Investigation of solute–solvent interactions in phenol compounds: accurate ab initio calculations...

Organic &Biomolecular Chemistry

PAPER

Cite this: Org. Biomol. Chem., 2013, 11,7400

Received 29th July 2013,Accepted 5th September 2013

DOI: 10.1039/c3ob41556b

www.rsc.org/obc

Investigation of solute–solvent interactions in phenolcompounds: accurate ab initio calculations of solventeffects on 1H NMR chemical shifts†

Michael G. Siskos,*a Vassiliki G. Kontogianni,a Constantinos G. Tsiafoulis,b

Andreas G. Tzakosa and Ioannis P. Gerothanassis*a

Accurate 1H chemical shifts of the –OH groups of polyphenol compounds can be calculated, compared

to experimental values, using a combination of DFT, polarizable continuum model (PCM) and discrete

solute–solvent hydrogen bond interactions. The study focuses on three molecular solutes: phenol,

4-methylcatechol and the natural product genkwanin in DMSO, acetone, acetonitrile, and chloroform.

Excellent linear correlation between experimental and computed chemical shifts (with the GIAO method

at the DFT/B3LYP/6-311++G(2d,p) level) was obtained with minimization of the solvation complexes at

the DFT/B3LYP/6-31+G(d) and DFT/B3LYP/6-311++G(d,p) level of theory with a correlation coefficient of

0.991. The use of the DFT/B3LYP/6-31+G(d) level of theory for minimization could provide an excellent

means for the accurate prediction of the experimental OH chemical shift range of over 8 ppm due to: (i)

strong intramolecular and solute–solvent intermolecular hydrogen bonds, (ii) flip-flop intramolecular

hydrogen bonds, and (iii) conformational effects of substituents of genkwanin. The combined use of

ab initio calculations and experimental 1H chemical shifts of phenol –OH groups provides a method of

primary interest in order to obtain detailed structural, conformation and electronic description of solute–

solvent interactions at a molecular level.

Introduction

Nuclear magnetic resonance (NMR) is one of the most power-ful and widely used spectroscopic techniques for the determi-nation of structure and dynamics of complex molecules insolution and in the solid state. Recently, the potential ofquantum mechanical (QM) methods has been shown for accu-rate chemical shift calculations at a modest computationalcost.1–4 However, in order to employ QM methods, the errorbetween predicted and experimental NMR data needs to be

within a few ppm for heteroatoms (such as 13C, 15N and 17O)and significantly smaller for 1H chemical shifts.

It is well recognized that NMR chemical shift depends onthe electron densities around the nuclei which can be influ-enced by the surrounding environment. Solvent dependentchemical shift variations in solution, therefore, contain impor-tant structural information on solute–solvent interactions suchas hydrogen bonding. Since the majority of NMR experimentsare performed in solution, a suitable treatment of the solventeffect is needed. The accurate determination of chemical shiftsin solution by ab initio computational methods, however,places severe demands on both the electron correlation pro-cedure used and the model of how individual solvent mole-cules interact with the solute molecules. Several theoreticalapproaches have been proposed for treating chemical shifts insolution.5,6 These approaches can be classified broadly intosemi-empirical7,8 or quantum chemical9,10 continuum modelsand molecular dynamics simulations (MD) with empirical orab initio force fields.11,12 The MD approach, in which anumber of liquid configurations of a given size are obtainedand treated as a supermolecule in a quantum chemical calcu-lation, has been successfully applied to investigate 1H and 17Ochemical shift variations in water clusters.13,14 The approachbased on molecular simulation has furthermore been refined

†Electronic supplementary information (ESI) available: Fig. S1. Temperaturedependencies of the –OH proton of phenol (1) in DMSO-d6, acetone-d6, aceto-nitrile-d3 and chloroform-d1. Fig. S2. Charge density (calculated by the Mullikenand natural bond orbital (NBO) at the DFT/B3LYP/6-31+G(d) level of theory) ofPh–O and –H of the intermolecular bond of 1 : 1 phenol (1) + solvent complexesas a function of δtheor. Fig. S3. Charge density (calculated by the Mulliken andnatural bond orbital (NBO) at the DFT/B3LYP/6-311++G(d,p) level of theory) ofPh–O and –H of the intermolecular bond of 1 : 1 phenol (1) + solvent complexesas a function of δtheor. See DOI: 10.1039/c3ob41556b

aSection of Organic Chemistry and Biochemistry, Department of Chemistry,

University of Ioannina, Ioannina GR 45110, Greece. E-mail: [email protected],

[email protected], [email protected], [email protected]; Fax: +30 2651008799;

Tel: +30 2651008389bNMR Center, University of Ioannina, Ioannina GR 45110, Greece.

E-mail: [email protected]

7400 | Org. Biomol. Chem., 2013, 11, 7400–7411 This journal is © The Royal Society of Chemistry 2013

www.rsc.org/obc

by adding a continuum solvent to the solute–solvent clustersso as to account for long-range electrostatic effects.15,16 Kleinet al.17 investigated the limits of the polarizable continuummodels (PCM) theory and the role of hydrogen bond geometryand cooperativity in ab initio calculations of 17O chemicalshifts of water clusters. Nevertheless, there has been a limitednumber of quantitative treatments of differential solventeffects on 1H and heteronuclear chemical shifts of H2O

18 andcomplex organic solutes.19,20

The chemical shifts of hydroxyl groups21 and more specifi-cally the phenol OH groups22 have rarely been investigated atthe ab initio level despite that they are among the most impor-tant and frequently encountered functional groups in organicand biomolecular compounds. It is of interest that around 7%of the current drugs contain phenol –OH groups (Drug Bank,http://www.drugbank.ca). This may be attributed to the factthat the use of solvent dependent chemical shift changes ofthe hydroxyl protons, in solution NMR, present experimentalchallenges for hydrogen bonding and conformational effectsdue to rapid exchange of the –OH protons with protons of theprotic solvents23,24 or with labile protons of solute moleculesand/or of the residual H2O in non-protic solvents.25 Recentwork from our laboratory has demonstrated that high resolu-tion 1H NMR resonances of phenol –OH groups can beobtained by the use of dry non-protic solvents, addition ofpicric acid and/or by decreasing the sample temperature.26

We report therein experimental and computed 1H chemicalshifts of hydroxyl protons of polyphenol –OH compounds(Scheme 1) with the combined use of DFT, conductor likepolarized continuum model (CPCM) theory and discretesolute–solvent hydrogen bonding interactions. The choice ofphenol compounds has been dictated by the fact that

significant chemical shift changes have been observed experi-mentally and the solvation state of hydroxyl protons wasshown to be a key factor in determining the experimentalvalue of the chemical shift.27 Solvent induced deformation ofthe electronic charge distribution, therefore, should be signifi-cant and accurate ab initio methods could become of primaryinterest in order to obtain a proper structural and electronicdescription of solute–solvent interactions.

Results and discussionExperimental OH 1H chemical shift

The multi-functional concentration dependence of the phenol–OH groups can be simplified by measuring the –OH chemicalshift of the phenolic compounds at concentration levels from5 to 8 mM in DMSO-d6, acetone-d6, CD3CN and from 0.5 to5 mM in CDCl3 solutions. Fig. S1† shows the temperaturedependence of the hydroxyl protons chemical shifts, Δδ/ΔT, ofphenol (1) in various solvents. The temperature dependentchanges in chemical shifts were found to be linear with coeffi-cient of determination R2 > 0.996. Due to the strong tempera-ture effect, all NMR chemical shifts are reported at 298 K(Table 1).

The chemical shifts of the –OH group of phenol (1) inDMSO-d6 (9.36 ppm), acetone-d6 (8.29 ppm), CD3CN(6.90 ppm), and CDCl3 (4.65 ppm) clearly demonstrate that themagnitude of the shifts is related to the strength of hydrogenbonding of the solvent with a differential solvent effect Δδ =δ(DMSO-d6) − δ(CDCl3) = 4.71 ppm (Fig. 1 and Table 1). In thecase of 4-methylcatechol (2) the two OH groups in an orthorelationship were found to be more shielded compared to theOH group of phenol (1). Assignment of the OH groups wasachieved with the use of 1H–13C HMBC experiments. Thedifferential solvent effects Δδ = δ(DMSO-d6) − δ(acetone-d6) of0.99 and 1.06 ppm and Δδ = δ(DMSO-d6) − δ(CD3CN) of 2.15and 2.19 ppm for the C-1 OH and C-2 OH groups of 4-methyl-catechol (2) were found to be similar to that of phenol(Table 1). This demonstrates no significant solvation differ-ences between the C-1 OH and C-2 OH groups of 4-methylcate-chol compared to that of phenol (1). In contrast, significantlysmaller chemical shift differences were observed for C-1 OHand C-2 OH groups of 4-methylcatechol between DMSO-d6 and

Scheme 1 Chemical formulas of phenol (1), 4-methylcatechol (2) and genkwa-nin (3).

Table 1 Chemical shifts and Δδ/ΔT values of hydroxyl protons of phenol (1), 4-methylcatechol (2) and genkwanin (3), in DMSO-d6a, acetone-d6

b, CD3CNc, and

CDCl3d and their shielding differences at 298 K

Compound δDMSO-d6Δδ/ΔTe δAcetone-d6

Δδ/ΔTeΔδ(δDMSO-d6

−δAcetone-d6

) δCD3CN Δδ/ΔTeΔδ(δDMSO-d6

−δCD3CN) δCDCl3 Δδ/ΔTe

Δδ (δDMSO-d6−

δCDCl3)

(1) C-1 OH 9.36 −5.4 8.29 (8.26) f −9.0 1.07 6.90 −6.7 2.46 4.65 −5.8 4.71(2) C-1 OH 8.57 −6.9 7.58 −8.9 0.99 6.42 −5.7 2.15 4.88 −5.9 3.69

C-2 OH 8.71 −7.1 7.65 −9.2 1.06 6.52 −5.8 2.19 5.02 −5.7 3.69(3) C-5 OH 12.95 −2.1 13.03 −1.4 −0.08 12.95 −0.8 0.00 12.93 c 0.02

C-4′ OH 10.56 −8.9 9.26 −8.9 1.30 7.70 −8.5 2.86 5.36 c 5.20

a Concentration C = 5 mM. b C = 5 mM. c C = 5 mM. d C = 0.5 mM, except for genkwanin (3) in which concentration could not be determined dueto low solubility. e Expressed in parts per 109 (ppb) per K. f The chemical shift in 90% acetone–10% acetone-d6.

Organic & Biomolecular Chemistry Paper

This journal is © The Royal Society of Chemistry 2013 Org. Biomol. Chem., 2013, 11, 7400–7411 | 7401

CDCl3 (Δδ = 3.69 ppm), compared to that in phenol (Δδ =4.71 ppm) which should be attributed to an intramolecularflip-flop hydrogen bonding28,29 in CDCl3 solution. Similar con-clusions cannot be drawn from the Δδ/ΔT temperature coeffi-cients (Table 1) which are very similar to CDCl3 for the phenol(1) and 4-methylcatechol (2) OH groups. This demonstratesthat the solvent induced chemical shift differences are morereliable indicators of the solvation and hydrogen bond statecompared to Δδ/ΔT values.

The chemical shifts and Δδ/ΔT values of the phenol OHprotons of the natural product genkwanin (3), in DMSO-d6,acetone-d6, CD3CN, and CDCl3 are illustrated in Table 1. Thechemical shift difference between DMSO-d6 and CDCl3 is5.20 ppm for C-4′ OH of genkwanin (Table 1). In contrast, verysmall chemical shift difference Δδ[(DMSO-d6) − (CDCl3)] ≈0.2 ppm was observed for the C-5 OH proton of genkwanin.Due to a strong intramolecular C-5 OH⋯OC-4 hydrogen

bond30 the surrounding solvent molecules around theC-5 hydroxyl proton are excluded, leading to a significantlyreduced solvation and a consequent small shielding solventdependence relative to that of the C-4′ OH proton. The pres-ence, therefore, of intramolecular hydrogen bond interactionscan be deduced from the solvent independent chemical shiftsof hydroxyl proton signals.

The large experimental 1H chemical shift range of phenolicOH groups of over 8 ppm due to hydrogen bonding andsolvent effects provides an excellent means for testing accurateab initio calculations of chemical shifts and, thus, descriptionof solute–solvent interactions at the atomic level. Surprisingly,the range of 17O chemical shifts of phenolic compounds is anorder of magnitude smaller than those of the carbonyl com-pounds31,32 and do not appear to correlate with the hydrogenbonding strength of the solvents.31,33,34

Ab initio calculations

Calculations of polarizable continuum model (PCM) vs.PCM-discrete phenol + solvent hydrogen bonded complexes-effects of basis set. The calculated chemical shifts of aromaticprotons of phenol (1) were found to be very close to the experi-mental values by using either HF or DFT calculations with avariety of hybrid functional and basis sets. In contrast, the cal-culated phenolic OH proton chemical shifts with the polarizedcontinuum model (δΟH(CHCl3) = 4.27 ppm, δΟH(MeCN) =4.44 ppm, δΟH(acetone) = 4.42 ppm and δOH(DMSO) =4.44 ppm) were found to deviate significantly from the experi-mental ones (δΟH(CDCl3) = 4.65 ppm, δΟH(CD3CN) = 6.90 ppm,δΟH(acetone-d6) = 8.29 ppm, and δOH(DMSO-d6) = 9.36 ppm(Table 1)), especially in the case of solvents of high dielectricconstant and hydrogen bonding strength. This is to beexpected since this model is the quantum mechanical formu-lation of the Onsager reaction field model, used to describethe bulk solvent effects, and does not include any specificsolvent–solute interactions like hydrogen bonds.22,35 In con-trast, the DFT method with the B3LYP hybrid functional36–38

6-31G(d), 6-31+G(d) and 6-311++G(d,p) basis set, asimplemented in the Gaussian 03 package,39 resulted in anexcellent improvement of the calculated OH chemical shiftwhen using discrete PhOH + solvent complexes. The GIAOmethod with the DFT/B3LYP/6-311++G(2d,p) functional wasimplemented by minimizing a discrete complex betweenPhOH and a single solvent molecule in the gas phase usingeither the DFT/B3LYP/6-31+G(d) or DFT/B3LYP/6-311++G(d,p)basis set (Table 2).

The computed geometries (Table 3) were then verified asminimum by frequency calculations at the same level of theory(no imaginary frequencies). To convert 1H-NMR chemicalshifts of the molecules to the ppm scale, the isotropic valuesof hydrogens in the molecules were subtracted from those ofthe hydrogens in tetramethylsilane (TMS) (the GIAO chemicalshifts of TMS were calculated at the same level of theory andits geometry with the same basis sets). Additional calculationswere carried out for the minimization of the PhOH + acetonecomplex using the cc-pVTZ method. The results indicated only

Fig. 1 1H NMR spectra (400 MHz, T = 298 K, number of scans = 8 to 128, totalexperimental time = 1 to 15 min) of (A) 4-methylcatechol (2) in (a) DMSO-d6

(C = 8 mM), (b) acetone-d6 (C = 6 mM), (c) CD3CN (C = 7 mM) with the additionof picric acid (2 μL of 8 mM), and (d) CDCl3 (C = 5 mM); (B) genkwanin (3) in(a) DMSO-d6 (C = 5 mM) with the addition of picric acid (4 μL of 10 mM),(b) acetone-d6 (C = 5 mM) with the addition of picric acid (2 μL of 8 mM) and(c) CD3CN (C = 5 mM) with the addition of picric acid (4 μL of 8 mM).

Paper Organic & Biomolecular Chemistry


a minor improvement in the calculated chemical shifts com-pared to the experimental value. Generally, very large basissets were not found to be necessary to reproduce accuratelythe experimental chemical shifts.

Structural details of 1 : 1 phenol (1) + solvent discrete hydro-gen bonded complexes. The minimum energy conformationfor the 1 : 1 phenol (1) + DMSO complex at the DFT/B3LYP/6-311++G(d,p) level of theory is shown in Fig. 2. In this confor-mation the DMSO molecule was found to interact with thephenolic –OH hydrogen atom through the SvO bond. The aro-matic ring, the OH group and the SvO group were found to bein the same plane, while the two methyl groups of DMSO areperpendicular and symmetrical to this plane. The stabilizationof this geometry may be attributed to the strong intermolecu-lar hydrogen bond O–H⋯OvS (distance of 1.734 Å, Table 3)

and the secondary hydrogen bonds between the phenolicoxygen and a hydrogen of methyl groups of DMSO (O⋯H–Cdistance of 2.720 Å). An almost identical conformation wasobtained by using the lower computational cost DFT/B3LYP/6-31+G(d) level of theory. This geometry, however, is a tran-sition state (one imaginary frequency) when using the simplebasis set 6-31G(d) without diffuse functions at the DFT/B3LYPand at the HF/B3LYP level of theory. In the minimum energyconformations, in these cases, the OvS bond of the DMSOmolecule was found to form torsional angles versus the phenolmolecule of 55° and 58°, respectively.

In the case of the 1 : 1 PhOH + MeCN complex and by usingthe DFT/B3LYP/6-311++G(d,p) level of theory, both moleculeswere found to be in the same plane (Fig. 3). The intermolecu-lar hydrogen bond between the (O)H⋯NuC atoms was foundto be 1.995 Å and the angle between the O–H⋯N atoms 171.5°(Table 3). An analogous geometry was observed with the DFT/B3LYP/6-31G+(d) level of theory (Table 3). Using the simplestDFT/B3LYP/6-31G(d) basis (without diffusion function), asmall deviation of ∼3° was observed in the dihedral anglebetween the phenyl ring and the CuN bond of the acetonitrilemolecule. A similar geometry was reported in the literature forthe 1 : 1 phenol + CH3CN complex at the B3LYP/6-31G(d,p),40

and MP2/6-31+G(d,p), MP2/6-31G(d), and B3LYP/6-31+G(d,p)41

computational levels.

Table 2 Calculated OH 1H–NMR chemical shifts (relative to TMS, ppm) of 1 : 1 PhOH + solvent complexes with the gauge invariant atomic orbitals (GIAO) methodat the DFT/B3LYP/6-311++G (2d,p) level of theory in the gas phase and by using the CPCM model

1 : 1 PhOH +solventcomplex

DFT/B3LYP 6-31+G(d)geometry optimization,gas phase

DFT/B3LYP 6-31+G(d)geometry optimization,CPCM

DFT/B3LYP 6-311++G(d,p)geometry optimization,gas phase

DFT/B3LYP 6-311++G(d,p)geometry optimization,CPCM

Experimentalvalues

PhOH + CHCl3 3.96 4.61 3.85 4.49 4.65PhOH + MeCN 6.43 6.80 6.42 6.79 6.90PhOH + acetone 8.60 8.95 8.48 8.83 8.29

8.71a

PhOH + DMSO 9.02 9.31 9.08 9.37 9.36

a Calculations using the DFT/B3LYP/cc-pVTZ method.

Table 3 Selected optimized geometrical data of 1 : 1 PhOH + solvent hydrogen bonded complexes with the DFT/B3LYP functional for various basis sets

1 : 1 PhOH + solventcomplex

Various basis sets atDFT/B3LYP functional

Distance(O)H⋯Xa

DistanceO(H)⋯Xa

AngleO–H⋯Xa

Dihedral anglesC1–O–H⋯Xb (C1–O–H⋯Y)b

PhOH + DMSO 6-311++G(d,p) 1.734 2.686 160.9 0(0)6-31+G(d) 1.753 2.716 162.6 0(0)6-31G(d) 1.743 2.707 162.9 123.2 (127.6)

PhOH + MeCN 6-311++G(d,p) 1.995 2.960 171.5 179.7 (179.8)6-31+G(d) 2.005 2.976 172.0 179.6 (179.6)6-31G(d) 1.998 2.971 173.9 −177.8 (−177.5)

PhOH + acetone 6-311++G(d,p) 1.843 2.806 168.5 165.4 (166.9)6-31+G(d) 1.844 2.815 169.2 166.4 (168.4)6-31G(d) 1.846 2.811 166.7 110.3 (116.6)cc-pVTZ 1.838 2.800 167.9 129.3 (132.8)

PhOH + CHCl3 6-311++G(d,p) 2.175 3.259 178.8c −179.0 (−179.1)6-31+G(d) 2.175 3.262 178.4c −179.3 (−179.4)6-31G(d) 2.141 3.228 179.0c −179.1 (−179.4)

a X = O for DMSO and acetone, X = N for CH3CN and X = C for CHCl3.bDihedral angles [C1–O–H⋯X] (X = O for DMSO and acetone, X = N for

CH3CN and X = H for CHCl3) and [C1–O–H⋯Y] (Y = S for DMSO, Y = C(O) for acetone, Y = C(N) for CH3CN and X = C(H) for CHCl3).c The O⋯H–

CCl3 angle.

Fig. 2 PhOH + DMSO 1 : 1 complex optimized at the DFT/B3LYP/6-311++G(d,p)(left) and DFT/B3LYP/6-31G(d) level of theory (right).



In the case of the 1 : 1 PhOH + acetone complex minimiz-ation calculations a different situation was observed. In allcases, the plane of the acetone molecule was found to deviatefrom the plane of the aromatic ring. The dihedral anglebetween the planes of two molecules was found to be stronglydependent upon the basis set used for minimum optimi-zations. When diffusion function was incorporated in the cal-culation, this angle was found to be smaller. For example, thecalculations at the DFT/B3LYP/6-311++G(d,p) (Fig. 4) and DFT/B3LYP/6-31+G(d) level of theory demonstrated values of 165.4°and 166.4° (Table 3), respectively, while with the 6-31G(d)basis set a significant change in the dihedral angle wasobserved (110.3°). An intermediate value (129.3°) was calcu-lated by using the Dunning’s correlation consistent basis setsTriple-zeta (cc-pVTZ) (Fig. 4 and Table 3). The internuclear dis-tance between (O)H and acetone oxygen was found to be1.843 Å and the O–H⋯O angle 168.5° at the 6-311++G(d,p)level of theory (Table 3).

In the minimum energy 1 : 1 PhOH + CHCl3 complex, byusing the DFT/B3LYP/6-311++G(d,p) level of theory, the CHCl3molecule was found to orient across the phenyl plane (Fig. 5).A typical medium strength σ-type linear hydrogen bond was

observed between the lone electron pair of the phenolicoxygen and the hydrogen of chloroform with H⋯O distance of2.175 Å and a Cipso–O⋯H angle of 132.5°. Using the 6-31+G(d)basis set, a similar geometry was found with a Cipso–O⋯Hangle of 131.7°. Interestingly, a similar geometry was reportedin the literature for the 1 : 1 phenol (1) + CH3X (X = CN, F, Cl)complexes using the MP2/6-31+G(d) and MPWB1 K/6-31+G(d)level of calculation.42

Mulliken and natural bond orbital analysis of 1 : 1 phenol(1) + solvent discrete hydrogen bonded complexes-effects of(O)H⋯X and O(H)⋯X distances. Table 4 represents aMulliken and natural bond orbital (NBO) analysis that hasbeen carried out for PhOH and 1 : 1 PhOH + solvent complexeswith the DFT/B3LYP/6-311++G(d,p) level of theory. The magni-tude of the NBO charge density on the phenolic oxygen andproton indicates a very poor correlation with 1H chemicalshifts with correlation coefficients of 0.696 and 0.715, respecti-vely (Fig. S2 and S3†). Correlations with the Mulliken chargedensity on the 1H chemical shifts were even worse. In contrast,increasing the distance of the (O)H⋯X hydrogen bond withoutchanging any other parameter has a very significant effect innuclear chemical shifts with the exception of the 1 : 1 PhOH +CHCl3 complex (Fig. 6).

Beyond 2.5 Å the increase in nuclear shielding was found tobe comparably moderate. For distances ≤2.1 Å the plots maybe accurately reproduced by a linear equation. The correlationcoefficients (R2) for the 1 : 1 PhOH + DMSO and PhOH +acetone complexes were found to be 0.982 and 0.993 anddemonstrate a very significant change in chemical shift of−6.08 ppm Å−1 and −6.22 ppm Å−1, respectively, upon increase

Fig. 3 PhOH + MeCN 1 : 1 complex optimized at the DFT/B3LYP/6-311++G(d,p)level of theory.

Fig. 4 PhOH + acetone 1 : 1 complex optimized at the DFT/B3LYP/6-311++G(d,p) (left) and at the DFT/B3LYP/cc-p-VTZ level of theory (right).

Fig. 5 PhOH + CHCl3 1 : 1 complex optimized at the DFT/B3LYP/6-311++G(d,p)level of theory.

Table 4 Charge distribution on the atoms of the intermolecular hydrogen bond in phenol + solvent complexes calculated by the Mulliken and natural bond orbital(NBO, in parenthesis) theory

(Ph)O H Xa Yb

PhOH −0.238 (−0.675) 0.254 (0.466)PhOH + CHCl3 −0.235 (−0.698) 0.275 (0.474) 0.117 (0.239) −0.464 (−0.315)PhOH + MeCN −0.346 (−0.699) 0.509 (0.501) −0.174 (−0.400) 0.199 (0.357)PhOH + acetone −0.301 (−0.711) 0.436 (0.496) −0.286 (−0.593) 0.350 (0.603)PhOH + DMSO −0.371 (−0.731) 0.403 (0.503) −0.435 (−0.979) 0.475 (1.152)

a X = O for DMSO and acetone, X = N for CH3CN and X = H for CHCl3.b Y = S for DMSO and Y = C for acetone, CH3CN and CHCl3.



in the (O)H⋯X hydrogen bond length. In the minimum energyconformers of the PhOH + DMSO, PhOH + acetone, and PhOH+ CH3CN complexes, the OH chemical shifts were found toexhibit a strong linear dependence on the R[(O)H⋯X] hydro-gen bond distance of −10.06 ppm Å−1 (R2 = 0.926) (Fig. 7(a)).A strong linear dependence was also observed for the phenol(1) + solvent complexes (including the phenol (1) + CHCl3complex) on the R[O(H)⋯X] hydrogen bond distances of−8.9 ppm Å−1 (R2 = 0.977) (Fig. 7(b)).

Interestingly, Bertolasi et al.43 suggested a linear correlationbetween crystallographic data and δ(OH) 1H chemical shifts ofthe form δ(OH, ppm) = −34.1(±2.6) R(O⋯O)(Å) + 100.3(±64.0)for a variety of molecules where the π-conjugated ⋯OvC–CvC–OH⋯β-diketone enol group was found to form intra-molecular O–H⋯O hydrogen bonds. Correlation of R[(O)H⋯O]hydrogen bond distances from X-ray diffraction with δ(1H)from solid state NMR of the form R[(O)H⋯O] = 5.04 −1.16lnδ(1H) + 0.0447δ(1H) was also suggested for crystallineaminoacids.44 Furthermore, chemical shift values of backboneamide protons in proteins have been shown to correlate withR−1 45 or R−3,46,47 where R is the hydrogen bond distance.However, ab initio predictions did not correlate well with theexperiment.48 It was suggested that although the hydrogenbond geometry is the most important parameter in determin-ing δ(NH) chemical shifts, long-range cooperative effects ofextended hydrogen networks make significant contributions.49

Structural details of 4-methylcatechol + solvent discretehydrogen bonded complexes. The geometry of the 1 : 2 sol-vation cluster of 4-methylcatechol (2) with two molecules ofDMSO is depicted in Fig. 8(a). The intramolecular flip-flophydrogen bond interaction of the C-1 OH and C-2 OH groupswas found to be weaker compared to the intermolecularσ hydrogen bond with the DMSO molecules, therefore, the OHgroups are in anti-configuration and both form hydrogen bondinteractions with the DMSO molecules. The hydrogen bondwith the C-2 OH was found to be slightly stronger than thatwith the C-1 OH group. This may be attributed to differences

in the hyperconjugation electronic effect of the CH3 group inthe para (Hammett σp- = −0.17) and meta (σm- = −0.07) posi-tion. The CH3 groups of DMSO molecules were found to beoriented perpendicular to the aromatic ring (as in the case ofthe PhOH + DMSO complex) forming simultaneously two sec-ondary intermolecular hydrogen bonds with the electron lonepairs of oxygen. The distance of the (O)–H⋯Ov(S) hydrogenbond was found to be 1.771 Å for C-1 OH and 1.769 Å for C-2OH using the DFT/B3LYP/6-311++G(d,p) level of theory.

The geometry of the 1 : 2 solvation cluster of 4-methylcate-chol (2) with two molecules of acetone is illustrated in Fig. 8(b)using the DFT/B3LYP/6-311++G(d,p) level of theory. Again theintramolecular flip-flop hydrogen bond interaction of the C-1

Fig. 6 The dependence of the OH proton chemical shifts, δOH (ppm), of the1 : 1 phenol (1) + solvent complexes vs. the distance R[(O)H⋯X] (X = O forDMSO (red) and acetone (green), X = N for MeCN (black), and X = C for CHCl3(blue).

Fig. 8 4-Methylcatechol 1 : 2 complexes with (a) DMSO, (b) acetone, and (c)CH3CN, optimized at the DFT/B3LYP/6-311++G(d,p) level of theory.

Fig. 7 The dependence of the OH proton chemical shift, δOH (ppm), in theminimum energy conformer, optimized at the DFT/B3LYP/6-311++G(d,p) levelof theory, of 1 : 1 phenol (1) + solvent complexes vs. R[(O)H⋯X] (a) and R[O(H)⋯X] (b) distances (X = O for DMSO and acetone, X = N for MeCN, and X = C forCHCl3).



OH and C-2 OH groups was found to be weaker compared tothe intermolecular hydrogen bond with the acetone molecules.The interatomic distance of the (O)–H⋯Ov(C) hydrogen bondwas found to be 1.877 Å for C-1 OH and 1.874 Å for C-2 OH.The dihedral angles between the acetone plane and thearomatic ring were found to be ∼51° and ∼49°, respectively,which are significantly different than the dihedral angle of thePhOH + acetone 1 : 1 complex (165.4°).

In the cluster of 4-methylcatechol (2) with two molecules ofCH3CN (Fig. 8(c)), the two solvation molecules are in the planeof the aromatic ring and form σ hydrogen bonds between thelong pair of the nitrogen with the C-1 OH and C-2 OH hydro-gens, which are in anti-configuration, with distances of 2.033 Åand 2.031 Å, respectively.

In the case of the 1 : 1 solvation complex of 4-methylcate-chol with a single molecule of CHCl3, an intramolecular flip-flop hydrogen bond interaction of the C-1 and C-2 OH groupswas observed. The interatomic distance of the hydrogen bondbetween the C-1 OH oxygen and the hydrogen of chloroformwas found to be 2.152 Å and the dihedral angle between theC–H of chloroform and the aromatic ring of only 1 degree,using the DFT/B3LYP/6-311++G(d,p) level of theory (Fig. 9(a)).The interatomic distance of the hydrogen bond between theC-2 OH oxygen and the hydrogen of chloroform was calculatedto be 2.152 Å and the dihedral angle between the C–H ofchloroform and the plane of the aromatic ring (or the dihedralangle C3–C2–O⋯H) of ∼19° (Fig. 9(b)). The chloroform mole-cule was found to orient out of the aromatic plane, presumablydue to lack of hyperconjugation with the methyl group.

Fig. 10 illustrates the electronic energy (kcal mol−1) of4-methylcatechol (2) as a function of the dihedral anglesC1–C2–O–H and C2–C1–O–H in the gas phase computed atthe DFT/B3LYP/6-31+G(d) level of theory. The conformer withan intramolecular flip-flop hydrogen bond was found to bemore stable by ΔΕ ≈ 4.32 kcal mol−1 (ΔG = 4.53 kcal mol−1)compared with the conformer with the two ortho OH groups intrans position.

Similar tendencies were observed using the CPCM model(Fig. 11). Again the conformer with an intramolecular flip-flophydrogen bond was found to be more stable by ΔΕ ≈ 2.24 kcalmol−1 (ΔG = 2.81 kcal mol−1) compared with the conformer ofthe two ortho OH groups in trans position. These results are inexcellent agreement with our experimental data which indi-cated significantly smaller chemical shift differences for C-1

OH and C-2 OH groups of 4-methylcatechol (2) betweenDMSO-d6 and CDCl3 (Δδ = 4.71 ppm), compared to that inphenol (1) (Δδ = 4.65 ppm) (Table 1) which should be attribu-ted to an intramolecular flip-flop hydrogen bonding28,29 inCDCl3 solution. The computed electronic energy difference ofthe two intramolecular C-1 OH⋯O(H) C-2 and C-2 OH⋯O(H)C-1 hydrogen bonded species was found to be only 0.05 kcalmol−1. Interestingly, the experimental data indicated the samechemical shift difference of 3.69 ppm between DMSO-d6 andCDCl3 for both C-1 OH and C-2 OH groups (Table 1). The twospecies, therefore, are almost of equal population in excellentagreement with the theoretical data.

Structural details of genkwanin + solvent discrete hydrogenbonded complexes. The natural product genkwanin (3) con-tains two hydroxyl groups, C-5 OH and C-4′ OH (Scheme 1)

Fig. 10 Electronic energy (kcal mol−1) of 4-methylcatechol as a function of thedihedral angles C1–C2–O–H and C2–C1–O–H, computed at the DFT/B3LYP/6-31+G(d) level of theory, in the gas phase (in black) and by using the CPCM(CHCl3) model (in red).

Fig. 11 Conformers A to D of the 1 : 1 genkwanin + DMSO complexes opti-mized at the DFT/B3LYP/6-311++G(d,p) level of theory.

Fig. 9 The 1 : 1 complex of 4-methylcatechol + CHCl3 optimized at theDFT/B3LYP/6-311++G(d,p) level of theory.



which are considered to possess C1 point group symmetry. Theoptimized molecular structures of the 1 : 1 complex of the C-4′OH group of genkwanin with a single DMSO molecule wereobtained with the use of the GaussView program and areshown in Fig. 11. Four different conformers were calculateddepending upon the conformation of the methoxy and C-4′OH groups. In all cases the OvS bond of the DMSO moleculewas found to be in the same plane with the phenyl group andthe two CH3– groups perpendicular to the phenyl ring formingsecondary interaction with the lone pairs of the oxygen of theC-4′ OH group. The orientation of the DMSO molecule wasfound to be very similar to that in the PhOH + DMSO complex(see discussion above). The dihedral angle between the flavone(C) and phenyl (B) rings was found to be ∼16°, due to thesteric repulsion between the C-2′ and C-6′ hydrogens with theC-3 hydrogen. Therefore, there are four 1 : 1 genkwanin +DMSO complexes close in energy (Table 5). The length of theC2–C1′ inter-ring bond (1.468 Å) clearly shows a double-bondcharacter and, thus, significant conjugation across the phenylring which is typical for flavonoid compounds.50 Interestingly,the dihedral angle C3–C2–C1′–C6′ varies between −11.06° and+10.59° with a mean value of −1.85° in the X-ray structuredeterminations of 16 flavonoids.27,51 Some typical structuralcharacteristics, like bond lengths, bond angles and dihedralangles for genkwanin + DMSO complexes with the use of DFT/B3LYPP/6-31+G(d) level of theory are presented in Table 5. Tothe best of our knowledge X-ray structural data of genkwaninare not available in the literature, therefore, our optimizedstructural parameters were compared with those of the crystalstructure of 4′,7-dimethoxy-5-hydroxyflavone.52 The agreementbetween the optimized and the experimental crystal structureis excellent.

A very strong intramolecular hydrogen bond between theC-5 OH⋯OC-4 groups was observed in all conformers. Anattempt to investigate the interaction of a solvent molecule,like DMSO, with the C-5 OH group by the use of DFT calcu-lations was unsuccessful. The DMSO molecule was displacedto a distance greater than 4 Å. This is in excellent agreementwith our experimental data which demonstrated very smallchemical shift difference Δδ[(DMSO-d6) − (CDCl3)] ≈ 0.02 ppmfor the C-5 OH proton of genkwanin (see discussion above).

Fig. 12 illustrates the effect of the conformation of the C-7OCH3 and C-4′ ΟH groups on the chemical shifts of the C-4′ΟH and C-5 OH protons, for the 1 : 1 complexes of genkwaninwith DMSO, acetone, CH3CN, and CHCl3. The conformation ofthe C-4′ ΟH group has a minor effect (<0.08 ppm) on thechemical shift of the C-4′ ΟH proton for all the complexesstudied, presumably due to the absence of substituents on thering B. Similarly the conformation of the C-7 OCH3 group hasa minor effect (≤0.03 ppm) on the C-4′ ΟH chemical shift. Theconformation of the C-4′ ΟH group has a minor effect on theC-5 OH chemical shift in the DMSO complex (≤0.03 ppm) anda shielding effect ≤0.17 ppm in CH3CN and acetone complexeswith both basis set geometry minimization. In contrast, a sig-nificant effect of the conformation of the C-7 OCH3 group onthe C-5 OH chemical shifts of 0.32 to 0.37 ppm was observedfor all the solvation complexes.

Comparison between calculated and experimental chemicalshift values. Fig. 13 shows the parity plot and Fig. 14 the histo-gram of the errors Δ(δexp − δcal) between the experimental andthe calculated (with the GIAO method at the DFT/B3LYP/6-311++G(2d,p) level) 1H solvent dependent chemical shifts withminimization of the solvation complexes at the DFT/B3LYP/6-31+G(d) and DFT/B3LYP/6-311++G(d,p) level of theory. TheR2 value of 0.991 in both cases shows excellent correlationbetween the calculated solvent dependent isotropic chemicalshifts of phenol OH protons and the experimental chemicalshifts for the test set. Furthermore, it may be concluded thatvery large basis sets for energy minimization are not necessaryto reproduce accurately 1H NMR chemical shifts. The histo-gram in Fig. 14 shows in more detail the distribution of theresiduals between the calculated and the experimental values.The calculated 1H chemical shifts in acetone had errors largerthan 0.3 ppm with the exception of the C-5 OH of genkwanin(3). However, even in these cases investigation with the DFT/B3LYP/6-311++G(d,p) level of theory was not able to reduce theerror. The significant Δ(δexp − δcal) error should not be attribu-ted to the 2D isotope shift of acetone-d6 (used in NMR experi-ments) compared to that in non-deuterated acetone since theexperimental chemical shift difference in the two solvents is0.03 ppm (Table 1) and, thus, negligible (this is in contrast tothe very significant isotope shift in the IR νCO stretching

Table 5 Structural characteristics of the 1 : 1 genkwanin + DMSO complexes of Fig. 11 with the use of DFT/B3LYP/6-31+G(d) and DFT/B3LYP/6-311++G(d,p) levelof theory

Conformer O6–H5⋯O4 C4vO4 C2–C1′ Dihedral angleb C3–C2–C1′–C6′ O4–H4′⋯OvS

A 1.7056 1.2567 1.4681 15.32 (−164.63) 1.70841.6904a 1.2504a 1.4664a 14.39a (−165.43)a 1.6947a

B 1.7141 1.2557 1.4682 16.41 (−163.30) 1.70811.7020a 1.2493a 1.4663a 15.98a (−163.75)a 1.6951a

C 1.7153 1.2557 1.4682 16.00 (−164.00) 1.70851.7036a 1.2432a 1.4665a 15.01a (−164.85)a 1.6920a

D 1.7056 1.2567 1.4681 15.32 (−164.63) 1.70891.6922a 1.2502a 1.4664a 13.69a (−166.20)a 1.6920a

a Structural characteristics of the genkwanin + DMSO complexes with the use of DFT/B3LYP/6-311++G(d,p) level of theory. b In parenthesis is thedihedral angle C3–C2–C1′–C2′.



vibration of the two solvents53). The Δ(δexp − δcal) error shouldbe attributed to the strong tendency of acetone, which has noparallel with DMSO and CH3CN, to form C1–O–H⋯O(C)dihedral angle which is strongly dependent on the basis setused (Table 3).

Interestingly, the conformations with the minimum elec-tronic energy and ΔG values of genkwanin in DMSO, acetone,CH3CN, and CHCl3 (Fig. 12) show the best agreement betweenexperimental and calculated chemical shift data of the C-5 OHproton. Therefore, we might expect that the C-5 OH chemical

shifts can be used as an internal sensor of the conformationstate of substituents of ring A in the family of flavonoids withover 8000 members occurring in nature.54

ExperimentalNMR

NMR experiments were performed on a Bruker AV-500 spectro-meter equipped with a TXI cryoprobe and on a Bruker AV-400

Fig. 12 The effect of conformation of the C-7 OCH3 and C-4’ OH groups on the chemical shifts of the C-4’ OH and C-5 OH protons for the 1 : 1 complexes of (a)genkwanin + DMSO, (b) genkwanin + Me2CO, (c) genkwanin + MeCN and (d) genkwanin + CHCl3, with the use of DFT/B3LYP/6-31+G(d) (data in blue) and DFT/B3LYP/6-311++G(d,p) (data in red) level of theory.



spectrometer. Samples were dissolved in 0.6 ml of deuteratedsolvent and transferred to 5 mm NMR tubes. All chemicalshifts were measured with reference to the internal standardMe3SiCD2CD2COONa, TSP-d4 (δH = 0.00 ppm) in DMSO-d6 orTMS in acetone-d6, CD3CN, and CDCl3. The amount of addedpicric acid (as an agent capable of sharpening the 1H NMRsignals of the hydroxyl groups26) was 2 to 4 μl from a stocksolution of 8 × 10−3 M in deuterated solvent. All spectra wereacquired with an acquisition time of 2.499 s, 64 K data pointsand 90° pulse length. The 2D 1H–13C HSQC and HMBC experi-ments were carried out using standard software. ExperimentalT1 values were found to be 2.5–3.0 s for the OH groups, thus,the pulse repetition time was set at 4 × T1 for obtaining accu-rate integration data.

Chemicals

Phenol (1) was obtained from Fluka, genkwanin (3) wasobtained from Extrasynthese (Genay, France), 4-methylcatechol(2) from Sigma-Aldrich, and picric acid from Ferak (Berlin,Germany). DMSO-d6, CD3CN, acetone-d6 and CDCl3 (NMRquality) were obtained from Deutero (Kastellaun, Germany).

Conclusions

This paper represents the first extensive analysis of solventeffects on 1H chemical shifts of OH groups of polyphenol com-pounds. The range of the 1H experimental chemical shifts ofover 8 ppm due to (i) strong intramolecular hydrogen bondinteractions, (ii) solute–solvent intermolecular hydrogenbonds, (iii) flip-flop intramolecular hydrogen bonds of phenolOH groups in ortho position and (iv) conformational effects of–OCH3 substituents can be calculated accurately using a com-bination of DFT, polarizable continuum model (PCM) and dis-crete solute–solvent interaction with a single solvent moleculeof each phenolic group. Excellent linear correlations betweenexperimental and computed chemical shifts were obtainedwithout using very large basis sets. In the minimum energyconformers of the phenol + solvent 1 : 1 complexes, the OHchemical shifts exhibit a strong linear dependence on theO(H)⋯X hydrogen bond length of −8.86 ppm Å−1. Thismethod, therefore, might be expected to be very effective indetermining solvent effects on 1H nuclear chemical shifts ofOH groups, thus, providing accurate structural and electronicdescription of solute–solvent interactions at a molecular level.Moreover, the role of the C-5 OH shielding as an internalsensor for the conformation of the substituents in ring A offlavonoids is emphasized. Further we expect that DFT calcu-lations of phenol OH chemical shifts might provide a highlysensitive measure of the hydrogen bond state of Tyr residues

Fig. 13 Calculated (at the GIAO DFT/B3LYP/6-311++G(2d,p) level of theory) vs.experimental values of the chemical shifts of the –OH protons of phenol (1),4-methylcatehol (2) and genkwanin (3) in different solvents with minimizationof the solvation complexes at the DFT/B3LYP/6-31+G(d) (A) and DFT/B3LYP/6-311++G(d,p) (B) level of theory.

Fig. 14 Histogram of the errors Δ(δexp − δcal) of the calculated (at the GIAODFT/B3LYP/6-311++G(2d,p) level of theory) 1H OH shieldings with minimizationof the solvation complexes at the DFT/B3LYP/6-31+G(d) and DFT/B3LYP/6-311++G(d,p) level of theory.



in proteins that are inaccessible by the conventional assess-ment of secondary structures.

Acknowledgements

Thanks are given to the Greek Community Support FrameworkIII, Regional Operational Program of Epirus 2000–2006 (MIS91629) for supportive the purchase of the AV 500 LC-NMR cryoinstrument.

Notes and references

1 G. A. Webb, in Shielding: Overview of Theoretical Methods.Encyclopedia of Nuclear Magnetic Resonance, Wiley,Chichester, England, 1996, pp. 4307–4318.

2 C. J. Jameson and A. C. de Dios, in The Nuclear ShieldingSurface: The Shielding as a Function of Molecular Geometryand Intermolecular Separation. Nuclear Magnetic Shieldingand Structure, Kluwer Academic Publishers, Dordrecht,1993, pp. 95–116.

3 J. C. Facelli, Concepts Magn. Reson., 2004, 20A, 42–69.4 C. Bonhomme, C. Gervais, F. Babonneau, C. Coelho,

F. Pourpoint, T. Azaïs, S. E. Ashbrook, J. M. Griffin,J. R. Yates, F. Mauri and C. J. Pickard, Chem. Rev., 2012,112, 5733–5779.

5 T. Helgaker, M. Jaszunski and K. Ruud, Chem. Rev., 1999,99, 293–352.

6 M. Kaupp, M. Buhl and V. G. Malkin, in Calculation of NMRand EPR Parameters: Theory and Applications, Willey-VCH,Weinheim, Germany, 2004.

7 G. Klopman, Chem. Phys. Lett., 1967, 1, 200.8 H. A. Germer, Theor. Chim. Acta, 1974, 34, 145–155.9 K. V. Mikkelsen, K. Ruud and T. Helgaker, Chem. Phys.

Lett., 1996, 253, 443–447.10 R. Cammi, B. Mennucci and J. Tomasi, J. Chem. Phys.,

1999, 110, 7627–7638.11 I. M. Svishchev and P. G. Kusalik, J. Am. Chem. Soc., 1993,

115, 8270–8274.12 Q. Cui and M. Karplus, J. Phys. Chem. B, 2000, 104, 3721–

3743.13 V. G. Malkin, O. L. Malkina, G. Steinebrunner and

H. Huber, Chem.–Eur. J., 1996, 2, 452–457.14 B. G. Pfrommer, F. Mauri and S. G. Louie, J. Am. Chem.

Soc., 2000, 122, 123–129.15 B. Mennucci, J. M. Martinez and J. Tomasi, J. Phys. Chem.

A, 2001, 105, 7287–7296.16 M. Cossi and O. Crescenzi, J. Chem. Phys., 2003, 118, 8863–

8872.17 R. A. Klein, B. Mennucci and J. Tomasi, J. Phys. Chem. A,

2004, 108, 5851–5863.18 T. S. Pennanen, J. Vaara, P. Lantto, A. J. Sillanpää,

K. Laasonen and J. Jokisaari, J. Am. Chem. Soc., 2004, 126,11093–11102.

19 M. Grayson, in Hydrogen Bonding and Nuclear Shielding.Some Calculations and Interpretations, In Recent ResearchDevelopments in Molecular Physics, Transworld ResearchNetwork, Trivandrum, India, 2004, vol. 2, 9.

20 R. E. Bulo, C. R. Jacob and L. Visscher, J. Phys. Chem. A,2008, 112, 2640–2647.

21 S. Bekiroglu, A. Sandström, L. Kenne and C. Sandström,Org. Biomol. Chem., 2004, 2, 200–205.

22 R. J. Abraham and M. Mobli, Magn. Reson. Chem., 2007, 45,865–877.

23 B. Adams and L. Lerner, J. Am. Chem. Soc., 1992, 114, 4827–4829.

24 L. Poppe and H. Vanhalbeek, Nat. Struct. Biol., 1994, 1,215–216.

25 P. Charisiadis, V. Exarchou, A. N. Troganis andI. P. Gerothanassis, Chem. Commun., 2010, 46, 3589–3591.

26 P. Charisiadis, A. Primikyri, V. Exarchou, A. Tzakos andI. P. Gerothanassis, J. Nat. Prod., 2011, 74, 2462–2466.

27 V. G. Kontogianni, P. Charisiadis, A. Primikyri,C. G. Pappas, V. Exarchou, A. G. Tzakos andI. P. Gerothanassis, Org. Biomol. Chem., 2013, 11, 1013–1025.

28 G. A. Jeffrey and W. Saenger, in Hydrogen Bonding in Biologi-cal Structures, Springer Verlag, Berlin, 1991.

29 W. Saenger, C. Betzel, B. E. Hingerty and G. M. Brown,Nature, 1982, 296, 581–583.

30 V. Exarchou, A. Troganis, I. P. Gerothanassis, M. Tsimidouand D. Boskou, Tetrahedron, 2002, 58, 7423–7429.

31 I. P. Gerothanassis, N. Birlirakis, C. Sakarellos andM. Marraud, J. Am. Chem. Soc., 1992, 114, 9043–9047.

32 A. M. Orendt, R. R. Biekofsky, A. B. Pomilio,R. H. Contreras and J. C. Facelli, J. Phys. Chem., 1991, 95,6179–6181.

33 I. P. Gerothanassis, Prog. Nucl. Magn. Reson. Spectrosc.,2010, 56, 95–197.

34 I. P. Gerothanassis, Prog. Nucl. Magn. Reson. Spectrosc.,2010, 57, 1–110.

35 R. J. Abraham and M. Mobli, in Modelling 1H NMR Spectraof Organic Compounds: Theory, Applications and NMR Predic-tion Software, John Wiley and Sons, Ltd, 2008.

36 A. D. Becke, J. Chem. Phys., 1993, 98, 5648–5652.37 A. D. Becke, Phys. Rev. A, 1988, 38, 3098–3100.38 C. Lee, W. Yang and R. P. Parr, Phys. Rev. B: Condens.

Matter, 1988, 37, 785–789.39 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Seuseria,

M. A. Robb, J. R. Cheeseman, J. A. Montgomery Jr.,T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam,S. S. Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi,G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji,M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa,M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai,M. Klene, X. Li, J. E. Knox, H. P. Hratchian, J. B. Cross,C. Adamo, J. Jaramillo, R. Comperts, R. E. Stratmann,O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli,J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth,P. Salvador, J. J. Dannenberg, V. G. Zakrzewski,



S. Dapprich, A. D. Daniels, M. C. Strain, O. Farkas,D. K. Malick, A. D. Rabuck, K. Raghavachari,J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford,J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko,P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith,M. A. Al-Laham, C. Y. Peng, A. Nanayakkara,M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen,M. W. Wong, C. Conzalez and J. A. Pople, Gaussian 03,revision D1, Gaussian, Inc., Pittsburgh, PA, 2003.

40 S. Melikova, D. Shchepkin and A. Koll, J. Mol. Struct., 1998,448, 239–246.

41 E. S. Kryachko and M. T. Nguyen, J. Phys. Chem. A, 2002,106, 4267–4271.

42 E. M. Cabaleiro-Lago, A. Pena-Gallego and J. Rodríguez-Otero, J. Chem. Phys., 2008, 128, 194311.

43 V. Bertolasi, P. Gilli, V. Ferretti and G. Gilli, J. Chem. Soc.,Perkin Trans. 2, 1997, 945–952.

44 A. McDermott and C. F. Ridenour, in Proton Chemical ShiftMeasurements in Biological Solids. Encyclopedia of NuclearMagnetic Resonance, Wiley, Sussex, England, 1996, pp.3820–3825.

45 D. S. Wishart, B. D. Sykes and F. M. Richards, J. Mol. Biol.,1991, 222, 311–333.

46 D. Sitkoff and D. A. Case, J. Am. Chem. Soc., 1997, 119,12262–12273.

47 G. Wagner, A. Pardi and K. Wüthrich, J. Am. Chem. Soc.,1983, 105, 5948–5949.

48 M. Barfield, J. Am. Chem. Soc., 2002, 124, 4158–4168.49 L. L. Parker, A. R. Houk and J. H. Jensen, J. Am. Chem. Soc.,

2006, 128, 9863–9872.50 G. Mariappan, N. Sundaraganesan and S. Manoharan,

Spectrochim. Acta, Part A, 2012, 95, 86–99.51 S. Domagala, P. Munshi, M. Ahmed, B. Guillot and

C. Jelsch, Acta Crystallogr., Sect. B: Struct. Sci., 2011, 67,63–78.

52 L. Q. Kou, X. L. Cheng and Z. T. Zhang, J. Chem. Crystal-logr., 2008, 38, 21–25.

53 R. A. Nyquist, in Interpreting Infrared, Raman and NuclearMagnetic Resonance Spectra, Elsevier, 2001.

54 Ø. M. Andersen and K. R. Markham, in Flavonoids: Chem-istry, Biochemistry & Applications, CRC, Taylor & Francis,Boca Raton, FL, 2006.



Investigation of solute–solvent interactions in phenol compounds: accurate ab initio calculations...

Documents

Transcript of Investigation of solute–solvent interactions in phenol compounds: accurate ab initio calculations...