A novel approach to the evaluation of the importance of steric and electronic effects in SNAr reactions: A computational, thermodynamic and 1H and 13C NMR study of meisenheimer-type adducts in the benzo[b]thiophene series

Article abstract of DOI:10.1002/ejoc.201000725

The synthetically useful nucleophilic attack on nitrobenzo[b]thiophenes, a starting point for ring-opening/ring-closure pathways to different heterocyclic systems, has been investigated in detail. 3-Nitrobenzo[b]thiophene (9) and 2-nitrobenzo[b]thiophene (10) react with sodium methoxide in either DMSO or methanol to give the relevant Meisenheimer-type adducts 9′ and 10′, identified by NMR spectroscopy. A UV study indicated that the equilibrium constants for the formation of 9′ at 293 K are 10.1 and 40700 Lmol^-1 in methanol and in DMSO, respectively. Competition reactions showed that the stability constant of 10′ is lower than that of 9′: accordingly, DFT [B3LYP/6-31+G(d,p)] calculations indicate that the formation of 9′ is thermodynamically more favoured than that of 10′ both in the gas phase and in DMSO. The reason for the opposite sequence in the stability constants previously found for the corresponding gem-dimethoxy Meisenheimer adducts 7′ and 8′ was therefore investigated in depth and appears to be a consequence of different steric interactions in the starting compounds, 2-methoxy-3-nitro-(7) and 3-methoxy-2-nitrobenzo[b]thiophene (8), respectively. A study of ¹³C NMR chemical shift changes accompanying the formation of adducts 9′ and 10′ confirms that the formation of the adduct exhibiting the larger stability constant is accompanied by a smaller π electron density redistribution, as we have previously found in other cases all governed by electronic effects. The opposite behaviour is observed in the formation of the gem-dimethoxy adducts 7′ and 8′, which is a consequence of the predominance of steric effects. Further outcomes of more general interest deal with the aromatic character of benzo[b]thiophenes. NMR spectroscopic data and calculated bond lengths show that in the studied reactions the benzene ring, unlike the thiophene one, is scarcely affected by methoxide addition, retaining its nearly full aromatic character. Benzocondensation increases the stability constants of σ-adducts mainly because of a marked reduction in the aromatic character of the thiophene ring in the substrates. ¹³C NMR chemical shifts can contribute to evaluations of whether or not steric effects are important in S_NAr reactions. Provided that electronic effects prevail, Meisenheimer-type adducts at the C atom in α position to S also exhibit the larger stability constants when the thiophene ring is benzo[b]-fused. Benzo[b]-condensation causes a dramatic decrease in the aromatic character of the thiophene ring.

Full text of DOI:10.1002/ejoc.201000725

FULL PAPER
DOI: 10.1002/ejoc.201000725
A Novel Approach to the Evaluation of the Importance of Steric and Electronic
1
13
Effects in S Ar Reactions: A Computational, Thermodynamic and H and C
N
NMR Study of “Meisenheimer-Type” Adducts in the Benzo[b]thiophene Series
[
a]
[b]
[a]
[a]
Giovanni Consiglio, Barbara Cosimelli, Susanna Guernelli, Camilla Zaira Lanza,
[c]
[d]
[d]
Fernando Sancassan,* Domenico Spinelli,* and Marco Stenta
Keywords: Reaction mechanisms / Aromatic substitution / Meisenheimer adducts / Sulfur heterocycles
The synthetically useful nucleophilic attack on nitrobenzo-
b]thiophenes, a starting point for ring-opening/ring-closure
nitro-(7) and 3-methoxy-2-nitrobenzo[b]thiophene (8),
13
[
respectively. A study of C NMR chemical shift changes ac-
companying the formation of adducts 9Ј and 10Ј confirms that
the formation of the adduct exhibiting the larger stability
constant is accompanied by a smaller π electron density re-
distribution, as we have previously found in other cases all
governed by electronic effects. The opposite behaviour is ob-
served in the formation of the gem-dimethoxy adducts 7Ј and
8Ј, which is a consequence of the predominance of steric ef-
fects. Further outcomes of more general interest deal with
the aromatic character of benzo[b]thiophenes. NMR spectro-
scopic data and calculated bond lengths show that in the
studied reactions the benzene ring, unlike the thiophene
one, is scarcely affected by methoxide addition, retaining its
nearly “full” aromatic character. Benzocondensation in-
creases the stability constants of σ-adducts mainly because
of a marked reduction in the aromatic character of the thio-
phene ring in the substrates.
pathways to different heterocyclic systems, has been investi-
gated in detail. 3-Nitrobenzo[b]thiophene (9) and 2-nitrob-
enzo[b]thiophene (10) react with sodium methoxide in either
DMSO or methanol to give the relevant “Meisenheimer-
type” adducts 9Ј and 10Ј, identified by NMR spectroscopy.
A UV study indicated that the equilibrium constants for the
formation of 9Ј at 293 K are 10.1 and 40700 Lmol– in meth-
anol and in DMSO, respectively. Competition reactions
showed that the stability constant of 10Ј is lower than that of
1
9Ј: accordingly, DFT [B3LYP/6-31+G(d,p)] calculations indi-
cate that the formation of 9Ј is thermodynamically more fav-
oured than that of 10Ј both in the gas phase and in DMSO.
The reason for the opposite sequence in the stability con-
stants previously found for the corresponding gem-dimeth-
oxy Meisenheimer adducts 7Ј and 8Ј was therefore investi-
gated in depth and appears to be a consequence of different
steric interactions in the starting compounds, 2-methoxy-3-
Introduction
to ring-opening products (with extrusion of hydrogen sul-
[
2]
fide) exhibiting broad synthetic usefulness. Conversely, 2-
The flexible chemical behaviour of thiophene-based ring
[2j]
[1g]
nitrothiophene, 3-nitrothiophene
thiophene
and 3-nitrobenzo[b]-
[
1]
systems is an everlasting and fascinating research field. In
particular, nucleophilic attack on nitro-activated thiophenes
and benzo[b]thiophenes can lead to ring-opening/ring-clo-
sure processes affording different hetero- and homocycles
[1h]
react with amines in the presence of silver ni-
trate to give ring-opening products with retention of the
sulfur, which can easily be alkylated. In particular, the ring-
opening product of 3-nitrobenzo[b]thiophene is an interest-
with decorations hardly obtainable in a “straightforward”
ing building block for the synthesis of several different het-
approach. Amine attack on 3,4-dinitrothiophene[
2a,2b]
leads
[2e]
erocyclic systems, such as thiochroman S,S-dioxides,
γ-
[
2f]
[2g]
[2h]
lactams, indoles and pyrrolidinone oxazines. Several
of the above-mentioned compounds have revealed analge-
[
[
[
a] Dipartimento di Chimica Organica “A. Mangini”,
via San Giacomo 11, 40126 Bologna
b] Dipartimento di Chimica Farmaceutica e Tossicologica,
via Montesano 49, 80131 Napoli
c] Dipartimento di Chimica e Chimica Industriale,
via Dodecaneso 31, 16146 Genova, Italy
Fax: +39-0103536118
[3a,3b]
sic, anti-exudative, and anti-inflammatory activities,
[3c–3e]
whereas in other cases their mutagenic
or polaro-
has been investigated in depth.
[
3f–3h]
graphic behaviour
All the synthetically useful ring-opening/ring-closure
protocols starting from 3-nitrobenzo[b]thiophene exhibit as
their first steps a nucleophilic attack on the fused thiophene
ring. We therefore decided to investigate nucleophilic attack
on nitrobenzo[b]thiophenes, through a detailed study of the
relevant “Meisenheimer-type” adducts.
E-mail: fernando.sancassan@unige.it
d] Dipartimento di Chimica “G. Ciamician”,
via Selmi 2, 40126, Bologna, Italy
[
Fax: +39-0512099456
E-mail: domenico.spinelli@unibo.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000725.
View this journal online at
wileyonlinelibrary.com
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5807

F. Sancassan, D. Spinelli et al.
FULL PAPER
These adducts have been studied as models of intermedi-
ates in nucleophilic aromatic substitutions occurring
[1a,4]
through the classic S Ar mechanism.
In some earlier
N
reports NMR spectroscopy was used only to identify the
adducts, but some authors[ soon afterwards stressed that,
5]
2
for those carbons retaining their sp hybridization during
1
3
the formation of the adduct, C chemical shift changes rel-
ative to the starting compounds can be good indicators of
variation in their π electron densities. Although the first
[
5a,5b]
attempts
to correlate sums of such chemical shift
changes and stability constants in homogeneous series of
Meisenheimer adducts met with some difficulties, we have
[
6a]
shown that such correlations do hold if restricted to sub-
stituents that exhibit the same kind of resonance effect (e.g.,
π-polarization rather than through-conjugation).
In this context we have carried out a comparative
A pioneering study by De Santis and Stegel several years
ago,[ however, showed that in the benzo[b]thiophene series
both the 2-methoxy-3-nitro and the 3-methoxy-2-nitro de-
rivatives (7 and 8, respectively) gave the corresponding
Meisenheimer adducts 7Ј and 8Ј and that the latter even
[
6a–6d]
study
of the reactions of sodium methoxide with
7]
some 4-nitro-2-X-thiophenes 1, 2-methoxy-3-nitro-5-X-
thiophenes 2, 2-nitro-4-X-thiophenes 3 and 2-methoxy-5-
nitro-3-X-thiophenes 4, yielding the corresponding σ ad-
ducts 1Ј–4Ј. In particular, we have found that in the se-
quence 1/1Ј, 3/3Ј, 2/2Ј, 4/4Ј for the same X group, the sta-
bility constants of the adducts increase as the sums of the
2
exhibits a slightly larger stability constant (6.0ϫ10 vs.
2
–1
3
.7ϫ10 Lmol in methanol, as determined by UV spec-
troscopy).
1
3
C chemical shift changes at C-3, C-4 and C-5 (Σ∆δ) on
going from 1–4 to the relevant adducts decrease. The expla-
At this stage, our current interest in S Ar reactions of
N
[
1a,2d,2i,2j,6]
sulfur heterocycles,
and particularly in those giv-
[
6d]
nation given
is that when ring carbons in the substrates
[
2]
ing access to synthetically useful processes, prompted us
to study the formation, stability, structures and π electron
distributions of “Meisenheimer-type” adducts 9Ј and 10Ј,
obtainable by sodium methoxide addition to 3-nitro-
benzo[b]thiophene (9) or 2-nitrobenzo[b]thiophene (10),
respectively, in either [D ]DMSO or [D ]MeOH, with par-
are already markedly shielded because of the natures of
substituents (e.g., OMe in 2 and 4) or their relative loca-
tions, a lower π electron distribution change is necessary to
form the adduct and so the relevant stability constant is
then larger.
6
4
ticular regard to the effect of the benzocondensation
Scheme 1).
(
Scheme 1.
Attempts have been made to prepare Meisenheimer-type
adducts at carbon atoms β to sulfur in nitro-activated thio-
[
6e]
phenes, but both 3-methoxy-2-nitrothiophene
and 2-ni-
Moreover, the previously studied formation of the ad-
[
6f,6g]
trothiophene itself
underwent methoxide attack at ducts 7Ј and 8Ј has been revisited in the light of the current
C-5. We therefore synthesized[
6h,6i]
the spiro-Meisenheimer results for 9Ј and 10Ј. The conclusions overcome the specific
adducts 5Ј and 6Ј in [D ]DMSO by treatment of 2-(2- problem of the relative reactivities of benzo[b]thiophene
6
hydroxyethoxy)-3-nitrothiophene (5) or 3-(2-hydroxy- carbons α and β to the sulfur atom, because they provide
ethoxy)-2-nitrothiophene (6), respectively, with sodium new insight into the aromatic character and general reactiv-
methoxide and showed[ that 6Ј has a lower stability con- ity of such fused ring systems and moreover they suggest a
stant than 5Ј, suggesting a similar sequence in the stability possible novel approach to the study of the relative impor-
6i]
constants of the corresponding gem-dimethoxy adducts.
tance of steric and electronic effects.
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Eur. J. Org. Chem. 2010, 5807–5816

N
Steric and Electronic Effects in S Ar Reactions
Table 1. H and 13C NMR chemical shifts for 3-nitrobenzo[b]thiophene (9) and its corresponding methoxide adduct 9Ј in [D
1
]DMSO.
4
]MeOH are reported in parentheses. For comparison, NMR spectroscopic data for 3-nitrothiophene (1a)
6
The corresponding data in [D
and its methoxide adduct 1Јa are also reported.
δ
9
∆δ
(9Ј–9)
δ
1a
∆δ
(1Јa–1a)
[
a]
[b]
1Јa[b]
[b]
9Ј
H-2
H-4
H-5
H-6
H-7
9.28
8.94)
8.47
8.52)
7.67
7.60)
7.59
7.52)
8.21
7.99)
6.31
(6.42)
7.07
(7.09)
6.86
(7.09)
6.97
–2.97
(–2.52)
–1.40
(–1.43)
–0.81
(–0.51)
–0.62
(–0.43)
–0.12
(0.23)
–
H-2
H-4
H-5
–
8.76
7.65
7.74
–
6.12
–2.64
–1.35
–1.92
–
(
6.30
5.82
–
(
(
(
(7.09)
8.09
–
–
–
–
(
(8.22)
3.20[
c]
CH
–
3.10
86.52
–
CH
3
–
3
–48.17[
d]
C-2
129.76
–43.24
[d]
C-2
136.08
87.91
(–46.97)[
–23.28
(–19.90)
4.02
(1.27)
–4.08
(–1.42)
–1.64
(–1.75)
–3.78
(–0.33)
–2.48
(–2.20)
–2.17
(1.10)
–
d]
(
134.91)
141.36
143.58)
129.48
131.32)
138.41
140.31)
122.92
124.56)
127.04
128.03)
126.27
127.46)
123.85
124.38)
(87.94)
118.08
(123.68)
133.50
(132.59)
134.33
(138.89)
121.28
(122.81)
123.26
(127.70)
123.79
(125.26)
121.68
(125.48)
52.90
C-3
C-3a
C-7a
C-4
C-5
C-6
C-7
C-3
C-4
C-5
–
148.01
122.97
–25.04
(
122.15
119.37
–2.78
(
128.90
114.50
–14.40
(
–
–
–
–
–
–
–
–
–
(
–
–
–
(
–
–
–
(
–
–
–
(
CH
3
–
–
–
CH
3
51.84
–
(49.84)
Σ∆δth[e]
Σ∆δ[f]
–
–23.3
–
–
–
–42.2
(
–20.1)
–33.4
–23.3)
–
–
–
(
[
a] [D
6
]DMSO chemical shifts from ref.[2k] [b] From ref.[6d,6k] [c] Obscured in [D
4
]MeOH. [d] Not included in the sums. [e] The sum includes
2
2
thiophene ring carbon atoms retaining sp hybridization. [f] The sum includes all ring carbons retaining sp hybridization.
1
Results and Discussion
For purposes of comparison, Table 1 also reports H and
1
3
C NMR spectroscopic data for the previously discus-
formation of the adduct 1Јa from 3-nitrothiophene
1a) in [D ]DMSO, which was accompanied by a similar
[
6d,6k]
NMR Evidence of Adducts 9Ј and 10Ј
sed
(
6
When 3-nitrobenzo[b]thiophene (9) in [D ]DMSO or in [D ] decrease in the chemical shifts of H-2, C-2 and C-3, with
6
4
1
MeOH is treated with an equimolar amount of sodium the J(C-2,H-2) value decreasing from 195.5 to 172.8 Hz
methoxide (6  in methanol), the adduct 9Ј is formed, as (ratio 0.88), but also with a noticeable decrease in the chem-
1
13
shown by the general upfield shift in the H and C NMR ical shift of C-5 (corresponding to C-7a in the benzo[b]thio-
spectroscopic data (see Table 1) and the quantitative re- phene system).
storation of 9 on acidification with trifluoroacetic acid.
When 2-nitrobenzo[b]thiophene (10) is treated with so-
As further support for the structural assignment, in the dium methoxide either in [D ]DMSO or in [D ]MeOH, the
6
4
1
3
C NMR spectrum in [D ]DMSO, the C-2 appears as a NMR signals of the starting compound are still visible, to-
6
sharp doublet of quartets, exhibiting a large decrease in gether with the signals (much smaller in [D ]MeOH) of a
4
1
J(C,H) value with respect to the starting compound 9 new species, which was identified as the adduct 10Ј on the
(from 194.1 to 169.1 Hz, ratio 0.87), consistently with its basis of general shielding with respect to the starting com-
reduced s character, whereas the new signal of the methoxy pound (see Table 2) and the recovery of 10 by simple acidifi-
carbon appears, as would be expected, as a quartet of dou- cation. In the [D ]DMSO spectrum of 10Ј the signal of C-
6
blets (J=141.4 and 5.0 Hz). The [D ]MeOH spectrum is af- 3 appears, as would be expected, as a doublet of multiplets,
4
1
fected by overlapping of signals and deuteration at C-2, so with J(C,H) reduced from 178.7 to 153.4 Hz (ratio 0.86),
its interpretation was assisted by spectra run in [D ]DMSO/ whereas the methoxy carbon exhibits a quartet of doublets
6
[
D ]MeOH mixtures to track the regular shift of each signal (J = 140.8 and 5.5 Hz). Further details are reported in the
4
as the methanol fraction increases.
Exp. Section.
Eur. J. Org. Chem. 2010, 5807–5816
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5809

F. Sancassan, D. Spinelli et al.
FULL PAPER
Table 2. H and 13C NMR chemical shifts for 2-nitrobenzo[b]thio- dipolar solvents.[4a] Here, as generally observed, logK lin-
1
e
6
phene (10) and its methoxide adduct 10Ј in [D ]DMSO. The corre-
sponding data in [D
early correlates with NDMSO [logKe = (1.01Ϯ0.05) +
3.61Ϯ0.21) NDMSO, n = 5, r = 0.995]. The good quality of
4
]MeOH are reported in parentheses.
(
δ
1
∆δ
(10Ј–10)
the correlation allowed us to calculate the K values in pure
e
0
10Ј
methanol as well as in pure DMSO by extrapolation (10.1
–1
3-H
4-H
5-H
6-H
7-H
8.61
8.34)
8.15
8.02)
7.68
7.52)
7.58
7.61)
8.13
7.95)
5.80
(6.00)
7.36
(7.40)
7.10
(7.19)
7.25
–2.81
(–2.34)
–0.79
(–0.62)
–0.58
(–0.33)
–0.33
(–0.36)
–0.88
(–0.63)
–
and 40738 Lmol , respectively). Further details are given
in the Experimental Section.
(
From the calculated values of the equilibrium constants
in methanol and in DMSO the relevant free energy changes
at 298 K were determined as –1.37 and –6.28 kcal, respec-
tively, thus indicating, particularly in DMSO, the higher
stability of the reaction products with respect to the starting
compounds. This is consistent with the NMR study, which
also showed that this conclusion can be extended to the
(
(
(
(7.25)
7.25
(
–
(7.32)
3.21[
a]
CH
C-2
3
150.45
108.99
(119.91)
79.73
–41.46
(–32.46)
–47.41[
(–46.26)[
1.02
(–1.12)
–0.29
(–1.76)
–2.32
(–2.12)
–2.99
(0.46)
1.36
equilibrium involving 10 in [D ]DMSO.
6
(
152.37)
127.14
127.03)
136.11
137.66)
139.79
141.51)
126.26
128.20)
129.52
127.21)
127.53
130.29)
123.41
123.97)
Interestingly enough, because of the effects of the benzo-
condensation on the aromaticity (see the discussion on this
point in the Conclusions) we have been able, for the first
time in a mononitro-substituted heterocycle not containing
b]
C-3
b]
(
(80.77)
137.13
(136.54)
139.50
(139.75)
123.94
(126.08)
126.53
(127.67)
128.89
(130.92)
121.48
(122.90)
53.87
C-3a
C-7a
C-4
(
pyridine-like nitrogen atoms, to calculate the K value for
e
(
the formation of the non-geminal “Meisenheimer-type” ad-
duct from 3-nitrobenzo[b]thiophene both in methanol and
in DMSO, by the above procedure.
(
C-5
(
C-6
(
(0.63)
–1.93
(–1.07)
–
Competition Reactions
C-7
(
The formation equilibria of the two adducts 9Ј and 10Ј
CH
3
–
–
–
both in [D ]DMSO and in [D ]MeOH were compared by
(51.16)
6
4
Σ∆δth[c]
Σ∆δ[d]
–
–40.7
mixing together solutions containing 9 and sodium meth-
oxide (0.5 equiv.) and solutions containing 10 and sodium
methoxide (0.5 equiv.). The subsequent trends to chemical
(
–35.3)
–46.6
–37.4)
–
(
1
equilibrium were monitored by H NMR spectroscopy. The
4
[a] Obscured in [D ]MeOH. [b] Not included in the sums. [c] The
equilibrium constant of 9Ј was found to be the larger in
both solvents. See the Exp. Section for details.
2
sum includes thiophene ring carbon atoms retaining sp hybridiza-
tion. [d] The sum includes all ring carbons retaining sp hybridiza-
2
tion.
DFT Calculations
UV Determination of the Equilibrium Constant of 9Ј
a) Energies
The equilibrium constants for the formation of 9Ј were
measured at 298 K through UV/Vis spectral measurements
The energies of 9, 9Ј, 10 and 10Ј were determined both
on solutions of 9 in the presence of increasing amounts of in the gas phase and in the presence of DMSO, simulated
[9]
sodium methoxide in several methanol/DMSO mixtures. by means of the implicit method (CPCM-SCRF). The
[
10]
The spectra of 9 and of 9Ј in methanol show maxima at calculation level adopted (DFT/B3LYP),
in conjunction
339 and 346 nm, respectively. The unusual and small ba- with the accurate Pople-type basis set 6–31+G(d,p), is able
thochromic shift now observed (∆λ = 7 nm) is comparable both to take correlation energy into account and to describe
to those observed in the formation of the adducts 2aЈ, 7Ј intramolecular interactions. All of the calculations were
[
6d,6g,7]
[11]
and 8Ј from the corresponding substrates 2a, 7 and 8.
performed with the Gaussian03 software.
Table 3 reports some calculated energy differences indi-
increasing sodium methoxide concentration. This effect had cating the relative stabilities of the products and the reac-
The equilibrium constant (K ) was found to increase with
e
[
8]
already been noted and related to ion-pair formation.
tants. It stands out that the examined 3-nitro derivatives (9
Graphic extrapolation of the K versus [MeONa] plot to and 9Ј) are more stable than the corresponding 2-nitro ones
e
zero concentration of sodium methoxide gave K values of (10 and 10Ј) and that the difference between the adducts
e
–
1
1
6
6.80, 26.93, 58.85, 74.55 and 215.5 Lmol for 9:1, 8:2, 7:3, is greater than that between the starting compounds. The
:4, and 1:1 MeOH/DMSO solutions, respectively. formation of the adduct 9Ј is thus calculated to be signifi-
As would be expected, K significantly increases with the cantly more favoured than that of 10Ј (see ∆∆E values in
e
DMSO molar fraction (NDMSO), much in keeping with the Table 3), although DMSO as solvent exhibits some levelling
well-known different solvating abilities of aprotic and protic effect with respect to the gas phase.
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Steric and Electronic Effects in S
N
Ar Reactions
–
1
Table 3. Calculated energy differences (kcalmol ).
Table 4. Calculated bond lengths [Å] and angles [°] for substrates
–10, adducts 7Ј–10Ј, and benzo[b]thiophene (BT) in DMSO. Ex-
perimentally determined values for thiophene (TH) from the litera-
ture are reported for purposes of comparison.
7
Gas phase
DMSO
∆E (10–9)
∆E (10Ј–9Ј)
∆∆E
1.77
9.38
7.61
1.59
4.93
3.34
TH[a] BT
7
8
9
10
7Ј
8Ј
9Ј
10Ј
b1
b2
b3
b4
1.71 1.754 1.750 1.762 1.715 1.754 1.937 1.778 1.843 1.779
1.37 1.361 1.399 1.394 1.373 1.370 1.520 1.532 1.507 1.504
1.42 1.444 1.457 1.439 1.452 1.428 1.453 1.527 1.454 1.512
1.37 1.420 1.414 1.415 1.419 1.425 1.421 1.398 1.419 1.405
1.71 1.760 1.765 1.754 1.763 1.756 1.770 1.777 1.783 1.783
b) Geometries
In order to find an explanation for this greater stability b5
constant of the “Meisenheimer-type” adduct 9Ј with respect b6
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
1.412 1.408 1.432 1.422 1.349 1.324 1.343 1.324
1.246 1.249 1.242 1.244 1.284 1.307 1.293 1.303
1.249 1.245 1.241 1.240 1.290 1.293 1.290 1.298
b7
b8
b9
b9Ј
to 10Ј and also for the opposite nature of the sequence in
the stability constants previously found[7] for the corre-
1.318 1.341 –
–
–
1.394 1.423 –
1.395 1.423 1.439 1.452
116.4 – 119.4
–
sponding gem-dimethoxy adducts 7Ј and 8Ј we calculated
–
–
–
–
the geometrical parameters of 7–10, 7Ј–10Ј and benzo[b]- b1-b6
117.0 –
119.5 –
b2-b6
b3-b6
b6-b7
b6-b8
b1-b9
b2-b9
b3-b9
b9-b10
122.4 128.8 120.2 125.5 119.0 128.5 120.2 126.0
124.4 – 125.4 – 125.0 – 125.5 –
119.8 117.4 118.9 117.7 121.1 118.5 120.6 119.6
118.2 119.7 118.3 118.8 120.4 122.5 120.7 121.3
thiophene by the same method as described above. Selected
results obtained for DMSO solutions are shown in Figure 1
and in Table 4, whereas more extensive data are given in the
Supporting Information.
121.9 –
125.8 129.9 –
119.0 –
119.3 120.0 –
–
–
–
–
–
108.1 –
09.5
118.4 114.2 114.8 114.3
09.1 114.5
105.8 –
11.8
116.9 116.9 114.5 114.4
17.0 117.0
105.4 –
1
–
–
–
–
–
–
1
–
–
105.9
1
1
[
a] See ref.[1a], p. 309.
can orient itself further from the nitro group (see Figure 1),
the molecule still being planar, with the full nitro group and
the methoxy carbon in the ring plane and only two methyl
protons out of it. Little steric hindrance is evident: the b2-
b6 and b6-b7 bond angles are not far from standard values
and only b2-b9 reaches 125.8° (see Figure 1 and Table 4).
In 3-methoxy-2-nitrobenzo[b]thiophene (8), in contrast, the
methoxy group cannot orientate itself towards the peri hy-
drogen 4-H and tends to point towards the nitro group but
conflicts with it (see Figure 1). The methoxy carbon is
therefore well out of the ring plane (b3–b9–b10 dihedral
–125.8°) and even the nitrogen of the nitro group is slightly
but significantly bent out of it (b3–b2–b6 dihedral –171.4°),
although the C–NO moiety as a whole is still planar. The
2
very large b2-b6 and b2-b9 bond angles (see Table 4), as
well as the short nonbonding distance (2.181 Å) between an
oxygen of the nitro group and a methoxy proton, are evi-
dence of the particularly marked steric hindrance in this
molecule.
With regard to the studied Meisenheimer adducts, the
calculations indicate that in 7Ј and 9Ј the tetrahedral carbon
C-2 is bent with respect to the general molecular plane (the
b4–b3–b2 values being 6.7 and 14.4°, respectively). We can
note that the dihedral value is lower for the gem-dimethoxy
adduct 7Ј, in which the overall steric crowding is greater but
balanced between the two sides of the ring plane, consist-
ently with previous findings from X-ray diffraction studies
Figure 1. Calculated geometries for the substrates 7–10 and the ad-
ducts 7Ј–10Ј.
[
12]
of Meisenheimer adducts in the benzene series.
Con-
The calculated geometries illustrate that the molecules of versely, adducts 8Ј and 10Ј each exhibit a tetrahedral carbon
the nitrobenzo[b]thiophenes 9 and 10 are entirely planar. In (i.e., C-3), which is α to the benzene ring and therefore
2-methoxy-3-nitrobenzo[b]thiophene (7) the methoxy group somewhat forced to be coplanar to it. This results in a
Eur. J. Org. Chem. 2010, 5807–5816
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5811

F. Sancassan, D. Spinelli et al.
FULL PAPER
nearly coplanar location of all the ring atoms of the gem- the direction of further reactivity, providing an explanation
[
1h]
dimethoxy adduct 8Ј, whereas in 10Ј C-3 and C-2 exhibit for, for example, the previous observation
that 3-ni-
small and opposite deviations from the general plane of the trobenzo[b]thiophene can react with secondary aliphatic
molecule. We can also note that in each of the monome- amines through cleavage of the b1 bond, yielding ring-open-
thoxy adducts 9Ј and 10Ј the methoxy substituent points ing products that give access to the syntheses of several dif-
[
2e–2h]
towards the nitro group (see Figure 1), which avoids the ferent heterocyclic systems
(see the Introduction). In
conflict through a marked bending of the nitrogen of the contrast, b5 shows only a small elongation (0.02 Å), and
nitro group out of the general plane (b4–b3–b6 160.4° in 9Ј, correspondently the ring cleavage was found to occur with
b3–b2–b6 152.6° in 10Ј), resulting in a marked pyramidaliz- sulfur retention (see the Introduction).
ation of the corresponding nitrated ring carbon, whereas
the C–NO moiety, as a whole, is still planar. In each of the
2
gem-dimethoxy adducts 7Ј and 8Ј the nitrogen of the nitro 13C NMR Chemical Shift Differences
group is bent to a much smaller extent (b4–b3–b6 177.6° in
A further contribution to the study of the formation of
Meisenheimer-like” adducts can come from study of the
7Ј, b3–b2–b6 174.8° in 8Ј) and the pyramidalization of the
“
nitrated carbon is much smaller, because the nitro group is
in conflict with a methoxy group on each side of the ring.
Interestingly, in the parent benzo[b]thiophene and in its
neutral derivatives 7–10 the calculated bond lengths in the
benzene ring (from b10 to b14, not shown in Table 4) are
very close to the 1.397 Å value of benzene itself, showing
differences generally within Ϯ0.01 Å, with only slightly
larger variations for b4 (see Table 4), the bond common to
the two rings. With regard to the other bonds of the thio-
phene ring, b1 and b5 are usually 0.04–0.05 Å longer in
neutral benzo[b]thiophenes than in thiophene itself. Thus,
unlike the benzene moiety, the thiophene ring does not
seem to retain much of its aromatic character as a conse-
quence of benzo[b]condensation. In this context we can
note that in benzo[b]thiophene the length of b4 (1.42 Å) is
more similar to the benzene value than to the thiophene
one. Only small bond length changes are observed as a con-
1
3
C chemical shift changes accompanying their formation.
In Tables 1, 2, 5 and 6 the 13C chemical shifts of the adducts
7
Ј–10Ј are compared with those of the corresponding sub-
strates 7–10. For purposes of comparison, the available data
for the corresponding adducts in the thiophene series are
also reported. In our previous extensive studies of Mei-
[
6a–6d,6h,6j,6k]
senheimer adducts
we have stressed that a rea-
sonable and self-consistent picture can be obtained by re-
garding the 13C chemical shift differences between the ad-
ducts and the corresponding substrates as mainly related to
i) hybridization change for the carbon undergoing meth-
oxide attack, and ii) π electron density variations for the
2
ring carbons retaining their sp hybridization.
Table 5. 13C NMR spectroscopic data for 2-methoxy-3-ni-
trobenzo[b]thiophene (7) and the relevant Meisenheimer adduct 7Ј
[6a]
6
in [D ]DMSO. For comparison, NMR spectroscopic data for 2-
sequence of nitration of benzo[b]thiophene, with the excep- methoxy-3-nitrothiophene (2) and the relevant adduct 2Ј are also
reported.
tion of b1 in 9: this is calculated to be appreciably shorter
than b5, as a possible consequence of a preferential reso-
nance interaction between the heterocyclic sulfur and the
coplanar 3-nitro group.
δ
7
∆δ
(7Ј–7)
δ
2
∆δ
(2Ј–2)
7Ј
2Ј
172.24 126.55 –45.69[a] C-2
168.42 126.26 –42.16[a]
C-2
Remarkably, the calculated bond lengths of the benzene C-3
122.46 112.40 –10.06
C-3a 129.89 134.19 4.30
C-7a 124.70 129.35 4.65
C-3
C-4
C-5
–
–
–
128.49 117.07 –11.42
121.61 120.50 –1.11
110.17 109.86 –0.31
ring, including b4, show even smaller variations on going
to the anions 7Ј–10Ј. Methoxide attack at C-2 does not pro-
duce any change even in the b3 bond length of 7Ј and 9Ј
with respect to 7 and 9, showing that the additional nega- C-6
tive charge is effectively confined on C-3 and the nitro
group. Correspondently, methoxide attack at C-3 does not
produce any shortening of the b1 values in 8Ј and 10Ј with
respect to 8 and 10, indicating that the additional negative
charge is confined on C-2 and the nitro group.
In all the adducts the nitro group bond lengths exhibit
the expected pattern: a ca. 0.08 Å shortening for the b6
value and a ca. 0.05 Å elongation for b7 and b8. The meth-
C-4
C-5
121.72 121.39 –0.33
126.99 123.55 –3.44
124.83 122.86 –1.97
122.87 120.53 –2.34
63.53 51.62 –11.91[
–
–
–
–
–
–
–
–
–
–
–
–
C-7
–
a]
CH
3
CH
Σ∆δth
–
3
63.16 51.76 –11.40
[
b]
[b]
Σ∆δth
Σ∆δ
–
–
–
–
–1.1
–9.2
–
–
–
–
–12.8
–
[c]
[
a] Not included in the sums. [b] The sum includes thiophene ring
2
carbons retaining sp hybridization. [c] The sum includes all ring
2
carbons retaining sp hybridization.
In this context we can explain the very marked change
oxy groups in 7Ј and 8Ј each show a 0.08 Å increase in b9, exhibited by the chemical shift of C-2 on going from 9 to
as the expected consequence of the release of conjugative 9Ј or from 7 to 7Ј and of C-3 on going from 10 to 10Ј or
interactions with the ring operative in the corresponding from 8 to 8Ј mainly on the basis of the hybridization change
substrates 7 and 8. It seems particularly interesting to note from sp2 to sp . This compares with the chemical shift
the marked elongations of b1 in 7Ј and 9Ј (∆λ = 0.187 and changes shown by the corresponding carbons in Mei-
3
0
1
.128 Å, respectively). Now the b1 lengths (1.937 and senheimer adducts in the thiophene series.
.843 Å, respectively) are even greater than literature tetra- More interestingly, the other chemical shift differences
). This shown in Tables 1, 2, 5 and 6, when large enough to be
[13a]
[13b]
hydrothiophene values (1.821 Å
and 1.840 Å
dramatic weakening of b1, even larger than expected, shows interpreted, can mainly be related to π electron density
5812
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5807–5816

Steric and Electronic Effects in S
N
Ar Reactions
Table 6. 13C NMR spectroscopic data for 3-methoxy-2-nitrobenzo- bearing the same substituents in different relative positions,
6
thiophene (8) and the relevant Meisenheimer adduct 8Ј in [D ]-
and also when comparing non-geminal and geminal Mei-
senheimer adducts.
DMSO. For comparison, NMR spectroscopic data[ for 5 and the
6i]
relevant spiro adduct 5Ј are also reported.
The benzo[b]thiophene gem-dimethoxy adducts 7Ј and 8Ј
exhibit the opposite behaviour, with the larger stability con-
stant being exhibited by 8Ј, the formation of which is ac-
companied by larger shielding of ring carbons. However,
our previous analysis of calculated geometries indicate that
this can be reasonably explained on the basis of the preva-
lence of steric effects over the electronic ones.
δ
8
∆δ
(8Ј–8)
δ
5
∆δ
(5Ј–5)
8Ј
5Ј
C-2
C-3
C-3a
C-7a
C-4
C-5
C-6
C-7
134.28 104.83 –29.45[
151.91 107.29 –44.62
131.31 135.92 4.61
134.68 136.85 2.17
124.54 124.27 –0.27
125.97 124.78 –1.19
130.69 129.93 –0.76
123.67 121.74 –1.93
C-2
C-3
C-4
C-5
–
–
–
129.3 108.7 –20.6
157.2 112.5 –44.7
118.0 123.4 5.5
133.1 124.5 –8.6
–
–
–
–
–
–
–
a]
[a]
–
–
–
–
–
–
–
–
–
–
–
–
–
CH
3
63.00
–
–
51.33
–
–
–11.67
–22.7
–26.8
–
Conclusions
[b]
[b]
Σ∆δth
Σ∆δth
–
–23.7
–
[c]
Σ∆δ
Both experimentally measured NMR chemical shifts and
calculated bond lengths show that the benzene ring carbon
carbons retaining sp hybridization. [c] The sum includes all ring atoms in the substrates 7–10 are scarcely affected by meth-
[
a] Not included in the sums. [b] The sum includes thiophene ring
2
2
carbons retaining sp hybridization.
oxide attack, providing evidence that the benzene ring re-
tains its full aromatic character and is therefore the only
changes accompanying the formation of the adducts, so we “really aromatic” ring.
can investigate how the shielding caused by the full negative
Accordingly, the Bird’s aromatic indexes[14] of benzene
charge is distributed over the ring carbons. As would be (IA 100) and thiophene (IA 81.5) in comparison with that
expected, the observed chemical shift differences are lower of benzo[b]thiophene (I 119) suggest a very modest contri-
A
for the gem-dimethoxy adducts 7Ј and 8Ј, because the bution of the thiophene system to the global aromaticity of
shielding introduced by the negative charge is partially bal- benzo[b]thiophene.
anced by the release of the +R effect that the methoxy
Overall, these data also appear highly consistent with the
group can exhibit in the starting substrates.
possible “non-aromatic” reactivity of the thiophene ring in
It stands out that the main shielding effect is observed benzo[b]thiophenes (e.g., with nucleophiles). With some
for the nitro-substituted carbon atoms (i.e., C-3 on com- amines, for instance, 10 gives Michael-type addition on the
parison of 9Ј and 9, or 7Ј and 7, and C-2 on comparison b2 double bond that can be followed by an oxidative pro-
[
1h]
of 10Ј and 10, or 8 and 8Ј), the effect being particularly cess (i.e., globally a ONSH reaction), whereas in contrast
large when the nitrated carbon is C-2 (methoxide attack at 9 undergoes ring-opening by cleavage of the b1 bond with
[
1h]
C-3). It can be noted that in all these benzo[b]thiophene some amines and silver nitrate.
adducts all the other sp carbons exhibit only small changes
2
In conclusion, we may call into question the assumption
relative to the corresponding starting compounds, because that the reactions between nitrobenzo[b]thiophenes and nu-
even C-7a in 9Ј does not exhibit the great shielding with cleophiles represent the first steps of S Ar reactions or
N
respect to the starting compound conversely shown by C-4 rather Michael additions. We think that the nitrobenzo[b]-
in 1aЈ with respect to 1a. Interestingly, all the carbons of the thiophenes studied, because of the very low aromatic char-
benzene ring exhibit small chemical shift differences. These acters of the thiophene rings in these systems, furnish an
findings are in close agreement with the results of the analy- interesting instance of borderline behaviour well in line with
sis of bond lengths showing that the negative charges of the their global reactivity. As a matter of fact, for instance, 3-
adducts 7Ј–10Ј are confined to their nitrated carbons and bromo-2-nitrobenzo[b]thiophene can give either normal
the nitro groups.
S Ar substitution with nucleophiles or S Ar substitution
N
N
nitro group rearrangement,[
2k–2n]
The sums of the chemical shift changes including all of accompanied by
the carbons retaining their sp hybridization are heavily af- whereas in contrast, 9 and 10 give ring-opening
fected by the shieldings of the nitrated carbons and are ONSH reactions,
a
2
[1h]
or
[
1h]
respectively, with amines. Moreover,
therefore more negative for the formation of the adduct 10Ј with sodium methoxide the same 9 and 10 give products
than for 9Ј and for the formation of the adduct 8Ј than for that can be regarded both as “Meisenheimer-like” adducts
7Ј. The results obtained for the monomethoxy adducts 9Ј and as Michael addition products. In our opinion this bor-
and 10Ј show that, once more, in a comparison of “Mei- derline behaviour represents one of the most intriguing as-
senheimer-like” adducts with the same substituents in dif- pects of the reactivity of nitrobenzo[b]thiophenes.
ferent relative positions, the adduct exhibiting the larger
stability constant is that showing the smaller π electron den- in methanol to be evaluated, as a direct consequence of the
sity change with respect to the starting compound. reduced aromaticity of the thiophene ring in 9, in which, in
Benzocondensation allowed the stability constant of 9Ј
Previously we have found the same behaviour in the thio- contrast, the resonance interaction between the heterocyclic
phene series when comparing the spiro-Meisenheimer ad- sulfur and the 3-nitro group is of some importance.
[
6h,6i]
ducts 5Ј with 6Ј
and when comparing the adducts 1Ј,
On comparing adducts 9Ј and 10Ј, obtained from sub-
[
6a–6d]
2Ј, 3Ј, and 4Ј:
that is, when we have compared adducts strates with the same substituents at different relative loca-
Eur. J. Org. Chem. 2010, 5807–5816
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5813

F. Sancassan, D. Spinelli et al.
FULL PAPER
tions, we have once more found that the larger stability con- case be easily identified on the basis of its particularly large de-
crease in chemical shift value with respect to the starting compound
and, in [D ]DMSO, on the basis of its expected fine structure and
6
stant is exhibited by the adduct of which the formation is
accompanied by the lower π electron density reorganiza-
1
3
J values (see Results and Discussion). The nitrated carbon could
be identified because of its singlet structure and its large decrease
in chemical shift. The individual carbons in the pairs C-3a and
C-7a, C-4 and C-7, and C-5 and C-6 were assigned by chemical
reasoning, although their assignment does not affect the conclu-
sions of this work.
tion, as evaluated on the basis of C NMR chemical shifts
(the so-called Σ∆δ values; see Tables 1, 2, 5 and 6).
Interestingly enough, the opposite is found for the corre-
sponding gem-dimethoxy adducts, in which steric hindrance
can overcome electronic effects, thus causing an only “ap-
1
3
parent” exception to the rule linking C chemical shifts
changes accompanying the formation of Meisenheimer-like
adducts to their stabilities.
Competition Reactions: Several competition reactions were carried
on under different conditions. In particular, when a solution of 3-
6
nitrobenzo[b]thiophene (9) in [D ]DMSO (0.17 ) was treated with
1
To the best of our knowledge this is the first example of MeONa (5.68  in MeOH, 0.5 equiv.), the H NMR spectrum
1
3
this unexpected behaviour. The above C NMR patterns showed the formation of the adduct 9Ј at a level of ca. 47%. When
have their counterparts in the shape of the UV/Vis spectra, an analogous solution of 2-nitrobenzo[b]thiophene (10) was treated
with MeONa (0.5 equiv.) the sharp multiplets of 10Ј could be de-
for which only a “small” shift of the maximum on going
tected, but the very heavy broadening of the absorptions of the
from 9 to 9Ј has been observed (∆λ = 7 nm). This gives
further support to some our previous comments[
6d]
starting compound did not allow the real extent of the Mei-
senheimer adduct formation to be determined. When the two solu-
tions were mixed, the peaks due to 9, 9Ј and 10Ј, together with the
humps due to 10, could be detected. At first, the level of formation
of 9Ј was ca. 60%, but it increased with time, becoming practically
quantitative. At the same time the absorptions due to 10Ј faded,
but it was not possible to follow the fate of 10 because of the heavy
broadening of its signals. After 2 h acidification with trifluoroacetic
on the
Meisenheimer adduct formation from 2a, indicating that
the situation can also be extended to benzo[b]thiophenes,
as also suggested by De Santis and Stegel.[
7]
Experimental Section
1
acid allowed us to obtain, after 4 h of further delay, a H NMR
Synthesis and Purification of Compounds: 3-Nitrobenzo[b]thio-
phene (9) and 2-nitrobenzo[b]thiophene (10) were synthesized and
purified according to literature procedures.[
spectrum showing the superposition of the patterns of the signals
of 9 and 10. The quantitative restoration of both of the starting
compounds shows that 10Ј did not decompose when the relevant
signals faded. We can therefore conclude that the equilibrium con-
15]
NMR Studies: 1H NMR spectra were run at 200 MHz and 13
C
stant of methoxide addition in [D
trobenzo[b]thiophene (9) than for 2-nitrobenzo[b]thiophene (10).
When a solution of 3-nitrobenzo[b]thiophene (9) in [D ]MeOH
0.06 ) was treated with MeONa (5.68  in MeOH, 0.5 equiv.),
6
]DMSO is larger for 3-ni-
NMR spectra at 50 MHz, always at 298 K. Chemical shifts are
reported in ppm (δ) downfield from internal TMS. The
4
INADEQUATE experiment was run at 75 MHz. Assignments for
(
6
-nitrobenzo[b]thiophene (9) in [D ,
]DMSO are taken from ref.[
2k]
3
1
the H NMR spectrum showed the formation of the adduct 9Ј at
level of ca. 45%. When an analogous solution of 2-nitrobenzo[b]-
thiophene (10) was treated with MeONa (0.5 equiv.) the level of
the formation of 10Ј was about 5%. Further MeONa was then
added (to a total of 3.25 equiv.) and 10Ј increased to nearly 20%.
but were further checked by a 2D-INADEQUATE experiment
showing, in particular, correlation of C-3a with both C-3 and C-4.
Assignments for 9 in [D
]DMSO/[D ]MeOH 3:1 and 1:1 mixtures. With regard to the
assignments of 2-nitrobenzo[b]thiophene (10), the weak signals of
the unprotonated C-3a and C-7a could be better studied in [D ]-
4
]MeOH were assisted by spectra run in
[D
6
4
1
Mixing of the two solutions produced a H NMR spectrum at first
6
showing more than 70% of 9Ј with respect to 9, together with a
decrease in 10Ј. After 1 h the percentages of the two adducts had
changed, with a significant increase in 9Ј. Acidification with tri-
DMSO spectra for solubility reasons: they both appeared as mul-
tiplets, exhibiting the primary structures of a quartet and a triplet,
and were safely assigned to C-7a and C-3a, respectively, on the
1
fluoroacetic acid then produced a H NMR spectrum showing the
3
basis of the different numbers of their J(C,H) couplings. The as-
superposition of the patterns of the starting compounds 9 and 10
6 4
signments in [D ]DMSO could then be translated to [D ]MeOH
with the assistance of spectra run in mixtures of the two solvents.
The procedure was reversed for the assignments of 4-H and 7-H,
because in [D ]MeOH the 4-H and 7-H doublets are not overlap-
4
ping and 4-H could be more safely identified by irradiation of 3-H
(
the H-2 singlet of 9 was smaller than at the start of the experiment
because of some deuteration). This experiment definitely shows
that the equilibrium constant of the methoxide addition is also
larger for 3-nitrobenzo[b]thiophene (9) than for 2-nitrobenzo[b]-
thiophene (10) in [D ]MeOH. All of the experiments were carried
4
out at 298 K.
in a NOEDIF experiment. The adduct 9Ј was obtained by treating
a solution of 9 (0.2 ) in [D
equimolar amount of sodium methoxide (freshly prepared 6  solu-
tion in methanol). When a solution of 10 (0.2 ) in [D ]DMSO was
treated with an equimolar amount of sodium methoxide the extent
6 4
]DMSO or in [D ]MeOH with an
UV Determination of the Equilibrium Constant of 9Ј: The equilib-
rium constants for the formation of 9Ј can be determined from
spectral measurements on methanolic solutions of 9 and sodium
methoxide containing variable amounts of DMSO, provided that
the extinction coefficients of substrate (ε ) and of adduct (ε ) are
s a
known. In fact:
6
1
of formation of 10Ј was about 65% in the readily acquired
H
NMR spectrum, fading to about 43% after 1 h. When the reaction
between 10 (saturated solution, 8 mg/0.7 mL) and sodium meth-
4
oxide (1 equiv.) was carried out in [D ]MeOH, only weak signals
of a new species could be detected together with those of the start-
ing 2-nitrobenzo[b]thiophene. With 3 equiv. of sodium methoxide
the new species was formed at a level of about 20% and with
1
0 equiv. at a level of 65%. With regard to the assignments of the
where D
rium, C
e
represents the optical density of the solution at equilib-
s
the total substrate concentration (the sodium methoxide
3
signals of the adducts 9Ј and 10Ј, the sp ring carbon could in each
5814
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Eur. J. Org. Chem. 2010, 5807–5816

N
Steric and Electronic Effects in S Ar Reactions
concentration, being in large excess over that of 9, is assumed to
be constant), and l the thickness of the cuvettes in cm. Measure-
ments were carried out with a Cary 1E spectrophotometer. The
UV/Vis (200–500 nm) spectrum of 9 in methanol shows an absorp-
tion maximum at 339 nm; the formation of the complex 9Ј causes a
definite although minor spectral change with a bathochromic shift.
Addition of increasing amounts of sodium methoxide causes an
increase in absorption with a change in the shape of the spectrum.
At a sodium methoxide concentration close to 0.5 , the substrate
is completely converted into the corresponding adduct, the absorp-
tion maximum being at 346 nm, and further increase in base con-
centration causes no further spectral change. The spectra for dif-
ferent methanol/DMSO mixtures were recorded at 298 K. Samples
were prepared by addition of a solution of the substrate and in-
creasing amounts of sodium methoxide to DMSO. All solutions
were thermostatted at 298 K. The concentrations used were
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Supporting Information (see also the footnote on the first page of
–4
–1

9
4
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1
13
this article): H and C NMR spectra of compounds 9Ј and 10Ј.
Additional DFT-calculated geometrical parameters of 7–10, of 7Ј–
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10Ј, of thiophene in DMSO.
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Financial support was provided by grants from the Universities of
Bologna and Genova and from the Ministero dell’Università e della
Ricerca (MIUR) (PRIN 20078J9L2A_005 and 20085E2LXC_001).
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Received: May 20, 2010
Published Online: August 31, 2010
5816
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Eur. J. Org. Chem. 2010, 5807–5816