VII I NAM J O U R N A L O F C H E M I S T R Y V O L . 50(1) 126-131 F E B R U A R Y 2012
MICROWAVE-ASSISTED SONOGASHIRA REACTION IN IIVIIDAZOLIUM- BASED IONIC LIQUIDS AS GREEN SOLVENTS
P h a n T h a n h Son N a m , L e Vu H a , N g u y e n T h a i A n h Ho Chl Minh City University of Technology
Received 29 N o v e m b e r 2010
A b s t r a c t
An easil\ accessible ionic liquid, l-butyl-3-melhylimidazolium hexafluorophosphale ([BMIM][PF,,|) was i,\nthcsized. and characterized using 'll and ''C NMR. and MS The ionic liquid was demonstraied to be an cfllcient and recyclable solvent for the Sonogashita reaction of iodobenzene and phenylacelylene lo form diphenylaccijlenc as itic principal produci It was also found that increasing the length o f t h c alkyl chain in the ionic liquid caused a significani diop in the reaction rale. Using the ionic liquid as the reaction solvent in conjunction with microwave irradiation, ihe reaction rate was dramalically enhanced, with over 9 5 % conversion being achieved wiihin 3 mm compared to conversions obtained after 6 hrs under conventional conditions. Furthermore, the ionic liquid - palladium catalyst system could be reused in subsequent reaction without a significant degradation in activity.
1. I N I R O D U C T I O N
Transition mctal-catalyzed cross-coupling reactions h a \ e gained popularity over the past thirty years in organic synthetic chemistry, as they represent ke\ steps in the building of more c o m p l e x molecules from simple precursors [ I ] The Soiiogashira cross-coupling of aryl halides with terminal alk>ncs has been widely employed in the synthesis of several biologically active molecules and functional materials, including anlimycotics, anlibiolics. liquid crystals, polymers, and optical or elcclronic materials [2]. Ionic liquids have recently been extensively evaluated as environmental- friendly or green alternatives to conventional organic solvents because their non-volatile nature can minimize the emission of toxic organic c o m p o u n d s and facilitate the separation of products and catalysts [3. 4]
During the past few y e a r s , a variety of ionic liquids have been investigated, in which dialkylimidazolium-based ionic liquids exhibit se\LTal advantages such as keeping the liquid condition under a wide range of tcmpcraUire and having excellent solubility for m a n y substrates and molecular catalysts [5. 6]. Wc recently employed ionic liquids as green solvents for the Heck reaction belwccn iodobenzene and s t j r e n e lo form trans- slilbenc as llie principal product [7. 8], In this paper, we wish to report for the first time in Vietnam, to our best k n o w l e d g e , ihe use of an lonie liquid.
[|}M1M|[PF„|. as Ihe green solvent for the SoiioL';>sbira reaction between iodobenzene and
phenylacelylene to form diphenylacetylene as the principal product under microwave irradiation.
2. E X P E R I M E N T A L
2 . 1 . Materials and Instrumentation
Chemicals were purchased from Sigma-Aldrich and Merck, and used as received without further purification H and C N M R spectra were recorded using a Bruker AV 500 spectrometer. M S speclra were recorded using a T h e r m o Finigan T S O 7 0 0 0 triple quadrupole. G C analyses were performed using a Shimadzu G C - 1 7 A equipped with a FID detector and a 30 m x 0.25 mm x 0 25 ^im DB-5 column, G C - M S analyses were performed using a Hewlett Packard G C - M S 5972 with a R T X - 5 M S column (length = 30 m, inner diameter = 0,25 mm, and film t h i c k n e s s = 0.5 [im). T h e temperature program for G C - M S analysis heated samples from 4 0 to 300"C at l O T / m i n and held them at 300"C for 5 min. Inlet temperature w a s set constant at 280"C, M S spectra were compared with the spectra gathered m the N I S T library. I I P L C - M S was conducted on a P4000/Spectra physic H P L C coupled wilh a T S Q 7 0 0 0 / T h e r m o Finnigan M S .
2.2. Synthesis of t h e Ionic Liquid
In a t \ p i c a l reaction. .V-melhylimidazole (20.68 g. 0 252 moi) and /i-butyl bromide (38,13 g. 0.278 moi) were added lo a 500 ml r o u n d - b o n o m fiask equipped with a Dimroth condenser. The mixture 126
VJC. Vol. 50(1). 2012
"a^ heated inlermittciltly in a modified household microwave oven (Sanyo-bM-2086W) al 80 W After the first heating for 10 s, the irradiation was paused for 5 s, and the reaction mixture was then lieated at the same power level for an additional 10 s. The procedure was repeated for a total irradiation time of 3 min. The resulting ionic liquid was then cooled, triturated and washed with ethylacetate (3 x 50 ml) and diethyl ether (3 x 50 ml) lo remove unreaeted starting materials The solvent residue was then removed by a rotovap at 5 0 T , affording 53 29 g of
!-bulyl-3-inethvlimida/oliuin bromide ([BMlM||Br|)(96%vield)
'H NMR (500 MHz. DMS0-d6): S = 0.887 (L 3H. CH,). 1 256 (m, 211; C//,CI1,), 1 770 (m. 2H;
C7/.CII,Cllj), 3.882 (s, 311. N-C//j). 4.204 (m, 211.
N-C//,), 7 778 (t. IH; N-C//=C), 7 856 (I. IH; N- CW=C). 9.340 (s. 111. N-C7/=N). "C NMR (125 MHz, DMS0-d6): S = 13.173 (C-CTl,). 18.652 (CH;), 31.279 (Cll,), 35 693 (N-CH,), 48.357(N- CIL). 122 172 (C=C-N), 123.461 (C=C-N). 136.435 (N-('=N). MS (ESI): m/z 139 (BMIM)'. 357 l(BMIM),Br| .
A plastic conical flask containing a mi.xture of [BlVllMJIBrl (25.10 g. 0.1 15 moi) and di,stilled water (50 ml) was imniersed in an ice bath for 30 min.
He.\afluorophosphorie acid (HPFo) 60% (20 ml, 0 147 moi) and water (50 ml) were then added dropvvise to prevent the temperature from rising significantly After stirring for 12 hrs at room leniperature, the upper acidic aqueous layer was separated by decantation and the lower ionic liquid portion was washed with cold water (10 x 50 ml) until the washings were no longer acidic. The ionic liquid was then heated under vacuum at 60°C to remove any excess water, affording 26.8! g of 1- butv l-3-inethvlimidazolium hexalluorophosphate ([BMIMllPril) (82% yield).
'H NMR (500 MHz, DMS0-d6): S = 0.905 (t, 3H: CH,). 1.262 (m, 211, CW,CH,), 1-771 (m, 2H;
CWjCHjCH.,), 3 846 (s, 3H; N-CHj), 4.157 (m, 2H;
N-C//,), 7 668 (t, IH; N-Cy/=C), 7.733 (t, HI; N- C//=C). 9.071 (s. 111. N-C//=N). "C NMR (125 MHz, DMS0-d6); rS = 13.141 (C-CH,), 18.711 (CH,), 31 276 (C'lL), 35.651 (N-C'l|,,). 48.509 (N- n i , ) , 122.193 (C-C-N), 123.542 (C=C-N), 136.444 (N-C=N) MS (F.SI); ml: 139 lUMlM]', 423
|(BMlM):PFi,) •
1-Hexvl-3-methylimidazolium
hexanuorophosphale ([HMIM][PFs]), and l-octyl-3- inethylimidazolium hexafluorophosphate (lOMIMlIPFsl) "'='•'= synthesized in a yield of 87%
and 90% respectively, using a similar procedure.
'H NMR (500 MHz, _ DMS0-d6) for IHMlMllPI S . 0.873 (t, 3H; CH,). 1.272 (m, 6H;
Phan Thanh .'.nit Vt//;;. ei al C//=C), 7.734 (I. IH; N-C//=C). 9.069 (s. 111. \ - ClI'N). "C NMR (125 MHz. DMS0-d6) 6 13.708 IC-CH,). 21799 (CIT), 25.085 (CU,).
29.266 (CH,), 30 487 (CH,), 35.651 (N-CII-,).
48.789 (N-(T1,). 122.191 (C=C-N). 123 540(C=C- N). 136.436 (N-C=N). MS (ESI); ml: (%) 167 [llMlMr,479[(llMlM),PF,,| .
'll NMR (500 Mllz.l).MSO-d6) for lOMlMllPFtJ c> = 0.860 (t. 311; CH,). 1 265 (m.
1011; CHjCHiCHiCHiCH,), 1.780 (m. 211. CH.).
3.845 (s, 311; N-C//,), 4.145 (m. 211; N-C//-). 7 674 (t. IH. N-C//=C), 7.741 (t, IH; N-C//=C). 9.076 (s.
111. N-fH=N). "C NMR (125 MHz. DMSO-d6); S
^ 13.870 (C-CHj), 22 390 (CH,). 26.085 (Cll,).
28.772 (CH,). 28.841 (Cll,), 30 137 (Cll;). 31.495 (Cll;). 36.642 (N-CH,). 50 003 (N-CIL). 121.860 (C=C-N). 123.641 (C=C-N), 137.076 (N-C=N). MS (ESI); ml: 195 [OMIM]\ 535 |(OMlM);PFJ.
2,3, Catalysis Studies
Unless otherwise stated. 1 mixture of iodobenzene (0.24 ml, 2.15 mmol). phenylacetylene (0.36 ml, 3.28 mmol), piperidine (0.64 ml. 6.47 mmol), and ?t-hexadecane (0.06 ml) as the internal standard in (BMIM^PFftJ (5 ml) were added to a round-boltom flask containing the required amount of palladium acetate catalyst and copper (1) iodide co-catalyst. The flask was heated in a modi lied household microwave oven (Sanyo-FM-2086W) at 200 W. Reaction conversions were monitored by withdrawing aliquots (0.1 ml) from the reaction mixture al different time intervals, and quenching with water (1 ml). The organic components were extracted into diethylether (3 ml), dried over Na,SO^
and analyzed by gas chromatography (GC) with reference to rt-hexadecane Product identity was also further confirmed by gas chromatography mass spectroscopy (GC-MS).
3. RESULTS AND DISCUSSION
' „ ' ,, C//,) 1 783 (m, 2H; CH:). 3.846 (s, 3H; N-
Scheme I: Synthesis of the l-butyl-3- methylimidazolium hexafiuorophosphate
([BMIM][PF6]) ionic liquid (I) The ionic liquid was synthesized according to a previously reported procedure [7] In view of the green chemistry, it was decided to explore the synthesis of l-butyl-3-iTielhylimida/olium bromide ([BMiM][Br]) using microwave irradaUon under 127
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solvent-free condition The anion metathesis reaction of l-butyI-3-mclhylimidazolium bromide with hexafiuorophosphoric acid was then carried out to prepare 1 -butyl-3-methylimidazolium hexafluorophosphate ([BM1M][PF6]), according to a literature procedure (Scheme 1) [9,10]. l-HexyI-3- metbylimidazolium hexafiuorophosphate ([HMIM][PF(,]). and l-octyl-3-melhylimida2olium hexafluorophosphale ([0M1M][PF6]) were also synthesized using similar procedure. The ionic liquids were characterized using 'H and '^C NMR, and MS, which were in good agreement with the lileratuic [7.9, 10].
The ionic liquid was evaluated for its suitability as a solvent initially for the Sonogashira reaction between iodobenzene and phenylacetylene to form
Microwave-assisted sonogashira ;vtK i • '' diphenylacetylene as the principal produci (SJicnic 2). The reaction was carried out using 2 mol^
Pd(0Ae)3 catalyst in the presence of Cul co-catalyst (molar ratio of Pd:Cu = 1:1). The efficiency of microwave irradiation in accelerating organic transformations has recently been proven in several different fields of organic chemistry, in which reaction times can be dramatically reduced from days and hours to minutes and seconds [11,12].
Microwave-assisted chemistry is usually performed in high boiling polar solvents such as DMSO. NMP and DMF due to their high dipole moments [13].
Owing to the high polarity and thermal stability of ionic liquids, it was decided lo carry out the Sonogashira reaction in [BMlM][PFh] under microwave irradiation.
dlphenylacetyler ' i "
n-hexadecane
Figure 1: GC analysis of the reaction mixture (1)
^h'
^—' [BMIU][PF6) [Pd]Microwave
Scheme 2: The Sonogashira reaction of iodobenzene and phenylacetylene in (BMIM][PF6] ionic liquid (2) It is generally accepted that a base is obviously necessary to neutralize the hydrogen halide produced as Ibe byproduct in the catalytic cycle of the Sonogashira reaction. The base is also required for the generation of the alkynyl copper intermediate in the catalytic cycle, allowing the iransmetallation step to occur [14], It was therefore decided to investigate the effect of bases on the reaction conversion, having carried the reaction in the presence of CH^COONa, NaiCO^, triethylamine, and piperidine, respectively. GC analysis of the reaction mixture from the GC-MS result indicated the formation of the principal product. Triethylamine was elTecli\eK employed in several Sonogashira processes using homogeneous palladium phosphine
complexes as catalysts [ 15]. In this research, however, the ionic liquid-mediated Sonogashira reaction in the presence of triethylamine occurred with significant slower rate than the case of piperidine and Na3C03. The reaction using triethylamine afforded a conversion of 79% after 180 s, while 92% and 95% conversions were obtained for the case of NaiCOj and piperidine, respectively (figure 2). Piperidine was therefore used as the base for the reaction in further experiments
With these results in mind, we then studied the effect of catalyst concentration on the reaction conversion, using [BMIM][PFG] as the solvent and piperidine as the base. As with previous reports, the higher the catalyst concentration was used, the higher the reaction rate was observed. Decreasing the catalyst concentration resulted in a drop in reaction rate, with 71% and 67%. conversions being obtained after 180 s at palladium concentrations of I mol% and 0.5 mo!%, respectively (figure 3). As mentioned earlier, a conversion of 95% was
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observed for the reaction using 2 mol% palladiuin 1 (2 mol% Pd(0Ac)2, 2 mol% Cul) gave a catalyst. The catalyst concentrations used in this conversionof 95% af^er 180 s. Decreasing the Pd;Cu study were comparable to those of several previous molar ratio lo 1 ;0.5 (2 mol% Pd(OAc);. 1 mol%
reports covering different aspects of the Sonogashira reaclion, where the palladium concentrations varied from less than 0.5 mol% to more than 3 mol%, depending on the nature of the catalysts as well as the substrates (2, 14]. It should be noted that several Sonogashira reactions required the presence of toxic and expensive phosphines [2, 14, 15]. The fact that the tonic liquid-mediated Sonogashira reaction under microwave irradiation exhibited high efficiency in the absence of phosphines therefore offered significant advantages.
Phan Thanh Son Nam, et al.
2
Cul) resulted in a slight drop in reaction rate, with 91% conversion still being achieved. Interestingly, it was found thai the reaction could afford 86%
conversion after 180 s in the absence of Cul (2 mol% Pd(0Ac)2) (figure 4). It should be noted that the reaction using 2 mol%o Pd(OAc); and 2 mol%
Cul carried out under conventional healing condition at 80°C gave a conversion of 82% after 6 hrs.
60 90 120 150 18 Time (s)
Figure 2: Effect of different bases on reaction conversions (3)
00 80 60 40 20 /
0 m 0 30 60
T
» 1 mol%
—4—0 5 mol%
90 120 150 1 ime (s)
80 Figure 3: Effect of catalyst concentration on
reaction conversions (3)
It was previously reported that the rate of the Sonogashira reaction could be significantly accelerated in the presence of Cul as a co-calalyst [2,14]. However, copper-free Sonogashira transformation could still occur, though under much harsh conditions. Indeed, both copper- and copper- free catalytic cycles for the Sonogashira reaction were previously proposed in the literature [16,17], We therefore decided to investigate the effect of Cul on the Sonogashira reaction carried out in rBMlM][PF6] under microwave irradiation. It was found that the reaction using Pd:Cu molar ratio of 1:
80 60 40 20 i
0 J 0 30
—•—2%,2%
— • — 2 % . ! %
—*—2%;0
60 90 120 150 Time (s)
180 Figure 4: Effect of Pd:Cu ratio on reaction
conversions (4) GO
80
40 20 y
0
Jr
0 30
— • — [ B M I M ]
— • ^ f H M I M ]
— * — [ O M I M ]
60 90 120 150 180 Time (s)
Figure 5: Effect of different ionic liquids on reaction conversions (5)
It was previously reported that several imidazoiium-based ionic liquids had polarities similar to those of polar aprotic solvents such as DMSO, DMF etc. [18]. Indeed, polar aprotic solvents such as DMF, DMA, MeCN etc. have been successfully employed for several transition metal- catalyzed organic h-ansformations such as the Heck, the Suzuki, and the Sonogashira reactions [19].
Nonpolar solvents have been shown to be not suitable for the Sonogashira reaction. In this research, it was found that increasing the length of the alkyl chain in the ionic liquid caused a significant drop in the reaction rate (Figure 5). The Sonogashira reaction carried out in the hexyl-based solvent afforded 83% conversion after 180 s.
Replacing the butyl group with the octyl group in the
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ionic liquid structure slowed down the reaction dramatically, with only 28% conversion being obtained after 180 s. This could be rationalized based on the fad that increasing the length of the alk)l group would decrease the polarity of the solvent.
In order to investigate the effect of different substituents on reaction conversions, the study was then extended to the reaction of substituted iodobenzenes containing electron-donating (i.e. 4- lodotoluene) and electron-withdrawing (i.e. 4'- iodoacetophenone) groups. All reactions were carried out in the [BMIM][PF6] ionic liquid under microwave irradiation, in the presence of 2 mol%
Pd(0Ac)2 catalyst and Cul co-catalyst (molar ratio of Pd:Cu - l;l). A conversion of 97%) was achieved after 180 s for the case of 4'-iodoacetophenone. As expected, the reaction of 4-iodoanisole with phenylacetylene proceeded with significantly slower rate than the case of iodobenzene, with a total conversion of 85% being achieved after 180 s (figure 6). fhis result indicated that the ionic liquid- mediated Sonogashira reaction was favored by electron-withdrawing groups on benzene ring, while electron-donating groups slowed down the cross- coupling processes. Indeed, the presence of electron- withdrawing groups in the arylhalide normally enhances the reaction rate in several palladium- catalyzed cross-coupling transformations [14].
Microwave-assisted sonogashira reatuoii Sonogashira reaction. As mentioned earlier, the Sonogashira reaction of iodobenzene and phenylacetylene was carried out under microwave irradiation in 180 s. After the first run. reaction products as well as unreaeted starting materials were separated from the ionic liquid by extraction with cyclohexane. The ionic liquid was then washed several times with cyclohexane. water, and then heated under vacuum at 60°C lo remove any excess water. The recovered ionic liquid containing the palladium catalyst was then reused in further reactions under identical conditions lo the first run.
without adding more Pd(OAc): or Cul. Interestingly, it was found that the recycled ionic liquid containing the Pd(OAc)i could be recycled and reused several times without a significant degradation in efficiency.
Indeed, a conversion of 93% was still achieved after 180 s in the sixth run (figure 7),
100
£ 80 i 60 E S 40 Q 20
0 1 2 3 4 5 6
mil
Run
30 60 90 120 150 18 Time (s)
Figure 6: Effect of different substituents on reaction conversions
Ionic liquids have been considered as green solvents not only due to their non-volatile nature, minimizing emission of toxic organic compounds, but also because of their reuse and recyclability [3- 6]. Furthermore, a crucial issue concerning the use of a precious metal catalyst is also its reuse and recyclability. We therefore investigated the possibility of recycling the solvent containing the Pd(OAc): catalyst in the ionic liquid-mediated
Figure 7: Catalyst and solvent recycling studies
4. CONCLUSIONS
In conclusion, an easily accessible ionic liquid, [BMIM][PF6], was synthesized and characterized using 'H and '^C NMR, and MS. The ionic liquid could be used as an efficient and recyclable solvent for the Sonogashira reaction of iodobenzene and phenylacetylene to form diphenylacetylene as the principal product. The reaction rate was significantly accelerated under microwave irradiation with over 95% conversion being achieved within 3 min compared to conversions obtained after 6 hrs under conventional conditions. Furthermore, the ionic liquid - palladium catalyst system could be reused in subsequent reaction without i significant degradation in efficiency The fact that the solvent - catalyst system could be recycled and reused therefore exhibited advantages over conventional organic solvents. Current research in our laboratory has been directed to the design of several ionic liquids for a wide range of organic transformations, and results will be published in due course.
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Corresponding author: P h a n T h a n h Son N a m
Ho Chi Minh City University of T e c h n o l o g y
268 L y T h u o n g Kiel, District 10, Ho Chi M i n h City, V i e t n a m T e l e p h o n e ; 3 8 6 4 7 2 5 6 (internal code 5681), fax; 3 8 6 3 7 5 0 4 , M o b i l e p h o n e 0 9 1 7 4 1 6 0 1 8
Email; ptsnam(S3hcmut.edu.vn or p t s n a m @ y a h o o . c o m .
