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

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1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
EDC Structure.png
EDC molecule ball.png
Names
Preferred IUPAC name
3-{[(Ethylimino)methylidene]amino}-N,N-dimethylpropan-1-amine
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.015.982 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • InChI=1S/C8H17N3/c1-4-9-8-10-6-5-7-11(2)3/h4-7H2,1-3H3 Yes check.svgY
    Key: LMDZBCPBFSXMTL-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C8H17N3/c1-4-9-8-10-6-5-7-11(2)3/h4-7H2,1-3H3
    Key: LMDZBCPBFSXMTL-UHFFFAOYAH
  • CCN=C=NCCCN(C)C
Properties
C8H17N3
Molar mass 155.245 g·mol−1
AppearanceColorless oil (freebase)
White solid (hydrochloride)
Melting point 112 °C (234 °F; 385 K) (hydrochloride)
soluble
Solubility soluble in DCM, DMF, and THF
Hazards
Safety data sheet (SDS) External MSDS (HCl Salt)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, EDAC or EDCI) is a water-soluble carbodiimide usually handled as the hydrochloride, which is a white solid. [1]

Contents

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 a dehydration reaction mediated by TsCl and TEA: [4]

Synthesis of EDC.png

Mechanism

The scheme above shows the general mechanistic steps for EDC-mediated coupling of carboxylic acids and amines under acidic conditions. The tetrahedral intermediate and the aminolysis steps are not shown explicitly. EDC Mechanism .tif
The scheme above shows the general mechanistic steps for EDC-mediated coupling of carboxylic acids and amines under acidic conditions. The tetrahedral intermediate and the aminolysis steps are not shown explicitly.

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. ↑ Richard S. Pottorf, Peter Szeto (2001). "1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide Hydrochloride". E-EROS Encyclopedia of Reagents for Organic Synthesis. doi:10.1002/047084289X.re062.
  2. ↑ Mitchell, D; Renda, A; Douds, C; Babitzke, P; Assmann, S; Bevilacqua, P (2019). "In vivo RNA structural probing of uracil and guanine base-pairing by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)". RNA. 25 (1): 147–157. doi: 10.1261/rna.067868.118 . PMC   6298566 . PMID   30341176.
  3. ↑ Wang, PY; Sexton, AN; Culligan, WJ; Simon, MD (2019). "Carbodiimide reagents for the chemical probing of RNA structure in cells". RNA. 25 (1): 135–146. doi: 10.1261/rna.067561.118 . PMC   6298570 . PMID   30389828.
  4. ↑ Sheehan, John; Cruickshank, Philip; Boshart, Gregory (1961). "A Convenient Synthesis of Water-Soluble Carbodiimides". J. Org. Chem. 26 (7): 2525. doi:10.1021/jo01351a600.
  5. ↑ Tsakos, Michail; Schaffert, Eva S.; Clement, Lise L.; Villadsen, Nikolaj L.; Poulsen, Thomas B. (2015). "Ester coupling reactions – an enduring challenge in the chemical synthesis of bioactive natural products" . Natural Product Reports. 32 (4): 605–632. doi:10.1039/C4NP00106K. PMID   25572105.
  6. ↑ "Carbodiimide Crosslinker Chemistry - US". www.thermofisher.com. Retrieved 2019-05-10.
  7. ↑ OECD (2010). Test No. 429: Skin Sensitisation: Local Lymph Node Assay. Paris: Organisation for Economic Co-operation and Development.
  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. 35 (6): 1011–1022. doi:10.1021/acs.chemrestox.2c00031. ISSN   0893-228X. PMC   9214767 . PMID   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. 22 (9): 1262–1275. doi:10.1021/acs.oprd.8b00193. ISSN   1083-6160.

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