Synthesis of chiral room temperature ionic liquids from amino acids - Application in chiral molecular recognition

Job/Unit: O20607

/KAP1

Date: 26-07-12 16:09:10

Pages: 15

FULL PAPER

DOI: 10.1002/ejoc.201200607

Synthesis of Chiral Room Temperature Ionic Liquids from Amino Acids –

Application in Chiral Molecular Recognition

Laura González,^[a]Belén Altava,*^[a]Michael Bolte,^[b]M. Isabel Burguete,^[a]

Eduardo García-Verdugo,^[a]and Santiago V. Luis*^[a]

Keywords: Ionic liquids / Chiral shift agents / Amino acids / Carboxylic acids / Molecular recognition

A series of structurally new room temperature chiral ionic

liquids based on an imidazolium group and derived from nat-

ural amino acids have been synthesized and studied as chiral

shift agents for the chiral discrimination of enantiomeric

carboxylate salts. This family of imidazolium salts can be pre-

pared by a simple synthetic approach and most of the compo-

nents are liquid at room temperature. The solid to liquid

transformation temperatures can be as low as –49 °C. The

analysis of the supramolecular structure of the resulting CILs

can be used advantageously to understand the potential for

the selective recognition of different hosts.

of easy structural tuneability is highly attractive and a con-

tinued effort is being currently devoted to the preparation

of chiral ionic liquids (CILs).^[11]CILs have additional po-

tential as chiral solvents,^[12]shift reagents,^[13]or enantiose-

lective catalysts.^[14]Furthermore, it has recently been shown

that the configuration of the resulting CILs plays an impor-

tant role in defining their final physical properties.^[15]

Within this context, our group has been involved in the

preparation and study of CILs prepared either from race-

mic materials,^[15]or from enantiomerically pure materials

obtained from the chiral pool.^[16]Here we report on the

preparation of a new family of CILs using natural amino

acids as the source of chirality and containing an amide

group as an essential structural feature.

The use of a flexible and simple synthetic approach al-

lows the preparation of a large variety of configurationally

and structurally diverse CILs (see Figure 1 for the general

structure). An analysis of the structure-properties relation-

ship has been carried out. The main structural variables

considered were the amino acid side chain residue (R), the

moiety attached to the nitrogen atom of the imidazolium

ring (R²), the fragment attached to the amide nitrogen atom

(R¹) and the counterion. The resulting salts have also been

investigated as chiral shift reagents (CSR) for chiral carb-

oxylates.

Introduction

Ionic liquids (ILs) are attracting considerable attention

as green reaction solvents,^[1]extraction liquids^[2]and elec-

trolyte materials,^[3]as well as structured media for other

technological applications such as their use for enhancing

the sensitivity of thermal lens measurements.^[1g,4]Most of

those applications involve the use of the so-called room-

temperature Ionic Liquids (RTILs) that have melting tem-

peratures below 100 °C,^[5]and were described in the work

of Walden in 1914. The potential applications of ILs are

closely related to their physicochemical properties, and

those depend on the interaction established between both

the cation and the anion.^[6]The nature of these components

can be easily varied and, thus, the large structural diversity

available for ILs plays an important role in our ability to

define their final properties, such as electrochemical sta-

bility,^[7]miscibility with water and/or organic solvents,^[8]

melting point,^[9]viscosity,^[10]and so on. In this regard much

work has been carried out to understand the influence of

the different structural parameters, such as the nature of

side chains or the presence of additional functional groups,

on the intrinsic properties of ILs. On the other hand, chiral-

ity plays a key role in organic chemistry. Therefore, the de-

sign and synthesis of enantiopure ILs with the possibility

[a] Department of Inorganic and Organic Chemistry, Universitat

Jaume I,

12070 Castellón, Spain

Fax: +34-96728214

E-mail: altava@qio.uji.es

luiss@qio.uji.es

Homepage: www.quimicasostenible.uji.es

[b] Institut fur Anorganische Chemie, J. W. Goethe-Universität

Frankfurt,

60438 Frankfurt/Main, Germany

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201200607.

Figure 1. General structure for CILs 7–12.

Eur. J. Org. Chem. 0000, 0–0

1

Job/Unit: O20607

/KAP1

Date: 26-07-12 16:09:10

Pages: 15

B. Altava, S. V. Luis et al.

FULL PAPER

Results and Discussion

Synthesis of CILs

cases, also in solution.^[6c,7,19]In order to analyze those

structures, different methodologies such as thermal analysis,

IR and NMR can be used.^[20]

Chiral α-amino amides 1–3, described previously by our

group,^[17]were used as precursors for the synthesis of chiral

ILs 7–12 having an imidazolium cation. Here, l-valine, l-

phenylalanine and l-leucine were used as starting materials

for introducing chirality [R = CH(CH₃)₂, CH₂Ph and

CH₂CH(CH₃)₂]. The imidazole ring was formed by reacting

formaldehyde, ammonium acetate, glyoxal and the chiral α-

amino amide to obtain compounds 4–6.^[18]The chiral imid-

azoles were then alkylated by using different alkyl chlorides,

bromides or iodides to give the corresponding imidazolium

salts 7–9. Finally, compounds 7–9 were converted into the

corresponding bistriflamides by anion exchange using

LiNTf₂. In general, it has been observed that the presence

of this anion is more appropriate for the preparation of

RTILs and for recognition studies.^[16]Thus, following the

general procedure depicted in Scheme 1, the imidazolium

chiral salts 10–12 were obtained in moderate yields. CILs

10–12 were liquid at room temperature with melting points

ranging from 2 to –49 °C.

TGA and DSC Analyses

As show in Table 1, all 23 compounds 7–12 are ionic li-

quids showing a phase transition temperature ranging from

61 °C for 7d to –49 °C for 11c, and thermal stability over

250 °C. As expected, substituting the halide anions for the

less coordinating NTf₂^–anion is accompanied by a decrease

in the melting point, in particular when the substitution of

Cl^–takes place. This change in the anion also gives a clear

increment in the thermal stability with values of T_dϾ

300 °C. In the same way, the tendency for formation of solid

ionic salts for the different anions decreases in the order

–

Cl^–Ͼ I^–Ͼ NTf₂(Table 1, Entries 2, 8 and 14). Indeed, or-

–

ganic salts containing NTf₂are RTILs for all the cases

studied with T_mϽ 20 °C, showing a phase transition tem-

perature ranging from 2 °C for 10d to –49 °C for 11c.

Table 1. Phase transition temperature (T_m) and decomposition tem-

perature (T_d) obtained for CILs 7–12.

Entry CILs

l-aa

R¹

R²

X^–

T_m[°C]^[a]T_d[°C]^[b]

1

2

3

4

5

6

7

8

7a

7b

7c

7d

7e

7f

7g

7h

8a

8b

8c

9a

10a

10b

10c

10d

10e

10f

10g

11a

11b

11c

12a

Phe

Val

Leu

Phe

Val

Leu

Bn

nBut

Bn

Me

I

Br

Cl

I

Cl

I

Br

I

NTf₂

51

35

24

61

32

18

48

43

17

–2

–8

17

280

320

322

327

285

290

250

325

320

315

305

310

400

375

400

355

380

340

310

330

395

nBut

Non

Bn

Me

nBut

Bn

nBut

Non

nBut

Me

nBut

Non

Bn

Me

nBut

Bn

nBut

Non

nBut

9

Bn

10

11

12

13

14

15

16

17

18

19

20

21

22

23

nBut

Bn

–1

–12

–20

2

–16

–23

–9

–20

–45

–49

–19

Bn

nBut

Bn

nBut

Bn

[a] Data obtained from DSC. [b] Data obtained from TGA.

Scheme 1. Synthesis of CILs.

The size and nature of the alkylating agent (R²), the sub-

stituent at the amide moiety (R¹) and the side chain derived

from the amino acid (R) also play a key role in determining

the melting point of the different enantiopure chiral imid-

azolium salts. An increase in the length of the alkylating

agent leads to a small decrease of the transition temperature

(T_m) (Table 1, Entries 21, 22 for l-valine derivatives, En-

tries 13–15 for l-phenylalanine derivatives). On the con-

The structures of the new CILs were characterized by

¹H NMR, ¹³C NMR, IR, MS, DSC, TGA and elemental

analysis.

Study of the Structure on the Solid and Solution States

The strong interaction between the imidazolium cation trary, the substitution of an alkyl group by a group contain-

and the corresponding anion through electrostatic forces ing an aromatic ring always induces an increase in the T_m.

and hydrogen bonding gives tightly associated ion pairs This increase is observed independently of the counterion

with well-defined structures, as well as defined supramo- and is valid for changes at the alkylating agent (R²), the

lecular structures in the solid and liquid states and, in some substituent at the amide fragment (R¹) or at the side chain

2

www.eurjoc.org

Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20607

/KAP1

Date: 26-07-12 16:09:10

Pages: 15

Synthesis of Chiral Room Temperature Ionic Liquids from Amino Acids

(R). The decrease in T_mwith the length of the alkyl chain hydrogen-bond interactions with the counterion, have a sig-

can be associated with the higher degree of disorder associ- nificant influence on their final macroscopic properties.^[21]

ated to the alkyl chain. However, the increase in T_mfor

The three-dimensional molecular structure of 7b was un-

benzylimidazolium salts must involve the presence of π–π ambiguously determined by using single-crystal X-ray dif-

interactions (i.e. in 10b), CH–π interactions or solvophobic fraction analysis (Figure 2). As expected, the iodide anion

forces (i.e. in 10f or 11a). The X-ray crystal structure ob- was in proximity to one amide N1–H proton and one imid-

tained for 7b (details follow) confirms the presence of an azolium moiety, and thus able to interact through hydrogen

intramolecular CH–π interaction between the butyl alkylat- bonding.^[22]In the crystal packing it can be observed that

ing agent and the aromatic ring from the Phe moiety. In the the hydrogen-bonding distances with the anion increase in

same way, the presence of a side chain, R, containing an the sequence NHϽ C5–HϽ C6–H. It should be noted that

aromatic ring also produces an increase in T_m, indepen- the N1–H and the imidazolium protons from a given cation

dently of the anion (See, for example, Table 1, Entries 2 ver- are bound to different anions within the crystal lattice.

sus 9 or 12, and 9 versus 21). A similar effect is observed

In the crystal packing structure an intramolecular CH–π

when the N-substituent at the amide moiety (R₁) is consid- interaction between the butyl group from the alkylating

ered. For instance, the substitution of the n-butyl group in agent and the aromatic ring from the Phe moiety can be

10e by a benzyl group in 10a is accompanied by an increase seen (C10–H to C43 distance 3.061 Å). Furthermore, dif-

in the T_mof 15 °C (Table 1, Entries 13 and 17).

ferent intermolecular edge-to-face π–π interactions can be

Experimental attenuated total reflectance (ATR)-FTIR detected, involving the aromatic ring from the substituent

1

and H NMR studies obtained for 7b, 7i and 10b strongly at the amide fragment of a molecule and the aromatic rings

support the stabilization effect of the amide NH-anion hy- derived from the Phe moieties of two additional molecules

drogen-bonding interactions, although secondary inter-cat- (π–π distances 2.897 and 2.899 Å).

ionic interactions (such as additional H bonding, π-stacking

or C–H–π bonding involving benzyl aromatic rings), as ob-

served in the crystal structures, could also contribute signif-

Computational Studies

icantly to the global stability of the salts. The stabilization

To understand the importance of the structural factors,

which were observed in the X-ray diffraction study, for the

molecule in solution, 7b was studied using the Monte Carlo

conformational search available in Spartan ’08.^[23]The re-

sulting minimum energy conformer was optimized at a semi

empirical level (PM6) in Gaussian 09.^[24]The optimized

structure obtained for 7b is shown in Figure 3. Similarly to

the crystal structure, the most stable conformer for 7b pres-

ents a predominant hydrogen bonding interaction between

the amide NH and the anion (iodide) (NH and anion dis-

tance 2.399 Å). A hydrogen-bond interaction between C5–

H and the anion is also present (C5–H and anion distance

2.755 Å).

effect decreases in all the CILs studied in the order halideϽ

–

NTf₂. It has been recognized that the presence of ad-

ditional functionalities in the CILs, which are able to form

Figure 3. Most stable conformer obtained for 7b using Gaussian

09 (semiempiric level PM6). Hydrogen bonds are denoted by dotted

lines.

ATR-FTIR Vibrational Spectroscopy and NMR Solution

Studies

ATR-FTIR spectroscopy was used to study the supra-

Figure 2. Molecular structure (top) and crystal packing (bottom)

for compound 7b, obtained by X-ray diffraction analysis.

molecular structure of the CILs 7a–12a.^[25]NMR spec-

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

3

Job/Unit: O20607

/KAP1

Date: 26-07-12 16:09:10

Pages: 15

B. Altava, S. V. Luis et al.

FULL PAPER

troscopy provides an average chemical shift for imidazolium ure 5 displays the changes observed in the wavenumbers of

protons and NH protons interacting with the anion, the different bands as a function of the temperature. When

whereas ATR-FTIR gives separate vibrational bands for the temperature is increased, most of the bands shift to

distinct species, such as ion pairs. The differences are owing lower wavenumbers except the signal corresponding to C–H

to the different time scales of these techniques.

asymmetric deformation at approximately 1450 cm^–1, which

In the ATR-FTIR spectra of 7a–12a, the bands between remains essentially unaltered, and the amide I band (ap-

3150 and 3000 cm^–1are considered diagnostic of the C–H proximately 1678 cm^–1), which shifts to higher values. This

stretching modes of the aromatic rings.^[6b,15]In this region, change suggests the presence of a significant degree of order

for the imidazolium aromatic ring, the vibrational bands at based on H-bonding involving the amide N–H that is partly

higher wavenumbers correspond to C6–H and C7–H relieved upon heating.

stretching modes, whereas vibrational bands at lower wave-

numbers correspond to the C5–H stretching mode.

In the partial ATR-FTIR spectra for 7b, 7h and 10b,

shown in Figure 4, vibrational bands observed at 3124 cm^–1

for 7b, 3096 cm^–1for 7h, and 3147 cm^–1for 10b can be as-

signed to C6–H and C7–H stretching modes. For 10b, the

vibrational band corresponding to C5–H is observed at

3110 cm^–1, whereas for 7b and 7h this band appears below

3075 and 3059 cm^–1and overlap with the bands corre-

sponding to the benzene ring.^[26]

Figure 5. Variation with the temperature of the wavenumbers for

the different bands of 7b. Grey triangle for amide I; grey circle

1453 cm^–1, grey square 1557.5 cm^–1; white square 3229.9 cm^–1;

black star 3059 cm^–1; white star 3213 cm^–1; white triangle amide II.

For 7b, 7h and 10b, the hydrogen-bonding interactions

between the imidazolium protons and the anion was also

studied by ¹H NMR spectroscopy, by using 10 mm solu-

Figure 4. Partial ATR-FTIR spectra for 7b (dotted line), 7h (dis-

continuous line) and 10b (continuous line) at 25 °C.

tions of the different CILs in CDCl₃(Figure 6). As can be

observed, with an increase in the Brønsted basicity of the

anions, significant and simultaneous downfield shifts were

observed for the imidazolium C5–H signal and that of the

amide proton (NH), indicating that both are strongly

bound to the anion. These data suggest a strong involve-

Vibrational bands observed at higher wavenumbers

(Ͼ 3150 cm^–1) can be assigned to N–H stretching modes

(3225 cm^–1for 7b, 3185 cm^–1for 7h and 3375 cm^–1for 10b,

Figure 4).

As can be seen, an increase in the Brønsted basicity of

the anion is accompanied by significant variations of the

NH stretching bands. Upon formation of the hydrogen

bond, the N–H bond is weakened and, thus, the frequency

of its stretching vibration normally decreases.^[27]Therefore,

the frequency observed for the vibrational N–H band fol-

lows the order ClϽ IϽ NTf₂(Figure 4). According to the

ATR-FTIR data, the hydrogen from the amide NH is the

one more strongly involved in hydrogen bonding with the

anion (Δν for the couple NTf₂/I, 150 cm^–1), followed by the

hydrogen at the C5 (Δν for the couple NTf₂/I Ͼ35 cm^–1),

whereas protons at C6 and C7 are much less affected (Δν

for the couple NTf₂/I, 23 cm^–1).

Several techniques, including variable-temperature infra-

red spectroscopy, have been used to monitor the change of

the intramolecular order and the supramolecular ordering

of different molecules.^[28]In this context, the ATR-FTIR

1

spectra of 7b at different temperatures were measured. Fig- Figure 6. Partial H NMR spectra for 7b, 7h and 10b.

4

www.eurjoc.org

Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20607

/KAP1

Date: 26-07-12 16:09:10

Pages: 15

Synthesis of Chiral Room Temperature Ionic Liquids from Amino Acids

ment of the NH and the C5–H in hydrogen bonding with

the anion, which is in good agreement with results from

other experimental techniques.^[29]For 10b a significant up-

field chemical shift for the chiral proton (C1–H) is observed

indicating the presence of a very different conformation for

this CIL containing bistriflamide as the anion.

Finally, the formation of supramolecular structures in

1

solution was studied obtaining the H NMR spectra of the

CILs at various concentrations in various solvents. The

analysis of the resulting data shows the existence of a criti-

cal aggregation concentration in solution.^[17b,30]These spec-

tra provide important data for a detailed study of the nature

of the intra- and intermolecular interactions taking place in

solution. Both of these aspects are critical for proper under-

standing of any experiments in which the corresponding

CILs are used for recognition and discrimination purposes.

1

Figure 7 shows the variations observed for the H NMR

signals of 7b at various concentrations in both CDCl₃and

CD₃CN. When the experiments were carried out in CDCl₃,

very small concentration-dependent changes in the ¹H

NMR chemical shifts were observed for the aromatic imid-

azolium protons C5–H, C7–H, and for the amide NH pro-

ton (Figure 7a). For example, when increasing the global

concentration of 7b from 1 to 58 mm, the corresponding ¹H

NMR spectra showed no significant shifts for the signals of

the amide NH (Δδ = –0.035 ppm) and the acidic C5–H

from the imidazolium moiety (Δδ = 0.063 ppm). Slightly

larger variations were observed for the signals of C7–H and

the chiral proton, the proton at the stereogenic carbon (Δδ

= –0.107 and 0.171 ppm, respectively). The data in CDCl₃

are consistent with a situation in which the low polarity of

the solvent favors a very strong association of the ion pair

in which the hydrogen bonding between the anion and the

Figure 7. Observed chemical shift changes with changing concen-

tration for a number of signals in the ¹H NMR spectra of 7b in

CDCl₃(a) and CD₃CN (b). (C5–H square, amide N1–H black cir-

cle, C6–H white circle, C7–H triangle and C1–H star).

1

amide hydrogen is prevalent (as indicated by the very low addition induced significant downfield H NMR chemical

field observed for the signal corresponding to this hydrogen shift variations for all the protons, similar to those observed

atom, δϾ 9.3 ppm). This strong ion-pair interaction hinders when increasing the concentration of 7b. Thus, the observed

any additional intermolecular associations upon increasing concentration-dependence of the chemical shifts (Figure 7b)

the concentration.

On the contrary, when the experiments were carried out ation between the anion and the cation in the ion pair.

in CD₃CN the chemical shift variations observed with the When the experiments were carried out in CD₃OD, no

can be mainly assigned to the normal changes in the associ-

changes in concentration were much more significant (Fig- concentration dependence was observed for C5–H, C6–H

ure 7b). For example, when increasing the concentration of and C7–H signals. This polar and hydrogen bonding sol-

7b from 1 to 64 mm, very significant variations in the shifts vent can clearly compete with cation-anion interactions and

for the signals of the amide N–H (Δδ = –0.812 ppm) and is able to achieve complete solvation of the components of

the C1–H (Δδ = –0.519 ppm) were observed. Δδ values were the ion pair (see Supporting Information).

smaller for the aromatic protons of the imidazolium ring

The chemical shift variation with concentration for these

(Δδ_C5–H= –0.255 ppm and Δδ_C7–H= –0.1 ppm; Figure 7b). protons was also studied for 10b and, as expected for the

The higher polarity of this solvent seems to produce solvent lower coordinating ability of the anion, very small changes

separated ion pairs, particularly at lower concentrations. In were observed when experiments were carried out in

addition, the amide N–H seems to be involved to a larger CDCl₃. For example, when increasing the global concentra-

extent in the interaction with the anion. The Δδ values ob- tion of 10b from 4 to 60 mm in CDCl₃, the corresponding

served for higher concentrations, in particular for amide ¹H NMR spectra showed no variation for the signals of the

protons, could be ascribed either to a strengthening of the amide NH (Δδ = 0.0 ppm) and no significant shifts for the

ion pairs or to the increase in the formation of hydrogen- acidic C5–H from the imidazolium moiety (Δδ = 0.05 ppm)

bonded aggregates. In order to better understand this situa- and for the signals of C6–H and the chiral proton (Δδ =

tion, an additional experiment was carried out in which the 0.07 and 0.08 ppm, respectively). On the other hand, when

concentration of the iodide anion was increased by adding the studies were carried out in CD₃CN, again no ¹H chemi-

INBut₄to a diluted solution of 7b (10 mm in CD₃CN). This cal shift variations with concentration were observed for

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

5

Job/Unit: O20607

/KAP1

Date: 26-07-12 16:09:10

Pages: 15

B. Altava, S. V. Luis et al.

FULL PAPER

10b (Δδ = 0 ppm for C5–H, C1–H, C7–H and C6–H; see enting just an intermolecular H-bond interaction between

Supporting Information). Thus, with the substitution of the C5–H and the anion (see Figure 10). The first one should

–

iodide anion by the less coordinating NTf₂anion, no ad- be favored in the tighter ion pair, whereas the second one

ditional intermolecular interactions were observed in both would predominate at higher temperatures and dilutions,

CDCl₃and CD₃CN, besides the ion pair association.

being entropically more favorable. In general, downfield

The ¹H NMR spectra for 7b in CD₃CN, CD₃Cl and chemical shift variations were observed for the other aro-

CD₃OD under the same conditions (Figure 8), show a matic and aliphatic protons of 7b (see Supporting Infor-

broad dispersion of the chemical shifts for C5–H, NH, C7– mation).

H and C1–H signals is observed. The C5–H, C6–H, C7–H

and N1–H signals are shifted downfield as the polarity of

non-protic solvents decrease [see Figure 8(a) and (c)]. These

variations can be ascribed to the degree of intimate ion-

pair interactions between N1–H, C5–H, C6–H and C7–H

hydrogen atom with the anion. In the protic solvent

[CD₃OD, Figure 8(b)] the cation is completely solvated

through polar and hydrogen bonding interactions, therefore

chemical shifts for C5–H, C7–H and C6–H appear at higher

chemical shifts than in CD₃CN. Simultaneously, the less po-

lar non-protic solvent [CDCl₃, Figure 8(a)] produces larger

downfield shifts for most of the signals, in particular for

the hydrogen bonded N1–H signal. This is explained by the

formation of a very strong intimate ion pair in this poorly

solvating solvent. The important shift observed for the C1–

H chiral proton suggests the involvement of an important

conformational change that could locate this proton in two

very different environments.

Figure 9. Variation in δ values C5–H (square), N1–H (circle) pro-

ton signals of 7b at different temperatures in CD₃CN at 10 mm.

Figure 10. Proposed conformational equilibrium for the intermo-

lecular interactions of NH, C5–H and anion.

Overall, the structural data obtained by X-ray diffrac-

tion, ATR-FTIR and NMR spectroscopy, and computa-

tional calculations suggest the presence of very strongly

intermolecular associated cation–anion ion-pairs, which

correlates well with the observed physical (T_m) properties

of these ionic liquids. Apart from anion–cation interactions,

X-ray diffraction data for 7b shows the presence of C–H–

π and π–π interactions, which can also have an important

influence on the macroscopic properties.

Figure 8. Partial ¹H NMR spectra for 7b (10 mm) in CDCl₃(a),

CD₃OD (b) and CD₃CN (c).

1

Finally, the H NMR spectra for a 10 mm solution of 7b

at various temperatures were obtained in CD₃CN (Fig-

ure 9).^[31]Small chemical shift variations with temperature

for the amide NH and C5–H signals were observed. The

values obtained for Δδ/T were approximately –2.3 ppb for

CILS as Chiral Shift Agents

To explore the potential of the new chiral ionic liquids

the amide NH. This is indicative of an intramolecular asso- for chiral recognition, the prepared ionic liquids were tested

ciation phenomenon connected to the formation of a more as chiral shift agents (CSA) for racemic triethylamine

or less tightly bound ion pair. Nevertheless, whereas the NH (TEA) mandelate salt. Mandelic acid has important medici-

signal moves upfield, the C5–H signal moves downfield nal applications; owing to its bacteriostatic properties it is

when increasing the temperature. This can be explained by employed for the treatment of urinary tract infections, using

considering the formation of two major conformers, one of either its calcium or ammonium salts.^[32]The pure form of

them involving a hydrogen bonding interaction between the (R)-mandelic acid is also used as a precursor for the synthe-

NH and the C5–H with the anion and the second one pres- sis of cephalosporin and penicillin.^[33–35]

6

www.eurjoc.org

Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20607

/KAP1

Date: 26-07-12 16:09:10

Pages: 15

Synthesis of Chiral Room Temperature Ionic Liquids from Amino Acids

¹H NMR spectroscopy was used to investigate the chiral Table 2. Selected ¹H chemical shift nonequivalences of the racemic

mandelate TEA salt in the presence of imidazolium salts 10–12 by

recognition ability of compound 10b. For this purpose, dif-

ferent mixtures of the corresponding CIL and the TEA salt

NMR (500 MHz) in CDCl₃at 30 °C.

Entry CILs

l-aa

R¹

R²

ΔΔδ (ppm)^[a,b]

of the mandelate were examined. As shown in Figure 11,

upon addition of the imidazolium receptor, the signal of the

methyl proton of the mandelate was downfield shifted and

splits into two peaks due to the formation of two dia-

stereomeric complexes between the CIL and the enantio-

mers of the guest, which confirms that chiral recognition

has occurred. When binding 10b, chemical shift values of

the TEA salt of the (R)- and (S)-mandelic acid exhibit 0.309

and 0.313 ppm downfield shifts, respectively. These results

suggest a different chemical environment for the two

enantiomers of the mandelate TEA salt, and that host-guest

complexes instantaneously formed.

1

2

3

4

5

6

7

8

9

10e

10f

Phe

nBut

Bn

Me

0

nBut

Non

Bn

10g

10h

10a

10b

10c

10d

overlapped

0

Me

nBut

Non

Bn

0.016^[c]

0.026^[d]

0.020

Bn

10

11

12

13

11a

11b

11c

12a

Val

Leu

Bn

nBut

Non

nBut

0.020

0.007

0

nBut

Bn

0.022

[a] All samples were prepared by mixing 1 equiv. of racemic TEA

mandelate salt and 2 equiv. of the chiral host (0.01 m in CDCl₃) in

NMR tubes. [b] ¹H chemical shift nonequivalences of the methylic

protons of the TEA salt of mandelic acid. [c] Samples prepared by

mixing 1.5 equiv. of racemic TEA mandelate salt and 1 equiv. of

chiral host (0.01 m in CDCl₃) in NMR tubes. [d] Sample prepared

by mixing 1 equiv. of racemic TEA mandelate and 4 equiv. of chiral

host (0.01 m in CDCl₃) in an NMR tube.

significant downfield shift variation was observed for the

amide NH, the imidazolium C5–H and the chiral C1–H

proton signals (Δδ = 1.783, 0.632 and 0.576 ppm, respec-

tively). This indicates the formation of complexes involving

strong hydrogen bonding interactions between the TEA salt

of the mandelic acid and 10b with the participation of the

amide NH and C5–H protons. On the other hand, small

chemical shift variations were observed for the C6–H and

C7–H proton signals, moving upfield (Δδ = –0.073 and

Figure 11. Partial ¹H NMR spectra (CDCl₃, 500 MHz) of (a) TEA

salt of mandelic acid. (b) TEA salt of mandelic acid after the ad-

dition of 4 equiv. of 10b Showing the splitting of the signal corre-

sponding to the CαH group.

To evaluate the chiral discrimination abilities of the dif- –0.084 ppm), suggesting the interactions with anion involv-

ferent chiral imidazolium salts 10–12, we measured the cor- ing these protons are less significant (see Supporting Infor-

1

responding H NMR spectra for the 2:1 mixtures of the mation). Finally, the stoichiometries of the complexes were

corresponding imidazolium salt and the TEA salt of the investigated by the Job plot method.^[36]The Job plot for the

mandelic acid in CDCl₃. The results are summarized in complexation of 10b with the TEA salt of the (R)-mandelic

Table 2 in which the shifts of the methylic hydrogen atoms acid exhibits a maximum at 0.5 molar fraction of guest,

for the TEA salt of the mandelic acid are shown. Chemical indicating a 1:1 complexation (see Supporting Infor-

shift nonequivalences were observed in many cases. Chiral mation).

imidazolium salts derived from l-phenylalanine, l-valine

The clear observation of non-equivalent chemical shifts

and l-leucine with benzyl amide groups were the best CSAs, for the two enantiomers of mandelic acid in the presence of

1

with H chemical shift nonequivalences of 0.020 ppm for some of the CILs 10–12 prompted us to explore the enan-

the methylic proton. In all cases, for the CILs studied, when tiomeric discriminating ability for other α-chiral carboxylic

R¹does not have an aromatic moiety, ΔΔδ observed is 0, acids. For this study we selected as receptors 10b, 11a and

which means that the aromatic amide moiety has an impor- 12a because these were the best CSAs for mandelate. As

tant role in the recognition abilities of these compounds.

shown in Table 3, all assayed CILs showed chemical shift

In general, for the supramolecular complexes formed in nonequivalences for the TEA salt of p-methoxy mandelic

solution, after the addition of the mandelate TEA salt, the acid (Table 3, Entries 4–6) ranging from 0.016 to

amide NH and C5–H proton signals from the receptors 0.028 ppm. On the other hand, receptor 11a was the best

studied moved downfield (ΔδϾ 0), suggesting the interac- CSA for the enantiodiscrimination of some pharmacologi-

tion between the CILs and the TEA salt of the mandelic cally active propionic acids, such as ibuprofen (Table 3, En-

acid by formation of supramolecular complexes.

tries 1–3). Moreover, chemical shift nonequivalence was ob-

For example, after the addition of 1 equiv. of the (R)- served for the racemic TEA salt of N-CBz-Phe when CILs

madelate TEA salt to a 10 mm solution of 10b in CDCl₃, a 10b, 11a and 12a were used as CSAs (Table 3, Entries 7–9).

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

7

Job/Unit: O20607

/KAP1

Date: 26-07-12 16:09:10

Pages: 15

B. Altava, S. V. Luis et al.

FULL PAPER

1

150 °C followed by cooling from 150 to –70 °C, both at a rate of

5 °C/min. The melting temperatures were determined at the onset

of the transition. Decomposition temperatures were measured

using a TG-STDA, heating samples from 20 to 400 °C at a rate of

5 °C/min. The reactions under microwave conditions were carried

out using a CEM Discover System Microwave, model 908010, the

temperature control was carried out using a surface infrared sensor.

CCDC-867607 contains the supplementary crystallographic data

for this paper. These data can be obtained free of charge from The

Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/

data_request/cif.

Table 3. H chemical non-equivalencies (ΔΔδ) of racemic carboxyl-

ate TEA salts using CILs as CSAs [500 MHz, CD₃Cl/CD₃OD

(1%), 303 K].

Entry Carboxylate racemic

TEA salt

CILs l-aa R¹R²

ΔΔδ

(ppm)^[a]

1

2

3

10b Phe Bn nBut 0.0^[b]

11a Val Bn nBut 0.014^[b]

12a Leu Bn nBut 0.010^[b]

ibuprofen

4

5

6

10b Phe Bn nBut 0.016^[b]

11a Val Bn nBut 0.028^[b]

12a Leu Bn nBut 0.027^[b]

p-methoxy mandelic acid

N-CBz-Phe

General Procedure for the Synthesis of Imidazole Derivatives 4a, 4b,

5a, 5b, 6a: To a mixture of glyoxal (40% aq., 1 equiv.) and formal-

dehyde (37% aq., 5 equiv.), the corresponding α-amino amide

(1 equiv.) and ammonium acetate (1 equiv.) were dissolved pre-

viously in CH₃OH and added. The reaction mixture was stirred at

room temperature for 48 h. The solvent was evaporated under re-

duced pressure and the resulting crude residue was treated with

saturated Na₂CO₃solution, extracted with CH₂Cl₂(3ϫ), dried

with anhydrous MgSO₄, filtered, and concentrated. The product

was purified by using flash chromatography (MeOH/CH₂Cl₂, 1:10)

to yield the corresponding imidazole derivatives 4a, 4b, 5a, 5b, and

6a.

7

8

9

10b Phe Bn nBut 0.010^[c]

11a Val Bn nBut 0.008^[c]

12a Leu Bn nBut 0.009^[c]

[a] All samples were prepared by mixing 1 equiv. of the racemic

acid (0.01 m in CDCl₃) and 2 equivalents of the chiral host (0.01 m

in CDCl₃) in NMR tubes. [b] ¹H chemical shift nonequivalences of

the α-methyl signal of the guest. [c] ¹H chemical shift nonequiva-

lences of the CBz methyl signal of the guest.

Conclusions

In conclusion, we have designed and synthesized a new

family of chiral room temperature ionic liquids based on

imidazolium salts derived from natural amino acids. Dif-

ferent studies have established the influence of the nature

of the side chain as well as the presence of additional func-

tional groups in the final CILs on their intrinsic physical

properties. Some of those CILs have been efficient as CSAs

for the discrimination of racemic mandelate salt and other

(S)-N-Benzyl-2-(1H-imidazol-1-yl)-3-phenylpropanamide (4a): The

reaction between glyoxal, formaldehyde, ammonium acetate and N-

benzyl amide of l-Phe gave a yellow oil (2.98 g, 49%). M.p. 21 °C.

[α]²_D⁵= –42.3 (c = 0.01, CHCl ). IR (ATR): ν

= 3217, 3032,

˜

3

max

2931, 1670, 1554, 1496, 1226, 1076 cm^–1. ¹H NMR (500 MHz,

CDCl₃, 30 °C): δ = 7.34 (s, 1 H, Im-H), 7.32–7.18 (m, 6 H, Ar-H),

7.12–6.97 (m, 6 H, Ar-H), 6.10 (br., 1 H, N-H), 4.74 (t, J = 7.1 Hz,

1 H, C*-H), 4.42 (dd, J = 14.6, 5.4 Hz, 1 H, CH₂Ph), 4.35 (dd, J

= 14.6, 5.4 Hz, 1 H, CH₂Ph), 3.62 (dd, J = 14.0, 5.3 Hz, 1 H,

CH₂Ph), 3.19 (dd, J = 13.3, 9.8 Hz, 1 H, CH₂Ph) ppm. ¹³C NMR

(126 MHz, CDCl₃, 30 °C): δ = 168.3, 137.4, 136.9, 136.8, 136.1,

129.7, 128.8, 128.7, 127.6, 127.2, 117.9, 117.99, 62.89, 43.7,

39.3 ppm. MS (ESI⁺): m/z (%) = 306 (100) [M + H]⁺. C₁₉H₁₉N₃O

0.5H₂O (315.4): calcd. C 72.59, H 6.41, N 13.37; found C 72.2, H

6.6, N 13.0.

1

carboxylate salts by H NMR spectroscopy. The formation

of diastereomeric complexes is fast and quantitative, and

can be analyzed in situ in a 500 MHz NMR spectrometer.

Further studies towards the application of these chiral ionic

liquids as chiral solvents and as organocatalysts are in pro-

gress.

(S)-N-Butyl-2-(1H-imidazol-1-yl)-3-phenylpropanamide (4b): The

reaction between glyoxal, formaldehyde, ammonium acetate and N-

butyl amide of l-Phe gave a yellow oil (3.96 g, 84%). M. p. 8 °C.

Experimental Section

General Experimental Methods: All reagents were purchased from

commercial suppliers and used as received. Chiral α-amino amides

were synthesized as described previously^[17a]whereas all the N-pro-

tected amino acids were commercially available. The NMR spectro-

scopic experiments were carried out at 500 or 125 MHz for ¹H

and ¹³C NMR, respectively. The chemical shifts are reported using

trimethylsilane as the internal standard. For chiral shift experi-

ments, samples were prepared by mixing CSA with several carbox-

ylic acids salts in CDCl₃. FTIR spectra were acquired with a MIR-

acle single-reflection ATR diamond/ZnSe accessory. Melting points

were measured by using a differential scanning calorimeter (DSC).

The instrument was calibrated for temperature and heat flow with

zinc and indium reference samples. Samples were placed in a

40 mL, hermetically sealed aluminium pan with a pinhole in the

top. An empty aluminium pan was used as the reference. Samples

were exposed to a flowing N₂atmosphere. Before the DSC test,

each sample was dried at 60 °C in a vacuum oven for 12 h, and

was further dried in situ in the differential scanning calorimeter by

holding the sample at 100 °C for 60 min because the presence of

volatiles, especially water, can affect the melting temperatures.

Melting transition temperatures were determined by using multiple

cycles (typically three) involving heating the sample from –70 to

[α]²_D⁵= –45.8 (c = 0.01, CHCl ). IR (ATR): ν

= 3228, 3035,

˜

3

max

2931, 2870, 1662, 1554, 1500, 1454, 1226, 1080 cm^–1. ¹H NMR

(300 MHz, CDCl₃, 30 °C): δ = 7.36 (s, 1 H, Im-H), 7.32 (s, 1 H,

Ar-H), 7.30–7.15 (m, 3 H, Ar-H), 7.10–6.99 (m, 4 H, Ar-H and

Im-H), 6.09 (br., 1 H, N-H), 4.8 (dd, J = 8.8, 6.0 Hz, 1 H, C*-H),

3.64 (dd, J = 14.0, 5.5 Hz, 1 H, CH₂Ph), 3.33–3.17 (m, 3 H, CH₂Ph,

NHCH₂Pr), 1.48–1.39 (m,

2 H, NHCH₂CH₂Et), 1.34–1.20

(m, 2 H, NHCH₂CH₂CH₂CH₃), 0.92 (t, J = 7.2 Hz, 3 H,

NHCH₂CH₂CH₂CH₃) ppm. ¹³C NMR (126 MHz, CDCl₃, 30 °C):

δ = 168.3, 136.9, 136.2, 129.5, 128.8, 128.6, 127.1, 117.9, 62.8, 39.4,

39.3, 31.2, 19.9, 13.6 ppm. MS (ESI⁺): m/z (%) = 272 (100) [M +

H]⁺. C₁₆H₂₁N₃O H₂O (289.4): calcd. C 66.44, H 7.95, N 14.53;

found C 66.4, H 7.9, N 14.3.

(S)-N-Benzyl-2-(1H-imidazol-1-yl)-3-methylbutanamide (5a): The

reaction between glyoxal, formaldehyde, ammonium acetate and N-

benzyl amide of l-Val gave a yellow oil (0.99 g, 80%). M. p. 5 °C.

[α]²_D⁵= –14.7 (c = 0.01, CHCl ). IR (ATR): ν

= 3218, 3150,

˜

3

max

3061, 2967, 2877, 1669, 1560, 1496, 1337, 1189, 1126, 1064 cm^–1.

¹H NMR (500 MHz, CDCl₃, 30 °C): δ = 7.50 (s, 1 H, Im-H), 7.32–

7.27 (m, 3 H, Ar-H), 7.19 (d, J = 6.9 Hz, 2 H, Ar-H), 7.13 (s, 1 H,

Im-H), 7.03 (s, 1 H, Im-H), 6.60 (br., 1 H, NH), 4.47 (dd, J =

8

www.eurjoc.org

Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20607

/KAP1

Date: 26-07-12 16:09:10

Pages: 15

Synthesis of Chiral Room Temperature Ionic Liquids from Amino Acids

14.6, 5.5 Hz, 1 H, NHCH₂Ph), 4.36 (dd, J = 14.6, 5.1 Hz, 1 H, 1 H, C*-H), 4.48 (dd, J = 14.8, 6.5 Hz, 1 H, NHCH₂Ph), 4.26 (dd,

NHCH₂Ph), 4.11 (d, J = 9.3 Hz, 1 H, C*-H), 2.57–2.46 (m, 1 H,

J = 14.8, 5.3 Hz, 1 H, NHCH₂Ph), 3.84 (s, 3 H, CH₃), 3.50–3.44

CH), 1.00 (d, J = 6.5 Hz, 3 H, CH₃), 0.77 (d, J = 6.5 Hz, 3 H, (dd, J = 13.5, 7.1 Hz, 1 H, CH₂Ph), 3.26 (dd, J = 13.7, 9.3 Hz, 1

CH₃) ppm. ¹³C NMR (126 MHz, CDCl₃, 30 °C): δ = 168.4, 137.4, H, CH₂Ph) ppm. ¹³C NMR (126 MHz, CDCl₃, 30 °C): δ = 166.6,

137.0, 129.5, 128.8, 127.8, 127.7, 118.33, 67.9, 43.8, 31.4, 19.5,

137.1, 135.9, 133.8, 129.2, 129.0, 128.5, 127.7, 127.3, 122.3, 121.9,

18.6 ppm. MS (ESI⁺): m/z (%) = 258.0 (100) [M + H]⁺. C₁₅H₁₉N₃O 62.2, 43.4, 39.2, 36.7 ppm. MS (ESI⁺): 320.2 (100) [M⁺]. MS (ESI^–):

1.5H₂O (283.3): calcd. C 63.38, H 7.75, N 14.78; found C 63.1, H

7.9, N 14.4.

m/z (%) = 0 126.9 (100) [I^–]. C₂₀H₂₂IN₃O·0.6H₂O (458.1): calcd. C

52.43, H 5.10, N 9.17; found C 52.8, H 5.5, N 9.5.

1-[(1S)-1-(Benzylcarbamoyl)-2-phenylethyl]-3-butyl-1H-imidazol-3-

ium Iodide (7b): The reaction between 4a and butyl iodide (Method

A) gave an orange solid (1.06 g, 96%). M. p. 35 °C. [α]²_D⁵= –27.4

(S)-N-Butyl-2-(1H-imidazol-1-yl)-3-methylbutanamide (5b): The re-

action between glyoxal, formaldehyde, ammonium acetate and N-

butyl amide of l-Val gave a yellow oil (0.53 g, 30%). M. p. –23 °C.

[α]²_D⁵= +5.8 (c = 0.01, CHCl ). IR (ATR): ν_max= 3229, 3109, 3067,

(c = 0.01, CHCl ). IR (ATR): ν_max= 3225, 3054, 2956, 2871, 1693,

˜

3

˜

3

1543, 1455, 1160 cm^–1. ¹H NMR (500 MHz, CDCl₃, 30 °C): δ =

9.39 (s, 1 H, Im-H), 8.63 (br., 1 H, NH), 7.81 (s, 1 H, Im-H), 7.30–

7.20 (m, 10 H, Ar-H), 7.04 (s, 1 H, Im-H), 6.75 (dd, J = 9.3, 6.7 Hz,

1 H, C*-H), 4.50 (dd, J = 14.8, 6.5 Hz, 1 H, NHCH₂Ph), 4.29 (dd,

J = 14.8, 5.4 Hz, 1 H, NHCH₂Ph), 4.06–3.95 (m, 2 H,

CH₂CH₂CH₂CH₃), 3.48 (t, J = 10 Hz, 1 H, CH₂Ph), 3.25 (dd, J =

13.8, 10.0 Hz, 1 H, CH₂Ph), 1.77–1.67 (m, 2 H, CH₂CH₂Et), 1.21–

1.14 (m, 2 H, CH₂CH₂CH₂CH₃), 0.92 (t, J = 7.3 Hz, 3 H,

CH₂CH₂CH₂CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃, 30 °C): δ =

167.3, 137.8, 135.8, 134.6, 129.8, 129.6, 129.1, 128.3, 128.2, 127.9,

122.4, 121.7, 62.8, 50.6, 44.0, 39.9, 32.4, 19.8, 13.9 ppm. MS

(ESI⁺): 362.3 (100) [M⁺]. MS (ESI^–): m/z (%) = 126.9 (100) [I^–].

C₂₃H₂₈IN₃O. 0.4H₂O (497.8): calcd. C 55.63, H 5.85, N 8.46; found

C 55.9, H 6.3, N 8.3.

2961, 2932, 2873, 1658, 1562, 1495, 1466, 1226 cm^–1. ¹H NMR

(300 MHz, CDCl₃, 30 °C): δ = 7.55 (s, 1 H, Im-H), 7.13 (s, 1 H,

Im-H), 7.07 (s, 1 H, Im-H), 6.02 (br., 1 H, NH), 4.06 (d, J = 9.2 Hz,

1 H, C*-H), 3.35–3.10 (m, 2 H, NHCH₂Pr), 2.60–2.45 (m, 1 H,

CH), 1.53–1.39 (m, 2 H, NHCH₂CH₂Et), 1.37–1.20 (m, 2 H,

NHCH₂CH₂CH₂CH₃), 1.00 (d, J = 6.4 Hz, 3 H, CH₃), 0.89 (t, J

= 7.1 Hz, 3 H, NHCH₂CH₂CH₂CH₃), 0.79 (d, J = 6.4 Hz, 3 H,

CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃, 30 °C): δ = 168.8, 136.7,

128.6, 118.7, 67.7, 39.4, 31.4, 31.2, 20.0, 19.4, 18.6, 13.6 ppm. MS

(ESI⁺): m/z (%) = 224.2 (100) [M + H]⁺. C₁₂H₂₁N₃O·0.4H₂O

(230.5): calcd. C 62.40, H 9.67, N 18.48; found C 62.8, H 9.4, N

18.1.

(S)-N-Benzyl-2-(1H-imidazol-1-yl)-4-methylpentanamide (6a): The

reaction between glyoxal, formaldehyde, ammonium acetate and N-

benzyl amide of l-Leu gave a yellow solid (0.63 g, 18%). M. p.

1-[(1S)-1-(Benzylcarbamoyl)-2-phenylethyl]-3-nonyl-1H-imidazol-3-

ium Bromide (7c): The reaction between 4a and nonyl bromide

98 °C. [α]²_D⁵= –9.0 (c = 0.01, CHCl ). IR (ATR): ν_max= 3256, 3063,

˜

3

(Method A) gave a white solid (0.26 g, 82%). M. p. 24 °C. [α]²_D⁵

=

2955, 2869, 1676, 1556, 1498, 1453, 1224, 1078 cm^–1. ¹H NMR

(300 MHz, CDCl₃, 30 °C): δ = 7.54 (s, 1 H, Im-H), 7.34–7.25 (m,

3 H, Ar-H), 7.16 (d, J = 7.2 Hz, 2 H, Ar-H), 7.11 (s, 1 H, Im-H),

7.01 (s, 1 H, Im-H), 5.93 (br., 1 H, NH), 4.70 (dd, J = 10.6, 4.8 Hz,

1 H, C*-H), 4.39 (d, J = 5.7 Hz, 2 H, NHCH₂Ph), 2.2–1.9 (m, 2

H, CH₂), 1.32–1.46 (m, 1 H, CH), 0.93 (d, J= 1.2 Hz, 3 H, CH₃),

0.91 (d, J= 1.4 Hz, 3 H, CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃,

30 °C): δ = 169.4, 137.5, 136.9, 129.8, 128.7, 127.6, 127.6, 117.8,

59.6, 43.6, 40.9, 24.5, 22.8, 21.4 ppm. MS (ESI⁺): m/z (%) = 272.2

(100) [M + H]⁺. C₁₆H₂₁N₃O·0.5H₂O (280.4): C 68.57, H 7.86, N

15.00; found C 68.5, H 8.2, N 14.7.

–34.1(c = 0.01, CHCl ). IR (ATR): ν

= 3202, 3061, 2923, 2854,

˜

3

max

1

1681, 1550, 1454, 1173 cm^–1. H NMR (300 MHz, CDCl₃, 30 °C):

δ = 9.54 (s, 1 H, Im-H), 9.23 (br., 1 H, NH), 7.83 (s, 1 H, Im-H),

7.31 (s, 2 H, Ar-H), 7.28–7.20 (m, 8 H, Ar-H), 7.09 (s, 1 H, Im-H),

6.82 (t, J = 7.8 Hz, 1 H, C*-H), 4.55 (dd, J = 14.9, 6.2 Hz, 1 H,

NHCH₂Ph), 4.31 (dd, J = 14.9, 4.6 Hz, 1 H, NHCH₂Ph), 4.10–

3.95 [m, 2 H, CH₂(CH₂)₇CH₃], 3.51 (dd, J = 14.0, 6.3 Hz, 1 H,

CH₂Ph), 3.36–3.18 (m, 1 H, CH₂Ph), 1.80–1.71 [m, 2 H,

CH₂CH₂(CH₂)₆CH₃], 1.30 [br., 10 H, CH₂CH₂(CH₂)₅CH₂CH₃],

1.25–1.15 [m, 2 H, (CH₂)₇CH₂CH₃], 0.93 [t, 3 H, (CH₂)₈CH₃] ppm.

¹³C NMR (126 MHz, CDCl₃, 30 °C): δ = 166.7, 135.9, 134.1, 132.8,

129.0, 129.0, 128.5, 127.7, 127.5, 127.2, 121.3, 120.7, 62.0, 50.3,

43.5, 38.8, 31.7, 29.9, 29.1, 29.1, 28.8, 26.0, 22.6, 14.0 ppm. MS

(ESI⁺): 432.3 (100) [M⁺]. MS (ESI^–): m/z (%) = 78.9 (100) [Br^–].

C₂₈H₃₈BrN₃O. 0.5H₂O (522.5): calcd. C 64.61, H 7.50, N 8.08;

found C 64.9, H 7.1, N 8.2.

General Procedure for the Synthesis of Imidazolium Salts 7a–h, 8a–

c, 9a

Method A: A mixture of the imidazole derivative (1 equiv.) and the

corresponding alkyl halide (5 equiv.) in CH₃CN was stirred for 48 h

at 60 °C. The solvent was evaporated under reduced pressure and

the resulting gummy product washed with hexane/diethyl ether

(2:1). The corresponding imidazolium halide salts 7a–c, 7e–h, 8a–

c were obtained following liquid-liquid extraction.

3-Benzyl-1-[(1S)-1-(benzylcarbamoyl)-2-phenylethyl]-1H-imidazol-3-

ium Chloride (7d): The reaction between 4a and benzyl chloride

(Method B) gave an orange solid (0.38 g, 86%). M. p. 61 °C. [α]²_D⁵

= –3.6 (c = 0.01, CHCl ). IR (ATR): ν_max= 3366, 3186, 3031, 1681,

˜

3

1555, 1455, 1154 cm^–1. ¹H NMR (300 MHz, CDCl₃, 30 °C): δ =

9.73 (s, 2 H, Im-H, NH), 7.73 (s, 1 H, Im-H), 7.45–7.19 (m, 13 H,

Ar-H), 7.03 (d, J = 6.9 Hz, 2 H, Ar-H), 6.93 (s, 1 H, Im-H), 6.77–

6.70 (m, 1 H, C*-H), 5.20 (d, J = 14.6 Hz, 1 H, CH₂Ph), 5.13 (d,

J = 14.6 Hz, 1 H, CH₂Ph), 4.49 (dd, J = 14.9, 6.3 Hz, 1 H,

NHCH₂Ph), 4.28 (dd, J = 14.7, 5.1 Hz, 1 H, NHCH₂Ph), 3.49 (dd,

J = 14.2, 5.6 Hz, 1 H, CH₂Ph), 3.24 (dd, J = 13.5, 10.5, Hz 1 H,

CH₂Ph) ppm. ¹³C NMR (126 MHz, CDCl₃, 30 °C): δ = 166.9,

137.6, 136.6, 134.3, 132.0, 129.7, 129.6, 129.1, 128.9, 128.4, 128.1,

127.6, 127.4, 127.1, 121.7, 120.8, 62.3, 53.5, 43.5, 38.7 ppm. MS

(ESI⁺): m/z (%) = 396.2 (100) [M⁺]. C₂₆H₂₆ClN₃O. H₂O (450.0):

calcd. C 69.40, H 6.27, N 9.34; found C 69.8, H 6.2, N 9.0.

Method B: The corresponding imidazole derivative (1 equiv.) and

an excess of alkyl halide (10 equiv.) were stirred in a microwave

(potency = 120 W; pressure = 250 psi; T = 150 °C) during 30 min.

After reaction a mixture of hexane/diethyl ether was added, to al-

low deposition of the product, which was filtered off and washed

with additional hexane/diethyl ether to obtain the corresponding

imidazolium halide salts 7d and 9a.

1-[(1S)-1-(Benzylcarbamoyl)-2-phenylethyl]-3-methyl-1H-imidazol-

3-ium Iodide (7a): The reaction between 4a and methyl iodide

(Method A) gave a yellow solid (0.33 g, 95%). M. p. 51 °C. [α]²_D⁵

=

–13.9 (c = 0.01, CHCl ). IR (ATR): ν_max= 3217, 3060, 2925, 2860,

˜

3

1681, 1549, 1454, 1161 cm^–1. H NMR (500 MHz, CDCl₃, 30 °C):

1

δ = 9.53 (s, 1 H, Im-H), 8.54 (br., 1 H, NH), 7.82 (s, 1 H, Im-H),

1-[(1S)-1-(Butylcarbamoyl)-2-phenylethyl]-3-methyl-1H-imidazol-

7.16–7.30 (m, 10 H, Ar-H), 7.06 (s, 1 H, Im-H), 6.74 (t, J = 7.9 Hz, 3-ium Iodide (7e): The reaction between 4b and methyl iodide

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

9

Job/Unit: O20607

/KAP1

Date: 26-07-12 16:09:10

Pages: 15

B. Altava, S. V. Luis et al.

(%) = 362.3 (100) [M⁺]. C₂₃H₂₈ClN₃O·0.5H₂O (407.0): calcd. C

FULL PAPER

(Method A) gave a brown solid (1.03 g, 92%). M. p. 32 °C. [α]²_D⁵

=

–16.2 (c = 0.01, CHCl ). IR (ATR): ν_max= 3248, 3063, 2956, 1675, 67.79, H 7.13, N 10.33; found C 67.7, H 7.1, N 10.2.

˜

3

1549, 1455, 1160 cm^–1. 1H NMR (300 MHz, CDCl₃, 30 °C): δ =

1-[(1S)-1-(Benzylcarbamoyl)-2-methylpropyl]-3-butyl-1H-imidazol-

9.42 (s, 1 H, Im-H), 8.01 (br., 1 H, NH), 7.82 (s, 1 H, Im-H), 7.27–

3-ium Iodide (8a): The reaction between 5a and butyl iodide

7.12 (m, 5 H, Ar-H), 7.19 (s, 1 H, Im-H), 6.56 (t, J = 8.0 Hz, 1 H,

(Method A) gave a brown oil (0.22 g, 74%). M. p. 17 °C. [α]²_D⁵

=

C*-H), 3.88 (s, 3 H, CH₃), 3.50–3.05 (m, 4 H, CH₂Ph,NHCH₂Pr),

1.50–1.36 (m, 2 H, NHCH₂CH₂Et), 1.30–1.15 (m, 2 H,

N H C H ₂C H ₂C H ₂C H ₃) , 0 . 8 4 ( t , J = 7 . 2 H z , 3 H ,

NHCH₂CH₂CH₂CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃, 30 °C): δ

= 166.4, 135.8, 133.9, 129.2, 129.0, 127.7, 122.3, 122.0, 62.2, 39.6,

39.2, 36.8, 30.8, 20.1, 13.6 ppm. MS (ESI⁺): 286.2 (100) [M⁺]. MS

(ESI^–): m/z (%) = 126.9 (100) [I^–]. C₁₇H₂₄IN₃O (413.3): calcd C

49.40, H 5.85, N 10.17; found C 49.8, H 6.2, N 10.0.

–18.7 (c = 0.01, CHCl ). IR (ATR): ν_max= 3221, 3061, 2963, 2934,

˜

3

2873, 1681, 1549, 1459, 1160 cm^–1. ¹H NMR (500 MHz, CDCl₃,

30 °C): δ = 9.70 (s, 1 H, Im-H), 8.65 (br., 1 H, NH), 7.83 (s, 1 H,

Im-H), 7.38–7.18 (m, 6 H, Ar-H, Im-H), 5.91 (d, J = 10.3 Hz, 1 H,

C*H), 4.52 (dd, J = 14.8, 6.5 Hz, 1 H, NHCH₂Ph), 4.28 (dd, J =

14.8, 5.4 Hz, 1 H, NHCH₂Ph), 4.20 (t, J = 7.3 Hz, 2 H, CH₂Pr),

2.52–2.40 (m, 1 H, CH), 1.91–1.86 (m, 2 H, CH₂CH₂Et), 1.40–1.37

(m, 2 H, CH₂CH₂CH₂CH₃), 1.05 (d, J = 6.5 Hz, 3 H, CH₃), 0.97

(t, J = 7.3 Hz, 3 H, CH₂CH₂CH₂CH₃), 0.82 (d, J = 6.6 Hz, 3 H,

CH₃) ppm. ¹³C NMR (126 MHz, CDCl₃, 30 °C): δ = 167.1, 137.4,

135.1, 128.5, 127.9, 127.3, 122.1, 121.3, 67.4, 50.2, 43.5, 31.9, 31.9,

19.4, 18.7, 18.3, 13.3 ppm. MS (ESI⁺): m/z = 314.0 (100) [M⁺]. MS

(ESI^–): m/z (%) = 127.0 (100) [I^–]. C₁₉H₂₈IN₃O (441.4): calcd. C

51.71, H 6.39, N 9.52; found C 52.1, H 6.6, N 9.7.

3-Butyl-1-[(1S)-1-(butylcarbamoyl)-2-phenylethyl]-1H-imidazol-3-

ium Iodide (7f): The reaction between 4b and butyl iodide (Method

A) gave an orange oil (0.61 g, 84%). M. p. 18 °C. [α]²_D⁵= –54.4 (c

= 0.01, CHCl ). IR (ATR): ν

= 3288, 3062, 2958, 2871, 1675,

˜

3

max

1549, 1456, 1158 cm^–1. ¹H NMR (300 MHz, CDCl₃, 30 °C): δ =

9.28 (s, 1 H, Im-H), 8.13 (br., 1 H, NH), 7.80 (s, 1 H, Im-H), 7.30–

7.1 (m, 6 H, Ar-H, Im-H), 6.57 (t, J = 9.6 Hz, 1 H, C*-H), 4.07 (t,

J = 6.9 Hz, 2 H, CH₂Pr), 3.48 (dd, J = 14.0, 6.1 Hz, 1 H, CH₂Ph),

3.31–3.07 (m, 3 H, CH₂Ph, NHCH₂Pr), 1.72 (m, J = 14.8, 7.3 Hz,

2 H, CH₂CH₂Et), 1.57–1.39 (m, 2 H, NHCH₂CH₂Et), 1.37–1.05

(m, 4 H, CH₂CH₂CH₂CH₃, NHCH₂CH₂CH₂CH₃), 0.97–0.80 (m,

6 H, CH₂CH₂CH₂CH₃, NHCH₂CH₂CH₂CH₃) ppm. ¹³C NMR

(126 MHz, CDCl₃, 30 °C): δ = 166.5, 134.9, 134.1, 129.1, 128.9,

127.5, 121.8, 121.5, 62.3, 50.0, 39.6, 39.3, 31.8, 30.8, 20.0, 19.2,

13.6, 13.3 ppm. MS (ESI⁺): m/z (%) = 328.2 (100) [M⁺]. MS (ESI^–):

m/z (%) = 126.9 (100) [I^–]. C₂₀H₃₀IN₃O (455.4): calcd. C 52.75, H

6.64, N 9.23; found C 53.3, H 6.3, N 9.24.

3-Butyl-1-[(1S)-1-(butylcarbamoyl)-2-methylpropyl]-1H-imidazol-

3-ium Iodide (8b): The reaction between 5b and butyl chloride

(Method A) gave a yellow oil (0.53, g, 98%). M. p. –2 °C. [α]²_D⁵

=

+3.6 (c = 0.01, CHCl ). IR (ATR): ν

= 3233, 3065, 2959, 2932,

˜

3

max

2873, 1671, 1548, 1463, 1157 cm^–1. ¹H NMR (300 MHz, CDCl₃,

30 °C): δ = (ppm): 9.70 (s, 1 H, Im-H), 8.08 (br., 1 H, NH), 7.85

(s, 1 H, Im-H), 7.32 (s, 1 H, Im-H), 5.89 (d, J = 10.3 Hz, 1 H, C*-

H), 4.23 (t, J = 7.2 Hz, 2 H, CH₂Pr), 3.38–3.23 (m, 1 H,

NHCH₂Pr), 3.22–3.07 (m, 1 H, NHCH₂Pr), 2.56–2.39 (m, 1 H,

CH), 1.99–1.85 (m, 2 H, CH₂CH₂Et), 1.58–1.51 (m, 2 H,

NHCH₂CH₂Et), 1.42–1.30 (m, 4 H, CH₂CH₂CH₂CH₃,

NHCH₂CH₂CH₂CH₃), 1.10 (d, J = 6.3 Hz, 3 H, CH₃), 0.98 (t, J

= 7.3 Hz, 3 H, CH₂CH₂CH₂CH₃), 0.88 (t, J = 7.4 Hz, 3 H,

NHCH₂CH₂CH₂CH₃), 0.83 (d, J = 6.5 Hz, 3 H, CH₃) ppm. ¹³C

NMR (126 MHz, CDCl₃, 30 °C): δ = 166.9, 134.6, 122.1, 121.9,

67.6, 50.2, 39.4, 31.9, 31.8, 30.8, 20.0, 19.3, 18.7, 18.3, 13.5,

13.3 ppm. MS (ESI⁺): 280.2 (100) [M⁺]. MS (ESI^–): m/z (%) =

127.1 (100) [I^–]. C₁₆H₃₀IN₃O (407.3): calcd. C 47.18, H 7.42, N

10.32; found C 47.6, H 7,8, N 10.2.

3-Benzyl-1-[(1S)-1-(butylcarbamoyl)-2-phenylethyl]-1H-imidazol-3-

ium Chloride (7g): The reaction between 4b and benzyl chloride

(Method A) gave a brown solid (0.84 g, 67.9%). M. p. 48 °C. [α]²_D⁵

= –48.2 (c = 0.01, CHCl ). IR (ATR): ν

= 3215, 3031, 2959,

˜

3

max

1

1673, 1556, 1456, 1155 cm^–1. H NMR (300 MHz, CDCl₃, 30 °C):

δ = 9.66 (s, 1 H, Im-H), 9.14 (br., 1 H, NH), 7.75 (s, 1 H, Im-H),

7.50–7.30 (m, 3 H, Ar-H), 7.21 (s, 5 H, Ar-H), 7.02 (d, J = 6.4 Hz,

2 H, Ar-H), 6.93 (s, 1 H, Im-H), 6.69 (dd, J = 10.1, 6.1 Hz, 1 H,

C*-H), 5.16 (d, J = 14.7 Hz, 1 H, CH₂Ph), 5.11 (d, J = 14.7 Hz, 1

H, CH₂Ph), 3.47 (dd, J = 14.4, 6.0 Hz, 1 H, CH₂Ph), 3.31–3.13 (m,

3 H, CH₂Ph, NHCH₂Pr), 1.54–1.46 (m, 2 H, NHCH₂CH₂Et),

1.33–1.26 (m, 2 H, NHCH₂CH₂CH₂CH₃), 0.87 (t, J = 7.2 Hz, 3 H,

NHCH₂CH₂CH₂CH₃) ppm. ¹³C NMR (126 MHz, CDCl₃, 30 °C):

δ = 166.6, 136.6, 134.4, 132.0, 129.7, 129.6, 129.0, 1289, 128.1,

127.4, 121.6, 120.8, 62.4, 39.6, 38.9, 30.9, 29.7, 20.1, 13.6 ppm. MS

(ESI⁺): m/z (%) = 362.2 (100) [M⁺]. C₂₃H₂₈ClN₃O·0.5H₂O (407.0):

calcd. C 67.90, H 7.13, N 10.33; found C 67.8, H 7.2, N 10.4.

1-[(1S)-1-(Butylcarbamoyl)-2-methylpropyl]-3-nonyl-1H-imidazol-

3-ium Bromide (8c): The reaction between 5b and nonyl bromide

(Method A) gave a brown oil (0.37 g, 88%). M. p. –8 °C. [α]²_D⁵

=

–4.4 (c = 0.01, CHCl ). IR (ATR): ν

= 3221, 3064, 2958, 2926,

˜

3

max

2856, 1672, 1551, 1465, 1158 cm^–1. ¹H NMR (300 MHz, CDCl₃,

30 °C): δ = 9.85 (s, 1 H, Im-H), 8.62 (br., 1 H, NH), 7.81 (s, 1 H,

Im-H), 7.21 (s, 1 H, Im-H), 5.83 (d, J = 10.7 Hz, 1 H, C*-H), 4.18

[t, J = 7.4 Hz, 2 H, CH₂(CH₂)₇CH₃], 3.37–3.24 (m, 1 H,

NHCH₂Pr), 3.17–3.05 (m, 1 H, NHCH₂Pr), 2.51–2.39 (m, 1 H,

CH), 2.00–1.90 [m, 2 H, CH₂CH₂(CH₂)₆CH₃], 1.64–1.49 (m, 2 H,

NHCH₂CH₂Et), 1.37–1.24 [m, 14 H, NHCH₂CH₂CH₂CH₃,

CH₂CH₂(CH₂)₆CH₃], 1.09 (d, J = 6.5 Hz, 3 H, CH₃), 0.9–0.84 [m,

6 H, (CH₂)₈CH₃, NHCH₂CH₂CH₂CH₃], 0.80 (d, J = 6.6 Hz, 3 H,

CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃, 30 °C): δ = 167.3, 136.0,

122.0, 121.2, 67.8, 50.6, 39.8, 31.9, 31.5, 31.2, 30.2, 29.4, 29.3, 29.0,

26.4, 22.8, 20.4, 19.0, 18.5, 14.2, 13.9 ppm. MS (ESI⁺): 350.3 (100)

[M⁺]. MS (ESI^–): m/z (%) = 79 (100) [Br^–]. C₂₁H₄₀BrN₃O. 0.8H₂O

(445.3): calcd. C 56.7, H 9.43, N 9.45; found C 56.7, H 9.3, N 9.6.

1-[(1S)-1-(Benzylcarbamoyl)-2-phenylethyl]-3-butyl-1H-imidazol-3-

ium Chloride (7h): The reaction between 4a and butyl chloride

(Method A) gave a yellow solid (0.05 g, 40%). M. p. 43 °C. [α]²_D⁵

=

–38.8 (c = 0.01, CHCl ). IR (ATR): ν_max= 3181, 3094, 3054, 2969,

˜

3

1680, 1558, 1452, 1297, 1173 cm^–1. ¹H NMR (500 MHz, CDCl₃,

30 °C): δ = 9.66 (br., 1 H, NH), 9.58 (s, 1 H, Im-H), 7.75 (s, 1 H,

Im-H), 7.24–7.17 (m, 10 H, Ar-H), 7.02 (s, 1 H, Im-H), 6.7–6.77

(m, 1 H, C*-H), 4.51 (dd, J = 14.2, 6.3 Hz, 1 H, NHCH₂Ph), 4.28

(dd, J = 14.3, 4.9 Hz, 1 H, NHCH₂Ph), 4.01 (m, 2 H, CH₂Pr), 3.49

(dd, J = 14.1, 6.0 Hz, 1 H, CH₂Ph), 3.25 (dd, J = 13.9, 10.3 Hz, 1

1-[(1S)-1-(Benzylcarbamoyl)-3-methylbutyl]-3-butyl-1H-imidazol-

H, CH₂Ph), 1.75 (s, 2 H, CH₂CH₂Et), 1.20–1.16 (m, 2 H, 3-ium Iodide (9a): The reaction between 6a and butyl iodide

CH₂CH₂CH₂CH₃), 0.94 (d, J = 6.6 Hz, 3 H, CH₂CH₂- (Method B) gave a brown oil (0.56 g, 98%). M. p. 17 °C. [α]²_D⁵

=

CH₂CH₃) ppm. ¹³C NMR (126 MHz, CDCl₃, 30 °C): δ = 166.9,

137.6, 136.4, 134.3, 129.1, 128.9, 128.5, 127.6, 127.5, 127.1, 121.5,

121.0, 62.3, 50.0, 43.5, 38.8, 31.8, 19.2, 13.3 ppm. MS (ESI⁺): m/z

–12.6 (c = 0.01, CHCl ). IR (ATR): ν_max= 3214, 3127, 3057, 2871,

˜

3

1

1679, 1547, 1455, 1160 cm^–1. H NMR (500 MHz, CDCl₃, 30 °C):

δ = 9.78 (s, 1 H, Im-H), 8.67 (br., 1 H, NH), 7.80 (s, 1 H, Im-H),

10

www.eurjoc.org

Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20607

/KAP1

Date: 26-07-12 16:09:10

Pages: 15

Synthesis of Chiral Room Temperature Ionic Liquids from Amino Acids

7.34–7.20 (m, 6 H, Ar-H, Im-H), 6.33 (t, J = 7.6 Hz, 1 H, C*-H),

4.49 (dd, J = 14.8, 6.4 Hz, 1 H, NHCH₂Ph), 4.29 (dd, J = 14.8,

H), 5.58–5.43 (m, 1 H, C*H), 4.48 (dd, J = 14.6, 6.3 Hz, 1 H,

NHCH₂Ph), 4.27 (dd, J = 14.7, 5.2 Hz, 1 H, NHCH₂Ph), 4.08–

5.5 Hz, 1 H, NHCH₂Ph), 4.18 [t, J = 7.3 Hz, 2 H, CH₂(CH₂)₂CH₃], 3.86 [m, 2 H, CH₂(CH₂)₇CH₃], 3.43 (dd, J = 13.8, 6.2 Hz, 1 H,

2 . 1 2 – 2 . 0 4 ( m , 1 H , C H ₂) , 1 . 9 2 – 1 . 8 0 ( m , 3 H , C H ₂, CH₂Ph), 3.22 (dd, J = 13.7, 9.5 Hz, 1 H, CH₂Ph), 1.75–1.65 [m, 2

CH₂CH₂CH₂CH₃), 1.46–1.32 (m, 3 H, CH, CH₂CH₂CH₂CH₃), H, CH₂CH₂(CH₂)₆CH₃], 1.26 [br., 10 H, CH₂CH₂(CH₂)₅CH₂CH₃],

0.99–0.95 (m, 9 H, CH₃, CH₂CH₂CH₂CH₃) ppm. ¹³C NMR 1.19–1.11 [m, 2 H, (CH₂)₇CH₂CH₃], 0.89 [t, J = 6.6 Hz, 3 H,

(75 MHz, CDCl₃, 30 °C): δ = 167.3, 137.4, 134.9, 128.5, 127.9, (CH₂)₈CH₃] ppm. ¹³C NMR (126 MHz, CDCl₃, 30 °C): δ = 166.3,

127.3, 121.8, 121.2, 60.2, 50.3, 43.5, 41.5, 31.8, 24.9, 22.6, 22.6,

19.5, 13.4 ppm. MS (ESI⁺): 328.1 (100) [M⁺]. . MS (ESI^–): m/z (%)

= 127.1 (100) [I^–]. C₂₀H₃₀IN₃O·0.8H₂O (469.8): calcd. C 51.13, H

6.78, N 8.94; found C 50.9, H 6.3, N 8.5.

136.8, 135.34, 133.5, 129.1, 128.8, 128.6, 127.9, 127.6, 127.5, 121.8,

121.3, 119.7 (CF₃), 63.3, 50.3, 43.9, 40.1, 31.7, 29.9, 29.1, 29.1,

28.7, 25.9, 22.6, 14.0 ppm. MS (ESI⁺): 432.3 [M⁺, 100]. MS (ESI^–):

–

m/z (%) = 280.0 (100) [NTf₂]. C₃₀H₃₈F₆N₄O₅S₂(712.76): calcd. C

50.55, H 5.37, N 7.86; found C 50.6, H 5.7, N 7.9.

General Procedure for the Synthesis of Imidazolium Salts 10a–h,

11a–c, 12a: A solution of lithium bis(trifluoromethane) sulfonimide

(1.1 equiv.) in MeOH was added to a solution of the corresponding

halide salt (1 equiv.) in MeOH, and the resulting mixture stirred

for 48 h. The solvent was then evaporated at reduced pressure, fur-

ther H₂O added, and the mixture extracted with CH₂Cl₂

(3 ϫ 20 mL). The organic phases were combined, dried with

MgSO₄, and the solvent evaporated under reduced pressure to af-

ford the corresponding imidazole salt 10a–h, 11a–c and 12a.

3-Benzyl-1-[(1S)-1-(benzylcarbamoyl)-2-phenylethyl]-1H-imidazol-3-

ium Triflamide. (10d): The reaction between 7d and bis(trifluoro-

methane) sulfonamide gave a yellow oil (0.49 g, 71%). M. p. 2 °C.

[α]²_D⁵= –26.0 (c = 0.01, CHCl ). IR (ATR): ν

= 3375, 3146,

˜

3

max

2934, 1683, 1549, 1456, 1348, 1185, 1132, 1054 cm^{–1 1}H NMR

.

(500 MHz, CDCl₃, 30 °C): δ = 8.69 (s, 1 H, Im-H), 7.80 (s, 1 H,

Im-H), 7.49 (br., 1 H, NH), 7.46–7.00 (m, 16 H, Ar-H, Im-H), 5.49

(dd, J = 9.0, 6.8 Hz, 1 H, C*H), 5.17 (d, J = 14.6 Hz, 1 H, CH₂Ph),

5.11 (d, J = 14.6 Hz, 1 H, CH₂Ph), 4.48 (dd, J = 14.7, 6.3 Hz, 1

H, NHCH₂Ph), 4.27 (dd, J = 14.7, 5.2 Hz, 1 H, NHCH₂Ph), 3.41

(dd, J = 13.6, 6.0 Hz, 1 H, CH₂Ph), 3.19 (dd, J = 13.8, 9.6 Hz, 1

H, CH₂Ph) ppm. ¹³C NMR (126 MHz, CDCl₃, 30 °C): δ = 166.2,

136.8, 135.3, 133.5, 131.7, 129.9, 129.7, 129.1, 128.8, 128.6, 128.4,

127.8, 127.6, 127.5, 122.0, 121.4, 119.7 (CF₃), 63.4, 53.7, 43.8,

40.1 ppm. MS (ESI⁺): 396.2 [M⁺, 100]. MS (ESI^–): m/z (%) = 280.0

1-[(1S)-1-(Benzylcarbamoyl)-2-phenylethyl]-3-methyl-1H-imidazol-

3-ium Triflamide (10a): The reaction between 7a and bis(trifluoro-

methane) sulfonamide gave a yellow oil (0.36 g, 90%). M. p. –1 °C.

[α]²_D⁵= –6.6 (c = 0.01, CHCl ). IR (ATR): ν_max= 3375, 3153, 2932,

˜

3

1684, 1551, 1456, 1348, 1182, 1133, 1053 cm^–1

.

¹H NMR

(300 MHz, CDCl₃, 30 °C): δ = 8.69 (s, 1 H, Im-H), 7.74 (s, 1 H,

Im-H), 7.36 (br., 1 H, NH), 7.33–7.20 (m, 6 H, Ar-H), 7.17 (s, 1

H, Im-H), 7.12–7.02 (m, 2 H, Ar-H), 5.45 (t, J = 7.6 Hz, 1 H, C*-

H), 4.47 (dd, J = 14.8, 6.4 Hz, 1 H, NHCH₂Ph), 4.24 (dd, J = 14.8,

5.1 Hz, 1 H, NHCH₂Ph), 3.83 (s, 3 H, CH₃), 3.44 (dd, J = 13.8,

7.1 Hz, 1 H, CH₂Ph), 3.24 (dd, J = 13.6, 8.5 Hz, 1 H, CH₂Ph) ppm.

¹³C NMR (126 MHz, CDCl₃, 30 °C): δ = 166.19, 136.78, 135.74,

133.5, 129.1, 128.9, 128.6, 127.9, 127.5, 127.5, 122.8, 122.0, 119.7

(CF₃), 63.5, 43.8, 40.0, 36.4 ppm. MS (ESI⁺): 320.2 (100) [M⁺]. MS

–

(100) [NTf₂]. C₂₈H₂₆F₆N₄O₅S₂·0.5H₂O (685.7): calcd. C 49.05, H

3.97, N 8.17; found C 49.4, H 4.3, N 8.3.

1-[(1S)-1-(Butylcarbamoyl)-2-phenylethyl]-3-methyl-1H-imidazol-

3-ium Triflamide. (10e): The reaction between 7e and bis(trifluoro-

methane) sulfonamide gave a brown oil (1.12 g, 84%). M. p. –16 °C.

[α]²_D⁵= –5.6 (c = 0.01, CHCl ). IR (ATR): ν_max= 3378, 3152, 2962,

˜

3

2875, 1681, 1551, 1457, 1183, 1133, 1054 cm^–1

.

¹H NMR

–

(ESI^–): m/z (%) = 280.0 (100) [NTf₂]. C₂₂H₂₂F₆N₄O₅S₂(600.5):

(500 MHz, CDCl₃, 30 °C): δ = 8.65 (s, ¹H: Im-H), 7.69 (s, 1 H, Im-

H), 7.30–7.10 (m, 6 H, Ar-H, Im-H), 6.87 (br., 1 H, NH), 5.31 (t,

J = 7.7 Hz, 1 H, C*H), 3.83 (s, 3 H, CH₃), 3.39 (m, J = 13.0,

7.7 Hz, 1 H, CH₂Ph), 3.22 (m, J = 13.5, 7.7 Hz, 2 H, NHCH₂Pr),

3.12–3.02 (m, 1 H, CH₂Ph), 1.35 (m, J = 14.1, 7.0 Hz, 2 H,

N H C H ₂C H ₂E t ) , 1 . 1 8 ( m , J = 1 4 . 4 , 7 . 0 H z , 2 H ,

N H C H ₂C H ₂C H ₂C H ₃) , 0 . 8 3 ( t , J = 7 . 2 H z , 3 H ,

NHCH₂CH₂CH₂CH₃) ppm. ¹³C NMR (126 MHz, CDCl₃, 30 °C):

δ = 166.1, 135.6, 133.6, 129.0, 129.0, 127.9, 122.9, 122.0, 119.7

(CF₃), 63.6, 40.0, 39.7, 36.4, 30.7, 19.7, 13.5 ppm. MS (ESI⁺): 286.2

[M⁺, 100]. MS (ESI^–): m/z (%) = 280.1 (100) [NTf₂^–].

C₁₉H₂₄F₆N₄O₅S₂(566.53): calcd. C 39.96, H 4.32, N 9.81; found

C 40.4, H 4.9, N 9.6.

calcd. C 44.00, H 3.69, N 9.33; found C 44.3, H 3.4, N 9.2.

1-[(1S)-1-(Benzylcarbamoyl)-2-phenylethyl]-3-butyl-1H-imidazol-3-

ium Triflamide (10b): The reaction between 7b and bis(trifluoro-

methane) sulfonamide gave a yellow oil (0.1 g, 75%). M. p. –12 °C.

[α]²_D⁵= –16.2 (c = 0.01, CHCl ). IR (ATR): ν

= 3375, 3147,

˜

3

max

2964, 2877, 1682, 1550, 1456, 1348, 1185, 1133, 1054 cm^{–1 1}H

.

NMR (300 MHz, CDCl₃, 30 °C): δ = 8.62 (s, 1 H, Im-H), 7.83 (s,

1 H, Im-H), 7.49 (br., 1 H, NH), 7.30–7.05 (m, 11 H, Ar-H, Im-

H), 5.58–5.39 (m, 1 H, C*H), 4.48 (dd, J = 14.7, 6.2 Hz, 1 H,

NHCH₂Ph), 4.28 (dd, J = 14.7, 5.1 Hz, 1 H, NHCH₂Ph), 4.10–

3.92 (m, 2 H, CH₂CH₂CH₂CH₃), 3.43 (dd, J = 13.7, 6.3 Hz, 1 H,

CH₂Ph), 3.21 (dd, J = 13.4, 9.8 Hz, 1 H, CH₂Ph), 1.74–1.65 (m, J

= 14.4, 7.1 Hz, 2 H, CH₂CH₂Et), 1.19–1.12 (m, J = 14.6, 7.2 Hz,

2 H , C H ₂C H ₂C H ₂C H ₃) , 0 . 9 1 ( t , J = 7 . 2 H z , 3 H ,

CH₂CH₂CH₂CH₃) ppm. ¹³C NMR (126 MHz, CDCl₃, 30 °C): δ =

166.3, 136.8, 135.3, 133.5, 129.1, 128.8, 128.6, 127.8, 127.6, 127.5,

121.8, 121.4, 119.7 (CF₃), 63.3, 50.0, 43.9, 40.1, 31.7, 19.1,

13.1 ppm. MS (ESI⁺): 362.3 (100) [M⁺]. MS (ESI^–): m/z (%) =

3-Butyl-1-[(1S)-1-(butylcarbamoyl)-2-phenylethyl]-1H-imidazol-3-

ium Triflamide (10f): The reaction between 7f and bis(trifluoro-

methane) sulfonamide gave a brown oil (0.45 g, 77%). M. p. –23 °C.

[α]²_D⁵= –18.2 (c = 0.01, CHCl ). IR (ATR): ν

= 3379, 3147,

˜

3

max

2962, 2875, 1678, 1550, 1457, 1348, 1185, 1133, 1055 cm^{–1 1}H

.

NMR (500 MHz, CDCl₃, 30 °C): δ = 8.58 (s, 1 H, Im-H), 7.78 (s,

1 H, Im-H), 7.37–7.10 (m, 6 H, Ar-H, Im-H), 7.02 (br., 1 H, NH),

5.37 (t, J = 9.2 Hz, 1 H, C*H), 4.06 (t, J = 7.1 Hz, 2 H, CH₂Pr),

3.47–3.38 (m, 1 H, CH₂Ph), 3.33–3.10 (m, 3 H, CH₂Ph,

NHCH₂Pr), 1.72 (m, J = 14.5, 7.2 Hz, 2 H, CH₂CH₂Et), 1.44 (m,

J = 14.1, 7.0 Hz, 2 H, NHCH₂CH₂Et), 1.31–1.12 (m, 4 H,

CH₂CH₂CH₂CH₃, NHCH₂CH₂CH₂CH₃), 0.95–0.85 (m, 6 H,

CH₂CH₂CH₂CH₃, NHCH₂CH₂CH₂CH₃) ppm. ¹³C NMR

–

280.1 (100) [NTf₂]. C₂₅H₂₈F₆N₄O₅S₂(642.63): calcd. C 46.72, H

4.39, N 8.72; found C 47.1, H 4.8, N 8.4.

1-[(1S)-1-(Benzylcarbamoyl)-2-phenylethyl]-3-nonyl-1H-imidazol-3-

ium Triflamide (10c): The reaction between 7c and bis(trifluoro-

methane) sulfonamide gave a yellow oil (0.24 g, 79 %). M. p.

–20 °C. [α]²_D⁵= –16.7 (c = 0.01, CHCl ). IR (ATR): ν

= 3373,

˜

3

max

3147, 2928, 2857, 1683, 1550, 1456, 1348, 1187, 1133, 1055 cm^–1.

¹H NMR (500 MHz, CDCl₃, 30 °C): δ = 8.62 (s, 1 H, Im-H), 7.82 (126 MHz, CDCl₃, 30 °C): δ = 166.2, 135.3, 133.7, 129.0, 128.8,

(s, 1 H, Im-H), 7.5 (s, 1 H, NH), 7.32–7.04 (m, 11 H, Ar-H, Im- 127.8, 121.8, 121.4, 119.7 (CF₃), 63.4, 50.0, 40.1, 39.7, 31.7, 30.7,

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

11

Job/Unit: O20607

/KAP1

Date: 26-07-12 16:09:10

Pages: 15

B. Altava, S. V. Luis et al.

FULL PAPER

19.8, 19.1, 13.5, 13.1 ppm. MS (ESI⁺): 328 (100) [M⁺]. MS (ESI^–):

m/z (%) = 280.1 (100) [NTf₂]. C₂₂H₃₀F₆N₄O₅S₂(608.61): calcd. C

43.42, H 4.97, N 9.21; found C 43.8, H 5.2, N 9.2.

methane) sulfonamide gave a yellow oil (0.1 g, 70%). M. p. –49 °C.

–

[α]²_D⁵= +6.6 (c = 0.01, CHCl ). IR (ATR): ν_max= 3382, 3146, 2929,

˜

3

2877, 1678, 1550, 1468, 1349, 1185, 1054 cm^–1

.

¹H NMR

(300 MHz, CDCl₃, 30 °C): δ = 8.95 (s, 1 H, Im-H), 7.77 (s, 1 H,

Im-H), 7.26 (s, 1 H, Im-H), 7.13 (t, J = 5.2 Hz, 1 H, NH), 4.72 (d,

J = 10.3 Hz, 1 H, C*H), 4.18 [t, J = 7.4 Hz, 2 H, CH₂(CH₂)₇CH₃],

3.3 (m, J = 13.3 Hz, 7 MHz, 1 H, NHCH₂Pr), 3.15 (m, J = 12.9 Hz,

7 MHz, 1 H, NHCH₂Pr), 2.47–2.28 (m, 1 H, CH), 1.92–1.84 [m, 2

H , C H ₂C H ₂( C H ₂) ₆C H ₃] , 1 . 5 0 ( m , J = 1 4 . 9 H z , 2 H ,

NHCH₂CH₂Et), 1.20–1.4 [m, 14 H, NHCH₂CH₂CH₂CH₃,

CH₂CH₂(CH₂)₆CH₃], 1.08 (d, J = 6.6 Hz, 3 H, CH₃), 0.83–0.95 [m,

6 H, (CH₂)₈CH₃, NHCH₂CH₂CH₂CH₃], 0.79 (d, J = 6.7 Hz, 3 H,

CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃, 30 °C): δ = 166.8, 135.5,

122.4, 122.1, 120.0 (CF₃), 68.9, 50.7, 39.9, 32.5, 31.9, 31.0, 30.2,

29.4, 29.2, 29.0, 26.3, 22.8, 20.1, 18.8, 18.3, 14.2, 13.7 ppm. MS

3-Benzyl-1-[(1S)-1-(butylcarbamoyl)-2-phenylethyl]-1H-imidazol-3-

ium Triflamide (10g): The reaction between 7g and bis(trifluoro-

methane) sulfonamide gave a brown oil (1.02 g, 83%). M. p. –9 °C.

[α]²_D⁵= –21.6 (c = 0.01, CHCl ). IR (ATR): ν

= 3378, 3144,

˜

3

max

2961, 2875, 1678, 1550, 1456, 1348, 1185, 1133, 1054 cm^{–1 1}H

.

NMR (500 MHz, CDCl₃, 30 °C): δ = 8.66 (s, 1 H, Im-H), 7.78 (s,

1 H, Im-H), 7.43–7.38 (m, 3 H, Ar-H), 7.25–7.21 (m, 3 H, Ar-H),

7.15–7.04 (m, 5 H, Ar-H, Im-H), 7.02 (br., 1 H, NH), 5.39 (dd, J

= 9.0, 6.6 Hz, 1 H, C*H), 5.18 (d, J = 14.6 Hz, 1 H, CH₂Ph), 5.13

(d, J = 14.6 Hz, 1 H, CH₂Ph), 3.39 (dd, J = 14.0, 6.5 Hz, 1 H,

CH₂Ph), 3.28–3.11 (m, 3 H, CH₂Ph, NHCH₂Pr), 1.40 (m, J = 14.3,

7.2 Hz, 2 H, NHCH₂CH₂Et), 1.23 (m, J = 15.0, 7.4 Hz, 2 H,

N H C H ₂C H ₂C H ₂C H ₃) , 0 . 8 6 ( t , J = 7 . 3 H z , 3 H ,

NHCH₂CH₂CH₂CH₃) ppm. ¹³C NMR (126 MHz, CDCl₃, 30 °C):

δ = 166.1, 135.3, 133.6, 131.7, 129.9, 129.6, 129.0, 128.8, 128.4,

127.8, 122.0, 121.4, 119.7 (CF₃), 63.5, 53.7, 39.7, 30.7, 19.8,

13.5 ppm. MS (ESI⁺): 362.2 (100) [M⁺]. MS (ESI^–): m/z (%) =

(ESI⁺): 350.3 [M⁺, 100]. MS (ESI^–): m/z (%) = 279.9 (100) [NTf₂].

–

C₂₃H₄₀F₆N₄O₅S₂(630.70): calcd. C 43.80, H 6.39, N 8.88; found

C 44.1, H 6.8, N 9.0.

1-[(1S)-1-(Benzylcarbamoyl)-3-methylbutyl]-3-butyl-1H-imidazol-

3-ium Triflamide (12a): The reaction between 9a and bis(trifluoro-

methane) sulfonamide gave a brown oil (0.12 g, 76%). M. p. –19 °C.

–

280.1 (100) [NTf₂]. C₂₅H₂₈F₆N₄O₅S₂(642.63): calcd. C 46.72, H

[α]²_D⁵= –5.0 (c = 0.01, CHCl ). IR (ATR): ν_max= 3372, 3145, 3077,

4.39, N 8.72; found C 47.0, H 4.4, N 8.5.

˜

3

2962, 2876, 1681, 1548, 1459, 1346, 1185, 1136, 1054 cm^{–1 1}H

.

1-[(1S)-1-(Benzylcarbamoyl)-2-methylpropyl]-3-butyl-1H-imidazol-

3-ium Triflamide (11a): The reaction between 8a and bis(trifluoro-

methane) sulfonamide gave a brown oil (0.25 g, 76%). M. p. –20 °C.

NMR (500 MHz, CDCl₃, 30 °C): δ = 9.07 (s, 1 H, Im-H), 7.74 (s,

1 H, Im-H), 7.66 (br., 1 H, NH), 7.34–7.23 (m, 5 H, Ar-H), 7.21

(s, 1 H, Im-H), 5.34 (t, J = 7.6 Hz, 1 H, C*H), 4.48 (dd, J = 14.7,

6.1 Hz, 1 H, NHCH₂Ph), 4.30 (dd, J = 14.7, 5.2 Hz, 1 H,

NHCH₂Ph), 4.17 [t, J = 7.3 Hz, 2 H, CH₂(CH₂)₂CH₃], 2.06–1.96

(m, J = 14.0, 7.1 Hz, 1 H, CH₂), 1.91–1.80 (m, 3 H, CH₂,

CH₂CH₂CH₂CH₃), 1.42–1.29 (m, 3 H, CH₂, CH₂CH₂CH₂CH₃),

0.99–0.92 (m, 9 H, CH₃, CH₂CH₂CH₂CH₃) ppm. ¹³C NMR

(126 MHz, CDCl₃, 30 °C): δ = 167.0, 137.1, 135.1, 128.6, 127.7,

127.5, 121.8, 121.5, 119.7 (CF₃), 61.0, 50.2, 43.9, 42.2, 31.8, 24.8,

22.1, 21.9, 19.3, 13.2 ppm. MS (ESI⁺): 328.1 [M⁺, 100]. MS (ESI^–):

[α]²_D⁵= +3.3 (c = 0.01, CHCl ). IR (ATR): ν_max= 3378, 3146, 2967,

˜

3

2878, 1684, 1551, 1468, 1353, 1196, 1058 cm^–1

.

¹H NMR

(300 MHz, CDCl₃, 30 °C): δ = 8.99 (s, 1 H, Im-H), 7.80 (s, 1 H,

Im-H), 7.62 (br., 1 H, NH), 7.35–7.20 (m, 6 H, Ar-H, Im-H), 4.79

(d, J = 10.2 Hz, 1 H, C*H), 4.50 (dd, J = 14.6, 6.1 Hz, 1 H,

NHCH₂Ph), 4.30 (dd, J = 14.6, 5.2 Hz, 1 H, NHCH₂Ph), 4.17 (t,

J = 7.2 Hz, 2 H, CH₂Pr), 2.45–2.31 (m, 1 H, CH), 1.86 (m, J =

14.5, 7.2 Hz, 2 H, CH₂CH₂Et), 1.33 (m, J = 14.3, 7.3 Hz, 2 H,

CH₂CH₂CH₂CH₃), 1.06–0.94 (m, 6 H, CH₃, CH₂CH₂CH₂CH₃),

0.78 (d, J = 6.5 Hz, 3 H, CH₃) ppm. ¹³C NMR (126 MHz, CDCl₃,

30 °C): δ = 166.7, 137.0, 135.2, 128.6, 127.8, 127.6, 122.2, 121.5,

119.7 (CF₃), 68.5, 50.2, 43.9, 32.4, 31.8, 19.3, 18.5, 18.0, 13.1 ppm.

MS (ESI⁺): m/z (%) = 314.0 (100) [M⁺]. MS (ESI^–): m/z (%) =

–

m/z (%) = 280.1 (100) [NTf₂]. C₂₂H₃₀F₆N₄O₅S₂(608.61): calcd. C

43.42, H 4.97, N 9.21; found C 43.8, H 5.4, N 9.4.

Supporting Information (see footnote on the first page of this arti-

cle): ¹H and ¹³C NMR spectra of the prepared compounds. ¹D

ROESY spectra for 7b, gCOSY spectra for 11a, variation of ¹H

chemical shifts with concentration for 7b in CD₃OD, variation of

¹H chemical shifts with concentration for 10b in CDCl₃, partial

FTIR spectra for 7b at different temperatures, variation of ¹H

chemical shifts for 7b at different temperatures in CD₃CN, ¹H

NMR spectra for 10b after the addition of 1 equiv. of the TEA salt

of (R)-mandelic acid, Job-plot for the complexation of 10b with

the TEA salt of the (R)-mandelic acid and crystallographic data

for 7b.

–

280.0 (100) [NTf₂]. C₂₁H₂₈F₆N₄O₅S₂(594.58): calcd. C 41.66, H

4.86, N 9.25; found C 42.0, H 5.2, N 9.6.

3-Butyl-1-[(1S)-1-(butylcarbamoyl)-2-methylpropyl]-1H-imidazol-

3-ium Triflamide (11b): The reaction between 8b and bis(trifluoro-

methane) sulfonamide gave a yellow oil (0.1 g, 72%). M. p. –45 °C.

[α]²_D⁵= +8.8 (c = 0.01, CHCl ). IR (ATR): ν_max= 3381, 3145, 2965,

˜

3

2936, 2877, 1677, 1551, 1469, 1348, 1133, 1053 cm^{–1 1}H NMR

.

(300 MHz, CDCl₃, 30 °C): δ = 8.98 (s, 1 H, Im-H), 7.80 (s, 1 H,

Im-H), 7.26 (s, 1 H, Im-H), 7.15 (s, 1 H, NH), 4.71 (d, J = 10.3 Hz,

1 H, C*H), 4.18 (t, J = 7.3 Hz, 2 H, CH₂Pr), 3.30 (m, J = 13.2,

6.6 Hz, 1 H, NHCH₂Pr), 3.15 (m, J = 12.8, 6.7 Hz, ¹H NHCH₂Pr),

2.43–2.27 (m, 1 H, CH), 1.88 (m, J = 14.9, 7.4 Hz, 2 H,

CH₂CH₂Et), 1.49 (m, J = 14.4, 7.1 Hz, 2 H, NHCH₂CH₂Et), 1.41–

1.27 (m, 4 H, NHCH₂CH₂CH₂CH₃, CH₂CH₂CH₂CH₃), 1.07 (d, J

= 6.5 Hz, 3 H, CH₃), 0.98 (t, J = 7.3 Hz, 3 H, CH₂CH₂CH₂CH₃),

0.90 (t, J = 7.2 Hz, 3 H, NHCH₂CH₂CH₂CH₃), 0.79 (d, J = 6.6 Hz,

3 H, CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃, 30 °C): δ = 166.8,

135.5, 122.4, 122.1, 120.0 (CF₃), 68.9, 50.4, 39.9, 32.5, 32.1, 31.0,

20.1, 19.6, 18.8, 18.3, 13.7, 13.4 ppm. MS (ESI⁺): m/z (%) = 280.2

(100) [M⁺]. MS (ESI^–): m/z (%) = 280.1 (100) [NTf₂^–].

C₁₈H₃₀F₆N₄O₅S₂(560.57): calcd. C 38.57, H 5.39, N 9.99; found

C 39.0, H 5.7, N 9.6.

Acknowledgments

This work was supported by the Spanish Ministerio de Ciencia e

Innovación (CTQ2008–04412; CTQ2011–28903-C02–01) and Fun-

dació Caixa Castelló-UJI (project P1–1B-2009–58 and P1–1A-

2007–09). L. G. thanks the Fundació Caixa Castelló-UJI for per-

sonal financial support. The authors are grateful to the Servicio

Central de Instrumentación Científica (SCIC) of the Universitat

Jaume I for the spectroscopic facilities. The authors thank V. Martí-

Centelles for the computational studies.

[1] a) M. Petkovic, K. R. Seddon, L. P. N. Rebelo, C. Silva Pereira,

Chem. Soc. Rev. 2011, 40, 1383–1403; b) A. Natrajan, D. Wen,

Green Chem. 2011, 13, 913–921; c) R. D. Rogers, K. R. Seddon

1-[(1S)-1-(Butylcarbamoyl)-2-methylpropyl]-3-nonyl-1H-imidazol-

3-ium Triflamide (11c): The reaction between 8c and bis(trifluoro-

12

www.eurjoc.org

Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20607

/KAP1

Date: 26-07-12 16:09:10

Pages: 15

Synthesis of Chiral Room Temperature Ionic Liquids from Amino Acids

(Eds.), Ionic Liquids as Green Solvents, Vol. 856, American

Chemical Society, Washington D.C., 2003; d) K. R. S. R. D.

Rogers, ACS Symp. Ser. 2003, 856, 620; e) J. Dupont, R. F.

Armstrong, Chirality 2005, 17, 281–292; l) B. Ni, A. D. Head-

ley, Chem. Eur. J. 2010, 16, 4426–4436; m) T. Payagala, D. W.

Armstrong, Chirality 2012, 24, 17–53.

de Souza, P. A. Z. Suarez, Chem. Rev. 2002, 102, 3667–3692; f)

T. Welton, Chem. Rev. 1999, 99, 2071–2084; g) P. Wasserscheid,

W. Keim, Angew. Chem. 2000, 112, 3926; Angew. Chem. Int.

Ed. 2000, 39, 3772–3789; h) K. Fukumoto, H. Ohno, Angew.

Chem. 2007, 119, 1884; Angew. Chem. Int. Ed. 2007, 46, 1852–

1855; i) J. P. Hallett, T. Welton, Chem. Rev. 2011, 111, 3508–

3576; j) V. I. Pârvulescu, C. Hardacre, Chem. Rev. 2007, 107,

2615–2665.

[12]

[13]

S. T. Handy, Chem. Eur. J. 2003, 9, 2938–2944.

a) A. Winkel, R. Wilhelm, Tetrahedron: Asymmetry 2009, 20,

2344–2350; b) V. Kumar, C. E. Olsen, S. J. C. Schäffer, V. S.

Parmar, S. V. Malhotra, Org. Lett. 2007, 9, 3905–3908; c) Y.

Ishida, H. Miyauchi, K. Saigo, Chem. Commun. 2002, 2240–

2241; d) M. L. Patil, C. V. L. Rao, S. Takizawa, K. Takenaka,

K. Onitsuka, H. Sasai, Tetrahedron 2007, 63, 12702–12711; e)

H. Clavier, L. Boulanger, N. Audic, L. Toupet, M. Mauduit,

J.-C. Guillemin, Chem. Commun. 2004, 1224–1225; f) A. Win-

kel, R. Wilhelm, Eur. J. Org. Chem. 2010, 5817–5824.

a) L. Zhang, S. Luo, X. Mi, S. Liu, Y. Qiao, H. Xu, J.-P. Cheng,

Org. Biomol. Chem. 2008, 6, 567–576; b) J. Baudoux, P. Jud-

einstein, D. Cahard, J.-C. Plaquevent, Tetrahedron Lett. 2005,

46, 1137–1140; c) O. Nguyen Van Buu, A. Aupoix, G. Vo-

Thanh, Tetrahedron 2009, 65, 2260–2265.

N. Ríos-Lombardía, E. Busto, V. Gotor-Fernández, V. Gotor,

R. Porcar, E. García-Verdugo, S. V. Luis, I. Alfonso, S. García-

Granda, A. Menéndez-Velázquez, Chem. Eur. J. 2010, 16, 836–

847.

B. Altava, D. S. Barbosa, M. I. Burguete, J. Escorihuela, S. V.

Luis, Tetrahedron: Asymmetry 2009, 20, 999–1003.

a) J. Becerril, M. Bolte, M. I. Burguete, F. Galindo, E. García-

España, S. V. Luis, J. F. Miravet, J. Am. Chem. Soc. 2003, 125,

6677–6686; b) M. I. Burguete, M. Collado, J. Escorihuela, F.

Galindo, E. Garcıa-Verdugo, S. V. Luis, M. J. Vicent, Tetrahe-

dron Lett. 2003, 44, 6891–6894; c) M. I. Burguete, M. Collado,

J. Escorihuela, S. V. Luis, Angew. Chem. 2007, 119, 9160–9163;

Angew. Chem. Int. Ed. 2007, 46, 9002–9005.

W. Bao, Z. Wang, Y. Li, J. Org. Chem. 2002, 68, 591–593.

a) L. Leclercq, M. Simard, A. R. Schmitzer, J. Mol. Struct.

2009, 918, 101–107; b) L. Leclercq, A. R. Schmitzer, J. Phys.

Chem. A 2008, 112, 4996–5001; c) A. G. Avent, P. A. Chaloner,

M. P. Day, K. R. Seddon, T. Welton, J. Chem. Soc., Dalton

Trans. 1994, 3405–3413.

a) K. Fumino, A. Wulf, R. Ludwig, Angew. Chem. 2008, 120,

3890–3894; b) N. E. Heimer, R. E. Del Sesto, Z. Meng, J. S.

Wilkes, W. R. Carper, J. Mol. Liq. 2006, 124, 84–95; c) S. A.

Katsyuba, P. J. Dyson, E. E. Vandyukova, A. V. Chernova, A.

Vidisˇ, Helv. Chim. Acta 2004, 87, 2556–2565; d) R. C. Remsing,

J. L. Wildin, A. L. Rapp, G. Moyna, J. Phys. Chem. B 2007,

111, 11619–11621; e) J. Palomar, V. R. Ferro, M. A. Gilarranz,

J. J. Rodriguez, J. Phys. Chem. B 2006, 111, 168–180; f) S. H.

Chung, R. Lopato, S. G. Greenbaum, H. Shirota, E. W.

Castner, J. F. Wishart, J. Phys. Chem. B 2007, 111, 4885–4893;

g) D. Bankmann, R. Giernoth, Prog. Nucl. Magn. Reson. Spec-

trosc. 2007, 51, 63–90; h) J.-F. Huang, P.-Y. Chen, I. W. Sun,

S. P. Wang, Inorg. Chim. Acta 2001, 320, 7–11; i) K. Fumino,

A. Wulf, R. Ludwig, Angew. Chem. 2008, 120, 3890; Angew.

Chem. Int. Ed. 2008, 47, 3830–3834; j) O. Höfft, S. Bahr, V.

Kempter, Langmuir 2008, 24, 11562–11566; k) A. Yokozeki,

D. J. Kasprzak, M. B. Shiflett, Phys. Chem. Chem. Phys. 2007,

9, 5018–5026.

[2]

[3]

a) C. F. Poole, J. Chromatogr. A 2004, 1037, 49–82; b) I. Kross-

ing, J. M. Slattery, C. Daguenet, P. J. Dyson, A. Oleinikova, H.

Weingärtner, J. Am. Chem. Soc. 2006, 128, 13427–13434.

a) M. C. Buzzeo, R. G. Evans, R. G. Compton, ChemPhys-

Chem 2004, 5, 1106–1120; b) C. Wakai, A. Oleinikova, M. Ott,

H. Weingärtner, J. Phys. Chem. B 2005, 109, 17028–17030; c)

A. Beyaz, W. S. Oh, V. P. Reddy, Colloids Surf. B 2004, 35, 119–

124; d) R. F. de Souza, J. C. Padilha, R. S. Gonçalves, J. Du-

pont, Electrochem. Commun. 2003, 5, 728–731; e) S.

Zein El Abedin, F. Endres, ChemPhysChem 2006, 7, 58–61; f)

Q. Zhu, Y. Song, X. Zhu, X. Wang, J. Electroanal. Chem. 2007,

601, 229–236; g) E. Stathatos, P. Lianos, V. Jovanovski, B. Orel,

J. Photochem. Photobiol. A: Chem. 2005, 169, 57–61; h) E.

Markevich, V. Baranchugov, D. Aurbach, Electrochem. Com-

mun. 2006, 8, 1331–1334; i) R. F. de Souza, J. C. Padilha, R. S.

Gonçalves, J. Rault-Berthelot, Electrochem. Commun. 2006, 8,

[14]

[15]

[16]

[17]

´

211–216; j) A. Lewandowski, A. Swiderska, Appl. Phys. A

2006, 82, 579–584.

[4]

[5]

a) R. D. Rogers, G. A. Voth, Acc. Chem. Res. 2007, 40, 1077–

1078; b) J. S. Wilkes, J. Mol. Catal. A 2004, 214, 11–17.

a) B. Kirchner, Top. Curr. Chem. 2010, 290, 213–262; b) P. Was-

serscheid, Nature 2006, 439, 797–797; c) M. J. Earle, J. M. S. S.

Esperanca, M. A. Gilea, J. N. Canongia Lopes, L. P. N. Rebelo,

J. W. Magee, K. R. Seddon, J. A. Widegren, Nature 2006, 439,

831–834.

a) T. L. Greaves, C. J. Drummond, Chem. Rev. 2007, 108, 206–

237; b) T. Köddermann, C. Wertz, A. Heintz, R. Ludwig,

ChemPhysChem 2006, 7, 1944–1949; c) F. Endres, S.

Zein El Abedin, Phys. Chem. Chem. Phys. 2006, 8, 2101–2116;

d) J. Dupont, P. A. Z. Suarez, Phys. Chem. Chem. Phys. 2006,

8, 2441–2452; e) R. Lungwitz, S. Spange, New J. Chem. 2008,

32, 392–394.

[18]

[19]

[6]

[20]

[7]

[8]

J. Dupont, J. Braz. Chem. Soc. 2004, 15, 341–350.

J. G. Huddleston, A. E. Visser, W. M. Reichert, H. D. Willauer,

G. A. Broker, R. D. Rogers, Green Chem. 2001, 3, 156–164.

a) U. Preiss, S. P. Verevkin, T. Koslowski, I. Krossing, Chem.

Eur. J. 2011, 17, 6508–6517; b) J. D. Holbrey, K. R. Seddon, J.

Chem. Soc., Dalton Trans. 1999, 2133–2140; c) H. Shirota, T.

Mandai, H. Fukazawa, T. Kato, J. Chem. Eng. Data 2011, 56,

2453–2459; d) J. S. Wilkes, M. J. Zaworotko, J. Chem. Soc.,

Chem. Commun. 1992, 965–967; e) S. Aparicio, M. Atilhan, F.

Karadas, Ind. Eng. Chem. Res. 2010, 49, 9580–9595.

[9]

[10]

[11]

Y. Qiao, J. Hu, H. Li, L. Hua, Y. Hu, B. Feng, Z. Hou, J.

Electrochem. Soc. 2010, 157, F124–F129.

[21]

a) C. Baudequin, J. Baudoux, J. Levillain, D. Cahard, A.-C.

Gaumont, J.-C. Plaquevent, Tetrahedron: Asymmetry 2003, 14,

3081–3093; b) C. Baudequin, D. Brégeon, J. Levillain, F. Gu-

illen, J.-C. Plaquevent, A.-C. Gaumont, Tetrahedron: Asym-

metry 2005, 16, 3921–3945; c) H. Ohno, K. Fukumoto, Acc.

Chem. Res. 2007, 40, 1122–1129; d) X. Chen, X. Li, A. Hu, F.

Wang, Tetrahedron: Asymmetry 2008, 19, 1–14; e) A. Winkel,

P. V. G. Reddy, R. Wilhelm, Synthesis 2008, 999–1016; f) K.

Bica, P. Gaertner, Eur. J. Org. Chem. 2008, 3235–3250; g) S.

Luo, L. Zhang, J.-P. Cheng, Chem. Asian J. 2009, 4, 1184–1195;

h) S. L. De Rooy, M. Li, D. K. Bwambok, B. El-Zahab, S.

Challa, I. M. Warner, Chirality 2011, 23, 54–62; i) G. Imperato,

B. König, C. Chiappe, Eur. J. Org. Chem. 2007, 1049–1058;

j) J.-C. Plaquevent, J. Levillain, F. Guillen, C. Malhiac, A.-C.

Gaumont, Chem. Rev. 2008, 108, 5035–5060; k) J. Ding, D. W.

a) F. Neve, A. Crispini, CrystEngComm 2007, 9, 698–703; b)

N. K. Sharma, M. D. Tickell, J. L. Anderson, J. Kaar, V. Pino,

B. F. Wicker, D. W. Armstrong, J. J. H. Davis, A. J. Russell,

Chem. Commun. 2006, 646–648; c) Z. Fei, T. J. Geldbach, D.

Zhao, P. J. Dyson, Chem. Eur. J. 2006, 12, 2122–2130; d) J. Y. Z.

Chiou, J. N. Chen, J. S. Lei, I. J. B. Lin, J. Mater. Chem. 2006,

16, 2972–2977; e) D. Zhao, Z. Fei, R. Scopelliti, P. J. Dyson,

Inorg. Chem. 2004, 43, 2197–2205; f) L. C. Branco, J. N. Rosa,

J. J. Moura Ramos, C. A. M. Afonso, Chem. Eur. J. 2002, 8,

3671–3677; g) G. D. Smith, O. Borodin, L. Li, H. Kim, Q. Liu,

J. E. Bara, D. L. Gin, R. Nobel, Phys. Chem. Chem. Phys. 2008,

10, 6301–6312; h) Q. Zhang, Z. Li, J. Zhang, S. Zhang, L. Zhu,

J. Yang, X. Zhang, Y. Deng, J. Phys. Chem. B 2007, 111, 2864–

2872; i) Z. Fei, W. H. Ang, D. Zhao, R. Scopelliti, E. E. Zver-

eva, S. A. Katsyuba, P. J. Dyson, J. Phys. Chem. B 2007, 111,

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

13

Job/Unit: O20607

/KAP1

Date: 26-07-12 16:09:10

Pages: 15

B. Altava, S. V. Luis et al.

FULL PAPER

10095–10108; j) D. Zhao, Z. Fei, W. Han Ang, R. Scopelliti,

P. J. Dyson, Eur. J. Inorg. Chem. 2007, 279–284.

[22] T. Steiner, Angew. Chem. 2002, 114, 50–80; Angew. Chem. Int.

Ed. 2002, 41, 48–76.

[23] B. J. Deppmeier, A. J. Driessen, T. S. Hehre, W. J. Hehre, J. A.

Johnson, P. E. Klunzinger, J. M. Leonard, I. N. Pham, W. J. Pi-

etro, Y. Jianguo, Spartan ‘08, build 132 (Mar 27 2009), Wave-

function Inc., 2009.

[29]

[30]

a) S. Zahn, F. Uhlig, J. Thar, C. Spickermann, B. Kirchner,

Angew. Chem. 2008, 120, 3695–3697; Angew. Chem. Int. Ed.

2008, 47, 3639–3641; b) S. Tsuzuki, H. Tokuda, M. Mikami,

Phys. Chem. Chem. Phys. 2007, 9, 4780–4784; c) K. Dong, S.

Zhang, D. Wang, X. Yao, J. Phys. Chem. A 2006, 110, 9775–

9782.

a) P. S. Schulz, K. Schneiders, P. Wasserscheid, Tetrahedron:

Asymmetry 2009, 20, 2479–2481; b) H. Tokuda, S. Tsuzuki,

M. A. B. H. Susan, K. Hayamizu, M. Watanabe, J. Phys.

Chem. B 2006, 110, 19593–19600; c) A. Wulf, K. Fumino, D.

Michalik, R. Ludwig, ChemPhysChem 2007, 8, 2265–2269; d)

C. S. Consorti, P. A. Z. Suarez, R. F. de Souza, R. A. Burrow,

D. H. Farrar, A. J. Lough, W. Loh, L. H. M. da Silva, J. Du-

pont, J. Phys. Chem. B 2005, 109, 4341–4349; e) A. Mele, C. D.

Tran, S. H. De Paoli Lacerda, Angew. Chem. 2003, 115, 4500;

Angew. Chem. Int. Ed. 2003, 42, 4364–4366.

[24] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,

M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B.

Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li,

H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Son-

nenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hase-

gawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai,

T. Vreven, J. J. A. Montgomery, J. E. Peralta, F. Ogliaro, M.

Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Starov-

erov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell,

J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M.

Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Ad-

amo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev,

A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Mar-

tin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador,

J. J. Dannenberg, S. Dapprich, A. D. Daniels, O. Farkas, J. B.

Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian 09,

Revision B.01, Gaussian, Inc., 2009.

[25] E. R. Talaty, S. Raja, V. J. Storhaug, A. Dölle, W. R. Carper, J.

Phys. Chem. B 2004, 108, 13177–13184.

[26] K. Fumino, A. Wulf, R. Ludwig, Angew. Chem. 2008, 120,

8859–8862; Angew. Chem. Int. Ed. 2008, 47, 8731–8734.

[27] H. S. Schrekker, D. O. Silva, M. A. Gelesky, M. P. Stracke,

C. M. L. Schrekker, R. S. Gonçalves, J. Dupont, J. Braz. Chem.

Soc. 2008, 19, 426–433.

[31]

[32]

a) K. Gademann, B. Jaun, D. Seebach, R. Perozzo, L. Sca-

pozza, G. Folkers, Helv. Chim. Acta 1999, 82, 1–11; b) J. N. S.

Evans, Biomolecular NMR Spectroscopy, Oxford University

Press, Oxford, 1995.

E. N. Cook, H. A. Buchtel, J. Am. Med. Assoc. 1936, 107,

1799–1800.

[33] P. Saravanan, V. K. Singh, Tetrahedron Lett. 1998, 39, 167–170.

[34] S. K. Mills, K. K. Schmiegel, J. Shaw, US Patent, 4,391,826,

1983.

[35] P. Q. A. Furlemmeier, K. Vogler, P. Lanz, US Patent 3957758,

1976.

[36] a) V. M. S. Gil, N. C. Oliveira, J. Chem. Educ. 1990, 67, 473; b)

P. Job, Ann. Chim. Farm. 1928, 9, 113–203.

Received: May 9, 2012

Published Online: ᭿

[28] a) C. B. Fox, G. A. Myers, J. M. Harris, Appl. Spectrosc. 2007,

61, 465–469; b) C. B. Fox, R. H. Uibel, J. M. Harris, J. Phys.

Chem. B 2007, 111, 11428–11436.

14

www.eurjoc.org

Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20607

/KAP1

Date: 26-07-12 16:09:10

Pages: 15

Synthesis of Chiral Room Temperature Ionic Liquids from Amino Acids

Ionic Liquids

New chiral room temperature ionic liquids,

based on an imidazolium group and de-

rived from natural amino acids, have been

synthesized and studied as chiral shift

agents for the chiral discrimination of en-

antiomeric carboxylate salts.

L. González, B. Altava,* M. Bolte,

M. I. Burguete, E. García-Verdugo,

S. V. Luis* ....................................... 1–15

Synthesis of Chiral Room Temperature

Ionic Liquids from Amino Acids – Appli-

cation in Chiral Molecular Recognition

Keywords: Ionic liquids

/ Chiral shift

agents / Amino acids / Carboxylic acids /

Molecular recognition

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

15

Article Doi

Synthesis of chiral room temperature ionic liquids from amino acids - Application in chiral molecular recognition

DOI: 10.1002/ejoc.201200607

Source and publish data:

Authors:

Article abstract of DOI:10.1002/ejoc.201200607

Full text of DOI:10.1002/ejoc.201200607

Products guided by the article

R&D Labs maybe for 1404563-33-2

Relevant to this article

Hot Product