Effect of pyridyl nitrogen on the conformational landscape of 7-azaserotonin: A computational study

Journal of Molecular Structure: THEOCHEM 902 (2009) 79–89

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Effect of pyridyl nitrogen on the conformational landscape of 7-azaserotonin: A computational study Himansu S. Biswal, Sanjay Wategaonkar * Department of Chemical Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai, Maharashtra 400005, India

a r t i c l e

i n f o

Article history: Received 8 October 2008 Received in revised form 17 February 2009 Accepted 17 February 2009 Available online 26 February 2009 Keywords: 7-Azaserotonin Serotonin DFT MP2 Atoms in molecules (AIM)

a b s t r a c t The conformational topology of gaseous neutral 7-azaserotonin has been investigated by employing systematic ab initio calculations. The whole conformational landscape has been explored by varying four dihedral angles which define the position of ethyl amine side chain and phenolic OH group with respect to the 7-azaindole plane. A total of 22 local minima have been located by geometry optimization of 216 possible trial structures at the B3LYP/6-31+G level of theory. With the exception of a few conformers, in most cases the OH-syn conformers were more stable than their OH-anti counterparts. Vibrational frequency analysis for all 22 conformers computed at B3LYP/6-31+G shows some interesting features in the pyrrole and pyridine CAH stretches. In some of the conformers the presence of intramolecular blue shifted H-bonding is confirmed using the atoms in molecules (AIM) analysis. The AIM analysis explains the differences in the relative energy order of various conformers compared to that observed in the case of serotonin. It also explains the behavior of the pyrrole and pyridine CAH stretches observed for some of the conformers. The conformational distribution of 7-azaserotonin at various temperatures is computed based on simple thermodynamic principle. At lower temperature of about 100 K only six conformers were significantly populated according to their electronic energies while at higher temperature of about 400 K the populations were determined by their vibrational partition functions. Ó 2009 Elsevier B.V. All rights reserved.

1. Introduction The biological functions of flexible bio-molecules like neurotransmitters intimately depend on the conformation that the molecules can adopt. There have been a lot of experimental and theoretical studies on multiconformer biomolecular systems in gas phase [1–5]. Among all the neurotransmitters serotonin has been studied extensively whose flexible ethylamine chain has attracted the most for the quantum chemical investigations. Depending on the orientation of the ethylamine chain it can adopt a number of conformations. Serotonin plays a vital role in biological processes that control the states like depression, anxiety, and sexuality. It is also involved in controlling appetite, behavior, emotions, sleep, and body temperature [6]. The stability of different conformers of serotonin is determined by the interaction of ethylamine chain with aromatic p-electron density [4,5]. The interest in the conformational studies on these large flexible biomolecules has been enhanced by the growing accuracy of quantum mechanical calculations. A great number of theoretical papers treating the conformational landscapes of serotonin and tryptamine have been published [4,5,7–11] both of which have an ethylamine side chain attached to an indole moiety. * Corresponding author. Tel.: +91 22 2278 2259; fax: +91 22 2278 2106. E-mail addresses: [email protected] (H.S. Biswal), [email protected] (S. Wategaonkar). 0166-1280/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.theochem.2009.02.015

We are interested in 7-azaserotonin (Fig. 1) which has 7-azaindole moiety instead. It has been shown that indole and 7-azaindole have different physical and photophysical properties and the difference is due to the presence of electron withdrawing pyridyl nitrogen in 7-azaindole [12–14]. The presence of the potent Hbond acceptor pyridyl nitrogen in 7-azaserotonin makes it biologically interesting, like 7-azaindole and its analogs [15]. It is also evident from the QSAR and photophysical study on 7-azamelatonin (which has similar structure as that of 7-azaserotonin) that it is a potential probe for receptor recognition [16,17]. As far as the authors are aware there is no such QSAR study on 7-azaserotonin, but the additional H-bond acceptor site in 7-azaserotonin compared to serotonin may enhance the ability of binding 7-azaserotonin to receptor site, so that the 7-azaserotonin may act as a potential agonist or antagonist of serotonin receptor. The purpose of current study is to explore the effect of pyridyl nitrogen in the ring on the conformational landscape of 7-azaserotonin. Moreover, three recent reports, one on the synthesis and photophysical study of 7-azaserotonin in condensed phase [18] and the other two on the conformational study of jet-cooled serotonin [3,5] encouraged us to investigate this molecule in gas phase by quantum chemical methods. We hope this study will compliment theoreticians to design appropriate force field method for 7-azaserotonin-receptor interaction and spectroscopists to assign the experimental spectra.

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H.S. Biswal, S. Wategaonkar / Journal of Molecular Structure: THEOCHEM 902 (2009) 79–89

Fig. 1. Schematic diagram of 7-azaserotonin, showing the structure and torsional naming and schematic illustration of the initial dihedral angle to generate different trial structures.

A systematic conformational search for 7-azaserotonin has been performed by varying four dihedral angles as shown in (Fig. 1) and in the same way as described by Mourik and Emson for serotonin [4]. The initial search was performed at lower moderate level of theory (AM1, PM3, SCF/3-21G and SCF/631G). Later all the stable structures were re-optimized at the B3LYP/6-31+G level of theory. To account for the electron correlation in the conformational preferences of 7-azaserotonin, the B3LYP optimized structures were subjected to the MP2 level calculations with 6-31+G basis set. The presence of intramolecular hydrogen bonds in some conformers was confirmed using the atoms in molecules (AIM) theory [19,20]. Conformational distributions at various temperatures were estimated according to the statistical principles with the accurate ab initio data. Our results are compared with the quantum chemical study of serotonin [4]. To the best of our knowledge there are no experimental vibrational spectra of 7-azaserotonin in the literature. So our results cannot be compared directly with the experiment, however the results are compared with the IR dip spectroscopic study of 7-azaindole [21] which bears the same chromophore as 7-azaserotonin and with jet-cooled spectra of serotonin [5] which has the same flexible ethylamine chain as 7-azaserotonin.

2. Computational details 2.1. Conformer nomenclature The structure of 7-azaserotonin depicted in Fig. 1 also shows the nomenclature that is used to denote the dihedral angles (UC, UN, Ulp, UOH) throughout this work. We use the same nomenclature as that used for serotonin [4] and tryptamine [8] in order to remain consistent with the earlier studies. Fig. 1 shows a conformer of 7-azaserotonin in which various dihedral angles are defined as follows: UC (CdACcACbACa) defines the position of the side chain with respect to the 7-azaindole plane, UN (CcACbACaAN1) defines the position of the amine group, Ulp (CbACaAN1Alp) defines the position of the nitrogen lone pair, and UOH (H3AOACAACB) defines the orientation of the OH group with respect to the pyrrole NH. The Anti and G terms denote the anti or gauche conformations of the CaAN1 bond with respect to the CcACb bond, respectively. For the gauche conformers the py and pd terms refers to the N1 atom

H.S. Biswal, S. Wategaonkar / Journal of Molecular Structure: THEOCHEM 902 (2009) 79–89

pointing towards the pyrrole ring or pyridine ring, respectively. The authors would like to mention here that the pd term is synonymous with the ph term used in the context of tryptamine and serotonin. The labels up, out and in are used for the orientation of the nitrogen (N1) lone pair whenever it is up, away from, and towards the 7-azaindole p-electron density, respectively. The conformers in which the entire side chain lies in the plane of the 7azaindole ring are denoted by the term IP (in-plane) and the labels ip and op are used for the orientation of the nitrogen (N1) lone pair whenever it is in plane and out of plane, respectively. The labels anti and syn indicate the position of H3 with respect to the pyrrole NH bond. 2.2. Electronic structure calculation Initial conformational search was done at lower levels like AM1 [22], PM3 [23,24], SCF/3-21G, and SCF/6-31G. AM1 is a very well established method for studying biological systems (for molecules containing only up to the 2nd row elements in general) and has been used earlier for the calculations of tryptamine derivatives [4,25] and melatonin [26]. The DFT/B3LYP method [27–29] was used to refine the 7-azaserotonin conformers obtained using the lower levels of theory as it is known to provide accurate molecular structure, the associated vibrational frequencies, and infrared intensities [30]. The harmonic frequencies computed at the B3LYP/6-31+G level of theory have been found to be in good agreement with the experiment [5,8,31–36]. The MP2 theory [37,38] provides better estimate of the conformational energy than DFT/B3LYP calculations when weak interactions like stacking and H-bonding are involved [39,40]. Therefore MP2 electronic energies were used for discussing relative stabilities of the conformers. All the calculations were performed with the Gaussian 98 [41] and Gaussian 03 [42] program package, using 6-31G and 6-31+G basis sets. The conformational space of 7-azaserotonin was explored through a systematic variation of four dihedral to generate a series of trial structures (Fig. 1). In the trial structures the conformations in which the side chain (Ca) is perpendicular to the 7azaindole plane and the ones in which the side chain (Ca) is in the plane of the rest of the molecule were considered. The conformations in which one of the two (Cb) H atoms is perpendicular to the 7-azaindole plane and the ones in which one of the two (Cb) H atoms is in the 7-azaindole plane were also considered. Initial dihedral angles to generate aforementioned four categories of trial structures are depicted in Fig. 1 leading to 216 possible structures for the 7-azaserotonin molecule. All these possible structures were geometry optimized at the lower levels of theory to minimize the number of distinguishable conformers. The refined structures were further subjected to the geometry optimization at the B3LYP/6-31+G and MP2/6-31+G level of theory in order to ascertain the structural accuracy and stability. Gaussian’s ultrafine integration grid was applied for B3LYP/631+G calculations. The AIM2000 package [43] was used to compute the topological properties of the electron density at the bond critical points (BCPs) in order to investigate the intramolecular hydrogen bonding interactions. B3LYP/6-31+G and B3LYP/ 6-311++G wavefunctions of the B3LYP/6-31+G optimized structures were used to calculate the electron density (qb) and the laplacian (r2qb) at BCPs. 2.3. Conformational distribution calculation The conformational distributions at different experimental temperatures were calculated according to the Boltzmann statistics and accurate ab initio data. The molecular partition function was factorized into its translational, rotational, vibrational, electronic,

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and nuclear components with the Born-Oppenheimer approximation and excluding ro-vibrational coupling, i.e., qtot = qtransqrotqvib qelecqnucl. The translational and nuclear partition functions are identical for all the conformers and are irrelevant for the equilibrium distribution. So the total partition function includes only the rotational, vibrational, and electronic partition functions and the expressions for their estimation can be found elsewhere [44,45]. Using the respective data for the various conformers, i.e., rotational constants, vibrational frequencies, and ground state electronic energies, the gas phase partition function for 7-azaserotonin can be calculated for a given temperature. The rotational partition functions depend only on the molecular geometry and were calculated from the respective rotational constants of the B3LYP/631+G(d) optimized structures. The electronic partition functions were calculated with the MP2/6-31+G(d) energies as they reflected conformational energies better than the DFT values when weak interactions are involved [39,40]. The vibrational partition functions were computed using the scaled B3LYP/6-31+G(d) frequencies. A scaling factor of 0.9611 was applied in order to match the 7-azaindole NH fundamental stretching frequency with the previously published experimental data [21].

3. Results and discussion 3.1. Conformers and energies 3.1.1. SCF/6-31G, B3LYP/6-31+G and MP2/6-31+G A total of 12 unique local minima conformers were found at the SCF/6-31G level. Out of the 12 conformers, one with the dihedral angles (UC, UN, Ulp) as (156.50°, 65.25°, 175.85°) was unstable on the B3LYP/6-31+G potential energy surface. Remaining 11 stable conformers were re-optimized at B3LYP/6-31+G level. Frequency calculations at the same level of theory for all 11 conformers confirmed the converged structures as true minima having no imaginary frequency. All the 11 B3LYP/6-31+G optimized structures (only the OH-syn counterparts) are shown in Fig. 2. Table 1 lists all the 11 conformers of 7-azaserotonin in the order of their relative electronic energies calculated at the B3LYP/631+G level of theory. A scaling factor of 0.9611 is applied for the zero point energy correction. The 11 conformers can be very easily grouped into four groups. The first three groups consist of conformers in which the carbon (Ca) is nearly perpendicular to the aromatic plane. The three groups are Gpd (conformer #3,7,11), Gpy (conformer #1,2,8), and Anti (conformer #4,5,6) in which the NH2 group is oriented towards the pyridyl ring, pyrrole ring, and away from the aromatic plane, respectively. Each of these three groups consist of three conformers in which the lone pair of electrons on the nitrogen atom is oriented towards aromatic p-electron density (in), away from it (out), and pointing upwards (up). The fourth group (IP) comprises of conformers in which the Ca carbon atom (and the entire side chain) lies in the plane of the molecule. Conformers #9 and #10 belong to this group. Table 1 also gives the corresponding conformer numbers for serotonin (from Ref. [4]). Two points may be noted immediately. One, only 11 conformers are stable in the present case as against 12 conformers in the case of serotonin; the conformer corresponding to #10 of serotonin is missing for 7-azaserotonin, vide infra. Secondly, unlike serotonin in the case of 7-azaserotonin the OH-syn conformers are more stable than their OH-anti counterparts, except for the Gpd(out) [#3] and Gpd(in) [#11] conformers, vide infra, on the B3LYP/6-31+G potential energy surface. Further, in the case of serotonin Gpy(out) [#1] conformer is the most stable for both the anti and syn forms whereas in 7-azaserotonin Gpy(out) [#1] is the most stable syn form; for the anti form the most stable conformer happens to be Gpd(out) [#3]. The stability of syn conformer

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Fig. 2. B3LYP/6-31+G(d) Optimized structures for the syn conformer.

Table 1 Relative energies (in kJ/mol) of 22 7-azaserotonin conformers (11 for OH-syn and 11 for OH-anti) calculated at B3LYP/6-31+G level of theory.

Table 2 Comparison of side chain dihedral angles (in degree) in the anti conformers of 7azaserotonin and serotonina computed at B3LYP/6-31+G level.

Conformera

Conformer

1 2 3 4 5 6 7 8 9 10 11

OH-syn

Gpy(out) Gpy(up) Gpd(out) Anti(up) Anti(py) Anti(pd) Gpd(up) Gpy(in) IP(ip) IP(op) Gpd(in)

Serotoninc

OH-anti b

b

D(Ee)

D(E0)

D(Ee)

D(E0)

0.00 1.40 2.12 2.63 2.94 3.06 4.00 4.70 5.67 6.18 8.20

0.00 1.01 2.20 1.83 2.21 2.25 3.60 4.67 5.04 5.32 7.76

1.20 2.36 0.64 3.90 4.50 3.53 5.64 5.63 6.96 6.98 6.55

1.17 2.00 1.10 3.09 3.70 2.82 5.16 5.51 6.37 6.17 6.69

1 3 2 5 6 4 7 8 9 11 12

a

The numbering scheme follows 7-azaserotonin (OH-syn) energy ordering. Zero point energy corrections from B3LYP/6-31+G calculations. The zero point energies are scaled by a factor of 0.9611. c The numbering scheme follows serotonin energy ordering from Ref. [4]. b

#1 is attributed to the fact that the nitrogen lone pair is oriented away from the 7-azaindole ring and one of the amino hydrogen is directed towards the 7-azaindole p-electron density. In the case of Gpy(in) [#8] and Gpd (in) [#11] conformers the nitrogen lone pair electron is directed towards the 7-azaindole p-electron density. The repulsion between the nitrogen lone pair and 7-azaindole p-electrons destabilizes these two conformers. Comparison of the side chain dihedral angles of 7-azaserotonin with that of serotonin is shown in Table 2. Apparently the dihedral angles are not very different compared to those in serotonin; the maximum difference was observed in UN of the Gpd(in) [#11] conformer. This indicates that the presence of pyridyl group has very little effect on the side chain geometry.

1 2 3 4 5 6 7 8 9 10 11

Gpy(out) Gpy(up) Gpd(out) Anti(up) Anti(py) Anti(pd) Gpd(up) Gpy(in) IP(ip) IP(op) Gpd(in)

UC

D(UC)b

UN

D(UN)b

UN

D(Ulp)b

76.0 73.3 82.5 75.1 75.6 76.0 92.0 148.5 180.0 179.3 62.0

0.3 1.0 1.3 1.1 0.9 0.3 0.2 2.1 0.0 0.5 1.8

63.9 62.6 63.5 179.1 178.9 175.0 61.6 66.8 180.0 178.9 83.0

0.0 0.1 1.5 0.3 0.3 0.1 0.1 0.2 0.0 0.0 3.1

55.2 178.1 51.0 179.6 53.2 54.8 178.1 57.1 180.0 53.0 48.8

1.0 0.3 2.6 0.3 0.7 0.2 0.6 1.4 0.0 0.9 0.1

a Anti conformer from Ref. [4]; although the conformer numbering is different from azaserotonin, the nomenclature is similar. b Differences in B3LYP values of serotonin and azaserotonin: U(B3LYP)azaserotoninU(B3LYP)serotonin.

We could not locate the conformer corresponding to conformer #10 of serotonin in our study of 7-azaserotonin at any level of theory, except at the SCF/6-31G level. Since conformer #7 and #10 of serotonin differ only in their UC dihedral angle and conformer #7 for both serotonin and 7-azaserotonin is same, i.e. Gpd(up) [Gph(up) in serotonin], a relaxed potential energy surface scan along UC was carried out to get an idea about the barrier height for inter conversion between the two conformers. Fig. 3 displays the relaxed PES for the syn conformer (Fig. 3a) and the anti conformer (Fig. 3b) at the SCF/3-21G, SCF/6-31G, and B3LYP/631+G levels of theory. No minima were found at UC  150° for both syn/anti pair at SCF/321G and B3LYP/6-31+G level. Very shallow minima exist on the SCF/6-31G potential energy surface with the barrier height of 0.36 and 0.50 kJ/mol for syn and anti conformers, respectively, which ultimately collapse into conformer #7.

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a

12

Rel. SCF Energy (kJ/mol)

10

SCF/321G* OH-syn SCF/6-31G* OH-syn B3LYP/6-31+G*OH-syn

8

6

4

2

0 60

80

100

120

140

160

180

ΦC (deg)

Rel. SCF Energy (kJ/mol)

b

12

10

SCF/321G* OH-anti SCF/631G* OH-anti B3LYP/631+G* OH-anti

of serotonin calculated at the DFT/B3LYP and MP2 level. At the MP2 level the energy differences between anti/syn conformational pairs of 7-azaserotonin are smaller compared to that of serotonin. Gpd(out)/anti [#3] conformer was found to be the most stable among all the conformers optimized at the MP2 level. This stabilization arises due to the weak H-bonding between the CCAH5 group and the NH2 group of the side chain (CCH5ANH2), vide infra. On the MP2 potential energy surface Gpy(in) [#8] and Gpd(in) [#11] conformers could not be optimized as the computation did not converge even after a large number of cycles. Similar observation was also reported by Zwier et al. [5] in the case of serotonin. One of the conformers in which the side chain lies in the plane of the molecule, viz., IP(op) [#10] collapsed into Anti(py) [#5] conformer at the MP2/6-31+G level while the other one, viz., IP(ip) [#9] survived. Conformers IP(ip) [#9] and IP(op) [#10] have a similar structure except that in conformer #9 the lone pair is pointing away from the CaACb bond (Table 4). In the case of conformer IP(op) [#10] the repulsion between the N1 lone pair (lp) and the CaACb bond pair (BP) makes it unstable at the MP2 level. Comparison between conformers #10 and #5 suggests that the UC for conformer #10 is 179.3° whereas that for #5 it is 75.6°. In Anti(py) [#5] conformer one of the H(a) atoms points towards the 7-azaindole p-electron density which perhaps lends it more stability through favorable H(a)-p-density interaction over conformer #10.

8

6

4

2

0 60

80

100

120

140

160

180

ΦC (deg) Fig. 3. Relaxed PES of UC dihedral for Gpd(up) conformers at SCF/321G, SCF/6-31G and B3LYP/6-31+G; (a) PES for OH-syn comformer, (b) PES for OH-anti conformer.

All the conformers found at the B3LYP level were re-optimized at the MP2/6-31+G level. The electronic energies obtained at the MP2 level were corrected for the zero point energies using the scaled frequencies obtained at the B3LYP/6-31+G level. Table 3 gives the zero point energy corrected relative energies of the anti/syn pairs of the 7-azaserotonin conformers along with those

3.1.2. SCF/3-21G Since the preliminary searches for the stable conformers were carried out at the SCF/3-21G level, it was thought prudent to compare these with those refined at the DFT/B3LYP and MP2 level using higher basis set, viz., 6-31+G. Fig. 4 shows the relative electronic energies of 11 7-azaserotonin conformers optimized at the three levels of theory. It can be seen that although the stability order remains same, the overall agreement of energy ordering in SCF and B3LYP was found to be excellent for the anti than that for the syn conformers. It can also be seen in Fig. 4b that for anti conformers, Gpd(out) [#3] is predicted to be the most stable conformer at all the levels of theory. For the syn conformers, the energy variation pattern for the Gpd(out) [#3] conformer was found to be similar at both the SCF and MP2 levels (Fig. 4a). One glaring disagreement between SCF and B3LYP values is that SCF overestimates the stability for the Gpd(out) [#3], Gpy(in) [#8], and Gpd(in) [#11] conformers. The energy differences between the anti/syn conformational pairs are very similar in SCF and MP2 levels and are much smaller than those at the B3LYP level. As far as the conformers #8 and #11 are concerned these did not converge to a stable geometry at the MP2 level and conformer #10 converged on the geometry of #5. Therefore the extra stabilization for conformers #8 and #11 at the SCF level is an unrealistic overestimation. The most stable conformer

Table 3 The relative energies (in kJ/mol) [zero point energya corrected] of the syn and anti conformers of 7-azaserotonin and serotinb at B3LYP and MP2 levels. Serotonin, DFT/6-31+G

Conformer

1 2 3 4 5 6 7 8 9 10 11 a b

Gpy(out) Gpy(up) Gpd(out) Anti(up) Anti(py) Anti(pd) Gpd(up) Gpy(in) IP(ip) IP(op) Gpd(in)

Serotonin, MP2/6-31+G

Azaserotonin, DFT/6-31+G

Azaserotonin, MP2/6-31+G

anti-5-OH

syn-5-OH

anti-5-OH

syn-5-OH

anti-5-OH

syn-5-OH

anti-5-OH

syn-5-OH

0.00 0.81 0.80 1.89 2.66 1.98 3.67 4.92 4.68 5.45 8.73

1.15 0.78 3.10 1.63 2.19 2.54 3.11 4.58 4.46 5.27 10.95

0.43 2.51 0.00 7.62 7.52 6.78 5.01 – – – –

1.82 4.56 4.69 9.33 8.91 9.33 6.36 – – – –

1.17 2.00 1.10 3.09 3.70 2.82 5.16 5.51 6.37 6.17 6.69

0.00 1.01 2.20 1.83 2.21 2.25 3.60 4.67 5.04 5.32 7.76

1.33 3.49 0.00 8.63 8.36 7.42 6.48 – 14.73 – –

0.93 3.49 2.33 8.18 7.61 7.70 5.70 – 14.24 – –

Zero point energy corrections using the B3LYP harmonic frequencies scaled by 0.9611. Refs. [4,5].

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Table 4 Comparison of side chain dihedral angle (in degree) of the OH-anti 7-azaserotonin conformers computed at A: SCF/3-21G, B: SCF/6-31G, C: MP2/6-31+G and D: B3LYP/6-31+G levels of theorya. Conformer

1 2 3 4 5 6 7 8 9 10 11 a

Gpy(out) Gpy(up) Gpd(out) Anti(up) Anti(py) Anti(pd) Gpd(up) Gpy(in) IP(ip) IP(op) Gpd(in)

UC

D(UC)a

B3LYP

A

B

76.0 73.3 82.5 75.1 75.6 76.0 92.0 148.5 180.0 179.3 62.0

2.3 3.5 2.1 1.7 1.9 1.9 5.8 1.2 0.0 0.8 1.1

0.5 0.1 0.2 0.8 0.3 0.6 1.9 7.8 0.0 0.3 5.0

UN

D(UN)a

(Ulp)a

D(Ulp)a

C

B3LYP

A

B

C

B3LYP

A

B

C

4.3 5.3 0.4 3.8 3.6 3.9 2.5 – 0.0 – –

63.9 62.6 63.5 179.1 178.9 175.0 61.6 66.8 180.0 178.9 83.0

1.0 0.8 0.8 0.2 1.0 1.5 0.1 1.9 0.0 1.0 1.4

1.1 0.1 0.4 0.1 0.5 1.1 0.1 1.2 0.0 0.7 2.5

2.9 3.9 2.2 0.3 0.4 0.6 2.6 – 0.0 – –

55.2 178.1 51.0 179.6 53.2 54.8 178.1 57.1 180.0 53.0 48.8

2.0 0.7 8.0 0.1 7.1 7.0 0.3 0.8 0.0 7.4 2.5

0.1 1.1 1.6 0.0 0.3 0.5 1.6 1.9 0.0 0.7 1.8

0.3 0.1 0.6 0.1 0.6 0.2 0.8 – 0.0 –

Differences relative to B3LYP values; i.e. Ui–UB3LYP, i=SCF, MP2.

at the MP2/6-31+G level is the syn Gpd(out) [#3] conformer while the syn Gpy(out) [#1] is the most stable at B3LYP/6-31+G level of theory. The energy difference between the most stable conformer and the least stable conformer is 15 kJ/mol at the MP2/6-31+G level and this difference is almost half (8 kJ/mol) at the B3LYP/ 6-31+G level. Table 4 gives the most important dihedral angles for the anti conformers calculated at four different levels of theory where the dihedrals calculated using the B3LYP functional were taken as reference. In Table 4, A represents SCF/3-21G, B represents SCF/6-31G, and C represents MP2/6-31+G calculation. The structural parameters for various conformers remain almost unchanged at all the four different levels of theory. The changes in side chain bond lengths were also found to be very small and the CcACb, CbACa, CaAN1 bond lengths were 1.50 ± 0.01 Å, 1.54 ± 0.01 Å, and 1.46 ± 0.02 Å, respectively at all the four levels of theory. Apparently, there was no difference in these bond lengths even at lower levels of theory like SCF/3-21G and SCF/6-31G compared to the B3LYP/6-31+G and MP2/6-31+G optimized structures. The rms difference in the CcACb, CACa, and CaAN1 bond distances at the SCF/3-21G and SCF/6-31G levels from the B3LYP/6-31+G optimized structures are 0.005, 0.010, and 0.005 Å and 0.006, 0.004, and 0.013 Å, respectively. Initial search for locating different conformers was also done by semi empirical methods like AM1 and PM3. The structural parameters and energies of AM1 and PM3 optimized structures differ a lot (data is not presented here) compared to the ab initio methods and hence will not be discussed here at all. However, from the above discussion it can be concluded that computationally less expensive level of theory like SCF/3-21G can be used for initial scans to locate different conformers of flexible molecules like 7azaserotonin. 3.1.3. Orientational preference of 5-OH group The 5-OH group in 7-azaserotonin can be oriented in two ways. When the OH hydrogen is on the same side of the pyrrole NH bond, it is called syn and when it is pointing away it is designated as anti. As mentioned earlier, in 7-azaserotonin the syn conformers are more stable than their anti counterparts (Table 1) except for the Gpd(out) [#3] and Gpd(in) [#11] conformers. This is in contrast to the observations reported for serotonin [3,5]. Although the syn conformers are more stable than the anti, the energy difference between the syn/anti pair is less in 7-azaserotonin compared to that in serotonin. This difference is largest for Anti(py) [#5] and Gpd(up) [#7] conformers (1.6 kJ/mol at B3LYP level) in 7-azaserotonin whereas it is 4 kJ/mol in serotonin [4]. To further confirm the stability order of the syn/anti pairs in Gpy(out) [#1], Gpd(out)[#3], and Gpd(in) [#11] conformers, relaxed potential energy surface scans were taken along the UOH dihedral angle which

are depicted in Fig. 5. In the case of Gpy(out) [#1] the syn conformer is more stable than anti with an interconversion barrier of 10.11 kJ/mol while for Gpd(out) and Gpd(in) the anti conformer is more stable than syn with a barrier height of 9.53 and 9.48 kJ/ mol, respectively. Interestingly, the OH stretching frequency is slightly blue shifted, by 2–5 cm1, for all anti conformers compared to syn conformers, which will be discussed in greater detail in Section 3.2. It is not clear as to why the stability of the syn conformers is greater than the anti in the case of 7-azaserotonin. Similar trend has also been observed previously for 3-hydroxy-pyridine [46] where the syn conformer was 200 cm1 (2.39 kJ/mol) more stable than the anti conformer, whereas in the case of b-naphthol the s-cis (analogous to anti) conformer is 353 cm1 (4.22 kJ/mol) more stable than s-trans (analogous to syn) conformer [47]. Hence the preference for the 5-OH orientation in 7-azaserotonin resembles that of 3-hydroxy pyridine while for that in serotonin is more like b-naphthol. We also observed same orientation preference for the 5-OH group in 5-hydroxy-indole and 5-hydroxy-7-azaindole as observed for serotonin and 7-azaserotonin, respectively [48]. So it can be concluded that the ethylamine side chain does not play any significant role in the orientational preferences of the 5-OH group, but the extra stability for the syn conformers is due to the presence of electron withdrawing pyridyl group. 3.2. Vibrational frequencies Vibrational frequencies for all stable conformers were computed at the B3LYP/6-31+G level of theory. It was observed that the pyrrole NAH stretching frequency remains same for all the conformers. Therefore a scaling factor of 0.9611 was applied to match the fundamental NAH stretching frequency with previously published experimental data [21]. In the Supplementary Information (SI)*, the complete assignments of all hydride stretching frequencies and their comparison with computed [4] and the experimentally observed [5] serotonin frequencies is provided. The frequency assignments were carried out by visualizing the normal modes in GaussView [49]. Table S1 of SI gives the assignments for the syn conformers while Table S2 gives the assignments for the anti conformers. The side chain CH stretching frequencies for all the 7-azaserotonin conformers match very well with those of the corresponding serotonin conformers. For the anti conformers, the OH stretching frequencies are same as those of serotonin while for the syn conformers they are red shifted up to 10 cm1. However, among the 7-azaserotonin conformers the OH stretching frequencies of the syn conformers are red shifted up to 5 cm1 relative to those of the anti conformers. Similar frequency shift for the anti/syn conformational pair was observed for 3-hydroxypyridine and 5-hydrox-

85

16 12

18 SCF/3-21G* OH-syn B3LYP/6-31+G* OH-syn MP2/6-31+G* OH-syn

8 4 0 -4 0

1

2

3

4 5 6 Conformer

7

8

9

10 11

12

Rel. SCF energy wrt. minimum (kJ/mol)

a Relative Energy (kJ/mol)

H.S. Biswal, S. Wategaonkar / Journal of Molecular Structure: THEOCHEM 902 (2009) 79–89

16

Gpy(out) Gph(out) Gph(in)

14 12 10 8 6 4 2 0

Relative Energy (kJ/mol)

b

16

-50

12

100

150

20

250

300

350

400

Fig. 5. Relaxed potential energy scan along UOH dihedral angle for Gpy(out), Gpd(out) and Gpd(in) conformer at B3LYP/6-31+G level.

8 4

a

0

1

2

3

4 5 6 Conformer

7

8

9

10 11

Correlation Coefficient: R= -0.99542

-38.0

-1

10

-34.0

-36.0

12

Δν ( cm )

0

8

a

Relative Energy (kJ/mol)

50

O-H dihedral (deg)

-4

c

0

SCF/3-21G* OH-anti B3LYP/6-31+G* OH-anti MP2/6-31+G* OH-anti

B3LYP/6-31+G* OH-syn B3LYP/6-31+G* OH-anti

6

-40.0

-42.0

4

-44.0 2 -3

-3

-3

-3

-3

-3

-3

2.40x10 2.55x10 2.70x10 2.85x10 3.00x10 3.15x10 3.30x10

0

a Δr (ang) 0

1

2

3

4 5 6 Conformer

7

8

9

10 11

12

b

Fig. 4. Comparison of the SCF, B3LYP, and MP2 relative electronic energies (in kJ/ mol) for (a) syn conformers, (b) anti conformers, and (c) syn/anti conformers at the B3LYP/6-31+G level; For each level of calculation the energies are normalized with respect to syn conformer#1.

50.5

50.0

Correlation Coefficient: R= -0.99780

-1

b

yazaindole [48]. Both antisymmetric and symmetric stretches of NH2 were same as those of the serotonin conformers. The pyrrole CH stretching frequency for all the conformers lies in the range 3130 ± 2 cm1 and was blue shifted by about 5 cm1 relative to that in serotonin with the exception of Gpy(in) [#8] conformer, for which it was 3160 cm1 for both the syn and anti forms. In this conformer the NH2 group is oriented towards the pyrrole CH, which facilitates the formation of the CHANH2 hydrogen bond, vide infra. The indole NH stretch was essentially same for all the conformers. The most striking feature was observed for the pyridine CH stretches. For the assignment of pyridine CH stretches, pyridine CH(opp) is used to denote the CH group opposite to pyridine nitrogen while pyridine CH(adj) is used to denote the CH vicinal to pyridine nitrogen. For all the anti conformers the pyridine CH(opp)

Δν (cm )

49.5

49.0

48.5

48.0 -3 -3 -3 -3 -3 -3 -3.85x10 -3.80x10 -3.75x10 -3.70x10 -3.65x10 -3.60x10

Δrb (ang) Fig. 6. Correlation between change in CAH bond length (Dm) and change in CAH stretching frequency (Dm) for anti/syn conformational pair of 7-azaserotonin. ðaÞ : Dma ¼ mðCC CH5 Þanti  mðCC CH5 Þsyn vs: Dr a ¼ rðCC CH5 Þanti  rðCC CH5 Þsyn . ðbÞ : Dmb ¼ mðCB CH4 Þanti  mðCB CH4 Þsyn vs: Dr b ¼ rðCB CH4 Þanti  rðCB CH4 Þsyn .

86

H.S. Biswal, S. Wategaonkar / Journal of Molecular Structure: THEOCHEM 902 (2009) 79–89

Table 5 Analysis of bond critical points (BCPs) between H-bond acceptors and H-bond donors for the 7-azaserotonin conformers those show intra molecular H-bonding. BCps are computed for B3LYP/6-31+G optimized structure at a: B3LYP/6-31+G and b:B3LYP/6-311++G. qb and r2qb in atomic units are the electron density and its Laplacian at the BCP. c: D in A is the distance between the BCP and the corresponding ring critical point (RCP). d: atoms involved in H-bonding, for atom labeling refer to Fig. 1. Conformera

BCPd

OH-anti, B3LYP/6-31+G 2

qb

r qb

e

D

0.0197 0.0371 0.0382

2.3839 0.0647 0.2442

0.83 1.98 1.32

Gpd(out) Gpd(in) Gpy(in)

CcH5–N1 CcH5–N1 CdH6–N1

0.0057 0.0124 0.0113

Conformerb

BCPd

OH-anti, B3LYP/6-311++G

Gpd(out) Gpd(in) Gpy(in)

CcH5–N1 CcH5–N1 CdH6–N1

OH-syn, B3LYP/6-31+G c

2

qb

r2qb

e

Dc

– 0.0113 0.0113

– 0.0345 0.0382

– 0.1076 0.2435

0.00 1.94 1.32

OH-syn, B3LYP/6-311++G c

qb

r qb

e

D

0.0069 0.0122 0.0113

0.0250 0.0340 0.0360

4.8134 0.0592 0.1998

0.38 1.95 1.28

stretch appears at 3045 ± 2 cm1 and the pyridine CH(adj) stretch lies in the range 3070 ± 2 cm1, which is in excellent agreement with that of 7-azaindole [21] with the exception of Gpd(out) [#3] and Gpd(in) [#11] conformers. In these two conformers the pyridine CH(opp) stretches were blue shifted by 13 and 18 cm1, respectively. This is attributed to the hydrogen bonding interaction between the side chain amino group N atom and the pyridine CH(opp) group (see Section 3.3). However, in all the syn conformers, the pyridine CH(opp) stretch was blue shifted up to 40 cm1 while the CH(adj) stretch was red shifted up to 50 cm1 relative to those in 7-azaindole [21]. The maximum blue shift in pyridine CH(opp) stretch was observed for the Gpd(in) [#11] and that for the pyrrole CH stretch was observed for the Gpy(in) [#8] conformers, where the side chain NH2 group forms H-bond with the pyridine CH(opp) and the pyrrole CH, respectively. The similar trend in dependencies of the pyridine CH stretching frequencies on the OH orientation, i.e., anti vs syn, were also noted in the case of 3hydroxypyridine and 5-hydroxyazaindole [48]. Therefore, the origin of the shifts in pyridine CH stretches has little to do with the presence of ethylamine side chain, except that it manifests in amplifying them in a few cases due to intramolecular hydrogen bonding effects. The bond lengths of pyridine CH(opp) in all the syn conformers are shorter than those in the anti conformers while the bond lengths of pyridine CH(adj) in all the syn conformers are longer than those in the anti conformers. These observations are consistent with the predicted blue and red shifts of the pyridine CH(opp) and CH(adj) stretches. In Fig. 6 the shifts in the stretching frequencies of pyridine CH(opp) and CH(adj) are plotted against the changes in their respective bond lengths for various conformers. The bond lengths and frequencies of the anti conformers are taken as the reference. The linear correlation co-efficient for pyridine CH(opp) of 0.995 and that for pyridine CH(adj) of 0.998 indicate that the frequency shifts are well correlated with the change in the bond lengths. 3.3. Intramolecular hydrogen bond Since some of the conformers show anomalous behavior in their hydride stretches we have looked for the intramolecular H-bonding interactions in the 7-azaserotonin conformers. AIM analysis was performed at the B3LYP/6-31+G and B3LYP/6-311++G level. The eight AIM criteria proposed by Popelier for the existence of Hbond [20,50,51] were applied systematically to find the true intramolecular H-bonds. The electron density (qb), the Laplacian (r2qb), the bond ellipticity (e), and the distance between the bond critical point (BCP) and ring critical point (RCP), D are listed for the three anti and two syn 7-azaserotonin conformers in Table 5. Molecular graph of Gpd(out), Gpd(in), and Gpy(in) syn/anti conformational pairs of 7-azaserotonin are shown in Fig. 7. All hydrogen

qb

r2qb

e

Dc

– 0.0111 0.0113

– 0.0314 0.0360

– 0.0924 0.1995

0.00 1.90 1.28

bonds are typical close shell interactions as the value of qb and r2qb lie in the proposed range of 0.002–0.035 au and 0.024– 0.139 au, respectively [50]. At both levels of theory no hydrogen bond was found for the syn Gpd(out) [#3/syn] conformer but it was present in the anti Gpd(out) [#3/anti] conformer. Although the CcH5AN1 H-bond (refer Fig. 1 for atom labels) is present in anti Gpd(out) [#3/anti] conformer, it is very weak because the ellipticity of the BCP is about an order of magnitude higher than that of the other hydrogen bonds (Table 5). Secondly, the distance from this BCP to the nearest RCP is 0.83 and 0.38 Å at the B3LYP/631+G and B3LYP/6-311++G levels, respectively, whereas for the anti Gpd(in) [#11/anti] conformer, this distance is 1.98 and 1.95 Å, respectively. Though the anti Gpd(out) [#3/anti] conformer forms a very weak H-bond it still provides greater stability to the conformer over its syn counterpart. The observed blue shifts in pyridine CH(opp) stretch in the case of the anti Gpd(out) [#3/anti] and anti Gpd(in) [#11/anti] conformers present examples of the intramolecular blue shifted hydrogen bonds. For the Gpd(in) [#11] conformer the anti conformer forms a stronger H-bond than its syn counterpart, providing more stability to the anti Gpd(in) [#11/anti] conformer relative to syn Gpd(in) [#11/syn] conformer (Fig. 4c). Both anti and syn Gpy(in) [#8] conformers form H-bonding (CDH6AN1) of almost equal strength as it can be seen in Table 5 that all the AIM parameters are same for both the conformers. This is also reflected in same amount of blue shift for pyrrole CAH stretching frequency in this conformer. 3.4. Population distribution of various conformers The population distribution of various conformers of gaseous 7azaserotonin at various temperatures is given in Table 6. Experimentally observed intensities for different conformers may not agree with the population distribution calculated solely on the basis of their respective electronic energies if 1) there were significant changes in the oscillator strengths, non-radiative paths, or Frank-Condon profiles from conformer to conformer, 2) if the population redistribution occurs among the conformers, and 3) if there were significant contributions from the vibrational partition functions at given temperature. Sturdy and Clary [52] have recently reported that for tryptamine the conformer population ordering at higher temperature (430 K) changes by applying torsional anharmonicity correction, although at lower temperature (100 K) the conformer population calculated with simple harmonic approximation matches fairly well with the experimentally observed intensities. Since there is no gas phase experimental data for 7azaserotonin we will rely on the serotonin experimental [5] data while comparing our findings. In the case of serotonin the conformer intensities follow the same order as their relative electronic energy order. The equilibrium populations of 7-azaserotonin were

H.S. Biswal, S. Wategaonkar / Journal of Molecular Structure: THEOCHEM 902 (2009) 79–89

87

Fig. 7. Molecular graph of Gpd(out) Fig. 7a, Gpd(in) Fig. 7b, and Gpy(in) Fig. 7c syn/anti conformational pairs of 7-azaserotonin. The large circles represent attractors attributed to atomic nuclei and the small circles show the bond critical points (red) and ring critical point (yellow). Solid lines represent the bond path. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

calculated using the simple harmonic approximation at various temperatures. The equilibrium conformational distributions for syn and anti conformers of 7-azaserotonin at different temperatures is shown in Table 6a and b, respectively. The temperature range from very low temperature to the source temperature of serotonin was covered. At lower temperature of about 100 K, only six (three for each of the syn/anti pair) most stable conformers may be populated in excess of 1% in the equilibrium distribution. For the syn 7-azaserotonin the most Gpd(out) [#3] {4%} and Gpy(up) [#2] {2.5%} while in anti 7-azaserotonin Gpd(out) [#3] {38%} was the most populated followed by Gpy(out) [#1] {20.5%}, and Gpy(up) [#2]

{2.4%}. For serotonin only eight conformers (five of the anti and three of the syn conformers) were observed experimentally [5]. As temperature increases the equilibrium distribution for different conformer changes as shown in Table 6. At 430 K the equilibrium distribution for syn 7-azaserotonin was Gpy(out) [#1] {16%} >Gpy(up) [#2] {9%} >Gpd(out) [#3] {7%} >Gpd(up) [#7] {5%} and for anti 7-azaserotonin it was Gpy(out) [#1] {14%} >Gpd(out) [#3] {10%} >Gpy(up) [#2] {9%} >Gpd(up) [#7] {5%}. The populations of the remaining conformers were less than 5% (See Table 6a and b). Note that the population of anti Gpy(out) [#1] conformer is higher than that of anti Gpd(out) [#3] conformer and similarly syn Gpy(up) [#2] conformer population is higher than that of syn

88

H.S. Biswal, S. Wategaonkar / Journal of Molecular Structure: THEOCHEM 902 (2009) 79–89

Table 6 Equilibrium distribution (%) of OH-syn 7-azaserotonin (Table 6a) and OH-anti 7-azaserotonin (Table 6b) conformers at various temperatures.

DE (kJ/mol)a

Conformer OH-syn (a) 1 2 3 4 5 6 7 9

Gpy(out) Gpy (up) Gpd(out) Anti (up) Anti(py) Anti(pd) Gpd(up) IP(ip)

Equilibrium distribution (%) 85 K

100 K

298 K

310 K

398 K

430 K

498 K

0.93 3.49 2.33 8.18 7.61 7.70 5.70 14.24

31.79 1.53 2.93 0.00 0.01 0.01 0.07 0.00

31.97 2.46 3.97 0.02 0.03 0.03 0.18 0.00

20.63 9.33 7.78 1.99 2.46 2.47 3.90 0.20

20.06 9.40 7.73 2.16 2.65 2.66 4.07 0.24

16.64 9.50 7.22 3.24 3.81 3.84 4.95 0.61

15.68 9.44 7.02 3.57 4.15 4.19 5.17 0.77

14.02 9.24 6.62 4.18 4.75 4.80 5.49 1.14

1.33 3.49 0.00 8.63 8.36 7.42 6.48 14.73

18.85 1.51 43.26 0.00 0.00 0.01 0.03 0.00

20.50 2.43 38.28 0.01 0.01 0.03 0.08 0.00

17.69 9.31 14.56 1.67 1.94 2.66 3.24 0.16

17.30 9.38 14.00 1.82 2.10 2.85 3.42 0.19

14.80 9.48 10.89 2.83 3.21 4.03 4.43 0.51

14.06 9.42 10.09 3.15 3.56 4.38 4.70 0.65

12.74 9.21 8.76 3.75 4.18 4.98 5.13 0.99

OH-anti (b) 1 2 3 4 5 6 7 9 a

Gpy(out) Gpy (up) Gpd(out) Anti (up) Anti(py) Anti(pd) Gpd(up) IP(ip)

MP2/6-31+G energy with zero point energy correction used B3LYP/6-31+G harmonic frequencies scaled by 0.9611.

Table 7 Comparison of ordering of the population of 7-azaserotonin conformers with that of serotonina (experimental) and tryptamine (experimentalb and theoreticalc) at 100 K. The conformer at the top of the each column is the most populated and the conformer at the bottom of each column is the least populated one. Tryptamine experimental

Gpy(out) Gpy(up) Gph(out) Anti(py) Anti(ph) Anti(up) Gph(up) a b c

Serotonin experimental

Azaserotonin theoretical

Harmonic 100 K

Tryptamine theoretical Correceted 100 K

anti-5-OH

syn-5-OH

anti-5-OH 100 K

syn-5-OH 100 K

Gpy(out) Gpy(up) Gph(out) Gph(up) Anti(ph) Anti(py) Anti(up)

Gpy(out) Gph(out) Gpy(up) Anti(ph) Anti(py) Anti(up) Gph(up)

Gpy(out) Gph(out) Gpy(up) Anti(py) Anti(up) – –

Gpy(out) Gpy(up) Gph(out) – – – –

Gpd(out) Gpy(out) Gpy(up) Gpd(up) Anti(pd) Anti(py) Anti(up)

Gpy(out) Gpd(out) Gpy(up) Gpd(up) Anti(py) Anti(pd) Anti(up)

Ref. [5]. Refs. [8,53,54]. Ref. [52].

Gpd(out) [#3] conformer although anti Gpy(out) [#1] and syn Gpy(up) [#2] are electronically less stable than anti Gpd(out) [#3] and syn Gph(out) [#2], respectively. This is due to favorable vibrational contribution at higher temperature for the anti Gpy(out) [#1] and syn Gpy(up) [#1] conformer than their respective counterparts. In Table 7, a comparison of the azaserotonin conformers population ordering at 100 K with that of tryptamine [8,52–54] and serotonin [5] is summarized. The relative populations of jet-cooled 7-azaserotonin may or may not be consistent with the calculated conformational distribution at the source temperature (450 K), due to the collisional relaxation and disposition of the energy barrier on the conformational potential energy surface. We hope that the equilibrium population analysis presented here will provide a basic guideline to assign different conformers experimentally. Whether or not to include the torsional anharmonicity correction in the calculation of equilibrium distribution must await the jet-cooled spectrum of 7-azaserotonin. 4. Conclusions From a pool of total 216 trial structures obtained by varying four dihedral angles viz. UOH, UC, UN, and Ulp, 22 (11 for syn and 11 for anti) local minimum conformers were identified using geometry optimization, first at the low level of theory like SCF/321G, later refined at the B3LYP/6-31+G level. In all the cases

OH-syn conformers were more stable than their anti counterpart, except for the Gpd(out) [#3] and Gpd(in) [#11] conformer. The barrier height for the Gpd(out)/syn to Gpd(out) /anti conversion was 9.53 kJ/mol while that for Gpd(in) it was 9.48 kJ/mol. Ethylamine side chain does not have any influence on the OH orientational preference as the same preference was observed for 5hydroxy-7-azaindole, although the reason for the stability of syn conformer over anti is not clear. At MP2/6-31+G level of theory, a total of 16 (8 for anti and 8 for syn) conformers were found to be stable. Gpy(in) [#8] and Gpd(in) [#11] did not converge and IP(op) [#10] collapsed into Anti(py) [#5]. The optimized geometrical parameters and energy ordering of the conformers at lower level of theory such as SCF/3-31G were found to be in good agreement with the structures obtained at higher levels of theory like B3LYP/6-31+G and MP2/6-31+G. Hence computationally less expensive lower level of theory can be applied for the preliminary geometry search for these types of flexible biomolecules. For all the 22 conformers, frequency calculations were done at B3LYP/6-31+G level of theory. In the case of anti conformers the OH stretching frequency was slightly blue shifted by 2–5 cm1 relative to that for their syn counterparts. All pyrrole CH stretching frequencies lie in the range 3130 ± 2 cm1 with the exception of Gpy(in) [#8] conformer. For both the syn and anti forms of this conformer the pyrrole CH stretch was blue shifted by about 30 cm1 due to the existence of the CHANH2 hydrogen bonding. Some

H.S. Biswal, S. Wategaonkar / Journal of Molecular Structure: THEOCHEM 902 (2009) 79–89

interesting observation was noted for the pyridine CH stretches. For all the anti conformers the pyridine CH(opp) stretches lie in the range of 3045 ± 2 cm1 and the pyridine CH(adj) stretches lie at 3070 ± 2 cm1 with the exception of Gpd(out) [#3] and Gpd(in) [#11] conformers. In these two conformers the pyridine CH(opp) stretches were blue shifted by 13 and 18 cm1, respectively. This was attributed to the hydrogen bonding interaction between the side chain amino group N atom and the pyridine CH(opp) group. In case of syn conformers, the pyridine CH(opp) stretch was blue shifted up to 40 cm1 while the CH(adj) stretch was red shifted up to 50 cm1. The maximum pyridine CH(opp) blue shift was observed for the Gpd(in) [#11] and the maximum pyrrole CH blue shift was observed for the Gpy(in) [#8] conformers in which the side chain NH2 group forms H-bond with the pyridine CH and the pyrrole CH, respectively. The intramolecular H-bonding properties of the six conformers, viz., Gpd(out), Gpd(in), and Gpy(in) syn/anti conformation pairs, which show anomalous behavior in the relative energy ordering and pyrrole CH and pyridine CH stretches were also investigated using the AIM theory with the B3LYP/6-31+G and B3LYP/6311++G densities. At both levels of theory no hydrogen bond was observed for the syn Gpd(out) [#3/syn] conformer but it was present in the anti Gpd(out) [#3/anti] conformer. This provides greater stability to the anti conformer over its syn counterpart. The existence of the hydrogen bond also explains the observed blue shifts in pyridine CH(opp) stretch in the anti Gpd(out) [#3/anti] and anti Gpd(in) [#11/anti] conformers. For the Gpd(in) [#11] conformers the anti conformer forms a stronger H-bond than its syn counterpart, providing more stability to the anti Gpd(in) [#11/anti] conformer relative to syn Gpd(in) [#11/syn] conformer. Both anti and syn Gpy(in) [#8] conformers form CDH6AN1 hydrogen bond of almost equal strength. This is also reflected in same amount of blue shift for pyrrole CAH stretching frequency in this conformer. The theoretical conformational distribution at various temperatures was estimated using MP2/6-31+G electronic energies and B3LYP/6-31+G frequencies. At lower temperature of about 100 K, only six (three for each syn/anti pair) most stable conformers are significantly populated, with the global minimum syn Gpd(out) conformer being the most populated one. At higher temperature of about 400 K, most of the conformers are populated with anti Gpy(out) conformer being the most populated one. Unlike its analogous molecules like tryptamine and serotonin no experimental data exists on this molecule in the gas phase. We hope that the computational efforts like frequency analysis, AIM analysis and population analysis presented here will provide a basic guideline to assign different conformers in future experiments on this molecule.

[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47]

Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.theochem.2009.02.015. References [1] A.G. Csaszar, A. Perczel, Prog. Biophys. Mol. Biol. 71 (1999) 243. [2] C. Desfrancois, S. Carles, J.P. Schermann, Chem. Rev. 100 (2000) 3943.

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