Sodium Hypochlorite Pentahydrate Crystals (NaOClÂ·5H2O): A

Subscriber access provided by READING UNIV

Review 2

Sodium Hypochlorite Pentahydrate Crystals (NaOCl·5HO): Convenient and Environmentally Benign Oxidant for Organic Synthesis Masayuki Kirihara, Tomohide Okada, Yukihiro Sugiyama, Miyako Akiyoshi, Takehiro Matsunaga, and Yoshikazu Kimura Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00288 • Publication Date (Web): 23 Oct 2017 Downloaded from http://pubs.acs.org on October 23, 2017

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 43

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

Organic Process Research & Development

Sodium

Hypochlorite

Pentahydrate

Crystals

(NaOCl·5H2O): Convenient and Environmentally Benign Oxidant for Organic Synthesis Masayuki Kirihara, a* Tomohide Okada,b Yukihiro Sugiyama,b Miyako Akiyoshi,c Takehiro Matsunaga,c Yoshikazu Kimura d * a

Department of Materials and Life Science, Shizuoka Institute of Science and Technology,

2200-2 Toyosawa, Fukuroi, Shizuoka 437-8555, Japan. b

R&D Department of Chemicals, Nippon Light Metal Company, Ltd., 480 Kambara,

Shimizu-ku, Shizuoka 421-3203, Japan c

Research Center for Explosion Safety, National Institute of Advanced Industrial Science

and Technology, 1-1-1 Higashi, Tsukuba-shi, Ibaraki 305-8565, Japan d

Research and Development Department, Iharanikkei Chemical Industry Co. Ltd., 5700-1

Kambara, Shimizu-ku, Shizuoka 421-3203, Japan

Corresponding Authors *E-mail (Masayuki Kirihara): [email protected] *E-mail (Yoshikazu Kimura): [email protected]

ACS Paragon Plus Environment

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

Page 2 of 43

TOC graphic O R

OH

O

R

R'

R

S

R

S

O O S R Cl

R'

R SH R

O

N

H

R'

R' cat. TEMPO

RCH2OH cat. TEMPO

R

O O S R R'

NaOCl5H 2O

Ts

R

N R

Ts O H

S

R

NaBr

OH R

H

S

CO2H

O O S R Br

O R

O

O


2

Page 3 of 43

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 Sodium hypochlorite pentahydrate (NaOCl·5H2O) crystals; Sodium hypochlorite; Oxidation; Alcohol; TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl); Organosulfur compounds

ABSTRACT

The novel oxidant of sodium hypochlorite pentahydrate (NaOCl·5H2O)

crystals is now available for industrial and laboratory use. It is superior to conventional aqueous sodium hypochlorite solutions (aq. NaOCl). The crystalline material is 44% NaOCl, contains minimal amounts of sodium hydroxide and sodium chloride, and the aqueous solution, which is prepared from NaOCl·5H2O and water, has a pH of 11~12. Examples of the selective organic synthesis using NaOCl·5H2O involve the oxidations of primary and secondary alcohols, selective oxidations to sulfoxide and sulfone, oxidative cleavage of disulfide to sulfonyl chloride and bromide, oxaziridine synthesis, and oxidative dearomatization of phenols.

1. Introduction In this review, novel production on a commercial basis of sodium hypochlorite pentahydrate (NaOCl·5H2O) and its application for organic syntheses is described. Although NaOCl·5H2O itself has been known since 1919 in the literature,1a nobody has been supplied on an industrial scale. In 2013, Nippon Light Metal Co. in Japan was the first to put sodium hypochlorite pentahydrate (NaOCl·5H2O) crystals on the market in the world.2,3 As the organic synthesis using NaOCl·5H2O as an oxidant has never been reported, we examined the performance of the NaOCl·5H2O compared to a conventional aqueous NaOCl solution (aq. NaOCl).


3


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

Page 4 of 43

Oxidation using aq. NaOCl4 is one of the most promising methods in process chemistry, because diluted aq. NaOCl is non-explosive, inexpensive, and the post-oxidation waste is harmless and nontoxic sodium chloride (NaCl). However, there are still some drawbacks when using the conventional aq. NaOCl as an oxidant of organic compounds. The process has an inherently poor volume efficiency because the concentration of conventional aq. NaOCl is only 8~13% (higher concentrations of the NaOCl solution are known to be unstable). Moreover, the pH of conventional aq. NaOCl is very high (~13; as adjusted with free NaOH to maintain stability), and the pH must sometimes be adjusted lower in order to speed up the rate or prevent decomposing the starting materials and/or products. Furthermore, conventional aq. NaOCl is not stable enough and the deteriorated NaOCl sometimes produces unsuccessful synthetic reactions. We expected that NaOCl·5H2O is a superior substitute of aq. NaOCl, and found several new types of oxidation reactions of organic molecules which had not been successful using conventional aq. NaOCl. In addition, a high volume efficiency of reactions, good stability in storage, and unnecessity pH adjustment prior to use, afforded simple methods for organic synthesis. Several oxidation reactions were found to occur as shown below. O R

OH

O

R

R'

R

S

R

S

O O S R Cl

R'

R SH R

O

N

H

R'

R' cat. TEMPO

RCH2OH cat. TEMPO

R

O O S R R'

NaOCl5H 2O

Ts

R

N R

Ts O H

S

R

NaBr

OH R

H

S

CO2H

O O S R Br

O R

O

O


4

Page 5 of 43

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 Synthetic applications of NaOCl·5H2O 2. Sodium hypochlorite pentahydrate (NaOCl·5H2O)2,5 As shown in Figure 1, NaOCl·5H2O is pale yellow crystals having the melting point of 25−27 °C. Notable features of NaOCl·5H2O include: (1) the NaOCl content is about 44 wt% (the following expressed as %; 3-4 times higher concentration versus conventional aq. NaOCl), (2) simple stoichiometric calculations, easy and accurate mass determination due to the crystalline nature of the compound, (3) the pH of aqueous solutions is ~11-12 since the solution contains less than 0.04~0.08% NaOH, and (4) the crystals are stable for 1 year below 7 °C. Currently, NaOCl·5H2O crystals are commercially available from several companies including us.3 m.p. NaOH NaCl pH

25−27 °C 0.04−0.08 wt% 0.1−0.5 wt% 11−12 (for the aqueous solution)

Figure 1 NaOCl·5H2O crystals. Reproduced with permission from reference 5. Copyright 2016 Elsevier.

3. Commercial synthesis of sodium hypochlorite pentahydrate (NaOCl·5H2O) crystals2,5 3-1. Development of the industrial preparation of NaOCl·5H2O Several preparation methods for NaOCl·5H2O have already been proposed,1 however, industrial applicable methods to prepare high purity NaOCl·5H2O crystals are unknown. We have recently found specified crystallization conditions for high-purity NaOCl·5H2O crystals based on the NaCl-NaOCl-H2O ternary phase diagram. Based on these findings, we have established an original method for manufacturing NaOCl·5H2O (Scheme 2) 2 and have been supplying this product to the market. Chlorine gas is added to a 45~48% NaOH solution to


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

Page 6 of 43

prepare a highly concentrated NaOCl solution. After removing of the precipitated NaCl by filtration, the filtrate is cooled to around 15 °C to precipitate the NaOCl·5H2O crystals, which are collected by centrifugal filtration. Cl2 45-48% aq. NaOH

aq. NaOCl + NaCl + NaOH

filtration

aq. NaOCl cooling + NaOH

NaCl

filtration

NaOCl5H2 O crystals

Soln. containing NaOH

Scheme 2 Industrial preparation of NaOCl·5H2O 3-2 Property of NaOCl·5H2O Analysis shows that the prepared NaOCl·5H2O contains only 0.1-0.5% NaCl and 0.04-0.08% NaOH. That is, the crystals prepared using this new method contain less free NaOH as well as less NaCl than the conventional aq. NaOCl. In addition, an aqueous solution of this product has a more ideal pH of 11-12 whereas that of the conventional aq. NaOCl is pH 13 and oxidations are faster due to the lower pH; vide infra. Stability of the product was evaluated at several temperature (Figure 3). These NaOCl·5H2O crystals, which contain 44% of NaOCl, are stable at lower temperature. However, the product gradually decomposed under an ambient temperature.

Figure 2 Stability of NaOCl·5H2O at several temperatures


6

Page 7 of 43

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


Further evaluation revealed that the NaOCl·5H2O crystals are quite stable in refrigerator. The concentration of NaOCl of the crystals is almost unchanged (44.2% →43.7%) even after 360 days at 7 °C (Figure 2). This means that 99% of the NaOCl was maintained (Table 1). This is in sharp contrast to the conventional aqueous NaOCl solution, whose concentration gradually drops to 11.3% from 13.6% of original concentration under the same condition. This means that 17% of NaOCl content decomposed during storage.

Table 1 Stability of NaOCl·5H2O crystals and conventional aq. NaOCl at 7 °C Substance NaOCl·5H2O

Original Concentration 1 yr. later concentration 44.2% 43.7%a (98.9% of the original concentration)

aq. NaOCl

13.6%

a

11.3%b (83.1% of the original concentration)

360 days later. b 361 days later. Reproduced with permission from reference 5. Copyright 2016 Elsevier.

Due to the instability of the conventional aq. NaOCl, titration is required to determine the exact concentration before use. On the contrary, the accurate mass of NaOCl·5H2O can be easily measured using a balance (Figure 3).

NaOCl・5H 2O Crystals （No need for titration）

Stable

Conventional aqueous NaOCｌ NaOCｌ (Need for titration) Figure 3 Advantage of NaOCl·5H2O crystals on conventional aqueous NaOCl


7


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

Page 8 of 43

3-3. Safety assessment of NaOCl·5H2O6 According to the testing method of explosives based on the Japanese Industrial Standards (JIS K 4810), the BAM friction test and the drop hammer test have been applied to the product (NaOCl·5H2O) (Table 2). The results of both tests were negative at classification 7 for the BAM friction test, and 8 for the drop hammer test. This means that NaOCl·5H2O is not an explosive compound under typical conditions. Table 2 Sensitivity test of NaOCl·5H2O based on JIS K 4810 Test

Condition

Result

JIS grade

Friction

Limiting load: 353 N

Negative

Class 7

Drop hammer

Limiting impact energy: 24.5 J

Negative

Class 8

Differential scanning calorimetry (DSC) has been done at a heating rate of 5 °C/min contacting with several materials [stainless (SUS304H), titanium, low density polyethylene (LD-PE), high density polyethylene (HD-PE) and polypropylene (PP)] in glass ampoule, and the results are shown in Figures 4 and 5. The sharp peak was observed at 100 °C in DSC measurement with SUS304H. This result means that stainless steel reacts with NaOCl·5H2O, thus stainless vessels cannot be used as reactors. On the other hand, titanium did not react with NaOCl·5H2O, thus the reaction of NaOCl·5H2O can be performed in titanium vessels as well as glass wares.


8

(NaOCl·5H2O) 55

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


29 17 69 31 Heat flow (W/g)

Page 9 of 43

367 J/g

342 J/g 447 397

102 284

287 J/g

(NaOCl·5H2O+SUS304H) 100 53 29 17

423 J/g

93 268 J/g

217 J/g 256

179

31 (NaOCl·5H2O+Ti) 29 56 110 321 J/g 18 30 0

69

425

334 J/g 437 392 271

274 J/g 100

200 300 Temperature (℃）

400

500

Figure 4 DSC data with SUS304H and titanium

The DSC data of NaOCl·5H2O with these resins (LD-PE, HD-PE and PP) showed that all of them were not affected by NaOCl·5H2O at ambient temperatures.


9


5

(NaOCl·5H2O)

342 J/g 447 397

367 J/g 102

55 29 17 69

284

31 287 J/g

Heat flow (W/g)

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

Page 10 of 43

(NaOCl·5H2O+LD-PE) 297 J/g 133 J/g 58 107 207 30 17 72 165 262 32

1006 J/g

264 J/g

(NaOCl·5H2O+HD-PE) 123 J/g 55 308 J/g 104 138 209 29 16 71 132 178 265 10 J/g 264 J/g 31 (NaOCl·5H2O+PP) 54 460 J/g 107 193 29 18

376

73

166 139 J/g

396

1297 J/g

393 263

1008 J/g

31 275 J/g 0

100

200 300 Temperature (℃)

400

500

Figure 5 DCS data with resins

4. Oxidation of alcohols with NaOCl·5H2O5,7 The synthesis of aldehydes or ketones by oxidation of the corresponding primary or secondary alcohols is one of the most important reactions in organic synthesis, and a high number of methods has been reported. 8 However, there are only a few methods that can be industrially applied, because most of the existing oxidations have serious drawbacks such as toxic or explosive property of the oxidants. The oxidation of alcohols using conventional aq. NaOCl catalyzed by TEMPO (2,2,6,6tetramethylpiperidine 1-oxyl)9 or AZADO (2-azaadamantane N-oxyl)10 have been reported. They appear to be economically and environmentally benign methods without the use of a metal catalyst.


10

Page 11 of 43

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


However, the process has an inherently poor volume efficiency because the concentration of the conventional aq. NaOCl solution is up to only 13%. Moreover, at the pH of the conventional aq. NaOCl (about 13), the reactions are very slow, thus the pH must be lowered (pH 8-9) with aqueous sodium hydrogen carbonate (aq. NaHCO3) in order to increase the rate.9b NaOCl·5H2O is expected to overcome these mentioned drawbacks.

4-1. Optimization of the reaction conditions The oxidations of 2-octanol were initially examined using NaOCl·5H2O crystals or the conventional aq. 13% NaOCl in dichloromethane (CH2Cl2) in the presence of 5 mol% tetrabutylammonium hydrogen sulfate (Bu4NHSO4) without pH adjustment with aq. NaHCO3 in the presence or absence of TEMPO or 1-Me-AZADO. The results are summarized in Table 4-1. In all cases, the NaOCl·5H2O crystals (runs 1, 3 and 7) showed more excellent results than those of the aq. 13% NaOCl (runs 2, 4 and 8). Table 3 Comparison with NaOCl·5H2O crystals and conventional aqueous NaOCl Bu 4NHSO4 5 mol%

OH + 1.2 eq. NaOCl 4

O

Nitroxyl radical in CH 2Cl2 5 °C

4

Run

NaOCl

Nitroxyl radical (mol%)

Time (h)

Yield (%)a

1

NaOCl·5H2O

-

24

78

2

aq. 13% NaOCl

-

27

9

3

NaOCl·5H2O

TEMPO (1)

1

97

4

aq. 13% NaOCl

TEMPO (1)

22

11

5

NaOCl·5H2O

TEMPO (0.1)

3

99

6

NaOCl·5H2O

1-Me-AZADO (1)

1

100

7

aq. 13% NaOCl

1-Me-AZADO (1)

24

99

a

Determined by GC analysis using internal standard method.


11


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

Page 12 of 43

We first postulated that the role of Bu4NHSO4 was as a phase transfer catalyst, however, it turned out to act as an acid based on the results shown in Tables 4 and 5. As shown in Table 4, the addition of Bu4NHSO4 to the 13% aq NaOCl (prepared from NaOCl·5H2O) dramatically reduced the pH value (9.6).

Table 4 Effect for quaternary ammonium salts and acid in the presence of TEMPOa OH 4 2-Octanol

b

TEMPO (0.01 equiv.) Bu4NX (0.005~0.05 equiv.) CH2Cl2, 5°C

4 2-Octanone

Yield of 2-Octanone (%) b

X (equiv.)

Additive

1

—

—

—

0.1

2

HSO4 0.005

—

—

40

73

98

—

3

Br 0.05

—

—

6

14

25

87 (22 h)

4

Cl 0.05

—

—

3

10

10

73

5

Cl 0.05

NaHSO 4H 2O 0.05 equiv.

—

19

25

—

69

6

Cl 0.05

NaHSO 4H 2O 0.05 equiv. +H2O 0.2 mL

97

99

—

—

—

7

—

NaHSO 4H 2O 0.05 equiv. +H2O 0.2 mL

46

98

—

—

—

Run

a

O

NaOCl5H 2O (1.2 equiv.)

0.5 h

1h

2h 0.1

3h 0.1

21 h 0.2 (23 h)

1 (10 mmol), NaOCl5H2O (12 mmol), TEMPO (0.1 mmol),Bu4 NX (0.05~0.5 mmol), CH2 Cl2 (30 mL) Yields were determined by GC using an internal standard method.

Table 5 pH of 13% aq. NaOCl (prepared from NaOCl·5H2O) with quaternary ammonium salts 13% aq. NaOCl*

Quaternary ammonium salt

pH

50 mmol

None

11.3

50 mmol

Bu4NHSO4 (2.5 mmol)

9.6

50 mmol

Bu4NBr (2.5 mmol)

11.4

50 mmol

Bu4NCl (2.5 mmol)

11.2

* Prepared from NaOCl·5H2O and ion-exchanged water


12

Page 13 of 43

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


Based on the results, the oxidation effectively occurred below pH 10. As mentioned below, the use of NaHSO4 in place of Bu4NHSO4 gave excellent results for the oxidation of 2octanol.

NaOH

NaOCl5H2O

0.08 wt% = 0.4 mol% Bu4NHSO4 or NaHSO4 neutralize 5 mol% Na2SO4 H2O

HCl

HOCl

aqueous phase TEMPO 1 mol%

organic phase R1

OH 2

R

R1

O

R2

Scheme 3 Proposed mechanism for the TEMPO-catalyzed oxidation of alcohols with NaOCl·5H2O Reproduced with permission from reference 5. Copyright 2016 Elsevier.

Next, we examined the reaction with concentrated aq. NaOCl which can be prepared by dissolving NaOCl·5H2O crystals with water. We also confirmed that the concentration of a NaOCl solution higher than 20% is stable for a few days for the reaction. However, almost no concentration effect was observed at 13, 20, and 31% NaOCl·5H2O. On the other hand, the use of the solid NaOCl·5H2O crystals dramatically increased the oxidation (Figure 4-1). The precise reason is not clear, but it may appear that a high concentration of the primary oxidant HOCl forms on the surface of the crystalline solid.


13


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

Page 14 of 43

Figure 6 Reaction of 2-octanol with several concentrations of aqueous NaOCl prepared from NaOCl·5H2O crystals and water; NaOCl·5H2O crystals (○); aq. 31% NaOCl (△); aq. 20% NaOCl (□); aq. 13% NaOCl (◇) ; conventional aq. 13% NaOCl (×). * 2-Octanol (10 mmol), NaOCl·5H2O (12 mmol), Bu4NHSO4 (0.5 mmol), TEMPO (0.1 mmol), CH2Cl2 (30 mL), and appropriate water.

The solvent effects were examined (Table 6) and ethyl acetate was found to be as good a reaction solvent as dichloromethane. Table 6 Results for the oxidation of 2-octanol in several solvents OH 4 2-Octanol a

O

NaOCl5H 2O (1.2 equiv.) TEMPO (0.01 equiv.) Bu4NHSO4 (0.05 equiv.) solvent (30 mL)

Solvent

Temperature (°C)

CH2 Cl2

4 2-Octanone

Yield of 2-Octanone (%) b 1h

2h

3h

4h

5

97

—

—

—

EtOAc

5

61

97

—

—

C6 H 5CH3

5

38

90

98

—

C6 H5 CF3

5

30

55

87

95

CH 3CN

5

53

54

53

52

AcOH

r.t.

18

78

90

90

a

2-Octanol (10 mmol)

b

Yields were determined by GC using an internal standard method.


14

Page 15 of 43

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


A large-scale (26.0 g of 2-octanol, 0.2 mol) example of the oxidation of 2-octanol was examined in ethyl acetate (Scheme 4). To maintain the reaction temperature below 20 °C, 2octanol was dropwise added for 15 min to a mixture of all reagents cooling in an ice-water bath. After stirring for 45 min at 0~20 °C, the reaction mixture was quenched with aqueous Na2SO3 followed by extraction with ethyl acetate, and distillation of the residue to produce 2octanone (23.2 g, 91% yield).

OH 4

26.0 g (200 mmol) 200 ml NaOCl・・5H2O TEMPO, Bu4NHSO4 in EtOAc

NaOCl・5H2O(1.2 eq., 39.5 g) TEMPO (0.01eq., 0.312 g) Bu4NHSO4 (0.05 eq., 3.4 g) EtOAc(80 mL),0-20°C, 1 h

O 4

23.2 g Isolated yield 91%

⇒Add 2-Octanol to the flask （Reaction temp. is controled at 0～20℃） ⇒Distilled yield 91%　　　　　　　　

Easy to scale-up using EtOAc Scheme 4 Large scale oxidation of 2-octanol in ethyl acetate

As an improved method, NaHSO4 was used instead of Bu4NHSO4. In method A, 2-octanol was dropwise added to the reaction mixture. In Method B, 30% NaOCl prepared from NaOCl·5H2O was dropwise added to the mixture. Both methods gave high yields of the desired 2-octanone within 1 h (Scheme 5). NaOCl·5H2O can be used in a slurry or highly concentrated solution.


15


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

OH 4 13.0 g (100 mmol)

NaOCl・ 5H 2 O (1.2 eq., 19.8 g) TEMPO (0.01 eq., 0.156 g) NaHSO4 (0.05 eq., 1.7 g) 0-20°C, 1 h

Method A (NaOCl・5H2O slurry)

Added to 2-Octanol Yield 96% 2-Octanol

NaOCl・5H2O + water (slurry) TEMPO NaHSO4・H2O

Page 16 of 43

O 4

Method B (aq. 30% NaOCl)

Added to aq. NaOCl Yield 97% 30% aq. NaOCl (from NaOCl・5H2O) 2-Octanol TEMPO NaHSO4・H2O

Scheme 5 Solvent free oxidation of 2-octanol catalyzed by NaHSO4·H2O

4-2. TEMPO-catalyzed oxidation of several alcohols with NaOCl·5H2O The optimized TEMPO-catalyzed oxidation with NaOCl·5H2O was applied to various primary alcohols (10 mmol) (Table 7). Use of an equimolar amount of NaOCl·5H2O gave the corresponding aldehydes in good yields. This optimized method using NaOCl·5H2O gives encouraging results with TEMPO. It is notable that the reaction of primary alcohols having a heteroaromatic moiety (pyridine, thiophene) effectively produced the desired aldehydes.


16

Page 17 of 43

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 7 Selective syntheses of aldehydes from primary alcoholsa 5 mol% Bu4 NHSO4 OH +

R

NaOCl5H 2O

Substrate

5

OH OH

OH

O

1 mol% TEMPO CH2Cl2

R

H

NaOCl5H2O (equiv.)

CH2Cl2 (mL)

Temp. (°C)

Time (h)

Yield (%) b

1.1

30

5

1

91

1.1

30

5

1

99

1.2

30

5

2

96

1.2 1.2

30 15

5 15

6 1

96 97

1.4 1.4 1.2 1.4

30 30 30 30

5 5 5 5

4 3 3 2

67 82 c 87 d 85 d

1.1

30

5

0.5

93

1.1

30

5

0.5

98

1.1

30

5

0.5

94

1.4

30

5

3

79

MeO O

OH

O OH

OH Cl OH NO2 OH N S OH

a Substrate : 10 mmol b Yields were determined by GC using an internal method c TEMPO 10 mol% d 1-Me-AZADO was used instead of TEMPO

The oxidations of secondary alcohols were then examined (Table 8). Both the TEMPO- and 1-Me-AZADO-catalyzed oxidations of sterically-hindered secondary alcohols were reported to give poor yields of the ketones using the conventional aq. NaOCl without pH adjustment using aq. NaHCO3. In contrast, the optimized method using NaOCl·5H2O gave excellent


17


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

Page 18 of 43

results with TEMPO even in the reaction of sterically-hindered alcohols (menthol and 2,6dimethyl-4-heptanol). Notably, the cheap TEMPO is useful as a catalyst for the oxidations.

Table 8 Results for the oxidation of secondary alcoholsa 5 mol% Bu4NHSO4 OH R1

R2

Substrate

+

NaOCl

1 mol% Nitroxyl radical

O R1

CH2Cl2 Nitroxyl radical

NaOCl (eq.)

R2

CH2Cl2 Temp. (mL) (°C)

Time (h)

Yield (%) b

OH

TEMPO

NaOCl5H2O (1.2)

10

5

0.5

(95)

TEMPO TEMPO

NaOCl5H2O (1.2) NaOCl5H2O (1.2)

30 10

5 15

1 0.67

97 (96)

TEMPO TEMPO 1-Me-AZADO

NaOCl5H2O (1.2) 12% aq. NaOCl (1.2) NaOCl5H2O (1.6) NaOCl5H2O (1.6) NaOCl5H2O (1.4)

30 30 10 8 30

5 5 15 15 rt

24 24 2 2.25 0.5

98 2 96 (92) 98

NaOCl5H2O (1.8) NaOCl5H2O (1.4)

10 30

15 rt

6 0.5

88 95

4 OH 3

OH

OH

a

TEMPO 1-Me-AZADO

All the reactions were performed without pH adjustment using aq. NaHCO3. were determined by GC using an internal standard method. Numbers in parentheses refer to isolated yields.

b Yields

For the oxidation of alcohols using the conventional aq. NaOCl catalyzed by TEMPO, primary alcohols are known to be easier and faster oxidized than secondary alcohols.9 Actually, the oxidation of an equimolar mixture of a primary alcohol (1-nonanol) and a secondary alcohol (2-nonanol) using the conventional aq. NaOCl catalyzed by 4-MeOTEMPO was reported to afford 90% nonanal and 10% 2-nonanone in the literature.9b


18

Page 19 of 43

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


Conversely, the reaction of an equimolar mixture of 1-octanol and 2-octanol with NaOCl·5H2O in the presence of TEMPO provided octanal in 47% yield and 2-octanone in 44% yield after 0.5 h. The 4-MeO-TEMPO catalyzed reaction exhibited a similar result (Table 9). Thus, the oxidation rates for primary and secondary alcohols under these conditions are not very different.

Table 9 Oxidation of an equimolar mixture of 1-octanol and 2-octanol with NaOCl·5H2O catalyzed by a nitroxyl radical OH 5 1-Octanol 5.0 mmol + OH 4

O NaOCl. 5H2 O (5 mmol) Nitroxyl radical (0.1 mmol) Bu 4NHSO4 (0.5 mmol) CH 2Cl2, 5 °C

2-Octanol 5.0 mmol

H 5 Octanal + O 4 2-Octanone

Nitroxyl Radical

Time (h)

Octanal

2-Octanone

TEMPO

0.5

47% (2.35 mmol)

44% (2.20 mmol)

4-MeO-TEMPO

1.0

48% (2.40 mmol)

37% (1.85 mmol)

* Yields were determined by GC using an internal standard method.

These results suggest that the reaction-mechanism of the nitroxyl radical catalyzed oxidation of alcohols using NaOCl·5H2O is different from the oxidation using the conventional aq. NaOCl. The oxidation of alcohols with NaOCl·5H2O/TEMPO/Bu4NHSO4 occurs under acidic to neutral conditions (Scheme 3 vide supra).5 We proposed a plausible mechanism involving intermediate C with hydride transfer (Scheme 6)5 based on the mechanism which was reported by Bobbitt et al. as an alternative for the TEMPO oxidation of alcohols under neutral or acidic conditions.11 Taking intermediate C into account, steric hindrance of the


19


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

Page 20 of 43

bulky secondary alcohols is likely relaxed, permitting the oxidation to occur. The interaction between the lone pair of the nitrogen atom and the hydrogen atom of the hydroxyl group in the alcohol plays an important role in this reaction mechanism.

N

[O]

[O]

O

TEMPO X N

N

OH O

A

R R'

HO H

-HX X H O

N O

O

H

R R'

R R'

C Scheme 6 The plausible reaction mechanism

5. Oxidation of organosulfur compounds 5-1. Selective oxidation of sulfides to sulfoxides12 Sulfoxides are important and useful compounds in organic synthesis, because they are frequently used as the intermediates for the construction of several important organic molecules. In addition to this, there are many biologically-important compounds containing a sulfoxide moiety. They are mainly prepared by the oxidation of the corresponding sulfides; however, it is sometimes difficult to stop the oxidation at the sulfoxide stage. Consequently, several selective sulfide oxidations have been developed to more effectively synthesize sulfoxides.13 Although they provide the desired sulfoxides in high yields, some are accompanied by large amounts of undesirable waste derived from the oxidants. As we emphasized in the introduction, NaOCl has several merits as an environmentally-


20

Page 21 of 43

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


benign

oxidant. Despite these merits, NaOCl has seldom been used for the synthesis of

sulfoxides from sulfides, because it is difficult to selectively obtain the desired sulfoxides without producing the over-oxidized sulfone. The use of TEMPO as a catalyst has been required to obtain the sulfoxides in high yields.14 We expected that the oxidation of sulfides with NaOCl·5H2O might be an excellent method for the selective preparation of sulfoxides.

5-1-1. Optimization of the reaction conditions The reactions of thioanisole with 1.1 equiv. of NaOCl (conventional 12 wt% aq. NaOCl solution or NaOCl·5H2O crystals) in acetonitrile were examined in the absence of a catalyst (Scheme 7). In the case of the NaOCl·5H2O crystals, the desired sulfoxide was selectively obtained in 18 min. Conversely, the conventional aq. NaOCl reacted more slowly with the sulfide to produce the sulfoxide in 79% yield accompanied by a certain amount of the overoxidized sulfone.

O

12% aq. NaOCl (1.1 equiv.) Ph

CH 3CN, r.t., 4 h Ph

S

CH 3

Sulfide

+

S

CH3 79% a

O O S + S Ph CH3 Ph CH3 a 5% 16% a

O

NaOCl5H 2 O (1.1 equiv.) CH3CN/H2 O (5:1 v/v) r.t., 18 min

Ph

S

+ CH3

98% b

Sulfoxide a b

O O S Ph CH3 2%b

Sulfone

Based on 1H NMR signal ratio (CH3 protons) Isolated yields

Scheme 7 Reaction of thioanisole with NaOCl

As we described in the previous chapters, the main difference between NaOCl·5H2O and aq.NaOCl is their pH values. Therefore, the reactivities of NaOCl·5H2O and conventional aq.


21


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

Page 22 of 43

NaOCl were compared while altering the pH with HCl or NaOH (Table 10). At pH 11, the reaction rapidly proceeded to selectively afford the desired sulfoxide (runs 1, 2). At pH 13, on the other hand, the reaction was not complete after 4 h, and a significant amount of overoxidized sulfone was produced along with the desired sulfoxide (runs 3, 4). As we had surmised, the selectivity of this reaction depends on the basicity of the reaction mixture. These results show that the ideal pH range for the selective production of the sulfoxide is 10−11.

Table 10 Reactivity of NaOCl·5H2O and conventional aqueous NaOCl solutions

Ph

S

12% aq. NaOCl (1.1 equiv.) CH3

O

CH3 CN, r.t.

CH3

O O S Ph CH3

Sulfoxide

Sulfone

Ph

Sulfide

S

+

1H

NMR ratios (%) (CH3 protons)

Run

NaOCl

pH

Time

1

Prepared from NaOCl5H 2O

11

20 min

1

99

0

2

Conventional aqueous solution + HCl

11

20 min

0

97

3

3

Prepared from NaOCl5H 2O + NaOH

13

4h

18

66

16

4

Conventional aqueous solution

13

4h

5

79

16

5

Prepared from NaOCl5H 2O + HCl

10

20 min

1

98

1

6


9

20 min

8

88

4

7


8

4h

37

8

55

8


7

4h

38

7

55

Sulfide Sulfoxide Sulfone

Although the conventional aqueous NaOCl adjusted to pH 11 with HCl can provide the desired sulfoxide in high yield, as a practical oxidant, it has some drawbacks (low concentration, unstable, etc.) as we mentioned in the earlier chapters. In addition, it is very important to add the correct amount of oxidant in order to prevent over-oxidation during the


22

Page 23 of 43

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


selective oxidation of sulfides to the corresponding sulfoxides. However, during storage of the conventional aq. NaOCl, the NaOCl concentration gradually decreases, even when it is stored in a refrigerator. Therefore, titration is required to determine the exact concentration before use. If a higher concentration of the NaOCl solution is desired (e.g., 20wt % NaOCl, as demonstrated in Table 13 entry 2, for gram-scale synthesis), it can be prepared from crystalline NaOCl·5H2O and water. This would be useful in large-scale syntheses due to the need for a high volume efficiency and reduced waste water. Consequently, NaOCl·5H2O is much more convenient than aqueous NaOCl for such applications. The survey of the solvent effects on the reaction of thioanisole with NaOCl·5H2O revealed that acetonitrile is appropriate solvent for this reaction. It selectively provided the sulfoxide in high yield with a shorter reaction time (run 1) among the several experimental conditions as shown in Table 11.

Table 11 Reaction of thioanisole (sulfide) with NaOCl·5H2O in a mixture of various organic solvents and water Ph

S

CH3

Sulfide Run

O

12% aq. NaOCl (1.1 equiv.) prepared from NaOCl・5H 2O

Ph

solvent/H 2O (5:1 v/v), r.t.

1

CH3CN

2

CH2Cl2

3

CH2Cl2 + 5 mol% Bu 4HSO4

4

EtOAc

5

EtOAc + 5 mol% Bu4NHSO4

6

toluene

7

toluene + 5 mol% Bu4NHSO4

CH3

Sulfoxide Time (h)

Solvent

S

+

O O S Ph CH3 Sulfone

1

H NMR ratios (%) (CH3 protons) Sulfoxide

Sulfone

0

98

2

50

43

7

13

68

19

24

8

69

23

3

13

68

19

24

42

4

54

4

38

7

55

0.3 24 3.5

Sulfide


23


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

Page 24 of 43

The acetonitrile/water ratios were variable to afford similar results between 5:1 and 50:1 (Table 12). In the absence of water (run 5), the reaction did not reach completion even after 20 h affording the sulfoxide in an unsatisfactory yield accompanied by a significant amount of the sulfone. Since NaOCl·5H2O crystals are hard to dissolve in pure acetonitrile, the reaction proceeds very slowly. Table 12 Optimization for the ratio of acetonitrile to water

5-1-3. Selective synthesis of sulfoxides from the reaction of sulfides with NaOCl·5H2O The optimized oxidation of sulfides with 1.1 equiv. of NaOCl·5H2O in aqueous acetonitrile was used for the synthesis of various sulfoxides (Table 13). The desired sulfoxides were selectively obtained in high yields in all cases. It is notable that an alkene moiety (entry 6) and a pyridine ring (entry 12) were inert under these reaction conditions.


24

Page 25 of 43

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 13 Reaction of sulfides with NaOCl·5H2O in aqueous acetonitrile R1

S

NaOCl5H 2O (1.1 equiv.)

R2

Sulfide

CH3CN/H2O (5:1 v/v )a, r.t.

(2 mmol)

Catalyst Free

O R1

S

+ R2

Sulfoxide

O O S 2 R R 1

Sulfone Isolated yield (%)

Entry

R1

R2

Time (min)

1

Ph

CH3

18

98

2

2b

Ph

CH3

20

96

3

3

4-MeOC 6H 4

CH3

6

99

1

4

4-ClC6H 4

CH3

11

93

5

5

4-O2 NC6H 4

CH3

10

83

7

6

Ph

CH2CH=CH 2

8

86

2

7

Ph

Bn

7

86

trace

8

Bn

Bn

10

89

trace

9

Bn

CH3

39

76

0

10

CH3 (CH 2) 9

CH3

9

quant.

0

11

Ph

Ph

25

95

5

12

2-Py

CH3

23

84

7

24

86

6

Sulfoxide

Sulfone

S 13 c

a

CH3CN (10 mL) and H2O (2 mL) were used. Thioanisole (2.48 g, 20 mmol), aqueous 20.6% NaOCl (7.59 g, 21 mmol) from NaOCl5H2O and CH3CN (100 mL) were used. A water bath (ca. 20°C) was used to control the reaction temperature for a gram-scale synthesis. c Dichloromethane was added to dissolve 1 in the solvent. Bu4 NHSO4 (0.05 equiv.) was also added. b

5-2. Efficient synthesis of sulfones from sulfides15 Synthetic studies of the sulfone by the oxidation of sulfides with NaOCl·5H2O and conventional aq. NaOCl were examined. Under the similar condition to sulfoxide synthesis using 2.4 eq. NaOCl·5H2O gave the desired sulfone in 78% yield along with α-chlorinated compounds. After solvent survey, aromatic hydrocarbons were found to be optimal solvents to give excellent results as shown in Table 14.


25


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

Page 26 of 43

Table 14 Solvent effect for the oxidation of thioanisole by NaOCla

Ph

S

13 wt% aq. NaOCl (2.4 eq.) prepaed from NaOCl5H2O CH3

Solvent, 20 °C

O + S Ph CH3

O O O + S S Ph CH3 Ph

Cl +

O O S Ph

Cl

(0.33 M)

Run

a b c

Solvent

Time (h)

Sufoxide

GC area %b ChloromethylSulfone sulfoxide

Chloromethylsulfone

1

Acetonitrile

6

8

78

5

9

2

Toluene

6

0

99

Sodium Hypochlorite Pentahydrate Crystals (NaOClÂ·5H2O): A

Recommend Documents