Oxazoline

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Oxazoline
Oxazolin2.svg
4-Oxazoline 3D Balls.png
Names
Preferred IUPAC name
4,5-Dihydro-1,3-oxazole
Other names
Δ2-oxazoline
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.007.274 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • InChI=1S/C3H5NO/c1-2-5-3-4-1/h3H,1-2H2 Yes check.svgY
    Key: IMSODMZESSGVBE-UHFFFAOYSA-N Yes check.svgY
  • N\1=C\OCC/1
Properties
C3H5NO
Molar mass 71.079 g·mol−1
Density 1.075unit? [1]
Boiling point 98 °C (208 °F; 371 K) [1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Oxazoline is a five-membered heterocyclic organic compound with the formula C3H5NO. It is the parent of a family of compounds called oxazolines (emphasis on plural), which contain non-hydrogenic substituents on carbon and/or nitrogen. Oxazolines are the unsaturated analogues of oxazolidines, and they are isomeric with isoxazolines, where the N and O are directly bonded. Two isomers of oxazoline are known, depending on the location of the double bond.

Contents

Oxazoline itself has no applications however oxazolines have been widely investigated for potential applications. These applications include use as ligands in asymmetric catalysis, as protecting groups for carboxylic acids and increasingly as monomers for the production of polymers.

Isomers

2-oxazoline, 3-oxazoline, and 4-oxazoline (from left to right) 2-,3-,4-Oxazoline.png
2‑oxazoline, 3‑oxazoline, and 4‑oxazoline (from left to right)
Three structural isomers of oxazoline are possible depending on the location of the double bond, however only 2‑oxazolines are common. 4‑Oxazolines are formed as intermediates during the production of certain azomethine ylides [2] but are otherwise rare. 3‑Oxazolines are even less common but have been synthesised photochemically [3] and by the ring opening of azirines. [4] These three forms do not readily interconvert and hence are not tautomers.

A fourth isomer exists in which the O and N atoms are adjacent, this is known as isoxazoline.

Synthesis

The synthesis of 2-oxazoline rings is well established and in general proceeds via the cyclisation of a 2-amino alcohol (typically obtained by the reduction of an amino acid) with a suitable functional group. [5] [6] [7] The overall mechanism is usually subject to Baldwin's rules.

From carboxylic acids

The usual route to oxazolines entails reaction of acyl chlorides with 2-amino alcohols. Thionyl chloride is commonly used to generate the acid chloride in situ, care being taken to maintain anhydrous conditions, as oxazolines can be ring-opened by chloride if the imine becomes protonated. [8] The reaction is typically performed at room temperature. If reagents milder than SOCl2 are required, oxalyl chloride can be used. [9] Aminomethyl propanol is a popular precursor amino alcohol. [10] [11]

Oxaz-via-SOCl2-2.png

Modification of the Appel reaction allows for the synthesis of oxazoline rings. [12] This method proceeds under relatively mild conditions, however, owing to the large amounts of triphenylphosphine oxide produced, is not ideal for large-scale reactions. The use of this method is becoming less common, due to carbon tetrachloride being restricted under the Montreal protocol.

Oxaz-via-Appel2.png

From aldehydes

The cyclisation of an amino alcohol and an aldehyde produces an intermediate oxazolidine which can be converted to an oxazoline by treatment with a halogen-based oxidising agent (e.g. NBS, [13] or iodine [14] ); this potentially proceeds via an imidoyl halide. The method has been shown to be effective for a wide range of aromatic and aliphatic aldehydes however electron rich aromatic R groups, such as phenols, are unsuitable as they preferentially undergo rapid electrophilic aromatic halogenation with the oxidising agent.

Oxaz-from-aldehyde.png

From nitriles

The use of catalytic amounts of ZnCl2 to generate oxazolines from nitriles was first described by Witte and Seeliger, [15] [16] and further developed by Bolm et al. [17] The reaction requires high temperatures to succeed and is typically performed in refluxing chlorobenzene under anhydrous conditions. A precise reaction mechanism has never been proposed, although it is likely similar to the Pinner reaction; preceding via an intermediate amidine. [18] [19] Limited research has been done into identifying alternative solvents or catalysts for the reaction. [20] [21]

Oxaz-via-ZnCl2.png

Applications

Ligands

Ligands containing a chiral 2-oxazoline ring are used in asymmetric catalysis due to their facile synthesis, wide range of forms and effectiveness for many types of catalytic transformation. [22] [23]

2-Substituted oxazolines possess a moderately hard N-donor. Chirality is easily incorporated by using 2-amino alcohols prepared by the reduction of amino acids; which are both optically pure and inexpensive. As the stereocentre in such oxazolines is adjacent to the coordinating N-atom, it can influence the selectivity of processes occurring at the metal centre. The ring is thermally stable [24] and resistant to nucleophiles, bases, radicals, and weak acids [25] as well as being fairly resistant to hydrolysis and oxidation; [5] thus it can be expected to remain stable in a wide range of reaction conditions.

Major classes of oxazoline based ligand include:

Notable specialist oxazoline ligands include:

Polymers

Some 2-oxazolines, such as 2-ethyl-2-oxazoline, undergo living cationic ring-opening polymerisation to form poly(2-oxazoline)s. [26] These are polyamides and can be regarded as analogues of peptides; they have numerous potential applications [27] and have received particular attention for their biomedical uses. [28] [29]

Poly(2-oxazoline)s.png

Analysis of fatty acids

The dimethyloxazoline (DMOX) derivatives of fatty acids are amenable to analysis by gas chromatography.

See also

Structural analogues

Other pages

Related Research Articles

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<span class="mw-page-title-main">Organolithium reagent</span> Chemical compounds containing C–Li bonds

In organometallic chemistry, organolithium reagents are chemical compounds that contain carbon–lithium (C–Li) bonds. These reagents are important in organic synthesis, and are frequently used to transfer the organic group or the lithium atom to the substrates in synthetic steps, through nucleophilic addition or simple deprotonation. Organolithium reagents are used in industry as an initiator for anionic polymerization, which leads to the production of various elastomers. They have also been applied in asymmetric synthesis in the pharmaceutical industry. Due to the large difference in electronegativity between the carbon atom and the lithium atom, the C−Li bond is highly ionic. Owing to the polar nature of the C−Li bond, organolithium reagents are good nucleophiles and strong bases. For laboratory organic synthesis, many organolithium reagents are commercially available in solution form. These reagents are highly reactive, and are sometimes pyrophoric.

<span class="mw-page-title-main">Oxazolidine</span> Chemical compound

Oxazolidine is a five-membered heterocycle ringwith the formula (CH2)3(NH)O.The O atom and NH groups are not mutually bonded, in contrast to isoxazolidine. Oxazolidines are derivatives of the parent oxazolidine owing to the presence of substituents on carbon and/or nitrogen. Oxazolines are unsaturated analogues of oxazolidines.

<span class="mw-page-title-main">Appel reaction</span>

The Appel reaction is an organic reaction that converts an alcohol into an alkyl chloride using triphenylphosphine and carbon tetrachloride. The use of carbon tetrabromide or bromine as a halide source will yield alkyl bromides, whereas using carbon tetraiodide, methyl iodide or iodine gives alkyl iodides. The reaction is credited to and named after Rolf Appel, it had however been described earlier. The use of this reaction is becoming less common, due to carbon tetrachloride being restricted under the Montreal protocol.

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<span class="mw-page-title-main">Chiral auxiliary</span> Stereogenic group placed on a molecule to encourage stereoselectivity in reactions

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The Letts nitrile synthesis is a chemical reaction of aromatic carboxylic acids with metal thiocyanates to form nitriles. The reaction includes the loss of carbon dioxide and potassium hydrosulfide. The polar basic substitution reaction was discovered in 1872 by Edmund A. Letts.

Bis(oxazoline) ligands (often abbreviated BOX ligands) are a class of privileged chiral ligands containing two oxazoline rings. They are typically C2‑symmetric and exist in a wide variety of forms; with structures based around CH2 or pyridine linkers being particularly common (often generalised BOX and PyBOX respectively). The coordination complexes of bis(oxazoline) ligands are used in asymmetric catalysis. These ligands are examples of C2-symmetric ligands.

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<span class="mw-page-title-main">Trisoxazolines</span>

Trisoxazolines are a class of tridentate, chiral ligands composed of three oxazoline rings. Despite being neutral they are able to form stable complexes with high oxidation state metals, such as rare earths, due to the chelate effect. The ligands have been investigated for molecular recognition and their complexes are used in asymmetric catalysts and polymerisation.

<span class="mw-page-title-main">Valinol</span> Chemical compound

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Metal-catalyzed C–H borylation reactions are transition metal catalyzed organic reactions that produce an organoboron compound through functionalization of aliphatic and aromatic C–H bonds and are therefore useful reactions for carbon–hydrogen bond activation. Metal-catalyzed C–H borylation reactions utilize transition metals to directly convert a C–H bond into a C–B bond. This route can be advantageous compared to traditional borylation reactions by making use of cheap and abundant hydrocarbon starting material, limiting prefunctionalized organic compounds, reducing toxic byproducts, and streamlining the synthesis of biologically important molecules. Boronic acids, and boronic esters are common boryl groups incorporated into organic molecules through borylation reactions. Boronic acids are trivalent boron-containing organic compounds that possess one alkyl substituent and two hydroxyl groups. Similarly, boronic esters possess one alkyl substituent and two ester groups. Boronic acids and esters are classified depending on the type of carbon group (R) directly bonded to boron, for example alkyl-, alkenyl-, alkynyl-, and aryl-boronic esters. The most common type of starting materials that incorporate boronic esters into organic compounds for transition metal catalyzed borylation reactions have the general formula (RO)2B-B(OR)2. For example, bis(pinacolato)diboron (B2Pin2), and bis(catecholato)diborane (B2Cat2) are common boron sources of this general formula.

<span class="mw-page-title-main">2-Ethyl-2-oxazoline</span> Chemical compound

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.

In homogeneous catalysis, C2-symmetric ligands refer to ligands that lack mirror symmetry but have C2 symmetry. Such ligands are usually bidentate and are valuable in catalysis. The C2 symmetry of ligands limits the number of possible reaction pathways and thereby increases enantioselectivity, relative to asymmetrical analogues. C2-symmetric ligands are a subset of chiral ligands. Chiral ligands, including C2-symmetric ligands, combine with metals or other groups to form chiral catalysts. These catalysts engage in enantioselective chemical synthesis, in which chirality in the catalyst yields chirality in the reaction product.

References

  1. 1 2 Wenker, H. (1938). "Syntheses from Ethanolamine. V. Synthesis of Δ2-Oxazoline and of 2,2'-Δ2-Dioxazoline". Journal of the American Chemical Society. 60 (9): 2152–2153. doi:10.1021/ja01276a036.
  2. ↑ Vedejs, E.; Grissom, J. W. (1988). "4-Oxazoline route to stabilized azomethine ylides. Controlled reduction of oxazolium salts". Journal of the American Chemical Society. 110 (10): 3238–3246. doi:10.1021/ja00218a038.
  3. ↑ Armesto, Diego; Ortiz, Maria J.; Pérez-Ossorio, Rafael; Horspool, William M. (1983). "A novel photochemical 1,2-acyl migration in an enol ester. The synthesis of 3-oxazoline derivatives". Tetrahedron Letters. 24 (11): 1197–1200. doi:10.1016/S0040-4039(00)86403-5.
  4. ↑ Sá, Marcus C. M.; Kascheres, Albert (1996). "Electronically Mediated Selectivity in Ring Opening of 1-Azirines. The 3-X Mode: Convenient Route to 3-Oxazolines". The Journal of Organic Chemistry. 61 (11): 3749–3752. doi:10.1021/jo9518866. PMID   11667224.
  5. 1 2 Wiley, Richard H.; Bennett, Leonard L. (1949). "The Chemistry of the Oxazolines". Chemical Reviews. 44 (3): 447–476. doi:10.1021/cr60139a002. S2CID   95217957.
  6. ↑ Frump, John A. (1971). "Oxazolines. Their preparation, reactions, and applications". Chemical Reviews. 71 (5): 483–505. doi:10.1021/cr60273a003.
  7. ↑ Gant, Thomas G.; Meyers, A.I. (1994). "The chemistry of 2-oxazolines (1985–present)". Tetrahedron. 50 (8): 2297–2360. doi:10.1016/S0040-4020(01)86953-2.
  8. ↑ Holerca, Marian N.; Percec, Virgil (2000). "1H NMR Spectroscopic Investigation of the Mechanism of 2-Substituted-2-Oxazoline Ring Formation and of the Hydrolysis of the Corresponding Oxazolinium Salts". European Journal of Organic Chemistry. 2000 (12): 2257–2263. doi:10.1002/1099-0690(200006)2000:12<2257::AID-EJOC2257>3.0.CO;2-2.
  9. ↑ Evans, David; Peterson, Gretchen S.; Johnson, Jeffrey S.; Barnes, David M.; Campos, Kevin R.; Woerpel, Keith A. (1998). "An Improved Procedure for the Preparation of 2,2-Bis[2-[4(S)- tert-butyl-1,3-oxazolinylpropane [(S,S)-tert-Butylbis(oxazoline)] and Derived Copper(II) Complexes". J. Org. Chem. 63 (13): 4541–4544. doi:10.1021/jo980296f.
  10. ↑ Albert I. Meyers; Mark E. Flanagan (1993). "2,2'-Dimethoxy-6-Formylbiphenyl". Org. Synth. 71: 107. doi:10.15227/orgsyn.071.0107.
  11. ↑ r. Sardini, Stephen; Stoltz, Brian M. (2021). "Discussion Addendum for: Preparation of (S)-tert-ButylPy Ox and Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids". Organic Syntheses. 98: 117–130. doi:10.15227/orgsyn.098.0117. PMC   9558615 . PMID   36247231. S2CID   235855642.
  12. ↑ Vorbrüggen, Helmut; Krolikiewicz, Konrad (1993). "A simple synthesis of Δ2-oxazines, Δ2-oxazines, Δ2-thiazolines and 2-substituted benzoxazoles". Tetrahedron. 49 (41): 9353–9372. doi:10.1016/0040-4020(93)80021-K.
  13. ↑ Schwekendiek, Kirsten; Glorius, Frank (2006). "Efficient Oxidative Synthesis of 2-Oxazolines". Synthesis. 2006 (18): 2996–3002. doi:10.1055/s-2006-950198.
  14. ↑ Ishihara, Midori; Togo, Hideo (2007). "Direct oxidative conversion of aldehydes and alcohols to 2-imidazolines and 2-oxazolines using molecular iodine". Tetrahedron. 63 (6): 1474–1480. doi:10.1016/j.tet.2006.11.077.
  15. ↑ Witte, Helmut; Seeliger, Wolfgang (1972). "Simple Synthesis of 2-Substituted 2-Oxazolines and 5,6-Dihydro-4H-1,3-oxazines". Angewandte Chemie International Edition in English. 11 (4): 287–288. doi:10.1002/anie.197202871.
  16. ↑ Witte, Helmut; Seeliger, Wolfgang (1974). "Cyclische Imidsäureester aus Nitrilen und Aminoalkoholen". Justus Liebigs Annalen der Chemie. 1974 (6): 996–1009. doi:10.1002/jlac.197419740615.
  17. ↑ Bolm, Carsten; Weickhardt, Konrad; Zehnder, Margareta; Ranff, Tobias (1991). "Synthesis of Optically Active Bis(2-oxazolines): Crystal Structure of a 1,2-Bis(2-oxazolinyl)benzene ZnCl2 Complex". Chemische Berichte. 124 (5): 1173–1180. doi:10.1002/cber.19911240532.
  18. ↑ Makarycheva-Mikhailova, A. V.; Kukushkin, V. Y.; Nazarov, A. A.; Garnovskii, D. A.; Pombeiro, A. J. L.; Haukka, M.; Keppler, B. K.; Galanski, M. (2003). "Amidines Derived from Pt(IV)-Mediated Nitrile−Amino Alcohol Coupling and Their Zn(II)-Catalyzed Conversion into Oxazolines". Inorganic Chemistry. 42 (8): 2805–13. doi:10.1021/ic034070t. PMID   12691592.
  19. ↑ i. Meyers, A.; Ann Hanagan, M.; l. Mazzu, A. (1981). "2-Oxazolines from Amides via Imidates". Heterocycles. 15: 361. doi:10.3987/S-1981-01-0361 (inactive 2024-03-07).{{cite journal}}: CS1 maint: DOI inactive as of March 2024 (link)
  20. ↑ Cornejo, A.; Fraile, J. M.; García, J. I.; Gil, M. J.; Martínez-Merino, V.; Mayoral, J. A.; Pires, E.; Villalba, I. (2005). "An Efficient and General One-Pot Method for the Synthesis of Chiral Bis(oxazoline) and Pyridine Bis(oxazoline) Ligands". Synlett (15): 2321–2324. doi:10.1055/s-2005-872672. hdl: 10261/270962 . S2CID   95389965.
  21. ↑ Aspinall, Helen C.; Bacsa, John; Beckingham, Oliver D.; Eden, Edward G. B.; Greeves, Nicholas; Hobbs, Matthew D.; Potjewyd, Frances; Schmidtmann, Marc; Thomas, Christopher D. (2014). "Adding the right (or left) twist to tris-chelate complexes – coordination chemistry of chiral oxazolylphenolates with M3+ ions (M = Al or lanthanide)" (PDF). Dalton Trans. 43 (3): 1434–1442. doi:10.1039/C3DT52366G. PMID   24201227. See the Supplementary Information for details
  22. ↑ McManus, Helen A.; Guiry, Patrick J. (2004). "Recent Developments in the Application of Oxazoline-Containing Ligands in Asymmetric Catalysis". Chemical Reviews. 104 (9): 4151–4202. doi:10.1021/cr040642v. PMID   15352789.
  23. ↑ Hargaden, Gráinne C.; Guiry, Patrick J. (2009). "Recent Applications of Oxazoline-Containing Ligands in Asymmetric Catalysis". Chemical Reviews. 109 (6): 2505–2550. doi:10.1021/cr800400z. PMID   19378971.
  24. ↑ Loo, Yim Fun; O'Kane, Ruairi; Jones, Anthony C.; Aspinall, Helen C.; Potter, Richard J.; Chalker, Paul R.; Bickley, Jamie F.; Taylor, Stephen; Smith, Lesley M. (2005). "Deposition of HfO2 and ZrO2 films by liquid injection MOCVD using new monomeric alkoxide precursors". Journal of Materials Chemistry. 15 (19): 1896. doi:10.1039/B417389A.
  25. ↑ Greene, T. W. (1991). Protective groups in organic synthesis, 2nd ed . New York: Wiley. pp.  265–266 & 433–436.
  26. ↑ Kobayashi, Shiro; Uyama, Hiroshi (15 January 2002). "Polymerization of cyclic imino ethers: From its discovery to the present state of the art". Journal of Polymer Science Part A: Polymer Chemistry. 40 (2): 192–209. Bibcode:2002JPoSA..40..192K. doi: 10.1002/pola.10090 .
  27. ↑ Hoogenboom, Richard (12 October 2009). "Poly(2-oxazoline)s: A Polymer Class with Numerous Potential Applications". Angewandte Chemie International Edition. 48 (43): 7978–7994. doi:10.1002/anie.200901607. PMID   19768817.
  28. ↑ Adams, Nico; Schubert, Ulrich S. (1 December 2007). "Poly(2-oxazolines) in biological and biomedical application contexts". Advanced Drug Delivery Reviews. 59 (15): 1504–1520. doi:10.1016/j.addr.2007.08.018. PMID   17904246.
  29. ↑ Kelly, Andrew M; Wiesbrock, Frank (15 October 2012). "Strategies for the Synthesis of Poly(2-Oxazoline)-Based Hydrogels". Macromolecular Rapid Communications. 33 (19): 1632–1647. doi:10.1002/marc.201200333. PMID   22811405.
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