compounds. Among the different organocatalysts evaluated for this reaction, pyrrolidine derivatives are those providing better results, being (L)proline the most commonly used.25,26,27 Although (L)-proline is a cheap and efficient catalyst for this reaction, some problems reduce its applicability. Thus, it displays a low solubility in most common solvents except water, where proline acts organocatalytically but is not enantioselective. Besides, competitive side reactions like the formation of oxazolidones and oxapyrrolizidines can appear.28 Therefore, different structural modifications of the (L)-proline skeleton have been developed to improve both yields and stereoselectivities for this reaction.29,30 Alternatively, the use of additives has also been evaluated to tune its catalytic efficiency.31 Among the different aldol reactions studied, the one between p-nitrobenzaldehyde (1) and acetone (2) (Scheme 1) has been used as a benchmark process to determine the catalytic efficiency of a wide variety of catalysts derived from (L)-proline. When this model reaction is performed in a conventional organic solvent such as DMSO (0.1 M in 1, and 4:1 DMSO:acetone ratio), the reaction takes place with 68% yield and ca. 75% e.e. In contrast, the same (L)-proline catalyst is not efficient for an ideally solvent-free process in pure acetone. The reaction requires large amounts of catalyst (30-40% molar loadings) and prolonged reaction times. The asymmetric induction achieved is good (ca. 65% e.e.), although the presence of secondary reactions reduce the selectivity of the process. This can be attributed to the low solubility of the catalyst under these reaction conditions.


5


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 36

Toma32 and Loh33 were pioneers in the use of ILs as solvents in the proline-catalysed reactions between acetone and various aldehydes. The results obtained using [BMIM][PF6] as the solvent for different conditions and substrates (43-68% yield and 65-76% e.e.) were very similar to those found under conventional conditions using DMSO (54-62% yield and 60-77% e.e.). These results can be taken as a basis for comparison in our studies. Thus, being a well stablished reaction, it is an ideal platform to try to rationalise the contributions of the ILs. In this context, it is also well established that the catalytic efficiency of (L)-proline for these reactions changes dramatically if water is used either as an additive (reactions "in the presence of water”) or as a solvent (reactions "in water"). Indeed, for reactions carried out "in the presence of water” the amount of water is a key factor determining the extension of the asymmetric induction and the suppression of the above mentioned parasite reactions.9,10 It seems likely that similar effects may be found for the case of ILs used either as co-solvents or as additives.

Scheme 1. Aldol model reaction between p-nitrobenzaldehyde and acetone catalyzed by (L)proline.


6

Page 7 of 36

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 1. Results of the aldol reaction between p-nitrobenzaldehyde (1.36 M) and acetone at different catalyst loadings in the presence of [BMIM][Cl]. Entry

Cat. (% molar)a

Conv. (%)b

Sel. (%)c

e.e. (%)d

1

10

> 99

96

48

2

20

> 99

95

47

3

40

> 99

99

45

4

60

> 99

92

47

a

p-nitrobenzaldehyde 1.36 M, 18 h, r.t., IL:(L)-proline 2.8:1 and acetone:RCHO 10:1 molar ratio. b Conversion calculated by 1H-NMR in the reaction crude. c Selectivity calculated by 1HNMR in the reaction crude. d Enantiomeric excess calculated by HPLC for the major enantiomer R [e.e. = (peak area (R) - peak area (S)) x 100/ total area (R+S)].

With this idea in mind, the effects of a non-chiral IL were first evaluated. 1-Butyl-3-methylimidazolium chloride ([BMIM][Cl]) was chosen as a simple and commercially available IL for these initial studies and the influence of different experimental parameters on this process was studied. Anhydrous reagents, solvents and additives were always used to minimize any interference from water. Thus, the effect of the catalyst:aldehyde ratio was firstly analyzed using a constant concentration of the aldehyde (1.37 M), a 10:1 molar ratio acetone:pnitrobenzaldehyde and maintaining a constant molar ratio [BMIM][Cl]:(L)-proline (2.8:1, Table 1). Under these conditions the IL:acetone molar ratio ranges from ca. 0.03 to ca. 0.18. The results obtained suggest that the use of the IL as an additive allows reducing the amount of catalyst used down to 10% molar without any significant variation of the results obtained in terms of yield (> 90%), selectivity (> 99%) and asymmetric induction (ca. 45% e.e.). However, the enantioselectivity obtained was inferior to those observed for the conventional system in the absence of the ILs in either DMSO or for the solvent-free reaction. Furthermore, it was even


7


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 36

lower than the one described for this reaction using other ILs as solvents (e.g. ca. 65% e.e. in [BMIM][PF6]).32 To better understand these discrepancies, the effect of the organocatalyst:IL ratio was evaluated. Hence, the model reaction was carried out using a constant loading of catalyst (40% molar relative to the aldehyde) and the same 2:1 molar ratio (10:1), but changing the [BMIM][Cl]:(L)-proline molar ratios, which provided different IL:acetone ratios (0-80 w %) (Table 2). The working concentrations ranged from 0.55 M to 0.13 M for the catalyst and from 1.36 M to 0.33 M for the aldehyde. In this case, a reaction time of 60 min was selected in order to obtain data on the role played by the IL not only on the selectivity but also on the activity. The results obtained are summarized in Table 2. As expected, the reaction did not proceed in the absence of the organocatalyst even in the presence of IL (Table 2, entry 1). The reaction catalyzed solely by (L)-proline in the absence of IL led to a limited conversion of the aldehyde to the corresponding aldol (10% yield, Table 2, entry 2). Longer reaction times were required to achieve a full conversion of the aldehyde (>90 % yield after 18 hours) with a good enantioselectivity (68 % e.e.). Furthermore, the spectra of this reaction mixture revealed the presence of oxazolidones and/or oxapyrrolizidines as secondary products.28 A different situation was found for reactions carried out in the presence of the IL. In all cases, the analysis by 1HNMR of the reaction mixture after 60 min of reaction indicated the full or almost full conversion of the aldehyde and the presence of dehydration product as the single secondary product. The higher catalytic activity of the (L)-proline in the presence of the IL can even be observed by the naked eye. Upon addition of p-nitrobenzaldehyde to the reaction mixtures the appearance of an intense color was observed associated to the formation of the products, increasing over the time


8

Page 9 of 36

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(Figure 1a). On the contrary, in the case of the reaction catalyzed by (L)-proline in the absence of IL, no evolution of color was observed in agreement with the low yield observed by NMR. Thus, it is clear that in this reaction the IL is not an innocent partner.34,35,36 As reported for the addition of water, the presence of the IL has a significant influence on the outcome of the reaction suppressing the formation of side reactions and enhancing the reaction rate.9 Regarding the enantioselectivity, an enhancement of the asymmetric induction was observed when larger amounts of IL were used, reaching 62 % e.e. for 80% weight IL:acetone (32.6:1 IL:proline) (Table 2, entry 7), a value comparable to those obtained using conventional solvents or pure ILs.


9


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 36

Figure 1. Evolution with time of the reaction mixtures for the aldol model reaction (RCHO:acetone:catalyst 1:10:0.4). a) with [BMIM][Cl], (I): [BMIM][Cl]:L-proline: (1:1); (II): [BMIM][Cl]:L-proline: (32.6:1); (III): [BMIM][Cl]:L-proline: (3:1); (IV): [BMIM][Cl]:L-proline: (6.6:1). b) Without [BMIM][Cl] (V). c) With CIL (VI): [(R,R)-trans-Cy6-OAc-Im-Bu][Cl]:Lproline (3:1).


10

Page 11 of 36

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 2. Results of the aldol reaction between p-nitrobenzaldehyde and acetone with different percentages of [BMIM][Cl] at a 40% molar loading of the catalyst.a

Entry

IL:acetone (w/w %) b

[BMIM][Cl]: (L)-prolinec

Conv. (%)d

Yield (%)d

e.e. (%)e

1

44

1:0

-

-

-

2

-

0:1

< 10

< 10

68

3

11

1:1

92

99

39

4

25

3:1

> 99

95

40

5

38

5.2:1

> 99

95

52

6

44

6.6:1

> 99

90

53

7

80

32.6:1

> 99

90

62

a

Relative to aldehyde, 10:1 molar ratio acetone:aldehyde, 60 min, r.t. b (g IL/(g IL+ g acetone)) x 100. c molar ratio. d Yield calculated by 1H-NMR in the reaction crude. e Enantiomeric excess calculated by HPLC for the major R enantiomer [e.e. = (peak area (R) - peak area (S)) x 100/ total area (R+S)].

The IL can play a dual role. The IL, like other additives, can affect the performance of the catalyst through the formation of a supramolecular system. In this regard, the protons of the imidazole ring, in particular the C2-H hydrogen and the anion can participate in hydrogen bonding interactions with the organocatalyst, affecting the transition state by which the reaction takes place and enhancing its intrinsic activity. On the other hand, the IL can also facilitate the dissolution of the catalyst, improving the results in terms of the observed activity. Figure 2 shows the pictures for the different [BMIM][Cl]:acetone mixtures considered in Table 2. The mixture with the lowest content of [BMIM][Cl] (11% weight in acetone) showed a biphasic liquid-liquid mixture. However, when the amount of [BMIM][Cl] was increased (above 25% weight of IL) the system evolved from a liquid-liquid biphasic mixture to a three-phasic


11


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 36

solid-liquid-liquid system that finally became a solid-liquid system for the highest concentration of the [BMIM][Cl] evaluated (80 % w/w).

Figure 2. Phase behavior of the different mixtures involved in the aldol model reaction. a) [BMIM][Cl] in acetone at different percentages. b) Enlarged view for [BMIM][Cl] 11% weight in acetone. c) [(R,R)-trans-Cy6-OAc-Im-Bu][Cl] 17% weight in acetone. d) [BMIM][Cl]:Lproline mixtures in acetone at different percentages of IL. e) Enlarged view for [BMIM][Cl]:Lproline: (1:1) in acetone. f) [(R,R)-trans-Cy6-OAc-Im-Bu][Cl]:L-proline (1:1) in acetone. Acetone:proline: 10:0.4 molar for d, e and f. When the same study was performed in the presence of a constant concentration of (L)-proline a slightly different situation was observed. Thus, mixtures having a [BMIM][Cl]-(L)-proline molar ratio of from 1:1 to 6.6:1 displayed a three-phasic solid-liquid-liquid system.


12

Page 13 of 36

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Unexpectedly, the system became homogenous for larger percentages of IL (e.g. 20:1) and for a 80 % by weight of [BMIM][Cl] in acetone a stable and homogenous organogel was obtained ([BMIM][Cl]:L-proline 36.6:1). The behavior of this gel resembles significantly the one observed previously for the so-called sponge-like ILs (SLILs).8 In this case, the presence of (L)proline seems to trigger the self-organization of [BMIM][Cl]. It is known that the polymeric supramolecular network present in ILs can generate, in some cases, nano-structures with polar and non-polar regions and the “inclusion” of the organocatalyst in this supramolecular structure can provide a modification of its catalytic efficiency.7 In order to analyze in more detail this situation, several mixtures of [BMIM][Cl]:(L)-proline in acetone-d6 having different ratios and a constant (L)-proline concentration (0.57 M) were studied by 1H-NMR (Figure 3). Independently of the heterogeneous nature of some of the samples, reasonable 1H-NMR spectra either on the acetone or on the IL phase could be obtained. The appearance of the peaks characteristic for [BMIM][Cl] in the acetone-d6 phase indicated a partial solubility of the IL in acetone. In the IL-rich phase, the signals for C4-H and C5-H of [BMIM][Cl] showed a broadening and a significant downfield shift (∆δ ≈ 0.7 ppm) by the increase in the IL:proline ratio. The signals for CH2-β, CH2-γ and CH3 of the imidazolium butyl group exhibited related upfield shifts (∆δ ≈ 0.2 ppm). A quantitative analysis was not possible for the more acidic C2-H proton of the imidazolium as it exchanges with the deuterium of the solvent. Thus, appreciable changes in the supramolecular structures present in the IL phase take place as a function of the IL:proline ratio.


13


0,8

∆δ ( ppm)

0,6 0,4 0,2 0,0 0

2

0

2

4

6

8

10

12

4

6

8

10

12

0,0 ∆δ ( ppm)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 36

-0,1

-0,2

[BMIM][Cl] conc. (M)

Figure 3. Right side: Variations observed in the 1H-NMR spectra of [BMIM][Cl] in acetone-d6. [BMIM][Cl] (0.029 M), [BMIM][Cl]:L-proline (1:1) (0.57 M), [BMIM][Cl]:L-proline (5:1) (2.9 M), and [BMIM][Cl]:L-proline (20:1) (11.5 M), represented in ascending order for the stacked spectra. The concentration of L-proline (except for the experiment with the pure IL) is 0.57 M in all cases. Left side: Top: representation of ∆δ for the signals corresponding to C4-H (black squares) and C5-H (red star) of [BMIM]; bottom: representation of ∆δ for the signals corresponding to CH2-β (black squares), CH2-γ (red star) and CH3 (blue triangles) of the aliphatic chain of [BMIM]). Also some proline could be observed in the acetone phase. Furthermore, also the (L)-proline signals experience some changes in their position with the increased IL:proline ratio, but the most remarkable observation is the much higher resolution of the signals for high concentrations of IL. This highlights the capacity of the IL additive to solvate individual proline molecules avoiding the formation of proline aggregates and favoring the increase in catalytic activity. This situation, however, seems not to favor the asymmetric induction (ca. 40 % e.e.) for low IL concentrations, as this most likely provides an IL solvation sphere around the proline, with a low level of supramolecular ordering. By using a large excess of IL, the supramolecular interactions


14

Page 15 of 36

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


result in a homogeneous solution or a highly organized organogel, to which (L)-proline appears to contribute significantly, providing an appropriate mass transfer for the catalytic process (Figure 4).3,4,5 This greater degree of supramolecular organization clearly results in a greater asymmetric induction (> 60 % e.e.). Figure 5 shows the FT-IR-ATR spectra for a [BMIM][Cl]:(L)-proline 1:1 mixture obtained after the evaporation of the acetone and for [BMIM][(L)-prolinate] obtained by the quantitative anion exchange of the chloride in the IL. FT-IR spectroscopy is a useful tool to study the inter and intramolecular interactions in ILs mixtures,7,37,38,39 and also to analyze the exact structure of the (L)-proline fragment in the mixture. In this regard, the band corresponding to the asymmetric stretching of the carbonyl (C=O) of the (L)-proline is found at 1609 cm-1 for an equimolecular mixture [BMIM][Cl]:(L)-proline (1:1). This band does not match with the one observed for [BMIM][(L)-prolinate] (1615 cm-1). Moreover, small deviations for the characteristics peaks of the (L)-proline are found when [BMIM][Cl]:(L)-proline (1:1) and (L)-proline are compared. This suggests an effective solvating the (L)-proline by [BMIM][Cl] (species A, Scheme 2) but seems to exclude the anion exchange on [BMIM][Cl] with the carboxylate of (L)-proline (species B, Scheme 2). This is also confirmed by the bands assigned to the imidazolium cation. Of particular relevance are the changes observed for the C-H stretching bands in the 3200-2800 cm-1 region associated with the C2-H, C4-H and C5-H vibrations in the imidazolium ring. Again, these bands are slightly different between both. The [BMIM][(L)-prolinate] salt shows a well-defined spectra for the C-H stretching bands with sharp peaks at 3090 cm-1 and 3151 cm-1 corresponding to C4H, C5-H and C2-H. However, for the [BMIM][Cl]:(L)-proline (1:1) mixture, they are less defined and shifted to lower wavenumbers appearing as a band shoulder at 3130 cm-1 (C2-H) and a broad peak at 3047 cm-1 including bands for C4-H, C5-H and the characteristics bands of L-


15


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 36

proline. This indicates that chloride-imidazolium interactions are still prevalent, although modified when compared with pure [BMIM][Cl] and excluded the exchange of the Cl- by Lprolinate in the mixture. Moreover, an additional band at 1551 cm-1 associated with the symmetrical vibration of the NH2+ group of (L)-proline, can also be observed in the mixture. As it is expected, this band is less important in the salt [BMIM][(L)-proline]. There are also some variations in the 1560 cm-1 C-C band attributable to the imidazolium ring. For the [BMIM][Cl]:(L)-proline (1:1) mixture it is observed at 1565 cm-1, while the full exchange of Clby (L)-prolinate shifts this band to a higher wavelength (1570 cm-1).

Scheme 2. Species for the direct interaction of (L)-proline with [BMIM][Cl].


16

Page 17 of 36

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 4. Schematic model of the supramolecular structure of imidazolium ILs net based on hydrogen bonding interactions induced by (L)-proline at high concentration of ILs ([BMIM][Cl]:(L)-proline 32.6:1).


17


Abs.

a)

3375

3000

2625

2250

1875

Wavenumber (cm-1)

b)

Abs.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 18 of 36

1600

1400

1200

1000

Wavenumber (cm-1) Figure 5. Selected regions for the IR-ATR spectra a) 3200-2800 cm-1. b) 1700-900 cm-1, [BMIM][Cl]:(L)-proline (1:1) (blue line) and [BMIM][(L)-prolinate] (red line).


18

Page 19 of 36

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 3. Results of the aldol reaction between p-nitrobenzaldehyde and acetone with different percentages of (R,R)-trans-Cy6-OAc-Im-Bu-Cl at a 40 % molar loading of the catalyst.a IL:acetone Entry

b

CIL:(L)-Proc

Conv. (%)d

Selec. (%)e

e.e. (%)f

(w/w %) 1

17

1:1

99

99

70

2

24

1.5:1

99

99

70

3

44

3.8:1

99

99

70

4

80

18.7:1

81

99

71

a

Calculated relative to aldehyde, 10:1 molar ratio acetone:aldehyde, 18 h at r.t. b (g IL/(g IL+ g de acetone)) x 100. c molar ratio. d Conversion calculated by 1H-NMR in the reaction crude. e Selectivity calculated by 1H-NMR in the reaction crude. f Enantiomeric excess calculated by HPLC for the major R enantiomer [e.e. = (peak area (R) - peak area (S)) x 100/ total area (R+S)].

According to the former, the hierarchical supramolecular order achieved in the presence of a non-chiral IL and proline can be used to tune the catalytic efficiency of the organocatalyst, including the enantioselectivity. The hydrogen bonding network between ILs, catalysts and substrates, strongly affect the reaction. Thus, it seems reasonable to assume that interesting effects may also be observed in terms of asymmetric induction when using Chiral Ionic Liquids (CILs). Indeed, some interesting effects have been reported for CILs in a few catalytic reactions.40,41,42,43,44 Therefore, we evaluated the aldol reaction in the presence of the CIL [(R,R)trans-Cy6-OAc-Im-Bu][Cl] that can be easily prepared by a synthetic methodology developed in our group.17 The reaction between p-nitrobenzaldehyde and acetone was performed under the experimental conditions used for [BMIM][Cl] involving different CIL:organocatalyst ratios and the results are summarized in Table 3. In this case, (R,R)-trans-Cy6-OAc-Im-Bu-Cl is liquid at room temperature (Tm = 19 °C) being fully soluble in acetone for the preparation of the different mixtures needed for the experiments


19


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 20 of 36

above described (Figure 1c and Figure 2c). Once again, the addition of the CIL (1 equivalent) improves the solubility of the catalyst (Figure 2f) enhancing the reaction rate in comparison with the reaction in acetone alone (Figure 1a vs. 1c, 99

98

-71c

3

(R,R)-trans-Cy6-OAc-Im-Bu-Cl

(L/D)-pro

> 99

95

--

4

(±)-trans-Cy6-OAc-Im-Bu-Cl

(L)-pro

> 99

95

71

5

(S,S)-trans-Cy6-OH-Im-Bu-Cl

(L)-pro

> 99

96

67

6


(D)-pro

> 99

78

-65c

7

(±)-trans-Cy6-OH-Im-Bu-Cl

(L)-pro

> 99

99

58

8

(±)-trans-Cy6-OH-Im-Bu-Cl

(D)-pro

> 99

77

-55c

a

Calculated relative to aldehyde, 10:1 molar ratio acetone:aldehyde. b Enantiomeric excess calculated by HPLC for the major R enantiomer [e.e. = (peak area (R) - peak area (S)) x 100/ total area (R+S)]. c major S enantiomer. d Conversion calculated by 1H-NMR in the reaction crude. e Selectivity calculated by 1H-NMR in the reaction crude.

North et al. have shown that the aldol reaction catalyzed by (L)-proline in propylene carbonate as the solvent provides a "match/mismatch" relationship between the configurations of the organocatalyst and the solvent (used in enantiopure form).45 Taking this into consideration, both (D)- and (±)-proline were also evaluated in the presence of an enantiopure IL. Moreover, the behavior of racemic ILs ((±)-trans-Cy6-OAc-Im-Bu-Cl) was similarly studied. The use of (D)proline in the presence of (R,R)-trans-Cy6-OAc-Im-Bu-Cl yielded similar enantiomeric excesses to those obtained with (L)-proline, although with (S) configuration (Table 5, entry 2). When the racemic (±)-proline was employed as the catalyst, the reaction produced only racemic aldol (Table 5, entry 3). However, when the racemic CILs and (L)-proline were used, the same


23


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 24 of 36

induction than for enantiopure CILs was observed (Table 5, entry 4). Hence, a classical "match/mismatch" effect between the organocatalyst and (R,R)-trans-Cy6-OAc-Im-Bu-Cl was not observed under these conditions. The model aldol reaction also gave good yields and selectivities when (S,S)-trans-Cy6-OH-ImBu-Cl was used. The two enantiomers of proline lead to a similar asymmetric induction (ca. 65 % e.e.) for the opposite enantiomers. This asymmetric induction is slightly lower than that observed for the acetylated analog. The presence of the OH group can facilitate the formation of strong intramolecular interactions, which may interfere in the formation of the corresponding interactions with the organocatalyst. The racemic CIL, in this case, lead to an additional slight drop of the enantiomeric excess (ca. 55 % e.e.) for both enantiomers of proline (Table 5, entries 7 and 8). A series of related CILs with different structural variations were also studied. In all cases, the above considered standard conditions for the model reaction were used for the different CILs. A 4:1 IL:organocatalyst ratio was always employed. The results obtained are summarized in Figure 7. In all cases the corresponding aldol could be isolated with good yields and selectivities. In general, the enantioselectivity achieved was not strongly affected by the structural variables studied. Thus, for example, the change from a five to a six-membered ring only produced a significant effect in the case of the acetylated CIL derivative. Also the nature of the nonfunctional alkyl chain or the relative position of the functional groups (cis/trans) seem to have a minor influence on the enantioselectivity, with variations lower than 5 % of e.e. in most cases. Finally, the aldol reaction between p-nitrobenzaldehyde and cyclohexanone was also studied (Scheme 3), because this is a reaction very sensitive to the nature of the organocatalyst, the


24

Page 25 of 36

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


solvent or the presence of additives.31 The reaction was carried out using either ILs or CILs as additives and the results are summarized in Table 6.

Figure 7. Results of the aldol reaction with different chiral imidazolium salts at room temperature for 20 hours in the presence of 40 % L-proline and a ratio CIL:catalyst (4:1).17 In all cases tested, the use of ILs led to slightly better yields for the corresponding aldols. When the reaction was performed in a mixture DMSO/cyclohexanone (4:1 volume) a 65 %yield was obtained, with a 68:32 anti/syn diastereoselectivity and enantioselectivities of 89 % e.e. and 67 % e.e. for the anti and syn isomers respectively (Table 6, entry 1). Once again, the nature of the IL had a great influence on the selectivity of the reaction. Thus, using [BMIM][Cl] as an additive, a higher anti/syn selectivity (82:18) but lower enantioselectivities 79% e.e. (anti) and 14% e.e. (syn) were obtained (Table 5, entries 1 and 2). Regarding the use of CILs, the best results in terms of enantioselectivity were obtained with the (R,R)-trans-Cy6-OAc-Im-Bu-Cl, providing a 90% e.e. for the aldol anti and a 80% e.e. for the syn. Notably, in the latter case, the enantiomer was obtained with the reverse configuration than the one observed in the previous


25


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 36

cases. This inversion was also observed when using the (S,S)-trans-Cy6-OH-Im-Bu-Cl as an additive, but the enantioselectivity achieved in this case was lower (56% e.e.).

Scheme 3. Aldol reaction between p-nitrobenzaldehyde and cyclohexanone.

Table 6. Results of the aldol reaction between p-nitrobenzaldehyde and cyclohexanone using different imidazolium salts, at room temperature for 23 hours with a 4:1 IL:catalyst ratio and a 40 % catalyst loading.a Entry

Additive

Conv. (%)c

Sel. (%)d

e.e.anti (%)b

e.e.syn (%)b

1

-

65

63:37

89

67

2

[BMIM][Cl]

83

82:18

79f

14f

3

(R,R)-trans-Cy6-OAc-Im-Bu-Cl

73

61:39

90f

-80e

4


75

72:28

84f

-56e

a

Calculated relative to aldehyde, 10:1 molar ratio cyclohexanone:aldehyde. b Enantiomeric excess calculated by HPLC for each diastereoisomer [e.e. = (major peak area - minor peak area) x 100/ total area]. No absolute configuration could be assigned. c Conversion calculated by 1HNMR in the reaction crude. d Selectivity calculated by 1H-NMR in the reaction crude for the anti/syn diastereoisomer ratio. e First major peak of the two peaks of the diastereoisomer in the HPLC. f Second major peak of the two peaks of the diastereoisomer in the HPLC.

CONCLUSIONS The catalytic behavior of (L)-proline was studied using ILs or CILs either as major components in the solvent mixture or as additives. The aldol reaction is a simple benchmark reaction allowing us to better understand the non-innocent nature of the ILs or CILs used as either solvent or


26

Page 27 of 36

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


additive. Our results suggest that the use of an IL can modulate not only the activity but also the selectivity and the enantioselectivity of the reaction and even, in some cases, the final topicity. The IL self-organization and the IL-organocatalyst interaction through H-bond and ion-pair contacts are likely to be key parameters for transferring the chiral information from the catalyst to the substrates involved in the reaction. In the case of CILs, establishing well-defined interactions involving the catalyst can be very relevant even for low concentrations of CILs and the results observed are similar for different amounts of CIL added. However, for the non-chiral ILs, a greater degree of organization can only be obtained by an increase in the concentration of the IL, which allows their self-organization in a well-defined structure, facilitating the better transfer of the chiral information.

EXPERIMENTAL Materials and methods All reagents were obtained from Sigma-Aldrich. Dry solvents were distilled over an adequate desiccant under nitrogen. To ensure anhydrous conditions for the aldol reactions, ILs were dried at 50 ºC under vacuum before use and acetone of the highest level of purity (anhydrous) was used and was always kept with 0.3 Å molecular sieves. Flash chromatography was performed using silica gel 60 (230-240 mesh). 1H-NMR experiments were carried out using a Varian INOVA 500 (1H-NMR, 500 MHz) spectrometer. The chemical shifts are given in delta (δ) values relative to TMS and the coupling constants (J) in Hertz (Hz). High performance liquid chromatography (HPLC) analyses were carried out in a Merck HITACHI LaChrom chromatograph UV detector at 254 nm using a Daicel Chiralcel OJ and Chiralpak AD column (25 cm × 4.6 mm I.D.).


27


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 28 of 36

Synthetic procedures Synthesis of CILs. Their synthesis was carried out as reported in the ref 17. General procedure for the aldol reaction (40% catalyst loading). Over a mixture of 0.4 mmol of L-proline, 10 mmoles of acetone or cyclohexanone and the corresponding amount of ionic liquid, 1 mmol of p-nitrobenzaldehyde was added. The resulting mixture was stirred for 2024 h at room temperature, following the reaction by TLC (Hex:AcOEt, 2:1). Then, 10 mL of chloroform were added and the mixture was washed with deionized water (3 x 5 mL). The organic phase was dried with anhydrous magnesium sulphate and the solvent was evaporated under reduced pressure. The resulting crude was purified by flash chromatography on silica gel (Hex:AcOEt, 2:1). Characterization 4-hydroxy-4-(4-nitrophenyl)butan-2-one. 1H-RMN (500 MHz, CDCl3): δ 2.10 (s, 3H, CH3), 2.78 (dd, 2H, J = 3.3, 6.6 Hz, CH2), 3.94 (s, 1H, OH), 5.17 (dt, 1H, J = 3.8, 7.7 Hz, CH), 7.44 (d, 2H, Ph), 8.02 (d, 2H, J = 8.9 Hz, Ph). Rf: 0.25 (hexane/ethyl acetate, 2:1). HPLC: 36.25 min (R) and 41.11 min (S) (Chiralcel OJ, Hex/IPA (90:10), flow: 0.75 mL/min, T: 30 ºC, λ: 254 nm). 2-(hydroxy(4-nitrophenyl)methyl)cyclohexanone. 1H-RMN (500 MHz, CDCl3): δ 1.32-1.78 (m, 5H), 2.26-2.53 (m, 4H), 4.02 (s, 1H, OH), 4.83 (d, 1H, J = 8.3 Hz, CH, anti), 5.41 (s, 1H, CH, syn), 7.44 (d, 2H, J = 8.5 Hz, Ph), 8.13 (d, 1H, J = 8.5 Hz, Ph). Rf: 0.27 (hexane/ethyl acetate, 2:1). HPLC: 16.23 min and 20.63 min (syn); 22.29 min (2S, 1’R) y 29.58 min (2R, 1’S) (anti) (Chiralpak AD, Hex/IPA (90:10), flow: 1 mL/min, T: 30 ºC, λ: 254 nm).


28

Page 29 of 36

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


AUTHOR INFORMATION Corresponding Author * Eduardo Garcia-Verdugo and Santiago V. Luis. Tel.: +34 964728239. Fax: +34 964728214. Email: [email protected], [email protected] Present Addresses Departamento de Química Inorgánica y Orgánica, Universidad Jaume I, Av. Sos Baynat s/n, 12071 Castellón, Spain. Funding Sources This work was partially supported by MINECO (CTQ2015-68429-R and CTQ2015-67927-R), Generalitat Valenciana (PROMETEO/2012/020) and UJI‐P1‐1B2013‐37 grants. Cooperation of the SCIC of the UJI for instrumental analyses is acknowledged. REFERENCES

1 Wasserscheid, P., Welton, T., Eds. Ionic liquids in synthesis; Wiley-VCH: Weinheim, 2008. 2 Hallett, J. P.; Welton, T. Room-temperature ionic liquids: solvents for synthesis and catalysis. Chem. Rev. 2011, 111 (5), 3508-3576. 3 Dupont, J. On the solid, liquid and solution structural organization of imidazolium ionic liquids. J. Braz. Chem. Soc. 2004, 15 (3), 341-350. 4 Dupont, J. From molten salts to ionic liquids: a “nano” journey. Acc. Chem. Res. 2011, 44 (11), 1223-1231.


29


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 30 of 36

5 Dupont, J.; Eberlin, M. N. Structure and physico-chemical properties of ionic liquids: what mass spectrometry is telling us. Curr. Org. Chem. 2013, 17 (16), 257-272 6 Hayes, R.; Warr, G.G.; Atkin, R. Structure and nanostructure in ionic liquids. Chem. Rev. 2015, 115 (13), 6357-6426 7 Stassen, H. K.; Ludwig, R.; Wulf, A.; Dupont, J. Imidazolium salt ion pairs in solution. Chem. Eur. J. 2015, 21 (23), 8324-8335. 8 Lozano, P.; Bernal, J. M.¸. Garcia-Verdugo, E; Sanchez-Gomez, G.; Vaultier, M; Burguete, M. I.; Luis. S. V. Sponge-like ionic liquids: a new platform for green biocatalytic chemical processes, Green Chem. 2015, 17, 3706-3717. 9 Jimeno, C., Water in asymmetric organocatalytic systems: a global perspective. Org. Biomol. Chem., 2016, 14, 6147-6164. 10 Mase, N.; Barbas, C. F. In water, on water, and by water: mimicking nature's aldolases with organocatalysis and water. Org. Biomol. Chem. 2010, 8, 4043-4050. 11 Dupont, J.; de Souza, R. F.; Suarez, P. A. Z. Ionic liquid (molten salt) phase organometallic catalysis. Chem. Rev. 2002, 102 (10), 3667-3692. 12 Bica, K.; Gaertner, P. Applications of chiral ionic liquids. Eur. J. Org. Chem. 2008, 19, 32353250. 13 Prechtl, M. H. G.; Scholten, J. D.; Neto, B. A. D.; Dupont, J. Application of Chiral Ionic Liquids for Asymmetric Induction in Catalysis. Curr. Org. Chem. 2009, 13 (13), 1259-1277. 14 Altava, B.; Barbosa, D. S.; Burguete, M. I.; Escorihuela, J.; Luis, S. V. Synthesis of new chiral imidazolium salts derived from amino acids: their evaluation in chiral molecular recognition. Tetrahedron: Asymmetry 2009, 20 (9), 999-1003.


30

Page 31 of 36

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


15 González, L.; Altava, B.; Bolte, M.; Burguete, M. I.; García-Verdugo, E.; Luis, S. V. Synthesis of chiral room temperature ionic liquids from amino acids-application in chiral molecular recognition. Eur. J. Org. Chem. 2012, 26, 4996-5009. 16 Gonzalez, L.; Escorihuela, J.; Altava, B.; Burguete, M. I.; Luis, S. V.; Quesada, R.; Vicent, C. Application of optically active chiral bis(imidazolium) salts as potential receptors of chiral dicarboxylate salts of biological relevance. Org. Biomol. Chem. 2015, 13 (19), 5450-5459. 17 Ríos-Lombardía, N.; Busto, E.; Gotor-Fernández, V.; Gotor, V.; Porcar, R.; García-Verdugo, E.; Luis, S. V.; Alfonso, I.; Garcia-Granda, S.; Menéndez-Velázquez, A. From salts to ionic liquids by systematic structural modifications: A rational approach towards the efficient modular synthesis of enantiopure imidazolium salts. Chem. Eur. J. 2010, 16 (3), 836-847. 18 Seebach, D.; Oei, H. A. Zum mechanismus der elektrochemischen pinakolisierung. Die erste asymmetrische elektrosynthese in chiralem medium. Angew. Chem. Int. Ed. Engl. 1975, 87 (17), 629-630. 19 Headley, A. D.; Ni, B. Chiral imidazolium ionic liquids: their synthesis and influence on the outcome of organic reactions. Aldrichimica Acta 2007, 40 (4), 107-117. 20 Limberger, J.; Leal, B.C.; Monteiro, A.L.; Dupont, J. Charge-tagged ligands: useful tools for immobilising complexes and detecting reaction species during catalysis. Chem. Sci. 2015, 6 (1), 77-94. 21 Kochetkov, S.V.; Kucherenko, A.S.; Zlotin, S.G. Asymmetric aldol reactions in ketone/ketone systems catalysed by ionic liquid-supported C2-symmetrical organocatalyst. Mendelev Commun. 2015, 25, 168-170.


31


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 32 of 36

22 Montroni, E.; Sanap, S.P.; Lombardo, M.; Quintavalla, A.; Trombini, C.; Dhavale, D.D. A New Robust and Efficient Ion-Tagged Proline Catalyst Carrying an Amide Spacer for the Asymmetric Aldol Reaction. Adv. Synth. Catal. 2011, 353 (17), 3234-3240. 23 Lombardo, M.; Trombini, C. Ionic Tags in Catalyst Optimization: Beyond Catalyst Recycling. ChemCatChem 2010, 2 (2), 135-145. 24 Dyson, P. J.; Jessop, P. G., Solvent effects in catalysis: rational improvements of catalysts via manipulation of solvent interactions, Catal. Sci. Technol., 2016, 6, 3302-3316 25 List, B.; Pojarliev, P.; Castello, C. Proline-catalyzed asymmetric aldol reactions between ketones and α-unsubstituted aldehydes. Org. Lett. 2001, 3 (4), 573-575. 26 List, B.; Lerner, R. A.; Barbas III, C. F. Proline-catalyzed direct asymmetric aldol reactions. J. Am. Chem. Soc. 2000, 122 (10), 2395-2396. 27 Sakthivel, K.; Notz, W.; Bui, T.; Barbas III, C. F. Amino acid catalyzed direct asymmetric aldol reactions: a bioorganic approach to catalytic asymmetric carbon−carbon bond-forming reactions. J. Am. Chem. Soc. 2001, 123 (22), 5260-5267. 28 Zotova, N.; Franzke, A.; Armstrong, A.; Blackmond, D. G. Clarification of the role of water in proline-mediated aldol reactions. J. Am. Chem. Soc. 2007, 129 (49), 15100-15101. 29 Mase, N.; Tanaka, F.; Barbas III, C. F. Synthesis of β-hydroxyaldehydes with stereogenic quaternary carbon centers by direct organocatalytic asymmetric aldol reactions. Angew. Chem. Int. Ed. 2004, 43 (18), 2420-2423. 30 Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Asymmetric direct aldol reaction assisted by water and a proline-derived tetrazole catalyst. Angew. Chem. Int. Ed. 2004, 43 (15), 1983-1986.


32

Page 33 of 36

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


31 Porcar, R.; Ríos-Lombardía, N.; Busto, E.; Gotor-Fernández, V.; Gotor, V.; Garcia-Verdugo, E.; Burguete, M. I.; Luis, S. V. Chemoenzymatic synthesis of optically active 2-(2′-or 4′substituted-1 H-imidazol-1-yl) cycloalkanols: chiral additives for (L)-proline. Catal. Sci. Technol. 2013, 3 (10), 2596-2601. 32 Kotrusz, P.; Kmentova, I.; Gotov, B.; Toma, S.; Solcaniova, E.; Proline-catalysed asymmetric aldol reaction in the room temperature ionic liquid [bmim]PF6. Chem. Commun. 2002, 21, 25102511. 33 Loh, T. P.; Feng, L. C.; Yang, H. Y.; Yang, J. Y. L-proline in an ionic liquid as an efficient and reusable catalyst for direct asymmetric aldol reactions. Tetrahedron Lett. 2002, 43 (48), 8741-8743. 34 Gonzalez, L.; Escorihuela, J.; Altava, B.; Burguete, M.I.; Luis, S. V. Chiral room temperature ionic liquids as enantioselective promoters for the asymmetric aldol reaction. Eur. J. Org. Chem. 2014, 24, 5356-5363. 35 Zhang, L.; Zhang, H.; Luo, H.; Zhou, X.; Cheng, G. Novel chiral ionic liquid (CIL) assisted selectivity enhancement to (L)-proline catalyzed asymmetric aldol reactions. J. Braz. Chem. Soc. 2011, 22 (9), 1736-1741. 36 Zhou, W.; Xu, L.-W.; Qiu, H.-Y.; Lai, G.-Q.; Xia, C.-G.; Jiang, J.-X. Synthesis of a novel chiral ionic liquid and its application in enantioselective aldol reactions. Helv. Chim. Acta 2008, 91 (1), 53-59. 37 Zheng, Y. Z.; Wang, N. N.; Luo, J. J.; Zhou. Y.; Yu Z. W, Hydrogen-bonding interactions between [BMIM][BF4] and acetonitrile, Phys.Chem. Chem. Phys., 2013, 15, 18055-18064.


33


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 34 of 36

38 Strauch, M.; Roth, C.; Kubatzki F.; Ludwig R. Formation of “Quasi” Contact or Solventseparated Ion Pairs in the Local Environment of Probe Molecules Dissolved in Ionic Liquids. ChemPhysChem, 2014, 15, 265-270. 39 A. Knorr, P. Stange, K. Fumino, F. Weinhold, R. Ludwig, Spectroscopic Evidence for Clusters of Like‐Charged Ions in Ionic Liquids Stabilized by Cooperative Hydrogen Bonding. ChemPhysChem 2016, 17, 458-462. 40 Schulz, P. S.; Muller, N.; Bosmann, A.; Wasserscheid, P. Effective chirality transfer in ionic liquids through ion-pairing effects. Angew. Chem. Int. Ed. 2007, 46 (8), 1293-1295. 41 Gausepohl, R.; Buskens, P.; Kleinen, J.; Bruckmann, A.; Lehmann, C. W.; Klankermayer, J.; Leitner, W. Highly enantioselective aza‐Baylis-Hillman reaction in a chiral reaction medium. Angew. Chem. Int. Ed. 2006, 45 (22), 3689-3692. 42 Branco, L. C.; Gois, P. M. P; Lourenço, N. M. T.; Kurteva, V. B.; Afonso C. A. M. Simple transformation of crystalline chiral natural anions to liquid medium and their use to induce chirality, Chem. Commun., 2006, 2371-2372. 43 Chen, D.; Schmitkamp, M.; Giancarlo F.; Klankermayer J.; Leitner W., Enantioselective Hydrogenation with Racemic and Enantiopure Binap in the Presence of a Chiral Ionic Liquid, Angew. Chem. Int. Ed., 2008, 47, 7339-7341. 44 Fukuhara, G.; Okazaki, T.; Lessi, M.; Nishijima, M.; Yang, C.; Mori, T.; Mele, A.; Bellina, F.; Chiappe, C.; Inoue, Y. Chiral ionic liquid-mediated photochirogenesis. Enantiodifferentiating photocyclodimerization of 2-anthracenecarboxylic acid. Org. Biomol. Chem. 2011, 9 (20), 71057112. 45 North, M.; Villuendas, P. A Chiral solvent effect in asymmetric organocatalysis. Org. Lett. 2010, 12 (10), 2378-2381.


34

Page 35 of 36


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment

35


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 36 of 36

Supramolecular interactions based on ionic liquids for tuning of the catalytic efficiency of (L)-proline Raul Porcar,a M. Isabel Burguete a Pedro Lozano, b Eduardo Garcia-Verdugo, a* Santiago V. Luis a* a

Departamento de Química Inorgánica y Orgánica, Universidad Jaume I, Av. Sos Baynat s/n, 12071 Castellón, Spain. E-mail: [email protected], [email protected]

b

Departamento de Bioquímica y Biología Molecular B e Inmunología, Facultad de Química, Universidad de Murcia, Campus de Excelencia Internacional Regional “Campus Mare Nostrum”, E-30100 Murcia, Spain

Table of Contents Graphic and Synopsis:

Supramolecular interactions involving ILs and proline determine the tuning of its activity, selectivity and enantioselectivity for the aldol reaction


36

Supramolecular Interactions Based on Ionic Liquids for Tuning of the

Recommend Documents