Contrasting conformational behavior of 5-methylsulfonyl-1,3-dioxane and -1,3-dithiane in the minimization of steric and electrostatic repulsive interactions

Article abstract of DOI:10.1016/S0040-4039(02)02308-0

The preparation of novel 1,3-dithiane derivatives, cis- and trans-2-tert-butyl-5-methylsulfonyl-1,3-dithiane, was achieved by acid-catalyzed condensation of 2-methylsulfonyl-1,3-propanedithiol with pivalaldehyde. The former dithiol was obtained from allyl

Full text of DOI:10.1016/S0040-4039(02)02308-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9369–9372
Contrasting conformational behavior of
5-methylsulfonyl-1,3-dioxane and -1,3-dithiane in the
minimization of steric and electrostatic repulsive interactions
J. Samuel Cruz-Sa´ncheza,b and Eusebio Juaristia,*
aDepartamento de Qu´ımica, Centro de Investigacio´n y de Estudios Avanzados del Instituto Polite´cnico Nacional,
Apartado Postal 14-740, 07000 Mexico, D.F., Mexico
bInstituto de Ciencias Ba´sicas de la Universidad Veracruzana, Dr. Luis Castelazo A. s/n, Col. Industrial-Animas,
91190 Xalapa, Ver., Mexico
Accepted 15 October 2002
Abstract—The preparation of novel 1,3-dithiane derivatives, cis- and trans-2-tert-butyl-5-methylsulfonyl-1,3-dithiane, was
achieved by acid-catalyzed condensation of 2-methylsulfonyl-1,3-propanedithiol with pivalaldehyde. The former dithiol was
obtained from allylmethylsulfide via the Knochel–Normant bromination–rearrangement protocol. Configurational and conforma-
1
tional assignment of cis- and trans-5 was based on H NMR analysis, and revealed that the trans isomer adopts a normal chair
conformation. By contrast, cis-5 adopts a twist-boat conformation in order to minimize the steric and electrostatic repulsive
interactions that an axial methylsulfonyl group engenders. Chemical equilibration cis-5 X trans-5 shows the latter to be more
stable by 1.50 kcal/mol. © 2002 Elsevier Science Ltd. All rights reserved.
The conformational behavior of monosubstituted
cyclohexanes effectively models larger and more com-
plex molecules. In particular, the free energy difference
for the axial X equatorial equilibrium in such mono-
substituted cyclohexanes (DG° valuesꢀA values) is a
convenient parameter that is a measure of steric size.1
In this context, Eliel and Kandasamy described the
conformational free energy differences for the methyl
sulfide, methyl sulfoxide, and methyl sulfone groups in
the cyclohexane ring.2 The reported values, −1.00,
−1.20, and −2.50 kcal/mol, respectively, clearly reflect
the steric requirements of the sulfur functions (Eq. (1)).
equatorial conformation (DG°=−1.82 kcal/mol in sol-
vent cyclohexane, Eq. (2)) than that measured for
(methylthio)cyclohexane, this being the result of a
repulsive interaction of the unshared electrons of sulfur
with the unshared electrons of the ring oxygens (the
so-called ‘repulsive gauche effect’5).
(2)
In strong contrast, a similarly placed methylsulfonyl
(CH3SO2) group prefers the axial conformation.4 This
unusual behavior was rationalized in terms of an attrac-
tive, electrostatic interaction between the (negative)
endocyclic oxygens and the (positive) sulfonyl sulfur
(Eq. (3)). That the methyl group at sulfur points into
the ring was established from the NMR evaluation of
1H NMR coupling constants.4 This particular orienta-
tion of the methylsulfonyl group minimizes electrostatic
repulsion between ring oxygens and sulfonyl oxygens
(Eq. (3)).
(1)
Whereas evaluation of steric effects is best achieved in
the cyclohexane framework, electrostatic and
stereoelectronic interactions are conveniently examined
in six-membered heterocyclic derivatives.3 For example,
Eliel et al.4 discovered that the CH3S group attached at
C(5) in a 1,3-dioxane has a stronger preference for the
Keywords: conformation; dithianes; dioxanes; sulfones; steric and
strain effects; electrostatic effects.
(3)
* Corresponding author. E-mail: juaristi@relaq.mx
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02308-0

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J. S. Cruz-Sa´nchez, E. Juaristi / Tetrahedron Letters 43 (2002) 9369–9372
In this context, the positions of equilibrium between
diastereomeric cis- and trans-5-(tert-butylthio)- and -5-
The synthesis of the desired diastereomeric 1,3-dithi-
anes cis-5 and trans-5 was accomplished according to
the route outlined in Scheme 1.9 Allylmercaptan was
methylated as described by Bland and Stammer,10 and
key dibromide 6 was obtained via the Knochel–Nor-
mant bromination–rearrangement protocol.11 In situ
oxidation with 2 equiv. of m-chloroperbenzoic acid
afforded sulfone 7 as white needles, and in 85% yield
(two steps). 1,3-Dithioacetate 8 was then obtained by
displacement with freshly prepared, activated potassium
thioacetate,12 and aminolysis was achieved with
(tert-butylsulfonyl)-2-isopropyl-1,3-dioxanes
were
reported by Juaristi et al.6 (Table 1). Although DG°
values for the sulfides are very similar, the difference in
conformational behavior for the sulfones is quite dra-
matic: the large preference of the methyl analogue for
the axial position (1.19 kcal/mol; Table 1) is reversed in
the tert-butyl derivative, where the equatorial isomer is
more stable by 1.14 kcal/mol.
A crystallographic X-ray diffraction study of cis-2-tert-
butyl-5-(tert-butylsulfonyl)-1,3-dioxane reveals that this
heterocycle exists in a chair conformation with the
substituent at C(5) being axial. The sulfonyl tert-butyl
group is outside the ring, suggesting that the steric
congestion that would be present if the alkyl group was
inside the ring is more severe than the electrostatic
ethylenediamine under
a
nitrogen atmosphere.13
Finally, condensation of 2-methylsulfonyl-1,3-propane-
dithiol 9 with pivalaldehyde under acidic conditions14
gave a mixture of cis-5 and trans-5, that were separated
and purified by chromatography.
1H NMR spectroscopic analysis led to the assignment
of both the configuration and conformation of cis- and
trans-5. Indeed, the less polar component exhibited a
proton coupling pattern that is only ascribable to trans-
5 in a chair conformation of the six-membered ring. In
repulsion between the (negative) oxygens, S+ꢁO−/d−O1,3
.
The most interesting feature of the crystallographic
data was, however, that they correspond to a confor-
mation with eclipsed SꢁO/CꢁC and C-t-Bu/CꢁH bonds6
(Eq. (4)). This bond eclipsing seems to be necessary to
mitigate gauche t-Bu/CH2 steric interactions present in
staggered rotamers.7
2
particular, Jgem=3Janti=12.6 Hz for the axial hydro-
gens at C(4,6), that are coupled to the axial hydrogen at
C(5). By contrast, cis-5 (more polar isomer) presents a
vicinal coupling constant between H(4,6) and H(5),
3Jvic=6.0 Hz, that is in line with a twist-boat conforma-
tion of the dithiane ring (Eq. (6)).
(4)
The difference in size, electronegativity, and bond
polarities associated with oxygen and sulfur, as well as
the availability of 3d orbitals in sulfur, are reflected in
contrasting conformational behavior for oxygen-con-
taining vis-a-vis sulfur-containing heterocycles.3a,b,8
Thus, we deemed it important to examine the confor-
mational preference of the methylsulfonyl group at C(5)
in 1,3-dithiane. In this paper, we report the chemical
equilibration of cis- and trans-2-tert-butyl-5-methylsul-
fonyl-1,3-dithiane (Eq. (5)). Two main questions are
whether attractive Sd−···d+SO2CH3 interactions are
reflected in an axial orientation of the 5-SO2CH3 group,
and whether, by analogy with the 1,3-dioxane analog
(see above), a methyl-inside rotamer is preferred.
(6)
The fact that cis-5 adopts a twist-boat conformation
indicates that the steric and electrostatic repulsion suf-
fered by an axial 5-methylsulfonyl group in the chair
conformation of the 1,3-dithiane heterocycle is large
enough to overcome the free energy difference between
the chair and twist-boat forms of 1,3-dithiane. Support
for the conclusion is gathered from the theoretical
(5)
Table 1. Conformational free energy differences (DG° val-
ues) for several 5-substituted 2-isopropyl-1,3-dioxanes4,6a
Compd
X
DG°, kcal/mol
Solvent
1
2
3
4
CH3S
CH3SO2
t-BuS
−1.8290.01
+1.1990.10
−1.9090.11
−1.1490.01
C6H12
CHCl3
CHCl3
CHCl3
t-BuSO2
Scheme 1.

J. S. Cruz-Sa´nchez, E. Juaristi / Tetrahedron Letters 43 (2002) 9369–9372
9371
Figure 1. Calculated (DFT, B3LYP/6-311+G**//B3LYP/6-31G*) relative energies of the chair trans-5 (Erel=0.0 kcal/mol), chair
cis-5 (Erel=7.11 kcal/mol), and 2,5-twist cis-5 (Erel=4.07 kcal/mol).
(DFT, B3LYP/6-311+G**//B3LYP/6-31G*) estimation
of the relative energies of the chair conformations for
trans-5 (relative E=0.0 kcal/mol) and cis-5 (relative
E=7.11 kcal/mol) (Fig. 1). By comparison, the 2,5-
twist-boat conformation of cis-5 is calculated to be
nearly 3.0 kcal/mol lower in energy than the chair form
(Fig. 1).15
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(7)
It is then apparent that the attractive electrostatic inter-
action that stabilizes the axial form of 5-methylsul-
fonyl-1,3-dioxane (Od−···d+SO2CH3; see entry 2 in Table
1) is not reproduced in the 1,3-dithiane analog; that is,
Sd−···d+SO2CH3 electrostatic attraction is not apprecia-
ble in cis-5. As a consequence, the heterocyclic struc-
ture adopts a twist-boat conformation that minimizes
the steric and electrostatic repulsions that an axial
methylsulfonyl group generates, and that benefits from
the increased entropy content of the flexible conformers
in 1,3-dithiane derivatives.16
Acknowledgements
We are indebted to CONACYT, Me´xico, for financial
support via grant 33023-E. We are also grateful to
Marcos Herna´ndez-Rodr´ıguez for the modelling studies
that are presented in Fig. 1, and to Mar´ıa Luisa Kaiser-
Carril, for technical assistance.
7. For discussions on eclipsing in organic compounds, see:
(a) Juaristi, E. Stable Eclipsed Conformations, In
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