Scalable and selective preparation of 3,3',5,5'-tetramethyl-2,2'-biphenol

Article abstract of DOI:10.1021/acs.oprd.6b00356

Biphenols are indispensable building blocks in ligand systems for organic catalysis. 3,3'5,5'-Tetramethyl-2,2'- biphenol is a particular versatile motif in different catalytic systems. We developed an easy to perform and scalable process to give access to large quantities of this important building block by the use of selenium dioxide, a common and readily available oxidizer.

Full text of DOI:10.1021/acs.oprd.6b00356

Subscriber access provided by University of Newcastle, Australia
Full Paper
Scalable and Selective Preparation of 3,3’,5,5’-Tetramethyl-2,2’-biphenol
Thomas Quell, Nadine Hecken, Katrin M. Dyballa, Robert Franke, and Siegfried R. R Waldvogel
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00356 • Publication Date (Web): 08 Dec 2016
Downloaded from http://pubs.acs.org on December 13, 2016
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 free 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 accessible to all
readers and 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.
Organic Process Research & Development 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 17
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Scalable and Selective Preparation of 3,3’,5,5’ꢀ
Tetramethylꢀ2,2’ꢀbiphenol
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
Thomas Quell†, Nadine Hecken†, Katrin M. Dyballa‡, Robert Franke‡,§, Siegfried R. Waldvogel†*
†Institut für Organische Chemie, Johannes GutenbergꢀUniversität Mainz, Duesbergweg 10ꢀ14,
Dꢀ55128 Mainz, Germany; Email: waldvogel@uniꢀmainz.de; ‡Evonik Industries AG, Paulꢀ
BaumannꢀStraße 1, Dꢀ45772 Marl, Germany; §Lehrstuhl für Theoretische Chemie, Ruhrꢀ
Universität Bochum, Dꢀ44780 Bochum, Germany.
ACS Paragon Plus Environment
1

Organic Process Research & Development
Page 2 of 17
1
2
3
4
Table of Contents Graphic
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
2

Page 3 of 17
Organic Process Research & Development
1
2
3
4
5
6
KEYWORDS: Biphenol, scalable, selenium dioxide, C,H activation, phenolꢀphenol coupling,
oxidation.
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
ABSTRACT: Biphenols are indispensable building blocks in ligand systems for organic
catalysis. 3,3’5,5’ꢀtetramethylꢀ2,2’ꢀbiphenol is a particular versatile motif in different catalytic
systems. We developed an easy to perform and scalable process to give access to large quantities
of this important building block by the use of selenium dioxide, a common and readily available
oxidizer.
INTRODUCTION
The structural motif of biphenol is present in numerous molecules like natural products,1,2
drugs,3,4 or in material science.5,6 Their outstanding significance as ligands for catalytic systems
classifies them as soꢀcalled “privileged ligands”.7–10 This issue underlines their importance for
scientific, and technical applications the steady high interest in an efficient scalable synthesis. In
particular, 3,3’,5,5’ꢀtetramethylꢀ2,2ꢀbiphenol (2) has widespread capability to act as backbone in
phosphorousꢀbased ligand systems: With this biphenol the rhodiumꢀcatalyzed hydroformylation
reaction was promoted,11,12 nickelꢀcatalyzed hydrocyanation,13 rhodiumꢀcatalyzed asymmetric
hydrogenation of prochiral olefins,14 or the enantioselective, copperꢀcatalyzed generation of
stereogenic centers is reported.15–17 This ligand is also appropriate for enantioselective addition
of arylboronic acids 18,19 as well as isoꢀ and syndioselective ROMP of norbonene.20 Additionally,
3,3’,5,5’ꢀtetramethylꢀ2,2ꢀbiphenol can be transformed into sodium[bis(3,3´,5,5´ꢀtetramethylꢀ
2,2´ꢀbiphenoxy)borate].21 This product is extraordinarily stable at electrochemical conditions and
ACS Paragon Plus Environment
3

Organic Process Research & Development
Page 4 of 17
1
2
3
4
5
6
applicable in electrochemical doubleꢀlayer capacitor electrolytes for capacitive energy
storage.22,23
7
8
9
The conversion of 2,4ꢀdimethylphenol (1) to the desired 3,3’,5,5’ꢀtetramethylꢀ2,2’ꢀbiphenol
turned out to be challenging.24,25 The direct CꢀH activation led to polycyclic byꢀproducts with a
high structural diversity.26–28 Nevertheless, a broad spectrum of oxidative methods was studied.
One approach is based on metal catalysts at aerobic conditions using cobalt,29 vanadium,30
ruthenium,31 or copper salts.32,33 Furthermore, iron(III)ꢀchloride,34 sodium hypochlorite,35 and
sodium persulfate12 claim to act as oxidizer in stoichiometric amounts. A more sophisticated
option deals with the anodic oxidation for direct CꢀH activation,36–38 or templateꢀsupported
oxidation approach.39 However, none of these methods can give access to large quantities of
3,3’,5,5’ꢀtetramethylꢀ2,2’ꢀbiphenol. Therefore, we have developed an easy to perform and
scalable protocol to synthesize and isolate the desired product 2.40 Our method is based on a
selenium dioxideꢀmediated, direct CꢀH activation of 2,4ꢀdimethylphenol (1). Selenium dioxide is
an easy to handle, versatile, and readily available oxidizer. This material is a coꢀproduct within
the roasting process of copper, lead, zinc, or iron ores and can be isolated from the fly ashes.41 In
the course of the 2,4ꢀdimethylphenol oxidation process, elemental selenium is coꢀformed. This
byꢀproduct can be easily separated by percolation and reoxidized by heating at aerobic
conditions.42 Therefore, selenium dioxide is an excellent reagent for academic and technical
applications.43,44
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
RESULTS AND DISCUSSION
We tried to elucidate the optimal reaction conditions to conduct the oxidation displayed in
Scheme 1, in order to be as selective as possible to facilitate the subsequent isolation and
purification steps.
ACS Paragon Plus Environment
4

Page 5 of 17
Organic Process Research & Development
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
Scheme 1. Selenium dioxide mediated coupling of 2,4ꢀdimethylphenol.
Simultaneously, yield and conversion should be high without the use of expensive or less
available ingredients. In addition, the application of potentially explosive reagents such as
peroxides should be avoided as well. The effect of different solvents is described in earlier
publications.40,45 These studies were conducted on a scale up to two grams with purification by
column chromatography. To simplify the optimization work for elucidation the parameters such
as reaction temperature, reaction time, and the amounts of selenium dioxide, we introduced an
internal reaction standard. It turned out, that 1,3ꢀdinitrobenzene is suitable for a quick and
reliable determination of data. The internal standard proved to be inert in the presence selenium
dioxide in boiling acetic acid. Even upon 16 hours no reaction was observed and 1,3ꢀ
dinitrobenzene was quantitatively recovered. With this in hand, we performed gas
chromatographic analysis (GC) with different ratios of 2,4ꢀdimethylphenol, 3,3’,5,5’ꢀ
tetramethylꢀ2,2’ꢀbiphenol, and 1,3ꢀdinitrobenzene to obtain calibration data. The determination
of conversion and yield was performed by GC. Figure 1 displays the amounts of 1 and 2 over the
reaction time. As anticipated, the fraction of 2,4ꢀdimethylphenol decreases over time. On the
other hand, 3,3’,5,5’ꢀtetramethylꢀ2,2’ꢀbiphenol is exponentially generated at the beginning, but
reached a maximum after approx. 180 minutes. Interestingly, the amount of 2 decreases
thereafter. Only little remains of 2,4ꢀdimethylphenol are left and 2 seems to undergo further
conversion. Such overꢀoxidations led to highꢀmolecular weight byꢀproducts. This observation is
ACS Paragon Plus Environment
5

Organic Process Research & Development
Page 6 of 17
1
2
3
4
5
6
7
8
9
provided by the high viscosity of the reaction mixture upon prolonged reaction times. Therefore,
it is important to optimize the reaction time to avoid oligomerization processes. In addition,
excessive consumption of starting material should be avoided and therefore, the conversion
should be stopped in time.
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
Figure 1. Amount of 2,4ꢀdimethylphenol and 3,3’,5,5’ꢀtetramethylꢀ2,2’ꢀbiphenol determined by
GCꢀanalysis during the reaction. Reaction conditions: acetic acid (45 mL), 2,4ꢀdimethylphenol
(4.0 g, 32.6 mmol, 1.0 eq.), 1,3ꢀdinitrobenzene (1.0 g, 5.9 mmol, 0.2 eq.), selenium dioxide (2.5
g, 22.9 mmol, 0.7 eq.), 85 °C.
After the reaction time, we investigated the eminently suitable equivalents of selenium dioxide.
Table 1 exhibits the results of this screening. The reaction times are comparable, but the yield
increases with larger amounts of selenium dioxide. We decided to perform further reactions with
0.7 equivalents. More of the oxidizer produces comparable yields but with higher efforts of
selenium dioxide, therefore 0.7 equivalents are the most economic compromise.
ACS Paragon Plus Environment
6

Page 7 of 17
Organic Process Research & Development
1
2
3
4
Table 1. Optimization of the selenium dioxide equivalents.
5
6
7
8
9
Entry
SeO2/ eq.
0.50
yield/ %a
Time/ min
180
1
2
3
4
5
6
43
45
64
69
70
70
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
0.55
180
0.60
150
0.70
180
0.80
200
1.00
180
Reaction conditions: acetic acid (45 mL), 2,4ꢀdimethylphenol (4.0 g, 32.6 mmol,1.0 eq.), 1,3ꢀ
a
dinitrobenzene (2.0 g, 5.9 mmol, 0.2 eq.), 85 °C. Yields were determined by GCꢀanalysis with
internal standard.
The quantity of acetic acid is also an important point for the latter technical application. We were
able to increase the concentration of 2,4ꢀdimethylphenol up to 0.18 g/mL without depression of
yield. Additionally, the optimal reaction time decreases then to 120 min. Further increase of the
concentration of starting material promotes the formation of high molecular byꢀproducts. Table 2
shows a series of experiments with different reaction conditions to confirm our internal standard
method by isolating the desired product. First, we performed the reaction in presence of 1,3ꢀ
dinitrobenzene to elucidate the optimal reaction time. Then we repeated the same experiment for
the previously appointed reaction time, but without 1,3ꢀdinitrobenzene. The more or less
identical results underline the value of the internal standard approach.
Table 2. Comparison of GCꢀdetermined yields and isolated yields.
Temperature
/°C
Concentration
of 1 / g/mL
GC
Isolated yield
/%
Entry
1
SeO2 /eq.
0.55
yield/%a
90
0.09
47
43
ACS Paragon Plus Environment
7

Organic Process Research & Development
Page 8 of 17
1
2
3
4
5
6
2
3
85
85
0.70
0.70
0.09
0.18
69
72
72
73
7
8
9
Reaction conditions: 2,4ꢀdimethylphenol (32.6 mmol,) in acetic acid. a Yields were determined
by GCꢀanalysis with 1,3ꢀdinitrobenzene as internal standard.
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
For a technically applicable synthesis, the workꢀup strategy should be as efficient as possible.
We developed two different protocols to workꢀup the reaction mixture. The first strategy (Figure
2) starts by quenching of the reaction by the addition of water (1 mL/g 2,4ꢀdimethylphenol). The
reaction mixture is filtered to remove elemental selenium, followed by an extraction by ethyl
acetate (8 mL/g 2,4ꢀdimethylphenol). Further washings with water (three times with 5 mL/g 2,4ꢀ
dimethylphenol) transfers the acetic acid into the aqueous layer. After drying over anhydrous
sodium sulfate, the ethyl acetate is distilled off at reduced pressure (300 to 12 mbar) at 60 °C
water bath temperature. Alternatively, residual water can by removed by azeotropic distillation
instead of using sodium sulfate. The residue still contains nonꢀconverted starting material. This
can be removed by vacuum distillation at 60 °C (10ꢀ3 mbar). The remaining solid is extracted by
boiling n-heptane (three times with 7 mL/g 2,4ꢀdimethylphenol). Within this step, only low
molecular weight products are dissolved. The heptane distilled off at reduced pressure (200 to 12
mbar) at 60 °C water bath temperature. In the last step, crude 2 is reꢀcrystallized from
cyclohexane: The residue is dissolved in boiling cyclohexane (2 mL/g residue) and chilled to
7 °C for 16 hours. The crystals are collected and washed with cold cyclohexane (7 °C).
crystallization
distillation
extraction
extraction
percolation
reaction
mixture
2
high molecular
byꢀproducts
nonꢀconverted 1
acetic acid
Se
Figure 2. Workꢀup scheme for protocol A.
ACS Paragon Plus Environment
8

Page 9 of 17
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
The workꢀup by protocol B (Figure 4) is more efficient, but requires a highly selective reaction
process, like the one we established by using selenium dioxide: After a given reaction time, the
mixture is poured onto ice (1.3 g per mL acetic acid), whereby the desired product, with small
amounts of byꢀproduct, precipitate (Figure 3a). The starting material remains in the water/acetic
acid solution (Figure 3b).
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
a)
b)
93%
84%
Figure 3. GCꢀdata of workꢀup protocol B: a) precipitate and b) water/ acetic acid filtrate.
Then the solid is collected and reꢀdissolved in ethyl acetate (3.3 mL/g 1). Insoluble selenium is
then filtered off for further use. The organic layer is washed by water (three times with 0,6 mL/g
starting material) to remove remaining traces of acetic acid. Then the solvent is, after drying over
anhydrous sodium sulfate, distilled off at reduced pressure. The residue is dissolved in boiling
cyclohexane (2 mL/g residue) and chilled to 7 °C for 16 hours to complete the crystallization.
The product was filtered off and washed with cold cyclohexane (7 °C). Both workꢀup protocols
A and B lead to identical yields of 68%.
crystallizationc
precipitationa
triturationb
reaction
mixture
2
Se
nonꢀconverted 1
acetic acid
Figure 4. Workꢀup scheme for protocol B.
ACS Paragon Plus Environment
9

Organic Process Research & Development
Page 10 of 17
1
2
3
4
5
6
7
8
9
Since both workꢀup procedures are potentially scalable, we started to scaleꢀup this reaction.
Two characteristics are important for such a process. First, mixing has to be on large scale as
good as on small scales. Figure 5a displays the GC data of a reaction involving a 100 g of 1 scale
mixed by a magnetic stirring device. Next to the desired product 2 (green), an unexpected byꢀ
product (red) was detected. Mass spectrometric studies indicate that the byꢀproduct is the
dehydrotrimer 3 of 1, which was previously reported.35 At these process conditions the byꢀ
product became dominant. Insufficient mixing seems to favors the formation of overꢀoxidation
products. Figure 5b displays the same reaction, stirred by a mechanical stirrer. The byꢀproduct is
almost completely suppressed and 3,3’,5,5’ꢀtetramethylꢀ2,2’ꢀbiphenol occurs as major product.
These results underline the importance of sufficient mixing for this particular transformation.
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
a)
31%
21% 24%
28%
55% <1%
b)
Figure 5. GCꢀdata of the reaction mixture after 4 hours. Reaction conditions: 2,4ꢀ
dimethylphenol (818 mmol, 0.09 g/mL, 1.0 eq.), selenium dioxide (572 mmol, 0.7 eq.), 70 °C in
acetic acid with a) mixing by magnetic stirring bar and b) mechanical stirring.
Second, the heat transfer is substantial for upscaling of the reaction. In the case of exothermic
reactions, inadequate heat dissipation can cause disastrous consequences by losing control over
the reaction. To avoid such problems, we investigated the reaction enthalpy at isothermic
conditions. These measurements were carried out with an EasyMax102 (MettlerꢀToledo GmbH,
Gießen, Germany) with HFCal for calorimetric studies. Initially, we determined the required
energy input to heat up the added selenium dioxide to reaction temperature. This allows
ACS Paragon Plus Environment
10

Page 11 of 17
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
calculation of the reaction heat (Figure 6a). Addition of selenium dioxide represents the starting
point. It takes 111 seconds to heat up to reaction temperature without the presence of 1.
Integration the heatꢀflow of this period gives us the required energy input for this part of the
process. The whole course of reaction is displayed in Figure 6b. Again, the addition of selenium
dioxide represents the starting point and the conversion, of 2,4ꢀdimethylphenol starts. At the
beginning the EasyMax system has to put in energy for 80 seconds to heat up the selenium
dioxide in order to reach reaction temperature of 85 °C. This period is shorter than without 2,4ꢀ
dimethylphenol because the reaction itself produces heat. After this time, the system has to
dissipate reaction heat. The heat of reaction was determined to ꢀ53.4 kJ per mole 1. These is
comparable to the esterification of ethanol with of acetyl chloride (ꢀ56.1 kJ/mol) or the
preparation of chloroethane using thionyl chloride (ꢀ54.4 kJ/mol).46 The exothermic character of
the reaction requires the dissipation of heat, whereby the moderate reaction process lowers the
demand of cooling devices.
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
a)
b)
Figure 6. Heat flow determination of a) addition of selenium dioxide to acetic acid without 1 and
b) oxidative coupling of 2,4ꢀdimethylphenol. Reaction conditions: acetic acid (57 mL), 2,4ꢀ
ACS Paragon Plus Environment
11

Organic Process Research & Development
Page 12 of 17
1
2
3
4
5
6
dimethylphenol (10.0 g, 81.9 mmol, 1.0 eq.), selenium dioxide (6.3 g, 57.3 mmol, 0.7 eq.) 85 °C
for 120 minutes.
7
8
9
Taking into consideration preceding experiments the selenium dioxideꢀmediated syntheses of
3,3’,5,5’ꢀtetramethylꢀ2,2’ꢀbiphenole is further scalable. Therefore, we tried to increase the
amounts of starting material. Initial studies were performed in screwꢀmountable culture tubes
(Figure 7a). For a good mixing, these tubes were filled with maximum 4 mL and heated in a steel
block. Further experiments were conducted in round bottom flasks equipped with reflux
condenser and heated by an oil bath (Figure 7b). Higher scales were performed in a reactor,
equipped with a mechanical stirrer, composed of one major stirring blade on the ground and
three additional blades at the top (Figure 7c). Two of these additional blades were adjusted
inversely to guarantee efficient mixing and keep the selenium dioxide homogeneously
distributed.
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)
b)
a)
x
45
x
20
0.5 g 1
10 g 1
450 g 1
Figure 7. Experimental setꢀup for different amounts of 1 a) 0.5 g, b) 10 g, and c) 450 g.
ACS Paragon Plus Environment
12

Page 13 of 17
Organic Process Research & Development
1
2
3
4
Table 3. Comparison of GCꢀdetermined yields and isolated yields.
5
6
7
8
9
Entry
m (1)/g
0.5
vessel
Isolated yield /%
n (
1
)/mmol
1
2
3
4
culture tube
69
69
68
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
10
81
round bottom flask
stirring reactor
450
3683
Reaction conditions: 2,4ꢀdimethylphenol (1) in acetic acid (0.18 g/mL) at 85 °C for 120 min.
In summary, we established an easy to perform and scalable reaction protocol to generate
selectively 3,3’,5,5’ꢀtetramethylꢀ2,2’biphenol. This valuable building block was obtained up to
305 g just by single action of selenium dioxide in acetic acid. Both are easy to handle and readily
available. The determination of the heatꢀflow resulted an exothermic but controllable character
of the reaction allowing a safe scaleꢀup of the reaction. The crucial points for the successful
scaleꢀup are efficient mixing during the transformation and thermal control. EXPERIMENTAL
SECTION
General. All starting materials, reagents and solvents are commercially available and were
used without further purification. Spectroscopy and spectrometry: 1H NMR and 13C NMR spectra
were recorded at 25 °C by using a Bruker AV II 400 (Bruker, Germany). Chemical shifts (δ) are
reported in parts per million (ppm) relative to traces of CHCl3 in the corresponding deuterated
solvent. High resolution mass spectra were obtained by using a QTof Ultima 3 (Waters, Milford,
Massachusetts) apparatus employing ESI+, a micrOTOFꢀQꢀspectrometer (Bruker), a MAT
95XL. Gas chromatography was performed on a Shimadzu GCꢀ2010 (Shimadzu, Japan) using a
HP 5 column (Agilent Technologies, USA; length: 30 m, inner diameter: 0.25 mm, film: 0.25
mm, carrier gas: hydrogen). Heatꢀflow measurement was conducted with a EasyMax102
(MettlerꢀToledo GmbH, Gießen, Germany) with HFCal for calorimetric studies.
ACS Paragon Plus Environment
13

Organic Process Research & Development
Page 14 of 17
1
2
3
4
5
6
7
8
9
Synthesis of 3,3’,5,5’-tetramethyl-2,2’-biphenol (large scale): 450 g 2,4ꢀdimethylphenol
(3.68 mol, 1.0 eq.) was dissolved in 2500 mL acetic acid and heated in a reactor, equipped with a
mechanical stirrer exhibiting four blades at a rotation speed of 142 rounds per minute. The
reaction was heated to 85 °C by a Haake NK22 thermostat. Once the temperature was steady,
286 g (2.58 mol) selenium dioxide were added and the reaction was kept at 85 °C for 120
minutes. After this, the mixture was poured onto 3.3 kg ice. When the mixture reached room
temperature, the precipitate was filtered off, suspended in 1.4 L ethyl acetate and filtered again.
This organic layer was washed three times with 0.2 L water and dried over sodium sulfate.
Distillation of the solvent provided 398 g of crude product, which was dissolved in 850 mL
cyclohexane and crystalized for 16 hours at 7 °C yielding 241 g of 3,3,’,5,5’ꢀtetramethylꢀ2,2’ꢀ
biphenol. To complete the crystallization, the volume of the motherꢀliquid was reduced to half
and crystalized ad 7 °C. Together 305 g (1.26 mol, 68%) 3,3,’,5,5’ꢀtetramethylꢀ2,2’ꢀbiphenol
were isolated
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
Synthesis of 3,3’,5,5’-tetramethyl-2,2’-biphenol (low scale): 10.0 g 2,4ꢀdimethylphenol
(0.081 mol, 1.0 eq.) was dissolved in 56 mL acetic acid in a round bottom flask equipped with
mechanical stirrer and reflux condenser. The solution was heated up to 85 °C in an oil bath. Once
the temperature was steady, 6.3 g (0.057 mol) selenium dioxide were added and the reaction was
kept at 85 °C for 120 minutes. After this, the mixture was poured onto 80 g ice. The purification
procedure was carried out as described above yielding 6.85 g (0.28 mol, 69%) 3,3,’,5,5’ꢀ
tetramethylꢀ2,2’ꢀbiphenol.
1H NMR (400 MHz, CDCl3) δ= 7.00ꢀ7.03 (m, 2H) 6.87ꢀ6.90 (m, 2H), 4.94 (s, 2H, OH), 2.30
(s, 12H).
13C NMR (100 MHz, CDCl3) δ= 149.26, 132.14, 130.14, 128.64, 125.31, 122.30, 20.57, 16.31.
Mp: 135 °C
ACS Paragon Plus Environment
14

Page 15 of 17
Organic Process Research & Development
1
2
3
4
GC purity > 98%
5
6
Analytical data in agreement with those previously reported.37
7
8
AUTHOR INFORMATION
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
Corresponding Author
* EꢀMail: waldvogel@uniꢀmainz.de.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
The authors highly appreciate the support by BMBFꢀEPSYLON (FKZ 13XP5016D). S.R.W. in
particular appreciates the donation of selenium dioxide by RETORTE GmbH (Arubis),
Röthenbach, Germany.
References
(1) Grimsdale, A. C.; Chan, K. L.; Martin, R. E.; Jokisz, P. G.; Holmes, A. B. Chem. Rev. 2009,
109, 897–1091.
(2) Bringmann, G.; Price Mortimer, A. J.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M.
Angew. Chem., Int. Ed. Engl. 2005, 44, 5384–5427.
(3) Bringmann, G.; Gulder, T.; Gulder, T. A. M.; Breuning, M. Chem. Rev. 2011, 111, 563–639.
(4) Nussbaum, F. von; Brands, M.; Hinzen, B.; Weigand, S.; Häbich, D. Angew. Chem., Int. Ed.
Engl. 2006, 45, 5072–5129.
(5) Pavel, D.; Ball, J. M.; Bhattacharya, S. N.; Shanks, R. A.; Hurduc, N. Comput. Theor.
Polym. Sci. 1997, 7, 7–11.
(6) Finkelmann, H.; Happ, M.; Portugal, M.; Ringsdorf, H. Makromol. Chem. 1978, 179, 2541–
2544.
(7) Brunel, J. M. Chem. Rev. 2005, 105, 857–897.
(8) Chen, Y.; Yekta, S.; Yudin, A. K. Chem. Rev. 2003, 103, 3155–3212.
(9) Franke, R.; Selent, D.; Börner, A. Chem. Rev. 2012, 112, 5675–5732.
(10) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014, 114, 9047–9153.
(11) Smith, S. E.; Rosendahl, T.; Hofmann, P. Organometallics 2011, 30, 3643–3651.
(12) Mormul, J.; Mulzer, M.; Rosendahl, T.; Rominger, F.; Limbach, M.; Hofmann, P.
Organometallics 2015, 34, 4102–4108.
(13) Garner, J. M.; Kruetzer, K. A.; Tam, W. WO 9906358, 2008.
(14) Monti, C.; Gennari, C.; Piarulli, U.; de Vries, J. G.; de Vries, André H. M.; Lefort, L.
Chem. Eur. J. 2005, 11, 6701–6717.
(15) d'Augustin, M.; Palais, L.; Alexakis, A. Angew. Chem., Int. Ed. Engl. 2005, 44, 1376–1378.
ACS Paragon Plus Environment
15

Organic Process Research & Development
Page 16 of 17
1
2
3
4
5
6
7
8
9
(16) Vuagnouxꢀd'Augustin, M.; Alexakis, A. Chem. Eur. J. 2007, 13, 9647–9662.
(17) Pang, Z.; Xing, A.; Wang, L. Chem. Res. Chin. Univ. 2015, 31, 756–760.
(18) Monti, C.; Gennari, C.; Piarulli, U. Chem. Commun. (Cambridge, U. K.) 2005, 42, 5281–
5283.
(19) Monti, C.; Gennari, C.; Piarulli, U. Chem. Eur. J. 2007, 13, 1547–1558.
(20) Hayano, S.; Nakama, Y. Macromolecules 2014, 47, 7797–7811.
(21) Malkowsky, I. M.; Fröhlich, R.; Griesbach, U.; Pütter, H.; Waldvogel, S. R. Eur. J. Inorg.
Chem. 2006, 8, 1690–1697.
(22) Francke, R.; Cericola, D.; Kötz, R.; Schnakenburg, G.; Waldvogel, S. R. Chem. Eur. J.
2011, 11,3082–3085.
(23) S. R. Waldvogel, I. M. Malkowsky, U. Griesbach, H. Pütter, A. Fischer, M. Hahn, R. Kötz,
Electrochem. Commun. 2009, 11, 1237–1242.
(24) Malkowsky, I. M.; Rommel, C. E.; Wedeking, K.; Fröhlich, R.; Bergander, K.; Nieger, M.;
Quaiser, C.; Griesbach, U.; Pütter, H.; Waldvogel, S. R. Eur. J. Org. Chem. 2006, 1, 241–245.
(25) Barjau, J.; Koenigs, P.; Kataeva, O.; Waldvogel, S. R. Synlett 2008, 15, 2309–2312.
(26) Barjau, J.; Schnakenburg, G.; Waldvogel, S. R. Angew. Chem., Int. Ed. 2011, 50, 1415–
1419.
(27) Barjau, J.; Schnakenburg, G.; Waldvogel, S. Synthesis 2011, 2011, 2054–2061.
(28) Barjau, J.; Fleischhauer, J.; Schnakenburg, G.; Waldvogel, S. R. Chem. Eur. J. 2011, 17,
14785–14791.
(29) Jiang, Q.; Sheng, W.; Tian, M.; Tang, J.; Guo, C. Eur. J. Org. Chem. 2013, 2013, 1861–
1866.
(30) Hwang, D.ꢀR.; Chen, C.ꢀP.; Uang, B.ꢀJ. Chem. Commun. 1999, 13, 1207–1208.
(31) Yadav, J. S.; Reddy, B. V. S.; Uma G. K.; Prasad, A. R. New J. Chem. 2003, 27, 1684–
1686.
(32) Rajender Reddy, K.; Rajgopal, K.; L. Kantam, M. Catal. Lett. 2007, 114, 36–40.
(33) Sharma, V. B.; Jain, S. L.; Sain, B. J. Mol. Catal. A: Chem. 2004, 219, 61–64.
(34) Wallis, P. J.; Booth, K. J.; Patti, A. F.; Scott, J. L. Green Chem. 2006, 8, 333–337.
(35) Neelamegam, R.; Palatnik, M. T.; FraserꢀRini, J.; Slifstein, M.; AbiꢀDargham, A.;
Easwaramoorthy, B. Tetrahedron Lett. 2010, 51, 2497–2499.
(36) Kirste, A.; Hayashi, S.; Schnakenburg, G.; Malkowsky, I. M.; Stecker, F.; Fischer, A.;
Fuchigami, T.; Waldvogel, S. R. Chem. Eur. J. 2011, 17, 14164–14169.
(37) Kirste, A.; Nieger, M.; Malkowsky, I. M.; Stecker, F.; Fischer, A.; Waldvogel, S. R. Chem.
Eur. J. 2009, 15, 2273–2277.
(38) Malkowsky, I. M.; Griesbach, U.; Pütter, H.; Waldvogel, S. R. Eur. J. Org. Chem. 2006,
2006, 4569–4572.
(39) Malkowsky, I. M.; Rommel, C. E.; Fröhlich, R.; Griesbach, U.; Pütter, H.; Waldvogel, S.
R. Chem. Eur. J. 2006, 12, 7482–7488.
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
(40) Quell, T.; Mirion, M.; Schollmeyer, D.; Dyballa, K. M.; Franke, R.; Waldvogel, S. R.
ChemistryOpen 2016, 5, 115–119.
(41) Riedel, E. Anorganische Chemie, 3., verb. Aufl.; De Gruyter: Berlin, New York, 1994.
(42) Brauer, G.; Stecher, P. G. Handbook of preparative inorganic chemistry, 2nd ed.;
Academic Press: New York, 1965.
(43) Hoekstra, J. W. in Handbook of reagents for organic synthesis; Eds.: Burke, D. S.;
Danheiser, R. L.: John Wiley & Sons: Chichester, 2004; pp 358–359.
ACS Paragon Plus Environment
16

Page 17 of 17
Organic Process Research & Development
1
2
3
4
5
6
(44) Organoselenium chemistry: Synthesis and reactions; Wirth, T., Ed.; WileyꢀVCHꢀVerl.:
Weinheim, 2012.
(45) Waldvogel, S. R.; Quell, T.; Beiser, N.; Dyballa, K.; Franke, R. Eur. J. Org. Chem. 2016,
7
8
9
4307–4310
(46) Furka, Á. Struct. Chem. 2009, 20, 781–788.
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