This journal is© the Owner Societies 2014 Phys. Chem. Chem. Phys.

Cite this:DOI: 10.1039/c3cp54169j

Competition between n - pAr* and conventionalhydrogen bonding (N–H� � �N) interactions: anab initio study of the complexes of 7-azaindoleand fluorosubstituted pyridines†

Santosh K. Singh, Sumit Kumar and Aloke Das*

In this work, we have investigated a subtle competition between a very weak n - pAr* interaction and a

very strong hydrogen bond (N–H� � �N) interaction present in the complexes of 7-azaindole with a series

of 2,6-substituted fluoropyridines and observed how the weak interaction modulates the overall

structural motif of these complexes in the presence of the strong interaction. We have studied the

structures and binding energies of these complexes using MP2 as well as dispersion-corrected DFT

calculations. It has been found that the strength of the N–H� � �N interaction in these complexes

decreases with increasing fluorination in the fluoropyridine ring while the proximity between the nitro-

gen atom in 7-azaindole and the aromatic ring of fluoropyridine increases through n - pAr* interaction.

Comparison of the binding energy values as well as structural parameters of these complexes calculated

at the B3LYP level with those obtained at the MP2, M05-2X, and B97-D levels of theory clearly indicates

that the dispersion effect is mostly responsible for this attractive n - pAr* interaction. This conclusion is

also supported by localized molecular orbital-energy decomposition analysis (LMO-EDA). The current

investigation is the first theoretical study on the n - pAr* interaction in the presence of a conventional

strong hydrogen bonding interaction in the molecular system. Thus the present study has great

significance for understanding the structures of the biomolecules as well as materials, as these

interactions are very often present there simultaneously.

Introduction

Supramolecular structures of biomolecules as well as importantbiological recognition processes i.e. protein–DNA, protein–protein,protein–carbohydrate, and protein–ligand interactions, aregoverned by a subtle balance among various weak non-covalentinteractions.1–10 These non-covalent interactions, which are alsothe backbones of the structures of the materials,11–13 generallyrange from conventional strong hydrogen bonding (O–H� � �O,N–H� � �O etc.) to unconventional weak hydrogen bonding(C–H� � �O, C–H� � �N etc.), p-hydrogen bonding (O–H� � �p,N–H� � �p, C–H� � �p, etc.), and dispersion dominated p-stackinginteractions. Undoubtedly, these intermolecular interactions,which rule the biological recognition processes as well assupramolecular structures in biology and materials, are well

recognized by the scientific community for many decades. But,very recently, a previously unexplored and counter-intuitiveweak non-covalent interaction named as lone pair (n) - p*interaction has been proved to be of significant importance inthe stabilization of the structures of the biomolecules as well asmaterials.14–51

The n - p* interactions reported in the literature aregenerally of two types: n - pAm* (amide) and n - pAr*(aromatic).39 The n - pAm* interaction is the delocalizationof the lone pair (lp) electrons on the oxygen atom of a carbonylgroup into the p* orbital of an adjacent carbonyl group generallypresent in the backbone of the proteins.14,39 This interactionfollows the Burgi–Dunitz trajectory (O� � �CQO distance r 3.2 Åand +O� � �CQO = 109 � 101) required for optimal overlap duringthe nucleophilic attack at the carbonyl carbon.52–55 On the otherhand, the n - pAr* interaction occurs through the overlapbetween the lone pair (lp) electrons on an electronegative atom(e.g. oxygen of a carbonyl group) with the p* orbitals of anaromatic ring.19,39,42,43 In this case, the geometrical requirementsfor the optimum interaction are given by the distance between thecarbonyl oxygen and the aromatic ring centroid (2.8–3.8 Å) as wellas the angle between the aryl and carbonyl planes (r901).19,39

Department of Chemistry, Indian Institute of Science Education and Research (IISER),

Dr Homi Bhabha Road, Pune-411008, Maharashtra, India.

E-mail: a.das@iiserpune.ac.in, aloke.das73@gmail.com

† Electronic supplementary information (ESI) available: Tables for the geome-trical parameters and decomposition of the total interaction energies of thecomplexes; NBO pictures of all the n - pAr* complexes. See DOI: 10.1039/c3cp54169j

Received 3rd October 2013,Accepted 31st October 2013

DOI: 10.1039/c3cp54169j

www.rsc.org/pccp

PCCP

PAPER

Publ

ishe

d on

04

Nov

embe

r 20

13. D

ownl

oade

d by

Ind

ian

Inst

itute

of

Scie

nce

Edu

catio

n &

Res

earc

h Pu

ne o

n 12

/12/

2013

10:

38:2

3.

View Article OnlineView Journal

Phys. Chem. Chem. Phys. This journal is© the Owner Societies 2014

The widespread presence of the n - p* interactions inproteins, nucleic acids, and solid state materials has also beendocumented from an extensive search of the X-ray crystalstructures in the Protein Data Bank (PDB) as well as CambridgeStructural Database (CSD).14,19,28,29,42–45 The n - pAr* interactionin the biological macromolecules was first reported by Egli andco-workers who demonstrated that the interaction of a lp ofdeoxyribose oxygen and adjacent guanidine base provides thestability in Z-DNA.28 Later, Egli and co-workers found out then - pAr* interaction between the lp on the oxygen of water and anucleobase in an RNA pseudoknot by employing high-resolutionX-ray crystallography.29 Exhaustive analysis of the protein crystalstructures has been performed by Sankararamakrishnan andco-workers who have pointed out the interactions between thecarbonyl oxygen and aromatic ring in the crystal structures ofabout 500 proteins.42,43 On the material front, a triazine-basedsupramolecular self-assembly shows the first evidence of then - pAr* interaction in the solid state.45,47–49 This interactionhas been named as a new supramolecular bond by Reedijk andco-workers who have done a thorough systematic search of then - pAr* interaction in the crystal structures deposited in theCSD.45

Although the n - p* interactions are ubiquitous, due to itscounter-intuitive nature, this interaction has been verified by variouscomputational methods to assess that the lp� � �p short contacts arenot merely due to the effect of the orientation of different structuralunits in the supramolecular systems.14–19,32–35,42,43 One of thevery first ab initio studies on the n - pAr* interaction is on thewater� � �hexafluorobenzene interaction as reported by Doughertyand co-workers.15 The origin of this non-covalent interaction hasalso been verified by studying cis/trans ratios in polypeptides,peptoids and thiopeptoids through NMR spectroscopy.16,22,24,27,39,50

These studies have strongly indicated that this non-covalentinteraction is neither charge–charge nor dipole–dipole but ratheran n - pAm* interaction. Very recently Amicangelo et al. havestudied the C6F6� � �H2O complex using matrix isolation IRspectroscopy and demonstrated that the stability of the complexis due to the n - pAr* interaction.35 It has also been reported bya few groups from theoretical calculations that the origin of theattractive n - pAr* interaction stems mainly from dispersioneffects.33,34

In spite of various computational investigations on the n -

p* interaction reported in the literature, most of the studiesare limited to the interaction between two carbonyl groups inthe polypeptides or an aromatic ring with either the lp of thecarbonyl group or the oxygen atom in water molecule. In thecurrent study, we have reported the n - pAr* interactionbetween the p-electron cloud of several fluorosubstituted pyridinesand a nitrogen lp of the pyridine moiety of 7-azaindole (7-AI),which is a model for the nucleic acid base adenine. The presentstudy also mimics the n - pAr* interaction present in the Z-DNA,which is reported by Egli and co-workers.28 This is the firsttheoretical study of the n - p* interaction in a system containinga strong N–H� � �N hydrogen bonding interaction. The mostsignificant part of the current investigation is to determinethe competition between a strong hydrogen bonding and a

weak n - p* interaction and how the latter one modulates thestructures of the molecular systems in the presence of theformer interaction. Our results also demonstrate that the n - p*interaction originates mostly due to the dispersion energy.

Here, we have investigated the structures, binding energies,and different components of the interaction energies of thecomplexes between 7-AI and all different types of fluorosubstitutedpyridines including the 2,6-substituted ones by using various wavefunctions as well as density functional theory calculations. In fact,the 7-AI� � �2-FP (2-fluoropyridine) complex has been studied pre-viously by both experiment as well as theory and a planar doublehydrogen bonded (N–H� � �N and C–H� � �N) structure of the complexhas been observed in the experiment.56 The present theoreticalstudy mostly focuses on how the fluorine substitution at specificpositions (2 and 6) in the pyridine ring introduces a new non-covalent interaction (n - p*), which replaces the C–H� � �Ninteraction as well as affects the strong N–H� � �N interaction inthe complex and modulates the overall structure.

Computational details

All the calculations except the energy decomposition analysis(EDA) were performed using the Gaussian 09 program pack-age.57 EDA was done using a localized molecular orbital (LMO)method introduced by Su et al.58 and implemented in GAMESS,USA.59 Various structures of the complexes of 7-AI with fluoro-substituted pyridines were optimized at the MP2 as well asB3LYP, M05-2X, and B97-D levels of theory using various basissets. Vibrational frequency calculations of all the optimizedstructures of the complexes were performed to confirm whetherthese are stable minima. An ultrafine numerical integrationgrid was used for all the DFT calculations. Binding energies ofvarious structures of the complexes were corrected from thebasis set superposition error (BSSE) using the counterpoisemethod of Boys and Bernardi.60 Natural bond orbital (NBO)analysis was performed using the NBO program available in theGaussian 09 software.61

Results and discussionStructures of the complexes

In the case of the 7-AI� � �2-FP complex reported in the literature,two in-plane double hydrogen bonded cyclic structures havebeen predicted from DFT calculations.56 It has been found thatthe structure with the N–H� � �N and C–H� � �N hydrogen bondsis more stable by about 2.5 kcal mol�1 than the one with theN–H� � �F and C–H� � �N hydrogen bonds. Only the most stablestructure of the dimer has been observed in the gas phaseexperiment.56 We have explored here the complexes of 7-AI withall other fluorinated pyridines through an ab initio study. Thefluorinated pyridines considered in this work for complexformation are 2-fluoropyridine (2-FP), 3-fluoropyridine (3-FP),4-fluoropyridine (4-FP), 5-fluoropyridine (5-FP), 2,3-difluoro-pyridine (2,3-FP), 2,4-difluoropyridine (2,4-FP), 2,5-difluoro-pyridine (2,5-FP), 2,6-difluoropyridine (2,6-FP), 3,5-difluoropyridine

Paper PCCP

Publ

ishe

d on

04

Nov

embe

r 20

13. D

ownl

oade

d by

Ind

ian

Inst

itute

of

Scie

nce

Edu

catio

n &

Res

earc

h Pu

ne o

n 12

/12/

2013

10:

38:2

3.

View Article Online

This journal is© the Owner Societies 2014 Phys. Chem. Chem. Phys.

(3,5-FP), 4,5-difluoropyridine (4,5-FP), 2,3,4-trifluoropyridine(2,3,4-FP), 2,3,5-trifluoropyridine (2,3,5-FP), 2,3,6-trifluoro-pyridine (2,3,6-FP), 2,4,5-trifluoropyridine (2,4,5-FP), 2,4,6-tri-fluoropyridine (2,4,6-FP), 3,4,5-trifluoropyridine (3,4,5-FP),2,3,4,5-tetrafluoropyridine (2,3,4,5-FP), 2,3,4,6-tetrafluoropyridine(2,3,4,6-FP), 2,3,5,6-tetrafluoropyridine (2,3,5,6-FP), and 2,3,4,5,6-pentafluoropyridine (2,3,4,5,6-FP). As the focus of the present workis on the competition between the N–H� � �N hydrogen bond andn - pAr* interactions, we will discuss only those structures ofthe complexes which contain N–H� � �N hydrogen bond. Fig. 1shows the most stable double hydrogen bonded structure(N–H� � �N and C–H� � �N bound) of all the complexes of 7-AI withfluoropyridines optimized at the M05-2X/cc-pVTZ level of theory.It has been found that all the fluoropyridines except the oneswith fluorine substitutions at both 2 and 6 positions form thistype of complex with 7-AI. The atom numbering scheme in thefluoropyridine has been shown in one of the complexes presentedin Fig. 1. Binding energies of these complexes calculated at theM05-2X/cc-pVTZ level of theory have been provided in Table 1.

A few selected intermolecular geometrical parameters(hydrogen bond distances and angles) of these complexes havealso been provided in Table 2. It seems from the data presentedin Tables 1 and 2 that there are no overall drastic changes in thegeometry as well as stability of these complexes by increasingthe number of fluorine substitutions in the pyridine molecule.It is, however, obvious that there is a systematic increase in theN–H� � �N hydrogen bond distance and decrease in the C–H� � �Nhydrogen bond distance with increasing fluorination of the FPmolecule. But it is quite interesting to see how the N–H� � �Nbound structure of the fluorosubstituted complexes of 7-AIchanges for the fluorine substitution at 2 and 6 positions ofpyridine simultaneously. Fig. 2 shows the initial and final

structures of the complexes of 7-AI with 2,6-FP, 2,4,6-FP,2,3,6-FP, 2,3,4,6-FP, 2,3,5,6-FP and 2,3,4,5,6-FP. The optimizationof the initial structures has been done at the M05-2X/cc-pVTZlevel of theory. It is obvious that the fluoropyridines havingfluorine substitutions at the 2 and 6 positions cannot make theC–H� � �N hydrogen bond with 7-AI while the N–H� � �N hydrogenbond is present there. Thus we have considered the initialgeometries of these six complexes provided in Fig. 2 as non-planar where the interplanar angle between 7-AI and fluoro-pyridine is 901 and only one hydrogen bond (N–H� � �N) ispresent. It is intriguing to note that the initial structure of allthe six complexes converges to a similar geometry which has acounter-intuitive attractive interaction between the nitrogen

Fig. 1 Double hydrogen bonded structures of all the complexes of 7-AI with fluoropyridines optimized at the M05-2X/cc-pVTZ level of theory.

Table 1 Binding energies (kcal mol�1) of all the double hydrogen bondedcomplexes of 7-AI and fluoropyridines calculated at the M05-2X/cc-pVTZlevel of theory

DEe DE0

7-AI� � �2-FP �8.18 �7.427-AI� � �3-FP �8.02 �7.237-AI� � �4-FP �8.38 �7.537-AI� � �5-FP �8.01 �7.167-AI� � �2,3-FP �7.74 �7.027-AI� � �2,4-FP �8.17 �7.397-AI� � �2,5-FP �7.88 �7.107-AI� � �3,5-FP �7.65 �6.867-AI� � �4,5-FP �8.03 �7.277-AI� � �2,3,4-FP �7.81 �7.037-AI� � �2,3,5-FP �7.50 �6.787-AI� � �2,4,5-FP �7.96 �7.237-AI� � �3,4,5-FP �7.73 �6.967-AI� � �2,3,4,5-FP �7.62 �6.92

DEe: BSSE corrected binding energy; DE0: BSSE + ZPE (zero pointenergy) corrected binding energy.

PCCP Paper

Publ

ishe

d on

04

Nov

embe

r 20

13. D

ownl

oade

d by

Ind

ian

Inst

itute

of

Scie

nce

Edu

catio

n &

Res

earc

h Pu

ne o

n 12

/12/

2013

10:

38:2

3.

View Article Online

Phys. Chem. Chem. Phys. This journal is© the Owner Societies 2014

atom of the pyridine moiety of 7-AI and the aromatic ring of thefluoropyridine (FP) moiety in addition to the presence of thestrong N–H� � �N hydrogen bonding interaction. This non-covalent interaction between the lone pair of electrons on thenitrogen atom of the pyridine moiety of 7-AI and the p-electroncloud of fluoropyridine is termed as a lp� � �p or n - pAr*interaction, which brings the nitrogen atom and the aromaticring close to each other resulting in additional stability of thestructure.

Fig. 3a shows the definition of a few important intermole-cular geometrical parameters of the n - pAr* complexes of 7-AIand fluorosubstituted pyridines. The N–H� � �N hydrogen bond

distance and angle are denoted by dN–H� � �N and yN–H� � �N, respec-tively. The parameter RN� � �Ar indicates the distance between thenitrogen atom of 7-AI and the centroid of the aromatic ring ofthe fluoropyridine, and this distance dictates the strength ofthe n - pAr* interaction. Fig. 3b–d show the plots of the RN� � �Ar,dN–H� � �N and yN–H� � �N values as a function of the increase of thefluorine substitution in the fluoropyridine moiety of the sixcomplexes of 7-AI with 2,6-substituted fluoropyridines calcu-lated at the B3LYP, M05-2X, B97-D and MP2 levels of theory. Inthe case of the M05-2X level, the data have been presented forboth cc-pVTZ and aug-cc-pVDZ (aVDZ) basis sets but only aVDZbasis set has been used for other levels of calculation. Thevalues corresponding to the Fig. 3b–d are also tabulated inTable S1 in the ESI.† It is quite obvious from the resultsprovided in Fig. 3b that the RN� � �Ar values in the six complexesof 7-AI with 2,6-substituted fluoropyridines calculated at all thelevels of theory except the B3LYP one falls in the regime of thedesignated distance (2.8–3.8 Å) for the n - pAr* interactionreported in the literature.19,39 It is important to note that theRN� � �Ar values of the complexes obtained at the B3LYP level oftheory are very far away from those calculated at other levels oftheory. This result clearly indicates that the dispersion force isthe primary origin of the n - pAr* interaction. B3LYP theoryfails to provide the right value of RN� � �Ar as it does not considerany dispersion interaction. On the other hand, the RN� � �Ar valuescalculated at the MP2 level clearly show an overestimation ofthe dispersion interaction.

It is also observed from Fig. 3b that the RN� � �Ar valuegradually decreases with increasing the number of fluorinesubstitutions in the fluoropyridine moiety of the complexes at

Table 2 Intermolecular geometrical parameters (hydrogen bond distancesand angles) of the double hydrogen bonded complexes of 7-AI andfluoropyridines calculated at the M05-2X/cc-pVTZ level of theory

dN–H� � �N (Å) dC–H� � �N (Å) a (1) b (1)

7-AI� � �2-FP 2.04 2.48 165 1497-AI� � �3-FP 2.02 2.47 168 1527-AI� � �4-FP 2.01 2.45 168 1527-AI� � �5-FP 2.02 2.44 167 1507-AI� � �2,3-FP 2.07 2.46 164 1497-AI� � �2,4-FP 2.06 2.44 163 1497-AI� � �2,5-FP 2.08 2.42 162 1477-AI� � �3,5-FP 2.05 2.42 166 1507-AI� � �4,5-FP 2.04 2.40 165 1507-AI� � �2,3,4-FP 2.08 2.42 163 1507-AI� � �2,3,5-FP 2.10 2.41 161 1487-AI� � �2,4,5-FP 2.09 2.39 161 1487-AI� � �3,4,5-FP 2.06 2.39 165 1517-AI� � �2,3,4,5-FP 2.12 2.36 160 149

dN–H� � �N, dC–H� � �N, a, and b are defined in Fig. 1.

Fig. 2 The initial and final structures of the complexes of 7-AI with 2,6-FP, 2,4,6-FP, 2,3,6-FP, 2,3,4,6-FP, 2,3,5,6-FP and 2,3,4,5,6-FP optimized at theM05-2X/cc-pVTZ level of theory.

Paper PCCP

Publ

ishe

d on

04

Nov

embe

r 20

13. D

ownl

oade

d by

Ind

ian

Inst

itute

of

Scie

nce

Edu

catio

n &

Res

earc

h Pu

ne o

n 12

/12/

2013

10:

38:2

3.

View Article Online

This journal is© the Owner Societies 2014 Phys. Chem. Chem. Phys.

all the levels of theory including the B3LYP. This result indicatesthat there is an increase in the electrostatic interaction between thenitrogen atom of the 7-AI and p-electron cloud of the FP with theincrease in the number of the fluorine atoms. Thus the n - pAr*interaction is facilitated through the increase of fluorine substitu-tions in the pyridine ring by making it electron deficient. But itshould be noted that the close proximity between the nitrogen atomand the aromatic ring is mostly due to the dispersion dominatedn - pAr* interaction, otherwise the B3LYP theory would give thecorrect result. At this point it is worth discussing the interactionbetween the 7-AI molecule and fluorine atoms in the FP incontributing to the final shape of the complexes shown in Fig. 2.As the polarizability of the fluorine atom is very low, the dispersioninteraction between the fluorine atoms and 7-AI molecule is negli-gible. But there will be very weak electrostatic interaction betweenthe 7-AI molecule and fluorine atoms in FP and this interaction is ofcourse much weaker compared to the N–H� � �N hydrogen bond andn - pAr* interactions present in the complexes.

The plots in Fig. 3c and d show that there is an increase inthe N–H� � �N hydrogen bond distance (dN–H� � �N) and decrease inthe N–H� � �N angle (yN–H� � �N) as the fluorine substitution in thepyridine ring increases. Similar trends have been observed atall the levels of calculation. The dN–H� � �N and yN–H� � �N values

calculated at the M05-2X/cc-pVTZ level of theory in the sixcomplexes of 7-AI with the 2,6 substituted fluoropyridines arein the range of 2.20–2.33 Å and 143–1391, respectively, while thecorresponding values in the double hydrogen bonded complexes of7-AI and fluoropyridines are 2.01–2.12 Å and 168–1601, respectively(see Table 2). According to the definition, the hydrogen bond isstronger the closer the hydrogen bond angle is to 1801, as well asthe smaller the hydrogen bond distance is.62 Thus it is noteworthythat the strength of the n - pAr* interaction increases at the cost ofa decrease in the strength of the conventional hydrogen bondinginteraction. It is quite spectacular to note here that despite thesubtle competition between the strong hydrogen bonding andweak n - pAr* interactions in the structures of these complexes,it is mostly the latter interaction that modulates the specificgeometry shown in Fig. 2.

Binding energies of the complexes of 7-AI with 2,6-substitutedfluoropyridines

It is quite interesting to see how the binding energies of thesen - pAr* bound complexes of 7-AI and fluorosubstitutedpyridines get affected by increasing the fluorine substitutionin the fluoropyridine ring. Fig. 4 shows the plots of the BSSE-corrected binding energies (DEe) of the complexes of 7-AI with

Fig. 3 (a) Definition of a few important intermolecular geometrical parameters of the n-pAr* complexes of 7-AI with 2,6-substituted fluoropyridines.(b)–(d) Plots of the RN� � �Ar, dN–H� � �N and yN–H� � �N values of the six complexes of 7-AI with 2,6-substituted fluoropyridines calculated at the B3LYP, B97-D,MP2 and M05-2X levels of theory.

PCCP Paper

Publ

ishe

d on

04

Nov

embe

r 20

13. D

ownl

oade

d by

Ind

ian

Inst

itute

of

Scie

nce

Edu

catio

n &

Res

earc

h Pu

ne o

n 12

/12/

2013

10:

38:2

3.

View Article Online

Phys. Chem. Chem. Phys. This journal is© the Owner Societies 2014

2,6-substituted fluoropyridines as a function of the increase ofthe fluorine substitution in the fluoropyridine ring calculatedat the MP2 level as well as various levels of DFT using aVDZbasis set. A gradual increase in the binding energy (about0.3 kcal mol�1 increase for each fluorine substitution) of thecomplexes with increasing the fluorine substitution has beenobserved at the MP2, M05-2X, and B97-D levels of theory. Onthe other hand, it is fascinating to note that there is a decreasein the binding energy of the complexes with increasing fluorinesubstitution at the B3LYP level of theory. This decrease in thebinding energy at the B3LYP level is observed as the strength ofthe N–H� � �N hydrogen bond decreases with increasing fluorinesubstitution in the fluoropyridine moiety of the complexes andthe B3LYP theory does not include the dispersion interaction,which is the origin of the n - pAr* interaction present there. Itcould be argued that the B3LYP theory would show systematicincrease in the binding energy of these complexes with increasingfluorine substitution in the fluoropyridine ring if the close proximityof the electron deficient aromatic ring and nitrogen atom in 7-AIwas governed by mostly electrostatic interactions.

In fact, it has been found that the binding energies of thecomplexes of 7-AI with 2,6-substituted fluoropyridines calculatedat the B3LYP level of theory are lower by about 3–4 kcal mol�1

relative to those obtained at the B97-D level of theory. Thus it isproved from the comparison of the results obtained from theB3LYP and dispersion-corrected DFT (B97-D, M05-2X) as well asMP2 calculations that the nitrogen atom in 7-AI and fluoro-pyridine ring come close to each other due to the n - pAr*interaction dominated by the dispersion forces. Recently, Yanget al. have investigated the n - pAr* interaction in the com-plexes of benzene and amines by using MP2 as well as variousDFT calculations.34 They have found that the B97-D functional

is superior to other dispersion-corrected DFT functionals forinvestigating structures containing the n - pAr* interaction.They have also reported that the B3LYP method does notprovide any minimum in the potential energy curves of thesecomplexes showing the variation of the intermolecular inter-action as a function of the intermolecular distance between thenitrogen lone pair and benzene ring in the complexes.

BSSE-corrected binding energies (DEe) of the complexes of7-AI with the 2,6-substituted fluoropyridines have also beencalculated using various other basis sets at the M05-2X level oftheory and this comparison has been presented in Table 3. It isinteresting to note that the binding energy values of all thecomplexes calculated at the M05-2X level using all the basis setsexcept the cc-pVDZ are very much similar. Thus it is obviousthat the cc-pVTZ basis set is sufficient enough to calculate thebinding energies of these complexes with reasonable accuracy.It is also apparent here that the basis set effect at the M05-2Xlevel is minimal if a basis set higher than cc-pVDZ is used.A similar kind of result has been reported recently for thep-stacked heterodimer of indole and hexafluorobenzene.63

Natural bond orbital (NBO) analysis

NBO analysis has been used for the quantitative determinationof the strength of the individual N–H� � �N and n - pAr* inter-actions present in the complexes of 7-AI with 2,6-substitutedfluoropyridines. In the case of the N–H� � �N hydrogen bondinginteraction, there is a charge transfer delocalization of the lonepair orbital on the nitrogen atom (nN(FP)) of the fluoropyridinering over the antibonding orbital of the N–H group (s*N–H(7-AI))of 7-AI. On the other hand, the n - pAr* interaction involvesdelocalization of the lone pair orbital of the nitrogen atom(nN(7-AI)) in the pyridine moiety of 7-AI over the antibondingp-orbitals (pFP*) of the fluoropyridine. The NBO interactionenergy is given by the second order perturbative energy E(2)

i-j*,where i and j denote the donor and acceptor orbitals, respec-tively.64 The E(2)

n-s* values for the N–H� � �N interaction as well asE(2)

n-p* values for the n - pAr* interaction in the complexes of7-AI with all the 2,6-substituted fluoropyridines calculated at theMP2/aVDZ level of theory have been provided in Table 4. In the caseof the n - pAr* interaction, the E(2)

n-p* value has a contribution fromthe overlap of the nN(7-AI) orbital with two antibonding p-orbitals(pCQN* and pCQC*) of fluoropyridine. The overlap between thedonor and acceptor orbitals involving the N–H� � �N and n -

pAr* interactions present in the 7-AI� � �2,3,4,5,6-FP complex hasbeen depicted in Fig. 5. For brevity, the overlap of the NBOs in

Fig. 4 Plots of the BSSE-corrected binding energies (DEe) of the com-plexes of 7-AI with 2,6-substituted fluoropyridines calculated at the MP2level as well as various levels of DFT.

Table 3 BSSE-corrected binding energies (DEe, kcal mol�1) of the com-plexes of 7-AI with the 2,6-substituted fluoropyridines calculated usingvarious basis sets at the M05-2X level of theory

cc-pVDZ cc-pVTZ cc-pVQZ aVDZ

7-AI� � �2,6-FP �4.90 �5.48 �5.47 �5.497-AI� � �2,4,6-FP �5.19 �5.86 �5.82 �5.857-AI� � �2,3,6-FP �5.04 �5.64 �5.60 �5.637-AI� � �2,3,4,6-FP �5.37 �6.05 �6.01 �6.037-AI� � �2,3,5,6-FP �5.24 �5.82 �5.76 �5.797-AI� � �2,3,4,5,6-FP �5.64 �6.27 �6.23 �6.26

Paper PCCP

Publ

ishe

d on

04

Nov

embe

r 20

13. D

ownl

oade

d by

Ind

ian

Inst

itute

of

Scie

nce

Edu

catio

n &

Res

earc

h Pu

ne o

n 12

/12/

2013

10:

38:2

3.

View Article Online

This journal is© the Owner Societies 2014 Phys. Chem. Chem. Phys.

the rest of the complexes of 7-AI with 2,6-substituted fluoropyr-idines has been provided in Fig. S1 of the ESI.†

The data presented in Table 4 reveal that there is no significantchange in the n - pAr* interaction energy (0.4–0.6 kcal mol�1)in the complexes with an increase of fluorination in the fluoro-pyridine. This trend in the E(2)

n-p* corresponds very well to theextremely slow decrease of the RN� � �Ar values of the complexespresented in Fig. 3b. It is important to note that the very smallmagnitude of the n - pAr* interaction energy of these com-plexes obtained here is quite reasonable because the twoaromatic moieties have a constraint to optimize this interactionin the presence of the strong N–H� � �N interaction. On the otherhand, the E(2)

n-s* value decreases systematically with increasingthe number of fluorine substitutions in the fluoropyridine ring.Thus the increase in the N–H� � �N hydrogen bond distance aswell as decrease in the +N–H� � �N with increasing fluorine

substitution for these complexes shown in Fig. 3c and d iscorrectly reflected in the NBO interaction energy of the hydrogenbond. It is worth mentioning here that the n - pAm* inter-action energy reported for the tertiary dimethyl amides is only0.27 kcal mol�1 and this small magnitude of interaction energycontributes significantly to the protein stability by showing theconformational preference of the trans amide over the cisconfiguration.22 We also observe here that the very weak n - pAr*interaction present in the complexes of 7-AI and 2,6-substitutedfluoropyridines can govern the basic structural motif.

Energy decomposition analysis (EDA)

Decomposition of the total interaction energy present in thecomplexes into different components can help in determiningthe origin of the n - pAr* interaction. The Localized MolecularOrbital (LMO) method has been used to fragment the totalinteraction energy (DEtotal) of the complexes into electrostatic(DEele), exchange (DEex), repulsion (DErep), polarization (DEpol),and dispersion (DEdisp) components.58 These different compo-nents of the total interaction energy of the complexes of 7-AIwith 2,6-substituted fluoropyridines stabilized by the n - pAr*and N–H� � �N interactions calculated at the M05-2X/cc-pVDZlevel of theory have been presented graphically in Fig. 6. Theresult indicates that all six complexes comprising of the n -

pAr* interaction have comparable amounts of electrostatic anddispersion components. A close look into the electrostatic anddispersion components of the total interaction energy of thecomplexes bound by both the n - pAr* and N–H� � �N inter-actions reveals that even the dispersion interaction is greatercompared to the electrostatic one as the number of fluorinesubstitutions in the fluoropyridine ring increases. It is quiteinteresting to compare the different components of the inter-action energy in these complexes with those present in thedouble hydrogen bonded (N–H� � �N and C–H� � �N) complexes of7-AI and fluoropyridines. Fig. 7 depicts the components of theinteraction energy in the double hydrogen bonded complexesof 7-AI with 2,3-FP, 2,3,4-FP and 2,3,4,5-FP. It is apparenthere that the dispersion contribution is almost half of the

Table 4 E(2)n-s* (N–H� � �N) and E(2)

n-p* (n - pAr*) values in kcal mol�1 forthe complexes of 7-AI and 2,6-substituted fluoropyridines calculated atthe MP2/aVDZ level of theory

E(2)n-s* (N–H� � �N) E(2)

n-p* (n - pAr*)

7-AI� � �2,6-FP 6.58 0.417-AI� � �2,4,6-FP 5.75 0.647-AI� � �2,3,6-FP 5.65 0.597-AI� � �2,3,4,6-FP 4.97 0.537-AI� � �2,3,5,6-FP 4.92 0.477-AI� � �2,3,4,5,6-FP 4.30 0.50

Fig. 5 Natural bond orbitals in the 7-AI� � �2,3,4,5,6-FP complex showing(a) N–H� � �N hydrogen bonding and (b) n - pAr* interactions.

Fig. 6 Different components of the total interaction energy of thecomplexes of 7-AI with 2,6-substituted fluoropyridines calculated at theM05-2X/cc-pVDZ level of theory using the LMO-EDA method.

PCCP Paper

Publ

ishe

d on

04

Nov

embe

r 20

13. D

ownl

oade

d by

Ind

ian

Inst

itute

of

Scie

nce

Edu

catio

n &

Res

earc

h Pu

ne o

n 12

/12/

2013

10:

38:2

3.

View Article Online

Phys. Chem. Chem. Phys. This journal is© the Owner Societies 2014

electrostatic component in all the three complexes of 7-AI andFP bound by the double hydrogen bonding interactions. Forbrevity, the energy decomposition of only three complexes hasbeen presented in Fig. 7. Quantitative data corresponding toFig. 6 and 7 have been tabulated and provided in Tables S2 andS3, respectively, in the ESI.†

It is also evident from Fig. 7 that the dispersion interactionenergy present in the double hydrogen bonded complexes isindependent of the increase of the fluorination in fluoropyridine,and this is due to the fact that fluorine has very low polarizability.Thus the increase in the dispersion interaction energy in thecomplexes of 7-AI with 2,6-substituted fluoropyridines is definitelynot due to the increasing number of the fluorine atoms but due tothe presence of the n - pAr* interaction. So it can be concludedfrom the energy decomposition analysis that the close proximity ofthe fluoropyridine ring and nitrogen atom of the pyridine moiety of7-AI in the complexes of 7-AI and 2,6-substituted fluoropyridinesshould be due to the major contribution from the dispersioninteraction. Otherwise the electrostatic component would increaserapidly compared to the dispersion one with increasing fluorina-tion in the pyridine ring of the 2,6-substituted fluoropyridines asthe p-electron cloud of the pyridine ring becomes more electrondeficient. Thus it is proved that the dispersion interaction is themajor source of the n - pAr* interaction.

Conclusions

In summary, we have studied the detailed structures and stabilityof the 1 : 1 complexes of 7-AI with a series of fluorosubstitutedpyridines by employing wave function theory as well as dispersion-corrected DFT calculations. We have found that the most stablestructure of the complexes of 7-AI with all the fluoropyridinesexcept the ones with fluorine substitution at 2 and 6 positions isdouble hydrogen bonded (N–H� � �N and C–H� � �N). Interestingly,the most stable structure of the complexes of 7-AI with2,6-substituted fluoropyridines has a geometry consisting ofN–H� � �N hydrogen bonding and n - pAr* interactions.

Our results show that the proximity of the nitrogen atom of7-AI and aromatic ring of the 2,6-substitued fluoropyridines in

these complexes increases with successive increase of the fluorinesubstitution in the fluoropyridine ring at the expense of thereduction of the strength of the N–H� � �N hydrogen bond inter-action. It has been confirmed from the NBO analysis that the closeproximity of the two electronegative centers in these complexes isdue to a very weak n - pAr* interaction, which is facilitatedthrough the increase in fluorination in the fluoropyridine ring. Theorigin of this n - pAr* interaction cannot be due to the electro-static interaction; otherwise the B3LYP level of calculation wouldcapture this non-covalent interaction. It has also been found thatthe binding energies of these complexes calculated at the B3LYPlevel are about 3–4 kcal mol�1 lower than those obtained at theB97-D level of theory. Thus it is concluded that the n - pAr*interaction is dispersive in nature. Energy decomposition analysisof the total interaction energy of these complexes also supportsthis conclusion as the increase of the dispersion component ismuch more rapid compared to that of the electrostatic componentwith increase in fluorination of the fluoropyridine ring. It is quiteintriguing to note that the n - pAr* interaction modulates thespecific structure of the 7-AI� � �2,6-substituted fluoropyridinesalthough this interaction is extremely weak compared to theconventional N–H� � �N hydrogen bonding interaction present inthe complexes. Our results on these complexes also suggest thatthe basis set effect is very minimal at the M05-2X level if a basis sethigher than cc-pVDZ is used.

Acknowledgements

The authors would like to acknowledge the financial supportreceived from Indian Institute of Science Education andResearch (IISER), Pune to carry out this research. S. K. thanksCouncil of Scientific and Industrial Research (CSIR), India forthe senior research fellowship (SRF). S. K. S. wishes to thankIISER Pune for the research fellowship. The Research supportfrom IISER Pune supercomputer facility is greatly acknowl-edged. This work is also supported by the Department ofScience and Technology (DST), India (Grant No. SR/S1/PC/0054/2010) and DST nanoscience unit of IISER (Grant No. SR/NM/NS-42/2009). The authors wish to acknowledge Dr AnirbanHazra of IISER Pune for fruitful discussion.

Notes and references

1 G. R. Desiraju and T. Steiner, The Weak Hydrogen Bond inStructural Chemistry and Biology, Oxford University Press,New York, 1999.

2 E. A. Meyer, R. K. Castellano and F. Diederich, Angew.Chem., Int. Ed., 2003, 42, 1210–1250.

3 L. M. Salonen, M. Ellermann and F. Diederich, Angew.Chem., Int. Ed., 2011, 50, 4808–4842.

4 W. Saenger, Principles of Nucleic Acid Structure, Springer-Verlag, New York, 1984.

5 S. K. Burley and G. A. Petsko, Science, 1985, 229, 23–28.6 G. A. Jeffrey and W. Saenger, Hydrogen Bonding in Biological

Structures, Springer-Verlag, Berlin, 1991.

Fig. 7 Different components of the total interaction energy of the doublehydrogen bonded complexes of 7-AI with 2,3-FP, 2,3,4-FP and 2,3,4,5-FPcalculated at the M05-2X/cc-pVDZ level of theory using the LMO-EDA method.

Paper PCCP

Publ

ishe

d on

04

Nov

embe

r 20

13. D

ownl

oade

d by

Ind

ian

Inst

itute

of

Scie

nce

Edu

catio

n &

Res

earc

h Pu

ne o

n 12

/12/

2013

10:

38:2

3.

View Article Online

This journal is© the Owner Societies 2014 Phys. Chem. Chem. Phys.

7 L. Serrano, M. Bycroft and A. R. Fersht, J. Mol. Biol., 1991,218, 465–475.

8 J. B. O. Mitchell, C. L. Nandi, I. K. McDonald, J. M. Thorntonand S. L. Price, J. Mol. Biol., 1994, 239, 315–331.

9 J.-M. Lehn, Supramolecular Chemistry: Concepts and Perspec-tives, John Wiley & Sons, New York, 1996.

10 J. W. Steed and J. L. Atwood, Supramolecular Chemistry: AConcise Introduction, John Wiley & Sons Inc, New York, 2000.

11 G. R. Desiraju, Angew. Chem., Int. Ed. Engl., 1995, 34, 2311–2327.12 G. R. Desiraju, Angew. Chem., Int. Ed., 2007, 46, 8342–8356.13 G. R. Desiraju, J. Am. Chem. Soc., 2013, 135, 9952–9967.14 G. J. Bartlett, A. Choudhary, R. T. Raines and

D. N. Woolfson, Nat. Chem. Biol., 2010, 6, 615–620.15 J. P. Gallivan and D. A. Dougherty, Org. Lett., 1999, 1, 103–106.16 J. A. Hodges and R. T. Raines, Org. Lett., 2006, 8, 4695–4697.17 A. Choudhary, K. J. Kamer and R. T. Raines, J. Org. Chem.,

2011, 76, 7933–7937.18 K. J. Kamer, A. Choudhary and R. T. Raines, J. Org. Chem.,

2013, 78, 2099–2103.19 M. Egli and S. Sarkhel, Acc. Chem. Res., 2007, 40, 197–205.20 M. P. Hinderaker and R. T. Raines, Protein Sci., 2003, 12,

1188–1194.21 A. Choudhary and R. T. Raines, Protein Sci., 2011, 20, 1077–1081.22 R. W. Newberry, B. VanVeller, I. A. Guzei and R. T. Raines,

J. Am. Chem. Soc., 2013, 135, 7843–7846.23 R. W. Newberry and R. T. Raines, Chem. Commun., 2013, 49,

7699–7701.24 A. Choudhary, D. Gandla, G. R. Krow and R. T. Raines, J. Am.

Chem. Soc., 2009, 131, 7244–7246.25 C. E. Jakobsche, A. Choudhary, S. J. Miller and R. T. Raines,

J. Am. Chem. Soc., 2010, 132, 6651–6653.26 M. D. Shoulders, F. W. Kotch, A. Choudhary, I. A. Guzei and

R. T. Raines, J. Am. Chem. Soc., 2010, 132, 10857–10865.27 C. Caumes, O. Roy, S. Faure and C. Taillefumier, J. Am.

Chem. Soc., 2012, 134, 9553–9556.28 M. Egli and R. V. Gessner, Proc. Natl. Acad. Sci. U. S. A., 1995,

92, 180–184.29 S. Sarkhel, A. Rich and M. Egli, J. Am. Chem. Soc., 2003, 125,

8998–8999.30 S. Blanco, J. C. Lopez, S. Mata and J. L. Alonso, Angew.

Chem., Int. Ed., 2010, 49, 9187–9192.31 C. Cabezas, J. L. Alonso, J. C. Lopez and S. Mata, Angew.

Chem., Int. Ed., 2012, 51, 1375–1378.32 B. W. Gung, Y. Zou, Z. Xu, J. C. Amicangelo, D. G. Irwin,

S. Ma and H. C. Zhou, J. Org. Chem., 2008, 73, 689–693.33 J. C. Amicangelo, B. W. Gung, D. G. Irwin and N. C. Romano,

Phys. Chem. Chem. Phys., 2008, 10, 2695–2705.34 T. Yang, J. J. An, X. Wang, D. Y. Wu, W. Chen and

J. S. Fossey, Phys. Chem. Chem. Phys., 2012, 14, 10747–10753.35 J. C. Amicangelo, D. G. Irwin, C. J. Lee, N. C. Romano and

N. L. Saxton, J. Phys. Chem. A, 2013, 117, 1336–1350.36 B. W. Gung, X. Xue and H. J. Reich, J. Org. Chem., 2005, 70,

7232–7237.37 I. Berger and M. Egli, Chem.–Eur. J., 1997, 3, 1400–1404.38 I. Berger, M. Egli and A. Rich, Proc. Natl. Acad. Sci. U. S. A.,

1996, 93, 12116–12121.

39 B. C. Gorske, B. L. Bastian, G. D. Geske and H. E. Blackwell,J. Am. Chem. Soc., 2007, 129, 8928–8929.

40 J. R. Stringer, J. A. Crapster, I. A. Guzei and H. E. Blackwell,J. Am. Chem. Soc., 2011, 133, 15559–15567.

41 B. C. Gorske, J. R. Stringer, B. L. Bastian, S. A.Fowler and H. E. Blackwell, J. Am. Chem. Soc., 2009, 131,16555–16567.

42 A. Jain, C. S. Purohit, S. Verma and R. Sankararamakrishnan,J. Phys. Chem. B, 2007, 111, 8680–8683.

43 A. Jain, V. Ramanathan and R. Sankararamakrishnan, ProteinSci., 2009, 18, 595–605.

44 A. Choudhary, K. J. Kamer, M. W. Powner, J. D. Sutherlandand R. T. Raines, ACS Chem. Biol., 2010, 5, 655–657.

45 T. J. Mooibroek, P. Gamez and J. Reedijk, CrystEngComm,2008, 10, 1501–1515.

46 T. K. Pal and R. Sankararamakrishnan, J. Phys. Chem. B,2010, 114, 1038–1049.

47 Z. Lu, P. Gamez, I. Mutikainen, U. Turpeinen and J. Reedijk,Cryst. Growth Des., 2007, 7, 1669–1671.

48 J. S. Costa, A. G. Castro, R. Pievo, O. Roubeau, B. Modec,B. Kozlevcar, S. J. Teat, P. Gamez and J. Reedijk, CrystEng-Comm, 2010, 12, 3057–3064.

49 T. J. Mooibroek, S. J. Teat, C. Massera, P. Gamez andJ. Reedijk, Cryst. Growth Des., 2006, 6, 1569–1574.

50 M. L. DeRider, S. J. Wilkens, M. J. Waddell, L. E. Bretscher,F. Weinhold, R. T. Raines and J. L. Markley, J. Am. Chem.Soc., 2002, 124, 2497–2505.

51 A. Nijamudheen, D. Jose, A. Shine and A. Datta, J. Phys.Chem. Lett., 2012, 3, 1493–1496.

52 H. B. Burgi, J. D. Dunitz and E. Shefter, J. Am. Chem. Soc.,1973, 95, 5065–5067.

53 H. B. Burgi, J. M. Lehn and G. Wipff, J. Am. Chem. Soc., 1974,96, 1956–1957.

54 H. B. Burgi, J. D. Dunitz and E. Shefter, Acta Crystallogr.,1974, B30, 1517–1527.

55 C. Fufezan, Proteins: Struct., Funct., Bioinf., 2010, 78, 2831–2838.56 S. Kumar, I. Kaul, P. Biswas and A. Das, J. Phys. Chem. A,

2011, 115, 10299–10308.57 M. J. Frisch, et al., GAUSSIAN 09, Revision B.01, Gaussian,

Inc., Wallingford CT, 2009.58 P. Su and H. Li, J. Chem. Phys., 2009, 131, 14102–14115.59 M. W. Schmidt, K. K. Baldridge, J. A. Boatz, S. T. Elbert,

M. S. Gordon, J. H. Jensen, S. Koseki, N. Matsunaga,K. A. Nguyen, S. Su, T. L. Windus, M. Dupuis andJ. A. Montgomery, J. Comput. Chem., 1993, 14, 1347–1363.

60 S. F. Boys and F. Bernardi, Mol. Phys., 1970, 19, 553–566.61 E. D. Glendening, A. E. Reed, J. E. Carpenter and

F. Weinhold, NBO Version 3.1, online at http://www.gaussian.com/g_tech/g_ur/m_citation.htm.

62 E. Arunan, G. R. Desiraju, R. A. Klein, J. Sadlej, S. Scheiner,I. Alkorta, D. C. Clary, R. H. Crabtree, J. J. Dannenber,P. Hobza, H. G. Kjaergaard, A. C. Legon, B. Mennucci andD. J. Nesbitt, Pure Appl. Chem., 2011, 83, 1637–1641.

63 S. Kumar and A. Das, J. Chem. Phys., 2013, 139, 104311–104317.64 A. E. Reed, L. A. Curtiss and F. Weinhold, Chem. Rev., 1988,

88, 899–926.

PCCP Paper

Publ

ishe

d on

04

Nov

embe

r 20

13. D

ownl

oade

d by

Ind

ian

Inst

itute

of

Scie

nce

Edu

catio

n &

Res

earc

h Pu

ne o

n 12

/12/

2013

10:

38:2

3.

View Article Online