A cascade reaction of imidazo[1,2-a ]pyridines with maleic anhydride: Formation of cross-conjugated mesomeric betaines

In recent years, organic donor-acceptor complexes have attracted much attention, leading to the development of new organic switchable, binary electronic materials with high data-storage capacity. Following addition of a solution of maleic anhydride to a solution of imidazo[1,2-a ]pyridine(s), a cascade reaction ensues, resulting in the formation of cross-conjugated mesomeric betaines (CCMB), wherein positive and negative charges are restricted exclusively to different parts of the molecule. Physico-chemical properties of the compounds revealed the existence of intramolecular charge-transfer phenomena which could stimulate their interest as potential luminescent materials.


Introduction
Cross-conjugated mesomeric betaines (CCMB) belong to the general class of mesomeric betaines (MB) which are neutral, conjugated molecules, representable only by dipolar structures.Both positive and negative charges are delocalized within the respective π-frameworks.Based on the extent of delocalization of the positive and negative charges, the heterocyclic mesomeric betaines have been classified broadly into three groups: conjugated mesomeric betaines (CMB), cross-conjugated mesomeric betaines (CCMB), and pseudocross-conjugated mesomeric betaines (PCCMB).Ylides, which can be represented satisfactorily by a 1,2-dipolar structure, are examples of CMBs.In CCMBs, the positive and negative charges are delocalized exclusively in different parts of the molecule.In PCCMBs, the two charges are delocalized effectively, but not exclusively, in different parts of the molecule. 1Potts and co-workers subsequently reported theoretical and experimental results of a variety of CCMBs and PCCMBs incorporating various heterocyclic skeletons. 2Ramsden highlighted the relationship between heterocyclic mesomeric betaines and isoconjugate alternant and non-alternant hydrocarbon dianions. 3One example each of CMB, CCMB and PCCMB are shown in Figure 1.Over the years, interesting applications have been expanded in various fields utilizing these reactive intermediates.For example, Padwa and co-workers developed an efficient stereo-controlled route to the isoschizozygane alkaloid core by using intramolecular 1,4-cycloaddition of a CCMB. 4 Nechaev et al. developed a facile multicomponent synthesis of indolizine-derived PCCMB with high level of functional compatibility making possible the preparation of a number of compounds for materials and medicinal chemistry. 5These have revealed unique molecular packing and structure-property relationships. 6n 1932, Diels and Alder reported a cascade reaction of pyridine with dimethyl acetylenedicarboxylate (DMAD) to yield two products whose structures could not be established at that time. 7Later, these compounds were identified as tetramethyl-4H-quinolizine-1,2,3,4-tetracarboxylate 8 and tetramethyl-9aHquinolizine-1,2,3,4-tetracarboxylate. 9Huisgen and co-workers subsequently rationalized the whole sequence of reactions by postulating an in situ generation of a 1,4-dipole from the reaction of pyridine with DMAD, followed by its 1,4-dipolar cycloaddition with a second molecule of DMAD (Scheme 1). 10 It was also emphasized that, in contrast to 1,3-dipoles, 1,4-dipoles can be generated in situ only, and cannot be isolated.

Scheme 1. Cascade reaction of pyridine with DMAD.
The nucleophilicity of N-1 in imidazo [1,2-a]pyridine is expected to be further substantiated by the lonepair of the pyridine-ring nitrogen atom.In view of this, we perceived the imidazo[1,2-a]pyridine molecule to be a suitable precursor for the generation of a 1,4-dipole from its reaction with DMAD.Upon looking into the literature, it was found that Cossio and co-workers carried out the reaction of substituted imidazo[1,2a]pyridines with benzyne, generated in situ from 2-(trimethylsilyl)phenyl trifluoromethylsulphonate, in which [8+2] cycloaddition occurred; however, no reaction of imidazo[1,2-a]pyridine with DMAD was reported. 11pon carrying out the reaction of imidazo[1,2-a]pyridine with DMAD, we succeeded in obtaining the first representative of CCMB isoconjugate with the odd non-alternant hydrocarbon anion (Scheme 2). 12Scheme 2. Formation of a CCMB from the reaction of imidazo[1,2-a]pyridine with DMAD.
The CCMBs are known to exhibit remarkable material properties and, thus, have garnered much attention in the field of materials chemistry for the development of new switchable materials with high data-storage capacity. 13They bind with a polymer to give film coatings which are quite stable and easy to handle and, therefore, have been a point of interest for the researchers to develop such polymerizable mesoionic scaffolds. 14This has been backed up by constant efforts to develop new synthetic protocols to enlarge the libraries of these structural motifs. 15urthermore, azaindolizines have received a great deal of attention in the last few decades owing to their bioactivity.There is a plethora of such compounds that are anti-microbial, anti-bacterial and anti-fungal in nature. 16Since these compounds are multifunctional, it seemed plausible to explore the possibilities of synthesizing CCMBs, which not only work as potential materials, but may also be bioactive.In order to synthesize such pharmaceutically interesting betaines, annulated pyridines were found to be a good starting material since they are a part of many medicinally active compounds. 17ike DMAD, 18 maleic anhydride 19 has also been found to be a versatile tool in organic synthesis due to the presence of an electron-deficient C=C functionality conjugated with a cyclic anhydride structure.For example, Cookson et al. reported the reaction of pyridazine with maleic anhydride to give an exo type cyclic 1:2-adduct (11) which was not polymeric in nature (Figure 2). 20This motivated us to investigate the reaction of imidazo[1,2-a]pyridines with maleic anhydride which led to the synthesis of new CCMBs.In addition, the synthesized products display intramolecular charge-transfer phenomena, which enhances the possibility of their use as luminescent materials.The results are presented herein.
The reaction of imidazo[1,2-a]pyridine with maleic anhydride proceeded almost similarly to its reaction with DMAD 12 , i.e., the reaction generates a 1,4-dipole (14) which subsequently reacts with a second molecule of maleic anhydride to form 15. Nevertheless, there are some distinct differences between the two reactions.In contrast to the reaction with DMAD, in the present case, the zwitter ion 15 does not cyclize at C-9, nor does a 1,5-alkyl shift take place.The non-occurrence of these two structural changes with maleic anhydride can be attributed to the absence of a conjugated -HC=CH-CH=CH-system between C-10 and C-16.
Unexpectedly, it was found that the further course of the reaction is determined by the nature of R at the 2-position.In the case of R = H, i.e., the 2-position being unsubstituted, the initially formed product, 15, undergoes a 1,3-H shift to give 16 as the final product.When R = Ph or p-substituted phenyl group, no further change takes place.As described later, both products have been duly characterized.We do not have any plausible explanation for this difference in their behaviors, however, as discussed later, the activation free energy barrier (ΔG # ) for a 1,3-H shift in the case of 15b substituted by the phenyl group at the 2-position is greater than that for the unsubstituted 15 by 4 kcal mol -1 .Thus, the differences in the behavior of 15b-d may be attributed to steric hindrance caused by the phenyl group.Although our repeated attempts to grow a single crystal were unsuccessful, the structures of the products 16 and 15b-d could be established unambiguously based on extensive spectral studies.The 1 H NMR spectrum of 16 is reproduced in Figure 3.
The most characteristic feature of the spectrum is the presence of three protons, HA, HB and HC, constituting an ABC spin system to give three sets of doublets of doublets (dd).Thus, three dds at δ 3.30 (dd, 2 JHH 17.2 Hz, 3 JHH 9.6 Hz), 3.44 (dd, 2 JHH 17.2 Hz, 3 JHH 4.8 Hz) and 5.69 (dd, 3 JHH 9.6 Hz, 3 JHH 4.8 Hz) could be assigned to the protons C-16HA, C-16HB and C-15HC, respectively.This structural feature is further corroborated by studying its 13 C NMR spectrum in conjunction with its 13 C DEPT 135 NMR spectrum reproduced in Figure 4.It is noteworthy that a 13 C NMR signal at δ 36.7 is reverted in the DEPT135 spectrum, confirming the presence of a CH2 moiety.Furthermore, the presence of only three carbonyl groups is confirmed by three 13 C NMR signals in the downfield region of δ160 -171 ppm which disappear in the DEPT135 spectrum.The absence of the enolic hydrogen atoms is further confirmed by the deuterium-exchange experiment in which no change was observed.The presence of the ABC spin system is confirmed by 2D-NMR spectra, namely the COSY and HMQC spectra.In the COSY spectrum, reproduced in the Supplementary Material (SM-S4), correlation contours can be seen between the 1 H NMR signals of the protons HA and HB on one side and HC on the other side.Furthermore, in the HMQC spectrum of the same compound (reproduced in SM-S4), correlation contours can be noted between the 1 H NMR signals of the protons HA and HB on the X axis with the 13 C NMR signal of C-16 on the Y axis, and, similarly, between the 1 H NMR signal of the proton HC on the X axis with the 13 C NMR signal of C-15 on the Y axis.
Contrary to this NMR data, no ABC spin system could be found in the 1 H NMR spectrum of 15b (reproduced in SM).Instead, two partially resolved doublets, at δ 4.21 ( 3 JHH 8.8 Hz) and δ 3.67 (unresolved), and two partially resolved triplets at δ 4.04 ( 3 JHH 9.0 Hz) and δ 3.82 (unresolved) could be assigned to the protons H-10, H-16, H-14 and H-15, respectively.Furthermore, in the 13 C NMR and 13 C DEPT135 experiments (reproduced in SM), no inverted peak for the CH2 group was observed, although the presence of three carbonyl groups could be substantiated.
Analogously, in 15c and 15d, similar peaks are expected to appear in the range of δ 3-4 ppm which apparently merged with the DMSO peak in their 1 H-NMR (See SM).
In addition, [M+H] + peaks of 16, and 15b-d, obtained at 315.2570, 391.3456, 421.3771, 437.0878, respectively, are in agreement with the molecular weights of the proposed structures.In the absence of X-ray crystal-structure analysis, it was not possible to determine the absolute configuration of any product.As discussed above, however, the two protons of the CH2 moiety in the product 16 are diastereotopic, constituting an ABC spin system with vicinal proton Hc.This indicates the presence of chirality in the molecule, which is confirmed by the optical activity measured for the compound 16 ([α]D 25° = -286.39°).As discussed later, the theoretical investigation and optimization of the geometry of 16 reveals the presence of an axis of chirality in these compounds.

Molecular electrostatic potential maps
The molecular electrostatic potential (MEP) maps visualized using GaussView 6 depict the distribution of electron densities in different regions of a molecule. 21The regions of the highest and least electron densities in the molecule are portrayed by the red and blue colours, respectively, and the electron densities decrease in the order red > orange > yellow > green > blue.Thus, on the basis of the colours in the MEP, it is possible to predict, qualitatively, the nucleophilic and electrophilic sites in the molecule. 22,23The MEP maps of the CCMBs 16 and 15b-d are shown in Figure 5.It may be noted that the blue colour is concentrated on the imidazolopyridinium part of the molecules, indicating its electron-deficient character, whereas the red colour is spread over the maleic anhydride part, revealing its electron-rich nature.This feature is evident in the frontier molecular orbitals (FMOs) which is also explained later.Furthermore, in the case of 15b-d, having a phenyl or p-substituted phenyl substituent group at the 2-position of imidazo[1,2-a]pyridine, the densities of the blue and red colours are further enhanced, revealing their increased electrophilic and nucleophilic characters, respectively.This aspect is reflected in a bathochromic shift in the UV-Vis absorption band in these cases, which is discussed later.

Frontier molecular orbitals and charge transfer phenomena
The location and separation of the FMOs are other characteristics of the CCMBs. 2,24The HOMO and LUMO of the product 16 are shown in Figure 6.It is noteworthy that, in accordance with the MEP maps described earlier, the HOMO is centered on the maleic anhydride part of the molecule, whereas the LUMO is located on the imidazopyridine part.Furthermore, these two parts face each other.This structural feature makes effective intramolecular charge transfer (ICT) possible, which is an important physical phenomenon present in the molecules having both electron-donating (D) and electron-accepting (A) substituent groups or regions. 25The ICT was found to be accompanied by twisting of the conformation, defined as twisted intramolecular charge transfer, abbreviated as TICT. 26Energies of the FMOs of the four CCMBs 16 and 15b-d are presented in Table 1.Interestingly, the energy gap between HOMO and LUMO of 16 is only 2.09 kcal mol -1 , which further decreases on substitution at the 2-position by the phenyl or substituted phenyl group.In 15d, it is reduced to 0.97 kcal mol -1 only (Figure 7) causing a bathochromic shift in the UV-Vis absorption which is discussed later.15d Figure 7.The HOMO-LUMO energy gaps in 16 and 15d.

Dipole moment and conductivity measurements
Dipole moment and electrical conductivity are important criteria of the molecules involved in charge transfer. 27Yates and co-workers determined dipole moments of p-(N,N-dimethylamino)benzonitrile systems in the ground and excited states, and change in the excited state was attributed to twisting of the conformation. 28We computed the dipole moments in the ground and excited states of the four compounds at the wB97XD/6-311+G(d,p) level.The three axes in CCMB 16 are shown in Figure 8.It may be noted that dipole moments of all of the compounds in the ground state are high.Substitution at the 2-position by the phenyl or the p-substituted phenyl group is accompanied by an increase in the dipole moment, this effect being expectedly maximized in the case of 15d having the p-nitrophenyl group.In the excited state, values of the dipole moments decrease in all the cases, which may be attributed to distortion of the conformations.
0][31][32] Zobel et al. studied the dependence of electrical conductivity of some CT complexes containing 7,7,8,8-tetracyano-p-quinodimethane (TCNQ) as an acceptor on temperature.A fast and monotonic decrease of conductivity with decreasing temperature was detected, which is a characteristic property of a regular semiconductor.Furthermore, on plotting ln[I] against 1/T (in Kelvin) at constant voltage, a straight line was obtained. 32e, therefore, determined the molar conductance of the four compounds at varying temperatures; the results are presented in Table 3.The graphs between ln[I] and 1/T (K) for the four compounds are shown in Figure 9.It is evident that all four compounds are electrically conducting; it is interesting to find that, in accordance with the earlier results, molar conductivity decreases with decreasing temperature.The fast and monotonic decrease of conductivity with decreasing temperature reveals regular semiconducting character needing thermal activation for the electrons and holes.The conductivity is small at low temperatures which is caused by lack of carriers.This monotonic decrease is also a strong hint that no phase transition occurs, at least between room temperature and ~200 K. Furthermore, specific conductance of 15c, having the electronreleasing OMe group is highest, whereas that of 15d, having the electron-withdrawing NO2 group, is smallest.

Fluorescence spectroscopy
4][35][36][37] The fluorescence emission spectrum is accompanied by a red shift, the magnitude of which is influenced by solvent, concentration, temperature and environment, i.e., the nature of the substituent groups.The fluorescence spectra of the compounds 16, and 15b,c are shown in Figure 10.The compound 15d did not fluoresce (discussed later).Several characteristic features are noteworthy.The excitation and emission spectra are almost mirror images, confirming it to be a 0-0 transition (S1 →S0).The emission is accompanied by a red shift, ranging from 27 to 63 nm.The magnitude of the red shift is highest in the case of 15c which has an electron-releasing OMe group.Moreover, in this case, excitation is detected at two wavelengths, 396 and 407 nm.As mentioned earlier, fluorescence could not be detected in the case of 15d which has a nitro group.It has been reported that, occasionally, a strong EWG such as a nitro group acts as quencher and the compound does not fluoresce. 38

Spectrophotometric studies and time-dependent DFT calculations
Spectrometric methods have been widely used for studying the CT complexes. 39,40In view of this, we investigated the intramolecular CT phenomenon in 16, and 15b-d with UV-Vis spectroscopy.The curves obtained are shown in Figure 11.A shoulder observed in the range of 280-320 nm can be assigned to the intramolecular CT complex.It is noteworthy that the λmax corresponding to CT excitation is very close to that observed in the fluorescence spectra.
In recent years, time-dependent density-functional theory (TDDFT) calculations have been employed extensively for studying properties of the electronically excited states (EES). 39With the help of TDDFT, various properties of the EES, such as the amount of the charge transfer, and changes in the geometric parameters resulting from the photon absorption by the CT complexes, could be determined successfully. 41,42e carried out TDDFT calculations of the CCMBs 16, and 15b-d at the wB97XD/6-311+G(d,p) level.The experimental and theoretically calculated values of the λmax are presented in Table 4.It may be noted that, except in the case of 16, theoretically calculated values of the λmax are shifted to longer wavelengths as compared to the experimentally-determined values.It has been reported earlier that TDDFT calculations underestimate CT excitation energies. 43

Theoretical investigation of the model reaction sequence
We investigated the following sequence of model reactions theoretically at the B3LYP/6-31+G(d) level using the Gaussian 16 suite of programs. 44(Scheme 4).As discussed earlier, in the absence of X-ray crystal structure analysis, absolute configuration could not be ascertained; however, an axis of chirality can be seen in the optimized geometry of the product 16 (Figure 13).  5.The free energy profiles of the whole sequence of reactions between imidazo[1,2-a]pyridine and maleic anhydride are depicted in Figure 14.The overall reaction is completed in three steps.The first step, having a high-activation free-energy barrier (ΔG # = 32.48kcal mol -1 ), is the rate-determining step.The reaction is endergonic (ΔG ° = 26.27kcal mol -1 ) which explains why the present reaction is much slower than the reaction of imidazo[1,2-a]pyridine with DMAD. 8From these data, it might be concluded that completion of reaction requires heating, however, it is not needed, possibly due to comparatively high ambient temperature (~ 30 °C).Furthermore, the last step involving a 1,3-H shift has an activation barrier of ΔG # = 12.66 kcal mol -1 , but the resulting species has the negative charge delocalized over a larger area which appears to be the driving force.As mentioned earlier, in the reaction of 2-phenyl-(or p-substituted phenyl) imidazo[1,2-a]pyridine with maleic anhydride, a 1,3-H shift does not take place.In view of this, we investigated the reaction of 2phenyl-imidazo[1,2-a]pyridine with maleic anhydride.Theoretical and thermodynamic data are presented in Table 5.It may be noted that, although the activation free energy barrier (ΔG # ) for the first step is lower than that for the reaction of unsubstituted imidazo[1,2-a]pyridine, the activation free energy barriers for the second and third steps are higher by ca. 3 and 4 kcal mol -1 , respectively.This may be the reason why a 1,3-H shift does not take place in the reaction of 2-substituted imidazo [1,2-a]pyridines.

Conclusions
The reactions of imidazo [1,2-a]pyridines with maleic anhydride afford new CCMBs.Physico-chemical studies, including dipole moments, electrical conductivity, fluorescence spectroscopy and UV-Vis spectroscopy reveal the existence of intramolecular charge-transfer phenomena and the luminescent character of these compounds.A theoretical investigation of the model reaction of imidazo[1,2-a]pyridine with maleic anhydride helps to rationalize whole sequence of reactions.MEP maps and FMOs show that negative and positive charges are restricted to two different parts of the molecule, in accordance with the characteristic structural feature of the CCMBs, and they face each other.The latter geometrical feature facilitates active intramolecular charge transfer and induces luminescent character in these compounds.

Experimental Section
General details.Commercially available imidazo[1,2-a]pyridine (12a) procured from Merck was directly used for the synthesis.Maleic anhydride was purified by sublimation prior to setting up the reaction.Solvents such as THF and acetonitrile were freshly dried and distilled according to known procedures.Melting points were measured in an open capillary and are reported as such without any correction.The UV-visible spectra were recorded on a Shimadzu 160 UV-vis spectrophotometer in the range of 200-800 nm with a quartz cell of 1-cm path length.The IR spectra were recorded on a Bruker FT IR spectrometer ALPHA II using KBr pellet.The wavenumbers (νmax) of the recorded IR signals are reported in cm -1 .The 1 H NMR spectra were obtained at 25 °C on a Jeol Resonance ECS 400 MHz NMR spectrometer and Bruker-DPX-300 MHz spectrometer while 13 C NMR, DEPT 135, COSY and HMQC spectra were scanned on Bruker-DPX-300 MHz spectrometer in the specified solvent, with TMS and TSP as internal references (specified where necessary).All of the chemical shifts are reported in parts per million (δ ppm).Coupling constants (J) are given in Hertz.Proton spectral multiplicities are abbreviated as -s: singlet, d: doublet, t: triplet, m: multiplet, q: quartet, dd: doublet of doublets.High resolution mass spectra (HRMS) were recorded with a Xevo G2-S Q Tof (Waters, USA) instrument by directly injecting the sample dissolved in 2 mL of methanol.Molar conductivities were measured using TIMPL Auto Ranging Digital Conductivity/TDS Meter TCM-15 of a 10 -3 M solution in DMSO for temperatures ranging from 10-60 °C.The fluorescence spectra were recorded on the Perkin Elmer LS 55 Fluorescence spectrometer in the range of 200-800 nm for the solutions of the compounds dissolved in DMSO.
General procedure for synthesis of 2-arylimidazo[1,2-a]pyridines (12b-d)-Aminopyridine (1.5g, 15.9 mmol), phenacyl bromide or p-substituted phenacyl bromide (15.9 mmol) and triethylamine (4.3 mL, 31.8 mmol, 2 equiv.)were dissolved in THF (5 mL) and 4Å molecular sieves (0.1 mol %) were added to the reaction mixture.It was refluxed at 50-55 °C for 6 hours.The progress of the reaction was monitored using TLC (hexane:ethyl acetate, 1:1 v/v).After completion of the reaction, the product was filtered over a sintered funnel.The filtrate was concentrated, and the product was purified by column chromatography over silica gel.The product was recrystallized from hot ethanol.

Figure 3 . 1 H
Figure 3. 1 H NMR spectrum of the product 16 depicting the ABC spin system.

Figure 4 .
Figure 4. 13 C NMR spectrum of 16 and its DEPT 135 version.

Figure 8 .
Figure 8.The three axes of the dipole moment of 16 computed at the wB97XD/6-311+G(d,p) level.

Figure 9 .
Figure 9. Temperature dependence of the molar conductivity of 16 and 15b-d.

Figure 10 .
Figure 10.The fluorescence excitation and emission spectra of the compounds 16, and 15b,c in DMSO at room temperature.

Figure 11 .
Figure 11.The electronic spectra of 16, and 15b-d in DMSO.

Table 1 .
Energies of the FMOs of the CCMBs 16 and 15b-d

Table 3 .
Variations of molar conductance of 16 and 15b-d with temperature in 10 -3 M DMSO

Table 4 .
Experimental and theoretically-calculated values of the λmax of 16 and 15b-d

Table 5 .
Thermodynamic data of the formation of 16 and 15b computed at the B3LYP/6-31+G(d) level ∆H o , ∆G # and ∆G o are in kcal mol-1