Computational evidence for intramolecular hydrogen bonding and nonbonding X···O interactions in 2'-haloflavonols Tânia A. O. Fonseca1, Matheus P. Freitas*1, Rodrigo A. Cormanich2, Teodorico C. Ramalho1, Cláudio F. Tormena2 and Roberto Rittner2 Full Research Paper Open Access Address: Beilstein J. Org. Chem. 2012, 8, 112–117. 1Chemistry Department, Federal University of Lavras, CP 3037, doi:10.3762/bjoc.8.12 37200-000, Lavras, MG, Brazil and 2Chemistry Institute, State University of Campinas, CP 6154, 13083-970, Campinas, Brazil Received: 03 November 2011 Accepted: 28 December 2011 Email: Published: 19 January 2012 Matheus P. Freitas* - [email protected] Associate Editor: J. Murphy * Corresponding author © 2012 Fonseca et al; licensee Beilstein-Institut. Keywords: License and terms: see end of document. conformational analysis; 2'-haloflavonols; intramolecular hydrogen bond; nonbonding interactions; theoretical calculations Abstract The conformational isomerism and stereoelectronic interactions present in 2'-haloflavonols were computationally analyzed. On the basis of the quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis, the conformer stabilities of 2'-haloflavonols were found to be dictated mainly by a C=O···H–O intramolecular hydrogen bond, but an unusual C–F···H–O hydrogen-bond and intramolecular C–X···O nonbonding interactions are also present in such compounds. Introduction Intermolecular hydrogen bonding (HB) is an interaction nonbonding F···O interactions, which were experimentally and governing self-assembly and is responsible for the architecture theoretically characterized in anthracene derivatives, and were and organization of molecular aggregates [1], and also pointed out to be the responsible interactions behind the unusual ligand–receptor interactions that are responsible for the bioac- “through-space” fluorine–fluorine spin–spin coupling in the tivity of compounds [2]. Moreover, intramolecular HB has been F···O···F fragment present in such a molecular system [5,6]. found to govern the conformational preference of molecules [3]. Although not completely understood, nonbonding F···O interac- Intramolecular HB involving halogens (X) is less common than tions, as well as many other unusual long-range interactions those involving oxygen or nitrogen as proton acceptors, while involving halogen atoms, are found in several molecular fluorine when bonded to carbon hardly ever participates in HB systems in the literature [7-9]. Such weak interactions are more [4]. Even more unusual stabilizing interactions are the ubiquitous than one imagines and can determine crystal struc- 111122 Beilstein J. Org. Chem. 2012, 8, 112–117. tures [10] and the binding of biological molecules [11] and may Supporting Information File 1). NBO analysis at the B3LYP/ possibly be the main forces in determining conformational pref- aug-cc-pVDZ level gives the hyperconjugation contribution for erences in molecular systems. this interaction (n → σ* ) as 6.9 kcal mol−1, while the (C=)O OH QTAIM data confirms the establishment of intramolecular HB 2'-Haloflavonols are important compounds with widespread use as a stable, electrostatic interaction (see below). as bioactive molecules (antioxidant, anti-inflammatory, antiviral, etc.) [12]. The goal of this work is to understand the Among the QTAIM descriptors, the Popelier [17] criteria are intramolecular forces determining the preferred conformations useful for the detection and characterization of HB’s, as of these molecules through the use of DFT theoretical calcula- employed here. The first Popelier criterion is the formation of a tions, quantum theory of atoms in molecules (QTAIM) [13-17] bond path between the atoms involved in HB. However, specu- and natural bond orbital (NBO) [18] methods. Possible lation about whether the bond paths obtained from QTAIM may intramolecular HB and nonbonding F···O interactions are represent steric interactions has been the topic of several discus- narrowly analyzed and the possible effects of such long-range sions in the literature [22,23]. Bader gave special attention to interactions in determining the rotational isomerism of such a question and considered it as a misinterpretation from the 2'-haloflavonols are discussed. QTAIM and physics itself. Indeed, Bader showed that the pres- ence of a bond path linking a pair of atoms fulfills the suffi- Results and Discussion cient and necessary conditions that the atoms are bonded to one 2'-Haloflavonols undergo rotational isomerization around the α another; therefore, the presence of a bond path (together with a [H–O–C–C(=O)] and β [C(X)–C–C–C(OH)] torsional angles BCP and an interatomic surface) always indicates an attractive (Figure 1), giving the energy minima obtained at the B3LYP/ interaction between two atoms [24-26]. aug-cc-pVDZ level depicted in Table 1. Flavonol itself (X = H) exhibits two stable conformers, with the most stable one having According to Table 2, both the Laplacian of the electronic the hydroxy hydrogen directed toward the carbonyl oxygen density ( ρ) and the total energy (H ) at the HB bond critical C (conformer A), establishing an intramolecular HB as the stabi- point (BCP) [27] are positive, and the |V |/G ratio [28] (where, C C lizing interaction of this conformation, in agreement with the V = potential energy and G = kinetic energy values at the C C crystal structure of 2'-methoxyflavonol [19] and with the bioac- critical points) is smaller than 1 for the HB’s, indicating the tive conformation of fisetin [20] and quercetin [21]. Moreover, electrostatic character of such interactions, except for the a weak (H)O···H–C HB also takes place in flavonol (see (C=)O···H(O) interaction in 2'-fluoroflavonol A, which is slightly covalent and, hence, stronger than the remaining ones. The distances between the atoms involved in long-range inter- actions depicted in Table 2 are always shorter than the sum of their van der Waals radii (the van der Waals radii are tabulated in [29]), i.e., such a geometric parameter is fulfilled by all of these interactions, indicating the possibility of their formation [30]. Indeed, when considering the Popelier criteria, the HB’s Figure 1: 2'-Haloflavonols and the α and β torsional angles. depicted in Figure 2 and Table 2 are stable and, hence, affect Table 1: Conformational energies (kcal mol−1), geometrical parameters (α and β torsional angles in degrees, and C–X distance in angstroms), and selected NBO electron delocalization (kcal mol−1) for 2'-haloflavonols. X Conf. Erel α β dC−X nO(=C)/σ*OH nX/σ*OH nX/π*C1C2 + C1C6 H A 0 0.0 0.0 1.08 0.8 + 6.1 — — D 9.8 168.5 315.4 1.08 — — — F A 0 1.1 220.0 1.35 0.6 + 5.0 — 19.2 + 6.0 B 0.5 2.0 49.3 1.35 0.5 + 4.4 — 19.7 + 6.4 C 7.8 150.7 43.0 1.37 — 1.1 + 2.6 + 4.6 15.7 + 6.3 D 8.5 172.9 121.4 1.35 — — 19.7 + 6.3 Cl A 0 0.9 232.0 1.76 0.6 + 4.6 — 13.0 + 3.3 D 7.9 174.8 114.0 1.75 — — 5.0 + 13.0 Br A 0 0.9 234.0 1.92 0.5 + 4.6 — 10.2 + 2.4 D 7.8 175.5 110.7 1.91 — — 4.0 + 10.1 113 Beilstein J. Org. Chem. 2012, 8, 112–117. Table 2: QTAIM parametersa (a.u.) and O/F/C···H/X distanceb (Å) obtained for selected interacting atoms. X (Conformer) O/F/C···H/X ρBCP ρBCP VC GC HC |VC|/GC H (A) (C=)O···H(O) 1.981 0.028 +0.108 −0.0232 −0.0232 0.0019 0.9243 (C=)O···H(C) 2.647 0.018 +0.074 −0.0124 −0.0124 0.0030 0.8052 H (B) C···H(O) 2.431 0.013 +0.045 −0.0008 −0.0008 0.0002 0.8889 F (A) (C=)O···H(O) 2.031 0.027 +0.091 −0.0229 −0.0229 −0.0001 1.0044 (H)O···H(C) 2.499 0.010 +0.041 −0.0071 −0.0071 0.0016 0.8161 (C)O(C)···F 2.703 0.012 +0.054 −0.0112 −0.0112 0.0011 0.9106 F (B) (C=)O···H(O) 2.057 0.025 +0.099 −0.0199 −0.0199 0.0024 0.8924 (H)O···F 2.794 0.010 +0.042 −0.0087 −0.0087 0.0009 0.9063 F (C) F···H(O) 1.853 0.028 +0.102 −0.0247 −0.0247 0.0005 0.9841 Cl (A) (C=)O···H(O) 2.047 0.025 +0.099 −0.0202 −0.0202 0.0023 0.8978 (C)O(C)···Cl 3.069 0.011 +0.043 −0.0076 −0.0076 0.0016 0.8352 Br (A) (C=)O···H(O) 2.050 0.025 +0.099 −0.0201 −0.0201 0.0023 0.8973 (C)O(C)···Br 3.189 0.010 +0.038 −0.0070 −0.0070 0.0013 0.8537 aρBCP = electronic density along with BCP; ρBCP = Laplacian of the electronic density along with BCP. bO/F/C···H/X = distance between long- range interacting oxygen/fluorine/carbon and hydrogen/halogen atoms. Figure 2: Stable conformers of 2'-fluoroflavonol. 114 Beilstein J. Org. Chem. 2012, 8, 112–117. the conformational preferences of the flavonols under study, rine is close to the hydroxy oxygen, is calculated to be 0.5 kcal except for the C…H(O) interaction of flavonol B (Table 3). The mol−1 less stable than A. According to the classical sense, this boldface values in the Table 3 are the reference atoms, i.e., energy difference would be attributed to dipolar repulsion hydrogen atoms that have smaller q(H), E(H), M (H) and V(H) between the polar bonds; however, the QTAIM calculations 1 than the reference establish a stable HB. indicate that the interaction between fluorine and oxygen is attractive, suggesting the establishment of a nonbonding F…O interaction of similar magnitude to that found in conformer A Table 3: QTAIM parameters (a.u.) for the hydrogen involved in HB and the halogens involved in electrostatic halogen bonding. (see the electronic density along with BCP and the Laplacian values in Table 2). In this case, the fluorine atom is the electron X (Conformer) q(Ω) E(Ω) M1(Ω) V(Ω) acceptor (QTAIM atomic charge of −0.620 for F against −1.093 H (A) for the hydroxy oxygen), which is not so uncommon, as stated H(O) +0.601 −0.356 0.145 17.921 in classical textbooks on aromatic electrophilic substitution, H(C) +0.082 −0.599 0.113 39.732 since a resonant structure with a C=F+ contribution can take H (B) place [31]; this is shown by NBO calculations, which indicate H(O) +0.567 −0.379 0.165 21.108 an interaction responsible for this resonance (n → π* ) of F C1C2 H(C) +0.045 −0.606 0.134 46.738 ca. 20 kcal mol−1 (Table 1). Therefore, the difference in F (A) stability between A and B can be estimated to be due to the H(O) +0.620 −0.331 0.151 17.809 weak HB H–O···H–C together with the slightly covalent char- H(C) +0.043 −0.605 0.121 44.374 acter of C=O···H–O in A. F (B) H(O) +0.599 −0.358 0.148 18.626 Moreover, conformer C is predicted to be more stable than D by F (C) 0.7 kcal mol−1. Again, the basic difference between them is the H(O) +0.623 −0.341 0.131 14.335 F (D) orientation of the fluorine atom, in which C experiences H(O) +0.567 −0.379 0.165 21.744 intramolecular HB O–H···F–C according to the electron delocal- H(C) +0.047 −0.604 0.134 47.458 izations obtained by NBO (sum of nF → σ*OH = 8.2 kcal Cl (A) mol−1), as well as by QTAIM results (Table 1 and Table 2). H(O) +0.598 −0.358 0.148 18.584 There is not an attractive interaction observed for D by means Cl (B) of QTAIM calculations; therefore, the energy difference H(O) +0.567 −0.379 0.165 22.029 between C and D is expected to be due to the intramolecular HB Br (A) O–H···F–C. Furthermore, the longer C–X distance and weaker H(O) +0.598 −0.358 0.148 18.584 n → π* electron delocalization in C than in the remaining Br (B) F CC conformers (Table 1) provide evidence that fluorine lone pairs H(O) +0.567 −0.379 0.165 22.029 in C are involved in intramolecular HB O–H···F–C instead of contributing to the resonant structure with C=F+. HB involving 2'-Fluoroflavonol exhibits four stable conformers, in which fluorine as a proton acceptor when bonded to carbon is unusual those with the hydroxy hydrogen directed toward the carbonyl [4], but it has been shown to be of secondary, not negligible, oxygen (A and B) are significantly more stable than the other importance for the conformational isomerism of 2'-fluo- two conformers (Table 1); clearly, the intramolecular HB roflavonol in this work. O–H···O=C plays the determinant role for the conformational isomerism of 2'-fluoroflavonol, as confirmed by NBO The conformational behaviours of chlorine and bromine deriva- (n → σ* ≥ 5 kcal mol−1) and QTAIM calculations tives are quite similar to each other, given the energy difference O(=C) OH (Table 1 and Table 2). The most stable form (A, Figure 2) has between the two stable conformers and their geometrical para- the hydroxy oxygen far from the fluorine atom bonded to the meters (Table 1 and Supporting Information File 1). According adjacent phenyl ring and, according to QTAIM data, it estab- to QTAIM calculations, conformer A of both 2'-haloflavonols lishes two other stabilizing interactions: Weak HB H–O···H–C experiences intramolecular HB C=O···H–O and, to a lesser and a nonbonding F…O interaction. 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