1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide explained

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, EDAC or EDCI) is a water-soluble carbodiimide usually handled as the hydrochloride.[1]

It is typically employed in the 4.0-6.0 pH range. It is generally used as a carboxyl activating agent for the coupling of primary amines to yield amide bonds. While other carbodiimides like dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide (DIC) are also employed for this purpose, EDC has the advantage that the urea byproduct formed (often challenging to remove in the case of DCC or DIC) can be washed away from the amide product using dilute acid. Additionally, EDC can also be used to activate phosphate groups in order to form phosphomonoesters and phosphodiesters. Common uses for this carbodiimide include peptide synthesis, protein crosslinking to nucleic acids, but also in the preparation of immunoconjugates. EDC is often used in combination with N-hydroxysuccinimide (NHS) for the immobilisation of large biomolecules. Recent work has also used EDC to assess the structure state of uracil nucleobases in RNA.[2] [3]

Preparation

EDC is commercially available. It may be prepared by coupling ethyl isocyanate to N,N-dimethylpropane-1,3-diamine to give a urea, followed by dehydration:[4]

Mechanism

EDC couples primary amines, and other nucleophiles,[5] to carboxylic acids by creating an activated ester leaving group. First, the carbonyl of the acid attacks the carbodiimide of EDC, and there is a subsequent proton transfer. The primary amine then attacks the carbonyl carbon of the acid which forms a tetrahedral intermediate before collapsing and discharging the urea byproduct. The desired amide is obtained.[6]

Safety

In vivo dermal sensitization studies according to OECD 429[7] confirmed EDC is a strong skin sensitizer, showing a response at <0.01 wt% in the Local Lymph Node Assay (LLNA) placing it in Globally Harmonized System of Classification and Labelling of Chemicals (GHS) Dermal Sensitization Category 1A.[8] Thermal hazard analysis by differential scanning calorimetry (DSC) shows EDC poses minimal explosion risks.[9]

References

  1. 1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide Hydrochloride. E-EROS Encyclopedia of Reagents for Organic Synthesis. 2001. Richard S. Pottorf, Peter Szeto. 10.1002/047084289X.re062.
  2. Mitchell . D . Renda . A . Douds . C . Babitzke . P . Assmann . S . Bevilacqua . P . In vivo RNA structural probing of uracil and guanine base-pairing by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) . RNA . 2019 . 25 . 1 . 147–157 . 10.1261/rna.067868.118. free . 30341176 . 6298566.
  3. Wang . PY . Sexton . AN . Culligan . WJ . Simon . MD . Carbodiimide reagents for the chemical probing of RNA structure in cells . RNA . 2019 . 25 . 1 . 135–146 . 10.1261/rna.067561.118. free . 30389828 . 6298570.
  4. 10.1021/jo01351a600 . 1961 . Sheehan, John . Cruickshank, Philip . Boshart, Gregory . A Convenient Synthesis of Water-Soluble Carbodiimides . . 26 . 2525 . 7.
  5. Ester coupling reactions – an enduring challenge in the chemical synthesis of bioactive natural products. 10.1039/C4NP00106K. 2015. Tsakos. Michail. Schaffert. Eva S.. Clement. Lise L.. Villadsen. Nikolaj L.. Poulsen. Thomas B.. Natural Product Reports. 32. 4. 605–632. 25572105.
  6. Web site: Carbodiimide Crosslinker Chemistry - US. www.thermofisher.com. en. 2019-05-10.
  7. Book: OECD . Test No. 429: Skin Sensitisation: Local Lymph Node Assay . 2010 . Organisation for Economic Co-operation and Development . Paris . en.
  8. Graham . Jessica C. . Trejo-Martin . Alejandra . Chilton . Martyn L. . Kostal . Jakub . Bercu . Joel . Beutner . Gregory L. . Bruen . Uma S. . Dolan . David G. . Gomez . Stephen . Hillegass . Jedd . Nicolette . John . Schmitz . Matthew . 2022-06-20 . An Evaluation of the Occupational Health Hazards of Peptide Couplers . Chemical Research in Toxicology . en . 35 . 6 . 1011–1022 . 10.1021/acs.chemrestox.2c00031 . 0893-228X . 9214767 . 35532537.
  9. Sperry . Jeffrey B. . Minteer . Christopher J. . Tao . JingYa . Johnson . Rebecca . Duzguner . Remzi . Hawksworth . Michael . Oke . Samantha . Richardson . Paul F. . Barnhart . Richard . Bill . David R. . Giusto . Robert A. . Weaver . John D. . 2018-09-21 . Thermal Stability Assessment of Peptide Coupling Reagents Commonly Used in Pharmaceutical Manufacturing . Organic Process Research & Development . en . 22 . 9 . 1262–1275 . 10.1021/acs.oprd.8b00193 . 1083-6160.

Further reading

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