Controlling chlorination versus cyclosulfonation of cis-diols using ionic liquid solvents

Article abstract of DOI:10.1039/c2nj40180k

Diol reactivity can be manipulated in ionic liquids to selectively give chlorinated or cyclic sulfite/sulfate products depending on the ionic liquid used and the presence or absence of base. In comparison with reactions in dichloromethane, the ionic liqui

Full text of DOI:10.1039/c2nj40180k

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PAPER
Controlling chlorination versus cyclosulfonation of cis-diols using ionic
liquid solventsw
Christopher Hardacre,*a Marie E. Migaud*b and Kerry Anne Nessb
Received (in Montpellier, France) 8th March 2012, Accepted 9th August 2012
DOI: 10.1039/c2nj40180k
Diol reactivity can be manipulated in ionic liquids to selectively give chlorinated or cyclic
sulfite/sulfate products depending on the ionic liquid used and the presence or absence of base.
In comparison with reactions in dichloromethane, the ionic liquid mediated reactions show
greatly improved yields and product stability.
Although chlorination of simple alcohols is a commonplace
1. Introduction
reaction, with numerous examples available, studies on the
Alkyl halides have widespread use as reagents for bulk alkyla-
exhaustive dichlorination of vicinal diols are much more limited.
tion, in the preparation of valuable synthetic intermediates, as
In most reports, diols are reacted with PCl3, PCl5 or HCl at high
temperatures, or alkenes are reacted with dihalogens.11,12 Alter-
radio labelled markers in diagnostics, and as bioactive sub-
stances in the pharmaceutical industry.1 Halogenated organics
natively, dichlorination can be achieved in 2 steps via a ditosyl
intermediate in average yields as described by Leiris et al.13 In
are also used in bulk as agrochemicals, pigments, and photo-
graphic materials. There are many approaches to prepare such
ILs, Villorbina et al. described dichlorination reactions in a
hydrophilic IL,12 using AlCl3Á6H2O in the presence of carboxylic
alkyl halides, with the most common protocols involving
conversion of alcohols, due to their ready availability. On
acids at temperatures over 100 1C, whereby starting from
glycerol, chlorohydrin esters were prepared as a mixture of
both laboratory and industrial scales, chlorinating agents such
as SOCl2, SO2Cl2, PCl3, PCl5, TMSCl, (COCl)2, PPh3/CCl4,
1,2- and 1,3-dichloro derivatives with varying success. The
phosgene or HCl gas are commonly used.2 In all cases,
variability in yields and product outcomes that are observed
handling of such reagents, the generation of HCl gas, and
across the range of dichlorination reactions, both in organic and IL
the facile occurrence of side reactions mean that alternative
solvents, needs to be addressed if improved reaction conditions and
synthetic processes would be highly valuable.
scale-up protocols are to be effectively implemented. Following our
There are a few examples of halogenation reactions in ionic
success in stabilising thionyl- and sulfuryl-chlorides in ILs thus
liquids (ILs) reported in the literature. Nucleophilic halogena-
enabling formation of sulfite and sulfate derivatives of carbo-
tion has been described in ILs with BrÀ, ClÀ, [BF4]À and
hydrates with much improved yields.14,15 We report here the
[PF6]À anions, whereas electrophilic substitutions have been
use of ILs to modulate chlorination versus sulfonation of a
range of diols. 2H NMR was used to monitor the reactions and
carried out in halide-containing ILs using acid catalysts with the
IL acting as the halogen source.3–9 For example, halogenation
demonstrates how the chemoselectivity and product distribu-
by SN2-type substitution reactions between alkyl mesylates and
tion can be controlled by using IL solvents.
KCl in the IL, [C4mim][BF4], was improved through enhanced
halide nucleophilicity in that solvent.3 However, in many cases,
2. Experimental
halogenation reactions in ILs are side reactions, leading to
undesirable by-products and reductions in yield and selectivity.1
Spectroscopic details
For example, significant decreases in yield were observed during
All 1H, 13C and 2H nuclear magnetic spectra were collected on
the nitration of arenes in chloride-based ILs, with chlorinated
aryls produced as the main products of the reaction.10
a Bruker Avance 500 spectrometer at 25 1C. The chemical
shifts are in parts per million (ppm). H data were measured
2
relative to an internal probe (capillary tube) of benzene-d6
(C6D6) referenced to 7.16 ppm. All other NMR spectra were
measured in CDCl3 (referenced to 7.27 ppm in 1H and 77.00 ppm
in 13C) unless otherwise stated.
a School of Chemistry and Chemical Engineering, David Keir Building,
Stranmillis Road, Queen’s University, Belfast, BT9 5AG, UK.
E-mail: c.hardacre@qub.ac.uk; Fax: +44 (0)28 9097 4687;
Tel: +44 (0)2890 974592
b School of Pharmacy, 97 Lisburn Road, Queen’s University, Belfast,
BT9 7BL, UK. E-mail: m.migaud@qub.ac.uk;
Preparation of air-equilibrated ‘wet’ ILs
Fax: +44 (0)289024 7794; Tel: +44 (0)2890 972689
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2nj40180k
1-Butyl-1-methyl-pyrrolidinium bis{(trifluoromethyl)sulfonyl}-
imide [C4mpyrr][NTf2] was prepared in house using standard
c
2316 New J. Chem., 2012, 36, 2316–2321
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literature methods from 1-butyl-1-methyl-pyrrolidinium bromide.16
The bromide content of the ionic liquid was measured using
ion chromatography and was below 5 ppm. The ionic liquid
was used without drying and was found to have a water
content of 0.03 wt% analysed via Karl Fischer titration.
1-Butyl-1-methyl-pyrrolidinium tris(pentafluoroethyl)trifluoro-
phosphate [C4mpyrr][FAP] was obtained from Merck KGa and
was used without drying and was found to have a water content
of 0.01 wt% analysed via Karl Fischer titration. The present
study was conducted in ‘wet’ ILs, which were left open to the air
prior to use to allow air equilibration. Prior to use, a sample of
each IL was removed for water content analysis via Karl
Fischer titration. Immobilised morpholine refers to polymer
bound morpholine purchased from Sigma-Aldrich.
(500 MHz, CDCl3) Àd 4.32 (s, 1H, CHDOS), 4.57
(s, 1H, CHDOS); 13C-NMR: (70 MHz, CDCl3) Àd 67.1
(t, 2CDHOSO).
Ethylene glycol sulfate-d2 1H-NMR: (500 MHz, CDCl3) Àd
3.40 (m, CHOSO2), 3.58 (m, CHOSO2), 3.67 (m, CHOSO2),
3.72 (m, CHOSO2); 2H-NMR: (500 MHz, CDCl3) Àd 4.43
(s, 1D, CHDOSO2), 4.03 (s, 1D, CHDOSO2), 3.90 (s, 1D,
CHDOSO2), 3.73 (s, 1D, CHDOSO2), 13C-NMR: (70 MHz,
CDCl3) Àd 66.4 (s, 2CDHOSO2).
2,3-Butanediol sulfite-d2 1H-NMR: (500 MHz, CDCl3)
Àd 1.55 (s, 3H, CH3SO), 1.47 (s, 3H, CH3SO); 2H-NMR:
(500 MHz, CDCl3) Àd 5.06 (s, 1H, CDSO), 4.66 (s, 1H,
CDSO); 13C-NMR: (70 MHz, CDCl3) Àd 20.4 (CDSO), 17.7
(CDSO), 15.7 (CH3), 14.3(CH3).
2,3-Butanediolsulfate-d2 2H-NMR: (500 MHz, CDCl3)
Àd 3.95 (s, 1D, CDOSO2) in FAP IL.
Synthesis of deuterated diols
Cyclohexanediol sulfite-d2 2H-NMR: (500 MHz, CDCl3)
Àd 5.29 (s, 2D, cis-CDOSO), 4.14 (s, 1D, trans-CDOSO), 3.53
(s, 1D, trans-CDOSO) in FAP IL.
The deuterated diols were synthesised from their corre-
sponding aldehydes and ketones (1 eq.) by reduction with
sodium borodeuteride (1.2 eq.) to give the primary and
secondary diols and the tertiary diol via a Grignard reaction
using iodomethane-d3 (1.2 eq.).
Ethylene glycol-d2 1H-NMR: (400 MHz, D2O) Àd 3.23
(s, 2H, 2CDHOH); 2H-NMR: (400 MHz, C6D6) Àd 3.62
(s, 2D, 2xCDHOH); 13C-NMR (70 MHz, D2O) Àd 62.1
(t, 2CDHOH).
Cyclohexandiol sulfate-d2 2H-NMR: (500 MHz, CDCl3)
Àd 5.25 (s, 2D, cis-CDOSO2), 4.19 (s, 1D, trans-CDOSO2),
4.01 (s, 1D, trans-CDOSO2), 3.78 (s, 1D, trans-CDOSO2), 3.67
(s, 1D, trans-CDOSO2) in FAP IL.
Formation of cyclic sulfites and sulfates in dichloromethane
To 2 ml of dichloromethane stirred under argon, was added
the diol (0.30 mmol) and immobilised morpholine (0.90 mmol).
Thionyl or sulfonyl chloride (0.36 mmol) was added to the
resulting suspension and the reaction mixture was allowed to
stir gently at room temperature overnight. Samples were then
added directly to NMR tubes with benzene-d6 probes and
were analysed by deuterium NMR spectroscopy.
2,3-Butanediol-d2 1H-NMR: (500 MHz, D2O) Àd 0.99
(s, 3H, CH3), 1.20 (s, 3H, CH3); 2H-NMR: (500 MHz,
C6D6) Àd 3.18 (s, 2D, CDCH3OH); 13C-NMR: (70 MHz,
D2O) Àd 17.4 (CDCH3OH), 16.5 (CH3).
Pinacol-d6 1H-NMR: (500 MHz, D2O) Àd 1.39 (m, CH3COH);
2H-NMR: (500 MHz, C6D6) Àd 1.38 (s, 3D, CD3COH);
13C-NMR: (70 MHz, D2O) Àd 216.4 (Cø), 32.0 (2CH3),
24.5 (2CD3).
Formation of cyclic sulfites and sulfates in ILs
1,2-Cyclohexanediol-d2 1H-NMR: (500 MHz, D2O) Àd 3.20
(s, 2H, CH2), 2.11 (t, 4H, 2xCH2), 1.76 (t, 2H, CH2);
2H-NMR: (500 MHz, C6D6) Àd 4.40 (s, 1D, trans-CDOH),
3.57 (s, 2D, cis-CDOH), 3.14 (s, 1H, trans-CDOH); 13C-NMR:
(70 MHz, D2O) Àd 78.0 (2CDOH), 34.6 (2CH2), 21.8 (2CH2).
1,2-Dichloroethane-d2 1H-NMR: (400 MHz, CH3CN) Àd
3.64 (s, 2H, 2CDHCl); 2H-NMR: (400 MHz, CH3CN) Àd 3.63
(s, 2D, CDHCl); 13C-NMR: (70 MHz, CH3CN) Àd 61.45
(t, 2CDHCl).
To 2 ml of IL stirred under argon, was added diol (0.30 mmol)
and immobilised morpholine (0.90 mmol). To the resulting
suspension was added thionyl or sulfonyl chloride (0.36 mmol)
and the reaction mixture allowed to stir gently at room
temperature for 24 h. Samples were then added directly to
NMR tubes with benzene-d6 probes and were analysed by
deuterium NMR spectroscopy.
Reaction monitoring
2,3-Dichlorobutane-d2 1H-NMR: (500 MHz, CH3CN)
Àd 1.13 (s, 3H, CH3), 1.10 (s, 3H, CH3); 2H-NMR:
(500 MHz, CH3CN) Àd 3.63 (s, 2D, CDCH3Cl); 13C-NMR:
(70 MHz, CH3CN) Àd 17.6 (CDCH3Cl), 15.5 (CH3).
2,3-Dichloro-2,3-dimethylbutane-d6 1H-NMR: (500 MHz,
Reactions were monitored after 24 h and 72 h with samples
taken directly from the reaction flask and analysed using
2H NMR with a deuterated benzene capillary as a reference.
All ratios were taken directly from the 2H NMR using the
ratio of deuterium peaks corresponding to starting material,
sulfite, sulfate and chlorination products.
2
CD3CN) Àd 1.10 (s, 3H CH3), 1.31 (s, 3H, CH3); H-NMR:
(500 MHz, CD3CN) Àd 1.26 (s, 3D, CD3), 1.05 (s, 3D, CD3);
13C-NMR: (70 MHz, CD3CN) Àd 179.7 (Cø), 25.0 (2CH3),
23.8 (2CD3).
3. Results and discussion
1,2-Dichlorocyclohexane-d2 1H-NMR: (500 MHz, CDCl3)
Àd 2.56 (t, 2H, CH2), 2.43 (t, 2H, CH2), 2.04 (m, 4H, 2xCH2);
2H-NMR: (500 MHz, CH3CN) Àd 2.31 (s, 1D, 2xCDCl);
13C-NMR: (70 MHz, CDCl3) Àd 36.6 (2CDCl), 23.8 (2CH2),
23.3 (2CH2).
The reaction of thionyl chloride and sulfonyl chloride in IL
solvents with a range of cis-diols, forming cyclic sulfite/sulfate
and dichlorinated derivatives was studied, and compared
with the analogous reactions in dichloromethane (DCM). In
order to examine the effects of the solvent on the com-
peting formation of chlorinated and cyclic diester products,
a range of diols (ethylene glycol, butane-2,3-diol, pinacol and
Ethylene glycol sulfite-d2 1H-NMR: (500 MHz, CDCl3)
2
Àd 4.66 (s, 1H, CHDOS), 4.33 (s, 1H, CHDOS); H-NMR:
c
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New J. Chem., 2012, 36, 2316–2321 2317

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Table 1 Formation and stability of cyclic sulfite and sulfate generated
from ethylene glycol (1) vs. dichlorination; in ILs and DCM after 24 h
Fig. 1 Deuteriated diols synthesised.
cyclohexane-1,2-diol, 1–4; Fig. 1) incorporating deuterium
labels were synthesised and used as diastereomeric mixtures,
2
allowing for H NMR to be used for in situ monitoring. The
%Products
synthesis of racemic diols was carried out by reduction of the
corresponding ketones or aldehydes to access the primary (1)
and secondary cis-diols (2, 4) and by the Grignard reaction to
prepare the tertiary diol (3). These diols were chosen in order
to identify mechanistic differences rising from their degree of
substitution and the effect of the ILs on SN1 vs. SN2 pathways.
The reactions with thionyl and sulfonyl chloride were carried
out by dissolving each diol in the solvent (IL or DCM) to yield a
solution to which the immobilised base was added (where used).
To the resulting system was then added SOCl2 or SO2Cl2 and
this mixture was stirred for 24 h. The use of the immobilised
base allowed for a simple workup by filtration of the resulting
immobilised morpholinium chloride salt. DCM reactions have
to be performed under anhydrous argon conditions whereas the
IL-based reactions could be conducted in air due to the
enhanced reagent stability of the reagents in ILs.14 After 24 h,
the reactions were sampled and analysed by 2H NMR spectro-
scopy, the results of which are shown in Tables 1–4. Two
hydrophobic ILs were used and compared with DCM, namely
1-butyl-1-methyl-pyrrolidinium bis{(trifluoromethyl)sulfonyl}-
imide [C4mpyrr][NTf2] and 1-butyl-1-methyl-pyrrolidinium
tris(pentafluoroethyl)trifluorophosphate, [C4mpyrr][FAP].
Equivalent reactions were also performed in 1-butyl-1-methyl-
pyrrolidinium tetrafluoroborate [C4mpyrr][BF4] and 1-butyl-1-
methyl-pyrrolidinium trifluoromethanesulfonate [C4mpyrr][OTf]
ILs; however, competing reactions between SOCl2 or SO2Cl2 and
the anions or decomposition products from the anions of the
ILs occurred, which prevented chlorination of the diols. For
example, fluorination of SOCl2 and generation of SOF2 (73 ppm
by 19F NMR) were rapidly observed when SOCl2 was dissolved
in [C4mpyrr][BF4]. It should be noted, attempts to conduct
fluorination reactions of diols using this in situ generated thionyl
fluoride in this solvent were unsuccessful. This behaviour of
SOCl2 and SO2Cl2 in similar ILs is consistent with previous
observations found upon dissolution of PCl3/POCl3 in such
hydrophilic ILs, whereby the counter ions or some of their
components do not remain inert towards the electrophilic
reagents (e.g. [BF4]À $ BF3 + FÀ).16
(1) (5) (6)
D
Entry Solvent
Base Reagent
1
2
3
[C4mpyrr][NTf2]
[C4mpyrr][FAP]
DCM
À
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
SO2Cl2
SO2Cl2
SO2Cl2
SO2Cl2
SO2Cl2
SO2Cl2
—
—
—
—
—
—
—
—
—
—
—
11
78
82
78
97
—
58
30
97
32
88
27
88
21
17
11 11
3
100
40
69
3
—
—
À
À
4
5
6
[C4mpyrr][NTf2]
[C4mpyrr][FAP]
DCM
+
+
+
À
—
—
—
—
—
7
8
9
[C4mpyrr][NTf2]
[C4mpyrr][FAP]
DCM
À
À
39 27
10
11
12
[C4mpyrr][NTf2]
[C4mpyrr][FAP]
DCM
+
+
+
12
73
1
—
—
—
D: decomposition products; no partial chlorination product was
detected.
Table 2 Formation and stability of cyclic sulfite and sulfate gener-
ated from butane-1,2-diol (2) vs. dichlorination, in IL and DCM, 24 h
reaction
%Products
(2) (7) (8)
D
Entry Solvent
Base Reagent
1
2
3
[C4mpyrr][NTf2]
[C4mpyrr][FAP]
DCM
À
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
SO2Cl2
SO2Cl2
SO2Cl2
SO2Cl2
SO2Cl2
SO2Cl2
—
—
—
—
—
—
—
—
13
—
—
—
44
55
60
28
70
45
33
39
11
25
46
25
28
27
1
—
—
2
2
6
5
28
18
37
72
27
52
65
54
68
74
52
70
À
À
4
5
6
[C4mpyrr][NTf2]
[C4mpyrr][FAP]
DCM
+
+
+
À
7
8
9
[C4mpyrr][NTf2]
[C4mpyrr][FAP]
DCM
À
À
10
11
12
[C4mpyrr][NTf2]
[C4mpyrr][FAP]
DCM
+
+
+
—
—
1
D: decomposition products; no partial chlorination product was
detected.
Table 1 shows the results from the reaction of ethylene
glycol with SOCl2 and SO2Cl2 in the presence, or absence of
immobilised base present in suspension, in [C4mpyrr][NTf2],
[C4mpyrr][FAP] and DCM. The formation of chlorinated or
cyclic sulfites/sulfates is dependent on the IL used, for example
the product distribution of reactions conducted in DCM and
[C4mpyrr][NTf2] is similar although the reactions in the IL
resulted in a higher conversion. In contrast, when these
reactions were conducted in [C4mpyrr][FAP], the selectivity
obtained was, in general, opposite to that found in DCM and
[C4mpyrr][NTf2] and where outcomes could be modulated by
the addition of base. For both ILs and DCM, the presence or
absence of base did have an effect on the selectivity, parti-
cularly where SO2Cl2 was used.
It is proposed that the outcomes of the reactions can be
potentially attributed to one or more changes in the physico-
chemical properties of the chloride ion during the reactions
under different conditions and solvents: (1) change in ClÀ
solubility, i.e. concentration; (2) change in ClÀ nucleophilicity;
and (3) difference in HCl solvation in the absence of base.
c
2318 New J. Chem., 2012, 36, 2316–2321
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Table 3 Formation and stability of cyclic sulfite and sulfate gener-
ated from pinacol (3) vs. chlorination, in IL and DCM, 24 h reaction
have examined extensively the effect of ILs on nucleophilic
substitution reactions, and found significant enhancements in
reactivity in ILs when compared with molecular solvents.17 In
reactions with SOCl2 (entries 1–3), predominantly the cyclic
sulfite was obtained, whereas in the reactions with SO2Cl2
(entries 7–9), the product distribution was highly dependent
on the solvent used. In the presence or absence of base,
[C4mpyrr][NTf2] favours cyclic sulfite or sulfate formation
(entries 1, 4 and 10).
%Products
The presence of immobilised base in the solution of SOCl2
or SO2Cl2 in [C4mpyrr][FAP] controls the reaction’s chemo-
selectivity, with quantitative chlorination found. Using the
[FAP]À based IL in the presence of base, increased formation
of the chlorinated product from 17% to 100% (with SOCl2)
and 3% to 73% (with SO2Cl2). In contrast, a decrease in
selectivity for the chlorinated product was observed in the
[NTf2]À based IL, and the same reaction without base (Scheme 1).
In the absence of base, this selectivity can be attributed to the
poor coordinating abilities of the IL cation with ClÀ and the
weak basicity of the IL anion thus facilitating the generation
and release of HCl(g) from the reaction mixture. Experiments
carried out where [C4mpyrr][Cl] was added following forma-
tion of the sulfite/sulfate showed that supplying the solution
with chloride ions caused the formation of the chlorinated
material by displacement of the sulfite/sulfate. In the presence
of base, it is proposed that the morpholinium chloride thus
generated remains as a tightly bonded ion pair when in
suspension in [C4mpyrr][NTf2] with little ClÀ available for
nucleophilic displacement. However, in [C4mpyrr][FAP], some
of the chloride ion is likely to remain in solution. Due to the
weaker Coulombic interaction of the [FAP]À with the
[C4mpyrr]+ cation compared with [NTf2]À the concentration
of chloride is likely to be larger in the [FAP]À based IL which
leads to the change in the observed chemoselectivity.
(3) (9) (10)
D
Entry Solvent
Base Reagent
1
2
3
[C4mpyrr][NTf2]
[C4mpyrr][FAP]
DCM
À
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
SO2Cl2
SO2Cl2
SO2Cl2
SO2Cl2
SO2Cl2
SO2Cl2
28
37
36
32
40
38
17
8
5
7
—
10
4
—
—
4
—
26
9
22
13
16
35
47
—
82
47
28
57
67
—
43
42
45
22
8
61
—
40
68
17
23
88
À
À
4
5
6
[C4mpyrr][NTf2]
[C4mpyrr][FAP]
DCM
+
+
+
À
7
8
9
[C4mpyrr][NTf2]
[C4mpyrr][FAP]
DCM
À
À
5
10
11
12
[C4mpyrr][NTf2]
[C4mpyrr][FAP]
DCM
+
+
+
—
—
—
12
D: decomposition products; no partial chlorination product was
detected.
Table 4 Formation and stability of cyclic sulfite and sulfate gener-
ated from cyclohexane-1,2-diol (4) (cis : trans 1 : 2 ratio) vs. chlorina-
tion, in IL and DCM, 24 h reaction
In addition, the greater hydrophobicity of [C4mpyrr][FAP]
compared with [C4mpyrr][NTf2] (B4 Â greater) results in a
lower saturation water content and less opportunity for the
hydrolysis of the sulfurylating reagents to occur in the IL
environment.13,17 The [FAP]À anion is also much larger than
the [NTf2]À and is an extremely poor hydrogen bond acceptor,
therefore can only weakly interact with the cation.18 This has
been shown to result in a 2.5-fold decrease in hydrogen bond
basicity compared to [NTf2]À. In the absence of base, the poor
%Products
(4) (11) (12)
D
Entry Solvent
Base Reagent
1
2
3
[C4mpyrr][NTf2]
[C4mpyrr][FAP]
DCM
À
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
SO2Cl2
SO2Cl2
SO2Cl2
SO2Cl2
SO2Cl2
SO2Cl2
—
—
—
—
—
85
—
—
1
—
76
7
100
23
93
100
66
14
100
25
99
100
100
100
—
—
—
—
—
—
—
—
—
—
—
—
À
À
4
5
6
[C4mpyrr][NTf2]
[C4mpyrr][FAP]
DCM
+
+
+
À
—
32
—
—
75
—
—
—
—
7
8
9
[C4mpyrr][NTf2]
[C4mpyrr][FAP]
DCM
À
À
10
11
12
[C4mpyrr][NTf2]
[C4mpyrr][FAP]
DCM
+
+
+
—
—
—
D: decomposition products; no partial chlorination product was
detected.
Entries 1, 2, 4, 5, 7 and 8 show that conversions using both
thionyl- and sulfonyl-chloride in ILs result in less decomposi-
tion products and greater conversion compared with the same
reactions carried out in DCM (entries 3, 6 and 9). In all cases,
higher chemoselectivity was achieved in [C4mpyrr][FAP]. This
is thought to be a result of the enhanced reactivity of the
thionyl and sulfuryl chloride in this IL when compared with
that in [C4mpyrr][NTf2] or DCM.12 Welton and co-workers
Scheme 1 Reaction in [C4mpyrr][FAP] IL in the presence and
absence of base.
c
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New J. Chem., 2012, 36, 2316–2321 2319

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hydrogen bonding accepting ability of the [FAP]À anion leads
to a reduced stabilisation of H+ from HCl generated from
either SOCl2 or SO2Cl2 and the diol and, therefore favours
formation of sulfite/sulfates from the diols with loss of HCl(g)
.
In contrast, the [NTf2]À with greater hydrogen-bonding
accepting ability leads to an increase in ClÀ present in solution
from the increased stabilisation of HCl and, therefore, to more
chlorinated products. Scheme 1 shows the mechanisms which
can be proposed to occur in the presence of base. All involve
the initial reaction of the sulfurylating reagent by attack of one
of the hydroxyls.
In the synthesis of chloro nitro alkanes in molecular solvents,
Novikov et al. showed that using equimolar amounts of base
and thionyl chloride resulted in the formation of the chlorinated
product in 72% yield.19 Increasing the amount of base led to an
increase in the formation of the cyclic sulfite product and a
decrease in the chlorinated product. It was proposed that the use
of an equimolar base to SOCl2 ratio increased chlorination
through the formation of a pyridinium thionyl chloride complex
which acted as a chlorinating agent. A similar increase in
chlorinated product formation is also observed when thionyl
chloride was reacted in DCM with immobilised morpholine.
When this set of reaction conditions is compared with the
analogous reactions in the absence of base (Table 1), the
selectivity to the chlorination product is increased from
11 to 40%. Novikov et al. proposed that the order of reagent
addition also has an effect on the reaction products. Therein,
the chlorosulfinates and cyclic sulfites were preferentially
formed on simple addition of thionyl chloride to the alcohol.18
When the secondary diol, butane-2,3-diol, was used, the
selectivity of the reaction was much more difficult to control
with formation of the sulfite and sulfate products favoured in
all cases. In addition, greater formation of decomposition
products was observed (Table 2). Compared with the control
reactions in DCM, the reactions in IL solvents generated the
sulfite/sulfate products in similar amounts. In some cases,
improvements were noted, which may be due to both increased
stability of the reagents in the IL as well as to the improved
stabilisation of the reaction intermediates and products in
this medium.14 Using [C4mpyrr][FAP] as the solvent gave
improved conversion compared with either the use of
[C4mpyrr][NTf2] or DCM. Unlike the reaction of ethylene
glycol in [C4mpyrr][FAP], the addition of base did not produce
a switch in reactivity and formation of chlorinated products,
indicating that this solvent has a passive role in the reaction.
Instead, the formation of cyclic sulfites and sulfates was
favoured, which is attributable to steric influences on the
reactivity of the systems (Scheme 2). The additional methyl
group reduces the accessibility of the electrophilic carbon
centre to chloride, base and also to the [FAP]À anion for
stabilisation of any intermediates, therefore, disfavouring the
chlorination reaction. Using [C4mpyrr][NTf2] as solvent in the
presence of base gave reduced formation of the sulfite/sulfate
products and greater decomposition. This difference in reac-
tivity could be attributed to the nature of the alcohol, whereby
generation of carbocationic intermediates has increased stability
in [NTf2]À than in [FAP]À based ILs, leading to E1 type elimina-
tion and rearrangement products, and unseen in ethylene glycol.
The reaction of isopropyl alcohol with PCl3 in [C4mpyrr][NTf2]
Scheme 2 Differences in primary and secondary reactivity due to
steric factors.
gives phosphites as products. However, some PCl3 always
remains unreacted due to competing consumption of the
alcohol by chlorination reaction and possible elimination.
Both observations are consistent with, and highlight the effects
of, the steric differences between primary and secondary
alcohols and the associated competing reactions.
With pinacol, a tertiary diol, reactions using both thionyl
chloride and sulfonyl chloride preferentially produce the
chlorinated product rather than cyclic sulfite/sulfates (Table 3).
This change in selectivity can be ascribed to the stability of the
tertiary carbocation intermediate favouring the SN1 mecha-
nism for facile nucleophilic substitution at the carbon centre
(Scheme 1). Unfortunately, the overall conversions from the
reactions of pinacol were also lower than those with primary
and secondary diols due to, in some cases, extensive decom-
position. For example, for the reaction in DCM with added
base, 88% of the starting pinacol decomposed. Although some
decomposition still occurred in the ILs, the IL solvents did
lead to reduced decomposition as well as improved chlorina-
tion when compared with those in DCM. Most notably, in the
reaction of pinacol with SO2Cl2 in [C4mpyrr][NTf2] (Table 3,
entry 7) where 87% conversion to the chlorinated product was
observed with no decomposition or sulfate formed. As
observed for ethylene glycol, the use of [C4mpyrr][FAP] IL
in the presence of base increases the amount of the chlorinated
product. In the presence of a base in [C4mpyrr][NTf2],
only small amounts of the sulfite/sulfate are formed. Notice-
ably, in comparative experiments, using the hydrophilic ILs,
[C4mpyrr][BF4] and [C4mpyrr][OTf], as solvents, formation of
the chlorinated products were favoured under all conditions,
although these conditions always generated a broader range of
side-products. The same was also true when cyclohexane-
1,2-diol was reacted in hydrophilic ILs.
The reactions of cyclohexane-1,2-diol (Table 4), although a
secondary diol, differ from those of butane-2,3-diol (Table 2).
Chlorinated products are preferentially, and in most cases,
exclusively formed in the reactions of the cyclic diol in DCM
and in [C4mpyrr][NTf2]. In [C4mpyrr][FAP], in the absence of
base, a marked preference for formation of the cyclic sulfites/
sulfates is observed, with production of the chlorinated product
c
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Table 5 Comparison of sulfonation and chlorination reactionsa
This preference for dichlorination can be attributed to the ILs
weak cation–anion interaction and increased hydrophobicity
resulting in improved stability and increased ClÀ concen-
tration when compared with [C4mpyrr][NTf2] and DCM.
Primary
NTf2
X
Secondary
FAP DCM NTf2 FAP
Diol
DCM
Solvent
Base
X
X
X
X
X
Product with SO SO SO Cl SO SO SO SO SO SO SO SO
SOCl2
4. Conclusions
Product with Cl SO|2 SO2 Cl Cl SO2 SO2 SO2 SO2 SO2 SO2 SO2
SO2Cl2
This study has shown that reactions with SOCl2 and SO2Cl2
can be applied in a more controlled manner in ILs than in the
most commonly used organic solvent, DCM. It was found that
the reaction conditions and the choice of IL could be tailored
to afford either the cyclic sulfite/sulfate or the chlorinated
products for all the diols used in this study, with the exception
of the secondary diol, which gave only limited success in
chlorination.
Tertiary
Cyclic
NTf2 FAP DCM NTf2 FAP
DCM
X
Solvent
Base
X
X
X
X
X
Product with SOCl2 Cl Cl Cl Cl Cl — Cl Cl SO2 Cl Cl —
Product with SO2Cl2 Cl Cl Cl Cl Cl SO2 Cl Cl SO2 Cl Cl Cl
a
Highest yields are in bold.
Acknowledgements
promoted by addition of base. The preferred formation of
chlorinated products from the cyclic diol may be caused by the
reduced flexibility, and increased steric hindrance, around the
carbon centres which favours the formation of a carbocation
rather than the SN2 transition state. The contrasting behaviour
in [C4mpyrr][FAP] here is consistent with the results using
ethylene glycol and butane-2,3-diol, and strongly suggests that
[C4mpyrr][FAP] provides an environment favouring cyclic
sulfite/sulfate formation in the absence of additional base.
The changes in selectivity in the presence and absence of base
can be attributed to the weak cation–anion interaction that
occurs in [C4mpyrr][FAP]. The reactions in ILs compared with
DCM gave higher or comparable conversion for both the
chlorination and the sulfite/sulfate formation. Furthermore,
the long-term stability of both the cyclic sulfites and sulfates
formed in the different ILs were assessed over a number of
weeks. All were stable in air at room temperature whereas the
sulfites and sulfates prepared in DCM only remained stable
over the same time period if maintained under an inert atmo-
sphere in sealed containers at 5 1C. The reactivity of the cis
diol vs. that of the trans diol towards thionyl and sulfuryl
chloride and the associated dichlorination reactions were not
investigated. Due to the chirality introduced by the mono-
oxygenated sulfur atom, the cyclic sulfite (11) is present in
solution as a racemic mixture of compounds having the following
chirality: RRS, RRR, SRS and SRR (+4 enantiomers). It is
likely that stereochemical factors combined to that of the
IL/base will have an effect on the products’ distribution.
However, the overall chemoselectivity of the system appears
to be maintained under the range of conditions which were
investigated as demonstrated by the reaction outcomes when
sulfuryl chloride was used as a reagent.
We would like to thank QUILL, Merck KGaA for the
donation of ionic liquids and an EPSRC portfolio partnership
(EP/D029538/1) for funding. We would also like to thank
Bruker for invaluable help with deuterium NMR and T1
experiments.
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Table 5 summarises the outcomes of all the reactions screened,
with primary, secondary, tertiary and cyclic cis-diols, for the
reactions with thionyl- and sulfonyl-chloride in the absence and
presence of additional base with DCM, [C4mpyrr][NTf2] and
[C4mpyrr][FAP] IL solvents. Chlorinated products are obtained
preferentially in [FAP]À based ILs in the presence of base for
all diol studied, with the exception of the linear secondary diols.
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c
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