A remarkable chiral recognition of racemic Mosher's acid salt by naturally derived chiral ionic liquids using 19F NMR spectroscopy

Article abstract of DOI:10.1039/c6ra02792j

A new class of d-xylose derived imidazolium-based chiral ionic liquids were designed and synthesized via simple tuning approaches. The developed chiral ionic liquids were tested for their chiral recognition properties with racemic Mosher's acid salt using ¹⁹F NMR spectroscopy. For the first time, we demonstrate the excellent enantioselective discrimination of the racemic salt using significantly less equivalents of carbohydrate derived chiral ionic liquids. We have determined the enantiomeric excess values of non-racemic mixtures of Mosher's acid salts using ¹⁹F NMR spectroscopy.

Full text of DOI:10.1039/c6ra02792j

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: S. Rajasekhara
Reddy and J. C. Rayadurgam, RSC Adv., 2016, DOI: 10.1039/C6RA02792J.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Please do not adjust margins
RSC Advances
Page 1 of 5
View Article Online
DOI: 10.1039/C6RA02792J
Journal Name
COMMUNICATION
A remarkable chiral recognition of racemic mosher’s acid salt by
naturally derived chiral ionic liquids using 19F NMR
Received 00th January 20xx,
Accepted 00th January 20xx
R. Jayachandra and Sabbasani Rajasekhara Reddy*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A new class of D-xylose derived imidazolium-based chiral ionic
liquids were designed and synthesized by simple tuning
approaches. The developed chiral ionic liquids were tested for
their chiral recognition property using racemic Mosher’s acid salt
by 19F NMR.For the first time, we demonstrate the excellent
enantioselective discrimination of racemic salt using very less
equivalents of cabohydrate derived chiral ionic liquids.
Determined the enantiomeric excess values of non-racemic
mixtures of Mosher’s acid salt by 19F NMR.
OCH3
OCH3
O
N
OH
OMe
CF3
OMe
CF3
OMe
N
X
F3C
CH3
CD3CN or CDCl3
*
Ph
COO
Ph
COO
(R)
OOC
Ph
Racemic
(S)
X= I, PF6, Tf2N, OTf and BF4
Scheme 1:Chiral Recognition of Racemic Mosher’s Acid Salt using D-xylose
Derived CILs
In modern organic chemistry, ionic liquids (ILs) showed
significant applications due to their outstanding physical,
chemical properties and they also displayed considerable
effect on reaction kinetics, specificity, recyclability and catalyst
recovery.1 Among the variety of ILs reported, chiral ionic
liquids(CILs) are of special interest, because of their ability to
influence the stereo chemical outcome of the reaction by
acting as either chiral solvent or chiral catalyst.2 CILs have
showed good applications in asymmetric synthesis,3
chromatography4 and stereoselective polymerization.5 Based
on the available literature, majority of the CILs were derived
from natural amino acids, because they provide the essential
source for chirality.6 Some of the CILs known for their chiral
recognition ability and they were used as NMR chiral shift
reagents for the discrimination of racemates.7 Malhotra and
co-workers were synthesized bis(ammonium) based CILs
derived from isomannide that showed good chiral recognition
of racemic Mosher’s acid salt.8
application in Michael addition reaction, where they were
used as recyclable chiral solvents as well as chiral catalysts.10
Further the hydrophobic D-galactose based IL was utilized for
the effective removal of Pb2+ ions from aqueous solution.11 In
continuation of our effort to synthesize some of the CCILs and
to study their applications in asymmetric transformations,
herein we report the synthesis of new imidazolium containing
D-xylose derived CILs. The synthesized CCILs were studied for
their chiral recognition property using racemic Mosher’s acid
salt (Scheme 1).
The synthetic route for the CCILs presented in this work is a
straightforward protocol starting from naturally originated D-
xylose which is cheap and readily available (Scheme 2). The
synthesis of D-xylose based CIL began with acid catalyzed
protection of D-xylose
deprotection using 0.1N HCl solution at room temperature,
which resulted (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol 3.12
1 in dry acetone, followed by selective
The major class of naturally occurring organic molecules in
nature are carbohydrates and are produced from various bio-
renewable sources. Although numerous reports are available
on the application of carbohydrate derivatives in achiral/chiral
synthesis, the reports on carbohydrate derived chiral ionic
liquids (CCILs) are very less in number.9 Recently, we reported
the synthesis of D-ribose and D-galactose based CILs and their
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 2 of 5
View Article Online
DOI: 10.1039/C6RA02792J
COMMUNICATION
Journal Name
yields. All the synthesized CCILs were liquids and stable at
room temperature.
O
O
O
HO
O
O
OH (i)
O
(ii)
OH
HO
O
O
OH
O
OH
1
2
3
OCH3
OCH3
O
O
OCH3
OCH3
O
(iv-a)
(iv-b)
(v)
O
(iii)
OTs
O
OTs
N
OH
O
N
4
5
6
OCH3
OCH3
OCH3
OCH3
O
O
∆δ(ppm) = 0.075
∆δ(ppm) = 0.069
∆δ(ppm) = 0.074
(vii)
(vi)
N
N
OH
N
N
OH
8 X= PF6
9 X= Tf2N
10 X= OTf
11 X= BF4
X
I
CH3
CH3
7
Scheme 2: Route of Synthesis for D-xylose Derived CCILs.
Reagents and conditions: (i) CuSO4, H2SO4, Me2CO, 24 h, rt (85%); (ii) HCl, H2O, 3 h, rt
(95%); (iii)p-TsCl, dry DCM, N-methyl imidazole, TEA, reflux (91%); (iv-a) TFA, MeOH,
reflux, 10 h (93%); (iv-b) K2CO3, MeOH, 3 h, rt; (v) Imidazole, Cs2CO3, DMF, 120 ᵒC,
overnight (90%); (vi) CH3I, rt, 6 h (91%); LiX, H2O, 24 h, rt (8-72%, 9-82%, 10- 76%, 11-
62%)
(a)
(b)
Table 1: ∆δ Values of CF3 Signals of Racemic Mosher’s acid Silver Salt in the Presence of
2 equiv. of CCILs (7-11)
Figure 1: Partial 19F NMR (376.5 MHz) spectra of CCIL 7 and racemic Mosher’s acid salt
complex. Splitting pattern of CF3 signal. (a) 2 equiv. of CCIL 7; (b) 4 equiv. of CCIL 7; (c) 6
equiv. of CCIL 7.
CCIL
Anion
[I]
Chemical Shift difference (∆δ)R/S in
Entry CCIL
Solvent
ppm[a]
0.062
0.031
0.045
NS
1
2
7
8
CD3CN
CDCl3
CDCl3
CDCl3
CDCl3
[PF6]
[Tf2N]
[OTf]
[BF4]
After the successful synthesis of the target CCILs (
Scheme 2), the chiral discrimination ability was evaluated by
studying the diastereomeric interaction between CCIL (10
7- 11,
3
9
4[b]
10
11
7
5
0.047
mg, 0.027 mmol) and racemic Mosher’s acid silver salt (4.6 mg,
0.013 mmol) in CD3CN (0.6 mL). The mixture was analyzed,
using 19F NMR. Clear splitting of CF3 signal was observed
[a]Recorded by 19F NMR at 376.5 MHz; [b] NS: No splitting for CF3 signal
Then compound
3 was converted to ditosylated compound
(Figure
1
(a)), which indicating its excellent chiral
discrimination property on racemic Mosher’s acid salt.15
Table 2: ∆δ Values of CF3 Signals of Racemic Mosher’s acid silver salt in the
presence of varied concentrations of CCIL 7.
((3aS,5S,6R,6aS)-2,2-dimethyl-5-
((tosyloxy)methyl)tetrahydrofuro[2,3-d][1,3]dioxol-6-yl
4-
methylbenzenesulfonate)
4
using
p-TSCl
and
N-
methylimidazole. The oxirane derivative of D-xylose ((1R, 2R,
5R)-2-(dimethoxymethyl)-3, 6-dioxabicyclo [3.1.0] hexane)
was synthesized from compound by acid promoted ring
5
Chemical Shift
CCIL 7
Racemic Mosher’s
Silver salt (Equiv.)
Entry
difference
(∆δ)R/S in ppm[a]
0.017
4
(Equiv.)
transposition followed by treating with potassium carbonate in
methanol at room temperature.13 The epoxide ring of
1
2
3
4
1
2
4
6
1
1
1
1
0.062
compound
5 was opened by nucleophilic attack of imidazole in
ᵒ
0.074
the presence of Cs2CO3 at 120 C to produce (2R, 3R, 4S)-2-
(dimethoxymethyl)-4-(1H-imidazol-1-yl) tetrahydrofuran-3-ol
0.075
[a]Recorded by 19F NMR at 376.5 MHz
6
. Finally compound
6
was quarternized using methyl iodide at
(1-((3S,4R,5R)-5-
room temperature, affording target CCIL
7
Broad peaks of CF3 signals were observed when the
experiments were performed using the remaining CCILs (8, 9,
(dimethoxymethyl)-4-hydroxytetrahydrofuran-3-yl)-3-methyl-
1H-imidazol-3-ium iodide)14 in good overall yield (56%) starting
10 and 11) at similar condition. In order to get clear splitting,
each CCIL was mixed with racemic salt in dry acetonitrile,
stirred for 10 min at room temperature, filtered and the
filtrate was distilled. The residual compound was dissolved in
from D-xylose. Furthermore, the iodo anion of compound
7
was exchanged with different fluorine containing anions by
simple anion metathesis in aqueous medium with very good
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 3 of 5
View Article Online
DOI: 10.1039/C6RA02792J
Journal Name
COMMUNICATION
CDCl3 and 19F NMR was recorded. CCILs
8,
9
and 11 have Further, CCIL
7
was employed in varied concentrations with
shown very good splitting for CF3 signal of racemic Mosher’s respect to racemic salt and the details are summarized in table
acid salt, while in case of CCIL 10 no splitting was observed. 2.16 From the table 2, it is evident that 2 equiv. (0.0450 mol/L)
The results are summarized in table- 1. Among all, CCIL
shown excellent optical resolution property using less mixture and almost saturation point was reached while using
equivalents (2 equiv.) in CD3CN itself. Next, we analyzed the 4, 6 equiv. of CCIL (Table 2 and Figure 1). The concentration
splitting pattern of racemic Mosher’s acid salt using CCIL by effect of CCIL on the magnitude of CF3 signal splitting is
7 have of CCIL was sufficient enough for clear separation of racemic
7
7
7
1
1H and 13C NMR. In case of H NMR, only broad peak (OMe of represented in figure 2. The highest splitting for CF3 signal of
Mosher’s acid salt) was observed and no clear splitting was racemic Mosher’s acid salt using CCILs have been rarely
noticed by 13C NMR.
reported
in
the literature (except Malhotra and coworkers in 2007).
Since, CCIL
7 have shown an excellent chiral discrimination
property, used for the determination of enantiomeric excess
values of non-racemic Mosher’s acid salt mixtures. Two
different ratio of non-racemic mixtures were prepared by
adding (S)-Mosher’s acid salt to racemic Mosher’s acid salt
((R/S) = 1:2 and 1:4 approximately). The ee value can be
determined from integration of CF3 signal by 19F NMR (Figure
3).
In conclusion, new D-xylose derived CILs have been
synthesized by simple modifications starting from D-xylose
with good overall yields. Studied their chiral recognition
property using racemic and non-racemic Mosher’s acid silver
salts, excellent discrimination was observed with very less
quantities of CCILs. The high resolution property of the CCILs
for racemic salt indicates their potential application as NMR
chiral shift reagents for various racemic carboxylic acids.
Further applications of these CCILs as chiral solvent and chiral
catalyst for various asymmetric transformations are being
underway in our laboratory.
Figure 2: Effect of concentration of CCIL 7 on s signal splitting of racemic Mosher’s acid
salt.
Acknowledgements
Funding from DST/SR/FT/CS-93/2011 (FAST-TRACK-SCHEME),
Govt. of India is gratefully acknowledged. We thank the DST-
FIST and VIT-SIF for providing FT-NMR facilities. We would like
to extend our sincerest thanks to Dr. V. Jayathirtha Rao (Head
& Chief scientist, CFC-division) and Mr. M. Sasi kumar, CSIR-
IICT-Hyderabad for their support.
Notes and references
1
(a) R. A. Sheldon, Green Chem., 2005, 7, 267-278; (b) K. R.
Seddon, J. Chem. Technol. Biotechnol., 1997, 68, 351-356; (c)
T. Welton,Chem. Rev., 1999, 99, 2071-2084; (d) P.
Wasserscheid and W. Keim, Chem. Int. Ed., 2000, 39, 3772-
3789; (e) R. Sheldon, Chem. Commun., 2001, 2399-2407; (f)
H. Zhao and S. V. Malhotra, Aldrichimica Acta, 2002, 35, 75-
83; (g) N. Jain, A. Kumar, S. Chauhan and S. Chauhan,
Tetrahedron, 2005, 61, 1015-1060.
2
3
(a) C. Baudequin, J. Baudoux, J. Levillain, D. Cahard, A.-C.
Gaumont and J.-C. Plaquevent, Tetrahedron: Asymmetry,
2003, 14, 3081-3093; (b) J. Ding and D. W. Armstrong,
Chirality, 2005, 17, 281-292; (c) C. Baudequin, D. Brégeon, J.
Levillain, F. Guillen, J.-C. Plaquevent and A.-C. Gaumont,
Tetrahedron: Asymmetry, 2005, 16, 3921-3945.
Figure 3: Determination of ee values of non-racemic Mosher’s acid salt by 19F
NMR. (R/S)= 1:2 (a); 1:4 (b) approximately.
(a) B. Pégot, G. Vo-Thanh, D. Gori and A. Loupy,Tetrahedron
Lett., 2004, 45, 6425-6428; (b) J. Ding, V. Desikan, X. Han, T.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 4 of 5
View Article Online
DOI: 10.1039/C6RA02792J
COMMUNICATION
Journal Name
L. Xiao, R. Ding, W. S. Jenks and D. W. Armstrong, Org. Lett.,
2005, 7, 335-337; (c) Z. Wang, Q. Wang, Y. Zhang and W.
crude compound was dissolved in 50% methanol/chloroform
and passed through neutral alumina, afforded colorless
liquid compound 7 in 91% yield.
Bao, Tetrahedron Lett., 2005, 46, 4657-4660; (d) J. Howarth,
K. Hanlon, D. Fayne and P. McCormac, Tetrahedron Lett.,
1997, 38, 3097-3100; (e) S. Luo, X. Mi, L. Zhang, S. Liu, H. Xu
and J. P. Cheng. Angew. Chem., Int. Ed., 2006, 45, 3093-3097;
(f) S. V. Malhotra and Y. Wang, Tetrahedron: Asymmetry,
2006, 17, 1032-1035.
(a) J. Ding, T. Welton and D. W. Armstrong, Anal. Chem.,
2004, 76, 6819-6822; (b) S. A. A. Rizvi and S. A. Shamsi, Anal.
Chem., 2006, 78, 7061-7069.
(a) T. Biedroń and P. Kubisa, Polym. Int., 2003, 52, 1584-
1588; (b) T. Biedroń and P. Kubisa, J. Polym. Sci. Part A:
Polym. Chem., 2005, 43, 3454-3459; (c) H.-y. Ma, X.-h. Wan,
X.-f. Chen and Q.-f. Zhou, Chin. J. Polym. Sci., 2003, 21, 265-
270.
Yield: 90%, Light brown colour liquid;
[α]
25 = +88.8 (c 1,
D
MeOH); 1H NMR (400 MHz, Chloroform-d) δ 9.84 (s, 1H),
7.72 (t, J = 2.0 Hz, 1H), 7.17 (t, J = 2.0 Hz, 1H), 5.41 (d, J = 4.8
Hz, 1H), 4.61 (d, J = 4.8 Hz, 1H), 4.51 (d, J = 3.6 Hz, 1H), 4.30
(dd, J = 11.2, 4.8 Hz, 1H), 4.20 (d, J = 11.2 Hz, 1H), 4.00 (s,
3H), 3.98 (dd, J = 4.8, 3.2 Hz, 1H), 3.46 (s, 3H), 3.44 (s, 3H);
13C NMR (100 MHz, Chloroform-d) δ 137.50, 122.69, 121.37,
103.66, 85.67, 78.69, 70.92, 68.34, 55.99, 55.55, 36.91;
HRMS (ESI) exact calculated mass for [M+]
4
5
(C11H19O4N2)requires m/z 243.1339, found m/z 243.1336; LR-
MS (ESI) ES+: 243.2, ES-: 126.9.
15 The racemic Mosher’s acid silver salt (4.6 mg, 0.013 mmol)
was mixed with CCIL 7 (10 mg, 0.027 mmol) in 0.6 mL of
6
7
(a) K. Fukumoto, M. Yoshizawa and H. Ohno, J. Am. Chem.
Soc., 2005, 127, 2398-2399; (b) X. Chen, X. Li, A. Hu and F.
Wang, Tetrahedron: Asymmetry, 2008, 19, 1-14; (c) H. Ohno
and K. Fukumoto, Acc. Chem. Res., 2007, 40, 1122-1129; (d)
M. Li, S. L. De Rooy, D. K. Bwambok, B. El-Zahab, J. F. DiTusa
and I. M. Warner, Chem. Commun., 2009, 6922-6924.
(a) P. Wasserscheid, A. Bösmann and C. Bolm, Chem.
Commun., 2002, 200-201; (b) H. Clavier, L. Boulanger, N.
Audic, L. Toupet, M. Mauduit and J.-C. Guillemin, Chem.
Commun., 2004, 1224-1225; (c) J. Levillain, G. Dubant, I.
Abrunhosa, M. Gulea and A.-C. Gaumont, Chem. Commun.,
2003, 2914-2915; (d) H.-S. Gao, Z.-G. Hu, J.-J. Wang, Z.-F. Qiu
and F.-Q. Fan, Aust. J. Chem., 2008, 61, 521-525; (e) M.
Vasiloiu, I. Cervenka, P. Gaertner, M. Weil, C. Schröder and K.
Bica, Tetrahedron: Asymmetry, 2015, 26, 1069-1082; (f) Y.
Ishida, H. Miyauchi and K. Saigo, Chem. Commun., 2002,
2240-2241; (g) Y. Ishida, D. Sasaki, H. Miyauchi and K. Saigo,
Tetrahedron Lett., 2004, 45, 9455-9459; (h) V. Jurčík and R.
Wilhelm, Tetrahedron: Asymmetry, 2006, 17, 801-810; (i) T.
Heckel, A. Winkel and R. Wilhelm, Tetrahedron: Asymmetry,
2013, 24, 1127-1133.
CD3CN and stirred for 10 min at room temperature to
exchange anions. The formed AgI precipitate was filtered
and filtrate was analyzed by 19F NMR (376.5 MHz). For CCILs
8-11, the racemic salt (1 equiv.) was mixed with each CIL (10
mg, 2equiv.) separately in dry ACN and stirred for 10 min.
Filtered the formed salts and concentrated the filtrate under
reduced pressure using rotary evaporator. The residual
compound was dissolved in CDCl3 and analyzed by 19F NMR.
16 Effect of CCIL
each time different concentrations of CCIL
6 eq) was mixed with racemic salt and studied the effect of
concentration of CCIL
for chiral discrimination by 19F NMR.
7
concentration: In another set of experiment,
7
(1 eq, 4 eq, and
7
8
9
V. Kumar, C. E. Olsen, S. J. Schäffer, V. S. Parmar and S. V.
Malhotra, Org.Lett., 2007,
(a) L. Poletti, C. Chiappe, L. Lay, D. Pieraccini, L. Polito and G.
Russo, Green Chem., 2007, , 337-341; (b) P. G. Plaza, B. A.
9, 3905-3908.
9
Bhongade and G. Singh, Synlett, 2008, 2008, 2973-2976; (c)
S. T. Handy, M. Okello and G. Dickenson, Org.Letters, 2003,
5, 2513-2515; (d) V. Kumar, C. Pei, C. E. Olsen, S. J. Schäffer,
V. S. Parmar and S. V. Malhotra, Tetrahedron: Asymmetry,
2008, 19, 664-671; (e) M. Quadir and E. Mathonneau US
11/656, 344, January 22, 2007; (f) M. A. Pereira, Mini-Rev.
Org. Chem., 2012,
Van Buu, A. Aupoix, B. Pegot and G. Vo-Thanh, Curr. Org.
Synth., 2012, , 53-64; (h) O. N. Van Buu, A. Aupoix, N. D. T.
Hong and G. Vo-Thanh, New J. Chem., 2009, 33, 2060-2072.
9, 243-260; (g) T.-K.-T. Truong, O. Nguyen
9
10 R. Jayachandra and S. R. Reddy, Trends Carbo. Res.,2015, 7,
60-67.
11 R. Jayachandra, R. Lakshmipathy and S. R. Reddy, J. Mol. Liq.,
DOI: http://dx.doi.org/10.1016/j.molliq.2015.11.060.
12 S. B. Ferreira, A. C. Sodero, M. F. Cardoso, E. S. Lima, C. R.
Kaiser, F. P. Silva Jr and V. F. Ferreira, J. Med. Chem., 2010,
53, 2364-2375.
13 S. K. Pandey, G. F. Jogdand, J. C. Oliveira, R. A. Mata, P. R.
Rajamohanan and C. V. Ramana, Chem. Eur. J., 2011, 17
12946-12954.
14 1-((3S, 4R, 5R)-5-(dimethoxymethyl)-4-
,
hydroxytetrahydrofuran-3-yl)-3-methyl-1H-imidazol-3-ium
iodide (7):To a stirred solution of compound (641 mg,
6
2.808 mmol) in dry acetonitrile (2 mL), charged methyl
iodide (598 mg/ 0.26 mL, 4.212 mmol). Stirred the reaction
mass at room temperature for 6 h. Upon completion of the
reaction, removed the solvent by vacuum distillation. The
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
RSC Advances
View Article Online
DOI: 10.1039/C6RA02792J
A remarkable chiral recognition of racemic mosher’s acid salt by naturally
derived chiral ionic liquids using 19F NMR
R. Jayachandra and SabbasaniRajasekhara Reddy*