Tautomeric Equilibria in Solutions of 2-Phenacylbenzimidazoles

Detailed NMR spectral analysis of DMSO-d6 solutions of the series of substituted 2-phenacylbenzimidazoles (ketimine form, K) reveals two from three tautomeric forms. Integrals of the H NMR signals are used in establishing the molar ratio of tautomers. The experimental analyses are supported by quantum-chemical calculations, which satisfactorily reproduced the experimental trends. Although the reported semiempirical quantum-chemical calculations show that enaminone E, i.e., 2-(1,3-dihydro-2Hbenzo[d]imidazol-2-ylidene)-1-phenylethan-1-one, was thermodynamically most stable, the results of MP2 ab initio calculations reveal the following order of stability: ketimine > enolimine > enaminone (substituents do not affect this sequence). C CPMAS NMR spectral data reveal that in the crystalline state the enolimine tautomerO is predominant in the p-CH3 and p-NO2 substituted congeners.


Introduction
It was found recently that in chloroform solution 2-phenacylbenzoxazoles (K in Scheme 1, X = O) are in equilibrium with (Z)-2-(benzo[d]oxazol-2-yl)-1-phenylethenols (enolimines, O) [1].Strong electron-donating substituents in the benzene ring were found to stabilize the K tautomer.The MP2 ab initio calculations supported the energetic preference of the O (over E) form. 13C CPMAS NMR spectra proved that in the crystalline state the ketimine tautomer K is predominant only in the p-NMe 2 substituted congener.On the other hand, enolimine forms O were detected when the substituent had less electron-donating character or when it had an electronaccepting nature [1].
Since the -N=C(-)CH 2 CO-moiety also is present in 2-phenacylbenzimidazoles (Scheme 1, X = NH), these compounds and 2-phenacylbenzoxazoles and 1-methyl-2phenacylbenzimidazoles are expected to behave similarly.However, in drawing such conclusions one has to be very careful: minor modifications in the molecule may affect the tautomeric equilibria significantly [1][2][3].Such understanding prompted us to see the effect of substitution of the ring oxygen atom in 2-phenacylbenzoxazoles and NCH 3 group in 1-methyl-2-phenacylbenzimidazoles by the NH group on their susceptibility to proton transfer.
In order to compare 2-phenacylbenzimidazoles with 2-phenacylbenzoxazoles and 1-methyl-2-phenacylbenzimidazoles studied earlier [1,2], the NMR spectra of the former compounds should be recorded from their deuterated chloroform solutions.Unfortunately, the crystals were sparingly soluble in that solvent, so it was substituted with DMSO-d 6 .
Due to the presence of the 2,3-dihydro-2-methylene-1Hbenzo [d]imidazole moiety in the molecules, both nitrogen atoms in the enaminone form E are equivalent (unless they are differentiated by the intramolecular hydrogen bond).
For the substituents studied, presence of the enolimine O in DMSO-d 6 solution has never been reported. 1H and 13 C as well as 1 H, 13 C HMBC NMR spectra suggest that K and E forms are present in such solution [4].There is no doubt about the presence of the former tautomer, but unequivocal distinguishing between enolimines and enaminones cannot be based only on the simple NMR spectra [1][2][3].It is why the 1 H, 13 C HMBC technique has been used earlier to prove which of K and E is present in solution [4].Using of the IR spectra to identify the form present in the crystalline state E [4] also seems unreliable.
The percent content of K form based on H10 integrals is given in Table 2.The accuracy of these data was supported by the evaluation based on signal intensities of the substituent protons and the literature data.In many cases, mainly electron delocalization was found to be responsible for tautomeric preferences but other effects, such as the strength of the intramolecular hydrogen bond, should be taken into account.
13 C CPMAS spectra of 2b and 2i show that only one tautomer is present in the solid state.The characteristic chemical shifts of 22.4 ppm (CH 3 ), 77.5 ppm (C10), and 177.2 ppm (C11) for 2a and 76.5 ppm (C10) and 175.3 ppm (C11) for 2i, suggest that it was the enolimine form O.

Substituent Effect on the Tautomeric Equilibrium.
As can be seen in Table 2, the tautomeric ratio in solutions of 2a-i depends strongly on the substituent.Electron-acceptor substituents increase acidic character of the methylene protons in the K forms and thus favour this tautomer (Scheme 4).In consequence, their proton transfer to the aza atom in these compounds is facile.

Quantum-Chemical Calculations.
The obtained experimental data seemed worthy of comparison with the results of the respective quantum-chemical calculations.Although semiempirical quantum-chemical calculations show that enaminone form E of 2d is thermodynamically more stable than ketimine form K of 2d [4], MP2 procedure is recommended as the most accurate and effective ab initio method for studying medium size molecules involving hydrogen bonds [16].It includes electron correlation so the calculated and experimental data are expected to be comparable [17].Some optimized bond lengths and dihedral angles in the molecules of 2-phenacylbenzimidazoles and their tautomers are presented in Table 3. Judging from the length of the hydrogen bond, it seems to be stronger in enolimines than in enaminones.Such an interaction is especially weak in ketimines.
The effect of the substituent on conformation of each tautomer is negligible.Twisting of the carbonyl group with respect to the neighbouring benzene ring in the ketimine molecules is equal to 10-15 ∘ (Table 3).The six-membered pseudorings, including the intramolecular hydrogen bonds in both enolimines and enaminones, are almost planar.The dihedral angle (Ψ) between the said benzene ring and C10-C11-O12 moiety in these two tautomers is comparable (ca 30 ∘ ).Although distances between H18 and methylene protons H10 in 2-phenacylbenzoxazoles were comparable [1], these in 2-phenacylbenzimidazoles (ketimines, K) are significantly differentiated (Table 3) because one of these methylene hydrogens experiences steric hindrance by the aryl ring.
The calculated energies of different tautomers (Table 4) prove the K form to be the most stable (both electron-donor and electron-acceptor substituents follow this rule).
The enolimine O is always less stable than ketimine K (the more electron-accepting is the substituent, the more stable is the enolimine form).As this can be seen in Scheme 3, the six-membered pseudoring including the NH ... O=C system in K is expected to be less aromatic than the respective pseudorings including the NH ... O=C and OH ... N moieties in E and O, respectively.The strong resonance assisted hydrogen bonds (RAHB), such as this present in the molecule of the later tautomer, are well known [18][19][20][21].The least stable tautomer is always E (both electrondonor and electron-acceptor substituents follow the rule).
It is noteworthy that O seems to be really more stable than E just because the benzene, pseudo, and imidazole rings are aromatic in the former tautomer, while in the enaminone that is the case for the benzene and pseudorings only (Scheme 3).Thus, from this point of view, 2phenacylbenzimidazoles resemble 2-phenacylbenzoxazoles [1] and 1-methyl-2-phenylbenzimidazoles [2].

Experimental Methods
Melting points were measured on a Boetius table and are uncorrected.Satisfactory elemental analyses (± 0.30 % for C, H and N) were obtained from Perkin Elmer 2400 Series II CHNS/O.

3.1.
Syntheses: General Procedure.Benzoyl chloride (0.04 mole) was added in one portion to the stirred solution of 2methylbenzimidazole 1 (1.46 g, 0.01 mole) and triethylamine (5.6 mL, 4.05 g, 0.04 mole) in diglyme (4 mL).Content of the reaction vessel was heated for 1 h on the boiling water bath.Dropwise addition of water (60 mL) to the stirred cold reaction mixture resulted in precipitation of (Z)-2-(1Hbenzo[d]imidazol-2-yl)-1-phenylvinyl benzoates.A solution of the crude material (0.006 mole) and morpholine (1.6 mL, 1,57 g, 0.018 mole) in methanol (9 mL) were heated under reflux with stirring for 10 min.Water (9 mL) was added to the boiling reaction mixture, which cooled to start precipitation.Crystallization of the collected solid from methanol affords pure 2-phenacylbenzimidazoles 2a-i.  1C and PFG 1 H, 13 C HMQC and HMBC spectra were recorded on a Bruker Avance DRX 500 spectrometer equipped with an inverse detection probehead and z-gradient accessory working at 500.13 MHz and 125.77MHz, respectively.The number of data points in PFG 1 H, 13 C HMQC and HMBC measurements were 1024 (f 2 ) x 256 (f 1 ).This matrix was zero filled to 2048 x 512 and apodized by a shifted sine bell window function along both axes prior to FT.

2-(1H-benzimidazol-2-yl)-1-(4-methoxyphenyl)ethan-1-one (2a
The solid state 13 C CPMAS NMR spectra were recorded on a Bruker Avance 400 FT NMR spectrometer using the samples packed in 4.0 mm o.d.zirconia rotors.The samples were spun at 10 KHz rate and >1000 transients were accumulated.The FIDs are apodized by 10 Hz exponential window before FT.The shifts are referenced to the C=O signal of glycine standard at =176.03 ppm.

Conclusions
In DMSO-d 6 solution, 2-phenacylbenzimidazoles (ketimine tautomeric form, K) are in equilibrium with (Z)-2-(1Hbenzo[d]imidazol-2-yl)-1-phenylethen-1-ol (enolimine form, O). 2-(1H-benzo[d]imidazol-2(3H)-ylidene-1-phenylethanones (enaminones E) were not detected (our findings are different from those reported earlier by other authors [4]).The molar ratio of different forms in solution (based on the integrals of 1 H NMR signals) depends on substituent.Electron-acceptor substituents increase the acidic character of the methylene protons in the ketimine forms K.In consequence, the transfer of such a proton to the carbonyl oxygen is very easy in these compounds.The calculated energies of different tautomers prove the ketimine form K including the OH ... N hydrogen bond to be the most stable (both electron-donor and electron-acceptor substituents follow this rule).The enolimine tautomers O are always less stable than ketimines K.The most labile tautomer is always enaminone E. Enolimine tautomers O were detected by solid state 13 C CPMAS NMR.

Table 2 :
Content of the K form (%) (solutions in DMSO-d 6 ).Based on integrals of the H10 signals (present paper).b Literature data collected from DMSO-d 6 solutions.c Values in parentheses are based on integrals of the substituent protons (CH 3 , 3.91 ppm for 2a (form K) and 3.87ppm for 2a (form O), 2.51 ppm for 2b (form K) and 2.37 ppm for 2b (form O), 2.51 ppm for 2c (form K) and 2.40 ppm for 2c (form O)).On the other hand, the 13 C chemical shifts can indicate the tautomer present in solution.C11 signals of other tautomers (O or E) are located in the range of 161-171 ppm (Table [2] Scheme 4: Resonance structure contributing to the stabilization of the 2-phenacylbenzimidazole tautomer K by electron-donating substituents.ofbenzoxazoles[1],1-methy-2-phenacylbenzimidazoles[2],andtheirenolimine or enaminone tautomers.Thus, the chemical shift values do not reveal whether another tautomer in DMSO-d 6 solution is O or E. One should keep in mind that signals of the N-H protons seen at >12 ppm are comparable to those of the hydroxyl protons in the enolimine tautomers of 2-phenacylbenzoxazoles[1].
a Distances to H18 from two distinct H10.