A Novel Route to Erucamide: Highly Selective Synthesis from

Research Article Cite This: ACS Sustainable Chem. Eng. 2018, 6, 11380−11385

pubs.acs.org/journal/ascecg

Novel Route to Erucamide: Highly Selective Synthesis from Acetonitrile at Room Temperature via a Photo-Fenton Process Navpreet K. Sethi,*,† Hisayoshi Kobayashi,*,‡ Biling Wu,*,§ Renhong Li,*,§ and Jie Fan*,† †

Key Lab of Applied Chemistry, Department of Chemistry, Zhejiang University, Hangzhou 310027, China Department of Chemistry and Materials Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan § Department of Materials Engineering, College of Material Textiles, Zhejiang Sci-Tech University, Hangzhou 310018, China Downloaded via LULEA UNIV OF TECHNOLOGY on September 14, 2018 at 12:55:50 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

‡

S Supporting Information *

ABSTRACT: A new route to the synthesis of a fatty acid Nderivative, erucamide, was discovered at room temperature with extremely high selectivity from an off-the-shelf reagent, acetonitrile, through a photo-Fenton process.

KEYWORDS: Erucamide, Room temperature, Acetonitrile, Photo-Fenton process, Highly selective

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INTRODUCTION

RESULTS AND DISCUSSION The irradiation of MeCN and peroxide was carried out in the absence and presence of silica support represented as series A and B in Table SI (brief) and Table SII (descriptive). Each irradiation experiment had four sets of reactions with variable concentration of the reagents as shown in Table SI. The irradiation for each sample was implemented by a UV lamp having a wavelength of 300 nm for a period of 2.5 h at room temperature in the dark. The reactions were continued for about 2 days (in the absence of radiation) under similar conditions. All the above irradiated samples were extracted by MeOH for a clear indication of the product(s) synthesized from these mixtures. Benzonitrile was used as an internal standard in all these reactions for quantification. Each extracted mixture was analyzed by GC-MS analysis. A part of the total sample volume was expended for this experiment. The details of the products formed in these irradiation reactions are described in Table SII in the Supporting Information. The results indicated that the presence of silica and the quantity of reagents have significant effect on the formation of erucamide both qualitatively as well as quantitatively (Table SIII). Series A indicated that erucamide is formed as one of the products. However, series B showed that relatively high yields can be formed only when silica is present within the same

Fatty acid N-derivatives, i.e., fatty acid nitriles and fatty acid amides, are considerably important molecules in the areas of chemistry1−6 as well as biochemistry.7−10 These molecules are present within living cells11−16 and bear renowned applications in industry3,4,8−10,17−20 in addition to therapeutics.11,12,21−27 The reported synthetic strategies include pyrolysis of biodegradable organic matter4,8,28−42 and ammoniolysis of fatty acid precursors,18,43−47 involving extremely high temperatures up to 700 °C. However, there is a sole example that has reported the use of low temperature instead (50 °C using fatty ester).44 In the current work, an innovative method to selectively synthesize a fatty acid N-derivative (erucamide) has been reported at room temperature. The methodology illustrates the formation of higher homologues from a lower nitrile (MeCN) by means of C−CN activation followed by C− H activation initiated by peroxy free radicals. It has been known that the MeCN molecule is capable of producing free •CN radicals, when irradiated by UV-light.48 However, from the best of our knowledge there is no report that indicates that irradiation of the MeCN molecule could form higher analogues up to C22 chain length. In this report, we demonstrate the synthesis of higher analogues of MeCN by a free radical mechanism initiated by peroxy free radicals further supported by DFT calculations. The products formed were analyzed by GC-MS analysis qualitatively as well as quantitatively. © 2018 American Chemical Society

Received: March 20, 2018 Revised: July 29, 2018 Published: August 3, 2018 11380

DOI: 10.1021/acssuschemeng.8b01177 ACS Sustainable Chem. Eng. 2018, 6, 11380−11385

Research Article

ACS Sustainable Chemistry & Engineering

Figure 1. GC-MS chromatograms showing concentration of erucamide with respect to other products and internal standard in (A) absence of silica and (B) presence of silica.

reaction. This difference associated with the presence of silica was clearly confirmed by the increase of percentage yields irrespective of the reagent quantities in series B (I−III). However, the quantity of the reagents has a little influence on the product yield in series B (except IV), but the selectivity is majorly affected by them as shown by B-I−B-III. On the other hand, excessive peroxide tends to diminish the free radical reaction as shown by IV. Above all, the best suited conditions for this reaction is indicated by series B-III. The latter has

been clearly illustrated with the chromatograms shown in Figure 1 both for series A and B in Figure 1A,B, respectively. Reaction Mechanism. For elucidation of the reaction mechanism, DFT calculations were conducted. For each elementary step, the transition state (TS) was characterized. Then, the intrinsic reaction coordinate (IRC) was evaluated in both directions. From the end point of IRC, the usual optimization run was performed, indicating that the reactants and products were seamlessly connected via the TS. 11381


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Figure 2. Structures as predicted by DFT calculations from steps A−D.

Figure 3. In situ C−H activation at the C13 position of the aliphatic nitriles.

According to our previously reported work,48 the hydroxyl (•OH) radicals formed by the photo-Fenton process react with CH3CN molecules producing •CH2CN radicals by means of proton abstraction forming •CH2CN radicals, Step A. This free radical species, •CH2CN, then react with other molecules of CH3CN, to form a free •CN radical and a propionitrile molecule, Step B. This molecule reacts further with other free radicals of •CH2CN and hence initiates a chain reaction shown in Figure 2. The energy required for Step A, the proton abstraction step, is exothermic (−23.4 kcal mol−1). However, the energies for

the rest of the steps (B−D) are endothermic and are at close proximity to one another, that is, 43.3, 42.0, and 42.2 kcal mol−1, respectively. The formation of the transition state, however, requires relatively higher energy as described in Table SIV. However, the total energy of these reactions is negative indicating that the reactions are spontaneous (Table SIV). The structures elucidated from the calculated data are given as Figure 2 for Steps A−D, respectively. However, IRC (reaction pathway) is only shown for Step C, Figure 2, for both reactants as well as products. In this pathway, the •CH2CN radical approaches the central −CH2− carbon in the propionitrile 11382


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ACS Sustainable Chemistry & Engineering molecule for •H abstraction. Once the butanenitrile molecule is formed, the •CN free radical is released. Since the energy difference for the three steps (B−D) is nearly the same, it indicates that the chain reaction does not require a very high energy to continue this reaction, and room temperature is apparently sufficient. The chain propagation of these reactions continues until a chain termination step is achieved. It is discernible from Steps B−D that there were free •CN radicals left unreacted in these reactions. It is expected that free •CN radicals will abstract protons from the medium to form HCN. Since the latter was never analyzed in any of the data, it was expected to have neutralized in the form of CO2 and H2O.49 In order to confirm this neutralization reaction, another supporting experiment of CO2 determination was carried out separately, given in the Supporting Information, Table SVII. The chain propagation for aliphatic nitriles continues until a sufficient chain length (C22, erucamide) is achieved. Thereafter, the molecule undergoes C−H activation at the C13 position. There is no direct evidence of C−H activation in aliphatic nitriles in higher analogues, but there are reported examples that indicate the C−H activation at the terminal carbon,50 nonterminal carbon,50 and other positions in aliphatic nitriles.51,52 All the reported examples involve the participation of metals. Since there is no metal involvement in the current reactions, the •OH free radicals are the only activation source that are most probably responsible for the C−H activation in higher nitriles. There is precedent that C− H activation can be achieved by •OH free radicals in aliphatic aldehydes in the aliphatic region irrespective of the functional group.53 Therefore, the proposed mechanism as shown in Figure 3 involves free •OH radicals. These free radicals approach the C13 carbon for •H abstraction, leading to a free radical intermediate, which uses a neighboring •H radical to form a double bond thereby releasing a •H radical along with a H2O molecule in the medium. The reason for the proton abstraction at the C13 position is most probably the stability of the intermediate. In series B, silica assists the process by increasing the surface area, availing the possibility of more coordination sites to the adhered nitrile molecules, and hence influences the yields. Because of the presence of excessive water molecules in the medium, hydrolysis of the higher nitriles is very well-favored; hence, formation of amides occurs. Role of Silica. For the study of the role of silica in-depth in such reactions, different experiments were carried out at silicas with different mesh sizes [80−100 (i), 200−300 (ii), and 300− 400 (iii)] and at three different temperatures (25, 30, and 35 °C) (Table SV). The range of temperature selection was not kept too high as it is a free radical reaction (discussed earlier). The reaction conditions used were kept as per sample B-III (standardized procedure). In samples at 25 °C, the longchained derivatives did not form at a lower mesh size (B-25-i), but as the size increased to (ii) B-25-ii and (iii) B-25-iii, the long-chained derivative of C17 chain length is formed. As the temperature is increased by 5 °C (30 °C), two new chain length derivatives of C12 and C18 are formed along with C17 (as formed previously at 25 °C). With a further increase in temperature to 35 °C, erucamide is formed as a product in all of the reactions (B-35-i, B-35-ii, and B-35-iii), but in addition to that, a range of different chain lengths is indicated. When the mesh size is higher, the number of long-chained derivatives

formed is greater, but at the same time the selectivity of the main product (erucamide) is compromised. The latter at 35 °C is shown in Table SVI for erucamide.

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CONCLUSIONS This is a first report of highly selective synthesis of a longchained fatty acid N-derivative, erucamide, discovered via irradiation of acetonitrile at room temperature. The reactions showed the potential of generation of higher analogues of similar derivatives when suitable conditions are employed. The range of experiments indicated the potential of the reactions and their influential ability on selectivity and performance. The DFT calculations supported the suggested mechanism which is C−CN bond activation along with in situ C−H activation due to peroxy free radicals. This long-chained analogue, erucamide, has valuable therapeutic properties, and thus, the methodology is useful for both pharmaceutical as well as synthetic laboratory operations.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acssuschemeng.8b01177. Irradiation experiment tables with different products formed, selectivity tables with percentage yield, DFT energy table, experimental of irradiation reactions, NMR spectroscopy data for erucamide, and CO2 determination experiment with quantity by GC (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: *E-mail: *E-mail: *E-mail: *E-mail:

[email protected]. (N.K.S.) [email protected]. (H.K.) [email protected]. (B.W.) [email protected]. (R.L.) [email protected]. (J.F.)

ORCID

Navpreet K. Sethi: 0000-0003-0243-5940 Jie Fan: 0000-0002-8380-6338 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We would like to thank Dr. Yaqin Liu and Associate Prof. Jiankai Zou from Department of Chemistry Zhejiang University, Hangzhou, China, for performing NMR spectroscopy and GC-MS spectrometry data collection for our samples.

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REFERENCES

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A Novel Route to Erucamide: Highly Selective Synthesis from

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