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Synthesis and applications of carbohydrate based chiral ionic liquids as chiral recognition agents and organocatalysts
Journal Pre-proof Synthesis and applications of carbohydrate based chiral ionic liquids as chiral recognition agents and organocatalysts Nirmaljeet Kaur, Harish Kumar Chopra PII:
S0167-7322(19)34274-6
DOI:
https://doi.org/10.1016/j.molliq.2019.111994
Reference:
MOLLIQ 111994
To appear in:
Journal of Molecular Liquids
Received Date: 30 July 2019 Revised Date:
14 October 2019
Accepted Date: 20 October 2019
Please cite this article as: N. Kaur, H.K. Chopra, Synthesis and applications of carbohydrate based chiral ionic liquids as chiral recognition agents and organocatalysts, Journal of Molecular Liquids (2019), doi: https://doi.org/10.1016/j.molliq.2019.111994. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.
Applications of Carbohydrate based Chiral Ionic Liquids as Chiral Recognition Agents and Organocatalysts Nirmaljeet Kaur and Harish Kumar Chopra* Department of Chemistry, Sant Longowal Institute of Engineering and Technology, Longowal-148106, Distt. Sangrur (Pb.), India: Email:[email protected] Tel: +91-1672-253204, Fax: +91-1672-280072. ___________________________________________________________________________ Graphical Abstract:
1
Synthesis and Applications of Carbohydrate based Chiral Ionic Liquids as Chiral
2
Recognition Agents and Organocatalysts
3
Nirmaljeet Kaur and Harish Kumar Chopra*
4
Department of Chemistry, Sant Longowal Institute of Engineering and Technology,
5
Longowal-148106, Distt. Sangrur (Pb.), India: Email:[email protected]
6
Tel: +91-1672-253204, Fax: +91-1672-280072.
7
___________________________________________________________________________
8
Abstract
9
Chiral ionic liquids (CILs) have shown a wide range of applications in variety of domains in
10
chemistry. Because of this, synthesis and applications of CILs have always been areas of
11
interest for research in the last 20 years. Present work describes, the synthesis of six
12
carbohydrate based chiral ionic liquids (CCILs) by following simple procedures and their
13
applications. Structures of the CCILs were confirmed through various analytical techniques
14
like NMR spectroscopy (1H,
15
were tested as chiral recognising agents using sodium salt of Mosher’s acid as model
16
substrate through 19F NMR spectroscopy. Further, CCILs were used as organocatalyst in the
17
enantioselective reduction of aromatic prochiral ketones to achieve corresponding chiral
18
secondary alcohols.
13
C,
11
B,
31
P,
19
F), EI-MS, and polarimetry. Designed CCILs
19 20
Keywords
21
Chiral recognition; enantiodifferentiation; organocatalyst; Mosher’s acid; CCILs; DABCO.
22 23 24 25 26 27 28 29 30 31 32 33 34 1
35
1. Introduction
36
Chiral ionic liquids are a sub-class of ionic liquids which possess similar properties like low
37
melting and boiling points, negligible vapour pressure, high thermal stability, electrical
38
conductivity and reusability [1-5]. CILs can be synthesized by two methods: asymmetric
39
synthesis and natural chiral pool (carbohydrates, amino acids, amino alcohols, alkaloids etc.)
40
[6-8]. Carrying such distinct properties, CILs play major role in wide range of applications
41
such as chiral recognition [9-10], organocatalysis [11-12], background electrolytes in
42
capillary electrophoresis [13-15], stationary phase additives in liquid and gas chromatography
43
[16-17], high performance liquid chromatography [18-19], liquid-liquid extraction [20] and
44
stereoselective polymerization [21-22]. Nowadays, chiral molecular recognition and
45
asymmetric organocatalysis are the two most intensively analysed applications of CILs [23-
46
24]. Both the terms include ‘chirality’ in their meanings and are highly useful for the
47
separation and synthesis of numerous essential enantioselective compounds. Different
48
mechanisms are followed by both the processes to obtain single enantiomer in major amount
49
of the product. Chiral recognition is observed due to the formation of diastereomeric complex
50
between CIL (host) and enantiomers of racemic salt (guest) [25]. According to A. Berthod,
51
chiral recognition involves ‘three point interaction’ model. This model predicts the attractive
52
or repulsive interactions of three groups of the chiral centre with enantiomers of racemic
53
moiety [26]. Different types of non-covalent molecular interactions are generated between the
54
host and guest molecules like electrostatic interactions, hydrogen bonding, π − π
55
interactions, van der waals forces and hydrophobic interactions which help in the separation
56
of enantiomers [27]. Several spectroscopic and chromatographic techniques are available to
57
check the separation of enantiomers of the molecules such as NMR spectroscopy,
58
fluorescence spectroscopy, circular dichroism, HPLC, gas chromatography, capillary
59
electrophoresis, capillary electrochromatography, micellar chromatography, supercritical
60
chromatography etc. [28]. Among these, NMR spectroscopy is the easiest and the most
61
reliable technique to determine the separation and enantiopurity of the compound by just
62
observing the chemical shift of the corresponding peaks. Chiral recognition through NMR
63
spectroscopy is based on two main approaches: the use of chiral solvating agent (CSA) and
64
enantiopure chiral derivatizing agent [29].
65
In the present report, CILs have been synthesized from derivative of D-galactose and 1,4-
66
Diazabicyclo[2.2.2]octane (DABCO), further these CILs have been employed as chiral
67
recognising agents for the enantiodifferentiation of sodium salt of Mosher’s acid and as
68
organocatalyst in the enantioselective reduction reactions of prochiral ketones. Galactose was 2
69
used as precursor for the preparation of CILs because it is abundantly present in nature,
70
thermally stable, easy to handle and number of chiral centres are present in its structure. The
71
synthesized CILs are advantageous in terms of easy availability of chiral carbohydrate
72
precursors, excellent yields, moderate reaction conditions and remarkable applications.
73
Separation of the enantiomers were analysed through
74
enantiomeric excess of the obtained secondary alcohols was determined by gas
75
chromatography.
76
2. Experimental
77
2.1 Materials and methods
78
All the chemicals: D-galactose (spectrochem), ZnCl2, imidazole, iodine (Alfa aesar),
79
triphenylphosphine, 1,4-diazabicyclo[2.2.2]octane (DABCO) (Sigma-Aldrich), NaBF4, KPF6,
80
NaBrCH2CH2SO3, NaCF3SO3, NaSbF6 (Sigma-Aldrich), were purchased from commercial
81
suppliers and are of high purity. Acetone was dried over molecular sieves of pore size 0.3nm.
82
Formation of the product was analysed through pre-coated Merck TLC silica gel 60 sheets.
83
Then characterization of the obtained products was done through 1H,
84
NMR spectroscopy on Bruker Avance II, 400 MHz NMR spectrometer. Mass of the
85
synthesized compounds were analysed on Shimadzu GCMS-QP 2010 Ultra in EI mode.
86
Optical activity of the synthesized CILs was recorded on Anton Paar polarimeter MCP 500 at
87
589 nm wavelength at room temperature. As the CILs were solid in nature, so their melting
88
points or decomposition temperatures were taken on digital melting point apparatus and
89
reported uncorrected. In application part of chiral recognition, 19F NMR was recorded on 400
90
MHz JEOL JNM ECS400 and BRUKER AVANCE NEO 500MHz NMR spectrometer.
91
Enantiomeric excess of the optically active secondary alcohols were analysed on Shimadzu
92
GCMS-QP 2010 Ultra in split mode using Rt-βDEXsm column (30 m × 0.25 mm × 0.25
93
µm) using FID as detector.
94
2.2 Procedure for the synthesis of (3aS,5R,5aS,8aR,8bS)- 2,2,7,7-tetramethyltetrahydro-3aH-
95
bis[1,3]dioxolo[4,5-b:4’5’-d]pyran-5-yl)methanol (1):
96
Protection of the hydroxyl groups in carbohydrate chemistry is a common trend with various
97
protecting groups. Similarly, here in this report, secondary ‘OH’ groups were protected by
98
acetone using ZnCl2 in the presence of H2SO4 as catalyst, by following the procedure
99
described in the literature [30].
19
F NMR spectroscopy and
13
C,
11
B,
31
P and
19
F
100
2.2.1 (3aS,5R,5aS,8aR,8bS)- 2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4’5’-
101
d]pyran-5-yl)methanol (1): transparent oil, 79% yield, 1H NMR (CDCl3, 400 MHz): δ 5.57-
102
5.55 (d, 1H, J= 5Hz ), 4.62-4.60 (dd, 1H, J= 7.9Hz), 4.34-4.32 (dd, 1H, 5Hz), 4.28-4.26 (dd, 3
103
1H, J=7.9Hz), 3.89-3.80 (m, 2H), 3.74-3.70 (q, 1H), 2.73 (broad s, 1H), 1.53 (s, 3H), 1.45 (s,
104
3H), 1.33 (s, 6H).
105
2.3 Procedure for the substitution of iodine at primary ‘OH’ group (2):
106
Iodination of primary ‘OH’ group by using iodine accompanied with imidazole and PPh3 was
107
done through a procedure as described in the literature [31].
108
2.3.1(3aS,5R,5aS,8aR,8bS)-5-(iodomethyl)-2,2,7,7-tetramethyltetrahydro-3aH-
109
bis[1,3]dioxolo[4,5-b:4’5’-d]pyran(2): transparent oil, yield 82%, [α]25D = -64.9 (c, 0.25,
110
CH3OH), 1H NMR (CDCl3, 400 MHz): δ 5.54-5.53 (d, 1H, J= 5Hz), 4.62-4.60 (dd, 1H, J= 7.8
111
Hz), 4.41-4.39 (dd, 1H, 7.8Hz), 4.31-4.29 (dd, 1H, J= 5Hz), 3.96-3.92 (m, 1H), 3.34-3.30 (q,
112
1H), 3.23-3.18 (1H), 1.54 (s, 3H), 1.44 (s, 3H), 1.35-1.33 (d, 6H).
113
MHz): 109.52, 108.87, 96.67, 71.55, 71.07, 70.52, 68.91, 29.69, 26.02, 25.94, 24.87, 24.42.
114
2.4 Procedure for the synthesis of 1-(((3aS,5S,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-
115
3aH-bis[1,3]dioxolo[4,5-b:4’,5’-d]pyran-5-yl)methyl)-4-aza-1-azoniabicyclo[2.2.2]
116
iodide(CIL 3):
117
Compound (3) was synthesized by simple and efficient method. 5mmol of compound (2) was
118
dissolved in acetonitrile with equimolar of DABCO. Reaction mixture was put on refluxing at
119
80oC for 4-5 days. Progress of the reaction was checked through TLC in CHCl3/CH3OH
120
solvent system. On completion of the reaction, crude was extracted with mixture of toluene
121
and diethyl ether several times to yield the pure product [32].
122
2.4.11-(((3aS,5S,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-
123
b:4’,5’-d]pyran-5-yl)methyl)-4-aza-1-azoniabicyclo[2.2.2] octane iodide(CIL 3):White solid,
124
yield 75%, [α]25D = -33.2 (c, 0.25, CH3OH), 1H NMR (CDCl3, 400 MHz): δ 5.54-5.53 (d, 1H,
125
J= 5Hz), 4.66-4.63 (dd, 1H, J=7.8Hz), 4.52-4.41 (m, 3H), 4.37-4.35 (dd, 1H, 5Hz), 4.05-3.98
126
(m, 3H), 3.68-3.61 (m, 3H), 3.46-3.40 (q, 1H), 3.25-3.21 (t, 6H), 1.58 (s, 3H), 1.43 (s, 3H),
127
1.33-1.31 (d, 6H). 13C NMR (CDCl3, 100 MHz): 109.99, 109.32, 96.37, 70.87, 70.61, 69.88,
128
63.50, 62.56, 53.85, 45.44, 26.13, 23.06, 24.69, 24.39. EI-MS m/z: 355 [M]+.
129
2.5 Procedure for the synthesis of CILs from 4-8:
130
Procedure of anion metathesis was followed for the synthesis of CILs from 4-8. 1mmol of
131
CIL (3) and little in excess than equimolar sodium and potassium inorganic salts were
132
dissolved in 10ml of distilled water. The reaction mixture was put on stirring for 8-10 h. Then
133
the crude was extracted with chloroform to obtain the desired product except for CILs 5 and 8
134
because they get precipitated after half an hour and was insoluble in water. So, CILs 5 and 8
135
were filtered from the mixture.
13
C NMR (CDCl3, 100
octane
4
136
2.5.11-(((3aS,5S,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-
137
b:4’,5’-d]pyran-5-yl)methyl)-4-aza-1-azoniabicyclo[2.2.2]octane tetrafluoroborate (CIL 4):
138
Off-white solid, yield 70%, [α]25D = -25.4, (c, 0.25, CH3OH), 1H NMR (CDCl3, 400 MHz): δ
139
5.54-5.52 (d, 1H, J= 5Hz), 4.66-4.63 (dd, 1H, J=7.8Hz), 4.46-4.43 (d, 1H, J=10.6Hz), 4.37-
140
4.35 (dd, 2H, J= 5Hz), 4.14-4.10 (d, 1H, J= 13.7Hz), 3.85-3.84 (d, 3H, J= 4Hz), 3.56-3.50 (q,
141
3H), 3.41-3.35 (q, 1H), 3.30-3.22 (m, 6H), 1.56 (s, 3H), 1.42 (s, 3H), 1.33-1.31 (d, 6H). 13C
142
NMR (CDCl3, 100 MHz): 109.95, 109.41, 96.42, 70.85, 70.63, 69.98, 63.28, 62.62, 53.91,
143
45.43, 29.70, 26.12, 25.98, 24.70, 24.25. EI-MS m/z: 355 [M]+.
144
2.5.21-(((3aS,5S,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-
145
b:4’,5’-d]pyran-5-yl)methyl)-4-aza-1-azoniabicyclo[2.2.2] octane hexafluorophosphate (CIL
146
5):White solid, yield 73%, [α]25D = -27.7 (c, 0.25, CH3CN), 1H NMR (CDCl3, 400 MHz): δ
147
5.58-5.56 (d, 1H, J=5Hz), 4.70-4.67 (dd, 1H, J=7.6Hz), 4.46-4.44 (dd, 1H, J=5Hz), 4.25-
148
4.20 (t, 2H,), 3.53 (s, 1H), 3.46-3.42 (m, 4H), 3.28-3.26 (m, 3H), 3.07-3.03 (q, 6H), 1.52 (s,
149
3H), 1.39 (s, 3H), 1.31 (s, 6H).
150
70.67, 69.57, 63.84, 62.08, 53.54, 45.06, 26.36, 26.19, 25.05, 24.68. EI-MS m/z: 355 [M]+.
151
2.5.31-(((3aS,5S,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-
152
b:4’,5’-d]pyran-5-yl)methyl)-4-aza-1-azoniabicyclo[2.2.2]octane bromoethanesulfonate (CIL
153
6): Light green solid, yield 69%, [α]25D = -32.5, (c, 0.25, CH3OH), 1H NMR (CDCl3, 400
154
MHz): δ 5.54-5.53 (d, 1H, J= 5Hz), 4.66-4.63 (dd, 1H, J=7.7Hz), 4.46-4.35 (m, 4H,), 4.01-
155
3.98 (t, 3H, 4.5Hz), 3.66-3.60 (dd, 3H, J=17.8Hz), 3.48-3.42 (t, 1H,), 3.26-3.22 (t, 6H), 1.58
156
(s, 3H), 1.44 (s, 3H), 1.33-1.31 (d, 6H). 13C NMR (CDCl3, 100 MHz): 109.95, 109.36, 96.38,
157
70.87, 70.59, 69.90, 62.61, 53.82, 45.42, 26.10, 26.00, 24.70, 24.29. EI-MS m/z: 355 [M]+.
158
2.5.41-(((3aS,5S,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-
159
b:4’,5’-d]pyran-5-yl)methyl)-4-aza-1-azoniabicyclo[2.2.2]octane trifluoromethanesulfonate
160
(CIL 7): Off-white solid, yield 72%, [α]25D = -26.3, (c, 0.25, CH3OH), 1H NMR (CDCl3, 400
161
MHz): δ 5.54-5.53 (d, 1H, J=5Hz), 4.66-4.63 (dd, 1H, J=7.8 Hz), 4.43-4.41(d, 1H, J=24.7),
162
4.37-4.34 (m, 2H), 4.15-4.11 (dd, 1H, J=14Hz), 3.92-3.87 (m, 3H), 3.59-3.52 (m, 3H), 3.48-
163
3.42 (t, 6H), 1.56 (s, 3H), 1.44 (s, 3H), 1.35-1.33 (d, 6H).
164
109.98, 109.38, 96.39, 70.91, 70.61, 69.89, 63.35, 62.59, 53.81, 45.38, 29.71, 25.95, 25.92,
165
24.69, 24.27. EI-MS m/z: 355 [M]+.
166
2.5.51-(((3aS,5S,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-
167
b:4’,5’-d]pyran-5-yl)methyl)-4-aza-1-azoniabicyclo[2.2.2]octane hexafluoroantimonate (CIL
168
8): White solid, yield 65%, [α]25D = - 28.7 (c, 0.25, CH3CN), 1H NMR (CDCl3, 400 MHz): δ
13
C NMR (CDCl3, 100 MHz): 109.84, 108.86, 96.34, 71.73,
13
C NMR (CDCl3, 100 MHz):
5
169
5.54-5.53 (d, 1H, J=5Hz), 4.65-4.63 (dd, 1H, J=7.8Hz ), 4.46-4.35 (m, 4H), 4.06-4.00 (m,
170
3H), 3.68-3.62 (m, 3H), 3.52-3.46 (t, 1H), 3.26-3.23 (t, 6H, J=7.5Hz), 1.58 (s, 3H), 1.44 (s,
171
3H), 1.35-1.33 (d, 6H).
172
69.86, 63.05, 62.55, 53.82, 45.42, 29.60, 26.13, 26.03, 24.70, 24.32. EI-MS m/z: 355 [M]+.
173
2.6 General procedure for the enantioselective reduction of prochiral ketones
174
Prochiral ketones (1mmol) were dissolved in a solution of 10 ml methanol. 10 mol% of CIL
175
was added to the above solution and stirred. Sodium borohydride (1.5mmol) was added in
176
portions over a period of 15 mins. The stirring was continued for 2-3 h and then the mixture
177
was extracted with dichloromethane/diethyl ether. Then, the organic layer was dried over
178
Na2SO4 and evaporates it on rotary evaporator to get the product [33]. Enantiomeric excess of
179
the alcohols was determined through GC.*
180
(-) 1-Phenylethanol: GC analysis Rt-βDEXsm column, split mode carrier gas helium,
181
makeup gas helium, column oven temperature= 120 oC, injection temperature 230 oC, flow
182
rate 0.80ml/min, t1= 10.62 min, t2= 10.81 min.
183
(-) 1-(2-Hydroxyphenyl)ethanol: GC analysis Rt-βDEXsm column, split mode carrier gas
184
helium, makeup gas helium, column oven temperature= 120 oC, injection temperature 230
185
o
186
(-)1-(4-Hydroxyphenyl)ethanol: GC analysis Rt-βDEXsm column, split mode carrier gas
187
helium, makeup gas helium, column oven temperature= 120 oC, injection temperature 230
188
o
189
(-)1-(4-Bromophenyl)ethanol: GC analysis Rt-βDEXsm column, split mode carrier gas
190
helium, makeup gas helium, column oven temperature= 120 oC, injection temperature 230
191
o
192
(-)1-(4-Methylphenyl)ethanol: GC analysis Rt-βDEXsm column, split mode carrier gas
193
helium, makeup gas helium, column oven temperature= 120 oC, injection temperature 230
194
o
195
(-)1-(4-Chlorophenyl)ethanol: GC analysis Rt-βDEXsm column, split mode carrier gas
196
helium, makeup gas helium, column oven temperature= 120 oC, injection temperature 230
197
o
198
(-)1-(4-Nitrophenyl)ethanol: GC analysis Rt-βDEXsm column, split mode carrier gas
199
helium, makeup gas helium, column oven temperature= 120 oC, injection temperature 230
200
o
201
*GC chromatograms are provided in supplementary information.
13
C NMR (CDCl3, 100 MHz): 109.98, 109.31, 96.36, 70.85, 70.59,
C, flow rate 0.80ml/min, t1= 18.90 min, t2= 19.04 min.
C, flow rate 0.80ml/min, t1= 16.53 min, t2= 16.70 min.
C, flow rate 0.80ml/min, t1= 17.95 min, t2= 18.01 min.
C, flow rate 0.80ml/min, t1= 12.72 min, t2= 12.90 min.
C, flow rate 0.80ml/min, t1= 15.99 min, t2= 16.09 min.
C, flow rate 0.80ml/min, t1=16.17 min, t2= 16.37 min.
202 6
203
2.7 Procedure for the chiral recognition using Mosher’s acid salt
204
0.013 mmol (4.6 mg) of sodium salt of Mosher’s acid was dissolved in acetonitrile (1ml) with
205
0.027 mmol (13 mg) of CIL 3. The reaction mixture was stirred for 12 h, so that anions get
206
exchanged. The solvent was filtered and evaporated. Residual was dissolved in CDCl3 and
207
analysed by NMR [34].
208
3. Results and discussion
209
A new series of carbohydrate based chiral ionic liquids have been synthesized with highly
210
nucleophilic amine, i.e., 1,4-Diazabicyclo[2.2.2]octane, under mild conditions. D-galactose
211
was used as an initiator for the synthesis of the desired CILs. In the first step, four secondary
212
hydroxyl groups of D-galactose were protected by acetone in presence of ZnCl2 and H2SO4 to
213
give (1). The primary ‘OH’ group of (1) was then replaced with iodide to give (2) which on
214
quaternization with a strong nucleophilic amine DABCO (Scheme 1) to gain CCIL (3). CCIL
215
(3) was then led to anion metathesis reaction with various sodium and potassium salts of
216
inorganic compounds to give CCILs 4-8. All the ILs was solid in nature, possessed nice
217
yields, had high decomposition temperatures, and was non-racemic in nature. Composition
218
and stability of all the CCILs were confirmed through various analytical techniques like 1H,
219
13
220
was detected through polarimetery. All the data has been provided in the supplementary
221
information.
C,
11
B,
31
P,
19
F NMR spectroscopy, EI-mass spectrometry, and their non-racemic nature
222 223
Scheme 1
224
All the important physical properties of the CCILs (3-8) have been displayed in Table 1.
225
There is little bit variation in the 1H spectra of all the CCILs, peaks corresponding to NCH2-
226
CH(on galactose ring). As observed in 1H spectra of the ILs with anion I- and SbF6-, the peaks 7
227
get merged and give multiplet but in rest of the cases, they are notified separately. It is also
228
possible that these protons might be helpful in chiral recognition application of sodium salt of
229
Mosher’s acid using CCILs as host.
230
Table 1: Important physical properties of CCILs (3-8) Entry
CCILs
Physical state
Yield (%)
Tda
1
I-
White solid
75%
189-192
-33.2
Off-white solid
70%
222-224
-25.4
-
b
[α]25D
2
BF4
3
PF6-
White solid
73%
249-252
-27.7
4
BrCH2CH2SO3-
Light green solid
69%
198-200
-32.5
5
CF3SO3-
Off-white solid
72%
178-182
-26.3
6
SbF6-
White solid
65%
202-206
-28.7
231 232
a
233
The specific rotations of the non-racemic ILs were shown in negative sign. I- exhibit
234
maximum optical activity than the rest CCILs and BF4- the minimum, the [α]25D values have
235
been shown in Fig 1. Decomposition temperature varies from 178 oC to 252 oC.
b
Decomposition temperature. For PF6- and SbF6-, acetonitrile was used while recording specific rotation.
236
237 238
Fig 1: Graphical representation of specific rotations of CCILs
239
3.1 Application of chiral recognition using Mosher’s acid salt with CCIL (3)
240
CCILs were tested as chiral recognizing agents using sodium salt of Mosher’s acid as analyte.
241
CCIL (3) and Mosher’s salt were mixed in acetonitrile for the anion exchange process for 12
242
h. Residual was dissolved in deuterated CHCl3 and analysed through 19F NMR. To check the
8
243
optimal amount of CCIL required for the recognition property, a variable amount of CCIL
244
was added against the constant amount of Mosher’s acid sodium salt. Data has been provided
245
in Table 2 and
246
the CCIL increased from 8 equiv. to 10 equiv., the magnitude of the splitting decreased from
247
25Hz to 20 Hz and no splitting was observed at lower concentrations of CIL.
248
Table 2: Chemical shift values (Hz) of Mosher’s acid salt with CCIL (3) CCIL (3) Mosher’s acid Chemical shift value Entry (Equiv.) sodium salt (Equiv.) in Hz a 1 2 1 NS b
19
F NMR spectra in the supplementary information. As the concentration of
2
4
1
NS
3
6
1
NS
4
8
1
25
5
10
1
20
249 250
a
Recorded by 19F NMR. b No Splitting.
251
Chiral recognition property and magnitude of the splitting exhibited by the CILs may also
252
depend upon the anion attached with cationic moiety, as evidenced from the literature that Cl,
253
BF4- and PF6- anions form strong ionic pairs with the guest and provide more
254
enantiodifferentiation than the other anions [35]. Second important reason behind chiral
255
recognition property may be the presence of aromatic ring in the host and guest which gives
256
magnetic anisotropic effect, provide π − π interactions and helps in separation of the
257
enantiomers of the guest [27]. Fig 2 demonstrates the chiral recognition mechanism in terms
258
of the different diastereomeric interactions between the CIL and the racemic Mosher’s acid
259
analyte.
260 261
Fig 2: Chiral recognition of Mosher’s acid salt using CCIL 3
262
3.2 Application of CCIL (3) as organocatalyst in asymmetric reduction reactions:
263
A number of reports are available in which CILs have been used as organocatalysts and
264
achieved high enantiomeric excess in many important reactions of organic chemistry like 9
265
Baylis-Hillman, Michael Addition, Diels-Alder, Aldol condensation etc. [36]. Similarly, here
266
in the present article, CCIL (3) was used as organocatalyst in the asymmetric reduction of
267
aromatic prochiral ketones to synthesize corresponding enantioselective secondary alcohols.
268
Products were obtained in high yields and produced low to moderate enantiomeric excess as
269
shown in Table 3. Procedure for the synthesis of enantioselective secondary alcohols, using
270
various substrates can be easily described from Scheme 2 shown below.
271 272 273
Scheme 2
274 275
Table 3: Description of enantiomeric excess using CCIL (3) Prochiral Ketone Entry Yield (%) Time (h) (1mmol) 1 Acetophenone 78 2.5
Ee(%) b
Solvent
17
MeOH
2
2-Hydroxy ACP a
63
3
6
MeOH
3
4- Hydroxy ACP
70
2
5
MeOH
4
4-Bromo ACP
81
2
9
MeOH
5
4-Methyl ACP
74
2
rac
MeOH
6
4-Chloro ACP
85
2
9
MeOH
7
4-Nitro ACP
80
3
6
MeOH
276 277
a
278
Above table reveals that racemic to moderate enantiomeric excess has been obtained,
279
acetophenone produced higher ee% than the other ketones and 4-methylacetophenone was
280
obtained as a racemic mixture, this trend in the enantioselectivity has already been described
281
in literature also [37-38]. But the yield of the secondary alcohols was good in all the cases.
282
4. Conclusions
283
It is concluded that carbohydrate-based chiral ionic liquids were synthesized using DABCO
284
as quaternizing agent. Synthesized chiral salts were employed as a chiral recognising agent
285
and as organocatalyst and they perform nicely in both the applications. Precursors used for
286
their synthesis part are natural and present abundantly in nature. So, they can be readily
287
prepared and can replace the expensive enantiodifferentiating agents and organocatalysts in
288
future.
b
ACP= acetophenone, rac= racemic Ee was analysed through chiral GC column.
289
10
290
Acknowledgement
291
Authors are highly thankful to the authorities of Sant Longowal Institute of Engineering and
292
Technology, Longowal for providing all the research facilities to carry out the research work.
293
Appendix A. Supplementary information
294
All the NMR spectra (both synthesis and application part), mass spectra, GC chromatograms
295
are provided in the supplementary information.
296
References:
297
[1] D. Chaturvedi, Recent developments on task specific ionic liquids, Curr. Org. Chem., 15
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(2011) 1236-1248.
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heterocycles, Min.Rev.Org.Chem., 14 (2017) 3–23.
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Asymmetric Organocatalysis. Curr. Org. Synth., 14 (2017) 488–510.
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Ionic Liquids: An Overview. Curr. Org. Synth., 15 (2018) 578–586.
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cyclodextrins: Evaluation of ionic liquid head groups for enantioseparation of neutral
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compounds in capillary electrophoresis, J. Chromatogr. A. 1360 (2014) 296–304.
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14
Applications of Carbohydrate based Chiral Ionic Liquids as Chiral Recognition Agents and Organocatalysts Nirmaljeet Kaur and Harish Kumar Chopra* Department of Chemistry, Sant Longowal Institute of Engineering and Technology, Longowal-148106, Distt. Sangrur (Pb.), India: Email:[email protected] Tel: +91-1672-253204, Fax: +91-1672-280072. ___________________________________________________________________________ Highlights •
Chiral ionic liquids (CILs) were synthesized from naturally abundant source Dgalactose and obtained with high yield.
•
Synthesized ILs was stable at the higher temperature.
•
CILs worked efficiently as a chiral recognising agent.
•
CILs worked as organocatalysts and produce moderate enantiomeric excess.
S0167-7322(19)34274-6
DOI:
https://doi.org/10.1016/j.molliq.2019.111994
Reference:
MOLLIQ 111994
To appear in:
Journal of Molecular Liquids
Received Date: 30 July 2019 Revised Date:
14 October 2019
Accepted Date: 20 October 2019
Please cite this article as: N. Kaur, H.K. Chopra, Synthesis and applications of carbohydrate based chiral ionic liquids as chiral recognition agents and organocatalysts, Journal of Molecular Liquids (2019), doi: https://doi.org/10.1016/j.molliq.2019.111994. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.
Applications of Carbohydrate based Chiral Ionic Liquids as Chiral Recognition Agents and Organocatalysts Nirmaljeet Kaur and Harish Kumar Chopra* Department of Chemistry, Sant Longowal Institute of Engineering and Technology, Longowal-148106, Distt. Sangrur (Pb.), India: Email:[email protected] Tel: +91-1672-253204, Fax: +91-1672-280072. ___________________________________________________________________________ Graphical Abstract:
1
Synthesis and Applications of Carbohydrate based Chiral Ionic Liquids as Chiral
2
Recognition Agents and Organocatalysts
3
Nirmaljeet Kaur and Harish Kumar Chopra*
4
Department of Chemistry, Sant Longowal Institute of Engineering and Technology,
5
Longowal-148106, Distt. Sangrur (Pb.), India: Email:[email protected]
6
Tel: +91-1672-253204, Fax: +91-1672-280072.
7
___________________________________________________________________________
8
Abstract
9
Chiral ionic liquids (CILs) have shown a wide range of applications in variety of domains in
10
chemistry. Because of this, synthesis and applications of CILs have always been areas of
11
interest for research in the last 20 years. Present work describes, the synthesis of six
12
carbohydrate based chiral ionic liquids (CCILs) by following simple procedures and their
13
applications. Structures of the CCILs were confirmed through various analytical techniques
14
like NMR spectroscopy (1H,
15
were tested as chiral recognising agents using sodium salt of Mosher’s acid as model
16
substrate through 19F NMR spectroscopy. Further, CCILs were used as organocatalyst in the
17
enantioselective reduction of aromatic prochiral ketones to achieve corresponding chiral
18
secondary alcohols.
13
C,
11
B,
31
P,
19
F), EI-MS, and polarimetry. Designed CCILs
19 20
Keywords
21
Chiral recognition; enantiodifferentiation; organocatalyst; Mosher’s acid; CCILs; DABCO.
22 23 24 25 26 27 28 29 30 31 32 33 34 1
35
1. Introduction
36
Chiral ionic liquids are a sub-class of ionic liquids which possess similar properties like low
37
melting and boiling points, negligible vapour pressure, high thermal stability, electrical
38
conductivity and reusability [1-5]. CILs can be synthesized by two methods: asymmetric
39
synthesis and natural chiral pool (carbohydrates, amino acids, amino alcohols, alkaloids etc.)
40
[6-8]. Carrying such distinct properties, CILs play major role in wide range of applications
41
such as chiral recognition [9-10], organocatalysis [11-12], background electrolytes in
42
capillary electrophoresis [13-15], stationary phase additives in liquid and gas chromatography
43
[16-17], high performance liquid chromatography [18-19], liquid-liquid extraction [20] and
44
stereoselective polymerization [21-22]. Nowadays, chiral molecular recognition and
45
asymmetric organocatalysis are the two most intensively analysed applications of CILs [23-
46
24]. Both the terms include ‘chirality’ in their meanings and are highly useful for the
47
separation and synthesis of numerous essential enantioselective compounds. Different
48
mechanisms are followed by both the processes to obtain single enantiomer in major amount
49
of the product. Chiral recognition is observed due to the formation of diastereomeric complex
50
between CIL (host) and enantiomers of racemic salt (guest) [25]. According to A. Berthod,
51
chiral recognition involves ‘three point interaction’ model. This model predicts the attractive
52
or repulsive interactions of three groups of the chiral centre with enantiomers of racemic
53
moiety [26]. Different types of non-covalent molecular interactions are generated between the
54
host and guest molecules like electrostatic interactions, hydrogen bonding, π − π
55
interactions, van der waals forces and hydrophobic interactions which help in the separation
56
of enantiomers [27]. Several spectroscopic and chromatographic techniques are available to
57
check the separation of enantiomers of the molecules such as NMR spectroscopy,
58
fluorescence spectroscopy, circular dichroism, HPLC, gas chromatography, capillary
59
electrophoresis, capillary electrochromatography, micellar chromatography, supercritical
60
chromatography etc. [28]. Among these, NMR spectroscopy is the easiest and the most
61
reliable technique to determine the separation and enantiopurity of the compound by just
62
observing the chemical shift of the corresponding peaks. Chiral recognition through NMR
63
spectroscopy is based on two main approaches: the use of chiral solvating agent (CSA) and
64
enantiopure chiral derivatizing agent [29].
65
In the present report, CILs have been synthesized from derivative of D-galactose and 1,4-
66
Diazabicyclo[2.2.2]octane (DABCO), further these CILs have been employed as chiral
67
recognising agents for the enantiodifferentiation of sodium salt of Mosher’s acid and as
68
organocatalyst in the enantioselective reduction reactions of prochiral ketones. Galactose was 2
69
used as precursor for the preparation of CILs because it is abundantly present in nature,
70
thermally stable, easy to handle and number of chiral centres are present in its structure. The
71
synthesized CILs are advantageous in terms of easy availability of chiral carbohydrate
72
precursors, excellent yields, moderate reaction conditions and remarkable applications.
73
Separation of the enantiomers were analysed through
74
enantiomeric excess of the obtained secondary alcohols was determined by gas
75
chromatography.
76
2. Experimental
77
2.1 Materials and methods
78
All the chemicals: D-galactose (spectrochem), ZnCl2, imidazole, iodine (Alfa aesar),
79
triphenylphosphine, 1,4-diazabicyclo[2.2.2]octane (DABCO) (Sigma-Aldrich), NaBF4, KPF6,
80
NaBrCH2CH2SO3, NaCF3SO3, NaSbF6 (Sigma-Aldrich), were purchased from commercial
81
suppliers and are of high purity. Acetone was dried over molecular sieves of pore size 0.3nm.
82
Formation of the product was analysed through pre-coated Merck TLC silica gel 60 sheets.
83
Then characterization of the obtained products was done through 1H,
84
NMR spectroscopy on Bruker Avance II, 400 MHz NMR spectrometer. Mass of the
85
synthesized compounds were analysed on Shimadzu GCMS-QP 2010 Ultra in EI mode.
86
Optical activity of the synthesized CILs was recorded on Anton Paar polarimeter MCP 500 at
87
589 nm wavelength at room temperature. As the CILs were solid in nature, so their melting
88
points or decomposition temperatures were taken on digital melting point apparatus and
89
reported uncorrected. In application part of chiral recognition, 19F NMR was recorded on 400
90
MHz JEOL JNM ECS400 and BRUKER AVANCE NEO 500MHz NMR spectrometer.
91
Enantiomeric excess of the optically active secondary alcohols were analysed on Shimadzu
92
GCMS-QP 2010 Ultra in split mode using Rt-βDEXsm column (30 m × 0.25 mm × 0.25
93
µm) using FID as detector.
94
2.2 Procedure for the synthesis of (3aS,5R,5aS,8aR,8bS)- 2,2,7,7-tetramethyltetrahydro-3aH-
95
bis[1,3]dioxolo[4,5-b:4’5’-d]pyran-5-yl)methanol (1):
96
Protection of the hydroxyl groups in carbohydrate chemistry is a common trend with various
97
protecting groups. Similarly, here in this report, secondary ‘OH’ groups were protected by
98
acetone using ZnCl2 in the presence of H2SO4 as catalyst, by following the procedure
99
described in the literature [30].
19
F NMR spectroscopy and
13
C,
11
B,
31
P and
19
F
100
2.2.1 (3aS,5R,5aS,8aR,8bS)- 2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4’5’-
101
d]pyran-5-yl)methanol (1): transparent oil, 79% yield, 1H NMR (CDCl3, 400 MHz): δ 5.57-
102
5.55 (d, 1H, J= 5Hz ), 4.62-4.60 (dd, 1H, J= 7.9Hz), 4.34-4.32 (dd, 1H, 5Hz), 4.28-4.26 (dd, 3
103
1H, J=7.9Hz), 3.89-3.80 (m, 2H), 3.74-3.70 (q, 1H), 2.73 (broad s, 1H), 1.53 (s, 3H), 1.45 (s,
104
3H), 1.33 (s, 6H).
105
2.3 Procedure for the substitution of iodine at primary ‘OH’ group (2):
106
Iodination of primary ‘OH’ group by using iodine accompanied with imidazole and PPh3 was
107
done through a procedure as described in the literature [31].
108
2.3.1(3aS,5R,5aS,8aR,8bS)-5-(iodomethyl)-2,2,7,7-tetramethyltetrahydro-3aH-
109
bis[1,3]dioxolo[4,5-b:4’5’-d]pyran(2): transparent oil, yield 82%, [α]25D = -64.9 (c, 0.25,
110
CH3OH), 1H NMR (CDCl3, 400 MHz): δ 5.54-5.53 (d, 1H, J= 5Hz), 4.62-4.60 (dd, 1H, J= 7.8
111
Hz), 4.41-4.39 (dd, 1H, 7.8Hz), 4.31-4.29 (dd, 1H, J= 5Hz), 3.96-3.92 (m, 1H), 3.34-3.30 (q,
112
1H), 3.23-3.18 (1H), 1.54 (s, 3H), 1.44 (s, 3H), 1.35-1.33 (d, 6H).
113
MHz): 109.52, 108.87, 96.67, 71.55, 71.07, 70.52, 68.91, 29.69, 26.02, 25.94, 24.87, 24.42.
114
2.4 Procedure for the synthesis of 1-(((3aS,5S,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-
115
3aH-bis[1,3]dioxolo[4,5-b:4’,5’-d]pyran-5-yl)methyl)-4-aza-1-azoniabicyclo[2.2.2]
116
iodide(CIL 3):
117
Compound (3) was synthesized by simple and efficient method. 5mmol of compound (2) was
118
dissolved in acetonitrile with equimolar of DABCO. Reaction mixture was put on refluxing at
119
80oC for 4-5 days. Progress of the reaction was checked through TLC in CHCl3/CH3OH
120
solvent system. On completion of the reaction, crude was extracted with mixture of toluene
121
and diethyl ether several times to yield the pure product [32].
122
2.4.11-(((3aS,5S,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-
123
b:4’,5’-d]pyran-5-yl)methyl)-4-aza-1-azoniabicyclo[2.2.2] octane iodide(CIL 3):White solid,
124
yield 75%, [α]25D = -33.2 (c, 0.25, CH3OH), 1H NMR (CDCl3, 400 MHz): δ 5.54-5.53 (d, 1H,
125
J= 5Hz), 4.66-4.63 (dd, 1H, J=7.8Hz), 4.52-4.41 (m, 3H), 4.37-4.35 (dd, 1H, 5Hz), 4.05-3.98
126
(m, 3H), 3.68-3.61 (m, 3H), 3.46-3.40 (q, 1H), 3.25-3.21 (t, 6H), 1.58 (s, 3H), 1.43 (s, 3H),
127
1.33-1.31 (d, 6H). 13C NMR (CDCl3, 100 MHz): 109.99, 109.32, 96.37, 70.87, 70.61, 69.88,
128
63.50, 62.56, 53.85, 45.44, 26.13, 23.06, 24.69, 24.39. EI-MS m/z: 355 [M]+.
129
2.5 Procedure for the synthesis of CILs from 4-8:
130
Procedure of anion metathesis was followed for the synthesis of CILs from 4-8. 1mmol of
131
CIL (3) and little in excess than equimolar sodium and potassium inorganic salts were
132
dissolved in 10ml of distilled water. The reaction mixture was put on stirring for 8-10 h. Then
133
the crude was extracted with chloroform to obtain the desired product except for CILs 5 and 8
134
because they get precipitated after half an hour and was insoluble in water. So, CILs 5 and 8
135
were filtered from the mixture.
13
C NMR (CDCl3, 100
octane
4
136
2.5.11-(((3aS,5S,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-
137
b:4’,5’-d]pyran-5-yl)methyl)-4-aza-1-azoniabicyclo[2.2.2]octane tetrafluoroborate (CIL 4):
138
Off-white solid, yield 70%, [α]25D = -25.4, (c, 0.25, CH3OH), 1H NMR (CDCl3, 400 MHz): δ
139
5.54-5.52 (d, 1H, J= 5Hz), 4.66-4.63 (dd, 1H, J=7.8Hz), 4.46-4.43 (d, 1H, J=10.6Hz), 4.37-
140
4.35 (dd, 2H, J= 5Hz), 4.14-4.10 (d, 1H, J= 13.7Hz), 3.85-3.84 (d, 3H, J= 4Hz), 3.56-3.50 (q,
141
3H), 3.41-3.35 (q, 1H), 3.30-3.22 (m, 6H), 1.56 (s, 3H), 1.42 (s, 3H), 1.33-1.31 (d, 6H). 13C
142
NMR (CDCl3, 100 MHz): 109.95, 109.41, 96.42, 70.85, 70.63, 69.98, 63.28, 62.62, 53.91,
143
45.43, 29.70, 26.12, 25.98, 24.70, 24.25. EI-MS m/z: 355 [M]+.
144
2.5.21-(((3aS,5S,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-
145
b:4’,5’-d]pyran-5-yl)methyl)-4-aza-1-azoniabicyclo[2.2.2] octane hexafluorophosphate (CIL
146
5):White solid, yield 73%, [α]25D = -27.7 (c, 0.25, CH3CN), 1H NMR (CDCl3, 400 MHz): δ
147
5.58-5.56 (d, 1H, J=5Hz), 4.70-4.67 (dd, 1H, J=7.6Hz), 4.46-4.44 (dd, 1H, J=5Hz), 4.25-
148
4.20 (t, 2H,), 3.53 (s, 1H), 3.46-3.42 (m, 4H), 3.28-3.26 (m, 3H), 3.07-3.03 (q, 6H), 1.52 (s,
149
3H), 1.39 (s, 3H), 1.31 (s, 6H).
150
70.67, 69.57, 63.84, 62.08, 53.54, 45.06, 26.36, 26.19, 25.05, 24.68. EI-MS m/z: 355 [M]+.
151
2.5.31-(((3aS,5S,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-
152
b:4’,5’-d]pyran-5-yl)methyl)-4-aza-1-azoniabicyclo[2.2.2]octane bromoethanesulfonate (CIL
153
6): Light green solid, yield 69%, [α]25D = -32.5, (c, 0.25, CH3OH), 1H NMR (CDCl3, 400
154
MHz): δ 5.54-5.53 (d, 1H, J= 5Hz), 4.66-4.63 (dd, 1H, J=7.7Hz), 4.46-4.35 (m, 4H,), 4.01-
155
3.98 (t, 3H, 4.5Hz), 3.66-3.60 (dd, 3H, J=17.8Hz), 3.48-3.42 (t, 1H,), 3.26-3.22 (t, 6H), 1.58
156
(s, 3H), 1.44 (s, 3H), 1.33-1.31 (d, 6H). 13C NMR (CDCl3, 100 MHz): 109.95, 109.36, 96.38,
157
70.87, 70.59, 69.90, 62.61, 53.82, 45.42, 26.10, 26.00, 24.70, 24.29. EI-MS m/z: 355 [M]+.
158
2.5.41-(((3aS,5S,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-
159
b:4’,5’-d]pyran-5-yl)methyl)-4-aza-1-azoniabicyclo[2.2.2]octane trifluoromethanesulfonate
160
(CIL 7): Off-white solid, yield 72%, [α]25D = -26.3, (c, 0.25, CH3OH), 1H NMR (CDCl3, 400
161
MHz): δ 5.54-5.53 (d, 1H, J=5Hz), 4.66-4.63 (dd, 1H, J=7.8 Hz), 4.43-4.41(d, 1H, J=24.7),
162
4.37-4.34 (m, 2H), 4.15-4.11 (dd, 1H, J=14Hz), 3.92-3.87 (m, 3H), 3.59-3.52 (m, 3H), 3.48-
163
3.42 (t, 6H), 1.56 (s, 3H), 1.44 (s, 3H), 1.35-1.33 (d, 6H).
164
109.98, 109.38, 96.39, 70.91, 70.61, 69.89, 63.35, 62.59, 53.81, 45.38, 29.71, 25.95, 25.92,
165
24.69, 24.27. EI-MS m/z: 355 [M]+.
166
2.5.51-(((3aS,5S,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-
167
b:4’,5’-d]pyran-5-yl)methyl)-4-aza-1-azoniabicyclo[2.2.2]octane hexafluoroantimonate (CIL
168
8): White solid, yield 65%, [α]25D = - 28.7 (c, 0.25, CH3CN), 1H NMR (CDCl3, 400 MHz): δ
13
C NMR (CDCl3, 100 MHz): 109.84, 108.86, 96.34, 71.73,
13
C NMR (CDCl3, 100 MHz):
5
169
5.54-5.53 (d, 1H, J=5Hz), 4.65-4.63 (dd, 1H, J=7.8Hz ), 4.46-4.35 (m, 4H), 4.06-4.00 (m,
170
3H), 3.68-3.62 (m, 3H), 3.52-3.46 (t, 1H), 3.26-3.23 (t, 6H, J=7.5Hz), 1.58 (s, 3H), 1.44 (s,
171
3H), 1.35-1.33 (d, 6H).
172
69.86, 63.05, 62.55, 53.82, 45.42, 29.60, 26.13, 26.03, 24.70, 24.32. EI-MS m/z: 355 [M]+.
173
2.6 General procedure for the enantioselective reduction of prochiral ketones
174
Prochiral ketones (1mmol) were dissolved in a solution of 10 ml methanol. 10 mol% of CIL
175
was added to the above solution and stirred. Sodium borohydride (1.5mmol) was added in
176
portions over a period of 15 mins. The stirring was continued for 2-3 h and then the mixture
177
was extracted with dichloromethane/diethyl ether. Then, the organic layer was dried over
178
Na2SO4 and evaporates it on rotary evaporator to get the product [33]. Enantiomeric excess of
179
the alcohols was determined through GC.*
180
(-) 1-Phenylethanol: GC analysis Rt-βDEXsm column, split mode carrier gas helium,
181
makeup gas helium, column oven temperature= 120 oC, injection temperature 230 oC, flow
182
rate 0.80ml/min, t1= 10.62 min, t2= 10.81 min.
183
(-) 1-(2-Hydroxyphenyl)ethanol: GC analysis Rt-βDEXsm column, split mode carrier gas
184
helium, makeup gas helium, column oven temperature= 120 oC, injection temperature 230
185
o
186
(-)1-(4-Hydroxyphenyl)ethanol: GC analysis Rt-βDEXsm column, split mode carrier gas
187
helium, makeup gas helium, column oven temperature= 120 oC, injection temperature 230
188
o
189
(-)1-(4-Bromophenyl)ethanol: GC analysis Rt-βDEXsm column, split mode carrier gas
190
helium, makeup gas helium, column oven temperature= 120 oC, injection temperature 230
191
o
192
(-)1-(4-Methylphenyl)ethanol: GC analysis Rt-βDEXsm column, split mode carrier gas
193
helium, makeup gas helium, column oven temperature= 120 oC, injection temperature 230
194
o
195
(-)1-(4-Chlorophenyl)ethanol: GC analysis Rt-βDEXsm column, split mode carrier gas
196
helium, makeup gas helium, column oven temperature= 120 oC, injection temperature 230
197
o
198
(-)1-(4-Nitrophenyl)ethanol: GC analysis Rt-βDEXsm column, split mode carrier gas
199
helium, makeup gas helium, column oven temperature= 120 oC, injection temperature 230
200
o
201
*GC chromatograms are provided in supplementary information.
13
C NMR (CDCl3, 100 MHz): 109.98, 109.31, 96.36, 70.85, 70.59,
C, flow rate 0.80ml/min, t1= 18.90 min, t2= 19.04 min.
C, flow rate 0.80ml/min, t1= 16.53 min, t2= 16.70 min.
C, flow rate 0.80ml/min, t1= 17.95 min, t2= 18.01 min.
C, flow rate 0.80ml/min, t1= 12.72 min, t2= 12.90 min.
C, flow rate 0.80ml/min, t1= 15.99 min, t2= 16.09 min.
C, flow rate 0.80ml/min, t1=16.17 min, t2= 16.37 min.
202 6
203
2.7 Procedure for the chiral recognition using Mosher’s acid salt
204
0.013 mmol (4.6 mg) of sodium salt of Mosher’s acid was dissolved in acetonitrile (1ml) with
205
0.027 mmol (13 mg) of CIL 3. The reaction mixture was stirred for 12 h, so that anions get
206
exchanged. The solvent was filtered and evaporated. Residual was dissolved in CDCl3 and
207
analysed by NMR [34].
208
3. Results and discussion
209
A new series of carbohydrate based chiral ionic liquids have been synthesized with highly
210
nucleophilic amine, i.e., 1,4-Diazabicyclo[2.2.2]octane, under mild conditions. D-galactose
211
was used as an initiator for the synthesis of the desired CILs. In the first step, four secondary
212
hydroxyl groups of D-galactose were protected by acetone in presence of ZnCl2 and H2SO4 to
213
give (1). The primary ‘OH’ group of (1) was then replaced with iodide to give (2) which on
214
quaternization with a strong nucleophilic amine DABCO (Scheme 1) to gain CCIL (3). CCIL
215
(3) was then led to anion metathesis reaction with various sodium and potassium salts of
216
inorganic compounds to give CCILs 4-8. All the ILs was solid in nature, possessed nice
217
yields, had high decomposition temperatures, and was non-racemic in nature. Composition
218
and stability of all the CCILs were confirmed through various analytical techniques like 1H,
219
13
220
was detected through polarimetery. All the data has been provided in the supplementary
221
information.
C,
11
B,
31
P,
19
F NMR spectroscopy, EI-mass spectrometry, and their non-racemic nature
222 223
Scheme 1
224
All the important physical properties of the CCILs (3-8) have been displayed in Table 1.
225
There is little bit variation in the 1H spectra of all the CCILs, peaks corresponding to NCH2-
226
CH(on galactose ring). As observed in 1H spectra of the ILs with anion I- and SbF6-, the peaks 7
227
get merged and give multiplet but in rest of the cases, they are notified separately. It is also
228
possible that these protons might be helpful in chiral recognition application of sodium salt of
229
Mosher’s acid using CCILs as host.
230
Table 1: Important physical properties of CCILs (3-8) Entry
CCILs
Physical state
Yield (%)
Tda
1
I-
White solid
75%
189-192
-33.2
Off-white solid
70%
222-224
-25.4
-
b
[α]25D
2
BF4
3
PF6-
White solid
73%
249-252
-27.7
4
BrCH2CH2SO3-
Light green solid
69%
198-200
-32.5
5
CF3SO3-
Off-white solid
72%
178-182
-26.3
6
SbF6-
White solid
65%
202-206
-28.7
231 232
a
233
The specific rotations of the non-racemic ILs were shown in negative sign. I- exhibit
234
maximum optical activity than the rest CCILs and BF4- the minimum, the [α]25D values have
235
been shown in Fig 1. Decomposition temperature varies from 178 oC to 252 oC.
b
Decomposition temperature. For PF6- and SbF6-, acetonitrile was used while recording specific rotation.
236
237 238
Fig 1: Graphical representation of specific rotations of CCILs
239
3.1 Application of chiral recognition using Mosher’s acid salt with CCIL (3)
240
CCILs were tested as chiral recognizing agents using sodium salt of Mosher’s acid as analyte.
241
CCIL (3) and Mosher’s salt were mixed in acetonitrile for the anion exchange process for 12
242
h. Residual was dissolved in deuterated CHCl3 and analysed through 19F NMR. To check the
8
243
optimal amount of CCIL required for the recognition property, a variable amount of CCIL
244
was added against the constant amount of Mosher’s acid sodium salt. Data has been provided
245
in Table 2 and
246
the CCIL increased from 8 equiv. to 10 equiv., the magnitude of the splitting decreased from
247
25Hz to 20 Hz and no splitting was observed at lower concentrations of CIL.
248
Table 2: Chemical shift values (Hz) of Mosher’s acid salt with CCIL (3) CCIL (3) Mosher’s acid Chemical shift value Entry (Equiv.) sodium salt (Equiv.) in Hz a 1 2 1 NS b
19
F NMR spectra in the supplementary information. As the concentration of
2
4
1
NS
3
6
1
NS
4
8
1
25
5
10
1
20
249 250
a
Recorded by 19F NMR. b No Splitting.
251
Chiral recognition property and magnitude of the splitting exhibited by the CILs may also
252
depend upon the anion attached with cationic moiety, as evidenced from the literature that Cl,
253
BF4- and PF6- anions form strong ionic pairs with the guest and provide more
254
enantiodifferentiation than the other anions [35]. Second important reason behind chiral
255
recognition property may be the presence of aromatic ring in the host and guest which gives
256
magnetic anisotropic effect, provide π − π interactions and helps in separation of the
257
enantiomers of the guest [27]. Fig 2 demonstrates the chiral recognition mechanism in terms
258
of the different diastereomeric interactions between the CIL and the racemic Mosher’s acid
259
analyte.
260 261
Fig 2: Chiral recognition of Mosher’s acid salt using CCIL 3
262
3.2 Application of CCIL (3) as organocatalyst in asymmetric reduction reactions:
263
A number of reports are available in which CILs have been used as organocatalysts and
264
achieved high enantiomeric excess in many important reactions of organic chemistry like 9
265
Baylis-Hillman, Michael Addition, Diels-Alder, Aldol condensation etc. [36]. Similarly, here
266
in the present article, CCIL (3) was used as organocatalyst in the asymmetric reduction of
267
aromatic prochiral ketones to synthesize corresponding enantioselective secondary alcohols.
268
Products were obtained in high yields and produced low to moderate enantiomeric excess as
269
shown in Table 3. Procedure for the synthesis of enantioselective secondary alcohols, using
270
various substrates can be easily described from Scheme 2 shown below.
271 272 273
Scheme 2
274 275
Table 3: Description of enantiomeric excess using CCIL (3) Prochiral Ketone Entry Yield (%) Time (h) (1mmol) 1 Acetophenone 78 2.5
Ee(%) b
Solvent
17
MeOH
2
2-Hydroxy ACP a
63
3
6
MeOH
3
4- Hydroxy ACP
70
2
5
MeOH
4
4-Bromo ACP
81
2
9
MeOH
5
4-Methyl ACP
74
2
rac
MeOH
6
4-Chloro ACP
85
2
9
MeOH
7
4-Nitro ACP
80
3
6
MeOH
276 277
a
278
Above table reveals that racemic to moderate enantiomeric excess has been obtained,
279
acetophenone produced higher ee% than the other ketones and 4-methylacetophenone was
280
obtained as a racemic mixture, this trend in the enantioselectivity has already been described
281
in literature also [37-38]. But the yield of the secondary alcohols was good in all the cases.
282
4. Conclusions
283
It is concluded that carbohydrate-based chiral ionic liquids were synthesized using DABCO
284
as quaternizing agent. Synthesized chiral salts were employed as a chiral recognising agent
285
and as organocatalyst and they perform nicely in both the applications. Precursors used for
286
their synthesis part are natural and present abundantly in nature. So, they can be readily
287
prepared and can replace the expensive enantiodifferentiating agents and organocatalysts in
288
future.
b
ACP= acetophenone, rac= racemic Ee was analysed through chiral GC column.
289
10
290
Acknowledgement
291
Authors are highly thankful to the authorities of Sant Longowal Institute of Engineering and
292
Technology, Longowal for providing all the research facilities to carry out the research work.
293
Appendix A. Supplementary information
294
All the NMR spectra (both synthesis and application part), mass spectra, GC chromatograms
295
are provided in the supplementary information.
296
References:
297
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14
Applications of Carbohydrate based Chiral Ionic Liquids as Chiral Recognition Agents and Organocatalysts Nirmaljeet Kaur and Harish Kumar Chopra* Department of Chemistry, Sant Longowal Institute of Engineering and Technology, Longowal-148106, Distt. Sangrur (Pb.), India: Email:[email protected] Tel: +91-1672-253204, Fax: +91-1672-280072. ___________________________________________________________________________ Highlights •
Chiral ionic liquids (CILs) were synthesized from naturally abundant source Dgalactose and obtained with high yield.
•
Synthesized ILs was stable at the higher temperature.
•
CILs worked efficiently as a chiral recognising agent.
•
CILs worked as organocatalysts and produce moderate enantiomeric excess.