Intramolecular H-bonding interaction in angular 3-π-EWG substituted imidazo[1,2-a]pyridines contributes to conformational preference
© Velázquez-Ponce et al.; licensee Chemistry Central Ltd. 2013
Received: 15 August 2012
Accepted: 17 January 2013
Published: 31 January 2013
The proton at position 5 of imidazo[1,2-a]pyridines substituted with an angular electron withdrawing group (EWG) at position 3, shows an unusual downfield chemical shift, which is usually explained in terms of a peri effect. However usage of this term is sometimes confusing. In this investigation, it is proposed that the aforementioned shift is in fact a combination of several factors: Anisotropy, long-distance mesomerism and an attractive intramolecular interaction of the electrostatic hydrogen bond type.
Theoretical calculations were performed aimed to obtain evidence of the existence of an intramolecular non-bonding interaction between H-5 and the oxygen atom of the EWG. Results derived from conformational and vibrational analysis at the DFT B3LYP/6-311++G(d,p) level of theory, the determination of Bond Critical Points derived from AIM theory, and the measurement of some geometrical parameters, support the hypothesis that the higher stability of the prevailing conformation in these molecules (that in which the oxygen of the EWG is oriented towards H-5) has its origin in an intramolecular interaction.
Computational calculations predicted correctly the conformational preferences in angular 3-π-EWG-substituted imidazo[1,2-a]pyridines. The existence of an electrostatic hydrogen bond between H-5 and the oxygen atom of the π-EWG was supported by several parameters, including X-ray crystallography. The existence of such structural array evidently impacts the H-5 chemical shift.
KeywordsImidazo[1,2-a]pyridine Peri effect Hydrogen bonding Conformational preference
From the structural point of view, this fused heterocycle is attractive as well. Substitution at position 3 of the heterocycle with an electron-withdrawing group (EWG), for instance a nitro group, shifts H-5 to low fields (ca. δ 9.4) . The H-5 of 7-methyl-3-nitroso-2-(pyridin-2-yl) imidazo[1,2-a]pyridine is shifted to δ 9.7 . In the latter case, the unusual chemical shift was explained in terms of a peri effect. An X-ray analysis of this compound showed that the oxygen atom of the nitroso group is oriented towards H-5, apparently justifying an anisotropic effect as responsible for the magnetic deshielding of the peri H-5. Paudler attributed the deshielding effect on H-5 of 3-substituted imidazo[1,2-a]pyridines to a through-space electric field effect .
H-5 chemical shift of some imidazo[1,2-a]pyridines substituted with angular EWG at position 3
In this study an interaction between the angular EWG at position 3 of the imidazo[1,2-a]pyridine ring system and H-5 of the same molecule is demonstrated by theoretical means. It is proposed that the establishment of such interaction may promote a preferred conformation of the group at position 3, independent of the substituent at position 2. The adoption of such conformation, which definitely impacts the H-5 chemical shift, should contribute to offer a more precise explanation of the nature of the peri effect.
Results and discussion
The interatomic distances between H-5 and ONO and between H-5 and OCHO were 2.265 Å and 2.321 Å , respectively. These represent smaller values than the corresponding sum of their van der Waals radii. The marked conformational preference shown by derivatives 4–7, supports the existence of an attractive intramolecular interaction between the oxygen atom of the electron-withdrawing group and H-5. Furthermore, such interaction should have a strong electrostatic character considering that the angular EWG located at the peri position would accumulate charge over the most electronegative oxygen atom. This, in turn, would lead to an attractive interaction onto H-5, which is attached to a carbon bonded to a nitrogen atom bearing a strong positive character.
Hydrogen bonding interaction
One of the most widely accepted criteria for validating the formation of an intramolecular H···X hydrogen bond is the magnitude of the interatomic distance between the atoms involved, which should be less than the sum of their van der Waals radii . However, from the theoretical point of view, and according to AIM theory , the requirement is the existence of a bond critical point of a particular nature  between the H···X atoms. Therefore in order to confirm the formation of a hydrogen interaction between H-5 and either the nitroso [C-H···O=N] or the formyl [C-H···O=C] oxygen, we carried out calculations aimed to determine the existence of bond critical points, employing the AIMAll program, starting from the wavefunctions of the described conformers obtained from the Gaussian 98 calculations.
Topological Parameters for BCP found between H-5 and O for conformers 6a and 7a and values for an electrostatic hydrogen bond (feature values)
d H· · · Y
H· · · O < 2.61
In order to have an idea of the electron withdrawing effect of the 3-angular substituent on the chemical shift of H-5, the imidazo[1,2-a]pyridine-3-carbonitrile 8, was synthesized from the corresponding imidazo[1,2-a]pyridine-3-carboxaldehyde oxime using acetic anhydride as the dehydrating agent . The experimental 1H NMR spectrum of 8 showed that indeed H-5 was not shifted to very low fields by the introduction of the linear nitrile group, δ 8.36 (CDCl3). As expected, the corresponding calculations showed that no critical point was found between H-5 and the nitrile (Figure 7). This suggests that the π-EWG geometry is mandatory and that the H-5 chemical shift shown in 8 involves solely the inductive and mesomeric effects of the nitrile group.
AIM Topological Parameters for the BCPs found for the conformers of 4 and 5
The observed chemical shifts for the peri H-5 of imidazo[1,2-a]pyridines caused by the EWG at 3, with no substituent at position 2, follow the order: PhC(O) > HC(O) > MeC(O) > O2N, i.e. the strongest electron-withdrawing group has a minor deshielding effect on H-5. It is possible that the observed decreased effect on the H-5 chemical shift might be a consequence of a charge distribution on the oxygen nitro atoms. The introduction of the phenyl ring shifts the H-5 signal to lower fields (Table 1).
Ab initio calculations were carried out with the Gaussian 98  for Linux, Gaussian 98 for Windows, and AIMAll  programs; visualization and geometry construction was done with the viewers Molden  and GaussView . The geometries of the structures under study were optimized, relative energies, preferred structural conformations, dihedral angle scans, and frequency analysis were carried out at the HF/3-21G and B3LYP/6-311++G(d,p) levels of theory. The AIM analyses were carried out starting from the B3LYP/6-311++G(d,p) wavefunctions and geometries.
The imidazo[1,2-a]pyridine derivatives used in this investigation were prepared following the protocols described in the references shown in Table 1 and identified by comparison of their physical data with those reported in the literature. 1H and 13C NMR spectral data were recorded at 300 and 75 MHz respectively using a Bruker DPX 300 MHz NMR spectrometer. H-5 chemical shifts (δ) are given in parts per million downfield from TMS (δ = 0). The X-ray diffraction analysis was carried out in an Oxford Diffraction Xcalibur S diffractometer.
Computational calculations predict correctly the conformational preferences in 3-π-EWG substituted imidazo[1,2-a]pyridines. When these π-EWG substituents meet the condition of being angular (aldehyde, acyl, nitroso), the thermodynamic equilibrium favors the conformer with the oxygen oriented towards H-5 of the imidazo[1,2-a]pyridine core. The existence of an electrostatic hydrogen bond between H-5 and the oxygen atom of the π-EWG is supported by the following facts: The geometries of the global minima already mentioned; the existence of critical points within the O···H inter-atomic space and the corresponding values of the electron density and the Laplacian of the electron density at these critical points; the magnitude of their interatomic distance is less than the sum of the van der Waals radii. With regards to the observed H-5 chemical shift caused by the angular EW groups at position 3, we concluded that this is an interplay of several factors which include the already mentioned electrostatic interaction along with a negative inductive EWG effect, anisotropy and long-distance mesomerism. The X-ray analysis performed on 3-nitroso-2-phenyl imidazo[1,2-a]pyridine, as well as other diffraction studies reported in the literature on analogous molecules, indicate that the solid-state geometry is closely related to the most stable conformational structures predicted by theoretical calculations.
Financial support from CONACYT México through grant 49937 is gratefully acknowledged. MVP thanks CONACYT for a graduate scholarship 44769. We thank Dr. Manuel Medina for helpful assistance in the use of software programs. HSZ, MECA, RJ, and HAJV are fellows of the COFAA and EDI fellowship programs of the IPN.
- Kazzouli SE, Griffon du Bellay A, Berteina-Raboin S, Delagrange P, Caignard DH, Guillaumet G: Design and synthesis of 2-phenyl imidazo[1,2-a]pyridines as a novel class of melatonin receptor ligands. Eur J Med Chem. 2011, 46: 4252-4257. 10.1016/j.ejmech.2011.06.030.View ArticleGoogle Scholar
- Gong YD, Cheon HG, Lee T, Sookkang N: A novel 3-(8-chloro-6-(trifluoromethyl) imidazo[1,2-a]pyridine-2-yl)phenyl acetate skeleton and pharmacophore model as glucagon-like peptide 1 receptor agonists. Bull Korean Chem Soc. 2010, 31: 3760-3764. 10.5012/bkcs.2010.31.12.3760.View ArticleGoogle Scholar
- Koubachi J, Kazzouli SE, Berteina-Raboin S, Mouaddib A, Guillaumet G: Synthesis of polysubstituted imidazo[1,2-a]pyridines via microwave-assisted one-pot cyclization Suzuki coupling palladium-catalyzed heteroarylation. J Org Chem. 2007, 72: 7650-7655. 10.1021/jo0712603. and references 1–11 thereinView ArticleGoogle Scholar
- Paudler WW, Chasman JN: CNDO/2 calculations of some polyazaindenes. J Heterocyclic Chem. 1973, 10: 499-501. 10.1002/jhet.5570100414.View ArticleGoogle Scholar
- Teulade JC, Escale R, Grassy G, Girard JP, Chapat JP: Reactivité de derives de l’imidazo[1,2-a]pyridine vis-à-vis de la reaction de nitration. Effets de substituant par RMN 13C et CNDO. Bull Soc Chim France II. 1979, 9-10: 529-536.Google Scholar
- Paolini JP, Robins RK: Aromaticity in heterocyclic systems. IV. Substitution reactions of imidazo[1,2-a]pyridine and related methyl derivatives. J Org Chem. 1965, 30: 4085-4090. 10.1021/jo01023a024.View ArticleGoogle Scholar
- Chaouni-Benabdallah A, Galtier C, Allouchi H, Kherbeche A, Debouzy JC, Teulade JC, Chavignon O, Witvruouw M, Pannecouque C, Balzarini J, de Clerq E, Enguehard C, Gueiffier A: Synthesis of 3-nitroso imidazo[1,2-a]pyridine derivatives as potential antiretroviral agents. Arch Pharm. 2001, 334: 224-228. 10.1002/1521-4184(200107)334:7<224::AID-ARDP224>3.0.CO;2-7.View ArticleGoogle Scholar
- Hand ES, Paudler WW: Downfield 1H NMR shifts induced by electron-rich substituents. Org Magn Res. 1980, 14: 52-54. 10.1002/mrc.1270140112.View ArticleGoogle Scholar
- Balasubramaniyan V: Peri Interaction in naphthalene derivatives. Chem Rev. 1966, 66: 567-641. 10.1021/cr60244a001.View ArticleGoogle Scholar
- Bouhrira K, Ouahiba F, Zerouahli D, Hamouti B, Zertoubi M, Benchat N: The inhibitive effect of 2-phenyl-3-nitroso imidazo[1,2-a]pyridine on the corrosion of steel in 0.5 M HCl acid solution. E-Journal of Chemistry. 2010, 7 (S1): S35-10.1155/2010/525606.View ArticleGoogle Scholar
- Koubachi J, Berteina-Raboin S, Mouaddib A, Guillaumet G: Pd/Cu-Catalyzed oxidative C-H alkenylation of imidazo[1,2-a]pyridines. Synthesis. 2009, 2: 271-Google Scholar
- Mareev AV, Tikhonov AV, Afonin AV, Ushakov IA, Medvedeva AS: Microwave-assisted direct solid-phase transformation of 3-trimethylsilyl- and 3-triethylgermyl-2-propynols into imidazo[1,2-a]pyridine 3-carbaldehyde. Russ J Org Chem. 2005, 41: 1397-1398. 10.1007/s11178-005-0355-z.View ArticleGoogle Scholar
- Gómez O, Salgado-Zamora H, Reyes A, Campos ME: A revised approach to the synthesis of 3-acyl imidazo[1,2-a]pyridines. Heterocycl Commun. 2010, 16: 99-103.View ArticleGoogle Scholar
- Starrett JE, Montzka TA, Crosswell AR, Cavanagh RL: Synthesis and biological activity of 3-substituted imidazo[1,2-a]pyridines as antiulcer agents. J Org Chem. 1989, 32: 2204-2212.Google Scholar
- Hand ES, Paudler WW: Imidazo[1,2-a]pyridine 1-oxide. Synthesis and chemistry of a novel type of N-oxide. J Org Chem. 1978, 43: 658-663. 10.1021/jo00398a030.View ArticleGoogle Scholar
- Ericsson JG: The chemistry of heterocyclic compounds: Systems with bridgehead nitrogen. Edited by: Mosby WL, Weissburger A. 1961, Wiley-Interscience, 461-505. 15Google Scholar
- Paudler WW, Blewitt HL: NMR spectra and π-electron densities of some imidazo[1,2-a]pyridines. Tetrahedron. 1965, 21: 353-361. 10.1016/S0040-4020(01)98274-2.View ArticleGoogle Scholar
- Blewitt HL: Indolizine and aza derivatives with additional nitrogens in the 5-membered ring. In Chemistry of Heterocyclic Compounds: Special Topics in Heterocyclic Chemistry. 1977, 30: 117-178. 10.1002/9780470187005. Published Online: Eds Weissberger A, Taylor EC. 2008Google Scholar
- Salgado-Zamora H, Velázquez M, Mejia D, Campos ME, Jiménez R, Cervantes H: Influence of the 2-aryl group on the ipso electrophilic substitution process of 2-aryl imidazo[1,2-a]pyridines. Heterocyclic Commun. 2008, 14: 27-32.View ArticleGoogle Scholar
- Kazhkenov Z-GM, Bush AA, Babaev EV: Dakin-West Trick in the design of novel 2-alkyl(aralkyl) derivatives of oxazolo[3,2-a]pyridines. Molecules. 2005, 10: 1109-1118. 10.3390/10091109.View ArticleGoogle Scholar
- Yu L, Lopez A, Anaflous A, El Bali B, Hamal A, Ericson E, Lawrence E, Heisler LE, McQuibban A, Giaever G, Nislow C, Boone Ch GW, Brown GW, Mohammed BM: Chemical-genetic profiling of imidazo[1,2-a]pyridines and pyrimidines reveals target pathways conserved between yeast and human cells. PLoS Genet. 2008, 4: e1000284-10.1371/journal.pgen.1000284.View ArticleGoogle Scholar
- Canizzaro CE, Houk KN: Magnitudes and chemical consequences of R3N+-C-H O=C hydrogen bonding. J Am Chem Soc. 2002, 124: 7163-7169. 10.1021/ja012417q.View ArticleGoogle Scholar
- Kuhn B, Mohr P, Stahl M: Intramolecular hydrogen bonding in medicinal chemistry. J Med Chem. 2010, 53: 2601-2611. 10.1021/jm100087s.View ArticleGoogle Scholar
- Anaflous A, Albay H, Benchat NE, El Bali B, Dusek M, Fejfarová K: 2-Phenyl imidazo[1,2-a]pyridine-3-carbaldehyde. Acta Cryst. 2008, E64: o927-Google Scholar
- Bibila Mayaya Bisseyou Y, Soro AP, Sissouma D, Giorgi M, Ebby N: 3-(3-Chlorophenyl)-1-(2-methyl imidazo[1,2-a]pyridin-3-yl)prop-2-en-1-one. Acta Cryst. 2007, E63: o4758-o4759.Google Scholar
- Bondi A: Van der Waals volumes and radii. J Phys Chem. 1964, 68: 441-451. 10.1021/j100785a001.View ArticleGoogle Scholar
- Bader RFB: Atoms in molecules, A Quantum Theory. 1990, Oxford, U.K: Oxford University PressGoogle Scholar
- Koch U, Popelier PLA: Characterization of C-H-O hydrogen bonds on the basis of the charge density. J Phys Chem. 1995, 99: 9747-9754. 10.1021/j100024a016.View ArticleGoogle Scholar
- Sobczyk L, Grabowsky SJ, Krygowski TM: Interrelation between H-bond and pi-electron delocalization. Chem Rev. 2005, 105: 3513-3560. 10.1021/cr030083c.View ArticleGoogle Scholar
- March J: Advanced organic chemistry. 1992, New York: John Wiley & Sons, 1038-4Google Scholar
- Popelier PLA: Characterization of a dihydrogen bond on the basis of the electron density. J Phys Chem A. 1998, 102: 1873-1878. 10.1021/jp9805048.View ArticleGoogle Scholar
- Rybakov VB, Babaev EV: 1-Methyl-3-(4-chlorobenzoyl) imidazo[1,2-a]pyridin-1-ium-2-olate. Acta Cryst. 2011, E67: o2814-Google Scholar
- Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Zakrzewski VG, Montgomery JA, Stratmann RE, Burant JC, Dapprich S, Millam JM, Daniels AD, Kudin KN, Strain MC, Farkas O, Tomasi J, Barone V, Cossi M, Cammi R, Mennucci B, Pomelli C, Adamo C, Clifford S, Ochterski J, Petersson GA, Ayala PY, Cui Q, Morokuma K, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Cioslowski J, Ortiz JV, Baboul AG, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Gomperts R, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Gonzalez C, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Andres JL, Gonzalez C, Head-Gordon M, Replogle ES, Pople JA: Gaussian 98, Revision A.7. 1998, Pittsburgh PA: Gaussian, IncGoogle Scholar
- Keith TA: AIMAll. 2009, v. 09.04.23Google Scholar
- Schaftenaar G, Noordik JH: MOLDEN: A pre- and post-processing program for molecular and electronic structures. J Comput.-Aided Mol. Design. 2000, 14: 123-134. 10.1023/A:1008193805436.View ArticleGoogle Scholar
- GaussView. 2000, Pittsburgh, PA: Gaussian, Inc, v. 2.1
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