Oxazoline is a five-membered

heterocyclic A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic chemistry is the branch of organic chemistry dealing with the synthesis, properties, and ...

organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The ...

with the formula . 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

oxazolidine An oxazolidine is a five-membered ring compound consisting of three carbon atoms, a nitrogen atom and an oxygen atom. The O atom and NH group are the 1 and 3 positions, respectively. In oxazolidine derivatives, there is always a carbon atom betwee ...

s, 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

ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...

s in

asymmetric catalysis Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as "a chemical reaction (or reaction sequence) in which one or more new elements of chirality are formed in a substrate molecul ...

, as

protecting groups A protecting group or protective group is introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction. It plays an important role in multistep organic synthesis. In many ...

for

carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...

s and increasingly as

monomer In chemistry, a monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization. Classification Mo ...

s for the production of

polymer A polymer (; Greek '' poly-'', "many" + ''-mer'', "part") is a substance or material consisting of very large molecules called macromolecules, composed of many repeating subunits. Due to their broad spectrum of properties, both synthetic a ...

Isomers

Synthesis

The synthesis of 2-oxazoline rings is well established and in general proceeds via the cyclisation of a 2-

amino alcohol In organic chemistry, alkanolamines are organic compounds that contain both hydroxyl () and amino (, , and ) functional groups on an alkane backbone. The term alkanolamine is a broad class term that is sometimes used as a subclassification. Meth ...

(typically obtained by the reduction of an

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

) with a suitable functional group. The overall mechanism is usually subject to

Baldwin's rules Baldwin's rules in organic chemistry are a series of guidelines outlining the relative favorabilities of ring closure reactions in alicyclic compounds. They were first proposed by Jack Baldwin in 1976. Baldwin's rules discuss the relative rates ...

From carboxylic acids

The usual route to oxazolines entails reaction of

acyl chloride In organic chemistry, an acyl chloride (or acid chloride) is an organic compound with the functional group . Their formula is usually written , where R is a side chain. They are reactive derivatives of carboxylic acids (). A specific example o ...

s with 2-amino alcohols.

Thionyl chloride Thionyl chloride is an inorganic compound with the chemical formula . It is a moderately volatile, colourless liquid with an unpleasant acrid odour. Thionyl chloride is primarily used as a chlorinating reagent, with approximately per year bein ...

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 The chloride ion is the anion (negatively charged ion) Cl−. It is formed when the element chlorine (a halogen) gains an electron or when a compound such as hydrogen chloride is dissolved in water or other polar solvents. Chloride salts ...

if the

imine In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bo ...

becomes protonated. The reaction is typically performed at room temperature. If reagents milder than SOCl₂ are required,

oxalyl chloride Oxalyl chloride is an organic chemical compound with the formula (COCl)2. This colorless, sharp-smelling liquid, the diacyl chloride of oxalic acid, is a useful reagent in organic synthesis. Preparation Oxalyl chloride was first prepared in 1892 ...

can be used.

Aminomethyl propanol Aminomethyl propanol is an organic compound with the formula H2NC(CH3)2CH2OH. It is colorless liquid that is classified as an alkanolamine. It is a useful buffer and a precursor to numerous other organic compounds. Synthesis Aminomethyl propano ...

is a popular precursor amino alcohol. :: Oxaz-via-SOCl2-2

Modification of the

Appel reaction 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 carb ...

allows for the synthesis of oxazoline rings. This method proceeds under relatively mild conditions, however, owing to the large amounts of

triphenylphosphine oxide Triphenylphosphine oxide (often abbreviated TPPO) is the organophosphorus compound with the formula OP(C6H5)3, also written as Ph3PO or PPh3O (Ph = C6H5). This colourless crystalline compound is a common but potentially useful waste product in ...

produced, is not ideal for large-scale reactions. The use of this method is becoming less common, due to

carbon tetrachloride Carbon tetrachloride, also known by many other names (such as tetrachloromethane, also IUPAC nomenclature of inorganic chemistry, recognised by the IUPAC, carbon tet in the cleaning industry, Halon-104 in firefighting, and Refrigerant-10 in HVAC ...

being restricted under the

Montreal protocol The Montreal Protocol is an international treaty designed to protect the ozone layer by phasing out the production of numerous substances that are responsible for ozone depletion Ozone depletion consists of two related events observed sinc ...

. ::

From aldehydes

The cyclisation of an amino alcohol and an

aldehyde In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...

produces an intermediate

which can be converted to an oxazoline by treatment with a halogen-based

oxidising agent An oxidizing agent (also known as an oxidant, oxidizer, electron recipient, or electron acceptor) is a substance in a redox chemical reaction that gains or " accepts"/"receives" an electron from a (called the , , or ). In other words, an oxi ...

(e.g. NBS, or

iodine Iodine is a chemical element with the symbol I and atomic number 53. The heaviest of the stable halogens, it exists as a semi-lustrous, non-metallic solid at standard conditions that melts to form a deep violet liquid at , and boils to a vi ...

); this potentially proceeds via an imidoyl halide. The method has been shown to be effective for a wide range of

aromatic In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...

and

aliphatic In organic chemistry, hydrocarbons ( compounds composed solely of carbon and hydrogen) are divided into two classes: aromatic compounds and aliphatic compounds (; G. ''aleiphar'', fat, oil). Aliphatic compounds can be saturated, like hexane, or ...

aldehydes however electron rich aromatic R groups, such as

phenols In organic chemistry, phenols, sometimes called phenolics, are a class of chemical compounds consisting of one or more hydroxyl groups (— O H) bonded directly to an aromatic hydrocarbon group. The simplest is phenol, . Phenolic compounds are c ...

, are unsuitable as they preferentially undergo rapid electrophilic aromatic halogenation with the oxidising agent. :: Oxaz-from-aldehyde

From nitriles

The use of catalytic amounts of ZnCl₂ to generate oxazolines from

nitriles In organic chemistry, a nitrile is any organic compound that has a functional group. The prefix ''cyano-'' is used interchangeably with the term ''nitrile'' in industrial literature. Nitriles are found in many useful compounds, including met ...

was first described by Witte and Seeliger, and further developed by Bolm ''et al''. The reaction requires high temperatures to succeed and is typically performed in refluxing

chlorobenzene Chlorobenzene is an aromatic organic compound with the chemical formula C6H5Cl. This colorless, flammable liquid is a common solvent and a widely used intermediate in the manufacture of other chemicals. Uses Historical The major use of chlorob ...

under

anhydrous A substance is anhydrous if it contains no water. Many processes in chemistry can be impeded by the presence of water; therefore, it is important that water-free reagents and techniques are used. In practice, however, it is very difficult to achie ...

conditions. A precise reaction mechanism has never been proposed, although it is likely similar to the

Pinner reaction The Pinner reaction refers to the acid catalysed reaction of a nitrile with an alcohol to form an imino ester salt (alkyl imidate salt); this is sometimes referred to as a Pinner salt. The reaction is named after Adolf Pinner, who first described ...

; preceding via an intermediate

amidine Amidines are organic compounds with the functional group RC(NR)NR2, where the R groups can be the same or different. They are the imine derivatives of amides (RC(O)NR2). The simplest amidine is formamidine, HC(=NH)NH2. Examples of amidines includ ...

. Limited research has been done into identifying alternative solvents or catalysts for the reaction. :: Oxaz-via-ZnCl2

Applications

Ligands

Ligands containing a chiral 2-oxazoline ring are used in

due to their facile synthesis, wide range of forms and effectiveness for many types of catalytic transformation. 2-Substituted oxazolines possess a moderately

hard Hard may refer to: * Hardness, resistance of physical materials to deformation or fracture * Hard water, water with high mineral content Arts and entertainment * ''Hard'' (TV series), a French TV series * Hard (band), a Hungarian hard rock supe ...

N-donor.

Chirality Chirality is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable from ...

is easily incorporated by using 2-

s prepared by the reduction of

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

; 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 and resistant to nucleophiles, bases, radicals, and weak acids as well as being fairly resistant to hydrolysis and oxidation; thus it can be expected to remain stable in a wide range of reaction conditions. Major classes of oxazoline based ligand include: * Bis-oxazolines (BOX) * Phosphinooxazolines (PHOX) for example

(S)-iPr-PHOX (''S'')-iPr-PHOX, or (''S'')-2- -(diphenylphosphino)phenyl4-isopropyl-4,5-dihydrooxazole, is a chiral, bidentate, ligand derived from the amino alcohol valinol. It is part of a broader class of phosphinooxazolines ligands and has found applicat ...

Notable specialist oxazoline ligands include: * Tris-oxazolines (TRISOX) * Bis(oxazolinato)s * Trisoxazolinylborate ligands

Polymers

Some 2-oxazolines, such as 2-ethyl-2-oxazoline, undergo living cationic ring-opening polymerisation to form poly(2-oxazoline)s. These are polyamides and can be regarded as analogues of

peptides Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A p ...

; they have numerous potential applications and have received particular attention for their biomedical uses. :: Poly(2-oxazoline)s

Analysis of fatty acids

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

References

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