Malaysian Journal of Analytical Sciences, Vol 28 No 6 (2024): 1374 - 1385

OPTIMISATION ON N-AMIDATION REACTION OF CINNAMIC ACID BY CARBODIIMIDE CATALYSIS

(Pengoptimuman Tindakbalas Pengamidaan-N Bagi Asid Sinamik Menggunakan Pemangkinan Karbodiimida)

Nadia Mohamed Yusoff¹ , Hanis Mohd Yusoff^1,2 and Asnuzilawati Asari^1,2,*

¹Faculty of Science and Marine Environment, Universiti Malaysia Terengganu, 21030 Kuala Nerus, Terengganu, Malaysia

²Advanced Nano Materials (ANoMa) Research Group, Faculty of Science and Marine Environment, Universiti Malaysia Terengganu, 21030 Kuala Nerus, Terengganu, Malaysia

^*Corresponding author: asnu@umt.edu.my

Received: 1 July 2024; Accepted: 26 August 2024; Published: 29 December 2024

Abstract

An amide moiety is often found in the structure of a molecule known to be physiologically active. The ability of amide groups in forming a hydrogen bond made it widely utilized in industrial and pharmaceutical chemistry. Cinnamic acid is a naturally occurring compound known for their wide range of pharmacological activity. Especially cinnamic acid with an amide moiety in their structure. Cinnamic acid amide derivatives have been reported to show good inhibition against a few viruses, such as Zika virus. Therefore, the amidation of cinnamic acid with amine was studied in this paper. Various protocols of amide coupling reaction have been developed since a decade ago. However, due to significant drawbacks such as toxic reactive reagent used, complexity and tedious procedures and poor product yield, amide coupling reactions have been continuously studied up till now. In this study, a direct N-amidation reaction of carboxylic acid and p-anisidine was optimised using a carbodiimide reagent and additives under different conditions of a reaction solvent, temperature, concentration of reagent and reaction time, to provide an efficient and environmentally friendly method for amide bond production. The most optimal reaction conditions were found with carbodiimide EDC.HCl and anhydrous THF solvent at 60˚C, 1:1:1.5 (cinnamic acid:p-anisidine:EDC.HCl) molar ratios, and a 150-minute reaction time. Under optimised conditions, the yield percentage of the amide product was 93.1%. The structure of synthesised compound, N-(4-methoxyphenyl)cinnamamide was characterised with Fourier transform infrared (FTIR), ¹H and ¹³C nuclear magnetic resonance (NMR) and mass spectrometry (MS) analysis. The use of single coupling reagent EDC.HCl made the reaction more efficient and simplified the work-up with less waste produced and high product yield. The data in this study may help for future studies with others molecule and improve the amidation reaction for a better sustainable approach.

Keywords: amide coupling reaction, N-amidation reaction, optimization reaction, carbodiimide reagent

Abstrak

Kumpulan amida sering dijumpai dalam struktur molekul yang diketahui aktif secara fisiologi. Kelebihan kumpulan amida menghasilkan interaksi ikatan hidrogen menjadikan ia digunakan secara meluas dalam industri dan kimia farmasi. Sinamik asid adalah sebatian semulajadi yang dikenali dengan pelbagai aktiviti biologi. Terutamanya sinamik asid yang mempunyai amida pada strukturnya. Terbitan sinamik asid amida dilaporkan perencat yang baik terhadap beberapa virus, seperti Zika virus. Oleh itu, amidasi sinamik asid dengan amin dikaji di dalam kertas ini. Pelbagai protokol tindakbalas gandingan amida telah dibangunkan sejak berdekad lalu. Namun disebabkan oleh kelemahan ketara seperti penggunaan reagen reaktif bertoksik dan hasil produk yang rendah, kajian tindakbalas gandingan amida telah berterusan sehingga kini. Dalam kajian ini, tindakbalas pengamidaan-N di antara asid karboksilik dan p-anisidina telah dioptimumkan menggunakan reagen karbodiimida dalam keadaan berbeza pelarut, suhu, kepekatan reagen dan masa tindakbalas, dengan tujuan untuk menghasilkan proses tindakbalas gandingan amida yang lebih ambien dan cekap bagi menghasilkan ikatan amida. Keadaan tindak balas yang paling optimum diperolehi dengan menggunakan karbodiimida EDC.HCl dan pelarut THF kontang pada suhu 60˚C, dengan nisbah molar bahan 1:1:1.5 (asid sinnamik:p-anisidina.HCl), dan masa tindak balas 150 minit. Di bawah keadaan yang dioptimumkan, peratus hasil produk amida adalah 93.1%. Struktur sebatian bahan, N-(4-methoxyphenyl)cinnamamide dicirikan dengan menggunakan Inframerah Transformasi Fourier (FTIR), 1H and ¹³C Resonans Magnetik Nuklear (RMN), dan spektrometri jisim (MS). Penggunaan EDC.HCl sebagai reagen tunggal membuatkan tindakbalas menjadi lebih cekap dan memudahkan kerja serta mengurangkan penjanaan sisa buangan dan hasil produk yang tinggi. Data dalam kajian ini dapat membantu kajian di masa depan dalam penambahbaikan tindak balas amidasi mengguna molekul yang lain bagi pendekatan pembangunan yang mampan.

Kata kunci: tindakbalas gandingan amida, tindakbalas pengamidaan-N, pengoptimuman tindakbalas, reagen karbodiimida

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