J. Phys. Chem. A 2010, 114, 6413–6422
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Theoretical Study of the Structures and Hydrogen-Bond Properties of New Alternated Heterocyclic Compounds Alexandra Tabatchnik, Virginie Blot, Muriel Pipelier, Didier Dubreuil, Eric Renault, and Jean-Yves Le Questel* UniVersite´ de Nantes, CEISAM UMR 6230, UFR des Sciences et des Techniques, 2 rue de la Houssinie`re, BP 92208, Nantes F-44000, France ReceiVed: February 15, 2010
The conformational preferences of a new bis-pyrrole derivative and its bis-pyridazine precursor have been investigated through quantum chemistry calculations (HF, DFT(MPWB1K), LMP2) and observations in the solid state. The global energetic minima are planar for both structures, with the conformational preferences being explained by π-electronic conjugation between the aromatic systems and the occurrence of intramolecular hydrogen bonds (HB). For the bis-pyridazine derivative, the all-anti preferred conformation results from CH · · · Nsp2 HB whereas the all-syn conformation of the bis-pyrrole is partly due to NH · · · Nsp2 HB. For both systems, the validity of the theoretical conformational features is confirmed through the excellent agreement with the experimental data available. Calculations of electrostatic potential computed on the molecular surface of the various structures and their building blocks allow the variations to be rationalized in terms of molecular structure and are used to analyze the HB donor and acceptor sites of the compounds. The HB interaction sites predicted from the quantum chemical calculations are confirmed through the HB interactions observed in relevant crystal structures. 1. Introduction Five-membered heterocyclic π-conjugated compounds such as pyrroles have attracted wide interest not only in material science, owing to their interesting optical, nonlinear optical, and electrical conduction properties,1-3 but also as building blocks of naturally occurring biologically active molecules. Indeed, pyrroles appear as structural motifs in marine alkaloids4 and pyrrole-imidazole alkaloids5 and have shown their potential in medicinal chemistry.6 Chemical ring contraction of six membered heterocycles appears an attractive alternative to provide pyrrole derivatives.7 Recently, the efficiency of electrochemical reduction for the ring contraction of pyridinyl-pyridazine derivatives into their pyrrole counterparts has been shown in our laboratory.8 The structure and the conformational behavior of functionalized 2,5-dipyridinyl-pyrroles from their 3,6-dipyridinyl-pyridazine precursors has been investigated through X-ray crystallography and theoretical calculations. Pyridyl-pyrroles sequences are interesting in terms of their hydrogen bonding properties since they constitute bifunctional molecules capable of interacting simultaneously as hydrogen bond acceptors and donors.9 Several experimental studies, mainly through 1H, 13C, and 15N NMR spectroscopy, have characterized the influence of intramolecular hydrogen bonding on the conformational preferences of such architectures.10,11 Furthermore, in these systems, hydrogen bonding has been prone to mediate hydrogen transfer.12 Pyridyl-pyrroles derivatives are particularly remarkable from this perspective since they constitute good models for the investigation of these processes in nitrogen-containing heterocyclic systems, whereas much of the work in the literature is focused on compounds in which an * To whom correspondence should be addressed. Telephone: 33 (0)2 51 12 55 63. Fax: 33 (0)2 51 12 55 67. E-mail: Jean-Yves.LeQuestel@ univ-nantes.fr.
oxygen atom is located at both donor and acceptor sites. Recently, experimental and theoretical studies have been reported on the structures and energetics of 2-(2′-pyridyl)pyrroles, their dimers, complexes, and excited states.12,13 From a theoretical point of view, computational chemistry has proved useful to (i) characterize the structural features,14,15 (ii) rationalize the physicochemical properties,16,17 and (iii) analyze the hydrogen bonding properties of the building blocks and oligomers.18 The results have been shown to be highly dependent on the level of theory used, and Hartree-Fock (HF), post-HF, and density functional theory (DFT) calculations have been reported in the literature. Such investigations have, for example, been published for poly-pyrroles,14,15 pyridyl-pyrroles9,19 and pyridyl-pyridazine ligands.20 In the present paper, we use various theoretical methods to characterize the structures and the conformational behavior of a new bipyridyl-bis-pyrrole 2 (2,6-bis[6-pyridin-2-yl)pyrrol2(1H)-yl]pyridine) and its bipyridyl-bis-pyridazine precursor 1 (2,6-bis[6-pyridin-2-yl)pyridazin-3-yl]pyridine) (Scheme 1 R ) H). The preparation of the precursor, its electrochemical behavior, and the electrochemical synthesis of the corresponding pyrrole will be described elsewhere.21 The structures, conformations, and energetics of the building blocks and of the constituting dimers and trimers have been considered successively through various levels of theory (HF, DFT, and LMP2). These theoretical data are compared to experimental observations in the solid state, through the Cambridge Structural Database (CSD) and the X-ray structural analysis of a dimethylated derivative of one of the compounds (2).21 The calculation of molecular electrostatic potential maps is used to (i) investigate the influence of chemical structure on the charge distribution, hence the electron-rich and electron-deficient sites, of the various compounds; (ii) analyze the influence of conformation on these properties; and (iii) throw light on the intramolecular hydrogen bonding interactions occurring in the two ligands.
10.1021/jp101394t 2010 American Chemical Society Published on Web 05/14/2010
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SCHEME 1: Chemical Structures of the Various Oligomers Considered in This Work and Their Corresponding Fragments
2. Experimental and Computational Methods Theoretical Methods. All the calculations were carried out using the Gaussian 0322 and Jaguar 6.023 packages. For the present investigation, the DFT methodology and, more precisely, the recent MPWB1K functional set up by Truhlar and coworkers24 were selected. Indeed, the excellent performance-tocost ratio of DFT computations make these methods very attractive, and hybrid meta functionals such as MPWB1K have been proven to surpass the most popular B3LYP functional for energy-barrierpredictionforkineticsandnonbondedinteractions.24-27 Preliminary relaxed scans of trimers 1a and 1b (Scheme 1) were performed at the HF/6-31G(d,p) level around the corresponding inter-ring bonds with a step of 10° over a range of 0-360°. These scans enabled, in a first crude approach, the positions of the various minima and the symmetry relations linking them to be visualized. For trimer 2b, we followed the method used in a recent investigation in our laboratory for 2a:8 starting from the syn-syn structure, a relaxed scan was performed around the second intercyclic bond with a step of 10° over a range of 0-180° without varying the dihedral angle around the first pyrrole-pyridine dimer. In the second step, starting from the syn-anti structure obtained from this conformational analysis, the orientation between the pyrrole-pyridine dimer and the first pyrrole ring was explored with the same step over the same range, to lead finally to the anti-anti conformer. This procedure allowed the potential energy surface (PES) of these trimers to be investigated in a reasonable computational time, taking into account the symmetry of the system. The harmonic frequencies were then computed at the same level of theory in order to characterize the stationary points (minima vs transition states (TSs)). The structures, energies, and vibrational properties of the most stable stationary points (minima and saddle points) were subsequently recomputed at the MPWB1K/6-31+G(d,p) level under C2V (or C2) symmetry constraints, if applicable, to reduce computational time. These calculations were done for the stationary points obtained for 1a, 1b, 2a, and 2b with R ) H. In this way, crude PES with more precise energetics were obtained. Since the conformational preferences of some of these compounds can be influenced by intramolecular hydrogen bonding interactions, single-point
calculations with the LMP2 methodology were undertaken. Indeed, such interactions can lead to overestimated energetics because of the basis set superposition error (BSSE). Although the evaluation of the BSSE is straightforward in the case of intermolecular interactions, it is a difficult task for intramolecular interactions and LMP2 has been shown to circumvent these errors.28,29 The structures of the minima were compared to the experimental observations available in the solid state. Molecular fittings were carried out using the Pymol program.30 The population of the various conformers was evaluated from the computed Gibbs energies through a Boltzmann distribution according to the relation:
pi )
e
-∆Gi0
n
∑e
/RT
-∆Gi0
/RT
i)1
Finally, the pentameric structures of the new bis-pyrrole derivative 2 and its bis-pyridazine precursor 1 were considered under C2V (or C2) symmetry constraints. Only selected conformers, in the light of the PES of the trimers and the experimental observations available in the solid state, were studied. They correspond to all syn and all anti conformers. Molecular electrostatic potential (MEP) maps were computed at the MPWB1K level on the building blocks and various oligomers using a 0.001 electron/bohr3 contour of the electronic density.31 Patterns with positive (Vs > 0) and negative (Vs < 0) regions were used to localize and analyze electron-deficient and electron-rich sites, respectively. 3. Results and Discussion Conformational Features of the Various Oligomers. Increased levels of sophistication were used to investigate the conformational profiles of the various trimers. Despite the planarity inherent in the building blocks of these compounds, the combination of the various degrees of freedom can lead to a large number of minima. Among them, only those having a significant Boltzmann population may play a role in the physicochemical properties of these compounds and their
Structural Features of New Heterocyclic Compounds
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TABLE 1: Relative Energies (kJ/mol) and Inter-Ring Torsion Angles (°) for the Stationary Points Obtained in the Conformational Analysis of 1a and 1b Trimers at the LMP2/6-311++G(d,p)//MPWB1K/6-31+G(d,p) Level 1a
1b
stationary point
∆E (kJ/mol)
NCCN (°)
NCCN (°)
conformer
∆E (kJ/mol)
NCCN (°)
NCCN (°)
anti-anti (min) TSa syn-syn (min)
0
180
180
63.4
39
39
anti-anti (min) TS anti-syn (min) TSa syn-syn (min)
0 20 15
180 171 176
180 85 36
49
-43
-43
a
This TS was not searched owing to the large difference in energy compared to the closest minimum.
Figure 1. Energetic profiles obtained at the LMP2/6-311++G(d,p)//MPWB1K/6-31+G(d,p) level for the rotation around the NCCN dihedral angles of pyridine-pyridazine (1a, 1b) trimers. The structures of selected stationary points are represented.
assembly into more complex oligomers. These populations depend on the minima relative energies and their interconversion barriers. Our selection of the most significant minima was guided by a Boltzmann population threshold. Thus, among the characterized minima, only those with a predicted Boltzmann population higher than 1% were considered. Pyridine-Pyridazine Trimers 1a and 1b. For 1a and1b, the preliminary NCCN conformational analyses carried out at the HF level led to five main minima. These conformations are all characterized by values of one of the inter-ring torsion angles close to 180°. In both cases, the absolute minimum corresponds to the anti-anti structure. The other minima are characterized by dihedral angles close to 40 or -40° and are related through the σV symmetry plane containing the saturated rings. The other combinations of the inter-ring dihedral angles characterized by nonplanar structures (e.g., for two dihedral angles of 40°) are located more than 45 kJ/mol above the absolute minimum and therefore were not considered. A noticeable difference between 1a and 1b trimers that appears from this preliminary analysis at the HF level concerns the energetic range covered by the various minima. For 1b, the secondary minima are significantly closer in energy to the absolute minimum than for 1a, since the relative energies computed for 1b conformers range from 25 to 22.5 kJ/mol, whereas the corresponding range for 1a is from 40 to 35 kJ/mol. Table 1 reports the dihedral angles and the relative energies recomputed at the LMP2/6-311++G(d,p)//MPWB1K/631+G(d,p) level for the main stationary points retained after the previous conformational analysis of 1a and 1b trimers, and Figure 1 shows the corresponding energetic profiles. The previous preliminary results are confirmed at the LMP2 level: the absolute minimum corresponds to the anti-anti conformation in both cases, the secondary minima being higher in energy from about 60 to 15 and 50 kJ/mol for 1a and 1b, respectively.
The rotation barrier between the two minima of 1a was not computed owing to their great energy difference. In the case of 1b, the rotation barrier between the closest minima (anti-anti and anti-syn), of 20 kJ/mol, is easily surmountable at room temperature. For the same reason as above, the second rotation barrier for 1b was not evaluated (difference in energy of about 50 kJ/mol between the second local minimum and the absolute minimum). Only one secondary minimum corresponding to the syn-syn conformation was therefore kept at the best level of theory in the case of 1a. However, this conformation is located about 60 kJ/mol above the absolute minimum. This is not the case for 1b, for which two secondary minima, located 15 and 49 kJ/ mol, respectively, above the absolute minimum, remain at the LMP2//MPWB1K level. It is therefore clear from these data that, for the two trimers 1a and 1b, the planar anti-anti structure is preferred, and the syn-syn conformer can safely be predicted to be present in minor quantities. The preference for the anti-anti conformation is probably due to the unfavorable electrostatic repulsion between the nitrogen lone pairs in the syn-syn conformer. It can also be attributed to intramolecular CH · · · Nsp2 hydrogen bond (HB) interactions. The theoretical HB distances are in agreement with the greater HB ability of the pyridazinic nitrogens compared to the pyridinic ones, the former being shorter (2.431 Å) than the latter (2.461 Å). To validate the structural trends revealed by the theoretical calculations in the isolated state, we undertook a search for 1a and 1b fragments in the 5.30 version of the Cambridge Structural Database (456637 entries).32 We considered three separate samples corresponding to (i) “free”, (ii) mono-, and (iii) bichelated (with metals) trimers. For each site, the two NCCN dihedral angles were measured. The results obtained are presented in Table 2.
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TABLE 2: NCCN Dihedral Angles Measured in Crystal Structures Found in the CSD for Free and/or Metal-Chelated 1a Fragments
a
N is the number of entries found in the CSD, and the number in brackets corresponds to the total number of observations.
TABLE 3: HB Geometries Observed in the CSD for Intraand Intermolecular Interactions for Fragments 1a
Figure 2. Superposition of the theoretical (blue) structure of the global minimum of 1a on the FIPZIO X-ray structure (purple).
No structures corresponding to and/or incorporating the 1b fragment were found in the CSD. Table 2 shows that the conformational features of 1a fragments are strongly dependent on the molecular environment, in particular the possibility of chelation with metallic centers, which forces the syn conformation. In the absence of chelation, the anti orientation of the pyridine and pyridazine units is clearly preferred, whereas the coordination with metallic centers forces the syn orientation. The conformational preferences of the free fragments are in agreement with the trends revealed through the theoretical calculations. The superposition of the theoretical structure of the global minimum for 1a on one representative experimental structure observed in the solid state (FIPZIO),33 taking into account all the atoms except H, leads to an rmsd of 0.13 Å (Figure 2). This result illustrates the close similarity between the two structures. Next, a search for CH · · · Nsp2 intra- and intermolecular HB was undertaken in the CSD in the sample of free pyridinepyridazine trimers to investigate, in the solid state, the propensity of these fragments to be involved in such interactions. All H atoms involved in nonbonded contact searches were placed in normalized positions.34 The HB lengths were expressed from the hydrogen (d) and heavy atom (D) positions of the HB donors respectively. To quantify the linearity and directionality of the interactions, we measured the θ (CH · · · N) and Φ (H · · · NC) HB angles. The carbon atom used to define the Φ angle corresponds to the one in para to the nitrogen atom involved in the HB. The cutoff distance criteria used for the database analyses of HB have been the subject of much discussion, mainly in the case of weak HB.35 In this work, we followed the recommendation of Desiraju and Steiner, that is to say we searched for the H · · · N contacts by using a long cutoff distance of 3.0 Å, which corresponds to the sum of van der Waals radii (1.55 Å for N and 1.20 Å for H) plus 0.25 Å. The ranges
HB interaction
D(C · · · Nsp2)
d(H · · · Nsp2)
CH · · · Nsp2
H · · · Nsp2Ca
Intra minimum maximum mean SD sample n
2.72 2.86 2.79 0.01 36
2.31 2.62 2.48 0.01 36
90.3 100.1 95.0 0.4 36
124.9 148.5 141.9 0.9 36
Inter minimum maximum mean SD sample n
3.25 3.96 3.53 0.02 79
2.32 3.00 2.71 0.02 79
93.7 173.2 134.6 2.0 79
90.6 173.5 132.8 2.4 79
a The carbon atom taken into account for this measurement is the one in para to the nitrogen atom involved in the HB.
considered for the HB linearity and directionality angles were 90 e θ (Φ) e 180°. Table 3 reports the geometries and statistics corresponding to these interactions. The mean value of the HB distances for intramolecular contacts, 2.48(1) Å, appears significantly less than the sum of the van der Waals radii involved (2.75 Å). As expected from the conformational features reported in Table 2, the probability of formation of the corresponding 5-membered HB motif is strong since Table 3 shows that all the fragments are involved in contacts with d below 2.75 Å. Of course, in the case of such weak intramolecular interactions, as reported by Desiraju and Steiner, it is difficult to decide whether they are really HB or forced consequences of the molecular structure.35 The mean value of the CH · · · N angle, 95.0(4) °, clearly supports a highly constrained HB motif. Table 3 shows that the mean value of the HB distances for intermolecular contacts, 2.71(2) Å, is not significantly different from the sum of the van der Waals radii involved (2.75 Å). However, it is worth noticing that among the 79 contacts, 26 are characterized by a d range of 2.319-2.614, leading to a mean value of 2.48(2). Furthermore, the corresponding range for the linearity angle θ is from 120.7 to 173.2, with a mean value of 146(3), close to the features reported by Desiraju and Steiner for weak HB involving Csp2-H donors.36 Indeed, as reported by Bishop and co-workers for other nitrogen heteroaromatic compounds,37-41 it is clear from the present statistical analysis that the aryl C-H · · · Nsp2 HB play an important role in the organization of the crystal structures of pyridinepyridazine fragments.
Structural Features of New Heterocyclic Compounds
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TABLE 4: Relative Energies (kJ/mol) and Inter-Ring Torsion Angles (°) for the Stationary Points Obtained in the Conformational Analysis of 2a and 2b Trimers at the LMP2/6-311++G(d,p)//MPWB1K/6-31+G(d,p) Level 2a
2b
stationary point
∆E (kJ/mol)
NCCN (°)
NCCN (°)
conformer
∆E (kJ/mol)
NCCN (°)
NCCN (°)
syn-syn (min) TS syn-anti (min) TS anti-anti(min)
0 30.5 15.4 52.3 41.3
0 -2 0 179 180.0
0 95 -180 96 180.0
syn-syn (min) TS syn-anti (min) TS anti-anti (min)
0 15.8 8.0 43.3 37.7
0 1 2 -179 -174
0 94 -169.0 95 -174
Pyridine-Pyrrole Trimers 2a and 2b. The conformational features of pyridine-pyrrole trimers are significantly different. As reported recently in our group in the case of 2a (QOBREF refcode),8 all the minima for the two trimers are planar, the global energetic minimum corresponding to the syn-syn conformation (NCCN dihedral angles of 0°). Table 4 reports the dihedral angles and the relative energies computed at the LMP2/6-311++G(d,p)//MPWB1K/6-31+G(d,p) level for 2b and Figure 3 compares the relevant energetic profiles for 2a and 2b. Despite the close similarity of the two energetic profiles, two significant differences are noticeable. They concern (i) the rotation barriers, which are systematically weaker by 15 and 9 kJ/mol, respectively, for the syn-syn to syn-anti and syn-anti to anti-anti conversion; and (ii) the difference in energy between the minima. The rotation barriers appear from 3 to 6 kJ/mol weaker in the case of 2b compared to 2a, for syn-syn to syn-anti and syn-anti to anti-anti interconversions, respectively. The first secondary minima (symmetric syn-anti and anti-syn structures) are located at about 13 kJ/mol from the global minimum, the anti-anti structure being higher in energy by about 36 (2a) and 34 (2b) kJ/mol. These results indicate that the preferred conformation corresponds in both cases to the syn-syn structure, since the populations calculated according to the Boltzmann distribution are 99 and 1%, respectively, for syn-syn and syn-anti (anti-syn) conformers. For 2a and 2b trimers, the anti-anti planar structures are therefore clearly not representative conformations of these fragments. The present theoretical results for 2b are in agreement with those reported recently by Trofimov and colleagues for bis(pyrrol-2-yl)pyridine through B3LYP/6-311G(d) calculations.42 However, it is worth noting that the barrier heights calculated by Trofimov and coworkers are systematically greater (from 9 to 17 kJ/mol) than
those obtained here. This is not the case for the minima energies, which are higher (syn-anti, +5 kJ/mol) or lower (anti-anti, -11 kJ/mol) than the values computed in the present work. These discrepancies reflect the differences in the level of theory applied in the two studies. Indeed, the single-point LMP2/6311++G(d,p) calculations considerably modify the PES in this case. This behavior can partly be attributed to large differences in terms of intramolecular hydrogen bonding interactions in 2a and 2b trimers, inducing significant intramolecular BSSE. As the LMP2 is known to eliminate BSSE to a large extent, the PES computed with this method should be free of such errors. Indeed, the (N)H · · · N HB are shorter (2.43 Å) in 2b compared to 2a (2.48 Å). In both cases, the conformational preferences can be attributed to intramolecular bifurcated NH · · · N HB interactions and strong π-electronic conjugation throughout the three aromatic systems. The conjugated character of the 2a and 2b molecular systems is clearly evidenced by the inter-ring carbon-carbon bond lengths of about 1.45 Å. The only structure found in the 5.30 version of the CSD for the 2a fragment corresponds to the one recently reported in our laboratory (QOBREF refcode).8 The theoretical data are validated by the crystallographic observations, the observed minimum corresponding to the syn-syn conformer. A search for the 2b fragment in the CSD led to two entries (KIXWAQ,43 VAWJEJ42). In the first, the structural features of the bis(pyrrol2-yl)pyridine units are very close to those obtained at the theoretical level since the trimer is almost perfectly planar, with NCCN torsion angles of about 0°. It is worth noticing that in this structure, bifurcated HB of the type NH · · · O occurs between the pyrrolic NH and oxygen atoms of cocrystallized DMSO molecules. These intermolecular interactions do not rule out the
Figure 3. Energetic profiles obtained at the LMP2/6-311++G(d,p)//MPWB1K/6-31+G(d,p) level for the rotation around the NCCN dihedral angles of pyridine-pyrrole (2a, 2b) trimers. The structures of selected stationary points are represented.
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Figure 4. Superposition of the theoretical (blue) structures of the 2a and 2b global minima on crystal structures (purple) of relevant compounds (QOBREF and VAWJEJ, respectively).
Figure 5. Superposition of the theoretical minima (blue) of 1 and 2 on the available experimental structures (purple): (a) the all-anti conformer of 1 is superimposed on the crystal structure of 3,6-bis(2′-pyridyl)pyridazine (VAWJEF recode); (b) the all-syn conformer of 2 is superimposed on the crystal structure.
intramolecular NH · · · N HB, the H · · · N distances being 2.42 and 2.48 Å. The probability of forming the 5-membered ring through intramolecular NH · · · N hydrogen bonding appears a characteristic feature of this system. This is not the case for the bis(pyrrole-2-yl)pyridine fragment in the KIXWAQ structure, since the NCCN torsion angles are close to 35°. In this crystal structure, three pyrrole-pyridine trimers 2b are bridged to form a cryptand-like bicyclic hexapyrrole.43 The crystal packing is characterized by NH · · · O hydrogen bonds with cocrystallized ethanol molecules located inside the crevices of these structures, whereas the HB acceptor potential of the pyridinic nitrogens is fulfilled by OH · · · N interactions. The superposition of the theoretical structures of 2a and 2b corresponding to the global minima on representative experimental structures (QOBREF,8 VAWJEJ,42 respectively), taking into account all the heavy atoms, leads to rmsd values of 0.12
and 0.03 Å (Figure 4). These weak values show the great agreement between theory and experiment for these oligomers. Pentameric Structures. In a second step, starting from the conformational features revealed by the experimental and theoretical data for the various trimeric components, we considered the pentameric 1 and 2 structures. Only the all-syn and all-anti conformers of 1 and 2 were examined. In both cases, the global minima are planar. The molecular fittings shown in Figure 5 confirm that this structural feature is maintained in the solid state. For 1, since no X-ray structure is available, the conformation of the global minimum was overlaid on the experimental structure of 3,6-bis(2′-pyridyl)pyridazine (FIPZIO)33 taking into account all atoms except H, leading to an rmsd of 0.13 Å. This value shows that the structural features of the bipyridylpyridazine trimer are conserved in the pentamer.
Structural Features of New Heterocyclic Compounds For 2, we compared the conformation of the theoretical global minimum to the X-ray crystallographic structure of one of its dimethylated derivatives (Scheme 1, R ) Me) analyzed in our laboratory.21,44 The rmsd value of 0.11 Å obtained considering the 27 heavy atoms illustrates the excellent agreement between the computational and experimental structures. In fact, in the crystal structure, a water molecule fully using its hydrogen bonding potential is “trapped” through the HB interactions with the NH of the inner pyrroles, its OH groups being in turn engaged in HB with the nitrogen atoms of the outer pyridine rings. As a consequence, the crystal packing of the structure is essentially characterized by π-π stacking interactions. The comparison of the geometry of the central pyridinyl-bispyrrole motif in the pentamer to that in the free trimer shows significant variations. The (N)H · · · Nsp2 HB thus appear longer in 2 (2.50 Å) than in 2b (2.43 Å). This feature is also evidenced by the (C)H H(C) distances, which are 2.35 and 2.38 Å, respectively, in 2 and 2b. These variations highlight the structural constraints on the features of the central trimeric components caused by the addition of new building blocks. Molecular Electrostatic Potential Analyses. Molecular electrostatic potentials (ESPs) have emerged as powerful predictive and interpretive tools in fields such as chemistry,45 rational drug design,46 and protein-ligand interactions.47 In these studies, colorful maps of ESPs are used to rationalize trends in chemical properties such as Lewis basicities,48 binding in host-guest complexes,20 and noncovalent interactions (cation/ π, π-π, etc.).49 Quantitative ESP descriptors, such as the minima (Vs,min) and maxima (Vs,max) computed on the van der Waals surface of molecules can be used to compare the electronrich and electron-poor sites of related molecules. In the field of supramolecular chemistry, for example, ESPs have been used recently to analyze the influence of anion-π interactions in the
J. Phys. Chem. A, Vol. 114, No. 22, 2010 6419 self-assembly reactions of Ag(I) complexes with π-acidic aromatic rings (3,6-bis(2′-pyridyl)-1,2,4,5-tetrazine (bptz) and 3,6-bis(2′-pyridyl)-1,2-pyridazine (bppn)). The ESP analyses have enabled the preferred structural motifs formed in the solid state in Ag(I) complexes with bptz and bppn to be rationalized. In the present work, we use ESP minima (Vs,min) and maxima (Vs,max) to (i) identify the HB acceptor and donor sites of the various compounds, respectively; (ii) quantify the nucleophilic and electrophilic character of these sites from the monomers to their oligomeric species; and (iii) analyze the influence of these properties on the conformational preferences observed in the solid state. The main Vs,min and Vs,max values (kJ.mol-1) of the various heterocyclic π-conjugated compounds, from the monomers to the oligomeric species, are reported in Figure 6. Monomers. In pyridazine, the Vs,min (-174) is located between the two Nsp2 nitrogen atoms. This value is significantly lower, by about 20 kJ/mol, than the corresponding one in pyridine (-155), located in the axis of the putative nitrogen lone pair. This increase in the nucleophilic character of pyridazine is attributed to the repulsion between the two nitrogen lone pairs and has been confirmed experimentally through the better hydrogen bond basicity of pyridazine compared to pyridine.50 It is also evidenced in the present work by the shorter intramolecular HB observed with pyridazinic compared to pyridinic Nsp2 nitrogen atoms (vide infra). The Vs,max of pyrrole (+192) is located on the H atom of the pyrrolic NH, axially with respect to the NH bond. Similarly, the Vs,max of pyridazine and pyridine, 114 and 79 kJ/mol, respectively, are situated at the end of the CH bonds. It is worth noticing that the HB donating ability of the CH groups of pyridazine appears significantly greater than that of pyridine. This result is coherent with the greater electron-withdrawing
Figure 6. ESP maps of the various building blocks and oligomers (positive values are shown in blue, negative values in red). Selected values (kJ/mol) are located with arrows.
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effect of the two nitrogen atoms in pyridazine compared to the effect exerted by one nitrogen atom in pyridine. The values of the minima and maxima of the ESPs in the monomers give indicators for the analysis of the corresponding atomic sites in the structural motifs formed in the various oligomers. From the Monomers to the Oligomers. The Vs,min of the pyridinic nitrogen decreases from -155 to -90 kJ/mol in 1a and to -102 kJ/mol in 2a. This weakening of the nucleophilic character can be attributed to the depletion of electron density on the Nsp2 nitrogen atoms induced by the CH · · · N hydrogen bonds in the two trimers 1a and 2a. It is worth noticing that the existence of the CH · · · N (1a) and NH · · · N (2a) HB induces a deviation of the electron density maximum from the axis of the putative Nsp2 lone pair. For 1b and 2b, all the electron density of the Nsp2 lone pair is involved in the three centers CH · · · N (1b) or NH · · · N HB (2b), since the values computed on the axis of the nitrogen lone pair are about 96 and 156 kJ/ mol, respectively, that is to say typical of the XH (X ) C, N) electron-poor groups. The same analysis, however, cannot be made between the various trimeric components since the structural motifs formed through intramolecular hydrogen bonding have very distinct features. Indeed, Figure 6 shows that two-center (1a) and threecenter (1b, 2a and 2b) HB can occur. Furthermore, different combinations of donor/acceptor groups manifest their contribution. Two donors can thus interact with one acceptor (1b, 2b) or one donor can be shared between two acceptors (2a). Nevertheless, the trends followed by the evolution of the Vs,min and Vs,max values are coherent with that expected from the number and type of HB formed in each structure. The weakest (least electron density) values are thus obtained for the motifs for which two HB donors interact with one acceptor (1b, 2b). The following values correspond to “simple” two-centers CH · · · N HB (1a), this sequence ending with the 1b substructure in which the pyrrolic NH group is shared between two pyridinic nitrogen atoms. The Vs,min value of the outer pyridine of 1, about -83 kJ/mol, is comparable with that around the Nsp2 nitrogen in 1a (-90 kJ/mol). The nitrogen lone pair of the central pyridine of 1 has lost all electron density owing to the threecenter CH · · · N HB, the situation being comparable to that observed in 1b. These data illustrate the greater depletion of electronic density on the nitrogen lone pair when this atom is involved in a three-center HB (1b) compared to the situation where it is involved in a two-center HB (1a). Similar trends are observed in the comparison of Vs,min values for central and outer pyridines of 2 (58 and -104 kJ/mol, respectively) to those computed for the pyridinic nitrogen in 2b (156 kJ/mol) and 2a (-102 kJ/mol) substructures. The significant difference observed for the values of the central pyridine in 2b and 2 can be attributed to an increase in the distances of the NH · · · N HB (from 2.43 to 2.50 Å) and of the NH HN pyrrolic hydrogen atom distances (from 2.85 to 2.95 Å). The Vs,min of pyridazine decreases from -174 to -161 kJ/ mol in 1b and to -143 kJ/mol in 1a. These significant variations reflect the influence on the electronic density of this site of the number of HB involving the pyridazinic nitrogens. Thus, when only one HB is formed (1b), the location of Vs,min is displaced from its initial position, in the middle of the two Nsp2 nitrogens, to the axis of the nitrogen lone pair not involved in hydrogen bonding (Figure 6). In this case, a high electron density is still retained, the value being 13 kJ/mol greater than that of pyridazine. Conversely, when the two nitrogens are engaged in HB (1a), a significant decrease in electron density is observed,
Tabatchnik et al. the Vs,min value being about 30 kJ/mol larger than that of the parent pyridazine molecule. The same trends are observed in 1, for which the Vs,min value around the pyridazinic nitrogens (-135 kJ.mol-1) is very close to that computed for 1a, and the ESP map showing in this zone a symmetric distribution of electron density compatible with the contribution of each nitrogen to HB interactions. The Vs,max of the pyrrolic NH have identical values in the monomer and the 2b substructure (192 kJ/mol), as this motif keeps a strong electrophilic character despite the intramolecular NH · · · N HB. This is not the case for 2a, in which the sharing of the NH between the two pyridinic nitrogens induces a large decrease in its electrophilic character (+48 kJ/mol). In 2, the situation is intermediate between the last two, the Vs,max around the pyrrolic NH being +84 kJ/mol. This behavior can be attributed to the variation in geometry of the various motifs from the trimers to the pentamer. Indeed, despite the similarity of the chemical environment, the increase in the distances (N)H · · · N (HB) and (N)H H(N) leads to a decrease in the electrophilic character. The consequences of hydrogen bonding interactions are also evidenced by the analysis of the Vs,max values of the CH groups of the pyridinic rings. These weaken from +79 for pyridine to +41 and +33 kJ/mol for 1b and 1a, respectively. In the same way, it is worth noticing that the CH groups not involved in intramolecular interactions in 1a conserve similar values (+82 kJ/mol) to those obtained in pyridine. In 1, two types of CH groups are also differentiated. The first corresponds to CH involved in CH · · · N HB with Vs,max values of +42 and +38 kJ/mol, the second to “free” CH with Vs,max values very close (+82 kJ/mol) to those computed in the pyridine monomer. For 2a and 2b substructures, the Vs,max values range from +75 to +78 kJ/mol, typical of CH groups that do not participate in intramolecular HB. The Vs,max values of the CH groups of pyridazine decrease from +114 in the monomer to 48 kJ/mol in 1a and to 107-110 kJ/mol in 1b. These significant differences indicate that in 1a, the electrophilic character of the CH groups is fully used in intramolecular HB whereas in 1b, in which the pyridazine rings are outer, the CH groups keep their electrophilic character. In 1, the significant variation observed for the CH Vs,max values (from 41 to 78 kJ/mol) reflects the difference in their chemical environment. On the whole, the ESP analysis from the monomers to the oligomeric species throws light on the variation in charge distribution as a function of the chemical environment and clearly supports the importance of intramolecular HB in the conformational preferences of the various chemical species. Preferred Interaction Sites of the Various Structures. The ESP results highlight the interaction sites of the various compounds. The Vs,min of 1 and 2 are thus located on the pyridazine units and on the nitrogen atoms of the outer pyridine rings, respectively (Figure 6). The Vs,max of 1 correspond to outer pyridinic CH and, to a lesser extent, pyridazinic CH. In 2, the corresponding sites are the pyrrolinic NH. It appears from these data that 1 should behave as a Lewis base through the pyridazinic nitrogens and as a Lewis acid through the outer pyridinic CH. The behavior of 2 is significantly different since the minimum energy structure shows that the electron-rich and electron-deficient zones of the molecule are located inside the bend formed by the molecular shape. This trend is in remarkable agreement with that revealed through the experimental crystal structure of the dimethylated derivative of 2, where a water molecule is fitted in the middle of the bend, with the OH groups
Structural Features of New Heterocyclic Compounds
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Figure 7. (a) ESP map of 2 showing the minima and maxima of electron density. (b) Superposition of the crystal structures of 2 (purple) and VAWJEJ (blue) showing the almost identical positions of the oxygen atoms of the cocrystallized water and DMSO molecules (selected H atoms have been removed for better clarity).
pointing toward the outer pyridinic nitrogen atoms and the oxygen in such a position that it can interact with the two pyrrolic NH groups (Figure 7b). This is also in good accordance with the crystal structure of the central trimeric component (3,6bis(pyrrol-2-yl)pyridine, refcode VAWJEJ) published recently by Trofimov et al..42 In this structure, the oxygen atom of a cocrystallized DMSO molecule sits perfectly in the extension of the NH bonds, using their electropositive character. Figure 7b indeed shows that the position of the oxygen atoms of the cocrystallized water and DMSO molecules are almost identical in the two crystal structures (only the heavy atoms of the common trimer have been superimposed) and correspond to the ESP maxima of oligomer 2 (Figure 7a). The remarkable agreement observed between the trends suggested in terms of intermolecular interactions by the ESP analysis and the experimental position of cocrystallized solvent molecules illustrates the value of ESP calculations for rationalizing and predicting molecular interactions of organic chemical species.
Observations in the CSD have indeed shown that these interactions participate in the organization of their crystal structures. (v) The analyses of the ESP of the various chemical species, from the monomers to the more complex oligomers, highlight the influence of the molecular environment on their structure and their potential, in terms of molecular interactions. The location of ESP minima and maxima is in remarkable agreement with the experimental positions of cocrystallized organic molecules. Acknowledgment. The authors gratefully acknowledge the IDRIS (Institut du De´veloppement et des Ressources en Informatique), the CINES (Centre Informatique National de l’Enseignement Supe´rieur), and the CCIPL (Centre de Calcul Intensif des Pays de la Loire) for grants of computer time. A. T. thanks the MENRT for Ph.D. financial support. References and Notes
4. Conclusions On the basis of crystallographic observations and gas-phase ab initio and DFT theoretical calculations on new bis-pyrrole and bis-pyridazine compounds, we have shown that: (i) The energetic minima of the molecules are planar owing to the strong π-electronic conjugation existing throughout the various aromatic systems of the compounds and intramolecular HB interactions. (ii) The unfavorable electrostatic repulsion between the nitrogen lone pairs in the all-syn conformation of the bispyridazine derivative induces a preference for the all-anti conformation. This latter arrangement is suitable for setting up intramolecular CH · · · Nsp2 HB. (iii) The preferred conformation of the bis-pyrrole derivative is conversely all-anti, this predilection resulting from intramolecular NH · · · Nsp2 HB. (iv) The structural features pointed out by the theoretical calculations are maintained in the solid state. A search in the CSD for representative compounds confirmed their planar character, the all-syn and all-anti arrangements being observed according to the molecular environment, in particular the possibility of chelation with metallic centers, which forces the all-syn conformation. (iv) The propensity of the aryl CH groups of such compounds to be involved in intra- and intermolecular HB is significant.
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