Anomeric effect enhancement in C-5-substituted 2-methoxytetrahydropyrans

Article abstract of DOI:10.1016/S0022-2860(97)00001-X

cis- and trans-2.5-Dimethoxytetrahydropyrans, cis-2,5-dimethoxy-6-methyltetrahydropyran and 2-methoxy-5-methyltetrahydropyran have been examined to see the effect of an OCH₃ group at position 5 on the degree of anomeric effect in substituted 2-methoxytetrahydropyrans. The present study shows that this group stabilises the C-2 electronegative substituent in the axial position. Semi-empirical and ab initio molecular orbital calculations support this view, AM1 calculation gives lower enthalpies as well as lower dipole moments for the compounds having an OCH₃ group in the axial position at C-2 over the equatorial form in 2-methoxytetrahydropyrans. This enhanced stabilisation is attributed to the electrostatic interaction between the partial positive charge at C-5 and the partial negative charge of the aglycone oxygen atom.

Full text of DOI:10.1016/S0022-2860(97)00001-X

MOLSTR 9752
Journal of Molecular Structure 412 (1997) 51–58
Anomeric effect enhancement in C-5-substituted
2-methoxytetrahydropyrans
,1
R.M. Srivastavaa,b,*, A.C. Pava˜oa, G.M. Seabraa, R.K. Brownb
aDepartamento de Qu´ımica Fundamental, Universidade Federal de Pernambuco, 50.670-901 Recife, PE, Brazil
bDepartment of Chemistry, University of Alberta, Edmonton, Alberta, Canada
Received 22 July 1996; revised 9 December 1996; accepted 9 December 1996
Abstract
cis- and trans-2,5-Dimethoxytetrahydropyrans, cis-2,5-dimethoxy-6-methyltetrahydropyran and 2-methoxy-5-methyltetra-
hydropyran have been examined to see the effect of an OCH3 group at position 5 on the degree of anomeric effect in substituted
2-methoxytetrahydropyrans. The present study shows that this group stabilises the C-2 electronegative substituent in the axial
position. Semi-empirical and ab initio molecular orbital calculations support this view. AM1 calculation gives lower enthalpies
as well as lower dipole moments for the compounds having an OCH3 group in the axial position at C-2 over the equatorial form
in 2-methoxytetrahydropyrans. This enhanced stabilisation is attributed to the electrostatic interaction between the partial
positive charge at C-5 and the partial negative charge of the aglycone oxygen atom. ᭧ 1997 Elsevier Science B.V.
Keywords: Anomeric effect; 2-Methoxytetrahydropyran; Conformation; AM1 calculations; HF/6-31g** basis set
1. Introduction
[5] demonstrated the preponderance of the trans iso-
mer (77%) over the cis isomer (23%). Several 2-
alkoxytetrahydropyrans have also been investigated
by Pierson and Runquist [7]. They found that the
anomeric effect for a series of 2-alkoxytetrahydro-
pyrans varies from 1.3 to 2.8 kcal mol−1. It has also
been shown [8] that an OCH3 group at position 4 in
2,4-dimethoxytetrahydropyran increases the anomeric
effect by 0.3 kcal mol−1. This stabilization energy
increase was attributed [8] to the intramolecular
dipolar attraction of the C-2 methoxy group by the
partial positive charges developed at C-4 and C-6 in
the molecule.
It is now generally believed that the anomeric effect
becomes significant when there is an overlap between
the unshared electrons of the ring oxygen and j*
orbital of the anticoplanar carbon-heteroatom at
position 2 in tetrahydropyrans [1]. The subject has
recently been reviewed [2]. The earliest important
studies on 2-substitued tetrahydropyrans were
published from 1964 through 1968, and the exis-
tence of the anomeric effect in such a system was
firmly established [3–6]. The acid equilibration
experiment in 2-methoxy-4-methyltetrahydropyran
Booth et al. [9] determined the DH0a → e and DSa0 → e
values of the conformational equilibria in 2-methoxy-
tetrahydropyran by variable temperature NMR
* Corresponding author, at: Departamento de Qu´ımica Funda-
mental, Universidade Federal de Pernambuco.
1 Deceased December 20th 1974.
0022-2860/97/$17.00 ᭧ 1997 Elsevier Science B.V. All rights reserved
PII S0022-2860(97)00001-X

52
R.M. Srivastava et al./Journal of Molecular Structure 412 (1997) 51–58
spectroscopy in varying solvent systems. They found
that replacement of toluene by methanol causes
increases in DHa0 → e and DSa0 → e. The solvent influence
on the magnitude of the anomeric effect has also been
studied by Praly and Lemieux [10] in 2-substituted
tetrahydropyrans. These authors explained the way
the solvent introduces competition between endo-
and exo-anomeric effects. We became interested in
seeing the variation caused by a C-5 methoxy sub-
stituent on the degree of anomeric effect in 2-
methoxytetrahydropyran (2-MOTHP). To our
knowledge, the influence of this group at C-5 has
not been studied before. By using simple methods
(theoretical and experimental), we have been able to
demonstrate the existence of the anomeric effect. This
report therefore shows that a methoxy group at posi-
tion 5 in 2-methoxytetrahydropyran does enhance
the anomeric effect.
account the force constants of the molecules, which
are the second energy derivatives with respect to the
coordinates. Positive second derivatives indicate that
the point is a minimum.
3. Experimental details
Boiling points are uncorrected. Elemental analyses
were performed by Mrs. Darlene Mahlow, Chemistry
Department, University of Alberta, Edmonton, Alta.
G.C. analyses were made with an F and M apparatus
(Model 700 using a column (1/8Љ × 12Ј) filled with
20% butanediol succinate (BDS) on chrom P (60–80
mesh). Helium was the carrier gas. The proton nuclear
magnetic resonance spectra were obtained with
Varian Associates A60 and HR100 instruments at
35Њ Ϯ 1 and 33Њ Ϯ 1 respectively. Unless otherwise
specified, deuteriochloroform was used as solvent and
tetramethylsilane as an internal reference.
2. Computational procedure
Fully optimised geometries of the trans and cis
forms with different axial and equatorial orientations
of the methoxy groups of 2,5-dimethoxytetrahydro-
pyrans (2,5-DMOTHP) and 2-methoxy-5-methyl-
tetrahydropyran (2-MO-5-METHP) were obtained
at semi-empirical and ab initio levels. The semi-
empirical AM1 molecular orbital calculations [11],
with the mopac 93 program [12,13], and the ab initio
Hartree–Fock Self-Consistent Field (HF-SCF) mole-
cular orbital calculations, with the gaussian Program
[14], were carried out on an IBM RISC 6000 compu-
ter. The ab initio geometry optimisation was obtained
with the STO-3G basis set. This is a relatively simple
basis set which in general gives good results in
describing the geometries of many systems. More
accurate single-point calculations using this optimised
STO-3G geometry were performed with the 6-31G**
basis set.
The conformations were optimised until a mini-
mum point was reached and the gradient norm
dropped below 0.01. The gradient represents the
energy derivative with respect to the coordinates,
and a low norm indicates that the conformation is at
(or very near to) an inflection point. The force-field
calculations [15] tests if the geometries are in fact at
the minimum energy level. This procedure takes into
4. Synthesis and characterisation of the model
compounds
4.1. 2-methoxy-5-methyl-3,4-dihydro-2H-pyran
Methacrolein (35.0 g, 0.45 mol; 90%.), hydro-
quinone (100 mg), and methylvinyl ether (150 ml)
were heated at 195ЊC for 17 h in an autoclave under
pressure (500 lbs) with stirring. Removal of methyl-
vinyl ether, after cooling the contents, yielded the
crude material (44.0 g). GC analysis at 110ЊC showed
two peaks in the area ratio of 1.0:0.3 in order of
increasing retention time. These peaks were presum-
ably due to 2-methoxy-5-methyl-3,4-dihydro-2H-
pyran
and
2,5-dimethyl-3,4-dihydro-2H-pyran-
2-carboxaldehyde as evidenced by two absorptions
at 1690 and 1750 cm−1 in the infrared spectrum.
Because of the difficulty in separation, the carbonyl
function was reduced to alcohol and then fractionated
(see below).
To the above mixture in methanol (50 ml) at 0ЊC
was added NaBH4 (1.70 g, 0.045 mol) portionwise
over 1.5 h, and then left overnight stirring at room
temperature. Removal of methanol by fractional
distillation left a liquid. This was diluted with water
(50 ml), extracted with methylene chloride, dried

53
R.M. Strivastava et al./Journal of Molecular Structure 412 (1997) 51–58
Table 1
Elemental analyses of compounds 7 and 8 and cis- and trans-2-MO-5-METHP
Compound
Molecular formula
Analysis, calculated (%)
Analysis, found (%)
C
H
C
H
7 and 8
C8H14O2
C7H14O2
67.57
64.58
9.92
10.84
67.59
64.47
10.22
10.83
cis- and trans-2-MO-5-METHP
(Na2SO4), filtered, and fractionally distilled to give
carbon were shaken at room temperature for 20 h at
40 p.s.i. under hydrogen atmosphere. Removal of the
catalyst by filtration and methanol by fractional dis-
tillation left a liquid which, upon distillation, provided
1.5 g (59%) of a colourless liquid, b.p. 85Њ/115 mm,
n 2D5 = 1.4216; lit. [17], n 2D0 = 1.4243. The proton
magnetic resonance spectrum showed that the
compound was indeed cis-2-methoxy-5-methyltetra-
hydropyran.
32.6 g (56.7%) of a colorless liquid, b.p. 145Њ/710
mm; n 2D5 = 1.4433; lit. [16], b.p. 56Њ/14 mm, n 2D3
=
1.4483. Gas chromatography produced a single peak.
The spectral analyses showed it to be 2-methoxy-5-
methyl-3,4-dihydro-2H-pyran.
Further distillation afforded 5.0 g (7.9%) of a
liquid, b.p. 80ЊC/8 mm. GC of this liquid showed
two peaks whose elemental analyses are given in
Table 1. Since the analysis corresponds to the
molecular formula C8H14O2, the two compounds
are: 2,5-dimethyl-3,4-dihydro-2H-pyran-2-methanol,
7, and exo- and/or endo-1,4-dimethyl-6,8-dioxa-
bicyclo[3.2.1] octane, 8. No further work was pursued
on these compounds.
4.3. Equilibration of cis-2-methoxy-5-
methyltetrahydropyran
The above compound (0.5 g) in methanol (5.0 ml)
containing p-toluenesulfonic acid monohydrate (50
mg) was refluxed for 6 h, and then left overnight at
room temperature with stirring. Addition of some
sodium methoxide neutralised the acid. The contents
were dissolved in ether (100 ml), washed with water
(4 × 3 ml), dried (Na2SO4), and filtered. Solvent
removal by fractional distillation left a crude liquid,
4.2. 2-methoxy-5-methyltetrahydropyran, 2-MO-5-
METHP, 9
2-Methoxy-5-methyl-3,4-dihydro-2H-pyran (2.5 g,
0.02 mol) in methanol (3 ml) and 5% palladium on
Table 2
Conformational percentages and free energy differences for 2-methoxytetrahydropyran, cis-2-methoxy-5-methyltetrahydropyran and cis- and
trans-2,5-dimethoxytetrahydropyrans
Compound
2-MOTHPc
Solvent
Chemical shifta (t)
Jobs (in Hz)a
NA
%
DGb/kcal mol−1
Neat
CCl4
5.57
5.59
5.57
5.40
5.58
5.47
5.58
5.45
7.0
6.6
7.0
4.4
4.6
5.1
5.6
5.6
61.5
66.0
61.5
95.0
92.0
85.9
79.5
79.5
0.29
0.40
0.29
1.79
1.49
1.10
0.82
0.82
CDCl3
CDCl3
CCl4
CDCl3
CCl4
cis-2-MO-5-METHPd
cis-2,5-DMOTHPe
trans-2,5-DMOTHPf
CDCl3
aFrom the 100 MHz NMR spectra. The error in J values may be Ϯ 0.2Hz.
bFrom the formula G = RTlnNA/(1 − NA), R = 1.987 cal deg− 1 mol− 1; T = 306ЊC
c2-MOTHP = 2-Methoxytetrahydropyran.
dcis-2-MO-5-METHP = 2-Methoxy-5-methyltetrahydropyran.
ecis-2,5-DMOTHP = cis-2,5-Dimethoxytetrrahydropyran.
ftrans-2,5-DMOTHP = trans-2,5-Dimethoxytetrahydropyran.

54
R.M. Srivastava et al./Journal of Molecular Structure 412 (1997) 51–58
which showed a ratio of a : b = 2 : 1 on the gas chro-
matogram (BDS column, 110ЊC). Distillation gave a
colourless liquid (0.2 g, 40%), b.p. 155ЊC (oil bath
temperature). Elemental analyses are listed in Table 1.
The 100 MHz NMR spectrum gave two anomeric
proton signals at t 5.40 (1H, t, J2,3eq + J2,3ax = 4.4 Hz),
and t 5.72 (1H, q, J2,3eq + J2,3ax = 9.6 Hz), respectively.
values are not unreasonable since similar JA values
have been observed in other cases. For example,
methyl 2,6-dideoxy-4-O-methyl-a-L-arabino-hexo-
pyranoside showed H-1 at d 4.68 with JA = 3.0 Hz
[21], and cyclohexyl 2,3-dideoxy-a-D-erythro-hexo-
pyranoside had the anomeric proton signal at d 4.97
(W/2 Ϸ 4.0 Hz), which means that the JA value for
such a system may be Յ 4.0 Hz [22]. Similarly, the
H-1 proton signal in methyl 4-amino-2,4,6-trideoxy-
3-O-methyl-b-L-arabinohexopyranoside appeared at
d 4.36 with a JB value of 12.0 Hz [23].
5. Results and discussion
The syntheses of the above model compounds have
already been described [18]. The published method
[7] was used to determine the proportion of two con-
formational (chair) isomers of both cis- and trans-2,5-
dimethoxytetrahydropyrans. From the total anomeric
proton coupling, Jobs = J2,3ax + J2,3eq, the percentage of
the chair conformer, which has the anomeric methoxy
group in the axial position (NA), and the anomeric
OCH3 function in the equatorial position (NB), was
obtained and the free energy difference calculated.
The model compounds employed by Pierson and
Runquist [7] to obtain the couplings of the two con-
formers were methyl 2-deoxy-a-D-glucopyranoside
(total anomeric proton coupling constant, JA = 4.7
Hz), and cis-2-methoxy-4-methyltetrahydropyran
(total anomeric proton width, JB = 10.5 Hz).
Before applying these values to cis- and trans-2,5-
dimethoxytetrahydropyrans, we re-examined 2-
MOTHP as a neat sample, as well as in CCl4 and
CDCl3, using a 100 MHz NMR spectrophotometer
and measured the J values more carefully. The
spacings of JA were 6.6 Hz (CCl4 ) and 7.0 Hz (neat
or in CDCl3), respectively (Table 2).
Previous workers [7] used a 60 MHz NMR instru-
ment and reported a J value of 6.3 Hz for the neat
sample of 2-methoxytetrahydropyran. Our results
for the neat sample of 2-methoxytetrahydropyran
gave a J value of 7.0 Hz which is 0.7 Hz more, and
therefore NA is 61.5%, not 72% as reported earlier [7].
Our measurements of the J values of this compound
agree with the ones cited by Lemieux and co-workers
[19]. Because of this discrepancy, we had no alter-
native but to choose other model compounds from
the literature [20]. These are trans-6-hydroxy-
methyl-2-methoxytetrahydropyran (JA = 4.0 Hz)
and methyl 2-deoxy-3,4,6-tri-O-acetyl-b-D-arabino-
hexopyranoside (JB = 11.8 Hz), respectively. These
Since the anomeric effect [3,7] is the sum of the
free energy difference between the two conformers
and the A value (0.6 kcal mol−1) [24] of the methoxy
group (Scheme 1), we get the values of the anomeric
effect for 2-MOTHP of 1.00 and 0.89 kcal mol−1 in
CCl4 and CDCl3, respectively.
Our value of the anomeric effect is lower than that
obtained by Pierson and Runquist [7]. Instead of using
the usual free energy values (G01 → 2 − G30 → 4) [25],
Booth and Khedair [26] employed DH0 values in
order to eliminate the temperature-dependent entropy
contributions. They found the value of the ‘‘anomeric
effect (DDH0)’’ for 2-MOTHP to be 0.75 kcal mol−1.
Booth and co-workers [26,27] also measured the equi-
librium constant of this compound at 143 K using 13C
NMR spectroscopy and obtained 79.6% axial confor-
mer. These methods appear more precise.
Next, we examined cis-2-methoxy-5-methyltetra-
hydropyran (cis-2-MO-5-METHP). The methyl
group at C-5 in 2-MOTHP shows an NA of 95.0%.
This conformer is favoured because in the alternate
conformation there are two problems: 1) the equator-
ial methoxy group will be in opposition to the
anomeric effect, and 2) the axial methyl group
will have a 1,3-diaxial interaction. In order to deter-
mine the anomeric effect in this case, we had to carry
out the equilibration experiment in the presence of an
acid. This provided cis- and trans-2-MO-5-METHP in
Scheme 1.

55
R.M. Strivastava et al./Journal of Molecular Structure 412 (1997) 51–58
Scheme 2.
the ratio of 2:1 as estimated by gas–liquid chro-
matography. The free energy difference comes to
0.41 kcal mol−1 and the anomeric effect to 1.0 kcal
mol−1, almost the same as in the case of 2-MOTHP
in CDCl3.
An interesting result was observed in the cases of
cis- and trans-2,5-dimethoxytetrahydropyrans (cis-
and trans-2,5-DMOTHP). The cis-DMOTHP pro-
vided the stable conformation to the extent of 92.0%
in CCl4. In CDCl3, NA was 85.9% since the solvent
of high dielectric constant increases the amount of
the more polar equatorial form [28].
alternate form 6b (Scheme 2). This kind of electro-
static attraction has been observed earlier [29] for
a series of trans-1,4-dihalocyclohexanes, and in 1-
H,4H-trans-1,4-di-(trifluoroacetoxy) cyclohexane-d8.
In order to determine the anomeric effect in cis- and
trans-2,5-DMOTHPs, the acid equilibration results
should be valuable. The literature [18] records an
equal preponderance of each isomer as a result of
such experiments. This means that both compounds,
5 and 6, have the same degree of anomeric effect.
Measurement of the JA value for trans-2,5-DMOTHP
either in CCl4 or CDCl3 gave the same value of
5.6 Hz (DG = 0.82), and the anomeric effect is 1.42.
The reason for no change in the JA value in the two
solvents is that 2,5-dimethoxy functions in tetrahydro-
pyran are stabler in axial orientations. This is not
surprising if one analyses 6a, where C-5-OCH3 has
one diaxial interaction with H-3. Again this inter-
action is neutralised to a great extent by the attractive
forces between the partial positive and negative
charges of C-2 and oxygen at position 5. The other
conformer, 6b, will have two unfavourable inter-
actions: the equatorial C-2-OCH3 group will be in
The trans-2,5-DMOTHP gave about 80% of the
axial form in both solvents (CCl4 and CDCl3). For
this compound, one would expect a high contribution
from the other conformer, where both methoxy groups
are equatorial. The reason for 6 having Ϸ 80% abun-
dance can be explained by considering the electro-
static attraction between the partial positive charge
at C-2 and the partial negative charge of oxygen of
˚
C-5-OCH3. The distance r2 (3.54 A) obtained by
the ab initio (STO-3G) molecular orbital calculations
˚
in 6a is smaller than the distance r2 (4.17 A) in the
Table 3
Bond angles, bond distances, total energy and dipole moments of compounds 2-MOTHP, cis-2-MO-5-METHP, and cis- and trans-2,5-
DMOTHP obtained by AM1 calculations
Hf/kcal mol−1
m(D)
DHf/kcal mol−1
˚
˚
Compound
Configuration at
C-2 and C-5
v1/Њ
v2/Њ
d1/A
d2/A
2-MOTHP
a
e
114.96
113.26
114.98
113.27
114.96
113.16
115.33
113.56
108.02
107.78
108.05
107.61
108.13
107.65
108.24
107.81
1.41
1.43
1.41
1.43
1.415
1.43
1.41
1.43
1.42
1.41
1.42
1.41
1.417
1.41
1.42
1.41
− 113.32
− 110.80
− 118.60
− 116.11
− 151.34
− 149.08
− 150.13
− 146.88
0.39
1.97
0.40
1.99
1.25
0.99
1.03
2.97
2.53
2.48
2.26
3.24
2-MO-5-METHP a,e
e,ea
2,5-DMOTHP
2,5-DMOTHP
a,e
e,eb
a,a
e,ab
aAcid-catalysed equilibrium.
bCalculated in this form assuming the change in configuration at C-2 after acid equilibration.

56
R.M. Srivastava et al./Journal of Molecular Structure 412 (1997) 51–58
opposition to the anomeric effect, and the distance (r2)
between C-2 and C-5-O- will increase, causing the
decrease in attraction between them.
calculated dipole moments in 2-MOTHP and 2-MO-
5-METHP indicate correctly that the axial orientation
is preferred over the equatorial. However, in the case
of 2,5-DMOTHP, the (a,e) form shows a higher dipole
moment than the (e,e) form. Initially, this may appear
somewhat surprising, but a close look indicates
clearly that it should be like this, because the two
methoxy groups disposed equatorially will cancel
the dipole moment to a certain extent. A similar result
was expected for the conformer having an (a,a)
arrangement and this indeed has been found.
Next, we turned our attention to ab initio molecular
orbital calculations. The result with 2-MOTHP, using
the STO-3G basis set for geometry optimisation
followed by the refinement of the electronic values
at 6-31G**, gave a satisfactory result. In 1989,
Wiberg and Murcko [30] examined this molecule
using the 3-21G* basis set and found that the axial
form was favoured over the equatorial conformation
by 1.33 kcal mol−1, in fair agreement with the experi-
ment. Compound 2-MO-5-METHP also provided
satisfactory results. However, the different forms of
2,5-DMOTHP afforded theoretical values (Table 4)
which do not coincide with the experimental results.
At this point, we have tried to do more work on these
compounds by including the solvent effect as well,
but at the HF level we could not obtain results
which showed good agreement with the experiment.
Of course, electronic correlation effects cannot be
neglected in these studies. Avoiding a more complex
computational task, by considering, for example, ab
initio calculations with interactions of configurations,
To gain further insight into the above work, we
investigated cis-2,5-dimethoxy-6-methyltetrahydro-
pyran. It is known [3] that acid-catalysed equilibration
of this product gives 74% of 2a,5a-dimethoxy-6b-
methyltetrahydropyran (a-anomer) and 26% of the
other isomer, 2b,5a-dimethoxy-6b-methyltetrahydro-
pyran (b-anomer). From this percentage, the DG value
is Ϸ 0.64 kcal mol−1 and the anomeric effect is 1.24.
Again, it clearly demonstrates that a methoxy group at
C-5 in tetrahydropyran does stabilise the C2-OCH3
function in the axial position. In addition, the MO
calculations show that the methoxy group at position
2 in THP in the axial form is more stable than in the
equatorial form. This is in agreement with the experi-
mental values (see Table 2). Both the theoretical and
experimental results support the anomeric effect.
Table 3 shows the data obtained by AM1 calcula-
tions. It can be seen that the bond angle c1 increases
and the bond length d1 decreases when the methoxy
group is oriented axially. Similarly, angle c1 becomes
smaller and d1 is larger when the substituent is dis-
posed equatorially. This supports the view that there
is overlap between the lone pair orbital of the ring
oxygen and the j* orbital of the carbon having an
electronegative substituent at C-2 in tetrahydropyran
[1].
The calculated enthalpies of formation (Table 3) for
all four compounds are in agreement since the axial
conformation is thermodynamically favoured. The
Table 4
Results of 6-31g**//sto-3g calculations
Solvent
Neat (vacuum)
CDCl3 (e = 4.806, 20ЊC)
E(Eh) m(D)
CCl4 (e = 2.23790, 20ЊC)
a
˚
Molecule
E(Eh)
m(D)
E(Eh)
m(D)
a0/A
1
2
9
9
5
5
6a
6b
a
e
− 383.9204738 0.27
− 383.9174696 2.25
− 422.9593852 0.27
− 422.9516811 2.57
− 497.7904084 1.59
− 497.7920556 3.34
− 497.7896921 1.46
− 497.7942050 1.43
− 383.9204827 0.30
− 383.9180746 2.48
− 422.9593930 0.29
− 422.9523877 2.82
− 497.7906635 1.75
− 497.7931874 3.67
− 497.7899093 1.59
− 497.7944105 1.59
− 383.9204792
− 383.9178372
− 422.9593900
− 422.9521072
− 497.7905599
− 497.7927397
− 497.7898263
− 497.7943290
0.29
2.39
0.28
2.75
1.69
3.56
1.55
1.54
4.24
4.23
4.38
4.39
4.47
4.48
4.47
4.47
a,e
e,e
a,e
e,a
a,a
e,e
aMolecular radius used for solvent effect calculations.

57
R.M. Strivastava et al./Journal of Molecular Structure 412 (1997) 51–58
we were able to present a correct description of the
anomeric effect based on the simple semiempirical
AM1 Hamiltonian. Tvaroska concluded that the
agreement of calculated results with the available
experimental data seems to be better for selected
semi-empirical methods than for some ab initio cal-
culations [31,32]. Woods et al. [33] have performed
MNDO, AM1, and PM3 semi-empirical calculations
on methanediol and were able to reproduce the
geometries, conformational energies, and proton
affinities associated with the anomeric effect. How-
ever, there are serious limitations with the AM1
Hamiltonian. This method is known to overestimate
strongly dipolar interactions and to fail to reproduce
quantitatively the hydrogen bonds [34]. Studies by
Buemi and co-workers concluded that AM1 results
are qualitatively acceptable, especially if comparisons
are made within a class of compounds [35]. Other
authors have found other difficulties when applying
the AM1 method to investigate the anomeric effect
[36]. In the present case, we have obtained good
results with the AM1 Hamiltonian, some of than
even better than ab initio ones. Therefore, we con-
clude that our molecules are suited for AM1 calcula-
tions and the great advantage of this method is that it
consumes far less computer time than the ab initio
calculations, and is much easier to apply for larger
molecules.
major stereoisomer. However, B should adopt a more
stable conformation D due to the anomeric effect.
Similarly, D, on acid equilibration, would give C as
a minor isomer. Again its stability is less and therefore
it should go to A because of the anomeric effect. In
short, acid equilibration of either A or D would lead
to a mixture of these two isomers in almost equal
quantity.
6. Conclusion
Our conclusion is that an electronegative sub-
stituent such as the OCH3 group at position 5 in
2-methoxytetrahydropyran does enhance the anome-
ric effect by attractive interactions. This phenomenon
has been observed for the first time for such an elec-
tronegative substituent. It has also been demonstrated
that simple AM1 molecular orbital calculations give
the correct view of the anomeric effect for these com-
pounds. Although we could not get the correct picture
of the anomeric effect of all compounds studied by
the present ab initio calculations using certain basis
sets, more sophisticated calculations of this nature are
needed for a better understanding.
Acknowledgements
Scheme 3 shows the acid equilibration result of
2,5-DMOTHP. It can be seen that treatment of com-
pound A with acid in methanol would give an equi-
librium mixture of A and B where A should be the
The authors thank Conselho Nacional de Desenvol-
vimento Cientı´fico e Tecnolo´gico (CNPq), Coordena-
doria de Aperfeic¸oamento de Pessoal de N´ıvel
Scheme 3.

58
R.M. Srivastava et al./Journal of Molecular Structure 412 (1997) 51–58
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J. Chem., 47 (1969) 4427.
Superior (CAPES), and National Research Council
of Canada for financial assistance.
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