An efficient synthesis of gem-diiodoolefins and (E)-iodoalkenes from propargylic amides with a Cu(I)/Cu(III) cycle

Abstract

gem-Dihaloalkenes are very important building blocks widely used in organic synthesis. However, the synthetic methods available for this functional group are very limited. Starting from an unexpected copper-catalyzed cyclization of propargylic amides, a new route for the synthesis of gem-dihaloalkenes was developed. According to the plausible Cu(I)/Cu(III) catalytic cycle, another oxidative iodination protocol was developed. Through this improved method, a series of gem-diiodoolefins were synthesized in high yields. In addition, (E)-iodoalkenes could also be synthesized efficiently using the same approach, which is complementary to the gold-catalyzed reaction giving (Z)-iodoalkenes. These iodoolefins could be further transformed into various trisubstituted or tetrasubstituted alkenes, enynes, dienes and trienes with palladium-catalyzed coupling reactions.

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1. Introduction

1,1-Dihalo-1-alkenes represent an important type of organic compounds. They exist in many bioactive natural products as well as pharmaceuticals (Scheme 1).¹ For example, deltamethrin^1a products bearing a gem-dibromoalkene functional group are among the most popular and widely used insecticides in the world. More importantly, 1,1-dihalo-1-alkenes are very valuable synthetic intermediates used in synthetic chemistry.² In the presence of a base or metal reagent, 1,1-dihalo-1-alkenes went through α-elimination generating vinylidene type intermediates, and the subsequent migration of H atoms or the alkyl group formed alkynes (Scheme 2). Thus 1,1-dihalo-1-alkenes are widely used as alkyne equivalents, such as the well-known Corey–Fuchs reaction.³ By using this method, the Kibayashi group realized the total synthesis of pumiliotoxin A and 225F from gem-dibromoalkenes.⁴ Recently, the blossoming of transition-metal catalyzed cross coupling reactions has made this gem-dihaolo-1-alkenes extremely useful in the synthesis of various important heterocycles (Scheme 2). For example, through the sequential intramolecular and intermolecular coupling reactions, Lautens et al. developed a series of efficient methods for the construction of multisubstituted indoles, benzofurans, and benzothiophenes.⁵ The Wu group developed an efficient synthetic method for polyfluoroarylpyrrolo[1,2-α]quinolines via palladium-catalyzed double arylation reactions of gem-dibromoalkenes.⁶

Scheme 1 Natural products and pharmaceuticals containing gem-dihaloalkenes.

Scheme 2 Synthesis of gem-dihaloalkenes and their synthetic applications.

1,1-Dihalo-1-alkenes are important building blocks in organic syntheses, however the synthetic methods available for this functional group are very limited. The current methods mostly focus on the Wittig type reaction between carbonyl compounds and tetrahalocarbon (Scheme 2).⁷ However, this protocol requires a large excess amount of triphenylphosphine (4–6 equiv.), which is not ideal from the point view of atom economy and green chemistry. The development of other practical synthetic methods is highly desirable. We have reported herein a facile synthesis of gem-diiodoolefins with a Cu(I)/Cu(III) catalytic cycle. Following this approach, various vinyl halides with different stereo-configurations could be easily prepared. The obtained gem-diiodoolefins were further transformed into tetrasubstituted olefins with the palladium-catalyzed cross coupling reactions.

2. Results and discussion

2.1 An unexpected synthesis of gem-diiodoalkenes from iodoalkynes with a Cu(I)/Cu(III) catalytic cycle

In recent years, haloalkynes have emerged as a type of powerful and versatile building blocks widely used in organic syntheses.⁸ The alkyne and halide parts, serving as two functional groups, were transformed into various functionalized alkynes and heterocycles through addition, cross coupling or cycloaddition reactions.⁹ As a continuation of our research interests in Pi acid transition-metal-catalyzed reactions,¹⁰ we studied the cyclization reaction of propargylic amide¹¹1a. When Ph₃PAuNTf₂ was used as the catalyst, the desired (Z)-iodoalkene 2a was isolated in 83% yield. However, this product was not stable, probably because it could isomerize into the aromatic oxazole through double bond migration (eqn (1), Scheme 3). To our surprise, when CuI was used as the catalyst, another unknown gem-diiodide product 3a was observed as the major product. Its structure was unambiguously characterized by NMR, Mass and also single crystal X-ray analysis (eqn (2), Scheme 3). Under these conditions, this product was isolated in 45% yield. However, its isolated yield is as high as 90% based on the iodine source. Through a detailed analysis of the reaction mixture, the de-iodine amide 4a was isolated in 42% yield.

Scheme 3 Gold or copper-catalyzed cyclization of propargylic amides.

Based on these results, a plausible Cu(I)–Cu(III) catalytic cycle was proposed for this unexpected reaction (Scheme 4).¹² Copper(I)-catalyzed intramolecular 5-exo-dig cyclization generated alkene copper intermediate M₁. Subsequent oxidative addition with alkyne iodide 1a formed the Cu(III) intermediate M₂, which went through reductive elimination generating gem-diiodide alkene 3a and another alkyne copper intermediate. Protonation of this intermediate formed the amide 4a and regenerated the copper(I) catalyst. It should be noted that Hu et al. also observed a similar mechanism in the reaction of AgCF₃, benzyne and alkyne iodide.¹³ Also, Boger and Gevorgyan demonstrated that haloalkynes could serve as an effective source of the corresponding X⁺ in their earlier reports.¹⁴

Scheme 4 Proposed Cu(I)–Cu(III) catalytic mechanism.

A screening of different copper catalysts indicated that this is a general reaction for all the copper salts tested (Table 1). Not only Cu(I), but also Cu(II) was effective for this transformation. Copper(II) was probably reduced to Cu(I) to catalyze this reaction. Among all the copper catalysts, the very cheap CuSO₄ was the optimal choice and the target diiodide 3a was isolated in 95% yield in DCE solution (entry 7). Other solvents led to reduced yields (entries 10–13). A blank test showed that a copper catalyst is necessary for this transformation (entry 14).

Table 1 Optimization of reaction conditions^a

Entry	Catalyst	Solvent	Yield^b (%)
a Reaction conditions: 1a (0.1 mmol), [Cu] (0.01 mmol) in the solvent (1 mL) was stirred at 70 °C for 3 h. b Isolated yields based on the iodine source.
1	CuI	DCE	90
2	CuCl	DCE	86
3	CuBr	DCE	72
4	CuPF6(CH3CN)4	DCE	50
5	IprCuI	DCE	69
6	Cu(acac)2	DCE	75
7	CuSO4	DCE	95
8	CuCl2	DCE	79
9	Cu(OAc)2	DCE	75
10	CuSO4	CH3CN	26
11	CuSO4	Dioxane	76
12	CuSO4	THF	84
13	CuSO4	Toluene	75
14	—	DCE	0

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With the optimized conditions established, the substrate scope was next examined (Table 2). Different substituents at the aromatic group, including methyl, methoxyl, and halogen did not affect the reaction (3b–3g). The styryl group and heterocycles are all tolerated in this reaction and the corresponding gem-diiodides were isolated in excellent yields (3h–3j). Aliphatic substrates gave the corresponding product in reduced yield (3k).

Table 2 Substrate scope^a

a Reaction conditions: 1 (0.2 mmol), CuSO₄ (0.02 mmol) in DCE (2 mL) was stirred at 70 °C for 3 h. Isolated yields were reported.

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2.2. Improved oxidative iodination toward gem-diiodoalkenes

In the above transformation, the yield was almost quantitatively calculated on the iodine element. However, half of the substrates were transformed into another propargylic amide 4a. To improve this atom economy issue, we proposed another reaction pathway to mimic the previous Cu(I)/Cu(III) cycle: CuI catalyzed a similar cyclization of 1a to form M₁. This Cu(I) intermediate M₁ could be oxidized into a similar Cu(III) intermediate by adding another strong oxidant, which also underwent reductive elimination to form the gem-diiodide 3a. Herein, CuI served as the cyclization catalyst and also the iodine source, so one equivalent of CuI is necessary. Moreover, to inhibit the oxidative addition of alkyne idodides to M₁, the choice of oxidant is very crucial for the success of this transformation. Then, a series of oxidants were tested (Table 3). It was found that selectfluor was the best oxidant, leading to the target 3a in 84% yield (entry 1). Other oxidants such as PhI(OAc)₂, DDQ, MCPBA, TBHP, H₂O₂ all led to reduced yields.

Table 3 Optimization of the oxidants^a

Entry	Oxidant (1.2 equiv.)	Yield^b (%)
a Reaction conditions: 1a (0.1 mmol), CuI (0.1 mmol) , oxidant (0.12 mmol) in the solvent (1 mL) was stirred at 70 °C for 3 h. b Isolated yields were reported.
1	Selectfluor	84
2	PhI(OAc)2	43
3	DDQ	28
4	K2S2O8	51
5	3-Chloroperbenzoic acid	57
6	tert-Butyl hydroperoxide	37
7	H2O2	12

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Then, the scope of this protocol was also tested (Table 4). Similarly, this reaction showed a very general scope. Different aromatic substituents, the styryl group, furan or thiophene substituents do not affect the reaction efficiency, and various gem-diiodide alkenes were prepared in good to excellent yields with this very simple procedure (3b–3k). Substrates bearing a quaternary carbon centre also reacted very well, generating the corresponding products in excellent yields (3l–3m). All these reactions did not require an inert atmosphere. Thus, such a simple procedure and mild conditions make this protocol very practical in organic syntheses.

Table 4 Substrate scope of the oxidative iodination reaction^a

a Reaction conditions: 1a (0.2 mmol), CuI (0.2 mmol), selectfluor (0.24 mmol), in CH₃CN (2 mL) was stirred at 70 °C for 3 h. Isolated yields were reported.

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2.3. Synthesis of (E)-1-iodo-1-alkenes with the oxidative iodination approach

In the gold-catalyzed cyclization reaction of 1a, (Z)-alkene 2a was observed. Similarly iodoalkyne 6 went through 5-exo-dig cyclization in the presence of a Ph₃PAuNTf₂ catalyst, giving a stable (Z)-alkene 7 in 83% yield (eqn (3)). If the current CuI mediated oxidative iodination reaction is applied to the propargylic amide 4a, the (E)-iodoalkene will be obtained. To our delight, this protocol works equally well on this substrate, generating the (E)-iodoalkene 5a in 77% yield under standard conditions. Other substituted substrates also worked very well and the results are summarized in Table 5. Thus, both configurations of the iodoalkenes could be obtained by gold or copper catalysis, which provided different options for synthetic chemists.

Table 5 Substrate scope of the synthesis of (E)-1-iodo-1-alkenes^a

a Reaction conditions: 1a (0.2 mmol), CuI (0.2 mmol), selectfluor (0.24 mmol), in CH₃CN (2 mL) was stirred at 70 °C for 3 h. Isolated yields were reported.

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In the current reaction, CuI catalyzed the first cyclization forming the Cu(I) intermediate, which was oxidized to a Cu(III) intermediate. It went through reductive elimination to form the final products (Scheme 5). When I₂ was used as the oxidant and also served as the iodine source, we were able to realize this reaction with only a catalytic amount of the Cu(I) catalyst. We tried the reaction using one equivalent of I₂ in the presence of CuSO₄ (10 mol%) as the catalyst (eqn (4) and (5)). The expected reactions did happen, however, relatively lower yields were obtained. All these data demonstrated the viability of a Cu(I)/Cu(III) catalytic cycle of this reaction.

Scheme 5 Iodination with a catalytic amount of Cu(I) catalyst.

2.4. Synthesis of trisubstituted and tetrasubstituted alkenes from iodoalkenes

In the next step, we took advantage of the C–I bond to install different functional groups to construct multisubstituted alkenes. Trisubstituted and tetrasubstituted alkenes are important motifs present in bioactive products and also organic functional materials. The regio and stereoselective synthesis of these molecules is still one of the most challenging subjects in organic syntheses.¹⁵ The obtained halogen substituted alkenes serve as a perfect template for us to install different functional groups using the palladium-catalyzed cross coupling reactions. Firstly, we chose the Suzuki reaction to install an aromatic group. As shown in Scheme 6, boronic acids coupled with (E)-alkene 5n and (Z)-alkene 7 smoothly and afforded the expected trisubstituted alkenes 8 and 12 in good yields. The Heck reaction of (E)-alkene 5n and (Z)-alkene 7 with methyl acrylate are also successful, giving the corresponding dienes in 84% and 76% yields. The palladium-catalyzed Sonogashira coupling reaction between 5n and a terminal alkyne was also successful and the expected enyne product 10 was isolated in 75% yield.

Scheme 6 Synthetic transformations of E-iodoalkene and Z-iodoalkene.

Then, we started to investigate whether we could construct tetra-substituted alkenes from gem-diiodoalkenes (Scheme 7). The Suzuki reaction of diiodide 3l and boronic acid in the presence of Pd₂(dba)₃ and P(o-tol)₃ afforded tetrasubstituted alkene 13 in 65% yield. The corresponding Heck reaction and Sonogashira coupling reaction of 3l were also successful, giving the conjugated triene 14 and enyne 15 in good yields. The structures are characterized by NMR and Mass experiments, and triene 14 was further confirmed by single crystal X-ray analysis.¹⁶

Scheme 7 Synthesis of functionalized tetrasubstituted alkenes from gem-diiodoalkene.

3. Conclusions

In summary, starting from an unexpected reaction of propargyl amides, we developed a new approach to the synthesis of gem-diiodoalkenes. This reaction features a very simple procedure, high efficiency and broad scope. Stereoselective synthesis of (E) or (Z)-iodoalkenes could also be achieved with copper catalysis or gold catalysis. A possible Cu(I)/Cu(III) catalytic cycle was proposed. The obtained iodoalkenes were successfully used in the further palladium-catalyzed Suzuki, Heck, and Sonogashira coupling reactions, allowing access to a wide variety of multi-substituted alkenes, dienes, trienes and enynes.

4. Experimental section

4.1 General procedure for the synthesis of 1-iodoalkynyl amides 1a–1m

The corresponding propynylamine (10 mmol) was dissolved in MeOH (30 mL). A solution of KOH (40 mmol) in H₂O (10 mL) was prepared, cooled to 0 °C, and added to the reaction mixture. I₂ (10 mmol) was added in one portion, and the solution was stirred at room temperature overnight. The reaction mixture was extracted with CH₂Cl₂. The organic phase was washed with saturated Na₂S₂O₃ solution, dried over Na₂SO₄, filtered, and concentrated in vacuo to yield the crude 1-iodopropynylamine. To a cooled solution of 1-iodopropynylamine in CH₂Cl₂ (20 mL) were added triethylamine (24 mmol), chloride (8 mmol) and 4-dimethylaminopyridine (0.8 mmol) and the resulting solution was allowed to reach room temperature. The reaction was stirred at room temperature for 3 h. Then it was diluted with water and the aqueous layer extracted with CH₂Cl₂. The combined organic layers were washed with satd. NaHCO₃ followed by water and brine, dried over Na₂SO₄ and concentrated under reduced pressure to obtain the crude 1-iodoalkynyl amides. Silica gel chromatography gave the desired 1-iodoalkynyl amides 1a–1m in 45%–72% yields respectively.

4.1.1 N-(3-Iodoprop-2-yn-1-yl)benzamide (1a). Yield: (1.91 g, 67%). ¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J = 7.3 Hz, 2H), 7.51 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H), 6.32 (s, 1H), 4.40 (d, J = 5.2 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 167.08, 133.72, 131.81, 128.62, 127.08, 89.70, 31.64, 0.01; HRMS (ESI, m/z) calcd for C₁₀H₈INO [M + H]⁺ 285.9723, found 285.9723.

4.2. General procedure for the synthesis of gem-diiodoalkenes (Table 2)

Compound 1a (0.2 mmol) was dissolved in DCE (1 mL), CuSO₄ (0.02 mmol) was added and the system was stirred at 70 °C for 3 h. The resulting mixture was washed with water and extracted with DCM. The organic layer was filtered on Celite and evaporated under reduced pressure. Purification by flash chromatography afforded the desired product 3a (38.95 mg, 95%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.96 (m, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.8 Hz, 2H), 4.61 (s, 2H). ¹³C NMR (100 MHz, DMSO-d₆) δ 161.39, 159.16, 132.92, 129.51, 127.92, 126.39, 61.64, −14.83. HRMS (ESI, m/z) calcd for C₁₀H₇I₂NO [M + H]⁺ 411.8690, found 411.8675.

4.3. General procedure for the synthesis of gem-diiodoalkenes (Table 4)

Compound 1a (0.2 mmol), CuI (0.2 mmol) and selectfluor (0.24 mmol) were dissolved in CH₃CN (2 mL). The system was stirred at 70 °C for 3 h. The resulting mixture was washed with water and extracted with DCM. The organic layer was filtered on Celite and evaporated under reduced pressure. Purification by flash chromatography afforded the desired product 3a (69.05 mg, 84%).

4.4. General procedure for the synthesis of (E)-1-iodo-1-alkenes (Table 5)

Compound 4a (0.2 mmol), CuI (0.2 mmol) and selectfluor (0.24 mmol) were dissolved in CH₃CN (2 mL). The system was stirred at 70 °C for 3 h. The resulting mixture was washed with water and extracted with DCM. The organic layer was filtered on Celite and evaporated under reduced pressure. Purification by flash chromatography afforded the desired product 5a (43.89 mg, 77%). ¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, J = 7.5 Hz, 2H), 7.55–7.33 (m, 3H), 5.77 (t, J = 2.8 Hz, 1H), 4.63 (d, J = 3.1 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 162.39, 157.43, 132.27, 128.93, 127.48, 126.08, 60.44, 49.30. HRMS (ESI, m/z) calcd for C₁₀H₈INO [M + H]⁺ 285.9723, found 285.9723.

4.5. General procedure for the gold-catalyzed synthesis of (Z)-4-(iodomethylene)-2-phenyl-3-oxa-1-azaspiro[4.5]dec-1-ene (7)

The compound 6 (1 mmol) was dissolved in DCM (10 ml) and PPh₃AuNTf₂ (0.05 mmol) was added. After stirring for 2 h at room temperature, water was added and the aqueous phase was extracted twice with DCM. After drying of the combined organic phases over Na₂SO₄, and filtration, the solvent was removed and the crude products were purified by column chromatography affording the pure product 7 (0.29 g, 83%). ¹H NMR (400 MHz, CDCl₃) δ 8.02 (d, J = 7.1 Hz, 2H), 7.51–7.42 (m, 3H), 5.05 (s, 1H), 1.89–1.52 (m, 10H). ¹³C NMR (100 MHz, CDCl₃) δ 168.38, 158.03, 131.87, 128.51, 128.37, 126.66. HRMS (ESI, m/z) calcd for C₁₅H₁₆INO [M + H]⁺ 354.0349, found 354.0346.

4.6. General procedure for the Suzuki reactions: synthesis of (E)-5-benzylidene-4,4-dimethyl-2-phenyl-4,5-dihydro-oxazole (6)

To a mixture of Pd(OAc)₂ (0.01 mmol), PPh₃ (0.02 mmol), Cs₂CO₃ (0.28 mmol), and PhB(OH)₂ (0.24 mmol) in dixoane (2 ml) under a N₂ atmosphere, compound 5n (0.2 mmol) was added. The system was stirred at 70 °C overnight. The resulting mixture was washed with water and extracted with DCM. The organic layer was filtered on Celite and evaporated under reduced pressure. Purification by flash chromatography afforded the desired product 8 (38.41 mg, 73%).¹H NMR (300 MHz, CDCl₃) δ 8.10–8.08 (m, 2H), 7.65 (d, J = 7.2 Hz, 2H), 7.55–7.52 (m, 3H), 7.50–7.37 (m, 2H), 7.25–7.20 (m, 1H), 5.55 (s, 1H), 1.54 (s, 6H). ¹³C NMR (75 MHz, CDCl₃) δ 160.15, 159.36, 134.53, 131.36, 128.11, 128.04, 127.75, 127.41, 126.36, 125.66, 98.87, 70.39, 29.17. HRMS (ESI, m/z) calcd for C₁₈H₁₇NO [M + H]⁺ 264.1383, found 264.1389.

4.7. General procedure for the Heck coupling reactions: synthesis of (2E,4E)-methyl 4-(4,4-dimethyl-2-phenyloxazol-5(4H)-ylidene)but-2-enoate (7)

To a mixture of Pd₂(dba)₃ (0.01 mmol), P(O-tol)₃ (0.04 mmol), and compound 5n (0.2 mmol) in CH₃CN (2 ml) under a N₂ atmosphere, methyl acrylate (0.4 mmol) and Et₃N (0.5 mmol) were added. The system was stirred at 80 °C overnight. The resulting mixture was washed with water and extracted with DCM. The organic layer was filtered on Celite and evaporated under reduced pressure. Purification by flash chromatography afforded the desired product 9 (45.53 mg, 84%).¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, J = 7.3 Hz, 2H), 7.62–7.50 (m, 2H), 7.46–7.42 (m, 2H), 6.11 (d, J = 12.6 Hz, 1H), 5.83 (d, J = 15.0 Hz, 1H), 3.76 (s, 3H), 1.65 (s, 6H). ¹³C NMR (75 MHz, CDCl₃) δ 169.70, 167.16, 159.17, 138.64, 132.00, 128.58, 128.13, 126.24, 118.47, 101.13, 70.76, 51.46, 51.47, 28.55. HRMS (ESI, m/z) calcd for C₁₆H₁₇NO₃ [M + H]⁺ 272.1281, found 264.1271.

4.8. General procedure for the Sonogashira coupling reactions: synthesis of (E)-5-(3-(4-methoxyphenyl)prop-2-yn-1-ylidene)-4,4-dimethyl-2-phenyl-4,5-dihydrooxazole (8)

To a mixture of Pd(PPh₃)₂Cl₂ (0.01 mmol), CuI (0.02 mmol), K₂CO₃ (0.5 mmol), and compound 5n (0.2 mmol) in THF (2 mL) under a N₂ atmosphere, 4-methoxyphenylacetylene (0.4 mmol) was added. The system was stirred at 65 °C overnight. The resulting mixture was washed with water and extracted with DCM. The organic layer was filtered on Celite and evaporated under reduced pressure. Purification by flash chromatography afforded the desired product 10 (47.55 mg, 75%).¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, J = 7.4 Hz, 2H), 7.53–7.49 (m, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 5.60 (s, 1H), 3.81 (s, 3H), 1.73 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 170.74, 158.88, 158.69, 131.77, 131.36, 128.03, 127.64, 125.97, 115.47, 113.56, 93.06, 84.99, 81.73, 70.67, 54.82, 25.85. HRMS (ESI, m/z) calcd for C₂₁H₁₉NO₂ [M + H]⁺ 318.1489, found 318.1483.

Acknowledgements

We are grateful for financial support from the fundamental research and subject construction funds of Shandong University (no 2014JC008, 104.205.2.5), and the china postdoctoral science foundation. We thank Prof. Dr Di Sun for the analysis of X-ray structure.

Notes and references

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16. CCDC 1046596 (3a) and 1046597 (14) contain the supplementary crystallographic data for this paper.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1046596 and 1046597. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5qo00043b

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