Remarkable Improvement of Organic Photoreaction Efficiency in the

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Remarkable Improvement of Organic Photoreaction Efficiency in the Flow Microreactor by the Slug Flow Condition Using Water Momoe Nakano, Yasuhiro Nishiyama, Hiroki Tanimoto, Tsumoru Morimoto, and Kiyomi Kakiuchi Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00181 • Publication Date (Web): 11 Aug 2016 Downloaded from http://pubs.acs.org on August 16, 2016

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Organic Process Research & Development

Remarkable Improvement of Organic Photoreaction Efficiency in the Flow Microreactor by the Slug Flow Condition Using Water Momoe Nakano, Yasuhiro Nishiyama,* Hiroki Tanimoto, Tsumoru Morimoto and Kiyomi Kakiuchi* Graduate School of Materials Science, Nara Institute of Science and Technology (NAIST), 89165 Takayama, Ikoma, Nara, 630-0101, Japan.

Corresponding Author *Phone: +81-743-72-6085, E-mail: [email protected] (Y. N.) *Phone: +81-743-72-6080, E-mail: [email protected] (K. K.)

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Abstract

A typical (Paternò-Büchi type) organic photoreaction is examined in flow microreactors. Compared to the results achieved for simple one-layer flow modes, slug flow conditions (with the unreactive reagent composed of organic solution and water) achieve higher efficiency (conversion and yield) irrespective of the light source, concentration, and solvent. Furthermore, remarkably high productivity is also observed when only 5% water is added as an unreactive reagent. This method is broadly applicable for achieving highly efficient organic photoreactions not only in the laboratory, but also on the industrial scale.

Keyword Flow microreactor; Slug flow; Paternò-Büchi type photoreaction; Organic photoreaction; Microphotochemistry

Introduction Organic photoreactions enable one-step (photoirradiation) synthesis of highly complex or strained compounds that are difficult to synthesize using conventional thermal reactions.1 For example, cyclobutane derivatives are highly important intermediates for the synthesis of various natural products.2 Despite being strained, these compounds are very easily and efficiently formed in [2+2] photocycloadditions between two olefins.3 Thus, various types of organic photoreactions have been investigated as a synthetic method complementary to thermal reactions. Despite this merit, organic photoreactions have been limited to lab-scale reactions only, due to the difficulty of efficient photoirradiation in typical batch reactors. Highly


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concentrated solutions or large apparatus disturb photon penetration according to the BeerLambert law: A=ɛ×c×l (where A is the absorbance, ɛ is the molecular absorption coefficient, c is the molar concentration, and l is the optical path length). To overcome these problems, flow microreactors4 with micrometer-size inner dimensions have been recently employed for organic photoreactions. Flow microreactors allow the reactions to proceed very efficiently due to their very short optical path length. In the past two decades, many examples of efficient photoreactions have been published.5 Our group has also reported diastereoselective [2+2] photocycloadditions of cyclohexenone derivatives (bearing menthylbased moieties as chiral auxiliaries) with ethylene gas6 and cyclopentene7 in flow microreactors (fluorinated ethylene-propylene copolymer (FEP) tubing as microcapillary reactors (inner diameter (i.d.) 1 mm)6, plate-type reactors (depth 100 µm7a or 200 µm7b), and Pyrex® tubes (i.d. 0.6 mm)7c), which are more efficient compared to batch reactors (Pyrex® test tube, i.d. 13 mm). Furthermore, we performed diastereoselective Paternò-Büchi type photoreactions of menthyl benzoylformate with 2,3-dimethyl-2-butene using FEP tubing as flow microreactors under slug flow conditions, where the slug was composed of organic solutions (toluene) and unreactive reagents (nitrogen gas or water).8 Generally, the slug flow condition is employed for heterogeneous reactions such as oxygenation using oxygen gas.9 For example, Oelgemöller et al. performed the photooxygenation of 1,5-dihydroxynaphthalene, furfural, α-terpinene, and citronellol with singlet oxygen sensitized by rose bengal in a glass column reactor.9c Under the slug flow condition, they reported a higher efficiency of photooxygenation than that under the oxygen bubble flow condition. They concluded that a slug flow pattern allowed for superior mass transfer and light transparency within a thin solvent layer along the side of the gas segment. Oxygen is an essential reagent in this context, however, nitrogen or water was shown in our


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previous report8 to be inert to the reaction. Nevertheless, surprisingly, the slug flow conditions utilizing the organic solution and water at a 1:1 flow rate ratio increased the photoreaction conversion twofold compared to normal (one-layer) flow conditions, although the diastereoselectivity was unchanged. The reasons for efficiency enhancement by slug flow conditions, however, remained unknown. In addition, the reactor productivity (obtained product amount) did not exceed the value for normal flow conditions, since the flow volume of organic solutions under slug flow conditions (1:1 flow rate ratio) was half of that under normal flow conditions. In order to determine the cause of the efficiency improvement and to achieve higher productivity under slug flow conditions, we selected ethyl benzoylformate as a simplified substrate and investigated its achiral Paternò-Büchi type photoreaction with 2,3-dimethyl-2butene10 in flow microreactors at various conditions (light source, solvent, concentration, and segment length ratio) (Scheme 1, Figure 1).

Scheme 1. Paternò-Büchi type photoreactions of ethyl benzoylformate with 2,3-dimethyl-2butene under various conditions.


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Figure 1. Reaction setup for Paternò-Büchi type photoreactions using FEP tube as flow microreactors.

Results and Discussion The transmission of light in each reactor In order to calculate the light penetration of substrate in each reactor, we firstly measured the absorption spectrum in toluene using a normal cuvette cell (Figure 2). The high pressure mercury lamp employed as a light source in this research, generally emits the peak light wavelength at both 313 nm and 365 nm. A molar extinction coefficient (ε) at each wavelength was determined as 277.3 (313 nm) and 45.1 (365 nm) (L mol-1 cm-1) respectively. From these values and the Beer-Lambert law, the light transmission (I/I0; I = transmitted light intensity, I0 = incident light intensity) for substrate solution at each wavelength was calculated as shown in Figure 3. As indicated by the vertical dotted line at 13.0 mm in Figure 3, most light cannot be transmitted through a sample solution in a Pyrex® test tube especially at 313 nm; however, a higher


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transmission was observed in an FEP tube (vertical dotted line at 1.0 mm), presumably due to its very short pathlength.

Molar extinction coefficient/L mol-1 cm-1

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Figure 2. UV-vis spectrum of substrate in toluene.

0.01 M 0.04 M 0.11 M 0.25 M

0.01 M 0.04 M 0.11 M 0.25 M


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Figure 3. Transmission spectrum of substrate in toluene at (a) 313 nm and (b) 365 nm in toluene (black: 0.01 M; blue: 0.04 M; green: 0.11 M; red: 0.25 M).

The effect of reactor and light source First, the reaction efficiency (conversion and yield) for various reaction vessels and light sources was examined (Table 1). Under the usual conditions of a flow microreactor, less than one tenth of the photoirradiation time required for batch conditions was necessary to achieve similar conversion and yield (entries 1, 2, 3, and 5). This efficiency increase is due to the short optical path length of a flow microreactor. Higher conversion and yield (over 1.5 times) were achieved under slug flow conditions (1:1 ratio) than under normal flow conditions for all photoirradiation times (entries 4 and 6 versus entries 3 and 5). Obviously, no product was observed in the water segments by 1H-NMR. In case of a simple black light (15 W), prolonged photoirradiation (1200 sec) was required to achieve similar conversion and yield (entries 3 and 7); however, it also improved photoreaction efficiency under slug flow conditions, although not by much (entries 7 and 8). These findings indicate that our previous results8 are not specific, and highly efficient photoreactions can always be observed under slug flow conditions.

Table 1. Paternò-Büchi type photoreactions in toluene conducted using different light sources and reaction vessels.a

Entry 1 2

Light sourceb

Methodc

A

Batch

Enhancement

Irr. Time (sec)

Conv. (%)d

Yield (%)d

Conv.

Yield

140

34

21

‒

‒

240

52

34

‒

‒


8

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3

One

4

Two

5

One

6

Two

7

B

8

One

10

20

1200

Two

32

21

‒

‒

55

36

1.7

1.7

54

34

‒

‒

80

51

1.5

1.5

32

24

‒

‒

37

27

1.2

1.2

a

[Sub.] = 0.01 M. b (A) 500-W high pressure mercury lamp. (B) 15-W black light. c ‘One’ stands for one-layer flow, ‘Two’ stands for slug flow. d Determined by gas chromatography.

In order to discuss the result at higher conversion, we further examined the time course of the reaction using a high pressure mercury lamp as a light source (Table 2). This photoreaction shows almost 90 % conversion, to the maximum (entries 9 and 13) due to the inhibition of photoexcitation by byproducts. The obvious improvement in conversion and yield under the slug flow condition was observed even at higher conversion. From the comparison of entry 7 and entry 12, the slug flow condition enables a reduction of the irradiation time to less than half (Figure 4).

Table 2. The time course of Paternò-Büchi type photoreactions in toluene by using microreactors.a Methodb

Irr. Time (sec)

Conv. (%)c

Yield (%)c

one

15

46

29

2

20

54

34

3

25

64

40

4

30

70

44

5

40

76

50

Entry 1


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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

6

50

82

53

7

55

84

53

8

60

86

56

9

90

88

54

15

68

44

11

20

80

51

12

25

85

54

13

30

88

57

10

a

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Two

[Sub.] = 0.01 M. b ‘One’ stands for one-layer flow, ‘Two’ stands for slug flow. c Determined by

gas chromatography.

Figure 4. The time course graphs of (a) conversion and (b) yield in Paternò-Büchi type photoreactions under one-layer condition (One) and slug flow condition (Two).

The effect of solvent


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Next, in order to understand why slug flow conditions improve photoreaction efficiency, various solvents were screened. As shown in Table 3, toluene, the most highly refractive index of the three solvents, showed the largest reaction efficiency improvement (entries 2, 4, and 6). Previously, we assumed that this improvement was caused by a combination of three factors:8 1) a very thin layer (< 0.1 mm) of organic solutions between the water layer and the wall of the FEP tubing, 2) vigorous stirring of the organic segment caused by the movement of water, 3) light confinement caused by the refractive index difference between organic solutions and water. As previously mentioned, a very thin layer generated along the side of the water segment is effective for the photoreaction to proceed. However, if the effect of 1) or 2) was only dominant factor, a similar enhancement would be obtained for all solvents, since these effects would be solventindependent. Actually, an obvious difference in results was obtained for each solvent. Thus, the improvement in photoreaction efficiency is caused by the cooperative effect of the thin solvent layer and photon confinement due to the difference in the refractive index between organic solvent and water (Figure 5).

Table 3. Paternò-Büchi type photoreactions conducted using various solvents in a flow microreactor.a

Entry 1 2 3 4

Solventb (R. I.) Toluene (1.50) Chloroform (1.44)

Methodc

Conv. (%)d

Yield (%)d

Enhancement Conv.

Yield

One

32

21

‒

‒

Two

55

36

1.7

1.7

One

46

25

‒

‒

Two

60

34

1.3

1.4


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5 6

n-hexane (1.37)

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One

29

21

‒

‒

Two

38

26

1.3

1.3

a

[Sub.] = 0.01 M. Irradiation time is 10 sec. b R. I. means refractive index. c ‘One’ stands for one-layer flow, ‘Two’ stands for slug flow. d Determined by gas chromatography.

Figure 5. Thin layer generated along water segments and light confinement in a flow microreactor under slug flow conditions; n stands for refractive index.

The effect of concentration Based on the results of the solvent screening, it can be expected that not only the thin organic solvent layer but also the light confinement effect under slug flow conditions can improve both the reaction efficiency and its productivity. By confining the light in organic solutions, reactions are expected to proceed smoothly even in harsh conditions. As a result, the difference between normal and slug flow conditions should increase. The reaction productivity for slug flow conditions normalized with respect to normal flow conditions (Pslug) is calculated as follows: Pslug = (yield increase) × (volume fraction of the organic solution). In order to exceed the productivity of normal flow conditions, the value of Pslug must exceed unity. In this case (1:1


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water/organic solvent ratio), a more than twofold yield increase is required, since the volume fraction of the organic solution in the 1:1 mixture is equal to 0.5. To verify our hypothesis, photoreactions were performed at various concentrations in harsh conditions (Table 4). The irradiation time was controlled to obtain similar conversions or yields for each normal flow condition. Longer photoirradiation times were required at higher concentrations, as anticipated from the Beer-Lambert Law (entries 1, 3, 5, and 7). The photoreaction proceeded more efficiently under slug flow conditions at every concentration used; however, contrary to our expectation, the reaction enhancement was hampered by increasing concentration (entries 2, 4, 6, and 8). Even if the light in organic solutions was confined, the photoreaction would obey the Beer-Lambert law, and would be suppressed in highly concentrated solutions.

Table 4. Paternò-Büchi type photoreactions in toluene in flow microreactors at various substrate concentrations.

Entry 1

Conc. (M)

Methoda

0.01

One

2 3 4 5

8

Yield (%)b

Conv.

Yield

10

32

21

‒

‒

55

36

1.7

1.7

One

34

25

‒

‒

50

38

1.5

1.5

31

22

‒

‒

40

31

1.3

1.4

30

23

‒

‒

41

31

1.4

1.3

25

Two 0.11

6 7

Conv. (%)b

Two 0.04

One

45

Two 0.25

One Two

Enhancement

Irr. Time (sec)

90

a

‘One’ stands for one-layer flow, ‘Two’ stands for slug flow. chromatography.

b

Determined by gas


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The effect of segment length Based on the solvent screening results, we concluded that the light confinement effect is one of the key factors for improving the reaction efficiency. This effect may also be influenced by segment length, which was also investigated (Table 5). The segment length can be easily controlled by changing the flow rates of organic solutions and water. In entries 2 and 3, changing the segment length while maintaining a 1:1 flow rate ratio, leads to very similar results. This indicates that the change of segment length from 2 mm to 4 mm does not influence the photoreaction efficiency; thus, the thin organic solvent layer mainly improves the reaction efficiency. Changing the flow rate ratio from 1:1 to 3:1 (organic solution:water) caused a small enhancement of the reaction efficiency (entries 2, 3, and 4). As the volume fraction of the organic solution is increased, the conditions in the capillary reactor gradually change to normal flow. Thus, it is easy to understand why the degree of enhancement was lowered in this case.

Table 5. Paternò-Büchi type photoreactions in toluene in flow microreactors with various segment length.a

Entry

Method

b

Length (Solution:water) (mm)

Conv. (%)c

Yield (%)

Enhancement c

Conv.

Yield

1

One

‒

32

21

‒

‒

2

Two

2:2d

55

36

1.7

1.7

3

4:4d

53

35

1.7

1.7

4

5:2e

48

31

1.5

1.5

a

[Sub.] = 0.01 M. Irradiation time is 10 sec. b ‘One’ stands for one-layer flow, ‘Two’ stands for slug flow. c Determined by gas chromatography. d Flow rate ratio is 1:1. e Flow rate ratio is 3:1 (organic solution:water).


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In our previous work, the same tendency was observed.8 Conversely, despite increasing the fraction of the organic solution, much higher yield and conversion were observed, compared to those obtained under normal flow conditions. It is expected that higher productivity could be achieved if the high yield and conversion were maintained for high flow rate ratios. Hence, we performed the photoreaction for various flow rate ratios (related to fractions of organic solution, e.g., a 9:1 ratio corresponds to a 90% fraction) (Table 6).

Table 6. The Pslug

value of Paternò-Büchi type photoreactions in toluene using flow

microreactors under various flow rate conditions.a Flow Rate Ratioc

Conv. (%)d

Yield (%)d

Conv.

Yield

One

‒

32

21

‒

‒

‒

Two

1:1

55

36

1.7

1.7

0.86

3

3:1

48

31

1.5

1.5

1.13

4

5:1

45

30

1.4

1.4

1.17

5

7:1

44

29

1.4

1.4

1.23

6

9:1

42

29

1.3

1.4

1.26

7

15:1

41

27

1.3

1.3

1.22

8

20:1

40

28

1.3

1.3

1.24

One

‒

30

23

‒

‒

‒

Two

1:1

41

31

1.4

1.3

0.65

11

5:1

35

26

1.2

1.1

0.92

12

20:1

35

28

1.2

1.2

1.14

Entry 1

Conc. (M)

Methodb

0.01

2

9 10

0.25

Enhancement Pslug


15


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a

Irradiation time is 10 sec (0.01 M) or 90 sec (0.25 M). b ‘One’ stands for one-layer flow, ‘Two’ stands for slug flow. c Ratio is organic solution:water. d Determined by gas chromatography.

Increasing the fraction of the organic solution caused a reduction of both conversion and yield. In addition, Pslug was less than 1 for the 1:1 ratio (entry 2), as already indicated. At ratios greater than 3:1 (entries 3 to 8), however, Pslug exceeded 1. As the ratios were increased, Pslug also gradually increased; consequently, Pslug = 1.2 was accomplished at a 20:1 ratio (entry 8). This result indicates that the presence of only 5% water as an unreactive reagent causes higher productivity. Under these conditions, the light confinement effect is expected not to be so predominant, since the environment in the flow microreactor resembles the normal flow conditions. Thus, the effects of a thin layer and/or vigorous stirring should also play a key role, in addition to the light confinement effect. Even at high concentrations (0.25 M), Pslug values greater than 1 were observed (entry 12). In addition, under the 20:1 condition, the slug flow mode enabled an efficient shortening of the irradiation time, even at higher conversion and yield (Table 7 and Figure 6). Therefore, the slug flow condition exhibits good potential for obtaining a greater amount of products compared to both batch reactors and flow microreactors under conditions of normal flow.

Table 7. The time course of Paternò-Büchi type photoreactions in toluene using microreactors both at one-layer flow and at 20:1 flow ratio condition.a Entry 1 2

Methodb

Irr. Time (sec)

Conv. (%)c

Yield (%)c

one

10

32

21

20

54

34


16

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3

25

64

40

4

30

70

44

5

40

76

50

6

50

82

53

7

55

84

53

8

60

86

56

10

40

28

10

20

65

44

11

30

79

53

12

35

82

55

13

40

86

60

9

Two

a

[Sub.] = 0.01 M. b ‘One’ stands for one-layer flow, ‘Two’ stands for slug flow. c Determined by gas chromatography.

Figure 6. The time course graphs of (a) conversion and (b) yield in Paternò-Büchi type photoreactions under one-layer condition (One) and slug flow condition at 20:1 flow rate ratio (Two).


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Page 18 of 24

Conclusions In this work, simple Paternò-Büchi type photoreactions were performed in flow microreactors. Dramatically improved photoreaction efficiency (conversion and yield) was observed, especially under slug flow conditions utilizing organic solutions and water. This improvement was observed irrespective of reaction substrate or light source. From the solvent screening results, it was determined that not only the thin organic solvent layer formed between water segment and tube wall but also the light confinement effect play key roles in improving the reaction efficiency, owing to the difference of refractive indices of organic solutions and water. Furthermore, changing the flow rate ratio influences the reaction efficiency. Specifically, for the 20:1 flow rate ratio, a 1.2 times higher productivity was achieved compared to that under normal flow conditions. Because the refractive index of organic solvents is one of key factors, this method is very effective for the improvement of organic photoreactions efficiency. In addition, since the water segments are easily separable after the photoreaction, it is expected that a water recycling system can be established relatively easily. George et al. have reported the efficient photochemical synthesis of artemisinin using a continuous flow reactor.11 Because the photoreaction proceeded in the homogeneous aqueous mixture of organic solvent, this example is clearly different from our system (heterogeneous slug flow condition); however, it achieved that solvents, photocatalysts, and aqueous acids could be used repeatedly in their system. Therefore, our method can also be further applied in industrial-scale organic photoreactions to obtain greater product volumes by establishing the recycle system.

Experimental section


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General Ethyl benzoylformate, 2,3-dimethyl-2-butene and pentadecane (Standard Material for GC) were purchased and used without further purification. Toluene, chloroform and n-hexane were purchased as a spectrograde solvent, and used without further purification.

Apparatus for photoreactions Both a 500 W high-pressure Hg lamp and a 15 W black light were utilized as the light source, with a Pyrex® immersion well. The reaction setup was placed in a MeOH-containing cooling bath for temperature controlling (10 °C). For the flow condition, the FEP tubing (i.d.: 1.0 mm; transmitted light λ>230 nm) was employed as an irradiation unit. The FEP tubing was tightly wrapped around a Pyrex® immersion well (Figure 7). The flow rates of both organic solutions containing substrates and water were controlled by a syringe pump. A µ-mixer (i.d.: 600 µm) was used as a T-shaped connecter.

Figure 7. The reaction setup of flow microreactors and each light source; (a) 500 W high pressure Hg lamp, (b) 15 W Black light.


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Photoreaction in a Pyrex® test tube (Batch condition) Substrate (8.0 µL, 0.050 mmol) and pentadecane (3.0 µL, 0.012 mmol, 0.24 eq.) were put in a Pyrex® test tube (i.d.: 13.0 mm; transmitted light λ>280 nm), and purged with nitrogen gas for 5 min at room temperature. Toluene (5 mL) in other flask was also purged with nitrogen gas for 5 min at room temperature, and was moved to the first Pyrex® test tube with a syringe. Then 2,3dimethyl-2-butene (12 µL, 0.10 mmol, 2.0 eq.) was added to the solution. A balloon containing nitrogen gas was attached to the top of the test tube. After photoirradiation, conversions and yields were determined by gas chromatography with pentadecane as an internal standard.

Photoreaction in a flow microreactor A 50 cm FEP tube (2 m FEP tube in case of black light irradiation owing to the long irradiation period) was utilized as an irradiation unit (Figure 7). Appropriate amount of substrate and pentadecane (0.24 eq.) were put in a flask, and purged with nitrogen gas for 5 min at room temperature. Toluene (10 mL) in other flask was also purged with nitrogen gas for 5 min at room temperature, and moved to the first flask with syringe. Then 2,3-dimethyl-2-butene (2.0 eq.) was added to the solution. This solution was loaded into a gas-tight syringe, and attached to a syringe pump. Water also was loaded into an another gas-tight syringe when performing the slug flow condition. T-shaped mixer inlets were connected to both gas-tight syringes, and the outlet was connected to the irradiation unit. The solution and water flow rate were controlled according the target irradiation time. After irradiation, conversions and yields were determined by gas chromatography with pentadecane as an internal standard.

Product analysis


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Analytical gas chromatography was carried out with a ZB-WAX plus column. The column oven temperature was maintained at 160 °C and the injection and detector were maintained at 200 °C. The carrier gas (helium gas) pressure was maintained at 200 kPa. The retention time of each compound was as below: substrate: 8.3 min; product: 12.8 min; pentadecane: 1.8 min.

note The authors declare no competing financial interest.

ACKNOWLEDGEMENT This work was supported in part by a Grant-in-Aid for Young Scientists (B) (No. 25870437), a Grant-in-Aid for Scientific Research (B) (No. 24310101, 15H03544) from the Japan Society for the Promotion of Science (JSPS), and a Grant-in-Aid for Scientific Research on Innovative Areas (No. 24106729, 16H01154) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT). Furthermore, NAIST under the project for “Green Photonics Research” supported this work. We would like to thank Editage (www.editage.jp) for English language editing.

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Remarkable Improvement of Organic Photoreaction Efficiency in the

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