Vibrational circular dichroism of 2,6-di-sec-butyl-4-methylpyridine and...

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Vibrational circular dichroism of 2,6-di-sec-butyl-4-methylpyridineand 2,6-di-sec-butyl-4-methylpyridine-N-oxide: theoretical evidenceon the existence of multiple –CH, –CH2, and –CH3� � �O intramolecularhydrogen bonds on the nitroxide oxygen

Florina Teodorescu a,b, Jean-Valère Naubron c, Cornelia Uncut�a a,�, Petru Ivan Filip a, Emeric Bartha a,Ana Maria Toader d, Isabela Costinela Man a,⇑a Center of Organic Chemistry ‘C.D. Nenitescu’ of Romanian Academy, 202B Splaiul Independentei, Sector 6, 060021 Bucharest, Romaniab Department of Technology and Catalysis, University of Bucharest, Faculty of Chemistry, 4-12 Regina Elisabeta Blv., Sector 3, 030018 Bucharest, Romaniac Spectropole, Universite Aix Marseille, Campus Scientifique de Saint Jérôme, Service 511, F-13397 Marseille, Franced ‘Ilie Murgulescu’ Institute of Physical Chemistry of the Romanian Academy, 202 Splaiul Independentei, Sector 6, 060021 Bucharest, Romania

a r t i c l e i n f o

Article history:Received 21 January 2014Revised 21 March 2014Accepted 10 April 2014

a b s t r a c t

Enantiopure (±)-2,6-di-sec-butyl-4-methylpyridine and its oxidized form (±)-2,6-di-sec-butyl-4-methyl-pyridine-N-oxide were prepared and then separated by chiral HPLC. Their stereochemical structuresand their conformational distribution in solution were investigated using vibrational circular dichroism(VCD) and infrared spectroscopy (IR) combined with density functional theory (DFT). The experimentalspectra have been compared with theoretical data. This comparison indicated that (�)-2,6-di-sec-butyl-4-methylpyridine and its oxidized form (+)-2,6-di-sec-butyl-4-methylpyridine-N-oxide have an(S,S)-configuration and exist in several conformations. The good fit confirms the reliability of the confor-mational analysis. Our results indicated that going from the reduced form to the oxidized one stronglyinfluences the type of conformers in solution. Moreover, DFT calculations showed that for all of the con-formers of (S,S)-2,6-di-sec-butyl-4-methylpyridine-N-oxide, the formation of four centered intramolecu-lar hydrogen bonds between the hydrogen of the –CH, –CH2, and –CH3 groups and the nitroxide oxygen ispossible. Moreover the stability of the conformers of both compounds is influenced by the all-trans struc-ture of the sec-butyl moieties.

� 2014 Elsevier Ltd. All rights reserved.

1. Introduction

Vibrational circular dichroism (VCD) spectroscopy represents apowerful tool among chiroptical techniques in the determinationof the absolute configuration and conformations of chiralmolecules.1–5 Configuration assignment is carried out based on acombined experimental and theoretical approach and includes sim-ulation, with ab initio models, of unpolarized and polarized infraredabsorption spectra that are compared with experimental data. Thisapproach also provides information on the different effects relatedto chiral molecules, such as the observation of odd–even effects insolutions of chiral alkyl alcohols,6 the identification of specificadsorptions that are characteristics for an entire class of compounds

(e.g., carbohydrates),7 or on different intra- or intermolecularinteractions with a direct impact on the stability or biologicalactivity of molecules or molecular assemblies.8–16 One such intra-molecular interaction results in the formation of hydrogen bondsD(onor)–H� � �A(cceptor).15,17–23 The concept of a hydrogen bondcontains a broad range of cases ranging from very strong to veryweak ones. The evidence for bond formation may be experimental,theoretical or a combination of both. There is a range of criteria toevidence hydrogen bonding; the greater the number of criteria thatare satisfied, the more reliable being the characterization as ahydrogen bond.24,25 On structural grounds, H-bonding is evidencedby short H� � �A distances and favorable D–H� � �A angles. Distances ofup to 3.0–3.2 Å can be accepted as a manifestation of a H-bond, whilean angular cut off can be set at >90� or somewhat more conserva-tively at >110�.26 Moreover the hydrogen bond is a complex interac-tion composed of several constituents, with its total energy beingsplit into contributions from electrostatics, polarization, chargetransfer, dispersion, and exchange repulsions. Depending on the

http://dx.doi.org/10.1016/j.tetasy.2014.04.0070957-4166/� 2014 Elsevier Ltd. All rights reserved.

⇑ Corresponding authors. Tel.: +40 21 316 79 00; fax: +40 21 312 16 01.E-mail address: [email protected] (I.C. Man).

� It is a privilege to dedicate this account to the memory of Cornelia Uncuta (1944–2012), from whose early work on pyridine class much has followed.

Tetrahedron: Asymmetry 25 (2014) 725–735

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bond strength, these contribute more or less to the total energy ofthe hydrogen bond. The C–H� � �O bond is one of a dozen of differenttypes of hydrogen bonds that are taken into account when explain-ing conformer stabilities. This is a weak interaction, but is widelyaccepted as a genuine hydrogen bond. It is mostly characterizedby electrostatic and dispersion contributions, and by the length ofthe H� � �O interaction in the range 2–3 Å while the bond angles arein the region (90–150�).27 The geometrical aspect related to thisC–H� � �O interaction observed by Desiraju et al. for simple alkynesand alkenes is that the more acidic a particular type of –CH (–CH3,–CH2, and –CH) group is, the shorter the H� � �O bonds are, whereasthe effect of the O atom basicity on the C–H� � �O bond length is farless noticeable than that of –CH group acidity.16,28–30 Moreover,depending on how the charge transfer within the molecularsystem take place, the length of the C–H bond involved in theformation of the C–H� � �O hydrogen bond, can be shortened20,22,31

or lengthened.32,33

The two molecules studied, 2,6-di-sec-butyl-4-methylpyridine(pyridine 1) and the oxidized form 2,6-di-sec-butyl-4-methylpyri-dine-N-oxide (pyridine-N-oxide 2), are valuable compoundsbecause of their potential applications in asymmetric catalysisand coordination chemistry,34–38 as well as their stereochemistrybeing an important aspect in catalysis. Therefore, it is importantto determine their configuration and conformation. Recently ithas been reported in another VCD study related to ligands contain-ing pyridine subunits that are important in the asymmetriccatalysis.39

The two molecules are flexible, with two symmetric stereogeniccenters at the 3 and 30 positions, according to the atomic number-ing used herein and as shown in Figure 1; besides the commonmethyl pyridine moiety, two different unbranched alkyl groups,methyl and ethyl are attached.

Herein our aim was to assign the absolute configuration of thenewly synthesized enantiomerically pure compounds by combin-ing VCD spectroscopy and DFT calculations so as to obtain struc-tural information and conformational distributions of these chiralcompounds in solution. We also wanted to compare the similarityand dissimilarity of the IR and VCD spectroscopic features of thetwo compounds because of their similar structure. Finally, withinthe conformers of pyridine-N-oxide 2, there are up to four possibleC–H� � �O interactions on the nitroxide oxygen (four centered intra-molecular hydrogen bonds); we have analyzed at a theoretical levelthe geometrical criteria that connect them within the concept ofintramolecular hydrogen bonds. The results of NBO analysis arediscussed.

2. Experimental

2.1. Synthesis and analysis

In Scheme 1 are presented the main steps of the synthesiswhich are detailed below.

2.1.1. Hexafluorophosphate salt 2,6-di-sec-butyl-4-methylpyrylium 3

In a three-necked flask, equipped with a reflux condenser, animmersed thermometer, a dropping funnel, and a magnetic stirrer,was placed anhydrous tert-butanol (3.47 g, 0.047 mol), previouslymolten and mixed with enough 2-methylbutyric anhydride to keepit from solidifying in the flask. The anhydride was then added tomake up a total of 83.2 g (0.45 mol). The mixture was stirred,and 60% HPF6 (7 mL, 0.047 mol) was added dropwise, slowly atfirst, until the temperature reached 70–80 �C. A color change toyellow and then brown was observed. The addition was continuedat a higher rate, so as to keep a gentle reflux. When all of the acidhad been added, stirring was continued for 2 h at 80 �C with exter-nal heating. The flask was cooled to room temperature, and theproduct was isolated by filtration with suction. The crude productwas washed on the filter with diethyl ether then air-dried; 8.57 gof off-white crystals were obtained (yield 52%). The crude productwas sufficiently pure for most purposes. An analytically pure sam-ple was obtained by recrystallization from 2-propanol; mp 82–83 �C; 1H NMR (300 MHz, CDCl3, 25 �C): d = 0.94 (t, 6H,J = 7.5 Hz), 1.42 (d, J = 6.9 Hz, 6H), 1.82 (m, 4H), 2.76 (3H, s), 3.19(sextet, J = 7.2 Hz, 2H), 7.71 ppm (s, 2H); elemental analysis calcd(%) for C14H23OPF6: C 47.73, H 6.58; found: C 47.81, H 6.60.

2.1.2. (±)-2,6-Di-sec-butyl-4-methylpyridine-N-oxide 2To pyrylium hexafluorophosphate 1.05 g (3 mmol) in 35 mL of

glacial acetic acid was added, with magnetic stirring, hydroxyl-amine hydrochloride (1.08 g, 15 mmol). The mixture was broughtto boiling, then crystalline sodium acetate (4.11 g, 30 mmol) wasadded at once. The mixture was heated at reflux for 2 h, then aceticacid was distilled off under vacuum and cold water was added. Themixture was extracted three times with diethyl ether, the organiclayer was neutralized with aqueous sodium dicarbonate and driedover sodium sulfate. Evaporation of the solvent gave 569 mg of anoil. The crude product was purified by column chromatography onsilica gel, with a mixture of pyridine-1-oxides (meso and ±) beingeluted with 230 mg of diethyl ether (yield 35%).

Separation of the meso and (±)-enantiomers was performed bychiral HPLC at room temperature on an (S,S)-WHELK-O1(250 � 4.6) column by elution with a flow rate of 1.0 mL/min. Themobile phase composition was hexane-2 propanol (90:10). The firsteluted enantiomer was collected between 11.5 and 12.5 min; themeso-form was collected between 13 and 14 min and the secondeluted enantiomer was collected between 15 and 16.5 min.[a]D

26 = +14.75 (c 3.05, CHCl3) for the first eluted enantiomer,[a]D

20 = �14.3 (c 2.65, CHCl3) for the second eluted enantiomer. 1HNMR (300 MHz, CDCl3, 25 �C): 0.94 (t, 6H, J = 7.4 Hz), 1.27 (d,J = 7.1 Hz, 6H), 1.53 (m, 2H), 1.76 (m, 2H), 2.33 (s, 3H), 3.75 (sextet,J = 7.1 Hz, 2H), 6.86 ppm (s, 2H).

2.1.3. (±)-2,6-Di-sec-butyl-4-methylpyridine 1A three-necked flask with a magnetic stirrer, an immersed ther-

mometer and a dropping funnel protected against humidity wasplaced in an ice bath at 3 �C. To (+)-2,6-di-sec-butyl-4-methylpyri-dine-N-oxide (78 mg, 0.35 mmol) in CHCl3 (1 mL) was added drop-wise phosphorous trichloride (100 ll, 1.15 mmol) in 0.5 mL ofCHCl3 while keeping the temperature at 3 �C. After 2 h, 100 ll ofphosphorous trichloride in 0.5 mL of CHCl3 was added. Stirringwas continued for 2 h at 3 �C, and then the reaction mixture was leftovernight at room temperature. Aqueous 5% sodium hydroxide solu-tion was added for neutralization and the mixture was extractedthree times with CHCl3. Evaporation of the solvent gave an oily prod-uct, which was purified by column chromatography on silica gel.Elution with 5% (v) diethyl ether/petroleum ether (40–67 �C) mix-ture gave 65 mg of 2,6-di-sec-butyl-4-methylpyridine (83% yield);

XHH

1

23

4

5

6

1'

2'3'

4'

5'

6'

ω

φ

ω'φ'

Figure 1. when X = N, the structure is 2,6-di-sec-butyl-4 methyl pyridine (pyridine1) and for X = N?O, the structure is 2,6-bis sec-butyl-4 methyl (pyridine-N-oxide2). The atoms are numbered this way throughout. /, /0 represent dihedral anglesbetween atoms C2C3–C4C5, and C2

0C30–C3

0C50 , while x, x0 are dihedral angles

between C1C2–C3H and C10C20–C3

0H0 .

726 F. Teodorescu et al. / Tetrahedron: Asymmetry 25 (2014) 725–735


according to polarimetric measurements, the dextrorotatory enan-tiomer (at k = 589 nm) was obtained.

The same protocol was used for reduction of (�) 2,6-di-sec-butyl-4-methylpyridine-N-oxide, and gave (�)-2,6-di-sec-butyl-4-methylpyridine.

The synthesized compounds were fully characterized by severalspectroscopic techniques. The 1H NMR spectra were recorded withVarian Gemini 300 BB instrument, operating at 300 MHz for 1H andat 75 MHz for 13C, in CDCl3 solution at room temperature. Thechemical shift (d) values are given in ppm from internal TMS, thecoupling constants J are in Hz. Analytical thin layer chromatogra-phy (TLC) was performed with silica gel F254 (Merck) on aluminumstrips (10 cm length). For column chromatography, silica gel 60(Merck) was used. Chiral high performance liquid chromatography(HPLC) analyses were performed with an Agilent Chromatograph1200 Series at room temperature. Optical rotations were measuredwith a 341 Perkin Elmer polarimeter using a 1 cm path length glasscell.

The infrared (IR) and vibrational circular dichroism (VCD) spec-tra were recorded on a Bruker PMA 50 accessory coupled to a Ver-tex70 Fourier transform infrared spectrometer. The spectralresolution was fixed to 4 cm�1 and the measurement region wasrestricted to 1800–800 cm�1 using an optical low pass filter beforethe photoelastic modulator to enhance the signal/noise ratio. Theaccumulation times were 2 h. The spectra were recorded in CD2Cl2

at 0.28 M for pyridine 1 and 0.22 M of pyridineoxide 2 at a pathlength of 250 lm. CaF2 was used for the window material. Forremoving the artifacts, the VCD spectra of (+)- and (�)-enantio-mers recorded under identical conditions were corrected by halfsubstraction.40 [a]D

20 = +7.35 (c 2.94, CHCl3); [a]D20 = �7.2 (c

2.72, CHCl3); 1H NMR (300 MHz, CDCl3, 25 �C): 0.82 (t, J = 7.5 Hz,6H), 1.23 (d, J = 6.9 Hz, 6H), 1.57 (m, 2H), 1.73 (m, 2H), 2.28 (s,3H), 2.72 (sextet, J = 6.9 Hz, 2H), 6.73 ppm (s, 2H).

2.2. Computational details

The conformational analysis of (S,S)-pyridine 1 and of (S,S)-pyr-idine-N-oxide 2 was carried out primarily at a lower level of the-ory. The analysis involved exploring the conformational energy

surface of the molecules, carrying out semiempirical AM1 calcula-tions as implemented in the package MOPAC 93.

The geometry optimization, and the IR and VCD spectra at den-sity functional theory (DFT) level were calculated using B3LYPfunctional and 6-31++G(d,p), 6-311++G(d,p) and TZVP basis setsand with B3PW91 functional and 6-311++G(d,p) and TZVP basissets as implemented in Gausian03 Revision E.0141 program pack-age. The best fit with the experimental data was obtained usingthe B3PW91/TZVP42 combination of functional and basis set. Sim-ilar combinations have been shown to give good results.1,43 Theimplicit solvent effect (CD2Cl2) was taken into consideration whenusing the polarisable continuum model (PCM) with integral equa-tion formalism variant (IEFPCM). Lorenzian line shapes with a halfwidth at half height of 4 cm�1 were used to simulate the IR andVCD spectra. NBO analyses were also calculated at the same levelof theory.

3. Results and discussion

3.1. IR and VCD spectra of pyridine 1 and pyridine-N-oxide 2enantiomers

Figure 2 shows experimental IR and VCD spectra of pyridine 1and pyridine-N-oxide 2 enantiomers obtained in CD2Cl2. The VCDspectra of both enantiomers showed good mirror images for bothcompounds.

By analyzing the similarities and differences of the spectra ofthe two compounds, it can be seen that the main similarity is thatthe most common bands appear at approximately the same fre-quency, with no major shifts, while the main difference is thechange in their intensities. The VCD bands of pyridine-N-oxide 2are more intense than the corresponding ones for pyridine 1.

An important aspect for both compounds is the VCD bands inthe region 1150–1000 cm�1, due to vibration of the sec-butyl moi-eties. This aspect was observed for the first time by Fujita et al. forthe simplest saturated hydrocarbon with a quaternary stereogeniccenter, 4-ethyl-4-methyloctane.44 The VCD spectra clearly showspecific characteristics, and intense, positive and negative bandsin this region, whereas the IR spectra show weak and broad bands

CH3COOH N+

CH3

C C

CH3CH3

H2C CH2

HH

CH3H3C

O-

N

CH3

C C

CH3CH3

H2C CH2

HH

CH3H3C

O

CH3

C C

PF6-

HO+

(EtMeCHCO)2O

(HPF6 60%)

CH3CH3

H2C CH2

HH

CH3H3C

NH2OH·HClCH3COONa·3H2O

3(±) / mesoratio 1/1

2(±) / mesoratio 1/1

2 (meso)

(+)-2

(-)-2

PCl3

CHCl3

PCl3

CHCl3

N

CH3

C C

CH3CH3

H2C CH2

HH

CH3H3C

(-)-1

(+)-1

chiral

HPLC

+

Scheme 1. Preparation of 2,6-di-sec-butyl-4 methylpyridine 1 and 2,6-di-sec-butyl-4-methylpyridine-N-oxide 2.

F. Teodorescu et al. / Tetrahedron: Asymmetry 25 (2014) 725–735 727


in this region. In the VCD spectrum of pyridine 1, a band appears asa split signal at 1060 (#24) and at 1080 (#25) cm�1. These signalsare among the most intense ones in the entire pyridine 1 VCD spec-trum. For the oxidized form, pyridine-N-oxide 2, one broader signalappears at 1076 cm�1 (#23).

A characteristic group of bands for pyridine are those producedby the vibrations of the pyridine ring (the valence ring t C–C vibra-tions). A group of ring stretching modes,45,46 for pyridine 1 are reg-istered at 1605.2 (#1) and at 1565.6 cm�1 (#2), while for pyridine-N-oxide 2, they appear at 1628.8 cm�1 (#1) and at 1556.4 cm�1

(#2). The IR spectra in Figure 2 confirm that the change in band posi-tions is less important than the change in their intensities whenchanging the substituent;47 in our case by oxidizing the heterocyclicnitrogen. These vibrations are not active in the VCD spectra.

Another ring vibration that can be identified, is the contributionof –CH and/or of the methyl group –CH3 deformations.45 In pyridine1 it was found at 1420.3 cm�1 (#7) while for pyridine-N-oxide 2, a

much more intense vibration was found at 1422.6 cm�1 (#6). Forthe oxidized form, it gives a weak signal in the VCD spectrum (#6).

Another vibration representative of the pyridine ring is the inplane of CH bending which is strongly coupled to the ring deforma-tion.48 The IR medium intense band of pyridine-N-oxide 2 from1169.4 cm�1 (#20) is assigned to this mode while in the VCD spec-trum, it is the most intense one. In the VCD spectrum of pyridine 1,this band is slightly shifted, appears at 1150 cm�1 (#22) and is themost intense in the spectrum, while in the IR spectrum no absorp-tion was registered in this region. The difference of the VCD inten-sity of this band for the two compounds is due to the participationof the oxygen electron lone pairs in conjugation with the ring.

Another group of bands in the IR spectra, are given by the bendingmodes of –CH3 (attached to the pyridine ring and of the sec-butylgroup) and/or of the –CH2.49 The broad medium bands at1461.6 cm�1 (#3–6 pyridine 1 and #3–5 pyridine-N-oxide 2) areassigned to the asymmetric bending of the –CH3 and –CH2 groups,while the symmetric bending frequencies are around 1378.6 cm�1

(#9/10) and 1381.4 cm�1 (#8–10) for pyridine 1 and pyridine-N-oxide 2. The signals of the –CH3 groups differ slightly if they areattached to the pyridine ring or if they belong to the sec-butyl moi-eties, but as shown in the literature, these shifts are not expected toexceed 20 cm�1.48 This can be explained by the fact that the signalsare broader. These vibrations give VCD bands but these are weak,with those in pyridine 1 being much weaker than those inpyridine-N-oxide 2.

The vibration mode characteristic for pyridine-N-oxide 2 only isthe N?O stretching mode. Depending on the measurement condi-tions and on the type of pyridine derivatives, the N?O stretchingmode is reported to appear in the range 1300–1200 cm�1.50–54 Weassign the strong bands at 1253.3 cm�1 (#17) and 1219.2 cm�1

(#19) to this vibration mode. In both cases, we expected that thevibration of N?O would couple with the ring vibrations, andthe –CH and sec-butyl –CH bends.

The three most intense VCD signals active in the spectrum ofpyridine N-oxide 2, the CH in plane deformation (1169.4 cm�1)and N?O stretching vibrations (from 1219.2 cm�1 respectively at1253.3 cm�1), might help in determining the stereochemical infor-mation for the structure assignment in similar pyridine-N-oxidechiral derivatives.

3.2. Conformational analysis of pyridine 1 and pyridine-N-oxide2

For reliable absolute configuration assignments, a thoroughconformational analysis is required in order to identify the major

Figure 2. Experimental IR (top) and VCD (bottom) spectra of (+)- and (�)-pyridine1 and (+)- and (�)-pyridine-N-oxide 2.

Figure 3. Contour maps of the 2D potential energy surface as a function of x (C1C2–C3H) and x0 (C02–C30H) dihedral angles, respectively, for (S,S)-pyridine 1 for (a)

(/, /0) = (60, 60) and (b) (/, /0) = (�60, �60). The energies of the diagrams are calculated relative to the least stable conformer of the two sets of data.



conformers of the molecule and their equilibrium distribution insolution at room temperature. As can be seen from their structures,the two molecules are flexible and may accommodate a substantialnumber of conformers. Assuming an (S,S)-configuration for the ste-reogenic centers, we considered torsion values relative to the dihe-dral angles: C1C2–C3H (x), C1

0C2–C30H (x0), C2C3–C4C5 (/) and

respectively around C20C30–C4

0C50 (/0), as illustrated in Figure 2.

The conformational analysis of pyridine 1 and pyridine-N-oxide2 started with an exploration of their conformational energy sur-face carried out at a semiempirical AM1 level by rotation aroundC2–C3 (x) and C2

0–C30 (x0) bonds by 10�, for two selected cases

(/, /0) = ((60, 60), (�60, �60)). The 2D contour maps are presentedin Figures 3 and 4. The diagrams are built based on the relativeenergy, while taking into account the least stable conformer ofthe two cases of the (/, /0) dihedral angles.

For both compounds, the most stable conformers were regis-tered for (/, /0) = (60, 60). Four minima are registered around (0,0), (0, 180/�180), (180/�180, 0) and (180/�180, 180/�180) ±�45� (see Figs. 3a and 4a). For the other case (/, /0) = (�60, �60)the conformers are much less stable and the registered minimadeviated from the above presented values by approximately ±45�(Figs. 3b and 4b). For pyridine 1 the largest and deepest area isat (0, 0) while for pyridine-N-oxide 2, it is at (180/�180, 180/�180). It is expected that for other values of (/, /0), the minimais also placed around (0, 0); (0, 180); (180, 0); (180, 180) or isdeviated by approximately the same values with ±45�.

Since the energetic minima in each case are placed aroundx � 0�/180 ± 45� and x0 � 0�/180 ± 45� values, for ease of notationwe will use the ±45 subscript, indicating the variation of the twodihedral angles (x, x0) from 0� to 180� angles with ±45�, as willbe shown. For the values �180 + 45� that are the same with��145� the subscript notation will be +45�. Therefore the con-formers to be calculated at a density functional theory (DFT) levelare obtained in the following manner (as seen in Fig. 5): the leftmoieties were obtained by varying the dihedral angle C2C3–C4C5

(/) with 60�, 180� and �60� combined with the values of the dihe-dral angle C1C2–C3H x � 0 ± 45� (labeled G+

+45, G+�45, T+45, T�45,

G�+45, G��45), respectively, x � 180 ± 45� (labeled G+⁄+45, G+⁄

�45,T⁄+45, T⁄�45, G�⁄+45, G�⁄�45), are joined with the right moietiesobtained in the same manner (labeled for x0 = 0 ± 45� and /0 = 60�, 180�, �60� g+

+45, g+�45, t+45, t�45, g�+45, g��45, respectively,

for x0 = 180�/±45� and /0 = 60�, 180�, �60� g+⁄+45, g+

�45, t⁄+45,t⁄�45, g�⁄+45, g�⁄�45). The resulting conformers can be grouped inA, B, C, and D type conformers (in total 144) as a function of thevalues of the two dihedral angles x and x0. Since B and D are

equivalent, the initial number of conformers to be calculated at aDFT level is reduced. Moreover, because of the symmetry of a partof the A and C type conformers, their number is reduced once more(e.g., AG+t and ATg+ are equivalent) to a maximum of 84. After thevibrational entropy was calculated and the free energy was cor-rected at 298.15 K, the relative stability of each conformer wasevaluated based on their free energies (Tables 1 and 2).

For pyridine 1, no matter which of the starting values of the two(x, x0) dihedral angles is used, most of them converge toward val-ues close to 0� and 180� as shown in Table 1, finally resulting in 21stable conformers. Because of this, we kept the simple notation ofthese conformers, without adding a ±45 subscript.

On the other hand for (S,S)-pyridine-N-oxide 2, the number ofpossible conformers is much larger. For a pair of (/, /0) dihedralangles, there are up to four different conformers resulting fromall four combinations of the (x, x0) dihedral angles. This is possiblefor the C type conformers, as seen in Table 2. The A type conform-ers converged toward unique conformers.

When comparing the most stable conformers of the two mole-cules, it became clear that the oxidation of the nitrogen signifi-cantly changes their distribution. From the data in the tables, itcan be seen that the most stable conformers for pyridine 1 are ofthe A type, making up to approximately 51% of the population,whereas for pyridine-N-oxide 2, the C type conformers are thedominant ones, representing approximately 85% of the population.The populations of conformers B are closer: 27.3% in 1, and 14.3% in2. The C type conformers appear at 20% in 1, while the Aconformers account for less than 1% of the population of 2.

A stabilization factor for both compounds is the all-transconformation adopted by the sec-butyl moieties. In Figure 6a–care graphically exemplified by the all-trans structure of thesec-butyl moieties for the A (G+g+), B (G+⁄

�45g+), C (G+⁄�45g+⁄

�45)conformers of pyridine-N-oxide 2 (the same is valid for the similarconformers of pyridine 1) that have both sec-butyl moieties in thisconformation. In the same figure is revealed the factor that signifi-cantly changes the distribution of the conformers from one com-pound to the other, namely the four simultaneous C–H� � �Ointeractions that form in the exemplified conformers, with themethine (–CH), methylene (–CH2) or methyl (–CH3) groups as thehydrogen donors and nitroxide oxygen as a four centered acceptor.In the A type conformers, the four C–H� � �O intramolecular hydrogenbonds are formed between the hydrogen of the –CH2 or –CH3 groupsand oxygen. In the B type conformers, there is one contact thatinvolves the hydrogen of the –CH group, while the other three areformed by hydrogens belonging to the –CH2, –CH3 groups. In the C

Figure 4. Contour maps of the 2D potential energy surface as a function of x (C1C2–C3H) and x0 (C02–C30H) dihedral angles, for (S,S)-pyridine-N-oxide 2; (a) for (/, /0) =

(60, 60) and (b) (/, /0) = (�60, �60). The energies of the diagrams are calculated relatively to the least stable conformer of the two sets of data.



type conformers, the hydrogens of the two –CH groups participatein the C–H� � �O interaction (C3H, C3

0H) while the other two belongto the –CH2, –CH3 groups. Their stereostructures have dihedralangles x, x0 close to 180 ± 45�, which are favorable to the formationof the two C3–H� � �O� � �H–C3

0 intramolecular hydrogen interactions,resulting in the lowest energy conformers (Table 2).

For (S,S)-pyridine 1 the most stable conformer is AG+g+ (30.5%Fig. 7a). The two sec-butyl moieties adopt an all-trans conformation.A similar all-trans conformation is also seen in the second most sta-ble conformer CG+⁄g+⁄ (15.3% Fig. 7b). In the case of the third moststable AG+t (11% Fig. 7c), one sec-butyl group adopts an all-trans con-formation while the methyl of the other butyl moiety adopts a

CH3

HCH3

HH

CH3

HH

HH3C

CH3

HH

CH3HX

H

H CH3H

H3CX

H

H3C HH

H3C

CH3

H HH

H3CX

CH3

H HCH3

H

H

H CH3CH3

H

H

H3C HCH3

H

H

CH3H

HH3C

H

CH3H

CH3H

H

CH3CH3

HH

G++45/G+-45

T+45/T-45

G-+45 /G--45

G+*+45/G+*-45

T*+45 /T*-45

G-*+45/G-*-45

g++45/ g+-45

t+45 /t-45

g-+45 /g--45

g+*+45/g+*-45

t*+45/t*-45

g-+45/ g--45*

X

X X

ω ≈ 00±450 ω ≈ 1800±450 ω' ≈ 00±450 ω' ≈ 1800±450

A (ω ≈ 0±450, ω' ≈ 0±450)B (ω ≈ 180 ±450, ω' ≈ 0±450)C (ω ≈ 180±450, ω' ≈ 180±450)D (ω ≈ 0±450, ω' ≈ 180±450)

Left moieties Right moieties

φ = 600

φ = 1800

φ = -600

φ ' = 600

φ' = 1800

φ' = -600

Figure 5. Conformations of (S,S)-pyridine 1 (X = N) and (S,S)-pyridine-N-oxide 2 (X = N?O) based on the dihedral angles C1C2–C3H x = 0�/180 ± 45� and C2C3–C4C5, / = 60�,180�, �60� (left moieties) and dihedral angles C1

0C20–C3

0H, x0 = 0 ± 45�/180 ± 45� and C20C30–C4

0C50 , /0 = 60�, 180�, �60� (right moieties). For each set of values of x, x0 , /, /0

form 144 conformers. For the ease of notation for the two dihedral angles x and x0 , we use the subscript ±45. The 180 ± 45� value is equivalent to �145� and is the value thatwill be found in tables.

Table 1Dihedral angle values, Gibbs energy, relative Gibbs energy and population of 21 conformers of (S,S) pyridine 1. Since almost all of the conformers considered convergedapproximately toward structures that have x x0 dihedral angles close to 0� or to 180�, we do not use the subscript notation for 1

Labela Optimized geometryb Energyc DGd Pop.e (%)

x x0 / /0 Gibbs

1 AG+g+ �3.7332 �3.4725 63.4736 63.4340 �601.802461 0.000 29.912 CG+⁄g+⁄ 178.4050 172.9883 60.7029 60.7581 �601.801807 0.410 14.963 AG+t �3.1287 2.6309 63.5004 171.9250 �601.801501 0.602 10.814 BG+⁄g+ 175.0300 �3.9243 61.1439 63.4798 �601.801422 0.652 9.945 ATt 1.5886 1.8511 172.8902 172.8043 �601.801337 0.705 9.096 BG+⁄t 176.7679 2.1782 60.8406 172.5473 �601.800929 0.961 5.907 BT⁄g+ �152.8716 �4.4681 170.3497 63.1475 �601.800870 0.998 5.548 BTt⁄ �163.4651 1.9742 170.1082 172.5945 �601.800599 1.168 4.169 CG+⁄t 177.6478 �148.3507 60.7349 170.3493 �601.800324 1.341 3.11

10 CTt �151.6779 �151.1648 170.2712 170.2417 �601.799849 1.639 1.8811 AG+g� �4.1250 23.7787 63.4803 �67.2556 �601.799225 2.031 0.9712 BG�⁄g+ �139.0612 �4.1717 �66.4606 63.1277 �601.799148 2.079 0.8913 CG+⁄g�⁄ 176.5111 �136.8303 60.5411 �66.4957 �601.799007 2.167 0.7714 CG�⁄t �135.7829 �171.7729 �67.0168 170.2814 �601.798988 2.179 0.7515 BG�⁄t �136.2482 2.7753 �65.4994 172.0979 �601.798705 2.357 0.5616 AG�t 22.3485 1.1820 �68.2797 172.7100 �601.798235 2.652 0.3417 BG+⁄g� 174.3806 26.4229 61.0968 �67.0082 �601.797701 2.987 0.1918 BG+⁄g� �156.7499 23.5649 170.1179 �67.1024 �601.7974 3.203 0.1319 CG�⁄g�⁄ �135.9106 �133.8839 �66.5758 �66.6875 �601.796635 3.656 0.0620 BG�⁄g� �136.5656 22.3779 �65.7212 �67.7117 �601.795742 4.216 0.0221 AG�g� 23.2139 23.6833 �67.5008 �67.3941 �601.795393 4.435 0.02

a See figures for the labels.b Dihedral angle.c In Hartrees.d Relative energy differences between Gibbs energies in kcal/mol.e Population based on Gibbs energies.



gauche conformation. The fourth most stable conformer BG+⁄g+⁄

(10.2% Fig. 7d) also takes a similar all-trans conformation for bothsec-butyl moieties. The energy difference between these conformersis less than 1 kcal mol�1.

For (S,S)-pyridine-N-oxide 2, the conformers with largest popu-lations are CG+⁄

�45g+⁄�45 and CT⁄+45/�45t⁄+45/�45, the energy differ-

ences between these conformers are less than 0.5 kcal mol�1. Themost stable conformer is CG+⁄

�45g+⁄�45. For this conformer a

unique structure was found; no matter which combination of dihe-dral values was used to start the optimization (G+⁄

+45g+⁄+45, G+⁄

+45

g+⁄�45, G+⁄

�45g+⁄+45, G+⁄

�45g+⁄�45). All of these structures converged

toward the same final structure G+⁄�45g+⁄

�45 (see Fig. 8a). The twosec-butyl moieties adopt the all-trans-conformation. The next threemost stable conformers are of the T⁄t⁄ type (see Fig. 8b–d) and thistime the sec-butyl moieties adopt a gauche conformation.

In conclusion, for (S,S)-pyridine 1, the all-trans configuration ofthe sec-butyl moieties determine the most stable conformers,while for the oxidized form the (S,S)-pyridine-N-oxide 2, the moststable type of conformers change completely, and are stabilized

mostly by two intramolecular hydrogen bonds between the hydro-gen of the two methine groups.

3.3. Determination of the absolute configuration by comparisonof the experimental and theoretical IR and VCD spectra

In Figures 9a and b and 10a and b, the population weighted IRand VCD spectra of the first nine or fifteen conformers of (S,S)-pyr-idine 1 or (S,S)-pyridine-N-oxide 2 are compared with the associ-ated experimental spectra. In the same figures are shown the IRand VCD spectra of the first four most stable conformers. The vibra-tional frequencies and IR and VCD intensities were constructedfrom calculated dipole and rotational strengths, while assuming alorentzian band shape with a half width at a half maximum of4 cm�1. Center band frequencies were shifted by multiplying by0.985 to facilitate a comparison with the experimental spectra.55,56

Overall, good agreements between the experimental and predictedVCD and IR spectra of both compounds in the entire range of fre-quencies were achieved. This agreement indicates that (�)-

Table 2Dihedral angle values, Gibbs energy, relative Gibbs energy and population of 23 conformers of (S,S)-pyridine-N-oxide 2. For A type conformers we did not use any subscriptnotation because most of them have (x, x0) close to 0�

Labela Converged geometryb Energyc DGd Pop.e (%)

x x0 / /0 Gibbs

1 CG+⁄�45g+⁄

�45 152.1 152.7 63.2 64.0 �676.964209 0.000 21.02 CT⁄+45t⁄�45 �146.2 147.7 167.7 166.6 �676.964061 0.093 18.03 CT⁄+45t⁄+45 �147.5 �147.5 170.0 169.3 �676.963805 0.254 13.74 CT⁄�45t⁄�45 146.1 146.2 167.0 166.8 �676.96373 0.301 12.65 CG�⁄+45t⁄�45 �143.9 147.4 �65.7 166.7 �676.962897 0.823 5.26 CG�⁄+45g+⁄

�45 �141.9 149.5 �65.2 63.9 �676.962648 0.980 4.07 CG�⁄+45t⁄+45 �141.3 �144.4 �65.1 167.8 �676.962604 1.007 3.88 CT⁄+45g+⁄

�45 �145.6 150.3 167.3 64.3 �676.962565 1.032 3.79 BT⁄�45t 147.2 0.4 166.9 166.1 �676.962455 1.101 3.3

10 BT⁄+45g+ �144.1 �1.1 166.4 56.2 �676.962147 1.294 2.411 BG+⁄

�45g+ 149.6 �2.6 64.5 56.4 �676.962132 1.303 2.312 BT⁄�45g+ 146.6 �2.4 166.9 54.7 �676.961938 1.425 1.913 BG+⁄

�45t 149.3 �0.6 64.3 167.9 �676.961923 1.434 1.914 CG�⁄�45g�⁄�45 �143.2 �143.0 �66.0 �65.6 �676.961673 1.591 1.415 CT⁄�45g+⁄

�45 151.9 143.5 171.4 64.9 �676.961601 1.637 1.316 BT⁄+45t �144.9 0.5 167.6 166.2 �676.961500 1.700 1.217 BG�⁄+45g+ �141.9 �1.9 �65.1 55.5 �676.961057 1.978 0.718 BG�⁄+45t �142.7 0.1 �64.9 165.1 �676.960668 2.222 0.519 AG+g+ �2.4 �2.6 55.4 55.3 �676.960448 2.360 0.420 AG+t �1.7 0.7 56.4 �114.3 �676.959949 2.673 0.221 ATt 0.0 �0.2 165.9 165.9 �676.959597 2.894 0.222 CG�⁄�45g+⁄

�45 138.3 151.6 �85.0 64.0 �676.959137 3.183 0.123 BG�⁄�45g+ 138.1 �1.0 �85.5 55.9 �676.958515 3.573 0.1

a See figures for the labels.b Dihedral angle.c In Hartrees.d Relative energy differences between Gibbs energies in kcal/mol.e Population based on Gibbs energies.

Figure 6. Top view above the oxygen (light gray). The all-trans conformation of the sec-butyl moieties and the intramolecular –CH� � �O interaction for each type of conformer(a) A type of conformer (G+g+). The hydrogens involved in the intramolecular hydrogen bonds belong to the –CH2 and –CH3 groups; (b) B type of conformer (G+⁄

�45g+) withone –CH� � �O, one �CH2� � �O, and two �CH3� � �O interactions; (c) C type of conformer (G+⁄

�45g+⁄�45) with two –CH� � �O and two –CH3� � �O interactions. Carbon medium gray,

oxygen—light gray, nitrogen—dark gray, and hydrogen light white.



pyridine-N-oxide 2 and its corresponding reduced form (+)pyridine 1 have an (S,S)-configuration.

As seen in Figures 9a and 10a, the IR spectra of the four moststable conformers of 1 and 2 are similar to the experimental spec-tra. The two bands corresponding to the C–C vibration of the pyr-idine ring (�1605–1629 cm�1 and �1556–1566 cm�1) arepredicted for all conformers of both molecules, but with differentintensities as shown for the experimental spectra: they are moreintense for pyridine 1 conformers and less intense for pyridine-N-oxide 2 conformers. Other groups of bands that are reasonablywell predicted for each individual conformer, including their inten-sities, are the ring stretching modes (at �1420 cm�1 that caninclude the contribution of the –CH and –CH2 bending) and thebending modes of the –CH2, –CH3 groups of the sec-butyl moieties(broad bands at �1461.6 cm�1). For the conformers of pyridine-N-oxide 2, the three main supplementary bands are also wellreproduced (the –CH bending mode of the pyridine ring,�1169 cm�1, and the N?O stretching modes coupled with the

bending of the –CH groups �1253.3 cm�1 and 1219.2 cm�1). Allother conformers (not shown here) have similar patterns.

For the VCD spectra, the situation is slightly more complex,since there are regions where the intensity and the sign of VCDbands of each conformer differ or are slightly shifted with respectto each other (see Figs. 9b and 10b). This highlights the sensitivityof VCD spectroscopy to small conformational changes. This can beeasily followed in the spectra of the three CT⁄t⁄ conformers (CT⁄+45

t⁄�45, CT⁄+45t⁄+45, CT⁄�45t⁄�45). For both compounds, the spectra ofthe most stable conformers, AG+g+ and CG+⁄

�45g+⁄�45 match the

best with the experimental spectrum. Most of the bands are moreintense than the experimental bands, but in the final populationweighted spectra, there are intensity cancelations, because theirpopulation does not exceed 50%. Thus, it results in much weakerVCD signals and patterns similar to the experimental ones.

Considering that the two molecules are fairly flexible and have asignificant number of relevant conformers with noticeably differ-ent VCD patterns, the overall agreement between the experimentaland the population weighted VCD spectra of both compounds isgood and supports the identified conformers and conformationaldistribution.

3.4. Geometrical evidence and NBO/NLMO analysis of the fourcentered intramolecular C–H� � �O hydrogen bonds in the conformers of pyridine-N-oxide 2

As mentioned earlier, within each conformer of pyridine-N-oxide 2 up to four C–H� � �O intramolecular hydrogen interactionscan form on the nitroxide oxygen. An important piece of evidencefor intramolecular hydrogen bonds is given by the H� � �O distancesand the C–H� � �O angles. The plot of these parameters in Figure 11is instructive with all of the conformers exhibiting geometricalparameters acceptable for the formation of the intramolecularhydrogen bonds and accordingly of the four centered contacts onthe nitroxide oxygen. With two exceptions, which are slightlyhigher than the limit of the Van der Waals separation value of2.75 Å, all of the other distances are smaller. The Van der Waalsseparation is based on a spherical O atom with r � 1.50 Å and aspheroidal H atom with a side-on radius rs � 1.25 Å. The shortestdistances are registered for the hydrogen belonging to the methinegroups (–CH) and are shorter with 0.4–0.5 Å than the Van derWaals separation (2.27–2.35 Å). As shown previously these arepossible in all of the C type conformers and in the B type conform-

Figure 8. Top view (above the oxygen) of the four most stable conformers of the (S,S)-pyridine-N-oxide 2 obtained by the DFT method at B3PW91 level (a) CG+⁄�45g+⁄

�45; (b)CT⁄+45t⁄�45; (c) CT⁄�45t⁄+45; (d) CT⁄�45t⁄�45. The lines indicate the x, x0 dihedral angles that are tilted with approximately ±45� from 0� to 180�/180�. White balls—hydrogen,light gray balls—oxygen, medium gray balls—carbon, dark gray balls—nitrogen.

Figure 7. Top view (above the oxygen) of the four most stable conformers of the(S,S)-pyridine 1 obtained by the DFT method at B3PW91 level (a) AG+g+; (b) CG+⁄g+⁄;(c) AG+t; (d) BG+⁄g+. The lines indicate the x, x0 dihedral angles. These are veryclose to the values of 0� and 180�. White balls—hydrogen, Light gray balls—oxygen,medium gray balls—carbon, dark gray balls—nitrogen.



ers for one sec-butyl moiety. Among these, the shortest distances�2.27 Å, are found in the conformers which have in their structurethe G+⁄, g+⁄ moieties (all-trans conformation of the sec-butyl moie-ties). This indicates that these are the strongest interactions. Themost stable conformer of pyridine-N-oxide 2, CG+⁄

�45g+⁄+45 is the

only structure that contains two of these shortest intramolecularhydrogen bonds (C3–H� � �O� � �C3

0–H). With regard to the H� � �Olengths of the interactions between the hydrogen belonging tothe methylene (–CH2) and methyl (–CH3) groups and oxygen, theseare longer and most of them range between 2.34 and 2.55 Å.Correlated with their length and also with the lower acidity ofthese groups, these interactions are expected to be weaker. Thelongest interactions �2.84–2.82 Å, which are found in the most

stable conformer, are not excluded from forming weak hydrogenbonds, because they are shorter than 3 Å.

Concerning the values of the C–H� � �O angle, they are higherthan 90� and range between 90� and 120� (see Fig. 11). Similarvalues have been reported for many other intramolecular bondsof the C–H� � �O type.57 The rule that the closer the angle is to180� the shorter the H� � �O distance is, is only preserved withineach type of interaction (C–H� � �O, HC–H� � �O, H2C–H� � �O). Forexample, for the methine groups (–CH) of both the B and C typeconformers, the bond angle increases when decreasing the bondlength. When performing the comparison among all types ofinteractions, this rule is not followed; this is because in pyridine-N-oxide 2, the intramolecular C–H� � �O bond angle is fixed by the

Figure 9. Comparison of the experimental and population weighted spectra of the nine most stable conformers of pyridine 1 calculated at the IEFPCM/B3PW91/TZVP level:(a) IR and (b) VCD spectra (two bottom traces). The four top spectra belong to the four most stable conformers.

Figure 10. Comparison of the experimental and population weighted spectra of the fifteen most stable conformers of pyridine-N-oxide 2 calculated at IEFPCM/B3PW91/TZVPlevel: (a) IR and (b) VCD spectra (two bottom traces). The four top spectra belong to the four most stable conformers.



molecular geometry. Therefore, the shortest distances formedbetween the hydrogen belonging to the –CH group have corre-sponding smaller angle values than the longer distances formedby the hydrogen belonging to the –CH2 and –CH3 groups.

Another geometrical feature related either to the intra- or inter-molecular hydrogen bond, is the relationship between the H� � �Olength and the length of the C–H bond. Within various studies ithas been shown that in some molecular systems, the formationof the C–H� � �O either intra- or intermolecular hydrogen bondshortens the corresponding CH bond.20,22,31,58 Moreover Scheineret al.32 in their studies of intermolecular complexes, showed thatregardless of whether the CH bond is stretched or shortened bythe formation of the H-bond, the CX (X = H or F) bonds that arenot directly involved in the H-bond are lengthened. In Figure 12are shown the C–H bond lengths belonging to the –CH2 and –CH3

groups involved in the C–H� � �O intramolecular interaction againstthe C–H bond lengths belonging to the same groups that are notinvolved in the interaction. Also shown are the C–H bond lengths

belonging to the two methine groups of the sec-butyl moietiesC3–H versus C3

0–H. Therefore, the bond lengths of the proton donor(–CH2, –CH3, –CH) directly involved in the C–H� � �O interaction areshorter than those not involved directly and the differencesbetween them are in the range 10�3–8 � 10�3 Å. In the A type con-formers both C3–H and C3

0–H bonds are longer than the corre-sponding ones involved in the intramolecular bonds in the B andC type conformers. The best evidence of bond variation can be seenin the B type conformers, where the bonds associated with theintramolecular interaction (C3–H) are shorter by 2 � 10�3–3 � 10�3 Å than the corresponding bonds not involved in this inter-action (C3

0–H). In the A and C type conformers, the differencesbetween the two bonds are much smaller and are of the order of10�4–10�5 Å. Unfortunately, in order to establish whether thereis bond shortening or lengthening, if there is a connection betweenthem or whether the electronic factors play a role in the origin ofthis behavior, our systems are quite complex while these aspectsare still under debate even for relatively simple systems.59,60

The NBO analysis carried out for all of the conformers, revealedweak intramolecular donor acceptor orbital interactions corre-sponding to the C–H� � �O contact: mostly LP(3)O ? BD⁄(1)C–H anddepending on the conformations from LP(1)O and LP(2)O ? BD⁄(1)-C–H with the second order perturbation energies smaller than0.5 kcal/mol. For cases that have H� � �O larger than the Van derWaals separation, no interactions were found. Moreover, the mostimportant interaction energies are related to the resonance in themolecule and the electron transfer from the third oxygen lone pairelectrons LP(3) O (pz orbital) to the antibonding acceptor p⁄ (N–C2) of the pyridine ring. Depending on the molecule conformations,the values range from 35 to 45 kcal/mol. This enhanced p⁄ (N–C2)NBO further conjugates with p⁄ (C–C1

0) resulting in the strongeststabilization of �65 kcal/mol. Therefore a high percentage of elec-tron density of the oxygen lone pair electrons, including LP(1) andLP(2), is delocalized onto the pyridine ring. This significantlyreduces the possibility of higher charge transfer to the four C–Hr⁄ antibonding orbitals. The natural localized molecular orbitalanalysis (NLMO) indicates the LP(3) O to be one of the most delocal-ized NLMO in all of the conformers with�85% ± 2 contribution fromthe localized LP(3) O parent NBO. The delocalization of �15% ± 2consists mainly of hybrids of pyridine N, C1, C2, C1

0, C20 atoms but

also of hybrids of the four hydrogen atoms that are implied in theintramolecular C–H� � �O contacts including those cases when theH� � �O distances are longer than the Van der Waals separation(�0.02–0.05% contribution from the hydrogens belonging to –CH2

and –CH3 groups and �0.06–0.09 contribution from the hydrogenbelonging to –CH). In order to gain a better understanding of the fac-tors influencing the characteristics of these intramolecular hydro-gen bonds, such as the electric field induced by the oxygenacceptor, the exchange repulsive, dispersion charge transfer, intra-molecular intrinsic effects and so on, different methods have to becombined and further studies carried out. However, through thedata presented herein we have managed to show evidence for theexistence of four centered C–H� � �O intramolecular bonds in all ofthe conformers of pyridine-N-oxide 2.

4. Conclusions

We have succeeded in synthesizing and separating enantiopure(�)- and (+) 2,6-di-sec-butyl-4-methylpyridine and its oxidizedforms (+)- and (�)-2,6-di-sec-butyl-4-methylpyridine-N-oxideand then characterized them using IR and VCD spectroscopy. Thesecharacterization methods were completed by DFT calculations toidentify the right configuration for each compound and to identifythe lowest energy conformers in CD2Cl2 by using the implicit sol-vent model.

Figure 11. Scatter plot of nonbonded interatomic distances d(H� � �O) against the(C–H� � �O) angle of all of the possible intramolecular hydrogen bonds between thehydrogen belonging to –CH, –CH2, and –CH3 and the nitroxide oxygen of the A, B,and C type of conformers of pyridine-N-oxide 2.

Figure 12. Scatter plot of Cn–H/Cn0–H bond lengths of (–CH2, –CH3) groups thatinteract with O against Cn–H/Cn0–H belonging to the same group (–CH2, –CH3) thatdo not interact with O. Exceptions are the A (C3–H vs C3

0–H) bond lengths wherenone of them interact with O and C (C3–H vs C3

0–H) bond lengths where both ofthem interact with O.



The comparison of experimental with ab initio predicted IR andVCD spectra indicate the following; (i) (+)-2,6-di-sec-butyl-4-methylpyridine-N-oxide and its reduced form (�)-2,6-di-sec-butyl-4-methylpyridine have an (S,S)-configuration; (ii) the goodfit between the experimental and theoretical spectra confirmsthe reliability of the conducted conformational analysis; (iii) ninepredominant conformers of (S,S)-pyridine 1 add up to 96% of thepopulation, with the first four most stable structures adding upto 67% of the population. The number of the most stable conform-ers for (S,S)-pyridine-N-oxide 2 with a population of over 1%increased to fifteen with the sum of their population over 96%and the first four most stable conformers adding up to 71% of thepopulation; (iv) in both compounds, one of the stabilizing factorsis the all-trans conformation adopted by the sec-butyl moieties.The G+, g+, G+⁄, g+⁄ conformers adopt an all-trans conformation.The most stable conformer of (S,S) pyridine 1 is G+g+, while thatof (S,S)-pyridine-N-oxide is G+⁄g+⁄; (v) in addition to the all-transeffect, the most stable conformers of (S,S)-pyridine-N-oxide 2 arestabilized by two simultaneous intramolecular hydrogen bondsbetween the methine hydrogens of the sec-butyl chains and thenitroxide oxygen of the pyridine ring (C3–H� � �O� � �H–C3

0). The moststable conformer CG+⁄

�45g+⁄�45 has the two shortest H� � �O

(�2.27 Å) and the two longest interactions (�2.82 Å); (vi) with afew exceptions, all of the H� � �O length values, together with thevalues of the corresponding C–H� � �O angles of all four possibleintramolecular hydrogen bonds that can form between the hydro-gen of the –CH, –CH2 and –CH3 donor groups and nitroxide oxygenacceptor of the pyridine ring, are within the accepted values thatcorrespond to weak hydrogen bonds; (viii) using NBO and NLMOanalysis, weak interactions between the oxygen electron lone pairsLP(1), LP(2) and LP(3) O and the C–H r⁄ antibonding orbitals of thefour C–H� � �O contacts were found; (ix) a uniform variationbetween the C–H bond lengths belonging to all proton donors –CH, –CH2, and –CH3 directly involved in the intramolecular interac-tion and those not involved directly was found.

Acknowledgements

F.T. acknowledge support from the strategic grant POSDRU/89/1.5/S/58852, Project ‘Postdoctoral programme for training scien-tific researchers’ cofinanced by the European Social Found withinthe Sectorial Operational Programme Human Resources Develop-ment 2007–2013. The research was supported in part from CNC-SIS–UEFISCSU, Romania (Project Number PNII—IDEI 53/2007) isgratefully acknowledged.

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