Development of a Robust Protocol for the Determination of Weak Acids' p KaValues in DMSO

Article abstract of DOI:10.1021/acs.joc.0c00909

Two methods for the determination of pKa values of weak acids are described, a direct titration with dimsyl potassium in the presence of an indicator and a back-titration in which an analyte/indicator mixture is deprotonated and then titrated with ammonium chloride. Both methods have been validated by measuring pKa values of compounds, for which values had been determined previously. The back-titration method was applied to measure pKa values of two 1,3-dithiane-derived bissulfoxides and a monosulfone.

Full text of DOI:10.1021/acs.joc.0c00909

Subscriber access provided by University of Glasgow Library
Note
Development of a Robust Protocol for the
a
Determination of Weak Acids’ pK Values in DMSO
Sebastian Jung, and Joachim Podlech
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00909 • Publication Date (Web): 17 Jul 2020
Downloaded from pubs.acs.org on July 18, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Development of a Robust Protocol for the
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
Determination of Weak Acids’ pKa Values in DMSO
Sebastian Jung, Joachim Podlech*
Institut für Organische Chemie, Karlsruher Institut für Technologie (KIT), Fritz-Haber-Weg 6,
76131 Karlsruhe, Germany
joachim.podlech@kit.edu
RECEIVED DATE
Title Running Head: Determination of pKa Values
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
1

The Journal of Organic Chemistry
Page 2 of 34
Abstract: Two methods for the determination of pKa values of weak acids are described, a
direct titration with dimsyl potassium in the presence of an indicator and a back titration in which
an analyte/indicator mixture is deprotonated and then titrated with ammonium chloride. Both
methods have been validated by measuring pKa values of compounds, for which values had
been determined previously. The back titration methods was applied to the measuring of pKa
values of two 1,3-dithiane-derived bissulfoxides and a monosulfone.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Keywords: C–H acidity / pKa values / Titration / UV absorption / Dithianes
A precise knowledge of pKa values significantly facilitates the understanding of organic
reactions including their thermodynamics, kinetics, their reaction mechanisms, and the resulting
selectivities.1
During our continuous efforts in the investigation of stereoelectronic effects in sulfur-based
functional groups,2-9 we measured and calculated pKa values6 of thiane- and dithiane-derived
sulfide, sulfoxide, and sulfone anions.4 Herein we present a simple and general method for the
measurement of pKa values of weakly C–H-acidic compounds.
ACS Paragon Plus Environment
2

Page 3 of 34
The Journal of Organic Chemistry
Only a small fraction of organic acids (AH) show strong acidities which can be determined in
1
2
3
4
5
6
7
8
9
aqueous solution. Since the early 1930s efforts were made to expand the acidity scales beyond
pKa = 14. In their seminal work Conant and Wheland presented the definition of relative pKa
values not dependent on the proton concentration; they can be expressed without explicit
consideration of the used solvent. The pKa value is here calculated relative to the known pKa
value of an indicator (IndH).10
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
‒
The balance between an indicator and a base (A ) leads to an equation allowing for the
calculation of the conjugate acid’s (AH) pKa value from the (known) indicator’s pKa value and
the equilibrium constant K. (A stepwise deviation of the relevant equations is given in the
Supporting Information.)
K
Ind + AH
IndH + A
pKa (AH) = pKa (IndH)  log(K)
Determination of pKa values is thus possible by measuring of the equilibrium concentrations
of the conjugate acids and bases of the analyte and an indicator with known pKa. Although the
solvent does not appear in these equations, it has an influence on the absolute and relative pKa
values of acids. Depending on the charge states of the acids and conjugate bases, the polarity
of the solvent and the ability to act as hydrogen bond acceptor or donor can shift the pKa values
for several orders of magnitude. For this reason pKa values of weak acids have been determined
ACS Paragon Plus Environment
3

The Journal of Organic Chemistry
Page 4 of 34
in various solvents, mostly in DMSO,1 in acetonitrile,11 in N,N-dimethylformamide (DMF),12 and
in cyclohexylamine.13 An excellent overview on this work has been given by Leito et al.14
The determination of weak acids’ pKa values was dominated by the tremendous amount of
work finished by Bordwell et al., who determined the acidity in DMSO of more than 1000
compounds.1 They used indicators whose deprotonated anions show absorbance in UV/Vis
spectra, allowing a spectroscopic measurement of their concentrations according to the Beer–
Lambert law. An indicator can only be used for pKa value determinations in a range of ±2 units
around its own pKa value. After the pKa scale in DMSO was established with the first measured
compounds, it could be expanded by the utilization of new indicators overlapping in its applicable
pKa range with the respective ranges of previously used indicators (Figure 1).15 This strategy is
now known as the overlapping or bracketing indicator method.16
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R
3
1
O
S
S
S
O
O
O
S
2
S
S
O
O
pKa Indicator range
R
Me
tBu
CH2tBu
Ph
4
MFH ( )
22.3
24.4

20.3 24.3
5
tBuFH ( )

22.4 26.4
18.322.3
15.919.9
6
NpFH ( ) 20.3
7
PhFH ( ) 17.9
Figure 1. Investigated Compounds 1–3. The Indicators 4–7 are Applicable in the Given pKa
Ranges.
ACS Paragon Plus Environment
4

Page 5 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Unfortunately, Bordwell’s method is (to the best of our knowledge) documented rather sparsely
15
in their publications. The possibly most detailed description is given in Ref.
and a short
summary hereof is given in the Supporting Information. A key feature of Bordwell’s method is its
generality. Any substance that can be deprotonated in equilibrium and being transparent at the
observed wavelengths can be measured. As the concentration of the analyte is smaller than the
concentration of the indicator, the rates of side reactions and effects of homoconjugation
(homoassociation)17 are reduced.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Alternative procedures have been reported by O'Donoghue18 and Leito.11, 19-24 Nevertheless,
these procedures were either not used for the determination of very high pKa values or the
analyte (anion) needs to show UV absorption. Furthermore, we considered the necessity of
performing the respective measurements in a glove box22-24 an inconvenient limitation.
Our own efforts to reproduce the protocol of Bordwell by using a quartz cell with a Schlenk
stopcock and gas-tight syringes ran more than disappointing. It turned out that gravimetric
determination of volumes gave erratic results due to variable argon pressures. Furthermore,
each removal from the argon line caused small contaminations with air. Even the very simple
punching of a needle trough the septum led to a significant decrease of absorbance, obviously
ACS Paragon Plus Environment
5

The Journal of Organic Chemistry
Page 6 of 34
due to introduction of oxygen. Another issue was a contamination of all DMSO solutions (except
for the DimK solution) with tiny amounts of ubiquitous acid. (Leito similarly reported the presence
of acidic contaminations in acetonitrile.23) Consequently, we envisioned a protocol mostly
avoiding these detrimental issues, allowing pKa measurements of very weak acids using
conventional laboratory equipment.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Direct Titration of Analyte/Indicator Mixtures. If a DimK solution of known concentration is
successively added to an analyte/indicator mixture, the acid dissociation constant K can be
calculated from the increase of absorbance. Ubiquitous acid contaminations do not interfere, as
long as the pKa values of these acids are considerably smaller than the analyte’s pKa value. A
small fraction of the initially added DimK solution neutralizes these contaminants before the
analyte/indicator equilibration is reached. As the base is added via syringe, its amount can be
measured volumetrically. No connecting/disconnecting of any part is necessary and a possible
contamination with oxygen is minimized. To reduce weighing errors in the alignment of the
analyte/indicator ratio we always used 1:1 mixtures. Each addition results in a data point,
allowing the calculation of a value for K. The instability of the DimK solution made an
independent determination of its concentration impractical; its concentration was instead
obtained by a curve fitting process if a sufficient number of data points is available. Four data
ACS Paragon Plus Environment
6

Page 7 of 34
The Journal of Organic Chemistry
points are the minimum number to fit the four parameters used in the final equation, while an
error can only be estimated with eight data points. Even more data points are preferable,
especially when the pKa value difference between analyte and indicator is large. Deviation of
the relevant equations is given in the Supporting Information.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
As indicators we used fluorene derivatives 4‒7, for which pKa values were provided by
Bordwell et al.15, 25 With MFH (4) as indicator, the published pKa value of indole was reproduced
with good accuracy (deviation <0.1 units). However, a significant attrition of the glass syringes
used for addition of DimK solution was observed. Following each addition of base, no further
change of the equilibrium was observed after 30–60 seconds, which allowed a rapid acquisition
of data points. With pyrrole, dithiane derivatives 1‒3, and other compounds it lasted more than
three minutes to reach the respective equilibria. In these cases non-satisfying fits were obtained
due to a decrease of the DimK concentration during the experiment. For these compounds an
alternative procedure was developed.
Back Titration of Analyte/Indicator Mixtures. A mixture of quantitatively deprotonated indicator
and analyte can be stored without deterioration much longer in the quartz cell than the DimK
solution can be kept in the syringe. Firstly, quartz is considerably less sensitive towards alkaline
solutions than the syringe’s glass and secondly, the conjugated bases are thermodynamically
ACS Paragon Plus Environment
7

The Journal of Organic Chemistry
Page 8 of 34
less basic and thus more stable than the dimsyl anion. This alternative protocol is initiated by
rapid addition of DimK solution to the analyte/indicator mixture until maximum absorbance is
reached. The actual measurement is then performed by portionwise addition of a proton source,
where we used an ammonium chloride solution. This proton donor is transparent in its
protonated and deprotonated states and seems to be not prone to detrimental side reactions.
The relevant equations are again given in the Supporting Information.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MFH (4), tBuFH (5), and PhFH (7) were synthesized by slight modification of published
protocols;26-27 particularly the purification processes were improved to obtain compounds of high
purity (Scheme 1). The published synthesis of 9-neopentylfluorene (NpFH, 6) required harsh
conditions and gave low yields.28 We considered a method published by Katz et al. for the
synthesis of similar compounds more useful:29 Condensation of fluorene (8) with pivaldehyde
and subsequent hydrogenation furnished NpFH (6) with high purity.
Scheme 1. Synthesis of Indicators.
ACS Paragon Plus Environment
8

Page 9 of 34
The Journal of Organic Chemistry
Me
1
2
3
4
5
BuLi; MeI
50%
8
4
(MFH)
R
6
7
O
1) RMgX
2) Et3SiH, BF3·OEt
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9
5
R = tBu ( , tBuFH), 52% (2 steps)
R = Ph ( , PhFH), 72% (2nd step)
7
tBu
1) BuLi; tBuCHO
2) POCl3, pyridine
3) H2, PtO2
62% (3 steps)
8
6
(NpFH)
The synthesis of the isomeric 1,3-dithiane dioxides 1, 2 and 3 has already been reported by
us5 and others.30-31 Here we present a simpler method for the synthesis of monoxide 11
(Scheme 2): Oxidation of 1,3-dithiane 10 with ozone afforded sulfoxide 11 with virtually
quantitative yield and high purity.
Scheme 2. Synthesis of Dithiane Dioxides.
S
10
S
O
S
O
S
quant.
O3
S
S
+
O
UHP
1
2
O
15%
15%
S
O
S
separated by chromatography
11
KMnO4
S
O
S
3
O
42%
ACS Paragon Plus Environment
9

The Journal of Organic Chemistry
Page 10 of 34
We validated the herein presented methods by determining the pKa values of compounds for
which data had already been published. The methods were established and optimized using
indole as analyte and MFH or tBuFH, respectively, as indicators. We additionally determined the
pKa values of indole, pyrrole, diphenylamine, and benzyl phenyl sulfone with the back titration
method; the obtained values turned out to be in good agreement with the published data (Table
1). Nevertheless, titrations of 2,2,2-trifluoroethanol and acetophenone were not successful. No
stationary absorbance was observed after addition of the base, possibly due to side reactions:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
–
Trifluoroethanolate is prone to fragmentation into formaldehyde and the CF3 anion, while
acetophenone is most likely undergoing an aldol reaction. The latter reaction probably was a
negligible problem with Bordwell’s protocol, since the analyte’s concentration was there kept
lower, thus decreasing the rate constant of intermolecular side reactions. Fluorene (FH) can be
used with reservations as indicator in the direct titration, but turned out to be not applicable in
the back titration, since a side reaction was observed at high concentrations of the base leading
to additional UV/Vis absorptions. (Problems with fluorene as indicator had already been reported
in the literature.32) Substituted fluorenes show different behavior in the presence of excess base:
Methylfluorene (MFH) shows an irreversible decrease of absorbance when additional DimK is
added, while tert-butylfluorene (tBuFH) turned out to be stable even at high base concentrations
ACS Paragon Plus Environment
10

Page 11 of 34
The Journal of Organic Chemistry
and is thus ideally suited for titrations with strong bases (see Supporting Information: titration of
pyrrole with MFH and tBuFH). To suppress adverse effects, it is recommended to avoid a distinct
overtitration and the presence of high base concentrations.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Measured pKa values.
Compound
indole
pKa (Indicator) Previously published pKa values
21.0 (MFH)
22.7 (MFH)
23.0 (tBuFH)
25.0 (tBuFH)
20.9533
23.0533
pyrrole
diphenylamine
24.9534
23.41
benzyl phenyl sulfone 23.4 (tBuFH)
acetophenone failed
24.715
2,2,2-trifluoroethanol failed
bissulfoxide (eq/eq) 1 23.4 (MFH)
23.4 (tBuFH)
23.451
25.4 (26.8)a
bissulfoxide (eq/ax) 2 24.9 (tBuFH)
24.1 (25.5)a
23.4 (25.5)a
sulfone 3
25.4 (tBuFH)
a Values predicted on DFT level, MP2 level is given in parenthesis. These values have been
calculated by us previously.6
ACS Paragon Plus Environment
11

The Journal of Organic Chemistry
Page 12 of 34
Fitting of the data is usually possible with an error below 0.1 pKa units, which is in accordance
with deviations in independent experiments. The protocol is very simple to perform and could
be reproduced even by undergraduate students after a short instruction.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We have previously published calculated and provisional experimental pKa values6 for 1,3-
dithiane dioxide isomers 1‒3 to correlate these values with stereoelectronic effects operative in
dithiane derivatives.3-5, 7 pKa values of these compounds could be successfully determined with
the new protocol. Identical pKa values for bissulfoxide 1 were determined with MFH and tBuFH
as indicators. Systematic deviations between experimental and calculated pKa values can be
expected; they are intrinsic possibilities with the method applied in the calculations. Possible
explanations for the discrepancies could be ion pairing or homoconjugation, i.e., the association
of protonated and deprotonated species, or of specific stabilizing interactions of the anions with
solvent molecules. These effects are not included in the solvent correction used for the quantum
chemical prediction of pKa values.
We developed a simple and robust protocol for the determination of pKa values, where a
simple Schlenk line is sufficient; a glove box is not required. An accuracy of ~0.1 pKa units, which
had already been reported by Bordwell et al. could be reproduced with our methods, provided
that no side reactions occur with the analyte or indicator. Though we used indicator/analyte
ACS Paragon Plus Environment
12

Page 13 of 34
The Journal of Organic Chemistry
ratios of 1:1 to reduce weighing errors, the methods are not limited to that ratio. Variations of
this ratio could possibly be useful for the investigation of homoconjugation and ion pairing. The
upper limit for pKa measurements with the indicators used by us is ~26.4. Bordwell stated for his
original method that acids with pKa ranges of 32–35 are difficult to measure in DMSO (pKa = 35)
due to leveling effects of the solvent.1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
It is likely that our protocols could be adapted for measurements in other solvents, especially
to the quite similar solvent acetonitrile, but our experience from the optimization of our protocols
leads one to assume that some alterations in detail would be necessary.
Experimental Section
General. Tetrahydrofuran (THF) and pentane were distilled from sodium benzophenone ketyl
radical prior to use. DMSO was distilled as described in the text. All moisture-sensitive reactions
were carried out under oxygen-free argon using oven-dried glassware and a vacuum line
(Schlenk technique). Liquids were handled with gas-tight syringes. Ozone was generated with
an ozone generator 300.5 (Erwin Sander Elektroapparatebau) from dry air. Flash column
chromatography was carried out using Merck silica gel 60 (230–400 mesh) and thin-layer
chromatography was carried out by using commercially available Merck F254 pre-coated sheets.
Spots were detected by fluorescence quenching and staining in an iodine chamber. NMR
ACS Paragon Plus Environment
13

The Journal of Organic Chemistry
Page 14 of 34
spectra were recorded on Bruker Avance AV 300, Bruker Avance 400, or Bruker Avance III HD
1
2
3
4
5
13
500 spectrometers. C NMR spectra were recorded with broad band decoupling and signals
6
7
8
9
were assigned by HSQC experiments. The spectra were calibrated using the residual solvent
signals. IR spectra were recorded on a Bruker FT-IR spectrometer ‘Alpha’ (Bruker) using ATR
on diamond. EI and FAB mass spectra were recorded with a Finnigan MAT-95 and APCI spectra
were recorded with a Q Exactive Orbitrap (Thermo Fisher). UV/Vis spectra were measured with
a Cary 60 UV-Vis (Agilent) spectrometer. We used a quartz cell with septum screw cap and a
UV/Vis spectrometer with a thermostatted holder for the measurements. Melting points were
measured with an Optimelt MPA100 apparatus and are not corrected. Most syntheses have
been performed according to literature procedures; these are only included in the supporting
information.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9-Methyl-9H-fluorene (MFH, 4). The compound was synthesized in slight modification of a
published procedure.26 BuLi (2.5 M in hexanes, 9.40 mL, 23.5 mmol) was added dropwise at –
78 °C to a solution of fluorene (3.00 g, 18.0 mmol) in THF (60 mL). The mixture was warmed to
rt to dissolve the precipitate and cooled again to –78 °C. MeI (1.70 mL, 3.85 g, 27.1 mmol) was
added dropwise. The mixture was allowed to warm to rt and concentrated at reduced pressure.
The residue was partitioned between CH2Cl2 (100 mL) and HO (50 mL) and the organic layer
ACS Paragon Plus Environment
14

Page 15 of 34
The Journal of Organic Chemistry
was washed with half-concentrated brine (50 mL), dried (Na2SO4), concentrated at reduced
pressure, dissolved in MeOH (25 mL) and stored overnight at –18 °C. The precipitated crystals
were filtered off and dried at reduced pressure to yield the product (1.63 g, 9.05 mmol, 50%) as
a colorless fine crystalline solid. m. p. 43–44 °C (MeOH) (44–46 °C).35 1H NMR (300 MHz,
acetone-d6): δ = 1.49 (d, 3J = 7.4 Hz, 3 H, CH3), 3.94 (q, 3J = 7.29 Hz, 1 H, 9-H), 7.27–7.40 (m,
4 H, Ar-H), 7.52–7.59 (m, 2 H, Ar-H), 7.80–7.85 (m, 2 H, Ar-H); the spectroscopic data are in full
agreement with reported data.26
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9-(tert-Butyl)-9H-fluoren-9-ol. The compound was synthesized in slight modification of a
published procedure.27 tBuMgCl (1.0 M in THF, 10.0 mL, 10.0 mmol) was added dropwise within
20 min at 0 °C to a solution of fluorenone (1.00 g, 5.55 mmol) in THF (40 mL). The mixture was
warmed to rt within 3 h, quenched with H2O (10 mL), diluted with EtOAc (100 mL), and washed
with saturated NH4Cl solution (3×50 mL). The combined aqueous layers were extracted with
EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL), dried
(Na2SO4), concentrated at reduced pressure, and purified by column chromatography (silica gel,
cyclohexane/EtOAc, 30:1) to yield the product (743 mg, 3.12 mmol, 56%) as a colorless viscous
oil. Rf = 0.22 (cyclohexane/EtOAc, 20:1). 1H NMR (300 MHz, CDCl3): δ = 1.02 [s, 9 H, C(CH3)3],
ACS Paragon Plus Environment
15

The Journal of Organic Chemistry
Page 16 of 34
3
3
1.93 (br s, 1 H, OH), 7.23 (dd, 3J ≈ J ≈ 7.9 Hz, 2 H, Ar-H), 7.34 (dd, 3J ≈ J ≈ 7.5 Hz, 2 H, Ar-
1
2
3
4
5
H), 7.55–7.62 (m, 4 H, Ar-H).
6
7
8
9
9-(tert-Butyl)-9H-fluorene (tBuFH, 5). The compound was synthesized in slight modification of
a published procedure.27 BF3·OEt2 (0.7 mL, 800 mg, 5.64 mmol) was added dropwise at 0 °C to
a solution of 9-(tert-butyl)-9H-fluoren-9-ol (672 mg, 2.82 mmol) and Et3SiH (0.9 mL, 656 mg,
5.64 mmol) in CH2Cl2 (6.5 mL) and the mixture was stirred for 1 h at 0 °C. Saturated aqueous
Na2CO3 solution (2 mL) and half-concentrated brine (10 mL) were added, the phases were
separated and the aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organic
layers were dried (Na2SO4), concentrated at reduced pressure, and purified by column
chromatography (silica gel, cyclohexane) to yield the product (583 mg, 2.62 mmol, 93%) as a
colorless solid. m. p. 101–103 °C (cyclohexane). Rf = 0.45 (cyclohexane). 1H NMR (300 MHz,
CDCl3): δ = 1.01 [s, 9 H, C(CH3)3], 3.77 (s, 1 H, 9-H), 7.23 (dd, 3J ≈ 3J ≈ 7.3 Hz, 2 H, Ar-H), 7.35
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
(dd, 3J ≈ J ≈ 7.4 Hz, 2 H, Ar-H), 7.60 (d, 3J = 7.5 Hz, 2 H, Ar-H), 7.73 (d, 3J = 7.5 Hz, 2 H, Ar-
H); the spectroscopic data are in full agreement with reported data.36
9-(2,2-Dimethylpropylidene)-9H-fluorene. The compound was synthesized according to a
published method.29 BuLi (2.5 M in hexanes, 3.6 mL, 9.15 mmol) was added dropwise at 0 °C
to a solution of fluorene (1.52 g, 9.14 mmol) in Et2O (10 mL) and the mixture was stirred at 0 °C
ACS Paragon Plus Environment
16

Page 17 of 34
The Journal of Organic Chemistry
for 5 min, then at rt for 5 min and then cooled again to 0 °C. A solution of tBuCHO (1.0 mL, 790
mg, 9.14 mmol) in Et2O (4.0 mL) was added and the mixture was stirred at 0 °C for 5 min and
was allowed to warm to rt. Saturated aqueous NH4Cl solution (30 mL) was added, the organic
layer was separated and the aqueous layer was extracted with EtOAc (30 mL). The combined
organic layers were washed with brine (30 mL), dried (Na2SO4), and concentrated at reduced
pressure. The crude mixture (2.36 g) of the title compound and 1-(fluoren-9-yl)-2,2-
dimethylpropane-1-ol (TLC) was dissolved in pyridine (25 mL). A mixture of POCl3 (13 mL) and
pyridine (13 mL) was added at 0 °C and the resulting mixture was stirred for 2 h at 100 °C. After
cooling to rt the mixture was poured onto ice water (150 mL) while a vivid exothermic reaction
was observed. The mixture was extracted with EtOAc (3×100 mL). The combined organic layers
were washed with aqueous CuSO4 solution (0.5 M, 2×100 mL), saturated aqueous NHCO3
solution (100 mL) and brine (100 mL), dried (Na2SO4), and concentrated at reduced pressure to
yield the product (2.04 g, 8.71 mmol, 95%) as a yellow oil, which was used in the next step
without further purification. Rf = 0.48 (cyclohexane, EtOAc, 100:1). 1H NMR (300 MHz, CDCl3):
δ = 1.59 [s, 9 H, C(CH3)3], 6.95 (s, 1 H, =CH), 7.26–7.42 (m, 4 H, Ar-H), 7.66–7.81 (m, 3 H, Ar-
H), 8.04–8.10 (m, 1 H, Ar-H); the spectroscopic data are in full agreement with reported data.37
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
17

The Journal of Organic Chemistry
Page 18 of 34
9-Neopentyl-9H-fluorene (NpFH, 6). The compound was synthesized using a published
protocol.29 A suspension of 9-(2,2-dimethylpropylidene)-9H-fluorene (2.00 g, 8.53 mmol) and
PtO2·H2O (100 mg, 0.408 mmol) in Et2O (25 mL) was stirred at rt for 3 h under an atmosphere
of H2 (balloon). Solid material was removed by passing the mixture through a pad of Celite® and
washing with Et2O. The mixture was concentrated at reduced pressure and the remnant was
dissolved in a minimum amount of hot EtOH, filtered hot and crystallized upon cooling to yield
the product (1.31 g, 5.55 mmol, 65%) as long colorless needles. m. p. 75–78 °C (EtOH) (79–80
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
°C).28, 38 Rf = 0.52 (cyclohexane/EtOAc, 100:1). H NMR (500 MHz, CDCl3): δ = 1.20 [s, 9 H,
1
C(CH3)3], 2.02 (d, 3J = 4.1 Hz, 2 H, CH2), 3.91 (t, 3J = 4.0 Hz, 1 H, 9-H), 7.33–7.41 (m, 4 H, 2-H,
3-H, 6-H, 7-H), 7.57 (br d, 3J = 7.5 Hz, 2 H, 1-H, 8-H or 4-H, 5-H), 7.78 (br d, 3J = 7.4 Hz, 2 H,
4-H, 5-H or 1-H, 8-H); 13C NMR (126 MHz, CDCl3) : δ = 30.5 [C(CH3)3], 31.4 [C(CH3)3], 44.7 (C-
9), 47.6 (CH2), 119.7 (C-4, C-5 or C-1, C-8), 124.5 (C-1, C-8 or C-4, C-5), 126.7 (C-2, C-7 or
C-3, C-6), 127.2 (C-3, C-6 or C-2, C-7), 140.7 (Cquart-Ar), 150.17 (Cquart-Ar); IR (ATR): = 3062,
휐
3040, 2949, 2929, 2861, 1908, 1464, 1445, 1393, 1364, 1281, 1235, 1152, 1099; MS (APCI):
m/z (%) = 252.1 (19), 251.1 (100), 235.1 (60), 179.1 (34), 121.1 (35); HRMS (APCI): m/z calcd
for C18H19 (M–H+): 235.1481; found 235.1478.
ACS Paragon Plus Environment
18

Page 19 of 34
The Journal of Organic Chemistry
9-Phenyl-9H-fluoren-9-ol. The compound was synthesized in slight modification of a published
1
2
3
4
procedure.27 PhBr (0.5 mL, 0.748 g, 4.76 mmol) was added to a suspension of magnesium
(turnings, 2.43 g, 100 mmol) in Et2O (50 mL). The reaction was initiated by addition of I2 (a small
grain) then further PhBr (10.0 mL, 15.0 g, 95.2 mmol) in Et2O (50 mL) was added dropwise
within 20 min. The mixture was heated for 80 min under reflux, then cooled to 0 °C. A solution
of fluorenone (9, 15.0 g, 83.3 mmol) in THF (50 mL) was added at 0 °C within 10 min. The
mixture was allowed to warm to rt and poured into saturated aqueous NH4Cl solution (300 mL).
The layers were separated and the aqueous layer was extracted with EtOAc (3×150 mL). The
combined organic layers were washed with H2O (2×150 mL) and brine (150 mL), dried (Na2SO4),
and concentrated at reduced pressure. A fraction of the crude product was purified by column
chromatography (silica gel, cyclohexane/EtOAc, 30:1) to yield the product as a highly viscous
oil. Despite a prolonged drying (5 h) at high vacuum, the product contained 9% residual EtOAc
(NMR). Nevertheless, the substance could be used in the next step without adverse effects. Rf
= 0.35 (cyclohexane, EtOAc, 10:1). 1H NMR (300 MHz, CDCl3): δ = 2.47 (s, 1 H, OH), 7.19–7.42
(m, 11 H, Ar-H), 7.68 (br d, 3J = 7.5 Hz, 2 H, Ar-H); the spectroscopic data are in full agreement
with reported data.39
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
19

The Journal of Organic Chemistry
Page 20 of 34
9-Phenyl-9H-fluorene (PhFH, 7). The compound was synthesized in slight modification of a
published procedure.27 BF3·OEt2 (0.9 mL, 1.01 g, 7.11 mmol) was added dropwise at 0 °C to a
solution of 9-phenyl-9H-fluoren-9-ol (purity: 91%; 918 mg, 3.55 mmol) and Et3SiH (1.1 mL, 826
mg, 7.11 mmol) in CH2Cl2 (8 mL) and the mixture was stirred at 0 °C for 40 min. Saturated
aqueous Na2CO3 solution (1 mL) and half-concentrated brine (20 mL) were added. The organic
layer was separated and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined
organic layers were dried (Na2SO4), concentrated at reduced pressure, and purified by column
chromatography (silica gel, cyclohexane) and by recrystallization (cyclohexane/hexanes, 1:1) to
yield the title compound (617 mg, 2.55 mmol, 72%) as colorless needles. m. p. 148 °C
(cyclohexane/hexanes). Rf = 0.18 (cyclohexane). 1H NMR (300 MHz, CDCl3): δ = 5.09 (s, 1 H,
9-H), 7.10–7.16 (m, 2 H, Ar-H), 7.23–7.46 (m, 9 H, Ar-H), 7.84 (br d, 3J = 7.6 Hz, 2 H, Ar-H); the
spectroscopic data are in full agreement with reported data.27
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
meso-2,4-Bis(4-toluenesulfonyloxy)pentane. The compound was synthesized in slight
modification of a published procedure.40 A solution of 2,4-pentanediol (mixture of isomers, 50.0
g, 480 mmol) in pyridine (100 mL) was added dropwise within 3 h at –10 °C to a solution of p-
TsCl (186 g, 974 mmol) in pyridine (500 mL). The mixture was stirred for 3 d at rt, then poured
onto a mixture of ice (300 g) and concentrated HCl (200 mL). The mixture was extracted with
ACS Paragon Plus Environment
20

Page 21 of 34
The Journal of Organic Chemistry
CH2Cl2 (3×250 mL). The combined organic layers were washed with 1 M HCl (3×100 mL),
aqueous Cu2SO4 solution (10%, 3×100 mL), and half-concentrated brine (100 mL), concentrated
at reduced pressure, dissolved in CH2Cl2 (100 mL), washed with 1 M HCl (3×100 mL) and half-
concentrated brine (100 mL) to remove residual pyridine, dried (Na2SO4), concentrated at
reduced pressure, and recrystallized repeatedly (5×, cyclohexane/EtOAc, 3:1) to yield the
product (26.5 g, 64.2 mmol, 13%) as voluminous colorless crystals. The mother liquors were
concentrated and combined to be used in further crystallizations. Repeated recrystallization
afforded additional product. 1H NMR (300 MHz, CDCl3): δ = 1.18 (d, 3J = 6.3 Hz, 6 H, 1-H, 5-H),
1.69 (dt, 2J = 14.4 Hz, 3J = 6.3 Hz, 1 H, 3-H), 2.04 (dt, 2J = 14.2 Hz, 3J = 7.0 Hz, 1 H, 3-Hʼ), 2.45
(s, 6 H, Ar-CH3), 4.57 (ddq, 3J ≈ 3J ≈ 3J ≈ 6.4 Hz, 2 H, 2-H), 7.33 (d, 3J = 8.0 Hz, 4 H, Ar-H), 7.75
(d, 3J = 8.3 Hz, 4 H, Ar-H).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
meso-Pentan-2,4-dithiol. The compound was synthesized in slight modification of a published
procedure.41 Na2S·9H2O (16.3 g, 67.8 mmol) was added portionwise within 15 min to a
suspension of S8 (4.50 g, 17.6 mmol) in DMF (375 mL). The mixture was stirred for 20 min at rt
and meso-2,4-bis(4-toluenesulfonyloxy)pentane (55.9 g, 136 mmol) was added. The mixture
was stirred for 3 d at 95 °C and poured onto ice (160 g). Concentrated HCl (10 mL) was added
and the mixture was extracted with cyclohexane (5×150 mL). The combined organic layers were
ACS Paragon Plus Environment
21

The Journal of Organic Chemistry
Page 22 of 34
washed with H2O (2×150 mL), dried (Na2SO4), and concentrated at reduced pressure (40 °C, p
> 50 mbar). Residual cyclohexane was removed by co-evaporation with acetone (30 mL) and
pentane (30 mL). The crude mixture of trithiane (7.72 g, 46.4 mmol, 34%) and dithiolane (10.2
g, 75 mmol, 56%) was used in the next step without further purification or separation.
The mixture (17.9 g) was dissolved in Et2O (150 mL) and added at 0 °C within 45 min to a
suspension of LiAlH4 (4.40 g, 116 mmol) in Et2O (75 mL). The mixture was allowed to warm to
rt and stirred at rt for 2.5 h. H2O (30 mL) and H2SO4 (10%, 250 mL) were added carefully. After
stirring at rt overnight the organic layer was separated and the aqueous phase was extracted
with Et2O (5×100 mL). The combined organic layers were washed with H2O (100 mL), dried
(Na2SO4), concentrated at reduced pressure, and distilled at reduced pressure (65–70 °C, 11
mbar). The distillate was dissolved in Et2O (100 mL) and the solvent was extracted with aqueous
KOH solution (20%, 3×100 mL). The combined aqueous layers were cooled, acidified with half-
concentrated H2SO4 (100 mL), and extracted with Et2O (3×100 mL). The combined organic
layers were washed with H2O, dried (Na2SO4), and concentrated at reduced pressure to yield
the product (4.23 g [6% Et2O], 29.2 mmol, 25%; 23% over 2 steps) as a yellow oil. Residual
Et2O cannot be removed without significant losses of the product. Nevertheless, it could be used
without prejudice in the next step.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
22

Page 23 of 34
The Journal of Organic Chemistry
For future experiments it is recommended to perform the acid/base extraction before the
1
2
3
4
5
6
7
8
9
1
3
3
distillation. H NMR (300 MHz, CDCl3): δ = 1.34 (d, J = 6.7 Hz, 6 H, 1-H, 5-H), 1.49 (d, J =
6.7 Hz, 2 H, SH), 1.77 (t, 3J = 7.3 Hz, 2 H, 3-H), 3.08 (dtq, 3J ≈ 3J ≈ 3J ≈ 6.9 Hz, 2 H, 2-H, 4-H);
the spectroscopic data are in full agreement with reported data.42
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
meso-4,6-Dimethyl-1,3-dithiane (10). The compound was synthesized in adaption of a
published procedure.43 A solution of meso-pentan-2,4-dithiol (4.22 g, 31.0 mmol) and
dimethoxymethane (2.7 mL, 2.36 g, 31.1 mmol) in CHCl3 (100 mL) was heated to reflux and a
solution of BF3·OEt2 (7.7 mL, 8.80 g, 62.0 mmol) in CHCl3 (100 mL) was added dropwise within
1 h. The mixture was stirred for 1 h at reflux, then cooled to rt, and quenched by addition of H2O
(150 mL). The organic layer was washed with saturated aqueous Na2CO3 solution (3×100 mL)
and H2O (50 mL), dried (Na2SO4), concentrated at reduced pressure, and purified by distillation
(100 °C, 15 mbar) to yield the product (3.75 g, 25.3 mmol, 82%) as a colorless solid. 1H NMR
(300 MHz, CDCl3): δ = 1.21 (d, 3J = 6.9 Hz, 6 H, 4-CH3, 6-CH3), 1.32 (dt, 2J = 13.9 Hz, 3J = 11.4
Hz, 1 H, 5-Hax), 2.07 (dt, 2J = 14.2 Hz, 3J = 2.2 Hz, 1 H, 5-Heq), 2.81 (dqd, 3J = 11.4 Hz, 3J = 6.8
Hz, 3J = 2.2 Hz, 2 H, 4-H, 6-H), 3.53 (d, 2J = 14.1 Hz, 1 H, 2-Heq), 4.06 (d, 2J = 14.1 Hz, 1 H, 2-
Hax).
ACS Paragon Plus Environment
23

The Journal of Organic Chemistry
Page 24 of 34
rac-(1S,4S,6R)-4,6-Dimethyl-1,3-dithiane-1-oxide (11). A stream of ozone (~160 mg, 3.32
mmol) was bubbled for 5 min at –40 °C through a solution of dithiane 10 (492 mg, 3.32 mmol)
in CH2Cl2 (100 mL). The volatiles were removed at reduced pressure to yield the title compound
(547 mg, 3.32 mg, quant.) as a colorless solid, which was used in the next steps without
additional purification. 1H NMR (300 MHz, CDCl3): δ = 1.21 (d, 3J = 6.8 Hz, 3 H, 4-CH3), 1.44 (d,
3J = 6.8 Hz, 3 H, 6-CH3), 1.92 (ddd, 2J = 15.0 Hz, 3J ≈ 3J ≈ 11.9 Hz, 1 H, 5-Hax), 2.27 (ddd, 2J =
15.0 Hz, 3J ≈ 3J ≈ 2.3 Hz, 1 H, 5-Heq), 2.69 (dqd, 3J = 12.1 Hz, 3J = 6.8 Hz, 3J = 2.3 Hz, 1 H, 6-
H), 3.05 (dqd, 3J = 11.4 Hz, 3J = 6.8 Hz, 3J = 2.2 Hz, 1 H, 4-H), 3.78 (d, 2J = 12.7 Hz, 1 H, 2-
Heq), 3.98 (d, 2J = 12.7 Hz, 1 H, 2-Hax); the spectroscopic data are in full agreement with reported
data.5
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
meso-(1S,3R,4S,6R)-4,6-Dimethyl-1,3-dithiane-1,3-dioxide (1) and rac-(1R,3R,4S,6R)-4,6-
Dimethyl-1,3-dithiane-1,3-dioxide (2). The compounds were synthesized in slight modification
of a published procedure.5 Finely ground urea hydrogen peroxide (UHP; 952 mg, 10.1 mmol)
was added to a solution of sulfoxide 11 (1.51 g, 9.20 mmol) in AcOH (50 mL). The mixture was
stirred at rt overnight and concentrated at reduced pressure. The residue was partitioned
between CH2Cl2 (50 mL) and saturated aqueous NaHCO3 solution (80 mL). The layers were
separated and the aqueous layer was extracted with CH2Cl2 (4×50 mL). The combined organic
ACS Paragon Plus Environment
24

Page 25 of 34
The Journal of Organic Chemistry
phases were concentrated at reduced pressure and purified by flash chromatography (silica gel,
CH2Cl2/MeOH, 50:1→30:1) to yield the bissulfoxides 1 (250 mg, 1.38 mmol, 15%) and 2 (256
mg, 1.42 mmol, 15%) as colorless solids. 1: m. p. 209–212 °C, decomp. (CH2Cl2/MeOH) (Lit:
199–210°C).5 Rf = 0.41 (CH2Cl2/MeOH, 10:1). 1H NMR (300 MHz, CDCl3): δ = 1.48 (d, 3J = 6.9
Hz, 6 H, 4-CH3, 6-CH3), 1.42–1.57 (m, 1 H, 5-Hax), 2.20 (dtd, 2J = 17.1 Hz, 3J = 2.4 Hz, 5J = 0.7
Hz, 1 H, 5-Heq), 2.90 (dqd, 3J = 12.4 Hz, 3J = 6.8 Hz, 3J = 2.4 Hz, 2 H, 4-H, 6-H), 3.89 (br d, 2J
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
= 10.9 Hz, 1 H, 2-Heq), 4.74 (d, J = 10.9 Hz, 1 H, 2-Hax). The spectroscopic data are in
agreement with those reported in literature.5 2: m. p. 200–202 °C, decomp. (CH2Cl2/MeOH) (Lit:
196–200°C ).5 Rf = 0.47 (CH2Cl2/MeOH 10:1). 1H NMR (300 MHz, CDCl3): δ = 1.40 (d, 3J = 7.0
Hz, 3 H, 4-CH3 or 6-CH3), 1.53 (d, 3J = 6.8 Hz, 3 H, 6-CH3 or 4-CH3), 1.98 (ddd, 2J = 16.0 Hz, 3J
3
3
≈ J ≈ 2.3 Hz, 1 H, 5-Heq), 2.58 (ddd, 2J = 16.0 Hz, 3J ≈ J ≈ 12.1 Hz, 1 H, 5-Hax), 2.90 (partly
covered, dqd, 3J = 12.0 Hz, 3J = 7.1 Hz, 3J = 2.4 Hz, 1 H, 4-H or 6-H), 2.99 (partly covered, dqd,
3J = 12.4 Hz, 3J = 6.9 Hz, 3J = 2.1 Hz, 1 H, 6-H or 4-H), 3.52 (d, 2J = 13.0 Hz, 1 H, 2-Heq), 4.66
2
(d, J = 13.0 Hz, 1 H, 2-Hax). The spectroscopic data are in agreement with those reported in
literature.5
rac-(4S,6R)-4,6-Dimethyl-1,3-dithiane-1,1-dioxide (3). The compound was synthesized in
slight modification of a published procedure.5 A solution of KMnO4 (441 mg, 2.79 mmol) in H2O
ACS Paragon Plus Environment
25

The Journal of Organic Chemistry
Page 26 of 34
(20 mL) was added dropwise at rt over 15 min to a solution of sulfoxide 11 (305 mg, 1.86 mmol)
in acetone (30 mL). After stirring overnight at rt the mixture was decolorized by addition of
saturated aqueous NaHSO3 solution and extracted with CH2Cl2 (4×50 mL). The combined
organic layers were washed with half-concentrated brine (40 mL), dried (Na2SO4), concentrated
at reduced pressure, and purified by two subsequent flash chromatographies (first: silica gel,
CH2Cl2→CH2Cl2/MeOH, 10:1; second: silica gel, CH2Cl2/Et2O, 5:1) and a recrystallization
(cyclohexane/EtOAc) to yield the product (142 mg, 0.788 mmol, 42%) as colorless woolly
crystals. m. p. 197–198 °C (cyclohexane/EtOAc) (198–200 °C).5 1H NMR (300 MHz, CDCl3): δ
= 1.28 (d, 3J = 6.8 Hz, 3 H, 4-CH3), 1.37 (d, 3J = 6.8 Hz, 3 H, 6-CH3), AB signal (partly covered,
δA = 2.31, δB = 2.23, JAB = 14.6 Hz; A part additional split: dd, 3J ≈ 3J ≈ 11.2 Hz; B part additional
split: dd, 3J ≈ 3J ≈ 3.3 Hz, 2 H, 5-H), 3.10 (dqd, 3J = 11.3 Hz, 3J = 7.1 Hz, 3J = 4.2 Hz, 1 H, 6-H),
3.19 (partly covered, dqd, 3J = 10.3 Hz, 3J = 6.9 Hz, 3J = 3.3 Hz, 1 H, 4-H), 3.69 (d, 2J = 14.6
Hz, 1 H, 2-Heq), 4.12 (d, 2J = 14.6 Hz, 1 H, 2-Hax). The spectroscopic data are in full agreement
with those reported in literature.5
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Supporting Information Available: Experimental details, spectra and scripts. This material is
available free of charge via the Internet at http://pubs.acs.org.
ACS Paragon Plus Environment
26

Page 27 of 34
The Journal of Organic Chemistry
Acknowledgment. We thank Marcel Schendel and Tobias C. Bentzel for their help within the
1
2
3
4
advanced lab courses.
5
6
7
8
9
References and Footnotes:
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1. Bordwell, F. G., Equilibrium Acidities in Dimethyl Sulfoxide Solution. Acc. Chem. Res. 1988,
21, 456-463.
2. Wedel, T.; Müller, M.; Podlech, J.; Goesmann, H.; Feldmann, C., Stereoelectronic Effects
in Cyclic Sulfoxides, Sulfones and Sulfilimines: Application of the Perlin Effect to Conformational
Analysis. Chem. Eur. J. 2007, 13, 4273-4281.
3. Ulshöfer, R.; Podlech, J., Stereoelectronic Effects in Vinyl Sulfoxides. J. Am. Chem. Soc.
2009, 131, 16618-16619.
4. Podlech, J., Stereoelectronic Effects in -Carbanions of Conformationally Constrained
Sulfides, Sulfoxides, and Sulfones. J. Phys. Chem. A 2010, 114, 8480-8487.
5. Ulshöfer, R.; Wedel, T.; Süveges, B.; Podlech, J., Conformationally Constrained Oxides of
1,3-Dithiane: Synthesis and NMR Spectroscopic Investigations. Eur. J. Org. Chem. 2012, 6867-
6877.
ACS Paragon Plus Environment
27

The Journal of Organic Chemistry
Page 28 of 34
6. Süveges, B. D.; Podlech, J., Dependence of Stereoelectronic and Charge Effects on pKa
Values of 1,3-Dithiane-Derived Sulfides, Sulfoxides, and Sulfones: An Experimental and
Computational Investigation. Eur. J. Org. Chem. 2015, 987-994.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7. Süveges, B. D.; Podlech, J., Stereoelectronic Effects in Conformations of Sulfide, Sulfoxide,
and Sulfone α-Carbanions. Tetrahedron 2015, 71, 9061-9066.
8. Weingand, D.; Podlech, J., Synthesis and Acidity of Conformationally Constrained 1,3-
Oxathiane S-Oxides. Tetrahedron Lett. 2016, 57, 5608-5610.
9. Jung, S.; Podlech, J., Stereoelectronic Effects: The γ-Gauche Effect in Sulfoxides. J. Phys.
Chem. A 2018, 122, 5764-5772.
10. Conant, J. B.; Wheland, G. W., The Study of Extremely Weak Acids. J. Am. Chem. Soc.
1932, 54, 1212-1221.
11. Kaupmees, K.; Tolstoluzhsky, N.; Raja, S.; Rueping, M.; Leito, I., On the Acidity and
Reactivity of Highly Effective Chiral Brønsted Acid Catalysts: Establishment of an Acidity Scale.
Angew. Chem. Int Ed. 2013, 52, 11569-11572.
12. Mansfeld, M.; Pařík, P.; Ludwig, M., Effect of para Substitution on Dissociation of N-
Phenylbenzenesulfonamides. Collect. Czech. Chem. Commun. 2004, 69, 1479-1490.
ACS Paragon Plus Environment
28

Page 29 of 34
The Journal of Organic Chemistry
13. Streitwieser, A.; Wang, D. Z.; Stratakis, M.; Facchetti, A.; Gareyev, R.; Abbotto, A.; Krom,
1
2
3
4
5
6
J. A.; Kilway, K. V., Extended lithium ion pair indicator scale in tetrahydrofuran. Can. J. Chem.
1998, 76, 765-769.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
14. Kütt, A.; Selberg, S.; Kaljurand, I.; Tshepelevitsh, S.; Heering, A.; Darnell, A.; Kaupmees,
K.; Piirsalu, M.; Leito, I., pKa Values in Organic Chemistry – Making Maximum Use of the
Available Data. Tetrahedron Lett. 2018, 59, 3738-3748.
15. Matthews, W. S.; Bares, J. E.; Bartmess, J. E.; Bordwell, F. G.; Cornforth, F. J.; Drucker,
G. E.; Margolin, Z.; McCallum, R. J.; McCollum, G. J.; Vanier, N. R., Equilibrium Acidities of
Carbon Acids. VI. Establishment of an Absolute Scale of Acidities in Dimethyl Sulfoxide Solution.
J. Am. Chem. Soc. 1975, 97, 7006-7014.
16. Konstandaras, N.; Dunn, M. H.; Luis, E. T.; Cole, M. L.; Harper, J. B., The pKa values of
N-aryl imidazolinium salts, their higher homologues, and formamidinium salts in dimethyl
sulfoxide. Org. Biomol. Chem. 2020, 18, 1910-1917.
17. Muller, P., Glossary of Terms Used in Physical Organic Chemistry (IUPAC
Recommendations 1994). Pure Appl. Chem. 1994, 66, 1077-1184.
ACS Paragon Plus Environment
29