Density functional theory calculations and experimental parameters for mutarotation of 6-deoxy-l-mannopyranosyl hydrazine

Article abstract of DOI:10.1016/j.tet.2006.09.090

The geometry and energy profiles of the mutarotation pathway present in the equilibrium of 6-deoxy-β-l-mannopyranosyl 2,4-dinitrophenylhydrazine (1a), 6-deoxy-l-mannose 2,4-dinitrophenylhydrazone (1b), and 6-deoxy-α-l-mannopyranosyl 2,4-dinitrophenylhydra

Full text of DOI:10.1016/j.tet.2006.09.090

Tetrahedron 62 (2006) 11916–11924
Density functional theory calculations and experimental
parameters for mutarotation of 6-deoxy-L-mannopyranosyl
hydrazine
a
Mabel Fragoso-Serrano, Rogelio Pereda-Miranda and Carlos M. Cerda-Garcıa-Rojas
a
b,
*
´
a
´
´
Departamento de Farmacia, Facultad de Quımica, Universidad Nacional Autoꢀnoma de Mexico,
Ciudad Universitaria, Mexico City 04510, Mexico
b
´
Departamento de Quımica, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional,
ꢀ
´
Apartado 14-740, Mexico City 07000, Mexico
Received 2 August 2006; revised 21 September 2006; accepted 22 September 2006
Available online 25 October 2006
Abstract—The geometry and energy profiles of the mutarotation pathway present in the equilibrium of 6-deoxy-b-L-mannopyranosyl 2,4-
dinitrophenylhydrazine (1a), 6-deoxy-L-mannose 2,4-dinitrophenylhydrazone (1b), and 6-deoxy-a-L-mannopyranosyl 2,4-dinitrophenylhy-
drazine (1c) were modeled by DFT calculations at B3LYP/6-31G(d) level affording DGDFT¼0.000 kcal/mol, DGDFT¼0.174 kcal/mol, and
DGDFT¼3.411 kcal/mol, respectively. Experimentally, the b-L-pyranose 1a occurs in 50% followed by the acyclic structure 1b in 44% as
well as by the a-L-anomer 1c in 6%. The conformations of 1a–c and their corresponding 2,3,4-triacetyl derivatives 2a–c were studied by mo-
lecular modeling and NMR spectroscopy. IR frequencies, NMR chemical shifts, and X-ray diffraction analysis were employed to compare
theoretical with experimental structural parameters.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
derivatives. It seems to depend on the structure and stereo-
chemistry of each particular carbohydrate as well as on
the acidity or basicity of the solution.5,6 The mutarotational
process has been often described as a tautomerism6
because of the prevalence of the equatorial N-glycosidic
anomer and the open chain glycosylhydrazone components,
both over that of the anomer carrying the N-moiety axially
oriented (e.g., 1a and 1b over 1c). In several hydrazine deriv-
atives, particularly for those of rhamnose and mannose, it
has also been proved that the predominant isomer in
the crystalline state7–9 is not always the one observed in
solution.5,6,10
Hydrazine derivatives play very important roles in agricul-
ture, pharmaceutical, and chemical industries, and in many
aspects of several emerging technologies.1 This wide class
of substances has attracted the attention of both synthetic2
and theoretical chemists3 because they represent relevant
models for reactivity exploration and the study of the confor-
mational behavior of nitrogen-containing substances. Com-
bination of hydrazine compounds with sugars affords
glycosylhydrazine derivatives, which increase the complex-
ity of the chemical structure and properties of the hydrazine
moiety. An interesting aspect of glycosylhydrazines, in par-
ticular of glycopyranosylhydrazines (e.g., 1a), is their ability
to establish an equilibrium with the corresponding acyclic
glycosylhydrazones (1b), which leads to the anomeric
form of the cyclic glycopyranosylhydrazines (e.g., 1c) as ex-
emplified in Scheme 1. This equilibrium can be studied un-
der terms comparable to those of sugars mutarotation.4
A major part of our ongoing research is directed toward the
application of molecular modeling in the stereochemical and
conformational elucidation of polyoxygenated molecules
derived from 6-deoxyhexoses.11,12 A theoretical methodol-
ogy to model and predict the mutarotational equilibrium
among the b-L-anomer 1a, the acyclic component 1b, and
the a-L-anomer 1c is described and compared to the results
obtained by NMR data. The geometric and energetic
mutarotational pathways were analyzed by density func-
tional theory calculations at B3LYP/6-31G(d) level.13 In
addition, the same protocols were applied to study the struc-
ture and conformation of acetyl derivatives 2a–c and 3.
Although theoretical approaches on the structure of
monosaccharides4,14–16 and glycopyranosylamines17 have
There is no fully delineated systematization that can explain
and predict the equilibrium for glycosylhydrazine
Keywords: Glycosylhydrazines; Mutarotation; DFT calculations; NMR;
X-ray analysis.
* Corresponding author. Tel.: +52 55 5061 3800x4035; fax: +52 55 5747
7137; e-mail: ccerda@cinvestav.mx
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.09.090

M. Fragoso-Serrano et al. / Tetrahedron 62 (2006) 11916–11924
11917
NO2
RO 4
RO
5
6
H
CH3
3
CH3
RO
RO
N
N
O
1
OH
N
2
RO
NO2
H
1''
H
NO2
NO2
H
RO
2''
N
N
RO
N
2'
H 1'
3''
4''
CH3
RO
O
6''
NO2
RO
NO2
5''
1a : R =H
2a : R = Ac
1b : R =H
2b : R = Ac
1c: R =H
2c: R = Ac
Scheme 1. Mutarotation in glycosylhydrazine derivatives.
recently been published, there are as yet no DFT structural
and mutarotational analyses of glycosylhydrazine deriva-
tives.
components, including the anomeric protons for 1a and 1c
at d 5.78 and 4.52, respectively, and the vinylic protons for
1b-E and 1b-Z at d 8.03 and 7.22, respectively. The intercon-
version between the a- and b-anomers was also registered by
the change in the specific rotation of compound 1a in acidic
solution.
NO2
OAc OAc
N
N
OAc OAc
H
NO2
NO2
3
H
NO2
OH OH
OH OH
N
N
N
NO2
N
H
2. Results and discussion
NO2
OH OH
OH OH
1b-Z
1b-E
6-Deoxy-L-mannose (L-rhamnose) treated with 2,4-dinitro-
phenylhydrazine produced, after crystallization in EtOH,
the stable cyclic 1-(6-deoxy-b-L-mannopyranosyl)-2-(2,4-
dinitrophenyl) hydrazine (1a) with a molecular formula of
C12H16N4O8. Its melting point (165–167 ꢀC) surprisingly
matched that previously reported for hydrazone 1b.18 How-
ever, NMR analysis supported our suspicion that the re-
ported open chain substance is in fact the b-L-pyranose 1a.
The signal for the anilinic NH was recorded at d 9.65 (s)
while the glycosidic NH was registered at d 5.78 and shown
to be coupled with the anomeric proton H-1 at d 4.16 (trans-
Scheme 2. E-Z Isomerization of 1b.
In order to study the structures of the acyclic components
and the a-L-pyranoside form, it was necessary to produce
substances that could be isolated for spectroscopic analysis
by NMR. Treating pure 1a with acetic anhydride in pyridine
afforded the following such substances: 1-(2,3,4-tri-O-
acetyl-6-deoxy-b-L-mannopyranosyl)-2-(2,4-dinitrophenyl)-
hydrazine (2a), 2,3,4-tri-O-acetyl-6-deoxy-L-mannose
2,4-dinitrophenylhydrazone (2b), and 1-(2,3,4-tri-O-acetyl-6-
deoxy-a-L-mannopyranosyl)-2-(2,4-dinitrophenyl)hydrazine
(2c), together with 2,3,4,5-tetra-O-acetyl-6-deoxy-L-man-
nose 2,4-dinitrophenylhydrazone (3). Additionally, treat-
ment of 1a with acetyl chloride afforded 3 as the main
product. Compounds 2a, 2b, and small amounts of 2c
were purified by normal phase HPLC. However, they equil-
ibrated to the original mixture (2a–c) after standing for 24 h
in individual acidic CDCl3 solutions. Linear derivative 2b
was obtained exclusively in its E-configuration.
1
diaxial coupling constant JNH,1¼11.5 Hz) in the H NMR
spectrum in DMSO-d6. The 13C NMR spectrum was also
consistent with that for the pyranoside structure for 1a,
e.g., the anomeric carbon C-1 at d 87.0. On addition of trace
amounts of hydrochloric acid, the DMSO-d6 solution of 1a
immediately produced a mixture of four major components
detectable through their anilinic NH protons at d 9.66, 9.67,
1
11.39, and 12.78 in the H NMR corresponding to the b-L-
anomer 1a, the a-L-anomer 1c, and the acyclic component
1b in its E and Z-configurations at the C]N double bond,
respectively (Scheme 2). The percentage of the isomers 1a
(50%), 1b-E (36%), 1b-Z (8%), and 1c (6%) was calculated
by the signal integrals of selected hydrogen atoms as can be
seen in Figure 1. Structural assignments were confirmed
through the signals for the anomeric carbon atoms at
d 87.0 for 1a and 87.9 for 1c, the signals for the C-1 sp2 car-
bon atoms at d 155.7 for 1b-E and d 152.9 for 1b-Z. These
assignments were further confirmed through a detailed anal-
ysis of the 2D NMR spectra of the mutarotational equili-
brated mixture, which included COSY, NOESY, gHSQC,
and gHMBC experiments. NOESY spectrum was particu-
larly useful in confirming the double bond geometry in the
1b-E and 1b-Z-isomers because of the strong interaction
between the anilinic NH and the vinylic H-1 signals only
observed in 1b-E but not in 1b-Z. The information provided
by the COSY, gHSQC, and gHMBC spectra allowed
the individual assignment of signals for the equilibrium
The 1H NMR spectrum of 2a clearly indicated the presence
of a pyranoside ring bearing three acetoxyl substituents. In
this case, the signal for the anilinic NH appeared at d 9.63
while the NH attached to the saccharide was at d 4.52 and
strongly coupled with the anomeric proton H-1 at d 4.40
(JNH,1¼11.4 Hz). Adding D2O permitted the assignment of
the labile hydrogen atoms. 13C NMR spectrum exhibited
the characteristic signal for the C-1 anomeric carbon at
d 85.7. The X-ray diffraction analysis of 2a confirmed the
structure and stereochemistry of this substance (Fig. 2),
which exhibited the 2,4-dinitrophenylhydrazine moiety in a
b-equatorial orientation at C1. The hydrogen atoms H1–H2
and H2–H3 of this 6-deoxymannose derivative (2a) were
found in a syn-clinal relationship while H3–H4 and H4–H5
appeared in an anti-periplanar orientation (Table 1). The py-
ranoside ring exists in a conformation close to the classical
chair, slightly distorted toward a twist-boat.

11918
M. Fragoso-Serrano et al. / Tetrahedron 62 (2006) 11916–11924
1a
H-6"
1b-E
H-6"
1b-E
H-1
1b-Z
1b-Z
1c
H-1
H-6"
H-6"
8.00
7.90
7.80
7.70
7.60
7.50
7.40
7.30
7.20
ppm (f1)
Figure 1. A section of the 1H NMR aromatic region (d 8.10–7.12) for the equilibrated mixture of 1-(6-deoxy-b-L-mannopyranosyl)-2-(2,4-dinitrophenyl)hy-
drazine (1a), 6-deoxy-L-mannose 2,4-dinitrophenylhydrazone (1b, E and Z-isomers), and 1-(6-deoxy-a-L-mannopyranosyl)-2-(2,4-dinitrophenyl)hydrazine
(1c) in DMSO-d6+HCl at 300 MHz.
Density functional theory calculations were used to analyze
the minimum energy pathway and the geometry of each com-
ponent in the mutarotational equilibrium (Scheme 1). Con-
formational distribution of compounds 1a–c and 2a–c was
individually calculated by molecular mechanics (MMFF)
through an extensive Monte Carlo random search.19 Due to
the presence of the hydrazine moiety, the conformational
analysis of the pyranoside rings of 1a, 1c, 2a, and 2c was
far more complicated than that expected for simple
hexose derivatives. However, in the absence of the usual
hydroxymethyl group, normally prominent in the
conformational properties of glucopyranosides, the difficul-
ties involved in this analysis were mitigated.15 A molecular
mechanics energy range of 0–10 kcal/mol was selected for
these calculations, which yielded a total of 30, 106, and 63
minimum energy conformations for compounds 1a, 1b,
and 1c, respectively. Low-energy conformations were corre-
0
lated to the rotations of the C1–N1–N2–C1 bonds, which
defined the conformation of the dinitrophenylhydrazine moi-
ety. The cooperative clockwise or counterclockwise orienta-
tions of the hydroxyl groups also played a relevant role in the
conformational distribution. Each conformational species
was geometry analyzed and selected according to the maxi-
mum number of cooperative hydrogen bonds. Using this fil-
tering criteria, 7, 27, and 10 conformations for 1a, 1b, and 1c,
respectively, were optimized by DFT calculations employing
the B3LYP method with the 6-31G(d) basis set. To ensure
a full exploration of the conformational space in linear deriv-
ative 1b, the distribution was additionally calculated through
a systematic search model11 of 54 conformational variants
resulting from rotation of the C2–C3, C3–C4, and C4–C5
bonds every 120ꢀ, as well as the C1–C2 bond by 180ꢀ. The
minimum energy structures were optimized by DFT calcula-
tions by employing the same method and basis set to yield
similar results as those obtained from the Monte Carlo
method, also within a 0–10 kcal relative range. Analysis of
the molecular geometry of each conformer revealed that
the physical principles that govern the conformational distri-
bution can be mainly defined by the presence of an intramo-
lecular hydrogen bond patterns as well as steric effects and
repulsive 1,3 oxygen–oxygen interactions. Table 2 contains
the 27 refined global and local minimum energy structures
ordered according to their stability and the corresponding
H–C–C–H dihedral angles found in the C1–C2–C3–C4–C5
fragment of 1b. Each rotameric species was named by using
the following descriptors: P for plus (ca. +60ꢀ), A for anti
(ca.+180ꢀ), and M for minus (ca. ꢁ60ꢀ) according to the
nearest value for the measured dihedral angles.
Figure 3 illustrates the DFT minimum energy pathway
for the mutarotational process from 1a to 1c involving six
key acyclic conformers of 1b in the E-configuration. The
Figure 2. Comparison between the DFT B3LYP/6-31G(d) molecular model
of 2a and its X-ray structure.

M. Fragoso-Serrano et al. / Tetrahedron 62 (2006) 11916–11924
11919
Table 1. DFT B3LYP/6-31G(d) dihedral angles (in deg) and calculateda versus observedb 1H–1H vicinal coupling constants (in hertz) for the global minimum of
pyranosides 1a, 1c, 2a, and four conformations of 2c (comparison between DFT and X-ray dihedral angles for 2a is shown)
Compound fH1–C–C–H2
J1,2(calcd) J1,2(obsd) fH2–C–C–H3 J2,3(calcd) J2,3(obsd) fH3–C–C–H4
J3,4(calcd) J3,4(obsd) fH4–C–C–H5
J4,5(calcd) J4,5(obsd)
1a
1c
ꢁ54.1
1.3
1.7
0.6
2.0
1.2
—
—
—
51.2
53.7
54.0 (53.5) 3.1
56.1
59.6
3.4
3.0
3.0
3.3
3.3
—
—
—
ꢁ176.3
ꢁ172.8
9.4
9.1
9.3
9.1
10.2
—
—
—
179.3
177.7
9.2
9.2
9.2
9.0
9.3
—
—
—
70.8
2ac
ꢁ55.0 (ꢁ49.3) 1.4
ꢁ173.0 (ꢁ174.4) 9.4
176.0 (ꢁ175.3) 9.2
2c-1
2c-2
2c-3
2c-4
2c-avg
71.3
103.7
168.1
166.0
2.4
1.5
8.4
8.2
5.1d
4.5
4.1
5.2
4.2
4.5d
ꢁ173.0
ꢁ163.8
ꢁ64.7
9.4
8.2
3.3
0.6
5.4d
173.4
116.9
73.6
9.1
2.8
1.3
8.6
5.5d
ꢁ51.1
—
4.1
ꢁ58.3
—
5.8
ꢁ103.2
—
5.0
163.2
—
6.9
a
Calculated from DFT dihedral angles via a generalized Karplus-type equation.
Measured in DMSO for 1a and 1c and in CDCl3 for 2a and 2c.
X-ray dihedral angles are shown in parenthesis.
Averaged value.
b
c
d
b-L-anomer (1a) is mainly found in a single conformation
with cooperative anticlockwise orientation of the hydroxyl
groups and a trans-diaxial orientation of the H1–C1–N1–H
moiety. For the open chain component 1b, conformer 1b-
MPAA, illustrated, is generated by the pyranoside ring open-
ing at the C1–O5 bond of 1a. The population of this highly
energetic conformer (Erel¼10.932 kcal/mol) moves toward
the more stable rotamer 1b-PPPP, which is in fact the pre-
dominant species for the linear component 1b and contains
four optimally-oriented cooperative hydrogen bonds in the
tetrahydroxylated chain. However, the rotameric population
is distributed to generate an equilibrium involving small
amounts of 1b-PPPA and 1b-PPAA, which ultimately leads
to the a-L-anomer 1c. The rotameric species of 1b that are
not depicted in Figure 3 but listed in Table 2 are also present
in the equilibrium according to the Boltzmann distribution,
and can be located in branches derived from the main
pathway for the mutarotational process. In the a-form, the
global minimum 1c (EDFT¼ꢁ1287.454180 au, Fig. 3) was
followed by a second one (EDFT¼ꢁ1745.451136 au) arising
from the pyranoside chair inversion at the point where the
hydrazine moiety and the hydroxyl group at C-2 adopted
an equatorial orientation. In this minimum energy con-
former, the methyl group at C-5 and the hydroxyl groups
at C-3 and C-4 remained axially oriented. This conforma-
tional inversion was further studied with peracetylated deriv-
ative 2c.
Table 1 lists the H–C–C–H torsion angles of the global
minimum for the cyclic substances 1a (EDFT
¼
ꢁ1287.460165 au) and 2a (EDFT¼ꢁ1745.459742 au), both
of which showed a prevalent conformation. In contrast,
a complex rotameric equilibrium was established in triacety-
lated derivative 2b in a similar way as that previously found
Table 2. DFT global and local minimum energy conformers and selected H–C–C–H dihedral angles for the acyclic component 1b
Conformera
EDFT
Erel
H1–H2
H2–H3
H3–H4
H4–H5
b
c
d
d
d
d
1b-PPPP
1b-MPPP
1b-MAMA
1b-MAPP
1b-PAAA
1b-PMPA
1b-PPPA
1b-MAPM
1b-AMPP
1b-PPMP
1b-PPPM
1b-MAAP
1b-MAAM
1b-PAMP
1b-PPAA
1b-MPPA
1b-AMAM
1b-MAPA
1b-MPAA
1b-AMAA
1b-PMAP
1b-PPMA
1b-MPAP
1b-AMMA
1b-AMPM
1b-APAA
1b-MAMM
ꢁ1287.454425
ꢁ1287.453216
ꢁ1287.449155
ꢁ1287.449031
ꢁ1287.446925
ꢁ1287.446698
ꢁ1287.446668
ꢁ1287.446631
ꢁ1287.446391
ꢁ1287.446275
ꢁ1287.445829
ꢁ1287.445533
ꢁ1287.445347
ꢁ1287.445205
ꢁ1287.444489
ꢁ1287.444379
ꢁ1287.443931
ꢁ1287.443230
ꢁ1287.442744
ꢁ1287.442687
ꢁ1287.442280
ꢁ1287.441215
ꢁ1287.441208
ꢁ1287.440794
ꢁ1287.439980
ꢁ1287.439708
ꢁ1287.439604
3.602
4.360
6.909
6.987
8.308
8.451
8.469
8.493
8.644
8.716
8.996
9.182
9.299
9.388
9.837
9.906
10.187
10.627
10.932
10.968
11.223
11.891
11.896
12.156
12.666
12.837
12.902
81.9
ꢁ51.5
ꢁ62.7
ꢁ59.2
77.4
80.0
72.7
ꢁ62.5
167.5
63.5
55.5
53.2
53.2
53.9
51.7
52.3
174.1
59.3
ꢁ161.6
ꢁ174.1
ꢁ175.5
ꢁ51.3
57.7
172.5
ꢁ176.8
ꢁ178.2
ꢁ50.4
58.8
ꢁ178.9
ꢁ60.6
64.1
ꢁ68.9
71.7
177.8
83.6
77.4
80.5
54.2
ꢁ63.7
56.2
ꢁ57.7
80.6
60.0
59.9
ꢁ62.3
ꢁ61.8
81.7
ꢁ168.7
ꢁ175.9
164.4
77.5
ꢁ175.7
174.1
ꢁ71.5
ꢁ172.6
72.7
85.1
ꢁ52.7
47.4
84.4
ꢁ165.2
ꢁ177.0
ꢁ53.7
ꢁ177.6
ꢁ165.2
ꢁ178.0
55.2
170.0
53.9
169.8
ꢁ58.5
177.6
ꢁ62.8
ꢁ53.2
175.2
ꢁ62.0
ꢁ41.3
175.8
55.9
53.2
ꢁ54.5
173.2
80.8
ꢁ56.0
ꢁ64.7
69.1
179.7
71.7
ꢁ169.7
173.2
143.2
ꢁ70.7
169.1
ꢁ64.5
60.6
54.4
ꢁ58.1
174.9
ꢁ161.8
177.5
ꢁ57.3
51.2
ꢁ62.8
ꢁ56.3
52.3
139.5
ꢁ60.1
169.5
a
Descriptors are based on H–C–C–H dihedral angles ca. +60ꢀ(P), ca. 180ꢀ(A), and ca. ꢁ60ꢀ(M) for the C1–C2–C3–C4–C5 fragment.
b
c
d
DFT B3LYP/6-31G(d) total energy in au.
Relative DFT energies (kcal/mol) are in reference to 1a (EDFT¼ꢁ1287.460165 au; 1 au¼627.51 kcal/mol).
H–C–C–H dihedral angle.

11920
M. Fragoso-Serrano et al. / Tetrahedron 62 (2006) 11916–11924
Erel = 10.932
1b-MPAA
Erel = 9.906
Erel = 9.837
1b-MPPA
1b-PPAA
Erel = 8.469
1b-PPPA
1b-MPPP
Erel = 4.360
1b-PPPP
1c
Erel = 3.602
Erel = 3.756
1a
rel = 0.000
E
Figure 3. DFT B3LYP/6-31G(d) minimum energy pathway for the mutarotational process from 1a to 1c. Relative energies are in kcal/mol referred to the global
minimum 1a.
for tetra-O-acetyl-6-deoxy-L-mannose derivatives.11 This
resemblance became evident from the J2,3¼8.5, J3,4¼1.9,
and J4,5¼8.5 Hz coupling constant values, which remained
very close in all the linear substances derived from this
carbohydrate. For pyranoside 2c, ring inversion occurred
between the two possible chair conformations (2c-1 and
2c-3) through two low-energy twisted-boat conformations
(2c-2 and 2c-4) as depicted in Figure 4. The equilibrium
between the four conformations in 2c (2c-1: EDFT
ꢁ1745.452419 au; 2c-2: EDFT¼ꢁ1745.451391 au; 2c-3:
¼
2c-1
2c-2
2c-3
2c-4
Figure 4. The conformational equilibrium of 2c.

M. Fragoso-Serrano et al. / Tetrahedron 62 (2006) 11916–11924
11921
Table 3. DFT B3LYP/6-31G(d) conformation for the O–C1–C2–C3–C4–C5 rings of 1a, 1c, 2a, and 2c
Compound
Conformational contributionsa
Ring conformation
Conformational parameters
fc
Chair
Boat
Twist-boat
Qb
qc
1ad
88
94
93
89
91
4
2
3
0
9
6
61
1
59
10
3
6
2
3
35
3
40
Between chair and half-chair
Distorted chair
Distorted chair
Distorted chair
Distorted chair
Between boat and twist-boat
Chair
Between boat and twist-boat
0.593
0.556
0.545
0.583
0.545
0.709
0.511
0.731
24.20
22.88
28.47
4.42
19.34
10.73
22.53
12.03
7.75
3.19
4.13
6.77
5.26
87.58
2.46
89.29
1cd
2ad
2ae
2c-1d
2c-2d
2c-3d
2c-4d
96
1
a
Quantitative contributions of basic conformations in percentage.
˚
Total puckering amplitude in A.
In degrees.
From density functional theory coordinates.
From X-ray diffraction coordinates.
b
c
d
e
EDFT¼ꢁ1745.455161 au; and 2c-4: EDFT¼ꢁ1745.451046 au)
was detectable from the averaged experimental coupling
constants (J1,2¼4.1, J2,3¼5.8, J3,4¼5.0, and J4,5¼6.9 Hz)
vibrational frequencies and thermal parameters were
calculated using the optimized B3LYP/6-31G(d,p) global
minimum structures of 1a, 1b, and 1c. The calculated fre-
quencies were scaled by a factor of 0.97 and compared
with the experimental frequencies measured in the IR spec-
trum of the mixture of 1a, 1b, and 1c at equilibrium. Figure 5
shows good agreement between the calculated and observed
values, validating the B3LYP/6-31G(d,p) thermodynamic
parameters for the mutarotational components. These values
were used for estimation of the relative populations of 1a,
1b-PPPP, and 1c according to the Gibbs free energy equa-
tion DG¼DHꢁTDS and DG¼ꢁRT ln K. These refined
calculations for the three main components also considered
the zero-point correction, and the thermal correction to
energy and enthalpy, providing more accurate values than
those reflected by the relative EDFT. The DG values
1
measured by spectral simulation. The calculated H NMR
couplings constants for the four conformations (2c-1 to
2c-4) and the averaged values are listed in Table 1. In this
equilibrium, the contributing factors to achieve the stability
of conformer 2c-3 over 2c-1 were the equatorial orientation
of the hydrazine moiety at C1, the largest group attached to
the six-membered ring; the interaction between the hydro-
0
gen atom at N1 and the oxygen atom of the pyranoside
˚
0
ring O1 in the O1–C1–N1 –H fragment (distance¼2.53 A)
and the interaction between the hydrogen atom attached to
0
N2 and the oxygen atom O1 in the fragment O1–C1–N1 –
0
˚
0
N2 –H (distance¼2.28 A).
Cremer and Pople polar set of parameters20 were calculated
using the DFT and X-ray coordinates for the quantitative
conformational description of the pyranoside minimum
energy structures (Table 3). The Altona equation was used
to convert dihedral angles into calculated vicinal coupling
constants (3JH–H).21 Calculated and observed 1H–1H vicinal
coupling constants showed a good correlation, which vali-
dated the DFT conformations for the rigid compounds 1a
and 2a, and for the mobile pyranoside 2c (Table 1).
were estimated as DGDFT¼0.000 kcal/mol for 1a, DGDFT¼
0.174 kcal/mol for 1b-PPPP, and DGDFT¼3.411 kcal/mol
for 1c, which yielded a predicted population at equilibrium
of 57.2%, 42.6%, and 0.2% for each species, respectively.
These theoretical results were in line with the 50%, 44%,
1600
1400
1200
1000
800
If only the relative DFT energy values of the structures in
mutarotation were considered (Fig. 3), the prevalent compo-
nent according to the Boltzmann distribution would be 1a.
However, by taking into account the thermodynamic factors,
a better prediction of the mutarotation composition at the
equilibrium was obtained. Table 4 presents the data obtained
by a thermochemical analysis in which the corresponding
Table 4. Thermochemical parameters (in kcal/mol) and population (in %)
for the mutarotational equilibrium calculated with the B3LYP/6-31G(d,p)
global minimum structures of 1a–c
a
b
b
b
b
DE0
DE298
DH298
DS298
DG298
pb
R2 = 0.9989
1a
1b
1c
0.000
1.035
3.591
0.000
1.462
3.632
0.000
0.4463
0.066
0.000
1.734
0.287
0.000
0.174
3.411
57.2
42.6
0.2
600
600
800
1000
1200
1400
1600
Experimental frequencies (cm-1)
a
Sum of electronic and zero-point energy.
b
Calculated at 298.15 K and 1 atm. For the 1a species the absolute values
are E0¼ꢁ1287.18993 au, E298¼ꢁ1287.16810 au, H298¼24.890 kcal/
mol, S298¼158.587 cal/mol K, and G298¼ꢁ1287.20379 au.
Figure 5. Comparison of the experimental infrared frequencies of com-
pound 1a with the corresponding calculated values obtained at the
B3LYP/6-31G(d,p) level of theory.

11922
M. Fragoso-Serrano et al. / Tetrahedron 62 (2006) 11916–11924
Table 5. Comparison between theoretical and experimental 13C NMR
chemical shifts for 1a
were determined on a Perkin–Elmer 16F PC or on a Buck
500 spectrophotometer. ORD was measured on a Perkin–
Elmer 341 or JASCO DIP-360 polarimeters. The 1H
(300 MHz), 13C (75.4 MHz), COSY, HMQC, and HMBC
experiments were conducted on a Varian Mercury 300 spec-
trometer. LRMS were measured on a JEOL JMS-AX505HA
mass spectrometer. HREIMS was determined on a Kratos
concept II H mass spectrometer and HRFABMS were mea-
sured on a JEOL DX 300 mass spectrometer.
a
b
c
Atom
dcalcd
dscaled
dexp
jdscaledꢁdexpj
C-10
C-40
C-20
C-50
C-30
C-60
C-1
C-3
C-4
C-5
C-2
C-6
135.1
125.0
118.7
117.1
112.2
101.0
80.3
66.7
66.5
65.9
63.5
145.3
135.2
128.9
127.3
122.4
111.2
90.5
76.9
76.7
76.1
73.7
149.0
135.3
128.3
129.8
123.2
116.0
87.0
73.7
73.1
72.0
69.8
3.7
0.1
0.6
2.5
0.8
4.8
3.5
3.2
3.6
4.1
3.9
1.4
4.1.1. General procedures for recording the mutarota-
tional equilibria. (a) NMR: solutions of pure samples
(5 mg) of 1a in DMSO-d6 (0.8 mL) and 2a–c in CDCl3
(0.8 mL) or DMSO-d6 (0.8 mL) were treated with 12.1 M
HCl in H2O (1 mL) in 5 mm NMR tubes. (b) Optical activity:
specific rotation of a solution of 1a (5 mg) in DMSO-d6
(0.8 mL) was monitored at room temperature, [a]D +35.0.
Treatment of this solution with 12.1 M HCl in H2O (1 mL)
provoked an immediate decrease in the optical activity
value, [a]D +0.3. This rotation remained constant during
the following 2 h.
9.3
19.5
18.1
a
Calculated at B3LYP/6-31G(d,p) level of theory using GIAO magnetic
shielding.
Calculated by linear fit of dcalcd versus dexp.
Measured at 300 MHz in DMSO-d6 solution.
b
c
and 6% observed NMR ratio (Fig. 1). The entropic contribu-
tion, estimated as DS1a,1b¼5.814 cal/mol K and agreeing
with the PM3 calculations for the mutarotation of glucopyra-
nosylamine derivatives,22 is notably important for the stabil-
ity of acyclic structure 1b. Finally, the experimental 13C
NMR chemical shifts for 1a were compared with these ob-
tained with isotropic magnetic shielding calculations using
the SCF GIAO method at DFT/B3LYP level of theory and
the basis set 6-31G(d,p). Diagnostic values for C-1 of each
species were in close agreement with those obtained exper-
imentally (Table 5).
4.1.2. pH measurements. The pH values were registered
with a VWR Scientific pHmeter (model 8000). A mixture
of DMSO-d6 (4.8 mL) and H2O (6 mL) has a pH 8.50. The
pH of a mixture of compound 1a (30 mg) in DMSO-d6
(4.8 mL) and 12.1 M HCl in H2O (6 mL) was 2.45 after
5 min of stirring while after 90 min it was 2.54. The acidity
of the mixture was raised to pH 2.14 after addition of a sec-
ond portion of HCl (6 mL).
4.1.2.1. (6-Deoxy-b-L-mannopyranosyl)-2-(2,4-dini-
trophenyl)hydrazine (1a). A solution of 2,4-dinitrophenyl-
hydrazine (0.3 g, 1.5 mmol) in sulfuric acid (0.5 mL) was
added to a mixture of H2O (2 mL) and EtOH (7 mL). The
mixture was added to a solution of L-rhamnose monohydrate
(0.5 g, 2.7 mmol) in EtOH (3 mL), left for 3 h at room tem-
perature and 16 h at 4 ꢀC. The product was crystallized as
orange flakes, which were filtered, washed with 5% sodium
bicarbonate solution and H2O and then recrystallized from
90% EtOH in H2O to afford 1a (313 mg, 33%). Orange
needles; mp 165–167 ꢀC (lit.18 164–165 ꢀC); IR (KBr)
nmax 3375, 1629, 1598, 1526, 1427, 1348, 1315, 1268,
1135, 1085, 1062, 1012, 968, 920, 900, 853, 835, 822,
777, 744, 718, 635 cmꢁ1; ORD (c 0.61, MeOH) [a]589
3. Conclusions
DFT calculations, NMR analysis, and X-ray diffraction stud-
ies of 6-deoxy-L-mannopyranosyl hydrazine were performed
in order to obtain conformational parameters. The DFT cal-
culated values for the equilibrium among the mutarotational
species 1a, 1b, and 1c could be further refined by taking into
consideration local conformers including all possible coop-
erative hydrogen bonded species and the inclusion of solvent
modeling. Nevertheless, this work shows that DFT calcula-
tions at B3LYP/6-31G(d,p) level represent suitable tools
to predict the thermodynamic properties, mutarotational
composition, stereochemical features, and conformational
preferences of glycosylhydrazines.
1
+34, [a]578 +37, [a]546 +39; H NMR (300 MHz, DMSO-
d6) d 9.65 (1H, br s), 8.83 (1H, d, J¼2.5 Hz), 8.30 (1H,
dd, J¼9.6, 2.5 Hz), 7.68 (1H, d, J¼9.6 Hz), 5.78 (1H, d,
J¼11.5 Hz), 5.01 (1H, d, J¼4.9 Hz), 4.83 (1H, d,
J¼4.9 Hz), 4.81 (1H, d, J¼5.2 Hz), 4.16 (1H, br d,
J¼11.5 Hz), 3.83 (1H, br t, J¼4.5 Hz), 3.28 (1H, m), 3.18
(1H, m), 3.13 (1H, m), 1.20 (3H, d, J¼5.7 Hz); 13C NMR
(75.4 MHz, DMSO-d6) d 149.0, 135.3, 129.8, 128.3,
123.2, 116.0, 87.0, 73.7, 73.1, 72.0, 69.8, 18.1; EIMS m/z
(rel int.) [M]+ 344 (1), [MꢁC4H9O3]+ 239 (8), 194 (11),
[239ꢁNO2]+ 193 (100), 184 (28), [C6H5N3O4]+ 183 (43),
177 (21), 167 (15), 153 (28), 129 (26), 91 (21), 85 (29);
HREIMS m/z 344.0957 (calcd for C12H16N4O8, 344.0968).
4. Experimental
4.1. General
Column chromatography was carried out with silica gel
(70–230 mesh) Merck. CDCl3 for NMR spectroscopy was
filtered through dry alumina prior to use. HPLC separations
were accomplished using an ISCO silica gel column (parti-
cle size: 10 mm; column size: 21.2 mmꢂ250 mm) on a
Waters (Milford, MA, USA) 600E multisolvent delivery
system equipped with a Waters 410 refractive index detector
connected to a computer (Optiflex 466/Dell). Control of the
equipment, data acquisition, processing, and management of
the chromatographic information was performed with the
Millennium 2000 software program (Waters). IR spectra
4.1.2.2. Acetylation of 1a. A solution of 1a (100 mg) in
pyridine (2.5 mL) was treated with acetic anhydride
(2.5 mL) at room temperature for 24 h. The reaction mixture
was worked-up11 and the residue was purified by HPLC in

M. Fragoso-Serrano et al. / Tetrahedron 62 (2006) 11916–11924
11923
aliquots of 20 mg (n-hexane–EtOAc, 1:1, flow rate¼6 mL/
min) to yield 3 (23.3 mg, 15.7%, tR¼15.5 min), 2a (50.0 mg,
36.6%, tR¼17.9 min), 2c (1.6 mg, 1.2%, tR¼21.8 min), and
2b (36.8 mg, 26.9%, tR¼26.8 min). Treatment of 1a
(100 mg) with acetyl chloride (5 mL) at room temperature
for 2 h followed by evaporation under a N2 flow and
HPLC purification gave 3 in better yields (73 mg, 49%).
d 171.5, 170.0, 169.6, 144.6, 143.8, 139.0, 130.3, 129.9,
123.2, 116.7, 73.5, 69.8, 69.0, 65.2, 20.9, 20.8, 20.7, 19.1;
FABMS m/z [M+H]+ 471, [M]+ 470, [MꢁC2H3O2]+ 411,
[MꢁC2H3O2ꢁ2C2H4O2]+ 291; HRFABMS m/z 471.1369
(calcd for C18H22N4O11+H, 471.1363).
4.1.2.4.2. 1-(2,3,4-Tri-O-acetyl-6-deoxy-a-L-mannopyra-
nosyl)-2-(2,4-dinitrophenyl)hydrazine (2c)
Yellow oil; IR (CHCl3) nmax 3575, 3557, 1790, 1731, 1604,
4.1.2.3. 1-(2,3,4-Tri-O-acetyl-6-deoxy-b-L-mannopyr-
anosyl)-2-(2,4-dinitrophenyl)hydrazine (2a). Yellow
prisms; mp 103–105 ꢀC; IR (CHCl3) nmax 3751, 3365, 1750,
1620, 1594, 1524, 1429, 1372, 1339, 1311, 1238, 1226,
1060, 926, 836 cmꢁ1; ORD (c 1.29, CHCl3) [a]589 +29,
[a]578 +29, [a]546 +31; 1H NMR (300 MHz, CDCl3) d 9.63
(1H, br s), 9.07 (1H, d, J¼2.7 Hz), 8.27 (1H, dd, J¼9.6,
2.7 Hz), 7.68 (1H, d, J¼9.6 Hz), 5.62 (1H, dd, J¼3.3,
1.2 Hz), 5.08 (1H, dd, J¼10.2, 9.3 Hz), 5.00 (1H, dd,
J¼3.3, 10.2 Hz), 4.52 (1H, d, J¼11.4 Hz), 4.40 (1H, dd,
J¼11.4, 1.2 Hz), 3.57 (1H, dq, 1H, J¼9.3, 6.3 Hz), 2.23,
2.08, 2.00 (3H each, 3s), 1.32 (3H, d, J¼6.3 Hz); 13C NMR
(75.4 MHz, CDCl3) d 170.1, 170.0, 169.8, 148.9, 137.3,
130.1, 129.7, 123.6, 115.6, 85.7, 72.1, 71.5, 70.1, 68.9,
20.7, 20.7, 20.5, 17.4; EIMS m/z (rel int.) [M]+ 470 (4), 411
(2), 306 (9), 291 (10), 273 (17), 213 (8), 193 (9), 171 (20),
153 (73), 129 (11), 111 (69), 83 (25), [C2H3O]+ 43 (100);
HREIMS m/z 470.1270 (calcd for C18H22N4O11, 470.1285).
1487, 1466, 1445, 1390, 1294, 1246, 1103, 1063, 975 cmꢁ1
;
ORD (c 0.15, CHCl3) [a]589 ꢁ19, [a]578 ꢁ20, [a]546 ꢁ22;
1H NMR (300 MHz, CDCl3) d 9.50 (1H, s), 9.11 (1H, d,
J¼2.5 Hz), 8.31 (1H, dd, J¼9.3, 2.5 Hz), 7.66 (1H, d,
J¼9.3 Hz), 5.29 (1H, dd, J¼7.1, 4.1 Hz), 5.26 (1H, dd, J¼
5.8, 4.1 Hz), 4.98 (1H, dd, J¼5.8, 5.0 Hz), 4.72 (1H, dd,
J¼6.9, 5.0 Hz), 4.44 (1H, d, J¼7.1 Hz), 4.11 (1H, quint, J¼
6.9 Hz), 2.15, 2.12, 2.09 (3H each, 3s), 1.36 (3H, d,
J¼6.9 Hz); 13C NMR (75.4 MHz, CDCl3) d 169.9, 169.6,
169.6, 149.3, 137.5, 130.2, 129.7, 123.8, 115.4, 83.9, 71.1,
70.3, 68.9, 66.8, 20.9, 20.8, 20.7, 16.9; EIMS m/z (rel int.)
[M]+ 470 (1), 446 (1), 306 (9), 291 (11), 273 (14), 213 (5),
193 (5), 171 (11), 153 (41), 129 (8), 111 (33), 83 (11),
[C2H3O]+ 43 (100); HREIMS m/z 470.1273 [M]+ (calcd
for C18H22N4O11, 470.1285).
4.1.2.4.3. 2,3,4,5-Tetra-O-acetyl-6-deoxy-L-mannose
2,4-dinitrophenylhydrazone (3)
Yellow oil; IR (CHCl3) nmax 3309, 1746, 1619, 1594, 1509,
4.1.2.4. X-ray analysis of 2a. The crystal
(0.22ꢂ0.25ꢂ0.46 mm) was obtained from EtOAc–hexane.
1437, 1373, 1340, 1235, 1147, 1062, 1038, 924, 837 cmꢁ1
;
It was monoclinic, space group C2, with a¼21.017(2),
ORD (c 1.14, CHCl3) [a]589 ꢁ14, [a]578 ꢁ15, [a]546 ꢁ17;
1H NMR (300 MHz, CDCl3) d 11.08 (1H, s), 9.12 (1H,
d, J¼2.5 Hz), 8.35 (1H, dd, J¼9.5, 2.5 Hz), 7.96 (1H,
d, J¼9.5 Hz), 7.35 (1H, dd, J¼6.0, 1.0 Hz), 5.58 (1H, dd,
J¼8.0, 3.0 Hz), 5.50 (1H, dd, J¼8.0, 6.0 Hz), 5.36 (1H,
dd, J¼8.5, 3.0 Hz), 5.04 (1H, dq, J¼8.5, 6.5 Hz), 2.12
(3H, s), 2.12 (3H, s), 2.06 (3H, s), 2.04 (3H, s), 1.24 (3H,
d, J¼6.5 Hz); 13C NMR (75.4 MHz, CDCl3) d 169.9,
169.9, 169.8, 169.4, 144.6, 144.0, 138.9, 130.1, 129.8,
123.1, 116.7, 70.9, 69.8, 68.7, 66.8, 21.0, 20.7, 20.7,
20.6, 16.3; EIMS (20 eV) m/z (rel int.) [M]+ 512 (0.1),
[MꢁC2H3O2]+ 453 (1), [453ꢁ2C2H4O2]+ 333 (2),
[333ꢁC2H2O]+ 291 (10), 290 (14), 251 (16), 129 (10), 117
(10), 111 (11), [C2H3O]+ 43 (100); FABMS m/z [M+Na]+
535; HRFABMS m/z 535.1288 [M+Na]+ (calcd for
C20H24N4O12+Na 535.1286).
3
˚
˚
b¼8.154(2), c¼13.591(2) A, cell volume¼2254.6 (7) A ,
rcalcd¼1.386 g/cm3 for Z¼4, MW¼470.40, and F(000)eꢁ¼
984. The intensity data were measured using Mo Ka radia-
˚
tion (l¼0.71073 A). Reflections, measured at 293 K within
a 2q range of 1.55–26.99ꢀ, were corrected for background,
Lorentz polarization, and absorption (m¼0.116 mmꢁ1),
while crystal decay was negligible. The structure was solved
by direct methods. For the structural refinement the non-
hydrogen atoms were treated anisotropically, and the hydro-
gen atoms, included in the structure factor calculation,
were refined isotropically. Final discrepancy indices were
RF¼5.65% and RW¼13.08% using a unit weight for 2947
reflections and refining 306 parameters. The final difference
Fourier map was essentially featureless, the highest residual
peaks having densities of 0.164 e/A3. Crystallographic data
for 2a have been deposited with the Cambridge Crystallo-
graphic Data Centre. Copies of the data can be obtained,
free of charge, on application to The Director, CCDC, 12
Union Road, Cambridge CB2 1EZ, UK. Fax: +44 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk.
4.1.3. Molecular modeling calculations. Geometry optimi-
zations were carried out using the MMFF94 force-field cal-
culations as implemented in the Spartan’04 program.23 The
systematic conformational search for the pyranoside rings
was achieved with the aid of Dreiding models considering
torsion angle movements of ca. 30ꢀ. The EMMFF values were
used as the convergence criterion and a further search with
the Monte Carlo protocol was carried without considering
energy cut off. All local minima were geometry optimized
by DFT at the B3LYP/6-31G(d) level using the Spartan’04
routines. The Altona equation was used to calculate vicinal
couplings from dihedral angles for each conformer.
Gaussian 03W24 were used to calculate the 13C NMR chem-
ical shifts at the B3LYP/6-31G(d,p) level. The thermo-
chemical parameters DE0, DE298, DH298, and DS298 were
calculated at the same level considering vibrational frequen-
cies at 298.15 K and 1 atm. These values were used for
4.1.2.4.1. 2,3,4,-Tri-O-acetyl-6-deoxy-L-mannose 2,4-di-
nitrophenylhydrazone (2b)
Yellow oil; IR (CHCl3) nmax 3559, 3363, 1748, 1619, 1594,
1526, 2511, 1425, 1372, 1342, 1312, 1246, 1138, 1063,
924 cmꢁ1; ORD (c 0.66, CHCl3) [a]589 +14, [a]578 +14,
1
[a]546 +17; H NMR (300 MHz, CDCl3) d 11.10 (1H, s),
9.12 (1H, d, J¼2.5 Hz), 8.37 (1H, dd, J¼9.3, 2.5 Hz), 7.91
(1H, d, J¼9.3 Hz), 7.43 (1H, br d, J¼5.2 Hz), 5.79 (1H,
dd, J¼8.5, 1.9 Hz), 5.54 (1H, dd, J¼8.5, 5.2 Hz), 5.11
(1H, dd, J¼8.5, 1.9 Hz), 3.72 (1H, ddq, J¼8.5, 6.1,
4.9 Hz), 2.81 (1H, d, J¼4.9 Hz), 2.13, 2.12, 2.10 (3H each,
3s), 1.20 (3H, d, J¼6.1 Hz); 13C NMR (75.4 MHz, CDCl3)

11924
M. Fragoso-Serrano et al. / Tetrahedron 62 (2006) 11916–11924
16. Tvaroska, I.; Taravel, F. R.; Utille, J. P.; Carver, J. P. Carbohydr.
Res. 2002, 337, 353–367.
17. Makowski, M.; Chmurzynski, L. THEOCHEM 2002, 579,
247–256.
estimation of the relative populations according to the fol-
lowing equations: DG¼DHꢁTDS and DG¼ꢁRT ln K.
Acknowledgements
´
18. Domınguez, J. A. J. Am. Chem. Soc. 1951, 73, 849.
19. Chang, G.; Guida, W. C.; Still, W. C. J. Am. Chem. Soc. 1989,
111, 4379–4386.
20. Cremer, D.; Pople, J. A. J. Am. Chem. Soc. 1975, 97, 1354–
1358.
21. Haasnoot, C. A. G.; de Leeuw, F. A. A. M.; Altona, C.
Tetrahedron 1980, 36, 2783–2792.
22. Smiataczowa, K.; Maj, K.; Skurski, P. Eur J. Org. Chem. 2001,
4269–4274.
This research was supported by grants from CONACyT
(45759-Q) and DGAPA, UNAM (IN214205-2). We wish
ꢀ
to thank Georgina Duarte and Margarita Guzman (USAI,
Facultad de Quımica, UNAM) for some of the mass spectra
´
measurements. We are most grateful to Professor Tony Durst
(Department of Chemistry, University of Ottawa) for provid-
ing facilities to record high-resolution mass spectra.
23. Kong, J.; White, C. A.; Krylov, A. I.; Sherrill, C. D.; Adamson,
R. D.; Furlani, T. R.; Lee, M. S.; Lee, A. M.; Gwaltney, S. R.;
Adams, T. R.; Ochsenfeld, C.; Gilbert, A. T. B.; Kedziora,
G. S.; Rassolov, V. A.; Maurice, D. R.; Nair, N.; Shao, Y.;
Besley, N. A.; Maslen, P. E.; Dombroski, J. P.; Daschel, H.;
Zhang, W.; Korambath, P. P.; Baker, J.; Byrd, E. F. C.; Van
Voorhis, T.; Oumi, M.; Hirata, S.; Hsu, C. P.; Ishikawa, N.;
Florian, J.; Warshel, A.; Johnson, B. G.; Gill, P. M. W.;
Head-Gordon, M.; Pople, J. A. J. Comput. Chem. 2000, 21,
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References and notes
1. Schmidt, E. W. Hydrazine and Its Derivatives: Preparation,
Properties, Applications; Wiley: New York, NY, 2001; pp
150–155.
2. Ragnarsson, U.; Fransson, B.; Grehn, L. J. Chem. Soc., Perkin
Trans. 1 2000, 1405–1409.
3. Wilcox, C. F.; Bauer, S. H. THEOCHEM 2003, 625, 1–6.
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24. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
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