Dependence of stereoelectronic and charge effects on pKa values of 1,3-dithiane-derived sulfides, sulfoxides, and sulfones: An experimental and computational investigation

Article abstract of DOI:10.1002/ejoc.201403409

The pK_a values of conformationally fixed 1,3-dithianes were investigated with experimental and theoretical methods to gain an insight into the influence of the relative orientation of the acidic proton and the stabilising S=O or S-C bonds. Experimental values were determined with a modification of the spectrophotometric method using overlapping indicators developed by Bordwell; theoretical values were obtained with the proton exchange methods using DFT calculations. It turned out that stereoelectronic stabilisation is important for sulfides and sulfoxides, whereas charge effects become dominant in sulfones. Deprotonation of the equatorial proton is favoured for most of the compounds except for the equatorial/ axial bis-sulfoxide.

Full text of DOI:10.1002/ejoc.201403409

FULL PAPER
DOI: 10.1002/ejoc.201403409
Dependence of Stereoelectronic and Charge Effects on pK Values of
a
1
,3-Dithiane-Derived Sulfides, Sulfoxides, and Sulfones: An Experimental and
Computational Investigation
[a]
[a]
Bastian D. Süveges and Joachim Podlech*
Keywords: Stereoelectronic effects / Sulfur heterocycles / Sulfoxides / Acidity / UV/Vis spectroscopy
The pK
a
values of conformationally fixed 1,3-dithianes were
with the proton exchange methods using DFT calculations.
It turned out that stereoelectronic stabilisation is important
for sulfides and sulfoxides, whereas charge effects become
dominant in sulfones. Deprotonation of the equatorial proton
is favoured for most of the compounds except for the equato-
rial/axial bis-sulfoxide.
investigated with experimental and theoretical methods to
gain an insight into the influence of the relative orientation
of the acidic proton and the stabilising S=O or S–C bonds.
Experimental values were determined with a modification of
the spectrophotometric method using overlapping indicators
developed by Bordwell; theoretical values were obtained
Introduction
We investigated stereoelectronic and charge effects of
sulfides, sulfoxides, and sulfones in 1,3-dithiane derivatives,
conformationally fixed by a cis-4,6-dimethyl (1–10) or a 5-
tert-butyl substitution (11–20). Chair conformations with
equatorial orientation of these substituents are more stable
Stereoelectronic effects have a crucial influence on molec-
ular properties such as structure, stability, selectivity and
reactivity. Their impact on the stability of specific configu-
rations and conformations, on the reactivity of compounds
and on the selectivity in chemical reactions has been studied
[
1]
in detail for most of the relevant functional groups. Espe-
cially Juaristi et al.,[ Alabugin et al., and our group
2]
[3]
[4]
have shown previously that stereoelectronic effects control
the properties of sulfides, sulfoxides, and sulfones. Never-
theless, whenever a function with a high partial charge such
as a sulfone is in the vicinity of a negative (partial) charge,
stabilisation is possible irrespective of the relative orienta-
tion of the functional groups (charge effect). A special focus
was laid on the stability of carbanions generated in situ,
which we investigated by analysis of diastereoselectivities,
of kinetics and with computational methods.[
5]
In this work we studied stereoelectronic and charge ef-
fects on pK values of sulfur-containing C–H-acidic com-
a
pounds. The measurement of equilibrium acidities of
weakly C–H-acidic compounds in dimethyl sulfoxide
(
DMSO) is well elaborated in the seminal work of Bordwell
[
6]
et al. and α-acidities of sulfides, sulfoxides, and sulfones
are listed in standard text books through their pK values.
a
Nevertheless, the influence of the relative orientation of
functional groups (C–S, S=O bonds) and the respective C–H
[
5]
bonds on the pK values has hardly been investigated.
a
[
a] Institut für Organische Chemie, Karlsruher Institut für
Technologie (KIT),
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
E-mail: joachim.podlech@kit.edu
http://www.ioc.kit.edu/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403409.
Eur. J. Org. Chem. 2015, 987–994
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
987

B. D. Süveges, J. Podlech
FULL PAPER
than axially substituted chairs by 7.20 and 11.3 kJ/mol, ues.[21] An absolute comparison of the calculated and mea-
[
8]
respectively. Furthermore, the chair conformation of these sured pK values is neither possible nor intended, because
a
substrates allows for the assignment of anionic lone pairs experimental pK values significantly higher than 14 must
a
as axial or equatorial; that is, to be in a clear orientation be regarded as approximate.
relative to stabilising bonds. α-Carbanions of compounds
ΔG*soln
1–20 are identified herein as 1–20-anion, where the indices pK (A-H) =
+ pK (Ref-H)
(1)
a
a
RTln(10)
eq and ax indicate an equatorial and axial anionic lone pair,
respectively.
Acidity is a property of the molecule, and measurement
of pK values gives no direct information on where in a
a
molecule a proton is leaving. In contrast, calculation of
acidities allows for the deprotonation of specific protons
Computation of Thermodynamic Acidities
The Gaussian 09 package[9] was used for the computa- and thus for easier accounting of the acidity. Different pKa
tion of pK values. All C–H-acidic compounds and the re- values for different protons can be calculated and given in
a
[
10]
spective carbanions were optimised with DFT (B3LYP)
this case. It should be kept in mind that a statistical correc-
[
11]
[12,13]
and MP2 methods at the 6-311++G(d,p)
level. Sin- tion of calculated pK values becomes necessary when two
a
gle-point calculations were performed with the aug-cc- or more hydrogen atoms in a molecule have approximately
pVTZ (DFT) and the aug-cc-pVDZ (MP2)[ basis sets, the same acidity.
14]
respectively. The NBO 3.1 program for natural bond orbital
Compounds 1–20 have estimated pK values of 21–36.
a
[
15,16]
analyses
was used as implemented in Gaussian 09. Recently it was reported that the MP2 method gives more
Stereoelectronic effects were quantified by deletion of the accurate results than the DFT method when pK values
a
[
22]
corresponding off-diagonal elements in the Fock matrix in above 34 are calculated.
We tested both methods for
the NBO basis. Charges were obtained as natural charges comparison of theoretical results and experimental data
from NBO calculations. All calculations were performed (Table 1).
with simulation of a DMSO solvent field, using the CPCM-
The α-acidity of compounds bearing a sulfur function
[
17]
SCRF method, which was reported to give good results (sulfides, sulfoxides, or sulfones) was expected to be ruled
[18]
in the computation of pK values in solvents.
by two parameters: (1) The orientation of the acidic C–H
a
Several quantum chemical methods have been presented bond in relation to the C–S or S=O bonds, and (2) the oxid-
[
19]
for the calculation of relative pK values of acids (A-H),
ation state of the sulfur atom; i.e., whether it is a sulfide,
a
of which the proton exchange method is most frequently a sulfoxide, or a sulfone. NBO analyses suggest that the
used and gives accurate results [Equation (1)]. Herein, the equatorial hydrogen atoms in position C-2 of most 1,3-di-
solvent-dependent free energy is compared with the experi- thiane-derived compounds should be significantly more
[20]
mental pK value of a reference acid (Ref-H). We chose acidic than the respective axial hydrogen atoms (Table 2).
a
fluorene (FH) as reference acid to enable the comparison Exceptions from this trend are observed when axial S=O
with data from two established tables with relative pK val- bonds are present in the molecule. The calculated acidity
a
Table 1. Calculated pK
values.[a]
a
Compound pK
a
μ[a] [D]
DFT (MP2)
Stabilization[b,c]
[kJ/mol]
Charge sulfur[b,d]
DFT (MP2)
1
1
2
2
3
3
4
4
5
5
6
6
7
8
8
9
9
1
1
Ǟ1-anioneq
Ǟ1-anionax
Ǟ2-anioneq
Ǟ2-anionax
Ǟ3-anioneq
Ǟ3-anionax
Ǟ4-anioneq
Ǟ4-anionax
Ǟ5-anioneq
Ǟ5-anionax
Ǟ6-anioneq
Ǟ6-anionax
Ǟ7-anionax
Ǟ8-anioneq
Ǟ8-anionax
Ǟ9-anioneq
Ǟ9-anionax
36.3 (38.8)
41.2 (42.8)
31.0 (33.0)
34.8 (35.7)
30.7 (33.0)
30.9 (32.5)
23.4 (25.5)
27.8 (29.1)
25.4 (26.8)
28.1 (29.2)
26.4 (28.3)
24.1 (25.5)
19.9 (20.9)
19.3 (20.8)
21.3 (22.4)
10.8 (11.3)
8.4 (8.7)
12.5 (13.0)
10.8 (11.1)
11.8 (11.9)
9.4 (9.3)
105.7
24.2
80.2
19.7
99.3
91.2
72.4
56.0
60.4
22.8
74.5
91.1
178.2
54.8
54.8
109.0
150.7
75.3
133.7
–0.30/–0.30
–0.42/–0.42
0.71/–0.27
0.58/–0.41
0.72/–0.31
0.59/–0.43
2.25/–0.29
2.06/–0.41
0.73/0.73
0.59/0.59
0.78/0.72
0.63/0.58
0.61/0.61
2.30/0.71
2.14/0.59
2.82/0.75
2.09/0.63
2.32/2.32
2.12/2.12
12.5 (12.8)
10.5 (10.5)
13.4 (13.9)
12.6 (13.0)
12.4 (13.2)
10.0 (10.4)
11.3 (12.0)
12.9 (13.6)
11.1 (11.5)
[
e]
[f]
[f]
18.1 (– )
12.7 (– )
17.2 (18.6)
12.3 (14.0)
14.5 (16.1)
11.1 (11.9)
13.2 (13.9)
11.3 (11.8)
0Ǟ10-anioneq
0Ǟ10-anionax
[a] Results for further derivatives are given in the Supporting Information. [b] Dipole moments, stabilisations, and charges are given for
the respective carbanions. [c] Summarised stabilisation (NBO) of the carbanionic lone pair by stereoelectronic interactions with C–S and
S=O bonds, cf. Table 2. [d] Electronic charge at the sulfur atoms. Obtained as natural charges from NBO calculations. [e] 7-anioneq was
not a minimum; see ref.[ [f] No minimum was achieved for 9-anioneq with MP2 methods.
4]
988
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Eur. J. Org. Chem. 2015, 987–994

pK
a
Values of 1,3-Dithiane Derivatives
Table 2. Stereoelectronic effects quantified by NBO analysis.[a]
Carbanion
-anioneq
-anionax
-anioneq
-anionax
-anioneq
-anionax
-anioneq
-anionax
-anioneq
-anionax
-anioneq
-anionax
n
C
Ǟσ*(S–Oeq
)
n
C
Ǟσ*(S–Oax
)
n
C
Ǟσ*(SO–Oeq
)
n
C
Ǟσ*(SO–Oax
)
n
C
Ǟσ*(S–C)
n
C
Ǟσ*(SOeq–C)
n
C
Ǟσ*(SOax–C)
n
C
Ǟσ*(SO
2
–C)
Σ
1
1
2
2
3
3
4
4
5
5
6
6
2ϫ 52.9
2ϫ 12.1
50.2
12.3
47.3
6.1
42.6
16.3
105.7
24.2
80.2
19.7
99.3
91.2
72.4
56.0
60.4
22.8
74.5
91.1
178.2
54.8
54.8
109.0
150.7
75.3
133.7
30.1
7.4
18.4
71.9
33.7
13.2
–[
b]
b]
7.4
31.3
22.5
8.4
[
–
2ϫ 4.8
2ϫ 4.4
2ϫ 25.4
2ϫ 7.0
28.1
[
b]
–
14.1
67.5
2ϫ 83.7
32.2
4.3
2ϫ 5.4
12.3
7.0
-anionax[
-anioneq
-anionax
-anioneq
-anionax
0-anioneq
0-anionax
c]
7
8
8
6.0
33.0
22.4
50.5
2ϫ 12.6
2ϫ 52.1
24.4
7.7
24.4
5.2
23.5
7.6
2ϫ 25.0
2ϫ 9.4
–[
b]
b]
b]
8.9
[
9
9
38.0
86.0
–
25.1
6.6
[
–
1
1
2ϫ 5.4
2ϫ 5.4
[
a] In kJ/mol. [b] Values below a threshold of 4.2 kJ/mol were not determined. [c] 7-anioneq was not a minimum; see ref.[4]
difference in the axial sulfoxide 3 (Ǟ 3-anion : pK = 30.7; fects seem to retreat into the background in the higher oxi-
eq
a
Ǟ3-anion : 30.9) is negligible. Both carbanions 3-anion
dised compounds in favour of charge effects. Although the
ax
eq
and 3-anionax are stabilised by stereoelectronic interactions stereoelectronic effects in carbanions 8-anioneq and 8-
to about the same extent (99.3 vs. 91.2 kJ/mol). In the equa- anionax are identical (54.8 kJ/mol), a significantly higher
torial/axial bis-sulfoxide 6, where the axial hydrogen is more acidity for the equatorial proton was calculated (pK = 19.3
a
acidic than the equatorial hydrogen (pK = 24.1 vs. 26.4), vs. 21.3). This effect is clearer in tetroxide 10, which is pref-
a
the summarised anion-stabilising stereoelectronic effects in erentially deprotonated in the equatorial position (pK =
a
6-anionax are higher than those in 6-anioneq [91.1 vs. 12.3 vs. 14.5), albeit with the axial carbanion 10-anionax
7
4.5 kJ/mol] because the n Ǟσ* stabilisation in 6- being significantly better stabilised by stereoelectronic ef-
C
S–O
anionax exceeds the two dominant n Ǟσ*S–C interactions fects (133.7 vs. 75.3 kJ/mol). Although trioxide 9 breaks this
C
in 6-anioneq (Table 2). Charge effects seem to be of minor trend, for the higher oxygenated compounds it is still no-
relevance in α-carbanions of sulfoxides; a significant charge ticeable that the difference of the pK values in 9 are much
a
at the sulfur atom would similarly stabilise an axial and an smaller for the two modes of deprotonation (ΔpK = 0.9)
a
equatorial lone pair and would thus lead to similar acidities than for most other compounds in this investigation. The
irrespective of the relative orientation of S=O or C–S importance of charge effects in comparison to stereoelec-
[23]
bonds.
tronic effects has recently been shown for S 2 reactions .
N
Dipole moments of the carbanions seem to have no sig- Stereoelectronic interactions are furthermore reflected in
nificant influence on the calculated acidities, and they structural parameters, especially bond length. These data,
hardly differ for the carbanions with axial and equatorial which are in full agreement with our interpretation, are
lone pairs. The respective carbanions with the lower dipole given in the Supporting Information.
moments always correspond to the less acidic C–H bonds,
except of bis-sulfoxide 6 and trioxide 9.
As a general but not striking trend in these dithiane de-
rivatives, we observed a deprotonation leading to these
Measurement of Thermodynamic Acidities
carbanions for which the summation of the relevant stereo-
The pK values of compounds 4–6 were determined with
a
electronic effects describes a better stabilisation. This is true a modification of the spectrophotometric method using
for compounds 1–6 and 9, but is not for trioxide 8 or tetrox- overlapping indicators developed by Bordwell et al.[ The
ide 10. In the axial sulfoxide 3, where stereoelectronic ef- method is based on a titration yielding the equilibrium con-
fects are very similar for the respective carbanions 3-anioneq stant Keq of the transprotonation between indicator (Ind-
and 3-anionax (99.3 vs. 91.2 kJ/mol), we calculated virtually H) and investigated C–H-acidic compound (A-H). Titration
identical acidities for the equatorial and the axial proton is started by using up the employed dimsyl potassium [pre-
24]
(
pK = 30.7 vs. 30.9, see above). These stereoelectronic ef- pared by deprotonation of dimethyl sulfoxide (DMSO) with
a
Eur. J. Org. Chem. 2015, 987–994
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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989

B. D. Süveges, J. Podlech
FULL PAPER
potassium hydride] with the indicator (Scheme 1). Back ti- applied analysis was confirmed by investigation of sub-
tration with small aliquots of the C–H-acidic compound stances with known pKa values from the literature. We
[27]
allowed for a UV/Vis spectroscopic determination of the chose acetophenone (pK = 24.7) and indole (21.0)
be-
a
concentration of the indicator. Decrease of the absorption cause their acidities are in the same range as those expected
provided enough data points for a calculation of the pKa for the compounds of interest. The acidity of the indicator
value. All titrations were performed in DMSO using should differ from that of the investigated compound by no
fluorene-based indicators with strict exclusion of oxygen more than 2 pK units. Consequently, we chose FH (pK =
a
a
[
27]
[27]
[27]
and water.
22.6 ) and tBuFH (24.4 ) for acetophenone (24.7 ),
and MFH (22.3 ) for indole (21.0[27]).
[27]
Results for indole match the published values perfectly
(
Table 3), whereas first experiments with acetophenone led
–
Scheme 1. Titration of the deprotonated indicator (Ind ) with the to irreproducible and in some cases not even analysable re-
investigated acid (A-H).
sults. Fluorene, which had been repeatedly used for pKa
measurements, is prone to a disturbing side reaction (see
[
25,26]
above) under the applied conditions.
This side reac-
In a variation of Bordwell’s method, we performed the
measurements in a (longer) 5 cm spectrophotometer cell
with a three-way stopcock and a septum. This allowed the
tion, the nature of which could not be determined, is signifi-
cantly reduced with shorter reaction times (and did not oc-
cur with 9-substituted fluorenes). Performing the measure-
–
5
–6
use of lower concentrations (10 –10 mmol/L instead of
–
3
–4
ment as rapidly as possible led to the determination of pKa
1
0 –10 mmol/L) and thus smaller amounts of the sub-
values that are in excellent agreement with published values
strates. On the one hand, this reduced the occurrence of
contact ion pairs but, on the other hand, entailed the risk
of an enhanced sensitivity for side reactions. With fluorene
(Table 3).
Table 3. Experimentally determined pK
exp.)
values.[a]
a
(FH) as indicator, we observed a new absorption band at
558 nm resulting from an unidentified side product (see the
pK
a
[b]
(
(calcd.)
(ref.)
Supporting Information). Steiner et al. previously men-
[
27]
tioned the occurrence of this absorption at higher concen- Acetophenone
24.7
21.0
21.4
22.3
22.5
–
–
–
–
–
22.1
18.2
24.7
21.0
–
[
27]
[
25]
Indole
trations and hints on this side reaction are present in the
23.4[
c]
c]
c]
literature, but have not been commented on.[26]
4
5
6
[
25.4
–
–
24.1[
[
5]
5]
2
2
1
5
25.4
24.0
40.9
26.4
17.8
22.0
22.0
24.9
39
29.0
18.2
23.5
[
6
,3-Dithiane[
d]
[28]
-SMe[
d]
d]
[28]
[29]
[30]
Me-SO-CH
As a consequence of the smaller concentrations used in Ph-SO-CH
Ph-SO -CH
2
[
2
-SOPh
-SMe[
d]
–
our protocol, the molar absorption coefficient (extinction
coefficient) needed to be determined in a separate measure- [a] The pK
2
2
a
values are reproducible to Ϯ0.5 units. [b] Calculated
with the DFT method (see above). [c] See Table 1. [d] These data
were included for comparison.
ment. Determination during the titration as in Bordwell’s
method would have led to inaccurate results with our proto-
col. The pKa values were determined by using Equa-
tions (2), (3), (4) and (5); a detailed deviation is given in the
Supporting Information.
The optimised protocol was used for measuring pK val-
a
ues of compounds 4–6. Quantum chemical calculations (see
above) allowed their acidities to be estimated and thus suit-
able indicators could be chosen that are within the limit of
Ind-H]eq·[A–]eq
Ind–]eq·[A-H]eq
[
[
K
eq
=
(2)
(3)
2
pK units.
a
A ]eq = [Ind–]eq – [Ind–]
–
All measurements were performed at least in duplicate
at different days with freshly prepared dimsyl potassium).
Every run generally provided at least six expedient Keq val-
(4) ues for every absorption maximum. Keq was calculated as
[
[
x
(
Abs
Ind–]eq
=
ε·d
the mean of all available values and was used in that form
for the calculation of the pK values. Deviation of the pKa
values obtained from different runs did not usually exceed
a
pK
a
(A-H) = pK
a
(Ind-H) – logKeq
(5)
Equation (5) reflects the observed equilibrium concentra- 0.5, which seems to be the maximum error made in these
tions given in Equation (2) and Equation (3). Every ad- experiments, when performed thoroughly. Compounds 4–6
dition of acid leads to a decrease of the indicator absorp- were surveyed with MFH, because this indicator gives rise
tion, and correlates directly with the concentration of the to UV absorptions with three maxima at 482, 516, and
deprotonated acid. This approximation (3) and Equa- 555 nm (Figures 1 and 2). Those above 500 nm were not
tion (4) enable a calculation of the pK value of the investi- superimposed by the absorbance of other compounds and
a
gated acid. The validity of the employed method and the were suitable for further analysis.
990
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a
pK Values of 1,3-Dithiane Derivatives
Figure 3. Absorbance of MFH during the addition of sulfone 4.
Figure 1. Absorbance of MFH during the addition of bis-sulfoxide 5.
an impact on the stability of the molecule and thus on the
thermodynamics of the deprotonation, are not significant.
Most of the effects countervail the others, but it should be
noted that a σC–HǞσ*S–C is significantly reduced when the
sulfur in this interaction is part of an axial sulfoxide group.
This leads to a reduced stability of sulfoxides 3 and 6 in
comparison with 2 and 5, respectively, and results in quite
similar pK values (2 is 2.8 kJ/mol more stable than 3; 5 is
a
9.9 kJ/mol more stable than 6). The higher acidity of sulf-
one 4 is not controlled by stereoelectronic effects, which are
again quite similar (72.4 kJ/mol) to those for 5 and 6, but
is ruled by charge effects because the charge of the sulfur
of the sulfone is significantly higher than that of the charges
of the sulfur atoms in a bis-sulfoxide (Table 1). The mea-
sured pK values of 5 and 6 are in good agreement with
a
those published for the conformationally flexible com-
Figure 2. Absorbance of MFH during the addition of bis-sulfoxide 6.
[7]
pounds 25 (pK = 22.0, Table 3) and 26 (24.9). Whereas
a
2
5 can be expected to be in a conformation (and have a
[
34]
stability) that is similar to that of 5 (cf. Ref. ), it seems to
be likely that 26 is somewhat more flexible and thus deviat-
ing from the rigid bis-sulfoxide 6. Nevertheless, calculation
An experimental pK value of 22.3 was determined for
a
bis-sulfoxide 5. Only data from maxima above 500 nm were
employed in the measurements when deviating values were
obtained from the maximum at approximately 480 nm.
of the most relevant n Ǟσ*
interaction in both com-
C
S–O(ax)
pounds showed a similar stabilisation in both compounds
6: 67.5 kJ/mol; 26: 61.1 kJ/mol).
With this, a pK value of 22.5 was obtained in both runs
a
(
for bis-sulfoxide 6.
The deviation of calculated and experimental pK values
a
(see below) prompted us to check the general trend of the
calculated pK values. For this we additionally determined
a
the acidity of sulfone 4 (Figure 3). From four runs we deter-
mined a pK value of 21.4, which is in line with the calcu-
a
lated value (23.4).
It should be kept in mind that the determination of pKa
values for very weakly acidic compounds does not generally
yield accurate numbers. This is true not only for an experi-
Kinetics of Michael-Type Addition Reactions
Previous kinetic investigations reported by Ulshöfer et
mental determination but also for computational methods, al. showed that Michael-type additions to axially and equa-
which are similarly calibrated with experimental values. torially oxygenated alkylidene sulfoxides are determined by
Nevertheless, relative pK values should be very meaning- stereoelectronic effects in the carbanions generated in situ
a
[
31]
ful. The measured pK values for bis-sulfoxides 5 and 6 are (Scheme 2).
a
almost identical, which correlates with the very similar
An axial sulfoxide group (in 32) leads to a preferential
stereoelectronic stabilisations in both of the respective carb- attack of piperidine from the bottom side of the alkene (dr
anions (60.4 vs. 74.5 kJ/mol). Stereoelectronic interactions 85:15), giving rise to the formation of an axial lone pair
in the corresponding protonated species 5 and 6, which have anti to the sulfoxide, stabilised by an n Ǟσ*
interaction.
991
C
S–O
Eur. J. Org. Chem. 2015, 987–994
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org

B. D. Süveges, J. Podlech
FULL PAPER
1
integration of the relevant signals in the H NMR spectra
over several weeks. Unfortunately, a detailed and quantita-
tive analysis was not possible because essential signals were
covered by solvent signals. Complete H/D exchange was ob-
served within a few days for compounds 5 and 6, whereas
no exchange could be detected for monosulfoxide 2. The
qualitative determination of the kinetic acidities is in line
with the thermodynamic acidities; that is, the smaller the
pK value, the higher the kinetic acidity.
a
Comparison of Calculated and Experimental pK Values
a
Scheme 2. Nucleophilic addition reactions to oxygenated 2-methyl-
idenedithiane derivatives.
We observed a reduced correlation of calculated and
measured pK values for compounds with a high dipole mo-
a
ment of the corresponding base (see above), a finding that
Transprotonation of the zwitterion 36-zi yields the equato-
rial product 36. Sulfoxide 33, with an equatorial S=O
group, is preferentially attacked from the top (dr 80:20).
The thus evolving equatorial lone pair (39-zi) is stabilised
[
33]
has been mentioned previously.
Nevertheless, no clear
trend in this dependency could be recognised. A selection
of calculated and experimentally determined pK values is
a
given in Table 4 together with the respective dipole mo-
ments.
by two n Ǟσ*
interactions (Ǟ 39). Since the former
C
C–S
stabilisation is significantly higher than the latter, a 100-
fold faster reaction of sulfoxide 32 than of 33 had been
observed.
[
31]
Table 4. Comparison of pK
a
values.
pK
a
Δ (pK
a
)[a]
μ [D][b]
Nevertheless, addition of piperidine to sulfone 31 does
not seem to be controlled by stereoelectronic effects in this
case. Although stereoelectronic stabilisation in the evolving
zwitterion 34-zi has about the same magnitude as in the
anion formed in the addition of piperidine to sulfoxide 32,
reaction of 31 is even faster. Whereas a complete turnover
of equatorial sulfoxide 33 was achieved within 71 hours and Indole
axial sulfoxide 32 reacted within 5 hours, we observed a Acetophenone
complete reaction of sulfone 31 at room temperature within
(
DFT)
(exp.)
c]
c]
c]
4
5
6
4
4
23.4[
21.4
22.3
22.5
30.7
–2.0
–3.1
–1.6
3.0
12.5
13.4
10.0
5.6
0.7
4.6
11.0
0.5
3.2
[
25.4
24.1[
0Ǟ40-anioneq
0Ǟ40-anionax
27.7
30.9
18.2
22.1
22.1
27.4
21.0
24.7
22.3
27.9
2.8
2.6
0.2
0.5
MFH
9
-Phenylxanthene
seconds when the reaction was performed in deuterated
1
a a a
[a] Δ (pK ) = pK (exp.) – pK (DFT). [b] Dipole moments of the
respective carbanions. [c] See Table 1.
methanol (monitored by H NMR spectroscopy). The
equatorially substituted product 34 was formed exclusively
in this reaction. Even when performed at –78 °C or in the
less polar solvent [D]chloroform, the reaction was still too
fast to be monitored by using NMR spectroscopy. Al-
though stereoelectronic effects contribute to the stability of
the carbanion on the sulfone, they seem to be significantly
outweighed by charge effects; that is, the evolving negative
charge next to the sulfur function is stabilised irrespective
of whether the nucleophile approaches from the top or the
bottom of the acceptor. The stereoselectivity might then be
a consequence of steric effects.
Deviation is highest for 40-anion , indole, and aceto-
eq
phenone (2.6–3 pK units), where the corresponding carb-
a
anions have a calculated dipole moment above 4.5 D. 40-
anionax and the anions of MFH and 9-phenylxanthene have
dipole moments below 3.2 D and give more accurately cal-
culated pK values. Possibly, a higher dipole moment leads
a
to a wider and/or tighter solvation shell, which is less accu-
rately described by the simulation using the CPCM-SCRF
method. Further examples corroborating this trend are
given in the Supporting Information.
Kinetic Acidities
To verify the results of the thermodynamic equilibrium
pK values, we determined kinetic acidities by measuring
a
rates for the H/D exchange in the 2-position of compounds
2, 5 and 6. This also allowed the kinetic acidities of the
mono and bis-sulfoxides to be compared. H/D exchange
was performed with D O, where the solubility was in-
2
creased by addition of [D ]DMSO as co-solvent. 1,4-Diaza-
6
bicylo[2.2.2]octane (DABCO) was used as exchange cata-
lyst, similar to quinuclidine which was employed pre-
[
32]
viously. The reaction was monitored by observation and
992
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 987–994

a
pK Values of 1,3-Dithiane Derivatives
solid (16.5 g, 59 mmol, 99%) that was sufficiently pure for the fur-
Conclusions
1
3
ther transformation. H NMR (300 MHz, CDCl
3
): δ = 1.28 (d, J
3
The calculation of C–H acidities of conformationally = 6.9 Hz, 6 H, 2ϫCH ), 1.32–1.36 (m, 1 H, 5-H ), 2.12 (dt, J =
3
eq
3
3
3
3
fixed oxygenated 1,3-dithiane derivatives with DFT meth- 13.8, J = 2.2 Hz, 1 H, 5-Hax), 2.91 (dqd, J = 13.8, J = 6.9, J =
), 7.42–7.47 (m, 2
ods showed that pK values are controlled by stereoelec- 2.2 Hz, 2 H, 4-H, 6-H), 4.67 (s, 3 H, 2-H, OCH
2
a
H, Ph), 7.53–7.59 (m, 1 H, Ph), 8.06–8.10 (m, 2 H, Ph) ppm.
tronic effects and by charge effects. The relative orientation
of the acidic proton and the stabilising S=O or S–C bonds
affect the acidities significantly. Stereoelectronic stabilisa-
rac-(1S,2S,4S,6R)-(Dimethyl-1-oxo-1,3-dithiane-2-yl)methyl Benzo-
ate: meso-(2S,4S,6R)-Dimethyl-1,3-dithiane-2-ylmethyl benzoate
tion is important for sulfides and sulfoxides, whereas charge (16.5 g, 59 mmol) was added to THF (100 mL). NaIO4 (12.8 g,
effects are dominant in sulfones. Deprotonation of the 60 mmol) in H O (100 mL) was added and the mixture was stirred
equatorial proton is favoured for most of the investigated for 64 h at room temp. The precipitate was filtered off and CH Cl
(10 mL) were added to
the residue. The aqueous layer was extracted with CH Cl (3ϫ
00 mL) and the organic layers were dried (Na SO ) and concen-
trated. Column chromatography (silica gel; CH Cl /MeOH, 50:1 to
0:1) gave a yellowish solid (13.7 g, 46.0 mmol, 78%). H NMR
2
2
2
(
50 mL) and saturated aqueous NaHCO
3
compounds, with the equatorial/axial bis-sulfoxide 6 being
the only exception. These findings are supported by mea-
surements of the thermodynamic and kinetic acidities of
several 1,3-dithiane derivatives, for which a modified proto-
col of Bordwell’s method has been developed.
2
2
1
2
4
2
2
1
2
(
3
300 MHz, [D
6
]acetone): δ = 1.20 (d, J = 6.9 Hz, 3 H, 4-CH
3
),
3
2
3
1
.40 (d, J = 6.8 Hz, 3 H, 6-CH ), 1.90 (ddd, J = 14.9, J = 11.8,
J = 11.8 Hz, 1 H, 5-Heq), 2.38 (ddd, J = 14.9, J = 2.5, J =
3
3
2
3
3
3
3
3
Experimental Section
ax
2.5 Hz, 1 H, 5-H ), 2.93 (dqd, J = 11.5, J = 6.9, J = 2.5 Hz, 1
H, 4-H or 6-H), 3.38 (dqd, J = 11.5, J = 6.8, J = 2.6 Hz, 1 H,
3
3
3
The preparation of compounds 1–6, 8, and 10–16, 18 and 20 has
3
3
6
-H or 4-H), 4.37 (dd, J = 4.4, J = 3.2 Hz, 1 H, 2-H), 4.81 (dd,
[
34]
been published.
2
3
2
3
a b
J = 12.2, J = 3.2 Hz, 1 H, OCH H ), 4.91 (dd, J = 12.2, J =
1
General: H NMR spectra were recorded with a Bruker AVANCE 4.4 Hz, 1 H, OCH H ), 7.50–7.59 (m, 2 H, Ph), 7.65–7.70 (m, 1 H,
a
b
3
00 and 13C NMR spectra with a Bruker Avance 400. pK
a
values
Ph), 8.02–8.07 (m, 2 H, Ph) ppm.
were measured with a spectrophotometer Cary 60 from Agilent
Technologies. IR spectra were recorded with a Bruker ALPHA in
the ATR modus and mass spectra with a Finnigan MAT-95. Gedu-
ran SI 60 silica gel was used for purification by column
chromatography.
rac-(2S,4S,6R)-(Dimethyl-1,1-dioxo-1,3-dithiane-2-yl)methyl Benzo-
ate:
benzoate (10.6 g, 35.0 mmol) was added to a mixture of acetone/
O (25:1, 100 mL). The mixture was cooled to 0 °C, KMnO
11.7 g, 73.0 mmol) was added and the mixture was stirred for 27 h
at room temp. The precipitate was removed by filtration and the
solid was washed with CH Cl (100 mL). The combined organic
layers were dried (Na SO ) and concentrated. Column chromatog-
raphy (silica gel; hexane/ethyl acetate, 1:1) gave a white solid
rac-(1S,2S,4S,6R)-(Dimethyl-1-oxo-1,3-dithiane-2-yl)methyl
®
H
2
4
(
9-Methylfluorene (MFH): nBuLi (1.6 m in hexane, 5.28 mL,
8.44 mmol) was added under an Ar atmosphere at –78 °C to a solu-
2
2
tion of fluorene (FH, 1.08 g, 6.49 mmol) in THF (25 mL). MeI
0.61 mL, 9.74 mmol) in THF (5 mL) was added dropwise within
0 min. The mixture was allowed to come to room temp. and the
reaction was quenched with saturated aqueous NH Cl (10 mL).
The aqueous phase was extracted with CH Cl (3ϫ 15 mL) and
the combined organic layers were dried (Na SO ), concentrated,
2
4
(
1
1
(
1
CH
2
6.96 g, 22.2 mmol, 63%). H NMR (300 MHz, [D
4
]MeOH): δ =
), 1.32 (d, J = 6.8 Hz, 3 H, 6-
3
), 2.18 (ddd, J = 14.4, J = 11.9, J = 11.9 Hz, 1 H, 5-Heq),
3
3
4
.26 (d, J = 6.9 Hz, 3 H, 4-CH
3
2
3
2
2
2
3
2
4
.32 (ddd, J = 14.4, J = 2.7, J = 2.7 Hz, 1 H, 5-Hax), 3.34–3.53
m, 2 H, 4-H, 6-H), 4.69 (dd, J = 12.1, J = 5.8 Hz, 1 H, OCH-
and purified by column chromatography (silica gel; hexanes/
EtOAc, 20:1) to give MFH (1.16 g, 6.43 mmol, 99%) as a white
solid.
2
3
(
3
3
a
H
b
), 4.82–4.86 (m, 1 H, OCH
a b
H ), 4.97 (dd, J = 5.5, J = 5.4 Hz,
1
H, 2-H), 7.46–7.51 (m, 2 H, Ph), 7.60–7.65 (m, 1 H, Ph), 8.04–
9
-tert-Butylfluorene (tBuFH): Freshly prepared[35] tBuMgCl (1 m in
8.07 (m, 2 H, Ph) ppm.
THF, 22.2 mL, 22.2 mmol) was added slowly under an Ar atmo-
sphere at –78 °C to a solution of fluorenone (2.00 g, 5.54 mmol) in
THF (10 mL). After stirring for 3 h at –78 °C and for 1 h at 0 °C,
rac-(4S,6R)-4,6-Dimethyl-2-methylene-1,3-dithiane
1,1-Dioxide
(
31): rac-(2S,4S,6R)-(Dimethyl-1,1-dioxo-1,3-dithiane-2-yl)methyl
benzoate (804 mg, 2.56 mmol), DBU (1.19 g, 7.68 mmol) and
tBuOH (1 mL) were added to CH Cl (25 mL). After stirring for
h at room temp., the reaction was quenched with H O (20 mL)
and 1 n HCl (10 mL). The organic layer was washed with 1 n HCl
20 mL) and saturated aqueous Na CO (3ϫ 20 mL, heated to
5 °C and cooled before addition), dried (Na SO ), and concen-
trated. Column chromatography (silica gel; hexane/ethyl acetate,
the reaction was quenched by addition of H
rated aqueous NH Cl (5 mL). Brine (15 mL) was added and the
aqueous phase was extracted EtOAc (3ϫ 20 mL). The organic lay-
ers were dried (Na SO ), concentrated, and purified by column
2
O (5 mL) and satu-
2
2
4
2
2
2
4
(
2
3
chromatography (silica gel; hexanes/EtOAc, 40:1) to give 9-
hydroxy-9-tert-butylfluorene (875 mg, 3.67 mmol, 66%) as white
crystals. This alcohol was reduced according to a published proto-
7
2
4
1
1
:1) gave 31 (328 mg, 1.71 mmol, 67%) as a white solid. H NMR
[
36]
col.
Column chromatography (silica gel; hexane) gave tBuFH
3
(
300 MHz, CDCl
J = 6.8 Hz, 3 H, 6-CH ), 2.24 (ddd, J = 14.8, J = 2.8, J =
3
3
): δ = 1.27 (d, J = 6.8 Hz, 3 H, 4-CH
3
), 1.41 (d,
(789 mg, 3.58 mmol, 98%) as a white solid.
3
2
3
3
2
3
3
meso-(2S,4S,6R)-Dimethyl-1,3-dithiane-2-ylmethyl Benzoate: meso-
2R,4S)-Pentane-2,4-dithiole (8.03 g, 59.0 mmol) and 2-oxoethyl
benzoate (10.8 g, 66.7 mmol) were added to CH Cl (100 mL).
Me SiCl (19.2 g, 177 mmol) was added and the mixture was stirred
and heated to reflux for 96 h, then poured into 1 n HCl (10 mL),
and saturated aqueous NaHCO (100 mL) was added carefully. The 58.7 (d), 127.8 (t), 144.6 (s) ppm. IR (ATR): ν˜ = 3097 (w), 3002
aqueous phase was extracted with CH Cl (3ϫ 50 mL). The or- (w), 2969 (w), 2916 (w), 1289 (s), 1145 (s), 962 (m), 800 (m), 742
ganic layers were dried (Na SO ) and concentrated to give a white
2.3 Hz, 1 H, 5-Heq), 2.50 (ddd, J = 14.8, J = 11.9, J = 11.8 Hz,
1 H, 5-Hax), 3.13 (dqd, J = 11.9, J = 6.8, J = 2.8 Hz, 1 H, 4-H
or 6-H), 3.35 (dqd, J = 11.8, J = 6.8, J = 2.3 Hz, 1 H, 6-H or 4
3
3
3
(
3
3
3
2
2
1
3
3
H), 6.12 (s, 1 H, 1Ј-H
a b
), 6.57 (s, 1 H, 1Ј-H ) ppm. C NMR
(100 MHz, [D ]MeOH): δ = 11.7 (q), 20.3 (q), 41.8 (d), 45.8 (d),
4
3
2
2
–
1
2
4
(m), 686 (s), 634 (m) cm . UV/Vis (CH
2
Cl
2
): λmax = 272 nm. MS
Eur. J. Org. Chem. 2015, 987–994
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org 993

B. D. Süveges, J. Podlech
FULL PAPER
+
(EI, 20 °C): m/z (%) = 192 (47) [M ], 113 (80), 55 (100). HRMS:
Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian 09,
revision A.02, Gaussian, Inc., Wallingford CT, 2009.
m/z calcd. for C 192.0279; found 192.0276.
7 12 2 2
H O S
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Received: November 16, 2014
Published Online: December 23, 2014
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