Interaction of small aromatic molecules: An <i>ab initio</i> studies on benzene and pyridine molecules

doi:10.4236/jbpc.2011.21005

Paper Menu >>

Journal Menu >>

Vol.2, No.1, 32-36 (2011) Journal of Biophysical Chemistry

doi: 0.4236/jbpc.2011.21005

Interaction of small aromatic molecules: An ab initio

studies on benzene and pyridine molecules

Bipul Bezbaruah, P. Hazarika, A. Gogoi, O.K. Medhi, C. Medhi*

Chemistry Department, Gauhati University, Guwahati, Assam, India; *Corresponding Author: chitrani@sify.com

Received 10 September 2010; revised 1 November 2010; accepted 22 November 2010.

ABSTRACT

The use of appropriate level of theories for

studying weak interactions such as stacking of

aromatic molecules has been an important as-

pect, since the high level methods have limita-

tions for application to large molecules. The

differences in the stacking energies of various

structures are found significant for identifying

the most favored stacked benzene rings and the

pyridine rings. The most favored structure of

benzene rings obtained from various methods

are similar, and also comparable with that of

reported accurate CCSD(T) method. The effect

of basis set in the stacking energies of MP2

calculations is small. Thus the moderately ac-

curate methods may be feasible for studying the

stacking interactions as demonstrated for ben-

zene and pyridine molecules.

Keywords: Ab Initio; Stacking; Basis Set; Benzene;

Pyridine

1. INTRODUCTION

The non bonded interactions between aromatic com-

pounds are considered to be an important aspect in bio-

logical systems, and other relevant areas like drug dis-

covery. These attractive intermolecular interactions are

also responsible for macromolecular aggregation, where

the medicinal property of a drug molecule may partly

depend on its recognition for a biological system [1-4].

The majority of medicinal agents contain aromatic sub-

stituents that provide one of the important groups related

to medicinal property. For example, the biological activ-

ity of many anticancer drugs, Amsacrine and Daunomy-

cin is believed to be related to the drug intercalation

within sequences of DNA, where the stacking interac-

tions between aromatic rings and base pairs usually take

place [1-4]. As a part of designing new intercalative

drugs, the stacking interactions between the aromatic

rings have been analyzed to achieve the sufficient struc-

tural requirement of the DNA binding domain of drugs.

So it is rather important to choose the most reliable

method to understand the structure and non-bonded in-

teractions of aromatic molecules. We note that the ben-

zene and the pyridine rings are the basic molecular parts

that constitute most biomolecules and drugs. At the first

sight, the stacking interactions of benzene-benzene and

pyridine-pyridine could represent the constituent units

for the stabilization of many large aromatic molecules.

So the studies on small aromatic molecules may be

given particular importance for better understanding of

stacking interactions among large aromatic molecules.

Ab initio calculations have been shown useful for

studying the non bonded interactions of aromatic mole-

cules [5-10]. The various levels of theories and basis sets

have been carefully chosen to calculate the interaction

energies of aromatic(-) and stacking types of interac-

tions that are responsible for the stabilization of double

helical DNA. It is evident that the studies of molecular

stacking require high level ab initio calculations. Many

theoretical studies are reported to predict the preferred

stacking interactions of benzene dimers, and thereby

provoking the importance of dipole-dipole and quadru-

pole-quadrupole interaction [5-6]. Similar studies on the

intermolecular interactions of cytosine dimers have been

calculated with MP2/6-31G** level, whereas less accu-

rate approach, the AMBER force field is also found use-

ful in certain cases despite of the lack of estimating dis-

persion energies in the calculations. The dispersion

forces, the short range exchange repulsions and electron

correlation are the essential factors for the overall as-

sessment of stacking interaction of molecules [7-10].

Comparison of different level of theories used in certain

investigations clearly indicate the choice of reasonably

accurate method that include proper basis set as well as

electron correlation in the calculations. As we know that

the London dispersion force is the instrumental binding

of stacked molecules, which is not described by Har-

tree-Fock theory. Therefore, the correlated descriptions

of electrons are must to produce even a qualitatively

accurate picture of weakly interacted molecules. It

B. Bezbaruah et al. / Journal of Biophysical Chemistry 2 (2 011) 32-36

should be noted that several newly developed functional

have shown to provide acceptable results for this type of

intermolecular interactions [10-13].

However, this method is still rather expensive for

large molecules, and it can only be applied to small

molecules such as benzene dimers. The CCSD(T)

method is currently believed to be the most accurate for

computing dispersion interactions provided the basis set

of aug-cc-pVTZ is included in the calculations [9-14].

The computational cost required for larger molecules

does not permit the application of accurate ab initio

methods. After thorough survey of the available studies

on the molecular stacking of small aromatic rings, there

are certain issues that need to be reinvestigated. The

present investigation aims to test the different level of ab

initio methods in predicting the stability of benzene and

pyridine dimers [15].

2. METHODOLOGY

The completely optimized geometries of benzene and

pyridine molecules with HF/6-31G** were taken for

calculating stacking energies. Single point calculations

on the stacked models have been carried out with MP2

as well as HF methods with some chosen basis set. The

two benzene rings may stack either in eclipsed (exact

- sandwiched form) or in staggered configuration

(Figure 1a). All the stacked configurations of benzene

rings have been analyzed by rotating the upper benzene

through different angles about the vertical axis at fixed

vertical separation (optimum distance of 3.3 Å). The

(a)

(b) (c)

Figure 1. (a) Staggered model of two stacked benzene mole-

cules, (b) Optimum stacked structure for lateral shifting along

positive axes with origin(0,0) for complete stacking, and (c)

Optimum stacked structure for lateral shifting along negative

axes with origin(0,0) for complete stacking.

single point calculations have been performed for all the

structures. The eclipsed form has been taken for con-

structing various stacked models by shifting one benzene

ring laterally along the plane of the other, and the most

favorable structures are shown in Figures 1b and 1c.

The interaction energies are computed from the fol-

lowing equation.

Interaction energies= EST – 2EM

EST and EM are the energies of stacked model and

monomer. All the calculations are carried out with Gaus-

sian 03 program code [15].

3. RESULTS AND DIS CUSSION

The relative changes of the stacking energies (MP2)

of different stacked benzene rings are shown in Figure 2,

and certain stable structures are located from the local

minima in the potential energy plots. However the cor-

responding potential energy plots of HF calculations

shown in Figure 3 cannot explain the stacking stabiliza-

tion of two benzene rings. The single point calculations

of all stacked models have been performed in this study,

since the complete geometry optimization may not be

advantageous to locate the local optimum structures. The

nature of the potential energy plots of MP2 and HF cal-

culations shown in Figures 2 and 3 is similar, but the HF

calculation fail to locate the local minima for stable

structures. The values are found significantly different,

and the MP2/6-31+G(d,p) and MP2/6-31+G(df,p) cal-

culations could estimate large negative interaction ener-

gies compared to that of HF calculations.

It is not surprising that the interaction energies of

HF/6-31G** and HF/6-31+G(d,p) calculations are all

positive, which is definitely due to the lack of dispersion

energies with these calculations. The series of results

could provide prior necessity of dispersion forces for the

stabilization of these stacked molecules. The results of

HF and MP2 level of theories reflect the extent of dis-

persion energies accounted in all these calculations. In-

deed, the electron correlations included in MP2 level

with diffused function in the basis set could estimate

more negative stacking energies, where the increase of

diffuse function in the basis set provides little change in

the energy values.

As we know that the stacking energies obtained from

HF calculation include columbic, induction, exchange

and some electron correlation energies, and the intermo-

lecular electron correlation necessary for the stabiliza-

tion of these stacked molecules cannot be calculated

with this method. However the stacking energies ob-

tained from this method may be taken for comparison

with the MP2 results. The present studies focus how the

stacking energies can be improved with the inclusion of

B. Bezbaruah et al. / Journal of Biophysical Chemistry 2 (2 011) 32-36

-6

-5

-4

-3

-2

-3.5 -2.5-1.5 -0.50.51.52.53.5

Lateral shifting (Ǻ)

Stacking energies

(kcal/mol)

MP2/6-31G** MP2/6-31+G(d,p) MP2/6-31+G(df,p)

Figure 2. Plots of benzene-benzene stacking energies versus lateral shifting in angstrom

with different basis sets in the MP2 method (for benzene-benzene staggered models).

-3.5-2.5 -1.5 -0.50.51.52.53.5

Lateral shifting (Ǻ)

Stacking energies

(kcal/mol)

HF/6-31G** HF/6-31+G(d,p)

Figure 3. Plots of benzene-benzene stacking energies versus lateral shifting in

angstrom with different basis sets in the HF method (for benzene-benzene stag-

gered models).

Table 1. Computed stacking energies of benzene-benzene and pyridine-pyridine rings for optimized stacked models with different

basis sets.

Stacking energies (kcal/mol)

Benzene-Benzene Pyridine-Pyridine

Basis sets

Eclipsed Staggered Eclipsed Staggered

HF/6-31G** 2.174 3.051 1.611 2.886

HF/6-31+G(d,p) 3.318 3.105 2.571 3.515

MP2/6-31G** -3.149 -3.898 -3.075 -6.236

MP2/6-31+G(d,p) -5.447 -5.594 -4.971 -6.448

MP2/6-31+G(df,p) -4.591 -5.506 -3.258 -6.462

diffused functions in the HF and MP2 level of calcula-

tions. The computed stacking energies of optimum

structures with various levels of calculations are summa-

rized in Table 1.

It may be noted that the difference of stacking ener-

gies obtained from HF/6-31G** and MP2/6-31G** cal-

culations is significantly large, whereas values of

MP2/6-31G**, MP2/6-31+G(d,p) and MP2/6-31+G(df,p)

are not so different (Table 1). However the most expen-

sive method, MP4 level of theory is particularly used in

most calculations on stacking interactions, but such high

level calculations cannot be applied to large molecule of

research interests. For general application one must test

the low level methods as well to extract some informa-

B. Bezbaruah et al. / Journal of Biophysical Chemistry 2 (2 011) 32-36

-6

-3

-3.5 -2.5-1.5 -0.50.51.52.53.5

Lateral shifting (Ǻ)

Stacking energies

(kcal/mol)

BB-3.0 BB-3.2 BB-3.4 BB-3.6 BB-3.8

Figure 4. Plots of stacking energies versus lateral shifting in angstrom (Ǻ) of ben-

zene molecules at different intermolecular distances with MP2/6-31+G(d,p)

tion. The change in stacking energies determined by

MP2 method with 6-31+G(d,p) and 6-31+G(df,p) may

be appropriate for qualitative explanations of these

non-bonded weak interactions. Our results show that the

stacking energies do not considerably vary with the in-

clusion of more diffuse functions in the basis set. The

stacking energies obtained from MP2/6-31+G(d,p) cal-

culations are found much better than the reported values

of MP2 and CCSD(T) methods with aug-cc-pVQZ and

aug-cc-pVDZ basis set [7,9]. The reported CCSD(T)

energy is –2.72 kcal/mol with basis set correction,

whereas the values for MP2/6-31+G(d,p) and

MP2/6-31+G(df,p) without basis set correction are

–5.447 kcal/mol and –4.591 kcal/mol. The single-point

MP2 calculations with 6-31+G(d,p) basis set have been

found useful in describing the stability of stacked ben-

zene and pyridine molecules. The calculated interaction

energies with 6-31+G(df,p) basis set does not show

much variation from that of 6-31+G(d,p) basis set (Table

1, Figure 2). The basis set superposition error at the

MP2 level is not so essential although there may be

slight effect on the dispersion energies.

Although the HF and other low level methods cannot

be used to calculate accurate stacking energies, it may be

useful for predicting at least the stabilization of counter

molecules qualitatively. As we can see that both the HF

and MP2 methods can locate similar regions for the sta-

bilization of stacked structures (Figures 2 and 3).

It is also important to locate the most favored -

stacking distance, so the stacking energies of two ben-

zene molecules at different vertical separations have

been calculated and the distance(vertical and lateral)

dependent variation of stacking energies are shown in

Figure 4. The stacked structures located within certain

conformational spaces of two benzene are found favor-

able as predicted from the results of MP2/6-31G(d,p)

calculations. The maxima and minima in the curves in-

dicate the two distinguishable regions of total and partial

stacking of aromatic rings(Figure 2, Figures 1(a-c)).

The repulsive interaction is found prominent in the total

stacking of the aromatic rings, and the maximum points

in the curves represent the unstable structures. Also the

repulsive interaction is found maximum at 3.0 Ǻ, and

gradually decreases due to the increase of electrostatic

interaction energies at longer distances.

As shown in Table 1, the extent of dispersion energies

included in the stacking energies of MP2/6-31G**,

MP2/6-31+G(d,p) and MP2/6-31+G(df,p) calculations

of benzene and pyridine molecules is distinct, whereas

the HF/6-31G** calculation cannot usually estimate

dispersion energies.

4. CONCLUSIONS

The extent of dispersion forces included in various cal-

culations may be useful for monitoring relative variation

of stacking interactions of aromatic molecules. The re-

sults of MP2 studies and the reported CCSD(T) calcula-

tions can provide similar information on the stacking of

benzene rings. Hence the MP2/6-31G+(d,p) and

MP2/6-31+G(df,p) may be feasible for explaining the

- type of stacking interaction qualitatively, and the

method may be applied to the computation of large

stacked molecules instead of other high level expensive

techniques.

5. ACKNOWLEDGMENTS

The authors thank Department of Science and Technology and Coun-

cil of Scientific Research, New Delhi, India, for financial assistance.

B. Bezbaruah et al. / Journal of Biophysical Chemistry 2 (2 011) 32-36

REFERENCES

[1] Castonguay, L.A., Rappe´, A.K. and Casewit, C.J. (1991)

Π-stacking and the platinum-catalyzed asymmetric hy-

droformylation reaction: A molecular modeling study.

Journal of the American Chemical Society, 113(19),

7177–7183.

doi:10.1021/ja00019a013

[2] Kolb, H.C., Andersson, P.G. and Sharpless, K.B. (1994)

Toward an understanding of the high enantioselectivity in

the osmium-catalyzed asymmetric dihydroxylation (AD).

1. Kinetics. Journal of the American Chemical Society,

116(4), 1278–1291.

doi:10.1021/ja00083a014

[3] Smith, D.A., Ulmer II, C.W., and Gilbert M.J. (1992)

Structural studies of aromatic amines and the dna

intercalating compounds m-amsa and o-amsa:

Comparison of mndo, am1, and pm3 to experimental and

ab initio results. Journal of Computational Chemistry, 13

(5), 640.

doi: 10.1002/jcc.540130514

[4] Barone, G., Guerra, C.F., Gambino, N., Silvestri, A.,

Lauria, A., Almerico, A.M. and Bickelhaupt, F.M. (2008)

Intercalation of daunomycin into stacked DNA base pairs.

DFT study of an anticancer drug. Journal of Biomolecu-

lar Structure and Dynamics, 26(1), 115-30.

[5] Gilman, A.G., Rall, T.W., Mies, A.S. and Taylor, P. (1993)

The pharmaceutical basis of therapeutics. 8th Ed.,

McGraw Hill, Inc., New York.

[6] Ishida, T., Doi, M., Ueda, H., Inoue, M. and Scheldrick,

G.M. (1988) Specific ring stacking interaction on the

tryptophan-7-methylguanine system: Comparative crys-

tallographic studies of indole derivatives-7-methylguani-

ne base, nucleoside, and nucleotide complexes. Journal

of the American Chemical Society, 110 (7), 2286–2294

doi:10.1021/ja00215a046

[7] Hobza, P., Selzle, H.L. and Schlag, E.W. (1994) Potential

energy surface of the benzene dimer: Ab initio theoretical

study. Journal of the American Chemical society, 116(8),

3500-3506.

doi:10.1021/ja00087a041

[8] Bernstein, E.R., Sun, S. (1996) Aromatic van der waals

clusters: Structure and nonrigidity. Journal of Physical

Chemistry, 100(32), 13348-13366.

doi:10.1021/jp960739o

[9] Hobza, P., Selzle, H.L., Schlag, E.W. (1996) Potential

energy surface for the benzene dimer. Results of ab initio

CCSD(T) calculations show two nearly isoenergetic

structures: T-Shaped and parallel-displaced. Journal of

Physical Chemistry, 100(48), 18790.

doi:10.1021/jp961239y

[10] Tsuzuki, S., Honda, K., Uchimaru, T., Mikami, M. and

Tanabe, K. (2002) Origin of attraction and directionality

of the π-π interaction: Model chemistry calculations of

benzene dimer interaction. Journal of the American

Chemical Society, 124(1), 104-112.

doi:10.1021/ja0105212

[11] Sinnokrot, M.O., Valeev, E. F. and Sherrill, C.D. (2002),

Estimates of the ab initio limit for π-π interactions: The

benzene dimer. Journal of the American Chemical Soci-

ety, 124(36), 10887-10893.

doi:10.1021/ja025896h

[12] Zhikol, O.A., Shishkin, O.V., Lyssenko, K.A. and

Leszczynski, J. (2005) Electron density distribution in

stacked benzene dimers: A new approach towards the es-

timation of stacking interaction energies. Journal of

Chemical Physics, 122(14), 144104.

doi:10.1063/1.1877092

[13] Parthasarathi, R., Subramanian, V. (2005) Stacking in-

teractions in benzene and cytosine dimers: From mo-

lecular electron density perspective. Structural Chemistry,

16(3), 243-255.

doi:10.1007/s11224-005-4455-8

[14] Steven, E.W., Anne, J.M, Peter, M, Timothy, M.S, and

Houk, K.N. (2010) Probing substituent effects in

aryl-aryl interactions using stereoselective diels-alder

cycloadditions. Journal of the American Chemical Soci-

ety, 132(10), 3304-3311.

doi:10.1021/ja903653j

[15] Frisch, M.J., Trucks, G.W., Schlegel, H.B., Gill, P.M.W.,

Johnson, B.G., Robb, M.A., Cheeseman, J.R., Keith, T.,

Petersson, G.A., Montgomery, J.A., Raghavachari, K.,

Al-Laham, M.A., Zakrzewaki, V.G., Ortiz, J.V., Fores-

mann, J.B., Ciolowski, J., Stefanov, B.B., Namayakkara,

A., Challacombe, M., Peng, C.Y., Ayala, P.Y., Chen, W.,

Wong, M.W., Andres, J.L., Replogle, E.S., Gomperts, R.,

Martin, R.L., Fox, D.J., Binkley, J.S., Defrees, D.J.,

Baker, J., Stewart, J. P., Head-Gordon, M., Gonzalez, C.,

and Pople, J.A.. Gaussian 03, Gaussian Inc., Pittsburgh

PA.