Thiazolium and Benzothiazolium Ionic Liquids

described a synthetic and systematic use of benzothiazole ring system as an "on-off" type of leaving group for the preparation of ketones ( 128 ) and carboxylic acid derivatives ( 129-132 ) from a variety of benzothiazoles, e.g . (R = H, Me, ph; R 1 = propyl, ph, cyclohexyl, CH:CHPh) (off state) via the corresponding benzothiazolium salts (on state) obtained by quaternization (on switch). A variety of such compounds (R ≠ H) underwent a carbon-carbon bond cleavage at the 2-position to give the corresponding ketones RCOR 1 on simple treatment with a base under mild reaction conditions. The similar reaction (R 1 = H) to aldehydes proceeded less efficiently. The oxidative reaction of a variety


Introduction
In a general perspective the term "ionic liquid" includes all classical molten salts (Visser 2002), even those which are composed of more thermally stable ions, such as sodium with chloride or potassium with nitrate. Although the term dates back as early as 1943 (Barrer 1943), in the language/field of chemistry an ionic liquid (IL) is specifically a salt having organic cation and organic/inorganic anion, which is liquid at room temperature or reaction temperature. Wasserscheid and Keim (Wasserscheid&Keim 2000) have proposed that an organic salt having a melting point below 100 o C could be called ionic liquid and this is indeed now one of the most widely accepted definitions of ionic liquids. Some scientists consider this set point as 150 o C (Huddleston et al. 2001). The low melting behaviour of ionic liquids is due to the poor coordination of the cations and anions. The strength of coordination depends upon the nature and structure of the cation and anion and a little unsymmetry in the structure may lead to decrease the coordination of the ions. The most common heteroaromatic based ionic liquids include imidazolium, thiazolium, tetrazolium, pyridinium etc. However thiazolium and benzothiazolium based ionic liquids are very scarcely studied. This chapter will describe the synthesis and applications of thiazolium and benzothiazolium based ionic liquids.

Thiazolium salts / ionic liquids
The thiazoles are known in chemistry mainly due to their presence in thiamine (Vitamin B 1 ) in the form of substituted thiazolium salt (Mcguinness et al. 2001). Thiazolium salts can be obtained successfully by a modification of the Hanztsch's thiazole synthsis. This method is particularly valuable for those thiazolium compounds in which the substutuent on the ring n i t r o g e n c a n n o t b e i n t r o d u c e d b y d i r e c t a l k y l a t i o n , f o r e x a m p l e , a r y l o r h e t e r o a r y l thiazolium salts. Todd et al. have reported a very convenient method for the preparation of Nalkylthiazolium salts. The method of Hantzsch thiazole synthesis was modified to obtain direct formation of thiazolium salts. N-substituted thioamides (e.g. 13) were used instead of the unsubstituted thioamides to obtain the desired thiazolium salts (e.g. 15) (Todd et al. 1936) www.intechopen.com Scheme 4. A convenient method for thiazolium salts.
Schöberl and Stock have reported the synthesis of N-Benzyl-2,4-dimethylthiazolium chloride followed by the ion exchange with potassium iodide to get N-Phenyl-2,4dimethylthiazolium iodide (18) from N-phenylthioacetanilide (16) and chloroacetone (17) (scheme-5) (Schöberl&Stock 1940). The reaction of N-methyl-p-dimethylaminothiobenzamide (20) with a number of -halo ketones (19a-19d) and one -halo aldehyde (19e) have been studied by Egan and his coworkers and they were able to get stable 4-hydroxy-2-thiazolinium derivatives , which were isolated as the iodide salts (21) (scheme-6) (Egan et al. 1968). The 4-hydroxy-2thiazolinium salts (21) were stable in neutral and basic media, but could be dehydrated to the thiazolium salts (22) by treating with methanolic hydrogen chloride. Dehydration could also be accomplished, although less conveniently, by treating with methanesulfonyl chloride containing sulfur dioxide in the presence of collidine (Hazen&Rosenburg 1964). There are many reviews and books regarding the synthesis and applications of thiazolium salts in different fields (Eicher et al. 2003). However thiazolium based ionic liquids have not been well documented in the literature. Many researchers have studied the preparation and applications of the thiazole based ionic liquids in different reactions. A brief account of that has been given here.  C]-labeled 3-benzyl and 3-methylthiazolium tetrafluoroborate (may be liquids in nature) and studied the reactions of benzaldehyde with thiazolium salts in Me 2 SO. They found that the reactions of thiazolium salts with aromatic aldehydes: panisaldehyde and cinnamaldehyde, in MeOH/MeONa, led to the formation of significant amounts of the corresponding dimethyl acetals, rather than to the benzoin products (Chen et al. 1994

Benzothiazolium salts and ionic liquids
Benzothiazoliums are also a part of many important dyes (Svetlichnyĭ et al. 2007) e.g Cyanine Dyes, Thioflavin T & S, (Stsiapura et al. 2007) (Sabaté&Saupe 2007) Direct yellow 7, Carnotine, Primuline, etc. In medicine the benzothiazolium salts play an important role, for example Riluzole a benzothiazole-based drug is used to treat amyotrophic lateral sclerosis. (Kitzman 2009 Mills (1922) prepared N-Ethylbenzothiazolium iodide (51) ), to be used in the synthesis of thiocyanine dyes, by heating the equimolar quantities of ethyl iodide and benzothiazole (50) (scheme-14) (Mills 1922  The corresponding perchlorate was prepared by treating the benzenethiol with perchloric acid (Evans&Smiles 1935  A direct synthesis of quaternary salts (e.g. alkylsulfates, iodides, bromides, perchlorates) of benzothiazole from 2-aminobenzenethiol has been narrated in literatue by Kiprianov and Pazenko. Fry and Kendall synthesized quaternary salts of 2-alkylsulfanylbenzothiazole and used them in the synthesis of thiacyanine dyes (Fry&Kendall 1951). Similar type of synthesis of 2-haloalkylsufanyl benzothiazolium salts was carried out by Knott in 1955(Knott 1955. Brooker (1951) prepared benzothiazolium salts from substituted benzothiazoline and ptoluensulfonate for further conversion to cyanine dyes (Brooker et al. 1951). Kiprianov (1957) studied the relative rates of formation of quaternary salts of 2methylbenzothiazole with methyl iodide, methyl sulfate, and methyl esters of sulfonic acids and p-nitrosulfonic acids. He found that the reaction with methyl 2-nitrobenzenesulfonate was six times faster than that with Me 2 SO 4 , while the methyl esters of the 2,3-and 2,4dinitrobenzenesulfonic acid reacted sixty times more rapidly than did Me 2 SO 4 . Such esters afford a method for very mild alkylation of very weak bases (Kiprianov&Tolmachev 1957).
Benzothiazolium salts have great use in the synthesis of different types of cyanine dyes while on the other hand the benzothiazolium salts have also been studied for their activity in different biological systems. In 1959 Pianka and Hall studied the fungi toxicity of 3ethylbenzothiazolium iodide and 3-ethylbenzoxazolium ethyl sulfate derivatives and activity was found to reside only in the cation (Pianka&Hall 1959). In the same year (1959) Leslie and co-workers patented a method for the preparation of quaternary salts of benzothiazole for making the thiacarbocyanine dyes. In 1961 Horwitz and co-workers prepared a benzothiazolium salt (76) from 6-(2-aminocarbonyl)ethoxy-2methylbenzothiazole (75, Scheme-22) for the use in preparation of different dyes. In 1967 Messmer and Gelleri prepared l,3-diphenyl[1,2,3]triazolo[5,1-b]-benzothiazolium and benzimidazolium bromide salts by the action of NBS on benzothiazol-2-yl-phenyl ketone phenyl hydrazone in ethyl acetate at room temperature (Messmer&Gelléri 1967). Vorsanger (1968) made the spectroscopic studies for the existence of carbenes generated from the heterocyclic bases which were prepared from the quaternary salt (78) of the benzothiazole with dietyl sulphate. Similar studies were made with 3deuteriomethylbenzothiazolium iodide (79) prepared by heating the CD 3 I with benzothiazole in a sealed ampule at 130 o C for 4 hours. He prepared the dimers of (78) and (79) by mixing themselves and also by mixing (80) and (81) separately to get the hybrid dimer (83) (Scheme-23) (Vorsanger 1968). In 1969 Garmaise et al. prepared a number of benzothiazolium salts (87) from 2alkylaminobenzenethiol (85) (Scheme-24). A study of the anthelmintic activity of the benzothiazolium salts in comparison to the dye thioflavin T was made. Compounds which showed activity were all closely related to thioflavin in that they had a 2-(pdialkylaminophenyl) substituent and were quaternized on the heterocyclic nitrogen atom (Garmaise et al. 1969

120
Scheme 34. 6, 7 and 8 membered hetrocycles from benzothiazolium salts Halgas et al. (1983) prepared a series of 3,4,6-substituted benzothiazolium salts and studied their plant growth regulatory and antimicrobial activities. They observed the stimulation and inhibitory effects of the prepared benzothiazolium salts on plants. The highest stimulation activity was found with 6-methyl-3-propoxycarbonylmethylbenzothiazolium bromide and 4-chloro-3-methylbenzothiazolium bromide, and the highest inhibitory effect was observed with 4-chloro-3-methylbenzothiazolium methyl sulfate, while all these benzothiazolium salts did not show any noticeable antimicrobial activity ). Other reports for the similar studies by the same group can be found in the literature ). Bryce et al. (1984) have reported the preparation of a highly conjugated bisbenzothiazoline (124) by the reaction of dimethyl cyclohexa-1,3-diene-1,4-diacetate (121) with 2-(methylamino)benzenethiol (122) in the presence of triphenylcarbenium tetrafluoroborate and the subsequent treatment of the resultant bisbenzothiazolium tetrafluoroborate (129) with triethylamine at 20 o C (Scheme-35) (Bryce et al. 1984).  have described a method for the preparation of polystyrene based benzothiazolium salts and their use to study their catalytic activity in the Michael addition reactions of , -unsaturated compounds . He also studied the catalytic activity of the benzothiazolium salts for the Michael addition reactions in the presence of triethylamine ). Sutoris et al. (1988) studied the effects of benzothiazolium compounds on the growth of sugar beet and vetch (Vicia sativa) as well as their sugar and chlorophyll contents. They found that most of the benzothiazolium salts possessed auxin-like activity. N-Methylbenzothiazolium bromide was found to stimulate sugar production in vetch at different concentrations and among the N-benzyl and substitutedbenzyl benzothiazolium salts, N-benzylbenzothiazolium bromide was found to be the most active compound. N-(methoxycarbonylmethyl)benzothiazolium bromide was found to be the most active compound for increasing chlorophyll contents in sugar beet leaf after treatment of the seed. Changing the methyl group for ethyl or propyl in benzothiazolium salt decreased chlorophyll contents (Sutoris et al. 1988 Chikashita et al. (1991) have described a synthetic and systematic use of benzothiazole ring system as an "on-off" type of leaving group for the preparation of ketones (128)  Scheme 36. Use of benzothiazole ring system as an "on-off" type of leaving group for the preparation of ketones and carboxylic acid derivatives.

(R 1 = H) with base and nonactivated MnO 2 in ethanol afforded the corresponding ethyl esters. This type of oxidative reaction could b e a l s o a c h i e v e d i n T H F w i t h d i f f e r e n t
nucleophiles, such as alcohol, water, thiol, and amine, to give the corresponding ester, carboxylic acid, thioester, and amide, respectively (scheme-36) (Chikashita et al. 1991). Riemer and Liebscher (1993) have described the synthesis of pyrimido[2,1-b]benzoxazolium, pyrimido[2,1-b]benzothiazolium salt (134) by the reaction of 3-isothiocyanato-2propeniminium salts with 2-aminothiophenol followed by cyclization using methyl iodide by a new condensation reaction (Riemer&Liebscher 1993).  Lopez-Celahorra et al. (1994) have narrated that the 3,3'-polymethylene-bridged benzothiazolium and thiazolium salts could be used as pre-catalysts for the benzoin condensation and that catalytic activity depends strongly on the methylene bridge length. The authors claimed that in aprotic medium, the catalytic activity was due to the bis(thiazolin-2-ylidene)s or bis(benzothiazolin-2-ylidene)s species (Lopez-Celahorra et al. 1994). Zimmermann and Klaus (1996) have reported a method in which the ring of the pyrylium and thiopyrylium salts (135) have been transformed to substituted benzene ring (136, 137) by treatment with anhydrobases derived from 1H-benzimidazolium and benzothioazolium salts (Scheme-37) (Zimmermann&Schmidt 1996). Hatrik and Zahradnik (1996) have claimed that the toxicity of benzothiazolium salts can be predicted by the neural network (NN) method. Results were found to be in good agreement with the previously used Free-Wilson method. They have used a number of benzothiazolium salts to calculate their toxicity by the NN method (Hatrík&Zahradník 1996). Kumar et al. prepared aza-enediyne analogues by the incorporation of N-propargyl moiety to 2-alkynylbenzothiazolium salts (139) and the aza-enediynes (140) were proven to be the modest DNA cleavage agents. The mechanism probably involves the formation of an adduct (141) prior to cleavage of DNA. They also observed DNA cleavage with the N-methyl-2alkynylbenzothiazolium salt, which lacks the aza-enediyne moiety (scheme-38) (Kumar et al. 2001).   et al. (2004) have prepared different benzothiazolium compounds by reaction of 5arylfuran-2-carboxaldehydes and furo[b]pyrrole type aldehydes with 2-methyl-3-methyl or ethyl benzothiazolium bromide. The new compounds were based on highly conjugated systems that have potential biological activity. Cyanine dye precursors can also be obtained by the reaction of furo[b]pyrrole type aldehydes with benzothiazolium salts (Puterová et al. 2004). Tseng et al. (2005) have used different benzothiazolium compounds (142 & 143) to study their activity for the inhibition of nitric oxide production in a cell culture system. They found that benzothiazolium salts have been the better inhibitors than N-methyl arginine (L-NMMA) a known inhibitor. They have demonstrated these results by the correlation of in vivo and in vitro activities using mouse paw edema (Tseng et al. 2005). Yang et al. (2007) synthesized a series of benzothiazolium compounds (144 and 145) which showed inhibitory activity against gastroenteritis virus (TGEV). They used swine testicle (ST) cells infected with transmissible gastroenteritis virus (TGEV) and an indirect immunofluorescent assay with antibodies against TGEV spike and nucleocapsid proteins to screen the benzothiazolium compounds that inhibit TGEV replication. The benzothiazolium compounds were found to have inhibitory activity against TGEV 3CL(pro) (Yang et al. 2007).

Thermal studies of benzothiazolium ionic liquids
The benzothiazolium salts/ionic liquids have been comprehensively studied by our group (Nadeem et al. 2010). The thermal studies such as TGA and DSC reveal important information about the stability and thermal behavior of these compounds. Decomposition temperatures of benzothiazolium iodide salts were determined by TGA, heating at 10 °C min -1 under dried air atmosphere and are reported (table-2) as (i) onset to 5 wt% mass loss (T 5%dec ) and (ii) onset to total mass loss (T dec ) (in parentheses).

Benzothiazolium iodide-chloroaluminate ionic liquid
The phase behaviour study of [C 11 BT]I-AlCl 3 mixtures have been carried out with the help of DSC to find the appropriate mole ratio of the aluminum chloride to the [C 11 BT]I-AlCl 3 mixture ( Figure-25). From figurr-25, it is evident that at mole ratio 0.5% the mixture of [C 11 BT]I-AlCl 3 gave lowest melting point (22.5 o C) which was checked by DSC. Figure-24 represents the phase diagram of the [C 2 mim]Cl-AlCl 3 system as a function of composition, X(AlCl 3 ) and figure-25 gives an account of the phase study of the Nundecylbenzothiazolium iodide-aluminum chloride system. It is obvious that the most distinctive feature of the chloroaluminate(III) system is its dependence on the apparent mole fraction of aluminium(III) chloride, the ionic liquid is acidic (Visser 2002), basic [X(AlCl 3 ) < 0.5], or neutral [X(AlCl 3 ) = 0.5], referring to the Franklin acidity and basicity (Franklin 1905(Franklin , 1924. This is frequently assumed to refer to the Lewis acidity and basicity. From figures 25 and 26, it is immediately clear that the liquid range of both the systems is very different from each other. The [C 2 mim]Cl-AlCl3 system is a low viscosity liquid at room temperature from X(AlCl 3 ) = 0.33 to X(AlCl 3 ) = 0.67{where X(AlCl 3 ) is the mole fraction of the nominal aluminium(III) content. While the room temperature liquidity of the C 11 BTI-AlCl 3 system starts at X(AlCl 3 ) = 0.45 and ends up to 0.55. Although the liquidus range of the C 11 BTI-AlCl 3 system is very low as compared to the imidazolium system, there is a eutectic point, which may be useful for different applications. The [C 2 mim]Cl-AlCl 3 system have been considered the first genuine example of an ionic liquid system that was liquid at room-temperature. So the C 11 BTI-AlCl 3 system would open up a field for electrochemistry specialists, and laid the foundations for the exploration in this field.

Comparison in catalyzing different organic reactions
6.1 Acyloin / benzoin condensation Davis and Forrester have studied the benzoin condensation promoted with a small (~ 5 mol %) quantity of triethylamine and thiazolium salts (160). The reaction was accomplished when the thiazolium based organic ionic liquid (OIL) was stirred under nitrogen as a clearly heterogeneous mixture with a toluene solution of benzaldehyde. The reaction gave about 80% conversion to benzoin (163)

Stetter reaction
Zhou et al. have used the 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide for the microwave-assisted intramolecular Stetter reaction using imidazolium-type room temperature ionic liquids (RTILs) as solvents. The intramolecular Stetter reaction of (E)methyl 4-(2-formylphenoxy) but-2-enoate was selected as a model to optimize the reaction conditions, using butylmethylimidazolium tetrafluoroborate [bmim] + [BF 4 ] -as the solvent. It is known that salts of various heterocycles, including imidazolium salts, can also be used as catalysts. Therefore, the ionic liquids used as solvent is also able to function as a catalyst, even if it is less active than the usual thiazolium salts, and the yields of the desired product in that case are very poor. Subsequently, it was observed that when the quantity of thiazolium salt increased from 5 to 15 mol%, the yield improved accordingly to 96%. Under microwave irradiation, a variety of aromatic substrates undergo the intramolecular Stetter www.intechopen.com reaction in imidazolium-type RTILs as solvents, with thiazolium salts and Et 3 N as catalysts. Under these conditions the reactions were finished in 5-20 min and the products could be isolated in good to excellent yields, usually higher than those obtained under conventional heating conditions. Furthermore, it was possible to recycle and reuse the ionic liquid and the catalyst thiazolium salts (Zhou et al. 2006 Imidazolium-type room temperature ionic liquids (RTILs) have been used for the Stetter reaction, affording the desired 1,4-dicarbonyl compounds (e.g. 167) in good yields together with the benzoin (e.g. 168). Thiazolium salts and Et 3 N are efficient catalysts for this reaction performed in ionic liquid. The possibility to recycle and reuse the solvent has been demonstrated, although it was not possible to recycle the thiazolium catalyst (Anjaiah et al. 2004).

As coupling reagent
Li and Xu prepared the 2-Bromo-3-ethyl-4-methylthiazolinium tetrafluoroborate (BEMT), which is a crystalline solid, and have been reported to be an efficient coupling reagent for hindered amino acids. It was used for the coupling of N-alkyl or , -dialkyl amino acids (Li&Xu 1999

Conclusion
This chapter provides a comprehensive information about the synthesis of thiazolium and benzothiazolium ion based salts and ionic liquids. it is evident that thiazolium and benzothiazolium ionic liquids can be as efficient solvents/catalysts as the other heterocyclic cation based ionic liquids could be (e.g. imidazolium). Although the quaternary salts of thiazolium and benzothiazolium have been studied since 18 th century but their exploitation as ionic liquids remained limited to a few reports in the literature. Based on the Scifinder information the only article on the benzothiazolium ionic liquids has been published by our group. Moreover, the phase behaviour study of [C 11 BT]I-AlCl 3 mixtures have been described where the appropriate mole ratio of the aluminum chloride to the [C 11 BT]I-AlCl 3 mixture ( Figure-25) have been found with the help of DSC. From the figur-25 it is clear that at mole ratio 0.5% the mixture of [C 11 BT]I-AlCl 3 gave lowest melting point (22.5 o C) which was checked by DSC. Here the use of thiazolium ionic liquids in different reactions (e.g. Acyloin condensation, Stetter reaction) as solvent/catalyst have also been included.

Acknowledgment
We gratefully acknowledge the assistance of Prof. Dr. Misbahul Ain Khan for the preparation of manuscript. We particularly thank Prof. Dr. Makshoof Athar for facilities at Institute of Chemistry, University of the Punjab Lahore, Pakistan. Special thanks to Prof. Khizar Iqbal Malik for helpful comments and additional information. www.intechopen.com