2-Ethyl-2-oxazoline explained

2-Ethyl-2-oxazoline (EtOx) is an oxazoline which is used particularly as a monomer for the cationic ring-opening polymerization to poly(2-alkyloxazoline)s. This type of polymers are under investigation as readily water-soluble and biocompatible materials for biomedical applications.

Production

From propionic acid and derivatives

Carboxylic acids, carboxylic esters, carboxylic amides and nitriles can react with 2-amino alcohols at 200 °C upon dehydration to the corresponding N-(2-hydroxy)carbamide, which react further at 260–280 °C upon dehydration to the 2-alkyl-2-oxazoline.

For example N-(2-hydroxyethyl)propionamide is first formed from propionic acid and ethanolamine in 74% yield which can be dehydrated to give 2-ethyl-2-oxazoline in about 75% yield.

Less drastic reaction conditions require the dehydration of the N-(2-hydroxyethyl)propionamide in vacuo in the presence of iron(III)chloride, which delivers the product in 90% yield.[1] An even higher yield of 96.2% is obtained by heating with zinc acetate.[2]

An economic one-pot reaction is heating the salt of propionic acid with ethanolamine at 200 °C in vacuo in the presence of zinc chloride yielding 82% 2-ethyl-2-oxazoline. From the water-containing distillate pure 2-ethyl-2-oxazoline can be isolated by extraction with diethylbenzene and subsequent distillation or by distillation only after addition of diethyl phosphite or dimethyldichlorosilane. The product can be dried to a residual water content of 10 ppm.[3]

In another one-pot reaction propionic acid is converted first with 2-aminoethanol to 2-hydroxyethylamide, than reacted with boric acid at 130 °C yielding a boric acid ester which is finally thermolyzed at 280 °C in 92% yield to 2-ethyl-2-oxazoline.

From propionic acid and thionyl chloride can be obtained propanoyl chloride, which reacts with ethanolamine in the presence of an acid scavenger (for example pyridine) to N-propionyl-2-aminoethanol. With further thionyl chloride this reacts further to 2-chloroethylamide. With the chloride ion as a better leaving group, this intermediate is cyclized by simple heating to the oxazoline. Water must be excluded due to the tendency of oxazolines towards ring-opening by chloride ions during protonation of the imine nitrogen.

The direct reaction of propanoyl chloride with 2-chloroethylamine hydrochloride in the presence of triethylamine avoids the formation of water.

From propanal

Propanal reacts with 2-aminoethanol in t-butanol to 2-ethyl-2-oxazoline in the presence of the iodinating reagent 1,3-diiodo-5,5-dimethylhydantoin (DIH) and potassium carbonate.

Properties

2-Ethyl-2-oxazoline is a readily water-soluble, colorless liquid which is also soluble in a variety of organic solvents and possesses an amine-like smell. Aqueous solutions react alkaline. The compound is stable in alkaline but hydrolyses under acid action.

Applications

In anhydrous form, 2-ethyl-2-oxazoline is mostly used as a monomer.

The cationic ring-opening polymerization of 2-ethyl-2-oxazoline can be initiated by alkylation with e.g. methyl tosylate or triflates (in particular methyl triflate) and leads to the water-soluble poly(2-ethyl-2-oxazoline) which is a propionyl-substituted linear polyethylenimine and can also be seen as a pseudo-polypeptide.

The polymerization of 2-ethyl-2-oxazoline can also be carried out as living cationic polymerization.[4]

Copolymers with other 2-alkyl-2-oxazolines[5] and other monomers[6] allow the preparation of random copolymers and block copolymers.

The copolymers obtained can be used as biocompatible drug carriers,[7] in coatings and adhesives, and in many other applications.[8]

The elimination of the propionyl group from poly (2-ethyl-2-oxazoline) yields linear polyethyleneimine.[9] [10]

Notes and References

  1. US. 4203900 . Process for preparing 2-oxazolines . 1980-05-20 . 1977-01-03 . M.E. Kaiser . The Dow Chemical Co..
  2. US. 4354029 . Preparation of 2-substituted 2-oxazolines with organic zinc salt catalysts . 1982-10-12 . 1981-11-30 . M.E. Kaiser, D.L. Larson . The Dow Chemical Co..
  3. US. 4281137 . Purification of 2-oxazolines . 1981-07-28 . 1980-02-20 . J.W. Sanner, P.W. Owen . The Dow Chemical Co..
  4. Guerrero-Sanchez . Carlos . Hoogenboom . Richard . Schubert . Ulrich S. . 2006 . Fast and “green” living cationic ring opening polymerization of 2-ethyl-2-oxazoline in ionic liquids under microwave irradiation . . en . 36 . 36 . 3797–3799 . 10.1039/B608364A . 1359-7345 . 16969461.
  5. Glassner . Mathias . Lava . Kathleen . de la Rosa . Victor R. . Hoogenboom . Richard . November 2014 . Tuning the LCST of poly(2‐cyclopropyl‐2‐oxazoline) via gradient copolymerization with 2‐ethyl‐2‐oxazoline . Journal of Polymer Science Part A: Polymer Chemistry . en . 52 . 21 . 3118–3122 . 10.1002/pola.27364 . 0887-624X.
  6. Motokucho . Suguru . Furukawa . Mutsuhisa . Kawashima . Masahiro . Kojio . Ken . Yoshinaga . Kohji . November 2013 . Physical properties of poly(tetrahydrofuran)-block-poly(2-ethyl-2-oxazoline) triblock copolymer . Polymer Journal . en . 45 . 11 . 1115–1119 . 10.1038/pj.2013.39 . 0032-3896 . free. 10069/40210 . free .
  7. de la Rosa . Victor R. . May 2014 . Poly(2-oxazoline)s as materials for biomedical applications . Journal of Materials Science: Materials in Medicine . en . 25 . 5 . 1211–1225 . 10.1007/s10856-013-5034-y . 0957-4530 . 23975334 . 1766066.
  8. Web site: Etox, 2-Ethyl-2-Oxazoline, Product Information Sheet. Polymer Chemistry Innovations, Inc.. 2016-07-19.
  9. US. 20100197888 . Method for manufacturing linear polyethyleneimine (PEI) for transfection purpose and linear PEI obtained with such method . 2010-08-05 . 2008-07-31 . A. Adib, F. Stock, P. Erbacher . Polyplus Transfection.
  10. Lambermont-Thijs . Hanneke M. L. . van der Woerdt . Friso S. . Baumgaertel . Anja . Bonami . Lies . Du Prez . Filip E. . Schubert . Ulrich S. . Hoogenboom . Richard . 2010-01-26 . Linear Poly(ethylene imine)s by Acidic Hydrolysis of Poly(2-oxazoline)s: Kinetic Screening, Thermal Properties, and Temperature-Induced Solubility Transitions . . en . 43 . 2 . 927–933 . 10.1021/ma9020455 . 0024-9297.