DOI 10.1515/hc-2013-0012 Heterocycl. Commun. 2013; 19(1): 1–11 Review Maged Henary* , Shirish Paranjpe and Eric A. Owens Synthesis and applications of benzothiazole containing cyanine dyes Abstract: Heterocyclic compounds are of immense inter- centers joined by a conjugated chain of odd number of est due to their extensive occurrence in nature as well as methine carbons or a conjugated system of double bonds. their applicability in the pharmaceutical industry. Benzo- This polymethine bridge connects an electron acceptor thiazole and its derivatives encompass an attractive heter- group at one end and an electron donor group at the other. ocyclic class that displays practical applications ranging Conjugation between the electron donor and acceptor from medicine to photography and agriculture, among groups results in delocalization of π electrons and hence other things. This review focuses on the synthesis and positive charge over the two nitrogen atoms. specific applications of various benzothiazole cyanine Examples of related cyanine dyes are shown in dyes. Benzothiazole-containing heterocyclic structures Figure 2 . Common names of the cyanine dyes are based are prominent throughout the literature and it is very on the number of methine carbons present in the poly- important to acknowledge their efficacy and applicability methine chain. In Figure 2 , the polymethine cyanine dyes as we discuss herein. are designated as mono-, tri-, penta-, and heptamethine cyanines for n = 0, 1, 2, and 3, respectively. The absorp- Keywords: benzothiazole; cyanine dyes; DNA binding; tion/emission wavelengths of the cyanine dyes depend semiconductors; sensitizers; synthesis. upon the length of the polymethine chain and the nature of the terminal groups. The monomethine and trimethine cyanine dyes usually absorb in the visible region (500 – 600 *Corresponding author: Maged Henary , Department of Chemistry, nm) of the electronic spectrum with each added (CH = CH) Georgia State University, Atlanta, GA 30303, USA, e-mail: [email protected] methine unit inducing a bathochromic shift of approxi- Shirish Paranjpe and Eric A. Owens: Department of Chemistry, mately 100 nm in the electronic spectrum resulting in Georgia State University, Atlanta, GA 30303, USA an absorption wavelength of 700 – 800 nm for penta- and heptamethine cyanines. The 4-pyrilium, 4-thiopyrilium, and benz[ c,d ]indolium heterocyclic end groups extend Introduction absorption/emission wavelength well into the near-infra- red region, whereas the presence of the benzoxazole end group results in a hypsochromic shift in the electronic Structural characteristics of carbocyanine spectrum. Polymethine cyanine dyes are generally classi dyes fied based on the nature of the end groups present on the polymethine chain. Dyes with two heterocyclic terminal Cyanine dyes are a unique class of compounds that have groups are referred to as closed chain cyanine dyes or a wide range of applications in numerous fields. The first generally referred to as cyanines. The two heterocycles in member of this type was reported by Williams in 1856 [ 1 ]. the cyanines can either be identical or different. Hemicya- The name cyano was given due to the beautiful blue (blue nines are characterized by the presence of one heterocy- – kyano in Greek) color of the dye. This dye was obtained clic and another non-cyclic end group. Dyes without a ter- by treatment of quinoline and 4-methylquinoline with minal heterocyclic moiety are defined as streptocyanines amyl iodide followed by reaction with ammonia. Vogel or open chain cyanines as shown in Figure 2 . in 1873 found that cyanine dyes can be used to increase Cyanine dyes are structurally classified as symmetric sensitivity of the photographic plate [ 2 ]. It was the turning or asymmetric cyanine dyes as depicted in Figure 3 . These point in the history of the cyanine dyes. symmetric and asymmetric cyanine dyes are quite differ- Cyanine dyes are a subclass of polymethine dyes. As ent with respect to spectral characteristics and nucleic shown in Figure 1 , polymethine dyes consist of two nitrogen acid binding behavior [ 3 ]. 2 M. Henary et al.: Benzothiazole containing cyanine dyes R R Electron N N Electron Synthesis and applications of benzothiazole n Acceptor R R Donor Polymethine cyanine dyes Chain The synthesis of the first benzothiazole cyanine dye was Figure 1 General structure of polymethine dyes. reported in the late 18th century [ 9 ]. It was synthesized by heating N -amylbenzothiazolium iodide and 2-methylben- zothiazole in the presence of ammonia. To date, a large R R R N N N N N N number of symmetric and asymmetric benzothiazole n n n R R R R R R cyanine dyes have been synthesized [ 10 – 12 ]. Streptocyanine Hemicyanine Cyanine Benzothiazole cyanine dyes are commonly classi- Figure 2 Classification of cyanine dyes. fied into four categories of mono-, tri-, penta-, and hep- tamethine cyanine dyes. The spectral range for these dyes extends approximately between 450 and 750 nm in the electronic spectrum. In the past few years, many syn- In the literature, it is recognized that in 1926, Koenig thetic routes to benzothiazole cyanine dyes have been identified the chromophoric nature of the polymethine developed. structure of the cyanine dye and reported the synthesis of the first chiral polymethine dye [ 4 , 5 ]. Since then many diffe rent types of cyanine dyes have been synthesized. The first bridged cyanine dye synthesis was published in Monomethine cyanine dyes 1933 where trimethine chain formed a part of cyclopen- tadiene ring [ 4 ]. In a review by Behera et al., it was dis- Monomethine benzothiazole cyanine dyes typically cussed that some naturally occurring cyanine dyes have absorb in the visible region (450 – 470 nm) of the elec- been isolated from Beta vulgaris and Amanita muscaria tronic spectrum depending on the substituents attached [ 5 ]. Cyanine dyes possess some characteristic properties to the benzothiazole core structure. These dyes are which include structure-dependent photochemical stabil- charac terized by a narrow absorption peak and high ity, narrow absorption band, high molar absorption coeffi- fluorescence intensity. They are best known for their cients (~10 5 m -1 cm -1 ), tendency to form aggregates in solu- nucleic acid binding properties. The oldest method tion, and relatively high fluorescence intensity. A large for the synthesis of the monomethine cyanine dyes number of cyanine dyes have been synthesized using dif- involves condensation of an N -alkyl-2-(methylthio)ben- ferent hetero cycles such as indolenine, quinoline, benzo- zothiazolium salt with another alkylated heterocycle xazole, and benzothiazole. with an activated methyl group [ 13 ]. This method was Benzothiazoles have a planar structure, which is an adopted for the synthesis of β -cyclodextrin functional- essential criterion for nucleic acid binding and hence for ized benzothiazole cyanine dye 1 (Equation 1) [ 14 ]. β - their applications as an effective biological marker [ 6 , 7 ]. Cyclodextrin possesses both a hydrophobic cavity and The use of benzothiazole compounds as in vivo imaging hydrophilic surface and is used for molecular recogni- agents for Alzheimer ’ s disease is considered to be a major tion as a drug delivery agent in pharmaceutics [ 15 ]. The breakthrough for benzothiazole studies [ 8 ]. medicines containing vitamins are generally unstable to light, heat, and oxygen, whereas the formation of inclusion complexes of vitamins with β -cyclodextrin Symmetrical cyanine dyes Asymmetrical cyanine dyes enhances the stability, solubility, and bioavailability of Me the drug [ 16 ]. Analysis of such inclusion interactions of S Me S S vitamins are commonly conducted by means of spec- N N N N 3 Me trophotometric titration using external agents such as TsO 2 Me Me Me dyes as spectral probes. The incorporation of the dye Me N molecule as host compound provides an option to easily Me Me recognize colorless guest molecules by direct titration. N N S Compound 1 was used to study supramolecular interac- I N tions of β -cyclodextrin directly by visible spectroscopy, TsO Me which is otherwise impossible due to an insufficient Figure 3 Classification of cyanine dyes. chromophore system. M. Henary et al.: Benzothiazole containing cyanine dyes 3 S N 4-chloropyridinium or quinolinium substrate in a basic S N Me Me medium [ 19 ]. This synthetic procedure has been used I Me TsO to synthesize dicationic and tricationic benzothiazole cyanine dyes (Equation 4). In this particular case, the N S (1) increased cationic charge helps increase water solubility N of the dye. I Me 1 Cl S The synthetic procedure shown above involves a Me major drawback of producing methyl mercaptan, which is N N I Me a toxic pollutant. Researchers have overcome this problem 2Br by developing a new procedure that uses 2-iminobenzo- thiazoline instead of 2-methylthiobenzothiazolium salt N [ 17 ]. This method can be used to synthesize symmetric and I N asymmetric cyanine dyes. In this procedure, cyanine dyes 1. Et3N, MeOH S N (4) are prepared by melting 2-iminobenzothiazoline with qua- 2. KI ternary heterocyclic salt containing 2- or 4-methyl groups, N as depicted in Equation 2. I Me 4 O2N S NH Several homodimeric benzothiazole cyanine dyes N Me N with polycationic charge on the overall cyanine dye have Me Me MeSO4 been published (Equation 5) [ 20 ]. O2N I KI S N (2) S Me N NMe -NH 2 2 3 N N N Me I Me I Me 2 Deligeorgiev et al. described a novel procedure for the synthesis of benzothiazole monocyanines, which involves NS Me S N Me heating a sulfobetaine salt of N -alkylbenzothiazolium compound with the quaternary salt of a heterocyclic com- Me Me Me Me (5) pound containing a reactive methyl group, as illustrated N N N N in Equation 3 [ 18 ]. These reactions are usually carried out 4I without solvent by heating the mixture to approximately 5 150 – 200 ° C. An alternative route to less thermostable com- Compounds 2 – 4 are structural analogs of the thia- pounds involves heating a solution in polar solvent.