Structure and spectroscopy of imidazo [1,2-a ]imidazoles and imidazo[1,2-a ]benzimidazoles

Two azapentalenes containing fused imidazoles have been synthesized and their NMR (solution and solid state) and UV properties recorded. Tautomerism in the case of imidazo[1,2-a ]benzimidazole (9 H tautomer) and the structure of the cations resulting from protonation in both cases have been determined. Ab initio calculations (HF/6-311G**) confirm the greater stability of 9 H over 1 H - imidazo[1,2-a ]benzimidazole tautomer.


Introduction
In search of systems that form cyclic motifs linked by intermolecular hydrogen bonds, we focused our attention on imidazo [1,2-a]imidazole 1 and its monobenzo derivative 2. These compounds, formally derived from pentalene, 1 can form dimers both in the solid state and in solution (Scheme 1).Parent imidazo [1,2-a]imidazole 1 has only one annular tautomer but imidazo [1,2-a]benzimidazole 2 can exist in two tautomeric forms depending if the proton is on the imidazole 2a or on the benzimidazole ring 2b.  a From reference 2; the liquid ammonia scale was transformed into internal nitromethane scale by the relationship 381.9 -ammonia. 6 the imidazol [1,2-a]imidazole series, the most significant results are the 6 J 26 coupling, useful for assignment purposes and the increase of the 3 J coupling constant on protonation.Notice also that in compound 3, the moiety bearing the N-methyl group has a 3 J 23 coupling constant of 2.3 Hz while the other moiety has a 3 J 56 = 1.4 Hz, this being related to the dipolar structure of azapentalenes.Similar comments hold for the imidazo [1,2-a]benzimidazole series concerning now the 3 J 23 coupling with values of 1.8 Hz (compound 2, tautomer 9H, see later on tautomerism), 1.6 Hz (compound 5) and 2.4-2.5 Hz (compound 4 and cations 2H + , 4H + and 5H + ).
Azapentalenes can be represented in a dipolar form with the positive charge (imidazolium) on the N-substituted ring and the negative charge (imidazolate) on the other ring. 1 The 13 C data summarized in Scheme 4 (average values for two carbon atoms) agree with those reported by Pugmire and Grant for imidazolium cations (C4 and C5 at 122.1 ppm) and imidazolate anions (C4 and C5 at 126.8 ppm). 7

Scheme 4
The CPMAS chemical shifts are remarkably alike those found in solution.The main differences found for 2 are that the nitrogen signals are shifted 17 ppm in opposite directions.We assign this behaviour to the 2b-2b dimeric structure of the crystal.Compound 1 does not present SSPT: carbons C-3 and C-5 coincide (they appear at 104.4 and 106.0 ppm in 3) but carbons C-2 and C-6 (see Figure 1) are well separated and resolved.The broadening of C-2 and C-7a is not related to tautomerism but most probably to dipolar couplings with N-1.

Protonation
The spectra of the cations reported in Tables 1-3, with the notation nH + , have been obtained in three ways: dissolving the cation in DMSO, adding 37% HCl (50 µL) to a DMSO solution (0.5 mL) of the base (5.10 -2 M for 1 H NMR and 5.10 -1 M for 13 C NMR) or recording the spectrum of the base in trifluoroacetic acid.Protonation results in large effects on all the signals.
Particularly noteworthy are the effects on 3 J( 1 H-1 H) (Table 1) and on 1 J( 1 H-13 C) coupling constants (Table 2).We have summarized in Scheme 5 the 13 C chemical shifts effects on αcarbons (Table 2) to the protonated nitrogen, and on the 15 N chemical shifts (Table 3), defined as ∆δ = δ (CDCl 3 ) -δ (CF 3 CO 2 H).They are very consistent and constitute the best method to determine the protonation site.

Solid state proton transfer (SSPT)
The necessary condition for SSPT is that the initial and final states should be degenerate or near degenerate. 8,9This is not the case for compound 2 where both tautomers are very different in energy.At the HF/6-311G** level, 10,11 tautomer 2b is 9.98 kJ mol -1 more stable than tautomer 2a.
Note that a transformation 2a-2b into 2b-2a will satisfy the requirements of degeneracy, but the heterodimer must be also much less stable than the 2b-2b homodimer.Only in dimer 1-1 SSPT would be possible, provided it crystallizes as a dimer, but we have been unable to obtain good single crystals suitable for X-ray crystallography.

Electronic spectra
We have recorded the electronic spectra of compounds 2, 4 and 5 in three solvents of different polarity (Table 4).a CyH: Cyclohexane, fine structure (vibrationally resolved).
The spectra (band 5) are sensitive to their polarity as defined by the Reichardt's solvent parameter ET(30): When adding HCl to the ethanol solution, the spectrum bands shifted to shorter wavelengths (formation of the 2H + cation: 274 nm, log ε = 3.83 and 280 nm, log ε =3.82).
Concerning tautomerism, the spectra of 2 are more similar to those of 5 than to those of 4. This is not very apparent from Table 4 but visual examination is conclusive.We should note that, in the case of 2, they depend on the concentration, on dilution in acetonitrile, the main band shift to shorter wavelengths (blue shift, hypsochromic effect).We assign this effect not to a modification of the tautomerism, 2b being always predominant, but the formation of 2b-2b homodimers.
It is safe to assume that the N-methylation does not modify the dipole moment and that the effect of the polarity of the solvent on the electronic spectra is related to the dipole moment of the solute.Those calculated for 2a (4.43 D) and 2b (2.98 D) explain why the slope of eq. ( 3) (isomer 5 corresponds to 2b) is nearly three times greater than that of eq. ( 2) (isomer 4 corresponds to 2a) (remember that when discussing dipole moments, the square of ⎧ is the additive property).In the case of 2 the slope (-0.44) is intermediate between those of 4 and 5, may be an indication of the presence of both tautomers.

Conclusions
The heterocyclic systems of imidazo[1,2-a]imidazole 1 and its monobenzo derivative 2 have interesting properties but none has shown SSPT.In the case of 2 this has been explained by a too great difference in energy between tautomers and only the possibility to observe the phenomenon in the excited state remain.For the parent system 1 two explanations are possible: either the system do not crystallize in cyclic dimers but forms catemers like imidazole or the crystals contain dimers but the activation barrier is too high.Some "symmetrical" pyrazoles that forms cyclic patterns do not present SSPT.  in HCl (12.5 ml 2 N) is refluxed for 30 min.The reaction mixture is then divided in two equal portions: one of these is evaporated under reduce pressure, the oily residue obtained is dissolved in MeOH, and next evaporated to dryness.Thus, salt 2H+ was obtained as a slightly gray powder, 930 mg; yield 96 %.The free base 2 (slightly yellow powder; 680 mg; yield 86 %) is recovered from the other portion by filtration of the precipitate obtained after addition of 10% aqueous NaHCO 3 until the pH reaches 8. 1-Methylimidazo[1,2-a]benzimidazole (4) and 9-methylimidazo[1,2-a] benzimidazole (5).To a magnetically stirred solution of 2 (1.70g, 10.8 mmol) and NaOH (476 mg, 11.9 mmol) in H 2 O (12 ml) containing 1 ml of MeOH, 1.18 ml of dimethyl sulfate (12.5 mmol) is added.The reaction mixture is stirred around 2 h and the methanol is evaporated under reduce pressure.A few ml of water (about 10 ml) is added and this aqueous solution is extracted with CH 2 Cl 2 (2 x 15 ml).The organic layers are washed with water, dried with Na 2 SO 4 and evaporated to dryness to afford the crude mixture (1.45 g) of the two N-methyl derivatives, that are in an about 1:2 (4/5) ratio, according to the 1 H NMR analysis (integration of the N-methyl signals).The two compounds are separated by flash column chromatography on silica gel (silica gel: 65 g; solvent: CH 2 Cl 2 /MeOH, 985:15).463 mg of 4 (mp 143 °C, yield 25 %, R f = 0.37, CH 2 Cl 2 /MeOH 94:6) and 944 mg of 5 (mp 49 °C, yield 51 %, R f = 0.41, CH 2 Cl 2 /MeOH 94:6) are obtained.A small quantity of compounds 4 and 5 was prepared in a high purity level for analytical purposes.114 mg of 4 (slightly yellow small crystals) are obtained by crystallization from isopropyl ether-MeOH; 47 mg of 5 (white powder) are obtained by crystallization from isopropyl ether.Isomer 4, Anal.Calcd.for C 10 H 9 N 3 : C 70.16, H 5.30, N 24.54.Found: C 70.31, H 5.18, N 24.51.Isomer 5, Anal: Found: C 70.22, H 5.32, N 24.24.

Table 2 .
13C NMR data (δ C ppm and coupling constants in Hz)