pyridinium based ionic liquid in the conversion of...
TRANSCRIPT
229
CHAPTER-7
Pyridinium based ionic liquid in the conversion of alcohols
to alkyl bromides in a modified Apple Reaction
Introduction
The conversion of alcohols to the corresponding alkylhalides is one of the
widely studied reactions in organic synthesis. To perform this transformation a
variety of reagents has been used and finds mention in many standard text books.
The synthesis of alkyl halides or haloalkanes are considered to be important as these
compounds have been widely used commercially as flame retardants, fire
extinguishers, propellants, solvents and pharmaceuticals. An estimated one fifth of
all pharmaceuticals contain halogen as one of the active moiety, specially fluorine is
an essential constituent atom in many drugs and pharmaceuticals.1 Paroxetine
(paxil), fluorouracil, ciprofloxacin (cipro), fluoxetine (Prozac), mefloquine and
fluconazole are a few drugs which contain the fluorine atom. Fluorocarbon
anesthetics reduce the hazard of flammability of diethyl ether and cyclopropane.
Perfluorinated alkanes are used as blood substitute. Moreover, haloalkanes are
widely used as synthon in organic synthesis. Haloalkanes are produced in nature
through an enzyme-mediated synthesis promoted by bacteria, fungi in sea
macroalgae (seaweeds). The biosynthetic pathway for natural chloroalkanes and
bromoalkanes involves the enzymes chloroperoxidase and bromoperoxidase
respectively. The annually estimated release of bromoethane in the oceans is
reported to be 1-2 million tons.2 More than 1600 halogenated organics have been
identified, with bromoalkanes being the most common haloalkanes. Although many
haloalkanes are considered as pollutants and toxins, the diverse beneficial and
widespread use makes these compounds demanding.
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Haloalkanes have been known for centuries. In the 15th
century, ethyl
chloride was produced synthetically for the first time and then in 19th
century the
systematic synthetic procedure of such compounds was developed. Generally,
haloalkanes are synthesized by the addition of halogens to alkenes,
dehydrohalogenation of alkenes, and the conversion of alcohols to alkyl halides. In
the later procedure a variety of reagents have been employed such as thionyl
chloride, phosphorus halides, N,N-diphenylchlorophenylmethyleniminium chloride,3
2-chlorobenzoxazolium salt,4 Vilsmier–Hack
5 and Viche salts.
6 The conversion of
alcohols to the corresponding halides is a challenging task as nucleophilic
displacement of the –OH group by a halogen is difficult because halogens are bad
leaving group. Although there are several methods of conversion of an alcoholic
group to a good leaving group prior to displacement by a halogen, the procedures are
less attractive from modern concept of organic synthesis as additional steps are
necessary and some of these steps may require toxic chemicals as well as toxic
reaction medium. None the less considering the wide applicability of haloalkanes,
synthetic organic chemists are encouraged to explore the possibility of using green
protocols for the synthesis of these compounds. Some of the important methods
developed for the conversion of alcohols to the alkylhalides include the following.
In 1985, J. J Brunet et al. introduced a procedure for the preparation of alkyl
iodide from corresponding alkyl α-chloroethyl carbonate and NaI by a direct
reaction between the alcohol, α-chloroethyl chloroformate and NaI and a mixed
solvent of acetone and toluene was used to carry out the reactions.7 The conversion
was also done via the formation of o-alkylisoureas from alcohols and di-
isopropylcarbodimide catalysed by a copper halide which on further treatment with
trifluoromethanesulphonic acid and tetrabutylammonium bromide or iodide gave
alkyl bromide or alkyl iodide respectively.8 Bromotriphenyl phosphonium salt was
used for the conversion of alcohols and tetrahydropyranyl ethers to corresponding
bromides.9 Dimethylphosgeniminium salt was used for the conversion of tetrahydro-
2-pyranyl protected alcohols into alkyl halides in presence of tetraalkylammonium
halides.10
F. Camps et al. reported a method where ROH with (F3CCO)2O in THF
231
gave RO2CCF3 as an intermediate which on further treatment with LiX in THF-
HMPT gave alkyl halides with 70-98% of yield.11
By this method Me(CH2)11I,
Me(CH2)13Cl, H2C:CH(CH2)9Br, AcOCH2CH:CHCH2Br were successfully
synthesized. For the conversion of n-butanol to n-bromobutane, a widely used
procedure was the heating of a mixure of n-butanol, NaBr, and a large amount of
concentrated H2SO4 under reflux condition and the product alkylhalide was removed
azeotropically together with water and unreacted n-butanol from reaction mixture,
followed by washing with concentrated H2SO4.12
In recent times, some of the important methods for the conversion of alcohol
to alkyl halide have appeared in literature out of which some of the most convenient
methods are reported here. A highly successful procedure for the direct conversion
of alcohols to the alkyl halides is the Mitsonobu reaction.13
In this reaction a poor
leaving group is converted to a good leaving group and the process involves
reaction of diethylazodicarboxylate (DEAD) with triphenyl phosphine to form an
intermediate which subsequently gives the halides. The reaction involves several
steps which are summarized in Scheme 7.1.
Scheme 7.1
R OH HX R X HO PPh3HN NH
EtO2C CO2EtN N
EtO2C CO2Et
+ ++.. .... ..PPh3
An efficient route to alkyl chlorides from alcohols have been reported by
Glacomelli.14
The procedure is based on the reaction of 2,4,6-trichloro [1,3,5]
triazine (TCT) with DMF followed by addition of CH2Cl2 solution of the reactant
alcohol. The reaction is reported to have given 100% conversion to the alkyl
chloride at ambient temperature. The reaction is also reported to be fast and was
232
found to go into completion in about 10-15 minutes. The reaction is shown in
Scheme 7.2
Scheme 7.2
R OH R Cl
N N
N ClCl
Cl
DMF/CH2Cl2
A mixture of Triphenylphosphine and 2,3-dichloro-5,6-dicyanobenzoquinone
in CH2Cl2 affords a complex which in the presence of a phase transfer catalyst of the
type R4NX , where X is a halogen, converts alcohols to alkyl halides . The procedure
is facile and selective and the conversion is carried out in neutral condition. A
variety of alcohols containing aromatic ring as well as acid sensitive groups have
been so converted.15
The transformation is shown in the Scheme 7.3.
Scheme 7.3
R OH R X
PPh3/ DDQ/ R4NX
CH2Cl2/ RT
Where X = Cl, Br
A novel one pot conversion of alcohols to alkyl halides was reported by Crosignani
and mediated by N,N'- diisopropylcarbodimide.16
233
7.1.1. Recent literature on the conversion of alcohols to alkyl halides
A supported reagent namely ROMP gel-Supported triphenylphosphine have
been used for the conversion under consideration.17
This reaction appears to be
unique because a solid supported reagent have been used and such reactions carries
along with it the added advantage of being environmentally benign associated with
the ease of product isolation at the end of the reaction. The conversion is shown in
the Scheme 7.4.
Scheme 7.4
R OH R Cl
2 eq
ROMG Gel-supported PPh3
CH2Cl2/ CCl4 (95 : 5)
45oC, 1.5-18 h
R = alkyl, benzyl
The use of fluorous phosphine is reported to have been used in the conversion of
alcohols to the alkyl bromides.18
The reaction yield have been observed to be
excellent and the reaction could be performed within a short time. The conversion is
shown in Scheme 7.5.
Scheme 7.5
R OH R Br 1 eq. CBr4
FC-72/ toluene (1:1). 50oC, 4-7 h
1 eq OCH2C7F15P
3
R = Alkyl
PPh2
n
ROMP Gel-supported PPh3
234
Stoichiometric bromotrichloromethane in acetonitrile can replace solvent quantities
of carbon tetrachloride in the synthesis of gem-dichloroalkenes from aldehydes in
the presence of triphenylphosphine. A facile synthesis of unsaturated bromides by a
metathesis reaction was demonstrated by Wagener et al.19
and the synthesis results
in the conversion of unsaturated alcohols to the corresponding bromides. The
reaction is shown in Scheme 7.6.
Scheme 7.6
OH Br1.1 eq. CBr4, 1.1 eq. PPh3
CH2Cl2, 0 oC-r.t., 2.5 h9 9
Finally, The Apple Reaction can be mentioned as an elegant reaction for the
conversion of alcohols to the alkyl halides under mild condition.20
The reaction
involves the use of triphenylphosphine and tetrahalomethanes (CCl4, CBr4) with
alcohols. The reaction is shown in scheme 7.7.
Scheme 7.7
R R' R R'
OH XCX4, PPh3
X = Br, Cl
This reaction is somewhat similar to the Mitsunobu Reaction, where the
combination of a phosphine, a diazo compound as a coupling reagent, and a
nucleophile are used to invert the stereochemistry of an alcohol or displace it. The
reaction proceeds by activation of the triphenylphosphine by reaction with the
tetrahalomethane, followed by attack of the alcohol oxygen at phosphorus to
235
generate an oxyphosphonium intermediate. The oxygen is then transformed into a
leaving group, and an SN2 displacement by halide takes place, proceeding with
inversion of configuration if the carbon is asymmetric. The mechanism proposed is
shown in Scheme 7.8.
Scheme 7.8
Br
Br BrBr
P Br
Ph
PhPh
P Br
Ph
PhPh
Ph3P + + +
+
CBr3
OH
HCBr3
O2
P
Ph
PhPh
OP
Ph
PhPh
OBr
Br
+ O PPh3
These methods mentioned above have some disadvantages which includes
the use of toxic as well as expensive chemicals. It has also been observed that the
catalyst as well as the medium and solvents are not amenable to reuse and finally the
process of product recovery is tedious and time consuming. To resolve the issue of
reducing experimental hazards it has been observed recently that ILs can be used to
perform the conversion of alcohols to alkyl halides and this method have been found
to be considerably effective. N. E. Leadbeater et al. used imidazolium based ILs as
reagents and solvents and microwave technique for the conversion of alcohols to
alkyl halides and then to nitriles in presence of acids.21
R. X. Ren et al. applied 1,3-
dialkylimidazolium halide based ILs as reagent for the conversion of butanol and
octanol to butyl halide and octyl halide respectively, in presence of different
Brönsted acid like HCl, H2SO4, CH3SO3H.22
Another application of imidazolium
based IL as reagent and solvent was carried out by H.-P. Nguyen et al. using direct
or MW heating in presence of paratoluenesulphonic acid.24
In this method long
chain alcohols (C8, C12, C14, C18) were converted to their respective alkyl halide and
the IL could be regenerated and reused.
236
7.2. Materials and methods
From the study of literature, it was found that the reported methods has some
disadvantages like use of costly and toxic reagent, long refluxing time, use of co-
solvent and low yield of the product. In most of the cases one of the common
problems found was recovery of the product which is troublesome due to lower
boiling point of alkyl halide. Some reagents were used to convert some specific kind
of alcohols and some processes are not acceptable from the green chemistry point of
view. The few reports that are available for the utilization of ILs for this conversion
cannot be termed as satisfactory because when 1-n-butyl-3-methylimidazolium
halide IL was used it was observed that long reaction time (5-30 hr) was found
necessary and the yield of the product was also reported to be low. This procedure
was also limited to the conversions of a few alcohols and cannot be considered as
being of general application. Further, when 1-octyl-3-methylimidazolium bromide
was used, only the long chain alcohol (C8, C12, C14, C18) could be converted to the
corresponding bromides efficiently. In another application of IL where 1-alkyl-3-
methyl imidazolium halide and MW technique was used high pressure was found
necessary. It was observed that only heptanol and decanol were converted in
moderate yield but with other alcohol (specially secondary, tertiary alcohol, benzyl
alcohol etc.) the reactions failed to proceed. Furthermore, the imidazolium based ILs
are found to be costly. To overcome all these disadvantages, the pyridinium based IL
was examined for their applicability in the conversion of alcohol to alkyl bromide
and the results establishes the superiority of the pyridinium based IL over the usual
imidazolium IL. The pyridinium based IL used in this study was prepared by a
simple procedure using cheap and easily available reagents as reported in Chapter
2.
In this work, 1-butyl-4-methyl pyridinium bromide was chosen to play a dual
role of a brominating agent as well as a medium for the conversion of alcohol to
alkyl bromide. The conversion was carried out in the presence of p-toluene
sulphonic acid (PTSA). By using this procedure not only longer chain alcohols but
237
also lower alcohols could be successfully converted to the corresponding alkyl
bromides. One of the major advantages found by using this IL is the complete
conversion of the substrate alcohols to the alkyl bromide and the work up procedure
was observed to be simple as the product could be recovered by simple decantation.
After the reaction was over the IL could be recovered in the sulphonate form and
recycled.
In a typical procedure, equimolar amount of alcohol, PTSA and the IL,
1-butyl-4-methyl pyridinium bromide were added in a RBF and heated at different
temperature under reflux condition for a time required for complete conversion. The
formations of products were confirmed by GC/MS and NMR spectroscopy. The
different temperature required and reaction times for the conversions of different
alcohols are shown in Table 7.1. The progress of the conversion was monitored for
complete conversion by a time resolved GC-MS experiment. In a typical example
the progress of the conversion of n-heptanol to n-heptyl bromide was monitored and
the results are shown in Figure 7.1. Aliquots were taken at time intervals of 0.5 hr,
1.5 hr, 2.5 hr and 5 hrs and the progress of the conversion monitored. It may also be
mentioned that the percentage conversion is dependent on the temperature of the
reaction. It was observed that with increase in reaction temperature, the time
required for complete conversion decreased. Instead of PTSA, the reaction was also
carried out in the presence of concentrated H2SO4. However, the use of this mineral
acid resulted in the formation of a variety of unidentifiable byproducts besides the
target molecule. Therefore, the use of concentrated H2SO4 as an alternative to PTSA
turns out to be synthetically not useful. It has also been observed that when the
reaction was carried out at temperatures lower than the optimum, the time required
for complete conversion was found to be higher. The reaction is shown in Scheme
7.9. All the results are summarized in Table 7.1. The products obtained were
characterized by NMR and Mass Spectra. Three representative GC-spectrum at
different time interval for the complete conversion of heptanol to bromoheptane are
shown in Figure 7.1. Figure 7.(2-3) showed the 1H and
13C NMR spectra of 1-
bromoheptane and Figure 7.(4-5) showed the mass spectra of bromocyclohexane
238
and 4-chlorobenzyl bromide. 1H NMR spectra of 1-butyl-4-methyl pyridinium
4-toluenesulphonate is shown in Figure 7.6.
Scheme 7.9
R OH R Br SO3NBr
+PTSA
N
+ H2O+
Yield= 100%
Table7.1: Synthesis of alkyl bromides from alcohols using 1-butyl-4-methyl
pyridinium bromide as brominating agent.
Entry Reactants Products Reaction
Temperture(°C)
Time
(h)
%
Conversion
01 Butanol Bromobutane 100 5 100
02 Pentanol Bromopentane 130 5 100
03 Pent-2-ol 2-Bromopentane 120 7 100
04 Hexanol Bromohexane 130 4 100
05 Cyclohexanol Bromocyclohexane 140 5 100
06 Heptanol Bromoheptane 130 5 100
07 Octanol Bromooctane 140 2.5 100
08 Benzyl alcohol Benzyl Bromide 140 0.5 100
09 4-chlorobenzyl
alcohol
4-chlorobenzyl
Bromide
140 1 100
239
Figure 7.1: GC for conversion of heptanol (GC peak at 1.43min) to heptyl bromide
(GC peak at 1.50 min).
Conversion after 1.5 hour
Conversion after 2.5 hour
Conversion after 5 hour
240
Figure 7.2
1H NMR Spectra of bromoheptane
Figure 7.3
13
C NMR Spectra of bromoheptane
Br
Br
241
Figure 7.4
Mass Spectra of bromocyclohexane ([M]+ = 162, [M+2]
+ = 164)
Figure 7.5
Mass spectra of 4-chloro benzyl bromide ([M]+
= 204, [M+2]+ = 206, [M+4]
+ = 208)
Br
Br
Cl
242
Figure 7.6
1H NMR Spectra of 1-butyl-4-methyl pyridinium-4-toluenesulphonate
7.3. Conclusion
In conclusion, it can be stated that a procedure have been developed for the
synthesis of alkyl bromide from alcohol where the IL was used as reagent for
bromination. The reaction was found to be efficient as complete conversion of the
alcohols to the corresponding bromide occurred with 100% atom economy
conforming to Green Chemistry requirements. The product recovery was also
simple. Additionally nonuse of VOC makes this reaction environmentally
favorable.
NSO3
243
7.4. Experimental section
GC/MS was carried out on a Perkin Elmer Clarus 600 Gas Chromatograph
and Clarus 600C Mass Spectrometer (Column 30.0m x 250µm). 1H and
13C NMR
was done on a Bruker 300 MHz instrument using CDCl3 as the solvent. γ-Picoline,
1-butyl bromide, various alcohols and paratoluene sulphonic acid were purchased
from Sigma Aldrich and were used as received. The IL 1-butyl-4-methyl pyridinium
bromide was prepared from γ-picoline as described in Chapter 2.
7.4.1. General procedure for the synthesis of alkyl bromide from
corresponding alcohol
A mixture of 5 mmol alcohol, 5 mmol p-toluenesulphonic acid and 5 mmol
1-butyl-4-methyl pyridinium bromide was heated under reflux condition, at different
temperature for different period of time as shown in Table 7.1 in an oil bath with
stirring. Reactions were monitored using GC/MS by withdrawing aliquot of reaction
mixture and dissolving it in diethylether before recording the GC/MS. In some
cases, namely in the reaction with n-octanol, benzylalcohol and
4-chlorobenzylalcohol, the progress of the reaction was monitored by TLC in silica
gel plates using petroleum ether (60-80°C) as the eluent. After completion of the
reaction, the product separated out as a distinct immiscible layer and this layer was
collected by a simple process of separation. The 1H-NMR spectra were taken
directly from the product separated without any further purification.
7.4.2. General procedure for the synthesis of 4-chlorobenzyl
bromide from 4-chlorobenzyl alcohol (Special case)
A mixture of 3 mmol 4-chlorobenzyl alcohol, 3 mmol p-toluene sulphonic
acid and 3mmol 1-butyl-4-methyl pyridinium bromide was heated at 140 °C in an
oil bath. The progress of the reactions was monitored by TLC technique in prepared
244
silica gel plates using petroleum ether (60-80oC) as the eluent. After completion of
the reaction, the products were extracted with diethyl ether, washed with water,
dried with anhydrous Na2SO4 and the solvent was evaporated. The products were
identified by 1H-NMR spectra and mass spectra.
7.4.3. Recovery of 1-butyl-4-methylpyridinium-p-toluenesulphonate
On completion of the bromination, the IL was found to have been
transformed to the p-toluenesulphonate anionic form. Petroleum ether (40-60°C)
was added to this and stirred for 5 minutes to remove any trace of the product
formed (alkyl bromide). The petroleum ether layer was separated out and the IL in
the form of 1-butyl-4-methylpyridinium-4-toluenesulphonate was recovered and
stored in desiccator. The recovered product was identified as the sulphonate form of
IL by NMR spectra. 1H NMR (300 MHz, CDCl3): δH ppm 8.915 (d, 2H, J = 6.3 Hz,
ArH), 7.740-7.685 (m, 4H, ArH), 7.112 (d, 2H, J = 7.8 Hz, ArH), 4.612 (t, 2H, J =
7.2 Hz, 2H, NCH2), 2.520 (s, 3H, ArCH3), 2.303 (s, 3H, ArCH3), 1.867-1.767 (m,
2H, CH2), 1.292-1.192 (m, 2H, CH2), 0.840 (t, 3H, J = 7.2 Hz, CH3); 13
C NMR (75
MHz, CDCl3): δ ppm 158.38, 143.51, 139.58, 128.50, 125.50, 60.44, 32.94, 21.61,
20.93, 18.79, 13.10.
245
7.4.4. Spectral data of some representative compounds
1-Bromobutane
1H NMR (300 MHz, CDCl3): δH ppm 3.417 (t, 2H, J = 6.9 Hz, CH2Br), 1.885-1.790
(m, 2H, CH2), 1.522-1.399 (m, 2H, CH2), 0.928 (t, 3H, J = 7.2 Hz, CH3).
13C NMR (75MHz, CDCl3): δ ppm 34.71, 33.72, 21.27, 13.16.
GC/Ms m/z (relative intensity) : 138 ([M+2]+) (12), 136 ([M]
+) (12), 121 (5), 119
(6), 109 (3), 107 (3), 88 (9), 86 (51), 84 (70), 83 (60), 57 (100), 56 (20), 55 (10), 49
(32), 47 (50), 41 (60).
1-Bromoheptane
1H NMR (300 MHz, CDCl3): δH ppm 3.410 (t, 2H, J = 6.9, CH2Br), 1.901-1.807 (m,
2H, CH2), 1.614-1.546 (m, 8H, 4CH2), 0.886 (t, 3H, J =6.9 Hz, CH3).
13C NMR (75MHz, CDCl3): δ ppm 34.06, 32.79, 31.60, 28.40, 28.09, 22.52, 14.02.
GC/Ms m/z (relative intensity): 180 ([M+2]+) (5), 178 ([M]
+) (5), 151 (5), 149 (5),
137 (46), 135 (52), 70 (21), 69 (26), 57 (100), 55 (54).
Br
Br
246
1-Bromooctane
1H NMR (300 MHz, CDCl3): δH ppm 3.406 (t, 2H, J = 6.9 Hz, CH2Br), 1.898-1.803
(m, 2H, CH2), 1.443-1.278 (m, 10H, 5CH2), 0.882 (t, 3H, J = 6.9 Hz, CH3).
13C NMR (75MHz, CDCl3): δ ppm; 34.04, 32.81, 31.78, 29.10, 18.71, 28.16, 22.61,
14.07.
GC/Ms m/z (relative intensity): 194 ([M+2]+) (5), 192 ([M]
+) (5), 151 (10), 149 (10),
137 (82), 135 (95), 123 (2), 121 (2), 109 (6), 107 (6), 83 (13), 71 (62), 69 (48), 57
(79), 55 (60), 43 (100), 41 (63).
Bromocyclohexane
1H NMR (300 MHz, CDCl3): δH ppm 4.215-4.153 (m, 1H, CHBr), 2.166-1.221 (m,
10H, 5CH2).
13C NMR (75MHz, CDCl3): δ ppm 53.54, 37.48, 35.44, 25.02.
GC/Ms m/z (relative intensity): 164 ([M+2]+) (3), 162 ([M]
+) (3), 83 (100), 67 (12),
55 (99), 41 (46).
Br
Br
247
Benzyl bromide
1H NMR (300 MHz, CDCl3): δH ppm 7.460-7.319 (m, 5H, ArH), 4.540 (s, 2H,
CH2Br).
13C NMR (75MHz, CDCl3): δ ppm 137.67, 128.95, 128.71, 128.33, 33.56.
GC/Ms m/z (relative intensity): 172 ([M+2]+) (12), 170 ([M]
+) (12), 92 (8), 91 (100),
89 (12), 65 (20), 63 (14), 51 (9), 39 (13).
4-Chlorobenzyl bromide
1H NMR (300 MHz, CDCl3): δH ppm 7.348-7.280 (m, 4H, ArH), 4.457 (s, 2H,
CH2Br).
13C NMR (75MHz, CDCl3): δ ppm 130.26, 128.96, 128.86, 128.52, 128.48, 128.15,
32.31.
GC/Ms m/z (relative intensity): 208 ([M+4]+) (2), 206 ([M+2]
+) (7), 204 ([M]
+) (5),
127 (33), 125 (100), 99 (6), 90 (7), 89 (32), 63 (12).
Br
Br
Cl
248
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