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.

230

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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