Rotational isomerism in 3,4-alkylenedioxy-2,5-bis[di(tert-butyl)hydroxymethyl]thiophenes

Article abstract of DOI:10.1002/poc.640

In 3,4-ethylenedioxy-2,5-bis[di(tert-butyl)hydroxymethyl]thiophene there are three rotational isomers, syn,syn (SS), anti,syn (AS) and anti,anti (AA) (syn, free; anti, hydrogen-bonded), differing in the number (zero, one or two) of alcohol hydrogen atoms intramolecularly hydrogen bonded to the oxygen atoms of the bridge. When a methyl group is introduced into the bridge the AS rotamer can be distinguished from SA [where the first character indicates the orientation of the - C(t-Bu)₂OH group closer to the substituent] by means of a ¹H NOESY experiment. Forms with 'free' OH groups are favoured by hydrogen-bonding solvents, but the AS:SA ratio for the methyl derivative is solvent independent, slightly favouring the AS isomer. Whatever the solvent, the methyl group has no significant effect upon the equilibrium rotamer ratios. Rotation barriers for the various equilibria are of the order of 20 kcal mol^-1. Copyright

Full text of DOI:10.1002/poc.640

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2003; 16: 361–368
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/poc.640
Rotational isomerism in 3,4-alkylenedioxy-2,5-bis[di(tert-
butyl)hydroxymethyl]thiophenes
John S.Lomas * and Christine Cordier
Interfaces, Traitements, Organisation et Dynamique des SysteÁmes, Universite de Paris 7, associe au CNRS, 1rue Guy de la Brosse, 75005
Paris, France
Received 24 January 2003; revised 10 March 2003; accepted 10 March 2003
ABSTRACT: In 3,4-ethylenedioxy-2,5-bis[di(tert-butyl)hydroxymethyl]thiophene there are three rotational isomers,
syn,syn (SS), anti,syn (AS) and anti,anti (AA) (syn, free; anti, hydrogen-bonded), differing in the number (zero, one or
two) of alcohol hydrogen atoms intramolecularly hydrogen bonded to the oxygen atoms of the bridge. When a methyl
epoc
group is introduced into the bridge the AS rotamer can be distinguished from SA [where the first character indicates
1
the orientation of the —C(t-Bu)2OH group closer to the substituent] by means of a H NOESY experiment. Forms
with ‘free’ OH groups are favoured by hydrogen-bonding solvents, but the AS:SA ratio for the methyl derivative is
solvent independent, slightly favouring the AS isomer. Whatever the solvent, the methyl group has no significant
effect upon the equilibrium rotamer ratios. Rotation barriers for the various equilibria are of the order of 20 kcal
molÀ1. Copyright  2003 John Wiley & Sons, Ltd.
Additional material for this paper is available from the epoc website at http://www.wiley.com/epoc
KEYWORDS: EDOT derivatives; rotamers; NMR; NOESY; solvent effects; rotation barriers
INTRODUCTION
AA, AS, SA and SS (A for anti, S for syn), but if the
alkylene bridge is symmetrical AS and SA are degen-
erate, reducing the number to three. In what follows,
unless stated otherwise, ‘AS/SA’ denotes AS and SA, i.e.
all species which are neither AA nor SS. The AS and SA
rotamers can be distinguished by introducing a sub-
stituent on the alkylene bridge, this giving rise to an
unusual case of conformational isomerism.
2-Alkoxyphenyl(a,a-dialkyl)methanols and the 3-alk-
oxythiophene analogues exist in two forms, with the
OH hydrogen either ‘free’ or intramolecularly bonded to
the alkoxy oxygen.1–4 When the alkyl groups are bulky,
such as tert-butyl, the rotamers can be distinguished on
the NMR time-scale at room temperature2,3 and in some
cases physically separated.1 The equilibrium constant for
rotational isomerization depends not only on the structure
but also on the solvent, hydrogen bond acceptor solvents
favouring the form in which the OH hydrogen is not
intramolecularly bonded. In the thiophene series, alkoxy
substituents at the 3- and 4-positions, including 3,4-
alkylenedioxy bridges, as in 3,4-ethylenedioxythiophene
(EDOT), have a very marked effect upon the equilibrium
isomer ratio, short bridges and small substituents
favouring the syn isomer at the expense of the intramol-
ecularly hydrogen-bonded anti isomer.4
We have now examined 3,4-alkylenedioxythiophene
derivatives where both the 2- and 5-positions are
occupied by di(tert-butyl)hydroxymethyl substituents.
This results in a system with two rotors which can be
oriented so that the OH group is either intramolecularly
hydrogen bonded or free. This leads to four rotamers,
RESULTS AND DISCUSSION
Synthesis
*Correspondence to: J. S. Lomas, Interfaces, Traitements, Organisa-
tion et Dynamique des Syste`mes, Universite´ de Paris 7, 1 rue Guy de la
Brosse, 75005 Paris, France.
E-mail: lomas@itodys.jussieu.fr
Lithiation of 2-H3 by 2 equiv. of n-butyllithium–TMEDA
Copyright  2003 John Wiley & Sons, Ltd.
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362
J. S. LOMAS AND C. CORDIER
Figure 1. 1H NMR spectrum of 3-H in benzene at 298 K. Expansion: tert-butyl group
region, 1.10±1.49 ppm
in hexane–diethyl ether under argon at room temperature
followed by reaction with 1 equiv. of di(tert-butyl)
ketone gave 3-H (yield 64%). 2-Methyl-2,3-dihydro-
thieno[3,4-b][1,4]dioxine (EDOT-Me, 1-Me) was syn-
thesized by a modification of the method described by
Kumar et al.5 By the same procedure as for 3-H, 3-Me
was prepared in 40% overall yield from 1-Me.
symmetrical isomers (AA 3.08 and SS 3.41 ppm), and to
a multiplet corresponding to the AS/SA isomer. The tert-
butyl groups are well resolved, it being possible to
distinguish those corresponding to the symmetrical
isomers (AA 1.36 and SS 1.25 ppm) and to the two types
in the non-symmetrical isomer (1.41 and 1.19 ppm,
corresponding to the anti and syn groups, respectively).
IR stretching modes at about 3569 cmÀ1 and 3608/
3624 cmÀ1 (mean values for 3-H and 3-Me) are charac-
teristic of intramolecularly hydrogen-bonded and free
OH groups, respectively.2–4 More detailed information
about the rotamers present and their relative concentra-
tions can only be obtained by NMR spectroscopy.
3-Me. The proton NMR spectrum in benzene (Fig. 2)
now shows four signals in the upfield OH region (1.94,
1.96, 1.98 and 1.99 ppm) and four in the downfield region
(5.15, 5.27, 5.35 and 5.47 ppm). The two upfield signals
(1.94 and 1.96 ppm) which have the same integrals as two
of the downfield signals (5.35 and 5.47 ppm) correspond
to 3-Me(AS) and 3-Me(SA), where the first character
inside the parentheses indicates the orientation of the
—C(t-Bu)2OH group closest to the substituent.
1H NMR spectroscopy
3-H. This compound presents three isomers in similar
amounts. The proton NMR spectrum in benzene (Fig. 1)
shows two signals in the downfield OH region (5.09 and
5.30 ppm) and two in the upfield region (1.94 and
1.98 ppm). One of the downfield signals (5.30 ppm) has
the same integral as one of the upfield signals (1.94 ppm):
these clearly belong to the anti,syn isomer, denoted in
what follows as 3-H(AS). Obviously, no distinction can
be made between AS and SA. The remaining upfield
(1.98 ppm) and downfield (5.09 ppm) signals correspond
to the syn,syn and anti,anti isomers [denoted 3-H(SS) and
3-H(AA)], respectively. The bridging methylene groups
are represented by two singlets, corresponding to the
A reasonable assumption is that the downfield signals
with the lower shifts (5.15 and 5.35 ppm), i.e. closer to
the values in 3-H, can be attributed to the hydrogen-
bonded OH protons of the —C(t-Bu)2OH group remote
from the methyl substituent on the bridge. Calculation
suggests that the hydroxy proton of the group with the
anti orientation closest to the methyl substituent should
˚
be about 3.5 A from one or two of the methyl hydrogens.
At such a distance it should be possible to observe NOE
1
in the H NMR spectrum. The methyl groups appear as
four well defined doublets (J = 6.4 Hz) upfield of the tert-
butyls. A NOESY experiment (Fig. 3) does indeed show
correlation peaks for the signals attributed to the AS
Copyright  2003 John Wiley & Sons, Ltd.
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ROTATIONAL ISOMERISM IN EDOT DERIVATIVES
363
hydroxy proton (5.47 ppm) and to the corresponding
methyl group, and also for one of the AA hydroxy
protons (that at 5.27 ppm) and its associated methyl
group, but not for the SA and SS rotamers. This confirms
that the signals at 1.94 and 5.35 ppm correspond to
3-Me(SA) and those at 1.96 and 5.47 ppm to 3-Me(AS).
The remaining pairs of upfield and downfield signals are
associated with the syn,syn and anti,anti isomers,
3-Me(SS) and 3-Me(AA), respectively.
batches, centred on 1.25 and 1.40 ppm, corresponding to
isomers with —C(t-Bu)2OH groups in the syn and anti
conformations, respectively. These were assigned to the
various isomers by simulation of the 1D spectrum, taking
the relative concentrations from the hydroxy proton
integrals (gNMR, version 4.1; Adept Scientific, Letch-
worth, UK). The strong cross peaks in the NOESY plot
correspond to contacts between the anti OH protons and
the tert-butyl groups on the same carbons; their positions
are consistent with the assignments made by simulation.
The same is true for the syn —C(t-Bu)2OH groups (not
shown).
The bridging methylene and methine groups are
represented by a complex multiplet ranging from 2.9 to
3.7 ppm. In benzene the tert-butyl signals fall into two
1
Figure 2. H NMR spectrum of 3-Me in benzene at 298 K. Expansion: tert-butyl group
region, 1.12±1.49 ppm
Copyright  2003 John Wiley & Sons, Ltd.
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364
J. S. LOMAS AND C. CORDIER
Figure 3. 1H NOESY experiment on 3-Me, showing dipolar correlation (ringed) between the
AS anti OH proton and the corresponding methyl group, and between the down®eld OH
proton of the AA rotamer and its methyl group. The much stronger cross peaks concern the
anti-oriented ÐC(t-Bu)2OH groups
Isomer ratios and molecular mechanics calcula-
tions
about 0.6 and 1.2 kcal molÀ1, respectively, i.e. approxi-
mately 0.6 kcal molÀ1 for each —C(t-Bu)2OH group in
the syn conformation. This may be considered as a very
satisfactory performance for a force field not specifically
parametrized for this type of molecule. There are two
possibilities: either these calculations underestimate the
strain in syn conformations or overestimate that in anti
conformations. The former would occur if the interac-
tions between the tert-butyl groups and the ethylenedioxy
bridge were slightly too weak, the latter if the strength of
the intramolecular hydrogen bonds was underestimated.
It should be noted, however, that force field calculations
refer to the gas phase, and that our experimental data
relate to solution, even if we have selected solvents of
low hydrogen-bonding ability.
The isomer ratio AA:AS/SA:SS for 3-H in benzene at
298 K is 1.26:2.00:0.39. That for 3-Me (AA:AS:SA:SS)
in the same solvent is 1.27:1.00:0.92:0.35, very close to
that for 3-H if the contributions from the AS and SA
rotamers are summed (Table 1). Very similar results are
obtained in benzene.
Molecular mechanics calculations (MMFF94 force
field,6,7 gas phase) on 3-H suggest that the stability order
should be SS > AS = SA > AA, with the SS isomer more
stable than AS or SA by 0.6 kcal molÀ1 (1 cal = 4.184 J)
and AS or SA more stable than AA by 0.4 kcal molÀ1
.
The reality is somewhat different, in that the order is
reversed and the differences are smaller than calculated:
SS is the least stable by 0.6 kcal molÀ1 relative to AS or
SA and AA the most stable by 0.2 kcal molÀ1, again
relative to AS or SA. This means that, relative to the AA
isomer, the errors for the AS or SA and SS isomers are
Results in various solvents (Table 1) indicate that there
is always a slight preference for the AS rotamer in 3-Me:
[AS]/[SA] ꢀ 1.1. MM calculations find 3-Me(SA)
0.16 kcal molÀ1 more stable than 3-Me(AS), whereas in
fact the former is slightly less stable than the latter, by
Table 1. Solvent effects on equilibrium constants for 3,4-ethylenedioxy-2,5-bis[di(tert-butyl)hydroxymethyl]thiophenes, 3-H and
3-Me, at 298 K: K1 = ([AS] ‡ [SA])/[AA]; K2 = [SS]/([AS] ‡ [SA])a
Compound
Solvent
AA (%)
AS (%)
SA (%)
SS (%)
Log K1
Log K2
3-Hb
3-Hb
3-Hb
3-Hb
3-Me
3-Me
3-Me
3-Me
Chloroform
Benzene
Pyridine
DMSO
Chloroform
Benzene
Pyridine
DMSO
37
34
3
26
27
24
15
27
28
25
15
26
27
24
15
25
26
23
15
10
11
49
69
9
10
49
69
0.15
0.21
1.22
1.53
0.12
0.18
1.18
1.58
À0.70
À0.69
0.00
1
0.36
39
36
3
À0.75
À0.74
0.01
1
0.36
a
Percentage compositions have been rounded to the nearest integer value: total = 100 Æ 1%.
For 3-H the AS and SA isomers are degenerate.
b
Copyright  2003 John Wiley & Sons, Ltd.
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ROTATIONAL ISOMERISM IN EDOT DERIVATIVES
365
0.06 kcal molÀ1. Again, the agreement is remarkably
good, even if the relative energy has the wrong sign.
temperature is raised, all the OH signals move upfield,
the displacement being about 10 times higher for syn than
for anti. This effect is 2–3 times greater in pyridine than
in DMSO.3,11 Since there are three isomers, no protons in
the 5-position and a complex pattern of overlapping tert-
butyl group signals in 3-Me and for 3-H in some solvents,
only the OH proton signals were used to measure rotation
barriers. For 3-H in toluene and dioxane the anti and syn
OH protons are downfield and upfield, respectively, of
the bridging protons, and in pyridine all the OH signals
remain downfield of the these protons.
Solvent effects
Naturally, in hydrogen bond acceptor solvents the
equilibria for both 3-H and 3-Me shift towards isomers
in which the —C(t-Bu)2OH group is in the syn con-
formation. Data for rotamer distributions and equilibrium
constants in chloroform, benzene, pyridine and DMSO
are listed in Table 1. The methyl substituent has no
significant effect on the overall isomer ratio. For these
solvents, there is little difference between Abraham’s
solute hydrogen bond basicity parameters8 and the
solvent parameters of Kamlet and Taft.9 Both give fair
correlations of log K1 and log K2 with gradients of about
1.9 Æ 0.1 and 1.4 Æ 0.2, respectively. The former value is
in keeping with data on 3,4-ethylenedioxy-2-[di(tert-
butyl)hydroxymethyl]thiophene in a greater variety of
solvents (1.82 Æ 0.18).3 Another way of appreciating the
difference in behaviour of the two equilibria is to plot log
K2 against log K1, which gives a linear correlation with
slope 0.75 Æ 0.03 (correlation coefficient 0.99668). It is
not clear why K2 should be less sensitive to solvent
variation than K1. One possibility is that in the SS isomer
the two OH groups are too close together to be efficiently
solvated by a hydrogen bond acceptor solvent. With
catechols and 1,8-naphthalenediols, where the two OH
groups are intramolecularly hydrogen bonded, DMSO
forms 1:1 complexes, and 1:2 complexes (diol–DMSO)
may be formed at high DMSO concentrations in carbon
tetrachloride.10 However, no information is available
concerning the equilibrium constants for the formation of
the latter. Solvent effects on equilibrium constants for
3-H, 3-Me and other analogous diols will be investigated
in detail in further work.
The activation entropies (Supplementary Material,
Table S3) for the AA „ AS=SA equilibrium in DMSO
follow the usual pattern, with the value for the AS/
SA → AA interconversion close to zero (0.8 cal molÀ1
K
À1) and that for AA → AS/SA about 7 cal molÀ1 KÀ1
lower (À6.0 cal molÀ1
K
À1). This difference in the
activation entropies is very similar to that observed for
the anti $ syn equilibrium of 2-[di(tert-butyl)hydroxy-
methyl]thiophenes (5.7 cal molÀ1 KÀ1),2 the rotation of a
—C(t-Bu)2OH group from anti to syn in hydrogen bond
acceptor solvents always being associated with the more
negative activation entropy.
In previous work, it was found that the ‘free’ →
‘hydrogen-bonded’ rotation barrier was virtually inde-
pendent of the solvent, the change in equilibrium constant
on going to a hydrogen-bonding solvent resulting almost
entirely from a decrease in the barrier for the reverse
reaction.1,3 In the present case this would imply that the
AS/SA → AA and SS → AS/SA barriers should be
solvent independent whereas those for AA → AS/SA
and AS/SA → SS should decrease as the hydrogen-
bonding capacity of the solvent increases. This expecta-
tion is roughly borne out by the results in Table 2.
Although the fact that there are twice as many OH
peaks in the 1H NMR spectra of 3-Me than in that of 3-H
makes it much more difficult to determine rotation
barriers, the AA „ AS and AA „ SA equilibria could
be examined in toluene. At a mean temperature of 381 K
the barriers are almost identical at 20.8 kcal molÀ1 for the
AA → AS and AA → SA interconversions and less than
0.1 kcal molÀ1 lower for the reverse. It is instructive to
compare these values with those for the corresponding
rotations in 3-H, calculated for the same temperature. We
Rotation barriers
In pyridine and DMSO the syn OH proton signals move
into much the same region of the NMR spectrum as those
of the anti OH protons. In these solvents, as the
Table 2. Rotation barriers (kcal molÀ1) for 3,4-ethylenedioxy-2,5-bis[di(tert-butyl)hydroxymethyl]thiophenes, 3-H and 3-Me:
DG≠(AA → AS/SA), DG≠(AS/SA → SS), DG≠(AS/SA → AA) and DG≠(SS → AS/SA)
Compound
Solvent
Tm (K)
DG≠(AA → AS/SA)
DG≠(AS/SA → SS)
DG≠(AS/SA → AA)
DG≠(SS → AS/SA)
3-H
3-H
3-H
3-H
3-Me
Toluene
Dioxane
Pyridine
DMSO
371
374
358
379
381
20.4 Æ 0.1
19.7 Æ 0.2
19.3 Æ 0.1
19.1 Æ 0.1
20.8 Æ 0.1b
21.1 Æ 0.1a
20.4 Æ 0.3
20.0 Æ 0.3
—
20.9 Æ 0.1
20.6 Æ 0.2
20.6 Æ 0.1
20.6 Æ 0.1
20.8 Æ 0.1b
20.2 Æ 0.1a
20.0 Æ 0.3
19.5 Æ 0.3
—
Toluene
—
—
a
Tm = 364 K.
b
Identical values for AS and SA.
Copyright  2003 John Wiley & Sons, Ltd.
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366
J. S. LOMAS AND C. CORDIER
would expect AS/SA → AA for 3-H to have the same
rotation barrier as AS → AA or SA → AA for 3-Me, i.e.
20.8 kcal molÀ1. In fact it is 20.9 kcal molÀ1, which is the
same to within the experimental error. However, for the
AA → AS/SA interconversion of 3-H there is a statistical
factor of two, since either anti group can rotate to give the
AS or SA isomer. This is equivalent to 0.5 kcal molÀ1 at
381 K, which means that the corresponding barrier
should be 20.3 kcal molÀ1 (20.8 À 0.5), which agrees
well with the experimental value of 20.4 kcal molÀ1. We
have not introduced this statistical correction (‘transmis-
sion coefficient’) in the calculation of the rotation barriers
listed in Table 2 (see the Experimental section for
details). This is at variance with the practice of Lunazzi’s
group, where a transmission coefficient of 0.5 is used in
such situations and the quoted rotation barrier is RTln2
less than would be obtained with a unitary value.12–14
EXPERIMENTAL
IR spectra were recorded in carbon tetrachloride on a
Nicolet Magna 860 FTIR spectrometer. All NMR
measurements except the NOESY experiment (see
below) were performed on a Bruker AS 200 FT
instrument operating at 200 MHz (proton) or 50 MHz
(carbon). Proton NMR chemical shifts in chloroform or
benzene at 298 K are given in ppm (reference values of
residual solvent protons: ꢀH = 7.26 and 7.16 ppm vs
TMS, respectively) and J in hertz. Carbon NMR
chemical shifts in chloroform or benzene at 298 K in
ppm (reference values: ꢀC = 77.0 and 128.0 ppm vs TMS,
respectively).
2-Methyl-2,3-dihydrothieno[3,4-b][1,4]dioxine (EDOT-
Me, 1-Me). This was prepared by a modification of the
method described by Kumar et al.5 allowing much
shorter reaction times. 2,5-Dicarbethoxy-3,4-dihydroxy-
thiophene (1 equiv.) was stirred under argon for 2 h at
110–120°C with 1 equiv. of 1,2-dibromopropane and 3
equiv. of anhydrous potassium carbonate in anhydrous
DMSO. The product was extracted into dichloromethane
and washed with water several times, then dried
(MgSO4). After evaporation of the solvent, the product
was purified by recrystallization from methanol. Hy-
drolysis by refluxing for 1 h with 4 equiv. of sodium
hydroxide in 1:1 methanol–water, followed by filtration
and acidification, gave the diacid, which, after drying in a
desiccator overnight, was decarboxylated by heating for
2 h at 160–170°C with copper chromite in freshly
distilled quinoline. The product mixture was taken up
in diethyl ether and water, the ether layer washed several
times with 2 M hydrochloric acid, then filtered and dried
(MgSO4), and the solvent evaporated to leave an oil,
which was purified by chromatography on alumina. Yield
from dicarbethoxy-3,4-dihydroxythiophene: 17% (lit.5
13%). ꢀC 16.2 (CH3), 69.4 (CH2), 70.0 (CH), 99.3 (CH),
141.4 (C3 or C4) and 142.1 (C3 or C4); ꢀH 1.34 (CH3, J
6.4), 3.82 (CH, J 8.6 and À 11.4), 4.13 (CH, J 2.0
and À 11.4), 4.27 (CH, J 2.0, 6.4 and 8.6), 6.30 (H2 or
H5, J 3.7) and 6.32 (H2 or H5, J 3.7).
CONCLUSION
When there is a —C(t-Bu)2OH group at the 2-position of
the thiophene ring in EDOT it is possible to distinguish
on the NMR time-scale at room temperature the situation
where the OH hydrogen is intramolecularly bonded to a
neighbouring oxygen atom in the 3,4-ethylenedioxy
bridge (anti, A) from that where it is ‘free’ (syn, S).3
Two such substituents, at the 2- and 5-positions, lead to
only three isomers, since the AS and SA forms are
degenerate. This degeneracy is removed by placing a
substituent on one of the bridging carbon atoms.
Although there has been much work on systems with
two or more identical rotors attached to a common stator,
often benzene12,15–20 or naphthalene13,21–30 and, less
frequently, a heteroaryl group,31 studies of solvent effects
on rotamer equilibria and kinetics have been notably
lacking. This is no doubt due to the fact that the low
temperatures required to measure generally small rota-
tion barriers seriously restrict the range of solvents which
can be used. Furthermore, in the absence of a polar
‘handle,’ such as an OH group, solvent effects may be
unimportant.
A particularly interesting case is that of a highly
hindered 1,5-naphthyl sulfoxide bearing two t-BuSO
moieties where all 10 possible stereoisomers have been
separated.30b In our system the introduction of chiral
groups in the place of —C(t-Bu)2OH would lead to seven
stereoisomers for the EDOT derivative and 28 for the
EDOT-Me analogue, where a further chiral centre is
present. In principle, such a system could be easily
achieved by the use of a non-symmetrical ketone instead
of di(tert-butyl) ketone, but it remains to be seen whether
it is possible to separate and characterize the various
stereoisomers.
Synthesis of 3-H and 3-Me. To a mixture of the
appropriate 2-[di(tert-butyl)hydroxymethyl]thiophene
(5 mmol) and TMEDA (10 mmol) in diethyl ether
(15 cm3) under argon at room temperature was added a
solution of n-butyllithium in hexane (1.6 M, 10 mmol).
After 15 min of stirring, di(tert-butyl) ketone (5 mmol)
was added. The mixture was stirred for a further 15 min,
then quenched with water and the organic materials were
extracted with diethyl ether. Washing with water, drying
and evaporation of solvent gave an oil from which the
alcohol was isolated by chromatography on alumina in
light petroleum (boiling range 35–60°C)–diethyl ether
mixtures.
Copyright  2003 John Wiley & Sons, Ltd.
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ROTATIONAL ISOMERISM IN EDOT DERIVATIVES
367
3,4-Ethylenedioxy-2,5-bis[di(tert-butyl)hydroxy-
deuterated solvents (0.5 cm3). Rotamer ratios (Table 2)
were determined by H NMR spectroscopy, integration
of the OH proton signals being used in most cases.
However, for 3-H the bridging methylene signals were in
some cases sufficiently well separated to be used as well.
1
methyl]thiophene, 3-H. Yield (from 2-H) 64%; m.p.
180°C; ꢁOH (cmÀ1) 3571, 3607, 3626 (found: C, 67.4; H,
10.1; S, 7.6. C24H42O4S requires C, 67.56; H, 9.92; S,
7.52%). AA: ꢀC (benzene) 29.5 (CH3), 42.7 or 43.3 (Cq),
63.9 (CH2), 86.8 (COH), 118.7 (C2 and C5) and 136.9
(C3 and C4); ꢀH (benzene) 1.36 (s, 4 t-Bu), 3.08 (s, 2
CH2) and 5.09 (s, 2 OH). AS/SA: ꢀC [benzene (the
position of attachment of the anti motif is designated as
C2)] 29.3 (CH3), 29.7 (CH3), 42.7 (Cq), 43.3 (Cq), 63.1
(CH2), 63.9 (CH2), 85.9 (COH), 86.8 (COH), 119.1 (C2),
124.8 (C5), 132.8 (C4) and 138.0 (C3); ꢀH (benzene) 1.19
(s, 2 t-Bu), 1.41 (s, 2 t-Bu), 1.94 (s, OH), 3.22 (2 CH, J
2.3, 6.1 and À 15.4), 3.27 (2 CH, J 2.3, 6.1 and À 15.4)
and 5.30 (s, OH). SS: ꢀC (benzene) 29.5 (CH3), 42.7 or
43.3 (Cq), 63.2 (CH2), 85.8 (COH), 124.4 (C2 and C5)
and 133.9 (C3 and C4); ꢀH (benzene) 1.25 (s, 4 t-Bu),
1.98 (s, 2 OH) and 3.40 (s, 2 CH2).
Rotation kinetics. Dynamic NMR was used. For 3-H,
both sets of OH protons could be studied in toluene,
dioxane and pyridine. In DMSO the signals of the anti
OH protons in the AA and AS/SA isomers as well as
those of the syn OH protons in the AS/SA and SS
rotamers are widely separated. Moreover, the syn OH
proton signals move upfield as the temperature increases
and become confused with those of the bridge protons.
This means that only AA „ AS=SA exchange can be
studied. Simulation of the OH proton signals by gNMR
gives the exchange rate and the relative concentrations of
the two species from which rate constants and the rotation
barriers are calculated. However, since the program
requires that one proton exchange with one proton in
another molecule (and not with two), the two equivalent
protons in the AA and SS isomers of 3-H have to be
represented by one, which means that the apparent
concentration of AA or SS exchanging with AS/SA is
doubled. This must be corrected before calculation of the
rotation barriers. This does not apply to 3-Me where the
AA isomer is represented by two peaks. No statistical
correction or transmission coefficient has been intro-
duced (see text). In dioxane and pyridine there was
considerable scatter of the activation energies (DG≠ in
kcal molÀ1) and anomalously high activation entropies.
The values listed (Table 2) are the means of 6–12 self-
consistent data points (i.e. following a roughly linear
Eyring plot) for the mean temperature at which the
corresponding rate data were recorded. The temperature
was checked by calibration against a Bruker 80%
ethylene glycol in DMSO-d6 standard and corrected
temperatures used for the calculation of activation
energies. Standard deviations of the activation energies
over the temperature range studied are given in Table 2
and activation parameters in the Supplementary Material,
Table S1.
Methyl-3,4-ethylenedioxy-2,5-bis[di(tert-butyl)hy-
droxymethyl]thiophene, 3-Me. Yield (from 1-Me)
40%; m.p. 101°C; ꢁOH (cmÀ1) 3568, 3609, 3622 (found:
C, 68.0; H, 10.2; S, 7.2. C25H44O4S requires C, 68.14; H,
10.06; S, 7.28%). AA: ꢀH (benzene) 0.56 (CH3, J 6.4),
1.36, 1.37, 1.37 and 1.39 (s, 4 t-Bu), 5.15 (s, OH) and 5.27
(s, OH). AS: ꢀH (benzene) 0.66 (CH3, J 6.4), 1.21, 1.23,
1.42 and 1.42 (s, 4 t-Bu), 1.96 (s, OH) and 5.47 (s, OH).
SA: ꢀH (benzene) 0.71 (CH3, J 6.4), 1.20, 1.20, 1.42 and
1.44 (s, 4 t-Bu), 1.94 (s, OH) and 5.35 (s, OH). SS: ꢀH
(benzene) 0.81 (CH3, J 6.4), 1.25, 1.26, 1.26 and 1.28 (s,
4 t-Bu), 1.98 (s, OH) and 1.99 (s, OH). The methine (3.3–
3.7 ppm) and methylene (2.9–3.3 ppm) signals could not
be attributed. The 13C NMR spectrum consists largely of
multiplets which could not be resolved or assigned except
to carbon type.
1
1H NOESY Experiment on 3-Me. For H–1H dipolar
contact analysis in 3-Me, a NOESY spectrum was
recorded in benzene (degassed by several pump–
freeze–thaw cycles and sealed under vacuum) on a
Bruker DRX-500 spectrometer equipped with a Silicon
Graphics workstation. A 5 mm broadband probe with
a z-gradient was used. The temperature was monitored
with a BCU 05 temperature unit and fixed at 299 K.
Data were processed on a Silicon Graphics station with
the help of GIFA (version 4.3).32 The 2D NOESY
experiment was acquired in the TPPI mode. It was
recorded with 2K points in t2 over 3.13 kHz and 448
points in t1. A 2.0 s relaxation delay and a mixing time of
600 ms were used for the 16 scans of each FID. Zero-
filling was added in F1. Shifted sine-bell window
functions were applied in both dimensions before Fourier
transformation. Baselines were corrected using a poly-
nomial function.
Molecular mechanics calculations. Molecular mechan-
ics calculations were performed using the MMFF94 force
field6,7 with the MMFF94 charge model in the Sybyl 6.8
package (Tripos, St. Louis, MO, USA). Calculated
energies (kcal molÀ1) are as follows: 3-H(AA) 134.23,
3-H(AS or SA) 133.84, 3-H(SS) 133.25, 3-Me(AA)
136.06, 3-Me(AS) 135.65, 3-Me(SA) 135.49, 3-Me(SS)
134.88. Internal coordinates (critical torsion angles) for
all fully optimized structures are listed in the Supple-
mentary Material, Tables S2 and S3, based on the
numbering system in the Supplementary Material, Fig.
S1.
Equilibrium constants for anti „ syn rotamerization.
Samples of the alcohols (ca 20 mg) were made up in
Copyright  2003 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2003; 16: 361–368

368
J. S. LOMAS AND C. CORDIER
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Copyright  2003 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2003; 16: 361–368