Stereoelectronic effects on 1H nuclear magnetic resonance chemical shifts in methoxybenzenes

Article abstract of DOI:10.1021/jo061757x

(Graph Presented) Investigation of all O-methyl ethers of 1,2,3-benzenetriol and 4-methyl-1,2,3-benzenetriol (3-16) by ¹H NMR spectroscopy and density-functional calculations disclosed practically useful conformational effects on ₁H

Full text of DOI:10.1021/jo061757x

1
Stereoelectronic Effects on H Nuclear Magnetic Resonance
Chemical Shifts in Methoxybenzenes
Maja Lambert, Lars Olsen, and Jerzy W. Jaroszewski*
Department of Medicinal Chemistry, The Danish UniVersity of Pharmaceutical Sciences,
UniVersitetsparken 2, DK-2100 Copenhagen, Denmark
jj@dfuni.dk
ReceiVed August 25, 2006
Investigation of all O-methyl ethers of 1,2,3-benzenetriol and 4-methyl-1,2,3-benzenetriol (3-16) by 1H
NMR spectroscopy and density-functional calculations disclosed practically useful conformational effects
1
on H NMR chemical shifts in the aromatic ring. While the conversion of phenol (2) to anisole (1)
1
causes only small positive changes of H NMR chemical shifts (∆δ < 0.08 ppm) that decrease in the
order Hortho > Hmeta > Hpara, the experimental O-methylation induced shifts in ortho-disubstituted phenols
are largest for Hpara, ∆δ ) 0.19 ( 0.02 ppm (n ) 11). The differences are due to different conformational
behavior of the OH and OCH3 groups; while the ortho-disubstituted OH group remains planar in
polyphenols due to hydrogen bonding and conjugative stabilization, the steric congestion in ortho-
disubstituted anisoles outweighs the conjugative effects and forces the Ar-OCH3 torsion out of the ring
plane, resulting in large stereoelectronic effects on the chemical shift of Hpara. Conformational searches
and geometry optimizations for 3-16 at the B3LYP/6-31G** level, followed by B3LYP/6-311++G-
(2d,2p) calculations for all low-energy conformers, gave excellent correlation between computed and
observed 1H NMR chemical shifts, including agreement between computed and observed chemical shift
changes caused by O-methylation. The observed regularities can aid structure elucidation of partly
O-methylated polyphenols, including many natural products and drugs, and are useful in connection
with chemical shift predictions by desktop computer programs.
Introduction
13C NMR chemical shifts.4,5 Thus, the chemical shift of the
methyl groups in the planar conformation A is about δ 56,
changing to about δ 61 when the methoxy group is forced out
of the aromatic ring plane.4
Conformation of the methoxy group in anisole (methoxy-
benzene, 1, Figure 1), its phase dependence, and the effects of
substituents have been the subject of many experimental and
theoretical studies.1 The energy barrier for rotation of the
methoxy group (Ar-OCH3) in unsubstituted anisole in the gas
phase was determined to be roughly 10 kJ/mol,2 and thus only
the planar conformation (conformation A, Figure 1), stabilized
by conjugative effects, is observed. Stable planar conformations
are retained in the presence of a single ortho substituent.3
However, perpendicular conformation of the methoxy group
(conformation B) is imposed in 2,6-disubstituted anisoles, and
the resulting redistribution of electron density is known to affect
1
By contrast, effects of methoxy group rotation on H NMR
chemical shifts have not been studied, even though conforma-
tion-dependent electron density release from the oxygen atom
is expected to influence chemical shifts of the aromatic ring
hydrogen atoms considerably and may be useful as a structural
assignment tool.6 1H NMR chemical shifts of simple aromatic
compounds can be calculated quite accurately by use of
empirical substituent rules or database-derived predictions
incorporated in widely used desktop computer programs for
prediction of 1H NMR spectra.7 However, the absence of explicit
10.1021/jo061757x CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/11/2006
J. Org. Chem. 2006, 71, 9449-9457
9449

Lambert et al.
calculated and observed chemical shifts. Due to the stereoelec-
tronic effects, the O-methylation induced shifts of aromatic ring
hydrogen atoms in ortho-disubstituted phenols6 are very much
different than those in phenol8 (2) itself. In this work we
demonstrate, by investigation of 1H NMR spectra of a series of
model compounds, that the effects of methoxy group conforma-
tion can be easily generalized, affording a set of practically
useful rules. The experimental data are corroborated by calcula-
tions with density functional theory (DFT) method,9 which
reproduces the effects very well.
Results and Discussion
FIGURE 1. Minimum- and maximum-energy conformations of anisole
(1) and phenol (2).
1
Synthesis and H NMR Spectra of Model Compounds.
The complete series of methyl ethers of 1,2,3-benzenetriol (3-
8) and 4-methyl-1,2,3-benzenetriol (9-16) were included in the
investigation. The latter compounds were prepared by reduction
of 2,3,4-trihydroxybenzaldehyde or 2,3,4-trimethoxybenzalde-
hyde followed by partial O-methylation or demethylation.10 The
products were isolated by preparative HPLC and their structures
were confirmed by 1D and 2D NMR experiments.
1H NMR spectra of 3-16 were recorded in chloroform-d with
50-70 mM solutions. To ensure that the determined chemical
shifts are not influenced by intermolecular interactions, the
spectra were recorded again after dilution of the samples by a
factor of 20, which did not affect the observed chemical shifts.
The changes of 1H NMR chemical shifts observed upon stepwise
O-methylation of 3 and 9 are shown in Schemes 1 and 2,
respectively. The absolute chemical shift values are reported in
the Supporting Information (Table S1). Whenever necessary,
heteronuclear single quantum coherence (HSQC), heteronuclear
multiple bond correlation (HMBC), and nuclear Overhauser
effect (NOESY) spectra were recorded for unambiguous reso-
nance assignments.
correction for stereoelectronic effects of methoxy groups,
resulting from different conformational behavior of hydroxy and
alkoxy groups, may lead to substantial differences between
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In the simplest possible case of O-methylation of a phenol
group, the conversion of phenol (2) to anisole (1) causes only
a small chemical shift change of Hortho (∆δ ) 0.08 ppm) and
8
Hmeta (∆δ ) 0.04 ppm), and has nearly no effect on Hpara
.
However, for the methyl ethers of 1,2,3-benzenetriol (3) and
4-methyl-1,2,3-benzenetriol (9), entirely different relationships
are observed (Schemes 1 and 2). Notably, O-methylation of
ortho-disubstituted hydroxyl groups caused a large shift of Hpara
by ∆δ ) 0.19 ( 0.02 ppm (mean ( standard deviation; n )
11), whereas only approximately half as large a shift of Hpara
was observed in the case of ortho-monosubstituted hydroxy
groups, ∆δ ) 0.11 ( 0.01 ppm (n ) 4). The remaining shifts
were considerably smaller. Thus, the shift of Hortho upon
O-methylation of ortho-monosubstituted hydroxy groups was
∆δ ) -0.03 ( 0.03 ppm (n ) 8). The O-methylation-induced
shifts of Hmeta were likewise small, ∆δ ) 0.05 ( 0.02 ppm (n
) 8) and δ ) 0.01 ( 0.02 ppm (n ) 12) for ortho-disubstituted
and ortho-monosubstituted phenol groups, respectively. It is
apparent that O-methylation-induced changes of aromatic ring
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9450 J. Org. Chem., Vol. 71, No. 25, 2006

1H NMR Chemical Shifts in Methoxybenzenes
1
SCHEME 1. Changes of H NMR Chemical Shifts of
energy for the nonplanar conformation of 2 as compared to 1
(Tables 1 and 2) is in agreement with previous results.2,14
Solvent effects on the calculated rotational barriers in 1 and 2
were small (Table 2). For partially O-methylated polyphenol
derivatives, hydrogen bonding is expected to contribute to
relative stability of individual conformers.15,16 The hydrogen-
bond enthalpy in 2-methoxyphenol (17) was previously esti-
mated to be 18.4 kJ/mol in vacuo,15 diminishing to below 3
kJ/mol in polar hydroxylic solvents.16 Accordingly, the DFT
calculations identified the planar conformation A stabilized by
an intramolecular hydrogen bond as a global energy minimum
(Table 2, Figure 2), in agreement with previous theoretical end
experimental studies.15-17 Interestingly, the next most stable
conformation identified in this work, both in vacuum and in
chloroform, was that with the methoxy group perpendicular to
the aromatic ring plane (conformation C, Figure 2), which still
allows for the intramolecular hydrogen bond. The energy
difference between conformations A and C of 17 corresponded
to the energy difference between conformations A and B of 2
(Table 2). Conformations without the intramolecular hydrogen
bond were considerably higher in energy, with a significant
difference between gas-phase and chloroform stability of
conformations B and D, which have a solvent-exposed hydroxy
group.
Aromatic Hydrogen Atoms during Stepwise O-Methylation
of 1,2,3-Benzenetriol (3)a
The change of the orientation of the ArO-H and ArO-CH3
bonds in anisole (1) and phenol (2) from planar toward
perpendicular (Figure 1) leads to systematic and significant
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G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
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03; Gaussian, Inc.: Wallingford, CT, 2004.
a For spectra (600 MHz) in chloroform-d.
hydrogens in polyoxygenated benzenes decrease in the order
Hpara . Hmeta ≈ Hortho and are entirely different from those
observed in phenol, where the shifts are small and decrease in
the order Hortho > Hmeta > Hpara.8 The particularly large shifts
are observed when the O-methylated hydroxy group is flanked
by two ortho substituents. Thus, while the effect of O-
methylation of phenol is attributable to differences in electrone-
gativity between the hydroxy and the methoxy group, the effects
observed in substituted anisole derivatives are stereoelectronic
in nature. The effect appears to be general and independent of
whether the ortho substituents are OCH3, OH, or CH3.
Stereoelectronic Effects of Methoxy Group Rotation on
1H Nuclear Shieldings in DFT Calculations. Three simple
model compounds, anisole (1), phenol (2), and 2-methoxyphenol
(guaiacol, 17), were studied by use of B3LYP theory in order
to assess trends on the 1H nuclear shielding constants. Initially,
differences between nuclear shieldings in the two conformations
of anisole (A and B, Figure 1) were calculated with different
basis sets (Table 1). Good basis-set independence was observed,
and further calculations were performed at the B3LYP/6-
311++G(2d,2p) level.11 Energy differences and nuclear shield-
ing constants for planar and nonplanar conformations of 1 and
2 (Figure 1), as well as for four low-energy conformations of
17 (Figure 2), which represents a structural motif present in
many of the compounds in Schemes 1 and 2, are shown in Table
2. The calculations12 were performed for molecules in vacuum
as well as in chloroform, by use of the conductorlike polarized
continuum (CPCM) solvent model.13
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2003, 24, 669-681.
(14) (a) Larsen, N. W. J. Mol. Struct. 1979, 51, 175-190. (b) Schaefer,
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The calculated rotational barriers for anisole (1) and phenol
(2) were about 12 and 15 kJ/mol, respectively. The increased
J. Org. Chem, Vol. 71, No. 25, 2006 9451

Lambert et al.
1
SCHEME 2. Changes of H NMR Chemical Shifts of Aromatic Hydrogen Atoms during Stepwise O-Methylation of
4-Methyl-1,2,3-benzenetriol (9)a
a For spectra (600 MHz) in chloroform-d.
1
TABLE 1. Energy Differences and Differences in H Nuclear Shieldings (σ) between Planar and Nonplanar Conformations of Anisole (1)
Calculated with Different Basis Sets
nuclear shielding difference ∆σ,a ppm
atom
6-31G**
6-311++G(2d,2p)
aug-cc-pVDZ
aug-cc-pVTZ
aug-cc-pVQZ
H-2
H-3
H-4
H-5
H-6
OCH3
-0.53
-0.10
-0.24
-0.08
-0.25
0.01
-0.45
-0.06
-0.25
-0.07
-0.21
0.02
-0.47
-0.02
-0.23
-0.08
-0.15
0.01
-0.39
-0.06
-0.25
-0.10
-0.10
0.01
-0.38
-0.04
-0.21
-0.05
-0.14
0.02
relative energy,a kJ/mol
12.9
12.4
13.7
13.2
13.3
a Conformation B relative to conformation A (see Figure 1).
changes of nuclear shielding of the hydrogen atoms in the
aromatic ring (Table 3), whereas practically no changes are
observed for the methoxy group itself (Table 2). The most
significant changes upon the rotation are observed for Hortho
that is originally syn-oriented to the OR group (H-2; ∆σ )
-0.45 ppm for 1 and -0.75 ppm for 2) as well as for Hpara
(H-4; ∆σ ) -0.25 ppm for 1 and -0.29 ppm for 2), whereas
with the ArO-R bond in the aromatic ring plane. The respective
differences diminish to 0.18 and 0.21 ppm in chloroform. In
17, the out-of-plane rotation of the methoxy group caused
changes of nuclear shieldings that closely parallel those observed
in 1 (Table 2). It is therefore concluded that neither the presence
of an ortho-oxygen atom nor hydrogen bonding influences the
1
stereoelectronic effect of the methoxy group on H shieldings
in the aromatic ring significantly.
Hmeta (H-3, H-5) are only weakly affected (Table 3). The trends
observed in vacuum and in chloroform are identical (Table 2).
For 1 and 2 in vacuum, the chemical shielding of Hortho changes
by 0.25 and 0.45 ppm, respectively, as the Ar-OR torsion
changes by 180° between the two isoenergetic conformations
Shieldings in Methyl Ethers of Polyphenols. The MMFF
force field18 was used to generate initial conformations of
compounds 3-16 by a Monte Carlo search. All conformations
within at least 25 kJ/mol from the calculated lowest-energy
conformation were geometry-optimized by use of B3LYP/6-
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9452 J. Org. Chem., Vol. 71, No. 25, 2006

1H NMR Chemical Shifts in Methoxybenzenes
TABLE 2. 1H Nuclear Shieldings (σ) and Relative Energies of Planar (A) and Nonplanar (B) Conformations of Anisole (1) and Phenol (2),
and Conformations A-D of 2-Methoxyphenol (17)a
nuclear shielding constant σ, ppm
anisole (1)
gas phase chloroform
phenol (2)
gas phase chloroform
2-methoxyphenol (17)
chloroform
gas phase
nucleus
A
B
A
B
A
B
A
B
A
B
C
D
A
B
C
D
H-2
H-3
H-4
H-5
H-6
OCH3
24.71 24.26 24.39 23.97 24.93 24.18 24.47 23.94
24.14 24.08 23.82 23.77 24.25 24.12 23.95 23.83 24.80 24.58 24.35 24.32 24.47 24.38 24.02 24.05
24.51 24.26 24.22 23.94 24.56 24.27 24.31 24.00 24.65 24.69 24.65 24.60 24.33 24.45 24.33 24.35
24.16 24.09 23.85 23.77 24.16 24.12 23.89 23.83 24.56 24.84 24.39 24.50 24.30 24.53 24.09 24.17
24.46 24.25 24.21 23.95 24.48 24.18 24.26 23.94 24.50 25.07 24.42 24.89 24.25 24.57 24.14 24.41
27.87 27.89 27.77 27.81
27.77 27.33 27.92 27.87 27.68 27.27 27.85 27.82
relative energy,b kJ/mol
0.0 12.4 0.0 11.5
0.0
14.5
0.0
15.2
0.0 29.6 11.2 24.7 0.0 21.0 10.2 12.0
a Structures were optimized with the B3LYP/6-31G** method and the energies as well as NMR shieldings were calculated at the B3LYP/6-311++G(2d,2p)
level in gas phase or by use of the CPCM model for chloroform. b Relative to conformation A (see Figures 1 and 2).
TABLE 4. Calculated Conformational Energies of Compounds
3-16
relative energy,a kJ/mol
compd
conformationb
gas phase
chloroform
3
4
5
6
7
8
8
8
9
2
2
2
2
2
2
3
4
2
3
2
2
3
2
2
2
2
3
2
3
4
5
9.4
27.8
13.8
7.7
9.4
4.7
10.6
13.8
1.8
10.0
16.2
6.9
13.1
29.6
38.4
7.0
5.9
20.9
10.1
8.5
16.2
7.3
15.2
16.0
10.0
6.2
11.5
8.8
9
10
11
11
12
13
14
15
15
16
16
16
16
9.9
31.1
39.8
7.7
-6.1
0.2
7.2
4.5
11.4
11.7
FIGURE 2. Four low-energy conformations of 2-methoxyphenol (17).
1.0
5.4
5.3
5.6
11.4
12.4
TABLE 3. Stereolectronic Effects of the Methoxy Group Rotation
in Anisole (1) and of the Hydroxy Group Rotation in Phenol (2) on
1H Nuclear Shieldings (σ)a
nuclear shielding for
C-O-C1-C2 torsion angle
a Relative to conformation 1; the energies were calculated by use of
B3LYP/6-311++G(2d,2p). b The conformations are labeled according to
increasing energy in the gas phase.
atom
0° 30°
60°
90°
120°
150°
180°
Anisole (1)
H-2
H-3
H-4
H-5
H-6
0
0
0
0
0
-0.17 -0.50 -0.45 -0.36 -0.27 -0.25
-0.03 -0.03 -0.06 -0.02
0.06
0.02
0
conformations were larger than 20 kJ/mol, both in the gas phase
and in the solvent (Table 4). The most stable conformations of
these compounds are those stabilized by intramolecular hydrogen
bonds (Figure 3). The stable conformations of 4 and 12 are
essentially planar, with two hydrogen bonds each; the high-
energy conformations of 4 and 12 are also nearly planar but
are stabilized with only one hydrogen bond. In the most stable
conformation of 13, the two ortho-disubstituted methoxy groups
are rotated out of plane by about 70° to the opposite faces of
the benzene ring (Figure 3). The stable conformations of 4, 12,
and 13, identified as deep, global energy minima, can be
regarded as accurate representations of actual structures present
during acquisition of the experimental 1H NMR data (Table S1).
The 1H NMR shieldings calculated for these conformations, both
in gas phase and in chloroform (Table 5), are plotted against
the experimental chemical shifts in Figure 4. The nuclear
shieldings calculated for the low-energy conformations of 4,
12, and 13 correlated far better with the experimental values
than those calculated for the high-energy conformations (Figure
3).
-0.03 -0.15 -0.25 -0.15 -0.03
0.05 -0.03 -0.07 -0.04 -0.04 -0.02
-0.02 -0.11 -0.21 -0.25
4.7 11.1 12.4 11.1
Phenol (2)
0.08
0.25
relative energy,b kJ/mol
0
4.7
0
H-2
H-3
H-4
H-5
H-6
0
0
0
0
0
-0.18 -0.52 -0.75 -0.72 -0.53 -0.45
-0.02 -0.09 -0.13 -0.12 -0.10 -0.09
-0.07 -0.20 -0.29 -0.20 -0.07
0
0.09
0.45
-0.02 -0.03 -0.04
0.00
0.07
0.27
-0.08 -0.26 -0.30 -0.06
relative energy,b kJ/mol
0
3.3 10.5 14.5 10.5
3.3
0
a Calculated in the gas phase at the B3LYP/6-311++G(2d,2p) level;
shieldings for 0 torsion angles are set to zero. b Relative to conformation
A; the energies were calculated by use of B3LYP/6-311++G(2d,2p).
31G**. Single-point energies and the 1H NMR shielding
constants were calculated with the 6-311++G(2d,2p) basis set,
both in the gas phase and in chloroform with the CPCM model
(Supporting Information, Tables S2-S7).12
For three of the compounds (4, 12, and 13), the differences
in energy between the most stable and the next most stable
J. Org. Chem, Vol. 71, No. 25, 2006 9453

Lambert et al.
chemical shifts by use of the above regression equations obtained
for 4, 12, and 13. The scatter plots in Figure 5 show the
relationships between the calculated and experimental chemical
shifts of the aromatic ring hydrogens, both for the lowest-energy
conformers and for averaged chemical shifts of all conformers
having relative energies within 4 or 8 kJ/mol.
Mean average errors for chemical shifts calculated by this
method are 0.11, 0.09, and 0.06 ppm for the minimum energy
conformations of 3-16, conformations with relative energies
up to 4 kJ/mol, and conformations with relative energies up to
8 kJ/mol, respectively, for the gas-phase conformations. For
chloroform data, the respective errors are 0.08, 0.08, and 0.06
ppm. It is apparent that chemical shifts averaged for the
conformer ensembles with energies within 8 kJ/mol from the
calculated lowest-energy conformations give the best agreement
with the experimental data. Mean average errors for individual
conformations of 3-16 are shown in Table S8 in the Supporting
Information. There is a clear tendency that less stable conforma-
tions give higher average errors. However, in many cases the
lowest-energy conformations are clearly not representative for
the experimental data. For example, the two most conspicuous
outliers in the vacuum data are the chemical shift of H-6 in
conformation 1 of compound 9 and the chemical shift of H-5
in conformation 1 of compound 15 (Figure 5). Conformation 1
of compound 9 has two hydrogen bonds with all hydroxy groups
in the ring plane and the hydroxy group at C-1 pointing toward
H-6, whereas conformation 2 of 9 has all hydroxy groups rotated
by 180°, which changes the chemical shift of H-6 significantly
(cf. Tables 2 and 3). Therefore, even a small contribution from
conformation 2 is expected to affect the average chemical shift
of H-6 significantly. For compound 15, conformation 1,
identified as a global energy minimum in vacuum, is consider-
ably less stable than conformation 2 in chloroform (Table 4). It
is therefore clear that conformation 1 of 15 is a very poor
representation of the real conformer population. Conformations
1 and 2 of 15 differ in the torsion angle of the methoxy group
at C-2, leading to substantial error of the chemical shift of H-5.
Therefore, the limited ability to identify correct conformer
populations that represent the actual solution situation, rather
than the ability of the DFT calculations to reproduce the
stereoelectronic effects, is the major source of discrepancies
between the calculated and the experimental results.
FIGURE 3. Global energy minima (conformation 1) and next lowest-
energy conformations (conformation 2) of compounds 4, 12, and 13.
1
TABLE 5. Calculated H Nuclear Shieldings (σ) for Compounds 4,
12, and 13a
calculated nuclear shielding σ, ppm
gas phase
chloroform
experimental
H-atom
chemical shift, δ
conf. 1
conf. 2
conf. 1
conf. 2
Compound 4
25.24
24.73
24.80
27.79
H-4
H-5
H-6
CH3
6.48
6.76
6.60
3.88
24.99
24.97
25.34
27.28
24.88
24.44
24.60
27.69
24.84
24.68
24.88
27.23
Compound 12
25.36
H-4
H-5
CH3
OCH3
6.38
6.61
2.20
3.85
25.11
25.05
29.52
27.34
25.04
24.61
29.39
27.74
24.94
24.76
29.43
27.29
24.89
29.41
27.82
Compound 13
24.67
H-5
H-6
CH3
2-OCH3
3-OCH3
6.77
6.62
2.18
3.92
3.83
25.19
25.12
29.01
27.31
27.43
24.38
24.57
29.44
27.62
27.68
24.91
24.90
28.95
27.25
27.35
24.82
29.48
27.68
27.73
a Calculated at the B3LYP/6-311++G(2d,2p) level; conformations 1 and
2 refer to the most stable and the next most stable conformation, respectively;
nuclear shieldings for all compounds 3-16 are given in the Supporting
Information (Tables S6 and S7).
When averaged shieldings of all conformations within 8 kJ/
mol for all compounds (3-16) are plotted against experimental
chemical shifts (i.e., without prior validation of the results for
the most reliably predicted conformations of 4, 12, and 13) and
converted to calculated chemical shifts by use of the resulting
regression lines (δ ) -0.635σ + 22.440, R2 ) 0.876 in the
gas phase; δ ) -0.665σ + 22.987, R2 ) 0.913 in chloroform),
the calculated and experimental chemical shifts agree with MAE
) 0.045 ppm (gas phase) or MAE ) 0.038 ppm (in chloroform);
see Figure 6.
The regression lines for all types of hydrogen atoms of the
low-energy conformations of compounds 4, 12, and 13 are δ
) -0.969σ + 30.748, with correlation coefficient R2 ) 0.997
and mean average error (MAE) of 0.07 ppm, in the gas phase
and δ ) -0.914σ + 29.128 (R2 ) 0.999, MAE 0.06) in
chloroform. For the aromatic ring hydrogens only, R2 ) 0.902
(MAE 0.10) in the gas phase and R2 ) 0.968 (MAE 0.07) in
chloroform. Thus, the calculated data (σ) in chloroform correlate
better with the experimental δ values (obtained in chloroform-
d).
For the remaining compounds (3, 5-11, and 14-16), energy
calculations suggest the presence of multiple conformations
close in energy (Table 4). In some cases (compounds 9, 15,
and 16) the relative stability of conformers changes between
the gas phase and chloroform (Table 4). Because the real,
quantitative conformer distributions for 3, 5-11, and 14-16
cannot be reliably deduced from the calculated relative energies,
the calculated nuclear shielding were averaged for all low-energy
conformers within either 4 or 8 kJ/mol and converted to
Calculation of O-Methylation-Induced Shifts. The confor-
mational behavior of an Ar-OR bond (R ) H, CH3) in a
polyphenol is governed by three major effects. The first is
stabilization of the planar conformation by delocalization of
nonbonding oxygen electrons into the aromatic ring (Table 2).
This is reflected by shortening of the Ar-OCH3 bond in 1 from
1.382 Å in the perpendicular conformation B to 1.367 Å in the
planar conformation A (Figure 1), as calculated in the present
work (the corresponding values for the Ar-OH bond in 2 are
1.389 and 1.368 Å). The energy of this stabilization is at least
9454 J. Org. Chem., Vol. 71, No. 25, 2006

1H NMR Chemical Shifts in Methoxybenzenes
1
FIGURE 4. (A) Relationship between observed H NMR chemical shifts (δ) and calculated nuclear shieldings (σ) for 4, 12, and 13 in gas phase
and chloroform; solid and open symbols represent the lowest and the next-lowest energy conformations (conformations 1 and 2, respectively; cf.
Figure 3). (B) Expansions of regions corresponding to hydrogen atoms attached to the aromatic ring. Solid lines represent best fits for the most
stable conformations (see text).
FIGURE 5. Comparison of observed and calculated chemical shifts of 3-16. For compounds 3, 5-11, and 14-16, the calculated nuclear shieldings
were converted to chemical shifts by use of the regression equations derived for all chemical shifts of compounds 4, 12, and 13 (Figure 4). Calculated
chemical shifts for the minimum-energy conformations, averaged chemical shifts for all conformations with calculated energies within 4 kJ/mol,
and averaged chemical shifts for all conformations with calculated energies within 8 kJ/mol are displayed separately.
12 kJ/mol (Tables 1 and 2). The second effect is the intramo-
lecular hydrogen bonding that stabilizes planar conformation
of the Ar-OH groups in a solvent-dependent manner.15,16 The
energy cost of breaking the hydrogen bond by rotation of the
Ar-OH bond away from a planar OCH3 acceptor group is quite
high,15,16 for example, 21 kJ/mol for 17 in chloroform (Table
2). This hydrogen-bond strength appears to be largely retained
when the OCH3 acceptor group is rotated out-of-plane, as the
energy difference between the hydrogen-bonded conformations
A and C of 17 equals the energetic penalty of rotation of the
Ar-OCH3 torsion out-of-plane in 1 (Table 2). The third effect
that controls the Ar-OR torsional angle is the steric repulsion
by neighboring ortho-substituents. As seen in Tables 4, S2, and
S3, the energetic penalty of retaining a planar conformation in
J. Org. Chem, Vol. 71, No. 25, 2006 9455

Lambert et al.
FIGURE 6. Comparison of observed and calculated chemical shifts
of 3-16. Calculated nuclear shieldings averaged for all conformations
within 8 kJ/mol were converted to calculated chemical shifts by use of
the regression equations for all compounds (see text).
FIGURE 7. Comparison of observed and calculated O-methylation
shifts in 3-16 (cf. Schemes 1 and 2).
ortho-disubstituted anisoles varies between about 10 kJ/mol in
cases where the OCH3 group acts at a hydrogen-bond acceptor
(conformation 2 of 5, conformation 3 of 11) to at least 16 kJ/
mol (conformation 4 of 8, conformation 2 of 13; Tables 4, S2,
and S3). The balance between these three effects determines
the conformer distribution for a particular, partly O-methylated
polyphenol, and the resulting Ar-OR torsion angle determines
the 1H NMR chemical shifts in the aromatic ring through
torsion-dependent electron density release into the aromatic ring.
Thus, the calculations confirm a very strong preference of
the hydroxy group to remain in the plane of the aromatic ring,
even for ortho-disubstituted phenols.19 In all but two cases of
hydroxy group conformations in compounds 3-16 (Tables 4,
S2, and S3), the hydroxy group is essentially coplanar with the
aromatic ring, regardless of whether the hydroxy group has one
or two ortho substituents (torsion angle 3.0° ( 4.1° in gas phase
and 4.4° ( 6.2° in chloroform, n ) 46). The two exceptions
are the 2-OH group in conformation 2 of 3 and the 2-OH group
in conformation 3 of 9. In these two cases the central hydroxy
group is essentially orthogonal to the ring and acts as a
hydrogen-bond acceptor for the two flanking hydroxy groups
(Tables S2 and S3). The energy of these conformations, which
must be considered specific for the 1,2,3-benzenetriol systems,
is about 6 kJ/mol higher than the energy of the conformations
with the central hydroxy group in the ring plane (in chloroform,
Table 4). In all other occurrences of the ortho-disubstituted
hydroxy groups in compounds 3-16 (n ) 21), the hydroxy
group is planar. Thus, in the case of ortho-disubstituted phenol
groups, the steric congestion never outweighs the stabilization
by hydrogen bonding. By contrast, the ortho-disubstituted
methoxy groups are always out-of-plane in all conformations
within 10 kJ/mol. Therefore, the O-methylation of an ortho-
disubstituted phenol group will cause rotation of the Ar-OR
torsion angle out of plane of the benzene ring as the steric effects
outweigh the conjugative effects, resulting in predictable (cf.
Table 3) changes of the chemical shifts.
of parent phenols and the corresponding methyl ethers, the
correlation must be considered as very good (MAE ) 0.033
ppm). The correlation is considerably better for compounds
9-16 (R2 ) 0.888, MAE 0.026 ppm) than for 3-8 (R2 ) 0.648,
MAE 0.044 ppm). The DFT-calculated O-methylation shift of
Hpara in ortho-disubstituted phenols is ∆δ ) 0.18 ( 0.04 ppm
(n ) 11), in excellent agreement with the experimental results
(∆δ ) 0.19 ( 0.02 ppm).
Applications. The downfield shift of Hpara of 0.2 ppm
observed upon O-methylation (and presumably upon O-al-
kylation in general) of ortho-disubstituted phenols must be
regarded as a useful structure elucidation aid. Many drugs,
including colchicine, etoposide, mescaline, podophylotoxin,
reserpine, and trimethoprim, contain a 1,2,3-trimethoxybenzene
moiety. Their metabolism involves demethylation to give partly
O-methylated 1,2,3-benzenetriol derivatives.20 Moreover, a vast
number of natural products contain partially O-methylated 1,2,3-
benzenetriol moieties. Structure elucidation of such compounds
can present a considerable challenge, requiring time-consuming
2D NMR experiments.6,21 Examples confirming the large shift
of Hpara upon O-methylation of an ortho-disubstituted phenol
groupincludeisoflavans,6isoflavanones,6naturaldibenzocycloocta-
dienes,21a natural terphenyls,21b isoflavones,21c acridone alka-
loids,21d homoflavonoids,21e and lignans.22 On the basis of the
observations described herein, the hydroxy and methoxy sub-
stituents attached to C-3 and C-5 in the natural lignan rupestrin
C, recently described by Suo et al.,22 should be interchanged.23
(20) See, for example, (a) Kawashiro, T.; Yamashita, K.; Zhao, X. J.;
Koyama, E.; Tani, M.; Chiba, K.; Ishizaki, T. J. Pharmacol. Exp. Ther.
1998, 286, 1294-1300. (b) Wu, D.; Otton, S. V.; Inaba, T.; Kalow, W.;
Sellers, E. M. Biochem. Pharmacol. 1997, 53, 1605-1612. (c) Tateishi,
T.; Soucek, P.; Caraco, Y.; Guengerich, F. P.; Wood, A. J. Biochem.
Pharmacol. 1997, 53, 111-116. (d) van Maanen, J. M.; de Vries, J.; Pappie,
D.; van den Akker, E.; Lafleur, V. M.; Retel, J.; van der Greef, J.; Pinedo,
H. M. Cancer Res. 1987, 47, 4658-4662. (e) Friis, C.; Gyrd-Hansen, N.;
Nielsen, P.; Nordholm, L.; Rasmussen, F. Pediatr. Pharmacol. (New York)
1984, 4, 231-238.
(21) For selected, recent examples of natural products identified by use
of 2D NMR that exhibit the expected O-methylation shifts of Hpara, see (a)
Shen, Y. C.; Liaw, C. C.; Cheng, Y. B.; Ahmed, A. F.; Lai, M. C.; Liou,
S. S.; Wu, T. S.; Kuo, Y. H.; Lin, Y. C. J. Nat. Prod. 2006, 69, 963-966.
(b) Zhang, C, Ondeyka, J. G.; Herath, K. B.; Guan, Z.; Collado, J.; Pelaez,
F.; Leavitt, P. S.; Gurnett, A.; Nare, B.; Liberator, P.; Singh, S. B. J. Nat.
Prod. 2006, 69, 710-712. (c) Maver, M.; Queiroz, E. F.; Wolfender, J.-L.;
Hostettmann, K. J. Nat. Prod. 2005, 68, 1094-1098. (d) Naidoo, D.;
Coombes, P. H.; Mulholland, D. A.; Crouch, N. R.; van den Bergh, A. J.
J. Phytochemistry 2005, 66, 1724-1728. (e) Lin, Y.-L.; Shen, C.-C.; Huang,
Y.-J.; Chang, Y.-Y. J. Nat. Prod. 2005, 68, 381-384.
A comparison between the experimental O-methylation shifts
(Schemes 1 and 2) and the O-methylation shifts calculated from
data in Figure 6 (calculated chemical shifts averaged for all
conformations within 8 kJ/mol, in chloroform) are shown in
Figure 7. Considering that the calculated O-methylation shifts
are differences between small numbers representing δ values
(19) (a) Allinger, N. L.; Maul, J. J.; Hickey, J. H. J. Org. Chem. 1970,
36, 2747-2752. (b) Brewster, M.; Pop, E.; Huang, M.-J.; Bodor, N.
THEOCHEM 1994, 303, 25-38. (c) Shigematsu, M.; Kobayashi, T.;
Yoshitani, K.; Tanahashi, M. J. Comput. Chem. Jpn. 2002, 1, 129-134.
9456 J. Org. Chem., Vol. 71, No. 25, 2006

1H NMR Chemical Shifts in Methoxybenzenes
Thus, simple comparison of 1H NMR chemical shift of aromatic
ring hydrogens of polyphenolic natural products and their
O-methylated analogues can provide immediate structural clues
or suggest a need of revision of a published structure.6,21,22 The
were demonstrated in a series of model compounds and
reproduced well by DFT calculations. The differences between
conformational properties of ortho-disubstituted hydroxy and
methoxy group, resulting from a balance between electronic,
steric, and hydrogen-bonding effects, cause stereoelectronic
effects on the 1H NMR chemical shifts that are useful for
determination of O-methylation patterns in polyphenols, the
structural motifs found in many natural products and some drugs.
This work demonstrates a general approach to improvement of
1H NMR chemical shift predictions by inclusion of stereoelec-
tronic effects that are identified in simple model compounds.
1
ability to extract as much information as possible from 1D H
NMR spectra alone is of special interest in cases where 2D NMR
experiments are not readily accessible, for example, when
modern high-throughput hyphenated HPLC-NMR methods24
or NMR probes with microcoils for mass-limited samples25 are
used.
1
Since the use of ab initio methods for H NMR spectra
predictions for large, conformationally flexible systems is
computationally and conceptually demanding,11 other ap-
Experimental Section
1
proaches to calculation of H NMR chemical shifts acquire
Synthesis of Compounds 9-16. 2,3,4-Trihydroxybenzaldehyde
(3 g, 20 mmol) was dissolved in 1 M NaOH (25 mL) and stirred
with (CH3)2SO4 (4.6 mL, 50 mmol) for 3 h at 80 °C under nitrogen;
approximately 35 mL of 1 M NaOH was added during this period
to maintain basic pH. The reaction mixture was stirred at room
temperature for 12 h and was then acidified with 4 N H2SO4 and
extracted with CH2Cl2, to yield 2.6 g of a mixture of mono- and
di-O-methylated 2,3,4-trihydroxybenzaldehydes.10a The mixture was
dissolved in THF (60 mL) and treated with NaBH3CN (5.2 g, 83
mmol) in nitrogen atmosphere, after which 2 N HCl (45 mL) was
added over a period of 30 min; the stirring was continued for 2.5
h, H2O (100 mL) was added, and the solution was extracted with
diethyl ether.10b This yielded 2.4 g of a mixture consisting of 9-14
and a number of dimerization products. Compounds 9 and 11-14
were isolated by preparative HPLC; compound 10 was characterized
by NMR in mixture with 11. Compound 16 was prepared in
approximately 50% yield by reduction of 2,3,4-trimethoxybenzal-
dehyde (1.4 g, 7 mmol) with NaBH3CN (4 g, 65mmol) by the
above-described procedure. Compound 15 was prepared by dem-
ethylation of 16 (0.45 g, 2.5 mmol) with BCl3 (1 M in CH2Cl2, 0.3
mL) in CH2Cl2 under nitrogen.10c After 2.5 h the reaction mixture
was quenched with ice and extracted with diethyl ether, the extract
was washed with saturated aqueous sodium tetraborate,10c and pure
15 was isolated by preparative HPLC. The phenols (especially 13-
15) were air-sensitive, their dilute solutions being progressively
oxidized to quinones and dimerization products.
growing popularity.7 Recognition of the fact that out-of-plane
rotation of an OR group attached to a benzene ring causes an
additional downfield shift of Hpara by 0.2 ppm can improve the
spectral predictions, regardless of whether the predictions are
based on tabulated substituent effects or databases of experi-
mental chemical shifts.7 More importantly, similar effects are
expected to be considerable for a number of other heteroatom-
containing substituents. The assessment of stereoelectronic
effects of such substituents on 1H NMR chemical shifts by the
DFT approach with simple model compounds, similarly to what
was done for the OR substituent in the present work, can be
regarded as a general approach leading to improved prediction
of 1H NMR chemical shifts in aromatics, heteroaromatics, and
olefins.
Conclusions
The stereoelectronic effects of hydroxy and methoxy group
1
rotation in substituted benzenes on H NMR chemical shifts
(22) Suo, M.-R.; Yang, J.-S.; Liu, Q.-H. J. Nat. Prod. 2006, 69, 682-
684.
(23) This conclusion is also supported4 by the 13C NMR data reported
by Suo et al.22 For reference values, see (a) Assoumatine, T.; Datta, P. K.;
Hooper, T. S.; Yvon, B. L.; Charlton, J. L. J. Org Chem. 2004, 69, 4140-
4144. (b) Wang, B. G.; Ebel, R.; Wang, C. Y.; Edrada, R. A.; Wray, V.;
Proksch, P. J. Nat. Prod. 2004, 67, 682-684. (c) DellaGreca, M.; Pinto,
G.; Pollio, A.; Previtera, L.; Temussi, F. Tetrahedron Lett. 2003, 44, 2779-
2780. (d) Neudorffer, A.; Deguin, B.; Hamel, C.; Fleury, M.-B.; Largeron,
M. Collect. Czech. Chem. Commun. 2003, 68, 1515-1530. (e) Chaves, M.
H.; Roque, N. F. Phytochemistry 1997, 46, 879-881.
Acknowledgment. Financial support to L.O. from the
Carlsberg Foundation is gratefully acknowledged. We are also
indebted to Drs. H. Franzyk and C. A. Olsen for valuable
discussions.
Supporting Information Available: General experimental and
(24) (a) Clarkson, C.; Stærk, D.; Hansen, S. H.; Smith, P. J.; Jaroszewski,
J. W. J. Nat. Prod. 2006, 69, 1280-1288. (b). Jaroszewski, J. W. Planta
Med. 2005, 71, 795-802. (c) Jaroszewski, J. W. Planta Med. 2005, 71,
691-700. (d) Clarkson, C.; Stærk, D.; Hansen, S. H.; Jaroszewski, J. W.
Anal. Chem. 2005, 77, 3547-3553.
(25) (a) Jansma, A.; Chuan, T.; Albrecht, R. W.; Olson, D. L.; Peck, T.
L.; Geierstanger, B. H. Anal. Chem. 2005, 77, 6509-6515. (b) Yoo, H. D.;
Cremin, P. A.; Zeng, L.; Garo, E.; Williams, C. T.; Lee, C. M.; Goering,
M. G.; O’Neil-Johnson, M.; Eldridge, G. R.; Hu, J. F. J. Nat. Prod. 2005,
68, 122-124. (c) Gronquist, M.; Meinwald, J.; Eisner, T.; Schroeder, F. C.
J. Am. Chem. Soc. 2005, 127, 10810-10811.
1
computational procedures, experimental H NMR shift data for
3-16 (Table S1), models and atomic coordinates of low-energy
conformers of 3-16 (Tables S2-S5), calculated nuclear shieldings
for all low-energy conformers of 3-16 in vacuum and in chloroform
(Tables S6 and S7), mean average errors of calculated chemical
1
shifts (Table S8), and H NMR spectra of 9-16. This material is
available free of charge via the Internet at http://pubs.acs.org.
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