Review of Indolizine chemistry
Scheme 14 Canonical forms contribution to the resonance hybrid of indolizine. 135
39 certain reaction characteristics similar to that of pyrrole and indole. 135 The weak basicity of indolizine relative to pyridine and quinoline (with pKa values of 5.19 and 4.90, respectively), reflects the delocalisation of the nitrogen lone pair into the aromatic π-cloud in indolizine.150 In fact, protonation may occur at C-1 and C-3 rather than at N – an observation consistent with the contribution of the canonical forms of 91 and 92 to the resonance hybrid structure (Scheme 14).135, 150 Various NMR studies have confirmed protonation on these carbons.151-153 It is a relatively unstable molecule with a partition coefficient value (log P) of 2.45. 150 The resonance energy of indolizines is significantly larger than that of pyrrole and therefore indolizine is best viewed as a 10π-electron aromatic system to which the three canonical forms in Scheme 14 contribute.135 The pyridine ring, which is a component of the indolizine, is generally stable and can permit various chemical transformations provided its aromaticity is maintained.139 Nuclear Magnetic Resonance (NMR) has established delocalisation throughout both rings. 135
40 molecular orbital (HOMO), whereas the lowest unoccupied molecular orbital is mostly located in the pyrridine ring favoring electophilic substitution in the pyrrole ring.
Scheme 15. Structural modification of the indolizine fluorophore, exploiting the most acidic proton of the indolizine.159
1.5.3.1.Modulation of indolizine optical properties
To uncover the full potential of indolizine derivatives, significant research efforts have addressed their stability,150, 154 inherent (and manipulated) optical,130, 159, 160 and medicinal properties.128, 161 The use of organic π-conjugated molecules as fluorescent probes and sensors is founded on the photoluminescence character of these molecules. Small, fluorescent molecules are particularly valuable for their ability to detect conditions in solutions, on surfaces or within biological systems, and their fluorescence is modulated by factors, such as pH or binding of specific analytes.152
Indolizines exhibit high fluorescence and have been used as luminescent materials, such as opto-electronic devices, dyes, sensors and probes.162, 163 Polycyclic indolizine derivatives have been identified as potential opto-electronic materials due to their ability to provide high- efficiency, long-wavelength fluorescence quantum yields.161
Typical fluorescence-based indicators exhibit a red-shift in emission upon protonation but, in indolizines, the emission is blue-shifted to a lower wavelength for systems susceptible to C- protonation that interupts conjugation in the molecule. The photophysical studies of a series of 6-amino-8-cyanobenzo[1,2-b]indolizines 96 by Outlaw et al.,152 showed blue-shifting upon titration with trifluoroacetic acid, and NMR analysis indicated that protonation occurred on the pyridine ring of the indolizine to give compound 97 with concomitant loss of aromaticity. The change in π-conjugation was thus responsible for the observed change in optical properties. In a different study, Zhang et al.,164 using NMR analysis, demonstrated that halochromism of 3,4- dicyanobenzo-5-imino-1,1-dimethyl[1,2-b]indolizine 98 was based on the protonation of the imine group to afford the corresponding indolizinium amine 99 (Scheme 16).
41 Scheme 16. Reversible protonation of amino-indolizine derivatives. 152, 164
The increasing applications of fluorescent probes has prompted ongoing research for dyes with diverse spectral and physicochemical properties, such as stable and biocompatible molecules possessing high fluorescent quantum yields, large Stokes shifts and significant molar absorption coefficients.160, 165 Kim et al.166 recently developed a novel indolizine-based fluorescent molecular framework, 9-aryldihydropyrrolo[3,4-b]indolizine-3-one, named Seoul- Fluor 100, which can be rationally modified to furnish a wide variety of photophysical properties. It has three different sites for synthetic modification or elaboration with substituents (R1 and R2) on the phenyl and pyridine rings used for electronic perturbation resulting in change in absorption (λabs) and emission (λem) wavelengths and N-substituents (R3) as functional handles for bioconjugation.
Structure photophysical properties relationship (SPPR) studies demonstrated that the Seoul- Fluor system 100 has: a manipulable emission spectrum covering the visible-colour range;
controllable quantum yields; and environment sensitive fluorescent properties that can be altered through intramolecular charge transfer processes.167,168 Using 2-(2- nitrophenyl)indolizines and aryl aldehydes, Park et al.169 successfully employed the oxidative Pictet-Spengler methodology to afford a series of indolizino[3,2-c]quinolines 101 which exhibited fluorescent properties that are ideal for cell imaging, such as high intensity in water, large Stokes shifts, which prevent self-quenching, and good solubility which minimises aggregation with proteins.
42 Figure 18. Fluorescent indolizines with potential biological applications.166
1.5.3.2. Molar absorptivity of indolizines.
The molar absorption coefficient (Ɛ) is an intrinsic property of a chemical entity that defines the absorptivity of light by a chemical entity at any given wavelength.170 Chemical entities with high molar absorption coefficients (also known as extinction coefficients) are sought for a range of applications in chemistry and medicine.171
The attainment of molecular entities with high molar absorption coefficients has presented significant challenges because extension of the necessary π-conjugated systems has not always guaranteed appreciable increases in molar absorptivity.170 Owing to their innate brightness which, in turn, is associated with excellent molar absorptivity, a limited number of fluorophores such as cyanine 102,172 borondipyrromethene (BODIPY) 103 and aza-BODIPY 104,173, 174 fluorescein 105 175 and rhodamine 106,176 have been extensively used as fluorescence organic dyes.
43 Figure 19. Chemical entities with high molecular extinction coefficients that are widely used as dyes.
In addition to their occurrence in living organisms, such as species of the genus dendrobates (poison dart frogs), monomorium (ants), dendrobium (orchids), tylophora and the leguminosae family (plants)135, 177 and their wide range of biological activities,133, 139, 178 indolizines have come to the fore as promising compounds with interesting scientific potential.179 They emit intense fluorescence and their ultraviolet-visible absorption properties are very sensitive to the influence of substituents thereby opening a wide range of possible applications.179, 180 For example, indolizines have been employed as a fluorescent moiety in modified β- cyclodextrins.181
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