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Oxazoline
Oxazoline
Oxazoline
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Oxazoline
Names
Preferred IUPAC name
4,5-Dihydro-1,3-oxazole
Other names
Δ2-oxazoline
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.007.274 Edit this at Wikidata
EC Number
  • 208-000-4
UNII
  • InChI=1S/C3H5NO/c1-2-5-3-4-1/h3H,1-2H2 checkY
    Key: IMSODMZESSGVBE-UHFFFAOYSA-N checkY
  • 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).
☒N verify (what is checkY☒N ?)

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.

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

[edit]
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

[edit]

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

[edit]

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]

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.

From aldehydes

[edit]

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.

From nitriles

[edit]

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]

Applications

[edit]

Ligands

[edit]
Main article: Bisoxazoline ligand

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

[edit]

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]

Analysis of fatty acids

[edit]

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

Protecting groups

[edit]
See also: Protecting groups

Oxazolines are a rare protecting group for esters.

See also

[edit]

Structural analogues

Other pages

  • Aminorex a drug bearing an oxazoline ring

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Oxazoline

View on Grokipedia
from Grokipedia
Oxazoline is a class of five-membered heterocyclic compounds characterized by a ring containing adjacent oxygen and nitrogen atoms, with the parent structure, 2-oxazoline (also known as 4,5-dihydro-1,3-oxazole), having the molecular formula C₃H₅NO and featuring an endo-cyclic imino ether functionality (–C=N–O–). These compounds are valued in for their versatility as chiral auxiliaries and ligands in metal-catalyzed asymmetric reactions, where the nitrogen and oxygen atoms provide effective σ-donation and coordination to transition metals, enabling high enantioselectivity in processes such as aldol additions, hydrogenations, and cyclopropanations. Oxazolines are typically synthesized via cyclodehydration of β-hydroxy amides or esters derived from amino alcohols and carboxylic acids, often using reagents like the or Mitsunobu conditions to form the ring efficiently. In , 2-oxazolines serve as monomers in living cationic (CROP), yielding poly(2-oxazoline)s that mimic (PEG) in and stealth properties while offering tunable hydrophilicity, thermal stability, and non-toxicity for applications in systems, such as paclitaxel-loaded micelles, and biocompatible coatings. Substituted oxazolines, particularly chiral variants with phenyl or benzyl groups at the 4- or 5-positions, enhance their utility in stereoselective transformations and scaffolds.

Fundamentals

Definition and Structure

Oxazoline is a five-membered unsaturated heterocyclic containing one oxygen atom and one atom separated by a carbon atom, forming a cyclic imino structure with the general molecular formula C₃H₅NO. This parent compound serves as the core scaffold for a family of derivatives known as oxazolines, which are characterized by their nonaromatic ring system. In the standard IUPAC numbering of the oxazoline ring, the oxygen occupies position 1, the adjacent carbon is position 2, the nitrogen is at position 3, followed by carbons at positions 4 and 5, completing the five-membered ring. The parent 2-oxazoline features a between carbon 2 and 3, resulting in the structure 4,5-dihydro-1,3-oxazole, where positions 4 and 5 are saturated CH₂ groups. This arrangement positions the heteroatoms in a 1,3-relationship, distinguishing it from other azoles. The structural diagram of the parent oxazoline ring depicts a with oxygen at one vertex (position 1) bonded to C2 and C5, C2 double-bonded to N3, N3 single-bonded to C4, and C4 single-bonded to C5, with typical five-membered ring bond angles around 108° and partial conjugation across the C=N bond contributing to some electron delocalization despite the absence of full . Oxazoline is nonaromatic, lacking the 6π electrons in a planar, cyclic, required for , but the enamine-like C=N-O moiety provides reactivity akin to a vinyl ether. In comparison, is the fully unsaturated and aromatic analog of oxazoline, featuring additional s for a delocalized 6π system, whereas is an with and oxygen in directly adjacent positions (1,2-relationship).

Nomenclature

The term "oxazoline" is derived from "," the fully unsaturated parent heterocycle, with the suffix "-ine" indicating partial saturation of the ring according to IUPAC heterocyclic conventions. This naming follows the Hantzsch-Widman system, which systematically constructs names for five-membered rings containing one oxygen and one atom, prioritizing the heteroatoms in numbering (O at position 1, N at position 3). The position of the endocyclic distinguishes the three primary isomers: 2-oxazoline features the double bond between C2 and N3, 3-oxazoline between N3 and C4, and 4-oxazoline between C4 and C5. Under IUPAC recommendations, the systematic names reflect the saturation pattern using "dihydro" prefixes with locants. The most common , 2-oxazoline, is named 4,5-dihydro-1,3-oxazole, a retained name alongside the trivial "2-oxazoline" particularly in . The 3-oxazoline is 2,5-dihydro-1,3-oxazole, while 4-oxazoline is 2,3-dihydro-1,3-oxazole. These names ensure clarity in distinguishing the isomers, which differ in reactivity due to the imino ether functionality's position. Brief reference to isomers highlights how naming conventions, such as these locant-based descriptors, facilitate identification across the three main types. Substituents on the oxazoline ring are named using standard substitutive , with locants assigned to prioritize the lowest numbers for heteroatoms and the . For example, a at the 2-position of the 2-oxazoline is designated 2-methyl-4,5-dihydro-1,3-oxazole. This approach avoids ambiguity with related heterocycles like (fully unsaturated) or isoxazole (with adjacent O-N atoms). Key derivatives may retain trivial names, such as 2-oxazolidinone for the saturated carbonyl analog (systematically 1,3-oxazolidin-2-one), which is structurally related but lacks the endocyclic . The evolved from early 19th-century literature, with the first oxazoline synthesized in by Andreasch via of allylurea, initially referred to simply as "oxazoline" without positional specification. By the mid-20th century, standardization occurred through IUPAC's heterocyclic guidelines, formalized in the and refined in subsequent recommendations like the and Blue Books, which established retained names and systematic alternatives to accommodate growing synthetic applications.

Properties

Physical Properties

Oxazolines, particularly simple 2-oxazolines, exist as colorless liquids or low-melting solids at room temperature. The parent 2-oxazoline is a low-melting solid with a melting point of 93–94 °C. In contrast, simple alkyl-substituted derivatives such as 2-methyloxazoline and 2-ethyl-2-oxazoline are colorless liquids. Boiling points of 2-oxazolines increase with the size of substituents at the 2-position due to enhanced van der Waals interactions. For example, the parent 2-oxazoline boils at approximately 96 °C at atmospheric pressure, while 2-methyloxazoline has a boiling point of 109.5–110.5 °C, and longer alkyl chains like ethyl further elevate this value to around 130–140 °C. These compounds exhibit high solubility in polar solvents, including , , and , attributed to the polar heteroatoms (oxygen and ) that enable hydrogen bonding and dipole interactions. Solubility is limited in nonpolar hydrocarbons such as hexane. For instance, 2-ethyl-2-oxazoline demonstrates ready with and a range of organic solvents. Spectroscopic characterization reveals distinctive features for 2-oxazolines. Infrared (IR) spectroscopy shows a characteristic absorption band for the C=N stretch at approximately 1650 cm⁻¹, reflecting the imino ether functionality. In ¹H nuclear magnetic resonance (NMR) spectra, the protons of the ring methylene groups (adjacent to oxygen and nitrogen) typically resonate in the 4–5 ppm range, such as at 4.29 ppm and 4.98 ppm for key CH₂ signals. The parent 2-oxazoline has a density of 1.075 g/cm³ at 20 °C and a of 1.438 at 20 °C, values that decrease slightly with alkyl substitution (e.g., 1.005 g/cm³ and 1.434 for 2-methyloxazoline).

Chemical Properties

The oxazoline ring, particularly in 2-oxazolines, exhibits considerable stability arising from the conjugation between the and the C=N , rendering it resistant to bases, radicals, and weak acids under ambient conditions. However, this stability is compromised under acidic conditions, where at the facilitates to yield N-(2-hydroxyethyl)amides. The reaction proceeds via nucleophilic attack by on the protonated C2 position, followed by ring opening: R-C=N+−CH2CH2O−+H2O→R-C(O)-NH-CH2CH2OH\text{R-C}=\overset{+}{\text{N}}-\text{CH}_2\text{CH}_2\text{O}^- + \text{H}_2\text{O} \rightarrow \text{R-C(O)-NH-CH}_2\text{CH}_2\text{OH} This process is well-documented for both monomeric and polymeric 2-oxazolines, with rates increasing at elevated temperatures or higher acid concentrations. The nitrogen atom in oxazolines imparts moderate basicity, with the available for or metal coordination; the pKa of the conjugate acid for 2-methyloxazoline is approximately 5.5, indicating weaker basicity compared to aliphatic amines but sufficient for catalytic roles in coordination chemistry. This property enables reversible without disrupting the ring under neutral conditions. At the C2 position, 2-oxazolines display pronounced electrophilicity due to the electron-deficient , making them susceptible to by amines, alcohols, or halides, which typically results in ring opening to form β-substituted amides. For instance, reaction with primary amines yields N-acyl ethylenediamines via SN2-like attack at C2. Such reactivity underscores the utility of oxazolines as protected forms of derivatives. Oxazolines demonstrate resistance to mild oxidizing agents like or at neutral pH, maintaining ring integrity, though stronger oxidants such as N-bromosuccinimide can convert them to oxazoles via dehydrogenation. In reduction, electrochemical or catalytic can transform 2-oxazolines to oxazolidines by saturating the C=N bond, with subsequent ring cleavage possible under forcing conditions. Thermally, 2-oxazolines exhibit good stability, with decomposition onset typically above 200°C in inert atmospheres, often involving retro-cycloaddition or formation; this surpasses the stability of 3- and 4-oxazolines, which are more prone to rearrangement due to less effective conjugation.

Isomers

2-Oxazolines

2-Oxazolines represent the predominant among oxazoline variants, featuring a five-membered heterocyclic ring with a positioned between carbon 2 (C2) and 3 (N3), which contributes to its thermodynamic favorability over other positional isomers. This structural arrangement results in an imino functionality that enhances stability, distinguishing it from the less common 3- and 4-oxazolines, which exhibit reduced prevalence due to lower stability. The general formula for 2-substituted 2-oxazolines is R-C₃H₄NO, where R denotes an alkyl, aryl, or other substituent at the C2 position. A representative example is 2-phenyl-2-oxazoline (C₉H₉NO), which exemplifies the class through its incorporation of an aryl group, leading to increased conjugation within the ring system. This conjugation imparts unique spectroscopic properties, including absorption in the ultraviolet region attributable to the C=N bond and associated electronic transitions. The vast majority of reported oxazoline compounds in the pertain to 2-oxazolines, attributable to their relative ease of synthesis and inherent stability compared to other isomers. Unlike 3-oxazolines, which display enamine-like reactivity and pronounced tautomerism due to the on facilitating proton shifts, 2-oxazolines exhibit minimal tautomerization due to the absence of an alpha hydrogen on the imino carbon, further underscoring their robustness. Simple 2-alkyl oxazolines have been produced industrially since the , with early developments by companies such as Dow Chemical enabling commercial applications of their polymers. This availability has facilitated widespread research and utilization in various chemical contexts.

3-Oxazolines

3-Oxazolines represent one of the three possible structural isomers of the oxazoline family, distinguished by a five-membered heterocyclic ring containing oxygen and , with the double bond positioned between the atom at position 3 and the carbon at position 4. This configuration imparts an imine-like character to the and overall -like properties to the molecule, reflected in the parent formula C3H5NOC_3H_5NO. The nature arises from the conjugation involving the lone pair and the adjacent carbon-carbon bond, enabling distinctive reactivity patterns, including nucleophilic behavior at the carbon position 5, as seen in reactions such as Michael additions and alkylations in stable derivatives like 3-(oxazolidin-2-ylidene)thiophen-2-one. Due to their enamine character and susceptibility to prototropic shifts, 3-oxazolines are notably less stable than the common 2-oxazoline counterpart and are prone to rearrangement into 2-oxazolines, which often occurs under mild conditions. As a result, 3-oxazolines are rarely isolated in pure form and are typically generated as transient intermediates in synthetic sequences, including those involving azirine ring openings or Strecker degradation models, where they serve limited roles before transforming. The first report of a 3-oxazoline appeared in 1969, when Rizzi identified 2-isopropyl-4,5-dimethyl-3-oxazoline as a minor product (4% yield) in the nonaqueous Strecker degradation of with 2,3-butanedione. This example highlights their niche occurrence in thermal processes, such as Maillard reactions contributing to aromas, where they act as precursors to Strecker aldehydes upon but are not extensively studied due to their instability. Unlike the widely utilized 2-oxazolines, the instability of 3-oxazolines restricts their practical applications, confining them primarily to mechanistic investigations or short-lived synthetic intermediates.

4-Oxazolines

4-Oxazolines represent the least common isomer among the oxazoline family, distinguished by a five-membered heterocyclic ring featuring a double bond between carbons 4 and 5, which creates an isolated alkene functionality. The general molecular formula is C₃H₅NO, and these compounds are frequently encountered in dihydro forms as transient species in synthetic sequences rather than as stable isolates. Due to their inherent instability arising from the allylic-like positioning of the C2 methylene relative to the C4=C5 double bond, which facilitates proton abstraction and rearrangement, 4-oxazolines are infrequently isolated and readily undergo isomerization to the more thermodynamically favored 2-oxazoline isomer under acidic or basic conditions, limiting their direct characterization and application. This sensitivity underscores their primary utility as synthetic intermediates, particularly in routes leading to fully aromatic oxazoles via oxidative processes. The structural arrangement in 4-oxazolines enables regioselective substitution reactions at the C2 site through or electrophilic activation, which facilitates the introduction of diverse substituents. Unlike isoxazolines, which possess adjacent and oxygen atoms conducive to 1,3-dipolar behavior, 4-oxazolines maintain separated heteroatoms in the ring, thereby exhibiting distinct reactivity profiles devoid of such characteristics.

Synthesis

From Carboxylic Acids and Derivatives

The synthesis of 2-oxazolines from derivatives typically involves the reaction of an (RCOCl) with 2-aminoethanol (H₂NCH₂CH₂OH) in the presence of a base such as triethylamine (Et₃N) to facilitate and cyclization. This process proceeds through initial nucleophilic acyl substitution to form an N-acylamino alcohol intermediate, followed by dehydrative cyclization wherein the hydroxyl oxygen attacks the amide carbonyl, eliminating water to form the oxazoline ring. A variation employs carboxylic acids directly in a one-pot procedure using thionyl chloride (SOCl₂) to generate the acyl chloride in situ, which then reacts with the amino alcohol under heating, often achieving yields of 70–90% for simple substrates. This method was first reported in 1938 by Henry Wenker, who synthesized the unsubstituted 2-oxazoline from ethanolamine and a carboxylic derivative, establishing the foundational approach for this class of heterocycles. The scope of this synthesis is broad for preparing 2-alkyl- and 2-aryloxazolines, with representative examples including 2-phenyloxazoline from derivatives and 2-methyloxazoline from acetic acid derivatives, both proceeding efficiently under mild conditions. However, sterically hindered substituents at the R group can lead to reduced yields or side reactions due to impeded cyclization, limiting applicability in such cases. The overall equation for the general method is: RCOCl+H2NCH2CH2OH→Et3N R−Δ2-oxazoline+HCl+H2O\mathrm{RCOCl + H_2NCH_2CH_2OH \xrightarrow{Et_3N} \ R-\Delta^2\text{-oxazoline} + HCl + H_2O}
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