F. Macedo Jr. et al. / Tetrahedron Letters 52 (2011) 1612–1614
1613
Scheme 2. Favored conformations of 2,5-dimethoxytoluene.
Table 1
Geometry minimization results to 2,5-dimethoxytoluene
Entry Method/
basis set
Dihedral C10–O–
C2–C1
Dihedral C11–O– Final energy
C5–C6
(kcal/mol)
Input
Output
Input
Output
1
2
3
MP2/6-31G
MP2/6-31G
DFT/B3LYP1/
75°
180°
75°
180°
180°
180°
0
180°
0
0
180°
0
À312709.97
À312710.22
À314051.51
6
-31G
DFT/B3LYP1/ 180°
-31G
DFT/B3LYP1/
-31G(d,p)
DFT/B3LYP1/ 180°
-31G(d,p)
4
5
6
180°
180°
180°
180°
0
180°
0
À314051.73
À314148.39
À314148.68
6
Figure 2. Observed NOE differences for 2,5-dimethoxytoluene.
75°
6
II while attack at position 3 would be precluded in both of the con-
formations (II and III).
To investigate this proposal, we used geometry minimiza-
tion with ab initio computational calculations (MP2) and DFT
180°
180°
6
(
B3LYP1) at the levels of 6-31G and 6-31G(d,p) basis set. As pre-
dicted, calculations based on inputs with a dihedral angle of 75°
As stated above, only a subtle tendency for electrophile en-
trance at position 4 created by the electronic influence of the aro-
matic methyl group could be predicted. However, even this should
be overshadowed by the methoxyl groups that have greater elec-
converged to a conformation in which OMe-C2 was orientated to-
7
wards position 3 with an angle of 180° (Table 1, entries 1, 3 and 5).
In addition, there was a slight preference for the C11–O–C5–C6
dihedral value of 180° (Fig. 1). An energy difference of only of
0.3 kcal/mol between the conformations with C11–O–C5–C6 at
tron donating character.
The experimental 3C NMR chemical shifts for C3 (d
1
C
111.2) and
1
80° and C11–O–C5–C6 at 0° was calculated (Table 1, entries 5
and 6).
These theoretical results were spectroscopically supported by
C
C4 (d 110.9) are in agreement with the similarity of the electronic
densities for these carbon atoms (these attributions were unequiv-
ocally confirmed by HSQC allied to NOE experiments).
NMR using quantitative NOE experiments (Fig. 2). Selective excita-
tion of H-3 revealed its closer proximity to hydrogens of Me-10
compared with the mean distance between H-4 and hydrogens
at Me-11. The former showed a signal enhancement of 2.8%
whereas the signal of the latter was increased only by 1.7%.
Besides, selective excitation of H-4 results in lower signal
enhancement for hydrogens of the OMe group at C-5, but compa-
rable with those for H-6 (1.3%). These experimental data also
agreed well with the slight preference for the periplanar conforma-
tion with C11–O–C5–C6 at 180° suggested theoretical calculations.
In conclusion, the results describe here indicate the contribu-
tion of a steric factor to regioselectivity in the acylation of
We therefore envisaged differential steric hindrance at posi-
tions 4 and 3 by the methoxyl groups at C5 and C2, respectively.
We suggest there is intensified hindrance at position 3 by OMe-
C2 that, because of a van der Waals repulsive interaction with
the methyl group at C1 (conformation I, Scheme 2), tends to adopt
a conformation in which OMe-C2 is orientated towards position 3
(
conformations II and III). This would result in an indirect steric ef-
fect of the aromatic methyl group on C3. Consequently, access of
the electrophile to position 4 would be favored in conformation
2
,5-dimethoxytoluene. The theoretical (MP2 and DFT) and NOE
experimental measurements were consistent with the indirect par-
ticipation of the aromatic methyl group in blocking electrophilic
attack at position 3 of the aromatic ring. To the best of our
knowledge, this is the first description of an indirect, remote steric
hindrance strong enough to influence the regiochemical outcome
of aromatic electrophilic substitution.
Acknowledgments
The authors thank Profs. Sérgio A. Fernandes (Departamento de
Química—UFV) and Silvio Cunha (Instituto de Química—UFBA) for
helpful discussions and Dra. Ivânia T.A. Schuquel (Departamento
de Química—UEM) for acquisition of NMR spectra. We also thank
to CNPq for fellowship to D.C.
Figure 1. Minimized geometry (6-31G) for 2,5-dimethoxytoluene.